Synthetic studies towards pectenotoxin-2: Synthesis of the nonanomeric 10-epi-ABCDE ring segment by kinetic spiroketalization

Article abstract of DOI:10.1002/ejoc.201001411

The synthesis of the nonanomeric 10-epi-ABCDE ring system of pectenotoxin-2 has been achieved by using a kinetic spiroketalization reaction. The synthesis of the spiroketalization precursor was achieved through a cross-metathesis/ hydrogenation sequence.

Full text of DOI:10.1002/ejoc.201001411

FULL PAPER
DOI: 10.1002/ejoc.201001411
Synthetic Studies towards Pectenotoxin-2: Synthesis of the Nonanomeric
10-epi-ABCDE Ring Segment by Kinetic Spiroketalization
Jatta E. Aho,[a] Antti Piisola,[b] K. Syam Krishnan,[b] and Petri M. Pihko*[b]
Keywords: Natural products / Spiro compounds / Anomeric effect / Enantioselectivity / Chirality
The synthesis of the nonanomeric 10-epi-ABCDE ring system
of pectenotoxin-2 has been achieved by using a kinetic spiro-
ketalization reaction. The synthesis of the spiroketalization
organometallic nucleophiles to the advanced CDE ring pre-
cursor. This addition reaction was investigated with dif-
ferently protected α,β-dioxygenated model aldehydes, which
precursor was achieved through a cross-metathesis/hydro- displayed similar anti-Felkin selectivities with organometal-
genation sequence. The formation of the epi-C10 isomer re- lic nucleophiles.
sulted from an unexpected anti-Felkin selective addition of
Introduction
In 1985, Yasumoto and co-workers reported the isolation
and characterization of a family of polyether macro-
lactones, the pectenotoxins (PTXs).[1] The pectenotoxin
family has since grown to comprise over 20 structurally re-
lated compounds (Figure 1). Originally isolated from scal-
lops (Patinopecten yessoensis),[1a] the actual producers of
PTXs are Dinophysis dinoflagellates, which are found in
coastal areas worldwide.[2]
The complex structure of the PTXs consist of a closed
macrolactone containing a spiroketal ring unit, three dif-
ferently substituted tetrahydrofurans, a bicyclic acetal ring
system, a cyclic hemiketal, and two sites of unsaturation in
the form of carbon–carbon double bonds. The main struc-
tural differences between the PTXs are the oxidation state
of C43 and the configuration of the C7 spiroketal center.
More recently, open-chained analogues, PTX seco acids
(PTXsa),[3] and analogues containing variations at the GH
ring system have also been isolated and characterized.
However, the most commonly found PTX in algae is PTX2,
which is reported to be produced by many different dino-
flagellate species of the genera Dinophysis and is found in
various parts of the world.[4] In tests with mice, PTX2 was
found to be one of the most toxic PTXs. It is a potent cyto-
toxin against a variety of lung, colon, and breast cancer
cell lines.[2b,5] The main target of PTX2 in cells is the actin
cytoskeleton, and the recently determined X-ray crystal
structure of PTX2 bound to G-actin reveals a shallow bind-
Figure 1. Structures of the pectenotoxins. Biosynthesis products
ing site and stresses the importance of the stereochemistry
(white); products produced by metabolism of shellfish (light grey);
artificial products formed by acid catalysis (dark grey).
[a] Department of Chemistry, Aalto University School of Science
and Technology,
Kemistintie 1, 02150 Espoo, Finland
[b] Department of Chemistry, University of Jyväskylä,
of the macrolactone ring, including the nonanomeric con-
P. O. Box 35, 40014 University of Jyväskylä, Finland
figuration present in the AB ring spiroketal.[6] Synthetic ac-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001411.
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Synthetic Studies towards Pectenotoxin-2
tion, including the nonanomeric R configuration at the C7 ter), Smith and co-workers had also obtained high Felkin-
spiro carbon, is therefore an important, but challenging, selectivities in a Corey–Chaykovsky reaction of an α,β-bis-
objective in marine natural product synthesis.[7,8]
Herein, we outline our progress towards the synthesis of
the nonanomeric ABCDE ring segment of PTX2. Although
the goal of the nonanomeric spiroketal was indeed reached
in these studies, the work also revealed a surprising anti-
Felkin selectivity in a key addition reaction to C10 alde-
hyde.
(alkoxy) aldehyde bearing a tertiary β-carbon.[11]
Results and Discussion
Strategy
We had previously reported that our otherwise robust
method of constructing the CDE or the CDEF ring systems
by final ozonolysis-triggered ketalization (Scheme 1) would
not be applicable to substrates bearing the fragile nonano-
meric spiroketal system.[9] This result indicated that our
initially envisioned ABC + F Ǟ ABCDEF strategy would
not work, and we would therefore need to postpone the
construction of the nonanomeric spiroketal until after the
cyclization of the DE ring ketal system.
Scheme 2. Selectivities in nucleophilic addition reactions to α,β-bis-
(alkoxy) aldehydes.
Synthesis of the epi-C10 ABCDE Ring System of PTX2
We initiated our study with the fully protected CDE ring
fragment 11 (Scheme 3). Selective deprotection at C10 was
possible in HF·pyridine, albeit in modest yield. The desired
aldehyde 13 was readily obtained by Swern oxidation and
was immediately engaged in the reaction with vinylmagne-
sium bromide. This reaction gave the desired allylic alcohol
14 in 83:17 diastereoselectivity. The stereochemistry of this
product (syn, as shown in Scheme 3) was not confirmed at
this juncture, because it was decided that decisive confirm-
ation would become available upon final conversion into
the ABCDE ring system of PTX2.
Scheme 1. Synthesis of the CDEF ring fragment of PTX2 and the
key strategic experiment.[9]
As such, our first task was to outline conditions that
would facilitate the union of the A ring and the CDE(F)
ring systems into a viable precursor for kinetic spiroketal-
ization. Given the high sensitivity of the spiroketalization
precursors (we sought precursors that would allow the ki-
netic spiroketalization to take place under very mild condi-
tions), the route would most likely have to be devised with
no protection at the C10 hydroxy group. Nucleophilic ad-
dition of a vinylmetal species to the CDE aldehyde 13 was
expected to afford the desired anti product 14 in a Felkin-
selective manner. We were encouraged by the reports of
Evans on nucleophilic additions to α,β-bis(alkoxy) alde-
Scheme 3. Synthesis of allylic alcohol 14 from the fully protected
CDE ring system 11.
Our initial idea was to couple the A and the CDE frag-
hydes that were, typically, highly Felkin-selective, especially ments using a Suzuki–Miyaura coupling (Scheme 4). To
with anti-α,β-bis(alkoxy) substituents (Scheme 2).[10] Al- this end, the previously prepared A ring lactone 15[12] was
though 13 cannot be readily classified as either anti or syn readily converted into the corresponding ketene acetal tri-
bis(alkoxy) aldehyde (the C12 stereocenter is a tertiary cen- flate using Comins’ reagent. The hydroboration of the all-
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P. M. Pihko et al.
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ylic alcohol 14, however, turned out to be highly problem-
atic. Extensive screening of different reagents (9-borabicy-
clo[3.3.1]nonane (9-BBN),[13] catecholborane,[14] thexylbor-
ane,[15] BH3·SMe2[16]) was unsuccessful, resulting in either
recovered starting material together with decomposition
products or in a large number of products, none of which
resembled the desired organoboron compounds.
Scheme 5. Cross-metathesis: model studies with allyl alcohol.
Figure 2. Hoveyda–Grubbs 2nd generation (22) and Grubbs 2nd
generation (23) catalysts.
Scheme 4. Attempts at Suzuki coupling were thwarted by the hy-
droboration step.
Cross-metathesis (CM) was then explored as an alterna-
tive mild method for linking the A and the CDE sub-
units.[17] To this end, the A ring lactone 15 was converted
into the corresponding vinyl ketone 19 in excellent yield
Scheme 6. Successful cross-metathesis with a more complex model
compound 24.
with vinylmagnesium bromide (Scheme 5). Initially, the CM though initial results were encouraging (entry 2) the CM
reaction was explored with simple allyl alcohol as the model protocol was not reproducible, and the undesired diene 27
compound. Interestingly, the use of Hoveyda–Grubbs cata- was formed as the major product. Diene 27 turned out to
lyst 22 led to the formation of the corresponding furan 20 be very unstable and attempts at partial hydrogenation of
instead of the desired enone 21 (Scheme 5). This result was the C8–C9 double bond only led to decomposition. The
ascribed to the Lewis acidic nature of the Hoveyda–Grubbs formation of 27 could be avoided by the use of pyridine
catalyst.[18] Attempts at buffering the reaction mixture with buffer, but the yields did not improve.
pyridine, 2,6-lutidine, or NaHCO3 did not help; however,
The selective hydrogenation of the C8–C9 double bond
the use of the Grubbs 2nd generation catalyst 23 (Figure 2) was then examined as a prelude to the key spiroketalization
did indeed provide the desired allyl alcohol in acceptable experiment (Table 2). With Wilkinson’s catalyst, the hydro-
yield (Scheme 5) and the reaction also worked with a more genation proceeded smoothly, however, during the course
complex model compound (Scheme 6).
of the reaction, the product underwent premature spiroket-
In the real system, the cross metathesis between 14 and alization to afford a 1:1 mixture of anomeric and nonanom-
19 was also successful with the Grubbs 2nd generation cata- eric spiroketals 29 and 30. Although buffering the reaction
lyst 23, affording 26 in 48–55% yields (plus 36–45% reco- mixture with 2,6-lutidine did not help (entry 2), the use of
vered 14) (Table 1, entry 1). In an attempt to improve the pyridine-buffered Pd/C nicely solved the problem, giving 28
yields, the use of Hoveyda–Grubbs 2nd generation catalyst as the sole product in nearly quantitative yield (entry 4).
was examined because it was believed that the formation of Without pyridine, the premature spiroketalization to form
the furan would not be a problem with this system. Al- 29 and 30 again took place (entry 3).
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Synthetic Studies towards Pectenotoxin-2
Table 1. Cross-metathesis approach to linkage of the A and CDE roketal, giving a 3:1 mixture of 30/29 (entry 1). In contrast,
ring systems.
the aqueous conditions gave a 1:1 mixture of 29 and 30.
The stereochemistry at the newly formed spiro center was
readily confirmed: the nonanomeric spiroketal 29 displayed
a characteristic NOESY cross-peak between the C3 and C8
protons[12] as well as a characteristic downfield 13C NMR
shift at the spiroketal carbon C7 (δ = 105.8 ppm, the corre-
sponding shift for C7 of 30 is δ = 108.0 ppm). Furthermore,
when the 1:1 mixture of 29 and 30 was treated with pyrid-
inium p-toluenesulfonate (PPTS) for 5 h, a 3:1 mixture of
the spiroketals favoring the anomeric spiroketal 29 was ob-
tained, confirming that 29 is the thermodynamically fa-
vored product.
Table 3. Kinetic spiroketalizations to form the ABCDE ring frag-
ment and key NOESY cross-peaks detected in the AB ring sys-
tem.[20]
Entry Catalyst
Product (% yield)
1
2
3
4
Grubbs 2nd gen. cat.
Hoveyda-Grubbs 2nd gen. cat.
Hoveyda-Grubbs 2nd gen. cat.
26 (48–55)
26 (50)
27 (52)
Hoveyda-Grubbs 2nd gen. cat. + pyridine 26 (48)
Table 2. Hydrogenation screens for enone 26.
Entry Acid
Solvent
ClCH2COOH CH2Cl2
Cl3CCOOH
ClCH2COOH 4:1 THF/H2O 20 h
Time
29:30 (% conversion)
1
2
3
0.5 h
1:3 (100)
1:1 (100)
1:1 (20)
4:1 THF/H2O 4 h
The stereochemistry at C10, however, could not be fully
confirmed by NOE experiments. We therefore decided to
convert the [6,5]-spiroketal system of the product into the
corresponding [6,6]-spiroketal system. This was readily
achieved by deprotection of the silyl protecting groups with
tetrabutylammonium fluoride (TBAF), followed by treat-
ment with p-toluenesulfonic acid (pTsOH) to afford the de-
sired [6,6]-spiroketal 31a (Scheme 7). The observed cou-
pling constant between the C10-H and C11-H was 1.1 Hz
(Scheme 7). To our dismay, this experiment confirmed that
Entry Catalyst
Additive
Product (% conversion)
1
2
3
4
Wilkinson
Wilkinson
Pd/C
–
29 and 30 (100)
no reaction
29 and 30 (100)
28 (100)
2,6-lutidine
–
pyridine
Pd/C
With precursor 28 in hand, the final controlled spiroket- the stereochemistry at C10 was (R), not (S) as expected
alization was investigated (Table 3), using both anhydrous from a Felkin–Anh or Cornforth-controlled addition (cf.
conditions (CH2Cl2/ClCH2COOH)[12] as well as our more Scheme 2).
recently developed aqueous conditions [tetrahydrofuran
Because in the final synthesis we would have to differen-
(THF)/H2O].[19] Surprisingly, the nonaqueous conditions tiate between the C11 and C14 hydroxy groups, we decided
afforded better selectivities towards the nonanomeric spi- to try an alternative protective group at C11 in an attempt
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P. M. Pihko et al.
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of the resulting alcohol 40 (not shown) provided the desired
aldehyde 41. Addition of vinylmagnesium bromide to 41
afforded the desired allylic alcohol 42 in 95:5 selectivity. The
C10–C11 coupling constant of 42 (J = 2.0 Hz) was nearly
identical to that of 14 (J = 2.4 Hz) (Scheme 8).
Although the observed anti-Felkin selectivity with the α-
[(p-methoxybenzyl)oxy] aldehyde 41 could, in retrospect, be
explained by the intervention of chelation control in the
nucleophilic addition,[21] this explanation could not be so
readily applied to the corresponding α-silyloxy compound
11, which gave the same selectivity. To allow us to test the
selectivities more rapidly as well as to allow the stereochem-
istry of the newly formed stereocenter to be checked in a
more straightforward manner, a set of model studies with
simpler α,β-dioxygenated aldehydes bearing a tertiary pro-
tected C-O system was carried out (Table 4).
Synthesis of the model compounds began with epoxid-
ation of commercially available acrylate 43. Acid-catalyzed
opening of the epoxide 44 with p-methoxybenzyl alcohol
gave the desired partially protected diol 45 with perfect
selectivity, but low yield. Protection of the free hydroxy
moiety with either a silyl group or a benzyl group yielded
esters 46 and 47, which were then reduced with LiAlH4 to
primary alcohols and oxidized with Dess–Martin
periodinane to form the aldehyde model compounds (Ϯ)-
50 and (Ϯ)-51 (Scheme 9).
Scheme 7. Confirmation of the stereochemistry at C10.
to reverse the selectivity (Scheme 8). We found that selective
protection of the 14-OH group in 32[9] could readily be
achieved with tert-butyldimethylsilyl trifluoromethanesulf-
onate (TBSOTf) in 2,6-lutidine. p-Methoxybenzyl (PMB)
protection of 33 under acidic conditions led to ester 34,
which was then carried through our CDE ring synthesis
Test reactions with the prepared model compounds were
sequence,[9] affording the fully protected CDE ring 39 sys- performed with a variety of nucleophiles under different re-
tem in a four-step sequence. Desilylation of the primary action conditions (Table 4). The results of the reactions
silyl group of 39 proceeded more cleanly than the corre- showed varying degrees of syn selectivity in each case. The
sponding reaction with 11 (Scheme 3) and Swern oxidation stereochemistries of the products were verified by forming
Scheme 8. Synthesis of the PMB protected CDE fragment and the JH10–H11 coupling constants of 14 and 42.
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Synthetic Studies towards Pectenotoxin-2
Table 4. Diastereoselectivities of nucleophilic additions to model compounds (Ϯ)-50 and (Ϯ)-51.
Entry
Model
Nucleophile
Solvent
Temperature [°C]
Time [h]
Additive
syn/anti[b]
1
2
3
4
5
6
7
8
9
50
50
50
51
51
51
51
51
51
MeMgBr
MeMgBr
VinylMgBr
MeLi[a]
MeMgBr
VinylMgBr
MeMgBr
MeMgBr
MeMgBr
THF
THF
THF
THF
THF
THF
CH2Cl2
toluene
MeCN
–78 to –30
–78 to 0
–78 to 0
–78 to –30
–78 to –30
–78 to 0
–78 to 0
–78 to 0
–78 to 0
1
5.5
5.5
1
1
5.5
2
–
2.0:1
2.1:1
1.6:1
4.7:1
3.6:1
4.1:1
22:1
BF3·Et2O
–
–
–
–
–
–
–
2
2
11:1
6.2:1
[a] In reactions with MeLi and 50, significant migration of the silyl group was observed. [b] The diastereoselectivities were determined
1
by H NMR analysis of the crude reaction mixtures obtained after workup (aq. NH4Cl). All reactions proceeded to Ͼ95% conversion.
Figure 3. Coupling constants of the acyclic addition products (cf.
Scheme 8).
Scheme 9. Preparation of model compounds (Ϯ)-50 and (Ϯ)-51.
control also displayed anti-Felkin selectivity when the β-
carbon was heavily substituted (two carbon chains and an
alkoxy substituent). Although several models could be con-
ceivably presented that account for these observations, at
present we simply wish to issue a cautionary note that the
usual Felkin/Cornforth selectivities appear to break down
with these heavily substituted substrates.
the cyclic PMP acetals (see the Supporting Information for
details). Additionally, a very clear trend for 1H coupling
constants for the syn and anti diastereomers could be ob-
served (Figure 3), allowing the stereochemistry of 42 to be
assigned by analogy.
Although higher syn selectivities were observed with the
test substrate 51 where the α-substituent was a benzyloxy
group, the silyl protected analogues 50 also displayed syn
selectivity, confirming the patterns observed with the at-
tempted Felkin-selective additions at C10 with the fully
armed CDE ring systems 13 and 42.
Conclusions
The unexpected breakdown of Felkin and Cornforth
A combination of cross-metathesis and hydrogenation
selectivities with the aldehydes studied herein cannot be can be used to afford complex spiroketalization precursors
readily reconciled with any of the known models. Chelation for kinetic spiroketalization reactions. Additionally, we have
with the β-oxy substituent would be expected to afford the demonstrated that the kinetic spiroketalization protocol de-
Felkin product. Although chelation to the α-substituent veloped for the AB ring spiroketal system of the pec-
would indeed afford the anti-Felkin product,[21] α-silyloxy tenotoxins, also works in more complex settings, such as the
aldehydes that are generally poor substrates for chelation synthesis of the nonanomeric 10-epi-ABCDE ring system
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P. M. Pihko et al.
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with satd. aq. NaHCO3 (2ϫ50 mL). The combined aqueous layers
were extracted with Et2O (2ϫ50 mL) and the combined organic
extracts were dried with Na2SO4 and concentrated. Purification of
the residue by flash chromatography (initially 10% EtOAc/hexanes,
finally MeOH) afforded the desired product 12 as light-yellow vis-
cous oil (0.76 g, 45 %). Other collected fractions contained the
starting material 11 (0.64 g) and a mixture of diol (2S,3R,5R)-2-
{(1S,3R,5S)-1-[(benzyloxy)methyl]-5-methyl-2,8-dioxabicyclo-
(3.2.1)octan-3-yl}-5-{(S)-1-[(tert-butyldimethylsilyl)oxy]-2-
hydroxyethyl}-5-methyltetrahydrofuran-3-ol and triol (S)-1-
((2R,4R,5S)-5-((1S,3R,5S)-1-[(benzyloxy)methyl]-5-methyl-2,8-di-
oxabicyclo[3.2.1]octan-3-yl)-4-hydroxy-2-methyltetrahydrofuran-2-
yl)ethane-1,2-diol (0.26 g). After a second reaction with the recy-
cled starting material, the desired product 12 was obtained in 58%
of the pectenotoxins. The unexpected anti-Felkin selective
addition of organometallic nucleophiles to the advanced
CDE ring precursor was investigated with differently pro-
tected α,β-dioxygenated model aldehydes, which displayed
similar anti-Felkin selectivities with organometallic nucleo-
philes. We are investigating the generality of this observa-
tion and the results will be published in due course.
Experimental Section
General Methods: All reactions were carried out under an argon
atmosphere in flame-dried glassware, unless otherwise noted. When
needed, nonaqueous reagents were transferred under argon by
using syringe or cannula techniques and dried prior to use. THF,
Et2O, and CH2Cl2 were obtained by passing deoxygenated solvents
through activated alumina columns (MBraun SPS-800 Series sol-
vent purification system). Et3N and iPr2NH were distilled from Na.
Allyl alcohol and DMSO were distilled from CaH2. TiCl4 was frac-
tionally distilled. TBSOTf was prepared with Corey’s procedure.[22]
DMP was prepared with Ireland’s procedure.[23] Other solvents and
reagents were used as obtained from the supplier, unless otherwise
noted. Analytical TLC was performed using Merck silica gel F254
(230–400 mesh) plates and analyzed by UV light or by staining
upon heating with anisaldehyde solution (2.8 mL anisaldehyde,
2 mL concd. H2SO4, 1.2 mL concd. CH3COOH, 100 mL EtOH),
vanillin solution (6 g vanillin, 5 mL concd. H2SO4, 3 mL glacial
acetic acid, 250 mL EtOH), or KMnO4 solution (1 g KMnO4, 6.7 g
K2CO3, 1.7 mL 1 m NaOH, 100 mL H2O). For silica gel
chromatography, the flash chromatography technique was used,
with Merck silica gel 60 (230–400 mesh) and p.a. grade solvents
unless otherwise noted.
combined yield (0.98 g). Rf = 0.49 (30% EtOAc/hexanes). [α]D
=
–12.2 (c = 1.00, CH Cl ). IR (film): ν = 3514, 2955, 2930, 2885,
˜
2
2
2857, 1472, 1463, 1254, 1120, 1110, 1067 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.33–7.25 (m, 5 H), 4.61 (ddAB, |JAB| =
12.3 Hz, Δv = 29.5 Hz, 2 H), 4.29 (dd, J = 4.4, 3.0 Hz, 1 H), 4.15
(ddd, J = 11.5, 8.0, 3.7 Hz, 1 H), 3.82 (dd, J = 8.0, 3.9 Hz, 1 H),
3.77 (dd, J = 10.6, 8.0 Hz, 1 H), 3.60 (dd, J = 8.2, 2.9 Hz, 1 H),
3.51 (ddAB, |JAB| = 10.7 Hz, Δv = 22.0 Hz, 2 H), 3.56–3.50 (m, 1
H), 2.94 (s, 1 H), 2.19 (dt, J = 13.2, 4.2 Hz, 1 H), 2.08–1.95 (m, 2
H), 1.92–1.83 (m, 2 H), 1.74–1.64 (m, 2 H), 1.51 (dd, J = 13.1,
3.9 Hz, 1 H), 1.37 (s, 3 H), 1.17 (s, 3 H), 0.90 (s, 9 H), 0.87 (s, 9
H), 0.09 (s, 3 H), 0.08 (s, 3 H), 0.05 (s, 3 H), –0.02 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 138.5, 128.4, 127.9, 127.6, 106.4,
85.7, 85.2, 81.0, 76.2, 73.8, 71.92, 71.87, 66.1, 64.7, 48.0, 40.7, 34.2,
31.8, 26.3, 26.1, 25.9, 20.5, 18.1 (2H), –3.8, –4.4, –4.5, –5.0 ppm.
HRMS (ESI+): calcd. for C34H60O7NaSi2 659.3775; found
659.3775 (Δ = 0.2 ppm).
(R)-2-((2R,4R,5R)-5-{(1S,3R,5S)-1-[(Benzyloxy)methyl]-5-methyl-
2,8-dioxabicyclo[3.2.1]octan-3-yl)-4-[(tert-butyldimethylsilyl)oxy]-
2-methyltetrahydrofuran-2-yl}-2-[(tert-butyldimethylsilyl)oxy]acetal-
dehyde (13): To a solution of oxalyl chloride (21 μL, 30 mg,
0.24 mmol, 120 mol-%) in CH2Cl2 (1.5 mL), was added DMSO
(36 μL, 40 mg, 0.5 mmol, 250 mol-%) at –50 °C. After stirring for
8 min, a solution of alcohol 12 (0.13 g, 0.2 mmol, 100 mol-%) in
CH2Cl2 (2.5 mL) was added. The resulting mixture was stirred for
45 min, keeping the temperature below –30 °C. Triethylamine
(0.13 mL, 91 mg, 0.90 mmol, 450 mol-%) was then added dropwise
and stirring was continued at –30 °C for an additional 10 min and
then the mixture was warmed to room temp. H2O (5 mL) was
added and the separated aqueous phase was extracted with CH2Cl2
(5 mL). The combined organic extracts were washed with brine
(10 mL), dried with Na2SO4 and concentrated. Purification of the
residue by flash chromatography (10% EtOAc/hexanes) afforded
the desired product 13 as light-yellow oil (0.12 g, 93%). Rf = 0.70
1H and 13C NMR spectra were recorded in either [D6]acetone,
CDCl3, CD3CN, or C6D6 with Bruker Avance 500, 400 or 250 spec-
trometers. The chemical shifts are reported in ppm relative to
CHCl3 (δ = 7.26 ppm), CHD2CN (δ = 1.94 ppm) or C6D5H (δ =
7.16 ppm) for 1H NMR spectroscopy. For the 13C NMR spectra,
the residual [D6]acetone (δ = 29.84 ppm), CDCl3 (δ = 77.0 ppm),
CD3CN (δ = 118.26 ppm) or C6D6 (δ = 128.06 ppm) were used as
internal standards. The enantiomeric excess (ee) of the products
were determined by HPLC analysis by comparison to the corre-
sponding racemic samples (Waters 501 pump and Waters 486 detec-
tor). Melting points (m.p.) were determined in open capillaries
using a Gallenkamp melting point apparatus. IR spectra were re-
corded with a Perkin–Elmer Spectrum One FTIR spectrometer.
Optical rotations were obtained with a Perkin–Elmer 343 polarime-
ter. High-resolution mass spectrometric data were measured using
MicroMass LCT Premier Spectrometer. Some of the high-resolu-
tion mass spectrometric data was obtained by the University of
Oulu with a Micromass LCT spectrometer. Elemental analyses
were recorded with a Perkin–Elmer 2400 CHN instrument by the
Elemental Analytical Services of the Department of Chemistry.
(30% EtOAc/hexanes). [α]D = –64.9 (c = 1.00, CH2Cl2). IR (film):
1
ν = 2954, 2930, 2857, 1736, 1255, 1105 cm–1. H NMR (400 MHz,
˜
CDCl3): δ = 9.80 (s, 1 H), 7.34–7.27 (m, 5 H), 4.62 (ddAB, JAB
=
12.3 Hz, Δv = 30.9 Hz, 2 H), 4.33 (dd, J = 4.6, 2.9 Hz, 1 H), 4.25
(s, 1 H), 4.18 (ddd, J = 11.0, 8.2, 4.1 Hz, 1 H), 3.65 (dd, J = 8.2,
2.8 Hz, 1 H), 3.52 (ddAB, JAB = 10.6 Hz, Δv = 21.3 Hz, 2 H), 2.19
(dt, J = 13.1, 4.7 Hz, 1 H), 2.17 (d, J = 14.0 Hz, 1 H), 2.01 (ddd,
(S)-2-((2R,4R,5R)-5-{(1S,3R,5S)-1-[(Benzyloxy)methyl]-5-methyl-
2,8-dioxabicyclo[3.2.1]octan-3-yl}-4-[(tert-butyldimethylsilyl)oxy]- J = 13.6, 9.2, 4.8 Hz, 1 H), 1.93–1.89 (m, 1 H), 1.85 (dd, J = 14.0,
2-methyltetrahydrofuran-2-yl)-2-[(tert-butyldimethylsilyl)oxy]- 5.0 Hz, 1 H), 1.76–1.57 (m, 4 H), 1.39 (s, 3 H), 1.13 (s, 3 H), 0.901
ethanol (12): To a solution of 11[9a] (2.0 g, 2.66 mmol, 100 mol-%)
in THF (8.0 mL), was added HF·pyridine (70% HF, 2.08 mL, 1.6 g,
80.0 mmol, 3000 mol-%) at room temp. The reaction mixture was
stirred at room temp. for 1.5 h before satd. aq. NaHCO3 (50 mL)
was added dropwise. The mixture was allowed to stir for 10 min,
and then the layers were separated. The organic layer was washed
(s, 9 H), 0.900 (s, 9 H), 0.11 (s, 3 H), 0.05 (s, 3 H), 0.01 (s, 3 H),
–0.0002 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 203.3,
138.5, 128.4, 127.9, 127.6, 106.4, 85.8, 84.1, 82.9, 81.1, 73.8, 72.1,
72.0, 66.4, 47.0, 40.7, 34.3, 31.9, 26.3, 26.1, 26.0, 22.8, 18.5, 18.1,
–3.8, –4.4, –4.9, –5.0 ppm. HRMS (ESI+): calcd. for C34H58O7-
NaSi2 657.3619; found 657.3605 (Δ = 2.1 ppm).
1688
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1682–1694

Synthetic Studies towards Pectenotoxin-2
(1S,2R)-1-((2R,4R,5R)-5-((1S,3R,5S)-1-[(Benzyloxy)methyl]-5-
warmed to reflux and stirred for 17 h. Solvent was evaporated and
methyl-2,8-dioxabicyclo[3.2.1]octan-3-yl)-4-[(tert-butyldimethyl- the residue was purified by flash chromatography (30% MTBE/
silyl)oxy]-2-methyltetrahydrofuran-2-yl)-1-[(tert-butyldimethylsilyl)- hexanes, 50 μL Et3N in 500 mL eluent) to give keto diol 26 as a
oxy]but-3-en-2-ol (14): To a solution of aldehyde 13 (0.10 g,
0.16 mmol, 100 mol-%) in THF (3.5 mL), was added vinylmagne-
sium bromide (1 m in THF, 0.64 mL, 0.64 mmol, 400 mol-%) at
–78 °C. The reaction mixture was stirred at –78 °C for 25 min and
then quenched with satd. aq. NH4Cl (4 mL). The reaction mixture
was warmed to room temp. and H2O (4 mL) was added to dissolve
the precipitate. The separated organic layer was dried with Na2SO4
and concentrated. Purification of the residue by flash chromatog-
raphy (initially 5 % EtOAc/hexanes, then 7 %, and finally 10 %
EtOAc/hexanes) afforded the major product 14 as a light-yellow
oil (71 mg, 67%). A mixture containing the major and the minor
diastereomers in 1:2 ratio (30 mg) was also isolated. Rf = 0.55 (30%
tanned oil (0.12 g, 52%). Rf = 0.27 (30% EtOAc/hexanes). [α]D
=
–7.9 (c = 1.00, CH Cl ). IR (film): ν = 3480, 2955, 2931, 2858,
˜
2
2
1694, 1472, 1255, 1111 cm–1. 1H NMR (400 MHz, CDCl3): δ =
7.68–7.65 (m, 4 H), 7.46–7.37 (m, 6 H), 7.33–7.32 (m, 5 H), 6.96
(dd, J = 15.9, 3.5 Hz, 1 H), 6.41 (dd, J = 15.8, 2.2 Hz, 1 H), 4.61
(ddAB, JAB = 12.3 Hz, Δv = 28.4 Hz, 2 H), 4.55–4.51 (m, 1 H), 4.29
(dd, J = 4.4, 2.9 Hz, 1 H), 4.13 (ddd, J = 11.4, 8.0, 3.7 Hz, 1 H),
3.93 (d, J = 3.2 Hz, 1 H), 3.87–3.84 (m, 1 H), 3.74 (dd, J = 10.4,
4.2 Hz, 1 H), 3.66 (dd, J = 10.1, 5.9 Hz, 1 H), 3.56 (dd, J = 8.2,
2.8 Hz, 1 H), 3.51 (ddAB, JAB = 10.7 Hz, Δv = 21.6 Hz, 2 H), 3.25
(d, J = 8.5 Hz, 1 H), 2.84 (d, J = 3.9 Hz, 1 H), 2.58 (dt, J = 7.5,
1.6 Hz, 2 H), 2.18 (dt, J = 13.0, 4.2 Hz, 1 H), 2.02–1.64 (m, 8 H),
EtOAc/hexanes). [α]D = –1.9 (c = 1.00, CH Cl ). IR (film): ν = 1.86 (dd, J = 13.9, 5.2 Hz, 1 H), 1.55 (dd, J = 13.1, 3.9 Hz, 1 H),
˜
2
2
3497, 2954, 2929, 2857, 1254, 1100 cm–1
.
1H NMR (400 MHz, 1.52–1.44 (m, 2 H), 1.39 (s, 3 H), 1.05 (s, 9 H), 1.05 (s, 3 H), 0.91
CDCl3): δ = 7.33–7.27 (m, 5 H), 5.95 (ddd, J = 17.3, 10.6, 4.3 Hz, (obscured d, 3 H), 0.906 (s, 9 H), 0.895 (s, 9 H), 0.11 (s, 3 H), 0.05
1 H), 5.31 (dd, J = 17.2, 1.9 Hz, 1 H), 5.13 (dd, J = 10.6, 1.9 Hz,
1 H), 4.62 (ddAB, |JAB| = 12.4 Hz, Δv = 30.7 Hz, 2 H,), 4.38 (ddd,
J = 9.1, 4.3, 2.2 Hz, 1 H), 4.29 (dd, J = 4.1, 3.1 Hz, 1 H), 4.14
(ddd, J = 11.4, 8.0, 3.7 Hz, 1 H), 3.82 (d, J = 2.4 Hz, 1 H), 3.56 (dd,
J = 8.2, 2.9 Hz, 1 H), 3.52 (ddAB, |JAB| = 10.5 Hz, Δv = 22.5 Hz, 2
H), 2.91 (d, J = 9.1 Hz, 1 H), 2.20 (dt, J = 13.0, 4.1 Hz, 1 H), 2.02–
1.95 (m, 2 H), 1.90–1.85 (m, 1 H), 1.84 (dd, J = 13.7, 5.3 Hz, 1 H),
1.75–1.65 (m, 2 H), 1.59–1.56 (m, 1 H), 1.39 (s, 3 H), 1.23 (s, 3 H),
0.902 (s, 9 H), 0.896 (s, 9 H), 0.10 (s, 3 H), 0.07 (s, 3 H), 0.05 (s, 3
H), –0.02 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.8,
138.5, 128.4, 127.9, 127.6, 114.1, 106.4, 84.8, 84.6, 81.1, 79.2, 73.8,
72.3, 72.1, 72.0, 66.2, 48.9, 40.8, 34.3, 31.8, 26.3, 26.12, 26.06, 22.3,
18.4, 18.1, –3.4, –4.0, –4.3, –5.0 ppm. HRMS (ESI+): calcd. for
C36H62O7NaSi2 685.3932; found 685.328 (Δ = 0.6 ppm).
(s, 3 H), 0.04 (s, 3 H), –0.01 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 200.1, 148.4, 138.5, 135.7, 133.2, 133.1, 130.1, 130.0,
129.9, 128.5, 128.4, 128.2, 127.92, 127.89, 126.6, 106.4, 85.0, 84.9,
81.1, 78.5, 74.7, 73.8, 72.0, 71.97, 71.94, 68.8, 66.0, 48.9, 41.0, 40.8,
39.3, 34.2, 33.9, 31.9, 27.0, 26.3, 26.05, 26.01, 22.3, 20.8, 19.3, 18.3,
18.1, 10.3, –3.6, –4.0, –4.3, –5.1 ppm. HRMS (ESI+): calcd. for
C60H94O10NaSi3 1081.6053; found 1081.6072 (Δ = 6.3 ppm).
(5S,6R,13S,14S)-5-((2R,4R,5R)-5-((1S,3R,5S)-1-[(Benzyloxy)-
methyl]-5-methyl-2,8-dioxabicyclo[3.2.1]octan-3-yl)-4-[(tert-butyl-
dimethylsilyl)oxy]-2-methyltetrahydrofuran-2-yl)-6,13-dihydroxy-
2,2,3,3,14,18,18-heptamethyl-17,17-diphenyl-4,16-dioxa-3,17-di-
silanonadecan-9-one (28): To a solution of ketone 26 (56 mg,
0.053 mmol, 100 mol-%) and pyridine (6.3 μL, 6.3 mg, 0.078 mmol,
150 mol-%) in EtOAc (5 mL), was added Pd on charcoal (11.2 mg
of 5% Pd catalyst, 0.005 mmol, 10 mol-%) under argon flow. The
reaction flask was repeatedly evacuated and flushed with H2. The
suspension was vigorously stirred under a H2 atmosphere for 4 h
and then filtered through Celite. The filter pad was washed with
EtOAc (2ϫ5 mL) and the combined filtrates were concentrated.
Purification of the residue by flash chromatography (30% EtOAc/
hexanes, 50 μL Et3N in 500 mL eluent) afforded the desired prod-
uct 28 as a colorless oil (53 mg, 94%). Rf = 0.25 (30% EtOAc/
(7S,8S)-9-[(tert-Butyldiphenylsilyl)oxy]-7-hydroxy-8-methylnon-1-
en-3-one (19): To a solution of 15[12] (0.11 g, 0.27 mmol, 100 mol-
%) in THF (3.0 mL), was added vinylmagnesium bromide (1 m in
THF, 0.33 mL, 0.33 mmol, 120 mol-%) at –78 °C. The reaction
mixture was stirred at –78 °C for 30 min and then quenched with
satd. aq. NH4Cl (3 mL). The reaction mixture was warmed to room
temp. and H2O (3 mL) was added to dissolve the precipitate. The
separated organic layer was washed with brine (3 mL), dried with
Na2SO4, and concentrated. Purification of the residue by flash
chromatography (20% EtOAc/hexanes) afforded the desired prod-
uct 19 as a light-yellow oil (0.11 g, 94%). Rf = 0.29 (30% EtOAc/
hexanes). [α]D = –5.9 (c = 1.00, CH Cl ). IR (film): ν = 3502, 2954,
˜
2
2
2930, 2857, 1713, 1472, 1254, 1111 cm–1
.
1H NMR (400 MHz,
CDCl3): δ = 7.68–7.65 (m, 4 H), 7.46–7.28 (m, 11 H), 4.62 (ddAB
,
Hexanes). [α]D = 0.6 (c = 1.00, CH Cl ). IR (film): ν = 3503, 2959, |JAB| = 12.4 Hz, Δv = 31.1 Hz, 2 H,), 4.29 (dd, J = 4.2, 3.1 Hz, 1
˜
2
2
2931, 2858, 1681, 1428, 1112 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 7.68–7.65 (m, 4 H), 7.46–7.37 (m, 6 H), 6.36 (dd, J = 17.7,
10.5 Hz, 1 H), 6.23 (dd, J = 17.7, 1.2 Hz, 1 H), 5.82 (dd, J = 10.5,
H), 4.14 (ddd, J = 12.0, 7.4, 4.0 Hz, 1 H), 3.85–3.82 (m, 1 H), 3.76–
3.62 (m, 4 H), 3.59–3.55 (m, 1 H), 3.52 (ddAB, |JAB| = 10.6 Hz, Δv
= 22.7 Hz, 2 H,), 2.84 (d, J = 3.8 Hz, 1 H), 2.65 (ddd, J = 15.9,
1.2 Hz, 1 H), 3.86 (m, 1 H), 3.75 (dd, J = 10.1, 4.2 Hz, 1 H), 3.66 8.3, 6.5 Hz, 1 H), 2.57 (d, J = 8.4 Hz, 1 H), 2.51–2.42 (m, 3 H),
(dd, J = 10.1, 6.0 Hz, 1 H), 2.84 (d, J = 4.0 Hz, 1 H), 2.63 (dt, J
= 7.3, 2.3 Hz, 2 H), 1.85–1.65 (m, 3 H), 1.57–1.37 (m, 2 H), 1.06
(s, 9 H), 0.90 (d, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 135.7, 133.2, 133.1, 130.0, 129.95, 128.2, 127.92,
127.86, 74.0, 68.7, 39.6, 39.3, 33.7, 27.0, 20.8, 19.3, 10.4 ppm.
2.19 (dt, J = 13.0, 4.0 Hz, 1 H), 2.02–1.42 (m, 14 H), 1.39 (s, 3 H),
1.06 (s, 9 H), 1.05 (s, 3 H), 0.91 (s, 9 H), 0.90 (s, 9 H), 0.89 (ob-
scured d, 3 H), 0.131 (s, 3 H), 0.129 (s, 3 H), 0.04 (s, 3 H), –0.02
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 211.9, 138.5,
135.8, 135.7, 133.2, 133.1, 130.0, 129.9, 128.4, 127.9, 127.89,
HRMS (ESI+): calcd. for C26H36O3NaSi 447.2331; found 447.2333 127.85, 127.6, 106.4, 84.4, 84.3, 81.1, 79.2, 74.0, 73.8, 72.1, 71.9,
(Δ = 0.3 ppm).
70.8, 68.8, 66.2, 48.5, 43.0, 40.8, 39.8, 39.3, 34.2, 33.9, 31.8, 30.1,
27.0, 26.3, 26.2, 26.1, 22.0, 20.6, 19.3, 18.5, 18.1, 10.4, –3.69, –3.73,
–4.4, –5.0 ppm. HRMS (ESI+): calcd. for C60H96O10NaSi3
1083.6209; found 1083.6238 (Δ = 9.6 ppm).
(5S,6R,13S,14S,E)-5-((2R,4R,5R)-5-((1S,3R,5S)-1-[(Benzyloxy)-
methyl]-5-methyl-2,8-dioxabicyclo[3.2.1]octan-3-yl)-4-[(tert-butyl-
dimethylsilyl)oxy]-2-methyltetrahydrofuran-2-yl)-6,13-dihydroxy-
2,2,3,3,14,18,18-heptamethyl-17,17-diphenyl-4,16-dioxa-3,17-di-
silanonadec-7-en-9-one (26): To a solution of ketone 19 (0.15 g,
0.34 mmol, 150 mol-%) and alcohol 14 (0.15 g, 0.23 mmol,
((S)-((2R,4R,5R)-5-((1S,3R,5S)-1-[(Benzyloxy)methyl]-5-methyl-
2,8-dioxabicyclo[3.2.1]octan-3-yl)-4-[(tert-butyldimethylsilyl)oxy]-
2-methyltetrahydrofuran-2-yl)((2R,5S,7S)-7-((S)-1-[(tert-butyldi-
100 mol-%) in CH2Cl2 (7 mL), was added Grubbs 2nd generation phenylsilyl)oxy]propan-2-yl)-1,6-dioxaspiro[4.5]decan-2-yl)meth-
catalyst (9.8 mg, 0.012 mmol, 5 mol-%). The reaction mixture was oxy)(tert-butyl)dimethylsilane (30): To a solution of ketone 28
Eur. J. Org. Chem. 2011, 1682–1694
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1689

P. M. Pihko et al.
(53 mg, 0.049 mmol, 100 mol-%) in CH2Cl2 (3.5 mL) was added H, 4-Hb), 0.43 (s, 3 H, 11-OSi-Mea), 0.36 (s, 3 H, 11-OSi-Meb),
FULL PAPER
chloroacetic acid (2.3 mg, 0.024 mol-%, 50 mol-%) at room temp.
The reaction mixture was stirred at room temp. for 1 h and then
diluted with CH2Cl2 (5 mL) and quenched with satd. aq. NaHCO3
(5 mL). The separated organic layer was dried with Na2SO4 and
concentrated. Purification of the residue by flash chromatography
(10% EtOAc/hexanes, 50 μL Et3N in 250 mL eluent) afforded the
nonanomeric isomer 30 as a colorless oil (15 mg, 29%) and a mix-
ture of the nonanomeric and anomeric isomer 29 (35 mg, combined
0.14 (s, 6 H, 14-OSi-Me2) ppm. 13C NMR (100 MHz, CD3CN): δ
= 139.5, 136.42, 136.37, 136.36, 134.8, 130.7, 130.6, 129.2, 128.74,
128.66, 128.62, 128.4, 107.0, 105.8, 85.7, 84.7, 84.6, 83.0, 81.5, 74.0,
73.4, 72.9, 72.7, 67.5, 66.6, 49.7, 42.1, 41.4, 40.4, 34.8, 34.7, 32.5,
28.5, 28.0, 27.3, 26.52, 26.47, 26.41, 21.1, 21.0, 19.8, 19.2, 18.6,
15.1, –2.7, –3.9, –4.4, –4.7 ppm. HRMS (ESI+): calcd. for
C60H94O9NaSi3 1065.6103; found 1065.6104 (Δ = 0.1 ppm).
(2S,3R,6S,8S)-2-((2R,4R,5S)-5-((1S,3R,5S)-1-[(Benzyloxy)meth-
yl]-5-methyl-2,8-dioxabicyclo[3.2.1]octan-3-yl)-4-hydroxy-2-meth-
yltetrahydrofuran-2-yl)-8-[(S)-1-hydroxypropan-2-yl]-1,7-dioxa-
spiro[5.5]undecan-3-ol (31a): To a solution of spiroketal 29 (6.0 mg,
0.006 mmol, 100 mol-%) in THF (0.5 mL), was added TBAF (1 m
in THF, 56 μL, 0.06 mmol, 1000 mol-%) at room temp. The reac-
tion mixture was stirred at room temp. for 24 h and then diluted
with Et2O (4 mL). The orange oil that separated from the solution
was separated from the solution, and the solvent was evaporated.
The crude product was dissolved in CH2Cl2 (1 mL) and pTsOH
(0.5 mg, 0.003 mmol, 50 mol-%) was added. The reaction mixture
was stirred at room temp. for 19 h then diluted with CH2Cl2 (4 mL)
and satd. aq. NaHCO3 (2 mL) was added. The layers were sepa-
rated and the organic layer was dried with Na2SO4 and concen-
trated. Purification of the residue by flash chromatography (90%
EtOAc/hexanes) afforded the [6,6]-spiroketal product 31 as a color-
less oil (2.8 mg, 86%). Rf = 0.26 (90% EtOAc/hexanes). [α]D = 1.7
total yield 98%). For 30: Rf = 0.38 (15% EtOAc/hexanes). [α]D
=
–13.2 (c = 0.50, CH Cl ). IR (film): ν = 2953, 2929, 2856, 1472,
˜
2
2
1106 cm–1. 1H NMR (400 MHz, C6D6): δ = 7.82–7.78 (m, 4 H,
TBDPS), 7.36–7.19 (m, 10 H, TBDPS, Bn), 7.11–7.07 (m, 1 H,
TBDPS), 4.54 (ddAB, |JAB| = 12.3 Hz, Δv = 23.9 Hz, 2 H, Bn), 4.40–
4.34 (m, 2 H, 16-H, 10-H), 4.22 (dd, J = 4.7, 2.8 Hz, 1 H, 14-H),
3.88 (d, J = 8.2 Hz, 1 H, 11-H), 3.85 (dd, J = 9.7, 7.3 Hz, 1 H, 1-
H), 3.80 (s, 2 H, 22-H), 3.62 (dd, J = 11.1, 2.9 Hz, 1 H, 15-H), 3.60
(dd, J = 9.7, 6.0 Hz, 1 H, 1-H), 3.58–3.56 (m, 1 H, 3-H), 2.41 (dt,
J = 13.2, 4.5 Hz, 1 H, 20-Ha), 2.32 (d, J = 13.9 Hz, 1 H, 13-Ha),
2.23–1.96 (m, 5 H, 6-Ha, 8-Ha, 9-H, 20-Hb), 1.86 (app t, J =
10.5 Hz, 1 H, 17-Hax), 1.82–1.49 (m, 11 H, 2-H, 4-H, 5-H, 6-Hb,
8-Hb, 13-Hb, 17-Heq, 19-H), 1.29 (s, 3 H, 43-H), 1.24 (s, 3 H, 42-
H), 1.19 (s, 9 H, TBDPS), 1.10 (s, 9 H, 14-OSi-tBu), 1.04 (s, 9 H,
11-OSi-tBu), 1.00 (d, J = 6.8 Hz, 3 H, 41-H), 0.48 (s, 3 H, 14-OSi-
Mea), 0.37 (s, 3 H, 14-OSi-Meb), 0.13 (s, 3 H, 11-OSi-Mea), 0.12 (s,
3 H, 11-OSi-Meb) ppm. 13C NMR (100 MHz, CD3CN): δ = 139.6,
136.4, 136.3, 134.80, 134.76, 130.6, 130.7, 129.2, 128.8, 128.75,
128.72, 128.4, 108.0, 107.0, 85.9, 84.6, 81.8, 81.4, 80.2, 74.0, 73.5,
72.94, 72.88, 67.2, 66.6, 49.2, 41.6, 41.3, 35.6, 34.7, 33.7, 32.5, 29.3,
28.9, 27.2, 26.7, 26.41, 26.37, 23.0, 21.8, 19.8, 19.3, 18.6, 11.6, –2.7,
–4.1, –4.2, –4.9 ppm. HRMS (ESI+): calcd. for C60H94O9NaSi3
1065.6103; found 1065.6095 (Δ = 0.8 ppm).
(c = 0.23, CH Cl ). IR (film): ν = 3401, 2918, 2850, 1454,
˜
2
2
1
1099 cm–1. H NMR (400 MHz, CD3CN): δ = 7.36–7.28 (m, 5 H,
Bn), 4.56 (s, 2 H, Bn), 4.19 (d, J = 10.7 Hz, 1 H, 14-OH), 4.19–
4.14 (m, 1 H, 16-H), 4.03–3.99 (m, 1 H, 14-H), 3.81–3.78 (m, 1 H,
10-H), 3.74 (ddd, J = 11.6, 5.1, 2.2 Hz, 1 H, 3-H), 3.56–3.53 (m, 1
H, 1-Ha), 3.51 (d, J = 1.1 Hz, 1 H, 11-H), 3.47 (s, 2 H, 22-H), 3.42
(dd, J = 7.9, 2.4 Hz, 1 H, 15-H), 3.39–3.33 (m, 1 H, 1-Hb), 2.77 (d,
J = 6.4 Hz, 1 H, 10-OH), 2.66 (dd, J = 6.5, 4.9 Hz, 1 H, 1-OH),
2.49 (d, J = 14.5 Hz, 1 H, 13-Ha), 2.12–2.07 (m, 2 H, 8-Ha, 20-Ha),
2.01–1.96 (m, 2 H, 4-Heq, 9-Ha), 1.87–1.75 (m, 4 H, 5-Ha, 13-Hb,
19-Ha, 20-Hb), 1.70–1.51 (m, 8 H, 2-H, 5-Hb, 6-Ha, 8-Hb, 9-Hb, 17-
H, 19-Hb), 1.47 (dd, J = 13.9, 5.1 Hz, 1 H, 6-Hb), 1.38 (ddd, J =
14.0, 4.5, 2.3 Hz, 1 H, 4-Hax), 1.29 (s, 3 H, 43-H), 1.20 (s, 3 H, 42-
H), 0.91 (d, J = 6.9 Hz, 3 H, 41-H) ppm. HRMS (ESI+): calcd. for
C32H48O9Na 599.3196; found 599.3219 (Δ = 3.8 ppm).
Equilibration Experiment
((S)-((2R,4R,5R)-5-((1S,3R,5S)-1-[(Benzyloxy)methyl]-5-methyl-
2,8-dioxabicyclo[3.2.1]octan-3-yl)-4-[(tert-butyldimethylsilyl)oxy]-
2-methyltetrahydrofuran-2-yl)((2R,5R,7S)-7-((S)-1-[(tert-butyldi-
phenylsilyl)oxy]propan-2-yl)-1,6-dioxaspiro[4.5]decan-2-yl)meth-
oxy)(tert-butyl)dimethylsilane (29): To a solution of a 1:1 mixture of
spiroketals 29 and 30 (40 mg, 0.038 mmol, 100 mol-%) in CH2Cl2
(2.0 mL), was added PPTS (1.9 mg, 0.0075 mmol, 20 mol-%) at
room temp. After 4 h, a second portion of PPTS (9.5 mg,
0.038 mmol, 100 mol-%) was added. Stirring was continued at
room temp. for 2 h, then the reaction mixture was diluted with
CH2Cl2 (5 mL) and quenched by addition of satd. aq. NaHCO3
(4 mL). The layers were separated and the organic layer was dried
with Na2SO4 and concentrated. Purification of the residue by flash
chromatography (10% EtOAc/hexanes, 25 μL Et3N in 125 mL elu-
ent) afforded the anomeric isomer 29 as a colorless oil (26.5 mg,
(2S,3R,5R)-Methyl 3-[(tert-Butyldimethylsilyl)oxy]-5-{(S)-2-[(tert-
butyldimethylsilyl)oxy]-1-hydroxyethyl}-5-methyltetrahydrofuran-
2-carboxylate (33): To a solution of (2S,3R,5R)-methyl 5-{(S)-2-
[(tert-butyldimethylsilyl)oxy]-1-hydroxyethyl}-3-hydroxy-5-meth-
yltetrahydrofuran-2-carboxylate (0.10 g, 0.3 mmol, 100 mol-%) in
CH2Cl2 (2 mL) at –78 °C, was added dropwise over a period of
30 min, a solution of 2,6-lutidine (70 μL, 0.6 mmol, 200 mol-%)
and TBSOTf (76 μL, 0.33 mmol, 110 mol-%) in CH2Cl2 (2 mL).
67%). For 29: Rf = 0.34 (15% EtOAc/hexanes). [α]D = 0.6 (c = The reaction was stirred at –78 °C for 25 min and then quenched
0.50, CH Cl ). IR (film): ν = 2953, 2929, 2856, 1472, 1110 cm–1. by addition of MeOH (1 mL). The solution was warmed to room
˜
2
2
1H NMR (400 MHz, C6D6): δ = 7.85–7.79 (m, 4 H, Si-Ph), 7.36– temp. then washed with H2O (2 mL) and brine (2 mL), dried with
7.18 (m, 10 H, Si-Ph, Bn), 7.10–7.06 (m, 1 H, Si-Ph), 4.54 (ddAB
,
Na2SO4, and concentrated. Purification of the residue by flash
chromatography (10% EtOAc/hexanes) afforded the desired prod-
uct 34 as a colorless viscous oil (0.12 g, 92%). Rf = 0.73 (50%
|JAB| = 12.3 Hz, Δv = 26.4 Hz, 2 H, Bn), 4.35 (ddd, J = 11.5, 8.0,
3.7 Hz, 1 H, 16-H), 4.20 (dd, J = 5.0, 3.2 Hz, 1 H, 14-H), 3.96–
3.86 (m, 3 H, 1-Ha, 3-H, 10-H), 3.81 (d, J = 7.8 Hz, 1 H, 11-H),
3.79 (s, 2 H, 22-H), 3.69 (dd, J = 9.9, 7.0 Hz, 1 H, 1-Hb), 3.64 (dd,
EtOAc/hexanes). [α]D = +17.7 (c = 1.00, CH Cl ). IR (film): ν =
˜
2
2
3451, 2954, 2931, 2858, 2886, 1770, 1737, 1473, 1463, 1256, 1100,
J = 8.2, 3.1 Hz, 1 H, 15-H), 2.37 (dt, J = 13.1, 4.3 Hz, 1 H, 20-H), 838, 778 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.72 (q, J =
2.37–2.28 (m, 1 H, 9-Ha), 2.28 (d, J = 14.1 Hz, 1 H, 13-Ha), 2.17 6.0 Hz, 1 H), 4.50 (d, J = 6.0 Hz, 1 H), 3.81 (t, J = 3.6 Hz, 1 H),
(ddd, J = 13.7, 9.2, 4.8 Hz, 1 H, 20-Ha), 1.99–1.83 (m, 5 H, 2-H,
6-Ha, 8-Ha, 9-Hb, 17-Hax), 1.74–1.38 (m, 9 H, 4-Ha, 5-H, 6-Hb, 8-
Hb, 13-Hb, 17-Heq, 19-H), 1.35 (d, J = 6.8 Hz, 3 H, 41-H), 1.30 (s,
3 H, 43-H), 1.22 (s, 9 H, 1O-Si-tBu), 1.15 (s, 3 H, 42-H), 1.09 (s, 9
H, 11-OSi-tBu), 1.07 (s, 9 H, 14-OSi-tBu), 1.04 (d, J = 6.8 Hz, 1
3.79 (dd, J = 13.2, 3.6 Hz, 1 H), 3.69 (dt, J = 13.2, 3.5 Hz, 1 H),
3.72 (s, 3 H), 2.42 (dd, J = 13.3, 5.6 Hz, 1 H), 1.84 (dd, J = 13.3,
6.3 Hz, 1 H), 1.23 (s, 3 H), 0.89 (s, 9 H), 0.86 (s, 9 H), 0.08 (s, 3
H), 0.073 (s, 3 H), 0.071 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 171.8, 87.1, 80.2, 75.9, 74.7, 63.8, 52.0,
1690
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1682–1694

Synthetic Studies towards Pectenotoxin-2
41.2, 26.0, 25.7, 24.0, 18.4, 18.0, –4.8, –5.2, –5.3, –5.4 ppm. HRMS
(ESI+): calcd. for C21H44O6NaSi3 471.2574; found 471.2553 (Δ =
4.5 ppm).
1.43 mL, 3.6 mmol, 200 mol-%) at 0 °C, and the reaction mixture
was stirred at 0 °C for 5 min. A portion of the LDA solution (0.5 m,
4.05 mL, 2.0 mmol, 110 mol-%) was transferred by using a syringe
to a solution of 5-[(benzyloxy)methyl]hex-5-en-2-one (36;[9b] 0.4 g,
1.8 mmol, 100 mol-%) in THF (10 mL) at –78 °C. After 10 min, a
solution of aldehyde 35 (1.14 g, 2.1 mmol, 115 mol-%) in THF
(10 mL) was added by cannula into the reaction mixture. Stirring
was continued at –78 °C for 10 min then satd. aq. NH4Cl (10 mL)
was added. The reaction mixture was warmed to room temp. and
then diluted with H2O (20 mL). The layers were separated and the
organic phase was washed with brine (20 mL), dried with Na2SO4,
and concentrated. Purification of the residue by flash chromatog-
raphy (initially 10% EtOAc/hexanes, finally 15% EtOAc/hexanes)
afforded ketone 37 as a light-yellow oil (0.72 g, 51%). The reaction
did not go to completion and small amounts of both starting mate-
rials were recovered. Rf = 0.42 (30% EtOAc/hexanes). [α]D = –1.0
(2S,3R,5R)-Methyl 3-[(tert-Butyldimethylsilyl)oxy]-5-{(S)-2-[(tert-
butyldimethylsilyl)oxy]-1-[(4-methoxybenzyl)oxy]ethyl}-5-methyl-
tetrahydrofuran-2-carboxylate (34): To a solution of compound 33
(1.4 g, 3.3 mmol, 100 mol-%) in CH2Cl2 (15 mL) at 0 °C, were
added p-methoxybenzyl trichloroacetimidate (1.73 mL, 8.3 mmol,
250 mol-%) and triphenylcarbenium tetrafluoroborate (0.11 g,
0.33 mmol, 10 mol-%). The reaction mixture was warmed to room
temp. and stirred for 2.5 h, then H2O (10 mL) was added and the
layers were separated. The organic phase was washed with brine
(10 mL), dried with Na2SO4, and concentrated. Purification of the
residue by flash chromatography (10% MTBE/hexanes) afforded
the desired product 34 as a colorless oil (1.40 g, 74%). Rf = 0.44
(20% EtOAc/hexanes). [α]D = –5.3 (c = 1.00, CH Cl ). IR (film): ν
˜
2
2
(c = 1.00, CH Cl ). IR (film): ν = 3503, 2954, 2930, 2885, 1708,
˜
2
2
= 2953, 2931, 2857, 2886, 1770, 1737, 1614, 1514, 1250, 1105, 837,
777 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.30–7.26 (m, 2 H),
6.88–6.84 (m, 2 H), 4.95 (d, J = 11.2 Hz, 1 H), 4.64 (ddd, J = 5.7,
5.0, 3.0 Hz, 1 H), 4.58 (d, J = 11.2 Hz, 1 H), 4.56 (d, J = 4.9 Hz,
1 H), 4.18 (dd, J = 10.5, 1.5 Hz, 1 H), 3.89 (dd, J = 7.6, 1.5 Hz, 1
H), 3.84–3.81 (m, 1 H), 3.80 (s, 3 H), 3.72 (s, 3 H), 2.30 (dd, J =
13.5, 3.0 Hz, 1 H), 1.87 (dd, J = 13.5, 5.8 Hz, 1 H), 1.18 (s, 3 H),
0.92 (s, 9 H), 0.87 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3 H), 0.05 (s, 3
H), 0.04 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.2,
159.0, 132.1, 129.6, 129.1, 128.1, 113.7, 85.8, 84.9, 82.5, 74.6, 73.8,
64.7, 55.4, 51.7, 45.6, 26.1, 25.8, 22.3, 18.3, 18.0, –4.5, –5.23, –5.25,
–5.3 ppm. HRMS (ESI+): calcd. for C29H52O7NaSi2 591.3149;
found 591.3138 (Δ = 1.9 ppm).
1514, 1250, 1103, 1070, 836, 776 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 7.35–7.29 (m, 5 H), 7.28–7.25 (m, 2 H), 6.88–6.84 (m,
2 H), 5.07 (dd, J = 2.0, 0.9 Hz, 1 H), 4.90 (t, J = 0.7 Hz, 1 H), 4.86
(d, J = 11.2 Hz, 1 H), 4.55 (d, J = 11.3 Hz, 1 H), 4.52–4.48 (m, 1
H), 4.49 (s, 2 H), 4.27 (td, J = 8.8, 2.2 Hz, 1 H), 3.99–3.96 (m, 1
H), 3.96 (s, 2 H), 3.79 (s, 3 H), 3.72 (dd, J = 10.9, 7.1 Hz, 1 H),
3.68 (dd, J = 8.1, 4.5 Hz, 1 H), 3.57 (dd, J = 7.1, 1.8 Hz, 1 H), 3.23
(br. s, 1 H), 2.83 (dd, J = 17.1, 2.5 Hz, 1 H), 2.66–2.59 (m, 3 H),
2.38 (t, J = 7.4 Hz, 2 H), 2.16 (dd, J = 13.5, 3.7 Hz, 1 H), 1.84 (dd,
J = 13.5, 5.9 Hz, 1 H), 1.10 (s, 3 H), 0.90 (s, 9 H), 0.896 (s, 9 H),
0.10 (s, 3 H), 0.08 (s, 3 H), 0.05 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 211.0, 159.1, 144.9, 138.4, 131.8, 129.2, 128.5, 127.9,
127.7, 113.8, 112.2, 85.8, 83.5, 82.8, 73.62, 73.58, 73.3, 72.1, 66.8,
64.8, 55.4, 46.5, 45.5, 41.7, 26.8, 26.1, 26.0, 22.4, 18.3, 18.2, –4.3,
–5.1, –5.17, –5.21 ppm. HRMS (ESI+): calcd. for C42H68O8NaSi2
779.4350; found 779.4353 (Δ = 0.4 ppm).
(2S,3R,5R)-3-[(tert-Butyldimethylsilyl)oxy]-5-{(S)-2-[(tert-butyl-
dimethylsilyl)oxy]-1-[(4-methoxybenzyl)oxy]ethyl}-5-methyltetra-
hydrofuran-2-carbaldehyde (35): To a solution of compound 34
(1.34 g, 2.4 mmol, 100 mol-%) in CH2Cl2 (25 mL) at –90 °C, was
added, dropwise, DIBAL-H (1 m in toluene, 2.6 mL, 2.6 mmol,
110 mol-%). The reaction mixture was stirred at –90 °C for 20 min
and then quenched by addition of MeOH (15 mL). The solution
was warmed to room temp. then satd. aq. Rochelle salt (20 mL)
was added and the reaction mixture was stirred for an additional
45 min. The layers were separated and the aqueous phase was ex-
tracted with EtOAc (20 mL). The combined organic extracts were
washed with brine (20 mL), dried with Na2SO4 and concentrated.
Purification of the residue by flash chromatography (15% MTBE/
hexanes) afforded aldehyde 35 as a light-yellow oil (1.19 g, 93%).
Rf = 0.58 (30% EtOAc/hexanes). [α]D = –25.6 (c = 1.00, CH2Cl2).
(1R,3S)-6-[(Benzyloxy)methyl]-1-((2R,3R,5R)-3-[(tert-butyldi-
methylsilyl)oxy]-5-{(S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-meth-
oxybenzyl)oxy]ethyl}-5-methyltetrahydrofuran-2-yl)-3-methylhept-6-
ene-1,3-diol (38): A stock triisopropoxymethyltitanium solution
(0.5 m) was prepared as follows: To gently cooled (ca. 5 °C), neat
titanium(IV) isopropoxide (4.46 mL, 15 mmol, 2586 mol-%) was
added, dropwise, titanium tetrachloride (0.54 mL, 5 mmol,
862 mol-%). The mixture was warmed to room temp. and stirred
for 5 min. Et2O (22.5 mL) was added and stirring was continued at
room temp. for 30 min. The reaction mixture was cooled to 0 °C
and MeLi (1.6 m in Et2O, 12.5 mL, 20 mmol, 3448 mol-%) was
added. The reaction mixture was stirred at 0 °C for 1 h, then a
portion of the triisopropoxymethyltitanium solution (0.5 m,
17.4 mL, 8.7 mmol, 1500 mol-%) was transferred by using a syringe
into a –78 °C solution of ketone 37 (0.44 g, 0.58 mmol, 100 mol-
%) in Et2O (13 mL). The reaction mixture was stirred at –78 °C for
10 min and then the dry-ice bath was changed into an ice-bath.
Stirring was continued at 0 °C for a further 10 min then the reac-
tion mixture was diluted with Et2O (10 mL) and 2 m HCl (10 mL)
was added dropwise. The layers were separated and the organic
phase was washed with 2 m HCl (10 mL) and brine (10 mL), dried
with Na2SO4, and concentrated. Purification of the residue by flash
chromatography (10% EtOAc/hexanes) afforded diol 38 as a color-
less oil (0.29 g, 65%). Rf = 0.24 (30% EtOAc/hexanes). [α]D = –9.7
IR (film): ν = 2954, 2930, 2857, 2885, 1737, 1514, 1250, 1076, 837,
˜
1
777 cm–1. H NMR (400 MHz, CDCl3): δ = 9.61 (d, J = 2.6 Hz, 1
H), 7.29–7.27 (m, 2 H), 6.88–6.86 (m, 2 H), 4.92 (d, J = 11.2 Hz,
1 H), 4.72 (ddd, J = 5.8, 5.1, 2.8 Hz, 1 H), 4.57 (d, J = 11.2 Hz, 1
H), 4.21 (dd, J = 5.0, 2.6 Hz, 1 H), 4.16 (dt, J = 9.3, 4.8 Hz, 1 H),
3.85–3.81 (m, 2 H), 3.80 (s, 3 H), 2.35 (dd, J = 13.7, 2.8 Hz, 1 H),
1.88 (dd, J = 13.6, 5.8 Hz, 1 H), 1.20 (s, 3 H), 0.92 (s, 9 H), 0.86
(s, 9 H), 0.10 (s, 3 H), 0.09 (s, 3 H), 0.04 (s, 3 H), 0.03 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 202.4, 159.1, 131.7, 129.6, 129.2,
128.1, 113.8, 86.7, 86.5, 85.2, 76.2, 73.7, 64.7, 55.4, 46.0, 26.0, 25.8,
22.5, 18.3, 18.1, –4.5, –5.19, –5.22, –5.3 ppm. HRMS (ESI+): calcd.
for C28H50O6NaSi2 561.3044; found 561.3055 (Δ = 2.0 ppm).
(R)-6-[(Benzyloxy)methyl]-1-((2R,3R,5R)-3-[(tert-butyldimethyl- (c = 1.00, CH Cl ). IR (film): ν = 3436, 2953, 2930, 2885, 2856,
˜
2
2
silyl)oxy]-5-{(S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-methoxy- 1249, 1103, 1070, 836, 776 cm–1. 1H NMR (400 MHz, CDCl3): δ =
benzyl)oxy]ethyl}-5-methyltetrahydrofuran-2-yl)-1-hydroxyhept-6-
en-3-one (37): A stock solution of LDA (0.5 m) was prepared as
follows: To a solution of diisopropylamine (0.49 mL, 3.8 mmol,
210 mol-%) in THF (5.3 mL), was added nBuLi (2.5 m in hexanes,
7.35–7.28 (m, 5 H), 7.28–7.24 (m, 2 H), 6.88–6.84 (m, 2 H), 5.07
(s, 1 H), 4.97 (s, 1 H), 4.85 (d, J = 11.3 Hz, 1 H), 4.62–4.57 (m, 1
H), 4.57 (d, J = 11.4 Hz, 1 H), 4.50 (s, 2 H), 4.22 (ddd, J = 10.2,
7.5, 2.6 Hz, 1 H), 3.98 (dd, J = 10.8, 1.8 Hz, 1 H), 3.98 (s, 2 H),
Eur. J. Org. Chem. 2011, 1682–1694
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1691

P. M. Pihko et al.
6.4, 4.7 Hz, 1 H), 3.63 (dd, J = 8.1, 2.9 Hz, 1 H), 3.52 (ddAB, |JAB
= 10.7 Hz, Δv = 20.7 Hz, 2 H), 2.67 (br. s, 1 H), 2.20 (td, J = 12.9,
4.2 Hz, 1 H), 2.15 (d, J = 14.1 Hz, 1 H), 1.99 (ddd, J = 13.5, 9.1,
4.7 Hz, 1 H), 1.88 (dd, J = 14.0, 5.2 Hz, 1 H), 1.88–1.84 (m, 1 H),
FULL PAPER
3.79 (s, 3 H), 3.73 (dd, J = 10.8, 7.0 Hz, 1 H), 3.64 (dd, J = 7.7,
5.0 Hz, 1 H), 3.52 (dd, J = 7.0, 1.8 Hz, 1 H), 2.23 (ddd, J = 15.1,
11.7, 4.0 Hz, 1 H), 2.14 (dd, J = 11.6, 4.8 Hz, 1 H), 2.08 (dd, J =
13.3, 5.1 Hz, 1 H), 1.91 (dd, J = 13.3, 6.3 Hz, 1 H), 1.87–1.81 (m,
|
2 H), 1.72 (dd, J = 14.6, 10.6 Hz, 1 H), 1.68 (dt, J = 6.3, 5.0 Hz, 1 1.74–1.66 (m, 2 H), 1.54 (dd, J = 13.1, 3.9 Hz, 1 H), 1.37 (s, 3 H),
H), 1.21 (s, 3 H), 1.11 (s, 3 H), 0.91 (s, 9 H), 0.90 (s, 9 H), 0.13 (s,
3 H), 0.10 (s, 3 H), 0.06 (s, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 159.1, 146.5, 138.6, 131.6, 129.3, 128.5, 127.79, 127.65,
1.20 (s, 3 H), 0.90 (s, 9 H), 0.03 (s, 3 H), –0.01 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.3, 138.4, 130.8, 129.2, 128.4,
127.9, 127.6, 114.0, 106.4, 85.2, 85.0, 82.8, 81.0, 73.8, 72.8, 72.2,
113.8, 111.2, 86.0, 83.3, 82.6, 74.4, 73.7, 73.3, 72.7, 72.1, 68.8, 64.7, 71.9, 66.3, 61.6, 55.4, 46.9, 40.7, 34.2, 31.8, 26.3, 26.1, 21.7, 18.1,
55.4, 45.2, 44.1, 39.0, 28.1, 27.9, 26.1, 25.9, 22.4, 18.3, 18.0, –4.1,
–5.1, –5.21, –5.23 ppm. HRMS (ESI+): calcd. for C43H72O8NaSi2
795.4663; found 795.4668 (Δ = 0.6 ppm).
–4.4, –5.0 ppm. HRMS (ESI+): calcd. for C36H54O8NaSi 665.3486;
found 665.3482 (Δ = 0.6 ppm).
(R)-2-((2R,4R,5R)-5-((1S,3R,5S)-1-[(Benzyloxy)methyl]-5-methyl-
((S)-2-((2R,4R,5R)-5-((1S,3R,5S)-1-[(Benzyloxy)methyl]-5-methyl- 2,8-dioxabicyclo[3.2.1]octan-3-yl)-4-[(tert-butyldimethylsilyl)oxy]-
2,8-dioxabicyclo[3.2.1]octan-3-yl)-4-[(tert-butyldimethylsilyl)oxy]- 2-methyltetrahydrofuran-2-yl)-2-[(4-methoxybenzyl)oxy]acetalde-
2-methyltetrahydrofuran-2-yl)-2-((4-methoxybenzyl)oxy)- hyde (41): To a solution of oxalyl chloride (12.5 μL, 0.14 mmol,
ethoxy)(tert-butyl)dimethylsilane (39): A three-necked flask was
charged with diol 38 (0.29 g, 0.38 mmol, 100 mol-%) in CH2Cl2
(5 mL) and cooled to –78 °C. Ozone was bubbled through the reac-
tion mixture for 30 s or until a blue color emerged. Oxygen was
then allowed to pass through the mixture for 3 min. Dimethyl sul-
fide (0.55 mL, 7.5 mmol, 2000 mol-%) was added and the reaction
mixture was warmed to room temp. and stirred for 3 h. Concentra-
tion and purification of the residue by flash chromatography (ini-
tially 7% EtOAc/hexanes, finally 10% EtOAc/hexanes) afforded the
desired product 39 as a colorless oil (0.19 g, 75%). Rf = 0.45 (30%
120 mol-%) in CH2Cl2 (0.6 mL), was added DMSO (21 μL,
0.3 mmol, 250 mol-%) at –50 °C. After stirring for 5 min, a solution
of alcohol 40 (77 mg, 0.12 mmol, 100 mol-%) in CH2Cl2 (1.2 mL)
was added. The resulting mixture was stirred for 20 min keeping the
temperature below –40 °C, then triethylamine (75 μL, 0.54 mmol,
450 mol-%) was added dropwise. The reaction mixture was warmed
to room temp. and stirred for 10 min. H2O (3 mL) was added and
the separated organic phase was washed with brine (5 mL), dried
with Na2SO4, and concentrated. Purification of the residue by flash
chromatography (10% EtOAc/hexanes) afforded the desired prod-
EtOAc/hexanes). [α]D = –6.2 (c = 1.00, CH Cl ). IR (film): ν = uct 41 as a colorless oil (66 mg, 86%). Rf = 0.38 (30% EtOAc/
˜
2
2
2954, 2930, 2884, 2857, 1515, 1250, 1103, 1072, 836, 776 cm–1. H
hexanes). [α]D = –29.5 (c = 1.00, CH Cl ). IR (film): ν = 2954,
˜
2 2
1
NMR (400 MHz, CDCl3): δ = 7.35–7.30 (m, 5 H), 7.29–7.25 (m, 2
2930, 2882, 2857, 1733, 1515, 1250, 1109, 1066, 834 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 9.84 (d, J = 1.1 Hz, 1 H), 7.34–7.29 (m, 5
H), 6.88–6.84 (m, 2 H), 4.92 (d, J = 11.2 Hz, 1 H), 4.62 (ddAB
,
|JAB| = 12.3 Hz, Δv = 33.5 Hz, 2 H), 4.52 (d, J = 11.2 Hz, 1 H), H), 7.29–7.26 (m, 2 H), 6.89–6.85 (m, 2 H), 4.67 (d, J = 10.9 Hz,
4.29 (dd, J = 4.2, 3.2 Hz, 1 H), 4.14 (td, J = 9.5, 3.9 Hz, 1 H), 4.07
(dd, J = 10.6, 0.9 Hz, 1 H), 3.80 (s, 3 H), 3.75 (dd, J = 10.7, 7.6 Hz,
1 H), 3.69 (dd, J = 7.5, 0.8 Hz, 1 H), 3.62 (dd, J = 8.0, 3.1 Hz, 1
H), 3.53 (ddAB, |JAB| = 10.7 Hz, Δv = 21.4 Hz, 2 H), 2.24 (d, J =
14.0 Hz, 1 H), 2.21 (td, J = 13.1, 4.3 Hz, 1 H), 2.01 (ddd, J = 13.5,
9.0, 4.7 Hz, 1 H), 1.86 (ddd, J = 12.4, 8.9, 3.9 Hz, 1 H), 1.77–1.65
1 H), 4.62 (ddAB, |JAB| = 12.3, Δv = 31.4 Hz, 2 H), 4.35 (dd, J =
4.4, 3.1 Hz, 1 H), 4.31 (d, J = 10.9 Hz, 1 H), 4.18 (ddd, J = 10.9,
8.2, 4.1 Hz, 1 H), 4.10 (d, J = 1.0 Hz, 1 H), 3.80 (s, 3 H), 3.69 (dd,
J = 8.2, 2.9 Hz, 1 H), 3.53 (ddAB, |JAB| = 10.7, Δv = 19.6 Hz, 2 H,),
2.24 (d, J = 14.0 Hz, 1 H), 2.22 (td, J = 13.3, 4.4 Hz, 1 H), 2.02
(ddd, J = 13.6, 9.2, 4.5 Hz, 1 H), 1.91 (ddd, J = 12.5, 9.0, 3.8 Hz,
(m, 3 H), 1.60 (dd, J = 13.1, 4.0 Hz, 1 H), 1.39 (s, 3 H), 1.09 (s, 3 1 H), 1.84 (dd, J = 14.1, 4.8 Hz, 1 H), 1.74 (dd, J = 13.3, 5.7 Hz,
H), 0.92 (s, 9 H), 0.90 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H), 0.04 (s,
3 H), –0.02 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.0,
138.5, 132.1, 129.0, 128.4, 127.9, 127.6, 113.7, 106.4, 86.2, 85.2,
83.2, 81.1, 73.8, 73.5, 72.5, 71.9, 66.8, 65.4, 55.4, 46.5, 40.7, 34.4,
1 H), 1.67 (d, J = 11.4 Hz, 1 H), 1.61 (dd, J = 13.1, 4.2 Hz, 1 H),
1.39 (s, 3 H), 1.20 (s, 3 H), 0.90 (s, 9 H), 0.04 (s, 3 H), 0.01 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 203.4, 159.5, 138.4,
130.1, 129.6, 128.4, 127.9, 127.6, 113.9, 106.4, 87.9, 86.1, 83.5, 81.1,
31.8, 26.3, 26.14, 26.11, 21.9, 18.4, 18.1, –4.3, –5.02, –5.05, 73.8, 72.5, 72.3, 72.0, 66.5, 55.4, 46.6, 40.7, 34.2, 31.8, 26.3, 26.1,
–5.2 ppm. HRMS (ESI+): calcd. for C42H68O8NaSi2 779.4350; 23.2, 18.1, –4.4, –5.0 ppm. HRMS (ESI+): calcd. for C36H52O8NaSi
found 779.4341 (Δ = 1.2 ppm).
663.3329; found 663.3334 (Δ = 0.8 ppm).
(S)-2-((2R,4R,5R)-5-((1S,3R,5S)-1-[(Benzyloxy)methyl]-5-methyl-
2,8-dioxabicyclo[3.2.1]octan-3-yl)-4-[(tert-butyldimethylsilyl)oxy]-
(1S,2R)-1-((2R,4R,5R)-5-((1S,3R,5S)-1-[(Benzyloxy)methyl]-5-
methyl-2,8-dioxabicyclo[3.2.1]octan-3-yl)-4-[(tert-butyldimethylsil-
2-methyltetrahydrofuran-2-yl)-2-[(4-methoxybenzyl)oxy]ethanol yl)oxy]-2-methyltetrahydrofuran-2-yl)-1-[(4-methoxybenzyl)oxy]-
(40): To a solution of compound 39 (0.12 g, 0.16 mmol, 100 mol- but-3-en-2-ol (42): To a solution of aldehyde 41 (38 mg, 0.06 mmol,
%) in THF (5.0 mL) was added, dropwise, HF·pyridine (70% HF, 100 mol-%) in THF (1.2 mL), was added vinylmagnesium bromide
0.20 mL, 0.22 g, 7.8 mmol, 5000 mol-%) at room temp. The reac-
tion mixture was stirred at room temp. for 30 min then satd. aq.
NaHCO3 (5 mL) was added dropwise. The layers were separated
(1 m in THF, 0.18 mL, 0.18 mmol, 300 mol-%) at –78 °C. The reac-
tion mixture was stirred at –78 °C for 20 min and then quenched
with satd. aq. NH4Cl (0.5 mL). The reaction mixture was warmed
and the organic layer was washed with satd. aq. NaHCO3 (5 mL), to room temp., H2O (1 mL) was added to dissolve the precipitate,
dried with Na2SO4, and concentrated. Purification of the residue
by flash chromatography (40% EtOAc/hexanes) afforded alcohol
40 as a colorless oil (90 mg, 89%). Rf = 0.10 (30% EtOAc/hexanes).
and the layers were separated. The organic phase was dried with
Na2SO4 and concentrated. Purification of the residue by flash
chromatography (20% EtOAc/hexanes) afforded allylic alcohol 42
[α]D = +0.7 (c = 1.00, CH Cl ). IR (film): ν = 3513, 2953, 2929, as a colorless oil (38 mg, 97%, ca. 20:1 dr). Rf = 0.42 (40% EtOAc/
˜
2
2
2883, 2857, 1514, 1249, 1100, 1066, 834 cm–1. 1H NMR (400 MHz,
hexanes). [α]D = +5.2 (c = 1.00, CH Cl ). IR (film): ν = 3523, 2954,
˜
2 2
CDCl3): δ = 7.35–7.26 (m, 5 H), 7.25–7.22 (m, 2 H), 6.89–6.85 (m, 2930, 2883, 2857, 1515, 1250, 1102, 1072 cm–1. 1H NMR
2 H), 4.62 (ddAB, |JAB| = 12.3 Hz, Δv = 30.1 Hz, 2 H), 4.56 (ddAB
,
(400 MHz, CDCl3): δ = 7.35–7.26 (m, 5 H), 7.25–7.22 (m, 2 H),
6.89–6.86 (m, 2 H), 6.02 (ddd, J = 17.2, 10.6, 4.5 Hz, 1 H), 5.36
(dt, J = 17.2, 1.8 Hz, 1 H), 5.14 (dt, J = 10.6, 1.8 Hz, 1 H), 4.62
|JAB| = 11.2 Hz, Δv = 24.1 Hz, 2 H), 4.33 (dd, J = 4.4, 3.1 Hz, 1
H), 4.14 (ddd, J = 11.5, 7.9, 3.7 Hz, 1 H), 3.83 (dd, J = 11.3, 7.1 Hz,
1 H), 3.80 (s, 3 H), 3.71 (dd, J = 11.0, 4.0 Hz, 1 H), 3.65 (dd, J = (ddAB, |JAB| = 12.3 Hz, Δv = 31.2 Hz, 2 H), 4.58 (ddAB, |JAB| =
1692
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Eur. J. Org. Chem. 2011, 1682–1694

Synthetic Studies towards Pectenotoxin-2
ogy and Detection (Ed.: L. M. Botana), Dekker, New York,
2000, pp. 289; b) V. Burgess, G. Shaw, Environ. Int. 2001, 27,
275.
10.9, Δv = 36.3 Hz, 2 H), 4.50 (br. s, 1 H), 4.33 (dd, J = 4.2, 3.2 Hz,
1 H), 4.12 (ddd, J = 11.4, 7.9, 3.7 Hz, 1 H), 3.80 (s, 3 H), 3.68 (d,
J = 2.0 Hz, 1 H), 3.63 (dd, J = 8.1, 2.9 Hz, 1 H), 3.53 (ddAB, |JAB
|
[3]
[4]
For references to the seco acids PTX2sa and 7-epi-PTX2sa, see:
a) M. Daiguji, M. Satake, K. J. James, A. Bishop, L. Macken-
zie, H. Naoki, T. Yasumoto, Chem. Lett. 1998, 7, 653; for fatty
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= 10.7 Hz, Δv = 20.3 Hz, 2 H,), 2.87 (d, J = 5.4 Hz, 1 H), 2.21 (td,
J = 13.2, 4.3 Hz, 1 H), 2.12 (d, J = 13.9 Hz, 1 H), 2.00 (ddd, J =
13.6, 9.1, 4.8 Hz, 1 H), 1.90–1.84 (m, 1 H), 1.85 (dd, J = 13.8,
5.0 Hz, 1 H), 1.75–1.67 (m, 2 H), 1.59 (dd, J = 13.2, 4.0 Hz, 1 H),
1.38 (s, 3 H), 1.25 (s, 3 H), 0.90 (s, 9 H), 0.04 (s, 3 H), –0.004 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 159.4, 141.6, 138.5,
130.5, 129.3, 128.4, 127.9, 127.6, 113.9, 113.7, 106.4, 85.0, 84.8,
84.4, 81.1, 74.6, 73.8, 72.3, 72.0, 70.3, 66.5, 55.4, 47.1, 40.8, 34.3,
31.8, 26.3, 26.1, 22.9, 18.1, –4.3, –5.1 ppm. HRMS (ESI+): calcd.
for C38H56O8NaSi 691.3642; found 691.3638 (Δ = 0.6 ppm).
General Method for Nucleophilic Addition with Aldehydes 50 or 51:
To a stirred solution of aldehyde 50 or 51 (50 mg) in solvent (2 mL)
at –78 °C, was added an excess of the organometallic reagent (150–
200 mol-%). After the addition was complete, the reaction mixture
was warmed slowly to the indicated temperature. The reactions
were quenched by addition of satd. aq. NH4Cl (2 mL) and the or-
ganic phase was separated. The aqueous phase was extracted with
Et2O (2ϫ2 mL) and the combined organic layers were washed with
brine (2 mL), dried with Na2SO4, and concentrated in vacuo. The
residue was analyzed by 1H NMR spectroscopy. If necessary, the
isomers were separated by chromatography and converted into the
corresponding PMP acetals (see the Supporting Information for
details).
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n) For a review covering all synthetic studies on the pec-
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental details for the interconversion of 29 and 30, syn-
theses of 16 as well as model compounds 50 and 51, details on the
assignment of relative stereochemistry, and copies of 1H and 13C
NMR spectra of new compounds.
Acknowledgments
Financial support has been provided by the Academy of Finland
(project numbers 123813/218573 and 217224), Onni Rannikko
Fund of the Finnish Foundation for Economic and Technology
Sciences (KAUTE), Alfred Kordelin Foundation, Association of
Finnish Chemical Societies, Orion Farmos Research Foundation,
Finnish Cultural Foundation, and the European Cooperation in
the Field of Science and Technology (COST), D28/CM0804 Ac-
tions. We thank Dr. Jari Koivisto and Mr. Reijo Kauppinen for
assistance with NMR experiments.
Org. Biomol. Chem. 2006, 4, 4048. See also ref.[8]
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anomeric spiroketal system of PTX2, see: D. Vellucci, S. D.
Rychnovsky, Org. Lett. 2007, 9, 711; for a review of nonanom-
eric spiroketals, see: J. E. Aho, P. M. Pihko, T. K. Rissa, Chem.
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P. M. Pihko et al.
FULL PAPER
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Received: October 15, 2010
Published Online: February 14, 2011
1694
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Eur. J. Org. Chem. 2011, 1682–1694