Towards the total synthesis of calyculin C: Preparation of the C 9-C25 spiroketal-dipropionate unit

Article abstract of DOI:10.1039/c0ob00092b

An asymmetric synthesis of the C₉-C₂₅ spiroketal fragment of calyculin C is described. Key steps include two crotylation reactions using successively BrowN′s reagent and (Z)-crotyltrifluorosilane for the formation of the anti, anti, anti stereotetrad, ynone formation by a Pd-catalyzed coupling of a thiol ester with a terminal alkyne and a double intramolecular hetero-Michael addition for the stereoselective construction of the spiroketal framework.

Full text of DOI:10.1039/c0ob00092b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Towards the total synthesis of calyculin C: preparation of the C9–C25
spiroketal-dipropionate unit†
Damien Habrant and Ari M. P. Koskinen*
Received 7th May 2010, Accepted 17th June 2010
DOI: 10.1039/c0ob00092b
An asymmetric synthesis of the C9–C25 spiroketal fragment of calyculin C is described. Key steps
include two crotylation reactions using successively Brown’s reagent and (Z)-crotyltrifluorosilane for
the formation of the anti, anti, anti stereotetrad, ynone formation by a Pd-catalyzed coupling of a thiol
ester with a terminal alkyne and a double intramolecular hetero-Michael addition for the
stereoselective construction of the spiroketal framework.
and efficiently inhibit protein phosphatases 1 and 2A (PP1 and
PP2A), two enzymes able to dephosphorylate serine/threonine
Introduction
residues of proteins in eukaryotic cells.10,11 PP2A has been implied
in several disease states, since a wide variety of cellular events
are regulated by reversible protein phosphorylation.12–14 Many
observations support the role of PP2A in tumorigenesis; PP2A
activity and expression are decreased in drug-resistant breast
cancer cells and Alzheimer’s disease, whereas targeted inhibition
of PP1 is a potential strategy for minimizing the symptoms
associated with Parkinson’s disease.15,16 Other naturally occurring
toxins bind to inhibit more or less selectively PP, i.e. okadaic
acid, microcystins, spirastrelloside or tautomycin.17 Even if these
compounds cover a wide structural diversity, it is interesting
to observe that some of the most active compounds contain a
spiroketal moiety in a conformationally flexible position. Our
group has earlier postulated that the spiroketal moiety in calyculins
plays a crucial role in binding to the phosphatase.18
Calyculins are a class of highly cytotoxic metabolites originally
isolated by Fusetani et al. from the marine sponge Discodermia
calyx, collected in the Gulf of Sagami, near Tokyo Bay. Calyculin
A was the first member of the family isolated, in 1986,1 later
followed by calyculins B–H.2,3 The different calyculins vary by
the substitution at C32 and the olefin geometry of the tetraene
moiety (Fig. 1). D. calyx remains today the primary source of
the natural products, the most abundant ones being calyculin
A and C, but Lamellomorpha strongylata has also been shown
to contain calyculins and structurally related calyculinamides.4
Other natural products belonging to the calyculin family include
calyculin J,5 calyculinamides A, B and J,4,5 des-N-methyl calyculin
A,5 dephosphocalyculin A,6 clavosines A–C,7 geometricin A8 and
swinhoeiamide A.9
The interesting biological profile coupled with their spellbinding
structure has made calyculins very attractive targets for synthetic
chemists. Massive efforts have been devoted to the synthesis of
these natural products, leading to the total syntheses of (ent)-
calyculin A by Evans,19 Shioiri20 and Barrett,21 calyculin A by
Masamune,22 (ent)-calyculins A and B by Smith23 and calyculin C
by Armstrong.24 In addition, the Trost group25 and our group26–29
have been involved in the synthesis of individual fragments. We
have recently reviewed these different syntheses, along with some
biological data.30
Results and discussion
Fig. 1 Structures of calyculins.
Retrosynthetic analysis
The C9–C25 spiroketal-dipropionate unit contains 11 of the total
16 chiral centres of calyculin C and therefore represents a very
challenging target. Our strategy for the construction of fully
protected spiroketal 1 relied on a double intramolecular hetero
Michael addition (DIHMA) process on ynone 2 (Scheme 1).
Ynone 2 was thought to arise from the coupling of the C9–C20
alkyne fragment 3 with the C21–C25 thiol ester moiety 4. In turn, we
planned to prepare alkyne 3 through a double crotylation sequence
starting from the known lactone 5.
The calyculins display a wide variety of biological activities. The
high cytotoxicity of calyculins relies on their ability to selectively
Laboratory of Organic Chemistry, Department of Chemistry, Aalto Uni-
versity, School of Science and Technology, PO Box 16100, Kemistintie 1,
FI-00076, Aalto, Finland. E-mail: ari.koskinen@tkk.fi; Fax: +358-9-470
22538; Tel: +358-9-470 22526
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of compounds 1, 2, 3, 7, 8, 9, 10a, 14a, 14b, 16, 17, 19, 20 and 21.
See DOI: 10.1039/c0ob00092b
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Scheme 2 Preparation of aldehyde 9
yields and reproducibility than the previously reported use of
L-Selectride for this reduction.29,35 TBS-protection of the newly-
formed alcohol proceeded well under classical conditions36 to yield
7. Removal of the benzyl protecting group of 7 by hydrogenolysis
furnished the primary alcohol 8, which was then converted to the
corresponding aldehyde 9 by Swern oxidation.
Compound 9 was then submitted to an asymmetric Brown’s
crotylation reaction, using trans-2-butene as the carbon input,
giving rise to the two homoallylic alcohols 10a and 10b, in a
6 : 1 diastereomeric ratio by 1H NMR (in favour of 10a according
to the Brown’s algorithm and previous results by Armstrong33)
and 73% overall yield (Scheme 3). The two isomers could not be
separated at this stage by classical chromatographic techniques
and the following reactions were carried out on the mixture of
homoallylic alcohols. Alkenes 10a and 10b were converted to
the corresponding aldehydes 11a and 11b by successive OsO4-
catalysed dihydroxylation and subsequent oxidative diol cleavage
by NaIO4. The mixture of 11a and 11b was then subjected to a
second crotylation reaction. At this stage, we decided to use the
methodology developed by Roush, using (Z)-crotyltrifluorosilane
12.37 This reaction has been shown to proceed via a bicyclic transi-
tion state in which the b-hydroxyl group is engaged in a chelate with
the (Z)-crotylsilane, affording the anti, anti dipropionate, without
any external source of chirality. However, the authors described
that a sequential acidic (1 N HCl, 15 min) and basic (NaOH 1 N,
1 h) workup was required in order to hydrolyse the intermediate
silylene ketals formed in the course of the reaction.
Scheme 1 Retrosynthetic plan
Double crotylation strategy
The preparation of the anti, anti, anti stereotetrad has proven to
be challenging.31 The use of crotylation reagents appeared to be
the most common method, however, some selectivity issues have
been observed. Barrett extensively used Brown’s reagents in his
formal synthesis of (ent)-calyculin A.32 With a strategy similar
to ours, Armstrong had described that the protecting group at
the C19 hydroxyl played an unexpected but significant role in the
asymmetric induction at C11.24,33 This property unfortunately led
to a poor diastereomeric ratio in the crotylation. We have recently
described a procedure on a model compound, using at first a
classical Brown’s crotylation followed by a second crotylation
using (Z)-crotyltrifluorosilane to overcome this problem.34
The synthesis commenced with lactone 5 (Scheme 2).35 Aldol
reaction between 3-(benzyloxy)-propanal and ethyl 2,2-dimethyl-
3-oxobutanoate, followed by dehydration, asymmetric dihydrox-
ylation and O-methylation provided the expected lactone 5 in
reasonable yields. Stereoselective reduction of 5 using potassium
superhydride in THF was performed in good yield (82%) and
selectivity (>7 : 1 by 1H NMR) to yield 6; superhydride gave better
Applied to our substrate 11, the crotylation reaction seemed to
proceed smoothly, however, after such workup and purification,
only a moderate amount (around 30%) of diols 13 could be
obtained. We assumed that the workup procedure was too harsh
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was enough to hydrolyse the silylene ketals. Indeed, after stirring
for 30 min at rt and simple filtration, the corresponding diols 13
were cleanly obtained. We therefore decided to run the 1,3-diol
protection without any further purification. After acid-catalyzed
reaction with 2-methoxypropene, the two diastereomer acetals
14a and 14b could be obtained and easily separated by simple
column chromatography. Analysis of these products indicate that
(1) the second crotylation occurred in a very selective manner, the
amount of the undesired syn isomers being detected at around 5%
1
by H NMR and (2) both 14a and 14b proved to be the 1,3-syn
acetonides according to the Rychnovsky’s rules,38 with 13C signals
of the acetonide at 19.6, 30.1 and 97.7 ppm for 14a and 19.6,
30.2 and 97.9 for 14b. Altogether, starting from the mixture of
homoallylic alcohols 10, this sequence allowed the synthesis of
14a in 66% and 14b in 53% yield, over 4 steps and involving a
single chromatographic purification.
Conversion to the alkyne
To convert 14a to the acetylenic compound 3, we decided to
use a similar strategy as the one we previously reported for the
construction of the C13–C25 segment.29 Lactone 14a was reduced in
the presence of an excess of LiAlH4. Surprisingly, the TBS group
was cleaved during the course of the reaction and triol 15 was
obtained (Scheme 4). This unexpected result left us with a triol,
whose two secondary hydroxyls could not be easily differentiated
for selective protection. We therefore decided to protect all three
free hydroxyl groups by TES, leading to compound 16. This was
then subjected to the conditions described by Spur for the selective
oxidation of primary silyl ethers,39 which appeared to be efficient in
our case. Indeed, after addition of 16 to a DMSO/oxalyl chloride
solution in CH2Cl2 at -78 ◦C, we observed that stirring the reaction
mixture for 1 h at -35 ◦C before addition of Et3N at -78 ◦C cleanly
cleaved and oxidized the primary TES to give aldehyde 17 in a
good isolated yield of 78%. Finally, homologation of aldehyde
17 to the corresponding terminal alkyne 3 was performed using
the Ohira–Bestmann method;40 the reaction required 48 h at rt to
reach completion and alkyne 3 was obtained in a good yield of
88%.
Coupling and spirocyclisation
Compound 4 was prepared according to our previously reported
procedure.29 For coupling of the two key intermediates 3 and
4, we decided to use the method developed by Fukayama
(CuI, PdCl2(dppf), P-(2-furyl)3 in a DMF/Et3N (5 : 1) mixture
at 50 ◦C).41 As already reported by us29 and Kuwahara in his total
synthesis of pteridic acids A and B,42 this reaction only gave a
moderate yield of the expected ynone. In this case ynone 2 was
obtained in an acceptable 50% yield (Scheme 5). The relatively
low yield is due to the oxidative homocoupling of the acetylenic
compound 3, leading to the formation of the corresponding
Glaser-type diyne 18. This side reaction precluded the reaction
to go to completion and unreacted thiol ester 4 could be recovered
(in our case, dimer 18 and 4 co-eluted during the purification
by flash chromatography and therefore could not be separated).
However, based on our previous studies on a model substrate, this
method proved to be the only one allowing the preparation of the
expected ynone.29
Scheme 3 The double crotylation strategy
for our substrate. Pleasingly, we found out that, after treating a
0.08 M solution of 11 in CH2Cl2 with 320 mol% of 12 in the
◦
presence of 300 mol% of DIPEA for 36 h at 0 C (as described
in the original procedure), simply adding silica gel to the mixture
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Scheme 4 Synthesis of alkyne 3
by Crimmins in 1990,43 and later elegantly used by Forsyth in a
number of total syntheses.44 In his 2009 preparation of the C3–
C14 domain of 7-deoxyokadaic acid, Forsyth used the DIHMA
protocol to efficiently convert a di-TES protected ynone to the
corresponding spiroketal, by simply treating the ynone with 120
mol% of p-TsOH in toluene for 24 h.45 We also applied these
conditions for the preparation of the C13–C35 fragment with an
acceptable yield.29 Unfortunately, applied to our substrate ynone
2, the same conditions (with a slightly larger excess of p-TsOH,
180 mol%, due to the presence of a third TES group) only
furnished the expected spiroketal 19 in a poor 33% yield. After
an optimization study on this reaction and some unsuccessful
attempts (TMSOTf in CH3CN–CH2Cl2, TBAF in THF, PPTS in
CH2Cl2, (+)-CSA in MeOH), we were pleased to find out that
the treatment of 2 with (+)-CSA (15 mol%) in a 4 : 1 mixture
of CH2Cl2–MeOH for 1 h at rt, followed by evaporation of the
solvent and subsequent treatment of the residue with p-TsOH (20
mol%) in toluene for 4 h furnished a mixture of two spiroketals,
19 and its TES-protected analog 20, with a combined yield of
78% (Scheme 6). This protocol turned up to be very efficient
for the spiroketal formation. After separation, 19 could be easily
converted to 20 under classical conditions (TESOTf, 2,6-luditine
in CH2Cl2, 85% yield). We then set up a 3-step sequence where
ynone 2 was successively treated with (+)-CSA and p-TsOH as
described above and, after simple filtration and concentration,
the mixture of spiroketals 19 and 20 was directly treated with
TESOTf. This allowed the efficient preparation of 20 from 2 in a
single operation, with a very satisfying 67% yield. Ketone 20 was
Scheme 5 Pd-catalyzed coupling of 3 and 4
With ynone 2 in hand, we then focused our attention on the key
spirocyclisation step. The DIHMA protocol was first introduced
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Scheme 6 Last steps to 1
then stereoselectively reduced with L-Selectride46 to yield 21, as a
single axial diastereomer (the axial configuration was confirmed
by examination of the IR spectra and a narrow O–H bond stretch
at 3542 cm-1, confirming the hydrogen bond between the hydrogen
of the newly-formed hydroxyl with the oxygen of the 5-membered
ring of the spiroketal). Finally, 21 was protected as its acetate ester,
by refluxing for two days in the presence of an excess of Ac2O and
Et3N in CH2Cl2, to complete the synthesis of 1 in an excellent
yield.
this orthogonally protected fragment should prove amenable for
the total synthesis of diverse members of the calyculin family.
Moreover, spiroketals 19, 20, 21 and 1 can be directly used to
study the binding to the phosphatase and therefore provide useful
information on the mode of action of calyculins and related
inhibitors of PP1 and 2A, since the spirocyclic part of the calyculins
is thought to play a crucial role in the binding.
Experimental section
Conclusions
General methods
In conclusion, we have achieved the synthesis of the fully protected
C9–C25 spiroketal dipropionate fragment 1 of calyculin C in 4%
yield over 19 steps based on the longest linear sequence starting
from lactone 5. We were able to build the key anti, anti, anti
stereotetrad via a highly selective double crotylation strategy. The
key spirocyclisation step proved the efficiency of the DIHMA
method and validated our planned strategy. We believe that
All moisture sensitive reactions were carried out under an argon at-
mosphere in flame-dried glassware. Dry oxygen free THF, CH2Cl2
and toluene were obtained by passing deoxygenated solvents
through activated alumina columns. MeOH was obtained by
distillation over magnesium methoxide, DMF by distillation over 4
˚
A molecular sieves and ninhydrin, Et3N and DMSO by distillation
˚
over CaH2 and storage over 4 A molecular sieves. Oxalyl chloride
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was freshly distilled prior to use. CuI was purified using a standard
method.47 Other solvents and reagents were used as obtained
from supplier. Analytical TLC were performed using silica gel
F254 (10–12 mm) plates and analyzed by UV light (254 or 366
nm) and by staining upon heating with standard permanganate
or phosphomolybdic acid solutions. Flash chromatography was
carried out on silica gel 60 (230–400 mesh) and p.a. grade solvents.
The 1H NMR and 13C NMR spectra were recorded in CDCl3 (1H
399.98 MHz; 13C 100.59 MHz) spectrometer. The chemical shifts
are reported in ppm relative to CHCl3 (d 7.26) for 1H NMR and
(d 77.16) for 13C NMR. Multiplicities are indicated by s (singlet),
d (doublet), t (triplet), q (quadruplet), m (multiplet), br (broad).
Coupling constants, J, are reported in Hertz. Melting points are
uncorrected.
9H), 1.20 (s, 3H), 1.24 (s, 3H), 1.69-1.78 (m, 1H), 1.84-1.92 (m,
1H), 2.17 (bs, 1H), 3.48 (s, 3H), 3.70-3.75 (m, 1H), 3.79-3.83 (m,
2H), 4.14 (d, J = 5.2 Hz, 1H), 4.43 (t, J = 5.5 Hz, 1H); 13C NMR
(CDCl3): d -3.9, -3.4, 18.4, 19.4, 24.6, 26.1, 33.1, 44.8, 59.1, 59.8,
76.9, 77.4, 83.0, 180.6; IR (nmax, thin film): 3436, 2954, 2931, 2859,
1775, 1472, 1464, 1390, 1132, 1100 cm-1; HRMS: calculated for
C16H32O5NaSi [M+Na]+: 355.1917, found: 355.1922.
(S)-3-((2R,3R)-3-(tert-butyldimethylsilyloxy)-4,4-dimethyl-5-
oxotetrahydrofuran-2-yl)-3-methoxypropanal 9. DMSO (0.3 mL,
3.5 mmol, 120 mol%) was added at -78 ◦C to a solution of oxalyl
chloride (0.3 mL, 3.8 mmol, 130 mol%) in CH2Cl2 (20 mL); gas
evolution was observed. After 15 min at -78 ◦C, a solution of
alcohol 8 (0.97 g, 2.9 mmol, 100 mol%) in CH2Cl2 (10 mL) was
added. The reaction mixture was stirred for 1 h at -78 ◦C before
addition of Et3N (1.2 mL, 8.7 mmol, 300 mol%). The solution was
allowed to warm to rt and CH2Cl2 was evaporated. The residue was
taken up with Et2O (30 mL) and a saturated aqueous solution of
NH4Cl (20 mL). After separation of phases, the organic layer was
dried over MgSO4 and concentrated in vacuo to give aldehyde 9
(4R,5S)-5-((S)-3-(benzyloxy)-1-methoxypropyl)-4-hydroxy-3,3-
dimethyldihydrofuran-2(3H)-one 6. Lactone 5 (3.5 g, 11.42 mmol,
100 mol%) was dissolved in THF (50 mL). The solution was cooled
◦
to -78 C and KHBEt3 (1 M in THF, 12.6 mL, 12.6 mmol, 110
mol%) was added. After 1 h 30 min, the reaction was quenched by
addition of a saturated aqueous solution of NH4Cl (20 mL). After
separation of phases, the aqueous phase was extracted with EtOAc
(30 mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo. Purification by flash chromatography
(Hex/AcOEt: 80 : 20 to 50 : 50) afforded compound 6 (2.88 g, 82%)
as a colourless oil. Spectral data were in agreement with those
previously reported.35
(0.96 g, quant.), as a colourless oil. Rf: 0.59 (Hex/EtOAc: 50 : 50);
1
[a]D = -20.7 (c 1, CHCl3); H NMR (CDCl3): d 0.11 (s, 3H),
20
0.12 (s, 3H), 0.95 (s, 9H), 1.21 (s, 3H), 1.26 (s, 3H), 2.76 (ddd, J
= 17.7, 6.0, 1.4 Hz, 1H), 2.82 (ddd, J = 17.7, 6.1, 1.1 Hz, 1H),
3.41 (s, 3H), 4.04 (dt, J = 6.1, 4.0 Hz, 1H), 4.22 (d, J = 6.5 Hz,
1H), 4.42 (dd, J = 6.4, 3.9 Hz, 1H), 9.84 (t, J = 1.1 Hz, 1H); 13C
NMR (CDCl3): d -4.1, -3.9, 18.4, 19.4, 26.0, 26.1, 43.8, 45.0, 58.2,
72.8, 77.1, 81.7, 108.8, 200.4; IR (nmax, thin film): 2955, 2932, 2589,
1777, 1724, 1472, 1390, 1257, 1132, 1098 cm-1; HRMS: calculated
for C16H30O5NaSi [M+Na]+: 353.1760, found: 353.1756.
(4R,5R)-5-((S)-3-(benzyloxy)-1-methoxypropyl)-4-(tert-butyldi-
methylsilyloxy)-3,3-dimethyldihydrofuran-2(3H)-one 7. Lactone
6 (2 g, 6.5 mmol, 100 mol%) was dissolved in CH2Cl2 (30 mL). The
solution was cooled to 0 ◦C and 2,6-lutidine (3.03 mL, 26 mmol,
400 mol%) and TBSOTf (3 mL, 13 mmol, 200 mol%) were
successively added. The mixture was stirred overnight at rt. The
reaction was quenched by addition of a saturated aqueous solution
of NH4Cl (20 mL). After separation of phases, the aqueous phase
was extracted with CH2Cl2 (15 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. Purification
by flash chromatography (Hex/EtOAc: 95 : 5 to 80 : 20) afforded
protected compound 7 (2.34 g, 85%), as a colourless oil. Rf:
(4R,5R)-4-(tert-butyldimethylsilyloxy)-5-((1S,3S,4R)-3-hydro-
xy-1-methoxy-4-methylhex-5-enyl)-3,3-dimethyl
dihydrofuran-
2(3H)-one 10a and (4R,5R)-4-((tert-butyl dimethylsilyl)oxy)-5-
((1S,3R, 4S)-3-hydroxy-1-methoxy-4-methylhex-5-en-1-yl)-3,3-
dimethyldihydrofuran-2(3H)-one 10b. To a solution of t-BuOK
(0.76 g, 6.7 mmol, 200 mol%) in THF (5 mL) were successively
added E-butene (3 mL) and n-BuLi (2.3 M in hexanes, 2.9 mL,
6.7 mmol, 200 mol%) at -78 ◦C. The yellow solution was stirred for
30 min at -45 ◦C. A solution of (+)-IpcBOMe (2.13 g, 6.7 mmol,
200 mol%) in THF (5 mL) was then added at -78 ◦C. After
30 min, BF3·OEt2 (0.85 mL, 6.7 mmol, 200 mol%) was added,
followed by a solution of aldehyde 9 (1.11 g, 3.4 mmol, 10◦0 mol%)
in THF (5 mL). The mixture was stirred for 2 h at -78 C, then
MeOH (5 mL) was added and the mixture was allowed to warm to
rt. Solvents were evaporated and the residue◦taken up in THF (20
mL) and H2O (10 mL). After cooling to 0 C sodium perborate
(1 g) was added and the mixture was stirred overnight at rt. More
water was added (20 mL) and, after extraction with EtOAc (40
mL), the organic layers were dried over MgSO4 and concentrated
in vacuo. Purification by flash chromatography (Hex/EtOAc:
95 : 5 to 75 : 25) afforded the homoallylic alcohols 10 (0.95 g,
73%) as a 6 : 1 mixture of diastereomers. Data for major isomer
10a (obtained from the mixture): Rf: 0.44 (Hex/EtOAc: 80 : 20);
1H NMR (CDCl3): d 0.09 (s, 3H), 0.10 (s, 3H), 0.93 (s, 9H), 1.06
(d, J = 6.8 Hz, 3H), 1.21 (s, 3H), 1.24 (s, 3H), 1.54-1.62 (m, 1H),
1.75 (ddd, J = 14.4, 6.0, 1.9 Hz, 1H), 2.15-2.22 (m, 1H), 2.72
(d, J = 2.2 Hz, 1H), 3.46 (s, 3H), 3.64-3.68 (m, 1H), 3.77 (q, J =
6.1 Hz, 1H), 4.17 (d, J = 5.2 Hz, 1H), 4.50 (t, J = 5.5 Hz, 1H),
5.06-5.12 (m, 2H), 5.78 (ddd, J = 17.0, 10.5, 8.2 Hz, 1H); 13C
0.57 (Hex/EtOAc: 70 : 30); [a]D = -13.3 (c 1, CHCl3); 1H NMR
20
(CDCl3): d 0.09 (s, 3H), 0.11 (s, 3H), 0.91 (s, 9H), 1.18 (s, 3H),
1.19 (s, 3H), 1.79-1.95 (m, 2H), 3.41 (s, 3H), 3.57-3.71 (m, 3H),
4.15 (d, J = 5.5 Hz, 1H), 4.43 (t, J = 5.5 Hz, 1H), 4.45-4.52 (m,
2H), 7.26-7.35 (m, 5H); 13C NMR (CDCl3): d -3.9, -3.4, 18.4, 19.4,
24.9, 26.1, 31.1, 44.6, 58.7, 66.3, 73.2, 75.3, 77.4, 82.9, 127.7, 127.8,
128.4, 138.4, 180.9; IR (nmax, thin film): 2983, 2930, 2858, 1777,
1463, 1389, 1259, 1134, 1101; HRMS: calculated for C23H38O5NaSi
[M+Na]+: 445.2386, found: 445.2388.
(4R,5R)-4-(tert-butyldimethylsilyloxy)-5-((S)-3-hydroxy-1-met-
hoxypropyl)-3,3-dimethyldihydrofuran-2(3H)-one 8. Benzyl pro-
tected lactone 7 (1.54 g, 3.64 mmol, 100 mol%) was dissolved in
EtOH (60 mL). Pd(OH)2 (20% on carbon, 0.307 g, 0.44 mmol,
10 mol%) was added. The mixture was flushed first by 3 cycles
vacuum/argon then 3 cycles vacuum/H2. After 1 h, the mixture
was filtered through a pad of Celite, washed with EtOH (30 mL)
and concentrated to yield alcohol 8 (1.21 g, quant.) as a white
solid. Rf: 0.26 (Hex/EtOAc: 50 : 50); Mp: 57 ◦C; [a]D = -17.4 (c
20
1, CHCl3); 1H NMR (CDCl3): d 0.09 (s, 3H), 0.10 (s, 3H), 0.93 (s,
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NMR (CDCl3): d -3.8, -3.4, 16.3, 18.5, 19.5, 24.8, 26.1, 34.2, 44.8,
45.2, 58.6, 72.3, 77.3, 77.5, 82.4, 116.4, 140.1, 180.8; IR (nmax, thin
film): 3501, 2958, 2931, 2859, 1773, 1472, 1390, 1132, 1101 cm-1;
HRMS: calculated for C20H38O5NaSi [M+Na]+: 409.2386, found:
409.2394.
2.5 Hz, 1H), 2.37-2.46 (m, 1H), 3.38 (dd, J = 10.2, 2.2 Hz, 1H),
3.45 (s, 3H), 3.48-3.53 (m, 1H), 3.71 (dt, J = 10.3, 2.5 Hz, 1H),
3.64 (ddd, J = 10.1, 5.1, 2.7 Hz, 1H), 4.12 (d, J = 5.7 Hz, 1H),
4.28 (t, J = 5.4 Hz, 1H), 4.94-5.00 (m, 2H), 5.83 (ddd, J = 17.1,
10.4, 9.0 Hz, 1H); NMR 13C (CDCl3): d -3.7, -3.6, 11.7, 18.2, 18.4,
19.4, 19.6, 25.1, 26.1, 30.2, 36.7, 36.8, 39.7, 44.5, 59.6, 70.2, 73.8,
77.3, 77.4, 84.7, 97.9, 115.0, 139.9, 181.0; IR (nmax, thin film): 2961,
2931, 2859, 1778, 1472, 1380, 1256, 1202 cm-1; HRMS: calculated
for C26H48O6NaSi [M+Na]+: 507.3118, found: 507.3105.
(4R,5R)-5-((S)-2-((4S,5S,6R)-6-((R)-but-3-en-2-yl)-2,2,5-trim-
ethyl-1,3-dioxan-4-yl)-1-methoxy ethyl)-4-(tert-butyl dimethylsily-
loxy)-3,3-dimethyldihydrofuran-2(3H)-one 14a and (4R,5R)-5-
((S)-2-((4R,5R,6S)-6-((S)-but-3-en-2-yl)-2,2,5-trimethyl-1,3-dio-
(5R,6R)-5-((S)-2-((4S,5S,6R)-6-((R)-but-3-en-2-yl)-2,2,5-trim-
ethyl-1,3-dioxan-4-yl)-1-methoxyethyl)-3,3,10,10-tetraethyl-7,7-
xan-4-yl)-1-methoxyethyl)-4-(tert-butyl
dimethyldihydrofuran-2(3H)-one 14b. To
dimethylsilyloxy)-3,3-
solution of
a
dimethyl-6-(triethylsilyloxy)-4,9-dioxa-3,10-disiladodecane
16.
homoallylic alcohols 10a and 10b (0.99 g, 2.6 mmol, 100
mol%) in a 10 : 3 : 1 mixture of t-BuOH/THF/H2O (14 mL) were
successively added OsO4 (2.5% in t-BuOH, 0.37 mL, 0.03 mmol,
5 mol%) and NMO (83 mg, 0.7 mmol, 120 mol%). After stirring
overnight at rt, the reaction was quenched by addition of a
saturated aqueous solution of NaHSO3 (5 mL) and the mixture
was stirred for 1 h at rt. After extraction with EtOAc (10 mL), the
organic layers were dried over MgSO4 and concentrated in vacuo.
The residue was taken up in THF (23.5 mL) and H2O (2.5 mL)
and treated with NaIO4 (1.64 g, 7.65 mmol, 300 mol%). After 1 h,
Et2O (20 mL) and H2O (20 mL) were added. After separation of
phases, the organic layer was dried over MgSO4 and concentrated
in vacuo to give a mixture of aldehydes 11.
To a suspension of LiAlH4 (0.171 g, 4.52 mmol, 200 mol%) in
THF (25 mL) was added a solution of 14a (1.09 g, 2.26 mmol,
100 mol%) in THF (15 mL) at 0 ◦C. The mixture was stirred
1 h at 0 ◦C and then quenched by successive addition of H2O
(0.2 mL), 15% NaOH (0.2 mL) and H2O (0.6 mL). After 30 min,
the precipitate was filtered and washed with EtOAc (20 mL).
The combined organic solution was dried over MgSO4 and
concentrated in vacuo to afford crude triol 15.
Triol 15 was then dissolved in CH2Cl2 (50 mL). 2,6-Lutidine
(3.58 mL, 30.7 mmol, 1200 mol%) and TESOTf (2.8 mL,
13.6 mmol, 600 mol%) were successively added at 0 ◦C. After 12 h
at rt, a saturated aqueous solution of NH4Cl (20 mL) was added
to the mixture. After separation of phases, the aqueous phase was
extracted with CH2Cl2 (20 mL). Combined organic extracts were
dried over MgSO4 and concentrated in vacuo. Purification by flash
chromatography (Hex/EtOAc: 100 : 0 to 95 : 5) afforded the tri-
protected compound 16 (1.16 g, 72% over 2 steps) as a colourless
˚
To a solution of aldehydes 11 in CH2Cl2 (32 mL) 4 A molecular
sieves (1 g) were added. After 30 min, the mixture was cooled to
◦
0 C. (Z)-crotyltrifluorosilane 12 (1.1 mL, 8.2 mmol, 320 mol%)
and DIPEA (1.3 mL, 7.7 mmol, 300 mol%) were successively
added. After 36 h at 0 ◦C, 1 g of silica was added to the mixture and,
after 30 min, the mixture was filtered through a short pad of silica.
After concentration, the residue was dissolved in CH2Cl2 (40
mL). 2-methoxypropene (1.2 mL, 12.8 mmol, 500 mol%) and
PPTS (31 mg, 0.13 mmol, 5 mol%) were added. After 30 min, the
reaction was stopped by addition of a saturated aqueous solution
of NaHCO3 (10 mL). After extraction with CH2Cl2 (20 mL),
the organic layer was dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography (Hex/EtOAc: 95 : 5
to 90 : 10) afforded compounds 14 (0.795 g, 65% global yield), as
a separable mixture of 14a (0.701 g, 66% over 4 steps from 10a)
as a white solid and 14b (0.094 g, 53% over 4 steps from 10b) as
a colourless oil. Data for 14a: Rf: 0.35 (Hex/EtOAc: 90 : 10); Mp:
oil. Rf: 0.66 (Hex/EtOAc: 95 : 5); [a]D = -31.3 (c 1, CHCl3); 1H
20
NMR (CDCl3): d 0.55-0.66 (m, 18H), 0.75 (d, J = 6.6 Hz, 3H),
0.87 (s, 3H), 0.91 (s, 3H), 0.94-0.99 (m, 27H), 1.05 (d, J = 6.9 Hz,
3H), 1.09-1.25 (m, 1H), 1.33 (s, 3H), 1.39 (s, 3H), 1.41-1.44 (m,
1H), 2.05-2.10 (m, 1H), 2.38-2.45 (m, 1H), 3.21-3.25 (m, 2H), 3.28
(s, 3H), 3.36 (dd, J = 10.3, 2.1 Hz, 1H), 3.44 (d, J = 9.4 Hz, 1H),
3.58-3.63 (m, 1H), 3.69 (d, J = 2.0 Hz, 1H), 3.84 (dd, J = 8.2,
1.9 Hz, 1H), 4.95-5.01 (m, 2H), 5.86 (ddd, J = 17.1, 10.4, 9.0 Hz,
1H); 13C NMR (CDCl3): d 4.6, 5.9, 6.0, 7.0, 7.3, 7.4, 12.1, 18.3,
19.5, 20.6, 22.4, 26.2, 30.3, 32.9, 36.3, 39.8, 41.1, 57.5, 69.9, 71.4,
75.4, 77.6, 81.0, 97.7, 114.8, 140.1; IR (nmax, thin film): 2956, 2912,
2877, 1461, 1416, 1379, 1238, 1201, 1095 cm-1; HRMS: calculated
for C38H80O6NaSi3 [M+Na]+: 739.5160, found: 739.5158.
89 ◦C; [a]D = -52.0 (c 0.1, CHCl3); 1H NMR (CDCl3): d 0.09 (s,
20
3H), 0.11 (s, 3H), 0.74 (d, J = 6.6 Hz, 3H), 0.92 (s, 9H), 1.03 (d, J
= 7.0 Hz, 3H), 1.19 (s, 3H), 1.23 (s, 3H), 1.23-1.29 (m, 1H), 1.31
(s, 3H), 1.36 (s, 3H), 1.64 (ddd, J = 14.2, 9.8, 3.3 Hz, 1H), 2.00
(ddd, J = 14.3, 8.7, 2.3 Hz, 1H), 2.36-2.44 (m, 1H), 3.32 (s, 3H),
3.33-3.37 (m, 1H), 3.58 (dt, J = 9.9, 2.2 Hz, 1H), 3.64 (dt, J = 8.7,
3.6 Hz, 1H), 4.28 (d, J = 6.4 Hz, 1H), 4.51 (dd, J = 6.4, 3.9 Hz,
1H), 4.95-5.00 (m, 2H), 5.82 (ddd, J = 17.2, 10.4, 9.1 Hz, 1H);
13C NMR (CDCl3): d -4.0, -3.7, 11.8, 18.2, 18.4, 19.5, 19.6, 26.0,
26.1, 30.1, 32.6, 36.5, 39.6, 43.8, 56.8, 70.5, 74.5, 77.4, 77.5, 80.8,
97.7, 115.1, 139.6, 181.3; IR (nmax, thin film): 2961, 2932, 2859,
1778, 1471, 1463, 1388, 1380, 1259, 1131 cm-1; HRMS: calculated
for C26H48O6NaSi [M+Na]+: 507.3118, found: 507.3112. Data for
(3R,4R,5S)-6-((4S,5S,6R)-6-((R)-but-3-en-2-yl)-2,2,5-trime-
thyl-1,3-dioxan-4-yl)-5-methoxy-2,2-dimethyl-3,4-bis(triethylsily-
loxy)hexanal 17. A solution of DMSO (98 ◦mL, 1.4 mmol, 880
mol%) in CH2Cl2 (1 mL) was cooled to -78 C. Oxalyl chloride
(59 mL, 0.7 mmol, 440 mol%) was added to the solution (gas
evolution was observed). TES-protected compound 16 (0.112 g,
0.16 mmol, 100 mol%) in CH2Cl2 (1 mL) was added. The solution
was stirred 20 min at -78 ◦C and then warmed to -35 ◦C and
stirred for 1 h at this temperature. The solution was then cooled
down to -78 ◦C and Et3N (0.33 mL, 2.35 mmol, 1500 mol%) was
added. The mixture was allowed to warm to rt and after 1 h,
a saturated aqueous solution of NH4Cl (2 mL) was added. After
separation of phases, the aqueous phase was extracted with EtOAc
(10 mL). The combined organic extracts were dried over MgSO4
and concentrated in vacuo. Purification by flash chromatography
(Hex/EtOAc: 100 : 0 to 95 : 5) afforded aldehyde 17 (74 mg, 78%)
14b: Rf: 0.20 (Hex/EtOAc: 90 : 10); [a]D = -8.6 (c 0.5, CHCl3);
20
NMR 1H (CDCl3): d 0.09 (s, 3H), 0.15 (s, 3H), 0.74 (d, J = 6.6 Hz,
3H), 0.94 (s, 9H), 1.05 (d, J = 6.9 Hz, 3H), 1.20 (s, 3H), 1.33 (s,
3H), 1.41 (s, 3H), 1.41-1.44 (m, 1H), 1.86 (ddd, J = 13.7, 11.1,
4370 | Org. Biomol. Chem., 2010, 8, 4364–4373
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as a colourless oil. Rf: 0.53 (Hex/EtOAc: 95 : 5); [a]D = -46.7 (c
0.98 (t, J = 7.9 Hz, 9H), 1.05 (s, 9H), 1.05 (d, J = 6.6 Hz, 3H),
1.13 (d, J = 7.0 Hz, 3H), 1.29 (s, 6H), 1.33 (s, 3H), 1.39 (s, 3H),
1.42-1.44 (m, 1H), 1.77 (q, J = 6.4 Hz, 2H), 2.06-2.10 (m, 1H),
2.37-2.45 (m, 1H), 2.52-2.58 (m, 1H), 3.27 (s, 3H), 3.29-3.31 (m,
2H), 3.37 (dd, J = 10.2, 2.1 Hz, 1H), 3.61-3.64 (m, 1H), 3.68 (t, J
= 6.4 Hz, 2H), 3.80 (d, J = 1.8 Hz, 1H), 3.97 (dd, J = 7.9, 1.7 Hz,
1H), 4.41-4.45 (m, 1H), 4.95-5.03 (m, 2H), 5.87 (ddd, J = 16.8,
10.0, 9.4 Hz, 1H), 7.35-7.44 (m, 6H), 7.64-7.68 (m, 4H); 13C NMR
(CDCl3): d 5.3, 5.8, 5.9, 7.1, 7.3, 7.4, 10.1, 12.0, 18.2, 19.3, 19.5,
25.9, 27.0, 30.3, 32.6, 36.1, 37.8, 38.7, 39.8, 53.7, 57.2, 60.9, 69.9,
71.2, 77.4, 77.6, 80.6, 81.7, 97.7, 102.0, 114.8, 127.8, 129.7, 133.8,
133.9, 135.7, 140.1, 190.1; IR (nmax, thin film): 2955, 2936, 2876,
2205, 1673, 1459, 1379, 1238, 1095 cm-1; HRMS: calculated for
C61H106O8NaSi4 [M+Na]+: 1101.6863, found: 1101.6896.
20
1, CHCl3) 1H NMR (CDCl3): d 0.57 (q, J = 7.9 Hz, 6H), 0.65 (q,
J = 7.7 Hz, 6H), 0.77 (d, J = 6.6 Hz, 3H), 0.93 (t, J = 7.9 Hz, 9H),
0.97 (t, J = 7.7 Hz, 9H), 1.03 (s, 3H), 1.04 (d, J = 7.2 Hz, 3H),
1.06 (s, 3H), 1.19-1.23 (m, 1H), 1.31 (s, 3H), 1.37 (s, 3H), 1.40-1.42
(m, 1H), 2.07-2.12 (m, 1H), 2.39-2.46 (m, 1H), 3.23 (s, 3H), 3.31-
3.35 (m, 1H), 3.37 (dd, J = 10.2, 2.1 Hz, 1H), 3.67 (t, J = 9.1 Hz,
1H), 3.93-3.95 (m, 2H), 4.96-5.03 (m, 2H), 5.85 (ddd, J = 16.9,
10.3, 9.0 Hz, 1H), 9.83 (s, 1H); 13C NMR (CDCl3): d 5.5, 6.0, 7.2,
7.3, 12.2, 18.2, 19.5, 19.9, 23.2, 30.3, 31.5, 36.1, 39.8, 49.5, 56.3,
70.0, 74.2, 77.6, 79.5, 80.2, 97.7, 115.0, 139.9, 206.5; IR (nmax, thin
film): 2956, 2937, 2876, 1717, 1458, 1379, 1257, 1201, 1094 cm-1;
HRMS: calculated for C32H64O6NaSi2 [M+Na]+: 623.4158, found:
623.4139.
(5R,6R)-5-((S)-2-((4S,5S,6R)-6-((R)-but-3-en-2-yl)-2,2,5-trim-
ethyl-1,3-dioxan-4-yl)-1-methoxyethyl)-3,3,8,8-tetraethyl-6-(2-
methylbut-3-yn-2-yl)-4,7-dioxa-3,8-disiladecane 3. Aldehyde 17
(0.40 g, 0.66 mmol, 100 mol%) was dissolved in MeOH (15 mL).
Ohira–Bestmann reagent (0.31 g, 1.65 mmol, 250 mol%) and
K2CO3 (0.228 g, 1.65 mmol, 250 mol%) were then successively
added and the mixture stirred at rt for 48 h. MeOH was evaporated
and the residue taken up in EtOAc (20 mL) and H2O (10 mL). After
separation of phases, the aqueous phase was extracted with EtOAc
(10 mL). The combined organic extracts were dried over MgSO4
and concentrated in vacuo. Purification by flash chromatography
(Hex/EtOAc: 100 : 0 to 95 : 5) afforded alkyne 3 (0.345 g, 88%)
(2S,3R,7S,8R)-2-((S)-2-((4S,5S,6R)-6-((R)-but-3-en-2-yl)-2,2,
5-trimethyl-1,3-dioxan-4-yl)-1-methoxyethyl)-7-(2-(tert-butyldiph-
enylsilyloxy)ethyl)-3-hydroxy-4,4,8-trimethyl-1,6-dioxaspiro[4.5]
decan-9-one 19. To a solution of ynone 2 (31 mg, 29 mmol,
100 mol%) in toluene (1 mL) was added p-TsOH (10 mg, 50
mmol, 180 mol%) and the mixture was stirred 24 h at rt. The
reaction was quenched by addition of a saturated aqueous
solution of NaHCO3 (0.5 mL) and H2O (0.5 mL). The mixture
was diluted with EtOAc (5 mL) and, after separation of phases,
the organic phase was dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography (Hex/EtOAc: 95 : 5
to 80 : 20) afforded spiroketal 19 (7 mg, 33%), as a colourless
as a colourless oil. Rf: 0.72 (Hex/EtOAc: 95 : 5); [a]D = -43.6 (c
oil. Rf: 0.44 (Hex/EtOAc: 80 : 20); [a]D = -64.3 (c 1, CHCl3);
20
20
1, CHCl3); 1H NMR (CDCl3): d 0.61-0.70 (m, 12H), 0.76 (d, J =
6.5 Hz, 3H), 0.92-1.00 (m, 18 H), 1.05 (d, J = 6.9 Hz, 3H), 1.24 (s,
3H), 1.25 (s, 3H), 1.35 (s, 3H), 1.39 (s, 3H), 1.40-1.46 (m, 2H), 2.07
(s, 1H), 2.08-2.14 (m, 1H), 2.38-2.46 (m, 1H), 3.25-3.31 (m, 4H),
3.36 (dd, J = 10.3, 2.1 Hz, 1H), 3.59-3.64 (m, 1H), 3.74 (d, J =
2.0 Hz, 1H), 4.04 (dd, J = 7.7, 1.9 Hz, 1H), 4.95-5.01 (m, 2H), 5.86
(ddd, J = 17.5, 10.4, 9.0 Hz, 1H); 13C NMR (CDCl3): 5.8, 5.9, 7.3,
7.4, 12.1, 18.2, 19.5, 25.4, 27.6, 30.2, 33.0, 36.2, 36.9, 39.7, 57.2,
1H NMR (CDCl3): d 0.61 (d, J = 6.5 Hz, 3H), 0.86 (s, 3H),
1.02-1.07 (m, 18H), 1.11 (s, 3H), 1.25 (s, 3H), 1.29-1.38 (m, 2H),
1.64-1.74 (m, 2H), 1.83-1.91 (m, 2H), 2.27-2.46 (m, 3H), 2.56 (d,
J = 14.8 Hz, 1H), 3.19 (dd, J = 10.3, 2.1 Hz, 1H), 3.29 (s, 3H),
3.44-3.46 (m, 1H), 3.58-3.65 (m, 2H), 3.74 (dt, J = 9.4, 4.8 Hz,
1H), 3.79 (dd, J = 7.7, 3.7 Hz, 1H), 3.92 (ddd, J = 9.0, 4.3, 2.9 Hz,
1H), 4.05 (dd, J = 9.0, 8.1 Hz, 1H), 4.94-5.01 (m, 2H), 5.81 (ddd,
J = 17.2, 10.2, 9.1 Hz, 1H), 7.36-7.45 (m, 6H), 7.63-7.66 (m,
4H); 13C NMR (CDCl3): d 10.8, 11.7, 17.2, 18.1, 19.3, 21.0, 27.0,
27.0, 30.0, 32.6, 34.9, 36.1, 39.6, 41.6, 48.3, 48.5, 56.3, 61.7, 68.4,
71.6, 76.4, 77.4, 77.4, 80.4, 97.8, 108.4, 115.2, 127.9, 129.9, 133.7,
135.6, 139.7, 210.0; IR (nmax, thin film): 3469, 2959, 2930, 2857,
1720, 1472, 1462, 1428, 1379, 1203, 1111 cm-1; HRMS: calculated
for C43H65O8Si [M+H]+: 737.4449, found: 737.4445.
69.5, 71.4, 74.5, 77.3, 77.7, 81.1, 92.3, 97.7, 114.8, 140.1; IR (nmax
,
thin film): 3309, 2955, 2937, 2877, 2111, 1460, 1379, 1238, 1202,
1097; HRMS: calculated for C33H64O5NaSi2 [M+Na]+: 619.4190,
found: 619.4181.
(6R,7R,12R,13R)-13-((S)-2-((4S,5S,6R)-6-((R)-but-3-en-2-yl)-
2,2,5-trimethyl-1,3-dioxan-4-yl)-1-methoxyethyl)-15,15-diethyl-2,
2,7,11,11-pentamethyl-3,3-diphenyl-6,12-bis(triethylsilyloxy)-4,
14-dioxa-3,15-disilaheptadec-9-yn-8-one 2. To a solution of thiol
ester 4 (49 mg, 71 mmol, 100 mol%) in DMF (0.15 mL) and Et3N
(45 mL) were successively added PdCl2(dppf) (6 mg, 7 mmol, 10
mol%), CuI (26 mg, 0.135 mmol, 190 mol%), P(2-furyl)3 (4 mg, 18
mmol, 25 mol%) and a solution of alkyne 3 (80 mg, 0.135 mmol,
190 mol%) in DMF (0.15 mL). The mixture was heated at 50 ◦C
for 3 h and then cooled to rt. Celite (0.1 g), Et2O (5 mL) and
H2O (2 mL) were added. After 10 min, the mixture was filtered
through a pad of Celite and the pad was washed with EtOAc
(10 mL). After separation of phases, the organic extracts were
washed with H2O (5 mL), dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography (Hex/EtOAc: 99 : 1
(2R,3R,7S,8R)-2-((S)-2-((4S,5S,6R)-6-((R)-but-3-en-2-yl)-
2,2,5-trimethyl-1,3-dioxan-4-yl)-1-methoxyethyl)-7-(2-((tert-but-
yldiphenylsilyl)oxy)ethyl) - 4,4,8 - trimethyl - 3 - ((triethylsilyl)oxy)-
1,6-dioxaspiro[4.5]decan-9-one 20. To a solution of ynone 2
(25.4 mg, 23.5 mmol, 100 mol%) in CH2Cl2 (0.60 mL) and MeOH
(0.15 mL) (+)-CSA (1 mg, 4.3 mmol, 15 mol%) was added. After
1 h and total consumption of the starting material, the solvent
was evaporated. The residue was taken up in toluene (1.5 mL)
and p-TsOH·H2O (1 mg, 5.2 mmol, 20 mol%) was added. After
4 h, the mixture was filtered and concentrated. The residue was
dissolved in CH2Cl2 (3 mL). To this solution were successively
added 2,6-lutidine (11 mL, 94.0 mmol, 400 mol%) and TESOTf
(11 mL, 47.0 mmol, 200 mol%) at 0 ◦C. The reaction mixture was
stirred at rt overnight and quenched by addition of a saturated
aqueous solution of NH4Cl (2 mL). After separation of phases, the
aqueous phase was extracted with CH2Cl2 (5 mL). The combined
organic extracts were dried over MgSO4 and concentrated in vacuo.
to 95 : 5) furnished ynone 2 (38 mg, 50%), as a colourless oil. Rf:
1
0.43 (Hex/EtOAc: 97 : 3); [a]D = -27.7 (c 1, CHCl3); H NMR
20
(CDCl3): d 0.54 (q, J = 7.9 Hz, 6H), 0.60-0.70 (m, 12H), 0.75 (d,
J = 6.6 Hz, 3H), 0.90 (t, J = 7.9 Hz, 9H), 0.95 (t, J = 7.9 Hz, 9H),
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Purification by flash chromatography (Hex/EtOAc: 95 : 5 to
NH4Cl (4 mL). After separation of phases, the aqueous phase was
extracted with CH2Cl2 (5 mL). The combined organic extracts
were dried over MgSO4 and concentrated in vacuo. Purification by
flash chromatography (Hex/EtOAc: 90 : 10) afforded spiroketal 1
90 : 10) afforded spiroketal 20 (13.4 mg, 67% over 3 steps) as a
colourless oil. Rf: 0.65 (Hex/EtOAc: 80 : 20); [a]D = -47.7 (c 1,
20
CHCl3); 1H NMR (CDCl3): d 0.53-0.59 (m, 9H), 0.88 (s, 3H), 0.94
(t, J = 7.9 Hz, 9H), 1.02 (s, 3H), 1.03-1.05 (m, 15H), 1.11 (s, 3H),
1.25 (s, 3H), 1.27-1.33 (m, 1H), 1.54 (dt, J = 13.8, 9.6 Hz, 1H),
1.61-1.67 (m, 1H), 1.83-1.97 (m, 2H), 2.24-2.29 (m, 1H), 2.33-2.37
(m, 2H), 2.49 (d, J = 15.4 Hz, 1H), 3.16-3.23 (m, 2H), 3.24 (s, 3H),
3.29-3.33 (m, 1H), 3.64 (dt, J = 9.7, 6.0 Hz, 1H), 3.68 (dd, J = 8.1,
1.7 Hz, 1H), 3.81 (dt, J = 9.9, 5.1 Hz, 1H), 3.95 (ddd, J = 9.5, 3.6,
2.9 Hz, 1H), 4.17 (d, J = 8.0 Hz, 1H), 4.94-5.00 (m, 2H), 5.81 (ddd,
J = 17.2, 10.3, 9.1 Hz, 1H), 7.35-7.43 (m, 6H), 7.65-7.67 (m, 4H);
13C NMR (CDCl3): d 5.1, 7.1, 10.9, 11.8, 16.9, 18.2, 19.3, 21.3,
26.3, 27.0, 30.0, 34.8, 34.9, 36.5, 39.6, 41.0, 48.1, 48.4, 57.0, 61.9,
67.7, 71.5, 74.7, 77.4, 78.3, 79.8, 97.6, 108.4, 115.1, 127.9, 129.8,
133.8, 135.5, 139.8, 210.0; IR (nmax, thin film): 2958, 2929, 2857,
1723, 1471, 1463, 1379, 1260, 1202, 1112 cm-1; HRMS: calculated
for C49H78O8NaSi2 [M+Na]+: 873.5133, found: 873.5140.
(28 mg, 96%) as a colourless oil. Rf: 0.54 (Hex/EtOAc: 80 : 20);
1
[a]D = -67.7 (c 1, CHCl3); H NMR (CDCl3): d 0.55 (q, J =
20
7.5 Hz, 3H), 0.55 (q, J = 8.1 Hz, 3H), 0.65 (d, J = 6.6 Hz, 3H),
0.84 (s, 3H), 0.87 (d, J = 7.1 Hz, 3H), 0.92 (s, 3H), 0.93 (t, J =
7.9 Hz, 9H), 1.03 (s, 9H), 1.04 (d, J = 4.4 Hz, 3H), 1.12 (s, 3H),
1.25-1.27 (m, 4H), 1.30-1.37 (m, 1H), 1.53-1.62 (m, 3H), 1.70-1.71
(m, 2H), 1.77-1.84 (m, 1H), 1.99 (s, 3H), 2.33-2.38 (m, 1H), 3.20
(dd, J = 10.3, 2.1 Hz, 1H), 3.25 (s, 3H), 3.26-3.32 (m, 2H), 3.64
(dt, J = 9.6, 5.2 Hz, 1H), 3.68 (dd, J = 8.3, 1.3 Hz, 1H), 3.80 (dt,
J = 9.7, 5.7 Hz, 1H), 4.05-4.09 (m, 1H), 4.17 (d, J = 8.3 Hz, 1H),
4.85 (dd, J = 5.7, 2.9 Hz, 1H), 4.94-5.01 (m, 2H), 5.83 (ddd, J =
17.2, 10.3, 9.1 Hz, 1H), 7.35-7.42 (m, 6H), 7.64-7.67 (m, 4H); 13
C
NMR (CDCl3): d 5.1, 7.1, 10.2, 11.8, 16.6, 18.2, 19.2, 19.3, 21.3,
21.8, 26.5, 27.0, 30.0, 35.0, 35.1, 35.9, 36.7, 39.7, 48.4, 57.0, 62.2,
64.0, 71.6, 72.4, 75.1, 77.4, 77.4, 79.9, 97.7, 105.8, 115.1, 127.8,
129.8, 134.0, 135.5, 139.9, 170.8; IR (nmax, thin film): 2958, 2931,
2858, 1732, 1472, 1462, 1378, 1112 cm-1; HRMS: calculated for
C51H82O9NaSi2 [M+Na]+: 917.5395, found: 917.5437.
(2R,3R,7S,8S,9R)-2-((S)-2-((4S,5S,6R)-6-((R)-but-3-en-2-yl)-
2,2,5-trimethyl-1,3-dioxan-4-yl)-1-methoxyethyl)-7-(2-((tert-buty-
ldiphenylsilyl)oxy)ethyl)-4,4,8-trimethyl-3-((triethylsilyl)oxy)-1,
6-dioxaspiro[4.5]decan-9-ol 21. To a solution of spiroketal 20
(75.0 mg, 0.088 mmol, 100 mol%) in THF (4 mL) was added
L-Selectride (1 M in THF, 0.26 mL, 0.26 mmol, 300 mol%) at -78
◦C. After stirring for 1 h 30 at -78 ◦C, MeOH (1 mL), 1 M NaOH (1
mL), 30% H2O2 (0.5 mL) and THF (6 mL) were successively added.
Notes and references
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◦
The reaction mixture was then allowed to warm to 0 C, stirred
for 30 min at 0 ◦C and finally 30 min at rt. Et2O (10 mL) and brine
(5 mL) were then added to the mixture. After extraction with Et2O
(10 mL), the combined organic extracts were dried over MgSO4
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20
(c 1, CHCl3); 1H NMR (CDCl3): d 0.55 (q, J = 7.7 Hz, 6H), 0.64
(d, J = 6.4 Hz, 3H), 0.81 (d, J = 7.1 Hz, 3H), 0.87 (s, 3H), 0.92
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2H), 3.63 (dt, J = 9.9, 5.7 Hz, 1H), 3.71-3.78 (m, 3H), 3.81 (dt, J =
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8.0 Hz, 1H), 4.94-5.00 (m, 2H), 5.82 (ddd, J = 17.2, 10.3, 9.1 Hz,
1H), 7.35-7.43 (m, 6H), 7.65-7.68 (m, 4H); 13C NMR (CDCl3): d
5.1, 7.1, 10.9, 11.8, 16.8, 18.2, 19.2, 19.3, 21.3, 27.0, 28.4, 30.0, 34.9,
36.0, 36.5, 38.1, 39.6, 48.3, 57.1, 62.3, 64.1, 70.9, 71.6, 74.9, 77.4,
78.3, 79.8, 97.6, 107.8, 115.1, 127.8, 129.7, 134.0, 135.5, 139.8; IR
(nmax, thin film): 3542, 2959, 2932, 2913, 2877, 1472, 1463, 1379,
1259, 1112 cm-1; HRMS: calculated for C49H80O8NaSi2 [M+Na]+:
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