A formal synthesis of SCH 351448

Article abstract of DOI:10.1021/ol201426c

An efficient formal synthesis of SCH 351448 was accomplished through the tandem cross-metathesis (CM)/oxa-Michael, the 1,4-syn aldol, the tandem oxidation/oxa-Michael, and the Suzuki coupling reaction.

Full text of DOI:10.1021/ol201426c

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3742–3745
A Formal Synthesis of SCH
351448
Heekwang Park,† Hyoungsu Kim,‡ and Jiyong Hong*,†
Department of Chemistry, Duke University, Durham, North Carolina 27708,
United States, and College of Pharmacy, Ajou University, Suwon 443-749, Korea
jiyong.hong@duke.edu
Received May 26, 2011
ABSTRACT
An efficient formal synthesis of SCH 351448 was accomplished through the tandem cross-metathesis (CM)/oxa-Michael, the 1,4-syn aldol, the
tandem oxidation/oxa-Michael, and the Suzuki coupling reaction.
Low-density lipoprotein receptor (LDL-R) is a mem-
brane-anchored, transmembrane receptor that plays an
important role in regulating plasma cholesterol levels.1
Increased levels of LDL-R leads to reduced cholesterol
levels and, therefore, is a promising strategy to treat
hypercholesterolemia. Hedge and co-workers screened
microbial fermentation broths and reported the isolation
and structure elucidation of SCH 351448 (1, Scheme 1), an
activator of the LDL-R obtained from a microorganism
belonging to Micromonospora sp.2 Due to its potential for
treating hypercholesterolemia, the synthesis of 1 has
attracted considerable interest from a number of groups,3,4
culminating in the first total synthesis by Lee and co-
workers.3a Herein, we report an efficient formal synthesis
of 1 using a combination of the tandem cross-metathesis
(CM)/oxa-Michael reaction and the tandem oxidation/
oxa-Michael reaction.
Our retrosynthetic plan for 1 relies on the tandem CM/
oxa-Michael reaction and the tandem oxidation/oxa-Mi-
chael reaction for the synthesis of the 2,6-cis-tetrahydro-
pyrans embedded in 1 (Scheme 1). We envisioned that the
Suzuki coupling reaction of 3 and 4 would complete the
monomeric unit 2, which would constitute a formal synth-
esis of 1. The tandem oxidation/oxa-Michael reaction in
conjuction with the dithiane coupling reaction was ex-
pected to afford 2,6-cis-tetrahydropyran 4 with excellent
stereoselectivity. The requisite epoxide 6 could be prepared
by the 1,4-syn aldol reaction of tetrahydropyran aldehyde
8 and ketone 9. We envisioned that the tandem CM/oxa-
Michael reaction of hydroxy alkene 10 and (E)-crotonal-
dehyde would smoothly proceed to provide 2,6-cis-tetra-
hydropyran aldehyde 8 under mild thermal conditions.
† Duke University.
‡ Ajou University.
(1) Goldstein, J. L.; Brown, M. S. Arterioscler. Thromb. Vasc. Biol.
2009, 29, 431–438.
(2) 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.
(3) For total and formal synthesis, 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) Soltani, O.; De Brabander, J. K. Org. Lett.
2005, 7, 2791–2793. (c) Bolshakov, S.; Leighton, J. L. Org. Lett. 2005, 7,
3809–3812. (d) Crimmins, M. T.; Vanier, G. S. Org. Lett. 2006, 8, 2887–
2890. (e) 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. (f) Chan, K.-P.; Ling, Y. H.; Loh,
T.-P. Chem. Commun. 2007, 939–941. (g) Cheung, L. L.; Marumoto, S.;
Anderson, C. D.; Rychnovsky, S. D. Org. Lett. 2008, 10, 3101–3104.
(4) For synthetic studies, see: (a) Bhattacharjee, A.; Soltani, O.; De
Brabander, J. K. Org. Lett. 2002, 4, 481–484. (b) Backes, J. R.; Koert, U.
Eur. J. Org. Chem. 2006, 2777–2785.
r
10.1021/ol201426c
Published on Web 06/21/2011
2011 American Chemical Society

Scheme 1. Retrosynthetic Plan for SCH 351448 (1)
Scheme 2. Synthesis of 2,6-cis-Tetrahydropyran Aldehyde 8
through the Tandem CM/Oxa-Michael Reaction
(60ꢀ77%, dr = 4ꢀ5:1).7ꢀ11 The conjugate addition step
required no activation by base or microwave7 and pro-
ceeded under mild thermal conditions. To the best of our
knowledge, this is the first successful example of the
tandem CM/Michael reaction with aldehyde substrates.
The Myers’ asymmetric alkylation reaction12 of 1212 and
1313 afforded the desired alkylation product 14 as a single
disastereomer in 97% yield. Treatment of 14 with CH3Li
afforded the corresponding methyl ketone 9 in 89% yield.
Table 1. 1,4-syn-Aldol Reaction of 8 and 9
The formal synthesis of SCH 351448 (1) started with the
preparation of 2,6-cis-tetrahydropyran aldehyde 8 and
ketone 9 (Scheme 2). Opening of the chiral epoxide 115
with 3-butenylmagnesium bromide provided hydroxy al-
kene 10. The CM reaction of 10 and (E)-crotonaldehyde in
the presence of HoveydaꢀGrubbs II catalyst6 and the
subsequent oxa-Michael reaction smoothly proceeded to
provide the desired 2,6-cis-tetrahydropyran aldehyde 8
enolization
conditions
reaction
yield
(%)a
entry
1
reagents
conditions
drb
(5) Nakata, T.; Matsukura, H.; Jian, D.; Nagashima, H. Tetrahedron
Lett. 1994, 35, 8229–8232.
(6) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J.
Am. Chem. Soc. 2000, 122, 8168–8179. (b) Gessler, S.; Randl, S.;
Blechert, S. Tetrahedron Lett. 2000, 41, 9973–9976.
c-Hex2BCl,
Et3N, Et2O
(ꢀ)-Ipc2BCl,
Et3N, Et2O
(ꢀ)-Ipc2BCl,
Et3N, Et2O
(ꢀ)-Ipc2BCl,
Et3N, Et2O
0 °C, 1 h
0 °C, 2 h
0 °C, 1 h
0 °C, 1 h
ꢀ78 °C, 1 h;
ꢀ20 °C, 14 h
ꢀ78 °C, 5 h
55
70
62
72
1.5:1
2
3
4
3:1
4:1
9:1
(7) Fuwa, H.; Noto, K.; Sasaki, M. Org. Lett. 2010, 12, 1636–1639.
(8) For the analogous tandem CM/aza-Michael reaction, see: (a)
Fustero, S.; Jimenez, D.; Sanchez-Rosello, M.; del Pozo, C. J. Am. Chem.
Soc. 2007, 129, 6700–6701. (b) Legeay, J.-C.; Lewis, W.; Stockman, R. A.
Chem. Commun. 2009, 2207–2209. (c) Cai, Q.; Zheng, C.; You, S.-L. Angew.
Chem., Int. Ed. 2010, 49, 8666–8669. (d) Fustero, S.; Monteagudo, S.;
Sanchez-Rosello, M.; Flores, S.; Barrio, P.; del Pozo, C. Chem.;Eur.
J. 2010, 16, 9835–9845.
ꢀ78 °C, 1 h;
ꢀ20 °C, 3 h
ꢀ78 °C, 2 h;
ꢀ20 °C, 16 h
a Combined yield of the isolated 15 and 150. b The diastereomeric
ratio (15:150) was determined by integration of the 1H NMR of the
mixture.
(9) For the analogous tandem CM/SN20 reaction, see: Lee, K.; Kim,
H.; Hong, J. Org. Lett. 2009, 11, 5202–5205.
(10) The tandem CM/oxa-Michael reaction of 10 and (E)-crotonal-
dehyde in the presence of Grubbs II catalyst (5 mol %, toluene, 110 °C,
14 h) provided a mixture of 8 and 80 (75%, dr = 1.5:1).
(11) The relative stereochemistry was determined to be cis by ex-
tensive 2D NMR studies (see the Supporting Information for details).
(12) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
Org. Lett., Vol. 13, No. 14, 2011
3743

With efficient routes to 8 and 9 in hand, we next
examined the coupling of 8 and 9 through the 1,4-syn aldol
reaction (Table 1). The aldol addition of 9 to 8 (c-Hex2BCl,
Et3N, Et2O)14 provided the desired β-hydroxy ketone 15
(55%), but with poor stereoselectivity (dr = 1.5:1, entry 1).
The 1,4-syn aldol reaction of 8 and 9 at ꢀ78 °C in the
presence of (ꢀ)-Ipc2BCl14 improved the stereoselectivity of
the reaction (dr = 3:1, entry 2). Surprisingly, a higher
reaction temperature and prolonged reaction time further
improved the stereoselectivity of the 1,4-syn aldol reaction
(dr = 9:1, entry 4).15 Despite the broad utility, the 1,4-syn
aldol reaction has rarely been applied in the stereoselective
synthesis of natural products.15,16
tandem oxidation/oxa-Michael reaction (Scheme 4). The
tandem oxidation/oxa-Michael reaction20,21 of 5 (MnO2,
CH2Cl2, 25 °C, 8 h) stereoselectively provided the desired
2,6-cis-tetrahydropyran aldehyde 20 with excellent yield
and stereoselectivity (90%, dr >20:1).11 One-carbon
homologation of aldehyde 20 was achieved by the Best-
mann reagent.22
Scheme 4. Synthesis of 2,6-cis-Tetrahydropyran Aldehyde 20
through the Tandem Oxidation/Oxa-Michael Reaction
1,3-anti Reduction,17 PMB-acetal protection, and DI-
BAL-reduction provided a mixture of 18 and 180 (3:1,
Scheme 3).11,18 MOM-protection, acetonide deprotection,
and epoxide formation19 set the stage for the installation of
the second 2,6-cis-tetrahydropyran moiety.
Scheme 3. Synthesis of Epoxide 6
Having successfully assembled both the 2,6-cis-tetrahy-
dropyran moieties in 1, we embarked on the final stage of
the synthesis of 1 (Scheme 5). The Suzuki coupling
reaction23 of alkyne 4 with triflate 324 provided the
€
(22) Roth, G. J.; Liepold, B.; Muller, S. G.; Bestmann, H. J. Synthesis
2004, 59–62.
The coupling reaction of epoxide 6 and dithiane 720
proceeded smoothly to provide allyl alcohol 5 for the key
(23) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483. (b)
Soderquist, J. A.; Matos, K.; Rane, A.; Ramos, J. Tetrahedron Lett.
1995, 36, 2401–2402. (c) Furstner, A.; Seidel, G. Tetrahedron 1995, 51,
11165–11176. (d) Furstner, A.; Nikolakis, K. Liebigs Ann. 1996, 2107–
2113.
€
€
(24) Uchiyama, M.; Ozawa, H.; Takuma, K.; Matsumoto, Y.;
Yonehara, M.; Hiroya, K.; Sakamoto, T. Org. Lett. 2006, 8, 5517–5520.
(25) The Sonogashira reaction of alkyne 23 and triflate 3 provided
only the homocoupling product of 23. Other coupling reactions (the
Negishi, the Stille, and the Heck reaction) did not provide the desired
coupling product.
(13) Koert, U.; Wagner, H.; Pidun, U. Chem. Ber. 1994, 127, 1447–1457.
(14) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett. 1989,
30, 7121–7124.
(15) Paterson, I.; Oballa, R. M. Tetrahedron Lett. 1997, 38, 8241–8244.
(16) Evans, D. A.; Ripin, D. H. B.; Halstead, D. P.; Campos, K. R. J.
Am. Chem. Soc. 1999, 121, 6816–6826.
(17) Evans, D. A.; Chapman, K. T.; Carreira, E. H. J. Am. Chem.
Soc. 1988, 110, 3560–3578.
(18) The configuration of the C9 stereocenter of 18 was determined
using the Kakisawa’s procedure, see: Ohtani, I.; Kusumi, T.; Kashman,
Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096.
(19) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203.
(20) Kim, H.; Park, Y.; Hong, J. Angew. Chem., Int. Ed. 2009, 48,
7577–7581.
(21) (a) Kim, H.; Hong, J. Org. Lett. 2010, 12, 2880–2883. (b) Lee, K.;
Kim, H.; Hong, J. Org. Lett. 2011, 13, 2722–2725.
3744
Org. Lett., Vol. 13, No. 14, 2011

Oxidation to carboxylic acid, formation of Bn ester, and
PMB-deprotection completed the synthesis of 2, which
proved identical in all respects with the known synthetic 2
reported by De Brabander and co-workers (see the Sup-
porting Information for details).3b
Scheme 5. Completion of a Formal Synthesis of SCH 351448 (1)
In summary, the utility of the tandem CM/oxa-Mi-
chael reaction and the tandem oxidation/oxa-Michael
reaction was demonstrated for the efficient formal
synthesis of SCH 351448 (1). The tandem reactions
proceeded under mild reaction conditions and required
no activation of oxygen nucleophiles and/or aldehydes.
It was also shown that the 1,4-syn aldol reaction and the
Suzuki coupling reaction were effective for the efficient
construction of the monomeric unit of 1. It is note-
worthy that all seven of the stereogenic centers in 2
was derived from three simple fragments 11ꢀ13 and
substrate-controlled reactions. The convergent route
should be broadly applicable to the synthesis of a diverse set
of analogues of 1 for further biological studies.
Acknowledgment. This work was supported by Duke
University. We are grateful to the NCBC (Grant No. 2008-
IDG-1010) for funding of NMR instrumentation and to
the NSF MRI Program (Award ID No. 0923097) for
funding of mass spectrometry instrumentation.
Supporting Information Available. General experimen-
tal procedures including spectroscopic and analytical
data along with copies of 1H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
corresponding coupling product 21.25 Simultaneous
Bn-deprotection, desulfurization, and reduction of al-
kyne 21 were accomplished by treatment with Raney-Ni.
Org. Lett., Vol. 13, No. 14, 2011
3745