From furan to open-chain systems. Synthesis of C1-C9 fragment of tylonolide

Article abstract of DOI:10.1016/j.tet.2003.10.071

Stereoselective synthesis of C1-C9 subunit of macrocyclic lactone - tylonolide is presented. Starting from 2-methylfuran and crotyl alcohol, a 2,5-disubstituted furan derivative was synthesized. Its oxidation leads to α,β-unsaturated dicarbonyl intermedia

Full text of DOI:10.1016/j.tet.2003.10.071

Tetrahedron 59 (2003) 10181–10186
From furan to open-chain systems. Synthesis of C1–C9 fragment
of tylonolide
Jerzy Raczkoa,b
,
*
aRD Chemipan, Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
bInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 29 August 2003; revised 2 October 2003; accepted 23 October 2003
Abstract—Stereoselective synthesis of C1–C9 subunit of macrocyclic lactone—tylonolide is presented. Starting from 2-methylfuran and
crotyl alcohol, a 2,5-disubstituted furan derivative was synthesized. Its oxidation leads to a,b-unsaturated dicarbonyl intermediate which has
been transformed into acyclic fragment bearing five consecutive asymmetric centers.
q 2003 Elsevier Ltd. All rights reserved.
The macrolide antibiotics have been the subject of extensive
research for over two decades.1 The synthetic efforts
directed towards these complex structures have resulted in
progress of important methodologies in particular acyclic
stereocontrol. Tylosin is a typical 16-membered ring
macrolide antibiotic that is used therapeutically in veter-
inary medicine. Tylonolide 1, the aglycon of tylosin, has
been the object of synthetic efforts by several research
groups.2,3
fragment, being the object of our studies, can be obtained by
condensation of 2-methylfuran with the epoxide 5, derived
from crotyl alcohol, and C-1 homologation of resulting diol.
Oxidative transformation of the furan ring leads to acyclic
enedione 3 which is easy to functionalize on both carbonyl
groups, and conjugated double bond (Scheme 1).
Towards this aim, the epoxide 5 (70% yield, 90% ee)5 was
treated with the aluminum derivative of 2-methylfuran 6,
readily obtained via treatment of lithium derivative with
diethylaluminum chloride, to give the diol 7 with 82% yield
and high 94:6 stereoselectivity.6 Attempts to perform this
condensation with a lithium derivative or by copper(I)
promoted methods were unsuccessful, only traces of desired
In continuing our studies on application of furan derivatives
in organic synthesis we have attempted the stereoselective
synthesis of the right wing of this molecule using the furan
ring as a convenient C-4 elongation unit.4 The eastern C-9
Scheme 1.
Keywords: furan ring; stereoselective synthesis; tylonolide; acyclic stereocontrol.
*
Tel.: 48226326335; fax: 48226324513; e-mail: raczko@icho.edu.pl
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.071

10182
J. Raczko / Tetrahedron 59 (2003) 10181–10186
Scheme 2. Reagents and conditions: (a) Et2O, 08C!RT, 16 h, 82% (b) NaH, N-Ts-imidazole, THF, 08C!RT, 1.5 h, 70% (c) KCN, MeOH, reflux 3 h, 96%.
Scheme 3. Reagents and conditions: (a) NaH, BnBr, Bu4NI, THF, 08C!RT, 5 h, 90% (b) Br2, MeCN–H2O, 2108C!RT, 2 h, 85% (c) CH3C(OCH3)3,
camphorsulfonic acid, MeOH, RT, 3 h, 84% (d) K-selectride, THF, 21008C, 0.5 h (e) camphorsulfonic acid, acetone, RT, 0.5 h, 78% (f) BOMCl, i-Pr2NEt,
CH2Cl2, reflux 6 h, 76% (g) CH2CHMgBr, CuBr·Me2S, TMSCl, HMPA, THF, 2788C, 1 h (h) camphorsulfonic acid, MeOH, RT, 0.5 h, 80%.
product were formed. We have also observed the conden-
sation products of furan metallated in 3- and 4-positions
(less than 5%). Diol 7 was then transformed into terminal
epoxide 8 in 70% yield by modified Fraser–Reid pro-
cedure,7 followed by C-1 elongation using potassium
cyanide (96% yield, Scheme 2).
reagents to a,b-unsaturated ketones which required a
protection of the neighbouring hydroxyl with the chelating
group benzyloxymethylene ether (BOM).10 The same
method was applied for introduction of the C-6 stereogenic
centre. Protection of the alcohol 13 with benzyloxy-
methylene chloride was performed in 76% yield to give
a,b-unsaturated ketone 14. At this stage, diastereoisomers
formed in reduction step were separated by column
chromatography. Conjugate addition of vinylmagnesium
bromide afforded, after desilylation of the resulting enol
ether, ketone 15 in 80% yield and 95:5 stereoselectivity
(Scheme 3).
The resulting alcohol 9 was benzylated (90% yield) and
converted into acyclic enedione 11 by oxidation of the furan
ring with Br2/MeCN/H2O system in 85% yield.8 Stereo-
selective reduction of the C-5 carbonyl group required the
regioselective protection of carbonyl C-8, executed in 84%
yield by simple trans-ketalization with a slight excess of
trimethyl ortoacetate. The best 1,3-syn stereoselectivity in
the reduction step was achieved using potassium di-sec-
butylborohydride (K-Selectride) at 21008C.9 After depro-
tection of the ‘terminal’ carbonyl group we obtained the
alcohol 13 in 78% overall yield and 9:1 stereoselectivity as a
mixture of diastereoisomers.
In a final step, for introduction of C-8 stereogenic center, we
applied hydroboration of the terminal olefin 16 in a process
proceeding simultaneously with hydroboration of the C-6
vinyl substituent (Scheme 4). Compound 16 was obtained
by olefination of the carbonyl group with methylene-
triphenylphosphorane in 51% yield. Unfortunately, this
olefin appeared to be very resistant to most of the known
hydroborating agents.11 Application of catechol-borane,
isopinocamphenylborane or thexylborane gave none of the
A few years ago we reported a novel TMSCl and copper(I)-
promoted stereoselective conjugated addition of Grignard
Scheme 4. Reagents and conditions: (a) BuLi, CH3PPh3I, benzene, RT, 3 h, 51% (b) BH3·THF, 08C, THF, 3 h, 60%.

J. Raczko / Tetrahedron 59 (2003) 10181–10186
10183
expected products. Fortunately, hydroboration with
BF3·THF provided the diol 17 in 60% yield as an
inseparable 3:1 mixture of diastereoisomers at C-8 center.
calculated for C13H18O5: C, 61.40; H, 7.14. Found: C,
61.67; H, 7.39.
1.1.2. (2S,3S)-3-(5-Methyl-furan-2-yl)-1,2-epoxybutane
8. To a stirred suspension of sodium hydride (80%,
264 mg, 8.79 mmol) in anhydrous THF (20 ml) diol 7
(680 mg, 4.0 mmol) in THF (5 ml) was added dropwise at
08C under argon atmosphere. After 5 min tosylimidazole
(893 mg, 4.0 mmol) was added, the reaction mixture was
allowed to reach RT (1.5 h) and quenched with water. The
aqueous layer was extracted with ether (3£), combined
organic phases were dried (MgSO4), evaporated while kept
cold (the epoxide is very volatile) and purified by column
chromatography (pentane/ether 98:2) to give 426 mg of 8
(70% yield) as a colourless oil: [a]D¼47.0 (c 0.6, CHCl3);
nmax (film, cm21) 3052, 2978, 2882, 1565, 1455, 1220,
1019, 953, 908, 8370, 783; dH (200 MHz, C6D6) 5.84 (d,
In conclusion, the furan-approach turned to be a very
convenient way for construction of acyclic fragments
bearing five consecutive asymmetric centers. As an example
we have synthesized C-1–C-9 fragment of tylonolide by
stereoselective functionalization of furan-originated acyclic
enedione 11 derived from 2-methylfuran. All new products
were fully characterized. Configuration of newly created
asymmetric centers was assigned on the bases of literature
evidences.
1. Experimental
1.1. General
0
0
0
0
0
0
J3 ,4 ¼3.1 Hz, 1H, 3 -H), 5.76 (dq, J3 ,4 ¼3.1 Hz, J4 ,6
¼
1.0 Hz, 1H, 40-H), 2.77 (ddd, J1A,2¼2.6 Hz, J1B,2¼3.7 Hz,
J2,3¼7.3 Hz, 1H, 2-H), 2.44 (dq, J2,3¼7.3 Hz, J3,4¼7.0 Hz,
1H, 3-H), 2.39 (ddAB, JAB¼5.2 Hz, J1B,2¼3.7 Hz, 1H,
1-HB), 2.34 (ddAB, JAB¼5.20 Hz, J1A,2¼2.6 Hz, 1H, 1-HA),
1H and 13C NMR spectra were recorded on a Bruker AM-
500 (500 and 125 MHz) and Varian Gemini (200 and
50 MHz). Chemical shifts are reported in ppm (d)
referenced to TMS, coupling constants are measured in
Hz. Mass spectra were carried out using an AMD-604
Intectra instrument. Optical rotations were measured on a
JASCO DIP-360 polarimeter. Infrared spectra were
recorded on a Perkin–Elmer 1640 FT-IR. Melting points
were determined with a Kofler hot stage apparatus and are
uncorrected. HPLC was carried out on a Knauer system
using DAD spectrophotometer for peak detection.
Anhydrous solvents have been dried according to standard
laboratory methods. Flash-chromatography was performed
according to Still et al.12 on silica gel (Kieselgel-60 200–
400 mesh, Merck).
0
0
2.01 (d, J4 ,6 ¼1.0 Hz, 3H, 6 -H), 1.29 (d, J3,4¼7.0 Hz, 3H,
4-H); dC (50 MHz, C6D6) 154.7 (C-50), 150.9 (C-20), 106.3
(C-30), 106.0 (C-40), 55.2 (C-2), 46.4 (C-1), 37.2 (C-3), 15.6
(C-4), 13.4 (C-60). Anal. calculated for C9H12O2: C, 71.03;
H, 7.95. Found: C, 71.30; H, 8.24.
1.1.3. (3R,4S)-3-Hydroxy-4-(5-methyl-furan-2-yl)-
pentanenitrile 9. The mixture of epoxide 8 (0.83 g,
5.45 mmol) and potassium cyanide (1.42 g, 21.80 mmol)
in methanol (20 ml) was stirred at 808C for 3 h. Methanol
was evaporated, the residue dissolved in ethyl acetate,
washed with brine and dried with MgSO4. Column
chromatography (CH2Cl2/MeOH 99:1) gave 938 mg (96%
yield) of the product as a colourless oil: [a]D¼47.0 (c 0.6,
CHCl3); nmax (film, cm21) 3453, 2977, 2924, 2254, 1614,
1.1.1. (2S,3S)-3-(5-Methyl-furan-2-yl)-butane-1,2-diol 7.
To a stirred solution of 2-methylfuran (1.35 ml, 15 mmol) in
dry ether (8 ml) under argon at 2788C was added
n-butyllithium (10 mmol, 1.6 M in hexane) and the reaction
mixture was left to reach RT (4 h). It was then cooled to 08C,
diethylaluminum chloride (10 mmol, 1.8 M in toluene) was
added dropwise and after 30 min at 08C the epoxide 5
(190 mg, 2.16 mmol) in ether (2 ml) was added. After 16 h
stirring at RT the reaction was carefully quenched with
water. The aqueous layer was extracted with ethyl acetate
(3£), combined organic phases were dried (MgSO4),
evaporated and purified by column chromatography
(CH2Cl2/MeOH 95:5) to give 302 mg of 7 (82% yield) as
1567, 1455, 1414, 1219, 1062, 1020, 939, 787; dH
0
0
0
(200 MHz, CDCl3) 6.01 (d, J3 ,4 ¼3.1 Hz, 1H, 3 -H), 5.89
0
0
0
0
0
(dq, J3 ,4 ¼3.1 Hz, J4 ,6 ¼1.0 Hz, 1H, 4 -H), 4.05 (m, 1H,
3-H), 2.99 (dq, J3,4¼6.8 Hz, J4,5¼7.1 Hz, 1H, 4-H), 2.59
(brs, 1H, OH), 2.52 (ddAB, JAB¼16.8 Hz, J2B,3¼4.7 Hz, 1H,
2-HB), 2.40 (ddAB, JAB¼16.8 Hz, J2A,3¼7.2 Hz, 1H, 2-HA),
0
0
0
2.26 (d, J4 ,6 ¼1.0 Hz, 3H, 6 -H), 1.31 (d, J4,5¼7.1 Hz, 3H,
5-H); dC (50 MHz, C6D6) 153.4 (C-50), 151.3 (C-20), 117.9
(C-1), 107.1 (C-30), 106.0 (C-40), 70.5 (C-3), 38.8 (C-4),
23.7 (C-2), 14.3 (C-5), 13.4 (C-60); m/z (EI) 179 (Mþ), 109
(M2C3H4NO); m/z (HR-EI) calculated for C10H13NO2
(Mþ) 179.09463, found 179.091. Anal. for acetate calcu-
lated for C12H15NO3: C, 65.14; H, 6.84; N, 6.33. Found: C,
65.11; H, 7.08; N, 6.52.
a yellow oil: [a]D¼10.4 (c 3.3, CDCl3); nmax (film, cm21
)
3406, 2970, 2882, 1746, 1721, 1454, 1377, 1069, 1020,0962,
0
0
786; dH (200 MHz, CDCl3) 5.94 (d, J3 ,4 ¼3.0 Hz, 1H, 3 -H),
0
0
0
0
0
5.87 (dq, J3 ,4 ¼3.0 Hz, J4 ,6 ¼0.95 Hz, 1H, 4 -H), 3.79 (ddd,
1.1.4. (3R,4S)-3-Benzyloxy-4-(5-methyl-furan-2-yl)-pen-
tanenitrile 10. To a stirred suspension of sodium hydride
(80%, 98 mg, 3.26 mmol) in anhydrous THF (2 ml) nitrile 9
(450 mg, 2.51 mmol) in THF (3 ml) was added dropwise at
08C under argon atmosphere. After 5 min benzyl bromide
(0.36 ml, 3.0 mmol) and a catalytical amount of tetrabutyl-
ammonium iodide (ca. 5 mg) were added and the reaction
mixture was stirred at RT for 5 h. Brine was added, the
aqueous layer was extracted with ethyl acetate (3£),
combined organic phases were dried (MgSO4), evaporated
and purified by column chromatography (hexane/ethyl
J1A,2¼7.5 Hz, J1B,2¼3.3 Hz, J2,3¼6.9 Hz, 1H, 2-H), 3.59
(ddAB, JAB¼11.4 Hz, J1B,2¼3.3 Hz, 1H, 1-HB), 3.47 (ddAB
,
JAB¼11.4 Hz, J1A,2¼7.5 Hz, 1H, 1-HA), 2.91 (dq, J2,3
¼
6.9 Hz, J3,4¼7.1 Hz, 1H, 3-H), 2.57 (brs, 1H, OH), 2.39
0
0
0
(brs, 1H, OH), 2.25 (d, J4 ,6 ¼0.95 Hz, 3H, 6 -H), 1.29 (d,
J3,4¼7.1 Hz, 3H, 4-H); dC (50 MHz, CDCl3) 154.9 (C-20),
150.8 (C-50), 106.2 (C-30), 105.9 (C-400), 75.0 (C-2), 64.8 (C-
1), 36.5 (C-3), 14.5 (C-4), 13.5 (C-6 ); m/z (EI) 170 (Mþ),
109 (M2C2H5O2); m/z (HR-EI) calculated for C9H14O3
(Mþ) 170.09430, found 170.094. Anal. for diacetate of 7

10184
J. Raczko / Tetrahedron 59 (2003) 10181–10186
acetate 95:5!8:2) to give 610 mg of 10 (90% yield) as a
colourless oil: [a]D¼23.93 (c 1.0, CHCl3); nmax (film,
cm21) 3032, 2976, 2922, 2880, 2249, 1566, 1455, 1417,
1351, 1218, 1095, 1072, 1020, 939, 787, 739, 698;; dH
2991, 2942, 2832, 2249, 1694, 1668, 1637, 1455, 1372,
1265, 1140, 1100, 1044, 986, 873, 745, 698; dH (200 MHz,
CDCl3) 7.30–7.40 (m, 5H, Ph), 6.68 (dAB, JAB¼15.8 Hz,
1H, H-6), 6.49 (dAB, JAB¼15.8 Hz, 1H, H-7), 4.72 (dAB
,
(200 MHz, CDCl3) 7.32–7.38 (m, 5H, Ph), 6.00 (d,
0
JAB¼11.3 Hz, 1H, CH2Ph), 4.56 (dAB, JAB¼11.3 Hz, 1H,
0
0
0
0
0
0
J3 ,4 ¼3.0 Hz, 1H, 3 -H), 5.88 (dq, J3 ,4 ¼3.0 Hz, J4 ,6
¼
CH2Ph), 3.94 (ddd, J2B,3¼4.5 Hz, J2A,3¼5.4 Hz, J3,4
7.5 Hz, 1H, 3-H), 3.18 (s, 6H, 2£OMe), 3.14 ((dq, J3,4
¼
¼
0.9 Hz, 1H, 40-H), 4.68 (dAB, JAB¼11.3 Hz, 1H, CH2Ph),
4.55 (dAB
,
JAB¼11.3 Hz, 1H, CH2Ph), 3.80 (ddd,
7.5 Hz, J4,Me¼7.1 Hz, 1H, 4-H), 2.67 (ddAB, JAB¼17.1 Hz,
J2B,3¼4.6 Hz, J2A,3¼6.2 Hz, J3,4¼7.3 Hz, 1H, 3-H), 3.06
J2B,3¼4.5 Hz, 1H, 2-HB), 2.52 (ddAB, JAB¼17.1 Hz, J2A,3¼
(dq, J3,4¼7.3 Hz, J4,5¼7.0 Hz, 1H, 4-H), 2.55 (ddAB, JAB
¼
¼
5.4 Hz, 1H, 2-HA), 1.39 (s, 3H, H-9), 1.25 (d, J4,Me¼7.1 Hz,
3H, 4-Me); dC (50 MHz, CDCl3) 201.2 (C-5), 147.1 (C-6),
137.1 (i-Ph), 129.4 (C-7), 128.5 (o-Ph), 128.1 (p-Ph), 128.0
(m-Ph), 117.3 (C-1), 99.3 (C-8), 75.4 (C-3), 72.9 (CH2Ph),
49.2 (2£OMe), 48.3 (C-4), 23.0 (C-9), 21.2 (C-2), 13.6
(4-Me); m/z (EI) 331 (Mþ), 316 (M2CH3), 300
(M2OCH3); m/z (HR-EI) calculated for C18H22NO3
(M2OCH3) 300.15952, found: 300.159.
16.9 Hz, J2B,3¼4.6 Hz, 1H, 2-HB), 2.38 (ddAB, JAB
0
0
16.9 Hz, J2A,3¼6.2 Hz, 1H, 2-HA), 2.25 (d, J4 ,6 ¼0.9 Hz,
3H, 60-H), 1.33 (d, J4,5¼7.0 Hz, 3H, 5-H); dC (50 MHz,
CDCl3) 153.5 (C-50), 151.1 (C-20), 137.4 (i-Ph), 128.2
(o-Ph), 128.0 (m,p-Ph), 117.7 (C-1), 107.1 (C-30), 106.1
(C-40), 77.8 (C-3), 73.0 (CH2Ph), 37.8 (C-4), 21.5 (C-2),
14.9 (C-5), 13.5 (C-60); m/z (EI) 269 (Mþ), 109, 91; m/z
(HR-EI) calculated for C17H19NO2 (Mþ) 269.14157, found
269.141. Anal. calculated for C17H19NO2: C, 75.81; H,
7.11; N, 5.20. Found: C, 76.06; H, 7.05; N, 5.18.
1.1.7. (3R,4S,5S)-3-Benzyloxy-5-hydroxy-4-methyl-8-
oxo-non-6-ene-nitrile 13. To
a stirred solution of
dimethoxynitrile 12 (740 mg, 2.23 mmol) in anhydrous
THF (25 ml) potassium tri-sec-butylborohydride (2.8 ml,
1 M in THF) was added dropwise at 21008C (liquid
nitrogen, ether). The reaction mixture was stirred for 30 min
and excess of borohydride was quenched with MeOH
(1 ml). H2O2 (20%, 1 ml) and NaOH (30%, 1 ml) were
added and the reaction mixture was stirred at RT for 15 min.
After addition of brine the aqueous layer was extracted with
ethyl acetate (3£), combined organic phases were evapor-
ated and redissolved in acetone (15 ml). Camphorosulfonic
acid monohydrate (20 mg) was added and the mixture was
stirred at RT for 30 min. After addition of triethylamine
(0.3 ml) and evaporation of solvents the residue was
dissolved in ethyl acetate and worked up as usual. Column
chromatography (hexane/ethyl acetate 8:2!6:4) gave
502 mg of 13 (78% yield) as a colourless oil (9:1 mixture
of diastereoisomers). For analytical purposes the major
isomer was isolated by preparative HPLC (Nucleosil-100,
hexane/ethyl acetate 8:2); [a]D¼211.7 (c 1.1, CHCl3); nmax
(film, cm21) 3459, 3032, 2927, 2249, 1676, 1630, 1455,
1421, 1360, 1257, 1099, 1059, 983, 741, 699; dH (200 MHz,
CDCl3) 7.29–7.43 (m, 5H, Ph), 6.74 (dd, J6,7¼15.9 Hz,
J5,6¼5.5 Hz, 1H, H-6), 6.28 (dd, J6,7¼15.9 Hz, J5,7¼1.5 Hz,
1.1.5. (3R,4S)-3-Benzyloxy-4-methyl-5,8-dioxo-non-6-
enenitrile 11. To a stirred solution of nitrile 10 (200 mg,
0.74 mmol) in 6:1 mixture of MeCN/H2O (6 ml) bromine
(154 mg, 0.96 mmol) in MeCN (2 ml) was added dropwise
at 2108C and the reaction mixture was stirred at 2108C for
15 min. The cooling bath was removed and the reaction was
stirred at RT for 2 h to complete cis/trans isomerization
(TLC, hexane/ethyl acetate 6:4). Brine was added, the
aqueous layer was extracted with ethyl acetate (3£),
combined organic phases were dried (MgSO4), evaporated
and purified by column chromatography (hexane/ethyl
acetate 7:3) to give 180 mg of 11 (85% yield) as a yellow
solid mp. 59–618C (hexane/ether); [a]D¼5.15 (c 1.6,
CHCl3); nmax (film, cm21) 3037, 2967, 2899, 2247, 1674,
1458, 1423, 1359, 1298, 1270, 1103, 1049, 996, 743, 700,
591, 477; dH (200 MHz, CDCl3) 7.35 (s, 5H, Ph), 6.88 (s,
2H, H-6, H-7), 4.73 (dAB, JAB¼11.4 Hz, 1H, CH2Ph), 4.55
(dAB, JAB¼11.4 Hz, 1H, CH2Ph), 3.97 (ddd, J2B,3¼4.8 Hz,
J2A,3¼5.6 Hz, J3,4¼6.8 Hz, 1H, 3-H), 3.22 (dq, J3,4¼6.8 Hz,
J4,Me¼7.1 Hz, 1H, 4-H), 2.68 (ddAB, JAB¼17.1 Hz, J2B,3
¼
4.8 Hz, 1H, 2-HB), 2.55 (ddAB, JAB¼17.1 Hz, J2A,3¼5.6 Hz,
1H, 2-HA), 2.34 (s, 3H, H-9), 1.26 (d, J4,Me¼7.1 Hz, 3H,
4-Me); dC (50 MHz, CDCl3) 201.2 (C-8), 197.7 (C-5), 137.6
(C-7), 136.8 (i-Ph), 135.5 (C-6), 128.6 (o-Ph), 128.3 (p-Ph),
128.1 (m-Ph), 117.1 (C-1), 75.0 (C-3), 72.9 (CH2Ph), 48.7
(C-4), 28.5 (C-9), 20.9 (C-2), 12.8 (4-Me); m/z (EI) 286
(MþH); m/z (HR-EI) calculated for C17H20NO3 (MþH)
286.14408, found 286.144. Anal. calculated for C17H19NO3:
C, 71.56; H, 6.71; N, 4.91. Found: C, 71.31; H, 6.73; N, 4.97.
1H, H-7), 4.73 (dAB, JAB¼11.4 Hz, 1H, CH2Ph), 4.55 (dAB
,
JAB¼11.4 Hz, 1H, CH2Ph), 4.21 (ddt, J5,OH¼J5,6¼5.5 Hz,
J4,5¼5.3 Hz, J5,7¼1.5 Hz, 1H, H-5), 4.14 (dt, J2A,3
¼
¼
J2B,3¼6.6 Hz, J3,4¼2.7 Hz, 1H, H-3), 2.73 (ddAB, JAB
16.8 Hz, J2A,3¼6.5 Hz, 1H, 2-HA), 2.64 (d, J5,OH¼5.5 Hz,
1H, OH), 2.53 (ddAB, JAB¼16.8 Hz, J2B,3¼6.7 Hz, 1H,
2-HB), 2.26 (s, 3H, 9-H), 1.96 (ddq, J3,4¼2.7 Hz, J4,5
¼
5.3 Hz, J4,Me¼7.1 Hz, 1H, 4-H), 1.03 (d, J4,Me¼7.1 Hz, 3H,
4-Me); dC (50 MHz, CDCl3) 198.1 (C-8), 147.0 (C-7), 136.8
(i-Ph), 130.7 (C-6), 128.7 (m-Ph), 128.4 (p-Ph), 128.1
(o-Ph), 117.5 (C-1), 75.0 (C-3), 73.5 (C-5), 72.7 (OCH2Ph),
41.6 (C-4), 27.6 (C-9), 20.4 (C-2), 10.6 (4-Me); m/z
(LSIMS) 310 (MþNa), 288 (MþH); m/z (HR-LSIMS)
calculated for C17H21NO3Na: 310.13983, found: 310.140.
Anal. calculated for C17H21NO3: C, 71.06; H, 7.37; N, 4.87.
Found: C, 70.82; H, 7.45; N, 4.99.
1.1.6. (3R,4S)-3-Benzyloxy-8,8-dimethoxy-4-methyl-5-
oxo-non-6-enenitrile 12. To a stirred solution of nitrile 11
(930 mg, 3.26 mmol) in anhydrous methanol (35 ml)
trimethyl orthoacetate (0.42 ml, 3.30 mmol) and camphor-
sulfonic acid monohydrate (25 mg, 0.10 mmol) were added.
The reaction mixture was stirred at RT for 3 h and quenched
by addition of triethylamine (0.1 ml), then brine was added,
the aqueous layer was extracted with ethyl acetate (3£),
combined organic phases were dried (MgSO4), evaporated
and purified by column chromatography (hexane/ethyl
acetate 9:1!8:2) to give 904 mg of 12 (84% yield) as a
1.1.8. (3R,4S,5S)-3-Benzyloxy-5-benzyloxymethoxy-4-
methyl-8-oxo-non-6-ene-nitrile 14. To
diastereomeric mixture of alcohol 13 (338 mg, 1.18 mmol)
a
stirred
colourless oil; [a]D¼4.0 (c 1.2, CHCl3); nmax (film, cm21
)

J. Raczko / Tetrahedron 59 (2003) 10181–10186
10185
and N-ethyldiisopropylamine (1 ml, 5.74 mmol) in dry
CH2Cl2 (10 ml) benzyl chloromethyl ether (60%, 1 ml,
4.31 mmol) was added under argon atmosphere. The
reaction was refluxed for 6 h, poured into brine, extracted
with ethyl acetate (3£) and dried over anhydrous MgSO4.
Column chromatography (hexane/ethyl acetate 8:2!6:4)
gave 365 mg (76% yield) of the pure diastereoisomer.
Colourless oil: [a]D¼225.3 (c 0.68, CHCl3); nmax (film,
cm21) 2921, 1672, 1630, 1451, 1356, 1254, 1097, 1027,
986, 738, 697; dH (200 MHz, CDCl3) 7.22–7.36 (m, 10H,
2£Ph), 6.60 (dd, J6,7¼16.1 Hz, J5,6¼7.7 Hz, 1H, 6-H), 6.17
(dd, J6,7¼16.1 Hz, 1H, 7-H), 4.70 (dAB, JAB¼6.9 Hz, 1H,
OCH2OBn), 4.68 (dAB, JAB¼11.4 Hz, 1H, OCH2Ph), 4.64
2.13 (s,3H, CH2COMe), 1.78–1.95 (m, 1H, 4-H), 0.98 (d,
J4,Me¼7.1 Hz, 3H, 4-Me); dC (50 MHz, CDCl3) 207.4
(CvO), 139.0 (C-7), 137.7 (i-Ph), 137.5 (i-Ph), 128.4,
127.9, 127.8, 127.7, 127.6, 127.4 (2£Ph), 117.9 (C-1), 116.6
(C-8), 96.8 (OCH2OBn), 84.5 (C-5), 74.4 (C-3), 72.1
(OCH2Ph), 70.3 (OCH2OCH2Ph), 42.6 (CH2COMe), 41.5
(C-4), 40.3 (C-6), 30.6 (CH2COMe), 21.1 (C-2), 10.6
(4-Me); m/z (LSIMS) 458 (MþNa), 436 (MþH); m/z
(HR-LSIMS) calculated for C27H33NO4Na: 458.23072,
found: 458.230. Anal. calculated for C27H33NO4: C,
74.45; H, 7.64; N, 3.22. Found: C, 74.34, H, 7.55, N, 2.80.
1.1.10. (3R,4S,5S,6R)-3-Benzyloxy-5-benzyloxymethoxy-
4-methyl-6-vinyl-8-methyl-non-8-ene-nitrile 16. To a
solution of methyltriphenylphosphonium iodide (280 mg,
0.69 mmol) in dry benzene (5 ml), under argon atmosphere
at RT was added n-butyllithium (0.44 ml, 1.6 M in hexane).
The resulting mixture was stirred for 1 h and then the ketone
15 (151 mg, 0.35 mmol) in benzene (3 ml) was slowly
added. The reaction mixture was stirred at RT for 3 h,
quenched by addition of brine, extracted with ethyl acetate
(3£), dried with MgSO4, evaporated and purified by column
chromatography (hexane/ethyl acetate 9:1!8:2) to give
77 mg of 16 (51% yield) as a colourless oil, 48 mg (32%) of
the substrate was recovered; [a]D¼212.3 (c 1.1, CHCl3);
nmax (film, cm21) 3082, 2916, 2258, 1492, 1462, 1348,
1098, 1015, 922, 740, 703; dH (200 MHz, CDCl3) 7.24–
7.37 (m, 10H, 2£Ph), 5.73 (ddd, J¼9.5 Hz, J¼8.4 Hz,
J¼17.9 Hz, 1H, CHvCH2), 5.07–5.11 (m, 1H, CHvCH2),
4.99–5.05 (m, 1H, CHvCH2), 4.76 (dAB, JAB¼6.7 Hz, 1H,
OCH2OBn), 4.72 (dAB, JAB¼6.7 Hz, 1H, OCH2OBn), 4.69
(dAB
,
JAB¼6.9 Hz, 1H, OCH2OBn), 4.62 (dAB
,
JAB¼11.9 Hz, 1H, OCH2OCH2Ph), 4.56 (dAB, JAB
¼
11.9 Hz, 1H, OCH2OCH2Ph), 4.50 (dAB, JAB¼11.4 Hz,
1H, OCH2Ph), 4.09–4.20 (m, 2H, 3-H, 5-H), 2.70 (ddAB
,
,
JAB¼16.9 Hz, J2A,3¼6.3 Hz, 1H, 2-HA), 2.53 (ddAB
JAB¼16.9 Hz, J2B,3¼6.8 Hz, 1H, 2-HB), 2.17 (s, 3H, 9-H),
1.90–2.08 (m, 1H, 4-H), 0.94 (d, J4,Me¼7.1 Hz, 3H, 4-Me);
dC (50 MHz, CDCl3) 197.9 (C-8), 144.8 (C-7), 137.5 (i-Ph),
137.3 (i-Ph), 132.6 (C-6), 128.5, 127.9, 127.8, 127.6, 127.5
(2£Ph), 117.7 (C-1), 93.4 (OCH2OBn), 78.5 (C-5), 74.3
(C-3), 72.6 (OCH2Ph), 70.1 (OCH2OCH2Ph), 41.8 (C-4),
27.2 (C-9), 21.1 (C-2), 9.9 (4-Me); m/z (LSIMS) 430
(MþNa), 408 (MþH); m/z (HR-LSIMS) calculated for
C25H29NO4Na: 430.19973, found: 430.199. Anal. calcu-
lated for C25H29NO4: C, 73.68; H, 7.17; N, 3.44. Found: C,
73.42, H, 7.08, N, 3.32.
1.1.9. (3R,4S,5S,6R)-3-Benzyloxy-5-benzyloxymethoxy-
4-methyl-6-(2-oxo-propyl)-oct-7-ene-nitrile 15. To a sus-
pension of CuBr·Me2S (26 mg, 0.12 mmol) and dry HMPA
(0.145 ml, 0.83 mmol) in dry THF (5 ml), under argon
atmosphere at 2788C was added a solution of vinyl-
magnesium bromide (1.25 ml, 1 M in THF) and stirred for
10 min. To this mixture was added a precooled solution of
14 (170 mg, 0.42 mmol) and TMSCl (0.08 ml, 0.63 mmol)
in THF (2 ml). The reaction was stirred at 2788C for 1 h,
aqueous NH4Cl was added to the mixture, which was then
extracted with ethyl acetate (3£) and evaporated under
reduced pressure. The residue was dissolved in MeOH
(6 ml), a catalytic amount of camphorsulfonic acid (ca.
10 mg) was added and the reaction mixture was stirred at
RT for 30 min. Then, brine was added, the aqueous layer
was extracted with ethyl acetate (3£), combined organic
phases were dried (MgSO4), evaporated and purified by
column chromatography (hexane/ethyl acetate 9:1) to give
146 mg of 15 (80% yield) as a colourless oil; [a]D¼220.5
(c 1.6, CHCl3); nmax (film, cm21) 3065, 2922, 2248, 1714,
1497, 1454, 1358, 1096, 1027, 924, 738, 699; dH (200 MHz,
(dAB, JAB¼11.9 Hz, 1H, OCH2OCH2Ph), 4.61 (dAB, JAB
11.9 Hz, 1H, OCH2OCH2Ph), 4.61–4.70 (m, 2H, CvCH2),
4.56 (dAB, JAB¼11.3 Hz, 1H, OCH2Ph), 4.48 (dAB
JAB¼11.3 Hz, 1H, OCH2Ph), 4.17 (ddd, J2A,3¼6.0 Hz,
¼
,
J2B,3¼6.9 Hz, J3,4¼2.5 Hz, 1H, 3-H), 3.53 (dd, J4,5
¼
7.9 Hz, J5,6¼3.4 Hz, 1H, 5-H), 2.68 (ddAB, JAB¼16.8 Hz,
J2A,3¼6.0 Hz, 1H, 2-HA), 2.49 (ddAB, JAB¼16.8 Hz,
J2B,3¼6.9 Hz, 1H, 2-HB), 2.44–2.61 (m, 1H, 6-H), 2.25
(ddAB, JAB¼14.5 Hz, J6,7A¼4.6 Hz, 1H, 7-HA), 2.13 (ddAB
,
JAB¼14.5 Hz, J6,7B¼10.4 Hz, 1H, 7-HB), 1.80–2.03 (m,
1H, 4-H), 1.68 (s, 3H, 8-Me), 1.00 (d, J¼7.1 Hz, 3H, 4-Me);
dC (50 MHz, CDCl3) 143.6 (C-8), 139.9 (CH-vinyl), 138.0
(i-Ph), 137.6 (i-Ph), 128.4, 128.3, 127.8, 127.7, 127.6, 127.5
(2£Ph), 118.0 (C-1), 116.2 (CH2-vinyl), 112.0 (CvCH2),
96.8 (OCH2OBn), 85.3 (C-5), 74.5 (C-3), 72.2 (OCH2Ph),
70.3 (OCH2OCH2Ph), 44.2 (C-6), 40.2 (C-4), 36.5 (C-7),
22.3 (9-Me) 21.3 (C-2), 10.7 (4-Me); m/z (LSIMS) 456
(MþNa), 434 (MþH); m/z (HR-LSIMS) calculated for
C28H35NO3Na: 456.25947, found: 456.259.
CDCl3) 7.23–7.37 (m, 10H, 2£Ph), 5.78 (ddd, J6,7
¼
1.1.11. (3R,4S,5S,6R)-3-Benzyloxy-5-benzyloxymethoxy-
4,8-dimethyl-9-hydroxy-6-(2-hydroxy-ethyl)-nonane-
nitrile 17. To a solution of 16 (40 mg, 0.092 mmol) in dry
THF (5 ml) was added borane-THF complex (1.5 ml, 1.0 M
in THF) at 08C. The reaction mixture was stirred for 3 h at
08C and quenched with H2O2 (0.5 ml) and NaOH (0.5 ml).
Brine was then added and the product was extracted with
Et2O (3£), dried and purified by column chromatography
(hexane/ethyl acetate 7:3!1:1) to give 26 mg of 17 (60%
yield) as a colorless oil (ca. 3:1 mixture of diastereo-
isomers); dH (500 MHz, CDCl3, major isomer) 7.27–7.36
(m, 10H, 2£Ph), 4.78 (dAB, JAB¼6.8 Hz, 1H, OCH2OBn),
10.0 Hz, J7,8A¼7.9 Hz, J7,8B¼17.7 Hz, 1H, 7-H), 5.08–
5.13 (m, 1H, 8-HA), 5.0–5.05 (m, 1H, 8-HB), 4.74 (dAB
JAB¼6.7 Hz, 1H, OCH2OBn), 4.70 (dAB, JAB¼6.7 Hz, 1H,
OCH2OBn), 4.67 (dAB, JAB¼11.8 Hz, 1H, OCH2OCH2Ph),
,
4.59 (dAB, JAB¼11.8 Hz, 1H, OCH2OCH2Ph), 4.54 (dAB
,
JAB¼11.5, 1H, OCH2Ph), 4.46 (dAB, JAB¼11.5 Hz, 1H,
OCH2Ph), 4.12 (ddd, J2A,3¼5.8 Hz, J2B,3¼7.1 Hz, J3,4
¼
2.7 Hz, 1H, 3-H), 3.53 (dd, J4,5¼7.7 Hz, J5,6¼3.8 Hz, 1H,
5-H), 2.87–3.02 (m, 1H, 6-H), 2.64 (ddAB, JAB¼16.8 Hz,
J2A,3¼5.8 Hz, 1H, 2-HA), 2.49 (ddAB, JAB¼16.8 Hz,
J2B,3¼7.1 Hz, 1H, 2-HB), 2.44–2.71 (m, 2H, CH2COMe),

10186
J. Raczko / Tetrahedron 59 (2003) 10181–10186
Y.; Hamada, T.; Yonemitsu, O. Chem. Pharm. Bull. 1987, 35,
2209.
4.75 (dAB, JAB¼6.8 Hz, 1H, OCH2OBn), 4.51–4.69 (m, 4H,
OCH2Ph x 2), 4.24 (dddAB, JAB¼10.9 Hz, J¼5.7 Hz,
3. Syntheses of fragments of tylonolide: (a) Lu, L. D.-L.
Tetrahedron Lett. 1982, 23, 1867. (b) Kitano, Y.; Kusakabe,
M.; Kobayashi, Y.; Sato, F. Chem. Lett. 1986, 523. (c)
Pearson, A. J.; Lai, Y.-S.; Lu, W.; Pinkerton, A. A. J. Org.
Chem. 1989, 54, 3882. (d) Hughes, A. B.; Stick, R. V.;
Tilbrook, D. M. G. Aust. J. Chem. 1990, 43, 1681. (e) Guanti,
G.; Banfi, L.; Ghiron, C.; Narisano, E. Tetrahedron Lett. 1991,
32, 267. (f) Marshall, J. A.; Yashunsky, D. V. J. Org. Chem.
1991, 56, 5493. (g) Marshall, J. A.; Crute, III, T. D.; His, J. D.
J¼0.6 Hz, 1H, 9-HA), 4.20 (dddAB
,
JAB¼10.9 Hz,
J¼6.1 Hz, J¼0.6 Hz, 1H, 9-HB), 4.07 (ddd, J2A,3¼7.0 Hz,
J2B,3¼5.7 Hz, J3,4¼2.8 Hz, 1H, 3-H), 3.99 (dd, J4,5¼6.3 Hz,
J5,6¼4.0 Hz, 1H, 5-H), 3.53–3.70 (m, 2H, CH2OH), 3.41–
3.52 (m, 2H, 2£OH), 2.70 (ddAB, JAB¼16.8 Hz, J2B,3
¼
5.7 Hz, 1H, 2-HB), 2.57 (ddAB, JAB¼16.8 Hz, J2A,3¼7.0 Hz,
1H, 2-HA), 1.87–2.07 (m, 1H, 4-H), 1.59–1.79 (m, 2H,
7-CH2), 1.35–1.47 (m, 1H, 6-H), 1.15–1.27 (m, 3H, C6–
CH2, 8-H), 1.00 (d, J¼7.0 Hz, 3H, Me), 0.93 (d, J¼6.7 Hz,
3H, Me); dC (125 MHz, CDCl3) 137.7 (i-Ph), 137.3 (i-Ph),
128.8, 128.5, 128.6, 127.8, 127.7, 127.4 (2£Ph), 118.1
(C-1), 96.8 (OCH2OBn), 84.8 (C-5), 74.6 (C-3), 71.7
(OCH2Ph), 70.4 (OCH2OCH2Ph), 40.9 (C-4), 28.9, 28.3
(2£CH2OH), 23.7 (C-7), 22.9 (C-2), 21.9 (C-6), 21.1
(6-CH2), 17.4 (C-8), 14.0 (8-Me), 10.9 (4-Me); m/z
(LSIMS) 492 (MþNa); m/z (HR-LSIMS) calculated for
C28H39NO5Na: 492.26461, found: 492.264.
´
J. Org. Chem. 1992, 57, 115. (h) Le Menez, P.; Fargeas, V.;
Berque, I.; Poisson, J.; Ardisson, J.; Lallemand, J.-Y.;
Pancrazi, A. J. Org. Chem. 1995, 60, 3592. (i) Berque, I.; Le
´
Menez, P.; Razon, P.; Pancrazi, A.; Ardisson, J.; Brion, J. D.
Synlett 1998, 1135.
4. (a) Pikul, S.; Raczko, J.; Ankner, K.; Jurczak, J. J. Am. Chem.
Soc. 1987, 109, 3981. (b) Raczko, J.; Jurczak, J. Studies in
Natural Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier:
Amsterdam, 1995; Vol. 16, p 639. (c) Raczko, J. Polish
J. Chem. 1999, 73, 77.
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