An alkylidene carbene C-H activation approach toward the enantioselective syntheses of spirolactams: Application to the synthesis of (-)-adalinine

Article

pubs.acs.org/joc

An Alkylidene Carbene C−H Activation Approach toward the

Enantioselective Syntheses of Spirolactams: Application to the

Synthesis of (−)-Adalinine

Krishna Annadi and Andrew G. H. Wee*

Department of Chemistry and Biochemistry, University of Regina, Regina, Saskatchewan, S4S 0A2, Canada

S

* Supporting Information

ABSTRACT: A method based on in situ alkylidene carbene generation-C−

H insertion reaction of 5-(3-oxobutyl)pyrrolidin-2-ones and 6-(3-

oxobutyl)piperidin-2-ones is developed for the enantioselective synthesis

of 1-azaspiro[4,4]non-6-ene-2-ones and 6-azaspiro[4,5]dec-1-ene-7-ones.

The required 5-(3-oxobutyl)pyrrolidin-2-ones and 6-(3-oxobutyl)piperidin-

2-ones are prepared from the Wacker oxidation of internal alkenes typiﬁed

by 5-(but-2-enyl)pyrrolidin-2-ones and 6-(but-2-enyl)piperidin-2-ones,

respectively. Excellent regioselectivity (≥92:8) is realized for the Wacker

oxidation, and high yields (78−89%) of the desired lactam ketones are

obtained. The results from further investigations into the Wacker oxidation

suggested that the high regioselectivity of the oxidation in these lactam alkenes might be due to the participation of the lactam

nitrogen via intramolecular coordination to Pd(II) during the reaction. Studies on alkylidene carbene generation-C−H insertion

reaction of the lactam ketones revealed that the reaction eﬃciency is sensitive to the reaction temperature and the amount of

lithio(trimethylsilyl)diazomethane employed, which led to the development of optimal reaction conditions for eﬀecting

alkylidene carbene generation-C−H insertion. Using the optimal reaction conditions, good to high yields (53−76%) of both γ-

and δ-lactam spirocycles were obtained. The synthetic utility of the spirolactams was demonstrated by the synthesis of

(−)-adalinine.

myeloma.¹The tricyclic alkaloid lepadiformine A (6) was found

INTRODUCTION

■

to show in vitro cytotoxicity against nasopharynx carcinoma and

Pyrrolidines and piperidines carrying a nitrogen-substituted

quaternary stereocenter are commonly found structural motifs

in many natural products, as exempliﬁed by 1−6 (Figure 1). In

non-small-cell lung carcinoma.²

A wide range of synthetic methods have been developed for

the construction of pyrrolidines and piperidines carrying a

nitrogen-substituted quaternary center.³However, the majority

addition to this interesting structural feature, several of these

of the studies reported are aimed at target-oriented synthesis⁴

natural products possess important biological activities. For

example, the alkaloid salinosporamide A (marizomib, 5) is a

potent inhibitor of the 20S proteasome enzyme and is currently

undergoing phase 1 clinical trial for the treatment of multiple

and, therefore, are not ﬂexible for the synthesis of other

structurally varied motifs. Further, a major challenge for the

enantioselective syntheses of these azaheterocycles is the

asymmetric creation of the nitrogen-substituted quaternary

stereocenter,⁵and because of this, most of the studies^{3e−g,i,4e,6}

are limited to racemic syntheses. The most commonly reported

methods for the enantioselective syntheses of pyrrolidines and

piperidines carrying a nitrogen-substituted quaternary center

include the addition of nucleophiles to iminium and N-

acyliminium ions,^3h,7alkylation of enolates derived from

pyrrolidine- and piperidine-2-carboxylates,⁸1,3-dipolar cyclo-

additions of alkenes and azomethine ylides,⁹oxidative

dearomatizations,¹⁰and [3,3]-sigmatropic-¹¹and semipinacol-

type rearrangements.¹²However, among these reported

approaches, limitations such as low overall eﬃciency,^11climited

substrate scope,^7b,10cand stereoselectivity issues^7a,12chave

hampered their wider synthetic applications.

Figure 1. Representative alkaloids possessing a nitrogen-substituted

quaternary stereocenter.

Received: November 9, 2015

A

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Alkylidene carbene C−H insertion reaction is an invaluable

synthetic tool for the functionalization of unactivated C−H

bonds.¹³This reaction usually proceeds with retention of

stereochemistry at the stereodeﬁned tertiary centers and,

therefore, is very useful for the formation of quaternary centers

with complete stereochemical control.¹⁴Previous studies¹⁵by

Hayes and other workers have shown that the 1,5-alkylidene

carbene C−H insertion reaction of pyrrolidine-based systems is

an eﬀective approach for the synthesis of spirocyclic pyrrolidine

compounds (Scheme 1a). In contrast, no studies of the

Scheme 2. Lactam Ketones 7a−e from BLLs 8a−c

Scheme 3. Preparation of δ-Lactam Ketone (S,S)-7e

Scheme 1. Alkylidene Carbene C−H Insertion Approach for

Synthesis of 1-Azaspirocycles

alkylidene carbene C−H insertion method have been applied to

piperidine-based systems for the construction of spirocyclic

piperidine compounds. Further, a survey of the literature also

showed that alkylidene carbene C−H insertion reactions of

lactams have not yet been reported. In this context, we have

investigated the alkylidene carbene generation-1,5-C−H

insertion of 5-(3-oxobutyl)pyrrolidin-2-ones and 6-(3-

oxobutyl)piperidin-2-ones to develop a general approach for

the enantioselective synthesis of spirolactams (Scheme 1b).

When compared to the simple pyrrolidine-based spirocycles,

the presence of a carbonyl group in the spirolactam products

would provide avenues to carry out synthetic transformations

on the lactam moiety and, therefore, would increase their

synthetic utility. Our studies showed that the eﬃciency of the

alkylidene carbene C−H insertion reaction in lactams is very

sensitive to the reaction conditions; however, under the

optimized conditions, both γ- and δ-lactams aﬀorded the

corresponding spirolactams in very good yields. The application

of the developed approach was successfully demonstrated in the

total synthesis of coccinellid alkaloid, (−)-adalinine (2, Figure

1).

lactam ketones 7a−d. Chemoselective reduction of the BLL-8c

with Red-Al at −78 °C eﬃciently gave the bicyclic lactol 9 in

81% yield. Wittig oleﬁnation of 9 with methylidenetriphenyl-

phosphorane (Ph₃PMeBr, KO^tBu), followed by the conversion

of the resulting alkenol to the MOM-ether 10, was achieved in

96% yield. At this stage, the isomerization of the terminal

alkene in 10 to the internal alkene in 11 was eﬀected by treating

10 with 10 mol % of Grubbs-II catalyst in the presence of N-

allyltritylamine¹⁷and N,N-diisopropylethylamine in reﬂuxing

toluene to provide 11 in 95% yield as an inseparable 3.5:1

mixture of E/Z diastereomers. Ozonolysis of 11, followed by

Horner−Wordsworth−Emmons (HWE) oleﬁnation of the

resulting crude aldehyde with dimethyl 2-oxopropylphospho-

nate gave the enone 12 in 67% yield. Catalytic hydrogenation

of 12 aﬀorded the required methyl ketone (S,S)-7e.

Although the δ-lactam ketone 7e was obtained in good

overall yield (47%) from BLL-8c, this route required a lengthy

seven-step sequence. To ﬁnd a more expedient way for the

preparation of lactam ketones 7a−d from the respective BLLs

8a,b^16b(Scheme 4), we investigated an alternative approach

that involved the Wacker oxidation of lactams carrying an

internal alkene side chain typiﬁed by 13 (Scheme 4). The

lactam alkenes 13 can be readily prepared from the nonracemic

BLLs 8.

RESULTS AND DISCUSSION

■

The preparation of enantiopure lactam ketones 7a−e required

for the alkylidene carbene C−H insertion studies was ﬁrst

investigated (Scheme 2). Compounds 7a−e would allow us to

assess (a) the inﬂuence of the N-protecting group (N-PMB vs

N-Bn) and (b) the eﬀect of C4 (or C5) substitution (OMOM

vs H) on the eﬃciency of the alkylidene carbene C−H

insertion reaction.

The lactam ketones 7a−e were prepared from the known

nonracemic bicyclic lactam lactones (BLLs) 8a−c, which we

previously reported.¹⁶Thus, the synthesis of N-PMB δ-lactam

ketone (S,S)-7e from BLL (S,S)-8c^16a(Scheme 3) was

undertaken ﬁrst in order to delineate a synthetic route, which

would also be applicable toward the preparation of other δ-

The requisite internal alkenes 13a−d were prepared

according to the route shown in Scheme 5. Reduction of the

BLLs 8a,b to the corresponding diastereomeric lactols 14a,b,

followed by Wittig oleﬁnation of 14a,b with ethylidenetriphe-

B

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Scheme 4. Wacker Oxidation Based Approach for Synthesis

of 7a−d

Table 1. Wacker Oxidation of Lactam Alkenes 13a−d

b

c

d

entry

substrate

dr

yield (%)

ratio (7:16)

1

2

3

4

(S,S)-13a

(R,R)-13b

(R)-13c

2.2:1

2.3:1

1.2:1

2.7:1

94

95

83

94

92:8

94:6

92:8

a

(S)-13d

a

Wacker oxidation of 13d under the conditions reported¹⁹by Grubbs

aﬀorded 7d and 16d in a ratio of 83:17, and in a combined 91% yield.

b

The stereochemistry of the double bond for the major diastereomers

in 13a−d was not determined due to the extensive overlap of oleﬁnic

Scheme 5. Lactam Alkenes 13a−d from BLLs 8a,b

c

1

proton signals in the H NMR spectrum. Combined yields of 7a−d

d

and 16a−d. Ratio based on the isolated yields of 7a−d and 16a−d.

between the standard Wacker and the modiﬁed conditions in

their work, we decided to test these conditions on lactam oleﬁn

13d since they are milder and require lower loadings of Pd

catalyst. However, oxidation under these conditions led to

lower regioselectivity, aﬀording 7d and 16d in a ratio of 83:17

compared to the 92:8 ratio observed under the standard

conditions. The combined yield of 7d and 16d under the

modiﬁed conditions was 91%.

The high regioselectivity observed in the Wacker oxidation of

lactam alkenes 13a−d is intriguing. It is reported^19,20that the

regioselectivity in Wacker oxidation of alkenes is found to be

inﬂuenced by the presence of coordinating groups that are in

close proximity to the double bond. For example, studies by

Feringa and co-workers^20dhave shown that Wacker oxidation

of allylic phthalimides selectively produced aldehydes as the

major products, where coordination of the imide group with

palladium was suggested as the regioselectivity controlling

factor. Thus, the presence of coordinating functional groups in

alkene substrates is assumed to predominately favor the

oxidation at the distal site of the double bond over the

proximal site. In our case, we surmise that the lactam ring might

have played a role in governing the regioselectivity of the

Wacker oxidation of 13a−d, possibly involving the coordina-

tion of nitrogen to palladium; coordination of carbonyl oxygen

to palladium was considered less likely for geometrical reasons.

The Wacker oxidation of alkenes 17a−d (Table 2) was next

investigated to test our hypothesis of lactam nitrogen

coordination. Studies on 13d, 17a−c will be useful to evaluate

the inﬂuence of the lactam ring on the regioselectivity in

internal as well as terminal alkenes. Further, Wacker oxidation

of 17d, in which the alkene functionality is allylic to the lactam

unit, is useful to test whether this substrate will behave similarly

to the lactam alkenes 13a−d (Table 1).

nylphosphorane (PPh₃EtBr, KO^tBu), gave the alkenols 15a,b as

inseparable mixtures of E/Z diastereomers in good yields. The

stereochemistry of the double bond in 15a,b was not

determined due to extensive overlap of the oleﬁnic proton

signals in the ¹H NMR spectrum. Subsequent protection of the

hydroxyl group in 15a,b as the MOM ether aﬀorded the lactam

alkenes 13a,b. Alcohols 15a,b were also subjected to

deoxygenation via tributyltin hydride reduction of their

thiocarbonate derivatives to obtain the lactam alkenes 13c,d.

With the lactam alkenes 13a−d in hand, their Wacker

oxidation was investigated, and the results are summarized in

Table 1. Thus, treating the lactam alkenes 13a−d under

standard¹⁸Wacker conditions (20 mol % PdCl₂, 1 equiv of

CuCl, O₂(1 atm), 1:1 v/v DMF/H₂O, 50 °C) preferentially

gave the desired methyl ketones 7a−d over the regioisomeric

ethyl ketones 16a−d (entries 1−4) in very good yields (78−

88%), and with excellent selectivity (≥92:8). It is useful to note

that the geometry of the alkene double bond in 13a−d had no

inﬂuence on the yield and regioselectivity of the Wacker

reaction (entries 1−4).

As mentioned above, Wacker oxidation of lactam alkene 13d

predominately favored the formation of methyl ketone 7d over

the ethyl ketone 16d (7d:16d = 92:8). In contrast, when alkene

17a²¹that does not possess any coordinating functional groups

was subjected to Wacker oxidation, the ketones 18a²³and 19a

(entry 2) were obtained in a ratio of 62:38, respectively, and in

a 30% combined yield. The observed regioselectivity in the

reaction of 17a is much lower when compared to that of 13d.

The Wacker oxidation of terminal alkenes 17b²²and 17c was

Grubbs and co-workers have recently reported¹⁹modiﬁed

conditions (5 mol % Pd(OAc)₂, 1 equiv of benzoquinone, 1.4

equiv of 49% aqueous HBF₄, O₂(1 atm), 7:1 v/v MeCN/H₂O,

rt) for the regioselective Wacker oxidation of acyclic internal

alkenes. Although no comparison studies were conducted

C

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

Table 2. Wacker Oxidation of Alkenes 17a−d

a

b

c

Result from Table 1, entry 4, included here for comparison purposes. (Z)-17a has been reported²¹in the literature. (R)-17b has been reported²²

in the literature. E/Z ratio of 17d was not determined due to the extensive overlap of signals in the ¹H NMR spectrum. 18a has been reported²³in

d

e

the literature. 19a has been reported²⁴in the literature. 19b has been reported²⁵in the literature. 19c has been reported²⁶in the literature.

f

g

h

i

j

k

Combined yield of regioisomeric products. Ratio based on the isolated yields of 7d and 16d. Ratio determined based on the ¹H NMR integration

l

of methyl singlet at δ 2.11 (18a) and the methyl triplet at δ 1.02 (19a). Ratio determined based on the ¹H NMR integration of benzylic methylene

proton doublets at δ 5.32 (18b) and δ 5.00 (19b).

next examined to determine whether the lactam group still has

any inﬂuence on regioselectivity. Wacker oxidation of the

lactam alkene 17b (entry 3) gave 18b and 19b²⁴(18b:19b =

22:78) in 85% combined yield, whereas the alkene 17c only

resulted in the formation of 19c²⁵(entry 4) in 68% yield.

Wacker oxidations of terminal alkenes are usually expected to

follow Markovnikov’s rule, as in the case of 17c, to give the

corresponding ketones as the predominant products. There-

fore, formation of the aldehyde 18b (19%) via anti-

Markovnikov type hydration of 17b suggests that the lactam

ring also has an inﬂuence on the regioselectivity in terminal

alkenes. The Wacker oxidation of 17d, in which the alkene

double bond is now allylic to the lactam unit, was examined

(entry 5). It was of interest to determine whether a similar

regioselectivity outcome, as was observed for the lactam oleﬁns

13a−d (Table 1), would result in the preferential formation of

the methyl ketone 18d over the ethyl ketone 19d. However,

none of the expected 18d and 19d were detected and only

unreacted 17d (90%) was recovered. The complete loss of

reactivity in 17d was unexpected and could be due to the

increased steric hindrance at the alkene functionality in 17d

when compared to the lactam alkenes 13a−d.

Overall, the results from the above studies (Table 2)

provided support for our hypothesis that the regioselectivity

observed in the Wacker oxidation of 13a−d might have been

inﬂuenced by the coordination of the lactam nitrogen to the

palladium. Most importantly, the ability of a weak electron

donor such as the lactam nitrogen to coordinate with the

palladium and thereby controlling the regioselectivity in

Wacker oxidation of lactam alkenes is noteworthy.

Having developed a more eﬃcient route for the preparation

of the lactam ketones 7a−e, we turned our attention toward the

alkylidene carbene generation-1,5-C−H insertion studies. We

chose to use Ohira’s protocol²⁷for the generation of alkylidene

carbenes by treatment of lactam ketones 7a−e with lithio-

trimethylsilyldiazomethane (LTDM). The reaction conditions

D

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

employed for the generation of alkylidene carbenes from

ketones using LTDM are basic. We chose the γ-lactam ketone

7a to develop optimal reaction conditions since it is more

sensitive to basic conditions when compared to the lactam

ketones 7b−e. The basic nature of LTDM can potentially cause

β-elimination in 7a via loss of the methylene hydrogen α- to the

lactam carbonyl group and the OMOM substituent and,

therefore, can interfere with the generation of the alkylidene

carbene.

also isolated in this reaction. We reasoned that the use of excess

LTDM might have led to the decomposition of 7a via

unidentiﬁed reaction pathways.

In parallel studies, we have also studied the C−H insertion of

δ-lactam ketone 7b under conditions B (Scheme 6), which led

Scheme 6. Alkylidene Carbene Generation-C−H Insertion of

7b under Conditions B

The alkylidene carbene generation-C−H insertion of 7a was

investigated under three diﬀerent reaction conditions A, B, and

C, and the results are summarized in Table 3.

Table 3. Optimization of Alkylidene Carbene Generation-

C−H Insertion Reaction Conditions

to the isolation of an unexpected bicyclic compound 24 (33%)

along with the C−H insertion product 20b (24%). This result

suggests that the use of 3 equiv of LTDM under conditions B

might have led to the formation of enolate 25 in competition

with the generation of the alkylidene carbene. The enolate 25 is

expected to be in equilibrium with 26, in which intramolecular

nucleophilic addition of the α-carbanion to the keto group

explains the formation of bicycle 24.

On the basis of the above results, we then investigated the

use of 1.9 equiv of LTDM and warming the reaction mixture

immediately to 0 °C after 20 min (conditions C). Under these

conditions, the spirolactam 20a was obtained in an improved

53% yield. A minor quantity of 23 (5%) was also isolated in this

reaction, which had likely resulted from base-mediated β-

elimination of the MOM group from the spirolactam 20a.

None of the rearrangement products that were observed under

conditions A were detected.

isolated yield (%)

a

entry

conditions

LTDM (equiv)

20a

21

22

23

1

2

3

A

B

C

1.9

3.0

1.9

40

25

53

19

8

5

a

Conditions A: reaction temperature was raised gradually over a

period of 1 h from −78 to 0 °C after 30 min of addition of 7a.

Conditions B: reaction temperature was raised immediately from −78

to 0 °C after 20 min of addition of 7a. Conditions C: reaction

temperature was raised immediately from −78 to 0 °C after 20 min of

addition of 7a.

The in situ generation of the alkylidene carbene from ketone

7a was performed under the most commonly employed

reaction conditions (entry 1, conditions A) as reported in the

literature.^15a,f,27Thus, LTDM was generated by treating

trimethylsilyldiazomethane (TMSDM, 2.0 equiv) with n-BuLi

(1.9 equiv) in THF at −78 °C, followed by the addition of a

THF solution of 7a after 45 min. The resulting brown colored

solution was stirred at −78 °C for 30 min, and then the

reaction temperature was gradually allowed to warm to 0 °C

over a period of 1 h. Under these conditions, the spirolactam

20a was isolated in 40% yield in addition to two unexpected

ketones 21 (19%) and 22 (8%). The formation of the

homologated ketones such as 21 and 22 is not usually observed

under LTDM reaction conditions, but is more commonly

encountered in Lewis acid catalyzed reactions of carbonyl

compounds with TMSDM.²⁸

The eﬀect of reaction temperature on the alkylidene carbene

generation and C−H insertion was next examined by warming

the reaction mixture immediately from −78 to 0 °C after 20

min of adding a THF solution of 7a to LTDM (entry 2,

conditions B). To ensure the complete consumption of ketone

17a, an excess of LTDM (3.0 equiv) was used. However, under

these conditions, the spirolactam 20a was obtained in only 25%

yield. A complex mixture of unidentiﬁed polar components was

Overall, conditions C provided the best results compared to

the conditions A and B that were tested for formation of the

spirolactam 20a. In comparison to the yields (53−65%)

obtained in the pyrrolidine-based substrates reported^15a−dby

Hayes and co-workers, and in spite of the base sensitivity of the

lactam ketone 7a, the yield obtained for 20a is comparable and

synthetically useful.

To further determine the scope of the reaction, structurally

varied γ- and δ-lactam ketones 7b−e were subjected to

alkylidene carbene generation-tertiary C−H insertion under

the optimized reaction conditions C, and the results are shown

in Table 4.

The alkylidene carbene generation-C−H insertion of lactam

ketones 7b−e (entries 1−4) under conditions C gave the

corresponding spirolactams 20b−e in good yields. A

comparison of the yields observed in the formation of 20b

(72%) and 20e (55%) indicates that the N-benzyl protecting

group is conducive toward more eﬃcient alkylidene carbene

generation-C−H insertion than the N-(p-methoxybenzyl)

group.²⁹Further, the large improvement in the yield of 20c

compared to 20a (53%, entry 3, Table 3) is likely due to the

absence of a competing β-elimination pathway in lactam ketone

7c. Importantly, generation of alkylidene carbene from lactam

ketones 7b−e led to the exclusive³⁰formation of 1,5-C−H

E

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

attention of synthetic chemists, and to date, three racemic³⁴

and three enantioselective³⁵syntheses have been reported.

Our retrosynthetic plan for (−)-adalinine starting from the

bicyclic lactam lactol (R,R)-14b (Scheme 5) is shown in

Scheme 7. Adalinine can be obtained from the keto-aldehyde

Table 4. Alkylidene Carbene Generation-C−H Insertion of

7b−e

Scheme 7. Retrosynthetic Plan for (−)-Adalinine

28 in a few steps. Oxidative cleavage of the alkene in

spirolactam 29 will provide the keto-aldehyde 28. The

alkylidene carbene C−H insertion reaction of the δ-lactam

ethyl ketone 30 is expected to provide the spirolactam

intermediate 29. The ketone 30 can be prepared from (R,R)-

14b following a similar route described for the preparation of

methyl ketone (S)-7d [(R,R)-14b → (S)-7d; Scheme 5 and

Table 1].

The synthesis of (−)-adalinine began with the conversion of

the lactol (R,R)-14b to the alkene 31 (Scheme 8). Thus, Wittig

Scheme 8. Preparation of Spirolactam 29

a

Isolated yield.

insertion products, and none of the alkyne products which

could have arisen from competing Fritsch−Buttenberg−

Wiechell rearrangement³¹were observed. Overall, the alkyli-

dene carbene generation-C−H insertion of lactam ketones 7a−

e was found to be successful for the formation of synthetically

very useful spirolactams 20a−e.

Having developed an eﬃcient approach for the enantiose-

lective synthesis of spirolactams, the synthesis of the coccinellid

alkaloid (−)-adalinine (2) was undertaken. Adalinine was

isolated³²as a minor component from the European two-

spotted ladybird beetle Adalia bipunctata along with the major

alkaloid (−)-adaline (27, Figure 2). The ladybird beetle exhibits

oleﬁnation of (R,R)-14b with propylidenetriphenylphosphor-

Figure 2. Alkaloids (−)-adalinine and (−)-adaline.

ane (PPh₃PrBr, KO^tBu) gave 31 as an inseparable mixture of

n

E/Z diastereomers (∼5:1) and in 88% yield. Deoxygenation of

the hydroxyl group in 31 via tributyltin hydride reduction of its

corresponding thiocarbonate aﬀorded 32. Wacker oxidation of

32 gave the ketone 30 as the major product over 33 with good

regioselectivity (∼91:9), which is in accordance with the

selectivity observed for the oxidation of alkenes 13a−d (Table

1). At this stage, the alkylidene carbene C−H insertion of the

lactam ketone 30 was carried out under the optimized reaction

a defense mechanism known as reﬂex bleeding against

predators by emitting droplets of these alkaloids. Biosynthetic

studies³³of (−)-adalinine have suggested that it is derived from

(−)-adaline involving a retro-Mannich reaction. The key

structural feature of adalinine is the presence of a nitrogen-

bearing quaternary stereocenter, which has attracted the

F

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

conditions (conditions C, Table 3) to form the spirolactam 29

in 60% yield. We also determined the enantiopurity of 29 by

HPLC on a chiral stationary phase (Chiralpak AD column;

95:5 v/v hexane/i-PrOH; ﬂow rate, 1.0 mL/min; t_R= 11.9 min

for (R)-29, and t_R= 13.1 min for (S)-29), which was found to

be 99% ee.³⁶This result conﬁrmed that the alkylidene carbene

C−H insertion also proceeded with retention of the

conﬁguration in the lactam ketones.

At this juncture, the retrosynthetic plan (Scheme 7) entailed

the formation of keto-aldehyde 28, from which the side chains

of adalinine can be installed. It was reasoned that the diﬀerence

in reactivity between the aldehyde and ketone groups in 28

should facilitate chemoselective transformation of the aldehyde

functionality. Exploratory studies on the chemoselective Wittig

oleﬁnation of the aldehyde moiety were conducted using

( )-28. Thus, ozonolysis of ( )-29³⁶in 4:1 v/v CH₂Cl₂/

MeOH at −78 °C, followed by reduction of the ozonide with

triphenylphosphine, gave the compound ( )-28 in 89% yield

(Scheme 9). Reaction of ( )-28 with (α-methoxyethylidene)-

oleﬁnation in the keto-aldehyde 28. To circumvent this

undesired competing reaction and to promote Wittig

oleﬁnation at the aldehyde group, we planned to chemo-

selectively protect the aldehyde group in 28, deoxygenate the

keto unit, and then unmask the aldehyde function. Thus, the

keto-aldehyde ( )-28 was subjected to the acid-mediated

acetalization using camphor sulfonic acid (50 mol %) in 1:1 v/v

CH₂Cl₂/MeOH to form the corresponding dimethyl acetal

derivative (Scheme 9). Surprisingly, the only compound

isolated in 82% yield was the cyclization product 37.

Compound 37 was obtained as a mixture of two diastereomers

in an approximately 18:1 ratio. The conversion of 28 to 37 was

complete within 10 min, suggesting that the cyclization is

instantaneous.

Informed by our studies on the attempted chemoselective

transformation of ( )-28, an alternative approach for the

conversion of 28 to adalinine was sought (Scheme 10).

Scheme 10. Conversion of Keto-aldehyde (S)-28 to

Adalinine

Scheme 9. Exploratory Chemoselective Transformations of

( )-28

triphenylphosphorane³⁷(PPh₃MeCH(OMe)Cl, NaHMDS)

did not give the expected enol ether 34, but instead led to

the unexpected formation of the intramolecular aldol

condensation product ( )-35³⁸in 45% yield (Scheme 9).

The Wittig oleﬁnation of ( )-28 with (methoxymethylene)-

triphenylphosphorane (PPh₃CH₂(OMe)Cl, NaHMDS) on the

other hand led to the enol ether 36. However, the yield of 36

(25−68%) was found to vary widely depending on the reaction

scale and the reaction was capricious. In cases where the yield

of 36 was very low, formation of side products from double

Wittig oleﬁnation of both aldehyde and ketone carbonyl groups

and/or intramolecular aldol reaction/condensation products

were observed. Attempts to improve the yields of the Wittig

reaction products by carefully optimizing reaction conditions

such as by using diﬀerent bases, reaction temperature,

concentration of the phosphorane, or the mode of addition

of phosphorane were in vain.

Accordingly, (S)-28, prepared from (S)-29 via ozonolysis, was

treated with KOH (3 equiv) in 3:1 v/v EtOH/CH₂Cl₂to eﬀect

intramolecular aldol condensation to obtain the spirocyclic

enone 35 in excellent yield (96%). Catalytic hydrogenation (40

psi H₂, Parr) of 35 in the presence of 10% Pd-C (10 mol %) in

ethanol gave an inseparable mixture of the ketone 38 along

with minor amounts of the allylic alcohols derived from

reduction of the ketone moiety and secondary alcohols formed

from reduction of both the alkene and the ketone units. The

hydrogenation of the enone 35 was also conducted in EtOAc to

test whether the formation of alcohols can be suppressed;

however, the reduction of 35 was found to be impractically

It is evident from the above studies that the intramolecular

aldol reaction/condensation is competitive with Wittig

G

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

slow. Further, attempted reduction of 35 with NaHSe³⁹

(generated in situ from selenium and NaBH₄in EtOH) only

led to the recovery of the unreacted starting material. The over

reduction of similar lactam enones to the lactam alcohols has

been previously observed in the studies^34aof Wardrop and co-

workers.

OD; hexane/i-PrOH (90:10, v/v); ﬂow rate, 1.0 mL/min; t_R=

10.9 min for (S)-2 and t_R= 12.1 min for (R)-2), which was

found to be >99% ee.⁴³

CONCLUSIONS

■

An alkylidene carbene generation-1,5-C−H insertion reaction

of 5-(3-oxobutyl)pyrrolidin-2-ones and 6-(3-oxobutyl)-

piperidin-2-ones was successfully developed for the enantiose-

lective formation of 7-methyl-1-azaspiro[4,4]non-6-ene-2-ones

and 2-methyl-6-azaspiro[4,5]dec-1-ene-7-ones, respectively.

The enantiopure γ- and δ-lactam ketones 7a−e required for

the alkylidene carbene C−H insertion reaction studies were

prepared from the corresponding chiral nonracemic bicyclic

lactam lactones 8a−c. Among the two diﬀerent routes that were

investigated for the synthesis of lactam ketones, the route based

on the Wacker oxidation of internal alkenes 13a−d was found

to be useful where high regioselectivity was realized. Further

studies on Wacker oxidation strongly suggested that the lactam

nitrogen may have played a role in inﬂuencing the

regioselectivity via internal coordination to palladium.

Since our attempts to suppress the formation of alcohols

were not successful, the crude mixture obtained from the

hydrogenation step was directly subjected to PDC oxidation.

This gave an inseparable mixture of the desired lactam ketone

38 (dr ∼ 1.8:1) and the starting enone 35 in a 7:1 ratio. The

overall yield of 38 is approximately 80% (determined based on

the integration of the methyl doublets in 38 at δ 0.89 and δ

1

0.95, and the methyl singlet in 35 at δ 1.69 in the H NMR

spectrum), over two steps.

Baeyer−Villiger oxidation of the 7:1 mixture of 38 and 35

with mCPBA in the presence of NaHCO₃in CH₂Cl₂gave the

pure lactone 39 in 69% yield (55% yield from 35, over three

steps). The lactone 39 was obtained as an inseparable mixture

of diastereomers in a 1.8:1 ratio. The enone 35 was also found

to react under the oxidation conditions; however, no attempt

was made to isolate the resulting products. Chemoselective

reduction of the lactone 39 to form the lactol 40 by treating

with DIBAL-H in CH₂Cl₂at −78 °C gave a complex mixture of

products, which made isolation diﬃcult. Therefore, the crude

product was directly subjected to Wittig oleﬁnation in the next

step without any puriﬁcation. Treating the crude lactol 40 with

ethylidenetriphenylphophorane (PPh₃EtBr, KHMDS) aﬀorded

the oleﬁn 42 (dr ∼ 1:1) in 25% yield over two steps. In order to

optimize the selective conversion of lactone 39 to lactol 40 and

to improve the overall yield of 42, the use of other reducing

r e a g e n t s s u c h a s R e d - A l a n d N a A l H ( O E t )

Careful studies to delineate reaction conditions for the

alkylidene carbene generation-C−H insertion revealed that the

eﬃciency of the C−H insertion reaction is sensitive to the

reaction temperature and the amount of lithiotrimethylsilyldia-

zomethane employed. These studies led to the development of

optimized reaction conditions for alkylidene carbene gener-

ation-C−H insertion that is applicable to both γ- and δ-lactam

ketones. Under the optimized conditions, synthetically useful

yields of spirolactams were obtained. When compared to the

pyrrolidine-based spirocycles reported by other workers,¹⁵the

spirolactams prepared in our study are more functionalized; the

presence of carbonyl and the OMOM groups in the lactam ring

would provide avenues for further synthetic transformations. In

our studies, the synthetic utility of the spirolactams was

demonstrated by the successful conversion of spirolactam 29 to

(−)-adalinine. Although the overall yield obtained for

(−)-adalinine is low (2.5% from (R,R)-8b, 17 steps) compared

to the previously reported syntheses,³⁵the utility of our

nonracemic spirolactams as intermediates in synthesis is clearly

demonstrated.

40

(OCH₂CH₂OCH₃)₂(generated in situ from Red-Al and

EtOH in THF) was investigated. However, reduction of 39

with these reagents also resulted in formation of a complex

mixture of products.

Because of the problems encountered in the direct

conversion of 39 to 40, a two-step procedure involving a

reduction−oxidation sequence was investigated for this trans-

formation. The lactone 39 was cleanly reduced⁴¹to the diol 41

with NaBH₄(2.5 equiv) in THF/MeOH at 65 °C in excellent

yield. Treating⁴²41 with catalytic amounts of TEMPO (20 mol

%) in the presence of N-chlorosuccinimide (1.5 equiv) and

tetrabutylammonium chloride (15 mol %) under biphasic

conditions gave the lactol 40. The lactol 40 was obtained as an

inseparable mixture together with small amounts of the

regenerated lactone 39. The unreacted diol 41 (33%) was

also recovered and recycled. Wittig oleﬁnation of the mixture of

40 and 39 in the next step gave the alkenol 42. The yield of

alkenol 42 is 38%, over two steps from 41. The lactone 39 did

not react under the Wittig reaction conditions and was

recovered.

The alkenol 42 was converted to adalinine in three steps.

Thus, catalytic hydrogenation (1 atm H₂, balloon) of 42 over

10% Pd-C (10 mol %) in EtOH gave 43 in quantitative yield.

N-Debenzylation of 43 under Birch reduction conditions,

followed by the oxidation^35cof the corresponding alcohol using

TPAP and NMO, gave (−)-adalinine (2) in 92% yield. The ¹H

and ¹³C NMR spectral data and [α]_D²³−29.8 (c 0.61, CH₂Cl₂)

{lit.^35c[α]_D²⁰−28.3 (c 1.6, CH₂Cl₂); lit.^35b[α]²_D⁰−30.4 (c 0.8,

CH₂Cl₂)} of (−)-2 are in good agreement with those reported

in the literature. Further, the enantiopurity of (−)-adalinine was

conﬁrmed by HPLC on a chiral stationary phase (Chiralcel

EXPERIMENTAL SECTION

■

General. IR spectra were recorded using either neat oil or ﬁlm

(CH₂Cl₂) on NaCl plates, and only the diagnostic absorptions were

reported. ¹H (300 or 500 MHz) and ¹³C{¹H} (75 or 125 MHz) NMR

spectra were recorded in CDCl₃unless stated otherwise. The residual

CHCl₃singlet at δ_H= 7.26 and the CDCl₃triplet centered at δ_C= 77.0

were used as internal references for ¹H and ¹³C NMR spectra,

respectively. High-resolution mass spectra in electron impact (EI) and

chemical ionization (CI) modes were recorded on a double focusing

sector ﬁeld mass spectrometer, in the ﬁeld desorption (FD) mode

using a time-of-ﬂight mass spectrometer, and in the electrospray

ionization (ESI) mode using a quadrupole time-of-ﬂight mass

spectrometer. Optical rotations were recorded at the Na_Dline.

Reaction progress was monitored by thin-layer chromatography on

silica gel 60_F254precoated (0.25 mm) on aluminum-backed sheets. Air-

and moisture-sensitive reactions were conducted under a static

pressure of argon. All organic extracts were dried over anhydrous

Na₂SO₄. Chromatographic puriﬁcation implies ﬂash column chroma-

tography, which was performed on silica gel 60 Å (230−400 mesh).

Dichloromethane, DMF, toluene, chloroform, methanol, and acetoni-

trile were dried by distillation from calcium hydride. THF and diethyl

ether were dried by distillation from sodium using sodium

benzophenone ketyl as indicator. Ethanol was dried by distillation

from Mg(OEt)₂. The preparation of bicyclic lactam lactones (S,S)-

H

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

8a,^16b(R,R)-8b,^16b(S,S)-8c,^16aand the allyl δ-lactam 10^16awere

previously reported.

was dissolved in MeOH (6 mL), and hydrogenated (1 atm, balloon)

over 10% palladium on carbon (8 mg). After 2.5 h at rt, the solution

was ﬁltered through a pad of Celite, and MeOH was evaporated under

reduced pressure. The crude product was puriﬁed by chromatography

(EtOAc) to give the ketone (S,S)-7e (74.5 mg, 95%) as a colorless oil:

[α]²_D³−60.2 (c 0.95, CHCl₃); IR (CH₂Cl₂) 3054, 2954, 2838, 1713,

1639, 1634 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ 7.13−7.21 (m, 2 H),

6.79−6.86 (m, 2 H), 5.27 (d, J = 14.8 Hz, 1 H), 4.55 (d, J = 6.6 Hz, 1

H), 4.51 (d, J = 6.6 Hz, 1 H), 3.86 (d, J = 14.8 Hz, 1 H), 3.70−3.80

(m, 4 H), 3.38 (ddd, J = 7.4, 4.7, 4.7 Hz, 1 H), 3.26 (s, 3 H), 2.40−

2.67 (m, 4 H), 2.10 (s, 3 H), 1.82−2.09 (m, 4 H); ¹³C NMR (CDCl₃,

75 MHz) δ 207.7, 169.1, 158.8, 129.2 (2 × ¹³C), 113.8, 73.2, 56.5,

55.4, 55.1, 47.9, 40.3, 29.8, 28.6, 23.1, 22.6; HRMS (EI-double

focusing sector ﬁeld) m/z: [M]⁺Calcd for C₁₉H₂₇NO₅349.1889;

Found 349.1881.

(5S,6S)-1-(p-Methoxybenzyl)-5-(methoxymethoxy)-6-(prop-

1-enyl)piperidin-2-one (11). To the allyl δ-lactam 10 (134 mg, 0.42

mmol) in toluene (8 mL) under argon at rt were sequentially added

allyltrityl amine (251 mg, 0.84 mmol), Grubbs-II catalyst (36 mg, 0.04

mmol), and DIPEA (0.07 mL, 0.42 mmol). The resulting wine red

color solution was then allowed to heat at reﬂux for 6 h, during which

time the color of the solution was changed to dark brown. Toluene

was evaporated under reduced pressure, and the crude product was

puriﬁed by chromatography (2:1 petroleum ether/EtOAc, then 1:1

petroleum ether/EtOAc) to give an inseparable E/Z mixture of 11

(127 mg, 95%) as a colorless oil: [α]²_D²+96.0 (c 0.67, CHCl₃); IR

(CH₂Cl₂) 3047, 2947, 2838, 1639, 1513 cm⁻¹; ¹H NMR (CDCl₃, 300

MHz) δ (E-11) 7.07−7.15 (m, 2 H), 6.76−6.84 (m, 2 H), 5.34−5.63

(m, 2 H), 5.30 (d, J = 14.6 Hz, 1 H), 4.58 (d, J = 6.9 Hz, 1 H), 4.55 (d,

J = 6.9 Hz, 1 H), 3.72−3.88 (m, 2 H), 3.75 (s, 3 H), 3.64 (d, J = 14.6

Hz, 1 H), 3.27 (s, 3 H), 2.37−2.71 (m, 2 H), 1.78−2.04 (m, 2 H), 1.75

(d, J = 5.6 Hz, 1 H); δ (discernible signals for Z-11) 5.74−5.86 (m, 1

H), 5.32 (d, J = 14.6 Hz, 1 H), 4.16 (dd, J = 9.9, 4.8 Hz, 1 H), 3.62 (d,

J = 14.6 Hz), 3.28 (s, 3 H), 1.53 (dd, J = 7.0, 1.7 Hz, 3 H); ¹³C NMR

(CDCl₃, 75 MHz) δ (E-11) 169.1, 158.7, 130.0, 129.2, 126.2, 113.8,

95.2, 72.9, 59.9, 55.5, 55.1, 46.8, 29.1, 23.4, 17.8 (discernible signals for

Z-11) 169.1, 129.6, 129.3, 126.3, 95.1, 72.2, 54.5, 46.2, 29.0, 23.9, 13.2;

HRMS (EI-double focusing sector ﬁeld) m/z: [M]⁺Calcd for

C₁₈H₂₅NO₄319.17836; Found 319.17841.

(3aS,6aS)-4-Benzyl-hexahydro-2-hydroxyfuro[3,2-b]pyrrol-

5-one (14a). A stock solution of 0.15 M Red-Al in toluene was made

by diluting Red-Al (1.0 mL, 65% w/w in toluene) with toluene (20

mL). To a solution of Red-Al (9.0 mL, 1.35 mmol, 0.15 M) at −78 °C

was added, under Ar, THF (1 mL), followed by a solution of the

known^16b(S,S)-8a (440 mg, 1.9 mmol) in THF (15 mL) via syringe

pump (rate of addition ∼ 4 mL/min; the ﬂask that held the solution of

8a and the syringe were rinsed with another 3.5 mL of THF). The

reaction mixture was stirred at −78 °C for 1 h, then quenched with a

few drops of MeOH, followed by saturated aqueous NH₄Cl (2 mL)

and allowed to warm to rt. All the volatiles were evaporated under

reduced pressure; the remaining residue was diluted with CH₂Cl₂(20

mL), and ﬁltered through a pad of Celite. The two layers were

separated, and the organic layer was washed once with brine. The

aqueous layer was saturated with solid NaCl and back-extracted into

CH₂Cl₂. The combined organic layers were dried over Na₂SO₄,

ﬁltered, and concentrated. Puriﬁcation by chromatography (1:3

petroleum ether/EtOAc, then EtOAc, followed by 10:1 EtOAc/

MeOH) aﬀorded the lactol (S,S)-14a (321 mg, 72%, 86% brsm) as an

oﬀ-white solid. The over-reduced diol (27 mg, 6%) and starting (S,S)-

8a (69 mg, 16%) were also isolated. (S,S)-14a: mp 125−126 °C; [α]_D²³

−127.7 (c 0.9, CHCl₃); IR (CH₂Cl₂) 3520−3220, 3055, 2987, 1687,

The ratio of the (E)- and (Z)-11 was ∼3.5:1, respectively, based on

1

integration of the methyl signals at δ 1.75 and δ 1.53 in the H NMR

spectrum.

(5S,6S)-1-(p-Methoxybenzyl)-5-(methoxymethoxy)-6-((E)-3-

oxobut-1-enyl)piperidin-2-one (12). An ozone-oxygen stream was

bubbled into a solution of 11 (137 mg, 0.43 mmol) in 4:1 v/v CH₂Cl₂

and MeOH (10 mL) at −78 °C for 15 s, at which time a pale blue

color remained in the solution and TLC analysis showed complete

conversion of the starting material. This solution was purged with

argon, and Me₂S (1.9 mL, 25.8 mmol) was added at −78 °C. The

reaction mixture was stirred for 2 h at −78 °C, followed by 30 min at

rt. The solvent was removed under reduced pressure, and the crude

aldehyde was dried under high vacuum over P₂O₅. The aldehyde was

dissolved in MeCN (2 mL) and was stored over molecular sieves prior

to use in the next step.

To powdered LiCl (22 mg, 0.51 mmol) in MeCN (6 mL) under

argon at rt was added dimethyl 2-oxopropylphosphonate (0.07 mL,

0.51 mmol), and the resulting suspension was stirred for 15 min. N,N-

Diisopropylethylamine (0.07 mL, 0.43 mmol) was added, and the

mixture was stirred for another 30 min, resulting in a clear colorless

solution. To this solution at 0 °C was then added the above aldehyde

in MeCN (2 mL) through cannula. The reaction mixture was stirred at

0 °C for 30 min and at rt, overnight. Saturated aqueous NH₄Cl was

added at 0 °C, and MeCN was evaporated under reduced pressure.

The crude residue was diluted with CH₂Cl₂(10 mL) and washed once

with brine. Excess solid NaCl was added to the aqueous layer, and the

aqueous phase was back-extracted with CH₂Cl₂(2 × 5 mL). The

combined organic layers were dried over Na₂SO₄, ﬁltered, and

concentrated. The crude product was puriﬁed by chromatography (1:2

petroleum ether/EtOAc, then 1:3 petroleum ether/EtOAc) to aﬀord

12 (99 mg, 67% over two steps) as a colorless oil: [α]²_D²−90.2 (c 0.61,

CHCl₃); IR (CH₂Cl₂) 2997, 2835, 2950, 2900, 1698, 1678, 1644

cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ 7.04−7.12 (m, 2 H), 6.75−6.83

(m, 2 H), 6.73 (dd, J = 16.2, 5.7 Hz, 1 H), 6.06 (dd, J = 16.2 Hz, 1 H),

5.25 (d, J = 14.7 Hz, 1 H), 4.58 (d, J = 6.9 Hz, 1 H), 4.54 (d, J = 6.9

Hz, 1 H), 4.10 (dd, J = 5.4, 5.4 Hz, 1 H), 3.85 (ddd, J = 10.2, 5.4, 5.4

Hz, 1 H), 3.73 (s, 3 H), 3.63 (d, J = 14.7 Hz, 1 H), 3.25 (s, 3 H), 2.59

(ddd, J = 18.1, 7.0, 3.9 Hz, 1 H), 2.46 (ddd, J = 18.1, 9.4, 7.7 Hz, 1 H),

2.22 (s, 3 H), 1.74−1.97 (m, 2 H); ¹³C NMR (CDCl₃, 75 MHz) δ

197.2, 168.9, 159.0, 142.3, 132.9, 129.3, 128.6, 113.9, 95.4, 73.0, 59.4,

55.6, 55.1, 47.8, 28.9, 27.4, 23.7; HRMS (EI-double focusing sector

ﬁeld) m/z: [M]⁺Calcd for C₁₉H₂₅NO₅347.1733; Found 347.1739.

(5S,6S)-1-(p-Methoxybenzyl)-5-(methoxymethoxy)-6-(3-

oxobutyl)piperidin-2-one (7e). The enone 12 (78 mg, 0.22 mmol)

1

1423 cm⁻¹; H NMR (CDCl₃, 300 MHz) δ (major diastereomer)

7.16−7.38 (m, 5 H), 5.52−5.62 (m, 1 H), 4.91 (d, J = 14.8 Hz, 1 H),

4.65−4.79 (m, 1 H), 4.10 (ddd, J = 5.5, 5.5, 5.5 Hz, 1 H), 3.95 (d, J =

14.8 Hz, 1 H), 3.56−3.66 (br m, 1 H), 2.51−2.84 (m, 2 H), 1.97−2.09

(m, 2 H); δ (discernible signals for minor diastereomer) 5.13 (d, J =

15.0 Hz, 1 H), 4.03 (dd, J = 6.3, 6.3 Hz, 1 H), 3.92 (d, J = 15.0 Hz, 1

H), 3.44−3.55 (br m, 1 H), 2.28 (d, J = 14.1 Hz, 1 H), 1.77−1.90 (m,

1 H); ¹³C NMR (CDCl3, 75 MHz) δ (major diastereomer) 172.6,

135.8, 128.7, 128.3, 127.8, 98.6, 73.7, 61.1, 44.7, 38.3, 37.6; δ (minor

diastereomer) 173.1, 128.3, 127.7, 99.0, 75.8, 61.0, 44.7, 40.1, 36.3.

HRMS (EI-double focusing sector ﬁeld) m/z: [M]⁺Calcd for

C₁₃H₁₅NO₃233.1052; Found 233.1045.

The diastereomeric ratio of (S,S)-14a was ∼1.5:1, based on

integration of the benzylic methylene protons at δ 5.13 and δ 4.91 in

1

the H NMR spectrum.

(3aR,7aR)-4-Benzyl-hexahydro-2-hydroxyfuro[3,2-b]pyridin-

5(6H)-one (14b). The lactol (R,R)-14b was prepared from the

known^16bbicyclic lactam lactone (R,R)-8b (533 mg, 2.17 mmol)

according to the procedure described for the preparation of (S,S)-14a.

Puriﬁcation by chromatography (1:3 petroleum ether/EtOAc, then

EtOAc) aﬀorded the lactol (R,R)-14b (394 mg, 74%, 81% brsm) as a

colorless oil. The starting (R,R)-8b (48 mg, 9%) was also recovered.

(R,R)-14b: [α]²_D¹−44.1 (c 0.75, CHCl₃); IR (neat) 3559−3110, 2933,

1

1628 cm⁻¹; H NMR (CDCl₃, 300 MHz) δ (major diastereomer)

7.18−7.36 (m, 5 H), 5.55 (d, J = 4.6 Hz, 1 H), 5.25−5.32 (br m, 1 H),

5.13 (d, J = 14.9 Hz, 1 H), 4.47 (ddd, J = 6.4, 2.8, 2.8 Hz, 1 H), 4.00−

4.10 (m, 1 H), 4.01 (d, J = 14.9 Hz, 1 H), 2.30−2.52 (m, 2 H), 2.22

(ddd, J = 13.4, 7.9, 1.1 Hz, 1 H), 1.97−2.13 (m, 1 H), 1.71−1.87 (m, 2

H); δ (discernible signals for minor diastereomer) 5.46−5.51 (m, 1

H), 5.40 (d, J = 15.1 Hz, 1 H), 5.17−5.23 (br s, 1 H), 4.26−4.33 (m, 1

H), 3.76 (ddd, J = 6.1, 6.1, 4.0 Hz, 1 H), 2.78 (ddd, J = 17.2, 12.9, 4.9

Hz, 1 H); ¹³C NMR (CDCl₃, 75 MHz) δ (major diastereomer) 171.1,

136.5, 128.4, 127.8, 127.3, 96.6, 72.0, 57.4, 47.9, 41.4, 27.2, 24.5; δ

I

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(minor diastereomer) 171.0, 136.4, 128.4, 127.7, 127.2, 97.3, 74.7,

57.3, 47.0, 38.8, 26.9, 24.2. HRMS (FD-TOF) m/z: [M]⁺Calcd for

C₁₄H₁₇NO₃247.1208; Found 247.1200.

distinguishable from the signals of 15b; Ph₃PO signals appeared

between 7.5 and 8.5 ppm].

(5R,6R)-1-Benzyl-6-(but-2-enyl)-5-hydroxypiperidin-2-one (15b).

1

The diastereomeric ratio of (R,R)-14b was ∼3:1, based on

IR (CH₂Cl₂) 3359−3118, 3058, 1632 cm⁻¹; H NMR (CDCl₃, 300

integration of the benzylic methylene proton signals at δ 5.13 and δ

MHz) δ (major diastereomer) 7.12−7.28 (m, 5 H), 5.39−5.58 (m, 2

H), 5.39 (d, J = 15.2 Hz, 1 H), 4.14−4.21 (br d, J = 3.8 Hz, 1 H),

3.86−3.95 (m, 1 H), 3.88 (d, J = 15.2 Hz, 1 H), 3.30−3.39 (m, 1 H),

2.32−2.67 (m, 4 H), 1.75−2.00 (m, 2 H), 1.58 (d, J = 6.2 Hz, 3 H); δ

(discernible signals for minor diastereomer) 5.35 (d, J = 15.2 Hz, 1 H),

4.11−4.18 (br d, J = 3.9 Hz, 1 H), 2.19−2.31 (m, 1 H), 1.62 (d, J = 5.5

Hz, 3 H). The ratio of Z- and E-alkenes was found to be 2.3:1, based

1

5.40 in the H NMR spectrum.

(4S,5S)-1-Benzyl-5-(but-2-enyl)-4-(methoxymethoxy)-

pyrrolidin-2-one (13a). Ph₃P⁺EtBr⁻(2.25 g, 6.3 mmol) was dried

under vacuum at 110 °C for 1 h and cooled to rt. The above salt was

suspended in THF (15 mL), and it was cooled to 0 °C under argon.

KO^tBu (744 mg, 6.3 mmol) was added in one portion, to the above

suspension. A bright yellow suspension resulted. After 45 min at 0 °C,

a solution of the lactol (S,S)-14a (245 mg, 1.05 mmol) in THF (8 mL)

was added via cannula, and the mixture was stirred for 1 h. Saturated

aqueous NH₄Cl (5 mL) was added, and the THF was evaporated oﬀ

under reduced pressure. The aqueous layer was extracted with CH₂Cl₂

(3 × 20 mL), dried over Na₂SO₄, ﬁltered, and concentrated.

Puriﬁcation by chromatography (1:4 petroleum ether/EtOAc)

aﬀorded the alkenol (S,S)-15a (249 mg, 97%) together with

triphenylphosphine oxide as an inseparable mixture. The alkenol was

obtained as a mixture of Z- and E-diastereomers.

1

on integration of the methyl doublets at δ 1.58 and δ 1.62 in the H

NMR spectrum.

In the second step, the alkenol (R,R)-15b (78 mg, 0.30 mmol) was

converted to the OMOM derivative (R,R)-13b. Puriﬁcation by

chromatography (2:1 petroleum ether/EtOAc) aﬀorded (R,R)-13b

(72.6 mg, 81%) as an inseparable mixture of the Z- and E-

diastereomers: Colorless oil; [α]²_D²+59.5 (c 1.09, CHCl₃); IR (neat)

1

3025, 2938, 2897, 1645, 1453, 1420 cm⁻¹; H NMR (CDCl₃, 300

MHz) δ (major diastereomer) 7.12−7.38 (m, 5 H), 5.33−5.65 (m, 3

H), 4.58 (d, J = 7.5 Hz, 1 H), 4.53 (d, J = 7.5 Hz, 1 H), 3.91 (d, J =

14.8 Hz, 1 H), 3.73−3.83 (m, 1 H), 3.33−3.45 (m, 1 H), 3.28 (s, 3 H),

2.35−2.74 (m, 4 H), 1.87−2.14 (m, 2 H), 1.60 (d, J = 6.7 Hz, 3 H); δ

(discernible signals for minor diastereomer) 2.26 (ddd, J = 14.1, 7.1,

7.1 Hz, 1 H), 1.66 (d, J = 6.0 Hz, 3 H); ¹³C NMR (CDCl₃, 75 MHz) δ

(major diastereomer) 169.4, 137.3, 128.5, 127.8, 127.2, 126.9, 126.4,

95.6, 72.9, 57.9, 55.6, 48.4, 28.8, 26.8, 23.4, 12.9; δ (discernible signals

for minor diastereomer) 169.5, 128.2, 127.8, 127.7, 58.2, 48.7, 32.5,

28.8, 23.3, 18.0; HRMS (ESI-QTOF) m/z: [M + Na]⁺Calcd for

C₁₈H₂₅NO₃Na 326.1732; Found 326.1729.

(4S,5S)-1-Benzyl-5-(but-2-enyl)-4-hydroxypyrrolidin-2-one (15a).

¹H NMR (CDCl₃, 300 MHz) δ (major diastereomer) 7.10−7.27 (m, 5

H), 5.30−5.51 (m, 2 H), 5.00 (d, J = 15.5 Hz, 1 H), 4.79−4.89 (br s, 1

H), 4.23−4.35 (m, 1 H), 3.90 (d, J = 15.5 Hz, 1 H), 3.29−3.40 (m, 1

H), 2.30−2.58 (m, 4 H), 1.45 (d, J = 6.05 Hz, 3 H); δ (discernible

signals for minor diastereomer) 4.94 (d, J = 15.2 Hz, 1 H), 3.92 (d, J =

15.2 Hz, 1 H), 1.54 (d, J = 4.3 Hz, 3 H). The ratio of Z- and E-alkenols

was found to be ∼2.2:1, based on integration of the methyl doublets at

1

δ 1.45 and δ 1.54 in the H NMR spectrum.

To the above alkenol (S,S)-15a (87 mg, 0.35 mmol) in DCE (4

mL) under Ar at rt were added tetrabutylammonium iodide (2 mg, 1.5

mol %), N,N-diisopropylethylamine (0.37 mL, 2.1 mmol), and MOM-

Cl (80 μL, 1.05 mmol) successively, and the resulting solution was

allowed to reﬂux, overnight. The reaction mixture was cooled to 0 °C

and diluted with CH₂Cl₂(5 mL), and saturated aqueous Na₂CO₃(2

mL) was added. After stirring the mixture for 15 min at the same

temperature, the biphasic solution was transferred into a separatory

funnel. The two layers were separated, and the organic layer was

washed once with brine. The aqueous layer was saturated with solid

NaCl and back-extracted into CH₂Cl₂. The combined organic layers

were dried over Na₂SO₄, ﬁltered, and concentrated. Puriﬁcation by

chromatography (2:1 petroleum ether/EtOAc) aﬀorded (S,S)-13a (97

mg, 95%) as an inseparable mixture of the Z- and E-diastereomers:

Colorless oil; [α]²_D²−45.8 (c 0.79, CHCl₃); IR (neat) 3008, 2938,

The ratio of Z- and E-alkenes was found to be ∼2.3:1, based on

integration of the methyl doublets at δ 1.60 and δ 1.66 in the ¹H NMR

spectrum.

(R)-1-Benzyl-5-(but-2-enyl)pyrrolidin-2-one (13c). To the

alkenol (S,S)-15a (148 mg, 0.60 mmol) in DCE (10 mL) under

argon at rt were added 4-(dimethylamino)pyridine (73 mg, 0.60

mmol), N,N-diisopropylethylamine (0.63 mL, 3.6 mmol), and

phenoxythiocarbonyl chloride (0.25 mL, 1.8 mmol) successively, and

the resulting solution was allowed to reﬂux, overnight. The reaction

mixture was cooled to rt, diluted with CH₂Cl₂, and washed

successively with saturated aqueous NaHCO₃(2 × 5 mL) and brine

(1 × 5 mL). The organic layer was dried over Na₂SO₄, ﬁltered, and

concentrated. Puriﬁcation by chromatography (4:1 petroleum ether/

EtOAc) gave the corresponding thiocarbonate (151 mg, 66%) as an

inseparable mixture of Z- and E-diastereomers.

1693, 1424 cm⁻¹

;

¹H NMR (CDCl₃, 300 MHz) δ (major

(S,S)-1-Benzyl-5-(but-2-enyl)-4-(phenoxythiocarbonyloxy)-

pyrrolidin-2-one. Orange oil; [α]²_D²+0.91 (c 1.43, CHCl₃); IR (neat)

3024, 2923, 1699 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ (major

diastereomer) 7.19−7.47 (m, 8 H), 7.02−7.11 (m, 2 H), 5.49−5.77

(m, 2 H), 5.21−5.35 (m, 1 H), 5.12 (d, J = 15.2 Hz, 1 H), 4.06 (d, J =

15.2 Hz, 1 H), 3.74−3.85 (m, 1 H), 2.69−2.95 (m, 2 H), 2.50 (dd, J =

6.8, 6.8 Hz, 2 H), 1.61 (d, J = 6.7 Hz, 3 H); δ (discernible signals for

minor diastereomer) 5.05 (d, J = 15.2 Hz, 1 H), 2.41 (dd, J = 6.7 Hz, 2

H), 1.66 (d, J = 6.5 Hz, 3 H); ¹³C NMR (CDCl₃, 75 MHz) δ (major

diastereomer) 194.1, 171.6, 153.1, 135.9, 129.6, 128.8, 127.9, 127.8,

127.7, 123.5, 121.7, 77.6, 59.3, 44.1, 37.4, 25.0, 13.0; δ (discernible

signals for minor diastereomer) 194.0, 171.6, 136.0, 129.9, 128.7,

127.9, 127.6, 124.4, 59.4, 37.3, 30.6, 18.1. The ratio of Z- and E-

thiocarbonates was found to be ∼2.2:1, based on integration of the

diastereomer) 7.13−7.35 (m, 5 H), 5.24−5.60 (m, 2 H), 5.08 (d, J

= 15.1 Hz, 1 H), 4.62 (d, J = 6.9 Hz, 1 H), 4.58 (d, J = 6.9 Hz, 1 H),

4.17−4.28 (m, 1 H), 3.95 (d, J = 15.1 Hz, 1 H), 3.47−3.58 (m, 1 H),

3.34 (s, 3 H), 2.47−2.67 (m, 2 H), 2.23−2.45 (m, 2 H), 1.53 (d, J =

6.7 Hz, 3 H); δ (discernible signals for minor diastereomer) 5.03 (d, J

= 15.1 Hz, 1 H), 1.62 (d, J = 6.1 Hz, 1 H); ¹³C NMR (CDCl₃, 75

MHz) δ (major diastereomer) 172.6, 136.4, 128.6, 127.7, 127.4, 126.8,

125.2, 96.0, 71.7, 60.1, 55.7, 43.9, 37.8, 24.8, 12.9; δ (discernible

signals for minor diastereomer) 172.4, 136.4, 128.7, 128.5, 127.4,

126.1, 44.0, 37.7, 30.4, 18.0; HRMS (ESI-QTOF) m/z: [M + Na]⁺

Calcd for C₁₇H₂₃NO₃Na 312.1576; Found 312.1561.

The ratio of Z- and E-alkenes was found to be ∼2.2:1, based on

integration of the methyl doublets at δ 1.53 and δ 1.62 in the ¹H NMR

spectrum.

1

benzylic methylene protons at δ 5.12 and δ 5.05 in the H NMR

spectrum.

(5R,6R)-1-Benzyl-6-(but-2-enyl)-5-(methoxymethoxy)-

piperidin-2-one (13b). Compound (R,R)-13b was prepared from

the lactol (R,R)-14b according to the two-step procedure described

above for the preparation of (S,S)-13a. Wittig oleﬁnation of the lactol

(R,R)-14b (200 mg, 0.81 mmol) with ethylidenetriphenylphosphorane

(4 equiv, Ph₃P⁺EtBr⁻, KO^tBu) gave the alkenol (R,R)-15b. Puriﬁcation

by chromatography (1:4 petroleum ether/EtOAc) aﬀorded the alkenol

(R,R)-15b (204 mg, 97%, dr ∼ 4:1) together with triphenylphosphine

oxide as an inseparable mixture. The alkenol was obtained as mixture

of Z- and E-diastereomers in a 2.3:1 ratio [Ph₃PO signals are clearly

To a mixture of AIBN (13 mg, 0.08 mmol) in degassed toluene (2

mL) at rt was added a solution of the thiocarbonate (151 mg, 0.40

mmol) in degassed toluene (4 mL) via cannula, followed by Bu₃SnH

(0.22 mL, 0.79 mmol). The reaction mixture was allowed to stir at 100

°C (oil bath) for 2 h, and cooled to rt. Toluene was evaporated under

reduced pressure, and the crude residue was diluted with EtOAc.

Aqueous KF (4 mL, 10% w/v) was added, and the biphasic mixture

was vigorously stirred for 30 min. The solution was vacuum ﬁltered

through a pad of Celite, and the two layers were separated. The

J

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

aqueous layer was re-extracted into EtOAc, and the combined organic

layers were dried over Na₂SO₄, ﬁltered, and concentrated. Puriﬁcation

by chromatography (1:1 petroleum ether/Et₂O then 1:2 petroleum

ether/Et₂O) aﬀorded the alkene (R)-13c (59.4 mg, 65.5%) as an

inseparable mixture of Z- and E-diastereomers: Colorless oil; [α]_D²²

−31.0 (c 0.72, CHCl₃); IR (neat) 3025, 2922, 2857, 1686, 1495 cm⁻¹;

¹H NMR (CDCl₃, 300 MHz) δ (major diastereomer) 7.12−7.29 (m, 5

H), 5.36−5.59 (m, 1 H), 5.10−5.24 (m, 1 H), 4.97 (d, J = 15.1 Hz, 1

H), 3.89 (d, J = 15.0 Hz, 1 H), 3.33−3.46 (m, 1 H), 2.15−2.48 (m, 3

H), 1.86−2.13 (m, 2 H), 1.57−1.74 (m, 1 H), 1.51 (d, J = 6.7 Hz, 3

H); δ (discernible signals for minor diastereomer) 4.93 (d, J = 14.8

Hz, 1 H), 1.57 (d, J = 6.2 Hz, 3 H); ¹³C NMR (CDCl₃, 75 MHz) δ

(diastereomeric signals are not distinguishable) 175.1(5), 175.1(1),

136.7, 136.6(7), 128.5(6), 128.5(4), 129.2, 127.9(3), 127.9(2), 127.5,

127.4, 127.3, 124.9, 124.1, 56.5, 35.8, 30.1, 30.0(9), 30.0(6), 23.4, 23.1,

18.0, 13.0; HRMS (ESI-QTOF) m/z: [M + Na]⁺Calcd for

C₁₅H₁₉NONa 252.1364; Found 252.1354.

stirred at 55 °C (oil bath) under an O₂atmosphere for 24 h. The

reaction mixture was diluted with CH₂Cl₂and ﬁltered through a pad of

Celite. CH₂Cl₂was evaporated on the rotatory evaporator, followed by

Kugelrohr distillation of the resulting mixture to remove DMF and

H₂O. In order to remove the residual Pd-Cu color impurities from the

crude product, it was dissolved in toluene (10 mL), NaBr (2.5 g) was

added, and the resulting suspension was reﬂuxed for 1 h. The reaction

mixture was ﬁltered through a pad of Celite, and the solvent was

removed under reduced pressure. The crude residue was puriﬁed by

chromatography.

Lactam Ketones 7a and 16a from Wacker Oxidation of (S,S)-

13a. Wacker oxidation of (S,S)-13a (49 mg, 0.17 mmol) according to

the general procedure aﬀorded the ketones 7a and 16a. Puriﬁcation by

chromatography (1:2 petroleum ether/EtOAc) gave 7a (44 mg, 87%)

and 16a (3.8 mg, 7%).

(4S,5S)-1-Benzyl-4-(methoxymethoxy)-5-(3-oxobutyl)pyrrolidin-

2-one (7a). Pale yellow oil; [α]²_D²−21.5 (c 0.72, CHCl₃); IR (CH₂Cl₂)

1

3056, 2941, 2897, 1716, 1690, 1439 cm⁻¹; H NMR (CDCl₃, 300

The ratio of Z- and E-alkenes was found to be ∼1.2:1, based on the

integration of benzylic methylene protons at δ 4.97 and δ 4.93 in the

¹H NMR spectrum.

MHz) δ 7.16−7.32 (m, 5 H), 4.95 (d, J = 15.1 Hz, 1 H), 4.60 (d, J =

6.8 Hz, 1 H), 4.55 (d, J = 6.8 Hz, 1 H), 4.24 (ddd, J = 6.1, 6.1, 6.1 Hz,

1 H), 3.96 (d, J = 15.1 Hz, 1 H), 3.51 (ddd, J = 6.1, 6.1, 6.1 Hz, 1 H),

3.30 (s, 3 H), 2.60 (d, J = 16.9, 6.9 Hz, 1 H), 2.49 (dd, J = 16.9, 5.7 Hz,

1 H), 2.41 (t, J = 7.4 Hz, 2 H), 2.04 (s, 3 H), 1.90 (td, J = 7.4, 6.7 Hz,

2 H); ¹³C NMR (CDCl₃, 75 MHz) δ 207.3, 172.1, 136.3, 128.5, 127.8,

127.4, 95.7, 71.3, 59.1, 55.8, 43.9, 38.8, 37.5, 29.7, 20.8; HRMS (EI-

double focusing sector ﬁeld) m/z: [M]⁺Calcd for C₁₇H₂₃NO₄

305.1627; Found 305.1618.

(4S,5S)-1-Benzyl-4-(methoxymethoxy)-5-(2-oxobutyl)pyrrolidin-

2-one (16a). Pale yellow oil; IR (CH₂Cl₂) 3055, 2983, 2933, 1712,

1692, 1624 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ 7.14−7.35 (m, 5 H),

4.76 (d, J = 15.2 Hz, 1 H), 4.52 (d, J = 6.8 Hz, 1 H), 4.49 (d, J = 6.8

Hz, 1 H), 4.36 (m, 1 H), 4.21 (ddd, J = 9.0, 6.5, 4.8 Hz, 1 H), 4.12 (d,

J = 15.2 Hz, 1 H), 3.29 (s, 3 H), 2.83 (dd, J = 17.1, 9.0 Hz, 1 H), 2.68

(dd, J = 17.1, 7.1 Hz, 1 H), 2.27−2.54 (m, 4 H), 0.99 (t, J = 7.5 Hz, 3

H). The minor ketone 16a was not fully characterized due to

insuﬃcient amount of material.

(S)-1-Benzyl-6-(but-2-enyl)piperidin-2-one (13d). Compound

(S)-13d was prepared from the alkenol (R,R)-15b according to the

two-step procedure described above for the preparation of (R)-13c.

The alkenol (R,R)-15b (136 mg, 0.52 mmol) was ﬁrst treated with

phenoxythiocarbonyl chloride (0.22 mL, 1.56 mmol) to form the

corresponding thiocarbonate derivative. Puriﬁcation by chromatog-

raphy (2:1 petroleum ether/EtOAc) gave the thiocarbonate (186 mg,

90%) as an inseparable mixture of Z- and E-diastereomers.

(5R,6R)-1-Benzyl-6-(but-2-enyl)-5-(phenoxythiocarbonyloxy)-

piperidin-2-one. Orange oil; [α]²_D³+24.6 (c 0.74, CHCl₃); IR (neat)

1

3028, 2957, 2936, 1650, 1590 cm⁻¹; H NMR (CDCl₃, 300 MHz) δ

(major diastereomer) 7.28−7.37 (m, 2 H), 7.11−7.28 (m, 6 H), 6.93−

7.00 (m, 2 H), 5.42−5.60 (m, 1 H), 5.21−5.42 (m, 3 H), 3.99 (d, J =

15.2 Hz, 1 H), 3.59−3.74 (m, 1 H), 2.48−2.73 (m, 2 H), 2.43 (t, J =

6.9 Hz, 2 H), 2.24−2.39 (m, 1 H), 1.99−2.13 (m, 1 H), 1.53 (dd, J =

6.8, 0.6 Hz, 3 H); δ (discernible signals for minor diastereomer) 4.00

(d, J = 15.2 Hz, 1 H), 1.59 (d, J = 6.3 Hz, 3 H); ¹³C NMR (CDCl₃, 75

MHz) δ (major diastereomer) 193.7, 169.0, 153.1, 136.8, 129.5, 128.6,

127.7, 127.4, 127.3, 126.6, 125.1, 121.7, 78.0, 56.5, 47.8, 28.2, 27.1,

22.2, 12.9; δ (discernible signals for minor diastereomer) 193.7, 169.1,

136.9, 129.3, 125.9, 56.9, 47.9, 32.9, 28.1, 18.0. The ratio of Z- and E-

thiocarbonates was found to be ∼2.3:1, based on the integration of

Lactam Ketones 7b and 16b from Wacker Oxidation of

(R,R)-13b. Wacker oxidation of (R,R)-13b (70 mg, 0.23 mmol)

according to the general procedure gave the ketones 7b and 16b.

Puriﬁcation by chromatography (1:2 petroleum ether/EtOAc)

aﬀorded 7b (64.6 mg, 88%) and 16b (4.4 mg, 7%).

(5R,6R)-1-Benzyl-5-(methoxymethoxy)-6-(3-oxobutyl)piperidin-2-

one (7b). Pale yellow oil; [α]_D²²+50.5 (c 1.74, CHCl₃); IR (neat) 2948,

1

methyl doublets at δ 1.53 and δ 1.59 in the H NMR spectrum.

1

2897, 1712, 1641, 1451 cm⁻¹; H NMR (CDCl₃, 300 MHz) δ 7.21−

The above thiocarbonate derivative (186 mg, 0.47 mmol) was

reduced with Bu₃SnH (0.26 mL, 0.93 mmol) in the presence of AIBN

(16 mg, 0.1 mmol) to form (S)-13d. Puriﬁcation by chromatography

(2:1 petroleum ether/EtOAc) aﬀorded (S)-13d (76.5 mg, 67%) as an

inseparable mixture of Z- and E-diastereomers: Colorless oil; [α]_D²²

+41.4 (c 0.85, CHCl₃); IR (neat) 3022, 2947, 1642, 1496, 1466, 1450,

1415, 1341, 1258 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ (major

diastereomer) 7.17−7.33 (m, 5 H), 5.44−5.61 (m, 1 H), 5.39 (d, J =

15.1 Hz, 1 H), 5.16−5.29 (m, 1 H), 3.97 (d, J = 15.1 Hz, 1 H), 3.21−

3.35 (m, 1 H), 2.09−2.53 (m, 4 H), 1.62−1.98 (m, 4 H), 1.58 (d, J =

6.8 Hz, 3 H); δ (discernible signals for minor diastereomer) 5.37 (d, J

= 15.1 Hz, 1 H), 3.94 (d, J = 15.1 Hz, 1 H), 1.62 (dd, J = 6.5, 1.0 Hz, 3

H); ¹³C NMR (CDCl₃, 75 MHz) δ (major diastereomer) 170.2, 137.6,

128.4, 127.5, 127.0, 126.7, 125.4, 55.1, 47.2, 31.9, 29.7, 26.2, 17.2, 12.8;

δ (discernible signals for minor diastereomer) 170.2, 128.5, 126.9,

126.3, 47.2, 35.4, 31.8, 26.0, 17.8, 17.0; HRMS (ESI-QTOF) m/z: [M

+ Na]⁺Calcd for C₁₆H₂₁NONa 266.1521; Found 266.1527.

7.41 (m, 5 H), 5.36 (d, J = 14.9 Hz, 1 H), 4.59 (d, J = 6.8 Hz, 1 H),

4.54 (d, J = 6.8 Hz, 1 H), 4.00 (d, J = 14.9 Hz, 1 H), 3.78−3.88 (m, 1

H), 3.41 (ddd, J = 8.0, 4.9, 4.9 Hz, 1 H), 3.29 (s, 3 H), 2.46−2.74 (m,

4 H), 2.13 (s, 3 H), 1.86−2.17 (m, 4 H); ¹³C NMR (CDCl₃, 75 MHz)

δ 207.7, 169.3, 137.2, 128.5, 127.9, 127.3, 95.3, 73.2, 56.9, 55.5, 48.6,

40.4, 29.8, 28.6, 23.1, 22.7; HRMS (EI-double focusing sector ﬁeld)

m/z: [M]⁺Calcd for C₁₈H₂₅NO₄319.1784; Found 319.1783.

(5R,6R)-1-Benzyl-5-(methoxymethoxy)-6-(2-oxobutyl)piperidin-2-

one (16b). Pale yellow oil; IR (CH₂Cl₂) 3056, 2949, 1715, 1642, 1460

cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ 7.12−7.31 (m, 5 H), 4.90 (d, J

= 14.6 Hz, 1 H), 4.42 (d, J = 6.8 Hz, 1 H), 4.37 (d, J = 6.8 Hz, 1 H),

4.15 (m, 1 H), 4.04 (d, J = 14.6 Hz, 1 H), 3.80 (ddd, J = 10.0, 4.3, 4.3

Hz, 1 H), 3.19 (s, 3 H), 2.86 (dd, J = 17.1, 6.1 Hz, 1 H), 2.08−2.67

(m, 5 H), 1.78−2.0 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H); ¹³C NMR

(CDCl₃, 75 MHz) δ 208.6, 169.0, 137.3, 128.6, 128.3, 128.2, 127.4,

95.1, 71.3, 55.6, 53.9, 49.0, 42.2, 36.6, 29.3, 23.6. The minor ketone

16b was not fully characterized due to insuﬃcient amount of material.

Lactam Ketones 7c and 16c from Wacker Oxidation of (R)-

13c. Wacker oxidation of (R)-13c (57.5 mg, 0.22 mmol) according to

the general procedure aﬀorded the ketones 7c and 16c. Puriﬁcation by

chromatography (1:2 petroleum ether/EtOAc, then 1:3 petroleum

ether/EtOAc) gave 7c (48 mg, 78%) and 16c (2.6 mg, 5%).

The ratio of Z- and E-alkenes was ∼2.7:1, based on the integration

1

of benzylic methylene signals at δ 3.97 and δ 3.94 in the H NMR

spectrum.

General Procedure for the Wacker Oxidation. PdCl₂(0.2

mmol) was weighed into the reaction ﬂask, and DMF/H₂O (5 mL, 1:1

v/v) was added. To the above brown color suspension was then added

CuCl (1 mmol), and the mixture was stirred under O₂(1 atm,

balloon) for 1 h at rt. The alkene (1 mmol) was dissolved in DMF (2.5

mL) and was transferred into the above solution via syringe, followed

by H₂O (2.5 mL). The resulting reddish brown solution was then

(S)-1-Benzyl-5-(3-oxobutyl)pyrrolidin-2-one (7c). Colorless oil;

[α]²_D²−58.7 (c 0.45, CHCl₃); IR (neat) 3031, 2934, 1716, 1683,

1492 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ 7.14−7.28 (m, 5 H), 4.87

(d, J = 15.0 Hz, 1 H), 3.93 (d, J = 15.0 Hz, 1 H), 3.39 (dddd, J = 8.3,

K

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

8.3, 5.4, 3.1 Hz, 1 H), 2.16−2.48 (m, 4 H), 2.02 (s, 3 H), 1.86−2.08

(m, 2 H), 1.47−1.62 (m, 2 H); ¹³C NMR (CDCl₃, 75 MHz) δ 207.1,

174.9, 136.6, 128.6, 128.0, 127.4, 56.0, 44.1, 38.0, 30.0, 29.9, 26.2, 23.4;

HRMS (EI-double focusing sector ﬁeld) m/z: [M]⁺Calcd for

C₁₅H₁₉NO₂245.1416; Found 245.1424.

two layers were separated, and the aqueous layer was back-extracted

into CH₂Cl₂. The combined organic layers were dried over Na₂SO₄,

ﬁltered, and concentrated. The crude N,O-acetal (1.60 g) was obtained

as a white solid, which, without any further puriﬁcation, was subjected

to allylation in the next step.

(S)-1-Benzyl-5-(2-oxobutyl)pyrrolidin-2-one (16c). Pale yellow oil;

1-Benzyl-6-hydroxypiperidin-2-one. IR (CH₂Cl₂) 3550−3115,

1

IR (CH₂Cl₂) 3054, 2928, 1714, 1682, 1495 cm⁻¹; H NMR (CDCl₃,

2958, 1617, 1483 cm⁻¹; H NMR (CDCl₃, 300 MHz) δ 7.20−7.24

300 MHz) δ 7.17−7.35 (m, 5 H), 4.68 (d, J = 15.2 Hz, 1 H), 4.20 (d, J

= 15.2 Hz, 1 H), 3.98 (ddd, J = 12.9, 8.3, 4.9 Hz, 1 H), 2.71 (dd, J =

15.0, 4.5 Hz, 1 H), 2.13−2.57 (m, 5 H), 1.56−1.69 (m, 1 H), 1.24−

1.40 (m, 1 H), 0.97 (t, J = 7.3 Hz, 3 H). Compound 16c was obtained

as an inseparable mixture together with a minor amount of the E/Z

enones resulting from a retro-Michael addition pathway in 16c (see ¹H

NMR spectrum of 16c in the Supporting Information).

Lactam Ketones 7d and 16d from Wacker Oxidation of (S)-

13d. Wacker oxidation of (S)-13d (81.4 mg, 0.33 mmol) according to

the general procedure gave the ketones 7d and 16d. Puriﬁcation by

chromatography (1:2 petroleum ether/EtOAc) aﬀorded 7d (75.5 mg,

87%) and 16d (6.1 mg, 7%).

(m, 5 H), 5.12 (d, J = 14.9 Hz, 1 H), 4.90 (ddd, J = 6.8, 3.4, 3.4 Hz, 1

H), 4.30 (d, J = 14.9 Hz, 1 H), 3.61 (br d, J = 6.8 Hz, 1 H), 2.51 (ddd,

J = 17.6, 9.0, 4.4 Hz, 1 H), 2.38 (ddd, J = 17.6, 10.4, 6.2 Hz, 1 H),

1.99−2.17 (m, 1 H), 1.62−1.96 (m, 3 H); ¹³C NMR (CDCl₃, 75

MHz) δ 170.6, 137.6, 128.6, 128.1, 127.3, 78.8, 46.9, 32.4, 30.9, 15.8.

To the above N,O-acetal (1.60 g) in dry CH₂Cl₂(30 mL) under Ar

was added allyltrimethylsilane (2.48 mL, 15.6 mmol), and the solution

was cooled to −78 °C. BF₃·Et₂O (1.96 mL, 15.6 mmol) was added

dropwise to the above mixture, and the resulting solution was stirred at

the same temperature for 30 min before allowing it to warm to rt,

overnight. The reaction mixture was cooled to 0 °C, and saturated

NaHCO₃was added. The organic layer was separated, and the

aqueous layer was back-extracted into CH₂Cl₂. The combined organic

layers were dried over Na₂SO₄, ﬁltered, and concentrated. Puriﬁcation

by chromatography (1:2 petroleum ether/Et₂O then 1:3 petroleum

ether/Et₂O) aﬀorded 17b (1.50 g, 83% over two steps) as a colorless

oil: IR (neat) 2949, 1636, 1468 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ

7.17−7.33 (m, 5 H), 5.54−5.70 (m, 1 H), 5.38 (d, J = 15.2 Hz, 1 H),

5.00−5.12 (m, 2 H), 3.96 (d, J = 15.2 Hz, 1 H), 3.32 (ddd, J = 13.7,

4.6, 4.6 Hz, 1 H), 2.37−2.51 (m, 3 H), 2.17−2.31 (m, 1 H), 1.60−1.95

(m, 4 H); ¹³C NMR (CDCl₃, 75 MHz) δ 170.2, 137.5, 133.9, 128.4,

127.6, 127.0, 118.0, 54.7, 47.2, 36.7, 31.8, 26.1, 17.0. (R)-17b has been

reported²²in the literature.

(S)-1-Benzyl-6-(3-oxobutyl)piperidin-2-one (7d). Pale yellow oil;

[α]²_D³+68.3 (c 0.58, CHCl₃); IR (neat) 2950, 2887, 1716, 1636, 1470

1

cm⁻¹; H NMR (CDCl₃, 300 MHz) δ 7.12−7.27 (m, 5 H), 5.29 (d, J

= 15.0 Hz, 1 H), 3.94 (d, J = 15.0 Hz, 1 H), 3.16−3.26 (m, 1 H),

2.35−2.45 (m, 2 H), 2.18−2.35 (m, 2 H), 2.03 (s, 3 H), 1.87−2.00

(m, 1 H), 1.50−1.88 (m, 5 H); ¹³C NMR (CDCl₃, 75 MHz) δ 207.1,

170.1, 137.6, 128.4, 127.7, 127.0, 54.5, 47.2, 39.2, 31.8, 29.9, 26.0, 25.4,

17.1; HRMS (EI-double focusing sector ﬁeld) m/z: [M]⁺Calcd for

C₁₆H₂₁NO₂259.1572; Found 259.1564.

(S)-1-Benzyl-6-(2-oxobutyl)piperidin-2-one (16d). Pale yellow oil;

1

IR (CH₂Cl₂) 3054, 2942, 1714, 1637, 1495 cm⁻¹; H NMR (CDCl₃,

300 MHz) δ 7.12−7.27 (m, 5 H), 4.97 (d, J = 15.0 Hz, 1 H), 4.05 (d, J

= 15.0 Hz. One H), 3.87−3.96 (m, 1 H), 2.63 (dd, J = 17.2, 4.4 Hz, 1

H), 2.55 (dd, J = 17.2, 8.1 Hz, 1 H), 2.38−2.47 (m, 2 H), 2.22 (q, J =

7.2 Hz, 2 H), 1.53−1.86 (m, 4 H), 0.93 (t, J = 7.2 Hz, 3 H); ¹³C NMR

(CDCl₃, 75 MHz) δ 208.7, 170.2, 137.6, 128.6, 127.8, 127.3, 51.8,

48.4, 45.5, 36.7, 31.8, 27.8, 17.3, 7.6. Compound 16d was obtained as

an inseparable mixture together with minor amount of the enone

resulting from a retro-Michael addition pathway in 16d (see ¹H NMR

spectrum of 16d in the Supporting Information).

1-Benzyl-6-(prop-1-enyl)piperidin-2-one (17d). The alkene

17d was prepared from the allyl δ-lactam 17b (65 mg, 0.28 mmol)

according to the procedure described for the preparation of 11.

Puriﬁcation by chromatography (2:1 petroleum ether/EtOAc)

aﬀorded 30 (58 mg, 89%) as an inseparable mixture of Z- and E-

diastereomers: Brown oil: IR (neat) 2945, 2920, 1641 cm⁻¹; ¹H NMR

(CDCl₃, 300 MHz) δ 7.15−7.33 (m, 5 H), 5.42 (d, J = 14.8 Hz, 1 H),

5.29−5.68 (m, 2 H), 3.77 (d, J = 14.8 Hz, 1 H), 3.69−3.80 (m, 1 H),

2.36−2.55 (m, 2 H), 1.71 (d, J = 6.2 Hz, 3 H), 1.60−1.95 (m, 4 H); δ

(discernible signals for the minor diastereomer) 4.07−4.16 (m, 1 H),

1.49 (dd, J = 6.9, 0.8 Hz, 3 H); ¹³C NMR (CDCl₃, 75 MHz) δ (major

diastereomer) 170.1, 137.8, 130.5, 128.4, 128.1, 127.9, 127.0, 57.7,

47.0, 32.2, 29.4, 17.5 (4), 17.5 (0); δ (discernible signals for the minor

diastereomer) 137.7, 130.9, 128.0, 52.3, 46.8, 32.4, 29.6, 18.4, 12.8;

HRMS (EI-double focusing sector ﬁeld) m/z: [M]⁺Calcd for

C₁₅H₁₉NO 229.1467; Found 229.1462.

1-Cyclohexyl-2-butene (17a). Ph₃P⁺EtBr⁻(1.05 g, 2.8 mmol)

was dried under vacuum at 110 °C for 1 h and cooled to rt. The above

salt was suspended in THF (6 mL), and KOt-Bu (331 mg, 2.8 mmol)

was added in one portion at 0 °C. A bright orange solution resulted, to

which, after 30 min at 0 °C, was added the 2-cyclohexylacetaldehyde

(235 mg, 1.9 mmol) in THF (2 mL) via cannula, and stirred for 1 h.

Saturated aqueous NH₄Cl (3 mL) was added, and the THF was

evaporated under reduced pressure. The aqueous layer was extracted

with CH₂Cl₂(3 × 10 mL), dried over Na₂SO₄, ﬁltered, and

concentrated. The crude product was puriﬁed by chromatography

(petroleum ether) to aﬀord 17a (141 mg, 55%) as an inseparable

mixture of Z- and E-diastereomers: Colorless oil; IR (CH₂Cl₂) 2925,

The ratio of E- and Z-17d could not be determined due to the

1

extensive overlap of signals in the H NMR spectrum.

Ketones 18a and 19a from Wacker Oxidation of 17a. Wacker

oxidation of 17a (45 mg, 0.33 mmol) according to the general

procedure aﬀorded the ketones 18a and 19a. Puriﬁcation by

chromatography (10:1 petroleum ether/Et₂O) gave an inseparable

mixture of 18a and 19a (15.3 mg) as a colorless oil in 30% combined

yield. The ratio of the ketones 18a and 19a was found to be 1.6:1,

based on the integration of the methyl singlet at δ 2.11 (18a) and the

1

2853, 1449 cm⁻¹; H NMR (CDCl₃, 300 MHz) δ (Z-17a) 5.34−5.54

(m, 2 H), 1.93 (dd, J = 6.7, 6.7 Hz, 2 H), 1.62−1.77 (m, 5 H), 1.59 (d,

J = 6.2 Hz, 3 H), 1.08−1.37 (m, 4 H), 0.81−1.00 (m, 2 H); δ

(discernible signals for E-17a) 1.86 (dd, J = 6.7, 6.7 Hz, 2 H); ¹³C

NMR (CDCl₃, 75 MHz) δ (Z-17a) 129.4, 124.2, 38.3, 34.6, 33.2, 26.6,

26.4, 12.8; δ (discernible signals for E-17a) 40.6, 38.1, 33.1, 17.9.

Compound Z-17a has been reported²¹in the literature.

1

methyl triplet at δ 1.02 (19a) in the H NMR spectrum.

4-Cyclohexylbutan-2-one (18a) and 1-Cyclohexylbutan-2-one

(19a). ¹H NMR (CDCl₃, 300 MHz) δ (extensive overlap of signals in

the cyclohexyl ring region of 18a and 19a) 0.78−0.98 (m), 1.10−1.33

(m), 1.54−1.74 (m); δ (discernible signals for 18a) 2.41 (t, J = 7.5 Hz,

2 H), 2.11 (s, 3 H), 1.40−1.50 (m, 2 H); δ (discernible signals for

19a) 2.37 (q, J = 7.3 Hz, 2 H), 2.25 (d, J = 6.9 Hz, 2 H), 1.02 (t, J =

7.3 Hz, 3 H). The ketones 18a²³and 19a²⁴have been reported in the

literature.

Compounds 18b and 19b from Wacker Oxidation of 17b.

Wacker oxidation of 17b (66 mg, 0.29 mmol) according to the general

procedure gave 18b and 19b. Puriﬁcation by chromatography (1:4

petroleum ether/EtOAc) aﬀorded a mixture of 18b and 19b (60.2 mg)

as a colorless oil in 85% combined yield. The ratio of 18b and 19b was

found to be 1:3.5, respectively, based on the integration of the benzylic

The ratio of Z- and E-alkenes was 5.5:1, respectively, based on

1

integration of the methyl signals at δ 1.93 and δ 1.86 in the H NMR

spectrum.

6-Allyl-1-benzylpiperidin-2-one (17b). To the known⁴⁴N-

benzyl glutarimide (1.60 g, 7.87 mmol) in THF (40 mL) at −78 °C

under Ar was added LiBEt₃H (11.8 mL, 1 M in THF), and the

solution was stirred at the same temperature for 30 min. The reaction

mixture was quenched with saturated NaHCO₃and was allowed to

warm to 0 °C. Aqueous H₂O₂(6 mL, 30%) was added dropwise, and

the resulting solution was stirred at the same temperature for 30 min

before allowing it to warm to rt. The solvent was evaporated under

reduced pressure, and the crude residue was diluted with CH₂Cl₂. The

L

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

1

proton signals at δ 5.32 (18b) and δ 5.00 (19b) in the H NMR

spectrum.

3061, 3032, 2924, 2849, 1694, 1663, 1605, 1495 cm⁻¹; ¹H NMR

(CDCl₃, 300 MHz) δ 7.10−7.30 (m, 5 H), 4.83−4.89 (m, 1 H), 4.57

(d, J = 6.7 Hz, 1 H), 4.53 (d, J = 6.7 Hz, 1 H), 4.35 (d, J = 15.0 Hz, 1

H), 4.19 (d, J = 15.0 Hz, 1 H), 4.04 (dd, J = 7.5, 7.5 Hz, 1 H), 3.26 (s,

3 H), 2.62 (dd, J = 16.2, 7.5 Hz, 1 H), 2.35−2.48 (m, 2 H), 2.09−2.18

(m, 2 H), 1.67 (s, 3 H), 1.53 (ddd, J = 14.4, 7.2, 7.2 Hz, 1 H); ¹³C

NMR (CDCl₃, 75 MHz) δ 171.4, 147.5, 138.8, 128.3, 127.7, 127.0,

126.0, 95.7, 79.6, 77.0, 55.4, 43.1, 36.8, 35.9, 28.0, 16.8; HRMS (EI-

double focusing sector ﬁeld) m/z: [M]⁺Calcd for C₁₈H₂₃NO₃

301.1678; Found 301.1685.

3-(1-Benzyl-6-oxopiperidin-2-yl)propanal (18b) and 1-Benzyl-6-

(2-oxopropyl)piperidin-2-one (19b). IR (CH₂Cl₂) 2952, 1717, 1635

cm⁻¹; H NMR (CDCl₃, 300 MHz) δ (extensive overlap of signals in

1

18b and 19b) 7.08−7.37 (m, 5 H), 2.55−2.76 (m), 2.31−2.54 (m),

1.55−1.92 (m); δ (discernible signals for 18b) δ 9.68 (s, 1 H), 5.32 (d,

J = 15.3 Hz, 1 H), 3.99 (d, J = 15.3 Hz, 1 H), 3.22−3.32 (m, 1 H); δ

(discernible signals for 19b) 5.00 (d, J = 15.1 Hz, 1 H), 4.08 (d, J =

15.1 Hz, 1 H), 3.86−3.98 (m, 1 H), 2.00 (s, 3 H); ¹³C NMR (CDCl₃,

75 MHz) δ (18b) 170.1, 137.4, 128.4, 127.7, 127.1, 54.5, 47.3, 39.8,

31.8, 26.0, 23.8, 17.1; δ (19b) 170.0, 137.3, 128.5, 127.6, 127.2, 51.4,

48.2, 46.5, 31.7, 30.4, 27.6, 17.1; Compound 19b²⁵has been reported

in the literature.

(4S,5S)-1-Benzyl-4-(methoxymethoxy)-5-(4-oxopentyl)pyrrolidin-

2-one (21). Colorless oil; [α]²_D²−5.4 (c 1.21, CHCl₃); IR (CH₂Cl₂)

1

3056, 2953, 1713, 1690, 1496 cm⁻¹; H NMR (CDCl₃, 300 MHz) δ

7.12−7.30 (m, 5 H), 5.00 (d, J = 15.1 Hz, 1 H), 4.67 (d, J = 6.9 Hz, 1

H), 4.61 (d, J = 6.9 Hz, 1 H), 4.23−4.32 (m, 1 H), 4.00 (d, J = 15.1

Hz, 1 H), 3.45−3.53 (m, 1 H), 3.36 (s, 3 H), 2.63 (dd, J = 16.9, 6.3

Hz, 1 H), 2.55 (dd, J = 16.9, 5.2 Hz, 1 H), 2.37 (t, J = 6.9 Hz, 2 H),

2.09 (s, 3 H), 1.43−1.80 (m, 4 H); ¹³C NMR (CDCl₃, 75 MHz) δ

208.1, 172.6, 136.5, 128.7, 127.5, 96.0, 71.5, 60.2, 56.0, 44.1, 43.4, 37.9,

29.9, 26.4, 19.4; HRMS (EI-double focusing sector ﬁeld) m/z: [M]⁺

Calcd for C₁₈H₂₅NO₄319.1784; Found 319.1782.

1-Cyclohexylpropan-2-one (19c). Wacker oxidation of allylcy-

clohexane (50 mg, 0.40 mmol) according to the general procedure

gave the ketone 19c. Puriﬁcation by chromatography (petroleum

ether) aﬀorded the ketone 19c (39 mg, 68%) as a colorless oil: IR

(neat) 2925, 2853, 1715 cm⁻¹; H NMR (CDCl₃, 300 MHz) δ 2.28

1

(d, J = 6.8 Hz, 2 H, CH₂C(O)Me), 2.11 (s, 3 H), 1.58−1.89 (m, 5 H),

1.03−1.35 (m, 4 H), 0.82−0.10 (m, 2 H); ¹³C NMR (CDCl₃, 75

MHz) δ 209, 51.5, 33.9, 33.2, 30.5, 26.2, 26.1. Compound 19c has

been reported²⁶in the literature.

(4S,5S)-1-Benzyl-4-(methoxymethoxy)-5-(3-oxopentyl)pyrrolidin-

2-one (22). Colorless oil; [α]²_D²−13.0 (c 0.71, CHCl₃); IR (CH₂Cl₂)

1

3056, 2941, 1712, 1691, 1496 cm⁻¹; H NMR (CDCl₃, 300 MHz) δ

General Procedure for the Alkylidene Carbene Generation-

C−H Insertion. Conditions A: To the yellow colored solution of

trimethylsilyldiazomethane (0.20 mmol, 2.0 M in hexane) in THF (2.5

mL) under argon at −78 °C was added n-BuLi (0.19 mmol, 1.85 M in

hexane) dropwise. The resulting yellow-orange solution was stirred at

−78 °C for 45 min, and the appropriate lactam ketone (0.1 mmol) in

THF (1 mL) was added dropwise via cannula (rinsed with 0.5 mL

THF). At this time, the color of the solution changed from yellow-

orange to brown. After stirring the reaction mixture for 30 min at −78

°C, the reaction temperature was gradually raised to 0 °C by itself. The

solution was stirred for another 30 min at 0 °C, saturated aqueous

NH₄Cl (1 mL) was added, and the reaction mixture was extracted with

EtOAc (3 × 5 mL). The aqueous layer was saturated with solid NaCl

and back-extracted into EtOAc. The combined organic layers were

dried over Na₂SO₄, ﬁltered, and concentrated. The crude product was

puriﬁed by chromatography.

7.12−7.30 (m, 5 H), 4.93 (d, J = 15.0 Hz, 1 H), 4.58 (d, J = 6.7 Hz, 1

H), 4.53 (d, J = 6.7 Hz, 1 H), 4.21 (m, 1 H), 3.93 (d, J = 15.0 Hz, 1

H), 3.49 (m, 1 H), 3.28 (s, 3 H), 2.58 (dd, J = 16.9, 6.9 Hz, 1 H), 2.47

(dd, J = 16.9, 6.0 Hz, 1 H), 2.36 (t, J = 7.2 Hz, 2 H), 2.29 (q, J = 7.3

Hz, 2 H), 1.89 (m, 2 H), 0.96 (t, J = 7.3 Hz, 3 H); ¹³C NMR (CDCl₃,

75 MHz) δ 210.3, 172.3, 136.4, 128.7, 128.0, 127.6, 95.9, 71.4, 59.4,

55.9, 44.1, 37.7, 37.6, 35.9, 21.0, 7.8; HRMS (ESI-QTOF) m/z: [M +

Na]⁺Calcd for C₁₈H₂₅NO₄Na 342.1681; Found 342.1683.

(S)-1-Benzyl-7-methyl-1-azaspiro[4,4]non-3,6-diene-2-one (23).

1

IR (CH₂Cl₂) 3054, 2919, 1680, 1424 cm⁻¹; H NMR (CDCl₃, 300

MHz) δ 7.26−7.38 (m, 5 H, Ar-H), 6.93 (d, J = 5.8 Hz, 1 H), 6.16 (d,

J = 5.8 Hz, 1 H), 4.77−4.81 (m, 1 H), 4.67 (d, J = 15.5 Hz, 1 H), 4.36

(d, J = 15.5 Hz, 1 H), 2.33−2.42 (m, 2 H), 2.09−2.21 (m, 1 H), 1.81−

1.93 (m, 1 H), 1.81 (d, J = 0.9 Hz, 3 H). Compound 23 was not fully

characterized due to insuﬃcient amount of material.

Conditions B: The lithiotrimethylsilyldiazomethane anion (3.0

equiv) was generated according to the same procedure described for

conditions A. However, after the addition of ketone, the reaction

mixture was stirred at −78 °C for 20 min and was directly allowed to

warm to 0 °C (ice−water bath). The solution was stirred for 30 min at

0 °C, and saturated aqueous NH₄Cl (1 mL) was added. A similar

workup procedure to that of conditions A was used for isolation of

products.

Conditions C: The lithiotrimethylsilyldiazomethane anion (1.9

equiv) was generated according to the same procedure described for

conditions A. However, after the addition of ketone, the reaction

mixture was stirred at −78 °C for 20 min and was directly allowed to

warm to 0 °C (ice−water bath). The evolution of N₂gas was observed

during the warming process. The solution was stirred for 30 min at 0

°C, and saturated aqueous NH₄Cl (1 mL) was added. A similar

workup procedure to that of conditions A was used for isolation of

products.

Compounds 20a, 21, 22, and 23 from Alkylidene Carbene

Generation-C−H Insertion Reaction of (S,S)-7a. Alkylidene

carbene generation-C−H insertion of (S,S)-7a (34.3 mg, 0.11

mmol) according to the general procedure described under conditions

A gave 20a, 21, and 22. Puriﬁcation by chromatography (2:1

petroleum ether/EtOAc, then 1:1 petroleum ether/EtOAc) aﬀorded

the spirolactam 20a (13.5 mg, 45%) and the homologated ketones 21

(6.7 mg, 19%) and 22 (2.7 mg, 8%). When the alkylidene carbene

generation-C−H insertion of (S,S)-7a (19.2 mg, 0.06 mmol) was

conducted under conditions C according to the general procedure, the

spirolactam 20a (9.8 mg, 53%) and the β-elimination product 23 (∼1

mg, 5%) were obtained.

Compounds 20b and 24 from Alkylidene Carbene Gen-

eration-C−H Insertion of (R,R)-7b. Alkylidene carbene generation-

C−H insertion of (R,R)-7b (34.2 mg, 0.11 mmol) according to the

general procedure under conditions B aﬀorded the spirolactam 20b

and the bicyclic alcohol 24. Puriﬁcation by chromatography (1:1

petroleum ether/EtOAc then EtOAc) gave 20b (8.0 mg, 24%) and 24

(11.2 mg, 33%). When alkylidene carbene generation-C−H insertion

of (R,R)-7b (26 mg, 0.08 mmol) was conducted under conditions C

according to the general procedure, the spirolactam 20b (18.5 mg,

72%) was obtained exclusively.

(5S,10R)-6-(Benzyl)-2-methyl-10-(methoxymethoxy)-6-azaspiro-

[4,5]dec-1-ene-7-one (20b). Colorless oil; [α]_D²²−84.1 (c 0.8,

1

CHCl₃); IR (neat) 3033, 2943, 2850, 1636 cm⁻¹; H NMR (CDCl₃,

300 MHz) δ 7.08−7.36 (m, 5 H), 4.89−4.96 (m, 1 H), 4.65 (d, J = 6.9

Hz, 1 H), 4.61 (d, J = 15.5 Hz, 1 H), 4.36 (d, J = 6.9 Hz, 1 H), 3.73

(dd, J = 9.1, 4.1 Hz, 1 H), 3.32 (s, 3 H), 2.44−2.72 (m, 2 H), 2.18−

2.41 (m, 3 H), 1.90−2.10 (m, 2 H), 1.71−1.85 (m, 1 H), 1.71 (s, 3

H); ¹³C NMR (CDCl₃, 75 MHz) δ 169.6, 145.9, 139.8, 128.1, 127.2,

126.9, 126.4, 95.5, 77.7, 76.4, 55.6, 46.3, 36.4, 31.3, 29.5, 23.7, 16.6;

HRMS (EI-double focusing sector ﬁeld) m/z: [M]⁺Calcd for

C₁₉H₂₅NO₃315.1834; Found 315.1829.

(1R,5R,9R)-6-Benzyl-2-hydroxy-9-(methoxymethoxy)-2-methyl-6-

aza-bicyclo[3.2.2]nonan-7-one (24). Colorless oil; [α]²_D²−6.5 (c 0.41,

1

CHCl₃); IR (CH₂Cl₂) 3548−3133, 3047, 2950, 1646 cm⁻¹; H NMR

(CDCl₃, 300 MHz) δ 7.07−7.33 (m, 5 H), 4.69 (d, J = 14.7 Hz, 1 H),

4.48 (d, J = 7.0 Hz, 1 H), 4.45 (d, J = 7.0 Hz, 1 H), 4.28 (d, J = 14.7

Hz, 1 H), 3.80 (ddd, J = 10.2, 5.6, 4.5 Hz, 1 H), 3.39−3.46 (m, 1 H),

3.22 (s, 3 H), 2.60 (d, J = 6.5 Hz, 1 H), 2.40 (ddd, J = 15.2, 10.5, 6.5

Hz, 1 H), 1.88−1.99 (m, 1 H), 1.60−1.77 (m, 3 H), 1.50 (ddd, J =

14.2, 7.1, 3.5 Hz, 1 H), 1.24 (s, 3 H); ¹³C NMR (CDCl₃, 125 MHz) δ

172.4, 137.1, 128.6, 128.3, 127.6, 96.2, 73.2, 71.2, 55.7, 55.5, 53.4, 49.4,

(4S,5R)-1-Benzyl-4-(methoxymethoxy)-7-methyl-1-azaspiro[4,4]-

non-6-ene-2-one (20a). [α]²_D³+79.0 (c 0.97, CHCl₃); IR (CH₂Cl₂)

M

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

34.5, 31.1, 29.8, 23.9. HRMS (ESI-QTOF) m/z: [M + Na]⁺Calcd for

C₁₈H₂₅NO₄Na 342.1681; Found 342.1671.

orange oil. The ratio of the two diastereomers cannot be determined

1

due to the extensive overlap of the signals in the H NMR spectrum:

(R)-1-Benzyl-7-methyl-1-azaspiro[4,4]non-6-ene-2-one

(20c). Alkylidene carbene generation-C−H insertion of the lactam

ketone (S)-7c (16 mg, 0.06 mmol) according to the general procedure

under conditions C gave the spirolactam 20c. Puriﬁcation by

chromatography (1:2 petroleum ether/EtOAc) aﬀorded 20c (11.9

mg, 76%) as a colorless oil: [α]²_D³+110.3 (c 1.17, CHCl₃); IR (neat)

[α]²_D²+40.5 (c 1.30, CHCl₃); IR (CH₂Cl₂) 2965, 2933, 1646, 1591

1

cm⁻¹; H NMR (CDCl₃, 300 MHz) δ (major diastereomer) 7.37−

7.45 (m, 2 H), 7.20−7.36 (m, 6 H), 7.02−7.09 (m, 2 H), 5.27−5.64

(m, 3 H), 5.44 (d, J = 15.1 Hz, 1 H), 4.04 (d, J = 15.1 Hz, 1 H), 3.68−

3.80 (m, 1 H), 2.57−2.81 (m, 2 H), 2.31−2.57 (m, 3 H), 1.94−2.22

(m, 3 H), 0.96 (t, J = 7.6 Hz, 3 H); δ (discernible signals for minor

diastereomer) 4.09 (d, J = 14.5 Hz, 1 H), 0.98 (t, J = 7.4 Hz, 3 H); ¹³C

NMR (CDCl₃, 75 MHz) δ (major diastereomer) 193.5, 168.8, 152.9,

136.6, 134.8, 129.3, 128.5, 127.5, 127.2, 126.5, 123.4, 121.5, 77.9, 56.5,

47.8, 28.0, 27.2, 22.0, 20.5, 13.9; δ (discernible signals for minor

diastereomer) 168.9, 136.8, 136.2, 127.5, 127.2, 123.5, 56.9, 32.7, 25.4,

15.1, 13.3. HRMS (FD-TOF) m/z: [M]⁺Calcd for C₂₄H₂₇NO₃S

409.1712; Found 409.1713.

1

3050, 2970, 2938, 2922, 2851, 1682, 1495 cm⁻¹; H NMR (CDCl₃,

300 MHz) δ 7.10−7.25 (m, 5 H), 4.88−4.93 (m, 1 H), 4.26 (d, J =

15.7 Hz, 1 H), 4.20 (d, J = 15.7 Hz, 1 H), 2.45 (dd, J = 16.4, 8.1 Hz, 1

H), 2.37 (dd, J = 16.4, 6.9 Hz, 1 H), 2.14 (dd, J = 6.8, 6.8 Hz, 2 H),

1.92 (dd, J = 7.7, 7.7 Hz, 2 H), 1.77−1.85 (m, 2 H); ¹³C NMR

(CDCl₃, 75 MHz) δ 174.5, 144.7, 139.2, 128.2, 128.1, 127.6, 126.8,

76.5, 43.2, 35.3, 35.0, 33.4, 30.2, 16.6; HRMS (EI-double focusing

sector ﬁeld) m/z: [M]⁺Calcd for C₁₆H₁₉NO 241.1467; Found

241.1471.

(S)-6-(Benzyl)-2-methyl-6-azaspiro[4,5]dec-1-ene-7-one

(20d). Alkylidene carbene generation-C−H insertion of the lactam

ketone (S)-7d (43 mg, 0.17 mmol) according to the general procedure

under conditions C gave the spirolactam 20d. Puriﬁcation by

chromatography (1:1 petroleum ether/EtOAc) aﬀorded 20d (26.7

mg, 62%) as a pale yellow oil: [α]²_D²−88.7 (c 0.87, CHCl₃); IR

(CH₂Cl₂) 3053, 2947, 1628, 1495 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz)

δ 7.21−7.30 (m, 2 H), 7.13−7.21 (m, 3 H), 5.02−5.07 (m, 1 H), 4.66

(d, J = 15.4 Hz, 1 H), 4.34 (d, J = 15.4 Hz, 1 H), 2.40−2.60 (m, 2 H),

2.13−2.34 (m, 2 H), 1.72−2.06 (m, 6 H), 1.68 (d, J = 1.0 Hz, 3 H);

¹³C NMR (CDCl₃, 75 MHz) δ 170.6, 142.7, 140.0, 130.0, 128.1, 127.0,

The above thiocarbonate (1.45 g) was subjected to free-radical-

mediated reduction in the next step to form 32. Puriﬁcation by

chromatography (2:1 petroleum ether/EtOAc) aﬀorded an inseparable

E/Z mixture of 32 (850 mg, 67%, 52% from 14b) as a colorless oil.

The ratio of the two diastereomers cannot be determined due to the

extensive overlap of the signals in the ¹H NMR spectrum: [α]_D²²+36.8

(c 1.1, CHCl₃); IR (CH₂Cl₂) 2957, 2873, 1640, 1450 cm⁻¹; ¹H NMR

(CDCl₃, 300 MHz) δ (major diastereomer) 5.40−5.52 (m, 1 H), 5.41

(d, J = 15.1 Hz, 1 H), 5.10−5.23 (m, 1 H), 3.97 (d, J = 15.1 Hz, 1 H),

3.29 (ddd, J = 13.6, 4.4, 4.4 Hz), 2.33−2.54 (m, 3 H), 2.18−2.32 (m, 1

H), 2.00 (dq, J = 7.2, 7.2 Hz, 2 H), 1.79−1.94 (m, 1 H), 1.58−1.79

(m, 3 H), 0.93 (t, J = 7.5 Hz, 3 H); δ (discernible signals for minor

diastereomer) 5.37 (d, J = 15.3 Hz, 1 H), 0.92 (t, J = 7.4 Hz, 3 H); ¹³C

NMR (CDCl₃, 75 MHz) δ (major diastereomer) 170.2, 137.6, 134.5,

128.4, 127.6, 127.0, 123.9, 55.2, 47.3, 31.9, 29.9, 26.2, 20.7, 17.2, 14.0;

δ (discernible signals for minor diastereomer) 170.2, 137.5, 135.7,

126.9, 124.1, 55.1, 35.4, 31.8, 26.0, 25.4, 17.0, 13.5; HRMS (ESI-

QTOF) m/z: [M + Na]⁺Calcd for C₁₇H₂₃NONa 280.1677; Found

280.1665.

126.3, 74.0, 46.2, 36.0, 35.6, 35.3, 18.2; HRMS (EI-double focusing

sector ﬁeld) m/z: [M]⁺Calcd for C₁₇H₂₁NO 255.1623; Found

255.1629.

(5R,10S)-6-(p-Methoxybenzyl)-10-(methoxymethoxy)-2-

methyl-6-azaspiro[4,5]dec-1-ene-7-one (20e). Alkylidene car-

bene generation-C−H insertion of the lactam ketone (S,S)-7d (28

mg, 0.08 mmol) according to the general procedure under conditions

C aﬀorded the spirolactam 20d. Puriﬁcation by chromatography (1:2

petroleum ether/EtOAc) gave 20d (15.1 mg, 55%) as a colorless oil:

[α]²_D³+65.0 (c 1.40, CHCl₃); IR (CH₂Cl₂) 3024, 2900, 1636, 1629

cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ 7.07−7.15 (m, 2 H), 6.76−6.84

(m, 2 H), 4.90−4.96 (m, 1 H), 4.64 (d, J = 6.9 Hz, 1 H), 4.56 (d, J =

15.1 Hz, 1 H), 4.55 (d, J = 6.9 Hz, 1 H), 4.28 (d, J = 15.1 Hz, 1 H),

3.78 (s, 3 H), 3.71 (dd, J = 9.4, 4.1 Hz, 1 H), 3.32 (s, 3 H), 2.64 (ddd,

J = 17.9, 6.4, 5.2 Hz, 1 H), 2.50 (ddd, J = 17.9, 9.3, 7.0 Hz, 1 H), 2.19−

2.40 (m, 3 H), 1.89−2.08 (m, 2 H), 1.73−1.84 (m, 1 H), 1.74 (s, 3

H); ¹³C NMR (CDCl3, 75 MHz) δ 169.6, 158.2, 147.7, 132.0, 128.4,

127.3, 113.5, 95.5, 77.6, 76.4, 55.6, 55.2, 45.7, 36.4, 31.3, 29.6, 23.7,

16.6; HRMS (EI-double focusing sector ﬁeld) m/z: [M]⁺Calcd for

C₂₀H₂₇NO₄345.1940; Found 345.1944.

(S)-1-Benzyl-6-(pent-2-enyl)piperidin-2-one ((S)-32). Wittig

oleﬁnation of the lactol (R,R)-14b (1.14 g, 4.61 mmol) with

propylidenetriphenylphosphorane (4 equiv, Ph₃P⁺n-PrBr⁻, KO^tBu)

was conducted similar to the procedure described for the preparation

of alkenol (S,S)-15a. Puriﬁcation by chromatography (1:2 petroleum

ether/EtOAc) aﬀorded an inseparable mixture of the alkenol 31 (1.10

g, 87.5%) and triphenylphosphine oxide as a white solid. The alkenol

31 was obtained as a mixture of E- and Z-diastereomers in a 1:5 ratio.

The ratio of the two diastereomers was determined based on the

integration of the methyl group signals at δ 0.85 and δ 0.92 in the ¹H

NMR spectrum: ¹H NMR (CDCl₃, 300 MHz) δ (major diastereomer)

7.05−7.23 (m, 5 H), 5.24−5.51 (m, 3 H), 3.98−4.05 (br m, 1 H),

3.77−3.89 (m, 2 H), 2.08−2.60 (m, 4 H), 1.68−2.02 (m, 4 H), 0.85 (t,

J = 7.5 Hz, 3 H); δ (discernible signals for minor diastereomer) 1.46−

1.63 (m, 1 H), 0.92 (td, J = 7.3, 1.0 Hz, 3 H).

Lactam Ketones 30 and 33 from Wacker Oxidation of 32.

Wacker oxidation of 32 (511 mg, 1.98 mmol) according to the general

procedure aﬀorded the ketones 30 and 33. Puriﬁcation by

chromatography (1:1 petroleum ether/EtOAc) gave 30 (411 mg,

76%) and 33 (49 mg, 8%).

(S)-1-Benzyl-6-(3-oxopentyl)piperidin-2-one (30). Colorless oil;

[α]²_D¹+64.1 (c 1.03, CHCl₃); IR (neat) 2941, 1713, 1636, 1495 cm⁻¹;

¹H NMR (CDCl₃, 300 MHz) δ 7.13−7.28 (m, 5 H), 5.30 (d, J = 15.0

Hz, 1 H), 3.94 (d, J = 15.0 Hz, 1 H), 3.21 (ddd, J = 8.8, 8.8, 4.9 Hz, 1

H), 2.40 (t, J = 6.5 Hz, 2 H), 2.16−2.39 (m, 4 H), 1.89−2.04 (m, 1

H), 1.49−1.89 (m, 5 H), 0.97 (t, J = 7.3 Hz, 3 H); ¹³C NMR (CDCl₃,

75 MHz) δ 209.9, 170.1, 137.7, 128.4, 127.8, 127.0, 54.6, 47.3, 37.9,

35.9, 31.8, 26.1, 25.6, 17.2, 7.7; HRMS (EI-double focusing sector

ﬁled) m/z: [M]⁺Calcd for C₁₇H₂₃NO₂273.1729; Found 273.1719.

1-Benzyl-6-(2-oxopentyl)piperidin-2-one (33). Colorless oil; IR

(CH₂Cl₂) 3054, 2961, 2877, 1711, 1635 cm⁻¹; ¹H NMR (CDCl₃, 300

MHz) δ 7.16−7.32 (m, 5 H), 5.02 (d, J = 15.0 Hz, 1 H), 4.08 (d, J =

15.0 Hz, 1 H), 3.90−3.99 (m, 1 H), 2.67 (dd, J = 17.0, 4.6 Hz, 1 H),

2.59 (dd, J = 17.0, 8.2 Hz, 1 H), 2.41−2.50 (m, 2 H), 2.23 (td, J = 7.4,

2.1 Hz, 2 H), 1.59−1.87 (m, 4 H), 1.52 (qt, J = 7.4, 7.4 Hz, 2 H), 0.86

(t, J = 7.4 Hz, 3 H). Compound 33 was obtained as an inseparable

mixture together with a minor amount of the enone resulting from a

retro-Michael addition pathway in 33 (see ¹H NMR spectrum of 33 in

the Supporting Information).

(S)-6-(Benzyl)-2-ethyl-6-azaspiro[4,5]dec-1-ene-7-one (29).

Alkylidene carbene generation-C−H insertion of the lactam ketone

30 (200 mg, 0.73 mmol) according to the general procedure under

conditions C gave the spirolactam 29. Puriﬁcation by chromatography

(1:1 petroleum ether/EtOAc) aﬀorded 29 (117 mg, 60%) as a

colorless oil: [α]²_D²+79.7 (c 1.45, CHCl₃); IR (neat) 2964, 2938, 2876,

The alkene 32 was prepared from the alkenol 31 following a two-

step (thiocarbonate formation−free-radical reduction) procedure

described for the preparation of (R)-13c. In the ﬁrst step, the alkenol

31 (1.10 g) was converted to the corresponding thiocarbonate

derivative. Puriﬁcation by chromatography (4:1 petroleum ether/

EtOAc, then 1:2 petroleum ether/EtOAc) gave an inseparable

diastereomeric mixture of the thiocarbonate (1.45 g, 88%) as an

1

2847, 1638, 1496 cm⁻¹; H NMR (CDCl₃, 300 MHz) 7.10−7.26 (m,

5 H), 4.98 (t, J = 1.6 Hz, 1 H), 4.69 (d, J = 15.4 Hz, 1 H), 4.25 (d, J =

15.4 Hz, 1 H), 2.37−2.58 (m, 2 H), 2.12−2.34 (m, 2 H), 1.66−2.03

(m, 8 H), 0.91 (t, J = 7.4 Hz, 3 H); ¹³C NMR (CDCl₃, 75 MHz) δ

170.4, 148.4, 139.9, 127.9, 127.7, 126.8, 126.1, 45.9, 35.9, 35.0, 33.4,

32.4, 23.9, 18.0, 11.7. HRMS (FD-TOF) m/z: [M]⁺Calcd for

N

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

C₁₈H₂₃NO 269.1780; Found 269.1790; HPLC: Chiralpak AD column

(4.6 mm × 250 mm); 95:5 v/v hexane/i-PrOH; ﬂow rate, 1.0 mL/

min; λ_max= 220 nm; t_R(R-29) = 11.9 min and t_R(S-29) = 13.1 min;

99% ee. The retention times for (R)- and (S)-29 were determined by

injecting a sample of ( )-29 for chiral HPLC analysis.

The ratio of Z- and E-alkenes was 1.2:1, based on the integration of

the oleﬁn proton doublets at δ 5.88 and δ 6.27 in the ¹H NMR

spectrum. The yield of 36 was found to vary widely (25−68%) in the

subsequent experiments.

1-Benzyl-9-ethyl-7,9-dimethoxy-8-oxa-1-azaspiro[5,5]-

decane-2-one (37). To the keto-aldehyde ( )-28 (7.2 mg, 0.024

mmol) in CH₂Cl₂and MeOH (0.8 mL, 1:1 v/v) under Ar at rt were

successively added molecular sieves (10 mg, 4 Å) and camphor

sulfonic acid (2.8 mg, 0.01 mmol), and the resulting solution was

stirred for 10 min. The reaction mixture was cooled to 0 °C, and

triethylamine (2 drops) was added. After stirring the mixture for 10

min, the solvent was evaporated under reduced pressure. Puriﬁcation

by chromatography (1:1 petroleum ether/EtOAc) aﬀorded ( )-37

(6.8 mg, 82%) as a mixture of two inseparable diastereomers:

(S)-1-Benzyl-6-oxo-2-(3-oxopentyl)piperidine-2-carb-

aldehyde (28). Ozone-oxygen stream gas was bubbled into a solution

of nonracemic (S)-(+)-29 (381 mg, 1.41 mmol) in 4:1 v/v CH₂Cl₂

and MeOH (20 mL) at −78 °C for 2 min, at which time a pale blue

color remained in the solution (TLC analysis showed complete

conversion of 29). The above solution was purged with argon, and

triphenylphosphine (443 mg, 1.69 mmol) was added at −78 °C. The

reaction mixture was gradually allowed to warm to rt over a period of 1

h and stirred for overnight. After evaporation of the solvent under

reduced pressure, the crude product was puriﬁed by chromatography

(Et₂O) to give (S)-(−)-28 (377 mg, 89%) as a white solid: mp 84−86

°C; [α]²_D²−102.8 (c 1.45, CHCl₃); IR (CH₂Cl₂) 3067, 2979, 2941,

1732, 1715, 1646 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz) δ 9.25 (s, 1 H),

7.00−7.19 (m, 5 H, Ar-H), 4.80 (d, J = 15.5 Hz, 1 H), 4.03 (d, J = 15.5

Hz, 1 H), 2.26−2.52 (m, 2 H), 1.75−2.22 (m, 7 H), 1.45−1.70 (m, 3

H), 0.75 (t, J = 7.4 Hz, 3 H); ¹³C NMR (CDCl₃, 75 MHz) δ 209.1,

200.2, 171.9, 138.5, 128.5, 128.1, 127.2, 70.4, 47.3, 35.5, 35.4, 32.3,

28.6, 26.4, 17.1, 7.6. HRMS (FD-TOF) m/z: [M]⁺Calcd for

C₁₈H₂₃NO₃301.1678; Found 301.1669.

1

Colorless oil; IR (CH₂Cl₂) 3054, 2968, 1640, 1496 cm⁻¹; H NMR

(CDCl₃, 300 MHz) δ (major diastereomer) 7.10−7.34 (m, 5 H), 5.08

(d, J = 16.0 Hz, 1 H), 4.52 (s, 1 H), 4.39 (d, J = 16.0 Hz, 1 H), 3.16 (s,

3 H), 2.81 (s, 3 H), 2.41−2.62 (m, 2 H), 2.18−2.38 (m, 2 H), 1.89−

2.04 (m, 1 H), 1.40−1.88 (m, 7 H), 0.85 (t, J = 7.6 Hz, 3 H); δ

(discernible signals for minor diastereomer) 3.53 (s, 3 H), 3.28 (s, 3

H); ¹³C NMR (CDCl₃, 125 MHz) δ (major diastereomer) 172.5,

139.1, 128.2, 127.1, 126.5, 101.4, 97.9, 60.8, 55.6, 47.5, 44.5, 32.9, 29.5,

28.3, 28.1, 24.5, 16.8, 7.5; HRMS (FD-TOF) m/z: [M]⁺Calcd for

C₂₀H₂₉NO₄347.2097; Found 347.2090.

The diastereomeric ratio of 37 was 18:1, based on the integration of

the methyl group singlets at δ 3.16 and δ 3.53 in the ¹H NMR

spectrum.

(S)-1-Benzyl-8-methyl-1-azaspiro[5,5]dec-7-ene-2,9-dione

(35). To a mixture of KOH (203 mg, 3.62 mmol) in EtOH (4 mL)

under argon at 0 °C was added a solution of the keto-aldehyde (S)-

(−)-28 (364 mg, 1.21 mmol) in 3:1 v/v EtOH and CH₂Cl₂(8 mL) via

cannula. The solution was stirred at 0 °C for 10 min before allowing it

to warm to rt, and left for overnight. The reaction mixture was cooled

to 0 °C, and saturated NH₄Cl was added. All the volatiles were

evaporated under reduced pressure, and the crude residue obtained

was diluted with CH₂Cl₂. The organic layer was washed with brine,

dried over Na₂SO₄, ﬁltered, and concentrated. Puriﬁcation by

chromatography (1:2 petroleum ether/EtOAc) aﬀorded the enone

(S)-(−)-35 (328 mg, 96%) as a colorless thick oil: [α]²_D²−71.9 (c 0.62,

(6S,8RS)-1-Benzyl-8-methyl-9-oxa-1-azaspiro[5,6]undecane-

2,10-dione (39). A solution of the enone (S)-(−)-35 (240 mg, 0.85

mmol) in 95% ethanol (20 mL) was shaken for 8 h under hydrogen

(40 psi, Parr) over 10% palladium on carbon (30 mg). The mixture

was ﬁltered through a pad of Celite, and the solvent was evaporated

under reduced pressure. The crude product (242 mg), without further

puriﬁcation, was subjected to oxidation using PDC (320 mg, 0.85

mmol) in CH₂Cl₂(15 mL) containing 3 Å crushed molecular sieves

(300 mg) under Ar. The resulting brown solution was stirred at rt for 8

h, and then the reaction mixture was diluted with Et₂O. Celite and 2-

propanol (0.5 mL) were added, the mixture was stirred for 15 min at rt

and ﬁltered, and the ﬁltrate was evaporated. Puriﬁcation by

chromatography (1:2 petroleum ether/EtOAc) gave an inseparable

mixture of the ketone 38 and the enone 35 (220 mg) as a colorless oil.

The ratio of 38 and 35 was 7:1, based on the integration of the methyl

doublets δ 0.89 and δ 0.95 (in 38) and the methyl singlet at δ 1.69 (in

1

CHCl₃); IR (CH₂Cl₂) 3055, 2955, 1678, 1638, 1450 cm⁻¹; H NMR

(CDCl₃, 300 MHz) δ 7.11−7.32 (m, 5 H), 6.34 (s, 1 H), 4.66 (d, J =

15.8 Hz, 1 H), 4.52 (d, J = 15.8 Hz, 1 H), 2.23−2.67 (m, 5 H), 2.00−

2.15 (m, 2 H), 1.80−1.98 (m, 3 H), 1.69 (s, 3 H); ¹³C NMR (CDCl₃,

75 MHz) δ 196.9, 170.4, 149.1, 138.9, 135.7, 128.1, 126.6, 126.5, 61.0,

46.6, 34.4, 32.1, 31.6, 31.2, 17.6, 15.6; HRMS (FD-TOF) m/z: [M]⁺

Calcd for C₁₈H₂₁NO₂283.1572; Found 283.1569.

1

35) in the H NMR spectrum.

1-Benzyl-6-(2′-methoxyvinyl)-6-(3″-oxopentyl)piperidin-2-

one (36). Ph₃P⁺CH₂(OMe)Cl⁻(55 mg, 0.15 mmol) was dried under

vacuum at 110 °C for 1 h and cooled to rt. The above salt was

suspended in THF (1 mL), and it was cooled to 0 °C under argon.

NaHMDS (0.15 mL, 1.0 M solution in toluene) was added to the

above suspension, and a bright orange solution resulted. After 20 min

at 0 °C, the keto-aldehyde ( )-28 (15.5 mg, 0.05 mmol) in THF (1

mL) was added via cannula. The reaction mixture was stirred at 0 °C

for 1 h, and then allowed to warm to rt and stirred for overnight.

Saturated aqueous NH₄Cl was added, and THF was evaporated under

reduced pressure. The aqueous layer was extracted with CH₂Cl₂(3 ×

5 mL), dried over Na₂SO₄, ﬁltered, and concentrated. The crude

product was puriﬁed by chromatography (2:1 petroleum ether/

EtOAc) to aﬀord ( )-36 (11.5 mg, 68%) as a colorless oil: IR

(CH₂Cl₂) 2939, 1715, 1638, 1495 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz)

δ (Z-36) 7.10−7.31 (m, 5 H), 5.88 (d, J = 7.2 Hz, 1 H), 5.00 (d, J =

15.5 Hz, 1 H), 4.12 (d, J = 7.2 Hz, 1 H), 4.05 (d, J = 15.5 Hz, 1 H),

3.55 (s, 3 H), 2.33−2.62 (m, 2 H), 1.55−2.25 (m, 10 H), 0.84 (t, J =

7.3 Hz, 3 H); δ (discernible signals for E-36) 6.27 (d, J = 13.0 Hz, 1

H), 4.93 (d, J = 15.4 Hz, 1 H), 4.60 (d, J = 13.0 Hz, 1 H), 4.16 (d, J =

15.4 Hz, 1 H), 3.41 (s, 3 H), 0.86 (t, J = 7.2 Hz, 3 H); ¹³C NMR

(CDCl₃, 75 MHz) δ (E- and Z-36) 210.4, 209.9, 172.5, 172.2, 148.8,

147.3, 140.1, 139.7, 128.3, 128.1, 128.0, 126.6, 126.4, 109.1, 107.2,

63.5, 62.6, 60.3, 56.1, 47.0, 46.4, 36.7, 36.5, 35.5, 35.4, 34.0, 33.5, 32.8,

32.7, 32.6, 31.8, 17.3, 16.4, 7.6, 7.6. HRMS (FD-TOF) m/z: [M]⁺

Calcd for C₂₀H₂₇NO₃329.1991; Found 329.1993.

(6S,8RS)-1-Benzyl-8-methyl-1-azaspiro[5,6]decane-2,9-

1

dione (38). IR (CH₂Cl₂) 2951, 1715, 1634 cm⁻¹; H NMR (CDCl₃,

300 MHz) δ (major diastereomer) 7.02−7.28 (m, 5 H), 4.80 (d, J =

16.6 Hz, 1 H), 4.69 (d, J = 16.6 Hz, 1 H), 2.05−2.73 (m, 7 H), 1.69−

2.00 (m, 5 H), 1.44 (dd, J = 15.1, 2.9 Hz, 1 H), 0.89 (d, J = 6.5 Hz, 3

H); δ (discernible signals for minor diastereomer) 4.51 (d, J = 16.0

Hz, 1 H), 0.95 (d, J = 6.4 Hz, 3 H); ¹³C NMR (CDCl₃, 75 MHz) δ

(major diastereomer) 212.5, 170.7, 139.1, 128.4, 126.7, 126.2, 59.2,

45.8, 42.7, 41.4, 41.2, 35.3, 32.2, 31.0, 16.4, 13.9; δ (minor

diastereomer) 210.3, 170.9, 139.0, 128.3, 126.5, 126.1, 59.5, 44.4,

40.7, 37.6, 36.0, 35.0, 32.2, 31.1, 16.6, 14.4. The ratio of diastereomeric

ketones 38 was 1.8:1, based on integration of the methyl doublets at δ

1

0.89 and δ 0.95 in the H NMR spectrum.

To the above 7:1 mixture of 38 and 35 (220 mg) in CH₂Cl₂(30

mL) under Ar at rt were successively added mCPBA (665 mg, 3.85

mmol) and solid NaHCO₃(323 mg, 3.85 mmol), and the resulting

white suspension was stirred at rt for 2 days. The reaction mixture was

diluted with CH₂Cl₂and cooled to 0 °C. Saturated aqueous Na₂S₂O₃

solution was added, and the resulting white suspension was stirred for

30 min. The mixture was ﬁltered through a pad of Celite, and the

solvent was evaporated under reduced pressure. The crude residue was

diluted with EtOAc and successively washed with saturated aqueous

NaHCO₃and brine. The organic layer was dried over Na₂SO₄, ﬁltered,

and concentrated. Puriﬁcation by chromatography (1:2 petroleum

ether/EtOAc, then 1:4 petroleum ether/EtOAc) gave an inseparable

mixture of the diastereomeric lactones 39 (141 mg, 55% from 35) as a

O

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

white solid: mp 142−145 °C; [α]²_D¹−30.5 (c 1.07, CHCl₃); IR

(CH₂Cl₂) 2954, 1723, 1634, 1495 cm⁻¹; ¹H NMR (CDCl₃, 300 MHz)

δ (major diastereomer) 7.04−7.34 (m, 5 H), 4.78 (d, J = 16.4 Hz, 1

H), 4.63−4.78 (m, 1 H), 4.53 (d, J = 16.4 Hz, 1 H), 2.84 (ddd, J =

17.4, 7.1, 5.1 Hz, 1 H), 2.37−2.72 (m, 3 H), 1.58−2.22 (m, 7 H), 1.20

(d, J = 6.2 Hz, 3 H); δ (discernible signals for minor diastereomer)

4.37−4.52 (m, 1 H), 1.29 (d, J = 6.2 Hz, 3 H); ¹³C NMR (CDCl₃, 75

MHz) δ (major diastereomer) 172.3, 170.8, 138.5, 128.5, 126.8, 126.2,

72.4, 60.7, 45.8, 44.8, 36.2, 31.8, 31.7, 30.6, 21.4, 16.0; δ (minor

diastereomer) 173.8, 170.7, 138.6, 128.4, 126.6, 126.1, 70.9, 60.7, 45.4,

44.9, 32.3, 32.2, 31.4, 29.5, 22.5, 16.1; HRMS (FD-TOF) m/z: [M]⁺

Calcd for C₁₈H₂₃NO₃301.1678; Found 301.1677.

mixture of lactol and lactone (42 mg) in THF (2 mL) via cannula. The

reaction mixture was stirred at 0 °C for 1 h and was allowed to warm

to rt for 8 h. Saturated aqueous NH₄Cl was added, and the THF was

evaporated under reduced pressure. The aqueous layer was extracted

with CH₂Cl₂(3 × 5 mL), dried over Na₂SO₄, ﬁltered, and

concentrated. The crude product was puriﬁed by chromatography

(Et₂O, then EtOAc) to aﬀord an inseparable diastereomeric mixture of

42 (25.1 mg, 38% over two steps) as a colorless oil. The lactone 39 (9

mg) was also recovered: [α]_D²³+5.4 (c 1.15, CHCl₃); IR (neat) 3567−

1

3159, 2961, 2930, 1622, 1438 cm⁻¹; H NMR (CDCl₃, 300 MHz) δ

7.14−7.33 (m, 5 H), 5.32−5.46 (m, 1 H), 5.08−5.22 (m, 1 H), 4.83

(d, J = 15.6 Hz, 0.5 H), 4.78 (d, J = 15.8 Hz, 0.5 H), 4.43 (d, J = 15.8

Hz, 0.5 H), 4.36 (d, J = 15.6 Hz, 0.5 H), 3.80−3.90 (m, 0.5 H), 3.68−

3.78 (m, 0.5 H), 2.41−2.64 (m, 2 H), 1.49−2.24 (m, 10 H), 1.09 (d, J

= 6.1 Hz, 1.5 H), 0.79 (d, J = 6.1 Hz, 1.5 H); ¹³C NMR (CDCl₃, 300

MHz) δ 172.9, 172.5, 139.5, 139.3, 129.3, 129.3, 128.4, 128.3, 127.4,

127.2, 126.7, 126.6, 124.4, 124.4, 64.5, 64.5, 62.9, 62.6, 47.8, 47.6, 45.4,

45.0, 39.6, 38.7, 33.0, 33.0, 31.4, 31.0, 26.0, 28.5, 21.5, 21.3, 17.1, 16.9,

12.7 (× 2); HRMS (FD-TOF) m/z: [M]⁺Calcd for C₂₀H₂₉NO₂

315.2198; Found 315.2200.

The ratio of diastereomeric lactones 39 was 1.8:1, based on

integration of the methyl doublets at δ 1.20 and δ 1.29 in the ¹H NMR

spectrum.

(6S,2′RS)-1-Benzyl-6-(2′-hydroxypropyl)-6-(3″-hydroxy-

propyl)piperidin-2-one (41). The lactone 39 (133 mg, 0.44 mmol)

was dissolved in THF (3 mL), and NaBH₄(43 mg, 1.10 mmol) was

added at rt, under Ar. The resulting white suspension was allowed to

reﬂux (65 °C, oil bath), and MeOH (0.35 mL) was added dropwise

over a period of 1 h. The mixture was stirred for an additional 1 h at 65

°C. The reaction mixture was cooled to 0 °C, and 1 M aqueous HCl

was added until the gas evolution was subsided. All the volatiles were

evaporated under reduced pressure, and the crude residue obtained

was diluted with CH₂Cl₂. The organic layer was washed once with

10% aqueous NaOH. The aqueous layer was saturated with solid NaCl

and back-extracted into CH₂Cl₂. The combined organic layers were

dried over Na₂SO₄, ﬁltered, and concentrated. Puriﬁcation by

chromatography (10:1 EtOAc/MeOH) aﬀorded an inseparable

diastereomeric mixture of the diols 41 (124 mg, 92%) as a colorless

oil: [α]²_D²−18.7 (c 2.10, CHCl₃); IR (neat) 3573−3108, 2957, 2878,

The ratio of diastereomeric alcohols 42 was ∼1.2:1, based on the

integration of the methyl doublets at δ 1.09 and δ 0.79 in the ¹H NMR

spectrum.

(6R,2′RS)-1-Benzyl-6-(2′-hydroxypropyl)-6-pentylpiperidin-

2-one (43). The alkenol 42 (24 mg, 0.08 mmol) was dissolved in

EtOH (3 mL) and subjected to the catalytic hydrogenation (1 atm H₂,

balloon) over 10% palladium on carbon (3 mg). After stirring for

overnight, the mixture was ﬁltered through a pad of Celite, and EtOH

was evaporated under reduced pressure. Puriﬁcation by chromatog-

raphy (1:2 petroleum ether/EtOAc) aﬀorded an inseparable

diastereomeric mixture of the alcohols 43 (24 mg, 100%) as a

colorless oil: [α]²_D³+8.9 (c 1.81, CHCl₃); IR (CH₂Cl₂) 3560−3120,

2958, 2931, 1634, 1615 cm⁻¹; ¹H NMR (CDCl₃, 500 MHz) δ (major

diastereomer) 7.15−7.29 (m, 5 H), 4.71 (d, J = 15.6 Hz, 1 H), 4.40 (d,

J = 15.6 Hz, 1 H), 3.70−3.78 (m, 1 H), 2.42−2.59 (m, 2 H), 2.09−

2.18 (m, 1 H), 1.45−1.91 (m, 8 H), 1.10 (d, J = 6.2 Hz, 3 H), 0.95−

1.27 (m, 5 H), 0.81 (t, J = 7.1 Hz, 3 H); δ (discernible signals for

minor diastereomer) 4.75 (d, J = 15.8 Hz, 1 H), 4.47 (d, J = 15.8 Hz, 1

H), 3.80−3.88 (m, 1 H), 1.98−2.05 (m, 1 H), 0.81 (t, J = 7.1 Hz, 3

H), 0.81 (t, J = 6.8 Hz, 3 H); ¹³C NMR (CDCl₃, 125 MHz) δ (major

diastereomer) 172.9, 139.4, 128.2, 127.4, 126.6, 64.6, 63.0, 48.0, 45.0,

40.1, 33.1, 32.1, 31.1, 25.6, 23.6, 22.5, 17.2, 13.9; δ (minor

diastereomer) 172.5, 139.7, 128.3, 127.3, 126.6, 64.5, 62.7, 47.7,

45.4, 39.3, 33.0, 32.0, 31.5, 26.0, 23.5, 22.5, 17.0, 13.9. HRMS (FD-

TOF) m/z: [M]⁺Calcd for C₂₀H₃₁NO₂317.2355; Found 317.2354.

The ratio of the diastereomeric alcohols 43 was ∼1.2:1, based on

integration of the hydroxymethine proton signals at δ 3.70−3.78 and δ

1

1613 cm⁻¹; H NMR (CDCl₃, 500 MHz) δ (major diastereomer)

7.14−7.28 (m, 5 H), 4.67 (d, J = 15.9 Hz, 1 H), 4.56 (d, J = 15.9 Hz, 1

H), 3.80−3.88 (m, 1 H), 3.29−3.40 (m, 2 H), 2.39−2.56 (m, 2 H),

1.98−2.18 (m, 3 H), 1.57−1.89 (m, 7 H), 1.42−1.55 (m, 1 H), 1.18−

1.31 (m, 1 H), 1.07 (d, J = 6.1 Hz, 3 H); δ (discernible signals for

minor diastereomer) 4.66 (d, J = 15.5 Hz, 1 H), 4.45 (d, J = 15.5 Hz, 1

H), 3.68−3.76 (m, 1 H), 0.83 (d, J = 6.1 Hz, 3 H); ¹³C NMR (CDCl₃,

75 MHz) δ (major diastereomer) 172.7, 139.5, 128.2, 127.2, 126.6,

64.3, 62.6, 62.2, 47.4, 45.4, 35.0, 32.8, 31.6, 27.0, 25.9, 16.8; ¹³C NMR

(CDCl₃, 75 MHz) δ (minor diastereomer) 173.0, 139.2, 128.2, 127.3,

126.6, 64.3, 62.8, 62.3, 47.8, 45.0, 36.0, 32.9, 31.0, 27.1, 25.5, 17.0;

HRMS (FD-TOF) m/z: [M]⁺Calcd for C₁₈H₂₇NO₃305.1991; Found

305.1994.

The ratio of the diastereomeric diols 41 was 1.8:1, based on

integration of the methyl doublets at δ 1.07 and δ 0.83 in the ¹H NMR

spectrum.

1

3.80−3.88 in the H NMR spectrum.

(6S,2′RS)-1-Benzyl-6-(2′-hydroxypropyl)-6-((Z)-pent-3″-

enyl)piperidin-2-one (42). To a solution of the diol 41 (63 mg, 0.21

mmol) in CH₂Cl₂(2 mL) at rt were successively added TEMPO (6.6

mg, 0.04 mmol) and tetrabutylammonium chloride (15 mg, 0.05

mmol). A buﬀer solution (pH = 8.7) containing a mixture of 0.5 M

aqueous NaHCO₃and 0.05 M aqueous K₂CO₃(1:1 v/v, 2 mL) was

added to the above reaction mixture, followed by N-chlorosuccinimide

(41 mg, 0.31 mmol). The resulting biphasic mixture was vigorously

stirred for 3 h at the ambient temperature and diluted with CH₂Cl₂.

The two layers were separated, and the organic layer was washed once

with brine. The aqueous layer was saturated with solid NaCl and back-

extracted into CH₂Cl₂. The combined organic layers were dried over

Na₂SO₄, ﬁltered, and concentrated. Puriﬁcation by chromatography

(1:4 petroleum ether/EtOAc, then 10:1 EtOAc/MeOH) aﬀorded an

inseparable mixture of the lactol 40 and the lactone 39 (42 mg) as a

colorless oil. The starting diol 41 (21 mg, 33%) was also recovered.

The mixture of lactone and the lactol was directly subjected to the

Wittig oleﬁnation in the next step.

(R)-(−)-Adalinine (2). Na metal was cut into small pieces and

washed three times with hexanes. To the liquid NH₃(5 mL) at −78

°C under argon was added Na metal (24 mg, 1.0 mmol), and the

resulting blue colored solution was stirred at −78 °C for 30 min. To

the above solution was then added 43 (18.5 mg, 0.06 mmol) in THF

(3 mL) via cannula, and the reaction mixture was stirred at −78 °C for

2.5 h. Solid NH₄Cl (28 mg) was added to the above solution at −78

°C, and the reaction temperature was allowed to gradually warm to rt,

by which time all of the ammonia had evaporated. The crude residue

was extracted with CH₂Cl₂(4 × 5 mL), and the combined organic

layers were dried over Na₂SO₄, ﬁltered, and concentrated. Puriﬁcation

by chromatography (10:1 EtOAc/MeOH) aﬀorded an inseparable

1.2:1 diastereomeric mixture of the debenzylated alcohol (12.2 mg,

92%) as a colorless oil. The ratio of diastereomers was determined

based on integration of the hydroxymethine proton signals at δ 4.06−

1

4.15 and δ 3.94−4.03 in the H NMR spectrum.

(6R,2′RS)-6-(2′-Hydroxypropyl)-6-pentylpiperidin-2-one. [α]_D²³

+15.0 (c 1.21, CHCl₃); IR (CH₂Cl₂) 3289, 3183 (br), 2961, 2930,

Ph₃P⁺EtBr⁻(152 mg, 0.41 mmol) was dried under vacuum at 110

°C for 1 h and cooled to rt. The above salt was suspended in THF (2

mL), and it was cooled to 0 °C under argon. KHMDS (0.78 mL, 0.5

M in toluene) was added to the above suspension. A bright orange

solution resulted, to which, after 15 min at 0 °C, was added the above

1

1645 cm⁻¹; H NMR (CDCl₃, 500 MHz) δ (major diastereomer)

7.57−7.67 (br s, 1 H), 4.25−4.33 (br s, 1 H), 4.06−4.15 (m, 1 H),

2.20−2.34 (m, 2 H), 1.50−1.82 (m, 8 H), 1.06−1.45 (m, 6 H), 1.21

(d, J = 6.1 Hz, 3 H), 0.88 (t, J = 6.8 Hz, 3 H); δ (discernible signals for

P

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

minor diastereomer) 6.49−6.55 (br s, 1 H), 3.94−4.03 (m, 1 H),

2.78−2.90 (br s, 1 H), 0.88 (t, J = 6.8 Hz, 3 H); ¹³C NMR (CDCl₃,

300 MHz) δ (major diastereomer) 171.7, 64.8, 57.1, 47.1, 37.8, 32.2,

31.9, 30.6, 25.4, 24.1, 22.5, 16.9, 14.0; δ (minor diastereomer) 172.7,

64.3, 56.8, 47.6, 41.7, 32.2, 31.6, 30.9, 25.5, 23.2, 22.5, 17.1, 14.0.

To a solution of the above debenzylated alcohol (8.3 mg, 0.04

mmol) in CH₂Cl₂(2 mL) under Ar at rt was successively added 4-

methylmorpholin N-oxide (6.5 mg, 0.05 mmol), crushed molecular

sieves (10 mg, 4 Å), and tetrapropylammonium perruthenate (2.5 mg,

20 mol %). The resulting green solution was stirred at rt for 1.5 h, at

which time TLC analysis showed complete conversion of the alcohol.

The reaction mixture was diluted with CH₂Cl₂and ﬁltered through a

pad of Celite. Saturated aqueous Na₂S₂O₃(1 mL) was added to the

ﬁltrate, and the mixture was stirred for 10 min. The two layers were

separated, and the aqueous layer was re-extracted with CH₂Cl₂(3 × 5

mL). The combined organic layers were dried over Na₂SO₄, ﬁltered,

and concentrated. Puriﬁcation by chromatography (EtOAc, then 20:1

Gartshore, C. J.; Illesinghe, J.; Jackson, W. R.; Robinson, A. J. Synthesis

2013, 45, 3118. (h) Xiao, K.-J.; Luo, J.-M.; Xia, X.-E.; Wang, Y.;

Huang, P.-Q. Chem. - Eur. J. 2013, 19, 13075. (i) Palmer, L. I.; Read de

Alaniz, J. Angew. Chem., Int. Ed. 2011, 50, 7167.

(4) (a) Perry, M. A.; Morin, M. D.; Slafer, B. W.; Rychnovsky, S. D. J.

Org. Chem. 2012, 77, 3390. (b) Lygo, B.; Kirton, E. H. M.; Lumley, C.

Org. Biomol. Chem. 2008, 6, 3085. (c) Taniguchi, T.; Ishibashi, H. Org.

Lett. 2008, 10, 4129. (d) Isaacson, J.; Loo, M.; Kobayashi, Y. Org. Lett.

2008, 10, 1461. (e) Liu, Q.; Ferreira, E. M.; Stoltz, B. M. J. Org. Chem.

2007, 72, 7352. (f) Kim, S.; Ko, H.; Lee, T.; Kim, D. J. Org. Chem.

2005, 70, 5756. (g) Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem.

2002, 67, 4337.

(5) For reviews on enantioselective methods for the formation of

quaternary centers: (a) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur.

J. Org. Chem. 2007, 2007, 5969. (b) Christoffers, J.; Baro, A. Adv.

Synth. Catal. 2005, 347, 1473. (c) Corey, E. J.; Guzman-Perez, A.

Angew. Chem. 1998, 110, 402.

(6) (a) Tietze, L. F.; Steck, P. L. Eur. J. Org. Chem. 2001, 2001, 4353.

(b) Huang, P.; Isayan, K.; Sarkissian, A.; Oh, T. J. Org. Chem. 1998, 63,

4500. (c) Godleski, S. A.; Meinhart, J. D.; Miller, D. J.; Van

Wallendael, S. Tetrahedron Lett. 1981, 22, 2247.

(7) (a) Fustero, S.; Mateu, N.; Simon-Fuentes, A.; Acena, J. L. Org.

Lett. 2010, 12, 3014. (b) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am.

Chem. Soc. 2005, 127, 1473. (c) Burgess, L. E.; Meyers, A. I. J. Am.

Chem. Soc. 1991, 113, 9858.

(8) (a) Kawabata, T.; Moriyama, K.; Kawakami, S.; Tsubaki, K. J. Am.

Chem. Soc. 2008, 130, 4153. (b) Ooi, T.; Miki, T.; Maruoka, K. Org.

Lett. 2005, 7, 191. (c) Huxford, T.; Simpkins, N. S. Synlett 2004, 2295.

(d) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem. Soc.

1983, 105, 5390.

(9) (a) Yamashita, Y.; Imaizumi, T.; Kobayashi, S. Angew. Chem., Int.

Ed. 2011, 50, 4893 and references therein. (b) Lin, S.; Deiana, L.;

Zhao, G.-L.; Sun, J.; Cordova, A. Angew. Chem., Int. Ed. 2011, 50, 7624.

(c) Najera, C.; de Gracia Retamosa, M.; Sansano, J. M.; de Cozar, A.;

Cossio, F. P. Eur. J. Org. Chem. 2007, 2007, 5038. (d) Barr, D. A.;

Dorrity, M. J.; Grigg, R.; Hargreaves, S.; Malone, J. F.; Montgomery, J.;

Redpath, J.; Stevenson, P.; Thornton-Pett, M. Tetrahedron 1995, 51,

273.

(10) (a) Liang, H.; Ciufolini, M. A. Chem. - Eur. J. 2010, 16, 13262.

(b) Wardrop, D. J.; Burge, M. S. J. Org. Chem. 2005, 70, 10271.

(c) Canesi, S.; Belmont, P.; Bouchu, D.; Rousset, L.; Ciufolini, M. A.

Tetrahedron Lett. 2002, 43, 5193.

1

EtOAc/MeOH) aﬀorded 2 (8.2 mg, 100%) as a colorless oil. The H

and ¹³C NMR spectral data of (R)-adalinine was found to be in good

agreement with the reported³⁵data: [α]_D²³−29.8 (c 0.61, CH₂Cl₂)

{lit.^35c[α]_D²⁰−28.3 (c 1.6, CH₂Cl₂); lit.^35b[α]²_D⁰−30.4 (c 0.8,

CH₂Cl₂)}; IR (CH₂Cl₂) 3379, 3054, 2957, 2936, 1714, 1654 cm⁻¹; ¹H

NMR (CDCl₃, 500 MHz) δ 6.55 (br s, 1 H), 2.70 (d, J = 17.8 Hz, 1

H), 2.62 (d, J = 17.8 Hz, 1 H), 2.25−2.33 (m, 2 H), 2.13 (s, 3 H),

1.50−1.87 (m, 6 H), 1.07−1.37 (m, 6 H), 0.87 (t, J = 6.3 Hz, 3 H);

¹³C NMR (CDCl₃, 75 MHz) δ 207.1, 171,4, 56.2, 51.3, 39.3, 31.9,

31.9, 31.4, 31.3, 23.9, 22.5, 17.3, 13.9. HRMS (FD-TOF) m/z: [M]⁺

Calcd for C₁₃H₂₃NO₂225.1729; Found 225.1720; HPLC: Chiralcel

OD column (4.6 mm × 250 mm); 90:10 v/v hexane/i-PrOH; ﬂow

rate, 1.0 mL/min; λ_max= 220 nm; t_R(S-2) = 10.9 min and t_R(R-2) =

12.1 min; >99% ee. The retention times for (R)- and (S)-2 were

determined by injecting a sample of ( )-2 for HPLC analysis.

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.joc.5b02582.

■

S

Copies of ¹H and ¹³C NMR spectra for all products, and

HPLC characterization data of compounds 29 and 2

(PDF)

(11) (a) In, J.; Lee, S.; Kwon, Y.; Kim, S. Chem. - Eur. J. 2014, 20,

17433. (b) Acharya, H. P.; Clive, D. L. J. J. Org. Chem. 2010, 75, 5223.

(c) Roy, S.; Spino, C. Org. Lett. 2006, 8, 939.

AUTHOR INFORMATION

Corresponding Author

*E-mail: Andrew.Wee@uregina.ca.

Notes

■

(12) (a) Fustero, S.; Albert, L.; Mateu, N.; Chiva, G.; Miro, J.;

Gonzalez, J.; Acena, J. L. Chem. - Eur. J. 2012, 18, 3753. (b) Planas, L.;

Perard-Viret, J.; Royer, J. J. Org. Chem. 2004, 69, 3087. (c) Fenster, M.

D. B.; Patrick, B. O.; Dake, G. R. Org. Lett. 2001, 3, 2109.

(13) For reviews on alkylidene carbenes: (a) Grainger, R. S.; Munro,

K. R. Tetrahedron 2015, 71, 7795. (b) Kirmse, W. Angew. Chem., Int.

Ed. Engl. 1997, 36, 1164. (c) Stang, P. J. Acc. Chem. Res. 1982, 15, 348.

(14) (a) Gilbert, J. C.; Giamalva, D. H.; Baze, M. E. J. Org. Chem.

1985, 50, 2557. (b) Taber, D. F.; Storck, P. H. J. Org. Chem. 2003, 68,

7768. (c) Taber, D. F.; Sikkander, M. I.; Storck, P. H. J. Org. Chem.

2007, 72, 4098. (d) Yun, S. Y.; Zheng, J.-C.; Lee, D. J. Am. Chem. Soc.

2009, 131, 8413.

(15) (a) Hameed, A.; Blake, A. J.; Hayes, C. J. J. Org. Chem. 2008, 73,

8045. (b) Esmieu, W. R.; Worden, S. M.; Catterick, D.; Wilson, C.;

Hayes, C. J. Org. Lett. 2008, 10, 3045. (c) Asari, A.; Angelov, P.; Auty,

J. M.; Hayes, C. J. Tetrahedron Lett. 2007, 48, 2631. (d) Mapitse, R.;

Hayes, C. J. Tetrahedron Lett. 2002, 43, 3541. (e) Whipp, C. J.; de

Turiso, F. G.-L. Tetrahedron Lett. 2008, 49, 5508. (f) Diaba, F.; Ricou,

E.; Bonjoch, J. Tetrahedron: Asymmetry 2006, 17, 1437.

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank the Natural Sciences and Engineering Research

Council, Canada, and the University of Regina for ﬁnancial

support.

REFERENCES

■

(1) Gulder, T. A. M.; Moore, B. S. Angew. Chem., Int. Ed. 2010, 49,

9346.

(2) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren,

J.; Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691.

(3) For reviews on synthesis of pyrrolidines and piperidines carrying

a nitrogen-substituted quaternary center: (a) Undheim, K. Synthesis

2015, 47, 2497. (b) Calaza, M. I.; Cativiela, C. Eur. J. Org. Chem. 2008,

2008, 3427. (c) Dake, G. Tetrahedron 2006, 62, 3467. (d) Kang, S. H.;

Kang, S. Y.; Lee, H.; Buglass, A. J. Chem. Rev. 2005, 105, 4537. For

recent work: (e) Zhu, D.-Y.; Zhang, Z.; Mou, X.-Q.; Tu, Y.-Q.; Zhang,

F.-M.; Peng, J.-B.; Wang, S.-H.; Zhang, S.-Y. Adv. Synth. Catal. 2015,

357, 747. (f) Kalaitzakis, D.; Antonatou, E.; Vassilikogiannakis, G.

Chem. Commun. 2014, 50, 400. (g) Wang, Z. J.; Spiccia, N. D.;

(16) (a) Annadi, K.; Wee, A. G. H. J. Org. Chem. 2015, 80, 5236.

(b) Wee, A. G. H.; Fan, G. J.; Bayirinoba, H. M. J. Org. Chem. 2009,

74, 8261.

(17) Hu, Y.-J.; Dominique, R.; Das, S. K.; Roy, R. Can. J. Chem. 2000,

78, 838.

Q

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

(18) (a) Tsuji, J.; Nagashima, H.; Nemoto, H. Org. Synth. 1984, 62, 9.

(b) Tsuji, J. Synthesis 1984, 1984, 369.

(19) Morandi, B.; Wickens, Z. K.; Grubbs, R. H. Angew. Chem., Int.

(40) Kanazawa, R.; Tokoroyama, T. Synthesis 1976, 1976, 526.

(41) Soai, K.; Oyamada, H.; Takase, M.; Ookawa, A. Bull. Chem. Soc.

Jpn. 1984, 57, 1948.

(42) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J.-L. J. Org. Chem.

1996, 61, 7452.

Ed. 2013, 52, 9751.

(20) The eﬀect of coordination on regioselectivity in Wacker

oxidation of alkenes: For reviews: (a) Dong, J. J.; Browne, W. R.;

Feringa, B. L. Angew. Chem., Int. Ed. 2015, 54, 734. (b) Guo, J.; Teo, P.

Dalton Trans. 2014, 43, 6952. (c) Muzart, J. Tetrahedron 2007, 63,

7505. Coordination effect in terminal alkenes: (d) Weiner, B.; Baeza,

A.; Jerphagnon, T.; Feringa, B. L. J. Am. Chem. Soc. 2009, 131, 9473.

(e) Choi, P. J.; Sperry, J.; Brimble, M. A. J. Org. Chem. 2010, 75, 7388.

(f) Pellissier, H.; Michellys, P.-Y.; Santelli, M. Tetrahedron 1997, 53,

7577. (g) Pellissier, H.; Michellys, P.-Y.; Santelli, M. Tetrahedron 1997,

53, 10733. Coordination effect in internal alkenes: (h) DeLuca, R. J.;

Edwards, J. L.; Steffens, L. D.; Michel, B. W.; Qiao, X.; Zhu, C.; Cook,

S. P.; Sigman, M. S. J. Org. Chem. 2013, 78, 1682. (i) Keinan, E.; Seth,

K. K.; Lamed, R. L. J. Am. Chem. Soc. 1986, 108, 3474.

(21) Qian, X.; Auffrant, A.; Felouat, A.; Gosmini, C. Angew. Chem.,

Int. Ed. 2011, 50, 10402.

(43) The synthesis of ( )-2 was also pursued following a similar

route for the preparation of (−)-2 from (+)-29. Compound ( )-2 was

used for HPLC analysis to determine the enantiopurity of

(−)-adalinine.

(44) Fuwa, H.; Kaneko, A.; Sugimoto, Y.; Tomita, T.; Iwatsubo, T.;

Sasaki, M. Heterocycles 2006, 70, 101.

(22) Thai, K.; Wang, L.; Dudding, T.; Bilodeau, F.; Gravel, M. Org.

Lett. 2010, 12, 5708.

(23) Tsukamoto, D.; Shiraishi, Y.; Hirai, T. J. Org. Chem. 2010, 75,

1450.

(24) Murato, K.; Yatsunami, T.; Iwasaki, S. Helv. Chim. Acta 1980,

63, 588.

(25) Huang, S.-Y.; Chang, Z.; Tuo, S.-C.; Gao, L.-H.; Wang, A.-E.;

Huang, P.-Q. Chem. Commun. 2013, 49, 7088.

(26) Genna, D. T.; Posner, G. H. Org. Lett. 2011, 13, 5358.

(27) Ohira, S.; Okai, K.; Moritani, T. J. Chem. Soc., Chem. Commun.

1992, 721.

(28) (a) Sun, C.; Li, J.; Demerzhan, S.; Lee, D. ARKIVOC 2011, 17.

(b) Snyder, S. A.; Wespe, D. A.; von Hof, J. M. J. Am. Chem. Soc. 2011,

133, 8850. (c) Sletten, E. M.; Nakamura, H.; Jewett, J. C.; Bertozzi, C.

R. J. Am. Chem. Soc. 2010, 132, 11799. (d) Dabrowski, J. A.; Moebius,

D. C.; Wommack, A. J.; Kornahrens, A. F.; Kingsbury, J. S. Org. Lett.

2010, 12, 3598.

(29) A comparison of the C5 hydroxyl protecting groups on the

eﬃciency of alkylidene carbene generation-C−H insertion by

replacement of MOM with a pivaloyl group in 7e led to a decrease

in the yield (28%) of the corresponding spirolactam product.

(30) Introduction of an OMe substituent at the C2 position of the 3-

oxobutyl side chain in 7e and also replacing the OMOM with OMe

did not give the expected tertiary C−H insertion spirolactam product.

Instead, the alkylidene carbene was found to insert into the primary

C−H bond of the OMe group in the 3-oxobutyl side chain, forming

the corresponding dihydrofuran product in 68% yield.

(31) Jahnke, E.; Tykwinski, R. R. Chem. Commun. 2010, 46, 3235.

(32) Lognay, G.; Hemptinne, J. L.; Chan, F. Y.; Gaspar, C. H.;

Marlier, M.; Braekman, J. C.; Daloze, D.; Pasteels, J. M. J. Nat. Prod.

1996, 59, 510.

(33) Laurent, P.; Lebrun, B.; Braekman, J. C.; Daloze, D.; Pasteels, J.

M. Tetrahedron 2001, 57, 3403.

(34) (a) Wardrop, D. J.; Landrie, C. L.; Ortiz, J. A. Synlett 2003,

1352. (b) Yamazaki, N.; Ito, T.; Kibayashi, C. Synlett 1999, 1999, 37.

(c) Broeders, F.; Braekman, J. C.; Daloze, D. Bull. Soc. Chim. Belg.

1997, 106, 377.

(35) (a) Honda, T.; Hisa, C. Tetrahedron Lett. 2009, 50, 4654.

(b) Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925. (c) Yamazaki, N.;

Ito, T.; Kibayashi, C. Tetrahedron Lett. 1999, 40, 739.

(36) The racemic spirolactam 29 was prepared from the alkylidene

1

carbene generation-C−H insertion of ( )-30. The H and ¹³C NMR

spectral data of ( )-29 are identical to those of (S)-29 described in the

Experimental Section.

(37) Earnshaw, C. E.; Wallis, C. J.; Warren, S. J. Chem. Soc., Perkin

Trans. 1 1979, 3099.

1

(38) The H and ¹³C NMR spectral data of ( )-35 are identical to

those of (S)-35 described in the Experimental Section.

(39) Nishiyama, Y.; Yoshida, M.; Ohkawa, S.; Hamanaka, S. J. Org.

Chem. 1991, 56, 6720.

R

DOI: 10.1021/acs.joc.5b02582

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

An alkylidene carbene C-H activation approach toward the enantioselective syntheses of spirolactams: Application to the synthesis of (-)-adalinine

DOI: 10.1021/acs.joc.5b02582

Source and publish data:

Authors:

Article abstract of DOI:10.1021/acs.joc.5b02582

Full text of DOI:10.1021/acs.joc.5b02582

Products guided by the article

R&D Labs maybe for 1448179-75-6

Relevant to this article

Hot Product