Domino functionalizations of the amino terminus of 6-aminopenicillanates with Ph3PCCO

Article abstract of DOI:10.1016/j.tetlet.2004.12.083

6-Aminopenicillanates, or the sulfoxides or the sulfones thereof, were N-acylated in a three-component reaction with an aldehyde and Ph₃PCCO to give the corresponding 6-(E-2′-alkenoyl)amides. This domino addition-Wittig alkenation sequence was extended by an additional Claisen rearrangement step in the side-chain in the case of 5g.

Full text of DOI:10.1016/j.tetlet.2004.12.083

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1127–1130
Domino functionalizations of the amino terminus of
6-aminopenicillanates with Ph3PCCO
Rainer Schobert* and Andreas Stangl
Organisch-Chemisches Laboratorium der Universita¨t, 95440 Bayreuth, Germany
Received 8 November 2004; revised 15 December 2004; accepted 17 December 2004
Available online 7 January 2005
Abstract—6-Aminopenicillanates, or the sulfoxides or the sulfones thereof, were N-acylated in a three-component reaction with an
aldehyde and Ph3PCCO to give the corresponding 6-(E-20-alkenoyl)amides. This domino addition–Wittig alkenation sequence was
extended by an additional Claisen rearrangement step in the side-chain in the case of 5g.
Ó 2004 Elsevier Ltd. All rights reserved.
A recent trend1 in the chemistry and medicinal refine-
ment of penicillins, complementing the quest for lacta-
mase resistant 6-acylamino derivatives, are covalent
conjugates of penams with other prominent drug targets
or biochemical shuttle systems such as peptides,2 or sid-
erophoric catechols.3 Hence new methods for the attach-
ment of functionalized side-arms to the 6-amino group
under conditions milder and more flexible than the
conventional treatment with acyl halides/auxiliary base
are still of interest. We have recently demonstrated the
domino reaction of ketenylidenetriphenylphosphorane,
Ph3P@C@C@O 1, with amines and aldehydes to give
a,b-unsaturated amides in good yields.4 In this letter
we evaluate the applicability of this one-pot approach
to the N-acylation of esters5 of 6-amino-penicillanic acid
(6-APA) 2.6,7
C-3, C-5 or C-6, leading to new diastereoisomers was
not detectable in any case by high resolution H and
1
13C NMR.
Compound 5 was alternatively prepared in two steps
and similar yields from the ammonium salt of 39 and 1
via the phosphonium salt 10.10 This was deprotonated
with DBU at ꢀ30 °C to give the corresponding ylide
4 (n = 0), which was immediately treated with the
respective aldehyde (Scheme 2). While an analogous
phosphonium salt could be obtained from methyl 7-
ammoniocephalosporanate, its deprotonation with a
range of bases including DBU, NaHCO3 and alumina
(Al2O3), even in the presence of an aldehyde, led to con-
comitant partial isomerization11 of the endocyclic C@C
bond and gave mixtures of the corresponding D2 and D3
6-aminoacylcephalosporanates (at best 1:7 in the case of
Al2O3/THF).
When a three-component mixture of the optically pure
methyl ester (3S,5R,6R)-35a of 2, ylide 1 and an alde-
hyde was stirred at room temperature for 12–16 h, the
corresponding E-a,b-unsaturated 6-acylaminopenicilla-
nates 5 were obtained in yields ranging from 60% to
80% via the intermediate acyl ylides 4, which are isolable
in the absence of an aldehyde (Scheme 1). The sulfoxide
65b and sulfone 85c reacted analogously, albeit more
slowly, furnishing the corresponding E-a,b-unsaturated
6-acylamino-1-oxo-penicillanates 7/9.8 Epimerization at
The above domino reactions can be extended by
further pericyclic steps. For example, the catecholic
penam derivative 5h can be directly synthesized12 from
1,
3
and 2-(20,40-hexadienyloxy)-3-methoxy-benz-
aldehyde13 by a domino acylylidation–Wittig alkena-
tion–Claisen rearrangement reaction as shown in
Scheme 3.
As a rule, antibiotic activity of penam derivatives re-
quires a free 3-carboxylic acid functionality, which is
best liberated in the last step by cleavage of esters
such as benzhydryl,14 benzyl15 or t-butyl.16 For in-
stance, 6-amidopenicillanic acid 1317 was available in
two steps and 40–50% overall yield by acidolysis of
Keywords: b-Lactams; Domino reaction; Wittig alkenation; Phospho-
rus ylides.
*
Corresponding author. Fax: +49 0921 552671; e-mail: rainer.
schobert@uni-bayreuth.de
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.083

1128
R. Schobert, A. Stangl / Tetrahedron Letters 46 (2005) 1127–1130
H
[O]n
S
H
[O]n
S
[O]n
S
N
+ Ph3PCCO (1)
+ RCHO
R
H2N
O
N
Ph3P
O
N
O
N
N
iv)
5: n = 0
7: n = 1
9: n = 2
O
O
CO2Me
CO2X
CO2Me
4
2: X = H, n = 0
yields [%]
i)
3: X = Me, n = 0
6: X = Me, n = 1
8: X = Me, n = 2
R
5
7
9
ii)
iii)
O
O
C
a:
76 63 50
b:
c:
2-furyl 56 52 48
3-pyridyl
53 50 48
52
d: 3-NMe-Indolyl
e:
f:
Bu 64
β-styryl
70
Scheme 1. Reagents and conditions: (i) CH2N2, CH2Cl2, rt, 95%; (ii) MeCN, m-CPBA, 0 °C, 30 min, 85%; (iii) MeCN, KMnO4/H2SO4, ꢀ10 °C,
75%; (iv) THF, rt, 12–16 h.
H
H
N
X
H2N
O
N
O
O
S
S
i)
S
Ph3P
Cl–
ii), iii)
+ 1
3•HCl
5
O
N
N
O
N
i)
O
O
CO2R1
CO2R1
CO2Me
11a: R1 = Bn
b: R1 = CHPh2
c: R1 = tBu
12a: R1 = Bn, X = CH=CH (77%)
b: R1 = CHPh2, X = CH=CH (73%)
c: R1 = tBu, X = CH=CH (68%)
10
Scheme 2. Reagents and conditions: (i) C6H6/THF, rt, 8 h, 85%; (ii)
CH2Cl2 + DBU, ꢀ30 °C; (iii) + RCHO, ꢀ30 °C rt, 8 h; 80–85%.
iii)
ii) iv)
13: R1 = H, X = CH=CH
14: R1 = H, X = (CH2)2
Scheme 4. Reagents and conditions: (i) 1, piperonal, THF, 60 °C, 12 h;
(ii) THF/HCO2H, 0 °C–rt, 30 min, 50%; (iii) CH2Cl2, anisole,
F3CCO2H, 0 °C–rt, 45 min, 61%; (iv) H2, 1 bar, EtOH/AcOEt,
PdO(H2O), 24–48 h, 72%.
t-butyl ester 12c18 with formic acid or of benzhydryl
ester 12b18 with trifluoroacetic acid/anisole.19 12b, like
the benzyl ester 12a,18 can alternatively be deprotected
with H2/PdO(OH2) with concomitant hydrogenation
of the olefinic double bond in the newly attached side
chain to yield 6-amidopenicillanic acid 1420 (Scheme
4).
O
H2N
H
N
S
O
i)
S
N
The necessity of protecting groups can be done away
with altogether by employing soluble carboxylates of
6-APA 2 in the three-component reaction with 1 and
aldehydes. The crown-ether complex 1521 of potassium
6-aminopenicillanate for one was reacted with 1 and
piperonal in THF/dioxane solution at room temperature
to furnish 13 in 50% yield after acidic hydrolysis22
(Scheme 5).
O
O
N
CO2
O
CO2R1
[K•18-Crown-6]
15
12d: R1 = [K•18-Crown-6]
13: R1 = H
ii)
Scheme 5. Reagents and conditions: (i) 1, piperonal, THF/dioxane 2:1,
rt, pH 7–8 (PhCO2H), 30 min; (ii) aq NaHCO3 + HC1, 0 °C (50%
overall).
OMe
OH
H
OMe
O
N
S
OMe
i)
ii)
NH
O
S
O
1 + 3 +
O
N
E
(50%)
(70%)
O
O
N
CO2Me
CHO
CO2Me
5g
5h
iii)
(60%)
Scheme 3. Reagents and conditions: (i) THF, 35 °C, 12 h; (ii) MeCN, 65 °C, 72 h; (iii) THF, 65 °C, 60 h.

R. Schobert, A. Stangl / Tetrahedron Letters 46 (2005) 1127–1130
1129
73 °C; 1H NMR (CDCl3): d 1.48 (3H, s), 1.65 (3H, s), 3.75
(3H, s), 4.42 (1H, s), 5.57 (1H, d, 3J 4.3 Hz), 5.63 (1H, dd,
References and notes
3
3
3J 4.3, 9.1 Hz), 6.01 (1H, d, J 14.7 Hz), 6.44 (1H, d, J
9.1 Hz), 6.80–6.90 (2H, m), 7.20–7.45 (6H, m); 13C NMR
(CDCl3): d 27.2, 31.5, 52.5, 58.8, 64.9, 68.3, 70.7, 122.2,
126.1, 127.2, 128.8, 136.1, 140.5, 143.1, 165.4, 168.3, 174.2.
1. Kidwai, M.; Sapra, P.; Bhushan, K. R. Curr. Med. Chem.
1999, 6, 195–215.
2. (a) Li, S.; Roberts, R. W. Chem. Biol. 2003, 10, 233–239;
(b) Zhao, Z.; Batley, M.; DÕAmbrosio, C.; Baldo, B. A.
J. Immunol. Methods 2000, 242, 43–51.
3. Heinisch, L.; Wittmann, S.; Stoiber, T.; Berg, A.; Ankel-
Fuchs, D.; Mo¨llmann, U. J. Med. Chem. 2002, 45, 3032–
3040.
4. Schobert, R.; Siegfried, S.; Gordon, G. J. Chem. Soc.,
Perkin Trans. 1 2001, 2393–2397.
5. (a) Compound 3 (5.10 g, 95%) from 6-APA 2 (5.0 g,
23.1 mmol) and CH2N2 (1.5 equiv) in Et2O/CH2Cl2; mp
48–50 °C; mmax (film)/cmꢀ1 3391, 2965, 1777, 1700; 1H
NMR (270 MHz, CDCl3): d 1.45 (3H, s), 1.61 (3H, s), 2.79
1
Compound 5g: mp 66 °C; H NMR(CDCl3): d 1.45 (3H,
s), 1.61 (3H, s), 1.69 (3H, d, J 6.6 Hz), 3.73 (3H, s), 3.80
3
(3H, s), 4.41 (1H, s), 4.47 (2H, d, 3J 6.4 Hz), 5.55 (1H, d, 3J
3
4.3 Hz), 5.60–5.75 (2H, m), 5.83 (1H, dd, J 4.3, 9.1 Hz),
5.95–6.10 (1H, m), 6.10–6.25 (1H, m), 6.51 (1H, d, 3J
15.8 Hz), 6.52 (1H, d, 3J 9.1 Hz), 6.80–6.90 (1H, m), 6.95–
7.15 (2H, m), 7.90 (1H, d, 3J 15.8 Hz); 13C NMR (CDCl3):
d 18.0, 26.7, 31.2, 52.3, 55.7, 58.6, 64.6, 68.1, 70.4, 73.8,
113.6, 119.1, 120.5, 121.7, 123.9, 125.4, 127.5, 130.6, 134.2,
137.9, 147.0, 153.1, 165.3, 168.1, 174.0. Satisfactory
microanalyses (C, 0.2; H, 0.1; N, 0.1) were obtained for
5a–g.
3
(2H, br, NH2), 3.72 (3H, s), 4.36 (1H, s), 4.59 (1H, d, J
5.7 Hz) 5.44 (1H, d, 3J 5.7 Hz); 13C NMR (75.5 MHz,
CDCl3): d 26.9, 31.3, 52.3, 62.7, 63.8, 69.6, 69.8, 168.5,
177.7; (b) Micetich, R. G.; Singh, R.; Shaw, C. J. Org.
Chem. 1986, 51, 1811–1815; (c) Bos, J. J.; Cuperus, R.;
Wielinga, R. Eur. Patent Appl. 0213685 A1, 1987; CAS
88209-17-0.
8. Compounds 7 or 9 were obtained from 1, the respective
aldehyde and sulfoxide 65b or sulfone 8,5c respectively,
following the protocol described for the synthesis of 5
1
(Ref. 7). Compound 7a: mp 98 °C; H NMR (CDCl3): d
1.14 (3H, s), 1.64 (3H, s), 3.74 (3H, s), 4.63 (1H, s), 5.04
(1H, d, 3J 4.7 Hz), 5.90 (2H, s), 6.12 (1H, dd, 3J 4.7,
10.1 Hz), 6.21 (1H, d, 3J 15.4 Hz), 6.70 (1H, d, 3J 7.9 Hz),
6.85–6.95 (2H, m), 7.23 (1H, d, 3J 10.1 Hz), 7.47 (1H, d, 3J
15.4 Hz); 13C NMR (DMSO-d6): d 17.9, 18.9, 52.8, 55.3,
65.6, 74.7, 76.3, 101.5, 106.3, 108.5, 118.9, 124.0, 129.1,
140.8, 148.0, 148.9, 165.1, 168.3, 174.3. Compound 7b: mp
91 °C; 1H NMR (CDCl3): d 1.19 (3H, s), 1.66 (3H, s), 3.76
(3H, s), 4.64 (1H, s), 5.05 (1H, d, 3J 4.5 Hz), 6.13 (1H, dd,
6. Compound 5a from 1, 3 and piperonal—typical proce-
dure: 1 (610 mg, 2.02 mmol), 3 (460 mg, 2.00 mmol),
piperonal (315 mg, 2.10 mmol) and dry THF (30 mL)
was stirred at rt for 12 h. The solvent was removed and the
residue was purified by column chromatography (silica gel
60; cyclohexane/ethyl acetate, 2:1, v/v; Rf 0.33); yield:
606 mg (76%), mp 76 °C; mmax (KBr)/cmꢀ1 1784, 1741,
1
1664, 1621; H NMR (270 MHz, CDCl3): d 1.39 (3H, s),
3
3J 4.5, 10.1 Hz), 6.28 (1H, d, J 15.3 Hz), 6.35–6.43 (1H,
1.55 (3H, s), 3.67 (3H, s), 4.34 (1H, s), 5.50 (1H, d, 3J
4.1 Hz), 5.75 (1H, dd, 3J 4.1, 7.7 Hz), 5.87 (2H, s), 6.29
(1H, d, 3J 15.4 Hz), 6.67 (1H, d, 3J 7.7 Hz), 6.80–7.00 (3H,
m), 7.48 (1H, d, 3J 15.4 Hz); 13C NMR (75.5 MHz,
DMSO-d6): d 26.8, 30.6, 52.2, 59.5, 64.2, 67.7, 70.1, 101.5,
106.5, 108.5, 118.8, 123.6, 128.8, 140.2, 148.0, 148.8, 165.1,
168.0, 173.8; m/z (EI) 404 (M+, 1%), 308 (20%), 175 (29%),
174 (100%).
3
3
m), 6.53 (1H, d, J 3.0 Hz), 7.23 (1H, d, J 10.1 Hz), 7.36
(1H, d, 3J 15.3 Hz), 7.40 (1H, d, 3J 1.7 Hz); 13C NMR
(DMSO-d6): d 18.7, 19.4, 53.0, 56.6, 66.4, 75.3, 76.9, 112.3,
114.7, 117.1, 129.6, 144.6, 151.0, 165.4, 168.4, 173.9.
1
Compound 7c: mp 96 °C; H NMR (CDCl3): d 1.18 (3H,
3
s), 1.67 (3H, s), 3.76 (3H, s), 4.65 (1H, s), 5.09 (1H, d, J
4.5 Hz), 6.13 (1H, dd, 3J 4.5, 9.9 Hz), 6.52 (1H, d, 3J
15.6 Hz), 7.35–7.55 (2H, m), 7.59 (1H, d, 3J 15.6 Hz),
7.70–7.80 (1H, m), 8.45–8.55 (1H, m), 8.68 (1H, s); 13C
NMR (CDCl3): d 18.7, 19.4, 53.1, 56.6, 60.4, 66.4, 77.0,
121.8, 123.9, 130.4, 134.6, 139.1, 149.4, 150.4, 164.8, 168.3,
173.6. Compound 9a: mp 95 °C (dec.); 1H NMR (CDCl3):
d 1.39 (3H, s), 1.60 (3H, s), 3.80 (3H, s), 4.55 (1H, s), 4.83
1
7. Compound 5b: mp 67 °C; H NMR (CDCl3): d 1.45 (3H,
s), 1.61 (3H, s), 3.74 (3H, s), 4.41 (1H, s), 5.56 (1H, d, J
3
4.3 Hz), 5.82 (1H, dd, 3J 4.3, 8.8 Hz), 6.35 (1H, d, 3J
3
15.2 Hz), 6.40–6.45 (1H, m), 6.55 (1H, d, J 3.2 Hz), 6.62
(1H, d, 3J 8.8 Hz), 7.40 (1H, d, 3J 15.2 Hz), 7.43 (1H, d, 3J
4.3 Hz); 13C NMR (DMSO-d6): d 26.6, 30.4, 52.5, 58.7,
64.1, 68.0, 70.1, 112.5, 114.6, 117.8, 133.4, 144.3, 150.8,
164.8, 167.9, 173.6. Compound 5c: mp 74 °C; 1H NMR
(CDCl3): d 1.42 (3H, s), 1.55 (3H, s), 3.70 (3H, s), 4.35
(1H, s), 5.54 (1H, d, 3J 4.2 Hz), 5.78 (1H, dd, 3J 4.2,
3
3
(1H, d, J 4.7 Hz), 5.98 (2H, s), 6.25 (1H, d, J 15.4 Hz),
6.28 (1H, dd, 3J 4.7, 10.2 Hz), 6.77 (1H, d, 3J 7.9 Hz),
6.95–7.10 (3H, m), 7.57 (1H, d, 3J 15.4 Hz); 13C NMR
(CDCl3): d 17.7, 20.2, 53.1, 57.3, 63.8, 64.8, 66.1, 101.5,
106.5, 108.5, 116.7, 124.5, 128.6, 143.4, 148.3, 149.6, 165.5,
167.1, 174.2. Compound 9b: mp 96 °C (dec.); 1H NMR
(CDCl3): d 1.36 (3H, s), 1.56 (3H, s), 3.78 (3H, s), 4.53
(1H, s), 4.82 (1H, d, 3J 4.6 Hz), 6.25 (1H, dd, 3J
4.6,10.2 Hz), 6.32 (1H, d, 3J 15.3 Hz), 6.41 (1H, dd,
3J 1.5, 3.2 Hz), 6.56 (1H, d, 3J 3.2 Hz), 7.11 (1H, d, 3J
10.2 Hz), 7.41 (1H, d, 3J 15.3 Hz), 7.42 (1H, d, 3J 1.5 Hz);
13C NMR (CDCl3): d 17.6, 20.1, 53.1, 57.1, 63.7, 64.6,
66.0, 112.2, 114.9, 116.3, 129.9, 144.6, 150.7, 165.4, 167.1,
174.1. Compound 9c: mp 98 °C (dec.); 1H NMR (CDCl3):
d 1.35 (3H, s), 1.55 (3H, s), 3.77 (3H, s), 4.51 (1H, s), 4.84
(1H, d, 3J 4.6 Hz), 6.23 (1H, dd, 3J 4.6, 10.2 Hz), 6.55 (1H,
d, 3J 15.7 Hz), 7.25–7.40 (2H, m), 7.55 (1H, d, 3J 15.7 Hz),
8.00–8.10 (1H, m), 8.45–8.55 (1H, m), 8.65 (1H, s); 13C
NMR (CDCl3): d 17.6, 20.1, 53.0, 57.1, 63.7, 64.7, 65.9,
121.0, 124.0, 130.4, 134.3, 139.7, 149.4, 150.6, 164.7, 167.0,
173.7. Satisfactory microanalyses (C, 0.2; H, 0.1; N, 0.1)
were obtained for all compounds.
3
8.6 Hz), 6.62 (1H, d, J 15.7 Hz), 7.15–7.25 (1H, m), 7.58
(1H, d, 3J 15.7 Hz), 7.61 (1H, d, 3J 8.6 Hz), 7.65–7.70 (1H,
m), 8.45–8.50 (1H, m), 8.66 (1H, s, br); 13C NMR
(DMSO-d6): d 26.9, 31.1, 52.3, 58.8, 64.6, 67.6, 70.5,
121.5, 123.6, 130.3, 134.4, 138.8, 149.1, 150.4, 164.6, 168.0,
173.7. Compound 5d: mp 82 °C; 1H NMR (CDCl3): d 1.42
(3H, s), 1.58 (3H, s), 3.76 (3H, s, OMe), 3.79 (3H, s, NMe),
4.43 (1H, s), 5.58 (1H, d, 3J 4.1 Hz), 5.67 (1H, d, 3J
12.4 Hz), 5.86 (1H, dd, 3J 4.1, 9.0 Hz), 6.42 (1H, d, 3J
9.0 Hz), 7.13 (1H, d, 3J 12.4 Hz), 7.10–7.35 (3H, m), 7.60–
7.70 (1H, m), 8.69 (1H, s); 13C NMR (CDCl3): d 27.0,
31.3, 33.1, 52.4. 58.7, 64.6, 68.2, 70.5, 109.6, 110.0, 112.6,
117.8, 120.5, 122.2, 128.9, 132.9, 135.1, 136.4, 166.3, 168.2,
174.5. Compound 5e: mp 59 °C; 1H NMR (CDCl3): d 0.87
(3H, t, 3J 8.1 Hz), 1.20–1.45 (4H, m), 1.47 (3H, s), 1.63
(3H, s), 2.10–2.25 (2H, m), 3.75 (3H, s), 4.41 (1H, s), 5.53
(1H, d, 3J 3.9 Hz), 5.70–5.85 (2H, m), 6.20 (1H, d, 3J
8.2 Hz), 6.89 (1H, dt, 3J 15.0, 7.4 Hz); 13C NMR (CDCl3):
d 13.9, 22.3, 27.2, 30.2, 31.5, 31.9, 52.5, 58.6, 64.9, 68.2,
70.6, 122.2, 147.6, 165.2, 168.2, 174.3. Compound 5f: mp
9. Pring, B. G.; Ekstroem, B.; Jalar, L. P.; Magni, L.; Molin,
M. Eur. J. Med. Chem. 1984, 19(2), 173–180.

1130
R. Schobert, A. Stangl / Tetrahedron Letters 46 (2005) 1127–1130
1
10. Compound 10: H NMR (270 MHz, CDCl3): d 1.40 (3H,
s), 1.68 (3H, s), 3.70 (3H, s), 4.41 (1H, s), 5.27 (1H, dd, J
1624, 1491, 1250; 1H NMR (300 MHz, CDCl3): d 1.30
(3H, s), 1.61 (3H, s), 4.50 (1H, s), 5.15 (2H, s, CH2Ph),
2
15.8, 13.8 Hz), 5.28 (1H, dd, 3J 4.2, 7.5 Hz), 5.35 (1H, d, 3J
3
5.56 (1H, d, J 4.2 Hz), 5.81 (1H, dd, J 4.2, 9.1 Hz), 5.96
3
2
3
(2H, s), 6.24 (1H, d, J 15.8 Hz), 6.37 (1H, d, J 9.1 Hz),
3
4.2 Hz), 5.52 (1H, dd, J 15.8, 14.2 Hz), 7.60–7.90 (15H,
m); 10.40 (1H, d, 3J 7.5 Hz); 13C NMR (75.5 MHz,
CDCl3): d 26.8, 31.7, 32.3, 52.2, 60.0, 64.6, 67.1, 70.4,
118.3, 133.2, 134.3, 134.9, 163.4, 168.5, 171.6. 31P NMR
(121.5 MHz, CDCl3): d 21.7.
3
3
6.73 (1H, d, J 7.5 Hz), 6.96 (1H, d, J 7.5 Hz), 6.98 (1H,
3
s), 7.20–7.35 (5H, m), 7.54 (1H, d, J 15.8 Hz); 13C NMR
(75 MHz, CDCl3): d 27.0, 31.6, 58.7, 64.9, 67.5, 69.1, 70.5,
101.5, 106.4, 108.5, 116.9, 124.4, 128.7, 128.7, 128.8, 130.0,
134.7, 142.8, 148.3, 149.4, 165.3, 167.5, 174.1; m/z (EI) 480
(M+, 18%), 250 (50%), 175 (88%), 91 (100%). Compound
12b (2.14 g, 3.83 mmol, 73%) from 11b (2.00 g,
5.25 mmol), 1 (1.68 g, 5.51 mmol) and piperonal (0.87 g,
5.78 mmol); Rf 0.65 (cyclohexane/ethyl acetate, 1:1); pale
yellow solid of mp 133–135 °C; mmax/cmꢀ1 1781, 1741,
1658, 1616, 1489, 1245; 1H NMR (300 MHz, CDCl3): d
1.26 (3H, s), 1.62 (3H, s), 4.53 (1H, s), 5.60 (1H, d, 3J
4.3 Hz), 5.85 (1H, dd, 3J 4.3, 9.0 Hz), 5.95 (2H, s), 6.26
(1H, d, 3J 15.5 Hz), 6.45 (1H, d, 3J 9.0 Hz), 6.76 (1H, d, 3J
7.7 Hz), 6.93 (1H, s, CHPh2), 6.95 (1H, d, 3J 7.7 Hz), 6.98
11. (a) Woodward, R. B.; Heusler, K.; Gosteli, J.; Oppolzer,
W.; Ramage, R.; Ranganathan, S.; Vorbruggen, H. J. Am.
Chem. Soc. 1966, 88, 852–853; (b) Morin, R. B.; Jackson,
R. B.; Mueller, R. A.; Lavagnino, E. R.; Scanlon, W. B.;
Andrews, S. L. J. Am. Chem. Soc. 1969, 91, 1401–1407; (c)
Bentley, P. H.; Brooks, G.; Zomaya, I. Tetrahedron Lett.
1976, 41, 3739–3742.
12. Compound 5h (583 mg, 60%) from 1 (610 mg, 2.02 mmol),
(460 mg, 2.00 mmol) and 2-(20,40-hexadienyloxy)-3-
3
methoxy-benzaldehyde13 (490 mg, 2.10 mmol); mp 79 °C;
mmax (KBr)/cmꢀ1 1784, 1751, 1665; H NMR (CDCl3): d
1
1.32 (3H, d, 3J 5.1 Hz), 1.47 (3H, s), 1.65 (3H, s), 3.35–3.50
(1H, m), 3.75 (3H, s), 3.85 (3H, s), 4.43 (1H, s), 4.99 (1H,
(1H, s), 7.25–7.45 (10H, m), 7.57 (1H, d, J 15.5 Hz); 13C
3
NMR (75 MHz, CDCl3): d 26.7, 31.9, 58.0, 65.0, 68.4,
70.5, 78.4, 101.4, 106.4, 108.5, 116.9, 124.3, 126.9, 127.5,
128.1, 128.4, 128.5, 128.6, 128.7, 138.9, 139.0, 165.2, 166.7,
173.9; m/z (EI) 556 (M+, 13%), 382 (10%), 230 (20%), 175
(98%), 168 (50%), 167 (100%). Compound 12c (1.13 g,
2.50 mmol, 68%) from 11c (1.00 g, 3.68 mmol), 1 (1.12 g,
3.70 mmol) and piperonal (0.57 g, 3.80 mmol); Rf 0.55
(cyclohexane/ethyl acetate, 2:1); pale yellow solid of mp
3
2
dd, J 10.1, J 1.5 Hz), 5.11 (1H, dd, J 16.9, J 1.5 Hz),
3
2
3
5.56 (1H, d, J 4.2 Hz), 5.90–5.73 (2H, m), 6.10–5.95 (1H,
m), 6.35–6.20 (1H, m), 6.42 (1H, d, 3J 9.1 Hz), 6.66 (1H, d,
4J 1.6 Hz), 6.67 (1H, d, 3J 15.8 Hz), 6.83 (1H, d, 4J
1.6 Hz), 7.79 (1H, d, 3J 15.8 Hz); 13C NMR (CDCl3): d
21.0, 27.1, 31.3, 41.7, 52.3, 56.2, 58.7, 64.7, 68.2, 70.6,
111.0, 115.8, 120.1, 120.3, 120.4, 129.6, 136.8, 137.0, 138.6,
139.2, 143.8, 146.7, 165.8, 168.2, 174.5; m/z (EI) 486 (M+,
8%), 298 (10%), 229 (8%), 174 (100%).
1
65 °C; mmax/cmꢀ1 1783, 1737, 1671, 1624, 1490, 1248; H
NMR (300 MHz, CDCl3): d 1.40 (9H, s, CMe3), 1.55 (3H,
s), 1.62 (3H, s), 4.30 (1H, s), 5.56 (1H, d, J 4.4 Hz), 5.83
3
13. Synthesis of 2-(20,40-hexadienyloxy)-3-methoxy-benzalde-
hyde: a suspension of o-vanillin (4.50 g, 29.6 mmol), (E-
2,E-4)-hexadienyl bromide (4.77 g, 29.6) and K2CO3
(5.52 g, 40.0 mmol) in DMF (30 mL) was vigorously
stirred at rt for 12 h. Toluene (150 mL) and water
(50 mL) were added and the pH was adjusted to 11–12
with 0.1 M aqueous NaOH. The organic phase was
separated, neutralized with satd NaHCO3 solution and
concentrated to leave a yellow oil. Purification (silica gel
60; cyclohexane/ethyl acetate, 10:1, v/v; Rf 0.50) gave
4.55 g (66 %) of a pale yellow solid, mp 42 °C.
14. (a) Petrusson, S.; Walley, S. G. Tetrahedron 1983, 39,
2465–2468; (b) Micetich, R.; Singh, R. Synthesis 1985,
693–695; (c) Smyth, T. P.; OÕDonnel, M. E.; OÕConnor, M.
J.; St Ledger, J. O. J. Org. Chem. 1998, 63, 7600–7618.
15. Hamilton, C. S.; Yasuhara, A.; Baldwin, J. E.; Lloyd, M.
D.; Rutledge, P. J. Bioorg. Med. Chem. Lett. 2001, 2511–
2514.
(1H, dd, 3J 4.4, 9.2 Hz), 5.95 (2H, s), 6.23 (1H, d, 3J
3
15.5 Hz), 6.25 (1H, d,3J 9.2 Hz), 6.76 (1H, d, J 7.7 Hz),
6.95 (1H, d, 3J 7.7 Hz), 6.98 (1H, s), 7.58 (1H, d, 3J
15.5 Hz); 13C NMR (75 MHz, CDCl3): d 26.9, 28.0, 32.1,
58.6, 64.7, 68.2, 70.9, 83.1, 101.5, 106.4, 108.5, 117.0,
124.3, 128.4, 142.8, 148.3, 149.5, 165.2, 166.7, 174.0; m/z
(EI) 446 (M+, 10%), 316 (30%), 175 (78%), 160 (100%).
19. Hakimelahi, G. H.; Shia, K.-S.; Xue, C.; Hakimelahi, S.;
Moosavi-Movahedi, A. A.; Saboury, A. A.; Soltani-Rad,
M. M.; Osyetrov, V.; Wang, K.-P.; Liao, J. H.; Luo, F.-T.
Bioorg. Med. Chem. 2002, 10, 3489–3498.
20. Compound 14: colourless solid of mp 152–154 °C; mmax
/
cmꢀ1 3330, 2955, 1728, 1650, 1615, 1499; 1H NMR
(270 MHz, CDCl3): d 1.32 (3H, s), 1.59 (3H, s), 2.45–2.55
(2H, m, COCH2), 2.80–2.90 (2H, m), 4.08 (1H, s, 3-H),
3
3
5.10 (1H, d, J 4.3 Hz, 5-H), 5.44 (1H, dd, J 4.3, 9.0 Hz,
3
3
6-H), 5.96 (2H, s), 6.45 (1H, d, J 9.0 Hz), 6.72 (1H, d, J
7.9 Hz), 6.90 (1H, d, 3J 7.9 Hz), 6.94 (1H, s), 8.10 (1H, br,
OH); 13C NMR (75 MHz, CDCl3): d 26.0, 26.4, 33.1, 37.8,
56.1, 56.5, 63.3, 73.2, 101.7, 106.2, 108.4, 124.0, 129.2,
148.2, 149.4, 166.8, 170.0, 170.5.
16. Veinberg, G.; Vorona, M.; Musel, D.; Grigan, N.;
Lukevics, E. J. Chem. Res. 1999, 270–271.
17. Compound 13: colourless solid of mp 149–150 °C; mmax
/
cmꢀ1 3336, 2959, 1734, 1664, 1616; H NMR (270 MHz,
CDCl3): d 1.35 (3H, s), 1.62 (3H, s), 4.10 (1H, s, 3-H), 5.08
(1H, d, 3J 4.3 Hz, 5-H), 5.42 (1H, dd, 3J 4.3, 8.8 Hz, 6-H),
5.95 (2H, s), 6.41 (1H, d, 3J 15.6 Hz), 6.50 (1H, d, 3J
1
21. Compound 15: colourless solid of mp 138 °C; mmax/cmꢀ1
3454, 2896, 1758, 1630, 1614, 1473, 1350; 1H NMR
(300 MHz, CDCl3): d 1.63 (6H, s, 2Me), 2.25 (2H, br,
NH2), 3.62 (24H, s, crown ether), 4.23 (1H, s, 3-H), 4.38
3
3
8.8 Hz), 6.72 (1H, d, J 8.1 Hz), 6.90 (1H, d, J 8.1 Hz),
3
3
3
6.96 (1H, s), 7.54 (1H, d, J 15.6 Hz), 8.12 (1H, br, OH);
(1H, d, J 6.1 Hz, 5-H), 5.59 (1H, d, J 6.1 Hz, 6-H); 13C
NMR (75 MHz, CDCl3): d 27.9, 33.2, 62.0, 64.3, 69.3,
70.2, 73.5, 172.2, 177.9.
13C NMR (68 MHz, CDCl3): d 26.3, 26.5, 55.8, 56.1, 63.6,
73.1, 101.5, 106.4, 108.5, 117.7, 124.2, 129.0, 142.2, 148.2,
149.3, 166.9, 170.4, 170.7.
22. Crude 12d was pre-purified by column chromatography
(silica gel 60; chloroform/ethyl acetate/methanol 3:1:1.5, v/
v/v, Rf 0.45) and dissolved in sat. aqueous NaHCO3. The
free acid 13 was precipitated by addition of diluted
aqueous HCl at 0 °C and extracted with ethyl acetate.
18. Compound 12a (1.59 g, 3.40 mmol, 77%) from 11a (1.32 g,
4.30 mmol), 1 (1.33 g, 4.40 mmol) and piperonal (0.68 g,
4.50 mmol); Rf 0.50 (cyclohexane/ethyl acetate, 1:1); pale
yellow solid of mp 91 °C; mmax/cmꢀ1 1782, 1746, 1675,