Synthesis of the bis-spiroacetal moiety of the shellfish toxins spirolides B and D using an iterative oxidative radical cyclization strategy

Article abstract of DOI:10.1039/b604334h

The enantioselective synthesis of the bis-spiroacetal fragment of the shellfish toxins, spirolides B 1 and D 2, is reported. The carbon framework was constructed via a Barbier reaction of dihydropyran 10 with aldehyde 11, followed by two oxidative radical cyclizations to construct the bis-spiroacetal ring system. A silyl-modified Prins cyclization and enantioselective crotylation successfully installed the stereocenters in the cyclization precursor 21. The initial unsaturated bis-spiroacetals 9a-d underwent equilibration during epoxidation to trans-epoxide 24 that was converted to tertiary alcohol 7. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b604334h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of the bis-spiroacetal moiety of the shellfish toxins spirolides
B and D using an iterative oxidative radical cyclization strategy†
Kai Meilert and Margaret A. Brimble*
Received 27th March 2006, Accepted 12th April 2006
First published as an Advance Article on the web 2nd May 2006
DOI: 10.1039/b604334h
The enantioselective synthesis of the bis-spiroacetal fragment of the shellfish toxins, spirolides B 1 and
D 2, is reported. The carbon framework was constructed via a Barbier reaction of dihydropyran 10 with
aldehyde 11, followed by two oxidative radical cyclizations to construct the bis-spiroacetal ring system.
A silyl-modified Prins cyclization and enantioselective crotylation successfully installed the
stereocenters in the cyclization precursor 21. The initial unsaturated bis-spiroacetals 9a–d underwent
equilibration during epoxidation to trans-epoxide 24 that was converted to tertiary alcohol 7.
A: LD50 250 lg kg−1) and are activators of L-type calcium
channels. These macrocycles contain a novel 6,5,5-bis-spiroacetal
ring system as well as an unusual 7,6-spiroimine moiety and bear
close resemblance to pinnatoxin A 6 (LD50 180 lg kg−1) which
was isolated from toxic extracts of the clam Pinna muricata and
has been linked to several major shellfish poisoning events in
Introduction
The spirolides A–D 1–5 (Fig. 1) comprise a novel family of
pharmacologically active macrocyclic imines found in the polar
lipid fraction obtained from the digestive glands of contaminated
mussels (Mytilus edulis), scallops (Placopecten magellanicus) and
Japan and China.4,5 The absolute stereochemistry of the spirolide
family of toxins has not been established to date, however, a
computer-generated relative assignment of 13-desmethyl spirolide
C 5 indicating the same relative stereochemistry as the related toxin
pinnatoxin A 65 in the region of their common structure, was later
reported.6 Preliminary pharmacological research into the mode of
action of the spirolides suggests that they are antagonists of the
muscarinic acetylcholine receptor.7
toxic plankton from the eastern coast of Nova Scotia, Canada.
Spirolides A–D 1–5 contain an unusual 5,5,6-bis-spiroacetal
moiety together with a rare 6,7-spirocyclic imine.1 Spirolides E
and F are keto amine hydrolysis derivatives resulting from the ring
opening of the cyclic imine suggesting that this functionality is
the pharmacophore responsible for toxicity.2 Recently, isolation
and culture of a toxic clone of the dinoflagellate Alexandrium
ostenfeldii obtained from the same aquaculture site allowed the
structural elucidation of three more congeners, spirolides A 1, C 3
and 13-desmethyl C 5.3 The spirolides A–D (1–5) cause potent
and characteristic symptoms in the mouse bioassay (spirolide
A total synthesis of the spirolides has not been reported to date,
however, an elegant total synthesis of pinnatoxin A 6 has been
reported by Kishi et al.8 wherein the BCD bis-spiroacetal ring
system was assembled via acid-catalyzed cyclization of a dione
precursor. A synthesis of the bis-spiroacetal core of spirolide
B 2 via acid-catalyzed cyclization of an acyclic triketone has
been communicated9 whilst partial syntheses of the bis-spiroacetal
moiety of the pinnatoxins are also discussed in a recent review
on the synthesis of bis-spiroacetal ring systems.10 Our interest in
the synthesis of natural products containing bis-spiroacetal ring
systems11 led us to pursue the synthesis of the bis-spiroacetal
ring system present in the spirolides using an oxidative radical
cyclization to construct the two five-membered rings in the 5,5,6-
bis-spiroacetal unit of the spirolides. In addition to our work on
the synthesis of model spiroimines12 related to the spirolides, we
have previously also reported the synthesis of a C10–C22 bis-
spiroacetal fragment lacking the C19 tertiary alcohol group, using
a double oxidative radical cyclization.13 However, problems were
encountered during the introduction of functionality at C19 and
the extension of the carbon framework at C22, thus prompting the
adoption of a modified synthetic plan in which disconnection of
the C23–C24 bond rather than the C22–C23 bond was a pivotal
step. The full details14 of this revised strategy are presented herein
providing rapid access to the fully functionalized C10–C23 bis-
spiroacetal fragment of spirolides B and D that is homologous to
our previous fragment.
Fig. 1 Structure of the spirolides and pinnatoxins.
Department of Chemistry, University of Auckland, 23 Symonds St.,
Auckland, New Zealand. E-mail: m.brimble@auckland.ac.nz; Fax: +64 9
3737422
† Electronic supplementary information (ESI) available: General experi-
1
mental details together with full experimental procedures, H NMR, 13C
NMR and mass spectral data for compounds 10–14 and 17–20. See DOI:
10.1039/b604334h
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Scheme 1 Retrosynthesis of spirolides B 2 and D 4.
Results and discussion
The key disconnection in our proposed retrosynthesis of spirolides
B 2 and D 4 (Scheme 1) involves NiII/CrII-mediated Kishi–Nozaki
coupling15 between an aldehyde and a vinyl iodide to form the C9–
C10 bond of the macrocyclic ring in a similar fashion to that used
by Kishi et al.8 in the synthesis of pinnatoxin A 6. Given that
our revised synthetic plan relied on the disconnection of the C23–
C24 bond rather than the C22–C23 bond, use of a Julia coupling
to effect the construction of the C23–C24 bond was envisaged
as a key step. Our attention therefore focused on the synthesis
of bis-spiroacetal 7, making use of a Julia methylenation16
for the subsequent union with spiroimine sulfone 8. This new
approach required access to dihydropyran 9 with the required
(S)-configuration at C22 using a silyl-modified Prins cyclization.
The two spiroacetal centres in unsaturated spiroacetal 9 are then
formed by oxidative radical cyclization of the alcohol resulting
from the Barbier coupling of this dihydropyran 10 with aldehyde
11, followed by deprotection of the tert-butyldiphenylsilyl ether
and execution of a second oxidative radical cyclization. The syn
stereochemistry in aldehyde 11 is available from an enantioselective
crotylation. The alkene in bis-spiroacetal 9 provides functionality
for subsequent installation of the tertiary alcohol. It is also
envisaged that the cis stereochemistry between the terminal rings
of the bis-spiroacetal will be established by equilibration after
incorporation into the macrocyclic ring. Thus, the initial synthesis
of trans-bis-spiroacetals 7 and 9 was required.
Scheme 2 Reagents and conditions and yields: (i) Me3SiC≡CH, BuLi,
Me3Al (cat.), toluene, −78 ◦C to room temp., 98%; (ii) DIBALH, Et2O,
room temp. then reflux, 24 h, 72%; (iii) InCl3, CH2Cl2, room temp., 48 h,
73%.
(Pd/CaCO3/Pb) gave variable selectivities. The optimum solvent
using Lindlar’s catalyst was found to be THF affording vinylsilane
14 as a 15 : 85 mixture of E/Z isomers in 69% yield when carried
out on a 200 mg scale. Somewhat surprisingly, scaling up of this
reaction to a 2 g scale afforded a reversed E/Z selectivity of 100 : 0.
Similar selectivity issues when effecting the semi-hydrogenation of
alkynes bearing a trimethylsilyl substituent have been reported by
others.20 The (Z)-configuration of vinylsilane 14 is crucial for the
formation of dihydropyran 10, as elimination of the trimethylsilyl
group from the resultant 6-membered ring formed from the (E)-
isomer is very slow (<10% conversion after 12 hours).
The synthesis of the dihydropyran fragment 10 was carried
out in 3 steps (51% overall yield), starting from enantiomerically
pure O-benzyl protected17 (R)-(+)-glycidol 12 (Scheme 2). Ring
opening of epoxide 12 with lithium trimethylsilylacetylide in the
presence of a catalytic amount of trimethylaluminium18 afforded
homopropargyl alcohol 13 in a higher yield than when using
a stoichiometric amount of boron trifluoride diethyl etherate.19
Vinylsilane 14 was initially prepared by semi-hydrogenation of
the corresponding acetylene 13 in the presence of a poisoned
catalyst. Use of the Rosenmund catalyst (Pd/BaSO4) gave mod-
erate E/Z selectivities and poor yields, while Lindlar’s catalyst
Fortunately, after the frustrating attempts to effect the stereos-
elective semi-hydrogenation of acetylene 13, hydroalumination21
of 13 in ether using DIBALH (1 M in hexane) gave the desired
vinylsilane 14 with high (Z)-selectivity (92 : 8). The desired
dihydropyran 10 was then prepared in low yield using a silyl-
modified Prins cyclization developed by Marko et al.22 by the
reaction of vinylsilane 14 with acetal 15 in dichloromethane
using trimethylsilyl triflate. The desired dihydropyran 10 was
later formed more efficiently using the Lewis acids indium
trichloride (72%) or iron trichloride (52%) in dichloromethane at
room temperature. For the indium trichloride-catalyzed reaction
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◦
t
Scheme 3 Reagents and conditions and yields: (i) (COCl)2, DMSO, Et3N, CH2Cl2, −78 C, 96%; (ii) (Z)-butene, BuOK, n-BuLi, (−)-(Ipc)2B(OMe),
BF3·Et2O, THF, −78 C, NaOH, H2O2, 72%; (iii) BuPh2SiCl, imid, DMF, 100 ◦C, 99%; (iv) BH3-DMS, THF, room temp., then H2O2, NaOH, 78%;
◦
t
(v) Dess–Martin periodinane, py, CH2Cl2, room temp., 84%.
the 1,3-cis isomer was the major product (cis–trans 77 : 23),
however this was of minor importance given that both isomers of
the dihydropyran can be used in the radical oxidative cyclization
step as an allylic oxocarbenium ion is formed at C6. The
relative configuration between C2 and C6 of the major isomer of
dihydropyran 10 was assigned as 1,3-cis due to the observation of
a strong correlation between H2 and H6 in the NOESY spectrum.
Aldehyde 11 was prepared in five steps from monoprotected
1,3-propanediol 1623,24 via reagent-controlled enantioselective
crotylation25 of aldehyde 17 using (Z)-2-butene and (−)-b-
methoxydiisopinocampheylborane to give (3R,4R)-alcohol 18 in
97% optical purity and dr >95 : 5 (Scheme 3). The absolute
configuration of ent-18 was assigned by X-ray diffraction of the
derived camphanic ester.26 The enantiomeric excess was measured
by 19F NMR after the formation of the Mosher ester using
similar methodology to an analogous aldehyde.13 After protection
as a tert-butyldiphenylsilyl ether 19, hydroboration with borane-
dimethylsulfide followed by oxidative work-up, afforded alcohol
20 that was oxidized with Dess–Martin periodinane to the desired
aldehyde 11.
With aldehyde 11 and bromide 10 in hand, attention next
turned to their union via the generation of a Grignard reagent
from bromide 10. Previous studies in our group13 have shown
that the coupling of similar substrates works best with the use
of Barbier’s conditions. Magnesium powder was dried under high
vacuum with a heat gun and after activation with iodine and
1,2-dibromoethane, a solution of bromide 10 and aldehyde 11
in diethyl ether was added dropwise. After heating for 3 hours
under reflux the coupled product 21 was isolated in 88% yield as
a ∼1 : 1 mixture of the diastereomers at C3ꢀ (Scheme 4). The two
diastereomers could be easily separated by flash chromatography,
but usually the mixture was used throughout the synthesis, as
equilibration of the bis-spiroacetal ring system was carried out at
a later stage. Activation of the magnesium powder was deemed
to be a crucial step before the addition of the iodine and 1,2-
dibromoethane.
hydrogen transfer to generate a carbon-centred radical, oxidation
of the radical to a cation and finally intramolecular trapping
of the cation by the hydroxyl group. The tert-butyldiphenyl silyl
ether in spiroacetal 22 was removed using tetrabutylammonium
fluoride with gentle heating at 80 ◦C resulting in the formation of
alcohol 23. The final bis-spiroacetal ring system was then formed
upon execution of a second oxidative radical cyclization providing
bis-spiroacetals 9a–d in 81% yield as a 1 : 1 : 1 : 1 mixture of
diastereomers.
Acid-catalyzed spiroacetalisation of the 1 : 1 : 1 : 1 mixture of
9a–d gave a ∼4 : 1 mixture of the two major isomers (9a and 9b)
together with trace quantities (<5%) of two other minor isomers
(Table 1). Interestingly, use of indium trichloride gave better results
than the commonly used reagents such as HF·py, PPTS, ZnBr2
or ZnCl2 affording a 87 : 13 mixture of the thermodynamically
favoured isomers 9a and 9b (entry 5). This is the first example
of the use of indium trichloride as a Lewis acid to effect the
equilibration of a mixture of spiroacetals allowing convergence to
one major diastereomer. The absolute configuration at C5 and C7
in isomer 9a was assigned unambiguously using 2D NMR NOESY
experiments, that showed clear correlations between H9 and H4,
and between 3-CH3 and H14, respectively (Table 1). Use of a
600 MHz spectrometer was essential in order to see the splitting
of the H2 and H9 resonances.
Introduction of the tertiary alcohol at C12 onto the unsat-
urated bis-spiroacetals 9a–d was initially investigated using a
hydroboration–oxidation sequence. Treatment of the unsaturated
Table 1 Equilibration of bis-spiroacetals 9a and 9b
With the basic carbon skeleton fully assembled, use of iterative
radical oxidative cyclizations then allows the formation of the bis-
spiroacetal. Irradiation of the mixture of alcohols 21 with a 60 W
standard desk lamp in the presence of iodobenzene diacetate and
iodine27 in cyclohexane afforded spiroacetal 22 as a mixture of
diastereomers in 86% yield. Spirocyclization takes place via the
formation of an alkoxy radical (generated from a hypoiodite), 1,5-
Entry
Conditions
9a : 9b (yield)
1
2
3
4
5
HF·Pyr, MeCN, room temp., 12 h
76 : 24 (81%)
∼81 : 19 (89%)
76 : 24 (95%)
∼83 : 17 (88%)
87 : 13 (85%)
PPTS (0.2 equiv), MeCN, room temp., 18 h
ZnBr2 (0.2 equiv), CH2Cl2, room temp., 19 h
ZnCl2 (0.2 equiv), CH2Cl2, room temp., 24 h
InCl3 (0.2 equiv), MeCN, room temp., 1 h
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Scheme 4 Reagents and conditions and yields: (i) 10, Mg, Br(CH2)2Br, I2, Et2O, room temp., 88%; (ii) PhI(OAc)2, I2, hm, cyclohexane, room temp., 86%;
(iii) Bu4NF, DMF, 80 ◦C, 82%; (iv) PhI(OAc)2, I2, hm, cyclohexane, room temp., 81%; (v) m-CPBA, CH2Cl2, 0 ◦C to room temp., 63%; (vi) DIBALH,
hexane, 0 ◦C, 54%; (viii) Dess–Martin periodinane, CH2Cl2, room temp., 88%; (viii) MeMgBr, Et2O, −78 ◦C, 86%.
bis-spiroacetals 9a–d with either BH3·SMe2 or BH3·THF resulted
in the complete disappearance of any starting material, but after
oxidation of the resultant alcohol using Dess–Martin periodinane
only low yields of the undesired C11 ketone could be isolated.
Use of different procedures known to be mild for the oxidation
of alkylboranes (H2O2, AcONa;28 oxone;29 or NaBO330) did not
result in improved yields.
of meta-chlorobenzoic acid and water in the mCPBA (mCPBA
purchased from Fluka contains ∼10% m-chlorobenzoic acid
and ∼20% H2O) effected equilibration of the mixture of bis-
spiroacetals 9a–d to the most thermodynamically favoured isomer
9a, that then underwent stereoselective epoxidation from the b-
face presumably due to the involvement of the neighbouring
oxygens in hydrogen bonding to the mCPBA.
Attempts to direct the formation of a ketone at C12 by the
use of a Wacker oxidation31 only afforded recovered starting
material (using PdCl2, CuCl and O2) or an intractable complex
mixture of products (using PdCl2 and 1,4-benzoquinone) in which
oxypalladation appeared to be directed towards the formation
of the undesired C11 ketone. Notably, starting with a 1 : 1 : 1 : 1
mixture of unsaturated bis-spiroacetals 9a–d, palladium-catalyzed
equilibration of the bis-spiroacetals was also observed to give
predominantly bis-spiroacetal 9a.
Epoxide 24 underwent regioselective reductive opening with
DIBALH in hexane and the resultant alcohol 25 was oxidized
to ketone 26 upon treatment with Dess–Martin periodinane. Use
of hexane as the solvent was crucial for the reductive opening
of epoxide 24. Additionally, the reaction was difficult to carry
to completion with starting material also being recovered from
the reaction. Addition of methylmagnesium bromide to ketone
26 proceeded stereoselectively from the axial direction affording
the desired tertiary alcohol 7 with the same stereochemistry as
that present in the spirolides. Ishiara and coworkers have similarly
reported the use of MeLi in THF to effect the stereoselective axial
introduction of the methyl group.9
Finally, treatment of the 1 : 1 : 1 : 1 mixture of bis-spiroacetals
9 with mCPBA afforded b-epoxide 24 as a single diastereomer to-
gether with recovered starting material. Remarkably, the presence
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The stereochemistries of epoxide 24 and tertiary alcohol 7
were assigned unambiguously by 2D NMR NOESY (Fig. 2). For
epoxide 24, correlations between H9 and H4, between H12 and
H13 and between 3-CH3 and H14 established the stereochemistry
as indicated. No correlations were observed between H9 and H11
or H12 as would be expected if epoxidation had taken place from
the a-face. For tertiary alcohol 7, clear correlations between H9
and H4 and between H2 and H11 clearly established the trans
arrangement of the oxygen atoms about the central ring. The
absolute configuration of the CH3 group at C12 was assigned by
the observed correlation with H13.
The trans stereochemistry of the bis-spiroacetal ring system
adopted by tertiary alcohol 7 represents the thermodynamically
favoured isomer and it is hoped that re-equilibration of the bis-
spiroacetal to the desired cis stereochemistry as found in the
spirolides will take place upon the incorporation of this moiety
into the larger macrocyclic system. A comparison of the 1H NMR
and 13C NMR chemical shifts recorded for trans bis-spiroacetal
7 with the analogous resonances in the cis bis-spiroacetal
moiety of natural product spirolide B 2 is summarized in
Table 2.
The present work demonstrates the efficient construction of
the bis-spiroacetal ring system present in the spirolides using an
iterative oxidative radical cyclization strategy. Use of InCl3 and
m-CPBA to effect the equilibration of the 6,5,5-bis-spiroacetal
ring system provides further examples of reagents to effect
spiroacetalizations in a stereoselective fashion. Furthermore, the
use of a silyl-modified Prins cyclization provides an efficient entry
to the dihydropyran unit of the cyclization precursor. Further
synthetic work towards the synthesis of spirolides B 2 and D
4 awaits the synthesis of the spiroimine unit of these marine
biotoxins.
Experimental
Electronic supplementary material
General experimental details together with full experimental
procedures, 1H NMR, 13C NMR and mass spectral data for
compounds 10–14 and 17–20 have been deposited as ESI.†
Fig. 2 Characteristic NOESY correlations for the assignment of the
absolute configuration of epoxide 24 and alcohol 7.
Table 2 Comparison of 1H NMR and 13C NMR data for trans bis-spiroacetal 7 with the cis bis-spiroacetal moiety of spirolide B 2
Carbon no. for
spirolide B 2
13C chemical shift (dC)
for spirolide B 2a
Carbon no.
for alcohol 7
13C chemical shift
1H chemical shift (dH)
for spirolide B 2c
1H chemical shift
(dH) for alcohol 7b
(dH) for alcohol 7d
10
11
12
13
14
15
16
17
18
19
20
21
22
39
40
75.1
37.1
81.5
35.1
42.5
116.3
35.4
30.8
111.1
69.8
35.8
29.0
68.3
15.1
20.9
2ꢀ
67.7
30.8
78.0
34.8
44.0
114.9
35.4
35.0
110.4
68.9
30.8
26.9
69.5
14.6
21.2
4.25
1.77, 2.02
4.38
2.46
2.24, 1.93
—
2.38, 2.04
2.16, 1.81
—
3.58
1.56
4.23
2.42
2.37, 1.75
—
2.21, 1.94
2.40, 1.76
—
1ꢀ
2
3
4
5
14
13
7
12
—
—
11
10
9
1.65 (2x)
1.62, 1.25
3.96
1.18
1.23
1.89, 1.67
1.63, 1.54
4.04
0.92
1.26
CH3C(3)
CH3C(12)
a Measured at 125 MHz in CDCl3. b Measured at 100 MHz in CDCl3. c Measured at 500 MHz in CDCl3. d Measured at 600 MHz in CDCl3.
2188 | Org. Biomol. Chem., 2006, 4, 2184–2192
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(3R,5R,6R)-1-(2S,6S)-6-[(Benzyloxy)methyl]-5,6-dihydro-2H-
pyran-2-yl-6-[tert-butyl(diphenyl)silyl]oxy-8-[(4-methoxybenzyl)oxy]-
5-methyl-3-octanol 21a and (3S,5R,6R)-1-(2S,6S)-6-[(benzyloxy)-
methyl]-5,6-dihydro-2H-pyran-2-yl-6-[tert-butyl(diphenyl)silyl]-
3-H), 3.28 (td, 1H, J 6.8 and 9.3, 8-Ha), 3.17 (td, 1H, J 7.0 and
9.3, 8-Hb), 2.63 (d, 1H, J 3.8, OH), 1.90–1.97 (m, 1H, 3ꢀ-Ha), 2.01–
2.11 (m, 1H, 3ꢀ-Hb), 1.73–1.78 (m, 2H, 7-H), 1.23–1.69 (m, 7H,
1-H, 2-H, 4-H, 5-H), 1.05 (s, 9H, (CH3)3CSi) and 0.90 (d, 3H,
J 6.9, CH3); dC (100 MHz; CDCl3) 158.9 (C, Carom(PMBn)), 138.3
(Ct, Carom(PMBn)), 136.0 (CH, PhSi), 135.9 (CH, PhSi), 134.7 (C,
PhSi), 133.9 (C, PhSi), 130.5 (C, Carom(Bn)), 130.0 (CH, Carom(Bn)),
129.6 (CH, PhSi), 129.4 (CH, PhSi), 129.1 (2 × CH, Carom(PMBn)),
128.3 (2 × CH, Carom(Bn)), 127.7 (2 × CH, Carom(Bn)), 127.6 (CH,
C-4ꢀ), 127.5 (2 × CH, PhSi), 127.4 (2 × CH, PhSi), 124.4 (CH, C-
5ꢀ), 113.6 (2 × CH, Carom(PMBn)), 74.7 (CH, C-3), 73.6 (CH, C-6),
73.4 (CH2, CH2Bn), 73.3 (CH, C-6ꢀ), 73.0 (CH2, C-1ꢀꢀ), 72.1 (CH2,
CH2PMBn), 69.9 (CH, C-2ꢀ), 67.3 (CH2, C-8), 55.2 (CH3, CH3O),
40.0 (CH2, C-4), 34.8 (CH, C-5), 33.6 (CH2, C-2), 33.0 (CH2, C-7),
31.7 (CH2, C-3ꢀ), 27.6 (CH2, C-1), 27.1 (CH3, (CH3)3CSi), 19.5 (C,
(CH3)3CSi) and 14.7 (CH3, CH3); MS (FAB) m/z 737 (0.8, [M +
H]+), 481 (0.5), 359 (1), 197 (5), 135 (11), 121 (100, [PMBn]+)
and 91 (26). HRMS (CI) m/z 737.4256 (calcd for C46H61O6Si
737.42352).
oxy-8-[(4-methoxybenzyl)oxy]-5-methyl-3-octanol
21b. Mag-
nesium powder (100 mg, 4.1 mmol) was dried under high vacuum
for one day. Diethyl ether (5 mL) was added, followed by
iodine (one crystal) and 1,2-dibromoethane (25 lL, 0.28 mmol,
0.3 equiv). The mixture was stirred until the iodine colour
disappeared, then a solution of aldehyde 11 (430 mg, 0.85 mmol)
and dihydropyran 10 (529 mg, 1.70 mmol) in Et2O (6 mL) was
added dropwise over one hour. After 3 hours diethyl ether (20 mL)
was added followed by sat. NaHCO3 (20 mL). If the reaction was
not complete after 3 hours, the solution was heated under reflux.
The aqueous phase was further extracted with diethyl ether (3 ×
50 mL) and the organic extracts were dried over MgSO4. Flash
chromatography of the residue obtained after concentration of
the solvent using hexane–diethyl ether (90 : 10 to 1 : 1) as the
eluent afforded the title compounds 21 (555 mg, 88%) as a mixture
of diastereomers and as a viscous colourless oil.
Spectroscopic data for less polar diastereomer 21a. tmax
(film)/cm−1 3445, 3070, 3030, 2930, 2855, 1613, 1585, 1515, 1465,
1425, 1365, 1305, 1245, 1175, 1110, 935, 820, 740, 700, 615; dH
(400 MHz; CDCl3) 7.66–7.70 (m, 4H, PhSi), 7.26–7.45 (m, 11H,
PhSi and ArH), 7.11 (d, 2H, J 8.6, ArH), 6.84 (d, 2H, J 8.6, ArH),
5.83 (tdd, 1H, J 1.7, 5.3 and 10.0, 5ꢀ-H), 5.62 (tdd, 1H, J 1.2, 2.2
and 10.0, 4ꢀ-H), 4.64 (d, 1H, J 12.3, CH2Bn), 4.58 (d, 1H, J 12.3,
CH2Bn), 4.19–4.21 (m, 1H, 6ꢀ-H), 4.16 (s, 2H, CH2PMBn), 3.81–
3.88 (m, 2H, 6-H, 2ꢀ-H), 3.81 (s, 3H, CH3O), 3.57–3.62 (m, 1H,
3-H), 3.57 (dd, 1H, J 6.4 and 10.8, 1ꢀꢀ-Ha), 3.49 (dd, 1H, J 5.4
and 10.8, 1ꢀꢀ-Hb), 3.33 (td, 1H, J 7.5 and 15.0, 8-Ha), 3.20 (td, 1H,
J 7.3 and 15.0, 8-Hb), 1.93–2.10 (m, 2H, 3ꢀ-H), 1.93–2.09 (m, 2H,
4-H), 1.82–1.96 (m, 2H, 2-H), 1.72–1.82 (m, 2H, 7-H), 1.55–1.70
(m, 2H, 1-H), 1.46–1.55 (m, 1H, 5-H), 1.07 (s, 9H, (CH3)3CSi)
and 0.84 (d, 3H, J 6.8, CH3); dC (100 MHz; CDCl3) 158.9 (C,
Carom(PMBn)), 138.3 (C, Carom(PMBn)), 136.1, 136.0 (4 × CH,
PhSi), 134.5 (C, PhSi), 134.0 (C, PhSi), 130.6 (C, Carom(Bn)), 130.2
(CH, Carom(Bn)), 129.6 (2 × CH, PhSi), 129.5 (CH, C-5ꢀ), 129.1
(2 × CH, Carom(PMBn)), 128.3 (2 × CH, Carom(Bn)), 127.7 (CH,
Carom(Bn)), 127.6 (CH, Carom(Bn)), 127.5, (CH, PhSi), 127.4 (CH,
PhSi), 124.2 (CH, C-4ꢀ), 113.6 (2 × CH, Carom(PMBn)), 75.3 (CH,
C-3), 74.8 (CH, C-6), 73.4 (CH2, CH2Bn), 73.3 (CH, C-6ꢀ), 73.0
(CH2, C-1ꢀꢀ), 72.2 (CH2, CH2PMBn), 69.3 (CH, C-2ꢀ), 67.3 (CH2,
C-8), 55.2 (CH3, CH3O), 40.5 (CH2, C-4), 35.0 (CH, C-5), 34.4
(CH2, C-2), 34.2 (CH2, C-7), 31.8 (CH2, C-3ꢀ), 27.6 (CH2, C-1),
27.1 (3 × CH3, (CH3)3CSi), 19.5 (C, (CH3)3CSi) and 14.7 (CH3,
CH3); MS (FAB) m/z (%) 737 (0.5, [M + H]+), 481 (0.5), 359 (1),
197 (4), 135 (11), 121 (100), 105 (2) and 91 (19, [Bn]+); HRMS (CI)
m/z 737.4237 calcd for C46H61O6Si 737.4235.
(2SR,3R)-Benzyl-(2-methyl-3-{[tert-butyl(diphenyl)silyl]oxy}-5-
[(5RS,7S)-(4-methoxybenzyl)oxy]-2-methylpentyl-1,6-dioxaspiro-
[4.5]dec-9-en-7-yl)methyl ether 22. A 1 : 1 mixture of alcohols
21 (90 mg, 0.12 mmol), with PhI(OAc)2 (78 mg, 0.24 mmol) and
iodine (68 mg, 0.27 mmol) in cyclohexane (10 mL) was degassed
with argon and irradiated with a desk lamp (60 W). After 2 hours
the mixture was diluted with diethyl ether (10 mL) then sat.
Na2S2O3 (5 mL) and sat. NaHCO3 (5 mL) were added. After
extraction with diethyl ether (3 × 20 mL), the organic extracts
were dried over MgSO4. Purification of the residue obtained
after concentration of the solvents at reduced pressure by flash
chromatography using hexane–diethyl ether (80 : 20) as the eluent
afforded the title spiroacetals 22 (92 mg, 86%) as a colourless oil
and as a 1 : 1 mixture of two diastereomers; tmax (film)/cm−1 3400,
3035, 2930, 2860, 1740, 1610, 1590, 1515, 1455, 1425, 1360, 1302,
1250, 1170, 1110, 1040, 820, 740, 700, 610; dH (400 MHz; CDCl3)
7.65–7.70 (m, 4H, PhSi), 7.26–7.43 (m, 11H, PhSi, ArH), 7.08 (d,
2H, J 8.7, ArH), 6.82 (d, 2H, J 8.7, ArH), 5.94 (ddd, 1H, J 1.9,
5.6 and 9.9, 9-H), 5.57 (ddd, 1H, J 1.3, 2.6 and 9.9, 10-H), 4.62
(d, 1H, J 12.4, CH2Bn), 4.59 (d, 1H, J 12.4, CH2Bn), 4.11–4.23
(m, 2H, 7-H, 2-H), 4.13, 4.11 (each d, 2H, J 11.9, CH2(PMBn)),
3.80 (s, 3H, CH3O), 3.75 (dt, 1H, J 2.7 and 6.1, 3ꢀ-H), 3.58 (dd,
1H, J 5.5 and 10.4, 1ꢀꢀ-Ha), 3.52 (dd, 1H, J 4.7 and 10.4, 1ꢀꢀ-Hb),
3.26 (td, 1H, J 6.8 and 9.1, 5ꢀ-Ha), 3.11 (td, 1H, J 7.2 and 9.1,
5ꢀ-Hb), 1.81–2.36 (m, 10H, 4ꢀ-Ha, 2ꢀ-H, 3-H, 4-H, 8-H, 1ꢀ-H), 1.71
(bq, 2H, J 6.8, 4ꢀ-Hb) 1.04 (s, 9H, (CH3)3CSi) and 0.86 (d, 3H,
J 6.8, CH3); dC (100 MHz; CDCl3) 158.8 (C, Carom(PMBn)), 138.4
(C, Carom(PMBn)), 136.1 (2 × CH, PhSi), 135.9 (2 × CH, PhSi),
134.7, 134.0 (each C, PhSi), 130.5 (C, Carom(Bn)), 129.4, 129.3,
129.1 (each CH, PhSi, Carom(Bn)), 129.0 (2 × CH, Carom(PMBn)),
128.2 (CH, C-9), 127.5 (2 × CH, Carom(Bn)), 127.4 (2 × CH,
Carom(Bn)), 127.4 (CH, C-10), 127.4 (2 × CH, PhSi), 127.3 (2 ×
CH, PhSi), 113.5 (2 × CH, Carom(PMBn)), 103.3 (C, C-5), 76.2
(CH, C-2), 74.6 (CH, C-3ꢀ), 73.0 (CH2, C-1ꢀꢀ), 72.6, 72.1 (each
CH2, CH2(Bn), CH2(PMBn)), 67.6 (CH, C-7), 67.3 (CH2, C-5ꢀ),
55.1 (CH3, CH3O), 38.3 (CH2, C-1ꢀ), 37.3 (CH2, C-4), 35.1 (CH,
C-2ꢀ), 33.5 (CH2, C-3), 31.2 (CH2, C-4ꢀ), 26.9 (CH2, C-8), 27.1
(CH3, (CH3)3CSi), 19.5 (C, (CH3)3CSi) and 14.2 (CH3, CH3); MS
(FAB) m/z (%) 735 (1.5, [M + H]+), 479 (1.5), 211 (1), 197 (5),
20
Spectroscopic data for more polar diastereomer 21b. [a] −1
589
(c = 0.15, CHCl3); tmax (film)/cm−1 3435, 3030, 2930, 2855, 1960,
1890, 1830, 1610, 1590, 1515, 1455, 1430, 1365, 1300, 1170, 1110,
1040, 820, 740, 700, 615; dH (400 MHz; CDCl3) 7.65–7.69 (m, 4H,
PhSi), 7.26–7.43 (m, 11H, PhSi, ArH), 7.09 (d, 2H, J 8.6, ArH),
6.83 (d, 2H, J 8.6, ArH), 5.83 (m, 1H, 5ꢀ-H), 5.58 (bd, 1H, J 10.3,
4ꢀ-H), 4.62 (d, 1H, J 12.2, CH2Bn), 4.55 (d, 1H, J 12.2, CH2Bn),
4.15–4.18 (m, 1H, 6ꢀ-H), 4.13 (s, 2H, CH2PMBn), 3.81–3.89 (m,
2H, 6-H, 2ꢀ-H), 3.80 (s, 3H, CH3O), 3.55 (dd, 1H, J 6.4 and 10.2,
1ꢀꢀ-Ha), 3.44 (dd, 1H, J 6.0 and 10.2, 1ꢀꢀ-Hb), 3.40–3.47 (m, 1H,
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135 (12), 121 (100), 107 (3) and 91 (25, [Bn]+). HRMS (CI) m/z
735.4073 (calcd for C46H59O6Si 735.4081).
55.1 (CH3, CH3O), 41.7 (CH2, C-1ꢀ), 38.2 (CH2, C-4), 36.2 (CH,
C-2ꢀ), 33.7 (CH2, C-4ꢀ), 30.9 (CH2, C-3), 26.8 (CH2, C-8) and 13.8
(CH3, CH3); MS (FAB) m/z (%) 497 (12, [M + H]+), 479 (8, [M +
H − H2O]+), 357 (2), 121 (100), 91 (39, [Bn]+); HRMS (FAB) m/z
497.2895 (calcd for C30H41O6 497.2903).
(2R,3R)-1-{(5RS,7S)-7-[(Benzyloxy)methyl]-1,6-dioxaspiro-
[4.5]dec-9-en-2-yl}-5-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanol
23. A solution of spiroacetals 22 (60 mg, 0.081 mmol, 1 equiv)
in DMF (2 mL) containing tetrabutylammonium fluoride
(2R,3R,5R,7R,9S)-9-[(Benzyloxy)methyl]-2-[(4-methoxybenzyl)-
oxy]ethyl-3-methyl-1,6,8-trioxadispiro[4.1.5.2]tetradec-11-ene 9a.
A mixture of spiroacetals 23 (34 mg, 0.068 mmol), PhI(OAc)2
(44 mg, 0.13 mmol) and iodine (38 mg, 0.15 mmol) in cyclohexane
(5 mL) was degassed with argon and irradiated with a desk
lamp (60 W). After 2 hours the mixture was diluted with diethyl
ether (5 mL) and sat. Na2S2O3 (3 mL) and sat. NaHCO3 (3 mL)
were added. After extraction with diethyl ether (3 × 10 mL), the
combined organic extracts were dried over MgSO4. Purification
by flash chromatography using hexane–diethyl ether (80 : 20) as
eluent afforded the title bis-spiroacetals 9 (28 mg, 81%) as a 1 : 1 :
1 : 1 mixture of diastereomers and as a colourless oil. Subsequent
equilibration using the conditions summarized afforded two
diasteromers 9a and 9b with varying ratios as reported in Table 1.
◦
(213 mg, 0.81 mmol) was heated to 80 C overnight. The cooled
reaction mixture was diluted with diethyl ether (5 mL) and water
(10 mL). The aqueous phase was extracted with diethyl ether
(3 × 5 mL) and the organic layers were dried over MgSO4. After
concentration of the solvents at reduced pressure purification
by flash chromatography using hexane–diethyl ether (1 : 1) as
the eluent afforded the title spiroacetals 23 (34 mg, 82%) as a
colourless oil and as a 1 : 1 mixture of diastereomers.
20
589
Spectroscopic data for less polar diastereomer 23a. [a] −32
(c = 0.18, CHCl3); tmax (film)/cm−1 3450, 2860, 1720, 1610, 1510,
1455, 1360, 1300, 1250, 1090, 1030, 990, 870, 820, 740, 700; dH
(400 MHz; CDCl3) 7.24–7.34 (m, 5H, ArH), 7.23 (d, 2H, J 8.7,
ArH), 6.85 (d, 2H, J 8.7, ArH), 5.95 (ddd, 1H, J 1.9, 5.6 and 9.8,
9-H), 5.62 (ddd, 1H, J 1.3, 2.6 and 9.8, 10-H), 4.60 (d, 1H, J 12.2,
CH2Bn), 4.56 (d, 1H, J 12.2, CH2Bn), 4.43 (s, 2H, CH2(PMBn)),
4.28 (dtd, 1H, J 3.5, 7.2 and 10.3, 2-H), 4.12–4.19 (m, 1H, 7-H),
3.77 (s, 3H, CH3O), 3.73 (dt, 1H, J 2.5 and 9.9, 3ꢀ-H), 3.57–3.78
(m, 2H, 5ꢀ-H), 3.56 (dd, 1H, J 5.7 and 10.5, 1ꢀꢀ-Ha), 3.50 (dd, 1H,
J 4.3 and 10.5, 1ꢀꢀ-Hb), 1.94–2.03 (m, 2H, 4-H), 1.78 (m, 1H, 2ꢀ-
H), 1.69–2.09 (m, 2H, 8-H), 1.66–1.78 (m, 2H, 4ꢀ-H), 1.54–2.22
(m, 2H, 3-H), 1.46–1.69 (m, 2H, 1ꢀ-H) and 0.90 (d, 3H, J 6.8,
CH3); dC (100 MHz; CDCl3) 159.1 (C, Carom(PMBn)), 138.4 (C,
Carom(PMBn)), 130.2 (C, Carom(Bn)), 129.2 (2 × CH, Carom(PMBn)),
128.6 (CH, C-10), 128.2 (2 × CH, Carom(Bn)), 128.0 (CH, C-9),
127.4 (2 × CH, Carom(Bn)), 127.3 (CH, Carom), 113.7 (2 × CH,
Carom(PMBn)), 103.6 (C, C-5), 76.6 (CH, C-2), 73.6 (CH, C-3ꢀ),
73.0 (CH2, CH2(Bn)), 72.8 (CH2, CH2(PMBn)), 72.5 (CH2, C-1ꢀꢀ),
69.1 (CH2, C-5ꢀ), 67.9 (CH, C-7), 55.1 (CH3, CH3O), 39.2 (CH2,
C-1ꢀ), 37.2 (CH2, C-4), 36.4 (CH, C-2ꢀ), 33.3 (CH2, C-4ꢀ), 31.3
(CH2, C-3), 26.7 (CH2, C-8) and 14.3 (CH3, CH3); MS (EI) m/z
(%) 496 (1, [M]+), 478 (1, [M − H2O]+), 425 (2), 384 (5), 320 (12),
307 (9), 266 (4), 199 (3), 157 (6), 121 (100) and 91 (56); HRMS
(EI) m/z 496.2819 (calcd for C30H40O6 496.2825).
20
589
Spectroscopic data for major diastereomer 9a. [a] − 23 (c =
0.25, CHCl3); tmax (film)/cm−1 3495, 2930, 2860, 2060, 1880, 1735,
1655, 1610, 1585, 1515, 1500, 1455, 1300, 1245, 1205, 1175, 1095,
1035, 1005, 980, 875, 820, 735, 700; dH (600 MHz; CDCl3) 7.26–
7.35 (m, 5H, ArH), 7.26 (d, 2H, J 8.5, ArH), 6.87 (d, 2H, J 8.5,
ArH), 5.97 (ddd, 1H, J 2.2, 5.5 and 9.9, 11-H), 5.70 (brd, 1H, J 9.9,
12-H), 4.59 (s, 2H, CH2Ph), 4.35 (s, 3H, CH2(PMBn)), 4.14–4.25
(m, 2H, 2-H, 9-H), 3.80 (s, 3H, CH3O), 3.38–3.64 (m, 4H, 2ꢀ-
H, 1ꢀꢀ-H), 2.50 (dq, 1H, J 14.1 and 7.4, 3-H), 2.28–2.40 (m, 2H,
4-Ha, 13-Ha), 1.89–2.11 (m, 5H, 13-Hb, 14-H, 10-H), 1.62–1.70
(m, 3H, 1ꢀ-H, 4-Hb) and 0.90 (d, 3H, J 7.0, CH3); dH (100 MHz;
CDCl3) 159.0 (C, Carom(PMBn)), 138.5 (C, Carom(PMBn)), 130.8 (C,
Carom(Bn)), 129.3 (2 × CH, Carom(PMBn)), 129.2 (CH, C12), 128.3
(2 × CH, Carom(Bn)), 128.1 (CH, C-11), 127.5 (3 × CH, Carom(Bn)),
114.6 (C, C-5), 113.7 (2 × CH, Carom(PMBn)), 103.4 (C, C-7), 78.6
(CH, C-2), 73.1 (CH2, CH2Ph), 72.8 (CH2, CH2Ar), 72.7 (CH2,
C-1ꢀꢀ), 68.0 (CH, C-9), 67.8 (CH2, C-2ꢀ), 55.3 (CH3, CH3O), 45.5
(CH2, C-4), 35.6, 36.9 (each CH2, C-13, C-14), 34.5 (CH, C-3),
31.1 (CH2, C-1ꢀ), 26.8 (CH2, C-10), 14.3 (CH3, CH3); MS (EI) m/z
(%) 494 (1, [M]+), 477 (9, [M − OH]+), 476 (25, [M − H2O]+), 403
(1, [M − Bn]+), 485 (1, [M − Bn − H2O]+), 373 (8, [M − PMBn]+),
358 (8), 355 (3, [M − PMBn − H2O]+), 229 (6), 203 (6), 157 (11),
137 (10), 121 (100), 91 (65); HRMS (EI) m/z 494.2668 (calcd for
C30H38O6 494.26684).
20
589
Spectroscopic data for more polar diastereomer 23b. [a] −34
(c = 0.07, CHCl3); tmax (film)/cm−1 3450, 2860, 1720, 1610, 1510,
1455, 1360, 1300, 1250, 1090, 1030, 990, 870, 820, 740, 700; dH
(400 MHz; CDCl3) 7.26–7.34 (m, 5H, ArH), 7.23 (d, 2H, J 8.5,
ArH), 6.85 (d, 2H, J 8.5, ArH), 5.90 (ddd, 1H, J 1.8, 4.4 and
9.9, 9-H), 5.60 (ddd, 1H, J 2.0, 3.0 and 9.9, 10-H), 4.56 (s, 2H,
CH2Bn), 4.41 (s, 2H, CH2(PMBn)), 4.24–4.30 (m, 1H, 2-H), 4.15–
4.21 (m, 1H, 7-H), 3.77 (s, 3H, CH3O), 3.73 (dt, 1H, J 2.6 and
10.1, 3ꢀ-H), 3.55–3.68 (m, 2H, 5ꢀ-H), 3.54 (dd, 1H, J 5.8 and 10.5,
1ꢀꢀ-Ha), 3.48 (dd, 1H, J 5.0 and 10.5, 1ꢀꢀ-Hb), 1.96–2.07 (each m,
2H, 8-H), 1.90–2.09 (each m, 2H, 3-H), 1.85–2.09 (each m, 2H,
4-H), 1.70–1.88 (each m, 2H, 1ꢀ-H), 1.69 (m, 1H, 2ꢀ-H), 1.63–1.77
(each m, 2H, 4ꢀ-H) and 0.90 (d, 3H, J 6.5, CH3); dC (100 MHz;
CDCl3) 159.1 (C, Carom(PMBn)), 138.4 (C, Carom(PMBn)), 130.1 (C,
Carom(Bn)), 129.2 (2 × CH, Carom(PMBn)), 128.5 (CH, C-9), 128.3
(CH, C-10), 128.2 (2 × CH, Carom(Bn)), 127.4 (2 × CH, Carom(Bn)),
127.3 (CH, Carom), 113.7 (2 × CH, Carom(PMBn)), 103.4 (C, C-5),
78.5 (CH, C-2), 73.5 (CH, C-3ꢀ), 73.0 (CH2, CH2(Bn)), 72.8 (CH2,
CH2(PMBn)), 72.6 (CH2, C-1ꢀꢀ), 69.3 (CH2, C-5ꢀ), 67.2 (CH, C-7),
Spectroscopic data for minor diastereomer 9b. dH (600 MHz;
CDCl3) 7.28–7.32 (m, 5H, ArH), 7.22 (d, 2H, J 8.5, ArH), 6.83 (d,
2H, J 8.5, ArH), 5.92–5.96 (m, 1H, 11-H), 5.58 (brd, 1H, J 9.9,
12-H), 4.44 (s, 2H, CH2Ph), 4.30 (s, 2H, CH2(PMBn)), 4.10–4.16
(m, 2H, 2-H, 9-H), 3.79 (s, 3H, CH3O), 3.38–3.42 (m, 4H, 2ꢀ-H,
1ꢀꢀ-H), 2.50 (m, 1H, 3-H), 2.20–2.33 (m, 2H, 4-Ha, 13-Ha), 1.72–
2.01 (m, 5H, 13-Hb, 14-H, 10-H), 1.61–1.69 (m, 3H, 1ꢀ-H, 4-Hb)
and 0.89 (m, 3H, CH3).
(2R,3R,5S,7R,9S,11R,12R)-9-[(Benzyloxy)methyl]-11,12-epoxy-
2-2-[(4-methoxybenzyl)oxy]ethyl-3-methyl-1,6,8-trioxadispiro-
[4.1.5.2]tetradecane 24. To a 1 : 1 : 1 : 1 mixture of bis-
spiroacetals 9a–d (60 mg, 0.12 mmol) in dichloromethane (2 mL)
at 0 ◦C was added m-CPBA (84 mg, 0.48 mmol). The solution was
allowed to warm to room temperature and left to stir overnight.
After 24 h the solution was cooled to 0 ◦C, filtered through a
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Celite pad and washed with cold dichloromethane. The organic
phase was washed with sat. NaHCO3 and dried (Na2SO4). After
concentration by removal of the solvents at reduced pressure the
residue was purified by flash chromatography using hexane–ethyl
acetate (2 : 1) as the eluent to afford recovered starting material
(22 mg) and the title epoxide 24 (35 mg, 63%) as a colourless oil;
391 (4), 219 (4), 178 (3), 165 (6), 121 (100) and 91 (42); HRMS
(FAB) m/z 512.2774 (calcd for C30H40O7 512.27733).
(2R,3R,5S,7R,9S)-9-[(Benzyloxy)methyl]-2-2-[(4-methoxy-
benzyl)oxy]ethyl-3-methyl-1,6,8-trioxadispiro[4.1.5.2]tetradecan-
12-one 26. To a solution of bis-spiroacetal alcohol 25 (5 mg,
9.70 lmol) and pyridine (2.4 lL, 29.25 lmol) in dichloromethane
(500 mL) was added Dess–Martin periodinane (8.3 mg, 19.5 lmol)
at room temperature. After 1 h more Dess–Martin periodinane
(8.3 mg) was added. After 3 hours, the solution was diluted with
dichloromethane (1 mL) and a sat. NaHCO3–sat. Na2SO3 (1 : 1)
solution (1 mL) was added. The aqueous phase was extracted with
dichloromethane (3 × 2 mL), dried over MgSO4 and the solvent
was removed under reduced pressure. The residue was purified
by flash chromatography using hexane–diethyl ether (5 : 4) as the
eluent to afford the title compound (4.5 mg, 88%) as a colourless
20
[a] +7 (c = 0.21, CHCl3); tmax (film)/cm−1 2955, 2925, 2855,
589
1725, 1615, 1585, 1515, 1455, 1360, 1300, 1250, 1210, 1175, 1100,
1035, 1010, 980, 830, 735, 700; dH (400 MHz; CDCl3) 7.27–7.34
(m, 5H, ArH), 7.26 (d, 2H, J 8.6, ArH), 6.87 (d, 2H, J 8.6, ArH),
4.54 (s, 2H, CH2Ph), 4.44 (s, 2H, CH2Ar), 4.24 (ddd, 1H, J 4.9,
7.2 and 8.6, 2-H), 4.06 (tdd, 1H, J 4.7, 6.0 and 9.4, 9-H), 3.80
(s, 3H, CH3O), 3.56 (m, 2H, 2ꢀ-H), 3.43 (dd, 2H, J 10.4, and
5.3, 1ꢀꢀ-H), 3.33–3.41 (m, 1H, 11-H), 3.00 (d, 1H, J 3.9, 12-H),
2.49 (sept, 1H, J 7.2, 3-H), 2.36 (m, 1H, 4-Ha), 2.33–2.05 (m,
4H, 13-H, 14-H), 1.75–1.91 (m, 2H, 10-H), 1.68 (m, 3H, 4-Hb,
1ꢀ-H), 0.91 (d, 3H, J 6.9, CH3); dC (100 MHz; CDCl3) 159.1 (C,
Carom(PMBn)), 138.3 (C, Carom(PMBn)), 130.6 (C, Carom(PMBn)),
129.2 (2 × CH, Carom(PMBn)), 128.3 (2 × CH, Carom(Bn)), 127.6
(CH, Carom(Bn)), 127.5 (CH, Carom(Bn)), 115.6 (C, C(5)), 113.7
(CH, Carom(PMBn)), 103.5 (C, C-7), 78.4 (CH, C-2), 73.2 (CH2,
C-1ꢀꢀ), 72.8 (CH2, CH2Ph), 72.4 (CH2, CH2Ar), 67.8 (CH2, C-2ꢀ),
66.1 (CH, C-9), 55.3 (CH3, CH3O), 52.5 (CH, C-12), 51.0 (CH,
C-11), 44.7 (CH2, C-4), 35.2, 34.7 (each CH2, C-13, C-14), 34.5
(CH, C-3), 31.0 (CH2, C-1ꢀ), 25.2 (CH2, C-10) and 14.3 (CH3,
CH3); MS (FAB) m/z (%) 511 (8, [M + H]+), 493 (6, [M − H2O]+),
373 (5), 121 (100) and 91 (42, [Bn]+); HRMS (FAB) m/z 511.2696
(calcd for C30H39O7 511.2685).
20
oil; [a] +27 (c = 0.41, CHCl3); tmax (film)/cm−1 2920, 2850, 1735,
589
1615, 1585, 1515, 1455, 1360, 1300, 1245, 1095, 1030, 995, 865, 825,
735; dH (400 MHz; CDCl3) 7.28–7.37 (m, 5H, ArH), 7.26 (d, 2H,
J 8.7, ArH), 6.88 (d, 2H, J 8.6, ArH), 4.59 (s, 2H, CH2Ph), 4.44
(dddd, 1H, J 2.5, 5.1, 7.5 and 11.7, 9-H), 4.42 (s, 2H, CH2Ar),
4.17 (ddd, 1H, J 4.2, 6.7 and 10.7, 2-H), 3.81 (s, 3H, CH3O), 3.56
(m, 1H, 2ꢀ-Ha), 3.55 (dd, 1H, J 5.1 and 10.1, 1ꢀꢀ-Ha), 3.48 (td, 1H,
J 6.1 and 10.2, 2ꢀꢀ-Hb), 3.45 (m, 1H, 1ꢀꢀ-Hb), 2.87 (dt, 1H, J 6.1,
14.0 and 14.0, 11-Ha), 2.80 (ddd, 1H, J 8.6, 10.9 and 13.0, 13-Ha),
2.49 (m, 1H, 3-H), 2.44 (ddd, 1H, J 14.0, 2.5 and 4.8, 11-Hb), 2.39
(dd, 1H, J 7.3 and 13.1, 4-Ha), 2.18 (ddd, 1H, J 8.2, 11.1 and
12.4, 14-Ha), 2.12 (tdd, 1H, J 2.5, 6.1 and 13.3, 10-Ha), 2.03 (ddd,
1H, J 2.8, 7.7 and 12.4, 14-Hb), 1.95 (dddd, 1H, J 4.8, 11.7, 14.0
and 14.0, 10-Hb), 1.74 (ddd, 1H, J 2.8, 8.2 and 13.0, 13-Hb), 1.71
(dd, 1H, J 7.7 and 13.1, 4-Hb), 1.65 (m, 2H, 1ꢀ-H) and 0.92 (d,
1H, J 7.0, CH3); dC (100 MHz; CDCl3) 202.0 (C, C-12), 159.1 (C,
Carom(PMBn)), 138.2 (C, Carom(Bn)), 130.7 (C, Carom(PMBn)), 129.3
(2 × CH, Carom(PMBn)), 128.4 (2 × CH, Carom(Bn)), 127.6 (CH,
Carom(Bn)), 127.5 (2 × CH, Carom(Bn)), 115.9 (C, C-5), 113.7 (2 ×
CH, Carom(PMBn)), 106.1 (C, C-7), 78.3 (CH, C-2), 73.4 (CH2,
CH2(Bn)), 72.8 (CH2, CH2(PMBn)), 72.3 (CH2, C-1ꢀꢀ), 69.4 (CH,
C-9), 67.7 (CH2, C-2ꢀ), 55.3 (CH3, CH3O), 45.0 (CH2, C-4), 35.5
(CH2, C-11), 34.6 (CH2, C-14), 34.4 (CH, C-3), 30.9 (CH2, C-1ꢀ),
30.5 (CH2, C-13), 30.3 (CH2, C-10) and 14.5 (CH3, CH3); MS
(FAB) m/z (%) 511 (9, [M + H]+), 493 (5, [M − H2O]+), 391 (6),
373 (5, [M− PMBnO]+), 273 (3), 219 (3), 121 (76) and 91 (35);
HRMS (FAB) m/z 511.2696 (calcd for C30H39O7 511.26824).
(2R,3R,5S,7R,9S,12R)-9-[(Benzyloxy)methyl]-2-2-[(4-methoxy-
benzyl)oxy]ethyl-3-methyl-1,6,8-trioxadispiro[4.1.5.2]tetradecan-
12-ol 25. To a solution of epoxide 24 (13 mg, 26.0 lmol) in dry
hexane (500 lL) at 0 ◦C was added DIBALH (1 M in hexane,
77 lL, 77.0 lmol). After 1 hour 1 M HCl (1 mL) was added and
the aqueous phase extracted with diethyl ether (3 × 2 mL). After
concentration by removal of the solvents at reduced pressure the
residue was purified by flash chromatography using hexane–ethyl
acetate (1 : 1) as the eluent to afford the title compound 25
20
589
(8.4 mg, 63%) as a colourless oil; [a] +2 (c = 0.11, CHCl3); tmax
(film)/cm−1 3435, 2925, 2855, 1725, 1615, 1515, 1455, 1360, 1300,
1245, 1175, 1100, 1035, 980, 870, 820, 745, 700, 620; dH (400 MHz;
CDCl3) 7.26–7.35 (m, 5H, ArH), 7.26 (d, 2H, J 8.4, ArH), 6.88
(d, 2H, J 8.4, ArH), 4.57 (s, 2H, CH2Ph), 4.44 (s, 2H, CH2Ar),
4.18 (ddd, 1H, J 4.9, 6.7 and 8.9, 2-H), 4.06 (dtd, 1H, J 2.7, 5.2
and 7.7, 9-H), 3.81 (s, 3H, CH3O), 3.57 (m, 1H, 12-H), 3.55 (m,
2H, 2ꢀ-H), 3.48 (m, 2H, 1ꢀꢀ-H), 2.47 (dq, 1H, J 14.2 and 7.2, 3-H),
2.34 (dd, 1H, J 7.2 and 13.1, 4-Ha), 1.94–2.25 (m, 5H, 11-Ha,
13-H, 14-H), 1.79 (ddd, 1H, J 3.2, 6.7 and 13.8, 11-Hb), 1.69 (m,
2H, 1ꢀ-H), 1.68 (m, 1H, 4-Hb), 1.62 (m, 1H, 10-Ha), 1.43 (m, 1H,
10-Hb) and 0.92 (d, 3H, J 7.0, CH3); dC (100 MHz; CDCl3) 159.1
(C, Carom(PMBn)), 138.4 (C, Carom(PMBn)), 130.6 (C, Carom(Bn)),
129.3 (2 × CH, Carom(PMBn)), 128.3 (2 × CH, Carom(Bn)),
127.5 (3 × CH, Carom(Bn)), 115.3 (C, C-5), 113.7 (2 × CH,
Carom(PMBn)), 106.8 (C, C-7), 78.0 (CH, C-2), 73.3 (CH2, C-1ꢀꢀ),
73.2 (CH2, CH2Ph), 72.8 (CH2, CH2Ar), 69.8 (CH, C-9), 69.7
(CH, C-12), 67.8 (CH2, C-2ꢀ), 55.3 (CH3, CH3O), 44.6 (CH2, C-4),
35.0, 34.8 (each CH2, C-13, C-14), 34.4 (CH, C-3), 30.9 (CH2,
C-1ꢀ), 26.6 (CH2, C-11), 21.3 (CH2, C-10) and 14.5 (CH3, CH3);
MS (FAB) m/z (%) 513 (2, [M + H]+), 495 (22, [M − H2O]+),
9-[(Benzyloxy)methyl]-2-2-[(4-methoxybenzyl)oxy]ethyl-3,12-
dimethyl-1,6,8-trioxadispiro[4.1.5.2]tetradecan-12-ol 7. To a so-
lution of bis-spiroacetal ketone 7 (5 mg, 9.79 lmol) in diethyl
ether (500 lL) at −78 ◦C was added dropwise a solution of
MeMgBr (3 M in ether, 6.52 lL, 19.58 mmol). After 2 hours,
a solution of sat. NH4Cl in MeOH was added (500 lL) and the
solution allowed to warm to room temperature. After evaporation
to dryness, the residue was purified by flash chromatography using
hexane–diethyl ether (80 : 20) as the eluent to afford the title
20
589
compound 7 (4.5 mg, 87%) as a colourless oil; [a] +38 (c =
0.29, CHCl3); tmax (film)/cm−1 2930, 2850, 1730, 1615, 1585, 1515,
1455, 1360, 1300, 1250, 1210, 1175, 1100, 1035, 1001, 980, 865,
820, 750, 700; dH (600 MHz, CDCl3) 7.28–7.37 (m, 5H, ArH), 7.26
(d, 2H, J 8.6, ArH), 6.88 (d, 2H, J 8.6, ArH), 4.57 (s, 2H, CH2Ar),
4.45 (d, 1H, J 11.3, CH2Ph), 4.41 (d, 1H, J 11.3, CH2Ph), 4.23
(ddd, 1H, J 4.1, 5.9 and 9.8, 2-H), 4.04 (dtd, 1H, J 3.4, 5.2 and
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8.0, 9-H), 3.81 (s, 3H, CH3O), 3.58 (m, 1H, 2ꢀ-Ha), 3.53 (m, 1H,
2ꢀ-Hb), 3.50 (dd, 1H, J 5.2 and 10.3, 1ꢀꢀ-Ha), 3.42 (dd, 1H, J 5.2
and 10.3, 1ꢀꢀ-Hb), 2.42 (m, 1H, 3-H), 2.40 (m, 1H, 13-Ha), 2.37 (m,
1H, 4-Ha), 2.21 (ddd, 1H, J 7.6, 12.2 and 12.2, 14-Ha), 1.94 (dd,
1H, J 7.6 and 12.2, 14-Hb), 1.89 (dt, 1H, J 4.6, and 13.3, 11-Ha),
1.76 (m, 1H, 13-Hb), 1.75 (m, 1H, 4-Hb), 1.67 (m, 1H, 11-Hb), 1.63
(ddd, 1H, J 2.5, 4.6 and 13.7, 10-Ha), 1.56 (m, 2H, 1ꢀ-H), 1.54 (m,
1H, 10-Hb), 1.26 (s, 3H, CH3) and 0.92 (d, 3H, J 6.9, CH3); dH
(100 MHz, CDCl3) 159.1 (C, Carom(PMBn)), 138.5 (C, Carom(Bn)),
130.6 (C, Carom(PMBn)), 129.4 (2 × CH, Carom(PMBn)), 128.3 (2 ×
CH, Carom(Bn)), 127.5 (3 × CH, Carom(Bn)), 114.9 (C, C-5), 113.7
(2 × CH, Carom(PMBn)), 110.4 (C, C-7), 78.0 (CH, C-2), 73.3, 73.2
(each CH2, CH2Ar, C-1ꢀꢀ), 72.2 (CH2, CH2Ph), 69.5 (CH, C-9),
68.9 (C, C-12), 67.7 (CH2, C-2ꢀ), 55.3 (CH3, CH3O), 44.0 (CH2,
C-4), 35.4, 35.0 (each CH2, C-13, C-14), 34.8 (CH, C-3), 30.8 (2 ×
CH2, C-1ꢀ, C-11), 26.9 (CH2, C-10), 21.2 (CH3, CH3) and 14.6
(CH3, CH3); MS (FAB) m/z (%) 527 (3, [M + H]+), 509 (11, [M −
H2O]+), 493 (2), 391 (26), 279 (9), 205 (8), 167 (12), 149 (58), 137
(21), 121 (100) and 91 (42). HRMS (FAB) m/z 527.30221 (calcd
for C31H43O7 = 527.3009).
9 J. Ishihara, T. Ishizaka, T. Suzuki and S. Hatakeyama, Tetrahedron
Lett., 2004, 45, 7855.
10 For a review on the synthesis of bis-spiroacetal-containing natural
products see: M. A. Brimble and D. P. Furkert, Curr. Org. Chem.,
2003, 7, 1461.
11 For an example of our previous work in this area see: M. A. Brimble,
P. R. Allen and H. Prabaharan, J. Chem. Soc., Perkin Trans. I, 2001,
379.
12 M. A. Brimble and M. Trzoss, Tetrahedron, 2004, 60, 5613.
13 M. A. Brimble and D. P. Furkert, Org. Biomol. Chem., 2004, 2,
x3573.
14 For an earlier communication on this work see: K. Meilert and M. A.
Brimble, Org. Lett., 2005, 7, 3497.
15 (a) K. Takai, K. Kimura, T. Kuroda, T. Hiyama and H. Nozaki,
Tetrahedron Lett., 1983, 24, 5281; (b) H. Jin, J. Uenishi, W. J. Christ and
Y. K i s h i , J. Am. Chem. Soc., 1986, 108, 5644; K. Takai, M. Tagashira,
T. Kuroda, K. Oshima, K. Utimoto and H. Nozaki, J. Am. Chem. Soc.,
1986, 108, 6048; (c) D. P. Stamos, X. C. Sheng, S. S. Chen and Y. Kishi,
Tetrahedron Lett., 1997, 38, 6355.
16 C. De Lima, M. Julia and J. N. Vepeaux, Synlett, 1992, 133.
17 M. T. Lai, E. Oh, Y. Shih and H.-W. Liu, J. Org. Chem., 1992, 57, 2471.
18 T. Ooi, N. Kagoshima, H. Ichikawa and K. Maruoka, J. Am. Chem.
Soc., 1999, 121, 3328.
19 Y. Ichikawa, M. Isobe, D.-L. Bai and T. Goto, Tetrahedron, 1987, 43,
4737.
20 (a) J. A. Soderquist and B. Santiago, Tetrahedron Lett., 1990, 31, 5113;
(b) M. C. McIntosh and S. M. Weinreb, J. Org. Chem., 1993, 58, 4823;
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35, 1507.
21 I. E. Marko and D. J. Bayston, Tetrahedron, 1994, 50, 7141.
22 The silyl-modified Prins cyclization and the silyl-modified Sakurai
cyclization are in fact the same reaction and the name silyl Prins is
adopted herein. See: (a) I. E. Marko, A. Mekhalfia, D. J. Bayston
and H. Adams, J. Org. Chem., 1992, 57, 2211; (b) A. P. Dobbs and S.
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Acknowledgements
The authors would like to thank the Swiss National Science
Foundation and the Royal Society of New Zealand Marsden Fund
for financial support, Michael Walker for helpful discussions con-
cerning NMR experiments and L. Ravi Sumoreeah for preliminary
experimentation on the silyl-modified Prins cyclization.
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2192 | Org. Biomol. Chem., 2006, 4, 2184–2192
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©