Total Synthesis of (+)-SCH 351448

Article abstract of DOI:10.1021/ja0315309

Total synthesis of SCH 351448 was accomplished employing the ring-closing olefin metathesis reaction for the preparation of the 28-membered macrodiolide. Copyright

Full text of DOI:10.1021/ja0315309

Published on Web 02/14/2004
Total Synthesis of (+)-SCH 351448
Eun Joo Kang, Eun Jin Cho, Young Eun Lee, Mi Kyung Ji, Dong Mok Shin, Young Keun Chung, and
Eun Lee*
School of Chemistry and Molecular Engineering, Seoul National UniVersity, Seoul 151-747, Korea
Received December 5, 2003; E-mail: eunlee@snu.ac.kr
Scheme 2. Preparation of the A Fragmenta
SCH 351448 (1) is a novel activator of low-density lipoprotein
receptor (LDL-R) promoter with an IC50 of 25 µM, which was
discovered from the organic extract of the fermentation broth of a
Micromonospora microorganism.1
The structure of 1 features a 28-membered macrodiolide consist-
ing of two identical hydroxy carboxylic acid units. We wish to
report here the first total synthesis of this intriguing molecule.2 The
synthetic plan called for double combination of units A and B, and
the olefin metathesis reaction was envisaged for macrodiolide
synthesis (Scheme 1).
Scheme 1 . Retrosynthetic Analysis
a (a) N-tosyl-(S)-valine, BH3‚THF, DCM; 2, Me2CC(OMe)(OTMS), -78
°C; (b) CHCCO2Me, NMM, MeCN; (c) concentrated HCl, MeOH; (d) I2,
Ph3P, imidazole, THF, 0 °C; (e) H3PO2, 1-ethylpiperidine, Et3B, EtOH; (f)
KOH, THF-H2O-MeOH (3:1:1); (g) BH3‚DMS, B(OMe)3, THF, 0 °C;
(h) SO3‚Pyr, TEA, DMSO-DCM (1:1), 0 °C; (i) CH2CHCH2B(lIpc)2, ether,
-78 °C; NaOH, H2O2, reflux; (j) NaHMDS, BnBr, THF-DMF (4:1), 0
°C to room temperature; (k) Ti(Oi-Pr)4, TMSCH2CH2OH, DME, 120 °C;
(l) OsO4, NMO, acetone-H2O (3:1); NaIO4; (m) (E)-CH3CHCHCH2B(dIpc)2,
THF, -78 °C; NaOH, H2O2, -78 °C to room temperature.
Scheme 3. Preparation of the B Fragmenta
Synthesis of the A fragment started with Mukaiyama aldol
reaction of the aldehyde 23 mediated by a chiral borane reagent.4
The secondary alcohol 3 obtained was converted into the â-alkoxy-
acrylate 4 via reaction with methyl propiolate, TBS deprotection,
and iodide substitution. Radical cyclization5 in the presence of
hypophosphite and triethylborane in ethanol6 proceeded efficiently
to yield the diester 5. Basic hydrolysis of 5 provided a monocar-
boxylic acid, and the corresponding aldehyde was converted into
the correct homoallylic alcohol (dr ) 9.6:1) via Brown allylation.
Benzyl protection and transesterification with 2-(TMS)ethanol led
to a new ester 6. The aldehyde obtained via oxidative cleavage
was converted into the homoallylic alcohol 7 (dr ) 14.1:1) via
Brown crotylation7 (Scheme 2).
a (a) TsCl, TEA, DCM, 0 °C; (b) PhSeSePh, NaBH4, EtOH; (c)
concentrated HCl, MeOH; (d) Bu2SnO, benzene, reflux (-H2O); BnBr,
TBAI, benzene, reflux; (e) CHCCO2Me, NMM, MeCN; (f) n-Bu3SnH,
AIBN, benzene (0.01 M), reflux; (g) LAH, THF, 0 °C; (h) SO3‚Pyr, TEA,
DMSO-DCM (1:1), 0 °C; (i) CBr4, HMPT, THF, -30 °C; (j) n-BuLi,
THF, -78 °C; (k) n-Bu3SnH, AIBN, benzene (0.02 M), reflux; (l)
PdCl2(PPh3)2, 13, LiCl, Ph3P, DMF (0.1 M), 120 °C; (m) H2, Pd/C, MeOH;
(n) SO3‚Pyr, TEA, DMSO-DCM (1:1), 0 °C; (o) Ph3PCH3+Br-, n-BuLi,
THF, 0 °C; 14, -78 °C to room temperature.
For the synthesis of the fragment B, the selenide 9 obtained from
88 was converted into 10 via regioselective benzylation and reaction
with methyl propiolate. Radical cyclization of 10 proceeded
smoothly in the presence of tributylstannane and AIBN to provide
the ester 11 in good yield. The aldehyde obtained from the ester
11 was converted into the homologous vinylstannane 12 via a
modified Corey-Fuchs protocol9 and hydrostannylation. Efficient
Stille coupling10 of 12 and 1311 led to an olefinic intermediate which
was transformed into the aldehyde 14 after hydrogenation-hydro-
genolysis and oxidation. The terminal olefin 15 was prepared from
14 via the Wittig reaction (Scheme 3).
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J. AM. CHEM. SOC. 2004, 126, 2680-2681
10.1021/ja0315309 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4. Preparation of the A-B Fragmenta
a (a) TBSOTf, 2,6-lutidine, DCM, 0 °C; (b) OsO4, NMO, acetone-H2O
(3:1); NaIO4; (c) NaBH4, EtOH; (d) 16, DIAD, Ph3P, THF, 0 °C; (e)
(NH4)6Mo7O24‚4H2O, H2O2, EtOH, 0 °C to room temperature; (f) NaHMDS,
ether, -78 °C; 14 (syringe pump, 30 min), -78 °C to room temperature;
(g) TsNHNH2, NaOAc, DME-H2O (1:1), reflux.
Figure 1. X-ray crystal structure of 1.
Scheme 5. Synthesis of SCH 351448a
Compound 1 appears to be a remarkable sodiophile. The
crystallographic data reveal a pseudo-C2-symmetric structure in
which the sodium cation is surrounded by eight oxygen atoms
(Figure 1).
Acknowledgment. This paper is dedicated to Prof. A. I. Scott
on the occasion of his 75th birthday. The authors thank the Ministry
of Science and Technology, Republic of Korea, and KISTEP for a
NRL grant (1999). BK21 graduate fellowship grants to E. J. Kang,
E. J. Cho, and Y. E. Lee are gratefully acknowledged. The authors
also thank Dr. V. R. Hegde (Schering Plough Research Institute)
for providing spectroscopic data of the natural sample.
Supporting Information Available: Selected experimental pro-
1
cedures, H and 13C NMR spectra of synthetic and natural samples of
1, and X-ray crystallographic structure of 1 (PDF and CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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(2) For previous synthetic efforts, see: Bhattacharjee, A.; Soltani, O.; De
Brabander, J. K. Org. Lett. 2002, 4, 481-484.
a (a) NaHMDS, THF, 0 °C; 18; (b) concentrated HCl, MeOH; (c)
NaHMDS, THF, 0 °C; 15, 0 °C; (d) 10 mol % Grubbs’ catalyst (2nd
generation), DCM (3 mM), 80 °C; (e) H2, Pd/C, MeOH-EtOAc (3:1); (f)
TBAF, THF; 4 N HCl (saturated with NaCl).
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A five-step sequence converted the homoallylic alcohol 7 into
the sulfone 17, which was efficiently coupled with the aldehyde
14 to generate the product olefin. The monomeric unit 18 was
obtained from the olefin via diimide reduction (Scheme 4).
The final assembly of the fragments was initiated by reacting
the sodium alkoxide derived from 7 with 18. The coupled product
was then converted into another alkoxide after TBS-deprotection,
which was used for the coupling with 15 to produce the diester 19.
Intramolecular olefin metathesis of 19 mediated by the second-
generation Grubbs catalyst12 proceeded smoothly, and the macro-
diolide 20 was obtained after hydrogenation-hydrogenolysis. (TMS)-
ethyl ester functionalities in 20 were removed by reaction with
TBAF, and the monosodium salt 1 was obtained when the reaction
mixture was equilibrated with 4 N hydrochloric acid saturated with
sodium chloride13 (Scheme 5).
(9) Drouet, K. E.; Theodorakis, E. A. J. Am. Chem. Soc. 1999, 121, 456-
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(13) Remarkably, equilibration with highly acidic solution was required for
isolation of the monosodium salt. The synthetic monosodium salt was
found to be the (+)-enantiomer: [R]13 +31.2 (c 0.73, CHCl3). The
D
specific rotation of the natural sample is unknown.
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