Convergent access to polycyclic cyclopentanoids from α,β- unsaturated acid chlorides and alkynes through a reductive coupling, nazarov cyclization sequence

Article abstract of DOI:10.1021/jo500040b

Reductive coupling of α,β-unsaturated acid chlorides A with alkynoyls B provides convergent access to Nazarov cyclization precursors, α-carboxy divinyl ketones C. Cyclization of C gives an intermediate oxyallyl cation intermediate D, which can be trapped with tethered arenes (Ar). The resultant products can be further cyclized through nucleophilic displacement of suitable leaving groups X by tethered OH groups to give lactones (in a subsequent step). Where X is a suitable chiral auxiliary (e.g., oxazolidinone) this strategy affords access to homochiral cyclopentanoids.

Full text of DOI:10.1021/jo500040b

Note
pubs.acs.org/joc
Convergent Access to Polycyclic Cyclopentanoids from α,β-
Unsaturated Acid Chlorides and Alkynes through a Reductive
Coupling, Nazarov Cyclization Sequence
Jason H. Chaplin,† Kristal Jackson,† Jonathan M. White,‡ and Bernard L. Flynn*,†
†Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052,
Australia
‡Bio21 Institute, School of Chemistry, University of Melbourne, Parkville, Victoria 3010, Australia
S
* Supporting Information
ABSTRACT: Reductive coupling of α,β-unsaturated acid chlorides A with alkynoyls B provides convergent access to Nazarov
cyclization precursors, α-carboxy divinyl ketones C. Cyclization of C gives an intermediate oxyallyl cation intermediate D, which
can be trapped with tethered arenes (Ar). The resultant products can be further cyclized through nucleophilic displacement of
suitable leaving groups X by tethered OH groups to give lactones (in a subsequent step). Where X is a suitable chiral auxiliary
(e.g., oxazolidinone) this strategy affords access to homochiral cyclopentanoids.
Scheme 1. Reductive Coupling Nazarov Cyclization
Sequence
n recent years the Nazarov cyclization of divinyl ketones to
Icyclopentenones has received considerable attention, with
significant improvements in methods for achieving enantiose-
lectivity (torquoselectivity) and for trapping reactive inter-
mediates in multistereocenter forming reactions.1−3 In order to
effectively exploit this synthetic versatility, concise and
convergent methods for the stereoselective synthesis of divinyl
ketones are also required. To this end, we recently described a
one-pot, two-stage reductive coupling process composed of a
regio- and stereoselective hydrostannylation of alkynoyls 2
followed by Stille-type coupling with α,β-unsaturated acid
chlorides 1 to give α-carboxydivinyl ketones 3, which undergo
Nazarov cyclizations to 5-carboxycyclopentenones 4.3h The
presence of the α-carbonyl (R3CO) in 3 promotes the
regioselective placement of the double bond to the distal side of
the cyclopentyl ring in 4. This carboxy unit can also be used as
a linker for labile chiral auxiliaries (R3 = chiral auxiliaries).
Oxazolidinone auxiliaries induce moderate to good levels of
stereoinduction upon cyclization 3 → 4 (R3 = N-oxazolidinyl)
and enable further enhancement of enantiopurity through ready
chromatographic separation of the two diastereomers prior to
auxiliary cleavage.3h Herein, we describe some useful extensions
of this reductive coupling/Nazarov cyclization protocol in the
convergent synthesis of ring-fused cyclopentyl systems through
trapping of the oxyallyl cation intermediate 5 with tethered
electron rich arenes and by nucleophilic displacement of
suitable leaving groups X (including X = N-oxazolidinyl) with
hydroxyl groups (Scheme 1).
example of this convergent approach to multistereocenter-
containing polycycles (Scheme 2). Synthesis of 14 commenced
with methyl bromotiglate 6,4 which was converted to acid
We initiated our studies in the racemic series, targeting a dual
arene trapping/lactonization process to generate 14 as an
Received: January 8, 2014
Published: March 27, 2014
© 2014 American Chemical Society
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chemical outcome was rationalized as arriving from conrotation
of the Lewis acid activated complex of E,Z-11. In the presence
of the Lewis acid (cupric triflate) the E,Z-11 and E,E-11
isomers are expected to be rapidly interconvertible with
cyclization from E,Z-11 complex providing the lowest energy
(least congested) transition state.2y,z The benzyl ether in 12 was
removed by hydrogenolysis to give phenol 13 (63%), which
underwent lactonization upon treatment with TFA to provide
the cis-fused lactone 14 (78%).
Scheme 2. Synthesis of Polycycle 14
We also examined the use of oxazolidinones in enantiose-
lective syntheses of a related ring-fused cyclopentanone 18
(Scheme 3). Thus, N-(alkynoyl)oxazolidinone 153h was
Scheme 3. Asymmetric Synthesis of Polycycle 18
coupled (reductive coupling) to acid chloride 7, to give divinyl
ketone 16 (58%). Unlike the corresponding ester and amides,
oxazolidone substituted α-carboxy divinyl ketones thermody-
namically favor the E,Z-stereochemistry.3h Cocyclization of 16
afforded the major diastereomer 17 (61%), which was readily
separated from the minor diastereomer 17′ resulting from the
opposite sense of conrotation (15%, not shown). X-ray crystal
structure analysis of 17 confirmed the predicted sense of
induction based on our earlier studies of oxazolidinone
controlled Nazarov cyclizations.3h,7 Refluxing 17 in dry
methanol in the presence of MeSO3H afforded the methyl
ester 18 (73%).
We also explored the intramolecular displacement of the
oxazolidinone auxiliary in the asymmetric synthesis of the
lactone 24 (Scheme 4). The benzyl butynyl ether 19 was
converted to 21 using our previously described procedure for
the one-pot preparation of N-(alkynoyl)oxazolidinones from
terminal alkynes.3h This involved lithiation of 19 and reaction
with carbon dioxide to afford a lithium carboxylate that was in
turn converted to a pivaloyl anhydride and reacted with the N-
chloride 7 in three steps.2i This involved substitution of the
bromo group in 6 for 3-methoxyphenol, followed by ester
hydrolysis and conversion of the resultant acid to the acid
chloride 7 (58% yield from 6).2i Preparation of the propynoyl
ester 9 commenced from benzyl protected isovanilin 85
(Scheme 2). Conversion of 8 into the gem-dibromostyrene 9
was followed generation of a lithium acetylide (Corey−Fuchs)
and addition of methyl chloroformate to give 10 (87%).
Reductive coupling of 7 and 10 afforded 11 as a single
stereoisomer E,Z-11, which isomerized completely to the
thermodynamic isomer E,E-11 upon chromatography. This
material could only be isolated in a semipure form (contained
tin byproducts) and was subjected directly to Nazarov
cyclization using cupric triflate in dichloromethane to give the
cocyclized product 12 (42% overall yield from 10). Only a
single diastereomer of 12 was observed, which was assigned
relative stereochemistry depicted (racemic).6 This stereo-
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melting point apparatus. Proton (1H) and carbon (13C) NMR spectra
were recorded at 300 MHz for proton and 75 MHz for carbon nuclei.
All NMR spectra were recorded in (D)chloroform (CDCl3) at 30 °C.
The protonicities of the carbon atoms observed in the carbon NMR
were determined using J-modulated spin−echo (JMOD) experiments.
1H NMR spectral data are recorded as follows: chemical shift δ (ppm),
multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet,
mc: centered multiplet, dd: doublet of doublets, dt: doublet of triplets,
br: broad), coupling constant(s) (J Hz), and relative integral. 13C
NMR spectral data are recorded as δ (ppm) with the protonicity of the
carbon given in parentheses. High-resolution mass spectra (HRMS)
were recorded on a time-of-flight mass spectrometer fitted with either
an electrospray (ESI) or atmospheric pressure ionization (APCI) ion
source. Infrared spectra were recorded on a Fourier transform
instrument and are given as wavenumbers cm−1. Tetrahydrofuran
(THF), methanol, and dichloromethane were dried using a
commercial solvent purification system (SPS). Thin layer chromatog-
raphy (TLC) was conducted on aluminum-backed 0.2 mm thick silica
gel 60 GF254 plates, and the chromatograms were visualized under a
254 nm UV lamp and/or by treatment with a reagent solution
[phosphomolybdic acid/95% ethanol (4 g:100 mL) dip] or
anisaldehyde dip (214 mL of EtOH, 8 mL of H2SO4, 2.4 mL of
AcOH, 5.9 mL of anisaldehyde) followed by heating. Flash column
chromatography was performed using silica 40−63 μm.
Scheme 4. Asymmetric Synthesis of Lactone 23
1,1-Dibromo-2-(2′-benzyloxy-4′-methoxy-phenyl)-ethene 9. Car-
bon tetrabromide (821 mg, 2.48 mmol) was added to a stirred solution
of triphenylphosphine (1.3 g, 4.96 mmol) in dichloromethane (15
mL) at 0 °C, and the reaction was allowed to stir for 10 min. To the
resultant red/orange solution, 2-benzyloxy-4-methoxy-benzaldehyde
85 (300 mg, 1.24 mmol) was added, and stirring was continued for 15
min. After this the reaction mixture was concentrated under reduced
pressure, the residue was subject to flash chromatography on silica-gel
(eluted with hexane/dichloromethane 2:1) to provide the product 9 as
1
a clear oil (491 mg, 99%): H NMR (CDCl3) δ 7.72 (d, J = 8.4 Hz,
1H), 7.61 (s, 1H), 7.42−7.29 (m, 5H), 6.52 (dd, J = 8.4, 2.4 Hz, 1H),
6.48 (d, J = 2.4 Hz, 1H), 5.08 (s, 2H), 3.80 (s, 3H); 13C NMR
(CDCl3) δ 161.1 (C), 157.0 (C), 136.5 (C), 132.3 (CH), 129.8 (CH),
128.6 (CH), 128.0 (CH), 127.2 (CH), 117.7 (C), 104.7 (CH), 99.8
(CH), 87.8 (C), 70.4 (CH2), 55.3 (CH3); IR (KBr, cm−1) 3030, 2938,
2836, 1607, 1578, 1500, 1458, 1296, 1262, 1197, 1165, 1117, 1038,
866, 835. This material did not provide suitable mass spectral data
under ESI conditions.
lithiated oxazolidinone 20, giving 21 (60%). This material was
coupled to tigloyl chloride (reductive coupling) to give divinyl
ketone 22 (65%). Nazarov cyclization of 22 afforded the major
diastereomer 23 (53%), which was readily separated from the
minor diastereomer (17%, not shown) by column chromatog-
raphy. The stereochemical assignment of 23 was based on our
earlier work (note, alkyl and aryl substituents vicinal to carboxy-
oxazolidinone auxiliary undergo Nazarov cyclization with an
opposite sense of conrotation).3h Sequential hydrogenolysis
and treatment with MeSO3H afforded lactone 24 (81% from
23). Interestingly, the benzyl ether in 23 was selectively cleaved
under these hydrogenation conditions, leaving the enone group
in 24 intact and thus available for further synthetic
manipulation.
These studies underscore the potential of the two step
reductive coupling/Nazarov cyclization protocol to provide
convergent access to ring-fused cyclopentanones from readily
accessible substrates: α,β-unsaturated acid chlorides and
terminal alkynes. This protocol is enhanced by the ready
accessibility N-(alkynoyl)oxazolidinones from terminal alkynes,
which can be utilized in this protocol to provide enantioen-
riched products through a combination moderate diastereose-
lection, ready separation of diastereomers, and convenient
auxiliary cleavage.
(2-Benzyloxy-4-methoxy-phenyl)-propynoic acid methyl ester 10.
n-Butyllithium (2.2 mL 2.7 M in hexane, 5.88 mmol,) was added to a
stirred solution of the gem-dibromostyrene 9 (1.14 g, 2.86 mmol) in
dry THF (25 mL) at −78 °C, and the reaction was allowed to warm to
rt, stirred for a further 15 min, and then recooled to −78 °C. Methyl
chloroformate (0.24 mL, 2.86 mmol) was added, and the reaction was
allowed to warm slowly to rt and then quenched with 10% w/v NH4Cl
(aq) (40 mL) and extracted with diethyl ether (2 × 40 mL). The
combined organic layers were washed with brine (20 mL), dried over
MgSO4, and the solvent was removed under a vacuum. The crude
residue was purified by silica-gel chromatography (sequential elution
with hexane/diethyl ether 9:1, 3:1, and 2:1) to give the product 10 as a
1
white solid (736 mg, 87%): mp = 67−68 °C; H NMR (CDCl3) δ
7.52−7.45 (m, 3H), 7.42−7.31 (m, 3H), 6.51−6.46 (m, 2H), 5.18 (s,
2H), 3.83 (s, 3H), 3.80 (s, 3H); 13C NMR (CDCl3) δ 163.1 (C),
162.3 (C), 154.8 (C), 136.3 (C), 136.0 (CH), 128.5 (CH), 127.8
(CH), 126.7 (CH), 106.0 (CH), 101.8 (C), 100.1 (CH), 84.6 (C),
83.9 (C), 70.3 (CH2), 55.4 (CH3), 52.5 (CH3); IR (KBr, cm−1) 3098,
3021, 2948, 2213, 1703, 1609, 1568, 1505, 1432, 1297, 1209, 1168,
+
1133, 1034, 999, 834; LRMS (ESI) m/z (%) 314 (M + NH4 , 85), 297
(M + H+, 100), 265 (95); HRMS (ESI) calcd for C18H17O4 (M + H+)
297.1127, found 297.1110.
rac-3-(2-Benzyloxy-4-methoxyphenyl)-7-methoxy-9b-methyl-1-
oxo-1,2,3,3a,4,9b-hexahydrocyclopenta[c]chromene-2-carboxylic
acid methyl ester 12. Tributyltin hydride (0.341 mL, 1.27 mmol) was
added dropwise to a stirred solution of Pd(PPh3)4 (72 mg 0.063
mmol) and alkyne 10 (450 mg, 1.25 mmol) in THF (5.0 mL) at 0 °C.
The reaction was allowed to warm to rt and stirred for 30 min. (E)-4-
EXPERIMENTAL SECTION
General Methods. All experiments were performed under an
anhydrous atmosphere of nitrogen in flame-dried glassware except
where indicated. Melting points were recorded with an electrothermal
■
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Note
(3-Methoxyphenoxy)-2-methylbut-2-enoyl chloride 72i (308.8 mg,
1.28 mmol) and CuCl (118 mg, 1.20 mmol) were then added, and the
mixture was stirred at rt for 18 h. After this time the reaction mixture
was diluted with ethyl acetate (25 mL), and the resultant solution
washed sequentially with 10% w/v NH4Cl (aq) (20 mL), 2 × 30% w/v
KF (aq) (15 mL) and brine (10 mL). The ethyl acetate layer was dried
over MgSO4 and concentrated onto silica gel (4 g) under a vacuum.
The solid residue was subjected to flash chromatography on silica gel
(sequential elution with hexane/ethyl acetate 5:1, 4:1, and 3:1) to
afford the crude dienone E,E-11 (372 mg), which was used directly in
the next step.
3H); 13C NMR (CDCl3) δ 206.8 (C), 161.1 (C), 160.5 (C), 160.2
(C), 154.5 (C), 151.4 (C), 129.9 (CH), 129.7 (CH), 112.5 (C), 112.1
(C), 111.4 (CH), 109.3 (CH), 102.8 (CH), 102.1 (CH), 61.0 (CH2),
55.7 (CH3), 55.4 (CH3), 51.0 (CH), 49.4 (CH), 47.3 (C), 34.9 (CH),
27.0 (CH3); IR (KBr, cm−1) 2959, 2930, 2840, 1775, 1740, 1617,
1584, 1504, 1443, 1277, 1242, 1157, 1030, 839; LRMS (ESI) m/z (%)
398 (M + H+, 100), 381 (M + H+, 20); HRMS (ESI) calcd for
C22H21O6 (M + H+) 381.1338, found 381.1330.
(S)-(2Z,4E)-2-Benzylidene-6-(3″-methoxyphenoxy)-4-methyl-1-
(2′-oxo-4′-phenyloxazolidin-3′-yl)-hex-4-ene-1,3-dione 16. Tributyl-
tin hydride (0.422 mL, 1.57 mmol) was added dropwise to a stirred
solution of Pd(PPh3)4 (89 mg, 0.077 mmol) and (S)-4-phenyl-3-(3-
phenylpropioloyl)oxazolidin-2-one 153h (450 mg, 1.54 mmol) in THF
(5.0 mL) at 0 °C. The reaction was allowed to warm to rt and stirred
for 30 min. (E)-4-(3-Methoxyphenoxy)-2-methylbut-2-enoyl chloride
Cupric triflate (500 mg, 1.38 mmol) was added to a stirred solution
of crude E,E-11 (372 mg) in dichloromethane (10 mL), and the
reaction was stirred at rt for 4 h and then quenched with saturated
NaHCO3 (aq) (20 mL) and extracted with dichloromethane (2 × 20
mL). The combined organic layers were dried over MgSO4, the
solvent was removed under a vacuum, and the crude residue was
purified by flash chromatography on silica-gel (sequential elution with
hexane/ethyl acetate 10:1, 5:1 and 2:1) to afford the product 12 as a
white solid (263 mg, 42% from 10): mp = 76−78 °C; 1H NMR
(CDCl3) δ 7.38 (mc, 5H), 7.19 (t, J = 8.8 Hz, 2H), 6.58 (d, J = 2.2 Hz,
1H), 6.50−6.46 (m, 2H), 6.38 (m, J = 2.6 Hz, 1H), 5.09−4.98 (m,
2H), 4.06 (dd, J = 11.5, 1.7 Hz, 1H), 3.98 (d, J = 11.1 Hz, 1H), 3.91
(dd, J = 11.5, 1.7 Hz, 1H), 3.84 (t, J = 11.1 Hz, 1H), 3.80 (s, 3H), 3.76
(s, 3H), 3.49 (s, 3H), 2.64 (dt, J = 11.1, 1.5 Hz, 1H), 1.27 (s, 3H); 13C
NMR (CDCl3) δ 209.7 (C), 168.5 (C), 160.3 (C), 159.9 (C), 157.6
(C), 154.6 (C), 136.1 (C), 132.2 (CH), 129.6 (CH), 128.7 (CH),
128.2 (CH), 127.6 (CH), 119.2 (C), 112.0 (C), 108.7 (CH), 104.7
(CH), 101.7 (CH), 100.4 (CH), 70.3 (CH2), 61.6 (CH2), 58.0 (CH),
55.3 (CH3), 55.1 (CH3), 52.1 (CH3), 48.3 (C), 44.8 (CH), 41.0
(CH), 25.7 (CH3); IR (KBr, cm−1) 2955, 2926, 2864, 1749, 1730,
1613, 1584, 1503, 1460, 1443, 1379, 1286, 1261, 1196, 1164, 1126,
7
2i (407.7 mg, 1.69 mmol) and CuCl (152 mg) were then added, and
the mixture was stirred at rt for 18 h. After this time the reaction
mixture was diluted with ethyl acetate (25 mL), and the resultant
solution washed sequentially with 10% w/v NH4Cl (aq) (20 mL), 2 ×
30% w/v KF(aq) (15 mL) and brine (10 mL), dried over MgSO4 and
concentrated onto silica (4 g), and the solid residue was subjected to
flash chromatography on silica gel (sequential elution with hexane/
dichloromethane/diethyl ether 10:10:1 and 5:5:1). The product 16
thus obtained was crystallized by trituration with a 2:1 mixture of
hexane and diethyl ether giving a pale yellow solid (453 mg, 58%): mp
= 110−111 °C; [α]25D = +65° (C = 0.98, CHCl3); 1H NMR (CDCl3)
δ 7.42 (br s, 5H), 7.39 (s, 1H), 7.20 (t, J = 5.4 Hz, 1H), 7.07 (mc, 5H),
6.63 (t, J = 5.1 Hz, 1H), 6.56−6.49 (m, 3H), 5.55 (dd, J = 8.4, 3.3 Hz,
1H), 4.79 (mc, 2H), 4.73 (t, J = 8.4 Hz, 1H), 4.36 (dd, J = 9.0, 3.3 Hz,
1H), 3.78 (s, 3H), 2.02 (s, 3H); 13C NMR (CDCl3) δ 194.9 (C),
165.9 (C), 160.8 (C), 159.4 (C), 152.8 (C), 144.0 (CH), 138.1 (C),
136.6 (CH), 136.2 (C), 134.3 (C), 132.6 (C), 130.3 (CH), 130.0
(CH), 129.6 (CH), 129.1 (CH), 128.8 (CH), 128.6 (CH), 126.7
(CH), 106.8 (CH), 106.7 (CH), 101.3 (CH), 70.4 (CH2), 64.5
(CH2), 57.3 (CH), 55.2 (CH3), 13.7 (CH3); IR (KBr, cm−1) 3063,
2965, 2926, 1788, 1699, 1633, 1614, 1602, 1489, 1450, 1384, 1327,
1265, 1214, 1150, 1119, 1034, 765; LRMS (ESI) m/z (%) 515 (M +
+
1034, 912, 834; LRMS (ESI) m/z (%) 520 (M + NH4 , 100), 503 (M
+
+ H+, 50); HRMS (ESI) calcd for C30H34NO7 (M + NH4 ) 520.2335,
found 520.2325.
rac-3-(2-Hydroxy-4-methoxyphenyl)-7-methoxy-9b-methyl-1-
oxo-1,2,3,3a,4,9b-hexahydrocyclopenta[c]chromene-2-caroxylic
acid methyl ester 13. A suspension of benzyl-protected substrate 12
(55 mg, 0.11 mmol) and 10% Pd/C (10 mg) in ethyl acetate (2 mL)
was stirred under an atmosphere of hydrogen (balloon) at 60 °C for
16 h. After this time the reaction was filtered through Celite, and the
solvent was removed under a vacuum to give a crude residue that was
purified by silica-gel chromatography (eluent hexane/ethyl acetate 3:1)
to afford the product 13 as a clear oil (29 mg, 65%): 1H NMR
(CDCl3) δ 7.24 (d, J = 8.7 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.49−
6.54 (m, 2H), 6.44 (dd, J = 7.5, 2.4 Hz, 2H), 6.39 (br s, 1H), 4.10 (dd,
J = 11.4, 1.5 Hz, 1H), 3.99 (dd, J = 11.4, 1.8 Hz, 1H), 3.91−3.75 (m,
2H), 3.78 (s, 3H), 3.77 (s, 3H), 3.61 (s, 3H), 2.56 (d, J = 11.1 Hz,
1H), 1.55 (s, 3H); 13C NMR (CDCl3) δ 208.8 (C), 169.4 (C), 160.0
(2 × C), 155.7 (C), 154.3 (C), 129.6 (CH), 129.2 (CH), 116.7 (C),
111.7 (C), 109.1 (CH), 106.8 (CH), 103.0 (CH), 101.9 (CH), 61.3
(CH2), 59.3 (CH), 55.2 (2 × CH3), 52.8 (CH3), 48.6 (C), 45.4 (CH),
37.4 (CH), 26.2 (CH3); IR (KBr, cm−1) 3404, 2958, 2929, 1749, 1730,
1616, 1580, 1503, 1441, 1288, 1242, 1199, 1165, 1121, 1033, 836, 799;
+
NH4 , 70), 498 (M + H+, 35), 335 (100); HRMS (ESI) calcd for
C30H28NO6 (M + H+) 498.1917, found 498.1921.
(4S,2′R,3′S,4′R,9b′R)-3-(7′-Methoxy-9b′-methyl-1′-oxo-3′-phe-
nyl-1′,2′,3′,3a′,4′,9b′-hexahydrocyclopenta[c]chromene-2′-carbon-
yl)-4-phenyloxazolidin-2-one 17. Cupric triflate (363 mg, 1.00
mmol) was added to a stirred solution of 16 (250 mg, 0.502 mmol)
in dry dichloromethane (15 mL) at 0 °C, and the reaction was allowed
to warm to rt and stirred for 30 h. After this time 5% w/v NaHCO3
(aq) (15 mL) was added, the phases were separated, and the aqueous
layer was extracted with dichloromethane (2 × 15 mL). The organic
fractions were combined, dried over MgSO4 and concentrated onto
silica gel (1 g) under a vacuum. The solid residue was subjected to
flash chromatography (elution with hexane/dichloromethane/diethyl
ether 20:20:1), which needed to be repeated on a series of mixed
fractions in order to achieve complete separation. This afforded the
major diastereomer 17 (152 mg, 61%) and the minor diastereomer 17
(38 mg, 15%). Major diastereomer 17: mp = 160−163 °C; [α]25
=
D
+189° (C = 1.02, CHCl3); 1H NMR (CDCl3) δ 7.37−7.24 (m, 10H),
7.18 (d, J = 8.7 Hz, 1H), 6.37 (dd, J = 8.7, 2.4 Hz, 1H), 6.33 (d, J = 2.4
Hz, 1H), 5.53 (d, J = 12.0 Hz, 1H), 5.24 (dd, J = 9.0, 2.7 Hz, 1H), 4.58
(t, J = 9.0 Hz, 1H), 4.15 (dd, J = 8.7, 2.7 Hz, 1H), 4.05 (d, J = 12.0 Hz,
1H), 3.94 (d, J = 12.0 Hz, 1H), 3.88 (t, J = 12.3 Hz, 1H), 3.71 (s, 3H),
2.27 (d, J = 12.3 Hz, 1H), 1.57 (s, 3H); 13C NMR (CDCl3) δ 207.8
(C), 166.0 (C), 159.8 (C), 154.3 (C), 153.7 (C), 139.0 (C), 137.9
(C), 129.3 (CH), 128.9 (CH), 128.8 (CH), 128.4 (CH), 128.0 (CH),
127.4 (CH), 125.7 (CH), 112.0 (C), 108.9 (CH), 101.7 (CH), 69.7
(CH2), 60.8 (CH2), 59.7 (CH), 57.7 (CH), 55.1 (CH3), 48.5 (CH),
48.5 (C), 41.5 (CH), 26.6 (CH3); IR (KBr, cm−1) 3030, 2999, 2910,
2864, 2832, 1763, 1755, 1693, 1611, 1580, 1497, 1461, 1389, 1359,
1309, 1206, 1165, 1113, 1028, 1005, 915, 837, 762; LRMS (ESI) m/z
+
LRMS (ESI) m/z (%) 430 (M + NH4 , 60), 413 (M + H+, 100);
HRMS (ESI) calcd for C23H25O7 (M + H+) 413.1600, found
413.1599.
rac-3,9-Dimethoxy-13a-methyl-6,6a,6b,12a-tetrahydro-13aH-
5,11-dioxadibenzo[a,g]flourene-12,13-dione 14. To a stirred
solution of phenol 13 (20 mg, 0.049 mmol) in dichloromethane (1
mL) was added trifluoroacetic acid (0.5 mL, excess), and the reaction
was stirred for 18 h at reflux. After this time the volatile materials were
removed by passing a stream of air over the reaction mixture, and the
crude residue was purified by flash chromatography on silica-gel
(eluent hexane/ethyl acetate 4:1) to give the product 14 as a clear oil
(14 mg, 78%): 1H NMR (CDCl3) δ 7.42 (d, J = 8.8 Hz, 1H), 7.26 (d, J
= 8.4 Hz, 1H), 6.76 (dd, J = 8.4, 2.5 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H),
6.56 (dd, J = 8.8, 2.6 Hz, 1H), 6.42 (d, J = 2.6 Hz, 1H), 4.34 (dd, J =
11.9, 2.2 Hz, 1H), 4.05 (dd, J = 11.9, 1.8 Hz, 1H), 3.80 (s, 3H), 3.76
(s, 3H), 3.61−3.50 (m, 2H), 2.07 (dt, J = 10.5, 2.0 Hz, 1H), 1.49 (s,
+
(%) 515 (M + NH4 , 100), 498 (M + H+, 65); HRMS (ESI) calcd for
C30H28NO6 (M + H+) 498.1917, found 498.1903. Minor diastereomer
1
17: mp = 190−194 °C; [α]25 = +45° (C = 0.27, CHCl3); H NMR
D
3662
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The Journal of Organic Chemistry
Note
+
(CDCl3) δ 7.36−7.28 (m, 6H), 7.21−7.11 (m, 3H), 6.84 (dd, J = 8.1,
1.5 Hz, 2H), 6.52 (dd, J = 8.7, 2.7 Hz, 1H), 6.37 (d, J = 2.7 Hz, 1H),
5.61 (d, J = 12.6 Hz, 1H), 5.33 (dd, J = 8.7, 3.3 Hz, 1H), 4.66 (t, J =
8.7 Hz, 1H), 4.13 (dd, J = 8.7, 3.3 Hz, 1H), 4.07 (dd, J = 11.4, 1.8 Hz,
1H), 3.96 (dd, J = 11.4, 1.8 Hz, 1H), 3.82 (t, J = 12.3 Hz, 1H), 3.75 (s,
3H), 2.32 (dt, J = 12.3, 1.8 Hz, 1H), 1.58 (s, 3H); 13C NMR (CDCl3)
δ 209.6 (C), 167.2 (C), 159.9 (C), 154.4 (C), 153.6 (C), 138.3 (C),
138.1 (C), 129.6 (CH), 128.9 (CH), 128.8 (CH), 128.3 (CH), 127.8
(CH), 127.5 (CH), 125.1 (CH), 112.2 (C), 109.1 (CH), 101.8 (CH),
69.8 (CH2), 60.8 (CH2), 59.2 (CH), 57.7 (CH), 55.1 (CH3), 48.8
(CH), 48.5 (C), 43.6 (CH), 26.7 (CH3); IR (KBr, cm−1) 3061, 3036,
2978, 2916, 2869, 1769, 1751, 1698, 1614, 1580, 1499, 1391, 1316,
1224, 1200, 1167, 1107, 1028, 841, 761; LRMS (ESI) m/z (%) 515
NH4 , 100), 350 (M + H+, 98); HRMS (ESI) calcd for C21H20NO4
(M + H+) 350.1392, found 350.1370.
(4′R),(2Z,4E)-2-(3″-Benzyloxypropylidene)-4-methyl-1-(2′-oxo-4′-
phenyloxazolidin-3′-yl)hex-4-ene-1,3-dione 22. Tributyltin hydride
(0.125 mL, 0.465 mmol) was added dropwise to a stirred solution of
Pd(PPh3)4 (26 mg 0.023 mmol) and alkyne 21 (160 mg, 0.458 mmol)
in THF (1.5 mL) at 0 °C. The reaction was allowed to warm to rt and
stirred for 30 min. Tigloyl chloride (52 μL, 0.480 mmol) and CuCl
(45 mg, 0.458 mmol) were then added, and the mixture was stirred at
rt for 18 h. After this time the reaction mixture was diluted with ethyl
acetate (10 mL), and the resultant solution washed sequentially with
10% w/v NH4Cl (aq) (10 mL), 2 × 30% w/v KF (aq) (10 mL) and
brine (10 mL), dried over MgSO4 and concentrated onto silica gel (4
g), and the solid residue was subjected to flash chromatography on
silica gel (sequential elution with hexane/ethyl acetate 3:1 and 2:1)
+
(M + NH4 , 60), 498 (M + H+, 50), 142 (70), 100 (100); HRMS
(ESI) calcd for C30H28NO6 (M + H+) 498.1917, found 498.1921.
(2R,3S,3aR,9bR)-7-Methoxy-9b-methyl-1-oxo-3-phenyl-
1,2,3,3a,4,9b-hexahydrocyclopenta[c]chromene-2-carboxylic acid
methyl ester 18. To a stirred solution of compound 17 (85 mg,
0.171 mmol) in a mixture of dry methanol (4 mL) and toluene (1 mL)
was added concentrated sulfuric acid (5 drops), and the reaction
heated to reflux for 5 d. After this time the reaction mixture was cooled
to rt and quenched with saturated NaHCO3 (aq) (15 mL) and
extracted with ethyl acetate (2 × 15 mL). The combined organic layers
were washed with brine (10 mL), dried over MgSO4 and concentrated
onto silica gel under reduced pressure. The solid residue was subjected
to flash chromatography (sequential elution with hexane/ethyl acetate
9:1 and 4:1) giving the product 18 as a resinous gum (45 mg, 73%):
1H NMR (CDCl3) δ 7.28−7.38 (m, 6H), 6.53 (dd, J = 9.0, 2.7 Hz,
giving the product 22 (131 mg, 65%) as a clear resin: [α]25 = −68°
D
(C = 1.11, CHCl3); 1H NMR (CDCl3) δ 7.28−7.41 (m, 10H), 6.72 (t,
J = 7.8 Hz, 1H), 6.57 (q, J = 6.9 Hz, 1H), 5.47 (dd, J = 8.7, 4.5 Hz,
1H), 4.65 (t, J = 8.7 Hz, 1H), 4.47 (s, 2H), 4.22 (dd, J = 8.7, 4.5 Hz,
1H), 3.55 (dt, J = 6.3, 1.5 Hz, 2H), 2.49 (dq, J = 6.3, 2.4 Hz, 2H), 1.86
(s, 3H), 1.81 (d, J = 6.9 Hz, 3H); 13C NMR (CDCl3) δ 194.6 (C),
165.5 (C), 153.0 (C), 145.8 (CH), 138.5 (C), 138.4 (CH), 138.3 (C),
133.2 (C), 135.4 (C), 129.2 (CH), 128.7 (CH), 128.5 (CH), 127.7
(CH) 126.0 (2 x CH), 72.9 (CH2), 70.5 (CH2), 68.3 (CH2), 57.9
(CH), 30.3 (CH2), 14.5 (CH3), 12.6 (CH3); IR (KBr, cm−1) 3545,
3366, 3061, 3033, 2922, 2859, 1785, 1694, 1634, 1454, 1385, 1327,
+
1278, 1206, 1110, 1080, 919; LRMS (ESI) m/z (%) 451 (M + NH4 ,
85), 434 (M + H+, 100), 271 (70); HRMS (ESI) calcd for C26H28NO5
(M + H+) 434.1967, found 434.1964.
1H), 6.43 (d, J = 2.7 Hz, 1H), 4.10 (dd, J = 11.7, 1.8 Hz, 1H), 3.98
(dd, J = 11.7, 1.8 Hz, 1H), 3.81 (t, J = 11.7 Hz, 1H), 3.78 (s, 3H), 3.60
(d, J = 11.7 Hz, 1H), 3.58 (s, 3H), 2.23 (dt, J = 11.7, 1.8 Hz, 1H), 1.55
(s, 3H); 13C NMR (CDCl3) δ 209.2 (C), 167.9 (C), 160.0 (C), 154.3
(C), 139.0 (C), 129.6 (CH), 128.9 (CH), 127.6 (CH), 127.5 (CH),
111.7 (C), 109.0 (CH), 101.9 (CH), 62.6 (C), 60.8 (CH2), 60.7
(CH), 55.2 (CH3), 52.4 (CH3), 48.6 (CH), 43.0 (CH), 26.4 (CH3);
IR (KBr, cm−1) 2958, 1769, 1729, 1612, 1579, 1497, 1444, 1327, 1239,
(R)-3-((1R,2R)-2-(2-(Benzyloxy)ethyl)-3,4-dimethyl-5-oxocyclo-
pent-3-ene-1-carbonyl)-4-phenyloxazolidin-2-one 23. To an ice-
cooled solution of dienone 22 (230 mg, 0.531 mmol) in dry
dichloromethane (10 mL) was added MeSO3H (0.035 mL, 0.53
mmol), and the reaction allowed to warm slowly to rt. After stirring for
5 h TLC analysis revealed complete consumption of the starting
material, and the reaction was quenched with saturated NaHCO3 (aq)
(15 mL) and extracted with dichloromethane (2 × 20 mL). The
combined organic layers were washed with brine (10 mL) dried over
MgSO4, and the solvent was removed under reduced pressure to give
an oily residue. 1H NMR analysis of this material revealed the presence
of 23 and its minor diastereomer in a 3:1 ratio. The crude material was
dissolved in dichloromethane and evaporated onto silica gel (1 g)
under reduced pressure. The solid residue was subjected to flash
chromatography (sequential elution−dichloromethane/hexanes/dieth-
yl ether; 10:10:1, 5:5:1, 5:5:2) to give the major diastereomer 23 as a
viscous oil (136 mg, 53%); the minor isomer (17%) was not
+
1196, 1165, 1032, 927, 838; LRMS (ESI) m/z (%) 384 (M + NH4 ,
50), 367 (M + H+, 100); HRMS (ESI) m/z calcd for C22H23O5 (M +
H+) 368.1579, found 368.1577.
(4R)-3-(5′-Benzyloxy-pent-2′-ynoyl)-4-phenyloxazolidin-2-one
21. To a stirred solution of the ((but-3-yn-1-yloxy)methyl)benzene 19
(320 mg, 2.0 mmol) in dry THF (6 mL) at −78 °C was added n-
butyllithium (0.74 mL, 2.7 M in hexanes, 2.0 mmol), and the reaction
allowed to warm to rt for 10 min. The solution was recooled to −78
°C, and gaseous carbon dioxide bubbled through the solution for 15
min, and the reaction allowed to warm to rt and stirred for 10 min.
After this time N2 (g) was bubbled through the solution for 5 min to
remove excess carbon dioxide. The solution was then cooled to 0 °C,
and pivaloyl chloride (0.246 mL, 2.0 mmol) was added. The reaction
was allowed to warm to rt and stirred for 1 h before being cooled to
−78 °C, at which point a solution of the lithium salt of (R)-4-phenyl-
oxazolidin-2-one 20 (1.90 mmol, prepared by addition of 1.90 mmol
of n-butyllithium to a solution of 1.90 mmol of (R)-4-phenyl-
oxazolidin-2-one in 8 mL of THF at −40 °C) was added via cannula at
(−40 °C). The resulting reaction was warmed slowly to rt, stirred for 2
h, and then quenched with 10% w/v NH4Cl (aq) (30 mL) and
extracted twice with ethyl acetate (2 × 40 mL). The combined organic
layers were washed with brine (30 mL), dried over MgSO4 and
concentrated onto silica gel under a vacuum. The solid residue was
subjected to flash chromatography on silica gel (sequential elution
characterized. Major diastereomer 23: [α]25 = +43° (C = 0.99,
D
CHCl3); 1H NMR (CDCl3) δ 7.20−7.33 (m, 8H), 7.18 (d, J = 6.0 Hz,
2H), 5.39 (dd, J = 8.7, 2.7 Hz, 1H), 4.99 (d, J = 2.4 Hz, 1H), 4.74 (t, J
= 8.7 Hz, 1H), 4.30 (dd, J = 8.7, 2.4 Hz, 1H), 4.20 (mc, 2H), 3.44−
3.51 (m, 1H), 3.34−3.41 (m, 1H), 3.32 (br s, 1H), 2.09−2.19 (m,
1H), 2.01 (s, 3H), 1.69 (s, 3H), 1.53−1.63 (m, 1H); 13C NMR
(CDCl3) δ 200.9 (C), 172.6 (C), 168.4 (C), 153.7 (C), 139.3 (C),
138.1 (C), 134.0 (C), 129.0 (CH), 128.5 (CH), 128.2 (CH), 127.5
(CH), 127.4 (CH), 125.8 (CH), 72.9 (CH2), 69.8 (CH2), 68.3 (CH2),
58.2 (CH), 56.5 (CH), 43.9 (CH), 31.8 (CH2), 15.1 (CH3), 8.2
(CH3); IR (KBr,cm−1) 3646, 3543, 3385, 3032, 2922, 2860, 1784,
1693, 1645, 1452, 1381, 1323, 1240, 1199, 1103, 920, 874; LRMS
+
(ESI) m/z (%) 451 (M + NH4 , 25), 434 (M + H+, 100); HRMS
(ESI) calcd for C26H28NO5 (M + H+) 434.1967, found 434.1968.
(4aR,7aS)-5,6-Dimethyl-3,4,4a,7a-tetrahydrocyclopenta[c]pyran-
1,7-dione 24. A solution of cyclopentenone 23 (89 mg, 0.205 mmol)
and 10% palladium on carbon (10 mg) in ethyl acetate (3 mL) was
stirred under an atmosphere of hydrogen at ambient pressure and
temperature for 30 h. After this time TLC analysis revealed
consumption of the starting material. The reaction mixture was
filtered through Celite, and the solvent was removed to give a solid
residue (76 mg). The crude material was dissolved in dichloromethane
(5 mL), treated with MeSO3H (2 drops) and allowed to stir overnight.
After this time the reaction was quenched with saturated NaHCO3
with hexane/ethyl acetate 4:1 and 2:1) giving 21 (398 mg, 60%) as a
1
viscous oil: [α]25 = −10° (C = 1.2, CHCl3); H NMR (CDCl3) δ
D
7.28−7.41 (m, 10H), 5.43 (dd, J = 8.7, 3.6 Hz, 1H), 4.68 (t, J = 8.7 Hz,
1H), 4.57 (s, 2H), 4.28 (dd, J = 8.7, 3.6 Hz, 1H), 3.69 (t, J = 6.9 Hz,
2H), 2.74 (t, J = 6.9 Hz, 2H); 13C NMR (CDCl3) δ 152.1 (C), 150.0
(C), 138.3 (C), 137.8 (C), 129.1 (CH), 128.7 (CH), 128.4 (CH),
128.3 (CH) 127.7(CH), 125.9 (CH), 95.2 (C), 74.2 (C), 73.0 (CH2),
69.8 (CH2), 67.0 (CH2), 57.4 (CH), 20.7 (CH2); IR (KBr, cm−1)
3649, 3562, 3064, 3032, 2916, 2868, 2237, 1790, 1667, 1491, 1455,
1384, 1331, 1202, 1093, 1036, 805; LRMS (ESI) m/z (%) 367 (M +
3663
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The Journal of Organic Chemistry
Note
(aq) (10 mL) and extracted with dichloromethane (2 × 15 mL). The
combined organic layers were washed with brine (10 mL), dried over
MgSO4 and concentrated onto silica gel (1 g) under reduced pressure.
The solid residue was subjected to flash chromatography (sequential
elution with hexane/ethyl acetate 1:3 and ethyl acetate) to give the
M. J.; West, F. G. Org. Lett. 2011, 13, 114. (q) Dhoro, F.; Tius, M. A. J.
Am. Chem. Soc. 2005, 127, 12472. (r) Dhoro, F.; Kristensen, T. E.;
Stockmann, V.; Yap, G. P. A.; Tius, M. A. J. Am. Chem. Soc. 2007, 129,
7256. (s) Raja, S.; Ieawsuwan, W.; Korotkov, V.; Rueping, M. Chem.
Asian J. 2012, 7, 2361. (t) Kerr, D. J.; Flynn, B. L. Org. Lett. 2012, 14,
1740. For trapping involving 1,2-Wagner−Meerwein rearrangement,
see: (u) Ohloff, G.; Schulte-Elte, K. H.; Demole, E. Helv. Chim. Acta
1971, 54, 2913. (v) Denmark, S. E.; Hite, G. A. Helv. Chim. Acta 1988,
71, 195. (w) Motoyoshiya, J.; Yazaki, T.; Hayashi, S. J. Org. Chem.
1991, 56, 735. (x) Chiu, P.; Li, S. L. Org. Lett. 2004, 6, 613. (y) He,
W.; Herrick, I. R.; Atesin, T. A.; Caruana, P. A.; Kellenberger, C. A.;
Frontier, A. J. J. Am. Chem. Soc. 2008, 130, 1003. (z) Huang, J.;
Leboeuf, D.; Frontier, A. J. J. Am. Chem. Soc. 2011, 132, 6307.
(3) For selected references on the asymmetric Nazarov reactions:
(a) Denmark, S. E.; Wallace, M. A.; Walker, C. B., Jr. J. Org. Chem.
1990, 55, 5545. (b) Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A.
J. Am. Chem. Soc. 2002, 124, 10091. (c) Kerr, D. J.; Metje, C.; Flynn, B.
L. Chem. Commun. 2003, 1380. (d) Liang, G.; Gradl, S. N.; Trauner,
D. Org. Lett. 2003, 5, 4931. (e) Aggarwal, V. K.; Belfield, J. A. Org. Lett.
2003, 5, 5075. (f) Rueping, M.; Leawsuwan, W.; Antonchick, A. P.;
Nachtsheim, B. J. Angew. Chem., Int. Ed. 2007, 46, 2097. (g) Walz, I.;
Togni, A. Chem. Commun. 2008, 4315. (h) Kerr, D. J.; White, J. M.;
Flynn, B. L. J. Org. Chem. 2010, 75, 7073. (i) Banaag, A. R.; Tius, M. A.
J. Org. Chem. 2008, 73, 8133. (j) Cao, P.; Deng, C.; Zhou, Y.-Y.; Sun,
X.-L.; Zheng, J.-C.; Xie, Z.; Tang, Y. Angew. Chem., Int. Ed. 2010, 49,
product 24 as a clear oil (30 mg, 81%): [α]25 = −167° (C = 0.90,
D
CHCl3); 1H NMR (CDCl3) δ 4.18 (dt, J = 11.4, 3.6 Hz, 1H), 3.89 (dt,
J = 11.4, 1.5 Hz, 1H), 3.52 (d, J = 6.9 Hz, 1H), 3.29 (br s, 1H), 2.25
(mc, 1H), 2.08 (s, 3H), 1.88 (d, J = 14.7 Hz, 1H), 1.80 (s, 3H); 13C
NMR (CDCl3) δ 198.2 (C), 168.6 (C), 166.3 (C), 138.3 (C), 63.6
(CH2), 52.2 (CH), 40.8 (CH), 25.9 (CH2), 14.8 (CH3), 8.4 (CH3);
IR (KBr, cm−1) 3466, 3362, 2974, 2897, 1732, 1687, 1643, 1437, 1386,
1329, 1276, 1213, 1188, 1159, 1063, 979, 940, 824, 766; LRMS (ESI)
+
m/z (%) 198 (M + NH4 , 20), 181 (M + H+, 100); HRMS (ESI) calcd
for C10H13O3 (M + H+) 181.0865, found 181.0859.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data for 17 (CIF) and copies of H and 13C
1
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: bernard.flynn@monash.edu.
■
4463. (k) Hutson, G. E.; Turkmen, Y. E.; Rawal, V. H. J. Am. Chem.
̈
Soc. 2013, 135, 4988.
Notes
(4) Ishii, H.; Ishige, M.; Matsushima, Y.; Tohojoh, T.; Ishikawa, T.;
Kawanabe, E. J. Chem. Soc., Perkin Trans. 1 1985, 2353.
(5) Lin, C.-F.; Yang, J.-S.; Chang, C.-Y.; Kuo, S.-C.; Lee, M.-R.;
Huang, L.-J. Bioorg. Med. Chem. 2005, 13, 1537.
(6) This stereochemical assignment is supported by the similar
coupling patterns seen in the relevant protons attached to the pyran
and cyclopentyl ring systems in the closely related structure 17, for
which an X-ray crystal structure was obtained.
The authors declare no competing financial interest.
REFERENCES
■
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(7) See the Supporting Information.
(2) Selected references on the interrupted Nazarov cyclization. For
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56, 10221. For heteroatomic nucleophiles: (l) Noyori, R.; Ohnishi, Y.;
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3664
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