Stereocontrolled synthesis of substituted chiral piperidines viaone-pot asymmetric 6π-azaelectrocyclization: Asymmetric syntheses of(-)-dendroprimine, (+)-7-epidendroprimine, (+)-5-epidendroprimine, and (+)-5,7-epidendroprimine

Article

pubs.acs.org/joc

Stereocontrolled Synthesis of Substituted Chiral Piperidines via

One-Pot Asymmetric 6π-Azaelectrocyclization: Asymmetric Syntheses of

(−)-Dendroprimine, (+)-7-Epidendroprimine, (+)-5-Epidendroprimine,

and (+)-5,7-Epidendroprimine

Toyoharu Kobayashi,*^,†,‡Futoshi Hasegawa,^†Yoshikatsu Hirose,^†Katsunori Tanaka,^†,§Hajime Mori,^∥

and Shigeo Katsumura*^,†

^†School of Science and Technology, Kwansei Gakuin University, Gakuen 2-1, Sanda, Hyogo 669-1337, Japan

^∥Industrial Technology Center of Wakayama Prefecture, Ogura 60, Wakayama 649-6261, Japan

S

* Supporting Information

ABSTRACT: The asymmetric one-pot 6π-azaelectrocyclization

of alkenyl vinyl stannane, ethyl (Z)-2-iodo-4-oxobutenoate, and

(−)-7-isopropyl-cis-aminoindanol in the presence of a Pd(0)

catalyst stereoselectively produced the tetracyclic aminoacetal

compounds, resulting from the four-bond formation accom-

panying by controlling the stereochemistry at the two

asymmetric centers. The produced cyclic aminoacetals can be

regarded as synthetic precursors of substituted chiral piper-

idines, and the syntheses of 2,4- and 2,4,6-substituted

piperidines were realized from the obtained aminoacetals by

the stereoselective hydrogenation of the double bond

conjugated with the C-4 ester group and alkylation at the

aminoacetal moiety. In addition, the stereoselective synthesis of

an indolizidine alkaloid, (−)-dendroprimine, and its three

stereoisomers, (+)-7-epidendroprimine, (+)-5-epidendroprimine, and (+)-5,7-epidendroprimine, were achieved.

controlled synthesis of polysubstituted piperidines has been a

current topic in the synthetic community.^2,3When enantio-

merically pure polysubstituted piperidines are easily accessible

resulting from the successful introduction of the desired alkyl

substituents to the desired positions of a chiral piperidine ring,

a widely applicable synthetic strategy for alkaloids consisting of

a polysubstitued piperidine ring will be envisioned.^2c,4

INTRODUCTION

■

The substituted piperidines can be regarded as one of the core

structures of naturally occurring alkaloids, including the indol

alkaloid (Figure 1).¹These functionalized six-member nitrogen

heterocycles have drawn a great deal of attention due to their

attractive pharmacological activities. Therefore, the stereo-

Recently, we achieved the highly stereoselective asymmetric

6π-azaelectrocyclization of conformationally flexible linear

1-azatrienes by utilizing 7-alkylsubstituted cis-aminoindanol

derivatives.⁵⁻⁷Our asymmetric azaelectrocyclization is based

on the discovery that the remarkable frontier-orbital interaction

between the HOMO and LUMO of 1-azatrienes significantly

accelerates the azaelectrocyclization in the presence of the

C-4 carbonyl and C-6 alkenyl or aryl substituents.^8,9This asym-

metric azaelectrocyclization provided the chiral tetracyclic

2,4-disubstituted 1,2,5,6-tetrahydropyridine in a high yield

with a high diastereoselectivity.

To establish the asymmetric 6π-azaelectrocyclization as a

new strategy for alkaloid synthesis, we reinvestigated our

previous method in terms of the operation, scale up, and the

Received: November 22, 2011

Published: January 19, 2012

Figure 1. Alkaroids including piperidine core.

1812

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

substrate preparation for this azaelectrocyclization. We

succeeded in the unique one-pot asymmetric 6π-azaelectrocyc-

lization, which led to the facile and stereocontrolled preparation

of the chiral tetrahydropyridine derivatives bearing a variety of

aromatic substituents at the C-2 position.¹⁰

temperature in the presence of MS 4 A to give the

corresponding protected aminoacetal. This procedure was

followed by the Stille-Migita coupling with vinyl stannanes 1

using the Pd₂(dba)₃/trifurylphospine catalyst in the presence of

LiCl at 80 °C to provide the corresponding tetrahydropyridine

1

To further pursue the possibility of our one-pot procedure

for natural product syntheses, we investigated the synthesis of

substituted chiral piperidines. Quite recently, this one-pot

protocol was applied to the synthesis of (−)-20-epiuleine

possessing the 2,3,4-trisubstituted piperidine core¹¹and

(−)-corynantheidine and (−)-corynantheidol possessing the

2,4,5-trisubstituted piperidine core.¹²We now report in

detail^10,13the stereoselective synthesis of 2,4-disubstituted

and 2,4,6-trisubstituted chiral piperidines and also describe

the stereoselective total syntheses of an indolizidine alkaloid,

(−)-dendroprimine, and its three diastereomers, (+)-5-

epidendroprimine, (+)-7-epidendroprimine, and (+)-5,7-epi-

dendroprimine by the one-pot asynmetric azaelectrocyclization

protocol in addition to the correction of the stereochemistry of

the previously reported (+)-5-epidendroprimin. We also

describe in this paper the analysis results of the extremely

high stereoselectivity caused by the one-pot procedure.

(−)-1a in 84% yield as an almost single isomer (40:1 by H

NMR analysis) (Scheme 2). The spectral data of (−)-1a were

Scheme 2. One-pot Azaelectrocyclization using (−)-7-

Isopropyl cis-1-Amino-2-indanol

in good agreement with those of the compound previously

obtained by the stepwise protocol.⁵Note that this one-pot

procedure successfully simultaneously created four new bonds

and produced better results than the previously developed

stepwise procedure⁵shown in Scheme 1 (84% and 40:1 for the

one-pot protocol vs 34% and 24:1 for the stepwise method).¹⁰

The developed one-pot procedure for the asymmetric

azaelectrocyclization was tolerated for the various aromatic

substituents at the C-2 position of the piperidines (Table 1).

Thus, a small chiral piperidine library bearing indolyl (entries 1

and 2), quinolyl (entry 3), pyridyl (entries 4 and 5), thiophenyl

(entry 6) and siloxyallyl derivatives (entry 7), were successfully

prepared. Noteworthy is the fact that all the tetracyclic

heterocycles could be efficiently obtained with a high

diastereoselectivity (from >12:1 to >20:1) and satisfactory

yields (67−80%).

RESULTS AND DISCUSSION

■

One-pot Azaelectrocyclization. We previously reported

the stepwise synthesis of tetracyclic 2,4-disubstituted tetrahy-

dropyridine (−)-1a,⁵a promising precursor for the preparation

of substituted piperidine derivatives, in 34% yield in three steps,

as shown in Scheme 1. The sequence involves the following

Scheme 1. Previous Asymmetric 6π-Azaelectrocyclization

Method toward Chiral Piperidines

High Diastereoselectivity of the One-pot Procedure.

The one-pot procedure afforded compound (−)-1a with a

higher diastereoselectivity (>40:1) than the stepwise procedure

(24:1), and other 2-aryl-substituted derivatives (−)-6a ∼

(−)-12a were also produced with a high stereoselectivity. In

comparison to the stepwise procedure, which was believed to

be a kinetically controlled one, because the reaction was

completed within 5 min at 24 °C in chloroform and the

asymmetric cyclization using (−)-a also proceeded at 24 °C,

the one-pot procedure required heating at 80 °C in DMF, and

therefore the cyclization step of this three-component one-pot

procedure must occur under thermodynamically controlled

conditions. We then tried to independently isomerize both

products of the cyclization, the major and minor products. Both

12a and 12a′ were isolated by column chromatography and, in

particular, 12a′ was collected from the reaction mixture of many

cyclization experiments. On the other hand, 12a was used for

the natural dendroprimin synthesis. The compound 12a′ was

dissolved in deuterated DMF in a NMR sample tube, and then

the time-course of its isomerization at both 70 and 80 °C was

steps: the Stille-Migita coupling of vinyl stannane 1 with vinyl

iodide 2, oxidation of the resulting allylic alcohol 3 by

manganese dioxide, and the reaction with the produced

aldehyde 4 and (−)-7-isopropyl-cis-1-amino-2-indanol (−)-a,

with resulted in the highly stereoselective 6π-azaelectrocycliza-

tion followed by an aminoacetal formation.

To more conveniently demonstrate our asymmetric azaelec-

trocyclization reaction for natural alkaloid synthesis, we

investigated a tandem one-pot procedure as a rapid and easy

preparation procedure for the polysubstituted chiral piperidine

synthesis by mixing the three components of vinyl stannane 1,

ethyl (Z)-2-iodo-4-oxobutenoate 5, and (−)-7-isopropyl-cis-1-

amino-2-indanol (−)-a in the presence of a palladium catalyst.

After various evaluations of solvents, additives, Pd(0)

catalysts and also the mixing order of the substrates, we finally

found the optimized conditions. Namely, vinyl iodide 5 and

aminoindanol (−)-a were first mixed in DMF at room

1

monitored by H NMR. The results are shown in Figure 2.

Heated at 70 °C, a small amount of 12a was detected in a large

amount of 12a′ by the ¹H NMR after 90 min. Heated at 80 °C,

12a′ gradually changed and 12a was clearly observed and the

ratio of the both compounds was 1:1 after 30 min. After 90

min, the amount of 12a increased and the ratio was 4:1, and

compound 12a became major with the ratio of >8:1 after 120

min. On the other hand, although 12a was heated at 80 °C,

1813

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

force field (MMFF94s) using the Monte Carlo conformational

search method with 1000 iteration steps. The calculation gave

the most stable conformation as shown in Figure 3.^15,16In this

Table 1. One-Pot Azaelectrocyclization Utilizing Variously

Substituted Vinyl Stannanes with Heterocycles

Figure 3. Conformational analysis of the cyclized products.

conformer, the substituent at the C-2 position on the piperidine

ring is the α-axial orientation, and no severe steric interaction

exists. On the other hand, in the case of minor isomer 12a′, the

substituent at the C-2 position on the tetrahydropyridine ring is

situated in β-equatorial. In this conformer, the steric interaction

between the isopropyl substitutent on the indan ring and the

alkoxypropenyl group at the C-2 position of the tetrahydropyr-

idine ring apparently exists. Thus, the major isomer 12a is

much more stable than 12a′, and hence 12a must be

preferentially produced in the one-pot procedure. In addition,

rough energy estimation of the stable conformations 12a and

12a′ by Spartan '02, showed that the conformation 12a is more

stable than that of 12a′ by 7.8 kcal/mol. The fact that the

tendency of the diastereoselectivity of the electrocyclization

depended on the substituent at the C-2 position could also be

explained by the conformational analysis described above.

Stereoselective Reduction of the Conjugated Ester

Group and Synthesis of 2,4-Disubstituted Piperidines.

To synthesize the 2,4-disubstituted piperidines, we examined

the stereoselective reduction of the conjugated double bond in

the intermediate (−)-1a, which can be readily prepared using

the one-pot azaelectrocyclization protocol (Scheme 2).

Although the substrate was decomposed by using Pd/C as a

hydrogenetion catalyst and both the conjugated double bond

and the aminoacetal moiety were reduced by applying PtO₂to

the hydrogenation, fortunately the chemoselective hydrogena-

tion of (−)-1a with W-2 Raney-Nickel was successful to produce

the desired C-4 β-ester 13 as a single stereoisomer in 87% yield.

Meanwhile, when (−)-1a was treated with magnesium in

methanol, the C-4 α-isomer 15 was stereoselectively produced

as a major product in the ratio of 5:1.¹⁷Since both diastereo-

isomers, 13 and 15, were selectively obtained by choosing the

reducing reagent, the next step was the removal of the Indane

moiety. The obtained saturated compounds 13 and 15 were

treated with DIBAL-H at −78 °C to provide the corresponding

diols in 79% and 83% yield, respectively, which were treated

with lead tetraacetate¹⁸in the presence of n-propylamine at

−50 °C to afford the desired piperidine compounds 14 and 16

in 75 and 69% yield, respectively (Scheme 3). At the procedure

of the oxidative cleavage of the Indane moiety, in the absence of

n-propylamine, the yield was much lower. The added

N-propylamine would not only catch the liberated acetic

acids to keep the reaction media to a basic condition but also

catch the produced aldehyde 17 resulting from the oxidative

cleavage of the aminoindanol moiety by lead tetraacetate

Figure 2. Equilibrium experiments of the cyclized products.

12a′ was not detected at all. These results obviously indicated

that the equilibrium existed between 12a and 12a′ at 80 °C, and

the equilibrium moved and almost converged to the more

stable 12a through the inward rotation of the disrotatory 6π-

azaelectrocyclization of the 1-azatirene A generated by the ring-

opening of 12a′. Thus, it was concluded that in the one-pot

procedure at 80 °C, the thermodynamically more stable

compound 12a was exclusively produced resulting from

converging the equilibrium of the 6π-azaelectrocyclization.

To analyze the stable conformation 12a, the molecular

modeling was performed by Spartan '02 (Wave function, Inc.,

Irvine, CA),¹⁴using default parameters and convergence

criteria. The conformations were caluculated with Merck

1814

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

Table 2. Stereocontrolled Synthesis of (2β,4α,6α)-

Trisubstituted Piperidine

Scheme 3. Stereocontrolled Synthesis of 2,4-Disubstituted

Piperidines

oxidation to avoid the further reaction of the generated

aldehyde 17 with the desired second amine 14 as described in

the plausible mechanism in Scheme 4. Thus, the synthetically

practical route for providing chiral 2,4-disubstituted tetra-

hydropyridines was established.

a

b

Isolated yields of α-isomer. Yield for mixture of isomers.

c

d

1

Determined by H NMR analysis of crude mixtures. Reaction was

e

carried out in toluene. Reaction was performed in DMF.

Scheme 4. Plausible Mechanism for Oxidative Cleavage of

Indane Moiety

methyl lithium itself and even in the combination with a Lewis

acid gave no reaction, and 19 was almost recovered (Table 2,

entries 1−3). On the other hand, the Grignard reagent

produced the alkylated product with high stereoselectivity

(entry 4 and 5). Thus, C-6 α-methyl derivative 20 was

exclusively obtained in 58% yield by a reaction with the

Grignard reagent (entry 4), and furthermore, when 19 was

treated with methylmagnesium iodide (20 equiv) and CuI (20

equiv) in ether (entry 5), the α-methyl isomer 20 was also

obtained in 81% yield. The high stereoselectivity of the

methylation of 19 could be explained by assuming that the

alkylation proceeded through the aggregated species of a

methylmetal (Mg or Cu) complex coordinating to the C-4 α-

hydroxymethyl group in addition to the hydroxyindane moiety

of the intermediary iminium ion (Scheme 6B), and the similar

Stereoselective Alkylation of C-4 α-Hydroxymethyl

and C-4 α-Benzyloxy Derivatives. Next, we planned to

synthesize the 2,4,6-trisubstituted piperidines by the stereo-

selective alkylation of the aminoacetal moiety. To realize these

alkylations by alkyllithium and Grignard reagents in a

stereoselective manner, the chemoselective reduction of the

C-4 ester group in both 13 and 15 was required. Fortunately,

we found that treatment of aminoacetal compounds 13 and 15

with Red-Al at room temperature clearly produced the desired

alcohols 18 and 19 in 99% yield, respectively (Scheme 5),

although LAH and DIBAL gave the corresponding diols.

Scheme 6. Plausible Mechanism of Alkyation on

Aminoacetal Moiety

Scheme 5. Chemoselective Reduction of Ester Group

With compounds 18 and 19 in hand, we attempted the

stereoselective alkylation of the aminoacetal moiety of the three

compounds, β-hydroxymethyl 18, α-hydroxymethyl 19 and α-

benzyloxymethyl 26 derivatives.¹⁹First, in the case of 19,

interpretation was applied to the highly stereoselective 1,4-

addition to the unsaturated ester moiety of the hydroxyindane

derivative D derived from (−)-6a (Figure 4).²⁰The

hydroxyindane moiety of the methylated compound 20 was

1815

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

Table 3. Stereoselective Synthesis of (2β,4α,6α)-

Trisubstituted Piperidine

a

yield

α:β

Figure 4. Other example of neighboring group participation by the

hydroxy group on indane.

b

entry

alkylating agent

(%)

(C-6 position)

1

2

3

MeLi (excess)

MeMgl (3 equiv)

84

79

1:3

1:2

then removed by a treatment with lead tetraacetate at −50 °C

in chloroform to produce (2β,4α,6α)-trisubstituted piperidine

21, the relative configurations of which were determined based

on NOE (Figure 5). The addition of n-propylamine was not

MeMgl (3 equiv),

Cul (3 equiv)

c

4

Me₃Al (5 equiv)

82

1:5

a

b

1

Yield for mixture of isomers. Determined by H NMR analysis of

c

crude mixtures. Reaction was carried out in toluene.

Stereoselective Alkylation of β-Hydroxymethyl and β-

Benzyloxyl Derivatives. We also attempted the reaction of

C-4 β-derivatives 18 and 31 with alkyl agents. In the case of

compound 18, the reaction with MeMgI and Me₃Al gave the

almost same results with the 4:1 diastereoselectivity (Table 4).

Figure 5. NOE studies of compounds 21, 23, and 25.

Table 4. Stereoselective Synthesis of (2β,4α,6α)-

Trisubstituted Piperidine

necessary in this case probably because of the crowded moiety

of the piperidine nitrogen. Other alkylating reagents, such as

trimethylaluminium gave low stereoselectivity and dimethylzinc

did not react (entries 6 and 7 of Table 2). Furthermore, the

reaction of 19 with vinylmagnesium bromide in the absence of

CuI provided the corresponding alkylated product 22 as a sole

stereoisomer, whose hydroxyindane moiety was removed with

lead tetraacetate to produce the vinyl derivative 23 in 62% yield

for 2 steps (entry 8). Surprisingly, the reaction of 19 with allyl

magnesium bromide afforded the β-oriented allyl derivative 25

in 60% yield after removing the hydroxyindane moiety by a lead

tetraacetate treatment. In this case, the alkylation obviously

proceeded from the opposite side of the C-4 hydroxymethyl

group, and therefore the aggregation of the Grignard reagent

around the C-4 hydroxymethyl group might not be formed.

To explore the effect of the C-4 hydroxymethyl group to the

highly stereoselective alkylation, we protected the hydroxyl

group of the compound 19 by a benzyl group to give

compound 26. The methylation of the compound 26 mainly

proceeded from the opposite site of the C-4 benzyloxymethyl

group (Table 3). Thus, a treatment with MeMgI selectively

provided C-6 β-methyl isomer 27 in a ratio of 3:1 (entry 2),

although no methylated product could be detected again by the

reaction with MeLi (entry 1), and the CuI additive did not

increase stereoselectivity (entry 3). The treatment of 26 with

Me₃Al in ether provided the same C-6β isomer 27 with the

highest selectivity of 5:1 (entry 4). Apparently, the steric factor

due to the benzyl protecting group overrode the coordination

of the Grignard reagent to the oxygen function at the C-4

position (Scheme 6C). Another stereoisomer, (2β,4α,6β)-

trisubstituted piperidine derivative 28, was obtained in 72%

yield after removal of the hydroxyindane moiety by a lead

tetraacetate treatment of the isolated 27.

a

yield

(%)

α:β

b

entry

alkylating agent

(C-6 position)

1

2

3

MeLi (excess)

MeMgI (20 equiv)

68

69

4:1

c

Me₃Al (15 equiv)

a

b

1

Yield for mixture of isomers. Determined by H NMR analysis of

c

crude mixtures. Reaction was carried out in toluene.

On the other hand, the reaction of C-4 β-benzyloxymethyl

derivative 31 with MeMgI stereoselectively provided C-6 α-

methyl isomer 32 in a ratio of 10:1, and (2β,4β,6α)-

trisubstitutedpiperidine 33 was obtained in 58% yield by an

oxidative cleavage of 32 with lead tetraacetate (Scheme 7).

Thus, we established the synthetic method of the three chiral

2,4,6-trisubstituted piperidine diastereomers 21, 28 and 33

from the common intermediate (−)-1a, which was easily

obtained by the one-pot azaelectrocyclization reaction.

Synthesis of (−)-Dendroprimine (34): Retrosynthetic

Analysis of (−)-Dendroprimine (34). To demonstrate the

established protocol for the polysubstituted piperidine syn-

thesis, we examined the asymmetric synthesis of an indolizidine

alkaloid, (−)-dendroprimine (34), which was isolated from

Dendrobium primulinum Lindl (Orchidaceae) and characterized

by Luning and his co-workers in 1965.^1aThe relative

configuration of the stereogenic centers of dendroprimine

was determined by the synthesis of the four racemic

diastereomers of this indolizidine alkaloid, and the absolute

1816

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

Scheme 8. Synthesis of C-4 β-Methyl Compound 37 via One-

Pot Azaelectrocyclization

Scheme 7. Stereoselective Synthesis of (2β,4α,6α)-

Trisubstituted Piperidine

configuration was also determined by the same group in

1972.^1b,cThe enantioselective synthesis of (−)-dendroprimine

(34) and its two isomers were reported by Gelas-Mialhe in

2004,²¹and the synthesis of (−)-5,7-epi-dendroprimene (54)

was reported by other two groups.²²

Our synthetic analysis of (−)-dendroprimine (34) is shown

in Figure 6. We envisioned that dendroprimine (34) could be

Scheme 9. Stereocontrolled Synthesis of (+)-7-

Epidendroprimine (42)

Figure 6. Synthetic strategy for (−)-dendroprimine (34) by one-pot

azaelectrocyclization protocol.

synthesized from 2,4,6-trisubstituted piperidine F, which was

prepared from the one-pot azaelectrocyclization product

(−)-12a by applying the established method for the 2,4,6-

trisubstituted piperidine synthesis.

Synthesis of 7-Epidendroprimine (42) from C-4 β-

Ester 35. The catalytic hydrogenation of (−)-12a, which can

be readily prepared using the one-pot azaelectrocyclization

protocol (Table 1, entry 7), with Raney-Nickel provided C-4 β-

ester 35 as a single stereoisomer in 64% yield. The ester 35 was

treated with Red-Al at room temperature to provide the

corresponding alcohol 36 in 99% yield resulting from the

chemoselective reduction of the ester group as similar to the

previously obtained result (Scheme 5). Considering the results

on the stereoselectivity described in Table 4 and Scheme 7, we

first converted the hydroxymethyl group to a methyl group to

obtain the better stereoselectivity at the methylation of the

aminoacetal moiety. This conversion was performed by the

Ueno’s method;²³tosylation of 36 followed by iodination and

radical reduction in one-pot provided methyl derivative 37 in

79% yield for 2 steps (Scheme 8).

treated with Me₃Al to provide the C-6 α-methyl derivative 38

with 17:1 diastereoselectivity in 67% yield. The removal of the

hydroxyl Indane moiety in 38 was successful by a catalytic

hydrogenation in the presence of palladium hydroxide, and the

resulting piperidine nitrogen was protected with Cbz in 79%

yield for two steps. The terminal TBS ether group was

converted into the corresponding methyl ester by a sequence of

removing TBS, Jones oxidation and esterification. The removal

of the Cbz group followed by heating the resulting amine in

toluene caused smooth cyclization to produced the correspond-

ing lactam derivative 41.²⁴Finally, the reduction of the lactam

carbonyl group of 41 with LiAlH₄under ether reflux condition

provided (+)-7-epidendroprimine (42) (Scheme 9), whose

spectral data were in good corresponding with those of the

reported ones.²¹

Synthesis of (−)-Dendroprimine (34) and (+)-5-

Epidendroprimine (55) from C-4 α-Ester 43. According

to the procedure established in Scheme 3, reduction of the

Synthesis of (+)-7-epidendroprimine from 37 was achieved

as shown in Scheme 9. Thus, C-4 methyl derivative 37 was

1817

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

conjugated ester double bond of 12a with magnesium in

methanol selectively provided the C-4 α-isomer 43 at a ratio of

4:1. The relative stereochemistry of the major isomer 43 was

unambiguously determined by X-ray crystallographic analysis

(see Supporting Information). Reduction of the ester group of

the isolated 43 with Red-Al followed by catalytic hydrogenation

using PtO₂afforded the corresponding alcohol 44 in 87% yield

for 2 steps (Scheme 10).

Scheme 10. Stereoselective Reduction of Conjugated Ester

Figure 7. Presumption of stereoselectivity of alkyation on aminoacetal

moiety.

To selectively obtain the C-6 α-methyl isomer as described in

Table 2, the methylation of the hydroxymethyl derivative 44

using MeMgI unexpectedly gave a 1:1 mixture of diastereomers

45 and 46, and the reaction with MeMgI and CuI provided the

compound 45 with the higher selectivity of 3:1, which were

isolable by column chromatography. Surprisingly, the reaction

with Me₃Al exclusively produced the undesired C-6 β-methyl

isomer 46 (Table 5).

Table 5. Stereoselective Synthesis of C-6 Methyl Isomers 45

and 46

Figure 8. Suggested selectivity of alkyation on aminoacetal moiety.

for two steps. Interconversion of the hydroxymethyl group of

the obtained 47 to the methyl group of 48 was successful by the

Puglis’s method,²⁶although the Ueno’s procedure applied to 47

was unsuccessful. Thus, 47 was treated with CBr₄/PPh₃

followed by NaBH₄reduction in DMSO to successfully

produce the methyl derivative 48 in 72% yield. The total

synthesis of (−)-dendroprimine (34) was achieved by the same

procedure to that of (+)-7-epidendroprimine (42) as shown in

Scheme 11.

b

entry

alkylating agent

yield(%)

45:46

a

1

2

MeMgl (15 equiv)

73

1:1

3:1

MeMgl (20 equiv),

Cul (20 equiv)

60

c

3

Me₃Al (15 equiv)

82

46 only

a

b

1

Yield for mixture of isomers. Determined by H NMR analysis of

c

crude mixtures. Reaction was carried out in toluene.

The spectral data (¹H and ¹³C NMR) of the synthesized

(−)-dendroprimine (34) were in good agreement with those

published in the literature.^1a,21From C-6 β-methyl compound

46, we also synthesized the (+)-5-epidendroprimine (55) by

the same procedure to that of (−)-dendroprimine (34) as show

in Scheme 12.

Obviously, the substituents at the C-2 position of the

piperidine ring influenced the stereoselectivity of the

methylation (compare 19 and 44 in Table 2 and Table 5).

The difference of the stereoselectivity might be caused by the

location of the hydroxyindane moiety. When the intermediary

iminium ion was generated from the aminoacetal group, in the

case of the siloxyallyl derivative, the Indane moiety would be

situated upside of the iminium ion in order to avoid the steric

interaction with the siloxyallyl group at the C-2 position

(Figure 7, G and Figure 8). On the other hand, in the case of

the phenyl derivative, the Indane moiety would exist downside

of the iminium ion, due to the π−π stacking with the phenyl

group at the C-2 position (Figure 7, H).²⁵

Thus, since we obtained the two kinds of stereoisomers at

the C-6 position, we planned to synthesize (−)-dendroprimine

(34) and 5-epidendroprimine (55) from 45 and 46,

respectively. The removal of the hydroxyl Indane moiety in

45 was achieved by a catalytic hydrogenation, and the resulting

piperidine nitrogen was protected by a Cbz group in 80% yield

In the case of (+)-7-epidendroprimine (42), although the

1

values of H chemical shifts of the both methyl groups were

slightly different from those of the reported data by Gelas-

Mialhe, these were well corresponded and the spectral data of

¹³C NMR were in good agreement with those of the reported

one. However, the spectral data of the synthesized (+)-5-

epidendroprimine (55) were not in agreement with, in

particular, both the chemical shift and coupling constant

assigned to the 7-methyl group and the every values of the

chemical shift of ¹³C NMR were clearly different each other as

shown in Table 6.

The synthesis of (−)-dendroprimine (34) reported by Gelas-

Mialhe is shown in Scheme 13. They synthesized a mixture of

1818

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

Scheme 11. Synthesis of (−)-Dendroprimine (34)

ent-(55) but 5,7-epidendroprimine ent-(63) as shown in

Scheme 14.

To confirm this hypothesis, we attempted the synthesis of

5,7-epidendroprimine (63) from 64, which might be obtained

by a reaction of compound 37 with the Grignard reagent. Thus,

the isolated C-4 methyl derivative 37 was treated with MeMgI

to produce the C-6 methyl derivatives as a 1:1 mixture of

diastereoisomers in 67% yield. Both stereoisomers were isolated

by column chromatography, and we completed the synthesis of

(+)-5,7-epidendroprimine (63) from compound 64 by the

same procedure to the synthesis of other diastereomers as

shown in Scheme 15. All the spectral data of (+)-5,7-

epidendroprimine (63) synthesized by us were in good

agreement with the data, which were reported as (+)-5-

epidendroprimine (55) by Gelas-Mialhe and co-workers

(Table 7).^21,27

As described above, we have concluded that, in Gelas-

Mialhe’s synthesis,^21,27the hydrogenation of compound 58 did

not produce the lactam 61 but 62 as a single stereoisomer and

5,7-epidendroprimine ent-(63) was derived from the lactam 62.

SUMMARY

■

In summary, we achieved the stereocontrolled synthesis of the

chiral 2,4-disubstitiuted and 2,4,6-trisubstituted piperidines

from the common synthetic intermediate which was obtained

by the unique one-pot protocol of the highly stereoselective

asymmetric azaelectrocyclization. The method was applied to

the synthesis of a natural indolizidine alkaloid, (−)-dendropri-

mine (34), and its three diastereomers. In particular, in the

synthesis of (+)-7-epidendroprimine (42), we could realize the

complete stereocontrol. Although generality in the stereo-

controlled introduction of the desired substituents on the

piperidine ring has not still been satisfactory such as from 45 to

46, the one-pot asymmetric 6π-azaelectrocyclization can be

regarded as a powerful method for alkaloid synthesis and also

synthesis of polysubstituted chiral piperidines which have a

variety of substituents at the C-2 position. Further applications

to the synthesis of 2,4,6-trisubsitituted piperidine derivatives

and also alkaloids consisted of this core structure, are currently

in progress in our laboratory.

Scheme 12. Synthesis of (+)-5-Epidendroprimine

EXPERIMENTAL SECTION

■

General. All commercially available reagents were used without

further purification. All solvents were used after distillation.

Diethylether, and benzene were refluxed over and distilled from

sodium. Dichloromethane and acetonitrile were refluxed over and

distilled from P₂O₅. Preparative separation was usually performed by

column chromatography on silica gel (60−200 mesh) and on

aluminum oxide deactivated with 5 w/% of H₂O. H NMR and ¹³C

1

compound 57 and 58 from 56 by employing the intramolecular

cyclization of the generated intermediary acyliminium ion,

which possessed the side chain substituted by an allylsilyl group

as an internal π-nucleophile. The catalytic hydrogenation of the

mixture of compounds 57 and 58 gave a mixture of lactam

derivatives 59, 60 and 61. The reduction of the mixture of these

compounds gave the corresponding indorizidine alkaloids

including (−)-dendroprimine (34). In their paper, however,

the determination of the relative configuration of the lactam 61,

which was the precursor of (−)-5-epidendroprimine ent-(55),

was not described. We then presumed that the correct

stereochemistry of the C-7 methyl group in lactam 61 would

not be C-7 β but C-7 α as shown in 62, and hence it was

supposed that they would synthesize not 5-epidendroprimine

NMR spectra were recorded on 400 MHz spectrometer and chemical

shifts were represented as δ-values relative to the internal standard

TMS. IR spectra were obtained on a FT-IR Spectrometer. Optical

rotations were measured on a polarimeterat a wavelength of 589 nm.

High resolution mass spectra (HRMS) were obtained by either an

electronspray ionization (ESI) or a fast atom bombardment (FAB),

and theoretical monoisotopic molecular masses were typically ≤5

ppm. Melting point was uncorrected.

One-pot Reaction by Using (−)-a, 1 and 5. To a solution of the

vinyliodide 5 (1.33 g, 5.23 mmol) and molecular sieve 4 Å (5.23 g) in

DMF (52 mL) was added (1S, 2R)-(−)-cis-1-amino-7-isopropylindan-

2-ol (−)-a (1.0 g, 5.23 mmol) at room temperature, and the mixture

was stirred for 30 min at this temperature. Then to this solution was

added lithium chloride (443 mg, 10.46 mmol), Tri(2-furyl)phosphine

(97 mg, 0.418 mmol) and Tris(dibenzylideneacetone)dipalladium(0)

(96 mg, 0.105 mmol) at room temperature, and the mixture was

1819

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

Table 6. Spectral Data of (−)-Dendroprimine (34), (+)-5-Epidendroprimine (55)

Scheme 13. Synthesis of (−)-Dendroprimine and its Two

Isomers by Gelas-Mialhe

Scheme 14. Presumption of Relative Configuration of the

Letam Obtained by Hydrogenation of 58

Scheme 15. Synthesis of (+)-5,7-Epidendroprimine (63)

stirred for 10 min at this temperature, then vinylstannane 1 (4.11 g,

10.46 mmol) was added to this solution. After the reaction mixture

was stirred at 80 °C for 1 h, 10% aqueous NH₃solution was added,

and the resulting mixture was extracted with ether. The organic layers

were combined, washed with brine, dried over MgSO₄, filtered and

concentrated in vacuo to give a 40:1 mixture of two stereoisomers

crude products. These isomers were successfully separated by column

1820

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

One-pot Reaction by using (−)-a, 5 and 7. To a solution of the

vinyliodide 5 (100 mg, 0.394 mmol) and molecular sieve 4 Å (394

mg) in DMF (2 mL) was added (1S, 2R)-(−)-cis-1-amino-7-

isopropylindan-2-ol (−)-a (90 mg, 0.473 mmol) at room temperature,

and the mixture was stirred for 30 min at this temperature. Then to

this solution was added lithium chloride (33 mg, 0.788 mmol), Tri(2-

furyl)phosphine (7 mg, 0.03 mmol) and Tris(dibenzylideneacetone)-

dipalladium(0) (7 mg, 0.008 mmol) at room temperature, and the

mixture was stirred for 10 min at this temperature, then vinylstannane

7 (451 mg, 0.788 mmol) was added to this solution. After the reaction

mixture was stirred at 80 °C for 1 h, 10% aqueous NH₃solution was

added, and the resulting mixture was extracted with ether. The organic

layers were combined, washed with brine, dried over MgSO₄, filtered

and concentrated in vacuo to give a 12:1 mixture of two stereoisomers

crude products. These isomers were not separated by column

chromatography on silica gel to give the 1,2,5,6-tetrahydropyridine

derivative (−)-7a and isomer (0.154 g, 67%) as a yellow foam. Data

for the major isomer (−)-7a: [α]²⁶_D−37.5 (c = 0.1, CHCl₃); IR (KBr

Table 7. Spectral Data of (+)-5,7-Epidendroprimine (63)

1

disk cm⁻¹) 1716, 1448, 1371, 1255, 1172, 1030; H NMR(400 MHz,

CDCl₃) δ 8.34 (1H, d, J = 8.5), 7.73 (dd, 2H, J = 8.7, 1.4), 7.52 (m,

1H), 7.43−7.36 (m, 3H), 7.31 (dd, 1H, J = 7.3, 7.3 Hz), 7.17 (dd, 1H,

J = 7.6, 7.6 Hz), 6.99 (d, 2H, J = 6.6), 6.89 (s, 1H), 6.57 (m, 1H), 5.23

(dd, 1H, J = 6.0, 3.0 Hz), 4.94 (m, 1H), 4.87 (d, 1H, J = 5.5 Hz), 4.47

(d, 1H, J = 4.6 Hz), 4.14 (m, 2H), 3.17 (m, 1H), 2.91 (qq, 1H, J = 6.9,

6.9 Hz), 2.77 (m, 1H), 2.60 (dddd, 1H, J = 19.0, 11.0, 3.9, 2.5 Hz),

1.25 (m, 3H), 1.02 (d, 3H, J = 6.9 Hz), 0.54 (d, 3H, J = 7.1 Hz): ¹³C

NMR (100 MHz, CDCl₃) δ 166.1, 147.6, 143.3, 141.6, 139.1, 137.7,

136.2, 136.1, 134.1, 129.4, 128.9, 126.1, 125.1, 124.2, 124.1, 123.5,

121.8, 120.7, 115.5, 114.0, 86.7, 75.6, 75.5, 60.7, 53.9, 39.4, 28.1, 25.3,

23.5, 23.0, 14.2; ESI HRMS m/z calcd for C₃₄H₃₄N₂O₅S [M⁺+ Na]

605.2086, found 605.2077; representative signals in its ¹H NMR (400

MHz, CDCl₃) δ 8.26 (dd, 1H, J = 8.5, 0.69 Hz), 8.20 (d, 1H, J = 8.5

Hz), 8.14 (d, 1H, J = 8.5 Hz), 6.12 (brs, 1H).

chromatography on silica gel (from 5 to 9% ethyl acetate in hexane) to

give the 1,2,5,6-tetrahydropyridine derivative (−)-1a (1.77 g, 84%) as

a yellow oil: [α]¹⁹−58.7 (c = 0.3, CHCl₃); IR (neat, cm⁻¹) 1717,

D

1267, 1242, 1032; ¹H NMR (400 MHz, CDCl₃) δ 7.43−7.33 (m, 5H),

7.17 (dd, 1H, J = 7.6, 7.6 Hz), 7.01 (d, 1H, J = 8.8 Hz), 6.99 (d, 1H,

J = 8.1 Hz), 6.80 (brs, 1H), 5.01−4.96 (m, 1H), 4.92 (d, 1H, J = 5.6

Hz), 4.48 (d, 1H, J = 4.4 Hz), 4.18 (m, 2H), 4.12 (dd, 1H, J = 6.1, 3.7

Hz), 3.15−3.25 (m, 2H), 2.79 (m, 1H), 2.70 (dddd, 1H, J = 19.3, 6.6,

2.2, 2.2 Hz), 2.62 (qq, 1H, J = 6.8, 6.8 Hz), 1.25 (t, 3H, J = 7.1 Hz),

1.01 (d, 3H, J = 6.8 Hz), 0.59 (d, 3H, J = 7.1 Hz); ¹³C NMR (100

MHz, CDCl₃) δ 166.3, 147.8, 143.1, 141.5, 138.3, 136.3, 129.4, 128.8,

128.4, 128.0, 124.0, 123.5, 121.6, 86.7, 75.0, 74.4, 62.2, 60.6, 39.6, 28.0,

25.5, 23.5, 22.8, 14.2; EI-HRMS m/z calcd for C₂₆H₂₉NO₃[M⁺]

403.2146, found 403.2137.

One-pot Reaction by using (−)-a, 5 and 8. To a solution of the

vinyliodide 5 (70 mg, 0.276 mmol) and molecular sieve 4 Å (276 mg)

in DMF (2.8 mL) was added (1S, 2R)-(−)-cis-1-amino-7-isopropy-

lindan-2-ol (−)-a (63 mg, 0.331 mmol) at room temperature, and the

mixture was stirred for 30 min at this temperature. Then to this

solution was added lithium chloride (23 mg, 0.552 mmol), Tri(2-

furyl)phosphine (5 mg, 0.022 mmol) and Tris(dibenzylideneacetone)-

dipalladium(0) (5 mg, 0.006 mmol) at room temperature, and the

mixture was stirred for 10 min at this temperature, then vinylstannane

8 (245 mg, 0.552 mmol) was added to this solution. After the reaction

mixture was stirred at 80 °C for 1 h, 10% aqueous NH₃solution was

added, and the resulting mixture was extracted with ether. The organic

layers were combined, washed with brine, dried over MgSO₄, filtered

and concentrated in vacuo to give a 15:1 mixture of two stereoisomers

crude products. These isomers were successfully separated by column

chromatography on silica gel (from 5 to 25% ethyl acetate in hexane)

to give the 1,2,5,6-tetrahydropyridine derivative (−)-8a (0.119 g, 74%)

One-pot Reaction by using (−)-a, 5 and 6. To a solution of the

vinyliodide 5 (100 mg, 0.394 mmol) and molecular sieve 4 Å (394

mg) in DMF (2 mL) was added (1S, 2R)-(−)-cis-1-amino-7-

isopropylindan-2-ol (−)-a (90 mg, 0.473 mmol) at room temperature,

and the mixture was stirred for 30 min at this temperature. Then to

this solution was added lithium chloride (33 mg, 0.788 mmol), Tri(2-

furyl)phosphine (7 mg, 0.03 mmol) and Tris(dibenzylideneacetone)-

dipalladium(0) (7 mg, 0.008 mmol) at room temperature, and the

mixture was stirred for 10 min at this temperature then vinylstannane

6 (462 mg, 0.788 mmol) was added to this solution. After the reaction

mixture was stirred at 80 °C for 1 h, 10% aqueous NH₃solution was

added, and the resulting mixture was extracted with ether. The organic

layers were combined, washed with brine, dried over MgSO₄, filtered

and concentrated in vacuo to give a 16:1 mixture of two stereoisomers

crude products. These isomers were successfully separated by column

chromatography on silica gel (from 5 to 25% ethyl acetate in hexane)

to give the 1,2,5,6-tetrahydropyridine derivative (−)-6a (0.169 g, 72%)

as a yellow oil. Data for the major isomer (−)-8a: [α]²⁷−34.3

D

(c 1.02, CHCl₃); IR (neat, cm⁻¹) 2961, 1714, 1670, 1475, 1460, 1258,

1

1115, 1032; H NMR(400 MHz, CDCl₃) δ 8.96 (d, 1H, J = 2.1 Hz),

as a yellow foam: [α]¹⁶−87.0 (c 0.7, CHCl₃); IR (KBr disk, cm⁻¹)

D

8.21 (d, 1H, J = 2.1 Hz), 8.17 (m, 1H), 7.85 (dd, 1H, J = 8.2, 1.1 Hz),

7.76 (ddd, 1H, J = 8.2, 6.8, 1.3 Hz), 7.60 (ddd, 1H, J = 8.0, 6.8, 1.1

Hz), 7.16 (dd, 1H, J = 7.6, 7.5 Hz), 6.98 (d, 2H, J = 8.0 Hz), 6.82 (dd,

1H, J = 3.4, 2.3 Hz), 5.04 (ddd, 1H, J = 5.1, 5.2, 2.2 Hz), 4.91 (d, 1H,

J = 5.5 Hz), 4.55 (dd, 1H, J = 4.8, 0.9 Hz), 4.36 (dd, 1H, J = 6.2, 3.4

Hz), 4.20 (qd, 2H, J = 7.1, 1.4 Hz), 3.22 (m, 1H), 2.86 (m, 1H), 2.78

(dddd, 1H, J = 19.4, 11.2, 4.8, 2.3 Hz), 2.49 (qq, 1H, J = 6.9, 6.9 Hz),

1.26 (t, 3H, J = 7.1 Hz), 1.0 (d, 3H, J = 6.9 Hz), 0.31 (d, 3H, J = 6.9

Hz) ; ¹³C NMR (100 MHz, CDCl₃) δ 165.9, 151.8, 148.0, 147.6,

143.2, 136.8, 135.8, 135.7, 134.3, 129.7, 129.3, 128.9, 127.7, 127.6,

127.0, 125.1, 123.5, 121.7, 86.5, 75.1, 74.5, 60.8, 60.2, 39.6, 28.3, 25.5,

23.3, 22.4, 14.2; ESI HRMS m/z calcd for C₂₉H₃₀N₂O₃[M⁺+ Na]

1715, 1447, 1373, 1260, 1175, 1113, 1030; ¹H NMR (400 MHz,

CDCl₃) δ 8.02 (d, 1H, J = 8.5 Hz), 7.84 (ddd, 2H, J = 8.8, 2.0, 2.0 Hz),

7.66 (s, 1H), 7.55 (d, 1H, J = 7.8 Hz), 7.35 (m, 1H), 7.28−7.18 (m,

3H), 7.13 (dd, 1H, J = 7.6, 7.6 Hz), 6.98 (d, 1H, J = 7.6 Hz), 6.89 (d,

1H, J = 7.6 Hz), 6.80 (dd, 1H, J = 3.7, 2.0 Hz), 5.00−4.94 (m, 2H),

4.52 (dd, 1H, J = 4.6, 1.2 Hz), 4.34 (dd, 1H, J = 6.3, 3.9 Hz), 4.17 (m,

2H), 3.23 (dd, 1H, J = 18.1, 5.9 Hz), 3.17 (d, 1H, J = 17.1 Hz), 2.84

(m, 1H), 2.77 (dddd, 1H, J = 19.5, 4.4, 4.4, 2,0 Hz), 2.52 (qq, 1H, J =

6.8, 6.8 Hz), 2.32 (s, 3H), 1.24 (t, 3H, J = 7.1 Hz), 0.52 (d, 3H, 6.6

Hz), 0.05 (d, 3H, J = 7.1 Hz): ¹³C NMR (100 MHz, CDCl₃) δ 166.0,

147.6, 145.1, 143.1, 137.4, 136.0, 135.6, 135.2, 130.0, 129.5, 128.8,

126.9, 125.0, 124.4, 123.3, 121.8, 121.6, 113.4, 86.6, 74.9, 74.3, 60.7,

54.4, 39.5, 27.6, 25.6, 22.5, 22.2, 21.5; EI HRMS m/z calcd. For

C₃₅H₃₆N₂O₅S[M⁺] 596.2343, found 596.2345: representative signals

in its ¹H NMR (400 MHz, CDCl₃) δ 6.68 (brs, 1H), 0.93 (d, 1H, J =

6.9 Hz).

1

477.2154, found 477.2160; representative signals in its H NMR(400

MHz, CDCl₃) δ 8.93 (dd, 1H, J = 5.0, 0.92 Hz), 6.78 (d, 1H, J = 3.0

Hz), 1.14 (d, 3H, J = 6.6 Hz).

One-pot Reaction by using (−)-a, 5 and 9. To a solution of the

vinyliodide 5 (100 mg, 0.394 mmol) and molecular sieve 4 Å (394 mg)

1821

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

in DMF (2 mL) was added (1S, 2R)-(−)-cis-1-amino-7-isopropylin-

dan-2-ol (−)-a (90 mg, 0.473 mmol) at room temperature, and the

mixture was stirred for 30 min at this temperature. Then to this

solution was added lithium chloride (33 mg, 0.788 mmol), Tri(2-

furyl)phosphine (7 mg, 0.03 mmol) and Tris(dibenzylideneacetone)-

dipalladium(0) (7 mg, 0.008 mmol) at room temperature, and the

mixture was stirred for 10 min at this temperature, then vinylstannane

9 (311 mg, 0.788 mmol) was added to this solution. After the reaction

mixture was stirred at 80 °C for 1 h, 10% aqueous NH₃solution was

added, and the resulting mixture was extracted with ether. The organic

layers were combined, washed with brine, dried over MgSO₄, filtered

and concentrated in vacuo to give a 16:1 mixture of two stereoisomers

crude products. These isomers were successfully separated by column

chromatography on silica gel (from 5 to 25% ethyl acetate in hexane)

to give the 1,2,5,6-tetrahydropyridine derivative (−)-9a (0.127 g, 80%)

Tri(2-furyl)phosphine (7 mg, 0.03 mmol) and Tris(dibenzyl-

ideneacetone)dipalladium(0) (7 mg, 0.008 mmol) at room tempera-

ture, and the mixture was stirred for 10 min at this temperature, then

vinylstannane 11 (315 mg, 0.788 mmol) was added to this solution.

After the reaction mixture was stirred at 80 °C for 1 h, 10% aqueous

NH₃solution was added, and the resulting mixture was extracted with

ether. The organic layers were combined, washed with brine, dried

over MgSO₄, filtered and concentrated in vacuo to give a 15:1 mixture

of two stereoisomers crude products. These isomers were successfully

separated by column chromatography on silica gel (from 5 to 25%

ethyl acetate in hexane) gave the 1,2,5,6-tetrahydropyridine derivative

(−)-11a (0.119 g, 74%) as a yellow oil. Data for the major isomer

(−)-11a: [α]²⁷−51.8 (c 0.8, CHCl₃); IR (neat, cm⁻¹) 1714, 1475,

D

1

1253, 1114, 1032; H NMR(400 MHz, CDCl₃) δ 7.37 (dd, 1H, J =

5.0, 3.0 Hz), 7.30 (dd, 1H, J = 3.0, 1.2 Hz), 7.18 (dd, 1H, J = 7.6, 7.6

Hz), 7.13 (dd, 1H, J = 5.0, 1.2 Hz), 7.03 (d, 1H, J = 7.6 Hz), 6.99

(d, 1H, J = 7.6 Hz), 6.79 (dd, 1H, J = 3.7, 2.1 Hz), 4.97 (d, 1H, J =

5.7 Hz), 4.95 (dd, 1H, J = 5.7, 2.1 Hz), 4.45 (d, 1H, J = 4.4 Hz), 4.28 (dd,

1H, J = 6.0, 3.7 Hz), 4.19 (m, 2H), 3.20 (m, 1H), 2.67−2.79(m, 3H),

1.26 (t, 3H, J = 7.1 Hz), 1.0 (d, 3H, J = 6.6 Hz), 0.74 (d, 3H, J = 7.1 Hz);

¹³C NMR (100 MHz, CDCl₃) δ 166.2, 147.8, 143.1, 142.4, 137.7, 136.3,

128.8, 128.2, 126.0, 124.3, 123.5, 123.3, 121.6, 86.5, 74.9, 74.4, 60.6, 57.1,

39.6, 28.2, 25.5, 23.6, 22.9, 14.2; ESI HRMS m/z calcd for C₂₄H₂₇NO₃S

[M⁺+ Na] 432.1609, found 432.1598; representative signals in its

¹H NMR(400 MHz, CDCl₃) δ 3.90 (dd, 1H, J = 9.2, 5.5 Hz), 3.84 (ddd,

1H, J = 6.0, 5.7, 2.8 Hz), 0.91 (d, 3H, J = 6.9 Hz).

as a yellow oil. Data for the major isomer (−)-9a: [α]²⁷−50.9 (c

D

1.02, CHCl₃); IR (neat, cm⁻¹) 2961, 1714, 1473, 1114, 1032; ¹H

NMR(400 MHz, CDCl₃) δ 8.60 (ddd, 1H, J = 5.0, 1.8, 0.92), 7.78

(ddd, 1H, J = 7.8, 7.6, 1.8 Hz), 7.50 (ddd, 1H, J = 7.8, 2.1, 1.2 Hz),

7.29 (ddd, 1H, J = 7.6, 5.0, 1.2 Hz), 7.17 (dd, 1H, J = 7.6, 7.6 Hz), 7.00

(d, 1H, J = 7.1 Hz), 6.99 (d, 1H, J = 7.3 Hz), 6.88 (dd, 1H, J = 2.3, 1.2

Hz), 5.11 (d, 1H, J = 5.5 Hz), 5.02 (ddd, 1H, J = 5.5, 5.3, 2.3 Hz), 4.49

(d, 1H, J = 4.4 Hz), 4.40 (dd, 1H, J = 6.4, 3.4 Hz), 4.20 (m, 2H), 3.20

(m, 1H), 2.82 (m, 1H), 2.69 (m, 1H), 2.51 (qq, 1H, J = 7.1, 6.9 Hz),

1.26 (t, 3H, J = 7.1 Hz), 1.00 (d, 3H, J = 6.6 Hz), 0.63 (d, 3H, J = 7.1

Hz), ¹³C NMR (100 MHz, CDCl₃) δ 166.1, 161.4, 148.7, 147.4, 143.3,

136.6, 136.5, 136.2, 128.8, 124.7, 124.2, 123.4, 122.9, 121.7, 86.4, 75.2,

74.5, 64.1, 60.7, 39.5, 28.2, 25.4, 23.3, 23.0, 14.2; ESI HRMS m/z calcd

for C₂₅H₂₈N₂O₃[M⁺+ Na] 427.1998, found 427.1990; representative

One-pot Reaction using (−)-a, 5 and 12. To a solution of the

vinyliodide 5 (1.5 g, 5.91 mmol) and molecular sieve 4 Å (5.91 g) in

DMF (60 mL) was added (1S, 2R)-(−)-cis-1-amino-7-isopropylindan-

2-ol (−)-a (1.13 g, 5.91 mmol) at room temperature, and the mixture

was stirred for 30 min at this temperature. Then to this solution was

added lithium chloride (500 mg, 11.81 mmol), Tri(2-furyl)phosphine

(110 mg, 0.472 mmol) and Tris(dibenzylideneacetone)dipalladium(0)

(108 mg, 0.118 mmol) at room temperature, and the mixture was

stirred for 10 min at this temperature, then vinylstannane 12 (5.76 g,

11.81 mmol) was added to this solution. After the reaction mixture

was stirred at 80 °C for 1 h, 10% aqueous NH₃solution was added,

and the resulting mixture was extracted with ether. The organic layers

were combined, washed with brine, dried over MgSO₄, filtered and

concentrated in vacuo to give a 20:1 mixture of two stereoisomer crude

products. These isomers were successfully separated by column

chromatography on silica gel (from 5 to 9% ethyl acetate in hexane) to

give the 1,2,5,6-tetrahydropyridine derivative (−)-12a (2.28 g, 78%) as

1

signals in its H NMR(400 MHz, CDCl₃) δ 6.12 (d, 1H, J = 7.6 Hz),

5.57 (d, 1H, J = 7.1 Hz), 3.90 (ddd, 1H, J = 7.8, 7.6, 1.8 Hz).

One-pot reaction by using (−)-a, 5 and 10. To a solution of the

vinyliodide 5 (100 mg, 0.394 mmol) and molecular sieve 4 Å (394

mg) in DMF (2 mL) was added (1S, 2R)-(−)-cis-1-amino-7-

isopropylindan-2-ol (−)-a (90 mg, 0.473 mmol) at room temperature,

and the mixture was stirred for 30 min at this temperature. Then to

this solution was added lithium chloride (33 mg, 0.788 mmol), Tri(2-

furyl)phosphine (7 mg, 0.03 mmol) and Tris(dibenzylideneacetone)-

dipalladium(0) (7 mg, 0.008 mmol) at room temperature, and the

mixture was stirred for 10 min at this temperature, then vinylstannane

10 (311 mg, 0.788 mmol) was added to this solution. After the

reaction mixture was stirred at 80 °C for 1 h, 10% aqueous NH₃

solution was added, and the resulting mixture was extracted with ether.

The organic layers were combined, washed with brine, dried over

MgSO₄, filtered and concentrated in vacuo to give a 17:1 mixture of

two stereoisomers crude products. These isomers were successfully

separated by column chromatography on silica gel (from 5 to 25%

ethyl acetate in hexane) to give the 1,2,5,6-tetrahydropyridine

derivative (−)-10a (0.124 g, 78%) as a yellow oil. Data for the

a yellow oil: [α]²¹−49.6 (c = 0.5, CHCl₃), IR (neat, cm⁻¹) 1717,

D

1

1462, 1254, 1113; H NMR (400 MHz, CDCl₃) δ 7.22 (dd, 1H, J =

7.6, 7.6 Hz), 7.13 (d, 1H, J = 7.6 Hz), 7.02 (d, 1H, J = 7.3 Hz), 6.73−

6.72 (m, 1H), 5.89 (dt, 1H, J = 15.4, 4.4 Hz), 5.80 (ddt, 1H, J = 15.1,

8.8, 1.5 Hz), 4.98 (d, 1H, J = 5.4 Hz), 4.84 (ddd, 1H, J = 5.6, 5.6, 2.0

Hz), 4.38 (d, 1H, J = 4.6 Hz), 4.26 (d, 2H, J = 4.2 Hz), 4.20 (q, 2H,

J = 7.1 Hz), 3.63−3.58 (m, 1H), 3.54 (qq, 1H, J = 6.8, 6.8 Hz), 3.20

(dd, 1H, J = 17.8, 5.6 Hz), 3.14 (brd, 1H, J = 17.3 Hz), 2.68 (dd, 1H,

J = 19.3, 3.2 Hz), 2.60−2.52 (m, 1H), 1.28 (t, 3H, J = 7.3 Hz), 1.22

(d, 3H, J = 6.8 Hz), 1.15 (d, 3H, J = 6.8 Hz), 0.94 (s, 9H), 0.11 (d, 6H,

J = 0.7 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 166.2, 147.6, 143.2,

137.9, 136.6, 133.2, 129.8, 128.7, 124.7, 123.5, 121.7, 86.4, 75.0, 74.0,

62.9, 60.6, 60.0, 39.6, 28.6, 26.0, 25.5, 23.5, 23.4, 18.4, 14.2, −5.3; EI-

HRMS m/z calcd for C₂₉H₄₃NO₄Si [M]⁺497.2959, found 497.2952.

Representative signals in its ¹H NMR (400 MHz, CDCl₃) δ 5.52 (ddt,

1H, J = 15.1, 10.0, 1.5 Hz), 4.95 (d, 1H, J = 6.1 Hz), 4.47 (ddd, 1H, J =

7.6, 7.6, 1.5 Hz), 4.42 (dd, 1H, J = 7.3, 1.0 Hz).

(−)-(β)-Ethylester Piperidine Derivative (−)-13. To a solution

of (−)-1a (402 mg, 0.99 mmol) in ethanol (3.0 mL) was added Raney-

Ni W2 (excess amount) at a room temperature. After the reaction

mixture was stirred under H₂atmosphere for 2 h, the catalyst was

removed by filtration and the filtrate was concentrated in vacuo to give

crude products, which were purified by column chromatography on

silica gel (5−13% ethyl acetate in hexane) gave the piperidine (β)-ester

derivative (−)-13 (349 mg, 87%) as a colorless oil: [α]²⁶−56.5

(c = 0.68, CHCl₃); IR (neat, cm⁻¹) 1732, 1593, 1315, 1179; ¹^DH NMR

(400 MHz, CDCl₃) δ7.48 (d, 1H, J = 7.1 Hz), 7.39−7.35 (m, 1H),

major isomer (−)-10a: [α]²⁷−35.8 (c 0.3, CHCl₃); IR (neat, cm⁻¹)

D

2959, 1712, 1476, 1030; ¹H NMR(400 MHz, CDCl₃) δ 8.67 (dd, 1H,

J = 2.2, 0.73 Hz), 8.64 (dd, 1H, J = 4.6, 1.7 Hz), 7.78 (ddd, 1H, J = 7.8,

4.2, 2.0 Hz), 7.38 (ddd, 1H, J = 7.8, 4.6, 0.73 Hz), 7.19 (dd, 1H, J =

7.6, 7.6 Hz), 7.01 (d, 2H, J = 7.8 Hz), 6.73 (dd, 1H, J = 3.7, 2.2 Hz),

4.99 (ddd, 1H, J = 5.4, 5.1, 2.4 Hz), 4.85 (d, 1H, J = 5.4 Hz), 4.49 (d,

1H, J = 4.1 Hz), 4.24−4.16 (m, 3H), 3.21 (m, 1H), 2.81 (m, 1H), 2.70

(dddd, 1H, J = 19.0, 11.2, 4.6, 2.4 Hz), 2.53 (qq, 1H, J = 6.8, 6.8 Hz),

1.27 (t, 3H, J = 7.1 Hz), 1.04 (d, 3H, J = 6.8 Hz), 0.63 (d, 3H, J = 7.1

Hz), ¹³C NMR (100 MHz, CDCl₃) δ 165.9, 150.2, 149.5, 147.5, 143.1,

137.2, 137.0, 136.8, 135.7, 128.9, 124.9, 123.5, 123.4, 121.7, 86.4, 75.0,

74.4, 60.7, 59.8, 39.5, 28.2, 25.4, 23.3, 22.6, 14.1; ESI HRMS m/z calcd

for C₂₅H₂₈N₂O₃[M⁺+ Na] 427.1998, found 427.1991; representative

signals in its ¹H NMR(400 MHz, CDCl₃) δ 6.86 (dd, 1H, J = 1.7, 0.7

Hz), 1.45 (t, 3H, J = 7.1 Hz), 0.45 (d, 3H, J = 7.1 Hz).

One-pot Reaction by using (−)-a, 5 and 11. To a solution of

the vinyliodide 5 (100 mg, 0.394 mmol) and molecular sieve 4 Å (394

mg) in DMF (2 mL) was added (1S, 2R)-(−)-cis-1-amino-7-

isopropylindan-2-ol (−)-a (90 mg, 0.473 mmol) at room temperature,

and the mixture was stirred for 30 min at this temperature. Then

to this solution was added lithium chloride (33 mg, 0.788 mmol),

1822

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

7.33−7.28 (m, 1H), 7.15 (dd, 1H, J = 7.6 Hz), 7.02 (d, 1H, J =

7.3 Hz), 6.96 (m, 1H), 4.93−4.90 (m, 1H), 4.73 (d, 1H, J = 5.4 Hz),

4.39 (dd, 1H, J = 2.7, 2.7 Hz), 4.11 (q, 2H, J = 7.1 Hz), 3.52 (dd, J =

12.0, 2.9 Hz), 3.19−3.05 (m, 2H), 3.01 (qq, 1H, J = 6.8, 6.8 Hz), 2.88

(dddd, 1H, J = 12.4, 12.4, 3.7, 3.7 Hz), 2.29 (dddd, 1H, J = 14.4, 4.2,

2.4, 2.4 Hz), 2.07 (ddd, 1H, J = 13.4, 5.9, 2.9 Hz), 2.00−1.86 (m, 2H),

1.21 (t, 3H, J = 7.1 Hz), 1.19 (d, 3H, J = 7.1 Hz), 0.66 (d, 3H, J = 7.1

Hz); ¹³C NMR (100 MHz, CDCl₃) δ 174.9, 147.7, 142.8, 142.7, 136.7,

128.8, 128.5, 128.1, 127.8, 123.5, 121.8, 89.0, 75.4, 73.3, 62.8, 60.4,

39.6, 36.3, 36.1, 29.0, 28.1, 23.7, 22.7, 14.2; ESI-HRMS m/z for calcd

for C₂₆H₃₂NO₃[M + H]⁺406.2382, found 406.2379.

(2.7 mL) was slowly added diisobutylaluminium hydride (1.1 mL,

1.10 mmol, 1 M in toluene) at −78 °C. After the mixture was stirred at

this temperature for 1 h, H₂O and saturated aqueous potassium

sodium tartrate tetrahydrate solution was carefully added, and the

resulting mixture was extracted with diethyl ether. The organic layers

were combined, washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo to give the crude products, which were purified

by column chromatography on silica gel (20−50% ethyl acetate in

hexane) to give the diol (83 mg, 83%) as a colorless oil.

To a solution of diol obtained above (69 mg, 0.254 mmol) in

CHCl₃(1.27 mL) was added n-propylamine (0.10 mL) and lead

tetraacetate (340 mg, 0.763 mmol) at −50 °C. After the mixture was

stirred at this temperature for 30 min, added to ice-1N aqueous NaOH

solution and the resulting mixture was extracted with chloroform. The

organic layers were combined, washed with brine, dried over MgSO₄,

filtered, and concentrated in vacuo to give the crude products, which

were purified by column chromatography on silica gel (from 0 to 20%

methanol in chloroform) to give the (−)-16 (27 mg, 75%) as a white

(2S,4R)-(−)-4-Hydroxymethyl-2-phenylpiperidine (−)-14. To

a solution of compound (−)-13 (150 mg, 0.370 mmol) of

dichloromethane (3.7 mL) was slowly added diisobutylaluminium

hydride (1.5 mL, 1.48 mmol, 1 M in toluene) at −78 °C. After the

mixture was stirred at this temperature for 1 h, H₂O and saturated

aqueous potassium sodium tartrate tetrahydrate solution was carefully

added, and the resulting mixture was extracted with diethyl ether. The

organic layers were combined, washed with brine, dried over MgSO₄,

filtered, and concentrated in vacuo to give the crude products, which

were purified by column chromatography on silica gel (20−50% ethyl

acetate in hexane) to give the diol (117 mg, 79%) as a colorless oil.

To a solution of diol obtained above (128 mg, 0.350 mmol) in

CHCl₃(1.75 mL) was added n-propylamine (0.14 mL) and lead

tetraacetate (465 mg, 1.05 mmol) at −50 °C. After the mixture was

stirred at this temperature for 30 min, it was added to ice-1N aqueous

NaOH solution and the resulting mixture was extracted with

chloroform. The organic layers were combined, washed with brine,

dried over MgSO₄, filtered, and concentrated in vacuo to give the crude

products, which were purified by column chromatography on silica gel

(from 0 to 20% methanol in chloroform) to give (−)-14 (43 mg, 69%)

amorphous solid: [α]²³−12.8 (c 0.3, MeOH); IR (KBr disk, cm⁻¹)

D

1

3263, 3117(br), 1605, 1451, 1325, 1059, 1038; H NMR(400 MHz,

CDCl₃) δ 7.39 − 7.37 (m, 2H), 7.34−7.30 (m, 2H), 7.25−7.21 (m,

1H), 3.88 (dd, 1H, J = 9.8, 3.2 Hz), 3.77−3.75 (m, 2H), 2.96−2.93

(m, 2H), 2.08−2.00 (m, 1H), 1.94−1.87 (m, 1H), 1.86−1.77) (m,

2H), 1.67−1.61 (m, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 144.5,

128.4, 126.9, 126.9, 64.2, 56.1, 42.2, 35.0, 34.8, 27.0; ESI HRMS m/z

calcd for C₁₂H₁₈NO [M + H]⁺192.1388, found 192.1391.

(−)-(β)-Hydroxymethyl Piperidine Derivative (−)-18. To a

solution of compound (−)-13 (304 mg, 0.75 mmol) of toluene (4

mL) was slowly added Red-Al (0.58 mL, >65 wt.% in toluene) at 0 °C.

After the mixture was stirred at this temperature for 30 min, H₂O and

saturated aqueous potassium sodium tartrate tetrahydrate solution was

carefully added, and the resulting mixture was extracted with ethyl

acetate. The organic layers were combined, washed with brine, dried

over MgSO₄, filtered, and concentrated in vacuo to give the crude

products, which were purified by column chromatography on silica gel

(20−50% ethyl acetate in hexane) to give the piperidine (β)-

hydroxymethyl derivative (−)-18 (270 mg, 99%) as a white crystalline

as a white amorphous solid: [α]²³−40.6 (c 0.3, MeOH); IR (neat,

D

cm⁻¹) 3289, 3165, 1262, 1096, 1044, 802; ¹H NMR(400 MHz,

CD₃OD) δ 7.37−7.30 (m, 4H), 7.26−7.21 (m, 1H), 3.65 (dd, 1H, J =

11.4, 2.1 Hz), 3.43 (dd, 2H, J = 6.0, 2.5 Hz), 3.21 (ddd, 1H, J = 12.4,

3.9, 1.8 Hz), 2.81 (ddd, 1H, J = 12.6, 2.3 Hz), 1.93−1.88 (m, 1H),

1.84−1.73 (m, 2H), 1.30−1.19 (m, 2H); ¹³C NMR (100 MHz,

CD₃OD) δ 145.2, 129.5, 128.4, 127.8, 68.2, 62.5, 40.7, 38.2, 29.5;

FAB-HRMS m/z calcd for C₁₂H₁₈NO [M + H]⁺192.1388, found

192.1388.

solid: mp = 109−114 °C, [α]²⁵−63.7 (c = 0.88, CHCl₃); IR (KBr

D

1

disk, cm⁻¹) 3378(br), 1593, 1454, 1190, 1038; H NMR (400 MHz,

CDCl₃) δ7.48 (d, 1H, J = 7.5 Hz), 7.37 (m, 1H), 7.29 (ddd, 1H, J =

7.2, 1.4, 1.4 Hz), 7.15 (dd, 1H, J = 7.6, 7.6 Hz), 7.02 (d, 1H, J = 7.6

Hz), 6.97 (d, 1H, J = 7.4, Hz), 4.92 (dd, 1H, J = 6.2, 5.7 Hz), 4.74 (d,

1H, J = 5.2 Hz), 4.39 (dd, 1H, J = 2.6, 2.6 Hz), 3.57−3.47 (m, 3H),

3.19−3.07 (m, 2H), 3.04 (qq, 1H, J = 7.0, 7.0 Hz), 2.11−2.06 (m,

2H), 1.88 (ddd, 1H, J = 12.9, 5.6, 2.7 Hz), 1.59−1.50 (m, 3H), 1.19

(d, 3H, J = 6.8 Hz), 0.66 (d, 3H, J = 7.0 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 147.7, 143.4, 142.9, 137.0, 128.7, 128.5, 128.1, 127.6, 123.4,

121.8, 89.5, 75.3, 73.3, 67.5, 63.1, 39.6, 37.1, 33.0, 29.5, 28.1, 23.7,

22.7; ESI-HRMS m/z calcd for C₂₄H₃₀NO₂[M + H]⁺364.2277, found

364.2269.

(−)-(α)-Ethylester Piperidine Derivative (−)-15. To magnesium

turning (1.21 g, 49.7 mmol) in methanol (5.0 mL) was added a

solution of the (−)-1a (1.34 g, 3.32 mmol) in methanol (28 mL) at

room temperature. After the mixture was stirred at this temperature for

2 h, H₂O and 2N aqueous HCl solution was carefully added, and the

pH of the solution was adjusted toward 7. The resulting mixture was

extracted with ethyl acetate. The organic layers were combined,

washed with brine, dried over MgSO₄, filtered and concentrated in

vacuo to give a 5:1 mixture (determined by ¹H NMR) of two

stereoisomer crude products. These isomers were successfully

separated by column chromatography on silica gel (from 5 to 13%

ethyl acetate in hexane) to give the piperidine (α)-ester derivative

(−)-15 (704 mg, 52%) as a white crystalline solid: mp = 86−89 °C,

(−)-(α)-Hydroxymethyl Piperidine Derivative (−)-19. To a

solution of compound (−)-15 (407 mg, 1.00 mmol) of toluene (5

mL) was slowly added Red-Al (0.67 mL, >65 wt.% in toluene) at 0 °C.

After the mixture was stirred at this temperature for 2 h, H₂O and

saturated aqueous potassium sodium tartrate tetrahydrate solution was

carefully added, and the resulting mixture was extracted with ethyl

acetate. The organic layers were combined, washed with brine, dried

over MgSO₄, filtered, and concentrated in vacuo to give the crude

products, which were purified by column chromatography on silica gel

(20−50% ethyl acetate in hexane) to give the piperidine (α)-

hydroxymethyl derivative (−)-19 (362 mg, 99%) as a white crystalline

[α]²³−52.4 (c 1.0, CHCl₃); IR (KBr disk, cm⁻¹) 1730, 1454, 1188,

D

1

1086; H NMR (400 MHz, CDCl₃) δ 7.53 (m, 1H), 7.38 (m, 1H),

7.30 (dddd, 1H, J = 6.3, 6.3, 1.2, 1.2 Hz), 7.13 (dd, 1H, J = 7.3, 7.3

Hz), 7.01 (d, 1H, J = 7.3 Hz), 6.94 (d, 1H, J = 6.8 Hz), 4.78 (dd, 1H,

J = 5.6, 5.6 Hz), 4.30−4.16 (m, 3H), 3.84 (dd, 1H, J = 12.0, 3.2 Hz),

3.16−2.98 (m, 3H), 2.66−2.61 (m, 2H), 2.25 (ddd, 1H, J = 13.7, 5.6,

2.7 Hz), 2.06 (ddd, 1H, J = 9.8, 6.6, 2.9 Hz), 1.84 (ddd, 1H, J = 12.0,

4.4, 1.7 Hz), 1.33 (t, 3H, J = 7.1 Hz), 1.15 (d, 3H, J = 6.8 Hz), 0.66 (d,

3H, J = 7.1 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 174.1, 147.6, 143.6,

143.1, 136.8, 128.9, 128.4, 128.1, 127.5, 123.3, 121.7, 88.6, 75.4, 73.6,

60.3, 59.1, 39.3, 34.2, 33.8, 28.1, 28.0, 23.6, 22.7, 14.2; FAB-HRMS m/

z calcd for C₂₆H₃₂NO₃[M + H]⁺406.2382, found 406.2394; Data for

solid: mp = 119−112 °C, [α]²³−60.9 (c 1.0 CHCl₃), IR (KBr disk,

D

1

cm⁻¹) 3416 (br), 1454, 1152, 1054; H NMR (400 MHz, CDCl₃) δ

7.50 (m, 1H), 7.37 (m, 1H), 7.29 (dddd, 1H, J = 7.3, 7.3, 1.5, 1.5 Hz),

7.15 (dd, 1H, J = 7.6, 7.6 Hz), 7.03 (d, 1H, J = 7.6 Hz), 6.96 (d, 1H,

J = 7.3 Hz), 4.87 (dd, 1H, J = 5.1, 5.1 Hz), 4.74 (d, 1H, J = 5.1 Hz), 4.33

(dd, 1H, J = 2.7, 2.7 Hz), 3.87−3.78 (m, 2H), 3.74 (dd, 1H, J = 11.5,

2.9 Hz), 3.18−3.02 (m, 3H), 2.10−1.99 (m, 3H), 1.89 (dddd, 1H, J =

13.4, 3.2, 1.7, 1.7 Hz), 1.20 (d, 3H, J = 6.6 Hz), 0.67 (d, 3H, J = 7.1

Hz); ¹³C NMR (100 MHz, CDCl₃) δ 147.7, 143.5, 142.7, 136.7, 128.9,

1

minor isomer 15′; H NMR (400 MHz, CDCl₃) δ 4.93 (dd, 1H, J =

5.3, 5.3 Hz), 4.74 (d, 1H, J = 5.3 Hz), 3.67 (s, 3H), 1.20 (d, 3H, J = 6.6

Hz), 0.67 (d, 3H, J = 6.9 Hz).

(2S,4S)-(−)-4-Hydroxymethyl-2-phenylpiperidine (−)-16. To

a solution of compound (−)-15 (111 mg, 0.274 mmol) of dichloromethane

1823

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

128.5, 128.1, 127.6, 123.5, 121.8, 89.0, 75.2, 73.5, 66.5, 58.8, 39.3, 35.6,

32.3, 28.1, 27.9, 23.7, 22.7; FAB-HRMS m/z calcd for C₂₄H₃₀NO₂

[M + H]⁺364.2277, found 364.2267.

7.24−7.21 (m, 1H), 5.85 (ddd, 1H, J = 17.2, 10.5, 6.2 Hz), 5.18 (m,

1H), 5.06 (m, 1H), 4.42−4.40 (m, 1H), 3.51 (d, 2H, J = 6.2 Hz),

3.36−3.31 (m, 1H), 2.38 (m, 1H, J = 13.5 Hz), 1.88−1.80 (m, 1H),

1.79−1.73 (m, 1H), 1.65 (ddd, 1H, J = 13.8, 13.8, 5.3 Hz), 1.06 (q,

1H, J = 11.8 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 142.7, 141.5, 128.5,

126.6, 126.2, 114.1, 68.1, 53.6, 52.4, 35.4, 34.1, 31.6; ESI-HRMS m/z

calcd for C₁₄H₂₀NO [M + H]⁺218.1545, found 218.1551.

(2S,4S,6R)-(−)-6-Allyl-4-Hydroxymethyl-2-phenylpiperidine

25. To a solution of compound 19 (56 mg, 0.154 mmol) in ether (1.5

mL) was added a 1.0 M solution of allylmagnesium bromide in THF

(3.08 mL, 3.08 mmol). After the mixture was stirred at room

temperature for 2 h, H₂O was added, and the resulting mixture was

extracted with ether. The organic layers were combined, washed with

brine, dried over MgSO₄, filtered and concentrated in vacuo to give

crude products which were purified by column chromatography on

silica gel (from 5 to 50% ethyl acetate in hexane) to give the piperidine

24 (49 mg, 78%) as a yellow oil.

(1S,2R)-(−)-cis-1-[(2S,4S,6R)-4-Hydroxymethyl-6-methyl-2-

phenylpiperidin-1-yl]-7-isopropylindan-2-ol (−)-20. To a sol-

ution of compound (−)-18 (186 mg, 0.512 mmol) in ether (5.8 mL)

was added a 1.0 M solution of methylmagnesium iodide in ether (11.5

mL, 11.5 mmol) prepared from methyl iodide (1.24 mL, 19.9 mmol),

magnesium turning (440 mg, 18.1 mmol), and ether (18.1 mL) at

0 °C. After the mixture was stirred at room temperature for 3 h, H₂O

was added, and the resulting mixture was extracted with ether. The

organic layers were combined, washed with brine, dried over MgSO₄,

filtered and concentrated in vacuo to give a 40:1 mixture (determined

1

by H NMR) of two stereoisomers crude products. These isomers

were successfully separated by column chromatography on silica gel

(from 5 to 50% ethyl acetate in hexane) to give the piperidine (−)-20

(113 mg, 58%) as a white amorphous solid: [α]²³−134.8 (c = 1.0,

D

1

CHCl₃); IR (KBr disk, cm⁻¹) 3416(br), 1447, 1387, 1080, 1049; H

To a solution of diol obtained above (43 mg, 0.118 mmol) in

CHCl₃(0.6 mL) was added n-propylamine (0.05 mL) and lead

tetraacetate (160 mg, 0.354 mmol) at −50 °C. After the mixture was

stirred at this temperature for 30 min, added to ice-1N aqueous NaOH

solution and the resulting mixture was extracted with chloroform. The

organic layers were combined, washed with brine, dried over MgSO₄,

filtered, and concentrated in vacuo to give the crude products which

were purified by column chromatography on silica gel (from 0 to 20%

methanol in chloroform) to give the 25 (21 mg, 77%) as a white

NMR (400 MHz, CDCl₃) δ7.31−7.16 (m, 7H), 6.95 (d, 1H, J = 7.3,

Hz), 4.76 (d, 1H, J = 7.3 Hz), 4.19−4.15 (m, 1H), 3.81−3.74 (m, 2H),

3.50−3.39 (m, 4H), 2.91 (dd, 1H, J = 15.6, 7.6 Hz), 2.27 (dd, 1H, J =

15.6, 9.3 Hz), 1.92−1.81 (m, 1H), 1.76 (m, 1H), 1.67 (m, 1H), 1.41

(d, 3H, J = 6.6 Hz), 1.40 (d, 3H, J = 6.8 Hz), 1.17 (d, 3H, J = 6.8

Hz),1.11(ddd, 1H, J = 12.9, 12.9, 6.1 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 146.9, 144.7, 142.7, 137.9, 129.1, 128.7, 127.2, 126.4, 123.1,

122.6, 74.1, 68.4, 59.0, 56.0, 50.4, 40.6, 36.8, 34.0, 31.5, 29.6, 25.9,

21.5, 21.3; FAB-HRMS m/z calcd for C₂₅H₃₄NO₂[M + H]⁺380.2590,

found 380.2580.

amorphous solid: [α]²²−34.6 (c = 0.25, CHCl₃); IR(neat, cm⁻¹)

D

3432(br), 3265, 1640, 1445, 1327, 1042; ¹H NMR (400 MHz, CDCl₃)

δ 7.38−7.37 (m, 2H), 7.31 (dd, 2H, J = 7.1, 7.1 Hz), 7.25−7.22 (m,

1H), 5.76 (dddd, 1H, J = 16.9, 10.1, 8.2, 6.4 Hz), 5.10 (d, 1H, J = 16.9

Hz), 5.05 (d, 1H, J = 10.1 Hz), 3.82 (d, 2H, J = 7.8 Hz), 3.79−3.78

(m, 1H), 2.92−2.85 (m, 1H), 2.24−2.18 (m, 1H), 2.15−2.08 (m, 2H),

1.85−1.68 (m, 3H), 1.46 (ddd, 1H, J = 12.6, 12.6, 5.5 Hz); ¹³C NMR

(100 MHz, CDCl₃) δ 144.9, 135.3, 128.4, 127.2, 126.7, 117.6, 64.0,

57.0, 51.7, 41.6, 35.6, 35.4, 32.7; ESI-HRMS m/z calcd for C₁₅H₂₂NO

[M + H]⁺232.1701, found 232.1701.

(2S,4S,6R)-(+)-4-Hydroxymethyl-6-methyl-2-phenylpiperi-

dine (+)-21. To a solution of compound (−)-20 (113 mg, 0.298

mmol) in CHCl₃(3 mL) was added lead tetraacetate (396 mg, 0.893

mmol) at −50 °C. After the mixture was stirred at this temperature for

30 min, added to ice-1N aqueous NaOH solution and the resulting

mixture was extracted with chloroform. The organic layers were

combined, washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo to give the crude products, which were purified

by column chromatography on silica gel (from 0 to 20% methanol in

(−)-(α)-Benzyl Ether Piperidine Derivative (−)-26. To a

solution of compound (−)-19 (104 mg, 0.29 mmol) of DMF (1.5

mL) was added sodium hydride (27 mg, 1.14 mmol) and benzyl

bromide (0.05 mL, 0.43 mmol) at 0 °C. After the reaction mixture was

stirred at room temperature for 4 h, H₂O was added, and the resulting

mixture was extracted with ethyl acetate. The organic layers were

combined, washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo to give the crude products, which were purified

by column chromatography on silica gel (2−9% ethyl acetate in

hexane) gave the piperidine (α)-benzyl ether derivative (−)-26 (126

mg, 97%) as a colorless oil: [α]²⁴_D−58.0 (c = 1.00, CHCl₃); IR (neat,

chloroform) to give the (+)-21 (39 mg, 64%) as a yellow oil: [α]²⁴

D

9.2 (c = 0.77, CHCl₃); IR (neat, cm⁻¹) 3314(br), 1454, 1377, 1053;

¹H NMR (400 MHz, CDCl₃) δ7.42 (m, 2H), 7.35 (m, 2H), 7.21 (m,

1H), 4.39 (d, 1H, J = 3.9 Hz), 3.48 (d, 2H, J = 6.1 Hz), 2.88 (ddq, 1H,

J = 13.4, 6.4, 2.9 Hz), 2.40−2.36 (m, 1H), 1.79 (dddd, 1H, J = 18.8,

12.9, 6.6, 3.7 Hz), 1.69 (m, 1H), 1.62 (ddd, 1H, J = 12.4, 12.4, 5.4 Hz),

1.10 (d, 3H, J = 6.3 Hz), 0.92(ddd, 1H, J = 12.0, 12.0, 12.0 Hz), ¹³C

NMR (100 MHz, CDCl3) δ 142.7, 128.5, 126.7, 126.2, 68.3, 54.0,

45.2, 37.6, 34.3, 31.6, 22.9; EI-HRMS m/z calcd for C₁₃H₁₉NO [M]⁺

205.1467, found 205.1467.

(2S,4S,6S)-(−)-4-Hydroxymethyl-2-phenyl-6-vinylpiperidine

23. To a solution of compound 19 (95 mg, 0.261 mmol) in ether (2.6

mL) was added a 1.0 M solution of vinylmagnesium bromide in THF

(5.23 mL, 5.23 mmol) prepared from vinyl bromide (1.6 g, 15.0

mmol), magnesium turning (243 mg, 10.0 mmol), and THF (10 mL).

After the mixture was stirred at room temperature for 4 h, H₂O was

added, and the resulting mixture was extracted with ether. The organic

layers were combined, washed with brine, dried over MgSO₄, filtered

and concentrated in vacuo to give crude products, which were purified

by column chromatography on silica gel (from 5 to 50% ethyl acetate

in hexane) to give the piperidine 22 (84 mg, 82%) as a yellow

amorphous.

1

cm⁻¹) 1454, 1090, 1036, 968; H NMR (400 MHz, CDCl₃) δ7.46−

7.28 (m, 10H), 7.13 (dd, 1H, J = 7.6, 7.6 Hz), 7.01 (d, 1H, J = 7.6 Hz),

6.94 (d, 1H, J = 7.3 Hz), 4.73 (dd, 1H, J = 5.4, 5.4 Hz), 4.68−4.62 (m,

2H), 4.49 (d, 1H, J = 12.2 Hz), 4.27 (dd, 1H, J = 2.7, 2.7 Hz), 3.88

(dd, 1H, J = 9.5, 9.5 Hz), 3.59 (dd, 1H, J = 9.3, 5.6 Hz), 3.42 (dd, 1H,

J = 11.5, 3.2 Hz), 3.14−3.00 (m, 3H), 2.18−2.16 (m, 1H), 2.05−1.90

(m, 4H), 1.20 (d, 3H, J = 6.6 Hz),0.67(d, 3H, J = 6.8 Hz); ¹³C NMR

(100 MHz, CDCl₃) δ 147.7, 143.5, 142.9, 138.9, 136.9, 128.9, 128.4,

128.3, 128.0, 127.7, 127.6, 127.4, 123.4, 121.7, 89.3, 77.3, 77.0, 76.7,

74.6, 73.3, 72.8, 71.9, 57.5, 39.5, 34.1, 30.5, 28.1, 27.7, 23.7, 22.7; FAB-

HRMS m/z calcd for C₃₁H₃₆NO₂[M + H]⁺454.2746, found

454.2758.

To a solution of diol obtained above (56 mg, 0.143 mmol) in

CHCl₃(1.0 mL) was added n-propylamine (0.06 mL) and lead

tetraacetate (190 mg, 0.429 mmol) at −50 °C. After the mixture was

stirred at this temperature for 30 min, added to ice-1N aqueous NaOH

solution and the resulting mixture was extracted with chloroform. The

organic layers were combined, washed with brine, dried over MgSO₄,

filtered, and concentrated in vacuo to give the crude products, which

were purified by column chromatography on silica gel (from 0 to 20%

methanol in chloroform) to give the 23 (24 mg, 76%) as a yellow oil:

[α]²²_D−5.7 (c = 0.26, CHCl₃); IR(neat, cm⁻¹) 3328(br), 1641, 1601,

1449, 1030; ¹H NMR (400 MHz, CDCl₃) δ 7.42−7.34 (m, 4H),

(1S,2R)-(−)-cis-1-[(2S,4S,6S)-4-Benzyloxymethyl-6-methyl-2-

phenylpiperidin-1-yl]-7-isopropylindan-2-ol (−)-27. To a sol-

ution of compound (−)-26 (118 mg, 0.260 mmol) in toluene (2.6

mL) was added a ca. 1.4 M trimethylaluminium in n-hexane (0.93 mL,

1.30 mmol) at 0 °C. After the mixture was stirred at room temperature

for 2 h, H₂O was carefully added, and the resulting mixture was

extracted with ether. The organic layers were combined, washed with

brine, dried over MgSO₄, filtered and concentrated in vacuo to give a

1

5:1 mixture (determined by H NMR) of two stereoisomers crude

products. These isomers were successfully separated by column

chromatography on silica gel (from 5 to 17% ethyl acetate in hexane)

1824

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

to give the piperidine compound (−)-15 (72 mg, 59%) as a colorless

chloroform) to give the (−)-30 (39 mg, 64%) as a white crystalline

oil; [α]²⁴−30.5 (c = 1.1, CHCl₃); IR (neat, cm⁻¹) 3416(br), 1589,

solid: mp =137−142 °C, [α]²⁵−7.5 (c = 0.3, CHCl₃); IR (neat,

D

1

1452, 1091; H NMR (400 MHz, CDCl₃) δ7.38−7.28 (m, 5H), 7.12

cm⁻¹) 3274, 2928, 2818, 1363, 1305, 1054, 756; ¹H NMR (400 MHz,

CDCl₃) δ 7.40−7.35 (m, 2H), 7.34−7.28 (m, 2H), 7.26−7.21 (m,

1H), 3.72 (dd, 1H, J = 11.4, 2.7 Hz), 3.52 (d, 2H, J = 6.0 Hz), 2.92−

2.83 (m, 1H,), 1.91−1.73 (m, 3H), 1.21−1.13 (m, 4H), 0.90 (ddd, 1H,

J = 11.9, 11.4, 11.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 144.9, 128.4,

127.1, 126.7, 68.1, 61.5, 52.3, 39.7, 37.2, 36.8, 22.8; ESI-HRMS m/z

calcd for C₁₃H₁₉NNaO (M+Na)⁺206.1545, found 206.1535.

(d, 2H, J = 4.2 Hz), 7.03−6.99 (m, 3H), 6.71 (d, 2H, J = 5.6 Hz), 6.57

(dd, 1H, J = 4.2, 4.2 Hz), 4.61−4.46 (m, 3H), 4.17−4.11 (m, 1H),

3.62 (dd, 1H, J = 8.5, 8.5 Hz), 3.50 (dd, 1H, J = 9.0, 6.6 Hz), 3.37−

3.29 (m, 1H), 3.07 (qq, 1H, J = 6.8, 6.8 Hz), 2.68 (dd, 1H, J = 15.9,

8.1 Hz), 2.13−2.07 (m, 1H), 1.96−1.91 (m, 1H), 1.77 (ddd, 1H, J =

14.6, 10.7, 6.1 Hz), 1.67 (ddd, 1H, J = 13.9, 4.2, 4.2 Hz), 1.51−1.47

(m, 1H), 1.42 (d, 3H, J = 6.8 Hz), 1.41 (d, 3H, J = 6.6 Hz), 1.33 (d,

3H, J = 5.9 Hz), 1.12(d, 1H, J = 6.6 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 146.2, 144.9, 143.5, 138.6, 137.8, 128.9, 128.4, 127.6, 127.6,

127.3, 126.2, 122.5, 73.0, 72.1, 69.9, 66.2, 57.8, 53.4, 40.7, 37.1, 35.7,

31.7, 30.2, 25.2, 24.2, 22.1; FAB-HRMS m/z calcd for C₃₂H₄₀NO₂

[M + H]⁺470.3059, found 470.3054.

(−)-(β)-Benzyl Ether Piperidine Derivative (−)-31. To a

solution of compound (−)-18 (162 mg, 0.45 mmol) of DMF (2

mL) was added sodium hydride (43 mg, 1.78 mmol) and benzyl

bromide (0.08 mL, 0.67 mmol) at 0 °C. After the reaction mixture was

stirred at room temperature for 4 h, H₂O was added, and the resulting

mixture was extracted with ethyl acetate. The organic layers were

combined, washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo to give the crude products which were purified

by column chromatography on silica gel (2−9% ethyl acetate in

hexane) to give the piperidine benzyl (β)-ether derivative (−)-31 (154

mg, 76%) as a colorless oil: [α]²⁵_D−48.3 (c = 1.11, CHCl₃); IR (neat,

cm⁻¹) 1452, 1084, 1019, 910; ¹H NMR (400 MHz, CDCl₃) δ7.47 (d,

1H, J = 7.2 Hz), 7.36 (dd, 2H, J = 7.0, 7.0 Hz), 7.33−7.22 (m, 6H),

7.14 (dd, 1H, J = 7.6, 7.6 Hz), 7.02 (d, 1H, J = 7.6 Hz), 6.96 (d, 1H,

J = 7.3 Hz), 4.91 (dd, 1H, J = 5.3, 5.3 Hz), 4.73 (d, 1H, J = 5.2 Hz),

4.51−4.44 (m, 2H), 4.37 (dd, 1H, J = 2.7, 2.7 Hz), 3.51 (dd, 1H, J =

11.9, 2.9 Hz), 3.38 (dd, 1H, J = 9.2, 5.4 Hz), 3.29 (dd, 1H, J = 9.2, 6.9

Hz), 3.18−3.09 (m, 2H), 3.04 (qq, 1H, J = 6.9, 6.9 Hz), 2.25 (dddd,

1H, J = 19.3, 12.4, 7.0, 3.8 Hz), 2.10−2.04 (m, 1H), 1.94 (ddd, 1H, J =

13.3, 5.7, 2.8 Hz), 1.61−1.51 (m, 3H), 1.19 (d, 3H, J = 6.8 Hz), 0.65

(d, 3H, J = 6.9 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 147.7, 143.5,

142.9, 138.5, 137.1, 128.8, 128.4, 128.3, 128.0, 127.5, 127.4, 123.3,

121.7, 89.6, 75.3, 74.8, 73.4, 72.9, 63.2, 39.6, 37.6, 30.7, 29.9, 28.0,

23.6, 22.7; ESI-HRMS m/z calcd for C₃₁H₃₆NO₂[M + H]⁺454.2746,

found 454.2740.

(2S,4S,6S)-(−)-4-Benzyloxymethyl-6-methyl-2-phenylpiperi-

dine (−)-28. To a solution of compound (−)-27 (70 mg, 0.149

mmol) in CHCl₃(1.5 mL) was added lead tetraacetate (198 mg, 0.447

mmol) at −50 °C. After the mixture was stirred at this temperature for

40 min, added to ice-1N aqueous NaOH solution and the resulting

mixture was extracted with chloroform. The organic layers were

combined, washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo to give the crude products, which were purified

by column chromatography on silica gel (from 0 to 9% methanol in

chloroform) to give the (−)-28 (33 mg, 72%) as a yellow oil: [α]²⁴

D

1

−7.0 (c = 1.0, CHCl₃); IR (neat, cm⁻¹) 1454, 1368, 1308, 1100; H

NMR (400 MHz, CDCl₃) δ7.36−7.21 (m, 10H), 4.59−4.52 (m, 2H),

3.77 (dd, 1H, J = 12.0, 2.6 Hz), 3.67−3.60 (m, 2H), 2.92 (ddq, 1H, J =

12.3, 6.2, 2.6 Hz), 2.29 (dddd, 1H J = 12.9, 12.9, 7.4, 2.2 Hz), 1.84

(ddd, 1H, J = 13.5, 4.2, 2.2 Hz), 1.73−1.65 (m, 2H), 1.40 (ddd, 1H,

J = 13.4, 11.9, 5.5 Hz), 1.04 (d, 3H, J = 6.2 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 138.6, 128.4, 128.4, 127.6, 127.6, 127.1, 126.7, 72.9, 71.4,

57.1, 48.0, 35.1, 34.9, 32.9, 22.9; ESI-HRMS m/z calcd for C₂₀H₂₆NO

[M + H]⁺296.2014, found 296.2024.

(1S,2R)-(−)-cis-1-[(2S,4R,6R)-4-Hydroxymethyl-6-methyl-2-

phenylpiperidin-1-yl]-7-isopropylindan-2-ol (−)-29. To a sol-

ution of compound (−)-18 (186 mg, 0.512 mmol) in ether (5.8 mL)

was added a 1.0 M solution of methylmagnesium iodide in ether (11.5

mL, 11.5 mmol) prepared from methyl iodide (1.24 mL, 19.9 mmol),

magnesium turning (440 mg, 18.1 mmol), and ether (18.1 mL) at

0 °C. After the mixture was stirred at room temperature for 3 h, H₂O

was added, and the resulting mixture was extracted with ether. The

organic layers were combined, washed with brine, dried over MgSO₄,

filtered and concentrated in vacuo to give a 4:1 mixture (this

compound existed its rotamers at 24 °C so that the diastereoselectivity

determined by ¹H NMR after crude product lead to compound

(−)-(30) of two stereoisomers crude products. These isomers were

successfully separated by column chromatography on silica gel (from 5

to 50% ethyl acetate in hexane) to give the piperidine (−)-29 (113 mg,

(1S,2R)-(−)-cis-1-[(2S,4R,6R)-4-Benzyloxymethyl-6-methyl-2-

phenylpiperidin-1-yl]-7-isopropylindan-2-ol (−)-32. To a sol-

ution of compound (−)-31 (98 mg, 0.270 mmol) in ether (2.7 mL)

was added a 1.0 M solution of methylmagnesium iodide in ether (1.35

mL, 1.35 mmol) prepared from methyl iodide (1.24 mL, 19.9 mmol),

magnesium turning (440 mg, 18.1 mmol), and ether (18.1 mL) at

0 °C. After the mixture was stirred at room temperature for 2 h, H₂O

was added, and the resulting mixture was extracted with ether. The

organic layers were combined, washed with brine, dried over MgSO₄,

filtered and concentrated in vacuo to give a 10:1 mixture (this

compound existed its rotamers at 24 °C so that the diastereoselectivity

determined by ¹H NMR after crude product led to compound

(−)-33) of two stereoisomer crude products. These isomers were

successfully separated by column chromatography on silica gel (from 3

to 5% ethyl acetate in hexane) to give the piperidine compound

68%) as a white crystalline solid: mp = 134−138 °C, [α]²⁴(c = 1.0,

(−)-32 (68 mg, 65%) as a colorless oil: [α]²⁵−28.2 (c = 0.56,

D

CHCl₃); IR (neat, cm⁻¹) 3427, 2924, 2866, 1591, 1451, 1385, 1085,

CHCl₃); IR (neat, cm⁻¹) 3451(br), 1738, 1591, 1454, 1364, 1087; The

obtained compound existed its rotamers at 24 °C, and all the signals in

their 1H and 13C NMR spectra were complex.; ESI-HRMS m/z calcd

for C₃₂H₄₀NO₂[M + H]⁺470.3059, found 470.3063.

1

762; H NMR (400 MHz, CDCl₃) δ 7.13−7.09 (m, 2H), 7.03−6.89

(m, 3H), 6.52−6.44 (m, 3H), 4.50 (d, 1H, J = 8.7 Hz), 4.15 (ddd, 1H,

J = 8.7, 8.7, 8.2 Hz), 3.64 (dd, 1H, J = 11.4, 3.7 Hz), 3.46 (d, 2H, J =

6.4 Hz), 3.30−3.20 (m, 1H), 3.13 (qq, 1H, J = 6.9, 6.9 Hz), 2.60 (dd,

1H, J = 16.0, 8.2 Hz), 2.05−1.97 (m, 1H), 1.79−1.68 (m, 2H), 1.54

(d, 3H, J = 6.9 Hz), 1.38 (d, 3H, J = 6.0 Hz), 1.30−1.08 (m, 6H); ¹³C

NMR (100 MHz, CDCl₃) δ 146.2, 144.3, 143.9, 137.6, 128.9, 128.0,

127.4, 126.4, 122.5, 122.5, 69.0, 67.4, 66.6, 62.4, 59.3, 41.5, 40.6, 38.8,

37.7, 32.1, 24.9, 24.4, 22.2; ESI-HRMS m/z calcd for C₂₅H₃₃NNaO₂

[M + Na]⁺402.2409, found 402.2419.

(2S,4R,6R)-(−)-4-Benzyloxymethyl-6-methyl-2-phenylpiperi-

dine (−)-33. To a solution of compound (−)-32 (61 mg, 0.130

mmol) in CHCl₃(1.0 mL) was added lead tetraacetate (173 mg, 0.390

mmol) at −50 °C. After the mixture was stirred at this temperature for

40 min, added to ice-1N aqueous NaOH solution and the resulting

mixture was extracted with chloroform. The organic layers were

combined, washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo to give the crude products which were purified

by column chromatography on silica gel (from 75 to 83% ethyl acetate

(2S,4R,6R)-(−)-4-Hydroxymethyl-6-methyl-2-phenylpiperi-

dine (−)-30. To a solution of compound (−)-29 (113 mg, 0.298

mmol) in CHCl₃(3 mL) were added lead tetraacetate (396 mg, 0.893

mmol) at −50 °C. After the mixture was stirred at this temperature for

30 min, added to ice-1N aqueous NaOH solution and the resulting

mixture was extracted with chloroform. The organic layers were

combined, washed with brine, dried over MgSO₄, filtered, and

concentrated in vacuo to give the crude products, which were purified

by column chromatography on silica gel (from 0 to 20% methanol in

in hexane) to give the (−)-33 (22 mg, 58%) as a yellow oil: [α]²⁵

D

−31.3 (c = 0.14, CHCl₃); IR (neat, cm⁻¹) 1602, 1452, 1366, 1105; ¹H

NMR (400 MHz, CDCl₃) δ7.37−7.20 (m, 10H), 4.51 (d, 1H, J = 16.9

Hz), 4.47 (d, 1H, J = 17.0 Hz), 4.00 (dd, 1H, J = 11.6, 2.5 Hz), 3.56

(ddq, 1H, J = 12.2, 6.8, 1.8 Hz), 3.32 (dd, 1H, J = 18.3, 9.0 Hz), 3.31

(dd, 1H, J = 18.9, 9.0 Hz), 2.20 (dddd, 1H, J = 19.2, 13.2, 7.0, 3.8 Hz),

1.99−1.94 (m, 1H), 1.67−1.61 (m, 2H), 1.50 (ddd, 1H, J = 12.7, 12.7,

1825

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

5.2 Hz), 1.29 (d, 1H, J = 6.9 Hz), 1.17 (ddd, 1H, J = 12.2, 12.2, 12.2

Hz); ¹³C NMR (100 MHz, CDCl₃) δ 145.4, 138.6, 128.3, 127.6, 127.5,

127.0, 126.7, 76.1, 73.1, 53.5, 47.8, 38.9, 33.7, 31.8, 19.1; ESI-HRMS

m/z calcd for C₂₀H₂₆NO [M + H]⁺296.2014, found 296.2024.

(−)-(β)-Ester Piperidine Derivative (−)-35. To a solution of

(−)-12a (1.73 g, 3.49 mmol) in ethanol (15.0 mL) was added Raney-

Ni W2 (excess amount) at a room temperature. After the reaction

mixture was stirred under H₂atmosphere for 2 h, the catalyst was

removed by filtration and the filtrate was concentrated in vacuo to give

crude products which were purified by column chromatography on

silica gel (5−10% ethyl acetate in hexane) to give the piperidine (β)-

56.4, 39.5, 33.0, 31.4, 29.4, 29.1, 28.9, 28.3, 25.9, 23.7, 21.6, 18.3, −5.3,

−5.3; ESI HRMS m/z calcd for C₃₄H₅₁NNaO₅SSi [M + Na]⁺

636.3155, found 636.3146.

(−)-(β)-Methyl Piperidine Derivative (−)-37. To a solution of

tosylate obtained above (89 mg, 0.145 mmol) and trin-butyltin hydride

(0.05 mL, 0.17 mmol) in dimetoxyethane (0.8 mL) was added 2,2′-

azobisisobutyronitrile (AIBN) (2 mg, 0.015 mmol) and sodium iodide

(43 mg, 0.29 mmol). After the mixture was stirred at 80 °C for 3 h,

H₂O was added, and the resulting mixture was extracted with ether.

The organic layers were combined, washed with brine, dried over

MgSO₄, filtered and concentrated in vacuo to give the crude products

which were purified by column chromatography on silica gel (2−5%

ethyl acetate in hexane) to give (−)-37 (58 mg, 91%) as a colorless oil;

[α]²⁸_D−79.9 (c 1.0 CHCl₃); IR (neat, cm⁻¹) 1742, 1593, 1460, 1254,

1102, 1040; ¹H NMR (400 MHz, CDCl₃) δ 7.20 (dd, 1H, J = 7.6, 7.6

Hz), 7.13 (d, 1H, J = 7.6 Hz), 7.01 (d, 1H, J = 7.1 Hz), 5.03 (d, 1H,

J = 5.3 Hz), 4.75−4.73 (m, 1H), 4.18 (dd, 1H, J = 2.7, 2.2 Hz), 3.72−

3.62 (m, 3H), 3.16−3.06 (m, 2H), 2.47−2.41 (m, 1H), 2.09−2.03 (m,

1H), 1.91 (ddd, 1H, J = 14.7, 5.5, 3.0 Hz), 1.81−1.66 (m, 3H), 1.55−

1.31 (m, 2H), 1.22 (d, 3H, J = 6.9 Hz), 1.20 (d, 3H, J = 7.1 Hz), 1.23−

1.19 (m, 1H), 0.94−0.87 (m, 1H), 0.90 (s, 9H), 0.89 (m, 3H), 0.07 (s,

6H); ¹³C NMR (100 MHz, CDCl₃) δ 147.4, 143.0, 137.6, 128.4,

123.4, 121.9, 90.0, 75.2, 72.8, 63.3, 57.1, 39.6, 39.2, 35.2, 29.1, 28.3,

25.9, 24.1, 23.7, 21.8, 18.3, −5.3, −5.3; ESI HRMS m/z calcd for

C₂₇H₄₆NO₂Si [M + H]⁺444.3298, found 444.3277.

ester derivative (−)-35 (1.12 g, 64%) as a colorless oil: [α]²³−73.5

D

(c = 0.70, CHCl₃); IR (neat, cm⁻¹) 1736, 1593, 1474, 1256, 1101; ¹H

NMR (400 MHz, CDCl₃) δ 7.21 (dd, 1H, J = 7.6, 7.3 Hz), 7.14 (d,

1H, J = 7.8 Hz), 7.02 (m, 1H), 5.04 (d, 1H, J = 5.1 Hz), 4.75 (ddd,

1H, J = 5.1, 5.1, 1.7 Hz), 4.24 (dd, 1H, J = 2.4, 2.4 Hz), 4.12 (q, 2H,

J = 7.1 Hz), 3.73−3.57 (m, 3H), 3.17−3.07 (m, 2H), 2.68 (dddd, 1H,

J = 12.7, 12.7, 3.2, 3.2 Hz), 2.50−2.43 (m, 1H), 2.19 (dddd, 1H, J =

14.1, 2.7, 2.7, 2.7 Hz), 2.14−2.09 (m, 1H), 1.79−1.68 (m, 2H), 1.53−

1.48 (m, 2H), 1.26 (dd, 2H, J = 7.3, 7.1 Hz), 1.24 (t, 3H, J = 7.3 Hz),

1.21 (d, 3H, J = 7.8 Hz), 1.01 (d, 3H, J = 6.8 Hz), 0.90 (s, 9H), 0.07

(s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 175.4, 147.5, 143.0, 137.1,

128.6, 123.6, 122.0, 89.0, 75.4, 72.8, 63.1, 60.4, 56.5, 39.6, 35.5, 33.0,

31.4, 29.2, 28.9, 28.4, 25.9, 23.8, 23.7, 18.3, 14.2, −5.3; ESI HRMS m/z

calcd for C₂₉H₄₈NO₄Si [M + H]⁺502.3353, found 502.3354.

(−)-(β)-Hydroxymethyl Piperidine Derivative (−)-36. To a

solution of compound (−)-35 (407 mg, 1.00 mmol) of toluene (5

mL) was slowly added Red-Al (0.67 mL, >65 wt.% in toluene) at 0 °C.

After the mixture was stirred at this temperature for 2 h, H₂O and

saturated aqueous potassium sodium tartrate tetrahydrate solution was

carefully added, and the resulting mixture was extracted with ethyl

acetate. The organic layers were combined, washed with brine, dried

over MgSO₄, filtered, and concentrated in vacuo to give the crude

products which were purified by column chromatography on silica gel

(20−50% ethyl acetate in hexane) to give the piperidine (α)-alcohol

(1S,2R)-(−)-cis-1-[(2R,4R,6R)-2-(1-tert-Butyldimethylsiloxy-

propenyl)-4,6-dimethylpiperidin-1-yl]-7-isopropylindan-2-ol

(−)-38. To a solution of (−)-37 (282 mg, 0.636 mmol) in toluene

(3.5 mL) was added trimethylaluminum (10% in hexane, 1.53 mL,

3.18 mmol) at 0 °C. After the mixture was warmed to room

temperature and stirred for an additional 2 h, H₂O was added, and the

resulting mixture was extracted with AcOEt. The organic layers were

combined, washed with H₂O, brine, dried over MgSO₄, filtered and

concentrated in vacuo to give a 17:1 mixture (determined by ¹H

NMR) of two stereoisomers crude products. These isomers were

successfully separated by column chromatography on silica gel

(gradually 3−5% ethyl acetate in hexane) to give (−)-38 (229 mg,

derivative (−)-36 (362 mg, 99%) as a white foam: [α]²³−79.8 (c =

D

0.7 CHCl₃); IR (KBr disk, cm⁻¹) 3420 (br), 1742, 1593, 1472, 1254,

75%) as a colorless oil; [α]²⁴−49.9 (c 1.0 CHCl₃); IR (neat, cm⁻¹)

1

1101; H NMR (400 MHz, CDCl₃) δ 7.20 (dd, 1H, J = 7.6, 7.6 Hz),

D

1

1591, 1460, 1385, 1254, 1098, 836; H NMR (400 MHz, CDCl₃) δ

7.14 (d, 1H, J = 7.1 Hz), 7.02 (m, 1H), 5.05 (d, 1H, J = 5.1 Hz), 4.75

(ddd, 1H J = 4.9, 4.9, 1.5 Hz), 4.25 (dd, 1H, J = 2.7, 2.7 Hz), 3.67 (qq,

1H, J = 7.0, 6.8 Hz), 3.55−3.43 (m, 3H), 3.17−3.07 (m, 2H), 2.50−

2.43 (m, 1H), 2.13−2.07 (m, 1H), 1.99−1.85 (m, 3H), 1.77−1.67 (m,

1H), 1.56−1.43 (m, 2H), 1.22 (d, 3H, J = 6.8 Hz), 1.20 (d, 3H, J = 7.1

Hz), 1.01−0.92 (m, 2H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (100

MHz, CDCl₃) δ 147.4, 143.0, 137.4, 128.5, 123.5, 122.0, 89.5, 75.3,

72.9, 67.8, 63.2, 56.7, 39.6, 33.5, 32.2, 31.6, 29.7, 29.0, 28.4, 25.9, 23.7,

18.3, −5.3; ESI HRMS m/z calcd for C₂₇H₄₆NO₃Si [M + H]⁺

460.3247, found 460.3270.

7.24 (dd, 1H, J = 7.6, 7.6 Hz), 7.12 (d, 1H, J = 7.8 Hz), 7.00 (d, 1H,

J = 7.3 Hz), 4.51 (d, 1H, J = 6.9 Hz), 4.10−4.05 (m, 1H), 3.74−3.64

(m, 2H), 3.36 (qq, 1H, J = 6.9, 6.9 Hz), 3.34−3.26 (m, 1H), 3.10 (dd,

1H, J = 15.8, 7.8 Hz), 2.70−2.60 (m, 2H), 1.79−1.66 (m, 4H), 1.63−

1.49 (m, 2H), 1.37 (d, 3H, J = 6.9 Hz), 1.17 (d, 3H, J = 7.1 Hz), 1.11

(d, 3H, J = 6.9 Hz), 0.95−0.83 (m, 2H), 0.90 (s, 9H), 0.81 (d, 3H, J =

6.1 Hz), 0.56 (ddd, 1H, J = 12.7, 12.7, 5.1 Hz), 0.07 (s, 6H); ¹³C NMR

(100 MHz, CDCl₃) δ 146.8, 142.8, 138.4, 128.9, 123.0, 122.5, 71.4,

63.2, 58.9, 53.6, 48.4, 41.3, 39.5, 36.9, 30.9, 30.8, 29.8, 26.1, 25.9, 25.5,

22.7, 21.3, 18.3, 18.1, −5.3; ESI HRMS m/z calcd for C₂₈H₅₀NO₂Si

[M + H]⁺460.3611, found 460,3598.

(2R,4R,6R)-(−)-N-Benzyzoxycalboyl-2-(2-(tert-butyldimethyl-

silyloxy)ethyl)-4,6-dimethylpiperidine (−)-39. A solution of

(−)-38 (126 mg, 0.27 mmol) and Pd(OH)₂/C (60 mg) in methanol

(1.5 mL) was stirred in an autoclave under 10 atmospheric pressure of

hydrogen at room temperature for 24 h. Then the catalyst was

removed by filtration and the filtrate was concentrated in vacuo to give

crude products. The crude product was reduced without further

purification.

Tosylate. To a solution of (−)-36 (561 mg, 1.22 mmol) in

dichloromethane (6 mL) was added 4-(dimethylamino)pyridine

(DMAP) (75 mg, 0.610 mmol), triethylamine (0.5 mL, 3.66 mmol),

and p-toluenesulfonyl chloride (349 mg, 1.83 mmol) at room

temperature. After the reaction mixture was stirred at room

temperature for 2 h, H₂O was added, and the resulting mixture was

extracted with ether. The organic layers were combined, washed with

brine, dried over MgSO₄, filtered and concentrated in vacuo to give the

crude products which were purified by column chromatography on

silica gel (10% ethyl acetate in hexane) to give corresponding tosylate

(642 mg, 86%) as a colorless oil; [α]²⁴−57.8 (c = 0.6 CHCl₃); IR

To a solution of the crude piperidine obtained above in

tetrahydrofurane (1.5 mL) and H₂O (1.5 mL) was added K₂CO₃

(378 mg, 2.73 mmol) and carbobenzoxy chloride (0.10 mL, 0.55

mmol) at 0 °C. After the mixture was stirred at 0 °C for 2 h, H₂O was

added, and the resulting mixture was extracted with ether. The organic

layers were combined, washed with brine, dried over MgSO₄, filtered

and concentrated in vacuo to give the crude products which were

purified by column chromatography on silica gel (gradually from 2 to

3.3% ethyl acetate in hexane) to give (−)-39 (91 mg, 79%) as a

D

1

(neat, cm⁻¹) 1740, 1597, 1462, 1362, 1252, 1178, 1098; H NMR

(400 MHz, CDCl₃) δ 7.77 (d, 2H, J = 8.4 Hz), 7.33 (d, 2H, J = 8.0

Hz), 7.22 (dd, 1H, J = 7.2, 7.2 Hz), 7.13 (d, 1H, J = 7.6 Hz), 7.00 (d,

1H, J = 5.2 Hz), 5.01 (d, 1H, J = 5.2 Hz), 4.73−4.70 (m, 1H), 4.18

(dd, 1H, J = 2.4, 2.4 Hz), 3.84 (ddd, 1H, J = 15.1, 9.5, 5.6 Hz), 3.71−

3.62 (m, 2H), 3.60 (qq, 1H, J = 6.8, 6.8 Hz), 3.13−3.04 (m, 2H),

2.43−2.37 (m, 1H), 2.10−2.01 (m, 2H), 1.85−1.81 (m, 2H), 1.67−

1.61 (m, 1H), 1.44 (ddd, 2H, J = 6.3, 6.3, 4.2 Hz), 1.33−1.30 (m, 1H),

1.19 (dd, 6H, J = 6.3, 6.3 Hz), 0.97−0.88 (m, 1H), 0.89 (s, 9H), 0.06

(s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 147.4, 144.7, 142.9, 137.0,

132.8, 129.8, 128.5, 127.9, 123.5, 121.9, 88.9, 75.3, 74.2, 72.7, 63.1,

colorless oil: [α]²⁴−15.8 (c = 0.3, CHCl₃); IR (neat, cm⁻¹) 1827,

D

1696, 1259, 1148, 1100; ¹H NMR (400 MHz, CDCl₃) δ7.36−7.28 (m,

5H), 5.14−5.08 (m, 2H), 4.22 (dddd, 1H, J = 14.6, 9.8, 6.9, 3.0 Hz),

1826

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

3.66−3.50 (m, 3H), 1.98−1.78 (m, 3H), 1.68−1.43 (m, 5H), 1.29

(ddd, 1H, J = 19.7, 13.1, 6.0 Hz), 1.24 (d, 3H, J = 6.9 Hz), 0.98 (d, 3H,

J = 6.6 Hz), 0.88 (s, 9H), 0.03 (s, 6H); ¹³C NMR (100 MHz, CDCl₃)

δ 155.9, 137.1, 128.4, 127.8, 127.8, 66.6, 63.1, 52.6, 48.4, 36.6, 33.8,

32.0, 26.0, 23.3, 23.1, 19.1, 18.3, −5.3; ESI HRMS m/z calcd for

C₂₄H₄₁NNaO₃Si [M + Na]⁺442.2753, found 442.2745.

1.20 (ddd, 1H, J = 12.6, 12.6, 5.7 Hz), 1.11 (d, 3H, J = 7.8 Hz), 0.91

(d, 3H, J = 6.3 Hz), 0.77 (ddd, 1H, J = 12.0, 12.0, 12.0 Hz); ¹³C NMR

(100 MHz, CDCl₃) δ 173.3, 53.0, 43.5, 42.3, 38.1, 30.6, 25.5, 25.1,

22.0, 16.7; ESI HRMS m/z calcd for C₁₀H₁₇NNaO [M + Na]⁺

190.1208, found 190.1215.

(+)-7-Epidendroprimine. To a solution of indoridizine (−)-41

(18 mg, 0.129 mmol) in ether (2 mL) was added lithium aluminum

hydride (14 mg, 0.369 mmol) at 0 °C. After the reaction mixture was

refluxed for 6 h, ice was slowly added, and the resulting mixture was

extracted with dichloromethane. The organic layers were combined,

dried over MgSO₄, filtered and concentrated in vacuo to give the crude

products which were purified by column chromatography on reverse

phase silica gel (9% trimethylamine in methanol) gave (+)-7-

(2R,4R,6R)-(−)-N-Benzyloxycalboyl-4,6-dimethyl-2-hydroxy-

propylpiperidine. To a solution of (−)-39 (121 mg, 0.155 mmol) in

tetrahydrofurane (1.5 mL) was added 2N aqueous HCl solution (0.75

mL) at 0 °C. After the mixture was stirred at room temperature for 1

h, saturated aqueous NaHCO₃solution was added, and the resulting

mixture was extracted with ether. The organic layers were combined,

washed with brine, dried over MgSO₄, filtered and concentrated in

vacuo to give the crude products which were purified by column

chromatography on silica gel (gradually from 25 to 50% ethyl acetate

epidendroprimine (13 mg, 81%) as a yellow oil: [α]²⁴9.2 (c = 0.3,

D

1

CHCl₃); IR (neat, cm⁻¹) 1458, 1373, 1260, 1173, 1154; H NMR

in hexane) to give alcohol (84 mg, 95%) as a colorless oil: [α]²⁴

D

(400 MHz, CDCl₃) δ3.35−3.29 (m, 1H), 2.80 (td, 1H, J = 8.5, 2.7

Hz), 2.53 (q, 1H, J = 8.8 Hz), 2.48−2.41 (m, 1H), 1.86−1.59 (m, 5H),

1.52−1.39 (m, 2H), 1.35−1.23 (m, 2H), 0.97 (d, 3H, J = 6.8 Hz), 0.91

(d, 3H, J = 6.3 Hz), 0.80 (q, 1H, J = 11.8 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ54.1, 49.9, 48.5, 40.5, 39.9, 30.7, 25.5, 22.3, 21.0, 9.8; ESI

HRMS m/z calcd for C₁₀H₂₀N [M + H]⁺154.1596, found 154.1593.

(−)-(α)-Ester Piperidine Derivative (−)-43. To magnesium

turning (488 mg, 20.1 mmol) in methanol (5.0 mL) was added a

solution of the (−)-12a (1.0 g, 2.01 mmol) in methanol (15 mL) at

room temperature. After the mixture was stirred at this temperature for

2 h, H₂O and 2N aqueous HCl solution was carefully added, and the

pH of the solution was adjusted toward 7. The resulting mixture was

extracted with ethyl acetate. The organic layers were combined,

washed with brine, dried over MgSO₄, filtered and concentrated in

vacuo to give a 4:1 mixture (determined by ¹H NMR) of two

stereoisomers crude products. These isomers were successfully

separated by column chromatography on silica gel (from 5 to 7%

ethyl acetate in hexane) to give the piperidine (α)-ester derivative

(−)-43 (581 mg, 58%) as a white crystalline solid: mp = 86−89 °C,

[α]²⁴_D−30.0 (c = 1.2, CHCl₃), IR (KBr disk, cm⁻¹) 1732, 1471, 1379,

1257, 1128; ¹H NMR (400 MHz, CDCl₃) δ 7.17 (dd, 1H, J = 7.3, 7.3

Hz), 7.10 (d, 1H, J = 7.3 Hz), 6.96 (m, 1H), 5.84 (dt, 1H, J = 15.4, 4.6

Hz), 5.73 (ddt, 1H, J = 15.4, 8.8, 1.5 Hz), 4.93 (d, 1H, J = 5.4 Hz),

4.68 (ddd, 1H, J = 5.4, 5.4, 2.0 Hz), 4.25−4.09 (m, 5H), 3.58 (qq, 1H,

J = 6.8, 6.8 Hz), 3.30 (ddd, 1H, J = 11.7, 8.5, 3.2 Hz), 3.12−3.03 (m,

2H), 2.56−2.50 (m, 2H), 2.12 (ddd, 1H, J = 13.7, 5.9, 2.9 Hz), 1.91

(ddd, 1H, J = 14.9, 6.6, 2.9 Hz), 1.55 (ddd, 1H, J = 13.7, 12.0, 4.6 Hz),

1.29 (t, 3H, J = 7.3 Hz), 1.25 (d, 3H, J = 6.8 Hz), 1.14 (d, 3H, J = 7.1

Hz), 0.93 (s, 9H), 0.08 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ

174.1, 147.4, 143.1, 137.3, 133.0, 132.3, 128.3, 123.2, 121.7, 87.7, 75.4,

72.7, 63.2, 60.3, 56.5, 39.6, 33.7, 31.8, 28.5, 27.8, 26.0, 23.5, 23.5, 18.4,

14.2, −5.2; FAB-HRMS m/z calcd for C₂₉H₄₆NO₄Si [M + H]⁺

500.3196, found 500.3198.

−9.63 (c = 0.8, CHCl₃); IR (neat, cm⁻¹) 3431(br), 1688, 1454, 1410,

1307, 1101, 1070; ¹H NMR (400 MHz, CDCl₃) δ 7.36−7.29 (m, 5H),

5.14 (d, 1H, J = 12.4 Hz), 5.10 (d, 1H, J = 12.4 Hz), 4.27−4.20 (m,

1H), 3.70−3.57 (m, 3H), 2.01 (brs, 1H), 1.99−1.85 (m, 3H), 1.70−

1.44 (m, 5H), 1.30 (ddd, 1H, J = 13.7, 5.9, 5.9 Hz), 1.23 (d, 3H, J =

6.9 Hz), 0.99 (d, 3H, J = 6.6 Hz); ¹³C NMR (100 MHz, CDCl₃) δ

156.0, 136.9, 128.4, 127.9, 127.9, 66.7, 62.3, 52.1, 48.3, 36.7, 33.9, 31.8,

29.5, 23.4, 22.9, 19.1; ESI HRMS m/z calcd for C₁₈H₂₇NNaO₃[M +

Na]⁺328.1889, found 328.1880.

(2R,4R,6R)-(+)-N-Benzyzoxycalboyl-4,6-dimethyl-2-methyl-

esterpropylpiperidine (+)-40. To a solution of alcohol obtained

above (139 mg, 0.455 mmol) in acetone (1 mL) was added 2.67 N

Jones reagent at 0 °C. After the reaction mixture was stirred for 1 h at

room temperature, brine was added, and the resulting mixture was

extracted with ethyl acetate. The organic layers were combined,

washed with 10% NaHSO₃solution and brine, dried over MgSO₄,

filtered, and concentrated in vacuo to give the crude products. The

crude product was reduced without further purification.

To a solution of the crude carboxylic acid obtained above in ethyl

acetate (2.5 mL) was added diazomethane prepared from nitro-

somethylurea (117 mg, 1.135 mmol), 30% aqueous NaOH solution

(0.5 mL) and ether (2.5 mL) at 0 °C. After the reaction mixture was

stirred for 30 min at 0 °C, saturated NH₄Cl solution was added, and

the resulting mixture was extracted with ethyl acetate. The organic

layers were combined, washed with brine, dried over MgSO₄, filtered

and concentrated in vacuo to give the crude products which were

purified by column chromatography on silica gel (gradually from 6 to

9% ethyl acetate in hexane) to give methyl ester (+)-40 (101 mg, 66%

for 2 steps) as a colorless oil: [α]²⁴1.1 (c = 0.3, CHCl₃); IR (neat,

D

cm⁻¹) 1738, 1698, 1437, 1404, 1305, 1265, 1128, 1100; ¹H NMR (400

MHz, CDCl₃) δ7.37−7.28 (m, 5H), 5.13 (d, 1H, J = 12.4 Hz), 5.09 (d,

1H, J = 12.2 Hz), 4.25 (dqd, 1H, J = 12.0, 6.6, 3.1 Hz), 3.68−3.59 (m,

1H), 3.63 (s, 3H), 2.37−2.33 (m, 2H), 2.31−2.20 (m, 1H), 1.96−1.78

(m, 3H), 1.59 (ddd, 1H, J = 13.7, 5.9, 3.2 Hz), 1.42 (ddd, 1H, J = 13.7,

11.7, 5.4 Hz), 1.28−1.19 (m, 1H), 1.22 (d, 3H, J = 6.8 Hz), 0.96 (d,

3H, J = 6.6 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 174.0, 156.0, 136.9,

128.4, 127.9, 127.9, 66.7, 52.1, 51.4, 48.7, 37.0, 35.5, 31.4, 30.6, 23.9,

23.0, 18.6; ESI HRMS m/z calcd for C₁₉H₂₇NNaO₄[M + Na]⁺

356.1838, found 356.1826.

(−)-(α)-Hydroxymethyl Piperidine Derivative. To a solution of

compound (−)-31 (700 mg, 1.40 mmol) of toluene (7 mL) was slowly

added Red-Al (1.13 mL, >65 wt.% in toluene) at 0 °C. After the

mixture was stirred at room temperature for 2 h, H₂O and saturated

aqueous potassium sodium tartrate tetrahydrate solution was carefully

added, and the resulting mixture was extracted with ethyl acetate. The

organic layers were combined, washed with brine, dried over MgSO₄,

filtered, and concentrated in vacuo to give the crude products which

were purified by column chromatography on silica gel (from 20 to

50% ethyl acetate in hexane) to give the piperidine (α)-alcohol

(5R,7R,8aR)-(−)-5,7-Dimethylindolizidine-3-one (−)-41. To a

solution of methylester (−)-40 (84 mg, 0.252 mmol) in methanol (1

mL) was added Pd/C (25 mg) at a room temperature. After the

reaction mixture was stirred under H₂atmosphere for 1 h, the catalyst

was removed by filtration and the filtrate was concentrated in vacuo to

give crude products. The crude product was reduced without further

purification.

derivative (604 mg, 94%) as a colorless oil: [α]²⁵−50.1 (c = 0.4,

D

CHCl₃); IR (neat, cm⁻¹) 3370(br), 1593, 1464, 1255, 1037; ¹H NMR

(400 MHz, CDCl₃) δ7.17 (dd, 1H, J = 7.6, 7.6 Hz), 7.12 (d, 1H, J =

7.3 Hz), 6.99 (m, 1H), 5.79 (dt, 1H, J = 15.4, 4.6 Hz), 5.70 (m, 1H, J =

15.4, 8.5 Hz), 5.02 (d, 1H, J = 5.5 Hz), 4.77 (ddd, 1H, J = 5.5, 4.2, 3.2

Hz), 4.20 (m, 2H), 3.80−3.69 (m, 2H), 3.58 (qq, 1H, J = 6.8, 6.8 Hz),

3.22 (ddd, 1H, J = 11.2, 8.5, 4.2 Hz), 3.12 (d, 2H, J = 3.4 Hz), 3.08−

3.04 (m, 1H), 1.95−1.92 (m, 2H), 1.77−1.66 (m, 2H), 1.25 (d, 3H,

J = 6.8 Hz), 1.15 (d, 3H, J = 6.8 Hz), 0.92 (s, 9H), 0.08 (s, 6H); ¹³C

NMR (100 MHz, CDCl₃) δ 147.5, 142.7, 137.2, 133.3, 132.2, 128.5,

123.4, 121.7, 88.0, 75.2, 72.7, 66.5, 63.2, 56.3, 39.5, 33.7, 31.6, 28.6,

After solution of the crude amine obtained above in toluene (1 mL)

was refluxed for 3 h, the reaction mixture was concentrated in vacuo to

give the crude products which were purified by column chromatog-

raphy on silica gel (ethyl acetate) to give indoridizine (−)-41 (29 mg,

71% for 2 steps) as a colorless oil: [α]²⁴_D−46.5 (c = 0.1, CHCl₃); IR

1

(neat, cm⁻¹) 1671, 1422, 1375, 1285; H NMR (400 MHz, CDCl₃)

δ4.36 (dq, 1H, J = 6.6, 6.6 Hz), 3.63−3.55 (m, 1H), 2.36−2.27 (m,

2H), 2.19−2.11 (m, 1H), 1.94−1.75 (m, 2H), 1.56−1.46 (m, 2H),

1827

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

27.7, 26.0, 23.5, 18.4, −5.2; FAB-HRMS m/z calcd for C₂₇H₄₄NO₃Si

[M + H]⁺458.3090, found 458.3090.

3.42−3.39 (m, 2H), 3.37−3.30 (m, 1H), 3.25−3.20 (m, 1H), 2.85 (dd,

1H, J = 15.6, 7.3 Hz), 2.63 (dd, 1H, J = 15.6, 8.8 Hz), 2.42 (m, 1H),

2.07−2.04 (m, 2H), 1.99−1.91 (m, 1H), 1.72−1.65 (m, 2H), 1.63−

1.60 (m,2H), 1.51−1.46 (m,1H), 1.45−1.35 (m, 1H), 1.39 (d, 3H, J =

7.1 Hz), 1.24−1.05 (m, 2H), 1.15 (d, 3H, J = 6.8 Hz), 1.13 (d, 3H, J =

6.3 Hz), 0.89 (s, 9H), 0.04 (s, 6H); ¹³C NMR (100 MHz, acetone-d₆)

δ 147.5, 143.4, 139.6, 129.7, 123.8, 123.1, 72.2, 68.9, 67.7, 63.5, 54.0,

53.1, 41.6, 34.6, 34.5, 32.2, 31.3, 29.0, 26.3, 26.1, 24.6, 22.1, 18.8, −5.1;

ESI HRMS m/z calcd for C₂₈H₅₀NO₃Si [M + H]⁺476.3560, found

476.3544.

(2R,4S,6R)-(−)-N-Benzyzoxycalboyl-2-(3-tert-butyldimethyl-

silyloxypropyl)-4-hydroxymethyl-6-methylpiperidine (−)-47. A

solution of (−)-45 (475 mg, 1.00 mmol) and Pd(OH)₂/C (100 mg)

in methanol (5.0 mL) was stirred in an autoclave under 10

atmospheric pressure of hydrogen at room temperature for 12 h.

Then the catalyst was removed by filtration and the filtrate was

concentrated in vacuo to give crude products. The crude product was

protected without further purification.

(−)-(α)-Hydroxymethyl Piperidine Derivative (−)-44. To a

solution of the alcohol compound obtained above (300 mg, 0.65

mmol) in THF (4.0 mL) was added PtO₂(30 mg) at room

temperature. After the reaction mixture was stirred under H₂

atmosphere for 3 h, the catalyst was removed by filtration and the

filtrate was concentrated in vacuo to give crude products which were

purified by column chromatography on silica gel (from 20 to 50%

ethyl acetate in hexane) to give the piperidine (α)-alcohol derivative

(−)-44 (277 mg, 92%) as a colorless oil: [α]²⁵−86.5 (c = 0.4,

D

CHCl₃); IR (neat, cm⁻¹) 3408(br), 1593, 1472, 1254, 1100, 1038; ¹H

NMR (400 MHz, CDCl₃) δ7.21 (dd, 1H, J = 7.6, 7.6 Hz), 7.14 (d, 1H,

J = 7.6 Hz), 7.01 (d, 1H, J = 7.3 Hz), 5.07 (d, 1H, J = 5.4 Hz), 4.71

(ddd, 1H, J = 4.9, 4.9, 1.5 Hz), 4.19 (dd, 1H, J = 2.9, 2.9 Hz), 3.75−

3.66 (m, 4H), 3.65 (qq, 1H, J = 6.8, 6.8 Hz), 3.16−3.06 (m, 2H), 3.01

(dd, 1H, J = 4.9, 4.9 Hz), 2.64 (dddd, 1H, J = 11.5, 8.8, 2.7, 2.7 Hz),

2.11 (dddd, 1H, J = 12.9, 12.9, 5.1, 2.7 Hz), 1.98−1.85 (m, 4H), 1.75−

1.66 (m, 1H), 1.56−1.35 (m, 3H), 1.22 (d, 3H, J = 6.6 Hz), 1.20 (d,

3H, J = 7.1 Hz), 0.90 (s, 9H), 0.07 (s, 6H); ¹³C NMR (100 MHz,

CDCl₃) δ 147.4, 142.8, 137.1, 128.5, 123.6, 121.9, 89.0, 75.1, 72.9,

66.2, 63.1, 39.4, 32.0, 31.9, 31.5, 29.0, 28.4, 27.8, 25.9, 23.8, 23.7, 18.3,

−5.3; FAB-HRMS m/z calcd for C₂₇H₄₆NO₃Si [M + H]⁺460.3247,

found 460.3224.

To a solution of the crude piperidine obtained above in

tetrahydropyrane (5 mL) and H₂O (5 mL) was added K₂CO₃(1.38 g,

9.98 mmol) and carbobenzoxy chloride (0.35 mL, 2.00 mmol) at

0 °C. After the mixture was stirred at 0 °C for 2 h, H₂O was added,

and the resulting mixture was extracted with ether. The organic layers

were combined, washed with brine, dried over MgSO₄, filtered and

concentrated in vacuo to give the crude products which were purified

by column chromatography on silica gel (gradually from 20 to 50%

ethyl acetate in hexane) to give (−)-47 (346 mg, 80%) as a colorless

(1S,2R)-(−)-cis-1-[(2R,4S,6R)-2-(3-tert-Butyldimethylsiloxy-

propyl)-4-hydroxymethyl-6-methylpiperidin-1-yl]-7-isopropy-

lindan-2-ol (−)-45M. To copper iodide (3.2 g, 16.8 mmol) in ether

(4.0 mL) was added a 1.0 M solution of methylmagnesium iodide in

ether (17.0 mL, 16.8 mmol) prepared from methyl iodide (1.24 mL,

19.9 mmol), magnesium turning (440 mg, 18.1 mmol), and ether

(18.1 mL) at 0 °C. The reaction mixture was stirred at this

temperature for 10 min and a solution of the (−)-44 (387 mg, 0.84

mmol) in ether (4.0 mL) was added dropwise at 0 °C. After the

mixture was stirred at 0 °C for 10 min and an additional 2 h at room

temperature, saturated aqueous NH₄Cl solution was added, and the

resulting mixture was extracted with ether. The organic layers were

combined, washed with brine, dried over MgSO₄, filtered and

concentrated in vacuo to give a 3:1 mixture (determined by ¹H

NMR) of two stereoisomers crude products. These isomers were

successfully separated by column chromatography on silica gel (from

25 to 50% ethyl acetate in hexane) to give the piperidine compound

(−)-45 (235 mg, 60%) as a white amorphous solid: [α]²³_D−55.8 (c =

0.3, CHCl₃); IR (KBr disk, cm⁻¹) 3414(br), 1462, 1389, 1253, 1093;

¹H NMR (400 MHz, CDCl₃) δ7.23 (dd, 1H, J = 7.6, 7.6 Hz), 7.11 (d,

1H J = 7.6 Hz), 7.00 (d, 1H, J = 7.3 Hz), 4.54 (d, 1H, 6.6 Hz), 4.11−

4.03 (m, 1H), 3.55 (dt, 2H, J = 6.6, 1.5 Hz), 3.57−3.53 (m, 1H),

3.40−3.31 (m, 1H), 3.37 (d, 2H, J = 5.9 Hz), 3.04 (dd, 1H, J = 15.9,

7.6 Hz), 2.63 (dd, 1H, J = 15.6, 9.3 Hz), 1.88−1.76 (m, 1H), 1.70 (m,

1H), 1.63−1.55 (m, 1H), 1.37 (d, 3H, J = 6.8 Hz), 1.30 (d, 3H, J = 6.8

Hz), 1.13 (d, 3H, J = 6.8 Hz), 1.17−0.99 (m, 2H), 0.91 (ddd, 2H, J =

13.2, 9.0, 3.9 Hz), 0.88 (s, 9H), 0.55(ddd, 1H, J = 12.9, 12.9, 5.1 Hz),

0.02(s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 146.5, 143.0, 138.0,

129.1, 122.9, 122.6, 72.3, 68.6, 63.1, 58.3, 52.8, 48.8, 40.7, 36.6, 33.9,

31.1, 29.8, 28.1, 27.9, 26.0, 21.2, 20.9, 18.3, −5.2; FAB-HRMS m/z

calcd for C₂₈H₅₀NO₃Si [M + H]⁺476.3560, found 476.3559.

oil: [α]²³−19.1 (c = 1.0, CHCl₃); IR (neat, cm⁻¹) 3449(br), 1688,

D

1408, 1256, 1100; ¹H NMR (400 MHz, CDCl₃) δ7.36−7.27 (m, 5H),

5.12 (d, 1H, J = 12.5 Hz), 5.09 (d, 1H, J = 12.5 Hz), 4.18−4.16 (m,

1H), 3.71 (dddd, 1H, J = 13.9, 6.8, 6.8, 4.4 Hz), 3.62−3.55 (m, 2H),

3.54−3.46 (m, 2H), 2.01 (ddd, 1H, J = 19.3, 13.2, 6.6 Hz), 1.88 (ddd,

1H, J = 13.9, 6.8, 4.4 Hz), 1.80−1.69 (m, 2H), 1.57−1.40 (m, 4H),

1.37 (d, 3H, J = 7.1 Hz), 1.34−1.26 (m, 1H), 0.88 (s, 9H), 0.03(s,

6H); ¹³C NMR (100 MHz, CDCl₃) δ 156.0, 137.0, 128.4, 127.8, 68.2,

66.6, 62.9, 52.4, 47.6, 32.6, 31.7, 29.9, 29.0, 28.5, 25.9, 22.4, 18.3, −5.3;

FAB-HRMS m/z calcd for C₂₄H₄₂NO₄Si [M + H]⁺436.2883, found

436.2881.

(2R,4S,6R)-(−)-N-Benzoxycalboyl-2-(3-tert-butyldimethylsily-

loxypropyl)-4-bromomethyl-6-methylpiperidine. To a solution

of (−)-47 (222 mg, 0.510 mmol) in dichloromethane (2.5 mL) was

added triethylamine (0.283 mL, 2.04 mmol), carbon tetrabromide

(507 mg, 1.53 mmol) and triphenylphosphine (535 mg, 2.04 mmol) at

0 °C and stirred, continued for an additional 5 min. After the mixture

was stirred at room temperature for 2 h, hexane was added, the

resulting precipitate was filtered, and the filtrate was concentrated in

vacuo to give crude products which were purified by column

chromatography on silica gel (gradually from 2 to 5% ethyl acetate

in hexane) to give the bromide derivative (224 mg, 88%) as a yellow

oil: [α]²³_D−11.3 (c = 0.4, CHCl₃); IR (neat, cm⁻¹) 1703, 1462, 1404,

1

1309, 1098; H NMR (400 MHz, CDCl₃) δ7.36−7.28 (m, 5H), 5.12

(d, 1H, J = 12.5 Hz), 5.09 (d, 1H, J = 12.5 Hz), 4.24−4.19 (m, 1H),

3.67−3.60 (m, 1H), 3.63−3.53 (m, 2H), 3.28 (d, 2H, J = 6.8 Hz),

2.18−2.09 (m, 1H), 1.94 (ddd, 1H, J = 13.9, 6.1, 4.4 Hz), 1.87 (ddd,

1H, J = 13.7, 5.1, 2.9 Hz), 1.78−1.68 (m, 1H), 1.53−1.45 (m, 4H),

1.41 (d, 3H, J = 6.8 Hz), 1.31 (ddd, 1H, J = 13.9, 8.3, 8.3 Hz), 0.88 (s,

9H), 0.03 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 156.0, 136.9,

128.4, 127.9, 66.7, 62.7, 52.6, 47.7, 39.4, 35.7, 32.5, 31.9, 29.8, 28.0,

25.9, 22.1, 18.3, −5.3; FAB-HRMS m/z calcd for C₂₄H₄₁BrNO₃Si

[M⁺+ H] 498.2039, found 498.2027.

(1S,2R)-(−)-cis-1-[(2R,4S,6S)-2-(3-tert-Butyldimethylsiloxy-

propyl)-4-hydroxymethyl-6-methylpiperidin-1-yl]-7-isopropy-

lindan-2-ol (−)-46. To a solution of compound (−)-44 (600 mg,

1.31 mmol) in toluene (6.5 mL) was added a ca. 1.4 M

trimethylaluminium in n-hexane (9.41 mL, 19.6 mmol) at 0 °C.

After the mixture was stirred at room temperature for 2 h, H₂O was

carefully added, and the resulting mixture was extracted with ether.

The organic layers were combined, washed with brine, dried over

MgSO₄, filtered and concentrated in vacuo to give a crude products

which were purified by column chromatography on silica gel (from 25

to 33% ethyl acetate in hexane) gave the piperidine compound (−)-46

(2R,4S,6R)-(−)-N-Benzoxycalboyl-2-(3-tert-butyldimethylsily-

loxypropyl)-4,6-dimethylpiperidine (−)-48. To a solution of

bromide derivative obtained above (215 mg, 0.431 mmol) in

dimethylsulfoxide (2.5 mL) was added sodium borohydride (65 mg,

1.73 mmol) at room temperature. After the mixture was stirred at

90 °C for 1 h, H₂O was added, and the resulting mixture was extracted

with ether. The organic layers were combined, washed with brine,

dried over MgSO₄, filtered and concentrated in vacuo to give the crude

products which were purified by column chromatography on silica gel

(3% ethyl acetate in hexane) to give (−)-48 (149 mg, 82%) as a

(508 mg, 82%) as a colorless oil; [α]²³−57.0 (c = 0.6, CHCl₃); IR

D

1

(KBr disk, cm⁻¹) 3435(br), 1742, 1462, 1385, 1254, 1090; H NMR

(400 MHz, acetone-d₆) δ7.25−7.16 (m, 2H), 7.00 (d, 1H, J = 7.1 Hz),

4.38 (d, 1H, J = 6.8 Hz), 4.12−4.06 (m, 1H), 3.55−3.51 (m, 2H),

1828

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

colorless oil: [α]²³−16.3 (c = 0.2, CHCl₃); IR (neat, cm⁻¹) 1705,

After solution of the crude amine obtained above in toluene (1 mL)

was refluxed for 3 h, the reaction mixture was concentrated in vacuo to

give the crude products which were purified by column chromatog-

raphy on silica gel (ethyl acetate) to give indorizidinone (−)-50 (29

mg, 71% for 2 steps) as a colorless oil: [α]²³_D−80.4 (c = 0.7, CHCl₃);

IR (neat, cm⁻¹) 1686, 1418, 1375, 1294; ¹H NMR (400 MHz, CDCl₃)

δ4.15 (dq, 1H, J = 13.4, 6.6 Hz), 3.78 (m, 1H), 2.35 (t, 2H, J = 8.8

Hz), 2.25−2.16 (m, 1H), 1.94−1.86 (m, 1H), 1.82 (ddd, 1H, J = 13.7,

7.1, 4.6 Hz), 1.62−1.48 (m, 3H), 1.27 (ddd, 1H, J = 12.7, 6.6, 6.6 Hz),

1.20 (d, 3H, J = 6.9 Hz), 1.09 (d, 3H, J = 7.1 Hz); ¹³C NMR (100

MHz, CDCl₃) δ 173.8, 49.0, 44.5, 39.0, 36.1, 30.5, 26.0, 25.9, 21.0,

19.9; FAB-HRMS m/z calcd for C₁₀H₁₈NO [M + H]⁺168.1388,

found 168.1389.

(−)-Dendroprimine (34). To a solution of indorizidinone (−)-50

(14 mg, 0.084 mmol) in ether (2 mL) was added lithium aluminum

hydride (6 mg, 0.158 mmol) at 0 °C. After the reaction mixture was

refluxed for 6 h, ice was slowly added, and the resulting mixture was

extracted with dichloromethane. The organic layers were combined,

dried over MgSO₄, filtered and concentrated in vacuo to give the crude

products which were purified by column chromatography on silica gel

on reverse phase silica gel (9% trimethylamine in methanol) to give

(−)-dendroprimine (8 mg, 62%) as a yellow oil: [α]²³_D1−36.9 (c = 0.1,

CHCl₃); IR (neat, cm⁻¹) 1458, 1373, 1100, 1051; H NMR (400

MHz, CDCl₃) δ3.16−3.07 (m, 2H), 2.80−2.72 (m, 1H), 2.35 (dddd,

1H, J = 11.7, 8.8, 5.9, 2.9 Hz), 1.89−1.50 (m, 8H), 1.04 (d, 3H, J = 5.9

Hz), 0.98−0.93 (1H, m), 0.91 (d, 3H, J = 6.3 Hz); ¹³C NMR (100

MHz, CDCl₃) δ60.0, 50.9, 49.8, 42.9, 35.1, 26.6, 25.3, 22.1, 21.9, 21.8;

FAB-HRMS m/z calcd for C₁₀H₂₀N [M + H]⁺154.1596, found

154.1595.

D

1

1458, 1404, 1309, 1258, 1099; H NMR (400 MHz, CDCl₃) δ7.35−

7.27 (m, 5H), 5.12 (d, 1H, J = 12.8 Hz), 5.09 (d, 1H, J = 12.8 Hz),

4.20−4.15 (m, 1H), 3.63−3.53 (m, 3H), 1.95−1.70 (m, 3H), 1.66

(ddd, 1H, J = 13.7, 4.9, 2.7 Hz), 1.55−1.44 (m, 3H), 1.40 (d, 3H, J =

6.8 Hz), 1.34 (ddd, 1H, J = 13.7, 12.0, 5.1 Hz), 1.15 (ddd, 1H, J =

13.4, 8.3, 8.3 Hz), 0.94 (d, 3H, J = 6.6 Hz), 0.88 (s, 9H), 0.03 (s, 6H);

¹³C NMR (100 MHz, CDCl₃) δ 156.1, 137.1, 128.4, 127.8, 127.7, 66.5,

62.9, 53.1, 48.3, 39.2, 35.1, 29.9, 28.0, 25.9, 24.3, 22.9, 22.2, 18.3, −5.3,

FAB-HRMS m/z calcd for C₂₄H₄₂NO₃Si [M + H]⁺420.2934, found

420.2928.

(2R,4S,6R)-(−)-N-Benzoxycalboyl-4,6-dimethyl-2-hydroxy-

propylpiperidine. To a solution of (−)-48 (65 mg, 0.155 mmol)

in tetrahydrofurane (1.0 mL) was added 2N aqueous HCl solution

(0.5 mL) at 0 °C. After the mixture was stirred at room temperature

for 1 h, saturated aqueous NaHCO₃solution was added, and the resulting

mixture was extracted with ether. The organic layers were combined,

washed with brine, dried over MgSO₄, filtered and concentrated in

vacuo to give the crude products which were purified by column

chromatography on silica gel (gradually from 25 to 50% ethyl acetate

in hexane) to give alcohol (47 mg, 100%) as a colorless oil: [α]²³

D

−23.2 (c = 0.4, CHCl₃); IR (neat, cm⁻¹) 3414(br), 1686, 1454, 1412,

1310, 1268, 1063; ¹H NMR (400 MHz, CDCl₃) δ 7.35−7.28 (m, 5H),

5.13 (d, 1H, J = 12.4 Hz), 5.08 (d, 1H, J = 12.4 Hz), 4.16 (ddq, 1H, J =

7.3, 5.1, 2.4 Hz), 3.70−3.63 (m, 1H), 3.63 (t, 2H, J = 6.1 Hz), 1.93−

1.74 (m, 3H), 1.66 (ddd, 1H, J = 15.9, 5.4, 2.4 Hz), 1.59−1.45 (m,

3H), 1.38 (d, 3H, J = 6.8 Hz), 1.42−1.35 (m, 1H), 1.17 (ddd, 1H, J =

13.7, 7.3, 7.3 Hz), 0.96 (d, 3H, J = 6.6 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 156.2, 137.0, 128.4, 127.8, 127.8, 66.6, 62.3, 52.6, 48.2, 38.4,

34.4, 29.4, 28.2, 23.7, 23.1, 22.3; FAB-HRMS m/z calcd for

C₁₈H₂₈NO₃[M + H]⁺306.2069, found 306.2071.

(2R,4S,6S)-(−)-N-Benzyzoxycalboyl-2-(3-tert-butyldimethyl-

silyloxypropyl)-4-hydroxymethyl-6-methylpiperidine (−)-51. A

solution of (−)-46 (509 mg, 1.07 mmol) and Pd(OH)₂/C (100 mg)

in methanol (5.0 mL) was stirred in an autoclave under 10

atmospheric pressure of hydrogen at room temperature for 12 h.

Then the catalyst was removed by filtration and the filtrate was

concentrated in vacuo to give crude products. The crude product was

protected without further purification.

(2R,4S,6R)-(−)-N-Benzoxycalboyl-4,6-dimethyl-3-methyles-

terpropylpiperidine (−)-49. To a solution of alcohol obtained

above (47 mg, 0.154 mmol) in acetone (1 mL) was added 2.67 N

Jones reagent at 0 °C. After the reaction mixture was stirred for 2 h at

room temperature, brine was added, and the resulting mixture was

extracted with ethyl acetate. The organic layers were combined,

washed with 10% NaHSO₃solution and brine, dried over MgSO₄,

filtered, and concentrated in vacuo to give the crude products. The

crude product was esterification without further purification.

To a solution of the crude carboxylic acid obtained above in ethyl

acetate (1 mL) was added diazomethane prepared from nitro-

somethylurea (242 mg, 0.385 mmol), 30% aqueous NaOH solution

(1.35 mL) and ether (5.0 mL) at 0 °C. After the reaction mixture was

stirred for 30 min at 0 °C, saturated NH₄Cl solution was added, and

the resulting mixture was extracted with ethyl acetate. The organic

layers were combined, washed with brine, dried over MgSO₄, filtered

and concentrated in vacuo to give the crude products which were

purified by column chromatography on silica gel (gradually from 6 to

9% ethyl acetate in hexane) to give methyl ester (−)-49 (32 mg, 63%

for 2 steps) as a colorless oil: [α]²³_D−24.9 (c = 0.4, CHCl₃); IR (neat,

cm⁻¹) 1738, 1705, 1454, 1412, 1307, 1262, 1170, 1061; ¹H NMR (400

MHz, CDCl₃) δ7.35−7.28 (m, 5H), 5.11 (d, 1H, J = 12.2 Hz), 5.08 (d,

1H, J = 12.2 Hz), 4.21 (dqd, 1H, J = 9.0, 6.6, 2.9 Hz), 3.62 (s, 3H),

3.58 (dddd, 1H, J = 13.7, 10.2, 6.8, 3.7 Hz), 2.31 (t, 2H, J = 7.8 Hz),

2.15−2.03 (m, 1H), 1.91−1.71 (m, 3H), 1.63 (ddd, 1H, J = 13.2, 4.6,

2.2 Hz), 1.39 (d, 3H, J = 6.8 Hz), 1.35 (ddd, 1H, J = 13.9, 12.2, 5.4

Hz), 1.15 (ddd, 1H, J = 13.4, 8.5, 8.5 Hz), 0.94 (d, 3H, J = 6.8 Hz);

¹³C NMR (100 MHz, CDCl₃) δ 173.8, 156.1, 137.0, 128.4, 127.8,

To a solution of the crude piperidine obtained above in

tetrahydropyrane (5.5 mL) and H₂O (5.5 mL) was added K₂CO₃

(1.48 g, 10.7 mmol) and carbobenzoxy chloride (0.38 mL, 2.14 mmol)

at 0 °C. After the mixture was stirred at 0 °C for 2 h, H₂O was added,

and the resulting mixture was extracted with ether. The organic layers

were combined, washed with brine, dried over MgSO₄, filtered and

concentrated in vacuo to give the crude products which was purified by

column chromatography on silica gel (gradually from 20 to 50% ethyl

acetate in hexane) to give (−)-51 (323 mg, 69%) as a colorless oil:

[α]²³_D−6.1 (c = 1.0, CHCl₃); IR (neat, cm⁻¹) 3457(br), 1694, 1414,

1

1327, 1254, 1100; H NMR (400 MHz, acetone-d₆) δ7.41−7.28 (m,

5H), 5.11 (m, 2H), 4.49−4.42 (m, 1H), 4.28−4.23 (m, 1H), 3.62−

3.61 (m, 2H), 3.40 (d, 2H, J = 5.8 Hz), 2.06−1.97 (m, 2H), 1.82−1.79

(m, 1H), 1.68−1.40 (m, 4H), 1.32−1.17 (m, 2H), 1.21 (d, 3H, J = 7.1

Hz), 0.89 (s, 9H), 0.04(s, 6H); ¹³C NMR (100 MHz, acetone-d₆) δ

156.0, 138.5, 129.2, 128.5, 67.9, 67.1, 63.5, 51.5, 47.0, 34.4, 32.7, 32.0,

31.5, 28.8, 26.3, 21.3, 18.8, −5.1; ESI HRMS m/z calcd for

C₂₄H₄₁NNaO₄Si [M + Na]⁺458.2703, found 458.2687.

(2R,4S,6S)-(−)-N-Benzoxycalboyl-2-(3-tert-butyldimethylsily-

loxypropyl)-4,6-dimethylpiperidine (−)-52. To a solution of

(−)-51 (323 mg, 0.741 mmol) in dichloromethane (4.0 mL) was

added triethylamine (0.411 mL, 2.966 mmol), carbon tetrabromide

(737 mg, 2.22 mmol) and triphenylphosphine (778 mg, 2.966 mmol)

at 0 °C and stirred continued for an additional 5 min. After the

mixture was stirred at room temperature for 2 h, hexane was added,

the resulting precipitate was filtered, and the filtrate was concentrated

in vacuo to give crude products which was purified by column

chromatography on silica gel (gradually from 2 to 5% ethyl acetate in

hexane) to give the bromide derivative (293 mg, 79%) as a yellow oil.

To a solution of bromide derivative obtained above (293 mg, 0.588

mmol) in dimethylsulfoxide (3.0 mL) was added sodium borohydride

(89 mg, 2.35 mmol) at room temperature. After the mixture was

stirred at 90 °C for 1 h, H₂O was added, and the resulting mixture was

127.8, 66.6, 52.8, 51.5, 48.6, 39.1, 35.4, 31.3, 26.9, 24.7, 22.8, 22.0;

FAB-HRMS m/z calcd for C₁₉H₂₈NO₄[M + H]⁺334.2018, found

334.2015.

(5R,7S,8aR)-(−)-5,7-Dimethylindolizidine-3-one (−)-50. To a

solution of methylester (−)-49 (84 mg, 0.252 mmol) in methanol (1

mL) was added Pd/C (25 mg) at a room temperature. After the

reaction mixture was stirred under H₂atmosphere for 2 h, the catalyst

was removed by filtration and the filtrate was concentrated in vacuo to

give crude products. The crude product was reduced without further

purification.

1829

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

extracted with ether. The organic layers were combined, washed with

brine, dried over MgSO₄, filtered and concentrated in vacuo to give the

crude products which was purified by column chromatography on

silica gel (3% ethyl acetate in hexane) to give (−)-52 (180 mg, 73%)

as a colorless oil: [α]²³_D−2.4 (c = 0.2, CHCl₃); IR (neat, cm⁻¹) 1696,

1460, 1412, 1323, 1101; ¹H NMR (400 MHz, acetone-d₆) δ7.41−7.28

(m, 5H), 5.14−5.08 (m, 2H), 4.44−4.38 (m, 1H), 4.22−4.17 (m, 1H),

3.61 (m, 2H), 2.06−2.04 (m, 1H), 2.01−1.89 (m, 1H), 1.70−1.37 (m,

5H), 1.28−1.09 (m, 2H), 1.20 (d, 3H, J = 6.8 Hz), 0.92 (d, 3H, J = 6.4

Hz), 0.89 (s, 9H), 0.04 (s, 6H); ¹³C NMR (100 MHz, acetone-d₆) δ

156.1, 138.5, 129.2, 128.5, 67.1, 63.5, 51.8, 47.3, 39.8, 37.3, 32.7, 31.6,

26.3, 22.6, 21.3, 20.5, 18.8, −5.1. ESI HRMS m/z calcd for

C₂₄H₄₁NNaO₃Si [M + Na]⁺442.2753, found 442.2747.

(2R,4S,6S)-(−)-N-Benzoxycalboyl-4,6-dimethyl-3-methyles-

terpropylpiperidine (−)-53. To a solution of (−)-52 (165 mg,

0.393 mmol) in tetrahydrofurane (2.0 mL) was added 2N aqueous

HCl solution (1.0 mL) at 0 °C. After the mixture was stirred at room

temperature for 1 h, saturated aqueous NaHCO₃solution was added,

and the resulting mixture was extracted with ether. The organic layers

were combined, washed with brine, dried over MgSO₄, filtered and

concentrated in vacuo to give the crude products which was purified by

column chromatography on silica gel (gradually from 25 to 50% ethyl

acetate in hexane) to give alcohol as a colorless oil.

(+)-5-Epidendroprimine (55). To a solution of indoridizine

(−)-54 (17 mg, 0.102 mmol) in ether (2 mL) was added lithium

aluminum hydride (14 mg, 0.369 mmol) at 0 °C. After the reaction

mixture was refluxed for 6 h, ice was slowly added, and the resulting

mixture was extracted with dichloromethane. The organic layers were

combined, dried over MgSO₄, filtered and concentrated in vacuo to

give the crude products which were purified by column chromatog-

raphy on reverse phase silica gel (9% trimethylamine in methanol) to

give (+)-5-epidendroprimine (55) (10 mg, 67%) as a yellow oil:

[α]²⁵_D46.0 (c = 0.3, CHCl₃); IR (neat, cm⁻¹) 1460, 1377, 1325, 1125;

¹H NMR (400 MHz, CDCl₃) δ3.23 (td, 1H, J = 8.5, 2.0 Hz), 2.30−

2.22 (m, 1H), 2.15−1.97 (m, 3H), 1.82−1.33 (m, 8H), 1.07 (d, 3H,

J = 6.1 Hz), 1.00 (d, 3H, J = 7.3 Hz); ¹³C NMR (100 MHz, CDCl₃)

δ58.5, 53.3, 51.6, 40.3, 36.9, 30.7, 26.8, 21.2, 20.3, 18.8; ESI HRMS m/z

calcd for C₁₀H₂₀N [M + H]⁺154.1596, found 154.1589.

(1S,2R)-(−)-cis-1-[(2R,4R,6S)-2-(1-tert-Butyldimethylsiloxy-

propenyl)-4,6-dimethylpiperidin-1-yl]-7-isopropylindan-2-ol

(−)-64. To a solution of compound (−)-37 (168 mg, 0.379 mmol) in

ether (3.8 mL) was added a 1.0 M solution of methylmagnesium

iodide in ether (1.90 mL, 1.90 mmol) prepared from methyl iodide

(1.24 mL, 19.9 mmol), magnesium turning (440 mg, 18.1 mmol), and

ether (18.1 mL) at 0 °C. After the mixture was stirred at room

temperature for 2 h, H₂O was added, and the resulting mixture was

extracted with ether. The organic layers were combined, washed with

brine, dried over MgSO₄, filtered and concentrated in vacuo to give a

1:1 mixture. These isomers were successfully separated by column

chromatography on silica gel (from 3 to 5% ethyl acetate in hexane) to

give the piperidine compound (−)-64 (71 mg, 41%) as a colorless oil:

To a solution of alcohol obtained above (115 mg, 0.377 mmol) in

acetone (2 mL) was added 2.67 N Jones reagent at 0 °C. After the

reaction mixture was stirred for 2 h at room temperature, brine was

added, and the resulting mixture was extracted with ethyl acetate. The

organic layers were combined, washed with 10% NaHSO₃solution and

brine, dried over MgSO₄, filtered, and concentrated in vacuo to give

the crude products. The crude product was esterification without

further purification.

[α]²³−28.3 (c = 0.8 CHCl₃); IR (neat, cm⁻¹) 3209, 1589, 1458,

D

1

1385, 1254, 1090; H NMR (400 MHz, CDCl₃) δ 7.21 (dd, 1H, J =

7.6, 7.6 Hz), 7.12 (d, 1H, J = 7.6 Hz), 6.99 (d, 1H, J = 7.3 Hz), 4.52 (d,

1H, J = 8.9 Hz), 4.35−4.29 (m, 1H), 3.37 (dd, 1H, J = 17.2, 8.7 Hz),

3.14−2.84 (m, 6H), 2.44−2.37 (m, 1H), 1.87 (ddd, 1H, J = 12.8, 6.4,

3.2 Hz), 1.75 (ddd, 1H, J = 13.5, 6.4, 3.2 Hz), 1.47−1.37 (m, 1H), 1.38

(d, 3H, J = 6.9 Hz), 1.22 (d, 3H, J = 6.0 Hz), 1.17−1.09 (m, 1H), 1.12

(d, 3H, J = 6.9 Hz), 1.05−0.96 (m, 1H), 0.91 (d, 3H, J = 6.4 Hz),

0.88−0.73 (m, 3H), 0.82 (s, 9H), 0.81 (d, 3H, J = 6.1 Hz), 0.59−0.48

(m, 1H), 0.07 (s, 3H), 0.06 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ

146.8, 142.4, 137.7, 129.0, 122.9, 122.7, 67.5, 67.4, 63.0, 58.9, 55.8,

44.2, 42.4, 41.3, 33.4, 31.8, 29.3, 29.0, 26.0, 24.8, 24.0, 22.1, 21.9, 18.3,

−5.3; ESI HRMS m/z calcd for C₂₈H₄₉NO₂Si [M + H]⁺460.3611,

found 460,3603.

(2R,4R,6S)-(+)-N-Benzyloxycalboyl-4,6-dimethyl-2-hydroxy-

propylpiperidine (+)-65. A solution of (−)-64 (204 mg, 0.44

mmol) and Pd(OH)₂/C (57 mg) in methanol (2.7 mL) was stirred in

an autoclave under 10 atmospheric pressure of hydrogen at room

temperature for 12 h. Then the catalyst was removed by filtration and

the filtrate was concentrated in vacuo to give crude products. The

crude product was reduced without further purification.

To a solution of the crude piperidine obtained above in

tetrahydrofurane (2.2 mL) and H₂O (2.2 mL) was added K₂CO₃

(600 mg, 4.45 mmol) and carbobenzoxy chloride (0.16 mL, 0.89

mmol) at 0 °C. After the mixture was stirred at 0 °C for 1 h, H₂O was

added, and the resulting mixture was extracted with ether. The organic

layers were combined, washed with brine, dried over MgSO₄, filtered

and concentrated in vacuo to give the crude products which were

purified by column chromatography on silica gel (gradually from 2 to

3.3% ethyl acetate in hexane) to give the Cbz compound (177 mg,

95%) as a colorless oil.

To a solution of the crude carboxylic acid obtained above in ethyl

acetate (2 mL) was added diazomethane prepared from nitro-

somethylurea (242 mg, 0.385 mmol), 30% aqueous NaOH solution

(1.25 mL) and ether (5.0 mL) at 0 °C. After the reaction mixture was

stirred for 30 min at 0 °C, saturated NH₄Cl solution was added, and

the resulting mixture was extracted with ethyl acetate. The organic

layers were combined, washed with brine, dried over MgSO₄, filtered

and concentrated in vacuo to give the crude products which were

purified by column chromatography on silica gel (gradually from 6 to

9% ethyl acetate in hexane) to give methyl ester (−)-53 (88 mg, 67%

for 3 steps) as a colorless oil: [α]²³_D−2.8 (c = 0.8, CHCl₃); IR (neat,

1

cm⁻¹) 1738, 1691, 1412, 1323, 1271, 1099; H NMR (400 MHz,

acetone-d₆) δ7.41−7.29 (m, 5H), 5.15 (d, 1H, J = 12.7 Hz), 5.07 (d,

1H, J = 12.7 Hz), 4.46−4.39 (m, 1H), 4.23 (m, 1H), 3.58 (s, 3H),

2.38−2.20 (m, 2H), 2.06−1.86 (m, 3H), 1.69−1.65 (m, 1H), 1.59−

1.55 (m, 1H), 1.29−1.13 (m, 2H), 1.21 (d, 3H, J = 7.1 Hz), 0.92 (d,

3H, J = 6.3 Hz); ¹³C NMR (100 MHz, acetone-d₆) δ 173.7, 156.1,

138.4, 129.2, 128.6, 67.2, 51.5, 51.3, 47.3, 39.6, 37.3, 32.3, 31.3, 22.5,

21.3, 20.5; ESI HRMS m/z calcd for C₁₉H₂₇NNaO₄[M + Na]⁺

356.1838, found 356.1852.

(5S,7S,8aR)-(−)-5,7-Dimethylindolizidine-3-one (−)-54. To a

solution of methylester (−)-53 (46 mg, 0.138 mmol) in methanol (1

mL) was added Pd/C (15 mg) at a room temperature. After the

reaction mixture was stirred under H₂atmosphere for 1 h, the catalyst

was removed by filtration and the filtrate was concentrated in vacuo to

give crude products. The crude product was reduced without further

purification.

After solution of the crude amine obtained above in toluene (1 mL)

was refluxed for 3 h, the reaction mixture was concentrated in vacuo to

give the crude products which were purified by column chromatog-

raphy on silica gel (ethyl acetate) to give indoridizine (−)-54 (17 mg,

To a solution of piperidine derivative obtained above in

tetrahydrofurane (2.0 mL) was added 2N aqueous HCl solution

(1.0 mL) at room temperature. After the mixture was stirred at room

temperature for 2 h, saturated aqueous NaHCO₃solution was added,

and the resulting mixture was extracted with ether. The organic layers

were combined, washed with brine, dried over MgSO₄, filtered and

concentrated in vacuo to give the crude products which were purified

by column chromatography on silica gel (gradually from 25 to 50%

ethyl acetate in hexane) to give (+)-65 (95 mg, 74%) as a colorless oil:

[α]²⁴_D7.08 (c = 0.28, CHCl₃); IR (neat, cm⁻¹) 3441(br), 1690, 1456,

74% for 2 steps) as a colorless oil: [α]²⁴9.77 (c = 0.6, CHCl₃); IR

D

1

(neat, cm⁻¹) 1686, 1414, 1377, 1312, 1275; H NMR (400 MHz,

CDCl₃) δ3.79−3.71 (m, 1H), 3.66−3.59 (m, 1H), 2.34−2.29 (m, 2H),

2.18−2.05 (m, 2H), 1.64−1.55 (m, 3H), 1.51−1.44 (m, 2H), 1.42 (d,

3H, J = 6.6 Hz), 1.04 (d, 3H, J = 7.1 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 174.7, 53.1, 46.2, 38.1, 37.5, 31.7, 26.7, 23.4, 20.6, 19.8; ESI

HRMS m/z calcd for C₁₀H₁₇NNaO [M + Na]⁺190.1208, found

190.122.

1

1416, 1321, 1098, 1007; H NMR (400 MHz, CDCl₃) δ 7.38−7.28

1830

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

(m, 5H), 5.16−5.09 (m, 2H), 4.28−4,14 (m, 2H), 3.64−3.61 (m, 2H),

2.17−2.10 (m, 1H), 1.95−1.88 (m, 1H), 1.78−1.71 (m, 1H), 1.61−

1.44 (m, 4H), 1.23 (d, 3H, J = 6.6 Hz), 1.08−0.94 (m, 2H), 0.92 (d,

3H, J = 6.6 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 156.4, 137.0, 128.4,

127.8, 127.7, 66.9, 62.5, 50.7, 48.4, 38.2, 37.1, 36.2, 29.1, 26.2, 23.9,

21.7; ESI HRMS m/z calcd for C₁₈H₂₇NNaO₃[M + Na]⁺328.1889,

found 328.1880.

(2R,4S,6S)-(+)-N-Benzyzoxycalboyl-4,6-dimethyl-2-methyl-

esterpropylpiperidine (+)-66. To a solution of (+)-65 (95 mg,

0.311 mmol) in acetone (2 mL) was added 2.67 N Jones reagent at 0 °C.

After the reaction mixture was stirred for 1 h at room temperature,

brine was added, and the resulting mixture was extracted with ethyl

acetate. The organic layers were combined, washed with 10% NaHSO₃

solution and brine, dried over MgSO₄, filtered, and concentrated in

vacuo to give the crude products. The crude product was reduced

without further purification.

ASSOCIATED CONTENT

■

S

* Supporting Information

1

Copies of H and ¹³C NMR spectra. This material is available

free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author

*Katsumura@kwansei.ac.jp; tkoba@toyaku.ac.jp

■

Present Addresses

^‡School of Life Sciences, Tokyo University of Pharmacy and Life

Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192−0392, Japan

^§Department of Chemistry, Graduate School of Science, Osaka

University, 1-1 Machikaneyama, Toyonaka, Osaka 560−0043,

Japan

To a solution of the crude carboxylic acid obtained above in ethyl

acetate (1.7 mL) was added diazomethane prepared from nitro-

somethylurea (80 mg, 0.778 mmol), 30% aqueous NaOH solution

(0.3 mL) and ether (1.7 mL) at 0 °C. After the reaction mixture was

stirred for 30 min at 0 °C, saturated NH₄Cl solution was added, and

the resulting mixture was extracted with ethyl acetate. The organic

layers were combined, washed with brine, dried over MgSO₄, filtered

and concentrated in vacuo to give the crude products. Column

chromatography on silica gel (gradually from 6 to 9% ethyl acetate in

hexane) to give methyl ester (+)-66 (80 mg, 78% for 2 steps) as a

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENTS

■

We thank Mr. Tamotsu Yamamoto at the Institute for Life

Science Research at Asahi Chemical Industry Co., Ltd., for his

X-ray crystallographic measurements. This work was financially

supported by a Grant-in-Aid for Science Research on Priority

Areas 16073222 from the Ministry of Education, Culture,

Sports, Science and Technology, Japan, and JSPS (Research

Fellowship for T.K.).

colorless oil: [α]²⁴10.6 (c = 1.2, CHCl₃); IR (neat, cm⁻¹) 1738,

D

1692, 1456, 1412, 1319, 1172, 1096, 1015; ¹H NMR (400 MHz,

CDCl₃) δ7.38−7.29 (m, 5H), 5.12 (d, 1H, J = 12.6 Hz), 5.09 (d, 1H,

J = 12.6 Hz), 4.30−4.23 (m, 1H), 4.21−4.13 (m, 1H), 3.62 (s, 3H),

2.39−2.26 (m, 2H), 2.18−2.10 (m, 1H), 2.00−1.87 (m, 2H), 1.84−

1.75 (m, 1H), 1.58−1.45 (m, 1H), 1.23 (d, 3H, J = 6.6 Hz), 1.11−1.02

(m, 1H), 0.98−0.90 (m, 1H), 0.92 (d, 3H, J = 6.6 Hz); ¹³C NMR (100

MHz, CDCl₃) δ 173.7, 156.4, 136.9, 128.5, 127.8, 127.7, 67.0, 51.6,

50.2, 48.7, 38.0, 36.9, 34.7, 31.1, 26.2, 23.6, 21.7; ESI HRMS m/z calcd

for C₂₄H₄₁NO₃Si [M + Na]⁺356.1838, found 356.1838.

REFERENCES

■

(1) Dendroprimine: (a) Luning, B.; Leander, K. Acta Chem. Scand.

1965, 19, 1607. (b) Luning, B.; Lundin, C. Acta Chem. Scand. 1967,

21, 2136. (c) Blomquist, L.; Leander, K.; Luning, B.; Rosenblom. J.

Acta Chem. Scand. 1972, 26, 3203 Hippodamine: (d) Tursch, B.;

Daloze, D.; Pasteels, J. M.; Caravador, A.; Braekman, J. C.; Hootele,

C.; Zimmermann, D. Bull. Soc. Chim. Belg. 1972, 81, 649. (e) Tursch,

B.; Daloze, D.; Braekman, J. C.; Hootele, C.; Caravador, A.; Losman,

D.; Karlsson, R. Tetrahedron Lett. 1974, 409. Uleine: (f) Bosch, J.;

Bonjoch, J. Pentacyclic Strychnos Indole Alkaloids. In Studies in

Natural Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amster-

dam, 1988; Vol. 1, pp 31−88. Guettardine: (g) Brillanceau, M. H.;

Kan-Fan, S.; Husson, H. −P. Tetrahedron Lett. 1984, 26, 2767.

Protometine: (h) Battersby, A. R.; Davidson, G. C.; Harper, B. J. T.

Chem. Ind. 1957, 983. (i) Battersby, A. R.; Harper, B. J. T. J. Chem. Soc.

1959, 1748.

(+)-5,7-Epidendroprimine. To a solution of methylester (+)-66

(80 mg, 0.240 mmol) in methanol (1.2 mL) was added Pd/C (30 mg)

at a room temperature. After the reaction mixture was stirred under H₂

atmosphere for 1 h, the catalyst was removed by filtration and the

filtrate was concentrated in vacuo to give crude products. The crude

product was reduced without further purification.

After solution of the crude amine obtained above in toluene (2.0

mL) was refluxed for 5 h, the reaction mixture was concentrated in

vacuo to give the crude products which were purified by column

chromatography on silica gel (ethyl acetate) to give indorizidinone (14

mg, 35% for 2 steps) as a colorless oil: [α]²²_D+63.7 (c = 0.4, CHCl₃);

(2) Review of piperidine synthesis was recently reported: (a) Buffat,

M. G. P. Tetrahedron 2004, 60, 1701. (b) Escolano, C.; Amat, M.;

Bosch, J. Chem.Eur. J. 2006, 12, 8189. (c) Amat, M.; Perez, M.;

Bosch, J. Synlett 2011, 143.

1

IR (neat, cm⁻¹) 1694, 1458, 1412, 1377, 1262; H NMR (400 MHz,

CDCl₃) δ3.34−3.26 (m, 1H), 3.24−3.15 (m, 1H), 2.39−2.25 (m, 2H),

2.13−2.05 (m, 1H), 1.80 (ddd, 1H, J = 12.8, 2.1, 2.1 Hz), 1.67 (d, 3H,

J = 6.6 Hz), 1.62−1.46 (m, 3H), 1.01−0.83 (m, 2H), 0.95 (d, 3H, J =

6.4 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 175.7, 59.9, 52.7, 43.6, 41.5,

32.2, 30.7, 25.2, 21.8, 19.8; ESI-HRMS m/z calcd for C₁₀H₁₈NNaO

[M + Na]⁺190.1208, found 190.1209.

(3) (a) Poupon, E.; Francois, D.; Kunesch, N.; Husson, H.-P. J. Org.

Chem. 2004, 69, 3836. (b) Goodenough, K. M.; Moran, W. J.; Raubo,

P.; Harrity, P. A. J. Org. Chem. 2005, 70, 207. (c) Monfray, J.; Gelas-

Mialhe, Y.; Gramain, J.-C.; Remuson, R. Tetrahedron: Asymmetry 2005,

16, 1025. (d) Dobbs, A. P.; Guesne, S. J. Synlett 2005, 18, 2101.

(e) Passarella, D.; Barilli, A.; Belinghieri, F.; Fassi, P.; Riva, S.;

Sacchetti, A.; Silvani, A.; Danieli, B. Tetrahedron: Asymmetry 2005, 16,

2225. (f) Gebauer, J.; Blechert, S. Synlett 2005, 18, 2826. (g) Wung,

R. P.; Fu, G. C. S. J. Am. Chem. Soc. 2005, 127, 12234. (h) Sales, M.;

Charette, A. B. Org. Lett. 2005, 7, 5773. (i) Pattenden, L. C.; Wybrow,

R. A. J.; Smith, S. A.; Harrity, J Org. Lett. 2006, 8, 3089. (j) Terada, M.;

Machioka, K.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 10336.

(k) Sarkar, N.; Banerjee, A.; Nelson, S. G. J. Am. Chem. Soc. 2008, 130,

9222. (l) Hayashi, Y.; Gotoh, H.; Masui, R.; Ishikawa, H. Angew.

Chem., Int. Ed. 2008, 47, 4012. (m) Ahari, M.; Perez, A.; Menant, C.;

Vasse, J.-L.; Szymoniak, J. Org. Lett. 2008, 10, 2473. (n) Fernandez-

To a solution of indorizidinone obtained above (14 mg, 0.084

mmol) in ether (1.3 mL) was added lithium aluminum hydride (5 mg,

0.132 mmol) at 0 °C. After the reaction mixture was refluxed for 2 h,

ice was slowly added, and the resulting mixture was extracted with

dichloromethane. The organic layers were combined, dried over

MgSO₄, filtered and concentrated in vacuo to give (+)-5,7-

epidendroprimine (11 mg, 86%) as a yellow oil: [α]²³+53.7 (c =

D

1

0.2, CHCl₃); IR (neat, cm⁻¹) 1456, 1373, 1205, 1043; H NMR (400

MHz, CDCl₃) δ3.22 (td, 1H, J = 8.7, 2.1 Hz), 2.07−1.42 (m, 9H),

1.32−1.25 (m, 1H), 1.10 (d, 3H, J = 6.2 Hz), 1.01−0.87 (m, 2H), 0.93

(d, 3H, J = 6.6 Hz); ¹³C NMR (100 MHz, CDCl₃) δ64.7, 58.1, 51.4,

43.2, 39.6, 31.4, 30.4, 22.0, 21.0, 20.7; ESI-HRMS m/z calcd for

C₁₀H₂₀N [M + H]⁺154.1596, found 154.1598.

Ibanez, M. A.; Maci_a, B.; Pizzuti, M. G.; Minnaard, A. J.; Feringa,

̃

B. L. Angew. Chem., Int. Ed. 2009, 48, 9339. (o) Chen, M. Z.; Micalizio,

G. C. Org. Lett. 2009, 11, 4982. (p) McLaughlin, N. P.; Evans, P.

1831

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

The Journal of Organic Chemistry

Article

J. Org. Chem. 2010, 75, 518. (q) Jarvis, S. B. D.; Charette, A. B. Org. Lett.

2011, 13, 3830.

(4) For examples: (a) Hirai, Y.; Terada, T.; Okaji, Y.; Yamazaki, T.;

Momose, T. Tetrahedron Lett. 1990, 33, 4775. (b) Amat, M.; Perez,

M.; Llor, N.; Escolano, C.; Luque, F. F.; Molins, E.; Bosch, J. J. Org.

Chem. 2004, 69, 8681.

(17) In this reaction, the β-isomer was converted into the

corresponding methyl ester.

(18) Suginome, H.; Umeda, H.; Masamune, T. Tetrahedron Lett.

1970, 11, 4571.

(19) Reduction and alkylation of aminoacetal. See: (a) Yamato, M.;

Hashigaki, K.; Ishikawa, S.; Qais, N. Tetrahedron Lett. 1988, 29, 6949.

(b) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron Lett. 1992,

33, 235. (c) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetraahedron

1994, 50, 1083. (d) Higashiyama, K.; Nakahata, K.; Takahashi, H. J.

Chem. Soc., Perkin. Trans. 1 1994, 351. (e) Higashiyama, K.; Kyo, H.;

Takahashi, H. Synlett 1998, 489. (f) Husson, H.-P.; Royer. J. Chem.

Soc. Rev. 1999, 28, 383.

(5) (a) Tanaka, K.; Katsumura, S. J. Am. Chem. Soc. 2002, 124, 9660.

(b) Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem.

2004, 69, 5906.

For review, see: (c) Tanaka, K.; Fukase, K.;

Katsumura, S. The Chemical Record 2010, 10, 119.

(6) Kobayashi, T; Tanaka, K.; Miwa, J.; Katsumura, S. Tetrahedron:

Asymmetry 2004, 15, 185.

(20) The similar neighboring group participation by a hydroxyl group

was observed in the highly stereoselective conjugated addition reaction

with ethylmagnesium bromide to the unsaturated ester moiety of

alcohol D to give the corresponding 2,3,4-trisubstituted piperidine E.¹¹

(21) Bollena, A. D. S.; Gelas-Mialhe, Y.; Gramain, J.-C.; Perret, A.;

Remuson, R. J. Nat. Prod. 2004, 67, 1029.

(22) (a) Diederich, M.; Nubbrmeyer, U. Synthesis 1999, 2, 286.

(b) Hsu, R.-T.; Cheng, L.-M.; Chang, N.-C.; Tai, H.-M. J. Org. Chem.

2002, 67, 5044.

(23) Ueno, Y.; Tanaka, C.; Okawara, M. Chem. Lett. 1983, 795.

(24) Herradon, B.; Sanchez-Sancho, F. Tetrahedron: Asymmetry 1998,

9, 1951.

(25) The aluminium alkoxide generated from the 4-hydroxymethyl

group would be far from the racted iminium ion. On the contrary, the

aluminium alkoxide generated from the aminoacetal would be close

enough to attack to the iminium ion to selectively produce the β-

isomer.

(7) Recently, Hsung and co-workers also reported the asymmetric

azaelectrocyclization, see: (a) Wei, L.-L.; Hsung, R. P.; Xiong, H.;

Mulder, J. A.; Nkansah, N. T. Org. Lett. 1999, 1, 2145. (b) Sklenicka,

H. M.; Hsung, R. P.; McLaughlin, M. J.; Wei., L.-L.; Gerasyuto, A. l.;

Brennessel, W. W. J. Am. Chem. Soc. 2002, 124, 10435. (c) Sydorenko,

N.; Hsung, R. P.; Vera, E. L. Org. Lett. 2006, 8, 2614. They also

applied this reaction toward alkaroid synthesis. See: (d) Hsung, R. P.;

Wei, L.-L.; Sklenicka, H. M.; Douglas, C. J.; McLaughlin, M. J.;

Mulder, J. A.; Yao, L. J. Org. Lett. 1999, 1, 509. (e) Sklenicka, H. M.;

Hsung, R. P.; Wei, L.-L.; McLaughlin, M. J.; Gerasyuto, A. I.; Degen,

S. J. Org. Lett. 2000, 2, 1161. (f) Sklenicka, H. M.; Hsung, R. P.;

McLaughlin, M. J.; Wei, L.-L.; Gerasyuto, A. I.; Brennessel, W. B.

J. Am. Chem. Soc. 2002, 124, 10435. (g) McLaughlin, M. J.; Hsung,

R. P.; Cole, K. P.; Hahn, J. M.; Wang, J. Org. Lett. 2002, 4, 2017. (h) Luo,

S.; Zificsak, C. A.; Hsung, R. P. Org. Lett. 2003, 5, 4709. (i) Sydorenko,

N.; Hsung, R. P.; Darwish, O. S.; Hahn, J. M.; Liu, J. J. Org. Chem. 2004,

69, 6732.

(26) Hutchins, R. O.; Kandasamy, D.; Dux, F. III; Maryanoff, C. A.;

Rotstein, D.; Goldsmith, B.; Burgoyne, W.; Cistone, F.; Dalessandro,

J.; Puglis, J. J. Org. Chem. 1978, 43, 2259.

(8) (a) Tanaka, K.; Mori, H.; Fujii, S.; Ikeda, M.; Itagaki, Y.;

Katsumura, S. Tetrahedron Lett. 1998, 39, 1185. (b) Tanaka, K.;

Kamatani, M.; Mori, H.; Fujii, S.; Ikeda, K.; Hisada, M.; Itagaki, Y.;

Katsumura, S. Tetrahedron 1999, 55, 1657. (c) Tanaka, K.; Katsumura,

S. J. Synth. Org. Chem. Jpn. 1999, 57, 876.

(27) Both enantiomers 55 and ent-55 were synthesized and reported

their optical rotations.²¹

(9) (a) Tanaka, K.; Katsumura, S. Org. Lett. 2000, 2, 373. (b) Tanaka,

K.; Mori, H.; Yamamoto, M.; Katsumura, S. J. Org. Chem. 2001, 66,

3099.

(10) Kobayashi, T.; Nakashima, M.; Hakogi, T.; Tanaka, K.;

Katsumura, S. Org. Lett. 2006, 8, 3809.

(11) Sakaguchi, T.; Kobayashi, S.; Katsumura, S. Org. Biomol. Chem.

2011, 9, 257.

(12) (a) Kobayashi, T.; Takeuchi, K.; Miwa, J.; Tsuchikawa, H.;

Katsumura, S. Chem. Commun. 2009, 3363. (b) Li, Y.; Kobayashi, T.;

Katsumura, S. Tetrahedron Lett. 2009, 50, 4482.

(13) Preliminary communication: Kobayashi, T.; Hasegawa, F.;

Tanaka, K.; Katsumura, S. Org. Lett. 2006, 8, 3813.

(14) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;

Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C.

J. Comput. Chem. 1990, 11, 440−467.

(15) Although further optimization of the MMFF structure 12a by a

B3LYP/6-31G(d) level using Gaussian 03¹⁶did not give the energy

minima, that of the analog (−)-1a, the C-2 Ph derivative, gave the very

similar structure to the structure 12a in Figure 3 (see Supporting

Information).

(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;

Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.

Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; illam, J. M.; Daniels,

A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.;

Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford,

S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.;

Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;

Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.;

Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.;

Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez,

C.; Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen, W.; Wong,

M. W.; Andres, J. L.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A.

Gaussian 03; Gaussian, Inc.: Pittsburgh, PA, 2003; http://www.

gaussian.com/.

1832

dx.doi.org/10.1021/jo202350z | J. Org. Chem. 2012, 77, 1812−1832

Article Doi

Stereocontrolled synthesis of substituted chiral piperidines viaone-pot asymmetric 6π-azaelectrocyclization: Asymmetric syntheses of(-)-dendroprimine, (+)-7-epidendroprimine, (+)-5-epidendroprimine, and (+)-5,7-epidendroprimine

DOI: 10.1021/jo202350z

Source and publish data:

Authors:

Article abstract of DOI:10.1021/jo202350z

Full text of DOI:10.1021/jo202350z

Products guided by the article

R&D Labs maybe for 1358526-95-0

Relevant to this article

Hot Product