Kinetic resolution of 4,5-dihydroxylated cyclopentenones

Article abstract of DOI:10.1016/j.tetasy.2003.11.024

An asymmetric synthesis of trans-4,5-dihydroxylated cyclopentenones has been developed. The method involves a lipase-mediated kinetic resolution.

Full text of DOI:10.1016/j.tetasy.2003.11.024

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 503–507
Kinetic resolution of 4,5-dihydroxylated cyclopentenones
Zac C. Etheridge and Stephen Caddick*
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, UK
Received 28 October 2003; accepted 20 November 2003
Abstract—An asymmetric synthesis of trans-4,5-dihydroxylated cyclopentenoneshasbeen developed. The method involvesa lipase-
mediated kinetic resolution.
ꢀ 2003 Elsevier Ltd. All rights reserved.
2
1. Introduction
noneshave been publihsed,
trans-adductshave been reported.
fewer syntheses of the
3–6
Within our labo-
The polyhydroxylated cyclopentane unit ispresent in a
number of natural products, such as Neocarzinostatin
chromophore, Kedarcidin chromophore, Trehazolin
and Terrein (Scheme 1).1
ratory, we have devised a convenient synthesis of race-
mic dihydroxylated cyclopentenone 1 from furfuryl
alcohol, attainable in quantitiesof up to 50 g, for use in
our studies towards the synthesis of Neocarzinostatin
chromophore.7 We have further manipulated 1 in order
to synthesise the enantiomer required in our synthesis, 2,
by use of some work by Hirama3 involving an enzymatic
desymmetrisation (Scheme 2).8
Dihydroxylated cyclopentenonesare versatile precursors
for the preparation of such natural products. Although
a number of routesto cis-dihydroxylated cyclopente-
O
O
O
OH
O
OMe
O
OH
OTBS
O
O
OH
O
MeO
OtBu
OAc
(+)-2
>98% ee
5steps
27%
4 steps
43%
O
O
Cl
N
NH
O
O
O
OH
(+)-1
O
O
O
OH
O
MeNH
Scheme 2.
HO
O
O
O
O
OH
OH
Neocarzinostatin chromophore
Kedarcidin chromophore
2. Results and discussion
O
HO
O
OH
HO
The longevity of the desymmetrisation pathway moti-
vated usto seek other alternativesfor the production of
an enantiomerically pure dihydroxylated cyclopente-
none. ( )-3 was subjected to kinetic resolution condi-
tions using Lipase (Amano AK), which had previously
been used successfully for the desymmetrisation path-
way. The resolution resulted in the desired enantiomer,
(+)-3 asthe unreacted alcohol in 39% and P98% ee and
the undesired enantiomer ())-2 asthe acetate in 38%
and P98% ee (Scheme 3).9
OH
OH
HO
OH
HO
N
OH
N
H
O
HO
Trehazolin
Terrein
Scheme 1.
Enantiomeric excesses were determined throughout by
comparison to known compounds3 and by the two-step
* Corresponding author. Tel.: +44-0207-6794694; fax: +44-01273678-
734; e-mail: s.caddick@ucl.ac.uk
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.024

504
Z. C. Etheridge, S. Caddick / Tetrahedron: Asymmetry 15 (2004) 503–507
O
which wasthen treated with 1 S-())-camphanic chloride.
Only one diastereomer of the resulting compound 6 was
observed, leading us to conclude that 1 wasbeing pro-
duced in P95% ee from the kinetic resolution, and that
under basic conditions, racemisation was occurring
(Scheme 6).
O
+
O
O
a), b)
c)
OH
OTBS
OTBS
OTBS
OAc
+
OtBu
OH
) - 3
OH
(
(
) - 1
( + ) - 3
( - ) - 2
+
>98% ee
>98% ee
Scheme 3. Reagentsand conditions: (a) TBS-Cl, DCM, Im, 0 ꢁC, 90%;
(b) TiCl4, DCM, )78 ꢁC, 73%; (c) lipase (Amano AK), vinyl acetate,
38% of 2, 39% of 3.
O
O
OH
O
O
O
O
O
sequence of Luche reduction9 of the ketone followed by
derivatisation of the resultant alcohol with 1S-())-
camphanic chloride.
b)
a)
OH
OH
O
OtBu
OtBu
OtBu
O
(+)-1
5
6
We sought to shorten further this route by resolving
compound ( )-1. After screening several lipases, we
found we were effectively able to synthesise acetate ())-4
in 50% yield and P95% ee. However, it appeared that
unreacted 1 wasa racemic mixture; derivatising it with
1S-())-camphanic chloride resulted in an approximate
1:1 mixture of diastereomers (Scheme 4).
Scheme 6. Reagentsand conditions: (a) CeCl 3Æ7H2O, NaBH4, MeOH,
0 ꢁC, 48% 5 as major diastereomer, 17% minor diastereomer; (b) 1S-
())-camphanic chloride, Et3N, DMAP, DCM, 90%.
Further confirmation of thisreuslt wasattained by
stirring (+)-1 in the presence of triethylamine; after 3 h
the optical rotation had been reduced to 0, indicating
racemisation. (+)-1 was also found to slowly racemise
upon standing.
O
O
O
a)
OAc
OH
OH
+
During the course of our studies, we have also sought to
synthesise cis-dihydroxylated cyclopentenonesfrom our
trans-derivatives. Although this has not been possible,
we did uncover an example of what would appear to be
a retro-Nazarov reaction, ashasbeen reported by
Harmata (Scheme 7).10
OtBu
(-)-4
OtBu
OtBu
(+)-1
b)
O
O
O
O
O
O
O
O
+
O
O
O
OtBu
OtBu
MeO
OH
(-)
O
(+)
OtBu
O
OtBu
Scheme 4. Reagents and conditions: (a) Lipase (Amano PS), vinyl
acetate, 36 ꢁC, 50% of ())-4, 45% of 1; (b) 1S-())-camphanic chloride,
Et3N, DMAP, DCM.
1
7
Scheme 7. Reagentsand condition:s THF, PPh 3, 4-methoxyphenol,
0 ꢁC then DIAD, rt, 14%.
We suspected that the conditions used to derivatise the
alcohol were inducing racemisation. This was notewor-
thy because the mechanism would necessarily require
the loss of stereochemistry at both the 4- and 5-posi-
tions. One possible explanation would be that the ring
contraction used for the synthesis of 1 might be revers-
ible (Scheme 5).
We propose one possible explanation for this is as fol-
lows. Conjugate addition of 4-methoxyphenol, followed
by loss of triphenylphosphine oxide results in cation 11.
Thisps eciesthen undergoesthe retro-Nazarov proces
to result in ring-opened compound 7 (Scheme 8).
O
O
OH
O
N
Ph
Ph
O
N
OiPr
iPrO
O
OH
O
O
OH
OH
OH
OH
OH
Ph
P
OtBu
OtBu
OtBu
OtBu
ArO
OtBu
ArO
OtBu
Scheme 5.
8
9
HO
OMe
In order to ascertain whether this was indeed the case,
we needed to determine whether unreacted 1 waspresent
in good enantiomeric purity at the completion of the
kinetic resolution. By first reducing the ketone, ring
opening of 1 should no longer be possible, and hence we
should then be able to determine the ee by derivatisation
with 1S-())-camphanic chloride. Thusunreacted 1 was
subjected to Luche reduction conditions9 to give diol 5,
O
OH
O
OPPh3
OtBu
ArO
OtBu
OtBu
ArO
ArO
7
11
10
Scheme 8.

Z. C. Etheridge, S. Caddick / Tetrahedron: Asymmetry 15 (2004) 503–507
505
In conclusion, we have simplified the asymmetric syn-
thesis of dihydroxylated cyclopentenones required for
our synthetic work towards Neocarzinostatin chromo-
phore, and uncovered some interesting side reactions of
compoundsof thistype.
(3 mL) at 0 ꢁC wasadded acetic anhydride (0.062 mL,
0.66 mmol) dropwise. The reaction mixture was stirred
at 0 ꢁC for 1 h, allowed to warm to room temperature
over 1 h 30 min then quenched with HCl (3 mL, 1 M
aqueousoslution). The organicswere extracted with
ethyl acetate (3 · 5 mL), washed with sodium bicarbon-
ate (5 mL, saturated solution), dried over magnesium
sulfate, filtered and concentrated in vacuo. Column
3. Experimental
chromatography eluting with 20% EtOAc/PE resulted in
30
D
CHCl3). The spectral details are in exact accordance
with those given for ())-2.
All glassware was oven or flame dried prior to use. All
reagents and solvents were purchased from commercial
sources and used as supplied or purified using standard
methods. Preparations were carried out under an inert
a colourless oil (0.13 g, 80%). ½aŠ ¼ þ145:4 (c 1.02,
1
atmosphere unless otherwise stated. H NMR spectra
were recorded on a Bruker spectrometer at 300 MHz
operating at ambient probe temperature. Coupling
constants were measured in hertz (Hz). 13C NMR
spectra were recorded at 75 MHz in CDCl3 using
residual CHCl3 asinternal reference. Infrared psectra
were recorded on a Perkin–Elmer 1710 FTIR spec-
trometer as thin films or solutions. Mass spectra were
recorded on a MS25 spectrometer. Analytical thin layer
3.1.2. (3S,4R,5R)-3-Acetoxy-4-tbutyldimethysilyloxy-5-
hydroxy-cyclopent-2-ene 3a. To (+)-2 (0.245 g, 0.91
mmol) and CeCl3Æ7H2O (0.45 g, 1.22 mmol) stirring in
methanol (4 mL) at 0 ꢁC wasadded NaBH
(0.05 g,
4
1.42 mmol) portionwise over 10 min. The reaction mixture
wastsirred at 0 ꢁC for 1 h 30 min then quenched with
ammonium chloride (5 mL, saturated solution), extracted
with ethyl acetate (5 ·4mL), was hed with brine (10mL),
dried over magnesium sulfate, filtered and concentrated in
vacuo. Column chromatography eluting with 20% EtOAc/
chromatography wascarried out uisng SIL G/UV
plates and visualised using standard procedures. Melting
pointsare uncorrected.
254
PE resulted in a colourless oil (0.196 g, 79%). Rf (10%
30
D
EtOAc/PE) 0.13. ½aŠ ¼ þ61:5 (c 1.00, CHCl3). mmax
3.1. (4S,5R)-4-Hydroxy-5-tbutyldimethylsilyoxy-cyclo-
penten-1-one (+)-3 and (4R,5S)-4-acetoxy-5-tbutyldi-
methylsilyoxy-cyclopenten-1-one ())-2
1
(cmÀ1) 3415 (OH), 2360, 1641 (C@O), 1025. H NMR
(300 MHz, CDCl3) d 5.83 (1H, d, J ¼ 6:0), 5.72 (1H, d,
J ¼ 6:0), 5.21–5.24 (1H, m), 4.38–4.40 (1H, m), 4.04 (1H,
t, J ¼ 3:8), 1.98 (3H, s ), 1.75 (1H, d,J ¼ 7:2), 0.81 (9H, s ),
0.03 (3H, s), 0.00 (3H, s). 13C NMR (75MHz, CDCl3) d
169.4, 134.3, 129.3, 84.8, 81.6, 79.5, 24.4, 19.7, 16.7, )4.6.
m=z (FAB) 295 (M+Na). HRMS (ES) calculated for
C13H25O4Si (M+H) 273.1522. Found 273.1526.
To ( )-3 (2.41 g, 10.57 mmol) stirring in benzene (10 mL)
wasadded Lipase AK followed by vinyl acetate (20 mL).
The reaction mixture wasstirred at 34 ꢁC for 10 h then
filtered and concentrated in vacuo. Column chroma-
tography eluting with 20–70% EtOAc/PE resulted in
(+)-3 asa white solid, mp 61–62 ꢁC, (0.951 g, 39%) and
())-2 asa colourlesoil (1.087 g, 38%). ( ))-2 Rf (20%
30
EtOAc/PE) 0.59. ½aŠ ¼ À143:4 (c 1.02, CHCl3). mmax
D
1
(cmÀ1) 2930, 2858, 1742 (C@O), 1473, 1370. H NMR
3.1.3. (3S,4R,5R)-3-Acetoxy-4-tbutyldimethylsilyloxy-5-
camphanoxycyclopent-2-ene 3b. To 3a (0.32 g, 1.19
mmol) stirring in DCM (5 mL) at 0 ꢁC wasadded 1 S())-
camphanic chloride (0.31 g, 1.43 mmol), DMAP (0.029 g,
0.24 mmol) and triethylamine (0.198 mL, 1.43 mmol). The
reaction mixture wasstirred for 30 min then quenched with
ammonium chloride (5 mL, saturated solution), extracted
with ether (3 ·5mL), was hed with brine (10mL), dried
over magnesium sulfate, filtered and concentrated in
vacuo. Column chromatography eluting with 10–20%
Et2O/PE resulted in a white solid, mp 74–75 ꢁC (0.34 g,
63%). Anal. Calcd for C23H36O7Si: C, 61.03; H, 8.02.
(300 MHz, CDCl3) d 7.23 (1H, dd, J ¼ 6:2, 1.7), 6.17
(1H, d, J ¼ 6:2), 5.56–5.52 (1H, m), 4.15 (1H, d,
J ¼ 2:6), 2.01 (3H, s), 0.79 (9H, s), 0.04 (3H, s), 0.00
(3H, s). 13C NMR (75 MHz, CDCl3) d 203.2, 171.9,
157.0, 135.8, 80.5, 79.8, 27.3, 22.5, 18.1, )3.00, )3.60.
m=z (EI) 271 (M+H). HRMS (ES) calculated for
C13H23O4Si (M+H) 271.1365. Found 271.1371. (+)-3 Rf
25
(20% EtOAc/PE) 0.24. ½aŠ ¼ þ91:8 (c 1.14, CHCl3).
D
mmax (cmÀ1) 2985, 1741 (C@O). 1H NMR (300 MHz,
CDCl3) d 7.18 (1H, dd, J ¼ 6:4, 1.5), 6.04 (1H, d,
J ¼ 6:4), 4.60–4.56 (1H, m), 3.99–3.93 (1H, m), 2.16–
2.14 (1H, m), 0.78 (9H, s), 0.04 (3H), 0.0 (3H, s). 13C
NMR (75 MHz, CDCl3) d 203.2, 158.8, 133.1, 82.7, 78.1,
26.2, 18.8, )4.1, )4.7. m=z (EI) 213 (M)CH3). HRMS
(ES) calculated for C11H21O3Si (M+H) 229.1260. Found
229.1262.
Found C, 61.14; H, 8.16. Rf (20% EtOAc/PE) 0.54.
18
D
½aŠ ¼ À28:9 (c 1.4, CHCl3). mmax (cmÀ1) 2959, 2932, 2858,
1790 (C@O), 1739 (C@O), 1472, 1397. 1H NMR
(300 MHz, CDCl3) d 5.91 (1H, d, J ¼ 6:0), 5.86 (1H, d,
J ¼ 6:0), 5.44–5.41 (1H, m), 5.34–5.29 (1H, m), 4.35–4.31
(1H, m), 2.40–2.31 (1H, m), 2.01 (3H, s), 1.97–1.81 (2H,
m), 1.67–1.58 (1H, m), 1.04 (3H, s), 0.99 (3H, s), 0.90 (3H,
s), 0.79 (9H, s), 0.00 (6H, s). 13C NMR (300 MHz, CDCl3)
d 178.3, 170.8, 167.5, 133.9, 132.0, 91.2, 84.4, 82.9, 82.5,
55.2, 54.6, 31.1, 29.4, 26.0, 21.3, 18.3, 17.3, 17.2, 10.1, )4.4,
)4.5. m=z (EI) 395 (M)C4H9). HRMS (ES) calculated for
C23H40O7SiN (M+NH4) 470.2569. Found 470.2572.
Determination of ee of (+)-3:
3.1.1. (4S,5R)-4-acetoxy-5-tbutyldimethylsilyoxy-cyclo-
penten-1-one (+)-2. To (+)-3 (0.136 g, 0.6 mmol) and
DMAP (0.007 g, 0.06 mmol) stirring in triethylamine

506
Z. C. Etheridge, S. Caddick / Tetrahedron: Asymmetry 15 (2004) 503–507
3.2. (4S,5R)-4-tButoxy-5-hydroxy-cyclopenten-1-one
(+)-1 and (4R,5S)-4-tbutoxy-5-acetoxy-cyclopenten-1-
one ())-4
nesium sulfate, filtered and concentrated in vacuo.
Column chromatography eluting with 25–50% Et2O/PE
resulted in a colourless oil (0.39 g, 76%, de P95%). Rf
18
(20% EtOAc/PE) 0.26. ½aŠ ¼ À13:1 (c 1.0, CHCl3). mmax
D
To ( )-1 (0.128 g, 0.75 mmol) and Lipase PS (0.5 g) was
added vinyl acetate (6 mL). The reaction mixture was
stirred at 40 ꢁC for 7 daysthen filtered and concentrated
in vacuo. Column chromatography eluting with 10–20%
EtOAc/PE resulted in ())-4 asa yellow oslid, mp 48–
50 ꢁC (0.082 g, 50%) and (+)-1 asan off-white solid, mp
(cmÀ1) 2974, 2935, 2874, 1793 (C@O), 1748 (C@O),
1
1471, 1448, 1367. H NMR (300 MHz, CDCl3) d 5.74
(1H, dt, J ¼ 5:9, 1.3), 5.60 (1H, dt, J ¼ 5:9, 1.5), 5.52–
5.50 (1H, m), 5.04 (1H, app. t, J ¼ 3:8), 4.44–4.42 (1H,
m), 2.30–2.21 (1H, m), 1.93 (3H, s), 1.90–1.70 (2H, m),
1.55–1.46 (1H, m), 1.04 (9H, s), 0.94 (6H, s), 0.82 (3H,
s). 13C NMR (75 MHz, CDCl3) d 178.5, 170.5, 167.1,
137.7, 129.5, 91.4, 86.0, 81.7, 78.5, 75.0, 55.2, 54.7, 31.0,
29.4, 28.5, 21.2, 17.0, 16.8, 10.1. m=z (EI) 294 (M)C4H9,
C2H3O). HRMS (ES) calculated for C21H34O7N
(M+NH4) 412.2335. Found 412.2331.
61–63 ꢁC (0.058 g, 45%). ())-4 Rf (20% EtOAc/PE) 0.30.
28
½aŠ ¼ À142:3 (c 1.0, CHCl3). mmax (cmÀ1) 3055, 2982,
D
1727 (C@O), 1630 (C@C). 1H NMR (300 MHz, CDCl3)
d 7.26 (1H, dd, J ¼ 6:2, 2.1), 6.21 (1H, dd, J ¼ 6:2, 1.5),
4.96 (1H, d, J ¼ 2:8), 4.75–4.80 (1H, m), 2.10 (3H, s),
1.19 (9H, s). 13C NMR (75 MHz, CDCl3) d 199.4, 170.4,
160.7, 133.0, 81.3, 75.6, 74.1, 28.5, 20.9. m=z (EI) 212
Determination of ee of (+)-1:
(M+). HRMS (ES) calculated for C11H20O4N (M+NH4)
28
D
230.1392. Found 230.1391. (+)-1 ½aŠ ¼ þ25:7 (c 1.0
CHCl3). mmax (cmÀ1) 3430 (OH), 2979, 1719 (C@O). 1615
1
(C@C), 1393. H NMR (300 MHz, CDCl3) d 7.29 (1H,
3.2.3. (3S,4S,5R)-3-tButoxy-4,5-dihydroxy-cyclopent-1-
ene 5. To (+)-1 (0.33 g, 1.94 mmol) stirring in methanol
(3.5 mL) at 0 ꢁC wasadded CeCl 3Æ7H2O (1.01 g,
2.72 mmol) followed by NaBH4 (0.103 g, 2.72 mmol)
portionwise over 15 min. The mixture was stirred for
30 min then quenched with ammonium chloride (5 mL,
saturated solution), extracted with ethyl acetate
(3 · 5 mL), washed with brine (10 mL), dried over mag-
nesium sulfate, filtered and concentrated in vacuo.
Column chromatography eluting with 25–70% EtOAc/
PE resulted in 5 asthe major diatsereomer asa col-
dd, J ¼ 6:0, 1.8), 6.17 (1H, d, J ¼ 6:0), 4.51–4.55 (1H,
m), 4.01 (1H, d, J ¼ 2:2), 2.81 (1H, br s), 1.25 (9H, s).
13C NMR (75 MHz, CDCl3) d 205.0, 161.5, 131.3, 80.7,
76.4, 75.1, 28.2. m=z (EI) 171 (M+H). HRMS (EI) cal-
culated for C8H11O3 (M)CH3) 155.0708. Found
155.0703.
Determination of ee of ())-4:
3.2.1. (3R,4S,5S)-3-tButoxy-4-acetoxy-5-hydroxycyclo-
pent-2-ene 4a. To ())-4 (0.538 g, 2.54 mmol) stirring in
ourless oil (0.156 g, 48%). Rf (30% EtOAc/PE) 0.31.
18
½aŠ ¼ þ11:4 (c 0.35, CHCl3). mmax (cmÀ1) 2974, 2856,
D
1
methanol (4 mL) at 0 ꢁC wasadded CeCl Æ7H2O (1.23 g,
1443, 1380, 1347. H NMR (300 MHz, CDCl3) d 5.73
3
3.3 mmol) followed by sodium borohydride (0.144 g,
3.81 mmol) portionwise over 20 min. The mixture was
stirred for a further 30 min then quenched with ammo-
nium chloride (3 mL, saturated solution), extracted with
ethyl acetate (3 · 5 mL), washed with brine (5 mL), dried
over magnesium sulfate, filtered and concentrated in
vacuo. Column chromatography eluting with 10%
(1H, dt, J ¼ 6:0, 1.5), 5.67 (1H, dt, J ¼ 6:0, 1.5), 4.40–
4.35 (1H, m), 4.25–4.23 (1H, m), 3.89 (1H, app. q,
J ¼ 4:5), 2.42 (1H, d, J ¼ 5:1), 2.16 (1H, d, J ¼ 8:1),
1.18 (9H, s). 13C NMR (75 MHz, CDCl3) d 135.0, 133.6,
88.5, 80.4, 80.2, 74.7, 28.8. m=z (ES) 172 (M+). HRMS
(ES) calculated for C9H20O3N (M+NH4) 190.1443.
Found 190.1446.
EtOAc/PE resulted in a colourless oil (0.305 g, 57%,
18
D
de P95%). Rf (20% EtOAc/PE) 0.25. ½aŠ ¼ À64:4 (c
0.8, CHCl3). mmax (cmÀ1) 3370 (OH), 3047, 2974, 2302,
1719 (C@O), 1421. H NMR (300 MHz, CDCl3) d 5.63
1
3.2.4. (3S,4R,5R)-3-tButoxy-4,5-biscamphanoxy-cyclo-
pent-2-ene 6. To 5 (0.141 g, 0.84 mmol) stirring in
DCM (4 mL) at 0 ꢁC wasadded (1 S)-())-camphanoyl
chloride (0.654 g, 3 mmol), DMAP (0.031 g, 0.25 mmol)
and triethylamine (0.277 mL, 2 mmol). The mixture was
allowed to warm to room temperature for 1 h then
quenched with ammonium chloride (4 mL, saturated
solution), extracted with ether (3 · 5 mL), washed with
brine (10 mL), dried over magnesium sulfate, filtered
and concentrated in vacuo. Column chromatography
eluting with 25–40% Et2O/PE resulted in a white solid,
(1H, dt, J ¼ 6:0, 1.5), 5.53 (1H, dt, J ¼ 6:0, 1.5), 4.49
(1H, app. t, J ¼ 4:2), 4.41–4.38 (1H, m), 4.26–4.30 (1H,
m), 3.43 (1H, br s), 1.95 (3H, s), 1.02 (9H, s). 13C NMR
(75 MHz, CDCl3) 173.3, 134.3, 132.8, 92.3, 79.5, 78.3,
74.6, 28.7, 21.3. m=z (EI) 215 (M+H). HRMS (ES) cal-
culated for C11H22O4N (M+NH4) 232.1549. Found
232.1547.
3.2.2. (3R,4S,5S)-3-tButoxy-4-acetoxy-5-camphanoxycy-
clopent-2-ene 4b. To 4a (0.28 g, 1.31 mmol) stirring in
DCM (2.5 mL) wasadded 1 S ())-camphanoyl chloride
(0.34 g, 1.57 mmol) and DMAP (0.032 g, 0.26 mmol).
mp 120–123 ꢁC (0.404 g, 90%, de P95%). Rf (30%
18
EtOAc/PE) 0.54. ½aŠ ¼ þ24:2 (c 0.75, CHCl3). mmax
D
1
(cmÀ1) 2369, 2375, 1787 (C@O), 1736 (C@O), 1421. H
The mixture wascooled to
0
ꢁC, triethylamine
NMR (300 MHz, CDCl3) d 5.72–5.70 (1H, m), 5.56–5.54
(2H, m), 5.13–5.11 (1H, m), 4.52–4.51 (1H, m), 2.31–
2.21 (2H, m), 1.93–1.65 (4H, m), 1.57–1.43 (2H, m),
1.00–0.81 (27H, m). 13C NMR (300 MHz, CDCl3)
(0.217 mL, 1.57 mmol) added and the mixture allowed to
warm to room temperature over 6 h then quenched with
ammonium chloride (3 mL), extracted with ether
(3 · 5 mL), washed with brine (5 mL), dried over mag-
d
178.9, 178.0, 171.9, 167.3, 137.7, 129.2, 91.3,

Z. C. Etheridge, S. Caddick / Tetrahedron: Asymmetry 15 (2004) 503–507
507
91.2, 87.6, 81.2, 78.5, 75.3, 55.4, 54.9, 31.1, 29.3, 28.6,
References and notes
17.0, 10.1. m=z (EI) 476 (M)C4H8). HRMS (CI)
calculated for C29H44O9N (M+NH4) 550.3016. Found
550.3016.
1. For isolation, characterisation and synthesis of Neocarzi-
nostatin: Ishida, N.; Miyuzaki, K.; Kumagi, K.; Riki-
maru, M. J. Antibiot. 1965, 18, 68; Goldberg, I. H.;
Strydom, D. J.; Holmquist, B.; Napier, M. A. Biochem.
Biophys. Res. Com. 1979, 89, 635; Edo, K.; Mizugaki, M.;
Koide, Y.; Seto, H.; Furihata, K.; Otake, N.; Ishida, N.
Tetrahedron Lett. 1985, 26, 331; Myers, A. G.; Proteau, P.
J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212;
Myers, A. G.; Liang, J.; Hammond, P. M.; Wu, Y.; Kuo,
E. Y. J. Am. Chem. Soc. 1998, 120, 5319; For isolation of
Kedarcidin: Leet, J. E.; Schroeder, D. R.; Hofstead, S. J.;
Golik, J.; Colson, K. L.; Huang, S.; Klohr, S. E.; Doyle, T.
W.; Matson, J. A. J. Am. Chem. Soc. 1992, 114, 7946; For
isolation of Trehazolin: Ando, O.; Satake, H.; Itoi, K.;
Sato, A.; Nakajima, M.; Takahashi, S.; Haruyama, H. J.
Antibiot. 1991, 44, 1165; For isolation of Terrein: Rai-
strick, H.; Smith, G. Biochem. J. 1935, 29, 606.
2. For some recent examples see: Siddiqi, S. M.; Schneller,
S. W.; Ikeda, S.; Snoeck, R.; Andrei, G.; Balzarini, J.; De
Clercq, E. Nucleos. Nucleot. 1993, 12, 185; Johnson,
C. R.; Nerurkar, B. M.; Golebiowski, A.; Sundram, H.;
Esker, J. L. J. Chem. Soc., Chem. Commun. 1995, 1139;
Ogasawara, K.; Muto, R. Tetrahedron Lett. 2001, 42,
4143; Moon, H. R.; Choi, W. J.; Kim, H. O.; Jeong, L. S.
Tetrahedron: Asymmetry 2002, 13, 1189; Jin, Y. H.; Chu,
C. K. Tetrahedron Lett. 2002, 43, 4141.
3.3. 1-(para-Methoxy)phenoxy-5-tbutoxy-penta-1,4-
dien-3-one 7
To ( )-1 (0.19 g, 1.12 mmol) stirring in THF (8 mL) was
added PPh3 (0.44 g, 1.68 mmol) followed by 4-meth-
oxyphenol (0.209 g, 1.68 mmol). The reaction mixture
wascooled to 0 ꢁC and DIAD (0.264 mL, 1.34 mmol)
added. The reaction mixture wasallowed to warm
slowly to room temperature over 16 h then concentrated
in vacuo. Column chromatography eluting with 10%
EtOAc/PE resulted in a yellow oil (0.042 g, 14%). Rf
(20% EtOAc/PE) 0.46. mmax (cmÀ1) 2974, 2929, 1727
(C@O), 1502 (C@C). 1H NMR (300 MHz, CDCl3) d
7.77 (1H, d, J ¼ 11:7), 7.73 (1H, d, J ¼ 12:1), 7.0 (2H, d,
J ¼ 9:1), 6.88 (2H, d, J ¼ 9:1), 5.89 (1H, d, J ¼ 12:1),
5.79 (1H, d, J ¼ 11:7), 3.80 (3H, s), 1.38 (9H, s). 13C
NMR (75 MHz, CDCl3) d 189.3, 158.9, 158.0, 157.1,
150.3, 119.6, 115.2, 111.0, 108.0, 80.6, 56.1, 28.6. m=z
(FAB) 277 (M+H). HRMS (ES) calculated for
C16H21O4 (M+H) 277.1440. Found 277.1444.
3. Hirama, M.; Oishi, T.; Iguchi, S.; Toyama, K. Synlett
1995, 1243.
4. Zwanenburg, B.; Klunder, A. J. H.; Houwen-Claassen,
A. A. M. Tetrahedron 1990, 46, 2593.
5. Hoffmann, H. M. R.; Kolb, H. C. Tetrahedron: Asym-
metry 1990, 1, 237.
6. Taylor, R. J. K.; McAllister, G. D. Tetrahedron Lett. 2001,
42, 1197.
7. Caddick, S.; Khan, S. J. Chem. Soc., Chem. Commun.
1995, 1971.
Acknowledgements
8. Caddick, S.; Cheung, S.; Doyle, V. E.; Frost, L. M.;
Soscia, M. G.; Delisser, V. M.; Williams, M. R. V.;
Etheridge, Z. C.; Khan, S.; Hitchcock, P. B.; Pairaudeau,
G.; Vile, S. Tetrahedron 2001, 57, 6295.
9. Luche, J. L.; Rodriguez-Hahn, L.; Crabbe, P. J. Chem.
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We gratefully acknowledge the financial support of the
EPSRC, BBSRC and AICR. We also acknowledge
GSK, AstraZeneca and Novartis. We also thank the
EPSRC Mass Spectrometry Service at Swansea and Drs.
Abdul-Sada, Tony Avent and Hitchcock for their con-
tribution to thiswork. We also thank Amano for the gift
of enzymes.
10. Harmata, M.; Lee, D. R. J. Am. Chem. Soc. 2002, 124,
14328.