Efficient asymmetric synthesis of (+)-SCH 351448

Article abstract of DOI:10.1021/ol0515006

(Chemical Equation Presented) An efficient and stereocontrolled total synthesis of (+)-SCH 351448, a novel activator of low-density lipoprotein receptor promoter, has been achieved with a longest linear sequence of 21 steps. Key steps include applications

Full text of DOI:10.1021/ol0515006

ORGANIC
LETTERS
2005
Vol. 7, No. 17
3809-3812
Efficient Asymmetric Synthesis of
)-SCH 351448
(+
Sergei Bolshakov and James L. Leighton*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
leighton@chem.columbia.edu
Received June 27, 2005
ABSTRACT
An efficient and stereocontrolled total synthesis of (+)-SCH 351448, a novel activator of low-density lipoprotein receptor promoter, has been
achieved with a longest linear sequence of 21 steps. Key steps include applications of the recently developed asymmetric allyl- and crotylsilane
reagents and a new protodesilylative version of the tandem silylformylation/allylsilylation reaction, which provides an efficient synthesis of
1,5-syn-diols.
In 2000, researchers at the Schering-Plough Research
Institute and Duke University reported the isolation and
structure elucidation of a dimeric polyketide they termed
SCH 351448 (1).1 The isolation of SCH 351448 was guided
by its activation of low-density lipoprotein receptor (LDL-
R) promoter. This intriguing biological activity2 and the novel
structure have combined to elicit attention from the synthetic
community,3 and two total syntheses have been recorded.4,5
Our retrosynthetic analysis envisioned the coupling of alcohol
2 with ester 3 (step A, Scheme 1), followed by deprotection
of the tert-butyldimethylsilyl (TBS) group and coupling of
the resultant alcohol with ester 46 (step B). Finally, ring-
closing metathesis (RCM, step C) would be followed by
hydrogenation of the alkene product accompanied by depro-
tection of the benzyl ethers and esters to provide the natural
product. Fragments 2 and 3 could arise from a common
intermediate 5. Our tandem silylformylation-allylsilylation
methodology7 seemed well-suited to the synthesis of the 1,5-
syn-diol in 5 but would require a previously unexplored
protodesilylation workup in place of the standard oxidative
procedure for triol synthesis.
Asymmetric allylation of aldehyde 6 using our recently
developed silane reagent ent-78 followed by lactonization
with p-TsOH provided lactone 8 in 72% yield (Scheme 2).
The ee of the allylation product was found to be 93%.
Addition of the lithium enolate derived from benzyl iso-
butyrate to lactone 8, and cis diastereoselective (>20:1)
reduction of the resulting lactol9 gave tetrahydropyran 9 in
68% yield (two steps). Oxidative cleavage of the alkene to
the corresponding aldehyde was followed by asymmetric
allylation using Brown’s protocol10 (g10:1 dr) to give alcohol
(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.
(2) (a) Brown, M. S.; Goldstein, J. L. Science 1986, 232, 34. (b) Brown,
M. S.; Goldstein, J. L. Cell 1997, 89, 331.
(3) (a) Bhattacharjee, A.; Soltani, O.; De Brabander, J. K. Org. Lett.
2002, 4, 481. (b) Soltani, O.; De Brabander, J. K. Angew. Chem., Int. Ed.
2005, 44, 1696.
(4) 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.
(5) Soltani, O.; De Brabander, J. K. Org. Lett. 2005, 7, 2791.
(6) Synthesis of this compound is detailed in Supporting Information.
(7) (a) Zacuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 8587.
(b) Zacuto, M. J.; O’Malley, S. J.; Leighton, J. L. Tetrahedron 2003, 59,
8889.
(8) Kubota, K.; Leighton, J. L. Angew. Chem., Int. Ed. 2003, 42, 946.
(9) Lewis, M. D.; Cha, K. C.; Kishi, Y. J. Am. Chem. Soc 1982, 104,
4976.
(10) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
10.1021/ol0515006 CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/20/2005

Scheme 1
Scheme 2
was poor (2.5:1) (Scheme 3). When the respective enantio-
meric allyl reagents were employed, alcohol 10a was the
major product with 2:1 and 5:1 dr for the Brown reagent
and allylsilane 7, respectively. As shown, similar observa-
tions have been recorded by Hoveyda using a different chiral
â-alkoxyaldehyde.13 It therefore appears, at least with these
two aldehydes, that the two protocols are complementary:
moderate to good selectivity for the 1,3-syn product can be
realized with the Brown protocol, while moderate to good
selectivity for the 1,3-anti product may be secured with our
allylsilane reagents. It should be noted that with â-benzyl-
oxyaldehydes, the allyl- and crotylsilane reagents 7 and 12
display excellent reagent control, overwhelming any substrate
10 in 80% yield (two steps). Protection of alcohol 10 as a
benzyl ether and oxidative cleavage of the alkene gave
aldehyde 11 in 89% yield (two steps). Asymmetric crotyl-
ation employing the enantiomer of crotylsilane 1211 gave
alcohol 13 as a single diastereomer (>20:1) in 80% yield.
Treatment of 13 with diallyl-diethylaminosilane6 provided
silyl ether 14, which was immediately subjected to the
rhodium-catalyzed tandem silylformylation-allylsilylation
reaction (5 mol % Rh(acac)(CO)2, 900 psi CO, PhH, 65 °C).7
Upon ventilation of the high-pressure reaction apparatus, the
residue was treated with n-Bu4NF in THF (reflux) to provide
diol 5 as a single diastereomer in 69% yield from 13. While
this protodesilylative version of our tandem silylformyl-
ation-allylsilylation reaction represents a relatively straight-
forward extension of the methodology, the difficulties
encountered by Hoveyda in attempting a protodesilylation
in a related â-hydroxysiloxane system12 had given us cause
for concern. That the reaction in the present system is indeed
smooth provides a direct synthesis of saturated 1,5-syn-diols
from homoallylic alcohols.
Scheme 3
The use of the Brown allylation protocol for the synthesis
of 10 is worthy of further comment. When the same allylation
was performed using allylsilane ent-7, the diastereoselectivity
(11) Hackman, B. M.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2004,
6, 4375.
(12) Hale, M. R.; Hoveyda, A. H. J. Org. Chem. 1992, 57, 1643.
3810
Org. Lett., Vol. 7, No. 17, 2005

bias, as demonstrated both by the conversion of 11 to 13
and by a similar set of experiments in our earlier work.8
Protection of diol 5 as the bis-triethylsilyl (TES) ether 16
(99%) was followed by hydroformylation using the linear-
selective Nixantphos ligand14 to give aldehyde 17 in 79%
yield (Scheme 4). Barbier-type allyl addition to 17 using the
protection of the alcohol as its tert-butyldimethylsilyl (TBS)
ether proceeded to give 3 in 99% yield.
With fragments 2 and 3 in hand, we were positioned to
investigate their coupling (Scheme 6). Thus, deprotonation
Scheme 6
Scheme 4
conditions of Luche15 and subsequent oxidation with the
Dess-Martin periodinane16 then produced allyl ketone 18
in 86% overall yield (two steps). Silyl ether deprotection
and diastereoselective (>20:1) lactol reduction9 were ac-
complished by treatment of 18 with Et3SiH and BF3‚OEt2,
leading to tetrahydropyran 2 in 67% yield.
of alcohol 2 with sodium hexamethyldisilazide (NaHMDS)
and addition of acetonide 3 led to the desired ester product,
and methanolysis of the TBS ether then produced alcohol
22 in 66% yield (two steps). Deprotonation of 22 with 2.5
equiv of NaHMDS and treatment with acetonide 46 provided
bis-benzoyl ester 23 in 63% yield. RCM then proceeded
smoothly using the second-generation Grubbs catalyst,18 and
the macrocycle product was subjected to hydrogenation over
Pd/C, resulting in reduction of the alkene, both benzyl ethers,
and both benzyl esters. After workup with 4 M HCl saturated
with NaCl,4 (+)-SCH 351448 was obtained in 57% yield
(two steps). The spectral data for our synthetic material
matched those of the natural compound.
Cross metathesis17 between 5 and enone 196 proceeded
smoothly using the second-generation Grubbs catalyst18 to
deliver enone 20 in 85% yield (Scheme 5). Conjugate
Scheme 5
The stereocontrolled synthesis of (+)-SCH 351448 was
achieved in 32 total steps (including the syntheses of 4 and
19) with a longest linear sequence of 21 steps (2.1% overall
yield) from 6. The synthesis of the stereochemistry-rich
fragment 5 was accomplished in an efficient 11 steps and
19% overall yield from 6, featured two applications of our
asymmetric allyl-/crotylation reagents (6f8 and 11f13), and
inspired the development of a simple protodesilylative
(13) Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H. J.
Am. Chem. Soc. 2004, 126, 12288. See Supporting Information.
(14) van der Veen, L. A.; Keeven, P. H.; Schoemaker, G. C.; Reek, J.
N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Lutz, M.; Spek, A. L.
Organometallics 2000, 19, 872.
(15) Petrier, C.; Luche, J. L. J. Org. Chem. 1985, 50, 910.
(16) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(17) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
(18) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 6543.
reduction was accomplished by hydrogenation over Lindlar’s
catalyst, and the resulting lactol was reduced with Et3SiH
and BF3‚OEt2 to give tetrahydropyran 21 as a single
diastereomer9 (>20:1) in 91% yield (two steps). Finally,
Org. Lett., Vol. 7, No. 17, 2005
3811

modification of the tandem silylformylation-allylsilylation
reaction for the synthesis of 1,5-syn-diols (14f5).
Supporting Information Available: Experimental pro-
cedures, characterization data, and stereochemical proofs.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by a grant
from the NIH (NIGMS, GM58133). We are grateful to
Amgen and Merck Research Laboratories for research
support as well.
OL0515006
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