Transmissive olefination route to putative "morinol I" lignans

Article abstract of DOI:10.1021/jo3001723

A series of morinol-type lignans were rapidly assembled using a Grignard-based transmissive olefination. In combination with palladium-catalyzed arylations, the strategy provides stereoselective access to (7Z,7′E), (7E,7′E), and (7E,7′Z) morinol diastereomers and the (7Z,8′E) and (7E,8′E) conjugated analogues. Critical for the E/Z stereoselectivity is a new, general method for converting alkenenitriles to alkenemethanols that circumvents the enal E/Z isomerization commonly encountered during conventional i-Bu₂AlH reduction.

Full text of DOI:10.1021/jo3001723

Note
pubs.acs.org/joc
Transmissive Olefination Route to Putative “Morinol I” Lignans
Lihua Yao,† Bhaskar Pitta,‡ P. C. Ravikumar,§ Matthew Purzycki, and Fraser F. Fleming*
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, Pennsylvania 15282-1530, United States
S
* Supporting Information
ABSTRACT: A series of morinol-type lignans were rapidly
assembled using a Grignard-based transmissive olefination. In
combination with palladium-catalyzed arylations, the strategy provides
stereoselective access to (7Z,7′E), (7E,7′E), and (7E,7′Z) morinol
diastereomers and the (7Z,8′E) and (7E,8′E) conjugated analogues.
Critical for the E/Z stereoselectivity is a new, general method for
converting alkenenitriles to alkenemethanols that circumvents the enal
E/Z isomerization commonly encountered during conventional i-
Bu2AlH reduction.
lkenenitrile pharmacophores are embedded within an
array of pharmaceuticals1 and natural products2 (Figure
1). In many instances, the nitrile plays a key role in receptor
ordered transition structure (Scheme 1).8 Addition of excess
Grignard reagent to Baylis−Hilman-derived9 hydroxyalkeneni-
A
Scheme 1. Transmissive Olefination Route to (Z)-
Alkenenitriles
triles 4 triggers a displacement that selectively affords (Z)-
alkenenitriles 6. Mechanistic probes are consistent with a
concerted reorganization through the magnesiate 5 in which
the slender10 nitrile group preferentially eclipses the carbinol
substituent R1.
Rapid access to (Z)-alkenenitriles from three readily available
components, an aldehyde, acrylonitrile, and a Grignard reagent,
appeared ideal for synthesizing and unraveling the structural
ambiguity of the neolignan morinol I. Morinol I is one of a
series of neolignans11 (Figure 2, 8−19) that were isolated
during a bioactivity guided isolation of extracts from the roots
of the traditional Chinese medicinal herb Morina chinensis.12
Among morinol metabolites, the proposed structure 7 for
morinol I is unique in having a skipped diene. All morinols,
except morinol I, formally have water added to the C7−C8
bond. The related neolignan galanganal (15), isolated from the
Zingiberaceae plant Alpinia galangal, has the same olefin
position as 7 but the opposite C7 alkene geometry.13
Intriguingly, the HMBC and NOESY correlations reported
for morinol I are not consistent with the skipped diene
structure 7 but require a conjugated C7−C8 C9′−C8′ diene.
Adding to the structural ambiguity is the secure structural
identification of morinols A−D, through synthesis,14 which do
contain a C7′−C8′ olefin. Unfortunately, neither a sample nor
Figure 1. Bioactive alkenenitriles.
binding as with the potent anti-HIV agent3 rilpivirine (1) where
the nitrile groups interact deep within the binding pocket.4
Consistent with the key role of the nitrile group, (E/Z)-
alkenenitrile diastereomers often exhibit significantly different
potencies as exemplified by the antitumor agent 2.5 A similar
interplay of substitution and E/Z geometry influences the
antitumor activity6 of calyculins A−H (3), unusual (E)- and
(Z)-tetraenenitriles from the marine sponges Discodermia calyx
and Lamellomorpha strongylata.2
Selective access to diastereomeric (E)- and (Z)-alkenenitriles
is challenging.7 In addressing this challenge, a stereoselective
synthesis of (Z)-alkenenitriles 6 was developed that hinges on
an intramolecular transmissive olefination through a highly
Received: January 27, 2012
Published: March 20, 2012
© 2012 American Chemical Society
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Note
Figure 2. Representative morinol-type lignans.
spectral data of morinol I are available, leaving synthesis as the
most promising method for determining the correct structure.15
The putative structure 7 of morinol I was rapidly assembled
through a five-step sequence featuring a transmissive olefination
(Scheme 2).8 Addition of excess vinylmagnesium bromide to
i-Bu2AlH reduction−hydrolysis sequence,19 in reversed nitrile
hydrolysis−reduction sequences,20 and through isomerization
of the resulting enal.21
After some exploratory forays,22 a stereoselective hydrolysis,
acylation, reduction sequence was developed (Scheme 3). The
Scheme 2. Transmissive Olefination Route to “Morinol I”
Scheme 3. Stereoselective Alkenenitrile to Hydroxymethyl
Conversion
the veratraldehyde-derived nitrile 209,16 afforded the (Z)-
alkenenitrile 21 that was subjected to a palladium-catalyzed
arylation14a with (3,4-dimethoxyphenyl)boronic acid (22) to
provide 23. Conventional i-Bu2AlH reduction17 of nitrile 23,
imine hydrolysis, and aldehyde reduction was irreproducible18
and gave varying ratios of lignan (7Z,7′E)-7 and the
diastereomer (7E,7′E)-7. Neither (7Z,7′E)-7 nor (7E,7′E)-7
exhibit spectral data matching that of the natural product,
although the NMR chemical shifts, such as the H NMR shift
for H7, appeared more consistent with the Z-configuration of
the C7 olefin.
Using the transmissive olefination strategy to prepare (Z)-C7
lignans corresponding to that of morinol I requires a
reproducible, stereoselective alkenenitrile to alkenol conversion.
The stereoselective reduction of alkenenitriles to allylic alcohols
is challenging because olefin isomerization can occur during the
sequence exploits the facile platinum-catalyzed hydrolysis of
nitriles23 (23 → 24) and the selective reduction of imides.24
Despite a lack of precedent for the reduction of alkeneamides,25
a brief survey of reducing agents and solvent identified LiBH4
in THF as effective for reducing imide 25 to (7Z,7′E)-alkenol 7
without any trace of the 7E-diastereomer.26
Having developed a robust method for controlling the
stereochemistry of the C7 olefin, (7Z,7′Z)-7 was targeted
because the data reported for morinol I suggested either the
geometry or position of the (7′Z)-olefin was incorrect (Scheme
1
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Note
Scheme 4. Invertive Trimethylsilyl Iodine Route to (7Z,7′Z)-7
4). Key to the synthesis of (7Z,7′Z)-7 was the serendipitous
discovery27 that the trimethylsilylalkene 26, obtained through
the transmissive olefination of 20 with trimethylsilylvinylmag-
nesium bromide (52%),28 underwent an efficient trimethylsilyl
iodine interchange with inversion of stereochemistry. Treating
vinylsilane 26 with N-iodosuccinimide in 1:1 dichloromethane/
hexafluoroisopropanol29 afforded the (Z)-iodide 2730 that was
subjected to palladium-catalyzed coupling31 with (3,4-
dimethoxyphenyl)boronic acid (22) to afford 28 with retention
of configuration. Subjecting 28 to the three-step hydrolysis,
acylation, and reduction efficiently provided (7Z,7′Z)-7 with no
erosion of olefin configuration.
reduction of nitrile 31 gave a 1:1 mixture of (7Z,8′E)-32 and
(7E,8′E)-32. Although (7Z,8′E)-32 exhibited several H NMR
1
resonances similar to that of morinol, significant spectral
differences are evident.
1
Graphing the H and 13C chemical shift differences between
morinol I and the lignan diastereomers (7Z,7′E)-7, (7E,7′E)-7,
(7E,7′Z)-7, (7Z,8′E)-32, and (7E,8′E)-32 highlights the regions
having the greatest discrepancy (Figure 3). Large differences in
Although morinol analogue (7Z,7′Z)-7 did not exhibit
spectral data corresponding to that of the target, during the
palladium-catalyzed coupling of 27, traces of a conjugated
dienenitrile were generated which exhibited a 1H NMR
methylene signal very similar to that reported for morinol I
(δ 3.47 and 3.55, respectively). Attempts to isomerize the
dienes (7Z,7′Z)-28 and (7Z,7′Z)-7 proved fruitless, inspiring a
new strategy based on the oxidative acetylation32 of 21. Using
the “original” oxidative acetylation protocol,32b nitrile 21 was
smoothly transformed into (7Z,8′E)-29 (Scheme 5). Palladium-
Scheme 5. Transmissive Olefination Route to the
Conjugated Morinol Analogue 32
Figure 3. 13C (top) and 1H NMR (bottom) Δδ for morinol
analogues.35
the 13C chemical shift exist for C9 and C9′ in the pentadiene
catalyzed arylation of 29 with (3,4-dimethoxyphenyl)boronic
acid (22) to afford (7Z,8′E)-dienenitrile 31 proceeded best by
employing the hydrazine ligand 30.33 A slight modification of
the hydrolysis, imide formation, and reduction was required
because the conventional Boc-anhydride/DMAP procedure
afforded the bis-Boc-acylimidodicarbonate.34 Deprotonating
the intermediate amide with BuLi and adding Boc anhydride
afforded the requisite imide that was reduced without incident
to the (7Z,8′E)-alcohol 32. As a point of comparison, the
sequential i-Bu2AlH reduction, imine hydrolysis, and NaBH4
fragment and for C1 of the aromatic ring.35 The H chemical
1
shift values for the aromatic protons are quite similar, whereas
H7, H7′, and H9′ show pronounced differences relative to those
reported for morinol I.35 The lack of clear chemical shift
correlations of regions within the synthetic lignans compared to
values reported for morinol I leave the exact identity of the
natural product in doubt.
Morinol-type lignans are readily assembled through
sequential transmissive olefinations and palladium-catalyzed
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Note
mmol) was added to a suspension of Mg (22.4 mg, 0.89 mmol) in cold
(0 °C) THF (0.8 mL). Neat (E)-(2-(trimethylsilyl)vinyl)bromide
(0.09 mL, 0.69 mmol) was added dropwise, and after 1 h at 0 °C, the
THF solution of the resulting Grignard reagent was added to a −20 °C
THF solution (3 mL) of 2-((3,4-dimethoxyphenyl)(hydroxy)methyl)
acrylonitrile 209,16 (50 mg, 0.23 mmol). After 3 h, the reaction mixture
was poured into aqueous, saturated NH4Cl (2 mL). The aqueous
phase was extracted with EtOAc (3 × 10 mL), and the combined
organic phase was washed with brine, dried (Na2SO4), concentrated,
and purified by radial chromatography (15% EtOAc in hexanes) to
afford 36.8 mg (52%) of nitrile 26 as a light yellow oil: IR (neat) 2954,
2206, 1600 cm−1; 1H NMR (CDCl3, 500 MHz) δ −0.01 (s, 9H), 3.16
(d, J = 6.6 Hz, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 5.88 (d, J = 18.0 Hz,
1H), 6.04 (dt, J = 18.0, 6.6 Hz, 1H), 6.84 (s, 1H), 6.87 (d, J = 7.8 Hz,
1H), 7.19 (dd, J = 7.8, 1.8 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H); 13C
NMR (CDCl3, 100 MHz) δ −1.32, 42.7, 55.9, 106.2, 110.1, 110.7,
119.4, 123.3, 126.6, 134.7, 140.3, 143.9, 148.8, 150.5 ppm; HRMS for
C17H23NO2Si [M + H+] calcd 302.1577, found 302.1563.
couplings. The sequence generates diaryl pentadienes with
excellent control over the E/Z geometry and features a new
strategy for converting (Z)-dienenitriles into (Z)-allylic
alcohols. In contrast to the conventional i-Bu2AlH reduction,
imine hydrolysis, NaBH4 reduction of alkenenitriles, the
platinum-catalyzed hydrolysis, imide formation, and reduction
smoothly generate allylic alcohols without any observable
isomerization. The versatility of the transmissive olefination and
the new reduction strategy is illustrated in the synthesis of five
morinol-type lignans in the quest to determine the structure of
the elusive natural product morinol I.
EXPERIMENTAL SECTION
■
(2Z, 4E)-2-(3, 4-Dimethoxybenzylidene)-5-(3, 4-
dimethoxyphenyl)pent-4-enamide (24). Solid Parkins23 catalyst
[bis(dimethylphosphinous acid-kP)dimethylphosphinyl-kP-
hydridoplatinum(II)] (0.5 mg, 0.0075 mmol) was added to an
ethanol/water solution (1:1, 20 mL) of 23 (54.8 mg, 0.15 mmol), and
then the reaction mixture was heated to reflux. After 15 h, the solution
was cooled, the solvent was evaporated, and then the residue was
purified by radial chromatography (70% EtOAc in hexanes) to afford
50.0 mg (87%) of the amide 24 as a white solid: mp 108−109 °C; IR
(2Z,4Z)-2-(3,4-Dimethoxybenzylidene)-5-iodopent-4-eneni-
trile (27). Solid N-iodosuccinimide (146.3 mg, 0.65 mmol) was added
to a 0 °C 1,1,1,3,3,3-hexafluoroisopropanol and dichloromethane (1:1)
solution (1.6 mL) of 26 (130 mg, 0.43 mmol). After 10 min, the
reaction mixture was poured into an aqueous, saturated NH4Cl
solution (2 mL). The aqueous phase was extracted with EtOAc (3 ×
10 mL), and the combined organic phase was washed with brine, dried
(Na2SO4), concentrated, and purified by radial chromatography (15%
EtOAc in hexanes) to afford 125 mg (82%) of nitrile 27 as a light
(solid) 3416, 3338, 2935, 1672, 1518 cm−1; H NMR (CDCl3, 500
1
MHz) δ 3.31 (d, J = 7.2 Hz, 2H), 3.86 (s, 3H), 3.88 (s, 6H), 3.91 (s,
3H), 5.42 (s, 2H), 6.14 (dt, J = 16.0, 7.2 Hz, 1H), 6.47 (d, J = 16.0 Hz,
1H), 6.57 (s, 1H), 6.82 (dd, J = 8.4, 2.0 Hz, 2H), 6.90−6.97 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ 39.8, 55.9, 56.0, 108.7, 111.0, 111.1,
1
yellow oil: IR (neat) 2934, 2206, 1597 cm−1; H NMR (CDCl3, 500
MHz) δ 3.26 (d, J = 6.6 Hz, 2H), 3.93 (s, 3H), 3.94 (s, 3H), 6.39 (dt, J
= 7.6, 7.6 Hz, 1H), 6.57 (dt, J = 7.6 Hz, 1.4 Hz, 1H), 6.89 (d, J = 8.4
Hz, 1H), 6.95 (s, 1H), 7.21 (dd, J = 8.4, 2.4 Hz, 1H), 7.52 (d, J = 2.4
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 40.8, 55.9 (2), 86.6, 104.0,
110.2, 110.7, 119.2, 123.4, 126.3, 135.6, 144.3, 148.8, 150.7 ppm;
HRMS for C14H14NO2I [M + Na+] calcd 377.9967, found 377.9944.
(2Z, 4Z)-2-(3, 4-Dimethoxybenzylidene)-5-(3, 4-
dimethoxyphenyl)pent-4-enenitrile (28). Solid (3,4-
dimethoxyphenyl)boronic acid (87.8 mg, 0.46 mmol), palladium
acetate (14.0 mg, 0.06 mmol), and triphenyl phosphine (32.5 mg, 0.12
mmol) were added to a rt, THF solution (8 mL) of 27 (100.0 mg, 0.31
mmol). After 12 h, the reaction mixture was poured into water (2 mL).
The aqueous phase was extracted with EtOAc (3 × 10 mL), and the
combined organic phase was washed with brine, dried (Na2SO4),
concentrated, and purified by radial chromatography (30% EtOAc in
hexanes) to afford 88.3 mg (78%) of nitrile 28 as a light yellow oil: IR
111.3, 119.3, 121.3, 124.3, 128.3, 130.2, 130.3, 132.3, 135.3, 148.7,
148.9, 149.0, 172.1 ppm; HRMS for C22H25NO5 [M + Na+] calcd
406.1631, found 406.1619.
tert-Butyl-(2Z,4E)-2-(3,4-dimethoxybenzylidene)-5-(3,4-
dimethoxyphenyl)pent-4-enoylcarbamate (25). Solid di-tert-
butyldicarbonate (43.4 mg, 0.20 mmol) and 4-dimethylaminopyridine
(1.2 mg, 0.01 mmol) were added to a rt, CH2Cl2 solution (5 mL) of
24 (40 mg, 0.10 mmol). After 20 h, the reaction mixture was poured
into dichloromethane (10 mL), the phases were separated, and the
organic phase was combined and then washed sequentially with 1 M
HCl (10 mL) and water (10 mL). The solvent was evaporated, and the
residue was then purified by radial chromatography (30% EtOAc in
hexanes) to afford 35.3 mg (73%) of imide 25 as a light yellow oil: IR
(neat) 2979, 1777, 1601 cm−1, 1H NMR (CDCl3, 500 MHz) δ 1.43 (s,
9H), 3.31 (d, J = 7.2 Hz, 2H), 3.87 (s, 3H), 3.88 (s, 3H), 3.89 (s, 3H),
3.90 (s, 3H), 6.22 (dt, J = 11.6, 7.2 Hz, 1H), 6.51 (d, J = 11.6 Hz, 1H),
6.51 (s, 1H), 6.80−7.02 (m, 7H); 13C NMR (CDCl3, 100 MHz) δ
27.8, 38.4, 55.8, 55.9, 84.6, 108.7, 110.8, 111.0, 111.1, 119.4, 124.0,
128.1, 130.5, 130.7, 132.7, 133.5, 148.6, 148.7, 149.0, 149.3, 170.7
ppm; HRMS for C27H33NO7 [M + H+] calcd 484.2336, found
484.2325.
1
(neat) 2931, 2206 cm−1; H NMR (CDCl3, 500 MHz) δ 3.39 (d, J =
7.8 Hz, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 3.93 (s, 3H),
5.72 (dt, J = 11.4, 7.2 Hz, 1H), 6.67 (d, J = 11.4 Hz, 1H), 6.83 (s, 1H),
6.85−6.89 (m, 3H), 6.91 (s, 1H), 7.19 (dd, J = 8.4, 1.8 Hz, 1H), 7.53
(d, J = 1.8 Hz, 1H); NOESY correlations between δ 5.72 and 6.67
established the Z-configuration of the disubstituted olefin; 13C NMR
(CDCl3, 100 MHz) δ 34.7, 55.9 (2), 106.8, 110.3, 110.8, 111.0, 111.9,
119.5, 121.1, 123.2, 124.9, 126.6, 129.3, 132.5, 143.6, 148.3, 148.7,
149.0, 150.7 ppm; HRMS for C22H23NO4 [M + Na+] calcd 388.1525,
found 388.1512.
(2Z, 4E)-2-(3, 4-Dimethoxybenzylidene)-5-(3, 4-
dimethoxyphenyl)pent-4-en-1-ol (7Z,7′E)-7. A THF solution
(0.13 mL) of lithium triethylborohydride (0.13 mmol, 1 M) was
added to a rt, THF solution (5 mL) of 25 (30 mg, 0.06 mmol). After 2
h, an aqueous solution (10 mL) of 30% H2O2 was added. After 30 min,
the aqueous phase was extracted with EtOAc (3 × 10 mL), and the
combined organic phase was washed with brine, dried (Na2SO4),
concentrated, and purified by radial chromatography (30% EtOAc in
hexanes) to afford 16.0 mg (72%) of alcohol (7Z,7′E)-7 as a light
(2Z, 4Z)-2-(3, 4-Dimethoxybenzylidene)-5-(3, 4-
dimethoxyphenyl)pent-4-enamide (i). Solid Parkins23 catalyst
[bis(dimethylphosphinous acid-kP)dimethylphosphinyl-kP-
hydridoplatinum(II)] (0.6 mg, 0.01 mmol) was added to an
ethanol/water solution (1:1, 20 mL) of 28 (80 mg, 0.22 mmol),
and then the reaction was heated to reflux. After 15 h, the solvent was
evaporated and the residue was purified by radial chromatography
(70% EtOAc in hexanes) to afford 95.1 mg (92%) of amide i as a
white solid: mp 101−102 °C; IR (solid) 3411, 3339, 2934, 2836, 1677,
1
yellow oil: IR (neat) 3520, 2935, 1598 cm−1; H NMR (CDCl3, 400
MHz) δ 1.59 (br s, 1H), 3.20 (d, J = 7.1 Hz, 2H), 3.88 (s, 6H), 3.89 (s,
3H), 3.91 (s, 3H), 4.34 (s, 2H), 6.20 (dt, J1 = 15.8 Hz, J2 = 7.1 Hz,
1H), 6.47 (d, J = 15.8 Hz, 1H), 6.50 (s, 1H), 6.84 (d, J = 8.3 Hz, 1H),
6.87 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 6.95
(dd, J1 = 8.1 Hz, J2 = 2.0, 1H), 6.98 (d, J = 2.0 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) δ 39.5, 55.8, 55.9, 55.9, 61.3, 108.6, 110.9, 111.1,
112.0, 119.1, 121.2, 126.0, 129.4, 129.8, 130.4, 131.7, 138.5, 148.1,
148.5, 148.6, 149.0 ppm; HRMS for C22H26O5 [M + Na+] calcd
393.1678, found 393.1696.
1
1601 cm−1; H NMR (CDCl3, 400 MHz) δ 3.48 (d, J = 7.6 Hz, 2H),
3.88 (s, 3H), 3.90 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 5.43 (s, 2H),
5.75 (dt, J = 11.6, 7.6 Hz, 1H), 6.59 (s, 1H), 6.61 (d, J = 11.6 Hz, 1H),
6.80−7.00 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 34.1, 55.9 (2),
111.0, 111.3, 111.9, 121.2 (2), 126.3, 128.3, 129.8 (2), 131.4, 135.2,
148.1, 148.7, 148.8, 172.3 ppm; HRMS for C22H25NO5 [M + Na+]
calcd 406.1631, found 406.1618.
(2Z,4E)-2-(3,4-Dimethoxybenzylidene)-5-(trimethylsilyl)-
pent-4-enenitrile (26). Neat 1,2-dibromoethane (0.01 mL, 0.07
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Note
tert-Butyl-((2Z,4Z)-2-(3,4-dimethoxybenzylidene)-5-(3,4-
dimethoxyphenyl)pent-4-enoyl)carbamate (ii). Solid di-tert-butyl
dicarbonate (136.8 mg, 0.63 mmol) and 4-dimethylaminopyridine (2.9
mg, 0.02 mmol) were added to a CH2Cl2, rt, solution (5 mL) of i (90
mg, 0.24 mmol). After 20 h, the reaction mixture was poured into
dichloromethane (10 mL) and washed sequentially with 1 M HCl (10
mL) and water (10 mL). The solvent was evaporated, and the residue
was then purified by radial chromatography (30% EtOAc in hexanes)
to afford 88.3 mg (76%) of imide ii as a light yellow oil: IR (neat)
3296, 2930, 1766, 1686 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.38 (s,
9H), 3.45 (d, J = 7.8 Hz, 2H), 3.85 (s, 3H), 3.88 (s, 3H), 3.89 (s, 3H),
3.91 (s, 3H), 5.73 (dt, J = 11.4, 7.2 Hz, 1H), 6.61 (d, J = 6.0 Hz, 1H),
6.62 (d, J = 6.0 Hz, 1H), 6.80−6.92 (m, 7H); 13C NMR (CDCl3, 100
MHz) δ 27.8, 33.6, 55.8, 55.9 (2), 82.7, 110.7, 110.8, 110.9, 111.6,
121.2, 125.6, 127.8, 129.6, 131.8, 134.6, 148.1, 148.6, 148.8, 149.0,
149.1 ppm; HRMS for C27H33NO7 [M + Na+] calcd 506.2155, found
506.2155.
110.9, 111.4, 112.0, 117.2, 120.7, 123.9, 126.8, 128.4, 131.6, 133.9,
142.2, 147.7, 149.0, 150.9 ppm; HRMS for C22H23NO4 [M + Na+]
calcd 388.1519, found 388.1521.
(2Z, 4E )-2-(3, 4-Dimethoxybenzylidene)-5-(3, 4-
dimethoxyphenyl)pent-4-enamide (iii). Solid Parkins23 catalyst
(bis(dimethylphosphinous acid-kP)dimethylphosphinyl-kP-
hydridoplatinum(II)) (4.5 mg, 0.5 mol %, 0.01 mmol) was added to
an ethanol−water (1:1, 20 mL) solution of 31 (75 mg, 0.21 mmol),
and then the reaction was heated to reflux. After 15 h, the solvent was
evaporated and the residue was purified by radial chromatography
(70% EtOAc in hexanes) to afford 74 mg (94%) of the amide iii as a
1
white solid: mp 144−146 °C; IR 3412, 3338, 1677 cm−1; H NMR
(CDCl3, 400 MHz) δ 3.45 (d, J = 4.8 Hz, 2H), 3.86 (s, 3H), 3.87 (s,
3H), 3.88 (s, 6H), 5.56 (br, s, 1H), 5.60 (br, s, 1H), 6.08−6.14 (m,
2H), 6.39 (s, 2H), 6.72−6.75 (m, 2H), 6.80−6.82 (m, 2H), 6.99−7.04
(m, 2H) ppm; 13C NMR (CDCl3, 400 MHz) δ 38.8, 55.8, 55.9, 56.0,
111.0, 111.2, 111.3, 112.1, 120.7, 121.8, 128.1, 129.5, 130.2, 132.1,
135.0, 147.5, 148.8, 148.9, 149.1, 171.5 ppm; HRMS for C22H25NO5
[M + Na+] calcd 406.1625, found 406.1632.
(1Z,4Z)-1,5-Bis(3,4-dimethoxyphenyl)penta-1,4-dien-2-ol
(7Z,7′Z)-7. A THF solution (0.34 mL) of lithium triethylborohydride
(0.34 mmol, 1 M) was added to a rt, THF solution (5 mL) of ii (80
mg, 0.17 mmol). After 2 h, an aqueous 30% solution (10 mL) of H2O2
was added. After 30 min, the aqueous phase was extracted with EtOAc
(3 × 10 mL), and the combined organic phase was washed with brine,
dried (Na2SO4), concentrated, and purified by radial chromatography
(30% EtOAc in hexanes) to afford 43.4 mg (69%) of alcohol (7Z,7′Z)-
tert-Butyl-((2Z,3E)-2-(3,4-dimethoxybenzylidene)-5-(3,4-
dimethoxyphenyl)pent-3-enoyl)carbamate (iv). A cyclohexane
solution of BuLi (2.0 M, 0.156 mmol) was added dropwise to a −78
°C THF (3 mL) solution of iii (60 mg, 0.156 mmol). After 1 h, a THF
(1.0 mL) solution of di-tert-butyl dicarbonate (34 mg, 0.156 mmol)
was added, and the reaction mixture was then allowed to warm slowly
to room temperature. After 16 h, saturated, aqueous ammonium
chloride (3 mL) was added followed by H2O (5 mL). The organic
layer was separated, the aqueous phase was extracted with EtOAc (2 ×
10 mL), and the combined organic phase was washed with brine, dried
(Na2SO4), concentrated, and purified by radial chromatography (50%
EtOAc in hexanes) to afford 52 mg (68%) of iv as a pale yellow
1
7 as a light yellow oil: IR (neat) 3517, 2925, 1514 cm−1; H NMR
(CDCl3, 400 MHz) δ 1.28 (s, 1H), 3.36 (d, J = 7.6 Hz, 2H), 3.88 (s,
6H), 3.89 (s, 3H), 3.91 (s, 3H), 4.35 (s, 2H), 5.82 (dt, J1 = 11.6 Hz, J2
= 7.6 Hz, 1H), 6.51(s, 1H), 6.66 (d, J = 11.6 Hz, 1H), 6.86 (d, J = 7.2
Hz, 1H), 6.87 (d, J = 7.2 Hz, 1H), 6.89 (s, 1H), 6.86 (d, J = 7.2 Hz,
1H), 6.93 (s, 1H), 6.94 (d, J = 7.2 Hz, 1H); 13C NMR (CDCl3, 400
MHz) δ 34.7, 55.9 (3), 77.2, 110.9, 111.9, 112.0, 121.1, 121.2, 128.0,
129.0, 130.0, 131.0, 138.7, 148.0 ppm; HRMS for C22H26O5 [M +
Na+] calcd 393.1678, found 393.1691.
(2E,4Z)-4-Cyano-5-(3,4-dimethoxyphenyl)penta-2,4-dien-1-
yl Acetate (29). Solid 1,4-benzoquinone (37.7 mg, 0.35 mmol),
palladium acetate (4.0 mg, 0.02 mmol), and 4 Å MS were added to a
DMSO/AcOH solution (1:1, 5 mL) of 21 (40 mg, 0.17 mmol). The
reaction was maintained at 40 °C under an air atmosphere using an
air-filled balloon to maintain a slight positive pressure. After 72 h, the
reaction mixture was poured into EtOAc (10 mL), the phases were
separated, and the organic phase was washed with water (3 × 5 mL),
dried (Na2SO4), concentrated, and purified by radial chromatography
(20% EtOAc in hexanes) to afford 203 mg (67%) of nitrile 29 as a
light yellow oil: IR (neat) 2254 cm−1; 1H NMR (CDCl3, 400 MHz) δ
2.14 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 4.74 (d, J = 6.0 Hz, 2H), 6.25
(dt, J = 15.8 Hz, 6.0 Hz, 1H), 6.41 (d, J = 15.8 Hz, 1H), 6.74 (s, 1H),
6.91 (d, J = 8.6 Hz, 1H), 7.01 (s, 1H), 7.27 (dd, J = 8.6 Hz, 2.2 Hz,
1H) 7.63 (d, J = 2.2 Hz, 1H); 13C NMR (CDCl3, 400 MHz) δ 21.0,
56.0, 63.8, 107.0, 110.6, 110.9, 116.2, 116.8, 124.5, 126.4, 127.0, 130.8,
144.4, 149.1, 151.4, 170.7 ppm; HRMS for C16H17NO4K [M + K+]
calcd 326.0789, found 326.0820.
(2Z, 3E)-2-(3, 4-Dimethoxybenzylidene)-5-(3, 4-
dimethoxyphenyl)pent-3-enenitrile (31). Solid (3,4-
dimethoxyphenyl)boronic acid (115 mg, 0.63 mmol) was added to a
rt DMF (1.5 mL) and H2O (0.5 mL) solution of 29 (150 mg, 0.522
mmol), K2CO3 (144 mg, 1.044 mmol), Pd(OAc)2 (2.33 mg, 0.01
mmol), and ligand (N,N′E,N,N′E)-N,N′-(ethane-1,2-diylidene)bis-
(piperidin-1-amine)33 (2.31 mg, 0.01 mmol). After 1 h, the mixture
was diluted with EtOAc and H2O (10 mL, 1:1). The organic layer was
separated, the aqueous phase was extracted with EtOAc (2 × 10 mL),
and the combined organic phase was washed with brine, dried
(Na2SO4), concentrated, and purified by radial chromatography (30%
EtOAc in hexanes) to afford 116 mg (61%) of 31 as a white solid (mp
102−104 °C): IR 1025, 1144, 1265, 1514, 1554, 1627, 2214, 2836,
2934 cm−1; 1H NMR (CDCl3, 400 MHz) δ 3.49 (d, J = 7.0 Hz, 2H),
3.88 (s, 3H), 3.89 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 6.10 (d, J = 15.3
Hz, 1H), 6.38 (dt, J = 15.3, 6.8 Hz, 1H), 6.72−6.77 (m, 2H), 6.83−
6.89 (m, 3H), 7.22 (dd, J = 8.4, 2.3 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H)
ppm; 13C NMR (CDCl3, 400 MHz) δ 38.4, 55.9, 56.0, 108.1, 110.5,
1
gummy liquid: IR 3280, 2934, 1767, cm−1; H NMR (CDCl3, 400
MHz) δ 1.39 (s, 9H), 3.44 (d, J = 5.8 Hz, 2H), 3.85 (s, 3H), 3.87 (s,
3H), 3.88 (s, 3H), 3.89 (s, 3H), 5.94−6.0 (m, 1H), 6.13 (d, J = 15.6
Hz, 1H), 6.44 (s, 1H), 6.71−6.74 (m, 2H), 6.79−6.82 (m, 2H), 6.90−
6.93 (m, 2H), 7.30 (s, 1H) ppm; 13C NMR (CDCl3, 400 MHz) δ 27.8,
38.8, 55.83, 55.89, 55.92, 55.98, 56.0, 82.9, 110.7, 111.1, 111.3, 112.1,
120.7, 132.0, 134.3, 136.0, 147.6, 148.9, 149.1, 149.3 ppm; HRMS for
C27H33NO7Na [M + Na+] calcd 506.2149, found 506.2142.
(2Z, 3E )-2-(3, 4-Dimethoxybenzylidene)-5-(3, 4-
dimethoxyphenyl)pent-3-en-1-ol (7Z,9′E)-32. A THF solution (5
mL) of lithium triethylborohydride (0.17 mL, 0.17 mmol) was added
to a 0 °C THF solution (3 mL) of iv (40 mg, 0.083 mmol), and then
the solution was allowed to warm slowly to rt. After 2 h, an aqueous
30% solution of H2O2 (6 mL) was added. After 30 min, the aqueous
phase was extracted with EtOAc (3 × 10 mL), and the combined
organic phase was washed with brine, dried (Na2SO4), concentrated,
and purified by radial chromatography (30% EtOAc in hexanes) to
afford 19 mg (62%) of (7Z,9′E)-32 as a light yellow oil: IR 1023, 1138,
1232, 1258, 1511, 1593, 1709, 2835, 2932, 3510 cm−1; 1H NMR
(CDCl3, 400 MHz) δ 3.47 (d, J = 6.5 Hz, 2H), 3.87 (s, 3H), 3.88 (s,
3H), 3.89 (s, 3H), 3.90 (s, 3H), 4.47 (br, d, 2H), 6.11 (dt, J1 = 15.8
Hz, J2 = 6.5 Hz, 1H), 6.20 (d, J = 15.8 Hz, 1H), 6.58 (s, 1H), 6.74 (d, J
= 2.0 Hz, 1H), 6.77 (dd, J1 = 8.0 Hz, J2 = 2.0, 1H), 6.82 (d, J = 8.0 Hz,
1H), 6.86 (d, J = 8.3 Hz, 1H), 6.97 (dd, J1 = 8.3 Hz, J2 = 2.0 Hz, 1H),
7.00 (d, J = 2.0 Hz, 1H) ppm; 13C NMR (CDCl3, 400 MHz) δ 39.1,
55.87, 55.90, 55.92, 55.98, 58.3, 111.0, 111.3, 112.0, 112.2, 120.5,
121.7, 129.1, 129.6, 132.7, 133.1, 133.3, 136.4, 147.5, 148.5, 148.7,
1
149.0 ppm; HMBC correlation of the H NMR hydroxymethyl signal
at δ 3.47 with the olefinic 13C signals at δ 133.3 and 136.4 confirms
that the olefins are conjugated; HRMS for C22H26O5Na [M + Na+]
calcd 393.1672, found 393.1697.
(2E, 3E)-2-(3, 4-Dimethoxy benzyl id ene )-5- (3, 4-
dimethoxyphenyl)pent-3-en-1-ol (7Z,9′E)-32 and (7E,9′E)-32. A
cyclohexane solution of diisobutylaluminum hydride (1.0 M, 0.58
mmol) was added dropwise to a −78 °C toluene (4 mL) solution of
31 (100 mg, 0.274 mmol). The cooling bath was removed and the
reaction allowed to slowly warm to rt. After 3 h, the reaction mixture
was cooled to −78 °C and ethanol (1 mL) and aqueous acetic acid
(50%, 1 mL) were added sequentially. After 15 min, the solution was
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The Journal of Organic Chemistry
Note
allowed to warm to rt, the organic layer was separated, the aqueous
phase was extracted with EtOAc (2 × 10 mL), and the combined
organic phase was washed with water, aqueous NaHCO3, and brine
and then dried (Na2SO4) and concentrated to give the corresponding
aldehyde (96 mg). The crude aldehyde (96 mg) was dissolved in
methanol (7 mg, 0.30 mmol) at room temperature, and solid NaBH4
was then added portionwise. After 15 min, saturated aqueous
ammonium chloride (2 mL) was added, followed by water. The
crude mixture was extracted with EtOAc (2 × 10 mL), NS the
combined organic phase was washed with brine, dried (Na2SO4),
concentrated, and purified by radial chromatography (35% EtOAc in
hexanes) to afford 57 mg (56%) of a 1:1 mixture of alcohols (7Z,9′E)-
32 and (7E, 9′E)-32 as a pale yellow oily liquid. For (7E,9′E)-32: IR
(9) Coelho, F.; Almeida, W. P.; Veronese, D.; Mateus, C. R.; Silva
Lopes, E. C.; Rossi, R. C.; Silveira, G; Pavam, C. H. Tetrahedron 2002,
58, 7437.
(10) The A value is only 0.2 kcal mol−1: Eliel, E. L.; Wilen, S. H.;
Mander, L. N. In Stereochemistry of Organic Compounds; Wiley: New
York, 1994; pp 696−697.
(11) (a) Zhu, Y.; Lu, Z.-P.; Xue, C.-B.; Wu, W.-S. Helv. Chim. Acta
2009, 92, 536. (b) Su, B.-N.; Takaishi, Y.; Duan, H.-Q.; Chen, B. J.
Nat. Prod. 1999, 62, 1363.
(12) Su, B.-N.; Takaishi, Y.; Kusumi, T. Tetrahedron 1999, 55, 14571.
(13) Morikawa, T.; Ando, S.; Matsuda, H.; Kataoka, S.; Muraoka, O.;
Yoshikawa, M. Chem. Pharm. Bull. 2005, 53, 625.
(14) (a) Ogura, K.; Sugahara, T.; Maruyama, M.; Akiyama, K.;
Yamauchi, S. Biosci. Biotechnol. Biochem. 2010, 74, 1641. (b) Yamauchi,
S.; Sugahara, T.; Akiyama, K.; Maruyama, M. J. Nat. Prod. 2007, 70,
549. (c) Yamauchi, S.; Uno, H. Org. Biomol. Chem. 2003, 1323.
(15) For a review of natural products with revised identities, see:
Nicolaou, K. C.; Snyder, S. A. Angew. Chem., Int. Ed. 2005, 44, 1012.
(16) Zhong, W; Liu, Y.; Guo, B. Heterocycles 2009, 78, 3053.
(17) Winterfeldt, E. Synthesis 1975, 10, 617.
(18) Monitoring the reaction revealed that the isomerization occurs
during hydrolysis of the intermediate imine. Use of different acids
(HCl, TsOH, citric acid) and different acid concentrations did not
identify reproducible conditions for the hydrolysis.
1
3504, 2933, 1592 cm−1; H NMR (CDCl3, 400 MHz) δ 3.42 (d, J =
6.9 Hz, 2H), 3.86 (s, 9H), 3.90 (s, 3H), 4.44 (br d, J = 2.8 Hz, 2H),
6.12 (dt, J1 = 16.2 Hz, J2 = 6.9 Hz, 1H), 6.56 (d, J = 16.2 Hz, 1H), 6.58
(s, 1H), 6.71 (s, 1H), 6.73 (d, J = 8.5, 1H), 6.82 (d, J = 8.5, 1H), 6.84
(d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.86 (s, 1H) ppm; 13C
NMR (CDCl3, 400 MHz) δ 39.4, 55.8, 55.9, 55.9, 56.0, 110.86, 111.3,
111.9, 112.6, 120.4, 122.2, 126.9, 128.2, 129.7, 131.3, 132.6, 136.1,
147.5, 148.2, 149.0 ppm; HRMS for C22H26O5Na [M + Na+] calcD
393.1672, found 393.1704.
ASSOCIATED CONTENT
■
S
* Supporting Information
(19) Díez, D.; Nunez, M. G.; Moro, R. F.; Lumeras, W.; Marcos, I. S.;
́
̃
1H NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Basabe, P.; Urones, J. G. Synlett 2006, 939.
(20) Yoneda, R.; Harusawa, S.; Kurihara, T. J. Chem. Soc., Perkin
Trans. 1 1988, 3163.
(21) (a) Henderson, A. P.; Bleasdale, C.; Delaney, K.; Lindstrom, A.
B.; Rappaport, S. M.; Waidyanatha, S.; Watson, W. P.; Golding, B. T.
Bioorg. Chem. 2005, 33, 363. (b) Xiao, X. Y.; Prestwich, G. D. Synth.
Commun. 1990, 20, 3125. (c) Trost, B. M.; Livingston, R. C. J. Am.
Chem. Soc. 1995, 117, 9586.
AUTHOR INFORMATION
Corresponding Author
*E-mail: flemingf@duq.edu.
■
(22) Neither LiAl(OEt)3Ha or various Raney-nickel mediated partial
reduction proceduresb‑d were effective. (a) Brown, H. C.; Garg, C. P. J.
Am. Chem. Soc. 1964, 86, 1085. (b) Khai, B. T.; Arcelli, A. J. Org. Chem.
1989, 54, 949. (c) van Es, T.; Staskun, B. J. Chem. Soc. 1965, 5775.
(d) Backeberg, O. G.; Staskun, B. J. Chem. Soc. 1962, 3961.
(23) Ghaffar, T.; Parkins, A. W. J. Mol. Catal. A 2000, 160, 249.
(24) As a representative example, see: Campbell, C. L.; Hassler, C.;
Ko, S. S.; Voss, M. E.; Guaciaro, M. A.; Carter, P. H.; Cherney, R. J. J.
Org. Chem. 2009, 74, 6368.
Present Addresses
†Mylan Pharmaceuticals Inc., 781 Chestnut Ridge Road,
Morgantown, WV 26505.
‡Biophore Pharmaceuticals, Prashant Nagar, Kukatpally,
Hyderabad AP 500 0072, India.
§School of Basic Sciences, Indian Institute of Technology,
Mandi HP 175001, India.
Notes
The authors declare no competing financial interest.
(25) For the reduction of primary amides via the bis-Boc-
acylimidodicarbonates, see: (a) Tagnarsson, U.; Grehn, L.; Monteiro,
L. S.; Maia, H. L. S. Synlett 2003, 2386. For the related reduction of a
saturated N-unsubstituted Boc acylcarbonate, see: (b) Nevill, C. R. Jr.;
Angell, P. T. Tetrahedron Lett. 1998, 39, 5671.
ACKNOWLEDGMENTS
Financial support from the National Institutes of Health
(2R15AI051352-03) is gratefully acknowledged.
■
(26) LiBH4 in THF was found to be far superior to the use of NaBH4
in a variety of solvents.
REFERENCES
■
(27) Originally prepared for a Suzuki−Miyaura cross-coupling of 25
which proved intractable: Farinola, G. M.; Fiandanese, V.; Mazzone,
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(29) Ilardi, E. A.; Stivala, C. E.; Zakarian, A. Org. Lett. 2008, 10, 1727.
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Note
(35) The shift values for C7′ and C9′ for (7Z,8′E)-32 and (7E,8′E)-32
are interposed in the table to accommodate the olefin transposition.
The greatest points of difference in the chemical shift data are
illustrated below with a full comparison provided in the Supporting
Information on page S35.
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