Total synthesis of (+)-pramanicin and stereochemical elucidation of the natural product

Article abstract of DOI:10.1039/a807988i

Total synthesis of(+)-pramanicin is achieved through a 'one pot' Michael addition of an aminosilyl zincate species to an α,β-unsaturated lactam and quenching of the resultant enolate with an α,β-unsaturated γ,δ-epoxy aldehyde.

Full text of DOI:10.1039/a807988i

Total synthesis of (+)-pramanicin and stereochemical elucidation of the natural
product
Anthony G. M. Barrett,*a John Head,b Marie L. Smitha and Nicholas S. Stocka
a Department of Chemistry, Imperial College of Science, Technology and Medicine, South Kensington, London, UK
SW7 2AY. E-mail: m.stow@ic.ac.uk
b Celltech Therapeutics, 216 Bath Rd, Slough, Berkshire, UK SL1 4EN
Received (in Liverpool, UK) 14th October 1998, Accepted 27th November 1998
Total synthesis of (+)-pramanicin is achieved through a ‘one
pot’ Michael addition of an aminosilyl zincate species to an
a,b-unsaturated lactam and quenching of the resultant
enolate with an a,b-unsaturated g,d-epoxy aldehyde.
addition of a silyl entity (masked hydroxy group) in a conjugate
fashion to 2 and trapping of the resultant enolate with the
aldehyde 3. The addition of this silyl group should occur in an
anti fashion to the TBDMS protected hydroxymethyl pendant,
thus establishing the correct stereochemistry of the secondary
alcohol following Tamao oxidation4 (Scheme 1).
Thus, reaction of lactam 2§ with a 1:1 mixture of (diethylami-
no)diphenylsilyllithium and diethylzinc at 278 °C and trapping
of the resulting enolate with the aldehyde 3 followed by
ethanolysis of the sensitive silylamine furnished compound 4
(60%). This reaction clearly establishes the complete carbon
backbone of pramanicin with a readily oxidisable alkoxysilyl
appendage. Confirmation of the stereochemical outcome of the
silyl zincate addition has been made via addition of the
phenyldimethylsilyl5 group to lactam 2 under identical condi-
tions and removal of the protecting groups to afford 11 for
single crystal X-ray analysis¶ (Scheme 2).
(2)-Pramanicin 1, recently isolated from a fungus belonging to
the Stagonospora species, contains a highly functionalised g-
lactam-based head group with a functionalised lipophilic side
chain.1 The isolated compound shows antifungal activity
towards various fungal pathogens including Candida albicans,
Candida parapsilosis and Cryptococcus neoformans. The latter
micro-organism is responsible for meningitis infection in AIDS
patients and therefore pramanicin 1 poses an interesting target
for synthesis. Recently, Harrison and co-workers have eluci-
dated the biosynthesis of pramanicin and showed that the
carbon skeleton derives from eight acetate units and a serine
residue.2† Herein we report the total synthesis of (+)-pramani-
cin 9 which unequivocally establishes the full relative and
absolute stereochemistry of the natural product.
Oxidation of the b-hydroxy lactam 4 to the corresponding
diketone 5 could only be accomplished using Dess–Martin
periodinane as oxidant. Chromium based reagents led to
extensive decomposition and no reaction was observed using
manganese dioxide. The diketone 5 proved to be unstable to
prolonged exposure to air and to chromatography thus preclud-
Retrosynthetically, pramanicin can be divided into two
fragments, the suitably protected lactam 2 derived from -
L
glutamic acid and the side chain epoxy aldehyde 3.‡ We
envisaged that these two components could be joined via the
O
O
O
O
OH
O
H
NH
3
HO
1
OH
O
OH
OH
O
O
O
H
O
i
ii
NBoc
NBoc
NBoc
(EtO)Ph2Si
(EtO)Ph2Si
OTBDMS
5
OTBDMS
OTBDMS
2
4
iii
O
O
O
O
O
OH
O
OH
iv–vi
NBoc
NH
(EtO)Ph2Si
HO
OTBDMS
OH
6
7
OH
O
O
NBoc
O
O
H
O
OH
vii–xi
NH
(EtO)Ph2Si
HO
8
9
OTBDMS
OH
Scheme 1 Reagents and conditions: i, (Et2N)Ph2SiLi, Et2Zn, 278 °C, then 3, THF, 278 °C, then EtOH, NH4Cl, 24 h, 60%; ii, Dess–Martin periodinane,
CH2Cl2, 0 to 25 °C; iii, dimethyldioxirane, Ni(acac)2 (cat.), acetone, H2O, 0 °C, 60% from 4; iv, MCPBA (3 equiv.), KHF2 (2.5 equiv.), DMF, 0 °C, 53%;
v, SiO2,45 °C, 0.1 mmHg, 84%; vi, H2SiF6 (20–25% aq.), THF, 0 to 25 °C, 53%; vii, Dess–Martin periodinane, CH2Cl2, 0 to 25 °C; viii, dimethyldioxirane,
Ni(acac)2 (cat.), acetone, H2O, 0 °C, 59% from 8; ix, MCPBA (3 equiv.), KHF2 (2.5 equiv.), DMF, 0 °C, 70%; x, TFA, CH2Cl2, 0 to 25 °C, 78%; xi, H2SiF6
(20–25% aq.), THF, 0 to 25 °C, 55%.
Chem. Commun., 1999, 133–134
133

O
O
product and that the side chain epoxide was trans, they did not
establish the stereochemistry of the side chain relative to the
lactam entity. In their paper, pramanicin was depicted (arbi-
trarily) as ent-7. This work clearly establishes the relative
stereochemistry to be as in isomer 9. However, the optical
i
ii,iii
2
NBoc
NH
PhMe2Si
PhMe2Si
OTBDMS
OH
25
rotation of isomer 9 ([a]D +28.8, c 0.21 in MeOH) is of
11
10
25
opposite sign to that reported for authentic pramanicin ([a]D
Scheme 2 Reagents and conditions: i, PhMe2SiLi, Et2Zn, THF, 278 °C,
99%; ii, TBAF, THF, 80%; iii, TFA, CH2Cl2, 85%.
231.5, c 0.21 in MeOH) and thus indicates the absolute
stereochemistry of pramanicin to be that of 1.∑
We thank Dr R. E. Schwartz at the Merck Research
Laboratories for the generous donation of authentic pramanicin,
GlaxoWellcome Research Ltd. for the endowment (to A. G. M.
B.), the Wolfson Foundation for establishing the Wolfson
Centre for Organic Chemistry in Medical Science at Imperial
College, the Royal Society for a Dorothy Hodgkin Fellowship
(to M. L. S.), Celltech Therapeutics for their financial support
(to N. S. S.) and the EPSRC.
ing its purification. Therefore immediate oxidation of the
diketone unit with dimethyldioxirane and a nickel(II) acet-
ylacetonate6 catalyst gave hydroxy dione 6 as a single
diastereoisomer in excellent overall yield (60%). The ethoxy-
(diphenyl)silyl group blocked the top face of the diketone
directing reaction to the opposite face and thus setting the
configuration of the tertiary alcohol as required. Tamao
oxidation of silane 6 proceeded smoothly at low temperature
with MCPBA as oxidant to produce the secondary alcohol with
retention of configuration as desired. The use of peracetic acid
or hydrogen peroxide as alternative oxidants gave only
intractable mixtures of products. Removal of the Boc group via
thermolysis on silica under vacuum7 followed by deprotection
of the TBDMS moiety using fluorosilicic acid8 furnished
compound 7 (Scheme 1). Comparison of 7 with authentic
pramanicin by NMR analysis revealed very slight differences in
the chemical shift of the protons associated with the alkene and
the epoxide ring system. Alternatively, synthesis of diastereo-
isomer 8 using ent-3 as the enolate quench (62%) and
elaboration as before yielded isomer 9. This diastereoisomer 9
was identical by 1H and 13C NMR spectroscopy with authentic
pramanicin (see Fig. 1). Whilst the Merck group1 established
the relative stereochemistry of the g-lactam ring of the natural
Notes and references
† Harrison and co-workers have also published a biomimetic synthesis of
the fatty acid side chain of pramanicin in racemic form; see ref. 3.
‡ Aldehyde 3 was prepared from (E)-dodec-2-enol via Sharpless asym-
metric epoxidation, oxidation to the aldehyde using Dess–Martin period-
inane, Horner–Emmons homologation under standard conditions and
reduction of the a,b-unsaturated ester using DIBAL-H followed by
oxidation to give aldehyde 3, again employing Dess–Martin periodinane as
oxidant (55% overall)
§ Lactam 2 was prepared from pyroglutamic acid methyl ester via NaBH4
reduction to the alcohol, protection of the alcohol as the TBDMS ether and
Boc protection of the amide under standard conditions. a-Selenation
employing LDA and phenylselenyl bromide followed by syn elimination
using hydrogen peroxide and pyridine afforded lactam 2 (46% overall).
¶ Full details of the X-ray crystallographic studies on lactam 11 will be
reported elsewhere.
∑ Note added at proof: Harrison and co-workers have recently determined
the absolute stereochemisty of the lactam entity of pramanicin from
biosynthetic considerations; see ref. 9.
1 R. E. Schwartz, G. L. Helms, E. A. Bolessa, K. E. Wilson, R. A.
Giacobbe, J. S. Tkacz, G. F. Bills, J. M. Liesch, D. L. Zink, J. E. Curotto,
B. Pramanik and J. C. Onishi, Tetrahedron, 1994, 50, 1675.
2 P. H. M. Harrison, D. W. Hughes and R. W. Riddoch, Chem. Commun.,
1998, 273.
3 C. Cow, D. Valentini and P. Harrison, Can. J. Chem., 1997, 75, 884.
4 K. Tamao, N. Ishida, T. Tanaka and M. Kumada, Organometallics, 1983,
2, 1694. For a review on the oxidation of the carbon–silicon bond see
G. R. Jones and Y. Landais, Tetrahedron, 1996, 52, 7599.
5 I. Fleming, R. Henning, D. C. Parker, H. E. Plaut and P. E. J. Sanderson,
J. Chem. Soc., Perkin Trans. 1, 1995, 317.
6 W. Adam and A. K. Smerz, Tetrahedron, 1996, 52, 5799.
7 T. Apelqvist and D. Wensbo, Tetrahedron Lett., 1996, 37, 1471
8 A. S. Pilcher and P. DeShong, J. Org. Chem., 1993, 58, 5130.
9 P. Duspara, S. I. Jenkins, D. W. Hughes and P. H. M. Harrison, Chem.
Commun., 1998, 2643.
Fig. 1 1H NMR (400 MHz, CDCl3) spectra showing olefinic resonance’s
(left) and protons a to epoxide (d ~ 1.6, right); top: diastereoisomer 7;
middle: diastereoisomer 9; bottom: authentic pramanicin.
Communication 8/07988I
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Chem. Commun., 1999, 133–134