Total Synthesis of (+)-SCH 351448: Efficiency via Chemoselectivity and Redox-Economy Powered by Metal Catalysis

Article abstract of DOI:10.1021/jacs.6b04917

The polyketide natural product (+)-SCH 351448, a macrodiolide ionophore bearing 14 stereogenic centers, is prepared in 14 steps (LLS). In eight prior syntheses, 22-32 steps were required. Multiple chemoselective and redox-economic functional group interco

Full text of DOI:10.1021/jacs.6b04917

Communication
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Total Synthesis of (+)-SCH 351448: Efficiency via Chemoselectivity
and Redox-Economy Powered by Metal Catalysis
Gang Wang and Michael J. Krische*
University of Texas at Austin, Department of Chemistry, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: The polyketide natural product (+)-SCH
351448, a macrodiolide ionophore bearing 14 stereogenic
centers, is prepared in 14 steps (LLS). In eight prior
syntheses, 22−32 steps were required. Multiple chemo-
selective and redox-economic functional group intercon-
versions collectively contribute to a step-change in
efficiency.
mong the many issues of selectivity that impact chemical
1
2
Asynthesis, chemoselectivity (site-selectivity), the ability
to discriminate between like or unlike functional groups, and
redox-economy3 have the greatest potential to impact step-
economy, which may be considered the primary indicator of
strategic efficiency4 in ideal chemical synthesis.5 Methods that
are chemoselective (site-selective) and redox-economic pre-
clude use of protecting groups and discrete oxidation level
adjustments, which for complex molecules may account for
over half the steps of a synthetic route even after intensive
process optimization.6−8 Guided by these concepts, we have
developed a lexicon of catalytic methods9 for the direct stereo-
and site-selective9c conversion of lower alcohols to higher
alcohols, as well as related carbonyl reductive couplings
mediated by 2-propanol.9 These methods bypass discrete
alcohol-to-carbonyl redox reactions and use of premetalated C-
nucleophiles and have been shown to streamline the synthesis
of diverse polyketide natural products.9d
Here, we sought to deploy multiple chemoselective and
redox-economic methodsthose developed within and beyond
our laboratoryto more broadly demonstrate the impact of
redox-economy and chemoselectivity on synthetic efficiency.
The type I polyketide (+)-SCH 351448,10,11 an ionophoric
macrodiolide bearing 14 stereogenic centers, is an ideal vehicle
for this purpose, as eight elegant prior syntheses are available to
serve as benchmarks (Figure 1).12−14 Previously, 22−32 steps
(LLS) were required to construct (+)-SCH 351448. Through
the use of methods that embody exclusive chemoselectivity
(site-selective modification of one functional group in the
presence of multiple like/unlike functional groups), inclusive
chemoselectivity (concomitant modification of multiple like/
unlike functional groups), and redox-economy, the synthesis of
(+)-SCH 351448 is now achieved in only 14 steps (LLS). An
analysis of reaction type for past and present syntheses suggest
the accumulation of chemoselective and redox-economic
processes manifest in the present route as an increased
proportion of skeletal construction events, an outcome that is
better aligned with the ideals of synthetic efficiency.5
Figure 1. Type I polyketide (+)-SCH 351448, depiction of the sodium
ion binding motif adapted from single crystal X-ray diffraction data and
summary of synthetic work including analysis of reaction type.a a For
graphical summaries of prior total syntheses, see Supporting
Information. Longest Linear Sequence (LLS); Total Steps (TS).
Only transformations in the longest linear sequence (LLS) are
c
considered in the analysis of reaction type. b Total syntheses. Formal
syntheses.
(+)-SCH 351448, a secondary metabolite of Micromonospora
sp. bacteria, was identified in connection with a bioassay-guided
fractionation aimed at the identification of cholesterol reducing
agents.10 Specifically, (+)-SCH 351448 is an activator of a low
density lipoprotein receptor (LDL-R) promoter (IC50 = 25
μM). As increased expression of LDL-R decreases blood serum
cholesterol levels,15 (+)-SCH 351448, the first small molecule
activator of the LDL-R promoter, has garnered interest from
synthetic chemists as a potential starting point for the design of
therapeutic agents for the treatment of hypercholesterole-
mia.12−14
Received: May 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b04917
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Journal of the American Chemical Society
Communication
Scheme 1. Retrosynthetic Analysis of (+)-SCH 351448
Scheme 2. Synthesis of Fragment A Using Four Consecutive
Metal Catalyzed Transformations
a
a
Yields are of material isolated by silica gel chromatography.
Enantioselectivity was determined by chiral stationary phase HPLC
analysis. Identical yields and diastereoselectivities are observed upon
use of recovered (S)-IrLn in the conversion of 2 to 3. See Supporting
Information for further details.
The synthesis of Fragment A is achieved using four
consecutive metal catalyzed transformations (Scheme 2).
Cross-metathesis of 5-hexen-1-ol 1 with cis-1,4-diacetoxy-2-
butene19 using the second generation Grubbs catalyst16,24
delivers the allylic acetate 2 in 87% yield as a 7:1 mixture of
alkene E/Z stereoisomers. Transfer hydrogenative C-allylation
of allylic acetate 2 using allyl acetate as the allyl donor provides
the homoallylic alcohol 3 in 62% yield and 96% enantiomeric
excess. Here, chemoselective activation of allylic acetates is
achieved by virtue of the fact that the stability of a late
transition metal−olefin π-complex decreases with increasing
degree of olefin substitution.25 Tsuji−Trost cyclization18
converts the homoallylic alcohol 3 to the 2,6-cis-disubstituted
pyran 4 with good levels of diastereoselectivity, as determined
Our retrosynthetic analysis of (+)-SCH 351448 is as follows
(Scheme 1). The symmetric macrodiolide is assembled from
Fragments A and B via esterification and cross-metathesis/ring-
closing metathesis (RCM) reactions.16 For the synthesis of
Fragment A, four consecutive metal catalyzed reactions are
employed: cross-metathesis to form alcohol 2,16,19 tandem
nucleophilic17a,b and electrophilic18 allylations to convert
alcohol 2 to pyran 4,19 and the Suzuki cross-coupling of
pyran 4 with aryl triflate 5.20 Fragment B is prepared in eight
steps from 5-hexen-1-ol 1. Key transformations include
Kiyooka’s variant of the enantioselective Mukaiyama aldol
reaction (applied to aldehyde 6)21 followed by Fuwa’s
cascading cross-metathesis-oxa-Michael cyclization22,23 to
form pyran 8, which upon sequential asymmetric transfer
hydrogenative allylation17a,b and crotylation17c,d deliver Frag-
ment B. The proposed synthesis of (+)-SCH 351448 exploits
several chemoselective and redox-economic transformations.
For example, the C−H allylation of alcohol 2 avoids discrete
alcohol-to-carbonyl redox reactions and requires chemo-
selective ionization of allylic carboxylate groups. The hydro-
boration of pyran 4 requires discrimination between allylic vs
homoallylic terminal olefin moieties. The two-step conversion
of aldehyde 6 to pyran 8 occurs in the absence of redox
reactions, whereas the final step of the synthesis, the
concomitant hydrogenation/hydrogenolysis of six functional
groups (two olefins, two benzyl ethers, two benzyl esters),
represents a redox event that embodies a high degree of
inclusive chemoselectivity. Although the endgames differ, it
should be noted that Fragments A and B appear as
intermediates in total syntheses by Lee12a,b (4 vs 16 steps)
and Panek (8 vs 18 steps),12h respectively.
19
1
by H NMR analysis. The Suzuki cross-coupling of pyran 4
with aryl triflate 5 requires chemoselective hydroboration of
allylic vs homoallylic ethers. Due to the negative inductive effect
of the pyran oxygen, the alkene moiety of the homoallylic ether
undergoes selective hydroboration with 9-BBN, enabling
formation of Fragment A in 55% yield, along with a 21%
yield of recovered pyran 4. Thus, Fragment A, previously made
in 16 steps (LLS),12a,b is now made in four steps (LLS).
The synthesis of Fragment B begins with Moffatt−Swern
oxidation of 5-hexen-1-ol 1 (Scheme 3).26 The resulting
aldehyde 6 is subjected to Kiyooka’s variant of the
enantioselective Mukaiyama aldol reaction21 to furnish the
neopentyl alcohol 7 in 70% yield and 93% ee. In alignment with
Fuwa’s observations,22,23 cross-metathesis of unsaturated
alcohol 7 with crotonaldehyde in the presence of substoichio-
metric quantities of (S)-camphorsulfonic acid using the second-
generation Hoveyda−Grubbs catalyst occurs with spontaneous
oxa-Michael cyclization to furnish the 2,6-disubstituted pyran 8
1
as a single diastereomer, as determined by H NMR analysis.
Exposure of aldehyde 8 to conditions for allylation via 2-
propanol mediated transfer hydrogenation enabled formation
of homoallylic alcohol 9, which upon benzylation and
B
DOI: 10.1021/jacs.6b04917
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Journal of the American Chemical Society
Communication
a
carbinol stereocenter. Conversion to the TBS ether completes
the synthesis of Fragment B in a total of eight steps (LLS).
Previously Fragment B was prepared in 18 steps (LLS).12h
The assembly of Fragments A and B to form (+)-SCH
351448 is accomplished in a stepwise manner through
successive esterification and cross-metathesis reactions
(Scheme 4). Initial attempts at the cross-metathesis of
Fragments A and B using conditions reported by Panek12h
suffered from competing isomerization.27 Using the second
generation Hoveyda−Grubbs catalyst in combination with 1,4-
benzoquinone,28 isomerization is suppressed and the desired
product of cross-metathesis 12 is formed in 53% yield.
Exposure of compound 12 to the secondary alcohol 11 in
the presence of sodium hexamethyldisilazide (NaHMDS)
provides the product of transesterification 13 in 80% yield.
This transformation was quite sensitive to moisture, and
optimal results required use of reactants dried through repeated
evaporation from benzene. Removal of the TBS protecting
group followed by a second transesterification provides
compound 14 in 85% yield. Finally, ring-closing metathesis
followed by concomitant hydrogenation and hydrogenolysis of
the two olefins, two benzyl ethers, and two benzylic esters
(inclusive chemoselection) provides (+)-SCH 351448 in 14
steps (LLS).29
Scheme 3. Synthesis of Fragment B
In summary, the macrodiolide ionophore (+)-SCH 351448, a
type I polyketide bearing 14 stereogenic centers, is prepared in
14 steps (LLS). In eight prior syntheses, 22−32 steps (LLS)
were required. An analysis of reaction type across each route
suggests enhanced efficiency may be attributed to the use of
multiple chemoselective and redox-economic3 functional group
a
Yields are of material isolated by silica gel chromatography.
Enantioselectivity was determined by chiral stationary phase HPLC
analysis. CSA refers to (S)-camphorsulfonic acid. Identical yields and
diastereoselectivities are observed upon use of recovered (R)-IrLn in
the conversion of 8 to 9. See Supporting Information for further
details.
̀
interconversions, a conclusion that adds clarity vis-a-vis strategy
selection amid an ever-expanding and evolving lexicon of
synthetic methods. Future studies will focus on the discovery,
development, and application of catalytic methods for
protecting-group-free skeletal assembly that merge redox and
C−C bond construction events.3
ozonolysis delivered aldehyde 10. Transfer hydrogenative
crotylation of 10 provided the homoallylic alcohol 11 with
good levels of anti-diastereoselectivity (12:1 dr) accompanied
by complete levels of stereocontrol at the newly formed
a
Scheme 4. Union of Fragments A and B and Total Synthesis of (+)-SCH 351448
a
Yields are of material isolated by silica gel chromatography. See Supporting Information for further details.
C
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Communication
(11) For a review on polyether ionophores, see: Kevin, D. A., II;
Meujo, D. A. F.; Hamann, M. T. Expert Opin. Drug Discovery 2009, 4,
109.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b04917.
■
S
(12) For total syntheses of (+)-SCH 351448, see: (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.;
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(f) Crimmins, M. T.; Vanier, G. S. Org. Lett. 2006, 8, 2887.
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Angew. Chem., Int. Ed. 2001, 40, 4544.
Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
Corresponding Author
*mkrische@mail.utexas.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038) and the NIH-
NIGMS (RO1-GM069445) are acknowledged for partial
support of this research.
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DOI: 10.1021/jacs.6b04917
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