Total synthesis of pyridovericin

Article abstract of DOI:10.1016/j.tet.2004.07.035

The total synthesis of the naturally occurring kinase inhibitor pyridovericin 1 is reported. A flexible and efficient synthesis has been accomplished in good yield from readily available 2,4-dihydroxypyridine. Pyridovericin is a key intermediate in our pr

Full text of DOI:10.1016/j.tet.2004.07.035

Tetrahedron 60 (2004) 9307–9317
Total synthesis of pyridovericin
Nageswara Rao Irlapati,a Robert M. Adlington,a Aurelia Conte,a Gareth J. Pritchard,b
Rodolfo Marquezc and Jack E. Baldwina,
*
aDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
bDepartment of Chemistry, University of Loughborough, Loughborough, Leicester 2LE11 3TU, UK
cSchool of Life Sciences, University of Dundee, Dundee DD1 4HN, UK
Received 21 May 2004; revised 23 June 2004; accepted 15 July 2004
Abstract—The total synthesis of the naturally occurring kinase inhibitor pyridovericin 1 is reported. A flexible and efficient synthesis has
been accomplished in good yield from readily available 2,4-dihydroxypyridine. Pyridovericin is a key intermediate in our proposed
biomimetic synthesis of pyridomacrolidin 2.
q 2004 Elsevier Ltd. All rights reserved.
As part of our studies towards the synthesis of novel
tyrosine kinase inhibitors, we have become particularly
interested in the biomimetic synthesis of pyridovericin 1 and
pyridomacrolidin 2. Pyridovericin and pyridomacrolidin are
novel metabolites isolated from the entomopathogenic
fungus Beauveria bassiana in 1998 by Nakagawa and co-
workers.1 Structurally, pyridovericin 1 and pyridomacroli-
din 2 contain the same p-hydroxyphenyl pyridone unit
present in the related fungal metabolites tenellin 3,2
bassianin 4,3 and ilicicolin H 5.4 Biologically, pyridovericin
1 and pyridomacrolidin 2 have been shown to inhibit the
protein tyrosine kinase (PTK) activity at concentrations of
100 mg/ml1 making them potential therapeutic leads against
a variety of proliferative and inflammatory diseases (Fig. 1).5
newly formed pyridone unit 10 generates tenellin 3
(Scheme 1).6,8
Although it is believed that the biosynthesis of pyridovericin
1 presumably follows a similar pathway as that of tenellin 3,
the biosynthesis of pyridomacrolidin 2 has not yet been
elucidated. However, it is possible to propose a biomimetic
formation of pyridomacrolidin 2 from pyridovericin 1 via a
number of simple steps (Scheme 2); (i) oxidation of
pyridovericin 1 to hydroxamic acid 11, (ii) further oxidation
to the acyl nitrone intermediate 12, (iii) 1,3-dipolar
cycloaddition9 with cephalosporolide B 13, and (iv)
re-aromatisation to form pyridomacrolidin 2. Cephalosporo-
lide B 13 is itself a natural product, and has been
independently isolated from the fungus Cephalosporium
aphidicola,10 although it has not yet been isolated from
B. bassiana.
Interest in this type of compounds has largely focussed on
the determination of the biosynthetic pathway for the
generation of tenellin 3, bassianin 4, and ilicicolin H 5.6–8
Biosynthetically, it has been shown through a series of
feeding experiments that tenellin 3 originates from a
polyketide chain 6 and the aromatic amino-acid L-phenyl-
alanine 7. Mechanistically, it has been proposed that
L-phenylalanine 7 combines with the polyketide 6 unit to
generate the acyltetramic acid intermediate 8. Oxidation of
acid 8 then generates the transient p-quinonemethide
intermediate 9, which undergoes a ring expansion to
generate the 2-pyridone ring 10. Finally, oxidation of the
Chemically, this novel class of compounds has elucidated a
significant amount of interest as demonstrated by the
synthetic work already published.11–15 Herein, we would
like to describe full details of our progress towards the
biomimetic synthesis of pyridomacrolidin 2 by reporting a
convergent and efficient total synthesis of pyridovericin 1
from readily available starting materials.16
Retrosynthetically, we envisaged that the core structure of
pyridovericin 1 could be constructed via addition of
lithiated pyridine 15 to aldehyde 16, giving after oxidation
the pyridomacrolidin precursor 14. The organolithium
reagent 15 would in turn be generated via metal–halogen
exchange from the corresponding bromide 17, which itself
could be synthesised via selective palladium-catalysed
Keywords: Pyridovericin; Pyridomacrolidin; Suzuki coupling; Metal–
halogen exchange.
* Corresponding author. Tel.: C44-1865275671; fax: C44-1865275632;
e-mail: jack.baldwin@chem.ox.ac.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.07.035

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N. R. Irlapati et al. / Tetrahedron 60 (2004) 9307–9317
Figure 1. Pyridovericin 1, pyridomacrolidin 2, and related analogues.
Scheme 1. Proposed biosynthesis of tenellin 3.
Scheme 2. Proposed biosynthesis of pyridomacrolidin 2.
mono-coupling between boronic acid 18 and dibromide 19
(Scheme 3).
separable mixture of coupled adducts 22 and 23, in which
the major product was the desired biaryl 22 (Scheme 4). The
regio-selectivity observed in this reaction is consistent with
the major coupling being at the less hindered C5 position
(Fig. 2).19
Our convergent synthesis began with commercially avail-
able 2,4-dihydroxypyridine 20, which was dibrominated at
the C3 and C5 positions17 and then bis-O-methylated18 to
give pyridine 21 in good yield. At this stage we decided to
perform a model reaction for Suzuki coupling with
commercially available 4-methoxyphenylboronic acid.
Coupling of bromo pyridine 21 and 4-methoxyphenyl
boronic acid under Suzuki-type conditions afforded a
At this point, the feasibility of the metal–halogen exchange
procedure was tested. Thus, treatment of bromo pyridine 22
with t-butyl lithium generated the desired lithiated inter-
mediate 24 which was subsequently trapped with a variety
of electrophiles (Table 1).

N. R. Irlapati et al. / Tetrahedron 60 (2004) 9307–9317
9309
Scheme 3. Retrosynthetic scheme for pyridovericin 1.
Scheme 4. Reagents and conditions: (a) Br2(2 eq.), 47% aq. HBr, r.t., 1h; (b) excess Mel, Ag2CO3, DCM, r.t., 5 days; (c) 4-methoxyphenylboronic acid,
Pd(PPh3)4, K2CO3, toluene:ethanol (4:1), reflux, 12h. Synthesis of pyridovericin core synthon 22.
Figure 2. Observed 2D NOESY’s of 22 and 23.
Table 1. Model additions to lithio-pyridine derivative 24
Entry
1
Electrophile
HCO2Et
Products (addition/protonation ratio)
Overall yield (%)
Quantitative
26:25
32:68
27
2
3
D2O
96
93
28:25
95:5
29:25
4
90
90:10
30:25
5
6
92
90:10
31:25
Quantiative
40:60

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N. R. Irlapati et al. / Tetrahedron 60 (2004) 9307–9317
Not surprisingly, suitable electrophiles were aldehydes
either lacking or with hindered a-hydrogens (entries 3, 4
and 5). We were particularly encouraged by the addition of
crotonaldehyde (entry 5), which resembles aldehyde 16 as
the proposed electrophile in our retrosynthetic analysis of
pyridovericin 1 (Scheme 3).
Our synthesis of the C7–C15 side-chain aldehyde began with
dimethyl-2-ethylmalonate 37, which was reduced to the
corresponding diol23 and then monoprotected24 to afford the
desired TBS-silyl ether 38 in good yield. Swern oxidation25
then Wittig olefination gave ester 39, which after reduction
followed by another Swern oxidation/Wittig olefination
sequence gave diene 40 in excellent overall yield. Finally,
reduction of the ester to the corresponding alcohol followed
by oxidation gave the desired TBS-protected aldehyde
intermediate 41, suitable for coupling to the pyridine unit
(Scheme 6).
After having succeeded in the regio-selective Suzuki
coupling and in the introduction of various electrophiles
to lithiated pyridine 24, we focussed our attention towards
the synthesis of tetrasubstituted pyridine core of pyridover-
icin 1. Synthesis of the required boronic acid coupling
partner began with 4-bromophenol 32, which was readily
protected under standard conditions20 to generate the
corresponding benzyl ether in good yield. Metal–halogen
exchange followed by treatment with boron triisoprop-
oxide21 proceeded cleanly to afford, after hydrolysis, the
desired boronic acid 33.
With the benzyl protected pyridine unit 34 and dienal 41
readily available, we focused our attention on the last steps
of the synthesis. Thus, metal–halogen exchange of bromo-
pyridine 34 followed by treatment with aldehyde 41 gave
the desired alcohol 42, together with the dehalogenated
product 43 (2.6:1) (Scheme 7). The formation of compound
43 is easily explained as the product of the deprotonation of
the aldehyde’s 3-position or from t-butyl bromide by-
product by the lithiated pyridine. Subsequent oxidation of
alcohol 42 afforded the fully protected pyridovericin 44 in
high yield and with no observable side products.
Synthesis of the tetrasubstituted pyridine coupling partner
was achieved by the reaction of pyridine 21 and boronic
acid 33 under slightly modified Suzuki-type conditions22
which generated a separable mixture of mono- and bis-
coupled adducts 34-36 (Scheme 5), in which the major
product was confirmed once again by nOe analysis as the
desired biaryl 34 (Fig. 3).19
The deprotection of compound 44 at this point proved to be
challenging, as most of the methods attempted for removal
of the protecting groups either resulted in no reaction or
caused complete decomposition of the starting material. It
was only after considerable experimentation that it was
found that in situ generated trimethylsilyl iodide26 success-
fully removed both methyl ethers and TBDMS to afford diol
45, however the benzyl group was left intact (Scheme 8).
Finally, removal of the adamant benzyl protecting group
was carefully effected using boron tribromide,27 to generate
Figure 3. Observed 2D NOESY’s of 34 and 35.
Scheme 5. Reagents and conditions: (a) BnBr, TBAl, NaH, THF, r.t., 4h; (b) (i) n-BuLi, B(O0Pr)3, THF, K78 8C then r.t., overnight; (ii) sat. NH4Cl; (c)
Pd(PPh3)4, Na2CO3, 4:1 toluene:ethanol, reflux, overnight. Modified synthesis of pyridovericin core 34.
Scheme 6. Reagents and conditions: (a) LAH, THF, r.t., overnight; (b) TBDMSCl, NaH, THF, r.t., overnight; (c) Swern, K78 8C; (d) PPh3C(CH3)CO2Et,
Benzene, reflux, 20h; (e) Dibal-H, THF; (f) Swern, K78 8C; (g) PPh3CHCO2Et, Tol., reflux, 20h; (h) Dibal-H, THF; (i) Swern, K78 8C. Synthesis of TBS-
protected aldehyde 41.

N. R. Irlapati et al. / Tetrahedron 60 (2004) 9307–9317
9311
Scheme 7. Reagents and conditions: (a) t-BuLi, 41, THF, K78 8C, 1h then r.t., 1h; (b) MnO2, DCM, r.t., 48h. Synthesis of protected pyridovericin 44.
Scheme 8. Reagents and conditions: (a) TMSCl, Nal, MeCN, r.t., 3 days; (b) BBr3, DCM, K78 8C, 1h. Completion of the synthesis of pyridovericin 1.
racemic pyridovericin 1 in thirteen steps for the longest
linear sequence. The spectral data (1H, 13C, HRMS, TLC)
for synthetic 1 exactly matched that reported for natural
pyridovericin 1.1 Furthermore, doping experiments of
synthetic and natural pyridovericin samples generated a
single set of NMR signals.
Low resolution mass spectra were recorded on V. G.
Micromass ZAB 1F and V. G. Masslab instruments as
appropriate with modes of ionisation being indicated as CI,
EI, ES or APCI with only molecular ions, molecular ion
fragments and major peaks being reported. High-resolution
mass spectrometry was measured on a Waters 2790-
Micromass LCT electrospray ionisation mass spectrometer
and on a VG autospec chemical ionisation mass spec-
trometer. Thin layer chromatography (TLC) was performed
using Merck aluminium foil backed sheets precoated with
Kieselgel 60F254. Column chromatography was carried out
on Sorbsile C60 (40–63 mm, 230–400 mesh) silica gel.
In conclusion, we have completed the total synthesis of
pyridovericin 1 starting from cheap and readily available
starting materials. Our synthesis is convergent, fast, efficient
and flexible enough to allow for the ready synthesis of a
variety of analogues if desired.
Elemental analyses were performed by David Lawrence at
Elemental Microanalysis Limited, Okehampton, Devon.
1. Experimental
1.1. General
All solvents and reagents were purified by standard
techniques reported in Perrin, D. D.; Amarego, W. L. F.
Purification of Laboratory Chemicals, 3rd ed.; Pergamon:
Oxford, 1988 or used as supplied from commercial sources
as appropriate. Solvents were removed under reduced
pressure using a Buchi R110 or R114 Rotavapor fitted
with a water or dry ice condenser as necessary. Final traces
of solvent were removed from samples using an Edwards
E2M5 high vacuum pump with pressures below 1 mm Hg.
Melting points were recorded using a Cambridge Instru-
ments Gallene III Kofler Block melting apparatus or a
Buchi 510 capillary apparatus and are uncorrected. NMR
spectra were recorded on a Bruker AMX-500, Bruker DQX-
400, Bruker DPX-400, Varian Gemini DPX-200 spec-
trometers. The following abbreviations are used: s, singlet;
d, doublet; t, triplet; m, multiplet; br, broad. Proton
1
assignments are supported by H–1H COSY where necess-
All experiments were carried out under inert atmosphere
unless otherwise stated.
ary. Data are reported in the following manner: chemical
shift (multiplicity, coupling constant, integration if appro-
priate). Chemical shifts (d) are reported in parts per million
(ppm) and coupling constants (J) are given in hertz to the
nearest 0.5 Hz.
1.1.1. 3,5-Dibromo-2,4-dimethoxy pyridine, 21. To a 0 8C
cooled and stirred solution of 2,4-dihydroxy pyridine 20
(4.0 g, 36.0 mmol) in 47% aqueous hydrobromic acid
(40 mL) was added bromine (4.1 mL, 79.3 mmol) and the
resulting mixture stirred at room temperature for 1 h. The
reaction mixture was diluted with water (100 mL), and
stirred for further 30 min at room temperature. The solid
product was then filtered, washed with water (75 mL), and
dried under vacuum. The crude residue was recrystallised
from 95% ethanol to afford 7.0 g (72%) of the known17 3,5-
dibromo-2,4-dihydroxy pyridine as a white solid, mp 245 8C
(dec.) (lit.17 225–240 8C dec.). nmax (KBr)/cmK1 3101,
2951, 1648, 1618, 1455, 1443, 1429, 1170; dH (200 MHz,
DMSO) 7.63 (s, 1H); dC (50 MHz, DMSO) 161.2, 160.1,
135.8, 98.1, 93.2; m/z (CIC) 272 (35%), 270 (MHC 79Br
81Br, 65%), 268 (30%), 112 (100%).
13C NMR spectra were recorded at 50.3, 100.6 and
125.8 MHz using Varian Gemini 200, Bruker DQX400,
Bruker DPX400 and Bruker AMX500 instruments. Carbon
spectra assignments are supported by DEPT-135 spectra,
13C–1H (HMQC and HMBC) correlations where necessary.
Chemical shifts are quoted in ppm and are referenced to the
appropriate residual solvent peak.
IR-spectra were recorded as a KBr disc or Neat (as
indicated) on a Perkin–Elmer Paragon 1000 Fourier Trans-
form spectrometer with internal referencing. Strong (s) and
medium (m) absorption bands are reported in wavenumbers
(cmK1).

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N. R. Irlapati et al. / Tetrahedron 60 (2004) 9307–9317
A heterogenous mixture of the above described 3,5-
dibromo-2,4-dihydroxy pyridine (6.60 g, 24.5 mmol),
methyl iodide (15 mL, 245.0 mmol) and silver carbonate
(13.54 g, 49.0 mmol) in dichloromethane (500 mL) was
stirred at 20 8C for 5 days. The reaction mixture was filtered
through celite, and the filtrate evaporated under vacuum.
The crude product was purified by flash column chroma-
tography (silica gel, 2% ethyl acetate in 30–40 petroleum
ether) to afford 4.65 g (64%) desired titled product 21 as a
white solid, mp 115–116 8C. nmax (KBr)/cmK1 2971, 2939,
1563, 1537, 1463, 1411, 1374, 1296, 1091, 1068; dH
(200 MHz, CDCl3) 8.17 (s, 1H), 3.99 (s, 3H), 3.96 (s, 3H);
dC (50 MHz, CDCl3) 162.4, 161.4, 147.2, 107.8, 102.4,
60.8, 55.1; m/z (CIC) 300 (20%), 298 (MHC 79Br 81Br,
60%), 296 (30%), 121 (100%).
pentanes (294 mL, 0.5 mmol). The reaction was then stirred
at K78 8C for 10 min before being treated with the freshly
distilled electrophile (0.27 mmol), and the resulting mixture
stirred at K78 8C for 1 h, then at room temperature for an
additional 1 h. The reaction was then quenched with
saturated ammonium chloride solution (5 mL) and the
mixture extracted with ethyl acetate (2!15 mL) after the
addition of water (5 mL). The combined organic extracts
were dried (MgSO4), filtered, and concentrated under
reduced pressure to afford a crude residue, which was
purified by flash column chromatography.
1.2.1. 2,4-Dimethoxy-5-(4-methoxyphenyl)pyridine, 25
(by-product). nmax (neat)/cmK1 2974, 2946, 1602, 1564,
1488, 1455, 1430, 1372, 1248, 1053, 832; dH (400 MHz,
CDCl3) 7.95 (s, 1H), 7.38 (d, JZ8.5 Hz, 2H), 6.95 (d, JZ
8.5 Hz, 2H), 6.27 (s, 1H), 3.95 (s, 3H), 3.83 (s, 3H), 3.82 (s,
3H); dC (100.6 MHz, CDCl3) 165.0, 164.8, 158.8, 146.7,
130.5, 127.3, 121.3, 113.7, 92.2, 55.4, 55.3, 53.5; m/z
(APCIC) 246 (MHC, 100%); HRMS (CIC) found
246.1125 (MHC) C14H16NO3 requires 246.1130.
1.1.2. 3-Bromo-2,4-dimethoxy-5-(p-methoxyphenyl)pyr-
idine, 22; 5-bromo-2,4-dimethoxy-3-(p-methoxyphenyl)-
pyridine, 23.19 To a solution of 3,5-dibromopyridine 21
(2.87 g, 9.7 mmol) in a 4:1 mixture of toluene/ethanol
(25 mL) was added a 2 M sodium carbonate solution
(20 mL), followed by 4-methoxyphenylboronic acid
(1.47 g, 9.7 mmol), and tetrakis(triphenylphosphine)palla-
dium(0) (558 mg, 0.5 mmol). The reaction mixture was then
refluxed for 12 h, before being cooled back down to room
temperature and partitioned in a 1:1 mixture of ethyl
acetate/water (100 mL). The phases were separated, and the
organic layer dried (MgSO4). The solvent was removed
under reduced pressure, and the crude residue purified by
flash column chromatography (9:1, hexane/ethyl acetate) to
afford 1.88 g (60%) of 3-bromo-2,4-dimethoxy-5-(p-meth-
oxyphenyl)pyridine 22, mp 114–115 8C and 626 mg (20%)
of 5-bromo-2,4-dimethoxy-3-(p-methoxyphenyl)pyridine
23, mp 119–120 8C as white solids (Fig. 2).
1.2.2. 2,4-Dimethoxy-5-(4-methoxyphenyl)pyridine-3-
carbaldehyde, 26. The lithiopyridine 24, was quenched
with freshly distilled ethyl formate to afford aldehyde 26 in
32% as a colourless oil. nmax (neat)/cmK1 2952, 2927, 2841,
1692, 1580, 1556, 1470, 1396, 1248, 1090; dH (500 MHz,
CDCl3) 10.48 (s, 1H), 8.24 (s, 1H), 7.41 (d, JZ9.0 Hz, 2H),
7.00 (d, JZ9.0 Hz, 2H), 4.08 (s, 3H), 3.87 (s, 3H), 3.61 (s,
3H); dC (125.8 MHz, CDCl3) 188.8, 167.8, 164.2, 159.4,
153.1, 130.1, 126.3, 124.9, 114.2, 111.7, 61.9, 55.2, 54.4; m/
z (APCIC) 274 (MHC, 100%), 246 (10%); HRMS (EIC)
found 274.1071 (MHC) C15H16NO4 requires 274.1079.
1.2.3. 3-Deuterio-2,4-dimethoxy-5-(4-methoxyphenyl)-
pyridine, 27. The lithiopyridine 24, was quenched with
D2O to give pyridine 27 in 96% as a colourless oil. nmax
(neat)/cmK1 2974, 2948, 2835, 1596, 1558, 1472, 1419,
1370, 1247, 1221, 1198, 1179, 1095, 1030, 832; dH
(400 MHz, CDCl3) 7.98 (s, 1H), 7.41 (d, JZ8.5 Hz, 2H),
6.97 (d, JZ8.5 Hz, 2H), 3.97 (s, 3H), 3.85 (s, 3H), 3.84 (s,
3H); dC (100.6 MHz, CDCl3) 165.0, 164.8, 158.8, 146.7,
130.4, 127.3, 121.2, 113.7, 92.1, 55.4, 55.3, 53.5; m/z
(APCIC) 247 (MHC, 100%); HRMS (CIC) found
247.1188 (MHC) C14H15DNO3 requires 247.1193.
Spectral data for 22.19 nmax (KBr)/cmK1 2972, 2935, 2938,
1562, 1514, 1463, 1394, 1117, 1089, 1006; dH (400 MHz,
CDCl3) 8.01 (s, 1H), 7.44 (d, JZ8.5 Hz, 2H), 6.98 (d, JZ
8.5 Hz, 2H), 4.05 (s, 3H), 3.86 (s, 3H), 3.54 (s, 3H); dC
(100.6 MHz, CDCl3) 163.1, 160.7, 159.3, 146.1, 130.0,
126.7, 125.8, 114.1, 101.3, 60.3, 55.3, 54.7; m/z (APCIC)
326 (MHC 81Br, 100%), 324 (80%); HRMS found 324.0242
(MHC 79Br). C14H15BrNO3 requires 324.0235. Anal. calcd
for C14H14BrNO3: C, 51.87; H, 4.35; N, 4.32. Found: C,
51.48; H, 4.38; N, 4.22.
Spectral data for 23.19 nmax (neat)/cmK1 2971, 2943, 2939,
1607, 1560, 1510, 1455, 1385, 1379, 1242, 1176, 1089,
1006; dH (400 MHz, CDCl3) 8.20 (s, 1H), 7.35 (d, JZ
8.5 Hz, 2H), 6.98 (d, JZ8.5 Hz, 2H), 3.88 (s, 3H), 3.87 (s,
3H), 3.47 (s, 3H); dC (100.6 MHz, CDCl3) 162.2, 162.1,
159.2, 147.1, 131.5, 123.8, 118.3, 113.6, 108.1, 60.5, 55.2,
54.2; m/z (APCIC) 326 (MHC 81Br, 100%), 324 (96%);
HRMS found 324.0224 (MHC 79Br). C14H15BrNO3
requires 324.0235. Anal. calcd for C14H14BrNO3: C,
51.87; H, 4.35; N, 4.32. Found: C, 51.86; H, 4.46; N, 4.07.
1.2.4. 1-[2,4-Dimethoxy-5-(4-methoxyphenyl)pyridin-3-
yl]-2-methylpropan-1-ol, 28. Pyridine 24, was quenched
with freshly distilled iso-butyraldehyde to afford alcohol 28
in 88% as a colourless oil. nmax (neat)/cmK1 3357, 2957,
2868, 2836, 1610, 1588, 1559, 1516, 1468, 1413, 1297,
1247, 1107; dH (400 MHz, CDCl3) 7.97 (s, 1H), 7.41 (d, JZ
9.0 Hz, 2H), 6.97 (d, JZ9.0 Hz, 2H), 4.66 (dd, JZ11.5,
9.0 Hz, 1H), 4.01 (s, 3H), 3.86 (s, 3H), 3.40 (s, 3H), 3.39 (d,
JZ11.5 Hz, 1H), 2.11 (m, 1H), 1.15 (d, JZ7.0 Hz, 3H),
0.80 (d, JZ7.0 Hz, 3H); dC (100.6 MHz, CDCl3) 163.5,
161.6, 159.1, 146.8, 129.9, 127.8, 124.5, 117.5, 114.0, 73.3,
60.6, 55.3, 53.6, 34.3, 19.5; m/z (APCIC) 318 (MHC,
100%), 300 (25%).
1.2. General procedure for the synthesis of 3-substituted-
2,4-dimethoxy-5-(4-methoxyphenyl)pyridine
A K78 8C solution of 3-bromo-2,4-dimethoxy-5-(4-meth-
oxyphenyl)pyridine 22 (80 mg, 0.25 mmol) in dry THF
(2 mL) was slowly treated with 1.7 M t-BuLi soln. in
1.2.5. 1-[2,4-Dimethoxy-5-(4-methoxyphenyl)pyridin-3-
yl]heptan-1-ol, 29. The lithiopyridine 24, was quenched
with freshly distilled heptanal to produce pyridine 29 in

N. R. Irlapati et al. / Tetrahedron 60 (2004) 9307–9317
9313
81% as a colourless oil. nmax (neat)/cmK1 3560, 2956, 2928,
2856, 1610, 1589, 1560, 1515, 1468, 1415, 1377, 1107,
1012, 833; dH (500 MHz, CDCl3) 7.98 (s, 1H), 7.42 (d, JZ
8.5 Hz, 2H), 6.98 (d, JZ8.5 Hz, 2H), 5.05 (m, 1H), 4.02 (s,
3H), 3.87 (s, 3H), 3.42 (s, 3H), 3.41 (d, JZ11.5 Hz, 1H),
1.92 (m, 1H), 1.73 (m, 1H), 1.54 (m, 1H), 1.32 (m, 7H), 0.89
(t, JZ6.5 Hz, 3H); dC (125.8 MHz, CDCl3) 162.9, 161.5,
159.1, 146.5, 129.9, 127.7, 124.6, 118.5, 114.0, 67.6, 60.6,
55.3, 53.6, 37.7, 31.7, 29.0, 26.2, 22.5, 14.1; m/z (APCIC)
360 (MHC, 100%), 342 (35%); HRMS (CIC) found
360.2178 (MHC) C21H30NO4 requires 360.2175.
(18 mL), and the resulting mixture refluxed for 12 h. The
reaction mixture was cooled to room temperature, and
diluted with ethyl acetate (100 mL). The organic layer was
washed with water (2!50 mL), brine (50 mL) and dried
(MgSO4). The solvent was evaporated under vacuum and
the crude product purified by flash column chromatography
(silica gel, 4% ethyl acetate in 30–40 petroleum ether), to
afford the desired titled products as white solids, 34, 1.40 g
(45%), mp 115–116 8C. 35, 450 mg (15%), mp 97–99 8C.
36, 32 mg (1%).
Spectral data for 34.19 nmax (neat)/cmK1 2971, 2947, 2939,
1561, 1584, 1514, 1470, 1410, 1379, 1243, 1087, 1006; dH
(200 MHz, CDCl3) 8.01 (s, 1H), 7.42 (m, 7H), 7.05 (d, JZ
7.0 Hz, 2H), 5.12 (s, 2H), 4.05 (s, 3H), 3.55 (s, 3H); dC
(100 MHz, CDCl3) 163.1, 160.8, 158.5, 146.1, 136.8, 130.1,
128.4, 128.1, 127.5, 127.0, 125.8, 114.9, 101.3, 70.0, 60.3,
54.7; m/z (CIC) 402 (MHC 81Br, 100%), 400 (90%);
HRMS (ESC) found 400.0540 (MHC79Br) C20H19BrNO3
requires 400.0548.
1.2.6. (2E)-1-[2,4-Dimethoxy-5-(4-methoxyphenyl)pyri-
din-3-yl]but-2-en-1-ol, 30. The pyridine 24, was quenched
with freshly distilled crotonaldehyde to produce allylic
alcohol 30 in 83% as a colourless oil. nmax (neat)/cmK1
3548, 2944, 2918, 2841, 1585, 1463, 1416, 1246, 1034,
1071; dH (400 MHz, CDCl3) 7.99 (s, 1H), 7.42 (d, JZ
8.5 Hz, 2H), 6.97 (d, JZ8.5 Hz, 2H), 5.87 (m, 1H), 5.71 (m,
1H), 5.54 (m, 1H), 4.02 (s, 3H), 3.86 (s, 3H), 3.72 (d, JZ
11.0 Hz, 1H), 3.41 (s, 3H), 1.71 (d, JZ6.5 Hz, 3H); dC
(100.6 MHz, CDCl3) 162.9, 161.4, 159.1, 146.9, 132.4,
129.9, 127.5, 126.8, 124.8, 117.5, 114.1, 67.9, 60.7, 55.3,
53.8, 17.7; m/z (APCIC) 316 (MHC, 100%); HRMS (ESC)
found 316.1563 (MHC) C18H22NO4 requires 316.1549.
Spectral data for 35.19 nmax (neat)/cmK1 2971, 2943, 2939,
1607, 1560, 1510, 1455, 1385, 1379, 1242, 1176, 1089,
1006; dH (200 MHz, CDCl3) 8.20 (s, 1H), 7.45 (m, 5H), 7.33
(d, JZ7.0 Hz, 2H), 7.05 (d, JZ7.0 Hz, 2H), 5.11 (s, 2H),
3.87 (s, 3H), 3.47 (s, 3H); dC (100 MHz, CDCl3) 162.7,
158.9, 147.6 (2C), 137.3, 132.0, 129.1, 128.5, 128.1, 124.6,
118.8, 114.9, 108.6, 70.5, 61.0, 54.7; m/z (CIC) 402 (MHC
81Br, 100%), 400 (90%); HRMS (ESC) found 400.0554
(MHC79Br) C20H19BrNO3 requires 400.0548.
1.2.7. 1-[2,4-Dimethoxy-5-(4-methoxyphenyl)pyridin-3-
yl]ethanol, 31. The lithiopyridine 24, was quenched with
freshly distilled acetaldehyde to yield alcohol 31 in 40% as a
colourless oil. nmax (neat)/cmK1 3436, 2957, 2950, 2836,
1610, 1590, 1561, 1470, 1297, 1178, 1055, 1032; dH
(400 MHz, CDCl3) 7.98 (s, 1H), 7.42 (d, JZ8.5 Hz, 2H),
6.98 (d, JZ8.5 Hz, 2H), 5.26 (dq, JZ11.5, 6.5 Hz, 1H),
4.03 (s, 3H), 3.86 (s, 3H), 3.63 (d, JZ11.5 Hz, 1H), 3.43 (s,
3H), 1.56 (d, JZ6.5 Hz, 3H); dC (100.6 MHz, CDCl3)
162.7, 161.5, 159.1, 146.6, 129.9, 127.6, 124.8, 119.2,
114.1, 63.6, 60.8, 55.3, 53.7, 23.8; m/z (APCIC) 290
(MHC, 100%), 272 (40%); HRMS (ESC) found 290.1394
(MHC) C16H20NO4 requires 290.1392.
Spectral data for 36. dH (200 MHz, CDCl3) 8.08 (s, 1H),
7.42 (m, 14H), 7.06 (d, JZ7.0 Hz, 4H), 5.11 (s, 4H), 3.92 (s,
3H), 3.23 (s, 3H); m/z (CIC) 504 (MHC, 100%).
1.2.10. 2-(tert-Butyldimethylsilanyloxymethyl)-1-buta-
nol, 38. To a 0 8C suspension of 60% sodium hydride
(1.88 g, 47.1 mmol) in THF (100 mL), was added dropwise
a solution of 2-ethylpropan-1,3-diol23 (4.90 g, 47.1 mmol)
in THF (30 mL) and the reaction mixture stirred at room
temperature for 1 h, during which time a large amount of an
opaque white precipitate formed. The reaction mixture was
cooled to 0 8C and a solution of tert-butyldimethylsilyl
chloride (7.11 g, 47.1 mmol) in THF (30 mL) was added
slowly. The reaction was warmed up and stirred at room
temperature overnight, and was then quenched with water
(100 mL) and extracted with ethyl acetate (3!100 mL).
The combined organic extracts were washed with water
(2!100 mL), brine (100 mL), dried (MgSO4) and evapor-
ated under reduced pressure. The crude product was purified
by flash column chromatography (silica gel, 5% ethyl
acetate in 30–40 petroleum ether) to afford 8.1 g, (79%) of
known24 desired titled product 38 as a clear oil. nmax (neat)/
cmK1 3368, 2957, 1472, 1255, 1091, 836; dH (200 MHz,
CDCl3) 3.80 (m, 4H), 2.92 (dd, JZ7.0, 5.0 Hz, 1H), 1.63
(m, 1H), 1.25 (m, 1H), 0.91 (t, JZ7.0 Hz, 3H), 0.90 (s, 9H),
0.06 (s, 6H); dC (50 MHz, CDCl3) 67.2, 66.4, 43.6, 25.7,
20.6, 18.1, 11.7, K5.57, K5.63; m/z (CIC) 219 (MHC,
100%).
1.2.8. p-Benzyloxyphenylboronic acid, 33. 4-Benzyloxy-
bromobenzene was prepared by following the literature
procedure20 as a white solid, mp 55–56 8C (lit.20 60–61 8C);
dH (200 MHz, CDCl3) 7.40, (m, 7H), 6.90 (d, JZ8.0 Hz,
2H), 5.05 (s, 2H); m/z (CI) 183 (10%), 121 (100%).
p-Benzyloxyphenylboronic acid, 33 was prepared from
4-benzyloxybromobenzene by following the literature
procedure21 as a white solid, mp 187–192 8C (lit.21 189–
194 8C); dH (250 MHz, CDCl3) 8.20 (d, JZ7.0 Hz, 2H),
7.40 (m, 5H), 7.12 (d, JZ7.0 Hz, 2H), 5.18 (s, 2H); dC
(50 MHz, CDCl3) 162.4, 137.6, 136.7, 128.7, 128.1, 127.6,
114.4, 69.9; m/z (CIC) 121 (100%).
1.2.9. 3-Bromo-2,4-dimethoxy-5-(p-benzyloxyphenyl)-
pyridine, 34; 5-bromo-2,4-dimethoxy-3-(p-benzyloxy-
phenyl)pyridine, 35; 3,5-di (p-benzyloxyphenyl)-2,4-
dimethoxypyridine, 36. A solution of 3,5-dibromo-2,4-
dimethoxy pyridine, 21 (2.30 g, 7.74 mmol) and p-benzyl-
oxyphenylboronic acid, 33 (1.75 g, 7.68 mmol) in a 4:1
mixture of a toluene/ethanol (22.5 mL) was sequentially
treated with tetrakis(triphenylphosphine)palladium(0)
(447 mg, 0.39 mmol), 2 M sodium carbonate solution
1.2.11. Ethyl-(2E)-4-(tert-butyldimethylsilanyloxy-
methyl)-2-methyl-2-hexenoate, 39. To a K78 8C solution
of oxalyl chloride (6.62 mL, 75.6 mmol) in

9314
N. R. Irlapati et al. / Tetrahedron 60 (2004) 9307–9317
dichloromethane (500 mL) was added dropwise a 1:1 (v/v)
solution of DMSO (10.72 mL, 151.2 mmol) in dichloro-
methane. After stirring at K78 8C for 10 min, a solution of
2-(tert-butyldimethylsilanyloxymethyl)-1-butanol, 38
(10.30 g, 47.2 mmol) in dichloromethane (45 mL) was
added dropwise and the resulting mixture stirred for
30 min at K78 8C. Triethylamine (42 mL, 302 mmol) was
then added slowly, and the reaction raised to room
temperature. After stirring for 1 h at room temperature,
water (200 mL) was added to the reaction mixture, and the
layers separated. The aqueous layer was extracted with
dichloromethane (3!150 mL) and the combined organic
phases washed with 1 M hydrochloric acid (2!150 mL),
5% aq. sodium bicarbonate (2!150 mL), brine (150 mL),
and dried (MgSO4). The solvent was then evaporated under
vacuum, to afford 10.20 g (100%) of the known25 2-(tert-
butyldimethylsilanyloxymethyl) butyraldehyde, as a clear
oil, which was used for next step without further
purification; dH (250 MHz, CDCl3) 9.69 (d, JZ2.5 Hz,
1H), 3.89 (d, JZ6.0 Hz, 2H), 2.32 (m, 1H), 1.72 (m, 1H),
1.52 (m, 1H), 0.97 (t, JZ7.0 Hz, 3H), 0.87 (s, 9H), 0.05 (s,
6H); dC (50 MHz, CDCl3) 204.8, 61.6, 55.8, 25.8, 18.5,
18.2, 11.4, K5.6.
4.05 (m, 2H), 3.48 (m, 2H), 2.37 (m, 1H), 1.72 (brs, 3H),
1.62 (m, 1H), 1.31 (t, JZ6.0 Hz, D2O exchangeable, 1H),
1.12 (m, 1H), 0.91 (s, 9H), 0.87 (t, JZ7.5 Hz, 3H), 0.05 (s,
6H); dC (50 MHz, CDCl3) 136.3, 127.8, 69.1, 66.5, 42.3,
25.9, 24.5, 18.4, 14.3, 11.7, K5.3.
To a K78 8C solution of oxalyl chloride (3.53 mL,
40.3 mmol) in dichloromethane (275 mL) was dropwise
added a 1:1 (v/v) solution of DMSO (5.71 mL, 80.6 mmol)
in dichloromethane (5.71 mL). After stirring for 10 min, a
solution of 4-(tert-butyldimethylsilanyloxymethyl)-2-
methyl-2-hexene-1-ol (6.50 g, 25.2 mmol) in dichloro-
methane (25 mL) was added dropwise and the resulting
mixture stirred for 30 min at K78 8C. Triethylamine
(22.4 mL, 161.2 mmol) was then added dropwise and the
reaction raised to room temperature. After stirring for 1 h at
room temperature, water (150 mL) was added to the
reaction mixture, and the layers separated. The aqueous
layer was extracted with dichloromethane (3!100 mL) and
the combined organic phases washed with 1 M hydrochloric
acid (2!100 mL), 5% aq. sodium bicarbonate (2!
100 mL), brine (100 mL), and dried (MgSO4). The solvent
was evaporated under vacuum, to afford 6.45 g (100%) of
(2E)-4-(tert-butyldimethylsilanyloxymethyl)-2-methylhex-
2-enal as a clear oil, which was used for next step without
further purification. nmax (neat)/cmK1 2959, 2930, 2858,
1693, 1644, 1472, 1255, 1102, 837; dH (250 MHz, CDCl3)
9.45 (s, 1H), 6.33 (dq, JZ10.0, 1.5 Hz, 1H), 3.63 (m, 2H),
2.73 (m, 1H), 1.81 (brs, 3H), 1.72 (m, 1H), 1.35 (m, 1H),
0.91 (s, 9H), 0.89 (t, JZ7.5 Hz, 3H), 0.03 (s, 6H); HRMS
(CIC) found 257.1933 (MHC) C14H29O2Si requires
257.1937.
A mixture of 2-(tert-butyldimethylsilanyloxymethyl)butyr-
aldehyde (10.20 g, 47.2 mmol) and (carbethoxyethylidene)-
triphenylphosphorane (34.2 g, 94.4 mmol) in benzene
(250 mL) was refluxed for 20 h. After cooling to room
temperature, the solvent was evaporated under vacuum and
the residue was purified by flash column chromatography
(silica gel, 3% ethyl acetate in 30–40 petroleum ether) to
afford 12.75 g, (90%) of the desired titled product 39 as a
clear oil. nmax (neat)/cmK1 2959, 1713, 1252, 1230, 1096,
837; dH (250 MHz, CDCl3) 6.57 (dq, JZ10.5, 1.5 Hz, 1H),
4.22 (q, JZ7.0 Hz, 2H), 3.55 (m, 2H), 2.56 (m, 1H), 1.88 (d,
JZ1.5 Hz, 3H), 1.62 (m, 1H), 1.35 (t, JZ7.0 Hz, 3H), 1.32
(m, 1H), 0.90 (s, 9H), 0.88 (t, JZ5.5 Hz, 3H), 0.06 (s, 3H),
0.05 (s, 3H); dC (50 MHz, CDCl3) 168.2, 143.8, 128.9, 65.6,
60.3, 43.5, 25.8, 24.0, 18.3, 14.3, 12.9, 11.7, K5.4, K5.5;
HRMS (CIC) found 301.2190 (MHC) C16H33O3Si requires
301.2199.
A mixture of (2E)-4-(tert-butyldimethylsilanyloxymethyl)-
2-methylhex-2-enal (6.45 g, 25.1 mmol) and (ethoxycarbo-
nylmethylidene)triphenylphosphorane
(17.53 g,
50.2 mmol) in toluene (150 mL) was refluxed for 20 h.
After cooling to room temperature, the solvent was
evaporated under reduced pressure, and the residue purified
by flash column chromatography (silica gel, 5% ethyl
acetate in 30–40 petroleum ether) to afford 7.80 g (95%) of
the desired titled product, 40 as a clear oil. nmax (neat)/cmK1
2959, 1716, 1625, 1471, 1366, 1298, 1258, 1173, 1100,
1034, 836; dH (250 MHz, CDCl3) 7.35 (d, JZ15.5 Hz, 1H),
5.82 (d, JZ15.5 Hz, 1H), 5.70 (dq, JZ10.0 Hz, 1.5 Hz,
1H), 4.24 (q, JZ7.0 Hz, 2H), 3.52 (m, 2H), 2.57 (m, 1H),
1.85 (brd, 3H), 1.62 (m, 1H), 1.33 (t, JZ7.0 Hz, 3H), 1.23
(m, 1H), 0.91 (s, 9H), 0.89 (t, JZ7.5 Hz, 3H), 0.05 (s, 3H),
0.04 (s, 3H); dC (50 MHz, CDCl3) 167.6, 149.7, 144.0,
134.0, 115.8, 66.0, 60.2, 43.5, 25.9, 24.4, 18.3, 14.4, 12.8,
11.8, K5.4; HRMS (CIC) found 327.2363 (MHC)
C18H35O3Si requires 327.2355.
1.2.12. (2E,4E)-6-(tert-Butyldimethylsilanyloxymethyl)-
4-methylocta-2,4-dienoicacid ethyl ester, 40. A K78 8C
solution of ethyl-(2E)-4-(tert-butyldimethylsilanyloxy-
methyl)-2-methyl-2-hexenoate, 39 (9.50 g, 31.7 mmol) in
THF (150 mL) was treated dropwise with a 1 M solution of
DiBAL-H in hexanes (66.5 mL, 66.5 mmol) and reaction
mixture stirred at K78 8C for 2 h. The reaction was then
sequentially warmed up to room temperature and then
cooled to 0 8C before being quenched with saturated sodium
potassium tartrate solution (200 mL) and the resulting
mixture stirred for 2 h. Ethyl acetate (150 mL) was then
added to the above reaction mixture and the layers
separated. The aqueous layer was extracted with ethyl
acetate (3!100 mL) and the combined organic layers
washed with brine (150 mL), dried (MgSO4), and evapor-
ated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, 10% ethyl acetate
in 30–40 petroleum ether) to afford 6.70 g (82%) of 4-(tert-
butyldimethylsilanyloxymethyl)-2-methyl-2-hexene-1-ol,
as a clear oil. nmax (neat)/cmK1 3338, 2957, 1255, 1102,
836; dH (250 MHz, CDCl3) 5.18 (dq, JZ10.0, 1.5 Hz, 1H),
1.2.13. (2E,4E)-6-(tert-Butyldimethylsilanyloxymethyl)-
4-methylocta-2,4-diene-1-al, 41. A K78 8C solution of
(2E,4E)-6-(tert-butyldimethylsilanyloxymethyl)-4-methy-
locta-2,4-dienoicacid ethyl ester, 40 (7.30 g, 22.4 mmol) in
THF (75 mL) was treated dropwise with a 1.5 M solution of
DiBAL-H in toluene (31 mL, 46.5 mmol) and reaction
mixture stirred at K78 8C for 2 h. The reaction was then
warmed up to room temperature, and then cooled back down
to 0 8C before being quenched with saturated sodium
potassium tartrate solution (100 mL) and the resulting

N. R. Irlapati et al. / Tetrahedron 60 (2004) 9307–9317
9315
mixture stirred for 2 h. Ethyl acetate (100 mL) was added to
the above reaction mixture and the layers separated. The
aqueous layer was extracted with ethyl acetate (3!100 mL)
and the combined organic layers washed with brine
(100 mL), dried (MgSO4), and evaporated under reduced
pressure. The residue was purified by flash column
chromatography (silica gel, 10% ethyl acetate in 30–40
petroleum ether) to afford 6.15 g (97%) of (2E,4E)-6-(tert-
butyldimethylsilanyloxymethyl)-4-methylocta-2,4-dien-1-
ol, as a clear oil. nmax (neat)/cmK1 3399, 2957, 1719, 1695,
1471, 1387, 1255, 1100, 1006, 776; dH (200 MHz, CDCl3)
6.27 (d, JZ15.5 Hz, 1H), 5.85 (dt, JZ15.5, 7.0 Hz, 1H),
5.24 (brd, JZ10.0 Hz, 1H), 4.21 (t, JZ6.0 Hz, 2H), 3.47
(m, 2H), 2.51 (m, 1H), 1.79 (d, JZ1.0 Hz, 3H), 1.61 (m,
1H), 1.29 (t, JZ6.0 Hz, D2O exchangeable, 1H), 1.21 (m,
1H), 0.91 (s, 9H), 0.87 (t, JZ7.0 Hz, 3H), 0.05 (s, 6H); dC
(50 MHz, CDCl3) 137.0, 135.3, 134.2, 125.4, 66.4, 64.0,
42.9, 25.9, 24.6, 18.4, 13.1, 11.7, K5.3, K5.4; HRMS
(CIC) found 285.2253 (MHC) C16H33O2Si requires
285.2250.
were separated, and the aqueous layer extracted with ethyl
acetate (3!15 mL). The combined organic layers were
washed with brine (15 mL), dried (MgSO4) and evaporated
under vacuum. The crude product was purified by flash
column chromatography (silica gel, 10% ethyl acetate in
30–40 petroleum ether) to afford the desired titled product
as an approximately (1:1) mixture of inseparable dia-
stereomers, 42 as an oil, 250 mg (58%) and 43, 50 mg
(22%), as a yellow solid.
Spectral data for 42. nmax (neat)/cmK1 3555, 2954, 1590,
1515, 1469, 1379, 1246, 1086, 833; dH (250 MHz, CDCl3)
8.03 (s, 1H), 7.52–7.35 (m, 7H), 7.09–7.07 (d, JZ6.5 Hz,
2H), 6.31 (dd, JZ15.5, 3.5 Hz, 1H), 5.94 (dd, JZ15.5,
7.0 Hz, 1H), 5.69 (dd, JZ12.0, 7.0 Hz, 1H), 5.22 (brd, JZ
10.0 Hz, 1H), 5.13 (s, 2H), 4.07–4.05 (s, 3H), 3.78–3.71 (m,
D2O exchangeable, 1H), 3.51–3.45 (m, 2H), 3.44–3.42 (2!
s, 3H), 2.56–2.42 (m, 1H), 1.80–1.78 (s, 3H), 1.72–1.62 (m,
1H), 1.32–1.11 (m, 1H), 0.88–0.78 (m, 12H), 0.04–0.03
(2!s, 3H), 0.01–0.00 (2!s, 3H); dC (50 MHz, CDCl3)
163.2, 161.5, 158.4, 147.0, 136.9, 135.8, 135.5, 135.3,
134.3, 130.0, 128.7, 128.1, 127.9, 127.7, 124.9, 117.6,
115.1, 70.1, 68.1, 66.4, 60.8, 53.9, 43.0, 25.9, 24.6, 18.4,
13.2, 11.7, K5.3; HRMS (CIC) found 604.3463 (MHC)
C36H50NO5Si requires 604.3458.
To a K78 8C solution of oxalyl chloride (0.23 mL,
2.6 mmol) in dichloromethane (25 mL), was dropwise
added a 1:1 (v/v) solution of DMSO (0.37 mL, 5.2 mmol)
in dichloromethane. After stirring for 10 min, a solution of
(2E,4E)-6-(tert-butyldimethylsilanyloxymethyl)-4-methyl-
octa-2,4-dien-1-ol (460 mg, 1.6 mmol) in dichloromethane
(2 mL) was added dropwise and the reaction mixture stirred
for 30 min at K78 8C. Triethylamine (1.44 mL, 10.4 mmol)
was then added dropwise and the reaction brought to room
temperature. After stirring for 1 h at room temperature,
water (15 mL) was added to the reaction mixture, and the
layers separated. The aqueous layer was extracted with
dichloromethane (3!15 mL) and the combined organic
phases washed with 1 M hydrochloric acid (2!15 mL), 5%
aq. sodium bicarbonate solution (2!15 mL), brine (15 mL),
and dried (MgSO4). The solvent was evaporated under
reduced pressure, to afford 456 mg (100%) the titled desired
product, 41 as an oil. The crude product was used for next
step without further purification. nmax (neat)/cmK1 2957,
2857, 1683, 1627, 1606, 1471, 1463, 1386, 1361, 1256, 970,
837; dH (250 MHz, CDCl3) 9.59 (d, JZ8.0 Hz, 1H), 7.16 (d,
JZ15.5 Hz, 1H), 6.13 (dd, JZ15.5, 8.0 Hz, 1H), 5.83 (brd,
JZ10.0 Hz, 1H), 3.57 (m, 2H), 2.52 (m, 1H), 1.87 (d, JZ
1.0 Hz, 3H), 1.62 (m, 1H), 1.32 (m, 1H), 0.91 (s, 9H), 0.89
(t, JZ7.5 Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H); dC (50 MHz,
CDCl3) 194.3, 157.9, 146.6, 134.5, 127.0, 65.8, 43.7, 25.9,
24.3, 18.3, 13.0, 11.7, K5.4.
Spectral data for 43. dH (250 MHz, CDCl3) 7.99 (s, 1H),
7.42 (m, 7H), 7.06 (d, JZ9.0 Hz, 2H), 6.31 (s, 1H), 5.13 (s,
2H), 3.99 (s, 3H),3.86 (s, 3H); m/z (CIC) 322 (MHC,
100%).
1.2.15. (2E,4E)-6-(tert-Butyldimethylsilanyloxymethyl)-
1-[5-(p-benzyloxyphenyl)-2,4-dimethoxy pyridine-3-yl]-
4-methylocta-2,4-dien-1-one, 44. A suspension of allylic
alcohol 42 (185 mg, 0.31 mmol) and activated manganese
dioxide, (400 mg, 4.60 mmol) in dichloromethane (10 mL)
was stirred at room temperature for 2 days. The reaction
mixture was then filtered, and the solid residue washed with
dichloromethane (25 mL). The combined filtrates were
evaporated under vacuum and the crude residue was purified
by flash column chromatography (silica gel, 10% ethyl
acetate in 30–40 petroleum ether) to afford 175 mg (95%) of
the desired pyridine 44 as a clear gum. nmax (neat)/cmK1
2957, 1651, 1588, 1559, 1514, 1466, 1410, 1379, 1325,
1273, 1247, 1177, 1095, 834; dH (250 MHz, CDCl3) 8.12 (s,
1H), 7.42 (m, 7H), 7.06 (d, JZ15.5 Hz, 1H), 7.04 (d, JZ
7.0 Hz, 2H), 6.45 (d, JZ15.5 Hz, 1H), 5.70 (d, JZ10.0 Hz,
1H), 5.14 (s, 2H), 3.95 (s, 3H), 3.50 (s, 3H), 3.49 (m, 2H),
2.61 (m, 1H), 1.88 (s, 3H), 1.57 (m, 1H), 1.23 (m, 1H), 0.89
(s, 9H), 0.83 (t, JZ7.0 Hz, 3H), 0.03 (s, 6H); dC (50 MHz,
CDCl3) 194.1, 163.0, 161.2, 158.5, 151.6, 148.5, 146.4,
136.9, 134.6, 130.1, 128.7, 128.1, 127.5 (2C), 126.5, 124.2,
115.5, 115.0, 70.1, 65.9, 61.1, 54.0, 43.8, 25.9, 24.3, 18.3,
13.0, 11.8, K5.3; HRMS (CIC) found 602.3303 (MHC)
C36H48NO5Si requires 602.3302.
1.2.14. (2E,4E)-6-(tert-Butyldimethylsilanyloxymethyl)-
1-[5-(p-benzyloxyphenyl)-2,4-dimethoxy-pyridine-3-yl]-
4-methylocta-2,4-dien-1-ol, 42 and 5-(p-benzyloxyphe-
nyl)-2,4-dimethoxy pyridine, 43. A solution of pyridine,
34 (283 mg, 0.71 mmol) in THF (10 mL) was cooled to
K78 8C and was then dropwise treated with a 1.5 M
solution of tert-butyl lithium in hexanes (0.94 mL,
1.4 mmol). After 30 min, a solution of aldehyde, 41
(200 mg, 0.71 mmol) in THF (2 mL) was added and the
resulting mixture stirred at K78 8C for 1 h. The reaction
was warmed up to room temperature, and stirred for an
additional 1 h. Saturated ammonium chloride solution
(10 mL) was then added to the reaction mixture, followed
by ethyl acetate (10 mL), and water (10 mL). The layers
1.2.16. (2E,4E)-6-(Hydroxymethyl)-1-[5-(p-benzyloxy-
phenyl)-2,4-dihydroxypyridine-3-yl]-4-methylocta-2,4-
dien-1-one, 45. To a K20 8C solution of pyridine, 44
(50 mg, 0.083 mmol) in acetonitrile (10 mL) was added
anhydrous sodium iodide (50 mg, 0.33 mmol) and tri-
methylsilyl chloride (32 mL, 0.25 mmol) and the reaction
slowly brought to room temperature over a period of 4 h.

9316
N. R. Irlapati et al. / Tetrahedron 60 (2004) 9307–9317
The reaction was stirred for 3 days at room temperature, and
then diluted with ethyl acetate (10 mL) and water (5 mL).
The phases were separated and the aqueous layer extracted
with ethyl acetate (3!10 mL). The combined organic
phases were washed with 5% aq. sodium bicarbonate
(10 mL), water (10 mL), brine (10 mL), dried (MgSO4) and
evaporated under vacuum. The crude residue was purified
by flash column chromatography (silica gel, 2% methanol in
chloroform) to afford 20 mg (53%) of the desired pyridone,
45, as a yellow solid, mp 199–200 8C. nmax (neat)/cmK1
3340, 2923, 1665, 1628, 1512, 1472, 1406, 1324, 1218,
1177, 1036, 827; dH (500 MHz, CDCl3) 10.70 (brs, D2O
exchangeable, 1H), 8.01 (d, JZ15.5 Hz, 1H), 7.68 (d, JZ
15.5 Hz, 1H), 7.39 (m, 8H), 7.04 (d, JZ8.0 Hz, 2H), 5.84
(d, JZ10.0 Hz, 1H), 5.11 (s, 2H), 3.65 (brs, 1H), 3.53 (t, JZ
8.5 Hz, 1H), 2.70 (m, 1H), 2.03 (s, 3H), 1.57 (m, 1H), 1.37
(brs, D2O exchangeable, 1H), 1.31 (m, 1H), 0.94 (t, JZ
7.0 Hz, 3H); dC (125 MHz, CDCl3) 195.1, 178.2, 164.0,
159.1, 150.4, 146.0, 138.5, 137.3 (2C), 130.7, 129.1, 128.5,
127.9, 125.6, 124.3, 115.9, 115.3, 107.2, 70.5, 66.5, 44.4,
24.9, 13.7, 12.1; HRMS (CIC) found 460.2123 (MHC)
C28H30NO5 requires 460.2124.
References and notes
1. (a) Takahashi, S.; Kakinuma, N.; Uchida, K.; Hashimoto, R.;
Yanagishima, T.; Nakagawa, A. J. Antibiot. 1998, 51, 596.
(b) Takahashi, S.; Kakinuma, N.; Uchida, K.; Hashimoto, R.;
Yanagishima, T.; Nakagawa, A. J. Antibiot. 1998, 51, 1051.
2. El Bayouni, S. H.; Brewer, D.; Vining, L. C. Can. J. Bot. 1968,
46, 441.
3. Wat, C.-K.; McInnes, A. G.; Smith, D. G.; Wright, J. C. L.;
Vining, L. C. Can. J. Chem. 1977, 55, 4090.
4. Matsumoto, M.; Minato, H. Tetrahedron Lett. 1976, 3827.
5. Levitzki, A.; Gazit, A. Science 1995, 267, 1782.
6. McInnes, A. G.; Smith, D. G.; Wat, C.-K.; Vining, L. C.;
Wright, J. L. C. J. Chem. Soc., Chem. Commun. 1974, 281.
7. Tanabe, M.; Urano, S. Tetrahedron 1983, 39, 3569.
8. Leete, E.; Kowanko, N.; Newmark, R. A.; Vining, L. C.;
McInnes, A. G.; Wright, J. L. C. Tetrahedron Lett. 1975, 4103.
9. Padwa, A.; 1,3-Diploar Cycloaddition Chemistry, Vol. 2;
Wiley-Interscience: New York, 1984.
10. Ackland, M. J.; Hanson, J. R.; Hitchcock, P. R.; Ratcliff, A. H.
J. Chem. Soc., Perkin Trans. 1 1985, 843.
11. Williams, D. R.; Lowder, P. D.; Gu, Y. G. Tetrahedron Lett.
1997, 38, 327.
1.2.17. (2E,4E)-6-(Hydroxymethyl)-1-[5-(p-hydroxyphe-
nyl)-2,4-dihydroxypyridine-3-yl]-4-methylocta-2,4-dien-
1-one, pyridovericin, 1. A solution of pyridone, 45 (25 mg,
0.054 mmol) in dichloromethane (10 mL) at K78 8C was
treated dropwise with a 1 M solution of boron tribromide in
dichloromethane (0.54 mL, 0.54 mmol). The reaction was
then stirred at K78 8C for 1 h, before methanol (100 mL)
was added, and the mixture kept at K78 8C for 10 min. The
reaction was then further quenched by the sequential
addition of water (5 mL), and ethyl acetate (5 mL). The
phases were separated and the aqueous layer extracted with
ethyl acetate (3!10 mL). The combined organic layers
were washed with 5% aq. sodium bicarbonate (10 mL),
brine (10 mL), dried (MgSO4) and evaporated under
vacuum. The crude residue was purified by flash column
chromatography (silica gel, 3% methanol in chloroform), to
afford 15 mg (75%) of pyridovericin 1, as a yellow solid, mp
203–206 8C (dec.). nmax (neat)/cmK1 3335, 2963, 1665,
1610, 1588, 1489, 1452, 1261, 1225, 1101, 1035, 799; dH
(500 MHz, DMSO) 17.56 (brs, D2O exchangeable, 1H),
11.61 (brs, D2O exchangeable, 1H), 9.48 (s, 1H), 8.00 (d,
JZ15.5 Hz, 1H), 7.54 (s, 1H), 7.51 (d, JZ15.5 Hz, 1H),
7.27 (d, JZ8.5 Hz, 2H), 6.78 (d, JZ8.5 Hz, 2H), 5.97 (d,
JZ10.0 Hz, 1H), 4.56 (t, JZ5.5 Hz, D2O exchangeable,
1H), 3.37 (m, 2H), 2.53 (m, 1H), 1.86 (s, 3H), 1.59 (m, 1H),
1.22 (m, 1H), 0.82 (t, JZ7.5 Hz, 3H); dC (125 MHz, CDCl3)
194.6, 177.7, 162.6, 157.6, 150.3, 148.4, 141.5, 135.4,
130.9, 124.3, 123.9, 115.8, 113.6, 106.7, 64.7, 44.4, 24.9,
13.7, 12.5; HRMS found 370.1664 (MHC) C21H24NO5
requires 370.1654.
12. Buck, J.; Madeley, J. P.; Adeley, J. P.; Pattenden, G. J. Chem.
Soc., Perkin Trans 1 1992, 67.
13. Rigby, J. H.; Qabar, M. J. Org. Chem. 1989, 54, 5853.
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15. Zhang, Q. S.; Curran, D. P.; Abstracts of Papers. 222th
National Meeting of the American Chemical Society, Chicago,
IL. American Chemical Society: Washington, DC, 2001;
ORGN-519.
16. Baldwin, J. E.; Adlington, R. M.; Conte, A.; Irlapati, N. R.;
Marquez, R.; Pritchard, G. J. Org. Lett. 2002, 4, 2125.
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18. Loppinet-Serani, A.; Charbonnier, F.; Rolando, C.; Huc, I.
J. Chem. Soc., Perkin Trans. 2 1998, 937.
19. The structures of 22 and 34 were corroborated by the observed
2D NOESY’s between the pyridine methyl ether group present
at the p-position and the pyridine proton at the 6-position to the
newly introduced phenyl ring, and the absence of 2D NOESY
between the pyridine methyl ether group present at o-position
and newly introduced phenyl ring. The structures of 23 and 35
were corroborated by the observed 2D NOESY’s between the
pyridine methyl ether groups present at p- and o-position to the
newly introduced phenyl ring, and the absence of 2D NOESY
between the pyridine proton at the 6-position to the newly
introduced phenyl ring (Figs. 2 and 3).
20. (a) Kanai, K.; Sakamoto, I.; Ogawa, S.; Suami, T. Bull. Chem.
Soc. Jpn 1987, 60, 1529. (b) Huston, R. C.; Neeley, A.;
Fayerweather, B. L.; D’Arcy, H. M.; Maxfield, F. H.; Ballard,
M. M.; Lewis, W. C. J. Am. Chem. Soc. 1933, 55, 2146.
21. (a) Piettre, S. R.; Andre, C.; Chanal, M. C.; Ducep, J. B.;
Lesur, B.; Piriou, F.; Raboisson, P.; Rondeau, J. M.; Schelcher,
C.; Zimmermann, P.; Ganzhorn, A. J. J. Med. Chem. 1997, 40,
4208. (b) Donnelly, D. M. X.; Finet, J. P.; Guiry, P. J.; Rea,
M. D. Synth. Commun. 1999, 29, 2719.
Acknowledgements
22. (a) Karig, G.; Spencer, J. A.; Gallagher, T. Org. Lett. 2001, 3,
835. (b) Sutherland, A.; Gallagher, T. J. Org. Chem. 2003, 68,
3352.
We are very indebted to Professor Akira Nakagawa (Teikyo
University) for generous amounts of an authentic sample of
pyridovericin 1. We thank the EPSRC for funding to A.C.
N.R.I thanks the Dr. Reddy’s Research Foundation (DRF),
Hyderabad, India for their support and financial assistance.
23. Eliel, E. L.; Hutchins, R. O. J. Am. Chem. Soc. 1969, 91, 2703.
24. (a) Ihara, M.; Taniguchi, N.; Fukumoto, K.; Kametani, T.
J. Chem. Soc., Chem. Commun. 1987, 19, 1438. (b) Ihara, M.;

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