The complete carbon framework of the macrocyclic marine natural product amphidinolide F has been prepared by a convergent synthetic route in which three fragments of similar size and complexity have been coupled. Key features of the syntheses of the fragments include the stereoselective construction of the tetrahydrofuran in the C1-C9 fragment by oxonium ylide (free or metal-bound) formation and rearrangement triggered by the direct generation of a rhodium carbenoid from 1-sulfonyl-1,2,3-triazole, the highly diastereoselective aldol reaction between a boron enolate and an aldehyde with 1,4-control to prepare the C10-C17 fragment, and the formation of the tetrahydrofuran in the C18-C29 fragment by intramolecular nucleophilic ring opening of an epoxide with a hydroxyl group under acidic conditions.
The complete carbon framework of the macrocyclic marine natural product amphidinolide F has been prepared by a convergent synthetic route in which three fragments of similar size and complexity have been coupled. Key features of the syntheses of the fragments include the stereoselective construction of the tetrahydrofuran in the C1-C9 fragment by oxonium ylide (free or metal-bound) formation and rearrangement triggered by the direct generation of a rhodium carbenoid from 1-sulfonyl-1,2,3-triazole, the highly diastereoselective aldol reaction between a boron enolate and an aldehyde with 1,4-control to prepare the C10-C17 fragment, and the formation of the tetrahydrofuran in the C18-C29 fragment by intramolecular nucleophilic ring opening of an epoxide with a hydroxyl group under acidic conditions.
The cytotoxic marine
natural product amphidinolide F was isolated
from a dinoflagellate associated with the Okinawan flatworm Amphiscolops magniviridis and its structure reported
by Kobayashi and co-workers in 1991 (Figure ).[1] Amphidinolide
F contains a macrolactone that is identical to the core of amphidinolide
C,[2] a natural product isolated by the Kobayashi
group and reported in 1988, but it bears a truncated side chain (C25–C29).
The natural products amphidinolide C2 and C3 share the same macrolactone
core structure but, in common with amphidinolide C, have longer and
more elaborate side chains than amphidinolide F (Figure ).
Figure 1
Amphidinolides F, C,
C2, and C3.
Amphidinolides F, C,
C2, and C3.Amphidinolides F, C, C2, and C3
are cytotoxic agents, but amphidinolide
C displays significantly higher activity against certain cancer cell
lines (e.g., L1210 murine lymphoma and KB epidermoid carcinoma cells)
than any of the other three.[3] This observation
suggests that the hydroxyl group in the side chain of amphidinolide
C confers enhanced cytotoxic activity by either hydrogen bonding or
covalent binding to its biological target at this site.The
size, stereochemical complexity, and biological activities
of amphidinolides F, C, C2, and C3, have made them attractive targets
for total synthesis and stimulated the development of new strategies
and synthetic methods that permit rapid access to key subunits found
in these natural products. Over the past two decades, substantial
portions of all four compounds have been synthesized by the groups
of Kobayashi (C1–C10; C17–C29),[4] Armstrong (C18–C29),[5] Carter (C7–C20),[6] Dai (C18–C26),[7] Ferrié (C1–C9),[8] Forsyth
(C1–C9; C11–C25; C1–C14; C15–C25),[9] Mohapatra (C1–C9; C19–C34),[10] Morken (C1–C15),[11] Pagenkopf (C1–C9; C18–C34),[12] Roush (C1–C9; C11–C29),[13] Spilling (C1–C9; C18–C29; C18–C34),[14] and Williams (C10–C25).[15] These meticulous and extensive synthetic studies have culminated
in the recent total syntheses of amphidinolides F and C by the groups
of Fürstner and Carter[16,17] and the total syntheses
of amphidinolides F and C2 by the group of Ferrié.[18]In previous publications, we have reported
the synthesis of the
C1–C17 fragment of amphidinolides F, C, C2, and C3 and the
C18–C34 fragment of amphidinolides of C, C2, and C3.[19] Our expectation was that the entire carbon skeleton
of each natural product would be obtained by the union of two fragments
of similar size and complexity through construction of the bond between
C17 and C18 (Figure ). Although our original strategy was both convergent and logical,
we were concerned about the number of steps required to prepare each
fragment and the somewhat limited options that would be available
for fragment coupling to complete the entire carbon framework. We
now report the design and implementation of a convergent second-generation
synthetic route to the entire carbon framework of amphidinolide F.
The new synthetic route is based on the concise and efficient synthesis
of three fragments of similar size and complexity and was designed
to provide greater flexibility in the final coupling sequence.The retrosynthetic analysis of amphidinolide F on which our second-generation
synthesis is based is shown in Figure . Two primary disconnections by scission of the bond
between C9 and C10 (green) or the lactone C–O bond (purple)
lead to intermediates (i and ii, respectively)
in which the macrocycle has been opened. Further disconnection of i through the ester C–O bond and the C17–C18
bond generates the three key fragments iii, iv, and v. Disconnection of the bond between C9 and C10
and the bond between C17 and C18 in carboxylic acid ii leads to the same fragments (iii–v). This analysis provides flexibility in fragment coupling in the
forward direction, with the formation of the macrocycle being accomplished
by either a standard macrolactonization reaction or an intramolecular
palladium-catalyzed Stille coupling reaction (Figure ).
Figure 2
Disconnection of amphidinolide F into the C1–C9,
C10–C17,
and C18–C29 fragments (iii–v).
Disconnection of amphidinolide F into the C1–C9,
C10–C17,
and C18–C29 fragments (iii–v).
Results and Discussion
Synthetic
studies commenced with the construction of the C1–C9
fragment of amphidinolide F. In our previous work, the tandem sequence
of copper-catalyzed carbenoid generation, oxonium ylide formation,
and rearrangement was used to synthesize an intermediate common to
both tetrahydrofuran-containing segments (C1–C7 and C18–C24).[19,20] However, subsequent elaboration of the C1–C7 unit to give
the C1–C9 fragment with the required level of stereocontrol
at C7 and C8 proved to be rather inefficient.[19a] Thus, for the second-generation approach, a highly functionalized
chiral pool starting material was selected and the pivotal catalytic
carbenoid generation, oxonium ylide formation, and rearrangement reaction
was modified so that the substituents at C7 and C8 were present prior
to construction of the tetrahydrofuran in the C1–C9 fragment.Synthesis of the C1–C9 fragment of amphidinolide F corresponding
to iii in the retrosynthetic analysis (Figure ) began with the high-yielding
conversion of commercially available tri-O-acetyl-d-glucal (1) into allyl ether 2 by
sequential ester cleavage, di-t-butylsilylene protection
of the 1,3-diol, and allylation of the remaining hydroxyl group by
deprotonation and O-alkylation with allyl bromide
(Scheme ). Acid-mediated
hydration of enol ether 2 delivered lactol 3, and the Ramirez olefination procedure was employed to convert this
masked aldehyde into 1,1-dibromoalkene 4.[21] Fluoride ion-mediated cleavage of the di-t-butylsilylene protecting group followed by tert-butyldimethylsilyl (TBS) protection of all three hydroxyl groups
of the resulting polar triol intermediate provided the fully protected
dibromoalkene 5. It was essential to buffer the desilylation
reaction with acetic acid to avoid decomposition of the dibromoalkene.
Treatment of dibromide 5 with n-butyllithium
resulted in sequential metal–halogen exchange, α-elimination,
and rearrangement to produce a lithiated terminal acetylene[22] that was reacted immediately with tosyl azide
to provide the isomerization-prone 1-sulfonyl-1,2,3-triazole 6,[23] the precursor required for
the key carbenoid reaction, which required rapid purification and
careful storage.
Scheme 1
Preparation of the Key Carbenoid Precursor Required
for the Synthesis
of the C1–C9 Fragment
Triazole 6 was converted into dihydrofuranone 8 by reaction with rhodium(II) acetate (1 mol %) in toluene
at reflux and treatment of the intermediate product with basic alumina
(Brockmann Grade III) according to the procedure devised by Boyer
(Scheme ).[24] The reaction is presumed to have occurred by
rhodium carbenoid generation from the diazo imine formed by Dimroth
equilibration of triazole 6,[25] followed by oxonium ylide (free or metal-bound) formation and apparent
[2,3]-sigmatropic rearrangement. In situ hydrolysis
of the intermediate imine 7 by exposure to basic alumina
afforded ketone 8 in a highly diastereoselective manner
(d.r. > 20:1). Ketone 8 was then converted into diene 9 by a Peterson olefination procedure in which the ketone
was reacted with the organocerium reagent generated from (trimethylsilyl)methylmagnesium
bromide, and the resulting hydroxysilane was treated with sodium bis(trimethylsilyl)amide
to effect elimination.[26] It was necessary
to use an organocerium reagent with reduced basicity to avoid epimerization
at the site adjacent to the carbonyl group (C3). Selective dihydroxylation
of the terminal alkene under standard Upjohn conditions produced 1,2-diol 10 as an inconsequential diastereomeric mixture. Subsequent
periodate cleavage of the diol and reduction of the resulting aldehyde
provided alcohol 11.
Scheme 2
Synthesis of the C1–C9 Fragment
by Rearrangement of a Free
or Rhodium-Bound Oxonium Ylide
Conversion of alcohol 11 into the fully elaborated
C1–C9 fragment was accomplished by the reaction sequence shown
in Scheme . Attempted
stereocontrolled conversion of the exocyclic alkene of alcohol 11 into the C4 methyl substituent by hydrogenation in the
presence of Crabtree’s catalyst was unsuccessful.[27] In contrast, rapid and highly diastereoselective
directed hydrogenation of the alkene was accomplished when an NHC–iridium(I)
complex developed by Kerr and co-workers was employed as the catalyst.[28] Immediate acylation of the hydroxyl group with
pivaloyl chloride afforded ester 12; hydrogenation and
esterification reactions could be performed in a one-pot fashion.
Subsequent selective cleavage of a single TBS ether to give primary
alcohol 13 was accomplished in good yield by treatment
of ester 12 with the hydrogen fluoride pyridine complex
at 0 °C. Oxidation of the alcohol to give the corresponding aldehyde 14 was performed by the use of the Dess–Martin protocol,
and alkyne 15 was obtained by the use of the Ohira–Bestmann
modification[29] of the Seyferth–Gilbert
homologation reaction.[30] The final step
required to complete the C1–C9 fragment was the conversion
of alkyne 15 into vinylic stannane 16. The
alkyne hydrostannation protocol developed by Kazmaier and co-workers
proved to be uniquely effective for this transformation.[31] Thus, the treatment of alkyne 15 with tri-n-butyltin hydride and a substoichiometric
amount (10 mol %) of Mo(CO)3(t-BuNC)3, along with butylated hydroxytoluene (BHT) as a radical inhibitor,
at 55 °C in tetrahydrofuran (THF) afforded the required vinylic
stannane 16 in a 69% yield as well as a small quantity
(16% yield) of the regioisomeric E-alkenyl stannane.
The isomeric stannanes were readily separable by chromatography on
silica gel.
Scheme 3
Elaboration of the C1–C9 Fragment to Enable
Palladium-Mediated
sp2–sp2 Coupling to the C10–C17
Fragment
The synthesis of the C10–C17
fragment corresponding to iv in the retrosynthetic analysis
(Figure ) commenced
with a diastereoselective aldol
reaction between a boron enolate derived from the known methyl ketone 17(32) and aldehyde 18, an intermediate that we had used in previous studies concerning
the synthesis of the amphidinolides (Scheme ).[19a] Thus, the
treatment of ketone 17 with dicyclohexylboron chloride
and triethylamine produced a boron enolate and subsequent aldol reaction
with aldehyde 18 produced β-hydroxyketone 19 in an 81% yield and with >20:1 diastereoselectivity.
This
result is consistent with the findings of Paterson and co-workers
who have reported highly syn-selective 1,4-stereoinduction
during aldol reactions of enolates generated from the benzyl ether
analogue of ketone 17 with aldehydes[33] and have used a closely related aldol reaction in their
synthesis of the marine natural product phorbaside A.[34] The stereochemical outcome of the reaction and the high
level of diastereocontrol can be explained by invoking the model proposed
by Paton and Goodman to account for the stereochemical outcome of
aldol reactions between aldehydes and boron enolates derived from
analogous ketones.[35]
Scheme 4
Synthesis of the
C10–C17 Fragment by Highly Diastereoselective
Aldol Coupling
β-Hydroxyketone 19 was then subjected to a highly
diastereoselective Evans–Tishchenko reduction reaction with
pivaldehyde to produce alcohol 20.[36] TBS protection of the free hydroxyl group and hydrogenolytic
cleavage of the PMB ether afforded alcohol 21. Oxidation
of the alcohol to give aldehyde 22 was followed by Seyferth–Gilbert
homologation according to the Ohira–Bestmann protocol.[29] The resulting alkyne 23 was converted
into alkenylsilane 24 by silylcupration and reaction
of the resulting organocopper intermediate with methyl iodide.[37] Treatment of silane 24 with N-iodosuccinimide resulted in the stereoretentive replacement
of the silyl group with iodine. Selective fluoride-mediated removal
of the TBS group to give a free primary hydroxyl group delivered iodide 25 required for the subsequent Stille coupling to the C1–C9
fragment 16.Two fragments corresponding to the
C18–C29 unit of amphidinolide
F were prepared so that two distinct coupling strategies for construction
of the C17–C18 bond could be explored. In previous studies,
the tetrahydrofuran had been constructed by the intramolecular reaction
of a metal carbenoid with an allyl ether, but for the purposes of
the second-generation approach, alternative ring construction methods
were explored.The syntheses of both C18–C29 variants
commenced with the
known epoxide 26, which can be prepared from d-aspartic acid in three steps.[38] Epoxide 26 was subjected to nucleophilic ring opening by reaction
with propargylmagnesium bromide in the presence of a substoichiometric
amount (1 mol %) of mercury(II) chloride to give alcohol 27,[39] which was TBS-protected to give alkyne 28 (Scheme ). Deprotonation of alkyne 28 with n-butyllithium and reaction of the resulting anion with formaldehyde
afforded propargylic alcohol 29. Lindlar reduction of
the alkyne delivered the Z-allylic alcohol 30, and subsequent Sharpless asymmetric epoxidation, with
(−)-diethyl d-tartrate as the ligand,[40] produced epoxide 31 (d.r. 9:1). Swern oxidation
of the alcohol produced aldehyde 32, and the Ohira–Bestmann
protocol was employed immediately to convert this compound into alkyne 33,[29] the cyclization precursor.
Scheme 5
Construction of the Tetrahydrofuran Precursor
Construction of the tetrahydrofuran-containing C18–C29
fragment
from epoxide 33 was now investigated (Scheme ). Fluoride ion-mediated removal
of both TBS groups and treatment of the resulting epoxy diol with
camphorsulfonic acid in dichloromethane at −40 °C resulted
in regioselective intramolecular nucleophilic opening of the epoxide
by the secondary alcohol to give the known tetrahydrofuran 34,[7] the structure of which was confirmed
by comparison of NMR data with that in the literature and by its conversion
into the primary t-butyldiphenylsilyl ether that
had been prepared in our previous studies on the synthesis of amphidinolides
C, C2, and C3.[19b] Immediate acylation of
the primary hydroxyl group with pivaloyl chloride then provided the
propargylic alcohol 35 in a 75% yield over three steps.
A copper-free Sonogashira coupling reaction[41] was then used to couple the alkyne to 1-bromo-2-methyl-1-propene,
and the subsequent TBS protection of the hydroxyl group delivered
enyne 36. Reductive cleavage of the pivaloyl ester, by
treatment with lithium aluminum hydride, provided primary alcohol 37, and this compound was converted into aldehyde 38 by oxidation with the Dess–Martin periodinane. The aldehyde
was then treated with 1,3-propanedithiol under Lewis acidic conditions
to give dithiane 39. Sequential cleavage of the TBS ether,
stereoselective partial alkyne reduction by treatment with Red-Al
to deliver the E-allylic alcohol in a highly stereoselective
manner, and reprotection of the free hydroxyl group as a triethylsilyl
(TES) ether afforded diene 40, corresponding to C18–C29
of the natural product, in a 47% yield over four steps. This fragment
was now ready for coupling to the C1–C17 unit.
Scheme 6
Synthesis
of the C18–C29 Dithiane Fragment
The second C18–C29 fragment was prepared from alkyne 34 by a significantly shorter route than that shown in Scheme . Sonogashira coupling
of the terminal alkyne to 1-bromo-2-methyl-1-propene afforded enyne 41 (Scheme ). The propargylic alcohol was then subjected to reduction with Red-Al
to deliver E-allylic alcohol 42, and
both hydroxyl groups were TES-protected to give diene 43 with an overall yield of 62% over three steps. This diene had been
prepared by Kobayashi and co-workers during the synthetic work performed
to establish the configuration of stereogenic centers in amphidinolide
C, and the data for our sample match those reported in the literature.[4] Selective cleavage of the primary TES ether to
produce alcohol 44 and subsequent oxidation with the
Dess–Martin periodinane afforded aldehyde 45.
It should be noted that this aldehyde is the direct TES ether analogue
of intermediates prepared by the groups of Armstrong and Ferrié
during their studies on the synthesis of amphidinolide F.[5,18] Direct formation of dithiane 40 by the Lewis acid mediated
reaction of aldehyde 45 with 1,3-propanedithiol was attempted
to shorten the sequence in Scheme , but decomposition of aldehyde 45 was
observed.
Scheme 7
Synthesis of the C18–C29 Aldehyde Fragment
The full carbon framework of amphidinolide F
was now assembled
by coupling of the C1–C9, C10–C17, and C18–C29
fragments (Scheme ). Alkenyl iodide 25 was first coupled to the vinylic
stannane 16 under modified Stille conditions to give
the C1–C17 fragment in an 82% yield.[42] The hydroxyl group at C17 was replaced with iodine under standard
iodination conditions to give the iodide 46 in 93% yield.
Deprotonation of dithiane 40 with t-butyllithium in THF-hexamethylphosphoramide (HMPA) and reaction
of the resulting anion with iodide 46 afforded the fully
coupled product 47, a compound that corresponds to the
entire C1–C29 framework of amphidinolide F. However, the coupled
product was obtained in only 13% yield and significant amounts of
both dithiane 40 (42%) and iodide 46 (51%)
were recovered from the reaction. Attempts to improve the yield of
this coupling reaction were not successful, and the product yield
was deemed to be unacceptably low.
Scheme 8
Fragment Coupling to Construct the
Complete C1–C29 Framework
of Amphidinolide F
To address the issue
of incomplete reaction and the resulting low
yield obtained when coupling iodide 46 to dithiane 40, reversal of the polarity of the fragments during the C–C
bond-forming reaction was investigated. In this case, aldehyde 45 was reacted with an organolithium reagent generated from
iodide 46. Thus, treatment of iodide 46 with t-butyllithium to effect the metal–halogen exchange
and addition of the resulting organolithium intermediate to aldehyde 45 was expected to deliver a diastereomeric mixture of alcohols 48. Unfortunately, treatment of iodide 46 with t-butyllithium followed by immediate addition of aldehyde 45 resulted in decomposition of the iodide instead of formation
of the required alcohol 48. Addition of t-butyllithium to a mixture of iodide 46 and aldehyde 45 in diethyl ether at −78 °C also failed to deliver
the required alcohol 48.In summary, the entire
carbon framework of amphidinolide F has
been assembled by the union of three fragments: stannane 16 (C1–C9), iodide 25 (C10–C17), and dithiane 40 (C18–29). The synthesis of each fragment has been
accomplished in a highly stereocontrolled manner. In the case of the
C1–C9 fragment, oxonium ylide (free or metal-bound) formation
and rearrangement initiated by the generation of a rhodium carbenoid
from a 1-sulfonyl-1,2,3-triazole has been used to assemble the tetrahydrofuran
with a high level of diastereocontrol at the C3 stereogenic center.
The C10–C17 fragment has been assembled by a stereoselective
aldol reaction of a boron enolate with 1,4-diastereocontrol followed
by an Evans–Tishchenko reduction reaction of the resulting
β-hydroxyketone. Efficient construction of the tetrahydrofuran
in the C18–C29 fragment has been accomplished by acid-promoted
intramolecular 5-exo nucleophilic ring opening of
an epoxide with a hydroxyl group. Further synthetic studies are required
to optimize fragment coupling and complete the synthesis of amphidinolide
F. The results of this work will be reported in due course.
Experimental Section
Reagents
were purchased from commercial suppliers and used without
purification unless otherwise stated. Air- and moisture-sensitive
reactions were performed under an atmosphere of argon in a flame-dried
apparatus. Tetrahydrofuran, toluene, acetonitrile, dichloromethane,
and diethyl ether were purified using a Pure-SolvTM 500 Solvent Purification
System. Petroleum ether used for chromatography was the 40–60
°C fraction. All reactions were monitored by thin-layer chromatography
(TLC) using Merck silica gel 60 covered aluminum backed plates F254.
TLC plates were visualized under UV light and stained using potassium
permanganate solution, acidic ethanolic anisaldehyde solution, or
phosphomolybdic acid solution. Flash column chromatography was performed
with silica gel (Fluorochem LC60A 35–70 μm or Geduran
Si 60 35–70 μm) as solid support. IR spectra were recorded
using a Shimadzu FT IR-8400S ATR instrument. The IR spectrum of each
compound (solid or liquid) was acquired directly on a thin layer at
ambient temperature. 1H NMR spectra were recorded on Bruker
Avance III 400 and 500 MHz spectrometers at ambient temperature. 13C NMR spectra were recorded on Bruker Avance III 400 and
500 MHz spectrometers at 101 and 126 MHz at ambient temperature, respectively.
Optical rotations were recorded using an Autopol V polarimeter. High-
and low-resolution mass spectra (HRMS) were performed by the use of
positive chemical ionization or electron impact ionization on a Jeol
MStation JMS-700 instrument or by the use of positive or negative
ion electrospray techniques on a Bruker micrOTOF-Q instrument. Elemental
analyses were carried out on an Exeter Analytical Elemental Analyser
EA 440. Melting points were recorded with an Electrothermal IA 9100
apparatus.
To a solution
of tri-O-acetyl-d-glucal (10.0 g, 36.7 mmol)
in MeOH (80 mL) at room temperature (rt) was added potassium carbonate
(51 mg, 0.37 mmol). The reaction mixture was stirred at rt for 16
h and then concentrated under reduced pressure to give the crude d-glucal, which was used in the next step without purification.
To a solution of d-glucal in N,N-dimethylformamide (DMF, 88 mL) at −40 °C was added di-tert-butylsilyl bis(trifluoromethanesulfonate) (13.1 mL,
40.2 mmol) by a syringe pump for 1 h. After complete addition of the
silylating agent, the reaction mixture was stirred at −40 °C
for 2 h. The reaction was quenched by the addition of pyridine (8
mL), and the mixture was diluted with diethyl ether (100 mL) and water
(100 mL). The phases were separated, and the aqueous phase was extracted
with diethyl ether (2 × 100 mL). The combined organic extracts
were washed with saturated aqueous sodium bicarbonate (100 mL) and
brine (100 mL), dried (anhydrous MgSO4), filtered, and
concentrated under reduced pressure to deliver the crude allylic alcohol,
which was used in the next step without further purification. To a
solution of alcohol in DMF (100 mL) at 0 °C was added sodium
hydride (2.20 g of a 60% dispersion in mineral oil, 55.0 mmol) portionwise,
and the resulting mixture was stirred at 0 °C for 10 min during
which time hydrogen evolution ceased. Allyl bromide (16.0 mL, 185
mmol) was added followed by the addition of tetra-n-butylammonium iodide (1.36 g, 3.68 mmol). The mixture was then allowed
to warm to rt and stirred at this temperature for 18 h. The reaction
was quenched by the addition of saturated aqueous ammonium chloride
(100 mL) and extracted with diethyl ether (3 × 200 mL). The combined
organic extracts were washed with saturated aqueous lithium chloride
(100 mL), dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure. The residue was purified by flash chromatography
on silica gel (pet. ether-diethyl ether, 100:1) to afford allyl ether 2 (10.7 g, 89% over three steps) as a colorless oil. R = 0.24 (pet. ether-diethyl ether, 50:1); [α]D31 −28 (c = 2.0, CHCl3); νmax. 2963,
2934, 2889, 2860, 1647, 869, 826, 768, 653 cm–1; 1H NMR (500 MHz, CDCl3) δ 6.27 (1H, ddd, J = 6.1, 1.8, 0.4 Hz), 5.94 (1H, ddt, J = 17.2, 10.4, 5.5 Hz), 5.31 (1H, dq, J = 17.2,
1.5 Hz), 5.17 (1H, dq, J = 10.4, 1.5 Hz), 4.71 (1H,
dd, J = 6.1, 1.8 Hz), 4.36 (1H, ddt, J = 13.1, 5.5, 1.5 Hz), 4.23 (1H, ddt, J = 13.1,
5.5, 1.5 Hz), 4.15 (1H, dd, J = 10.4, 5.0 Hz), 4.12
(1H, dd, J = 10.4, 7.0 Hz), 4.08 (1H, dt, J = 7.0, 1.8 Hz), 3.96 (1H, t, J = 10.4
Hz), 3.81 (1H, td, J = 10.4, 5.0 Hz), 1.07 (9H, s),
1.00 (9H, s); 13C{1H} NMR (126 MHz, CDCl3) δ 144.2, 135.6, 116.8, 102.8, 77.0, 76.7, 72.9, 71.5,
66.2, 27.7, 27.2, 22.9, 20.1; LRMS (CI, isobutane) m/z (intensity) 326.9 [M + H]+ (86), 268.9
(100); HRMS (ESI+) m/z: [M + Na]+ calcd for C17H30NaO4Si 349.1806;
found 349.1801. Anal. calcd for C17H30O4Si: C, 62.54%; H, 9.26%, found: C, 62.51%; H, 9.39%.
Cerium(III) chloride heptahydrate (6.74
g, 18.1 mmol) was added to a 100 mL round-bottomed flask and dried
under vacuum at 120 °C (temperature increased gradually from
rt in an oil bath) for 2 h, then at 140 °C for 2 h, and at 160
°C for a further 2 h. The flask was allowed to cool to rt and
was purged with argon (10 min). THF (23 mL) was added, and the mixture
was stirred at rt for 2 h under argon to give the cerium(III) chloride–THF
complex as a white precipitate. A solution of (chloromethyl)trimethylsilane
(2.53 mL, 18.1 mmol) in THF (10 mL) was added dropwise to a suspension
of magnesium turnings (401 mg, 16.5 mmol) and 1,2-dibromoethane (2
drops) in THF (4 mL). Formation of the Grignard reagent was accomplished
by heating (oil bath) the mixture to reflux, followed by the slow
addition of (chloromethyl)trimethylsilane to maintain reflux. The
Grignard reagent was stirred at rt for 2 h and then added to the cerium(III)
chloride–THF complex at −78 °C. The resulting gray
mixture was stirred at −78 °C for 30 min, and then a solution
of ketone 8 (2.30 g, 4.13 mmol) in THF (4 mL) was added.
The reaction mixture was stirred at −78 °C for 1 h, and
the flask was then removed from the cold bath. The mixture was stirred
at rt for a further period of 18 h and then cooled to 0 °C. Saturated
aqueous ammonium chloride (10 mL) was added at 0 °C, and the
mixture was stirred for 20 min. Water (40 mL) was added, and the mixture
was extracted with diethyl ether (3 × 50 mL). The combined organic
extracts were washed with brine (30 mL), dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure to give
the crude tertiary alcohol as a pale yellow oil. The crude alcohol
was dissolved in THF (45 mL) at rt, and sodium bis(trimethylsilyl)amide
(8.25 mL of a 2.0 M solution in THF, 16.5 mmol) was added for 30 s.
The solution was stirred at rt for 5 min and then heated (oil bath)
to reflux for 1.5 h. The mixture was then cooled to rt and quenched
by the addition of saturated aqueous ammonium chloride (50 mL). The
biphasic mixture was diluted with diethyl ether (50 mL) and water
(20 mL), the layers were separated, and the aqueous layer was extracted
with diethyl ether (2 × 50 mL). The combined organic extracts
were dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure. The residue was purified by flash chromatography
on silica gel (pet. ether-ethyl acetate, 200:1) to afford diene 9 (1.83 g, 80% over two steps) as a colorless oil. R = 0.82 (pet. ether-ethyl acetate, 40:1); [α]D24 −39 (c = 1.1, CHCl3); νmax. 2953,
2929, 2886, 2857, 831, 774 cm–1; 1H NMR
(400 MHz, CDCl3) δ 5.87 (1H, ddt, J = 17.2, 10.2, 5.9 Hz), 5.08 (1H, dq, J = 17.2,
1.6 Hz), 5.05 (1H, dq, J = 10.2, 1.6 Hz), 4.97 (1H,
q, J = 2.1 Hz,), 4.83 (1H, q, J =
2.1 Hz), 4.44–4.39 (1H, m), 4.07 (1H, q, J = 7.2 Hz), 3.82 (1H, dd, J = 9.9, 5.9 Hz), 3.69
(1H, td, J = 5.9, 1.5 Hz), 3.63 (1H, dd, J = 7.2, 1.5 Hz), 3.44 (1H, dd, J = 9.9,
5.9 Hz), 2.60 (1H, ddt, J = 15.5, 7.2, 2.1 Hz), 2.40–2.32
(1H, m), 2.32–2.22 (2H, m), 0.89 (9H, s), 0.89 (9H, s), 0.88
(9H, s), 0.08 (3H, s), 0.07 (3H, s), 0.07 (3H, s), 0.06 (3H, s), 0.04
(6H, s); 13C{1H} NMR (101 MHz, CDCl3) δ 151.5, 135.3, 116.9, 104.8, 79.4, 79.3, 79.0, 75.7, 64.3,
40.0, 36.0, 26.2, 26.2, 26.2, 18.6, 18.5, 18.4, −4.3, −4.4,
−4.5, −4.5, −5.3, −5.3; HRMS (ESI+) m/z: [M + Na]+ calcd for C29H60NaO4Si3 579.3692; found
579.3666.
Osmium tetroxide (730 μL of a 2.5%
solution in t-butanol, ca. 0.07 mmol) was added to
a solution of diene 9 (2.00 g, 3.59 mmol) and N-methylmorpholine-N-oxide (505 mg, 4.31
mmol) in a 10:1 mixture of THF and water (49.5 mL) at rt. The solution
was stirred at rt for 16 h, and then the reaction was quenched by
the addition of solid sodium sulfite (1.8 g). The mixture was stirred
at rt for 30 min before dichloromethane (80 mL) and water (50 mL)
were added. The phases were separated, and the aqueous phase was extracted
with dichloromethane (2 × 50 mL). The combined organic extracts
were dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure to afford the crude diol 10, which
was subjected to oxidative diol cleavage without purification. Sodium
periodate (1.54 g, 7.20 mmol) was added to a stirred solution of the
crude diol 10 in a mixture of THF and water (4:1, 50 mL) at rt. The
mixture was stirred at rt for 1.5 h, diluted with water (40 mL), and
extracted with diethyl ether (3 × 40 mL). The combined organic
extracts were dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure to deliver the crude aldehyde, which was subjected
to reduction without purification. The crude aldehyde was dissolved
in ethanol (36 mL) at rt, and sodium borohydride (143 mg, 3.78 mmol)
was added. The mixture was stirred at rt for 1 h and then concentrated
under reduced pressure. Dichloromethane (20 mL) and water (20 mL)
were added, and the phases were separated. The aqueous phase was extracted
with further dichloromethane (2 × 20 mL), and the combined organic
extracts were dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure. The residue was purified by flash chromatography
on silica gel (pet. ether-ethyl acetate, 19:1) to yield alcohol 11 (1.09 g, 54% over three steps) as a colorless oil. R = 0.14 (pet. ether-ethyl acetate, 19:1); [α]D24 −23 (c = 1.0, CHCl3); νmax. 3409,
2953, 2929, 2886, 2857, 831, 774, 668 cm–1; 1H NMR (500 MHz, CDCl3) δ 4.98 (1H, q, J = 2.0 Hz), 4.81 (1H, q, J = 2.0 Hz),
4.58 (1H, bdd, J = 5.7, 2.0 Hz), 4.13 (1H, q, J = 7.4 Hz), 3.84–3.76 (2H, m), 3.77 (1H, dd, J = 9.9, 6.3 Hz), 3.68 (1H, td, J = 6.3,
1.1 Hz), 3.65 (1H, dd, J = 7.4, 1.1 Hz), 3.43 (1H,
dd, J = 9.9, 6.3 Hz), 2.74 (1H, dd, J = 6.6, 4.1 Hz, OH), 2.63 (1H, ddt, J = 15.6, 7.4,
2.0 Hz,), 2.37 (1H, ddt, J = 15.6, 7.4, 2.0 Hz),
1.83–1.72 (2H, m), 0.88 (9H, s), 0.88 (18H, s), 0.07 (3H, s),
0.07 (3H, s), 0.07 (3H, s), 0.05 (3H, s), 0.03 (6H, s); 13C{1H} NMR (126 MHz, CDCl3) δ 151.4, 104.9,
79.9, 79.0, 78.8, 75.8, 64.2, 61.6, 37.0, 35.9, 26.2, 26.2, 26.1,
18.5, 18.5, 18.4, −4.2, −4.4, −4.4, −4.4,
−5.3, −5.3; LRMS (CI, isobutane) m/z (intensity) 561.4 [M + H]+ (100); HRMS (CI,
isobutane) m/z: [M + H]+ calcd for C28H61O5Si3 561.3827; found 561.3831.
A solution of [Ir(cod)(IMes)(PPh3)]PF6 (19.7 mg, 19.4 μmol) and alcohol 11 (1.09 g, 1.94 mmol) in dichloromethane (40 mL) was cooled
to −78 °C. The flask was purged three times with hydrogen,
and the cooling bath was removed. The solution was stirred under an
atmosphere of hydrogen at rt for 1 h, and then the atmosphere was
replaced with argon. Pyridine (629 μL, 7.81 mmol) and trimethylacetyl
chloride (718 μL, 5.87 mmol) were added sequentially, and the
mixture was stirred at rt for 22 h. The reaction was quenched by the
addition of 1 M aqueous hydrochloric acid (40 mL), and the mixture
was extracted with diethyl ether (3 × 60 mL). The combined organic
extracts were washed with 1 M aqueous sodium hydroxide (40 mL) and
saturated aqueous copper(II) sulfate (50 mL), dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure to afford
the crude pivaloyl ester 12, which was used in the next
step without purification. To a solution of crude ester 12 in THF (200 mL) at 0 °C was added a stock solution of HF·pyridine
(11.5 mL). The mixture was stirred at 0 °C for 24 h, and the
reaction was then quenched by the addition of saturated aqueous sodium
bicarbonate (250 mL). The mixture was extracted with diethyl ether
(3 × 100 mL), and the combined organic extracts were washed with
brine (80 mL), dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure. The residue was purified by flash chromatography
on silica gel (pet. ether-ethyl acetate, 19:1 to 10:1) to give alcohol 13 (787 mg, 76% over 2 steps) as a colorless oil. R = 0.31 (pet. ether-ethyl acetate, 9:1); [α]D23 −17 (c = 0.5, CHCl3); νmax. 3445,
2958, 2930, 2884, 2857, 1730, 835, 777 cm–1; 1H NMR (500 MHz, CDCl3) δ 4.18 (1H, ddd, J = 11.1, 6.9, 5.6 Hz), 4.14–4.05 (2H, m), 4.02 (1H,
dt, J = 8.3, 5.0 Hz), 3.80–3.73 (2H, m), 3.63
(1H, dd, J = 3.6, 1.8 Hz), 3.54–3.47 (1H,
m), 3.28–3.24 (1H, m, OH), 2.31–2.24 (1H, m), 2.08 (1H,
ddd, J = 12.3, 8.8, 7.0 Hz), 1.82–1.70 (2H,
m), 1.64 (1H, ddd, J = 12.3, 7.0, 2.0 Hz), 1.19 (9H,
s), 0.91 (3H, d, J = 7.0 Hz), 0.90 (9H, s), 0.90
(9H, s), 0.12 (3H, s), 0.09 (3H, s), 0.08 (3H, s), 0.08 (3H, s); 13C{1H} NMR (126 MHz, CDCl3) δ
178.6, 79.1, 79.0, 78.2, 75.7, 62.9, 62.3, 38.8, 36.5, 36.3, 30.1,
27.3, 26.2, 26.1, 18.6, 18.4, 14.3, −4.0, −4.5, −4.5,
−4.8; HRMS (ESI+) m/z: [M
+ Na]+ calcd for C27H56NaO6Si2 555.3508; found 555.3484.
Pyridine (1.09 mL,
13.5 mmol) and Dess–Martin periodinane (1.90 g, 4.48 mmol)
were added sequentially to a solution of alcohol 13 (597
mg, 1.12 mmol) in dichloromethane (18 mL) at rt. The solution was
stirred at rt for 3 h, and the reaction was quenched by the addition
of saturated aqueous sodium sulfite (40 mL) and saturated aqueous
sodium bicarbonate (40 mL). The mixture was extracted with diethyl
ether (3 × 40 mL), and the combined organic extracts were washed
with saturated aqueous sodium bicarbonate (40 mL) and saturated aqueous
copper(II) sulfate (80 mL), then dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure to give the
crude aldehyde 14, which was used directly in the next
step without purification. Anhydrous potassium carbonate (464 mg,
3.36 mmol) was added to a solution of the Ohira–Bestmann reagent
(861 mg, 4.48 mmol) in methanol (18 mL) at 0 °C. The mixture
was stirred at this temperature for 1 h, and then a solution of the
crude aldehyde in THF (9 mL) was added dropwise. Stirring was continued
at 0 °C for 1 h, and the mixture was then warmed to rt and stirred
for an additional 15 min. The reaction was quenched with saturated
aqueous ammonium chloride (40 mL), and the aqueous phase was extracted
with diethyl ether (3 × 40 mL). The combined organic extracts
were washed with brine (50 mL), dried (anhydrous MgSO4),
filtered, and concentrated under reduced pressure. The resulting residue
was purified by flash chromatography on silica gel (pet. ether-ethyl
acetate, 50:1) to yield alkyne 15 (443 mg, 75% over two
steps) as a colorless oil. R = 0.50 (pet.
ether-ethyl acetate, 20:1); [α]D22 −30 (c = 1.0, CHCl3); νmax. 2958, 2929, 2886, 2858, 1730, 832,
776 cm–1; 1H NMR (500 MHz, CDCl3) δ 4.38 (1H, dd, J = 4.2, 2.2 Hz), 4.20 (1H,
ddd, J = 11.2, 7.0, 5.7 Hz), 4.15 (1H, ddd, J = 8.2, 7.1, 5.6 Hz), 4.11 (1H, ddd, J = 11.2, 7.7, 6.8 Hz), 3.94 (1H, dt, J = 8.4, 5.0
Hz), 3.57 (1H, dd, J = 5.6, 4.2 Hz), 2.36 (1H, d, J = 2.2 Hz), 2.29–2.21 (1H, m), 2.11 (1H, ddd, J = 12.3, 8.2, 7.2 Hz), 1.78–1.67 (2H, m), 1.63 (1H,
ddd, J = 12.3, 7.1, 2.6 Hz), 1.19 (9H, s), 0.91 (3H,
d, J = 7.0 Hz), 0.90 (9H, s), 0.90 (9H, s), 0.13
(3H, s), 0.12 (3H, s), 0.11 (3H, s), 0.09 (3H, s); 13C
NMR (126 MHz, CDCl3) δ 178.7, 84.4, 78.9, 78.0, 77.3,
74.0, 65.7, 62.7, 38.8, 36.4, 36.0, 30.5, 27.4, 26.3, 25.9, 18.6,
18.4, 14.3, −3.9, −4.0, −4.5, −5.0; HRMS
(ESI+) m/z: [M + Na]+ calcd for C28H54NaO5Si2 549.3402; found 549.3390.
A solution of methyl ketone 17 (1.40 g, 6.30 mmol) in diethyl ether (4 mL) was added to a solution
of dicyclohexylboron chloride (3.35 g, 15.8 mmol) in diethyl ether
(24 mL) at 0 °C. Triethylamine was added dropwise, and the resulting
suspension was stirred at 0 °C for 1 h. The mixture was cooled
to −78 °C, then a solution of aldehyde 18 (1.53 g, 7.56 mmol) in diethyl ether (4 mL) was added, and the resulting
mixture was stirred at −78 °C for 2 h. The mixture was
then warmed to 0 °C, and the reaction was quenched by the sequential
addition of methanol (12 mL), aqueous pH 7 buffer (24 mL), and 30%
aqueous hydrogen peroxide (24 mL). The resulting mixture was stirred
vigorously at rt for 1 h. The phases were separated, and the aqueous
phase was extracted with diethyl ether (2 × 25 mL). The combined
organic extracts were washed with brine (40 mL), dried (anhydrous
MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (pet.
ether-ethyl acetate, 19:1 to 9:1) to afford hydroxyketone 19 (2.17 g, 81%, d.r. > 20:1) as a colorless oil. R = 0.35 (pet. ether-ethyl acetate, 4:1); [α]D23 −15 (c = 1.5, CHCl3); νmax. 3510,
2955, 2930, 2857, 1708, 1513, 834, 775 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.20 (2H, d, J = 8.6 Hz), 6.86 (2H, d, J = 8.6 Hz),
4.42 (1H, d, J = 11.7 Hz), 4.38 (1H, d, J = 11.7 Hz), 4.30–4.23 (1H, m), 3.79 (3H, s), 3.67 (1H, dd, J = 9.9, 4.6 Hz), 3.61 (1H, dd, J = 9.9,
5.9 Hz), 3.58 (1H, dd, J = 9.0, 8.0 Hz), 3.45 (1H,
dd, J = 9.0, 5.3 Hz), 3.29 (1H, d, J = 2.7 Hz, OH), 2.93–2.85 (1H, m), 2.70 (1H, dd, J = 17.0, 9.1 Hz), 2.58 (1H, dd, J = 17.0, 3.4 Hz),
1.73–1.64 (1H, m), 1.06 (3H, d, J = 7.1 Hz),
0.89 (3H, d, J = 6.9 Hz), 0.89 (9H, s), 0.05 (6H,
s); 13C{1H} NMR (126 MHz, CDCl3)
δ 213.7, 159.4, 130.1, 129.4, 113.9, 73.1, 72.0, 69.3, 66.9,
55.4, 47.0, 46.9, 39.5, 26.0, 18.3, 13.3, 10.9, −5.4, −5.4;
HRMS (ESI+) m/z: [M + Na]+ calcd for C23H40NaO5Si 447.2537;
found 447.2548.
Samarium powder
(451 mg, 3.00 mmol) was added to a flame-dried round-bottomed flask.
The flask was evacuated and refilled with argon three times before
THF (20 mL) was added. Iodine (508 mg, 2.00 mmol) was added, and the
resulting brown slurry was heated (oil bath) at 50 °C for 18
h to give a dark blue solution of samarium(II) iodide (approximately
0.1 M). The solution was allowed to cool and settle to rt over 1 h
and then used directly in the Evans–Tischenko reaction. To
a solution of freshly distilled pivaldehyde (3.81 mL, 35.1 mmol) in
THF (8.2 mL) at −30 °C was added samarium(II) iodide (11.7
mL of a 0.1 M solution in THF, 1.17 mmol). The resulting mixture was
stirred at −30 °C for 10 min. A solution of hydroxyketone 19 (2.40 g, 5.65 mmol) in THF (8.2 mL) was added, and the
reaction mixture was stirred for 3 h maintaining the temperature between
−10 and −20 °C. The reaction was quenched by the
addition of saturated aqueous sodium bicarbonate (20 mL), and the
mixture was extracted with diethyl ether (3 × 20 mL). The combined
organic extracts were washed with brine (30 mL), dried (anhydrous
MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (pet.
ether-ethyl acetate, 20:1) to yield alcohol 20 (2.18
g, 76%, d.r. > 10:1) as a colorless oil. R = 0.21 (pet. ether-ethyl acetate, 19:1); [α]D23 −10 (c = 0.5, CHCl3); νmax. 3517, 2957, 2929,
2858, 1707, 1513, 836, 775 cm–1; 1H NMR
(400 MHz, CDCl3) δ 7.25–7.21 (2H, m), 6.88–6.84
(2H, m), 5.22 (1H, ddd, J = 10.7, 3.3, 2.7 Hz), 4.43
(1H, d, J = 11.8 Hz), 4.40 (1H, d, J = 11.8 Hz), 3.80 (3H, s), 3.51–3.38 (5H, m), 3.38–3.30
(1H, m), 1.89–1.80 (2H, m), 1.74 (1H, ddd, J = 14.0, 10.7, 2.3 Hz), 1.52 (1H, ddd, J = 14.0,
10.7, 2.7 Hz), 1.20 (9H, s), 0.93 (3H, d, J = 6.9
Hz), 0.92 (3H, d, J = 6.9 Hz), 0.88 (9H, s), 0.02
(3H, s), 0.01 (3H, s); 13C{1H} NMR (101 MHz,
CDCl3) δ 179.4, 159.3, 130.7, 129.3, 113.9, 73.2,
73.0, 71.2, 69.9, 65.1, 55.4, 40.3, 39.2, 38.9, 37.5, 27.4, 26.0,
18.3, 14.0, 11.5, −5.3; HRMS (ESI+) m/z: [M + Na]+ calcd for C28H50NaO6Si 533.3269; found 533.3271.
To a solution of
alcohol 20 (2.18 g, 4.27 mmol) in dichloromethane (21
mL) at −78 °C were sequentially added 2,6-lutidine (1.49
mL, 12.9 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate
(1.47 mL, 6.40 mmol). The mixture was stirred at −78 °C
for 1.5 h, and the reaction was then quenched by the addition of saturated
aqueous sodium bicarbonate (20 mL). The resulting mixture was extracted
with diethyl ether (3 × 30 mL), and the combined organic extracts
were washed with saturated aqueous copper(II) sulfate (30 mL) and
brine (30 mL), dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure. The residue was filtered through a short pad
of silica gel (pet. ether-ethyl acetate, 20:1) to deliver the crude
silyl ether, which was used directly in the next step without purification.
A mixture of silyl ether and Pearlman’s catalyst (20 wt %,
599 mg, 0.85 mmol) in ethanol at rt was purged three times with hydrogen,
and the reaction was stirred under an atmosphere of hydrogen at rt
for 2 h. The mixture was filtered to remove the catalyst and concentrated
under reduced pressure. The residue was purified by flash chromatography
on silica gel (pet. ether-ethyl acetate, 20:1) to afford primary alcohol 21 (1.85 g, 86% over two steps) as a colorless oil. R = 0.42 (pet. ether-ethyl acetate, 9:1); [α]D22 −10 (c = 0.9, CHCl3); νmax. 3510,
2956, 2929, 2858, 1728, 835, 774 cm–1; 1H NMR (400 MHz, CDCl3) δ 4.99 (1H, ddd, J = 7.8, 5.5, 3.0 Hz), 3.84 (1H, dt, J =
11.1, 3.5 Hz), 3.75 (1H, td, J = 6.3, 2.7 Hz), 3.55–3.49
(1H, m), 3.46 (1H, dd, J = 9.4, 6.9 Hz), 3.39 (1H,
dd, J = 9.4, 6.5 Hz), 2.37 (1H, dd, J = 7.4, 3.5 Hz), 1.89–1.79 (2H, m), 1.79–1.68 (2H,
m), 1.18 (9H, s), 1.01 (3H, d, J = 7.1 Hz), 0.93
(3H, d, J = 7.0 Hz), 0.89 (9H, s), 0.87 (9H, s),
0.09 (3H, s), 0.07 (3H, s), 0.01 (3H, s), 0.01 (3H, s); 13C NMR (101 MHz, CDCl3) δ 178.0, 73.7, 71.9, 64.8,
64.7, 39.6, 39.4, 39.1, 36.7, 27.4, 26.0, 18.4, 18.1, 13.9, 11.2,
−4.3, −4.5, −5.3, −5.4; HRMS (ESI+) m/z: [M + Na]+ calcd for C26H56NaO5Si2 527.3558; found
527.3539.
2,2,6,6-Tetramethyl-1-piperidinyloxy
(50 mg, 0.32 mmol) and (diacetoxyiodo)benzene (1.13 g, 3.51 mmol)
were added sequentially to a solution of alcohol 21 (1.61
g, 3.19 mmol) in dichloromethane (16 mL) at rt. The mixture was stirred
at rt for 5 h, and the reaction was quenched by the addition of water
(20 mL). The resulting mixture was extracted with diethyl ether (3
× 25 mL), and the combined organic extracts were washed with
brine (20 mL), dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure. The residue was filtered rapidly through a
short pad of silica gel (pet. ether-ethyl acetate, 30:1) to give the
crude aldehyde 22, which was used directly in the subsequent
alkyne-forming reaction without purification. Anhydrous potassium
(1.32 g, 9.55 mmol) was added to a solution of the Ohira–Bestmann
reagent (2.45 g, 12.8 mmol) in methanol (15 mL) at 0 °C. The
mixture was stirred for 1 h at this temperature, and then a solution
of the crude aldehyde 22 in THF (7.5 mL) was added dropwise.
Stirring was continued at 0 °C for 1 h, and the mixture was then
warmed to rt and stirred for an additional 15 min. The reaction was
quenched by the addition of saturated aqueous ammonium chloride (40
mL), and the resulting mixture was extracted with diethyl ether (3
× 40 mL). The combined organic extracts were washed with brine
(50 mL), dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel (pet. ether-ethyl acetate, 100:1) to
yield alkyne 23 (1.16 g, 73% over two steps) as a colorless
oil. R = 0.72 (pet. ether-ethyl acetate,
20:1); [α]D22 −11 (c = 1.1, CHCl3); νmax. 3315, 2957, 2930, 2886, 2859, 1727, 836, 775 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.02 (1H,
ddd, J = 9.9, 3.7, 2.2 Hz), 3.71 (1H, ddd, J = 9.2, 3.7, 2.0 Hz), 3.55 (1H, dd, J =
9.9, 5.5 Hz), 3.40 (1H, dd, J = 9.9, 6.9 Hz), 2.63–2.56
(1H, m), 2.05 (1H, d, J = 2.5 Hz), 2.03–1.93
(1H, m), 1.92–1.82 (1H, m), 1.59 (1H, ddd, J = 14.3, 9.2, 2.2 Hz), 1.20 (9H, s), 1.13 (3H, d, J = 7.1 Hz), 0.93 (3H, d, J = 7.0 Hz), 0.88 (18H,
s), 0.09 (3H, s), 0.03 (3H, s), 0.02 (3H, s), 0.02 (3H, s); 13C{1H} NMR (101 MHz, CDCl3) δ 177.9, 86.2,
72.4, 71.3, 70.1, 64.9, 40.4, 39.1, 35.3, 32.6, 27.5, 26.1, 26.0,
18.4, 18.2, 13.6, 12.0, −4.5, −4.5, −5.3, −5.3;
HRMS (ESI+) m/z: [M + Na]+ calcd for C27H54NaO4Si2 521.3453; found 521.3427.
Lithium metal (312
mg, 45.0 mmol) was added to a flame-dried round-bottomed flask. The
flask was evacuated and refilled with argon before THF (20 mL) was
added. The mixture was cooled to 0 °C, and freshly distilled
chloro(dimethyl)-phenylsilane (1.66 mL, 9.89 mmol) was added. The
resulting mixture was stirred at 0 °C for 6 h, giving a dark
red solution of dimethylphenylsilyllithium (approximate concentration
0.5 M), and the solution was used immediately for the reaction. Copper(I)
cyanide (270 mg, 3.01 mmol) was added to a flame-dried round-bottomed
flask and dried at 55 °C (oil bath) under high vacuum overnight.
The flask was cooled to 0 °C and refilled with argon before THF
(6.5 mL) was added. A solution of dimethylphenylsilyllithium (12.0
mL of a 0.5 M solution in THF, 6.01 mmol) was then added in one portion.
The resulting blood red solution was stirred at 0 °C for 30 min
during which time the color changed from red to purple. A solution
of alkyne 23 (1.00 g, 2.00 mmol) in THF (17 mL) was added,
and the reaction was stirred at 0 °C for 1 h. Iodomethane (1.25
mL, 20.1 mmol) was added, and stirring was continued at 0 °C
for an additional 1 h. The reaction was quenched by the addition of
ammonium hydroxide (30% v/v in water, 40 mL) and diethyl ether (25
mL) under vigorous stirring. The biphasic mixture was partitioned
between water (80 mL) and diethyl ether (40 mL), and the aqueous layer
was extracted with diethyl ether (3 × 50 mL). The combined organic
extracts were washed with water (3 × 40 mL) and brine (65 mL),
dried (anhydrous MgSO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (pet. ether-ethyl acetate, 200:1) to give vinylic silane 24 (1.17 g, 90%) as a colorless oil. R = 0.74 (pet. ether-ethyl acetate, 20:1); [α]D25 −4.8 (c = 1.0, CHCl3); νmax. 2956,
2929, 2885, 2857, 2360, 2337, 1727, 834, 774 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.55–7.52
(2H, m), 7.35–7.32 (3H, m), 5.45 (1H, bs), 5.03 (1H, dt, J = 9.7, 2.8 Hz), 3.80 (1H, ddd, J = 9.4,
3.5, 2.0 Hz), 3.57 (1H, dd, J = 9.9, 5.3 Hz), 3.36
(1H, dd, J = 9.9, 7.5 Hz), 2.39 (1H, bqd, J = 7.0, 3.5 Hz), 1.90–1.84 (1H, m), 1.73 (3H, s),
1.58 (1H, ddd, J = 14.4, 9.7, 2.0 Hz), 1.49 (1H,
ddd, J = 14.4, 9.4, 2.8 Hz), 1.15 (9H, s), 1.04 (3H,
d, J = 7.0 Hz), 0.93 (3H, d, J =
7.0 Hz), 0.91 (9H, s), 0.89 (9H, s), 0.37 (3H, s), 0.36 (3H, s), 0.09
(3H, s), 0.06 (3H, s), 0.03 (3H, s), 0.03 (3H, s); 13C{1H} NMR (101 MHz, CDCl3) δ 177.7, 157.9, 140.2,
133.9, 128.8, 127.9, 121.6, 72.5, 70.4, 65.0, 50.0, 40.5, 39.0, 33.8,
27.5, 26.1, 22.8, 18.4, 18.2, 12.0, 11.7, −0.7, −0.8,
−4.2, −4.5, −5.3; HRMS (ESI+) m/z: [M + Na]+ calcd for C36H68NaO4Si3 671.4318; found 671.4292.
A solution of freshly
recrystallized N-iodosuccinimide (700 mg, 3.11 mmol)
in acetonitrile (3.6 mL) was added dropwise to a solution of alkenylsilane 24 (400 mg, 0.62 mmol) in a mixture of acetonitrile and benzene
(2.5:1; 5 mL) at 0 °C. The bright red mixture was stirred at
0 °C for 4 h, and the reaction was then quenched with saturated
aqueous sodium sulfite (8 mL) under vigorous stirring. The resulting
colorless mixture was extracted with diethyl ether (3 × 15 mL).
The combined organic extracts were washed with water (20 mL) and brine
(20 mL), dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure. The resulting residue was filtered rapidly
through a short pad (ca. 5 cm) of silica gel (from pure pentane to
pentane-diethyl ether, 200:1) to afford crude vinylic iodide, which
was immediately used in the next step without purification. Pyridine
(4 mL) and HF·pyridine (70% HF, 4 mL) were added sequentially
to a solution of crude iodide in THF (60 mL) at 0 °C. The resulting
solution was stirred at 0 °C until TLC indicated complete consumption
of the starting material (24–36 h). The reaction was quenched
by the addition of saturated aqueous sodium bicarbonate until gas
evolution ceased, and the mixture was extracted with diethyl ether
(3 × 50 mL). The combined organic extracts were washed with brine
(50 mL), dried (anhydrous MgSO4), filtered, and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel (pet. ether-ethyl acetate, 20:1 to 10:1)
to give alcohol 25 (206 mg, 63% over two steps) as a
colorless oil. R = 0.11 (pet. ether-ethyl
acetate, 19:1); [α]D21 +14 (c = 1.0, CHCl3); νmax. 3491, 2957, 2930, 2883, 2858, 1725, 1708,
836, 806, 775 cm–1; 1H NMR (400 MHz,
CDCl3) δ 6.03–6.01 (1H, m), 5.21 (1H, dt, J = 9.8, 2.3), 3.73 (1H, ddd, J = 9.3,
3.9, 2.3 Hz), 3.40 (1H, ddd, J = 13.0, 11.1, 5.4
Hz), 3.13–3.06 (2H, m), 2.54–2.47 (1H, m), 1.85 (3H,
d, J = 0.8 Hz), 1.84–1.77 (1H, m), 1.65 (1H,
ddd, J = 14.4, 9.8, 2.3 Hz), 1.40 (1H, ddd, J = 14.4, 9.3, 2.3 Hz), 1.21 (9H, s), 1.05 (3H, d, J = 7.0 Hz), 0.89 (9H, s), 0.77 (3H, d, J = 7.0 Hz), 0.07 (3H, s), 0.05 (3H, s); 13C{1H} NMR (101 MHz, CDCl3) δ 179.9, 148.8, 77.6, 70.6,
70.4, 64.5, 48.7, 40.7, 39.3, 35.6, 27.5, 26.0, 24.6, 18.2, 12.4,
9.8, −4.0,–4.6; LRMS (CI, isobutane) m/z (intensity) 527.0 [M + H]+ (15), 395.0
(15), 113.1 (38), 73.1 (100); HRMS (CI, isobutane) m/z: [M + H]+ calcd for C22H44O4SiI 527.2054; found 527.2052.
To a suspension of magnesium turnings (2.19
g, 90.1 mmol) in diethyl ether (45 mL) at rt were added mercury(II)
chloride (122 mg, 0.449 mmol, 1 mol %) and iodine (two crystals).
The mixture was cooled to 0 °C, and propargyl bromide (80 wt
% in toluene, 5.0 mL, 45 mmol) was added dropwise. The mixture was
cooled until reflux stabilized. The reaction mixture was then heated
(oil bath) at reflux for 1 h, and the resulting yellow solution was
then allowed to cool to rt. To a solution of epoxide 26 (1.94 g, 9.59 mmol) in diethyl ether (200 mL) at −78 °C
was added a freshly prepared solution of propargylmagnesium bromide
(29 mL of a 1.0 M solution in diethyl ether, 29 mmol) dropwise. The
resulting mixture was stirred at −78 °C for 30 min and
at rt for 1.5 h. The reaction mixture was cooled to 0 °C, and
saturated aqueous ammonium chloride (200 mL) was added. The phases
were separated, and the aqueous phase was extracted with diethyl ether
(4 × 160 mL). The combined organic extracts were washed with
brine (400 mL), dried (anhydrous MgSO4), filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel (pet. ether-diethyl ether, 80:20) to deliver alcohol 27 (1.57 g, 68%) as a yellow oil. R = 0.37 (pet. ether-diethyl ether, 80:20); [α]D24 +26.9 (c = 1.11, CHCl3); νmax. 3444,
3315, 2951, 2929, 2884, 2858, 662 cm–1; 1H NMR (400 MHz, CDCl3) δ 4.00–3.93 (1H, m),
3.91 (1H, app dt, J = 9.9, 4.7 Hz), 3.87–3.80
(1H, m), 3.51 (1H, d, J = 2.3 Hz), 2.34 (2H, ddd, J = 7.7, 6.9, 2.7 Hz), 1.95 (1H, t, J =
2.7 Hz), 1.76–1.60 (4H, m), 0.90 (9H, s), 0.08 (3H, s), 0.08
(3H, s); 13C{1H} NMR (101 MHz, CDCl3) δ 84.6, 71.0, 68.5, 62.9, 38.3, 36.2, 26.0, 18.3, 14.9, −5.4,
−5.4; HRMS (ESI+) m/z: [M
+ Na]+ calcd for C13H26NaO2Si 265.1594; found 265.1588.
To a solution of alkyne 28 (3.85 g, 10.8 mmol) in THF (54 mL) at −78 °C was added n-BuLi (5.7 mL of a 2.1 M solution in hexanes, 12 mmol)
dropwise. The resulting solution was stirred at −78 °C
for 1 h before the addition of paraformaldehyde (1.12 g, 37.3 mmol)
in one portion. The reaction mixture was allowed to warm to rt for
10 min and stirred at 40 °C for 45 min. The solution was allowed
to cool to rt, and 1 M aqueous sodium hydroxide (50 mL) was added.
The biphasic mixture was stirred vigorously at rt for 45 min, and
the phases were separated. The organic layer was washed with saturated
aqueous ammonium chloride (50 mL), and the phases were separated.
The aqueous phase was extracted with diethyl ether (3 × 50 mL),
and the combined organic extracts were washed with brine (150 mL),
dried (anhydrous MgSO4), filtered, and concentrated. The
residue was purified by flash chromatography on silica gel (pet. ether-diethyl
ether, 80:20) to provide propargylic alcohol 29 (3.69
g, 88%) as a yellow oil. R = 0.33 (pet.
ether-diethyl ether, 80:20); [α]D22 +5.5 (c = 1.1, CHCl3); νmax. 3353, 2954, 2929, 2884, 2857 cm–1; 1H NMR (500 MHz, CDCl3) δ
4.24 (2H, dt, J = 6.1, 2.1 Hz), 3.94–3.88
(1H, m), 3.66 (2H, t, J = 6.6 Hz), 2.27 (2H, tt, J = 7.3, 2.1 Hz), 1.74–1.59 (4H, m), 1.49 (1H, t, J = 6.1 Hz), 0.89 (9H, s), 0.88 (9H, s), 0.06 (3H, s), 0.06
(3H, s), 0.04 (6H, s); 13C{1H} NMR (126 MHz,
CDCl3) δ 86.7, 78.6, 68.3, 59.8, 51.6, 40.1, 36.1,
26.1, 26.0, 18.4, 18.2, 14.9, −4.4, −4.4, −5.2;
HRMS (ESI+) m/z: [M + Na]+ calcd for C20H42NaO3Si2 409.2565; found 409.2566.
To
a solution of propargylic alcohol 29 (4.50 g, 11.6 mmol)
in pet. ether (58 mL) at rt was added quinoline (1.80 mL, 15.2 mmol)
slowly, followed by palladium on calcium carbonate (5 wt %, poisoned
with lead, 495 mg, 0.233 mmol, 2 mol %). The reaction mixture was
purged with hydrogen three times and then stirred at rt under a hydrogen
atmosphere for 1.5 h. The mixture was filtered through a celite pad,
and the solids were washed with diethyl ether (5 × 50 mL). The
filtrates were concentrated, and the residue was purified by flash
chromatography on silica gel (pet. ether-diethyl ether, 80:20) to
provide allylic alcohol 30 (4.30 g, 95%) as a light yellow
oil. R = 0.28 (pet. ether-diethyl ether,
80:20); [α]D20 −5.4 (c = 1.0, CHCl3);
νmax. 3327, 2954, 2929, 2885, 2858, 832, 772 cm–1; 1H NMR (400 MHz, CDCl3) δ
5.64–5.57 (1H, m), 5.57–5.49 (1H, m), 4.25–4.14
(2H, m), 3.84 (1H, app p, J = 5.7 Hz), 3.66 (2H,
t, J = 6.5 Hz), 2.22–2.03 (2H, m), 1.69–1.62
(2H, m), 1.58–1.47 (2H, m), 1.31 (1H, t, J = 5.7 Hz), 0.89 (18H, s), 0.05 (3H, s), 0.05 (3H, s), 0.04 (6H,
s); 13C{1H} NMR (126 MHz, CDCl3)
δ 133.0, 128.6, 69.0, 60.0, 58.7, 40.0, 37.3, 26.1, 26.0, 23.3,
18.4, 18.2, −4.3, −4.4, −5.2, −5.2; HRMS
(ESI+) m/z: [M + Na]+ calcd for C20H44NaO3Si2 411.2721, found 411.2714.
To a suspension of 4 Å MS (1.0 g)
in dichloromethane (21 mL) at −20 °C were added d-(−)-diethyltartrate (0.263 mL, 1.54 mmol), titanium(IV) isopropoxide
(0.379 mL, 1.28 mmol), and t-butyl hydroperoxide
(8.1 mL of a 1.9 M solution in dichloromethane, 15 mmol) sequentially.
The resulting mixture was stirred at −20 °C for 30 min
before the dropwise addition of allylic alcohol 30 (1.99
g, 5.13 mmol) in dichloromethane (6 mL) for 10 min. The reaction mixture
was stirred at −20 °C for 24 h. The reaction was quenched
by the addition of water (7.3 mL) at 0 °C, and the mixture was
stirred for 45 min while warming to rt. Aqueous sodium hydroxide (30%)
saturated with sodium chloride (1.6 mL) was added, and the mixture
was stirred vigorously for 45 min. The phases were separated, and
the milky, aqueous phase was extracted with dichloromethane (3 ×
30 mL). The combined organic extracts were washed with brine (90 mL),
dried (anhydrous MgSO4), filtered, and concentrated. The
residue was purified by flash chromatography on silica gel (pet. ether-ethyl
acetate, 80:20) to afford epoxide 31 (1.88 g, 91%) as
a colorless oil. R = 0.33 (pet. ether-ethyl
acetate, 80:20); [α]D20 −5.1 (c = 1.1, CHCl3); νmax. 3407, 2954, 2929, 2885, 2857, 1254,
832, 773 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.92–3.85 (1H, m), 3.82 (1H, ddd, J = 12.0, 7.2, 4.6 Hz), 3.70 (1H, ddd, J = 12.0, 6.6, 5.3 Hz), 3.66 (2H, t, J = 6.4 Hz),
3.16 (1H, ddd, J = 6.6, 4.6, 4.4 Hz), 3.02 (1H, app
td, J = 6.3, 4.4 Hz), 1.81 (1H, dd, J = 7.2, 5.3 Hz), 1.78–1.47 (6H, m), 0.89 (9H, s), 0.88 (9H,
s), 0.06 (3H, s), 0.05 (3H, s), 0.04 (6H, s); 13C{1H} NMR (126 MHz, CDCl3) δ 68.9, 60.9, 59.9,
57.4, 56.9, 40.3, 34.0, 26.1, 26.0, 23.8, 18.4, 18.2, −4.3,
−4.4, −5.2, −5.2; LRMS (CI+, isobutane) m/z (intensity) 405.3 (100%), 273.2 (34%);
HRMS (CI+, isobutane) m/z: [M +
H]+ calcd for C20H45O4Si2 405.2856; found 405.2851.
To a solution of oxalyl chloride (1.60 mL, 18.7
mmol) in dichloromethane (25 mL) at −78 °C was added a
solution of dimethyl sulfoxide (2.89 mL, 40.7 mmol) in dichloromethane
(4 mL) dropwise. The resulting solution was stirred at −78
°C for 20 min before the slow addition of alcohol 31 (3.43 g, 8.47 mmol) in dichloromethane (13 mL). The reaction mixture
was stirred at −78 °C for 1.5 h, and triethylamine (5.91
mL, 42.4 mmol) was added. The mixture was stirred at rt for 1 h, and
the reaction was quenched by the addition of saturated aqueous ammonium
chloride (40 mL). The phases were separated, and the aqueous phase
was extracted with dichloromethane (3 × 40 mL). The combined
organic extracts were washed with brine (120 mL), dried (anhydrous
MgSO4), filtered, and concentrated. The crude aldehyde 32 was used directly in the next step without purification.
To a solution of dimethyl(1-diazo-2-oxopropyl)phosphonate (1.79 g,
9.32 mmol) in methanol (38 mL) at 0 °C was added potassium carbonate
(1.64 g, 11.9 mmol) in one portion. The mixture was stirred at 0 °C
for 1.5 h before the dropwise addition of the crude aldehyde 32 in THF (19 mL). The resulting yellow suspension was stirred
at 0 °C for 2 h and at rt for 45 min. The reaction was quenched
by the addition of saturated aqueous ammonium chloride (50 mL). The
mixture was filtered through a plug of cotton wool, and the phases
were separated. The aqueous phase was extracted with diethyl ether
(3 × 50 mL), and the combined organic extracts were washed with
brine (150 mL), dried (anhydrous MgSO4), filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel (pet. ether-diethyl ether, 95:5) to provide alkyne 33 (1.85 g, 55% over two steps) as a colorless oil. R = 0.28 (pet. ether-diethyl ether, 95:5); [α]D24 −15.6
(c = 1.00, CHCl3); νmax. 3314, 2954, 2929, 2885, 2857, 1253, 773, 662 cm–1; 1H NMR (400 MHz, CDCl3) δ 3.92–3.85
(1H, m), 3.70–3.64 (2H, m), 3.42 (1H, dd, J = 4.0, 1.7 Hz), 3.07–3.02 (1H, m), 2.33 (1H, d, J = 1.7 Hz), 1.84–1.56 (6H, m), 0.89 (9H, s), 0.88 (9H, s),
0.06 (6H, s), 0.04 (6H, s); 13C NMR (126 MHz, CDCl3) δ 79.0, 73.6, 69.0, 60.0, 58.0, 45.0, 40.2, 33.3,
26.1, 26.0, 25.4, 18.4, 18.2, −4.3, −4.4, −5.2;
LRMS (CI+, isobutane) m/z (intensity)
399.3 (100%), 267.2 (34%); HRMS (CI+, isobutane) m/z: [M + H]+ calcd for C21H43O3Si2 399.2751; found 399.2756.
To a solution of epoxide 33 (920 mg, 2.31 mmol) in THF (15 mL) at 0 °C was added tetra-n-butylammonium fluoride (6.9 mL of a 1.0 M in solution
in THF, 6.9 mmol) dropwise. The resulting solution was stirred at
rt for 2.5 h. The reaction was quenched by the addition of saturated
aqueous ammonium chloride (15 mL). The phases were separated, and
the aqueous phase was extracted with ethyl acetate (3 × 15 mL).
The combined organic extracts were washed with brine (45 mL), dried
(anhydrous MgSO4), filtered, and concentrated. The residue
was filtered rapidly through a short pad of silica gel (ethyl acetate)
to give the crude diol, which was used in the subsequent cyclization
reaction without further purification. R = 0.41 (EtOAc); 1H NMR (500 MHz, CDCl3) δ
4.02–3.95 (1H, m), 3.94–3.82 (2H, m), 3.46 (1H, dd, J = 4.0, 1.7 Hz), 3.12–3.07 (1H, m), 2.37 (1H, d, J = 1.7 Hz), 1.95–1.86 (1H, m), 1.85–1.78
(1H, m), 1.78–1.67 (4H, m); 13C{1H} NMR
(126 MHz, CDCl3) δ 78.8, 74.0, 71.6, 62.0, 57.9,
45.0, 38.5, 34.0, 25.6; HRMS (ESI+) m/z: [M + Na]+ calcd for C9H14NaO3 193.0835; found 193.0830.To a solution of crude diol
(391 mg) in dichloromethane (23 mL) at −40 °C was added
(1S)-(+)-camphorsulfonic acid (53 mg, 0.23 mmol).
The resulting mixture was stirred at −40 °C for 10 min
and at rt for 30 min. The reaction was quenched by the addition of
triethylamine (96 μL, 0.72 mmol), and the solution was concentrated.
The residue was filtered rapidly through a short pad of silica gel
(ethyl acetate) to give the crude tetrahydrofuran 34,
which was used directly in the next step without purification. R = 0.38 (EtOAc); 1H NMR (400 MHz,
CDCl3) δ 4.25–4.17 (2H, m), 4.16–4.09
(1H, m), 3.79 (2H, app t, J = 5.7 Hz), 2.69 (1H,
br s), 2.56 (1H, br s), 2.44 (1H, d, J = 2.2 Hz),
2.16–2.06 (2H, m), 1.91–1.82 (1H, m), 1.81–1.76
(2H, m), 1.70–1.59 (1H, m); 13C{1H} NMR
(126 MHz, CDCl3) δ 82.1, 81.8, 79.7, 73.9, 65.1,
61.3, 37.5, 32.3, 27.9.To a solution of crude tetrahydrofuran 34 in dichloromethane
(12 mL) at 0 °C were added pyridine (0.28 mL, 3.5 mmol) and,
after 5 min, trimethylacetyl chloride (305 mg, 2.53 mmol). The resulting
solution was stirred at 0 °C for 10 min and at rt for 22 h. The
reaction was quenched by the addition of saturated aqueous sodium
bicarbonate (9 mL). The phases were separated, and the aqueous phase
was extracted with ethyl acetate (3 × 10 mL). The combined organic
extracts were washed with brine (30 mL), dried (anhydrous MgSO4), filtered, and concentrated. The residue was purified by
flash chromatography on silica gel (pet. ether-ethyl acetate, 70:30)
to provide pivalate ester 35 (442 mg, 75% over three
steps) as a colorless oil. R = 0.49 (pet.
ether-ethyl acetate, 70:30); [α]D24 −12.6 (c =
1.04, CHCl3); νmax. 3447, 3284, 2972,
2936, 2910, 2875, 1724, 772, 654 cm–1; 1H NMR (500 MHz, CDCl3) δ 4.23–4.12 (3H, m),
4.09 (1H, app q, J = 7.0 Hz), 4.07–4.00 (1H,
m), 2.53 (1H, d, J = 4.3 Hz), 2.43 (1H, d, J = 2.2 Hz), 2.16–2.00 (2H, m), 1.95–1.87
(1H, m), 1.86–1.77 (2H, m), 1.65–1.56 (1H, m), 1.19
(9H, s); 13C NMR (126 MHz, CDCl3) δ 178.6,
81.9, 81.5, 77.0, 73.7, 65.1, 61.7, 38.7, 34.5, 32.0, 28.0, 27.2;
LRMS (CI+, isobutane) m/z (intensity)
255.19 (100%), 229.18 (17%); HRMS (CI+, isobutane) m/z: [M + H]+ calcd for C14H23O4 255.1596; found 255.1593.
To a suspension of tetrakis(triphenylphosphine)palladium(0)
(25 mg, 22 μmol, 4 mol %) in pyrrolidine (700 μL) at rt
was added 1-bromo-2-methyl-1-propene (174 mg, 1.29 mmol) followed,
after 5 min, by the dropwise addition of alkyne 35 (109
mg, 0.429 mmol) in pyrrolidine (700 μL). The resulting yellow
solution was stirred at 50 °C for 16 h. The reaction mixture
was allowed to cool to rt, and then saturated aqueous ammonium chloride
(3 mL) was added. The phases were separated, and the aqueous phase
was extracted with diethyl ether (3 × 5 mL). The combined organic
extracts were dried (anhydrous MgSO4), filtered, and concentrated.
The residue was purified by flash chromatography on silica gel (pet.
ether-ethyl acetate, 80:20) to give the title alcohol (116 mg, 88%)
as a light yellow oil. R = 0.26 (pet.
ether-ethyl acetate, 80:20); [α]D27 +12.6 (c = 2.32, CHCl3); νmax. 3443, 2969, 2934, 2911, 2874, 2212,
1726, 772 cm–1; 1H NMR (400 MHz, CDCl3) δ 5.28–5.25 (1H, m), 4.37–4.32 (1H,
m), 4.22–4.12 (2H, m), 4.12–4.00 (2H, m), 2.49 (1H,
d, J = 4.0 Hz), 2.18–1.99 (2H, m), 1.96–1.87
(1H, m), 1.88 (3H, br s), 1.87–1.78 (2H, m), 1.80 (3H, br s),
1.65–1.54 (1H, m), 1.19 (9H, s); 13C{1H} NMR (126 MHz, CDCl3) δ 178.7, 149.7, 104.7, 89.0,
83.9, 82.1, 76.9, 66.2, 61.9, 38.9, 34.7, 32.2, 28.3, 27.3, 24.9,
21.2; HRMS (ESI+) m/z: [M + Na]+ calcd for C18H28NaO4 331.1880;
found 331.1870.
To a solution of
alcohol (174 mg g, 0.564 mmol) in dichloromethane (6 mL) at −78
°C were added 2,6-lutidine (170 μL, 1.46 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (168 μL,
0.732 mmol) sequentially. The resulting solution was stirred at −78
°C for 30 min, and water (2 mL) was added. The biphasic mixture
was allowed to warm to rt, and the phases were separated. The aqueous
phase was extracted with dichloromethane (3 × 3 mL), and the
combined organic extracts were washed with brine (10 mL), dried (anhydrous
MgSO4), filtered, and concentrated. The residue was purified
by flash chromatography on silica gel (pet. ether-ethyl acetate, 95:5)
to give enyne 36 (225 mg, 94%) as a colorless oil. R = 0.26 (pet. ether-ethyl acetate, 95:5); [α]D25 −13.1
(c = 2.40, CHCl3); νmax. 2957, 2930, 2907, 2886, 2857, 2211, 1730, 835, 775, 669 cm–1; 1H NMR (500 MHz, CDCl3) δ
5.27–5.23 (1H, m), 4.51 (1H, dd, J = 5.8,
1.4 Hz,), 4.20–4.04 (4H, m), 2.11–2.03 (2H, m), 2.01–1.93
(1H, m), 1.93–1.84 (1H, m), 1.87 (3H, br s), 1.83–1.74
(1H, m), 1.79 (3H, br s), 1.56–1.48 (1H, m), 1.18 (9H, s),
0.90 (9H, s), 0.12 (3H, s), 0.11 (3H, s); 13C{1H} NMR (126 MHz, CDCl3) δ 178.6, 148.7, 105.1, 90.6,
83.3, 81.8, 76.8, 67.0, 62.1, 38.8, 34.8, 32.3, 28.0, 27.3, 26.0,
24.9, 21.1, 18.5, −4.5, −4.8; HRMS (ESI+) m/z: [M + Na]+ calcd for C24H42NaO4Si 445.2745; found 445.2734.
To a solution of ester 36 (478
mg, 1.13 mmol) in diethyl ether (16 mL) at −20 °C was
added lithium aluminum hydride (107 mg, 2.82 mmol) in one portion.
The resulting solution was stirred at −20 °C for 20 min
before the dropwise addition of water (0.11 mL), 15% aqueous sodium
hydroxide (0.11 mL), and water (0.33 mL). The mixture was stirred
vigorously at rt for 20 min and then filtered through a cotton plug.
The filtrate was concentrated, and the residue was purified by flash
chromatography on silica gel (pet. ether-ethyl acetate, 80:20) to
give alcohol 37 (369 mg, 96%) as a colorless oil. R = 0.30 (pet. ether-ethyl acetate, 80:20);
[α]D26 −17.5 (c = 2.00, CHCl3); νmax. 3410, 2954, 2929, 2883, 2857, 2206, 835, 776, 668 cm–1; 1H NMR (500 MHz, CDCl3) δ
5.27–5.25 (1H, m), 4.48 (1H, dd, J = 6.1,
1.7 Hz), 4.23–4.16 (1H, m), 4.10 (1H, ddd, J = 7.6, 6.5, 6.1 Hz), 3.82–3.73 (2H, m), 2.90 (1H, dd, J = 7.0, 4.2 Hz), 2.11–2.03 (2H, m), 1.98–1.88
(1H, m), 1.87 (3H, br s), 1.79 (3H, br s), 1.78–1.73 (2H, m),
1.62–1.54 (1H, m), 0.90 (9H, s), 0.13 (3H, s), 0.11 (3H, s); 13C{1H} NMR (126 MHz, CDCl3) δ
148.9, 105.0, 90.4, 83.4, 82.3, 80.4, 66.9, 62.0, 37.3, 32.5, 27.8,
25.9, 24.9, 21.1, 18.4, −4.5, −4.8; LRMS (CI+, isobutane) m/z (intensity) 339.1 (19%), 263.1 (27%),
207.1 (100%), 135.0 (23%); HRMS (CI+, isobutane) m/z: [M + H]+ calcd for C19H35O3Si 339.2355; found 339.2351.
To a suspension of magnesium bromide ethyl etherate (238 mg, 0.922
mmol) in diethyl ether (5 mL) at rt was added 1,3-propanedithiol (86
μL, 0.85 mmol) followed by a solution of aldehyde 38 (239 mg, 0.710 mmol) in diethyl ether (2 mL). The resulting mixture
was stirred at rt for 1.5 h, and water (7 mL) was added. The phases
were separated, and the aqueous phase was extracted with diethyl ether
(3 × 7 mL). The combined organic extracts were washed with brine
(20 mL), dried (anhydrous MgSO4), filtered, and concentrated.
The residue was used directly in the next step without further purification.To a solution of the crude dithiane 39 (303 mg) in
THF (7 mL) at 0 °C was added tetra-n-butylammonium
fluoride (1.4 mL of a 1.0 M solution in THF, 1.4 mmol) dropwise. The
resulting solution was stirred at rt for 1 h, and then water (7 mL)
was added. The phases were separated, and the aqueous phase was extracted
with diethyl ether (3 × 7 mL). The combined organic extracts
were washed with brine (20 mL), dried (anhydrous MgSO4),
filtered, and concentrated. The residue was used directly in the next
step without purification.To a solution of the crude propargylic
alcohol (155 mg) in THF
(10 mL) at 0 °C was added sodium bis(2-methoxyethoxy)aluminum
hydride (670 μL of a ≥65 wt % in toluene, 2.2 mmol) dropwise.
The resulting cloudy mixture was stirred at rt for 30 min and then
cooled to 0 °C, and saturated aqueous potassium sodium tartrate
(20 mL) was added. The phases were separated, and the aqueous phase
was extracted with diethyl ether (3 × 20 mL). The combined organic
extracts were washed with brine (50 mL), dried (anhydrous MgSO4), filtered, and concentrated. The residue was used directly
in the next step without purification.To a solution of crude
allylic alcohol (156 mg) in dichloromethane
(10 mL) at −78 °C were added 2,6-lutidine (0.17 mL, 1.5
mmol) and triethylsilyl trifluoromethanesulfonate (0.17 mL, 0.74 mmol)
sequentially. The resulting solution was stirred at −78 °C
for 30 min, and then water (8 mL) was added. The biphasic mixture
was allowed to warm to rt, and the phases were separated. The aqueous
phase was extracted with dichloromethane (3 × 8 mL), and the
combined organic extracts were washed with brine (35 mL), dried (anhydrous
MgSO4), filtered, and concentrated. The residue was purified
by flash chromatography on silica gel (pet. ether-ethyl acetate, 98:2)
to deliver diene 40 (141 mg, 0.33 mmol, 47% over four
steps) as a colorless oil. R = 0.36 (pet.
ether-ethyl acetate, 95:5); [α]D29 +27.1 (c = 1.10, CHCl3); νmax. 2953, 2930, 2911, 2874, 2859, 1728,
740, 727 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.46 (1H, ddd, J = 15.1, 11.0,
1.1 Hz), 5.82 (1H, br d, J = 11.0 Hz), 5.52 (1H,
dd, J = 15.1, 5.8 Hz), 4.21 (1H, dd, J = 9.6, 4.9 Hz), 4.24–4.15 (2H, m), 3.93 (1H, ddd, J = 8.0, 7.1, 6.3 Hz), 2.94–2.77 (4H, m), 2.16–2.06
(1H, m), 2.03–1.78 (5H, m), 1.77 (3H, br s), 1.75 (3H, br s),
1.68 (1H, app ddt, J = 12.6, 9.0, 8.0 Hz), 1.45 (1H,
app dtd, J = 11.8, 9.0, 8.1 Hz), 0.96 (9H, t, J = 7.9 Hz), 0.62 (6H, q, J = 7.9 Hz); 13C{1H} NMR (126 MHz, CDCl3) δ
135.2, 129.9, 127.7, 124.9, 82.4, 75.6, 75.5, 44.7, 41.8, 32.3, 30.7,
30.2, 27.4, 26.2, 26.1, 18.4, 7.1, 5.1; HRMS (ESI+) m/z: [M + Na]+ calcd for C22H40NaO2S2Si 451.2131; found 451.2110.
To a suspension of tetrakis(triphenylphosphine)palladium(0)
(120 mg, 0.104 mmol, 5 mol %) in pyrrolidine (2.3 mL) at rt was added
1-bromo-2-methyl-1-propene (842 mg, 6.24 mmol) followed, after 5 min,
by the dropwise addition of alkyne 34 (354 mg, 2.08 mmol)
in pyrrolidine (2.3 mL). The resulting yellow solution was stirred
at 50 °C (oil bath) for 16 h. The reaction mixture was allowed
to cool to rt, followed by the addition of saturated aqueous ammonium
chloride (10 mL). The phases were separated, and the aqueous phase
was extracted with diethyl ether (3 × 10 mL). The combined organic
extracts were dried (anhydrous MgSO4), filtered, and concentrated.
The crude enyne 41 was used directly in the next step
without further purification.To a solution of crude enyne 41 (409 mg) in THF (40 mL) at 0 °C was added sodium bis(2-methoxyethoxy)aluminum
hydride (2.46 mL of a ≥65 wt % solution in toluene, ∼7.9
mmol) dropwise. The resulting cloudy mixture was stirred at rt for
30 min and cooled to 0 °C before the dropwise addition of saturated
aqueous potassium sodium tartrate solution (40 mL). The phases were
separated, and the aqueous phase was extracted with diethyl ether
(3 × 40 mL). The combined organic extracts were washed with brine
(120 mL), dried (anhydrous MgSO4), filtered, and concentrated.
The crude diene 42 was used directly in the next step
without purification.To a solution of crude diene 42 (364 mg) in dichloromethane
(15 mL) at −78 °C were added 2,6-lutidine (1.12 mL, 9.67
mmol) and triethylsilyl trifluoromethanesulfonate (1.09 mL, 6.02 mmol)
sequentially. The resulting solution was stirred at −78 °C
for 45 min. Water (15 mL) was added, and the biphasic mixture was
allowed to warm to rt. The phases were separated, and the aqueous
phase was extracted with dichloromethane (3 × 15 mL). The combined
organic extracts were dried (anhydrous MgSO4), filtered,
and concentrated. The residue was purified by flash chromatography
on silica gel (pet. ether-ethyl acetate, 98:2) to deliver diene 43 (590 mg, 62% over three steps) as a colorless oil. R = 0.28 (pet. ether-ethyl acetate, 98:2); [α]D24 +13.5 (c = 2.13, CHCl3) {Lit.[4] [α]D20 +13 (c = 1.0, CHCl3)}; νmax. 2955, 2938, 2911, 2876, 743, 727 cm–1; 1H NMR (400 MHz, CDCl3) δ 6.45 (1H, ddd, J = 15.2, 11.0, 1.4 Hz), 5.82 (1H, br d, J = 11.0 Hz), 5.54 (1H, dd, J = 15.2, 5.9 Hz), 4.18
(1H, app td, J = 5.9, 1.4 Hz), 3.97 (1H, app ddt, J = 8.2, 7.7, 5.5 Hz), 3.92 (1H, app td, J = 7.3, 5.9 Hz), 3.78–3.62 (2H, m), 1.96 (1H, dddd, J = 11.7, 8.3, 5.5, 3.2 Hz), 1.91–1.79 (2H, m), 1.77
(3H, br s), 1.75 (3H, br s), 1.73–1.61 (2H, m), 1.46 (1H, app
ddt, J = 11.7, 9.8, 8.2 Hz), 0.96 (9H, t, J = 7.9 Hz), 0.95 (9H, t, J = 7.9 Hz),
0.64–0.56 (12H, m); 13C{1H} NMR (101
MHz, CDCl3) δ 135.0, 130.1, 127.6, 124.9, 82.2, 76.8,
75.6, 60.6, 39.2, 32.5, 27.5, 26.1, 18.4, 7.0, 6.9, 5.2, 4.6; HRMS
(ESI+) m/z: [M + Na]+ calcd for C25H50NaO3Si2 477.3191; found 477.3198.
Figure 1
Figure 2
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8