Divergent method to trans -5-hydroxy-6-alkynyl/alkenyl-2-piperidinones: Syntheses of (-)-epiquinamide and (+)-swainsonine

Article abstract of DOI:10.1021/acs.joc.5b00803

An efficient diastereoselective approach to access trans-5-hydroxy-6-alkynyl/alkenyl-2-piperidinones has been developed through nucleophilic addition of α-chiral aldimines using alkynyl/alkenyl Grignard reagents. The diastereoselectivity of alkenyl in C-6

Full text of DOI:10.1021/acs.joc.5b00803

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Article
Divergent Method to trans-5-Hydroxy-6-alkynyl/alkenyl-2-
piperidinones: Syntheses of (-)-Epiquinamide and (+)-Swainsonine
Chang-Mei Si, Zhuo-Ya Mao, Han-Qing Dong, Zhen-Ting Du, Bang-Guo Wei, and Guo-Qiang Lin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00803 • Publication Date (Web): 14 May 2015
Downloaded from http://pubs.acs.org on May 17, 2015
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Divergent Method to trans-5-Hydroxy-6-alkynyl/alkenyl-2-piperidinones:
Syntheses of (-)-Epiquinamide and (+)-Swainsonine
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ChangꢀMei Si, †,‡ ZhuoꢀYa Mao, †,‡ HanꢀQing Dong, §,# ZhenꢀTing Du,‡ BangꢀGuo
Wei*,† and GuoꢀQiang Lin†,§
†
School of Pharmacy, Department of Chemistry and Institutes of Biomedical Sciences,
Fudan University, 220 Handan Road, Shanghai 200433, China
‡College of Science, Northwest Agriculture and Forestry University, Shaanxi,
Yangling, 712100, China
§Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, China;
#Present Address: Arvinas Inc., 5 Science Park, New Haven, CT 06511, USA
bgwei1974@fudan.edu.cn
Abstract
OH
OH
OTBS
H
O
O
S
R1
1.
MgBr
(S)
OH
MeO
N
O
N
N
2. Boc2O
OTBS
Boc
R
(+)-Swainsonine ent-5
dr up to 99:1
10a~r
NHAc
OTBS
O
O
(R/S)
1. R2CH=CR1MgBr
N
S
MeO
N
O
N
R2
2. Boc2O
OTBS
Boc R1
(-)-Epiquinamide 3
dr up to 99:1
13a~e
An
efficient
diastereoselective
approach
to
access
transꢀ5ꢀhydroxyꢀ6ꢀalkynyl/alkenylꢀ2ꢀpiperidinones has been developed through
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nucleophilic addition of αꢀchiral aldimines using alkynyl/alkenyl Grignard reagents.
The diastereoselectivity of alkenyl in Cꢀ6 position of 2ꢀpiperidinone was controlled
by αꢀalkoxy substitution, while the alkynyl was controlled by the coordination of the
αꢀalkoxy substitution and stereochemistry of sulfinamide. The utility of this
straightforward cascade process is demonstrated by the asymmetric synthesis of the
(ꢀ)ꢀepiquinamide and (+)ꢀswainsonine.
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Introduction
Chiral functionalized piperidines are common framework shared by many bioactive
alkaloids, azasugars and pharmaceutical agents (Figure 1).1 In past decades,
tremendous efforts have been devoted to the stereoselective preparation of trans or
cisꢀ 5ꢀhydroxyꢀ6ꢀsubstitutedꢀ2ꢀpiperidinones 1 and the corresponding amines 2
(2ꢀsubstitutedꢀ3ꢀpiperidinols). Although a number of powerful approaches have been
reported,2ꢀ3 direct construction of 5ꢀhydroxyꢀ6ꢀalkynyl/alkenylꢀ2ꢀpiperidinones 1 and
2ꢀalkynyl/alkenylꢀ3ꢀpiperidinols 2 is still quite limited. In 2009, Pyne and coꢀworkers
first demonstrated the synthesis of cis/transꢀ5ꢀhydroxyꢀ6ꢀalkynylꢀ2ꢀpiperidinones
using BF3·Et2Oꢀcatalyzed coupling reactions of Nꢀacyliminium ions and potassium
alkynyltrifluoroborates.4
In
2012,
Caprio
and
coꢀworkers
prepared
transꢀ2ꢀalkynylꢀ3ꢀhydroxy Nꢀhydroxypiperidines through nucleophilic addition of
organometallic reagents to cyclic nitrone.3a
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Ph
O
OH
R
NHAc
O
Bn
OH
H
NH2
N
BocHN
X
N
N
N
H
H
O
Bn
7
8
9
1 X= C=O
2 X= CH2
L-685,458 4
(-)-Epiquinamide 3
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OH
OH
H
OH
H
O
NH2
N
H2N
OH
O
O
O
N
O
Aliskiren 6
(-)-Swainsonine 5
Figure 1. The structures of several bioactive products.
Following the pioneering work of Ellman and Davis, asymmetric addition of imines
bearing chiral auxiliaries (e.g. Nꢀtertꢀbutanesulfinamide and Nꢀtoluenesulfinamide)
with organometallic reagents has become a versatile and practical way for the
efficient synthesis of chiral amines.5ꢀ7 However, the application of alkynyl anions for
this nucleophilic addition is very rare. Ellman and Qing’s group achieved the addition
of lithium acetylides to Nꢀtertꢀbutanesulfinyl ketimines using AlMe3 as a mandatory
additive,8a,c whereas Hou and coꢀworkers investigated the addition of various alkynes
using LiHMDS as a base.8b Recently, Lin and coꢀworkers reported the addition of
corresponding Grignard reagents to Nꢀtertꢀbutanesulfinyl imines.9 While making
efforts to extend the nucleophilic addition of chiral imines into the divergent
synthesis of bioactive natural products,10 we found that enantioenriched
Nꢀtertꢀbutanesulfinyl iminoacetates could undergo tertꢀbutyl migrationꢀaddition upon
the treatment with organozinc reagents.11 In addition, we discovered an intramolecular
tandem sequence to afford transꢀ5ꢀhydroxyꢀ6ꢀalkyl/arylꢀ2ꢀpiperidinone skeleton by
reacting αꢀchiral aldimines 7 with alkyl or aryl Grignard reagents (Figure 2, eq. 1).12
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Under the optimized reaction conditions, the substitutions of Cꢀ5 and Cꢀ6 were
predominantly in transꢀ2,3ꢀform and the stereochemistry at Cꢀ6 position was solely
controlled by αꢀOTBS group. Encouraged by this novel cascade reaction, we began to
investigate the nucleophilic addition using alkynyl or alkenyl magnesium reagents,
which would provide one of the most straightforward methods to
transꢀ5ꢀhydroxyꢀ6ꢀalkynyl/alkenylꢀ2ꢀpiperidinones. Herein we report our results of
this oneꢀpot cascade process starting from αꢀchiral aldimines and alkynyl/alkenyl
magnesium reagents (Figure 2, eq 2 and 3), as well as its application in the
asymmetric syntheses of (ꢀ)ꢀepiquinamide 3 and (+)ꢀswainsonine entꢀ5.
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Our Previous works12
OTBS
O
O
S
R/S
RMgX
-78 oC
(1)
(2)
MeO
N
O
N
R
H
OTBS
R = alkyl and aryl, dr up to 99:1
This work
OTBS
MgBr
O
O
S
(S)
R
1
1.
MeO
N
O
N
2. Boc2O
OTBS
Boc
R1
trans-10a~r dr up to 99:1
7
OTBS
O
O
S
R/S
1. R2CH=CR1MgBr
2. Boc2O
(3)
MeO
N
O
N
R2
OTBS
Boc R1
13a~e dr up to 99:1
7
Figure 2 Our protocol to access transꢀ5ꢀhydroxyꢀ6ꢀalkynyl/alkenylꢀ2ꢀpiperidinones.
Results and Discussion
Our investigation started with the intramolecular cascade reaction of αꢀchiral
aldimines (S, SRS)ꢀ712 and mꢀmethylphenylethynyl magnesium bromide. As shown in
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Table 1, no desired additionꢀcyclization product 8a was generated at ꢀ78 oC. However,
when the reaction mixture was warmed to room temperature, the desired lactam 8a
was observed, which was coꢀeluted with the sulfoxide byꢀproduct 9a in flash silica gel
chromatography. Fortunately, complete separation was achieved when the lactamꢀNH
was protected as NꢀBoc, and the imide 10a was obtained in 49% yield (over two
steps). It is worth mentioning that the crude 8a was found to be unstable, especially
in CDCl3 solution, while the NꢀBoc imide 10a showed excellent stability. Despite the
acceptable yield of 10a, the diastereoselectivity of this cascade reaction was very low
(dr = 74:26) (Table 1, entry 2). Interestingly, when optically pure (S, SS)ꢀ and (S, SR)ꢀ
aldimines 7 were subjected to the above conditions respectively, (S, SS)ꢀaldimine 7
gave the desired product as a transꢀ isomer in 73% yield with high diastereoselectivity
(dr = 99:1) (Table 1, entry 3), while (S, SR)ꢀ7 produced a mixture of two isomers in
32% yield with moderate diastereoselectivity (trans:cis=15:85) (Table 1, entry 4). We
attempted to improve the stereoselectivity for the substrate (S, SR)ꢀ7 using different
Lewis acids, such as In(OTf)313 and AlMe3,8a,c but the efforts turned out to be fruitless
(Table 1, entries 5ꢀ7). Different solvents were also examined for the reaction of (S,
SRS)ꢀ7 and mꢀmethylphenylethynyl magnesium bromide, both DCM and Et2O proved
to be less favored (Table 1, entries 8ꢀ9).
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Table 1. Optimization of the tandem process.
OTBS
O
(S,SS)-7
BrMg
S
+
R
O
N
P
R
(S,SR)-7
(S,SRS)-7
9a
R = m-CH3C6H4CC-
8a, P=H
Boc2O
10a, P=Boc
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Entry[a] Imine
Solvent
LA
Yield trans/cis[d]
%
[c]
1[b]
2
3
4
5
6
7
8
(S,SRS)ꢀ7
THF
THF
THF
THF
THF
THF
THF
DCM
Et2O
ꢀꢀ
ꢀꢀ
ꢀꢀ
ꢀꢀ
NR
49
73
ꢀꢀ
(S,SRS)ꢀ7
(S,SS)ꢀ7
(S,SR)ꢀ7
(S,SR)ꢀ7
(S,SR)ꢀ7
(S,SR)ꢀ7
(S,SRS)ꢀ7
(S,SRS)ꢀ7
74:26
99:1
15:85
ꢀꢀ
ꢀꢀ
ꢀꢀ
32
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In(OTf)3
AlMe3
ZnCl2
ꢀꢀ
NR
NR
NR
28
99:1
99:1
9
ꢀꢀ
44
[a] The reactions were performed with αꢀchiral substituted aldimines 7 (1.0 mmol),
mꢀmethylphenylethynyl magnesium bromide (3 mL, 1.0 M in THF) at ꢀ78oCꢀrt, then
the crude product was treated with Boc2O (2.0 mmol), DMAP (1.0 mmol) and TEA
(5.0 mmol) in DMF for 24 h. [b] The reaction temperature was ꢀ78 oC. [c] Isolated
yield. [d] dr was determined by HPLC or 1H NMR.
Next, we turned our attention to investigate the scope and limitation of alkynyl
Grignard reagents for this tandem additionꢀcyclization with αꢀchiral aldimines 7. A
variety of substituted alkynyl Grignard reagents were examined under the above
optimal conditions, as summarized in Table 2. As for the reactions with (S,
SS)ꢀaldimine 7, various substituents at phenylacetylene Grignard reagents were
tolerated. Regardless of their electron properties and substitution positions at the
phenyl ring, the tandem sequence proceeded smoothly with high diastereoselectivities
in 62ꢀ73% yields (Table 2, entries 1ꢀ10). Alkyl or substituted alkyl substituents of
acetylene Grignard reagents were also screened, and they showed excellent tolerance
as well (Table 2, entries 11ꢀ16). It is worth mentioning that silyl substituted alkyne
and simple acetylene (R=H) Grignard reagents could provide the desired products in
high diastereoselectivities (Table 2, entries 17ꢀ 18). As for the reactions with the chiral
imine (S, SR)ꢀ7, both aryl and alkyl susbtituted acetylene Grignard reagents still
provided the cisꢀlactams in poor yields and diastereoselectivities (Table 2, entries
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19ꢀ22).
5
6
7
Table 2. The reactions with different alkynyl Grignard reagents with 7.
8
9
OTBS
OTBS
1. RCCMgBr
THF, -78oC~rt
(S,SS)-7
or
+
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O
N
O
N
(S,SR)-7
2. Boc2O, DMF
Boc
R
Boc
R
trans-10a-r
cis-10a-l
Entry[a]
R
Yield %[b]
73
trans/cis[c]
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
15:85
13:87
5:95
22:78
7
10a-r
1
2
3
4
5
6
7
8
3ꢀMeꢀC6H4ꢀ
(S,SS)
(S,SS)
(S,SS)
(S,SS)
(S,SS)
(S,SS)
(S,SS)
(S,SS)
(S,SS)
(S,SS)
transꢀ10a
transꢀ10b
transꢀ10c
transꢀ10d
transꢀ10e
transꢀ10f
transꢀ10g
transꢀ10h
transꢀ10i
transꢀ10j
transꢀ10k
transꢀ10l
transꢀ10m
transꢀ10n
transꢀ10o
transꢀ10p
transꢀ10q
transꢀ10r
cisꢀ10a
2ꢀClꢀC6H4ꢀ
3ꢀBrꢀC6H4ꢀ
4ꢀMeꢀC6H4ꢀ
4ꢀFꢀC6H4ꢀ
4ꢀClꢀC6H4ꢀ
4ꢀBrꢀC6H4ꢀ
4ꢀMeOC6H4ꢀ
4ꢀpropylC6H4ꢀ
C6H5ꢀ
65
63
71
66
63
62
69
65
66
67
64
66
57
62
69
58
9
10
11
12
13
14
15
16
17
18
19
20
21
22
TBSOCH2CH2ꢀ (S,SS)
CH3(CH2)3CH2ꢀ (S,SS)
CH2SPh
CH2OBn
CH2OTBS
tertꢀbutyl
Si(CH3)3
H
3ꢀMeꢀC6H4ꢀ
4ꢀClꢀC6H4ꢀ
TBSOCH2CH2ꢀ (S,SR)
CH3(CH2)3CH2ꢀ (S,SR)
(S,SS)
(S,SS)
(S,SS)
(S,SS)
(S,SS)
(S,SS)
(S,SR)
(S,SR)
71
32
28
23
cisꢀ10f
cisꢀ10k
cisꢀ10l
27
[a] The reactions were performed with αꢀchiral aldimines (S, SS)ꢀ7 or (S, SR)ꢀ7 (1.0
mmol), alkynyl Grignard reagents (3 mL, 1.0 M in THF) in dry THF (5 mL) at ꢀ78
oCꢀrt for overnight, then the crude product was treated with Boc2O (2.0 mmol),
DMAP (1.0 mmol) and TEA (5.0 mmol) in DMF for 24 h. [b] Isolated yield. [c] dr
was determined by HPLC or 1H NMR.
The stereochemistry of the products transꢀ10a-r was unambiguously assigned as
transꢀform by Xꢀray crystallography of compound 10f (see Supporting Information).
The remaining isomers were assigned transꢀform based on the compounds having a
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coupling constant of similar magnitude (J for protons H5 (CHOTBS) and H6
(CHꢀalkyne).
7
8
9
Then, we turned our attention to investigate the tandem process of αꢀchiral aldimines
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(S,SRS)ꢀ7 with alkenyl Grignard reagents. When (S,SRS)ꢀ7 was treated with
o
vinylmagnesium bromide at –78 C, the desired product 11a was obtained. Because
11a was inseparable from the byꢀproduct sulfoxide 12a by flash silica gel
chromatography, the crude amide 11a was converted to its imide 13a, which was
isolated in 26% yield (over two steps) with high diastereoselectivity (dr > 99:1)
(Table 3, entry 1). When the reaction temperature of nucleophilic addition step was
slowly warmed to rt overnight, the yield of corresponding imide 13a was greatly
improved to 64% with high diastereoselectivity (dr > 99:1) (Table 3, entry 2). In
order to understand the influence of chiral sulfinyl auxiliary on the stereoselectivity
outcome, both (S,SS)ꢀ7 and (S,SR)ꢀ7 were applied to this tandem reaction, respectively.
In both cases, the desired transꢀ isomer was obtained with very high
diastereoselectivities (dr > 99:1), and (S,SS)ꢀ7 offered slightly better yield than
(S,SR)ꢀ7 (Table 3, entries 3 and 4). Probably the steric hindrance of (S,SR)ꢀ7 slightly
affected the nucleophilic attack of Grignard reagent to SꢀN bond during the step to
cleave auxiliary.12 With optimal conditions in hand, a survey of different substituted
alkenyl Grignard reagents were examined for (S,SRS)ꢀ7, as summarized in Table 3.
When alkyl substituted vinylmagnesium bromide was used, the tandem
additionꢀcyclization proceeded smoothly with high diastereoselectivity and in 61%
yield (Table 3, entry 5). Although phenyl and paraꢀmethylphenyl substituted vinyl
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Grignard reagents could provide similar yields compared to vinylmagnesium bromide
(Table 3, entries 6ꢀ7), the αꢀnaphthyl substituted vinylmagnesium bromide led to
lower yield for the desired lactams 13e (Table 3, entry 8). It is worth mentioning that
all products 13b-e, as mixtures of Z/E isomers (ca. 1:1), showed excellent
diastereoselectivities. These results indicated that the generation of stereogenic center
at the Cꢀ6 position was solely controlled by αꢀOTBS group7d in this tandem sequence
starting from αꢀchiral aldimines 7 and alkenyl Grignard reagents.
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Table 3. The reactions with different alkenyl Grignard reagents with 7.
O
S
OTBS
(S,SS)-7
(S,SR)-7
(S,SRS)-7
R2CH=CR1MgBr
THF, -78 oC~rt
+
R2
O
N
P
R2
R1
12a-e
R1
trans-11a-e, P=H
Boc2O
trans-13a-e, P=Boc
Entry[a]
Yield%[c] trans/cis[d]
7
R1
R2
H
H
H
H
H
13a-e
13a
13a
13a
13a
13b
13c
1[b]
2
(S,SRS) H
(S,SRS) H
(S,SS)
(S,SR)
(S,SRS)
(S,SRS) H
(S,SRS) H
(S,SRS) H
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99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
3
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7
8
H
H
Et-
C6H5ꢀ
pꢀCH3C6H4ꢀ 13d
αꢀNaphthylꢀ
13e
[a] The reactions were performed with αꢀchiral substituted aldimines 7 (1.0 mmol),
alkenyl Grignard reagents (3 mL, 1.0 M in THF) in dry THF (5 mL) at ꢀ78 oC to rt for
overnight, then the crude product was treated with Boc2O (2.0 mmol), DMAP (1.0
mmol) and TEA (5.0 mmol) in DMF for 24 h. [b] The reaction temperature was ꢀ78oC.
[c] Isolated yield. [d] dr was determined by HPLC or 1H NMR, and E/Z isomers were
isolated by silica gel chromatography.
With chiral lactams 11a in hand, we focused on the total synthesis of (ꢀ)ꢀepiquinamide
3, an alkaloid isolated from the skin of Ecuadorian frog Epipedobates tricolor in
2003.14a,b (ꢀ)ꢀEpiquinamide 3 represents a new structural class of nicotinic agonist,
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selective for nicotinic receptor containing the β2ꢀsubunit,14c and is considered to be a
lead compound in the development of new therapeutics for neuronal receptors.
Recently, the initially isolated group has found that the synthetic epiquinamide was
inactive at nicotinic receptors.14d Due to its scarcity from natural sources (240 ꢁg from
183 frogs) and inaccurately potential use in drug development, both enantiomers of
epiquinamide 3 have attracted considerable attention and several asymmetric routes
have been reported in past years.15 As a continuation of our program for asymmetric
synthesis of natural products including epiquinamide 315l, our synthesis started with
the crude lactam 11a, which was derived from the tandem process of (S,SRS)ꢀ7 with
vinylmagnesium bromide. Upon the treatment with lithium aluminium hydride
(LiAlH4) and subsequent protection with diꢀtertꢀbutyl dicarbonate (Boc2O), NꢀBoc
piperidine 14 was obtained in 48% yield. After the hydroxyl group in 14 was
converted to TBS ether, NꢀBoc group was cleaved by trifluoroacetic acid (TFA) and
the resultant amine was coupled with butꢀ3ꢀenoic acid using diethyl
phosphorocyanidate (DEPC)16 to give the corresponding amide 16 in 79% overall
yield. The subsequent ring closure using Grubbs secondꢀgeneration catalyst17
successfully afforded the bicyclic compound 17 in 97% yield. Upon the reduction of
the carbonꢀcarbon double bond and cleavage of OꢀTBS protection group, the alcohol
18 was obtained in 84% yield. The Xꢀray crystallography of 18 further confirmed the
formation of transꢀ isomer during the nucleophilic attack and cyclization step (see
Supporting Information). Oxidation of 18 with DessꢀMartin periodinane (DMP)18
gave the desired ketone 19 in quantitative yield. Oxime formation with NH2OMeꢂHCl,
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followed by subsequent reduction with BH3·THF and acetylation (Ac2O, NaOH), led
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to the desired (ꢀ)ꢀepiquinamide 3 {[α]D25 = ꢀ20.3 (c 0.65, CHCl3), lit.15b [α]D20 = ꢀ25 (c
8
9
0.26, CHCl3); lit.15d [α]D = ꢀ22 (c 0.5, CHCl3} in 67% isolated yield. The
25
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spectroscopic and physical data of the synthetic (ꢀ)ꢀepiquinamide 3 were identical to
the reported data.15b,15d Thus, based this epiquinamide 3 was synthesized in 6.2%
overall yield by 19 steps from the Lꢀglutamic acid.
OTBS
OH
c
a
b
11a
N
N
Boc
Boc
14
15
OH
OTBS
OTBS
e
d
N
N
N
O
O
f
O
18
NHAc
17
16
O
g
N
N
O
19
(-)-Epiquinamide 3
Scheme 1. Asymmetric synthesis of (ꢀ)ꢀepiquinamide 3. Reagents and conditions: a. (1) LiAlH4,
THF, reflux, overnight; (2) Boc2O, TEA, NaHCO3, DCM, 12h, 48% (2 steps); b. TBSCl, DMAP,
imidazole, DMF, 24h, quantitative yield; c. (1) TFA, DCM, 0 oC, 3.5h; (2) butꢀ3ꢀenoic acid, DEPC,
o
TEA, DMF 0 Cꢀrt, overnight, 79% (2 steps); d. Grubbs 2nd, CH2Cl2, reflux, 12h, 97%; e. Pd/C,
MeOH, H2, rt, 5h, then 6N HCl, overnight, 84%; f. DMP, DCM, 0.5h, rt, quantitative yield; g. (1)
NH2OMe·HCl, pyridine, 0.5 h; (2) borane (1M in THF), THF, 50oC, 4 h; (3) Ac2O, 1M NaOH,
dioxane, rt, 3 h, 67% (3 steps).
Another example for the application of this tandem process αꢀchiral aldimine 7 with
alkynyl Grignard reagents was demonstrated by the asymmetric synthesis of natural
product (+)ꢀswainsonine entꢀ5, which was isolated from the fungus rhizoctonia
legumincola,19 other plant and fungi.20 (+)ꢀSwainsonine entꢀ5 exhibited lysosomal
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αꢀmannosidase, mannosidase II inhibitory properties,21 and is being tested as a new
treatment for cancer, HIV, and immunological.22 Furthermore, this attractive molecule
was the first glycoprotein processing inhibitor selected for clinical evaluation as an
anticancer drug.23 In the past decades, due to its important bioactivities and attractive
structure, swainsonine has become a classic target for the demonstration of new
synthetic methods and/or strategies relevant to indolizidine synthesis.24ꢀ26 The facile
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preparation of chiral
δꢀlactam 10r allowed us to construct indolizidine skeleton
through ringꢀclosing metathesis. As shown in Scheme 2, crude
δꢀlactam 10r was
hydrogenated by hydrogen in the presence of Lindlar catalyst (PdꢀBaSO4, quinoline)
and subsequently alkylated with allyl bromide to give the bisꢀolefin 20 in 67% yield.
The subsequent ring closure successfully afforded the bicyclic intermediate 21 using
Grubbs secondꢀgeneration catalyst17 in 93% yield. Next, the dihydroxylation of alkene
21 with NMO in the presence of 0.1 equiv K2Os2O2(OH)4 resulted in the desired
cisꢀdiol 22 as the single isomer in 94% yield. Finally, 22 was subjected to reduction
o
with LiAlH4 at 60 C and desilylation with HCl/MeOH, affording (+)ꢀSwainsonine
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24
entꢀ5 {[α]D = +84.6 (c 1.20, CH3OH), lit.25a [α]D = +83.3 (c 0.5, CH3OH); lit.25b
21
o
o
[α]D = +84.3 (c 1.02, H2O); mp 143ꢀ144 C; lit.25a mp 143ꢀ145 C} in 87% yield.
The spectroscopic and physical data of the synthetic (+)ꢀswainsonine entꢀ5 and its
hydrochloride salt were identical to the reported data.25
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OTBS
N
TBSO
O
H
N
a
b
c
10r
O
21
9
20
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TBSO
O
OH
OH
H
N
OH
H
d
OH
OH
N
(+)-Swainsonine ent-5
22
Scheme 2. Asymmetric synthesis of (+)ꢀswainsonine entꢀ5. Reagents and conditions: a. (1) 5%
PdꢀBaSO4, quinoline, MeOH, 0oC, 3h; (2) AllylBr, NaH, DMF, 0 oC ~ rt, 67% (2 steps); b. Grubbs
2nd, CH2Cl2, reflux, 12h, 93%; c. K2Os2O2(OH)4, NMO, tꢀBuOH/H2O, overnight, 94%; d. (1)
LAH, THF, reflux, overnight; (2) 1M HClꢀMeOH overnight, rt, 87% (2 steps).
Conclusion
In summary, we established a convenient and oneꢀpot method for highly
diastereoselective synthesis of transꢀ5ꢀhydroxyꢀ6ꢀalkynylꢀ2ꢀpiperidinones 10a-r by
the reactions of (S,SS)ꢀ7 with alkynyl Grignard reagents. As for the tandem process of
(S,SRS)ꢀ7
with
alkenyl
Grignard
reagents,
the
desired
transꢀ5ꢀhydroxyꢀ6ꢀalkenylꢀ2ꢀpiperidinones 13a-e were also obtained and the
stereochemistry at stereogenic center of Cꢀ6 was solely controlled by αꢀalkoxy
substitution. The synthetic application of this methodology was demonstrated by the
concise syntheses of (ꢀ)ꢀepiquinamide 3 and (+)ꢀswainsonine entꢀ5. Especially,
(+)ꢀswainsonine 5 was synthesized in 14 steps from cheap Lꢀglutamic acid in 16.8%
overall yield
Experimental Section
General: THF was distilled from sodium/benzophenone. Reactions were monitored
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by thin layer chromatography (TLC) on glass plates coated with silica gel with
fluorescent indicator. Flash chromatography was performed on silica gel (300–400)
with Petroleum / EtOAc as eluent. Optical rotations were measured on a polarimeter
with a sodium lamp. HRMS were measured on a LCMSꢀITꢀTOF apparatus. IR spectra
were recorded using film on a Fourier Transform Infrared Spectrometer. NMR spectra
were recorded at 400 MHz or 500 MHz, and chemical shifts are reported in δ (ppm)
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1
13
referenced to an internal TMS standard for H NMR and CDCl3 (77.0 ppm) for C
NMR.
General procedure for synthesis of 10a-r and 13a-e: To a solution of compound 7
(363 mg, 1.00 mmol) in anhydrous THF (5 mL) was treated with a solution of
o
alkynyl/alkenyl Grignard reagents (3 mL, 1 M in THF) at ꢀ78 Cꢀrt overnight. The
mixture was quenched with a saturated NH4Cl aqueous solution and extracted with
EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried,
filtrated and concentrated. The crude, Boc2O (436 mg, 2.00 mmol) and DMAP (122
mg, 1.00 mmol) were stirred in DMF (5 mL), before TEA (0.7 mL, 5.00 mmol) was
dropped then the reaction mixture was stirred for 24h. The mixture was quenched
with a saturated NH4Cl aqueous solution and extracted with EtOAc (30 mL × 4). The
combined organic layers were washed with water (30 mL × 2) and brine, dried,
filtrated and concentrated. The residue was purified by flash chromatography on silica
gel (PE/EA = 15/1) to give 10a-r and 13a-e.
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3-(tert-butyldimethylsilyloxy)-6-oxo-2-(2-m-tolylethynyl)piperidine-1-carboxylate
transꢀ10a
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Yellow oil (322 mg, 73%); [α]D25 = ꢀ17.0 (c 1.52, CHCl3); IR (film): νmax 2958, 2930,
2895, 2857, 1775, 1723, 1473, 1367, 1292, 1251, 1145, 1107, 1087, 1002, 889, 837,
779 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.26ꢀ7.13 (m, 4H), 5.12 (dd, J = 3.0, 1.8 Hz,
1H), 4.33ꢀ4.28 (m, 1H), 2.77 (ddd, J = 18.0, 10.4, 7.4 Hz, 1H), 2.61 (ddd, J = 17.4,
7.4, 3.2 Hz, 1H), 2.51ꢀ2.41 (m, 1H), 2.34 (s, 3H), 1.90ꢀ1.81 (m, 1H), 1.57 (s, 9H),
13
0.91 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 170.3,
151.9, 138.0, 132.2, 129.6, 128.7, 128.2, 121.8, 85.4, 85.2, 83.2, 67.9, 54.6, 29.9, 28.0,
26.1, 25.6, 21.1, 17.9, ꢀ4.9, ꢀ5.0 ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C25H37NO4SiNa 466.2390, found: 466.2403.
(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-2-(2-(2-chlorophenyl)ethynyl)-6-oxopiperidine-1-ca
rboxylate transꢀ10b
25
Colorless oil (301 mg, 65%); [α]D = ꢀ25.7 (c 1.78, CHCl3); IR (film): νmax 2954,
2932, 2896, 2855, 1780, 1724, 1473, 1367, 1293, 1252, 1146, 1112, 1008, 888, 838,
1
779, 761 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.47ꢀ7.38 (m, 2H), 7.31ꢀ7.19 (m, 2H),
5.17 (dd, J = 3.0, 1.8, Hz, 1H), 4.37ꢀ4.33 (m, 1H), 2.76 (ddd, J = 17.8, 10.2, 7.4 Hz,
1H), 2.64 (ddd, J = 17.2, 7.6, 3.2 Hz, 1H), 2.59ꢀ2.49 (m, 1H), 1.91ꢀ1.82 (m, 1H), 1.56
13
(s, 9H), 0.90 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ
170.3, 151.9, 136.3, 133.4, 129.8, 129.3, 126.5, 122.0, 90.8, 83.3, 82.1, 67.9, 54.6,
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29.9, 28.0, 26.2, 25.6, 17.9, ꢀ4.8, ꢀ5.0 ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd
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6
7
for C24H34ClNO4SiNa: 486.1843, found: 486.1848.
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2-(2-(3-bromophenyl)ethynyl)-3-(tert-butyldimethylsilyloxy)-6-oxopiperidine-1-c
arboxylate transꢀ10c
25
Colorless oil (319 mg, 63%); [α]D = ꢀ14.1 (c 1.70, CHCl3); IR (film): νmax 2954,
2931, 2879, 2854, 1775, 1723, 1589, 1556, 1471, 1369, 1293, 1252, 1145, 1108, 1086,
1
1008, 887, 838, 779, 684 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.58ꢀ7.55 (m, 1H),
7.50ꢀ7.46 (m, 1H), 7.36ꢀ7.32 (m, 1H), 7.22ꢀ7.17 (m, 1H), 5.11 (dd, J = 2.8, 2.0 Hz,
1H), 4.32ꢀ4.28 (m, 1H), 2.77 (ddd, J = 18.0, 10.4, 7.2 Hz, 1H), 2.59 (ddd, J = 17.2,
7.2, 3.2 Hz, 1H), 2.47ꢀ2.37 (m, 1H), 1.91ꢀ1.82 (m, 1H), 1.56 (s, 9H), 0.90 (s, 9H),
13
0.15 (s, 3H), 0.14 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 170.1, 152.0, 134.4,
131.9, 130.3, 129.8, 124.0, 122.1, 87.0, 83.7, 83.4, 67.8, 54.5, 29.9, 28.0, 26.2, 25.6,
17.9, ꢀ4.8, ꢀ5.0 ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C24H3479BrNO4SiNa: 530.1338, found: 530.1334, [M + Na]+ Calcd for
C24H3481BrNO4SiNa: 532.1318, found: 532.1319.
(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-6-oxo-2-(2-p-tolylethynyl)piperidine-1-carboxylate
transꢀ10d
25
Colorless oil (314 mg, 71%); [α]D = ꢀ16.4 (c 1.10, CHCl3); IR (film): νmax 2957,
2926, 2897, 2854, 2367, 2340, 1769, 1722, 1508, 1459, 1369, 1292, 1250, 1146, 1106,
1002, 889, 840, 777 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.33ꢀ7.29 (m, 2H), 7.16ꢀ7.11
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(m, 2H), 5.11 (dd, J = 3.2, 2.0 Hz, 1H), 4.32ꢀ4.29 (m, 1H), 2.76 (ddd, J = 18.0, 10.4,
7.6 Hz, 1H), 2.60 (ddd, J = 17.2, 7.2, 3.2 Hz, 1H), 2.50ꢀ2.41 (m, 1H), 2.36 (s, 3H),
1.89ꢀ1.80 (m, 1H), 1.56 (s, 9H), 0.91 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 170.3, 151.9, 138.9, 131.6, 129.1, 120.0, 85.4, 85.0, 83.2,
67.9, 54.7, 29.9, 28.0, 26.1, 25.6, 21.5, 18.0, ꢀ4.8, ꢀ5.0 ppm; HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C25H37NO4SiNa: 466.2390, found: 466.2378.
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(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-2-(2-(4-fluorophenyl)ethynyl)-6-oxopiperidine-1-ca
rboxylate transꢀ10e
25
White solid (295 mg, 66%), m.p 83ꢀ84oC; [α]D = ꢀ13.9 (c 0.72, CHCl3); IR (film):
νmax 2958, 2928, 2854, 1775, 1715, 1505, 1472, 1368, 1293, 1248, 1144, 1105, 1089,
1
1013, 832, 776 cmꢀ1; 19F NMR (376 MHz, CDCl3) δ ꢀ110.14 ppm; H NMR (400
MHz, CDCl3) δ 7.43ꢀ7.36 (m, 2H), 7.06ꢀ6.98 (m, 2H), 5.11 (dd, J = 3.0, 1.8 Hz, 1H),
4.32ꢀ4.29 (m, 1H), 2.77 (ddd, J = 18.0, 10.4, 7.2 Hz, 1H), 2.60 (ddd, J = 17.2, 7.2, 3.2
Hz, 1H), 2.49ꢀ2.39 (m, 1H), 1.91ꢀ1.82 (m, 1H), 1.56 (s, 9H), 0.93ꢀ0.89 (m, 9H), 0.15
13
(s, 3H), 0.14 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 170.2, 162.7 (d, J = 248.7
Hz), 152.0, 133.7 (d, J = 8.3 Hz), 118.2 (d, J = 3.1 Hz), 115.6 (d, J = 21.9 Hz), 85.4,
84.2, 83.3, 67.9, 54.6, 29.9, 28.0, 26.1, 25.6, 18.0, ꢀ4.9, ꢀ5.0 ppm; HRMS (ESIꢀTOF)
m/z: [M + Na]+ Calcd for C24H34FNO4SiNa: 470.2139, found: 470.2130.
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3-(tert-butyldimethylsilyloxy)-2-(2-(4-chlorophenyl)ethynyl)-6-oxopiperidine-1-ca
rboxylate transꢀ10f
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White solid (292 mg, 63%), m.p105ꢀ106oC; [α]D25 = ꢀ14.1 (c 1.42, CHCl3); IR (film):
νmax 2953, 2930, 2895, 2857, 1775, 1723, 1487, 1364, 1292, 1249, 1146, 1108, 1090,
1016, 889, 837, 779 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.36ꢀ7.28 (m, 4H), 5.11 (dd,
J = 3.0, 1.8 Hz, 1H), 4.32ꢀ4.27 (m, 1H), 2.77 (ddd, J = 18.2, 10.6, 7.4 Hz, 1H), 2.59
(ddd, J = 17.6, 7.4, 3.2 Hz, 1H), 2.47ꢀ2.37 (m, 1H), 1.90ꢀ1.81 (m, 1H), 1.55 (s, 9H),
13
0.90 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 170.2,
152.0, 134.8, 132.9, 128.7, 120.5, 86.7, 84.1, 83.3, 67.8, 54.6, 29.9, 28.0, 26.1, 25.6,
17.9, ꢀ4.9, ꢀ5.0 ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C24H34ClNO4SiNa:
486.1843, found: 486.1845.
(2R,3S)-tert-Butyl
2-(2-(4-bromophenyl)ethynyl)-3-(tert-butyldimethylsilyloxy)-6-oxopiperidine-1-c
arboxylate transꢀ10g
25
Pale yellow solid (314 mg, 62%), m.p 87ꢀ88oC; [α]D = ꢀ11.6 (c 1.86, CHCl3); IR
(film): νmax 2953, 2931, 2895, 2860, 1780, 1723, 1484, 1369, 1293, 1250, 1145, 1106,
1009, 887, 843, 779 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.49ꢀ7.44 (m, 2H), 7.30ꢀ7.25
(m, 2H), 5.10 (dd, J = 2.8, 2.0 Hz, 1H), 4.33ꢀ4.27 (m, 1H), 2.77 (ddd, J = 18.0, 10.8,
7.2 Hz, 1H), 2.58 (ddd, J = 17.6, 7.2, 3.2 Hz, 1H), 2.47ꢀ2.37 (m, 1H), 1.90ꢀ1.81 (m,
13
1H), 1.56 (s, 9H), 0.90 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H) ppm; C NMR (100 MHz,
CDCl3) δ 169.0, 150.8, 132.0, 130.5, 121.9, 119.8, 85.7, 83.0, 82.2, 66.6, 53.5, 28.7,
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26.8, 25.0, 24.4, 16.8, ꢀ6.0, ꢀ6.2 ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C24H3479BrNO4SiNa: 530.1338, found: 530.1346; Calcd for C24H3481BrNO4SiNa:
532.1318, found: 532.1333.
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(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-2-(2-(4-methoxyphenyl)ethynyl)-6-oxopiperidine-1-
carboxylate transꢀ10h
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Colorless oil (317 mg, 69%); [α]D = ꢀ14.4 (c 1.22, CHCl3); IR (film): νmax 2954,
2931, 2899, 2860, 1774, 1723, 1610, 1510, 1468, 1367, 1291, 1249, 1146, 1107, 1030,
1008, 886, 836, 779 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.38ꢀ7.32 (m, 2H), 6.88ꢀ6.83
(m, 2H), 5.11 (dd, J = 3.2, 2.0 Hz, 1H), 4.32ꢀ4.27 (m, 1H), 3.83 (s, 3H), 2.76 (ddd, J =
18.0, 10.4, 7.4 Hz, 1H), 2.60 (ddd, J = 17.2, 7.2, 3.2 Hz, 1H), 2.51ꢀ2.40 (m, 1H),
1.89ꢀ1.80 (m, 1H), 1.56 (s, 9H), 0.90 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H) ppm; 13C
NMR (100 MHz, CDCl3) δ 168.4, 157.9, 150.0, 131.2, 112.1, 112.0, 83.2, 82.3, 81.2,
66.0, 53.3, 52..8, 27.9, 26.0, 24.1, 23.6, 16.0, ꢀ6.8, ꢀ7.0 ppm; HRMS (ESIꢀTOF) m/z:
[M + Na]+ Calcd for C25H37NO5SiNa: 482.2339, found: 482.2345.
(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-6-oxo-2-(2-(4-propylphenyl)ethynyl)piperidine-1-c
arboxylate transꢀ10i
25
Colorless oil (306 mg, 65%); [α]D = ꢀ14.8 (c 1.25, CHCl3); IR (film): νmax 2956,
2930, 2895, 2858, 2361, 1775, 1723, 1473, 1369, 1293, 1250, 1145, 1107, 1009, 887,
1
838, 777 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.35ꢀ7.31 (m, 2H), 7.16ꢀ7.11 (m, 2H),
5.12 (dd, J = 2.8, 2.0 Hz, 1H), 4.32ꢀ4.28 (m, 1H), 2.76 (ddd, J = 18.0, 10.4, 7.4 Hz,
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1H), 2.66ꢀ2.55 (m, 3H), 2.51ꢀ2.41 (m, 1H),1.89ꢀ1.80 (m, 1H), 1.69ꢀ1.60 (m, 2H), 1.56
(s, 9H), 0.94 (t, 3H), 0.91 (s, 9H), 0.15 (s, 3H), 0.13 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 169.8, 151.4, 143.1, 131.1, 128.0, 118.7, 84.9, 84.5, 82.7, 67.5, 54.2, 37.4,
29.4, 27.5, 25.5, 25.1, 23.8, 17.5, 13.2, ꢀ5.3, ꢀ5.5 ppm; HRMS (ESIꢀTOF) m/z: [M +
Na]+ Calcd for C27H41NO4SiNa: 494.2703, found: 494.2719.
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(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-6-oxo-2-(2-phenylethynyl)piperidine-1-carboxylate
transꢀ10j
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White solid (283 mg, 66%), m.p 62ꢀ63oC; [α]D = ꢀ15.7 (c 1.29, CHCl3); IR (film):
νmax 2953, 2931, 2895, 2855, 1780, 1723, 1367, 1293, 1250, 1145, 1106, 1013, 891,
836, 779, 756, 689 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.45ꢀ7.30 (m, 5H), 5.13 (dd, J
= 3.0, 1.8 Hz, 1H), 4.35ꢀ4.30 (m, 1H), 2.77 (ddd, J = 18.0, 10.8, 7.6 Hz, 1H), 2.61
(ddd, J = 17.6, 7.2, 3.2 Hz, 1H), 2.50ꢀ2.40 (m, 1H), 1.90ꢀ1.81 (m, 1H), 1.57 (s, 9H),
13
0.91 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 170.2,
151.9, 131.7, 128.7, 128.3, 122.0, 85.6, 85.2, 83.2, 67.9, 54.6, 29.8, 28.0, 26.1, 25.6,
17.9, ꢀ4.9, ꢀ5.0 ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C24H35NO4SiNa:
452.2233, found: 452.2241.
(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-2-(4-(tert-butyldimethylsilyloxy)but-1-ynyl)-6-oxop
iperidine-1-carboxylate transꢀ10k
25
Colorless oil (342 mg, 67%); [α]D = ꢀ13.7 (c 0.95, CHCl3); IR (film): νmax 2954,
2930, 2857, 1775, 1724, 1368, 1294, 1253, 1148, 1105, 1006, 837, 776 cmꢀ1; 1H NMR
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(400 MHz, CDCl3) δ 4.90ꢀ4.85 (m, 1H), 4.17 (dd, J = 6.4, 3.2 Hz, 1H), 3.72ꢀ3.67 (m,
2H), 2.70 (ddd, J = 18.0, 10.4, 7.2 Hz, 1H), 2.53 (ddd, J = 17.2, 7.2, 3.2 Hz, 1H),
2.43ꢀ2.33 (m, 3H), 1.81ꢀ1.73 (m, 1H), 1.54 (s, 9H), 0.91 (s, 9H), 0.88 (s, 9H), 0.10 (s,
6H), 0.08 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 170.4, 152.1, 83.1, 83.0, 77.9,
68.0, 61.6, 54.2, 29.9, 28.0, 25.9, 25.8, 25.6, 23.1, 18.3, 17.9, ꢀ4.9, ꢀ5.0, ꢀ5.3 ppm;
HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C26H49NO5Si2Na: 534.3047, found:
534.3045.
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(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-2-(hept-1-ynyl)-6-oxopiperidine-1-carboxylate
transꢀ10l
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Colorless oil (271 mg, 64%); [α]D = ꢀ10.5 (c 0.97, CHCl3); IR (film): νmax 2958,
2930, 2858, 1775, 1723, 1407, 1366, 1293, 1252, 1150, 1103, 1005, 887, 840, 775
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 4.90ꢀ4.85 (m, 1H), 4.18ꢀ4.14 (m, 1H), 2.71 (ddd,
J = 18.0, 10.4, 7.4 Hz, 1H), 2.53 (ddd, J = 17.2, 7.2, 3.2 Hz, 1H), 2.43ꢀ2.33 (m, 1H),
2.21ꢀ2.14 (m, 2H), 1.80ꢀ1.73 (m, 1H), 1.54 (s, 9H), 1.52ꢀ1.45 (m, 2H), 1.40ꢀ1.26 (m,
13
4H), 0.94ꢀ0.89 (m, 3H), 0.88 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H) ppm; C NMR (100
MHz, CDCl3) δ 170.4, 152.0, 86.1, 82.9, 68.1, 54.3, 31.0, 29.8, 28.1, 27.9, 25.8, 25.6,
22.1, 18.6, 17.9, 13.9, ꢀ4.9, ꢀ5.0 ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for
C23H41NO4SiNa: 446.2703, found: 446.2711.
(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-6-oxo-2-(3-(phenylthio)prop-1-ynyl)piperidine-1-ca
rboxylate transꢀ10m
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Colorless oil (314 mg, 66%); [α]D = ꢀ17.5 (c 1.68, CHCl3); IR (film): νmax 2956,
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2928, 2893, 2856, 1775, 1723, 1583, 1473, 1368, 1294, 1252, 1144, 1105, 1089, 1003,
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9
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891, 837, 776, 744, 689 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.44ꢀ7.39 (m, 2H),
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7.36ꢀ7.30 (m, 2H), 7.29ꢀ7.23 (m, 1H), 4.86ꢀ4.82 (m, 1H), 4.05ꢀ4.02 (m, 1H),
3.68ꢀ3.58 (m, 2H), 2.62 (ddd, J = 18.0, 10.4, 7.6 Hz, 1H), 2.36 (ddd, J = 17.6, 7.6, 3.2
Hz, 1H), 2.11ꢀ2.02 (m, 1H), 1.68ꢀ1.59 (m, 1H), 1.52 (s, 9H), 0.86 (s, 9H), 0.07 (s, 6H)
13
ppm; C NMR (100 MHz, CDCl3) δ 170.1, 151.9, 134.5, 130.5, 128.9, 127.1, 83.1,
81.3, 80.1, 67.7, 54.0, 29.7, 27.9, 25.8, 25.5, 22.8, 17.9, ꢀ4.9, ꢀ5.1 ppm; HRMS
(ESIꢀTOF) m/z: [M + Na]+ Calcd for C25H37NO4SSiNa: 498.2110, found: 498.2128.
(2R,3S)-tert-Butyl
2-(3-(benzyloxy)prop-1-ynyl)-3-(tert-butyldimethylsilyloxy)-6-oxopiperidine-1-ca
rboxylate transꢀ10n
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Pale yellow solid (270 mg, 57%), m.p 50ꢀ51oC; [α]D = ꢀ10.9 (c 1.23, CHCl3); IR
(film): νmax 2954, 2931, 2898, 2857, 2356, 1775, 1723, 1609, 1472, 1457, 1367, 1293,
1
1252, 1147, 1087, 1005, 893, 837, 779, 745 cmꢀ1; H NMR (400 MHz, CDCl3) δ
7.40ꢀ7.30 (m, 5H), 4.99ꢀ4.95 (m, 1H), 4.58 (s, 2H), 4.24ꢀ4.21 (m, 1H), 4.20 (d, J =
1.6 Hz, 1H), 2.74 (ddd, J = 18.0, 10.8, 7.2 Hz, 1H), 2.55 (ddd, J = 17.6, 7.2, 3.2 Hz,
1H), 2.42ꢀ2.32 (m, 1H), 1.86ꢀ1.77 (m, 1H), 1.55 (s, 9H), 0.89 (s, 9H), 0.12 (s, 3H),
13
0.11 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 170.2, 152.1, 137.2, 128.5, 128.1,
128.0, 83.3, 83.2, 81.4, 71.8, 67.7, 57.3, 54.1, 29.8, 28.0, 26.0, 25.6, 17.9, ꢀ4.9, ꢀ5.0
ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C26H39NO5SiNa: 496.2495, found:
496.2496.
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3-(tert-butyldimethylsilyloxy)-2-(3-(tert-butyldimethylsilyloxy)prop-1-ynyl)-6-oxo
piperidine-1-carboxylate transꢀ10o
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Colorless oil (308 mg, 62%); [α]D = ꢀ12.5 (c 0.97, CHCl3); IR (film): νmax 2955,
2929, 2895, 2854, 1775, 1724, 1463, 1364, 1293, 1252, 1147, 1086, 1008, 891, 835,
776 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 4.96ꢀ4.93 (m, 1H), 4.32 (d, J = 1.6 Hz, 1H ),
4.23ꢀ4.18 (m, 1H), 2.72 (ddd, J = 18.0, 10.4, 7.2 Hz, 1H), 2.53 (ddd, J = 17.2, 7.2, 3.2
Hz, 1H), 2.43ꢀ2.33 (m, 1H), 1.84ꢀ1.75 (m, 1H), 1.54 (s, 9H), 0.91 (s, 9H), 0.88 (s, 9H),
13
0.12 (s, 6H), 0.10 (s, 6H) ppm; C NMR (100 MHz, CDCl3) δ 170.2, 151.9, 84.0,
83.1, 81.3, 67.7, 54.0, 51.6, 29.8, 27.9, 25.9, 25.7, 25.6, 18.2, 17.9, ꢀ4.9, ꢀ5.1, ꢀ5.2
ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C25H47NO5Si2Na: 520.2890, found:
520.2895.
(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-2-(3,3-dimethylbut-1-ynyl)-6-oxopiperidine-1-carb
oxylate transꢀ10p
Colorless oil (282 mg, 69%); [α]D25 = ꢀ7.5 (c 1.19, CHCl3); IR (film): νmax 2969, 2931,
2895, 2858, 1780, 1723, 1479, 1364, 1287, 1251, 1147, 1105, 1008, 891, 832, 778
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 4.85 (dd, J = 3.0, 1.8 Hz, 1H), 4.16ꢀ4.12 (m, 1H),
2.69 (ddd, J = 18.0, 10.4, 7.6 Hz, 1H), 2.54 (ddd, J = 17.6, 7.6, 3.2 Hz, 1H), 2.40ꢀ2.29
(m, 1H), 1.80ꢀ1.72 (m, 1H), 1.54 (s, 9H), 1.20 (s, 9H), 0.88 (s, 9H), 0.11 (s, 3H), 0.10
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 170.5, 151.8, 94.1, 82.9, 75.3, 68.1, 54.3,
30.8, 29.8, 28.0, 27.4, 25.7, 25.6, 17.9, ꢀ4.9, ꢀ5.0 ppm; HRMS (ESIꢀTOF) m/z: [M +
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Na]+ Calcd for C22H39NO4SiNa: 432.2546, found: 432.2551.
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3-(tert-butyldimethylsilyloxy)-6-oxo-2-(2-(trimethylsilyl)ethynyl)piperidine-1-car
boxylate transꢀ10q
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White solid (247 mg, 58%), m.p 42ꢀ43oC; [α]D = ꢀ10.4 (c 0.98, CHCl3); IR (film):
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νmax 2958, 2926, 2895, 2860, 2169, 1780, 1725, 1473, 1369, 1287, 1251, 1145, 1106,
1040, 1003, 974, 842, 777, 648 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 4.88 (dd, J = 2.8,
2.0 Hz, 1H), 4.23ꢀ4.18 (m, 1H), 2.71 (ddd, J = 18.0, 10.4, 7.2 Hz, 1H), 2.56 (ddd, J =
17.2, 7.2, 3.2 Hz, 1H), 2.41ꢀ2.31 (m, 1H), 1.83ꢀ1.74 (m, 1H), 1.55 (s, 9H), 0.90ꢀ0.86
13
(m, 9H), 0.19ꢀ0.16 (m, 9H), 0.13ꢀ0.10 (m, 6H) ppm; C NMR (100 MHz, CDCl3) δ
170.2, 151.7, 101.9, 90.3, 83.2, 67.9, 54.8, 29.8, 27.9, 25.8, 25.6, 17.9, ꢀ0.2, ꢀ4.9, ꢀ5.0
ppm; HRMS (ESIꢀTOF) m/z: [M + Na]+ Calcd for C21H39NO4Si2Na: 448.2315, found:
448.2305.
(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-2-ethynyl-6-oxopiperidine-1-carboxylate transꢀ10r
Colorless oil (251 mg, 71%); [α]D25 = ꢀ8.7 (c 1.18, CHCl3); IR (film): νmax 3248, 2955,
2928, 2895, 2855, 1775, 1724, 1606, 1471, 1369, 1332, 1295, 1252, 1147, 1108, 1010,
887, 840, 777, 726, 671 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 4.89 (dd, J = 5.2, 2.4 Hz,
1H), 4.25ꢀ4.20 (m, 1H), 2.73 (ddd, J = 18.0, 10.8, 7.6 Hz, 1H), 2.55 (ddd, J = 17.6,
7.2, 3.2 Hz, 1H), 2.43 (d, J = 2.4 Hz, 1H ), 2.42ꢀ2.35 (m, 1H), 1.86ꢀ1.70 (m, 1H), 1.54
(s, 9H), 0.88 (s, 9H), 0.11 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ 168.2, 150.1,
81.5, 78.6, 71.8, 65.8, 52.0, 27.9, 26.1, 24.0, 23.7, 16.1, ꢀ6.7, ꢀ6.9 ppm; HRMS
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(ESIꢀTOF) m/z: [M + Na]+ Calcd for C18H31NO4SiNa: 376.1920, found: 376.1916.
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3-(tert-butyldimethylsilyloxy)-6-oxo-2-(2-m-tolylethynyl)piperidine-1-carboxylate
cis-10a
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Yellow oil (142 mg, 32%); [α]D = ꢀ5.5 (c 1.62, CHCl3); IR (film): νmax 2955, 2930,
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2857, 1775, 1727, 1463, 1368, 1291, 1252, 1149, 882, 838, 779 cmꢀ1; H NMR (400
MHz, CDCl3) δ 7.25ꢀ7.10 (m, 4H), 5.14 (dd, J = 4.8, 1.2 Hz, 1H), 4.10 (ddd, J = 10.4,
5.2, 4.4 Hz, 1H), 2.84 (ddd, J = 17.6, 8.4, 4.4 Hz, 1H), 2.52 (ddd, J = 16.8, 8.4, 7.6 Hz,
1H), 2.32 (s, 3H), 2.28ꢀ2.19 (m, 1H), 2.00ꢀ1.90 (m, 1H), 1.55 (s, 9H), 0.93 (s, 9H),
13
0.15 (s, 3H), 0.12 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 169.9, 151.3, 137.9,
132.3, 129.3, 128.8, 128.1, 122.5, 85.3, 84.5, 83.7, 67.9, 53.4, 32.0, 28.0, 26.7, 25.7,
21.2, 18.0, ꢀ4.5, ꢀ4.7 ppm; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C25H38NO4Si:
444.2570, found: 444.2551.
(2S,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-2-(2-(4-chlorophenyl)ethynyl)-6-oxopiperidine-1-ca
rboxylate cis-10f
25
Yellow oil (130 mg, 28%); [α]D = ꢀ5.5 (c 1.63, CHCl3); IR (film): νmax 2954, 2930,
2849, 1775, 1728, 1489, 1368, 1292, 1252, 1150, 1003, 882, 837, 777 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 7.36ꢀ7.31 (m, 2H), 7.30ꢀ7.25 (m, 2H), 5.14 (dd, J = 4.8, 1.2 Hz,
1H), 4.11 (ddd, J = 10.0, 5.2, 4.4 Hz, 1H), 2.82 (ddd, J = 17.6, 8.0, 4.4 Hz, 1H), 2.53
(ddd, J = 17.2, 8.4, 7.6 Hz, 1H), 2.28ꢀ2.16 (m, 1H), 2.00ꢀ1.90 (m, 1H), 1.55 (s, 9H),
13
0.92 (s, 9H), 0.14 (s, 3H), 0.12 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 169.8,
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151.3, 134.4, 133.0, 128.6, 121.1, 86.0, 83.9, 83.8, 67.7, 53.4, 32.0, 28.0, 26.9, 25.6,
18.0, ꢀ4.7, ꢀ4.8 ppm; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C24H35ClNO4Si:
464.2024, found: 464.2024.
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(2S,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-2-(4-(tert-butyldimethylsilyloxy)but-1-ynyl)-6-oxop
iperidine-1-carboxylate cis-10k
Colorless oil (118 mg, 23%); [α]D25 = ꢀ3.8 (c 1.38, CHCl3); IR (film): νmax 2955, 2930,
2857, 1776, 1727, 1474, 1368, 1292, 1254, 1143, 883, 838, 777 cmꢀ1; H NMR (400
1
MHz, CDCl3) δ 4.84 (dd, J = 4.8, 2.0 Hz, 1H), 3.93 (ddd, J = 10.4, 5.2, 4.4 Hz, 1H),
3.66ꢀ3.61 (m, 2H), 2.72 (ddd, J = 17.6, 8.4, 4.4 Hz, 1H), 2.46ꢀ2.33 (m, 3H), 2.16ꢀ2.05
(m, 1H), 1.87ꢀ1.78 (m, 1H), 1.47 (s, 9H), 0.85 (s, 9H), 0.83 (s, 9H), 0.05 (s, 3H), 0.03
13
(s, 3H), 0.00 (s, 6H) ppm; C NMR (100 MHz, CDCl3) δ 170.0, 151.4, 83.4, 82.4,
76.5, 67.7, 61.9, 52.8, 32.0, 28.0, 26.5, 25.9, 25.7, 23.2, 18.3, 18.0, ꢀ4.6, ꢀ4.8, ꢀ5.3
ppm; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C26H50NO5Si2: 512.3228, found:
512.3225.
(2S,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-2-(hept-1-ynyl)-6-oxopiperidine-1-carboxylate
cis-10l
Colorless oil (114 mg, 27%); [α]D25 = ꢀ4.7 (c 0.93, CHCl3); IR (film): νmax 2957, 2931,
2858, 1776, 1727, 1463, 1368, 1291, 1254, 1145, 882, 838, 777 cmꢀ1; H NMR (400
1
MHz, CDCl3) δ 4.89 (dd, J = 4.8, 2.0 Hz, 1H), 3.98 (ddd, J = 10.4, 5.2, 4.4 Hz, 1H),
2.78 (ddd, J = 17.6, 8.4, 4.4 Hz, 1H), 2.47 (ddd, J = 17.6, 8.4, 7.6 Hz, 1H), 2.23ꢀ2.10
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(m, 3H), 1.94ꢀ1.83 (m, 1H), 1.53 (s, 9H), 1.51ꢀ1.44 (m, 2H), 1.40ꢀ1.25 (m, 4H), 0.91
(s, 9H), 0.90ꢀ0.85 (m, 3H), 0.11 (s, 3H), 0.09 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3) δ 170.1, 151.4, 85.9, 83.4, 75.4, 67.8, 52.9, 32.0, 30.9, 28.2, 28.0, 26.5, 25.7,
22.2, 18.7, 18.0, 14.0, ꢀ4.6, ꢀ4.8 ppm; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C23H42NO4Si: 424.2883, found: 424.2882.
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(2R,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-6-oxo-2-vinylpiperidine-1-carboxylate 13a
25
White solid (227 mg, 64%), m.p 47ꢀ48oC; [α]D = +36.3 (c 0.93, CHCl3); IR (film):
νmax 2953, 2932, 2855, 1770, 1721, 1370, 1252, 1090, 1003, 838, 777 cmꢀ1; 1H NMR
(400 MHz, CDCl3) δ 5.66 (ddd, J = 16.8, 10.4, 4.8 Hz, 1H), 5.16ꢀ5.08 (m, 2H),
4.65ꢀ4.60 (m, 1H), 3.95ꢀ3.92 (m, 1H), 2.63 (ddd, J = 18.8, 11.2, 7.6 Hz, 1H), 2.31
(ddd, J = 17.6, 7.2, 2.4 Hz, 1H), 1.93ꢀ1.83 (m, 1H), 1.67ꢀ1.58 (m, 1H), 1.39 (s, 9H),
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0.79 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 171.0,
152.4, 135.8, 116.7, 82.6, 67.3, 64.7, 29.5, 27.9, 25.6, 24.8, 17.9, ꢀ4.9, ꢀ5.0 ppm;
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C18H34NO4Si: 356.2257, found: 356.2254.
(2R,3S)-tert-Butyl
2-(but-1-en-2-yl)-3-(tert-butyldimethylsilyloxy)-6-oxopiperidine-1-carboxylate
13b
25
Colorless oil (234 mg, 61%); [α]D = +37.0 (c 1.41, CHCl3); IR (film): νmax 2956,
2926, 2855, 1772, 1720, 1452, 1368, 1253, 1151, 1107, 1087, 1007, 893, 838, 777
cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 5.00ꢀ4.96 (m, 1H), 4.95ꢀ4.92 (m, 1H), 4.62ꢀ4.57
(m, 1H), 4.10 (ddd, J = 4.8, 2.8, 2.0 Hz, 1H), 2.73 (ddd, J = 18.8, 11.6, 7.6 Hz, 1H),
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2.43 (ddd, J = 18.0, 7.2, 2.0 Hz, 1H), 2.17ꢀ2.01 (m, 2H), 2.00ꢀ1.90 (m, 1H), 1.70ꢀ1.62
(m, 1H), 1.47 (s, 9H), 1.15ꢀ1.08 (m, 3H), 0.89 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3) δ 171.0, 152.0, 148.8, 109.6, 82.2, 66.9, 65.3, 29.0, 27.5,
26.5, 25.2, 23.8, 17.6, 11.7, ꢀ5.2, ꢀ5.3 ppm; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd
for C20H38NO4Si: 384.2570, found: 384.2563.
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(2R,3S,E)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-6-oxo-2-styrylpiperidine-1-carboxylate E-13c
White solid (118 mg, 28%), m.p 147ꢀ148oC; [α]D25 = + 9.0 (c 1.12, CHCl3); IR (film):
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νmax 2926, 2854, 1754, 1253, 1151, 1074, 986, 836, 777 cmꢀ1; H NMR (400 MHz,
CDCl3) δ 7.40ꢀ7.25 (m, 5H), 6.53 (dd, J = 16.0, 1.2 Hz, 1H), 6.09 (dd, J = 16.0, 6.0
Hz, 1H), 4.91ꢀ4.86 (m, 1H), 4.14ꢀ4.09 (m, 1H), 2.79 (ddd, J = 18.4, 11.2, 7.6 Hz, 1H),
2.49 (ddd, J = 17.6, 6.8, 2.4 Hz, 1H), 2.11ꢀ2.01 (m, 1H), 1.84ꢀ1.75 (m, 1H), 1.50 (s,
9H), 0.92 (s, 9H), 0.15 (s, 3H), 0.13 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ
171.0, 152.4, 136.1, 132.0, 128.7, 128.0, 126.9, 126.5, 82.9, 67.8, 64.6, 29.6, 27.9,
25.6, 25.2, 18.0, ꢀ4.8, ꢀ4.9 ppm; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C24H38NO4Si: 432.2570, found: 432.2567.
(2R,3S,Z)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-6-oxo-2-styrylpiperidine-1-carboxylate Z-13c
25
Colorless oil (117 mg, 27%); [α]D = + 97.2 (c 1.29, CHCl3); IR (film): νmax 2955,
2930, 2849, 1770, 1718, 1367, 1292, 1252, 1149, 1107, 1088, 893, 837, 776 cmꢀ1; 1H
NMR (400 MHz, CDCl3) δ 7.42ꢀ7.27 (m, 5H), 6.59 (d, J = 11.6 Hz, 1H), 5.48 (dd, J =
11.6, 8.8 Hz, 1H), 5.29ꢀ5.24 (m, 1H), 4.08ꢀ4.04 (m, 1H), 2.78 (ddd, J = 19.2, 11.6, 8.0
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Hz, 1H), 2.51 (ddd, J = 18.0, 7.6, 2.4 Hz, 1H), 2.13ꢀ2.02 (m, 1H), 1.86ꢀ1.77 (m, 1H),
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1.33 (s, 9H), 0.86 (s, 9H), 0.002ꢀ0.004 (m, 6H) ppm; C NMR (100 MHz, CDCl3) δ
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170.5, 152.1, 136.1, 131.8, 130.3, 128.6, 128.4, 127.7, 82.7, 67.7, 60.8, 29.5, 27.7,
25.7, 25.6, 17.9, ꢀ4.9, ꢀ5.0 ppm; HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C24H38NO4Si: 432.2570, found: 432.2569.
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(2S,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-6-oxo-2-(2-m-tolylethynyl)piperidine-1-carboxylate
E-13d
White solid (138 mg, 31%), m.p 115ꢀ116oC; [α]D25 = + 9.5 (c 1.17, CHCl3); IR (film):
νmax 2954, 2930, 2844, 1770, 1719, 1368, 1252, 1150, 1106, 1086, 1008, 986, 837,
1
776 cmꢀ1; H NMR (400 MHz, CDCl3) δ 7.27ꢀ7.22 (m, 2H), 7.15ꢀ7.10 (m, 2H), 6.47
(d, J = 16.0 Hz, 1H), 6.01 (dd, J = 16.0, 6.0 Hz, 1H), 4.87ꢀ4.82 (m, 1H), 4.10ꢀ4.06 (m,
1H), 2.76 (ddd, J = 18.4, 11.2, 7.6 Hz, 1H), 2.46 (ddd, J = 17.6, 6.8, 2.4 Hz, 1H), 2.33
(s, 3H), 2.09ꢀ1.99 (m, 1H), 1.81ꢀ1.72 (m, 1H), 1.48 (s, 9H), 0.90 (s, 9H), 0.13 (s, 3H),
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0.11 (s, 3H) ppm; C NMR (100 MHz, CDCl3) δ 170.9, 152.3, 137.9, 133.2, 131.8,
129.3, 126.3, 125.7, 82.7, 67.8, 64.5, 29.6, 27.9, 25.6, 25.1, 21.1, 17.9, ꢀ4.9, ꢀ5.0 ppm;
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C25H40NO4Si: 446.2727, found: 446.2718.
(2S,3S)-tert-Butyl
3-(tert-butyldimethylsilyloxy)-6-oxo-2-(2-m-tolylethynyl)piperidine-1-carboxylate
Z-13d
Pale yellow oil (138 mg, 31%); [α]D25 = + 81.8 (c 1.65, CHCl3); IR (film): νmax 2953,
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