Stereoselective synthesis of the C15-C26 fragment of the antitumor agent (-)-dictyostatin

Article abstract of DOI:10.1039/c0ob00491j

The synthesis of the C15-C26 fragment of (-)-dictyostatin is reported in 10 steps and 28% overall yield. The key steps are the two stereoselective sulfoxide-directed processes: a Reformatsky-type reaction and a β-keto sulfoxide reduction.

Full text of DOI:10.1039/c0ob00491j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereoselective synthesis of the C15–C26 fragment of the antitumor agent
(-)-dictyostatin†
Leticia Ferreiro-Mederos,a,b Silvia Vila-Gisbert,a Antonio Urbano,*a M. Carmen Carren˜o*a and
Franc¸oise Colobert*b
Received 26th July 2010, Accepted 30th September 2010
DOI: 10.1039/c0ob00491j
The synthesis of the C15–C26 fragment of (-)-dictyostatin is reported in 10 steps and 28% overall yield.
The key steps are the two stereoselective sulfoxide-directed processes: a Reformatsky-type reaction
and a b-keto sulfoxide reduction.
was determined in 2004 by Paterson and coworkers based on a
Introduction
combination of extensive high field NMR studies and molecular
modelling.3 This assignment was later validated through the
independent and concurrent total syntheses of (-)-dictyostatin by
the Paterson and Curran groups.4
The marine-derived macrolactone (-)-dictyostatin (Scheme 1) was
first isolated in small amounts by Pettit and coworkers from the
Maldives sponge Spongia sp. in 19941 and more recently by Wright
and coworkers from the Caribbean Corallistidae sponges in 2003.2
Dictyostatin displays low nanomolar cytotoxicity towards a
range of human cancer cell lines including those with a multidrug-
resistant phenotype.5 Its significant therapeutic potential and
relationship to discodermolide6 has stimulated many synthetic
efforts over the last few years7 including several total syntheses
of (-)-dictyostatin8 and related hybrids9 and analogs,10 as well as
the preparation of different fragments.11
In relation with a program devoted to asymmetric synthesis
mediated by sulfoxides,12 we have described a highly stereoselective
Reformatsky-type reaction of chiral a-bromo-a¢-sulfinyl ketones
with aldehydes in the presence of SmI2.13 Herein, we report the
synthesis of the C15–C26 unit of dictyostatin (1 in Scheme 1), with
five stereocenters and the terminal (Z)-1,3-diene moiety, using two
sulfoxide-directed processes: a Reformatsky-type reaction and a b-
keto sulfoxide reduction,14 to generate the syn-syn stereotriad at
C19–C21 of the final target with high levels of stereocontrol.
Results and discussion
Our retrosynthetic analysis of the C15–C26 fragment of dictyo-
statin 1 is depicted in Scheme 1. The left part of the molecule would
be accessible through a Julia reaction between the known sulfone
2, derived from Roche ester, and the appropriately protected
aldehyde intermediate 3, whereas the formation of the right diene
moiety of the synthetic target would be possible through a two-step
Nozaki–Hiyama allylation/Peterson olefination process between
the silyl bromide 4 and the aldehyde obtained after debenzylation
and oxidation of a suitable intermediate derived from 3. The
key aldehyde 3 could be obtained after the well-established
diastereoselective reduction of the b-ketosulfoxide moiety present
in 5, selective diol protection and Pummerer reaction.15 Finally,
derivative 5 would be formed using our Reformatsky-type reac-
tion between the known a-bromo-a¢-sulfinyl ketone 6 and the
aldehyde 7, also derived from Roche ester. The development of
a methodology allowing the synthesis of some stereoisomers of
the stereotriad is highly important. With our methodology, up to
four diastereomers of the stereotriad could be easily accessible in a
stereocontrolled manner depending on the absolute configuration
Scheme 1 Retrosynthesis of 1, the C15–C26 fragment of (-)-Dictyostatin.
Dictyostatin comprises a 26-carbon polyketide backbone with
11 stereocentres, featuring a 22-membered macrolide (C1–C21),
an (E,Z)-dienoate moiety (C1–C5), a (Z)-olefin (C10–C11) and a
terminal (Z)-1,3-diene (C23–C26). Their relative stereochemistry
aDepartamento de Qu´ımica Orga´nica (Mo´dulo 01), Universidad Auto´noma
de Madrid, 28049, Madrid, Spain. E-mail: antonio.urbano@uam.es,
carmen.carrenno@uam.es
bLaboratoire de Ste´re´ochimie, Universite´ de Strasbourg, ECPM 25 rue
Becquerel, 67087, Strasbourg Cedex 2, France
† Electronic supplementary information (ESI) available: Experimental
procedures for (S)-7 and copies of 1H- and 13C-NMR spectra for all new
compounds. See DOI: 10.1039/c0ob00491j
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of the sulfoxide and/or the conditions chosen to effect the
reduction step of the b-ketosulfoxide.
pure 11 containing the syn-syn stereotriad with the correct
absolute configuration present in natural dictyostatin. The relative
syn disposition of the diol moiety of 11 was demonstrated,
after transformation into acetonide 12 (acetone dimethyl acetal,
PPTS, acetone, rt, 96%), by applying the 13C NMR criterion
described by Rychnovsky18 and Evans.19 Compound 12 showed
differentiated chemical shifts of the two geminal methyl groups of
the dioxolane moiety in the 13C NMR spectrum (19.66 and 29.75
ppm, respectively), as a consequence of the chair conformation
adopted by the heterocyclic fragment, with bulkier substituents
adopting an equatorial disposition. We could also confirm the
relative stereochemistry on the basis of the observed NOESY
correlations between protons H3 and H5 situated in a 1,3-diaxial
disposition. This structural assignment also allowed us to establish
the relative syn configuration of the methyl group at C-4 of
compound 12 by measuring the two small coupling constants (J =
2.0 Hz) in the 1H NMR spectrum between H4 and H3/H5, which
are only possible if H4 adopts an equatorial disposition (Scheme 2).
Once the syn-syn stereotriad at C19–C21 of the final target was
installed, we turned our attention to the selective mono protection
of the diol moiety of 11. This task proved to be arduous and after
much experimentation we found that the treatment of diol 11
with NaH in the presence of PMBBr (DMF, 0 ◦C to rt) gave
rise to the exclusive protection of the hydroxyl group at C-5
affording the PMB ether derivative 13 in 88% yield.20 The selective
protection of the OH b to the sulfoxide in the presence of another g-
carbinol was unprecedented. The stabilization of the intermediate
b-alkoxide by the proximal sulfinyl oxygen could be the origin
of such a chemoselective reaction. The subsequent protection of
the carbinol at C-3 of 13 was easily achieved by treatment with
Thus, the synthesis of the C15–C26 fragment of dictyostatin
started with the Reformatsky-type reaction between the a-bromo-
a¢-tert-butylsulfinyl ketone (SR)-6,13a,b as a mixture of epimers at
the C stereocenter, and the known aldehyde (S)-7 (Scheme 2).16
Under the typical experimental conditions (SmI2, THF, -78 ◦C),
we could obtained the Reformatsky adduct syn-5 with good
diastereoselectivity (88 : 12 dr)17 and yield (87%).
◦
TBDMSOTf and 2,6-lutidine (CH2Cl2, 0 C to rt), affording the
differently protected triol 14 in 95% yield.
With 14 successfully synthesized, we undertook the transfor-
mation of the sulfoxide in order to install the left fragment of the
C15–C26 unit of dictyostatin (Scheme 3).
Thus, after submitting sulfoxide 14 to the Pummerer reaction (i.
2,4,6-collidine, TFAA, 0 ◦C; ii. NaHCO3), aldehyde 3 was obtained
in 84% yield, after chromatographic purification. The modified
Julia reaction21 of compound 3 with known sulfone 2,22 (LiHMDS,
THF, -78 ◦C to rt), furnished the differently protected tetraol
derivative 15 with 90% yield.
At this point, it was interesting to perform simultaneously the
reduction of the double bond and the deprotection of the benzyl
alcohol at the right end of compound 15. With this aim, we
initially submitted derivative 15 to hydrogenation in the presence
of Pd(OH)2 (MeOH, rt). Under these conditions (Scheme 3),
the double bond of 15 was hydrogenated and the benzyl group
hydrogenolyzed, but the PMB protecting group at C-5 was also
cleaved, giving rise to the corresponding diol 16, in 40% yield.
Next, we tried to perform the required double reduction
process by treatment of 15 with hydrogen in the presence of
Scheme 2 Four-step stereoselective synthesis of advanced intermediate
14 from known compounds 6 and 7.
Next, we performed the protection of the OH group of carbinol
5 as the corresponding OTBDMS ether 8 (TBDMSOTf, lutidine,
CH2Cl2, 0 ◦C to rt, 56%) followed by the diastereoselective
sulfoxide-directed DIBAL-H reduction (THF, -78 ◦C) of the
carbonyl group, to afford carbinol 9 in 54% yield, after chro-
matographic purification. Nevertheless, all attempts to carry out
the protection of alcohol 9, for example as its PMB ether (NaH,
PMBBr, DMF, 0 ◦C), led to migration of the silyl group at C-3 to
yield quantitatively carbinol 10, which, in our hands, proved to be
unreactive to further alcohol protection.
With this result in hand, we decided to carry out the stereoselec-
tive reduction step on unprotected carbinol 5. Thus, the treatment
of the hydroxy ketone 5 (76% de) with 2.4 equiv of DIBALH in
THF at -78 ◦C furnished the corresponding diol 11 (76% de).
The minor component of the mixture could be removed after
one recrystallization affording, in 81% yield, diastereoisomerically
R
RANEYꢀ Ni (EtOH, rt), as depicted in Scheme 3. In this case,
we could observe the formation of the desired saturated primary
alcohol 18 but always accompanied with variable amounts of a
secondary product (depending on the experimental conditions),
later identified as compound 17, in which one of the aromatic
rings of the OTBDPS protecting group at C-9 of 15, had been also
fully hydrogenated to the corresponding cyclohexane ring. Finally,
we could successfully achieve the required goal by using a one-pot
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at 300 and 75 MHz, respectively. All reactions were monitored
by thin layer chromatography that was performed on pre-coated
sheets of silica gel 60, and flash column chromatography was done
with silica gel 60 (230–400 mesh) from Merck. Eluting solvents
are indicated in the text. The apparatus for inert atmosphere
experiments was dried by flaming in a stream of dry argon.
Diisopropylamine was used freshly distilled over KOH. NaH
was washed before use with several portions of hexane. CH2Cl2
was pre-dried over CaCl2, distilled over P2O5 and carefully
kept under an argon atmosphere. Dry THF was distilled from
sodium/benzophenone ketyl. All other reagent quality solvents
were pre-dried over activated molecular sieves and kept under an
argon atmosphere. For routine work-ups, hydrolysis was carried
out with water, extractions with CH2Cl2, and solvent drying with
MgSO4.
(3R,4S,5S)-6-(Benzyloxy)-1-[(R)-tert-butylsulfinyl]-4-hydroxy-
3,5-dimethylhexan-2-one (5)
A solution of SmI2 was freshly prepared by a rapid addition of
diiodomethane (184 mL, 2.3 mmol, 2.0 equiv.) in THF (25 mL) to
samarium powder (376 mg, 2.5 mmol, 2.2 equiv.) at 10 ◦C, under
an Ar atmosphere (do not use a N2 atmosphere). The mixture was
stirred at the same temperature for 1 h in the dark. The solution
turned dark blue and was cooled to -78 ◦C. A solution of g-
bromo-b-ketosulfoxide 613b (290 mg, 1.1 mmol, 1 equiv.) in THF
(3.1 mL) was slowly added and the mixture stirred for 10 min.
Then, a solution of aldehyde (S)-726 (see ESI†) (263 mg, 1.4 mmol,
1.3 equiv.) in THF (3.1 mL) was added dropwise. The resulting
mixture was stirred for 90 min at -78 ◦C and quenched by the
successive addition of HCl 0.1 M (20 mL) and brine (20 mL).
EtOAc (20 mL) was added and the aqueous phase was extracted
with more EtOAc (4 ¥ 20 mL). The organic phase was washed
with saturated aqueous solution of Na2S2O3 (2 ¥ 40 mL) and
brine (40 mL). After work-up and flash chromatography over de-
metalled silica gel27 (EtOAc) without pressure, compound 5 was
obtained, as a 88 : 12 mixture of diastereoisomers, as a yellow oil
(349 mg, 87% yield): Rf 0.38 (MeOH–EtOAc–CH2Cl2 0.3 : 2 : 6);
[a]2D0 = +145.7 (c 0.5, CHCl3); 1H NMR d 7.35–7.26 (m, 5H), 4.53
(s, 2H), 4.07 (dd, J = 9.0 and 3.0 Hz, 1H), 3.66 and 3.52 (AB
system, J = 13.5 Hz, 2H), 3.62 (dd, J = 9.0 and 4.8 Hz, 1H), 3.58
(dd, J = 9.0 and 6.3 Hz, 1H), 2.82 (dq, J = 6.9 and 3.0 Hz, 1H),
1.96 (m, 1H), 1.29 (s, 9H), 1.19 (d, J = 6.9 Hz, 3H), 0.93 (d, J =
6.9 Hz, 3H); 13C NMR d 206.1, 138.0, 128.4, 127.7, 127.7; 74.5,
74.0, 73.5, 56.1, 54.3, 36.0, 22.8, 13.8, 8.0. HRMS (FAB+) calcd
for C19H30O4S [M + H]+ 355.1943, found 355.1943.
Scheme 3 Completion of the synthesis of 1, the C15–C26 unit of
(-)-dictyostatin.
two-step procedure comprising first the treatment of compound 15
R
with RANEYꢀ Ni (EtOH, rt) to afford the unsaturated alcohol
19 (which can be isolated), followed by in situ hydrogenation of
the double bond of 19 giving rise to the saturated carbinol 18, in
82% yield for the one-pot two-step process (Scheme 3).
With compound 18 in hand, we undertook the final steps of
the synthesis to construct the right part of the C15–C26 unit of
dictyostatin, the terminal (Z)-1,3-diene moiety. We chose the pro-
tocol used by Paterson in the total synthesis of discodermolide.23
Thus, the Dess–Martin oxidation (DMP, CH2Cl2, rt) of alcohol
18 furnished the corresponding aldehyde, which, without further
purification, was submitted to a Nozaki–Hiyama24 allylation
followed by a Peterson olefination protocol25 (i. CrCl2, silyl
bromide 4, THF, rt, 16 h; ii. KH, THF, 0 ◦C to rt), to afford
diene 1, the C15–C26 fragment of (-)-dictyostatin, with a 76%
yield for the three last steps.
(3R,4S,5S)-6-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)-
1-[(R)-tert-butylsulfinyl]-3,5-dimethylhexan-2-one (8)
2,6-Lutidine (215 mL, 1.85 mmol, 4.0 equiv.) was added dropwise
to a solution of Reformatsky adduct 5 (76% de) (217 mg,
0.46 mmol, 1.0 equiv.) in CH2Cl2 (3 mL) at 0 ◦C, followed by
the addition of TBDMSOTf (160 mL, 0.69 mmol, 1.5 equiv.).
The reaction mixture was stirred at room temperature for 48 h
and hydrolyzed with an aqueous saturated solution of NH4Cl
(3 mL). After work-up and flash chromatography (hexane–EtOAc
3 : 2), compound 8 was obtained as a colourless oil (123 mg, 56%
yield): Rf 0.75 (EtOAc); [a]2D0 = +45.5 (c 0.85, acetone); 1H NMR d
Experimental
General
Melting points were obtained in open capillary tubes and are
1
uncorrected. H and 13C NMR spectra were recorded in CDCl3
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7.34–7.28 (m, 5H), 4.47 (s, 2H), 4.07 (t, J = 6.0 Hz, 1H), 3.6–3.5 (m,
1H), 3.55 (s, 2H), 3.37 (dd, J = 6.0 and 9.0 Hz, 1H), 3.15–3.05 (m,
1H), 2.0–1.9 (m, 1H), 1.18 (s, 9H), 1.19 (d, J = 6.9 Hz, 3H), 0.93 (d,
J = 6.9 Hz, 3H), 0.88 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H); 13C NMR d
205.7, 138.5, 128.4, 127.6, 127.5, 74.1, 73.1, 72.1, 58.1, 54.1, 50.6,
38.9, 26.1, 22.7, 18.3, 14.6, 13.1, -3.9, -4.2; HRMS (FAB+) calcd
for C25H45O4SSi [M + H]+ 469.2808, found 469.2808.
(9.04 mL, 13.4 mmol, 2.4 equiv.) was slowly added at -78 ◦C and
stirred under these conditions for 3 h. The reaction was hydrolyzed
with methanol (20 mL) and a saturated solution of sodium and
potassium tartrate (60 mL). After the addition of EtOAc (20 mL),
the mixture was vigorously stirred for 2 h, the aqueous layer was
extracted with EtOAc (3 ¥ 30 mL) and the organic layers washed
with brine. After work-up and crystallisation in Et2O (100 mL)
and acetone (1 mL) at -20 ◦C over 2 days, diol 11 was obtained as
a white solid (1.60 g, 81% yield): mp 106–107 ◦C; Rf 0.21 (EtOAc);
(2S,3S,4S,5S)-6-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)-1-
[(R)-tert-butylsulfinyl]-3,5-dimethylhexan-2-ol (9)
1
[a]2D0 = +122.7 (c 1, CHCl3); H NMR d 7.37–7.27 (m, 5H), 4.54
(s, 2H), 4.47 (d, J = 9.3 Hz, 1H), 4.50 (s, 1H), 4.18 (s, 1H), 3.84 (d,
J = 9.0 Hz), 3.62 (dd, J = 3.8 and 13.6 Hz, 1H), 3.45 (dd, J = 9.6
and 13.6 Hz, 1H), 2.72 (dd, J = 9.9 and 12.6 Hz, 1H), 2.41 (dd, J =
2.7 and 12.6 Hz, 1H), 2.02 (m, 1H), 1.72 (dq, J = 1.7 and 6.7 Hz,
1H), 1.26 (s, 9H), 0.97 (d, J = 7.0 Hz, 3H), 0.72 (d, J = 6.9 Hz, 3H);
13C NMR d 137.2, 128.6, 128.0, 127.8, 82.4, 74.0, 71.0, 52.7, 51.6,
39.0, 35.8, 22.9, 12.8, 4.8. HMRS (FAB+) calcd for C19H32O4S [M
+ H]+ 357.2100, found 357.2095.
A solution of DIBAL-H 1.5 M in toluene (120 mL, 0.18 mmol,
2.4 equiv.) was added dropwise to a solution of ketone 8 (35.5 mg,
0.075 mmol, 1 equiv.) in THF (1.5 mL) at -78 ◦C, and stirred
under these conditions for 3 h. The reaction was hydrolyzed
with methanol (4 mL) and a saturated solution of sodium and
potassium tartrate (4 mL). After the addition of EtOAc (4 mL), the
mixture was vigorously stirred for 2 h, the aqueous layer extracted
with EtOAc (3 ¥ 10 mL) and the organic layers washed with brine.
After work-up and flash chromatography (hexane–EtOAc 2 : 3),
carbinol 9 was obtained as a colourless oil (19.1 mg, 54% yield):
(4S,5R,6S)-4-[(S)-1-(Benzyloxy)propan-2-yl]-6-[(R)-tert-
butylsulfinylmethyl]-2,2,5-trimethyl-1,3-dioxane (12)
1
Rf 0.34 (hexane–EtOAc 3 : 2); [a]2D0 = +18.0 (c 0.2, acetone); H
NMR d 7.37–7.27 (m, 5H), 4.51 and 4.46 (AB system, J = 6.0 Hz,
2H); 4.36–4.32 (m, 1H), 3.89 (t, J = 3.0 Hz, 1H), 3.65 (broad s, 1H),
3.52 (dd, J = 6.0 and 9.0 Hz, 1H), 3.32 (dd, J = 6.0 and 9.0 Hz,
1H), 2.61 (dd, J = 9.0 and 12.0 Hz, 1H), 2.46 (dd, J = 3.0 and
12.0 Hz, 1H), 2.21–2.13 (m, 1H), 1.88–1.83 (m, 1H), 1.23 (s, 9H),
0.98 (d, J = 6.0 Hz, 3H), 0.95 (d, J = 6.0 Hz, 3H), 0.08 (s, 3H), 0.05
(s, 3H); 13C NMR d 138.5, 128.3, 127.7, 127.5, 77.2, 73.7, 72.9,
69.9, 53.7, 45.0, 44.1, 36.2, 26.1, 22.6, 18.4, 12.2, 11.7, -3.9, -4.3.
HRMS (FAB+) calcd for C25H47O4SSi [M + H]+ 471.2964, found
471.2968.
To a solution of diol 11 (0.47 g, 1.32 mmol, 1 equiv.) in acetone
(8.25 mL), 2,2-dimethoxypropane (6.48 mL, 52.68 mmol, 40
equiv.) and p-toluenesulfonic acid (0.1 g, 0.39 mmol, 0.3 equiv.)
were added. The reaction mixture was stirred overnight at room
temperature and quenched with a saturated solution of Na2CO3.
After extraction with EtOAc (5 ¥ 20 ml) and work-up, compound
12 was obtained as a yellowish oil (0.501 g, 96% yield): Rf 0.74
(EtOAc–MeOH 9 : 1); [a]D20 = +82.7 (c 1, CHCl3); 1H NMR d 7.29–
7.34 (m, 5H), 4.54 and 4.46 (AB system, J = 12.1 Hz, 2H); 4.5–4.4
(m, 1H), 3.81 (dd, J = 1.7 and 10.1 Hz, 1H), 3.57 (dd, J = 2.9 and
8.7 Hz, 1H), 3.44 (dd, J = 6.2 and 8.7 Hz, 1H), 2.64 (dd, J = 10.4
and 12.4 Hz, 1H), 2.37 (dd, J = 2.1 and 12.5 Hz, 1H), 1.86 (dtd,
J = 3.0, 6.6 and 9.6 Hz, 1H), 1,57 (m, 1H), 1.44 (s, 3H), 1.39 (s,
3H), 1.27 (s, 9H), 0.93 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 6.9 Hz, 3H);
13C NMR d 138.9, 128.3, 127.4, 127.3, 99.6, 73.9, 73.2, 72.1, 67.7,
52.6, 49.9, 35.3, 33.2, 29.8, 19.7, 22.8, 12.6, 5.1. HRMS (FAB+)
calcd for C22H36O4S (M + H)+ 397.2413, found 397.2411.
(2S,3S,4R,5S)-1-(Benzyloxy)-5-(tert-butyldimethylsilyloxy)-6-
[(R)-tert-butylsulfinyl]-2,4-dimethylhexan-3-ol (10)
To a solution of compound 9 (65.5 mg, 0.14 mmol, 1 equiv) in
DMF (460 mL), NaH 60% in mineral oil (6 mg, 0.153 mmol,
1.1 equiv.) was added at 0 ◦C. Then, p-methoxybenzyl bromide
(30.3 mL, 0.21 mmol, 1.5 equiv.) was added dropwise and the
resulting mixture was stirred for 3 h at 0 ◦C and hydrolyzed with
an aqueous saturated solution of NH4Cl (0.5 mL). After work-
up and flash chromatography (hexane–EtOAc 1 : 2), compound
10 was obtained as a colourless oil (65.0 mg, 99% yield): Rf 0.5
(EtOAc); [a]2D0 = +5.55 (c 0.63, CHCl3); 1H NMR d 7.37–7.27 (m,
5H), 4.55 and 4.50 (AB system, J = 12.0 Hz, 2H), 4.19 (ddd, J =
1.0, 5.7 and 9.0 Hz, 1H), 3.90 (d, J = 8.7 Hz, 1H), 3.62 (dd, J =
3.0 and 9.0 Hz, 1H); 3.52 (dd, J = 6.0 and 9.0 Hz, 1H), 3.50 (br
s, 1H), 2.80 (dd, J = 9.0 and 12.0 Hz, 1H), 2.60 (dd, J = 3.0 and
12.0 Hz, 1H), 1.88–1.83 (m, 1H), 1.23 (s, 9H), 0.91 (s, 9H), 0.92
(d, J = 6.0 Hz, 3H), 0.83 (d, J = 6.0 Hz, 3H), 0.20 (s, 3H), 0.10 (s,
3H); 13C NMR d 138.5, 128.5, 127.8, 127.7, 76.4, 73.9, 73.5, 70.2,
53.4, 52.3, 41.3, 36.6, 25.9, 23.0, 18.3, 14.2, 9.1, -4.1, -4.5. HRMS
(ES+) calcd for C25H47O4SSi [M + H]+ 471.2948, found 471.2956.
(2S,3S,4R,5S)-1-(Benzyloxy)-6-[(R)-tert-butylsulfinyl]-5-(4-
methoxybenzyloxy)-2,4-dimethylhexan-3-ol (13)
To mineral oil-free NaH (124 mg, 3.12 mmol, 1.1 equiv.), a solution
of diol 11 (1.01 g, 2.83 mmol, 1.0 equiv.) in DMF (9.4 mL)
was added dropwise at 0 ◦C. After stirring for 15 min at 0 ◦C,
PMBBr (611 mL, 4.24 mmol, 1.5 equiv.) was slowly added. The
reaction mixture was stirred for 4 h at 0 ◦C and overnight at
room temperature, and was quenched with NH4Cl. After work-up
and flash chromatography (hexane–EtOAc 3 : 1), carbinol 13 was
obtained as a colourless oil (1.18 g, 88% yield); Rf 0.30 (MeOH–
EtOAc 1 : 9); [a]2D0 = +72.5 (c 0.85, acetone); 1H NMR d 7.36–7.27
(m, 7H), 6.86 (d, J = 8.7 Hz, 2H), 4.62 and 4.52 (AB system, J =
12.0 Hz, 2H); 4.50 and 4.46 (AB system, J = 12.0 Hz, 2H), 4.03
(ddd, J = 3.0, 6.0 and 9.0 Hz, 1H), 3.80 (s, 1H), 3.77 (d, J = 12.0 Hz,
1H), 3.47 (m, 3H), 2.85 (dd, J = 9.0 and 13.2 Hz, 1H), 2.68 (dd,
J = 3.0 and 13.2 Hz, 1H), 2.05–1.88 (m, 2H), 1.25 (s, 9H), 0.94
(d, J = 7.2 Hz, 3H), 0.80 (d, J = 7.2 Hz, 3H); 13C NMR d 159.3,
137.8, 130.4, 129.7, 128.4, 127.7, 113.8, 77.3, 75.9, 74.8, 73.8, 55.3,
(2S,3R,4S,5S)-6-(Benzyloxy)-1-[(R)-tert-butylsulfinyl]-3,5-
dimethylhexane-2,4-diol (11)
To a solution of ketone 5 (76% de) (1.98 g, 5.6 mmol, 1 equiv.)
in THF (136 mL), a solution of DIBAL-H 1.5 M in toluene
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53.4, 52.6, 49.5, 38.0, 36.4, 22.9, 13.9, 8.6. HRMS (FAB+) calcd
for C27H40O5S [M + H]+ 477.2667, found 477.2675.
solution turned dark orange and was stirred for 30 min at -78 ◦C
and 30 min at 0 ◦C. To this mixture, cooled at -78 ◦C, a solution
of aldehyde 3 (205 mg, 0.40 mmol, 1 equiv.) in THF (666 mL) was
added via a cannula. After additional stirring for 12 h at -78 ◦C,
the reaction was allowed to warm to room temperature for 10 h.
The mixture was quenched with a saturated aqueous solution of
NH4Cl and extracted with EtOAc and CH2Cl2. After work-up and
flash chromatography (hexane, then hexane–EtOAc 1 : 99), olefin
15 was obtained as a colourless wax (285 mg, 90% yield): Rf 0.68
(hexane–EtOAc 5 : 1); [a]D20 = +30.0 (c 0.56, acetone); 1H NMR d
7.70 (d, J = 7.7 Hz, 2H), 7.68 (d, J = 7.7 Hz, 2H), 7.36 (m, 11 H),
7.17 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 5.59 (dd, J = 7.5
and 15.6 Hz, 1H), 5.29 (dd, J = 8.5 and 15.9 Hz, 1H), 4.46 (d, J =
11.5 Hz, 1H), 4.41 (s, 2H), 4.17 (d, J = 11.5 Hz, 1H), 3.78 (s, 3H),
3.69 (dd, J = 3.2 and 4.7 Hz, 1H), 3.53 (m, 4H), 3.22 (dd, J = 7.6
and 9.1 Hz, 1H), 2.41 (qd, J = 6.8 and 13.4 Hz, 1H), 1.95 (ddd, J =
5.2, 7.0 and 12.3 Hz, 1H), 1.73 (m, 1H), 1.07 (s, 9H), 1.01 (d, 3H,
J = 6.8 Hz), 0.96 (d, 3H, J = 6.8 Hz), 0.92 (d, 3H, J = 7.0 Hz), 0.84
(s, 9H), 0.02 (s, 3H), -0.03 (s, 3H); 13C NMR d 159.3, 139.1, 138.3,
135.9, 134.3, 134.2, 131.4, 129.9, 129.8, 128.6, 128.0, 127.8, 127.7,
114.0, 81.9, 76.9, 74.2, 73.3, 73.3, 69.7, 69.1, 55.6, 41.5, 39.9, 39.5,
27.3, 26.5, 19.7, 18.8, 17.5, 14.9, 11.6, -3.4, -3.6; HRMS (ES)
calcd for C49H70O5Si2 [M + Na]+ 817.4654, found 817.4634.
(2S,3S,4S,5S)-1-(Benzyloxy)-3-(tert-butyldimethylsilyloxy)-
6-[(R)-tert-butylsulfinyl]-5-(4-methoxybenzyloxy)-2,4-
dimethylhexane (14)
To a solution of carbinol 13 (1.18 g, 2.47 mmol, 1.0 equiv.) in
DMF (13 mL), 2,6-lutidine (1.15 mL, 9.88 mmol, 4.0 equiv.) and
TBDMSOTf (880 mL, 3.84 mmol, 1.5 equiv.) were successively
added at 0 ◦C. The reaction mixture was stirred overnight at
room temperature and more TBDMSOTf (283 mL, 1.23 mmol,
0.5 equiv.) was added. After stirring for 12 h, more TBDMSOTf
(283 mL, 1.23 mmol, 0.5 equiv.) was added and the reaction was
continued for 6 h. After hydrolysis with NH4Cl, work-up and flash
chromatography (hexane, then hexane–EtOAc 2 : 1, then hexane–
EtOAc 1 : 2), compound 14 was obtained as a colourless oil (1.39 g,
1
95% yield): Rf 0.66 (EtOAc); [a]2D0 = +43.5 (c 1.2, acetone); H
NMR d 7.35–7.23 (m, 7H), 6.84 (d, J = 12.0 Hz, 2H), 4.65 and
4.50 (AB system, J = 10.8 Hz, 2H), 4.44 (s, 2H), 4.03 (ddd, J = 2.2,
5.8 and 8.4 Hz, 1H), 3.84 (t, J = 3.8 Hz, 1H), 3.78 (s, 3H), 3.45 (dd,
J = 6.6 and 9.4 Hz, 1H), 3.29 (dd, J = 7.2 and 9.4 Hz, 1H), 2.68
(dd, J = 2.8 and 13.2 Hz, 1H), 2.6–2.5 (m, 1H), 2.16–1.97 (m, 2H),
1.22 (s, 9H), 1.01 (d, J = 7.1 Hz, 3H), 0.80 (d, J = 6.9 Hz, 3H), 0.89
(s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR d 159.3, 138.7, 130.5,
129.7, 128.3, 127.4, 113.8, 46.1, 73.4, 73.0, 72.8, 55.3, 52.6, 50.4,
40.3, 39.3, 26.1, 22.9, 18.4, 13.9, 12.0, -3.7, -3.9. HRMS (FAB+)
calcd for C33H54O5SSi [M + H]+ 591.3562, found 591.3540.
(2S,3S,4S,5R,8S)-3-(tert-Butyldimethylsilyloxy)-9-(tert-
butyldiphenylsilyloxy)-2,4,8-trimethylnonane-1,5-diol (16)
To a solution of olefin 15 (20 mg, 0.025 mmol, 1 equiv.) in MeOH
(3 mL), Pd(OH)2 (9 mg, 0.025 mmol, 1 equiv.) was added. Then,
H2 was bubbled into the solution with a balloon and stirred under
H2 atmosphere overnight. The reaction mixture was filtered over
celite, rinsed several times with EtOAc. After evaporation of the
solvent and flash chromatography (hexane–EtOAc 1 : 1), diol 16
was obtained as a colourless wax (5.8 mg, 40% yield); Rf 0.53
(2S,3S,4S,5S)-6-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)-2-(4-
methoxybenzyloxy)-3,5-dimethylhexanal (3)
To a solution of sulfoxide 14 (600 mg, 1.01 mmol, 1 equiv.) in
CH3CN (12 mL), 2,4,6-collidine (403 mL, 3.05 mmol, 3.0 equiv.)
and trifluoroacetic anhydride (702 mL, 5.05 mmol, 5.0 equiv.) were
1
◦
(hexane–EtOAc 1 : 1); [a]2D0 = -5.6 (c 0.58, CHCl3); H NMR d
successively ◦added at 0 C. The reaction mixture was stirred for
7.68 (d, J = 7.5 Hz, 2H), 7.68 (d, J = 7.5 Hz, 2H), 7.53–7.32 (m,
6H), 3.81–3.77 (m, 1H), 3.72–3.69 (m, 1H), 3.60 (d, J = 9.0 Hz,
2H), 3.50 (m, 2H), 2.49 (br s, 2H), 2.21–2.12 (m, 1H); 1.73–1.27
(m, 6H), 1.06 (s, 9H), 0.95–0.91 (m, 9H), 0.92 (s, 9H), 0.11 (s, 3H),
0.07 (s, 3H); 13C NMR d 135.6, 134.0, 129.5, 127.6, 78.2, 72.6,
68.8, 65.8, 41.7, 37.7, 35.9, 32.5, 29.8, 26.9, 26.0, 19.3, 18.2, 16.9,
15.6, 9.5, -3.9, -4.2. HRMS (ES) calcd for C34H58O4Si2 [M + Na]+
609.3765, found 609.3782.
15 min at 0 C, quenched with an aqueous saturated solution of
NaHCO3 (15 mL) and the resulting solution was stirred for 2 h at
room temperature. After extraction with EtOAc (4 ¥ 15 mL), work-
up and flash chromatography (hexane–EtOAc 3 : 1), aldehyde 3
was obtained as a colourless wax (425 mg, 84%): [a]2D0 = +80.6 (c
1
0.63, acetone); H NMR d 9.54 (d, J = 4.7 Hz, 1H), 7.39–7.26
(m, 7H), 6.90 (d, J = 8.7 Hz, 2H), 4.62 and 4.48 (AB system, J =
11.9 Hz, 2H), 4.47 (s, 2H), 3.83 (s, 3H), 3.79 (dd, J = 3.1 and 6.4 Hz,
1H), 3.70 (t, J = 4.6 Hz, 1H), 3.55 (dd, J = 5.9 and 9.1 Hz, 1H),
3.25 (dd, J = 6.9 and 9.1 Hz, 1H), 2.27–3.17 (m, 1H), 2.04–1.94
(m, 1H), 0.99 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.90
(s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR d 203.5, 159.5, 138.6,
129.8, 129.5, 129.2, 128.3, 127.6 113.9 84.2, 74.2, 73.1, 72.3, 55.3,
37.8, 26.2, 18.4, 15.1, 14.2, 11.3, -3.8, -4.0. HRMS (ES) calcd for
C29H44O5Si [M + H]+ 501.3010, found 501.3030.
(2S,3S,4S,5R,8S)-9-(tert-Butyl(cyclohexyl)(phenyl)silyloxy)-3-
(tert-butyldimethylsilyloxy)-5-(4-methoxybenzyloxy)-2,4,8-
trimethylnonan-1-ol (17)
To a solution of olefin 15 (75 mg, 0.094 mmol, 1 equiv.) in EtOH
R
(10 mL), activated RANEYꢀ Ni was added at room temperature,
followed by bubbling H2 into the solution with a balloon and
stirred for 7 days at atmospheric pressure. The reaction mixture
was carefully filtered over celite, which must never dry, and rinsed
several times with EtOAc. After evaporation of the solvent alcohol
17 was obtained as a colourless wax (50.8 mg, 75% yield): Rf 0.23
(6S,9R,10S,11S,7E)-11-[(S)-1-(Benzyloxy)propan-2-yl]-9-(4-
methoxybenzyloxy)-2,2,6,10,13,13,14,14-octamethyl-3,3-diphenyl-
4,12-dioxa-3,13-disilapentadec-7-ene (15)
To a well-stirred solution of sulfone 222 (509.7 mg, 1.00 mmol,
2.5 equiv.) in THF (10.0 mL) at -78 ◦C, a solution of lithium
bis(trimethylsilyl)amide (TMS2NLi) 1.0 M in THF (960 mL,
0.96 mmol, 2.4 equiv.) was slowly added via a syringe. The resulting
(hexane–EtOAc 5 : 1); [a]D20 = -7.1 (c 1.9, acetone); H NMR d
1
7.57 (d, J = 8.0 Hz, 2H), 7.36–7.34 (m, 3H), 7.15 (d, J = 8.0 Hz,
2H); 6.75 (d, J = 8.0 Hz, 2H), 4.43 and 4.28 (AB system, J =
12.0 Hz, 2H), 3.79 (s, 3H), 3.76–3.66 (m, 1H), 3.68–3.62 (m, 3H),
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3.50–3.48 (m, 1H), 3.32–3.30 (m, 1H), 2.55 (br s, 1H), 1.94–1.61
(m, 7H), 1.34–1.25 (m, 11H), 0.97 (s, 9H), 0.97–0.87 (m, 9H), 0.92
(s, 9H), 0.13 (s, 3H), 0.11 (s, 3H); 13C NMR d 159.2, 135.5, 134.8,
130.7, 129.5, 128.9, 127.4, 113.8, 81.0, 76.3, 71.4, 69.1, 65.3, 55.3,
39.4, 38.9, 36.5, 29.7, 28.4, 27.4, 27.0, 26.2, 25.0, 19.3, 18.3, 16.9,
14.6, 11.6, -3.5, -3.9. HRMS (ES) calcd for C42H73O5Si2 [M + H]+
713.4986, found 713.4995.
(5S,6S,7R,10S)-5-[(S,Z)-Hexa-3,5-dien-2-yl)-7-(4-
methoxybenzyloxy)-2,2,3,3,6,10,14,14-octamethyl-13,13-diphenyl-
4,12-dioxa-3,13-disilapentadecane (1)
To a solution of alcohol 18 (242 mg, 0.34 mmol, 1.0 equiv.) in
CH2Cl2 (3.5 mL), Dess–Martin periodinane (320 mg, 0.75 mmol,
2.2 equiv.) was added. After stirring for 30 min, hexane (1 mL)
was added and the resulting white suspension was purified directly
by flash chromatography (hexane, then hexane–EtOAc 95 : 5) to
obtain the corresponding aldehyde, which was re-dissolved in THF
(10 mL) along with bromo allyl silane 4 (335 mg, 1.74 mmol,
5.8 equiv.). The resulting solution was added via a cannula to a
suspension of CrCl2 (402 mg, 3.30 mmol, 11.0 equiv.) in THF
(2.2 mL). The reaction mixture was stirred overnight at room
temperature and the resulting suspension was partitioned between
a pH 7 buffer (8 mL) and extracted with EtOAc (3 ¥ 15 mL). After
work-up, the resulting residue was dissolved in THF (4.2 mL)
and added via a cannula to a well-stirred suspension of KH,
pre-washed with hexane, (160 mg, 1.2 mmol, 4.0 equiv.) in THF
(4.2 mL) at 0 ◦C. The reaction mixture was stirred for 2 h at room
temperature and the resulting brown suspension was transferred
via a cannula into H2O (5 mL) and extracted with Et2O (3 ¥ 10 mL).
After work-up and flash chromatography (hexane–EtOAc 95 : 5),
diene 1 was obtained as a colourless wax (190 mg, 76% yield over
three steps): Rf 0.8 (hexane–EtOAc 6 : 1); [a]2D0 = +13.2 (c 0.46,
CHCl3); 1H NMR d 7.56 (d, J = 8.6 Hz, 2H), 7.54 (d, J = 7.6 Hz,
2H), (m, 2H), 7.35–7.33 (m, 6H), 7.21 (d, J = 7.6 Hz, 2H), 6.87
(d, J = 8.6 Hz, 2H), 6.47–6.33 (m, 1H), 5.95 (t, J = 11.0 Hz, 1H),
5.50 (t, J = 10.4 Hz, 1H), 5.12 (d, J = 16.6 Hz, 1H), 5.03 (d, J =
9.9 Hz, 1H), 4.45 and 4.25 (AB system, J = 11.4 Hz, 2H), 3.80
(s, 3H), 3.70–3.57 (m, 3H), 3.27 (dd, J = 10.3 and 5.9 Hz, 1H),
2.70 (m, 1H), 1.98–1.26 (m, 7H), 0.98–0.90 (m, 9H), 0.96 (s, 9H),
0.90 (s, 9H), 0.05 (s, 6H); 13C NMR d 159.1, 135.6, 134.7, 134.1,
132.5, 131.1, 129.5, 128.9, 127.6, 117.1, 113.7, 79.3, 76.8, 70.8,
68.9, 55.3, 40.0, 36.3, 35.9, 28.9, 28.3, 26.9, 26.3, 19.3, 18.9, 18.5,
16.8, 10.8, -3.3, -3.4. HRMS (ESI+) calcd for C45H69O4Si2 [M +
H]+ 729.4716, found 729.4728.
(2S,3S,4S,5R,8S,6E)-3-(tert-Butyldimethylsilyloxy)-9-(tert-
butyldiphenylsilyloxy)-5-(4-methoxybenzyloxy)-2,4,8-
trimethylnon-6-en-1-ol (19)
To a solution of olefin 15 (168 mg, 0.23 mmol, 1 equiv.) in EtOH
R
(18 mL), activated RANEYꢀ Ni was added at room temperature.
The reaction mixture was stirred until complete consumption of
all starting material by TLC. The reaction mixture was carefully
filtered over celite, which must never dry, and rinsed several
times with EtOAc. After evaporation of the solvent and flash
chromatography, alcohol 19 was obtained as a colourless wax
(83 mg, 52% yield): Rf 0.24 (hexane–EtOAc 5 : 1); [a]2D0 = -21.3 (c
1
0.6, acetone); H NMR d 7.68 (d, J = 7.7 Hz, 2H), 7.66 (d, J =
7.7 Hz, 2H), 7.40 (m, 6H), 7.15 (d, J = 7.7 Hz, 2H), 6.72 (d, J =
7.7 Hz, 2H), 5.62 (dd, J = 7.5 and 15.6 Hz, 1H), 5.34 (dd, J = 8.5
and 15.9 Hz, 1H), 4.48 and 4.19 (AB system, J = 12.0 Hz, 2H),
3.86 (t, J = 3.9 Hz, 1H), 3.79 (s, 3H), 3.66–3.44 (m, 5H), 2.68 (t,
J = 3.0 Hz, 1H), 2.41 (qd, J = 6.8 and 13.4 Hz, 1H), 1.95 (m, 1H),
1.73 (m, 1H), 1.03 (s, 9H), 1.01 (d, J = 6.8 Hz, 3H), 0.96 (d, J =
6.8 Hz, 3H); 0.92 (d, J = 7.0 Hz, 3H), 0.84 (s, 9H), 0.11 (s, 3H),
0.07 (s, 3H); 13C NMR d 159.3, 137.6, 134.3, 134.2, 132.8, 129.9,
128.6, 128.0, 127.8, 112.7, 80.9, 74.7, 73.3, 69.3, 68.7, 65.4, 55.2,
40.7, 40.3, 39.5, 26.9, 26.0, 18.3, 17.3, 17.0, 13.5, 12.1, -3.8, -4.0.
HRMS (ES) calcd for C42H64O5Si2 [M + Na]+ 727.4184, found
727.4183.
(2S,3S,4S,5R,8S)-3-(tert-Butyldimethylsilyloxy)-9-(tert-
butyldiphenylsilyloxy)-5-(4-methoxybenzyloxy)-2,4,8-
trimethylnonan-1-ol (18)
To a solution of olefin 15 (327 mg, 0.41 mmol, 1 equiv.) in EtOH
Conclusion
R
(40 mL), activated RANEYꢀ Ni was added at room temperature.
The reaction mixture was stirred until complete consumption of all
starting material by TLC. Then, H2 was bubbled into the solution
with a balloon and stirred for 20 min at atmospheric pressure.
The reaction mixture was carefully filtered over celite, which must
never dry, and rinsed several times with EtOAc. After evaporation
of the solvent and flash chromatography (hexane–EtOAc 4 : 1),
alcohol 18 was obtained as a colourless wax (242 mg, 82% yield):
We have successfully achieved a short and highly stereoselective
preparation of the C15–C26 fragment of the antitumor agent
(-)-dictyostatin in only 10 steps and 28% overall yield, starting
from the known bromo keto sulfoxide 6 and aldehyde 7. Our
synthesis of the natural product fragment, with five stereocenters
and the terminal (Z)-1,3-diene moiety, features two enantiopure
sulfoxide-directed processes, a Reformatsky-type reaction fol-
lowed by a ketone reduction, as the key steps to efficiently generate
the syn-syn stereotriad at C19–C21 of the final target, with high
levels of stereocontrol. Although this exact fragment had not
been previously prepared, our synthesis occurred in an overall
yield similar to other approaches of different northern fragments
obtained from Roche’s ester reported in the literature.4a,b,8e,11b,c,i
With respect to the stereoselectivity, our asymmetric reduction
step took place in a highly diastereoselective manner, whereas the
diastereoselectivity of the Reformatsky-type reaction is slightly
lower than those resulting from aldol reactions4a,b,11b,c,i used by
other authors.
1
Rf 0.23 (hexane–EtOAc 5 : 1); [a]2D0 = +13.2 (c 0.46, CHCl3); H
NMR d 7.68 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.44–
7.34 (m, 6H), 7.21 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.40
and 4.25 (AB system, J = 11.1 Hz, 2H), 3.79 (s, 3H), 3.74 (t, J =
4.9 Hz, 1H), 3.66 (m, 1H), 3.55–3.42 (m, 3H), 3.30–3.25 (m, 1H),
2.52 (broad s, 1H), 1.94–1.77 (m, 2H), 1.69–1.49 (m, 5H), 1.06 (s,
9H), 0.97–0.87 (m, 18H), 0.06 (d, J = 10.7 Hz, 6H);13C NMR d
159.2, 135.6, 134.0, 130.7, 129.5, 129.5, 127.6, 113.8, 80.9, 76.3,
71.3, 68.8, 65.3, 55.3, 39.4, 38.9, 36.1, 29.5, 28.4, 26.9, 26.2, 19.3,
18.3, 16.8, 14.7, 11.6, -3.6, -3.9; HRMS (ES) calcd for C42H66O5Si2
[M + H]+ 707.4529, found 707.4521.
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Acknowledgements
We thank Ministerio de Ciencia e Innovacio´n of Spain (Grant
CTQ2008-04691) and CNRS and Ministe`re de la Recherche
(France) for financial support. L.F.-M and S.V. thank Comunidad
Auto´noma de Madrid (Spain) for fellowships.
12 Review: (a) M. C. Carren˜o, G. Herna´ndez-Torres, M. Ribagorda and
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