Total Synthesis of (+)-Cryptocaryol A Using a Prins Cyclization/Reductive Cleavage Sequence

Article abstract of DOI:10.1021/acs.joc.5b01323

The total synthesis of (+)-cryptocaryol A was achieved in 20 steps from (R)-glycidol. The key steps were a Prins cyclization/reductive cleavage sequence to construct the C5-C11 polyol fragment, a diastereoselective aldol reaction to control the stereogeni

Full text of DOI:10.1021/acs.joc.5b01323

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Total Synthesis of (+)ꢀCryptocaryol A Using a Prins Cyclization/Reductive
Cleavage Sequence
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Elodie BRUN, Véronique BELLOSTA and Janine COSSY*
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Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI) ꢀ UMR 8231 ꢀ ESPCI
ParisTech/CNRS/PSL Research University, 10 rue Vauquelin, 75231 Paris Cedex 05, France
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janine.cossy@espci.fr
Abstract: The total synthesis of (+)ꢀcryptocaryol A was achieved in 20 steps from (R)ꢀglycidol.
The key steps were a Prins cyclization/reductive cleavage sequence to construct the C5ꢀC11
polyol fragment, a diastereoselective aldol reaction to control the stereogenic center at C13 and a
stereocontrolled reduction to introduce the stereogenic center at C15.
INTRODUCTION
Plants of the genus Cryptocarya have been identified as a rich source of secondary
metabolites bearing a 5,6ꢀdihydroꢀαꢀpyrone moiety.1 Due to their important biological activities,
these latter compounds have attracted considerable synthetic interest.2 Our group has previously
reported the synthesis of some members of this family, including passifloricin,3 (–)ꢀpironetin,4
strictifolione,5 and fostriecin,6 and more recently, we became interested in the synthesis of
(+)ꢀcryptocaryol A.
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Cryptocaryol A, in concomitance with cryptocaryols BꢀH (Figure 1), were isolated by
Gustafson et al. in 2011 from the Papua New Guinea collection of the plant Cryptocarya sp.7
These compounds have been reported to act as Pdcd4 (programmed cell death 4) stabilizers with
EC50 values between 1.3 and 4.9 µM, Pdcd4 being a tumorgenesis and invasion suppressor
protein,8,9,10,11 whose expression is downꢀregulated in several cancers.12 Thus, the stabilization of
the expression of Pdcd4 might help to improve the efficiency of chemotherapies.13
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For our part, we were particularly interested in the synthesis of (+)ꢀcryptocaryol A. The
structure of (+)ꢀcryptocaryol A was established by spectroscopic studies by Gustafson et al.7 and
then revised in 2013 by O’Doherty and Wang.14 Cryptocaryol A is constituted by a 5,6ꢀdihydroꢀ
αꢀpyrone and a 1,3ꢀpolyol segment. Three total syntheses of this molecule have been reported up
to date: one total synthesis related to the first reported structure of cryptocaryol A,15 and two total
syntheses of the revised structure of (+)ꢀcryptocaryol A14 and its enantiomer.16 Herein, we would
like to report the total synthesis of (+)ꢀcryptocaryol A by using our recently developed Prins
cyclization/reductive cleavage sequence17 to control four of the six stereogenic centers present in
this molecule.
Figure 1. Cryptocaryols AꢀH
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The synthesis of (+)ꢀcryptocaryol A was envisaged from aldehyde A and heptadecanꢀ2ꢀ
one by using a diastereoselective reagent controlled boronꢀmediated aldol reaction to control the
stereogenic center at C13 (Scheme 1). The lactone in compound A would be formed by utilizing
a ringꢀclosing metathesis applied to the unsaturated ester B, which would be synthesized from C
by reductive cleavage. The bisꢀtetrahydropyran C would be the result of a Prins cyclization
between the homoallylic alcohol D and the tetrahydropyranyl aldehyde E, which would be
obtained by a Prins cyclization in between aldehyde 1 and (S)ꢀhomoallylic alcohol 2.
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Scheme 1. Retrosynthesis
O
O
2
3
1
O
OH OH OH OH OH
O
OR OR OR
O
O
13
5
7
9
11
15
5
7
9
11
H
14
14
RCM
A
Cryptocaryol A
Aldol reaction
OR
OR
O
5
11
13
O
OR OR OR
3
7
9
I
I
5
7
9
11
O
O
H
H
B
C
OR
OH
11
O
BnO
O
OH
9
13
R'O
OR'
OTs
3
7
9
13
H
O
H
H
1
E
2
D
RESULTS AND DISCUSSION
The synthesis of (+)ꢀcryptocaryol A started with the preparation of 1 and 2 (Scheme 2).
Aldehyde 118 was prepared in 52.5% overall yield from the commercially available 1,3ꢀ
propanediol 3 after monoprotection (NaH, BnBr, nꢀBu4NI, THF, rt, 7 h, 70%) and oxidation
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(PCC, NaOAc, 4Å MS, CH2Cl2, rt, 3 h, 75%). In parallel, the optically active (S)ꢀhomoallylic
alcohol 2 was synthesized from (R)ꢀglycidol 4 in 2 steps. After tosylation (TsCl, Et3N, DMAP,
CH2Cl2, 0 °C to rt, 3 h, 98%), the epoxide was opened by treatment with vinylmagnesium
bromide (1.6 equiv) in the presence of a catalytic amount of Li2CuCl4 (0.06 equiv, THF, ˗ 40 °C,
3 h, 96%) to produce the desired (S)ꢀhomoallylic alcohol 2.
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Scheme 2. Synthesis of the required starting substrates
1) NaH, BnBr
nBu4NI
THF
rt, 7 h (70%)
OH OH
BnO
O
9
H
2) PCC
NaOAc, 4Å MS
CH2Cl2
1
3
rt, 3 h (75%)
1) TsCl
Et3N, DMAP
CH2Cl2
OH
13
O
13
OTs
OH
0 °C - rt, 3 h
(S)
2) Li2CuCl4 (6 mol %)
(R)-glycidol 4
2
MgBr (1.6 equiv)
THF
-40 °C, 3 h
94%
Having aldehyde 1 and the optically active homoallylic alcohol 2 in hand, a first Prins
cyclization19 was performed between these two compounds using TFA (26 equiv, CH2Cl2, rt, 3
h)20 to produce, via the formation of intermediates F and G and after neutralization, a
diastereomeric mixture of tetrahydropyranyl alcohols 5 and 5’ (5/5’ = 25:75) in favor of the
undesired 2,4,6ꢀcis,cisꢀisomer 5’20 (Scheme 3). To convert 5’ into 5, the mixture of 5 and 5’ was
oxidized (DMP, CH2Cl2, rt, 2.5 h) to the corresponding tetrahydropyranone 6 (70% overall yield
from 1 and 2) and then diastereoselectively reduced. To control the stereogenic center at C11, an
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equatorial attack of a hydride was required. Thus, the sterically hindered reducing agent
Lꢀselectride (1.4 equiv, THF, ꢀ78 °C, 1 h) was used and alcohols 5 and 5’ were obtained as a
80:20 mixture. After separation of the diastereomers by flash column chromatography on silica
gel, alcohol 5 was isolated in 73% yield (Scheme 3).
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To synthesize the bisꢀtetrahydropyran of type C, a second Prins cyclization was envisaged
and 5 had to be transformed into an aldehyde of type E. The trisubstituted tetrahydropyran 5 was
transformed into aldehyde 7 in three steps. After protection of 5 as a tertꢀbutyldiphenylsilyl ether
(TBDPSCl, Imidazole, CH2Cl2, rt, 14 h), followed by a hydrogenolysis (Pd/C 5 mol %, H2,
MeOH/EtOAc = 3:1, rt, 16 h) and an oxidation of the resulting primary alcohol, the desired
aldehyde 7 was isolated in 70% overall yield (Scheme 3).
Scheme 3. Synthesis of the tetrahydropyran of type E
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Compound 7 was then involved in a second Prins cyclization using the (R)ꢀhomoallylic
alcohol entꢀ221 [TFA (26 equiv), CH2Cl2, rt, 3 h, 55%], affording the bisꢀtetrahydropyran as a
mixture of diastereomers, which was oxidized to ketone 8 [DMP (1.5 equiv), CH2Cl2, rt, 2 h,
96%] (Scheme 4) and then reduced. To control the stereogenic center at C5, the ketone in 8 was
reduced by NaBH4, affording a mixture of diastereomeric alcohols 9 and 9’ in a 95:5 ratio. After
separation by flash column chromatography on silica gel, 9 was isolated in 86% yield (Scheme
4). This obtained functionalized bisꢀtetrahydropyran 9 is the key element in the synthesis of
cryptocaryol A and it has to be transformed into a polyketide of type B to obtain the C1ꢀC13
fragment.
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Scheme 4. Synthesis of bisꢀtetrahydropyran 9
To perform the ringꢀopening of the bisꢀtetrahydropyran 9 with zinc, the tosylate 9 was
treated with NaI [10 equiv, acetone, µw, 120 °C, 2 h, 91%]20 to form the corresponding bisꢀ
iodide 10 (Scheme 5). As the reductive ringꢀopening of 10 would liberate three free hydroxyl
groups, and as the hydroxyl at C5 has to be transformed to an ester to construct the lactone core
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by ringꢀclosing metathesis, we took advantage of the presence of the free hydroxyl group at C5 in
the bisꢀtetrahydropyran 10 to introduce the unsaturated ester. Thus, 10 was transformed to ester
11 (acryloyl chloride, iPr2NEt, CH2Cl2, 0 °C to rt, 3.5 h, 96%) and the latter was reductively
cleaved by treatment with zinc to produce polyol 12 in 88% yield. After protection (TBSOTf,
2,6ꢀlutidine, CH2Cl2) and ringꢀclosing metathesis using the first generation Grubbs catalyst (c =
0.01 M, CH2Cl2, 45 °C, 2.5 h), lactone 13 was isolated in 89% overall yield (Scheme 5).
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Scheme 5. Synthesis of the C1ꢀC13 fragment
The proof of the relative stereochemistry between the substituents at C5, C7 and C9 in 12
is based on the structure elucidation of two previously synthesized compounds 12’17 and 12’’,17
(Figure 2). Analysis of the 13C NMR spectra of 12’ using Kishi’s 13C NMR database in CD3OD22
revealed the presence of a syn,anti or an anti,syn motif between the hydroxyls at C5, C7 and C9.
Moreover, acetonide 12’’17 allowed to confirm the syn relationship between the hydroxyl groups
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at C7 and C9.23 Thus, the stereochemistry of the substituents at C5, C7 and C9 in compound 12
was assumed to be anti,syn and was confirmed latter on by completion of the synthesis of
(+)ꢀcryptocaryol A.
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Figure 2.
To introduce the stereogenic center at C13, a chemoselective ozonolysis of the terminal
double bond in 13 was performed by carefully monitoring the reaction by TLC and, after a few
minutes, aldehyde 14 was isolated in 80% yield (Scheme 6). This aldehyde was then involved in
a boronꢀmediated aldol reaction with heptadecanꢀ2ꢀone to afford the diastereomeric aldols 15 and
15’ as an inseparable mixture which contains also aldehyde 14 as a retroaldol reaction could not
be avoided during the workꢀup (MeOH/buffer pH =7/H2O2 = 1:1:1).24 A stereoselective reduction
of the ketone at C15 using Me4NBH(OAc)3 (10 equiv) was performed to obtain an antiꢀrelative
stereochemistry between the hydroxyl groups at C13 and C15.25 Diols 16 and 16’ were isolated in
37% yield over the two steps, again as a mixture of two inseparable diastereomers in a 75:25
ratio.26 Fortunately, after treatment of these two diastereomers with HF.CH3CN (rt, 2.5 h),
(+)ꢀcryptocaryol A was separated and isolated in 50% yield proving, a posteriori, that the major
isomers 15 and 16 possess the required absolute configuration for the synthesis of this natural
product. The 1H NMR and 13C NMR spectral data and optical rotation [synthetic: [α] D 20 + 15 (c
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0.2, MeOH), reported:14 [α] D + 14 (c 0.2, MeOH)] for the synthetic cryptocaryol A matched
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with the reported data for (+)ꢀcryptocaryol A.
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Scheme 6. Completion of the synthesis
The total synthesis of (+)ꢀcryptocaryol A was accomplished in 20 steps from the
commercially available (R)ꢀglycidol with an overall yield of 1.6%. The first stereogenic center of
(+)ꢀcryptocaryol A was induced by (R)ꢀglycidol and the five other stereogenic centers were
controlled by diastereoselective reactions. Three of them were controlled by two Prins
cyclization/oxidation/reduction sequences, one by a boronꢀmediated aldol reaction and the sixth
one by a directed 1,3ꢀreduction of a βꢀhydroxyketone. This synthesis of cryptocaryol A is shorter
than the previous syntheses reported by Reddy and Mohapatra (28 steps)15 and O’Doherty and
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Wang (23 steps),14 and slightly longer than the synthesis recently reported by Dias et al. (17
steps)16 but as efficient in terms of overall yield (1.6% versus 1.4%).
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EXPERIMENTAL SECTION
General experimental methods: All reactions were carried out under anhydrous conditions,
using flameꢀdried glassware and under an argon atmosphere. CH2Cl2, Et3N and iPr2NEt were
distilled from CaH2; Et2O and THF were distilled from Na/benzophenone. Other reagents were
obtained from commercial suppliers and used as received. TLC was performed on silica gel
plates with UV and pꢀanisaldehyde or KMnO4 stain visualization. Flash chromatography was
performed on silica gel (230ꢀ400 mesh). Optical rotations were measured using a polarimeter
with a 1 dm path length. Infrared (IR) spectra were recorded on an ATR plate, wave numbers are
1
indicated in cmꢀ1. H NMR spectra were recorded at 400 MHz in CDCl3 or CD3OD and data are
reported as follows: chemical shift in ppm from tetramethylsilane as an internal standard,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintuplet, m = multiplet or
overlap of nonꢀequivalent resonances, br = broad), integration. 13C NMR spectra were recorded at
100 MHz in CDCl3 or CD3OD and data are reported as follows: chemical shift in ppm from
tetramethylsilane with the solvent as an internal standard (CDCl3, 77.16 ppm or CD3OD, 49.00
ppm). Mass spectra were realized with a gas chromatographꢀmass spectrometer by electronic
impact. High resolution mass spectra (HRMS) were performed with an orbitrap mass analyzer by
electrospray ionization.
Synthesis of 1
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3ꢀ(Benzyloxy)propanꢀ1ꢀol: To a suspension of sodium hydride (60 % in oil, 1.6 g, 40
mmol, 1 equiv) in dry THF (80 mL) was added dropwise 1,3ꢀpropanediol (2.9 mL, 40 mmol, 1
equiv). The mixture was stirred at rt for 45 min. nꢀBu4NI was then added (7.4 g, 20 mmol, 0.5
equiv), and benzylbromide (4.8 mL, 40 mmol, 1 equiv) was added dropwise. The reaction
mixture was stirred for 7 h and quenched by addition of H2O (80 mL). The phases were separated
and the aqueous layer was extracted with Et2O (3 × 80 mL). The combined organic layers were
washed with brine, dried over MgSO4, filtered and concentrated under vacuum. The crude
material was then purified by flash column chromatography on silica gel (petroleum ether/EtOAc
= 8:2) to afford 3ꢀ(benzyloxy)propanꢀ1ꢀol (4.67 g, 28.1 mmol, 70%) as a yellow oil. The spectral
data match those reported in the literature.18 IR: ν 3375, 3030, 2943, 2863, 1496, 1454, 1365,
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1
1205, 1073, 1026, 972, 910 cmꢀ1; H NMR (CDCl3, 400 MHz): δ 7.38 ꢀ 7.26 (m, 5H), 4.53 (s,
2H), 3.79 (t, J = 5.7 Hz, 2H), 3.67 (t, J = 5.7 Hz, 2H), 2.27 (br s, 1H, OH), 1.87 (quint, J = 5.7
Hz, 2H); 13C NMR (CDCl3, 100 MHz): δ 138.1, 128.5 (2C), 127.73, 127.69 (2C), 73.2, 69.1,
61.5, 32.2; MS (EI) m/z: 166 (M+., 2), 147 (3), 130 (1), 120 (3), 107 (BnO+, 97), 91 (Bn+, 100),
79 (29), 77 (Ph+, 13), 65 (19), 51 (7).
3ꢀ(Benzyloxy)propanꢀ1ꢀal (1): To a solution of 3ꢀ(benzyloxy)propanꢀ1ꢀol (990 mg, 5.96
mmol, 1 equiv) in dry CH2Cl2 (45 mL) were added molecular sieves 4Å (2.2 g), NaOAc (150 mg,
1.83 mmol, 0.3 equiv) and PCC (1.93 g, 8.95 mmol, 1.5 equiv). The reaction mixture was stirred
for 3 h, and Et2O (400 mL) was added. After stirring for an additional 2 h, the mixture was
filtered on florisil® and concentrated under vacuum. The crude material was then purified by
flash column chromatography on silica gel (petroleum ether/EtOAc = 8:2) to afford 3ꢀ
(benzyloxy)propanꢀ1ꢀal 1 (733 mg, 4.47 mmol, 75%) as a yellow oil. The spectral data match
those reported in the literature.18 IR: ν 3031, 2862, 2732, 1722, 1496, 1454, 1395, 1363, 1205,
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1092, 1028, 909 cmꢀ1; H NMR (CDCl3, 400 MHz): δ 9.80 (t, J = 1.8 Hz, 1H), 7.38ꢀ7.27 (m,
5H), 4.54 (s, 2H), 3.82 (t, J = 6.1 Hz, 2H), 2.70 (td, J = 6.1 and J = 1.8 Hz, 2H); 13C NMR
(CDCl3, 100 MHz): δ 201.2, 137.9, 128.5 (2C), 127.8, 127.7 (2C), 73.3, 63.9, 43.9; MS (EI) m/z:
164 (M+., 1), 146 (1), 120 (8), 107 (BnO+, 100), 91 (Bn+, 97), 79 (44), 77 (Ph+, 22), 65 (21), 57
(10), 51 (12).
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{(2S,6S)ꢀ6ꢀ[2ꢀ(Benzyloxy)ethyl]ꢀ4ꢀoxotetrahydroꢀ2Hꢀpyranꢀ2ꢀyl}
methyl
4ꢀ
methylbenzene sulfonate (6): To a solution of homoallylic alcohol 217 (934 mg, 3.65 mmol, 1.5
equiv) and aldehyde 1 (400 mg, 2.44 mmol, 1.0 equiv) in dry CH2Cl2 (11.5 mL) was added
dropwise TFA (4.7 mL, 63 mmol, 26 equiv). The mixture was stirred for 3 h at rt, and treated
with a saturated aqueous NaHCO3 solution (15 mL). The pH was adjusted to pH > 7 by addition
of Et3N and the resulting mixture was stirred at rt for 3 h and then diluted with EtOAc. The layers
were separated and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined
organic layers were washed with brine, dried over MgSO4, filtered and concentrated under
vacuum. Purification of the crude material by flash column chromatography on silica gel
(petroleum ether/EtOAc = 66:34 to 5:5) afforded a mixture of the two diastereomeric alcohols 5’
and 5 in a 3:1 ratio (718 mg, 1.71 mmol, 70%) as a gummy liquid.
To a solution of the tetrahydropyranyl alcohols (mixture of diastereomers 5 and 5’, 512 mg, 1.22
mmol, 1.0 equiv) in dry CH2Cl2 (12 mL) was added DessꢀMartin periodinane (775 mg, 1.83 mg,
1.5 equiv). The mixture was stirred at rt for 2.5 h. Hexane (24 mL) was then added, the resulting
precipitate was filtered through a pad of Celite®. The filtrate was concentrated under vacuum and
purification of the resulting crude material by flash column chromatography on silica gel
(petroleum ether/EtOAc = 7/3) afforded ketone 6 (510 mg, 1.22 mmol, quant.) as a colorless
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gummy liquid. [α] D + 12.2 (c 0.55, CHCl3), IR: ν 3060, 2922, 2865, 1721, 1598, 1454, 1360,
5
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1266, 1189, 1176, 1096, 983, 814 cmꢀ1; H NMR (CDCl3, 400 MHz): δ 7.78 (br d, J = 8.3 Hz,
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2H), 7.36ꢀ7.25 (m, 7H), 4.48 (d, J = 12.0 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4.09ꢀ4.01 (m, 2H),
3.81ꢀ3.71 (m, 2H), 3.58ꢀ3.47 (m, 2H), 2.43 (s, 3H), 2.37 (dd, J = 14.7 and J = 2.3 Hz, 1H), 2.28
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(br d, J = 7.8 Hz, 2H), 2.22 (dd, J = 14.6 and J = 11.6 Hz, 1H), 1.88ꢀ1.73 (m, 2H); C NMR
(CDCl3, 100 MHz): δ 205.3, 145.1, 138.3, 132.8, 129.9 (2C), 128.4 (2C), 128.0 (2C), 127.7 (3C),
74.1, 73.8, 73.1, 71.0, 65.7, 47.4, 43.2, 36.2, 21.7; HRMS (ESI): Calculated for C22H26O6SNa [M
+ Na]+: 441.1342, found: 441.1346.
{(2S,4S,6S)ꢀ6ꢀ[2ꢀ(Benzyloxy)ethyl]ꢀ4ꢀhydroxytetrahydroꢀ2Hꢀpyranꢀ2ꢀyl}methyl
4ꢀ
methyl benzenesulfonate (5): To a solution of ketone 6 (454 mg, 1.08 mmol, 1.0 equiv) in dry
THF (15 mL), cooled to −78 °C, was added LꢀSelectride (1 M in THF, 1.5 mL, 1.5 mmol, 1.4
equiv). The mixture was stirred at −78 °C for 1 h and then quenched by addition of a saturated
aqueous Rochelle salts solution (15 mL) and H2O (15 mL). The mixture was warmed to rt and
diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc.
The combined organic layers were washed with H2O, then brine, dried over MgSO4, filtered and
concentrated under vacuum. The crude material was then purified by flash column
chromatography on silica gel (petroleum ether/EtOAc = 6:4) and the alcohol 5 was isolated (332
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mg, 0.790 mmol, 73%) as a single diastereomer and as a colorless gummy liquid. [α] D − 22.2
(c 0.58, CHCl3), IR: ν 3428, 3032, 2920, 2869, 1598, 1496, 1454, 1357, 1267, 1189, 1175, 1096,
1075, 975, 915, 813 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ 7.77 (br d, J = 8.4 Hz, 2H), 7.36ꢀ7.25
(m, 7H), 4.49 (d, J = 12.1 Hz, 1H), 4.46 (d, J = 12.1 Hz, 1H), 4.25 (m, 1H), 4.03ꢀ3.86 (m, 4H),
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3.56ꢀ3.46 (m, 2H), 2.43 (s, 3H), 1.70ꢀ1.56 (m, 4H), 1.52ꢀ1.39 (m, 2H), 1.41 (br s, 1H, OH); C
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NMR (CDCl3, 100 MHz): δ 144.7, 138.6, 133.0, 129.8 (2C), 128.4 (2C), 128.0 (2C), 127.7 (2C),
127.6, 73.0, 72.5, 69.1, 68.8, 66.5, 64.0, 38.4, 36.1, 34.2, 21.7; MS (EI) m/z: 283 (1), 267 (3), 241
(3), 223 (2), 197 (5), 195 (2), 146 (8), 125 (9), 107 (BnO+,19), 91 (100), 79 (13), 73 (16), 67 (13),
65 (13), 55 (10); HRMS (ESI): Calculated for C22H28O6SNa [M + Na]+: 443.1499, found:
443.1499.
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Synthesis of 7
{(2S,4S,6S)ꢀ6ꢀ[2ꢀ(Benzyloxy)ethyl]ꢀ4ꢀ[(tertꢀbutyldiphenylsilyl)oxy]tetrahydroꢀ2Hꢀ
pyranꢀ2ꢀyl}methyl 4ꢀmethylbenzenesulfonate (5a): To a solution of alcohol 5 (328 mg, 0.780
mmol, 1.0 equiv) and imidazole (106 mg, 1.56 mmol, 2.0 equiv) in dry CH2Cl2 (4.4 mL) was
added TBDPSCl (0.30 mL, 1.16 mmol, 1.5 equiv) dropwise. After 16 h at rt, H2O (6 mL) was
added to the reaction mixture. The layers were separated and the aqueous layer was extracted
with CH2Cl2 (3 × 20 mL). The combined organic layers were then dried over MgSO4, filtered and
concentrated under vacuum. The crude material was then purified by flash column
chromatography on silica gel (petroleum ether/EtOAc = 95:5 to 9:1) to afford the silylated
20
compound 5a (488 mg, 0.741 mmol, 95%) as a colorless gummy liquid. [α] D − 6.7 (c 0.95,
CHCl3); IR: ν 3070, 2929, 2857, 1599, 1472, 1454, 1428, 1361, 1189, 1176, 1105, 1078, 1037,
1
981, 909, 821 cmꢀ1; H NMR (CDCl3, 400 MHz): δ 7.78 (br d, J = 8.3 Hz, 2H), 7.63ꢀ7.60 (m,
4H), 7.47ꢀ7.27 (m, 13H), 4.52 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.21 (m, 1H), 4.13
(m, 1H), 4.06 (m, 1H), 3.98ꢀ3.88 (m, 2H), 3.54ꢀ3.48 (m, 2H), 2.42 (s, 3H), 1.72ꢀ1.62 (m, 2H),
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1.53 (m, 1H), 1.44 (m, 1H), 1.28ꢀ1.17 (m, 2H), 1.07 (s, 9H); C NMR (CDCl3, 100 MHz): δ
144.6, 138.7, 135.7 (4C), 133.9 (2C), 133.2, 129.82, 129.79, 129.7 (2C), 128.4 (2C), 128.0 (2C),
127.73 (2C), 127.69 (2C), 127.6 (2C), 127.5, 73.0, 72.8, 69.4, 69.2, 66.8, 65.5, 38.6, 36.1, 34.6,
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27.0 (3C), 21.7, 19.3; MS (EI) m/z: 279 (6), 278 (38), 277 (100), 201 (12), 183 (14), 152 (12), 77
(Ph+, 26), 51 (15); HRMS (ESI): Calculated for C38H46O6SSiNa [M + Na]+: 681.2677, found:
681.2681.
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{(2S,4S,6S)ꢀ4ꢀ[(tertꢀButyldiphenylsilyl)oxy]ꢀ6ꢀ(2ꢀhydroxyethyl)tetrahydroꢀ2Hꢀpyranꢀ
2ꢀyl}methyl 4ꢀmethylbenzenesulfonate (5b): To a solution of benzyl alcohol 5a (454 mg, 0.688
mmol, 1.0 equiv) in a mixture of EtOAc (1.6 mL) and MeOH (4.9 mL) was added palladium on
activated charcoal (10% in weight, 36 mg, 0.034 mmol, 0.05 equiv). The medium was placed
under a hydrogen atmosphere (1 atm) and stirred for 16 h. The mixture was then replaced under
an argon atmosphere, filtered through a pad of Celite® and concentrated under vacuum. The crude
material was then purified by flash column chromatography on silica gel (petroleum ether/EtOAc
20
= 7:3) to afford the alcohol 5b (372 mg, 0.655 mmol, 95%) as a colorless gummy liquid. [α] D
− 3.0 (c 1.05, CHCl3); IR: ν 3529, 3071, 2930, 2858, 1598, 1472, 1427, 1360, 1189, 1176, 1104,
1068, 1039, 977, 946, 909, 887, 820 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ 7.79 (br d, J = 8.3 Hz,
2H), 7.63ꢀ7.60 (m, 4H), 7.46ꢀ7.41 (m, 2H), 7.40ꢀ7.35 (m, 4H), 7.33 (d, J = 8.3 Hz, 2H), 4.26ꢀ
4.19 (m, 2H), 4.13 (m, 1H), 3.98 (dd, J = 10.5 and J = 3.5 Hz, 1H), 3.91 (dd, J = 10.5 and J = 6.7
Hz, 1H), 3.80ꢀ3.70 (m, 2H), 2.57 (br s, 1H, OH), 2.44 (s, 3H), 1.68ꢀ1.55 (m, 2H), 1.50ꢀ1.41 (br
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tapp, J = 1.6 Hz, 2H), 1.34ꢀ1.23 (br qapp, J = 1.2 Hz, 2H), 1.07 (s, 9H); C NMR (CDCl3, 100
MHz): δ 144.9, 135.7 (4C), 133.7 (2C), 133.0, 129.90 (2C), 129.88 (2C), 127.9 (2C), 127.78
(2C), 127.74 (2C), 72.8, 72.4, 69.7, 65.2, 61.4, 38.4, 37.7, 34.3, 27.0 (3C), 21.7, 19.3; MS (EI)
m/z: 339 (17), 225 (10), 221 (21), 200 (20), 199 (100), 197 (13), 183 (20), 181 (15), 139 (16), 121
(10), 105 (10), 97 (38), 95 (20), 81 (14), 79 (16), 78 (13), 77 (28), 57 (12), 55 (10); HRMS (ESI):
Calculated for C31H40O6SSiNa [M + Na]+: 591.2207, found: 591.2204.
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{(2S,4S,6S)ꢀ4ꢀ[(tertꢀButyldiphenylsilyl)oxy]ꢀ6ꢀ(2ꢀoxoethyl)tetrahydroꢀ2Hꢀpyranꢀ2ꢀ
yl}methyl 4ꢀmethylbenzenesulfonate (7): To a solution of alcohol 5b (372 mg, 0.655 mmol, 1.0
equiv) in dry CH2Cl2 (3 mL) were added NMO (114 mg, 0.98 mmol, 1.5 equiv), molecular sieves
4Å (315 mg) and tetrapropylammonium perruthenate (11.4 mg, 0.033 mmol, 0.05 equiv). The
mixture was stirred at rt for 2 h, then filtered through a pad of silica, washed with EtOAc and
concentrated under vacuum. The crude material was then purified by flash column
chromatography on silica gel (petroleum ether/EtOAc = 8:2) to afford the aldehyde 7 (290 mg,
0.512 mmol, 78%) as a colorless gummy liquid. [α] D 20 + 2.7 (c 0.52, CHCl3); IR: ν 3071, 2970,
2930, 2858, 1725, 1598, 1472, 1427, 1360, 1189, 1176, 1105, 1075, 1037, 981, 909, 820 cmꢀ1; 1H
NMR (CDCl3, 400 MHz): δ 9.68 (t, J = 2.3 Hz, 1H), 7.76 (br d, J = 8.4 Hz, 2H), 7.61 (m, 4H),
7.47ꢀ7.35 (m, 6H), 7.32 (br d, J = 8.4 Hz, 2H), 4.42 (m, 1H), 4.25ꢀ4.17 (m, 2H), 3.98ꢀ3.89 (m,
2H), 2.44 (s, 3H), 2.41 (ddd, J = 16.4, J = 8.1 and J = 2.7 Hz, 1H), 2.32 (ddd, J = 16.4, J = 4.9
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and J = 2.0 Hz, 1H), 1.56ꢀ1.43 (m, 2H), 1.31ꢀ1.21 (br qapp, J = 1.3 Hz, 2H), 1.07 (s, 9H); C
NMR (CDCl3, 100 MHz): δ 201.2, 144.8, 135.7 (4C), 133.6 (2C), 133.0, 129.9 (2C), 129.8 (2C),
128.0 (2C), 127.8 (4C), 72.4, 69.7, 67.6, 65.1, 49.3, 38.1, 34.2, 27.0 (3C), 21.7, 19.3; HRMS
(ESI): Calculated for C31H38O6SSiNa [M + Na]+: 589.2051, found: 589.2049.
{(2S,4S,6S)ꢀ4ꢀ[(tertꢀButyldiphenylsilyl)oxy]ꢀ6ꢀ[((2R,6R)ꢀ4ꢀoxoꢀ6ꢀ
(tosyloxymethyl)tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)methyl]tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl}methyl
4ꢀ
methylbenzenesulfonate (8): To a solution of homoallylic alcohol entꢀ2 (387 mg, 1.51 mmol,
1.5 equiv) and aldehyde 7 (570 mg, 1.01 mmol, 1.0 equiv) in dry CH2Cl2 (8.5 mL) was added
dropwise TFA (1.96 mL, 26.2 mmol, 26 equiv). The mixture was stirred for 3 h at rt, and treated
with a saturated aqueous solution of NaHCO3 (15 mL). The pH was adjusted to a value pH > 7 by
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addition of Et3N and the resulting mixture was stirred at rt for an additional 2 h and then diluted
with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 20
mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and
concentrated under vacuum. The crude material was then purified by flash column
chromatography on silica gel (petroleum ether/EtOAc = 6:4 to 5:5) to afford the
tetrahydropyranyl alcohol as a mixture of diastereomers (cis/trans = 75:25, 456 mg, 0.556 mmol,
55%) and as a gummy liquid. To a solution of alcohols (mixture of diastereomers, 456 mg, 0.556
mmol, 1.0 equiv) in dry CH2Cl2 (6 mL) was added DessꢀMartin periodinane (470 mg, 1.11 mmol,
2.0 equiv). The mixture was stirred at rt for 2 h. Hexane was then added, the resulting precipitate
was filtered through a pad of Celite®. The filtrate was concentrated under vacuum and
purification of the crude material by flash column chromatography on silica gel (petroleum
ether/EtOAc = 7:3) afforded the corresponding ketone 8 (439 mg, 0.534 mmol, 96%) as a gummy
liquid. [α] D 20 + 3.3 (c 0.9, CHCl3); IR: ν 3028, 2930, 2858, 1722, 1599, 1495, 1454, 1428, 1361,
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1347, 1189, 1177, 1160, 1096, 1029, 981, 815 cmꢀ1; H NMR (CDCl3, 400 MHz): δ 7.80ꢀ7.75
(m, 4H), 7.62ꢀ7.56 (m, 4H), 7.46ꢀ7.30 (m, 10H), 4.21 (m, 1H), 4.11 (m, 1H), 4.06 (d, J = 4.6 Hz,
2H), 3.98 (m, 1H), 3.94 (d, J = 4.8 Hz, 2H), 3.78 (m, 1H), 3.66 (m, 1H), 2.43 (s, 3H), 2.42 (s,
3H), 2.40ꢀ2.30 (m, 3H), 2.22 (dd, J = 14.3 and J = 11.3 Hz, 1H), 1.77 (m, 1H), 1.48ꢀ1.39 (m,
3H), 1.30ꢀ1.17 (m, 2H), 1.04 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 205.4, 145.1, 144.8,
135.64 (2C), 135.61 (2C), 133.75, 133.72, 133.1, 132.7, 129.96 (2C), 129.92, 129.90, 129.86
(2C), 127.98 (2C), 127.93 (2C), 127.8 (4C), 73.84, 73.75, 72.5, 71.0, 69.6, 68.0, 65.3, 47.0, 43.3,
41.6, 38.3, 34.4, 27.0 (3C), 21.7 (2C), 19.2; HRMS (ESI): Calculated for C43H52O10S2SiNa [M +
Na]+: 843.2663, found: 843.2672.
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{(2S,4S,6S)ꢀ4ꢀ[(tertꢀButyldiphenylsilyl)oxy]ꢀ6ꢀ[((2S,4S,6R)ꢀ4ꢀhydroxyꢀ6ꢀ
5
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(tosyloxymethyl)ꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)methyl]tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl}methyl
4ꢀ
7
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methylbenzene sulfonate (9):17 To a solution of ketone 8 (424 mg, 0.516 mmol, 1.0 equiv) in
anhydrous MeOH (26.8 mL), cooled to −40 °C was added NaBH4 (40 mg, 1.04 mmol, 2.0 equiv).
The mixture was stirred at −40 °C for 1 h and then quenched by addition of H2O (20 mL). The
mixture was warmed to rt, MeOH was evaporated under vacuum and the residue diluted with
EtOAc (60 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 ×
40 mL). The combined organic layers were washed with brine (80 mL), dried over MgSO4,
filtered and concentrated under vacuum. The crude material was then purified by flash column
chromatography on silica gel (petroleum ether/EtOAc = 6:4) and the alcohol 9 (364 mg, 0.440
mmol, 86%) was isolated as a single diastereomer and as a colorless gummy liquid. [α] D 20 + 1.2
(c 2.3, CHCl3); IR: ν 3537, 3020, 2928, 2857, 1599, 1428, 1360, 1215, 1189, 1176, 1098, 1038,
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1020, 981, 815 cmꢀ1; H NMR (CDCl3, 400 MHz): δ 7.78 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.3
Hz, 2H), 7.62ꢀ7.56 (m, 4H), 7.46ꢀ7.28 (m, 10H), 4.19 (m, 1H), 4.13 (m, 1H), 4.03ꢀ3.89 (m, 5H),
3.77 (m, 1H), 3.53 (m, 1H), 3.38 (m, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 1.99ꢀ1.91 (m, 3H), 1.67 (m,
1H), 1.48ꢀ1.40 (m, 2H), 1.38ꢀ1.11 (m, 5H), 1.03 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 144.85,
144.81, 135.68 (2C), 135.63 (2C), 133.84, 133.78, 133.1, 132.9, 129.85 (6C), 128.0 (2C), 127.9
(2C), 127.76 (2C), 127.74 (2C), 72.83, 72.81, 72.5, 71.9, 69.7, 68.4, 67.5, 65.4, 41.4, 40.3, 38.3,
37.0, 34.5, 27.0 (3C), 21.7 (2C), 19.2; HRMS (ESI): Calculated for C43H54O10S2SiNa [M + Na]+:
845.2820, found: 845.2825.
(2S,4S,6R)ꢀ2ꢀ{[(2S,4S,6S)ꢀ4ꢀ(tertꢀButyldiphenylsilyl)oxyꢀ6ꢀ(iodomethyl)tetrahydroꢀ
2Hꢀpyranꢀ2ꢀyl]methyl}ꢀ6ꢀ(iodomethyl)tetrahydroꢀ2Hꢀpyranꢀ4ꢀol (10):17 To a solution of
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tosylated bisꢀtetrahydropyran 9 (351 mg, 0.426 mmol, 1.0 equiv) in pure acetone (7.5 mL) was
added NaI (639 mg, 4.26 mmol, 10 equiv). The mixture was heated at 120 °C under microwave
irradiation, in a sealed vial, for 2 h. H2O (4.5 mL) and EtOAc (4.5 mL) were then added. The
layers were separated, the aqueous layer was extracted with EtOAc (10 mL) and the combined
organic layers were dried over MgSO4, filtered and concentrated under vacuum. The crude
material was then purified by flash column chromatography on silica gel (petroleum ether/EtOAc
= 75:25) to afford the the bisꢀiodinated compound 10 (285 mg, 0.39 mmol, 91%) as a gummy
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liquid. [α] D − 9.7 (c 1.65, CHCl3); IR: ν 3385, 3070, 2927, 2856, 1589, 1471, 1427, 1362,
1185, 1106, 1080, 1036, 919 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ 7.66ꢀ7.61 (m, 4H), 7.46ꢀ7.35
(m, 6H), 4.22 (m, 1H), 4.14 (m, 1H), 3.96ꢀ3.84 (m, 2H), 3.62 (m, 1H), 3.36 (m, 1H), 3.21ꢀ3.09
(m, 4H), 2.22 (m, 1H), 2.06 (m, 1H), 1.91 (m, 1H), 1.76 (m, 1H), 1.66 (br s, 1H, OH), 1.55ꢀ1.47
(m, 2H), 1.34ꢀ1.15 (m, 4H), 1.09 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 135.7 (4C), 133.9
(2C), 129.8 (2C), 127.7 (4C), 75.0, 72.7, 71.8, 69.1, 67.9, 66.0, 41.5, 40.8, 40.1, 38.7, 38.5, 27.1
(3C), 19.3, 10.4, 8.8; HRMS (ESI): Calculated for C29H40I2O4SiNa [M + Na]+: 757.0677, found:
757.0679.
(2R,4S,6R)ꢀ2ꢀ{[(2S,4S,6S)ꢀ4ꢀ(tertꢀButyldiphenylsilyl)oxyꢀ6ꢀ(iodomethyl)tetrahydroꢀ
2Hꢀpyranꢀ2ꢀyl]methyl}ꢀ6ꢀ(iodomethyl)tetrahydroꢀ2Hꢀpyranꢀ4ꢀyl acrylate (11): To a solution
of alcohol 10 (285 mg, 0.388 mmol, 1.0 equiv) in dry CH2Cl2 (5.4 mL) cooled to 0 °C were
added diisopropylethylamine (0.38 mL, 2.30 mmol, 5.9 equiv) and acryloyl chloride (0.090 mL,
1.11 mmol, 2.9 equiv) dropwise. The mixture was warmed to rt and stirred for 3.5 h. The reaction
was quenched by addition of H2O (5 mL). The layers were separated and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over MgSO4,
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filtered and concentrated under vacuum. The crude material was then purified by flash column
chromatography on silica gel (petroleum ether/EtOAc = 90:10) to afford the protected bisꢀ
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tetrahydropyran 11 (295 mg, 0.374 mmol, 96%) as a colorless very viscous liquid. [α] D − 5.6
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(c 0.33, CHCl3); IR: ν 2954, 2928, 2856, 1725, 1619, 1471, 1428, 1406, 1361, 1297, 1255, 1189,
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1158, 1107, 1083, 1050, 1003, 836 cmꢀ1; H NMR (CDCl3, 400 MHz): δ 7.68ꢀ7.62 (m, 4H),
7.47ꢀ7.36 (m, 6H), 6.43 (dd, J = 17.3 and J = 1.4 Hz, 1H), 6.12 (dd, J = 17.3 and J = 10.4 Hz,
1H), 5.85 (dd, J = 10.4 and J = 1.4 Hz, 1H), 5.05 (m, 1H), 4.23 (m, 1H), 4.16 (m, 1H), 3.94 (m,
1H), 3.66 (m, 1H), 3.41 (dtd, J = 11.1, J = 5.7 and J = 1.9 Hz, 1H), 3.17 (d, J = 5.7 Hz, 2H), 3.14
(d, J = 5.9 Hz, 2H), 2.29 (br d, J = 12.2 Hz, 1H), 2.05 (br d, J = 12.3 Hz, 1H), 1.91 (quintapp,
J = 7.1 Hz, 1H), 1.78 (m, 1H), 1.58ꢀ1.48 (m, 2H), 1.46ꢀ1.21 (m, 4H), 1.09 (s, 9H); 13C NMR
(CDCl3, 100 MHz): δ 165.5, 135.76 (2C), 135.72 (2C), 133.94, 133.93, 131.0, 129.8 (2C), 128.6,
127.75 (2C), 127.74 (2C), 74.6, 72.5, 71.7, 70.1, 69.0, 66.0, 41.6, 38.7, 38.4, 37.1, 36.5, 27.1
(3C), 19.4, 10.3, 8.5; HRMS (ESI): Calculated for C32H42I2O5SiNa [M + Na]+: 811.0783, found:
811.0782.
(4R,6R,8S,10R)ꢀ10ꢀ(tertꢀButyldiphenylsilyl)oxyꢀ6,8ꢀdihydroxytridecaꢀ1,12ꢀdienꢀ4ꢀyl
acrylate (12): To a solution of iodinated bisꢀtetrahydropyran 11 (290 mg, 0.368 mmol, 1.0 equiv)
in a mixture of THF (10 mL) and H2O (2.5 mL) was added activated zinc (722 mg, 11.04 mmol,
30 equiv). The mixture was heated at 70 °C in a sealed vial for 1 h, and was then filtered through
a pad of Celite®. The layers were separated and the aqueous layer was extracted with EtOAc (3 ×
15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under
vacuum. The crude material was purified by flash column chromatography on silica gel
(petroleum ether/EtOAc = 80:20) to afford the protected tetraol 12 (174 mg, 0.324 mmol, 88%)
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as a colorless oil. [α] D 20 − 27.6 (c 1.1, CHCl3); IR: ν 3429, 3073, 2932, 2857, 1721, 1639, 1472,
1428, 1407, 1362, 1296, 1199, 1110, 1079, 997, 917 cmꢀ1; 1H NMR (CDCl3, 400 MHz): δ 7.70ꢀ
7.64 (m, 4H), 7.45ꢀ7.33 (m, 6H), 6.47 (br d, J = 17.3 Hz, 1H), 6.16 (dd, J = 17.3 Hz, J = 10.4 Hz,
1H), 5.90 (br d, J = 10.4 Hz, 1H), 5.76 (m, 1H), 5.64 (m, 1H), 5.17 (m, 1H), 5.10 (br d, J = 18.0
Hz, 1H), 5.09 (br d, J = 9.7 Hz, 1H), 4.93 (br d, J = 10.2 Hz, 1H), 4.85 (br d, J = 17.2 Hz, 1H),
3.98ꢀ3.89 (m, 3H), 3.76 (br s, 1H), 3.62 (br tapp, J = 9.5 Hz, 1H), 2.37 (br tapp, J = 6.2 Hz, 2H),
2.25ꢀ2.12 (m, 2H), 1.67 (m, 1H), 1.60ꢀ1.48 (m, 3H), 1.39 (m, 1H), 1.28 (m, 1H), 1.04 (s, 9H); 13C
NMR (CDCl3, 100 MHz): δ 167.1, 135.92 (2C), 135.90 (2C), 134.3, 134.2, 133.8, 133.3, 131.7,
129.8, 129.7, 128.2, 127.7 (2C), 127.5 (2C), 118.1, 117.4, 71.8, 70.7, 70.2, 68.2, 43.6, 42.9, 42.6,
41.7, 39.2, 27.0 (3C), 19.3; HRMS (ESI): Calculated for C32H44O5SiNa [M + Na]+: 559.2850,
found: 559.2847.
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Synthesis of 13
(4R,6S,8S,10R)ꢀ6,8ꢀbis[(tertꢀButyldimethylsilyl)oxy]ꢀ10ꢀ(tertꢀbutyldiphenylsilyl)oxy
tridecaꢀ1,12ꢀdienꢀ4ꢀyl acrylate (12a): To a solution of diol 12 (98 mg, 0.18 mmol, 1.0 equiv) in
CH2Cl2 (4.4 mL) cooled to ꢀ78 °C were added 2,6ꢀlutidine (0.13 mL, 1.1 mmol, 6.1 equiv) and
then TBSOTf (0.17 mL, 0.74 mmol, 4.0 equiv). The mixture was stirred at ꢀ78 °C and after 1 h,
the reaction was quenched by addition of H2O (4 mL) and the mixture was warmed to rt. The
layers were separated and the aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The
crude material was purified by flash column chromatography on silica gel (petroleum
ether/EtOAc = 98:2) to afford the protected tetraol 12a (130 mg, 0.170 mmol, 93%) as a colorless
oil. [α] D 20 − 35.2 (c 1.2, CHCl3); IR: ν 3073, 2954, 2929, 2894, 2857, 1724, 1639, 1472, 1463,
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1428, 1406, 1383, 1361, 1296, 1256, 1193, 1111, 1064, 1004, 984, 917, 836 cmꢀ1; H NMR
(CDCl3, 400 MHz): δ 7.72ꢀ7.66 (m, 4H), 7.46ꢀ7.34 (m, 6H), 6.39 (dd, J = 17.3 and J = 1.5 Hz,
1H), 6.09 (dd, J = 17.3 and J = 10.4 Hz, 1H), 5.78 (dd, J = 10.4 and J = 1.5 Hz, 1H), 5.75 (m,
1H), 5.62 (m, 1H), 5.11ꢀ5.03 (m, 3H), 4.93 (dd, J = 10.2 and J = 2.0 Hz, 1H), 4.84 (dd, J = 17.1
and J = 2.0 Hz, 1H), 3.93ꢀ3.75 (m, 3H), 2.42ꢀ2.28 (m, 2H), 2.20ꢀ2.08 (m, 2H), 1.83 (ddd, J =
14.2, J = 10.1 and J = 2.3 Hz, 1H), 1.74 (m, 1H), 1.66ꢀ1.52 (m, 2H), 1.47ꢀ1.37 (m, 2H), 1.07 (s,
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9H), 0.87 (s, 9H), 0.86 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H), ꢀ0.01 (s, 3H), ꢀ0.04 (s, 3H); C NMR
(CDCl3, 100 MHz): δ 165.8, 135.91 (2C), 135.85 (2C), 134.4, 134.0 (2C), 133.5, 130.3, 129.7,
129.6, 128.9, 127.7 (2C), 127.5 (2C), 117.8, 117.2, 70.9, 70.6, 66.8, 65.8, 46.2, 45.1, 41.8, 40.8,
39.1, 27.1 (3C), 25.9 (6C), 19.4, 17.93, 17.90, ꢀ3.96, ꢀ4.01, ꢀ4.2, ꢀ4.9; HRMS (ESI): Calculated
for C44H72O5Si3Na [M + Na]+: 787.4580, found: 787.4586.
(R)ꢀ6ꢀ[(2S,4S,6R)ꢀ2,4ꢀbis(tertꢀButyldimethylsilyloxy)ꢀ6ꢀ(tertꢀ
butyldiphenylsilyloxy)nonꢀ8ꢀenꢀ1ꢀyl)ꢀ5,6ꢀdihydroꢀ2Hꢀpyranꢀ2ꢀone (13): To a solution of
diene 12a (127 mg, 0.166 mmol, 1.0 equiv) in CH2Cl2 (17 mL) was added the 1st generation
Grubbs catalyst (14 mg, 0.017 mmol, 0.1 equiv). The mixture was heated at reflux for 3 h. The
reaction mixture was then cooled to rt and concentrated under vacuum. The crude material was
purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 93:7) to afford
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the unsaturated lactone 13 (117 mg, 0.159 mmol, 96%) as a brown oil. [α] D − 19.8 (c 1.3,
CHCl3); IR: ν 3073, 3017, 2953, 2930, 2893, 2857, 1722, 1472, 1463, 1428, 1387, 1252, 1217,
1110, 1059, 1004, 917, 836, 823 cmꢀ1; H NMR (CDCl3, 400 MHz): δ 7.70ꢀ7.65 (m, 4H), 7.45ꢀ
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7.32 (m, 6H), 6.85 (ddd, J = 9.6, J = 5.5 and J = 2.5 Hz, 1H), 6.01 (br dd, J = 9.7 and J = 1.6 Hz,
1H), 5.65 (ddt, J = 17.3, J = 10.2 and J = 7.0 Hz, 1H), 4.96 (dd, J = 10.2 and J = 1.9 Hz, 1H),
4.85 (dd, J = 17.1 and J = 1.7 Hz, 1H), 4.53 (m, 1H), 4.10 (m, 1H), 3.88 (m, 1H), 3.82 (m, 1H),
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2.27ꢀ2.04 (m, 4H), 1.91 (ddd, J = 14.0, J = 9.8 and J = 2.3 Hz, 1H), 1.80ꢀ1.53 (m, 3H), 1.45ꢀ1.37
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(m, 2H), 1.05 (s, 9H), 0.85 (s, 18H), 0.08 (s, 3H), 0.04 (s, 6H), 0.03 (s, 3H); C NMR (CDCl3,
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100 MHz): δ 164.0, 144.9, 135.91 (2C), 135.88 (2C), 134.4, 134.34, 134.25, 129.6 (2C), 127.6
(2C), 127.5 (2C), 121.7, 117.3, 74.2, 70.6, 66.6, 65.0, 46.0, 44.8, 42.4, 41.7, 30.1, 27.1 (3C), 25.9
(6C), 19.4, 18.0, 17.9, ꢀ4.2 (2C), ꢀ4.7 (2C); HRMS (ESI): Calculated for C42H68O5Si3Na [M +
Na]+: 759.4267, found: 759.4272.
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(4R,6S,8S,10R)ꢀ10ꢀ[(tertꢀButyldiphenylsilyl)oxy]tridecaꢀ1,12ꢀdieneꢀ4,6,8ꢀtriol (12’):17
To a solution iodinated bisꢀtetrahydropyran 10 (32 mg, 0.044 mmol, 1.0 equiv) in pure ethanol (1
mL) were added activated zinc (86 mg, 1.31 mmol, 30 equiv) and NH4Cl (23.5 mg, 0.44 mmol,
10 equiv). The mixture was heated at 90 °C in a sealed vial for 4 h, then diluted with EtOAc,
filtered through a pad of Celite® and concentrated under vacuum. The crude material was then
purified by column chromatography on silica gel (petroleum ether/EtOAc = 7:3 to 65:35) to
afford the tetraol 12’ (16 mg, 0.033 mmol, 76%) as a colorless oil. [α] D 20 − 25.2 (c 0.75, CHCl3);
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IR: ν 3358, 3072, 2932, 2857, 1641, 1428, 1362, 1110, 1090, 998, 915, 822 cmꢀ1; H NMR
(CDCl3, 400 MHz): δ 7.73ꢀ7.68 (m, 4H), 7.48ꢀ7.36 (m, 6H), 5.83 (m, 1H), 5.54 (m, 1H), 5.16ꢀ
5.08 (m, 2H), 4.92 (dapp, 1H, J = 10.2 Hz), 4.80 (dapp, 1H, J = 17.3 Hz), 4.15 (m, 1H), 4.06 (m,
1H), 4.00ꢀ3.93 (m, 2H), 2.32ꢀ2.21 (m, 2H), 2.13 (tapp, 2H, J = 6.6 Hz), 1.73ꢀ1.53 (m, 5H), 1.35
13
(m, 1H), 1.05 (s, 9H); C NMR (CDCl3, 100 MHz): δ 135.88 (2C), 135.86 (2C), 134.9, 133.9,
133.3 (2C), 130.0, 129.8, 127.8 (2C), 127.6 (2C), 117.74, 117.67, 73.1, 71.8, 70.4, 68.1, 43.5,
13
42.9, 42.12, 42.08, 42.06, 27.0 (3C), 19.3; C NMR (CD3OD, 100 MHz): δ 137.12 (2C), 137.09
(2C), 136.3, 135.8, 135.5, 135.3, 130.9 (2C), 128.8 (2C), 128.7 (2C), 117.7, 117.4, 72.0, 68.61,
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68.55, 68.3, 45.6, 45.4, 44.8, 43.8, 42.3, 27.7 (3C), 20.2; HRMS (ESI): Calculated for
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C29H42O4SiNa [M + Na]+: 505.2745, found: 505.2742.
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(3S,5S,7S)ꢀ5,7ꢀbis(tertꢀButyldimethylsilyloxy)ꢀ3ꢀ(tertꢀbutyldiphenylsilyloxy)ꢀ8ꢀ((2R)ꢀ
6ꢀoxoꢀ3,6ꢀdihydroꢀ2Hꢀpyranꢀ2ꢀyl)octanal (14): A solution of alkene 13 (92.0 mg, 0.125 mmol,
1.0 equiv) in CH2Cl2 (6.1 mL) was cooled to ꢀ78 °C. Ozone was bubbled through the solution
and the reaction was monitored by TLC to prevent the ozonolysis of the α,βꢀunsaturated ester
double bond. After completion of the reaction, oxygen and then argon were bubbled through the
solution. PPh3 (50 mg, 0.19 mmol, 1.5 equiv) was then added and the solution was progressively
warmed to rt overnight. The reaction mixture was dried over MgSO4, filtered and concentrated
under vacuum. The crude material was purified by flash column chromatography on silica gel
(petroleum ether/EtOAc = 93:7 to 9:1) to afford the aldehyde 14 (74 mg, 0.10 mmol, 80%) as a
colorless viscous liquid. [α] D 20 − 3.6 (c 1.0, CHCl3); IR: ν 3072, 2954, 2930, 2894, 2857, 2712,
1726, 1590, 1472, 1463, 1428, 1388, 1362, 1253, 1110, 1063, 1024, 1005, 937, 836, 824 cmꢀ1; 1H
NMR (CDCl3, 400 MHz): δ 9.67 (dd, J = 3.1 Hz, J = 1.7 Hz, 1H), 7.69ꢀ7.64 (m, 4H), 7.46ꢀ7.34
(m, 6H), 6.86 (m, 1H), 6.01 (m, 1H), 4.50 (m, 1H), 4.37 (quint, J = 6.0 Hz, 1H), 4.03 (m, 1H),
3.80 (quint, J = 6.0 Hz, 1H), 2.55 (ddd, J = 15.8 Hz, J = 5.2 Hz, J = 1.6 Hz, 1H), 2.43 (ddd, J =
15.8 Hz, J = 5.6 Hz, J = 3.2 Hz, 1H), 2.28ꢀ2.20 (m, 2H), 1.87ꢀ1.74 (m, 3H), 1.60 (ddd, J = 14.0, J
= 6.9 and J = 4.4 Hz, 1H), 1.48ꢀ1.34 (m, 2H), 1.04 (s, 9H), 0.85 (s, 9H), 0.81 (s, 9H), 0.04 (s,
3H), 0.03 (s, 6H), ꢀ0.03 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 202.0, 164.0, 145.0, 135.9 (4C),
133.7, 133.5, 130.0, 129.9, 127.8 (2C), 127.7 (2C), 121.6, 74.3, 66.9, 66.3, 64.9, 50.3, 45.8, 45.3,
42.4, 30.1, 27.0 (3C), 25.89 (3C), 25.85 (3C), 19.3, 18.0, 17.9, ꢀ4.16 (2C), ꢀ4.24, ꢀ4.7; HRMS
(ESI): Calculated for C41H66O6Si3Na [M + Na]+: 761.4059, found: 761.4065.
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(R)ꢀ6ꢀ{(2S,4S,6R,8R,10S)ꢀ2,4ꢀbis[(tertꢀButyldimethylsilyl)oxy]ꢀ6ꢀ[(tertꢀ
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9
butyldiphenylsilyl)oxy]ꢀ8,10ꢀdihydroxypentacosyl}ꢀ5,6ꢀdihydroꢀ2Hꢀpyranꢀ2ꢀone (16): To a
solution of heptadecanꢀ2ꢀone (18.8 mg, 0.0739 mmol, 1.3 equiv) in freshly distilled pentane (0.5
mL), cooled to 0 °C, were added Et3N (24 µL, 0.17 mmol, 3.0 equiv) and
chlorodicyclohexylborane (0.15 mL, 1M in hexanes, 0.15 mmol, 2.6 equiv). The mixture was
stirred at 0 °C for 2 h and then cooled to ꢀ78 °C. A solution of aldehyde 14 (41 mg, 0.055 mmol,
1.0 equiv) in pentane (1 mL) was then added and the mixture was stirred at ꢀ78 °C and
progressively warmed to ꢀ40 °C. After 4 h at ꢀ40 °C, the reaction was quenched by the addition of
a mixture of MeOH/pH = 7 buffer/35% aqueous H2O2 = 1:1:1 (1.5 mL) and the solution was
progressively warmed to rt overnight. A saturated aqueous Na2S2O3 solution (1.5 mL) was then
added dropwise and the mixture was stirred for 30 min. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried
over MgSO4, filtered and concentrated under vacuum. The crude material was purified by flash
column chromatography on silica gel (petroleum ether/EtOAc = 95:5 to 9:1) to afford a fraction
containing the hydroxyketone as a mixture of diastereomers 15 and 15’, accompanied with the
inseparable residual aldehyde 14 and as a colorless liquid. This mixture was then dissolved in
CH3CN (1.6 mL) and glacial acetic acid (1.6 mL) was added. The solution was cooled to ꢀ20 °C
and Me4NBH(OAc)3 (80 mg, 0.305 mmol, 10 equiv) was added. The reaction mixture was stirred
at ꢀ20 °C for 7 h and then quenched by the addition of a saturated aqueous NaHCO3 solution (5
mL) dropwise. After stirring for 1 h, the mixture was diluted with EtOAc, the layers were
separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with a saturated aqueous NaHCO3 solution (2 × 10 mL), then with brine (10
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mL), dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified
by flash column chromatography on silica gel (petroleum ether/EtOAc = 9:1 to 8:2) to afford the
diol (20 mg, 0.020 mmol, 37%) as a mixture of diastereomers 16 and 16’ in a 75:25 ratio in favor
of the desired syn,antiꢀisomer and as a colorless oil. IR (mixture of diastereomers): ν 3446, 2926,
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2855, 1715, 1471, 1428, 1388, 1361, 1254, 1108, 1059, 1004, 908, 836, 824 cmꢀ1; H NMR
(CDCl3, 400 MHz, syn major diastereomer): δ 7.73ꢀ7.66 (m, 4H), 7.44ꢀ7.34 (m, 6H), 6.87 (ddd, J
= 9.4, J = 5.4 and J = 2.9 Hz, 1H), 6.00 (br d, J = 9.9 Hz, 1H), 4.50 (m, 1H), 4.25 (m, 1H), 4.08ꢀ
3.93 (m, 3H), 3.80 (m, 1H), 3.18 (br s, 1H, OH), 3.05 (br s, 1H, OH), 2.27ꢀ2.18 (m, 2H), 2.13 (m,
1H), 1.82ꢀ1.54 (m, 4H), 1.53ꢀ1.20 (m, 33H), 1.03 (s, 9H), 0.88 (t, J = 6.6 Hz, 3H), 0.84 (s, 18H),
0.02 (s, 3H), 0.00 (s, 3H), ꢀ0.02 (s, 6H); 13C NMR (CDCl3, 100 MHz, syn major diastereomer): δ
164.8, 145.7, 135.8 (4C), 134.4, 134.3, 129.7 (2C), 127.7 (4C), 121.3, 74.7, 70.8, 68.2, 67.0,
66.7, 64.8, 44.0 (2C), 43.9, 43.8, 42.7, 37.6, 31.9, 29.9, 29.7 (9C), 29.4, 27.0 (3C), 25.9 (6C),
25.8, 22.7, 19.4, 17.91, 17.87, 14.2, ꢀ4.2, ꢀ4.5 (2C), ꢀ4.8; HRMS (ESI): Calculated for
C58H102O7Si3Na [M + Na]+: 1017.6826, found: 1017.6811.
(+)ꢀCryptocaryol A: To a solution of diols 16 and 16’ (mixture of diastereomers, 19 mg,
0.019 mmol, 1 equiv) in dry MeCN (0.8 mL) stirred at rt was added HF (48% aqueous solution,
0.080 mL, 0.19 mmol, 100 equiv) dropwise. The mixture was stirred at rt for 2.5 h, a saturated
aqueous NaHCO3 solution (1 mL) was added dropwise and the solution was stirred for 30 min.
The mixture was diluted with CH2Cl2 (5 mL), the layers were separated and the aqueous layer
was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried over Na2SO4,
filtered and concentrated under vacuum. The crude material was purified by preparative TLC
(CH2Cl2/MeOH = 9:1) to afford pure (+)ꢀcryptocaryol A (5 mg, 9.5 µmol, 50%) as a white
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amorphous solid. The spectral data are in agreement with those reported in the literature.14,15,16
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[α] D 20 + 15 (c 0.2, MeOH); [α] D litt + 14 (c 0.2, MeOH);14 IR: ν 3401, 2917, 2850, 1721, 1596,
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1456, 1410, 1265, 1136, 1097, 1018, 843 cmꢀ1; H NMR (CD3OD, 400 MHz): δ 7.05 (ddd, J =
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9.8, J = 6.0 and J = 2.7 Hz, 1H), 5.98 (br d, J = 9.8 Hz, 1H), 4.72 (m, 1H), 4.09 (m, 1H), 4.05ꢀ
3.95 (m, 3H), 3.81 (m, 1H), 2.50ꢀ2.32 (m, 2H), 1.95 (ddd, J = 14.4, J = 9.9 and J = 2.4 Hz, 1H),
1.73ꢀ1.54 (m, 7H), 1.52 (tapp, J = 6.0 Hz, 2H), 1.47ꢀ1.41 (m, 2H), 1.35ꢀ1.28 (m, 26H), 0.90 (t, J =
13
6.9 Hz, 3H), OH not visible; C NMR (CD3OD, 100 MHz): δ 166.9, 148.5, 121.4, 76.6, 70.1,
69.9, 69.1, 68.2, 66.5, 46.0, 45.9, 45.7, 45.2, 43.8, 39.2, 33.1, 30.9, 30.8 (9C), 30.5, 26.8, 23.7,
14.4; HRMS (ESI): Calculated for C30H56O7Na [M + Na]+: 551.3918, found: 551.3913.
ACKNOWLEDGMENTS
The authors thank the Ministère de l’Enseignement Supérieur et de la Recherche for funding.
SUPPORTING INFORMATION
1
Copies of H and 13C NMR spectra for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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20 G. Sabitha, N. M. Reddy, M. N. Prasad, and J. S. Yadav, Helv. Chim. Acta, 2009, 92, 967–976.
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(R)ꢀHomoallylic alcohol entꢀ2 was synthesized from (S)ꢀglycidol using the same strategy
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All attempts to improve the diastereoselectivity of the aldol reaction using chiral boron
enolates were unsuccessful. The desired product could not be detected and only the starting
aldehyde was recovered.
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