Diastereoselective synthesis of the C17-C30 fragment of amphidinol 3

Article abstract of DOI:10.1039/c2ob26641e

The diastereoselective synthesis of the C17-C30 fragment of amphidinol 3 (AM3) 1 was achieved from the enantio-enriched aldehyde 20, Weinreb amide 14 and 2-bromo-3-(trimethylsilyl)propene, which was used as a bifunctional conjunctive reagent. The absolute configuration of the stereogenic centers, in both aldehyde 20 and Weinreb amide 14, were efficiently controlled by using (+)-(R)-methyl-p-tolylsulfoxide as the unique source of chirality.

Full text of DOI:10.1039/c2ob26641e

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PAPER
Diastereoselective synthesis of the C17–C30 fragment of amphidinol 3†
Nicolas Rival,a Damien Hazelard,a Gilles Hanquet,a Thomas Kreuzer,a Charlelie Bensoussan,b
Sébastien Reymond,b Janine Cossyb and Françoise Colobert*a
Received 17th August 2012, Accepted 12th October 2012
DOI: 10.1039/c2ob26641e
The diastereoselective synthesis of the C17–C30 fragment of amphidinol 3 (AM3) 1 was achieved from
the enantio-enriched aldehyde 20, Weinreb amide 14 and 2-bromo-3-(trimethylsilyl)propene, which was
used as a bifunctional conjunctive reagent. The absolute configuration of the stereogenic centers, in both
aldehyde 20 and Weinreb amide 14, were efficiently controlled by using (+)-(R)-methyl-p-tolylsulfoxide
as the unique source of chirality.
(AM14 and AM15) closely related to AM7, with a truncated
Introduction
polyhydroxyl chain and a modified polyene part, were extracted
from the same organism,4b and the biological activities of these
Amphidinols (AMs) are fascinating biologically active polyke-
tide metabolites that exhibit potent hemolytic activity against
human erythrocytes as well as antifungal activity.1 Since the first
isolation and identification of amphidinol 1 in 19912 from the
marine dinoflagellates of the Amphidinium genus,3 nearly 20
closely related toxins have been isolated from the dinoflagellates
Amphidinium klebsii and Amphidinium carterae1,4 along with
similar structurally related compounds such as luteophanol A,5
lingshuiol A,6 and karatungiol.7 More recently, a structurally
closely related structure called karlotoxin, which possesses
hemolytic activity, was not isolated from Amphidinium but from
another source, Karlodinium veneficum.8 Amphidinols, unlike
polycyclic ethers isolated from other dinoflagellates, are mainly
characterized by linear polyketides and polyolefins. Among
those, amphidinol 3 (AM3) 1, which was isolated in 1996 from
Amphidinium klebsii,3 has the most potent hemolytic and anti-
fungal activities. It is worth noting that, among the known anti-
fungal agents, amphidinol 3 and all AMs are unique as they
possess neither nitrogenous polycycles present in synthetic
drugs, nor macrocyclic structures commonly found in polyene-
macrolide antibiotics. A hairpin conformation of amphidinols
acting by a facial amphiphilic interaction with membrane lipids
or by penetration of the hydrophobic chain in the membrane has
been proposed to account for membrane permeabilizing activi-
ties.9 A few years ago, two new homologues of amphidinols
short-chained AMs have been investigated and compared with
known homologues. This study has shown that the hydrophobi-
city of the polyene chain of AMs dramatically affects the mem-
brane-disrupting activity and that the polyhydroxyl chain
moderately modulates the potency of the biological activity.
The potent antifungal activity displayed by AM3 1, which
exceeds that of commercial antifungal compounds such as
amphotericin B, has prompted the interest of biologists in study-
ing its mechanism of action which is believed to be different
from that of amphotericin B.10 Thus, amphidinols may provide
an interesting model to gain a better understanding of the mech-
anism of antifungal activities, which eventually could help to
develop better drugs for treatment of AIDS-related diseases and
those upon transplantation.
Although the total synthesis of AM3 has not yet been realized,
several creative approaches to polyol,3b,11 pyranyl11b–d,12 and
polyene12e,f,13 fragments have been reported by several teams
including the contribution from Rychnovsky et al. toward the
synthesis of the most advanced fragment C1–C52.11b
Presently, we expand on our successful approaches to the
C53–C67 polyene fragment13a,b and the C18–C30 polyol frag-
ment11a by defining a new strategy to the C17–C30 fragment A
bearing a terminal olefin at the C30 position. Our previously
designed Julia–Kocienski olefination strategy allowing the
stereoselective construction of the C30–C31 double bond has
been abandoned because Rychnovsky observed very low reactiv-
ity of the C31-aldehyde towards a large panel of nucleophiles.11b
Consequently, we decided to disconnect AM3 1 at the C31–C32
bond and use a Nozaki–Hiyama–Kishi coupling to form this
bond.14
aCNRS/Université de Strasbourg (ECPM), UMR 7509, 25 Rue
Becquerel, F-67087 Strasbourg, France.
E-mail: francoise.colobert@unistra.fr; Fax: +33 (0)3.68.85.27.42;
Tel: +33 (0)3.68.85.27.44
bESPCI Paris Tech, CNRS, Laboratoire de Chimie organique, 10 rue
Vauquelin, 75231-PARIS Cedex 05, France. E-mail: janine.cossy@espci.fr;
Fax: +33 (0)1.40.79.44.25; Tel: +33 (0)1.40.79.44.29
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26641e
On the basis of the retrosynthetic plan illustrated in Scheme 1,
the C17–C30 fragment A could be obtained from three subunits:
(1) an optically active α-hydroxyaldehyde E; (2) a bifunctional
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Scheme 1 Retrosynthetic analysis of the C17–C30 fragment A of AM3-1.
2-bromo-3-(trimethylsilyl)propene; (3) an optically active
Weinreb amide D possessing a syn 1,3-diol. By combining the
ability to metalate a vinyl bromide and the nucleophilicity of an
allylsilane, the readily available 2-bromo-3-(trimethylsilyl)-
propene could serve as a dianion equivalent.15
Our initial strategy focused on a diastereoselective addition of
allylsilane to aldehyde E through the Cram-chelate transition
state, followed by the addition of the resulting vinyl bromide C
to Weinreb amide D. A chemo- and diastereoselective reduction
of the exo-methylene group of the C23–C24 enone16 in fragment
B using L-selectride and subsequent diastereoselective reduction
of the ketone by Zn(BH4)2 would control the stereogenic center
at C23 and C24 present in compound A. Enantioselective prep-
aration of aldehyde E and Weinreb amide D from γ-butyro-
lactone 2 and pentenoic acid 9 would be performed using
(+)-(R)-methyl-p-tolylsulfoxide as the unique source of chirality
(Scheme 1).
Scheme 2 Synthesis of aldehyde 8 (fragment C17–C21).
Results and discussion
at C20 (DIBAL-H, 99%)18 followed by protection of the
obtained β-hydroxysulfoxide 6 with benzyl bromide and a sub-
sequent Pummerer rearrangement of the resulting sulfoxide 7
(2,4,6-collidine, TFAA, then NaHCO3, 88%) provided the
enantiopure aldehyde 819 in 53% overall yield (Scheme 2).
The second fragment, Weinreb amide 14, was prepared from
β,δ-dihydroxy-sulfoxide 12 in two steps (Scheme 3). The syn-
thesis of 12 was realized from protected β-ketoester 10, obtained
in two steps from pentenoic acid 9 in 72% yield via the corre-
sponding imidazolide derivative. Addition of two equivalents of
(+)-(R)-lithio-methyl-p-tolyl-sulfoxide to 10, followed by a
The synthesis of aldehyde 8 started with the ring-opening of
lactone 2 under basic conditions (NaOH, EtOH, 95%) to furnish
ω-hydroxycarboxylate 3 which was subsequently transformed
into the protected ester 4 (MeI, DMF then TPDPSCl, imid.,
91%). This compound was treated with the lithiated anion of
(+)-(R)-methyl-p-tolyl-sulfoxide (2 equiv.) to produce β-ketosulf-
oxide 5 (99%). It is worth noting that the direct condensation of
the chiral sulfoxide on butyrolactone 217 was possible, however,
in lower yield in 5 (68% instead of 90%). From β-ketosulfoxide
5, a sulfoxide-directed diastereoselective reduction of the ketone
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Scheme 5 Synthesis of vinyl bromide 22.
Scheme 3 Synthesis of Weinreb amide 14 (fragment C24–C30).
Scheme 6 Synthesis of allylic alcohol 24.
Scheme 4 Synthesis of enone 17 and reduction attempts of the methyl-
ene group at C23.
leading to enone 17 in 70% yield, this latter corresponds to the
C17–C30 fragment (Scheme 4).
Having synthesized enone 17, we turned our attention to the
reduction of the exo-methylene group at C23 to obtain α-methyl
ketone 18. This transformation was troublesome due to a com-
peting reduction of the terminal double bond. According to the
literature, we anticipated that the use of L-selectride could afford
the desired configuration at C23.16 However, after examining an
array of conditions, including NiCl2/NaBH4,16 the recovery of
the starting material and/or its decomposition was observed
(Scheme 4).
Due to these difficulties, the transformation of the terminal
double bond into a methyl ketone, prior to reduction of the exo-
methylene group, was examined. This alternative presents
several advantages: (1) the methyl ketone can be easily trans-
formed to a vinyl iodide which will be a good candidate for a
Nozaki–Hiyama–Kishi coupling;24 (2) the chemoselective
reduction of the exo-methylene group could be facilitated and (3)
the stereochemical outcomes of this reduction should be easily
assigned by chemical correlation to a fragment previously
described by Paquette et al.11d To gain better access to this frag-
ment, the protecting group of the secondary hydroxy in aldehyde
8 was modified (Scheme 5). A PMB-ether was selected instead
of a benzyl ether in order to allow for selective removal of the
protecting group. Interestingly, the PMB removal proceeded
diastereoselective reduction by DIBAL-H of the resulting β-keto-
sulfoxide, led to β-hydroxysulfoxide 11 (dr > 98.5 : 1.5). Sub-
sequent deprotection of 11 under acidic conditions followed by a
Prasad–Narasaka syn-diastereoselective reduction (Et2BOMe/
NaBH4, THF/MeOH, −78 °C)20 afforded dihydroxysulfoxide
1221 (40% overall yield from 9). After acetonide protection of 12
followed by a TFAA-induced Pummerer rearrangement, alde-
hyde 13 was isolated in 85% yield. Oxidation of the latter under
Pinnick conditions22 followed by treatment with N,O-dimethyl-
hydroxylamine hydrochloride delivered Weinreb amide 14 in
76% yield. Thus, compound 14 was obtained in 11 steps from 9
with an overall yield of 26% (Scheme 3).
With both compounds 8 and 14 in our hands, the synthesis of
the C17–C30 fragment was undertaken. Treatment of commer-
cially available 2-bromo-3-(trimethylsilyl)propene with TiCl4 in
CH2Cl2 at −78 °C23 followed by the addition of aldehyde 8 pro-
vided compound 15 (C17–C23 fragment) with an 8.5/1 diaster-
eomeric ratio in favor of syn 1,2-diol 15, which was isolated in
85% yield. After protection of the hydroxyl group at C21 as a
TBDPS-ether and treatment with tert-BuLi (Et2O at −78 °C),
the organolithium intermediate was added to Weinreb amide 14,
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Scheme 7 Access to Paquette et al.’s fragment.
quantitatively during the condensation of 20 with 2-bromo-3-(tri-
methylsilyl)propene in the presence of TiCl4, producing diol 21
with excellent yield and diastereoselectivity (dr > 97.5 : 2.5;
yield = 85%). After protection of the resulting syn 1,2-diol as an
isopropylidene acetal, 22 was isolated in 98% yield (Scheme 5).
Access to allylic alcohol 24 (fragment C17–C30) was
acquired according to two pathways (Scheme 6).
The first one was a direct condensation of the lithium deriva-
tive generated from vinyl bromide 22 (t-BuLi, Et2O, −78 °C)
with aldehyde 13 providing the desired allylic alcohol 24 in 62%
yield with rather good diastereoselectivity (dr = 6 : 1). It is worth
noting that the use of MgBr2 as an additive did not give better
yield and stereoselectivity in 24. The second pathway, which
allowed the confirmation of the relative configuration of the
major diastereoisomer obtained previously, was achieved from
enone 23 resulting from the condensation of the lithium deriva-
tive generated from vinylic bromide 22 with Weinreb amide 14,
followed by a stereoselective reduction of the obtained enone 23
with Zn(BH4)2 in the presence of cerium chloride,25 producing
24 in 28% overall yield with a dr up to 97.5 : 2.5.
To transform enone 23 and alcohol 24 into fragment C17–
C30, a Wacker oxidation of these compounds was achieved to
furnish the corresponding methylketones 25 and 26 (PdCl2,
Cu(OAc)2, O2, DMA/H2O) respectively in good 82 and 85% yields
(Scheme 7). The stereoselective reduction of the exo-methylene
group in 26 was performed under 80 bars of hydrogen in the
presence of Pd/C in good yield (99%) however with poor diaster-
eoselectivity as 28 and 28′ were obtained in a ratio of 65/35.26
On the other hand, hydrogenation of 25 with Wilkinson’s cata-
lyst, RhCl(P(C6H5)3)3, provided ketone 27 and 27′ in 83% yield,
as a mixture of diastereoisomers (dr = 75 : 25). A highly
diastereoselective reduction (dr > 98.5 : 1.5) of ketone 27 and
27′, as a 75/25 mixture of two diastereoisomers, took place
when Zn(BH4)2 was used as the reductive agent as alcohols 28
and 28′ were obtained with the same ratio of 75/25, the major
isomer being the major compound obtained by hydrogenation of
26. Finally, the fragment previously reported by Paquette
et al.11d was prepared from separated minor diastereoisomer 28′
in two steps (BOMCl, DIEPA then TBAF) showing unambigu-
ously that compound 28′ possesses the desired absolute
configuration27 at C23 (Scheme 7).
Conclusion
In conclusion, we report herein an efficient coupling of the
bifunctional 2-bromo-3-(trimethylsilyl)propene with aldehyde 20
and aldehyde 13 as well as the coupling of vinyl bromide 22
with Weinreb amide 14 to obtain the C17–C30 fragment of
amphidinol 3. Starting from butyrolactone 8 and pentenoic acid
10, the absolute configuration of the stereocenters in aldehydes
20 and 13 has been highly controlled using (+)-(R)-methyl-p-
tolylsulfoxide as the unique source of chirality. Either reduction
of the exo-methylene group at C23 and then the ketone at C24 in
the C17–C30 skeleton or the opposite gave the corresponding
fragment C17–C30 of amphidinol 3.
Experimental section
General
Reagents and solvents were purchased as reagent grade and used
without further purification. THF was distilled over sodium
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benzophenone ketyl. Dichloromethane was distilled over CaH2
and acetonitrile over P2O5. Flash column chromatography (FC)
was performed using silica gel 60 for preparative column chrom-
atography (40–63 mm), unless specifically noted otherwise.
Demetallated silica gel was prepared according to a published
procedure.28 Thin layer chromatography (TLC) was performed
on glass sheets coated with silica gel 60 F254 (otherwise stated),
visualization by UV light or through staining with phosphomo-
lybdic acid, KMnO4 or vanillin. Optical rotations were measured
on a polarimeter with a sodium lamp and are reported as
follows: αD (c g per 100 mL, solvent). NMR spectra (1H and
13C) were recorded on a 300 MHz or 400 MHz spectrometer.
Chemical shifts are reported in ppm with the solvent (CDCl3)
resonance as the δ 7.26 ppm (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, s ap = apparent singlet, mc = multi-
plet center, coupling constants Hz, integration). Carbon NMR
(13C NMR) spectra were also run at various field strengths as
indicated. Spectra were recorded in CDCl3 using residual
undeuterated solvent (77 ppm) as an internal reference. Infra red
(IR) spectra were recorded on a diamond ATR spectrometer
using neat samples. Infra red frequencies are reported in wave-
numbers (cm−1), intensities were determined qualitatively and
are reported as strong (s), medium (m) or weak (w). Solid Lewis
acids were flame-dried in the reaction flask under vacuum and
under argon before use.
1.60 mmol). The resulting solution was stirred for 5 h at −78 °C,
quenched with 2 mL of MeOH, diluted with 10 mL of EtOAc,
hydrolyzed with an aqueous saturated solution of sodium-potass-
ium tartrate (10 mL) and stirred overnight until a clear phase-sep-
aration occurred. The aqueous phase was extracted with EtOAc
(3 × 20 mL) and the combined organic layers were washed with
brine (20 mL), dried over Na2SO4, filtered and concentrated
under reduced pressure. Purification of the residue by flash
column chromatography on demetallated silica gel (EtOAc/
cyclohexane: 1/1) gave the β-hydroxysulfoxide 6 as a colorless
oil (611 mg, 1.27 mmol, 99%): [α]2D5 +120.0° (c = 1.15 in
CHCl3); Rf 0.37 (EtOAc/cyclohexane: 1/1); 1H NMR (300 MHz,
CDCl3) δ 7.62–7.66 (m, 4H), 7.51–7.53 (m, 2H), 7.32–7.45 (m,
8H), 4.17–4.24 (m, 1H), 3.61–3.69 (m, 2H), 2.85 (AB of ABX,
JAB = 13.4 Hz, JAX = 9.8 Hz, JBX = 2.0 Hz, Δν = 102.9 Hz,
2H), 2.42 (s, 3H), 1.54–1.68 (m, 4H), 1.03 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 141.5, 139.9, 135.55, 135.5, 133.65, 133.6,
130.1, 130.0, 129.6, 127.6, 124.0, 124.0, 66.6, 63.8, 61.7, 34.0,
28.3, 26.8, 21.4, 19.2; IR: 3365, 2930, 2858, 1472, 1428, 1390,
1110, 1085, 1027, 1010, 908, 823, 807, 729, 700, 687 cm−1
;
HRMS ES m/z (M + Li)+ calcd for C28H36LiO3SSi 487.2310,
found 487.2274.
Synthesis of ((S)-4-(benzyloxy)-5-((R)-p-tolylsulfinyl)pentyl-
oxy)(tert-butyl)diphenylsilane 7. A solution of alcohol
6
(958 mg, 1.99 mmol) in 5 mL of THF was added dropwise at
0 °C to a solution of oil-free sodium hydride (96 mg,
3.99 mmol) in 20 mL of THF. The reaction mixture was stirred
for 30 min, prior to the addition of benzyl bromide (592 μL,
4.98 mmol). After 30 min at 0 °C and 3 h at room temperature
the resulting solution was carefully hydrolyzed by adding 5 mL
of an aqueous saturated solution of NH4Cl. The aqueous layer
was extracted with EtOAc (3 × 20 mL) and the combined
organic layers were washed with brine (20 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure. The
crude material was purified by flash column chromatography on
silica gel (EtOAc/cyclohexane: 2/5) to give the benzyl ether 7
(854 mg, 1.49 mmol, 75%) as a colorless oil: [α]2D5 +91.2° (c =
1.43 in CHCl3); Rf 0.60 (EtOAc/cyclohexane: 1/1); 1H NMR
(300 MHz, CDCl3) δ 7.62–7.67 (m, 4H), 7.46–7.47 (m, 2H),
7.27–7.43 (m, 13H), 4.67 (AB, JAB = 11.0 Hz, Δν = 11.5 Hz,
2H), 4.07–4.14 (X of ABX, m, 1H), 3.65 (t, J = 6.1 Hz, 2H),
2.82–2.91 (AB of ABX, m, 2H), 2.42 (s, 3 H), 1.52–1.85 (m,
4 H), 1.04 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 141.6, 141.3,
138.0, 135.5, 133.8, 130.0, 129.6, 128.4, 128.1, 127.8, 127.6,
123.8, 73.2, 72.3, 64.6, 63.6, 30.2, 27.6, 26.9, 21.4, 19.2; IR
2930, 2857, 1494, 1472, 1455, 1428, 1105, 1086, 1045, 1016,
998, 938, 822, 807, 738, 699 cm−1; HRMS ES m/z (M + Na)+
calcd for C35H42NaO3SSi 593.2516, found 593.2472.
Synthesis of (R)-5-(tert-butyldiphenylsilyloxy)-1-(p-tolylsulfinyl)-
pentan-2-one 5. To a solution of diisopropylamine (1.59 mL,
11.35 mmol) in 15 mL of THF cooled at −78 °C was added
dropwise n-BuLi (6.48 mL, 1.60 M in hexane, 10.37 mmol).
The resulting solution was stirred for 1 h at −78 °C, prior to the
addition of
a solution of (+)-(R)-methyl-p-tolyl-sulfoxide
(1.52 g, 9.87 mmol) in 12 mL of THF at −78 °C. After stirring
for 1 h at −78 °C, the anion solution was transferred via a trans-
fer syringe to a −78 °C cold solution of the ester 4 (1.76 g,
4.94 mmol) in 18 mL of THF and stirred for 1 h. The reaction
mixture was then diluted with 20 mL of Et2O, hydrolyzed with
aqueous saturated NH4Cl (20 mL) and washed with brine
(20 mL). The organic layer was dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified
by flash column chromatography on demetallated silica gel
(Et2O) to furnish the β-ketosulfoxide 5 as a colorless oil (2.34 g,
4.89 mmol, 99%): [α]D25 +90.6° (c = 1.43 in CHCl3), Rf 0.63
1
(Et2O); H NMR (300 MHz, CDCl3) δ 7.61–7.64 (m, 4H), 7.52
(B of A2B2, JAB = 8.1 Hz, Δν = 63.3 Hz, 2H), 7.35–7.45 (m,
6H), 7.31 (A of A2B2, JAB = 8.1 Hz, Δν = 63.3 Hz, 2H), 3.79
(AB, JAB = 13.5 Hz, Δν = 34.7 Hz, 2H), 3.63 (t, J = 6.1 Hz,
2H), 2.49–2.68 (m, 2H), 2.40 (s, 3H), 1.74–1.83 (m, 2H), 1.04
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 201.4, 142.1, 139.8,
135.5, 133.6, 130.0, 129.6, 127.7, 124.01, 68.2, 62.7, 41.5,
26.9, 26.1, 21.5, 19.2; IR:2931, 2858, 1712, 1590, 1494, 1472,
1428, 1390, 1362, 1110, 1056, 963, 823, 810, 741, 705,
688 cm−1; HRMS ES m/z (M + Li)+ calcd for C28H34LiO3SSi
485.2152, found 485.2100.
Synthesis of (S)-2-(benzyloxy)-5-(tert-butyldiphenylsilyloxy)-
pentanal 8. To a solution of sulfoxide 7 (850 mg, 1.49 mmol) in
12 mL of MeCN cooled at 0 °C was added dropwise sub-
sequently 2,4,6-collidine (595 μL, 4.47 mmol) and trifluoroace-
tic anhydride (1.56 g, 1.04 mL, 7.45 mmol). The reaction
mixture was stirred for 30 min, prior to the addition of 12 mL of
an aqueous saturated solution of NaHCO3, warmed to room
temperature and stirred for 1 h at this temperature. The aqueous
layer was extracted with EtOAc (3 × 15 mL) and the combined
Synthesis of (S)-5-(tert-butyldiphenylsilyloxy)-1-((R)-p-tolyl-
sulfinyl)pentan-2-ol 6. To a solution of β-ketosulfoxide 5
(614 mg, 1.28 mmol) in 10 mL of THF cooled at −78 °C was
added dropwise DIBAL-H (1.60 mL, 1.0 M in toluene,
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1
organic layers were washed with brine (15 mL), dried over
Na2SO4, filtered and concentrated under reduced pressure. Purifi-
cation of the residue by flash column chromatography on silica
gel (EtOAc/cyclohexane: 1/9) gave the aldehyde 8 (585 mg,
1.31 mmol, 88%) as a colorless oil: [α]2D5 −30.6° (c = 1.03 in
CHCl3); Rf 0.46 (EtOAc/cyclohexane: 1/10); 1H NMR
(300 MHz, CDCl3) δ 9.65 (d, J = 2.0 Hz, 1H); 7.65–7.68 (m,
4H), 7.29–7.47 (m, 11H), 4.59 (AB, JAB = 11.7 Hz, Δν =
41.7 Hz, 2H), 3.78 (ddd, J = 7.4 Hz, J = 5.2 Hz, J = 2.0 Hz,
1H), 3.64 (t, J = 6.0 Hz, 2H), 1.57–1.93 (m, 4H), 1.06 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 203.5, 137.3, 135.5, 133.8,
129.6, 128.5, 128.0, 128.0, 127.6, 83.2, 72.4, 63.2, 27.7, 26.9,
26.419, 19.209; IR: 2858, 1733, 1472, 1455, 1428, 1106, 1090,
1028, 1007, 998, 937, 823, 794, 738, 699 cm−1, Anal calcd for
C28H34O3Si: C, 75.29; H, 7.67; found C, 75.23; H, 7.598.
Rf 0.46 (EtOAc/cyclohexane: 4/1); H NMR (300 MHz, CDCl3)
δ 7.54 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 5.69–5.85
(m, 1H), 4.99 (d, J = 18.3, 1H), 4.94 (d, J = 10.2, 1H),
4.42–4.53 (m, 1H), 3.89–3.99 (m, 4H), 2.77–2.93 (m, 2 H), 2.41
(s, 3 H), 2.01–2.13 (m, 2 H), 1.82–1.89 (m, 2 H), 1.61–1.73 (m,
2 H); 13C NMR (75 MHz, CDCl3) δ 141.2, 140.5, 137.8, 129.8,
123.7, 114.4, 110.7, 64.6, 64.5, 62.7, 42.6, 36.3, 27.7, 21.2; IR
3359, 2927, 1710, 1641, 1492, 1398, 1305, 1085, 1030, 911,
810 cm−1; HRMS ES m/z (M + Na)+ calcd for C17H24NaO4S
347.1288, found 347.1247.
Synthesis of (2S)-2-hydroxy-1((R)-p-tolylsulfinyl)-oct-7-en-4-
one. Acetal 11 (1.09 g, 3.36 mmol) in 35 mL of acetone was
treated with ( )-10-camphorsulfonic acid (170 mg, 0.73 mmol).
The reaction was stirred for 24 h and diluted with 20 mL of
CH2Cl2. The organic phase was washed with a saturated
NaHCO3 solution (2 × 10 mL). The aqueous phase was extracted
with CH2Cl2 (3 × 20 mL) and the combined organic layers were
washed with brine (20 mL), dried over MgSO4, filtered and con-
centrated under reduced pressure affording hydroxyketone as a
solid, which was directly used for the next step without further
purification. For analysis, a sample was recrystallized in ether to
give a white solid: m.p. 73–75 °C; [α]2D5 +228.6° (c = 0.61 in
CHCl3); Rf 0.45 (EtOAc/cyclohexane: 4/1); 1H NMR (300 MHz,
CDCl3) δ 7.53 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H),
5.69–5.86 (m, 1H), 5.01 (d, J = 17.1, 1H), 4.98 (d, J = 10.2,
Synthesis of 1-(2-but-3-enyl-1,3-dioxolan-2-yl)-3-((R)-p-tolyl-
sulfinyl)propan-2-one. To
(6.4 mL, 45.4 mmol) in 50 mL of THF cooled at −78 °C was
added dropwise n-BuLi (28.4 mL, 1.60 in hexane,
a
solution of diisopropylamine
M
45.4 mmol). The resulting solution was stirred for 1 h at −78 °C,
prior to the addition of a solution of (+)-(R)-methyl-p-tolyl-sulf-
oxide (7.0 g, 45.4 mmol) in 40 mL of THF at −78 °C. After stir-
ring for 1 h at −78 °C, a solution of ester 10 (4.31 g,
20.17 mmol) in 40 mL of THF was added dropwise. The reac-
tion mixture was stirred for 5 h at −78 °C, hydrolyzed with an
aqueous saturated solution of NH4Cl (150 mL) and warmed to
room temperature. The aqueous layer was extracted with EtOAc
(3 × 100 mL) and the combined organic layers were washed
with brine (100 mL), dried over Na2SO4, filtered and concen-
trated in vacuo. Purification of the crude by flash column chrom-
atography on silica gel (EtOAc/cyclohexane: 1/1 → 7/3)
afforded the sulfoxide as a yellow oil (4.61 g, 14.25 mmol,
72%): [α]2D5 +135.7° (c = 0.79 in CHCl3); Rf 0.25 (EtOAc/cyclo-
hexane: 1/1); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz,
2H), 7.31 (d, J = 7.8 Hz, 2H), 5.65–5.82 (m, 1H), 4.97 (dq, J =
17.1 Hz, J = 2.4 Hz, 1H), 4.91 (dq, J = 10.2 Hz, J = 2.7 Hz,
1H), 3.90–3.98 (m, 6H), 2.84 (AB, JAB = 13.5 Hz, Δν =
29.7 Hz, 2H), 2.40 (s, 3 H), 2.00–2.12 (m, 2 H), 1.63–1.72 (m,
2 H); 13C NMR (75 MHz, CDCl3) δ 199.2, 142.0, 139.7, 137.8,
130.0, 124.1, 114.6, 109.1, 69.0, 64.9, 51.8, 37.0, 27.5, 21.4; IR
2922, 1708, 1641, 1494, 1359, 1306, 1085, 1035, 950, 911,
809 cm−1; HRMS ES m/z (M + Li)+ calcd for C17H22LiO4S
329.1394, found 329.1385.
1H), 4.57–4.68 (m, 1H), 2.90 (AB of ABX, JAB = 13.5, JAX
=
9.5 Hz, JBX = 2.7 Hz, Δν = 86.24 Hz, 2H), 2.64–2.70 (m, 2H),
2.45–2.56 (m, 2 H), 2.43 (s, 3 H), 2.26–2.36 (m, 2 H); 13C
NMR (75 MHz, CDCl3) δ 209.0, 141.6, 136.6, 130.1, 123.9,
123.9, 115.5, 65.8, 63.4, 48.6, 42.6, 27.3, 21.4; IR 3361, 2907,
1710, 1641, 1494, 1376, 1049, 1038, 905, 808 cm−1; HRMS ES
m/z (M + Na)+ calcd for C15H20NaO3S 303.1025, found
303.0989.
Synthesis of (2S,4S)-7-(4-methoxybenzyloxy)-1-((R)-p-tolyl-
sulfinyl)octane-2,4-diol 12. Diethylmethoxy borane (4 mL, 1.0
M in THF, 4 mmol) was added dropwise to crude hydroxyketone
(vide supra) (874 mg, 3.12 mmol) in 40 mL of THF/MeOH
(4/1) at −78 °C. The resulting mixture was stirred for 20 min, prior
to the addition of sodium borohydride (138 mg, 4.06 mmol).
The reaction was stirred for 4 h at −78 °C and was quenched
with 38 mL of acetic acid, warmed up to room temperature,
diluted with EtOAc (50 mL) and treated with a saturated
NaHCO3 solution up to pH = 6. The aqueous phase was
extracted with EtOAc (3 × 100 mL) and the combined organic
layers were washed with brine (100 mL), dried over MgSO4,
filtered and concentrated under reduced pressure. The residue
was taken up in MeOH, heated and concentrated in vacuo. This
procedure was repeated four times. The residue was purified by
flash column chromatography on silica gel (EtOAc/cyclohexane:
6/4) affording the diol 12 as a white solid (704 mg, 2.49 mmol,
80% over two steps): m.p. 110–114 °C; [α]2D5 +230.3° (c = 1.00
in CHCl3), Rf 0.33 (EtOAc/cyclohexane: 4/1); 1H NMR
(300 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.35 (d, J =
8.1 Hz, 2H), 5.71–5.88 (m, 1H), 5.01 (dd, J = 17.3, J = 1.7,
1H), 4.95 (d, J = 10.7 Hz, 1H), 4.38–4.55 (m, 1H), 3.81–3.97
Synthesis of (S)-1-(2-but-3-enyl-1,3-dioxolan-2-yl)-3-((R)-p-
tolylsulfinyl)propan-2-ol 11. Dibal-H (17 mL, 1.0 M in toluene,
17 mmol) was added dropwise to β-ketosulfoxide (vide supra)
(2.2 g, 6.83 mmol) dissolved in 100 mL of THF cooled at
−78 °C. The resulting solution was stirred for 2 h at −78 °C,
quenched with 20 mL of MeOH, diluted with 65 mL of EtOAc,
hydrolyzed with a saturated sodium-potassium tartrate solution
(65 mL) and stirred overnight. The aqueous phase was extracted
with EtOAc (3 × 100 mL) and the combined organic layers were
washed with brine, dried over MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel (EtOAc/cyclohexane: 1/1
→ 6/4) affording the β-hydroxysulfoxide 11 as a white solid
(2.19 g, 6.75 mmol, 99%): [α]2D5 +206.7° (c = 1.00 in CHCl3);
(m, 1H), 3.61 (s broad, 2 H), 2.87 (ABX, JAB = 13.2 Hz, JAX
9.6 Hz, JBX = 1.8 Hz, Δν = 116.3 Hz, 2H), 2.42 (s, 3 H),
=
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2.02–2.24 (m, 2 H), 1.41–1.75 (m, 4 H); 13C NMR (75 MHz,
CDCl3) δ 141.7, 139.4, 138.3, 130.1, 124.0, 114.9, 71.3, 67.4,
62.2, 42.7, 36.9, 29.6, 21.4; IR 3284, 2907, 1641, 1494, 1450,
1318, 1105, 1084, 1034, 910, 810 cm−1; HRMS ES m/z
(M + Li)+ calcd for C15H22LiO3S 289.1445, found 289.1407.
solvents were removed under reduced pressure. The aqueous
layer was extracted 3 times with EtOAc and the combined
organic layers were washed with brine, dried over Na2SO4,
filtered and concentrated under reduced pressure to give the
crude acid, which was used for the next step without purification.
To a solution of the crude acid in 4 mL of CH2Cl2 was added
portionwise carbonyldiimidazole (184 mg, 1.14 mmol). The
reaction mixture was stirred for 1 h at room temperature, prior to
the addition of N,O-dimethylhydroxylamine hydrochloride
(110 mg, 1.13 mmol). The reaction mixture was stirred overnight
at room temperature, filtered to remove insoluble materials and
concentrated under reduced pressure. Purification of the residue
by flash column chromatography on silica gel (EtOAc/cyclo-
hexane: 20/80) gave the amide 14 as a colorless oil (146.7 mg,
0.57 mmol, 76%): [α]D25 −24.1° (c = 0.86 in CHCl3); Rf 0.4
(EtOAc/cyclohexane: 1/1); 1H NMR (300 MHz, CDCl3)
δ 5.71–5.88 (m, 1H), 4.91–5.07 (m, 2H), 4.82 (d, J = 10.2 Hz,
1 H), 3.84–3.97 (m, 1H), 3.73 (s, 3H), 3.19 (s, 3 H), 2.03–2.24
(m, 2 H), 1.49–1.87 (m, 4H), 1.47 (s, 3 H), 1.44 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 170.9, 138.0, 114.8, 99.2, 67.8, 67.0,
61.6, 35.2, 32.3, 32.0, 30.0, 29.0, 19.4; IR 2992, 2937, 1671,
Synthesis of (4S,6S)-4-(3-(4-methoxybenzyloxy)butyl-2,2-
dimethyl-6(R)-p-tolylsulfinylmethyl)-1,3-dioxane. 2,2-Dimethoxy-
propane (4.5 mL, 36.7 mmol) and PPTS (109 mg, 433 μmol)
were added to diol 12 (608 mg, 1.45 mmol) in 14 mL of acetone
at room temperature. The reaction was stirred for 16 h, hydro-
lyzed with 10 mL of a saturated NaHCO3 solution and poured in
30 mL of EtOAc. The aqueous layer was extracted with EtOAc
(3 × 20 mL) and the combined organic layers were washed with
brine (30 mL), dried over Na2SO4, filtered and concentrated
under reduced pressure. Purification of the residue by flash
column chromatography on silica gel (EtOAc/cyclohexane: 2/1)
gave the acetal as a solid (352 mg, 1.09 mmol, 95%): m.
p. 59–61 °C; [α]2D5 +204.7° (c = 0.51 in CHCl3); Rf 0.76
1
(EtOAc/cyclohexane: 4/1); H NMR (300 MHz, CDCl3) δ 7.54
(d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 5.72–5.87 (m,
1H), 4.93–5.06 (m, 2 H), 4.42–4.57 (m, 1H), 3.85–3.97 (m, 1H),
2.70–2.86 (m, 2 H), 2.41 (s, 3 H), 2.01–2.25 (m, 2 H), 1.52 (s, 3
H), 1.45–1.70 (m, 2 H), 1.44 (s, 3 H), 1.17–1.38 (m, 2 H); 13C
NMR (75 MHz, CDCl3) δ 141.3, 138.0, 130.0, 123.8, 114.8,
99.2, 67.9, 65.0, 63.5, 36.4, 35.2, 30.0, 29.0, 21.3, 21.3, 19.8;
IR 2993, 2937, 1638, 1494, 1436, 1376, 1263, 1195, 1170,
1053, 1033, 807 cm−1; HRMS ES m/z (M + Li)+ calcd for
C18H16LiO3S 329.1758, found 329.1711.
1642, 1440, 1380, 1258, 1199, 1165, 1115, 972, 912 cm−1
;
HRMS ES m/z (M + Li)+ calcd for C13H23LiO4 264.1782, found
264.1768.
Synthesis of (4S,5S)-5-(benzyloxy)-2–8-(tert-butyldiphenylsilyl-
oxy)oct-1-en-4-ol 15. To a solution of aldehyde 8 (460 mg,
1.03 mmol) in 8 mL of CH2Cl2 was added dropwise at −78 °C a
solution of TiCl4 (1.03 mL, 1.0 M in CH2Cl2, 1.03 mmol), fol-
lowed by the dropwise addition of 2-bromo-3-(trimethylsilyl)
propene (199 mg, 1.03 mmol). The reaction mixture was stirred
for 2 h 30 min at −78 °C, 30 min at 0 °C and hydrolyzed with
an aqueous saturated solution of NH4Cl (8 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 10 mL) and the combined
organic layers were washed with brine (10 mL), dried over
Na2SO4, filtered and concentrated in vacuo. The crude material
was purified by flash column chromatography on silica gel
(EtOAc/cyclohexane: 1/6) to give the alcohol 15 (495 mg,
0.87 mmol, 85%) as a colourless oil as the favoured diastereomer
(8.5/1): [α]2D5 +7.6° (c = 1.10 in CHCl3); Rf 0.48 (EtOAc/cyclo-
hexane: 1/5); 1H NMR (300 MHz, CDCl3) δ 7.67–7.71 (m, 4H),
7.28–7.47 (m, 11H), 5.63 (d, J = 1.6 Hz, 1H), 5.50 (d, J = 1.6
Hz, 1H), 4.57 (AB, JAB = 11.4 Hz, Δν = 47.7 Hz, 2H),
3.93–3.98 (X of ABX, m, 1H), 3.71 (t, J = 5.9 Hz, 2H), 3.39 (dt
as q, J = 5.2 Hz, 1H), 2.51–2.68 (AB of ABX, m, 2H), 2.09 (s,
br., 1H), 1.59–1.87 (m, 4H), 1.08 (s, 9 H); 13C NMR (75 MHz,
CDCl3) δ 138.1, 135.6, 133.9, 130.7, 129.6, 128.5, 127.9, 127.8,
127.6, 119.2, 80.2, 72.0, 70.1, 63.8, 45.5, 28.2, 26.9, 26.2, 19.2;
IR 3461, 2931, 2858, 1472, 1455, 1428, 1390, 1207, 1105,
1088, 1070, 1028, 998, 938, 889, 797, 738, 699 cm−1; HRMS
ES m/z (M + Li)+ calcd for C31H39BrLiO3Si 573.2007, found
573.1943.
Synthesis of (4S,6S)-6-(3-(4-methoxybenzyloxy)butyl)-2,2-
dimethyl-1,3-dioxane-4-carbaldehyde
13. 2,4,6-Collidine
(0.72 mL, 5.54 mmol) and trifluoroacetic anhydride (1.2 mL,
8.63 mmol) were added dropwise subsequently to a solution of
sulfoxide (vide supra) (568 mg, 1.76 mmol) in 20 mL of MeCN
cooled at 0 °C. The reaction mixture was stirred for 45 min,
prior to the addition of 20 mL of a saturated NaHCO3 solution,
warmed to room temperature and stirred for 1 h 30 min. The
aqueous layer was extracted with EtOAc (3 × 100 mL) and the
combined organic layers were washed with brine (30 mL), dried
over Na2SO4, filtered and concentrated under reduced pressure.
Purification of the residue by flash column chromatography on
silica gel (EtOAc/cyclohexane: 5/95 → 20/80) gave the aldehyde
13 as a colorless oil (325 mg, 1.58 mmol, 90%): [α]2D5 −37.9° (c
1
= 0.33 in CHCl3); Rf 0.37 (EtOAc/cyclohexane: 1/3); H NMR
(300 MHz, CDCl3) δ 9.59 (s, 1H), 5.72–5.88 (m, 1H),
4.93–5.09 (m, 2H), 4.28 (dd, J = 12.3 Hz, 3.0 Hz, 1H),
3.53–4.00 (m, 1H), 2.03–2.25 (m, 2H), 1.49–1.68 (m, 2H), 1.47
(s, 3H), 1.46 (s, 3H), 1.31 (q, J = 12.0 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 201.3, 137.9, 115.0, 99.1, 74.1, 67.5, 35.2,
31.0, 29.8, 28.9, 19.5; IR: 2993, 2927, 1739, 1641, 1435, 1380,
1267, 1201, 1111, 911 cm−1; HRMS ES m/z (M + Li)+ calcd for
C11H18LiO3 205.1411, found 205.1395.
Synthesis of (4S,6S)-6-(but-3-enyl)-N-methoxy-N,2,2-trimethyl-
1,3-dioxane-4-carboxamide 14. To aldehyde 13 (148 mg,
0.75 mmol) in 14 mL of t-BuOH and 14 mL of water was added
subsequently KH2PO4 (605 mg, 4.45 mmol), 2-methyl-2-butene
(3.92 g, 6.4 mL, 56 mmol) and NaClO2 (227 mg, 2.51 mmol).
The reaction mixture was stirred for 5 h 30 min and organic
Synthesis of (5S,6S)-6-(benzyloxy)-5-(2-bromoallyl)-2,2,3,312,
12-hexamethyl-11,11-diphenyl-4,10-dioxa-3,11-disilatridecane 16.
A solution of alcohol 15 (300 mg, 532 μmol) in 3 mL of DMF
was treated subsequently with imidazole (72 mg, 1.06 mmol),
N,N-dimethylaminopyridine (2 mg, 16.4 μmol) and TBSCl
(120 mg, 798 mmol) at room temperature. After 16 h the
9424 | Org. Biomol. Chem., 2012, 10, 9418–9428
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reaction mixture was poured on diethyl ether/H2O (1/1) (20 mL).
The organic layer was washed with distilled water (3 × 10 mL).
The aqueous layer was extracted with Et2O (3 × 20 mL) and the
combined organic layers were washed with brine (10 mL), dried
over Na2SO4, filtered and concentrated under reduced pressure.
Purification of the residue by flash column chromatography on
silica gel (EtOAc/cyclohexane: 1/40) afforded the silylether 16
(347 mg, 0.51, 96%) as a colorless oil: [α]2D5 −16.5° (c = 1.00 in
CHCl3); Rf: 0.46 (EtOAc/cyclohexane: 1/40); 1H NMR
(300 MHz, CDCl3) δ 7.67–7.70 (m, 4H), 7.67–7.70 (m, 4H),
7.27–7.46 (m, 11H), 5.61 (s, 1H), 5.45 (d, J = 1.2 Hz, 1H), 4.57
(AB, JAB = 11.5 Hz, Δν = 44.4 Hz, 2H), 4.18–4.23 (X of ABX,
m, 1H), 3.62–3.76 (m, 2H), 3.34–3.39 (m, 1H), 2.29–2.75 (AB
of ABX, m, 2H), 1.26–1.88 (m, 4H), 1.07 (s, 9H), 0.87 (s, 9H),
0.07 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.5,
135.6, 134.1, 132.5, 129.5, 128.3, 128.0, 127.6, 127.6, 119.2,
81.3, 72.1, 69.3, 64.2, 43.7, 29.9, 26.9, 25.8, 25.1, 19.2, 18.0,
−4.5, −4.5; IR 2954, 2929, 2893, 2857, 1472, 1463, 1428,
1389, 1361, 1251, 1091, 1028, 1006, 957, 936, 885, 826, 810,
776, 738, 699 cm−1; HRMS ES m/z (M + Li)+ calcd for
C37H53BrLiO3Si2 687.2871, found 687.2845.
trichloracetimidate‡ (1.53 g, 5.745 mmol) and Yb(OTf)3·H2O
(124 mg, 0.20 mmol). The resulting mixture was stirred for 16 h
at room temperature and hydrolyzed with 15 mL of distilled
water. The aqueous layer was extracted with EtOAc (3 × 15 mL)
and the combined organic layers were washed with brine
(15 mL), dried over Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel (EtOAc/cyclohexane: 1/1) to give
the protected alcohol 22 as a yellow oil (2.01 g, 3.41 mmol,
80%): [α]2D5 +55.73° (c = 1.50 in CHCl3); Rf 0.29 (EtOAc/cyclo-
1
hexane: 1/2); H NMR (300 MHz, CDCl3) δ 6.7–7.6 (m, 18H),
4.52 (AB, JAB = 8.7 Hz, Δν = 8.95 Hz, 2H), 3.97 (m, 1H), 3.71
(s, 3H), 3.56 (t, J = 6.3 Hz, 2H), 2.76 (m, 2H), 2.32 (s, 3H),
1.40–1.70 (m, 4H), 0.95 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
159.4, 141.6, 141.3, 135.5, 133.9, 130.2, 130.0, 129.7, 129.6,
127.6, 123.8, 113.9, 72.9, 72.0, 64.6, 63.6, 55.3, 30.2, 27.7,
26.9, 21.4, 19.20; IR: 2931, 2857, 1726, 1612, 1587, 1513,
1494, 1463, 1427, 1390, 1359, 1302, 1246, 1174, 1109, 1085,
1033, 1013, 937, 821, 808, 741, 701, 687 cm−1; HRMS ES m/z
(M + Na)+ calcd for C36H44NaO4SSi2 623.262, found 623.262.
Synthesis of (S)-5-(tert-butyldiphenylsilyloxy)-2-(4-methoxy-
benzyloxy)-pentanal 20. To a solution of sulfoxide 19 (950 mg,
1.62 mmol) in 16 mL of MeCN cooled at 0 °C was added drop-
wise subsequently 2,4,6-collidine (537 mg, 0.6 mL, 4.88 mmol)
and trifluoroacetic anhydride (1.2 mL, 8.1 mmol). The reaction
mixture was stirred for 30 min, prior to the addition of 65 mL of
a saturated solution of NaHCO3, warmed to room temperature
and stirred for 1 h. The aqueous layer was extracted with EtOAc
(3 × 50 mL) and the combined organic layers were washed with
brine (50 mL), dried over Na2SO4, filtered and concentrated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel (EtOAc/cyclohexane: 1/9)
to give the aldehyde 20 (683 mg, 1.42 mmol, 88%) as a brown
oil: [α]2D5 −19.6° (c = 1.00 in CHCl3), Rf 0.21 (EtOAc/cyclo-
hexane: 1/3); 1H NMR (300 MHz, CDCl3) δ 9.65 (d, J = 2.1 Hz,
1H), 6.8–7.7 (m, 14H), 4.50 (AB, JAB = 9 Hz; Δν = 34.15 Hz,
2H), 3.80 (s, 3H), 3.70 (m, 1H), 3.64 (t, J = 6 Hz, 2H),
1.57–1.98 (m, 4H), 1.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
203.7, 159.5, 135.6, 133.8, 129.7, 129.6, 129.4, 127.5, 113.9,
82.9, 72.1, 63.2, 55.3, 27.7, 26.9, 26.4, 19.2; IR: 3071, 2931,
2857, 1732, 1612, 1587, 1513, 1471, 1463, 1427, 1389, 1373,
1361, 1302, 1246, 1173, 1106, 1088, 1034, 1007, 997, 937, 821,
741, 700, 687 cm−1; HRMS ES m/z (M + Na)+ calcd for
C29H36NaO4Si 499.228, found 499.225.
Synthesis of (4S,5S)-5-(benzyloxy)-1-((4S,6S)-6-(but-3-en-1-yl)-2,
2-dimethyl-1,3-dioxan-4-yl)-4-((tert-butyldimethylsilyl)oxy)-8-((tert-
butyldiphenylsilyl)oxy)-2-methyleneoctan-1-one 17. To a solution
of vinyl bromide 16 (243 mg, 0.36 mmol) in 3.5 mL of Et2O
cooled at −78 °C was added dropwise t-BuLi (0.46 mL, 1.7 M
in pentane, 0.78 mmol). The reaction mixture was stirred for
40 min at −78 °C and a solution of amide 14 (50 mg,
0.19 mmol) in 2.5 mL of Et2O was added via a cannula. The
temperature was gradually increased until 0 °C during 3 h and
the reaction mixture was quenched with an aqueous saturated
solution of NH4Cl. The mixture was extracted 3 times with Et2O
and the combined organic layers were washed with brine, dried
over Na2SO4, filtered and concentrated in vacuo. The crude
material was purified by flash column chromatography on silica
gel (EtOAc/cyclohexane: 1/30) yielding the coupling compound
17 (106 mg, 0.13 mmol, 70%) as a colourless oil: [α]2D5 −21.6°
(c = 1.0 in CHCl3); Rf 0.65 (EtOAc/cyclohexane: 1/6); 1H NMR
(300 MHz, CDCl3) δ 7.64–7.69 (m, 5H), 7.28–7.44 (m, 10H),
6.25 (d, J = 0.6 Hz, 1H), 5.90 (s, 1H), 5.71–5.89 (m, 1H),
4.94–5.08 (m, 2H), 4.87 (dd, J = 10.8 Hz, J = 3.6 Hz, 1H), 4.59
(AB, JAB = 11.4 Hz, Δν = 79.6 Hz, 2H), 3.98–4.06 (m, 1H),
3.82–3.97. (m, 1H), 3.55–3.76 (m, 2H), 3.28–3.36 (m, 1H), 2.83
(dd, J = 12.9 Hz, J = 2.7 Hz, 1H), 2.05–2.24 (m, 3H), 1.75–1.87
(m, 2H), 1.50–1.71 (m, 6H), 1.49 (s, 3H), 1.45 (s, 3H), 1.05 (s,
9H), 0.83 (s, 9H), −0.07 (s, 3H), −0.09 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 198.1, 143.2, 138.8, 138.1, 135.6, 134.1,
129.6, 129.5, 128.3, 128.0, 127.55, 127.5, 114.9, 99.2, 81.5,
71.6, 71.5, 70.3, 67.9, 64.3, 35.3, 34.2, 33.1, 30.0, 29.99, 29.0,
26.9, 25.9, 24.7, 19.3, 19.2, 17.9, −4.4; IR 2929, 2856, 1683,
1641, 1380, 1255, 1201, 1106, 1085, 936, 826, 775, 738,
700 cm−1; HRMS ES m/z (M + Li)+ calcd for C48H70LiO6Si2
805.4866, found 805.4823.
Synthesis of (4S,5S)-2-bromo-8-(tert-butyldiphenylsilyloxy)oct-
1-ene-4,5-diol 21. To a solution of aldehyde 20 (253 mg,
0.53 mmol) in 4 mL of CH2Cl2 was added dropwise at −78 °C a
solution of TiCl4 (0.5 mL, 1.0 M in CH2Cl2, 0.53 mmol), fol-
lowed by the dropwise addition of 2-bromo-3-(trimethylsilyl)
propene (100 mg, 0.53 mmol). The reaction mixture was stirred
for 3 h at −78 °C and hydrolyzed with a saturated solution of
NH4Cl (4 mL). The aqueous layer was extracted with CH2Cl2
(3 × 5 mL) and the combined organic layers were washed with
brine (5 mL), dried over Na2SO4, filtered and concentrated
Synthesis of tert-butyl((S)-4-(4-methoxybenzyloxy)-5-((R)-p-
tolylsulfinyl)pentyloxy)-diphenylsilane 19. To
β-hydroxysulfoxide 6 (1.85 g, 3.83 mmol) in 20 mL of THF at
room temperature was added methoxybenzyl-
a solution of
‡J. E. Audis, L. Boisvert, A. D. Patten, A. Villalobos, S. J. Danishefsky,
J. Org. Chem., 1989, 54, 3738.
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in vacuo. The crude material was purified by flash column
chromatography on silica gel (EtOAc/cyclohexane: 1/6) giving
the diol 21 as a colorless oil as the only syn diastereomer
(215 mg, 0.45 mmol, 85%): [α]2D5 −3.23° (c = 1.07, CHCl3); Rf
0.53 (EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.25–7.55 (m,
10H), 5.59 (d, J = 1.08 Hz, 1H), 5.40 (d, J = 1.59 Hz, 1H), 3.66
(m, 1H), 3.59 (t, J = 3.27 Hz, 2H), 3.40 (m, 1H), 2.87 (m, 1H),
2.51 (m, 2H), 2.25 (m, 1H, OH), 1.45–1.68 (m, 4H), 0.93 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 135.6, 133.5, 130.6, 129.8,
127.7, 119.6, 72.9, 71.7, 64.2, 46.0, 31.0, 28.7, 26.9, 19.2; IR:
3397, 2930, 2856, 1738, 1631, 1472, 1427, 1389, 1245, 1106,
889, 822, 739, 700, 687 cm−1; HRMS ES m/z (M + Na)+ calcd
for C24H33BrNaO3Si 499.127, found 499.128.
(m, 2H), 1.49 (s, 3H), 1.44 (s, 3H), 1.35 (s, 3H), 1.34 (s 3H),
1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.1, 142.5, 138.1,
135.6, 134.0, 129.5, 128.4, 127.6, 115.0, 108.1, 99.2, 80.6, 78.9,
71.4, 67.9, 63.7, 35.3, 35.1, 32.9, 30.2, 30.0, 29.0, 27.3, 27.3,
26.9, 26.9, 19.4, 19.2; IR: 3072, 2986, 2931, 2858, 1731, 1684,
1641, 1589, 1428, 1378, 1252, 1200, 1164, 1109, 1088, 996,
962, 938, 912, 865, 822, 740 710, 687 cm−1; HRMS ES m/z
(M + Na)+ calcd for C38H54NaO6Si 657.358, found 657.360.
Synthesis of (R)-1-((4S,6S)-6-(but-3-enyl)-2,2-dimethyl-1,3-
dioxan-4-yl)-2-(((4R,5R)-5-(3-(tert-butyldiphenylsilyloxy)propyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)methyl)prop-2-en-1-ol 24
Way A: stereoselective reduction of enone 23. To a solution of
enone 23 (173 mg, 0.273 mmol) in 10 mL of Et2O cooled at
0 °C was added CeCl3 (20 mg, 0.082 mmol) and dropwise a
freshly prepared solution of Zn(BH4)2 (1.15 mL. 0.183 M in
Et2O, 0.210 mmol). The mixture was stirred for 20 min at 0 °C
and quenched with 10 mL of an NH4Cl saturated solution. The
mixture was extracted 3 times with Et2O and the combined
organic layers were dried over Na2SO4, filtered and concentrated
in vacuo. The crude material was purified by flash column
chromatography on silica gel (EtOAc/cyclohexane: 1/15 then
1/6) giving the alcohol (69 mg, 0.11 mmol, 40%) as a colorless
oil as the trans diastereomer 24 only.
Synthesis of (3-((4S,5S)-5-(2-bromoallyl)-2,2-dimethyl-1,3-dioxolan-
4-yl)propoxy)(tert-butyl)diphenylsilane 22. To a solution of diol
21 (120 mg, 0.25 mmol) in 3 mL of acetone and 0.9 mL of 2,2-
dimethoxypropane was added PPTS (22 mg, 0.093 mmol) at
room temperature. The reaction mixture was stirred for 16 h,
hydrolyzed with 2 mL of a saturated solution of NaHCO3 and
poured into 30 mL of EtOAc. The aqueous layer was extracted
with EtOAc (3 × 6 mL) and the combined organic layers were
washed with brine (5 mL), dried over Na2SO4, filtered and con-
centrated in vacuo. Purification of the residue by flash column
chromatography on silica gel (EtOAc/cyclohexane: 2/98) gave
the acetal 22 (127 mg, 0.25 mmol, 98%) as a colorless oil: [α]D25
−12.37° (c = 1.03, CHCl3); Rf 0.81 (EtOAc/cyclohexane: 1/4);
1H NMR (300 MHz, CDCl3) δ 7.26–7.68 (m, 10H), 5.72 (d, J =
0.9 Hz, 1H), 5.50 (d, J = 1.5 Hz, 1H), 3.95 (td, J = 7.68 Hz, J =
4.68 Hz, 1H), 3.7 (m, 3H), 2.65 (AB (ABX), JAB = 15 Hz, JAX
= 7.5 Hz, JBX = 4.5 Hz, Δν = 43.88 Hz, 2H), 1.5–1.8 (m, 4H),
1.39 (s, 3H), 1.37 (s, 3H), 1.05 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 135.6, 134.0, 129.6, 129.4, 127.6, 119.1, 108.5, 80.4,
78.1, 63.6, 45.3, 29.3, 29.0, 27.3, 27.2, 26.9, 19.2; HRMS ES
m/z (M + Na)+ calcd for C27H37BrNaO3Si 539.159, found
539.159.
Way B: stereoselective addition of vinyl bromide 22 to aldehyde
13 in the presence of magnesium bromide. Dibromomethane
(1.25 g, 6.65 mmol) in 1.7 mL of distillated toluene was added
dropwise over 30 min in a solution of magnesium (173 mg,
7.11 mmol) in 5 mL of distillated Et2O at RT. The reaction was
stirred for 30 min at RT and was clarified for 1 h 30 min (solu-
tion supposed at 1 M).
t-BuLi (1.7 M in hexane, 270 μL, 0.457 mmol) was added
dropwise in a solution of vinyl bromide 22 (107.5 mg,
0.21 mmol) in 3 mL of THF at −78 °C. The reaction was stirred
for 30 min at −78 °C and turned to deep yellow. MgBr2 solution
(1 M, 210 μL, 0.210 mmol) was added at −78 °C, and the reac-
tion was stirred for 30 min at −78 °C. Aldehyde 13 (33 mg,
0.166 mmol) in 2 mL of dichloromethane was added via a
cannula. The reaction was stirred for 1 h 30 min at −78 °C and
allowed to warm to RT.
Synthesis of 1-((4S,6S)-6-(but-3-enyl)-2,2-dimethyl-1,3-dioxan-
4-yl)-2-(((4R,5R)-5-(3-(tert-butyldiphenylsilyloxy)propyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)methyl)prop-2-en-1-one 23. To a sol-
ution of vinyl bromide 22 (600 mg, 1.16 mmol) in 15 mL of
Et2O cooled at −78 °C was added dropwise t-BuLi (1.36 mL,
1.7 M in pentane, 2.32 mmol). The reaction mixture was stirred
for 40 min at −78 °C and a solution of amide 14 (150 mg,
0.58 mmol) in 15 mL of Et2O was added via a cannula. The
temperature was gradually increased until 0 °C during 3 h and
the reaction mixture was quenched with an aqueous saturated
solution of NH4Cl. The mixture was extracted 3 times with Et2O
and the combined organic layers were washed with brine, dried
over Na2SO4, filtered and concentrated in vacuo. The crude
material was purified by flash column chromatography on silica
gel (EtOAc/cyclohexane: 1/30) yielding the coupling compound
23 (246 mg, 0.40 mmol, 70%) as a colorless oil: [α]2D5 −9.41° (c
The reaction was hydrolyzed with NH4Cl solution, aqueous
phase extracted three times with DCM. Organic phases were
washed with brine, dried over Na2SO4, filtrated and evaporated.
Diastereoisomers (5.5/1) were separated by flash chromatography
(EtOAc/cyclohexane 1/6), giving the alcohol 24 (58 mg,
0.091 mmol, 55%) as a colorless oil.
Way C: stereoselective addition of vinyl bromide 22 to aldehyde
13. t-BuLi (1.7 M in hexane, 173 μL, 0.295 mmol) was added
dropwise in a solution of vinyl bromide 22 (70 mg, 0.136 mmol)
in 2 mL of distillated Et2O at −78 °C. The reaction was stirred
for 45 min at −78 °C, the solution turned to deep yellow. Alde-
hyde 13 (14 mg, 0.067 mmol) in 2 mL of Et2O was added via a
cannula to the reaction, and the reaction was stirred for 2 h at
−78 °C. The reaction was allowed to warm to RT and was hydro-
lyzed with NH4Cl solution. The aqueous phase was extracted
three times with Et2O, organic phases were washed with brine,
dried over Na2SO4, filtrated, evaporated. The two diastereoi-
somers (6/1) were separated by flash chromatography (EtOAc/
1
= 0.505 in CHCl3); Rf 0.65 (EtOAc/cyclohexane: 1/6); H NMR
(300 MHz, CDCl3) δ 7.3–7.7 (m, 10H), 6.24 (s, 1H), 6.01 (s,
3
1H), 5.79 (ddt, Jtrans = 16.86 Hz, Jcis = 10.05 Hz, J = 6.6 Hz,
1H), 4.97 (m, 2H), 4.91 (dd, J = 11.64 Hz, J = 2.79 Hz, 1H),
3.75 (m, 1H), 3.45–3.7 (m, 4H), 2.45 (AB (ABX), JAB
=
22.5 Hz, JAX = 2.7 Hz, JBX = 8.1 Hz, Δν = 88.95 Hz, 2H), 2.1
9426 | Org. Biomol. Chem., 2012, 10, 9418–9428
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cyclohexane 1/6), giving the alcohol 26 (27 mg, 0.042 mmol,
62%) as a colorless oil.
corresponding pivalate (16.5 mg, 0.022 mmol, 88%); [α]D25
−14.72° (c = 1.03, CHCl3); Rf 0.72 (EtOAc/cyclohexane 2/3);
1H NMR (300 MHz, CDCl3) δ 7.30–7.61 (m, 10H), 5.10 (d, J =
4.8 Hz, 1H), 5.05 (d, J = 3.3 Hz, 2H), 4.01 (m, 1H), 3.55–3.76
(m, 5H), 2.41–2.47 (m, 2H), 2.15–2.25 (m, 2H), 2.07 (s, 3H),
1.4 (m, 8H), 1.05–1.35 (m, 21H), 0.97 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 208.6, 177.0, 141.9, 135.5, 133.9, 129.5,
127.6, 114.3, 108.1, 98.6, 80.8, 79.3, 76.9, 69.3, 67.7, 63.7,
39.0, 38.7, 36.4, 31.9, 30.0, 29.9, 29.7, 29.1, 27.4, 27.3, 27.2,
26.9, 19.6, 19.2; HRMS ES m/z (M + Na)+ calcd for
C43H64NaO8Si 759.424, found 759.426.
Major diastereoisomer [α]2D5 −22.71° (c = 1.035 in CHCl3), Rf
1
0.28 (EtOAc/cyclohexane: 1/6); H NMR (300 MHz, CDCl3) δ
7.30–7.70 (m, 10H), 5.79 (ddt, Jtrans = 17.01 Hz, Jcis = 10.17 Hz,
3J = 6.75 Hz, 1H), 5.21 (s, 1H), 5.07 (s, 1H), 4.97 (m, 2H), 4.05
(m, 1H), 3.95 (m, 1H), 3.80 (m, 1H), 3.6–3.75 (m, 4H), 3.15 (m,
1H), 2.27 (d, J = 5.7 Hz, 2H), 2.12 (m, 2H), 1.1–18 (m, 20H),
1.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 144.1, 138.3, 135.6,
134.0, 129.6, 127.6, 115.5, 114.7, 108.3, 98.6, 81.0, 80.7, 76.6,
70.64, 68.0, 63.6, 35.8, 35.5, 31.1, 30.1, 29.2, 29.0, 28.8, 27.7,
27.2, 26.9, 19.8, 19.2; IR: 3473, 3072, 2988, 2930, 2857, 1741,
1641, 1472, 1462, 1428, 1378, 1239, 1199, 1165, 1109, 1089,
1047, 990, 909, 823, 740, 701, 687 cm−1; HRMS ES m/z
(M + Na)+ calcd for C38H56NaO6Si 659.374, found 659.378.
Synthesis of 4-((4S,6S)-6-((1R)-3-((4R,5R)-5-(3-((tert-butyldi-
phenylsilyl)oxy)propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-hydroxy-
2-methylpropyl)-2,2-dimethyl-1,3-dioxan-4-yl)butan-2-one 28.
Pd/C (4 mg, 10% WT) was added to a solution of 26 (32 mg,
0.05 mmol) in 5 mL of MeOH in an autoclave. The autoclave
was purged three times with H2 and the reaction was stirred over-
night over 80 bars of H2 at RT. The reaction was filtrated over
celite, concentrated and purified by flash chromatography
(EtOAc/hexane 1/4) affording the hydrogenated compound as a
mixture of two diastereoisomers 28 and 28′ (31 mg,
1
Minor diastereoisomer, Rf 0.24 (EtOAc/cyclohexane: 1/6); H
NMR (300 MHz, CDCl3) δ 7.30–7.70 (m, 10H), 5.79 (m, 1H),
5.10 (s, 1H), 5.03 (s, 1H), 4.97 (m, 2H), 4.25 (m, 1H), 3.6–3.95
(m, 6H), 3.15 (m, 1H), 2.10–2.32 (m, 4H), 1.1–1.8 (m, 20H),
1.05 (s, 3H).
Synthesis of 4-((4S,6S)-6-((R)-2-(((4R,5R)-5-(3-(tert-butyldi-
phenylsilyloxy)propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-
1-hydroxyallyl)-2,2-dimethyl-1,3-dioxan-4-yl)butan-2-one 26.
To a solution of alcohol 24 (20 mg, 0.030 mmol) in a mixture of
2 mL of dimethylacetamide and 0.7 mL of water was added
Cu(OAc)2 (13 mg, 0.065 mmol) and PdCl2 (3 mg, 0.016 mmol).
The flask was connected with a balloon of O2 and the reaction
mixture was stirred for 3 days at room temperature. The reaction
mixture was extracted 3 times with ethyl acetate and the com-
bined organic layers were washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The crude material
was purified by flash column chromatography on silica gel
(EtOAc/hexane 1/4), giving the methyl ketone 26 (16.6 mg,
0.025 mmol, 85%) as a colorless oil: [α]2D5 −21.03° (c = 0.98,
1
0.048 mmol, 99%): Rf 0.41–0.44 (EtOAc/cyclohexane 2/3); H
NMR (300 MHz, CDCl3) δ 7.36–7.68 (m, 10H), 3.5–3.95 (m),
3.31 (t, J = 6.16 Hz), 2.95 (m), 2.54 (m), 2.15 (s, 3H), 1.97 (m),
1.45–1.90 (m), 1.30–1.45 (m, 12H), 1.05 (s, 9H), 1.10 (d, J =
7.04 Hz, 3H), 0.91 (d, J = 6.76 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 208.6, 208.6, 135.5, 133.9, 129.5, 127.6, 108.1, 108.2,
98.4, 98.4, 81.0, 81.3, 78.3, 79.5, 77.2, 77.2, 69.1, 69.9, 67.9,
68.1, 63.5, 63.6, 39.1, 39.1, 34.8, 31.9, 32.3, 31.7, 30.3, 30.3,
30.1, 29.9, 29.0, 28.8, 28.9, 27.2, 27.3, 26.8, 19.6, 19.7, 19.2,
14.0, 16.2; HRMS ES m/z (M + Na) calcd for C38H58NaO7Si
677.391, found 677.384.
Compound 27 was really unstable and was consequently
directly reduced to 28 and 28′.
1
CHCl3); Rf 0.25 (EtOAc/cyclohexane 1/4); H NMR (300 MHz,
Synthesis of Paquette’s fragment 4-((4S,6S)-6-((1R)-1-((benzyl-
oxy)methoxy)-3-((4S,5S)-5-(3-hydroxypropyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)-2-methylpropyl)-2,2-dimethyl-1,3-dioxan-4-yl)-
butan-2-one. BOMCl (75%, 25 μL, 0.132 mmol) was added to
a solution of 32 (28 mg, 0.044 mmol), DIPEA (50 μL,
0.27 mmol) and Bn4NI (2 mg, 4.4 μmol) in CH2Cl2 (2 mL). The
reaction was stirred for four days at RT and then quenched with
water (2 mL). The aqueous phase was extracted three times with
CH2Cl2; the organic phases were washed with brine, dried over
Na2SO4, and evaporated giving 33, which was directly used for
the next step without further purification. TBAF (40 μL, 1 M,
0.040 mmol) was added to a solution of 33 (14 mg,
0.019 mmol) in THF (1 mL). The reaction was stirred for 6 h at
RT and quenched with brine. The aqueous phase was extracted
three times with EtOAc, and the organic phases were dried over
Na2SO4, filtrated, concentrated and purified by flash chromato-
graphy (EtOAc/hexane 1/6) affording Paquette et al.’s fragment
(15.3 mg, 0.028 mmol, 65%).
CDCl3) δ 7.26–7.68 (m, 10H), 5.21 (s, 1H, 17), 5.07 (s, 1H),
4.05 (d, J = 5.01 Hz, 1H), 3.95 (m, 1H), 3.80 (m, 1H), 3.6–3.75
(m, 4H), 2.52 (t, J = 2.47 Hz, 2H), 2.26 (d, J = 5.7 Hz, 2H),
2.13 (s, 3H), 1.5–1.9 (m, 6H), 1.2–1.45 (m, 14H), 1.05 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 208.6, 144.1, 135.6, 133.9,
129.6, 127.6, 115.6, 108.3, 98.6, 81.0, 80.7, 76.6, 70.6, 67.9,
63.6, 39.1, 35.8, 31.1, 30.3, 30.0, 29.9, 29.0, 28.8, 27.3, 27.2,
26.9, 19.8, 19.2; HRMS ES m/z (M + Na)+ calcd for
C38H56NaO6Si 659.374, found 659.378.
Synthesis of (R)-2-(((4S,5S)-5-(3-((tert-butyldiphenylsilyl)oxy)-
propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((4S,6S)-2,2-
dimethyl-6-(3-oxobutyl)-1,3-dioxan-4-yl)allyl pivalate. To a sol-
ution of 26 (16 mg, 0.025 mmol) and DMAP (1 mg,
0.009 mmol) in pyridine (2 mL) was added pivaloyl chloride
(5 μL, 0.038 mmol) at 0 °C. The reaction was stirred at 70 °C
for 24 h, and then cooled down to RT and MeOH (200 μL) was
added. The reaction was stirred for 1 h at RT and then concen-
trated under reduced pressure and diluted with EtOAc. The solu-
tion was washed respectively with 1 N HCl, a saturated solution
of NaHCO3, and water. The organic layer was dried over
Na2SO4, filtrated and evaporated. The crude was purified by
flash chromatography (EtOAc/hexane 1/6) affording the
Acknowledgements
We are grateful to the Centre National de la Recherche Scien-
tifique (CNRS), the Ministère de l’Education Nationale et de la
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9418–9428 | 9427

View Article Online
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a doctoral grant to N. R. and C. B.
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2
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