Asymmetric vinylogous Mannich reactions: A versatile approach to functionalized heterocycles

Article abstract of DOI:10.1021/ol2020384

Asymmetric vinylogous Mannich reaction (VMR) of 2-(tert- butyldimethylsilyloxy)furan (TBSOF, 1) with (R_S)- or (S _S)-t-BS-imines (3) furnished 5-aminoalkylbutenolides 7a-k in 75-87% yields with anti/syn ratios ranging from 75:25 to 97:3. Butenolides 7a-f,k were readily converted into substituted lactones 8 and 5 and 6-substituted 5-hydroxypiperidin-2-ones 11a-g, which are, in turn, key intermediates for the synthesis of many bioactive compounds.

Full text of DOI:10.1021/ol2020384

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4938–4941
Asymmetric Vinylogous Mannich
Reactions: A Versatile Approach to
Functionalized Heterocycles
Shu-Tang Ruan,† Jie-Min Luo,† Yu Du,† and Pei-Qiang Huang*,†,‡
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province,
Xiamen University, Xiamen, Fujian 361005, P. R. China, and State Key Laboratory of
Bioorganic and Natural Products Chemistry, 354 Fenglin Lu, Shanghai 200032, P. R. China
pqhuang@xmu.edu.cn
Received July 28, 2011
ABSTRACT
Asymmetric vinylogous Mannich reaction (VMR) of 2-(tert-butyldimethylsilyloxy)furan (TBSOF, 1) with (RS)- or (SS)-t-BS-imines (3) furnished
5-aminoalkylbutenolides 7aÀk in 75À87% yields with anti/syn ratios ranging from 75:25 to 97:3. Butenolides 7aÀf,k were readily converted into
substituted lactones 8 and 5 and 6-substituted 5-hydroxypiperidin-2-ones 11aÀg, which are, in turn, key intermediates for the synthesis of many
bioactive compounds.
Functionalized heterocycles constitute the core struc-
tures of a large number of bioactive natural products and
pharmaceuticals. Thanks to seminal work by Casiraghi,
2-trialkylsilyloxyfuran (e.g., TBSOF, 1)-based reactions
have become a powerful methodology for the efficient
synthesis of highly functionalized heterocycles.1À3 In this
regard, Martin’s group haspioneered the use ofvinylogous
Mannich reactions (VMR)1À3 in the efficient synthesis of
complex alkaloids.2
Similarly, Davis p-toluenesulfinimines4 and Ellman
N-tert-butanesulfinimines (t-BS-imines, 3)4b,5,6 have gained
great success as versatile chiral amine templates in recent
years.4,5 However, the use of cyclic silyl ketene acetal as a
class of versatile nucleophiles for additions to these systems
has largely been ignored.6
We envisioned that a combination of the powerful
methodology of TBSOF-based vinylogous Mannich reac-
tion (VMR) with this chiral sulfinamide-based methodol-
ogy might provide a versatile and general approach to
chiral nonracemic butenolides A, 6-substituted 5-hydro-
xypiperidin-2-ones B, functionalized lactones C, 2,6-dis-
ubstituted piperidin-3-ols D, and substituted γ-hydroxy-δ-
amino acids E (Scheme 1).
2,6-Disubstituted piperidin-3-ols (D) are a common
framework shared by many bioactive alkaloids and aza-
sugars. A number of methods have been developed for
their synthesis. Many of them have used 5-hydroxypiper-
idin-2-ones B as key intermediates.7 Our group has re-
cently developed a one-pot reductive alkylation of lactams
such as B to give the corresponding piperidines D, which
greatly improves the efficiency of this approach.8 On the
other hand, substituted γ-hydroxy-δ-amino acids E are
found as motifs of many bioactive compounds. For ex-
ample, L-685,458 (4) is a potent inhibitor of γ-secretase
(IC50 = 17 nM) and of potential therapeutic benefit in the
treatment of Alzheimer’s disease and other neurological
disorders (Figure 1).9,10 The γ-hydroxy-δ-amino acid
(1) For recent reviews on silyloxydiene, see: (a) Casiraghi, G.;
Battistini, L.; Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111,
3076–3154. (b) Casiraghi, G.; Zanardi, F.; Battistini, L.; Rassu, G.
Synlett 2009, 1525–1542.
(2) For reviews on vinylogous Mannich-type reactions, see: (a) Bur,
S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221–3242. (b) Martin, S. F.
Acc. Chem. Res. 2002, 35, 895–904.
r
10.1021/ol2020384
Published on Web 08/19/2011
2011 American Chemical Society

known methods12 (Table 1). After screening the reaction
conditions for the VMR, the optimal reaction conditions
were defined as treating a CH2Cl2 solution of TBSOF
(1, 1.5 equiv) and t-BS-imine (3a, 1.0 equiv) with TMSOTf
(1.0 equiv) at À78 °C for 1 h. Only two separable diaster-
eomers7a (dr = 91:9) were obtainedin a combinedyield of
82%. The relative stereochemistry of the major product of
(SS)-7a was elucidated as SS,4S,5R by X-ray diffraction
analysis (cf. Supporting Information), while the minor
diastereomer of (RS)-7k was determined to be RS,4S,5S
by its conversion into a known compound13 (Supporting
Information).
Scheme 1. Synthetic Potential of the Asymmetric VMR
The reactions of either enantiomer of various t-BS-imines
(3aÀk) with TBSOF (1) are summarized in Table 1. In all
Table 1. Vinylogous Mannich Reactions of t-BS-Imines 3 with 1
residue of 4 could be synthesized by ring opening of lactone
5.10a,11 We report herein the results of this investigation.
t-BS*-imines
3 (% yield)c
major diastereomer of
7 (anti/syn)d,f (% yield)e,f
entry
1
aldehyde
n-PrCHO
(SS)-3a (85)a (SS,4S,5R)-7a (91:9) (82)
(RS)-3a (85)a (RS,4R,5S)-7a (93:7) (81)
(SS)-3b (83)a (SS,4S,5R)-7b (97:3) (86)
(RS)-3b (90)a (RS,4R,5S)-7b (97:3) (84)
(SS)-3c (75)a (SS,4S,5R)-7c (92:8) (87)
(RS)-3c (81)a (RS,4R,5S)-7c (90:10) (82)
(SS)-3d (82)a (SS,4S,5R)-7d (91:9) (80)
(RS)-3d (82)a (RS,4R,5S)-7d (89:11) (78)
(RS)-3e (90)a (RS,4R,5S)-7e (82:18) (76)
(SS)-3f (82)a (SS,4S,5R)-7f (93:7) (75)
(RS)-3f (88)a (RS,4R,5S)-7f (93:7) (77)
Figure 1. Structure of L-685,458 (4) and its lactone precursor 5.
2
3
4
i-PrCHO
t-BS-Imines 3aÀk were prepared from either enantio-
mer of N-tert-butanesulfinamide (6) and aldehydes by the
n-C7H15CHO
PhCH2CHO
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6
MeCHO
PhCHO
7
3-MeOPhCH2CHO (SS)-3g (78)a (SS,4S,5R)-7g (89:11) (84)
2,4-Cl2PhCHO
(SS)-3h (75)b (SS,4S,5R)-7h (81:19) (85)
2,5-(MeO)2PhCHO (SS)-3i (80)b (SS,4S,5R)-7i (78:22) (82)
8
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9
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4-ClPhCHO
(SS)-3j (86)b (SS,4S,5R)-7j (81:19) (78)
(RS)-3k (87)a (RS,4R,5S)-7k (75:25) (80)
BnOCH2CHO
a Method A: MgSO4, PPTS, CH2Cl2, rt, 16 h. b Method B: CuSO4,
CH2Cl2, rt, 20 h. c Yield of isolated E-product. d Ratios determined by
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Org. Lett., Vol. 13, No. 18, 2011
4939

cases, two diastereomers were obtained in yields that varied
from 75% to 87% with a dr that ranged from 75:25 to 97:3.
We next turned our attention to the synthesis of the
precursor (2R,4R,5S-5) of the γ-hydroxy-δ-amino acid
residue of L-685,458 (4). Catalytic hydrogenation of
(RS,4R,5S)-7d (Table 1, entry 4) gave lactone (RS)-8d in
93% yield (Scheme 2). Deprotonation of (RS)-8d with
LDA and reaction of the resulting enolate with benzalde-
hyde gave the desired carbinol, which without separation
was dehydrated (Ac2O, Et3N, 120À140 °C) to afford R,β-
unsaturated lactone 9 in 73% yield. Cleavage of the chiral
auxiliary (4 M HCl, MeOH) followed by reprotection gave
the known N-Boc-protected derivative 10 in 84% yield.
Hydrogenation of 10 (10% Pd/C, 60 psi H2) produced the
known lactone 5 in 97% yield as a single diastereomer
(Scheme 2).10a Its physical and spectroscopic data were
identical with those reported {[R]20D À68.9 (c 1.04, CHCl3),
We next focused on the synthesis of 6-substituted 5-
hydroxypiperidin-2-ones. Butenolides (RS,4R,5S)-7aÀf,k
were hydrogenated to give the corresponding lactones
(RS)-8aÀg in good yield (Table 2). Cleavage of the sulfinyl
group under acidic conditions followed by base-promoted
cyclization (DBU in toluene or K2CO3 in MeOH)14 pro-
duced the 6-substituted 5-hydroxypiperidin-2-ones 11aÀg.
Among the synthesized products, 11b, 11dÀg or their
enantiomers are known compounds. The physical and
spectroscopic data of 11d were identical with those re-
ported {[R]20 À34.4 (c 1.2, MeOH); lit.15 [R]23 À37.9
D
D
(c 1.2, MeOH), and the data of the others are available in
the Supporting Information.
Table 2. Synthesis of 6-Substituted 5-Hydroxypiperidin-2-ones
11aÀg
lit.10a [R]20 À69.5 (c 1.02, CHCl3); mp 127.0À128.6 °C,
D
lit.11b mp 127À128.5 °C}.
Scheme 2. Synthesis of Lactone Precursor 5
entry
R
(RS)-8 (% yield)c
(5R,6S)-11 (% yield)c
1
2
3
4
5
6
7
n-PrCH2
i-PrCH2
n-C6H13CH2
PhCH2
CH3
8a (91)
8b (95)
8c (92)
8d (93)
8e (93)
8f (92)
8g (89)
11a (70),a (87)b
11b (80),a (72)b
11c (77)b
11d (78)a
11e (65)a
Ph
11f (76)b
BnOCH2
11g (70)b
a Method A: DBU, toluene, reflux. b Method B: K2CO3, MeOH, rt.
c Isolated yield.
Compound 11g was protected with TBSCl (imid.,
DMAP, CH2Cl2) to produce TBS ether 12, whose spectral
data were identical with those reported.16,17b The synthesis
of 12 constitutes a formal synthesis of (À)-deoxoproso-
phylline (13).16 In addition, Rapoport and co-workers
have converted ent-11g into 14; moreover, 14 is a versatile
intermediate that can be elaborated to 15, 16, and 17
(Scheme 3).17
A plausible interpretation of stereochemical outcome in
these VMR processes is depicted in Figure 2. Since only 1
equiv of Lewis acid (TMSOTf) is required for the reaction,
a monocoordinated species with the preferred confor-
mation4c shown by F is thought to be involved. Because
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4940
Org. Lett., Vol. 13, No. 18, 2011

Scheme 3. Synthetic Applications of Piperidin-2-one 11g
Figure 2. Plausible transition state for the VMR.
compound 12 constitutes a formal asymmetric synthesis of
(À)-deoxoprosophylline (13). In addition, compound 11g
serves asa key intermediate for the asymmetric synthesis of
mannolactam (15), deoxymannojirimycin (16), and proso-
pinine (17).
the re face of the imine is sterically shielded by the O-LA, the
nucleophile TBSOF3l,s,u probably approaches from the si
face of the imine, via the favored transition state G, to form
the 4,5-erythro (anti)-adduct as the major diastereomer.
In summary, 4,5-anti-selective vinylogous Mannich re-
actions between t-BS-imines 3aÀk and TBSOF (1) have
been developed. They provide a versatile and general
asymmetric approach to 4,5-anti-4-aminoalkylbutenolides
7 and 6-substituted trans-5-hydroxypiperidin-2-ones 11, as
well as functionalized lactones 5 and 8. Lactone 5 is a key
intermediate for the asymmetric synthesis of the potent
γ-secretase inhibitor L-685,458 (4), while the synthesis of
Acknowledgment. The authors are grateful to the Na-
tional Basic Research Program (973 Program) of China
(Grant No. 2010CB833200) and NSF of China (20832005;
21072160) for financial support.
Supporting Information Available. Detailed experimen-
1
tal procedures, characterizations, and copies of H and
13C NMR spectra of all new compounds; X-ray structure
and crystallographic data in CIF format of compound
(SS)-7a. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 18, 2011
4941