A concise synthesis of (+)-SCH 351448

Article abstract of DOI:10.1021/ol0510769

(Chemical Equation Presented) We describe a highly convergent synthetic approach to the natural product (+)-SCH 351448 (1) - a hexane-soluble heptacoordinate monosodium salt of a C₂-symmetrical macrocyclic dilactone. Our approach implements a p

Full text of DOI:10.1021/ol0510769

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2791-2793
A Concise Synthesis of (+)-SCH 351448
Omid Soltani and Jef K. De Brabander*
Department of Biochemistry, The UniVersity of Texas Southwestern Medical Center at
Dallas, 5323 Harry Hines BouleVard, Dallas, Texas 75390-9038
jdebra@biochem.swmed.edu
Received May 10, 2005
ABSTRACT
We describe a highly convergent synthetic approach to the natural product (
salt of a C2-symmetrical macrocyclic dilactone. Our approach implements a photochemical acylation as the key step to combine two nearly
identical but orthogonal C1 C29 fragments, followed by a base-induced intramolecular acylation and deprotection to yield the natural product.
+)-SCH 351448 (1)sa hexane-soluble heptacoordinate monosodium
−
Our interest in naturally produced small molecules of
structural novelty and potential biological significance led
us to take note of SCH 351448 (1, Figure 1)sa hexane-
soluble material purified from a Micromonospora sp. fer-
mentation broth.1 The reported ability of natural 1 to activate
transcription from the low-density lipoprotein (LDL) receptor
promoter is of mechanistic and biomedical importance.2 The
single-crystal X-ray structure of 1 shows a remarkable
topology. The ionized and un-ionized carboxy groups are
intramolecularly hydrogen-bonded and together with the
phenol and hydroxy groups accommodate a heptacoordinate
sodium ion in the interior cavity of a hydrophobic globular
structure.1 At this point, it remains unclear whether 1
functions by mediating sodium or other ion transport across
membranes or whether the role of the chelated sodium ion
is structural; i.e., does 1 behave as a hydrophobic small
molecule ligand for a cellular receptor? To answer these and
related questions, we initiated a synthetic program to provide
material for future structural, physicochemical, and biological
studies. Herein, we communicate a short and scalable
synthesis of SCH 351448.3,4
Taking maximal advantage of the dimeric nature of 1, we
hoped to identify viable esterification/lactonization strategies
to combine two identical or closely related C1-C29 fragments
(Figure 1). Recently, we reported that photolysis of
2-Ph-benzo[1,3]dioxinones (I, R ) Ph) in the presence of
alcohols is a powerful method for the synthesis of otherwise
difficult to access sterically hindered salicylate esters (eq 1).5
These studies revealed that the corresponding 2-Me-benzodi-
oxinones (I, R ) Me) do not photolyze to the powerful
acylating quinoketene intermediate II.5
(1) Hegde, V. R.; Puar, M. S.; Dai, P.; Patel, M.; Gullo, V. P.; Das, P.
R.; Bond, R. W.; McPhail, A. T. Tetrahedron Lett. 2000, 41, 1351-1354.
(2) (a) Brown, M. S.; Goldstein, J. L. Science 1986, 232, 34-47.
(b) Brown, M. S.; Goldstein, J. L. Cell 1997, 89, 331-340.
In an ideal approach, dilactones would be accessible
directly from photochemical homodimerization of a photo-
10.1021/ol0510769 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/21/2005

Scheme 1
Figure 1. Symmetry-based approach for the synthesis of SCH
351448.
responsive fragment with a free C11-alcohol (A1)sa reason-
able prospectus based on our finding that photolysis of
benzodioxinone I (R ) Ph, R′ ) -O(CH2)7OH) yielded
dilactone 2 as the major product besides monolactone (eq
1).6 Alternatively, a hydroxy-protected photoactive fragment
(A2) would be photolyzed in the presence of an orthogonal
photosilent acyl-acceptor fragment (A3) to yield an ester
dimer, necessitating a subsequent nonphotochemical lacton-
ization.
To fully explore the above-mentioned dimerization strate-
gies, we prepared a series of differentially protected frag-
ments as shown in Scheme 1. Our point of departure was
the â-hydroxyketone 3, prepared in multigram quantities as
described previously.4 Anti-selective reduction with
Me4N(AcO)3BH7 provided an anti-diol (82%)4 which was
differentially protected by treatment with TBSCl (80%)4
followed by TMSCl (88%) to yield bis-silyl ether 4.
Alternatively, a C9-OMOM-protected fragment 5 was syn-
thesized by Evans-Tishchenko reduction of 3 (MeCHO and
SmI2, 82%),8 followed by protection (f C9-OMOM, 95%),
acetate removal (f C11-OH), and TMS protection (f 5,
70% for two steps). The terminal olefin of fragments 4/5
served as a handle for C-C bond formation with aryl triflates
6a,b. Thus, palladium-catalyzed cross-coupling of in situ
prepared B-alkyl derivatives of 4/5 (9-BBN, THF, 23 °C)
with aryl triflates 6a,b under Suzuki-Miyaura conditions
(aq K3PO4, cat. PdCl2dppf, DMF, 23 °C) provided products
7b,d,f,g after removal of the C11-TMS ether with
HF‚pyridine.9,10
Next (Scheme 2), we performed a series of experiments
designed to obtain dimeric lactones directly by ultraviolet
irradiation (300 nm, 0.1 M in CH2Cl2, 1 h) of unprotected
(C11-OH) photoactive monomers 7b, 7f, or 7c (from 7b by
prolonged exposure to HF‚pyridine, Scheme 1). Unfortu-
nately, intramolecular lactonization was the dominant path-
way, providing C11-lactone 8f (34% yield) from alcohol 7f
(16% recovered) and a separable 2:1 mixture of regioisomeric
lactones 8c and 9c (38% yield) from diol substrate 7c (30%
recovered). Interestingly, photolysis of the monohydroxy
(3) Total synthesis: Kang, E. J.; Cho, E. J.; Lee, Y. E.; Ji, M. K.; Shin,
D. M.; Chung, Y. K.; Lee, E. J. Am. Chem. Soc. 2004, 126, 2680-2681.
(4) For synthetic studies from our lab, see: Bhattacharjee, A.; Soltani,
O.; De Brabander, J. K. Org. Lett. 2002, 4, 481-484.
(5) (a) Soltani, O.; De Brabander, J. K. Angew. Chem., Int. Ed. 2005,
44, 1696-1699. (b) Garc´ıa-Fortanet, J.; DeBergh, J. R.; De Brabander, J.
K. Org. Lett. 2005, 7, 685-688.
(6) (a) See the Supporting Information. (b) For a similar observation
with thermally generated acyclic ω-hydroxy-ketoketenes, see: Chen, C.;
Quinn, E. K.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1993, 58, 5011-
5014.
(7) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
(8) Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112, 6447-
6449.
(9) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201-
2208.
(10) TMS protection gave optimal results for this fragment coupling.
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Org. Lett., Vol. 7, No. 13, 2005

Scheme 2
Scheme 3
substrate 7b was accompanied by silyl migration to yield
two regioisomeric lactones 8b and 9b in a ratio of 5:1 (54%
yield).
The intrinsic propensity for intramolecular cyclization of
7b,c,f necessitated a circumvention to stage an enforced
heterodimerization of an orthogonal photosilent/photoactive
pair. Unfortunately, irradiation (300 nm, CH2Cl2, 1 h) of a
mixture of 7a (1 equiv) and 7d (3 equiv) did not provide
the desired ester dimer but yielded a TBS-transposed
monolactone 9b (∼10%) from intramolecular cyclization of
7a, unreacted 7d (10-15%) and a diol 7h (from 7d, 65%)
as shown in Scheme 2. Based on this result, we (1)
exchanged the labile C11-OTMS in the photoreactive partner
for a trifluoroacetate (7e, 92% from 7b, Scheme 1) to
eliminate intramolecular cyclization, and (2) flanked the
C11-alcohol in the acyl-acceptor fragment with a C9-OMOM
(i.e., 7g) to decrease steric hindrance around the C11-alcohol
and increase stability.
treatment with 48% aq HF in MeCN, followed by hexane
extraction from aq HCl (4 N, saturated with NaCl),3 yielded
1 contaminated with a minor byproduct (80%).12 HPLC
purification yielded pure material with 1H and 13C NMR and
mass spectral data in complete agreement with those reported
for natural1 and synthetic3 1.13
Acknowledgment. This work was supported by the
National Institutes of Health (CA 90349), the Robert A.
Welch Foundation (I-1422), and Merck Research Labora-
tories. J.K.D.B. is a fellow of the Alfred P. Sloan Foundation.
As shown in Scheme 3, irradiation (300 nm, CH2Cl2, 1 h)
of a mixture of 7e (0.2 M, 1 equiv) and 7g (2 equiv) did
yield the desired ester 10 in 60% yield based on consumed
7e (7e,g recovered in 50% and 80% respectively). With this
key event accomplished, lactone 12 was obtained in 50%
yield by treatment of alcohol 11 (from 10 by trifluoroacetate
removal, 94%), with NaHMDS (THF, -78 °C).3,11 Finally,
hydrogenolytic debenzylation gave diacid 13, which upon
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra
for new compounds, synthetic 1, and natural 1. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0510769
(12) 1H NMR shifts corresponding to this byproduct were also visible
1
in the spectrum of the natural product (from ref 3). Comparison H NMR
spectra are provided in the Supporting Information.
(13) Our material was dextrorotatory: [R]20D ) +22.4 (c 0.10, CHCl3),
similar to synthetic 1 of ref 3: [R]13D ) +31.2 (c 0.73, CHCl3). The specific
rotation and absolute configuration of the natural sample were not reported.
(11) Bhattacharjee A.; De Brabander, J. K. Tetrahedron Lett. 2000, 41,
8069-8073.
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