Enantiodivergent synthesis of (+)- and (-)-isolaurepan

Article abstract of DOI:10.1016/j.tet.2012.08.094

The enantiodivergent synthesis of (+)-and (-)-isolaurepan was achieved from a common chiral template easily available from tri-O-acetyl-d-glucal, using as key step a diastereoselective thermal Claisen rearrangement, combined with a ring expansion reaction using trimethylsilyldiazomethane.

Full text of DOI:10.1016/j.tet.2012.08.094

Tetrahedron 68 (2012) 8994e9003
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Tetrahedron
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Enantiodivergent synthesis of (þ)- and (ꢀ)-isolaurepan
Gonzalo Pazos, Manuel Perez, Zoila Gandara, Generosa Gomez , Yagamare Fall
*
*
ꢀ
ꢀ
ꢀ
ꢀ
Departamento de Química Organica, Facultad de Química, Universidad de Vigo, 36200 Vigo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2012
Received in revised form 21 June 2012
Accepted 29 August 2012
Available online 4 September 2012
The enantiodivergent synthesis of (þ)-and (ꢀ)-isolaurepan was achieved from a common chiral template
easily available from tri-O-acetyl- -glucal, using as key step a diastereoselective thermal Claisen re-
arrangement, combined with a ring expansion reaction using trimethylsilyldiazomethane.
Ó 2012 Elsevier Ltd. All rights reserved.
D
Keywords:
Marine toxins
Enantioselective synthesis
Claisen rearrangement
2,6-syn-Disubstituted tetrahydropyrans
1. Introduction
synthetic targets. (þ)-Isolaurepan (3) and (ꢀ)-isolaurepan (4) are
fully saturated analogues of 1 and 2, respectively, and of other chiral
oxepene and oxepane derivatives.5
A large number of marine natural products contain a medium
ring ether in their structures and present a wide range of biological
activities.1 The synthesis of these unique structures constitutes
Several reports of the stereoselective construction of racemic
cis-2,7-disubstituted oxepanes have appeared,2e,6 but there are
very few syntheses of nonracemic species such as (þ)-isolaurepan7
and only one for the synthesis of (ꢀ)-isolaurepan.8
a
considerable challenge for organic chemists.2 (þ)-Iso-
laurepinnacin (1)3 and (þ)-neoisoprelaurefucin (2),4 which were
both isolated from species of the genus Laurencia and contain a 2,7-
disubstituted oxepane core (Fig.1), have received much attention as
The work proposed in this paper is part of the overall objective
of our research group directed toward the synthesis of ether rings
as components of a large number of natural products.9 In a pre-
liminary communication we reported an enantioselective synthesis
of (þ)-isolaurepan.10
2. Results and discussion
In this paper, we describe the enantioselective synthesis of
(þ)-isolaurepan and (ꢀ)-isolaurepan, both obtained from com-
mercially available tri-O-acetyl- -glucal (5) (Scheme 1). Our syn-
D
thetic strategy is based in the intermediate 2,6-cis-disubstituted
tetrahydropyran 6, obtained through a thermal Claisen rearrange-
ment.11 From this compound and following analogues synthetic
route were afforded oxepanes 7 and 8 by ring expansion with tri-
methylsilyldiazomethane.12 A subsequent WolfeKishner reaction
and side chain manipulation afforded (þ)-isolaurepan (3) and
(ꢀ)-isolaurepan (4).
Fig. 1. Structures of representative Laurencia acetogenin metabolites.
2.1. Synthesis of (D)-isolaurepan
The procedure started with the synthesis of compound 9, fol-
* Corresponding author. Fax: þ34 986 81 22 62; e-mail addresses: ggomez@
lowing the procedure described by Mori and Hayashi,13 in two steps
ꢀ
uvigo.es (G. Gomez), yagamare@uvigo.es (Y. Fall).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.08.094

G. Pazos et al. / Tetrahedron 68 (2012) 8994e9003
8995
compound was successfully obtained by two alternative routes,
which differed in the catalyst used. Thus, the reaction of allylic al-
cohol 9 with ethyl vinyl ether gave enolether 12 in 80% and 72%
17
yields by catalysis with Hg(OAc)2 or Pd(OAc)2,18 respectively.
Following purification by column chromatography, compound 12
underwent a Claisen rearrangement when heated in toluene at
185 ꢁC, giving aldehyde 6 in 95% yield.
NMR spectroscopy confirmed the presence of single di-
astereoisomer as a reaction product. The high stereoselectivity
obtained can be explained by conformational effects of the ring
substituents in equatorial position. The stereochemistry of 6 was
confirmed by NOE experiments (Scheme 3).
Scheme 3. NOE-NMR of aldehyde 6.
With aldehyde 6 in hand, we addressed the transformation of its
side chains and the expansion of its ring (Scheme 4).
Wittig reaction over 6 afforded an 80% yield of diene 13, which
upon hydrogenation on Pd/C gave 14 in nearly quantitative yield.
Removal of the silyl protecting group of 14, followed by selective
protection of the primary alcohol provided alcohol 15, which was
converted into ketone 16 in 80% yield. The crucial oxepane for-
mation was accomplished by reaction of 16 with trimethylsi-
lyldiazomethane in the presence of BF3$OEt2 in CH2Cl2 at ꢀ78 ꢁC,
which gave the seven-membered ketone 7 in 60%. In this reaction
was also isolated 8% of its isomeric ketone after acidic hydrolysis of
the intermediary trimethylsilyl enolether. WolfeKishner reaction
of 7 afforded oxepane 17 in 58% yield.19 Removal of the silyl pro-
tecting group of 17 with TBAF gave the known alcohol 18,7a,c which
was transformed into alkyne 19 by alkylation of the corresponding
triflate. Finally, alkyne 19 was uneventfully converted into the
Scheme 1. Retrosynthetic analysis.
from 514 in 85% yield (Scheme 2). This compound presents a latent
allylic alcohol, which underwent a thermal Claisen rearrangement.
The preparation of aldehyde 6 from allylic alcohol 9 via ester 11 was
at first frustrated, by the yield of 11 being only 30% when obtained
by Johnson rearrangement.15 The Eschenmoser [3,3]-sigmatropic
rearrangement of alcohol 9 to amide 1016 was also unsuccessful,
recovering only part of the starting material without conversion.
As the Johnson orthoester rearrangement and the Eschenmoser
variant involve the in situ generation of an allyl vinyl ether, we
decided to change our strategy and use the classical Claisen rear-
rangement, by previous preparation of allyl vinyl ether 12. This
Scheme 2. Reagents and conditions: (a) i. K2CO3, MeOH; ii. tBu2Si(OTf)2, DMF, Py; (b) MeC(OMe)3, TMBA, 160 ꢁC; (c) MeC(OMe)2NMe2, toluene, 120 ꢁC; (d) ethyl vinyl ether,
Hg(OAc)2, 65 ꢁC; (e) ethyl vinyl ether, Pd(OAc)2, Bipy, CF3CO2H, Et3N, 80 ꢁC; (f) toluene, 185 ꢁC, 5 h.

8996
G. Pazos et al. / Tetrahedron 68 (2012) 8994e9003
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
O
O
O
O
O
Si
O
S
O
(a)
Si
O
i
O
Si
O
(a)
O
13
82%
O
20
H
O
H
O
80%
6
6
(b)
(b)
99%
94%
t-Bu
t-Bu
t-Bu
t-Bu
OH
OH
O
O
Si
O
Si
O
(c)
(c)
OTBDPS
OTBDPS
OTBDPS
n-Hex
O
15
n-Pr
O
22
n-Hex
O
14
O
21
82%
92%
(d)
80% (d)
82%
O
O
O
O
(e)
(e)
60%
OTBDPS
OTBDPS
OTBDPS
OH
O
8
n-Pr
55%
OTBDPS
OTBDPS
66%
n-Pr
n-Pr
O
23
O
7
n-Hex
n-Hex
O
16
(f)
58% (f)
(g)
(g)
95%
O
25
O
24
96%
n-Pr
OH
O
17
O
18
n-Hex
n-Hex
(h)
64%
(h)
76%
(i)
O
4
O
26
n-Pr
n-Pr
(i)
79%
TMS
96%
O
3
n-Hex
O
19
n-Hex
Scheme 5. Reagents and conditions: (a) n-MePPh3Br, n-BuLi, THF, 0 ꢁC; (b) H2, Pd/C
(10%), MeOH; (c) i. TBAF, THF, rt; ii. TBDPSCl, imidazole, DMAP, DMF; (d) TPAP, NMO,
CH2Cl2, molecular sieves; (e) i. TMSCHN2, BF3$OEt2, CH2Cl2, ꢀ78 ꢁC; ii. PPTS, MeOH; (f)
i. NH2NHTs, MeOH, 70 ꢁC, molecular sieves; ii. NaBH3CN, DMF, 130 ꢁC; (g) TBAF, THF;
(h) i. (COCl)2, DMSO, Et3N, CH2Cl2; ii. n-C5H11PPh3I, n-BuLi, THF, 0 ꢁC; (i) H2, Pd/C (10%),
MeOH.
Scheme 4. Reagents and conditions: (a) n-BuPPh3Br, n-BuLi, THF, 0 ꢁC; (b) H2, Pd/C
(10%), MeOH; (c) i. TBAF, THF, rt; ii. TBDPSCl, imidazole, DMAP, DMF; (d) TPAP, NMO,
CH2Cl2, molecular sieves; (e) (i) TMSCHN2, BF3$OEt2, CH2Cl2, ꢀ78 ꢁC; ii. PPTS, MeOH;
(f) i. NH2NHTs, MeOH, 70 ꢁC, molecular sieves; ii. NaBH3CN, DMF, 130 ꢁC; (g) TBAF, THF;
(h) i. Tf2O, CH2Cl2, Py, ꢀ15 ꢁC; ii. TMSCCH, n-BuLi, THF/DMPU, 0 ꢁC; (i) i. TBAF, THF; ii.
H2, Pd/C (10%), MeOH.
commercially available tri-O-acetyl- -glucal (5). Furthermore, in-
D
termediate 6 is a valuable building block that will allow us to ex-
tend our work on racemic polyoxacyclic compounds20 to the
enantioselective synthesis of polyoxacycles with transecisetrans
stereochemistry, present in several natural products.
target (þ)-isolaurepan 3 in 79% yield. All attempts to obtain 3 di-
rectly from alcohol 18 by the method described in the literature7a
were unsuccessful.
2.2. Synthesis of (L)-isolaurepan
4. Experimental
(ꢀ)-Isolaurepan was obtained from aldehyde 6 by a synthetic
sequence similar to that used for the synthesis of (þ)-isolaurepan
(Scheme 5).
4.1. General methods
Solvents were purified and dried by standard procedures before
Wittig reaction of 6 followed by hydrogenation on Pd/C gave 21
in very good yields. Deprotection of silyl ether group of 21, followed
by selective protection of the primary alcohol provided compound
22 in 82% overall yield. The free secondary alcohol was converted
into ketone 23 in 82% yield by treatment with TPAP. With the same
procedure used by (þ)-isolaurepan, the reaction of 23 with trime-
thylsilyldiazomethane at ꢀ78 ꢁC, furnished the seven-membered
ketone 8 in 66% and 7% yield of its isomeric ketone. The oxepane
24 was obtained by WolfeKishner reaction of 8 in 55% yield,19 and
removal of the silyl protecting group of 24 with TBAF gave the
known alcohol 25.8 Swern oxidation of alcohol 25, followed by
Wittig reaction gave the alkene 26 in 64% yield. Finally, hydroge-
nation of 26 on Pd/C afforded the desired (ꢀ)-isolaurepan 4 in
nearly quantitative yield.
use. Melting points uncorrected.1H and 13C NMR spectra were
recorded in
100.61 MHz 13C) using TMS as internal standard (chemical shifts in
values, J in hertz). Mass spectrometry was carried out with
a
Bruker ARX-400 spectrometer (400 MHz 1H,
d
a Hewlett Packard 5988A spectrometer. Flash chromatography (FC)
was performed on silica gel (Merck 60, 230e400 mesh); analytical
TLC was performed on plates precoated with silica gel (Merck 60
F254, 0.25 mm).
4.2. Methyl 2-((4aR,6S,8aS)-2,2-di-tert-butyl-4,4a,6,8a-tetra-
hydropyrano[3,2-d][1,3,2]dioxasilin-6-yl)acetate (11)
To a solution of alcohol 9 (50 mg, 0.18 mmol) and CH3C(OCH3)3
(2 mL) was added a catalytic amount of 2,4,6-trimethylbenzoic acid
(TMBA) and the mixture was heated in a sealed tube at 160 ꢁC for
48 h. The solvent was rotatory evaporated to give a residue, which
was chromatographed on silica gel using 4% EtOAc/hexane as elu-
ent, affording 11 (18 mg, 30%) as a colorless liquid, Rf: 0.37 (10%
3. Conclusions
In conclusion, we have developed an efficient and enantiose-
lective synthesis of (þ)-isolaurepan and (ꢀ)-isolaurepan from

G. Pazos et al. / Tetrahedron 68 (2012) 8994e9003
8997
20
EtOAc/hexane); [
a
]
D
þ27.41 (c 1.82, MeOH); IR (film), cmꢀ1
:
H-4), 3.54 (1H, ddd, J¼10.34, 8.52, 5.08 Hz, H-4a), 2.57 (2H, dd,
J¼6.05, 2.06 Hz, CH2eCHO), 1.05 (9H, s, CH3etBu), 0.99 (9H, s,
2938.98, 2861.84, 1743.33, 1126.22, 1095.37, 860.09; H NMR (CDCl3,
d
): 5.82 (1H, d, J¼10.3 Hz, H-8), 5.58 (1H, d, J¼10.3 Hz, H-7),
CH3etBu); C NMR (CDCl3,
d): 200.4 (C]O), 131.2 (CH-8), 127.8 (CH-
4.59e4.54 (1H, m, H-6), 4.32 (1H, dd, J¼8.3, 1.2 Hz, H-8a), 4.09 (1H,
dd, J¼9.96, 5.03 Hz, H-4), 3.78 (1H, t, J¼10.24 Hz, H-4), 3.63 (3H, s,
OCH3), 3.45 (1H, ddd, J¼10.4, 8.5, 5.1 Hz, H-4a), 2.46e2.41 (2H, m,
CH2eC]O), 1.03 (9H, s, CH3etBu), 0.97 (9H, s, CH3etBu); C
7), 74.7 (CH-4a), 70.9 (CH-6), 70.0 (CH-8a), 67.0 (CH2-4), 48.3
(CH2eCHO), 27.5 (CH3etBu), 27.0 (CH3etBu), 22.7 (CetBu), 20.0
(CetBu); MS (FABþ) [m/z, (%)]: 313 (Mþþ1, 6), 312 (Mþ, 7), 311
(Mþꢀ1, 21), 283 (MþꢀCHO, 11), 270 (23), 269 (MþꢀCH2CHO, 100),
t
NMR (CDCl3,
d
): 171.0 (C]O), 130.8 (CH-8), 128.2 (CH-7), 74.7 (CH-
268 (13), 267 (15), 255 (Mþꢀ Bu, 17), 239 (20), 213 (21), 211 (19),
4a), 72.1 (CH-6), 69.9 (CH-8a), 67.1 (CH2-4), 51.8 (OCH3), 40.1
(CH2eC]O), 27.5 (CH3etBu), 27.1 (CH3etBu), 22.7 (CetBu), 20.1
(CetBu); MS (FABþ) [m/z, (%)]: 343 (Mþþ1, 46), 342 (Mþ, 20), 341
201 (27); HRMS (FABþ): 313.1757 calculated for C16H29O4Si, found
313.1790.
(Mþꢀ1, 55), 286 (19), 285 (Mþꢀ Bu, 86), 270 (21), 269
t
4.5. (4aR,6S,8aS)-2,2-Di-tert-butyl-6-(hex-20-enyl)-4,4a,6,8a-
tetrahydropyrano[3,2-d][1,3,2]dioxasiline (13)
(MþꢀCH2CO2Me, 100), 239 (10), 219 (19), 211 (14), 201 (36), 167
(16); HRMS (FABþ): 343.1863 calculated for C17H31O5Si, found
343.1859.
To a suspension of butyltriphenylphosphonium bromide (5.73 g,
14.35 mmol) in THF (30 mL) at 0 ꢁC was added n-BuLi (5.7 mL of
a 2.5 M solution in hexane, 14.35 mmol) and stirring was continued
for 20 min whereupon the color of the mixture turned to orange. A
solution of aldehyde 6 (3.2 g, 10.25 mmol) in THF (30 mL) was
added via cannula and the mixture stirred for 20 min then
quenched with an aqueous saturated solution of NH4Cl (50 mL) and
the product extracted with EtOAc (3ꢂ60 mL). The combined or-
ganic phases were dried, filtered, and evaporated to give a residue,
which was chromatographed on silica gel using 2% EtOAc/hexane as
4.3. (4aR,8R,8aS)-2,2-Di-tert-butyl-8-(vinyloxy)-4,4a,8,8a-tet-
rahydropyrano[3,2-d][1,3,2]dioxasiline (12)
Method A: A solution of allylic alcohol 9 (5.2 g, 18.2 mmol) and
Hg(OAc)2 (1.74 g, 5.46 mmol) in ethyl vinyl ether (40 mL) in a sealed
tube was heated at 65 ꢁC for 4 days, adding Hg(OAc)2 (1.74 g,
5.46 mmol) every 24 h. The mixture was washed with water
(3ꢂ35 mL) and brine (3ꢂ35 mL) and the solvent removed under
vacuum to afford a residue, which was chromatographed on silica
gel using 2% EtOAc/hexane as eluent, affording 12 (4.5 g, 80%) as
a colorless liquid; 0.5 g (10%) of the starting allylic alcohol was
recovered.
Method B: To a solution of 9 (1.95 g, 6.81 mmol), Pd(OAc)2
(46 mg, 0.2 mmol) and bipyridine (32 mg, 0.2 mmol) in ethyl vinyl
ether (30 mL) was added Et3N (1.9 mL, 13.62 mmol). The resulting
suspension was stirred at room temperature for 5 min. Trifluoro-
eluent, affording diene 13 (2.7 g, 80%) as a colorless liquid; Rf: 0.62
20
(30% EtOAc/hexane); [
a
]
D
þ52.31 (c 1.67, MeOH); IR (film, cmꢀ1):
2954.28, 2935.13, 2865.48, 1650.77, 1469,49, 1126.22; H NMR
(CDCl3,
d
): 5.85 (1H, d, J¼10.34 Hz, H-8), 5.63 (1H, m, H-7),
5.54e5.46 (1H, m, H-20), 5.45e5.33 (1H, m, H-30), 4.43e4.35 (1H, m,
H-8a), 4.23e4.19 (1H, m, H-6), 4.17 (1H, dd, J¼9.98, 4.94 Hz, H-4),
3.87 (1H, t, J¼10.22, H-4), 3.50 (1H, ddd, J¼10.49, 8.52, 5.06 Hz,
H-4a), 2.27 (1H, dd, J¼8.49, 5.87 Hz, H-10), 2.05e1.94 (1H, m, H-40),
1.37 (1H, dt, J¼22.05, 7.34 Hz, H-50), 1.05 (9H, s, CH3etBu), 0.99 (9H,
acetic acid (52 mL, 0.68 mmol) was added and the mixture heated in
a sealed tube at 80 ꢁC for 3 days. The solvent was removed under
vacuum to afford a residue, which was chromatographed on silica
gel using 5% EtOAc/hexane as eluent, affording 12 (1.5 g, 72%) as
a colorless liquid; Rf: 0.63 (30% EtOAc/hexane); 0.34 g (17%) of the
s, CH3etBu), 0.89 (3H, t, J¼7.34 Hz, H-60); C NMR (CDCl3,
d): 132.5
(CH-20), 129.9 (CH-8), 129.2 (CH-7), 124.2 (CH-30), 75.3 (CH-6), 74.7
(CH-4a), 70.3 (CH-8a), 67.3 (CH2-4), 33.2 (CH2-10), 29.5 (CH2-40),
27.5 (CH3etBu), 27.1 (CH3etBu), 22.7 (CetBu), 22.5 (CH2-50), 20.0
(CetBu), 13.8 (CH3-60); MS (FABþ) [m/z, (%)]: 353 (Mþþ1, 26), 352
starting allylic alcohol was recovered; [
IR (film), cmꢀ1
1095.37, 1122.37; H NMR (CDCl3,
a
]
20 ꢀ77.39 (c 2.88, MeOH);
D
:
2938.98, 2982.71, 2865.47, 1639.27, 1473.35,
(Mþ, 26), 351 (Mþꢀ1, 67), 296 (30), 295 (Mþꢀ Bu, 100), 285 (23),
t
d
): 6.53 (1H, dd, J¼14.00, 6.44 Hz,
269 (MþꢀCH2CHCHCH2CH2CH3, 46), 267 (27), 239 (28), 213 (45),
211 (29), 201 (33), 183 (22), 171 (21), 169 (21), 167 (24), 165 (28), 163
(22), 161 (23); HRMS (FABþ): 352.2434 calculated for C20H36O3Si,
found 353.2434.
H-10), 6.32 (1H, dd, J¼6.03, 1.24 Hz, H-6), 4.78 (1H, dd, J¼6.03,
1.88 Hz, H-7), 4.43e4.36 (2H, m, H-10, H-20), 4.18 (1H, dd, J¼10.30,
4.94 Hz, H-4), 4.13 (1H, dd, J¼10.30, 7.08 Hz, H-8a), 4.03 (1H, dd,
J¼6.44, 1.35 Hz, H-20), 3.98 (1H, t, J¼10.30 Hz, H-4), 3.90e3.81 (1H,
m, H-4a), 1.06 (9H, s, CH3etBu), 1.00 (9H, s, CH3etBu); C NMR
(CDCl3,
d
): 151.2 (CH-10), 144.7 (CH-6), 100.6 (CH-7), 88.9 (CH2-20),
4.6. (4aR,6S,8aS)-2,2-Di-tert-butyl-6-hexylhexahydropyrano
[3,2-d][1,3,2]dioxasiline (14)
77.4 (CH-8), 75.2 (CH-8a), 72.5 (CH-4a), 65.9 (CH2-4), 27.3
(CeCH3etBu), 26.9 (CeCH3etBu), 22.7 (CetBu), 19.8 (CetBu); MS
(FABþ) [m/z, (%)]: 313 (Mþþ1, 4), 312 (Mþ, 3), 311 (Mþꢀ1, 9), 270
A suspension of 13 (2.68 g, 10.42 mmol) and Pd/C (10%) (1.6 g,
0.2 mmol) in MeOH (40 mL) was stirred under H2 atmosphere for
10 h. The mixture was filtered through CeliteÒ and the filtrate
t
(23), 269 (MþꢀOCHCH2, 100), 268 (8), 255 (Mþꢀ Bu, 7), 213 (8), 201
(5); HRMS (FABþ): 313.1757 calculated for C16H29O4Si, found
313.1790.
concentrated under vacuum to give pure 14 (2.68 g, 99%) as a col-
20
orless liquid; Rf: 0.62 (30% EtOAc/hexane); [
a
]
D
ꢀ17.03 (c 2.20,
4.4. 2-((4aR,6S,8aS)-2,2-Di-tert-butyl-4,4a,6,8a-tetrahydropyr-
ano[3,2-d][1,3,2]dioxasilin-6-yl)acetaldehyde (6)
MeOH); IR (film, cmꢀ1): 2954.78, 2865.09, 2935.17, 1468,79,
1125.99, 1047.28; H NMR (CDCl3,
d
): 4.07 (1H, dd, J¼10.15, 4.89 Hz,
H-4), 3.81 (1H, t, J¼10.15 Hz, H-4), 3.71 (1H, ddd, J¼10.63, 9.15,
4.56 Hz, H-6), 3.36e3.24 (2H, m, H-8a, H-4a), 2.13e2.06 (1H, m,
H-8), 1.76e1.67 (1H, m, H-7), 1.54e1.41 (2H, m, H-10, H-8), 1.41e1.32
(3H, m, H-10, H-20, H-7), 1.31e1.20 (7H, m, H-20, 2H-30, 2H-40, 2H-50),
1.03 (9H, s, CH3eetBu), 0.98 (9H, s, CH3etBu), 0.87 (3H, t, J¼6.81 Hz,
A solution of 12 (4.2 g, 13.46 mmol) in toluene (40 mL) was
heated to 185 ꢁC in a sealed tube for 5 h. The solvent was removed
under vacuum to afford a residue, which was chromatographed on
silica gel using 2% EtOAc/hexane as eluent, affording aldehyde 6
(4 g, 95%) as a white solid; mp¼68e69 ꢁC, Rf: 0.6 (30% EtOAc/
3H-60); C NMR (CDCl3,
d): 77.9 (CH-8a or CH-4a), 77.6 (CH-8a or
20
hexane); [
a]
þ21.44 (c 1.73, MeOH); IR (film, cmꢀ1): 2938.98,
CH-4a), 74.10 (CH-6), 67.25 (CH2-4), 35.76 (CH2-10), 32.67 (CH2-8),
31.77 (CH2-40), 30.98 (CH2-7), 29.31 (CH2-30), 27.49 (CH3etBu), 27.13
(CH3etBu), 25.68 (CH2-20), 22.63 (CetBu), 22.59 (CH2-50), 19.92
(CetBu), 14.06 (CH3-60); MS (FABþ) [m/z, (%)]: 357 (Mþþ1, 28), 356
D
2861.34, 1727.91, 1473.35, 1130.08, 1091.51, 860.09; H NMR (CDCl3,
d
): 9.75 (1H, t, J¼2.06 Hz, CHO), 5.93 (1H, d, J¼10.34 Hz, H-8),
5.68e5.61 (1H, m, H-7), 4.77e4.67 (1H, m, H-6), 4.43e4.36 (1H, m,
H-8a), 4.16 (1H, dd, J¼9.97, 5.05 Hz, H-4), 3.84 (1H, t, J¼10.24 Hz,
t
(Mþ, 18), 355 (Mþꢀ1, 61), 339 (10), 300 (23), 299 (Mþꢀ Bu, 100),

8998
G. Pazos et al. / Tetrahedron 68 (2012) 8994e9003
297 (12), 227 (14), 201 (15); HRMS (FABþ): 357.2747 calculated for
20H41O3Si, found 357.2845.
(CDCl3, d): 7.78e7.69 (4H, m, PheHo), 7.45e7.35 (6H, m, Php,m),
C
4.06e3.93 (3H, m, H-6, CH2eOTBDPS), 3.67 (1H, m, H-2), 2.68e2.58
(1H, m, H-4), 2.48e2.38 (1H, m, H-4), 2.08e1.88 (2H, m, H-5),
1.73e1.61 (1H, m, H-10),1.61e1.48 (2H, m, H-10, H-20),1.45e1.24 (7H,
m, H-20, 2H-30, 2H-40, 2H-50), 1.04 (9H, s, CH3etBu), 0.91 (3H, t,
4.7. (2R,3S,6S)-2-((tert-Butyldiphenylsilyloxy)methyl)-6-
hexyltetrahydro-2H-pyran-3-ol (15)
J¼6.60 Hz, 3H-60); C NMR (CDCl3,
d): 209.7 (C]O), 135.7 and 135.6
To a solution of 14 (2.55 g, 7.14 mmol) in THF (35 mL) was added
TBAF (21.4 mL of a 1 M solution in THF, 21.4 mmol) and the mixture
was stirred at room temperature for 20 h. The solvent was evapo-
rated to afford a residue, which was chromatographed on silica gel
(CHoePh), 133.5 and 133.4 (CePh), 129.5 (CHpePh), 127.6 and 127.5
(CHmePh), 83.8 (CH-6), 75.41 (CH-2), 63.6 (CH2eOTBDPS), 37.5
(CH2-4), 35.9 (CH2-10), 31.8 (CH2-5), 30.4 (CH2-40), 29.3 (CH2-30),
26.6 (CH3etBu), 25.6 (CH2-20), 22.6 (CH2-50),19.2 (CetBu),14.1 (CH3-
60); MS (FABþ) [m/z, (%)]: 453 (Mþþ1, 5), 452 (Mþ, 9), 451 (Mþꢀ1,
using 50% EtOAc/hexane as eluent, affording diol 140 (1.5 g, 96%) as
20
t
a white solid; mp¼62e63 ꢁC, Rf: 0.1 (30% EtOAc/hexane); [
a
]
20), 435 (18), 395 (Mþꢀ Bu, 24), 375 (MþꢀPh, 16), 374 (22), 373
D
þ22.66 (c 1.56, MeOH); IR (film, cmꢀ1): 3301.54, 2927.29, 2854.13,
(43), 297 (21), 257 (28), 241 (51), 239 (24), 237 (30), 223 (18), 221
(34), 213 (MþꢀTBDPS,13), 200 (19), 199 (100),198 (18),199 (84),183
(23), 180 (26),171 (36), 167 (16), 165 (29), 163 (49); HRMS (FABþ):
452.2747 calculated for C28H40O3Si, found 452.2747.
1060.66, 771.38; H NMR (CDCl3,
d
): 3.82 (1H, dd, J¼11.43, 3.99 Hz,
CH2eOH), 3.75 (1H, dd, J¼11.43, 4.90 Hz, CH2eOH), 3.52 (1H, td,
J¼10.68, 10.56, 4.74 Hz, H-3), 3.34e3.25 (1H, m, H-6), 3.16 (1H, td,
J¼8.95, 4.35, 4.35 Hz, H-2), 2.69 (2H, br s, 2OH), 2.12e2.03 (1H, m,
H-4), 1.75e1.67 (1H, m, H-5), 1.55e1.43 (2H, m, H-10, H-4), 1.42e1.31
(3H, m, H-10, H-20, H-5), 1.33e1.21 (7H, m, H-20, 2H-30, 2H-40, 2H-50),
4.9. (2R,7S)-2-((tert-Butyldiphenylsilyloxy)methyl)-7-
hexyloxepan-3-one (7) and (2S,7S)-2-((tert-butyldiphenylsily-
loxy)methyl)-7-hexyloxepan-4-one (70)
0.88 (3H, t, J¼5.92 Hz, H-60); C NMR (CDCl3,
d): 81.1 (CH-2), 77.5
(CH-6), 67.7 (CH-3), 63.4 (CH2eOH), 35.7 (CH2-10), 32.5 (CH2-4),
31.7 (CH2-40), 30.8 (CH2-5), 29.3 (CH2-30), 25.7 (CH2-20), 22.6 (CH2-
50), 14.0 (CH3-60); MS (FABþ) [m/z, (%)]: 217 (Mþþ1, 50), 216 (Mþ,
14), 215 (Mþꢀ1, 83), 213 (11), 200 (10), 199 (MþꢀOH, 56), 198 (11),
197 (12), 186 (21), 181 (27), 163 (19); HRMS (FABþ): 217.1725 cal-
culated for C12H25O3, found 217.1759.
To a solution of ketone 16 (2.32 g, 5.12 mmol) in CH2Cl2 (40 mL)
at ꢀ78 ꢁC were added BF3$OEt2 (0.77 mL, 6.14 mmol) and TMSCHN2
(2.68 mL of a 2 M solution in hexane, 5.37 mmol). The mixture was
stirred at ꢀ78 ꢁC for 30 min before adding an aqueous saturated
solution of NaHCO3 (30 mL). The organic phase was separated and
the aqueous phase extracted with EtOAc (3ꢂ30 mL). The combined
organic phases were washed with water (3ꢂ30 mL), brine
(3ꢂ30 mL), dried, filtered, and evaporated to give a residue, which
was dissolved in MeOH (40 mL). PPTS (1.92 g, 7.68 mmol) was
added and the mixture stirred at room temperature for 1 h. The
product was extracted with EtOAc (3ꢂ30 mL) and the combined
organic phases washed with an aqueous saturated solution of
NaHCO3 (3ꢂ30 mL) and brine (3ꢂ30 mL). Drying, filtration, and
solvent evaporation afforded a residue, which was chromato-
graphed on silica gel using 1% EtOAc/hexane as eluent, affording
ketone 7 (1.45 g, 60%) along with its isomeric ketone 70 (0.14 g, 8%).
The selective protection of the primary alcohol of diol 140 was
carried out as follows: to a solution of 140 (1.55 g, 7.14 mmol) in DMF
(30 mL) were added imidazole (0.58 g, 8.57 mmol), TBDPSCl
(2.22 mL, 8.57 mmol), and a catalytic amount of DMAP. The mixture
was stirred at room temperature for 30 min and diluted with EtOAc
(50 mL). The resulting organic phase was washed with water
(3ꢂ40 mL) and brine (3ꢂ40 mL), filtered, and evaporated to give
a residue, which was chromatographed on silica gel using 5%
EtOAc/hexane as eluent, affording alcohol 15 (3.15 g, 96%) as a col-
orless liquid; Rf: 0.5 (30% EtOAc/hexane); [
IR (film, cmꢀ1): 3451.96, 2931.27, 2857.99, 1461.78, 1106.94, 701.96;
H NMR (CDCl3, ): 7.72e7.67 (4H, m, PheHo), 7.47e7.36 (6H, m,
a]
20 6.16 (c 2.27, MeOH);
D
d
Php,m), 3.90 (1H, dd, J¼10.11, 4.69 Hz, CH2eOTBDPS), 3.78 (1H, dd,
J¼10.11, 7.66 Hz, CH2eOTBDPS), 3.68e3.60 (1H, m, H-2), 3.54 (1H, s,
OH), 3.34e3.20 (2H, m, H-3, H-6), 2.16e2.07 (1H, m, H-4), 1.72e1.63
(1H, m, H-5),1.54e1.41 (2H, m, H-10, H-4),1.40e1.28 (3H, m, H-10, H-
20, H-5), 1.28e1.20 (7H, m, H-20, 2H-30, 2H-40, 2H-50), 1.06 (9H, s,
4.9.1. Compound 7. Colorless liquid; Rf: 0.48 (20% EtOAc/hexane);
20
[a
]
þ41.47 (c 1.51, MeOH); IR (film, cmꢀ1): 2931.27, 2857.99,
D
1716.34, 1110.82, 701.96; H NMR (CDCl3,
d): 7.79e7.65 (4H, m,
PheHo), 7.45e7.34 (6H, m, Php,m), 3.96 (1H, dd, J¼10.65, 4.41 Hz,
CH2eOTBDPS), 3.89 (1H, dd, J¼10.65, 2.06 Hz, CH2eOTBDPS),
3.81e3.78 (1H, m, H-2), 3.25e3.16 (1H, m, H-7), 3.08e2.96 (1H, m,
H-4), 2.44 (1H, dd, J¼11.20, 6.63 Hz, H-4), 2.04e1.93 (1H, m, H-5),
1.86e1.78 (1H, m, H-10), 1.73e1.57 (2H, m, H-6, H-10), 1.55e1.40 (3H,
m, H-20, H-5, H-6), 1.40e1.18 (7H, m, H-20, 2H-30, 2H-40, 2H-50), 1.03
CH3etBu), 0.86 (3H, t, J¼6.81 Hz, H-60); C NMR (CDCl3,
d): 135.6 and
135.6 (CHoePh), 132.6 and 132.6 (CePh), 129.9 (CHpePh), 127.79
and 127.8 (CHmePh), 79.2 (CH-2), 77.3 (CH-6), 70.9 (CH-3), 67.3
(CH2eOTBDPS), 35.8 (CH2-10), 31.8 (CH2-4), 31.8 (CH2-40), 30.4
(CH2-5), 29.3 (CH2-30), 26.8 (CH3etBu), 25.6 (CH2-20), 22.6 (CH2-50),
19.1 (CetBu), 14.0 (CH3-60); MS (FABþ) [m/z, (%)]: 454 (Mþ, 4), 453
(9H, s, CH3etBu), 0.87 (3H, t, J¼6.36 Hz, 3H-60); C NMR (CDCl3,
d):
216.6 (C]O), 135.8 and 135.6 (CHoePh), 133.2 and 133.1 (CePh),
129.6 and 129.6 (CHpePh), 127.6 and 127.5 (CHmePh), 87.6 (CH-2),
83.7 (CH-7), 66.2 (CH2eOTBDPS), 43.2 (CH2-4), 37.3 (CH2-6), 36.3
(CH2-10), 31.8 (CH2-40), 29.3 (CH2-30), 26.6 (CH3etBu), 25.6 (CH2-20),
23.7 (CH2-5), 22.6 (CH2-50), 19.2 (CetBu), 14.1 (CH3-60); MS (FABþ)
[m/z, (%)]: 467 (Mþþ1, 4), 466 (Mþ, 3), 465 (Mþꢀ1, 6), 449 (24), 411
t
(Mþꢀ1, 9), 398 (15), 397 (Mþꢀ Bu, 44), 379 (11), 377 (MþꢀPh, 26),
359 (16), 319 (14), 299 (12), 241 (20), 221 (15), 200 (19), 199 (100),
198 (11), 197 (48), 183 (19), 181 (37), 167 (11), 165 (18), 163 (41), 161
(24); HRMS (FABþ): 454.2903 calculated for C28H42O3Si, found
454.2903.
t
(12), 410 (34), 409 (Mþꢀ Bu, 100), 390 (15), 389 (MþꢀPh, 29), 331
4.8. (2R,6S)-2-((tert-Butyldiphenylsilyloxy)methyl)-6-
hexyldihydro-2H-pyran-3(4H)-one (16)
(25), 311 (15), 242 (17), 241 (68), 239 (14), 227 (MþꢀTBDPS, 7), 223
(20), 221 (37); HRMS (FABþ): 467.2903 calculated for C29H43O3Si,
found 467.2981.
To a solution of alcohol 15 (3.05 g, 6.71 mmol) in CH2Cl2 (50 mL)
were added 4 A molecular sieves (2 g), NMO (2.35 g, 20.14 mmol),
4.9.2. Compound 70. Colorless liquid; Rf: 0.40 (20% EtOAc/hexane);
ꢁ
20
and a catalytic amount of TPAP. The resulting greenish solution was
stirred at room temperature for 18 h. The solvent was evaporated to
afford a residue, which was chromatographed on silica gel using 5%
EtOAc/hexane as eluent, affording ketone 16 (2.4 g, 80%) as a col-
[a
]
ꢀ39.7 (c 1.59, MeOH); IR (film, cmꢀ1): 2931.27, 2857.99,
D
1708.62, 1110.82, 701.96; H NMR (CDCl3, d): 7.70e7.64 (4H, m,
PheHo), 7.46e7.35 (6H, m, Php,m), 3.91e3.83 (1H, m, H-2), 3.73 (1H,
dd, J¼10.15, 6.06 Hz, CH2eOTBDPS), 3.50 (1H, dd, J¼10.10, 5.82 Hz,
CH2eOTBDPS), 3.47e3.44 (1H, m, H-7), 2.79e2.68 (2H, m, H-3,
H-5), 2.58e2.49 (2H, m, H-3, H-5), 1.86e1.78 (1H, m, H-6),
orless liquid; Rf: 0.62 (30% EtOAc/hexane); [
a
]
20 þ1.59 (c 1, MeOH);
D
IR (film, cmꢀ1): 2931.27, 2861.84, 1724.05, 1280.65, 1114.65; H NMR

G. Pazos et al. / Tetrahedron 68 (2012) 8994e9003
8999
1.66e1.54 (1H, m, H-6), 1.52e1.35 (3H, m, 2H-10, H-20), 1.35e1.17
(7H, m, H-20, 2H-30, 2H-40, 2H-50), 1.05 (9H, s, CH3etBu), 0.85 (3H, t,
was added and the organic phase washed with water (3ꢂ20 mL)
and brine (3ꢂ20 mL), dried, filtered, and evaporated to give a resi-
due, which was chromatographed on silica gel using 1% EtOAc/
hexane as eluent, affording oxepane 17 (175 mg, 61%) as a gray
J¼6.54, 6.54 Hz, 3H-60); C NMR (CDCl3,
d): 211.6 (C]O), 135.6 and
135.5 (CHoePh), 133.3 and 133.19 (CePh), 129.7 and 129.6
(CHpePh), 127.7 and 127.6 (CHmePh), 83.4 (CH-7), 76.9 (CH-2), 66.5
(CH2eOTBDPS), 48.5 (CH2-3), 42.2 (CH2-5), 36.6 (CH2-10), 32.4
(CH2-6), 31.7 (CH2-40), 29.2 (CH2-30), 26.7 (CH3etBu), 25.9 (CH2-20),
22.6 (CH2-50), 19.1 (CetBu), 14.1 (CH3-60); MS (FABþ) [m/z, (%)]: 467
liquid; Rf: 0.63 (20% EtOAc/hexane); [
a
]
20 ꢀ8.08 (c 0.91, MeOH); IR
D
(film, cmꢀ1): 2927.41, 2857.99, 1457.92, 1106.94, 1002.23; H NMR
(CDCl3, d): 7.73e7.67 (4H, m, PheHo), 7.45e7.35 (6H, m, Php,m), 3.69
(1H, dd, J¼9.92, 6.32 Hz, CH2eOTBDPS), 3.64e3.57 (1H, m, H-7),
3.47 (1H, dd, J¼9.92, 5.69 Hz, CH2eOTBDPS), 3.44e3.38 (1H, m, H-
2), 1.81e1.59 (4H, m, H-10, H-20, H-3, H-6), 1.58e1.39 (6H, m, H-3,
2H-4, 2H-5, H-6), 1.38e1.18 (8H, m, H-10 H-20, 2H-30, 2H-40, 2H-50),
1.06 (9H, s, CH3etBu), 0.87 (3H, t, J¼6.80 Hz, 3H-60); C NMR (CDCl3,
t
(Mþþ1, 4), 466 (Mþ, 4), 465 (Mþꢀ1, 7), 409 (Mþꢀ Bu, 100), 389
(MþꢀPh, 29), 331 (27), 311 (16), 241 (30), 227 (MþꢀTBDPS, 8), 221
(17), 200 (15), 199 (76), 197 (48), 193 (23), 181 (25), 200 (19), 163
(26); HRMS (FABþ): 467.2903 calculated for C29H43O3Si, found
467.2981.
d): 135.6 (CHoePh), 133.8 and 133.8 (CePh), 129.5 and 129.5
(CHpePh), 127.5 and 127.5 (CHmePh), 80.5 (CH-7), 80.4 (CH-2), 67.2
(CH2eOTBDPS), 37.3 (CH2-6), 36.8 (CH2-10), 32.3 (CH2-3), 31.8
(CH2-40), 29.4 (CH2-30), 26.8 (CH3etBu), 26.2 (CH2-5), 25.5 (CH2-20),
24.8 (CH2-4), 22.6 (CH2-50), 19.2 (CetBu), 14.1 (CH3-60); MS (FABþ)
4.10. tert-Butyl(((2S,7S)-7-hexyloxepan-2-yl)methoxy)diphe-
nylsilane (17)
t
To a solution of ketone 7 (380 mg, 0.81 mmol) in MeOH (20 mL)
[m/z, (%)]: 452 (Mþ, 4), 465 (Mþꢀ1, 6), 396 (14), 395 (Mþꢀ Bu, 100),
were added NH2NHTs (167 mg, 0.89 mmol), PTSA (9 mg, 48
m
mol),
375 (MþꢀPh,13), 241 (12), 239 (11), 229 (11), 223 (11), 200 (22),199
(100), 198 (13), 197 (45); HRMS (FABþ): 453.3111 calculated for
ꢁ
ꢁ
and 4 A molecular sieves (300 mg). The mixture was stirred at 70 C
for 33 h. The organic solvent was removed under vacuum and the
residue was dissolved in CH2Cl2, washed with water (3ꢂ15 mL) and
brine (3ꢂ15 mL), dried, filtered, and evaporated to give a residue,
which was chromatographed on silica gel using 5% EtOAc/hexane as
eluent, affording hydrazones 7a (400 mg, 78%) and 7b (90 mg, 17%).
C29H45O2Si, found 453.3189.
4.11. ((2S,7S)-7-Hexyloxepan-2-yl)methanol (18)
To a solution of 17 (50 mg, 0.11 mmol) in THF (2 mL) was added
TBAF (110 mL of a 1 M solution in THF, 0.11 mmol) and the mixture
4.10.1. Compound 7a. Colorless liquid; Rf: 0.27 (20% EtOAc/hex-
stirred at room temperature for 4 h. The solvent was evaporated to
give a residue, which was chromatographed on silica gel using 1%
20
ane); [
a
]
þ60.04 (c 1.53, MeOH); IR (film, cmꢀ1): 3220.54,
D
2929.34, 2857.99, 1342.21, 1168.65, 1112.73, 703.89; H NMR (CDCl3,
EtOAc/hexane as eluent, affording alcohol 18 (22 mg, 95%) as
20
d): 7.72e7.67 (4H, m, PheHo), 7.67e7.61 (2H, m, TseHo), 7.46e7.32
a colorless liquid; Rf: 0.36 (20% EtOAc/hexane); [
a
]
ꢀ2.07 (c 1,
D
(6H, m, Php,m), 7.09 (2H, d, J¼8.14 Hz, TseHm), 4.12 (1H, dd, J¼6.46,
3.52 Hz, H-2), 3.74 (1H, dd, J¼10.86, 3.52 Hz, CH2eOTBDPS), 3.65
(1H, dd, J¼10.86, 6.46 Hz, CH2eOTBDPS), 3.18e3.10 (1H, m, H-7),
2.33 (3H, s, CH3ePh), 2.24e2.15 (1H, m, H-4), 1.85e1.77 (1H, m, H-
4), 1.68e1.61 (2H, m, H-10, H-5), 1.58e1.33 (5H, m, H-10, H-20, 2H-6,
H-5), 1.33e1.17 (7H, m, H-20, 2H-30, 2H-40, 2H-50), 0.99 (9H, s,
MeOH); IR (film, cmꢀ1): 3448.15, 2927.37, 2858.09, 1457.91, 1106.94,
1002.28; H NMR (CDCl3, d): 3.64e3.55 (1H, m, H-2), 3.51e3.40 (3H,
m, CH2eOH, H-7), 2.24e2.17 (1H, s, OH), 1.79e1.38 (12H, m, 2H-10,
2H-200, 2H-3, 2H-4, 2H-5, 2H-6), 1.36e1.22 (6H, m, 2H-30, 2H-40, 2H-
50), 0.87 (3H, t, J¼6.59 Hz, 3H-60); C NMR (CDCl3,
d): 81.1 (CH-7),
80.3 (CH-2), 66.5 (CH2eOH), 37.2 (CH2-6), 36.7 (CH2-10), 32.0 (CH2-
3), 31.8 (CH2-40), 29.3 (CH2-30), 26.3 (CH2-5), 25.4 (CH2-20), 25.1
(CH2-4), 22.6 (CH2-50), 14.1 (CH3-60); MS (FABþ) [m/z, (%)]: 215
(Mþþ1, 7), 214 (Mþ, 6), 213 (Mþꢀ1, 15), 183 (100), 165 (67); HRMS
(FABþ): 215.1933 calculated for C13H27O2, found 215.1903.
CH3etBu), 0.86 (3H, t, J¼6.97 Hz, 3H-60); C NMR (CDCl3,
d): 161.8
(C]N), 143.8 (CeTs), 135.6 and 135.6 (CHoePh), 134.9 (CHpeTs),
133.5 and 133.4 (CePh), 129.6 and 129.5 (CHpePh), 129.3 (CHoeTs),
127.8 (CHmeTs), 127.5 and 127.51 (CHmePh), 83.1 (CH-7), 81.1 (CH-
2), 66.3 (CH2eOTBDPS), 37.2 (CH2-6), 35.9 (CH2-10), 31.7 (CH2-40),
29.3 (CH2-30), 26.7 (CH3etBu), 25.6 (CH2-20), 23.7 (CH2-4), 22.6
(CH2-50), 21.5 (CH2-5), 19.1 (CetBu), 14.1 (CH3-60); MS (FABþ) [m/z,
(%)]: 637 (Mþþ3, 19), 636 (Mþþ2, 47), 635 (Mþþ1, 100), 633 (Mþꢀ1,
4.12. (3-((2S,7S)-7-Hexyloxepan-2-yl)prop-1-ynyl)trimethylsi-
lane (19)
t
5), 578 (13), 577 (Mþꢀ Bu, 30), 213 (11), 199 (33), 197 (22), 163 (11);
To a solution of alcohol 18 (33 mg, 0.15 mmol) in pyridine (40
m
L)
HRMS (FABþ): 635.3261 calculated for C36H51N2O4SSi, found
635.3294.
and CH2Cl2 (4 mL) at ꢀ15 ꢁC was added dropwise Tf2O (42
mL). The
mixture was stirred for 30 min at ꢀ15 ꢁC, then diluted with CH2Cl2
(15 mL), washed with water (3ꢂ10 mL) and brine (3ꢂ10 mL), dried,
filtered, and evaporated to give a residue, which was chromato-
graphed on silica gel using 2% EtOAc/hexane as eluent, affording
4.10.2. Compound 7b. Colorless liquid; Rf: 0.35 (20% EtOAc/hex-
ane); H NMR (CDCl3, d): 8.47 (1H, s, NH), 7.51e7.43 (6H, m, PheHo,
TseHo), 7.42e7.31 (6H, m, Php,m), 7.04 (2H, d, J¼8.12 Hz, TseHm),
4.73 (1H, dd, J¼6.25, 4.59 Hz, H-2), 3.90 (dd, J¼9.56, 4.59 Hz,
CH2eOTBDPS), 3.49 (1H, m, CH2eOTBDPS), 3.11e3.02 (1H, m, H-7),
2.30 (3H,s, CH3ePh), 2.14 (1H, t, J¼11.87 Hz, H-7), 1.90e1.80 (1H, m,
H-4), 1.64e1.56 (2H, m, H-10, H-5), 1.54e1.37 (5H, m, H-10, H-20, 2H-
6, H-5), 1.37e1.19 (7H, m, H-20, 2H-30, 2H-40, 2H-50), 1.02 (9H, s,
CH3etBu), 0.89 (3H, t, J¼6.88 Hz, 3H-60); MS (FABþ) [m/z, (%)]: 637
(Mþþ3, 20), 636 (Mþþ2, 47), 635 (Mþþ1, 100), 633 (Mþꢀ1, 4), 578
triflate 180 (45 mg, 85%) as a colorless liquid; Rf: 0.42 (20% EtOAc/
20
hexane); [
a]
ꢀ7.14 (c 0.91, MeOH); IR (film, cmꢀ1): 2929.34,
D
2857.99, 1373.68, 1249.65, 1176.36, 1031.73; H NMR (CDCl3, d): 4.39
(1H, dd, J¼10.21, 7.79 Hz, CH2eOTf), 4.34 (dd, J¼10.21, 3.79 Hz,
CH2eOTf), 3.86e3.78 (1H, m, H-2), 3.48e3.41 (1H, m, H-7),
1.81e1.60 (4H, m, H-10, H-20, H-3, H-6), 1.58e1.41 (6H, m, H-3, 2H-4,
2H-5, H-6), 1.39e1.21 (8H, m, H-10 H-20, 2H-30, 2H-40, 2H-50), 0.88
(3H, t, J¼6.80 Hz, 3H-60); C NMR (CDCl3,
d): 123.4, 120.2 and 117.0
t
(11), 577 (Mþꢀ Bu, 26), 213 (9), 199 (28), 197 (18), 163 (9); HRMS
(CF3), 81.7 (CH-7), 78.5 (CH2eOTf), 76.8 (CH-2), 36.9 (CH2-6), 36.6
(CH2-10), 31.8 (CH2-3), 31.4 (CH2-40), 29.3 (CH2-30), 25.9 (CH2-5),
24.9 (CH2-20), 24.8 (CH2-4), 22.6 (CH2-50), 14.0 (CH3-60); MS (FABþ)
[m/z, (%)]: 347 (Mþþ1, 52), 346 (Mþ, 19), 345 (Mþꢀ1, 99), 343 (12),
289 (12), 271 (15), 261 (47), 259 (13), 213 (MþꢀSO2CF3, 14), 209
(26), 198 (19), 197 (MþꢀOTf, 100), 195 (25), 193 (19), 183 (20), 179
(16), 177 (18), 169 (36), 165 (15); HRMS (FABþ): 347.1406 calculated
for C14H26F3O4S, found 347.1504.
(FABþ): 635.3261 calculated for C36H50N2O4SSi, found 635.3281.
To a solution of 7a (400 mg, 0.63 mmol) in DMF (20 mL) were
added NaBH3CN (158 mg, 2.52 mmol) and PTSA (33 mg,
0.176 mmol) and the mixture was stirred at 130 ꢁC for 2 h. NaBH3CN
(158 mg, 2.52 mmol) and PTSA (33 mg, 0.176 mmol) were again
added to the mixture and stirring was continued for 3 h. The
mixture was allowed to reach room temperature. EtOAc (20 mL)

9000
G. Pazos et al. / Tetrahedron 68 (2012) 8994e9003
To a solution of trimethylsilyl acetylene (105
m
L, 0.75 mmol) and
4.14. (4aR,6S,8aS)-6-Allyl-2,2-di-tert-butyl-4,4a,6,8a-tetrahy-
dropyrano[3,2-d][1,3,2]dioxasiline (20)
DMPU (0.5 mL) in THF (1 mL) at 0 ꢁC was added n-BuLi (300
mL of
a 2.5 M solution in hexanes, 0.75 mmol) and the mixture stirred for
20 min affording a bright yellow solution. Triflate 180 (53 mg,
0.15 mmol) in THF (1 mL) was added via cannula and the mixture
stirred at 0 ꢁC for 30 min. After quenching with an aqueous satu-
rated solution of NH4Cl (10 mL), the product was extracted with
EtOAc (3ꢂ10 mL). The combined organic phases were dried, fil-
tered, and evaporated to give a residue, which was chromato-
graphed on silica gel using 1% EtOAc/hexane as eluent, affording
alkyne 19 (40 mg, 88%) as a colorless liquid; Rf: 0.66 (20% EtOAc/
To
a suspension of methyltriphenylphosphonium bromide
(5.08 g, 14.22 mmol) in THF (35 mL) at 0 ꢁC was added n-BuLi
(5.68 mL of a 2.5 M solution in hexane, 14.22 mmol) and stirring
was continued for 20 min whereupon the color of the mixture
turned to orange. A solution of aldehyde 6 (3.17 g, 10.16 mmol) in
THF (35 mL) was added via cannula and the mixture stirred for
25 min. Then the reaction was quenched with an aqueous saturated
solution of NH4Cl (20 mL) and the product extracted with EtOAc
(3ꢂ50 mL). The combined organic phases were dried, filtered, and
evaporated to give a residue, which was chromatographed on silica
hexane); [
a
]
20 þ8.16 (c 1, MeOH); IR (film, cmꢀ1): 2927.41, 2857.99,
D
1457.92, 1106.94, 1002.23; H NMR (CDCl3, d): 3.66e3.57 (1H, m, H-
2), 3.46e3.37 (1H, m, H-7), 2.47 (1H, dd, J¼16.72, 6.58 Hz, H-100),
2.29 (1H, dd, J¼16.72, 7.01 Hz, H-100), 1.93e1.83 (1H, m, H-6),
1.78e1.42 (9H, m, H-10, H-20, 2H-3, 2H-4, 2H-5, H-6), 1.40e1.20 (8H,
m, H-10 H-20, 2H-30, 2H-40, 2H-50), 0.87 (3H, t, J¼6.16 Hz, 3H-60), 0.14
gel using 2% EtOAc/hexane as eluent, affording diene 20 (2.62 g,
22
83%) as a white solid; mp¼61 ꢁC, Rf: 0.69 (20% EtOAc/hexane); [
a]
D
þ6.66 (c 1.25, CHCl3); IR (NaCl, cmꢀ1): 2938.98, 2865.79, 1735.62,
1643.02, 1473.35, 1126.22, 1095.37; H NMR (CDCl3, d): 5.85 (1H, m,
(9H, s, CH3-Si); C NMR (CDCl3,
d
): 104.9 (C-300), 85.3 (C-200), 80.4
H-8), 5.78 (1H, m, H-20), 5.64 (1H, m, H-7), 5.09 (1H, m, H-30), 4.38
(1H, m, H-8a), 4.26 (1H, m, H-6), 4.17 (1H, dd, J¼9.9, 5.0 Hz, H-4),
3.87 (1H, t, J¼10.2 Hz, H-4), 3.50 (1H, ddd, J¼10.5, 8.5, 5.1 Hz, H-4a),
2.28 (1H, m, H-10), 1.05 (9H, s, CH3etBu), 0.99 (9H, s, CH3etBu); C
(CH-7), 78.6 (CH-2), 37.2 (CH2-6), 36.6 (CH2-10), 35.5 (CH2-3), 31.8
(CH2-40), 29.3 (CH2-30), 28.0 (CH2-100), 26.2 (CH2-5), 25.5 (CH2-20),
24.7 (CH2-4), 22.7 (CH2-50), 14.1 (CH3-60), 0.07 (SieCH3); MS (FABþ)
[m/z, (%)]: 295 (Mþþ1, 100), 294 (Mþ, 25), 293 (Mþꢀ1, 93), 279 (12),
227 (12), 226 (43), 209 (16), 195 (8), 184 (12), 183 (88), 181 (15), 167
(11), 166 (11), 165 (51), 163 (13); HRMS (FABþ): 295.2379 calculated
for C18H35OSi, found 295.2457.
NMR (CDCl3, d
): 133.7 (CH-20), 130.0 (CH-8), 129.1 (CH-7), 117.4
(CH2-30), 74.9 (CH-6), 74.7 (CH-4a), 70.3 (CH-8a), 67.2 (CH2-4), 39.6
(CH2-10), 27.5 (CH3etBu), 27.1 (CH3etBu), 22.6 (CetBu), 20.0
(CetBu); MS (FABþ) [m/z, (%)]: 311 (Mþþ1, 18), 310 (Mþ, 29), 310
t
(Mþꢀ1, 11), 253 (Mþꢀ Bu, 100), 269 (MþꢀCH2CHCH2, 31), 196 (19),
4.13. (2S,7R)-2-Hexyl-7-propyloxepane (3) [(D)-isolaurepan]
To a solution of 19 (30 mg, 0.1 mmol) in THF (3 mL) was added
170 (33); HRMS (FABþ): 310.2004 calculated for C17H30O3Si, found
310.2014.
TBAF (100
m
L of a 1 M solution in THF, 0.1 mmol) and the mixture
4.15. (4aR,6S,8aS)-2,2-Di-tert-butyl-6-propylhexahydropyrano
[3,2-d][1,3,2]dioxasiline (21)
stirred at room temperature for 9 h. The solvent was evaporated to
give a residue, which was chromatographed on silica gel using 1%
EtOAc/hexane as eluent, affording alkyne 190(18 mg, 81%) as a col-
A suspension of 20 (2.5 g, 8.06 mmol) and Pd/C (10%) (241 mg) in
MeOH (35 mL) was stirred under H2 atmosphere for 10 h. The
mixture was filtered through CeliteÒ and the filtered solution was
concentrated under vacuum to give pure 21 (2.45 g, 97%) as a white
20
orless liquid; Rf: 0.61 (20% EtOAc/hexane); [
a
]
ꢀ3.53 (c 0.71,
D
MeOH); IR (film, cmꢀ1): 3298.14, 2927.41, 2857.99, 1457.82, 1106.95,
1002.23; H NMR (CDCl3, ): 3.66e3.57 (1H, m, H-7), 3.47e3.38 (1H,
d
m, H-2), 2.42 (1H, ddd, J¼16.56, 6.11, 2.04 Hz, H-100), 2.27 (1H, ddd,
J¼16.56, 6.65, 1.95 Hz, H-100), 1.95 (1H, s, H-300), 1.93e1.83 (1H, m, H-
3), 1.76e1.41 (9H, m, H-10, H-200, H-3, 2H-4, 2H-5, 2H-6), 1.39e1.21
(8H, m, H-10 H-20, 2H-30, 2H-4 , 2H-50), 0.87 (3H, t, J¼6.16 Hz, 3H-
solid; mp¼64 ꢁC, Rf: 0.7 (20% EtOAc/hexane); IR (NaCl, cmꢀ1):
22
2954.63, 2865.35, 2935.18, 1469.02, 1125.99, 1047.33; [
a
]
ꢀ42.21
D
(c 1.18, CHCl3); H NMR (CDCl3,
d
): 4.07 (1H, dd, J¼10.08, 4.86 Hz, H-
4), 3.81 (1H, t, J¼10.22 Hz, H-4), 3.73e3.68 (1H, m, H-6), 3.39e3.23
(2H, m, H-4a,H-8a), 2.13e2.07 (1H, m, H-8), 1.76e1.68 (1H, m, H-7),
1.53e1.23 (6H, m, H-7, H-8, 2H-10, 2H-20), 1.03 (9H, s, CH3etBu), 0.98
60); C NMR (CDCl3, ): 82.1 (C-200), 80.5 (CH-2), 78.4 (CH-7), 69.1 (C-
d
300), 37.2 (CH2-3), 36.6 (CH2-10), 35.4 (CH2-6), 31.9 (CH2-40), 29.3
(CH2-30), 26.6 (CH2-100), 26.2 (CH2-4), 25.4 (CH2-20), 24.7 (CH2-5),
22.6 (CH2-50), 14.1 (CH3-60); MS (FABþ) [m/z, (%)]: 223 (Mþþ1, 18),
222 (Mþ, 5), 221 (Mþꢀ1, 18), 219 (18), 207 (7), 191 (5), 183 (7), 176
(6); HRMS (FABþ): 222.1984 calculated for C15H27O, found
222.2062.
(9H, s, CH3etBu), 0.89 (3H, s, J¼6.91 Hz, 3H-30); C NMR (CDCl3,
d):
77.5 (CH-4a or CH-8a), 77.5 (CH-4a or CH-8a), 74.1 (CH-6), 67.2
(CH2-4), 37.8 (CH2-10), 32.6 (CH2-8), 30.9 (CH2-7), 27.4 (CH3etBu),
27.1 (CH3etBu), 22.6 (CetBu), 19.9 (CetBu), 18.9 (CH2-20), 14.1 (CH3-
30); MS (FABþ) [m/z, (%)]: 315 (Mþþ1, 31), 314 (Mþ, 24), 313 (Mþꢀ1,
t
A suspension of alkyne 190(18 mg, 81
(17 mg, 1.62
mmol) and Pd/C (10%)
46), 257 (Mþꢀ Bu, 100), 184 (16), 171 (14); HRMS (FABþ): 315.2277
mmol) in MeOH (2 mL) was stirred under H2 atmo-
calculated for C17H35O3Si, found 315.2269.
sphere for 24 h. The catalyst was removed by filtration over CeliteÒ
and the filtrate was concentrated under vacuum to give a residue,
which was chromatographed on silica gel using 1% EtOAc/hexane as
eluent, affording oxepane 3 (18 mg, 98%) as a colorless liquid; Rf:
4.16. (2R,3S,6S)-2-((tert-Butyldiphenylsilyloxy)methyl)-6-
propyltetrahydro-2H-pyran-3-ol (22)
20
20
0.64 (20% EtOAc/hexane); [
a]
þ1.72 (c 0.94, CHCl3); lit.7a
[a
]
To a solution of 21 (1.8 g, 5.73 mmol) in THF (30 mL) was added
TBAF (17.2 mL of a 1 M solution in THF, 17.2 mmol) and the mixture
was stirred at room temperature for 20 h. The solvent was evapo-
rated to afford a residue, which was chromatographed on silica gel
using 50% EtOAc/hexane as eluent, affording diol 210 (0.98 g, 99%) as
D
D
þ1.5 (c 0.97, CHCl3); IR (film, cmꢀ1): 2950.43, 2920.25, 2851.33,
1464.99, 1375.89, 1142.79; H NMR (CDCl3, d): 3.42e3.32 (2H, m, H2,
H-7),1.75e1.59 (4H, m, H-10, H-20, H-3, H-6),1.58e1.39 (8H, m, H-100,
H-200, H-3, 2H-4, 2H-5, H-6), 1.38e1.21 (10H, m, H-10 H-20, H-100, H-
200 2H-30, 2H-40, 2H-50), 0.92e0.84 (6H, m, 3H-300, 3H-60); C NMR
a white solid; mp¼64 ꢁC, Rf: 0.4 (50% EtOAc/hexane); IR (NaCl,
cmꢀ1): 3305.56, 2927.32, 2853.99, 1060.64, 772.26; [
a]
ꢀ11.25 (c
23
(CDCl3,
d
): 80.30 (C-2 or C-7), 80.03 (C-2 or C-7), 39.59 (CH2-100),
D
37.40 (CH2-3), 36.89 (CH2-10), 36.84 (CH2-6), 31.87 (CH2-40), 29.30
(CH2-30), 26.25 (CH2-4), 25.30 (CH2-5), 25.26 (CH2-20), 22.63 (CH2-
50), 19.45 (CH2-5), 14.08 (CH3-300 or CH3-60), 14.04 (CH3-300 or CH3-
60); MS (FABþ) [m/z, (%)]: 227 (Mþþ1, 5), 226 (Mþ, 6), 225 (Mþꢀ1,
7), 183 (26), 179 (10), 167 (13), 166 (11), 165 (29), 163 (12); HRMS
(FABþ): 226.2297 calculated for C15H30O, found 226.2292.
1, CHCl3); H NMR (CDCl3,
d
): 3.82 (1H, dd, J¼11.41, 4.09 Hz, CH2OH),
3.75 (1H, dd, J¼11.43, 4.99 Hz, CH2OH), 3.52 (1H, m, H-3), 3.32 (1H,
m, H-6), 3.16 (1H, td, J¼9.12, 4.53, 4.52 Hz, H-2), 2.59 (2H, s, 2OH),
2.08 (1H, m, H-4), 1.70 (1H, m, H-5), 1.54e1.23 (6H, m, H-4, H-5, 2H-
10, 2H-20), 0.89 (3H, t, J¼6.98 Hz, 3H-30); C NMR (CDCl3,
d): 81.1 (CH-
2), 77.3 (CH-6), 67.7 (CH-3), 63.4 (CH2eOH), 37.8 (CH2-10), 32.5

G. Pazos et al. / Tetrahedron 68 (2012) 8994e9003
9001
(CH2-4), 30.8 (CH2-5), 18.9 (CH2-20), 14.1 (CH3-30); MS (FABþ) [m/z,
(%)]: 175 (Mþþ1, 28), 174 (Mþ, 18), 173 (Mþꢀ1, 49), 162 (12), 157
(MþꢀOH, 61); HRMS (FABþ): 174.1256 calculated for C9H18O3,
found 174.1251.
which was dissolved in MeOH (15 mL). PPTS (0.65 g, 2.61 mmol)
was added and the mixture stirred at room temperature for 1 h. The
product was extracted with EtOAc (3ꢂ15 mL) and the combined
organic phases were washed with an aqueous saturated solution of
NaHCO3 (3ꢂ50 mL) and brine (3ꢂ50 mL). Drying, filtration, and
solvent evaporation afforded a residue, which was chromato-
graphed on silica gel using 1% EtOAc/hexane as eluent, affording
ketone 8 (0.49 g, 66%) along with its isomeric ketone 80 (51 mg, 7%).
To a solution of 210 (0.98 g, 5.6 mmol) in DMF (25 mL) were
added imidazole (0.45 g, 6.72 mmol), TBDPSCl (1.75 mL,
6.72 mmol), and a catalytic amount of DMAP. The mixture was
stirred at room temperature for 30 min and diluted with EtOAc
(40 mL). The resulting organic phase was washed with water
(3ꢂ15 mL) and brine (3ꢂ15 mL), filtered, and evaporated to give
a residue, which was chromatographed on silica gel using 5%
EtOAc/hexane as eluent, affording alcohol 22 (2.28 g, 98%) as
a colorless liquid; Rf: 0.5 (30% EtOAc/hexane); IR (NaCl, cmꢀ1):
4.18.1. Compound 8. Colorless liquid; Rf: 0.52 (20% EtOAc/hexane);
27
IR (NaCl, cmꢀ1): 2931.29, 2857.09, 1715.14, 1110.64, 700.99; [
a
]
D
þ21.25 (c 1.07, CHCl3); H NMR (CDCl3,
d): 7.76 (2H, m, HoePh), 7.68
(2H, m, Hp,mePh), 7.40 (6H, m, PheHp,m), 3.96 (1H, dd, J¼10.70,
4.51 Hz, CH2eOTBDPS), 3.89 (1H, dd, J¼10.68, 2.72 Hz,
CH2eOTBDPS), 3.79 (1H, dd, J¼4.47, 2.75 Hz, H-2), 3.27e3.19
(1H, m, H-7), 3.04 (1H, m, H-4), 2.44 (1H, dd, J¼11.35, 6.66 Hz, H-4),
1.98 (1H, m, H-5), 1.82 (1H, m, H-10), 1.65 (2H, m, H-10, H-5),
1.58e1.27 (4H, m, 2H-20, 2H-6), 1.03 (9H, s, CH3etBu), 0.91 (3H, t,
3423.63, 2931.02, 2857.35, 1461.79, 1106.89, 701.91; [
1.66, CHCl3); H NMR (CDCl3,
a
]
24 þ28.92 (c
D
d
): 7.76e7.69 (4H, m, HoePh),
7.49e7.37 (6H, m, Hp,mePh), 3.92 (1H, dd, J¼10.09, 4.67 Hz,
CH2eOTBDPS), 3.79 (1H, dd, J¼10.06, 7.70 Hz, CH2eOTBDPS),
3.70e3.58 (2H, m, H-3, OH), 3.36e3.24 (2H, m, H-2, H-6), 2.17e2.09
(1H, m, H-4), 1.75e1.66 (1H, m, H-5), 1.56e1.23 (6H, m, H-4, H-5,
2H-10, 2H-20), 1.08 (9H, s, CH3etBu), 0.88 (3H, t, J¼6.79 Hz, 3H-30); C
J¼7.19 Hz, 3H-30); C NMR (CDCl3,
d): 216.6 (C]O), 135.8 and 135.6
(CHoePh), 133.3 and 133.2 (CePh), 129.6 and 129.6 (CHpePh), 127.6
and 127.5 (CHmePh), 87.6 (CH-2), 83.4 (CH-7), 66.2 (CH2eOTBDPS),
43.2 (CH2-4), 39.4 (CH2-6), 36.4 (CH2-10), 26.7 (CH3etBu),
23.7 (CH2-5), 19.2 (CetBu), 18.8 (CH2-20), 14.1 (CH3-30); MS (FABþ)
[m/z, (%)]: 425 (Mþþ1, 7), 424 (Mþ, 12), 423 (Mþꢀ1, 8), 406 (22),
NMR (CDCl3, d): 135.66 and 135.62 (CHoePh), 132.7 and 132.6
(CePh), 129.9 and 129.6 (CHpePh), 127.8 and 127.7 (CHmePh), 79.2
(CH-2), 77.0 (CH-6), 70.9 (CH-3), 67.3 (CH2eOTBDPS), 37.9 (CH2-10),
31.8 (CH2-4), 30.4 (CH2-5), 26.8 (CH3etBu), 26.6 (CH3etBu), 19.1
(CetBu), 18.8 (CH2-20), 14.1 (CH3-30); MS (FABþ) [m/z, (%)]: 412 (Mþ,
t
382 (Mþꢀ Bu, 100), 347 (MþꢀPh, 31), 199 (62), 185 (MþꢀTBDPS,
t
16), 411 (Mþꢀ1, 18), 355 (Mþꢀ Bu, 52), 324 (18), 289 (19), 252 (21),
11); HRMS (FABþ): 424.2434 calculated for C26H36O3Si, found
424.2433.
251 (18), 197 (15), 181 (14); HRMS (FABþ): 412.2434 calculated for
C
25H36O3Si, found 412.2433.
4.18.2. Compound 80. Colorless liquid; Rf: 0.43 (20% EtOAc/hexane);
27
4.17. (2R,6S)-2-((tert-Butyldiphenylsilyloxy)methyl)-6-
propyldihydro-2H-pyran-3(4H)-one (23)
IR (NaCl, cmꢀ1): 2931.32, 2856.98, 1716.25, 1109.85, 701.87; [
a
]
D
ꢀ2.32 (c 0.85, CHCl3); H NMR (CDCl3,
d): 7.62 (4H, m, HoePh), 7.41
(6H, m, Hp,mePh), 3.86 (1H, m, H-2), 3.73 (1H, dd, J¼10.29, 6.02 Hz,
CH2eOTBDPS), 3.51 (1H, dd, J¼10.25, 5.96 Hz, CH2eOTBDPS), 3.47
(1H, m, H-7), 2.74 (2H, m, H-3, H-5), 2.55 (2H, m, H-3, H-5), 2.01
(1H, m, H-6), 1.85 (1H, m, H-6), 1.73e1.23 (4H, m, 2H-10, 2H-20), 1.06
To a solution of alcohol 22 (2.2 g, 5.33 mmol) in CH2Cl2 (40 mL)
ꢁ
were added 4 A molecular sieves (1 g), NMO (1.87 g, 16.01 mmol),
and a catalytic amount of TPAP. The resulting greenish solution was
stirred at room temperature for 18 h. The solvent was evaporated to
afford a residue, which was chromatographed on silica gel using 5%
EtOAc/hexane as eluent, affording ketone 23 (1.8 g, 82%) as a col-
(9H, s, CH3etBu), 0.88 (3H, t, J¼7.09 Hz, 3H-30); C NMR (CDCl3,
d):
211.7 (C]O), 135.6 and 135.5 (CHoePh), 133.4 (CePh), 129.77 and
129.73 (CHpePh), 127.8 and 127.7 (CHmePh), 83.1 (CH-7), 76.9 (CH-
2), 66.6 (CH2eOTBDPS), 48.6 (CH2-3), 42.2 (CH2-5), 38.7 (CH2-10),
32.4 (CH2-6), 26.8 (CH3etBu), 20.2 (CetBu), 19.1 (CH2-20), 14.0 (CH3-
30); MS (FABþ) [m/z, (%)]: 425 (Mþþ1, 11), 424 (Mþ, 14), 423 (Mþꢀ1,
orless liquid; Rf: 0.71 (30% EtOAc/hexane); IR (NaCl, cmꢀ1): 2930.17,
23
2861.02, 1729.76, 1280.64, 1114.79; [
NMR (CDCl3,
a]
ꢀ8.95 (c 1.12, CHCl3); H
D
d): 7.75 (4H, m, HoePh), 7.41 (6H, m, Hp,mePh), 4.01
t
(3H, m, H-6, CH2eOTBDPS), 3.69 (1H, ddd, J¼11.28, 7.73, 3.97 Hz, H-
2), 2.63 (1H, m, H-4), 2.44 (1H, m, H-4), 2.03 (1H, m, H-5), 1.94 (1H,
m, H-5), 1.68 (2H, m, 2H-10), 1.61e1.42 (2H, m, 2H-20), 1.05 (9H, s,
9), 406 (25), 382 (Mþꢀ Bu, 100), 348 (32), 347 (MþꢀPh, 28), 201
(15), 199 (26), 197 (12); HRMS (FABþ): 424.2433 calculated for
C26H36O3Si, found 424.2429.
CH3etBu), 0.99 (3H, t, J¼7.11 Hz, 3H-30); C NMR (CDCl3,
d): 209.8
(C]O), 135.8 and 135.7 (CHoePh), 133.6 and 133.5 (CePh), 129.65
and 129.61 (CHpePh), 127.7 and 127.6 (CHmePh), 83.1 (CH-6), 75.2
(CH-2), 63.7 (CH2eOTBDPS), 38.1 (CH2-4), 37.5 (CH2-10), 30.4 (CH2-
5), 26.7 (CH3etBu), 26.6 (CH3etBu), 19.3 (CetBu), 18.9 (CH2-20), 14.1
(CH3-30); MS (FABþ) [m/z, (%)]: 411 (Mþþ1, 9), 410 (Mþ, 14), 353
(MþetBu, 39), 322 (21), 287 (18), 225 (28), 224 (17), 195 (13), 181
(19), 169 (21), 165 (31), 164 (19); HRMS (FABþ): 411.2277 calculated
for C25H35O3Si, found 411.2262.
4.19. tert-Butyldiphenyl(((2S,7S)-7-propyloxepan-2-yl)me-
thoxy)silane (24)
To a solution of ketone 8 (0.52 g, 1.22 mmol) in MeOH (15 mL)
were added NH2NHTs (0.27 g, 1.47 mmol), PTSA (14 mg,
ꢁ
0.073 mmol), and 4 A molecular sieves (300 mg). The mixture was
stirred at 70 ꢁC for 12 h. The organic solvent was removed under
vacuum and the residue was dissolved in CH2Cl2, washed with
water (3ꢂ15 mL) and brine (3ꢂ15 mL), dried, filtered, and evapo-
rated under reduced pressure. The residue obtained was diluted in
DMF (12 mL) whereupon NaBH3CN (0.25 g, 4.04 mmol) and PTSA
(38 mg, 0.2 mmol) were added and the mixture was stirred at
130 ꢁC for 6 h. The mixture was allowed to reach room temperature.
EtOAc (20 mL) was added and the organic phase washed with water
(3ꢂ20 mL) and brine (20 mL), dried, filtered, and evaporated to give
a residue, which was chromatographed on silica gel using 3%
EtOAc/hexane as eluent, affording oxepane 24 (0.27 g, 55%) as
a gray liquid; Rf: 0.63 (20% EtOAc/hexane); IR (NaCl, cmꢀ1): 2927.25,
4.18. (2R,7S)-2-((tert-Butyldiphenylsilyloxy)methyl)-7-
propyloxepan-3-one (8) and (2S,7S)-2-((tert-butyldiphenylsi-
lyloxy)methyl)-7-propyloxepan-4-one (80)
To a solution of ketone 23 (0.71 g, 1.74 mmol) in CH2Cl2 (15 mL)
at ꢀ78 ꢁC were added BF3$OEt2 (0.26 mL, 2.09 mmol) and TMSCHN2
(0.91 mL of a 2 M solution in hexane, 1.82 mmol). An aqueous
saturated solution of NaHCO3 (15 mL) was added and the mixture
was stirred at ꢀ78 ꢁC for 30 min. The organic phase was separated
and the aqueous phase extracted with EtOAc (3ꢂ15 mL). The
combined organic phases were washed with water (3ꢂ30 mL),
brine (3ꢂ30 mL), dried, filtered, and evaporated to give a residue,
2857.98, 1457.69, 1107.01, 1002.24; [
(CDCl3,
a
]
26 ꢀ13.40 (c 1, CHCl3); H NMR
D
d
): 7.83e7.76 (4H, m, HoePh), 7.44e7.34 (6H, m, Hp,mePh),
3.69 (1H, dd, J¼9.36, 6.31 Hz, CH2eOTBDPS), 3.63e3.56 (1H, m, H-

9002
G. Pazos et al. / Tetrahedron 68 (2012) 8994e9003
7), 3.47 (1H, dd, J¼9.96, 5.67 Hz, CH2eOTBDPS), 3.44e3.39 (1H, m,
H-2), 1.82e1.41 (9H, m, 2H-10, 2H-3, 2H-4, H-5, 2H-6), 1.39e1.20
(3H, m, 2H-20, H-5), 1.06 (9H, s, CH3etBu), 0.88 (3H, t, J¼7.11 Hz, 3H-
4.22. (2R,7S)-2-Hexyl-7-propyloxepane (4) [(L)-isolaurepan]
A suspension of alkene 26 (25 mg, 0.11 mmol) and Pd/C (10%)
(4 mg) in MeOH (2 mL) was stirred under H2 atmosphere for 12 h.
The catalyst was removed by filtration over CeliteÒ and the filtrate
concentrated under vacuum to give (ꢀ)-isolaurepan (24 mg, 96%) as
a colorless liquid; Rf: 0.64 (20% EtOAc/hexane); IR (NaCl, cmꢀ1):
30); C NMR (CDCl3,
d): 135.6 (CHoePh), 133.8 (CePh), 129.5
(CHpePh), 127.55 and 127.52 (CHmePh), 80.5 (CH-7), 80.2 (CH-2),
67.2 (CH2eOTBDPS), 39.4 (CH2-10), 36.8 (CH2-6), 32.4 (CH2-3), 26.8
(CH3etBu), 25.5 (CH2-5), 24.8 (CH2-4), 19.3 (CH2-20), 19.2 (CetBu),
14.1 (CH3-30); MS (FABþ) [m/z, (%)]: 410 (Mþ, 9), 409 (Mþꢀ1, 7), 354
2950.40, 2920.20, 2850.98, 1464.28, 1375.88, 1142.82; [
a
]
25 ꢀ1.86 (c
D
t
(18), 353 (Mþꢀ Bu, 100), 333 (MþꢀPh, 17), 199 (15), 197 (12), 187
0.94, CHCl3); H NMR (CDCl3, d): 3.36 (2H, m, H2, H-6), 1.75e1.61
(10), 181 (14), 161 (19); HRMS (FABþ): 410.2631 calculated for
(4H, m, H-10, H-20, H-3, H-6), 1.59e1.40 (8H, m, H-100, H-200, H-3,
2H-4, 2H-5, H-6), 1.39e1.19 (10H, m, H-10 H-20, H-100, H-200 2H-30,
C
26H38O2Si, found 410.2629.
2H-400, 2H-500), 0.92e0.85 (6H, m, 3H30, 3H-600); C NMR (CDCl3,
d):
80.3 (CH-2 or CH-7), 80.1 (CH-2 or CH-7), 39.6 (CH2-10), 37.4 (CH2-
3), 36.9 (CH2-100), 36.8 (CH2-6), 31.9 (CH2-40), 29.3 (CH2-300), 26.2
(CH2-4), 25.3 (CH2-5), 25.3 (CH2-200), 22.6 (CH2-50), 19.1 (CH2-20),
14.0 (CH3-30 or CH3-600), 13.1 (CH3-30 or CH3-600); MS (ESI) [m/z, (%)]:
227 (Mþþ1, 8), 226 (Mþ, 11), 225 (Mþꢀ1, 10), 183 (31), 167 (17);
HRMS (ESI): 226.2297 calculated for C15H30O, found 226.2294.
4.20. ((2S,7S)-7-Propyloxepan-2-yl)methanol (25)
To a solution of 24 (0.23 g, 0.56 mmol) in THF (10 mL) was added
TBAF (0.84 mL of a 1 M solution in THF, 0.84 mmol) and the mixture
stirred at room temperature for 12 h. The solvent was evaporated to
give a residue, which was chromatographed on silica gel using 10%
EtOAc/hexane as eluent, affording alcohol 25 (92 mg, 96%) as
a colorless liquid; Rf: 0.31 (20% EtOAc/hexane); IR (NaCl, cmꢀ1):
Acknowledgements
3449.46, 2927.68, 2857.36, 1457.81, 1106.90, 1001.36; [
0.92, CHCl3); H NMR (CDCl3,
a
]
26 ꢀ8.33 (c
D
This work was financially supported by the Spanish Ministry of
Education and Science (CTQ2007-61788) and the Xunta de
Galicia (INCITE08PXIB314253PR, INCITE08ENA314019ES, and
INCITE08PXIB314255PR). The work of the NMR and MS divisions of
the research support services of the University of Vigo (CACTI) is
d
): 3.64 (1H, m, H-2), 3.48 (3H, m, H-2,
CH2eOH),1.85e1.20 (12H, m, 2H-10, 2H-20, 2H-3, 2H-4, 2H-5, 2H-6),
0.92 (3H, t, J¼7.10 Hz, 3H-30); C NMR (CDCl3,
d): 80.7 (CH-7), 80.3
(CH-2), 66.4 (CH2eOH), 39.3 (CH2-6), 36.6 (CH2-10), 31.9 (CH2-3),
25.3 (CH2-5), 25.0 (CH2-4), 19.5 (CH2-20), 14.0 (CH3-30); MS (ESI) [m/
z, (%)]: 173 (Mþþ1, 25), 172 (Mþ, 19), 171 (Mþꢀ1, 132), 155 (MþꢀOH,
33), 154 (12); HRMS (ESI): 173.1473 calculated for C10H21O2, found
173.1469.
ꢀ
ꢀ
also gratefully acknowledged. Zoila Gandara and Manuel Perez
~
thank the Xunta de Galicia for an Angeles Alvarino contract and
Gonzalo Pazos, the University of Vigo for a Ph D fellowship.
Supplementary data
4.21. (2S,7S)-2-(Hex-1-enyl)-7-propyloxepane (26)
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.08.094.
To a solution of (COCl)2 (260
mL, 0.52 mmol) in CH2Cl2 (1 mL) at
0
ꢁC was added DMSO (48
mL, 0.68 mmol) and the stirring was
continued for 30 min. Then, a solution of alcohol 25 (30 mg,
References and notes
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2927.36, 2857.98, 1659.36, 1459.87, 1106.08; [
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ꢀ4.82 (c 0.78,
D
CHCl3); H NMR (CDCl3, d
): 5.45 (1H, m, H-10), 5.38 (1H, m, H-20),
~
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ꢀ~
ꢀ
ꢀ
ꢀ
ꢀ
Commun. 2009, 3552; (b) Zuniga, A.; Perez, M.; Pazos, G.; Gomez, G.; Fall, Y.
ꢀ~
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(CH-200), 130.3 (CH-100), 79.5 (CH-2), 75.9 (CH-7), 39.4 (CH2-10), 37.1
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(Mþꢀ1, 11), 167 (21), 166 (19); HRMS (ESI): 224.2140 calculated for
ꢀ~
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
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15H28O, found 224.2138.

G. Pazos et al. / Tetrahedron 68 (2012) 8994e9003
9003
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