Total Synthesis of Natural (+)-Lasonolide A

Article abstract of DOI:10.1002/anie.200352016

The diastereoselective differentiation of two methylene groups of a cyclic acetal is a unique feature of a highly enantioselective total synthesis of natural (+)-Iasonolide A (see picture), which is used to create the C22 quaternary asymmetric center. Other key strategies are the use of a sulfone-sulfide as a three-carbon fragment with two latent trans double bonds and macrocyclization through an intramolecular Horner-Emmons reaction.

Full text of DOI:10.1002/anie.200352016

Angewandte
Chemie
Natural Product Synthesis
Total Synthesis of Natural (+)-Lasonolide A**
Sung Ho Kang,* Suk Youn Kang, Chul Min Kim,
Hyeong-wook Choi, Hyuk-Sang Jun,
Byeong Moon Lee, Chul Min Park, and Joon Won Jeong
The novel 20-membered macrolide lasonolide A (1) was
isolated from the Caribbean marine sponge Forcepia sp.[1]
Lasonolide A displayed antitumor activity by inhibiting the
in vitro proliferation of A-549 human lung carcinoma cells
and interdicting cell adhesion in a cell assay for the detection
of signal-transduction agents.[2] The relative stereochemistry
of lasonolide A was originally proposed incorrectly based on
extensive 2D NMR spectroscopic studies. Its structure was
[*] Prof. Dr. S. H. Kang, S. Y. Kang, C. M. Kim, H.-w. Choi, H.-S. Jun,
B. M. Lee, C. M. Park, J. W. Jeong
Department of Chemistry
Center for Molecular Design and Synthesis
School of Molecular Science (BK 21)
Korea Advanced Institute of Science and Technology
Daejeon 305-701 (Korea)
Fax: (+82)42-869-2810
E-mail: shkang@kaist.ac.kr
[**] This work was supported by a grant from the Korea Research
Foundation (KRF-2002–070-C00058).
Angew. Chem. Int. Ed. 2003, 42, 4779 –4782
DOI: 10.1002/anie.200352016
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Communications
later revised as 1, with the stereochemistry of the
hydroxy-substituted epimerizable C28 center and the
absolute configuration shown, based on synthetic
studies.[3,4] The intriguing structural features and
significant biological activity of this natural product
led us to undertake its total synthesis. Herein, we
describe a highly enantioselective total synthesis of
the natural (+)-lasonolide A (1).
Retrosynthetically, we envisaged that double
bonds could be introduced at C25 by a Wittig
olefination of 27, at C2 by an intramolecular
Horner–Emmons reaction of the a,b-unsaturated
aldehyde derived from 25, and at C14 and C17 by
the Julia–Kocienski sulfone-coupling protocol[5]
´
(Scheme 3). Formation of the two cis-2,6-disubstituted
tetrahydropyran rings by iodoetherification of 7 in the
case of the A ring (Scheme 1) and by the intra-
molecular Michael addition of 19 in the case of the
B ring (Scheme 2) was planned, and the choice of
protecting groups turned out to be crucial for high
stereoselectivity to be observed in these transforma-
tions. It was planned to install the C22 quaternary
chiral center through the thermodynamic equilibra-
tion of 4.
To secure subunit 16 with the tetrahydropyran
ring A, the known alcohol 2[6] was oxidized and then
allylated with the allylboronate (R,R)-3 of Roush
et al.[7] to give the homoallylic alcohol 4 with 78% ee
(Scheme 1). The next step was contrived to differ-
entiate the two methylene groups of the 1,3-dioxane
ring diastereoselectively and put in place the C22
quaternary stereogenic center. Based on the pre-
sumed increased thermodynamic stability caused by
hydrogen bonding between the axial hydroxymethyl
group and the two oxygen atoms of the acetal as
suggested in 6, the tandem conversion of 4 into the
Scheme 1. a) (COCl)2, DMSO, CH2Cl2, ꢀ788C, then Et3N, ꢀ78!08C; b) (R,R)-3,
4-Š MS, PhMe, ꢀ788C!RT; 2n NaOH, 08C, 86% (for steps a and b);
c) PhCHO (3 equiv), CF3CO2H (4 equiv), PhMe, ꢀ20!08C, 82% (after one recy-
cling step); d) (S,S)-3, 4-Š MS, PhMe, ꢀ788C!RT; 2n NaOH, 08C, 77% (for
steps a and d); e) I2, K2CO3, MeCN, ꢀ30!ꢀ208C, 95%; f) BzONa, NMP,
1008C, 97%; g) O3, NaHCO3, MeOH, ꢀ788C; NaBH4, 08C, 96%; h) H2,
10% Pd/C, HOAc, MeOH, room temperature, 89%; i) TBSCl, imidazole, DMF,
08C, 95%; j) TESOTf, 2,6-lutidine, CH2Cl2, 08C, 98%; k) K2CO3, MeOH, room
temperature, 91%; l) Dess–Martin periodinane, pyridine, CH2Cl2, room tempera-
ture; m) 13, DEAD, Ph3P, THF, 08C, 81%; n) (NH4)6Mo7O24·4H2O, H2O2, phos-
phate buffer (pH 7.6), THF, EtOH, room temperature; o) 14, DEAD, Ph3P, THF,
08C, 75% (for steps n and o); p) KHMDS, DME, ꢀ708C!RT, 95% (for steps l
benzylidene 5 was explored extensively under a and p); q) p-TsOH·H2O, MeOH, room temperature; r) TBSCl, imidazole, DMF,
variety of acidic conditions. A remarkable result was
room temperature, 88% (for steps n, q, and r). DMSO=dimethyl sulfoxide,
MS=molecular sieves, Bz=benzoyl, NMP=1-methyl-2-pyrrolidinone,
observed when 4 was treated with benzaldehyde in the
TBS=tert-butyldimethylsilyl, DMF=N,N-dimethylformamide, TES=triethylsilyl,
presence of trifluoroacetic acid (4 equiv). This reac-
Tf =trifluoromethanesulfonyl, DEAD=diethyl azodicarboxylate, HMDS=bis(tri-
methylsilyl)amide, DME=1,2-dimethoxyethane, Ts=toluenesulfonyl.
tion furnished a 5:1 separable mixture of the desired
benzylidene 5 and the diastereomeric acetal with the
hydroxymethyl group in an equatorial position, in
72% combined yield. Two other diastereomers in
which the benzylidene acetal was formed with the two
primary hydroxy groups were produced in 24% combined
yield. After one recycling step with the undesired diastereo-
meric benzylidenes, compound 5 was produced in a total yield
of 82%. Swern oxidation[8] of 5, followed by a second
asymmetric allylation, this time with (S,S)-3, gave the alcohol
7 with an enhanced ee value of 91%. It was found that the
cyclic acetal protecting group was beneficial for the stereo-
selective formation of ring A. Compound 7 underwent
cyclization in the presence of iodine to afford a 27:1 mixture
of the cis-2,6-disubstituted tetrahydropyran 8 and the corre-
sponding trans isomer. The iodide 8 was subjected to a
reaction sequence involving substitution, ozonolysis, a reduc-
tive workup, and removal of the benzylidene group by
hydrogenolysis. The primary and secondary hydroxy groups
of the resulting triol 9 were differentially silylated with TBSCl
and TESOTf, respectively, and the benzoate group was then
hydrolyzed to provide the alcohol 10.
We chose the disulfone equivalent 15 as a suitably
functionalized substrate for the introduction of the three
carbon atoms required in the target fragment in addition to
those present in the alcohol 10 and the later introduction of
the trans double bonds at C14 and C17. The diol 12 was
treated with the tetrazolethiol 13 under Mitsunobu condi-
tions, and the product was oxidized to the corresponding
sulfone and then converted into the sulfone–sulfide 15
through a second Mitsunobu reaction with the thiazolethiol
14. The coupling of the aldehyde 11, derived from 10, with 15
was carried out in the presence of KHMDS to give the
expected diastereomeric alkenes (trans/cis 31:1), which were
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separated by chromatography. The synthesis of the subunit 16
was completed by oxidation and protecting-group manipu-
lation of the trans olefinic sulfide. Whereas the heptamolyb-
date oxidation of the sulfide to the sulfone under normal
conditions[9] proceeded very slowly with partial desilylation,
the reaction in the presence of a phosphate buffer was
efficient and reached completion within a few hours.
The synthesis of subunit 23, which contains tetrahydro-
pyran B, started with the p-methoxybenzylation of the known
alcohol 17,[10] followed by oxidative cleavage and asymmetric
allylation according to the method of Brown et al.[11] to yield
the homoallylic alcohol 18, no diastereoisomers of which
could be isolated in appreciable amounts (Scheme 2). After
oxidative cleavage of the double bond and conversion of the
resulting aldehyde into conjugated ethyl esters (trans/cis
24:1), the trans isomer was subjected to silylation of the
alcohol functionality and oxidative removal of the PMB
protecting group to furnish the hydroxyester 19. The intra-
molecular Michael addition of 19 produced the cis-2,6-
disubstituted tetrahydropyran 20 as a single stereoisomer.
Compound 20 was reduced to the corresponding aldehyde
and then treated under olefination conditions to give the
expected conjugated esters (trans/cis 22:1). The trans isomer
was then sequentially reduced, debenzylated, and monosilyl-
ated to afford the alcohol 21. Swern oxidation of 21 followed
by olefination with the trifluoroethyl phosphonate of Still and
Gennari[12] provided the conjugated ester 22 (cis/trans 6.6:1).
As all attempts at the desilylation of TIPS-protected lasono-
lide A proved abortive in the last stage of our synthesis, the
TIPS group of the cis conjugated ester 22 was exchanged for a
TBS group, and the resulting ester was reduced to the
aldehyde to yield the tetrahydropyran subunit 23.
Scheme 2. a) NaH, PMBCl, nBu4NI, DMF, THF, room temperature, 97%;
=
b) OsO4, NaIO4, H2O, THF, room temperature; c) (ꢀ)-Ipc2BCH2CH CH2, Et2O,
=
ꢀ788C; 3n NaOH, H2O2, room temperature, 74% (for steps b and c); d) Ph3P
CHCOOEt, PhH, reflux, 87% (for steps b and d); e) TIPSOTf, 2,6-lutidine,
CH2Cl2, 08C, 98%; f) DDQ, H2O, CH2Cl2, room temperature, 87%; g) NaH,
THF, ꢀ78!ꢀ208C, 81%; h) DIBAL, CH2Cl2, ꢀ788C; i) EtO2CCH2PO(OEt)2,
NaH, THF, ꢀ788C, 89% (for steps h and i); j) DIBAL, CH2Cl2, ꢀ788C, 91%;
k) Li, NH3 (liq), THF, ꢀ788C, 87%; l) NaH, TBSCl, THF, 08C, 94%; m) (COCl)2,
DMSO, CH2Cl2, ꢀ788C, then Et3N, ꢀ78!08C; n) MeO2CCH(Me)-
PO(OCH2CF3)2, KHMDS, [18]crown-6, THF, ꢀ788C, 79% (for steps m and n);
o) TBAF, THF, room temperature; p) TBSOTf, 2,6-lutidine, CH2Cl2, 08C;
q) DIBAL, CH2Cl2, ꢀ788C, 88% (for steps o–q). PMB=p-methoxybenzyl, Ipc=i-
sopinocamphenyl, TIPS=triisopropylsilyl, DDQ=2,3-dichloro-5,6-dicyano-1,4-
benzoquinone, DIBAL=diisobutylaluminum hydride, TBAF=tetrabutylammo-
nium fluoride.
A mixture of the C3–C14 and C15–C25 subunits 16 and 23
was treated with LiHMDS to give a mixture of the coupling
product 24 and its cis isomer at the newly formed double bond
in a > 20:1 ratio (Scheme 3). As the trans,trans-2,4-dienyl
carboxylic acid prepared from 24 and substituted with a
hydroxy group at C21 was resistant to macrolactonization in
our hands, compound 24 was converted into the phospho-
noacetate 25 so that a Horner–Emmons olefination could be
employed for the macrocyclization. After removal of the two
sterically less hindered TBS groups of 25, the resulting diol
was subjected to allylic oxidation and cyclization mediated by
K2CO3 in the presence of [18]crown-6[13] to furnish the
macrolactone 26 smoothly. Compound 26 was then oxidized
to the aldehyde 27. The C26–C35 side chain required for the
construction of the complete lasonolide A skeleton was
obtained as the phosphonium salt 30 from the known
acetonide 28[14] and alcohol 29[15] by acid-mediated esterifica-
tion, followed by silylation and nucleophilic substitution with
PPh3. The Wittig olefination of 27 and 30 was most effective in
the presence of KHMDS, and the protected lasonolide A 31
was desilylated uneventfully to produce the natural (+)-
lasonolide A (1), all physical and spectroscopic data of which
were identical to those reported in the literature.[1,3]
Scheme 3. a) LiHMDS, DME, ꢀ708C!RT, 82%; b) HO2CCH2PO(OEt)2, DCC,
DMAP, CH2Cl2, room temperature, 94%; c) PPTS, MeOH, room temperature, 91%;
d) MnO2, EtOAc, room temperature; e) K2CO3, [18]crown-6, PhMe, 70!808C, 71%
(for steps d and e); f) Dess–Martin periodinane, pyridine, CH2Cl2, room tempera-
ture; g) p-TsOH·H2O, PhMe, room temperature, 85%; h) TESOTf, 2,6-lutidine,
CH2Cl2, 08C; i) Ph3P, MeCN, reflux, 88% (for steps h and i); j) KHMDS, THF,
ꢀ608C, 86% (for steps f and j); k) HF·py, pyridine, THF, room temperature, 87%.
DCC=1,3-dicyclohexylcarbodiimide, DMAP=4-dimethylaminopyridine, PPTS=pyri-
dinium p-toluenesulfonate, py=pyridine.
In summary, we have reported a highly enantioselective
total synthesis of natural (+)-lasonolide A. The synthesis is
characterized by a diastereoselective differentiation step to
create the C22 quaternary asymmetric center, the develop-
ment of the sulfone–sulfide 15 as a three-carbon fragment
with two latent trans double bonds, cyclizations to form the
two cis-2,6-disubstituted tetrahydropyrans, and an intramo-
lecular Horner–Emmons reaction to effect macrocyclization.
Angew. Chem. Int. Ed. 2003, 42, 4779 –4782
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The longest linear synthetic sequence exploited the ready
availability of the alcohol 17 in 26 steps and 7.4% overall
yield.
Received: May 30, 2003 [Z52016]
Keywords: allylation · macrolides · natural products ·
.
olefination · total synthesis
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