Synthesis of the C(7)-C(20) fragment of spirotoamides A, B and C

Article abstract of DOI:10.21577/0103-5053.20190126

This work describes the preparation of the C(7)-C(20) fragment of spirotoamides A to C in a very elegant fashion, achievement very high levels of stereocontrol. The synthesis has been accomplished by a sequence involving 14 steps (0.36percent overall yiel

Full text of DOI:10.21577/0103-5053.20190126

http://dx.doi.org/10.21577/0103-5053.20190126
J. Braz. Chem. Soc., Vol. 00, No. 00, 1-12, 2019
Printed in Brazil - ©2019 Sociedade Brasileira de Química
Communication
Synthesis of the C(7)-C(20) Fragment of Spirotoamides A, B and C
Allan F. C. Rossiniaa and Luiz C. Dias *,a
aInstituto de Química, Universidade Estadual de Campinas,
Rua Monteiro Lobato, 270, 13083-970 Campinas-SP, Brazil
This work describes the preparation of the C(7)-C(20) fragment of spirotoamides A to C in
a very elegant fashion, achievement very high levels of stereocontrol. The synthesis has been
accomplished by a sequence involving 14 steps (0.36% overall yield, average of 81% for each step)
in high diastereo and enantioselectivity, employing, as determining steps, asymmetric Mukaiyama
and boron-mediated 1,5-anti promoted aldol reactions between α-methyl-β-hydroxyketones and
aldehydes.
Keywords: total synthesis, natural products, aldol reactions, Mukaiyama reaction,
spirotoamides
Introduction
Results and Discussion
Recently, four new polyketides containing 6,6-spiroketal
cores with two anomeric effects, and terminal amide were
isolated. SpirotoamidesA and B in 2012 by Nogawa et al.1
and the spirotoamides C and D in 2017 by Yang et al.2
All compounds were isolated from a fraction of the
microbial metabolite of Streptomyces griseochromogenes
JC82-1223,3 presenting 9 or 10 stereogenic centers, in
which the fragment containing the spiroketal contains 7
of them.
Having only the structural knowledge from their
isolation, the high structural complexity of such compounds
inspired us to prepare the C(7)-C(20) fragment, similar to
spirotoamidesA to C, which contains the same stereogenic
centers of spiroketal (Figure 1).
Our disconnection strategy is summarized in Scheme 1.
Intermediate 4 (C(7)-C(20) fragment) can be obtained
by a Mukaiyama aldol reaction (key step) between
the aldehyde 5 and the enolsilane 6. The enolsilane 6
(C(7)-C(16) fragment), in turn, can be obtained by
a boron-mediated aldol reaction between α-methyl-
β-hydroxyketone 9 (C(12)-C(16) fragment) and the
aldehyde 10 (C(7)-C(11) fragment). Both the aldehyde 5
and the methylketone 9 can be prepared by the boron-
mediated aldol reaction in good levels of 1,4-anti induction
between α-hydroxyethylketone 8 and acetaldehyde (7)
(Scheme 1).
Our approach to the C(7)-C(20) fragment of
spirotoamides A, B and C began with the asymmetric
Figure 1. Structure of spirotoamides A, B and C and fragment C7-C20.
*e-mail: ldias@iqm.unicamp.br

2
Synthesis of the C(7)-C(20) Fragment of Spirotoamides A, B and C
J. Braz. Chem. Soc.
Scheme 1. Retrosynthetic analysis.
alkylation of the Evans auxiliary4 11 with 3-iodo-
2-methylprop-1-ene (13), leading to the formation of the
alkylation product 12 in 82% yield and diastereoselectivity
(ds) of > 95:05. Reduction of 12 in the presence of
LiAlH4 led to the formation of alcohol 14 in 95% isolated
yield.4 Alcohol 14 was subjected to oxidation following
Swern reaction conditions,5 resulting in the aldehyde 10
(C(7)-C(11) fragment) in quantitative yield (Scheme 2).
In the meantime, ethyl ketone 8 was reacted with
acetaldehyde (7) in an asymmetric 1,4-anti induced aldol
reaction leading to the formation of the aldol adduct 15 in
81% yield and ds > 95:05, according to literature procedure.6
Subsequently, the alcohol 15 was subjected to reaction with
p-methoxybenzyl (PMB) trichloroacetimidate, resulting
in the PMB ether 16 in 84% yield.6 Ketone 16 was then
treated with LiBH4 followed by oxidative cleavage reaction,
leading to formation of the aldehyde 17 in 98% yield for
two steps,7 thereafter the aldehyde 17 was reacted with
MeLi,8 leading to a mixture of diastereoisomers which were
transformed into methylketone 9 through Swern oxidation
(Scheme 3).5
In an analogous manner, aldehyde 5 can be prepared by
subjecting aldol adduct 15 to protection reaction in presence
of tert-butyldimethylsilyl trifluoromethanesulfonate
(TBSOTf),6 followed by reduction with LiBH4 and
oxidative cleavage (Scheme 4).7
Aldehyde 10, previously prepared (Scheme 2), was
employed in the aldol reaction with the boron enolate
Scheme 2. Synthesis of aldehyde 10.

Vol. 00, No. 00, 2019
Rossini and Dias
3
Scheme 3. Synthesis of α-methyl-β-hydroxyketone 9.
Scheme 4. Synthesis of α-methyl-β-hydroxyaldehyde 5.
formed from methylketone 9, leading to the formation of the
aldol adduct 19 in good yield and ds > 95:05 (Scheme 5).9
In the next step, alcohol 19 was diastereoselectively
reduced under Evans-Saksena reaction conditions, using
Me4NHB(OAc)3 as a complexing agent and camphorsulfonic
acid (CSA) in acetic acid, resulting in diol 20 in high yield and
excellent diastereoselectivity in favor of the 1,3-anti isomer.10
Subsequently, diol 20 was subjected to the protection reaction
with 2,2-dimethoxypropane (DMP) catalyzed by CSA for
12h,10 resultinginacetonide21in91%yield.Theacetonide21
made it possible to determine the relative stereochemistry
of C(11) and C(13) by 13C nuclear magnetic resonance
(NMR) analysis according to Rychnovsky’s method.11
The observed 13C NMR chemical shifts at d 24.5, 24.4 and
100.1 ppm are characteristic of a trans acetonide (Scheme 6).
For the determination of C(14) and C(15) absolute
configurations, PMB ether 20 was subjected to cyclization
reaction in the presence of 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) and molecular sieves,10 leading
to the formation of the p-methoxyphenyl (PMP) acetal 22
characteristic of hydrogens in a trans relationship and
selective nuclear Overhauser effect (NOE) experiment
showed increments of 5.61% between Ha and Hb and of
4.90% between Ha and Hc, possibly for hydrogen atoms in
1,3-diaxial positions (Scheme 7).
Subsequently, the PMP acetal 22 was subjected to
cyclization under acidic conditions, leading to the formation
of the hydrofuran 23 in 79% yield.12 Compound 23 was
analyzed by nuclear Overhauser effect spectroscopy
(NOESY; from this experiment, two chemical shifts
were selected, 1.21 and 1.31 ppm), allowing to visualize
increments of 0.48% between Ha and Mea, 0.64% between
Hb and Mea, 1.27% between Hc and Mea and 0.72% between
Hd and Meb, according to Felkin relationship between C(10)
and C(11) (Scheme 8).
Reaction of diol 20 with chloromethyl methyl ether
(MOMCl) and N,N-diisopropylethylamine (DIPEA) in
dichloromethane resulted in the formation of intermediate
24,13 which in the presence of DDQ was transformed into
alcohol 25,10 which after oxidation under Dess-Martin
conditions afforded methylketone 26 in 97% yield.14
Methylketone 26 was converted to the enolsilane 6 in
1
in 79% yield. H NMR analysis showed coupling
between hydrogens Hb-Hd (10.2 Hz) and Hc-Hd (9.8 Hz),
Scheme 5. Preparation of aldol adduct 19.

4
Synthesis of the C(7)-C(20) Fragment of Spirotoamides A, B and C
J. Braz. Chem. Soc.
Scheme 6. Synthesis of acetonide 21 and indirect determination of the stereochemistry of diol 20.
Scheme 7. Determination of the stereochemistry of the aldol adduct 19.
Scheme 8. Determination of the relative stereochemistry of hydrofuran 23.

Vol. 00, No. 00, 2019
Rossini and Dias
5
the presence of lithium diisopropylamide (LDA) and
trimethylsilyl chloride (TMSCl) in 91% isolated yield
(Scheme 9).15
With the requisite C(7)-C(16) and C(17)-C(20)
fragments in hand, their coupling (key step) was undertaken
using Mukaiyama conditions,16 with selective 1,3-anti
induction, leading to the product of interest (4) in 89% yield
and diastereoselectivity > 95:05 (Scheme 10).
1H NMR analysis following theABX method17 gave us
indications that the relative stereochemistry between C18
methyl and C17 hydroxyl is 1,3-anti. It can be seen that
adduct 4 has coupling constants for Ha of 8.0 Hz (expected
7.8-10.0 Hz) and Hb of 4.6 Hz (expected 1.1-5.4 Hz). The
experimental values are consistent with a Felkin compound,
therefore confirms the 1,3-anti induction (Scheme 10).
Conclusions
In conclusion, we have described an efficient asymmetric
synthesis of the C(7)-C(20) fragment of spirotoamides A,
B and C. This approach required 14 steps for the longest
linear sequence (0.36% overall yield, average of 81% for
each step). The determinant steps of this work involved the
boron-mediated 1,5-anti aldol reaction between α-methyl-
β-hydroxyketone 9 and aldehyde 10 and the induction
promoted by the Mukaiyama aldol reaction between
α-methyl-β-hydroxyaldehyde 5 and enolsilane 6. As a
result, the C(7)-C(20) fragment can be obtained in highly
diastereoselective form and all the stereocenters could
be determined during the synthesis or by derivatization.
Extension of this work toward completion on the synthesis
Scheme 9. Synthesis of the enolsilane 6.
Scheme 10. Mukaiyama aldol reaction (key step) for the preparation of the C(7)-C(19) fragment.

6
Synthesis of the C(7)-C(20) Fragment of Spirotoamides A, B and C
J. Braz. Chem. Soc.
of spirotoamides A, B, and C is underway and results will
be described in due course.
(cm−1). High-resolution mass spectrometry (HRMS) were
measured using electrospray ionization (ESI) (Thermo
Scientific LTQ, FT Ultra).
Experimental
Synthesis, characterization and spectra data of aldehyde
All reactions were carried out under an atmosphere
of argon with dry solvents under anhydrous conditions
unless otherwise stated. Tetrahydrofuran (THF) and diethyl
ether (Et2O) were distilled from sodium/benzophenone
prior to use. Triethylamine (Et3N), 2,6-lutidine,
N,N-dimethylethylamine (DMEA), DIPEA,
dichloromethane (CH2Cl2), and acetonitrile (MeCN)
were distilled from calcium hydride prior to use. Acetic
acid (AcOH) was fractionally distilled from acetic
anhydride and chromium (VI) oxide prior to use. CSA was
recrystallized from ethyl acetate. All other reagents were
used without further purification, unless otherwise stated.
The purification of reaction products was performed by flash
column chromatography using silica gel (230-400 mesh).
Organic solutions were concentrated under reduced
pressure on a Büchi rotary evaporator R-215, B-491.
Reactions were monitored by thin layer chromatography
carried out on silica-gel 60 and GF (5-40 μm thickness)
plates with fluorescent indicator, and visualization was
accomplished using UV light, phosphomolybdic acid
(PMA), KMnO4 or vanillin followed by heating. Optical
rotations were measured on a PerkinElmer 341 polarimeter
with a sodium lamp using a 1.0 cm cell and are reported
as follows: [α]DT(°C) (c (g per 100 mL), solvent). Melting
points were measured with a Buchi M-565 equipment
10 (C(7)-C(11) fragment)
(R)-4-Benzyl-3-((S)-2,4-dimethylpent-4-enoyl)oxazolidin-
2-one (12)
To a 250 mL flask containing n-BuLi (47.7 mmol,
19.0 mL, 2.5 M in hexane) in THF (50 mL) at –78 °C
was added diisopropylamine (DIPA) (47.7 mmol, 4.82 g,
6.7 mL). The reaction mixture was stirred for 1 h at −78 °C.
Subsequently, a solution containing the oxazolidinone 11
(44.6 mmol, 10.40 g in 20 mL of THF) was added via
cannula and the mixture was stirred at −78 °C for a further
30 min. Thereafter, the alkyl iodide 13 (90 mmol, 17.00 g,
10.4 mL) was added dropwise. The reaction was stirred
at −78 °C for 1 h and at −40 °C for 2 h. The reaction was
warmed to 0 °C, then the mixture was washed with saturated
aqueous ammonium chloride solution (50 mL), which was
extracted with dichloromethane (CH2Cl2) (4 × 50 mL). The
organic phase was dried with MgSO4. After filtration, the
solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography using
silica gel as the stationary phase and hexane/ethyl acetate
(17:3) as the eluent to afford the corresponding alkylation
product 12 (yellow oil) in 10.40 g, 82% yield (36.6 mmol).
Rf: 0.30, UV/PMA (Hex:EtOAc, 17:3); [α]D20 –54.2 (c 1.0,
CH2Cl2); IR (attenuated total reflectance (ATR)) ν / cm-1
3074, 3030, 2975, 2936, 1775, 1697, 1455, 1385, 1207,
1
and are uncorrected. H and proton-decoupled 13C NMR
1
spectrum were acquired on a Bruker DPX250 (250 MHz
for 1H NMR and 62.5 MHz for 13C NMR), Bruker Avance
400 (400 MHz for 1H NMR and 100 MHz for 13C NMR),
1195, 701; H NMR (500 MHz, CDCl3) d 7.35-7.31 (m,
2H), 7.29-7.25 (m, 1H), 7.22-7.20 (m, 2H), 4.81 (br s, 1H),
4.76 (br s, 1H), 4.69 (ddt, J 7.4, 6.6, 3.2 Hz, 1H), 4.19
(dd, J 8.9, 7.8 Hz, 1H), 4.15 (dd, J 9.1, 3.1 Hz, 1H), 4.03
(apparent sextet, J 7.1 Hz, 1H), 3.27 (dd, J 13.4, 3.2 Hz,
1H), 2.71 (dd, J 13.4, 9.7 Hz, 1H), 2.57 (dd, J 13.8, 7.0 Hz,
1H), 2.09 (dd, J 13.8, 7.5 Hz, 1H), 1.78 (s, 3H), 1.16 (d,
J 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) d 176.9, 153.1,
142.9, 135.3, 129.4, 128.9, 127.3, 112.5, 65.9, 55.3, 41.8,
37.9, 35.5, 22.2, 16.6.
1
Bruker Avance 500 (500 MHz for H and 125 MHz for
1
13C NMR), or Bruker Avance 600 (600 MHz for H and
150 MHz for 13C NMR). Chemical shifts (d) are reported
in ppm using residual undeuterated solvent as an internal
standard (CHCl3 at 7.26 ppm and TMS at 0.00 ppm for
1H NMR spectrum and CDCl3 at 77.0 ppm for 13C NMR
spectrum). Multiplicity data are reported as follows:
s = singlet, br s = broad singlet, d = doublet, t = triplet,
q = quartet, dd = doublet of doublets, ddd = doublet of
doublet of doublets, dt = doublet of triplets, dq = doublet
of quartets, ddt = doublet of doublets of triplets, td = triplet
of doublets, tt = triplet of triplets, tq = triplet of quartets,
qdd = quartet of doublets of doublets, and m = multiplet.
The multiplicity is followed by the coupling constant(s)
in Hz and integration. Infrared spectrum (IR) was recorded
on PerkinElmer Spectrum Two spectrometer. Wavelengths
of maximum absorbance (max) are quoted in wavenumbers
(S)-2,4-Dimethylpent-4-en-1-ol (14)
To a flask containing compound 12 (1 equiv.,
28.0 mmol, 8.00 g), it was added methanol (1.1 equiv.,
32 mmol, 1.3 mL) in Et2O (mL). The mixture was cooled
to 0 °C, LiBH4 (1 equiv., 28.0 mmol, 16.0 mL, 2 M in
tetrahydrofuran) was added and the mixture stirred at
0 °C for 45 min. The reaction was then warmed to room
temperature and was stirred for 90 min, then the reaction
was quenched in the presence of NaOH (4.50 g in 50 mL

Vol. 00, No. 00, 2019
Rossini and Dias
7
of water) and extracted with ethyl ether (Et2O) (3 × 80 mL).
The organic phase was dried with MgSO4. After filtration
the solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography using
silica gel as the stationary phase and pentane/ethyl ether
(2:1) as eluent, resulting in alcohol 14 (colorless oil) in
3.46 g, 95% yield (26.6 mmol). Rf: 0.34, PMA (Hex:Et2O,
2:1); [α]D20 –5.7 (c 2.0, CH2Cl2); IR (ATR) ν / cm-1 3338,
3075, 2956, 2918, 2873, 1651; 1H NMR (500 MHz, CDCl3)
d 4.76 (br s, 1H), 4.71 (br s, 1H), 3.50 (dd, J 10.6, 5.5 Hz,
1H), 3.43 (dd, J 10.6, 5.6 Hz, 2H), 2.18-2.10 (m, 1H), 1.97
(s, 1H), 1.90-1.80 (m, 1H), 1.72 (s, 3H), 0.90 (d, J 6.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 144.4, 111.6, 68.2,
42.2, 33.5, 22.1, 16.5.
reaction mixture was then cooled to −78 °C, followed
by a dropwise addition of the acetaldehyde (5 equiv.,
24.0 mmol, 1.0570 g, 1.3 mL in 20 mL of Et2O, via
cannula). After 1 h at −78 °C the mixture was warmed to
−20 °C (freezer) and stirred for 14 h. The temperature was
raised to 0 °C, followed by the slow addition of MeOH
(20 mL), phosphate buffer pH 7 (20 mL) and H2O2 30%
solution (20 mL). The reaction was stirred at 0 °C for
1 h, then the mixture was extracted with dichloromethane
(CH2Cl2) (3 × 50 mL). The organic phase was dried with
MgSO4. After filtration the solvent was evaporated under
reduced pressure and the residue was purified by flash
column chromatography using silica gel as the stationary
phase and dichloromethane/ethyl ether (4:1) as the eluent
to give the aldol adduct 15 (off-white solid) in 0.9720 g,
81% yield (3.9 mmol) and ds > 95:05. Rf: 0.49, PMA
(CH2Cl2:Et2O, 4:1); [α]D20 +38.1 (c 1.4, CHCl3); mp 85.2-
86.7 °C; IR (ATR) ν / cm-1 3348, 2976, 2935, 2880, 1732,
1719, 1602, 1585, 1485, 1451, 1264, 1111, 1006, 706;
1H NMR (500 MHz, CDCl3) d 8.08 (dd, J 8.4, 1.3 Hz, 2H),
7.59 (t, J 7.4, 1.3 Hz, 1H), 7.46 (t, J 7.7 Hz, 2H), 5.44 (q,
J 7.1 Hz, 1H), 3.98 (pentet, J 6.4 Hz, 1H), 2.81 (pentet,
J 7.2 Hz, 1H), 2.51 (br s, 1H), 1.57 (d, J 7.1 Hz, 3H), 1.25 (d,
J 7.2 Hz, 3H), 1.23 (d, J 6.4 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 211.7, 165.8, 133.3, 129.7, 129.4, 128.4, 74.5,
69.4, 49.9, 20.8, 15.8, 14.4.
(S)-2,4-Dimethylpent-4-enal (10)
To a flask of 15 mL containing oxalyl chloride (3 equiv.,
3 mmol, 0.5908 g, 0.40 mL) in dichloromethane (5 mL) was
added dimethyl sulfoxide (DMSO; 5.5 equiv., 5.5 mmol,
0.4297 g, 0.39 mL). The mixture was stirred at −78 °C for
30 min. Then the alcohol 14 (1 equiv., 1 mmol, 0.1142 g)
was added and the mixture stirred at −78 °C for a further
30 min. The mixture was warmed to 0 °C followed by
addition of triethylamine (12 equiv., 12 mmol, 1.1673 g,
1.6 mL) while stirring at 0 °C for 90 min. The reaction
was washed with saturated aqueous ammonium chloride
solution (NH4Cl) (20 mL), which was extracted with ethyl
ether (Et2O) (3 × 30 mL). The organic phase was dried with
MgSO4. After filtration, the solvent was evaporated under
reduced pressure, giving aldehyde 10 (yellowish oil) in
0.1122 g, in quantitative yield (1 mmol). Rf: 0.50, PMA
(Hex:EtOAc, 9:1); [α]D20 +3.7 (c 2.0, CH2Cl2); IR (ATR)
ν / cm-1 3074, 2955, 2920, 2871, 2855, 1724, 1650, 1457;
1H NMR (500 MHz, CDCl3) d 9.64 (d, J 1.9 Hz, 1H),
4.82 (br s, 1H), 4.73 (br s, 1H), 2.58-2.51 (m, 1H), 2.17
(d, J 16.3 Hz, 1H), 2.03 (dd, J 14.3, 8.0 Hz, 1H), 1.73 (s,
3H), 1.08 (d, J 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 204.8, 142.2, 112.8, 44.2, 38.8, 22.2, 13.4.
(2S,4R,5R)-5-((4-Methoxybenzyl)oxy)-4-methyl-
3-oxohexan-2-yl benzoate (16)
To a mixture with p-methoxybenzyl alcohol (1.5 equiv.,
36.0 mmol, 4.9740 g, 4.4 mL) in diethyl ether (19 mL) at
room temperature under an inert atmosphere, it was added
sodium hydride in mineral oil (0.15 equiv., 3.6 mmol,
0.1440 g of NaH). The suspension was stirred for 1 h.
The mixture was cooled to 0 °C followed by addition of
trichloroacetonitrile (1.5 equiv., 36.0 mmol, 5.1980 g,
3.6 mL) over 15 min. The mixture was maintained at 0 °C
for 5 min and at room temperature for a further 1 h. The
reaction was washed with saturated NaHCO3 (20 mL).
The organic phase was dried with MgSO4. After filtration,
the solvent was evaporated under reduced pressure.
To the residue, it was added the alcohol 15 (1 equiv.,
24.0 mmol, 6.00 g), CSA (0.2 equiv., 4.8 mmol, 1.12 g)
and CH2Cl2 (40 mL). The reaction mixture was stirred at
room temperature for 18 h. Subsequently, the reaction was
washed with saturated aqueous NaHCO3 solution (200 mL),
which was extracted with Et2O (4 × 100 mL). The organic
phase was dried with MgSO4. The product was purified
by flash column chromatography on hexane/ethyl acetate
(9:1) as eluent, providing a colorless oil (16) in 7.4683 g,
84% yield (20.2 mmol). Rf: 0.12, PMA (Hex:EtOAc, 9:1);
Synthesis, characterization and spectra data of ketone 9
(C(12)-C(16) fragment)
(2S,4R,5R)-5-Hydroxy-4-methyl-3-oxohexan-2-yl benzoate
(15)
To a 100 mL flask containing dicyclohexylborane
chloride ((c-C6H11)2BCl) (1.5 equiv., 7.2 mmol,
1.5270 g, 1.60 mL) in 20 mL of diethyl ether at −78 °C
dimethylethylamine (Me2NEt) (11.8 equiv., 8.6 mmol,
0.2632 g, 0.38 mL) and ethylketone 8 (4.8 mmol, 1.00 g
in 20 mL of Et2O, via cannula) were added dropwise. The
mixture was warmed to 0 °C and was stirred for 2 h. The

8
Synthesis of the C(7)-C(20) Fragment of Spirotoamides A, B and C
J. Braz. Chem. Soc.
[α]D20 –26.6 (c 2.0, CHCl3); IR (ATR) ν / cm-1 3064, 3034,
2975, 2937, 2909, 2879, 2837, 1716, 1613, 1513, 1451,
1246, 1114, 1028, 823, 712; 1H NMR (500 MHz, CDCl3)
d 8.08 (d, J 7.2 Hz, 2H), 7.57 (t, J 7.4 Hz, 1H), 7.44 (t,
J 7.7 Hz, 2H), 7.16 (d, J 8.6 Hz, 2H), 6.83 (d, J 8.6 Hz,
2H), 5.37 (q, J 7.0 Hz, 1H), 4.42 (d, J 10.8 Hz, 1H), 4.27
(d, J 10.8 Hz, 1H), 3.78 (s, 3H), 2.94 (dq, J 14.2, 7.1 Hz,
1H), 1.47 (d, J 7.0 Hz, 3H), 1.18 (d, J 6.2 Hz, 3H), 1.14 (d,
J 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 209.9, 165.8,
159.0, 133.1, 130.5, 129.8, 129.3, 128.3, 113.6, 76.8, 75.1,
71.1, 55.2, 49.0, 16.7, 15.2, 13.6.
45.0 mmol, 28.1 mL, 1.6 M in THF) dropwise. The mixture
was stirred at −78 °C for 30 min, subsequently warmed
to −30 °C and stirred for an additional 1 h. Then, buffer
solution pH 7 (120 mL) was added. The mixture was
extracted with Et2O (4 × 80 mL), washed with saturated
sodium chloride (NaCl) solution (100 mL). The organic
phase was dried with MgSO4. After filtration, the solvent
was evaporated under reduced pressure, and the mixture
of alcohols was used in the next step without purification.
To a 250 mL flask containing oxalyl chloride (1.5 equiv.,
30.0 mmol, 3.8079 g, 2.4 mL) in dichloromethane (120 mL,
0.25 M) at −78 °C, it was added DMSO (3.0 equiv.,
60.0 mmol, 4.6878 g, 4.3 mL). The mixture was stirred at
−78 °C for 30 min. Thereafter, the pre-prepared mixture of
the alcohols was added and stirred at −78 °C for 30 min.
The mixture was warmed to 0 °C followed by addition of
triethylamine (Et3N) (5 equiv., 100.0 mmol, 10,1190 g,
14.0 mL), and stirred at 0 °C for 90 min. The reaction was
washed with saturated aqueous NH4Cl solution (100 mL)
and extracted with Et2O (3 × 100 mL). The organic phase
was washed with water (100 mL), saturated aqueous NaCl
solution (100 mL), and dried over MgSO4. After filtration,
the solvent was evaporated under reduced pressure,
affording a yellowish oil (9) in 4.4899 g, 95% yield over two
steps (19.0 mmol), and was used in the next step without
purification. Rf: 0.32, PMA (Hex:EtOAc, 4:1); [α]D20 –37.9
(c 2.4, CHCl3); IR (ATR) ν / cm-1 2973, 2936, 2911, 2878,
2837, 1711, 1613, 1513, 1456, 1377, 1355, 1245, 1033,
821; 1H NMR (400 MHz, CDCl3) d 7.20 (d, J 8.7 Hz, 2H),
6.86 (d, J 8.7 Hz, 2H), 4.48 (d, J 11.0 Hz, 1H), 4.32 (d,
J 11.0 Hz, 1H), 3.79 (s, 3H), 3.71 (dq, J 8.2, 6.1 Hz, 1H),
2.73 (pentet, J 7.2, 1H), 2.15 (s, 3H), 1.17 (d, J 6.2 Hz,
3H), 1.02 (d, J 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 212.1, 159.0, 130.4, 129.2, 113.7, 76.7, 70.6, 55.2, 52.6,
30.0, 16.6, 12.6.
(2R,3R)-3-((4-Methoxybenzyl)oxy)-2-methylbutanal (17)
To a 500 mL flask containing the benzoate ester 16
(1 equiv., 20.0 mmol, 5.3670 g) in THF (20 mL) at −78 °C
and argon atmosphere, lithium borohydride (LiBH4)
(10 equiv., 200.0 mmol, 100.0 mL, 2 M in THF) was
added. The mixture was stirred at −78 °C for 10 min, then
warmed to room temperature and stirred for a further 12 h.
The reaction was cooled to 0 °C, then 100 mL of water
was added and the mixture was washed with saturated
aqueous ammonium chloride solution (NH4Cl) (100 mL),
then extracted with Et2O (4 × 100 mL). The organic
phase was dried with MgSO4. After filtration, the solvent
was evaporated under pressure. To the mixture of diols,
methanol (200 mL), water (100 mL) and sodium periodate
(NaIO4) (5 equiv., 100.0 mmol, 21.4877 g) were added. The
reaction mixture was stirred for 1 h at room temperature.
Subsequently, distilled water (100 mL) was added to the
reaction, which was extracted with Et2O (3 × 100 mL).
The organic phase was dried with MgSO4. After filtration
the solvent was evaporated under reduced pressure and
the residue was purified by flash column chromatography
using silica gel as the stationary phase and hexane/EtOAc
(4:1) as eluent to afford a colorless oil (17) in 4.3567 g,
98% yield (19.6 mmol). Rf: 0.32, PMA (Hex:EtOAc, 4:1);
[α]D20 –46.7 (c 2.0, CHCl3); IR (ATR) ν / cm-1 2974, 2936,
2876, 2831, 2718, 1722, 1612, 1513, 1245, 1033, 819;
1H NMR (400 MHz, CDCl3) d 9.70 (d, J 2.4 Hz, 1H), 7.23
(d, J 8.6 Hz, 2H), 6.87 (d, J 8.7 Hz, 2H), 4.54 (d, J 11.3 Hz,
1H), 4.37 (d, J 11.3 Hz, 1H), 3.79 (s, 3H), 3.78-3.74 (m,
1H), 2.53 (apparent pentet, J 7.1 and 2.4 Hz, 1H), 1.23 (d,
J 6.3 Hz, 3H), 1.06 (d, J 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 204.5, 159.1, 130.2, 129.2, 113.7, 74.8, 70.3,
55.2, 51.7, 16.8, 10.0.
Synthesis, characterization and spectra data of aldehyde 5
(C(17)-C(19) fragment)
(2S,4R,5R)-5-((tert-Butyldimethylsilyl)oxy)-4-methyl-
3-oxohexan-2-yl benzoate (18)
To a flask, it was added the alcohol 15 (1 equiv.,
5.0 mmol, 1.2515 g) in dichloromethane (50 mL). The
reaction mixture was cooled to −78 °C, 2,6-lutidine
(2.0 equiv., 10.0 mmol, 1.15 mL) and TBSOTf (1.5 equiv.,
7.5 mmol, 1.70 mL) were added. The reaction was stirred
for 1 h at −78 °C. Then, the reaction was washed with
saturated aqueous solution of NaHCO3 (100 mL) and
extracted with Et2O (3 × 100 mL). The organic phase
was dried with MgSO4. The product was purified by flash
column chromatography on hexane/dichloromethane (1:1)
(3R,4R)-4-((4-Methoxybenzyl)oxy)-3-methylpentan-2-one
(9)
To a 250 mL flask containing the aldehyde 17 (1 equiv.,
20.0 mmol, 4.4456 g) in Et2O (80 mL) at −78 °C and argon
atmosphere was added methyllithium (MeLi) (3 equiv.,

Vol. 00, No. 00, 2019
Rossini and Dias
9
as eluent to provide aldol 18 (colorless oil) adduct in 1.80 g,
99% yield (4.9 mmol). Rf: 0.41, PMA (Hex:CH2Cl2, 1:1);
[α]D20 –15.5 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3065, 2956,
2930, 2886, 2858, 1721, 1603, 1586, 1472, 1452, 1380,
1266, 1116, 711; 1H NMR (250 MHz, CDCl3) d 8.08 (dt,
J 7.0, 1.5 Hz, 2H), 7.57 (tt, J 7.3, 2.0 Hz, 1H), 7.45 (tt, J 6.4,
1.5 Hz, 2H), 5.41 (q, J 7.0 Hz, 1H), 4.06 (dq, J 8.4, 6.1 Hz,
1H), 2.85 (dq, J 14.1, 7.1 Hz, 1H), 1.52 (d, J 7.0 Hz, 3H),
1.15 (d, J 6.1 Hz, 3H), 1.09 (d, J 7.1 Hz, 3H), 0.84 (s, 9H),
0.04 (s, 3H), –0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 209.4, 165.7, 133.2, 129.8, 129.7, 128.4, 75.1, 70.1, 50.5,
25.8, 21.1, 17.9, 15.2, 13.8, –4.7, –4.9; HRMS (ESI) m/z,
calcd. for [M + Na]+: 387.19621, found: 387.19548.
J 8.6 Hz, 2H, ArH), 4.76 (s, 1H, H-7), 4.68 (s, 1H, H-7),
4.48 (d, J 10.8 Hz, 1H), 4.25 (d, J 10.8 Hz, 1H), 3.95 (ddd,
J 9.5, 3.6, 2.7 Hz, 1H, H-11), 3.79 (s, 3H, OCH3), 3.68
(dq, J 8.7, 6.1 Hz, 1H, H-15), 2.98 (br s, 1H, OH), 2.72
(dq, J 8.7, 7.0 Hz, 1H, H-14), 2.64 (dd, J 17.6, 2.4 Hz, 1H,
H-12), 2.55 (dd, J 17.6, 9.6 Hz, 1H, H-12), 2.15 (dd, J 13.4,
5.3 Hz, 1H, H-9), 1.80 (dd, J 13.5, 9.3 Hz, 1H, H-9), 1.68
(s, 1H, H-22), 1.66-1.60 (m, 1H, H-10), 1.20 (d, J 6.1 Hz,
3H, H-16), 1.01 (d, J 7.0 Hz, 3H, H-23), 0.80 (d, J 6.8 Hz,
3H, H-24); 13C NMR (125 MHz, CDCl3) d 215.9, 159.2,
144.1, 130.2, 129.4, 113.7, 111.9, 77.6, 70.8, 70.0, 55.2,
52.2, 47.8, 41.4, 35.4, 22.1, 16.9, 13.8, 13.0; HRMS (ESI)
m/z, calcd. for [M + Na]+: 371.21983, found: 371.21912.
(2R,3R)-3-((tert-Butyldimethylsilyl)oxy)-2-methylbutanal (5)
The aldehyde 5 was prepared under the same conditions
as showed for the preparation of compound 17, resulting
in a colorless oil in 0.5302 g, 98% yield. Rf: 0.40, PMA
(Hex:EtOAc, 9:1); [α]D20 –48.1 (c 1.0, benzene); IR (ATR)
ν / cm-1 2957, 2931, 2886, 2858, 2711, 1727, 1473, 1463,
1253, 1115, 1005; 1H NMR (400 MHz, CDCl3) d 9.74 (d,
J 2.6 Hz, 1H), 4.02 (pentet, J 6.2 Hz, 1H), 2.36 (qdd, J 7.0,
5.8, 2.6 Hz, 1H), 1.21 (d, J 6.3 Hz, 3H), 1.06 (d, J 7.0 Hz,
3H), 0.86 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 205.2, 69.8, 53.6, 26.0, 21.7, 17.9,
10.6, 8.9, –4.2, –5.0.
(2R,3S,4S,6S,7S)-2-((4-Methoxybenzyl)oxy)-
3,7,9-trimethyldec-9-ene-4,6-diol (20)
To a flask containing tetramethylammonium
triacetoxyborohydride (4.0 equiv., 28.0 mmol, 7.3563 g)
in acetonitrile (MeCN) (21.0 mL), it was added glacial
acetic acid (AcOH) (21.0 mL). The mixture was stirred for
30 min. Then, the reaction was cooled to −40 °C, followed
by the addition of a solution of the alcohol 19 (1.0 equiv.,
7.0 mmol, 2.4394 g) in AcOH (21.0 mL), dropwise via
the cannula and a mixture of CSA (0.5 equiv., 3.5 mmol,
0.8131 g), anhydrous MeCN (21.0 mL) and glacial AcOH
(21.0 mL). The reaction mixture was stirred at −20 °C
for 48 h. Subsequently, the mixture was transferred to an
Erlenmeyer flask under stirring with saturated aqueous
solution of NaHCO3 (250 mL).After the total gas evolution,
a saturated solution of Rochelle’s salt (KNaC4H4O6)
(250 mL) and CH2Cl2 (250 mL) was added. The resulting
mixture was stirred at room temperature for 3 h. Thereafter,
the mixture was extracted with CH2Cl2 (4 × 100 mL). The
organic phase was dried with MgSO4. After filtration the
solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography
using stationary phase silica gel and hexane/ethyl acetate
(3:2) as eluent to provide diol 20 (yellow oil) at 2.2817 g,
93% yield (6.5 mmol) and ds > 95:05. Rf: 0.31, UV/PMA
(Hex:EtOAc, 3:2); [α]D20 –8.1 (c 1.0, CHCl3); IR (ATR)
ν / cm-1 3403, 3073, 2967, 2934, 2912, 2838, 1613, 1514,
Synthesis and characterization, spectra data and
stereochemistry determination of diol 20
(2R,3R,6S,7S)-6-Hydroxy-2-((4-methoxybenzyl)oxy)-
3,7,9-trimethyldec-9-en-4-one (19)
To a flask containing methyl ketone 9 (1.0 equiv.,
8.5 mmol, 2.0086 g) in Et2O (170 mL, 0.05 M) at −30 °C,
it was added slowly (c-hex)2BCl (2.0 equiv., 17.0 mmol,
3.6066 g, 3.7 mL) and Et3N (2.1 equiv., 17.8 mmol,
1.7996 g, 2.5 mL), resulting in a white solution. After
the addition of Et3N, the mixture was cooled to −78 °C.
Subsequently, the aldehyde 17 (3.0 equiv., 25.5 mmol,
2.8603 g) was added dropwise. The reaction mixture was
stirred at −78 °C. After 1 h, methanol (MeOH) (170 mL)
was added to the reaction, which was warmed to room
temperature. The solvent was evaporated under vacuum and
the residue was purified by flash column chromatography
using silica gel as the stationary phase and hexane/ethyl
acetate (4:1) as eluent to provide aldol 19 (colorless oil)
adduct in 2.4881 g, 84% yield (7.1 mmol) and ds > 95:05.
Rf: 0.23, PMA (Hex:EtOAc, 4:1); [α]D20 –32.1 (c 1.0,
CHCl3); IR (ATR) ν / cm-1 3485, 3073, 2967, 2931, 2879,
1708, 1614, 1514, 1378, 1249, 1104, 1036, 824; 1H NMR
(500 MHz, CDCl3) d 7.17 (d, J 8.6 Hz, 2H, ArH), 6.85 (d,
1
1455, 1376, 1248, 1036, 888, 821; H NMR (600 MHz,
CDCl3) d 7.25 (d, J 8.6 Hz, 2H), 6.87 (d, J 8.6 Hz, 2H), 4.75
(s, 1H), 4.69 (s, 1H), 4.59 (d, J 11.1 Hz, 1H), 4.52 (s, 1H),
4.36 (d, J 11.1 Hz, 1H), 3.88-3.81 (m, 2H), 3.79 (s, 3H),
3.55 (dq, J 8.0, 6.1 Hz, 1H), 3.16 (br s, 1H), 2.20 (dd, J 13.5,
4.9 Hz, 1H), 1.82 (dt, J 15.2, 9.1 Hz, 2H), 1.75-1.70 (m,
2H), 1.69 (s, 3H), 1.53 (ddd, J 14.5, 6.8, 1.9 Hz, 1H), 1.26
(d, J 6.1 Hz, 3H), 0.86 (d, J 6.8 Hz, 3H), 0.79 (d, J 6.9 Hz,
3H); 13C NMR (150 MHz, CDCl3) d 159.3, 144.5, 129.9,
129.5, 113.9, 111.6, 80.3, 73.9, 71.3, 70.3, 55.2, 43.4, 41.5,

10
Synthesis of the C(7)-C(20) Fragment of Spirotoamides A, B and C
J. Braz. Chem. Soc.
36.5, 22.1, 17.3, 13.9, 13.0; HRMS (ESI) m/z, calcd. for
5.51 (s, 1H), 4.77 (s, 1H), 4.70 (s, 1H), 3.91 (ddd, J 9.9, 3.8,
1.7 Hz, 1H), 3.79 (s, 3H), 3.75 (ddd, J 10.2, 7.7, 2.8 Hz,
1H), 3.58 (dq, J 9.8, 6.1 Hz, 1H), 2.40 (br s, 1H), 2.20
(dd, J 13.5, 5.0 Hz, 1H), 1.92-1.84 (m, 2H), 1.77-1.62 (m,
5H), 1.62-1.53 (m, 1H), 1.33 (d, J 6.1 Hz, 3H), 0.87 (d,
J 6.8 Hz, 3H), 0.85 (d, J 6.7 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 159.8, 144.4, 131.2, 113.6, 111.7, 100.5, 80.0,
78.5, 70.6, 55.3, 41.7, 39.7, 36.4, 36.2, 22.1, 19.4, 13.7,
12.3; HRMS (ESI) m/z, calcd. for [M + Na]+: 371.21918,
found: 371.21983.
[M + Na]+: 373.23548, found: 373.23481.
(4S,6S)-4-((2R,3R)-3-((4-Methoxybenzyl)oxy)butan-2-yl)-
2,2-dimethyl-6-((S)-4-methylpent-4-en-2-yl)-1,3-dioxane
(21)
To a 250 mL flask containing the diol 20 (1 equiv.,
2.0 mmol, 0.7010 g) in 2,2-dimethoxypropane (70 mL),
CSA (0.1 equiv., 0.2 mmol, 0.0465 g) was added. The
reaction mixture was stirred for 12 h at room temperature.
Subsequently, the reaction was diluted with Et2O (50 mL),
followed by saturated aqueous solution of NaHCO3 (50 mL)
and extraction with Et2O (3 × 50 mL). The organic phase
was dried over MgSO4. After filtration the solvent was
evaporated under reduced pressure and the residue was
purified by flash column chromatography using silica gel
as the stationary phase and hexane/EtOAc (9:1) as eluent
to provide acetonide 21 (colorless oil) in 0.7108 g, 91%
yield (1.8 mmol). Rf: 0.43, UV/PMA (Hex:EtOAc, 9:1);
[α]D20 –40.7 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3074, 2982,
2968, 2836, 1613, 1513, 1457, 1376, 1240, 1224, 1108,
(2R,4R,5R,6S)-2-(4-Methoxyphenyl)-4,5-dimethyl-
6-(((2S,3S)-3,5,5-trimethyltetrahydrofuran-2-yl)methyl)-
1,3-dioxane (23)
To a solution containing the acetal 24 (1 equiv.,
9.4 μmol, 3.3 mg) in MeCN (1 mL, 0.01 M), it was added
HCl(aq) (37%) (0.5 equiv., 4.7 μmol, 0.4 μL). The reaction
mixture was stirred for 24 h. Subsequently, the reaction was
washed with saturated aqueous solution NaHCO3 (10 mL)
and extracted with Et2O (3 × 15 mL). The organic phase
was dried with MgSO4. After filtration the solvent was
evaporated under reduced pressure and the residue was
purified by flash column chromatography using silica gel as
the stationary phase and hexane/EtOAc (9:1) as the eluent
to give the hydrofuran 23 in 2.6 mg, 79% yield (7.4 μmol).
Rf: 0.16, PMA (Hex:EtOAc, 9:1); [α]D20 –54.7 (c 0.35,
CHCl3); IR (ATR) ν / cm-1 2967, 2931, 2889, 2838, 1615,
1518, 1457, 1379, 1248, 1036, 826; 1H NMR (600 MHz,
CDCl3) d 7.44-7.41 (m, 2H,ArH), 6.89-6.85 (m, 2H,ArH),
5.56 (s, 1H, OC(H)O), 4.27 (ddd, J 9.8, 6.6, 2.9 Hz, 1H,
H-11), 3.79 (s, 3H, OCH3), 3.68 (td, J 10.1, 1.4 Hz, 1H,
H-13), 3.57 (dq, J 9.7, 6.1 Hz, 1H, H-15), 2.43 (apparent
septet, J 7.2 Hz, 1H, H-10), 1.92 (dd, J 12.3, 7.4 Hz, 1H,
H-9), 1.75 (ddd, J 13.9, 10.2, 1.5 Hz, 1H, H-12), 1.50-1.44
(m, 2H, H-9 and H-12), 1.39 (tq, J 9.8, 6.7 Hz, 1H, H-14),
1.31 (d, J 6.1 Hz, 3H, H-16), 1.31 (s, 3H, H-7), 1.21 (s, 3H,
H-22), 0.95 (d, J 7.0 Hz, 3H, H-23), 0.85 (d, J 6.6 Hz, 3H,
H-24); 13C NMR (150 MHz, CDCl3) d 159.6, 131.8, 127.3,
113.4, 99.9, 79.3, 78.9, 78.4, 76.8, 55.3, 46.6, 41.2, 36.5,
34.5, 30.8, 29.2, 19.5, 14.8, 12.5; HRMS (ESI) m/z, calcd.
for [M + Na]+: 371.21909, found: 371.21983.
1
1038, 886, 820; H NMR (500 MHz, CDCl3) d 7.26 (d,
J 8.5 Hz, 2H), 6.86 (d, J 8.6 Hz, 2H), 4.76 (s, 1H), 4.68
(s, 1H), 4.45 (d, J 11.3 Hz, 1H), 4.40 (d, J 11.3 Hz, 1H),
3.63 (td, J 9.1, 6.1 Hz, 1H), 3.53 (dt, J 9.8, 6.1 Hz, 1H),
3.79 (s, 3H), 3.75 (dq, J 6.2, 5.1 Hz, 1H), 2.15 (dd, J 13.6,
4.8 Hz, 1H), 2.03-1.95 (m, 1H), 1.74 (dd, J 13.2, 9.8 Hz,
1H), 1.70-1.52 (m, 6H), 1.30 (s, 3H), 1.29 (s, 3H), 1.08 (d,
J 6.3 Hz, 3H), 0.86 (d, J 6.5 Hz, 3H), 0.84 (d, J 6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3) d 158.9, 144.0, 131.4, 129.1,
113.7, 111.8, 100.1, 74.4, 69.9, 69.8, 68.0, 55.2, 41.8, 40.9,
35.4, 34.6, 24.5, 24.4, 22.1, 14.7, 14.3, 8.9; HRMS (ESI)
m/z, calcd. for [M + Na]+: 413.26592, found: 413.26678.
(2S,3S)-1-((2R,4S,5R,6R)-2-(4-Methoxyphenyl)-
5,6-dimethyl-1,3-dioxan-4-yl)-3,5-dimethylhex-5-en-2-ol
(22)
To a flask containing diol 20 (1 equiv., 57.1 μmol,
20 mg) in CH2Cl2 (2 mL, 0.03 M) under argon atmosphere
was added activated 4 Å molecular sieves (36 mg). After
15 min, the mixture was cooled to −10 °C followed by
addition of DDQ (1.25 equiv., 32.0 μmol, 32 mg). The
mixture was stirred for 5 min at −10 °C and 2 h at 0 °C. Then
the reaction was purified by flash column chromatography
using silica gel as the stationary phase and hexane/
EtOAc (9:1) as the eluent, affording acetal 22 (yellowish
oil) in 15.7 mg, 79% yield (45.1 μmol). Rf: 0.12, PMA
(Hex:EtOAc, 9:1); [α]D20 –4.9 (c 0.5, CHCl3); IR (ATR)
ν / cm-1 3497, 3073, 2968, 2933, 2892, 2840, 1615, 1518,
1455, 1401, 1250, 1075, 1035, 826; 1H NMR (500 MHz,
CDCl3) d 7.40 (d, J 8.7 Hz, 2H), 6.87 (d, J 8.7 Hz, 2H),
Synthesis and characterization, spectra data of enolsilane
6 (C(7)-C(16) fragment)
(2R,3R,4S,6S,7S)-4,6-Bis(methoxymethoxy)-
3,7,9-trimethyldec-9-en-2-ol (25)
To a flask containing the diol 21 (1 equiv., 2.0 mmol,
0.702 g) in CH2Cl2 (20 mL, 0.1 M) at 0 °C, it was added
DIPEA (9 equiv., 36.0 mmol, 4.6520 g, 6.2 mL) and
MOMCl (6 equiv., 24.0 mmol, 2.8980 g, 2.73 mL). The

Vol. 00, No. 00, 2019
Rossini and Dias
11
reaction mixture was stirred for 12 h at room temperature.
Subsequently, saturated aqueous solution of NH4Cl
(10 mL) was added, followed by extraction with CH2Cl2
(3 × 10 mL). The organic phase was dried with MgSO4.
After filtration, the solvent was evaporated under reduced
pressure. To a mixture of PMB ether 24, it was added a
mixture of CH2Cl2:phosphate buffer pH 7 (9:1) (35 mL,
0.5 M) at 0 °C, followed by the addition of DDQ (1.5 equiv.,
3.0 mmol, 0.7175 g). The reaction was stirred at 0 °C for
90 min, then the reaction was quenched with a saturated
aqueous solution of NaHCO3 (100 mL). The reaction
mixture was filtered through Celite and washed with
CH2Cl2 (6 × 70 mL). The solvent was evaporated under
reduced pressure and the residue was purified by flash
column chromatography using silica gel as the stationary
phase and hexane/ethyl acetate (7:3) as eluent to provide
the alcohol 25 (colorless oil) in 0.5031 g, 79% yield for
two steps (1.6 mmol). Rf: 0.16, vanillin (Hex/EtOAc, 7:3);
[α]D20 –37.1 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3437, 3074,
2996, 2934, 2889, 1649, 1455, 1377, 1147, 1093, 1039,
918; 1H NMR (500 MHz, CDCl3) d 4.78-4.63 (m, 6H), 4.01
(ddd, J 8.5, 4.0, 1.4 Hz, 1H), 3.68 (dt, J 7.4, 2.4 Hz, 1H),
3.57 (dq, J 8.5, 6.2 Hz, 1H), 3.42 (s, 3H), 3.39 (s, 3H), 2.27
(dd, J 13.5, 3.7 Hz, 1H), 2.03-1.93 (m, 1H), 1.79-1.68 (m,
6H), 1.58 (ddd, J 14.7, 9.5, 1.3 Hz, 1H), 1.48 (ddd, J 15.0,
8.8, 1.8 Hz, 1H), 1.22 (d, J 6.2 Hz, 3H), 0.85 (d, J 6.9 Hz,
3H), 0.84 (d, J 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 144.3, 111.6, 96.9, 96.1, 80.7, 76.9, 69.8, 55.9, 55.7,
44.5, 39.8, 34.6, 32.1, 22.2, 21.4, 14.9, 10.8; HRMS (ESI)
m/z, calcd. for [M + Na]+: 341.22985, found: 341.22976.
(500 MHz, CDCl3) d 4.75 (s, 1H), 4.72-4.67 (m, 5H),
4.07 (ddd, J 9.4, 5.5, 1.5 Hz, 1H), 3.65 (dt, J 7.6, 2.4 Hz,
1H), 3.41 (s, 3H), 3.38 (s, 3H), 2.98-2.91 (apparent pentet,
J 6.5 Hz, 1H), 2.27-2.18 (m, 1H), 2.20 (s, 3H), 2.00-1.92
(m, 1H), 1.76-1.68 (m, 1H), 1.69 (s, 3H), 1.50 (ddd, J 14.6,
9.7, 1.8 Hz, 1H), 1.36 (ddd, J 14.7, 9.8, 1.6 Hz, 1H),
1.08 (d, J 7.0 Hz, 3H), 0.82 (d, J 6.9 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 210.2, 144.3, 111.6, 97.1, 97.0, 79.5,
76.7, 55.9, 55.8, 51.7, 39.7, 34.7, 33.2, 29.6, 22.2, 14.9,
10.5; HRMS (ESI) m/z, calcd. for [M + Na]+: 339.21420,
found: 339.21421.
(5S,6S,8S)-6-(Methoxymethoxy)-2,2,5-trimethyl-
4-methylene-8-((S)-4-methylpent-4-en-2-yl)-3,9,11-trioxa-
2-siladodecane (6)
To a solution containing LDA (2.0 equiv., 0.6 mmol,
1.2 mL of a 0.5 M solution in THF) in THF (5 mL) at
−78 °C, it was added TMSCl (6.0 equiv., 1.8 mmol,
0.2151 g, 0.25 mL) and sequentially the ketone 26 (1 equiv.,
0.3 mmol, 0.9481 g) in THF (2 mL) via cannula. The
mixture was stirred at −78 °C for 30 min. After this time,
the reaction was warmed to room temperature and it was
added hexane (30 mL) to the reaction. The organic layer
was washed with saturated aqueous solution of NaHCO3
(30 mL) and dried with MgSO4. After filtration, the
solvent was evaporated under reduced pressure, resulting
in enolsilane 6 (colorless oil) in 0.1061 g, 91% yield
(0.55 mmol). Rf: 0.57, PMA (Hex:EtOAc, 4:1); [α]D20 –2.5
(c 1.0, CHCl3); IR (ATR) ν / cm-1 3074, 2989, 2958, 2822,
1651, 1619, 1456, 1376, 1252, 1149, 1096, 912, 841;
1H NMR (250 MHz, CDCl3) d 4.77-4.65 (m, 6H), 4.12-4.06
(m, 2H), 3.90 (ddd, J 9.8, 4.8, 1.9 Hz, 1H), 3.64 (dt, J 7.0,
3.0 Hz, 1H), 3.39 (s, 6H), 2.50 (dq, J 6.9, 5.0 Hz, 1H), 2.27
(dd, J 13.2, 3.4 Hz, 1H), 1.97 (ddd, J 13.8, 6.9, 3.7 Hz, 1H),
1.74 (dd, J 13.3, 10.5 Hz, 1H), 1.69 (s, 3H), 1.57-1.49 (m,
1H), 1.47-1.34 (m, 1H), 1.00 (d, J 7.0 Hz, 3H), 0.82 (d,
J 6.8 Hz, 3H), 0.21 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 160.5, 144.6, 111.5, 96.9, 89.9, 79.6, 77.4, 55.8, 55.7,
43.9, 39.9, 34.8, 32.1, 22.2, 14.9, 11.8, 5.4; HRMS (ESI)
m/z, calcd. for [M+Na]+: 411.25372, found: 411.25373.
( 3 S , 4 S , 6 S , 7 S ) - 4 , 6 - B i s ( m e t h ox y m e t h ox y ) -
3,7,9-trimethyldec-9-en-2-one (26)
To a solution containing the alcohol 25 (1 equiv.,
0.9 mmol, 0.3180 g) in CH2Cl2 (3 mL), it was added
NaHCO3 (2.4 equiv., 0.21 mmol, 0.1764 g) and DMP
(1.2 equiv., 1.08 mmol, 0.4578 g). The reaction mixture
was stirred at room temperature for 90 min. The reaction
was washed with saturated aqueous solution of NaHCO3
(30 mL) and Na2SO3 (30 mL) and stirred at room
temperature for 10 min. This mixture was extracted with
dichloromethane (4 × 30 mL). The organic layer was
washed with saturated aqueous solution of NaCl (20 mL)
and dried with MgSO4. After filtration the solvent was
evaporated under reduced pressure and the residue was
purified by flash column chromatography using silica gel
as the stationary phase and hexane/EtOAc (4:1) as eluent
to afford methyl ketone 26 (colorless oil) in 0.2761 g, 97%
yield (0.9 mmol). Rf: 0.17, PMA (Hex:EtOAc, 4:1); [α]D20
–5.1 (c 1.0, CHCl3); IR (ATR) ν / cm-1 3074, 2962, 2934,
2890, 2824, 1712, 1455, 1366, 1148, 1092, 917; 1H NMR
Key step and characterization, spectra data of adduct 4
(C(7)-C(20) fragment)
(5S,7S,8S,12S,13R)-11-Hydroxy-7-(methoxymethoxy)-
8,12,13,15,15,16,16-heptamethyl-5-((S)-4-methylpent-4-en-
2-yl)-2,4,14-trioxa-15-silaheptadecan-9-one (4)
To a flask containing the enolsilane 6 (1 equiv.,
0.85 mmol, 0.3303 g), and the aldehyde 5 (1.25 equiv.,
1.1 mmol, 0.2400 g) in CH2Cl2 (10 mL) at −78 °C, it was
added BF3.Et2O (1.25 equiv., 1.1 mmol, 1.1 mL). The

12
Synthesis of the C(7)-C(20) Fragment of Spirotoamides A, B and C
J. Braz. Chem. Soc.
reaction mixture was stirred at −78 °C for 90 min. The
reaction was washed with saturated aqueous solution
of NaHCO3 (30 mL), extracted with dichloromethane
(3 × 30 mL) and dried with MgSO4. After filtration the
solvent was evaporated under reduced pressure and the
residue was purified by flash column chromatography
using silica gel as the stationary phase and hexane/EtOAc
(4:1) as eluent, resulting in aldol adduct 4 (colorless oil)
in 0.4031 g, 89% yield (0.76 mmol) and ds > 95:05. Rf:
0.30, PMA (Hex:EtOAc, 4:1); [α]D20 –7.1 (c 1.0, CHCl3);
IR (ATR) ν / cm-1 3503, 3074, 2957, 2931, 2888, 2857,
1709, 1649, 1462, 1377, 1254, 1148, 1094, 1036, 918, 836,
775; 1H NMR (500 MHz, CDCl3) d 4.70 (s, 1H), 4.66-4.58
(m, 5H), 4.58-4.53 (m, 1H), 4.01 (dd, J 7.8, 6.4 Hz, 1H),
3.86 (dq, J 6.2, 4.0 Hz, 1H), 3.60 (d, J 10.1 Hz, 1H), 3.45
(s, 1H), 3.35 (s, 3H), 3.32 (s, 3H), 2.93 (apparent pentet,
J 6.7 Hz, 1H), 2.73 (dd, J 16.8, 8.0 Hz, 1H), 2.41 (dd, J 16.8,
4.6 Hz, 1H), 2.19 (dd, J 13.5, 3.4 Hz, 1H), 1.95-1.88 (m,
1H), 1.69-1.62 (m, 1H), 1.64 (s, 3H), 1.44 (ddd, J 14.4,
9.5, 1.3 Hz, 1H), 1.41-1.35 (m, 1H), 1.31 (ddd, J 14.3, 9.9,
0.9 Hz, 1H), 1.23 (d, J 6.3 Hz, 3H), 1.02 (d, J 6.9 Hz, 3H),
0.92 (d, J 7.1 Hz, 3H), 0.84 (s, 9H), 0.76 (d, J 6.9 Hz, 3H),
0.04 (s, 6H); 13C NMR (125 MHz, CDCl3) d 211.7, 144.1,
111.5, 96.9, 79.4, 76.6, 73.4, 66.2, 55.7, 55.7, 51.4, 47.7,
42.7, 39.5, 34.5, 33.1, 25.7, 22.1, 21.8, 17.8, 14.8, 11.0,
10.4, –4.4, –5.2; HRMS (ESI) m/z, calcd. for [M + Na]+:
555.36875, found: 555.36878.
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Supplementary Information
Supplementary information (characterization data and
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1
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Acknowledgments
We are grateful to FAPESP (2015/50655-9) for financial
support. A. F. C. R. thanks CNPq (160646/2014-6) for
fellowships.
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Submitted: April 3, 2019
Published online: June 6, 2019
This is an open-access article distributed under the terms of the Creative Commons Attribution License.