Synthesis of the Core Structure of Palhinine A

Article abstract of DOI:10.1002/ejoc.202100216

We present a strategy to the core structure of the alkaloid palhinine A passing through a 2,5-difunctionalized cyclohexenone. This enone was prepared by a domino Michael/aldol condensation sequence. An allylation reaction on the cyclohexenone followed by

Full text of DOI:10.1002/ejoc.202100216

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Synthesis of the Core Structure of Palhinine A
[a]
[a]
Dominik Gaugele and Martin E. Maier*
We present a strategy to the core structure of the alkaloid
palhinine A passing through a 2,5-difunctionalized cyclohex-
enone. This enone was prepared by a domino Michael/aldol
condensation sequence. An allylation reaction on the cyclo-
hexenone followed by oxy-Cope rearrangement introduced an
allyl group at C3. After the generation of an aldehyde function
on the terminus of the C5 substituent, an intramolecular aldol
reaction led to a bicyclo[2.2.2]octanone. The five-membered
ring of the core structure could be established by an intra-
molecular nitrile oxide-alkene [3+2]-cycloaddition. Prior to this
key transformation, the keto function was converted to an
alkene and the allyl group to an oxime.
Introduction
Plants of the genus Lycopodium are the source of a wide
collection of alkaloids. They are classified into the four main
classes phlegmarine (1), lycodine (2), lycopodine (3), and
[1]
fawcettimine (4). Some of the Lycopodium alkaloids show
promising biological activities, for example, inhibitory activity
on acetylcholinesterase. In 2010, a new Lycopodium alkaloid,
[2]
palhinine A (5) was described (Figure 1). It can be considered
a derivative of fawcettimine where the hemiaminal has opened
to a nine-membered azonane ring, the methyl group at C15
functionalized, the stereochemistry at C15 epimerized, and a
[3]
new ring formed to C4. This results in an isotwistane core
structure. In the meantime, four additional palhinines (B, C, D
and isopalhinine A) were isolated (Figure 1). Regarding their
bioactivity not much has been reported so far. Nevertheless,
due to their novel structures, the palhinines have attracted a lot
of interest from organic chemists.
Their key questions are how to prepare the central
isotwistane core and when to fashion the nine-membered
azacycle. The retrosynthesis of the central isotwistane system
itself is fairly obvious (Figure 2). The central six-membered ring
is the maximal bridged ring since this ring is bridged at four
atoms with another ring. Accordingly, band cuts to these atoms
Figure 1. Structures of four main classes of alkaloids that originate from
lysine and the fawcettimine derivatives called palhinines. The C4À C12 bond
in the depiction of palhinine A (5) is highlighted in blue.
[4]
should lead to suitable simplified starting materials.
The challenge is rather the implementation of the synthesis
[5]
in the laboratory. So far total syntheses of palhinine A were
reported by the groups of Fan and Hsieh. In the synthesis of
[6]
Fan et al. an intramolecular Diels-Alder reaction of triene 10
directly led to the isotwistane 11. However, due to the
transannular strain the formation of the azonane ring by
[
a] Dr. D. Gaugele, Prof. Dr. M. E. Maier
Eberhard Karls Universität Tübingen, Institut für Organische Chemie,
Auf der Morgenstelle 18, 72076 Tübingen, Germany
E-mail: martin.e.maier@uni-tuebingen.de
http://www.oc1.chemie.uni-tuebingen.de
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100216
©
2021 The Authors. European Journal of Organic Chemistry published by
Figure 2. Maximally bridged ring in the isotwistane core of palhinine A (5).
Violett dots: bridgehead atoms where the six-membered ring is bridged with
another ring; grey dots: other atoms of the six-membered (maximally
bridged ring).
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution Non-Commercial License, which permits use,
distribution and reproduction in any medium, provided the original work is
properly cited and is not used for commercial purposes.
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classical ring-closing reactions was not possible. Eventually, an
the nine-membered azonane ring via an azidoketal fragmenta-
tion reaction.
[11]
intramolecular nitrone-alkene cycloaddition (12 to 13) provided
a solution to this problem. In the synthesis of Hsieh et al., a
masked ortho-benzoquinone, fused to the nine-membered
azacycle, was reacted with acrolein to the tricyclic compound Results and Discussion
[7]
1
5. After the conversion of cycloadduct 15 to aldehyde 16 a
radical cyclization led to 17, which was converted to 5 in three
steps (Scheme 1).
Since in our previous route some functionality on the
isotwistane core was lacking, we sought to modify our original
plan. Thus, in order to form the five-membered ring an
intramolecular nitrile oxide-alkene cycloaddition was envisioned
Various groups, including our own, reported synthetic
[5]
studies that led to the palhinine A core structure. To fashion
the bicyclo[2.2.2]octane skeleton, Diels-Alder reactions of cyclic
[12]
(Scheme 2).
This would also introduce a functional group
[8]
[9]
[10]
dienes, radical cyclization, or domino Michael reactions
handle at C4. A suitable functionalized bicyclo[2.2.2]octane
precursor 20 would be obtained by a transannular aldol
reaction. In this paper, we describe the realization of these
plans.
were used. A study by Fan et al. aimed at the construction of
We started with the synthesis of cyclohexenone 21. For this,
we required enal 22 and 3-keto ester 23. Enal 22 was prepared
[
13]
by a cross-metathesis reaction between 3-butenol derivative
2
[
14]
4 and crotonaldehyde in presence of the nitro Grela catalyst
2
5 (1 mol%) (Scheme 3). For the synthesis of keto ester 23 we
[15]
used a Weiler alkylation
with the alkyl bromide 29, prepared in two steps from 1,3-
of tert-butyl 3-oxobutanoate (26)
[16]
Scheme 1. Key steps in the known total syntheses of palhinine A (5).
Scheme 2. Plan for the synthesis of the core structure 18 featuring a
transannular aldol reaction and an intramolecular [3+2] nitrile oxide-alkene
cycloaddition.
Scheme 3. Synthesis of enal 22, β-keto ester 23 and their combination to
cyclohexanone 21.
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propanediol (27). Following a procedure of Carreira et al., we
reacted enal 22 with keto ester 23 in a domino Michael/
was hampered by the formation of diastereomers, for example
in the reaction of 20 with TBSOTf or MOMCl. Luckily, protection
of the hydroxy function as pivalate 34 using pivaloyl chloride in
presence of DMAP proceeded efficiently in 91%. The relative
configuration at C2 could be proven by NOESY-spectroscopy.
intramolecular aldol condensation using DBU in acetonitrile as
[
17,18]
base.
The superfluous carboxylic function was subsequently
[19]
removed under Krapcho conditions. This way a 47% yield of
cyclohexenone 21 was obtained.
1
Thus, 2-H shows NOESY correlations to 5- and 6-H. In the H
We were then faced with the challenge of introducing an
allyl group in the 3-position of enone 21. As it turned out,
conjugate addition of allyltrimethylsilane in presence of Lewis
spectrum, these protons appear at δ=1.84–2.00 ppm and are
not overlapping with other peaks. Since we intended to form
the third ring by an intramolecular cycloaddition reaction,
ketone 34 was converted to exocyclic alkene 35 by a Wittig
reaction. Best results were obtained using KOtBu (10 equiv) as a
base in toluene.
[8b,20]
acids (BF ·Et O, TiCl ) caused decomposition.
The reaction
3
2
4
of allylmagnesium chloride with or without CuI only led to 1,2-
addition. We assume that the axial attack of the Grignard
reagent on half-chair conformer A leads to tertiary alcohol 30
The terminal mono-substituted double bond of diene 35
was then converted to an aldehyde by a domino sequence
consisting of dihydroxylation and periodate cleavage of the
(Scheme 4). The relative stereochemistry of 30 was assigned
based on model A, which features an axial attack on the half-
[21]
[24]
chair conformer. Due to signal overlaps in the H,H-NOESY
spectrum n the region 1.0–2.5 ppm no unambiguous cross-
peaks could be found. However, the later successful formation
of the polycycles validated the assignment. A subsequent
anionic oxy-Cope rearrangement using KH (1.5 equiv) in pres-
ence of 18-crown-6 (1.1 equiv) led to cyclohexanone 31 in 54%
intermediate diol. Crude aldehyde 36 was directly converted
to oxime 37 (Scheme 5). Oxime 37 formed as a mixture of two
isomers. While the isomers could be separated by chromatog-
raphy, in solution (CDCl ) they isomerized to the original E/Z-
3
[25]
13
mixture. This is evident from the C NMR spectrum where
several peaks appear as pairs (for example, C2, 7-CH ). The
2
[22,23]
[26]
yield.
This compound is epimeric at the 2-position (ratio
intramolecular nitrile oxide-alkene cycloaddition proceeded
~
2:1) which is inconsequential. Following the oxidative cleav-
in 57% using aqueous NaOCl in dichloromethane in presence
[
27]
age of the PMB ether, the resulting alcohol 32 was oxidized to
aldehyde 33 using the Dess-Martin periodinane reagent. Upon
treatment with potassium carbonate in methanol, keto alde-
hyde 33 yielded the bicyclic aldol product 20 as a single
diastereomer. The subsequent protection of the hydroxyl group
of Et N for the generation of the dipole from oxime. Other
3
conditions for the oxidation of the oxime to the nitrile oxide
[28]
caused decomposition of substrate 37.
The methylene
protons at C3 are diastereotopic and appear at δ=4.27 (3-exo-
H) and 3.99 (3-endo-H) ppm. Relatively large shift differences
are also seen for the protons at C7, C8, C9, and C1’. The imine
carbon (C8a) appears at δ=173.9 ppm. Saponification of the
pivalic ester 38 gave tetracyclic alcohol 39. Inspection of the
H,H-NOESY spectrum of 39 allowed assignment of the diaster-
eotopic methylene protons exo-3/endo-3 and endo-8/exo-8. For
example, exo-3-H shows cross-peaks to the 1’-H protons,
whereas endo-3 shows a correlation with one of the 9-H
Scheme 4. Introduction of an allyl group via oxy-Cope rearrangement and
formation of the bicyclic system by transannular aldol reaction.
Scheme 5. Intramolecular nitrile oxide-alkene cycloaddition to form tetracy-
clic isoxazoline 38 and its conversion to ketones 18 and 40.
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protons. Subsequent oxidation of alcohol 39 delivered ketone
8. This tetracyclic isoxazoline 18 was obtained quite pure.
room temperature, the volatile constituents were removed in
vacuo. The residue was purified by flash chromatography (petro-
leum ether/ethyl acetate, 10:1 to 3:1) to give enal 22 (9.42 g,
1
Similar to the situation in 39, the H,H-NOESY spectrum of
ketone 18 allowed for the assignment of the 3-H and 8-H
protons. Finally, it was possible to cleave the isoxazoline ring
4
2.76 mmol, 80%) as a slightly brownish oil. R =0.17 (n-hexane/
f
1
ethyl acetate, 4:1); H NMR (400 MHz, CDCl ): δ [ppm]=2.63 (ddd,
3
J=12.9, 6.3, 1.5 Hz, 2H, 4-H), 3.62 (t, J=6.2 Hz, 2H, 5-H), 3.81 (s, 3H,
[29]
with molybdenum hexacarbonyl in acetonitrile,
albeit in
OCH ), 4.47 (s, 2H, ArCH ), 6.14–6.23 (m, 1H, 2-H), 6.84–6.94 (m, 3H,
3
2
1
3
moderate yield and not in high purity. This way, the tricyclic
core structure of palhinine A, diketo alcohol 40 was obtained.
Even though 40 was not very pure, all hydrogen and carbon
atoms could be assigned by 2D-NMR spectroscopy. The two
carbonyl groups appear at δ=218.7 and 213.1 ppm, respec-
tively. There is no indication of hemiacetal formation between
3-H, HAr), 7.25–7.30 (m, 2H, HAr), 9.52 (d, J=7.9 Hz, 1H, 1-H); C NMR
(
100 MHz, CDCl ): δ [ppm]=32.9 (C-4), 55.1 (OCH ), 67.4 (C-5), 72.6
3
3
(ArCH ), 113.7 (C ), 129.2 (C ), 129.8 (C ), 134.0 (C-2), 155.2 (C-3),
2 Ar Ar Ar
1
59.2 (C ), 193.8 (C-1).
Ar
[16]
3
1
1
-(Benzyloxy)propan-1-ol (28). Sodium pieces (504 mg, 22 mmol,
.25 equiv) were added to propanediol (27) (7.61 mL, 8.01 g,
05 mmol, 6 equiv) at room temperature. After the reaction had
the CH OH and C7.
2
subsided a little, the reaction mixture was stirred for 1.5 h at 110°C
to completely dissolve the sodium. Thereafter, the heating was
switched off, KI (30 mg, 0.2 μmol, 0.01 equiv) was added followed
by the dropwise addition of benzyl bromide (2.09 mL, 3.00 g,
Conclusion
18 mmol, 1 equiv). The mixture was then stirred vigorously and
heated to 110°C for 3 h and then stirred for 16.5 h at room
temperature. After adding water (30 mL), the mixture was extracted
with diethyl ether (3×30 mL). The combined organic layers were
washed with aqueous Na S O solution (10%, 30 mL), dried over
We developed a strategy towards the core structure of the
alkaloid palhinine A, which features a central isotwistane ring
system. In order to create the polycyclic system, two key bond-
forming reactions were used. The first one is an intramolecular
2
2
3
Na SO , filtered, and concentrated in vacuo. After purification by
2
4
À 2
°
C), benzyl
(transannular) aldol reaction of keto aldehyde 33 to give the
Kugelrohr (bulb to bulb) distillation (8×10 mbar, 140
ether 28 (2.64 g, 15.87 mmol, 90%) was obtained as a colorless oil.
bicyclo[2.2.2]octanone derivative 20. After some functional
group manipulations, oxime 37 was obtained. Its conversion to
an intermediate nitrile oxide initiated an intramolecular [3+2]-
cycloaddition to give tetracyclic isoxazoline 38. This compound
could be converted to tricyclic diketone 40. Future studies
might probe a similar strategy where the azonane ring of
palhinine A is installed at an earlier stage.
1
R =0.30 (n-hexane/ethyl acetate, 1:1); H NMR (400 MHz, CDCl ): δ
f
3
[
3
ppm]=1.85 (tt, J=5.9, 5.9 Hz, 2H, 2-H), 3.63 (t, J=5.9 Hz, 2H, 1-H),
.73 (t, J=5.8 Hz, 2H, 3-H), 4.50 (s, 2H, PhCH ), 7.25–7.38 (m, 5H,
2
1
3
H ); C NMR (100 MHz, CDCl ): δ [ppm]=32.0 (C-2), 61.0 (C-1), 68.7
Ar
3
(C-3), 73.0 (PhCH
), 127.5 (CAr), 127.5 (CAr), 128.2 (CAr), 138.0 (CAr).
2
[16]
(
(3-Bromopropoxy)methyl)benzene (29). CBr (9.27 g, 27.94 mmol,
4
1
1
.8 equiv) was added to a solution of benzyl ether 28 (2.58 g,
5.52 mmol) in dry dichloromethane (40 mL) at 0°C. Subsequently,
PPh (5.09 g, 19.40 mmol, 1.25 equiv) was added portionwise,
3
whereupon the solution turned yellow. After 10 min, the cooling
bath was removed and a solid precipitated. After 18 h at room
temperature, the precipitate was removed by filtration through a
frit and the filtrate was concentrated in vacuo. Purification of the
Experimental Section
General. All reactions were performed under nitrogen atmosphere.
All solvents used in the reactions were purified before use. The
progress of the reactions was followed by TLC (POLYGRAM SIL G/
UV254). Flash chromatography was performed on silica gel Silica M,
À 1
brown residue by two bulb to bulb distillations (8×10 mbar, 1st
distillation: 190°C, 2nd distillation: 130°C), gave bromide 29 (3.34 g,
0
.04–0.63 mm, from Machery-Nagel GmbH & Co. KG, Germany.
14.59 mmol, 94%) as a slightly yellowish oil. R =0.50 (n-hexane/
f
1
Distilled petroleum ether with a boiling range of 40–60°C was
used. Dry tetrahydrofuran and toluene were distilled from sodium
and benzophenone, whereas CH Cl and DMSO were distilled from
ethyl acetate, 5:1); H NMR (400 MHz, CDCl ): δ [ppm]=2.15 (tt, J=
3
6.2, 6.3 Hz, 2H, 2-H), 3.55 (t, J=6.6 Hz, 2H, 3-H), 3.62 (t, J=5.8 Hz,
1
3
2
2
2H, 1-H), 4.54 (s, 2H, PhCH ), 7.27–7.42 (m, 5H, H ); C NMR
2
Ar
CaH . Acetonitrile (CH CN) was distilled from P O . Methanol and
(100 MHz, CDCl ): δ [ppm]=30.6 (C-3), 32.8 (C-2), 67.6 (C-1), 73.0
2
3
2
5
3
Ethanol were used in HPLC grade quality. All commercially available
compounds (abcr, Acros, Aldrich, Fluka, Merck, and TCI) were used
(PhCH ), 127.6 (C ), 127.6 (C ), 128.3 (C ), 138.2 (C ).
2
Ar
Ar
Ar
Ar
1
13
tert-Butyl 7-(benzyloxy)-3-oxoheptanoate (23). NaH (1.51 g,
2.85 mmol, 3.6 equiv, 2.51 g of a 60% mineral oil suspension) was
without purification. H (400.160 MHz) and C (100.620 MHz)
spectra were recorded on a Bruker Avance 400 III HD spectrometer.
Some of the spectra were acquired on a Bruker AMX 600
6
washed with dry n-hexane (3×10 mL), then slurried with dry THF
1
13
(131 mL, 0.4 m) and cooled to 0°C. At the same temperature, tert-
spectrometer ( H NMR at 600.139 MHz, C NMR at 150.90 MHz).
1
butyl acetoacetate (26) (8.69 mL, 8.29 g, 52.38 mmol, 3 equiv) was
slowly added dropwise to the NaH suspension, with vigorous
evolution of gas. After being stirred for 15 min, n-butyllithium
CDCl3 was used as solvent at room temperature. The H NMR
spectra were referenced to the residual signal of the non-
1
3
deuterated solvent component (CDCl 7.25 ppm) and the C NMR
3
(
2.5 m in hexane, 20.95 mL, 3.36 g, 52.38 mmol, 3 equiv) was added
spectra to the signal of the deuterated solvent (CDCl 77.0 ppm).
3
1
13
dropwise at 0°C. The color changed from colorless to yellow. After
Peak assignments were made by NMR spectroscopy ( H, C, DEPT-
35, H,H-COSY, HSQC, NOESY, and HMBC). HRMS (ESI-TOF) analysis
was performed on Bruker maXis 4G system.
[16]
1
1
.5 h at 0°C, a solution of bromide
29 (4.00 g, 17.46 mmol,
1
equiv) in dry THF (15 mL) was added dropwise at the same
temperature. The dropping funnel was rinsed with dry THF (2×
3 mL). The cooling bath was removed and stirring continued at
[
13]
(
(
E)-5-((4-Methoxybenzyl)oxy)pent-2-enal (22). To a solution of 1-
[13]
4-methoxybenzyloxy)-but-3-en (24) (10.25 g, 53.31 mmol) in dry,
room temperature. After 2 h, saturated aqueous NH Cl solution
4
degassed dichloromethane (100 mL, 0.5 m) were added crotonalde-
hyde (22 mL, 18.7 g, 266 mmol, 5 equiv) and nitro-Grela catalyst 25
(200 mL), diethyl ether (100 mL), and water (20 mL) were added.
The layers were separated and the aqueous layer was extracted
with diethyl ether (3×100 mL). The combined organic layers were
(
356 mg, 0.53 mmol, 0.01 equiv) all at once at room temperature.
The mixture was then refluxed for 16 h. After cooling the mixture to
dried over MgSO , filtered, and concentrated in vacuo. The crude
4
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product was kept on a rotary evaporator at 60°C and at 3.7 mbar
vacuo to give a colorless oil. The crude product was used for the
for 6 h in order to remove as much of the excess tert-butyl
acetoacetate (26) as possible. After purification by flash chromatog-
raphy (petroleum ether/ethyl acetate, 10:1 to 3:1) β-keto ester 23
next reaction step without further purification. R =0.23 (n-hexane/
f
ethyl acetate, 2:1). For analytical purposes, a sample was purified
by flash chromatography (petroleum ether/ethyl acetate, 2:1). The
diastereomeric ratio was determined from the integrals of the
(
3.45 g, 11.25 mmol, 64%) was obtained as a colorless oil. R =0.35
n-hexane/ethyl acetate, 4:1); H NMR (400 MHz, CDCl ): δ [ppm]=
f
1
1
(
protons at the 3-position, which yielded a ratio of 5.7:1. H NMR
3
1
.46 (s, 9H, C(CH ) ), 1.57–1.75 (m, 4H, 5-H, 6-H), 2.55 (t, J=7.2 Hz,
(400 MHz, CDCl ): δ [ppm]=1.09 (t, J=12.3 Hz, 1H, 6-H), 1.44–1.52
3
3
3
2
H, 4-H), 3.32 (s, 2H, 2-H), 3.47 (t, J=6.1 Hz, 2H, 7-H), 4.49 (s, 2 H,
(m, 2H, 1’’’-H), 1.55–1.65 (m, 1H, 4-H), 1.68–1.85 (m, 3H, 5-H, 2’’-H),
1.92 (d, J=12.4 Hz, 1H, 6-H), 1.97–2.08 (m, 2H, 4-H, 1’’-H), 2.14–2.24
(m, 2H, 1’-H, 1’’-H), 2.28–2.41 (m, 1H, 1-H), 3.36–3.50 (m, 4H, 3’’-H,
2’’’-H), 3.73 (s, 3H, OCH ), 4.30–4.38 (m, 2H, PMPCH ), 4.42 (s, 2H,
13
PhCH ), 7.25–7.38 (m, 5H, H ); C NMR (100 MHz, CDCl ): δ [ppm]=
2
Ar
3
2
7
0.2 (C-5), 27.9 (C(CH ) ), 29.0 (C-6), 42.5 (C-4), 50.6 (C-2), 69.9 (C-7),
2.9 (PhCH ), 81.8 (C(CH ) ), 127.5 (C ), 127.6 (C ), 128.3 (C ), 138.5
3 3
2
3 3
Ar
Ar
Ar
3
2
(
3
C ), 166.4 (C-1), 203.1 (C-3); HRMS (ESI-TOF): calcd. for C H O
29.17233 [M+Na] , found 329.17242.
PhCH ), 4.96–5.09 (m, 2H, 3’-H), 5.31–5.36 (m, 1H, 3-H), 5.72–5.85 (m,
Ar
18 26
4
2
+
13
1H, 2’-H), 6.77–6.84 (m, 2H, H ), 7.15–7.30 (m, 7H, H ); C NMR
Ar
Ar
(
(
7
(
1
100 MHz, CDCl ): δ [ppm]=25.9 (C-1’’), 28.9 (C-5), 29.1 (C-2’’), 32.4
3
2
2
1
-(3-(Benzyloxy)propyl)-5-(2-((4-methoxybenzyl)oxy)ethyl)cyclohex-
-enone (21). To a solution of β-keto ester 23 (6.52 g, 21.27 mmol,
.05 equiv) and enal 22 (4.48 g, 20.34 mmol, 1 equiv) in dry
C-4), 36.3 (C-1’’’), 42.1 (C-6), 43.3 (C-1’), 55.2 (OCH ), 67.7 (C-2’’’),
3
0.1 (C-3’’), 72.6 (PMPCH ), 72.7 (PhCH ), 73.5 (C-1), 113.7 (C ), 118.3
2 2 Ar
C-3’), 122.5 (C-3), 127.5 (C ), 127.6 (C ), 128.3 (C ), 129.2 (C ),
Ar Ar Ar Ar
acetonitrile (40 mL) was added at 0°C DBU (6.07 mL, 6.19 g,
30.5 (C ), 133.9 (C-2’), 138.4 (C ), 142.0 (C-2), 159.1 (C ); HRMS
Ar Ar Ar
+
4
0.68 mmol, 2 equiv). The cooling bath was removed and stirring
(
ESI-TOF): calcd. for C H O 473.26623 [M+Na] , found 473.26667.
29 38 4
continued for 1.5 h at room temperature. After the starting
materials could no longer be seen in the TLC, the mixture was
heated to 80°C for a further 2 h. The reaction mixture was cooled
rel-(3R,5S)-3-Allyl-2-(3-(benzyloxy)propyl)-5-(2-((4-methoxybenzyl)
oxy)ethyl)cyclohexanone (31). To suspension of KH (35%
a
to room temperature before a saturated aqueous NH Cl solution
suspension in paraffin oil, 1.72 g, 15.01 mmol, 1.5 equiv) in dry THF
(80 mL) was added 18-crown-6 (2.91 g, 11.00 mmol, 1.1 equiv) at
room temperature. Then a solution of the crude product 30 from
the previous reaction in dry THF (5 mL) was slowly added dropwise
at room temperature and the dropping funnel was rinsed with dry
THF (3×5 mL). The reaction mixture was refluxed for 2.5 h, then
cooled to room temperature before dry methanol (0.5 mL) was
added. This was followed by the addition of saturated aqueous
4
(100 mL) and ethyl acetate (100 mL) were added. The layers were
separated and the aqueous layer was extracted with ethyl acetate
3×100 mL). The combined organic layers were washed with
(
saturated aqueous NaCl solution (100 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was used for
the decarboxylation step without further purification. R =0.37 (n-
hexane/ethyl acetate, 2:1).
f
NH Cl solution (100 mL) and diethyl ether (50 mL). The layers were
separated and the aqueous layer was extracted with diethyl ether
4
LiCl (8.62 g, 203.42 mmol, 10 equiv) and water (6.8 mL) were added
at room temperature to a solution of the crude product from the
previous step in dimethyl sulfoxide (68 mL, 0.3 m), followed by
refluxing of the mixture. After an internal temperature of 153°C
(
3×100 mL). The combined organic layers were washed with
saturated aqueous NaCl solution (5×100 mL), dried over MgSO4,
filtered and concentrated in vacuo. After purification by flash
chromatography (petroleum ether/ethyl acetate, 3:1 to 1:1), cyclo-
hexanone 31 (2.44 g, 5.42 mmol, 54% over 2 steps, epimeric at C-2)
had been reached, the reaction mixture was held at the same
temperature for 45 min. The reaction mixture was then cooled to
0
°C before water (200 ml) and diethyl ether (100 ml) were added.
was obtained as light yellowish oil. R =0.59 (n-nexane/ethyl
f
The layers were separated and the aqueous layer was extracted
with diethyl ether (3×100 mL). The combined organic layers were
washed with saturated aqueous NaCl solution (5×100 mL), dried
1
acetate, 1:1); H NMR (400 MHz, CDCl ): δ [ppm]=1.26–2.59 (m,
3
1
5H), 3.41–3.54 (m, 4H), 3.79 (s, 3H, OCH ), 4.39 (s, 2H), 4.46–4.52
3
(m, 2H), 4.94–5.15 (m, 2H), 5.60–5.89 (m, 1H), 6.85–6.96 (m, 2H, H ),
Ar
over MgSO , filtered and concentrated in vacuo. After purification
13
4
7
.23–7.42 (m, 7H, HAr); C NMR (100 MHz, CDCl ): δ [ppm]=22.9,
3
by repeated flash chromatography (petroleum ether/ethyl acetate,
2
6.9, 27.5, 27.6, 31.3, 31.7, 31.7, 31.8, 34.5, 35.7, 36.6, 37.9, 39.2, 39.9,
3
:1 to 1:1), cyclohexenone 21 (4.10 g, 10.05 mmol, 47% over 2
45.1, 48.3, 53.9, 54.4, 55.2 (OCH ), 67.3, 67.5, 69.8, 70.3, 72.6, 72.7,
3
steps) was obtained as a slightly brownish oil. R =0.27 (n-hexane/
ethyl acetate, 2:1); H NMR (400 MHz, CDCl ): δ [ppm]=1.61–1.80
f
7
2.8, 72.8, 113.7, 116.3, 116.8, 127.5, 127.6, 127.6, 128.3, 128.3,
1
3
129.2, 129.2, 130.4, 136.0, 136.4, 138.5, 138.5, 159.1, 212.1 (CO),
(
m, 4H, 2’-H, 1’’-H), 2.01–2.16 (m, 2H, 5-H, 6-H), 2.19–2.33 (m, 3H, 4-
+
2
14.1 (CO); HRMS (ESI-TOF): calcd. for C H O 473.26623 [M+Na] ,
2
9
38
4
H, 1’-H), 2.42 (dt, J=18.2, 4.7 Hz, 1H, 4-H), 2.55 (ddd, J=15.7, 3.5,
found 473.26667.
1
4
6
.3 Hz, 1H, 6-H), 3.44–3.55 (m, 4H, 3’-H, 2’’-H), 3.82 (s, 3H, OCH3),
.44 (s, 2H, PMPCH ), 4.51 (s, 2H, PhCH ), 6.64–6.71 (m, 1H, 3-H),
rel-(3R,5S)-3-Allyl-2-(3-(benzyloxy)propyl)-5-(2-hydroxyethyl)
2
2
13
.87–6.94 (m, 2H, H ), 7.25–7.40 (m, 7H, H ); C NMR (100 MHz,
cyclohexanone (32). To a solution of PMB ether 31 (2.33 g,
5.17 mmol) in dry dichloromethane (52 mL, 0.1 m) were added at
0°C water (2.6 mL) and DDQ (1.41 g, 6.21 mmol, 1.2 equiv). The
mixture was stirred at 0°C for 6 h. The color changed from green to
Ar
Ar
CDCl ): δ [ppm]=26.1 (C-1’), 28.4 (C-2’), 32.4 (C-4), 32.5 (C-5), 35.4
3
(
7
C-1’’), 44.6 (C-6), 55.2 (OCH ), 67.1 (C-2’’), 69.7 (C3’), 72.7 (PMPCH ),
3
2
2.8 (PhCH ), 113.8 (C ), 127.4 (C ), 127.7 (C ), 128.3 (C ), 129.2
2 Ar Ar Ar Ar
(
(
C ), 130.3 (C ), 138.5 (C ), 139.0 (C-2), 144.5 (C-3), 159.1 (C ), 199.3
orange-red. Thereafter, saturated aqueous NaHCO solution
Ar
Ar
Ar
Ar
3
+
C-1); HRMS (ESI-TOF): calcd. for C H O 431.21928 [M+Na] ,
(100 mL) and diethyl ether (100 mL) were added. After vigorous
shaking in the separating funnel, the aqueous layer turned to a
distinct red color. The layers were separated and the aqueous layer
was extracted with diethyl ether (3×100 mL). The combined
26
32
4
found 431.21944.
rel-(1R,5S)-1-Allyl-2-(3-(benzyloxy)propyl)-5-(2-((4-methoxybenzyl)
oxy)ethyl)cyclohex-2-enol (30). Allyl magnesium chloride in THF
organic layers were dried over MgSO , filtered and concentrated in
4
(8.83 mL, 1.7 m, 15.01 mmol, 1.5 equiv) was added to a solution of
vacuo. After purification by flash chromatography (petroleum
ether/ethyl acetate, 1:1 to 2:3), alcohol 32 (1.52 g, 4.94 mmol,
enone 21 (4.09 g, 10.00 mmol) in dry THF (100 mL, 0.1 m) at 0°C.
After complete addition, the cooling bath was removed and stirring
continued for 45 min at room temperature. Then, saturated
8
0
9%) was obtained as a C2 epimeric mixture as a yellowish oil. R =
f
1
.22 (n-hexane/ethyl acetate, 1:1); H NMR (400 MHz, CDCl ): δ
3
aqueous NH Cl solution (100 mL) and diethyl ether (50 mL) were
4
[
4
2
ppm]=1.21–2.55 (m, 16H), 3.40–3.50 (m, 2H), 3.58–3.67 (m, 2H),
added to the mixture. The layers were separated and the aqueous
layer was extracted with diethyl ether (3×100 mL). The combined
.44–4.49 (m, 2H, PhCH ), 4.94–5.09 (m, 2H, 3’-H), 5.58–5.83 (m, 1H,
2
13
’H), 7.22–7.37 (m, 5H, HAr); C NMR (100 MHz, CDCl ): δ [ppm]=
3
organic layers were dried over MgSO , filtered and concentrated in
4
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Full Papers
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2
3
2.9, 26.8, 27.4, 27.6, 30.9, 31.1, 31.7, 31.8, 34.5, 34.8, 37.9, 38.4, 39.2,
9.3, 39.7, 45.0, 53.9 (C-2), 54.4 (C-2), 60.1, 60.2, 69.8, 70.3, 72.8
mixture was extracted with diethyl ether (3×15 mL). The combined
organic layers were successively washed with saturated aqueous
(
(
PhCH ), 72.8 (PhCH ), 116.3 (C-3’), 116.9 (C-3’), 127.5 (C ), 127.6
NaHCO solution (3×10 mL) and saturated aqueous NaCl solution
2
2
Ar
3
C ), 127.6 (C ), 128.3 (C ), 128.3 (C ), 136.0 (C-2’), 136.5 (C-2’),
(15 mL), dried over MgSO , filtered, and concentrated in vacuo.
Ar
Ar
Ar
Ar
4
1
38.4 (C ), 138.5 (C ), 212.1 (CO), 214.1 (CO); HRMS (ESI-TOF): calcd.
After purification by flash chromatography (petroleum ether/ethyl
Ar
Ar
+
for C H O 352.20872 [M+Na] , found 352.20892.
acetate, 10:1), pivalate 34 (487 mg, 1.18 mmol, 91%) was obtained
21
30
3
1
as a colorless oil. R =0.64 (n-hexane/ethyl acetate, 1:1); H NMR
f
rel-2-((1S,3R)-3-Allyl-4-(3-(benzyloxy)propyl)-5-oxocyclohexyl)
acetaldehyde (33). To a solution of alcohol 32 (2.33 g, 5.17 mmol) in
dry dichloromethane (52 mL, 0.1 m), NaHCO (2.27 g, 27.00 mmol,
6
After 30 min, the cooling bath was removed and the mixture stirred
for a further 1.5 h at room temperature. Saturated aqueous NaHCO
solution (25 mL) and saturated aqueous NaS O solution (25 mL)
were then added. The mixture was stirred for 5 min before diethyl
ether (50 mL) was added. The layers were separated and the
aqueous layer was extracted with diethyl ether (3×50 mL). The
combined organic layers were dried over MgSO , filtered and
concentrated in vacuo. After purification by flash chromatography
(
400 MHz, CDCl ): δ [ppm]=1.12 (s, 9H, C(CH ) ), 1.21–1.29 (m, 1H,
-H), 1.37–1.64 (m, 5H, 3-H, 1’-H, 1’’-H, 2’’-H), 1.73–2.00 (m, 3H, 6-H,
-H, 1’’-H), 2.20–2.36 (m, 5H, 4-H, 3-H, 8-H, 1’-H), 3.41–3.51 (m, 2H,
3
3
3
5
5
3
1
3
equiv) and DMP (2.29 g, 5.40 mmol, 1.2 equiv) were added at 0°C.
’’-H), 4.49 (s, 2H, PhCH ), 4.89–5.08 (m, 2H, 3’-H), 5.15 (d, J=8.6 Hz,
2
13
H, 2-H), 5.59–5.73 (m, 1H, 2’-H), 7.25–7.37 (m, 5H, HAr); C NMR
3
(
100 MHz, CDCl ): δ [ppm]=21.2 (C-1’’), 22.5 (C-2’’), 26.7 (C-4), 26.8
3
2
3
(C(CH ) ), 32.2 (C-5), 32.8 (C-6), 34.6 (C-3), 36.4 (C-1’), 38.5 (C(CH ) ),
3
3
3 3
4
3
4.3 (C-8), 52.4 (C-1), 70.3 (C-2), 70.6 (C-3’’), 72.8 (PhCH ), 117.0 (C-
2
’), 127.3 (C ), 127.5 (C ), 128.2 (C ), 135.5 (C-2’), 138.4 (C ), 177.3
Ar
Ar
Ar
Ar
(
tBuCO ), 213.0 (C-7); HRMS (ESI-TOF): calcd. for C H O 435.25058
2 26 36 4
+
4
[
M+Na] , found 435.25063.
(
(
petroleum ether/ethyl acetate, 4:1 to 3:1) aldehyde 33 1.37 g
rel-(1S,2S,4R,6R)-6-Allyl-1-(3-(benzyloxy)propyl)-7-methylenebicyclo
[2.2.2]octan-2-yl pivalate (35). KOtBu (283 mg, 2.52 mmol, 10 equiv)
4.16 mmol, 92%) was obtained as a C2 epimeric mixture as a
1
slightly yellowish oil. R =0.55 (n-hexane/ethyl acetate, 1:1); H NMR
was added all at once to
a
suspension of meth-
f
(
400 MHz, CDCl ): δ [ppm]=1.26–2.67 (m, 15H), 3.39–3.51 (m, 2H,
yltriphenylphosphonium bromide (900 mg, 2.52 mmol, 10 equiv) in
3
3
’’-H), 4.43–4.52 (m, 2H, PhCH ), 4.95–5.10 (m, 2H, 3’-H), 5.59–5.80
dry toluene (1 mL) under an argon atmosphere at 0°C. The ice bath
2
1
3
(m, 1H, 2’-H), 7.25–7.37 (m, 5H, H ), 9.67–9.73 (m, 1H, CHO);
C
was removed and stirring was continued for 20 min at room
temperature, the suspension turning strongly yellow color. A
solution of ketone 34 (104 mg, 252 μmol) in dry toluene (0.5 mL)
was added dropwise at room temperature. The flask containing the
ketone solution was washed with dry toluene (3×0.5 mL), which
also was added to the reaction mixture. The reaction was heated to
100°C in a sealed flask for 18 h. After cooling to room temperature,
Ar
NMR (100 MHz, CDCl ): δ [ppm]=22.9, 26.8, 27.5, 27.6, 28.8, 29.0,
3
3
1.6, 31.7, 34.3, 37.8, 39.2, 39.7, 44.7, 47.6, 49.3, 50.1, 53.7 (C-4), 54.2
(C-4), 69.8, 70.2, 72.8, 72.9, 116.7 (C-3’), 117.3 (C-3’), 127.5 (CAr),
1
27.5 (C ), 127.6 (C ), 127.6 (C ), 128.3 (C ), 128.3 (C ), 135.6 (C-2’),
Ar Ar Ar Ar Ar
1
36.1 (C-2’), 138.5 (C ), 138.5 (C ), 200.5 (CHO), 200.6 (CHO), 210.7
Ar
Ar
(C-5), 212.8 (C-5); HRMS (ESI-TOF): calcd. for C H O 383.21928 [M
21
28
3
+
+
Na+CH OH] , found 383.21946.
water (5 mL) and diethyl ether (5 mL) were added to the reaction
mixture. The layers were separated and the aqueous layer was
extracted with diethyl ether (3×5 mL). The combined organic layers
were washed with saturated aqueous NaCl solution (5 mL).
Petroleum ether was added up to a mixing ratio of petroleum
ether/diethyl ether of 3:1, which made the solution cloudy. Then
3
rel-(1R,4S,6R,7S)-6-Allyl-1-(3-(benzyloxy)propyl)-7-hydroxybicyclo
2.2.2]octan-2-one (20). To a solution of keto aldehyde 33 (1.36 g,
[
4
.14 mmol) in dry methanol (83 mL, 0.05 m), K CO3 (687 mg,
2
4
.97 mmol, 1.2 equiv) was added all at once at 0°C (ice-water). The
reaction was left in the cooling bath overnight so that the
temperature slowly reached room temperature. After 20 h, most of
the methanol was removed on a rotary evaporator and the residue
taken up with aqueous pH 7 phosphate buffer solution (100 mL,
MgSO was added to the mixture. This mixture was filtered through
4
celite and the filtrate was concentrated in vacuo. The residue was
taken up in diethyl ether (2 mL) and petroleum ether (6 mL) was
added, whereupon the solution became cloudy again. This mixture
was filtered again through celite. Silica gel (1 spatula tip) was added
and then the volatile constituents are removed in vacuo until the
silica gel was free-flowing. After purification by flash chromatog-
raphy (petroleum ether/ethyl acetate, 15:1), alkene 35 (70 mg,
À 1
À 1
pH 7, 3.42 gL
NaH PO ·2H O, 7.26 gL
Na HPO ·2H O) and
2 4 2
2
4
2
diethyl ether (100 mL). The layers were separated and the aqueous
layer was extracted with diethyl ether (3×100 mL). The combined
organic layers were dried over MgSO , filtered, and concentrated in
vacuo. After purification by flash chromatography (petroleum
ether/ethyl acetate, 5:1), hydroxy ketone 20 (770 mg, 2.34 mmol,
4
1
70 μmol, 68%) was obtained as a slightly brownish oil. R =0.70 (n-
f
1
hexane/ethyl acetate, 1:1); H NMR (400 MHz, CDCl ): δ [ppm]=
3
5
7%) was obtained as a colorless oil. R =0.32 (n-hexane/ethyl
f
1
1
1
.02–1.09 (m, 1H, 5-H), 1.12 (s, 9H, C(CH ) ), 1.26–1.33 (m, 1H, 3-H),
.39–1.60 (m, 4H, 1’’-H, 2’’-H), 1.60–1.71 (m, 3H, 5-H, 6-H, 1’-H), 1.82–
.87 (m, 1H, 4-H), 2.06–2.20 (m, 2H, 3-H, 1’-H), 2.22–2.36 (m, 2H, 8-
1
3 3
acetate, 1:1); H NMR (400 MHz, CDCl ): δ [ppm]=1.20–1.29 (m, 1H,
3
5
1
3
-H), 1.40–1.62 (m, 4H, 8-H, 1’-H, 2’’-H), 1.72–1.85 (m, 4H, 4-H, 5-H,
’’-H), 2.08–2.33 (m, 5H, 3-H, 6-H, 8-H, 1’-H), 2.42 (bs, 1H, OH), 3.41–
.57 (m, 2H, 3’’-H), 4.05 (dd, J=2.3, 9.4 Hz, 1H, 7-H), 4.50 (s, 2H,
H), 3.37–3.49 (m, 2H, 3’’-H), 4.44–4.52 (m, 2H, PhCH ), 4.80 (bs, 1H,
2
7
-CH ), 4.92 (dd, J=2.3, 9.1 Hz, 1H, 2-H), 4.93–5.03 (m, 3H, 3’-H, 7-
2
PhCH ), 4.94–5.02 (m, 2H, 3’-H), 5.56–5.69 (m, 1H, 2’-H), 7.26–7.36
13
2
CH ), 5.65–5.77 (m, 1H, 2’-H), 7.22–7.36 (m, 5H, H ); C NMR
13
2
Ar
(
(
m, 5H, HAr); C NMR (100 MHz, CDCl ): δ [ppm]=20.5 (C-1’’), 21.9
C-2’’), 26.9 (C-4), 32.0 (C-5), 32.9 (C-6), 36.0 (C-8), 36.9 (C-1’), 44.5 (C-
3
(
(
(
100 MHz, CDCl ): δ [ppm]=23.0 (C-1’’), 24.6 (C-2’’), 25.6 (C-4), 27.0
3
C(CH ) ), 32.4 (C-5), 33.3 (C-6), 35.2 (C-3), 35.5 (C-1’), 36.1 (C-8), 38.6
3
3
3
(
), 54.9 (C-1), 68.6 (C-7), 70.8 (C-3’’), 73.3 (PhCH ), 116.8 (C-3’), 127.7
2
C(CH ) ), 43.1 (C-1), 70.9 (C-3’’), 70.9 (C-2), 72.7 (PhCH ), 109.6 (7-
3
3
2
C ), 127.8 (C ), 128.4 (C ), 135.8 (C-2’), 137.9 (C ), 215.1 (C-2);
Ar Ar Ar Ar
+
CH ), 115.9 (C-3’), 127.4 (C ), 127.5 (C ), 128.3 (C ), 137.1 (C-2’),
2
Ar
Ar
Ar
HRMS (ESI-TOF): calcd. for C H O 351.19307 [M+Na] , found
3
21
28
3
1
38.6 (C ), 147.1 (C-7), 177.8 (tBuCO ); HRMS (ESI-TOF): calcd. for
Ar 2
+
51.19307.
C H O 433.27132 [M+Na] , found 433.27164.
2
7
38
3
rel-(1R,2S,4S,6R)-6-Allyl-1-(3-(benzyloxy)propyl)-7-oxobicyclo[2.2.2]
octan-2-yl pivalate (34). To a solution of hydroxy ketone 20
rel-(1S,2S,4R,7S)-1-(3-(Benzyloxy)propyl)-6-methylene-7-(2-oxoethyl)
bicyclo[2.2.2]octan-2-yl pivalate (36). To a solution of alkene 35
(
424 mg, 1.30 mmol) in dry dichloromethane (13 mL), were added
(
70 mg, 170 μmol) in a mixture of THF (2 mL) and water (0.4 mL)
pivaloyl chloride (847 μL, 830 mg, 6.46 mmol, 5 equiv) and DMAP
were added K OsO ·2H O (1 mg, 2 μmol, 0.01 equiv) and NMO·H O
2
4
2
2
(
867 mg, 7.10 mmol, 5.5 equiv) at 0°C. After the DMAP had
(
25 mg, 188 μmol, 1.1 equiv). After 15 min at 0°C, the cooling bath
completely dissolved, the cooling bath was removed and the
mixture stirred at room temperature for 22 h. After adding
was removed and the mixture stirred at room temperature. After
1
h, acetone was added (0.2 mL) whereupon the solution changed
saturated aqueous NH Cl solution (15 mL) and water (5 mL), the
4
Eur. J. Org. Chem. 2021, 2549–2556
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© 2021 The Authors. European Journal of Organic Chemistry published
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Full Papers
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from cloudy/colorless to clear/slightly brownish. After 22.5 h at
NaHCO solution (1 mL), solid NaHSO (1 spatula tip) and diethyl
3 3
room temperature, solid NaHSO (3 spatula tips) was added, and
ether (2 mL) were added. The layers were separated and the
aqueous layer was extracted with diethyl ether (3×2 mL). The
combined organic layers were washed successively with water
(2 mL) and saturated aqueous NaCl solution (2 mL), dried over
3
stirring continued for 15 min. Water (5 mL) and chloroform (5 mL)
were added. The layers were separated and the aqueous layer was
extracted with chloroform (3×5 mL). The combined organic layers
were washed with saturated aqueous NaCl solution (5 mL), dried
MgSO , filtered and concentrated in vacuo. After purification by
4
over MgSO , filtered, and concentrated in vacuo. Flash chromatog-
raphy (petroleum ether/ethyl acetate, 1:3) gave crude diol (80 mg,
mixture of isomers) as a slightly brownish oil, which was used for
flash chromatography (n-hexane/ethyl acetate, 5:1 to 3:1), isoxazo-
4
line 38 (13 mg, 31 μmol, 57%) was obtained as a colorless oil. R =
f
1
0.48 (n-hexane/ethyl acetate, 1:1); H NMR (300 MHz, CDCl ): δ
3
the next step without further purification. R =0.12 (n-hexane/ethyl
acetate, 1:1);
[ppm]=1.12 (s, 9H, C(CH ) ), 1.27–1.34 (m, 1H, syn-5-H), 1.45–1.55
(m, 4H, 7-H, 1’-H, 2’-H), 1.78–1.98 (m, 4H, 6-H, 7-H, 9-H, 1’-H), 2.08–
f
3 3
2
3
8
4
.25 (m, 3H, anti-5-H, 8-H, 9-H), 2.55–2.68 (m, 2H, 7a-H, 8-H), 3.31–
.45 (m, 2H, 3’-H), 3.99 (d, J=8.5 Hz, 1H, endo-3-H), 4.27 (d, J=
The crude diol from the previous step was dissolved in a solution of
THF (4 mL) and water (1 mL). NaIO (192 mg, 0.90 mmol, 5.3 equiv)
4
.5 Hz, 1H, exo-3-H), 4.44 (s, 2H, PhCH ), 5.03 (dd, J=2.8, 9.7 Hz, 1H,
2
was added all at once at room temperature. After 30 min, saturated
aqueous NaCl solution (5 mL) and dichloromethane (5 mL) were
added. The layers were separated and the aqueous layer was
extracted with dichloromethane (3×5 mL). The combined organic
layers were washed with saturated aqueous NaCl solution (5 mL),
13
-H), 7.26–7.33 (m, 5H, HAr); C NMR (75 MHz, CDCl ): δ [ppm]=23.7
3
(
(
(
(
C-6), 24.1 (C-2’), 25.5 (C-1’), 27.1 (C(CH ) ), 31.3 (C-8), 37.0 (C-7), 37.9
C-5), 38.6 (C(CH ) ), 39.3 (C-7a), 40.5 (C-9), 43.4 (quart C-3a/3b), 64.3
quart C-3a/3b), 68.2 (C-4), 70.2 (C-3’), 72.9 (PhCH ), 77.8 (C-3), 127.5
C ), 127.6 (C ), 128.3 (C ), 138.3 (C ), 173.9 (C-8a), 177.5 (tBuCO );
3 3
3
3
2
Ar
Ar
Ar
Ar
2
dried over MgSO , filtered, and concentrated in vacuo. After flash
+
4
HRMS (ESI-TOF): calcd. for C H NO 448.24583 [M+Na] , found
2
6
35
4
chromatography (n-hexane/ethyl acetate 2:1), the crude aldehyde
4
48.24595.
3
6 was used for the next step without further purification. R =0.62
f
(
n-hexane/ethyl acetate, 1:1).
3b-(3-(Benzyloxy)propyl)-3,3b,4,5,6,7,7a,8-octahydro-3a,6-metha-
noindeno[2,1-c]isoxazol-4-ol (39). A solution of TBAOH in methanol
rel-(1S,2S,4R,6S)-1-(3-(Benzyloxy)propyl)-6-(2-(hydroxyimino)ethyl)-7-
methylenebicyclo[2.2.2]octan-2-yl pivalate (37). To a solution of the
crude aldehyde 36 from the previous step in a mixture of
acetonitrile (5 mL) and water (1 mL), hydroxylamine hydrochloride
(
1 m, 305 μL, 305 μmol, 10 equiv) was added to a solution of
pivalate 38 (13 mg, 31 μmol) in dry methanol (0.3 mL) at room
temperature followed by stirring of the mixture for 40 h at 60°C in
a closed flask. After being cooled to room temperature, the mixture
(
1
(
14 mg, 201 μmol, 1.2 equiv) and sodium acetate (19 mg, 234 μmol,
.4 equiv) were added. After 30 min at room temperature, water
5 mL) and chloroform (5 mL) were added. The layers were
separated and the aqueous layer was extracted with chloroform
3×5 mL). The combined organic layers were washed with
was treated with aqueous saturated NH Cl solution (2 mL) and
4
extracted with diethyl ether (3×2 mL). The combined organic layers
were washed with saturated aqueous NaCl solution, dried over
MgSO , filtered, and concentrated in vacuo. After purification by
4
(
flash chromatography (n-hexane/ethyl acetate, 1:1), alcohol 39
saturated aqueous NaHCO3 solution (5 mL), dried over MgSO4,
filtered, and concentrated in vacuo. After purification by flash
chromatography (petroleum ether/ethyl acetate, 5:1 to 3:1),
aldoxime 37 (56 mg, 131 μmol, 77% over 3 steps) was obtained.
The oxime appears as two isomers which could be separated but
after a short time restored the equilibrium: aldoxime 37a [29 mg,
(
0
6 mg, 18 μmol, 58%) was obtained as a slightly yellowish oil. R =
f
1
.18 (n-hexane/ethyl acetate, 1:1); H NMR (400 MHz, CDCl ): δ
3
[
1
ppm]=1.04–1.13 (m, 1H, 1’-H), 1.38 (dq, J=13.6, 3.1 Hz, 1H, 5-H),
.47 (dt, J=13.9, 3.4, 3.2 Hz, 1H, 7-H), 1.50–1.74 (m, 4H, 1’-H, 2’-H,
OH), 1.78–1.92 (m, 3H, 6, 7-H, 9-H), 1.99–2.14 (m, 2H, 5-H, 9-H), 2.17
(
d, J=17.9 Hz, 1H, endo-8-H), 2.47 (dd, J=9.1, 6.9 Hz, 1H, 7a-H), 2.60
6
8 μmol, 40%; R =0.57 (n-hexane/ethyl acetate, 1:1)] as a white
f
(dd, J=17.9, 6.6 Hz, 1H, exo-8-H), 3.37–3.55 (m, 2H, 3’-H), 3.98 (d,
amorphous solid and aldoxime 37b [27 mg, 63 μmol, 37%, R =0.47
f
J=8.8 Hz, 1H, endo-3-H), 4.05 (dd, J=9.9, 3.3 Hz, 1H, 4-H), 4.21 (d,
J=8.7 Hz, 1H, exo-3-H), 4.49 (s, 2H, PhCH ), 7.25–7.38 (m, 5H, H );
13
(
n-hexane/ethyl acetate, 1:1)] as a white amorphous solid. The NMR
1
2
Ar
spectra show the presence of both isomers. H NMR (400 MHz,
C NMR (100 MHz, CDCl ): δ [ppm]=23.6 (C-2’), 24.1 (C-6), 24.8 (C-
’), 31.2 (C-8), 37.1 (C-7), 39.4 (C-5, 7a), 40.7 (C-9), 45.5 (quart-C-3a/
3
CDCl ): δ [ppm]=0.98–1.13 (m, 10H), 1.26–1.35 (m, 1H), 1.39–1.60
3
1
3
(
m, 4H), 1.67–1.94 (m, 3H), 2.06–2.39 (m, 4H), 3.35–3.49 (m, 2H, 3’’-
b), 64.0 (quart-C-3a/3b), 64.5 (C-4), 70.4 (C-3’), 73.3 (PhCH ), 77.8
2
H), 4.47 (s, 2H, PhCH ), 4.84 (d, J=11.5 Hz, 1H, 7-CH ), 4.92 (dt, J=
2
2
(
C-3), 127.8 (C ), 128.5 (C ), 137.9 (C ), 174.2 (C-8a); HRMS (ESI-
Ar Ar Ar
+
1
.9, 9.0 Hz, 1H, 2-H), 4.99 (d, J=9.8 Hz, 7-CH ), 7.20–7.38 (m, 6H, 2’-
2
TOF): calcd. for C H NO 364.18831 [M+Na] , found 364.18851.
13
21 27
3
H, HAr); C NMR (100 MHz, CDCl ): δ [ppm]=22.9, 23.0, 24.7, 24.7,
3
2
4
7
1
1
5.4, 25.5, 26.9 (C(CH ) ), 31.2, 31.4, 31.8, 32.3, 32.7, 35.1, 36.0, 38.6,
3b-(3-(Benzyloxy)propyl)-3b,5,6,7,7a,8-hexahydro-3a,6-methanoin-
deno[2,1-c]isoxazol-4(3H)-one (18). To a solution of alcohol 39
(6 mg, 18 μmol) in dry dichloromethane (0.35 mL) solid NaHCO3
(9 mg, 105 μmol, 6 equiv) and Dess-Martin periodinane (11 mg,
26 μmol, 1.5 equiv) were added. The mixture was kept at 0°C for
3
3
2.9, 42.9, 70.6 (C-2), 70.6 (C-2), 70.6 (C-3’’), 70.7 (C-3’’), 72.7 (PhCH2),
2.7 (PhCH ), 110.3 (C-1’’’), 110.5 (7-CH ), 127.4 (C ), 127.4 (C ),
2
2
Ar
Ar
27.5 (C ), 127.5 (C ), 128.3 (C ), 138.5 (C ), 138.6 (C ), 146.2 (C-7),
Ar
Ar
Ar
Ar
Ar
46.3 (C-7), 151.1 (C-2’), 177.8 (tBuCO ); HRMS (ESI-TOF): calcd. for
2
+
C H NO 450.26148 [M+Na] , found 450.26152.
0.5 h, after which it was stirred at room temperature for further
2
6
37
4
1
.5 h. For the work-up, saturated aqueous NaHCO solution (2 mL)
3
3
b-(3-(Benzyloxy)propyl)-3,3b,4,5,6,7,7a,8-octahydro-3a,6-metha-
noindeno[2,1-c]isoxazol-4-yl pivalate (38). To a solution of aldoxime
7 (23 mg, 54 μmol) in a mixture of dichloromethane (0.5 mL) and
and dichloromethane (2 mL) were added. After separation of the
layers, the aqueous layer was extracted with dichloromethane (3×
3
2
mL). The combined organic layers were dried over MgSO , filtered,
4
triethylamine (8 μL, 59 μmol, 1.1 equiv), water (0.2 mL) was added
and concentrated in vacuo. After purification by flash chromatog-
at 0°C. To the vigorously stirred mixture, aqueous NaOCl solution
raphy (n-hexane/ethyl acetate, 2:1), ketone 18 (5 mg, 15 μmol,
(6%, 0.16 mL, 3 equiv) was added at the same temperature,
8
3%) was obtained as a colorless oil. R =0.39 (n-hexane/ethyl
f
whereupon the solution briefly turned brown and then immediately
became colorless again. After 30 min, the cooling bath was
removed and stirring was continued for additional 30 min. There-
after, additional aqueous NaOCl solution (6%, 0.16 mL, 3 equiv) was
added. After 1 h and a further hour, additional portions of aqueous
NaOCl solution (6%, 0.16 mL, 3 equiv) were added. One hour after
the last addition of aqueous NaOCl solution, saturated aqueous
1
acetate, 1:2); H NMR (400 MHz, CDCl ): δ [ppm]=1.00–1.09 (m, 1H,
3
1
2
’-H), 1.40–1.52 (m, 1H, 2’-H), 1.65–1.89 (m, 4H, 7-H, 9-H, 1’-H, 2’-H),
.08–2.17 (m, 1H, 7-H), 2.18–2.22 (m, 2H, 5-H), 2.22–2.28 (m, 1H, 6-
H), 2.33–2.42 (m, 2H, 8-H, 9-H), 2.66 (dd, J=17.9, 6.1 Hz, 1H, exo-8-
H), 2.90 (dd, J=9.8, 6.6 Hz, 1H, 7a-H), 3.40–3.57 (m, 2H, 3’-H), 3.84
(d, J=8.8 Hz, 1H, endo-3-H), 4.09 (d, J=8.7 Hz, 1H, exo-3-H), 4.44–
Eur. J. Org. Chem. 2021, 2549–2556
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2555
© 2021 The Authors. European Journal of Organic Chemistry published
by Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100216
1
3
4
.52 (m, 2H, PhCH ), 7.26–7.37 (m, 5H, H ); C NMR (100 MHz,
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C-7), 40.3 (C-9), 40.7 (C-7a), 46.1 (C-5), 54.5 (C-3a), 68.4 (C-3b), 70.4
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[
(
(
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.2 equiv) was added at room temperature to a solution of
isoxazolinone 18 (5 mg, 15 μmol) in a mixture of acetonitrile
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(
9
0°C in a closed flask for 2 h. After cooling, the reaction mixture
[
was filtered through celite and the filtrate was extracted with
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4
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1
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7
1
1
.03 (m, 1H, 1’-H), 1.45–1.51 (m, 1H, 2’-H), 1.63–1.67 (m, 1H, 4-H),
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[
4
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2
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3
(
m, 1H, CH OH), 4.43–4.53 (m, 2H, PhCH ), 7.26–7.37 (m, 5H, H ); C
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2
A
r
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3
2
008, 130, 6018–6024.
3
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1
0.8 (C-3a), 33.6 (C-8), 36.1 (C-4), 44.7 (C-6), 45.5 (C-8), 55.4 (quart-C-
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2
27.7 (C ), 128.4 (C ), 138.5 (C ), 213.1 (C-7), 218.7 (C-2); HRMS
Ar
Ar
Ar
[
+
(ESI-TOF): calcd. for C H O 365.17233 [M+Na] , found 365.17192.
21 26 4
1
19, 7815–7817.
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Acknowledgements
Financial support by the state of Baden-Württemberg, Germany is
gratefully acknowledged. Open access funding enabled and
organized by Projekt DEAL.
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·
Domino reactions
·
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Manuscript received: February 22, 2021
Revised manuscript received: April 8, 2021
Accepted manuscript online: April 13, 2021
Zhang, X.-T. An, Y.-X. Cao, C.-A. Fan, J. Am. Chem. Soc. 2017, 139, 4282–
4285.
Eur. J. Org. Chem. 2021, 2549–2556
www.eurjoc.org
2556
© 2021 The Authors. European Journal of Organic Chemistry published
by Wiley-VCH GmbH