Biomimetic Approach Toward Enterocin and Deoxyenterocin

Article abstract of DOI:10.1021/acs.joc.8b02273

Enterocin (vulgamycin) is a structurally remarkable natural product with significant antibiotic activity. The synthesis of a linear polyketide resembling a biosynthetic precursor was achieved using an unusual acyloin reaction. A diazo group was introduced as a protecting group for an enolizable ketone. We were unable to bring about the envisioned biomimetic aldol addition cascade and gained insights into the feasibility of this process by DFT calculations. As an alternative approach to enterocin, we developed a Cu-catalyzed intramolecular cyclopropanation followed by a MgI₂-induced fragmentation to install the 2-oxabicyclo[3.3.1]nonane core of the natural product.

Full text of DOI:10.1021/acs.joc.8b02273

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Article
A Biomimetic Approach Towards Enterocin and Deoxyenterocin
Antonio Rizzo, Robert Mayer, and Dirk Trauner
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 06 Dec 2018
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A Biomimetic Approach Towards Enterocin and
Deoxyenterocin
Antonio Rizzo,a Robert Mayera and Dirk Traunera,b*
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aDepartment of Chemistry
Ludwig-Maximilians-Universität München
Butenandtstraße 5–13, 81377 München (Germany)
bDepartment of Chemistry, New York University
100 Washington Square East, Room 712
New York, NY 10003
Email: dirktrauner@nyu.edu
Abstract: Enterocin (vulgamycin) is a structurally remarkable natural product with
significant antibiotic activity. The synthesis of a linear polyketide resembling a biosynthetic
precursor was achieved using an unusual acyloin reaction. A diazo group was introduced as
a protecting group for an enolizable ketone. We were unable to bring about the envisioned
biomimetic aldol addition cascade and gained insights into the feasibility of this process by
DFT calculations. As an alternative approach to enterocin, we developed a Cu-catalyzed
intramolecular cyclopropanation followed by a MgI2-induced fragmentation to install the 2-
oxabicyclo[3.3.1]nonane core of the natural product.
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Introduction
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The sheer challenge of synthesizing highly oxygenated natural products has long inspired
and motivated synthetic chemists to push the boundaries of organic synthesis. To this day,
they still represent a strong impetus for the development of effective synthetic strategies and
enabling methodologies. In this regard, (−)-enterocin (1) stands as an unsolved synthetic
problem. In the late 1970s, the Miyairi1a and Seto1b groups independently reported the
isolation of a new polyketide natural product from terrestrial strains of Streptomyces which
they respectively named enterocin (1) and vulgamycin (Figure 1). The relative configuration
of 1 was elucidated by NMR analysis,1b and the absolute configuration was unequivocally
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determined by X-ray crystallographic analysis of a benzoylated derivative (3).1c In 1991,1d
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third isolation of 1 from a different strain of Steptomyces was reported. Shortly thereafter,
Fenical1e reisolated the molecule from a marine ascidian of the genus Didemnum together
with its biosynethetic precursor (−)-deoxyenterocin (2) and minor amounts of enterocin-5-
behenate (5) and enterocin-5-arachidate (6), suggesting their origin from endophytic
microorganisms. Moreover, both 1 and 2 present marked bioactivities as enterocin is a
bacteriostatic antibiotic1a,b and deoxyenterocin exhibits inhibitory activity against the H1N1
influenza virus.1g
Figure 1. Enterocin polyketides; X-ray of derivatized enterocin.1c
Structurally, enterocin (1) provides a daunting challenge for synthesis, featuring a rigid oxa-
protoadamantane2 core adorned with a complicated oxygenation pattern. (Figure 2). This
rare skeleton is found only in a handful of biosynthetically unrelated compounds such as the
trixanolides (7),3a anisatinic acid (8),3b and a few from the annotinolides series (9 and 10),3c
none of which have been prepared by total synthesis. Enterocin’s seven contiguous
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stereocenters are situated on the core. Four of them bear a hydroxy group while the other
two are attached to a benzoyl and an α-pyronyl residue, respectively.
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Figure 2. Oxa-protoadamantane and natural products containing the protoadamantane core.
Despite the considerable challenge provided by 1, only three synthetic studies have been
published to date. In 1986 Khuong-Huu4a demonstrated that the 2-oxabicyclo[3.3.1]nonane
core (11) could be derived from (−)-quinic acid (Figure 3), and in 2017 Bach reported a
convergent strategy to 12 utilizing a Mukaiyama aldol reaction.4b,c More recently, we have
disclosed an ongoing study based on the late-stage functionalization of a bicyclic scaffold
prepared by an intramolecular Cu-mediated Barbier cyclization (13).4d Herein, we wish to
report our initial biomimetic studies towards enterocin, which failed to provide the target
molecule, showed the limits of biomimetic cascade reactions and resulted in pyrone building
blocks4e-g and protecting group strategies that should be useful to the synthetic community.
Figure 3. Synthetic approaches to enterocin (1).
As established by Moore,5 the biosynthetic pathway toward enterocin proceeds via a
Favorskii-like oxidative rearrangement of linear polyketide I and lactonization to II (Scheme
1). The tricyclic core is then formed by a two-fold aldol reaction (III). Inspired by this
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biosythetic proposal, we developed a retrosynthesis of enterocin that relied on two aldol
closures to assemble its bicyclo[3.2.1]octane core. These aldol disconnections were
previously proposed in the synthetic study by Bach et al.4b However, the precursor could not
be obtained, highlighting that, besides the final cyclization, a major challenge lies in the
efficient preparation of a polyhydroxylated substrate with several enolizable carbons. Indeed,
disconnection of the aforementioned bonds unraveled linear, fully functionalized, polyketide-
like intermediate IV. We sought to assemble this biomimetic precursor by the addition of a
pyrone segment onto an aldehyde (V), which in turn could arise from the oxidative cleavage
of a terminal olefin (VI). The resulting chiral triketide fragment was envisioned to be
constructed using an unusual intermolecular acyloin reaction which, to the best of our
knowledge, is unreported in the setting of complex natural product synthesis. Such
disconnection at C2 – C3 greatly simplified the preparation of this linear precursor to known
compounds.
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Scheme 1. Retrosynthetic analysis consisting of two biomimetic aldol reactions and an intramolecular acyloin
reaction.
Results and Discussion
The synthesis commenced with Sharpless asymmetric epoxidation of divinyl carbinol
followed by benzyl protection providing epoxide 12 on a multigram scale with excellent ee
(Scheme 2).6a We were then faced with a seemingly straightforward cyanation of 12, but
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soon found that reported methods were cumbersome on larger scales, requiring excess
amounts of KCN, long reaction times, and providing only moderate regioselectivities.
Therefore, we employed lithium cyanohydrin 13 as an air stable LiCN source.6b This reagent
delivered the cyanide with perfect regioselectivity and allowed for the direct silylation of the
crude mixture to afford nitrile 14, which was then reduced to aldehyde 15 using DIBAL−H.
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Scheme 2. Construction of the central aldehyde 15 with LiOC(Me)2CN (13).
With 15 in hand, we explored the intermolecular acyloin fragment coupling (Scheme 3).7a-c
Using precatalyst 17, hydroxy b-keto ester 18 could indeed be obtained, albeit in low yield.
The mass balance was attributed to dimerization of 15. After adjusting the reaction
stoichiometry, we were able to isolate 18 as a 2:1 mixture of diastereomers at C2 in good
yield. Interestingly, the TMS-protected analogue could be obtained in comparable yield with
an improved 4:1 diastereomeric ratio (see Experimental section and S.I., compound S4).
Although the assignment of the C2 configuration was not possible, these results suggest that
stereocontrol may be imparted by either a chiral catalyst or by introduction of a chiral
auxiliary into ester 16. Such studies were postponed in order to first confirm the feasibility of
the full route.
Scheme 3. Execution of the key NHC mediated acyloin coupling.
After coupling of the first two fragments, we proceeded to treat phosphonate 198 with n-BuLi
and directly added the ozonolysis product of 18 to the resulting stabilized phosphorus ylide
(Scheme 4).9 This one-pot protocol yielded the expected vinyl pyrone 20 in moderate
amounts and with complete (E)-selectivity. This was the first time we reached the full carbon
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count of enterocin (1), but any attempts to functionalize olefin 20, such as hydration,
dihydroxylation or epoxidation, to yield β-keto pyrone 22 were unsuccessful (see Supporting
Information, Table S1). Additionally, all attempts to add a pyrone fragment to aldehyde 21, via
Roskamp reaction10 of diazo-pyrone 23 or by metalation of pyrones 24 or 25, failed (see
Supporting Information, Table S2). Though, compound 23 (X-Ray shown in Scheme 4) could
be a useful building block for a variety of a-pyrone natural products.
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Scheme 4. Attempted fragment coupling to linear precursor 22.
In view of these unsuccessful attempts, we decided to assemble the linear precursor through
an inverted order of events wherein the pyrone was first added to a less functionalized
central fragment followed by acyloin coupling, which was deemed chemoselective enough to
avoid unwanted side-reactions. In order to rapidly test the feasibility of this strategy, we first
pursued the synthesis of a linear precursor that corresponded to (−)-deoxyenterocin (2),
which lacks the C5 hydroxyl (Figure 1). Elaboration of known dithiane 26 (≥ 97% ee)11
delivered multigram quantities of enantioenriched 27 for coupling with pyrone 25 (Scheme
5). Despite the challenges encountered in regioselective deprotonations of pyrones,12
metalation with LDA in Et2O followed by addition of 27 and Dess-Martin oxidation delivered
ketone 28 in moderate, yet reliable yields. Surprisingly, the oxidative cleavage of the terminal
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alkene of 28 proved problematic. Moreover, a variety of dihydroxylation conditions resulted in
complex mixtures and degradation. We presumed that the high acidity of the β-ketopyrone
protons13 interfered with the desired reaction outcome. After experimentation with enol
ethers, acetals and reduced analogues, we devised an unusual protecting group strategy by
diazotization of compound 28.
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Scheme 5. Second generation approach to the construction of a biomimetic precursor.
Pyrone 28 underwent smooth diazotransfer using p-ABSA to yield 29 in quantitative yield.
Following this protection, it was indeed possible to mildly oxidize the terminal alkene of 29 by
OsO4/BAIB to the corresponding aldehyde 30. Thereafter, the chemoselective coupling of α-
ketoester 16 with 30 yielded complete carbon chain precursor 31 as an inseparable mixture
of diastereomers, with each carbon at the correct oxidation state. As we described above in
the case of compounds 18 and S4 (Scheme 3), the diastereomeric ratio at the newly formed
stereocenter is dependent on the protecting group present on the β-hydroxyl to the aldehyde.
The lower yield in comparison to 18 was attributed to the more facile dimerization of the
aldehyde. Removal of the diazo protecting group could then be achieved using n-Bu3SnH
with either irradiation (Rayonet 420 nm)14 or heating with Cu(acac)2 to cleanly deliver 32
(Scheme 6).15 The final debenzylation could be accomplished with BCl3, albeit in moderate
yield. Thus, we have established a diazo group as a methylene protecting group in this
particular context.
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Scheme 6. Mild and orthogonal removal of the masking diazo-group and debenzylation.
With ample material to screen the biomimetic two-fold aldol/lactonization, pyrone 33 was
subjected to a variety of amine bases and organocatalysts (Table 1, entry 1-4). No productive
reaction occurred under these conditions.
Entry
1
Conditions
L-Proline
Result
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Schreiner's thiourea
Takemoto’s catalyst
LiCl, DBU
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LDA
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Zn(OTf)2
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S.M. + Decomp.
S.M.
10% HCl(aq.), D
TiCl4, n-Bu3N
Hg(ClO4)2•3H2O
p-TSA, toluene, D
CeCl3, AcOH, D
CaN(Tf)2, D
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S.M.
34 / 35
34 / 35
34 / 35
Table 1. Representative conditions screened for the bioinspired aldol cascade. For a complete list see Supporting
Information, Table S3.
Stronger bases such as t-BuOK, DBU or LDA led to complete degradation of 33 (entry 5-7).
Use of Lewis acids was also fruitless,16a-d although under the influence of CeCl3, CaN(Tf)2 or
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p-TSA, the formation of traces of two diastereomeric dihydro-3(2H)-furanone adducts (34 /
35) was observed (entry 12-14).16a,b These products presumably arise from the elimination of
the tertiary hydroxyl group and subsequent intramolecular oxa-Michael addition (Scheme 7).
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Scheme 7. Efforts to enact the biomimetic ring-closure led to the isolation of traces of dihydro-3(2H)-furanones 34
/ 35.
We have also studied the proposed cyclization of 33 to 2 in silico (Scheme 8) employing DFT
calculations at the B3LYP-D3/6-311++G(3df,2pd) // B3LYP-D3/6-31G(d,p) level of theory in
aqueous solution.17 These calculations revealed that cyclization of 33 to deoxyenterocin (2) is
energetically disfavored by +39 kJ/mol, with the final transesterification to the natural product
being the only energetically favorable step in the entire process. In agreement with our
experimental results, the cyclization to dihydro-3(2H)-furanones 34 and 35 was found to be
significantly exergonic (−32 and −39 kJ/mol) and therefore constitutes the thermodynamic
minimum of the whole sequence. While these calculations do not provide information on the
kinetic preference of formation of 34 and 35 vs 2, they do provide a rational for the absence
of formation of 2. Due to the level of endergonicity (+39.3 kJ/mol) of its formation, one would
require the latter to be an irreversible process, leading to a rate-determining step over 120
kJ/mol - an infeasible process under the reaction conditions.
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Scheme 8. Gibbs energy profile for cyclization to 2 and furanones 34 and 35 from linear precursor 33 as
calculated at the B3LYP-D3/6-311++G(3df,2pd) // B3LYP-D3/6-31G(d,p) level of theory in aqueous solution.
Due to the inability to effect the biomimetic cascade, we began to explore the diazo group in
C−H insertions. As the deprotection with tin hydride is a controlled insertion into a Sn−H
bond, we surmised that the diazo group might also undergo a productive C−H insertion with
an appropriate catalyst. Although challenging, an analysis of the scaffold’s electronics
suggested that such a closure may be possible (Scheme 9). The formation of a four-
membered ring was deemed unlikely due to lactone deactivation, whereas the lower electron
density of C5 over C6 could disfavor closure to a cyclopentane. Therefore, proceeding from
compound 36,4d we selectively executed an allylic oxidation of the ether bridge in the
presence of the α-diazo group using PCC.18 Notably, oxidation attempts on an unprotected
substrate were ineffective. Subsequent dihydroxylation19 stereoselectively delivered diol 37
and, after treatment with 2,2-DMP, acetonide 38 was isolated. We speculated that use of
acetonide 38 may suppress undesired retro-aldol reactivity. This sequence advanced us to
two possible substrates to enact the carbenoid insertion. Additionally, we prepared desoxo 39
to serve as a stereoelectronically differentiated substrate. Notably, the unoptimized yields of
this sequence demonstrate that in principle the diazo group is stable under certain acidic and
oxidative conditions.
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Scheme 9. Construction of diazo compounds for intramolecular C−H insertion.
Several commercially available Rh- and Cu-based catalysts were subjected to the diazo
substrates by reverse addition, but in all cases decomposition ensued (Scheme 9, see
Supporting Information for a complete list of the screened catalysts, Table S4). This
recalcitrance toward bicycle construction by C−H insertion led us to explore a more reactive
partner for the diazo group. As olefins show high rates for carbenoid addition20 we decided to
use compound 36 as a platform to explore this possibility and, after cyclization, implement a
late-stage functionalization strategy (Scheme 10).
Scheme 10. Design considerations for 2-oxabicyclo[3.3.1]nonane synthesis by cyclopropanation and its execution
and fragmentation.
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Thus, compound 36 was subjected to Rh- and Cu-based catalysts to induce an
intramolecular cyclopropanation to compound 43. Eventually, only Cu(TBS)2,21 as
popularized by Corey,22 proved capable of cleanly delivering the tricyclic adduct in good yield,
forging the 2-oxabicyclo[3.3.1]nonane scaffold for the first time. After considerable
optimization (see Supporting Information, Table S5), freshly prepared MgI2 was found to
afford enol ether 44 in moderate yield.23 This compound proved to be stable enough to be
isolated, but decomposed under a variety of conditions. Attempts to dihydroxylate, epoxidize
or ring-open the enol ether were met with failure, possibly due to the juxtaposition of the
acidic α-pyrone proton and the endocyclic enol ether.
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In conclusion, we report two synthetic approaches to (−)-enterocin (1) and (−)-
deoxyenterocin (2). The first bioinspired strategy comprised the synthesis of a linear
precursor which upon double aldol cyclization would form the congested framework of the
enterocins. This work introduced the diazo group as a useful protecting group for acidic
methylene protons and proved the viability of an intermolecular acyloin reaction. The final
cyclization cascade could not be realized under a variety of conditions. We provided a
rationalization of such result by performing DFT calculations that support the endergonic
nature of this process.
In a second approach, we elected to use the diazo protecting group as part of a metal
carbenoid insertion strategy to bypass the elusive aldol reactivity. Although a C-H insertion
could not be executed, a Cu-catalyzed intramolecular cyclopropanation proved capable of
constructing the 2-oxabicyclo[3.3.1]nonane bicyclic structure of enterocin. The results
presented herein motivate, and perhaps necessitate, a late-stage functionalization strategy to
reach enterocin.
Experimental Section
Magnetic stirring was applied to all the reactions. If air or moisture sensitive, the reactions
were carried out under nitrogen atmosphere using standard Schlenk techniques in oven-
dried glassware (150 °C oven temperature) and then further dried under vacuum with a heat-
gun at 500 °C. All reaction temperatures were recorded using an external thermometer
placed into the baths. Reactions under cryogenic conditions were carried out in a Dewar
vessel filled with acetone/dry ice (–78 °C to –10 °C) or distilled water/ice (0 °C). High
temperature reactions were conducted using a heated silicon oil bath in reaction vessels
equipped with a reflux condenser or in a pressure tube. Tetrahydrofuran (THF) and diethyl
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ether (Et2O) were distilled over sodium and benzophenone prior to use. Dichloromethane
(CH2Cl2), triethylamine (Et3N) and diisopropylethylamine (DIPEA) were distilled over calcium
hydride under a nitrogen atmosphere. All other solvents were purchased from Acros Organics
as ‘extra dry’ reagents. All other reagents with a purity > 95% were obtained from commercial
sources (Sigma Aldrich, Acros, TCI, Chempur, Alfa Aesar) and used without further
purification. Flash column chromatography was performed with Merck silica gel 60 (0.040-
0.063 mm). For thin layer chromatography (TLC) Merck silica gel 60 F254 glassbacked
plates were used. Visualization was done under UV light at 254 nm. Ceric ammonium
molybdate (CAM), p-anisaldehyde (PAA) and potassium permanganate (KMnO4) solutions
were used as stains and subsequent heating was used to visualize the result. High
resolution mass spectra (HRMS) were recorded using a Finnigan MAT 95 instrument by
electron impact ([EI] double-focusing magnetic sector mass spectrometer) or a Thermo
Finnigan LTQ FT Ultra Fourier Transform Ion Cyclotron Resonance spectrometer using
electrospray ionization (ESI). Infrared spectra (IR) were recorded from 4000 cm−1 to
600 cm−1 on a PERKIN ELMER Spectrum BX II, FT-IR instrument. Detection: SMITHS
DETECTION DuraSamplIR II Diamond ATR sensor. The frequencies of absorption (cm−1)
data are reported. NMR spectra (1H NMR, 13C{1H} NMR and 31P{1H} NMR) were recorded in
deuterated chloroform (CDCl3), benzene (C6D6) or methanol (CD3OD) on a Bruker Avance III
HD 400 MHz spectrometer, a Varian VXR400 S spectrometer, a Varian 600 spectrometer or a
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Bruker Avance III HD 800 MHz spectrometer. H NMR spectra are reported as follows: δ
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(chemical shift) in ppm (multiplicity, coupling constant J in Hz, number of protons). C NMR
spectra are reported as follows: δ (chemical shift) in ppm. Multiplicities abbreviations are
reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, br = broad,
m = multiplet, or combinations thereof. For internal reference the residual solvent peaks of
CDCl3 (δH = 7.26 ppm, δC = 77.16 ppm), C6D6 (δH = 7.16 ppm, δC = 128.06 ppm) and CD3OD
(δH = 4.87 ppm, δC = 49.00 ppm) were used. Two dimensional NMR data (COSY, HMBC,
HSQC and NOESY experiments) were used for assignment. Optical rotation values were
recorded on an Anton Paar MCP 200 polarimeter. Specific rotation:
= (α × 100) / (c ×
d). Wavelength (λ) is reported in nm. Temperature (T) is reported in °C. Recorded optical
rotation is α. Concentration c is in 1 g/100 mL and length of the cuvette (d) is in dm. Specific
rotation: 10−1·deg·cm2·g−1. Sodium D line (λ = 589 nm) is indicated by D. X-ray diffraction
analysis was carried out by Dr. Peter Mayer (Ludwig-Maximilians-Universität München). The
data collections were done on a Bruker D8 Venture using Mo Kα-radiation (λ = 0.71073 Å,
graphite monochromator). For all systems, geometry optimizations and frequency
calculations were performed at the B3LYP/6-31G(d,p) level of theory with the IEFPCM
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solvation model for water and Grimme’s D3 dispersion correction with the Gaussian set of
codes (for details and references see the SI). Enthalpy corrections obtained with B3LYP/6-
31G(d,p) were subsequently combined with single point energies of the optimized structures
at the B3LYP-D3/6-311++G(3df,2pd) (IEFPCM=water) level. A free energy correction +1.89
kcal/mol was applied to all free energies to consider the conversion from gas phase (1 atm)
to liquid phase (1 M).
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Epoxide (S1). A flame dried flask under argon was charged with oven dried 4 Å MS (4.5 g)
and dry CH2Cl2 (124 mL). Then, the reaction vessel was cooled to −20 °C and (+)-DIPT
(2.25 mL, 10.7 mmol, 0.18 eq.) and freshly distilled Ti(i-PrO)4 (2.80 mL, 9.50 mmol, 0.16 eq.)
were added to the mixture. Subsequently, TBHP (21.6 mL, 118.8 mmol, 2.0 eq., 5.5 M in
decane over 4 Å MS) was added dropwise and the reaction was stirred for 15 minutes. Then,
neat divinylcarbinol (5.00 g, 59.4 mmol, 1.0 eq.) was added and a sudden color change to
orange was observed. The reaction was placed in a −25 °C freezer for 7 days. Subsequently,
the reaction was diluted with a mixture of acetone (100 mL), H2O (10 mL) and citric acid
monohydrate (1.26 g). The reaction was stirred at RT for 1 h. Afterwards, the solution was
filtered over celite, the filtrate was extracted three times with Et2O, the combined organic
fractions were washed with brine, dried over MgSO4, filtered and the solvent was removed
under reduced pressure. The crude product was purified by FCC (Et2O/pent 1:2) to afford
epoxide S1 (4.36 g, 43.6 mmol, 73%) as a colorless oil.
Rf: 0.3, EtOAc/i-hex 4:6, CAM, no UV.
: +63.0 (c = 1.5, CHCl3). Literature:
:
+57.3 (c = 0.96, CHCl3).24c 1H NMR (400 MHz, CDCl3) δ = 5.85 (ddd, J = 17.0, 10.5, 6.3 Hz,
1H), 5.41 (dt, J = 17.2, 1.3 Hz, 1H), 5.28 (dt, J = 10.4, 1.2 Hz, 1H), 4.38 – 4.35 (m, 1H), 3.12
– 3.10 (m, 1H), 2.82 (dd, J = 5.0, 2.8 Hz, 1H), 2.77 (dd, J = 5.0, 4.0 Hz, 1H). C{1H} NMR
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(101 MHz, CDCl3) δ = 135.5, 117.9, 70.2, 54.0, 43.6. IR (ATR, neat): nmax = 3398 (b), 3082
(w), 2992 (w), 2875 (w), 1645 (w), 1427 (m), 1251 (s) 1026 (m), 993 (m), 930 (s), 885 (s),
833 (m) cm−1. HRMS-EI (m/z): calc. for C5H7O2 [M−H]•+: 99.0441; found: 99.0440.
Benzyl ether (12). A flame dried flask under argon was sequentially charged with S1 (3.43 g,
34.3 mmol, 1.0 eq.), dry THF (80 mL), BnBr (4.89 mL, 41.1 mmol, 1.2 eq.) and TBAI (1.26 g,
3.43 mmol, 0.1 eq.). The reaction vessel was cooled to −20 °C. Then, NaH (1.5 g,
37.5 mmol, 1.1 eq., 60% dispersion in mineral oil) was added to the suspension and the
reaction was stirred for 10 minutes. Afterwards, the cooling bath was removed and the
reaction was monitored by TLC until completion (ca. 5 h). Then, the reaction was quenched
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by addition of sat. NH4Cl(aq.). The aqueous phase was extracted three times with Et2O, the
combined organic fractions were washed with brine, dried over MgSO4, filtered and the
solvent was removed under reduced pressure. The crude product was purified by FCC
(Et2O/pent 5:95) to afford benzylether 12 (5.87 g, 30.9 mmol, 90%) as a colorless oil.
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Rf: 0.8, Et2O/pent 1:2, CAM, no UV.
: +35.9 (c = 0.9, CHCl3). Literature:
+35.3
(c = 0.93, CHCl3).24c 1H NMR (400 MHz, CDCl3) δ = 7.37 – 7.27 (m, 5H), 5.87 – 5.79 (m, 1H),
5.38 – 5.33 (m, 2H), 4.64 (d, J = 11.9 Hz, 1H), 4.47 (d, J = 11.9 Hz, 1H), 3.81 (ddt, J = 7.4,
4.2, 1.0 Hz, 1H), 3.09 (td, J = 4.1, 2.6 Hz, 1H), 2.78 (dd, J = 5.2, 4.0 Hz, 1H), 2.69 (dd, J =
5.2, 2.6 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ = 138.2, 134.6, 128.5, 127.8, 127.8,
119.8, 79.5, 70.8, 53.4, 45.0. IR (ATR, neat): nmax = 3064 (w), 2990 (w), 2863 (w), 1644 (w),
1606 (w), 1496 (w), 1454 (m), 1251 (w), 1065 (s), 932 (m), 882 (m), 735 (s), 697 (s) cm−1.
HRMS-EI (m/z): calc. for C10H11 [M−C2H3O2]•+: 131.0855; found: 131.0855.
Nitrile (14). A flame dried flask under argon, equipped with a reflux condenser, was charged
sequentially with 12 (1.00 g, 5.26 mmol, 1.0 eq.), dry THF (60 mL), Li-cyanohydrin 13 (1.05 g,
11.5 mmol, 2.2 eq.) and the reaction vessel was heated to 60 °C. The reaction was monitored
by TLC until completion (ca. 1.5 h). Then, the reaction was cooled to RT, the solvent was
removed under reduced pressure and the residue partitioned between H2O and Et2O. The
aqueous phase was extracted three times with Et2O, the combined organic fractions were
washed with brine, dried over MgSO4, filtered and the solvent was removed under reduced
pressure. The crude alcohol was used in the next step without further purification. Rf: 0.2, i-
hex:EtOAc 8:2, CAM, UV.
A flame dried flask under argon was charged sequentially with the crude alcohol, dry CH2Cl2
(60 mL), 2,6-lutidine (1.60 mL, 13.8 mmol, 2.6 eq.) and the reaction vessel was cooled to
0 °C. Neat TBSOTf (1.44 mL, 6.27 mmol, 1.2 eq.) was added dropwise and the reaction was
stirred for 10 minutes at the same temperature. Then, the cooling bath was removed and the
reaction was monitored by TLC until completion (ca. 3 h). Afterwards, the reaction was
quenched by addition of sat. NaHCO3(aq). The aqueous phase was extracted three times with
EtOAc, the combined organic fractions were washed with brine, dried over MgSO4, filtered
and the solvent was removed under reduced pressure. The crude product was purified by
FCC (EtOAc/i-hex 1:9) to afford 14 (1.57 g, 4.75 mmol, 90%) as a yellow oil.
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Rf: 0.7, i-hex:EtOAc 8:2, CAM, PAA (yellow), UV.
: +15.7 (c = 0.7, CHCl3). H NMR
(400 MHz, CDCl3) δ = 7.37 – 7.28 (m, 5H), 5.75 (ddd, J = 17.6, 10.5, 7.5 Hz, 1H), 5.42 – 5.36
(m, 2H), 4.61 (d, J = 11.5 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 3.90 (q, J = 5.4 Hz, 1H), 3.80 (t,
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J = 6.7 Hz, 1H), 2.72 (dd, J = 16.7, 5.5 Hz, 1H), 2.51 (dd, J = 16.7, 4.4 Hz, 1H), 0.89 (s, 9H),
0.11 (s, 3H), 0.05 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ = 138.0, 135.1, 128.6, 128.1,
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127.9, 120.8, 118.0, 82.7, 71.1, 70.8, 25.9, 23.2, 18.1, −4.2, −4.6. IR (ATR, neat): nmax
=
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3067 (w), 3032 (w), 2929 (w), 2857 (w), 1471 (w), 1414 (w), 1252 (s), 1108 (s), 994 (m), 924
(m), 836 (s), 777 (s), 697 (m) cm−1. HRMS-ESI (m/z): calc. for C19H33N2O2Si [M+NH4]+:
349.2306; found: 349.2306.
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Aldehyde (15). A flame dried flask under argon charged with nitrile 14 (2.07 g, 6.24 mmol,
1.0 eq.) and dry toluene (65 mL) was cooled to −50 °C. A solution of DIBAL-H (9.39 mL,
9.39 mmol, 1.5 eq., 1 M in toluene) was added in a single aliquot and the reaction was
monitored by TLC until completion (ca. 3 h). Afterwards, the reaction was quenched by
addition of EtOH, allowed to warm to RT, a sat. solution of Rochelle’s salt was added under
vigorous stirring and the mixture stirred for 30 minutes. Then, the aqueous phase was
extracted three times with Et2O, the combined organic fractions were washed with brine,
dried with MgSO4, filtered and the solvent was removed under reduced pressure. The crude
product was purified by FCC (EtOAc/i-hex 5:95) to afford aldehyde 15 (1.67 g, 4.99 mmol,
80%) as a yellow oil.
Rf: 0.5, i-hex:EtOAc 8:2, CAM, PAA (blue), UV.
: +20.0 (c = 0.1, CHCl3). 1H NMR (400
MHz, CDCl3) δ = 9.78 (t, J = 2.5 Hz, 1H), 7.36 – 7.27 (m, 5H), 5.76 (ddd, J = 17.6, 10.4, 7.5
Hz, 1H), 5.37 – 5.28 (m, 2H), 4.59 (d, J = 11.8 Hz, 1H), 4.39 (d, J = 11.7 Hz, 1H), 4.21 (q, J =
5.5 Hz, 1H), 3.73 (dd, J = 7.5, 5.1 Hz, 1H), 2.65 (ddd, J = 15.9, 5.7, 2.5 Hz, 1H), 2.53 (ddd, J
= 15.9, 5.6, 2.4 Hz, 1H), 0.85 (s, 9H), 0.05 (d, J = 2.4 Hz, 6H). 13C{1H} NMR (101 MHz,
CDCl3) δ = 201.6, 138.2, 135.6, 128.5, 128.0, 127.7, 120.0, 83.8, 71.0, 70.8, 48.2, 25.9,
18.2, −4.1, −4.6. IR (ATR, neat): nmax = 2928 (m), 2856 (m), 1724 (s), 1472 (w), 1252 (s),
1103 (s), 836 (s), 777 (s), 698 (m) cm−1. HRMS-ESI (m/z): calc. for C19H34NO3Si [M+NH4]+:
352.2302; found: 352.2303.
Acyloin (18). A flame dried flask under argon was charged with oven dried 4 Å MS (0.2 g), α-
ketoester 16 (0.74 g, 3.60 mmol, 6.0 eq.) and pre-catalyst 17 (0.02 g, 0.06 mmol,
0.2 eq.).Then, a solution of aldehyde 15 (0.2 g, 0.60 mmol, 1.0 eq.) in dry CH2Cl2 (5 mL +
1 mL to rinse) was added and the mixture was stirred for 5 minutes. Subsequently, dry DIPEA
(0.11 mL, 0.65 mmol, 1.0 eq.) was added and the solution turned yellow. The reaction was
monitored by TLC until completion (ca. 4 h). The reaction mixture was eluted directly with
EtOAc over a silica pad and the solvent removed under reduced pressure. The crude product
was purified by FCC (EtOAc/i-hex 8:2, long column) to afford acyloin 18 (0.2 g, 0.37 mmol,
61%, 1.9:1 d.r.) as an amorphous yellow solid.
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Rf: 0.6, i-hex:EtOAc 8:2, CAM, PAA (blue), UV. H NMR (400 MHz, CDCl3, * denotes minor
diastereomer) δ = 7.90 – 7.85 (m, 2H+2H*), 7.61 – 7.57 (m, 1H+1H*), 7.45 (t, J = 7.7 Hz,
2H+2H*), 7.32 (d, J = 4.2 Hz, 5H+5H*), 5.80 (dddd, J = 17.8, 10.3, 7.6, 2.3 Hz, 1H+1H*),
5.40 – 5.16 (m, 2H+2H*), 4.58 (dd, J = 11.8, 5.2 Hz, 1H+1H*), 4.43 – 4.37 (m, 2H+2H*), 3.88
(dd, J = 18.0, 7.8 Hz, 1H+1H*), 3.75 (d, J = 4.4 Hz, 3H+3H*), 3.70 (dd, J = 7.8, 4.0 Hz,
1H+1H*), 3.56 (dd, J = 18.0, 3.3 Hz, 1H+1H*), 3.13 (dd, J = 18.1, 6.6 Hz, 1H), 3.05 (dd, J =
18.6, 4.4 Hz, 1H*), 2.84 (dd, J = 18.6, 6.9 Hz, 1H*), 2.75 (dd, J = 18.1, 5.0 Hz, 1H), 0.83 (d, J
= 9.3 Hz, 9H+9H*), 0.07 – 0.03 (m, 6H+6H*). 13C{1H} NMR (101 MHz, CDCl3) δ = 204.3,
197.7, 197.5, 170.8, 138.6, 136.18, 136.15, 135.4, 134.0, 128.8, 128.39, 128.37, 127.90,
127.86, 127.53, 127.50, 119.9, 119.7, 84.2, 83.9, 82.6, 82.5, 70.5, 70.2, 70.0, 53.8, 53.7,
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44.3, 44.0, 42.1, 42.0, 26.1, 26.0, 18.3, 18.3, −4.2, −4.2, −4.7, −4.8. IR (ATR, neat): nmax
=
3490 (bw), 3066 (w), 2928 (w), 2855 (w), 1746 (m), 1724 (s), 1686 (m), 1358 (m), 1249 (m),
1216 (s), 1091 (s), 832 (s), 777 (s), 688 (m) cm−1. HRMS-ESI (m/z): calc. for C30H44NO7Si
[M+NH4]+: 558.2882; Found: 558.2885.
Nitrile (S2). A flame dried flask under argon, equipped with a reflux condenser, was charged
sequentially with 12 (1.00 g, 5.26 mmol, 1.0 eq.), dry THF (60 mL), Li-cyanohydrin 13 (1.05 g,
11.5 mmol, 2.2 eq.) and the reaction vessel was heated to 60 °C. The reaction was monitored
by TLC until completion (ca. 1.5 h). Then, the reaction was cooled to RT, the solvent was
removed under reduced pressure and the residue partitioned between H2O and Et2O. The
aqueous phase was extracted three times with Et2O, the combined organic fractions were
washed with brine, dried over MgSO4, filtered and the solvent was removed under reduced
pressure. The crude alcohol was used in the next step without further purification. Rf: 0.2, i-
hex:EtOAc 8:2, CAM, UV.
A flame dried flask under argon was charged sequentially with the crude alcohol, dry CH2Cl2
(60 mL), 2,6-lutidine (1.60 mL, 13.8 mmol, 2.6 eq.) and the reaction vessel was cooled to 0
°C. Neat TMSOTf (1.14 mL, 6.30 mmol, 1.2 eq.) was added dropwise and the reaction was
stirred for 10 minutes at the same temperature. Then, the cooling bath was removed and the
reaction was monitored by TLC until completion (ca. 3 h). Afterwards, the reaction was
quenched by addition of sat. NaHCO3(aq). The aqueous phase was extracted three times with
EtOAc, the combined organic fractions were washed with brine, dried over MgSO4, filtered
and the solvent was removed under reduced pressure. The crude product was purified by
FCC (EtOAc/i-hex 5:95) to afford S2 (1.37 g, 4.73 mmol, 90%) as a yellow oil.
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: +30.8 (c = 0.5, CHCl3). H NMR
(400 MHz, CDCl3) δ = 7.37 – 7.28 (m, 5H), 5.73 (ddd, J = 17.5, 10.4, 7.4 Hz, 1H), 5.42 – 5.35
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(m, 2H), 4.62 (d, J = 11.6 Hz, 1H), 4.38 (d, J = 11.6 Hz, 1H), 3.91 (td, J = 6.2, 4.7 Hz, 1H),
3.72 (t, J = 6.9 Hz, 1H), 2.65 – 2.56 (m, 2H), 0.12 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ
= 137.9, 135.1, 128.6, 128.1, 128.0, 120.8, 118.3, 82.6, 71.0, 70.9, 23.4, 0.5. IR (ATR, neat):
nmax = 3066 (w), 3032 (w), 2957 (w), 2897 (w), 1454 (w), 1415 (w), 1250 (s), 1107 (s), 994
(w), 925 (m), 839 (s), 749 (m), 697 (m) cm−1. HRMS-EI (m/z): calc. for C16H23NO2Si [M]+•:
289.1493; found: 289.1495.
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Aldehyde (S3). A flame dried flask under argon charged with S2 (1.37 g, 4.73 mmol, 1.0 eq.)
dry toluene (40 mL) was cooled to −50 °C. A solution of DIBAL-H (6.65 mL, 6.65 mmol,
1.4 eq., 1 M in toluene) was added in a single aliquot and the reaction was monitored by TLC
until completion (ca. 3 h). Afterwards, the reaction was quenched by addition of EtOH,
allowed to warm to RT, a sat. solution of Rochelle’s salt was added under vigorous stirring
and the mixture stirred for 30 minutes. Then, the aqueous phase was extracted three times
with Et2O, the combined organic fractions were washed with brine, dried over MgSO4, filtered
and the solvent was removed under reduced pressure. The crude product was purified by
FCC (EtOAc/i-hex 5:95) to afford aldehyde S3 (0.94 g, 3.21 mmol, 68%) as a yellow oil.
Rf: 0.7, i-hex:EtOAc 8:2, CAM, PAA (blue), UV.
: +39.8 (c = 1.0, CHCl3). 1H NMR (400
MHz, CDCl3) δ = 9.76 (t, J = 2.3 Hz, 1H), 7.36 – 7.28 (m, 5H), 5.76 (ddd, J = 17.6, 10.4, 7.6
Hz, 1H), 5.39 – 5.28 (m, 2H), 4.61 (d, J = 11.8 Hz, 1H), 4.37 (d, J = 11.8 Hz, 1H), 4.22 (q, J =
5.9 Hz, 1H), 3.68 (dd, J = 7.5, 5.5 Hz, 1H), 2.67 – 2.55 (m, 2H), 0.09 (s, 6H). C{1H} NMR
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(101 MHz, CDCl3) δ = 201.5, 138.1, 135.6, 128.5, 128.1, 127.8, 120.1, 83.5, 70.6, 70.6, 48.2,
0.5. IR (ATR, neat): nmax = 3066 (w), 2956 (w), 2724 (w), 1724 (s), 1454 (w), 1249 (s), 1091
(bs), 995 (m), 838 (s), 748 (s), 697 (s) cm−1. HRMS-EI (m/z): calc. for C15H21O3Si [M−CH3]+•:
277.1254; found: 277.1264.
Acyloin (S4). A flame dried flask under argon was charged with oven dried 4 Å MS (0.3 g), α-
ketoester 16 (0.63 g, 3.06 mmol, 3.0 eq.) and pre-catalyst 17 (0.04 g, 0.1 mmol, 0.1 eq.).
Then, a solution of aldehyde S3 (0.3 g, 1.03 mmol, 1 eq.) in dry CH2Cl2 (18 mL + 2 ml to
rinse) was added and the mixture stirred for 5 minutes. Subsequently, dry DIPEA (0.18 mL,
1.06 mmol, 1.0 eq.) was added and the solution turned yellow. The reaction was monitored
by TLC until completion (ca. 6 h). The reaction mixture was eluted directly with EtOAc over a
silica pad and the solvent was removed under reduced pressure. The crude product was
purified by FCC (EtOAc/i-hex 8:2, long column) to afford acyloin S4 (0.27 g, 0.54 mmol, 54%,
4:1 d.r.) as colorless oil.
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Rf: 0.7, i-hex:EtOAc 7:3, CAM, UV. 1H NMR (400 MHz, CDCl3, * denotes minor diastereomer)
δ = 7.92 – 7.88 (m, 2H+2H*), 7.59 (t, J = 7.4 Hz, 1H+1H*), 7.46 (t, J = 7.6 Hz, 2H+2H*), 7.32
(d, J = 4.1 Hz, 5H+5H*), 5.78 (ddd, J = 17.7, 10.4, 7.7 Hz, 1H+1H*), 5.37 – 5.25 (m,
2H+2H*), 4.62 – 4.52 (m, 2H+2H*), 4.40 – 4.30 (m, 2H+2H*), 3.89 (dd, J = 17.9, 13.5 Hz,
1H+1H*), 3.77 (d, J = 2.5 Hz, 3H+3H*), 3.66 (dd, J = 7.7, 5.1 Hz, 1H+1H*), 3.60 (d, J = 17.8
Hz, 1H+1H*), 3.19 – 3.11 (m, 1H), 3.04 (dd, J = 18.3, 3.4 Hz, 1H*), 2.90 (dd, J = 18.2, 8.3 Hz,
1H*), 2.77 (dd, J = 17.7, 3.6 Hz, 1H), 0.09 (s, 9H), 0.07 (s, 9H*). 13C{1H} NMR (101 MHz,
CDCl3) δ = 204.6, 204.5, 197.5, 197.3, 171.3, 170.73, 170.67, 138.5, 136.2, 135.6, 135.5,
133.98, 133.95, 128.9, 128.43, 128.37, 127.9, 127.6, 120.0, 119.9, 83.6, 83.5, 82.6, 82.5,
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77.4, 70.5, 60.6, 53.8, 53.7, 44.2, 43.8, 42.1, 41.8, 21.2, 14.4, 0.6, 0.5. IR (ATR, neat): nmax
=
3485 (bw), 3066 (w), 2955 (w), 2903 (w), 1745 (m), 1723 (s), 1685 (m), 1597 (w), 1449 (m),
1354 (m), 1247 (s), 1216 (s), 1089 (s), 1070 (s), 1001 (m), 929 (m), 839 (s), 753 (s), 688 (s)
cm−1. HRMS-ESI (m/z): calc. for C27H38NO7Si [M+NH4]+: 516.2412; found: 516.2409.
Bromo-pyrone (24). A flask was charged with 4-hydroxy-6-methyl-2-pyrone (1.00 g,
7.93 mmol, 1.0 eq.), CCl4 (165 mL), NBS (1.39 g, 7.90 mmol, 1.0 eq.), AIBN (0.12 g,
0.73 mmol, 0.1 eq.). The mixture was stirred at 80 °C and illuminated with a 160 W
floodlamp. The mixture was monitored by TLC until completion (ca. 1 h). Afterwards, the
solvent was distilled under reduced pressure and the crude product was purified by FCC
(EtOAc/i-hex 4:6) to afford 24 (0.92 g, 4.20 mmol, 53%) as a yellow solid.25
Rf: 0.4, i-hex:EtOAc 1:1, CAM, UV. 1H NMR (400 MHz, CDCl3) δ = 6.09 (s, 1H), 5.49 (s, 1H),
4.11 (s, 2H), 3.82 (s, 3H).13C{1H} NMR (101 MHz, CDCl3) δ = 170.5, 163.6, 158.7, 102.4,
89.7, 56.3, 26.7. IR (ATR, neat): nmax = 3032 (w), 1703 (s), 1649 (s), 1565 (s), 1459 (m), 1411
(m), 1333 (w), 1254 (s), 1149 (m), 942 (m), 815 (s) cm−1. HRMS-ESI (m/z): calc. for
C7H8BrO3 [M+H]+: 218.9651; found: 218.9651.
Phosphonate (19). A flask equipped with a reflux condenser was charged with 24 (0.20 g,
0.91 mmol, 1.0 eq.) and P(OMe)3 (0.2 mL, 1.70 mmol, 1.9 eq.) at RT. Then, the reaction was
heated to 60 °C and was monitored by TLC until completion (ca. 5 h). Afterwards, the
reaction was directly purified by FCC (EtOAc/i-hex 2:1 then MeOH/EtOAc 4:96) to afford
phosphonate 19 (0.26 g, 0.92 mmol, quant.) as a white solid.26
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Rf: 0.3, MeOH:EtOAc 4:96, KMnO4, UV. H NMR (400 MHz, CDCl3) δ = 6.01 (t, J = 2.9 Hz,
1H), 5.45 (d, J = 2.1 Hz, 1H), 3.82 (s, 3H), 3.80 (d, J = 3.2 Hz, 6H), 3.04 (d, J = 22.0 Hz, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ = 171.0, 164.1, 155.8, 102.9, 88.5, 56.1, 53.4, 32.2, 30.8.
31P NMR (162 MHz, CDCl3) δ = 23.42. IR (ATR, neat): nmax = 3085 (w), 2957 (w), 2916 (w),
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1721 (s), 1650 (s), 1565 (s), 1414 (m), 1242 (s), 1183 (m), 1022 (s), 938 (m), 843 (s), 792 (s),
693 (m) cm−1. HRMS-EI (m/z): calc. for C9H13O6P [M]+•: 248.0444; found: 248.0445.
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Alkene (20). A flame dried flask under argon was charged with acyloin 18 (0.020 g,
0.037 mmol, 1.0 eq.), pyridine (12 µL, 0.15 mmol, 4.0 eq.) and dry CH2Cl2 (0.55 mL). Then
the mixture was cooled to −78 °C. A stream of ozone was passed through the reaction for
160 seconds and then the solution was purged with a N2 stream. The reaction was monitored
by TLC for completion. The solution was cannulated directly into the following reaction. Rf:
0.7, i-hex:EtOAc 7:3, CAM, UV.
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A flame dried flask under argon was charged with phosphonate 19 (0.01 g, 0.04 mmol,
1.1 eq.), dry THF (0.40 mL) and cooled to −78 °C. A solution of n-BuLi (0.04 mL, 0.04 mmol,
1.15 eq, 1 M in hexanes) was added and the reaction was stirred for 30 minutes. Then, the
solution of ozonolyzed 18 was cannulated into the mixture, stirred at the same temperature
for 1 h and then the cooling bath was removed. The reaction was monitored by TLC until
completion (ca. 2 h). Afterwards, the reaction was quenched by addition of sat. NH4Cl(aq.), the
aqueous phase was extracted three times with EtOAc, the combined organic fractions were
washed with brine, dried over Na2SO4, filtered and the solvent was removed under reduced
pressure. The crude product was purified by FCC (EtOAc/i-hex 4:6) to afford alkene 20
(6.30 mg, 0.0095 mmol, 26%) as a yellow oil.
Rf: 0.6, i-hex:EtOAc 1:1, CAM, UV. 1H NMR (400 MHz, CDCl3, * denotes minor diastereomer)
δ = 7.89 – 7.84 (m, 2H+2H*), 7.59 (t, J = 7.0 Hz, 1H+1H*), 7.45 (t, J = 7.6 Hz, 2H+2H*), 7.34
– 7.32 (m, 5H+5H*), 6.61 (ddd, J = 15.7, 6.4, 4.0 Hz, 1H+1H*), 6.19 (dd, J = 15.7, 11.0 Hz,
1H+1H*), 5.85 (dd, J = 9.0, 2.1 Hz, 1H+1H*), 5.48 (d, J = 2.6 Hz, 1H+1H*), 4.58 (q, J = 5.3
Hz, 2H+2H*), 4.54 – 4.46 (m, 1H+1H*), 4.46 – 4.36 (m, 1H+1H*), 4.04 – 3.96 (m, 1H+1H*),
3.88 (dd, J = 18.0, 13.0 Hz, 1H+1H*), 3.81 (s, 3H+3H*), 3.75 (d, J = 6.5 Hz, 3H+3H*), 3.55
(d, J = 17.9 Hz, 1H+1H*), 3.19 (dd, J = 18.0, 6.5 Hz, 1H), 3.08 (dd, J = 18.5, 4.4 Hz, 1H*),
2.89 (dd, J = 18.5, 6.8 Hz, 1H*), 2.75 (dd, J = 18.0, 4.8 Hz, 1H), 0.84 (s, 9H), 0.82 (s, 9H*),
0.06 (s, 6H+6H*). 13C{1H} NMR (101 MHz, CDCl3) δ = 204.1, 197.5, 171.1, 170.7, 164.0,
157.7, 138.1, 136.1, 135.6, 134.0, 128.9, 128.5, 128.5, 128.4, 128.0, 127.9, 127.8, 127.8,
124.4, 124.3, 101.5, 101.5, 89.3, 82.6, 71.7, 70.3, 67.3, 56.1, 53.8, 52.9, 44.3, 44.0, 42.0,
41.7, 29.9, 26.0, 24.0, 18.2, -4.3, -4.8. IR (ATR, neat): nmax = 3460 (bw), 3064 (w), 2953 (w),
2928 (w), 2856 (w), 1721 (s), 1690 (m), 1559 (s), 1451 (m), 1248 (s), 1218 (s), 1095 (m),
1036 (m), 832 (s), 777 (s), 732 (m), 689 (m) cm−1. HRMS-ESI (m/z): calc. for C36H48NO10Si
[M+NH4]+: 682.3042; found: 682.3049.
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Aldehyde (21). A flame dried flask under argon was charged with acyloin 18 (0.020 g,
0.037 mmol, 1.0 eq.), pyridine (12 µL, 0.15 mmol, 4.0 eq.) and dry CH2Cl2 (0.55 mL). Then it
was cooled to −78 °C. A stream of ozone was passed through the reaction for 1.4 minutes
and then the solution was purged with a N2 stream. The reaction was monitored by TLC for
completion. The solution was passed through a pad of silica gel (EtOAc) to afford crude 21.
Rf: 0.7, i-hex:EtOAc 7:3, CAM, UV. HRMS-ESI (m/z): calc. for C29H42NO8Si [M+NH4]+:
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560.2674; found: 560.2680. The crude H NMR spectrum is available in the Supporting
Information.
Azido-pyrone (S5). A flask was charged with 24 (0.20 g, 0.91 mmol, 1.0 eq.), dry DMF
(165 mL) and NaN3 (0.11 g, 1.69 mmol, 1.9 eq.). The heterogeneous orange mixture was
stirred at RT and monitored by TLC until completion (ca. 1 h). Afterwards, the reaction was
partitioned between H2O and EtOAc, the aqueous phase was extracted three times with
EtOAc, the combined organic fractions were washed with brine, dried over MgSO4, filtered
and the solvent was removed under reduced pressure. The crude product was purified by
FCC (EtOAc/i-hex 1:1) to afford S5 (0.17 g, 0.94 mmol, quant.) as a white solid.
Rf: 0.4, i-hex:EtOAc 1:1, CAM, UV. 1H NMR (400 MHz, CDCl3) δ = 6.04 – 6.03 (m, 1H), 5.48
(t, J = 1.6 Hz, 1H), 4.13 (s, 2H), 3.83 (d, J = 1.0 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ =
170.7, 163.6, 158.7, 101.0, 89.1, 56.3, 51.0. IR (ATR, neat): nmax = 3082 (w), 2107 (s), 1731
(s), 1707 (s), 1652 (s), 1569 (s), 1453 (m), 1415 (m), 1249 (w), 1137 (s), 914 (m), 829 (s)
cm−1. HRMS-ESI (m/z): calc. for C7H8N3O3 [M+H]+: 182.0560; found: 182.0561.
Diazo-pyrone (23). A flask was charged with S5 (0.10 g, 0.55 mmol, 1.0 eq.), THF (1.0 mL),
H2O (0.15 mL) and perfluorophenyl-3-(diphenylphosphanyl)propanoate (0.25 g, 0.60 mmol,
1.1 eq.). The heterogeneous yellow mixture was stirred at RT and monitored by TLC until
completion (ca. 1 h). Afterwards, a solution of sat. NaHCO3(aq.) (1 mL) was added (gas
evolution!). The heterogeneous orange mixture was monitored by TLC until completion (ca.
2 h). Then, the reaction was partitioned between H2O and CH2Cl2, the aqueous phase was
extracted three times with CH2Cl2, the combined organic fractions were washed with brine,
dried with Na2SO4, filtered and the solvent was removed under reduced pressure. The crude
product was purified by FCC (EtOAc/i-hex 2:8) to afford diazo-pyrone 23 (0.05 g, 0.30 mmol,
55%) as an orange solid.
Rf: 0.4, i-hex:EtOAc 1:1, CAM, UV. 1H NMR (400 MHz, CDCl3) δ = 5.56 (t, J = 1.5 Hz, 1H),
5.24 (t, J = 1.5 Hz, 1H), 4.94 (d, J = 1.0 Hz, 1H), 3.79 (d, J = 1.0 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ = 171.8, 163.6, 155.5, 91.8, 84.3, 55.9, 48.5. IR (ATR, neat): nmax = 3288 (b),
3064 (m), 2148 (w), 2077 (s), 1714 (s), 1616 (m), 1545 (m), 1407 (m), 1243 (m), 1171 (m),
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1042 (m), 946 (w), 807 (m) cm−1. HRMS-ESI (m/z): calc. for C7H7N2O3 [M+H]+: 167.0451;
found: 167.0451.
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Ether (S6). A flame dried flask under argon was charged with alcohol 264d (3.00 g,
14.7 mmol, 1.0 eq.) and dry THF (36 mL). The solution was cooled to −20 °C. To this were
added sequentially BnBr (2.30 mL, 19.4 mmol, 1.3 eq.), TBAI (0.54 g, 1.46 mmol, 0.1 eq.)
and NaH (60% dispersion in mineral oil, 0.77 g, 19.3 mmol, 1.3 eq.). The reaction mixture
was allowed to warm to RT and was monitored by TLC until completion (ca. 10 h).
Afterwards, the reaction was quenched by addition of NH4Cl(aq.), the aqueous phase was
extracted three times with Et2O, the combined organic fractions were washed with brine,
dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude
product was purified by FCC (EtOAc/i-hex 5:95) to afford ether S6 (3.80 g, 12.9 mmol, 88%)
as a yellow oil.
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Rf: 0.6, i-hex:EtOAc 9:1, CAM, UV.
: −38.3 (c = 1.0, CHCl3). H NMR (400 MHz,
CDCl3) δ = 7.38 – 7.27 (m, 5H), 5.88 – 5.77 (m, 1H), 5.14 – 5.07 (m, 2H), 4.65 – 4.62 (d, 1H),
4.52 – 4.49 (d, 1H), 4.20 – 4.16 (m, 1H), 3.83 – 3.77 (m, 1H), 2.91 – 2.74 (m, 4H), 2.42 –
2.30 (m, 2H), 2.14 – 1.82 (m, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ = 138.8, 134.2, 128.5,
128.0, 127.7, 117.9, 75.2, 71.7, 44.1, 40.2, 38.6, 30.5, 30.1, 26.2. IR (ATR, neat): nmax
=
2898 (w), 1640 (w), 1496 (w), 1453 (w), 1422 (w), 1347 (w),n1275 (w), 1243 (w), 1206 (w),
1179 (w), 1088 (m), 1068 (s), 1027 (m), 992 (m), 908 (m), 734 (s), 695 (s), 663 (w) cm−1.
HRMS-EI (m/z): calc. for C16H22OS2 [M]+•: 294.1112; found: 294.1104.
Aldehyde (27). A flask was charged sequentially with ether S6 (3.80 g, 12.9 mmol, 1.0 eq.),
MeCN/H2O (9/1, 165 mL), MeI (8.05 mL, 129 mmol, 10.0 eq.) and CaCO3 (6.45 g,
64.5 mmol, 5.0 eq.). The reaction mixture was heated to 45 °C and it was monitored by TLC
until completion (ca. 8 h). Afterwards, the solvent was removed and the residue was
partitioned between EtOAc and H2O, the aqueous phase was extracted three times with
EtOAc, the combined organic fractions were washed with brine, dried over MgSO4, filtered
and the solvent was removed under reduced pressure. The crude product was purified by
FCC (EtOAc/i-hex 1:9) to afford aldehyde 27 (2.07 g, 10.1 mmol, 78%) as a colorless oil.
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Rf: 0.4, i-hex:EtOAc 9:1, CAM, UV.
: −43.3 (c = 1.0, CHCl3). H NMR (400 MHz,
CDCl3) δ = 9.71 (s, 1H), 7.30 – 7.18 (m, 5H), 5.80 – 5.70 (m, 1H), 5.09 – 5.05 (m, 2H), 4.57 –
4.54 (d, 1H), 4.47 – 4.44 (d, 1H), 4.00 – 3.94 (m, 1H), 2.65 – 2.58 (m, 1H), 2.53 – 2.47 (m,
1H), 2.42 – 2.28 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ = 201.4, 138.1, 133.6, 128.5,
127.8, 118.4, 73.7, 71.3, 48.0, 38.3. IR (ATR, neat): nmax = 3066 (w), 2863 (w), 2729 (w),
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1722 (s), 1641 (w), 1496 (w), 1454 (w), 1346 (m), 1206 (w), 1090 (m), 1069 (mw), 1027 (m),
995 (m), 916 (m), 735 (s), 696 (s) cm−1. HRMS-EI (m/z): calc. for C13H16O2 [M]+•: 204.1145;
found: 204.1143.
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Ketone (28). A flame dried flask under argon was charged with pyrone 25 (1.85 g, 13.2 mmol,
1.3 eq.), HMPA (2.65 mL, 15.2 mmol, 1.5 eq.) and dry Et2O (70 mL). This solution was cooled
to −78 °C and a freshly prepared solution of LDA (12.7 mL, 12.9 mmol, 1.3 eq., 1.02 M in
THF) was added slowly. The reaction was stirred at the same temperature for 40 minutes.
Then, a solution of aldehyde 27 (2.07 g, 10.1 mmol, 1.0 eq.) in dry Et2O (30.0 mL) was added
dropwise and the reaction mixture was stirred for 1.5 h. Afterwards, the reaction was
quenched by addition of Na2SO4•10 H2O (2 eq.) and was allowed to warm to RT. The
precipitate was filtered, dried over MgSO4, filtered and the solvent was removed under
reduced pressure. The crude product was passed through a silica pad (EtOAc/i-hex 4:6 to
6:4) to afford the crude alcohol as a yellow oil that was carried through to the next step
without further purification. Rf: 0.7, i-hex:EtOAc 2:3, CAM, UV. HRMS-EI (m/z): calc. for
C20H24O5 [M]+•: 344.1618. Found: 344.1634.
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A flame dried flask under argon was charged with the crude alcohol, dry CH2Cl2 (75 mL) and
it was cooled to 0 °C. To this solution was added DMP (3.80 g, 8.96 mmol, 0.9 eq.) and it was
stirred at the same temperature for 5 minutes. Then, the cooling bath was removed and the
reaction was monitored by TLC until completion (ca. 3 h). Afterwards, the reaction was
quenched by addition of a mixture of sat. Na2S2O3(aq.) and sat. NaHCO3(aq.) (1:1). The
aqueous phase was extracted three times with EtOAc, the combined organic fractions were
washed with brine, dried over MgSO4, filtered and the solvent was removed under reduced
pressure. The crude product was purified by FCC (EtOAc/i-hex 3:7 to 4:6) to afford ketone 28
(1.90 g, 5.55 mmol, 55% over two steps) as a colorless solid.
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Rf: 0.6, i-hex:EtOAc 2:8, CAM, UV.
: −36.4 (c = 0.3, CHCl3). H NMR (400 MHz,
CDCl3) δ = 7.29 – 7.21 (m, 5H), 5.78 – 5.70 (m, 2H), 5.37 (d, J = 2.2 Hz, 1H), 5.08 – 5.03 (m,
2H), 4.54 (d, J = 11.3 Hz, 1H), 4.40 (d, J = 11.2 Hz, 1H), 3.96 (ddt, J = 8.2, 6.6, 4.7 Hz, 1H),
3.72 (s, 3H), 3.45 (s, 2H), 2.72 (dd, J = 16.1, 8.2 Hz, 1H), 2.54 (dd, J = 16.1, 4.3 Hz, 1H),
2.34 – 2.27 (m, 2H). C{1H} NMR (101 MHz, CDCl3) δ = 202.5, 170.9, 164.4, 157.7, 138.2,
13
133.7, 128.6, 128.0, 127.9, 118.5, 103.1, 88.6, 75.0, 71.9, 56.1, 48.2, 47.5, 38.3. IR (ATR,
neat): nmax = 3080 (w), 2918 (m), 1712 (s), 1645 (m), 1565 (s), 1454 (m), 1420 (m), 1394 (m),
1318 (m), 1256 (m), 1129 (m), 1063 (m), 1031 (m), 997 (m), 940 (m), 909 (m), 852 (m), 742
(m), 698 (m) cm−1. HRMS-ESI (m/z): calc. for C20H23O5 [M+H]+: 343.1540; found: 343.1541.
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Diazo (29). A flame dried flask under argon was charged with ketone 28 (0.92 g, 2.69 mmol,
1.0 eq.), dry MeCN (19 mL) and p-ABSA (0.77 g, 3.21 mmol, 1.2 equiv). To this solution Et3N
(0.58 mL, 4.18 mmol, 1.5 eq.) was added dropwise. The orange suspension was monitored
by TLC until completion (ca. 10 h). Afterwards, it was concentrated to the volume of ca. 3 mL
and purified by FCC (EtOAc/i-hex 3:7) to afford diazo 29 (0.99 g, 2.69 mmol, quant.) as an
orange oil.
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Rf: 0.5, i-hex:EtOAc 1:1, CAM, UV.
: −37.3 (c = 0.5, CHCl3). H NMR (800 MHz,
CDCl3) δ = 7.31 – 7.29 (m, 2H), 7.27 – 7.25 (m, 3H), 6.89 (s, 1H), 5.84 – 5.79 (m, 1H), 5.36
(d, J = 2.3 Hz, 1H), 5.15 – 5.13 (m, 2H), 4.63 (d, J = 11.5 Hz, 1H), 4.45 (d, J = 11.4 Hz, 1H),
4.06 – 4.01 (m, 1H), 3.82 (s, 3H), 2.83 – 2.80 (m, 1H), 2.61 – 2.59 (m, 1H), 2.44 – 2.37 (m,
2H). 13C{1H} NMR (201 MHz, CDCl3) δ = 188.8, 171.8, 162.4, 148.9, 138.0, 133.4, 128.6,
128.0, 127.9, 118.7, 98.7, 86.8, 76.1, 75.2, 72.1, 56.1, 44.3, 38.5. IR (ATR, neat): nmax
=
3107 (vw), 3077 (vw), 3029 (vw), 2978 (vw), 2942 (vw), 2908 (vw), 2361 (vw), 2340 (vw),
2099 (s), 1725 (vs), 1651 (s), 1618 (s), 1545 (vs), 1496 (w), 1454 (m), 1408 (s), 1377 (s),
1282 (w), 1228 (vs), 1185 (m), 1086 (m), 1065 (s), 1025 (m), 987 (s), 960 (s), 917 (m), 874
(m), 829 (s), 800 (s), 737 (m), 697 (s) cm−1. HRMS-ESI (m/z): calc. for C19H21O4
[M−N2−CO+H]+: 313.1434; found: 313.1449.
Aldehyde (30). A flask was charged sequentially with diazo 29 (1.00 g, 2.71 mmol, 1.0 eq.),
acetone/H2O (10/1, 20 mL), NMO (0.38 g, 3.24 mmol, 1.2 eq.) and 2,6-lutidine (0.62 mL,
5.34 mmol, 2.0 eq.). Then, OsO4 (0.30 mL, 0.05 mmol, 0.02 eq., 4% in H2O) was added and
the reaction was monitored by TLC until completion (ca. 8 h). Upon completion, BAIB (1.04 g,
3.23 mmol, 1.2 eq.) was added and the reaction was monitored by TLC until completion (ca.
4 h). Afterwards, the reaction was quenched by addition of sat. Na2S2O3(aq.). The aqueous
phase was extracted three times with EtOAc, the combined organic fractions were washed
with sat. CuSO4(aq.), brine, dried over MgSO4, filtered and the solvent was removed under
reduced pressure. The crude product was purified by FCC (EtOAc/i-hex 1:1) to afford
aldehyde 30 (0.56 g, 1.51 mmol, 56%) as a yellow oil.
R
f diol: 0.14, i-hex:EtOAc 2:8, CAM, UV. Rf: 0.5, i-hex:EtOAc 2:8, CAM, UV.
: +17.5 (c
= 0.05, CHCl3). 1H NMR (800 MHz, CDCl3) δ = 9.79 (s, 1H), 7.33 – 7.26 (m, 6H), 5.36 (d, J =
2.3 Hz, 1H), 4.60 (d, J = 11.4 Hz, 1H), 4.52 (d, J = 11.4 Hz, 1H), 4.50 – 4.47 (m, 1H), 3.83 (s,
3H), 2.91 (dd, J = 15.1, 7.1 Hz, 1H), 2.82 – 2.75 (m, 3H). 13C{1H} NMR (201 MHz, CDCl3) δ =
200.0, 187.7, 171.8, 162.3, 148.4, 137.5, 128.7, 128.3, 128.1, 98.9, 87.0, 75.1, 72.7, 71.3,
56.2, 48.3, 44.3. IR (ATR, neat): nmax = 2952 (vs), 2917 (vs), 2838 (m), 2395 (w), 1725 (s, b),
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1647 (w), 1567 (m), 1455 (vs), 1408 (w), 1377 (vs), 1253 (m), 1166 (m), 998 (w), 974 (w),
810 (w), 760 (s) cm−1. HRMS-ESI (m/z): calc. for C19H17N2O6 [M−H]−: 369.1092; found:
369.1099.
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Acyloin (31). A flame dried flask under argon was charged with oven dried 4 Å MS (0.60 g),
α-ketoester 16 (3.00 g, 14.5 mmol, 10.0 eq.) and pre-catalyst 17 (0.05 g, 0.15 mmol, 0.1 eq.).
Then, a solution of aldehyde 30 (0.56 g, 1.51 mmol, 1.0 eq.) in dry CH2Cl2 (20 mL + 10 mL to
rinse) was added and the mixture stirred for 5 minutes. Subsequently, dry DIPEA (0.26 mL,
1.53 mmol, 1.0 eq.) was added and the solution turned yellow. The reaction was monitored
by TLC until completion (ca. 4 h). The reaction mixture was eluted directly with EtOAc over a
silica pad and the solvent was removed under reduced pressure. The crude product was
purified by FCC (EtOAc/i-hex 1:1 to 8:2, long column) to afford acyloin 31 (0.37 g, 0.64 mmol,
42%, 1.3:1 d.r.) as an amorphous yellow solid.
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Rf: 0.4, i-hex:EtOAc 4:6, CAM, UV. 1H NMR (800 MHz, CHCl3, * denotes minor diastereomer)
δ = 7.92 (tt, 2H+2H*), 7.60 (tt, J = 7.3, 1.3 Hz, 1H+1H*), 7.47 (tt, 2H+2H*), 7.31 – 7.27 (m,
3H+3H*), 7.26 – 7.23 (m, 2H+2H*), 6.87 (s, 1H+1H*), 5.35 (d, J = 2.3 Hz, 1H+1H*), 4.63 –
4.58 (m, 2H+2H*), 4.49 – 4.45 (m, 2H+2H*), 3.87 (d, J = 17.8 Hz, 1H+1H*), 3.82 (d, J = 1.7
Hz, 3H+3H*), 3.78 (s, 3H), 3.74 (s, 3H*), 3.73 – 3.71 (m, 1H+1H*), 3.28 (dd, J = 17.7, 5.5 Hz,
1H), 3.15 (dd, J = 17.7, 6.2 Hz, 1H*), 3.07 (dd, J = 17.7, 6.0 Hz, 1H*), 2.97 (dd, J = 17.7, 6.6
Hz, 1H), 2.91 (dd, J = 15.0, 7.4 Hz, 1H*), 2.86 (dd, J = 14.9, 7.1 Hz, 1H), 2.81 (ddd, J = 15.0,
9.1, 4.7 Hz, 1H+1H*). 13C{1H} NMR (201 MHz, CDCl3) δ = 204.62, 204.59, 197.5, 197.4,
187.97, 187.95, 171.8, 170.48, 170.45, 162.4, 148.7, 137.73, 137.70, 136.1, 134.2, 128.9,
128.59, 128.56, 128.4, 128.1, 128.0, 98.82, 98.79, 86.9, 82.62, 82.58, 75.1, 72.8, 72.7,
72.41, 72.37, 56.1, 54.0, 53.9, 44.32, 44.25, 44.24, 44.1, 41.6, 41.3. IR (ATR, neat): nmax
=
3458 (b), 3108 (vw), 3088 (vw), 3064 (vw), 3030 (vw), 2950 (vw), 2920 (vw), 2361 (vw), 2341
(vw), 2250 (vw), 2102 (m), 1720 (vs), 1687 (m), 1651 (s), 1618 (m), 1597 (m), 1580 (w), 1546
(s), 1496 (vw), 1453 (m), 1410 (m), 1382 (m), 1357 (m), 1282 (m), 1230 (vs), 1185 (m), 1087
(m), 1069 (m), 1025 (m), 1001 (m), 988 (m), 960 (m), 911 (m), 878 (m), 822 (m), 803 (m),
753 (m), 729 (s), 689 (s) cm−1. HRMS-ESI (m/z): calc. for C30H32N3O10 [M+NH4]+: 594. 2082;
found: 594.2088.
Ketone (32). A flame dried flask under argon was charged with acyloin 31 (0.25 g, 0.43 mmol,
1.0 eq.), n-Bu3SnH (1.14 mL, 4.31 mmol, 10.0 eq.), Cu(acac)2 (1 mg, 0.004 mmol, 0.01 eq.)
and dry benzene (17 mL, degassed by sparging with argon for 20 minutes). Then, the
solution was immersed in a preheated 80 °C oil bath. The reaction was monitored by TLC
until completion (ca. 1 h). Afterwards, the reaction mixture was cooled to RT and directly
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charged on a silica column (EtOAc/i-hex 4:6 to 7:3) to afford ketone 32 (0.12 g, 0.22 mmol,
51%) as an amorphous yellow solid.
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Rf: 0.7, i-hex:EtOAc 2:8, CAM, UV. 1H NMR (800 MHz, CHCl3, * denotes minor diastereomer)
δ = 7.92 (ddd, J = 8.5, 6.4, 1.3 Hz, 2H+2H*), 7.60 (tt, J = 7.4, 1.3 Hz, 1H+1H*), 7.47 (tt, J =
7.5, 1.1 Hz, 2H+2H*), 7.34 – 7.27 (m, 5H+5H*), 5.87 (t, J = 2.2 Hz, 1H+1H*), 5.44 (dd, J =
2.3, 0.8 Hz, 1H+1H*), 4.62 – 4.54 (m, 2H+2H*), 4.51 (dd, J = 11.2, 5.1 Hz, 1H+1H*), 4.47 –
4.43 (m, 1H+1H*), 3.87 (dd, J = 17.8, 12.4 Hz, 1H+1H*), 3.79 (d, J = 2.5 Hz, 3H+3H*), 3.74
(d, J = 29.3 Hz, 3H+3H*), 3.70 (dd, J = 17.8, 3.3 Hz, 1H+1H*), 3.52 (d, J = 3.7 Hz, 2H+2H*),
3.27 (dd, J = 17.4, 5.8 Hz, 1H*), 3.09 – 3.03 (m, 1H+1H*), 2.90 – 2.87 (m, 1H+1H*), 2.83 (dd,
J = 16.4, 6.8 Hz, 1H), 2.78 (ddd, J = 16.4, 5.2, 2.1 Hz, 1H+1H*). 13C{1H} NMR (201 MHz,
CDCl3) δ = 204.6, 204.5, 201.74, 201.72, 197.53, 197.45, 170.9, 170.53, 170.46, 157.52,
157.49, 138.01, 137.98, 136.1, 134.10, 134.10, 128.9, 128.58, 128.55, 128.4, 128.11,
128.09, 127.97, 127.95, 103.21, 103.20, 88.63, 88.62, 82.62, 82.56, 72.5, 71.66, 71.64, 56.1,
53.92, 53.90, 48.0, 47.6, 47.5, 44.2, 44.1, 41.7, 41.5. IR (ATR, neat): nmax = 3443 (b), 3089
(vw), 3063 (vw), 3031 (vw), 2951 (vw), 2924 (vw), 2851 (vw), 2106 (vw), 1720 (vs), 1650 (m),
1597 (w), 1567 (s), 1496 (w), 1453 (m), 1413 (m), 1356 (m), 1250 (s), 1219 (m), 1182 (m),
1143 (m), 1089 (m), 1070 (m), 1030 (m), 1001 (w), 943 (w), 819 (w), 755 (w), 738 (w), 691
(w) cm−1. HRMS-ESI (m/z): calc. for C30H34NO10 [M+NH4]+: 568.2177; found: 568.2186.
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Alcohol (33). A flame dried flask under argon was charged with ketone 32 (20.0 mg,
0.036 mmol, 1.0 eq.), pentamethylbenzene (31.0 mg, 0.21 mmol, 5.8 eq.) and dry CH2Cl2
(0.2 mL). The solution was cooled to –78 °C. Then, BCl3 (0.1 mL, 0.10 mmol, 3.0 eq., 1 M in
CH2Cl2) was added dropwise and the color changed to yellow. The reaction was monitored
by TLC until completion (ca. 1 h) and then it was quenched by addition of MeOH. The cooling
bath was removed, the mixture was allowed to reach RT and then the solvent was removed
under reduced pressure. The crude product was purified by FCC (EtOAc/i-hex 9:1 to 1:0) to
afford alcohol 33 (6.2 mg, 14 µmol, 39%) as a yellow oil.
Rf: 0.2, i-hex:EtOAc 2:8, CAM, UV. 1H NMR (800 MHz, CHCl3, * denotes minor diastereomer)
δ = 7.94 (ddd, J = 8.3, 2.1, 1.2 Hz, 2H+2H*), 7.61 (ddt, J = 7.4, 6.4, 1.1 Hz, 1H+1H*), 7.50 –
7.46 (m, 2H+2H*), 5.93 (d, J = 2.1 Hz, 1H+1H*), 5.46 (d, J = 2.2 Hz, 1H+1H*), 4.63 (s,
1H+1H*), 4.63 – 4.57 (m, 2H+2H*), 3.89 (dd, J = 17.8, 10.7 Hz, 1H+1H*), 3.83 (d, J = 1.3 Hz,
3H+3H*), 3.80 (s, 3H+3H*), 3.76 (dd, J = 17.8, 5.4 Hz, 1H+1H*), 3.60 (d, J = 3.2 Hz,
2H+2H*), 3.18 – 3.05 (m, 1H+1H*), 3.06 (dd, J = 17.7, 4.1 Hz, 1H*), 2.89 (dd, J = 17.7, 8.1
Hz, 1H*), 2.85 (dd, J = 17.6, 4.1 Hz, 1H), 2.80 (ddd, J = 17.1, 8.0, 2.1 Hz, 1H+1H*), 2.75
(ddd, J = 17.1, 4.2, 1.6 Hz, 1H+1H*). 13C{1H} NMR (201 MHz, CDCl3) δ = 207.0, 206.0,
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202.9, 170.7, 170.3, 164.1, 157.1, 135.9, 134.1, 128.8, 128.3, 103.2, 88.5, 82.3, 64.1, 56.0,
53.9, 48.4, 47.7, 44.2, 43.1, 31.0, 29.7. IR (ATR, neat): nmax = 3440 (b), 2948 (vw), 2849
(vw), 1717 (vs), 1647 (m), 1566 (vs), 1450 (s), 1411 (s), 1247 (s), 1220 (m), 1143 (m), 1037
(m), 942 (m), 815 (w), 755 (w), 738 (w), 689 (s) cm−1. HRMS-ESI (m/z): calc. for C23H28NO10
[M+NH4]+: 478.1708; found: 478.1714.
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Crude data for 34 / 35. HRMS-ESI (m/z): calc. for C23H23O9 [M+H]+: 443.1337; found:
1
443.1341. The stereochemistry at C2 is not assigned. Crude H NMR and HSQC data are
available in the Supporting Information.
Diol (37). A flame dried flask under argon was charged with 4 Å MS (1.0 g), diazo 364d
(0.49 g, 1.24 mmol, 1.0 eq.), pyridine (0.6 mL, 7.43 mmol, 6.0 eq.), PCC (1.07 g, 4.96 mmol,
4.0 eq.) and dry CH2Cl2 (12.5 mL). The mixture was heated at 40 °C and it was monitored by
TLC until completion (ca. 20 h, after 12 h additional 2.8 eq. of PCC were added). Afterwards,
the reaction was cooled to RT and celite was added. This mixture was poured into a pad of
celite impregnated with EtOAc, filtered and the cake washed with more EtOAc. The solvent
was removed under reduced pressure and the residue passed through a silica pad (EtOAc/i-
hex 6:3) to afford the crude lactone (0.24 g) which was used in the next step without further
purification. Rf: 0.4, i-hex:EtOAc 1:1, CAM, UV.
A flask was charged sequentially with the crude lactone, THF/H2O (5/1, 5.0 mL) and NMO
(0.14 g, 1.19 mmol, 1.0 eq.). Then, OsO4 (0.08 mL, 12.5 µmol, 0.01 eq., 4% in H2O) was
added and the reaction was monitored by TLC until completion (ca. 2 h). Upon complete
conversion, the reaction was quenched by adding a solution of sat. Na2S2O3(aq.). The aqueous
phase was extracted three times with EtOAc, the combined organic fractions were washed
with brine, dried over MgSO4, filtered and the solvent was removed under reduced pressure.
The crude product was purified by FCC (MeOH/Acetone/CH2Cl2 2:8:90) to afford diol 37
(0.14 g, 0.32 mmol, 26%) as a yellow solid.
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Rf: 0.2, i-hex:EtOAc 2:8, CAM, UV.
: −11.7 (c = 3.2, CHCl3). H NMR (800 MHz,
CDCl3) δ = 7.29 – 7.27 (m, 2H), 7.21 – 7.19 (m, 1H), 7.17 – 7.16 (m, 2H), 6.92 – 6.81 (m,
1H), 5.37 (d, J = 2.3 Hz, 1H), 5.32 – 5.29 (m, 1H), 4.13 (dd, J = 3.5, 2.4 Hz, 1H), 3.82 (s, 3H),
2.97 – 2.91 (m, 2H), 2.76 – 2.73 (m, 1H), 2.64 (ddd, J = 13.6, 11.5, 5.3 Hz, 1H), 2.28 – 2.26
(m, 2H), 2.02 – 1.96 (m, 2H). 13C{1H} NMR (201 MHz, CDCl3) δ = 185.6, 175.9, 171.7, 162.2,
140.7, 128.8, 128.5, 126.4, 99.2, 87.1, 76.1, 75.0, 69.8, 56.2, 43.6, 42.9, 39.4, 32.0, 29.9,
29.3. IR (ATR, neat): nmax = 2919 (w), 2850 (w), 2106 (m), 1641 (s), 1453 (m), 1407 (m),
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1232 (m), 1124 (w), 1016 (m), 810 (m), 699 (m) cm−1. HRMS-ESI (m/z): calc. for C22H26O8N3
[M+NH4]+: 460.1714; found: 460.1717.
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Acetonide (38). A flask was charged sequentially with 37 (57.0 mg, 0.13 mmol, 1.0 eq.), dry
CH2Cl2 (1.3 mL), 2,2-DMP (25 µL, 0.20 mmol, 1.6 eq.) and p-TSA (3.0 mg, 17 µmol, 0.1 eq.).
The reaction was monitored by TLC until completion (ca. 2 h). Upon full conversion, the
reaction was quenched by addition of a solution of sat. NaHCO3(aq.). The aqueous phase was
extracted three times with EtOAc, the combined organic fractions were washed with brine,
dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude
product was purified by FCC (EtOAc/i-hex 6:4) to afford 38 (17 mg, 35 µmol, 27%) as a
yellow solid.
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Rf: 0.7, i-hex:EtOAc 2:8, CAM, UV.
: +2.1 (c = 0.5, CHCl3). 1H NMR (800 MHz, CDCl3)
δ = 7.28 (t, J = 7.6 Hz, 2H), 7.21 – 7.17 (m, 3H), 6.85 (s, 1H), 5.36 (d, J = 2.2 Hz, 1H), 5.24
(dddd, J = 11.9, 7.2, 5.2, 2.5 Hz, 1H), 4.38 (dd, J = 3.6, 2.1 Hz, 1H), 3.81 (s, 3H), 3.01 (dd, J
= 15.6, 6.7 Hz, 1H), 2.85 (dd, J = 15.7, 5.1 Hz, 1H), 2.77 (td, J = 12.9, 5.2 Hz, 1H), 2.64 (td, J
= 12.9, 4.9 Hz, 1H), 2.38 (ddd, J = 15.0, 3.6, 2.6 Hz, 1H), 2.24 (ddd, J = 14.0, 12.3, 4.9 Hz,
1H), 2.17 – 2.13 (m, 1H), 2.04 – 1.98 (m, 1H), 1.46 (d, J = 17.3 Hz, 6H). C{1H} NMR (201
13
MHz, CDCl3) δ = 185.7, 171.7, 162.2, 148.0, 140.6, 128.7, 128.4, 126.5, 110.4, 99.2, 87.1,
80.6, 75.5, 75.2, 71.8, 56.2, 43.9, 37.6, 31.1, 30.0, 27.3, 26.8. IR (ATR, neat): nmax = 2925
(w), 2853 (w), 2104 (vw), 1723 (s), 1568 (s), 1256 (m), 1176 (m), 1089 (m), 1024 (m), 813
(m), 699 (m) cm−1. HRMS-ESI (m/z): calc. for C25H30O8N3 [M+NH4]+: 500.2027; found:
500.2031.
TMS diol (39). A flask under air was charged with AD-mix-α (0.60 g) and t-BuOH/H2O
(1.8 mL, 1/1). The flask was closed with a stopper and stirred at RT for 30 min. Diazo 36
(0.14 g, 0.35 mmol, 1.0 eq.) and MeSO2NH2 (0.07 g, 0.74 mmol, 2.0 eq.) were added to the
mixture. The reaction was monitored by TLC analysis until completion (ca. 20 h). Afterwards,
the reaction was quenched with solid Na2S2O3 (0.8 g), stirred for 15 minutes and then
partitioned between H2O/EtOAc. The aqueous phase was extracted three times with EtOAc,
the combined organic phases were dried with Na2SO4, filtered and the solvent was removed
1
under reduced pressure. The crude oil (crude H NMR 1.6:1 d.r.) was purified by FCC
(MeOH/Acetone/CH2Cl2 2.5:2.5:95) to afford the separated diols. Both were contaminated
with inseparable MeSO2NH2 and were therefore used in the next step without further
purification. Rf diol: 0.4, i-hex:EtOAc 2:8, CAM, UV. Rf diol’: 0.2, i-hex:EtOAc 2:8, CAM, UV.
A flame dried flask under argon was charged sequentially with one crude alcohol, dry CH2Cl2
(2 mL), 2,6-lutidine (0.14 mL, 1.2 mmol) and the reaction vessel was cooled to 0 °C. Neat
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TMSOTf (0.1 mL, 0.55 mmol) was added dropwise and the reaction was stirred for
10 minutes at the same temperature. Then, the cooling bath was removed and the reaction
was monitored by TLC until completion (ca. 2 h). Afterwards, the reaction was quenched by
addition of sat. NaHCO3(aq). The aqueous phase was extracted three times with EtOAc, the
combined organic fractions were washed with brine, dried over MgSO4, filtered and the
solvent was removed under reduced pressure. The crude product was purified by FCC
(EtOAc/i-hex 3:7) to afford 39 (56.0 mg, 0.1 mmol, 27% over 2 steps) as a yellow oil.
Structural determination was performed by analysis of the 2D NMR data (NOESY) of both
diasteromers.
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Rf : 0.6, i-hex:EtOAc 6:4, CAM, UV.
: +12.8 (c = 0.9, CHCl3). 1H NMR (800 MHz, C6D6)
δ = 7.23 – 7.19 (m, 4H), 7.12 – 7.07 (m, 1H), 5.08 (t, J = 2.3 Hz, 1H), 4.23 (td, J = 7.4, 3.8
Hz, 1H), 3.86 (d, J = 10.4 Hz, 1H), 3.78 – 3.77 (m, 1H), 3.43 (dd, J = 10.4, 1.4 Hz, 1H), 2.87
(dd, J = 5.9, 4.4 Hz, 3H), 2.74 (td, J = 12.8, 4.5 Hz, 1H), 2.62 (td, J = 12.8, 5.5 Hz, 1H), 2.21
– 2.17 (m, 1H), 2.07 – 2.03 (m, 2H), 1.88 – 1.84 (m, 2H), 1.49 (dddd, J = 23.3, 14.2, 11.5, 2.8
Hz, 2H), 0.16 (s, 9H), 0.12 (s, 9H). 13C{1H} NMR (201 MHz, C6D6) δ = 187.8, 171.3, 161.1,
149.3, 142.9, 128.9, 128.7, 128.4, 128.3, 126.3, 98.3, 86.8, 75.0, 70.7, 69.7, 69.5, 55.1, 44.9,
39.3, 37.7, 32.2, 29.7, 3.1, 0.6. IR (ATR, neat): nmax = 3026 (vw), 2955 (w), 2103 (s), 1731
(s), 1656 (m), 1549 (s), 1409 (m), 1230 (s), 1124 (m), 1077 (m), 834 (s), 698 (m) cm−1.
HRMS-ESI (m/z): calc. for C28H44O7N3Si2 [M+NH4]+: 590.2712; found: 590.2723.
1
TMS diol (39’). H NMR (800 MHz, C6D6) δ = 7.18 – 7.14 (m, 5H), 7.06 (tt, J = 7.1, 1.4 Hz,
1H), 5.09 (d, J = 2.3 Hz, 1H), 3.79 (d, J = 11.9 Hz, 1H), 3.66 (dddd, J = 11.7, 7.7, 4.1, 2.1 Hz,
1H), 3.32 (dd, J = 11.3, 4.7 Hz, 1H), 2.88 (s, 3H), 2.86 (d, J = 11.9 Hz, 1H), 2.65 (ddd, J =
13.8, 12.5, 4.5 Hz, 1H), 2.48 – 2.36 (m, 2H), 2.14 (ddd, J = 13.9, 12.9, 4.5 Hz, 1H), 2.05 (dd,
J = 14.7, 4.1 Hz, 1H), 1.84 (q, J = 11.7 Hz, 1H), 1.46 (ddd, J = 12.3, 4.7, 2.1 Hz, 1H), 1.38
(ddd, J = 14.0, 12.5, 5.3 Hz, 1H), 0.32 (s, 9H), 0.05 (s, 9H). 13C{1H} NMR (201 MHz, C6D6) δ
= 187.6, 171.3, 161.0, 149.4, 142.6, 128.9, 128.5, 128.4, 128.3, 126.3, 125.5, 98.2, 75.7,
75.2, 74.2, 73.9, 73.2, 55.1, 45.2, 37.5, 36.8, 29.7, 3.3, 0.5.
Enol (44). A flame dried flask under argon was sequentially charged with Mg turnings (0.81 g,
33.3 mmol, 1.25 eq.) and dry Et2O (100 mL). Under vigorous stirring, I2 (7.00 g, 27.6 mmol,
1.0 eq.), was added and the reaction vessel was placed in a 40 °C preheated oil bath. The
reaction mixture turned from dark brown to milky white. Then the solids were filtered under
argon, washed three times with dry Et2O and dried under high vacuum. This material was
used without further purification in the following reaction.
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