Total synthesis of IKD-8344

Article abstract of DOI:10.1002/anie.200602860

(Chemical Equation Presented) Complete construction: The total synthesis of IKD-8344, a novel 28-membered ring macrodiolide antibiotic (see structure), was accomplished by employing Williamson ether synthesis, β-alkoxymethacrylate radical cyclization, and

Full text of DOI:10.1002/anie.200602860

Communications
Natural Products
DOI: 10.1002/anie.200602860
Total Synthesis of IKD-8344**
Woo Han Kim, Sung Kil Hong, Sang Min Lim, Min-
Ae Ju, Soon Kyu Jung, Yong Wook Kim, Jae Hoon Jung,
Min Sang Kwon, and Eun Lee*
IKD-8344 (1, Scheme 1) is a novel 28-membered ring macro-
diolide antibiotic from an unidentified alkalophilic Actino-
mycete, strain no. 8344,[1] which exhibits potent anthelmintic
activity against Trichinella spiralis and strong cytotoxicity
against L5178Y mouse leukemia cells with an IC50 value of
0.54 ngmLꢀ1.[1] More recently, it was also isolated from
Streptomyces sp. A6792 and selective antifungal activities
against the mycelial form of Candida albicans were noted.[2]
The unique bioactivities and stereochemical complexities
of the molecule make it an attractive synthetic target. The
monomeric seco acid A (Scheme 1) contains three methyl
branches and three oxolane units: a threo (C2–C3)–trans (C3–
C6) array is connected to a threo (C9–C10)–cis (C10–C13)
arrangement, which is flanked by another threo (C16–C17)–
trans (C17–C20) unit. Efficient and stereoselective construc-
tion and assemblage of these structural units is not trivial, and
[*] W. H. Kim, S. K. Hong, S. M. Lim, M.-A. Ju, S. K. Jung, Y. W. Kim,
J. H. Jung, M. S. Kwon, Prof. E. Lee
Department of Chemistry
College of Natural Sciences
Seoul National University
Seoul 151-747 (Korea)
Fax: (+82)2-889-1568
E-mail: eunlee@snu.ac.kr
[**] This work was supported by a grant from the Center for Bioactive
Molecular Hybrids (Yonsei University and KOSEF), and a grant from
MarineBio21, Ministry of Maritime Affairs and Fisheries, Korea.
BK21 graduate fellowship grants to W.H.K., S.K.H., S.M.L., S.K.J.,
and Y.W.K. are gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 1. Retrosynthetic analysis.
the difficulty therein is manifested by the absence of reports
on the total synthesis of IKD-8344 (1) in the literature.[3] In
the retrosynthetic analysis, synthesis of 1 would be accom-
plished through dimerization of the monomeric seco acid A,
which may be prepared by coupling of fragments B and D.
Fragment B may be obtained by radical cyclization of the b-
alkoxymethacrylate derivative C, which should be accessible
from fragment D. A reliable synthesis of fragment D is
prerequisite for a successful total synthesis of this intriguing
molecule, which is described in this communication.
Scheme 2. Preparation of the B fragment. a) 2, Bu2BOTf, NEt3, CH2Cl2,
ꢀ40!08C; 3, ꢀ788C; b) LiBH4, diethyl ether, 08C!RT; c) TBDPSCl,
imidazole, CH2Cl2; d) MsCl, NEt3, CH2Cl2, 08C!RT; e) CSA, MeOH;
f) NaHMDS, THF, 08C!RT; g) MsCl, NEt3, CH2Cl2, 08C!RT;
h) TBAF, THF; i) PCC, 4-Š MS, CH2Cl2; j) CH2CHCH2SiMe3, TiCl4,
CH2Cl2, ꢀ788C; k) LiAlH4, diethyl ether, 08C!RT; l) NaHMDS, BnBr,
THF/DMF (5:1), 08C!RT; m) O3, CH2Cl2, ꢀ788C; Ph3P;
n) CH2CHCH2SnBu3, MgBr2·Et2O, CH2Cl2; o) O3, CH2Cl2, ꢀ788C; Ph3P;
p) NaBH4, MeOH, 08C!RT; q) TsCl, NEt3, CH2Cl2, 08C; r) 10, PPTS,
benzene, reflux; s) NaI, acetone, reflux; t) Bu3SnH, Et3B, toluene, air,
ꢀ788C. Tf=trifluoromethanesulfonyl, TBDPS=tert-butyldiphenylsilyl,
Ms=methanesulfonyl, CSA=(ꢁ)-camphorsulfonic acid,
Synthesis of the B fragment commenced with the aldol
reaction of aldehyde 3[4] with the boron enolate of the chiral
imide 2 (Scheme 2).[5] Reduction of the product aldol imide
and silyl protection of the primary hydroxy group afforded
alcohol 4. The threo–trans oxolane derivative 5 was obtained
by mesylation of 4, acetonide deprotection, and treatment
with base. The corresponding mesylate 6 was converted into
aldehyde 7 by silyl deprotection and PCC oxidation. Reaction
of 7 with allyltrimethylsilane in the presence of titanium
chloride led to a 4:1 mixture,[6] favoring 8, of the homoallylic
alcohols. At this point, the mesyloxy group was removed
through LiAlH4 reduction, and the aldehyde obtained by
ozonolysis after benzyl protection was converted stereoselec-
tively into the homoallylic alcohol 9 by reaction with
allyltributylstannane in the presence of magnesium bromide
etherate.[7] Iodide 11 was obtained from 9 by ozonolysis,
sodium borohydride reduction, tosylation of the primary
hydroxy group, reaction with the dimethyl acetal 10,[8] and
iodide substitution. Radical cyclization[9] of b-alkoxymetha-
crylate 11 proceeded smoothly to produce selectively (10:1)
the threo–cis oxolane product 12 in good yield (Scheme 2).[10]
Coupling of fragments B and D was problematic. For
example, the dithiane derivative prepared from ester 12 was
not amenable to the reaction with mesylate 6. After consid-
erable exploration, it was found that efficient coupling was
possible by employing a Wittig reaction. Aldehyde 13 was
HMDS=1,1,1,3,3,3-hexamethyldisilazane, TBAF=tetrabutylammo-
nium fluoride, PCC=pyridinium chlorochromate, Bn=benzyl, Ts=to-
luene-4-sulfonyl, PPTS=pyridinium p-toluenesulfonate.
prepared from the primary alcohol 5 (Scheme 3). Ester 12 was
converted into the corresponding phosphonium salt by
lithium borohydride reduction, iodide substitution, and
reaction with triphenylphosphine, and the ylide obtained
from the phosphonium salt reacted with aldehyde 13 to
produce olefin 14 in good yield. A mixture of epoxides was
obtained from 14 by oxidation with mCPBA. Reaction of the
mixture with excess lithium aluminum hydride, Dess–Martin
oxidation of the diol produced, and chlorite oxidation of the
aldehyde functionality provided regioselectively (12:1) the
correct keto carboxylic acid 15. Use of diisobutylaluminum
hydride (DIBAH) as the reducing agent eventually produced
the alternative ketone as the major product. The monomeric
seco acid 16 was prepared by hydrogenolysis. The secondary
alcohol 17 was obtained from 15 by TBDPS protection and
hydrogenolysis (Scheme 3).
Direct macrodiolide formation of the monomeric seco
acid 16 did not proceed. A relatively low yield of the
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Scheme 5. Synthesis of IKD-8344. a) 15 (1.0 equiv), 2,4,6-Cl3PhCOCl
(1.7 equiv), NEt3 (3.5 equiv), THF (0.025m); 17 (1.3 equiv), DMAP
(3.0 equiv), benzene (0.02m); b) conc. HCl, MeOH; c) H2, Pd(OH)2/C,
EtOAc; d) 2,4,6-Cl3PhCOCl (40 equiv); NEt3 (60 equiv), DMAP
(20 equiv), toluene (0.15 mm), reflux.
Experimental Section
Scheme 3. Preparation of the A fragment. a) SO3·pyridine, NEt3,
Ester 12: nBu3SnH (0.018 mL, 0.07 mmol) and Et3B (1.0m in hexane,
0.088 mL) were added to a solution of iodide 11 (31 mg, 0.058 mmol)
in toluene (6 mL) at ꢀ788C. The resulting solution was stirred for 1 h
under air at ꢀ788C. Concentration and purification of the residue by
flash column chromatography (hexanes/EtOAc, 4:1) furnished ester
12 (21.5 mg, 91%): Rf = 0.31 (hexanes/EtOAc, 4:1); 1H NMR
(300 MHz, CDCl3): d = 7.33–7.24 (m, 5H), 4.53 and 4.47 (AB q,
2H, JAB = 11.3 Hz), 4.08–3.99 (m, 3H), 3.86–3.78 (m, 2H), 3.69 (s,
3H), 2.60–2.55 (m, 1H), 2.05–1.90 (m, 6H), 1.70–1.39 (m, 5H), 1.19
(d, 3H, J = 6.0 Hz), 1.11 (d, 3H, J = 7.0 Hz), 0.82 ppm (d, 3H, J =
6.9 Hz); 13C NMR (75 MHz, CDCl3): d = 175.5, 139.2, 128.2, 127.7,
127.2, 80.0, 79.6, 77.9, 77.2, 74.6, 71.6, 51.6, 45.2, 40.6, 36.5, 33.9, 31.6,
30.7, 28.4, 21.4, 13.1, 10.0 ppm; IR (neat): nmax = 3029, 2967, 2877,
1739, 1455, 1376, 1197, 1068, 736, 698 cmꢀ1; MS (CI): m/z (relative
intensity): 405 [M+ + 1] (81), 297 (100), 295 (28), 279 (11), 213 (63),
183 (31), 157 (42), 91 (23); HRMS (CI): calcd for C24H37O5 [M+ + 1]:
405.2641; found: 405.2641; [a]2D7 = + 14.0 (c = 1.16, CHCl3).
DMSO/CH2Cl2 (1:1); b) LiBH4, diethyl ether, 08C!RT; c) I2, Ph3P,
imidazole, THF, 08C!RT; d) Ph3P, MeCN, reflux; e) BuLi, THF,
ꢀ788C; 13; f) mCPBA, CH2Cl2, 08C; g) LiAlH4, diethyl ether, 08C;
h) Dess–Martin periodinane (3.0 equiv), CH2Cl2; i) NaClO2 (1.3 equiv),
NaH2PO4 (1.3 equiv), tBuOH/2-methyl-2-butene/H2O (10:5:1); j) H2,
Pd/C, MeOH; k) TBDPSCl (4.0 equiv), imidazole (7.0 equiv), DMAP
(0.5 equiv), CH2Cl2; l) H2, Pd(OH)2/C, EtOAc. mCPBA=3-chloroperox-
ybenzoic acid, DMAP=4-dimethylaminopyridine.
macrolide product 18 was obtained under a variety of
conditions (Scheme 4).[11] The coupling reaction of 15 and
17, however, proceeded efficiently under standard Yamaguchi
IKD-8344 (1): The dimeric seco acid 20 (15 mg, 0.017 mmol) was
dissolved in toluene (113 mL). NEt3 (0.15 mL, 1.04 mmol), 2,4,6-
trichlorobenzoyl chloride (0.11 mL, 0.70 mmol), and DMAP (42 mg,
0.35 mmol) were added at room temperature, and then the solution
was heated under reflux for 4 h. The reaction was quenched by
addition of saturated NH4Cl solution (100 mL) and the reaction
mixture was extracted with CH2Cl2 (150 mL ” 3). The organic extracts
were dried over MgSO4, filtered, and concentrated. Purification of the
residue by flash column chromatography (hexanes/EtOAc, 2:1) gave
IKD-8344 (1, 9.5 mg, 65%): Rf = 0.28 (hexanes/EtOAc, 2:1);
1H NMR (300 MHz, CDCl3): d = 5.32–5.28 (m, 2H), 4.38–4.31 (m,
2H), 4.15–4.01 (m, 4H), 3.96–3.87 (m, 4H), 3.82–3.76 (m, 2H), 2.95–
2.83 (m, 4H), 2.46–2.26 (m, 6H), 2.19–2.13 (m, 2H), 2.03–1.90 (m,
9H), 1.81–1.73 (m, 3H), 1.68–1.59 (m, 5H), 1.51–1.38 (m, 9H), 1.18
(d, 6H, J = 6.0 Hz), 1.09 (d, 6H, J = 7.4 Hz), 1.00 (d, 6H, J = 7.3 Hz),
0.83 ppm (d, 6H, J = 7.5 Hz); 13C NMR (75 MHz, CDCl3): d = 212.0,
175.1, 80.5, 80.0, 79.5, 75.2, 74.9, 74.8, 72.2, 53.4, 45.6, 45.6, 41.1, 36.2,
33.9, 32.1, 30.9, 30.7, 29.6, 29.4, 21.2, 14.4, 13.7, 10.9 ppm; MS (FAB):
m/z (relative intensity): 867 [M+ + Na] (58), 883 (45), 845 (14), 423
(12), 307 (22), 289 (11), 209 (43), 154 (83), 85 (100); HRMS (FAB):
Scheme 4. Cyclization of the seco acid. a) CDIC (2.5 equiv), Cs2CO3
(1.0 equiv), CH2Cl2 (0.02m), 08C; DMAP (20 equiv). CDIC=2-chloro-
1,3-dimethylimidazolinium chloride, s.m.=recovered starting material.
conditions to afford ester 19 (Scheme 5). The dimeric seco
acid 20 was obtained efficiently through TBDPS deprotection
and hydrogenolysis. IKD-8344 (1)[12] was finally obtained
upon lactonization of 20 under modified Yamaguchi condi-
tions (Scheme 5).[13]
The present synthesis is another example of the applica-
tion of b-alkoxymethacrylate radical cyclization reactions[9]
for the stereoselective construction of complex oxacyclic
natural products.
calcd for C48H76O12Na [M+ + Na]: 867.5235; found: 867.5239; [a]1D5
+ 39.7 (c = 0.25, CHCl3).
=
Received: July 18, 2006
Published online: October 2, 2006
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Keywords: anticancer agents · antifungal agents ·
.
macrodiolides · natural products · total synthesis
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