Synthetic studies toward the CD spiroketal of spongistatins

Article abstract of DOI:10.1002/ejoc.200901285

Starting from the readily available meso-1,1' -methylenebis(8-oxabicyclo[3. 2.1]oct-6-en-3-one) (1), meso-1,1'-methylenebis[(4Ae,4'S,6fi,6'S)-4,6- dioxycyclohept-l-en-l-yl]tetrasilyl ethers 7 and 8 were obtained and transformed into all-syn 1,3,5,11,13,15-hexahydroxypentadeca-7,9-dione derivatives 9 and 10. The conversion of these intermediates into spiroketals was not successful. An alternative strategy based on the sequential and stereoselective functionalization of 1 afforded a 1-(2,4,6,8-tetrahydroxyoctyl)cyclohept-1-ene- 4,6-diol derivative [(+)-15, 94% ee], Ozonolysis of the cycloheptene moiety of (+)-19 provided the equatorial/axial spiroketal (+)21. Pivaloylation of its primary alcohol moiety and Meerwein methylation of the remaining secondary alcohol unit furnished (-)-24, a potential precursor of the ketal isomer of the CD fragment found in spongistatins 1 and 2.

Full text of DOI:10.1002/ejoc.200901285

FULL PAPER
DOI: 10.1002/ejoc.200901285
Synthetic Studies toward the CD Spiroketal of Spongistatins
Sylvain Favre,[a][‡] Sandrine Gerber-Lemaire,*[a] and Pierre Vogel[a]
Keywords: Spiro compounds / Polyketides / Natural products / Desymmetrization / Alcoholysis
Starting from the readily available meso-1,1Ј-methyl-
a 1-(2,4,6,8-tetrahydroxyoctyl)cyclohept-1-ene-4,6-diol de-
enebis(8-oxabicyclo[3.2.1]oct-6-en-3-one) (1), meso-1,1Ј-meth- rivative [(+)-15, 94% ee]. Ozonolysis of the cycloheptene
ylenebis[(4R,4ЈS,6R,6ЈS)-4,6-dioxycyclohept-1-en-1-yl]tetrasil- moiety of (+)-19 provided the equatorial/axial spiroketal (+)-
yl ethers 7 and 8 were obtained and transformed into all-syn
1,3,5,11,13,15-hexahydroxypentadeca-7,9-dione derivatives 9 methylation of the remaining secondary alcohol unit fur-
and 10. The conversion of these intermediates into spiro- nished (–)-24, a potential precursor of the ketal isomer of the
21. Pivaloylation of its primary alcohol moiety and Meerwein
ketals was not successful. An alternative strategy based on the CD fragment found in spongistatins 1 and 2.
sequential and stereoselective functionalization of 1 afforded
Introduction
Spiroketals and in particular their 6,6-congeners are key
structural elements of a variety of natural products of bio-
logical interest, for example, marine macrolides, ionophores
and polyether antibiotics.[1] The spiroketal fragments are
often very important for the biological activity of the com-
pounds containing them. In particular, spongistatins (al-
tohyrtins), which were isolated from marine sponges of the
genus Spongia by three research groups in 1993,[2] display
two highly oxygenated 6,6-spiroketals in their macrolactone
skeleton (Figure 1). These marine macrolides are potent
cancer cell growth inhibitors and thus appear to represent
promising leads for the development of new anti-cancer
agents.[3] Nevertheless, their use in clinical evaluation is lim-
ited by their low natural abundance, which has stimulated
organic chemists to develop efficient synthetic routes to ad-
dress this supply issue.[4]
In addition to seminal reports by the groups of Evans,[5]
Kishi,[6] Paterson,[7] Smith,[8] Crimmins,[9] Heathcock[10]
and Ley[11] on the total syntheses of spongistatins 1 and
2, much effort has been devoted to the implementation of
straightforward and high-yielding pathways towards the
ABCD “northern” hemisphere[12] and the EF tetrahydropy-
ran subunits.[13] Our group has been involved for several
years in the development of innovative and non-iterative
strategies towards the stereocontrolled synthesis of C15 po-
lyketides and their analogues.[14] Following the recent re-
[a] Laboratory of Glycochemistry and Asymmetric Synthesis, In-
Figure 1. Representative members of the spongistatin (altohyrtins)
family.
stitute of Chemical Sciences and Engineering, Ecole Polytech-
nique Fédérale de Lausanne,
Batochime, 1015 Lausanne, Switzerland
Fax: +41-21-693-9355
E-mail: Sandrine.Gerber@epfl.ch
ports on the synthesis of the polyol subunit of the polyene
macrolide antibiotic RK-397[15] and on an advanced pre-
cursor of the AB spiroketal of spongistatins,[12j] we report
[‡] Current address: Syngenta, 1870 Monthey, Switzerland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901285.
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S. Favre, S. Gerber-Lemaire, P. Vogel
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herein the application of this methodology to the prepara-
tion of potential intermediates of the CD spiroketal frag-
ment.
Results and Discussion
The strategies envisaged for the synthesis of the CD spi-
roketal A (Scheme 1) involve the obtention of the keto po-
lyol precursor B either from diketone C by desymmetri-
zation (path A) or from functionalized cycloheptene D by
oxidative cleavage of the olefin and selective reduction of
the resulting aldehyde (path B). Intermediate C should arise
from the simultaneous functionalization of the diolefin
meso-E, whereas cycloheptene D should result from the
stereoselective transformation of the meso-E, which can be
produced from the readily accessible diketone 1.[14c]
Diketone 1 was converted into the exo-diacetate 2 as pre-
viously reported.[14d] For the approach by path A, silyl
ethers were envisaged as protecting moieties on the C15 skel-
eton. Boron trichloride mediated opening of the oxa bridges
followed by treatment with silyl triflates afforded chlori-
nated cycloheptenes 3 and 4 in 79 and 76% yields, respec-
tively (Scheme 2). A sequence of reductive dechlorination
followed by replacement of the acetyl groups by tert-butyl-
dimethyl or triethylsilyl moieties delivered fully protected
tetrols 7 and 8, respectively.
Scheme 2. Synthesis of the cycloheptene precursors (R = TES,
TBS).
ketone functionalities or inducing decomposition of the
Diketone intermediates of type C were prepared by oxi- starting materials. The use of K-selectride afforded the ex-
dative cleavage of both olefins followed by selective re- pected 1,3-diketone 9 in low yields. Gratifyingly, the reduc-
duction of the aldehyde moieties in situ (Scheme 3). All our ing agent resulting from a mixture of BH3 and 1-amino-
attempts at the dihydroxylation (KMnO4 or OsO4 cat./ ethanol provided an efficient and selective reduction of the
NMO) of dienes 7 and 8 led to decomposition of the start- aldehyde moieties to deliver the 1,3-diketones 9 and 10 in
ing diolefins. Ozonolysis at –78 °C followed by reductive 72 and 75% yields, respectively (two steps). Unfortunately,
treatment with dimethyl sulfide afforded intermediate dial- all our attempts to desymmetrize the 1,3-diketones 9 and
dehydes, which were further reduced in situ to the corre- 10 by enantioselective reduction of one oxo group[16] failed
sponding 1,3-diketones 9 and 10. Treatment with several to produce the expected β-hydroxy ketone in reasonable
hydrides such as NaBH(OAc)3, NaBH4, DIBAL-H or BH3 yields. Typically, by using the Corey–Bakshi–Shibata (CBS)
was not successful, either giving back the starting material methodology,[17] a low conversion (63% yield of recovered
or leading to unselective reduction of both the aldehyde and starting material) led to a mixture of the diastereoisomeric
Scheme 1. Retrosynthetic scheme for the CD spiroketal of spongistatins.
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Synthetic Studies toward the CD Spiroketal of Spongistatins
alcohols 11 and 12 in yields of 10% along with diol 13 (26% 10% of PPTS resulted in a very slow removal of the acet-
yield). Variation of the solvent, the nature of the borane onide moiety, the use of a catalytic amount of p-TsOH in
and the amount of hydride did not give satisfying results. dichloromethane provided a rapid access to diol (+)-19 in
The low yields did not allow conclusive measurement of the 73% yield and established the functionalities for the spiro-
asymmetric induction by the Mosher ester methodology.[18] cyclization step.
As an alternative, reduction of the double bond in the keto
enols 9 and 10 was attempted, but the olefin could not be
hydrogenated. As the desymmetrization of the linear di-
ketones 9 and 10 was not successful, another approach
based on the early-stage desymmetrization of cycloheptene
derivatives of type meso-E (Scheme 1) was developed.
Scheme 4. Stereoselective functionalization following path B.
Opening of the second cycloheptene was achieved by
ozonolysis followed by reductive treatment of the interme-
diate ozonide first with dimethyl sulfide and then with K-
Scheme 3. Exploration of path A.
Selectride to provide the intermediate hemiketal 20 as a
Following path B (Scheme 1) and our previous report,[16] mixture of two diastereoisomers (Scheme 5). The latter was
diolefin meso-2 was converted into the semi-protected hexol not isolated but submitted directly to acidic treatment. The
(+)-15 (Scheme 4). The key reaction of this sequence was use of camphorsulfonic acid led to decomposition of the
the Sharpless asymmetric dihydroxylation reaction for the starting hemiketal. Milder acids such as acetic acid failed
desymmetrization of meso-E to give intermediate diol (–)- to induce spirocyclization. In the presence of trifluoroacetic
14 with 94% ee. Etherification of the remaining secondary acid, partial removal of the primary tert-butyldimethylsilyl
alcohol of (+)-15 in the presence of PMBCl and sodium ether resulted in only 23% yield of the expected spiroketal
hydride led to an inseparable 1:1 mixture of the expected (+)-21. By tuning the strength of the acid, optimal condi-
derivative and the product of migration of the p-meth- tions were achieved with dichloroacetic acid, which af-
oxybenzoyl from the C-1 to the C-6 position of the cyclo- forded (+)-21 in 50% yield from triol (+)-19 (three steps).
heptene. Other sources of the p-methoxybenzoyl group such The structure of the spiroketal was assigned on the basis
1
3
as p-methoxybenzyl trichloroacetimidate (PMBTCA) in the of its 2D NOESY H NMR spectrum. The JH,H coupling
presence of Ph3CBF4 did not prevent the migration of the constants observed for protons 2Ј-H, 3Ј-H, 4Ј-H, 8Ј-H, 9Ј-
ester moiety. Finally, the alcohol at the C-6 position was H and 10Ј-H as well as diagnostic NOEs (2Ј-H/4Ј-H) estab-
eventually protected as a tert-butyldimethylsilyl ether in lished the chair conformation of the two rings with the tert-
high yield (95%). Discrimination between the two p-meth- butyldimethylsilyl ether at C-10Ј being in the axial position.
oxybenzoyl moieties was achieved by alcoholysis in the Cross-peaks between the signals of 5Ј-H and 11Ј-H proved
presence of potassium isopropoxide generated in situ, which the axial orientation of the O-7Ј atom, whereas NOEs be-
afforded alcohol (–)-17 in 83% yield based on recovered tween 5Ј-H/8Ј-H established the equatorial position of O-
starting material (50% yield). Careful monitoring of the re- 1Ј. The configuration of spiroketal (+)-21 was thus assigned
action allowed the reaction to be stopped as soon as the as equatorial/axial whereas the natural target presents an
diol (–)-18 appeared. This was isolated in 5% yield and axial/equatorial configuration of the CD spiroketal. Appar-
could easily be converted back into the starting material ently, the silyl ether moiety at C-10Ј prevents the hydrogen
(+)-16 by esterification. Although treatment of (–)-17 with bridge necessary for the stabilization of the naturally occur-
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S. Favre, S. Gerber-Lemaire, P. Vogel
FULL PAPER
ring configuration, as depicted in the expected analogue 22, tion of the natural axial/equatorial configuration. This syn-
which does not contain the silyl ether moiety.[4] The final thetic route and the previous preparation of a precursor of
functionalizations involved the selective protection of the the AB spiroketal illustrate the high versatility of bicyclic
primary alcohol as a pivaloate ester and methylation of the templates of type E for the asymmetric synthesis of natural
alcohol at C-4Ј in the presence of the Meerwein salt to af- polyketides and their analogues.
ford (–)-24 (66% yield) as a potential highly advanced pre-
cursor of the CD spiroketal of spongistatins.
Experimental Section
General: All commercially available reagents and solvents (Fluka,
Aldrich, Acros) were used without further purification. For reac-
tions requiring anhydrous conditions, dry solvents were bought
(Fluka, Aldrich). Unless otherwise noted, experiments were carried
out under argon. Reactions were monitored by TLC (Merck silica
gel 60F254 plates) with detection by UV light, KMnO4 or Pancaldi
reagents [(NH4)6MoO4, Ce(SO4), H2SO4, H2O]. Purifications were
performed by flash chromatography on silica gel (Merck no. 9385
silica gel 60, 240–400 mesh).
1H NMR spectra were recorded with the Bruker ARX-400 and
DPX-400 spectrometers at 400 MHz and the Bruker AVII-800
spectrometers at 800 MHz. Chemical shifts are given in ppm rela-
tive to the residual 1H solvent signal (MeOD: δ = 3.34 ppm; CDCl3:
δ = 7.27 ppm; C6D6: δ = 7.30 ppm) as the internal reference. 1H
NMR assignments were confirmed by 2D COSY spectra. The mul-
tiplicities given reflect apparent signal patterns. 13C NMR spectra
were recorded with the same instrument as above at 101 MHz.
Chemical shifts are given in ppm relative to the residual 13C solvent
signal (MeOD: δ = 49 ppm; CDCl3: δ = 77 ppm; C6D6: δ =
128.5 ppm). 13C NMR assignments were confirmed by 2D HSQC
spectra. Coupling constants J are given in Hz for all NMR data.
IR spectra were recorded with a Perkin–Elmer Paragon 1000 FT-
IR spectrometer. Mass spectra were recorded with the following
instruments: MALDI-TOF: Axima-CFR+ spectrometer, Kratos;
ESI-Q: Finnigan SSQ 710C spectrometer, Thermoquest; ESI-
HRMS: Q-Tof Ultima spectrometer, Micromass. Elemental analy-
ses were performed at Ilse Beetz, 96301, Kronach, Germany using
an EPFL-ISIC-LCS instrument. Optical Rotations were deter-
mined at 25 °C with a Jasco P-1020 polarimeter; [α] values are given
in units of 10–1 degcm2 g–1.
Methylenebis[(1R,1ЈS,5S,5ЈR,6R,6ЈS)-5-chloro-6-(triethylsilyloxy)cy-
clohept-3-ene-1,3-diyl] Diacetate (3): A 1.0  solution of BCl3 in
DCM (8.6 mL, 3 equiv.) was added dropwise to a stirred solution
of 2 (1 g, 2.9 mmol) in anhydrous DCM (28 mL) at 0 °C. After
stirring at 0 °C for 4 h, a saturated aqueous solution of NaHCO3
(2ϫ30 mL) was added slowly under vigorous stirring and the aque-
ous layer was extracted with DCM (3ϫ20 mL). The combined or-
ganic extracts were dried (MgSO4) and concentrated in vacuo. The
residue was taken up in anhydrous DCM (28 mL) and cooled to
–78 °C. 2,6-Lutidine (2.5 mL, 21.5 mmol 7.5 equiv.) and TESOTf
(2 mL, 8.6 mmol, 3 equiv.) were added. After stirring at –78 °C for
Scheme 5. Spiroketalization and final functionalizations.
Conclusions
We have described the synthesis of an advanced precur-
sor of the CD spiroketal of spongistatins 1 and 2 in 3%
overall yield from the previously reported meso diketone 1 1 h, the mixture was poured into a saturated aqueous solution of
NaHCO3 (25 mL) and extracted with DCM (3ϫ20 mL). The com-
bined organic extracts were dried (MgSO4) and concentrated in
vacuo. Purification by chromatography on silica gel (Et2O/PE, 1:9)
afforded 3 as a colourless oil (1.46 g, 79%). Rf = 0.3 (Et2O/PE,
in 21 steps requiring the isolation of only 12 intermediates.
A sequence of highly stereoselective transformations al-
lowed the installation of the functionalities of the natural
target on the starting bicyclic template. The presence of a
protecting group at C-10Ј prevented the direct formation of
the natural axial/equatorial configuration at the spiro centre
and the thermodynamically favoured axial/axial isomer was
never observed. Removal of the silyl ethers and equilibra-
1:9). IR (film): ν = 2955, 2915, 1730, 1370, 1245, 1100, 1025, 830,
˜
3
770 cm–1 1H NMR (400 MHz, CDCl3): δ = 5.75 (d, JH,H
. =
3
3
8.3 Hz, 2 H, 4-H, 4Ј-H), 4.60 (dddd, JH,H = 11.4, JH,H = 11.4,
3JH,H = 2.8, 3JH,H = 2.8 Hz, 2 H, 1-H, 1Ј-H), 4.46 (dd, 3JH,H = 2.8,
3JH,H = 8.3 Hz, 2 H, 5-H, 5Ј-H), 3.94 (dt, JH,H = 11.4, JH,H
=
3
3
tion in the presence of metal cations such as Mg2+ [5a]
Zn2+ [10b] Ca2+[8a] or Hg2+[11d] should promote the forma- (s, 2 H, 8-H2), 2.47 (q, 2JH,H = 11.4, 3JH,H = 11.4, 3JH,H = 11.4 Hz,
,
2.8, 3JH,H = 2.8 Hz, 2 H, 6-H, 6Ј-H), 2.78 (m, 2 H, 2-H, 2Ј-H), 2.76
,
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Synthetic Studies toward the CD Spiroketal of Spongistatins
2 H, 7-H, 7Ј-H), 2.04 (m, 4 H, 7-H, 7Ј-H, 2-H, 2Ј-H), 2.03 (s, 6 H, 1265, 1180, 740 cm–1. H NMR (400 MHz, CDCl3): δ = 5.51 (m,
1
3
3
3
3
2 OAc), 0.96 [t, JH,H = 7.8 Hz, 18 H, CH3 (TES)], 0.61 [q, JH,H 2 H, 4-H, 4Ј-H), 4.49 (tt, JH,H = 11.4, JH,H = 2.5 Hz, 2 H, 1-H,
= 7.8 Hz, 12 H, CH2 (TES)] ppm. 13C NMR (101 MHz, CDCl3):
δ = 170.1, 141.1, 125.5, 69.3, 69.1, 63.5, 51.0, 40.4, 36.5, 21.3, 6.8,
4.7 ppm. HRMS (ESI): calcd. for C31H54Cl2O6Si2Na [M + Na]+
671.2734; found 671.2724.
1Ј-H); 3.53 (tt, JH,H = 10.5, JH,H = 3.1 Hz, 2 H, 6-H, 6ЈH), 2.70
3
3
2
2
(d, JH,H = 14.2 Hz, 1 H, 8-H2), 2.64 (d, JH,H = 14.2 Hz, 1 H, 8-
H2), 2.37 (dd, 2JH,H = 12.3, 3JH,H = 12.3 Hz, 2 H, 2-H, 2Ј-H), 2.26–
2
2.21 (m, 6 H, 5-H2, 5Ј-H2, 7-H, 7Ј-H), 2.05 (d, JH,H = 12.3 Hz, 2
H, 2-H, 2Ј-H), 2.02 (s, 6 H, 2 OAc), 1.78 (q, JH,H = 11.4, JH,H
2
3
=
Methylenebis{(1R,1ЈS,5S,5ЈR,6R,6ЈS)-5-chloro-6-[(tert-butyl)(di-
methyl)silyloxy]cyclohept-3-ene-1,3-diyl} Diacetate (4): A 1.0 
solution of BCl3 in DCM (5.7 mL, 5 equiv.) was added dropwise
to a stirred solution of 2 (400 mg, 1.15 mmol) in anhydrous DCM
(11 mL) at 0 °C. After stirring at 0 °C for 4 h, a saturated aqueous
solution of NaHCO3 (2ϫ30 mL) was added slowly under vigorous
stirring. The aqueous layer was extracted with DCM (3ϫ20 mL)
and the combined organic extracts were dried (MgSO4) and con-
centrated in vacuo. The residue was taken up in anhydrous DCM
(11 mL) and cooled to –78 °C. 2,6-Lutidine (0.9 mL, 8 mmol
7 equiv.) and TBSOTf (0.8 mL, 3.4 mmol, 3 equiv.) were added. Af-
ter stirring at –78 °C for 1 h, the mixture was poured into a satu-
rated aqueous solution of NaHCO3 (25 mL) and extracted with
DCM (3 ϫ 20 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Purification by chromatog-
raphy on silica gel (Et2O/PE, 1:10) afforded 4 as a colourless oil
3
11.4, JH,H = 11.4 Hz, 2 H, 7-H, 7Ј-H), 0.88 [s, 18 H, (CH3)3CSi],
0.06, 0.05 [2 s, 12 H, (CH3)2Si] ppm. 13C NMR (101 MHz, CDCl3):
δ = 170.0, 136.9, 124.6, 69.3, 68.0, 49.6, 47.8, 37.5, 36.9, 25.9, 21.4,
18.1, –4.8 ppm. HRMS (ESI): calcd. for C31H57O6Si2 [M + H]+
581.3694; found 581.3688.
1,1Ј-Methylenebis[(4R,4ЈS,6R,6ЈS)-4,6-bis(triethylsilyloxy)cyclo-
hept-1-ene] (7): K2CO3 (380 mg, 2.75 mmol, 4 equiv.) was added to
a solution of 5 (400 mg, 0.69 mmol) in MeOH (7 mL). After stir-
ring at 25 °C for 2 h, the mixture was poured into a saturated aque-
ous solution of NaHCO3 (30 mL) and extracted with EtOAc
(3 ϫ 30 mL). The combined organic extracts were washed with
brine, dried (MgSO4) and concentrated in vacuo. The residue was
taken up in anhydrous DCM (7 mL) and cooled to –78 °C. 2,6-
Lutidine (0.15 mL, 1.27 mmol, 7.5 equiv.) and TESOTf (0.12 mL,
0.51 mmol, 3 equiv.) were added dropwise. After stirring at –78 °C
for 1 h, the mixture was poured into a saturated aqueous solution
of NaHCO3 (30 mL) and extracted with DCM (3ϫ30 mL). The
combined organic extracts were dried (MgSO4) and concentrated
in vacuo. Purification by chromatography on silica gel (Et2O/PE,
1:25) afforded 7 as a colourless oil (493 mg, 91%). Rf = 0.33 (Et2O/
(569 mg, 76 %). R = 0.37 (Et O/PE, 1:9). IR (film): ν = 3440
˜
f
2
(H2O), 2930, 2855, 1737, 1240, 1105, 1025, 840 cm–1. 1H NMR
3
(400 MHz, CDCl3): δ = 5.73 (d, JH,H = 8.3 Hz, 2 H, 4-H, 4Ј-H),
4.61 (dddd, 3JH,H = 11.4, 3JH,H = 11.4, 3JH,H = 2.7, 3JH,H = 2.7 Hz,
3
3
2 H, 1-H, 1Ј-H), 4.45 (d, JH,H = 2.7, JH,H = 8.3 Hz, 2 H, 5-H,
3
3
3
PE, 1:25). IR (film): ν = 2950, 2875, 1455, 1240, 1060, 1005,
˜
5Ј-H), 3.94 (dt, JH,H = 11.4, JH,H = 2.7, JH,H = 2.7 Hz, 2 H, 6-
740 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.53 (m, 2 H, 2-H, 2Ј-
2
H, 6Ј-H), 2.76 (m, 4 H, 2-H, 2Ј-H, 8-H2), 2.45 (q, JH,H = 11.4,
3
3
3JH,H = 11.4, JH,H = 11.4 Hz, 2 H, 7-H, 7Ј-H), 2.04 (m, 10 H, 7-
3
H), 4.45 (t, JH,H = 10.8, JH,H = 10.8 Hz, 2 H, 4-H, 4Ј-H), 3.32
3
3
(t, JH,H = 10.8, JH,H = 10.8 Hz, 2 H, 6-H, 6Ј-H), 2.60 (s, 2 H, 8-
H2), 2.30–2.19 (m, 8 H, 3-H2, 3Ј-H2, 5-H, 5Ј-H, 7-H, 7Ј-H), 2.07
(d, JH,H = 13.3 Hz, 2 H, 7-H, 7Ј-H), 1.80 (q, JH,H = 10.8, JH,H
H, 7Ј-H, 2-H, 2Ј-H, 2 OAc), 0.89 [s, 18 H, (CH3)3CSi], 0.08 [s, 12
H, (CH3)2Si] ppm. 13C NMR (101 MHz, CDCl3): δ = 170.1, 141.0,
125.6, 69.4, 69.0, 63.3, 51.0, 40.3, 36.6, 25.7, 21.3, 18.0, –4.6,
–4.9 ppm. HRMS (ESI): calcd. for C31H54Cl2O6Si2Na [M + Na]+
671.2734; found 671.2731.
2
2
3
3
3
= 10.8, JH,H = 10.8 Hz, 2 H, 5-H, 5Ј-H), 0.96 [t, JH,H = 8.0 Hz,
18 H, CH3 (TES)], 0.94 [t, 3JH,H = 8.9 Hz, 18 H, CH3 (TES)], 0.59
3
3
[q, JH,H = 8.0 Hz, 12 H, CH2 (TES)], 0.52 [q, JH,H = 8.9 Hz, 12
H, CH2 (TES)] ppm. 13C NMR (101 MHz, CDCl3): δ = 137.6,
124.6, 68.2, 67.7, 52.9, 50.8, 40.3, 37.8, 6.8, 6.4, 4.7, 4.6 ppm.
HRMS (ESI): calcd. for C39H80O4Si4Na [M + Na]+ 747.5031;
found 747.5056.
Methylenebis[(1R,1ЈS,6R,6ЈS)-6-(triethylsilyloxy)cyclohept-3-ene-
1,3-diyl] Diacetate (5): Bu3SnH (1.5 mL, 5.8 mmol, 3 equiv.) and
AIBN (32 mg, 0.19 mmol, 0.1 equiv.) were added to a solution of
3 in toluene (7 mL) and the mixture was warmed to 80 °C. After
stirring at 80 °C for 3 h, the mixture was concentrated in vacuo.
Purification by chromatography on silica gel (Et2O/PE, 1:9) af-
forded 5 as a colourless oil (609 mg, 57%). Rf = 0.72 (Et2O/PE,
1,1Ј-Methylenebis{(4R,4ЈS,6R,6ЈS)-4,6-bis[(tert-butyl)(dimethyl)silyl-
oxy]cyclohept-1-ene} (8): K2CO3 (216 mg, 1.56 mmol, 4 equiv.) was
added to a solution of 6 (227 mg, 0.39 mmol) in MeOH (4 mL).
After stirring at 25 °C for 2 h, the mixture was poured into a satu-
rated solution of NaHCO3 (10 mL) and extracted with EtOAc
(10 mL, 3 times). The combined organic extracts were washed with
brine, dried (MgSO4) and concentrated in vacuo. The residue was
taken up in anhydrous DCM (4 mL) and cooled to –78 °C. 2,6-
Lutidine (0.3 mL, 2.7 mmol, 7 equiv.) and TBSOTf (0.27 mL,
1.17 mmol, 3 equiv.) were added dropwise. After stirring at –78 °C
for 1 h, the mixture was poured into a saturated aqueous solution
of NaHCO3 (10 mL) and extracted with DCM (3ϫ10 mL). The
combined organic extracts were dried (MgSO4) and concentrated
in vacuo. Purification by chromatography on silica gel (Et2O/PE,
1:50) afforded 8 as a colourless oil (204 mg, 72%). Rf = 0.37 (Et2O/
1:9). IR (film): ν = 2955, 2925, 1730, 1370, 1265, 1245, 1020,
˜
770 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.51 (m, 2 H, 4-H, 4Ј-
3
3
H), 4.49 (t, JH,H = 11.4 Hz, 2 H, 1-H, 1Ј-H), 3.53 (t, JH,H
=
11.4 Hz, 2 H, 6-H, 6Ј-H), 2.69 (d, 2JH,H = 14.5 Hz, 1 H, 8-H2), 2.67
2
(d, JH,H = 14.5 Hz, 1 H, 8-H2), 2.35 (m, 2 H, 2-H, 2Ј-H), 2.24 (m,
6 H, 5-H2, 5Ј-H2, 7-H, 7Ј-H), 2.07 (m, 2 H, 2-H, 2Ј-H), 2.02 (s, 6
H, 2 OAc), 1.80 (q, JH,H = 11.4, JH,H = 11.4, JH,H = 11.4 Hz, 2
2
3
3
3
H, 7-H, 7Ј-H), 0.95 [t, JH,H = 8.0 Hz, 18 H, CH3 (TES)], 0.60
[q, JH,H = 8.0 Hz, 12 H, CH2 (TES)] ppm. 13C NMR (101 MHz,
3
CDCl3): δ = 170.0, 136.9, 124.6, 69.3, 67.7, 49.6, 47.9, 37.6, 36.9,
21.4, 6.8, 4.7 ppm. HRMS (ESI): calcd. for C31H56O6Si2Na [M +
Na]+ 603.3513; found 603.3505.
Methylenebis{(1R,1ЈS,6R,6ЈS)-6-[(tert-butyl)(dimethyl)silyloxy]cy-
clohept-3-ene-1,3-diyl} Diacetate (6): Bu3SnH (0.9 mL, 3.5 mmol,
4 equiv.) and AIBN (14 mg, 0.09 mmol, 0.1 equiv.) were added to
a solution of 4 in toluene (4 mL) and the mixture was warmed to
80 °C. After stirring at 80 °C for 5 h, the mixture was concentrated
in vacuo. Purification by chromatography on silica gel (Et2O/PE,
1:13 to 1:10) afforded 6 as a colourless oil (279 mg, 55%). Rf =
PE, 1:75). IR (film): ν = 3300 (H O), 2915, 2850, 1470, 1265, 1180,
˜
2
1050, 735 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.52 (m, 2 H, 2-
3
3
H, 2Ј-H), 3.45 (t, JH,H = 10.7, JH,H = 10.7 Hz, 2 H, 4-H, 4Ј-H),
3
3
3.34 (t, JH,H = 10.7, JH,H = 10.7 Hz, 2 H, 6-H, 6Ј-H), 2.59 (s, 2
H, 8-H2), 2.27–2.18 (m, 8 H, 3-H2, 3Ј-H2, 5-H, 5Ј-H, 7-H, 7Ј-H),
2.05 (m, 2 H, 7-H, 7Ј-H), 1.75 (q, 2JH,H = 10.7, 3JH,H = 10.7, 3JH,H
= 10.7 Hz, 2 H, 5-H, 5Ј-H), 0.89 [s, 36 H, (CH3)3CSi], 0.61 [s, 24
0.70 (Et O/PE, 1:9). IR (film): ν = 3220, 2915, 2850, 1730, 1470, H, (CH3)2Si] ppm. 13C NMR (101 MHz, CDCl3): δ = 137.6, 124.6,
˜
2
Eur. J. Org. Chem. 2010, 1895–1903
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1899

S. Favre, S. Gerber-Lemaire, P. Vogel
FULL PAPER
68.5, 68.0, 52.7, 50.7, 40.2, 37.8, 25.9, 18.3, –4.7, –4.8 ppm. HRMS
flash chromatography on silica gel (EtOAct/PE, 1:10 to 1:6) to af-
ford (+)-16 as a colourless oil (1.1 g, 95%). Rf = 0.27 (EtOAc/PE,
(ESI): calcd. for C39H81O4Si4 [M + H]+ 725.5212; found 725.5253.
1:8). IR (film): ν = 2930, 2855, 1710, 1605, 1510, 1255, 1165, 1100,
˜
(3S,5S,8Z,11R,13R)-1,9,15-Trihydroxy-3,5,11,13-tetrakis(triethylsil-
yloxy)pentadec-8-en-7-one (9): After degassing the solution using
O2, a stream of ozone was passed at –78 °C through a solution of
7 (25 mg, 0.035 mmol) in DCM (0.5 mL) for 1 min. A stream of
O2 was again passed through the mixture for 1 min and Me2S
(0.01 mL, 0.138 mmol, 4 equiv.) was then added dropwise. After
stirring at –78 °C for 5 min, a solution of 1-aminoethanol
(0.002 mL, 0.034 mmol, 1 equiv.) in BH3·THF (1  in THF,
0.075 mL, 2.2 equiv.) was added dropwise. After stirring at –78 °C
for 1 h, the solution was allowed to warm up to 0 °C. After an
additional hour, methanol (10 mL) was added and the solvents
were removed under reduced pressure. The residue was purified by
flash chromatography on silica gel (DCM/MeOH, 99:1) to afford
9 as a colourless oil (19 mg, 72%). Rf = 0.50 (DCM/MeOH, 98:2).
1
3
835, 770 cm–1. H NMR (400 MHz, CDCl3): δ = 7.99 (d, JH,H
=
3
8.9 Hz, 4 H, COC6H4OCH3), 6.92 (d, JH,H = 8.9 Hz, 4 H, CO-
C6H4OCH3), 5.54 (t, 3JH,H = 6.8 Hz, 1 H, 3-H), 5.35 (m, 1 H, 2ЈЈЈ-
H), 4.81 (m, 1 H, 1-H), 3.98 (m, 1 H, 6ЈЈ-H), 3.90 (m, 1 H, 4ЈЈ-H),
3
3.87 (s, 6 H, 2 COC6H4OCH3), 3.70 (t, JH,H = 6.5 Hz, 2 H, 4ЈЈЈ-
3
3
H2), 3.62 (br. t, JH,H = 10.2, JH,H = 10.2 Hz, 1 H, 6-H2), 2.47–
2
3
2.34 (m, 4 H, 5-H, 7-H, 2-H2), 2.28 (dd, JH,H = 14.1, JH,H
7.1 Hz, 1 H, 1Ј-H), 2.18 (d, JH,H = 13.9 Hz, 5-H), 2.05 (dd, JH,H
= 14.1, JH,H = 5.9 Hz, 1 H, 1Ј-H), 2.01–1.90 (m, 4 H, 1ЈЈЈ-H, 3ЈЈЈ-
=
2
2
3
2
3
3
H2, 7-H), 1.82 (ddd, JH,H = 14.5, JH,H = 5.2, JH,H = 5.2 Hz, 1
H, 1ЈЈЈ-H), 1.64–1.55 (m, 2 H, 5ЈЈ-H2), 1.29 [s, 3 H, (CH3)2C(2ЈЈ)],
1.26 [s, 3 H, (CH3)2C(2ЈЈ)], 0.88 [s, 9 H, (CH3)3CSi], 0.87 [2s, 9 H,
(CH3)3CSi], 0.08 [s, 3 H, (CH3)2Si], 0.07 [s, 3 H, (CH3)2Si], 0.02 [s,
6 H, (CH3)2Si] ppm. 13C NMR (101 MHz, CDCl3): δ = 165.7,
165.4, 163.3, 137.6, 131.5, 123.0, 122.7, 113.5, 100.3, 69.8, 69.4,
67.6, 65.0, 63.9, 59.6, 55.4, 47.8, 45.9, 42.2, 40.4, 38.5, 37.4, 33.5,
25.9, 25.8, 24.8, 24.7, 18.3, 18.1, –4.7, –5.4 ppm. HRMS (ESI):
calcd. for C46H73O10Si2 [M + H]+ 841.4742; found 841.4756.
C46H72O10Si2 (841.2): C 65.68, H 8.63; found C 65.90, H 8.37.
IR (film): ν = 2950, 2915, 1600, 1455, 1375, 1265, 1070, 1000,
˜
745 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.52 (s, 1 H, 8-H), 4.16
3
3
(t, JH,H = 5.6 Hz, 3-H, 13-H), 4.10 (t, JH,H = 5.2 Hz, 2 H, 5-H,
11-H), 3.82 (m, 2 H, 1-H, 15-H), 3.73 (m, 2 H, 1-H, 15-H), 2.45
(m, 4 H, 6-H2, 10-H2), 1.89 (m, 2 H, 2-H, 14-H), 1.74–1.61 (m, 6
3
H, 4-H2, 12-H2, 2-H, 14-H), 0.98 [t, JH,H = 7.7 Hz, 18 H, CH3
(TES)], 0.96 [t, JH,H = 7.7 Hz, 18 H, CH3 (TES)], 0.61 [m, 24 H,
25
25
25
[α]52859 = +3, [α] = +7, [α] = +13, [α] = +17 (c = 0.15, DCM).
577
435
405
3
(–)-(2R)-4-[(tert-Butyl)(dimethyl)silyloxy]-1-[(4S,6R)-6-({(4S,6R)-6-
[(tert-butyl)(dimethyl)silyloxy]-4-hydroxycyclohept-1-en-1-
yl}methyl)-2,2-dimethyl-1,3-dioxan-4-yl]but-2-yl 4-Methoxybenzo-
ate [(–)-17] and (–)-(1S,6R)-6-[(tert-Butyl)(dimethyl)silyloxy]-4-
[((4R,6R)-6-{(2R)-4-[(tert-butyl)(dimethyl)silyloxy]-2-
hydroxybutyl}-2,2-dimethyl-1,3-dioxan-4-yl)methyl]cyclohept-3-en-
1-ol [(–)-18]: Potassium (300 mg, 7.7 mmol, 5 equiv.) was added to
a solution of (+)-16 (1.2 g, 1.54 mmol) in 2-propanol (15 mL) at
0 °C. The reaction was carefully monitored by TLC and poured
into a saturated aqueous solution of NaHCO3 (80 mL) as traces of
diol (–)-18 [Rf = 0.3 (EtOAc/PE, 1:4)] appeared. After extraction
with DCM (3ϫ80 mL) the combined organic extracts were dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash chromatography on silica gel (EtOAc/PE, 1:8 to 2:1) to afford
(+)-15 [480 mg, 39%; Rf = 0.84 (EtOAc/PE, 1:4)], the desired free
alcohol (–)-17 as a colourless oil [504 mg, 50%; Rf = 0.46 (EtOAc/
PE, 1:4)] and diol (–)-18 [41 mg, 5%; Rf = 0.3 (EtOAc/PE, 1:4)].
CH2 (TES)] ppm. 13C NMR (101 MHz, CDCl3): δ = 191.3, 102.4,
68.9, 66.9, 60.1, 46.9, 44.5, 37.7, 6.8, 5.0 ppm. MS (ESI): m/z = 794
[M + H]+. HRMS (ESI): calcd. for C39H85O8Si4 [M + H]+
793.5322; found 793.5334.
(3S,5S,8Z,11R,13R)-1,9,15-Trihydroxy-3,5,11,13-tetrakis[(tert-but-
yl)(dimethyl)silyloxy]pentadec-8-en-7-one (10): After degassing the
solution using O2, a stream of ozone was passed at –78 °C through
a solution of 8 (25 mg, 0.035 mmol) in DCM (0.5 mL) for 1 min.
A stream of O2 was again passed through the mixture for 1 min
and Me2S (0.01 mL, 0.138 mmol, 4 equiv.) was then added drop-
wise. After stirring at –78 °C for 5 min, a solution of 1-amino-
ethanol (0.002 mL, 0.034 mmol, 1 equiv.) in BH3·THF (1  in
THF, 0.075 mL, 2.2 equiv.) was added dropwise. After stirring at
–78 °C for 1 h, the solution was allowed to warm to 0 °C. After an
additional hour, methanol (10 mL) was added and the solvents
were removed under reduced pressure. The residue was purified by
flash chromatography on silica gel (DCM/MeOH, 99:1) to afford
10 as a colourless oil (20 mg, 75%). Rf = 0.48 (DCM/MeOH, 98:2).
Data for (–)-17: IR (film): ν = 2930, 2855, 1710, 1605, 1510, 1255,
˜
1
1165, 1095, 835, 770 cm–1. H NMR (400 MHz, CDCl3): δ = 7.98
IR (film): ν = 2930, 2855, 1715, 1600, 1462, 1360, 1250, 1070, 1005,
˜
3
3
(d, JH,H = 8.9 Hz, 2 H, COC6H4OCH3), 6.92 (d, JH,H = 8.9 Hz,
1
830, 770 cm–1. H NMR (400 MHz, CDCl3): δ = 5.53 (s, 1 H, 8-
3
2 H, COC6H4OCH3), 5.50 (t, JH,H = 6.7 Hz, 1 H, 2ЈЈЈ-H), 5.35
H), 4.14 (t, 3JH,H = 6.4 Hz, 2 H, 3-H, 13-H), 4.07 (t, 3JH,H = 5.6 Hz,
(m, 1 H, 2-H), 3.96 (m, 1 H, 4Ј-H), 3.90 (m, 1 H, 6Ј-H), 3.87 (s, 3
2 H, 5-H, 11-H), 3.81 (m, 2 H, 1-H, 15-H), 3.73 (m, 2 H, 1-H, 15-
3
H, COC6H4OCH3), 3.73 (m, 1 H, 6ЈЈЈ-H), 3.70 (t, JH,H = 6.7 Hz,
2
H), 2.43 (d, JH,H = 6.0 Hz, 4 H, 6-H2, 10-H2), 1.87 (m, 2 H, 2-H,
2
3
2 H, 4-H2), 3.66 (m, 1 H, 4ЈЈЈ-H), 2.38 (dd, JH,H = 14.2, JH,H
=
3
14-H), 1.74 (t, JH,H = 6.4 Hz, 4 H, 4-H2, 12-H2), 1.72–1.65 (m, 2
9.3 Hz, 1 H, 7ЈЈЈ-H), 2.32–2.20 (m, 4 H, 3ЈЈЈ-H2, 1ЈЈ-H, 7ЈЈЈ-H),
H, 2-H, 14-H), 0.90 [s, 18 H, (CH3)3CSi], 0.88 [s, 18 H, (CH3)3CSi],
0.10 [s, 12 H, (CH3)2Si], 0.06 [s, 6 H, (CH3)2Si], 0.04 [s, 6 H, (CH3)
2Si] ppm. 13C NMR (101 MHz, CDCl3): δ = 191.3, 102.6, 68.6,
67.0, 59.8, 46.6, 44.4, 37.8, 25.8, 17.9, 4.4, –4.6, –4.7 ppm. HRMS
(ESI): calcd. for C39H85O8Si4 [M + H]+ 793.5322; found 793.5349.
2
2
2.15 (br. d, JH,H = 12.9 Hz, 1 H, 5ЈЈЈ-H), 2.05 (dd, JH,H = 13.9,
3JH,H = 5.9 Hz, 1 H, 1ЈЈ-H), 1.99–1.88 (m, 4 H, 1-H, 3-H2, 5ЈЈЈ-H),
2
3
3
1.82 (ddd, JH,H = 14.2, JH,H = 5.1, JH,H = 5.1 Hz, 1 H, 1-H),
1.67–1.55 (m, 2 H, 5Ј-H2), 1.26 [s, 3 H, (CH3)2C(2Ј)], 1.27 [s, 3 H,
(CH3)2C(2Ј)], 0.89 [s, 9 H, (CH3)3CSi], 0.87 [2 s, 9 H, (CH3)3CSi],
0.07 [s, 6 H, (CH3)2Si], 0.01 [s, 6 H, (CH3)2Si] ppm. 13C NMR
(101 MHz, CDCl3): δ = 165.6, 163.2, 137.1, 131.5, 123.4, 123.1,
113.5, 100.2, 69.4, 67.9, 67.6, 64.9, 63.9, 59.5, 55.4, 49.2, 46.1, 41.2,
40.4, 38.5, 37.4, 36.4, 25.9, 25.8, 24.8, 24.7, 18.2, 18.0, –4.7, –4.8,
–5.4, –5.5 ppm. HRMS (ESI): calcd. for C38H66O8Si2Na [M +
Na]+ 729.4194; found 729.4168. C38H66O8Si2 (707.1): C 64.55, H
(+)-(1S,6R)-6-[(tert-Butyl)(dimethyl)silyloxy]-4-[((4R,6S)-6-{(2R)-4-
[(tert-butyl)(dimethyl)silyloxy]-2-(4-methoxybenzoyloxy)butyl}-2,2-
dimethyl-1,3-dioxan-4-yl)methyl]cyclohept-3-en-1-yl 4-Methoxy-
benzoate [(+)-16]: 2,6-Lutidine (0.5 mL, 4.11 mmol, 3 equiv.) and
TBSOTf (0.47 mL, 2.06 mmol, 1.5 equiv.) were added dropwise at
–78 °C to a solution of (+)-15 (1 g, 1.37 mmol) in DCM (14 mL).
After stirring at –78 °C for 30 min, the mixture was poured into a
saturated aqueous solution of NaHCO3 (50 mL) and extracted with
DCM (3 ϫ 50 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. The residue was purified by
25
25
9.41; found C 64.75, H 9.28. [α]
= –3, [α]
= +3 (c = 0.15,
589
577
DCM).
Data for (–)-18: IR (film): ν = 2930, 2855, 1470, 1380, 1255, 1095,
˜
1
3
835, 775 cm–1. H NMR (400 MHz, CDCl3): δ = 5.51 (t, JH,H
=
1900
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1895–1903

Synthetic Studies toward the CD Spiroketal of Spongistatins
6.4 Hz, 1 H, 3-H), 4.05 (m, 1 H, 6ЈЈ-H), 3.94–3.87 (m, 2 H, 2ЈЈЈ-H,
chromatography on silica gel (DCM/MeOH, 98:2) to afford (+)-21
4ЈЈ-H), 3.79 (m, 1 H, 4ЈЈЈ-H), 3.71 (m, 1 H, 6-H), 3.66 (m, 1 H, 1- as a colourless oil [60 mg, 50%, four steps starting from the triol
2
3
H), 3.66 (m, 1 H, 4ЈЈ-H), 2.39 (dd, JH,H = 14.7, JH,H = 9.6 Hz, 1 (+)-19]. R = 0.34 (AcOEt/EP, 1:1). IR (film): ν = 2955, 2930, 2855,
˜
f
2
1
H, 5-H), 2.32–2.22 (m, 4 H, 2-H2, 1Ј-H, 5-H), 2.14 (br. d, JH,H
=
1710, 1605, 1255, 110, 835, 775 cm–1. H NMR (400 MHz, C6D6):
2
3
3
3
13.1 Hz, 1 H, 7-H), 2.07 (dd, JH,H = 14.4, JH,H = 6.4 Hz, 1 H,
δ = 8.38 (d, JH,H = 8.9 Hz, 2 H, COC6H4OCH3), 6.86 (d, JH,H =
1Ј-H), 1.91 (m, 1 H, 7-H), 1.69–1.56 (m, 6 H, 1ЈЈЈ-H2, 3ЈЈЈ-H2, 5ЈЈ- 8.6 Hz, 2 H, COC6H4OCH3), 5.90 (dddd, 3JH,H = 6.4, 3JH,H = 6.4,
3
3
H2), 1.36 [s, 3 H, (CH3)2C(2Ј)], 1.34 [s, 3 H, (CH3)2C(2Ј)], 0.89 [s,
18 H, (CH3)3CSi], 0.07 [s, 6 H, (CH3)2Si], 0.06 [s, 6 H, (CH3)2-
Si] ppm. 13C NMR (101 MHz, CDCl3): δ = 136.9, 123.6, 100.4,
69.3, 67.9, 67.6, 66.7, 64.9, 61.1, 49.2, 46.2, 42.8, 41.2, 39.4, 38.4,
3JH,H = 12.0, JH,H = 12.0 Hz, 1 H, 2-H), 4.40 (ddd, JH,H = 11.1,
3
3
3JH,H = 5.5, JH,H = 5.5 Hz, 1 H, 2Ј-H), 4.27 (dddd, JH,H = 9.6,
3
3
3JH,H = 9.6, JH,H = 4.0, JH,H = 4.0 Hz, 1 H, 8Ј-H), 4.15 (br. t,
3JH,H = 4.0 Hz, 1 H, 10Ј-H), 4.09 (dddd, JH,H = 11.1, JH,H
=
=
3
3
3
3
3
36.4, 25.8, 24.8, 18.2, 18.0, –4.8, –5.4 ppm. HRMS (ESI): calcd. for
11.1, JH,H = 5.5, JH,H = 5.5 Hz, 1 H, 4Ј-H), 3.88 (t, JH,H
C30H61O6Si2 [M + H]+ 573.4007; found 573.3983. [α]
= –16,
6.4 Hz, 2 H, 4-H2), 3.79 (m, 2 H, 2ЈЈ-H2), 3.30 (s, 3 H, CO-
C6H4OCH3), 3.01 (dd, JH,H = 13.8, JH,H = 3.7 Hz, 1 H, 5Ј-H),
25
589
25
2
3
[α] = –51 (c = 0.1, DCM).
577
3
3
3
2.29 (ddd, JH,H = 13.8, JH,H = 6.9, JH,H = 6.9 Hz, 1 H, 1-H),
(+)-(3R,5S,7R)-1-[(tert-Butyl)(dimethyl)silyloxy]-8-{(4S,6R)-6-
[(tert-butyl)(dimethyl)silyloxy]-4-hydroxycyclohept-1-en-1-yl}-5,7-di-
hydroxyoct-3-yl 4-Methoxybenzoate [(+)-19]: pTsOH (11 mg,
0.06 mmol, 0.05 equiv.) was added to a solution of (–)-17 (814 mg,
1.15 mmol) in DCM (24 mL) at 0 °C. After 8 h, the reaction was
poured into a saturated aqueous solution of NaHCO3 (50 mL) and
extracted with EtOAc (3ϫ50 mL). The combined organic extracts
were washed with brine, dried (MgSO4) and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel
(DCM/MeOH, 99:1 to 98:2) to afford (+)-19 as a colourless oil
2
3
3
2.17 (ddd, JH,H = 6.5, JH,H = 6.5, JH,H = 6.5 Hz, 2 H, 3-H2),
2
2.07 (br. dd, JH,H = 11.1 Hz, 1 H, 3Ј-H), 1.93 (m, 1 H, 1-H), 1.90
(m, 2 H, 11Ј-H2), 1.83, 1.65 (2 m, 2 H, 1ЈЈ-H2), 1.58 (ddd, JH,H
9.6, JH,H = 9.6, JH,H = 4.0 Hz, 1 H, 9Ј-H), 1.49 (m, 1 H, 9Ј-H),
1.36 (m, 1 H, 5Ј-H), 1.13 (m, JH,H = 11.1, JH,H = 11.1, JH,H
2
=
3
3
2
3
3
=
11.1 Hz, 1 H, 3Ј-H), 1.14 [s, 9 H, (CH3)3CSi], 1.08 [s, 9 H,
(CH3)3CSi], 0.21 [s, 3 H, (CH3)2Si], 0.19 [s, 3 H, (CH3)2Si], 0.13 [s,
3 H, (CH3)2Si], 0.12 [s, 3 H, (CH3)2Si] ppm. 13C NMR (101 MHz,
C6D6): δ = 166.3, 164.1, 132.6, 124.4, 114.4, 99.9, 69.8, 68.5, 66.9,
65.6, 64.9, 61.1, 60.3, 55.3, 44.1, 42.8, 41.9, 41.7, 39.5, 39.2, 38.3,
26.7, 26.5, 19.0, 17.8, –5.0, –5.1, –5.2, –5.6 ppm. HRMS (ESI):
calcd. for C35H62O9Si2Na [M + Na]+ 705.3830; found 705.3859.
(560 mg, 73%). R = 0.48 (DCM/MeOH, 98:2). IR (film): ν = 3385,
˜
f
2925, 2855, 1705, 1605, 1510, 1255, 1165, 1100, 1030, 835 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.98 (d, JH,H = 8.9 Hz, 2 H,
3
25
25
[α] = +3, [α] = –22 (c = 0.12, DCM).
3
589
577
COC6H4OCH3), 6.92 (d, JH,H = 8.9 Hz, 2 H, COC6H4OCH3),
5.60 (t, JH,H = 6.8 Hz, 1 H, 2Ј-H), 5.32 (m, 1 H, 3-H), 4.11 (m, 1
H, 5-H), 3.99 (m, 1 H, 7-H), 3.86 (s, 3 H, COC6H4OCH3), 3.84
3
(–)-(2R)-4-[(tert-Butyl)(dimethyl)silyloxy]-1-{(2S,4S,6R,8S,10S)-10-
[(tert-butyl)(dimethyl)silyloxy]-8-[2-(2,2-dimethylpropanoyloxy)-
(m, 1 H, 4Ј-H), 3.73 (m, 3 H, 1-H2, 6Ј-H), 3.13, 2.49 [d, 2 H, ethyl]-4-hydroxy-1,7-dioxaspiro[5.5]undec-2-yl}but-2-yl 4-Methoxy-
C(OH)], 2.44–2.35 (m, 2 H, 7Ј-H, 3Ј-H), 2.29 (m, 2 H, 7Ј-H, 3Ј-H), benzoate [(–)-23]: A solution of pivaloyl chloride (5 µL, 0.04 mmol,
2
2.18 (br. d, JH,H = 6.5 Hz, 2 H, 8-H2), 2.04–1.97 (m, 5 H, 4-H, 2-
1.5 equiv.) in DCM/Py (0.15 mL, 1:3) was added dropwise to a
solution of (+)-21 (16 mg, 0.023 mmol) in DCM/Py (0.15 mL, 1:3)
2
3
3
H2, 5Ј-H2), 1.87 (dt, JH,H = 14.2, JH,H = 4.9, JH,H = 4.9 Hz, 1
H, 4-H), 1.66 (m, 2 H, 6-H2), 0.87 [s, 18 H, (CH3)3CSi], 0.07 [s, 3 at 0 °C. The mixture was stirred at 0 °C for 5 h. The reaction was
H, (CH3)2Si], 0.06 [s, 3 H, (CH3)2Si], 0.01 [s, 6 H, (CH3)2Si] ppm.
poured into a saturated aqueous solution of NaHCO3 (10 mL) and
13C NMR (101 MHz, CDCl3): δ = 166.1, 63.4, 137.7, 131.6, 125.0, extracted with DCM (3ϫ10 mL). The combined organic extracts
122.7, 113.6, 70.2, 68.1, 67.5, 66.7, 66.3, 59.6, 55.4, 48.5, 48.1, 42.5, were dried (MgSO4) and concentrated in vacuo. The residue was
42.3, 40.7, 37.6, 36.1, 25.9, 25.7, 18.2, 17.9, –4.8, –5.0, –5.4,
–5.5 ppm. HRMS (ESI): calcd. for C35H63O8Si2 [M + H]+
667.4061; found 667.4039. C35H62O8Si2 (667.0): C 63.02, H 9.37;
purified by flash chromatography on silica gel (AcOEt/EP, 1:4) to
afford (–)-23 as a colourless oil (13 mg, 72%), Rf = 0.38 (AcOEt/
EP, 1:4). IR (film): ν = 2925, 2855, 1715, 1605, 1510, 1465, 1255,
˜
25
25
25
found C 63.18, H 9.40. [α]
[α] = +30 (c = 0.2, DCM).
405
= +10, [α]
= +14, [α] = +23,
1165, 1100, 835, 770 cm–1. 1H NMR (400 MHz, C6D6): δ = 8.37
589
577
435
25
3
3
(d, JH,H = 8.6 Hz, 2 H, COC6H4OCH3), 6.86 (d, JH,H = 8.6 Hz,
3
3
3
2 H, COC6H4OCH3), 5.92 (dddd, JH,H = 6.1, JH,H = 6.1, JH,H
= 12.3, JH,H = 12.3 Hz, 1 H, 2-H), 4.41 (m, 1 H, 2Ј-H), 4.38 (m,
(+)-(2R)-4-[(tert-Butyl)(dimethyl)silyloxy]-1-{(2S,4S,6R,8S,10S)-10-
[(tert-butyl)(dimethyl)silyloxy]-4-hydroxy-8-(2-hydroxyethyl)-1,7-di-
oxaspiro[5.5]undec-2-yl}but-2-yl 4-Methoxybenzoate [(+)-21]: A
stream of ozone was passed at –78 °C through a solution of (+)-19
(120 mg, 0.18 mmol) in DCM (6 mL) for 2 min. A stream of O2
was passed through the mixture for 2 min and Me2S (0.03 mL,
0.36 mmol, 2 equiv.) was then added dropwise. After stirring at
–78 °C for 5 min the solvents were evaporated under reduced pres-
sure at –35 °C. The residue was dissolved in THF (6 mL) and co-
oled to –78 °C. At –78 °C, K-selectride (1  in THF, 0.2 mL,
0.2 mmol, 1.1 equiv.) was added dropwise. After stirring at –78 °C
for 1 h, semi-saturated NH4Cl in MeOH was added and the sol-
vents were removed in vacuo. The residue was filtered through a
pad of silica gel (DCM/MeOH, 97:3) to afford a mixture of hemi-
ketals 20. Dichloroacetic acid (1.5 µL, 0.018 mmol, 0.1 equiv.) was
added to a solution of the crude hemiketals in toluene (2.4 mL) at
0 °C. After 5 min the solution was warmed to 25 °C. After 20 min
the reaction mixture was poured into a saturated solution of
NaHCO3 (20 mL) and extracted with EtOAc (3 ϫ20 mL). The
combined organic extracts were washed with brine, dried (MgSO4)
and concentrated in vacuo. The residue was purified by flash
3
2 H, 2ЈЈ-H2), 4.23 (m, 1 H, 8Ј-H), 4.13 (m, 1 H, 10Ј-H), 4.03 (m, 1
3
H, 4Ј-H), 3.89 (t, JH,H = 6.2 Hz, 2 H, 4-H2), 3.31 (s, 3 H, CO-
2
3
C6H4OCH3), 3.01 (dd, JH,H = 13.3, JH,H = 4.0 Hz, 1 H, 5Ј-H),
3
3
3
2.30 (ddd, JH,H = 13.8, JH,H = 6.9, JH,H = 6.9 Hz, 1 H, 1-H),
2.19 (m, 2 H, 3-H2), 2.02 (br. dd, 2JH,H = 12.2 Hz, 1 H, 3Ј-H), 1.92
(m, 1 H, 1-H), 1.89 (m, 2 H, 11Ј-H2), 1.84 (m, 2 H, 1ЈЈ-H2), 1.48
(m, 2 H, 9Ј-H2), 1.37 [s, 9 H, COC(CH3)3], 1.33 (m, 1 H, 5Ј-H),
1.27 (m, 1 H, 3Ј-H), 1.14 [s, 9 H, (CH3)3CSi], 1.08 [s, 9 H, (CH3)
3CSi], 0.21 [s, 3 H, (CH3)2Si], 0.19 [s, 3 H, (CH3)2Si], 0.13 [s, 3 H,
(CH3)2Si], 0.12 [s, 3 H, (CH3)2Si] ppm. 13C NMR (101 MHz,
C6D6): δ = 178.2, 166.1, 164.1, 132.5, 124.4, 114.4, 99.6, 69.8, 66.6,
65.9, 65.4, 65.0, 61.4, 60.4, 55.3, 44.1, 42.7, 42.0, 41.6, 39.4, 38.3,
36.0, 27.9, 26.6, 26.5, 23.6, 18.9, 17.4, –4.4, –4.5, –4.8 ppm. HRMS
(ESI): calcd. for C40H70O10Si2Na [M + Na]+ 789.4405; found
25
25
789.4376. [α] = –5, [α] = +13 (c = 0.1, DCM).
589
577
(–)-(2R)-4-[(tert-Butyl)(dimethyl)silyloxy]-1-{(2S,4S,6R,8S,10S)-10-
[(tert-butyl)(dimethyl)silyloxy]-8-[2-(2,2-dimethylpropanoyloxy)-
ethyl]-4-methoxy-1,7-dioxaspiro[5.5]undec-2-yl}but-2-yl 4-Methoxy-
benzoate [(–)-24]: Me3OBF4 (20 mg, 0.14 mmol, 9 equiv.) was
Eur. J. Org. Chem. 2010, 1895–1903
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1901

S. Favre, S. Gerber-Lemaire, P. Vogel
FULL PAPER
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added to a solution of (–)-23 (12 mg, 0.015 mmol) and a proton
sponge (37 mg, 0.17 mmol, 11 equiv.) in DCM (0.3 mL) at 0 °C.
The mixture was stirred at 0 °C for 30 min. The reaction was
poured into a saturated aqueous solution of NaHCO3 (10 mL) and
extracted with DCM (3ϫ10 mL). The combined organic extracts
were washed with citric acid (10 mL, 10% w/w), dried (MgSO4)
and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (AcOEt/EP, 1:8) to afford (–)-24 as a
colourless oil (8 mg, 66%). R = 0.31 (AcOEt/EP, 1:8). IR (film): ν
˜
f
= 2955, 2925, 2885, 1730, 1715, 1605, 1510, 1460, 1255, 1165, 1095,
3
835 cm–1. 1H NMR (400 MHz, C6D6): δ = 8.37 (d, JH,H = 8.5 Hz,
3
2
H, COC6H4OCH3), 6.85 (d, JH,H
=
8.5 Hz,
2
H, CO-
[4]
[5]
3
3
3
C6H4OCH3), 5.95 (dddd, JH,H = 6.2, JH,H = 6.2, JH,H = 12.0,
3JH,H = 12.0 Hz, 1 H, 2-H), 4.45 (m, 1 H, 2Ј-H), 4.40 (t, JH,H
=
=
3
3
3
3
5.5 Hz, 2 H, 2ЈЈ-H2), 4.24 (dddd, JH,H = 6.2, JH,H = 6.2, JH,H
3
12.0, JH,H = 12.0 Hz, 1 H, 8Ј-H), 4.12 (m, 1 H, 10Ј-H), 3.90 (t,
3JH,H = 6.3 Hz, 2 H, 4-H2), 3.78 (m, 1 H, 4Ј-H), 3.40 [s, 3 H, C(4Ј)
OCH3], 3.31 (s, 3 H, COC6H4OCH3), 3.18 (dd, 2JH,H = 13.6, 3JH,H
= 3.5 Hz, 1 H, 5Ј-H), 2.33 (m, 1 H, 3Ј-H), 2.30 (m, 1 H, 1-H), 2.20
2
3
3
(ddd, JH,H = 6.5, JH,H = 6.5, JH,H = 6.5 Hz, 1 H, 3-H2), 1.96
(m, 1 H, 1-H), 1.89 (m, 4 H, 11Ј-H2, 1ЈЈ-H2), 1.47 (m, 3 H, 5Ј-H,
9Ј-H2), 1.40 (m, 1 H, 3Ј-H), 1.36 [s, 9 H, COC(CH3)3], 1.13 [s, 9
H, (CH3)3CSi], 1.07 [s, 9 H, (CH3)3CSi], 0.21 [s, 3 H, (CH3)2Si],
0.19 [s, 3 H, (CH3)2Si], 0.11 [s, 3 H, (CH3)2Si], 0.09 [s, 3 H, (CH3)2-
Si] ppm. 13C NMR (101 MHz, C6D6): δ = 178.1, 166.1, 164.1,
132.5, 124.4, 114.4, 99.6, 73.9, 69.9, 66.7, 65.9, 65.5, 61.5, 60.4,
55.5, 55.3, 44.2, 41.7, 39.8, 39.4, 38.2, 36.2, 27.8, 26.6, 26.4, 23.6,
8.9, 18.5, –4.2, –4.4, –4.6 ppm. HRMS (ESI): calcd. for C41H72O10-
Si2Na [M + Na]+ 803.4562; found 803.4549. C41H72O10Si2 (781.2):
[6]
[7]
25
25
C 63.04, H 9.29; found C 63.11, H 9.32. [α] = –11, [α] = –16,
589
577
25
25
[α] = –29, [α] = –36 (c = 0.14, DCM).
435
405
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and full analytical data (in-
1
cluding H, 13C and 2D spectra) for compounds 3–10, (+)-16, (–)-
17, (–)-18, (+)-19, (+)-21, (–)-23 and (–)-24.
Acknowledgments
We thank the Swiss National Science Foundation for its generous
financial support. We are grateful to Mr. Martial Rey (NMR spec-
trometry service, ISIC, EPFL), Dr. Laure Menin and Mr. Francisco
Sepulveda (MS service, ISIC, EPFL) for technical help.
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Received: November 9, 2009
Published Online: February 15, 2010
Eur. J. Org. Chem. 2010, 1895–1903
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