Synthetic approaches towards laulimalide: Synthesis of the C12-C29 fragment

Article abstract of DOI:10.1055/s-1998-1934

A synthesis of the C₁₂-C₂₉ fragment of laulimalide 1 is described. This synthesis involves the Julia trans-olefination as a key step.

Full text of DOI:10.1055/s-1998-1934

November 1998
SYNLETT
1209
Synthetic Approaches towards Laulimalide: Synthesis of the C12-C29 Fragment
Atsushi Shimizu, Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Yokohama 223-8522, Japan
Fax +81-45-563-5967; E-mail: nisiyama@chem.keio.ac.jp
Received 17 August 1998
Abstract: A synthesis of the C12-C29 fragment of laulimalide 1 is
described. This synthesis involves the Julia trans-olefination as a key
step.
OTBS
OTBS
I
OTBS
5
OTBS
H
+
O
O
Laulimalide 1 (also identified as fijianolide B) is a 20-membered
macrolide, possessing potent cytotoxic activity (IC50=15 ng/mL)
against the KB cell line.1 The first isolation from Indonesian marine
sponge, Hyattella sp. was reported by Moore in 1988,1 and
independently by Crews in 1988 from a different marine sponge,
Spongia mycofijiensis.2 The absolute configuration of 1 was determined
by Higa in 1996, based on the X-ray crystallographic analysis.3
Contrary to an attractive macrolide structure including nine chiral
centers and five double bonds, few synthetic investigations4 related to
this molecule have been reported, probably owing to no information of
the absolute configuration until the above-mentioned crystallographic
analysis. We report herein a synthesis of the C12-C29 fragment which
was effectively constructed by the Julia trans-olefination.5
11
H
O
OMOM
O
N
H
H
O
OMOM
Bn
7
6
Scheme 2
on reduction with LiAlH4, provided alcohol 13. Protection of the
primary alcohol as a TBDPS group; the acetal protective group was
submitted to a reductive opening reaction with DIBAL to give a primary
alcohol as a major isomer. Subsequent oxidation of the primary alcohol
gave the desired key intermediate 8.
Retrosynthetically as can be seen in Scheme 1, the sensitive epoxide
bestriding between the C16 and C17 positions, would be introduced by
the Sharpless protocol6 at the final stage of the synthetic process.
Accordingly the target molecule 1 could be transformed into olefin 2,
which was subsequently divided into two fragments 3 and 4. In this
context, a model coupling study employing 5 and 6 as substituents,7
confirmed the production of the desired stereochemistry at the C11
position (Scheme 2). Fragment 3 could be divided into aldehyde 8 and
phenylsulfone 9.
Synthesis of the coupling partner 9 was initiated from methyl ester 14
derived from L-malic acid. Thus, treatment of 14 with
(MeO)2P(O)CH2Li resulted in the formation of intermediate 15.
Coupling of 15 and 16 according to the Jørgensen protocol10 gave α,β-
unsaturated ketone 17. Diastereoselective reduction of the C20 ketone
with L-Selectride furnished the desired 20S-alcohol 18. Removal of the
TBS group, followed by protection of the resulting diol as an
isopropylidene group afforded 19. Deprotection of the MPM group,
then phenylsulfonylation of the primary alcohol via a mesyl ester gave
the coupling partner 9.
Synthesis of the key intermediate 8 was started from dimethyl ester 10,
derived from L-glutamic acid8 (Scheme 3). Regioselective reduction,
followed by protection of the resulting diol as a 4-methoxybenzylidene
group afforded methyl ester 11. Usual two-step reductive-oxidative
manipulation of the ester portion in 11 gave aldehyde 12. Reaction of
aldehyde 12 with the Eschenmoser’s reagent9 provided an enal, which,
At the final stage, the aldehyde 8 and the sulfone 9 were coupled by
means of Julia reaction employing nBuLi as a base, followed by the
reductive elimination procedure. Because of the unstable character of
H
O
OR
H
HO
H
H
O
OH
16
17
H
29
O
OR
H
O
O
H
O
O
12
O
O
11
H
28
2
Laulimalide (1)
OR
H
O
O
H
CHO
PhSO2
O
OR
O
OR
+
I
3
OMPM
O
TBDPSO
O
O
N
COOR
H
H
O
8
9
Bn
4
Scheme 1

1210
LETTERS
SYNLETT
aldehyde 8, the total yield of this coupling reaction was unsatisfactory
(32% in 3 steps). However this reaction gave rise to the required trans
olefin between the C16-C17 positions as a sole product. Deprotection of
a TBDPS group, then halogenation of the primary alcohol via a mesyl
ester gave the desired allyl iodide 3 (71% in 3 steps).
MeOOC
COOMe
OH
MeOOC
i
O
O
MP
10
OHC
11
TBDPSO
iii
O
O
ii
O
O
MP
In conclusion, we have successfully synthesized the C12-C29 fragment 3
of laulimalide, and further investigation toward the total synthesis of
this natural product is now in progress.
MP
13
12
CHO
OMPM
MP= 4-MeOC6H4
iv
TBDPSO
8
References
(1) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J.; Paul, V. J. J.
Reagents and Conditions: i, a)BH3•Me2S, THF, 0 °C, 97%; b)
4-MeOC6H4CH(OMe)2, PPTS, CH2Cl2, 78%. ii, a) LiAlH4, THF, 0
°C, 91%; b) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 99%. iii, a)
CH2=N+(CH3)2I-, Et3N, CH2Cl2, 78%; b) LiAlH4, THF, 0 °C, 98%; c)
TBDPSCl, Et3N, CH2Cl2, 96%. iv, a) DIBAL-H, CH2Cl2, -78 °C,
60% (with regioisomer 12%); b) (COCl)2, DMSO, Et3N, CH2Cl2,
-78 °C, 89%
Org. Chem. 1988, 53, 3644.
(2) Fijianolide B has the same relative structure as laulimalide:
Quiñoà, E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988, 53, 3642.
(3) Jefford, C. W.; Bernardinelli, G.; Tanaka, J.; Higa, T. Tetrahedron
Lett. 1996, 37, 159.
(4) CAS online indicated that the following investigations had been
published.
Scheme 3
a) Upinder, S. Diss. Abstr. Int. B 1995, 55, 4858. b) Ghosh, A. K.;
Mathivanan, P.; Cappiello, J. Tetrahedron Lett. 1997, 38, 2427.
O
O
P
OMe
OMe
(5) Julia, M.; Paris, J. M. Tetrahedron Lett. 1973, 14, 4833.
MPMO
MPMO
COOMe
OTBS
i
(6) Sharpless, K. B.; Michaelson, R. J. Am. Chem. Soc. 1973, 95,
OTBS
6136.
14
ii
15
(7) Shimizu, A.; Nishiyama, S. Tetrahedron Lett. 1997, 38, 6011.
O
(8) Ravid, U.; Silverstein, R.; Smith, L. R. Tetrahedron 1978, 34,
H
MPMO
O
1449.
OHC
H
OTBS
(9) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. Ed. Engl. 1971, 10, 330.
O
16
17
(10) Graven, A.; Johannsen, M.; Jørgensen, K. A. Chem. Commun.
1996, 2373.
OH
(11) Selected 1H-NMR data (CDCl3):
H
MPMO
O
iii
iv
8: δ 1.06 (9H, s), 2.35 (1H, dd, J=7.92, 13.8 Hz), 2.46 (1H, dd,
J=5.28, 13.8 Hz), 3.79 (3H, s), 3.83 (1H, ddd, J=1.98, 5.28, 7.92
Hz), 4.12 (2H, s), 4.40 (1H, d, J=11.5 Hz), 4.48 (1H, d, J=11.5
Hz), 4.99 (1H, s), 5.27 (1H, s), 6.82 (2H, d, J=8.58 Hz), 7.16 (2H,
d, J=8.58 Hz), 7.34-7.46 (6H, complex), 7.64-7.68 (4H, complex),
9.55 (1H, d, J=1.98 Hz).
OTBS
18
O
H
MPMO
O
v
9
O
9: δ 1.35 (6H, s), 1.84-2.17 (4H, complex), 3.15 (1H, ddd, J=4.62,
11.2, 13.9 Hz), 3.67 (1H, ddd, 1H, J=4.95, 11.6, 13.9 Hz), 3.67
(1H, ddd, J=3.30, 8.58, 11.9 Hz), 3.97-4.07 (2H, complex), 4.19
(2H, brs), 5.42 (1H, brs), 5.65 (1H, dd, J=6.92, 15.5 Hz), 5.89
(1H, dd, J=5.28, 15.5 Hz), 7.55-7.70 (3H, complex), 7.90-7.93
(2H, complex).
19
O
H
O
vi
OMPM
O
I
3: δ 1.42 (3H, s), 1.43 (3H, s), 1.70 (3H, s), 1.91 (1H, brd), 2.05
(1H, m), 2.34-2.51 (4H, complex), 3.77 (1H, m), 3.80 (3H, s),
3.86-3.95 (3H, complex), 4.03-4.12 (2H, complex), 4.18 (2H,
brs), 4.27 (1H, d, J=11.7 Hz), 4.51 (1H, d, J=11.7 Hz), 4.95 (1H,
s), 5.28 (1H, s), 5.41 (1H, brs), 5.47 (1H, dd, J=7.81, 15.4 Hz),
5.68-5.75 (2H, complex), 5.90 (1H, ddd, J=3.91, 5.37, 16.2 Hz),
6.86 (2H, d, J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz).
3
Reagents and Conditions: i, (MeO)2P(O)CH2Li, THF, -78 °C, 94%.
ii, NaH, 16, THF, 0 °C, 60%. iii, Li(s-Bu)3BH, THF, -78 °C. iv, a)
TBAF, THF; b) Me2C(OMe)2, PPTS, acetone, 35% in 3 steps. v, a)
DDQ, H2O-CH2Cl2 (1:10); b) MsCl, Et3N, CH2Cl2 , 95% in 2 steps; c)
PhSO2Na, NaI, DMF, 80 °C, 48%. vi, a) nBuLi, 8, Et2O; b) Ac2O,
pyridine; c) 5% Na-Hg, EtOAc-MeOH (1:1), -20 °C, 32% in 3 steps;
d) TBAF, THF; e) MsCl, Et3N, CH2Cl2; f) NaI, acetone, 71% in 3
steps.
Scheme 4