Assignment of absolute configuration to SCH 351448 via total synthesis

Article abstract of DOI:10.1021/ol8011474

(Chemical Equation Presented) The synthesis and absolute configuration of SCH 351448, an interesting ionophoric natural product, are reported herein. Mukaiyama aldol-Prins and segment-coupling Prins reactions were employed to construct the constituent tetrahydropyrans of SCH 351448. Efforts to assemble the C₂-symmetric core of the natural product by a templated olefin metathesis strategy are described; however, a stepwise fragment assembly was ultimately utilized to complete the target molecule.

Full text of DOI:10.1021/ol8011474

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3101-3104
Assignment of Absolute Configuration
to SCH 351448 via Total Synthesis†
Lael L. Cheung, Shinji Marumoto, Christopher D. Anderson, and Scott
D. Rychnovsky*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California, IrVine,
California 92697-2025
srychnoV@uci.edu
Received May 20, 2008
ABSTRACT
The synthesis and absolute configuration of SCH 351448, an interesting ionophoric natural product, are reported herein. Mukaiyama aldol-Prins
and segment-coupling Prins reactions were employed to construct the constituent tetrahydropyrans of SCH 351448. Efforts to assemble the
C2-symmetric core of the natural product by a templated olefin metathesis strategy are described; however, a stepwise fragment assembly
was ultimately utilized to complete the target molecule.
In 2000, Hegde and co-workers from Schering-Plough
Research Institute and Duke University reported the isolation
of the dimeric sodiated polyketide SCH 351448 (1) from an
unspecified Micromonospora sp.1 Compound 1 was found
to be a selective activator of the low-density lipoprotein
receptor (LDLR) promoter, a genetic sequence responsible
for modulating expression of the surface receptor for LDL.
Increased expression of LDLR has been shown to decrease
blood serum cholesterol levels, thereby offering a potential
therapy for hypercholesterolemia.2
Compound 1 is the only known small-molecule activator
of the LDLR promoter and has drawn appreciable scrutiny,
as evinced by several total3–6 and partial7,8 syntheses of the
(+)-enantiomer. In addition to completing the first total
synthesis, Lee noted the high binding affinity of compound
1 for Ca2+ ion at near-physiological pH. This affinity for
calcium may be pertinent to the biologicalactivityof com-
pound 1.9 We report a new synthesis of compound 1 using
Mukaiyama aldol-Prins (MAP) and segment-coupling Prins
reactions to prepare the constituent tetrahydropyrans. Fur-
thermore, we have determined the heretofore unknown
absolute stereochemistry of the natural enantiomer.
The monomeric subunits of compound 1 were dissected
into the tetrahydropyranyl fragments 2 and 3 (Figure 1).
Fragment 2 would be prepared by a MAP reaction between
the homoallylic enol ether 4 and aldehyde 5.10 Fragment 3
would be derived from tetrahydropyran 6, which would be
(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, 2680–2681. (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, 6321–6329.
† This paper is dedicated to Professor Madeline Joullie´ at the University
of Pennsylvania for her inspirational and unwavering commitment to
chemical research and education.
(4) Soltani, O.; De Brabander, J. K. Org. Lett. 2005, 7, 2791–2793.
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(6) Crimmins, M. T.; Vanier, G. S. Org. Lett. 2006, 8, 2887–2890.
(7) Backes, J. R.; Koert, U. Eur. J. Org. Chem. 2006, 2777–2785.
(8) Chan, K.-P.; Ling, Y. H.; Loh, T.-P. Chem. Commun. 2007, 939–
941.
(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.
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10.1021/ol8011474 CCC: $40.75
Published on Web 06/11/2008
2008 American Chemical Society

Scheme 1. Synthesis of Tetrahydropyranyl Fragments 13 and 14
Figure 1. Retrosynthetic analysis of SCH 351448 (1)
triflate 1316 provided a provisional C14-C29 segment
containing a benzyl ether and an E-alkene. Hydrogenation
revealed a primary alcohol that was later oxidized to aldehyde
14. Julia-Kocien´ski olefination of aldehyde 14 gave alkene
15.3 Both aldehyde 14 and alkene 15 were used in subsequent
studies.
Synthesis of the C1-C13 fragment of compound 1 began
with alcohol 17,17 prepared by asymmetric crotylation18 of
aldehyde 7 (Scheme 2). Benzyl ether formation, TIPS
deprotection, and oxidation provided aldehyde 18, the
electrophilic component for the MAP reaction. Asymmetric
allylation19 of aldehyde 19 furnished alcohol 20. Vinyl
exchange20 catalyzed by Hg(TFA)2 converted alcohol 20 to
homoallylic enol ether 21, the nucleophilic component for
the MAP reaction.
Enol ether 21 and aldehyde 18 were subjected to TiBr4-
promoted MAP reaction in the presence of 2,6-di-tert-
butylmethylpyridine (2,6-DTBMP), a hindered base, at -78
°C (Scheme 2). The resultant adduct was isolated in 76%
yield as a mixture of C9,C11-anti/syn epimers favoring the
desired anti disposition by ca. 3:1. The superfluous bromide
was removed by radical-mediated reduction and the C9,C11-
anti/syn epimers were separated by flash chromatography.
The C9 alcohol was protected as the SEM ether 22.
Hydrolysis and a stepwise oxidation of intermediate 22 gave
prepared by segment-coupling Prins reaction.11 Departing
from other reported strategies, we envisioned that a one-pot
cross-metathesis/ring-closing metathesis (CM/RCM) event
would unite two identical C1-C29 monomers and form the
macrocycle of compound 1.12 The appropriate chemo- and
regioselectivities would be dictated by a Ca2+ template12c
in the dimerization/macrocyclization cascade.
Synthesis of the C14-C29 fragment of compound 1 began
with asymmetric allylation13 of aldehyde 714 to yield alcohol
8 (Scheme 1). Conversion of alcohol 8 to R-acetoxy ether
9, followed by segment-coupling Prins reaction with SnBr4,
furnished an epimeric mixture of C17-bromotetrahydropy-
rans, which was homogenized into alcohol 10. Oxidation of
alcohol 10 to an intermediate aldehyde and subsequent
olefination through Takai’s procedure provided vinyl bor-
onate 12.15 Suzuki coupling of vinyl boronate 12 with aryl
(10) (a) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001,
123, 8420–8421. (b) Patterson, B.; Marumoto, S.; Rychnovsky, S. D. Org.
Lett. 2003, 5, 3163–3166. (c) Patterson, B.; Rychnovsky, S. D. Synlett 2004,
543–545. (d) Van Orden, L. J.; Patterson, B. D.; Rychnovsky, S. D. J. Org.
Chem. 2007, 72, 5784–5793. (e) Gesinski, M. R.; Van Orden, L. J.;
Rychnovsky, S. D. Synlett 2008, 363–366.
(11) Rychnovsky, S. D.; Hu, Y. Q.; Ellsworth, B. Tetrahedron Lett. 1998,
39, 7271–7274.
(12) For examples of ion-templated metathesis, see: (a) Mohr, B.; Weck,
M.; Sauvage, J.-P.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36,
1308–1310. (b) Ng, K.-Y.; Cowley, A. R.; Beer, P. D. Chem. Commun.
2006, 3676–3678. (c) Akine, S.; Kagiyama, S.; Nabeshima, T. Inorg. Chem.
2007, 46, 9525–9527.
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341–342. (b) La Cruz, T. E.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1873–
1875.
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115, 8467–8468.
(18) Bhat, K. S.; Brown, H. C. J. Am. Chem. 1986, 108, 5919–5923.
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2001, 2560–2561.
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15347.
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Bull. Chem. Soc. Jpn. 2004, 77, 1581–1586.
(20) Gurjar, M. K.; Krishna, L. M.; Reddy, B. S.; Chorghade, M. S.
Synthesis 2000, 557–560.
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Org. Lett., Vol. 10, No. 14, 2008

Scheme 2
.
Synthesis of the C1-C13 Ester 22 Using a
Scheme 3
. Attempted Template-Directed CM/RCM To Form
Mukaiyama Aldol-Prins Reaction
Macrodiolide Chelate 27 from Ca2+ salts 25 and 26
Table 1. Screen of Conditions for Templated CM/RCM
the acid, which was protected as a TMSE ester 23 by
Mitsunobu reaction. DDQ deprotection of benzyl ether 23
yielded alcohol 24, poised for coupling.
substrate
catalysta
conditionsb
outcomec
25
25
25
25
25
25
26
26
Grubbs I
Grubbs I
Grubbs II
Grubbs II
Grubbs-Hoveyda
Grubbs Variantc
Grubbs II
23 °C, 12 h
60 °C, 6 h
23 °C, 12 h
60 °C, 8 h
45 °C, 8 h
45 °C, 8 h
25
25 + 28
25
25 + 28
25
25
To expedite macrodiolide formation, an ion-templated CM/
RCM cascade was examined (Scheme 3). We proposed that
a Ca2+ complex comprised of two monomeric ligands would
be predisposed toward a synthetically convergent dimeriza-
tion/cyclization cascade. Hence, alcohol 24 was esterified
with the dioxinone of alkene 14. Global deprotection with
TFA furnished the free acid, which was then treated with
stoichiometric CaO in CH2Cl2 to yield Ca2+ salt 25.21
Unfortunately, treatment of salt 25 with a variety of
metathesis catalysts22 never led to the dimeric product 27
(Table 1). The CM/RCM cascade was further attempted using
Hoye’s relay tactic23 to ensure alkene activation, but substrate
26 led only to compound 25 upon treatment with metathesis
23 °C, 12 h
23-45 °C, 12 h
25
25
Grubbs-Hoveyda
a For the catalyst structures, see ref 21. b All reactions were run in
CH2Cl2. c All reactions were monitored by mass spectrometry.
catalysts. While these experiments confirmed that substrate
26 underwent relay metathesis to extrude cyclopentene, the
resultant ruthenium-alkylidene funneled to the unreactive
complex 25. After these disappointing results, we redirected
our efforts to a more conventional strategy for completing
the synthesis of compound 1.
The sequence that ultimately proved fruitful mirrored Lee’s
route to the macrocycle of compound 1 (Scheme 4).
Ozonlysis of the terminal alkene in THP 23 followed by
(21) The most drastic change upon formation of calcium salt 25 from
the free acid is found in their 13C NMR spectra, wherein the signal for the
C1 carbon of the acid (δ 180.8 ppm) disappears after exposure to CaO.
Furthermore, there are noticeable changes in peak patterns for the 60-90
ppm region: the free acid exhibits six signals whereas the calcium complex
25 exhibits only five (two of the peaks have become coincident). The
differences seen in the 1H NMR spectra are subtle, consisting primarily of
broadening of three peaks appearing between 2.5 and 4.0 ppm. Both
compounds show an identical parent molecular ion (M + Na+) by ES-MS.
For references regarding NMR studies of calcium coordination complexes
please see: (a) Chen, C.-S.; Wu, S.-H.; Wu, Y.-Y.; Fang, J.-M.; Wu, T. H.
Org. Lett. 2007, 9, 2985–2988. (b) Akine, S.; Taniguchi, T.; Nabeshima,
T. J. Am. Chem. Soc. 2006, 128, 15765–15774. (c) Akine, S.; Taniguchi,
T.; Saiki, T.; Nabeshima, T. J. Am. Chem. Soc. 2005, 127, 540–541. (d)
Nabeshima, T.; Takahashi, T.; Hanami, T.; Kikuchi, A.; Kawabe, T.; Yano,
Y. J. Org. Chem. 1998, 63, 3802–3803.
(22) (a) Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs,
R. H.; Schrodi, Y. Org. Lett. 2007, 9, 1589–1592. (b) Garber, S. B.;
Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 8168–8179. (c) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org.
Lett. 1999, 1, 953–956. (d) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs,
R. H Angew. Chem., Int. Ed. Engl. 1995, 34, 2039–2041.
(23) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H.
J. Am. Chem. Soc. 2004, 126, 10210–10211.
Org. Lett., Vol. 10, No. 14, 2008
3103

Scheme 4. Assembly of (+)-SCH 351448 (1) by Sequential Esterification and RCM
reductive workup provided an intermediate alcohol, which
was substituted with 1-phenyl-1H-tetrazole-5-thiol (29) and
then oxidized to sulfone 30. Julia-Kocien´ski coupling with
aldehyde 14 using NaHMDS gave an inconsequential 1:1
E/Z mixture of alkenes, which was reduced with diimide to
furnish dioxinone 31. Esterification with alcohol 24 and
subsequent benzyl deprotection with DDQ gave the alcohol
32. Esterification with dioxinone 15 afforded the acyclic
diene, which underwent ring-closing metathesis upon treat-
ment with the Grubbs-Hoveyda catalyst to produce mac-
rocycle 33 in 93% yield. Diimide reduction, global depro-
tection, and metalation delivered SCH 351448 (1) as the (+)-
enantiomer of sodium salt A described by Lee.
authentic material, the identity of natural and synthetic (+)-
SCH 351448 was further confirmed by comparison of their
CD spectra.25
The synthesis of (+)-SCH 351448 was achieved by using
MAP and segment-coupling Prins reactions to construct the
two pairs of THPs. A templated CM/RCM cascade proved
to be a nonviable strategy, and thus the macrodiolide was
assembled by iterative esterifications followed by RCM. The
absolute configuration of natural SCH 351448 was deter-
mined to be identical to that of the (+)-enantiomer. This
synthesis illustrates the utility of Prins cyclizations in natural
product synthesis.
The absolute configuration of the natural enantiomer of
compound 1 had remained unknown. Through the generous
gift from the Schering-Plough Research Institute of an
authentic sample of compound 1, the absolute configuration
of the natural product could then be established. Proton and
carbon data for synthetic 1 (sodium salt A) were identical
to that reported for the natural product.1 The specific rotations
of the synthetic and natural compounds 1 (sodium salts A)
were both positive.24 Because of the limited quantity of
Acknowledgment. This work was supported by the
National Institute of General Medical Sciences (GM-43854).
We thank Dr. Vinod Hegde and the Schering-Plough
Research Institute for providing us with an authentic sample
of SCH 351448.
Supporting Information Available: Characterization data
and experimental procedures for all compounds described
are included. This material is available free of charge via
the Internet at http://pubs.acs.org.
(24) Synthetic (+)-SCH 351448: [R]23 ) +80 (c ) 1.0, CHCl3).
D
Natural SCH 351448: [R]23 ) +26 (c ) 1.0, CHCl3). Both of these
OL8011474
D
rotations were obtained from newly acid-equilibrated samples (ref 1). The
reported rotation of synthetic (+)-SCH 351448 has varied from +22.4 to
+79.9.
(25) CD spectra are provided in the Supporting Information.
3104
Org. Lett., Vol. 10, No. 14, 2008