Intramolecular Diels-Alder Approaches to the Decalin Core of Verongidolide: The Origin of the exo-Selectivity, a DFT Analysis

Article abstract of DOI:10.1021/acs.joc.8b00566

Verongidolide is a natural macrolactone recently isolated from a New Caledonia sponge, Verongidolae. The structure of this natural product is similar to the structure of superstolides, also isolated from a New Caledonian sponge, Neosiphonia superstes. From a biological point of view, verongidolide and superstolides A and B present potent cytotoxicity against human oral carcinoma KB (0.3 nM). By comparing the ¹H NMR chemical shifts as well as the coupling constants, we conclude that verongidolide possesses a cis-decalin core and we hypothesize that the relative configuration of the cis-decalin core is similar to the one of superstolide A. To verify this hypothesis, intramolecular and transannular Diels-Alder reactions were attempted to construct the decalin core. Unexpectedly, the selectivity of the Diels-Alder reactions was exo and an in-depth DFT calculation of the key reaction mechanism was achieved in order to understand the factors controlling this unexpected selectivity.

Full text of DOI:10.1021/acs.joc.8b00566

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Article
Intramolecular Diels-Alder approaches to the decalin core of
verongidolide. The origin of the exo-selectivity: a DFT analysis.
Baba Maiga-Wandiam, Andrei Corbu, Georges Massiot, Francois Sautel,
Peiyuan Yu, Bernice Wan-Yi Lin, Kendall N. Houk, and Janine Cossy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00566 • Publication Date (Web): 01 May 2018
Downloaded from http://pubs.acs.org on May 1, 2018
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Intramolecular DielsꢀAlder approaches to the decalin core of verongidolide.
The origin of the exoꢀselectivity: a DFT analysis.
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Baba MaigaꢀWandiam,† Andrei Corbu,† Georges Massiot,‡ François Sautel,§ Peiyuan Yu,⊥ Bernice WanꢀYi
Lin,⊥ K. N. Houk,⊥ Janine Cossy†*
†Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI),
ESPCI Paris, PSL Research University, CNRS, 10 rue Vauquelin, 75231 Paris, France.
‡ Université de Reims ChampagneꢀArdenne, Institut de Chimie Moléculaire de
Reims, CNRS, UFR des Sciences Exactes et Naturelles, Campus Sciences, Moulin de la
Housse, 51687 Reims Cedex 2, France.
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§ CNRS/Pierre Fabre USR 3388, Centre de Recherche et Développement Pierre Fabre, 3
avenue Hubert Curien, 31035 Toulouse Cedex 01, France
⊥Department of Chemistry and Biochemistry, University of California, Los Angeles, CA
90065, United States
Abstract
Verongidolide, is a natural macrolactone recently isolated from a New Caledonia sponge,
Verongidolae. The structure of this natural product is similar to the structure of superstolides,
also isolated from a New Caledonian sponge, Neosiphonia superstes. From a biological point
of view, verongidolide and superstolides A and B present potent cytotoxicity against human
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oral carcinoma KB (0.3 nM). By comparing the HꢀNMR chemical shifts as well as the
coupling constants, we conclude that verongidolide possesses a cisꢀdecalin core and we
hypothesize that the relative configuration of the cisꢀdecalin core is similar to the one of
superstolide A. To verify this hypothesis, an intramolecular and a transannular DielsꢀAlder
were attempted to construct the decalin core. Unexpectedly, the selectivity of the DielsꢀAlder
reactions was exo and an inꢀdepth DFT calculation of the key reaction mechanism was
achieved in order to understand the factors controlling this unexpected selectivity.
Introduction
Macrolactone 1, is a natural product recently isolated from a New Caledonia sponge,
Verongidolae, to which we gave the name verongidolide.1 The structure of this natural
product is similar to the structure of superstolides, also isolated from a New Caledonian
sponge, Neosiphonia superstes (Figure 1).2 From a biological point of view, verongidolide
and superstolides A and B present a potent cytotoxicity against human oral carcinoma KB
(0.3 nM).
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Figure 1. Natural macrolactones: verongidolide and superstolide A
If the planar structure of verongidolide was established, no reliable information about
the relative and absolute configuration of the stereogenic centers was reported. By comparing
the structure of the decalin core of verongidolide to the structure of superstolide A, one can
notice that verongidolide possesses a glycosidic substituent at C13 and a methyl at C15 versus
a carbamate group at C13 and a hydrogen at C15 for superstolide A. Structural differences
can also be noticed in the macrolactone region. The macrolactone of verongidolide is not
substituted by a methyl at C19 as in superstolide A and a conjugated diene is present instead
of a triene in superstolide A. A major difference between verongidolide and superstolide A is
the side chain at C23. In verongidolide, the side chain possesses a trisubstituted oxazole ring
and a terminal nitrile group and in the case of superstolide A the side chain is constituted by a
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Nꢀacetyl 1,2ꢀamino alcohol. By comparing the HꢀNMR spectra of both natural products, we
conclude that verongidolide has a cisꢀdecalin core and we hypothesize that the relative
configurations of the substituents on the cisꢀdecalin are similar to the ones of superstolide A.3
Results and Discussion
Based on precedents, two DielsꢀAlder type of reactions4 can be used to access a cisꢀdecalin
system present in macrocyclic compounds, either an intramolecular DielsꢀAlder reaction
(IMDA) or a transannular DielsꢀAlder reaction (TADA).5 At first, we chose to study an
IMDA reaction to produce the cisꢀdecalin system present in verongidolide.6 To access the cisꢀ
decalin A, according to an endoꢀselective IMDA process, the required triene B possessing a
(Z)ꢀα,βꢀunsaturated ester and a (Z,E)ꢀdiene has to be synthesized (Scheme 1).
Scheme 1. Retrosynthetic analysis: access to the verongidolide decalin core by IMDA
The synthesis of triene B started from methyl 3,3ꢀdimethoxy propionate 2. After treatement of
2 with the Weinreb amine hydrochloride under basic conditions (iPrMgCl, THF, −10 °C to
0 °C) followed by the addition of methanol, in the presence of K2CO3 (cat.), 3 was isolated in
70% yield (over the 2 steps). The transformation of 3 to (R)ꢀhydroxyaldehyde 6 was achieved
in 4 steps. After converting acetal 3 into ketone 4 by addition of propynylmagnesium bromide
(THF, −78 °C to 0 °C, 94%),7 the ketone was enantioselectively reduced by applying a
Noyori asymmetric hydrogen transfer using TsꢀDPENꢀRuCl(pꢀcymene) I (10 mol %, iPrOHꢀ
CH2Cl2) to produce 5 in 66% yield with an excellent ee (ee = 90%).8 The reaction needed a
high loading in Noyori’s catalyst (10 mol%), to increase the reaction rate, as at lower loading
(5 mol%), a competitive reduction of the triple bond was eroding the yields in the desired
propargylic alcohol 5. After an alcohol protection/acetal hydrolysis sequence (TBSOTf, 2,6ꢀ
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lutidine then TESOTf, 2,6ꢀlutidine), aldehyde 6 was isolated in 98% yield. The control of the
stereogenic center at C13 was achieved by applying an enantioselective Brown allylboration
to aldehyde 6. Thus, treatment of 6 with (−)Ipc2BAllyl II led to homoallylic alcohol 7 with an
excellent diastereoselectivity (dr>96:4).9 The resulting hydroxyl group in 7 was methylated
(NaH, MeI, 0 °C to rt, 99%) and, after a selective oxidative cleavage of the double bond
(OsO4, NMO then NaIO4), aldehyde 9 was isolated in 69% yield. By using two face selective
agents (I and II), the control of the stereogenic centers at C11 and C13 was achieved with an
excellent diastereoꢀ and enantioselectivity (Scheme 2).
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Scheme 2. Synthesis of aldehyde 9
With aldehyde 9 in hand, this compound was transformed to the precursor of the DielsꢀAlder
adduct in three steps. The first step, to install the required (Z)ꢀα,βꢀunsaturated ester, was a
StillꢀGennari olefination [KHMDS, 18ꢀcrownꢀ6, (CF3CH2CO)2POꢀCH(Me)CO2Me] which
afforded 10 in 74% yield with a Z/E ratio of 94:6.10 The (Z,E)ꢀdiene counterpart was
introduced by using a palladiumꢀcatalyzed stereoselective hydrostannlyation of the alkyne
group [PdCl2(PPh3)2, nBu3SnH, THF, 0 °C, 86%] followed by a Stille coupling reaction of the
ensued vinylstannane 11 with (E)ꢀ3ꢀiodopropenol. The required DielsꢀAlder precursor 12 was
isolated in 85% yield and with an excellent (Z,E) selectivity (Scheme 3).11
Scheme 3. Synthesis of the DielsꢀAlder precursor 12
Intermediate 12 was heated at 210 °C in toluene under microwave irradiation. Unfortunately,
the transꢀdecalin 13 was obtained as the major product in 60% yield, which corresponds to the
exoꢀadduct (JH9ꢀH14 = 10.9 Hz) accompanied by the tricyclic lactone 14 possessing a cisꢀ
decalin ring system (7%) (JH9ꢀH14 = 4.8 Hz), which corresponds to the endoꢀadduct (Scheme 4,
eq 1).12 It is worth mentioning that, during the total synthesis of superstolide A, compound III
was transformed to a mixture of decalins IV by using an IMDA process, IVa being the major
product (63%, 6:2:1) (Scheme 4, eq 2).4a The major difference between precursors 12 and III,
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being the methyl group on the diene at C15 thus, we suspected this methyl group to be at the
origin of the favored exoꢀtransition state during the transformation of 12 to the DielsꢀAlder
adducts (Figure 3).13
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Scheme 4. Intramolecular DielsꢀAlder reaction
As the endoꢀIMDA did not produce the cisꢀdecalin system, we have envisaged the addition of
an extra strain in the exoꢀtransition state by switching to a transannular DielsꢀAlder (TADA)
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reaction by targeting directly lactone 14.
This lactone may be synthesized from
macrolactone 20 available from the already prepared enyne 8 (5 steps) (Scheme 5).15 At first,
a selective dihydroxylation was performed (OsO4, t-BuOH, THF, H2O, 93%) followed by a
stereoselective hydrostannylation to produce 16 [n-Bu3SnH, PdCl2(PPh3)2, THF, 0 °C, 46%].
A Stille coupling was realized, under Fürstner et al.16 conditions between vinylstannane 16
and vinyl iodide 17 (CuTC, Pd(PPh3)4, [Ph2PO2][TBA], DMF). Diene 18 was isolated in 62%
yield and, after oxidative cleavage of the diol (NaIO4, 62%), the resulting aldehyde 19 was
engaged in an intramolecular StillꢀGennari olefination to produce the desired macrocyclic
lactone 20. This lactone was heated under microwave irradiation at 130 °C and also at 210 °C
but, again, the transꢀdecalin 21 was obtained in 55% and 47% yield respectively (Scheme 3).
The transꢀjunction of the 5ꢀmembered ring lactone was not sufficient to counterbalance the
presence of the methyl group at C15, as even the TADA reaction proceeded according to an
exoꢀprocess.
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Scheme 5. Transꢀannular DielsꢀAlder approach
To verify whether the methyl group at C15 is the main contributor to the exoꢀDielsꢀAlder
pathway or if other reasons were responsible of the exoꢀtransition state, DFT calculations of
the transition states were undertaken. In previous studies, we have shown that the
computation of transition states energies can be performed reliably for complex and difficult
DielsꢀAlder reactions.17 Simplified models, where a TBS protecting group was replaced by a
methyl group, e.g. trienes III’, 12’ and 20’ were studied (Figures 2ꢀ4). In the case of III’, a
triene without a C15 methyl group (as in superstolide A), the endoꢀtransition state (endoꢀTS1)
is favored compared to the exoꢀtransition state (exoꢀTS1) by 2.2 kcal/mol. In the case of 12’,
in which a methyl group is present at C15, the exoꢀTS2 transition state is more stable than the
endoꢀTS1 transition state by 1.3 kcal/mol (Figure 2). The endo transition structure has
unfavorable steric interactions between the methyl group and the axial hydrogens on the
tether. Thus, the presence of a methyl group is reversing the endo/exo selectivity of the IMDA
reaction.
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Figure 2. Transition structures for the IMDA reactions of substrates with and without the methyl group on the 3ꢀposition of
the diene. Free energies are in kcal/mol.
For the relevant model 12’, both the endo and exo pathways were fully modeled, and the
relative stabilities of the resulting exoꢀ13’ and endoꢀ14’ decalins were calculated. There is no
significant difference between them (0.3 kcal/mol). These theoretical results suggest that the
DielsꢀAlder reaction, in the case of 12’, is under kinetic control (Figure 3). Two additional
endoꢀ and exoꢀ transition structures were also computed (Figure S1). Their energies are higher
than that of exoꢀTS1 by 2.6 and 5.3 kcal/mol, respectively. The corresponding products were
not observed experimentally, in agreement with the computed barriers.
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MeO
H
H
OH
MeO
CO2Me
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exo-13’
ΔG = −28.5
exo-TS2
MeO
Me
ΔG‡ = 23.3
OH
MeO
CO2Me
12’
ΔG‡ = 0
MeO
H
H
OH
MeO
CO2Me
endo-14’
ΔG = −28.8
endo-TS2
ΔG‡ = 24.6 (ΔΔG‡ = 1.3)
Figure 3. Full pathway for the IMDA reaction of 12’ that leads to the corresponding exo- and endoꢀproducts, respectively.
Free energies are in kcal/mol.
We next explored the TADA reaction pathway on the model macrolactone 20’ (Figure 4). As
predicted, the exo product that has a transꢀfused [5,6]ꢀbicyclic structure is much less stable
than the endo product by 10.8 kcal/mol (Figure 4). The transition structures are more
synchronous in the TADA reaction. The activation energies are ~3 kcal/mol higher than the
corresponding IMDA reactions. However, the exoꢀtransition state exoꢀTS3 is still favored
over the endoꢀTS3 by 1.2 kcal/mol. The experimentally observed selectivity could be
explained by the irreversibility of the reaction (still under kinetic control).
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MeO
H
H
H
MeO
O
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O
9
exo-21’
ΔG = −26.9
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exo-TS3
ΔG‡ = 26.6
MeO
MeO
20’
O
O
ΔG‡ = 0
MeO
H
MeO
H
O
O
endo-21’
ΔG = −37.7
endo-TS3
ΔG‡ = 27.8 (ΔΔG‡ = 1.2)
Figure 4. Full pathway for the TADA reaction of 20’ that leads to the corresponding exo and endo products, respectively.
Free energies are in kcal/mol.
Based on the experimental results and on the calculations, the access to the cisꢀdecalin core of
verongidolide will be difficult through an IMDA or a TADA process applied to diverse
trienes having a methyl group at C15. In consequence, another approach to synthesize the cisꢀ
decalin core of verongidolide is under investigation in our laboratory and will be reported in
due course.
Experimental Section
Computational details
All density functional theory (DFT) calculations were performed using Gaussian 09. 18
Geometry optimizations and frequency calculations were performed at the M06ꢀ2X/6ꢀ31G(d)
level of theory.19 Normal vibrational mode analysis confirmed that optimized structures are
minima or transition structures. Truhlar’s quasiharmonic correction was used to compute
molecular entropies to reduce error caused by the breakdown of the harmonic oscillator
approximation.20 More accurate M06ꢀ2X/6ꢀ311+G(d,p) singleꢀpoint energies with the SMD
solvation model were computed.21 All reported energies are Gibbs free energies determined
by summing these higher level singleꢀpoint electronic energies and ZPE and thermal
corrections determined at the lower level.
Experimental section
General Experimental Methods. All moisture and oxygen sensitive reactions were carried
out in ovenꢀdried glassware under an argon atmosphere. THF, Et2O, and CH2Cl2 were dried
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using a purificator. Acetone, petroleum ether (PE), pentane, and ethyl acetate (EtOAc) were
used as received. Commercially available reagents were used as received. Reactions run at
room temperature were performed between 20 and 25 °C. Reactions run under microwave
heating were performed in a microwave reactor, the temperature being controlled by an IR
sensor that was calibrated by an internal probe. Solvent evaporations were conducted under
reduced pressure at temperatures less than 45 °C. TLC was performed on silica gel plates
visualized either with a UV lamp (254 nm) or using a staining solution (pꢀanisaldehyde or
KMnO4) followed by heating. Column chromatography was carried out under positive
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pressure using silica gel (MerckꢀKieselgel 60, 230−400) and the indicated solvents [v/v; used
without purification, including petroleum ether (boiling range 40−60 °C)]. 1H NMR spectra of
samples were run at 400 MHz, and chemical shifts are given in ppm (δ) comparatively to the
residual solvent signal, which was used as an internal reference (benzeneꢀd6: δ = 2.16 ppm;
CDCl3: δ = 7.26 ppm). Coupling constants (J) are given in Hertz (Hz), and the following
abbreviations are used to describe the signal multiplicity: s (singlet), br (broad), d (doublet), t
(triplet), q (quadruplet), quint (quintuplet), and m (multiplet, massif). 13 C NMR spectra of the
samples were run at 100 MHz. Chemical shifts are given in ppm (δ) comparatively to the
residual solvent signal, which was used as an internal reference (benzeneꢀd6: δ = 128.06 ppm;
CDCl3: δ = 77.0 ppm). Infrared (IR) spectra were recorded neat (IRFT), and wavenumbers are
indicated in cm−1. Highꢀresolution mass spectra (HRMS) were performed using ESI and a
TOF mass analyzer.
N,3,3-Trimethoxy-N-methylpropanamide (3).7 To a solution of N,Oꢀdimethylhydroxylamine
hydrochloride (8.32 g, 85.34 mmol, 1.1 equiv) in THF (155 mL), cooled to −10 °C, was
added dropwise iPrMgCl (2M in THF, 89.2 mL, 178.43 mmol, 2.3 equiv). The mixture was
stirred for 10 min at the same temperature, then methyl 3,3ꢀdimethoxypropionate (11 mL,
77.58 mmol, 1 equiv) was added dropwise and the reaction was allowed to warm to room
temperature and stirred for 24 h. A second portion of iPrMgCl (2M in THF, 30 mL, 60 mmol,
0.7 equiv) was added and the reaction was stirred for 3 h. After confirming completion by GC
monitoring, the reaction mixture was poured into a mixture of ice and a saturated aqueous
solution of NH4Cl. The phases were separated and the aqueous layer was extracted three
times with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4,
filtered and concentrated under vacuum. The crude product obtained was contaminated with
35% of MeOH elimination byproduct. A solution of the crude product obtained above in
MeOH (85 mL) was treated with potassium carbonate (1.98 g, 14.33 mmol, 18.5 mol %) and
the mixture was stirred at room temperature for 4.5 h with concomitant GC monitoring. After
complete conversion of MeOH elimination byproduct, the solvent was evaporated in vacuo.
The residue obtained was diluted with CH2Cl2 and washed with water and brine. The
combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure. The crude product was purified by silica gel column chromatography
(PE/EtOAc = 5:5 to 3:7) to afford the Weinreb amide 3 as a colorless oil (9.67 g, 70%). IR
1
(neat) 1656, 1609, 1442, 1388, 1235, 1182, 1118, 1063, 995, 921, 836, cmꢀ1; HꢀNMR (400
MHz, CDCl3)
δ (ppm) 4.84 (t, J = 5.7 Hz, 1H), 3.67 (s, 3H), 3.37 (s, 6H), 3.16 (s, 3H), 2.75
(d, J = 5.7 Hz, 2H); 13CꢀNMR (100 MHz, CDCl3)
δ (ppm) 170.4, 102.2, 61.3, 54.1 (2C), 36.3,
31.8; MS (EI) m/z (%) 177 (M+•, <1), 146 ([MꢀOMe]+, 10), 117(19), 104(15), 85 (39), 75
(100), 60 (9).
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1,1-Dimethoxyhex-4-yn-3-one (4). To a solution of Weinreb amide 3 (9.28 g, 52.74 mmol, 1
equiv) in THF (300 mL), cooled to −78 °C, was added dropwise 1ꢀpropynylmagnesium
bromide (0.5 M solution in THF, 115 mL, 57.61 mmol, 1.1 equiv) over 30 min. The mixture
was stirred for 10 min at −78 °C, then it was warmed to 0 °C and stirred for 14 h. The
reaction mixture was poured into a cold saturated aqueous solution of ammonium chloride
and diluted with EtOAc. The phases were separated and the aqueous layer was extracted three
times with EtOAc. The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified
by silica gel column chromatography (PE/EtOAc = 9:1 to 4:1) to afford ketone 4 as an orange
oil (7.74 g, 94%). IR (neat) 1671, 1444, 1364, 1252, 1165, 1116, 1072, 1052, 1000, 974 cmꢀ1;
1HꢀNMR (400 MHz, CDCl3) δ (ppm) 4.91 (t, J = 5.8 Hz, 1H), 3.33 (s, 6H), 2.83 (d, J = 5.8
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Hz, 2H), 2.00 (s, 3H); CꢀNMR (100 MHz, CDCl3) δ (ppm) 183.5, 100.6, 91.0, 80.2, 53.4 (,
2C), 48.7, 4.0; HRMS (ESI) m/z [M+Na]+ calculated for (C8H12O3)Na+: 179.0679, found:
179.0679.
(S)-1,1-Dimethoxyhex-4-yn-3-ol (5). To a solution of propargylic ketone 3 (6.36 g, 40.75
mmol, 1 equiv) in iPrOH (764 mL) and CH2Cl2 (30 mL) at room temperature was added
Noyori catalyst I [(S,S)ꢀRu] (2.44 g, 4.07 mmol, 10 mol %) in CH2Cl2 (11 mL). The reaction
mixture was stirred for 2.5 h and then concentrated under vacuum. The crude mixture was
purified by silica gel column chromatography (PE/EtOAc = 4:1) to afford the propargylic
alcohol 5 as a light yellow oil (4.25 g, 66%) along with the an over reduction byproduct as a
yellow oil (1.96 g, 30%, see SI for details). [α
]2ꢀ0 – 11.0 (c = 1.0, CHCl3); IR (neat) 1385,
1190, 1190, 1123, 1052, 912, 831, 755 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3) δ (ppm) 4.68 (t, J =
5.8 Hz, 1H), 4.48 (tq, J = 5.7, 2.2 Hz, 1H), 3.36 (s, 3H), 3.34 (s, 3H), 1.98 (t, J = 5.8 Hz, 2H),
1.83 (d, J = 2.0 Hz, 3H); 13CꢀNMR (100 MHz, CDCl3) δ (ppm) 102.8, 81.0, 79.5, 59.3, 53.4,
53.1, 39.8, 3.5; HRMS (ESI) m/z [M+Na]+ calculated for (C8H14O3)Na+: 181.0835, found:
181.0836. The OH group was not detected in the 1HꢀNMR.
(S)-(S)-1,1-dimethoxyhex-4-yn-3-yl 3,3,3-trifluoro-2-methoxy-2-phenylpropanoate, Mosher
ester of 5. To a solution of propargylic alcohol 5 (10.1 mg, 64
(1.1 mL) at room temperature was added pyridine (16 L, 198
Sꢀ(−)ꢀMTPACl (23 L, 122 mol, 1.9 equiv). The mixture was stirred at room temperature
ꢀmol, 1 equiv) in dry CH2Cl2
ꢀ
ꢀmol, 3.1 equiv), followed by
ꢀ
ꢀ
for 19 h and then quenched with water. After dilution with Et2O, the phases were separated
and the aqueous layer was extracted twice with Et2O. The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum.
After proton NMR analysis, the crude product was purified by preparativeꢀTLC plate to
afford the Mosher ester as a colorless oil (13 mg, 54.2%, dr = 95:5). [
CHCl3); IR (neat)
2948, 1750, 1451, 1390, 1270, 1248, 1167, 1123, 990, 963, 754, 648 cmꢀ
1; HꢀNMR (400 MHz, CDCl3)
7.55ꢀ7.53 (m, 2H), 7.42ꢀ7.38 (m, 3H), 5.53 (ddq, J = 8.1,
α
]2ꢀ0 + 2.0 (c = 1.0,
ν
1
δ
6.3, 2.1, 1H), 4.50 (t, J = 5.9 Hz, 1H), 3.55 (d, J = 1.0 Hz, 3H), 3.33 (s, 3H), 3.31 (s, 3H),
13
2.21ꢀ2.15 (m, 1H), 2.09 (td, J = 14.0, 6.2 Hz, 1H), 1.83 (d, J = 2.0 Hz, 3H); CꢀNMR (100
MHz, CDCl3)
δ 165.5, 132.0, 129.6 (2C), 128.3, 127.5 (2C), 101.0, 83.4, 74.9, 63.9, 55.5,
53.1, 53.0, 37.9, 3.5; HRMS (ESI) m/z [M+Na]+ calculated for (C18H21F3O5)Na+: 397.1233,
found: 397.1230.
(S)-tert-butyl((1,1-dimethoxyhex-4-yn-3-yl)oxy)dimethylsilane, TBS protected ether of 5. To a
solution of propargylic alcohol 5 (5.09 g, 32.14 mmol) in CH2Cl2 (184 mL) at −78 °C was
added 2,6ꢀlutidine (8.2 mL, 70.71 mmol, 2.2 equiv), followed by TBSOTf (11.08 mL, 48.21
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mmol, 1.5 equiv). The mixture was stirred at −78 °C for 0.5 h and at 0 °C for 2 h. The
reaction was quenched by addition of a saturated aqueous solution of NaHCO3 and the phases
were separated. The aqueous layer was extracted twice with CH2Cl2 and the combined
organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration and
concentration under vacuum, the crude product was obtained and purified by silica gel
column chromatography (PE/EtOAc = 10:0.2 to 10:0.3) to afford quantitatively the protected
alcohol as an orange oil (8.76 g). [
α
]2ꢀ0 – 48.8 (c = 1.0, CHCl3); IR (neat) 2955, 1472, 1386,
(ppm) 4.53
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1362, 1251, 1190, 1148, 972, 833, 776, 666 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3)
δ
(dd, J = 6.7, 5.0 Hz, 1H), 4.40 (ddq, J = 8.1, 5.6, 2.2 Hz, 1H), 3.32 (s, 3H), 3.31 (s, 3H), 1.99ꢀ
1.86 (m, 2H), 1.81 (d, J = 2.2 Hz, 3H), 0.89 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); 13CꢀNMR (100
MHz, CDCl3)
δ (ppm) 101.7, 80.4, 80.3, 59.8, 53.10, 52.6, 41.8, 25.8 (3C), 18.1, 3.5, −4.5,
−5.1; HRMS (ESI) m/z calculated for (C14H28O3Si)Na+: 295.1700, found: 295.1704.
(S)-3-[(tert-Butyldimethylsilyl)oxy]hex-4-ynal (6). To a solution of TBSꢀprotected alcohol 5
(7.53 g, 27.63 mmol, 1 equiv) in CH2Cl2 (270 mL), cooled to −78 °C, was added 2,6ꢀlutidine
(9.64 mL, 82.91 mmol, 3 equiv), followed by TESOTf (12.5 mL, 55.27 mmol, 2 equiv). The
mixture was warmed to 0 °C and stirred for 2 h at the same temperature. After confirming the
disappearance of the starting material by TLC or GC analysis, the reaction mixture was
quenched by addition of water and stirred for 1 h at 0 °C. The phases were separated and the
aqueous layer was extracted twice with CH2Cl2. The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude
product was purified by silica gel column chromatography (PE/EtOAc = 95:5) to afford the
aldehyde 6 as an orange oil (6.25 g, quant.). [
α
]2ꢀ0 – 58.9 (c = 1.0, CHCl3); IR (neat) 1727,
(ppm) 9.81 (t, J = 2.3 Hz,
1472, 1342, 1252, 1087, 1005, cmꢀ1; 1HꢀNMR (400 MHz, CDCl3)
δ
1H), 4.81 (ddq, J = 6.7, 5.1, 2.1 Hz, 1H), 2.71 (ddd, J = 16.1, 6.6, 2.5 Hz, 1H), 2.63 (ddd, J =
16.1, 5.0, 2.2 Hz, 1H), 1.82 (d, J = 2.1, 3H), 0.87 (s, 9H), 0.14 (s, 3H), 0.10 (s, 3H); 13CꢀNMR
(100 MHz, CDCl3)
δ (ppm) 200.1, 81.9, 79.2, 58.5, 51.7, 25.7 (3C), 18.1, 3.5, −4.5, −5.2;
HRMS (ESI) m/z calculated for (C12H22O2Si)Na+: 249.1281, found: 249.1283.
(4S,6S)-6-[(tert-Butyldimethylsilyl)oxy]non-1-en-7-yn-4-ol (7).
A
(−)ꢀIpc2B(allyl)borane
solution (1M in pentane, 25 mL, 25 mmol, 1 equiv) was added to a round bottom flask
containing anhydrous Et2O (50 mL) and cooled to −100 °C (MeOH, liq N2). To this solution,
was slowly added along the side of the flask, via cannula, a solution of aldehyde 6 (5.66 g, 25
mmol, 1 equiv) in Et2O (25 mL). The mixture was stirred for 2 h at −100 °C, then methanol (1
mL) was added to quench the reaction. The reaction mixture was allowed to warm to room
temperature, and then NaOH (3N, 10 mL) was added, followed by H2O2 (20 mL). After
stirring for 8 h at room temperature, the reaction mixture was diluted with Et2O and water.
The phases were separated and the aqueous layer was extracted with Et2O three times. The
combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under vacuum. The crude product was purified by silica gel column
chromatography (PE/EtOAc = 10:0.3 to 95:5) to afford the alcohol 7 as a colorless oil (5.37 g,
20
ꢀ
80%, dr = 96:4). [
α]
–41.9 (c = 1.0, CHCl3); IR (neat) 1471, 1361, 1251, 1146, 1071, 1003,
913, 834 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3) δ(ppm) 5.83 (ddd, J = 17.1, 10.3, 7.2 Hz, 1H),
5.13ꢀ5.07 (m, 2H), 4.55 (tq, J = 6.8, 2.2 Hz, 1H), 3.89 (m, J = 6.0 Hz, 1H), 2.25ꢀ2.21 (m, 2H),
1.82ꢀ1.78 (m, 2H), 1.81 (d, J = 2.1 Hz, 3H), 0.90 (s, 9H), 0.16 (s, 3H), 0.14 (s, 3H); 13CꢀNMR
(100 MHz, CDCl3) δ(ppm) 134.6, 117.6, 81.3, 80.2, 69.8, 63.1, 44.6, 41.9, 25.7 (3C), 18.0,
3.5,
−4.3, −
5.0; HRMS (ESI) m/z calculated for (C15H28O2Si)Na+: 291.1751, found: 291.1749.
The OH group was not detected in the 1HꢀNMR.
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tert-Butyl[((4S,6S)-6-methoxynon-8-en-2-yn-4-yl)oxy]dimethylsilane (8). To a solution of
alcohol 7 (4.71 g, 17.55 mmol, 1 equiv) in THF (180 mL) at 0 °C was added NaH (60%
dispersion in mineral oil, 2.81 g, 70.21 mmol, 4 equiv). The reaction mixture was stirred at
0 °C for 10 min, then MeI (7.65 mL, 122.86 mmol, 7 equiv) was added. The resulting mixture
was stirred at room temperature for 19 h, and then the reaction was quenched by addition of a
saturated aqueous solution of NH4Cl. The phases were separated and the aqueous layer was
extracted twice with Et2O. The combined organic extracts were dried over anhydrous Na2SO4,
filtered, and concentrated in vacuo. The crude product was purified by silica gel column
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chromatography (PE/EtOAc = 98:2 to 95:5) to afford enyne 8 as a colorless oil (4.96 g,
20
quant.). [
α]
– 17.8 (c = 1.0, CHCl3); IR (neat) 1641, 1471, 1462, 1360, 1250, 1149,
ꢀ
1076 cmꢀ1; 1HꢀNMR (400 MHz, CDCl3)
δ (ppm) 5.82 (ddt, J = 17.1, 10.2, 7.0 Hz, 1H), 5.11ꢀ
5.04 (m, 2H), 4.48 (ddq, J = 8.2, 6.1, 2.1 Hz, 1H), 3.45 (dtd, J = 8.1, 5.7, 4.6 Hz, 1H), 3.33 (s,
3H), 2.29 (dddt, J = 7.1, 5.8, 2.6, 1.5 Hz, 2H) 1.90ꢀ1.79 (m, 1H), 1.83 (d, J = 2.1 Hz, 3H),
1.71 (ddd, J = 13.7, 8.2, 4.6, 1H), 0.89 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); 13CꢀNMR (100
MHz, CDCl3)
δ (ppm) 134.5, 117.1, 80.6, 80.5, 77.5, 60.9, 56.7, 43.1, 37.9, 25.8 (3C), 18.2,
3.5, 4.5,
−
−
5.0; HRMS (ESI) m/z calculated for (C16H30O2Si)Na+: 305.1907, found 305.1904.
(3R,5S)-5-[(tert-Butyldimethylsilyl)oxy]-3-methoxyoct-6-ynal (9). To a solution of enyne 8
(2.0 g, 7.09 mmol, 1 equiv) in tꢀBuOH/THF/H2O (64:12.8:6.4 mL) at room temperature was
added 4ꢀmethylmorpholine Nꢀoxide (NMO) (1.41 g, 12.05 mmol, 1.7 equiv), followed by
OsO4 (2.5% wt in tBuOH, 4.6 mL, 0.35 mmol, 0.05 equiv). The reaction mixture was stirred
for 2 h at room temperature and then quenched by addition of a saturated aqueous solution of
Na2S2O3. After dilution with EtOAc, the phases were separated and the aqueous layer was
extracted three times with EtOAc. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product
was purified by silica gel column chromatography (PE/EtOAc = 1:1 to 2:3) to afford the
corresponding diol as a yellow oil (2.09 g, 93%, dr = 60:40). To a solution of the diol
intermediate (2.82 g, 8.29 mmol, 1 equiv) in THF (30 mL) and H2O (30 mL) at room
temperature was added NaIO4 (5.32 g, 24.88 mmol, 3 equiv). The mixture was stirred for 2 h
at room temperature, and then quenched by addition of a saturated aqueous solution of
Na2S2O3. The phases were separated and the aqueous layer was extracted three times with
EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated under vacuum. The crude material was purified by silica gel column
chromatography (PE/EtOAc = 9:1) to yield aldehyde 9 as a colorless oil (1.77 g, 75%). [α
]2ꢀ0 –
29.1 (CHCl3, c = 1.0); IR (neat) 1713, 1463, 1362, 1252, 1147, 1084, 1005, 939, 911 cmꢀ1;
1HꢀNMR (400 MHz, CDCl3) δ (ppm) 9.79 (t, J = 2.2 Hz, 1H), 4.49 (ddq, J = 6.8, 6.2, 2.0 Hz,
1H), 3.96 (qd, J = 6.6, 5.0 Hz, 1H), 3.34 (s, 3H), 2.69ꢀ2.57 (m, 2H), 2.03 (dt, J = 13.8, 6.4 Hz,
1H), 1.83 (d, J = 2.2 Hz, 3H), 1.82ꢀ1.72 (m, 1H), 0.88 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H); 13Cꢀ
NMR (100 MHz, CDCl3) δ (ppm) 201.4, 81.1, 80.0, 73.7, 60.5, 56.9, 48.3, 42.9, 25.8 (3C),
18.1, 3.5,
−4.5, −
5.1; HRMS (ESI) m/z [M+Na]+ calculated for (C15H28O3Si)Na+: 307.1700,
found: 307.1701.
(5S,7S,Z)-Methyl 7-[(tert-butyldimethylsilyl)oxy]-5-methoxy-2-methyldec-2-en-8-ynoate (10).
To a solution of methyl 2ꢀ(bis(2,2,2ꢀtrifluoroethoxy)phosphoryl)propanoate (1.70 g, purity =
90%, 4.61 mmol, 1.2 equiv) and 18ꢀcrownꢀ6 ether (5.07 g, 19.2 mmol, 5 equiv) in anhydrous
THF (62 mL), cooled to
− 78 °C, was added dropwise a solution of KHMDS (0.5 M in
toluene, 9.2 mL, 4.61 mmol, 1.2 equiv). The mixture was stirred for 30 min at the same
temperature, and then a solution of aldehyde 9 (1.09 g, 3.84 mmol, 1 equiv) in THF (14 mL)
was added dropwise. After stirring for 1 h, the reaction was quenched with a saturated
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aqueous solution of NH4Cl. The mixture was diluted with Et2O and extracted three times. The
combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and
concentrated under vacuum. The crude material was purified by silica gel column
6
7
8
9
chromatography (PE/EtOAc = 10:0.5) to yield the α,βꢀunsaturated ester 10 as a colorless oil
(1.0 g, 74%). [
α
]2ꢀ0 – 13.3 (c = 1.0, CHCl3); IR (neat) 1717, 1460, 1435, 1361, 1249, 1222,
1
1131, 1085, cmꢀ1; HꢀNMR (400 MHz, CDCl3)
δ (ppm) 6.02 (td, J = 7.2, 1.5 Hz, 1H), 4.47
(ddq, J = 7.8, 6.3, 2.0 Hz, 1H), 3.73 (s, 3H), 3.52ꢀ3.48 (m, 1H), 3.33 (s, 3H), 2.73 (ddt, J =
7.3, 5.6, 1.8 Hz, 2H), 1.91 (q, J = 1.9 Hz, 4H), 1.83 (d, J = 2.2 Hz, 3H), 1.68 (ddd, J = 13.7,
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7.9, 4.8 Hz, 1H), 0.88 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H); 13CꢀNMR (100 MHz, CDCl3)
δ
(ppm) 168.2, 138.8, 128.5, 80.6, 80.5, 77.4, 60.9, 56.6, 51.2, 43.2, 33.1, 25.8 (3C), 20.80,
18.2, 3.53,
377.2118.
−4.5, −
5.0; HRMS (ESI) m/z calculated for (C19H34O4Si)Na+: 377.2118, found:
(2Z,5S,7S,8E)-Methyl 7-[(tert-butyldimethylsilyl)oxy]-5-methoxy-2-methyl-9-(tributylstannyl)
deca-2,8-dienoate (11). To a solution of alkyne 10 (819 mg, 2.31 mmol) in dry THF (26 mL),
cooled to 0 °C, was added PdCl2(PPh3)2 (162 mg, 0,231 mmol, 10 mol %), followed by a slow
syringe pump addition of Bu3SnH (870 ꢀL, 3.23 mmol, 1.4 equiv) over 1 h. The reaction
mixture was stirred at 0 °C for 1 h, then concentrated under vacuum. The crude mixture was
purified by silica gel column chromatography (PE/EtOAc = 98:2 to 97:3) to afford the vinyl
stannane 11 as a colorless oil (1.28 g, 86%).Error! Bookmark not defined.
[
α]
– 2.7 (c = 1.0,
20
ꢀ
CHCl3); IR (neat) 1720, 1460, 1435, 1376, 1250, 1220, 1136, 1073, 1004, 963, 939 cmꢀ1; 1Hꢀ
NMR (400 MHz, CDCl3) δ (ppm) 6.01 (td, J = 7.1, 1.6 Hz, 1H), 5.44 (dq, J = 8.3, 1.9 Hz,
1H), 4.66 (dt, J = 8.2, 6.7 Hz, 1H), 3.72 (s, 3H), 3.28 (s, 4H), 2.76 (m, 2H), 1.91 (d, J = 1.5
Hz, 3H), 1.85 (d, J = 1.7 Hz, 4H), 1.54ꢀ1.38 (m, 7H), 1.35ꢀ1.25 (m, 6H), 0.90ꢀ0.86 (m, 24H),
13
0.03 (s, 3H), 0.02 (s, 3H); CꢀNMR (100 MHz, CDCl3)
δ (ppm) 168.2, 144.3, 139.1, 138.1,
128.3, 77.3, 65.6, 56.0, 51.2, 42.1, 32.7, 29.2 (3C), 27.4 (3C), 25.9 (3C), 20.8, 19.4, 18.2, 13.7
(3C), 9.1 (3C), 4.2,
4.9; HRMS (ESI) m/z calculated for (C31H62O4SiSn)Na+: 669.3332,
found: 669.3332.
−
−
(E)-3-iodoprop-2-en-1-ol. To a suspension of Cp2ZrCl2 (7.0 g, 24 mmol, 1.2 equiv) in THF
(90 mL) at 0 °C was added DIBALꢀH (1M in THF, 22 mL, 22 mmol, 1.1 equiv). The reaction
mixture was stirred for 0.5 h in the dark to obtain a white suspension of Schwartz reagent
(Cp2ZrHCl). Meanwhile, in another flask, propargyl alcohol (1.2 mL, 20 mmol, 1 equiv) was
added dropwise in a solution of DIBALꢀH (1M in THF, 24 mL, 24 mmol, 1.2 equiv) at −78
°C. After stirring at 0 °C for 0.5 h, the deprotonated solution of propargyl alcohol was added
via cannula to the white suspension of Schwartz reagent at 0 °C and stirring was continued for
2 h at the same temperature. The reaction was then cooled down to −78 °C and a solution of
iodine (7.61 g, 30 mmol, 1.5 equiv) in THF (20 mL) was added dropwise via cannula. The
resulting mixture was stirred at −78 °C for 0.5 h, and then quenched by addition of a saturated
aqueous solution of ammonium chloride. The mixture was diluted with Et2O and extracted
three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered
and concentrated under vacuum. The crude product was purified by silica gel column
chromatography (PE/EtOAc = 8:2) to afford the vinyl iodide as a yellow oil (2.45, 67%). IR
1
(neat) 3300 (br), 2917, 1606, 1414, 1359, 1280, , 962, 927, 751, 662 cmꢀ1; HꢀNMR (400
MHz, CDCl3)
δ (ppm) 6.69 (dt, J = 14.6, 5.5 Hz, 1H), 6.39 (dt, J = 14.5, 1.6 Hz, 1H), 4.09
13
(dd, J = 5.4, 1.6 Hz, 2H), 1.86 (s, 1H); CꢀNMR (100 MHz, CDCl3)δ (ppm) 144.6, 77.8,
65.1; MS (EI) m/z (%) 184 (M+•, 12), 183 (1), 167 (2), 153 (2), 127 (19), 57 (100), 55 (12), 53
(2). Analytical data are in agreement with those reported in the literature.22
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(2Z,5S,7S,8E,10E)-Methyl
7-[(tert-butyldimethylsilyl)oxy]-12-hydroxy-5-methoxy-2,9-
dimethyldodeca-2,8,10-trienoate (12). A solution of vinyl stannane 11 (929 mg, 1.44 mmol, 1
equiv) and (E)ꢀ3ꢀiodopropꢀ2ꢀenꢀ1ꢀol (794 mg, 4.32 mmol, 3 equiv) in freshly distilled DMF
was degassed for 45 min. The degassed solution was then added to a round bottom flask
containing flame dried [Ph2PO2][NBu4] (1.32 g, 2.88 mmol, 2 equiv). Copperꢀthiophene
carboxylate (CuTC) (549 mg, 2.88 mmol, 2 equiv) was then added, followed by Pd(PPh3)4
(166.3 mg, 0.144 mmol, 10 mol %) and the mixture was stirred at room temperature for 2 h.
The reaction was quenched with water and diluted with Et2O. The phases were separated and
the aqueous layer was extracted three times with Et2O. The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum.
The crude mixture was purified by silica gel column chromatography to yield the triene 12 as
4
5
6
7
8
9
10
11
12
13
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15
16
17
18
19
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21
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a yellow oil (502 mg, 85%).Error! Bookmark not defined.
[
α
]2ꢀ0 + 2.8 (c = 1.0, CHCl3); IR (neat)
1
1716, 1459, 1435, 1362, 1249, 1217, 1137, 1083, 1064 cmꢀ1; HꢀNMR (400 MHz, CDCl3)
δ
(ppm) 6.25 (dt, J = 15.7, 1.5 Hz, 1H), 6.0 (ddd, J = 7.6, 6.4, 1.7 Hz, 1H), 5.79 (dt, J = 15.6,
6.0 Hz, 1H), 5.37 (d, J = 9.5 Hz, 1H), 4.62 (ddd, J = 9.0, 7.3, 6.3 Hz, 1H), 4.22 (dd, J = 6.0,
1.5 Hz, 2H), 3.72 (s, 3H), 3.27 (s, 3H), 3.27ꢀ3.22 (m, 1H), 2.82ꢀ2.65 (m, 2H), 1.91 (q, J =1.6
Hz, 3H), 1.85 (dd, J = 13.8, 7.1 Hz, 1H), 1.76 (d, J = 1.2 Hz, 3H) 1.45 (ddd, J = 13.8, 7.3, 5.1
Hz, 1H), 0.85 (s, 9H), 0.02 (s, 3H), ꢀ0.02 (s, 3H); 13CꢀNMR (100 MHz, CDCl3)
δ
(ppm)
168.2, 138.8, 136.0 (2C), 132.2, 128.5, 127.1, 77.0, 66.7, 63.8, 56.0, 51.3, 42.4, 32.6, 25.8
(3C), 20.8, 18.1, 12.8,
−4.2, −
4.8; HRMS (ESI) m/z calculated for (C22H40O5Si)Na+:
435.2537, found: 435.2539. The OH group was not detected in the 1HꢀNMR.
(1R,2R,4aR,5S,7S,8aR)-Methyl 5-[(tert-butyldimethylsilyl)oxy]-2-(hydroxymethyl)-7-methoxy
-1,4-dimethyl-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate
(exoꢀ13)
and
(3aS,5aS,6S,8S,9aR,9bR)-6-[(tert-butyldimethylsilyl)oxy]-8-methoxy-5,9b-dimethyl-
3,3a,5a,6,7,8,9,9a-octahydronaphtho[1,2-c]furan-1(9bH)-one (endo-14). In a microwave vial
was added triene 12 (74.5 mg, 0.18 mmol, 1 equiv), followed by toluene (16 mL), argon was
then bubbled into the solution for 0.5 h. The vial was then fitted with a cap and heated at
210 °C in a microwave reactor for 3.5 h. The reaction was then concentrated under vacuum
and purified by silica gel column chromatography (PE/EtOAc = 8:2 to 7:3) to afford the exoꢀ
decalin 13 as a colorless oil (45 mg, 60%) along with a minor product, the endoꢀdecalin 14
(yellow oil, 6 mg, 8%). Major Product (exoꢀ13): [
α
]2ꢀ0 – 9.7 (c = 1.0, CHCl3); IR (neat) 1726,
1
1462, 1377, 1255, 1209, 1146, 1118, 1078, 1006, 774, 736, 702, 669, 595 cmꢀ1; HꢀNMR
(400 MHz, benzeneꢀd6)
δ (ppm) 5.40 (dt, J = 5.8, 1.8, 1H), 3.57 (ddd, J =10.8, 9.5, 4.3 Hz,
1H), 3.48 (dd, J = 11.2, 4.6, 1H), 3.40 (dd, J = 11.2, 5.5 Hz, 1H), 3.24 (s, 3H), 3.19 (s, 3H),
2.98 (tt, J = 11.0, 4.4 Hz, 1H), 2.84ꢀ2.77 (m, 1H), 2.50ꢀ2.44 (m, 1H), 2.41 (t, J = 10.8 Hz,
1H), 2.26 (ddt, J = 12.2, 4.5, 2.2 Hz, 1H), 2.04 (s, 3H), 1.78 (q, J =12.1 Hz, 1H), 1.65 (q, J =
11.5 Hz, 1H), 1.48 (ddd, J = 12.7, 10.2, 2.3, 1H), 1.19 (s, 3H), 0.94 (s, 9H), 0.07 (s, 6H); 13Cꢀ
NMR (100 MHz, benzeneꢀd6)
δ (ppm) 176.4, 140.2, 124.9, 77.5, 74.7, 62.6, 55.6, 51.2, 49.7,
47.2, 45.4, 44.1, 40.2, 32.4, 26.4 (3C), 25.1, 22.2, 18.3, –3.1, –3.7; HRMS (ESI) m/z
calculated for (C22H40O5Si)Na+: 435.2537, found: 435.2536. The OH group was not detected
in the 1HꢀNMR.
Minor product (lactone endoꢀ14) [
α
]2ꢀ0 – 32.0 (c = 0.8, CHCl3); IR (neat) 1767, 1725, 1453,
1
1381, 1255, 1223, 1108, 1086, 1003 cmꢀ1; HꢀNMR (400 MHz, CDCl3)
δ (ppm) 5.35 (br s,
1H), 4.38 (dd, J = 10.0, 8.8 Hz, 1H), 3.81 (dd, J = 10.4, 8.9 Hz, 1H), 3.72ꢀ3.67 (m, 1H), 3.30
(s, 3H), 3.11 (tt, J = 11.0, 4.5 Hz, 1H), 2.77ꢀ2.72 (m, 1H), 2.55 (br s, 1H), 2.08ꢀ2.03 (m, 1H),
1.91 (s, 3H), 1.77ꢀ1.73 (m, 1H), 1.63 (ddd, J = 13.1, 3.7, 3.1 Hz, 1H), 1.47ꢀ1.37 (m, 1H), 1.31
(s, 3H), 1.28ꢀ1.22 (m, 1H), 0.90 (s, 9H), 0.08 (2s, 6H); 13CꢀNMR (100 MHz, CDCl3)
δ (ppm)
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181.6, 135.7, 120.0, 76.9, 72.4, 70.2, 56.1, 43.8, 41.6, 40.4, 39.0, 37.8, 30.0, 25.8 (3C), 24.4,
23.4, 17.9, –4.8 (2C); HRMS (ESI) m/z calculated for (C21H36O4Si)Na+: 403.2275, found:
403.2277.
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7
8
9
(E)-3-iodoallyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)propanoate (17). To a stirred solution
of methyl 2ꢀ(bis(2,2,2ꢀtrifluoroethoxy)phosphoryl)propanoate 23 (415.2 mg, 1.25 mmol, 1
equiv) in 0.1M phosphate buffer (pH = 7.4) (31.5 mL) and acetone (3.5 mL) was added PLE
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(Sigma, Eꢀ2884, 28.1 mg/mL, 163
ꢀL, 1000 UN) and the mixture was stirred at room
temperature for 23 h. The reaction was quenched by addition of 10% aqueous solution of
hydrochloric acid and diluted with EtOAc. The phases were separated and the aqueous layer
was extracted three times with EtOAc. The combined organic layers were washed with brine,
dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified
by silica gel column chromatography (CHCl3/MeOH = 9:1) to afford the corresponding 2ꢀ
1
(bis(2,2,2ꢀtrifluoroethoxy)phosphoryl)propanoic acid as a white solid (337 mg, 85%). Hꢀ
NMR (400 MHz, methanolꢀd4) δ (ppm) 4.65ꢀ4.53 (m, 4H), 3.16 (dq, J = 22.3, 7.4 Hz, 1H),
1.43 (dd, J = 20, 7.4 Hz, 3H). Analytical data are in agreement with those reported in the
literature.24
To a solution of 2ꢀ(bis(2,2,2ꢀtrifluoroethoxy)phosphoryl)propanoic acid (535 mg, 1.68 mmol,
1 equiv) in CH2Cl2 (4 mL) was added a catalytic amount of DMF (2 drops) and the mixture
was cooled down to 0 °C. Oxalyl chloride (213
dropwise and the reaction mixture was stirred for 20 min at 0 °C. The reaction was then warm
to room temperature and stirred for 2 h. The volatiles were removed under reduced pressure
and the crude acyl chloride was used as such in the next step. To a solution of (E)ꢀ3ꢀiodopropꢀ
2ꢀenꢀ1ꢀol (619 mg, 3.36 mmol, 2 equiv) in CH2Cl2 (6.3 mL), cooled to 0 °C, was added
ꢀL, 2.523 mmol, 1.5 equiv) was added
pyridine (204 ꢀL, 2.52 mmol, 1.5 equiv) and DMAP (10.27 mg, 84 ꢀmol, 0.05 equiv). To the
obtained solution was added at 0 °C a solution of the crude acyl chloride obtained above in
CH2Cl2 (2.5 mL). The reaction was then warmed to room temperature and stirred overnight.
The reaction was quenched by addition of a saturated aqueous solution of NaHCO3 and
extracted three times with CH2Cl2. The combined organic layers were washed with brine,
dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified
by silica gel column chromatography (PE/EtOAc = 8:2) to afford the phosphonate 17 as a
colorless oil (501 mg, 62%). IR (neat) 2969, 1740, 1613, 1293, 1260, 1164, 961, 863, 841,
1
658 cmꢀ1; HꢀNMR (400 MHz, C6D6) δ (ppm) 6.18 (dt, J = 14.7, 5.9 Hz, 1H), 6.07 (dt, J =
14.6, 1.4 Hz, 1H), 4.03ꢀ3.89 (m, 6H), 2.65 (dq, J = 23.4, 7.4 Hz, 1H), 1.15 (dd, J = 19.0, 7.4
13
Hz, 3H); CꢀNMR (100 MHz, C6D6) δ (ppm) 167.7, 138.8, 81.9, 66.6, 62.4 (2C), 39.5 (d, Jd
= 139.2 Hz), 11.32 (d, Jd = 6.45 Hz); HRMS (ESI) m/z [M+Na]+ calculated for
(C10H12F6IO5P)Na+: 506.9263, found: 506.9252.
(2E,4E,6S,8R)-6-[(tert-Butyldimethylsilyl)oxy]-8-methoxy-4-methyl-10-oxodeca-2,4-
dien-1-yl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]propanoate (19). To a stirred solution of
the intermediate diol, precursor to aldehyde 9, obtained as a mixture of diastereoisomers (400
mg, 1.26 mmol) in dry THF (15 mL), cooled to 0 °C, was added PdCl2(PPh3)2 (88.7 mg, 0,126
mmol, 10 mol %), followed by a slow addition using a syringe pump of Bu3SnH (476 ꢀL,
1.77 mmol, 1.4 equiv) over 1 h. The mixture was stirred at 0 °C for 1 h and then concentrated
under vacuum. The crude product was filtered over a silica gel pad (PE/EtOAc = 6:4 to 5:5) to
afford the vinyl stannane 16 as a mixture of diastereoisomers (386 mg, 50%) which was
directly involved in the Stille coupling. A solution of vinyl stannane 16 (227 mg, 374
equiv) and vinyl iodide 17 (235 mg, 486 mol, 1.3 equiv) in distilled DMF (10 mL) was
degassed for 45 min. This solution was added to a round bottom flask containing flame dried
ꢀmol, 1
ꢀ
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[Ph2PO2][NBu4] (344 mg, 0.75 mmol, 2 equiv). Copperꢀthiophene carboxylate (CuTC) (143
mg, 748 ꢀmol, 2 equiv) was then added, followed by Pd(PPh3)4 (43.2 mg, 37.4 ꢀmol, 10 mol
4
5
6
7
8
9
%) and the reaction mixture was stirred at room temperature for 3 h. The reaction was
quenched by addition of water and diluted with Et2O. The phases were separated and the
aqueous layer was extracted three times with Et2O. The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude
product was purified by silica gel column chromatography (PE/EtOAc = 6:4 to 7:3) to yield
diol 18 as a mixture of diastereoisomers (148 mg, 62%). To a solution of the product obtained
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above (148 mg, 219
added NaIO4 (141 mg, 658
ꢀ
mol, 1 equiv) in THF (2 mL) and H2O (2 mL) at room temperature was
ꢀmol, 3 equiv). The mixture was stirred for 2 h at room
temperature and then quenched by addition of a saturated aqueous solution of sodium
thiosulfate. The phases were separated and the aqueous layer was extracted three times with
EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4,
filtered and concentrated under vacuum. The crude mixture was purified by silica gel column
chromatography (PE/EtOAc = 7:3 to 6:4) to yield aldehyde 19 as a yellow oil (87 mg, 62%).
[α
]2ꢀ0 – 7.2 (c = 1.0, CHCl3); IR (neat) 1729, 1460, 1420, 1385, 1297, 1420, 1073, 963 cmꢀ1;
1HꢀNMR (400 MHz, CDCl3) δ (ppm) 9.79 (t, J = 2.3 Hz, 1H), 6.31 (dd, J = 15.6, 0.7 Hz, 1H),
5.70 (dt, J = 16.0, 6.7, Hz, 1H), 5.45 (d, J = 8.9 Hz, 1H), 4.73ꢀ4.68 (m, 2H), 4.63 (dt, J = 8.9,
6.6 Hz, 1H), 4.48ꢀ4.35 (m, 4H), 3.70 (dq, J = 7.1, 5.8 Hz, 1H), 3.28 (s, 3H), 3.30ꢀ3.17 (m,
1H), 2.63ꢀ2.60 (m, 2H), 1.96 (dt, J = 13.8, 6.9, Hz, 1H), 1.76 (d, J = 1.2 Hz, 3H), 1.57ꢀ1.49
(m, 4H), 0.86 (s, 9H), 0.02 (s, 3H), ꢀ0.02 (s, 3H); 13CꢀNMR (100 MHz, CDCl3) δ (ppm)
201.3, 168.2, 139.7, 137.1, 131.9, 120.8, 73.3, 66.8, 66.4, 62.8ꢀ62.3 (2C), 56.3, 47.7, 42.3,
39.5 (dd, Jd = 140.0 Hz), 25.8 (3C), 18.0, 12.6, 11.6 (qd, Jd = 6.4 Hz), –4.3, –4.9; HRMS
(ESI) m/z [M+Na]+ calculated for (C25H41F6O8PSi)Na+: 665.2105, found: 665,2106. The
carbons of the CF3 groups were not detected in the 13CꢀNMR.
(3Z,6S,8S,9E,11E)-8-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-3,10-dimethyloxacyclotrideca-
3,9,11-trien-2-one (20). To a solution of 18ꢀcrownꢀ6 ether (518 mg, 1.96 mmol, 12 equiv) in
toluene (167 mL) was added potassium carbonate (135.5 mg, 0.980 mmol, 6 equiv) and the
mixture was stirred for 3 h at room temperature. A solution of aldehyde 19 (105 mg, 163.4
ꢀmol, 1 equiv) in toluene (167 mL) was then added via cannula to the reaction mixture. The
reaction was then allowed to stir at room temperature for two days. After dilution with Et2O,
the mixture was washed with water and brine. The combined aqueous layers were extracted
twice with Et2O. The combined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The crude mixture was purified by silica gel column
chromatography (PE/EtOAc = 9:1) to afford lactone 20 as a colorless oil (32.6 mg, 52.4%).
[α
]2ꢀ0 – 49.5 (c = 1.0, CHCl3); IR (neat) 1710, 1459, 1385, 1361, 1250, 1207, 1136, 1084, 966
cmꢀ1; 1HꢀNMR (400 MHz, CDCl3) δ (ppm) 6.27 (d, J = 15.7 Hz, 1H), 6.06 (ddd, J = 9.1, 6.2,
1.7 Hz, 1H), 5.71 (ddd, J = 15.8, 7.2, 5.5 Hz, 1H), 5.38 (d, J = 8.8 Hz, 1H), 4.83 (dd, J = 12.9,
5.4 Hz, 1H), 4.63ꢀ4.53 (m, 2H), 3.26 (s, 3H), 3.36ꢀ3.20 (m, 1H), 2.99 (ddd, J = 14.8, 9.1, 4.4
Hz, 1H), 2.53 (ddd, J = 15.2, 6.4, 5.7, Hz, 1H), 1.94 (s, 3H), 1.87 (td, J = 14.1, 7.1 Hz, 1H),
13
1.66 (s, 3H), 1.42 (dt, J = 13.9, 6.2 Hz, 1H), 0.87 (s, 9H), 0.03 (s, 3H), ꢀ0.02 (s, 3H); Cꢀ
NMR (100 MHz, CDCl3) δ (ppm) 167.8, 138.2, 137.5, 137.0, 131.7, 129.2, 122.0, 76.9, 66.8,
64.9, 56.1, 42.4, 32.6, 25.8 (3C), 21.0, 18.1, 12.7, –4.2, –4.9; HRMS (ESI) m/z [M+Na]+
calculated for (C21H36O4Si)Na+: 403, 2275, found: 403.2276.
(3aR,5aR,6S,8S,9aR,9bR)-6-[(tert-Butyldimethylsilyl)oxy]-8-methoxy-5,9b-dimethyl-
3,3a,5a,6,7,8,9,9a-octahydronaphtho[1,2-c]furan-1(9bH)-one (21). A microwave vial was
charged with lactone 20 (14.6 mg, 38
ꢀmol, 1 equiv) in toluene (4.2 mL), then it was
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degassed by purging with Ar for 0.5 h. The vial was then fitted with a cap and heated at
130 °C in a microwave reactor for 8 h. The reaction mixture was then concentrated under
reduced pressure and purified by silica gel column chromatography (PE/EtOAc = 9:1) to
afford lactone 21 as a light yellow oil (8 mg, 55%). [α
]2ꢀ0 + 59.7 (c = 1.0, CHCl3); IR (neat)
1727, 1462, 1376, 1362, 1252, 1104, 1083, 1007, 969 cmꢀ1; 1HꢀNMR (400 MHz, benzeneꢀd6)
δ (ppm) 4.86 (d quint, J = 3.9, 2.1 Hz, 1H), 4.39 (t, J = 11.8 Hz, 1H), 4.10ꢀ3.99 (m, 1H), 3.68
(ddd, J = 11.2, 9.9, 4.6 Hz, 1H), 3.43ꢀ3.32 (m, 1H), 3.14 (s, 3H), 2.75 (tdd, J = 10.9, 4.0, 3.2
Hz, 1H), 2.43 (d sext, J = 11.5, 2.8, Hz, 1H), 2.28 (br t, J = 10.4 Hz, 1H), 2.14 (dt, J = 12.3,
3.5 Hz, 1H), 1.92 (s, 3H), 1.58ꢀ1.40 (m, 2H), 1.16 (s, 3H), 0.95 (s, 9H), 0.70 (br td, J = 12.6,
3.6 Hz, 1H), 0.11 (s, 3H), 0.10 (s, 3H); 13CꢀNMR (100 MHz, benzeneꢀd6) δ (ppm) 175.8,
141.9, 121.6, 76.9, 70.9, 62.7, 55.6, 49.7, 48.0, 47.1, 42.4, 41.2, 32.8, 26.3 (3C), 21.4, 19.6,
18.3, –2.4, –3.6; HRMS (ESI) m/z [M+Na]+ calculated for (C21H36O4Si)Na+: 403.2275, found:
403.2276.
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Supporting Information Available:
NMR data for compounds 3ꢀ21 and computational data.
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References
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1 Carletti, I.; Massiot, G. Macrolides Utiles Comme Agents Anticancereux. 2014, EP2951189
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2 a) D'Auria, M. V.; Debitus, C.; Paloma, L. G.; Minale, L.; Zampella, A. Superstolide A: a
Potent Cytotoxic Macrolide of a New Type From the New Caledonian Deep Water Marine
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3 Natural products coupling constants JH9ꢀ14 = 8 Hz ; M. Badertscher, P. Bühlmann, E. Pretsch,
Structure Determination of Organic Compounds, Springer Berlin Heidelberg, Berlin,
Heidelberg, 2009, 162ꢀ173.
4 a) Roush, W. R.; Champoux, J. A.; Peterson, B. C. Diastereoselective Synthesis of the Cisꢀ
Octahydronaphthalene Nucleus of Superstolides a and B. Tetrahedron Lett. 1996, 37, 8989; b)
Tortosa, M.; Yakelis, N. A.; Roush, W. R. Total Synthesis of (+)ꢀSuperstolide A. J. Am.
Chem. Soc. 2008, 130, 2722; c) Tortosa, M.; Yakelis, N. A.; Roush, W. R. Total Synthesis of
(+)ꢀSuperstolide A. J. Org. Chem. 2008, 73, 9657.
5
Reviews of DielsꢀAlder and applications in similar cases: Takao, K.ꢀI.; Munakata, R.;
Tadano, K.ꢀI. Recent Advances in Natural Product Synthesis by Using Intramolecular
Diels−Alder Reactions. Chem. Rev. 2005, 105, 4779; Juhl, M.; Tanner, D. Recent
Applications of Intramolecular Diels–Alder Reactions to Natural Product Synthesis. Chem.
Soc. Rev. 2009, 38, 2983; Marsault, E.; Toró, A.; Nowak, P.; Deslongchamps, P. The
Transannular Diels–Alder Strategy: Applications to Total Synthesis. Tetrahedron 2001, 57,
4243; Reyes, E.; Uria, U.; Carrillo, L.; Vicario, J. L. Transannular Reactions in Asymmetric
Total Synthesis. Tetrahedron 2014, 70, 9461; Heravi, M. M.; Vavsari, V. F. Recent
Applications of Intramolecular Diels–Alder Reaction in Total Synthesis of Natural Products.
RSC Adv. 2015, 5, 50890; Dhambri, S.; Mohammad, S.; Van Buu, O. N.; Galvani, G.; Meyer,
Y.; Lannou, M. I.; Sorin, G.; Ardisson, J. Recent Advances in the Synthesis of Natural
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