Synthesis of model ring systems related to C10-C18 analogues of the mycalamides/theopederins

Article abstract of DOI:10.1016/j.tetlet.2003.11.141

Conjugate addition to D-galactose-derived pyranones 8 and 10, with in situ enolate alkylation, or protonation, provides pyranones 11-13 or 16-19. These are related to the C10-C18 fragment of the mycalamides and provide a short entry to C10, C11, C14 and C

Full text of DOI:10.1016/j.tetlet.2003.11.141

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1215–1217
Synthesis of model ring systems related to C10–C18 analogues
of the mycalamides/theopederinsq
John M. Gardiner,* Richard Mills and Thomas Fessard
Department of Chemistry, UMIST, PO Box 88, Manchester M60 1QD, UK
Received 8 January 2003; revised 21 November 2003; accepted 28 November 2003
Abstract—Conjugate addition to D-galactose-derived pyranones 8 and 10, with in situ enolate alkylation, or protonation, provides
pyranones 11–13 or 16–19. These are related to the C10–C18 fragment of the mycalamides and provide a short entry to C10, C11,
C14 and C15 stereocentres. This approach is relevant to introduction of the side-chain and analogues thereof, and allows for
variable C14 functionality. Two side-chain analogues, both C14 monomethylated diastereomers, the C14 unsubstituted system and
the natural product-related C14 dimethyl functionality are prepared, and C13 epimeric functionality introduced.
Ó 2003 Elsevier Ltd. All rights reserved.
Sponges of the genus Mycale and Theonella, have yiel-
ded a range of potently bioactive compounds sharing an
unusual ring system, constituting the mycalamides (e.g.,
1 and 2),1a theopederins (extended and/or lactol/lactone
containing side-chains)1b and Onnamide A (15-carbon
guanidine-terminated side-chain).1c Their ring system is
closely related to pederin1d (from the terrestrial blister
beetle, Paederus fuscipes), which lacks the methylene
acetal ring B and has a C13 hydroxyl group. The
mycalamides show strong in vivo antiviral activity,2a
potent inhibition of DNA and protein biosynthesis,
promising antitumour activity (low nanomolar),2b;c and
show powerful immunosuppressant activities, with
comparable or better in vitro efficacy than cyclosporin
A, rapamycin or FK506.2d
OR
OH
16
14
MeO
O
O
OH
H
C
O
10
N
OMe
13
A
B
O
O
1 Mycalamide A (R=H)
2 Mycalamide B (R=Me)
OH
OH
MeO
OH
CO2H
O
O
H2N
OMe
O
O
3
4
There have been several total or partial syntheses of the
mycalamides, pederin and theopederin systems reported
since 1990.3 Poor diastereocontrol on dihydroxylation
of C17,C18 alkene precursors (even using matched AD)
has been a recurrent problem. Retrosynthetic discon-
nection provides components, 3 and 4 (Scheme 1). The
aminal function at C10 has been introduced previously
either through azidation of the C10 lactol (via the C10
carboxylate)3b;c;d and subsequent separation, or through
Scheme 1.
Curtius rearrangement from the C10 carboxylate.3e;f;h
Carbamate protected variants of 4 have proven invalu-
able in completing assembly of the ÔleftÕ and ÔrightÕ hand
fragments and analogues.3e;h
Targeting modified analogues is encouraged by natural
product degradation studies showing various groups can
be altered while retaining biological activity,4 and by the
structural diversity of bioactive natural products. Sev-
eral ring C and side-chain-modified unnatural analogues
have also been reported.5
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.11.141
* Corresponding author. Tel.: +44-161-200-4530; e-mail: john.gardiner
@umist.ac.uk
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.141

1216
J. M. Gardiner et al. / Tetrahedron Letters 45 (2004) 1215–1217
Our particular aims were to develop methodology
applicable to new structural analogues at C13, C14 and
the side-chain terminus of the mycalamide system.
Conjugate additions to 8 and 10 were first evaluated
using butyl cuprates. Treatment of pyranone 8 with
the dibutyl cuprate n-Bu2Cu(CN)Li2 (or n-Bu2Cu-
(CN)(MgCl)2), with proton quench, gave 11.
We envisaged that the C15–C16 C–C bond could be
introduced by stereoselective conjugate addition on a
precursor pyranone with in situ trapping (at C14) of the
intermediate enolate. This maps 4 back to a pyranone of
Trapping of the intermediate enolate with MeI gave 12.
The relative stereochemistry of 11 and 12 was estab-
lished from coupling constants and NOED analyses.
Conjugate addition to 10, with concomitant enolate
trapping using methyl iodide, afforded 13. Reduction of
13 with sodium borohydride gave a single diastereoiso-
meric alcohol (89% yield), which was methylated (NaH,
MeI) to yield 14, a dideoxy homologue of the C ring
functionality (C13 relative stereochemistry epimeric).
type 5, suggesting
D-galactose as starting material
(Scheme 2). This approach should allow entry to the
natural gem-dimethyl system (using 5, R1 ¼ Me, trap-
ping with methyl electrophile) and also to various
potential side chain and C14 analogues not readily
available by other means, by simply changing one or
more of the conjugate nucleophile, the nature of R1 on
the substrate, and on the enolate trapping employed.
This would also avoid the use of AD on a terminal
(allyl) C17,C18 alkene. (Late stage elaboration at C11 to
intercept known intermediates is envisaged.)
A quite direct entry to the mycalamide side-chain would
be conjugate addition to 10 of a protected diol-con-
taining nucleophile, or some precursor, which could
avoid the AD of terminal unsubstituted alkene inter-
mediates. Thus, copper-catalysed conjugate addition of
2-(1,3-dioxan-1-yl)ethylmagnesium bromide to 8 and 10
proceeded smoothly, and in both cases the reaction
could be quenched by addition of a proton, or by
trapping in situ with methyl iodide (Scheme 4), giving all
C14 isomeric options, 16–19. The acetal was envisaged
as precursor to C17-deoxy analogues, and also to enol
ether systems as better substrates for double diastereo-
control using AD methods. Reduction of 16–19 with
sodium borohydride gave a single product alcohol,
whose relative stereochemistry was established in the
case of 20 and the derived methyl ether 21 by NMR.9
We intended to use non-acyl protection of the hydroxyls
of the conjugate acceptors 5. Thus, 3,4,6-tri-O-acetyl-
galactal 6 was directly converted to the tri-O-benzyl-
D
-
-
D
galactal derivative 7 using NaOH and BnCl under phase
transfer conditions (Scheme 3).6 Treatment of 7 with
iodobenzene diacetate provided (2R,3S)-3-(benzyloxy)-
2-((benzyloxy)methyl)-2,3-dihydro-pyran-4-one
8
in
good yield.7 Pyranone 8 was converted into methylated
analogue 10 by conversion to iodide 9 and then methyl
insertion using tetramethyltin, CuI, AsPh3 and
PdCl2(PhCN)2 in NMP.8 This methylated analogue
provides a second conjugate addition substrate amen-
able to accessing the gem-dimethyl C14 functionality of
the natural products. A range of side-chain variants and
alternative substituents at C14 could be introduced via
intermediates 8 and 10.
This establishes that C3 epimers of the natural product
can be provided (alternative choice of reducing agent in
directing analogous reductions to the natural product
C3 configuration is also well known).3b–d;g;h Deprotec-
tion of the acetal provided aldehyde 22. This interme-
diate is a precursor to reduction to a C17-deoxy
analogue of the mycalamide 1,2-dihydroxy side-chain,
or potentially to AD of the derived enol ether for
introduction of C17,C18 hydroxylation, or elaboration
to other side-chain analogue syntheses.
OH
R1
OH
O
O
4
O
OH
Elaboration of the C10 hydroxymethyl group to higher
oxidation level would provide a route to intercept
methods used by others3 to provide the aminoacetal
function of 4. The current approach is also amenable to
OR OR
OH OH
5
D-galactose
Scheme 2. Retrosynthesis from 4.
Me
O
I
O
O
O
O
b
d
c
41%
65%
60%
OR
O
O
OBn OBn
OR OR
OR OR
OBn OBn
6 R=Ac
8
9
10
a
45%
7 R=Bn
R2
R
n-Bu
Me
e
e
O
R1
30-50%
f, g
89%
30-50%
O
Me
OMe
14
11 R=R1=H, R2=n-Bu
12 R=Me, R1=H, R2=n-Bu
13 R=R1=Me, R2=n-Bu
O
OBn OBn
OBn OBn
Scheme 3. Reagents and conditions: (a) 50% aq NaOH, t-BuOH, n-Bu4NHSO4, BnCl, C6H6; (b) PhI(OAc)2, p-TsOH, MeCN; (c) I2, Py, CCl4; (d)
Me4Sn, PdCl2(PhCN)2, CuI, AsPh3, NMP; (e) n-Bu2Cu(CN)Li2 then NH4Cl or MeI, HMPA; (f) NaBH4, MeOH; (g) NaH, MeI.

J. M. Gardiner et al. / Tetrahedron Letters 45 (2004) 1215–1217
1217
O
O
O
O
O
17
R1
O
R
a
d
R
R
b
O
R1
O
R1
O
R1
O
30-50%
70%
60-70%
13
O
10
OR2
OMe
OBn OBn
OBn OBn
OBn OBn
OBn OBn
8
R1=H
10 R1=Me
16 R=H, R1=H
17 R=H, R1=Me
18 R=Me, R1=H
19 R=R1=Me
20 R2=H
22
c
21 R2=Me
Scheme 4. Reagents and conditions: (a) 2-(1,3-dioxan-1-yl)ethylmagnesium bromide, CuCN then NH4Cl or MeI, HMPA; (b) NaBH4, MeOH; (c)
NaH, MeI, (d) CSA, H2O.
(d) Galvin, F.; Freeman, G. J.; Razi-Wolf, Z.; Bencerraf, B.;
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Kishi, Y. J. Org. Chem. 1990, 55, 4242–4245; (c) Hong,
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W. Tetrahedron Lett. 1995, 36, 1581–1584; (f) Breitfelder,
S.; Schlapbach, A.; Hoffmann, R. W. Synthesis 1998, 468–
478; (g) Kocienski, P.; Narquizian, R.; Raubo, P.; Smith,
C.; Boyle, F. T. Synlett 1998, 869–872; (h) Kocienski, P.;
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elaborating the C15-branched side-chain towards fur-
ther novel analogues.
In summary, the conjugate addition trapping is viable
for a short entry to precursors to the right-hand side unit
of the natural products and specifically to C14 variants,
and the chemistry should be amenable to a further range
of C13, C14 and side-chain analogues. The C15 stereo-
chemistry can be introduced with high control, and with
concurrent flexibility for structural and stereochemical
variations at C14. This route provides access to either
diastereomeric C14 monomethyl functionality, or to the
nonmethylated system (as these are analogues unavail-
able by degradation/semi-synthesis or in most other
syntheses, in such a divergent way), and affords the C13
epimer of the natural stereochemistry (already intro-
duced by others).
4. (a) Thompson, A. M.; Blunt, J. W.; Munro, M. H. G.;
Perry, N. B. J. Chem. Soc., Perkin Trans. 1 1995, 1233–
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6. Chmielewski, M.; Fokt, I.; Grodner, J.; Grynkiewicz, G.;
Szeja, W. J. Carbohydr. Chem. 1989, 8, 735–744 (45% yield
of 7 over 4 days, with both 4,6-di-O-benzyl- and 3,6-di-O-
benzyl-d-galactal formed).
Acknowledgements
We thank EPSRC for studentship 94310715 (to R.M.),
Dr. Robin Pritchard (UMIST) for X-ray structure
analyses (9 and 10) and Bruker UK for obtaining
500 MHz COSY and GOESY NMR analyses of 20 and
21. Some NMR and IR characterisation used instru-
mentation funded through EPSRC grants GR/L52246
(NMR), GR/M30135 (IR).
7. The structures of both 9 and 10 were unambiguously
confirmed by X-ray structure analyses. CCDC22630 and
CCDC226231 contain the supplementary crystallographic
data for this paper. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.
html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033; e-mail: deposit@
ccdc.cam.ac.uk).
8. (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113,
9585–9595; (b) Johnson, C. R.; Adams, J. P.; Braun, M.
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922; (c) Bellina, F.; Carpita, A.; Ciucci, D.; De Santis, M.;
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