Directed studies towards the total synthesis of (+)-13-deoxytedanolide: Simple and convenient synthesis of the C8-C16 fragment

Article abstract of DOI:10.1039/c3ob40674a

A straightforward synthesis of the enantioenriched C8-C16 south part of (+)-13-deoxytedanolide has been reported. The strength of this approach relies on the preparation of similar functionalized fragments via the transformation of a unique dihydrofuran b

Full text of DOI:10.1039/c3ob40674a

Organic &
Biomolecular Chemistry
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PAPER
Directed studies towards the total synthesis of
+)-13-deoxytedanolide: simple and convenient
synthesis of the C8–C16 fragment†
(
Cite this: Org. Biomol. Chem., 2013, 11,
882
4
Sébastien Meiries, Alexandra Bartoli, Mélanie Decostanzi, Jean-Luc Parrain* and
Laurent Commeiras*
Received 4th April 2013,
Accepted 21st May 2013
A straightforward synthesis of the enantioenriched C8–C16 south part of (+)-13-deoxytedanolide has
been reported. The strength of this approach relies on the preparation of similar functionalized frag-
ments via the transformation of a unique dihydrofuran building block through a 1,2-metallate
rearrangement.
DOI: 10.1039/c3ob40674a
www.rsc.org/obc
Introduction
1
2
Tedanolides and candidaspongiolides (Fig. 1) are naturally
occurring marine macrolides that possess a unique architec-
tural complexity and display remarkable antitumor activity
against various cell lines. More precisely, (+)-13-deoxytedano-
lide 2, which is one of the three members of the tedanolides
family, was isolated by Fusetani et al. from the Japanese sea
1
b
sponge Mycale adhaerens. Interestingly, among all the teda-
nolide congeners, macrolactone 2 exhibited interesting biologi-
3
cal activity against P388 murine leukemia cells with an IC
9
=
0
5
4 pg mol− . Its cytotoxicity is thought to be related to the
1
inhibition of protein synthesis by competing with deacylated
4
tRNAs for E site (located in the eukaryotic ribosome) binding.
Fig. 1 Structures of tedanolides and candidaspongiolides.
It is worth noting that it is the first example of a macrolide to
inhibit the eukaryotic ribosome.
The unique architecture and biological properties of teda-
5
nolides have triggered considerable synthetic efforts and still
constitute a significant and attractive synthetic challenge,
given the numerous labile aldol units, the fragile trisubstituted
α-hydroxy-epoxide, the disubstituted (Z)-double bond and the
trisubstituted (E)-olefin encased in an 18-membered macrolide
framework, punctuated with up to 13 stereogenic centers.
Herein, to address this challenge, we described a straight-
forward and highly convergent strategy for the stereocontrolled
synthesis of C8–C16 fragment 6 of (+)-13-deoxytedanolide 2
(Scheme 1). Our convergent and simple approach is based on
Aix Marseille Université, CNRS, iSm2 UMR 7313, 13397 Marseille, France.
E-mail: jl.parrain@univ-amu.fr, laurent.commeiras@univ-amu.fr;
Fax: +33 4 91 28 91 87; Tel: +33 4 91 28 89 14, +33 4 91 28 89 26
†
Electronic supplementary information (ESI) available: Synthesis procedures,
1
13
H and C NMR spectra for all compounds. See DOI: 10.1039/c3ob40674a
Scheme 1 Retrosynthesis analysis.
4
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the preparation of two equally-functionalized homoallylic vinylcuprates generated with total control of the diastereo-
alcohols 10 and 11, which could be readily prepared from a selectivity can be quenched with various electrophiles to afford
similar 1,2-metallate rearrangement using both enantiomers diversely substituted double bonds. In the presence of
of the 3-methyl-2,3-dihydrofuran 12. The assembly of these Bu(Bu
3
Sn)CuLi,
LiCN,
2-lithio-4-methyl-4,5-dihydrofuran
two fragments via a nucleophilic addition followed by further enantiomers undergo this dyotropic rearrangement to give the
transformations should provide the C8–C16 fragment of 2.
4 4
corresponding vinyl cuprates. Hydrolysis (NH Cl–NH OH) or
alkylation (MeI trapping) of these last intermediates furnished
the desired functionalized homoallylic alcohols 10 (99%) and
1
1 (76%) respectively with total control of the (E)-geometry of
Results and discussion
the double bond.
The synthesis of homoallylic alcohols 10 and 11 requires the
Before coupling homoallylic alcohols together, several
preparation of the optically pure (R)- and (S)-3-methyl-2,3- classic organic transformations were necessary (Scheme 3).
dihydrofurans 12 (Scheme 2). After an overview of the methods First of all, vinyl stannane 10 was turned into the corres-
6
7
developed by the groups of Ardisson and Jamisson, Evan’s ponding vinyl iodide 17 with total retention of the configur-
oxazolidinone procedure appeared to be the best synthetic ation of the double bond, by simple treatment of 10 with a
1
3,14
path for the preparation of (S)-12 and (R)-12 and the further solution of iodine in diethyl ether (91%).
The primary
installment of the stereogenic centers in C10 and C14.
alcohol 17 was then protected as TBS silyl ether 8, in 94%
Starting from the known (S)-propionyl oxazolidinone yield, to furnish the first functionalized fragment. It must be
8
(
S)-13, the diastereoselective alkylation (performed on a >20 g noted that the iododestannylation reaction and the TBS protec-
scale) using allyl iodide furnished the desired oxazolidinone tion steps can be successfully inverted without a significant
9
(
S)-14 in good yield (82%) and in excellent dr (>20 : 1).
effect on the overall yield. In parallel, the alcohol 11 was trans-
Removal of the chiral auxiliary was performed with lithium formed into the corresponding vinyl iodide 18 (98% yield) and
borohydride to give, in 73% yield, the volatile alkenol (R)-15 the latter was smoothly oxidised with Dess–Martin periodi-
1
5
and the recovered oxazolinone which was successfully reused nane without any detectable epimerization at C10. Although
9
,10
in the sequence.
phine (PPh
) reductive treatment reliably provided the lactol column chromatography for characterization, it proved to be
R)-16 (56%) which was ultimately dehydrated under acidic sensitive to extensive manipulations. Therefore it was usually
conditions to yield the (R)-3-methyl-2,3-dihydrofuran (R)-12, in taken on crude to the next synthetic step.
Ozonolysis followed by triphenylphos- the obtained aldehyde 9 was successfully purified by flash
3
(
6
,11
a multi-gram scale (85%).
The same process was also
The assembly of fragments 9 (C8–C11) and 8 (C12–C15) was
employed to access the opposite (S)-enantiomer of the then accomplished via a nucleophilic addition reaction. The
dihydrofuran 12, starting this time from (R)-propionyl oxazoli- iodine–lithium exchange of 8 proceeded rapidly and cleanly at
dinone (R)-13. Dihydrofurans (R)-12 and (S)-12 were prepared −100 °C and the resulting intermediate vinyllithium 19 was
over 4 steps in 29% and 38% yields from (S)-13 and (R)-13 added to aldehyde 9 to furnish the desired alcohol 20 in a 3 : 1
respectively. With the two dihydrofuran enantiomers 12 in diastereoisomeric ratio in 71% yield. These conditions for this
hand, we proceeded to perform the 1,2-cuprate rearrange- temperamental addition step were crucial for optimal and
12
ment to access homoallylic alcohols 10 and 11. This one-step reproducible results. Whereas the addition of molecular sieves
process employing the pre-made Lipshutz reagent allows or the order of addition was quite negligible, the freshness of
the preparation of di- or tri-substituted functionalized the unstable aldehyde 9 appeared to be crucial for the success
double bonds via a dyotropic rearrangement. The intermediate of the coupling. The reaction was found to be extremely fast at
Scheme 2 Synthesis of enantiopure dihydrofurans and functionalized homoallylic alcohol.
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Scheme 3 Synthesis of a C8–C16 fragment.
−
100 °C but was generally warmed up to −78 °C for 1 h to
Conclusions
secure full conversion. The alcohol 20 was then smoothly oxi-
dized to the corresponding enone 21 with buffered Dess– In summary, we have accomplished an enantioselective syn-
Martin periodinane in excellent yield (98%) with no epimerisa- thesis of C8–C16 fragment 6 of (+)-13-deoxytedanolide 2. The
tion. The resulting α,β-unsaturated ketone 21 was then synthesis featured the preparation of two equally-functiona-
reduced to the corresponding ketone 22 with commercially lized homoallylic alcohols via a 1,2-metallate rearrangement
available Stryker’s reagent in 99% yield. Alternatively, double using both enantiomers of the 3-methyl-2,3-dihydrofuran 12.
bond reduction to 20 using Crabtree or Wilkinson’s catalysts This simple and convergent strategy should allow the synthesis
2
under H proved to be unsuccessful. At this stage, a large of analogues of the tedanolide family.
number of conditions were used to protect ketones 21 and 22
as acetals, dithianes or hydrazones. However, all our attempts
were unsuccessful as both ketones appeared to be surprisingly
unreactive under usual methods and decomposed under more
drastic conditions. Alternatively, ketone 22 was reduced with
Experimental section
General procedure
Dibal-H in good yield (71%) giving the desired alcohol 23 as a All reagents were obtained from commercial sources and used
separable 1 : 1 diastereoisomeric mixture. Our initial strategy as supplied unless otherwise stated. Anhydrous THF, Et O,
2
was to carry on the synthesis with the 1 : 1 diastereoisomeric toluene and CH Cl were obtained from an MBraun® SPS-800
2
2
mixture and ultimately oxidise the C11-alcohol to the corres- solvent purification system. Light petroleum refers to the frac-
ponding desired ketone present in tedanolides. However, for a tion of petrol ether that was distilled between 40 °C and 65 °C.
better clarity of characterization data, the reduction was The reaction mixtures were magnetically stirred and monitored
further optimised using diastereoselective Corey–Bakshi– by TLC, which were performed on Merck® 60F254 plates and
1
6
Shibata’s reduction.
achieved under 254 nm UV light, visualized with an aqueous
(R)- and (S)-Me-CBS reagents provided a 1 : 6 and 3 : 1 ratio solution of potassium permanganate or an ethanolic solution
of diastereoisomers in 65% and 99% yield respectively. Accord- of molybdophosphoric acid, followed by treatment with a heat
ing to Corey–Bakshi–Shibata’s reduction model, we can assume gun. Flash chromatography was performed with Merck®
that reduction reaction performed with the (R)-Me-CBS reagent Kieselgel 60 (230–400) mesh silica gel. NMR data were
would furnish mostly (11S)-23 while (11R)-23 would be obtained recorded on Bruker Avance 300 and 400 spectrometers in C D
6
6
using (S)-Me-CBS. At the end of the synthesis, vinyl iodide or CDCl and chemical shifts (δ) were given in ppm relative to
3
1
(
11R)-23 was turned quantitatively into the corresponding bis- the residual non-deuterated solvent signal for H NMR (C D :
6
6
TBS protected analogue 7. The primary TBS ether group of 7 7.16 ppm) (CDCl : 7.26 ppm) and relative to the deuterated
3
1
3
was then selectively cleaved under mild acidic conditions to solvent signal for
C NMR (C D : 128.06 ppm) (CDCl :
6 6 3
provide the primary alcohol 24 (99% yield). The latter was 77.16 ppm); coupling constants (J) are in Hertz, and the classi-
further oxidized (85%) and the aldehyde 25 was reacted with cal abbreviations are used to describe the signal multiplicity
methylmagnesium bromide to furnish the secondary alcohol 26 (s = singlet, d = doublet, t = triplet, sept = septet, m = multi-
(92%) as a 1 : 1.5 mixture of two diastereomers. Finally, a sub- plet, dd = doublet of doublets, dt = doublets of triplets, br =
sequent DMP oxidation afforded the desired C8–C16 fragment 6 broad, etc.). NMR spectra were assigned using information
as a single isomer in 91% yield over two steps.
ascertained from DEPT, COSY and HMQC experiments.
4
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9
Compound 14. To a stirred solution of oxazolidinone (S)-13 42 mmol), PTSA (16 mg, 0.084 mmol) and quinoline (2.27 mL)
(20.05 g, 86 mmol) in THF (240 mL) was added dropwise was heated from 160 to 245 °C. The distillated furan (bp =
NaHMDS (1.0 M in THF, 90 mL, 90 mmol) at −78 °C. The reac- 80–90 °C) was separated from water and filtered through a pad
tion mixture was allowed to stir for 1 h at −78 °C, then allyl of anhydrous Na SO to give, after further purification by dis-
iodide (11.8 mL, 129 mmol) was added. The mixture was tillation (T760 mmHg = 72 °C) over CaH , (R)-12 (3.04 g, 85%).
2
4
2
stirred at −78 °C for 3 h (until complete disappearance of start-
(S)-12 (3.72 g, 59% yield over two steps) was obtained using
ing material), then quenched at −78 °C with an aqueous satu- the same procedure starting from (S)-15 (7.55 g, 75 mmol).
1
rated NH Cl solution. The aqueous layer was extracted with
H NMR (400 MHz, CDCl ) δ 1.07 (3H, d, J = 6.8 Hz, CH ),
4
3
3
Et
drous MgSO
was purified by flash silica gel chromatography (light pet- CH), 6.29 (1H, t, J = 2.5 Hz, CH); C NMR (50 MHz, CDCl3)
roleum–Et O, 8 : 2) to give (S)-14 (18.42 g, 82% yield). δ 20.6 (CH ), 36.5 (CH), 76.7 (CH ), 106.3 (CH), 145.2 (CH).
R)-14 (5.19 g, 95% yield) was obtained using the same pro-
cedure starting from (R)-14 (4.88 g, 21 mmol).
2
O and the combined organic layers were dried over anhy- 2.98–3.07 (1H, m, CH), 3.85 (1H, dd, J = 8.8 and 6.8 Hz, CH
2
),
4
and concentrated under vacuum. The residue 4.37 (1H, dd, J = 9.8 and 8.8 Hz, CH
2
3
), 4.93 (1H, t, J = 2.5 Hz,
1
2
3
2
(
Compound 10. A solution of dihydrofuran (R)-12 (720 mg,
8.56 mmol) in anhydrous THF (8.8 mL) was cooled down to
= −39.0 (c 1, −60 °C and subjected to slow addition of t-BuLi (1.6 M in
1
9
19
D
(S)-14 [α]
D
= +38.0 (c 1, CHCl
3
); (R)-14 [α]
1
CHCl
3
); H NMR (300 MHz, CDCl ) δ 1.18 (3H, d, J = 6.8 Hz, pentane, 6.94 mL, 11.1 mmol). After 10 min at −60 °C, the
3
CH ), 2.19–2.28 (1H, m, CH ), 2.48–2.57 (1H, m, CH ), 2.69 reaction mixture was stirred at 0 °C for 50 min. In a different
3
2
2
(
3
1H, dd, J = 13.4 and 9.8 Hz, CH
.2 Hz, CH
CH ), 4.64–4.71 (1H, m, CH), 5.04–5.13 (2H, m, CH ), 5.76–5.89 being subjected to the slow addition of n-BuLi (2.5 M in
2
), 3.27 (1H, dd, J = 13.4 and flask, a solution of CuCN (1.53 g, 17.1 mmol) in anhydrous
), 3.36 (1H, m, J = 6.8 Hz, CH), 4.11–4.21 (2H, m, THF (49 mL) was prepared and cooled down to −78 °C before
2
2
2
1
3
(
7
(
m, 1H, CH), 7.20–7.35 (5H, m, CHAr); C NMR (CDCl
5 MHz) δ 16.5 (CH ), 37.2 (CH), 38.0 (CH ), 38.1 (CH ), 55.4 warm up to −60 °C, causing the CuCN to solubilize and
CH), 66.1 (CH ), 117.3 (CH ), 127.4 (CH ), 129.0 (2 × CH ), forming a clear yellow solution. The reaction mixture was
3
,
hexanes, 13.7 mL, 34.2 mmol). The mixture was allowed to
3
2
2
2
2
Ar
Ar
1
29.5 (2 × CHAr), 135.4 (CH), 135.5 (CAr), 153.2 (C), 176.6 (C).
Compound 15.
recooled to −78 °C and n-Bu
To a stirred solution of (S)-14 (39.5 g, slowly added to it, resulting in a slight change of colour. The
14 mmol) in Et O (900 mL) was added at 0 °C absolute EtOH orange mixture was then stirred at −78 °C for 15 min until no
3
SnH (9.07 mL, 34.2 mmol) was
9
,10
1
2
(
10.1 mL, 173 mmol), followed by LiBH
4
(4 M in THF, 43.3 mL, more hydrogen was released. The first solution was rapidly
1
73 mmol). The reaction mixture was allowed to warm up to cannulated to the Lipshutz’ reagent solution at −78 °C and the
room temperature overnight, then was quenched with an resulting mixture was then placed in an ice bath. After 2 h at
aqueous solution of NaOH (1 M, 880 mL) and was stirred until 0 °C, the reaction mixture was quenched by addition of a 4 : 1
both layers became clear. The aqueous layer was extracted with solution of saturated NH
4 4
Cl and 30% NH OH (11 mL). A satu-
Et O and the combined organic layers were washed with a rated solution of brine was added and the phases were sepa-
2
saturated aqueous NaCl solution, dried over anhydrous MgSO
4
rated. The aqueous layer was extracted with diethyl ether and
and concentrated under vacuum. The residue was purified by the organic fractions were combined and dried over anhydrous
flash silica gel chromatography (light petroleum–EtOAc, 1 : 1) Na SO . The solvents were evaporated under reduced pressure
2
4
to give (R)-15 (10.56 g, 73% yield) and the recovered starting to afford a crude oil, which was purified by flash column
oxazolidinone (18.66 g, 73%).
chromatography (light petroleum–Et
2
O, 1/99 to 8/2). The pure
(
S)-15 (10.46 g, 99% yield) was obtained using the same pro- vinyl stannane 10 (3.2 g, 99%) was obtained as a clear and col-
2
4
1
cedure starting from (R)-14 (28.56 g, 104 mmol).
ourless viscous oil. [α]
= −2.6 (c 1, (400 MHz, CDCl
D
+21.4, (c 1.0, CHCl
3
); H NMR
1
9
24
D
(R)-15 [α]
D
= +4.3 (c 1, CHCl
3
); (S)-15 [α]
3
) δ 0.84–0.90 (15H, m, 3 × CH
3
and 3 × CH ),
2
1
CHCl ); H NMR (200 MHz, CDCl ) δ 0.92 (3H, d, J = 6.7 Hz, 1.02 (3H, d, J = 6.8 Hz, CH ), 1.24–1.53 (12H, m, 6 × CH ),
3
3
3
2
CH
3
), 1.37 (1H, br s, OH), 1.65–1.82 (1H, m, CH), 1.87–2.01 2.34–2.44 (1H, m, CH), 3.38–3.44 (1H, m, CH
2
), 3.47–3.53 (1H,
3
(1H, m, CH
2
), 2.11–2.25 (1H, m, CH
2 2 2
), 3.40–3.55 (2H, m, CH ), m, CH ), 5.79 (1H, dd, J = 19.0 and 7.0 Hz, JSn–H = 70 Hz, CH),
1
3
2
13
4
.99–5.09 (2H, m, CH ), 5.71–5.92 (m, 1H, CH), C NMR 5.99 (1H, br d, J = 19.0 Hz,
J
= 18 Hz, CH); C NMR
Sn–C = 334 Hz), 13.4 (3 ×
2
Sn–H
1
(
(
50 MHz, CDCl
CH ), 116.1 (CH
Compound 12.
5 mmol) in dichloromethane (150 mL), at −78 °C, was CH,
3
) δ 16.4 (CH
3
), 35.6 (CH), 37.9 (CH
2
), 67.7 (75 MHz, CDCl
CH ), 16.1 (CH
JSn–C = 21 Hz), 44.5 (CH, J
3
) δ 9.5 (3 × CH
2
3
,
J
2
2
), 137.1 (CH).
3
3
), 27.3 (3 × CH
2
, JSn–C = 54 Hz), 29.2 (3 × CH
= 57 Hz), 66.9 (CH ), 129.5 (C3,
2
2
,
6
,11
2
3
Toa stirred solution of (R)-15 (7.51 g,
Sn–C
2
7
JSn–C = 23 Hz), 151.2 (CH); IR (thin film) νmax = 3325,
bubbled ozone until completion as indicated by the disappear- 2956, 2923, 2871, 2852, 1597, 1455, 1376, 1072, 1031,
ance of the characteristic color of sudan red III. The reaction 990 cm− ; LRMS m/z (ESI) 399 (M + Na) ; HRMS m/z (ESI) calcd
1
+
+
mixture was then purged with argon and quenched with PPh
21.6 g, 82 mmol). The mixture was allowed to warm up to
3
for C17
H
37OSn [M + H] : 377.1860, found 377.1861.
(
Compound 11. A solution of dihydrofuran (S)-12 (840 mg,
room temperature and was stirred overnight before being con- 9.99 mmol) in anhydrous THF (10.3 mL) was cooled down to
centrated under vacuum. The residue was purified by distilla- −60 °C and subjected to the slow addition of t-BuLi (1.6 M in
tion under reduced pressure (T65.8 mbar = 80 °C) to give (R)-16 pentane, 8.08 mL, 12.9 mmol). After 10 min at −60 °C, the
(4.32 g, 56% yield). A solution of the above (R)-16 (4.32, reaction mixture was stirred at 0 °C for 50 min. In a different
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flask, a solution of CuCN (1.78 g, 19.9 mmol) in anhydrous
Compound 8. A solution of alcohol 17 (1.55 g, 7.31 mmol)
THF (57.0 mL) was prepared and cooled down to −78 °C in anhydrous dichloromethane (27 mL) was treated with tert-
before being subjected to the slow addition of n-BuLi (2.5 M in butyldimethylsilyl chloride (775 mg, 10.28 mmol) and imida-
hexanes, 16.0 mL, 40.0 mmol). The mixture was allowed to zole (0.775 g, 11.38 mmol) at room temperature. The reaction
warm up to −60 °C, causing the CuCN to solubilize and mixture was stirred overnight before being transferred to a
forming a clear yellow solution. The reaction mixture was separating funnel and washed with water. The organic fraction
recooled to −78 °C and n-Bu SnH (10.6 mL, 39.4 mmol) was was dried over anhydrous Na SO , filtered and concentrated
3 2 4
slowly added to it, resulting in a slight change of colour. The under reduced pressure to give a clear and colourless crude
orange mixture was then stirred at −78 °C for 15 min until no oil. Purification by flash column chromatography (light pet-
more hydrogen was released. The first solution was rapidly roleum–Et
2
O, 1/0 to 9/1) afforded the pure vinyl iodide 8
2
5
cannulated to the Lipshutz’ reagent solution at −78 °C and the (2.23 g, 94%) as a clear colourless oil. [α] +20.8, (c 1.0,
D
1
resulting mixture was then placed in an ice bath. After 2 h at CHCl
°C, the reaction mixture was recooled to −30 °C before being (9H, s, 3 × CH
treated with iodomethane (6.2 mL, 0.1 mol) passed through a m, CH), 3.45 (1H, dd, J = 9.8 and 6.4 Hz, CH ), 3.48 (1H, dd, J =
3
); H NMR (400 MHz, CDCl
3
3
) δ 0.05 (6H, s, 2 × CH ), 0.90
0
3
), 1.01 (3H, d, J = 6.8 Hz, CH
3
), 2.33–2.40 (1H,
2
plug of basic alumina. The reaction mixture was allowed to 9.8 and 6.4 Hz, CH
warm up to room temperature and was stirred for 3 h before (1H, dd, J = 14.6 and 6.5 Hz, CH); C NMR (100 MHz, CDCl
being quenched by addition of a 4 : 1 solution of saturated δ −5.2 (2 × CH ), 15.7 (CH ), 18.4 (C), 26.0 (3 × CH ), 43.3 (CH),
2
), 6.06 (1H, br dd, J = 14.6 Hz, CH), 6.49
1
3
3
)
3
3
3
4 4 2
NH Cl and 30% NH OH (13 mL). A saturated solution of brine 67.0 (CH ), 75.2 (CH), 149.2 (CH); IR (thin film) νmax = 2955,
was added and the phases were separated. The aqueous layer 2928, 2856, 1605, 1471, 1386, 1361, 1252, 1187, 1088, 1024,
was extracted with diethyl ether and the organic fractions were 1006, 947 cm− ; LRMS m/z (ESI) 349 (M + Na) ; HRMS m/z
1
+
+
combined and dried over anhydrous Na
were evaporated under reduced pressure to afford a crude oil,
which was purified by flash column chromatography (light pet- 6.94 mmol) in anhydrous diethyl ether (40 mL) was treated
roleum–Et O, 1/99 to 8/2). The pure vinyl stannane 11 (2.94 g, with a premade solution of iodine (2.10 g, 8.27 mmol) in dry
6%) was obtained as a yellow to colourless clear viscous oil. diethyl ether (40 mL) at 0 °C. After 2 h at room temperature,
2
SO
4
. The solvents (ESI) calcd for C11
H
24OSiI [M + H] : 327.0636, found 327.0640.
Compound 18. A solution of vinyl stannane 11 (2.70 g,
2
7
2
1
1
[α]
−31.8 (c 1.0, CHCl3); H NMR (400 MHz, CDCl3) the dark brown reaction mixture was quenched by addition of
D
δ 0.84–0.98 (18H, 4 × CH and 3 × CH ), 1.16–1.56 (12H, m, an aqueous solution of potassium fluoride (1.0 M, 16 mL) and
3
2
3
6
2
× CH
2 3
), 1.88 (3H, d, J = 1.9 Hz, JSn–H = 44 Hz, CH ), acetone (16 mL) and was stirred for 1 h. The resulting suspen-
.77–2.99 (1H, m, CH), 3.30–3.36 (1H, m, CH ), 3.43–3.50 (1H, sion was then filtered through Celite® and flushed with ethyl
2
3
2
m, CH ), 5.23 (1H, dq, J = 9.0 and 1.9 Hz, JSn–H = 70 Hz, CH); acetate. The organics were washed with a saturated solution of
1
3
1
C NMR (75 MHz, CDCl and were dried over anhydrous MgSO
3 × CH ), 16.9 (CH ), 19.7 (CH ), 27.5 (C9, 3 × CH , J = 54 under reduced pressure afforded a crude yellow oil which was
Sn–C
3
) δ 9.3 (3 × CH
2
, JSn–C = 322 Hz), 13.8 Na
2
S
2
O
3
4
. Concentration
3
(
3
3
2
3
2
3
Hz), 29.3 (3 × CH
6
2
, JSn–C = 20 Hz), 35.3 (CH
3
, JSn–C = 53 Hz), purified by flash column chromatography (light petroleum–
O, 7/3 to 1/1) to yield the pure vinyl iodide 18 (1.54 g, 98%)
2
7.7 (CH ), 141.2 (C), 143.1 (CH, JSn–C = 24 Hz); IR (thin film) Et
2
2
2
5
νmax = 3330, 2955, 2924, 2871, 2850, 1456, 1377, 1071, 1030, as a yellowish to colourless viscous oil. [α] −31.3, (c 1.0,
9
D
70 cm− ; HRMS (ESI) m/z calcd for C18
1
H
39OSn [M + H] : CHCl
+
1
) δ 0.95 (3H, d, J = 6.8 Hz,
3 3
); H NMR (400 MHz, CDCl
3
91.2017, found 391.2017.
CH ), 1.82–1.85 (1H, m, OH), 2.41 (3H, d, J = 1.5 Hz, CH
3
3
),
1
4
Compound 17. A solution of vinyl stannane 10 (3.44 g, 2.57–2.68 (1H, m, CH), 3.36–3.51 (2H, m, CH ), 5.96 (1H, br
2
1
3
9
.17 mmol) in anhydrous diethyl ether (40 mL) was treated dq, J = 9.8, 1.5 Hz, CH); C NMR (100 MHz, CDCl
), 28.2 (CH ), 38.6 (CH), 67.0 (CH ), 95.6 (CH), 143.6 (CH);
diethyl ether (40 mL) at 0 °C. After 2 h at room temperature, IR (thin film) νmax = 3332, 2958, 2926, 2870, 1635, 1429, 1377,
3
) δ 16.4
with a premade solution of iodine (2.70 g, 10.6 mmol) in dry (CH
3
3
2
−
1
the dark brown reaction mixture was quenched by addition of 1217, 1119, 1076, 1030, 996, cm ; LRMS m/z (ESI) 249 (M +
an aqueous solution of potassium fluoride (1.0 M, 20 mL) and Na) ; HRMS m/z (ESI) calcd for C
+
+
6
H
15NOI [M + NH
4
] :
acetone (20 mL) and was stirred for 1 h. The resulting suspen- 244.0193, found 244.0185.
sion was then filtered through Celite® and flushed with ethyl
Compound 9. A solution of alcohol 11 (1.54 g, 6.81 mmol)
acetate. The organics were washed with a saturated solution of in dichloromethane (55 mL) was cooled down to 0 °C and
Na S O (3 × 50 mL) and were dried over anhydrous MgSO . treated with Dess–Martin periodinane (1.06 g, 2.50 mmol).
2
2
3
4
Concentration under reduced pressure afforded a crude yellow The pink–red reaction mixture was allowed to warm up slowly
oil which was purified by flash column chromatography (light (kept slightly below 20 °C) and was treated with additional
petroleum–Et O, 7/3 to 1/1) to yield the pure vinyl iodide 17 Dess–Martin periodinane (2 × 1.06 g, 2 × 2.50 mmol, added in
2
(
1.75 g, 91%) as a yellowish to colourless viscous oil. 2 portions every 30 min). The reaction mixture was quenched
25
1
D 3 3
[α] +23.1, (c 1.0, CHCl ); H NMR (300 MHz, CDCl ) δ 1.00 (3H, at 0 °C by addition of a 1 : 1 mixture of saturated aqueous solu-
d, J = 6.8 Hz, CH ), 1.88–1.92 (1H, m, OH), 2.33–2.46 (1H, m, tions of Na S O and NaHCO (40 mL). The biphasic mixture
3
2
2
3
3
2
CH), 3.40–3.53 (2H, m, CH ), 6.12 (1H, d, J = 14.5 Hz, CH), 6.45 was stirred at 0 °C until both phases become clear and was
1
3
(
1H, dd, J = 14.5 and 7.9 Hz, CH); C NMR (75 MHz, CDCl
3
)
then transferred to a separating funnel containing diethyl
ether. The phases were separated and the organic layer was
δ 15.6 (CH ), 43.4 (CH), 66.5 (CH ), 76.2 (CH), 148.6 (CH).
3
2
4
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washed with the Na –NaHCO
Paper
2
S
2
O
3
3
, then with water. The Na
2
S
2
O
3
and NaHCO
3
(6 mL). The biphasic mixture was stirred
organic fraction was subsequently dried over anhydrous at 0 °C until both phases become clear and was then trans-
Na SO , filtered and concentrated under reduced pressure at ferred to a separating funnel containing diethyl ether. The
2
4
room temperature. The resulting smelly colourless crude oil phases were separated and the organic layer was washed with
was then rapidly taken on crude to the next reaction as it was saturated aqueous solutions of Na S O , NaHCO , then with
2
2
3
3
proved to degrade fairly quickly as it turns pink/brown. A water. The organic fraction was subsequently dried over anhy-
sample was further purified (80%) by flash chromatography drous Na SO , filtered and concentrated under reduced
2
4
1
(
(
light petroleum–Et O, 7/3) for analytical analysis. H NMR pressure at room temperature. The resulting unclear yellowish
2
400 MHz, CDCl
3
3
) δ 1.21 (3H, d, J = 7.0 Hz, CH ), 2.46 (3H, d, crude oil was then purified by flash column chromatography
J = 1.5 Hz, CH
3
), 3.23–3.31 (1H, m, CH), 6.06 (1H, br dq, J = (light petroleum–Et
2
O, 8/2) to yield the pure enone 21 (49 mg,
13
21
9
.3, 1.5 Hz, CH), 9.51 (1H, d, J = 1.7 Hz, CH); C NMR 98%) as a clear colourless viscous oil. [α] +52.5 (c 1.0, CHCl3);
D
1
(
(
100 MHz, CDCl
CH), 136.6 (CH), 199.3 (CHO).
Compound 20. A solution of iodide 8 (1.85 g, 5.67 mmol) in CH ), 2.12 (3H, br d, J = 1.5 Hz, CH ), 2.22 (1H, app sept, J =
3
) δ 13.8 (CH
3
), 28.4 (CH
3
), 48.8 (CH), 98.1
H NMR (400 MHz, C
6
D
6
) δ 0.00 (6H, s, 2 × CH
3
), 0.82 (3H, d,
3 3
J = 6.8 Hz, CH ), 0.94 (9H, s, 3 × CH ), 0.99 (3H, d, J = 7.0 Hz,
3
3
anhydrous diethyl ether (40 mL) containing a small piece of 6.3 Hz, CH), 3.19 (1H, dq, J = 9.8 and 7.0 Hz, CH), 3.28 (2H, d,
CaH was treated with n-BuLi (2.5 M in hexanes, 2.30 mL, J = 6.0 Hz, CH ), 6.06 (1H, br dd, J = 15.8 and 1.3 Hz, CH), 6.25
.75 mmol) at −100 °C. The reaction mixture was allowed to (1H, br dq, J = 9.8 and 1.5 Hz, CH), 6.90 (1H, dd, J = 15.8 and
2
2
5
1
3
warm up to −78 °C and was stirred for 30 min before being 7.3 Hz, CH); C NMR (100 MHz, C
recooled to −100 °C. The previous solution was then quickly (CH ), 16.3 (CH ), 18.5 (C), 26.1 (3 × CH
cannulated to a −100 °C premade solution of crude aldehyde 9 (CH), 47.2 (CH), 67.1 (CH ), 96.1 (C), 127.5 (CH), 140.3 (CH),
6
D
6
) δ −5.3 (2 × CH
3
), 15.7
), 39.6
3
3
3
), 27.9 (CH
3
2
(1.52 g, 6.8 mmol) in dry diethyl ether (25 mL) containing a 149.8 (CH), 196.9 (C); IR (thin film) νmax = 2955, 2927, 2854,
2
small piece of CaH . The reaction mixture was allowed to 1697, 1673, 1626, 1471, 1459, 1253, 1189, 1129, 1097, 1084,
warm up slowly at −78 °C and was stirred for 15 min before 1029, 980 cm− ; LRMS m/z (ESI) 445 (M + Na) ; HRMS m/z
1
+
+
being quenched by addition of a saturated solution of NH
15 mL) (caution: water reacts violently with CaH !!!). The cold 423.1211.
bath was removed straight away and the biphasic mixture was Compound 22. A solution of enone 21 (776 mg, 1.84 mmol)
4
Cl (ESI) calcd for C17
H
32
O
2
SiI [M + H] : 423.1211, found
(
2
stirred for 15 min to be then placed in a separating funnel. in anhydrous toluene (44 mL) and water (107 μL, 5 μmol) was
The phases were separated and the ether layer was washed degassed in bubbling argon for 20 min at room temperature.
with water. The organics were dried over anhydrous Na SO
Fresh hexa(triphenylphosphine copper hydride) (950 mg,
2
4
and subsequently filtered. Concentration under reduced 0.48 mmol, 2.9 eq. of hydride) was quickly poured into the
pressure afforded an unclear yellow oil (3.85 g) which was puri- reaction mixture which was stirred until completion (∼15 min)
fied by flash column chromatography (light petroleum–Et O, as indicated by TLC analysis. The solution was directly loaded
2
8
3
/2 to 0/1) to yield the pure allylic alcohol 20 (1.72 g, 71%) as a onto silica and was purified by flash column chromatography
: 1 inseparable mixture of diastereoisomers. Major diastereo- (100% light petroleum) with no prior workup. Concentration
1
isomer only: H NMR (400 MHz, CDCl ) δ 0.05 (6H, s, 2 × CH ), under reduced pressure afforded the crude ketone 22 as a
3
3
0
.89 (1H, s, 3 × CH
3
), 1.00 (6H, d, J = 6.8 Hz, 2 × CH
3
), 1.66 yellow oil containing triphenylphosphine oxide as the main
(1H, br s, OH), 2.29–2.36 (1H, m, CH), 2.39 (3H, d, J = 1.5 Hz, impurity. Triphenylphosphine oxide crystallized out from the
CH ), 2.50–2.59 (1H, m, CH), 3.40 (1H, dd, J = 9.8 and 6.8 Hz, neat oil when exposed to the air and was removed by addition
3
CH
2 2
), 3.49 (1H, dd, J = 9.8 and 6.3 Hz, CH ), 3.88 (1H, app br t, of light petroleum and subsequent filtration. Evaporation of
J = 6.5 Hz, CH), 5.45 (1H, br dd, J = 15.6 and 6.8 Hz, CH), 5.60 the solvents gave the pure ketone 22 (775 mg, 99%) as a clear
2
2
1
(
1H, br dd, J = 15.6 and 6.3 Hz, CH), 5.99 (1H, br dq, J = 9.8 colourless oil. [α] +65.6, (c 1.0, CHCl ); H NMR (400 MHz,
D
3
1
3
and 1.5 Hz, CH); C NMR (100 MHz, CDCl
5.9 (CH ), 16.5 (CH ), 18.3 (C), 25.9 (3 × CH
3
) δ −5.3 (2 × CH
3
), CDCl
3
) δ 0.05 (6H, s, 2 × CH
3 3 3
), 28.1 (CH ), 39.0 0.90 (9H, s, 3 × CH ), 1.16 (3H, d, J = 6.8 Hz, CH ), 1.30–1.43
3
3
), 0.87 (3H, d, J = 6.6 Hz, CH ),
1
3
3
3
(
CH), 41.7 (CH), 67.9 (CH ), 76.3 (CH), 94.6 (CI), 129.8 (CH), (1H, m, CH ), 1.51–1.62 (1H, m, CH), 1.62–1.73 (1H, m, CH ),
2
2
2
1
2
35.8 (CH), 142.9 (CH); IR (thin film) νmax = 3419, 2958, 2930, 2.36–2.55 (2H, m, CH
2
), 2.46 (3H, d, J = 1.5 Hz, CH
3
), 3.33–3.40
−
1
858, 1638, 1473, 1388, 1257, 1089, 1009, 974 cm ; LRMS m/z (1H, m, CH), 3.42 (2H, d, J = 5.9 Hz, CH
2
), 6.12 (1H, dq, J =
+
13
(ESI) 447 (M + Na) ; HRMS m/z (ESI) calcd for C H NO SiI 10.0 and 1.5 Hz, CH); C NMR (100 MHz, CDCl ) δ −5.2 (2 ×
1
7
37
2
3
+
[
M + NH
Compound 21. A solution of alcohol 20 (50 mg, 0.12 mmol) (CH
in dichloromethane (2.5 mL) was cooled down to 0 °C and 96.1 (C), 139.9 (CH), 209.9 (C); IR (thin film) νmax = 2955, 2929,
4
] : 442.1633, found 442.1633.
CH
3
), 16.3 (CH
3
), 16.8 (CH
3
), 18.5 (C), 26.1 (3 × CH
3
), 27.4
2
), 28.1 (CH
), 35.4 (CH), 38.8 (CH ), 48.7 (CH), 68.2 (CH ),
3 2 2
3
treated with solid NaHCO (12 mg, 0.142 mmol) and Dess– 2883, 2856, 1716, 1472, 1462, 1434, 1252, 1117, 1091, 1037,
Martin periodinane (60 mg, 0.142 mmol). The reaction 1028, 1005 cm− ; LRMS m/z (ESI) 447 (M + Na) ; HRMS m/z
1
+
+
mixture was allowed to warm up slowly to room temperature (ESI) calcd for C H O SiI [M + H] : 425.1367, found
1
7
34 2
and was stirred for 1 h until completion as indicated by TLC 425.1367.
analysis. The reaction mixture was quenched at 0 °C by Compound 23. Procedure A:
addition of a 1 : 1 mixture of saturated aqueous solutions of (775 mg, 1.83 mmol) in anhydrous diethyl ether (15 mL) was
A
solution of ketone 22
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treated with a solution of Dibal-H (1.0 M in hexanes, 3.51 mL, 1.25 (1H, br s, OH), 1.35–1.46 (1H, m, CH
2
), 1.48–1.60 (2H, m,
3
.51 mmol) at −78 °C. After 10 min at −78 °C, the reaction CH and CH ), 2.17 (3H, d, J = 1.5 Hz, CH ), 2.19–2.27 (1H, m,
2
3
mixture was quenched by addition of ethyl acetate (5 mL), CH), 3.03–3.11 (1H, m, CH), 3.34 (1H, dd, J = 9.8 and 5.6 Hz,
then with a saturated solution of NaHCO (10 mL). After stir- CH ), 3.41 (1H, dd, J = 9.8 and 5.6 Hz, CH ), 6.08 (1H, dq, J =
ring the biphasic mixture for 15 min at room temperature, the 10.0 and 1.5 Hz, CH); C NMR (75 MHz, C D ) δ −5.1 (2 ×
3
2
2
1
3
6
6
phases were separated and the ether layer was filtered through CH
a short pad of Celite®. Concentration under reduced pressure (CH
provided a clear and colourless crude oil containing a 75.2 (CH), 94.1 (C), 144.5 (CH); IR (thin film) νmax = 3358,
3
), 15.5 (CH
3
), 17.3 (CH
3
), 18.6 (C), 26.3 (3 × CH
3
), 28.0
3
), 29.8 (CH
2
), 32.4 (CH ), 36.1 (CH), 42.0 (CH), 68.3 (CH
2
2
),
−
1
1
: 1 mixture of diastereoisomers (S)-23 and (R)-23. Several puri- 2954, 2928, 2856, 1633, 1462, 1378, 1361, 1252, 1092 cm ;
+
fications by flash column chromatography (light petroleum– LRMS m/z (ESI) 449 (M + Na) ; HRMS m/z (ESI) calcd for
+
Et O, 9/1 to 8/2) enable the complete separation of both dia- C H O SiI [M + H] : 427.1524, found 427.1521.
2
17 36 2
stereoisomers (238 mg, 31%) and (313 mg, 40%) as clear and
Compound 7. A solution of alcohol 23 (235 mg, 0.55 mmol)
colourless oils.
in anhydrous dichloromethane (5 mL) was cooled down to
Procedure B: To a stirred solution of ketone 22 (10 mg, −78 °C and treated with 2,6-lutidine (146 μL, 1.26 mmol) fol-
.023 mmol) in THF (0.6 mL) was added at −55 °C (S)-CBS lowed by tert-butyldimethylsilyl trifluoromethanesulfonate
0
(
1.0 M in THF, 45 μL, 0.045 mmol) followed by BH ·THF (1 M (146 μl, 0.64 mmol). Completion was achieved within 10 min
3
in THF, 45 μL, 0.045 mmol). The solution was stirred at −55 °C at −78 °C as indicated by TLC analysis and the reaction
until completion (20 min) and allowed to warm up to room mixture was quenched by addition of a saturated solution of
temperature for 1 h. The reaction mixture was quenched with NH
4
Cl (5 mL). The reaction mixture was transferred to a sepa-
an aqueous saturated solution of NaHCO , the layers were sep- rating funnel containing diethyl ether and the organics were
3
arated and the aqueous phase was extracted with Et
2
O. The washed with water. After drying over anhydrous Na
2 4
SO , and
combined organic layers were dried over anhydrous Na
2
SO subsequent filtration, the solvents were evaporated under
4
,
filtered and concentrated under reduced pressure at room reduced pressure. The resulting crude oil was purified by flash
temperature. The resulting crude oil was then purified by flash column chromatography (100% light petroleum) to give the
2
column chromatography (light petroleum–Et O, 9/1) to yield pure bis-TBS protected diol 7 (297 mg, 99%) as a clear colour-
2
5
1
the pure 23 (10 mg, 99%) as a 3 : 1 separable mixture of dia- less oil. [α] −33.3, (c 1.0, CHCl ); H NMR (300 MHz, C D ) δ
D
3
6 6
3
6
stereomers. Major diastereomer (11R)-23: [α]
D
−23.0, (c 1.0, 0.07 (6H, s, 2 × CH
3 6 6 3 3 3 3
CHCl ); H NMR (300 MHz, C D ) δ 0.07 (6H, s, 2 × CH ), 0.79 Hz, CH ), 0.90 (3H, d, J = 6.5 Hz, CH ), 0.98 (9H, s, 3 × CH ),
3
), 0.08 (6H, s, 2 × CH
3
), 0.85 (3H, d, J = 6.8
1
(
3H, d, J = 6.9 Hz, CH ), 0.87 (3H, d, J = 6.7 Hz, CH ), 0.98 (9H, 1.00 (9H, s, 3 × CH ), 1.10–1.20 (1H, m, CH ), 1.33–1.61 (4H,
3
3
3
2
s, 3 × CH
3
), 1.19–1.45 (5H, m, 2 × CH
2
and OH), 1.51–1.61 (1H, m, CH
2
and CH
2
and CH), 2.24 (3H, d, J = 1.5 Hz, CH
), 6.24
.05–3.11 (1H, m, CH), 3.33–3.42 (1H, m, CH ), 6.16 (1H, br (1H, dq, J = 10.0 and 1.4 Hz, CH); C NMR (100 MHz, C D ) δ
3
),
3 2
m, CH), 2.12–2.24 (1H, m, CH), 2.17 (3H, d, J = 1.3 Hz, CH ), 2.37–2.49 (1H, m, CH), 3.35–3.45 (3H, m, CH and CH
3
dq, J = 10.0 and 1.3 Hz, CH); C NMR (75 MHz, C
1
3
2
6 6
1
3
6
D
6
) δ −5.1 −5.2 (2 × CH
3
), −4.1 (CH
3
), −4.0 (CH
3
), 16.4 (CH
3
), 16.9 (CH
), 28.0 (CH
3
),
),
(
2 × CH
3
), 16.8 (CH
3
), 17.1 (CH
3
), 18.6 (C), 26.3 (3 × CH ), 28.1 18.3 (C), 18.6 (CH
3
3
), 26.2 (3 × CH
3
), 26.2 (3 × CH
3
3
(
7
2
CH ), 29.7 (CH ), 32.4 (CH ), 36.0 (CH), 41.9 (CH), 68.6 (CH ), 28.7 (CH ), 32.1 (CH ), 36.4 (CH), 40.8 (CH), 68.5 (CH ), 75.9
3 2 2 2 2 2 2
+
4.9 (CH), 94.6 (C), 143.5 (CH); IR (thin film) νmax = 3397, (CH), 94.1 (C), 144.3 (CH); LRMS m/z (ESI) 563 (M + Na) ;
−
1
+
954, 2928, 2856, 1462, 1377, 1361, 1251, 1090 cm ; LRMS HRMS m/z (ESI) calcd for C23
H
53NO
2
Si
2
I [M + NH
4
] : 558.2654,
+
m/z (ESI) 449 (M + Na) ; HRMS m/z (ESI) calcd for C H O SiI found 558.2651.
1
7
36 2
+
[M + H] : 427.1524, found 427.1523.
Compound 24. Bis-TBS protected diol
7
(260 mg,
Procedure C: To a stirred solution of ketone 22 (17 mg, 0.48 mmol) was diluted in a 1 : 1 mixture of regular dichloro-
.04 mmol) in THF (1 mL) was added at −55 °C (R)-CBS (1.0 M methane and methanol (3.2 mL) in a round bottom flask open
0
3
in THF, 79 μL, 0.079 mmol) followed by BH ·THF (1 M in THF, to the air. The solution was cooled down to 0 °C and was
7
9 μL, 0.079 mmol). The solution was stirred at −55 °C until treated with 10-camphorsulfonic acid (27 mg, 0.12 mmol). The
completion (20 min) and allowed to warm up to room tempera- reaction mixture was stirred at 0 °C until complete disappear-
ture for 1 h. The reaction mixture was quenched with an ance of the starting material as indicated by TLC (45 min) and
aqueous saturated solution of NaHCO
3
, the layers were sepa- was then quenched by addition of solid sodium bicarbonate
rated and the aqueous phase was extracted with Et O. The (90 mg, mmol) at 0 °C. After stirring the suspension for
2
combined organic layers were dried over anhydrous Na
2
SO
4
,
10 min at 0 °C, then 10 min at room temperature, it was fil-
filtered and concentrated under reduced pressure at room tered through a piece of cotton wool and concentrated. The
temperature. The resulting crude oil was then purified by flash residue was diluted with diethyl ether (5 mL) and filtered
column chromatography (light petroleum–Et
2
O, 9/1) to yield through Celite®. Concentration under reduced pressure gave a
the pure 23 (12 mg, 75%) as a 1 : 6 separable mixture of dia- clear yellowish crude oil which was purified by flash column
3
6
stereomers. Major diastereomer (11S)-23: [α] −31.8, (c 1.0, chromatography (light petroleum–Et O, 9/1 to 1/1) to yield the
D
2
1
CHCl
3
); H NMR (300 MHz, C
6
D
6
) δ 0.07 (6H, s, 2 × CH
), 0.89 (3H, d, J = 6.4 Hz, CH
3
), 0.84 pure alcohol 24 (205 mg, 99%) as a clear and colourless oil.
2
5
1
(
3H, d, J = 6.8 Hz, CH
3
3
), 0.98 (9H, [α]
D
3 6 6
−32.8, (c 1.0, CHCl ); H NMR (400 MHz, C D ) δ 0.05
s, 3 × CH ), 0.99–1.06 (1H, m, CH ), 1.11–1.21 (1H, m, CH ), (3H, s, CH ), 0.06 (3H, s, CH ), 0.83 (2 × 3H, 2 × d overlapped,
3
2
2
3
3
4
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J = 6.7 Hz, 2 × CH ), 0.97 (9H, s, 3 × CH
Paper
3
3
), 1.01–1.06 (1H, m, not described because the mixture of diastereomers. IR (thin
CH ), 1.29–1.49 (4H, m, CH and CH and CH), 2.22 (3H, d, J = film) νmax = 3364, 2957, 2928, 2883, 2857, 1471, 1461, 1406,
2
2
2
−1
1
6
.5 Hz, CH
.0 Hz, CH
3
), 2.35–2.44 (1H, m, CH), 3.17 (1H, dd, J = 10.0 and 1378, 1361, 1253, 1065, 1027, 1004, 942 cm ; LRMS m/z (ESI)
), 3.23 (1H, dd, J = 10.3 and 5.5 Hz, CH ), 3.33 (1H, 463 (M + Na) ; HRMS m/z (ESI) calcd for C18H O SiI [M + H] :
2 38 2
+
+
2
q, J = 5.0 Hz, CH), 6.23 (1H, br dq, J = 10.0 and 1.5 Hz, CH); 441.1680, found 441.1667.
1
3
C NMR (75 MHz, C
6.8 (CH ), 18.3 (C), 26.2 (3 × CH
CH ), 36.2 (CH), 40.7 (CH), 67.9 (CH ), 75.8 (CH), 94.1 (C), treated with the DMP reagent (365 mg, 0.86 mmol). After
6
D
6
) δ −4.2 (CH
3
), −4.1 (CH
3
), 16.5 (CH
3
),
Compound 6. A solution of alcohol 26 (140 mg, 0.32 mmol)
1
(
1
3
3
), 28.0 (CH
3
), 28.6 (CH
2
), 32.2 in dichloromethane (7 mL) was cooled down to 0 °C and
2
2
+
44.2 (CH); LRMS m/z (ESI) 449 (M + Na) ; HRMS m/z (ESI) 10 min at 0 °C, the reaction mixture was allowed to warm up
+
calcd for C17
H
36
O
2
SiI [M + H] : 427.1524, found 427.1517.
slowly and was stirred at room temperature until completion
Compound 25. A solution of alcohol 24 (200 mg, (45 min) as indicated by TLC analysis. The reaction mixture
0
0
1
.47 mmol) in dichloromethane (12 mL) was cooled down to was quenched at 0 °C by addition of a 1 : 1 mixture of saturated
2 2 3 3
°C and treated with Dess–Martin periodinane (440 mg, aqueous solutions of Na S O and NaHCO (40 mL). The
.04 mmol). The reaction mixture was allowed to warm up biphasic mixture was stirred at 0 °C until both phases become
slowly and was stirred at room temperature until completion clear and was then transferred to a separating funnel contain-
30 min) as indicated by TLC analysis. The reaction mixture ing diethyl ether. The phases were separated and the organic
was quenched at 0 °C by addition of a 1 : 1 mixture of saturated layer was washed with the Na S O , NaHCO and then with
(
2
2
3
3
aqueous solutions of Na
biphasic mixture was stirred at 0 °C until both phases become drous Na
2
S
2
O
3
and NaHCO
3
(44 mL). The water. The organic fraction was subsequently dried over anhy-
SO , filtered and concentrated under reduced
2
4
clear and was then transferred to a separating funnel contain- pressure at room temperature. The resulting clear yellowish
ing diethyl ether. The phases were separated and the organic crude oil was then purified by flash column chromatography
layer was washed with Na
2 2 3 3 2
S O , NaHCO and then with water. (light petroleum–Et O, 99/1 to 9/1) to yield the pure ketone 6
3
6
The organic fraction was subsequently dried over anhydrous (126 mg, 91%) as a clear and colourless oil. [α] −28.6, (c 1.0,
D
1
Na
2
SO
4
, filtered and concentrated under reduced pressure at CHCl
3
); H NMR (300 MHz, C
6
D
6
) δ 0.03 (3H, s, CH
3
), 0.04
room temperature. The resulting clear and colourless crude oil (3H, s, CH
3
), 0.79 (3H, d, J = 6.8 Hz, CH
3
), 0.87 (3H, d, J = 7.0
was then purified by flash column chromatography (light pet- Hz, CH ), 0.95 (9H, s, 3 × CH ), 1.15–1.38 (3H, m, CH and
3
3
2
roleum–Et
2
O, 99/1 to 9/1) to yield the pure sensitive aldehyde CH
2
), 1.49–1.59 (1H, m, CH
2
), 1.75 (3H, s, CH
3
), 2.01–2.10 (1H,
2
8
2
5 (170 mg, 85%) as a clear and colourless oil. [α]
D
3
−46.0, m, CH), 2.21 (3H, d, J = 1.5 Hz, CH ), 2.28–2.40 (1H, m, CH),
1
(
c 1.0, CHCl ); H NMR (300 MHz, C D ) δ 0.00 (3H, s, CH ), 3.26–3.31 (1H, m, CH), 6.17 (1H, br dq, J = 10.0 and 1.5 Hz,
3
6
6
3
1
3
0
7
1
.03 (3H, s, CH
.1 Hz, CH
3
), 0.77 (3H, d, J = 6.9 Hz, CH
), 1.07–1.16 (1H, m, CH
.18–1.32 (2H, m, CH ), 1.41–1.56 (1H, m, CH ), 1.73–1.84 (1H, (CH ), 28.3 (CH ), 32.3 (CH ), 40.7 (CH), 47.0 (CH), 75.4 (CH),
3
), 0.78 (3H, d, J = CH); C NMR (75 MHz, C
6
D
6
) δ −4.2 (CH
3
), −4.1 (CH
3
), 16.3
3
), 0.94 (9H, s, 3 × CH
3
2
), (CH ), 16.5 (CH ), 18.3 (C), 26.2 (3 × CH
3
3
3
), 27.8 (CH
3
), 28.0
2
2
3
2
2
m, CH), 2.20 (3H, d, J = 1.5 Hz, CH
3
), 2.24–2.41 (1H, m, CH), 94.3 (CH), 144.0 (CH), 209.6 (CH); IR (thin film) νmax = 2955,
3
1
C
.26 (1H, q, J = 5.5 Hz, CH), 6.14 (1H, br dq, J = 10.0 and 2929, 2856, 1713, 1471, 1461, 1378, 1359, 1253, 1170, 1067,
1
3
−1
+
.5 Hz, CH), 9.30 (1H, d, J = 1.3 Hz, CH); C NMR (75 MHz, 1043, 1026, 1006, 940 cm ; LRMS m/z (ESI) 461 (M + Na) ;
+
6
D
6
) δ −4.2 (CH
3
), −4.1 (CH
3
), 13.3 (CH
), 27.9 (CH
3
), 16.2 (CH ), 18.3 HRMS m/z (ESI) calcd for C18
2
), 31.6 (CH ), 40.8 found 439.1517.
3
36 2
H O SiI [M + H] : 439.1524,
(CH
3
), 25.8 (CH ), 26.1 (3 × CH
2
3
3
(CH), 46.2 (CH), 75.2 (CH), 94.3 (C), 144.0 (CH), 202.9 (CH); IR
(
1
(
thin film) νmax = 2256, 2931, 2858, 1709, 1472, 1464, 1379,
−
1
361, 1254, 1067, 1045, 1027, 1006 cm ; LRMS m/z (ESI) 447
+
Acknowledgements
M + Na) .
Compound 26. A solution of pure aldehyde 25 (160 mg,
Aix-Marseille Université is gratefully acknowledged for finan-
cial support for S.M. J.-F. Betzer is also acknowledged for
fruitful discussion.
0
.377 mmol) in anhydrous diethyl ether (2.4 mL) was cooled
down to −78 °C and treated with methylmagnesium bromide
3.0 M in diethyl ether, 310 μL, 0.93 mmol). Completion was
(
achieved within 15 min as indicated by TLC analysis and the
reaction mixture was then quenched by addition of a saturated
solution of NH Cl (2.4 mL) at −78 °C. The mixture was allowed
to stir at room temperature for 10 min and was then trans-
4
Notes and references
ferred to a separating funnel. The phases were separated and
the ethereal layer was dried over anhydrous Na SO . Concen-
2 4
tration under reduced pressure gave the crude secondary
alcohol 26. Purification by flash column chromatography
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(
(
1
light petroleum–Et
152 mg, 92%) as a clear and colourless oil and as a
: 1.5 mixture of unseparable diastereoisomers. The alcohol is
2
O, 9/1) provided the pure alcohol 26
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890 | Org. Biomol. Chem., 2013, 11, 4882–4890
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