Synthesis of an advanced intermediate of the jatrophane diterpene Pl-4: A dibromide coupling approach

Article abstract of DOI:10.1021/jo401480t

The preparation of an advanced intermediate toward the synthesis of the jatrophane diterpene Pl-4 is described. The key step is a regioselective chelation-controlled lithiation of the (Z)-configured bromide in the corresponding vinyl dibromide precursor. The method outlined within this Article is suitable for the facile access of sterically hindered internal vinyl halides for further coupling reactions.

Full text of DOI:10.1021/jo401480t

Article
pubs.acs.org/joc
Synthesis of an Advanced Intermediate of the Jatrophane Diterpene
Pl‑4: A Dibromide Coupling Approach
Rita Furst and Uwe Rinner*
̈
Institute of Organic Chemistry, University of Vienna, Wahringer Straße 38, 1090 Vienna, Austria
̈
S
* Supporting Information
ABSTRACT: The preparation of an advanced intermediate
toward the synthesis of the jatrophane diterpene Pl-4 is
described. The key step is a regioselective chelation-controlled
lithiation of the (Z)-configured bromide in the corresponding
vinyl dibromide precursor. The method outlined within this
Article is suitable for the facile access of sterically hindered
internal vinyl halides for further coupling reactions.
retrosynthetically outlined in Scheme 1. The synthetic
approach is based on a report by Braun and co-workers who
INTRODUCTION
■
A general characteristic of members of the Euphorbiaceae plant
family, commonly referred to as spurges, is the milky latex that
has been identified as a rich source of structurally complex and
intriguing terpene-based natural products. Over the past
decades, phytochemists have shown great interest in the active
ingredients of the Euphorbia species, and a vast number of
diterpenes of the jatrophane, tigliane, ingenane, and lathyrane
frameworks have been isolated.1
Scheme 1. Retrosynthetic Analysis of Pl-4 (1)
Some of these complex natural products show promising
biological properties, including cytotoxic, antiviral, multidrug-
resistance reversing (MDR), and antitumor activities,2−5 and
recently, an ingenol ester has been approved for the topical
treatment of precancerous skin conditions.6,7 Thus, it is not
surprising that several Euphorbia species have been employed
in traditional herbal folk medicines, mainly to treat cancerous
conditions, swellings, and warts.8 In particular, the MDR-
reversing properties, more precisely, the selective inhibition of
the ATP-dependent efflux pump p-glycoprotein, are of great
interest to modern cancer research. The overexpression of p-
glycoprotein in the cancer cells of malignant tumors is a serious
problem in chemotherapy. The elaboration of synthetic routes
to jatrophane diterpenes is of importance for the development
of novel anticancer drugs that could potentially address this
problem.
In 2003, Pl-4 (1) was isolated by Hohmann et al. from
Euphorbia platyphyllos, an annual herbaceous plant that is found
in different climate regions.9 Pl-4 belongs to the family of
jatrophane diterpenes and is characterized by a highly
functionalized five-membered ring that is annulated to a 12-
membered macrocycle. Despite the challenging structural
properties, only a few approaches to jatrophane diterpenes
have been reported.10−24
showed that selective alkylation of the more hindered bromide
can be achieved through coordination of the intermediate
organolithium species to a chelating functionality in the α-
position to the vinyl dibromide.25 Furthermore, Braun
demonstrated that the chiral information of the chelating
MEM group in the lithium species is transferred to the reaction
partner to deliver the corresponding secondary alcohol in a
diastereoselective manner.
Surprisingly, this protocol has not yet been applied to total
synthesis, especially because this reaction sequence provides
access to sterically hindered vinyl halides that could serve as
RESULTS AND DISCUSSION
■
Herein, we present a concise route to a highly advanced
intermediate of Pl-4 via a regioselective lithiation/alkylation
sequence of geminal dibromide 3 as a key step, which is
Received: July 9, 2013
© XXXX American Chemical Society
A
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a
useful building blocks for further coupling reactions. The
absence of applications is even more striking because other
procedures to hindered vinyl halides, for example, via
hydrometalation reactions using substituted alkynes, are not
reliable on structurally complex substrates.26,27
Scheme 2. Preparation of Dibromide 14
As outlined in Scheme 1, a ring-closing metathesis (RCM)
reaction was envisaged to be the final operation to establish the
jatrophane framework. The cyclopentane ring would be closed
via an NHK-coupling reaction of key intermediate 2, which is
available through the previously mentioned selective lithiation/
alkylation sequence of dibromide 3 and aldehyde 4. The
northern fragment (aldehyde 4) should become accessible via
the coupling of Roche ester-derived bromide 6 and aldehyde 5.
Dibromide 3 would be elaborated from aldehyde 8 and methyl
isobutyrate (7). D-Ribose could be employed as an ideal and
inexpensive starting material from the chiral pool for the
preparation of intermediate 8.
The first approach toward dibromide 3 started with methyl
ketone 10, readily available from D-ribose in 60% yield, via a
five-step procedure.20 The addition of vinylmagnesium bromide
to methyl ketone 10 afforded terminal alkene 11 in excellent
yield as the only detectable isomer after MEM protection of the
newly formed tertiary alcohol.28,29 Deprotection of the vicinal
silyl ethers and subsequent periodate cleavage delivered
aldehyde 8, which served as a substrate for the aldol reaction
with methyl isobutyrate to give alcohol 12 in 78% yield as a 3:1
mixture of diastereomers.30 Protection of the hydroxy group
and subsequent ozonolysis delivered aldehyde 13, the precursor
for the installation of the dibromide, in good overall yield.
With aldehyde 13 in hand, the installation of the
dibromoolefin was pursued. As outlined in Table 1, the
a
Reagents and conditions: (a) vinyl-MgBr, THF, 0 °C to rt, 92%; (b)
MEMCl, DIPEA, DCM, 0 to 50 °C, 97%; (c) TBAF, THF, 0 °C to rt,
quant.; (d) NaIO4, DCM, 0 °C to rt, 90%; (e) 7, LDA, THF, −20 °C;
then 8, 78%, dr 3:1; (f) MOMCl, DIPEA, DCM, 0 to 50 °C, 67%; and
(g) O3, DCM, −78 °C; PPh3, 90%.
a
Scheme 3. Preparation of Dibromide 16
Table 1. Reagents and Conditions for the Formation of
Dibromide 14
reagents
PPh3, CBr4
temperature
solvent
yield (%)
a
Reagents and conditions: (a) O3, DCM, −78 °C; DMS, 84%; (b) t-
0 °C to rt
0 to 50 °C
0 °C to rt
reflux
CH2Cl2
CH2Cl2
CH2Cl2
dioxane
THF
0
BuOK, THF, PPh3CH3Br, −20 to 0 °C, 85%; and (c) MEMCl,
DIPEA, DCE, 100 °C, 87%.
PPh3, CBr4, 2,6-lutidine
PPh3, CBr4, Zn
0
0
PPh3CHBr3, t-BuOK, Zn
PPh3CHBr3, t-BuOK
PPh3CHBr3, t-BuOK
0
0 °C to rt
0 °C to rt
12
17
installation of the geminal dimethyl group were postponed until
after the closure of the cyclopentane ring.
toluene
Conditions for the crucial, regioselective lithiation/alkylation
of dibromide 16 were first elaborated using known aldehyde 17
(Scheme 4).34 In accordance with Braun’s publication, we
found that the temperature is of crucial importance for the
selective lithiation and the reaction mixture has to be kept
between −105 and −110 °C to prevent the formation of the
terminal alkyne, the product of the competing Corey−Fuchs
reaction.31 We were pleased to learn that lithiation of
dibromide 16 and subsequent addition of aldehyde 17 at
−110 °C delivered the desired adduct 19. Although the product
was obtained as a 1:1 diastereomeric mixture with respect to
the newly formed hydroxy moiety, we showed that lithiation of
the (Z)-configurated bromide occurs prefentially, which can be
explained via the formation of chelated intermediate 18.25 The
selective attack and formation of the trans double bond in vinyl
halide 19 was confirmed by termination of the lithiation
reaction after 30 min at −108 °C with methanol. The resulting
1H NMR spectroscopic analysis showed unreacted starting
material, the terminal alkyne, and the exclusive formation of the
trans-vinyl bromide. The double-bond geometry could be easily
identified by the assignment of the3J coupling constant, which
reaction of PPh3 and CBr4 for the in situ generation of the ylide
resulted in no reaction. Also, the addition of activated zinc
dust31 or 2,6-lutidine32 did not lead to any detectable amounts
of 14. Reaction of aldehyde 13 with the preformed Wittig salt
and t-BuOK as base allowed the isolation of 14 in low yield
(Scheme 2).33 Presumably, the steric hindrance of the MEM
group as well as chelating effects in close proximity to the
aldehyde is responsible for the observed results. Because of the
inability to improve the yield of the Wittig transformation at
this stage, the sequence was abandoned.
In a slightly modified approach, outlined in Scheme 3, we
decided to introduce the dibromide segment prior to
introducing the bulky MEM group. Thus, ozonolysis of the
terminal alkene in 15 was followed by Wittig olefination and
MEM protection of the resulting tertiary alcohol to afford 16 in
59% overall yield.
We decided to employ dibromide 16 earlier than originally
planned in the key lithiation/alkylation sequence to keep the
substrate as structurally simple as possible for this novel
transformation. Further elaboration of the alkyl chain and the
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a
a
Scheme 4. Coupling Reaction with Dibromide 16
Scheme 5. Preparation of Northern Fragment 4
a
Reagents and conditions: (a) n-BuLi, Et2O, −116 to −108 °C; then
17, 40%, dr 1:1.
a
Reagents and conditions: (a) PMB-trichloroacetimidate, CSA, rt; (b)
DIBAL-H, THF, −78 °C; (c) CBr4, PPh3, 70% (over three steps); (d)
22, toluene, −78 °C, 71% (70% ee); (e) MOMCl, DIPEA, DCM, 0 °C
to rt, 95%; (f) TBAF, THF, 0° to rt, 80%; (g) NMO, TPAP, DCM,
78%; (h) 6, t-BuLi, Et2O, −78 °C; MgBr2; 5, 96%, dr 9:1; (i) TESCl,
imidazole, DMAP, DCM, 93%; (j) DDQ, DCM, phosphate buffer pH
7 to 8, 90%; and (k) SO3.py, NEt3, DMSO, DCM, 0 °C, 93%.
amounts to 14 Hz. As a consequence, the electrophile was
introduced at the more hindered position, and the diastereo-
meric mixture of alcohol 19 was isolated in 40% overall yield.
With these promising results in hand, the synthesis of the
northern fragment of Pl-4 was launched. The sequence started
with Roush crotylation35 of aldehyde 21,36 which is readily
available from ethylene glycol following a known two-step
procedure.37 Next, MOM protection of the secondary alcohol
followed by deprotection of the primary TBS group with TBAF
and oxidation of the resulting alcohol under Parikh−Doering
reaction conditions resulted in the isolation of aldehyde 5.
Bromide 6, the coupling partner for aldehyde 5, was
synthesized from a commercially available Roche ester (20)
via protection of the hydroxy moiety, reduction of the methyl
ester, and subsequent bromination of the resulting alcohol.38
Lithiation of the bromide followed by in situ formation of the
corresponding Grignard reagent39,40 and addition of aldehyde 5
allowed the isolation of secondary alcohol 24 in a 9:1
diasteromeric ratio and in excellent yield (96%).30 The
formation of two diastereomeric secondary alcohols does not
decrease the overall efficiency of the synthesis, as the position
will be oxidized at a later point. The preparation of the
northern part 4 was concluded after TES protection, cleavage
of the PMB group, and oxidation of the primary alcohol
(Scheme 5).
With aldehyde 4 in hand, the selective lithiation and coupling
reaction of dibromide 16 was accomplished under the carefully
controlled conditions described above. We were pleased to
isolate desired vinyl bromide 25 in excellent yield, which was
ultimately protected as benzoate 26 (Scheme 6). The
diastereomers of unprotected bromide 25 were easily separated
by silica gel chromatography, and the respective stereo-
chemistries were determined by the modified Mosher ester
analysis.41,42 Advanced intermediate 25 was obtained as a 1:1
mixture of diastereomers, which is in contrast to Braun’s
findings, who reported excellent diastereoselectivity with
structurally simple substrates. We were hoping to observe
similar preferences and, in accordance with Braun’s results, the
predominant formation of the desired diastereomer. However,
with two structurally complex chiral substrates, the reaction of a
mismatched pair is possible. Inversion of the undesired
stereoisomer is envisaged to increase the overall efficiency of
the route.
Scheme 6. Coupling of Dibromide 16 and Completion of
Advanced Fragment 26
a
a
Reagents and conditions: (a) 16, n-BuLi, −112 to −108 °C, Et2O;
then 4, 74%, dr 1:1 and (b) BzCl, DMAP, NEt3, DCM, 71%.
CONCLUSIONS
■
We have established a concise route to a highly advanced
intermediate toward the synthesis of Pl-4. Strategies toward the
closure of the cyclopentane moiety of the diteperpene have to
be elaborated, which will take place at a later point because we
are currently experiencing extenuating circumstances and the
project is on hold until the relocation of the group.
The route features a regioselective lithiation of the more
hindered side of an unsymmetrical vinyl dibromide; thus,
generating a species that can be used in a further coupling
reaction to establish the cyclopentane motif in the jatrophane
diterpene. This method constitutes a valuable alternative to the
preparation of internal vinyl halides via hydrometalation
reactions and allows the selective, stepwise introduction of
functionalities and the preparation of highly substituted alkenes.
EXPERIMENTAL SECTION
■
General Methods. All nonaqueous reactions were carried out
under a positive pressure of argon using oven-dried (100 °C) or flame-
dried glassware (under vacuum), unless noted otherwise.
THF was dried by distillation from potassium under argon. Diethyl
ether, dimethoxyethane, and toluene were purified by distillation and
dried by distillation from sodium/benzophenone ketyl under argon.
C
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DMSO and N,N-dimethylformamide were dried by distillation from
calcium hydride under reduced pressure. DCM was purified by
distillation and dried by distillation from phosphor pentoxide and
passage over aluminum oxide (neutral activity). Dry solvents were
32.5 mmol, 5.0 equiv) was added to the solution followed by the
dropwise addition of MEMCl (3.7 mL, 32.5 mmol, 5.0 equiv) over 5
min. The cooling bath was removed, and the reaction mixture was
stirred for 1 h at room temperature followed by 3 h at 50 °C before it
was quenched by the addition of water (10 mL). The layers were
separated, and the aqueous phase was extracted with DCM (3 × 50
mL). The combined organic extracts were dried over MgSO4 and
filtered, and the solvent was removed under vacuum. Further
purification by flash column chromatography (hexanes/EtOAc 19:1
to 9:1) afforded alkene 11 (3.46 g, 97%) as a colorless oil. [α]2D0 −3.1
(c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.03 (s, 3H), 0.04 (s,
3H), 0.09 (s, 6H), 0.90 (s, 18H), 1.31 (s, 3H), 1.44 (s, 3H), 1.49 (s,
3H), 3.38 (s, 3H), 3.51−3.55 (m, 2H), 3.56−3.67 (m, 2H), 3.79−3.89
(m, 2H), 4.06 (d, J = 7.0 Hz, 1H), 4.20 (dd, J = 7.0, 2.5 Hz, 1H),
4.23−4.28 (m, 1H), 4.73 (d, J = 7.8 Hz, 1H), 4.89 (d, J = 7.8 Hz, 1H),
5.25−5.28 (m, 1H), 5.31 (s, 1H), 5.98−6.07 (m, 1H). 13C NMR (100
MHz, CDCl3): δ −5.3 (CH3), −5.1 (CH3), −4.5 (CH3), −3.7 (CH3),
18.5 (C), 18.6 (C), 21.7 (CH3), 25.0 (CH3), 26.22 (CH3), 26.25
(CH3), 26.3 (CH3), 59.1 (CH3), 66.9 (CH2), 67.4 (CH2), 72.0 (CH2),
73.8 (CH), 79.1 (C), 82.2 (CH), 82.8 (CH), 91.0 (CH2), 107.6 (C),
117.1 (CH2), 139.6 (CH). IR (ATR) ν 2930, 2885, 2857, 2363, 2343,
1462, 1380, 1253, 1213, 1086, 1005, 988, 938, 834, 777 cm−1. HRMS
(ESI) calcd for C27H56O7Si2Na [M + Na]+, 571.3463; found,
571.3461.
(R)-1-((4R,5R)-5-((R)-2-((2-Methoxyethoxy)methoxy)but-3-en-2-
yl)-2,2-dimethyl-1,3-dioxolan-4-yl)ethane-1,2-diol (S1). A solution
of TBS protected diol 11 (2.5 g, 4.55 mmol, 1.0 equiv) in THF (23
mL) was treated with a solution of TBAF (1.0 M in THF, 18.2 mL,
18.2 mmol, 4.0 equiv) at 0 °C. After the addition, the cooling bath was
removed, and the reaction mixture was stirred for 3 h at room
temperature. As TLC analysis of the reaction mixture indicated
unreacted starting material, the reaction mixture was cooled to 0 °C
before one additional equiv (4.55 mL) of the TBAF solution was
added. The resulting solution was warmed to room temperature and
stirred for 2 h. The reaction was terminated by the addition of a
saturated NH4Cl solution (50 mL), the two layers were separated, and
the aqueous phase was extracted with EtOAc (3 × 50 mL). The
combined organic extracts were dried over Na2SO4 and filtered, and
the solvent was removed under reduced pressure. The crude product
was further purified by flash column chromatography (hexanes/EtOAc
1:1 to pure EtOAc) to afford diol S1 (1.45 g) in quantitative yield as a
colorless oil. [α]2D0 −51.3 (c 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 1.32 (s, 3H), 1.41 (s, 3H), 1.51 (s, 3H), 2.19−2.29 (m,
1H), 3.38 (s, 3H), 3.52−3.56 (m, 2H), 3.60−3.70 (m, 2H), 3.76−3.87
(m, 2H), 4.08−4.19 (m, 3H), 4.38 (bs, 1H), 4.82 (d, J = 7.0 Hz, 1H),
4.96 (d, J = 7.0 Hz, 1H), 5.31 (dd, J = 11.0, 1.0 Hz, 1H), 5.33 (dd, J =
17.6, 1.0 Hz, 1H), 6.15 (dd, J = 17.6, 11.0 Hz, 1H). 13C NMR (100
MHz, CDCl3): δ 23.0 (CH3), 25.2 (CH3), 27.2 (CH3), 59.2 (CH3),
65.1 (CH2), 68.1 (CH2), 68.8 (CH), 71.9 (CH2), 78.9 (CH), 81.0
(C), 82.6 (CH), 91.1 (CH2), 108.4 (C), 117.4 (CH2), 138.5 (CH). IR
(ATR) ν 3433, 2985, 2930, 2364, 1458, 1371, 1253, 1216, 1053, 1003,
932, 871, 782 cm−1. HRMS (ESI) calcd for C15H28O7Na [M + Na]+,
343.1733; found, 343.1728.
́
stored under an argon atmosphere over molecular sieves (4 Å).
Triethylamine, diisopropylethylamine, and diisopropylamine were
distilled from calcium hydride under an atmosphere of argon prior to
use.
All other commercially available reagents were used without further
purification. Unless indicated otherwise, reactions were magnetically
stirred and monitored by thin layer chromatography using silica gel 60-
F254 glass plates. The plates were developed with a mixture of
hexane/EtOAc or toluene/EtOAc. Unless the compound was colored,
UV-active spots were detected at longwave UV (254 nm) or shortwave
(180 nm). Most plates were additionally treated with one of the
following visualization reagents: CAM (H2SO4 (concd, 22 mL),
phosphormolybdic acid (20 g), Ce(SO4)2 (0.5 g), and 378 mL H2O))
or silica gel impregnated with iodine.
Flash column chromatography was performed with silica gel 60
(0.040−0.063 μm, 240−400 mesh).
Optical rotations were measured at the sodium D line with a 100
mm path length cell and are reported as follows: [α]TD, concentration
(g/100 mL), and solvent.
NMR spectra were recorded either on a 400 or 600 MHz
spectrometer. Unless stated otherwise, all NMR spectra were
measured in CDCl3 solutions and referenced to the residual CDCl3
signal (1H, δ = 7.26, 13C, δ = 77.16). All 1H and 13C shifts are given in
ppm (s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q =
quartet, quint = quintet, m = multiplet, and br = broadened signal).
Coupling constants J are given in Hz. The assignments of proton
resonances were confirmed, when possible, by correlated spectroscopy
(COSY, HSQC, HMBC, TOCSY, and NOESY).
IR spectra are reported in wave numbers (cm−1). All compounds
were measured using a single reflection monolithic diamond ATR
module.
High-resolution mass spectra were performed on a mass
spectrometer using ESI-mode and a UHR-TOF (Qq-TOF) mass
analyzer (acetonitrile/MeOH 1:1, +1% H2O).
(R)-2-((4R,5S)-2,2-Dimethyl-5-((R)-2,2,3,3,8,8,9,9-octamethyl-4,7-
dioxa-3,8-disiladecan-5-yl)-1,3-dioxolan-4-yl)but-3-en-2-ol (15). To
a solution of methyl ketone 10 (5.5 g, 12.7 mmol, 1.0 equiv) in THF
(180 mL) was added a solution of vinylmagnesium bromide (1.0 M in
THF, 38.1 mL, 38.1 mmol, 3.0 equiv) at 0 °C via a syringe. The
reaction mixture was stirred for 1 h at 0 °C and then for 90 min at
room temperature. After TLC analysis indicated the complete
consumption of the starting material, the reaction was quenched by
the addition of water (50 mL). The layers were separated, and the
aqueous phase was extracted with EtOAc (3 × 100 mL). The
combined organic extracts were dried over Na2SO4 and filtered, and
the solvent was removed under reduced pressure. After purification of
the crude material by flash column chromatography (hexanes/EtOAc
19:1 to 9:1), tertiary alcohol 15 (5.39 g) was isolated in 92% yield as a
light-yellow oil. [α]D20 −7.7 (c 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 0.06 (s, 6H), 0.18 (s, 3H), 0.19 (s, 3H), 0.90 (s, 9H), 0.92
(s, 9H), 1.31 (s, 3H), 1.33 (s, 3H), 1.46 (s, 3H), 3.75 (dd, J = 11.5, 3.8
Hz, 1H), 3.84 (dd, J = 11.5, 3.0 Hz, 1H), 4.04 (s, 1H), 4.08 (d, J = 6.5
Hz, 1H), 4.32 (dd, J = 8.0, 6.5 Hz, 1H), 4.41−4.46 (m, 1H), 5.09 (dd,
J = 10.8, 2.0 Hz, 1H), 5.44 (dd, J = 17.6, 2.0 Hz, 1H), 6.25 (dd, J =
17.6, 10.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ −5.4 (CH3),
−5.2 (CH3), −3.6 (CH3), −3.1 (CH3), 18.58 (C), 18.60 (C), 24.7
(CH3), 26.1 (CH3), 26.3 (CH3), 26.9 (CH3), 28.4 (CH3), 64.2 (CH2),
72.8 (CH), 73.9 (C), 77.3 (CH), 82.8 (CH), 107.4 (C), 112.7 (CH2),
143.0 (CH). IR (ATR) ν 3450, 2955, 2930, 2886, 2359, 2342, 1472,
1463, 1381, 1254, 1213, 1193, 1141, 1083, 1059, 930, 834, 779 cm−1.
HRMS (ESI) calcd for C23H48O5Si2Na [M + Na]+, 483.2938; found,
483.2939.
(4S,5R)-5-((R)-2-((2-Methoxyethoxy)methoxy)but-3-en-2-yl)-2,2-
dimethyl-1,3-dioxolane-4-carbaldehyde (8). Diol S1 (1.45 g, 4.5
mmol, 1.0 equiv) was dissolved in DCM (22 mL) and cooled to 0 °C,
and a solution of NaIO4 (1.44 g, 6.75 mmol, 1.5 equiv) in water (15
mL) was added. The solution was warmed to room temperature and
stirred for 2 h 15 min. The biphasic mixture was diluted with water (15
mL) and DCM (15 mL), the phases were separated, and the aqueous
phase was extracted with DCM (3 × 30 mL). The combined organic
extracts were dried over MgSO4 and filtered, and the solvent was
removed in vacuo. Further purification by flash column chromato-
graphy (hexanes/EtOAc 1:1) delivered aldehyde 8 (1.16 g) as a
colorless oil in 90% yield. [α]2D0 −44.1 (c 1.0, CHCl3). H NMR (400
1
MHz, CDCl3): δ 1.38 (s, 3H), 1.42 (s, 3H), 1.59 (s, 3H), 3.37 (s, 3H),
3.50−3.55 (m, 2H), 3.56−3.62 (m, 1H), 3.70−3.76 (m, 1H), 4.29 (d, J
= 7.0 Hz, 1H), 4.41 (dd, J = 7.0, 3.5 Hz, 1H), 4.67 (d, J = 7.3 Hz, 1H),
4.84 (d, J = 7.3 Hz, 1H), 5.29 (dd, J = 17.6, 1.0 Hz, 1H), 5.32 (dd, J =
11.0, 1.0 Hz, 1H), 6.03 (dd, J = 17.6, 11.0 Hz, 1H), 9.61 (d, J = 3.5 Hz,
(R)-5-((4S,5R)-5-((R)-2-((2-Methoxyethoxy)methoxy)but-3-en-2-
yl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2,3,3,8,8,9,9-octamethyl-4,7-
dioxa-3,8-disiladecane (11). Alcohol 15 (3.0 g, 6.5 mmol, 1.0 equiv)
was dissolved in DCM (5 mL) and cooled to 0 °C. DIPEA (5.5 mL,
D
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1H). 13C NMR (100 MHz, CDCl3): δ 21.1 (CH3), 25.4 (CH3), 27.4
(CH3), 59.1 (CH3), 67.7 (CH2), 71.9 (CH2), 78.4 (C), 81.8 (CH),
86.2 (CH), 91.3 (CH2), 110.8 (C), 117.7 (CH2), 138.9 (CH), 197.8
(CH). IR (ATR) ν 2987, 2938, 2880, 1730, 1457, 1415, 1377, 1249,
1216, 1162, 1077, 1020, 933 cm−1. HRMS (ESI) calcd for
C14H24O6Na [M + Na]+, 311.1471; found, 311.1468.
methylpropanoate (S3). For proof of the stereochemistry of alcohol
12. Alkene S2 (the major diastereomer from above, 78 mg, 0.18 mmol,
1.0 equiv) was dissolved in DCM (7.0 mL) and cooled to −78 °C
before a stream of ozone was bubbled through the mixture until the
characteristic blue color persisted (3 min). The reaction mixture was
purged with argon to displace the excess ozone, and a colorless
solution was obtained. After the addition of dimethylsulfide (15 μL,
0.23 mmol, 1.3 equiv), the reaction mixture was allowed to warm to
room temperature over 12 h. The solvent was removed under reduced
pressure, and the crude product was purified by filtration over a short
plug of silica gel (hexanes/EtOAc 5:1), affording a diastereomeric,
inseparable mixture of the corresponding lactols (24 mg) in 34% yield.
The diastereomeric mixture of lactols was dissolved in DCM (1 mL)
and cooled to 0 °C. NaHCO3 (11 mg, 0.134 mmol, 2.2 equiv) and
Dess−Martin periodinane (52 mg, 0.122 mmol, 2.0 equiv) were added
sequentially. The cooling bath was removed, and the resulting reaction
mixture was stirred for 2 h at room temperature before it was
quenched by the addition of a saturated, aqueous solution of Na2S2O3
(5 mL). The two layers were separated and the aqueous phase was
extracted with DCM (3 × 10 mL). The organic extracts were dried
over Na2SO4 and filtered, and the solvent was removed under reduced
pressure. The crude lactone was further purified by flash column
chromatography (hexanes/EtOAc 3:1 to 2:1) to afford S3 (16 mg) in
67% yield as a colorless oil. [α]2D0 −30.3 (c 0.8, CHCl3). 1H NMR (400
MHz, CDCl3): δ 1.30 (s, 3H), 1.34 (s, 3H), 1.36 (s, 3H), 1.41 (s, 3H),
1.57 (s, 3H), 3.36 (s, 3H), 3.49−3.54 (m, 2H), 3.65−3.74 (m, 2H),
3.69 (s, 3H), 4.33 (d, J = 7.6 Hz, 1H), 4.62 (dd, J = 7.6, 1.8 Hz, 1H),
4.80 (d, J = 6.8 Hz, 1H), 4.86 (d, J = 6.8 Hz, 1H), 5.27 (d, J = 1.8 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 17.3 (CH3), 21.7 (CH3), 21.9
(CH3), 24.3 (CH3), 26.2 (CH3-15), 45.9 (C), 52.4 (OCH3), 59.2
(OCH3), 68.4 (CH2), 71.8 (CH2), 73.1 (CH), 76.9 (C), 78.4 (CH),
79.1 (CH), 91.5 (CH2), 110.1 (C), 169.5(C), 176.5 (C). IR (ATR) ν
2993, 2954, 2877, 2356, 1758, 1724, 1473, 1459, 1379, 1348, 1298,
1268, 1216, 1142, 1126, 1069, 1015, 978, 775 cm−1. HRMS (ESI)
calcd for C18H30O9Na [M + Na]+, 413.1788; found, 413.1788.
Methyl-3-((4R,5R)-5-((R)-2-((2-methoxyethoxy)methoxy)but-3-
en-2-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(methoxymethoxy)-2,2-
dimethylpropanoate (S2). A solution of DIPA (1.4 mL, 10.0 mmol)
in dry THF (6 mL) was treated with n-BuLi (2.5 M in hexanes, 4.0
mL, 10.0 mmol) at −20 °C, and the resulting reaction mixture was
stirred for 15 min at that temperature. To 5.3 mL of the LDA solution
(4.62 mmol, 3.3 equiv), neat methylisobutyrate (0.48 mL, 4.2 mmol,
3.0 equiv) was added at −20 °C. The reaction mixture was stirred for 2
h 30 min before a solution of aldehyde 8 (400 mg, 1.4 mmol, 1.0
equiv) in THF (1.5 mL) was added. The resulting light-yellow
solution was warmed to 5 °C over 3 h until TLC showed the total
consumption of the starting material. The reaction was quenched by
the addition of a saturated NH4Cl solution (15 mL). After separation
of the layers, the aqueous phase was extracted with EtOAc (3 × 50
mL). The combined organic extracts were dried over Na2SO4 and
filtered, and the solvent was removed under reduced pressure. The
crude product was purified by flash column chromatography (hexanes/
EtOAc 9:1 to 5:1), delivering an inseparable 3:1 diastereomeric
mixture of secondary alcohols 12 and 12a (424 mg) as a colorless oil
in 78% yield, which was directly used for the next reaction.
The 3:1 diastereomeric mixture of the secondary alcohols from
above (12, 12a, 424 mg, 1.09 mmol, 1.0 equiv) was dissolved in DCM
(2 mL) and cooled to 0 °C. The resulting solution was treated with
DIPEA (0.57 mL, 3.27 mmol, 3.0 equiv) followed by the dropwise
addition of MOMCl (0.41 mL, 5.45 mmol, 5.0 equiv) over 5 min. The
reaction mixture was allowed to warm to room temperature and was
heated to 50 °C for 12 h. The reaction was terminated by the addition
of water (10 mL), the layers were separated, and the aqueous phase
was extracted with DCM (3 × 20 mL). The organic extracts were
dried over MgSO4 and filtered, and the solvent was removed under
reduced pressure. The crude diastereomeric mixture was separated by
flash column chromatography (hexanes/EtOAc 9:1 to 5:1), delivering
97 mg (21%) of the minor and 315 mg (67%) of the major desired
diastereomer, methylester S2, as colorless oils. Major diastereomer
(S)-Methyl-3-((4R,5R)-5-((S)-2-((2-methoxyethoxy)methoxy)-1-ox-
opropan-2-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(methoxyme-
thoxy)-2,2-dimethylpropanoate (13). Alkene S2 (200 mg, 0.46
mmol, 1.0 equiv) was dissolved in DCM (12 mL) and cooled to −78
°C, and a stream of ozone was bubbled through the mixture until the
characteristic blue color persisted (3 min). The reaction mixture was
purged with argon to displace the excess ozone, and a colorless
solution was obtained. After the addition of PPh3 (181 mg, 0.69 mmol,
1.5 equiv), the reaction mixture was allowed to warm to room
temperature over 12 h. The solvent was removed under reduced
pressure, and the crude product was purified by flash column
chromatography (hexanes/EtOAc 3:1), delivering aldehyde 13 (180
(S2): [α]2D0 −50.0 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ
1
1.19 (s, 3H), 1.26 (s, 3H), 1.28 (s, 3H), 1.29 (s, 3H), 1.43 (s, 3H),
3.37 (s, 3H), 3.39 (s, 3H), 3.50−3.59 (m, 3H), 3.62 (s, 3H), 3.76−
3.83 (m, 1H), 4.03 (d, J = 5.8 Hz, 1H), 4.10 (dd, J = 8.9, 5.8 Hz, 1H),
4.64 (d, J = 8.9 Hz, 1H), 4.642 (d, J = 7.8 Hz, 1H), 4.78 (d, J = 6.0 Hz,
1H), 4.80 (d, J = 6.0 Hz, 1H), 4.88 (d, J = 7.8 Hz, 1H), 5.24−5.35 (m,
2H), 6.17 (dd, J = 17.4, 11.2 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ 17.4 (CH3), 21.5 (CH3), 24.7 (CH3), 25.3 (CH3), 26.7 (CH3), 46.9
(C), 51.3 (CH3), 56.3 (CH3), 59.1 (CH3), 67.1 (CH2), 71.9 (CH2),
78.9 (CH), 79.3 (CH), 80.4 (C), 82.3 (CH), 90.4 (CH2), 99.0 (CH2),
107.2 (C), 118.7 (CH2), 138.7 (CH), 176.9 (C). IR (ATR) ν 2986,
2878, 2855, 2366, 1746, 1724, 1472, 1415, 368, 1295, 1217, 1193,
1101, 1036, 945, 873, 833 cm−1. HRMS (ESI) calcd for C21H38O9Na
[M + Na]+, 457.2416; found, 457.2416. Minor diastereomer: [α]2D2
mg, 90%) as a colorless oil. [α]2D1 −81.5° (c 1.0, CHCl3). H NMR
1
(400 MHz, CDCl3): δ 1.24 (s, 3H), 1.32 (s, 3H), 1.34 (s, 3H), 1.43 (s,
3H), 1.47 (s, 3H), 3.34 (s, 3H), 3.37 (s, 3H), 3.50−3.56 (m, 2H), 3.68
(s, 3H), 3.72−3.79 (m, 1H), 3.80−3.88 (m, 1H), 4.05 (d, J = 5.8 Hz,
1H), 4.45 (bt, J = 5.6 Hz, 1H), 4.53 (d, J = 6.8 Hz, 1H), 4.70 (d, J =
5.5 Hz, 1H), 4.72 (d, J = 6.8 Hz, 1H), 4.87 (d, J = 7.5 Hz, 1H), 4.92
(d, J = 7.5 Hz, 1H), 9.81 (s, 1H). 13C NMR (100 MHz, CDCl3): δ
17.4 (CH3), 20.5 (CH3), 23.1 (CH3), 25.0 (CH3), 26.3 (CH3), 47.7
(C), 52.0 (CH3), 56.5 (CH3), 59.2 (CH3), 68.1 (CH2), 71.1 (CH2),
76.4 (CH), 77.3 (CH), 82.7 (CH), 82.8 (C), 91.3 (CH2), 97.8 (CH2),
108.2 (C), 177.2 (C), 202.0 (CH). IR (ATR) ν 2985, 2951, 1733,
1470, 1435, 1368, 1254, 1194, 1155, 1098, 1078, 1050, 1032, 987, 884
cm−1. HRMS (ESI) calcd for C20H36O10 [M]+, 436.2308; found,
436.2316.
1
−97.6 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ 1.23 (s, 3H),
1.30 (s, 3H), 1.34 (s, 3H), 1.45 (s, 6H), 3.35 (s, 3H), 3.37 (s, 3H),
3.51−3.56 (m, 2H), 3.58−3.64 (m, 1H), 3.67 (s, 3H), 3.79−3.85 (m,
1H), 3.88 (d, J = 5.8 Hz, 1H), 4.37 (dd, J = 6.1, 5.8 Hz, 1H), 4.62 (d, J
= 6.6 Hz, 1H), 4.71 (d, J = 7.3 Hz, 1H), 4.72 (d, J = 6.1 Hz, 1H), 4.87
(d, J = 6.6 Hz, 1H), 4.89 (d, J = 7.3 Hz, 1H), 5.24−5.34 (m, 2H), 6.17
(dd, J = 17.6, 11.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 20.5
(CH3), 22.1 (CH3), 22.7 (CH3), 25.3 (CH3), 26.5 (CH3), 47.8 (C),
51.9 (CH3), 56.3 (CH3), 59.1 (CH3), 67.4 (CH2), 71.9 (CH2), 76.2
(CH), 76.8 (CH), 79.7 (C), 83.8 (CH), 90.8 (CH2), 97.6 (CH2),
107.6 (C), 117.9 (CH2), 139.2 (CH). IR (ATR) ν 2986, 2878, 2855,
2366, 1746, 1724, 1472, 1415, 368, 1295, 1217, 1193, 1101, 1036, 945,
873, 833 cm−1. HRMS (ESI) calcd for C21H38O9Na [M + Na]+,
457.2416; found, 457.2414.
(S)-Methyl-3-((4R,5R)-5-((R)-4,4-dibromo-2-((2-methoxyethoxy)-
methoxy)but-3-en-2-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(methox-
ymethoxy)-2,2-dimethylpropanoate (14). For the preparation of the
Wittig salt (dibromomethyl)triphenylphosphonium bromide (S4),
tetrabromomethane (16.4 g, 49.4 mmol, 1.0 equiv) was added to a
solution of triphenylphosphine (26 g, 99.1 mmol, 2.0 equiv) in 240
mL of methylene chloride at 0 °C. The resulting red reaction mixture
was stirred for 30 min. Water (8 mL) was added, and the resulting
yellow mixture was stirred vigorously for 15 min at 0 °C. The two
Methyl-2-((3aR,4S,7S,7aR)-7-((2-methoxyethoxy)methoxy)-2,2,7-
trimethyl-6-oxotetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yl)-2-
E
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Article
phases were separated, the organic layer was dried, and the solvent was
evaporated. The crude Wittig-salt was precipitated by the addition of
acetonitrile (150 mL). The yellow solid was filtered, acetonitrile (150
mL) was added, and the suspension was heated to reflux (110 °C) for
20 h. The suspension was filtered, and the solid was washed once with
20 mL of acetonitrile and dried under vacuum, affording 18.7 g (74%)
of the Wittig-salt (S4).43
the solvent was removed under vacuum. After purification of the crude
product by flash column chromatography (hexanes/EtOAc 19:1), 1.89
g (85%) of dibromide S6 were isolated as a slightly yellow oil. [α]D20
1
−9.9 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ 0.08 (s, 3H),
0.081 (s, 3H), 0.22 (s, 3H), 0.23 (s, 3H), 0.91 (s, 9H), 0.93 (s, 9H),
1.34 (s, 3H), 1.46 (s, 3H), 1.48 (s, 3H), 3.80 (dd, J = 11.3, 3.8 Hz,
1H), 3.91 (dd, J = 11.3, 3.4 Hz, 1H), 4.01 (d, J = 6.5 Hz, 1H), 4.25−
4.31 (m, 1H), 4.38 (dd, J = 7.9, 6.5 Hz, 1H), 4.46 (bs, 1H), 6.97 (s,
1H). 13C NMR (100 MHz, CDCl3): δ −5.4 (CH3), −5.2 (CH3), −3.5
(CH3), −3.3 (CH3), 18.56 (C), 18.65 (C), 24.5 (CH3), 25.5 (CH3),
26.1 (CH3), 26.3 (CH3), 27.0 (CH3), 64.1 (CH2), 73.4 (CH), 75.0
(C), 76.6 (CH), 83.2 (CH), 88.0 (C), 107.6 (C), 140.5 (CH). IR
(ATR) ν 3415, 2930, 2858, 1598, 1471, 1383, 1256, 1213, 1142, 1062,
980, 935, 885, 835, 812, 780 cm−1. HRMS (ESI) calcd for
C23H4679Br81BrO5Si2Na [M + Na]+, 641.1128; found, 641.1133.
(R)-5-((4S,5R)-5-((R)-4,4-Dibromo-2-((2-methoxyethoxy)-
methoxy)but-3-en-2-yl)-2,2-dimethyl-1,3-dioxolan-4-yl)-
2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (16). To a
solution of alcohol S6 (188 mg, 0.3 mmol, 1.0 equiv) in 1,2-
dichloroethane (1.0 mL) was added DIPEA (0.26 mL, 1.5 mmol, 5.0
equiv) followed by the dropwise addition of MEMCl (0.171 mL, 1.5
mmol, 5.0 equiv) at 0 °C over 5 min. The reaction mixture was
allowed to warm to room temperature before it was heated at 100 °C
(sealed round-bottomed flask) for 12 h. The reaction was quenched by
the addition of water (5 mL), the layers were separated, and the
aqueous layer was extracted with DCM (3 × 10 mL). The combined
organic extracts were dried over MgSO4 and filtered, and the solvent
was removed under vacuum. Further purification by flash column
chromatography (hexanes/EtOAc 19:1) afforded dibromide 16 (183
To a suspension of Wittig-salt S4 (180 mg, 0.35 mmol, 5.0 equiv) in
THF (2.5 mL) was added t-BuOK (39 mg, 0.35 mmol, 5.0 equiv) in
one portion at 0 °C. The resulting brown suspension was stirred for 30
min before a solution of aldehyde 13 (30 mg, 0.07 mmol, 1.0 equiv) in
THF (0.5 mL) was added. The resulting reaction mixture was then
stirred for 1 h at 0 °C followed by 12 h at room temperature. The
reaction was terminated by the addition of brine (5 mL), the layers
were separated, and the aqueous phase was extracted with EtOAc (3 ×
10 mL). The combined organic extracts were dried over Na2SO4 and
filtered, and the solvent was removed under vacuum. After purification
of the crude product by flash column chromatography (hexanes/
EtOAc 5:1), dibromide 14 was isolated as a colorless oil (5 mg, 17%).
[α]2D0 −77.6 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ 1.21 (s,
1
3H), 1.33 (s, 3H), 1.36 (s, 3H), 1.52 (s, 3H), 1.67 (s, 3H), 3.37 (s,
3H), 3.39 (s, 3H), 3.53−3.57 (m, 2H), 3.66−3.72 (m, 1H), 3.68 (s,
3H), 3.78−3.84 (m, 1H), 4.03 (d, J = 6.5 Hz, 1H), 4.37 (dd, J = 6.5,
3.9 Hz, 1H), 4.62 (d, J = 3.9 Hz, 1H), 4.65 (d, J = 6.8 Hz, 1H), 4.79
(d, J = 6.8 Hz, 1H), 4.81 (d, J = 7.8 Hz, 1H), 4.99 (d, J = 7.8 Hz, 1H),
7.04 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 20.4 (CH3), 21.9
(CH3), 23.3 (CH3), 25.0 (CH3), 26.6 (CH3), 48.2 (C), 52.0 (CH3),
56.5 (CH3), 59.2 (CH3), 68.0 (CH2), 72.0 (CH2), 76.1 (CH), 78.2
(CH), 80.8 (C), 83.3 (CH), 88.9 (C), 91.5 (CH2), 98.8 (CH2), 108.0
(C), 139.9 (CH), 177.4 (C). IR (ATR) ν 2930, 2888, 2855, 2361,
2341, 1724, 1613, 1514, 1463, 1379, 1369, 1250, 1216, 1136, 1090,
1031, 941, 873, 810, 776 cm−1. HRMS (ESI) calcd for
C21H3679Br81BrO9Na [M + Na]+, 615.0604; found, 615.0599.
mg, 87%) as a light-yellow oil. [α]2D0 −17.0 (c 1.0, CHCl3). H NMR
1
(400 MHz, CDCl3): δ 0.06 (s, 3H), 0.065 (s, 3H), 0.12 (s, 6H), 0.90
(s, 9H), 0.91 (s, 9H), 1.34 (s, 3H), 1.47 (s, 3H), 1.65 (s, 3H), 3.39 (s,
3H), 3.51−3.58 (m, 2H), 3.60−3.74 (m, 2H), 3.78−3.86 (m, 2H),
4.15−4.21 (m, 1H), 4.26 (dd, J = 6.8, 3.0 Hz, 1H), 4.33 (d, J = 6.8 Hz,
1H), 4.84 (d, J = 7.8 Hz, 1H), 4.94 (d, J = 7.8 Hz, 1H), 6.85 (s, 1H).
13C NMR (100 MHz, CDCl3): δ −5.2 (CH3), −5.1 (CH3), −4.3
(CH3), −3.8 (CH3), 18.5 (C), 18.6 (C), 21.8 (CH3), 25.0 (CH3),
26.25 (CH3), 26.30 (CH3), 26.4 (CH3), 59.2 (CH3), 66.3 (CH2), 67.8
(CH2), 71.9 (CH2), 73.5 (CH), 80.7 (C), 80.9 (CH), 81.4 (CH), 89.1
(C), 91.6 (CH2), 107.7 (C), 140.3 (CH). IR (ATR) ν 2930, 2886,
2858, 2359, 2342, 1471, 1381, 1254, 1215, 1088, 987, 939, 835, 750
cm−1. HRMS (ESI) calcd for C27H5479Br81BrO7Si2Na [M + Na]+,
729.1652; found, 729.1665.
(S)-2-((4R,5S)-2,2-Dimethyl-5-((R)-2,2,3,3,8,8,9,9-octamethyl-4,7-
dioxa-3,8-disiladecan-5-yl)-1,3-dioxolan-4-yl)-2-hydroxypropanal
(S5). Alkene 15 (500 mg, 1.09 mmol, 1.0 equiv) was dissolved in
DCM (28 mL) and cooled to −78 °C. A stream of ozone was bubble
through the reaction mixture (4 min) until the blue color persisted
followed by a stream of argon to displace the excess ozone. After the
addition of DMS (0.83 mL, 10.9 mmol, 10.0 equiv), the colorless
solution was allowed to warm to room temperature over a period of 12
h. The reaction mixture was washed with brine (30 mL), the layers
were separated, the organic phase was dried over Na2SO4 and filtered,
and the solvent was removed under reduced pressure. Further
purification by flash column chromatography (hexanes/EtOAc 9:1)
delivered aldehyde S5 (522 mg) in 84% yield as a colorless oil. [α]D20
(S)-4-((tert-Butyldimethylsilyl)oxy)-2-methylbutan-1-ol (S7). Alco-
hol S7 was prepared by Myers alkylation and subsequent reductive
cleavage of the chiral auxiliary following the published protocol.34 1H
NMR (400 MHz, CDCl3): δ 0.08 (s, 6H), 0.90 (s, 9H), 0.92 (d, J =
6.8 Hz, 3H), 1.52−1.59 (m, 2H), 1.75−1.85 (m, 2H), 2.93 (dd, J =
7.5, 5.2 Hz, 1H), 3.42 (ddd, J = 10.9, 7.0, 5.2 Hz, 1H), 3.51 (ddd, J =
10.9, 7.5, 4.8 Hz, 1H), 3.62−3.69 (m, 1H), 3.73−3.80 (m, 1H). These
spectral characteristics are identical to those previously reported.44
(S)-4-((tert-Butyldimethylsilyl)oxy)-2-methylbutanal (17). To a
solution of IBX (1.92 g, 6.87 mmol, 1.5 equiv) in DMSO (15 mL)
was added alcohol S7 (1.0 g, 4.58 mmol, 1.0 equiv) in DMSO (1.5
mL), and the reaction mixture was stirred for 90 min at room
temperature. As TLC showed the total consumption of the starting
material, the reaction was terminated by the addition of water (15 mL)
at 0 °C. The resulting suspension was filtered over a plug of Celite, and
the filtrate was diluted with Et2O (20 mL). The layers were separated,
and the aqueous phase was extracted with Et2O (3 × 50 mL). The
combined organic fractions were washed with water (50 mL) and
brine (50 mL) and dried over MgSO4. After filtration, the solvent was
removed under reduced pressure. The crude material was purified by
flash column chromatography (hexanes/EtOAc 19:1 to 9:1),
delivering aldehyde 17 (619 mg) in 62% yield as a colorless oil.
1
−34.4 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ 0.07 (s, 6H),
0.18 (s, 6H), 0.90 (s, 9H), 0.92 (s, 9H), 1.32 (s, 3H), 1.36 (s, 3H),
1.45 (s, 3H), 3.73 (dd, J = 10.8, 4.3 Hz, 1H), 3.82 (dd, J = 10.8, 5.0
Hz, 1H), 4.22−4.27 (m, 1H), 4.26 (d, J = 6.0 Hz, 1H), 4.29 (bs, 1H),
4.39 (dd, J = 6.0, 5.8 Hz, 1H), 9.72 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ −5.35 (CH3), −5.30 (CH3), −4.0 (CH3), −3.8 (CH3), 18.5
(C), 18.6 (C), 21.6 (CH3), 25.1 (CH3), 26.1 (CH3), 26.2 (CH3), 26.6
(CH3), 64.3 (CH2), 72.8 (CH), 77.7 (CH), 78.5 (C), 81.1 (CH),
108.0 (C), 203.4 (CH). IR (ATR) ν 3473, 2930, 2858, 2362, 1737,
1463, 1381, 1253, 1216, 1147, 1082, 1046, 939, 832, 777 cm−1. HRMS
(ESI) calcd for C22H46O6Si2Na [M + Na]+, 485.2731; found,
485.2733.
(R)-4,4-Dibromo-2-((4R,5S)-2,2-dimethyl-5-((R)-2,2,3,3,8,8,9,9-oc-
tamethyl-4,7-dioxa-3,8-disiladecan-5-yl)-1,3-dioxolan-4-yl)but-3-
en-2-ol (S6). To a suspension of Wittig-salt S4 (9.3 g, 18.1 mmol, 5.0
equiv) in THF (135 mL) was added t-BuOK (2.03 g, 18.1 mmol, 5.0
equiv) in three portions at 0 °C. The resulting brown suspension was
stirred for 2 min at 0 °C before it was cooled to −20 °C and a solution
of aldehyde S5 (1.67 g, 3.61 mmol, 1.0 equiv) in THF (12 mL) was
added. The reaction mixture was stirred for 1 h 30 min at −20 °C and
15 min at 0 °C. The reaction was terminated by the addition of a
saturated NH4Cl solution (50 mL). After separation of the two layers,
the aqueous phase was extracted with EtOAc (3 × 100 mL). The
combined organic extracts were dried over Na2SO4 and filtered, and
[α]2D0 +19.1 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ 0.04 (s,
1
6H), 0.88 (s, 9H), 1.11 (d, J = 7.0 Hz, 3H), 1.58−1.68 (m, 1H), 1.90−
2.01 (m, 1H), 2.44−2.56 (m, 1H), 3.62−3.74 (m, 2H), 9.65 (d, J = 1.8
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ −5.32 (CH3), −5.31
(CH3), 13.3 (CH3), 18.4 (C), 26.0 (CH3), 33.9 (CH2), 43.7 (CH),
F
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60.4 (CH2), 205.0 (CH). IR (ATR) ν 2954, 2929, 2857, 1728, 1472,
1462, 1388, 1254, 1097, 1005, 881, 834, 776 cm−1. HRMS (ESI) calcd
for C11H24O2SiNa [M + Na]+, 239.1443; found, 239.1440. These
spectral characteristics are identical to those previously reported.45
(8R,12S,E)-10-Bromo-8-((4R,5S)-2,2-dimethyl-5-((R)-
2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)-1,3-diox-
olan-4-yl)-8,12,16,16,17,17-hexamethyl-2,5,7,15-tetraoxa-16-si-
laoctadec-9-en-11-ol (19). To a solution of dibromide 16 (75 mg,
0.107 mmol, 1.0 equiv) in dry Et2O (0.53 mL) was added n-BuLi (2.01
M in hexanes, 48 μL, 0.103 mmol, 0.96 equiv) at −108 °C (liquid
nitrogen/ethanol cooling bath) dropwise over 3 min. The reaction
mixture was stirred for 1 h with the temperature kept between −116
and −108 °C. A solution of aldehyde 17 (46 mg, 0.214 mmol, 2.0
equiv) in Et2O (0.5 mL) was added over 5 min, and the colorless
solution was stirred for 2 h in the same temperature range. The
reaction was terminated by the addition of a saturated NH4Cl solution
(2 mL) at −108 °C. After warming to room temperature, the layers
were separated, and the organic phase was extracted with EtOAc (3 ×
10 mL). The combined organic extracts were dried over Na2SO4, and
filtered, and the solvent was removed under reduced pressure. The
crude 1.25:1 mixture of the corresponding diastereomeric secondary
alcohols was purified by flash column chromatography (hexanes/
EtOAc 19:1 to 9:1), affording both diastereomers as colorless oils
(19a, less polar, 20 mg; 19b, more polar, 16 mg) in 40% overall yield.
19a: [α]2D0 −12.0 (c 0.3, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.05
(s, 6H, CH3-TBS), 0.06 (s, 3H, CH3-TBS), 0.08 (s, 3H, CH3-TBS),
0.11 (s, 6H, CH3-TBS), 0.89 (s, 9H, CH3-tBu-TBS), 0.91 (s, 9H, CH3-
tBu-TBS), 0.913 (s, 9H, CH3-tBu-TBS), 1.07 (d, J = 6.6 Hz, 3H, CH3-
12), 1.07−1.10 (m, 1H, CH2-2b), 1.33 (s, 3H, CH3-21), 1.46 (s, 3H,
CH3-20), 1.55 (s, 3H, CH3-14), 1.58−1.67 (m, 1H, CH2-2a), 1.81−
1.90 (m, 1H, CH-3), 3.37 (s, 3H, OCH3-18), 3.47 (bd, J = 3.3 Hz, 1H,
OH-13), 3.51−3.54 (m, 2H, CH2-17a,b), 3.61−3.67 (m, 3H, CH2-16b,
1b, 11b), 3.68−3.73 (m, 1H, CH2-1a), 3.81−3.85 (m, 1H, CH2-11a),
3.89−3.93 (m, 1H, CH2-16a), 4.11 (d, J = 7.0 Hz, 1H, CH-8), 4.17−
4.22 (m, 1H, CH-10), 4.25 (dd, J = 7.0, 2.3 Hz, CH-9), 4.42 (dd, J =
9.3, 3.3 Hz, 1H, CH-4), 4.73 (d, J = 7.3 Hz, 1H, CH2-15b), 5.03 (d, J =
7.3 Hz, 1H, CH2-15a), 6.13 (s, 1H, CH-6). 13C NMR (100 MHz,
CDCl3): δ −5.2 (CH3-TBS), −5.13 (CH3-TBS), −5.12 (CH3-TBS),
−5.0 (CH3-TBS), −4.3 (CH3-TBS), −3.6 (CH3-TBS), 16.1 (CH3-12),
18.4 (C-TBS), 18.5 (C-TBS), 18.8 (C-TBS), 24.9 (CH3-21), 25.4
(CH3-14), 26.1 (CH3-tBu-TBS), 26.2 (CH3-20), 26.23 (CH3-tBu-
TBS), 26.4 (CH3-tBu-TBS), 34.8 (CH-3), 36.1 (CH2-2), 59.2 (OCH3-
18), 61.6 (CH2-1), 67.0 (CH2-11), 68.4 (CH2-16), 71.8 (CH2-17),
73.7 (CH-10), 74.1 (CH-4), 80.0 (C-7), 81.8 (CH-9), 82.1 (CH-8),
92.1 (CH2-15), 107.8 (C-19), 135.8 (CH-6), 136.6 (C-5). IR (ATR) ν
3470, 2953, 2929, 2857, 2363, 2342, 1472, 1462, 1380, 1253, 1211,
1088, 1006, 989, 939, 834, 776, 735 cm−1. HRMS (ESI) calcd for
C38H7981BrO9Si3Na [M + Na]+, 867.4093; found, 867.4099. 19b: [α]2D0
(R,R)-Diisopropyl Tartrate (E)-Crotylboronate (22).35 To a mixture
of t-BuOK (16.4 g, 146 mmol, 1.0 equiv) in THF (120 mL) was added
trans-2-butene (14.2 mL, 153.3 mmol, 1.05 equiv, trans-2-butene was
condensed from a gas lecture bottle into a rubber-stoppered 25 mL
graduated Schlenk flask immersed in liquid nitrogen) via a cannula at
−78 °C. Although the subsequent, dropwise addition of a solution of
n-BuLi (2.5 M in hexanes, 58.4 mL, 146 mmol, 1.0 equiv) occurred
over 20 min, the internal temperature of the (E)-crotylpotassium
solution did not rise above −65 °C. After complete addition, the
reaction mixture was warmed to −50 °C and was maintained at that
temperature for 25 min until it was recooled to −78 °C.
Triisopropylborate (34 mL, 146 mmol, 1.0 equiv) was added slowly
over 15 min, and the internal temperature did not rise above −65 °C.
After complete addition, the resulting mixture was stirred for 10 min at
−78 °C. The reaction was quenched by pouring the mixture into a
separatory funnel containing HCl (300 mL, 1 M). The phases were
separated, and the aqueous layer was extracted with EtOAc (3 × 200
mL). The combined organic extracts were dried over Na2SO4, filtered,
and treated with diethanolamine (11.2 mL, 116.8 mmol, 0.8 equiv).
The solution was stirred over 4 Å molecular sieves (25 g) in an argon
atmosphere for 3 h. The suspension was filtered, the solvent was
removed under reduced pressure, and the resulting white solid was
recrystallized from a mixture of Et2O and DCM (the solid was
suspended and heated to reflux in Et2O (20 mL) and DCM was added
dropwise until the solid was dissolved), affording S8 (14.0 g) in 57%
1
yield as a white crystalline solid. mp 121−123 °C. H NMR (400
MHz, CDCl3): δ 1.37 (d, J = 7.8 Hz, 2H), 1.63 (dd, J = 6.3, 1.5 Hz,
3H), 2.73−2.86 (m, 2H), 3.14−3.30 (m, 2H), 3.82−3.95 (m, 2H),
3.96−4.08 (m, 2H), 4.29 (bs, 1H), 5.22−5.34 (m, 1H), 5.62−5.74 (m,
1H).
A suspension of S8 and (R,R)-diisopropyl tartrate (5.37 g, 63.5
mmol, 1.0 equiv) in Et2O (150 mL) was treated with brine (150 mL)
and stirred for 5 min at room temperature. The phases were separated,
and the aqueous layer was extracted with Et2O (3 × 100 mL). The
combined fractions were dried over MgSO4 and filtered, and the
solvent was removed under vacuum, delivering 9.4 g (quant.) of 22 as
1
a light-yellow oil. H NMR (400 MHz, CDCl3): δ 1.28 (s, 6H), 1.30
(s, 6H), 1.62−1.67 (m, 3H), 1.80−1.86 (m, 2H), 4.76 (s, 2H), 5.07−
5.17 (m, 2H), 5.45−5.51 (m, 2H). These spectral characteristics are
identical to those previously reported.35
(2S,3S)-1-((tert-Butyldimethylsilyl)oxy)-3-methylpent-4-en-2-ol
(23). A solution of crude (E)-crotylboronate (22, 9.41 g, 31.6 mmol,
1.2 equiv) in toluene (165 mL) was cooled to −78 °C, and aldehyde
21 (4.58 g, 26.3 mmol, 1.0 equiv) dissolved in toluene (20 mL) was
added dropwise over 5 min. The reaction mixture was stirred for 4 h at
−78 °C before it was quenched by the addition of an aqueous NaOH
solution (30 mL, 2 M) at −78 °C. The mixture was allowed to warm
to 0 °C and was stirred at that temperature for 20 min before it was
filtered over a pad of Celite. The aqueous layer was extracted with
EtOAc (3 × 150 mL). The combined organic fractions were dried over
K2CO3 and filtered, and the solvent was removed under reduced
pressure. The crude product was further purified by flash column
chromatography (hexanes/EtOAc 40:1 to 19:1) to give secondary
alcohol 23 (4.28 g) in 71% yield as a colorless oil. The enantiomeric
excess (70% ee) of the product was determined by Mosher ester
1
+3.4 (c 0.75, CHCl3). H NMR (400 MHz, CDCl3): δ 0.04 (s, 3H,
CH3-TBS), 0.05 (s, 3H, CH3-TBS), 0.07 (s, 6H, CH3-TBS), 0.10 (s,
3H, CH3-TBS), 0.11 (s, 3H, CH3-TBS), 0.88−0.91 (m, 30H, CH3-
tBu-TBS, CH3-12), 1.33 (s, 3H, CH3-21), 1.42−1.46 (m, 1H, CH2-
2b), 1.47 (s, 3H, CH3-20), 1.53 (s, 3H, CH3-14), 1.84−1.93 (m, 1H,
CH-3), 1.95−2.02 (m, 1H, CH2-2a), 3.37 (s, 3H, OCH3-18), 3.52−
3.55 (m, 2H, CH2-17a, b), 3.62 (dd, J = 6.8, 10.5 Hz, 1H, CH2-11b),
3.64−3.83 (m, 6H, CH2− 16a,b, 11a,b, 1a,b, OH-13), 4.01−4.05 (m,
1H, CH-10), 4.17 (d, J = 7.0 Hz, 1H, CH-8), 4.19 (dd, J = 7.0, 1.9 Hz,
1H, CH-9), 4.48 (dd, J = 9.2, 5.3 Hz, 1H, CH-4), 4.86 (d, J = 7.2 Hz,
1H, CH2-15b), 4.95 (d, J = 7.2 Hz, 1H, CH2-15a), 6.16 (s, 1H, CH-6).
13C NMR (100 MHz, CDCl3): δ −5.3 (CH3-TBS), −5.2 (CH3-TBS),
−5.17 (CH3-TBS), −5.1 (CH3-TBS), −4.3 (CH3-TBS), −3.8 (CH3-
TBS), 17.5 (CH3-12), 18.4 (C-TBS), 18.5 (C-TBS), 23.1 (CH3-14),
25.0 (CH3-21), 26.1 (CH3-tBu-TBS), 26.2 (CH3-tBu-TBS), 26.25
(CH3-tBu-TBS), 26.3 (CH3-20), 36.6 (CH-3), 36.7 (CH2-2), 59.2
(OCH3-18), 61.2 (CH2-1), 66.7 (CH2-11), 68.0 (CH2-16), 71.9 (CH2-
17), 72.2 (CH-10), 74.4 (CH-4), 80.0 (C-7), 81.3 (CH-9), 82.3 (CH-
8), 91.6 (CH2-15), 107.7 (C-19), 135.9 (CH-6), 136.7 (C-5). IR
(ATR) ν 3470, 2953, 2929, 2857, 2363, 2342, 1472, 1462, 1380, 1253,
1211, 1088, 1006, 989, 939, 834, 776, 735 cm−1. HRMS (ESI) calcd
for C38H7981BrO9Si3Na [M + Na]+, 867.4093; found, 867.4087.
analysis. [α]2D0 −1.4 (c 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ
1
0.07 (s, 6H), 0.90 (s, 9H), 1.05 (d, J = 6.8 Hz, 3H), 2.25−2.36 (m,
1H), 3.37 (d, J = 3.0 Hz, 1H), 3.48−3.54 (m, 2H), 3.61−3.69 (m,
1H), 5.03−5.07 (m, 1H), 5.07−5.10 (m, 1H), 5.81−5.92 (m, 1H). 13C
NMR (100 MHz, CDCl3): δ −5.24 (CH3), −5.18 (CH3), 16.3 (CH3),
18.4 (C), 26.0 (CH3), 40.6 (CH), 65.4 (CH2), 75.0 (CH), 115.2
(CH2), 140.5 (CH). IR (ATR) ν 3630, 3076, 2882, 2360, 2342, 1471,
1389, 1254, 1103, 1036, 1005, 913, 836 cm−1. HRMS (ESI) calcd for
C12H26O2SiNa [M + Na]+, 253.1600; found, 253.1607.
(S)-5-((S)-But-3-en-2-yl)-8,8,9,9-tetramethyl-2,4,7-trioxa-8-silade-
cane (S9). A solution of secondary alcohol 23 (2.46 g, 10.7 mmol, 1.0
equiv) in DCM (3 mL) was treated consecutively with DIPEA (5.57
mL, 32.1 mmol, 3.0 equiv) and MOMCl (2.44 mL, 32.1 mmol, 1.0
equiv) at 0 °C. The reaction mixture was stirred for 12 h at room
temperature before it was quenched by the addition of water (10 mL).
G
dx.doi.org/10.1021/jo401480t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
The layers were separated, and the aqueous phase was extracted with
DCM (3 × 15 mL). The combined organic extracts were dried over
Na2SO4 and filtered, and the solvent was removed under reduced
pressure. The resulting crude material was purified by flash column
chromatography (hexanes/EtOAc 19:1), affording S9 (2.79 g) in 95%
were dried over Na2SO4 and filtered, and the solvent was removed
under reduced pressure. The resulting crude 9:1 mixture of secondary
alcohols was purified by flash column chromatography (hexanes/
EtOAc 9:1 to 5:1), providing 24 (342 mg) and 24a (38 mg) as
colorless oils in 96% overall yield. Major diastereomer (24): [α]2D0 +6.3
yield as a colorless oil. [α]2D0 −17.7 (c 1.0, CHCl3). H NMR (400
(c 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ 0.93 (d, J = 6.6 Hz,
1
1
MHz, CDCl3): δ 0.05 (s, 6H), 0.90 (s, 9H), 1.07 (d, J = 7.0 Hz, 3H),
2.45−2.55 (m, 1H), 3.39 (s, 3H), 3.48−3.54 (m, 1H), 3.58−3.64 (m,
2H), 4.65 (d, J = 6.7 Hz, 1H), 4.79 (d, J = 6.7 Hz, 1H), 5.01−5.03 (m,
1H), 5.04−5.08 (m 1H), 5.77−5.89 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ −5.29 (CH3), −5.26 (CH3), 16.6 (CH3), 18.4 (C), 26.0
(CH3), 39.5 (CH), 55.7 (CH3), 64.1 (CH2), 82.0 (CH), 97.1 (CH2),
115.0 (CH2), 140.3 (CH). IR (ATR) ν 2952, 2855, 2360, 2341, 1513,
1462, 1372, 1249, 1148, 1095, 1036, 836 cm−1. HRMS (ESI) calcd for
C14H30O3SiNa [M + Na]+, 297.1862; found, 297.1851.
(2S,3S)-2-(Methoxymethoxy)-3-methylpent-4-en-1-ol (S10). To a
solution of alkene S9 (4.62 g, 16.8 mmol, 1.0 equiv) in THF (85 mL)
was added a solution of TBAF (1.0 M in THF, 25.2 mL, 25.2 mmol,
1.5 equiv) at 0 °C. After the addition, the cooling bath was removed,
and the reaction mixture was stirred for 3 h at room temperature. TLC
showed the total consumption of the starting material, and the reaction
was quenched by the addition of a saturated, aqueous NH4Cl solution
(30 mL). The aqueous phase was extracted with EtOAc (3 × 50 mL).
The combined organic fractions were dried over Na2SO4 and filtered,
and the solvents were removed in vacuo. The crude material was
purified by flash column chromatography (hexanes/EtOAc 9:1 to 3:1),
delivering S10 (2.15 g, 80%) as a colorless oil. [α]2D0 +46.8 (c 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 1.05 (s, 3H), 2.38−2.49 (m,
1H), 2.95 (dd, J = 8.7, 4.0 Hz, 1H), 3.43 (s, 3H), 3.43−3.47 (m, 1H),
3.52−3.64 (m, 2H), 4.67 (d, J = 6.8 Hz, 1H), 4.76 (d, J = 6.8 Hz, 1H),
5.0−5.03 (m, 1H), 5.03−5.08 (m, 1H), 5.81 (ddd, J = 17.3, 10.5, 7.7
Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 16.3 (CH3), 40.4 (CH),
55.9 (CH3), 64.1 (CH2), 86.1 (CH), 97.8 (CH2), 115.2 (CH2), 140.0
(CH). IR (ATR) ν 3424, 2360, 2340, 1514, 1462, 1418, 1372, 1251,
1213, 1149, 1102, 1036, 915 cm−1. HRMS (ESI) calcd for C8H16O3Na
[M + Na]+, 183.0997; found, 183.0992.
3H), 1.07 (d, J = 6.8 Hz, 3H), 1.22−1.31 (m, 1H), 1.52 (ddd, J = 13.8,
10.5, 4.3 Hz, 1H), 2.08−2.16 (m, 1H), 2.43−2.56 (m, 1H), 3.18 (dd, J
= 5.9, 3.9 Hz, 1H), 3.23 (d, J = 3.9 Hz, 1H), 3.27−3.31 (m, 2H), 3.42
(s, 3H), 3.62−3.69 (m, 1H), 3.80 (s, 3H), 4.44 (s, 2H), 4.67 (d, J = 6.8
Hz, 1H), 4.76 (d, J = 6.8 Hz, 1H), 4.99−5.02 (m, 1H), 5.02−5.06 (m,
1H), 5.76−5.88 (m, 1H), 6.84−6.90 (m, 2H), 7.22−7.28 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ 16.9 (CH3), 17.7 (CH3), 30.4 (CH), 37.9
(CH2), 40.0 (CH), 55.4 (CH3), 56.2 (CH3), 69.8 (CH), 72.6 (CH2),
76.3 (CH2), 88.7 (CH), 98.9 (CH2), 113.6 (CH), 115.3 (CH2), 129.3
(CH), 130.8 (C), 139.9 (CH), 159.2 (C). IR (ATR) ν 3460, 2932,
2359, 2341, 1512, 1459, 1363, 1301, 1245, 1172, 1147, 1092, 1031,
914, 821 cm−1. HRMS (ESI) calcd for C20H32O5Na [M + Na]+,
375.2148; found, 375.2141. Minor diastereomer (24a): [α]2D0 +0.9 (c
0.6, CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.98 (d, J = 6.8 Hz, 3H),
1.07 (d, J = 7.1 Hz, 3H), 1.29−1.37 (m, 1H), 1.50−1.59 (m, 1H),
1.99−2.13 (m, 1H), 2.41−2.55 (m, 1H), 3.07 (d, J = 4.5 Hz, 1H), 3.18
(dd, J = 5.9, 3.9 Hz, 1H), 3.28−3.37 (m, 2H), 3.41 (s, 3H), 3.62−3.72
(m, 1H), 3.80 (s, 3H), 4.42 (s, 2H), 4.67 (d, J = 6.8 Hz, 1H), 4.76 (d, J
= 6.8 Hz, 1H), 4.98−5.05 (m, 2H), 5.76−5.87 (m, 1H), 6.83−6.90 (m,
2H), 7.21−7.27 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 17.5
(CH3), 18.7 (CH3), 30.3 (CH), 38.1 (CH2), 40.0 (CH), 55.4 (CH3),
56.2 (CH3), 69.9 (CH), 72.9 (CH2), 75.0 (CH2), 88.0 (CH), 98.8
(CH2), 113.8 (CH), 115.3 (CH2), 129.3 (CH), 130.9 (C), 139.9
(CH), 159.1 (C). IR (ATR) ν 3460, 2932, 2359, 2341, 1512, 1459,
1363, 1301, 1245, 1172, 1147, 1092, 1031, 914, 821 cm−1. HRMS
(ESI) calcd for C20H32O5Na [M + Na]+, 375.2148; found, 375.2145.
(5S)-5-((S)-But-3-en-2-yl)-8,8-diethyl-6-((S)-3-((4-methoxybenzyl)-
oxy)-2-methylpropyl)-2,4,7-trioxa-8-siladecane (S11). To a solution
of secondary alcohol 24 (660 mg, 1.9 mmol, 1.0 equiv), imidazole
(259 mg, 3.8 mmol, 2.0 equiv), and 4-dimethylaminopyridine (4 mg,
0.03 mmol, 0.02 equiv) in DCM (9.5 mL) was added chlorotri-
ethylsilane (0.64 mL, 3.8 mmol, 2.0 equiv) at 0 °C. The reaction
mixture was stirred for 12 h at room temperature. The reaction was
quenched by the addition of a saturated, aqueous solution of NaHCO3
(10 mL). The layers were separated, and the aqueous phase was
extracted with DCM (3 × 20 mL). The combined organic fractions
were dried over Na2SO4 and filtered, and the solvent was removed
under reduced pressure. The product was purified by flash column
chromatography (hexanes/EtOAc 9:1), affording S11 (0.82 g) in 93%
(2S,3S)-2-(Methoxymethoxy)-3-methylpent-4-enal (5). To a sol-
ution of alcohol S10 (2.0 g, 12.5 mmol, 1.0 equiv) in DCM (125 mL)
were added N-methylmorpholine-N-oxide (2.2 g, 18.8 mmol, 1.5
equiv) and 4 Å molecular sieves (8 g) at room temperature. After the
addition of tetrapropylammonium perruthenate (220 mg, 0.63 mmol,
0.05 equiv), the reaction mixture was stirred for 2 h at room
temperature. The suspension was filtered through a plug of silica (silica
packed with DCM), and the product was eluted with a mixture of
pentane and Et2O (9:1). The solvents were removed under reduced
pressure. Because of the volatility of the product, the pressure was
maintained at 200 mbar, and aldehyde 5 (1.54 g) was isolated in 78%
yield as a colorless oil. [α]2D0 −21.1 (c 1.0, CHCl3). H NMR (400
1
MHz, CDCl3): δ 0.61 (quart, J = 7.9 Hz, 6H), 0.93 (d, J = 6.7 Hz,
3H), 0.96 (t, J = 7.9 Hz, 9H), 1.08 (d, J = 7.1 Hz, 3H), 1.29 (ddd, J =
13.7, 9.7, 3.2 Hz, 1H), 1.58 (ddd, J = 13.7, 8.9, 3.2 Hz, 1H), 1.88−2.01
(m, 1H), 2.44−2.56 (m, 1H), 3.22 (dd, J = 9.3, 7.0 Hz, 1H), 3.27−
3.32 (m, 2H), 3.38 (s, 3H), 3.81 (s, 3H), 3.86−3.92 (m, 1H), 4.42 (s,
2H), 4.61 (d, J = 6.8 Hz, 1H), 4.69 (d, J = 6.8 Hz, 1H), 4.95−5.03 (m,
2H), 5.87 (ddd, J = 17.3, 10.3, 8.2 Hz, 1H), 6.84−6.90 (m, 2H), 7.22−
7.29 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 5.4 (CH2), 7.1 (CH3),
17.2 (CH3), 18.9 (CH3), 29.8 (CH), 36.8 (CH2), 39.0 (CH), 55.4
(CH3), 56.0 (CH3), 72.1 (CH), 72.6 (CH2), 76.4 (CH2), 84.9 (CH),
98.1 (CH2), 113.9 (CH), 114.3 (CH2), 129.2 (CH), 131.1 (C), 141.8
(CH), 159.2 (C). IR (ATR) ν 2953, 2930, 2876, 2362, 2341, 1513,
1461, 1302, 1249, 1147, 1099, 1037, 1004, 912, 837 cm−1. HRMS
(ESI) calcd for C26H46O5SiNa [M + Na]+, 489.3013; found, 489.3008.
(2S,5S,6S)-5-(Methoxymethoxy)-2,6-dimethyl-4-((triethylsilyl)-
oxy)oct-7-en-1-ol (S12). To a solution of alkene S11 (722 mg, 1.55
mmol, 1.0 equiv) in DCM (77 mL) were added phosphate-buffer (pH
7 to 8, 1 M, 8 mL) and DDQ (529 mg, 2.33 mmol, 1.5 equiv) at 0 °C.
The reaction mixture was stirred for 30 min at 0 °C and 1 h 30 min at
room temperature. The reaction was quenched by the addition of a
saturated, aqueous solution of NaHCO3 (30 mL). The layers were
separated, and the aqueous phase was extracted with DCM (3 × 100
mL). The combined organic extracts were dried over Na2SO4 and
filtered, and the solvent was removed under reduced pressure. The
yield as a colorless oil. [α]2D0 −31.6 (c 1.0, CHCl3). H NMR (400
1
MHz, CDCl3): δ 1.13 (d, J = 7.0 Hz, 3H), 2.65−2.75 (m, 1H), 3.41 (s,
3H), 3.81 (dd, J = 5.0, 2.3 Hz, 1H), 4.69 (d, J = 6.5 Hz, 1H), 4.74 (d, J
= 6.5 Hz, 1H), 5.06−5.12 (m, 2H), 5.77−5.89 (m, 1H), 9.61 (d, J =
2.3 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 16.3 (CH3), 39.8 (CH),
56.2 (CH3), 85.7 (CH), 97.2 (CH2), 116.4 (CH2), 138.1 (CH), 203.2
(CH). IR (ATR) ν 2970, 2896, 2827, 1733, 1456, 1378, 1216, 1152,
1103, 1038, 920 cm−1. HRMS (ESI) calcd for C8H14O3Na [M + Na]+,
181.0841; found, 181.0837.
(2S,5S,6S)-1-((4-Methoxybenzyl)oxy)-5-(methoxymethoxy)-2,6-
dimethyloct-7-en-4-ol (24). A solution of bromide 6 (590 mg, 2.16
mmol, 2.0 equiv) in Et2O (17 mL) was cooled to −78 °C, and a
solution of t-BuLi (1.6 M in pentane, 2.84 mL, 4.54 mmol, 4.2 equiv)
was added dropwise over 3 min. The reaction mixture was stirred for
10 min at that temperature before a freshly prepared solution of
magnesium bromide (1.0 M, 2.48 mL, 2.48 mmol, 2.3 equiv) was
added. After 10 min at −78 °C, a solution of aldehyde 5 (171 mg, 1.08
mmol, 1.0 equiv) in Et2O (6.8 mL) was added dropwise over 3 min.
The reaction mixture was allowed to stir at −78 °C for 90 min until
TLC control showed total consumption of aldehyde 5. The reaction
was terminated by the addition of saturated, aqueous NH4Cl solution
(10 mL). The layers were separated, and the aqueous phase was
extracted with EtOAc (3 × 20 mL). The combined organic extracts
H
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crude product was purified by flash column chromatography (hexanes/
EtOAc 9:1) to afford primary alcohol S12 (481 mg) in 90% yield as a
colorless oil. [α]2D0 −27.9 (c 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): δ 0.63 (quart, J = 7.9 Hz, 6H), 0.94 (d, J = 6.7 Hz, 3H), 0.97
(t, J = 7.9 Hz, 9H), 1.10 (d, J = 7.0 Hz, 3H), 1.35 (ddd, J = 13.9, 9.0,
2.7 Hz, 1H), 1.50−1.62 (m, 2H), 1.74−1.85 (m, 1H), 2.46−2.58 (m,
1H), 3.31 (bt, J = 5.1 Hz, 1H), 3.38 (s, 3H), 3.46 (bt, J = 5.9 Hz, 2H),
3.91 (ddd, J = 9.0, 5.1, 2.7 Hz, 1H), 4.62 (d, J = 6.8 Hz, 1H), 4.69 (d, J
= 6.8 Hz, 1H), 4.95−5.06 (m, 2H), 5.88 (ddd, J = 17.3, 10.3, 8.3 Hz,
1H). 13C NMR (100 MHz, CDCl3): δ 5.4 (CH2), 7.1 (CH3), 16.9
(CH3), 19.0 (CH3), 32.6 (CH), 36.3 (CH2), 38.9 (CH), 56.0 (CH3),
69.2 (CH2), 72.5 (CH), 84.9 (CH), 98.1 (CH2), 114.4 (CH2), 141.8
(CH). IR (ATR) ν 3449, 2953, 2876, 2359, 2340, 1790, 1513, 1458,
1415, 1377, 1301, 1245, 1147, 1098, 1034, 913, 725 cm−1. HRMS
(ESI) calcd for C18H38O4SiNa [M + Na]+, 369.2437; found, 369.2430.
(2S,5S,6S)-5-(Methoxymethoxy)-2,6-dimethyl-4-((triethylsilyl)-
oxy)oct-7-enal (4). To a mixture of alcohol S12 (911 mg, 2.6 mmol,
1.0 equiv) and DMSO (2.01 mL, 31.2 mmol, 12.0 equiv) in DCM (13
mL) were added triethylamine (2.16 mL, 15.6 mmol, 6.0 equiv) and
SO3·pyridine (1.24 g, 7.8 mmol, 3.0 equiv) at 0 °C. After the addition,
the cooling bath was removed and the reaction mixture was stirred for
3 h at room temperature. The reaction was terminated by the addition
of water (10 mL). The layers were separated, and the aqueous phase
was extracted with DCM (3 × 15 mL). The combined organic extracts
were dried over Na2SO4 and filtered, and the solvent was removed
under reduced pressure. The crude product was purified by flash
column chromatography (hexanes/EtOAc 19:1), delivering aldehyde 4
(830 mg) in 93% yield as a colorless oil. [α]2D0 −8.3 (c 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3): δ 0.62 (quart, J = 7.9 Hz, 6H), 0.97 (t, J =
7.9 Hz, 9H), 1.09 (d, J = 4.3 Hz, 3H), 1.10 (d, J = 4.3 Hz, 3H), 1.49
(ddd, J = 14.1, 7.9, 3.3 Hz, 1H), 1.98 (ddd, J = 14.1, 8.8, 5.5 Hz, 1H),
2.45−2.60 (m, 2H), 3.32 (bt, J = 4.9 Hz, 1H), 3.37 (s, 3H), 3.92 (ddd,
J = 8.8, 5.2, 3.7 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 4.68 (d, J = 6.8 Hz,
1H), 4.97−5.07 (m, 2H), 5.88 (ddd, J = 17.3, 10.2, 8.3 Hz, 1H), 9.61
(d, J = 1.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 5.3 (CH2), 7.1
(CH3), 13.8 (CH3), 19.1 (CH3), 33.4 (CH2), 38.8 (CH), 43.5 (CH),
56.0 (CH3), 72.0 (CH), 84.6 (CH), 98.1 (CH2), 114.6 (CH2), 141.6
(CH), 205.1 (CH). IR (ATR) ν 2954, 2931, 2359, 2341, 1727, 1460,
1380, 1251, 1218, 1145, 1098, 1056, 1036, 1005, 947, 877, 725 cm−1.
HRMS (ESI) calcd for C18H36O4SiNa [M + Na]+, 367.2281; found,
367.2276.
(3R,4S,5S)-5-((S)-3-((4-Methoxybenzyl)oxy)-2-methylpropyl)-4-
(methoxymethoxy)-3-methyldihydrofuran-2(3H)-one (S13). For
proof of the stereochemistry of alcohol 24. The major diastereomer
of secondary alcohol 24 (80 mg, 0.23 mmol, 1.0 equiv) was dissolved
in a 1:1 solvent mixture of DCM (2.3 mL) and methanol (2.3 mL).
Pyridine (185 μL, 2.3 mmol, 10.0 equiv) and Sudan III (less than 0.1
mg, just enough to get a slightly red-colored reaction mixture) were
added at room temperature. A stream of ozone was bubbled through
the reaction mixture at −78 °C until the solution turned colorless (2
min). Excess ozone was removed by purging the reaction mixture with
argon. After the addition of PPh3 (72 mg, 0.28 mmol, 1.2 equiv), the
colorless solution was allowed to warm to room temperature over a
period of 12 h. The reaction mixture was diluted with DCM (10 mL)
and washed with a saturated, aqueous solution of NH4Cl (10 mL).
The phases were separated, the organic layer was dried over Na2SO4
and filtered, and the solvent was removed under reduced pressure. The
crude material was purified by filtration over a short plug of silica
delivering an inseparable mixture of the corresponding diastereomeric
lactols (44 mg, 54%) as a colorless oil, which was immediately used for
the next reaction.
15), 1.26 (d, J = 7.1 Hz, 3H, CH3-14), 1.47 (ddd, J = 14.1, 8.5, 4.0 Hz,
1H, CH2-5b), 1.94−2.15 (m, 2H, CH2-5a, CH-6), 2.71 (dquart, J =
7.1, 5.3 Hz, 1H, CH-2), 3.32 (dd, J = 9.2, 5.7 Hz, 1H, CH2-7b), 3.36
(dd, J = 9.2, 6.2 Hz, 1H, CH2-7a), 3.39 (s, 3H, OCH3-17), 3.80 (s, 3H,
OCH3-13), 4.22 (dd, J = 5.3, 3.3 Hz, 1H, CH-3), 4.43 (s, 2H, CH2-8a,
b), 4.43−4.48 (m, 1H, CH-4), 4.63 (s, 2H, CH2-16a, b), 6.84−6.89
(m, 2H, CH-11, 11a), 7.21−7.26 (m, 2H, CH-10, 10a). 13C NMR
(100 MHz, CDCl3): δ 9.3 (CH3-14), 17.2 (CH3-15), 30.5 (CH-6),
33.7 (CH2-5) 42.0 (CH-2), 55.7 (OCH3-13), 56.8 (OCH3-17), 72.9
(CH2-8), 75.8 (CH2-7), 78.8 (CH-3), 80.7 (CH-4), 97.7 (CH2-16),
114.1 (CH-11, 11a), 129.5 (CH-10, 10a), 131.1 (C-9), 159.2 (C-12),
178.2 (C-1). IR (ATR) ν 2937, 2853, 2365, 2339, 1773, 1513, 1462,
1376, 1302, 1247, 1211, 1174, 1154, 1125, 1089, 997, 964, 882, 820
cm−1. HRMS (ESI) calcd for C19H28O6Na [M + Na]+, 375.1784;
found, 375.1784.
Bromide (25). Dibromide 16 (80 mg, 0.114 mmol, 2.0 equiv) was
dissolved in dry Et2O (0.57 mL) and cooled to −115 °C (liquid
nitrogen/ethanol cooling bath), and a solution of n-BuLi (2.0 M in
hexanes, 60 μL, 0.114 mmol, 2.0 equiv) was added dropwise over 3
min. The reaction mixture was stirred for 1 h 15 min with the
temperature kept between −112 and −108 °C. Aldehyde 4 (20 mg,
0.057 mmol, 1.0 equiv) in Et2O (0.25 mL) was added over a period of
20 min via syringe pump, and the colorless solution was stirred for 1 h
between −112 and −108 °C and for 90 min between −100 and −105
°C. The reaction was terminated by the addition of saturated, aqueous
NH4Cl solution (1.5 mL) at −100 °C. After warming to room
temperature, the layers were separated, and the organic phase was
extracted with EtOAc (3 × 10 mL). The combined organic extracts
were dried over Na2SO4 and filtered, and the solvent was removed
under reduced pressure. The crude 1:1 mixture of the corresponding
diastereomeric secondary alcohols was purified by flash column
chromatography (hexanes/EtOAc 19:1 to 9:1), and diastereomers 25
(20 mg, less polar) and 25a (21 mg, more polar) were obtained in
74% overall yield as colorless oils. Diastereomer 25: [α]2D0 −21.1 (c 0.9,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 0.06 (s, 3H, CH3-TBS), 0.08
(s, 3H, CH3-TBS), 0.11 (s, 6H, CH3-TBS), 0.58−0.66 (m, 6H, CH2-
TES), 0.90 (s, 9H, CH3-tBu-TBS), 0.91 (s, 9H, CH3-tBu-TBS), 0.97
(t, J = 8.0 Hz, 9H, CH3-TES), 1.02−1.09 (m, 1H, CH2-6b), 1.07 (d, J
= 6.6 Hz, 3H, CH3-17), 1.10 (d, J = 6.6 Hz, 3H, CH3-16), 1.32 (s, 3H,
CH3-21 or 22), 1.46 (s, 3H, CH3-21 or 22), 1.47−1.54 (m, 1H, CH2-
6a), 1.55 (s, 3H, CH3-19), 1.92−2.0 (m, 1H, CH-7), 2.45−2.52 (m,
1H, CH-3), 3.31 (dd, J = 5.3, 5.1 Hz, 1H, CH-4), 3.36 (s, 3H, OCH3-
MEM), 3.38 (s, 3H, OCH3-MOM), 3.48−3.55 (m, 3H, CH2-MEM,
OH-18), 3.62−3.68 (m, 2H, CH2-MEM, CH2-15b), 3.83 (dd, J = 10.5,
1.5 Hz, 1H, CH2-15a), 3.88−3.92 (m, 2H, CH2-MEM, CH-5), 4.09 (d,
J = 7.2 Hz, 1H, CH-12), 4.19−4.22 (m, 1H, CH-14), 4.24 (dd, J = 7.2,
2.6 Hz, 1H, CH-13), 4.41 (dd, J = 9,2, 3.0 Hz, 1H, CH-8), 4.61 (d, J =
6.8 Hz, 1H, CH2-MOM), 4.70 (d, J = 6.8 Hz, 1H, CH2-MOM), 4.73
(d, J = 7.5 Hz, 1H, CH2-MEM), 4.96 (dd, J = 10.3, 2.0 Hz, 1H, CH2-
1b), 4.98−5.02 (m, 1H, CH2-1a), 5.03 (d, J = 7.5 Hz, 1H, CH2-
MEM), 5.82−5.90 (m, 1H, CH-2), 6.14 (s, 1H, CH-10). 13C NMR
(100 MHz, CDCl3): δ −5.2 (CH3-TBS), −5.0 (CH3-TBS), −4.2
(CH3-TBS), −3.6 (CH3-TBS), 5.3 (CH2-TES), 7.2 (CH3-TES), 16.0
(CH3-17), 18.4 (C-tBu-TBS), 18.8 (C-tBu-TBS), 19.2 (CH3-16), 24.9
(CH3-21 or 22), 25.5 (CH3-19), 26.2 (CH3-21 or 22), 26.22 (CH3-
tBu-TBS), 26.4 (CH3-tBu-TBS), 34.0 (CH-7), 35.1 (CH2-6), 39.0
(CH-3), 56.0 (OCH3-MOM), 59.2 (OCH3-MEM), 66.9 (CH2-15),
68.3 (CH2-MEM), 71.6 (CH-5), 71.8 (CH2-MEM), 73.6 (CH-14),
74.4 (CH-8), 79.8 (C-11), 81.7 (CH-13), 82.2 (CH-12), 84.7 (CH-4),
92.2 (CH2-MEM), 98.1 (CH2-MOM), 107.7 (C-20), 114.3 (CH2-1),
135.8 (CH-10), 136.3 (C-9), 141.8 (CH-2). IR (ATR) ν 3462, 2954,
2929, 2856, 1461, 1380, 1252, 1211, 1101, 1067, 1036, 1005, 911, 834,
776 cm−1. HRMS (ESI) calcd for C45H9181BrO11Si3Na [M + Na]+,
995.4930; found, 995.4933. Diastereomer 25a: [α]2D0 −12.7 (c 1.15,
To a solution of the mixture of lactols (30 mg, 0.085 mmol, 1.0
equiv) in DCM (1.3 mL) was added PCC (37 mg, 0.17 mmol, 2.0
equiv) at room temperature, and the reaction mixture was stirred at
that temperature for 12 h. To the resulting suspension was added one
spatula of silica gel, and the solvent was removed under reduced
pressure. The absorbed product was purified by flash column
chromatography (hexanes/EtOAc 3:1), and lactone S13 (27 mg)
was obtained in 90% yield as a light-yellow oil. [α]2D0 −25.6 (c 0.75,
CHCl3). 1H NMR (400 MHz, CDCl3): δ 1.0 (d, J = 6.6 Hz, 3H, CH3-
1
CHCl3). H NMR (400 MHz, CDCl3): δ 0.046 (s, 3H, CH3-TBS),
0.051 (s, 3H, CH3-TBS), 0.10 (s, 3H, CH3-TBS), 0.11 (s, 3H, CH3-
TBS), 0.64 (quart, J = 7.7 Hz, 6H, CH2-TES), 0.87 (d, J = 6.8 Hz, 3H,
CH3-17), 0.89 (s, 9H, CH3-tBu-TBS), 0.90 (s, 9H, CH3-tBu-TBS),
0.98 (t, J = 7.7 Hz, 9H, CH3-TES), 1.11 (d, J = 7.0 Hz, 3H, CH3-16),
1.26−1.30 (m, 1H, CH2-6b), 1.32 (s, 3H, CH3-21 or 22), 1.46 (s, 3H,
I
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CH3-21 or 22), 1.54 (s, 3H, CH3-19), 1.85−1.93 (m 1H, CH2-6a),
2.03−2.10 (m 1H, CH-7), 2.47−2.55 (m, 1H, CH-3), 2.79−2.91 (bs,
1H, OH-18), 3.32 (dd, J = 5.5, 5.3 Hz, 1H, CH-4), 3.37 (s, 3H, OCH3-
MEM), 3.38 (s, 3H, OCH3-MOM), 3.52−3.54 (m, 2H, CH2-MEM),
3.62 (dd, J = 10.9, 7.2 Hz, 1H, CH2-15b), 3.69−3.74 (m, 1H, CH2-
MEM), 3.77−3.82 (m, 2H, CH2-MEM, CH2-15a), 3.88−3.92 (m, 1H,
CH-5), 4.03−4.07 (m, 1H, CH-14), 4.17 (d, J = 7.0 Hz, 1H, CH-12),
4.20 (dd, J = 7.0, 2.0 Hz, 1H, CH-13), 4.41 (dd, J = 9.4, 6.6 Hz, 1H,
CH-8), 4.62 (d, J = 7.0 Hz, 1H, CH2-MOM), 4.71 (d, J = 7.0 Hz, 1H,
CH2-MOM), 4.87 (d, J = 7.2 Hz, 1H, CH2-MEM), 4.94 (d, J = 7.2 Hz,
1H, CH2-MEM), 4.96−5.0 (m, 2H, CH2-1a, b), 5.83−5.91 (m, 1H,
CH-2), 6.18 (s, 1H, CH-10). 13C NMR (100 MHz, CDCl3): δ −5.3
(CH3-TBS), −5.1 (CH3-TBS), −4.3 (CH3-TBS), −3.8 (CH3-TBS),
5.32 (CH2-TES), 7.2 (CH3-TES), 16.7 (CH3-17), 18.4 (C-tBu-TBS),
18.5 (C-tBu-TBS), 18.9 (CH3-16), 23.2 (CH3-19), 25.0 (CH3-21 or
22), 26.2 (CH3-tBu-TBS), 26.25 (CH3-tBu-TBS), 26.3 (CH3-21 or
22), 35.2 (CH-7), 35.4 (CH2-6), 39.0 (CH-3), 56.0 (OCH3-MOM),
59.2 (OCH3-MEM), 66.7 (CH2-15), 68.0 (CH2-MEM), 71.9 (CH2-
MEM), 72.5 (CH-5), 74.3 (CH-14), 74.6 (CH-8), 79.9 (C-11), 81.3
(CH-13), 82.3 (CH-12), 85.1 (CH-4), 91.6 (CH2-MEM), 98.2 (CH2-
MOM), 107.7 (C-20), 114.4 (CH2-1), 135.9 (CH-10), 136.7 (C-9),
141.7 (CH-2). IR (ATR) ν 3462, 2954, 2929, 2856, 1461, 1380, 1252,
1211, 1101, 1067, 1036, 1005, 911, 834, 776 cm−1. HRMS (ESI) calcd
for C45H9181BrO11Si3Na [M + Na]+, 995.4930; found, 995.4936.
Mosher Ester S14. To a solution of secondary alcohol 25a (5 mg,
0.005 mmol, 1.0 equiv) in DCM (0.15 mL) were added NEt3 (9 μL,
0.06 mmol, 12.0 equiv), DMAP (0.6 mg, 0.005 mmol, 1.0 equiv), and
S-(+)-Mosher’s acid chloride (2 μL, 0.01 mmol, 2.0 equiv) sequently
at room temperature. The reaction mixture was stirred for 14 h at
room temperature. As TLC control showed total consumption of the
starting material, the reaction was terminated by the addition of a
saturated, aqueous solution of NH4Cl (1 mL), and the resulting
mixture was diluted with DCM (3 mL). The layers were separated,
and the aqueous phase was extracted with DCM (3 × 5 mL). The
combined organic fractions were dried over Na2SO4 and filtered, and
the solvent was removed under reduced pressure. The crude material
was purified by flash column chromatography (hexanes/EtOAc 19:1 to
9:1) to afford Mosher ester S14 (5 mg) in 85% yield as a colorless oil.
= 12.0, 12.0 Hz, 1H), 1.25 (s, 3H), 1.45 (s, 3H), 1.43−1.49 (m, 1H),
1.62 (s, 3H), 2.20−2.27 (m, 1H), 2.27−2.33 (m, 1H), 3.17 (t, J = 5.6
Hz, 1H), 3.37 (s, 3H), 3.371 (s, 3H), 3.49−3.57 (m, 2H), 3.58 (s,
3H), 3.64 (dd, J = 10.5, 7.5 Hz, 1H), 3.67−3.72 (m, 1H), 3.76 (dd, J =
10.5, 1.5 Hz, 1H), 3.79−3.85 (m, 2H), 4.15−4.19 (m, 1H), 4.23−4.27
(m, 2H), 4.58 (d, J = 7.0 Hz, 1H), 4.63 (d, J = 7.0 Hz, 1H), 4.89 (d, J
= 7.2 Hz, 1H), 4.92−4.94 (m, 1H), 4.95 (bs, 1H), 5.07 (d, J = 7.2 Hz,
1H), 5.80 (ddd, J = 16.7, 10.8, 8.1 Hz, 1H), 5.96 (d, J = 9.8 Hz, 1H),
6.58 (s, 1H), 7.36−7.40 (m, 3H), 7.56−7.60 (m, 2H). 13C NMR (100
MHz, CDCl3): δ −5.1 (CH3), −5.0 (CH3), −4.3 (CH3), −3.6 (CH3),
5.2 (CH2), 7.0 (CH3), 15.6 (CH3), 18.4 (C), 18.5 (CH3), 18.7 (C),
23.8 (CH3), 24.7 (CH3), 26.2 (CH3), 26.3 (CH3), 26.4 (CH3), 32.8
(CH), 34.7 (CH2), 39.1 (CH), 55.8 (CH3), 56.0 (CH3), 59.2 (CH3),
67.0 (CH2), 68.0 (CH2), 71.5 (CH), 71.9 (CH2), 73.6 (CH), 77.9
(CH), 80.2 (C), 82.0 (CH), 82.5 (CH), 85.0 (CH), 91.6 (CH2), 98.1
(CH2), 107.7 (C), 114.3 (CH2), 122.5 (C), 124.4 (C), 125.3 (C),
127.5 (CH), 128.5 (CH), 129.7 (CH), 132.3 (C), 140.4 (CH), 141.7
(CH), 166.4 (C). 19F NMR (565 MHz, CDCl3): δ −70.93 (s). IR
(ATR) ν 2956, 2929, 2855, 2366, 1746, 1707, 1472, 1461, 1415, 1386,
1293, 1252, 1170, 1100, 1065, 1004, 916, 859, 811, 743 cm−1. HRMS
(ESI) calcd for C55H9881BrF3O13Si3Na [M + Na]+, 1211.5328; found,
1211.5338.
Bromide 26. To a solution of secondary alcohol 25 (12 mg, 0.012
mmol, 1.0 equiv) in DCM (0.15 mL) were added NEt3 (22 μL, 0.144
mmol, 12.0 equiv), DMAP (1.5 mg, 0.012 mmol, 1.0 equiv), and
benzoyl chloride (2.8 μL, 0.024 mmol, 2.0 equiv) at 0 °C. After the
addition, the cooling bath was removed, and the reaction mixture was
allowed to stir at room temperature for 5 h. As TLC control showed
remaining starting material, 2 equiv of benzoyl chloride (2.8 μL, 0.024
mmol) were added at room temperature, and the reaction mixture was
stirred for 5 h. The reaction was quenched by the addition of a
saturated, aqueous solution of NH4Cl (1 mL), and the resulting
mixture was diluted with DCM (5 mL). The layers were separated,
and the aqueous phase was extracted with DCM (3 × 10 mL). The
combined organic fractions were dried over Na2SO4 and filtered, and
the solvent was removed under reduced pressure. The crude material
was purified by flash column chromatography (hexanes/EtOAc 9:1) to
afford bromide 26 (9 mg) in 71% yield as a colorless oil. [α]2D0 −15.8
(c 0.46, CHCl3). 1H NMR (400 MHz, CDCl3): δ −0.01 (s, 3H), 0.00
(s, 6H), 0.01 (s, 3H), 0.64 (q, J = 7.9 Hz, 6H), 0.77 (s, 9H), 0.86 (s,
9H), 0.99 (t, J = 7.9 Hz, 9H), 1.01 (d, J = 7.0 Hz, 3H), 1.12 (d, J = 7.0
Hz, 3H), 1.27−1.36 (m, 1H), 1.41 (s, 3H), 1.44 (s, 3H), 1.58 (s, 3H),
1.64−1.75 (m, 1H), 2.26−2.39 (m, 1H), 2.47−2.56 (m, 1H), 3.33 (bt,
J = 5.2 Hz, 1H), 3.37 (s, 3H), 3.38 (s, 3H), 3.52−3.60 (m, 3H), 3.67−
3.71 (m, 1H), 3.73−3.81 (m, 2H), 3.82−3.86 (m, 1H), 3.88−3.95 (m,
1H), 4.00 (dd, J = 6.8, 1.8 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 4.70 (d, J
= 6.8 Hz, 1H), 4.76 (d, J = 6.8 Hz, 1H), 4.93−5.04 (m, 3H), 5.11 (d, J
= 7.3 Hz, 1H), 5.87 (ddd, J = 17.5, 10.2, 8.4 Hz, 1H), 6.18 (d, J = 9.3
Hz, 1H), 6.35 (s, 1H). 7.41−7.48 (m, 2H), 7.53−7.60 (m, 1H), 8.04−
8.11 (m, 2H). 13C NMR (100 MHz, CDCl3): δ −5.4 (CH3), −5.2
(CH3), −4.5 (CH3), −3.9 (CH3), 5.4 (CH2), 7.2 (CH3), 15.6 (CH3),
18.4 (C), 18.5 (C), 19.1 (CH3), 22.4 (CH3), 25.1 (CH3), 26.2 (CH3),
33.6 (CH), 34.6 (CH2), 39.1 (CH), 56.0 (CH3), 59.1 (CH3), 67.1
(CH2), 67.7 (CH2), 71.6 (CH), 72.0 (CH2), 74.9 (CH), 76.9 (CH),
79.6 (C), 81.6 (CH), 82.4 (CH), 84.7 (CH), 91.7 (CH2), 98.2 (CH2),
107.9 (C), 114.4 (CH2), 128.5 (CH), 129.2 (C), 130.1 (CH), 130.2
(C), 133.2 (CH), 139.5 (CH), 141.7 (CH), 165.5 (C). IR (ATR) ν
2957, 2927, 2877, 2854, 1718, 1471, 1452, 1381, 1300, 1250, 1213,
1176, 1111, 1067, 1006, 989, 968, 889, 834, 777, 711 cm−1. HRMS
(ESI) calcd for C52H9581BrO12Si3Na [M + Na]+, 1099.5192; found,
1099.5210.
[α]2D0 +2.0 (c 0.2, CHCl3). H NMR (400 MHz, CDCl3): δ 0.05 (s,
1
3H), 0.06 (s, 3H), 0.07 (s, 3H), 0.075 (s, 3H), 0.60 (quart, J = 7.9 Hz,
6H), 0.90 (s, 18H), 0.95 (t, J = 7.9 Hz, 9H), 1.0 (d, J = 7.0 Hz, 3H),
1.07 (d, J = 7.0 Hz, 3H), 1.22−1.29 (m, 1H), 1.31 (s, 3H), 1.46 (s,
3H), 1.70 (s, 3H), 1.66−1.74 (m, 1H), 2.21−2.30 (m, 1H), 2.41−2.49
(m, 1H), 3.27 (t, J = 5.2 Hz, 1H), 3.37 (s, 3H), 3.38 (s, 3H), 3.49−
3.58 (m, 5H), 3.64 (dd, J = 10.5, 7.3 Hz, 1H), 3.70−3.75 (m, 1H),
3.77 (dd, J = 10.5, 1.9 Hz, 1H), 3.80−3.85 (m, 1H), 3.87−3.91 (m,
1H), 4.16−4.19 (m, 1H), 4.26 (dd, J = 7.3, 1.8 Hz, 1H), 4.30 (d, J =
7.3 Hz, 1H), 4.62 (d, J = 7.0 Hz, 1H), 4.68 (d, J = 7.0 Hz, 1H), 4.88−
4.96 (m, 3H), 5.06 (d, J = 7.3 Hz, 1H), 5.83 (ddd, J = 17.3, 10.3, 8.3
Hz, 1H), 5.90 (d, J = 9.8 Hz, 1H), 6.54 (s, 1H), 7.36−7.42 (m, 3H),
7.51−7.55 (m, 2H). 13C NMR (100 MHz, CDCl3): δ −5.1 (CH3),
−5.0 (CH3), −4.2 (CH3), −3.6 (CH3), 5.2 (CH2), 7.1 (CH3), 15.7
(CH3), 18.4 (C), 18.6 (C), 19.2 (CH3), 23.8 (CH3), 24.8 (CH3), 26.2
(CH3), 26.3 (CH3), 26.4 (CH3), 32.8 (CH), 35.0 (CH2), 38.8 (CH),
55.9 (CH3), 56.0 (CH3), 59.2 (CH3), 66.9 (CH2), 68.1 (CH2), 71.7
(CH), 72.0 (CH2), 73.6 (CH), 78.1 (CH), 80.1 (C), 82.0 (CH), 82.5
(CH), 85.2 (CH), 91.6 (CH2), 98.2 (CH2), 107.7 (C), 114.5 (CH2),
122.5 (C), 124.4 (C), 125.3 (C), 127.8 (CH), 128.5 (CH), 129.7
(CH), 131.8 (C), 140.1 (CH), 141.5 (CH), 166.3 (C). 19F NMR (565
MHz, CDCl3): δ −72.13 (s). IR (ATR) ν 2956, 2929, 2855, 2366,
1746, 1707, 1472, 1461, 1415, 1386, 1293, 1252, 1170, 1100, 1065,
1004, 916, 859, 811, 743 cm−1. HRMS (ESI) calcd for
C55H9881BrF3O13Si3Na [M + Na]+, 1211.5328; found, 1211.5350.
Mosher Ester S15. Mosher ester S15 was prepared following the
same procedure as described above. Using enantiomeric R-
(−)-Mosher’s acid chloride, S15 (5 mg) was afforded in 85% yield
ASSOCIATED CONTENT
■
S
* Supporting Information
as a colorless oil. [α]2D0 −31.0 (c 0.3, CHCl3). H NMR (400 MHz,
1
NMR spectra of all compounds, NOE analysis of S3 and S13,
and Mosher ester analysis of S14 and S15. This material is
available free of charge via the Internet at http://pubs.acs.org.
CDCl3): δ 0.06 (s, 3H), 0.065 (s, 3H), 0.07 (s, 3H), 0.072 (s, 3H),
0.56 (quart, J = 8.0 Hz, 6H), 0.90 (s, 9H), 0.91 (s, 9H), 0.93 (t, J = 8.0
Hz, 9H), 0.99 (d, J = 4.5 Hz, 3H), 1.0 (d, J = 4.5 Hz, 3H), 1.18 (dd, J
J
dx.doi.org/10.1021/jo401480t | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(31) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769.
(32) Yin, N.; Wang, G.; Qian, M. X.; Negishi, E. Angew. Chem., Int.
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84, 1745.
AUTHOR INFORMATION
Corresponding Author
*E-mail: uwe.rinner@univie.ac.at.
Notes
■
(34) Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428.
(35) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339.
(36) The ee of the product was determined by Mosher ester analysis.
(37) McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
R.F. is the recipient of a DOC-fFORTE-fellowship of the
Austrian Academy of Sciences at the Department of Organic
Chemistry, University of Vienna. The authors thank the NMR
department at the Unversity of Vienna for assistance. The
Fonds zur Forderung der wissenschaftlichen Forschung
̈
(Austrian Science Fund, FWF) is gratefully acknowledged for
financial support of this work (project no. FWF-P20697-N19).
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K
dx.doi.org/10.1021/jo401480t | J. Org. Chem. XXXX, XXX, XXX−XXX