A concise enantioselective total synthesis of rhizoxin D

Article abstract of DOI:10.1016/S0040-4039(01)02154-2

A new and convergent synthesis of the antitumour macrolide rhizoxin D 2 is described. The synthesis features a Wadsworth-Emmons olefination and a facile intramolecular Stille reaction to elaborate the 16-membered macrocyclic core 5 from the vinyl iodide 3

Full text of DOI:10.1016/S0040-4039(01)02154-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 493–497
A concise enantioselective total synthesis of rhizoxin D
Ian S. Mitchell, Gerald Pattenden* and Jeffrey P. Stonehouse
School of Chemistry, The University of Nottingham, Nottingham NG7 2RD, UK
Received 15 October 2001; accepted 8 November 2001
Abstract—A new and convergent synthesis of the antitumour macrolide rhizoxin D 2 is described. The synthesis features a
Wadsworth–Emmons olefination and a facile intramolecular Stille reaction to elaborate the 16-membered macrocyclic core 5 from
the vinyl iodide 3 and the vinyl stannane 4 as key steps. © 2002 Elsevier Science Ltd. All rights reserved.
Rhizoxin 1 is a novel macrolide isolated from the
pathogenic fungus Rhizopus chinensis,1 which shows
powerful antitumour and antifungal activity.2 Indeed,
the compound has now undergone extensive clinical
trials as a potential drug candidate.3 Rhizoxin D 2 is a
congener of rhizoxin 1 from R. chinensis4 and this
didesepoxy compound is the likely biogenetic precursor
of 1. The rhizoxins have attracted considerable interest
within the synthetic chemistry community,5 and a total
synthesis of rhizoxin 1,6 together with four total synthe-
ses of rhizoxin D 2,7 have been published. We now
describe a new enantioselective synthesis of rhizoxin D
2 which features a facile intramolecular Stille coupling
reaction as the key step.
Thus, an Evans aldol reaction between (R)-4-benzyl-3-
propionyloxazolidin-2-one8 and the known a,b-unsatu-
rated aldehyde 69 first gave the corresponding imide 7,
as a single diastereoisomer, in 85% yield. The imide 7
was next converted into the aldehyde 9 in three
straightforward steps via the intermediate alcohol 8
(Scheme 2). A Mukaiyama aldol reaction between the
aldehyde 9 and the silyl enol ether 1010 at −78°C, under
chelation-control, using AlMe2Cl as the Lewis acid,11
then gave the aldol 11 with >96% diastereoselectivity
and in 81% yield. The diastereoselectivity was deter-
mined following separation of the two aldol isomers
1
and H NMR studies, in combination with comparison
of NMR data with those of the alternative diastereoiso-
Our synthetic strategy to rhizoxin D 2 was based on
elaboration of the phosphonate substituted vinyl iodide
3 and the d-lactone substituted vinyl stannane 4 frag-
ments, and their coupling leading to the core macro-
cyclic lactone 5 via a Wadsworth–Emmons olefination,
followed by an intramolecular Stille reaction as key
steps (Scheme 1).
mer which was produced from reaction of 9 with 10 in
the presence of BF3·OEt2.12 Reduction of the aldol 11
using tetramethylammonium triacetoxyborohydride
next led to the 1,3-anti diol 1213 which, in two steps,
was converted into the key phosphonate substituted
vinyl iodide 3 (Scheme 2).
The chiral d-lactone substituted vinyl stannane 4 was
prepared starting from the known a,b-unsaturated ester
14.14 Reduction of 14 to the corresponding primary
alcohol, followed by vinyl ether formation and Claisen
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02154-2

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I. S. Mitchell et al. / Tetrahedron Letters 43 (2002) 493–497
Scheme 1.
Scheme 2. Reagents and conditions: (i) Bu2BOTf, Et3N, (R)-4-benzyl-3-propionyloxazolidin-2-one, CH2Cl2, −78°C“0°C, 85%; (ii)
MeOTf, 2,6-di-tert-butyl-4-methylpyridine, CHCl3, reflux, 6 h, 84%; (iii) LiBH4, MeOH, Et2O, 0°C, 1 h, 80%; (iv) Dess–Martin,
CH2Cl2, rt, 1 h, 99%; (v) BH(NMe4)(OAc)3, AcOH, MeCN, −30°C, 18 h, 83%; (vi) TBSOTf, 2,6-lutidine, −78°C, 15 min, 77%;
(vii) diethylphosphonoacetic acid, DCC, DMAP, 0°C“rt, 2 h, 86%.
rearrangement, first gave the racemic g,d-unsaturated
aldehyde 15. An Evans aldol reaction between 15 and
(4S,5R)-4-methyl-5-phenyl-3-propionyloxazolidin-2-one
next led to a 1:1 mixture of the diastereoisomeric imides
16 and 17 in a combined 79% yield (Scheme 3). The
diastereoisomers were separated by chromatography,
and their stereochemistries followed unambiguously
from analysis of relevant coupling data in the NMR
spectra of the corresponding d-lactones, 18 and 19,
produced from them,15 viz. Jvic 7 and 6 Hz for 18; Jvic
11 and 6 Hz for 19.
underwent
a
smooth reaction with dimethyl
diazomethylphosphonate16 leading to the terminal acet-
ylene 23. The acetylene 23 was converted into the
E-vinyl stannane 2417 which was then deprotected,
followed by oxidation, leading to the aldehyde vinyl
stannane 4 (Scheme 4).
Interestingly, the diastereoisomer 17, with the ‘incor-
rect’ stereochemistry for rhizoxin, could also be con-
verted into the same 1,5-diol intermediate 21 by the
series of reactions described in Scheme 5, thereby allow-
ing recycling of this easily available precursor.
The diastereoisomer 16, with the ‘correct’ stereochem-
istry for rhizoxin, was next reduced with LiBH4 leading
to the corresponding primary alcohol, which was then
protected as its PMB ether 20. A straightforward
hydroboration–oxidation procedure converted the
alkene 20 into the 1,5-diol 21, which was then oxidised
to the d-lactone 22. Deprotection of the PMB group in
22 followed by Dess–Martin oxidation of the resulting
primary alcohol next produced an aldehyde which
A Wadsworth–Emmons olefination reaction between
the phosphonate 3 and the aldehyde 4, under Masa-
mune–Roush conditions,18 led exclusively to the E-
alkene 25 in
a pleasing 74% yield. When this
stannane–iodide 25 was treated with AsPh3–Pd(0)
dibenzylideneacetone19 in degassed DMF at 70°C for 5
h, it underwent smooth intramolecular sp2–sp2 cross-
coupling with preservation of the double bond

I. S. Mitchell et al. / Tetrahedron Letters 43 (2002) 493–497
495
Scheme 3. Reagents and conditions: (i) DIBAL-H, THF, −78°C, 1 h, 93%; (ii) EtOCHꢀCH2, Hg(O2CCF3)2, rt, 8 h, 78%; (iii)
170°C, sealed tube, 36 h, 97%; (iv) Bu2BOTf, Et3N, (4S,5R)-5-methyl-4-phenyl-3-propionyloxazolidin-2-one, CH2Cl2, −78°C“
0°C, 2 h, 79%.
Scheme 4. Reagents and conditions: (i) LiBH4, MeOH, Et2O, 0°C, 2 h, 70%; (ii) PMBO(NꢀH)CCl3, CSA, CH2Cl2, −20°C“0°C,
72 h, 60%; (iii) 9-BBN-H, 0°C“rt, 12 h, then NaOH, H2O2, 0°C, 4 h, 91%; (iv) Ag2CO3/Celite, PhH, reflux, 3 h, 91%; (v) DDQ,
CH2Cl2, rt, 2 h, 100%; (vi) Dess–Martin, CH2Cl2, rt, 1 h, 84%; (vii) (MeO)2(O)PCHN2, KOtBu, THF, −78°C, 2 h, 100%; (viii)
NBS, AgNO3, acetone, 1 h, then Pd(PPh3)4, Bu3SnH, THF, rt, 3 h, 70%; (ix) TBAF, TsOH, THF, rt, 3 h, 70%; (x) Dess–Martin,
pyr, CH2Cl2, rt, 1 h, 70%.
geometries in the precursor leading to the 16-membered
macrocyclic lactone core 5 in rhizoxin in an acceptable
48% yield (Scheme 6). Selective removal of the primary
TBDPS protecting group in 5, followed by oxidation of
the resulting allylic alcohol with MnO2 next gave the
a,b-unsaturated aldehyde 26. A Horner olefination
reaction between 26 and the oxazole substituted phos-
phine oxide 27, at −78°C in the presence of KHMDS,
next led to the all E-conjugated triene,20 which on
deprotection with HF/pyridine produced (+)-rhizoxin D
2 as a solid. The synthetic rhizoxin showed chiroptic
and NMR spectroscopic data which were identical to
those reported for the natural product.4
Acknowledgements
We thank Merck Sharp and Dohme (studentship to
I.S.M.) and the E.P.S.R.C. together with Aventis (stu-
dentship to J.P.S.) for support. We also thank Dr. D.
A. Entwistle for modelling the key Stille reaction and
G. Rescourscino for synthesising the phosphine oxide

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I. S. Mitchell et al. / Tetrahedron Letters 43 (2002) 493–497
Scheme 5. Reagents and conditions: (i) LiBH4, MeOH, Et2O, 0°C, 2 h, 96%; (ii) PMBO(NꢀH)CCl3, CSA, CH2Cl2, −20°C“0°C,
72 h, 62%; (iii) TBAF, THF, rt, 2 h, 99%; (iv) TBSCl, Imid., CH2Cl2, rt, 2 h, 82%; (v) 9-BBN-H, 0°C“rt, 12 h, then NaOH,
H2O2, 0°C, 4 h, 95%; (vi) TBDPSCl, Imid., CH2Cl2, rt, 2 h, 96%; (vii) PPTS, EtOH, 60°C, 2 h, 72%.
Scheme 6. Reagents and conditions: (i) LiCl, DBU, MeCN, 0°C“rt, 1 h, 74%; (ii) Pd2dba3, AsPh3, DMF, 70°C, 5 h, 48%; (iii)
TBAF/AcOH (1:1), THF, rt, 8 h, 74%; (iv) MnO2, CH2Cl2, rt, 3 h, 100%; (v) KHMDS, THF, −78°C“0°C, 1 h, 38%; (vi) HF/Pyr,
pyr, THF, rt, 48 h, 78%.
27. Finally, we thank Professor David Williams for
helpful correspondence and for provision of NMR
spectroscopic data for his synthetic rhizoxin D.
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