Synthesis of pyrenolide D analogues

Article abstract of DOI:10.1055/s-2008-1077976

We present a short, enantiospecific synthesis of four hydroxylated analogues of pyrenolide D from D-glucose based on furan oxidative spirocyclisation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1077976

LETTER
2083
Synthesis of Pyrenolide D Analogues
P
yrenolide
e
D Analog
rues emy Robertson,* Kiri Stevens, Sébastien Naud
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK
Fax +44(1865)285002; E-mail: jeremy.robertson@chem.ox.ac.uk
Received 28 April 2008
Dedicated to Professor Sir Jack Baldwin, FRS on the occasion of his 70th birthday
Abstract: We present a short, enantiospecific synthesis of four hy-
droxylated analogues of pyrenolide D from D-glucose based on fu-
ran oxidative spirocyclisation.
O
Li
O
O
O
O
Me
Me
O
O
Key words: butenolides, furans, lactones, oxidations, spiro com-
pounds
HO
O
Me
Me
S
O
O
O
6
O
The structure of a new metabolite of Pyrenophora teres,
pyrenolide I, was first reported in 19881 following a sur-
vey of fungal metabolites that induce abnormal hyphal
morphology in Cochliobolus lunatus. This structure was
later refined, the compound renamed pyrenolide D (1,
Figure 1), and further bioactivity data reported (cytotoxic
to HL-60 cells, IC50 4 mg mL–1).2 To date, there has been
a single total synthesis of pyrenolide D, by Gin and co-
workers, who reported an efficient eleven-step route from
tri-O-acetyl-D-galactal.3 In this Letter we outline a com-
parably short route to four stereoisomeric pyrenolide D
analogues (2–5) that are potential synthetic precursors to
pyrenolide D itself.
Scheme 1
O[P′]
H
X
O
O
Y
O[P]
O
O
OH
HO
O[P]
O
H
O
X = H, OH
[P],[P′] = protecting groups
Y = Me, OH
2-furyllithium
Me
Me
O
O
H
O
O
O
O
H
O
Me
Me
Me
Me
O
O
HO
[P]O
8
7
H
H
H
10
Me
HO
7
HO
O
O
O
O
1
2
9
8
5
OH
O
OH
3
Scheme 2
5
6
4
3
7
2
8
6
4
O
9
O
O
1
OH
OH
OH
O
H
O
H
H
dehyde (of general structure 7). This overall approach is
summarised retrosynthetically in Scheme 2.
O
O
1, pyrenolide D
2, 5-α-OH
4, 5-β-OH
3, 5-α-OH
5, 5-β-OH
Knapp’s group published details of a synthesis of the allo-
diastereomer of compound 7, bearing a tert-butyldiphen-
ylsilyl substituent;9 however, we were unsuccessful in ap-
plying this procedure to the synthesis of the required
glucose derivative {7, [P] = TBDPS}; the diol cleavage to
release the aldehyde was not a clean reaction, and the al-
dehyde was somewhat unstable towards chromatography
on silica. For this reason, we progressed the route through
the known PMB ether (9,10 Scheme 3) and, after selective
hydrolysis of the 5,6-acetonide, application of Shing’s
mild conditions11 for diol cleavage led to aldehyde 1012 in
almost quantitative yield from diacetone glucose (8).
Figure 1 Numbering conventions for pyrenolide D and analogues
2–5
In designing our current route to the tricyclic framework
of pyrenolide D we intended to develop further the
peracid-mediated spirocyclisation of 2-(w-hydroxyalkyl)-
furans that we had employed in the synthesis of the spiro-
acetal core of the lituarines.4 This process has its concep-
tual roots in Bohlmann’s studies on spirocyclic bis(acety-
lene) enol ethers5 and many variants on this theme have
appeared in the intervening period.6 With this in mind, the
problem reduces to the union of a ‘carbohydrate fragment’
and furan. Preliminary attempts7 to achieve this union
through direct alkylation of a xylose-derived cyclic sul-
fate (6,8 Scheme 1) with 2-furyllithium were unsuccessful
so we selected an addition to the much more reactive al-
The addition of 2-furyl organometallics to similar alde-
hydes has been reported to proceed in moderate to good
yields in varying diastereomeric ratio.13 In our hands ad-
dition of 2-furyllithium at –78 °C formed two diaste-
reomers (11 and 12) that were isolated in ca. 1:1.4 ratio
(see below for stereochemical assignment). We were
pleased to find that oxidative removal of the PMB group
proceeded cleanly, without interference by the furan
SYNLETT 2008, No. 14, pp 2083–2086
2
2
.0
8
.2
0
0
8
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077976; Art ID: D13608ST
© Georg Thieme Verlag Stuttgart · New York

2084
J. Robertson et al.
LETTER
ring,14 and the stage was set to effect oxidative spirocycli- acetonitrile, or 4 M hydrochloric acid in THF but more
sation under our standard conditions.4
forcing conditions (8 M hydrochloric acid or hydrochloric
acid–methanol mixtures at reflux) led to decomposition.
Addition of an excess of MCPBA to a dichloromethane
solution of hydroxyalkyl furans 13 or 14 resulted in rapid Various concentrations of aqueous TFA, with or without
consumption of the starting material but oxidation up to a co-solvent, have been used for 1,2-acetonide deprotec-
the butenolide level barely progressed, even after 72 tions in furanose substrates and, for example, use of a 50%
hours; therefore, the reactions were stopped at the inter- solution was employed for an intransigent fluorinated
mediate lactol stage (not shown) and the products imme- substrate which, nevertheless, took three days to reach
diately taken up with PDC in DMF. In each case the completion.18 However, application of similar conditions
butenolides (15, 16) were obtained as a mixture of separa- to compounds 15 and 16 gave incomplete reactions, isom-
ble spiro-diastereomers with the major isomers (15a, 16b) erisation at the spiro-centre, and significant decomposi-
shown to have the butenolide ring oxygen anti-disposed to tion. Fortunately, acceptable deprotections were even-
the TBSO substituent. The diagnostic NOE difference and tually achieved with an aqueous HF–acetonitrile mix-
2D-NOESY correlations shown in Figure 2 were used to ture;19 although the isolated yields were moderate at best,
support the stereochemistry depicted for diastereomeric the final products (2–5, Scheme 4) could be readily isolat-
furan adducts 11 and 12 and all subsequent compounds. In ed and the spiro-centre stereochemistry appeared to be un-
addition, the structure of intermediate 16b was secured by affected.
X-ray crystal structure analysis, details of which will be
described elsewhere.
H
H
H
R
O
R
O
H
O
O
H
H
O
O
Me
Me
Me
Me
Me
Me
O
O
O
O
O
O
H
OHC
O
H
O
H
O
(i)
(ii),(iii)
95%
O
O
8
O
O
15a
15b
O
Me
Me
98%
Me
Me
O
O
PMBO
OH
O
O
weak or absent
PMBO
OH
10
9
H
H
H
R
O
R
O
H
O
O
H
H
H
H
O
O
O
O
(iv)
O
O
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
O
O
O
PMBO
O
H
O
H
PMBO
O
O
16a
16b
11, 34%
12, 48%
(v) 82%
(vi) 87%
(v) 74%
(vi) 80%
Figure 2 Diagnostic NOE(SY) data for diastereomers of 15 and 16
TBSO
TBSO
H
HO
H
H
O
OH
O
O
aq HF, MeCN
48–84 h
O
O
15, 16
Me
Me
Me
Me
O
O
O
OH
O
O
O
H
HO
HO
13
14
O
2, 29% 3, 44%
4, 29% 5, 42%
(vii) 79%
(vii) 90%
Scheme 4
H
H
TBSO
O
TBSO
O
O
O
O
O
In summary, this route makes effective use of the furan
oxidative spirocyclisation to provide fully functionalised
pyrenolide D analogues in just eight steps from diacetone
glucose (8). A description of our efforts to achieve a total
synthesis of pyrenolide D, using this route and others, plus
relevant bioassay results will follow in due course.
Me
Me
Me
Me
O
O
O
O
H
H
O
O
15a,b (5.6:1)
16a,b (1:35)
Scheme 3 Reagents and conditions:15 (i) NaH, PMBCl, Bu4N+I–,
THF, 72 h; (ii) AcOH (70%, aq), 24 h; (iii) NaIO4–SiO2, CH2Cl2, 0.5
h; (iv) furan–BuLi, THF, –78 °C, 1 h then r.t.; (v) TBSCl, imidazole,
DMF, 16 h; (vi) DDQ, aq CH2Cl2, 3 h; (vii) MCPBA, CH2Cl2, 5–16
h then PDC, MS 4 Å, DMF, 3 h.
Data20 for 15a
Off-white solid; Rf = 0.66 (Et2O–PE, 5:1); mp 84 °C; [a]D25 +160.1
(c 1.0, CHCl3). IR (KBr): nmax = 3104 (s), 2988 (s), 2961 (s), 2935
(s), 2861 (s), 1786 (br), 1473 (s), 1462 (s), 1412 (s), 1384 (s), 1373
(s), 1250 (br), 1166 (s), 1095 (s), 1038 (s), 965 (s), 938 (s), 915 (s),
850 (br) cm–1. 1H NMR (500 MHz, CDCl3): d = 0.06 (3 H, s) and
0.14 [3 H, s, Si(CH3)2], 0.89 [9 H, s, SiC(CH3)3], 1.37 (3 H, s) and
1.51 [3 H, s, C(CH3)2], 4.39 (1 H, d, J = 4.5 Hz, H-5), 4.68 (1 H, d,
J = 4.0 Hz, H-2), 4.80 (1 H, d, J = 4.5 Hz, H-3), 4.95 (1 H, t, J = 4.5
Hz, H-4), 6.01 (1 H, d, J = 4.0 Hz, H-1), 6.17 (1 H, d, J = 5.5 Hz, H-8),
From this point it simply remained to remove both the si-
lyl and acetonide protecting groups to afford the pyreno-
lide D analogues 2–5. This proved to be a nontrivial task.
For example, application of PdCl2(MeCN)2 in (wet) ace-
tone or acetonitrile16 gave no reaction, as did 70% aque-
ous acetic acid, and aqueous fluorosilicic acid in tert-
butanol.17 Selective removal of the silyl group could be
achieved with TBAF in THF, aqueous fluorosilicic acid in
Synlett 2008, No. 14, 2083–2086 © Thieme Stuttgart · New York

LETTER
Pyrenolide D Analogues
Data for 3 (5.5:1 Ratio of Anomers)
2085
7.25 (1 H, d, J = 5.5 Hz, H-7). 13C NMR (125 MHz, CDCl3): d = –
5.1, –4.8, 18.3, 25.7, 27.3, 27.5, 78.0, 82.5, 84.2, 85.8, 107.3, 113.1,
115.3, 124.0, 151.3, 169.4. HRMS: m/z calcd for C18H28O7SiNa
[MNa+]: 407.1497; found: 407.1494.
17
Yellow oil; Rf = 0.19 (EtOAc–acetone, 19:1); [a]D –54.8 (c 1.0,
acetone). IR (film): nmax = 3356 (br), 2962 (s), 1949 (s), 1698 (s),
1
1087 (br) cm–1. H NMR (400 MHz, acetone-d6): d (major ano-
mer) = 4.12–4.19 (1 H, m, H-2), 4.28 (1 H, d, J = 4.5 Hz, H-5), 4.39–
4.46 (1 H, m, 2-OH), 4.72 (1 H, d, J = 5.0 Hz, H-4), 4.89 (1 H, dd,
J = 5.0, 2.0 Hz, H-3), 5.18 (1 H, d, J = 4.5 Hz, 5-OH), 5.48–5.58 (2
H, m, H-1, 1-OH), 6.33 (1 H, d, J = 6.0 Hz, H-8), 7.45 (1 H, d, J =
6.0 Hz, H-7); peaks attributable to the minor anomer were observed
at d = 5.32, 6.35, 7.51. 13C NMR (100 MHz, acetone-d6): d = 76.4,
81.3, 85.6, 91.7, 98.9, 116.5, 124.7, 151.7, 169.9. HRMS: m/z calcd
for C9H10O7Na [MNa+]: 253.0319; found: 253.0319.
Data for 15b
25
White powder; Rf = 0.54 (Et2O–PE, 5:1); mp 142 °C; [a]D –25.2
(c 1.0, CHCl3). IR (KBr): nmax = 2991 (s), 2949 (br), 2850 (s), 1770
(s), 1250 (s), 1200 (s), 1160 (s), 1095 (s), 1038 (s), 1005 (s), 940 (s)
cm–1. 1H NMR (500 MHz, CDCl3): d = 0.05 (3 H, s) and 0.13 [3 H,
s, Si(CH3)2], 0.86 [9 H, s, SiC(CH3)3], 1.36 (3 H, s) and 1.51 [3 H,
s, C(CH3)2], 4.10 (1 H, d, J = 4.5 Hz, H-5), 4.71 (1 H, d, J = 3.5 Hz,
H-2), 4.80 (1 H, d, J = 4.5 Hz, H-3), 4.85 (1 H, t, J = 4.5 Hz, H-4),
6.22 (1 H, d, J = 3.5 Hz, H-1), 6.24 (1 H, d, J = 5.5 Hz, H-8), 6.96
(1 H, d, J = 5.5 Hz, H-7). 13C NMR (125 MHz, CDCl3): d = –5.0, –4.7,
18.1, 25.5, 27.0, 27.6, 75.8, 79.9, 85.5, 86.1, 107.4, 111.1, 113.0,
126.2, 149.6, 169.3. HRMS: m/z calcd for C18H28O7SiNa [MNa+]:
407.1497; found: 407.1490.
Data for 4 (2:1 Ratio of Anomers)
21
Yellow oil; Rf = 0.31 (EtOAc); [a]D +99.0 (c 0.5, acetone). IR
(film): nmax = 3384 (br), 2961 (s), 1769 (s), 1261 (s), 1084 (s), 924
1
(s) cm–1. H NMR (500 MHz, acetone-d6): d (major anomer) =
4.15–4.20 (1 H, m, H-2), 4.22–4.26 (1H, m, H-5), 4.61 (1 H, d, J =
9.0 Hz, 2-OH), 4.70 (1 H, d, J = 5.5 Hz, H-4), 4.78 (1 H, d, J = 4.0
Hz, 5-OH), 5.25 (1 H, t, J = 5.5 Hz, H-3), 5.52 (1 H, d, J = 5.0 Hz,
H-1), 6.35 (1 H, d, J = 6.0 Hz, H-8), 6.53 (1 H, d, J = 5.0 Hz, 1-OH),
7.53 (1 H, d, J = 6.0 Hz, H-7); d (minor anomer) = 4.15–4.20 (1 H,
m, H-2), 4.22–4.26 (1 H, m, H-5), 4.47 (1 H, d, J = 6.5 Hz, 2-OH),
4.45 (1 H, d, J = 4.5 Hz, 5-OH), 4.75 (1 H, dd, J = 5.5, 3.0 Hz, H-4),
4.96 (1 H, t, J = 5.5 Hz, H-3), 5.55 (1 H, dd, J = 8.0, 4.0 Hz, H-1),
5.65 (1 H, d, J = 8.0 Hz, 1-OH), 6.33 (1 H, d, J = 5.5 Hz, H-8), 7.48
(1 H, d, J = 5.5 Hz, H-7). 13C NMR (125 MHz, acetone-d6): d (major
anomer) = 76.7, 80.5, 84.7, 91.1, 106.5, 117.5, 125.4, 152.3, 170.0;
d (minor anomer) = 76.7, 77.2, 80.0, 89.7, 101.1, 117.5, 125.4,
152.3, 170.0. HRMS: m/z calcd for C9H10O7Na [MNa+]: 253.0319;
found: 253.0315.
Data for 16a
Off-white solid; Rf = 0.65 (Et2O–PE, 5:1); mp 74 °C; [a]D19 +82.0
(c 1.0, CHCl3). IR (KBr): nmax = (KBr): 2959 (s), 2936 (s), 1776 (s),
1760 (s), 1402 (s), 1262 (s), 1215 (s), 1164 (s), 1131 (s), 1083 (s),
1042 (s), 1011 (s), 919 (s), 870 (s) cm–1. H NMR (500 MHz,
1
CDCl3): d = 0.03 (3 H, s) and 0.10 [3 H, s, Si(CH3)2], 0.87 [9 H, s,
SiC(CH3)3], 1.36 (3 H, s) and 1.51 [3 H, s, C(CH3)2], 4.25 (1 H, d,
J = 2.0 Hz, H-5), 4.71 (1 H, d, J = 3.5 Hz, H-2), 4.78 (1 H, dd, J =
4.5, 2.0 Hz, H-4), 4.95 (1 H, d, J = 4.5 Hz, H-3), 5.96 (1 H, d, J =
3.5 Hz, H-1), 6.20 (1 H, d, J = 5.5 Hz, H-8), 7.08 (1 H, d, J = 5.5
Hz, H-7). 13C NMR (125 MHz, CDCl3): d = –5.2, –5.0, 17.9, 25.5,
26.8, 27.3, 80.3, 83.3, 86.7, 88.4, 105.9, 112.7, 113.2, 125.1, 149.9,
169.1. HRMS: m/z calcd for C18H28O7SiNa [MNa+]: 407.1497;
found: 407.1494.
Data for 5 (5:1 Ratio of Anomers)
Yellow oil; Rf = 0.16 (EtOAc–acetone, 19:1); [a]D +7.8 (c 0.5,
22
Data for 16b
acetone). IR (thin film): nmax = 3385 (br), 2961 (s), 2926 (s), 1765
(s), 1261 (s), 1082 (s), 1025 (s) cm–1. 1H NMR (500 MHz, acetone-
d6): d (major anomer) = 3.98 (1 H, d, J = 12.0 Hz, 5-OH), 4.16–4.20
(1 H, m, H-2), 4.32 (1 H, dd, J = 12.0, 5.0 Hz, H-5), 4.53 (1 H, d, J
= 5.5 Hz, 2-OH), 4.70 (1 H, dd, J = 5.0, 1.5 Hz, H-3), 4.80 (1 H, t,
J = 5.0 Hz, H-4), 5.47 (1 H, d, J = 8.0 Hz, 1-OH), 5.66 (1 H, dd, J =
8.0, 4.0 Hz, H-1), 6.30 (1 H, d, J = 5.5 Hz, H-8), 7.34 (1 H, d, J =
5.5 Hz, H-7). 13C NMR (125 MHz, acetone-d6): d = 75.8, 77.2, 78.1,
89.0, 99.6, 112.5, 125.4, 152.8, 170.9. HRMS: m/z calcd for
C9H10O7Na [MNa+]: 253.0319; found: 253.0315.
25
White powder; Rf = 0.72 (Et2O–PE, 5:1); mp 102 °C; [a]D –85.7
(c 1.0, CHCl3). IR (KBr): nmax = 2987 (s), 2944 (br), 2866 (s), 1780
(br), 1389 (s), 1289 (s), 1261 (s), 1234 (s), 1165 (s), 1131 (s), 1107
(s), 1083 (s), 1046 (s), 1007 (s), 917 (s), 871 (s) cm–1. 1H NMR (500
MHz, CDCl3): d = 0.07 (3 H, s) and 0.13 [3 H, s, Si(CH3)2], 0.91 [9
H, s, SiC(CH3)3], 1.36 (3 H, s) and 1.52 [3 H, s, C(CH3)2], 4.30 (1
H, s, H-5), 4.71 (1 H, d, J = 3.5 Hz, H-2), 4.74 (1 H, d, J = 4.5 Hz,
H-4), 5.01 (1 H, d, J = 4.5 Hz, H-3), 6.12 (1 H, d, J = 3.5 Hz, H-1),
6.24 (1 H, d, J = 5.5 Hz, H-8), 7.23 (1 H, d, J = 5.5 Hz, H-7). 13
C
NMR (125 MHz, CDCl3): d = –2.2, 1.3, 18.0, 25.7, 26.8, 27.5, 81.9,
84.4, 87.8, 88.6, 107.1, 113.0, 115.7, 124.9, 150.3, 169.5. HRMS:
m/z calcd for C18H28O7SiNa [MNa+]: 407.1497; found: 407.1486.
Acknowledgment
We are grateful to the European Union for a Marie Curie Fellowship
(MEIF-CT2006-039126 to SN), and to Drs B. Odell and T. D. W.
Claridge for their assistance with NMR analysis. We also thank Dr.
E. A. Anderson for suggesting the deprotection conditions that were
successful in providing compounds 2–5, and Andrew Tyrrell for ob-
taining X-ray confirmation of the structure of compound 16b.
Data for 2 (2:1 Ratio of Anomers)
Yellow oil; Rf = 0.25 (EtOAc–acetone, 19:1); [a]D +56.2 (c 0.5,
17
acetone). IR (film): nmax = 3386 (br), 2960 (s), 1773 (s), 1260 (s),
1090 (br), 689 (s) cm–1. 1H NMR (500 MHz, acetone-d6): d (major
anomer) = 4.20 (1 H, d, J = 4.5 Hz, H-2), 4.60 (1 H, d, J = 4.5 Hz,
2-OH), 4.64 (1 H, dd, J = 8.0, 4.0 Hz, H-5), 4.69 (1 H, d, J = 6.5 Hz,
H-3), 4.80 (1 H, d, J = 8.0 Hz, 5-OH), 4.85 (1 H, dd, J = 6.5, 4.0 Hz,
H-4), 5.41 (1 H, d, J = 4.0 Hz, H-1), 5.54 (1 H, d, J = 4.0 Hz, 1-OH),
6.29 (1 H, d, J = 5.5 Hz, H-8), 7.36 (1 H, d, J = 5.5 Hz, H-7); d (mi-
nor anomer) = 4.10–4.14 (1H, m, H-2), 4.29 (1 H, d, J = 7.0 Hz, 2-
OH), 4.36 (1 H, dd, J = 8.0, 3.5 Hz, H-5), 4.73–4.78 (2 H, m, H-3,4),
4.90 (1 H, d, J = 8.0 Hz, 5-OH), 5.44 (1 H, dd, J = 7.0, 4.0 Hz, H-1),
5.63 (1 H, d, J = 7.0 Hz, 1-OH), 6.31 (1 H, d, J = 5.5 Hz, H-8), 7.45
(1 H, d, J = 5.5 Hz, H-7). 13C NMR (125 MHz, acetone-d6): d (major
anomer) = 80.6, 81.4, 89.3, 89.4, 106.3, 114.5, 125.9, 152.0, 170.4;
d (minor anomer) = 77.1, 80.0, 85.2, 88.7, 100.4, 115.1, 125.9,
151.8, 170.3. HRMS: m/z calcd for C9H10O7Na [MNa+]: 253.0319;
found; 253.0316.
References and Notes
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(4) Robertson, J.; Meo, P.; Dallimore, J. W. P.; Doyle, B. M.;
Hoarau, C. Org. Lett. 2004, 6, 3861.
Synlett 2008, No. 14, 2083–2086 © Thieme Stuttgart · New York

2086
J. Robertson et al.
LETTER
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(15) All reactions were run at 20 °C except where stated.
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(20) NMR assignments are numbered according to carbohydrate
conventions (as Figure 1). Only strong or characterising IR
peaks are given.
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