Studies in marine macrolide synthesis: Stereocontrolled synthesis of a C21-C34 subunit of the aplyronines

Article abstract of DOI:10.1016/S0040-4039(02)01217-0

The C21-C34 subunit 27 of the aplyronines, containing eight stereocentres and a terminal N-methyl-N-vinylformamide moiety, was prepared using the Horner-Wadsworth-Emmons coupling of β-ketophosphonate 5 with aldehyde 19. The two stereotetrad sequences were constructed by chiral ketone aldol reactions, while the N-methyl-N-vinylformamide was introduced using a novel Wittig olefination.

Full text of DOI:10.1016/S0040-4039(02)01217-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6005–6008
Studies in marine macrolide synthesis: stereocontrolled synthesis
of a C21–C34 subunit of the aplyronines
Ian Paterson,* Simon B. Blakey and Cameron J. Cowden
University Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
Received 27 May 2002; accepted 24 June 2002
Abstract—The C21–C34 subunit 27 of the aplyronines, containing eight stereocentres and a terminal N-methyl-N-vinylformamide
moiety, was prepared using the Horner–Wadsworth–Emmons coupling of b-ketophosphonate 5 with aldehyde 19. The two
stereotetrad sequences were constructed by chiral ketone aldol reactions, while the N-methyl-N-vinylformamide was introduced
using a novel Wittig olefination. © 2002 Elsevier Science Ltd. All rights reserved.
Aplyronine A (1, Scheme 1) is an unusual 24-membered
marine macrolide which was first isolated in 1993,
along with two congeners, aplyronines B (2) and C (3),
from the Japanese sea hare Aplysia kurodai by Yamada
and co-workers.1 The aplyronines displayed potent
cytotoxicity in vitro against a range of cancer cell lines
including P388 leukaemia, Lewis lung carcinoma and
B16 melanoma. Furthermore, aplyronine A exhibited
pronounced in vivo activity against a range of tumour
cells in xenograft experiments.1,2 Aplyronine A has been
shown to function as a novel actin depolymerising
agent,3 by accelerating fibrous actin depolymerisation
and sequestering globular actin. Recently, an actin-
dependent cell cycle checkpoint that ensures the proper
orientation of microtubule spindles during metaphase
has been uncovered by Gachet and Hyams and co-
workers,4 and although the biochemical pathway
responsible for this checkpoint is still undefined, this
may be linked to the antimitotic activity of the
aplyronines.
The potent antitumour activity and novel actin-binding
properties of the aplyronines has led to interest in
evaluating their chemotherapeutic potential,3 as well as
attracting synthetic attention towards this unique group
of marine macrolides.2,5–7 Notably, the Yamada group
established the absolute configuration by completing
the first total synthesis of aplyronines A–C.2 We have
OR2 OR1
O
1
NMe2
OAc
O
O
OMe
O
OH
O
Me
N
Aplyronine A (1), R1 =
, R2 = H
OMe
NMe2
H
MeO
23
O
34
O
Aplyronine B (2), R1 = H, R2 =
Aplyronine C (3), R1 = R2 = H
OMe
NMe2
PMP
O
O
O
1
OMe
O
OH
O
O
OTES
27
(MeO)2P
+
MeO
OTIPS
34
28
N
H
Me
4
5
Scheme 1.
* Corresponding author. Fax: +44-1223-336362; e-mail: ip100@cus.cam.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01217-0

6006
I. Paterson et al. / Tetrahedron Letters 43 (2002) 6005–6008
adopted an alternative strategy for the stereocontrolled
synthesis of the aplyronines, which is potentially shorter
and relies upon a key Horner–Wadsworth–Emmons
(HWE) coupling of a suitable C27 aldehyde, derived
from the previously described macrolide 4,5 with the
b-ketophosphonate 5 for elaboration of the side chain.
We now report a synthesis of the C28–C34 phospho-
nate 5 and demonstrate its use in the HWE-based
construction of an advanced C21–C34 fragment of the
aplyronines. The strategic decision to incorporate the
terminal N-methyl-N-vinyl formamide in subunit 5
with cis-geometry and to carry this potentially sensitive
moiety through to the closing stages of the synthesis
before isomerisation, contrasts with established
approaches in which the required trans-alkenyl for-
mamide is generally introduced by a testing, late-stage,
condensation reaction with a highly functionalised
aldehyde.2,7
with NaIO4 to give aldehyde 12 (87%). Following our
standard conditions,9 Wittig olefination of aldehyde 12
with ylide 13, generated in situ by the addition of
LiHMDS to phosphonium salt 14, proceeded smoothly
to give cis-alkene 15 in 72% yield. After PMB ether
cleavage with DDQ to give 16, the liberated C29
hydroxyl group was oxidised with catalytic TPAP and
NMO10 to give aldehyde 17 (80%). Addition of lithiated
methyl dimethylphosphonate to aldehyde 17 gave the
desired hydroxyphosphonate 18 in 72% yield. Subse-
quent oxidation, again using the TPAP/NMO protocol,
provided b-ketophosphonate 5 in nine steps and 17%
yield from ketone 6. Notably, the vinyl formamide was
carried through this sequence of reactions without com-
plication. In contrast to trans-N-methyl-N-vinyl for-
mamides, which tend to exist as mixtures of rotamers in
solution at ambient temperature, the corresponding
cis-isomers appear as a single rotamer by 1H NMR
spectroscopy. As this facilitates analysis, we decided to
retain the cis-geometry in 5 for as long as possible
through the remainder of the synthesis.
The synthesis of the C28–C34 phosphonate subunit 5,
containing the terminal N-methyl-N-vinyl formamide,
is outlined in Scheme 2. Enolisation of lactate-derived
ketone 6 using (c-Hex)2BCl/Me2NEt gave the (E)-
boron enolate 7.8 Addition of freshly prepared aldehyde
8 gave, on oxidative workup, anti-aldol adduct 9 in
94% yield with >95% diastereoselectivity. Notably, the
high level of stereoinduction exerted by the enolate
leads here to anti-Felkin attack on the a-chiral alde-
hyde. Treatment of 9 with TESOTf and 2,6-lutidine
gave TES ether 10 (92%). Reduction by LiBH4 then
furnished 1,2-diol 11 which was oxidatively cleaved
In preparation for examining the key HWE coupling
step, the C21–C27 aldehyde 19 was prepared from the
previously described aldol adduct 20 (Scheme 3).5a Sub-
jection of b-hydroxyketone 20 to Evans–Tishchenko
reduction conditions11 gave the desired monoprotected
1,3-anti diol 21. HF·pyridine mediated removal of the
TIPS ether then gave diol 22 cleanly (91%). Subsequent
selective oxidation of the primary alcohol using cata-
O
c-Hex2B
PMBO
H
O
O
OR
O
TESO
OH
29
a
8
c
OBz
OBz
OBz
OH
PMBO
PMBO
33
(94%)
(90%)
7
9 R = H
10 R = TES
11
6
b
(87%)
d
(92%)
OTES
TESO
O
OTES
f
R
PMBO
PMBO
H
(72%)
(73%)
N
H
N
H
Me
Me
12
O
O
16 R = CH2OH
17 R = CHO
15
g
Ph3P+
Ph3P
Cl–
H
(80%)
e
N
H
O
N
h
Me
Me
(72%)
O
13
14
O
OH OTES
O
O
OTES
i
(MeO)2P
(MeO)2P
34
28
(81%)
N
H
N
H
Me
Me
18
O
5
O
Scheme 2. (a) (c-Hex)2BCl, Me2NEt, Et2O, 0°C, 1 h; 8, −78“−20°C, 16 h; (b) TESOTf, 2,6-lutidine, CH2Cl2, −78°C, 2 h; (c)
LiBH4, THF, −78°C“rt, 24 h; (d) NaIO4, MeOH/pH 7 buffer, 0°C“rt, 2 h; (e) LiHMDS, THF, −78°C“rt; 12, −78°C, 2 h; (f)
,
DDQ, CH2Cl2/pH 7 buffer, rt, 0.5 h; (g) 10 mol% TPAP, NMO, 4 A molecular sieves, CH2Cl2, rt, 0.5 h; (h) (MeO)2POCH3,
,
,
n-BuLi, 4 A mol. sieves, THF, −78°C, 4 h; (i) 10 mol% TPAP, NMO, 4 A molecular sieves, CH2Cl2, rt, 1 h.

I. Paterson et al. / Tetrahedron Letters 43 (2002) 6005–6008
6007
particularly hindered nature of this hydroxyl group.
However, treatment of 23 with TESCl and imidazole in
DMF gave the bis-TES ether 24 in high yield (87%). By
using mild hydrolysis conditions (AcOH/THF/H2O),
selective deprotection of the C31 TES ether was
achieved to give alcohol 25. Stryker’s reagent
([Ph3P·CuH]6) was then employed to reduce selectively
the enone functionality in a 1,4-sense, providing ketone
26 (75%).14 Our synthesis of fragment 27,15 correspond-
ing to an advanced C21–C34 subunit of the aplyroni-
nes, was then concluded by performing an
Evans–Tishchenko reduction on 26 using acetaldehyde.
This served to set simultaneously the configuration of
the C29 hydroxyl-bearing stereocentre and introduce
the required C31 acetate.
Whilst retaining the cis-geometry of the terminal vinyl
formamide through the above reaction sequence proved
1
useful in simplifying the H NMR spectra, ultimately it
needs to be isomerised to the trans-geometry in the
presence of the full aplyronine functionality. To date,
this transformation has been demonstrated in a series
of model substrates using iodine under light-free condi-
tions.9 For example, the cis-vinylformamide 28 (pre-
pared in 94% yield by acylation of 16 with
(R,S)-N,N-dimethylalanine using DCC, DMAP,
CH2Cl2) was isomerised cleanly to the corresponding
trans-N-methyl-N-vinylformamide 29 in 79% yield
(Scheme 5).
Scheme 3. (a) iso-butyraldehyde, SmI2 (20 mol%), THF, 0°C,
2.5 h; (b) HF·pyridine, THF, rt, 7 h; (c) cat. TEMPO,
PhI(OAc)2, rt, 2 h.
lytic TEMPO, with iodobenzene diacetate (BAIB) as a
co-oxidant, as developed by Piancatelli and co-work-
ers,12 provided the desired aldehyde 19 (90%) without
any oxidation at C25.
In conclusion, we have prepared the b-ketophospho-
nate 5 to be employed as a highly functionalised C28–
C34 side chain coupling unit for the aplyronines. The
synthesis features a boron-mediated anti-aldol reaction
of the chiral ketone 6 to set up the stereochemistry and
a novel Wittig olefination to introduce the N-methyl-N-
vinylformamide moiety. An advanced C21–C34 frag-
ment 27 for the aplyronines was then assembled by a
testing HWE coupling between 5 and aldehyde 19 and
elaboration of the resulting enone 23. Studies towards
completing a total synthesis of the aplyronines using
this chemistry are currently under investigation.
In order to form the C27–C28 bond of the aplyronines,
the crucial HWE reaction between aldehyde 19 and
b-ketophosphonate 5 was carried out using the LiCl/
DBU conditions of Masamune and Roush,13 producing
the (E)-enone 23 in 52% yield (Scheme 4). Subsequent
attempts to protect the C25 alcohol as either a PMB or
TBS ether proved unsuccessful, presumably due to the
Scheme 4. (a) LiCl, DBU, THF/MeCN, rt, 3 h; (b) TESCl, imidazole, DMF, rt, 2 h; (c) AcOH/THF/H2O, 40°C, 4 h; (d)
[Ph3P·CuH]6, C6H6, rt, 1 h; (e) SmI2, CH3CHO, THF, −5°C, 2.5 h.

6008
I. Paterson et al. / Tetrahedron Letters 43 (2002) 6005–6008
6. Marshall, J. A.; Johns, B. A. J. Org. Chem. 2000, 65,
1501.
7. For reviews on bioactive marine macrolide synthesis, see:
(a) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95,
2041; (b) Yeung, K.-S.; Paterson, I. Angew. Chem., Int.
Ed. 2002, 41, in press.
8. (a) Paterson, I.; Wallace, D. J.; Vela´zquez, S. M. Tetra-
hedron Lett. 1994, 35, 9083; (b) Paterson, I.; Wallace, D.
J. Tetrahedron Lett. 1994, 35, 9087; (c) Paterson, I.;
Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639.
9. Paterson, I.; Cowden, C. J.; Watson, C. Synlett 1996,
209.
10. Ley, S. V.; Norman, J.; Griffith, W. D.; Marsden, S. D.
Synthesis 1994, 639.
11. Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990,
112, 6447.
12. De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.;
Piancatelli, G. J. Org. Chem. 1997, 62, 6974.
13. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A.
P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron
Lett. 1984, 25, 2183.
Scheme 5.
Acknowledgements
14. Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J.
Am. Chem. Soc. 1988, 110, 291.
15. All new compounds gave spectroscopic data in agreement
with the structures indicated. Compound 27 was isolated
as a colourless oil: Rf 0.19 (40% EtOAc/40–60 pet. ether);
IR (film) 3406 (s br, O-H), 2963 (s, C-H), 1734 (s, CꢀO),
We thank the EPSRC, the British Council (Common-
wealth Scholarship to SBB), Merck Sharp & Dohme
and Trinity College, Cambridge, for support.
1
1715 (s, CꢀO), 1684 (s, CꢀO), 1647 cm−1; H NMR (500
MHz, CDCl3) lH 8.15 (1H, s, NCH
ArH), 7.26 (2H, m, ArH), 5.98 (1H, d, J=8.7 Hz, C1H
5.25 (1H, dd, J=10.7, 9.0 Hz, C2H,), 5.16 (1H, m, C12H
4.80 (1H, dd, J=10.2, 3.0 Hz, C4H
J=11.8 Hz, ArCH2O), 3.46 (2H, m, BnOCH2
m, C6HOH, C10HOTES), 3.02 (3H, s, NCH3
m, C3H), 2.49 (2H, septet, J=7.0 Hz, C2%H
2.15 (3H, s, C(O)CH3), 1.94 (1H, m, C13HAHB), 1.86 (1H,
m, C13HAHB), 1.77 (1H, m, C11H), 1.68 (1H, m, C5H),
1.55 (2H, obs, C8HAHB, C9H), 1.39 (3H, m, C7H2
C8HAHB), 1.13 (3H, d, J=7.0 Hz, (C3%H3 A
J=7.1 Hz, (C3%H3)B), 1.06 (3H, d, J=6.8 Hz, C3HCH3
0.93 (15H, ap t, J=8.0 Hz, C9HCH3
Si(CH2CH3)3), 0.77 (3H, d, J=6.9 Hz, C5HCH3
(6H, q, J=8.0 Hz, Si(CH2
CH3)3); 13C NMR (100 MHz,
6
O), 7.33 (3H, m,
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