Enantioselective total synthesis of (+)-SCH 351448

Article abstract of DOI:10.1021/ol061073b

A stereoselective synthesis of SCH 351448 has been completed. Twelve of the fourteen stereogenic centers were established through chiral enolate reactions, and six key C-C bonds were formed by metathesis reactions.

Full text of DOI:10.1021/ol061073b

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2887-2890
Enantioselective Total Synthesis of
)-SCH 351448
(+
Michael T. Crimmins* and Grace S. Vanier
Venable and Kenan Laboratories of Chemistry,
UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599
crimmins@email.unc.edu
Received May 2, 2006
ABSTRACT
A stereoselective synthesis of SCH 351448 has been completed. Twelve of the fourteen stereogenic centers were established through chiral
enolate reactions, and six key C C bonds were formed by metathesis reactions.
−
Hedge and co-workers at the Schering-Plough Research
Institute recently reported the bioassay-guided isolation of
a microbial metabolite, designated SCH 351448 (1), from
the extracts of Micromonospora sp.1 SCH 351448 (1)
selectively activates (ED50 ) 25 µM) transcription from the
low-density lipoprotein receptor (LDL-R) promoter. Uptake
of low-density lipoprotein (LDL) from the blood serum is
controlled by the LDL-R, and regulation of the LDL-R
promoter transcription can allow for control of cholesterol
levels.2 SCH 351448 is the only known agent that is a
selective activator of LDL-R. The biological potential as well
as the remarkably novel diolide structure of SCH 351448
have marked it as an important synthetic target with three
total syntheses already recorded.3-5
Our strategy for the synthesis of SCH 351448 centered
on the use of chiral enolate technology to establish 12 of the
14 required stereocenters and the utilization of olefin meta-
thesis for the formation of six C-C bonds (C4-C5, C4′-C5′,
C16-C17, C16′-C17′, C20-C21, C20′-C21′). Thus, SCH
351448 could be derived from subunits 2, 3, and 4 (Scheme
1) by esterification of the C11 and C11′ hydroxyls, cross
metathesis to form the C20′-21′ bond, hydrogenation of the
double bonds, and final adjustment of the C1 oxidation state.
This strategy provided substantial flexibility in determining
the optimal order of the operations for the assembly of the
key fragments. Subunits 2 and 3 would be derived from
polyene 5, which would be prepared by a diastereoselective
aldol reaction to construct the C11-C12 bond and establish
the required stereochemical configuration at C11 and C12.
(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) 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. (b) Kang, E. J.; Cho, E.
J.; Ji, M. K.; Lee, Y. E.; Shin, D. M.; Choi, S. Y.; Chung, Y. K.; Kim,
J.-S.; Kim, H.-J.; Lee, S.-G.; Lah, M. S.; Lee, E. J. Org. Chem. 2005, 70,
6321.
The synthesis began with the preparation of the C1-C11
subunit 6 as illustrated in Scheme 2. Addition of acrolein to
a solution of the chlorotitanium enolate of N-propionyl
thiazolidinethione 7 provided the aldol adduct 8 (97%, >98:2
dr).6 Direct transesterification of the thioimide with isobu-
tanol gave the isobutyl ester, which was alkylated under
Frater-Seebach conditions7 to deliver ester 9. The ester 9
was reduced, and the resultant diol was selectively protected
(4) Soltani, O.; De Brabander, J. K. Org. Lett. 2005, 7, 2791.
(5) Bolshakov, S.; Leighton, J. L. Org. Lett. 2005, 7, 3809.
10.1021/ol061073b CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/02/2006

of the alcohol of the aldol adduct as its MOM ether gave
the imide 16 in 84% yield over two steps (10:1 dr). The
C1-C11 fragment was completed by reductive removal of
the auxiliary and subsequent oxidation of the alcohol under
Swern11 conditions to provide the aldehyde 6 in good yield.
The C12-C20 subunit was constructed as shown in
Scheme 3. Allylic alcohol 17 was readily available in large
quantities in high enantiomeric purity through a Sharpless
kinetic resolution12 of the corresponding racemic alcohol.
The alcohol 17 was converted in the usual manner to the
glycolic acid, which was transformed to the N-acyloxazoli-
dinone 19 in excellent yield by acylation of (S)-lithio-4-
benzyl-2-oxazolidinone with the mixed anhydride of the
glycolic acid. Alkylation of the sodium enolate of imide 19
with allyl iodide8 served to selectively establish the C19
stereocenter providing alcohol 20 after reductive removal of
the auxiliary. Oxidation of the primary alcohol 20 to the
aldehyde was followed by a Wittig methylenation to produce
the triene 21. Completion of the C12-C20 fragment was
accomplished in three steps by removal of the TIPS ether,
Jones oxidation of the primary alcohol to the corresponding
acid, and formation of the N-acyloxazolidinethione 7 via
acylation of (R)-lithio-4-benzyl-2-oxazolidinethione with the
intermediate acid chloride.
Scheme 1
The C1-C11 fragment 6 and the C12-C20 subunit 7 were
joined as illustrated in Scheme 4. The critical C11-C12 bond
was formed with excellent stereocontrol by execution of a
diastereoselective syn aldol addition6 between the chlorotitani-
um enolate of thioimide 7 and aldehyde 6. The reaction pro-
ceeded in 81% yield and >15:1 diastereoselectivity for the
required isomer 22, thus introducing the remaining two stereo-
genic centers of each monomeric unit of the diolide. The
C12 methyl group was introduced by reduction of the carbon-
yl group of the N-acyloxazolidinethione to the methyl group
in an efficient sequence. The aldol adduct was protected as
the TMS ether, whereupon the N-acyloxazolidinethione was
reduced with sodium borohydride to give a primary alcohol.
The alcohol was deoxygenated by conversion to its mesylate
followed by reduction with LiEt3BH to give the desired C1-
C20 fragment 5. The polyene 5 contains C1-C20 of each
of the monomeric halves of SCH 351448.
With a workable route to polyene 5, we turned to the issue
of attaching the salicylic acid unit and assembling the
monomers. An ambitious tandem metathesis reaction was
envisioned at this point to complete the monomer by forming
three carbon-carbon double bonds in a single operation: the
closure of both the hydropyran rings and attachment of the
salicylic acid unit of SCH 351448. In the event, exposure of
polyene 5 to the Grubbs catalyst13 (10 mol %, 0.05 M in
CH2Cl2) in the presence of dioxenone 4 (10 equiv) provided
an excellent yield (88%) of the triene 23 containing all the
required carbons for the diolide monomer. This double-ring
as the corresponding primary TIPS ether 10. The secondary
alcohol 10 was alkylated with sodium bromoacetate, where-
upon the glycolic acid obtained was converted to the N-acyl
oxazolidinone 12 via the mixed anhydride. The C7 stereo-
center was established by alkylation of the sodium enolate
of imide 12 with allyl iodide.8 Reductive removal of the
auxiliary provided the alcohol 13 as a single diastereomer.
One carbon homologation of alcohol 13 to aldehyde 14 was
efficiently achieved by direct conversion of the alcohol 13
to the nitrile9 followed by reduction of the nitrile to the
aldehyde with i-Bu2AlH. The C9 stereocenter was incorpo-
rated by exploiting the Phillips10 N-acetyloxazolidinethione
15 in an aldol addition to aldehyde 14. Immediate protection
(6) (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775. (b)
Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894.
(7) Seebach, D.; Aebi, J.; Wasmuth, D. Org. Synth. 1985, 63, 109.
(8) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2,
2165.
(10) Guz, N. R.; Phillips, A. J. Org. Lett. 2002, 4, 2253.
(11) Mancuso, A. J.; Huang, S. J.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(12) Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(13) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. (b) Chatterjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
(9) Andrus, M. B.; Hicken, E. J.; Meredith, E. L.; Simmons, B. L.;
Cannon, J. F. Org. Lett. 2003, 5, 3859.
2888
Org. Lett., Vol. 8, No. 13, 2006

Scheme 2
closing metathesis-cross metathesis demonstrates the re-
the presence of dioxenone 4 gave the dioxenone 24 in good
yield, albeit somewhat lower than in the conversion of
polyene 5 to dioxenone 23.
markable selectivity accessible in metathesis reactions.
Hydrogenation of the triene with Rh/Al2O3 delivered the
saturated monomer 2.
With the two monomers joined, it remained only to close
the macrocycle and adjust the oxidation states at C1 and C1′.
Hydrogenation of the three isolated alkenes was readily
achieved by catalysis with Rh/Al2O3, whereupon the C11
TMS ether was removed. Macrolactonization was ac-
complished under basic conditions to provide the macrolide
25. Removal of the TIPS ethers, two-stage oxidation of the
primary alcohols to the carboxylic acids, and cleavage of
the MOM ethers provided SCH 351448, identical to that
previously reported.1,3-5
To summarize, a stereoselective synthesis of SCH 351448
has been completed (30 steps; longest linear sequence)
relying on the use of titanium enolates of N-acylthioimides
to establish eight of the required stereocenters and alkylation
of glycolyloxazolidinones to incorporate four stereogenic
Although it would be desirable at this point to assemble
the two monomers into the macrodiolide, all attempts to
accomplish the transformation directly have been unsuccess-
ful. This has clearly been a problem in other approaches as
well.3-5 As an alternative, assembly of the diolide in a
stepwise manner was investigated. To this end, silyl ether 5
was converted the alcohol by removal of the TMS ether with
mild acid, whereupon the polyene was exposed to the Grubbs
catalyst [Cl2(PCy3)2RudCHPh, 10 mol %, 0.001 M in CH2-
Cl2] in the absence of dioxenone 4 to produce the bishydro-
pyran 3. When alcohol 3 and dioxenone 2 were exposed to
NaN(SiMe3)2 in THF, esterification at the C11 hydroxyl
occurred in good yield. Subsequent exposure of the product
to the Grubbs catalyst13 (10 mol %, 0.05 M in CH2Cl2) in
Scheme 3
Org. Lett., Vol. 8, No. 13, 2006
2889

Scheme 4
centers. Additionally, six carbon-carbon bonds were con-
structed through olefin metathesis reactions.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support of this work by the
National Institute of General Medical Sciences (GM38904)
is acknowledged with thanks.
OL061073B
2890
Org. Lett., Vol. 8, No. 13, 2006