Synthesis of a chiral building block for highly functionalized polycyclic ethers

Article abstract of DOI:10.1039/c4ob01439a

An efficient procedure for preparing enantiopure polycyclic ethers is reported. The protocol is based on the photo-oxidation/conjugate addition sequence over a chiral functionalized furan, which was prepared from commercially available tri-O-acetyl-d-gluc

Full text of DOI:10.1039/c4ob01439a

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Synthesis of a chiral building block for highly
functionalized polycyclic ethers†
Cite this: DOI: 10.1039/c4ob01439a
G. Pazos, M. Pérez,* Z. Gándara, G. Gómez and Y. Fall*
Received 9th July 2014,
Accepted 29th July 2014
An efficient procedure for preparing enantiopure polycyclic ethers is reported. The protocol is based on
the photo-oxidation/conjugate addition sequence over a chiral functionalized furan, which was prepared
from commercially available tri-O-acetyl-D-glucal. The Michael addition step afforded two products with
the same absolute configuration from a mixture of diastereomers.
DOI: 10.1039/c4ob01439a
www.rsc.org/obc
Introduction
Polycyclic ethers are the structural basis of many natural pro-
ducts such as the so-called marine ladder toxins, a family of
red tide toxins with a highly complex unusual molecular archi-
tecture, a series of fused cyclic ethers having regular trans–syn–
trans stereochemistry.1 Some representative examples includ-
ing the brevetoxins (1 and 2),2 ciguatoxin (3),3 and yessotoxin
(4),4 among others, are depicted in Fig. 1. In addition to the
interesting biological properties including the neurotoxicity
and antimicrobial activity of these compounds, their challeng-
ing molecular architecture and their scarcity in natural
sources have attracted the attention of the synthetic commu-
nity. This family of compounds indeed represents challenging
synthetic targets for organic chemists, chemical synthesis
being a practical way of supplying samples to allow further
investigation of their biological activities. Among the different
total syntheses of this type of compound it is worth citing the
impressive work of Nicolaou and co-workers on brevetoxins A
and B,2a–d and that of Hirama and co-workers on ciguatoxin.3
Due to the highly repetitive nature of these structures, many
research groups designed iterative approaches to access these
rings.1f We recently developed a new method for the synthesis
of oxacyclic compounds from furan, we coined the furan
approach.5 We successfully applied this method to the syn-
thesis of chiral butenolides,6 natural products,7 racemic poly-
oxepanes8 and trans-fused bistetrahydropyrans.9 The scope
and limitations of this powerful methodology continue to be
our main concern. Here we report its extension to the syn-
Fig. 1 Structures of some marine ladder toxins.
thesis of enantiopure trans-fused polycyclic tetrahydropyrans 5
and 6, structural motifs which are commonly present in the
ladder toxins and related natural products.
Results and discussion
Departamento de Química Orgánica, Facultad de Química, Universidad de Vigo,
36200 Vigo, Spain. E-mail: yagamare@uvigo.es, manuperez@uvigo.es
†Electronic supplementary information (ESI) available: Experimental proce-
Our retrosynthetic strategy for the synthesis of 5 and 6 is
depicted in Scheme 1.
We anticipated that we could easily access three of the
chiral centers present in ketone 8, starting from commercially
available tri-O-acetyl-D-glucal and using a Claisen rearrangement
dures and full spectroscopic data for all new compounds. CCDC 988171.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ob01439a
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Scheme 1 Retrosynthetic analysis of trans-fused tetrahydropyrans 5
and 6.
Scheme 3 Synthesis of chiral furan 9.
deprotection of the silyl ethers with TBAF gave the diol 16 in
87% overall yield. The selective iodination of the primary
hydroxyl group of diol 16, followed by protection of the second-
ary hydroxyl group as TBS ether using t-butyldimethylsilyl tri-
fluoromethanesulfonate (TBSOTf) gave iodide 17 in 88%
overall yield. Iodide 17, on reaction with lithiated furan
afforded the targeted chiral furan 9 in 74% yield, together with
alkene 18 in 13% yield.
During the last ten years we used our furan approach to
access racemic heterocyclic compounds,5,12 some of them are
depicted in Scheme 4.
Scheme 2 Synthesis of ketone 8.
as we already showed in our recently published synthesis of
isolaurepan.10 Accordingly, as outlined in Scheme 2, enantio-
pure aldehyde 10 was obtained in high yield through a
thermal Claisen rearrangement. Reduction of aldehyde 10 fol-
lowed by orthogonal protection of the resulting alcohol
afforded compound 11 in 88% overall yield. The hydroboration
of the double bond followed by oxidation gave a mixture of
inseparable alcohols in positions 4 and 5. After TPAP oxidation
of the mixture of alcohols, the resulting ketones could be sepa-
rated by chromatography over silica gel, affording the desired
ketone 8 in 60% overall yield, together with 30% of its regio-
isomer. Mori et al.11 used the same starting material (tri-O-
acetyl-D-glucal) but a different strategy to prepare a similar
ketone (Scheme 2).
Our strategy competes favorably with Mori’s approach and
can be carried out on a large scale. With ketone 8 in hand, the
stage was then set for the preparation of chiral furan 9 as out-
lined in Scheme 3.
Reduction of ketone 8 with sodium borohydride afforded
chiral alcohol 14. The protection with MOMCl and subsequent
Scheme 4 Fall et al. approach to polycyclic compounds.
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Scheme 5 Synthesis of polyoxacycles 5 and 6.
Scheme 6 Proposed mechanism for the formation of 5.
Scheme 7 Confirmation of the stereochemistry of 5.
Fig. 2 X-ray structure (ORTEP) of 6.
We now wanted to further enlarge the scope of our strategy
by tackling the synthesis of enantiopure polycyclic ethers.
Accordingly, as outlined in Scheme 5, chiral furan 9 was sub-
jected to singlet oxygen oxidation affording 76% yield of meth-
oxybutenolide 26 as a 60/40 diastereoisomeric mixture.
TBAF mediated cyclization furnished a mixture of lactones
5 and 6 which were separated by chromatography on silica gel
affording 5 in 20% yield and 6 in 60% yield. The structure of
the major product 6 was confirmed unambiguously as shown
in Fig. 2, by X-ray crystallographic analysis of the crystals
obtained by recrystallization from a mixture of hexane and
ethyl ether.13
Scheme 8 Iterative polyether synthesis through the furan approach.
Formation of compound 5 can be rationalized by the loss of
the methoxy group (intermediate I) followed by a hetero
Michael addition (intermediate II) and final addition of H2O
(Scheme 6).
Conclusions
Compound 5 was transformed into the more stable acetate In conclusion, starting from commercially available tri-O-
derivative 27 and the relative stereochemistry was confirmed acetyl-D-glucal, we developed
highly flexible approach
by 2D-NOESY experiments (Scheme 7).
towards chiral trans-fused polycyclic tetrahydropyrans, struc-
a
Lactones 5 and 6 can be opened and transformed into tural motifs which are commonly present in the ladder toxins
chiral furan 28,9 which through the photo-oxidation/conjugate and related natural products. Work is now in progress for the
addition sequence would lead to new polycyclic compounds synthesis of marine toxins using our furan approach as an
(Scheme 8).
iterative strategy.
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72.6 (CH2-PMP), 70.3 (CH-8), 67.2 (CH2-5), 65.9 (CH2-2′), 55.2
(OCH3-PMB), 35.4 (CH2-1′), 27.5 (CH3-tBu), 27.1 (CH3-tBu),
22.6 (C-tBu), 20.0 (C-tBu); MS (ESI) [m/z, (%)]: 457 (M+ + Na,
Experimental
General
Solvents were purified and dried by standard procedures 100), 315 (17); HRMS (ESI): 457.2380 calcd for C24H38NaO5Si,
before use. Melting points are uncorrected. 1H NMR and found 457.2390.
13C NMR spectra were recorded with a Bruker ARX-400 spectro-
(1S,6R,8S)-3,3-Ditert-butyl-8-(2′-p-methoxybenzyloxyethyl)-
meter (400 MHz for H NMR, 100.61 MHz for 13C NMR) using 2,4,7-trioxy-3-silinebicyclic[4,4,0]decan-10-ol (11a) and (1S,6R,8S)-
TMS as the internal standard (chemical shifts in δ values, J in 3,3-ditert-butyl-8-(2′-p-methoxybenzyloxyethyl)-2,4,7-trioxy-3-siline-
Hz). Flash chromatography (FC) was performed on silica gel bicyclic[4,4,0]decan-9-ol (11b). To a solution of 11 (4 g,
(Merck 60, 230–400 mesh); analytical TLC was performed on 9.21 mmol) in THF (40 mL) cooled at 0 °C was added BH3·THF
plates precoated with silica gel (Merck 60 F254, 0.25 mm); (18.42 mL of a 1 M solution in THF, 18.42 mmol) and stirring
mass spectra (FAB, EI) were recorded using a FISONS VG and was continued for 30 min. Then, 3 M aqueous solution of
electrospray ionization (ESI-MS) spectra were recorded using a NaOH (7.5 mL) and 30% aqueous solution of H2O2 (2.04 mL)
Bruker FTMS APEXIII. Melting points were obtained in open were added; the reaction was allowed to reach room tempera-
capillary tubes and are not corrected. Optical rotations were ture and was stirred for 12 h. The reaction was quenched
obtained using a Jasco P-2000 polarimeter. IR spectra were with water (30 mL) and the product was extracted with EtOAc
1
recorded with a JASCO FT/I(R)-6100 spectrophotometer.
(3 × 40 mL). The combined organic phases were dried, filtered
(1S,6R,8S)-3,3-Ditert-butyl-8-(2′-p-methoxybenzyloxyethyl)- and evaporated. Finally, the residue was filtered through silica
2,4,7-trioxy-3-silinebicyclic[4,4,0]dec-9-ene (11). To a solution gel (30% EtOAC–hexane) to give a mixture of alcohols 11a and 11b.
of aldehyde 10 (6.28 g, 20.12 mmol) in MeOH (30 mL) cooled
(1S,6R,8S)-3,3-Ditert-butyl-8-(2′-p-methoxybenzyloxyethyl)-
at 0 °C was slowly added NaBH4 (913 mg, 24.15 mmol) and the 2,4,7-trioxy-3-silinebicyclic[4,4,0]dec-9-one (8) and(1S,6R,8S)-
mixture was stirred for 30 min under the same conditions. 3,3-ditert-butyl-8-(2′-p-methoxybenzyloxyethyl)-2,4,7-trioxy-3-siline-
Then, water (30 mL) was added and the product was extracted bicyclic[4,4,0]dec-10-one (8a). To a solution of a mixture of
with EtOAc (3 × 50 mL). The organic phase was washed with alcohols 11a and 11b (4 g, 8.83 mmol) in CH2Cl2 (40 mL) were
water (3 × 150 mL) and brine (150 mL), dried over Na2SO4 and added 4 Å molecular sieves (2 g), NMO (3.10 g, 25 mmol) and
the solvent was evaporated under reduced pressure affording a a catalytic amount of TPAP. The resulting greenish solution
white solid.
was stirred at room temperature for 12 h. The solvent was rota-
To a solution of PMBOH (3.76 mL, 30.18 mmol) in THF tory evaporated to afford a residue which was chromato-
(50 mL) cooled at 0 °C was added NaH (60%) (72 mg, 3 mmol) graphed on silica gel using 5% EtOAc–hexane as the eluent,
and the mixture was stirred for 1 h under the same conditions. affording ketone 8 (2.4 g, 60%) along with its isomeric ketone
Then, CCl3CN (3 mL, 3.18 mmol) was added and stirred for 8a (1.23 g, 31%).
30 min and a saturated aqueous solution of NaHCO3 (30 mL)
Compound 8. White solid, m.p. = 81 °C, Rf: 0.62 (30%
was added. The resulting mixture was extracted with EtOAc EtOAc–hexane); IR (NaCl, cm−1): 2962.13, 2934.16, 2880.17,
(2 × 40 mL) and the combined organic phases were washed 2859.92, 1727.91, 1513.85, 1132.05; [α]2D6 = −16.54 (c 1.86,
with brine (70 mL), dried over Na2SO4 and the solvent was CHCl3); H-NMR (CDCl3, δ): 7.23 (2H, d, J = 8.6 Hz, Ho-PMB),
1
removed under reduced pressure affording a residue which 6.87 (2H, d, J = 8.6 Hz, Hm-PMB), 4.42 (1H, d, J = 11.6 Hz,
was dissolved in CH2Cl2 (40 mL). The alcohol which was CH2-PMP), 4.38 (1H, d, J = 11.6 Hz, CH2-PMP), 4.19 (1H, dd, J =
obtained in the first step and a catalytic amount of PPTS were 10.3, 5.0 Hz, H-5), 4.09 (1H, ddd, J = 10.9, 9.4, 5.7 Hz, H-1),
added and the mixture stirred was for 48 h. Then, a saturated 3.98 (1H, dd, J = 7.7, 4.2 Hz, H-8), 3.85 (1H, t, J = 10.2 Hz, H-5),
aqueous solution of NaHCO3 (40 mL) was added and the 3.80 (3H, s, OCH3-PMB), 3.57 (3H, m, 2H-2′, H-6), 2.97 (1H, dd,
resulting organic phase was washed with water (3 × 40 mL) J = 15.7, 5.7 Hz, H-10), 2.42 (1H, dd, J = 15.7, 11.0 Hz, H-10),
and brine (40 mL), filtered and evaporated to yield a residue 2.19 (1H, m, H-1′), 1.77 (1H, m, H-1′), 1.04 (9H, s, CH3-tBu),
which was chromatographed on silica gel using 1% EtOAc– 1.01 (9H, s, CH3-tBu); 13C-NMR (CDCl3, δ): 205.1 (CvO), 159.2
hexane as the eluent, affording compound 11 (7.52 g, 89%) as (Cp-PMB), 130.4 (C-PMB), 129.2 (CHo-PMB), 113.7 (CHm-
a white solid; m.p. = 60 °C; Rf: 0.55 (20% EtOAc–hexane); PMB), 79.6 (CH-8), 76.1 (CH-6), 73.1 (CH-1), 72.4 (CH2-PMP),
IR (NaCl, cm−1): 2960.30, 2933.69, 2880.69, 2859.36, 1647.83, 66.5 (CH2-5), 65.2 (CH2-2′), 55.2 (OCH3-PMB), 48.1 (CH2-10),
1132.58; [α]2D2 = −14.51 (c 1.43, CHCl3); 1H-NMR (CDCl3, δ): 29.4 (CH2-1′), 27.3 (CH3-tBu), 27.0 (CH3-tBu), 22.6 (C-tBu), 19.9
7.26 (2H, d, J = 8.7 Hz, Ho-PMB), 6.88 (2H, d, J = 8.7 Hz, (C-tBu); MS (ESI) [m/z, (%)]: 473 (M+ + Na, 100), 313 (30);
Hm-PMB), 5.83 (1H, d, J = 10.3 Hz, H-9, H-10), 5.64 (1H, d, J = HRMS (ESI): 473.2329 calcd for C24H38NaO6Si, found
10.3 Hz, H-9, H-10), 4.43 (2H, s, CH2-PMP), 4.37 (2H, m, H-1, 473.2319.
H-8), 4.16 (1H, dd, J = 10.0, 5.1 Hz, H-5), 3.85 (1H, t, J = 10.0
Compound 8a. White solid, m.p. = 76 °C, Rf: 0.5 (30%
Hz, H-5), 3.80 (3H, s, OCH3-PMB), 3.54 (3H, m, 2H-2′, H-6), EtOAc–hexane); IR (NaCl, cm−1): 2961.98, 2933.69, 2880.17,
1.85 (1H, m, H-1′), 1.74 (1H, m, H-1′), 1.06 (9H, s, CH3-tBu), 2858.24, 1736.58, 1512.79, 1247.57, 1133.94; [α]D24 = −19.34
1.00 (9H, s, CH3-tBu); 13C-NMR (CDCl3, δ): 159.1 (Cp-PMB), (c 1.60, CHCl3); 1H-NMR (CDCl3, δ): 7.22 (2H, d, J = 8.3 Hz,
130.5 (C-PMB), 129.7 (CH-9, CH-10), 129.6 (CH-9, CH-10), Ho-PMB), 6.87 (2H, d, J = 8.3 Hz, Hm-PMB), 4.41 (3H, m,
129.2 (CHo-PMB), 113.7 (CHm-PMB), 74.6 (CH-6), 72.8 (CH-1), CH2-PMB, H-1), 4.16 (1H, dd, J = 10.0, 4.6 Hz, H-5), 3.95 (1H, t,
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J = 10.2 Hz, H-5), 3.88 (1H, m, H-6), 3.79 (3H, s, OCH3-PMB), (1H, d, J = 6.9 Hz, CH2-MOM), 4.47 (1H, d, J = 11.6 Hz,
3.52 (3H, 2H-2′, H-8), 2.51 (1H, dd, J = 13.7, 2.4 Hz, H-9), 2.43 CH2-PMP), 4.40 (1H, d, J = 11.6 Hz, CH2-PMP), 4.05 (1H, dd, J =
(1H, m, H-9), 1.83 (2H, m, 2H-1′), 1.04 (9H, s, CH3-tBu), 1.00 10.1, 4.9 Hz, H-5), 3.80 (3H, s, OCH3-PMB), 3.74 (1H, t, J =
(9H, s, CH3-tBu); 13C-NMR (CDCl3, δ): 202.4 (CvO), 159.2 10.1 Hz, H-5), 3.73 (1H, m, H-9), 3.55 (2H, dd, J = 7.9, 6.1 Hz,
(Cp-PMB), 130.2 (C-PMB), 129.2 (CHo-PMB), 113.7 (CHm- 2H-2′), 3.37 (3H, s, OCH3-MOM), 3.33 (2H, m, H-1, H-8), 3.24
PMB), 80.1 (CH-1), 77.0 (CH-8), 75.7 (CH-6), 72.6 (CH2-PMP), (1H, dt, J = 10.1, 4.9 Hz, H-6), 2.58 (1H, m, H-10), 2.16 (1H, m,
66.7 (CH2-5), 65.3 (CH2-2′), 55.2 (OCH3-PMB), 47.3 (CH2-9), H-1′), 1.55 (1H, m, H-10), 1.47 (1H, m, H-1′), 1.03 (9H, s,
36.0 (CH2-1′), 27.3 (CH3-tBu), 26.9 (CH3-tBu), 22.6 (C-tBu), 20.1 CH3-tBu), 0.99 (9H, s, CH3-tBu); 13C-NMR (CDCl3, δ): 159.1
(C-tBu); MS (ESI) [m/z, (%)]: 473 (M+ + Na, 100), 338 (21), (Cp-PMB), 130.6 (C-PMB), 129.2 (CHo-PMB), 113.7 (CHm-
313 (12); HRMS (ESI): 473.2329 calcd for C24H38NaO6Si, found PMB), 95.2 (CH2-MOM), 77.5 (CH-8), 76.8 (CH-6), 74.5 (CH-1),
473.2328.
72.4 (CH2-PMP), 72.3 (CH-9), 66.8 (CH2-5), 66.1 (CH2-2′), 55.6
(1S,6R,8S,9R)-3,3-Ditert-butyl-8-(2′-p-methoxybenzyloxyethyl)- (OCH3-OMOM), 55.2 (OCH3-PMB), 39.3 (CH2-10), 31.9 (CH2-1′),
2,4,7-trioxy-3-silinebicyclic[4,4,0]dec-9-ol (14). To a solution of 27.4 (CH3-tBu), 27.0 (CH3-tBu), 22.6 (C-tBu), 19.9 (C-tBu); MS
ketone 8 (2.33 g, 5.15 mmol) in MeOH (20 mL) and CH2Cl2 (ESI) [m/z, (%)]: 520 (M+ + 1 + Na, 27), 519 (M+ + Na, 100);
(20 mL) cooled at −78 °C was slowly added NaBH4 (292 mg, HRMS (ESI): 519.2748 calcd for C26H44NaO7Si, found
7.72 mmol) and the mixture was stirred for 1 h under the 519.2747.
same conditions. Then, water (40 mL) was added and the
(1S,2R,4S,5R)-2-Hydroxymethyl-4-(2′-p-methoxybenzyloxyethyl)-
product was extracted with EtOAc (3 × 40 mL) and the organic 5-(methoxymethoxy)-3-tetrahydro-2H-pyran-1-ol (16). To a solu-
phases were washed with water (3 × 100 mL) and brine tion of 16 (1 g, 2.04 mmol) in THF (10 mL) was added TBAF
(100 mL), dried over Na2SO4 and the solvent was evaporated (6.6 mL of a 1 M solution in THF, 6.6 mmol) and the mixture
under reduced pressure affording alcohol 14 (2.34 g, 99%) as a was stirred at room temperature for 12 h, quenched with an
white solid; m.p. = 115 °C, Rf: 0.25 (20% EtOAc–hexane); IR aqueous saturated solution of NH4Cl (15 mL) and the product
(NaCl, cm−1): 3420.14, 2960.23, 2933.87, 2859.92, 1513.85, was extracted with EtOAc (3 × 20 mL). The combined organic
1092.48; [α]2D5 = −25.13 (c 1.48, CHCl3); 1H-NMR (CDCl3, δ): phases were dried, filtered and evaporated to give a residue
7.24 (2H, d, J = 8.5 Hz, Ho-PMB), 6.88 (2H, d, J = 8.5 Hz, which was chromatographed on silica gel using 70% EtOAc–
Hm-PMB), 4.46 (1H, d, J = 11.4 Hz, CH2-PMP), 4.43 (1H, d, J = hexane as the eluent, affording diol 16 (690 mg, 96%) as a
11.4 Hz, CH2-PMP), 4.08 (1H, dd, J = 10.0, 4.8 Hz, H-5), 3.79 colourless liquid; Rf: 0.30 (EtOAc); IR (NaCl, cm−1): 3428.36,
(3H, s, OCH3-PMB), 3.73 (2H, m, H-1, H-5), 3.58 (2H, m, 2920.98, 2884.25, 1512.89, 1248.96, 1098.36; [α]3D0 = +37.35
2H-2′), 3.39 (1H, m, H-9), 3.22 (2H, m, H-6, H-8), 2.44 (1H, m, (c 1.69, CHCl3); 1H-NMR (CDCl3, δ): 7.25 (2H, d, J = 8.6 Hz, Ho-
H-10), 1.99 (1H, m, H-1′), 1.84 (1H, m, H-1′), 1.47 (1H, dd, J = PMB), 6.87 (2H, d, J = 8.6 Hz, Hm-PMB), 4.69 (1H, d, J =
22.3, 11.1 Hz, H-10), 1.03 (9H, s, CH3-tBu), 0.98 (9H, s, 6.9 Hz, CH2-MOM), 4.59 (1H, d, J = 6.9 Hz, CH2-MOM), 4.46
CH3-tBu); 13C-NMR (CDCl3, δ): 159.3 (Cp-PMB), 129.4 (1H, d, J = 11.6 Hz, CH2-PMP), 4.40 (1H, d, J = 11.6 Hz,
(CHo-PMB), 128.5 (C-PMB), 113.8 (CHm-PMB), 81.0 (CH-8), CH2-PMP), 3.79 (3H, s, OCH3-PMB), 3.72 (2H, m, CH2-OH),
77.1 (CH-6), 72.8 (CH2-PMB), 72.5 (CH-1), 69.2 (CH-9), 66.8 3.58 (3H, m, 2H-2′, H-5), 3.35 (3H, s, OCH3-MOM), 3.29 (2H,
(CH2-5), 66.5 (CH2-2′), 55.2 (OCH3-PMB), 41.1 (CH2-10), 33.5 m, H-1, H-4), 3.12 (1H, m, H-2), 2.95 (1H, s, OH), 2.50 (1H, m,
(CH2-1′), 27.4 (CH3-tBu), 27.1 (CH3-tBu), 22.5 (C-tBu), 19.8 H-6), 2.17 (1H, m, H-1′), 1.60 (1H, m, H-1′), 1.45 (1H, dd, J =
(C-tBu); MS (ESI) [m/z, (%)]: 475 (M+ + Na, 100); HRMS (ESI): 22.2, 11.3 Hz, H-6); 13C-NMR (CDCl3, δ): 159.1 (Cp-PMB), 130.4
475.2486 calcd for C24H40NaO6Si, found 475.2486.
(C-PMB), 129.3 (CHo-PMB), 113.7 (CHm-PMB), 95.3 (CH2-
(1S,6R,8S,9R)-3,3-Ditert-butyl-8-(2′-p-methoxybenzyloxyethyl)- MOM), 80.7 (CH-2), 77.3 (CH-4), 74.5 (CH-1), 72.5 (CH2-PMP),
9-(methoxymethoxy)-2,4,7-trioxy-3-silinebicyclic[4,4,0]decane 66.3 (CH-5), 66.2 (CH2-2′), 62.9 (CH2-OH), 55.6 (OCH3-OMOM),
(15). To a solution of alcohol 14 (1 g, 2.21 mmol) in CH2Cl2 55.2 (OCH3-PMB), 39.1 (CH2-6), 31.9 (CH2-1′); MS (ESI)
(10 mL) was added DIPEA (1.93 mL, 11.06 mmol) and the [m/z, (%)]: 379 (M+ + Na, 100); HRMS (ESI): 379.1727 calcd for
mixture was stirred for 10 min, cooled to 0 °C and MOMCl C18H28NaO7, found 379.1726.
(839 µL, 11.06 mmol) was added. Stirring was continued for
(2S,3R,5S,6S)-5-(tert-Butyldimethylsililoxy)-2-(2′-p-methoxy-
12 h allowing the mixture to gradually reach room temp- benzyloxyethyl)-3-(methoxymethoxy)-6-iodomethyl-1-tetrahydro-
erature. The reaction was quenched with water (10 mL) and 2H-pyrane (17). To a solution of diol 16 (570 mg, 1.6 mmol) in
was extracted with CH2Cl2 (2 × 10 mL). The combined organic THF (15 mL) were added PPh3 (630 mg, 2.4 mmol) and imid-
layers were washed with H2O (30 mL) and brine (30 mL) and azole (326 mg, 4.80 mmol). When the mixture was completely
were dried over Na2SO4 and the solvent was evaporated under dissolved, I2 (487 mg, 1.92 mmol) was added at 0 °C. The solu-
reduced pressure. The residue was chromatographed on silica tion was stirred till it reached room temperature for 2 h and
gel using 3% EtOAc–hexane as the eluent, affording compound then a saturated aqueous solution of NaHCO3 (30 mL) was
15 (1.01 g, 93%) as a colourless liquid; Rf: 0.51 (20% EtOAc– added. The resulting mixture was extracted with EtOAc (2 ×
hexane); IR (NaCl, cm−1): 2960.65, 2932.78, 2859.15, 1512.89, 30 mL) and the organic phases were washed with a 10%
1092.47, 854.35; [α]2D6 = −43.56 (c 2.80, CHCl3); 1H-NMR aqueous solution of Na2S2O4 (60 mL) and brine (60 mL), dried
(CDCl3, δ): 7.25 (2H, d, J = 8.6 Hz, Ho-PMB), 6.87 (2H, d, J = over Na2SO4 and the solvent was removed under reduced
8.6 Hz, Hm-PMB), 4.72 (1H, d, J = 6.9 Hz, CH2-MOM), 4.60 pressure. The obtained residue was dissolved in CH2Cl2
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(10 mL) and pyridine (2 mL), cooled to 0 °C and TBSOTf (C-PMB), 129.2 (CHo-PMB), 113.6 (CHm-PMB), 110.2 (CH-4
(441 µL, 1.92 mmol) was added and the mixture was stirred to furan), 106.1 (CH-3 furan), 95.2 (CH2-MOM), 80.4 (CH-6), 77.1
room temperature for 2 h. Water (15 mL) was added and the (CH-2), 74.7 (CH-5), 72.6 (CH2-PMP), 70.0 (CH-3), 66.3 (CH2-2′),
organic phase was washed with a 10% aqueous solution of 55.5 (OCH3-OMOM), 55.2 (OCH3-PMB), 40.2 (CH2-4), 32.1
HCl (2 × 10 mL) and brine (10 mL), dried over Na2SO4 and the (CH2-1′), 30.6 (CH2-furan), 25.7 (CH3-tBu), 17.9 (C-tBu), −4.1
solvent was filtered and evaporated to give a residue which was (CH3-Si), −4.8 (CH3-Si); MS (ESI) [m/z, (%)]: 543 (M+ + Na,
chromatographed on silica gel using 5% EtOAc–hexane as the 100), 521 (M+ + 1, 18); HRMS (ESI): 543.2748 calcd for
eluent, affording iodide 17 (750 mg, 80%) as a colourless C28H44NaO7Si, found 543.2745.
liquid; Rf: 0.52 (30% EtOAc–hexane); IR (NaCl, cm−1): 2920.98,
Compound 18. Yellow liquid, Rf: 0.16 (20% EtOAc–hexane);
2884.17, 1512.66, 1247.58, 1095.78, 789.37; [α]2D6 = −1.10 IR (NaCl, cm−1): 3469.31, 2953.45, 2930.31, 2882.78, 2856.06,
(c 1.20, CHCl3); 1H-NMR (CDCl3, δ): 7.28 (2H, d, J = 8.6 Hz, 1513.85, 1034.62; [α]D30 = −6.13 (c 1.75, CHCl3); 1H-NMR
Ho-PMB), 6.87 (2H, d, J = 8.6 Hz, Hm-PMB), 4.69 (1H, d, J = (CDCl3, δ): 7.25 (2H, d, J = 8.6 Hz, Ho-PMB), 6.87 (2H, d, J = 8.6
6.9 Hz, CH2-MOM), 4.59 (1H, d, J = 6.9 Hz, CH2-MOM), 4.47 Hz, Hm-PMB), 5.79 (1H, ddd, J = 17.1, 10.3, 6.6 Hz, H-7), 5.15
(2H, s, CH2-PMB), 3.80 (3H, s, OCH3-PMB), 3.66 (2H, m, (1H, d, 17.1 Hz, H-8), 5.06 (1H, d, 10.3 Hz, H-8), 4.67 (1H, d,
2H-2′), 3.47 (1H, m, H-3), 3.35 (3H, s, OCH3-MOM), 3.34 (3H, J = 6.8 Hz, CH2-MOM), 4.61 (1H, d, J = 6.8 Hz, CH2-MOM), 4.45
m, H-2, H-5, H-6), 3.16 (1H, dd, 1H, J = 10.3, 7.4 Hz, CH2-I), (2H, s, CH2-PMP), 4.29 (1H, dd, J = 12.2, 6.6 Hz, H-6), 3.79 (3H,
2.94 (1H, m, CH2-I), 2.39 (1H, m, H-4), 2.16 (1H, m, H-1′), 1.62 s, OCH3-PMB), 3.75 (1H, ddd, J = 12.3, 5.8, 3.1 Hz, H-4), 3.62
(1H, m, H-1′), 1.49 (1H, dd, J = 22.4, 11.0 Hz, H-4), 0.88 (9H, s, (3H, m, H-3, 2H-1), 3.40 (3H, s, OCH3-MOM), 1.86 (1H, m,
CH3-tBu), 0.10 (3H, s, CH3-Si), 0.09 (3H, s, CH3-Si); 13C-NMR H-5), 1.74 (2H, m, 2H-2), 1.62 (1H, ddd, J = 14.3, 7.5, 3.8 Hz,
(CDCl3, δ): 159.0 (Cp-PMB), 130.7 (C-PMB), 129.3 (CHo-PMB), H-5), 0.89 (9H, s, CH3-tBu), 0.06 (3H, s, CH3-Si), 0.04 (3H, s,
113.6 (CHm-PMB), 95.3 (CH2-MOM), 80.3 (CH-6), 77.3 (CH-2), CH3-Si); 13C-NMR (CDCl3, δ): 159.1 (Cp-PMB), 141.0 (CH-7),
74.5 (CH-5), 72.6 (CH2-PMP), 70.2 (CH-3), 66.2 (CH2-2′), 55.5 130.3 (C-PMB), 129.2 (CHo-PMB), 114.5 (CH2-8), 113.7
(OCH3-OMOM), 55.2 (OCH3-PMB), 39.7 (CH2-4), 31.9 (CH2-1′), (CHm-PMB), 97.2 (CH2-MOM), 80.5 (CH-3), 72.7 (CH2-PMP),
25.7 (CH3-tBu), 17.8 (C-tBu), 7.9 (CH2-I), −4.0 (CH3-Si), −4.6 71.4 (CH-4, CH-6), 71.3 (CH-4, CH-6), 67.9 (CH2-1), 55.7 (OCH3-
(CH3-Si); MS (ESI) [m/z, (%)]: 603 (M+ + Na, 100), 580 (M+ + 1, OMOM), 55.2 (OCH3-PMB), 39.3 (CH2-5), 31.8 (CH2-2), 25.8
26), 519 (48), 283 (60); HRMS (ESI): 603.1609 calcd for (CH3-tBu), 18.1 (C-tBu), −4.4 (CH3-Si), −4.9 (CH3-Si); MS (ESI)
C24H41INaO6Si, found 603.1617.
(2R,3S,5R,6S)-3-(tert-Butyldimethylsilyloxy)-2-(furanylmethyl)- 477.2642 calcd for C24H42NaO6Si, found 477.2638.
6-(2′-p-methoxybenzyloxyethyl)-5-(methoxymethoxy)-1-tetrahydro- (2′R,3′S,5′R,6′S)-5-[3′-(tert-Butyldimethylsilyloxy)-6′-(2″-p-methoxy-
[m/z, (%)]: 477 (M+ + Na, 100), 455 (M+ + 1, 76); HRMS (ESI):
2H-pyrane (9) and(3S,4R,6S)-6-(tert-butyldimethylsilyloxy)-1- benzyloxyethyl)-5′-(methoxymethoxy)-1′-(tetrahydro-2H-pyran-
(2′-p-methoxybenzyloxyethyl)-4-(methoxymethoxy)-oct-7-en-3-ol 2-yl)methyl]-5-methoxy-5H-furan-2-one (26). A solution of
(18). To a solution of furan (320 µL, 4.40 mmol) in THF compound 9 (370 mg, 0.71 mmol) and a catalytic amount of
(5 mL) at 0 °C was added n-BuLi (1.76 mL of a 2.5 M solution 4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein disodium salt
in hexanes, 4.40 mmol) and the mixture was stirred for 30 min (Rose Bengal) in MeOH (5 mL), previously purged with O2, was
affording a yellow solution. Iodide 17 (640 mg, 1.10 mmol) in cooled at −78 °C, irradiated with a 200 W lamp for 1 h, and
THF (4 mL) was added via a cannula and the mixture was stirred under an oxygen atmosphere. The solvent was evapor-
stirred at 0 °C for 3 h. After quenching with water (15 mL), the ated, and the residue was rapidly filtered through a column on
product was extracted with EtOAc (3 × 20 mL). The combined silica gel (50% EtOAc–hexane) in order to get rid of the cata-
organic phases were dried, filtered and evaporated to give a lyst. After solvent evaporation the residue was dissolved in pyri-
residue which was chromatographed on silica gel using 2% dine (4 mL) and Ac2O (452 µL) and DMAP (catalytic) were
EtOAc–hexane as the eluent, affording compound 9 (420 mg, added at 0 °C. The reaction mixture was stirred for 12 h at
74%) and alcohol 18 (85 mg, 13%).
room temperature, then water (20 mL) was added and the
Compound 9. Yellow liquid, Rf: 0.35 (20% EtOAc–hexane); product was extracted with EtOAc (3 × 20 mL). The combined
IR (NaCl, cm−1): 2920.25, 2884.15, 1614.78, 1244.08, 1095.15; organic phases were washed with a 10% aqueous solution of
1
[α]2D6 = −5.95 (c 1.41, CHCl3); H-NMR (CDCl3, δ): 7.27 (1H, d, HCl (2 × 50 mL) and brine (50 mL), dried over Na2SO4 and the
J = 1.8, H-5 furan), 7.22 (2H, d, J = 8.6 Hz, Ho-PMB), 6.87 (2H, solvent was filtered and evaporated to give a residue which was
d, J = 8.6 Hz, Hm-PMB), 6.27 (1H, dd, J = 2.9, 1.9 Hz, H-4 chromatographed on silica gel using 5% EtOAc–hexane as the
furan), 6.05 (1H, d, J = 2.9 Hz, H-3), 4.70 (1H, d, J = 6.9 Hz, eluent, affording compound 26 (305 mg, 76%) as a colourless
CH2-MOM), 4.58 (1H, d, J = 6.9 Hz, CH2-MOM), 4.33 (2H, s, liquid; Rf: 0.27 (20% EtOAc–hexane); IR (NaCl, cm−1): 2953.45,
1
CH2-PMP), 3.80 (3H, s, OCH3-PMB), 3.54–3.25 (6H, m, H-2, 2932.23, 2886.92, 2857.99, 1776.12, 1249.65, 1100.19; H-NMR
2H-2′, H-3, H-5, H-6), 3.36 (3H, s, OCH3-MOM), 3.13 (1H, dd, (CDCl3, δ): (major diastereomer); 7.25 (2H, m, Ho-PMB), 7.00
J = 15.4, 1.5 Hz, CH2-furan), 2.59 (1H, dd, J = 15.4, 9.3 Hz, CH2- (1H, d, J = 5.6 Hz, H-4), 6.87 (2H, m, Hm-PMB), 5.93 (1H, d, J =
furan), 2.41 (1H, dt, J = 10.8, 4.2 Hz, H-4), 2.15 (1H, m, H-1′), 5.6 Hz, H-3), 4.69 (1H, d, J = 6.9 Hz, CH2-MOM), 4.58 (1H, d,
1.56 (1H, m, H-1′), 1.49 (1H, dd, J = 22.2, 10.9 Hz, H-4), 0.90 J = 6.9 Hz, CH2-MOM), 4.44 (2H, s, CH2-PMP), 3.78 (3H, s,
(9H, s, CH3-tBu), 0.09 (6H, s, CH3-Si); 13C-NMR (CDCl3, δ): OCH3-PMB), 3.54 (1H, dd, J = 7.3 5.8 Hz), 3.45 (2H, m), 3.34
159.1 (Cp-PMB), 153.3 (C-2 furan), 140.6 (CH-5 furan), 130.7 (3H, s, OCH3-MOM), 3.26 (2H, m), 3.18 (1H, s, OCH3),
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2.90 (1H, m), 2.71 (1H, m, H-1), 2.38 (1H, m, H-1), 2.16 (2H, m, (C-PMB), 129.54 (CHo-PMB), 113.90 (CHm-PMB), 104.24 (C-7),
H-1″, H-4′), 1.49 (2H, m, H-1″, H-4′), 0.87 (9H, s, CH3-tBu), 0.05 95.61 (CH2-OMOM), 77.41 (CH), 76.58 (CH), 74.71 (CH), 74.06
(6H, s, CH3-Si); 13C-NMR (CDCl3, δ):(major diastereomer); (CH), 73.04 (CH), 72.47 (CH2-PMB), 65.89 (CH2-2′), 55.71 (CH3-
170.1 (CvO), 159.1 (Cp-PMB), 155.3 (CH-4), 130.3 (C-PMB), OMOM), 55.36 (CH3-PMB), 38.04 (CH2), 36.33 (CH2), 35.68
129.2 (CHo-PMB), 122.4 (CH-3), 113.7 (CHm-PMB), 110.0 (C-5), (CH2), 31.89 (CH2); MS (ESI) [m/z, (%)]: 503.18 (26), 461.17
95.2 (CH2-MOM), 77.5 (CH-6′), 77.2 (CH-2′), 74.4 (CH2-PMB), (M+ + 1 + Na, 100), 445.18 (10); HRMS (ESI): 475.17962 calcd
72.5 (CH-5′), 69.6 (CH-3′), 66.5 (CH2-2″), 55.5 (OCH3-OMOM), for C22H30NaO9, found 461.17820.
55.2 (OCH3-PMB), 51.1 (OCH3), 39.9 (CH2-4′), 39.3 (CH2-1),
(1S,3R,7R,9R,11S,12R)-7-Acetoxy-11-(2′-p-methoxybenzyl-
31.9 (CH2-1″), 25.6 (CH3-tBu), 17.8 (C-tBu), −4.1 (CH3-Si), −4.8 oxyethyl)-12-(methoxymethoxy)-2,6,10-trioxytricyclic[7,4,0,03,7]-
(CH3-Si); MS (ESI) [m/z, (%)]: 589 (M+ + Na, 100); HRMS (ESI): tridecan-5-one (27). To a solution of alcohol (1) (25 mg,
589.2803 calcd forC29H46NaO9Si, found 589.2801.
0.06 mmol) in DCM (1.0 mL) was added Py (77 µL, 0.30 mmol)
(1S,3R,7R,9R,11S,12R)-7-Methoxy-11-(2′-p-methoxybenzyl- and Ac2O (13 µL, 0.12 mmol) at r.t. The reaction mixture was
oxyethyl)-12-(methoxymethoxy)-2,6,10-trioxytricyclic[7,4,0,03,7]- stirred at r.t. for 16 h. Then it was quenched with water (5 mL)
tridecan-5-one (6) and (1S,3R,7R,9R,11S,12R)-7-hydroxy-11- and the product was extracted with EtOAc (3 × 10 mL). The
(2′-p-methoxybenzyloxyethyl)-12-(methoxymethoxy)-2,6,10-trioxy- combined organic phases were dried, filtered and evaporated
tricyclic[7,4,0,03,7]tridecan-5-one (5). To
a solution of 26 to give a residue which was chromatographed on silica gel
(275 mg, 0.49 mmol) in THF (2 mL) was added TBAF (1.47 mL using 10% EtOAc–hexane as the eluent, affording compound
of a 1 M solution in THF, 1.47 mmol) and the mixture was 27 (23 mg, 80%) as a colourless oil; Rf: 0.13 (20% EtOAc–
stirred at room temperature for 24 h. Then it was quenched hexane); IR (NaCl, cm−1): 2932.58, 1789.23, 1732.56, 1611.87,
1
with an aqueous saturated solution of NH4Cl (10 mL) and the 1513.45, 1039.26, 825.36; [α]2D1 = −45.5 (c 1.0, CHCl3); H-NMR
product was extracted with EtOAc (3 × 10 mL). The combined (CDCl3, δ): 7.24 (2H, d, J = 8.7 Hz, Ho-PMB), 6.85 (2H, d, J =
organic phases were dried, filtered and evaporated to give a 8.7 Hz, Hm-PMB), 4.41 (4H, m, CH2-OMOM, CH2-PMP), 3.95
residue which was chromatographed on silica gel using 5% (1H, d, J = 3.9 Hz, H-3), 3.71–3.56 (2H, m; CH-2′), 3.38 (3H, s,
EtOAc–hexane as the eluent, affording compound 2 (129 mg, CH3-PMB), 3.30 (1H, m, H-11), 3.24–3.12 (3H, m, H-12, H-8),
60%) and compound 1 (40 mg, 20%).
3.10 (3H, s, CH3-OMOM), 2.97 (1H, m, H-9), 2.81 (1H, m, H-1),
Compound 6: white solid; m.p. = 115 °C, Rf: 0.21 (20% 2.31 (2H, m, 1H-13, 1H-1′), 2.22 (1H, m, H-4), 2.09 (1H, m,
EtOAc–hexane); IR (NaCl, cm−1): 2933.20, 2887.88, 1796.37, H-4), 1.68 (1H, m, 1H-1′), 1.38 (3H, s, CH3-OAc), 1.30 (1H, m,
1425.89, 1090.55, 1036.55; [α]2D1 = −39.88 (c 1.45, CHCl3); 1H-13); 13C-NMR (CDCl3, δ): 173.24 (C-OAc), 167.74 (CvO),
1H-NMR (CDCl3, δ): 7.24 (2H, d, J = 8.6 Hz, Ho-PMB), 6.87 (2H, d, 159.82 (C-PMB), 131.34 (C-PMB), 129.46 (Co-PMB), 114.13
J = 8.6 Hz, Hm-PMB), 4.68 (1H, d, J = 6.9 Hz, CH2-OMOM), (Cm-PMB), 106.70 (C-7), 95.57 (CH2-OMOM), 77.55 (CH-11),
4.59 (1H, d, J = 6.9 Hz, CH2-OMOM), 4.47 (1H, d, J = 11.7 Hz, 75.16 (CH-12, CH-3), 74.20 (CH-1), 73.07 (CH-9), 72.83 (CH2-
CH2-PMB), 4.38 (1H, d, J = 11.7 Hz, CH2-PMB), 3.96 (1H, d, J = PMP), 66.28 (CH2-2′), 55.32 (CH3-OMOM), 54.87 (CH3-PMB),
4.4 Hz, H-9), 3.80 (3H, s, OCH3-PMB), 3.55 (2H, m, 2H-2′), 3.36 35.95 (CH2-13), 35.11 (CH2-8), 35.00 (CH2-4), 32.71 (CH-1′),
(3H, s, OCH3), 3.34 (3H, s, OCH3-OMOM), 3.32 (2H, m, H-1, 21.01 (CH3-OAc); MS (ESI) [m/z, (%)]: 503.23 (M+ + 1 + Na, 100),
H-11), 3.07 (2H, m, H-3, H-12), 2.88 (1H, dd, J = 17.3, 4.5 Hz, 427.25 (13), 415.89 (28); HRMS (ESI): 503.14856 calcd for
H-8), 2.72 (1H, dd, J = 13.1, 4.5 Hz, H-4), 2.45 (1H, m, H-13), C24H32NaO10, found 503.14867.
2.39 (1H, d, J = 17.3 Hz, H-8), 2.16 (1H, m, H-1′), 1.57 (2H, m,
H-1′, H-4), 1.43 (1H, m, H-13); 13C-NMR (CDCl3, δ): 175.1
(CvO), 159.1 (Cp-PMB), 130.5 (C-PMB), 129.2 (CHo-PMB),
113.6 (CHm-PMB), 106.5 (C-7), 95.4 (CH2-MOM), 77.4 (CH-1),
Acknowledgements
76.7 (CH-9), 74.6 (CH-11), 73.8 (CH-12), 73.0 (CH-3), 72.4 (CH2- This work was supported financially by the Xunta de Galicia
PMP), 65.8 (CH2-2′), 55.6 (OCH3-OMOM), 55.2 (OCH3-PMB), (CN 2012/184). The work of the NMR and MS divisions of the
49.8 (OCH3), 36.3 (CH2-8), 35.6 (CH2-13), 33.6 (CH2-4), 31.9 research support services of the University of Vigo (CACTI) is
(CH2-1′); MS (ESI) [m/z, (%)]: 476 (M+ + 1 + Na, 31), 475 also gratefully acknowledged. Z. G. and M. P. thank the Xunta
(M+ + Na, 100), 338 (44); HRMS (ESI): 475.1911 calcd for de Galicia for Angeles Alvariño contracts.
C23H32NaO9, found 475.1917.
Compound 5: white solid; m.p. = 140–143 °C, Rf: 0.13 (20%
EtOAc–hexane); IR (NaCl, cm−1): 3359.39, 2928.38, 1785.76,
1729.83, 1611.23, 1512.88, 1105.98, 1037.52, 909.27, 822.49;
Notes and references
[α]2D1 = −25.6 (c 1.0, CHCl3); 1H-NMR (CDCl3, δ): 7.25 (2H, d, J =
7.2 Hz, Ho-PMB), 6.91 (2H, d, J = 8.8 Hz, Hm-PMB), 4.65 (2H,
m, CH2-OMOM), 4.44 (2H, m, CH2-PMP), 4.03 (1H, d, J =
4.3 Hz, H-3), 3.82 (3H, s, CH3-PMB), 3.56 (2H, m, H-2′), 3.35
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