Total synthesis of (+)-SCH 351448

Article abstract of DOI:10.1021/ol201863b

A convergent synthesis of (+)-SCH 351448 (1), a monosodium salt of a C ₂-symmetric macrodiolide, is described. Our approach is based on a [4 + 2] annulation with a chiral allyl silane (anti-5c) to assemble the pyran subunits. Homodimerization w

Full text of DOI:10.1021/ol201863b

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4652–4655
Total Synthesis of (þ)-SCH 351448
Kaicheng Zhu and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
Development, Metcalf Center for Science and Engineering, Boston University,
590 Commonwealth Avenue, Boston, Massachusetts 02215, United States
panek@bu.edu
Received July 11, 2011
ABSTRACT
A convergent synthesis of (þ)-SCH 351448 (1), a monosodium salt of a C2-symmetric macrodiolide, is described. Our approach is based on a
[4 þ 2] annulation with a chiral allyl silane (anti-5c) to assemble the pyran subunits. Homodimerization was carried out in a stepwise fashion; initial
esterification at C290 followed by macrocyclization at C29 afforded the desired macrodiolide.
In 2000, Hedge and co-workers reported the bioassay-
guided isolation of a microbial metabolite, named SCH
351448 (1), from the organic extract of Micromonospora
sp.1 SCH 351448 is a novel activator (ED50 = 25 μM) for a
low-density lipoprotein receptor promoter, which is im-
portant for the treatment of hypercholesterolemia.2
The structure of SCH 351448 (1) was determined by
single-crystal X-ray analysis and exhibited a hepta-coordi-
nated sodium ion positioned in the interior cavity of the
hydrophobic skeletal array.1 Its structure consisted of a
28-membered macrodiolide comprised of two identical
hydroxy carboxylic acid monomeric subunits. The intri-
guing structure and unique bioactivity of 1 have led to
several total synthesis programs being initiated by the
synthetic community.3
Our retrosynthetic analysis of this target (Figure 1)
began with a disconnection of the C29/C290 ester bonds
to yield the monomeric subunit 2. The latter was envi-
sioned to come from an olefin cross metathesis of frag-
ments 3 and 4. Fragment 3 could arise from an asymmetric
allylation and crotylation ofthe cis-2,6-dihydropyrancore,
which would be formed from a [4 þ 2] annulation reaction4
of allylsilane anti-5c with aldehyde 6a. Similarly, fragment
4 would be derived from silane anti-5c and aldehyde 6b.
We have previously reported a highly diastereo- and
enantioselective [4 þ 2] annulation between aldehydes and
syn allylsilanes.4 However, early experiments at applying
the annulation to form dihydropyran products 7 from
silanes syn-5b/syn-5c and aldehyde 6a (Scheme 1, eq 1)
gave inconsistent results and thus were not synthetically
useful. Previously, Roush had reported the construction of
cis-2,6-disubstituted dihydropyrans using anti-allylsilanes
derived from the asymmetric γ-silyl allylboration of an
aldehyde.5 In that report, the favored pathway was
thought to proceed via a boat-like TS-A which fashioned
the cis-isomer as the major product, while the trans-isomer
was suggested to form via the unfavored chairlike TS-B
(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.
(3) For previous total syntheses, 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, 2680–2681. (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.; Lee, E. J. Org. Chem. 2005, 70, 6321–6329. (c) Soltani,
O.; De Brabander, J. K. Org. Lett. 2005, 7, 2791–2793. (d) Bolshakov, S.;
Leighton, J. L. Org. Lett. 2005, 7, 3809–3812. (e) Crimmins, M. T.;
Vanier, G. S. Org. Lett. 2006, 8, 2887–2890. (f) Cheung, L. L.; Rychnovsky,
S. D. Org. Lett. 2008, 10, 3101–3104. For the partial syntheses, see: (g)
Backes, J. R.; Koert, U. Eur. J. Org. Chem. 2006, 12, 2777–2785. (h) Chan,
K.-P.; Ling, Y. H.; Loh, T.-P. Chem. Commun. 2007, 939–941. (i) Park, H.;
Kim, H.; Hong, J. Org. Lett. 2011, 13, 3742–3745.
(4) Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004, 126, 2425–2430.
(5) Roush, W. R.; Dilley, G. J. Synlett 2001, SI, 955–959.
r
10.1021/ol201863b
Published on Web 08/11/2011
2011 American Chemical Society

aldehydes to produce 2,6-cis dihydropyrans 7; the results
are summarized in Table 1. One proposed mechanism that
accounts for the stereochemical course of the annulation
involves the equilibration between a twist boat-like TS-C
and a chairlike TS-D, where TS-C avoids the steric desta-
bilizing trans-diaxial orientation versus TS-D (Scheme 1,
eqs 4 and 5).
Table 1. Synthesis of cis-Dihydropyrans via [4 þ 2] Annulation
major
yield
dr
entry
aldehyde
anti-silane isomera (%)b (cis/trans)c
1
2
3
4
5
6
R = PhCH2
R = PhCH2
R = PhCH2
R = n-C4H9
R = n-C4H9
R = n-C4H9
5a
5b
5c
5a
5b
5c
7a
7b
7c
7d
7e
7f
30
46
83
25
58
81
10:1
13:1
17:1
10:1
12:1
18:1
a Stereochemistry of the dihydropyrans was assigned by NOE ex-
periments. b Yields were based on pure materials isolated by chromato-
graphy on SiO2. c The product ratios were determined by 1H NMR
(400 MHz).
Figure 1. Retrosynthetic analysis of SCH 351448 (1).
Synthesis of the C1ꢀC13 fragment began with the
knownR,R0-dimethylaldehyde6a6 (Scheme2).Annulation
ofsilane anti-5cand aldehyde 6aproceeded smoothly in the
presence of TMSOTf to afford the desired dihydropyran 8
in 83% yield (dr 13:1). Hydrogenation of 8 afforded a
primary alcohol which was later oxidized to aldehyde 9 in
80% yield over two steps. Further oxidation under Pinnick
oxidation conditions7 and protection afforded benzyl ester
10. An SN2 displacement of the mesitylate in compound 10
with NaCN followed by Raney-nickel mediated partial
reduction8 of the resulting nitrile afforded aldehyde 11
in 60% yield, after hydrolysis of the intermediate imine.
Scheme 1. Possible Transition States for the [4 þ 2] Annulation
Scheme 2. Synthesis of C1ꢀC13 Fragment
(Scheme 1). In that context, we have observed that anti-
silanes such as 5 participate in a [4 þ 2]-annulation with
Org. Lett., Vol. 13, No. 17, 2011
4653

Asymmetric allylation of 11 using Brown’s protocol9-
furnishedthe desired secondary homoallylic alcohol, which
was subsequently protected as benzyl ether 12. Oxidative
cleavage of alkene 12 followed by asymmetric crotylation
of the resulting aldehyde using Brown’s(E)-crotyl borane10
afforded the anti-homoallylic alcohol, which was protected
as its TBS ether to provide olefin 3 as one of the coupling
partners in 60% yield over three steps.
Synthesis of the C14ꢀC29 fragment (Scheme 3) began
with aryl triflate 13,11 which was subjected to a Sonogashira
cross-coupling to afford propargylic alcohol 14 in 85%
yield. Catalytic hydrogenation of alkyne 14 in the presence
of Pd/C followed by PCC oxidation provided aldehyde 6b.
With advanced intermediates 3 and 4 available in
useful amounts, we were now positioned to investigate
methods for their union. Cross metathesis between 3 and 4
(Scheme 4) proceeded smoothly using the Grubbsꢀ
Hoveyda second generation catalyst,14 which delivered
the (E)-olefin. This material was then subjected to diimide
reduction3a to afford advanced intermediate 20. Deprotec-
tion of 20 provided seco acid 2, which was poised for the
homodimerization experiments.
Scheme 4. Attempted Template-Directed Macrodimerization
Scheme 3. Synthesis of C14ꢀC29 Fragment
A synthetic strategy to construct the C2-symmetrical
macrodiolide core of cycloviracin B1 has been described by
€
nization reaction promoted by 2-chloro-1,3-dimethylimi-
dazolinium chloride (DMC).16 Inspired by this work, we
investigated a similar strategy for macrodiolide formation.
Unfortunately, treatment of seco acid 2 with DMC/
DMAP and suitable additives17 only led to the undesired
14-membered lactone 2318 without formation of dimeric
product 22. After these disappointments, we evaluated a
Annulation between aldehyde 6b and silane anti-5c furn-
ished the desireddihydropyran, whichwashydrogenatedto
give 15 in 70% yield over two steps. Subsequent SN2
displacement of the mesitylate in 15 yielded an iodide,
which was further converted to acetate 16 in 60% yield
overtwo steps. A Sc(OTf)3 catalyzedhydrolysis12 of acetate
16 provided primary alcohol 17 in 91% yield, which was
Furstner.15 It involved a template-directed macrodilacto-
then subjected to a Swern oxidation, followed by a Ju-
ꢀ
3e
liaꢀKocienski olefination with sulfone 18,13 to give al-
kene 19 in 80% yield. Opening of the dioxinone ring in 19
afforded the intermediate phenol, which was converted to
the β-silyl ester 4.
(14) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168–8179. (b) Chatterjee, A. K.; Choi,
T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–
11370.
€
(15) Furstner, A.; Albert, M.; Mlynarski, J.; Matheu, M.; DeClercq,
(6) Yang, Y.; Wang, J.; Kayser, M. Tetrahedron: Asymmetry 2007,
18, 2021–2025.
(7) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37,
2091–2096.
(8) Ghosh, A. K.; Moon, D. K. Org. Lett. 2007, 9, 2425–2427.
(9) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092–
2093.
(10) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919–
5923.
(11) Uchiyama,M.;Ozawa,H.;Takuma,K.;Matsumoto,Y.;Yonehara,
M.; Hiroya, K.; Sakamoto, T. Org. Lett. 2006, 8, 5517–5520.
(12) Kajiro, H.; Mitamura, S.; Mori, A.; Hiyama, T. Bull. Chem. Soc.
Jpn. 1999, 72, 1553–1560.
E. J. Am. Chem. Soc. 2003, 125, 13132–13142.
(16) (a) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 5832–5835. (b)
Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984–6887. (c) Isobe, T.;
Ishikawa, T. J. Org. Chem. 1999, 64, 6989–6992. (d) Fujisawa, T.; Mori,
T.; Fukumoto, K.; Sato, T. Chem. Lett. 1982, 11, 1891–1895.
€
(17) (a) Furstner, A. In Templated Organic Synthesis; Diederich, F.,
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 2000; pp 249ꢀ273. (b) Typical
procedure: the additive (2.0 equiv) is added at 0 °C to a solution of seco
acid 2 (20 mg, 0.023 mmol) and 2-chloro-1,3-dimethylimidazolinium
chloride (10 mg, 0.059 mmol) in CH2Cl2 (1.1 mL), and the resulting
mixture is stirred for 1 h at that temperature. DMAP (7.2 mg, 0.059
mmol) is then introduced, and stirring is continued for 16 h at ambient
temperature; additives: NaH, KH, CaH2, Na2CO3, Cs2CO3.
(18) Similar 14-membered lactones were also reported in the previous
syntheses by Lee and Rychnovsky.
(13) Leburn, M. ꢀE.; Le Marquand, P.; Berthelette, C. J. Org. Chem.
2006, 71, 2009–2013.
4654
Org. Lett., Vol. 13, No. 17, 2011

stepwise pathway to complete the synthesis, as illustrated
in Scheme 5.
and addition of dioxinone 24 led to the desired monoester
product, which was protected to afford 25 in 60% yield
over two steps. Deprotection of the monoester provided
the seco acid, which was subjected to a DMC/DMAP-
promoted esterification16 reaction to achieve macrocycle
formation; 22 was obtained in 50% yield over two steps.
Lastly, deprotection followed by workup with 4 M HCl
saturated with NaCl3a delivered SCH 351448 (1) as its
monosodium salt in 70% yield. The spectral data for our
synthetic material matched those reported for the natural
product.3
Scheme 5. Assemly of 1 by Dioxinone Ring-Opening and
Macrocyclization
In summary, we have described a convergent, enantio-
selective total synthesis of (þ)-SCH 351448 that proceeds
in 2.3% overall yield from readily available allylsilane anti-
5c. Synthetic highlights of our route include a [4 þ 2]
annulation strategy using silane anti-5c to ultimately con-
struct the tetrahydropyran ring systems in fragments 3 and
4. Olefin cross metathesis was utilized in the union of two
advanced fragments to generate the monomeric subunit.
A metal-template directed macrodilactonization strategy
proved unsuccessful. Thus, the macrodiolide was as-
sembled through a two-step sequence involving dioxinone
ring opening with concomitant esterification followed by
DMC/DMAP-mediated macrocyclization.
Acknowledgment. Financial support was obtained from
NIH CA 53604. We are grateful to Prof. John Snyder,
Dr. Paul Ralifo, and Dr. Norman Lee (Chemical Instru-
mentation Center at Boston University) for helpful discus-
sions and assistance with NMR and HRMS experiments.
The reaction sequence that ultimately proved successful
utilized Lee’s method of esterification,3a which was facili-
tated by dioxinone ring opening. Cross metathesis be-
tween 19 and 3 afforded the intermediate alkene, which
was reduced with diimide to deliver dioxinone 24. TBS
deprotection of 20 gave alcohol 21 in 91% yield
(Scheme 4). Deprotonation of alcohol 21 with NaHMDS
Supporting Information Available. Experimental de-
tails and selected spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 17, 2011
4655