Diastereoconvergent synthesis of trans -5-hydroxy-6-substituted-2- piperidinones by addition-cyclization-deprotection process

Article abstract of DOI:10.1021/ol5020812

A diastereoselective one-pot approach to access trans-5-hydroxy-6- substituted-2-piperidinones by an addition-cyclization-deprotection process has been developed, in which the stereogenic center at the C-6 position was solely controlled by α-OTBS group. The utility of this transformation is demonstrated by the asymmetric synthesis of the enantiomer of (-)-CP-99,994.

Full text of DOI:10.1021/ol5020812

Letter
pubs.acs.org/OrgLett
Diastereoconvergent Synthesis of trans-5-Hydroxy-6-Substituted-2-
Piperidinones by Addition−Cyclization−Deprotection Process
Chang-Mei Si,†,‡ Wei Huang,† Zhen-Ting Du,‡ Bang-Guo Wei,*,† and Guo-Qiang Lin†
†Department of Chemistry and Institute of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China
‡College of Science, Northwest Agriculture and Forestry University, Shaanxi Yangling 712100, P.R. China
S
* Supporting Information
ABSTRACT: A diastereoselective one-pot approach to access
trans-5-hydroxy-6-substituted-2-piperidinones by an addition−
cyclization−deprotection process has been developed, in which
the stereogenic center at the C-6 position was solely controlled
by α-OTBS group. The utility of this transformation is
demonstrated by the asymmetric synthesis of the enantiomer
of (−)-CP-99,994.
he discovery of a novel enantioselective reaction or
versatile methodology for efficient carbon−carbon bond
formation is one of the most challenging tasks in organic
synthesis.1 As a prime instance, the effective approach for the
synthesis of chiral functionalized trans-5-hydroxy-6-substituted-
2-piperidinones 1 (Figure 1) is very important in synthetic and
In the past decade, chiral N-tert-butanesulfinamide and N-
toluenesulfinamide, pioneered by Ellman and Davis respec-
tively, are undoubtedly one of the most efficient classes of
auxiliaries in modern organic synthesis,9−11 especially for the
asymmetric synthesis of chiral amines and their derivatives. The
latter are extensively used as important intermediates for chiral
ligands, agrochemicals, and pharmaceuticals.12 In continuation
of our efforts to explore utility of N-tert-butanesulfinyl imines,
we have accomplished the synthesis of several bioactive natural
products and their analogues.13 Very recently, we reported a
novel migration−addition of enantioenriched N-tert-butanesul-
finyl iminoacetate through an intermolecular radical pathway.14
As shown in Figure 2, Ellman has achieved a controllable
Grignard addition to α-alkoxyaldimines, which could afford 1,2-
syn or 1,2-anti amino alcohol from different diastereomers and
under different reaction conditions (eqs 1 and 2 in Figure 2).15
In this work, we report a one-pot cascade process for highly
diastereoselective synthesis of versatile trans-5-hydroxy-6-
substituted-2-piperidinone skeleton 1 in good yields with high
diastereoselectivities (eq 3), as well as the application in the
asymmetric synthesis of (−)-CP-99,994 ent-4. The stereogenic
center of C-6 was solely controlled by the α-alkoxy substitution.
As shown in Scheme 1, α-chiral N-sulfinyl aldimines 7a−f
were prepared to investigate our tandem reaction. The chiral
ester 6 was prepared from L-glutamic acid using the known
procedure.16 Further conversion to the desired α-chiral N-
sulfinyl aldimines 7a−e were achieved through the following
three steps: regioselective desilylation,16b oxidation with Dess−
Martin periodinane17 and subsequent condensation with
racemic alkylsulfinamide in the presence of anhydrous cupric
sulfate.18 Meantime, α-chiral N-tert-butylsulfone aldimine 7f
was prepared from 7e through oxidation by m-CPBA in 65%
yield.
T
Figure 1. Structures of several natural products.
medicinal chemistry, because it serves as a substructure for
numerous biologically relevant alkaloids and pharmaceutical
agents.2 Typical examples include antimalarial (+)-febrifugine
2,3 antibiotic and anesthetic Prosopis alkaloid (+)-prosophylline
3,4 as well as a clinical agent (+)-CP-99,994 4, which displays a
variety of biological activities including neurogenic inflamma-
tion, pain transmission, and regulation of the immune
response.5 Moreover, the trans-2-alkyl-3-hydroxypiperidine
unit is also embedded in the bicyclic structure of hydroxylated
indolizidines, such as the α-mannosidase inhibitor (−)-swain-
sonine 5.6 As a result, the asymmetric synthesis of 1, or its
effective precursor, has attracted significant attention.7,8
Received: July 16, 2014
© XXXX American Chemical Society
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Letter
Table 1. Optimization of the Tandem Reactions
a
b
c
entry
R
PhMgBr (equiv)
solvent
Y%
trans:cis
1
2
3
4
5
6
7
8
9
SOTol
SOPr-i
SOPr-n
SOBu-i
SO2Bu-t
SOBu-t
SOBu-t
SOBu-t
SOBu-t
3.0
3.0
3.0
3.0
3.0
3.0
1.0
2.0
3.0
THF
THF
THF
THF
THF
THF
THF
THF
DCM
39
35
41
57
0
99:1
99:1
99:1
99:1
−
99:1
99:1
99:1
99:1
77
21
49
43
a
The reactions were performed with α-chiral substituted aldimines
7a−f (1.0 mmol), phenylmagnesium bromide (3 mL, 1.0 M in THF)
b
c
in dry THF (5 mL) at −78 °C for 3 h. Isolated yield. dr was
1
determined by HPLC or H NMR.
weaken the S−N bond, leading to further nucleophilic
displacement by excessive Grignard reagent. Actually, we
isolated the byproducts, phenyl sulfoxides 9 in this
process.18b,19 Different amounts of Grignard reagent were
also screened, and the results suggested that the Grignard
addition to the aldimine and the cleavage of sulfinamide took
place simultaneously (Table 1 entries 7−8). The effect of
different chiral auxiliary in aldimine 7 was also studied. As
shown in Table 3 (in the Supporting Information [SI]), both
(S,SS)-7e and (S,SR)-7e generated the same product 8a. Their
corresponding enantiomers (R,SS)-7e and (R,SR)-7e were also
subjected to the optimized conditions, both producing the
desired enantiomer of 8a (see the results of Table 3 and chiral
HPLC in SI). This result suggested that the chiral sulfinamide
moiety was not involved in the stereocontrol of this addition
process.
Figure 2. Our strategy to access chiral δ-lactams.
Scheme 1. Preparation of α-Chiral Aldimines 7a−f
Next, we turned our attention to investigate the scope and
limitation of this intramolecular tandem addition−cyclization. A
survey of different Grignard reagents was examined under the
optimal conditions, as summarized in Table 2. When para- or
meta-substituted phenyl Grignard reagents were used, the
intramolecular tandem addition−cyclization proceeded
smoothly with high diastereoselectivities in excellent yields
(Table 2, entries 2−9). But ortho-substituted phenylmagnesium
reagents led to significantly lower yields of desired products
8j−k (Table 2, entries 10−11). Interestingly, 2-fluorophenyl-
magnesium bromide did not result in any desired addition−
cyclization product (Table 2, entry 12). Bicyclic Grignard
reagents, including α- and β-naphthyl magnesium bromides,
also afforded the desired lactams, with the less hindered β-
naphthyl magnesium bromide more efficient for this tandem
process (Table 2, entries 13−14). Several sp3 hybridized
Grignard reagents were also screened, and the results showed
that the steric dramatically affected the yields of products 8o−q
(Table 2, entries 15−17). It is worth mentioning that tert-
butylmagnesium chloride did not attack the aldimine at all, and
the starting material was fully recovered (Table 2, entry 18).
Although BnMgBr could give corresponding product 8s in 51%
yield (Table 2, entry 19), the reaction with allylMgBr was very
messy (Table 2, entry 20). Unfortunately, γ-lactam 10 was also
tried by this process, but the yield was very low in the same
Then, the intramolecular tandem reactions of α-chiral
aldimines 7a−f with Grignard reagents were investigated.
When α-chiral aldimine 7a was treated with phenylmagnesium
bromide at −78 °C, the desired product 8a was obtained with
high diastereoselectivity (dr > 99:1) in 39% yield (Table 1
entry 1). To improve the yield of this interesting chiral lactam
8a, various aldimines with different alkyl groups at sulfur (7b−
f) were screened, and the results are summarized in Table 1
(entries 2−6). Delightfully, α-chiral N-tert-butylsulfinyl aldi-
mine 7e significantly increased the yield of 8a, up to 77%
(Table 1 entry 6). When N-tert-butylsulfone aldimine 7f was
used, the reaction was very messy, and no desired product was
formed (Table 1 entry 5). In addition, the reaction in
tetrahydrofuran (THF) offered better conversion than in
dichloromethane (DCM) (Table 1 entries 6 and 9). This
tandem process likely went through a N-sulfinyl substituted
lactam intermediate, which was formed through the attack of N
anion toward the ester. The presence of N-carbonyl would
B
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Letter
synthetic (−)-CP-99,994 dihydrochloride ent-4 were identical
Table 2. Reactions with different Grignard reagents
to the reported data.5,21
Scheme 2. Application in Asymmetric Synthesis of (−)-CP-
99,994·2HCl ent-4
a
b
c
entry
R
8a−t
Y%
trans:cis
1
Ph
8a
8b
8c
8d
8e
8f
77
98:2
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
--
2
4-MePh
4-MeOPh
4-FPh
93
89
93
82
95
90
84
89
45
40
3
4
5
4-PhPh
3-MePh
3-MeOPh
3-CF3Ph
3-FPh
6
7
8g
8h
8i
8
9
10
11
12
13
14
15
16
17
18
19
20
2-MePh
2-MeOPh
2-FPh
8j
8k
8l
In summary, we established a novel and one-pot approach for
highly diastereoselective synthesis of versatile chiral building
blocks 1 by treatment of α-alkoxyaldimines containing the ω-
ester group with Grignard reagents. The reaction went through
an intramolecular tandem sequence of addition−cyclization−
deprotection, and the stereogenic center of C-6 was solely
controlled by α-alkoxy substitution. This novel approach
provides an efficient synthesis of libraries of chiral trans-5-
hydroxy-6-substituted-2-piperidinones with synthetic value. In
addition, the utility of chiral δ-lactams 8a in the enantioselective
synthesis of specific targets has been demonstrated by a concise
synthetic route to (−)-CP-99,994 ent-4.
complex
92
β-naphthyl
α-naphthyl
cyclopropyl
pentyl
8m
8n
8o
8p
8q
8r
8s
8t
99:1
99:1
99:1
99:1
99:1
−
53
74
65
isopropyl
tert-butyl
Bn
48
NR
51
99:1
Allyl
complex
−
a
The reactions were performed with α-chiral substituted aldimines 7e
(1.01 mmol), Grignard reagents (3 mL, 1.0 M in THF) in dry THF (5
b
c
mL) at −78 °C for 3 h. Isolated yield. dr was determined by HPLC
or H NMR.
1
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure and characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
condition19 (see SI). To our disappointment, the efforts to
prepare seven-membered lactam 11 turned out to be fruitless.
Instead, the simple imine-addition product 12 was obtained
with good diastereoselectivity (dr = 95:5) in 61% yield (see
SI).20
The relative configurations of the products 8a−s were
unambiguously assigned as trans-form by X-ray crystallo-
graphical analysis of compound 8m (see SI).
AUTHOR INFORMATION
Corresponding Author
■
*bgwei1974@fudan.edu.cn
Notes
The authors declare no competing financial interest.
With chiral lactams 8a−s in hand, we turned our attention to
utilize this novel approach in the synthesis of natural products
and pharmaceutical agents. (+)-CP-99,994 (4) is a nonpeptidic
neurokinin NK1 receptor antagonist5 with a variety of
biological activities.20 Treatment of chiral δ-lactam 8a with
lithium aluminum hydride (LiAlH4) at 60 °C gave the
piperidine 13, which was treated with Boc2O in DCM in the
presence of catalytic amount DMAP to give compound 14 in
83% overall yield. Oxidation of 14 with Dess−Martin
periodinane (DMP),17 followed by oxime formation with O-
methyl hydroxyamine hydrochloride (NH2OMe·HCl) and
subsequent reduction with borane, produced the desired cis-
2,3-disubstituted amine 15 with high diastereoselectivity (dr =
95:5) in 71% overall yield. The introduction of an o-
methoxybenzyl group was accomplished by the reaction with
2-methoxybenzaldehyde in the presence of sodium borohydride
(NaBH4). Finally, the N-Boc protective group was removed by
a saturated solution of hydrogen chloride in methanol to give
(−)-CP-99,994·2HCl ent-4 {[α]25D = −87.1 (c 0.36, CH3OH);
lit.21i +87.5 [α]23D (c 0.74, CH3OH) for 4} in quantitative yield
(Scheme 2). The spectroscopic and physical data of the
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21272041, 21072034, 20832005) for financial support. The
authors also thank Dr. Han-Qing Dong (Arvinas Inc.) for
helpful suggestions.
REFERENCES
■
(1) (a) Ojima, I. Catalytic Asymmetric Synthesis; Wiley-VCH:
Weinheim, 2000. (b) Tsuji, J. Transition Metal Reagents and Catalysts:
Innovations in Organic Synthesis; Wiley: Chichester, 2000.
(2) For selected synthesis of 5-hydroxy-2-piperidinones, see: (a) Liu,
L.-X.; Ruan, Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem. 2004, 69,
6001. (b) Andres
Lett. 2006, 47, 5317. (c) Gonzal
Carretero, J. C. Org. Lett. 2008, 10, 4335. (d) Garrido, M.; García, M.;
Sanchez, M. R.; Díez, D.; Urones, J. G. SYNLETT 2010, 387.
(e) Prevost, S.; Phansavath, P.; Haddad, M. Tetrahedron: Asymmetry
́
, J. M.; Pedrosa, R.; Per
́
ez-Encabo, A. Tetrahedron
́
ez, A. S.; Arrayas
́
, R. G.; Rivero, M. R.;
́
́
2010, 21, 16. (f) Ruan, S.-T.; Luo, J.-M.; Du, Y.; Huang, P.-Q. Org.
Lett. 2011, 13, 4938. (g) Tan, C. K.; Le, C.; Yeung, Y.-Y. Chem.
Commun. 2012, 48, 5793. (h) Pansare, S. V.; Paul, E. K. Org. Biomol.
C
dx.doi.org/10.1021/ol5020812 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. 2012, 10, 2119. For selected synthesis of 3-piperidinols, see:
(i) Archibald, G.; Lin, C.-P.; Boyd, P.; Barker, D.; Caprio, V. J. Org.
Chem. 2012, 77, 7968. (j) Huy, P. H.; Koskinen, A. M. P. Org. Lett.
2013, 15, 5178. (k) Huy, P. H.; Westphal, J. C.; Koskinen, A. M. P.
Beilstein J. Org. Chem. 2014, 10, 369.
(m) Lemire, A.; Grenon, M.; Pourashraf, M.; Charette, A. B. Org. Lett.
2004, 6, 3517. (n) Takahashi, K.; Nakano, H.; Fujita, R. Tetrahedron
Lett. 2005, 46, 8927. (o) Xu, X. N.; Furukawa, T.; Okino, T.; Miyabe,
H.; Takemoto, Y. Chem.Eur. J. 2006, 12, 466.
(3) Koepfli, J. B.; Mead, J. F.; Brockman, J. A., Jr. J. Am. Chem. Soc.
1947, 69, 1837.
(4) Ratle, G.; Monseur, X.; Das, B. C.; Yassi, J.; Khuong-Huu, Q.;
Goutarel, R. Bull. Soc. Chim. Fr. 1966, 9, 2945.
(5) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.;
Snider, R. M. J. Med. Chem. 1992, 35, 4911.
(6) (a) Guengerich, F. P.; DiMari, S. J.; Broquist, H. P. J. Am. Chem.
Soc. 1973, 95, 2055.
(7) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435. (b) Reynolds, T.
Phytochemistry 2005, 66, 1399. (c) Remuson, R.; Gelas-Mialhe, Y.
Mini-Rev. Org. Chem. 2008, 5, 193.
(8) (a) Buffat, M. G. P. Tetrahedron 2004, 60, 1701. (b) Escolano, C.;
Amat, M.; Bosch, J. Chem.Eur. J. 2006, 12, 8199. (c) Kallstrom, S.;
Leino, R. Bioorg. Med. Chem. 2008, 16, 601.
(9) (a) Zhou, P.; Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60,
8003. (b) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869.
(10) (a) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res.
2002, 35, 984. (b) Lin, G. Q.; Xu, M. H.; Zhong, Y. W.; Sun, X. W.
Acc. Chem. Res. 2008, 41, 831. (c) Ferreira, F.; Botuha, C.; Chemla, F.;
Perez-Luna, A. Chem. Soc. Rev. 2009, 38, 1162. (d) Robak, M. T.;
Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600.
(11) (a) Davis, F. A.; McCoull, W. J. Org. Chem. 1999, 64, 3396.
(b) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66,
8772. (c) Staas, D. D.; Savage, K. L.; Homnick, C. F.; Tsou, N. N.;
Ball, R. G. J. Org. Chem. 2002, 67, 8276. (d) Zhong, Y. W.; Dong, Y.
Z.; Fang, K.; Izumi, K.; Xu, M. H.; Lin, G. Q. J. Am. Chem. Soc. 2005,
127, 11956.
(12) (a) Barrett, G. C. Chemistry and Biochemistry of the Amino Acids;
Chapman & Hall: London, 1985. (b) Jones, J. Amino Acid and Peptide
Synthesis; Oxford University Press: London, 1992. (c) Seyden-Penne,
J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; Wiley: New
York, 1995. (d) Blaser, H. U. Chem. Rev. 1992, 92, 935.
(13) Xarnod, C.; Huang, W.; Ren, R. G.; Liu, R. C.; Wei, B. G.
Tetrahedron 2012, 68, 6688.
(14) Huang, W.; Ye, J. L.; Zheng, W.; Dong, H. Q.; Wei, B. G. J. Org.
Chem. 2013, 78, 11229.
(15) Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9948.
(16) (a) Marshall, J. A.; Piettre, A.; Paige, M. A.; Valeriote, F. J. Org.
Chem. 2003, 68, 1780. (b) Winkler, J. W.; Uddin, J.; Serhan, C. N.;
Petasis, N. A. Org. Lett. 2013, 15, 1424.
(17) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(c) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64,
4537.
(18) (a) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268.
(b) Liu, G. C.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J.
Org. Chem. 1999, 64, 1278.
(19) For the preparation of compound 10 and its material see
Supporting Information.
(20) For the preparation of compound 12 and its material see
Supporting Information.
(21) (a) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett. 1999,
40, 5071. (b) Yamazaki, N.; Atobe, M.; Kibayashi, C. Tetrahedron Lett.
2002, 43, 7979. (c) Tsuritani, N.; Yamada, K.; Yoshikawa, N.;
Shibasaki, M. Chem. Lett. 2002, 276. (d) Huang, P. Q.; Liu, L. X.; Wei,
B. G.; Ruan, Y. P. Org. Lett. 2003, 5, 1927. (e) Atobe, M.; Yamazaki,
N.; Kibayashi, C. J. Org. Chem. 2004, 69, 5595. (f) Oshitari, T.;
Mandai, T. Synlett 2006, 3395. (g) Davis, F. A.; Zhang, Y. F.; Li, D. Y.
Tetrahedron Lett. 2007, 48, 7838. (h) Liu, R. H.; Fang, K.; Wang, B.;
Xu, M. H.; Lin, G. Q. J. Org. Chem. 2008, 73, 3307. (i) Fu, R. Z.; Zhao,
B. G.; Shi, Y. J. Org. Chem. 2009, 74, 7577. (j) Garrido, N. M.; Garcia,
M.; Sanchez, M. R.; Diez, D.; Urones, J. G. Synlett 2010, 387.
(k) Pansare, S. V.; Paul, E. K. Org. Biomol Chem. 2012, 10, 2119.
(l) Sultane, P. R.; Bhat, R. G. J. Org. Chem. 2012, 77, 11349.
D
dx.doi.org/10.1021/ol5020812 | Org. Lett. XXXX, XXX, XXX−XXX