Synthesis of the bis-spiroacetal core of the antimitotic agent spirastrellolide B

Article abstract of DOI:10.1021/jo201729t

The spirastrellolides are a family of potent antimitotic agents isolated from the marine sponge Spirastrella coccinea. Synthetic studies toward the DEF bis-spiroacetal core of spirastrellolide B are reported. A modular approach was pursued by the use of t

Full text of DOI:10.1021/jo201729t

Article
pubs.acs.org/joc
Synthesis of the Bis-Spiroacetal Core of the Antimitotic Agent
Spirastrellolide B
Jack Li-Yang Chen and Margaret A. Brimble*
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand
S
* Supporting Information
ABSTRACT: The spirastrellolides are a family of potent
antimitotic agents isolated from the marine sponge Spirastrella
coccinea. Synthetic studies toward the DEF bis-spiroacetal core
of spirastrellolide B are reported. A modular approach was
pursued by the use of two dithiane disconnections to enable a
highly convergent synthesis. The ease of lithiation and
nucleophilicity of these 2-substituted-1,3-dithianes were
investigated during the course of the synthesis, and the
alkylations were found to proceed most efficiently at elevated temperatures. Formation of the [5,6,6]-bis-spiroacetal ring system
was achieved via a double dithiane deprotection/spiroacetalization strategy.
modular strategies, with disconnections made to isolate each of
the regions of known relative stereochemistry. The complex
structure of the spirastrellolides has generated a great deal of
interest within the synthetic community,3 and of particular
interest to our research group is the intriguing DEF-bis-
spiroacetal.4 Our preliminary results on the use of a double
dithiane deprotection/spiroacetalization strategy to construct
the [5,6,6]-bis-spiroacetal core was described in a previous
communication.5 Herein, we disclose the full details of our
synthetic efforts toward the DEF bis-spiroacetal of spirastrello-
lide B, in particular highlighting the two carefully optimized
dithiane alkylations to construct our highly functionalized
cyclization precursor.6
INTRODUCTION
■
The spirastrellolides are a family of polyketide macrolides
isolated from the marine sponge Spirastrella coccinea that
exhibit potent antimitotic activity.1 The spirastrellolides exhibit
this activity not by the disruption of tubulin/spindle formation
like other sponges' macrolide antimitotics (e.g., the spongista-
tins and laulimalides), but by their potent inhibiton of Ser/Thr
protein phosphatase PP2A (IC50 = 1 nM). PP2A is an enzyme
involved in cellular signaling that is emerging as a novel
medicinal target for the treatment of cancer.2 The ability to
synthesize the spirastrellolides is therefore important not only
for its potential as a therapeutic agent but also for its use as a
biological tool in the investigation of PP2A function.
Spirastrellolide A (1, Figure 1) was the first member of its
family to be isolated in 20031c and allowed the determination of
RESULTS AND DISCUSSION
■
We envisaged synthesis of the interesting [5,6,6]-bis-spiroacetal
of spirastrellolide B using a highly convergent route involving
two dithiane alkylations. Formation of the key tricyclic bis-
spiroacetal would be achieved using a double dithiane
deprotection/spiroacetalization strategy. The structure of the
DEF bis-spiroacetal moiety benefits from full anomeric
stabilization, and in addition, all of its substituents occupy
equatorial positions. The desired configuration at C31 and C35
should therefore result from bis-dithiane deprotection of acyclic
precursor 4 (Scheme 1) under equilibrating conditions to form
the desired bis-spiroacetal 3. Acyclic precursor 4 is accessible
via alkylation of dithiane 6 with iodide 5, which in turn is
prepared via union of dithiane 7 with epoxide 8. These two
successive dithiane alkylations considerably simplify the carbon
backbone of the target into three smaller fragments, thereby
facilitating a highly convergent approach to DEF bis-spiroacetal
3.
Figure 1. Spirastrellolides A and B and the DEF bis-spiroacetal.
the relative stereochemistry within each of the C3−C7 (A),
C9−C24 (BC), and C27−C38 (DEF) fragments. The absolute
configuration of the macrolide core was not determined until
the availability of a crystalline derivative of spirastrellolide B (2)
in 2007.1b Early synthetic strategies therefore relied on highly
Received: August 21, 2011
Published: October 13, 2011
© 2011 American Chemical Society
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Scheme 1. Retrosynthesis of DEF Bis-Spiroacetal 3
The initial objective was to construct the dithiane C32−35
fragment 7 and investigate its use as an umpolung alkylating
agent. Synthesis began with Sharpless epoxidation7 of allylic
alcohol 9 (Scheme 2), which was readily available from 1,3-
Table 1. Examination of Conditions for the Lithiation of
Dithiane 11
Scheme 2. Synthesis of Dithiane Fragment 11
base
used
temp
time
deuteration
(%)
additives
none
(°C)
(min)
1
2
3
4
t-BuLi
t-BuLi
s-BuLi
s-BuLi
−78
−78
−50
−50
30
60
15
30
0
<5
0
10% HMPA
none
DMPU/
TMEDA
<5
5
6
n-BuLi
n-BuLi
none
none
−20
rt
60
5
<5
<5
propanediol in 58% yield over a four step sequence.
Regioselective epoxide opening with trimethylaluminium8
followed by oxidative cleavage then afforded aldehyde 10.
The lability of the PMB group precluded the conventional use
of BF3·Et2O after the installation of the dithiane moiety, which
was successfully formed by the treatment of aldehyde 10 with
1,3-propanedithiol in the presence of CoCl2.9 Dithiane 11,
however, proved ineffective for subsequent alkylation reactions,
and deuterium exchange experiments were conducted to
investigate the ease of lithiation at C2 of the 1,3-dithiane. To
our surprise, treatment of dithiane 11 with a variety of bases,
with or without additives such as HMPA and DMPU, failed to
give any significant metalation (see Table 1). This difficulty in
lithiation may be due to donation of electron density from the π
system of the PMB group to the C−S σ* of the dithiane, thus
reducing the ability of the σ* to increase the acidity of the α-
hydrogen (Figure 2).10 Efforts were thus directed toward
finding an alternative protecting group for dithiane fragment
11.
Deprotection of the PMB ether was first attempted using
DDQ but resulted in low yields of 20−50%. The use of
BF3·Me2S proved effective in removing the PMB ether, which
was readily converted to TBS ether 12 in 68% yield over the
two steps (Scheme 3). Lithiation of TBS-protected dithiane 12
was now readily achievable, though the results varied greatly
with temperature. Although most dithiane alkylations are
performed at temperatures of −20 °C or below, we found
lithiation to be most efficient using n-BuLi at 0 °C or room
Figure 2. Proposed explanation for the slow deprotonation of dithiane
11.
Scheme 3. Synthesis of Dithiane Fragment 12
temperature following short reaction times (entries 7−8, Table
2). The deuterium exchange experiments conducted using n-
BuLi at −20 °C (entries 3−5, Table 2) initially revealed an
increase and then a decrease in deuterium incorporation, which
suggests the lithiated species has a limited lifetime in solution.
The use of a 4:1 mixture of n-BuLi−Bu2Mg11 (entry 11, Table
2) was shown to greatly increase the lifetime of the metalated
species.
Synthesis of epoxide fragment 8 (Scheme 4) began with an
investigation into the Sharpless dihydroxylation12 of allylic
chlorides 14a and 14b, both readily available from the
corresponding allylic alcohol. Initial investigations were
performed with TBDPS-protected allylic chloride 14a, where
the anthraquinone (AQN)13 linker (90% ee) was found to be
superior to both the phthalazine (PHAL) and pyrimidine
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over the two steps. Attempts to convert alcohol 15 into the
requisite iodide using either Appel or Finkelstein conditions
only resulted in decomposition of the starting material. From
the previous literature, it appears that in the presence of a
proximal leaving group, 2,2-disubstituted dithianes readily
undergo intramolecular alkylation to form unstable ring-
expanded products.15 To circumvent this problem, alcohol 15
was first oxidized using tetrapropyl ammonium perruthenate
(TPAP)/NMO16 and converted to N-TBS-tosylhydrazone 17
in order to attempt a Myers reductive coupling17 to bring
together fragments 17 and 6.
Table 2. Examination of Conditions for the Lithiation of
Dithiane 12
temp
time
deuteration
(%)
base used
t-BuLi
additives
none
10%
(°C)
(min)
1
2
−78
−78
30
60
15
10
t-BuLi
HMPA
Synthesis of the dithiane C25−C31 fragment 6 utilized triol
19 (Scheme 6), which was derived from D-(+)-ribonic acid γ-
lactone (20) in 45% over five steps.18 Initial attempts to
convert this 1,2,4-triol (19) into epoxide 21 via a two-step
sulfonation/displacement sequence were met with difficulties.
Following careful experimentation, it was discovered that the
most efficient way to generate this epoxide and avoid side
reactions was to treat triol 19 with potassium hexamethyldi-
silazide (KHMDS) for a short period of time at high dilution,
followed immediately by the addition of N-(2,4,6-
triisopropylbenzenesulfonyl)imidazole.19 Following EOM pro-
tection, epoxide 21 was isolated in 53% yield over these two
steps. Alkylation of epoxide 21 with lithiated-1,3-dithiane
followed by methylation then provided the desired C25−C31
dithiane fragment 6.
3
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
none
−20
−20
−20
0
5
15
60
5
11
41
22
44
81
81
0
4
none
5
none
6
none
7
none
0
15
5
8
none
rt
9
TMEDA
DMPU
none
−20
0
90
15
60
10
11
76
72
n-BuLi−B
rt
u2Mg
Scheme 4. Synthesis of Epoxide 8
The lithiation of dithiane 6 was investigated using conditions
successfully employed for the alkylation of dithiane C32−C35
fragment 12. n-BuLi appeared sufficient to achieve lithiation
using a short reaction time (entries 1−3, Table 4), but when
these conditions were employed for the alkylation with model
iodide 22 (entries 1−2, Table 5), no product was observed.
Treatment of dithiane 6 with t-BuLi in 10% HMPA−THF
achieved efficient lithiation at −78 °C (entry 5, Table 4) and
was accompanied by a deep red coloration. Successful
alkylation with model iodide 22 (entry 3, Table 5) was
achieved under these conditions.
These latter conditions were next employed in the
investigation of the reductive alkylation of 6 with N-TBS-
tosylhydrazone 17. Although we were able to demonstrate
successful union of a model N-TBS-tosylhydrazone (23) with
lithio-1,3-dithiane (Scheme 7), attempts to alkylate 2-
substituted dithiane 6 with advanced N-TBS-tosylhydrazone
17 were unsuccessful (Scheme 8). Following several alkylation
attempts, only full recovery of both starting materials was
observed. Attention thus turned to the use of aldehyde 18 for
later alkylations, with the hope that the resulting superfluous
hydroxyl group formed could be readily removed via Barton−
McCombie deoxygenation.20
(PYR) linkers (72−74% ee; entries 1−4, Table 3). Further
improved results were achieved with PMB-protected 14b as the
Table 3. Asymmetric Dihydroxylation of Allylic Alcohol 14
R
chiral ligand (ligand/mol %) OsO4 (mol %) ee (%)
1
2
3
4
5
TBDPS
TBDPS
TBDPS
TBDPS
PMB
(DHQ)2PHAL/5
(DHQ)2PHAL/10
(DHQ)2PYR/5
(DHQ)2AQN/5
(DHQ)2AQN/5
1
72
74
73
90
94
0.25
1
1
1
Although the t-BuLi/HMPA conditions were suitable to
achieve efficient alkylation of model iodide 22 with dithiane 6
(entry 3, Table 5), the same conditions failed to achieve
alkylation of dithiane 6 with the required aldehyde 18 (Scheme
9). It is uncertain whether higher temperatures were needed for
alkylation to proceed; however when n- or t-BuLi was used,
higher temperatures resulted in rapid decomposition of the
anion. An efficient way to generate the dithiane anion at a
higher temperature was again found to involve the use of a 4:1
mixture of n-BuLi−Bu2Mg (entry 6, Table 4). Under these
conditions, the metalated anion as observed by the deep red
coloration was maintained for over an hour at room
temperature. Use of this mixed organometallic reagent finally
allowed effective union of dithiane 6 and aldehyde 18 to afford
substrate, which allowed access to the desired diol in 94% ee,
superior to the previously reported example using PHAL (88%
ee).14 Subsequent treatment with NaOH to form the epoxy
alcohol followed by protection as an ethoxymethyl (EOM)
ether provided epoxide 8 in 72% over 4 steps.
Union of dithiane 12 and epoxide 8 (Scheme 5) was
efficiently achieved by treatment of dithiane 12 (1.6 equiv) with
n-BuLi at room temperature, followed by the addition of
epoxide 8. The coupled product was isolated in quantitative
yield, and excess dithiane 12 was fully recovered. Protection of
the resulting secondary alcohol as a benzyl ether, followed by
treatment with TBAF afforded primary alcohol 15 in 82% yield
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Scheme 5. Synthesis of N-TBS Hydrazone Derivative 17
Scheme 6. Synthesis of C25−C31 Dithiane Fragment 6
Table 5. Conditions Attempted for the Model Alkylation of
Dithiane 6
base
used
time
additives
none
temp (°C)
(min)
result (%)
1
2
3
n-BuLi
n-BuLi
t-BuLi
−78 to
−50
15
15
15
no
reaction
DMPU (2 equiv)
10% HMPA
−78 to
no
reaction
−50
Table 4. Conditions Attempted for the Lithiation of Dithiane
6
−78
73
Scheme 7. Successful Union of a Model N-TBS-
tosylhydrazone (23) with Lithio-1,3-dithiane
time
deuteration
(%)
base used
n-BuLi
additives
none
temp (°C)
(min)
1
2
3
rt
5
30
15
50
24
75
n-BuLi
n-BuLi
none
none
−78
−78 to
−50
4
5
6
t-BuLi
t-BuLi
10%
−78 to
−50
−78
30
15
5
39
90
85
HMPA
10%
HMPA
was decided to first investigate the crucial double dithiane
deprotection/spiroacetalization sequence and to perform the
deoxygenation following bis-spiroacetal formation.
n-BuLi−
none
rt
Bu2Mg
The C32 secondary alcohol was first protected as a methyl
ether to allow investigation of the bis-dithiane deprotection−
bis-spiroacetalization sequence (Scheme 10).23 Several meth-
ods were examined for the double EOM deprotection, with best
results found to be the use of PPTS in t-BuOH24 to furnish the
corresponding diol in 66% yield. Gratifyingly, the bis-dithiane
deprotection step was accomplished by treatment of the diol
with HgCl2, resulting in concomitant bis-spiroacetalization to
generate the desired bis-spiroacetal 26 as a single diaster-
eoisomer in 62% yield. The double anomerically stabilized
bis-dithiane 24 in 78% yield as a 3:2 mixture of diastereomers
(Scheme 9). The epimeric alcohols 24 were separated by
preparative TLC.
A large number of attempts to remove the superfluous
hydroxyl group of alcohol 24 using Barton−McCombie,
Martin’s sulfurane,21 chlorodiphenylsilane/InCl3,22 and mesy-
lation/LiAlH4 conditions were unsuccessful. At this point, it
was postulated that the presence of the two dithiane moieties
were impeding further functionalization of the alcohol. Thus it
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Scheme 8. Unsuccessful Alkylation of 2-Substituted Dithiane 6 with Advanced N-TBS-tosylhydrazone 17
Scheme 9. Synthesis of Bis-Dithiane 24
Scheme 10. Synthesis of Bis-Spiroacetal 26
Scheme 11. Synthesis of Bis-Spiroacetal 27
(Scheme 12), the structure of which was confirmed by the
presence of characteristic carbonyl carbon at δ 211.9 in the 13
configuration was confirmed by a strong NOE correlation
between the C27 and C38 methine protons, and the R
stereochemistry at C32 was established by analysis of coupling
constants.
C
NMR spectrum. These results demonstrate the highly sterically
hindered nature of the C32 hydroxyl group. Attempts to use
Martin’s sulfurane and mesylation/LiAlH4 conditions were also
unsuccessful. It was therefore concluded that in spite of our
earlier misleading communication,5 deoxygenation of alcohol
27 could not be achieved. Similar difficulties were also
experienced using the epimeric equatorial C32 alcohol.
Attempts to effect mesylation of alcohol 27 and subsequent
elimination to an alkene that could be reduced also met with no
success.
Following successful demonstration of the bis-dithiane
deprotection−tandem spiroacetalization methodology, further
synthetic efforts were undertaken to investigate the late-stage
deoxygenation step. Treatment of unprotected alcohol 24b
with PPTS in t-BuOH at 85 °C provided the corresponding
triol (Scheme 11). Upon addition of HgCl2, the desired bis-
spiroacetal 27 was formed in 74% yield as a single diastereomer,
with no sign of competing cyclizations. The stereochemistry of
this fully anomerically stabilized bis-spiroacetal was also
confirmed by analysis of NOE correlations.
CONCLUSION
■
In summary, we have shown that the core of the DEF bis-
spiroacetal ring system of spirastrellolide B can be accessed
using a double dithiane deprotection/spiroacetalization strat-
egy. Synthesis of the acyclic precursor required careful
Attempts to form the xanthate and phenoxythiocarbonyl
derivatives of bis-spiroacetal 27 were met with disappointment,
and efforts to form the thiocarbonylimidazole derivative
resulted in the formation of ring-opened derivative 2825
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18
= 0.26; [α]D = +14.3 (c 0.78, CHCl3); HRMS found (FAB)
M+, 222.1259, C13H18O3 requires 222.1256; IR (film) 2934,
2860, 2717, 1723, 1613, 1513, 1247, 1174, 1097, 1034, 821
cm−1; 1H NMR (400 MHz, CDCl3) δ 9.63 (d, 1H, J = 2.0 Hz),
7.23 (d, 2H, J = 8.7 Hz), 6.87 (d, 2H, J = 8.7 Hz), 4.40 (s, 2H),
3.79 (s, 3H), 3.54−3.45 (m, 2H), 2.56−2.48 (m, 1H), 2.07−
1.98 (m, 1H), 1.71−1.63 (m, 1H), 1.09 (d, 3H, J = 7.0 Hz);
13C NMR (100 MHz, CDCl3) δ 204.6, 159.1, 130.2, 129.2,
113.7, 72.6, 67.0, 55.2, 43.7, 30.8, 13.2; m/z (EI) 222 (M+, 1%),
152 (6), 137 (62), 121 (100), 107 (4), 91 (4), 85 (3), 77 (9).
(S)-2-(4-(4-Methoxybenzyloxy)butan-2-yl)-1,3-dithiane
(11). To a solution of aldehyde 10 (446 mg, 2.01 mmol) in
CH3CN (10 mL) was added 1,3-propanedithiol (0.242 mL,
2.41 mmol) followed by a catalytic amount of CoCl2·6H2O
(23.9 mg, 0.100 mmol), and the mixture was stirred at rt for 2
h. The reaction mixture was then concentrated and purified by
flash chromatography (hexanes/EtOAc 9:1) to afford the title
compound 11 (504 mg, 1.61 mmol, 80%) as a colorless oil: Rf
Scheme 12. Attempts to Form the Thiocarbonylimidazole
Derivative of Bis-Spiroacetal 27
optimization of the dithiane alkylation conditions. Although
dithiane alkylations are conventionally performed at low
temperatures, the best results for our substrates were obtained
at room temperature following short reaction times. These
alkylations include the alkylation of 2-substituted-1,3-dithianes
with an epoxide and an aldehyde. The latter method required
the use of the mixed organometallic reagent n-BuLi−Bu2Mg to
prolong the lifetime of the lithiated anion in order to facilitate
nucleophilic attack. Efforts are ongoing to improve the current
synthesis and to construct the DEF bis-spiroacetal without the
extraneous C32 hydroxyl group. In the meantime, the current
synthetic route can be used to access C32 oxygenated
analogues of the DEF bis-spiroacetal in order to investigate
their PP2A activity.
23
(hexanes/EtOAc 3:1) = 0.42; [α]D = +6.3 (c 0.80, CHCl3);
HRMS found (EI) M+, 312.1223, C16H24O2S2 requires
312.1218; IR (film) 2954, 2931, 2899, 2859, 1611, 1511,
1
1239, 1172, 1089, 1032, 818, 753, 518 cm−1; H NMR (300
MHz, CDCl3) δ 7.26 (d, 2H, J = 8.8 Hz), 6.87 (d, 2H, J = 8.8
Hz), 4.43 (s, 2H), 4.11 (d, 1H, J = 4.0 Hz), 3.80 (s, 3H), 3.56−
3.44 (m, 2H), 2.94−2.80 (m, 4H), 2.16−2.04 (m, 2H, 2-H),
2.01−1.90 (m, 1H), 1.89−1.74 (m, 1H), 1.59 (ddt, 1H, J =
14.1, 8.2, 6.0 Hz), 1.08 (d, 3H, J = 7.0 Hz); 13C NMR (75
MHz, CDCl3) δ 159.1, 130.7, 129.2, 113.8, 72.4, 67.7, 55.3,
55.3, 35.4, 33.8, 31.1, 30.8, 26.4, 17.0; m/z (EI) 312 (M+,
3.5%), 191 (100), 173 (10), 121 (90), 119 (35), 107 (6), 85
(17), 41 (10).
(S)-2-(1,3-Dithian-2-yl)butan-4-ol. To a stirred solution of
BF3·OEt2 (0.493 mL, 6.64 mmol) in CH2Cl2 (5 mL) was added
Me2S (0.493 mL, 6.64 mmol), and the mixture was stirred at rt
for 20 min. A solution of PMB ether 11 (217 mg, 0.694 mmol)
in CH2Cl2 (2 mL) was added, and the mixture was stirred at rt
for a further 20 min. The reaction was quenched by the
addition of saturated aq NaHCO3 (10 mL) and stirred at rt for
20 min. The layers were separated, and the aqueous layer was
extracted with EtOAc (2 × 15 mL). The organic layers were
combined, washed with brine, dried over MgSO4, and
concentrated in vacuo. Purification by flash chromatography
(hexanes/EtOAc 1:1) afforded the title compound (107 mg,
0.556 mmol, 80%) as a colorless oil: Rf (hexanes/EtOAc 1:1) =
EXPERIMENTAL SECTION
■
Synthesis of Dithiane C32−C35 Fragment 7. (2S,3S)-
5-(4-Methoxybenzyloxy)-3-methylpentane-1,2-diol.26 To a
stirred solution of the epoxy alcohol (1.98 g, 8.31 mmol) in
CH2Cl2 (35 mL) and hexanes (16 mL) was added dropwise
trimethylaluminium (18.3 mL, 2.0 M in hexanes, 35.6 mmol) at
0 °C, and the mixture was allowed to warm to rt and stirred
overnight. The reaction mixture was diluted with Et2O (60
mL), H2O (1.4 mL) was added, and the mixture was stirred
vigorously at rt until a white gelatinous precipitate formed. To
the mixture was added 1.3 M NaOH (4.2 mL), and the mixture
was stirred vigorously until a white gel formed on the surface of
the flask and the bulk of the solution became clear. The liquid
was decanted, and the white solid gel was extracted with Et2O
(2 × 60 mL). The combined organic layers were dried over
MgSO4, concentrated in vacuo, and purified by flash
chromatography (hexanes/EtOAc 1:9) to afford the title
compound (1.64 g, 6.46 mmol, 78%) as a colorless oil.
(S)-4-(4-Methoxybenzyloxy)-2-methylbutanal (10). To a
stirred solution of sodium periodate (1.50 g, 6.99 mmol) in a
1:1 mixture of THF−H2O (26 mL) was added dropwise a
solution of the diol (1.62 g, 6.36 mmol) in THF (10 mL), and
the mixture was stirred at rt for 15 min. To the resulting cloudy
solution was added a 2:1 mixture of PhH−Et2O (75 mL), and
the organic layer was washed with H2O (20 mL), dried over
MgSO4, and concentrated in vacuo. The crude aldehyde 10
(1.40 g, 6.29 mmol, 99%) was isolated as a colorless oil and
used in the next reaction without further purification. A sample
of the product was purified by flash chromatography (hexanes/
EtOAc 9:1) for spectroscopic analysis: Rf (hexanes/EtOAc 9:1)
24
0.39; [α]D = −3.6 (c 0.72, CHCl3); HRMS found (ESI) M+ +
Na, 215.0527, C8H16NaOS2 requires 215.0535; IR (film) 3368
br, 2930, 2896, 1454, 1422, 1379, 1276, 1084, 1053, 1009, 907,
765 cm−1; 1H NMR (300 MHz, CDCl3) δ 4.18 (d, 1H, J = 4.2
Hz), 3.80−3.63 (m, 2H), 2.97−2.81 (m, 4H), 2.17−2.03 (m,
2H, 2-H), 1.97−1.76 (m, 3H), 1.60 (ddt, 1H, J = 14.0, 8.1, 6.0
Hz), 1.69 (d, 3H, J = 6.8 Hz); 13C NMR (75 MHz, CDCl3) δ
60.8, 55.3, 36.9, 35.3, 31.0, 30.8, 26.3, 17.1; m/z (ESI) 215 (M+
+ Na, 100%), 188 (28), 171 (61), 143 (10), 126 (13), 100
(22).
(S)-2-(4-(tert-Butyldimethylsilyloxy)butan-2-yl)-1,3-di-
thiane (12).5 To a stirred solution of the alcohol (312 mg,
1.63 mmol) in CH2Cl2 (16 mL) at rt were added triethylamine
(0.679 mL, 4.88 mmol), tert-butyldimethylsilyl chloride (367
mg, 2.44 mmol), and N,N-dimethyl-4-aminopyridine (20 mg,
0.16 mmol), and the mixture was stirred for 2.5 h at this
temperature. Saturated aq NH4Cl (10 mL) was added, the
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 20 mL). The organic layers were combined,
9422
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Article
washed with brine, dried over MgSO4, and concentrated in
vacuo. Purification by flash chromatography (hexanes/EtOAc
30:1) afforded the title compound 12 (423 mg, 1.38 mmol,
85%) as a colorless oil.
mL, 5.87 mmol) at 0 °C, and the mixture was stirred at rt for 1
h. The mixture was cooled to −20 °C, and a solution of allylic
alcohol 9 (1.03 g, 4.63 mmol) in CH2Cl2 (5 mL) was added
dropwise. After stirring for 30 min at 0 °C, the mixture was
warmed to rt and stirred overnight. H2O (10 mL) was added,
the layers were separated, and the organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo.
Purification by flash chromatography (hexanes/EtOAc 9:1)
afforded the title compound 14b (1.04 g, 4.31 mmol, 93%) as a
light yellow oil: Rf (hexanes/EtOAc 9:1) = 0.33; HRMS found
(ESI) (M + Na)+ 263.0803 and [(M + 2) + Na]+ 265.0775,
C13H1735ClNaO2 requires 263.0809 and C13H1737ClNaO2
requires 265.0780; IR (film) 2950, 2935, 2904, 2856, 1612,
1512, 1464, 1441, 1361, 1302, 1245, 1172, 1094, 1033, 966,
815, 672 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.27 (d, 2H, J =
8.7 Hz), 6.89 (d, 2H, J = 8.7 Hz), 5.82 (dt, 1H, J = 15.2, 6.5
Hz), 5.74−5.64 (m, 1H), 4.45 (s, 2H), 4.04 (dd, 2H, J = 6.8,
0.7 Hz), 3.81 (s, 3H), 3.51 (t, 2H, J = 6.6 Hz), 2.38 (dtd, 2H, J
= 6.6, 6.6, 0.8 Hz); 13C NMR (75 MHz, CDCl3) δ 159.2, 132.3,
130.3, 129.2, 127.6, 113.7, 72.5, 68.9, 55.2, 45.1, 32.5; m/z
(ESI) 263 (M+ + Na, 5%), 227 (12), 137 (25), 121 (100).
(2R,3S)-1-Chloro-5-(4-methoxybenzyloxy)pentane-2,3-
diol. A solution of (DHQ)2AQN (36 mg, 0.042 mmol),
osmium tetroxide (0.14 mL; 2.5 wt % solution in t-butanol,
0.010 mmol), K3[Fe(CN)6] (2.05 g, 6.23 mmol), K2CO3 (861
mg, 6.23 mmol), NaHCO3 (523 mg, 6.23 mmol), and
methanesulfonamide (174 mg, 2.08 mmol) in a 1:1 mixture
of t-butanol−H2O (12.5 mL) was treated with a solution of
allylic halide 14b (509 mg, 2.11 mmol) in t-butanol (2 mL),
and the mixture was stirred at 0 °C for 14 h. Na2S2O5 (1.98 g)
was added portionwise over 30 min with vigorous bubbling,
and the mixture was stirred at rt for 1 h. The layers were
separated, and the aqueous layer was extracted with EtOAc (3
× 20 mL). The combined organic layers were washed with 1 M
aq KOH (8 mL), 1 M aq HCl (8 mL), and brine, dried over
MgSO4, and concentrated in vacuo. Purification by flash
chromatography (hexanes/EtOAc 2:3) afforded the title
compound (560 mg, 2.07 mmol, 81%, 94% ee) as a colorless
Synthesis of epoxide C36−C40 fragment 8. (E)-5-
(tert-Butyldiphenylsilyloxy)-1-chloropent-2-ene (14a). To a
stirred solution of N-chlorosuccinimide (2.39 g, 17.9 mmol) in
CH2Cl2 (30 mL) was added Me2S (1.32 mL, 17.9 mmol) at 0
°C, and the mixture was stirred at rt for 1.5 h. The mixture was
cooled to −20 °C, and a solution of allylic alcohol 13 (2.03 g,
5.96 mmol) in CH2Cl2 (10 mL) was added dropwise. After
stirring for 30 min at 0 °C, the mixture was warmed to rt and
stirred for a further 2 h. H2O (15 mL) was added, the layers
were separated, and the organic layer was washed with brine,
dried over MgSO4, and concentrated in vacuo. Purification by
flash chromatography (hexanes/EtOAc 20:1) afforded the title
compound 14a (2.02 g, 5.63 mmol, 94%) as a colorless oil: Rf
(hexanes/EtOAc 20:1) = 0.38; HRMS found (FAB) MH+
359.1598 and (M + 2)H+ 361.1558, C21H2835ClOSi requires
359.1598 and C21H2837ClOSi requires 361.1569; IR (film)
3071, 2956, 2930, 2857, 1472, 1427, 1111, 966, 823, 737, 701,
687, 613 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.68−7.65 (m,
4H), 7.42−7.34 (m, 6H), 5.80 (dtd, 1H, J = 15.2, 6.8, 0.8 Hz),
5.68 (dtt, 1H, J = 15.2, 6.8, 1.1 Hz), 4.02 (dd, 2H, J = 6.8, 0.8
Hz), 3.73 (t, 2H, J = 6.5 Hz), 2.33 (dtd, 2H, J = 6.8, 6.5, 1.1
Hz), 1.05 (s, 9H, OSitBuPh2); 13C NMR (100 MHz, CDCl3) δ
135.6, 133.8, 132.5, 129.6, 127.8, 127.6, 63.1, 45.2, 35.4, 26.8,
19.2; m/z (EI) 301 (7%), 265 (11), 247 (58), 217 (100), 181
(17), 135 (16), 91 (39).
(2R,3S)-5-(tert-Butyldiphenylsilyloxy)-1-chloropentane-
2,3-diol. A stirred solution of dihydroquinine (DHQ)2AQN
(92 mg, 0.11 mmol), osmium tetroxide (0.30 mL; 2.5 wt %
solution in t-butanol, 0.021 mmol), K3[Fe(CN)6] (2.09 g, 6.35
mmol), K2CO3 (877 mg, 6.35 mmol), NaHCO3 (531 mg, 6.32
mmol), and methanesulfonamide (205 mg, 2.16 mmol) in t-
butanol/H2O (1:1) (11 mL) was treated with a solution of
allylic halide 14a (767 mg, 2.14 mmol) in t-butanol (2 mL),
and the mixture was stirred at 0 °C for 2 d. Na2S2O5 (2.02 g)
was added portionwise over 30 min with vigorous bubbling,
and the mixture was stirred at rt for 1 h. The layers were
separated, and the aqueous layer was extracted with EtOAc (3
× 20 mL). The combined organic layers were washed with 1 M
KOH (8 mL), 1 M HCl (8 mL), and brine, dried over MgSO4,
and concentrated in vacuo. Purification by flash chromatog-
raphy (hexanes/EtOAc 7:3) afforded the title compound (840
mg, 2.14 mmol, 91%, 90% ee) as a colorless oil that solidified on
standing in vacuo overnight to form a colorless solid (mp 50−
17
oil: Rf (hexanes/EtOAc 2:3) = 0.36; [α]D = +15.0 (c 0.99,
CHCl3); HRMS found (ESI) (M + Na)+ 297.0863 and [(M +
2) + Na]+ 299.0836, C13H1935ClNaO4 requires 297.0864 and
C13H1737ClNaO2 requires 299.0834; IR (film) 3312 br (OH),
2954, 2924, 2906, 2870, 1614, 1517, 1453, 1430, 1305, 1255,
1179, 1163, 1129, 1074, 1054, 1033, 1008, 990, 927, 850, 810,
760, 695 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.24 (d, 2H, J =
8.7 Hz), 6.89 (d, 2H, J = 8.7 Hz), 4.46 (s, 2H), 3.97 (dt, 1H, J =
8.8, 2.8 Hz), 3.81 (s, 3H), 3.73−3.53 (m, 5H), 3.27 (br s, 1H),
2.91 (br s, 1H), 2.03−1.90 (m, 1H), 1.76 (dddd, 1H, J = 14.7,
5.0, 3.6, 3.6 Hz); 13C NMR (75 MHz, CDCl3) δ 159.4, 129.6,
129.4, 113.9, 74.0, 73.1, 70.6, 68.1, 55.3, 45.8, 33.1; m/z (ESI)
297 (M+ + Na, 4%), 195 (9), 177 (5), 121 (100).
26
53 °C): Rf (hexanes/EtOAc 7:3) = 0.27; [α]D = +8.35 (c
0.80, CHCl3); HRMS found (FAB) MH+ 393.1655 and (M +
2)H+ 395.1631, C21H3035ClO3Si requires 393.1653 and
C21H3037ClO3Si requires 395.1623; IR (film) 3417 br, 3071,
2958, 2931, 2858, 1472, 1427, 1112, 922, 757, 702, 614 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.68−7.66 (m, 4H), 7.47−7.38
(m, 6H), 4.10−4.06 (m, 1H), 3.91−3.89 (m, 2H), 3.70−3.64
(m, 2H), 3.61−3.56 (m, 1H), 3.48 (d, 1H, J = 3.5 Hz), 2.89 (d,
1H, J = 6.3 Hz), 1.97−1.88 (m, 1H), 1.72−1.64 (m, 1H), 1.06
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 135.5, 132.7, 129.9,
127.8, 74.0, 70.6, 62.7, 45.7, 35.0, 26.8, 19.0; m/z (EI) 317
(1%), 257 (21), 227 (27), 199 (100), 181 (14), 139 (18), 135
(17), 91 (34).
(2S,3S)-1,2-Epoxy-5-(4-methoxybenzyloxy)-3-pentanol.
To a stirred solution of the chlorodiol (517 mg, 1.88 mmol) in
THF (3.5 mL) was added pulverized NaOH (188 mg, 4.71
mmol) at 0 °C. After stirring for 1.5 h, Et2O (20 mL) and H2O
(5 mL) were added, the layers were separated, and the aqueous
layer was extracted with Et2O (3 × 20 mL). The combined
organic layers were washed with saturated aq NH4Cl (10 mL)
and brine, dried over MgSO4, and concentrated in vacuo.
Purification by flash chromatography (hexanes/EtOAc 2:3)
afforded the title compound (406 mg, 1.70 mmol, 91%) as a
colorless oil: Rf (hexanes/EtOAc 2:3) = 0.32; [α]D19 = +3.6 (c
1.10, CHCl3); HRMS found (ESI) (M + Na)+ 261.1093,
(E)-1-Chloro-5-(4-methoxybenzyloxy)pent-2-ene (14b).
To a stirred solution of N-chlorosuccinimide (784 mg, 5.87
mmol) in CH2Cl2 (15 mL) was added dimethyl sulfide (0.434
9423
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Article
C13H18NaO4 requires 261.1097; IR (film) 3423 br, 2935, 2856,
1612, 1512, 1302, 1244, 1174, 1087, 1030, 910, 814, 755 cm−1;
1H NMR (300 MHz, CDCl3) δ 7.24 (d, 2H, J = 8.7 Hz), 6.87
(d, 2H, J = 8.7 Hz), 4.47 (d, 1H, J = 11.5 Hz), 4.42 (d, 1H, J =
11.5 Hz), 3.79 (s, 3H), 3.73−3.59 (m, 3H), 2.99 (ddd, 1H, J =
4.7, 4.0, 2.8 Hz), 2.76 (dd, 1H, J = 5.0, 4.0 Hz), 2.70 (dd, 1H, J
= 5.0, 2.8 Hz), 1.88 (q, 2H, J = 6.0 Hz); 13C NMR (75 MHz,
CDCl3) δ 159.2, 130.0, 129.2, 113.7, 72.8, 69.9, 67.1, 55.2, 55.1,
44.5, 33.8; m/z (ESI) 261 (M+ + Na, 100%), 251 (12), 145
(8), 135 (8), 121 (24).
159.1, 138.7, 130.7, 129.2, 128.1, 128.0, 127.3, 113.7, 94.3, 76.9,
72.9, 72.4, 71.6, 67.1, 63.6, 61.9, 59.2, 55.3, 35.4, 35.1, 34.6,
29.6, 26.0, 25.7, 25.5, 25.3, 18.3, 15.1, 14.5, −5.3, −5.3; m/z
(ESI) 715 (M+ + Na, 100%), 649 (3), 541 (5), 419 (4), 299
(5), 121 (9).
(S)-3-(2-((2′S,3′S)-2′-(Benzyloxy)-3′-(ethoxymethoxy)-5′-
(4-methoxybenzyloxy)pentan-1′-yl)-1,3-dithian-2-yl)butan-
1-ol (15). To the neat silyl protected ether (326 mg, 0.47
mmol) was added a solution of TBAF (5.0 mL; 1.0 M in THF,
5.0 mmol) at rt, and the mixture was stirred at this temperature
overnight. Saturated aq NaHCO3 (10 mL) was added, the
layers were separated, and the aqueous phase was extracted
with CH2Cl2 (2 × 15 mL). The combined organic layers were
washed with brine, dried over MgSO4, and concentrated to a
volume of ∼5 mL before being purified by flash chromatog-
raphy (hexanes/EtOAc 3:2) to afford the title compound (265
mg, 0.46 mmol, 97%) as a colorless oil: Rf (hexanes/EtOAc
( 2 S , 3 S ) - 1 , 2 - E p o x y - 3 - ( e t h o x y m e t h o x y ) - 5 - ( 4 -
methylbenzyloxy)pentane (8).5 To a stirred solution of the
epoxy alcohol (183 mg, 0.77 mmol) and diisopropylethylamine
(0.535 mL, 3.07 mmol) in CH2Cl2 (7.5 mL) was added
ethoxymethyl chloride (0.142 mL, 1.54 mmol) at rt. The
mixture was allowed to stir for 2 d before saturated aq NH4Cl
(15 mL) was added. The layers were separated, and the
aqueous phase was extracted with EtOAc (3 × 15 mL). The
combined organic layers were washed with brine, dried over
MgSO4, concentrated in vacuo, and purified by flash
chromatography (hexanes/EtOAc 3:1 to 1:1) to afford the
title compound 8 (197 mg, 0.67 mmol, 87%) as a colorless oil.
First Coupling and Elaboration. (S)-1-(tert-Butyldime-
thylsilyloxy)-3-(2-((2′S,3′S)-3′-(ethoxymethoxy)-2′-hydroxy-
5′-(4-methoxybenzyloxy)pentan-1′-yl)-1,3-dithian-2-yl)-
butane.5 To a stirred solution of dithiane 8 (319 mg, 1.04
mmol) in THF (10 mL) was added n-BuLi (0.65 mL; 1.6 M in
hexanes, 1.04 mmol) at rt under N2, and the mixture was stirred
for 5 min at this temperature. A solution of epoxide 12 (193
mg, 0.65 mmol) was added, and the mixture was stirred for 10
min at rt before being quenched by the addition of saturated aq
NH4Cl (5 mL). EtOAc (10 mL) was added, the layers were
separated, and the aqueous phase was extracted with EtOAc (2
× 10 mL). The combined organic layers were washed with
brine, dried over MgSO4, concentrated in vacuo, and purified
by flash chromatography (hexanes/EtOAc 3:1) to afford the
title compound (385 mg, 0.64 mmol, 98%) as a colorless oil.
(S)-3-(2-((2′S,3′S)-2′-(Benzyloxy)-3′-(ethoxymethoxy)-5′-
(4-methoxybenzyloxy)pentan-1′-yl)-1,3-dithian-2-yl)-1-(tert-
butyldimethylsilyloxy)butane. To a stirred solution of the
secondary alcohol (334 mg, 0.55 mmol) in THF (5.6 mL) at rt
under N2 was added benzyl bromide (0.390 mL, 3.32 mmol)
followed by KH (148 mg; 30 wt % dispersion in mineral oil,
1.11 mmol). The mixture was stirred for 5 h before being
quenched with saturated aq NH4Cl (5 mL). EtOAc (10 mL)
was added, the layers were separated, and the aqueous phase
was extracted with EtOAc (2 × 10 mL). The combined organic
layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. Purification by flash chromatography
(100% hexanes to hexanes/EtOAc 9:1) afforded the title
compound (326 mg, 0.47 mmol, 85%) as a colorless oil: Rf
(100% hexanes to hexanes/EtOAc 9:1) = 0.23; [α]D17 = −48.6
(c 0.91, CHCl3); HRMS found (ESI) MH+, 693.3686,
C37H61O6S2Si requires 693.3673; IR (film) 2950, 2928, 2885,
2855, 1613, 1513, 1463, 1388, 1361, 1247, 1089, 1033, 903,
833, 775, 735, 698 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.35−
7.21 (m, 7H), 6.86 (d, 2H, J = 8.8 Hz), 4.76 (d, 1H, J = 7.0
Hz), 4.67 (d, 1H, J = 7.0 Hz), 4.64 (d, 1H, J = 10.9 Hz), 4.56
(d, 1H, J = 10.9 Hz), 4.42 (s, 2H), 4.04−3.98 (m, 2H), 3.80 (s,
3H), 3.74−3.50 (m, 6H), 2.90−2.66 (m, 4H), 2.45−2.23 (m,
3H), 2.14−1.87 (m, 4H), 1.75−1.65 (m, 1H), 1.37−1.26 (m,
1H), 1.22 (t, 3H, J = 7.1 Hz), 1.11 (d, 3H, J = 6.7 Hz), 0.90 (s,
9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
16
1:1) = 0.27; [α]D = −49.3 (c 0.58, CHCl3); HRMS found
(ESI) (M + Na)+, 601.2636, C31H46NaO6S2 requires 601.2628;
IR (film) 2930, 2876, 1612, 1513, 1454, 1364, 1302, 1246,
1
1180, 1093, 1029, 819, 743, 698 cm−1; H NMR (300 MHz,
CDCl3) δ 7.34−7.22 (m, 7H), 6.86 (d, 2H, J = 8.7 Hz), 4.76 (d,
1H, J = 6.9 Hz), 4.67 (d, 1H, J = 6.9 Hz), 4.58 (s, 2H), 4.43 (s,
2H), 4.05−3.96 (m, 2H), 3.80 (s, 3H), 3.73 (ddd, 1H, J = 10.6,
6.9, 4.5 Hz), 3.63 (q, 2H, J = 7.0 Hz), 3.59−3.50 (m, 3H),
2.93−2.64 (m, 4H), 2.39−2.29 (m, 2H), 2.25−2.15 (m, 1H),
2.14−2.02 (m, 2H), 2.00−1.80 (m, 2H), 1.70 (dddd, 1H, J =
14.2, 8.8, 5.4, 5.4 Hz), 1.42 (dddd, 1H, 13.8, 9.7, 5.6, 4.5 Hz),
1.22 (t, 3H, J = 7.0 Hz), 1.12 (d, 3H, J = 6.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 159.1, 138.5, 130.6, 129.2, 128.2, 128.0,
127.4, 113.7, 94.4, 77.0, 72.9, 72.4, 71.7, 67.0, 63.7, 61.7, 59.0,
55.3, 35.6, 35.4, 34.6, 29.6, 25.8, 25.4, 25.3, 15.1, 14.7; m/z
(ESI) 601 (M+ + Na, 100%), 493 (48), 385 (24), 347 (24), 313
(36), 217 (12), 121 (90).
(S)-3-(2-((2′S,3′S)-2′-(Benzyloxy)-3′-(ethoxymethoxy)-5′-
(4-methoxybenzyloxy)pentan-1′-yl)-1,3-dithian-2-yl)butanal
(18).5 To a stirred solution of alcohol 15 (64 mg, 0.11 mmol)
in CH2Cl2 (2 mL) were added 4 Å MS (50 mg), N-
methylmorpholine-N-oxide (22 mg, 0.19 mmol), and tetra-n-
propylammonium perruthenate (4 mg, 0.011 mmol), and the
mixture was stirred at rt. After 20 min, the mixture was quickly
filtered through a plug of silica (2 cm), and the silica was
flushed with hexanes/EtOAc 2:1 (5 mL). The filtrate was
concentrated in vacuo to afford pure title compound 18 (55
mg, 0.10 mmol, 86%) as a colorless oil.
(S)-3-(2-((2′S,3′S)-2′-(Benzyloxy)-3′-(ethoxymethoxy)-5′-
(4-methoxybenzyloxy)pentan-1′-yl)-1,3-dithian-2-yl)butanal
toluenesulfonylhydrazone. To a stirred solution of aldehyde
18 (15 mg, 0.026 mmol) in THF (1 mL) was added
tosylhydrazine (5 mg, 0.026 mmol) at rt, and the solution
was stirred for 20 min. Concentration and purification by flash
chromatography (hexanes/EtOAc 1:2) afforded the title
compound (19 mg, 0.025 mmol, 95%) as a colorless oil: Rf
(hexanes/EtOAc 1:1) = 0.20; [α]D16 = −47.2 (c 0.95, CHCl3);
HRMS found (ESI) (M + Na)+, 767.2837, C38H52N2NaO7S3
requires 767.2829; IR (film) 3203, 3065, 3034, 2927, 2857,
1612, 1513, 1453, 1361, 1247, 1166, 1093, 1030, 813, 701, 669;
1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.5 Hz, 2H), 7.54
(br s, 1H), 7.30−7.22 (m, 9H), 7.05 (dd, J = 6.2, 4.3 Hz, 1H),
7.85 (d, J = 8.5 Hz, 2H), 4.72 (d, J = 6.9 Hz, 1H), 4.64 (d, J =
6.9 Hz, 1H), 4.56 (d, J = 11.1 Hz, 1H), 4.52 (d, J = 11.1 Hz,
1H), 4.42 (s, 3H), 4.02−3.98 (m, 1H), 3.95−3.92 (m, 1H),
3.79 (s, 3H), 3.64−3.50 (m, 4H), 2.92−2.78 (m, 2H), 2.73−
9424
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2.59 (m, 2H), 2.40 (s, 3H), 2.33−2.12 (m, 3H), 2.09−1.88 (m,
3H), 1.86−1.77 (m, 1H), 1.70−1.61 (m, 1H), 1.20 (t, J = 7.0
Hz, 3H), 0.91 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 159.1, 152.8, 150.0, 144.0, 138.4, 135.3, 130.6, 129.6,
129.2, 128.2, 128.0, 127.9, 127.6, 127.4, 113.7, 94.4, 77.0, 72.7,
72.4, 71.6, 67.0, 63.6, 58.3, 55.3, 37.1, 35.5, 34.6, 29.5, 25.7,
25.5, 25.1, 21.5, 15.1, 14.4; m/z (ESI) 767 (M+ + Na, 100%),
611 (6), 583 (20), 557 (8), 347 (20), 303 (12), 121 (12). To
form the N-TBS hydrazone derivative (17), a solution of the
above tosyl hydrazone (19 mg, 0.025 mmol) in THF (0.5 mL)
at −78 °C was treated with NEt3 (5 mg, 0.05 mmol) followed
by TBSOTf (9.8 mg, 0.035 mmol) and stirred for 20 min. The
reaction was quenched with MeOH, diluted with hexanes,
washed with saturated NaHCO3 and brine, dried over MgSO4,
filtered, and concentrated to afford 17, which was used without
further purification.
title compound (1.48 g, 2.77 mmol, 88%) as a colorless oil: Rf
(hexanes/EtOAc 3:1) = 0.28; [α]D20 = −30.2 (c 1.96, CHCl3);
HRMS found (EI) M+, 534.2303, C28H42O4S2Si requires
534.2294; IR (film) 3461br, 2931, 2899, 2857, 1472, 1427,
1390, 1104, 1028, 823, 752, 697, 666, 613 cm−1; 1H NMR (300
MHz, CDCl3) δ 7.68−7.65 (m, 4H), 7.45−7.36 (m, 6H), 4.83
(d, 1H, J = 6.8 Hz), 4.73 (d, 1H, J = 6.8 Hz), 4.30 (dd, 1H, J =
9.9, 4.8 Hz), 4.24−4.14 (m, 1H), 3.99−3.91 (m, 1H), 3.79−
3.44 (m, 4H), 2.96−2.77 (m, 4H), 2.16−2.04 (m, 1H), 1.97−
1.73 (m, 3H), 1.59−1.54 (m, 2H), 1.20 (t, 3H, J = 7.2 Hz),
1.05 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 135.5, 133.2,
129.7, 127.7, 96.0, 76.5, 66.8, 64.1, 64.1, 44.0, 42.6, 38.8, 30.3,
29.9, 26.8, 26.0, 19.1, 15.0; m/z (EI) 534 (M+, 0.2%), 516 (M+
− H2O, 0.1), 431 (23), 293 (10), 267 (11), 241 (91), 207 (30),
199 (100), 163 (46), 135 (33), 119 (62), 59 (39), 44 (99).
(2S,4S)-1-(tert-Butyldiphenylsilyloxy)-5-(1,3-dithian-2-yl)-
2-(ethoxymethoxy)-4-methoxypentane (6).5 To a stirred
solution of the secondary alcohol (314 mg, 0.59 mmol) in
THF (6 mL) at rt was added methyl iodide (0.110 mL, 1.76
mmol), followed by potassium tert-butoxide (99 mg, 0.88
mmol) in one portion. The reaction was quenched after 10 min
by the addition of saturated aq NH4Cl (2 mL), the layers were
separated, and the aqueous layer was extracted with EtOAc (2
× 15 mL). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo.
Purification by flash chromatography (hexanes/EtOAc 9:1)
afforded the title compound 6 (263 mg, 0.48 mmol, 82%) as a
colorless oil.
Final Coupling and Elaboration. (2S,4S)-1-(tert-Butyl-
diphenylsilyloxy)-5-(2-(3′-(tert-butyldiphenylsilyloxy)propan-
1′-yl)-1,3-dithian-2-yl)-2-(ethoxymethoxy)-4-methoxypen-
tane. To a stirred solution of dithiane 6 (20 mg, 0.036 mmol)
in a 10:1 mixture of THF−HMPA (0.3 mL) at −78 °C was
added t-BuLi (0.023 mL; 1.7 M solution in heptane, 0.038
mmol), and the mixture was stirred at this temperature for 15
min. To this mixture was added a solution of iodide 22 (7.8 mg,
0.018 mmol) in THF−HMPA (10:1; 0.2 mL), and the mixture
was stirred at −78 °C for 30 min before being quenched by the
addtion of saturated aq NH4Cl (2 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc (2
× 5 mL). The organic layers were combined, washed with
brine, dried over MgSO4, and concentrated in vacuo.
Purification by flash chromatography (hexane/EtOAc 9:1)
afforded the title compound (11.3 mg, 0.013 mmol, 73%) as a
colorless oil: Rf (hexanes/EtOAc 9:1) = 0.25; [α]D22 = −10.2 (c
0.53, CHCl3); HRMS found (ESI) (M + Na)+, 867.3944,
C48H68NaO5S2Si2 requires 867.3939; IR (film) 2930, 2900,
1472, 1427, 1389, 1106, 1031, 823, 755, 740, 700, 613 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.70−7.66 (m, 8H), 7.43−7.35
(m, 12H), 4.80 (d, 1H, J = 6.8 Hz), 4.71 (d, 1H, J = 6.8 Hz),
3.84−3.79 (m, 1H), 3.73−3.60 (m, 6H), 3.57−3.50 (m, 1H),
3.30 (s, 3H), 2.88−2.67 (m, 4H), 2.12−2.02 (m, 3H), 1.99−
1.86 (m, 3H), 1.85−1.68 (m, 4H), 1.13 (t, 3H, J = 7.0 Hz), 2 ×
1.05 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 135.6, 133.5,
129.6, 127.6, 95.1, 75.7, 75.0, 66.7, 63.9, 56.1, 52.5, 44.1, 38.4,
35.5, 27.9, 26.9, 26.8, 26.1, 25.2, 19.2, 15.1.
Synthesis of Dithiane C25−C31 Fragment 6. (2S,4S)-
1-(tert-Butyldiphenylsilyloxy)-2-(ethoxymethoxy)-4,5-epoxy-
pentane (21). To a stirred solution of triol 19 (998 mg, 2.66
mmol) in THF (120 mL) was added KHMDS (6.90 mL, 0.5 M
solution in toluene, 3.46 mmol) at rt, and the solution was
stirred for 5 min. 1-(2,4,6-Triisopropyltoluenesulfonyl)-
imidazole (1.16 g, 3.46 mmol) was added in one portion, and
the reaction was stirred for 1 h at rt. Saturated aq NH4Cl (10
mL) was added, the layers were separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 50 mL). The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. The residue was taken up in CH2Cl2 (30
mL), and to the mixture were added triethylamine (2.80 mL,
16.0 mmol) and ethoxymethyl chloride (0.724 mL, 8.00
mmol). This mixture was allowed to stir at rt for 2 d before the
addition of saturated aq NH4Cl (15 mL). The layers were
separated, and the aqueous phase was extracted with EtOAc (3
× 50 mL). The combined organic layers were washed with
brine, dried over MgSO4, concentrated in vacuo, and purified
by flash chromatography (hexanes/EtOAc 3:1) to afford the
title compound 21 (582 mg, 1.40 mmol, 53% over the two
18
steps) as a colorless oil: Rf (hexanes/EtOAc 3:1) = 0.43; [α]D
= −25.9 (c 1.10, CHCl3); HRMS found (FAB) MH+, 415.2296,
C24H35O4Si requires 415.2305; IR νmax (film) 2927, 2856,
1472, 1427, 1390, 1184, 1110, 1029, 822, 740, 697, 613, 518
cm−1; H NMR (300 MHz, CDCl3) δ 7.68−7.65 (m, 4H),
1
7.46−7.35 (m, 6H), 4.78 (d, 1H, J = 6.8 Hz), 4.72 (d, 1H, J =
6.8 Hz), 3.91 (dddd, 1H, J = 7.9, 5.3, 5.3, 4.8 Hz), 3.74−3.52
(m, 4H), 3.08−3.02 (m, 1H), 2.77 (dd, 1H, J = 5.1, 4.0 Hz),
2.49 (dd, 1H, J = 5.0, 2.7 Hz), 1.85−1.68 (m, 2H), 1.15 (t, 3H,
J = 7.1 Hz), 1.05 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ
135.6, 133.4, 129.7, 127.7, 94.7, 75.5, 66.1, 63.4, 49.5, 47.6,
35.4, 26.8, 19.2, 15.0; m/z (EI) 357 (M+ − tBu, 2.5%), 327 (6),
281 (12), 241 (40), 227 (19), 199 (26), 183 (27), 163 (37),
135 (25), 91(31), 59 (100), 41 (18).
(2S,4S)-1-(tert-Butyldiphenylsilyloxy)-5-(1,3-dithian-2-yl)-
2-(ethoxymethoxy)-4-pentanol. To a stirred solution of 1,3-
dithiane (1.14 g, 9.47 mmol) in THF (16 mL) under N2 at −20
°C was added n-BuLi (5.92 mL; 1.6 M in hexanes, 9.47 mmol),
and the mixture was stirred for 30 min. To this mixture was
added a solution of epoxide 21 (1.31 mg, 3.16 mmol) in THF
(3.5 mL), and the mixture was stirred at 0 °C for 1 h. The
reaction was quenched by the addition of saturated aq NH4Cl
(5 mL), the layers were separated, and the aqueous phase was
extracted with EtOAc (2 × 30 mL). The combined organic
layers were washed with brine, dried over MgSO4, and purified
by flash chromatography (hexanes/EtOAc 3:1) to afford the
(1R,3S)-3-(2-((2′S,3′S)-2′-(Benzyloxy)-3′-(ethoxymethoxy)-
5′-(4-methoxybenzyloxy)pentan-1′-yl)-1,3-dithian-2-yl)-1-(2-
((2″S,4″S)-5″-(tert-butyldiphenylsilyloxy)-4″-(ethoxyme-
thoxy)-2″-methoxypentan-1″-yl)-1,3-dithian-2-yl)butan-1-ol
(24a) and (1S,3S)-3-(2-((2′S,3′S)-2′-(Benzyloxy)-3′-(ethoxy-
methoxy)-5′-(4-methoxybenzyloxy)-pentan-1′-yl)-1,3-dithi-
an-2-yl)-1-(2-((2″S,4″S)-5″-(tert-butyldiphenylsilyloxy)-4″-
9425
dx.doi.org/10.1021/jo201729t|J. Org. Chem. 2011, 76, 9417−9428

The Journal of Organic Chemistry
Article
(ethoxymethoxy)-2″-methoxypentan-1″-yl)-1,3-dithian-2-
yl)butan-1-ol (24b).5 To a stirred solution of dithiane 6 (138
mg, 0.25 mmol) in THF (4 mL) were added a premixed
solution of n-BuLi (0.126 mL; 1.6 M in hexane, 0.202 mmol)
and di-n-butylmagnesium (0.050 mL; 1.0 M solution in
heptane, 0.050 mmol), and the mixture was stirred for 20
min at rt. To this mixture was added a solution of aldehyde 18
(55 mg, 0.10 mmol) in THF (1 mL), and the resulting mixture
was stirred for 10 min before being quenched by saturated aq
NH4Cl (5 mL). EtOAc (10 mL) was added, the layers were
separated, and the aqueous phase was extracted with EtOAc (2
× 10 mL). The combined organic layers were washed with
brine, dried over MgSO4, concentrated in vacuo, and purified
by flash chromatography (hexanes/EtOAc 9:1 to 3:1) to afford
a 3:2 ratio of diastereomeric alcohols 24a and 24b (84 mg, 0.08
mmol, 78%) as a colorless oil and recovered dithiane 6 (85 mg,
0.16 mmol) also as a colorless oil. For characterization
purposes, the diastereomeric alcohols were separated by
preparative thin layer chromatography (PTLC) (hexanes/
EtOAc 3:1) to separately afford alcohols 24a (48 mg, 0.043
1H, J = 6.9 Hz), 4.78 (d, 1H, J = 6.9 Hz), 4.77 (d, 1H, J = 6.8
Hz), 4.66 (d, 1H, J = 6.8 Hz), 4.64 (d, 1H, J = 11.3 Hz), 4.57
(d, 1H, J = 11.3 Hz), 4.41 (s, 2H), 4.09−4.03 (m, 2H), 3.90−
3.82 (m, 2H), 3.80 (s, 3H), 3.75−3.50 (m, 9H), 3.44 (s, 3H),
3.33 (s, 3H), 3.05−2.56 (m, 9H), 2.48 (d, 1H, J = 15.4 Hz),
2.24 (dd, 1H, J = 15.5, 4.8 Hz), 2.19−2.04 (m, 3H), 2.02−1.82
(m, 5H), 1.78−1.67 (m, 3H), 1.43 (dt, 1H, J = 14.5, 8.0 Hz),
1.24 (d, 3H, J = 6.8 Hz), 1.21 (t, 3H, J = 7.1 Hz), 1.16 (t, 3H, J
= 7.1 Hz), 1.05 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 159.1,
138.7, 135.7, 133.6, 130.7, 129.6, 129.2, 128.2, 127.6, 127.3,
127.2, 113.7, 95.3, 94.3, 87.4, 77.6, 76.0, 75.1, 72.4, 72.4, 71.4,
67.1, 67.1, 63.6, 63.3, 60.8, 60.4, 57.5, 55.9, 55.3, 40.5, 39.1,
39.1, 35.7, 34.5, 29.6, 26.9, 26.7, 26.4, 25.9, 25.6, 25.5, 24.7,
19.2, 16.5, 15.1, 15.1; m/z (ESI) 1162 (M+ + Na, 100%), 1055
(23), 963 (7), 873 (7), 731 (8), 657 (7), 583 (14), 495 (15),
423 (12).
(1R,3S)-3-(2-((2′S,3′S)-2′-(Benzyloxy)-3′-hydroxy-5′-(4-
methoxybenzyloxy)pentan-1′-yl)-1,3-dithian-2-yl)-1-(2-
((2″S,4″S)-5″-(tert-butyldiphenylsilyloxy)-4″-hydroxy-2″-me-
thoxypentan-1″-yl)-1,3-dithian-2-yl)-1-methoxybutane. To
a stirred solution of bisdithiane 25 (21.5 mg, 0.019 mmol) in t-
butanol (0.6 mL) was added pyridinium p-toluenesulfonate (46
mg, 0.18 mmol), and the mixture was heated at reflux for 5.5 h.
To the solution was added CH2Cl2 (0.2 mL), and the mixture
was introduced directly onto the PTLC plate and purified by
PTLC (hexanes/EtOAc 3:1) to afford the title compound (12.9
mg, 0.013 mmol, 66%) as a colorless oil: Rf (hexanes/EtOAc
mmol) and 24b (32 mg, 0.028 mmol), both as colorless oils.
20
Bisdithiane 24a: Rf (hexanes/EtOAc 3:1) = 0.25; [α]D
=
−29.8 (c 1.07, CHCl3); HRMS found (ESI) (M + Na)+,
1147.4917, C60H88NaO10S4Si requires 1147.4922; IR (film)
2930, 2889, 2857, 1725, 1612, 1513, 1461, 1427, 1390, 1362,
1
1276, 1247, 1180, 1095, 1031, 823, 751, 701, 613 cm−1; H
NMR (300 MHz, CDCl3) δ 7.70−7.67 (m, 4H), 7.45−7.23 (m,
13H), 6.86 (d, 2H, J = 8.6 Hz), 4.78 (d, 1H, J = 7.0 Hz), 4.77
(d, 1H, J = 7.0 Hz), 4.72 (d, 1H, J = 7.0 Hz), 4.67 (d, 1H, J =
7.0 Hz), 4.60 (s, 2H), 4.42 (s, 2H), 4.06−4.03 (m, 2H), 3.89−
3.73 (m, 7H), 3.70−3.50 (m, 8H), 3.29 (s, 3H), 2.92−2.59 (m,
9H), 2.41 (d, 1H, J = 15.6 Hz), 2.34−2.26 (m, 1H), 2.25 (dd,
1H, J = 15.6, 7.5 Hz), 2.17−1.84 (m, 8H), 1.80−1.65 (m, 2H),
1.43−1.33 (m, 1H), 1.27 (d, 3H, J = 6.5 Hz), 1.21 (t, 3H, J =
7.1 Hz), 1.14 (t, 3H, J = 7.1 Hz), 1.06 (s, 9 H); 13C NMR (75
MHz, CDCl3) δ 159.1, 138.6, 135.6, 133.4, 130.7, 129.7, 129.2,
128.2, 127.9, 127.7, 127.3, 113.7, 94.8, 94.3, 77.3, 75.8, 75.7,
75.4, 72.7, 72.4, 71.7, 67.1, 66.3, 63.6, 63.4, 60.1, 58.6, 55.6,
55.3, 40.0, 39.7, 37.0, 34.8, 34.5, 29.6, 26.9, 26.1, 25.9, 25.6,
25.4, 25.4, 24.9, 19.2, 16.7, 15.1, 15.1; m/z (ESI) 1147 (M+ +
Na, 100%), 1039 (92), 931 (73), 857 (38), 599 (37), 495 (25),
423 (33).
17
2:1) = 0.19; [α]D = −23.8 (c 0.75, CHCl3); HRMS found
(ESI) (M + Na)+, 1045.4233, C55H78NaO8S4Si requires
1045.4241; IR (film) 2925, 2856, 1732, 1612, 1513, 1462,
1427, 1361, 1247, 1088, 1035, 909, 822, 737, 702, 612 cm−1;
1H NMR (300 MHz, CDCl3) δ 7.70−7.67 (m, 4H), 7.46−7.35
(m, 6H), 7.32−7.23 (m, 7H), 6.88 (d, 2H, J = 8.7 Hz), 4.71 (d,
1H, J = 11.4 Hz), 4.60 (d, 1H, J = 11.4 Hz), 4.45 (s, 2H), 4.09−
3.91 (m, 4H), 3.81 (s, 3H), 3.73 (dt, 1H, J = 9.2, 4.8 Hz),
3.68−3.55 (m, 4H), 3.47 (s, 3H), 3.36 (s, 3H), 3.08−2.61 (m,
9H), 2.53 (d, 1H, J = 15.4 Hz), 2.30 (dd, 1H, J = 15.5, 5.4 Hz),
2.29−2.20 (m, 1H), 2.11 (dd, 1H, J = 15.4, 7.5 Hz), 1.99−1.78
(m, 8H), 1.60 (ddd, 1H, J = 14.7, 6.8, 2.8 Hz), 1.44 (dt, 1H, J =
14.9, 8.2 Hz), 1.27 (d, 3H, J = 6.2 Hz), 1.07 (s, 9 H); 13C NMR
(75 MHz, CDCl3) δ 159.3, 138.8, 135.6, 133.4, 130.1, 129.7,
129.4, 128.3, 127.7, 127.4, 127.3, 113.9, 87.3, 79.6, 77.2, 73.1,
72.0, 71.9, 69.7, 69.5, 68.2, 61.0, 60.0, 57.6, 56.6, 55.3, 40.4,
39.0, 38.5, 35.5, 34.9, 31.3, 26.9, 26.7, 26.4, 26.0, 25.7, 25.3,
24.7, 19.3, 16.7; m/z (ESI) 1045 (M+ + Na, 98%), 937 (100),
907 (10), 829 (55), 715 (32), 607 (48), 525 (12), 437 (12),
365 (13).
(1R,3S)-3-(2-((2′S,3′S)-2′-(Benzyloxy)-3′-(ethoxymethoxy)-
5′-(4-methoxybenzyloxy)pentan-1′-yl)-1,3-dithian-2-yl)-1-(2-
((2″S,4″S)-5″-(tert-butyldiphenylsilyloxy)-4″-(ethoxyme-
thoxy)-2″-methoxypentan-1″-yl)-1,3-dithian-2-yl)-1-methox-
ybutane (25). To a stirred solution of alcohol 24a (29 mg,
0.026 mmol) and methyl iodide (0.2 mL, 3.21 mmol) in THF
(1 mL) was added KH (35 mg; 30 wt % dispersion in mineral
oil, 0.26 mmol) at rt, and the mixture was stirred overnight
under N2. Saturated aq NH4Cl was added (4 mL), followed by
EtOAc (5 mL), and the layers were separated. The aqueous
layer was extracted with EtOAc (2 × 10 mL), and the
combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. Purification by PTLC
(hexanes/EtOAc 4:1) afforded the title compound 25 (26 mg,
0.023, 89%) as a colorless oil: Rf (hexanes/EtOAc 3:1) = 0.38;
(2S,3S,5R,7S,9S,11S,13R,15S)-3-(Benzyloxy)-9-((tert-
butyldiphenylsilyloxy)methyl)-2-(1′-(4-methoxybenzyloxy)-
ethan-2′-yl)-11-methoxy-13-methoxy-15-methyl-1,6,8-
trioxadispiro[4.1.5.3]pentadecane (26). To a stirred solution
of the diol (9.6 mg, 0.0094 mmol) in a 4:1 mixture of
CH3CN−H2O (0.5 mL) was added HgCl2 (15 mg, 0.055
mmol), and the resulting mixture was stirred at 0 °C for 5 h.
The reaction was quenched by the addition of saturated aq
NaHCO3 (2 mL), and the resulting mixture was extracted with
EtOAc (2 × 5 mL). The combined organic layers were washed
with brine, dried over MgSO4, concentrated in vacuo, and
purified by flash chromatography (hexanes/EtOAc 4:1) to
afford the title compound 26 (4.8 mg, 0.0058 mmol, 62%) as a
colorless oil: Rf (hexanes/EtOAc 3:1) = 0.38; [α]D20 = +6.7 (c
0.32, EtOAc); HRMS found (ESI) (M + Na)+, 847.4214,
C49H64NaO9Si requires 847.4212; IR (film) 2955, 2927, 1728,
20
[α]D = −41.9 (c 0.67, CHCl3); HRMS found (ESI) (M +
Na)+, 1161.5081, C61H90NaO10S4Si requires 1161.5078; IR
(film) 2960, 2927, 2857, 1727, 1613, 1513, 1463, 1454, 1427,
1391, 1362, 1247, 1178, 1092, 1032, 822, 740, 701, 614 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.70−7.67 (m, 4H), 7.43−7.35
(m, 6H), 7.33−7.22 (m, 7H), 6.85 (d, 2H, J = 8.5 Hz), 4.86 (d,
9426
dx.doi.org/10.1021/jo201729t|J. Org. Chem. 2011, 76, 9417−9428

The Journal of Organic Chemistry
Article
1613, 1587, 1513, 1463, 1456, 1428, 1380, 1360, 1247, 1110,
1095, 1072, 1010, 951, 822, 739, 701, 606 cm−1; 1H NMR (300
MHz, CDCl3) δ 7.72−7.67 (m, 4H), 7.40−7.26 (m, 11H), 7.11
(d, 2H, J = 8.6 Hz), 6.79 (d, 2H, J = 8.6 Hz), 4.52 (d, 1H, J =
11.9 Hz), 4.34 (d, 1H, J = 11.9 Hz), 4.24−4.18 (m, 1H), 4.19
(d, 1H, J = 11.6 Hz), 4.14 (d, 1H, J = 11.6 Hz), 4.09−4.04 (m,
1H), 3.89−3.76 (m, 5H), 3.73−3.63 (m, 2H), 3.49−3.36 (m,
2H), 3.37 (s, 3H), 3.35 (s, 3H), 3.03 (dd, 1H, J = 11.4, 3.9 Hz),
2.25 (br d, 1H, J = 11.8 Hz), 2.18−2.16 (m, 2H), 2.01−1.76
(m, 5H), 1.67 (dt, 1H, J = 11.6, 3.5 Hz), 1.35−1.22 (m, 2H),
1.05 (s, 9 H), 0.95 (d, 3H, J = 6.5 Hz); 13C NMR (75 MHz,
CDCl3) δ 159.0, 138.4, 135.9, 135.7, 134.0, 133.5, 130.8, 129.5,
129.1, 128.3, 127.6, 127.6, 127.4, 127.3, 113.6, 107.8, 99.7, 81.8,
79.9, 78.3, 73.6, 72.3, 71.1, 69.6, 67.6, 66.5, 57.2, 2 × 55.3, 63.7,
38.1, 37.9, 34.0, 29.2, 27.3, 26.9, 19.3, 16.4; m/z (ESI) 847 (M+
+ Na, 29%), 739 (100), 721 (13), 551 (8), 479 (17), 451 (31),
425 (33), 121 (15).
1.88−1.69 (m, 2H), 1.26−1.24 (m, 1H), 1.03−1.00 (m, 12H);
13C NMR (75 MHz, CDCl3) δ 211.9, 159.0, 137.8, 136.9,
135.5, 132.9, 129.8, 129.1, 128.3, 128.1, 127.8, 127.7, 127.5,
127.3, 115.4, 113.7, 82.5, 81.7, 78.8, 78.1, 73.2, 72.5, 71.1, 67.3,
64.4, 57.2, 55.3, 41.5, 40.9, 39.9, 36.1, 35.5, 29.7, 26.7, 19.2,
12.1; m/z (ESI) 921 (MH+, 0.5%), 397 (18), 259 (49), 189
(19), 139 (73), 121 (100).
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: m.brimble@auckland.ac.nz.
■
(1S,3S)-3-(2-((2′S,3′S)-2′-(Benzyloxy)-3′-hydroxy-5′-(4-me-
thoxybenzyloxy)-pentan-1′-yl)-1,3-dithian-2-yl)-1-(2-
((2″S,4″S)-5″-(tert-butyldiphenylsilyloxy)-4″-hydroxy-2″-me-
thoxypentan-1″-yl)-1,3-dithian-2-yl)-butan-1-ol.5 To a
stirred solution of bisdithiane 24b (8.2 mg, 0.007 mmol) in
t-butanol (0.4 mL) was added pyridinium p-toluenesulfonate
(17 mg, 0.068 mmol), and the mixture was heated at reflux for
2 h. To the solution was added CH2Cl2 (0.2 mL), and the
mixture was introduced directly onto the PTLC plate and
purified by PTLC (hexanes/EtOAc 3:1) to afford the title
compound (4.6 mg, 0.004 mmol, 63%) as a colorless oil.
(2S,3S,5R,7S,9S,11S,13S,15S)-3-(Benzyloxy)-9-
((-butyldiphenylsilyloxy)methyl)-2-(1′-(4-methoxybenzyloxy)-
ethan-2′-yl)-13-hydroxy-11-methoxy-15-methyl-1,6,8-
trioxadispiro[4.1.5.3]pentadecane (27).5 To a stirred solution
of the triol (4.4 mg, 0.004 mmol) in a 4:1 mixture of CH3CN−
H2O (0.5 mL) was added HgCl2 (15 mg, 0.055 mmol), and the
resulting mixture was stirred at 0 °C for 2 h. The reaction was
quenched by the addition of saturated aq NaHCO3 (2 mL),
and the resulting mixture was extracted with EtOAc (2 × 5
mL). The combined organic layers were washed with brine,
dried over MgSO4, concentrated in vacuo, and purified by flash
chromatography (hexanes/EtOAc 4:1) to afford the title
compound 27 (2.7 mg, 0.003 mmol, 74%) as a colorless oil.
(2S,4S)-6-((2S,4S,5R,7S,8S)-8-(Benzyloxy)-7-(2-((4-
methoxybenzyl)oxy)ethyl)-4-methyl-1,6-dioxaspiro[4.4]-
nonan-2-yl)-1-((tert-butyldiphenylsilyl)oxy)-4-methoxy-6-ox-
ohexan-2-yl 1H-imidazole-1-carbothioate (28).25 To a
stirred solution of alcohol 27 (1.7 mg, 2.1 μmol) in THF
(0.6 mL) was added 1,1′-thiocarbonyldiimidazole (9 mg, 0.050
mmol), and the mixture was heated at reflux for 48 h. The
mixture was then introduced directly onto the PTLC plate and
purified by PTLC (hexanes/EtOAc 2:1) to afford the title
compound 28 (1.5 mg, 1.6 μmol, 78%) as a colorless oil: Rf
(hexanes/EtOAc 2:1) = 0.19; [α]D20 = −26.5 (c 0.10, CHCl3);
HRMS found (ESI) MH+, 921.4171, C52H65N2O9SSi requires
921.4175; IR νmax (film) 2961, 2929, 2857, 1710, 1615, 1514,
1463, 1386, 1284, 1247, 1096, 1027, 969, 824, 741, 702 cm−1;
1H NMR (300 MHz, CDCl3) δ 8.34 (br s), 7.63−7.55 (m, 5H),
7.43−7.25 (m, 11H), 7.20 (d, 2H, J = 8.8 Hz), 7.04 (br s, 1H),
6.82 (d, 2H, J = 8.8 Hz), 5.89−5.82 (m, 1H), 4.53 (d, 1H, J =
12.1 Hz), 4.42−4.24 (m, 5H), 4.11−4.06 (m, 1H), 3.96 (dd,
1H, J = 11.6, 3.5 Hz), 3.79 (dd, 1H, J = 11.6, 4.7 Hz), 3.77 (s,
3H), 3.74−3.65 (m, 1H), 3.56−3.49 (m, 2H), 3.22 (s, 3H),
2.99 (dd, 1H, J = 17.6, 4.8 Hz), 2.75 (dd, 1H, J = 17.6, 7.3 Hz),
2.36−2.27 (m, 2H), 2.18−2.04 (m, 3H), 2.01−1.93 (m, 1H),
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