Formal total synthesis of mandelalide A

Article abstract of DOI:10.1007/s12039-019-1600-2

Abstract: In this article the formal total synthesis of mandelalide A has been described in details. The highly convergent and flexible strategy developed for mandelalide A involved the construction of key building blocks ent-9 and 7, and their assembly t

Full text of DOI:10.1007/s12039-019-1600-2

J. Chem. Sci.
(2019) 131:25
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-019-1600-2
REGULAR ARTICLE
Formal total synthesis of mandelalide A
V YAMINIa, K MAHENDER REDDYa,b, A SHIVA KRISHNAa, J K LAKSHMIc and
SUBHASH GHOSHa,∗
aOrganic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad,
Telangana 500 007, India
bDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA
cCentre for NMR and Structural Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad,
Telangana 500 007, India
E-mail: subhash@iict.res.in
MS received 26 November 2018; revised 24 January 2019; accepted 5 February 2019
Abstract. In this article the formal total synthesis of mandelalide A has been described in details. The highly
convergent and flexible strategy developed for mandelalide A involved the construction of key building blocks
ent-9 and 7, and their assembly to the target compound. For the synthesis and coupling of these building
blocks, the Brown’s crotylation, Sharpless asymmetric dihydroxylation followed by in situ Williamson type
etherification, modified Prins cyclization, Masamune-Roush olefination and Heck cyclization were employed,
the latter being crucial for the highly stereoselective formation of the macrocycle of mandelalide A. Initially,
Julia Kocienski olefination, ring-closing metathesis reaction were investigated for the synthesis of the aglycone
of the proposed structure of the mandelalide A, and found to be unsuccessful.
Keywords. Cytotoxic; Heck cyclization; natural products; ring closing metathesis; total synthesis.
1. Introduction
in unusual E, Z-configured diene. The macrocycle is
decorated with 9 chiral centres, a tri-substituted THF
unitandtri-substitutedTHPmoietyglycosylatedwithan
unusual L-rhamnose derived pyranoside. The inimitable
structural features and promising biological activities
together with natural scarcity rendered mandelalide A, a
fascinating synthetic target for natural product chemists
to attempt its total synthesis. Pioneering efforts from the
group led by Frustner resulted in the first total synthesis
of the proposed structure of mandelalide A (1) and dis-
closed the incorrect structural assignment of the original
molecule.4a Shortly thereafter Tao et al., achieved the
herculean task of structural revision and establishment
of the absolute stereochemistry of mandelalide A, by
synthesizing a series of its structural variants.4b Sub-
sequently Frustner et al., also synthesized the actual
structure of mandelalide A and confirmed the struc-
tural revision made by Tao et al.,4c Recently, three
more total syntheses from the groups of Altmann,4d
Secondary metabolites produced by marine organisms
are a rich source of lead molecules for cancer therapy
and already many anticancer drugs have been developed
based on marine natural products which are in clinical
use.1
Mandelalides A-D are a new class of macrolides,
isolated by Mc. Phail et al., from Lissoclinum ascid-
ian from South Africa in 2012.2 Initial bioassay results
revealed that among the mandelalides A-D, mande-
lalide A (Figure 1) showed the most potent biological
activity against human NCI- H460 lung cancer cells
(IC50, 12 nM) and mouse Neuro-2A neuroblastoma
cells (IC50, 29 nM). Very recently mandelalides E-L
have been isolated by the same group and reported
the structure-activity relationship studies.3 Architec-
turally, mandelalide A is a 24-membered macrolide
containing three olefinic bonds, two of which were
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-019-1600-2) contains
supplementary material, which is available to authorized users.
0123456789().: V,-vol

25 Page 2 of 24
J. Chem. Sci.
(2019) 131:25
2.2 (3R,4S)-6-(tert-Butyldimethylsilyloxy)-4-(4-met
hoxybenzyloxy)-3-methylhexan-1-ol (16)
To a stirred solution of 11 (20 g, 54.50 mmol) in dry THF
(150 mL) was added BH3·SMe2 (6 mL, 60.0 mmol) at 0 ◦C
under nitrogen atmosphere. The reaction mixture was stirred
for another 12 h at the same temperature and then treated
with aqueous NaOH (3 M solution, 100 mL), 30% H2O2
(50 mL). After stirring for 2 h at room temperature, the mix-
ture was extracted with EtOAc (2 × 150 mL). The combined
organic extracts were washed sequentially with saturated
aqueous Na2S2O3 (40 mL), brine (40 mL) and dried over
Na2SO4. Evaporation of the solvent under reduced pressure
gave crude residue which was purified by column chromatog-
raphy (SiO2, 60–120 mesh, 12% EtOAc/hexane) to furnish
16 (17.6 g, 83%) as colourless oil. R f = 0.5 (SiO2, 20%
Figure 1. Proposed and revised struc-
tures of mandelalide A.
25
EtOAc/hexane); [α]D = −10.6 (c 0.3, CHCl3); IR (Neat):
Smith,4e Carter4f andonesyntheticstudyfromthegroup
of Sabitha4g were reported. Due to its high biological
significance and formidable composition of structure,
it led us to design and develop a divergent strategy
for the synthesis of mandelalide A and we success-
fully achieved the synthesis of aglycone of the proposed
structure of mandelalide A via intramolecular Heck
cyclization as a key step.5 In this article, we wish to
report the synthetic study of the proposed structure of
mandelalide A and the formal total synthesis of mande-
lalide A in detail.
νmax
3391, 2927, 2855, 1612, 1513, 1462, 1301, 1248, 1173,
1
1059, 834, 776 cm−1; H NMR (300 MHz, CDCl3): δ 7.24
(d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 4.45
(ABq, J = 10.8 Hz, 2H), 3.79 (s, 3H), 3.73–3.67 (m, 3H),
3.64–3.59 (m, 1H), 3.49–3.45 (m, 1H), 1.99–1.94 (m, 1H),
1.72–1.67 (m, 2H), 1.62–1.55 (m, 1H), 1.53–1.48 (m, 1H),
0.93 (d, J = 6.7 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 3H), 0.03
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 159.1, 130.8, 129.3,
113.7, 79.4, 71.5, 60.6, 59.8, 55.2, 35.5, 33.6, 32.6, 25.9,
18.3, 15.2, –5.30, –5.32. HRMS (ESI): [M + Na]+ calcd. for
C21H38O4NaSi 405.2431, found 405.2439.
2.3 tert-Butyl ((3S,4R,E)-8-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)-3-(4-methoxybenzyloxy)-4-methyloct-6-
enyloxy)dimethylsilane (17)
2. Experimental
To a stirred solution of 16 (16 g, 41.88 mmol) in dry CH2Cl2
(150 mL) was added NaHCO3 (3.52 g, 41.88 mmol) followed
by Dess-Martin periodinane (26.6 g, 62.82 mmol) at 0 ◦C
2.1 General experimental methods
All the reactions were performed in oven-dried glass under nitrogen atmosphere. After being stirred for 1 h at rt,
apparatus under nitrogen or argon atmosphere under mag- the reaction mixture was quenched with saturated aqueous
netic stirring. Standard methods were used to make anhy- NaHCO3 (50 mL) and Na2S2O3 (80 mL) and extracted with
drous solvents. Unless otherwise noted, commercially avail- EtOAc (2 × 500 mL). The combined organic extracts were
able reagents were used without further purification. Glass washed with water (40 mL) and brine (40 mL) and dried over
columns packed with silica gel (60–120 or 100–200 mesh) Na2SO4. Evaporation of the solvent under reduced pressure
were used for column chromatography. 1H and 13C NMR was furnished crude aldehyde which was passed through a short
recorded on 400 MHz, 500 MHz and 100 MHz, 125 MHz pad of silica gel and used as such for the next reaction.
spectrometer, respectively, in CDCl3 solvent using TMS as
To a stirred solution of sulfone 12 (21.2 g, 62.82 mmol)
an internal standard. Chemical shifts are measured as ppm in THF (100 mL) at −78 ◦C was added KHMDS (125.6 mL,
values relative to internal CHCl3 δ 7.26 or TMS δ 0.0 0.5 M in toluene, 62.82 mmol) under argon atmosphere. After
1
1
for H NMR and CHCl3 δ 77 for 13C NMR. In H NMR stirring for 30min, the crude aldehyde in THF (30 mL) was
multiplicity defined as: s=singlet; d=doublet; t=triplet; added to the reaction mixture at −78 ◦C via cannula. After
q=quartet; dd=doublet of doublet; ddd=doublet of doublet beingstirredfor3hat −78 ◦C, thereactionwasquenchedwith
of doublet; dt=doublet of triplet; m=multiplet; brs=broad water (10 mL) and extracted with EtOAc (2 × 400 mL). The
singlet. Horiba sepa 300 polarimeter was used to record opti- combined organic layers were washed with brine (40 mL),
cal rotation using a 2 mL cell with a 10 mm path length. dried over Na2SO4, and concentrated under vacuo. Purifica-
Alpha(Bruker)infraredspectrophotometerwasusedtorecord tion of the residue by column chromatography (SiO2, 60–120
FTIR spectra. Either a TOF or a double focusing spectrome- mesh, 7% EtOAc/hexane) afforded 17 (16.4 g, 81% yield
ter was used to obtain high-resolution mass spectra (HRMS) over two steps) as a colourless oil. R f = 0.5 (SiO2, 10%
25
[ESI]+.
EtOAc/hexane); [α]D = −25.0 (c 3, CHCl3); IR (Neat):

J. Chem. Sci.
νmax
(2019) 131:25
Page 3 of 24
25
2954, 2930, 2856, 1612, 1512, 1462, 1369, 1301, 1246, reduced pressure provided the mesylate compound which was
1172, 1156,1062, 1037, 831, 774 cm−1; 1H NMR (500 MHz, used directly without further purification.
CDCl3): δ 7.25 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz,
The above mesylate compound was added to a solution of
2H), 5.48 (dt, J = 15.1, 6.7 Hz, 1H), 5.38 (dt, J = 15.1, AD-mix-β (67.6 g) and MeSO2NH2 (4.6 g, 48.4 mmol) in t-
6.7 Hz, 1H), 4.42 (ABq, J = 10.9 Hz, 2H), 4.14–4.07 (m, BuOH:water (1:1, 500 mL) at 0 ◦C. The reaction mixture was
1H), 4.03–3.97 (m, 1H), 3.80 (s, 3H), 3.72–3.65 (m, 2H), stirred for 72 h at this temperature before being quenched by
3.59–3.53 (m, 1H), 3.41 (q, J = 4.2 Hz, 1H), 2.43–2.33 (m, slow addition of Na2S2O5 (69.0 g, 363 mmol) and stirred for
1H), 2.26–2.16 (m, 1H), 2.15–2.06 (m, 1H), 1.89–1.79 (m, additional 0.5 h. Then the reaction mixture was diluted with
2H), 1.69–1.61 (m, 2H), 1.41 (s, 3H), 1.35 (s, 3H), 0.91–0.81 water, and extracted with EtOAc (2 × 400 mL).The com-
(m, 12H), 0.04 (s, 6H). 13C NMR (125 MHz, CDCl3): δ bined organic layers were washed with water (40 mL), brine
159.0, 132.1, 131.1, 129.2, 126.2, 113.7, 108.8, 78.8, 75.6, (40 mL), dried over Na2SO4 and concentrated under vacuo.
71.2, 68.8, 59.9, 55.2, 36.8, 36.2, 35.7, 33.2, 26.8, 25.9, 25.6, Purification of the residue by column chromatography (SiO2,
18.2, 14.4, –5.28, –5.33. HRMS (ESI): [M + Na]+ calcd. for 13% EtOAc/hexane) afforded 9 (7.4 g, 81% yield over two
C28H48O5NaSi = 515.3163, found 515.3165.
steps) as clear oil. R f = 0.3 (SiO2, 20% EtOAc/hexane);
25
ν
[α]D = +22.2 (c 0.45, CHCl3); IR (Neat):
3463 (br),
max
2955, 2859, 1461, 1370, 1253, 1095, 1063, 834, 776 cm−1
;
1H NMR (300 MHz, CDCl3) : δ4.37–4.31 (m, 1H), 4.10 (dd,
J = 8.0, 5.9 Hz, 1H), 4.02–3.96 (m, 1H), 3.79–3.66 (m, 3H),
3.62–3.54 (m, 2H), 2.64 (brs, OH), 2.37 (q, J = 7.3 Hz, 1H),
2.06 (dt, J = 14.3, 7.2 Hz, 1H), 1.72–1.53 (m, 4H), 1.41 (s,
3H), 1.37 (s, 3H), 1.35–1.29 (m, 1H), 0.95 (d, J = 7 Hz,
3H), 0.9 (s, 9H), 0.06 (s, 6H). 13C NMR (75 MHz, CDCl3): δ
108.4, 81.8, 78.7, 73.5, 71.9, 69.8, 60.8, 37.8, 36.2, 35.7, 34.0,
26.9, 25.9, 25.7, 18.4, 14.9, –5.4. HRMS (ESI): [M + Na]+
calcd. for C20H40O5NaSi = 411.2537, found 411.2529.
2.4 (3S,4R,E)-1-(tert-Butyldimethylsilyloxy)-8-((R)
-2,2-dimethyl-1,3-dioxolan-4-yl)-4-methyloct-6-en-3-
ol (10)
To a stirred solution of 17 (15 g, 30.8 mmol) in CHCl3:
pH = 7 phosphate buffer (20:1, 100 ml) was added DDQ
(13.8 g, 60.8 mmol) at 0 ◦C. After stirring for 2 h at room
temperature, the reaction mixture was quenched with satu-
rated aqueous NaHCO3 (100 mL) and extracted with EtOAc
(2 × 400 mL). The combined organic extracts were washed
with water (30 mL), brine (30 mL), dried over Na2SO4 and
concentrated under vacuo. Purification of the residue by col-
umn chromatography (SiO2, 10% EtOAc/hexane) to afford
10 (10.74 g, 94% yield) as a clear oil. R f = 0.3 (SiO2, 15%
2.6 (2-((2R,3R,5R)-5-((R)-1-(Benzyloxy)-2-((R)-2,2-
dimethyl-1,3-dioxolan-4-yl)ethyl)-3-methyltetrahydro
furan-2-yl)ethoxy)(tert-butyl)dimethylsilane (18)
25
EtOAc/hexane); [α]D = −2.0 (c 0.7, CHCl3); IR (Neat):
To a stirred solution of 9 (2 g, 5.15 mmol) in THF (20 mL)
at 0 ◦C, was added sodium hydride portion wise (0.41 g, 60%
dispersion in oil, 10.3 mmol) under nitrogen atmosphere.
After being stirred for 15 min at 0 ◦C, was added BnBr
(0.91 mL, 7.73 mmol) slowly followed by TBAI (0.19 g,
0.51 mmol). The reaction mixture was stirred for 12 h at
room temperature and quenched carefully at 0 ◦C by slow
addition of saturated aqueous NH4Cl solution (10 mL). Then
it was extracted with EtOAc (2 × 50 mL). The combined
organic extracts were washed with water (15 mL), brine
(15 mL), dried over Na2SO4 and concentrated under vacuo.
The residue was purified by column chromatography (SiO2,
5% EtOAc/hexane) to afford 18 (2.26 g, 92% yield over
two steps) as a colourless liquid. R f = 0.6 (SiO2, 10%
νmax3509 (br), 2931, 2858, 1462, 1370, 1253, 1156, 1064,
1
971, 835, 777 cm−1; H NMR (500 MHz, CDCl3) δ 5.56–
5.48 (m, 1H), 5.43–5.36 (m, 1H), 4.11 (q, J = 6.6 Hz,
1H), 4.03–3.98 (m, 1H), 3.94–3.90 (m, 1H), 3.83–3.78 (m,
1H), 3.65–3.61 (m, 1H), 3.59–3.55 (m, 1H), 3.44 (brs, OH),
2.42–2.35 (m, 1H), 2.27–2.19 (m, 2H), 1.92–1.85 (m, 1H),
1.66–1.60 (m, 3H), 1.41 (s, 3H), 1.35 (s, 3H), 0.9 (s, 9H),
0.86 (d, J = 6.9 Hz, 3H), 0.08 (s, 6H). 13C NMR (125 MHz,
CDCl3): δ 132.2, 126.1, 108.8, 75.7, 75.6, 68.8, 63.1, 38.8,
36.8, 35.5, 34.6, 26.8, 25.8, 25.6, 18.0, 15.1, –5.58, –5.56.
HRMS (ESI): [M + Na]+ calcd. for C20H40O4NaSi =
395.2588, found 395.2591.
25
EtOAc/hexane); [α]D = +57.1 (c 0.35, CHCl3); IR (Neat):
2.5 (R)-1-((2R,4R,5R)-5-(2-(tert-Butyldimethylsilylo
xy)ethyl)-4-methyltetrahydrofuran-2-yl)-2-((R)-2,2-di
methyl-1,3-dioxolan-4-yl)ethanol (9)
νmax
2955, 2928, 2856, 1457, 1376, 1253, 1219, 1094, 1069,
939, 834, 772, 697, 672 cm−1 1H NMR (300 MHz): δ
;
7.39–7.25 (m, 5 H), 4.91 (d, J = 11.1 Hz, 1H), 4.59 (d,
J = 11.1 Hz, 1H), 4.29–4.20 (m, 1H), 4.05–3.92 (m, 2H),
To a stirred solution of 10 (9 g, 24.2 mmol) in dry CH2Cl2 3.90–3.71 (m, 3H), 3.62–3.47 (m, 2H), 2.34 (p, J = 7.2 Hz,
(70 mL) was added Et3N (5.2 mL, 36.2 mmol) followed by 1H), 2.06 (dt, J = 14.2, 7.0 Hz, 1H), 1.72–1.67 (m, 4H), 1.40
MsCl (2.6 mL, 31.46 mmol) dropwise at 0 ◦C under nitrogen (s, 3H), 1.34 (s, 3H), 1.28–1.20 (m, 1H), 0.96 (d, J = 7.0 Hz,
atmosphere and stirred for 1.5 h at rt. Then the reaction mix- 3H), 0.89 (s, 9H), 0.05 (s, 6H). 13C NMR (75 MHz): δ 138.9,
ture was quenched with saturated aqueous NaHCO3 (30 mL) 128.3, 128.0, 127.4, 108.3, 82.2, 79.9, 78.2, 73.9, 73.3, 69.9,
and extracted with EtOAc (2 × 400 mL). The combined 61.0, 36.6, 36.1, 35.4, 34.4, 27.0, 25.9, 25.80, 18.4, 15.3, –5.3.
organiclayerswerewashedwithwater(40mL), brine(40mL) HRMS (ESI): [M+Na]+ calcd. for C27H46O5NaSi 501.3006,
and dried over Na2SO4. Evaporation of the solvent under found 501.3012.

25 Page 4 of 24
J. Chem. Sci.
(2019) 131:25
2.7 2-((2R,3R,5R)-5-((R)-1-(Benzyloxy)-2-((R)-2,2-di (2 × 50 mL). The combined organic extracts were washed
with water (10 mL), brine (10 mL), dried over Na2SO4 and
concentrated under vacuo. The residue was purified by col-
umn chromatography (SiO2, 5% EtOAc/hexane) to afford 20
(1.05 g, 83% yield) as a viscous liquid. R f = 0.45 (SiO2,
methyl-1,3-dioxolan-4-yl)ethyl)-3-methyltetrahydrofur
an-2-yl)ethanol (19)
TBAF (1 M in THF, 8.36 mL, 8.36 mmol) was added to a
stirred solution of 18 (2 g, 4.18 mmol) in dry THF (15 mL)
at 0 ◦C. The reaction mixture was warmed to room temper-
ature and stirred for 3 h. It was quenched with saturated
aqueous NH4Cl (10 mL) solution and both the layers were
separated. Aqueous layer was further extracted with EtOAc
(2 × 50 mL). The combined organic layers were washed
with water (20 mL), brine (20 mL), dried over Na2SO4 and
concentrated under vacuo. The residue was purified by col-
umn chromatography (SiO2, 27% EtOAc/hexane) to afford 19
(1.36 g, 90% yield) as a viscous liquid. R f = 0.2 (SiO2, 30%
25
10% EtOAc/hexane); [α]D = +44.00 (c 0.25, CHCl3); IR
ν
(Neat): max 2935, 2843, 2322, 1720, 1648, 1456, 1367, 1334,
1227, 1175, 1134, 1074, 950, 844, 761, 700, 672, 616 cm−1
;
1H NMR (500 MHz, CDCl3): δ 7.36–7.30 (m, 5H), 6.44
(dt, J = 11.4, 7.1 Hz, 1H), 5.87 (dt, J = 11.4, 1.8 Hz,
1H), 4.87 (d, J = 11.2 Hz, 1H), 4.56 (d, J = 11.2 Hz,
1H), 4.28–4.20 (m, 1H), 4.01 (dt, J = 8.0, 4.8 Hz, 2H),
3.93–3.87 (m, 1H), 3.71 (s, 3H), 3.60–3.55 (m, 1H), 3.5 (t,
J = 7.7 Hz, 1H), 2.93–2.85 (m, 1H), 2.75–2.67 (m, 1H),
2.44–2.36 (m, 1H), 2.06–2.00 (m, 1H), 1.72–1.65 (m, 1H),
1.64–1.60 (m, 1H), 1.40 (s, 3H), 1.34 (s, 3H), 1.33–1.27
(m, 1H), 1.02 (d, J = 6.86 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ 168.8, 148.3, 138.9, 128.3, 128.0, 127.5, 120.1,
108.4, 82.9, 80.9, 79.9, 73.9, 73.3, 69.9, 59.9, 36.3, 36.13,
35.9, 31.5, 27.1, 25.8, 14.8. HRMS (ESI): [M + Na]+ calcd.
for C24H34O6Na 441.2252, found 441. 2250.
25
EtOAc/hexane); [α]D = +60.4 (c 0.7, CHCl3); IR (Neat):
νmax
3611 (br), 2920, 2851, 2310, 1549, 1460, 1377, 1214,
1056, 939, 834, 772, 697, 672 cm−1; H NMR (600 MHz,
CDCl3): δ 7.37–7.31 (m, 5H), 4.81 (d, J = 11.1 Hz, 1H),
4.62 (d, J = 11.1 Hz, 1H), 4.26 (p, J = 6.6 Hz, 1H), 4.08–
4.00 (m, 2H), 3.90 (dd, J = 15.5, 6.6 Hz, 1H), 3.90–3.70
(m, 2H), 3.67–3.61 (m, 1H), 3.50 (t, J = 7.6 Hz, 1H), 2.40–
2.33 (m, 1H), 2.03 (dt, J = 12.5, 6.2 Hz, 1H), 1.77–1.64
(m, 4H), 1.62–1.55 (m, 1H), 1.40 (s, 3H), 1.34 (s, 3H), 1.32–
1.27 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 138.6, 128.3, 127.9, 127.6, 108.5, 82.3, 81.6, 79.4,
73.9, 73.1, 69.9, 61.9, 36.3, 36.2, 35.9, 33.2, 27.1, 25.8, 15.2.
HRMS (ESI): [M + Na]+ calcd. for C21H32O5Na 387.2142,
found 387.2149.
1
2.9 (Z)-4-((2R,3R,5R)-5-((R)-1-(tert-Butyldiphenyls
ilyloxy)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-
3-methyltetrahydrofuran-2-yl)but-2-en-1-ol (8)
To a stirred solution of 20 (0.800 g, 1.91 mmol) in dry CH2Cl2
(10 mL), was added DIBAL-H (1.53 mL, 2.5 M in hex-
ane, 3.82 mmol) dropwise at −78 ◦C and stirred for 30 min.
The reaction was then quenched by slow addition of dry
methanol and brought to room temperature. Saturated aque-
ous potassium-sodium tartrate (5 mL) solution was added to
the reaction mixture and stirred for 2 h until two clear layers
2.8 (Z)-Methyl 4-((2R,3R,5R)-5-((R)-1-(tert-butyldip
henylsilyloxy)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)
ethyl)-3-methyltetrahydrofuran-2-yl)but-2-enoate (20)
To a stirred solution of 19 (1.1 g, 3.03 mmol) in dry CH2Cl2 were separated. Reaction mixture was extracted with EtOAc
(15 mL) was added NaHCO3 (0.25 g, 3.03 mmol) followed by (2 × 30 mL). The combined organic extracts were washed
Dess-Martin periodinane (2.56 g, 6.06 mmol) at 0 ◦C under with water (10 mL), brine (10 mL), dried over Na2SO4 and
nitrogen atmosphere. After being stirred for 2 h at room tem- concentrated under vacuo. The residue was purified by col-
perature, the reaction mixture was quenched with saturated umn chromatography (SiO2, 20% EtOAc/hexane) to afford 8
aqueous NaHCO3 (15 mL) and saturated aqueous Na2S2O3 (0.68 g, 89% yield) as a colourless liquid. R f = 0.2 (SiO2,
(15 mL) and extracted with EtOAc (2 × 50 mL). The com- 25% EtOAc/hexane); [α]2D5 = +38.00 (c 0.5, CHCl3); IR
ν
bined organic extracts were washed with water (10 mL), brine (Neat):
3425, 2942, 2851, 2330, 1651, 1462, 1371, 1334,
max
(10 mL), dried over Na2SO4. Evaporation of the solvent under 1228, 1176, 1135, 1074, 950, 848, 762, 701, 672, 616 cm−1
;
reduced pressure furnished crude aldehyde, which was passed 1H NMR (500 MHz, CDCl3): δ 7.37–7.27 (m, 5H), 5.78–
through a short pad of silica gel and used as such for the next 5.70 (m, 1H), 5.66–5.59 (m, 1H), 4.80 (d, J = 11.2 Hz,
reaction.
1H), 4.59 (d, J = 11.2 Hz, 1H), 4.27–4.18 (m, 2H), 4.06
To a stirred suspension of (CF3CH2O)2P(O)CH2COOMe (dd, J = 12.6, 6.2 Hz, 1H), 4.02 (dd, J = 8.1, 5.9 Hz,
(1.22 mL, 5.75 mmol) and 18-crown-6 (1.51 g, 5.75 mmol) 1H), 3.90–3.87 (m, 2H), 3.64 (ddd, J = 9.8, 6.3, 2.7 Hz,
in THF (10 mL) at −40 ◦C, KHMDS (0.5 M in toluene, 1H), 3.51 (t, J = 7.4 Hz, 1H), 2.40–2.27 (m, 2H), 2.14–
9.68 mL, 4.84 mmol) was added slowly. After 15 min stir- 2.08 (m, 1H), 2.06–1.99 (m, 1H), 1.76–1.64 (m, 2H), 1.40
ring at the same temperature, the reaction mixture was cooled (s, 3H), 1.33 (s, 3H), 1.36–1.31 (m, 1H), 0.99 (d, J =
to −78 ◦C and stirred for another 30 min. Then a solution 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 138.6, 130.2,
of the above aldehyde in dry THF (10 mL) was added drop- 129.8, 128.3, 128.1, 127.6, 108.4, 81.4, 80.9, 78.8, 73.8,
wise via cannula. After being stirred at −78 ◦C for 1 h, the 73.4, 69.9, 58.3, 35.9, 35.6, 29.5, 27.0, 25.8, 15.0. HRMS
reaction was quenched by the careful addition of saturated (ESI): [M + Na]+ calcd. for C23H34O5Na 413.2307, found
aqueous NaHCO3 (10 mL). Then it was extracted with EtOAc 413.2299.

J. Chem. Sci.
(2019) 131:25
Page 5 of 24
25
ν
2.10 (4S,6R)-7-(tert-Butyldiphenylsilyloxy)-6-methyl
hept-1-en-4-ol (21)
(c 0.4, CHCl3); IR (Neat): max 2957, 2932, 2858, 1732, 1612,
1427, 1247, 1181, 1108, 1036, 822, 703 cm−1; H NMR
(500 MHz, CDCl3): δ 7.68–7.64 (m, 4H), 7.45–7.36 (m, 6H),
1
Ozone was bubbled into a stirred solution of 14 (11.4 g, 7.24 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 5.80–
33.64 mmol) in CH2Cl2 (800 mL) at −78 ◦C until a light blue 5.65 (m, 1H), 5.11–5.02 (m, 3H), 4.45 (ABq, J = 12.2 Hz,
colour persisted. After being stirred for 15 min Ar was bub- 2H), 3.79 (s, 3H), 3.71 (t, J = 6.5 Hz, 2H), 3.50–3.44 (m,
bled through the solution until the blue colour was discharged. 2H), 2.57 (t, J = 6.5 Hz, 2H), 2.33–2.28 (m, 2H), 1.81–1.70
Dimethyl sulfide (24.8 mL, 841 mmol) was added at −78 ◦C, (m, 2H), 1.34–1.23 (m, 1H), 1.06 (s, 9H), 0.92 (d, J = 6.7 Hz,
and the mixture was warmed slowly to room temperature and 3H). 13C NMR (75 MHz, CDCl3): δ 171.2, 159.2, 135.6,
stirred for 40 min. The solvent was removed under vacuo and 133.9, 133.6, 130.2, 129.5, 129.2, 127.6, 117.6, 113.7, 72.7,
the residue was purified by flash column chromatography to 71.3, 69.2, 65.5, 55.2, 39.5, 37.4, 35.4, 32.2, 26.9, 19.3, 16.3.
afford aldehyde which was used directly in the next step.
HRMS (ESI): [M + H]+ calcd. for C35H47O5Si 575.3187,
To a stirred solution of (–)–Ipc2BOMe (15.96 g, found 575.3182.
50.46 mmol) in anhydrous diethyl ether (120 mL) at −78 ◦C
was added allylmagnesium bromide (1 M in diethyl ether,
2.12 (2R,4S,6S)-2-((R)-3-(tert-Butyldiphenylsilyloxy)
47 mL, 47 mmol), and the reaction mixture was stirred at
room temperature for 1 h before being cooled to −78 ◦C.
A solution of above aldehyde in diethyl ether (30 mL) was
added dropwise to this suspension, and allowed to stir for
8 h at −78 ◦C. To this mixture were added a solution of
10% aqueous NaOH (50 mL) and 30% H2O2 (50 mL). After
being stirred at room temperature for overnight, the resul-
tant mixture was diluted with H2O and extracted with EtOAc
(3 × 500 mL). The combined organic extracts were washed
with brine (100 mL) and dried over Na2SO4 and concentrated
under vacuo. The residue was purified by column chromatog-
raphy (SiO2, 6% EtOAc/hexane) to afford 21 (9.4 g, 72% two
steps) as oily liquid. R f = 0.4 (SiO2, 10% EtOAc/hexane);
-2-methylpropyl)-6-(2-(4-methoxybenzyloxy)ethyl)
tetrahydro-2H-pyran-4-ol (23)
To a stirred solution of ester 13 (10 g, 17.42 mmol) in dry
CH2Cl2 (80 mL) was added DIBAL-H (1 M in toluene,
35 mL, 34.8 mmol) dropwise via syringe at −78 ◦C under
nitrogen atmosphere. After 45 min, the reaction was treated
sequentially with pyridine (4.4 mL, 52.2 mmol) dropwise via
syringe, a solution of DMAP (4.24 g, 34.84 mmol) in CH2Cl2
(15 mL) dropwise via cannula and acetic anhydride (9.8 mL,
104.4 mmol) dropwise via syringe. After being stirred for 14 h
at −78 ◦C, the reaction mixture was then warmed to 0 ◦C and
stirred for an additional 30 min and then the reaction was
quenched at 0 ◦C with saturated aqueous NH4Cl (40 mL)
and saturated aqueous sodium potassium tartrate (30 mL).
The mixture was stirred at room temperature vigorously for
30 min and extracted with EtOAc (2×400 mL). The combined
organic extracts were washed with ice-cooled 1 M solution
of sodium bisulfate (2 ×50 mL), saturated aqueous NaHCO3
(2×50 mL), brine (30 mL) and dried over Na2SO4. Evapora-
tion of the solvent under reduced pressure afforded the crude
α-acetoxy ether which was used directly in the next reaction.
To a stirred solution of α-acetoxy ether in dry hexane
(150 mL) at 0 ◦C acetic acid (5 mL, 217.5 mmol) was
added followed by dropwise addition of BF3 · OEt2 (0.3 mL,
1.74 mmol). Then the reaction mixture was stirred for 2 h
before being quenched with saturated aqueous NaHCO3
(20 mL) and extracted with EtOAc (2 × 200 mL). The com-
25
ν
[α]D = +8.6 (c 0.9, CHCl3); IR (Neat):
3396, 2363,
max
1641, 1107, 701 cm−1
;
1H NMR (500 MHz, CDCl3): δ
7.69–7.65 (m, 4H), 7.45–7.36 (m, 6H), 5.89–5.79 (m, 1H),
5.14–5.12 (m, 1H), 5.11–5.10 (m, 1H), 3.79–3.73 (m, 1H),
3.52–3.49(m, 2H), 2.45(brs, OH), 2.29–2.17(m, 2H), 1.89(q,
J = 6.7 Hz, 1 H), 1.55–1.48 (m, 1H), 1.36 (dddd, J = 14.2,
7.6, 3.0 Hz, 1H), 1.06 (s, 9H), 0.89 (d, J = 6.7 Hz, 3H).
13C NMR (125 MHz, CDCl3): δ 135.6, 135.0, 133.5, 129.6,
127.6, 117.6, 69.8, 69.0, 42.6, 41.7, 33.3, 26.8, 19.2, 17.2.
HRMS (ESI): [M+Na]+ calcd. for C24H34O2SiNa 405.2225,
found 405.2228.
2.11 (4S,6R)-7-(tert-Butyldiphenylsilyloxy)-6-methyl
hept-1-en-4-yl 3-(4-methoxybenzyloxy) propanoate(13)
To a stirred solution of alcohol 21 (8 g, 20.94 mmol) and bined organic extracts were washed with brine (20 mL), dried
acid 22 (8.2 g, 41.88 mmol) previously azeotrope with dry over Na2SO4 and concentrated under vacuo. The crude mate-
benzene, in dry CH2Cl2 (80 mL) was added DCC (8.6 g, rial was then dissolved in 50 mL methanol and potassium
41.88 mmol) followed by DMAP (0.6 g, 4.18 mmol) at carbonate (4.8 g, 34.8 mmol). After being stirred for 3 h,
0 ◦C under nitrogen atmosphere. The reaction mixture was methanol was evaporated under reduced pressure and water
stirred for 12 h at room temperature before being quenched (10 mL) was added to the reaction mixture and extracted
with H2O (20 mL). Hexane (400 mL) was added and the with EtOAc (2 × 400 mL). The combined organic extracts
white precipitate was filtered off and the residue was washed were washed with brine (40 mL), dried over Na2SO4 and
with hexane/CH2Cl2 (2:1, 300 mL). The combined filtrate concentrated under vacuo. Purification of the residue by
and washings were washed with saturated aqueous NaHCO3 columnchromatography(SiO2, 25%EtOAc/hexane)afforded
(20 mL), brine (30 mL) and dried over anhydrous Na2SO4. 23 (4.4 g, 45% over three steps) as a colour less oil.R f = 0.3
25
Purification of the residue by column chromatography (SiO2, (SiO2, 30% EtOAc/hexane); [α]D = −4.5 (c 1.1, CHCl3);
6% EtOAc/hexane) afforded 13 (11.1 g, 93%) as a colour less IR (Neat): νmax3378, 2930, 2857, 1612, 1510, 1247, 1106,
25
1
oil. R f = 0.5 (SiO2, 10% EtOAc/hexane); [α]D = +15.6 819, 742, 702, 613 cm−1; H NMR (500 MHz, CDCl3): δ

25 Page 6 of 24
J. Chem. Sci.
(2019) 131:25
7.68–7.65 (m, 4H), 7.44–7.35 (m, 6H), 7.24 (d, J = 8.5 Hz, (c 0.9, CHCl3); IR (Neat): νmax 3565, 2922, 2853, 1728,
2H), 6.86 (d, J = 8.5 Hz, 2H), 4.39 (s, 2H), 3.78 (s, 1512, 1374, 1250, 1074, 837, 776 cm−1; 1H NMR (500 MHz,
3H), 3.77–3.72 (m, 1H), 3.58–3.49 (m, 3H), 3.46-3.39 (m, CDCl3): δ 7.25 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.6 Hz,
2H), 3.35–3.29 (m, 1H), 1.97–1.84 (m, 3H), 1.82–1.70 (m, 2H), 4.42 (ABq, J = 11.6 Hz, 2H), 3.80 (s, 3H), 3.79–3.72
1H), 1.66–1.60 (m, 2H), 1.27–1.20 (m, 2H), 1.16–1.07 (m, (m, 1H), 3.60–3.53 (m, 1H), 3.53–3.47 (m, 3H), 3.40–3.34
1H), 1.06 (s, 9H), 0.95 (d, J = 6.7 Hz, 3H). 13C NMR (m, 2H), 1.84–1.71 (m, 6H), 1.59–1.52 (m, 1H), 1.33 (ddd,
(125 MHz, CDCl3): δ 159.1, 135.6, 134.0, 133.9, 130.6,
J = 14.6, 5.9, 2.0 Hz, 1H), 1.24–1.17 (m, 1H), 0.91 (d,
J = 6.9 Hz, 3H), 0.87 (s, 9H), 0.05 (s, 6H). 13C NMR
129.5, 129.2, 127.5, 113.7, 73.0, 72.7, 72.3, 69.2, 68.3, 66.5,
55.2, 41.8, 41.3, 39.6, 36.2, 32.1, 26.9, 19.3, 16.6. HRMS (125 MHz, CDCl3): δ 159.1, 130.6, 129.3, 113.7, 74.8, 72.8,
(ESI): [M+Na]+ calcd. for C35H48O5NaSi 599.3163, found 72.7, 68.6, 68.3, 66.2, 55.2, 42.5, 41.5, 41.0, 36.1, 34.2, 25.8,
599.3173.
18.1, 17.9, –4.53, –4.55. HRMS (ESI): [M + Na]+ calcd. for
C25H44O5NaSi 475.2850, found 475.2840.
To a stirred solution of 25 (1.6 g, 3.54 mmol) in dry
CH2Cl2 (20 mL) was added NaHCO3 (0.29 g, 3.54 mmol)
and Dess Martin periodinane (2.4 g, 5.30 mmol) at 0 ◦C
under N2 atmosphere. After 2 h stirring at rt, the reac-
tion mixture was quenched with saturated aqueous NaHCO3
(10 mL) and Na2S2O3 (20 mL) and extracted with EtOAc
(2 × 200 mL). The combined organic extracts were washed
with water (10 mL), brine (20 mL), dried over Na2SO4, con-
centrated under vacuo and the residue was purified by flash
column chromatography to afford aldehyde 7 in quantitative
yield and used directly in the next step.
2.13 tert-Butyl((R)-3-((2R,4S,6S)-4-(tert-butyldimeth
ylsilyloxy)-6-(2-(4-methoxybenzyloxy)ethyl)tetrahydro
-2H-pyran-2-yl)-2-methylpropoxy)diphenylsilane (24)
To a stirred solution of 23 (3.6 g, 6.26 mmol) in dry CH2Cl2
(30 mL) was added 2, 6-lutidine (2 mL, 18.78 mmol) fol-
lowed by TBSOTf (1.6 mL, 6.88 mmol) at 0 ◦C under nitrogen
atmosphere. The reaction mixture was stirred for 1 h at room
temperature, before being quenched with saturated aque-
ous NaHCO3 (10 mL) solution and extracted with EtOAc
(2 × 100 mL). The combined organic extracts were washed
with saturated aqueous CuSO4 (20 mL), water (20 mL), brine
(20 mL), dried over Na2SO4 and concentrated under vacuo.
Purification of the residue by column chromatography (SiO2,
5% EtOAc/hexane) afforded 24 (3.9 g, 93%) as a clear oil.
2.15 2-((2R,3R,5R)-5-((R)-2-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)-1-(4-methoxybenzyloxy)ethyl)-3-methy
ltetrahydrofuran-2-yl)ethanol (30)
25
R f = 0.4 (SiO2, 10% EtOAc/hexane); [α]D = −7.7 (c 1.75,
To a stirred solution of compound 9 (3.0 g, 7.73 mmol) in
THF (50 mL) was added NaH (0.59 g, 15.46 mmol) at 0 ◦C
under nitrogen atmosphere. After being stirred for 10min,
PMBBr(1.35mL, 9.27mmol)andTBAI(0.285g, 0.77mmol)
were added sequentially to it and stirred for another 12 h at
room temperature. Then the reaction mixture was quenched
carefully with saturated NH4Cl (20 mL) and extracted with
EtOAc (2 × 150 mL). The combined organic extracts were
washedwithwater(20mL), brine(20mL), driedoverNa2SO4
and concentrated under vacuo, which was passed through a
short pad of silica gel and used as such for the next reaction.
To the stirred solution of above PMB protected compound
in THF (50 mL), was added TBAF (1 M in THF, 15.46 mL,
15.46 mmol) at 0 ◦C under nitrogen atmosphere. The reac-
tion mixture was warmed to room temperature and stirred for
2 h, before being quenched with saturated aqueous NH4Cl
(20 mL) solution and both the layers were separated. Aque-
ous layer was further extracted with EtOAc (2×150 mL). The
combined organic extracts were washed with water (20 mL),
ν
CHCl3); IR (Neat): max 2931, 2857, 1612, 1512,1366, 1249,
1084, 834, 777, 702, cm−1; 1H NMR (500 MHz, CDCl3): δ
7.69–7.65 (m, 4H), 7.43–7.35 (m, 6H), 7.24 (d, J = 8.5 Hz,
2H), 6.86 (d, J = 8.6 Hz, 2H), 4.39 (s, 2H), 3.79–3.70
(m, 2H), 3.79 (s, 3H), 3.59–3.49 (m, 3H), 3.47–3.39 (m,
1H), 3.37–3.30 (m, 1H), 2.00–1.92 (m, 1H), 1.81-1.69 (m,
3H), 1.66–1.59 (m, 2H), 1.25–1.15 (m, 3H), 1.06 (s, 9H),
0.96 (d, J = 6.7 Hz, 3H), 0.89 (s, 9H), 0.06 (s, 6H).
13C NMR (125 MHz, CDCl3): δ 159.1, 135.6, 134.0, 133.9,
130.6, 129.4, 129.2, 127.5, 113.7, 73.0, 72.8, 72.2, 69.3,
68.9, 66.6, 55.2, 42.4, 41.9, 39.6, 36.3, 32.1, 26.9, 25.8, 19.3,
18.1, 16.5, –4.53, –4.51. HRMS (ESI): [M + Na]+ calcd. for
C41H62O5NaSi2 713.4028, found 713.4035.
2.14 (R)-3-((2R,4S,6S)-4-(tert-Butyldimethylsilyloxy)
-6-(2-(4-methoxybenzyloxy)ethyl)tetrahydro-2H-pyran
-2-yl)-2-methylpropan-1-ol (25)
To the stirred solution of 24 (3.6 g, 5.2 mmol) in THF (50 mL) brine (20 mL), dried over Na2SO4 and concentrated under
and water (2 mL) was added 18-crown-6 (17.8 g, 67.6 mmol) vacuo. The residue was purified by column chromatogra-
followed by KOH (14.8 g, 250 mmol). The reaction mixture phy (SiO2, 30% EtOAc/hexane) to afford 30 (2.77 g, 91%
wasstirredfor2hatroomtemperature, beforebeingquenched yield over two steps) as a viscous liquid. R f = 0.3 (SiO2,
25
with water (10 mL) and extracted with EtOAc (2 × 200 mL). 25% EtOAc/hexane); [α]D = +42.0 (c 0.4, CHCl3); IR
ν
The combined organic extracts were washed with brine (Neat): max 3727, 2921, 2852, 1730, 1612, 1513, 1462, 1374,
(20 mL), dried over Na2SO4 and concentrated under vacuo. 1247, 1057, 821, 772, 722, 667 cm−1;1 H NMR (400 MHz,
The residue was purified by column chromatography (SiO2, CDCl3) : δ 7.27 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz,
15% EtOAc/hexane) to afford 25 (1.78 g, 82%) as a yellow 2H), 4.73 (d, J = 10.7 Hz, 1H), 4.54 (d, J = 10.7 Hz,
25
liquid. R f =0.3 (SiO2, 20% EtOAc/hexane); [α]D = +5.6 1H), 4.28–21 (m, 1H), 4.08–3.99 (m, 2H), 3.91–3.84 (m, 3H),

J. Chem. Sci.
(2019) 131:25
Page 7 of 24
25
3.79 (s, 3H), 3.65–3.59 (m, 1H), 3.42 (t, J = 7.7 Hz, 1H), 1H), 1.67 (ddd, J = 13.9, 7.8, 2.6 Hz, 1H), 1.63–1.60 (m,
2.36 (p, J = 7.3 Hz, 1H), 2.06–1.98 (m, 1H), 1.78–1.55 (m, 1H), 1.39 (s, 3H), 1.34 (s, 3H), 1.32–1.27 (m, 1H), 0.97 (d,
5H), 1.40 (s, 3H), 1.34 (s, 3H), 0.97 (d, J = 7.0 Hz, 3H).
J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 159.1,
13C NMR (100 MHz, CDCl3): δ 159.2, 130. 8, 129.6, 113.8, 132.3, 131.2, 130.3, 129.7, 129.3, 117.3, 113.7, 108.3, 82.1,
108.5, 82.4, 81.7, 79.0, 73.7, 73.1, 69.9, 62.0, 55.2, 36.3, 36.2 81.3, 79.3, 73.6, 73.4, 70.0, 55.2, 36.5, 36.1, 35.5, 29.9, 27.1,
35.9, 33.2, 27.1, 25.8, 15.2. HRMS (ESI): [M + Na]+ calcd. 25.8, 15.1. HRMS (ESI): [M + H]+ calcd. for C25H37O5
for C22H34O6Na 417.2247, found 417.2248.
417.2649, found 417.2646.
2.16 (R)-4-((R)-2-(4-methoxybenzyloxy)-2-((2R,4R,
5R)-4-methyl-5-((Z)-penta-2,4-dienyl)tetrahydrofuran
-2-yl)ethyl)-2,2-dimethyl-1,3-dioxolane (31)
2.17 (2R,4R)-4-(4-methoxybenzyloxy)-4-((2R,4R,5R)
-4-methyl-5-((Z)-penta-2,4-dienyl)tetrahydrofuran-2-
yl)butane-1,2-diol (32)
To a stirred solution of 30 (2.5 g, 6.34 mmol) in dry CH2Cl2
(20 mL) was added NaHCO3 (0.52 g, 6.34 mmol) and
Dess-Martin periodinane (4.0 g, 9.51 mmol) at 0 ◦C under
nitrogen atmosphere. After 2 h stirring at room temperature,
the reaction mixture was quenched with saturated aqueous
NaHCO3 (20 mL) and saturated aqueous Na2S2O3 (20 mL)
and extracted with EtOAc (2 × 150 mL). The combined
organic extracts were washed with water (20 mL), brine
(20 mL) and dried over Na2SO4. Evaporation of the solvent
under reduced pressure furnished crude aldehyde, which was
passed through a short pad of silica gel and used as such for
the next reaction. To a stirred suspension of chromium (II)
chloride (8.57 g, 69.74 mmol) in dry THF (20 mL) at 0 ◦C
under Ar atmosphere was added a suspension of above alde-
hyde in dry THF (20 mL) with (1-Bromoallyl)trimethylsilane
(7.37 g, 38.04 mmol) via cannula. The reaction mixture was
warmed to rt and stirred for 12 h at that temperature, and
the resultant deep purple suspension was quenched by the
addition of PH = 7 buffer and both the layers were sepa-
rated. The aqueous layer was further extracted with EtOAc
(2 × 150 mL). The combined organic layers were washed
with water (20 mL), brine (20 mL), dried over Na2SO4 and
concentrated under vacuo.
To a stirred solution of 31 (2.0 g, 4.80 mmol) in dry
MeOH (20 mL), CSA (0.223 mg, 0.96 mmol) was added at
0 ◦C under nitrogen atmosphere. The reaction mixture was
warmed to room temperature and stirred for 8 h before being
quenched with saturated aqueous NaHCO3 (20 mL) solu-
tion and both the layers were separated. Aqueous layer was
further extracted with EtOAc (2×150 mL), brine (20 mL)
dried over Na2SO4 and concentrated under vacuo. The
residue was purified by column chromatography (SiO2, 39%
EtOAc/hexane) to afford 32 (1.71 g, 95% yield over two steps)
as a viscous liquid. R f = 0.2 (SiO2, 40% EtOAc/hexane);
25
ν
[α]D = +23.1 (c 0.2, CHCl3); IR (Neat):
3382, 2954,
max
2927, 2855, 1615, 1514, 1458, 1376, 1251, 1062, 834, 778,
671 cm−1;1 H NMR (500 MHz, CDCl3)δ 7.28 (d, J =
8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 6.64 (dt, J = 16.8,
10.6 Hz, 1H), 6.08 (t, J = 10.6 Hz, 1H), 5.55 (dd, J = 16.7,
7.4 Hz, 1H), 5.21 (d, J = 16.8 Hz, 1H), 5.12 (d, J = 9.6 Hz,
1H), 4.77 (d, J = 11.2 Hz, 1H), 4.59 (d, J = 11.2 Hz,
1H), 4.00–3.92 (m, 2H), 3.91–3.85 (m, 1H), 3.79 (s, 3H),
3.63–3.55 (m, 2H), 3.44–3.39 (m, 1H), 2.41–2.29 (m, 3H),
2.07–2.00 (m, 1H), 1.66–1.58 (m, 2H), 1.45 (ddd, J = 14.3,
8.0, 2.6 Hz, 1H), 0.98 (d, J = 11.2 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 159.2, 132.3, 130.7, 130.4, 129.9, 129.1,
117.4, 113.8, 81.7, 81.4, 78.6, 72.9, 69.1, 66.9, 55.2, 36.5,
35.4, 34.3, 29.8, 15.1. HRMS (ESI): [M + H]+ calcd. for
C22H33O5 377.2331, found 377.2330.
The crude residue was dissolved in THF (20 mL) and
added to a stirred solution of KH (7.62 g, 30% wt suspen-
sion, 57.06 mmol) in THF (20 mL) via cannula at 0 ◦C under
nitrogen atmosphere. The reaction mixture was warmed to rt
and stirred for 2 h. Then the reaction mixture was cautiously
poured into ice cooled water (50 mL) and extracted with
2.18 (2R,4R)-1-(tert-Butyldimethylsilyloxy)-4-(4-met
EtOAc (2 × 150 mL), washed with brine (20 mL), dried over hoxybenzyloxy)-4-((2R,4R,5R)-4-methyl-5-((Z)-penta-
Na2SO4 and concentrated under vacuo. The residue was puri-
fied by column chromatography (SiO2, 12% EtOAc/hexane)
2,4-dienyl)tetrahydrofuran-2-yl)butan-2-ol (29)
to afford 31 (2.32 g, 88% yield over two steps) as a viscous liq- To a stirred solution of 32 (1.5 g, 3.98 mmol) in CH2Cl2
25
uid. R f = 0.4 (SiO2, 15% EtOAc/hexane); [α]D = +27.6 (20 mL), imidazole (0.29 g, 4.38 mmol) and TBSCl (0.66 g,
νmax
(c 0.45, CHCl3); IR (Neat):
2954, 2929, 2857, 1615, 4.38 mmol) were added sequentially at 0 ◦C under nitro-
1514, 1463, 1372, 1251, 1062, 1001, 834, 777, 667 cm−1
;
gen atmosphere. The reaction mixture was warmed to room
1H NMR (500 MHz, CDCl3): δ 7.28 (d, J = 8.7 Hz, 2H), temperature and stirred for 4 h before being quenched with
6.85 (d, J = 8.7 Hz, 2H), 6.65 (dddd, J = 16.8, 11.1, saturated aqueous NH4Cl (20 mL) solution and extracted
10.1, 1.1 Hz, 1H), 6.08 (t, J = 11.0 Hz, 1H), 5.56 (dd, with EtOAc (2×100 mL). The combined organic extracts
J = 18.0, 7.4 Hz, 1H), 5.20 (dd, J = 16.9, 1.8 Hz, 1H), were washed with water (10 mL), brine (10 mL), dried over
5.11 (d, J = 10.2 Hz, 1H), 4.80 (d, J = 11.0 Hz, 1H), 4.51 Na2SO4 and concentrated in vacuo. The residue was puri-
(d, J = 11.0 Hz, 1H), 4.25–4.19 (m, 1H), 4.0 (dd, J = 8.1, fied by column chromatography (SiO2, 8% EtOAc/hexane)
5.8 Hz, 1H), 3.94–3.90 (m, 1H), 3.86 (dt, J = 9.3, 6.8 Hz, to afford 29 (1.78 g, 94% yield over two steps) as clear
25
1H), 3.80 (s, 3H), 3.56 (ddd, J = 10.2, 7.0, 2.6 Hz, 1H), oil. R f = 0.4 (SiO2, 15% EtOAc/hexane); [α] = +7.2
3.49 (t, J = 7.8 Hz, 1H), 2.38–2.31 (m, 3H), 2.07–2.01 (m, (c 2.22, CHCl3). IR (neat):
2952, 2930, 2D860, 1618,
νmax

25 Page 8 of 24
J. Chem. Sci.
(2019) 131:25
1518, 1461, 1384, 1255, 1063, 831, 779, 674 cm−1;1 H NMR saturated aqueous NaHCO3 (10 mL) and extracted with
(500 MHz, CDCl3) : δ 7.24 (d, J = 8.7 Hz, 2H), 6.85 (d, EtOAc (2×100 mL). The combined organic extracts were
J = 8.7 Hz, 2H), 6.65 (dddd, J = 16.9, 11.1,10.1, 1.1 Hz, washedwithwater(10mL), brine(10mL), driedoverNa2SO4
1H), 6.08 (t, J = 11.0 Hz, 1H), 5.56 (dd, J = 10.5, 7.5 Hz, and concentrated under vacuo. Purification of the residue by
1H), 5.20 (dd, J = 16.9, 1.8 Hz, 1H), 5.11 (d, J = 10.1 Hz, column chromatography (SiO2, 7% EtOAc/hexane) afforded
1H), 4.81 (d, J = 11.0 Hz, 1H), 4.57 (d, J = 11.0 Hz, 1H), 35 (0.8 g, 92%) as clear oil. R f
=
0.3(SiO2, 10%
25
3.95–3.88 (m, 2H), 3.88–3.82 (m, 1H), 3.79 (s, 3H), 3.66 (dd, EtOAc/hexane); [α]D = −4.3 (c 1.6, CHCl3); IR (Neat):
νmax
J = 12.5, 7.0 Hz, 1H), 3.55 (dd, J = 9.9, 4.2 Hz, 1H),
3398, 3077, 2928, 2856, 1464, 1374, 1253, 1075, 911,
3.42 (dd, J = 9.9, 6.8 Hz, 1H), 2.71 (brs, 1H), 2.40–2.29 839, 775 cm−1;1 H NMR (500 MHz, CDCl3): δ 5.70 (ddd,
(m, 3H), 2.07–2.00 (m, 1H), 1.69–1.57 (m, 2H), 1.52–1.48
J = 17.3, 10.2, 7.6 Hz, 1H), 4.98–4.88 (m, 2H), 3.82–
(m, 1H), 0.98 (d, J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.01 (s, 3.71 (m, 3H), 3.56–3.50 (m, 1H), 3.38–3.32 (m, 1H), 2.76
6H). 13C NMR (125 MHz, CDCl3): δ 159.1, 132.2, 131.2, (brs, OH), 2.28 (q, J = 7.0 Hz, 1H), 1.84–1.60 (m, 5H),
130.3, 129.8, 129.3, 117.3, 113.7, 82.2, 81.3, 79.2, 73.4, 68.7, 1.35–1.15 (m, 3H), 1.0 (d, J = 6.7 Hz, 3H), 0.88 (s, 9H),
67.4, 55.2, 36.6, 35.5, 34.9, 29.9, 25.8, 18.3, 15.1, –5.3, –5.4. 0.05 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 144.2, 112.5,
HRMS (ESI): [M+Na]+ calcd. for C28H46O5SiNa 513.3018, 76.1, 73.9, 68.5, 61.5, 42.5, 41.7, 41.5, 37.7, 34.3, 25.8,
found 513.3013.
19.9, 18.1, –4.55, –4.57. HRMS (ESI): [M + H]+ calcd. for
C18H37O3Si 329.2506, found 329.2505.
2.19 tert-Butyl((2S,4S,6R)-2-(2-(4-methoxybenzylo
xy)ethyl)-6-((R)-2-methylbut-3-enyl)tetrahydro-2H-
pyran-4-yloxy)dimethylsilane (34)
2.21 (E)-((2R,4R)-1-(tert-Butyldimethylsilyloxy)-4-
(4-methoxybenzyloxy)-4-((2R,4R,5R)-4-methyl-5-((Z)-
penta-2,4-dienyl)tetrahydrofuran-2-yl)butan-2-yl)
4-((2S,4R,6R)-4-(tert-butyldimethylsilyloxy)
-6-((R)-2-methylbut-3-enyl)tetrahydro-2H-pyran-2-
yl)but-2-enoate (26)
To a stirred solution of sulfone 33 (2.4 g, 10.62 mmol) in
THF (30 mL) at −78 ◦C was added NaHMDS (7.0 mL, 1 M
in THF, 7.08 mmol) under argon atmosphere. After being
stirred for 30min the crude aldehyde 7 in THF (20 mL)
was added at −78 ◦C to the reaction mixture via cannula.
The reaction mixture was slowly warmed to room tempera-
ture and stirred for 12 h before being quenched with water
(10 mL) and extracted with EtOAc (2 x 200 mL). The com-
bined organic extracts were washed with brine (20 mL),
dried over Na2SO4, and concentrated under vacuo. Purifi-
cation of the residue by column chromatography (SiO2, 4%
To a stirred solution of 35 (0.7 g, 2.132 mmol) in dry CH2Cl2
(40 mL) was added NaHCO3 (0.172 g, 2.132 mmol) and
Dess Martin periodinane (1.36 g, 3.20 mmol) at 0 ◦C under
N2 atmosphere. After 2 h stirring at rt, the reaction mixture
was quenched with saturated aqueous NaHCO3 (20 mL) and
Na2S2O3 (20 mL) and extracted with EtOAc (2×50 mL). The
combined organic extracts were washed with water (20 mL)
brine (30 mL), dried over Na2SO4 and concentrated under
vacuo gave the residue that was purified by flash column chro-
matography to afford aldehyde 28 which was used directly in
the next step.
To a stirred solution of 29 (0.433 mg, 0.913 mmol) in
dry CH2Cl2 (10 mL) was added diethyl phosphonoacetic
acid (0.22 mL, 1.367 mmol) followed by DMAP (0.022 g,
0.182 mmol) at 0 ◦C under nitrogen atmosphere. The reac-
tion mixture was stirred for 10 min at 0 ◦C, and then EDCI
(0.349 g, 1.822 mmol) was added to it. After 4 h of stir-
ring at room temperature, the reaction mixture was quenched
by the addition of water (5 mL) and extracted with EtOAc
(2×40 mL). The combined organic extracts were washed
with brine (5 mL) and dried over Na2SO4. Evaporation of the
solvent under vacuo afforded crude ester compound which
was passed through a short pad of silica and used as such for
the next reaction.
EtOAc/hexane) afforded 34 (1.35 g, 82% over two steps) as
25
yellow oil. R f = 0.5(SiO2, 10% EtOAc/hexane); [α]D
=
−11.7 (c 0.45, CHCl3); IR (Neat): νmax 2928, 2856, 1513,
1462, 1360, 1248, 1076, 836, 775 cm−1;1 H NMR (500 MHz,
CDCl3) : δ 7.25 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz,
2H), 5.79–5.70 (m, 1H), 4.98-4.88 (m, 2H), 4.42 (s, 2H),
3.80 (s, 3H), 3.78–3.71 (m, 1H), 3.62–3.56 (m, 1H), 3.55–
3.50 (m, 1H), 3.46–3.40 (m, 1H), 3.32–3.26 (m, 1H), 2.35
(q, J = 7.0 Hz, 1H), 1.82–1.71 (m, 3H), 1.66–1.60 (m, 1H),
1.3–1.14 (m, 4H), 0.99 (d, J = 6.5 Hz, 3H), 0.88 (s, 9H),
0.05 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 159.1, 144.6,
130.6, 129.2, 113.7, 112.1, 73.2, 72.7, 72.3, 68.9, 66.5, 55.2,
42.5, 41.88, 41.84, 36.2, 33.8, 25.8, 19.4, 18.1, –4.5. HRMS
(ESI): [M+Na]+ calcd. for C26H44O4NaSi 471.2901, found
471.2913.
2.20 2-((2S,4S,6R)-4-(tert-Butyldimethylsilyloxy)-6-
((R)-2-methylbut-3-enyl)tetrahydro-2H-pyran-2-yl)
ethanol (35)
To a mixture of phosphonate compound (0.433 g,
0.913 mmol) and LiCl (0.074 g, 1.826 mmol) in dry MeCN
(10 mL) was added DBU (0.14 mL, 0.913 mmol) at 0 ◦C under
To a stirred solution of 34 (1.2 g, 2.68 mmol) in CHCl3: argon atmosphere. After being stirred for 15 min at room tem-
pH = 7 phosphate buffer (20:1, 15 mL) was added DDQ perature, the reaction mixture was again cooled to 0 ◦C and
(1.2 g, 5.36 mmol) at 0 ◦C. The reaction mixture was stirred a solution of aldehyde 28 (0.300 g, 0.913 mmol) in MeCN
for 2 h at room temperature, before being quenched with (5 mL) was added drop wise via cannula. Then the reaction

J. Chem. Sci.
(2019) 131:25
Page 9 of 24
25
mixture was stirred for 12 h at room temperature before being 18.3, 18.2, 15.6, –4.0, –4.8, –5.3. HRMS (ESI): [M + Na]+
quenched by the addition of water (5 mL) and extracted with calcd. for C26H54O5NaSi2 525.3402, found 525.3412.
EtOAc (2 × 50 mL). The combined organic extracts were
washed with brine (10 mL), dried over Na2SO4, and con-
centrated under vacuo. The residue was purified by column
chromatography (SiO2, 60–120 mesh, 8% EtOAc/hexane) to
2.23 2-((2R,3R,5R)-5-((R)-1-(tert-Butyldimethylsily
loxy)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-
methyltetrahydrofuran-2-yl)ethanol (39)
afford 26 (0.61 g, 80% over two steps) as colourless oil.
25
R f = 0.45 (SiO2, 15% EtOAc/hexane); [α] = +22.5
2963, 2930, D2856, 1714,
To a stirred solution of 40 (1.5 g, 2.99 mmol) in dry THF
(10 mL) in a polypropylene vial, was added HF-Py complex
(70%, 0.4 mL) at 0 ◦C. The reaction mixture was warmed
to room temperature and stirred for 12 h. Then the reac-
tion mixture was cautiously poured into a saturated aqueous
NaHCO3solution and stirred for 30 min. Then both the
layers were separated, aqueous layer was further extracted
with EtOAc (2 × 50 mL). The combined organic layers
were washed with saturated aqueous CuSO4 (8 mL), water
(5 mL), brine (5 mL) and dried over Na2SO4. Purifica-
tion of the residue by column chromatography (SiO2, 25%
EtOAc/hexane) afforded 39 (1.0 g, 88% yield) as a colourless
νmax
(c 0.4, CHCl3); IR (Neat):
1614, 1586, 1461, 1248, 831, 779, 674 cm−1 1H NMR
;
(500 MHz, CDCl3): δ 7.30 (d, J = 8.6 Hz, 2H), 6.99 (dt,
J = 15.6, 7.2 Hz, 1H), 6.83 (d, J = 8.6 Hz, 2H), 6.63 (dt,
J = 16.7, 10.2 Hz, 1H), 6.07 (t, J = 10.8 Hz, 1H), 5.89 (d,
J = 15.7 Hz, 1H), 5.71 (ddd, J = 17.3, 10.2, 7.2 Hz, 1H),
5.58–5.51 (m, 1H), 5.27–5.16 (m, 2H), 5.09 (d, J = 10.2 Hz,
1H), 4.98–4.88 (m, 2H), 4.72 (d, J = 10.2 Hz, 1H), 4.40 (d,
J = 10.2 Hz, 1H), 3.93–3.85 (m, 2H), 3.78 (s, 3H), 3.76–3.71
(m, 2H), 3.63 (ddd, J = 11.0, 5.0, 2.5 Hz, 1H), 3.43–3.34
(m, 2H), 3.32–3.26 (m, 1H), 2.47–2.40 (m, 1H), 2.38–2.28
(m, 4H), 2.09–1.98 (m, 2H), 1.84–1.73 (m, 3H), 1.69–1.59
(m, 2H), 1.34–1.12 (m, 4H), 1.00–0.96 (m, 6H), 0.88 (s, 9H),
0.86 (s, 9H), 0.05 (d, J = 1.8 Hz, 6H), 0.01 (d, J=3.6 Hz, 6H).
13C NMR (125 MHz, CDCl3): δ 165.9, 159.0, 145.4, 144.4,
132.3, 131.1, 130.3, 129.9, 129.3, 123.2, 117.3, 115.1, 113.7,
112.4, 81.9, 81.3, 78.4, 74.1, 73.5, 71.4, 68.7, 64.9, 55.2, 42.4,
41.5, 41.4, 38.8, 36.4, 35.4, 34.0, 32.9, 29.9, 25.8, 19.9, 18.3,
18.1, 15.2, –4.5, –5.3. HRMS (ESI): [M + Na]+ calcd. for
C48H80O8Si2Na 863.5299, found 863.5291.
25
liquid. R f = 0.2 (SiO2, 30% EtOAc/hexane); [α]D = +18.7
νmax
(c 0.65, CHCl3); IR (Neat):
3444, 2955, 2857, 1471,
1370, 1249, 1214, 1058, 836, 777 cm−1;1 H NMR (300 MHz,
CDCl3) : δ 4.28–4.17 (m, 1H), 4.07–3.88 (m, 3H), 3.82–3.72
(m, 3H), 3.48 (t, J = 7.5 Hz, 1H), 2.39–2.27 (m, 1H), 2.00–
1.90 (m, 1H), 1.78–1.50 (m, 4H), 1.38 (s, 3H), 1.32 (s, 3H),
1.31–1.27 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H), 0.89 (s, 9H),
0.09 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 108.6, 82.0, 81.2,
72.5, 70.7, 69.9, 61.8, 37.1, 35.6, 34.8, 33.0, 27.0, 25.9, 25.7,
18.1, 15.2, –4.1, –4.7. HRMS (ESI): [M + Na]+ calcd. for
C20H40O5NaSi 411.2537, found 411.2542.
2.22 tert-Butyl-(2-((2R,3R,5R)-5-((R)-1-(tert-butyldi
methylsilyloxy)-2-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)
ethyl)-3-methyltetrahydrofuran-2-yl)ethoxy)dimethyls
ilane (40)
2.24 tert-Butyl ((R)-2-((R)-2,2-dimethyl-1,3-dioxol
an-4-yl)-1-((2R,4R,5R)-5-((Z)-3-iodoallyl)-4-methy
ltetrahydrofuran-2-yl)ethoxy)dimethylsilane (38)
To a stirred solution of 9 (1.5 g, 3.86 mmol) in dry CH2Cl2
(15 mL) was added 2,6-lutidine (1.4 mL, 11.59 mmol) fol- To a stirred solution of 39 (0.9 g, 2.32 mmol) in dry CH2Cl2
lowed by TBSOTf (1.0 mL, 4.25 mmol) at 0 ◦C under nitrogen (10 mL) were added NaHCO3 (0.18 g, 2.32 mmol) and Dess-
atmosphere. The reaction mixture was stirred for another Martin periodinane (1.5 g, 3.48 mmol) sequentially at 0 ◦C
2 h at room temperature, before being quenched with satu- under nitrogen atmosphere. Then the reaction mixture was
rated aqueous NaHCO3 (3 mL) and extracted with EtOAc stirredfor2hatroomtemperaturebeforebeingquenchedwith
(2×100 ml). The combined organic extracts were washed saturated aqueous NaHCO3 (8 mL) and saturated aqueous
with saturated aqueous CuSO4 (8 mL), water (5 mL), brine Na2S2O3 (8 mL) and extracted with EtOAc (2×50 mL). The
(5 mL), dried over Na2SO4 and concentrated under vacuo. combined organic extracts were washed with water (5 mL),
Purification of the residue by column chromatography (SiO2, brine (5 mL) and dried over Na2SO4. Evaporation of the sol-
5% EtOAc/hexane) afforded 40 (1.8 g, 95%) as a clear oil. vent furnished crude aldehyde, which was passed through a
25
R f = 0.5 (SiO2, 10% EtOAc/hexane); [α] = +30.3 short pad of silica gel and used as such for the next reaction.
2954, 2931,D2858, 1466,
To a suspension of iodomethyl triphenylphosphonium
νmax
(c 0.6, CHCl3); IR (Neat):
1374, 1251, 1092, 834, 776, 666 cm−1; 1H NMR (500 MHz, iodide (3.68 g, 6.96 mmol) in anhydrous THF (20 mL) was
CDCl3): δ 4.29–4.23 (m, 1H), 4.04 (dd, J = 7.8, 5.9 Hz, added NaHMDS (6.95 mL, 1.0 M in THF, 6.95 mmol) at
1H), 3.89–3.83 (m, 2H), 3.80–3.75 (m, 1H), 3.71–3.64 (m, 0 ◦C under argon atmosphere. Then the reaction mixture was
2H), 3.48 (t, J = 7.7 Hz, 1H), 2.26 (qt, J = 7.2 Hz, 1H), stirred for another 15 min at 0 ◦C before being cooled to
1.97 (dt, J = 14.5, 7.2 Hz, 1H), 1.70–1.58 (m, 3H), 1.53–1.47 −78 ◦C and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimi-
(m, 1H), 1.39 (s, 3H), 1.33 (s, 3H), 1.26–1.18 (m, 1H), 0.91 dinone (DMPU) (1.4 mL, 11.6 mmol) was added followed
(d, J = 7 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.09 (s, 6H), by the above aldehyde in dry THF (5 mL) via cannula. After
0.05 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 108.5, 81.6, 78.2, 2 h stirring at −78 ◦C, the reaction mixture was quenched
72.5, 71.7, 70.0, 61.2, 37.0, 35.5, 35.3, 34.3, 27.1, 26.0, 25.8, by addition of saturated aqueous NH4Cl (3 mL) and stirred

25 Page 10 of 24
J. Chem. Sci.
(2019) 131:25
for 1 h at rt and extracted with EtOAc (2×100 mL). The atmosphere. Then the reaction mixture was stirred for 3 h at rt
combined organic extracts were washed with water (5 mL), before being quenched with saturated aqueous NH4Cl (3 mL)
brine (5 mL), dried over Na2SO4 and concentrated under and extracted with EtOAc (2×50 mL). The combined organic
vacuo. Purification of the residue by column chromatogra- extracts were washed with brine (5 mL), dried over Na2SO4
phy (SiO2, 5% EtOAc/hexane) afforded 38 (0.97 g, 78% and concentrated under vacuo. Purification of the residue by
over two steps) as a viscous liquid. R f = 0.6 (SiO2, 10% column chromatography (SiO2, 7% EtOAc/hexane) afforded
25
EtOAc/hexane); [α]D = +15.4 (c 1.2, CHCl3); IR (Neat): 41 (0.52 g, 95%) as oily liquid. R f = 0.2 (SiO2, 10%
25
νmax
2954, 2929, 2857, 1463, 1372, 1251, 1062, 1001, 834, EtOAc /hexane); [α]D = +22.0 (c 1.4, CHCl3); IR (Neat):
1
777, 667 cm−1; H NMR (500 MHz, CDCl3): δ 6.32 (dd,
2953, 2928, 2856, 1465, 1367, 1252, 1094, 1002, 837,
νmax
J = 13.7, 6.5 Hz, 1H), 6.26 (dt, J = 7.5, 1.4 Hz, 1H), 4.28– 776, 672 cm−1; H NMR (500 MHz, CDCl3): δ 6.32 (dd,
1
4.22 (m, 1H), 4.04 (dd, J = 7.8, 5.9 Hz, 1H), 3.95–3.87 (m,
J = 13.5, 6.5 Hz, 1H), 6.25 (dt, J = 7.5, 1.2 Hz, 1H), 3.96–
2H), 3.72 (dt, J = 12.8, 6.4 Hz, 1H), 3.50 (t, J = 7.6 Hz, 3.91 (m, 2H), 3.87–3.79 (m, 2H), 3.53 (dd, J = 9.7, 4.8 Hz,
1H), 2.34 (q, J = 7.3 Hz, 1H), 2.25–2.21 (m, 2H), 1.98 (dt, 1H), 3.47 (dd, J = 9.9, 6.7 Hz, 1H), 2.96 (brs, OH), 2.34 (q,
J = 14.1, 7.3 Hz, 1H), 1.68 (ddd, J = 13.5, 8.8, 2.4 Hz,
J = 7.3, 1H), 2.26–2.21 (m, 2H), 2.05–1.97 (m, 1H), 1.56–
1H), 1.52 (ddd, J = 13.7, 9.9, 3.8 Hz, 1H), 1.40 (s, 3H), 1.50 (m, 1H), 1.30–1.23 (m, 2H), 0.98 (d, J = 7 Hz, 3H),
1.33 (s, 3H), 1.31–1.27 (m, 1H), 0.98 (d, J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.11 (s, 3H), 0.1 (s, 3H), 0.06 (s,
0.88 (s, 9H), 0.09 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 6H).13C NMR (125 MHz, CDCl3): δ 138.9, 83.3, 81.7, 80.0,
138.9, 108.6, 83.3, 81.9, 79.9, 72.5, 71.6, 70.0, 37.0, 36.9, 72.8, 68.6, 67.6, 36.9, 36.5, 35.66, 35.64, 25.9, 25.8, 18.26,
35.6, 35.3, 27.1, 26.0, 25.8, 18.2, 15.3, –4.0, –4.7. HRMS 18.23, 15.4, –4.1, –4.9, –5.4. HRMS (ESI): [M + H]+ calcd.
(ESI): [M+Na]+ calcd. for C21H39O4INaSi 533.1554, found for C24H50IO4Si2 585.2290, found 585.2288.
533.1563.
2.25 (2R,4R)-4-(tert-Butyldimethylsilyloxy)-4-((2R,
2.27 (6R,8R)-8-((2R,4R,5R)-5-((Z)-3-Iodoallyl)-4-
4R,5R)-5-((Z)-3-iodoallyl)-4-methyltetrahydrofuran-2-
methyltetrahydrofuran-2-yl)-2,2,3,3,10,10,11,11-octa
yl)butane-1,2-diol (S1)
methyl-4,9-dioxa-3,10-disiladodecan-6-yl 2-(diethoxy
phosphoryl) acetate (37)
To a stirred solution of 38 (0.70 g, 1.37 mmol) in dry
CH3CN (8 mL) was added CuCl2·H2O (0.70 g, 4.12 mmol)
at −5 ◦C portion wise. Then the reaction mixture was stirred
for 2 h before being quenched with H2O (3 mL) and extracted
with EtOAc (3×30 mL). The combined organic extracts
were washed with brine (5 mL), dried over Na2SO4 and
concentrated under vacuo. Purification of the residue by col-
umn chromatography (SiO2, 35% EtOAc/hexane) afforded
S1 (0.72 g, 88%) as a clear oil. R f = 0.2 (SiO2, 40%
To a stirred solution of 41 (0.45 g, 0.77 mmol) in dry CH2Cl2
(5 mL) was added diethyl phosphono acetic acid (0.4 mL,
2.31 mmol) followed by DMAP (0.019 g, 0.154 mmol) at
0 ◦C under nitrogen atmosphere. Then the reaction mixture
was stirred for 10 min at 0 ◦C and EDCI (0.45 g, 2.31 mmol)
was added to it. After being stirred for 4 h at room tempera-
ture, the reaction mixture was quenched by the addition of
water and extracted with EtOAc (2 × 50 mL). The com-
bined organic extracts were washed with brine (5 mL),
dried over Na2SO4 and concentrated under vacuo. Purifica-
tion of the residue by column chromatography (SiO2, 30%
EtOAc/hexane) afforded 37 (0.55 g, 93%) as a yellow oil.
25
EtOAc/hexane); [α]D = +13.2 (c 0.5, CHCl3); IR (Neat):
νmax
3733, 3370, 2928, 2856, 2313, 1515, 1463, 1251, 1089,
835, 777 cm−1;1 H NMR (500 MHz, CDCl3): δ 6.32 (dd,
J = 13.4, 6.1 Hz, 1H), 6.27 (dt, J = 7.5, 1.4 Hz, 1H), 3.99–
3.94 (m, 2H), 3.93–3.88 (m, 2H), 3.60 (dd, J = 11.1, 3.5 Hz,
1H), 3.44 (dd, J = 11.1, 6.4 Hz, 1H), 2.37 (q, J = 7.3 Hz,
1H), 2.27–2.23 (m, 2H), 2.06–2.00 (m, 1H), 1.80–1.72 (m,
1H), 1.52 (dq, J = 14.6, 2.2 Hz, 1H), 1.29–1.23 (m, 1H), 0.99
(d, J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.11 (s, 6H). 13C NMR
(125 MHz, CDCl3): δ 138.7, 83.6, 81.1, 80.1, 73.6, 69.1, 67.2,
36.9, 36.1, 35.9, 35.6, 25.9, 18.1, 15.4, –4.3, –4.9. HRMS
(ESI): [M + H]+ calcd. for C18H36O4ISi 471.1422, found
471.1416.
25
R f = 0.2 (SiO2, 40% EtOAc/hexane); [α] = +24.8
2927, 2856,D1737, 1465,
νmax
(c 0.45, CHCl3); IR (Neat):
1391, 1259, 1102, 1053, 1027, 970, 838, 778, 669 cm−1
;
1H NMR (500 MHz, CDCl3): δ 6.31 (dd, J = 13.6, 6.5 Hz,
1H), 6.25 (dt, J = 7.3, 1.2 Hz, 1H), 5.07–5.01 (m, 1H),
4.20–4.14 (m, 4H), 3.94–3.88 (m, 1H), 3.80–3.71 (m, 2H),
3.65 (qd, J = 10.7, 4.7 Hz, 2H), 2.97 (s, 1H), 2.63 (d,
J = 21.5 Hz, 2H), 2.25–2.21 (m, 2H), 2.05–1.97 (m, 1H),
1.79 (ddd, J = 14.3, 9.4, 2.6 Hz, 1H), 1.68 (ddd, J = 14.2,
9.2, 2.8 Hz, 1H), 1.34 (td, J = 7.0, 2.6 Hz, 6H), 1.30–1.27
(m, 1H), 0.98 (d, J = 7.0 Hz, 3H), 0.87 (s, 9H), 0.86 (s, 9H),
0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H). 13C NMR
(125 MHz, CDCl3): δ 165.3, 138.9, 83.3, 81.6, 80.0, 73.3,
70.9, 64.3, 62.63, 62.60, 37.0, 35.4, 35.2, 34.9, 34.3, 33.8,
2.26 (6R,8R)-8-((2R,4R,5R)-5-((Z)-3-Iodoallyl)-4-
methyltetrahydrofuran-2-yl)-2,2,3,3,10,10,11,11-
octamethyl-4,9-dioxa-3,10-disiladodecan-6-ol (41)
To a stirred solution of S1 (0.45 g, 0.95 mmol) in dry 25.9, 25.8, 18.2, 18.17, 16.4, 15.4, –4.0, –4.9, –5.4. HRMS
CH2Cl2 (5 mL) was added imidazole (0.1 g, 1.43 mmol) fol- (ESI): [M + Na]+ calcd. for C30H60INaO8PSi2 785.2501,
lowed by TBSCl (0.21 g, 1.43 mmol) at 0 ◦C under nitrogen found 785.2492.

J. Chem. Sci.
(2019) 131:25
Page 11 of 24
25
2.28 (E)-((6R,8R)-8-((2R,4R,5R)-5-((Z)-3-Iodoallyl)
-4-methyltetrahydrofuran-2-yl)-2,2,3,3,10,10,11,11-
octamethyl-4,9-dioxa-3,10-disiladodecan-6-yl) 4-((2S,
4R,6R)-4-(4-methoxybenzyloxy)-6-((R)-2-methylbut-3-
enyl)tetrahydro-2H-pyran-2-yl)but-2-enoate (36)
afforded 42 (0.075 g, 60%) as a colourless oil. R f = 0.35
25
(SiO2, 10% EtOAc/hexane); [α]D = −4.5 (c 0.5, CHCl3);
IR (Neat): νmax 2929, 2857, 1729, 1465, 1370, 1254, 1174,
1090, 838, 776, 621 cm−1;1 H NMR (500 MHz, CDCl3): δ
7.0 (ddd, J = 15.5, 9.0, 4.7 Hz 1H), 6.32 (dd, J = 15.1,
10.6Hz, 1H), 6.03(t, J = 10.8Hz, 1H), 5.93(d, J = 15.7Hz,
1H), 5.54 (dd, J = 15.1, 7.4 Hz, 1H), 5.37–5.29 (m, 1H),
5.02–4.97 (m, 1H), 3.94–3.88 (m, 1H), 3.81–3.66 (m, 5H),
3.45–3.88 (m, 1H), 3.36–3.29 (m, 1H), 2.56–2.48 (m, 1H),
2.44–2.36 (m, 2H), 2.35–2.28 (m, 2H), 2.05–1.93 (m, 2H),
1.89–1.81 (m, 1H), 1.78–1.68 (m, 2H), 1.65–1.59 (m, 2H),
1.42–1.28 (m, 3H), 1.22–1.13 (m, 1H), 1.01 (d, J = 6.7 Hz,
3H), 0.99 (d, J = 7.1 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.85
(s, 9H), 0.06 (s, 6H), 0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H),
–0.09 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 166.2, 144.9,
140.9, 130.4, 127.3, 124.1, 123.3, 82.1, 81.2, 73.2, 72.5, 71.3,
68.8, 64.5, 43.2, 42.1, 40.8, 37.9, 35.9, 35.3, 34.2, 32.5, 30.7,
26.1, 25.8, 19.7, 18.22, 18.2, 18.1, 14.9, –3.9, –4.5, –5.27, –
5.3, –5.4. HRMS (ESI): [M+Na]+ calcd. for C44H82O7NaSi3
829.5260, found 829.5264.
To a mixture of compound 37 (0.28 g, 0.36 mmol) and LiCl
(0.03 g, 0.609 mmol) in MeCN (3 mL) was added DBU
(0.05 mL, 0.304 mmol) at 0 ◦C under argon atmosphere.
After being stirred for 15 min at room temperature, the mix-
ture was again cooled to 0 ◦C and a solution of aldehyde 28
(0.100 g, 0.304 mmol) in MeCN (3 mL) was added dropwise
via cannula. Then the reaction mixture was stirred for 12 h
at room temperature before being quenched by the addition
of water and extracted with EtOAc (2×20 mL). The com-
bined organic extracts were washed with brine (5 mL), dried
over Na2SO4, and concentrated under vacuo. Purification of
the residue by column chromatography (SiO2, 60–120 mesh,
3% EtOAc/hexane) afforded 36 (0.22 g, 78% over two steps)
as a colorless oil. R f = 0.5 (SiO2, 10% EtOAc/hexane);
25
ν
[α]D = +17.5 (c 0.4, CHCl3); IR (Neat):
2927, 2856,
max
1722, 1464, 1370, 1254, 1174, 1076, 998, 837, 776, 671cm−1
;
1H NMR (500 MHz, CDCl3): δ 6.96 (dt, J = 15.4, 7.2 Hz,
2.30 (1R,3R,4E,6Z,9R,10R,12R,13R,15R,18E,21S,
1H), 6.32 (dd, J = 13.5, 7.0 Hz, 1H), 6.26 (dt, J = 7.3, 23R)-13,23-Dihydroxy-15-(hydroxymethyl)-3,10-dim
1.4 Hz, 1H), 5.87 (dt, J = 15.7, 1.0 Hz, 1H), 5.71 (ddd,
ethyl-16,25,26-trioxatricyclo[19.3.1.19,12]hexacosa-
J = 17.5, 10.3, 7.6 Hz, 1H), 5.04–4.99 (m, 1H), 4.97–4.88
4,6,18-trien-17-one (43)
(m, 2H), 3.95–3.90 (m, 1H), 3.79–3.67 (m, 5H), 3.39–3.33
(m, 1H), 3.32–3.26 (m, 1H), 2.47–2.40 (m, 1H), 2.37–2.29
(m, 3H), 2.26–2.22 (m, 2H), 2.04–1.98 (m, 1H), 1.88–1.74
(m, 2H), 1.70–1.60 (m, 3H), 1.34–1.20 (m, 4H), 0.99 (d,
J = 6.5 Hz, 3H), 0.98 (d, J = 7.0 Hz, 3H), 0.88 (s, 9H), 0.87
(s, 9H), 0.86 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H),
0.03 (s, 3H), 0.02 (s, 3H), 0.01 (s, 3H). 13C NMR (125 MHz,
CDCl3);δ 166.0, 145.3, 144.4, 138.9, 123.3, 112.4, 83.3, 81.7,
80.0, 74.1, 73.5, 71.7, 71.1, 68.7, 64.5, 42.4, 41.4, 41.3, 38.8,
37.0, 35.5, 35.2, 34.3, 34.0, 26.0, 25.8, 19.9, 18.2, 18.1, 18.0,
15.3, –4.0, –4.50, –4.53, –4.9, –5.3. HRMS (ESI): [M+Na]+
calcd. for C44H83O7INaSi3 957.4389, found 957.4383.
To a stirred solution of 42 (0.045 g, 0.055 mmol) in dry
MeCN (8 mL) in a polypropylene vial, was added HF-Py
complex (70%, 0.6 mL) at 0 ◦C. The reaction mixture was
warmed to room temperature and stirred for another 36 h.
Then the reaction mixture was cautiously poured into satu-
rated aqueous NaHCO3 (8 mL) and stirred for 30 min. Then
both the layers were separated, aqueous layer was further
extractedwithEtOAc(3×30mL). Thecombinedorganiclay-
ers were washed with saturated aqueous CuSO4 (8 mL), water
(8 mL), brine (8 mL) and dried over Na2SO4. The solvent
was evaporated under vacuo. Purification of the residue by
column chromatography (SiO2, 6% MeOH/CHCl3) afforded
43 (22 mg, 90% yield) as a colour less semi solid. R f = 0.3
25
2.29 (1R,3R,4E,6Z,9R,10R,12R,13R,15R,18E,21S,
23R)-13,23-bis((tert-Butyldimethylsilyl)oxy)-15-(((tert
-butyldimethylsilyl)oxy)methyl)-3,10-dimethyl-16,25,
26-trioxatricyclo[19.3.1.19,12]hexacosa-4,6,18-trien-
17-one (42)
(SiO2, 10% MeOH/CHCl3); [α]D = −6.0 (c 0.6, EtOAc); IR
(Neat): νmax 3441, 3368, 3267, 2923, 2854, 1741, 1711, 1459,
1176, 1048, 953 cm−1; 1H NMR (500 MHz, CDCl3): δ 7.06
(ddd, J = 15.1, 8.5, 5.5 Hz, 1H), 6.25 (dd, J = 15.2, 10.8 Hz,
1H), 6.02 (t, J = 10.8 Hz, 1H), 5.94 (d, J = 15.5 Hz, 1H),
5.63 (dd, J = 15.2, 7.5 Hz, 1H), 5.31–5.23 (m, 2H), 4.07–
To a stirred solution of vinyl iodide 36 (0.15 g, 0.134 mmol) 4.01 (m, 1H), 3.83–3.77 (m, 2H), 3.75–3.70 (m, 1H), 3.67
which was previously azeotroped with benzene, in dry DMF (dd, J = 11.9, 5.3 Hz, 1H), 3.49–3.42 (m, 2H), 3.37–3.31
(30 mL) was added Cs2CO3 (0.09 g, 0.273 mmol), Et3N (m, 1H), 2.52–2.41 (m, 3H), 2.40–2.28 (m, 2H), 2.18–2.11
(0.045mL, 0.192mmol)andPd(OAc)2 (0.051g, 0.241mmol) (m, 1H), 2.09–2.03 (m, 1H), 1.94–1.85 (m, 1H), 1.82–1.52
sequentially at rt under argon atmosphere. Then the reaction (m, 5H), 1.36–1.28 (m, 2H), 1.17–1.09 (m, 1H), 1.02 (d,
mixture was stirred for 2 days at room temperature before
J = 6.7 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H). 13C NMR
being quenched by the addition of water and extracted with (125 MHz, CDCl3): δ 167.1, 146.4, 140.6, 130.2, 126.3,
EtOAc (2×45 mL). The combined organic extracts were 123.6, 122.7, 82.4, 81.1, 73.3, 72.7, 72.2, 72.1, 68.2, 65.5,
washed with brine (8 mL), dried over Na2SO4, and con- 42.6, 41.3, 40.4, 38.1, 36.8, 35.7, 33.9, 32.5, 30.9, 19.8, 14.5.
centrated under vacuo. Purification of the residue by column HRMS (ESI): [M + NH4]+ calcd. for C26H44O7N 482.3112,
chromatography (SiO2, 60–120 mesh, 3.5% EtOAc/hexane) found 487.3127.

25 Page 12 of 24
J. Chem. Sci.
(2019) 131:25
2.31 tert-Butyl((S)-1-((2S,4S,5S)-5-(2-(tert-butyldim
ethylsilyloxy)ethyl)-4-methyltetrahydrofuran-2-yl)-2-
((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)diphenylsi
lane (48)
3.25 (t, J = 7.7 Hz, 1H), 2.21 (p, J = 7.2 Hz, 1H), 1.90 (ddd,
J = 12.4, 7.8, 7.5 Hz, 1H), 1.78 (ddd, J = 13.7, 8.5, 3.9 Hz,
1H), 1.60 (ddd, J = 13.8, 8.0, 4.2 Hz, 1H), 1.55–1.49 (m,
1H), 1.48–1.42 (m, 1H), 1.37–1.32 (m, 1H), 1.31 (s, 3H), 1.21
(s, 3H), 1.04 (s, 9H), 0.81 (d, J = 7.0 Hz, 3H). 13C NMR
(125 MHz, CDCl3): δ 136.0, 135.9, 134.2, 134.0, 129.5,
129.4, 127.4, 127.3, 108.5, 81.3, 80.4, 72.4, 72.3, 69.5, 61.4,
37.2, 35.5, 35.0, 32.9, 27.0, 27.0, 25.6, 19.6, 15.2. HRMS
(ESI): [M + Na]+ calcd. for C30H44O5NaSi = 535.2854,
found 535.2855.
To a stirred solution of ent-9 (1.5 g, 3.86 mmol) in CH2Cl2
(20 mL), imidazole (0.39 g, 5.79 mmol) and TBDPSCl
(1.50 mL, 5.79 mmol) were added sequentially at 0 ◦C under
nitrogen atmosphere. Then the reaction mixture was stirred
for 24 h at room temperature before being quenched with
saturated aqueous NH4Cl (10 mL) solution and extracted
with EtOAc. The combined organic extracts were washed
with water (20 mL), brine (20 mL), dried over Na2SO4 and
concentrated under vacuo. The residue was purified by col-
umn chromatography (SiO2, 8% EtOAc/hexane) to afford 48
(2.27 g, 94% yield over two steps) as a clear oil. R f = 0.7
2.33 tert-Butyl((S)-2-((S)-2,2-dimethyl-1,3-dioxolan-
4-yl)-1-((2S,4S,5S)-5-((Z)-3-iodoallyl)-4-methyltetra
hydrofuran-2-yl)ethoxy)diphenylsilane (49)
25
(SiO2, 20% EtOAc/hexane); [α]D = −11.2 (c 1.1, CHCl3);
To a stirred solution of 47 (1.3 g, 2.53 mmol) in dry CH2Cl2
(15 mL) were added NaHCO3 (0.20 g, 2.53 mmol) and Dess-
Martin periodinane (1.60 g, 3.79 mmol) sequentially at 0 ◦C
under nitrogen atmosphere. Then the reaction mixture was
stirredfor2hatroomtemperaturebeforebeingquenchedwith
saturated aqueous NaHCO3 (8 mL) and saturated aqueous
Na2S2O3 (8 mL) and extracted with EtOAc (2×50 mL). The
combined organic extracts were washed with water (5 mL),
brine (5 mL) and dried over Na2SO4. Evaporation of the sol-
vent furnished crude aldehyde, which was passed through a
short pad of silica gel and used as such for the next reaction.
To a suspension of iodomethyl triphenylphosphonium
iodide (4.01 g, 7.59 mmol) in anhydrous THF (25 mL)
was added NaHMDS (7.59 mL, 1.0 M in THF, 7.59 mmol)
at 0 ◦C under argon atmosphere. Then the reaction mix-
ture was stirred for another 15 min at 0 ◦C before being
cooled to −78 ◦C and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)
-pyrimidinone (DMPU) (1.52 mL, 12.65 mmol) was added
followed by the addition of above aldehyde in dry THF
(10 mL) via cannula. After 2 h stirring at −78 ◦C, the reac-
tion mixture was quenched by addition of saturated aqueous
NH4Cl (5 mL) and stirred for 1 h at rt and extracted with
ν
IR (Neat):
2958, 2860, 1463, 1371, 1254, 1097, 1065,
max
1
831, 741, 702, 609 cm−1; H NMR (500 MHz, CDCl3): δ
7.74–7.63 (m, 4H), 7.43–7.28 (m, 6H), 4.16 (ddd, J = 12.9,
7.9, 5.2 Hz, 1H), 4.03–3.99 (m, 1H), 3.84 (dd, J = 7.6,
5.8 Hz, 1H), 3.72–3.66 (m, 2H), 3.62–3.49 (m, 2H), 3.21
(t, J = 7.8 Hz, 1H), 2.18 (p, J = 7.0 Hz, 1H), 1.93 (dt,
J = 12.3, 7.4, 1H), 1.78 (ddd, J = 13.5, 8.2, 3.9 Hz, 1H),
1.61–1.54 (m, 1H), 1.50 (dd, J = 13.6, 7.0 Hz, 1H), 1.31
(s, 3H), 1.36–1.27 (m, 1H), 1.26–1.22 (m, 1H), 1.21 (s, 3H),
1.06 (s, 9H), 0.89 (s, 9H), 0.81 (d, J = 7.0 Hz, 3H), 0.03
(s, 6H). 13C NMR (125 MHz, CDCl3): δ 136.0, 135.9, 134.4,
134.2, 129.4, 127.3, 127.3, 108.4, 80.7, 78.1, 72.64, 72.5,
69.6, 61.0, 37.0, 35.3, 35.1, 34.1, 27.1, 26.9, 26.0, 25.7, 19.6,
18.3, 15.5, –5.3, –5.3. HRMS (ESI): [M + H]+ calcd. for
C36H59O5Si2 = 627.3909, found 627.3902.
2.32 2-((2S,3S,5S)-5-((S)-1-(tert-Butyldiphenylsilyl
oxy)-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-3-
methyltetrahydrofuran-2-yl)ethanol (47)
To a stirred solution of 48 (2 g, 3.18 mmol) in dry THF EtOAc (2×60 mL). The combined organic extracts were
(15 mL) in a polypropylene vial, was added HF-Py complex washedwithwater(10mL), brine(10mL), driedoverNa2SO4
(70%, 0.6 mL) at 0 ◦C. The reaction mixture was warmed and concentrated under vacuo. Purification of the residue by
to room temperature and stirred for 16 h. Then the reac- column chromatography (SiO2, 5% EtOAc/hexane) afforded
tion mixture was cautiously poured into saturated aqueous 49 (1.23 g, 77% over two steps) as a viscous liquid. R f = 0.6
25
NaHCO3 and stirred for 30 min. Then both the layers were (SiO2, 10% EtOAc/hexane); [α]D = −39.8 (c 1.1, CHCl3);
ν
separated, aqueous layer was further extracted with EtOAc IR (Neat):
2927, 2856, 2311, 1515, 1463, 1426, 1380,
max
(2 × 50 mL). The combined organic layers were washed with 1106, 1061, 821, 740, 702, 609 cm−1 ; H NMR (500 MHz,
1
saturated aqueous CuSO4 (6 mL), water (5 mL), brine (5 mL), CDCl3): δ 7.74–7.69 (m, 4H), 7.43–7.33 (m, 6H), 6.04 (dt,
dried over Na2SO4 and concentrated under vacuo. Purifica-
J = 7.3, 1.5 Hz, 1H), 5.75 (dt, J = 7.3, 5.5 Hz, 1H), 4.28–
tion of the residue by column chromatography (SiO2, 15% 4.22 (m, 1H), 3.99–3.94 (m, 1H), 3.90 (dd, J = 7.7, 5.8 Hz,
EtOAc/hexane) afforded compound 47 (1.45 g, 89% in three 1H), 3.69 (dt, J = 8.8, 6.8 Hz, 1H), 3.63 (ddd, J = 10.9, 6.7,
steps) as clear oil. R f = 0.3 (SiO2, 25% EtOAc in petroleum 4.3 Hz, 1H), 3.31 (t, J = 7.7 Hz, 1H), 2.21–2.14 (m, 1H),
25
ν
ether). [α]D = −19.2 (c 3.2, CHCl3); IR (neat):
3457, 2.08–2.02 (m, 1H), 1.99–1.91(m, 2H), 1.74 (ddd, J = 13.8,
max
2955, 2926, 2855, 2749, 1456, 1378, 1243, 1191, 1084, 8.5, 3.6 Hz, 1H), 1.59 (ddd, J = 12.8, 8.4, 4.1 Hz, 1H), 1.32
1021, 968, 823, 741, 703, 610 cm−1 ; H NMR (500 MHz, (s, 3H), 1.23 (s, 3H), 1.25–1.21 (m, 1H), 1.03 (s, 9H), 0.89
1
CDCl3): δ 7.75–7.70 (m, 4H), 7.44–7.34 (m, 6H), 4.18–4.12 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 139.1,
(m, 1H), 4.01 (ddd, J = 8.1, 5.3, 4.1 Hz, 1H), 3.83 (dd, 136.1, 136.0, 134.5, 134.0, 129.3, 129.2, 127.3, 127.2, 108.1,
J = 7.6, 5.8 Hz, 1H), 3.79–3.74 (m, 2H), 3.58–3.49 (m, 2H), 82.6, 81.2, 79.7, 73.0, 72.5, 69.7, 37.3, 36.5, 35.5, 35.4, 27.1,

J. Chem. Sci.
(2019) 131:25
Page 13 of 24
25
27.0, 25.7, 19.7, 15.3. HRMS (ESI): [M + Na]+ calcd. for
C31H43IO4NaSi = 657.1882, found 657.1875.
J = 14.9, 8.7, 6.7 Hz, 1H), 1.05 (s, 9H), 1.04 (s, 9H), 0.74
(d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 139.0,
136.1, 136.0, 135.5, 134.8, 133.8, 133.4, 129.7, 129.6, 129.4,
129.2, 127.7, 127.4, 127.2, 82.6, 81.0, 79.9, 73.6, 68.8, 68.3,
36.7, 36.4, 35.8, 35.3, 27.1, 26.8, 19.6, 19.2, 15.4. HRMS
(ESI): [M+H]+ calcd. for C44H58IO4Si2 = 833.2920, found
833.2917.
2.34 (2S,4S)-4-(tert-Butyldiphenylsilyloxy)-4-((2S,
4S,5S)-5-((Z)-3-iodoallyl)-4-methyltetrahydrofuran-
2-yl)butane-1,2-diol (50)
To a stirred solution of 49 (1.0 g, 1.57 mmol) in dry CH3CN
(10 mL) was added CuCl2·H2O (0.80 g, 4.71 mmol) at
−5 ◦C portion wise. Then the reaction mixture was stirred for
2 h before being quenched with H2O (5 mL) and extracted
2.36 (6S,8S)-8-((2S,4S,5S)-5-((Z)-3-Iodoallyl)-4-met
hyltetrahydrofuran-2-yl)-2,2,11,11-tetramethyl-3,3,10,
10-tetraphenyl-4,9-dioxa-3,10-disiladodecan-6-yl
with EtOAc (3×30 mL). The combined organic extracts 2-(diethoxyphosphoryl)acetate (46)
were washed with brine (5 mL), dried over Na2SO4 and
To a stirred solution of 51 (0.7 g, 0.83 mmol) in dry CH2Cl2
concentrated under vacuo. The residue was purified by col-
umn chromatography (SiO2, 29% EtOAc/hexane) to afford
50 (0.89 g, 95% yield over two steps) as a viscous liq-
(10 mL) was added diethyl phosphono acetic acid (0.4 mL,
2.50 mmol) followed by DMAP (0.020 g, 0.166 mmol) at
0 ◦C under nitrogen atmosphere. Then the reaction mixture
was stirred for 10 min at 0 ◦C, and EDCI (0.479 g, 2.50 mmol)
was added to it. After being stirred for 4 h at rt, the reaction
mixture was quenched by the addition of water and extracted
with EtOAc (2 × 50 mL). The combined organic extracts
were washed with brine (10 mL), dried over Na2SO4 and
concentrated under vacuo. Purification of the residue by col-
umn chromatography (SiO2, 35% EtOAc/hexane) afforded
46 (0.79 g, 95%) as yellow oil. R f = 0.3 (SiO2, 45%
25
uid. R f =0.2 (SiO2, 30% EtOAc/hexane); [α]D = −44.6
νmax
(c 1.3, CHCl3); IR (Neat):
3396, 2928, 2856, 1515,
1464, 1426, 1388, 1106, 821, 740, 701, 608 cm−1 ; H NMR
(400 MHz, CDCl3): δ 7.73–7.67 (m, 4H), 7.45–7.35 (m, 6H),
6.09 (dt, J = 7.2, 1.5 Hz, 1H), 5.89–5.83 (m, 1H), 3.99–
3.92 (m, 2H), 3.79–3.70 (m, 2H), 3.43 (dd, J = 11.0,
3.2 Hz, 1H), 3.28 (dd, J = 11.0, 6.4 Hz, 1H), 2.30 (brs,
2H), 2.27 (p, J = 7.1 Hz, 1H), 2.13–2.09 (m, 1H), 2.08–
2.04 (m, 2H), 1.71 (ddd, J = 14.5, 10.4, 4.1 Hz, 1H), 1.44
(ddd, J = 14.2, 5.5, 1.8 Hz, 1H), 1.28–1.21 (m, 1H), 0.99
(s, 9H), 0.82 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz,
CDCl3): δ 138. 7, 136.1, 135.0, 133.8, 133.5, 129.7, 129.5,
127.6, 127.3, 83.1, 80.6, 80.1, 73.7, 69.0, 67.0, 36.4, 36.2,
35.7, 35.2, 27.0, 19.5, 15.5. HRMS (ESI): [M + H]+ calcd.
for C28H40IO4Si = 595.1744, found 595.1742.
1
25
EtOAc/hexane); [α]D = −40.3 (c 0.6, CHCl3); IR (Neat):
νmax
2928, 2857, 1737, 1693, 1515, 1466, 1428, 1391,
1
1266, 1108, 1027, 971, 820, 740, 702, 611 cm−1; H NMR
(500 MHz, CDCl3): δ 7.70–7.67 (m, 2H), 7.65–7.61 (m, 6H),
7.46–7.28 (m, 12H), 5.98 (dt, J = 7.5, 7.3 Hz, 1H), 5.60
(dt, J = 7.4, 5.3 Hz, 1H), 5.27–5.21 (m, 1H), 4.10–3.01 (m,
4H), 3.75 (ddd, J = 11.0, 7.2, 4.1 Hz, 1H), 3.68–3.62 (m,
2H), 3.59–3.62 (m, 2H), 2.71–2.69 (dd, J = 21.3, 4.0 Hz,
2H), 2.15 (p, J = 7.1 Hz, 1H), 2.06–2.00 (m, 1H), 1.97–
1.90 (m, 2H), 1.82–1.77 (m, 1H), 1.68–1.62 (m, 2H), 1.23
(dt, J = 7.1, 2.1 Hz, 6H), 1.04 (s, 9H), 1.01 (s, 9H), 0.75 (d,
J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 165.00,
139.1, 136.2, 135.8, 135.6, 135.5, 134.8, 133.6, 133.3, 129.7,
129.3, 129.0, 127.7, 127.4, 127.0, 82.5, 80.9, 79.7, 72.7, 72.8,
72.5, 64.9, 62.6, 62.5, 60.4, 35.9, 35.2, 35.1, 27.2, 26.8,
19.6, 19.2, 16.3, 15.5. HRMS (ESI): [M + Na]+ calcd. for
C50H68INaO8PSi2 = 1033.3146, found 1033.3135.
2.35 (6S,8S)-8-((2S,4S,5S)-5-((Z)-3-Iodoallyl)-4-met
hyltetrahydrofuran-2-yl)-2,2,11,11-tetramethyl-3,3,10,
10-tetraphenyl-4,9-dioxa-3,10-disiladodecan-6-ol (51)
To a stirred solution of 50 (0.7 g, 1.17 mmol) in CH2Cl2
(10 mL), imidazole (0.12 g, 1.76 mmol) and TBDPSCl
(0.45 mL, 1.76 mmol) were added sequentially at 0 ◦C.
The reaction mixture was stirred for 4 h at room tempera-
ture before being quenched with saturated aqueous NH4Cl
(5 mL) solution and extracted with EtOAc (2 × 50 mL).
The combined organic extracts were washed with water
(10 mL), brine (10 mL), dried over Na2SO4 and concentrated
in vacuo. Purification of the residue by column chromatog-
raphy (SiO2, 9% EtOAc/hexane) afforded 51 (0.93 g, 95%)
as clear oil. R f = 0.45 (SiO2, 15% EtOAc in petroleum
2.37 (E)-((6S,8S)-8-((2S,4S,5S)-5-((Z)-3-Iodoallyl)-
4-methyltetrahydrofuran-2-yl)-2,2,11,11-tetramethyl-
3,3,10,10-tetraphenyl-4,9-dioxa-3,10-disiladodecan
-6-yl) 4-((2S,4R,6R)-4-(tert-butyldimethylsilyloxy)-6-
25
ν
ether). [α]D = −35.9 (c 1, CHCl3); IR (neat):
3395, ((R)-2-methylbut-3-enyl)tetrahydro-2H-pyran-2-yl)but
max
2925, 2855, 2311, 1514, 1465, 1427, 1108, 1107, 819, 740,
-2-enoate (45)
701, 609 cm−1; H NMR (500 MHz, CDCl3) : δ 7.75–7.69
1
(m, 4H), 7.65–7.62 (m, 4H), 7.45–7.32 (m, 12H), 6.01 (dt, To a mixture of compound 46 (0.369 g, 0.365 mmol) and
J = 7.3, 1.5 Hz, 1H), 5.72 (dt, J = 7.3, 5.5 Hz, 1H), LiCl (0.024 g, 0.608 mmol) in MeCN (6 mL) was added
4.04–3.98 (m, 1H), 3.92–3.86 (m, 1H), 3.80 (dd, J = 15.5, DBU(0.045mL, 0304mmol)at0 ◦Cunderargonatmosphere.
7.2 Hz, 1H), 3.65 (ddd, J = 9.9, 6.4, 4.2 Hz, 1H), 3.47 (d, After being stirred for 15 min at room temperature, the mix-
J = 5.3 Hz, 2H), 2.19 (p, J = 7.0 Hz, 1H), 2.09–2.02 ture was again cooled to 0 ◦C and a solution of aldehyde 28
(m, 1H), 2.00–1.92 (m, 2H), 1.61–1.56 (m, 2H), 1.17 (ddd, (0.100 g, 0.304 mmol) in MeCN (5 mL) was added dropwise

25 Page 14 of 24
J. Chem. Sci.
(2019) 131:25
via cannula. Then the reaction mixture was stirred for 12 h 2H), 3.63–3.60 (m, 2H), 3.55 (dd, J = 10.8, 4.9 Hz, 1H),
at room temperature before being quenched by the addition 3.40–3.35 (m, 1H), 3.31–3.26 (m, 1H), 2.40 (dd, J = 13.5,
of water and extracted with EtOAc (2×20 mL). The com- 7.0 Hz, 1H), 2.37–2.30 (m, 1H), 2.18–2.11 (m, 2H), 2.00 (dt,
bined organic extracts were washed with brine (5 mL), dried
J = 13.9, 7.2 Hz, 1H), 1.92 (ddd, J = 14.3, 8.3, 3.0 Hz, 1H),
over Na2SO4, and concentrated under vacuo. Purification of 1.83–1.71 (m, 4H), 1.65–1.60 (m, 1H), 1.38 (ddd, J = 13.1,
the residue by column chromatography (SiO2, 60–120 mesh, 7.6, 5.5 Hz, 1H), 1.34–1.28 (m, 2H), 1.24–1.17 (m, 2H), 1.00
6% EtOAc/hexane) afforded 45 (0.284 g, 79% two steps) (s, 18H), 0.96 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 7.1 Hz,
as a colorless oil. R f = 0.5 (SiO2, 10% EtOAc/hexane); 3H) 0.87 (s, 9H), 0.06 (s, 6H) ppm. 13C NMR (175 MHz,
25
ν
[α]D = −19.4 (c 1, CHCl3); IR (Neat):
2929, 2857, CDCl3): δ 165.7, 145.2, 140.1, 136.0, 135.9, 135.6, 135.6,
max
1723, 1658, 1518, 1466, 1428, 1379, 1257, 1172, 1074, 999, 134.7, 134.0, 133.5, 133.4, 129.9, 129.5, 129.3, 127.6, 127.3,
837, 776, 740, 610 cm−1; H NMR (500 MHz, CDCl3): δ 127.3, 126.8, 124.3, 123.3, 81.2, 80.1, 73.8, 73.2, 72.7, 71.6,
1
7.68–7.60 (m, 8H), 7.45–7.27 (m, 12H), 6.91 (dt, J = 15.7, 68.8, 65.5, 43.0, 41.9, 41.8, 38.5, 35.7, 34.4, 34.1, 33.3, 30.2,
7.3 Hz, 1H), 5.96 (dt, J = 7.3, 1.3 Hz, 1H), 5.76 (dt, 27.2, 26.7, 25.8, 20.2, 19.5, 19.2, 18.1, 15.2, −4.5. HRMS
J = 15.6, 1.3 Hz, 1H), 5.69 (dd, J = 17.5, 10.2 Hz, 1H), (ESI): [M + NH4]+ calcd. for C64H94O7NSi3 1072.6332,
5.55 (dt, J = 7.3, 5.2 Hz, 1H), 5.29–5.23 (m, 1H), 4.93 (dt, found 1072.6339.
J = 17.2, 1.3 Hz, 1H), 4.92–4.88 (m, 1H), 3.77–3.64 (m,
5H), 3.54 (ddd, J = 9.7, 6.4, 4.1 Hz, 1H), 3.40–3.34 (m,
1H), 3.33–3.27 (m, 1H), 2.47–2.40 (m, 1H), 2.36–2.29 (m,
3. Results and Discussion
2H), 2.11 (p, J = 6.8 Hz, 1H), 2.04–1.75 (m, 6H), 1.68–1.56
(m, 2H), 1.36–1.14 (m, 4H), 1.04 (s, 9H), 1.00 (s, 9H), 0.98
As mentioned above, we started working on the total
(d, J = 6.7 Hz, 3H), 0.88 (s, 9H), 0.68 (d, J = 7.0 Hz, 3H),
synthesis of mandelalide A after its immediate isolation.
Therefore initially we targeted the proposed structure of
mandelalide A. Thus retrosynthetically, we envisioned
that late-stage glycosylation of the macrocycle 3 with
L-Rhamnose derived acetamide using regular protocols
0.06 (s, 3H), 0.05 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
165.7, 145.1, 144.4, 139.2, 136.2, 135.9, 135.6, 135.5, 135.0,
133.5, 133.4, 129.6, 129.2, 128.9, 127.6, 127.6, 127.4, 127.0,
123.9, 112.4, 82.4, 80.0, 79.7, 74.1, 73.6, 72.8, 71.4, 68.7,
65.3, 42.4, 41.4, 38.8, 36.3, 36.0, 35.2, 35.1, 34.0, 27.2, 26.8,
25.8, 20.1, 19.8, 19.2, 18.1, 15.5, –4.5, –4.5. HRMS (ESI): would construct the proposed structure of the natural
[M+NH4]+ calcd. for C64H95O7NISi3 = 1200.5461, found
product in its protected form (Scheme 1). Disconnec-
tion of macrocycle 3 led to the two key building blocks
1200.5455.
6 and 7 with similar complexity, required for its con-
struction using Julia-Kocienski olefination6 followed by
Yamaguchi/Shina macrolactonization. We realized that
2.38 (1R,3R,4E,6Z,9S,10S,12S,13S,15S,18E,21S,
23R)-23-((tert-Butyldimethylsilyl)oxy)-13-((tert-buty
ldiphenylsilyl)oxy)-15-(((tert-butyldiphenylsilyl)oxy)
methyl)-3,10-dimethyl-16,25,26-trioxatricyclo
the compound 6 could be obtained from 9 using Still-
Gennari olefination7 which in turn could be obtained
from10bymeansofSharplessasymmetricdihydroxyla-
[19.3.1.19,12]hexacosa-4,6,18-trien-17-one (44)
tion8 with concomitant Williamson type etherification.9
Compound 10 could be synthesized via coupling of 11
and 12 by means of Julia-Kocienski olefination. Com-
pound 7 was expected to be synthesized from ester 13
using Prins cyclization.
To a stirred solution of vinyl iodide 45 (0.1 g, 0.084 mmol)
which was previously azeotroped with benzene, in dry DMF
(20 mL) were added Cs2CO3 (0.046 g, 0.142 mmol), Et3N
(0.014 mL, 0.10 mmol) and Pd(OAc)2 (0.028 g, 0.126 mmol)
sequentially at rt under argon atmosphere. Then the reaction
mixture was stirred for 24 h at room temperature before being
As a manifestation of our synthetic strategy, the con-
struction of building block 6 commenced (Scheme 2)
quenched by the addition of water and extracted with EtOAc from the known compound 11, which was prepared from
(2×30 mL). The combined organic extracts were washed with
compound 15 in two steps according to the reported
procedure.10 Hydroboration of 11 with BH3·SMe2 fol-
brine (5 mL), dried over Na2SO4, and concentrated under
vacuo. Purification of the residue by column chromatog-
raphy (SiO2, 60–120 mesh, 5% EtOAc/hexane) afforded
lowed by oxidation with H2O2furnished primary alcohol
16 in 83% yield. The primary alcohol 16 was subjected
44 (0.059 g, 67%) as colourless oil. R f = 0.35 (SiO2,
to DMP oxidation to provide an aldehyde, which on
25
10% EtOAc/hexane); [α]D = +14.8 (c 0.15, CH2Cl2); IR
Julia-Kocienski olefination6 with known sulfone 1211
afforded E-olefinic compound 17 in 81% yield over two
steps.
(Neat): νmax 2927, 2856, 1722, 1653, 1464, 1428, 1380, 1258,
1
1173, 1108, 1075, 833, 776, 739, 703, 611 cm−1; H NMR
(700MHz, CDCl3): δ 7.66–7.60(m, 8H), 7.43–7.26(m, 12H),
6.89 (ddd, J = 15.6, 7.7, 6.0 Hz, 1H), 6.22 (dd, J = 15.1,
11.0 Hz, 1H), 5.94 (t, J = 10.8 Hz, 1H), 5.84 (dt, J = 15.8,
1.2 Hz, 1H), 5.53 (dd, J = 15.2, 8.1 Hz, 1H), 5.23–5.17 (m,
The oxidative deprotection of PMB ether with DDQ
gave secondary alcohol 10 in 94% yield.12 Mesylation
of the free hydroxyl group in 10 followed by Sharp-
2H), 4.02 (ddd, J = 8.7, 5.6, 3.0 Hz, 1H), 3.79–3.69 (m, less asymmetric dihydroxylation using AD-mix-β

J. Chem. Sci.
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Page 15 of 24
25
Scheme 1. Retrosynthetic analysis of the proposed structure of mandelalide A.
furnished diol, which underwent intramolecular ester 20 (E:Z = 96:4) in 80% yield (over two steps).
cycloetherification and furnished the tetrahydrofuran DIBAL-H mediated reduction of the α, β-unsaturated
ring 9 in 81% yield over two steps. Benzyl protection of ester completed the synthesis of Z-allylic alcohol frag-
the secondary hydroxyl of 9 with BnBr and NaH in the ment 8 in 90% yield.
presence of catalytic amount of TBAI in THF gave com-
After synthesizing the alcohol fragment 8, we turned
pound 18 that was treated with TBAF in THF to furnish our attention to the synthesis of pyran fragment 7 from
primary alcohol 19 in 85% yield over two steps. Oxida- theknowncompound1413 (Scheme3). Ozonolysisof14
tion of the primary alcohol 19 was carried out with DMP furnished an aldehyde, which was subjected to Brown’s
to give an aldehyde, which was subjected to Z-selective allylation14 with (–)-Ipc2BOMe and allyl magnesium
Still-Gennari olefination7 to provide α, β-unsaturated bromide at −78 ◦C to give the alcohol 21 in 72% yield

25 Page 16 of 24
J. Chem. Sci.
(2019) 131:25
Scheme 2. Synthesis of alcohol fragment 8.
over two steps, with excellent diastereoselectivity (dr > units via Julia-Kocienski olefination to accomplish the
20:1). Prins cyclization15 between aldehyde 22a and the crucial coupled product 5 (Scheme 4). Accordingly,
homoallylic alcohol 21 was unsuccessful to produce the compound 8 was converted to sulfone under Mitsunobu
desired product 23. Therefore we planned to synthe- conditions17 followed by oxidation and then subjected
size the tetrahydropyran unit via segment coupling Prins to Julia-Kocienski olefination with aldehyde 7, under
cyclization.16 Accordingly, acylation of alcohol 21 with assorted conditions as shown in Table 1, which were
acid 22 was carried out under DCC-DMAP conditions preceded abortive to furnish precursor for macrocycliza-
to provide compound 13 in 93% yield. The controlled tion. Thus, this strategy was not pursued further for the
reduction of ester 13 with DIBAL-H gave a hemiacetal, synthesis of 3.
which on acetyl protection followed by BF3·OEt2 and
The failure of Julia-Kocienski olefination forced us
acetic acid-mediated Prins cyclization in hexane at 0 ◦C to devise an alternate strategy. We anticipated that the
and deprotection of the C4-OAc of resulting pyran ring pre-installation of the α, β-unsaturated double bond
afforded desired pyran alcohol 23 in 50% yield (over at C2-C3 position followed by late-stage ring closing
three steps). Protection of resulting hydroxyl group of metathesis protocol might provide the desired macro-
23 as its TBS ether and subsequent efficient removal of cycle 3. As depicted in Scheme 5, Masamune-Roush
the TBDPS group under basic conditions furnished pri- olefination18 between27and28wouldgive26thatcould
mary alcohol 25 in 77% yield over two steps. Finally, be cyclized via a ring-closing metathesis reaction.19 The
DMP oxidation of primary alcohol 25 furnished alde- phosphonate 27 would be obtained from 29, which in
hyde 7 in quantitative yield.
turncouldbeobtainedfrom30viaoxidationfollowedby
After synthesizing these two key building blocks, Nozaki-Hiyama reaction20 and Peterson-type syn elim-
we focused our attention to the stitching of these ination.21

J. Chem. Sci.
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Page 17 of 24
25
Scheme 3. Synthesis of pyran fragment 7.
Scheme 4. Coupling of fragments 6 and 7 using Julia-Kocienski olefination.
Table 1. Screened conditions Julia-Kocienski olefination.
Entry
Conditions
Temperature
Time
Yield
1
2
3
KHMDS, THF
n-BuLi, THF
t-BuLi, THF
−78 ◦C
−78 ◦C
−78 ◦C
2.5 h
1.5 h
1.5 h
0%
0%
0%

25 Page 18 of 24
J. Chem. Sci.
(2019) 131:25
Scheme 5. Modified strategy for the construction of macrocycle 3.
Scheme 6. Synthesis of diene fragment 29.
As per the retrosynthetic plan the synthesis to furnish the required (Z)-diene compound 31 in 85%
commenced from compound 9 (Scheme 6), which on yield. Acetonide deprotection and chemoselective pro-
PMB-protection as its PMB ether followed by TBS tection of primary alcohol as its TBS ether provided
deprotection with TBAF in THF furnished primary alco- compound 29 in 90% yield.
hol 30 in 90% yield over two steps. Oxidation of 30 with
The synthesis of the aldehyde 28 is depicted in
DMP furnished an aldehyde, which was subjected to Scheme 7. Olefination of aldehyde 7 via modified Julia
Nozaki-Hiyama reaction with allyl chromium reagent22 reaction with known sulfone 3323 gave olefin compound
generated in situ from allyl TMS bromide and chromium 34 in 80% yield over two steps. Deprotection of PMB
(II) chloride followed by Peterson–type syn elimination group afforded a primary alcohol 35 in 95% yield, which

J. Chem. Sci.
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Page 19 of 24
25
Scheme 7. Synthesis of pyran aldehyde fragment 28.
Scheme 8. Coupling of fragments for the synthesis of macrocycle 3.
Table 2. Screened conditions for ring closing metathesis reaction.
Entry
Catalyst
Conditions
Yield
1
2
3
Grubbs I (10%)
Grubbs II (10%)
Hoveyda-Grubbs catalyst (10%)
CH2Cl2, 12 h, rt
Toluene, 12 h, rt
Toluene, 12 h, rt
0%
0%
0%
on oxidation with DMP gave aldehyde 28 in quantitative in Scheme 1 and 5), we decided at this juncture to
yield. follow the sequence depicted in Scheme 9. We realized
With the two key fragments in hand, we focused our that a compound 36 would give the desired aglycone via
attention on the stereocontrolled union of these frag- intramolecular Heck cyclization5 and the compound 36
ments (Scheme 8) to reach the desired macrocycle. To wouldbeaccessedfrom37and28viaMasamune-Roush
this end, 29 was acylated with diethyl phosphonoacetic olefination. The phosphonate 37 could be obtained from
acid to give a phosphonate intermediate which under- 38, via protecting group manipulation followed by acy-
went Masamune-Roush18 smoothly with the aldehyde lation with diethyl phosphonoacetic acid. The vinyl
28 and furnished ring-closing metathesis precursor 26 in iodide compound 38 would be obtained from 39 via
80% yield. Now the stage was set for the crucial macro- oxidation followed by Stork-Zhao Wittig olefination.24
cyclization, but miserably the ring-closing metathesis
reaction under a variety of conditions, as shown in Table from compound 9 (Scheme 10), which on TBS pro-
2 had failed to provide the desired cyclised product. tection followed by selective removal of primary TBS
Thus the synthesis of phosphonate 37 commenced
Having professed the difficulties in synthesizing the furnished compound 39 in 84% yield over two steps.
macrocycle 3 with either of the two sequences (as shown DMP-oxidation of the primary alcohol 39 gave an

25 Page 20 of 24
J. Chem. Sci.
(2019) 131:25
Scheme 9. Retrosynthetic analysis for construction of macrocycle 3 using intramolecular Heck cyclization.
Scheme 10. Synthesis of phosphonate 37.
aldehyde which on Stork-Zhao-Wittig24 afforded the
Now to synthesize the aglycone of the mandelalide
Z-vinyl iodide 38 in 78% yield (Z/E = 96/4) over A (1) via intramolecular Heck cyclization, Masamune-
two steps. The deprotection of acetonide in presence Roush olefination reaction between 37 and 28 was car-
of TBS was a difficult task. Under acidic conditions, ried out to give compound 36 in 78% yield
TBS deprotection along with acetonide deprotection (Scheme 11).18 Now the stage was set to carry out the
occurred. Finally, CuCl2 · 2H2O in CH3CN at −5 ◦C intramolecular Heck cyclization5 by using Pd(OAc)2
deprotected the acetonide without affecting TBS group in the presence of Cs2CO3 to give fully protected
in 88% yield.25 Chemoselective protection of primary aglycone 42 in 59% yield which on global depro-
alcohol as its TBS ether followed by esterification with tection using HF·Py resulted in the aglycone of the
diethyl phosphonoacetic acid completed the synthesis proposed structure of mandelalide A 43 in 85%
of phosphonate fragment 37 in 93% yield.
yield5.

J. Chem. Sci.
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Page 21 of 24
25
Scheme 11. Synthesis of proposed mandelalide A aglycone.
Scheme 12. Final strategy for the construction of precise mandelalide A (2).
Now at this stage, the structure of mandelalide was had to synthesize the aglycone with orthogonal pro-
revised to 2 (Figure 1) and we had decided to synthe- tecting groups at C24-OH, C23-OH and C7-OH. Thus,
size the actual structure of mandelalide A. However to mandelalide A could be synthesized from aglycone 44
synthesize the revised structure of mandelalide A, we via the selective deprotection of TBS at C7-OH followed

25 Page 22 of 24
J. Chem. Sci.
(2019) 131:25
Scheme 13. Formal total synthesis of mandelalide A (2).
by glycosidation. Fully protected aglycone 44 could be sort of reactions as described in Scheme 2. TBDPS pro-
obtained from compound 45 via intramolecular Heck tection of the secondary alcohol of ent-9 gave compound
cyclization, which in turn could be obtained from 46 48 in 90% yield, which on treatment with HF · Py in
and 29 via Masamune-Roush olefination. Finally, com- THF at 0 ◦C furnished primary alcohol 47 in 86% yield.
pound 46 would be obtained from ent-9 via compound Oxidation of the primary alcohol 47 was carried out
47.
with DMP to give an aldehyde, which on reaction with
Thus our synthesis started with the ent-9 compound, the ylide generated from [Ph3PCH2I]+I− with KHMDS
which was synthesized from ent-11 following the same gave Z-vinyl iodide 49 in 75% yield (Z/E = 96/4) over

J. Chem. Sci.
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Page 23 of 24
25
two steps. Acetonide deprotection with CuCl2 ·2H2O at
−5 ◦C gave diol 50 in 88% yield. Selectively primary
alcohol was protected as TBDPS ether to give com-
pound 51 followed by acylation of secondary alcohol
with diethyl phosphonoacetic acid under EDCI/DMP
conditions afforded the phosphonate 46 in 90% yield.
Now the coupling reaction between aldehyde 28 and
phosphonate 46 was accomplished by Masamune-
Roush olefination18 in presence of DBU and LiCl faith-
fully delivered compound 45 in 77% yield, which on
intramolecular Heck cyclization5 afforded compound
444c in 63% yield, whose spectral and analytical data
were in good agreement with the literature report.
2012 Mandelalides A–D, cytotoxic macrolides from a
new Lissoclinum species of South African Tunicate J.
Org. Chem. 77 6066
3. Nazari M, Serrill J D, Wan X, Nguyen M H, Anklin C,
Gallegos D A, Smith III A B, Ishmael J E and Mc Phail
K L 2017 New mandelalides expand a macrolide series
of mitochondrial inhibitors J. Med. Chem. 60 7850
4. (a) Willwacher J and Fürstner A 2014 Catalysis-based
total synthesis of putative mandelalide A Angew. Chem.
Int. Ed. 53 4217; (b) Lei H, Yan J, Yu J, Liu Y, Wang Z,
Xu Z and Ye T 2014 Total synthesis and stereochem-
ical reassignment of mandelalide A Angew. Chem. Int.
Ed. 53 1; (c) Willwacher J, Heggen H, Wirtz C, Thiel
W and Fürstner A 2015 Total synthesis, stereochemi-
cal revision, and biological reassessment of mandelalide
A: Chemical mimicry of intrafamily relationships Chem.
Eur J. 21 1; (d) Brìtsch T M, Bucher P and Altmann K H
2015 Total Synthesis and biological assessment of man-
delalide A Chem. Eur. J. 22 1292; (e) Nguyen M H,
Imanishi M, Kurogi T and Smith III A B 2016 Total
synthesis of (-)-mandelalide A exploiting anion relay
chemistry (ARC): Identification of a type II ARC/CuCN
cross-coupling protocol J. Am. Chem. Soc. 138 3675; (f)
Veerasamy N, Ghosh A, Li J, Watanabe K, Serrill J D,
Ishmael J E, Mc Phail K L and Carter R G 2016 Enantios-
elective total synthesis of mandelalide A and isomande-
lalide A: Discovery of a cytotoxic ring-expanded isomer
J. Am. Chem. Soc. 138 770; (g) Anki Reddy P, Anki
Reddy S and Sabitha G 2017 Synthetic studies toward
the revised aglycone of mandelalide A Chem. Select 2
1032
4. Conclusions
In summary, a formal total synthesis of mandelalide
A (2) has been achieved in 31 total steps (17 longest
linear sequences from compound 15) with 10.2% over-
all yield by utilizing intramolecular Heck cyclization
as a key step. The other key reactions utilized in the
synthesis are Julia-Kocienski olefination, asymmetric
dihydroxylation followed by in situ cycloetherification
and Masamune-Roush olefination reactions. The strat-
egy developed here is highly flexible for the synthesis
of analogues of nanomolar cytotoxic agent mandelalide
A, that could be potentially useful in the field of non-
small cell lung cancer (NSCLC). The Julia-Kocienski
olefination and the ring closing metathesis were also
investigated for the union of the building blocks and
stereoselective formation of macrocycle 3 and found
unsuccessful as a means to construct the mandelalide A.
5. (a) Reddy K M, Yamini V, Singarapu K K and Ghosh
S 2014 Synthesis of proposed aglycone of mandelalide
A Org. Lett. 16 2658; (b) Bhatt U, Christmann M,
Quitschalle M, Claus E and Kalesse M 2011 The first
total synthesis of (+)-ratjadone J. Org. Chem. 66 1885;
(c) Jagel J and Maier M E 2009 Formal total synthesis of
palmerolide A Synthesis. 2881; (d) For reviews related to
the Heck reaction, see: Link J T 2002 The intramolecular
Heck reaction Org. React. 60 157
Supplementary Information (SI)
6. (a) Liu P and Jacobsen E N 2001 Total synthesis of
(+)-ambruticin J. Am. Chem. Soc. 123 10772; (b) Julia
M and Paris J M 1973 Synthesis A l’aide De Sul-
fones V(+)- Methode DeSynthese Generale De Doubles
Liaisons Tetrahedron. Lett. 14 4833; (c) Blakemore
P R, Cole W J, Kocienski P J and Morley A1998
A stereoselective synthesis of trans-1,2-disubstituted
alkenes based on the condensation of aldehydes with
metallated 1-phenyl-1H-tetrazol-5-yl sulfones Synlett
26; (d) KocienskiP J, Bell A and Blakemore P R
2000 1-tert-Butyl-1H-tetrazol-5-yl sulfones in the mod-
ified Julia olefination Synlett 365; (e) For a recent
review on thistopic, see: Blakemore P R 2002 The
modified Julia olefination: Alkene Synthesis via The
condensation of metallated heteroarylalkylsulfones with
carbonyl compounds J. Chem. Soc. Perkin. Trans. 1
2563
1H and 13C NMR spectra of all new compounds are available
in Supplementary Information at www.ias.ac.in/chemsci.
Acknowledgements
V.Y thanks CSIR, New Delhi for the research fellowship. S.G
is thankful to CSIR for funding through ORIGIN and CSIR-
Young Scientist Research Grant.
Note: IICT Manuscript Communication Number IICT/Pubs/
2018/319.
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