Enantioselective, palladium-catalyzed α-arylation of N-Boc pyrrolidine: In situ react IR spectroscopic monitoring, scope, and synthetic applications

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pubs.acs.org/joc

Enantioselective, Palladium-Catalyzed r-Arylation of N-Boc

Pyrrolidine: In Situ React IR Spectroscopic Monitoring, Scope,

and Synthetic Applications

Graeme Barker,^†Julia L. McGrath,^†Artis Klapars,^‡Darren Stead,^†George Zhou,^‡Kevin R. Campos,*^,‡

and Peter O’Brien*^,†

^†Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K.

^‡Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, United States

S Supporting Information

b

ABSTRACT: A comprehensive study of the enantioselective

Pd-catalyzed R-arylation of N-Boc pyrrolidine has been carried

out. The protocol involves deprotonation of N-Boc pyrrolidine

using s-BuLi/(ꢀ)-sparteine in TBME or Et₂O at ꢀ78 °C,

transmetalation with ZnCl₂and Negishi coupling using Pd-

(OAc)₂, t-Bu₃P-HBF₄and the aryl bromide. This paper reports

several new features including in situ React IR spectroscopic

monitoring of the process; use of (ꢀ)-sparteine and the

(+)-sparteine surrogate to access products with opposite conﬁgura-

tion; development of a catalytic asymmetric lithiationꢀNegishi

coupling reaction; extension to a wide range of heteroaromatic bromides; total synthesis of (R)-crispine A, (S)-nicotine and (S)-SIB-

1508Y via short synthetic routes; and examples of R-vinylation of N-Boc pyrrolidine using vinyl bromides exempliﬁed by the total

synthesis of naturally occurring (+)-maackiamine (thus establishing its conﬁguration as (R)). In this way, the full scope and

limitations of the methodology are delineated.

’ INTRODUCTION

R-Arylated nitrogen heterocycles represent an important

pharmacophore in biologically active compounds. Indeed, there

are three examples in the 2009 “Top 200 Pharmaceutical

Products by Worldwide Sales”:¹Zetia (a cholesterol regulator),

Cialis (treatment of erectile dysfunction) and Vesicare (treatment of

urinary incontinence) (Figure 1). As a subset of R-arylated

nitrogen heterocycles, biologically active pyrrolidines are espe-

cially prevalent, featuring in natural products and potential

pharmaceuticals (Figure 2). Examples of natural products in-

clude (S)-nicotine, which as well as being a major constituent of

tobacco exhibits important pharmacological eﬀects on central

nervous system (CNS) diseases;²(R)-crispine A, which shows

cytotoxic activity against SKOV3, KB and HeLa human cancer

lines;³and (R)-harmicine, which shows anti-leishmania activity.⁴

The activity of (S)-nicotine at nicotinic acetylcholine receptors

led to the synthesis and evaluation of nicotine analogues (S)-ABT

418 for the treatment of Alzheimer’s disease⁵and (S)-SIB

1508Y for the treatment of Parkinson’s disease.⁶Another exam-

ple of an important R-arylated pyrrolidine is the non-peptide

cholecystokinin (CCK) antagonist (S,R)-RP-66803.⁷In addi-

tion, R-arylated pyrrolidines are important structural motifs

in chiral auxiliaries,⁸chiral catalysts for transition metals⁹and

chiral organocatalysts.¹⁰Our interest in R-arylated pyrrolidines

was initiated by the need to develop a practical and large-scale

Figure 1. Examples of R-arylated nitrogen heterocycles from the “Top

200 Pharmaceutical Products by Wordwide Sales in 2009”.¹

asymmetric synthesis of the glucokinase activator (R)-1.¹¹Ulti-

mately, we developed a novel procedure for the R-arylation of

N-Boc pyrrolidine¹²and implemented this technology in an

eﬃcient synthesis of (R)-1.¹³

Our overall aim was to develop new, general and versatile

methodology for the asymmetric synthesis of structurally diverse

R-arylated pyrrolidines such as those shown in Figure 2. An

overview of the previous synthetic approaches to R-arylated

Received: June 2, 2011

Published: June 29, 2011

r

2011 American Chemical Society

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The Journal of Organic Chemistry

FEATURED ARTICLE

Scheme 2

provides the most convergent synthetic approach to (R)-12.²³

The aryl group would be installed using a Pd-catalyzed Negishi

coupling²⁴of an organozinc reagent such as (S)-13 which could

be obtained from the enantioenriched organolithium intermedi-

ate (S)-14 (via transmetalation with ZnCl₂). Access to organo-

lithium reagent (S)-14 is possible using s-BuLi/(ꢀ)-sparteine-

mediated asymmetric deprotonation of N-Boc pyrrolidine 15, as

pioneered by Beak et al.^25,26Of note, the antipodal R-arylated

pyrrolidines (S)-12 could be accessed using the (+)-sparteine

surrogate²⁷or Alexakis diamine (S,S)-16.^28,29Other aspects of

the route outlined in Scheme 2 with encouraging precedent

included the documented conﬁgurational stability of secondary

organozinc reagents,³⁰the Pd-catalyzed Negishi couplings of

achiral secondary organozinc reagents with aryl halides³¹and

Dieter and Li’s development of a CuCN-catalyzed Pd-coupling

of lithiated N-Boc pyrrolidine with aryl iodides as a route to

racemic R-arylated pyrrolidines.³²

Figure 2. Examples of biologially active R-arylated pyrrolidines.

Scheme 1

The successful development and optimization of the approach

outlined in Scheme 2 was the subject of our preliminary com-

munication.¹²The optimized method involved deprotonation of

N-Boc pyrrolidine 15 using s-BuLi/(ꢀ)-sparteine in TBME

33

at ꢀ78 °C, transmetalation with 0.6 equiv of ZnCl₂and

34

Negishi coupling using Pd(OAc)₂, t-Bu₃P-HBF₄and the aryl

bromide. In this way, a wide range of arylated N-Boc pyrrolidines

was prepared (60ꢀ87%, 96:4 er), and a number of groups have

subsequently made use of this methodology. For example,

Jacobsen and co-workers prepared a range of chiral R-aryl

pyrrolidine organocatalysts,¹⁰Coldham and Leonori described

the synthesis of racemic R-aryl N-Boc piperidines using s-BuLi/

TMEDA-mediated lithiation,³⁵Sutton et al. reported the parallel

synthesis of inhibitors of heat shock protein 90,³⁶Metallinos and

Xu have carried out the synthesis of an R-arylated bicyclic urea³⁷

and Coldham et al.³⁸and Beng and Gawley³⁹have independently

reported the synthesis of enantioenriched R-aryl N-Boc piper-

idines. Most recently, Knochel has described the diastereoselec-

tive arylation of 4-substituted N-Boc piperidines using a

lithiationꢀNegishi coupling approach.⁴⁰We have also applied

the methodology to a concise formal synthesis of the CCK

antagonist (S,R)-RP-66803 (Figure 2)²⁹and an R-aryl N-Boc

piperidine,⁴¹as well as developing a diamine-free lithiationꢀ

arylation of N-Boc pyrrolidine, a N-Boc imidazolidine and a

N-Boc piperazine.⁴²In this paper, we now describe important

new features of the enantioselective Pd-catalyzed R-arylation of

N-Boc pyrrolidine 15 including in situ React IR spectroscopic

monitoring of the process, use of (ꢀ)-sparteine and the (+)-

sparteine surrogate to access products with opposite conﬁgura-

tion, development of a catalytic asymmetric lithiationꢀNegishi

pyrrolidine (R)- or (S)-2 is summarized in Scheme 1. There have

been several reports on chiral auxiliary approaches including the

use of 1,3-oxazolidine 3¹⁴and bicyclic lactam 4¹⁵derived from

phenylglycinol, reduction of a valine-derived iminium ion 5¹⁶and

nucleophilic addition to Ellman’s tert-butylsulﬁnyl imines 6,¹⁷7¹⁸

and 8.¹⁹Two examples of catalytic asymmetric syntheses of 2

have been described: a Pd-catalyzed Heck reaction of ene

carbamate 9 followed by hydrogenation²⁰and a chiral titano-

cene-mediated reduction of imine 10.²¹Finally, lithiationꢀ

cyclization of N-Boc chloroamine 11 using s-BuLi and a stoichio-

metric amount of (ꢀ)-sparteine has also been used to prepare

2.²²Unfortunately, none of the methods in Scheme 1 appeared

suitable for our purposes because they suﬀered from one or more

of the following limitations: long synthetic sequences, low yields,

lack of generality and modest diastereo- or enantioselectivity.

Furthermore, simple variation of the aryl group and ready access

to R-arylated pyrrolidines with (R)- or (S)-conﬁguration were

not facilitated by any of the routes.

Our approach to N-Boc protected R-arylated pyrrolidines

(R)-12, shown in Scheme 2, addresses all of the aforementioned

limitations. In contrast to the other routes in Scheme 1, a discon-

nection between the pyrrolidine ring and the aryl substituent

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FEATURED ARTICLE

Scheme 3

coupling reaction and extension to a wide range of heteroaro-

matic bromides. In addition, we also report the total synthesis of

(R)-crispine A, (S)-nicotine and (S)-SIB-1508Y and examples of

R-vinylation of N-Boc pyrrolidine using vinyl bromides exem-

pliﬁed by the total synthesis of naturally occurring (+)-maack-

iamine (thus establishing its conﬁguration as (R)).

Figure 3. In situ React IR spectroscopic monitoring of the lithiation of

N-Boc pyrrolidine 15.

’ RESULTS AND DISCUSSION

In Situ React IR Spectroscopic Monitoring of the

LithiationꢀTransmetalationꢀR-Arylation. The conversion

of N-Boc pyrrolidine 15 into (R)-17 (82% yield, 96:4 er) via

our optimized one-pot process of asymmetric deprotonationꢀ

transmetalationꢀNegishi coupling is shown in Scheme 3. The

limiting reagent was bromobenzene, and the method utilized 1.2

equiv of s-BuLi/(ꢀ)-sparteine/N-Boc pyrrolidine 15 together

with 0.6 equiv of ZnCl₂relative to the lithiated N-Boc pyrroli-

dine. The high enantioselectivity indicates that transmeta-

lation from lithium to zinc must occur below ꢀ60 °C since

lithiated N-Boc pyrrolidine is configurationally unstable at higher

temperatures.^25,43,44Furthermore, the organozinc intermediate

(which was not chraracterised but could be formulated as RZnCl,

R₂Zn or R₃ZnLi) must be configurationally stable at 20 °C. The

combination of Pd(OAc)₂and t-Bu₃P-HBF₄gave the best results

for the Negishi coupling step, as previously described.¹²

As part of the optimization study, each stage of the deproto-

nationꢀtransmetalationꢀNegishi coupling process was studied

using in situ React IR spectroscopy. In particular, it was found that

the ν_CdOof the Boc group was a suitable spectroscopic handle

for monitoring the reaction. Thus, IR spectroscopy of a solution

of (ꢀ)-sparteine and N-Boc pyrrolidine 15 in TBME at ꢀ70 °C

gave a peak at 1697 cm^ꢀ1that was assigned to ν_CdOin N-Boc

pyrrolidine 15. As soon as s-BuLi was added, a new peak at

1644 cm^ꢀ1was visible in the IR spectrum (Figure 3) that was

assigned to ν_CdOin lithiated N-Boc pyrrolidine (S)-14 on the

basis of comparison with our previous work on the React IR

Figure 4. In situ React IR spectroscopic monitoring of the transmetala-

tion step (lithium to zinc).

spectroscopic monitoring of lithiated N-Boc piperidine (ν_CdO

=

1644 cm^ꢀ1).⁴¹Of note, lithiation of N-Boc pyrrolidine 15 using

s-BuLi/(ꢀ)-sparteine was complete within 60 min, indicating

that it is not necessary to carry out such lithiations over long

time periods (typically 4ꢀ6 h²⁵). On close inspection, there

was evidence of a prelithiation complex formed by s-BuLi/

(ꢀ)-sparteine complexing to the carbonyl of the Boc group

(ν_CdO= 1675 cm^ꢀ1). This was, however, a ﬂeeting intermediate

presumably because lithiation from the prelithiation complex

occurred readily.

Next, the transmetalation of lithium to zinc was monitored.

Thus, addition of 1.0 equiv of ZnCl₂led to little change to the IR

spectra at ꢀ70 °C (Figure 4). However, upon warming to 20 °C,

a new, broader peak was observed (ν_CdO= 1653 cm^ꢀ1) that was

assigned to an organozinc species (RZnCl, R₂Zn or R₃ZnLi).

Finally, it was also possible to follow the Negishi coupling step in

a similar manner. After addition of bromobenzene, Pd(OAc)₂

Figure 5. In situ React IR spectroscopic monitoring of the Negishi

coupling step.

and t-Bu₃P-HBF₄, a new peak at 1702 cm^ꢀ1(assigned to ν_CdOin

the product, R-aryl pyrrolidine (R)-17) was observed (Figure 5).

Thus, we have demonstrated that in situ React IR spectroscopy is

a useful tool for monitoring and optimizing this type of

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FEATURED ARTICLE

Table 1. Asymmetric DeprotonationꢀTransmetallationꢀ

Negishi Coupling of N-Boc Pyrrolidine 15

Scheme 4

(ꢀ)-sparteine can be generated using the (+)-sparteine

surrogate²⁷and Alexakis diamine (S,S)-16.^28,29Use of the

“sparteine-like” (+)-sparteine surrogate was successful: R-aryl

pyrrolidines (S)-17 (entry 4, 71%, 95:5 er) and (S)-18 (entry 6,

69%, 95:5 er) were obtained in yields and enantioselectivity

comparable to those obtained using (ꢀ)-sparteine (compare

with entries 1 and 5, respectively). In contrast, lithiation with s-

BuLi/diamine (R,R)-16 and subsequent transmetalationꢀ

Negishi coupling gave pyrrolidine (R)-17 in high enantioselec-

tivity (95:5 er) but moderate 35% yield (entry 3). Attempts to

improve the yield using Pd₂(dba)₃or Pd(OAc)₂with Hartwig’s

Ru-phos⁴⁵or Buchwald’s Q-phos⁴⁶were unsuccessful. We

believe that diamine (R,R)-16 can interfere with the Negishi

coupling step (presumably by coordination to palladium) since

we have also observed low yields in attempted racemic lithiation

(using s-BuLi/TMEDA)ꢀtransmetalationꢀNegishi couplings

with N-Boc pyrrolidine 15. A 12% yield of rac-18 (entry 7) is

representative, and we conclude that TMEDA and “TMEDA-

like” diamines such as (R,R)-16 should be avoided. However, this

eﬀect does depend on the N-Boc heterocycle since high-yielding

syntheses of racemic R-aryl N-Boc piperidines using s-BuLi/

TMEDA-mediated lithiation have been described.^35,40

Our deprotonationꢀtransmetalationꢀNegishi coupling pro-

cess is also suitable for natural product synthesis, and the cyto-

toxic alkaloid (R)-crispine A, isolated from Carduus Crispus,³

was selected as an appropriate target. In recent times, (R)- or

(S)-crispine A has proved to be a popular target molecule, and

several asymmetric strategies have been reported.⁴⁷The shortest

route to (R)-crispine A is 3 steps (32% overall yield) and is also

the most recently reported synthesis.^47kFor our approach, we

adopted a concise route from N-Boc pyrrolidine 15 via a

connective strategy that was distinct to all previous approaches;

(ꢀ)-sparteine was utilized as it would provide the naturally

occurring (R)-conﬁguration (Scheme 4). Thus, N-Boc pyrroli-

dine 15 was deprotonated using s-BuLi/(ꢀ)-sparteine in TBME

and subjected to transmetalation and Negishi coupling with

known⁴⁸aryl bromide 23. This gave adduct (R)-22 in 70% yield

and 96:4 er. Deprotection of the Boc group using TFA in CH₂Cl₂

led to racemization. Presumably, the CꢀN bond of the pyrro-

lidine ring is readily cleaved under these acidic conditions since

the resulting carbocation would be stabilized by the electron-rich

aromatic ring. In contrast, use of Me₃SiCl/MeOH to cleave the

Boc group gave no loss of er, and cyclization to lactam (R)-24

ensued (95% yield, 96:4 er). Finally, borane reduction of the

lactam delivered (R)-crispine A (82% yield, 97:3 er). This is an

eﬃcient synthesis of (R)-crispine A (54% yield over 3 steps from

entry

Ar-Br

diamine

solventproductyield (%)^aer (R:S)^b

1

2

3

4

5

6

7

8

9

PhBr

PhI

(ꢀ)-sp

TBME (R)-17

Et₂O (R)-17

82

56

35

71

69

12

71

79

82

96:4

95:5

(ꢀ)-sp

PhBr

(R,R)-16

(+)-sp surrogate Et₂O (S)-17

(ꢀ)-sp Et₂O (R)-18

(+)-sp surrogate Et₂O (S)-18

5:95

95:5

5:95

o-CF₃C₆H₄Br

TMEDA

Et₂O rac-18

TBME (R)-19

TBME (R)-20

TBME (R)-21

o-CO₂MeC₆H₄Br(ꢀ)-sp

1-Naphthyl-Br (ꢀ)-sp

96:4

95:5

10 2-Naphthyl-Br (ꢀ)-sp

^aYield after puriﬁcation by column chromatography. ^bEnantiomeric

ratio (er) determined by CSP-HPLC.

lithiationꢀtransmetalationꢀNegishi coupling process. Such an

approach could prove very useful for related types of lithiationꢀ

transmetalation processes.

r-Arylation Using Simple Aryl Bromides: Synthesis of (R)-

Crispine A. To start with, the scope of the originally reported

asymmetric deprotonationꢀtransmetalationꢀNegishi coupling

process was explored. In Table 1, a selection of new results

(entries 2ꢀ10) are compared with the result using (ꢀ)-sparteine

and bromobenzene (entry 1, 82% yield, 96:4 er). Deprotonation

with s-BuLi/(ꢀ)-sparteine and Negishi reaction with iodobenzene

gave R-aryl pyrrolidine (R)-17 (96:4 er) in 56% yield (Table 1,

entry 2), which shows that although aryl iodides are compatible

coupling partners, they are inferior to aryl bromides. We had

previously shown¹²that chlorobenzene was also less efficient (48%

yield, 96:4 er) and that aryl triflates and aryl tosylates gave <5% yield

under the same conditions. Thus, aryl bromides are the coupling

partners of choice for this process. The reaction works equally well in

Et₂O or in TBME as solvent (Table 1, entries 1, 4ꢀ6 and 8ꢀ10).

Four new examples using (ꢀ)-sparteine are shown in Table 1 and

allowed the synthesis of CF₃-containing (R)-18 (entry 5, 69%, 95:5

er), methyl ester-containing (R)-19 (entry 8, 71%, 96:4 er) and

naphthyl-substituted pyrrolidines (R)-20 (entry 9, 79%, 96:4 er) and

(R)-21 (entry 10, 82%, 95:5 er).

As part of this study, we have also shown that R-aryl

pyrrolidines with conﬁguration opposite to that obtained with

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Table 2. Catalytic Asymmetric DeprotonationꢀTransmetal-

lationꢀNegishi Coupling of N-Boc Pyrrolidine 15

Scheme 5

was prepared in 91:9ꢀ96:4 er (Table 2, entries 1, 3, 5 and 7ꢀ8)

using only 0.25 equiv of the chiral diamine. The improved results of

the (+)-sparteine surrogate compared to those using (ꢀ)-sparteine

in two-ligand catalytic asymmetric deprotonations have been

noted before and can be explained by a more eﬃcient catalysis

caused by a higher reactivity of the s-BuLi/(+)ꢀsparteine surrogate

complex.^49a,b

In previous work, it has been shown that better enantioselec-

tivity with (ꢀ)-sparteine can be observed using slightly diﬀerent

lithiation conditions and a higher loading of (ꢀ)-sparteine: 1.6

equiv of s-BuLi, 0.3 equiv of (ꢀ)-sparteine and 1.3 equiv of di-i-

Pr-bispidine 25.^49cUnder these conditions, we were able to

prepare pyrrolidines (R)-19 and (R)-26 in 89:11 er, but surpris-

ingly, there was no improvement in enantioselectivity in the

formation of CF₃-substituted pyrrolidine (R)-18 (80:20 er)

(Scheme 5). Thus, we conclude that the Negishi protocol

can be run eﬀectively under a two-ligand catalytic asymmetric

deprotonation manifold using either (ꢀ)-sparteine or the (+)-

sparteine surrogate.

entry

Ar-Br

diamine

(+)-sp surrogateTBME^c(S)-17

(ꢀ)-sp Et₂O (R)-18

(+)-sp surrogateEt₂O (S)-18

Et₂O (R)-19

2-Naphthyl-Br (+)-sp surrogateTBME^c(S)-21

Et₂O (R)-26

solvent productyield (%)^aer (R:S)^b

1

2

3

4

5

6

7

8

PhBr

80

76

75

50

77

50

87

85

5:95

80:20

9:91

o-CF₃C₆H₄Br

o-CO₂MeC₆H₄Br(ꢀ)-sp

81:19

4:96

o-MeOC₆H₄Br (ꢀ)-sp

o-MeOC₆H₄Br (+)-sp surrogateEt₂O (S)-26

p-CO₂MeC₆H₄Br(+)-sp surrogateTBME^c(S)-27

80:20

4:96

7:93

^aYield after puriﬁcation by column chromatography. ^bEnantiomeric

ratio (er) determined by CSP-HPLC. ^c0.35 equiv of ZnCl₂used for the

transmetalation step.

bromide 23) and demonstrates the synthetic potential of the

methodology.

r-Arylation Using Heteroaryl Bromides: Synthesis of (S)-

SIB-1508Y and (S)-Nicotine. Since aromatic heterocycles are

key structural features of many pharmaceuticals and are present

in the Alzheimer’s drug (S)-ABT 418, the Parkinson’s drug (S)-

SIB 1508Y and glucokinase activator (R)-1 (Figure 2), we carried

out lithiationꢀtransmetalationꢀNegishi coupling with an

array of heterocyclic aryl bromides. Previously, we had reported

the successful coupling with 3-bromopyridine, a Boc-protected

bromoindole and even an unprotected bromoindole.¹²We

extended the study to include protected pyrroles, a thiophene,

thiazoles and functionalized pyridines. In all cases, R-aryl pyrro-

lidines (R)-28ꢀ36 were formed in good yield (58ꢀ76%) and

high enantioselectivity (94:6ꢀ97:3 er) (Scheme 6).

Catalytic Asymmetric Lithiationꢀr-Arylation of N-Boc

Pyrrolidine. Next, we planned to determine whether the trans-

metalationꢀNegishi coupling protocol was compatible with the

two-ligand catalytic asymmetric deprotonation methodology

developed in our group.⁴⁹In 2005, we disclosed that efficient

asymmetric deprotonation of N-Boc pyrrolidine 15 could be

achieved using s-BuLi and substoichiometric amounts (0.2ꢀ0.3

equiv) of (ꢀ)-sparteine or the (+)-sparteine surrogate provided

that a second diamine, di-i-Pr-bispidine 25, is present.^48aThis

process is referred to as two-ligand catalysis, and the second

diamine ligand was required to enable recycling of the chiral

ligand. Thus, two-ligand catalytic asymmetric deprotonationꢀ

transmetalationꢀNegishi coupling was explored (Table 2).

The standard procedure involved deprotonation of N-Boc

pyrrolidine 15 using 1.0 equiv of s-BuLi, 0.25 equiv of

(ꢀ)-sparteine or the (+)-sparteine surrogate and 1.0 equiv of

di-i-Pr-bispidine 25 in Et₂O or TBME at ꢀ78 °C for 4ꢀ5 h.

Transmetalation was accomplished using 0.6 equiv of ZnCl₂, and

Negishi coupling was carried out in the usual way (aryl bromide,

Pd(OAc)₂and t-Bu₃P-HBF₄, 20 °C, 16 h). With (ꢀ)-sparteine,

these conditions gave disappointing results as R-aryl pyrrolidines

(R)-18, (R)-19 and (R)-26 were generated in only ∼80:20 er

(Table 2, entries 2, 4 and 6). In contrast, the (+)-sparteine

surrogate faired much better, and a range of R-aryl pyrrolidines

The results observed with the diﬀerent bromopyridines are

worthy of further comment. Under standard Negishi coupling

conditions (Pd(OAc)₂and t-Bu₃P-HBF₄, 20 °C, 16 h) with

3-bromopyridine, adduct (R)-33 was formed in only 15% yield.

By carrying out the Negishi reaction for 16 h at 60 °C, a

signiﬁcant improvement was observed: adduct (R)-33 was iso-

lated in 60% yield. We suspect that the nitrogen in 3-bromopyr-

idine can coordinate to the Pd and interfere with the Pd coupling

step. It appears that such interference only occurs for a pyridine

with a sterically unhindered nitrogen lone pair since 2-bromo-

pyridine (f (R)-34, 71%) and 2-substituted 3-bromopyridines

(f (R)-35, 76%; f (R)-36, 70%) gave high yields from Negishi

reactions conducted at 20 °C. Finally, a catalytic asymmetric

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Scheme 6

Scheme 7

Scheme 8

deprotonation variant (1.0 equiv of s-BuLi, 0.25 equiv of (+)-

sparteine surrogate and 1.0 equiv of di-i-Pr-bispidine 25) was

used to prepare R-aryl pyrrolidine (S)-34 in 70% yield and

94:6 er.

Next, we set about applying the methodology to the total

synthesis of the Parkinson’s drug (S)-SIB 1508Y⁶and naturally

occurring (S)-nicotine.²In both cases, the conﬁguration dictated

that the (+)-sparteine surrogate would be required. Our con-

vergent synthetic approach would involve disconnection be-

tween the pyrrolidine ring and the pyridyl group and is a

strategy not previously adopted in accessing the R-pyridyl

pyrrolidine motif. There has been limited published work on

the synthesis of (S)-SIB 1508Y,⁵⁰and Comins’ ﬁve-step synthesis

from (S)-nicotine is the shortest.^50eOur synthesis is depicted in

Scheme 7. Thus, stoichiometric lithiation of N-Boc pyrrolidine

15 using s-BuLi/(+)-sparteine surrogate and subsequent trans-

metalationꢀNegishi coupling with bromopyridine 38 (prepared

from 3,5-dibromopyridine, see Experimental Section) (at 60 °C)

delivered R-aryl pyrrolidine (S)-37 in 44% yield. The best way of

converting (S)-37 into (S)-SIB 1508Y involved Boc deprotection

with TFA, ﬂuoride-mediated removal of the trimethylsilyl group

and EschweilerꢀClarke N-methylation. These reactions were

carried out without intermediate puriﬁcation, and (S)-SIB 1508Y

was isolated in 52% yield. Analysis by ¹H NMR spectroscopy in

the presence of (S)-2,2,2-triﬂuoro-1-(9-anthryl)-ethanol indi-

cated that (S)-SIB 1508Y was formed with 92:8 er.

EschweilerꢀClarke N-methylation aﬀorded (S)-nicotine in 96%

yield and 92:8 er (by ¹H NMR spectroscopy in the presence of

(S)-2,2,2-triﬂuoro-1-(9-anthryl)-ethanol). This two-step cataly-

tic asymmetric synthesis of (S)-nicotine (44% overall yield) is the

most direct approach reported to date.

r-Vinylation of N-Boc Pyrrolidine: Synthesis of (R)-(+)-

Maackiamine. Finally, a preliminary study on extending the

Negishi coupling methodology to vinylation was carried out.

Recently, Beng and Gawley have disclosed the first examples of

lithiationꢀtransmetalationꢀNegishi coupling to prepare two R-

vinyl piperidines.³⁹In our hands, we found that changing the Pd

source from Pd(OAc)₂to Pd₂(dba)₃gave optimal results, and

four examples are summarized in Scheme 9. In all cases, good

yields (67ꢀ73%) of products (R)-39ꢀ42 were obtained. R-Vinyl

pyrrolidines (R)-39 and (R)-40 were formed with 95:5 and

97:3 er, respectively. Although the er values of R-vinyl pyrroli-

dines (R,E)-41 and (R,Z)-42 were not determined (as suitable

CSP-HPLC conditions could not be found), we were able to

show that the E/Z stereochemistry in the starting vinyl bromides

was maintained in the products.

A similar approach was successful for the synthesis of naturally

occurring (S)-nicotine.⁵¹In this case, we adopted a catalytic

asymmetric deprotonation using 1.0 equiv of s-BuLi, 0.25 equiv

of (+)-sparteine surrogate and 1.0 equiv of di-i-Pr-bispidine 25.

Subsequent transmetalation and Negishi coupling with 3-bro-

mopyridine at 60 °C gave R-aryl pyrrolidine (S)-33 in 46% yield

(Scheme 8). Then, the Boc group was removed using TFA, and

The R-vinylation methodology was then applied to the total

synthesis of (R)-maackiamine. The isolation of maackiamine

from the ﬂower of the Amur maackia tree, Maackia amurensis,

was reported in 1989, and the absolute conﬁguration was not

determined.⁵²There has been no directed synthetic eﬀorts

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Scheme 9

(S)-2,2,2-triﬂuoro-1-(9-anthryl)-ethanol) in 54% yield. Our synthetic

sample exhibited [R]_D+12.8 (c 1.0 in EtOH), which had the same

sign as that reported for natural maackiamine ([R]_D+110 (c 0.01

in EtOH)), although we cannot explain the discrepancy in the

magnitude of the two [R]_Dvalues. The use of s-BuLi/(ꢀ)-sparteine

for the asymmetric deprotonation and its well-established prefer-

ence for removal of the pro-S proton (vide infra)²⁵thus established

the absolute conﬁguration of natural maackiamine as (R).

’ CONCLUSION

In summary, the scope of the enantioselective Pd-catalyzed

R-arylation of N-Boc pyrrolidine 15 has been explored. We be-

lieve that the methodology represents an important addition

to the armory of synthetic chemists working in academia and

in the pharmaceutical industry. Indeed, many groups have

already realized the utility of the methodology for their own

studies.^10,9,35ꢀ42Of note, we have shown that (ꢀ)-sparteine and

the (+)-sparteine surrogate allow access to products with oppo-

site conﬁguration and the approach can be coupled with two-

ligand catalytic asymmetric deprotonation. Furthermore, concise

syntheses of (R)-crispine A, (S)-nicotine and (S)-SIB-1508Y

together with the ﬁrst asymmetric synthesis of (R)-maackiamine

exemplify the synthetic utility of the methodology.

Scheme 10

’ EXPERIMENTAL SECTION

General. Water is distilled water. Brine refers to a saturated aqueous

solution of NaCl. Et₂O and TBME were freshly distilled from sodium

and benzophenone ketyl. (ꢀ)-Sparteine and N-Boc pyrrolidine were

distilled over CaH₂before use. Petrol refers to the fraction of petroleum

ether boiling in the range 40ꢀ60 °C. All reactions were carried out under

O₂-free Ar using oven-dried and/or flame-dried glassware. s-BuLi was

titrated against N-benzylbenzamide⁵⁵or N-pivaloyl-o-toluamide before

use. N-Boc pyrrolidine 15,²Alexakis’ diamine (R,R)-16³and di-i-Pr-

bispidine 25⁴were prepared according to the published procedures.

Flash column chromatography was carried out using Chemie GmbH

silica (220ꢀ440 mesh) or silica gel 60 (0.04ꢀ0.063 mm particle size).

Thin layer chromatography was carried out using F₂₅₄aluminum-backed

silica plates. ¹H (400 MHz) and ¹³C (100.6 MHz) NMR spectra were

recorded on a ꢀ400 MHz instrument with an internal deuterium lock.

Chemical shifts are quoted as parts per million and referenced to CHCl₃

(δ_H7.27) and or CDCl₃(δ_C77.0, central line of triplet). ¹³C NMR

spectra were recorded with broadband proton decoupling. ¹³C NMR

spectra were assigned using DEPT experiments. Coupling constants (J)

are quoted in hertz. IR spectra were recorded on a FTIR spectrometer.

Boiling points given for compounds puriﬁed by Kugelrohr distillation

correspond to the oven temperature during distillation. Electrospray

high and low resolution mass spectra were recorded on a microOTOF

spectrometer. Chiral stationary phase HPLC was performed with a

multiple wavelength, UVꢀvis diode array detector; integration was

performed at 210, 230, and 250 nm. Optical rotations were recorded

at 20 °C (using the sodium D line; 259 nm), and [R]_Dvalues are given in

toward maackiamine, although Fitch and Djerassi did in fact

report a synthesis of rac-maackiamine in 1974,⁵³some 25 years

before the isolation and characterization of natural maackiamine!

Our synthesis of (R)-maackiamine is shown in Scheme 10.

Asymmetric deprotonation of N-Boc pyrrolidine 15 was accom-

plished using s-BuLi and stoichiometric (ꢀ)-sparteine in TBME

(ꢀ78 °C, 90 min). Then, addition of ZnCl₂was followed by

Negishi coupling with vinyl bromide 43 (prepared in 3 steps from

piperidine, see Experimental Section) using Pd₂(dba)₃to give R-

vinyl pyrrolidine (R)-44 in 56% yield and 95:5 er (CSP-HPLC).

Boc deprotection using TFA gave maackiamine in high yield

(96%), but analysis by ¹H NMR spectroscopy in the presence of

(S)-2,2,2-triﬂuoro-1-(9-anthryl)-ethanol indicated that complete

racemization had occurred. Presumably, cleavage of the CꢀN

bond of the pyrrolidine ring via participation of the nucleophilic

enamine can occur under the acidic conditions. Such an issue

upon Boc deprotection may be a general problem with electron-

rich R-aryl or R-vinyl substituents as racemization was also

observed in the synthesis of (R)-crispine A. To solve this race-

mization problem, a non-acidic method for the removal of the

Boc protecting group was required, and we turned to Ohfune’s

TBDMSOTf/pyridine methodology.⁵⁴Reaction of R-vinyl pyrro-

lidine (R)-44 with TBDMSOTf/pyridine in CH₂Cl₂at room

temperature for 16 h gave an intermediate silyloxy carbonyl

compound. Treatment of this with CsF then delivered (R)-maack-

units of 10^ꢀ1deg cm³g^ꢀ1

.

An FTIR analyzer, ReactIR 4000 with a MCT detector, a KBr beam

splitter and an ATR probe (DiComp) was used for all experiments. The

DiComp probe was interfaced to a 250-mL glass vessel. A mechanical

stirrer at 200 rpm provided adequate agitation. Nitrogen purge on the IR

system was maintained throughout any experiment, and nitrogen back-

ground was used in computing the absorbance spectra. Each spectrum

represents 32 co-added scans measured at a spectral resolution of 4 cm^ꢀ1

in the 4000ꢀ650 cm^ꢀ1range with the HappꢀGenzel apodization.

General Procedure A: Stoichiometric LithiationꢀNegishi

Coupling in TBME. s-BuLi (4.8 mL of a 1.2 M solution in cyclohexane,

1

iamine of 95:5 er (by H NMR spectroscopy in the presence of

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5.7 mmol, 1.0 equiv) was added dropwise to a stirred solution of N-Boc

pyrrolidine 15 (1.2 mL, 5.7 mmol) and (ꢀ)-sparteine (1.3 mL, 5.7

mmol, 1.0 equiv) in TBME (12 mL) at ꢀ78 °C under N₂(keeping the

internal temperature below ꢀ68 °C). The resulting solution was stirred

at ꢀ74 °C for 3 h. Then, ZnCl₂(3.4 mL of a 1.0 M solution in Et₂O, 3.4

mmol, 0.6 equiv) was added dropwise (keeping the internal temperature

below ꢀ68 °C), and the resulting solution was stirred at ꢀ74 °C for 30

min. Then, the solution was allowed to warm to 20 °C and stirred at

20 °C for 30 min. The aryl bromide or vinyl bromide (4.75 mmol, 0.83

equiv) was added. A mixture of Pd(OAc)₂(51 mg, 0.23 mmol, 0.04

equiv) or Pd₂(dba)₃(200 mg, 0.23 mmol, 0.02 equiv) and t-Bu₃PHBF₄

(83 mg, 0.285 mmol, 0.05 equiv) was added in one portion, and the

resulting solution was stirred at 20 °C for 16 h. Then, 35% NH₄OH_(aq)

(0.35 mL) was added, and the solution was stirred at rt for 1 h. The solids

were removed by filtration through Celite and washed with TBME

(60 mL). The filtrate was washed with 1 M HCl _(aq)(50 mL) and water

(2 ꢁ 50 mL), dried (Na₂SO₄) and evaporated under reduced pressure to

give the crude product.

General Procedure B: Catalytic LithiationꢀNegishi Cou-

pling in TBME (0.25 equiv of Diamine). s-BuLi (4.8 mL of a 1.2 M

solution in cyclohexane, 5.7 mmol, 1.0 equiv) was added dropwise to a

stirred solution of N-Boc pyrrolidine 15 (1.2 mL, 5.7 mmol), (+)-

sparteine surrogate (291 μL, 1.4 mmol, 0.25 equiv) and di-i-Pr-bispidine

25 (1.23 mL, 5.7 mmol, 1.0 equiv) in TBME (12 mL) at ꢀ78 °C under

N₂(keeping the internal temperature below ꢀ68 °C). The resulting

solution was stirred at ꢀ74 °C for 3 h. Then, ZnCl₂(2.0 mL of a 1.0 M

solution in Et₂O, 2.0 mmol, 0.35 equiv) was added dropwise (keeping

the internal temperature below ꢀ68 °C), and the resulting solution was

stirred at ꢀ74 °C for 30 min. Then, the solution was allowed to warm to

20 °C and stirred at 20 °C for 30 min. The aryl bromide (4.75 mmol,

0.83 equiv) was added. A mixture of Pd(OAc)₂(51 mg, 0.23 mmol, 0.04

equiv) and t-Bu₃PHBF₄(83 mg, 0.285 mmol, 0.05 equiv) was added in

one portion, and the resulting solution was stirred at 20 °C for 16 h.

Then, 35% NH₄OH_(aq)(0.35 mL) was added, and the solution was

stirred at rt for 1 h. The solids were removed by filtration through Celite

and washed with TBME (60 mL). The filtrate was washed with 1 M HCl

_(aq)(50 mL) and water (2 ꢁ 50 mL), dried (Na₂SO₄) and evaporated

under reduced pressure to give the crude product.

General Procedure C: Catalytic LithiationꢀNegishi Cou-

pling in Et₂O (0.25 equiv of Diamine). s-BuLi (2.2 mL of a 1.3 M

solution in cyclohexane, 2.9 mmol, 1.0 equiv) was added dropwise to a

stirred solution of (ꢀ)-sparteine or (+)-sparteine surrogate (0.7 mmol,

0.25 equiv) and di-i-Pr-bispidine 25 (606 mg, 2.9 mmol, 1.0 equiv) in

Et₂O (6 mL) at ꢀ78 °C under Ar. After stirring at ꢀ78 °C for 15 min, a

solution of N-Boc pyrrolidine 15 (493 mg, 505 μL, 2.9 mmol) in Et₂O

(1 mL) was added dropwise. The resulting solution was stirred at

ꢀ78 °C for 4 h. Then, ZnCl₂(1.7 mL of a 1.0 M solution in Et₂O, 1.7

mmol, 0.6 equiv) was added dropwise, and the resulting solution was

stirred at ꢀ78 °C for 30 min. Then, the solution was allowed to warm to

rt and stirred at rt for 30 min. The aryl bromide (2.0 mmol, 0.83 equiv)

was added. A mixture of Pd(OAc)₂(31 mg, 0.14 mmol, 0.05 equiv) and

t-Bu₃PHBF₄(32 mg, 0.18 mmol, 0.06 equiv) was added in one portion,

the resulting solution was stirred at rt for 16 h. Then, 35% NH₄OH_(aq)

(0.2 mL) was added, and the solution was stirred at rt for 1 h. The

solids were removed by filtration through Celite and washed with Et₂O

(2 ꢁ 10 mL). The filtrate was washed with 1 M HCl_(aq)(20 mL) and

water (2 ꢁ 20 mL), dried (MgSO₄) and evaporated under reducted

pressure to give the crude product.

N-Boc pyrrolidine 15 (214 mg, 1.25 mmol) in Et₂O (1 mL) was added

dropwise. The resulting solution was stirred at ꢀ78 °C for 4 h. Then,

ZnCl₂(750 μL of a 1.0 M solution in Et₂O, 0.75 mmol, 0.6 equiv) was

added dropwise, and the resulting solution was stirred at ꢀ78 °C for 30

min. Then, the solution was allowed to warm to rt and stirred at rt for 30

min. The aryl bromide (0.9 mmol, 0.83 equiv) was added. A mixture of

Pd(OAc)₂(14 mg, 0.06 mmol, 0.05 equiv) and t-Bu₃PHBF₄(14 mg,

0.08 mmol, 0.06 equiv) was added in one portion, and the resulting

solution was stirred at rt for 16 h. Then, 35% NH₄OH_(aq)(0.2 mL) was

added, and the solution was stirred at rt for 1 h. The solids were removed

by filtration through Celite and washed with Et₂O (2 ꢁ 10 mL). The

filtrate was washed with 1 M HCl_(aq)(20 mL) and water (2 ꢁ 20 mL),

dried (MgSO₄) and evaporated under reducted pressure to give the

crude product.

React IR Spectroscopic Monitoring of the Lithiationꢀ

TransmetalationꢀNegishi Coupling of N-Boc Pyrrolidine

15 (see Figures 3, 4, and 5). TBME (63 mL) was added to a vessel

equipped with a stirrer bar, thermocouple and ReactIR probe under N₂.

Then N-Boc pyrrolidine 15 (3.0 mL, 0.017 mol) was added to the vessel

followed by (ꢀ)-sparteine (3.1 mL, 0.0176 mol, 1.0 equiv). The stirred

reaction was cooled to ꢀ70 °C and aged for 1 h (for stability of readout

on React IR). Then, s-BuLi (14 mL of a 1.26 M solution in cyclohexane,

0.0176 mol, 1.0 equiv) was added at ꢀ70 °C, keeping the temperature

below ꢀ65 °C, and the reaction was aged for 3 h at ꢀ70 °C. Then, ZnCl₂

(12 mL of a 1.0 M solution in Et₂O, 0.012 mol, 0.7 equiv) was added

dropwise (keeping the internal temperature below ꢀ68 °C), and the

resulting solution was stirred at ꢀ70 °C for 30 min. Then, the solution

was allowed to warm to 20 °C and stirred at 20 °C for 30 min.

Bromobenzene (1.5 mL, 0.0145 mol, 0.83 equiv) was added. A mixture

of Pd(OAc)₂(153 mg, 0.7 mmol, 0.04 equiv) and t-Bu₃PHBF₄(250 mg,

0.9 mmol, 0.05 equiv) was added in one portion, and the resulting

solution was stirred at 20 °C for 16 h.

For N-Boc pyrrolidine 15, a ν_CdOpeak at 1697 cm^ꢀ1was observed.

After addition of (ꢀ)-sparteine and then s-BuLi, a new peak at

1644 cm^ꢀ1was observed, which was assigned to ν_CdOin the lithiated

intermediate (S)-14. On close inspection, there was evidence of a

prelithiation complex formed by s-BuLi/(ꢀ)-sparteine complexing to

the carbonyl of the Boc group (ν_CdO= 1675 cm^ꢀ1). After a lithiation

time of 60 min, complete lithiation of N-Boc pyrrolidine 15 to give

lithiated intermediate (S)-14 was observed. After addition of ZnCl₂,

there was little change to the IR spectra at ꢀ70 °C. However, upon

warming to 20 °C, a new, broader peak at ν_CdO= 1653 cm^ꢀ1was

observed that was assigned to an organozinc species (RZnCl, R₂ZN or

R₃ZnLi). After addition of bromobenzene, Pd(OAc)₂and t-Bu₃P-HBF₄,

a new peak at 1702 cm^ꢀ1(assigned to ν_CdOin the product, R-aryl

pyrrolidine (R)-17) was observed.

(R)-N-(tert-Butoxycarbonyl)-2-phenyl Pyrrolidine (R)-17

(Table 1, entry 1). Using general procedure A, s-BuLi (4.8 mL of a

1.2 M solution in cyclohexane, 5.7 mmol, 1.0 equiv), N-Boc pyrrolidine

15 (1.2 mL, 5.7 mmol) and (ꢀ)-sparteine (1.3 mL, 5.7 mmol, 1.0 equiv)

in TBME (12 mL), ZnCl₂(3.4 mL of a 1.0 M solution in Et₂O, 3.4 mmol,

0.6 equiv), Pd(OAc)₂(51 mg, 0.23 mmol, 0.04 equiv), t-Bu₃PHBF₄

(83 mg, 0.285 mmol, 0.05 equiv) and bromobenzene (746 mg, 500 μL,

4.75 mmol, 0.83 equiv) gave the crude product. Purification by flash

column chromatography on silica with 4:1 CH₂Cl₂ꢀhexanes and then

9:1 CH₂Cl₂ꢀhexanes as eluent gave phenyl pyrrolidine (R)-17 (962 mg,

82%, 96:4 er by CSP-HPLC) as a white solid, mp 61.9ꢀ62.7 °C; [R]_D

+85.3 (c 1.9 in acetone); R_f(CH₂Cl₂) 0.4; ¹H NMR (400 MHz, CDCl₃)

(75:25 mixture of rotamers) δ 7.35ꢀ7.25 (m, 2H), 7.25ꢀ7.08 (m, 3H),

4.97 (br s, 0.25H), 4.76 (br s, 0.75H), 3.87ꢀ3.34 (m, 2H), 2.32 (br s,

1H), 2.04ꢀ1.74 (m, 3H), 1.46 (br s, 2.25H), 1.18 (br s, 6.75H); ¹³C

NMR (100.6 MHz, CDCl₃) (rotamers) δ 154.6 (C), 145.1 (C), 128.1

(CH), 126.4 (CH), 125.5 (CH), 125.1 (CH), 80.1 (C), 79.1 (C), 61.3

(CH), 47.2 (CH₂), 47.1 (CH₂), 36.0 (CH₂), 35.9 (CH₂), 28.4 (CH₃),

General Procedure D: Catalytic LithiationꢀNegishi Cou-

pling in Et₂O (0.3 equiv of Diamine). s-BuLi (1.5 mL of a 1.3 M

solution in cyclohexane, 2.0 mmol, 1.6 equiv) was added dropwise to a

stirred solution of (ꢀ)-sparteine (88 mg, 0.4 mmol, 0.3 equiv) and di-i-

Pr-bispidine 25 (342 mg, 1.6 mmol, 1.3 equiv) in Et₂O (6 mL)

at ꢀ78 °C under Ar. After stirring at ꢀ78 °C for 15 min, a solution of

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28.1 (CH₃), 23.4 (CH₂), 23.2 (CH₂); HPLC chiralpak AD-H (99:1

heptaneꢀi-PrOH, 0.5 mL min^ꢀ1) (R)-17 12.2 min, (S)-17 12.9 min.

Spectroscopic data consistent with those reported in the literature.¹²

(R)-N-(tert-Butoxycarbonyl)-2-phenyl Pyrrolidine (R)-17

(Table 1, entry 2). Using general procedure A, s-BuLi (4.8 mL of a

1.2 M solution in cyclohexane, 5.7 mmol, 1.0 equiv), N-Boc pyrroli-

dine 15 (1.2 mL, 5.7 mmol) and (ꢀ)-sparteine (1.3 mL, 5.7 mmol, 1.0

equiv) in TBME (12 mL), ZnCl₂(4.0 mL of a 1.0 M solution in Et₂O,

4.0 mmol, 0.7 equiv), Pd(OAc)₂(51 mg, 0.23 mmol, 0.04 equiv),

t-Bu₃PHBF₄(83 mg, 0.285 mmol, 0.05 equiv) and iodobenzene

(530 μL, 4.75 mmol, 0.83 equiv) gave the crude product. Purification

by flash column chromatography on silica with 4:1 CH₂Cl₂ꢀhexane

and then 9:1 CH₂Cl₂ꢀhexane as eluent gave phenyl pyrrolidine

(R)-17 (657 mg, 56%, 96:4 er by CSP-HPLC) as a white solid.

(R)-N-(tert-Butoxycarbonyl)-2-phenyl Pyrrolidine (R)-17

(Table 1, entry 3). s-BuLi (1.32 mL of a 1.3 M solution in hexanes,

1.75 mmol, 1.0 equiv) was added dropwise to a stirred solution of

N-Boc pyrrolidine 15 (314 mg, 307 μL, 1.75 mmol) and Alexakis’

diamine (R,R)-16 (543 mg, 1.75 mmol, 1.0 equiv) in Et₂O (3.5 mL) at

ꢀ78 °C under Ar. The resulting solution was stirred at ꢀ78 °C for 3 h.

Then, ZnCl₂(1.04 mL of a 1.0 M solution in Et₂O, 1.04 mmol, 0.6

equiv) was added dropwise, and the resulting solution was stirred at

ꢀ78 °C for 30 min. Then, the solution was allowed to warm to rt and

stirred at rt for 20 min. Bromobenzene (228 mg, 153 μL, 1.46 mmol,

0.83 equiv) was added. A mixture of Pd(OAc)₂(16 mg, 0.07 mmol,

0.04 equiv) and t-Bu₃PHBF₄(25 mg, 0.09 mmol, 0.05 equiv) was

added in one portion, and the resulting solution was stirred at rt for

16 h. Then, 35% NH₄OH_(aq)(0.15 mL) was added, and the solution

was stirred at rt for 1 h. The solids were removed by filtration through

Celite and washed with Et₂O (20 mL). The filtrate was washed with

1 M HCl_(aq)(15 mL) and water (2 ꢁ 15 mL), dried (MgSO₄) and

evaporated under reduced pressure to give the crude product.

Purification by flash column chromatography on silica with CH₂Cl₂

as eluent gave phenyl pyrrolidine (R)-17 (135 mg, 35%, 95:5 er by

CSP-HPLC) as a colorless oil, [R]_D+81.6 (c 0.2 in acetone). Other Pd

catalysts/ligands were explored to improve the yield: Pd₂(dba)₃/

t-Bu₃PHBF₄gave 36% yield; Pd(OAc)₂/CTS-Q-PHOS gave 29%

yield; Pd(OAc)₂/Ru-PHOS gave 13% yield.

mg, 391 μL, 2.0 mmol, 1.0 equiv) in Et₂O (6 mL) at ꢀ78 °C under Ar.

The resulting solution was stirred at ꢀ78 °C for 4 h. Then, ZnCl₂

(1.2 mL of a 1.0 M solution in Et₂O, 1.2 mmol, 0.6 equiv) was added

dropwise, and the resulting solution was stirred at ꢀ78 °C for 30 min.

Then, the solution was allowed to warm to rt and stirred at rt for 30

min. ortho-Bromobenzotrifluoride (383 mg, 230 μL, 1.7 mmol, 0.83

equiv) was added. A mixture of Pd(OAc)₂(22 mg, 0.1 mmol, 0.05

equiv) and t-Bu₃PHBF₄(22 mg, 0.125 mmol, 0.06 equiv) was added in

one portion, and the resulting solution was stirred at rt for 16 h. Then,

35% NH₄OH_(aq)(0.2 mL) was added, and the solution was stirred at rt

for 1 h. The solids were removed by filtration through Celite and

washed with Et₂O (20 mL). The filtrate was washed with 1 M HCl_(aq)

(20 mL) and water (2 ꢁ 20 mL), dried (MgSO₄) and evaporated under

reducted pressure to give the crude product. Purification by flash

column chromatography on silica with 99:1 CH₂Cl₂ꢀacetone as

eluent gave aryl pyrrolidine (R)-18 (370 mg, 69%, 95:5 er by CSP-

HPLC) as a white solid, mp 80ꢀ81 °C; [R]_D+51.5 (c 1.1 in CHCl₃);

R_f(99:1 CH₂Cl₂ꢀacetone) 0.8; ¹H NMR (400 MHz, CDCl₃) (80:20

mixture of rotamers) δ 7.68ꢀ7.58 (m, 1H), 7.57ꢀ7.43 (m, 1H),

7.38ꢀ7.26 (m, 2H), 5.38ꢀ5.30 (m, 0.2H), 5.19ꢀ5.11 (m, 0.8H),

3.80ꢀ3.64 (m, 2H), 2.48ꢀ2.39 (m, 1H), 2.05ꢀ1.84 (m, 2H),

1.83ꢀ1.72 (m, 1H), 1.47 (s, 1.8H), 1.12 (s, 7.2H); ¹³C NMR (100.6

MHz, CDCl₃) (rotamers) δ ¹³C NMR (100.6 MHz, CDCl₃)

(rotamers) δ 154.3 (C), 154.1 (C), 144.7 (C), 132.1 (CH), 131.9

(CH), 127.6 (q, J = 3.0 Hz, CH), 126.6 (CH) 126.5 (q, J = 24.0 Hz, C),

126.4 (CH), 126.0 (CH), 125.4 (q, J = 6.0 Hz, CH), 123.0 (C), 79.4

(C), 77.2 (C), 57.6 (CH), 47.4 (CH₂), 35.9 (CH₂), 28.4 (CH₃), 27.9

(CH₃), 23.0 (CH₂); HPLC chiralpak AD (99:1 hexaneꢀi-PrOH,

0.7 mL min^ꢀ1) (R)-18 8.8 min, (S)-18 10.3 min. Spectroscopic data

consistent with those reported in the literature.⁴²

(S)-2-(2-Trifluoromethylphenyl)pyrrolidine-1-carboxylic

acid tert-Butyl Ester (S)-18 (Table 1, entry 6). A solution of

N-Boc pyrrolidine 15 (342 mg, 350 μL, 2.0 mmol) in Et₂O (1 mL) was

added dropwise to a stirred solution of s-BuLi (1.7 mL of a 1.2 M

solution in cyclohexane, 2.0 mmol, 1.0 equiv) and (+)-sparteine

surrogate (288 mg, 2.0 mmol, 1.0 equiv) in Et₂O (6 mL) at ꢀ78 °C

under Ar. The resulting solution was stirred at ꢀ78 °C for 4 h. Then,

ZnCl₂(1.2 mL of a 1.0 M solution in Et₂O, 1.2 mmol, 0.6 equiv) was

added dropwise, and the resulting solution was stirred at ꢀ78 °C for

30 min. Then, the solution was allowed to warm to rt and stirred at rt

for 30 min. o-Bromobenzotrifluoride (383 mg, 230 μL, 1.7 mmol, 0.83

equiv) was added. A mixture of Pd(OAc)₂(22 mg, 0.1 mmol, 0.05

equiv) and t-Bu₃PHBF₄(22 mg, 0.125 mmol, 0.06 equiv) was added in

one portion, and the resulting solution was stirred at rt for 16 h. Then,

35% NH₄OH_(aq)(0.2 mL) was added, and the solution was stirred at rt

for 1 h. The solids were removed by filtration through Celite and

washed with Et₂O (20 mL). The filtrate was washed with 1 M HCl_(aq)

(20 mL) and water (2 ꢁ 20 mL), dried (MgSO₄), and evaporated

under reducted pressure to give the crude product. Purification by flash

column chromatography on silica with 99:1 CH₂Cl₂ꢀacetone as

eluent gave aryl pyrrolidine (R)-18 (370 mg, 69%, 95:5 er by CSP-

HPLC) as a white solid, mp 80ꢀ81 °C; [R]_Dꢀ46.5 (c 1.1 in CHCl₃).

rac-2-(2-Trifluoromethylphenyl)pyrrolidine-1-carboxylic

Acid tert-Butyl Ester rac-18 (Table 1, entry 7). s-BuLi (1.54 mL

of a 1.3 M solution in hexanes, 2.0 mmol, 1.0 equiv) was added dropwise

to a stirred solution of N-Boc pyrrolidine 15 (342 mg, 350 μL, 2.0

mmol) and TMEDA (232 mg, 299 μL, 2.0 mmol, 1.0 equiv) in Et₂O

(7 mL) at ꢀ78 °C under Ar. The resulting solution was stirred at

ꢀ78 °C for 1 h. Then, ZnCl₂(5.2 mL of a 0.5 M solution in THF, 2.6

mmol, 1.3 equiv) was added dropwise, and the resulting solution was

stirred at ꢀ78 °C for 30 min. Then, the solution was allowed to warm to

rt and stirred at rt for 20 min. o-Bromobenzotrifluoride (593 mg, 359 μL,

2.6 mmol, 1.3 equiv) was added. A mixture of Pd(OAc)₂(22 mg, 0.1

mmol, 0.05 equiv) and t-Bu₃PHBF₄(22 mg, 0.125 mmol, 0.06 equiv)

(S)-N-(tert-Butoxycarbonyl)-2-phenyl Pyrrolidine (S)-17

(Table 1, entry 4). s-BuLi (2.81 mL of a 1.2 M solution in hexanes,

3.4 mmol, 1.0 equiv) was added dropwise to a stirred solution of N-

Boc pyrrolidine 15 (591 μL, 3.4 mmol) and (+)-sparteine surrogate

(656 mg, 3.4 mmol, 1.0 equiv) in Et₂O (11 mL) at ꢀ78 °C under Ar.

The resulting solution was stirred at ꢀ78 °C for 3 h. Then, ZnCl₂

(2.0 mL of a 1.0 M solution in Et₂O, 2.0 mmol, 0.6 equiv) was added

dropwise, and the resulting solution was stirred at ꢀ78 °C for 30 min.

Then, the solution was allowed to warm to rt and stirred at rt for

20 min. Bromobenzene (356 μL, 3.4 mmol, 1.0 equiv) was added.

A mixture of Pd(OAc)₂(30 mg, 0.14 mmol, 0.04 equiv) and

t-Bu₃PHBF₄(49 mg, 0.17 mmol, 0.05 equiv) was added in one

portion, and the resulting solution was stirred at rt for 16 h. Then,

35% NH₄OH_(aq)(0.15 mL) was added, and the solution was stirred at

rt for 1 h. The solids were removed by filtration through Celite and

washed with Et₂O (20 mL). The filtrate was washed with 1 M HCl_(aq)

(15 mL) and water (2 ꢁ 15 mL), dried (MgSO₄) and evaporated

under reduced pressure to give the crude product. Purification by

flash column chromatography on silica with CH₂Cl₂as eluent gave

phenyl pyrrolidine (S)-17 (595 mg, 71%, 95:5 er by CSP-HPLC) as a

colorless oil, [R]_Dꢀ87.3 (c 1.4 in acetone).

(R)-2-(2-Trifluoromethylphenyl)pyrrolidine-1-carboxylic

Acid tert-Butyl Ester (R)-18 (Table 1, entry 5). A solution of N-

Boc pyrrolidine 15 (342 mg, 350 μL, 2.0 mmol) in Et₂O (1 mL) was

added dropwise to a stirred solution of s-BuLi (1.7 mL of a 1.2 M

solution in cyclohexane, 2.0 mmol, 1.0 equiv) and (ꢀ)-sparteine (469

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The Journal of Organic Chemistry

FEATURED ARTICLE

was added in one portion, and the resulting solution was stirred at rt for

16 h. Then, 35% NH₄OH_(aq)(0.2 mL) was added, and the solution was

stirred at rt for 1 h. The solids were removed by filtration through Celite

and washed with Et₂O (20 mL). The filtrate was washed with 1 M

HCl_(aq)(30 mL) and brine (30 mL), dried (MgSO₄) and evaporated

under reduced pressure to give the crude product. Purification by flash

column chromatography on silica with 99:1 CH₂Cl₂ꢀacetone as eluent

gave aryl pyrrolidine rac-17 (77 mg, 12%) as a yellow oil.

5.7 mmol, 1.0 equiv) in TBME (12 mL), ZnCl₂(3.4 mL of a 1.2 M

solution in Et₂O, 3.4 mmol, 0.6 equiv), Pd(OAc)₂(51 mg, 0.23 mmol,

0.04 equiv), t-Bu₃PHBF₄(83 mg, 0.285 mmol, 0.05 equiv) and

2-naphthyl bromide (1.03 g, 4.75 mmol, 0.83 equiv) gave the crude

product. Purification by flash column chromatography on silica with

47.5:47.5:5 hexaneꢀCH₂Cl₂ꢀTBME as eluent gave 2-naphthyl pyrro-

lidine (R)-21 (1.2 g, 82%, 95:5 er by CSP-HPLC) as a white solid, mp

90ꢀ92 °C; [R]_D+108.7 (c 1.1 in CHCl₃); IR (CHCl₃) 3008, 2977,

1

1683 (CdO), 1402, 1367, 1166, 1113 cm^ꢀ1; H NMR (400 MHz,

(R)-2-(2-Methoxycarbonylphenyl)pyrrolidine-1-carboxylic

Acid tert-Butyl Ester (R)-19 (Table 1, entry 8). Using general

procedure A, s-BuLi (11.1 mL of a 1.3 M solution in cyclohexane, 14.4

mmol, 1.0 equiv), N-Boc pyrrolidine 15 (2.5 mL, 14.4 mmol) and (ꢀ)-

sparteine (3.3 mL, 14.4 mmol, 1.0 equiv) in TBME (30 mL), ZnCl₂

(7.2 mL of a 1.0 M solution in Et₂O, 7.2 mmol, 0.50 equiv), Pd(OAc)₂

(108 mg, 0.48 mmol, 0.033 equiv), t-Bu₃PHBF₄(174 mg, 0.60 mmol,

0.042 equiv) and methyl-2-bromobenzoate (1.68 mL, 12.0 mmol, 0.83

equiv) gave the crude product. Purification by flash column chroma-

tography on silica with 10:1 hexaneꢀEtOAc and then 6:1 hexa-

neꢀEtOAc as eluent gave aryl pyrrolidine (R)-19 (2.74 g, 71%, 96:4

CDCl₃) (75:25 mixture of rotamers) δ 7.90ꢀ7.75 (m, 3H), 7.60 (s,

1H), 7.54ꢀ7.39 (m, 2H), 7.38ꢀ7.29 (m, 1H), 5.13 (br s, 0.25H), 4.96

(d, J = 4.0 Hz, 0.75H), 3.71 (d, J = 5.0 Hz, 1.5H), 3.60 (br s, 0.5H),

2.50ꢀ2.24 (m, 1H), 2.04ꢀ1.81 (m, 3H), 1.48 (s, 2.25H), 1.15 (m,

6.75H); ¹³C NMR (100.6 MHz, CDCl₃) (rotamers) δ 155.1 (C), 155.0

(C), 142.7 (C), 133.5 (C), 132.7 (C), 128.2 (CH), 127.9 (CH), 127.8

(CH), 126.2 (CH), 125.5 (CH), 124.3 (CH), 124.0 (CH), 79.2 (C),

61.2 (CH), 60.7 (CH), 47.2 (CH₂), 46.9 (CH₂), 35.5 (CH₂), 34.4

(CH₂), 28.2 (CH₃), 27.8 (CH₃), 23.2 (CH₂), 22.8 (CH₂); MS (ESI) m/

z 320 [(M + Na)⁺, 65], 298 [(M + H)⁺, 8], 242 (100), 114 (13); HRMS

(ESI) m/z calcd for C₁₉H₂₃NO₂(M + Na)⁺320.1621, found 320.1622

(ꢀ0.2 ppm error); HPLC chiralpak AD-H (99:1 heptaneꢀi-PrOH,

1.0 mL min^ꢀ1) (R)-21 6.8 min, (S)-21 7.4 min.

1

er by CSP-HPLC) as a colorless oil, R_f(4:1 petrolꢀEtOAc) 0.3; H

NMR (400 MHz, CDCl₃) (70:30 mixture of rotamers) δ 7.97ꢀ7.80 (m,

1H), 7.49ꢀ7.43 (m, 1H), 7.33ꢀ7.24 (m, 2H), 5.69 (br d, J = 7.5 Hz,

0.3H), 5.51 (dt, J = 7.5, 4.5 Hz, 0.7H), 3.92ꢀ3.85 (m, 3.3H), 3.68ꢀ3.61

(m, 1.7H), 2.62ꢀ2.41 (m, 1H), 1.85ꢀ1.72 (m, 3H), 1.43 (s, 2.7H), 1.12

(s, 6.3H); ¹³C NMR (100.6 MHz, CDCl₃) (rotamers) δ 167.6 (C),

154.3 (C), 147.3 (C), 132.0 (CH), 130.2 (CH), 127.9 (C), 126.1 (CH),

125.8 (CH), 79.0 (C), 58.7 (CH₃), 51.9 (CH), 47.6 (CH₂), 47.3 (CH₂),

35.5 (CH₂), 34.6 (CH₂), 28.5 (CH₃), 28.0 (CH₃), 23.1 (CH₂); HPLC

chiralpak AD-H (99:1 heptaneꢀi-PrOH, 0.7 mL min^ꢀ1) (R)-19 5.7

min, (S)-19 7.1 min. Spectroscopic data consistent with those reported

in the literature.⁴²

(R)-2-(4,5-Dimethoxy-2-methoxycarbonylmethylphenyl)

pyrrolidine-1-carboxylic Acid tert-Butyl Ester (R)-22(Scheme4).

Using general procedure A, s-BuLi (4.8 mL of a 1.2 M solution in

cyclohexane, 5.7 mmol, 1.0 equiv), N-Boc pyrrolidine 15 (1.2 mL, 5.7

mmol) and (ꢀ)-sparteine (1.3 mL, 5.7 mmol, 1.0 equiv) in TBME (12 mL),

ZnCl₂(3.4 mL of a 1.2 M solution in Et₂O, 3.4 mmol, 0.6 equiv), Pd(OAc)₂

(51 mg, 0.23 mmol, 0.04 equiv), t-Bu₃PHBF₄(83 mg, 0.285 mmol, 0.05

equiv) and aryl bromide 23⁴⁸(1.37 g, 4.75 mmol, 0.83 equiv) gave the crude

product. Purification by flash column chromatography on silica with 60:40

hexaneꢀEtOAc and then 50:50 hexaneꢀEtOAc as eluent gave aryl

pyrrolidine (R)-22 (1.2 g, 70%, 96.5:3.5 er by CSP-SFC) as a brown solid,

mp 45ꢀ46 °C; [R]_D+66.4 (c 1.0 in CHCl₃); IR (CHCl₃) 2974, 1737

(R)-(2-Naphthalen-1-yl)pyrrolidine-1-carboxylic Acid tert-

Butyl Ester (R)-20 (Table 1, entry 9). Using general procedure A, s-

BuLi (4.8 mL of a 1.2 M solution in cyclohexane, 5.7 mmol, 1.0 equiv),

N-Boc pyrrolidine 15 (1.2 mL, 5.7 mmol) and (ꢀ)-sparteine (1.3 mL,

5.7 mmol, 1.0 equiv) in TBME (12 mL), ZnCl₂(3.4 mL of a 1.0 M

solution in Et₂O, 3.4 mmol, 0.6 equiv), Pd(OAc)₂(51 mg, 0.23 mmol,

0.04 equiv), t-Bu₃PHBF₄(83 mg, 0.285 mmol, 0.05 equiv) and

1-naphthyl bromide (700 μL, 4.75 mmol, 0.83 equiv) gave the crude

product. Purification by flash column chromatography on silica with

47.5:47.5:5 hexaneꢀCH₂Cl₂ꢀTBME as eluent gave 1-naphthyl pyrro-

lidine (R)-20 (1.1 g, 79%, 96:4 er by CSP-HPLC) as a white solid, mp

94ꢀ95 °C; [R]_D+72.4 (c 1.2 in CHCl₃); IR (CHCl₃) 3008, 2978, 2878,

1683 (CdO), 1402, 1366, 1246, 1156, 1124 cm^ꢀ1; ¹H NMR (400 MHz,

CDCl₃) (65:35 mixture of rotamers) δ 8.03 (br d, J = 8.0 Hz, 1H), 7.90

(br d, J = 8.0 Hz, 0.65H), 7.86 (br d, J = 8.0 Hz, 0.35H), 7.79ꢀ7.70 (m,

1H), 7.58ꢀ7.38 (m, 3H), 7.28 (br d, J = 7.0 Hz, 0.65H), 7.25 (br d, J =

7.0 Hz, 0.35H), 5.79 (br d, J = 8.5 Hz, 0.35H), 5.62 (dd, J = 8.5, 2.5 Hz,

0.65H), 3.90ꢀ3.50 (m, 2H), 2.58ꢀ2.33 (m, 1H), 2.05ꢀ1.76 (m, 3H),

1.51 (s, 3.15H), 1.11 (s, 5.85H); ¹³C NMR (100.6 MHz, CDCl₃)

(rotamers) δ 154.9 (C), 140.2 (C), 139.0 (C), 134.3 (C), 134.0 (C),

130.4 (C), 129.0 (CH), 128.9 (CH), 127.4 (CH), 127.2 (CH), 125.9

(CH), 125.5 (CH), 125.4 (CH), 123.5 (CH), 123.1 (CH), 122.0 (CH),

121.5 (CH), 79.3 (C), 79.1 (C), 58.0 (CH), 57.8 (CH), 47.0 (CH₂),

46.7 (CH₂), 34.0 (CH₂), 33.0 (CH₂), 28.2 (CH₃), 27.8 (CH₃), 23.1

(CH₂), 22.6 (CH₂); MS (ESI) m/z 320 [(M + Na)⁺, 100], 298 [(M +

H)⁺, 11], 242 (99), 114 (47); HRMS (ESI) m/z calcd for C₁₉H₂₃NO₂

(M + Na)⁺320.1621, found 320.1623 (ꢀ0.7 ppm error); HPLC

chiralpak AD-H (99:1 heptaneꢀi-PrOH, 1.0 mL min^ꢀ1) (R)-20 5.6

min, (S)-20 7.8 min.

(CdO, CO₂Me), 1690 (CdO, Boc), 1516, 1399, 1366, 1265, 1163 cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃) (75:25 mixture of rotamers) δ 6.70 (s, 1H),

6.62 (s, 1H), 5.11ꢀ4.82 (m, 1H), 3.85 (br s, 3H), 3.80 (s, 3H), 3.67 (s, 3H),

3.76ꢀ3.44 (m, 4H), 2.39ꢀ2.17 (m, 1H), 2.03ꢀ1.77 (m, 2H), 1.77ꢀ1.61

(m, 1H), 1.41 (s, 2.25H), 1.14 (s, 6.75H); ¹³C NMR (100.6 MHz, CDCl₃)

(rotamers) δ 172.4 (C), 154.8 (C), 148.6 (C), 147.7 (C), 136.5 (C), 122.7

(C), 113.6 (CH), 108.3 (CH), 79.2 (C), 57.5 (CH), 55.7 (CH₃), 51.8

(CH₃), 47.3 (CH₂), 47.2 (CH₂), 37.7 (CH₂), 35.0 (CH₂), 28.1 (CH₃),

27.8 (CH₃), 23.1 (CH₂); MS (ESI) m/z 402 [(M + Na)⁺, 100], 380 [(M +

H)⁺], 40, 324 (42), 280 (32); HRMS (ESI) m/z calcd for C₂₀H₂₉NO₆(M

+ Na)⁺402.1887, found 402.1884 (+0.7 ppm error); SFC chiralpak OJ-H

(isocratic 4%MeOH/CO₂, 1.5 mL min^ꢀ1, 200 bar, 35 °C) (R)-22 3.6 min,

(S)-22 3.1 min.

(R)-8,9-Dimethoxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-R]

isoquinolin-5-one (R)-24 (Scheme 4). Me₃SiCl (7.1 mL, 55.8

mmol) was added dropwise (maintaining the temperature below 25 °C)

to a stirred solution of aryl pyrrolidine (R)-22 (5.2 g, 13.7 mmol) in

MeOH (81 mL) at 20 °C. The resulting solution was stirred at 20 °C for

16 h. TBME (100 mL) was added and the organic solution was washed

with 1 M Na₂CO_3(aq)(2 ꢁ 50 mL). The combined aqueous washings

were back-extracted with CH₂Cl₂(2 ꢁ 25 mL). Then, the combined

organic layers were dried (MgSO₄) and evaporated under reduced

pressure to give the crude product. Purification by flash column

chromatography on silica with 90:10 EtOAcꢀMeOH as eluent gave

lactam (R)-24 (4.2 g, 95%, 96:4 er by CSP-SFC) as a yellow solid, mp

131ꢀ132 °C; [R]_D+109.6 (c 1.0 in CHCl₃); IR (CHCl₃) 3005, 1639

(CdO), 1519, 1454, 1217, 754 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃) δ

6.67 (s, 1H), 6.66 (s, 1H), 4.67ꢀ4.49 (m, 1H), 3.87 (s, 3H), 3.86

(s, 3H), 3.71ꢀ3.42 (m, 4H), 2.66ꢀ2.52 (m, 1H), 2.21ꢀ2.08 (m, 1H),

2.08ꢀ1.92 (m, 1H), 1.92ꢀ1.78 (m, 1H); ¹³C NMR (100.6 MHz,

(R)-(2-Naphthalen-2-yl)pyrrolidine-1-carboxylic Acid tert-

Butyl Ester (R)-21 (Table 1, entry 10). Using general procedure A,

s-BuLi (4.8 mL of a 1.2 M solution in cyclohexane, 5.7 mmol, 1.0 equiv),

N-Boc pyrrolidine 15 (1.2 mL, 5.7 mmol) and (ꢀ)-sparteine (1.3 mL,

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FEATURED ARTICLE

CDCl₃) 168.0 (C), 148.8 (C), 148.1 (C), 128.2 (C), 125.1 (C), 110.3

(CH), 107.7 (CH), 59.4 (CH), 56.0 (CH₃), 55.9 (CH₃), 44.5 (CH₂),

37.9 (CH₂), 31.5 (CH₂), 22.7 (CH₂); MS (ESI) m/z 270 [(M + Na)⁺,

49], 248 [(M + H)⁺, 100]; HRMS (ESI) m/z calcd for C₁₄H₁₇NO₃(M

+ H)⁺248.1281, found 248.1281 (ꢀ0.1 ppm error); SFC chiralpak AD-

di-i-Pr-bispidine 25 (606 mg, 2.9 mmol, 1.0 equiv) in Et₂O (7 mL),

ZnCl₂(1.7 mL of a 1.0 M solution in Et₂O, 1.7 mmol, 0.6 equiv),

Pd(OAc)₂(31 mg, 0.14 mmol, 0.05 equiv), t-Bu₃PHBF₄(32 mg, 0.18

mmol, 0.06 equiv) and o-bromobenzotrifluoride (434 mg, 263 μL, 2.0

mmol, 0.83 equiv) gave the crude product. Purification by flash column

chromatography on silica with 99:1 CH₂Cl₂ꢀacetone as eluent gave

aryl pyrrolidine (S)-18 (481 mg, 75%, 91:9 er by CSP-HPLC) as a

white solid, [R]_Dꢀ42.2 (c 1.4 in CHCl₃).

H column (250 ꢁ 4.6 mm, isocratic 15% MeOH/CO₂, 1.5 mL min^ꢀ1

,

200 bar, 35 °C) (R)-24 9.6 min, (S)-24 8.9 min.

(R)-Crispine A (Scheme 4). Borane (4.0 mL of a 1.0 M solution in

THF) was added dropwise over 15 min to a stirred suspension of lactam

(R)-24 (200 mg, 0.81 mmol) in THF (10 mL) at 0 °C. The resulting

mixture was stirred at room temperature for 30 min and then heated at

40 °C for 7 h. After cooling to 0 °C, water (3.0 mL) was added dropwise

(CAUTION ꢀ significant foaming due to hydrogen evolution). Then, 6

M HCl_(aq)(5 mL) was added, and the resulting mixture was stirred and

heated at 50 °C for 5 h (to cleave the amine-borane complex of the

product). After cooling to room temperature, TBME was added and the

mixture was basified by the addition of 10 M NaOH_(aq)(3 mL). The two

layers were separated and the organic layer was washed with water

(2 ꢁ 20 mL). Then, the combined organic layers were evaporated under

reduced pressure to give the crude product. Purification by flash column

chromatography on silica with 20:1:1 CH₂Cl₂ꢀ28% NH_3(aq)ꢀMeOH

as eluent gave (R)-(+)-crispine A (155 mg, 82%, 97:3 er by CSP-SFC) as

an off-white solid, [R]_D+90.8 (c 0.79 in MeOH)(lit.,^47d[R]_D+95.2

(c 1.5 in MeOH)); ¹H NMR (400 MHz, CDCl₃) δ 6.63 (s, 1H), 6.58

(s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.42 (t, J = 8.3 Hz, 1H), 3.23ꢀ3.16

(m, 1H), 3.12ꢀ2.98 (m, 2H), 2.73ꢀ2.70 (m, 1H), 2.67ꢀ2.61 (m, 1H),

2.55 (q, J = 8.8 Hz, 1H), 2.37ꢀ2.27 (m, 1H), 2.10ꢀ1.81 (m, 2H),

1.78ꢀ1.67 (m, 1H); ¹³C NMR (100.6 MHz, CDCl₃) δ 147.4, 147.3,

131.2, 126.3, 111.5, 109.0, 63.0, 56.0, 55.9, 53.2, 48.4, 30.5, 28.1, 22.3;

SFC chiralcel OD-H (i-PrOH/i-BuNH₂modifier, 0.7 mL min^ꢀ1) (R)-24

9.4 min, (S)-24 9.0 min. Spectroscopic data consistent with those reported

in the literature.^47d

(R)-2-(2-Methoxycarbonylphenyl)pyrrolidine-1-carboxylic

Acid tert-Butyl Ester (R)-19 (Table 2, entry 4). Using general

procedure C, s-BuLi (1.55 mL of a 1.3 M solution in cyclohexane, 2.0

mmol, 1.0 equiv), N-Boc pyrrolidine 15 (344 mg, 2.0 mmol), (ꢀ)-

sparteine (118 mg, 0.5 mmol, 0.25 equiv), di-i-Pr-bispidine 25 (423 mg,

2.0 mmol, 1.0 equiv) in Et₂O (7 mL), ZnCl₂(1.2 mL of a 1.0 M solution

in Et₂O, 1.2 mmol, 0.6 equiv), Pd(OAc)₂(22 mg, 0.1 mmol, 0.05 equiv),

t-Bu₃PHBF₄(22 mg, 0.13 mmol, 0.06 equiv) and methyl 2-bromo-

benzoate (198 μL, 1.4 mmol, 0.83 equiv) gave the crude product.

Purification by flash column chromatography on silica with 4:1 pet-

rolꢀEt₂O as eluent gave aryl pyrrolidine (R)-19 (309 mg, 50%, 81:19 er

by CSP-HPLC) as a colorless oil, [R]_D+14.9 (c 1.4 in CHCl₃); HPLC

chiralpak AD (99:1 hexaneꢀi-PrOH, 0.7 mL min^ꢀ1) (R)-19 5.7 min,

(S)-19 7.1 min.

(S)-(2-Naphthalen-2-yl)pyrrolidine-1-carboxylic Acid tert-

Butyl Ester (S)-21 (Table 2, entry 5). Using general procedure B,

s-BuLi (4.8 mL of a 1.2 M solution in cyclohexane, 5.7 mmol, 1.0 equiv),

N-Boc pyrrolidine 15 (1.2 mL, 5.7 mmol), (+)-sparteine surrogate

(275 μL, 1.4 mmol, 0.25 equiv) and di-i-Pr-bispidine 25 (1.3 mL, 5.7 mmol,

1.0 equiv) in TBME (12 mL), ZnCl₂(1.7 mL of a 1.2 M solution in

Et₂O, 2.0 mmol, 0.35 equiv), Pd(OAc)₂(51 mg, 0.23 mmol, 0.04 equiv),

t-Bu₃PHBF₄(83 mg, 0.285 mmol, 0.05 equiv) and 2-naphthyl bromide

(1.03 g, 4.75 mmol, 0.83 equiv) gave the crude product. Purification

by flash column chromatography on silica with 47.5:47.5:5 hexaneꢀ

CH₂Cl₂ꢀTBME as eluent gave 2-naphthyl pyrrolidine (S)-17 (1.1 g, 80%,

95:5 er by CSP-HPLC) as a white solid.

(R)-2-(2-Methoxyphenyl)pyrrolidine-1-carboxylicAcidtert-

Butyl Ester (R)-26 (Table 2, entry 6). Using general procedure C,

s-BuLi (1.55 mL of a 1.3 M solution in cyclohexane, 2.0 mmol, 1.0 equiv),

N-Boc pyrrolidine 15 (348 mg, 2.0 mmol), (ꢀ)-sparteine (119 mg, 0.5

mmol, 0.25 equiv), di-i-Pr-bispidine 25 (427 mg, 2.0 mmol, 1.0 equiv) in

Et₂O (7 mL), ZnCl₂(1.2 mL of a 1.0 M solution in Et₂O, 1.2 mmol, 0.6

equiv), Pd(OAc)₂(22 mg, 0.1 mmol, 0.05 equiv), t-Bu₃PHBF₄(23 mg,

0.13 mmol, 0.06 equiv) and o-bromoanisole (177 μL, 1.4 mmol, 0.83

equiv) gave the crude product. Purification by flash column chromatog-

raphy on silica with CH₂Cl₂as eluent gave aryl pyrrolidine (R)-26 (196

mg, 50%, 80:20 er by CSP-HPLC) as a colorless oil, [R]_D+23.6 (c 1.0 in

acetone); R_f(98:2 CH₂Cl₂ꢀacetone) 0.2; ¹H NMR (400 MHz, CDCl₃)

(70:30 mixture of rotamers) δ 7.26ꢀ7.13 (m, 1H), 7.06 (d, J = 7.5 Hz,

0.7H), 7.01 (d, J= 7.5Hz, 0.3H), 6.89 (t, J= 7.5Hz, 1H), 6.85 (brd, J= 8.0

Hz, 1H), 5.25 (br d, J = 7.5 Hz, 0.3H), 5.18ꢀ5.01 (m, 0.7H), 3.83 (s, 3H),

3.69ꢀ3.40 (m, 2H), 2.38ꢀ2.12 (m, 1H), 1.94ꢀ1.71 (m, 3H), 1.47 (s,

2.7H), 1.19 (s, 6.3H); ¹³C NMR (100.6 MHz, CDCl₃) (rotamers) δ

156.1 (C), 154.6 (C), 132.9 (C), 127.5 (C), 127.3 (CH), 125.9 (CH),

120.1 (CH), 110.3 (CH), 110.1 (CH), 79.0 (C), 78.8 (C), 56.1 (CH₃),

55.3 (CH), 55.2 (CH), 47.2 (CH₂), 46.8 (CH₂), 33.9 (CH₂), 32.8

(CH₂), 28.5 (CH₃), 28.1 (CH₃), 23.1 (CH₂); HPLC chiralpak AD (99:1

hexaneꢀi-PrOH, 0.5 mL min^ꢀ1) (S)-26 19.6 min, (R)-26 22.8 min.

Spectroscopic data consistent with those reported in the literature.⁴²

(S)-2-(2-Methoxyphenyl)pyrrolidine-1-carboxylic Acid tert-

Butyl Ester (S)-26 (Table 2, entry 7). Using general procedure C,

s-BuLi (1.7 mL of a 1.3 M solution in cyclohexane, 2.0 mmol, 1.0 equiv),

N-Boc pyrrolidine 15 (342 mg, 350 μL, 2.0 mmol), (+)-sparteine

surrogate (97 mg, 0.5 mmol, 0.25 equiv), di-i-Pr-bispidine 25 (421

mg, 2.0 mmol, 1.0 equiv) in Et₂O (7 mL), ZnCl₂(1.2 mL of a 1.0 M

solution in Et₂O, 1.2 mmol, 0.6 equiv), Pd(OAc)₂(22 mg, 0.1 mmol,

(S)-N-(tert-Butoxycarbonyl)-2-phenyl Pyrrolidine (S)-17

(Table 2, entry 1). Using general procedure B, s-BuLi (4.8 mL of a

1.2 M solution in cyclohexane, 5.7 mmol, 1.0 equiv), N-Boc pyrro-

lidine 15 (1.2 mL, 5.7 mmol), (+)-sparteine surrogate (275 μL, 1.4

mmol, 0.25 equiv) and di-i-Pr-bispidine 25 (1.3 mL, 5.7 mmol, 1.0

equiv) in TBME (12 mL), ZnCl₂(1.7 mL of a 1.2 M solution in Et₂O,

2.0 mmol, 0.35 equiv), Pd(OAc)₂(51 mg, 0.23 mmol, 0.04 equiv),

t-Bu₃PHBF₄(83 mg, 0.285 mmol, 0.05 equiv) and bromobenzene

(746 mg, 500 μL, 4.75 mmol, 0.83 equiv) gave the crude product.

Purification by flash column chromatography on silica with 4:1

CH₂Cl₂ꢀhexane and then 9:1 CH₂Cl₂ꢀhexane as eluent gave phenyl

pyrrolidine (S)-17 (937 mg, 80%, 95:5 er by CSP-HPLC) as a

white solid.

(R)-2-(2-Trifluoromethylphenyl)pyrrolidine-1-carboxylic

Acid tert-Butyl Ester (R)-18 (Table 2, entry 2). Using general

procedure C, s-BuLi (1.3 mL of a 1.3 M solution in cyclohexane, 1.64

mmol, 1.0 equiv), N-Boc pyrrolidine 15 (280 mg, 1.64 mmol), (ꢀ)-

sparteine (96 mg, 0.4 mmol, 0.25 equiv), di-i-Pr-bispidine 25 (345 mg,

1.64 mmol, 1.0 equiv) in Et₂O (7 mL), ZnCl₂(1.0 mL of a 1.0 M

solution in Et₂O, 1.0 mmol, 0.6 equiv), Pd(OAc)₂(18 mg, 0.08 mmol,

0.05 equiv), t-Bu₃PHBF₄(18 mg, 0.10 mmol, 0.06 equiv) and

o-bromobenzotrifluoride (159 μL, 1.15 mmol, 0.83 equiv) gave the

crude product. Purification by flash column chromatography on silica

with 99:1 CH₂Cl₂ꢀacetone as eluent gave aryl pyrrolidine (R)-18 (278

mg, 76%, 80:20 er by CSP-HPLC) as a white solid, [R]_D+40.7 (c 1.3 in

CHCl₃); HPLC chiralpak AD (99:1 hexaneꢀi-PrOH, 0.7 mL min^ꢀ1

)

(R)-18 9.8 min, (S)-18 11.4 min.

(S)-2-(2-Trifluoromethylphenyl)pyrrolidine-1-carboxylic

Acid tert-Butyl Ester (S)-18 (Table 2, entry 3). Using general

procedure C, s-BuLi (2.2 mL of a 1.3 M solution in cyclohexane,

2.9 mmol, 1.0 equiv), N-Boc pyrrolidine 15 (493 mg, 505 μL,

2.9 mmol), (+)-sparteine surrogate (139 mg, 0.7 mmol, 0.25 equiv),

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0.05 equiv), t-Bu₃PHBF₄(22 mg, 0.125 mmol, 0.06 equiv) and o-

bromoanisole (318 mg, 210 μL, 1.7 mmol, 0.83 equiv) gave the crude

product. Purification by flash column chromatography on silica with

CH₂Cl₂as eluent gave aryl pyrrolidine (S)-26 (410 mg, 87%, 96:4 er by

CSP-HPLC) as a colorless oil, [R]_Dꢀ65.5 (c 1.2 in CHCl₃).

colorless oil, [R]_D+59.8 (c 1.0 in acetone); HPLC chiralpak AD (99:1

hexaneꢀi-PrOH, 0.5 mL min^ꢀ1) (S)-26 18.9 min, (R)-26 21.5 min.

(R)-1⁰-(Toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1⁰H-[2,2⁰]

bipyrrolyl-1-carboxylic Acid tert-Butyl Ester (R)-28 (Scheme 6).

Using general procedure A, s-BuLi (1.0 mL of a 1.2 M solution in cyclo-

hexane, 1.2 mmol, 1.0 equiv), N-Boc pyrrolidine 15 (250 μL, 1.2 mmol)

and (ꢀ)-sparteine (260 μL, 1.2 mmol, 1.0 equiv) in TBME (3 mL), ZnCl₂

(710 μL of a 1.0 M solution in Et₂O, 0.7 mmol, 0.6 equiv), Pd(OAc)₂

(8 mg, 0.05 mmol, 0.04 equiv), t-Bu₃PHBF₄(12 mg, 0.06 mmol, 0.05 equiv)

and the appropriate aryl bromide (250 mg, 1.0 mmol, 0.83 equiv) gave the

crude product. Purification by flash column chromatography on silica with

70:30 hexaneꢀEtOAc as eluent gave aryl pyrrolidine (R)-28 (140 mg, 58%,

95:5 er by CSP-HPLC) as an orange solid, mp 104ꢀ105 °C; [R]_D+27.4

(c1.2 in CHCl₃);IR(CHCl₃) 3008, 2979, 1683 (CdO), 1401, 1368, 1172,

(S)-2-(4-Methoxycarbonylphenyl)pyrrolidine-1-carboxylic

Acid tert-Butyl Ester (S)-27 (Table 2, entry 8). Using general

procedure B, s-BuLi (4.8 mL of a 1.2 M solution in cyclohexane, 5.7

mmol, 1.0 equiv), N-Boc pyrrolidine 15 (1.2 mL, 5.7 mmol), (+)-

sparteine surrogate (275 μL, 1.4 mmol, 0.25 equiv) and di-i-Pr-bispidine

25 (1.03 g, 5.7 mmol, 1.0 equiv) in TBME (12 mL), ZnCl₂(1.7 mL of a

1.2 M solution in Et₂O, 2.0 mmol, 0.35 equiv), Pd(OAc)₂(51 mg, 0.23

mmol, 0.04 equiv), t-Bu₃PHBF₄(83 mg, 0.285 mmol, 0.05 equiv) and

methyl 4-bromobenzoate (1.02 g, 4.75 mmol, 0.83 equiv) gave the crude

product. Purification by flash column chromatography on silica with

80:20 hexaneꢀEtOAc and then 75:25 hexaneꢀEtOAc as eluent gave

aryl pyrrolidine (S)-27 (1.0 g, 85%, 93:7 er by CSP-HPLC) as a white

solid, R_f(3:1 petrolꢀEt₂O) 0.2; ¹H NMR (400 MHz, CDCl₃) (70:30

mixture of rotamers) δ 7.97 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H),

4.96 (br s, 0.3H), 4.79 (br s, 0.7H), 3.90 (s, 3H), 3.71ꢀ3.51 (m, 2H),

2.46ꢀ2.21 (m, 1H), 1.99ꢀ1.79 (m, 3H), 1.45 (s, 2.7H), 1.16 (s, 6.3H);

¹³C NMR (100.6 MHz, CDCl₃) (rotamers) δ 166.9 (C), 154.4 (C),

150.6 (C), 129.7 (CH), 129.6 (CH), 128.4 (C), 125.4 (CH), 79.4 (C),

61.1 (CH₃), 52.0 (CH), 47.1 (CH₂), 35.9 (CH₂), 34.7 (CH₂),

28.4 (CH₃), 28.1 (CH₃), 23.5 (CH₂), 23.2 (CH₂); HPLC chiralpak

AD-H (98:2 heptaneꢀi-PrOH, 1.0 mL min^ꢀ1) (R)-27 10.8 min, (S)-27

11.4 min. Spectroscopic data consistent with those reported in the

literature.⁴²

1

1061, 749, 675 cm^ꢀ1; H NMR (400 MHz, CDCl₃) (70:30 mixture of

rotamers) δ 7.71 (d, J = 7.5 Hz, 2H), 7.26 (d, J = 7.5 Hz, 2H), 7.09 (br s,

0.7H), 7.04 (br s, 0.3H), 6.94 (br s, 0.3H), 6.90 (s, 0.7H), 6.15 (br s, 1H),

4.83 (br s, 0.3H), 4.66 (d, J = 3.5 Hz, 0.7H), 3.44 (br s, 1.4H), 3.34 (br s,

0.6H), 2.38 (s, 3H), 2.10 (br s, 1H), 1.94ꢀ1.68 (m, 3H), 1.43 (s, 2.7H),

1.16 (s, 6.3H,); ¹³C NMR (100.6 MHz, CDCl₃) (rotamers) δ 154.8 (C),

145.1 (C), 136.4 (C), 133.1 (C), 130.1 (CH), 127.0 (CH), 121.1 (CH),

116.9 (CH), 113.1 (CH), 112.3 (CH), 79.0 (C), 54.2 (CH), 54.1 (CH),

46.05 (CH₂), 45.98 (CH₂), 33.8 (CH₂), 27.9 (CH₃), 26.7 (CH₂), 21.2

(CH₃); MS (ESI) m/z 413 [(M + Na)⁺, 100], 391 [(M + H)⁺, 11], 335

(63), 207 (14), 114 (44); HRMS (ESI) m/z calcd for C₂₀H₂₆N₂SO₄(M +

Na)⁺413.1505, found 413.1495 (+2.6 ppm error); HPLC chiralpak AD-H

(90:10 hexaneꢀi-PrOH, 1.0 mL min^ꢀ1) (R)-28 10.3 min, (S)-28 8.1 min.

(R)-1⁰-Triisopropylsilanyl-2,3,4,5-tetrahydro-1⁰H-[2,3⁰]

bipyrrolyl-1-carboxylic Acid tert-Butyl Ester (R)-29 (Scheme 6).

Using general procedure A, s-BuLi (1.0 mL of a 1.2 M solution in

cyclohexane, 1.2 mmol, 1.0 equiv), N-Boc pyrrolidine 15 (250 μL, 1.2

mmol) and (ꢀ)-sparteine (260 μL, 1.2 mmol, 1.0 equiv) in TBME

(3 mL), ZnCl₂(710 μL of a 1.0 M solution in Et₂O, 0.7 mmol, 0.6

equiv), Pd(OAc)₂(8 mg, 0.05 mmol, 0.04 equiv), t-Bu₃PHBF₄(12 mg,

0.06 mmol, 0.05 equiv) and the appropriate aryl bromide (252 mg, 1.0

mmol, 0.83 equiv) gave the crude product. Purification by flash column

chromatography on silica with 90:10 hexaneꢀEtOAc as eluent gave aryl

pyrrolidine (R)-29 (250 mg, 76%, 94:6 er by CSP-HPLC) as a colorless

oil, R_f0.8 (6:4 petrolꢀEt₂O); [R]_D+51.6 (c 1.0 in CHCl₃); IR (film)

(R)-2-(2-Trifluoromethylphenyl)pyrrolidine-1-carboxylic

Acid tert-Butyl Ester (R)-18 (Scheme 5). Using general proce-

dure D, s-BuLi (1.5 mL of a 1.3 M solution in cyclohexane, 2.0 mmol,

1.6 equiv), N-Boc pyrrolidine 15 (216 mg, 1.25 mmol), (ꢀ)-sparteine

(89 mg, 0.4 mmol, 0.3 equiv) and di-i-Pr-bispidine 25 (342 mg, 1.6

mmol, 1.3 equiv) in Et₂O (7 mL), ZnCl₂(750 μL of a 1.0 M solution in

Et₂O, 0.75 mmol, 0.6 equiv), Pd(OAc)₂(14 mg, 0.06 mmol, 0.05

equiv), t-Bu₃PHBF₄(14 mg, 0.08 mmol, 0.06 equiv) and methyl

2-bromobenzoate (123 μL, 0.9 mmol, 0.83 equiv) gave the crude

product. Purification by flash column chromatography on silica with

4:1 petrolꢀEt₂O as eluent gave aryl pyrrolidine (R)-19 (189 mg,

71%, 89:11 er by CSP-HPLC) as a colorless oil, [R]_D+16.4 (c 1.0 in

CHCl₃).

(R)-2-(2-Methoxycarbonylphenyl)pyrrolidine-1-carboxylic

Acid tert-Butyl Ester (R)-19 (Scheme 5). Using general procedure

D, s-BuLi (1.5 mL of a 1.3 M solution in cyclohexane, 2.0 mmol, 1.6

equiv), N-Boc pyrrolidine 15 (214 mg, 1.25 mmol), (ꢀ)-sparteine (88

mg, 0.4 mmol, 0.3 equiv) and di-i-Pr-bispidine 25 (342 mg, 1.6 mmol,

1.3 equiv) in Et₂O (7 mL), ZnCl₂(750 μL of a 1.0 M solution in Et₂O,

0.75 mmol, 0.6 equiv), Pd(OAc)₂(14 mg, 0.06 mmol, 0.05 equiv),

t-Bu₃PHBF₄(14 mg, 0.08 mmol, 0.06 equiv) and methyl 2-bromo-

benzoate (123 μL, 0.9 mmol, 0.83 equiv) gave the crude product.

Purification by flash column chromatography on silica with 4:1 petrolꢀ

Et₂O as eluent gave aryl pyrrolidine (R)-19 (189 mg, 71%, 89:11 er by

CSP-HPLC) as a colorless oil, [R]_D+16.4 (c 1.0 in CHCl₃).

(R)-2-(2-Methoxyphenyl)pyrrolidine-1-carboxylic Acidtert-

Butyl Ester (R)-26 (Table 2, entry 6). Using general procedure D,

s-BuLi (1.75 mL of a 1.3 M solution in cyclohexane, 2.3 mmol, 1.6 equiv),

N-Boc pyrrolidine 15 (243 mg, 1.4 mmol), (ꢀ)-sparteine (100 mg, 0.43

mmol, 0.3 equiv) and di-i-Pr-bispidine 25 (388 mg, 1.85 mmol, 1.3

equiv) in Et₂O (7 mL), ZnCl₂(852 μL of a 1.0 M solution in Et₂O,

0.85 mmol, 0.6 equiv), Pd(OAc)₂(16 mg, 0.07 mmol, 0.05 equiv),

t-Bu₃PHBF₄(16 mg, 0.09 mmol, 0.06 equiv) and o-bromoanisole

(124 μL, 1.0 mmol, 0.83 equiv) gave the crude product. Purification

by flash column chromatography on silica with CH₂Cl₂as eluent gave

aryl pyrrolidine (R)-26 (253 mg, 92%, 89:11 er by CSP-HPLC) as a

2946, 2867, 1694 (CdO), 1464, 1393, 1365, 1169, 1099, 884, 659 cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃) (85:15 mixture of rotamers) δ 6.66 (t, J =

2.0 Hz, 1H), 6.53 (br s, 1H), 6.12 (br s, 1H), 4.99 (br s, 0.15H), 4.87

(br s, 0.85H), 3.46 (br s, 2H), 2.18ꢀ2.02 (m, 1H), 2.02ꢀ1.74 (m, 3H),

1.38 (septet, J = 7.5 Hz, 3H), 1.35 (br s, 1.35H), 1.07 (br s, 15.3H), 1.05

(br s, 2.7H), 1.04 (s, 7.65H); ¹³C NMR (100.6 MHz, CDCl₃) (rotamers) δ

155.2 (C), 124.1 (CH), 121.5 (C), 120.7 (CH), 108.8 (CH), 78.7 (C),

54.9 (CH), 45.7 (CH₂), 34.1 (CH₂), 28.2(CH₃), 22.8 (CH₂), 17.5 (CH₃),

17.4 (CH₃), 11.9 (CH), 11.3 (CH); MS (ESI) m/z 415 [(M + Na)⁺, 100],

393 [(M + H)⁺, 58], 337 (85), 224 (39), 209 (11), 114 (25); HRMS

(ESI) m/z calcd for C₂₂H₄₀N₂O₂Si (M + H)⁺393.2932, found 393.2925

(+1.6 ppm error); HPLC chiralpak AD-H (98:2 hexaneꢀi-PrOH, 1.0 mL

min^ꢀ1) (R)-29 2.1 min, (S)-29 2.7 min.

(R)-2-Thiophen-3-ylpyrrolidine-1-carboxylic Acid tert-Bu-

tyl Ester (R)-30 (Scheme 6). Using general procedure A, s-BuLi

(1.0 mL of a 1.2 M solution in cyclohexane, 1.2 mmol, 1.0 equiv), N-Boc

pyrrolidine 15 (250 μL, 1.2 mmol) and (ꢀ)-sparteine (260 μL, 1.2

mmol, 1.0 equiv) in TBME (3 mL), ZnCl₂(710 μL of a 1.0 M solution in

Et₂O, 0.7 mmol, 0.6 equiv), Pd(OAc)₂(8 mg, 0.05 mmol, 0.04 equiv),

t-Bu₃PHBF₄(12 mg, 0.06 mmol, 0.05 equiv) and the appropriate aryl

bromide (163 mg, 1.0 mmol, 0.83 equiv) gave the crude product.

Purification by flash column chromatography on silica with 85:15

hexaneꢀEtOAc as eluent gave aryl pyrrolidine (R)-30 (140 mg, 72%,

94:6 er by CSP-HPLC) as a colorless oil, R_f0.4 (6:4 petrolꢀEtOAc);

[R]_D+114.8 (c 1.0 in CHCl₃); IR (film) 2974, 2877, 1692 (CdO),

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1392, 1366, 1169, 1112, 776 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃) (65:35

mixture of rotamers) δ 7.23 (dd, J = 5.0, 3.0 Hz, 1H), 6.96 (br s, 1H),

6.92 (br s, 1H), 5.03 (br s, 0.35H), 4.87 (br d, J = 5.0 Hz, 0.65H), 3.53

(br s, 1.3H), 3.43 (br s, 0.7H), 2.35ꢀ2.08 (m, 1H), 2.03ꢀ1.77 (m, 3H),

1.45 (s, 3.25H), 1.25 (s, 5.85H); ¹³C NMR (100.6 MHz, CDCl₃)

(rotamers) δ 154.9 (C), 146.2 (C), 126.0 (CH), 125.8 (CH), 125.6

(CH), 119.7 (CH), 79.1 (C), 57.0 (CH), 56.6 (CH), 46.4 (CH₂), 46.1

(CH₂), 34.2 (CH₂), 33.0 (CH₂), 28.1 (CH₃), 27.9 (CH₃), 23.3 (CH₂),

22.8 (CH₂); MS (ESI) m/z 276 [(M + Na)⁺, 73], 254 [(M + H)⁺, 12],

198 (100), 114 (40); HRMS (ESI) m/z calcd for C₁₃H₁₉NO₂S

(M + Na)⁺276.1029, found 276.1033 (ꢀ1.6 ppm error); HPLC

chiralpak AD-H (95:5 hexaneꢀi-PrOH, 0.5 mL min^ꢀ1) (R)-30 6.5 min,

(S)-30 7.0 min.

(R)-2-Pyridin-3-ylpyrrolidine-1-carboxylic Acid tert-Butyl

Ester (R)-33 (Scheme 6). Using general procedure A, s-BuLi (1.0 mL

of a 1.2 M solution in cyclohexane, 1.2 mmol, 1.0 equiv), N-Boc

pyrrolidine 15 (250 μL, 1.2 mmol) and (ꢀ)-sparteine (260 μL, 1.2

mmol, 1.0 equiv) in TBME (3 mL), ZnCl₂(710 μL of a 1.0 M solution in

Et₂O, 0.7 mmol, 0.6 equiv), Pd(OAc)₂(8 mg, 0.05 mmol, 0.04 equiv), t-

Bu₃PHBF₄(12 mg, 0.06 mmol, 0.05 equiv) and the appropriate aryl

bromide (80 μL, 1.0 mmol, 0.83 equiv) gave the crude product.

Purification by flash column chromatography on silica with 40:60

hexaneꢀEtOAc as eluent gave aryl pyrrolidine (R)-33 (37 mg, 15%,

96:4 er by CSP-HPLC) as a colorless oil, HPLC chiralpak AD-H

(isocratic 80:20 heptaneꢀi-PrOH, 0.7 mL min^ꢀ1) (R)-33 3.77 min,

(S)-33 3.45 min. Carrying out the Negishi coupling at 60 °C gave a 60%

yield of (R)-33, as previously reported.¹²

2-((R)-1-tert-Butoxycarbonylpyrrolidin-2-yl)-4-methylthia-

zole-5-carboxylic Acid Ethyl Ester (R)-31 (Scheme 6). Using

general procedure A, s-BuLi (1.0 mL of a 1.2 M solution in cyclohexane,

1.2 mmol, 1.0 equiv), N-Boc pyrrolidine 15 (250 μL, 1.2 mmol) and

(ꢀ)-sparteine (260 μL, 1.2 mmol, 1.0 equiv) in TBME (3 mL), ZnCl₂

(710 μL of a 1.0 M solution in Et₂O, 0.7 mmol, 0.6 equiv), Pd(OAc)₂

(8 mg, 0.05 mmol, 0.04 equiv), t-Bu₃PHBF₄(12 mg, 0.06 mmol, 0.05

equiv) and the appropriate aryl bromide (208 mg, 1.0 mmol, 0.83 equiv)

gave the crude product. Purification by flash column chromatography on

silica with 70:30 hexaneꢀEtOAc as eluent gave aryl pyrrolidine (R)-31

(150 mg, 67%, 94:6 er by CSP-HPLC) as a colorless oil, R_f0.3 in (6:4

petrolꢀEtOAc); [R]_D+8.9 (c 1.0 in CHCl₃); IR (film) 2977, 2933,

1703 (CdO, CO₂Et + Boc), 1385, 1320, 1261, 1167, 1092 cm^ꢀ1; ¹H

NMR (400 MHz, CDCl₃) (60:40 mixture of rotamers) δ 5.14 (d, J = 7.5

Hz, 0.4H), 5.03 (d, J = 7.0 Hz, 0.6H), 4.29 (q, J = 7.0 Hz, 2H), 3.69ꢀ

3.33 (m, 2H), 2.67 (s, 3H), 2.43ꢀ2.21 (m, 1H), 2.21ꢀ2.06 (m, 1H),

2.00ꢀ1.82 (m, 2H), 1.46 (s, 3.6H), 1.32 (br s, 8.4H); ¹³C NMR (100.6

MHz, CDCl₃) (rotamers) δ 179.2 (C), 178.4 (C), 162.7 (C), 160.8 (C),

160.6 (C), 155.0 (C), 154.5 (C), 121.7 (C), 121.5 (C), 80.4 (CMe₃),

80.2 (C), 61.0 (CH₂), 59.5 (CH), 59.2 (CH), 46.8 (CH₂), 46.3 (CH₂),

33.7 (CH₂), 32.6 (CH₂), 28.1 (CH₃), 27.9 (CH₃), 23.6 (CH₂), 22.7

(CH₂), 17.1 (CH₃), 13.9 (CH₃); MS (ESI) m/z 363 [(M + Na)⁺, 19],

341 [(M + H)⁺, 100], 285 (59); HRMS (ESI) m/z calcd for

C₁₆H₂₄N₂O₄S (M + H)⁺341.1530, found 341.1529 (+0.1 ppm error);

HPLC chiralpak AD-H (95:5 hexaneꢀi-PrOH, 1.0 mL min^ꢀ1) (R)-31

6.7 min, (S)-31 6.3 min.

(R)-2-Pyridin-2-ylpyrrolidine-1-carboxylic Acid tert-Butyl

Ester (R)-34 (Scheme 6). Using general procedure A, s-BuLi (1.0 mL

of a 1.2 M solution in cyclohexane, 1.2 mmol, 1.0 equiv), N-Boc

pyrrolidine 15 (250 μL, 1.2 mmol) and (ꢀ)-sparteine (260 μL, 1.2

mmol, 1.0 equiv) in TBME (3 mL), ZnCl₂(710 μL of a 1.0 M solution in

Et₂O, 0.7 mmol, 0.6 equiv), Pd(OAc)₂(8 mg, 0.05 mmol, 0.04 equiv),

t-Bu₃PHBF₄(12 mg, 0.06 mmol, 0.05 equiv) and the appropriate aryl

bromide (80 μL, 1.0 mmol, 0.83 equiv) gave the crude product.

Purification by flash column chromatography on silica with 30:70

hexaneꢀEtOAc as eluent gave aryl pyrrolidine (R)-34 (165 mg, 71%,

94:6 er by CSP-HPLC) as a colorless oil, R_f0.2 (6:4 petrolꢀEtOAc);

[R]_D+67.6 (c 1.0 in CHCl₃); IR (CHCl₃) 2978, 1686 (CdO), 1456,

1399 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃) (65:35 mixture of rotamers)

δ 8.49 (d, J = 4.0 Hz, 1H), 7.64ꢀ7.53 (m, 1H), 7.23ꢀ6.98 (m, 2H), 4.95

(br d, J = 5.0 Hz, 0.35H), 4.82 (dd, J = 8.0, 4.5 Hz, 0.65H), 3.69ꢀ3.37

(m, 2H), 2.48ꢀ2.16 (m, 1H), 2.10ꢀ1.72 (m, 3H), 1.40 (s, 3.15H), 1.13

(s, 5.85H); ¹³C NMR (100.6 MHz, CDCl₃) (rotamers) δ 164.1 (C),

162.9 (C), 154.9 (C), 154.8 (C), 149.5 (CH), 149.1 (CH), 136.6 (CH),

136.5 (CH), 121.9 (CH), 121.7 (CH), 120.2 (CH), 119.7 (CH), 79.2

(C), 62.6 (CH), 61.9 (CH), 47.1 (CH₂), 46.8 (CH₂), 33.9 (CH₂), 33.6

(CH₂), 28.1 (CH₃), 27.7 (CH₃), 23.6 (CH₂), 22.8 (CH₂); MS (ESI) m/

z 271 [(M + Na)⁺, 13], 249 [(M + H)⁺, 100], 193 (56), 149 (37); HRMS

(ESI) m/z calcd for C₁₄H₂₀N₂O₂(M + H)⁺249.1598, found 249.1597

(+0.4 ppm error); HPLC chiralpak AD-H (90:10 hexaneꢀi-PrOH, 1.0 mL

min^ꢀ1) (R)-34 3.5 min, (S)-34 5.3 min.

(R)-2-(4-Methyl-2-Phenylthiazol-5-yl)pyrrolidine-1-carboxylic

Acid tert-Butyl Ester (R)-32 (Scheme 6). Using general procedure

A, s-BuLi (1.0 mL of a 1.2 M solution in cyclohexane, 1.2 mmol, 1.0

equiv), N-Boc pyrrolidine 15 (250 μL, 1.2 mmol) and (ꢀ)-sparteine

(260 μL, 1.2 mmol, 1.0 equiv) in TBME (3 mL), ZnCl₂(710 μL of a 1.0

M solution in Et₂O, 0.7 mmol, 0.6 equiv), Pd(OAc)₂(8 mg, 0.05 mmol,

0.04 equiv), t-Bu₃PHBF₄(12 mg, 0.06 mmol, 0.05 equiv) and the

appropriate aryl bromide (254 mg, 1.0 mmol, 0.83 equiv) gave the crude

product. Purification by flash column chromatography on silica with

70:30 hexaneꢀEtOAc as eluent gave aryl pyrrolidine (R)-32 (127 mg,

75%, 96:4 er by CSP-HPLC) as a colorless oil, R_f0.3 (6:4 pet-

rolꢀEtOAc); [R]_D+ 34.2 (c 1.0 in CHCl₃); IR (film) 2974, 1692

(CdO), 1458, 1398, 1249, 1165, 1115, 763, 733, 691 cm^ꢀ1; ¹H NMR

(400 MHz, CDCl₃) (70:30 mixture of rotamers) δ 7.87 (d, J = 6.5 Hz,

2H), 7.45ꢀ7.33 (m, 3H), 5.17 (br s, 0.3H), 5.02 (br s, 0.7H), 3.69ꢀ3.32

(m, 2H), 2.43 (s, 3H), 2.32 (br s, 1H), 2.16ꢀ2.01 (m, 1H), 2.00ꢀ1.80

(m, 2H), 1.42 (s, 2.7H), 1.28 (s, 6.3H); ¹³C NMR (100.6 MHz, CDCl₃)

(rotamers) δ 164.3 (C), 154.6 (C), 147.83 (C), 147.82 (C), 134.1 (C),

129.8 (C), 129.3 (C), 129.0 (CH), 127.1 (CH), 126.3 (CH), 79.7 (C),

54.3 (CH), 46.2 (CH₂), 34.8 (CH₂), 34.7 (CH₂), 28.1 (CH₃), 23.6

(CH₂), 23.0 (CH₂), 15.0 (CH₃); MS (ESI) m/z 345 [(M + H)⁺, 100];

HRMS (ESI) m/z calcd for C₁₉H₂₄N₂O₂S (M + H)⁺345.1631, found

345.1631 (+0.2 ppm error); HPLC chiralpak AD-H (95:5 hexaneꢀ

i-PrOH, 1.0 mL min^ꢀ1) (R)-32 3.9 min, (S)-32 3.5 min.

(R)-2-(2-Cyanopyridin-3-yl)pyrrolidine-1-carboxylic Acid tert-

Butyl Ester (R)-35 (Scheme 6). Using general procedure A, s-BuLi

(1.0 mL of a 1.2 M solution in cyclohexane, 1.2 mmol, 1.0 equiv), N-Boc

pyrrolidine 15 (250 μL, 1.2 mmol) and (ꢀ)-sparteine (260 μL, 1.2

mmol, 1.0 equiv) in TBME (3 mL), ZnCl₂(710 μL of a 1.0 M solution in

Et₂O, 0.7 mmol, 0.6 equiv), Pd(OAc)₂(8 mg, 0.05 mmol, 0.04 equiv),

t-Bu₃PHBF₄(12 mg, 0.06 mmol, 0.05 equiv) and the appropriate aryl

bromide (184 mg, 1.0 mmol, 0.83 equiv) gave the crude product.

Purification by flash column chromatography on silica with 30:70

hexaneꢀEtOAc and then EtOAc as eluent gave aryl pyrrolidine

(R)-35 (202 mg, 76%, 94:6 er by CSP-HPLC) as a white solid, mp

118ꢀ119 °C; [R]_D+35.8 (c 0.9 in CHCl₃); IR (CHCl₃) 3018, 1980

1

(CꢂN), 1691 (CdO), 1386, 1368, 1217, 1158, 1124, 748 cm^ꢀ1; H

NMR (400 MHz, CDCl₃) (70:30 mixture of rotamers) δ 8.60 (br d, J =

4.0 Hz, 0.7H), 8.57 (br s, 0.3H), 7.69 (br d, J = 7.5 Hz, 0.7H), 7.62 (br d,

J = 7.5 Hz, 0.3H), 7.57ꢀ7.30 (m, 1H), 5.17 (br s, 0.3H), 5.12 (t, J = 7.0

Hz, 0.7H), 3.79ꢀ3.68 (m, 0.6H), 3.68ꢀ3.55 (m, 1.4H), 2.65ꢀ2.43 (m,

1H), 2.05ꢀ1.75 (m, 3H), 1.43 (s, 2.7H), 1.17 (s, 6.3H); ¹³C NMR

(100.6 MHz, CDCl₃) (rotamers) δ 154.4 (C), 154.2 (C), 149.6 (CH),

149.4 (C), 146.4 (C), 134.1 (CH), 132.0 (C), 127.0 (CH), 116.0 (C),

80.2 (C), 58.4 (CH), 58.1 (CH), 47.5 (CH₂), 47.2 (CH₂), 35.2 (CH₂),

34.1 (CH₂), 28.1 (CH₃), 27.7 (CH₃), 23.7 (CH₂), 23.4 (CH₂); MS

(ESI) m/z 296 [(M + Na)⁺, 100], 274 [(M + H)⁺, 96], 218 (24), 174

(20); HRMS (ESI) m/z calcd for C₁₅H₁₉N₃O₂(M + H)⁺274.1550,

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found 274.1551 (ꢀ0.2 ppm error); HPLC chiralpak AD-H (90:10

hexaneꢀi-PrOH, 1.0 mL min^ꢀ1) (R)-35 4.4 min, (S)-35 5.1 min.

(R)-2-(2-Fluoro-5-methylpyridin-3-yl)pyrrolidine-1-carboxylic

Acid tert-Butyl Ester (R)-36 (Scheme 6). Using general procedure

A, s-BuLi (1.0 mL of a 1.2 M solution in cyclohexane, 1.2 mmol, 1.0

equiv), N-Boc pyrrolidine 15 (250 μL, 1.2 mmol) and (ꢀ)-sparteine

(260 μL, 1.2 mmol, 1.0 equiv) in TBME (3 mL), ZnCl₂(710 μL of a 1.0

M solution in Et₂O, 0.7 mmol, 0.6 equiv), Pd(OAc)₂(8 mg, 0.05 mmol,

0.04 equiv), t-Bu₃PHBF₄(12 mg, 0.06 mmol, 0.05 equiv) and the

appropriate aryl bromide (190 mg, 1.0 mmol, 0.83 equiv) gave the crude

product. Purification by flash column chromatography on silica with

70:30 hexaneꢀEtOAc as eluent gave aryl pyrrolidine (R)-36 (190 mg,

70%, 97:3 er by CSP-HPLC) as a white solid, mp 63ꢀ64 °C; [R]_D

+101.4 (c = 1.1 in CHCl₃); IR (CHCl₃) 2981, 1688 (CdO), 1455, 1400,

1367, 1163, 756 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃) (70:30 mixture of

rotamers) δ 7.87 (s, 0.7H), 7.84 (s, 0.3H), 7.35 (d, J = 9.0 Hz, 0.7H),

7.28 (d, J = 9.0 Hz, 0.3H), 5.04 (d, J = 7.0 Hz, 0.3H), 4.99ꢀ4.86

(m, 0.7H), 3.71ꢀ3.39 (m, 2H), 2.43ꢀ2.20 (m, 1H), 2.28 (s, 3H),

1.98ꢀ1.72 (m, 3H), 1.45 (s, 2.7H), 1.21 (s, 6.3H); ¹³C NMR (100.6

MHz, CDCl₃) (rotamers) δ159.4 (d, J= 238.0 Hz, C), 154.6 (C), 145.3 (d,

J = 14.5 Hz, CH), 138.3 (d, J = 5.0 Hz, CH), 130.9 (d, J = 4.5 Hz, C), 125.7

(C), 79.7 (C), 55.4 (CH), 54.9 (CH), 47.0 (CH₂), 46.7 (CH₂), 33.7

(CH₂), 32.4 (CH₂), 28.1 (CH₃), 27.8 (CH₃), 23.3 (CH₂), 22.9 (CH₂),

17.2 (CH₃), 17.1 (CH₃); MS (ESI) m/z 303 [(M + Na)⁺, 61], 281 [(M +

H)⁺, 100], 225 (11); HRMS (ESI) m/z calcd for C₁₅H₂₁N₂O₂F (M +

Na)⁺303.1479, found 303.1481 (ꢀ0.5 ppm error); HPLC chiralpak AD-H

(98:2 heptaneꢀi-PrOH, 1.0 mL min^ꢀ1) (R)-36 7.2 min, (S)-36 8.0 min.

3-Bromo-5-trimethylsilylethynylpyridine 38 (Scheme 7).

Trimethylsilylacetylene (622 μL, 4.40 mmol) was added dropwise

to a stirred solution of 3,5-dibromopyridine (947 mg, 4.00 mmol), CuI

(76 mg, 0.40 mmol) and Pd(PPh₃)₂Cl₂(281 mg, 0.40 mmol) in Et₃N

(1.4 mL) at rt under Ar. The resulting solution was stirred at rt for 16 h.

Then, water (6 mL) was added, and the resulting solution was extacted

with Et₂O (3 ꢁ 6 mL). The combined organic extracts were dried

(Na₂SO₄) and evaporated under reduced pressure to give the crude

product. Purification by flash column chromatography on silica with 4:1

petrolꢀCH₂Cl₂as eluent gave bromopyridine 38 (666 mg, 72%) as a

brown oil, ¹H NMR (400 MHz, CDCl₃) δ 8.62 (br s, 2H), 7.90 (s, 1H),

0.27 (s, 9H); ¹³C NMR (100.6 MHz, CDCl₃) δ 151.0 (CH), 150.3

(CH), 141.5 (CH), 122.0 (C), 120.2 (C), 100.3 (C), 99.7 (C), ꢀ0.7

(CH₃). Spectroscopic data consistent with those reported in the

literature.⁵⁶

(S)-2-(5-Trimethylsilylethynylpyridin-3-yl)pyrrolidine-1-

carboxylic Acid tert-Butyl Ester (S)-37 (Scheme 7). s-BuLi

(1.0 mL of a 1.3 M solution in hexanes, 1.3 mmol, 1.3 equiv) was added

dropwise to a stirred solution of N-Boc pyrrolidine 15 (171 mg, 175 μL,

1.0 mmol) and (+)-sparteine surrogate (213 mg, 1.3 mmol, 1.3 equiv)

in Et₂O (7 mL) at ꢀ78 °C under Ar. The resulting solution was

stirred at ꢀ78 °C for 1 h. Then, ZnCl₂(0.6 mL of a 1.0 M solution in

Et₂O, 0.6 mmol, 0.6 equiv) was added dropwise, and the resulting

solution was stirred at ꢀ78 °C for 30 min. Then, the solution was

allowed to warm to rt and stirred for 30 min. A solution of

bromopyridine 38 (178 mg, 0.7 mmol, 0.7 equiv) in TBME (5 mL)

was added. A mixture of Pd(OAc)₂(11 mg, 0.05 mmol, 0.05 equiv)

and t-Bu₃PBHF₄(11 mg, 0.06 mmol, 0.06 equiv) was added in one

portion. The reaction flask was transferred to a preheated oil bath and

the solution was stirred and heated at reflux for 16 h. After cooling to

rt, 35% NH₄OH_(aq)(0.3 mL) was added, and the resulting mixture was

stirred at rt for 1 h. The solids were removed by filtration through a

pad of Celite and washed with Et₂O (20 mL). The filtrate was washed

with water (10 mL) and saturated brine (10 mL), dried (Na₂SO₄) and

evaporated under reduced pressure to give the crude product.

Purification by flash column chromatography on silica with 93:7

CH₂Cl₂ꢀMeOH as eluent gave pyridylpyrrolidine (S)-37 (75 mg,

44%, 92:8 er by NMR spectroscopy of a derivative in the presence of

(S)-2,2,2-trifluoro-1-(9-anthryl)-ethanol) as a yellow oil, R_f(93:7

CH₂Cl₂ꢀMeOH) 0.4; [R]_Dꢀ57.3 (c 1.0 in CHCl₃); IR (film)

2973, 2880, 2159, 1697 (CdO), 1448, 1392, 1366, 1250, 1164,

1

1115, 846, 757 cm^ꢀ1; H NMR (400 MHz, CDCl₃) (70:30 mixture

of rotamers) δ 8.56 (br s, 1H), 8.40 (br s, 1H), 7.54 (s, 1H), 4.91 (br s,

0.3H), 4.75 (br s, 0.7H), 3.62 (br s, 2H), 2.34 (br s, 1H), 1.98ꢀ1.69

(m, 3H), 1.45 (br s, 2.7H), 1.21 (br s, 6.3H), 0.25 (s, 9H); ¹³C NMR

(100.6 MHz, CDCl₃) (rotamers) δ 154.1 (C), 150.1 (CH), 146.6

(CH), 139.4 (C) 137.0 (C), 135.7 (CH), 101.3 (C), 98.1 (C), 79.7

(C), 58.7 (CH), 58.5 (CH), 47.0 (CH₂), 35.6 (CH₂), 34.3 (CH₂),

28.3 (CH₃), 28.0 (CH₃), 23.2 (CH₂), ꢀ0.3 (CH₃); MS (ESI) m/z 345

[(M + H)⁺, 100]; HRMS (ESI) m/z calcd for C₁₉H₂₈N₂O₂Si

(M + H)⁺345.1993, found 345.1995 (ꢀ0.7 ppm error).

(S)-3-Ethynyl-5-pyrrolidin-2-ylpyridine (Scheme 7). TFA

(466 mg, 304 μL, 4.09 mmol) was added dropwise to a stirred solution

of pyridylpyrrolidine (50 mg, 0.2 mmol) in CH₂Cl₂(4 mL) at rt under

Ar. The resulting solution was stirred at rt for 2 h. Then, the solvent and

excess TFA were evaporated under reduced pressure. Water (5 mL)

was added to the residue and 5 M NaOH_(aq)was added dropwise until

pH 14. CsF (310 mg, 2.04 mmol) was added, and the resulting solution

was stirred at rt under air for 1 h. The solution was adjusted to pH 1 by

addition of 5 M HCl_(aq), and the resulting solution was extracted

with CH₂Cl₂(3 ꢁ 6 mL). The aqueous layer was adjusted to pH 14

by addition of 5 M NaOH_(aq)and extracted with Et₂O (8 ꢁ 15 mL).

The combined organic extracts were dried (Na₂SO₄) and evaporated

under reduced pressure to give (S)-3-ethynyl-5-pyrrolidin-2-ylpyridine

(26 mg, 76%) as a yellow oil, [R]_Dꢀ100.8 (c 0.5 in CHCl₃); IR (CHCl₃)

1

3292 (NH), 2964, 2871, 1444, 1416, 892, 711 cm^ꢀ1; H NMR (400

MHz, CDCl₃) δ 8.67 (d, J = 2.0 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 7.82

(t, J = 2.0 Hz), 4.16 (t, J = 7.5 Hz, 1H), 3.19 (s, 1H), 3.22ꢀ3.14

(m, 1H), 3.09ꢀ3.02 (m, 1H), 2.27ꢀ2.17 (m, 1H), 2.12 (br s, 1H),

2.00ꢀ1.80 (m, 2H), 1.70ꢀ1.60 (m, 1H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 151.0 (CH), 148.1 (CH), 140.1 (C), 137.2 (CH), 118.8 (C),

80.6 (CH), 80.2 (C), 59.4 (CH), 46.9 (CH₂), 34.4 (CH₂), 25.5 (CH₂);

MS (ESI) m/z 173 [(M + H)⁺, 100], 156 (13); HRMS (ESI) m/z calcd

for C₁₁H₁₂N₂(M + H)⁺173.1073, found 173.1077 (ꢀ1.9 ppm error).

(S)-(+)-5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine (S)-

SIB1508Y (Scheme 7). Formic acid (34 mg, 22 μL, 0.75 mmol) was

added to a stirred solution of (S)-3-ethynyl-5-pyrrolidin-2-ylpyridine

(26 mg, 0.15 mmol) and parafomaldehyde (22 mg, 0.75 mmol) in

water (3 mL) at rt. The resulting solution was stirred and heated at

reflux for 16 h. Then, 5 M NaOH_(aq)(2 mL) was added and the

aqueous solution was extracted with Et₂O (8 ꢁ 8 mL). The combined

organic layers were dried (Na₂SO₄) and evaporated under reduced

pressure to give (S)-SIB1508Y (19 mg, 68%, 92:8 er by NMR spectro-

scopy in the presence of (S)-2,2,2-trifluoro-1-(9-anthryl)-ethanol) as

a colorless oil, [R]_Dꢀ78.7 (c 0.7 in EtOH) (lit.,⁵⁷[R]_Dꢀ162.0 (c 0.8

in EtOH)); ¹H NMR (400 MHz, CDCl₃) δ 8.69 (d, J = 2.0 Hz, 1H),

8.49 (d, J = 2.0 Hz, 1H), 7.81 (t, J = 2.0 Hz, 1H), 3.24 (ddd, J = 9.5,

7.5, 2.0 Hz, 1H), 3.20 (s, 1H), 3.10 (t, J = 8.0 Hz, 1H), 2.32 (q, J = 9.5

Hz, 1H), 2.27ꢀ2.18 (m, 1H), 2.17 (s, 3H), 2.04ꢀ1.90 (m, 1H),

1.89ꢀ1.76 (m, 1H), 1.75ꢀ1.63 (m, 1H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 151.5 (CH), 149.0 (CH), 138.5 (C), 138.0 (CH), 119.1 (C),

80.5 (C), 80.3 (CH), 68.4 (CH), 56.9 (CH₂), 40.4 (CH₃), 35.2 (CH₂),

22.7 (CH₂). Spectroscopic data consistent with those reported in the

literature.⁵⁷

Determination of the Enantiomeric Ratio of (S)-(+)-

5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine (S)-SIB1508Y

(Scheme 7). Enantiomeric ratio was determined by high resolution ¹H

NMR spectroscopy (400 MHz, CDCl₃) in the presence of 4.0 equiv of

(S)-2,2,2-trifluoro-1-(9-anthryl)-ethanol. A 0.036 M solution of

SIB1508Y was prepared by dissolving SIB1508Y (4 mg, 0.021 mmol)

in CDCl₃(0.6 mL). Then, (S)-2,2,2-trifluoro-1-(9-anthryl)-ethanol

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(24 mg, 0.087 mmol) was added. Diagnostic signals: ¹H NMR (400 MHz,

4H), 2.01ꢀ1.88 (m, 1H), 1.86ꢀ1.65 (m, 2H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 149.4 (CH), 148.5 (CH), 138.6 (C), 134.7 (CH), 123.4

(CH), 68.7 (CH), 56.9 (CH₂), 40.2 (CH₃), 35.1 (CH₂), 22.5 (CH₂).

Spectroscopic data consistent with those reported in the literature.^51a

Determination of the Enantiomeric Ratio of (S)-Nicotine

(Scheme 8). Enantiomeric ratio was determined by high resolution ¹H

NMR spectroscopy (400 MHz, CDCl₃) in the presence of 4.0 equiv of

(S)-2,2,2-trifluoro-1-(9-anthryl)-ethanol. A 0.052 M solution of nicotine

was prepared by dissolving nicotine (5 mg, 0.031 mmol) in CDCl₃

(0.6 mL). Then, (S)-2,2,2-trifluoro-1-(9-anthryl)-ethanol (34 mg, 0.12

mmol) was added. Diagnostic signals: ¹H NMR (400 MHz, CDCl₃) δ

1.92 (NMe, major), 1.89 (NMe, minor). Integration of the major and

minor NMe signals in the ¹H NMR spectra indicated that (S)-nicotine

was present in 92:8 er. Enantiomeric ratio was determined by high

resolution ¹H NMR spectroscopy (400 MHz, CDCl₃) in the presence of

4.0 equiv of (R)-2,2,2-trifluoro-1-(9-anthryl)-ethanol. A 0.026 M solu-

tion of nicotine was prepared by dissolving nicotine (3 mg, 0.018 mmol)

in CDCl₃(0.7 mL). Then, (R)-2,2,2-trifluoro-1-(9-anthryl)-ethanol (20

mg, 0.072 mmol) was added. Diagnostic signals: ¹H NMR (400 MHz,

CDCl₃) δ 1.98 (NMe, minor), 1.95 (NMe, major). Integration of the

CDCl₃) δ 2.03 (NMe, major), 1.98 (NMe, minor). Integration of the

1

major and minor NMe signals in the H NMR spectra indicated that

(S)-SIB1508Y was present in 92:8 er. Enantiomeric ratio was deter-

mined by high resolution ¹H NMR spectroscopy (400 MHz, CDCl₃) in

the presence of 4.0 equiv of (R)-2,2,2-trifluoro-1-(9-anthryl)-ethanol.

A 0.031 M solution of SIB1508Y was prepared by dissolving SIB1508Y

(4 mg, 0.021 mmol) in CDCl₃(0.7 mL). Then, (R)-2,2,2-trifluoro-1-

(9-anthryl)-ehtanol (24 mg, 0.087 mmol) was added. Diagnostic

signals: ¹H NMR (400 MHz, CDCl₃) δ 2.04 (NMe, minor), 1.99

(NMe, major). Integration of the major and minor NMR signals in the

¹H NMR spectra indicated that (S)-SIB1508Y was present in 92:8 er.

(S)-2-Pyridin-3-ylpyrrolidine-1-carboxylic Acid tert-Butyl

Ester (S)-33 (Scheme 8). s-BuLi (1.7 mL of a 1.3 M solution in

hexanes, 2.2 mmol, 1.0 equiv) was added dropwise to a stirred solution of

(+)-sparteine surrogate (97 mg, 0.5 mmol, 0.25 equiv) and di-i-Pr-

bispidine 25 (467 mg, 2.2 mmol, 1.0 equiv) in Et₂O (6 mL) at ꢀ78 °C

under Ar. After stirring at ꢀ78 °C for 15 min, a solution of N-Boc

pyrrolidine 15 (380 mg, 390 μL, 2.2 mmol) in Et₂O (1 mL) was added

dropwise. The resulting solution was stirred at ꢀ78 °C for 5 h. Then,

ZnCl₂(1.3 mL of a 1.0 M solution in Et₂O, 1.3 mmol, 0.6 equiv) was

added dropwise, and the resulting solution was stirred at ꢀ78 °C for

30 min. Then, the solution was allowed to warm to rt and stirred for

30 min. A solution of 3-bromopyridine (246 mg, 153 μL, 1.6 mmol, 0.7

equiv) in TBME (5 mL) was added. A mixture of Pd(OAc)₂(25 mg, 0.11

mmol, 0.05 equiv) and t-Bu₃PBHF₄(25 mg, 0.11 mmol, 0.06 equiv) was

added in one portion. The reaction flask was transferred to a preheated oil

bath and the solution was stirred and heated at reflux for 16 h. After cooling

to rt, 35% NH₄OH_(aq)(0.3 mL) was added, and the resulting mixture was

stirred at rt for 1 h. The solids were removed by filtration through a pad

of Celite and washed with Et₂O (20 mL). The filtrate was washed with

water (10 mL) and saturated brine (10 mL), dried (Na₂SO₄) and

evaporated under reduced pressure to give the crude product. Purifica-

tion by flash column chromatography on silica with 6:4 petrolꢀEtOAc

as eluent gave pyridylpyrrolidine (S)-33 (179 mg, 46%, 92:8 er by NMR

spectroscopy of a derivative in the presence of (S)-2,2,2-trifluoro-1-(9-

anthryl)-ethanol) as a colorless oil, [R]_D+80.0 (c 1.0 in CH₂Cl₂) (lit.,¹²

[R]_Dꢀ83.6 (c 1.55 in CH₂Cl₂) for (R)-33 of 94:6 er); ¹H NMR (400

MHz, CDCl₃) (60:40 mixture of rotamers) δ 8.45ꢀ8.43 (m, 2H),

7.50ꢀ7.43 (m, 1H), 7.25ꢀ7.16 (m, 1H), 4.93 (br s, 0.4H), 4.75 (br s,

0.6H), 3.64ꢀ3.46 (m, 2H), 2.40ꢀ2.25 (m, 1H), 1.95ꢀ1.77 (m, 3H),

1.42 (s, 3.6H), 1.17 (s, 5.4H). Spectroscopic data consistent with those

reported in the literature.¹²

1

major and minor NMe signals in the H NMR spectra indicated that

(S)-nicotine was present in 92:8 er.

(R)-2-(2-Methylpropenyl)pyrrolidine-1-carboxylic Acid tert-

Butyl Ester (R)-39 (Scheme 9). Using general procedure A, s-BuLi

(3.7 mL of a 1.3 M solution in cyclohexane, 4.8 mmol, 1.0 equiv), N-Boc

pyrrolidine 15 (0.84 mL, 4.8 mmol) and (ꢀ)-sparteine (1.1 mL, 4.8

mmol, 1.0 equiv) in TBME (10 mL), ZnCl₂(2.4 mL of a 1.0 M solution

in Et₂O, 2.4 mmol, 0.5 equiv), Pd(OAc)₂(36 mg, 0.16 mmol, 0.03

equiv), t-Bu₃PHBF₄(58 mg, 0.20 mmol, 0.04 equiv) and the appropriate

vinyl bromide (410 μL, 4.0 mmol, 0.83 equiv) gave the crude product.

Purification by flash column chromatography on silica with 15:1

hexaneꢀEtOAc as eluent gave vinyl pyrrolidine (R)-39 (659 mg, 73%,

95:5 er by CSP-HPLC) as a colorless oil, R_f0.3 (5:1 petrolꢀEt₂O);

[R]_Dꢀ28.0 (c 1.0 in CHCl₃); IR (CHCl₃) 2974, 2930, 2875, 1693

1

(CdO), 1453, 1394, 1366, 1169, 1107 cm^ꢀ1; H NMR (400 MHz,

CDCl₃) δ 5.05 (br d, J = 7.0 Hz, 1H), 4.39 (br s, 1H), 3.53ꢀ3.22 (m,

2H), 2.07ꢀ1.95 (m, 1H), 1.92ꢀ1.74 (m, 2H), 1.673 (s, 3H), 1.670

(s, 3H), 1.61ꢀ1.48 (m, 1H), 1.41 (s, 9H); ¹³C NMR (100.6 MHz,

CDCl₃) δ 155.2 (C), 131.2 (C), 127.2 (CH), 78.7 (C), 55.1 (CH), 46.1

(CH₂), 33.0 (CH₂), 28.3 (CH₃), 25.4 (CH₃), 23.5 (CH₃), 23.4 (CH₂);

MS (ESI) m/z 248 [(M + Na)⁺, 100], 170 (58), 114 (54); HRMS (ESI)

m/z calcd for C₁₃H₂₃NO₂(M + Na)⁺248.1621, found 248.1619 (+0.9

ppm error); chiralcel OD-H (97:3 heptaneꢀi-PrOH, 0.5 mL min^ꢀ1

(R)-39 7.0 min, (S)-39 7.6 min.

)

(S)-Nicotine (Scheme 8). TFA (1.01 g, 658 μL, 8.86 mmol) was

added dropwise to a stirred solution of aryl pyrrolidine (S)-33 (110 mg,

0.44 mmol, 92:8 er) in CH₂Cl₂(6 mL) at rt under Ar. The resulting

solution was stirred at rt for 2 h. Then, the solvent was evaporated under

reduced pressure. Et₂O and 5 M NaOH_(aq)(6 mL) were added to the

residue. The two layers were separated, and the aqueous layer was

extracted with Et₂O (7 ꢁ 5 mL). The combined organic layers were

dried (Na₂SO₄) and evaporated under reduced pressure. Then, water

(7 mL), paraformaldehyde (80 mg, 2.66 mmol) and formic acid (123

mg, 80 μL, 2.66 mmol) were added. The resulting solution was stirred

and heated at reflux for 16 h. The solvent was evaporated under reduced

pressure, and 5 M NaOH_(aq)(5 mL) and Et₂O (25 mL) were added

to the residue. The two layers were separated, and the aqueous layer

was extracted with Et₂O (7 ꢁ 25 mL). The combined organic layers

were dried (Na₂SO₄) and evaporated under reduced pressure to give

(S)-nicotine (68 mg, 96%, 92:8 er by NMR spectroscopy in the presence

of 1-(9-anthryl)-2,2,2-trifluoroethanol) as a colorless oil, [R]_Dꢀ81.0

(c 1.0 in EtOH) (lit.,^51a[R]_Dꢀ145.0 (c 1.0 in EtOH) for (S)-nicotine of

99% ee); ¹H NMR (400 Hz, CDCl₃) δ 8.52 (s, 1H), 8.47 (dd, J = 5.0, 1.5

Hz, 1H), 7.70ꢀ7.65 (m, 1H), 7.24 (dd, J = 8.0, 5.0 Hz), 3.22 (t, J = 7.5

Hz, 1H), 3.06 (t, J = 8.5 Hz, 1H), 2.34ꢀ2.25 (m, 1H), 2.24ꢀ2.07 (m,

(R)-2-(1-Trimethylsilylvinyl)pyrrolidine-1-carboxylic Acid

tert-Butyl Ester (R)-40 (Scheme 9). Using general procedure A,

s-BuLi (4.8 mL of a 1.2 M solution in cyclohexane, 5.7 mmol, 1.0 equiv),

N-Boc pyrrolidine 15 (1.2 mL, 5.7 mmol) and (ꢀ)-sparteine (1.3 mL,

5.7 mmol, 1.0 equiv) in TBME (12 mL), ZnCl₂(3.4 mL of a 1.0 M

solution in Et₂O, 3.4 mmol, 0.6 equiv), Pd₂(dba)₃(105 mg, 0.23 mmol,

0.04 equiv), t-Bu₃PHBF₄(83 mg, 0.285 mmol, 0.05 equiv) and the

appropriate vinyl bromide (740 μL, 4.75 mmol, 0.83 equiv) gave the

crude product. Purification by flash column chromatography on silica

with 95:5 hexaneꢀEtOAc as eluent gave vinyl pyrrolidine (R)-40 (870

mg, 68%, 97:3 er by CSP-HPLC) as a colorless oil, R_f0.2 (9:1

petrolꢀEt₂O); [R]_D+111.6 (c 0.7 in CHCl₃); IR (CHCl₃) 2957,

1694 (CdO), 1400, 1365, 1248, 1170, 1122, 863, 839 cm^ꢀ^{1 1}H

;

NMR (400 MHz, CDCl₃) (50:50 mixture of rotamers) δ 5.89 (br s,

0.5H), 5.85 (br s, 0.5H), 5.64 (d, J = 1.0 Hz, 0.5H), 5.60 (d, J = 1.0 Hz,

0.5H), 4.20 (br s, 1H), 3.40 (br s, 2H), 2.12ꢀ1.90 (m, 1H), 1.84ꢀ1.66

(m, 3H), 1.40 (br s, 9H), 0.04 (s, 9H); ¹³C NMR (100.6 MHz, CDCl₃)

δ 155.1 (C), 146.6 (CH₂), 128.3 (C), 79.0 (C), 61.0 (CH), 46.1 (CH₂),

31.8 (CH₂), 28.2 (CH₃), 22.5 (CH₂), ꢀ1.6 (CH₃); MS (ESI) m/z 292

[M + Na)⁺, 78], 214 (100), 198 (11), HRMS (ESI) m/z calcd for

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C₁₄H₂₇NO₂Si (M + Na)⁺292.1703, found 292.1703 (+0.2 ppm error);

chiralpak AD-H (99:1 heptaneꢀi-PrOH, 0.5 mL min^ꢀ1) (R)-40 8.2

min, (S)-40 10.2 min.

layers were evaporated under reduced pressure until a sticky residue

remained. Et₂O (100 mL) was added to the residue, and the solution was

dried (MgSO₄) and evaporated under reduced pressure to give dode-

cahydro-4a,8a,12a-triazatriphenylene (2.72 g, 56%) as a colorless oil, ¹H

NMR (400 MHz, CDCl₃) δ 3.08 (dt, J = 11.0, 5.0 Hz, 3H, NCH), 2.76

(br d, J = 5.5 Hz, 3H, NCH), 2.04ꢀ1.91 (m, 3H, NCH), 1.76ꢀ1.58

(R)-((E)-2-Propenyl)pyrrolidine-1-carboxylic Acid tert-Butyl

Ester (R,E)-41 (Scheme 9). Using general procedure A, s-BuLi

(4.8 mL of a 1.2 M solution in cyclohexane, 5.7 mmol, 1.0 equiv), N-

Boc pyrrolidine 15 (1.2 mL, 5.7 mmol) and (ꢀ)-sparteine (1.3 mL, 5.7

mmol, 1.0 equiv) in TBME (12 mL), ZnCl₂(3.4 mL of a 1.0 M solution

in Et₂O, 3.4 mmol, 0.6 equiv), Pd₂(dba)₃(105 mg, 0.23 mmol, 0.04

equiv), t-Bu₃PHBF₄(83 mg, 0.285 mmol, 0.05 equiv) and the appro-

priate (E)-vinyl bromide (410 μL, 4.75 mmol, 0.83 equiv) gave the crude

product. Purification by flash column chromatography on silica with

95:5 hexaneꢀEtOAc as eluent gave vinyl pyrrolidine (R,E)-41 (670 mg,

67%) as a colorless oil, R_f0.2 (5:1 petrolꢀEt₂O); [R]_Dꢀ4.5 (c 1.1 in

CHCl₃); IR (CHCl₃) 2976, 1682 (CdO), 1404, 1366, 1169,

1118 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃) (50:50 mixture of rotamers)

δ 5.47 (br s, 1H), 5.34 (br s, 1H), 4.53 (br s, 0.5 H), 4.16 (br s, 0.5H),

3.36 (br s, 2H), 2.08ꢀ1.90 (m, 1H), 1.85ꢀ1.76 (m, 2H), 1.660 (dd, J =

6.5, 1.0 Hz, 1.5H,), 1.657 (dd, J = 6.5, 1.0 Hz, 1.5H), 1.59ꢀ1.51 (m, 1H),

1.43 (br s, 9H); ¹³C NMR (100.6 MHz, CDCl₃) δ 155.4 (C), 132.0

(CH), 125.2 (CH), 78.9 (C), 58.6 (CH), 53.8 (CH₃), 45.9 (CH₂), 32.2

(CH₂), 28.2 (CH₃), 22.6 (CH₂); MS (ESI) m/z 234 [(M + Na)⁺, 83],

156 (100), 114 (21); HRMS (ESI) m/z calcd for C₁₂H₂₁NO₂(M +

Na)⁺234.1465, found 234.1462 (+1.3 ppm error). Spectroscopic data

consistent with those reported in the literature.⁵⁸

(R)-((Z)-2-Propenyl)pyrrolidine-1-carboxylic Acid tert-Butyl

Ester (R,Z)-42 (Scheme 9). Using general procedure A, s-BuLi

(4.8 mL of a 1.2 M solution in cyclohexane, 5.7 mmol, 1.0 equiv),

N-Boc pyrrolidine 15 (1.2 mL, 5.7 mmol) and (ꢀ)-sparteine (1.3 mL,

5.7 mmol, 1.0 equiv) in TBME (12 mL), ZnCl₂(3.4 mL of a 1.0 M

solution in Et₂O, 3.4 mmol, 0.6 equiv), Pd₂(dba)₃(105 mg, 0.23 mmol,

0.04 equiv), t-Bu₃PHBF₄(83 mg, 0.285 mmol, 0.05 equiv) and the

appropriate (Z)-vinyl bromide (400 μL, 4.75 mmol, 0.83 equiv) gave the

crude product. Purification by flash column chromatography on silica

with 95:5 hexaneꢀEtOAc as eluent gave vinyl pyrrolidine (R,Z)-42 (670

mg, 67%) as a colorless oil, R_f0.2 (5:1 petrolꢀEt₂O); [R]_Dꢀ46.2

(c 0.6 in CHCl₃); IR (CHCl₃) 2978, 1681 (CdO), 1401, 1367, 1167,

1117 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃) δ 5.43 (br s, 1H), 5.32 (br s,

1H), 4.52 (br s, 1H), 3.39 (br s, 2H), 2.14ꢀ1.98 (m, 1H), 1.91ꢀ1.76

(m, 2H), 1.67 (br s, 3H), 1.63ꢀ1.54 (m, 1H), 1.42 (s, 9H); ¹³C NMR

(100.6 MHz, CDCl₃) δ 155.1 (C), 133.0 (CH), 129.3 (CH), 79.0 (C),

59.2 (CH), 53.8 (CH₃), 46.1 (CH₂), 32.9 (CH₂), 28.3 (CH₃), 28.1

(CH₂); MS (ESI) m/z 234 [(M + Na)⁺, 100], 156 (94), 114 (22);

HRMS (ESI) m/z calcd for C₁₂H₂₁NO₂(M + Na)⁺234.1465, found

234.1462 (+0.9 ppm error).

(m, 9H, CH₂), 1.57ꢀ1.46 (m, 6H, CH₂), 1.31ꢀ1.18 (m, 3H, CH₂); ¹³

C

NMR (100.6 MHz, CDCl₃) δ 81.8 (CH), 46.0 (CH₂), 28.7 (CH₂), 25.3

(CH₂), 21.8 (CH₂). Spectroscopic data consistent with those reported

in the literature.⁵⁹

1-(3,4-Dihydro-2H-pyridin-1-yl)ethanone.

A solution of dodecahydro-4a,8a,12a-triazatriphenylene (2.72 g,

10.91 mmol) in acetic anhydride (48 mL) was stirred and heated at

50 °C under Ar for 16 h. After cooling to rt, EtOAc (55 mL) was added,

and the solution was washed with 1 M NaOH_(aq)(3 ꢁ 30 mL) and water

(2 ꢁ 30 mL) and evaporated under reduced pressure. Saturated

Na₂CO_3(aq)(40 mL) was added to the residue, and the resulting

aqueous solution was extracted with EtOAc (10 ꢁ 60 mL). The

combined organic extracts were dried (MgSO₄) and evaporated under

reduced pressure to give 1-(3,4-dihydro-2H-pyridin-1-yl)ethanone

1

(2.66 g, 65%) as a brown oil, H NMR (400 MHz, CDCl₃) (70:30

mixture of rotamers) δ 7.07 (dt, J = 8.5, 2.0 Hz, 0.3H, NCHd), 6.47 (dt,

J = 8.5, 2.0 Hz, 0.7H, NCHd), 4.96 (dt, J = 8.5, 4.0 Hz, 0.3H,

NCHdCH), 4.86 (dt, J = 8.5, 4.0 Hz, 0.7H, NCHdCH), 3.58 (t, J =

6.0 Hz, 1.4H, NCH₂), 3.48 (t, J = 6.0 Hz, 0.6H, NCH₂), 2.05 (s, 2.1H,

Me), 2.04 (s, 0.9H, Me), 2.01ꢀ1.94 (m, 2H, CH₂), 1.81ꢀ1.67 (m, 2H,

CH₂); ¹³C NMR (100.6 MHz, CDCl₃) (rotamers) δ 174.0 (C), 168.5

(C), 125.8 (CH), 123.8 (CH), 108.7 (CH), 108.4 (CH), 44.0 (CH₂),

39.8 (CH₂), 21.6 (CH₂), 21.3 (CH₃), 21.2 (CH₂), 21.0 (CH₂), 20.9

(CH₃), 20.8 (CH₂). Spectroscopic data consistent with those reported

in the literature.⁶⁰

1-(4-Bromo-3,4-dihydro-2H-pyridin-1-yl)ethanone 43. Bromine

(356 mg, 115 μL, 2.23 mmol) was added dropwise to a stirred solution of

1-(3,4-dihydro-2H-pyridin-1-yl)ethanone (250 mg, 2.00 mmol) in CH₂Cl₂

(8 mL) at ꢀ78 °C under Ar until an orange color persisted. Then, i-Pr₂NEt

(283 mg, 381 μL, 2.19 mmol) was added, and the resulting solution was

allowed to warm to rt and stirred for 45 min. Saturated Na₂S₂O_3(aq)(8 mL)

was added, and the two layers were separated. The aqueous layer was extracted

with CH₂Cl₂(3 ꢁ 18 mL), and the combined organic layers were dried

(MgSO₄) and evaporated under reduced pressure to give the crude product.

Purification by flash column chromatography on silica with 7:3 petrolꢀEtOAc

as eluent gave vinyl bromide 43 (534 mg, 91%) as a colorless oil, R_f(7:3

petrolꢀEtOAc) 0.3; IR (film) 2931, 1640 (CdO), 1392, 1349, 1296, 1257,

986, 730 cm^ꢀ1; ¹H NMR (400 MHz, CDCl₃) (70:30 mixture of rotamers)

δ 7.55 (t, J = 1.5 Hz, 0.3H), 6.91 (t, J = 1.5 Hz, 0.7H), 3.69ꢀ3.63 (m, 1.4H),

3.58ꢀ3.53 (m, 0.6H), 2.51ꢀ2.42 (m, 2H), 2.15 (s, 2.1H), 2.13 (s, 0.9H),

2.03ꢀ1.06 (m, 2H); ¹³C NMR (100.6 MHz, CDCl₃) (rotamers) δ 168.4

(C), 167.8 (C), 126.7 (CH), 124.9 (CH), 108.2 (C), 42.8 (CH₂), 38.5

(CH₂), 31.2 (CH₂), 31.0 (CH₂), 21.6 (CH₃), 21.3 (CH₃); MS (ESI) m/z

204 [(M + H)⁺, 11], 148 (33), 126 (100); HRMS (ESI) m/z calcd for

C₇H₁₀NO⁷⁹Br (M + H)⁺204.0019, found 204.0019 (ꢀ0.4 ppm error).

(R)-2-(1-Acetyl-1,4,5,6-tetrahydropyridin-3-yl)pyrrolidine-1-

carboxylic Acid tert-Butyl Ester (R)-44 (Scheme 10). s-BuLi

(2.3 mL of a 1.3 M solution in hexanes, 3.0 mmol, 1.3 equiv) was added

dropwise to a stirred solution of (ꢀ)-sparteine (690 μL, 3.0 mmol, 1.3

equiv) in TBME (6 mL) at ꢀ78 °C under Ar. After stirring at ꢀ78 °C for

15 min, a solution of N-Boc pyrrolidine 15 (395 mg, 405 μL, 2.3 mmol)

in TBME (1 mL) was added dropwise. The resulting solution was stirred

at ꢀ78 °C for 90 min. Then, ZnCl₂(1.39 mL of a 1.0 M solution in Et₂O,

Dodecahydro-4a,8a,12a-triazatriphenylene.

Piperidine (5.0 g, 5.9 mL, 58.7 mmol) was added dropwise to a stirred

solution of N-chlorosuccinimide (8.34 g, 62.5 mmol) in Et₂O (60 mL)

at rt under Ar. The resulting mixture was stirred at rt for 2 h, and the

solids were removed by ﬁltration. The ﬁltrate was washed with water

(2 ꢁ 35 mL), dried (Na₂SO₄) and evaporated under reduced pressure to

give an oily residue. A solution of NaOMe in MeOH [freshly prepared

by dissolving Na (1.53 g, 66.7 mmol) in MeOH (35 mL)] was added to

the oily residue at rt under Ar. The resulting solution was stirred and

heated at reﬂux for 45 min. After cooling to rt, water was added until all

the solids had dissolved. The layers were separated, and the aqueous

layer was extracted with Et₂O (3 ꢁ 125 mL). The combined organic

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1.39 mmol, 0.6 equiv) was added dropwise, and the resulting solution

was stirred at ꢀ78 °C for 30 min. Then, the solution was allowed to

warm to rt and stirred for 30 min. A solution of vinyl bromide 43

(330 mg, 1.62 mmol, 0.7 equiv) in TBME (2 mL) was added. A mixture

of Pd₂dba₃(52 mg, 0.06 mmol, 0.03 equiv) and t-Bu₃PHBF₄(26 mg,

0.14 mmol, 0.06 equiv) was added in one portion, and the resulting

mixture was stirred at rt for 72 h. Then, 35% NH₄OH_(aq)(0.4 mL) was

added, and the resulting mixture was stirred at rt for 1 h. The solids were

removed by filtration through a pad of Celite and washed with Et₂O

(2 ꢁ 10 mL). The filtrate was washed with 10% NH₄Cl_(aq)(2 ꢁ 25 mL),

dried (MgSO₄) and evaporated under reduced pressure to give the crude

product. Purification by flash column chromatography on silica with 8:2

EtOAcꢀpetrol as eluent gave N-Boc maackiamine (R)-44 (266 mg,

56%, 95:5 er by CSP-HPLC) as a colorless oil, R_f(8:2 EtOAcꢀpetrol)

0.3; [R]_D+40.9 (c 1.0 in CHCl₃); IR(film) 2972, 2930, 1692 (CdO),

1649 (CdO), 1394, 1366, 1331, 1258, 1165, 1113, 754 cm^ꢀ1; ¹H NMR

(400 MHz, CDCl₃) (70:30 mixture of rotamers) δ 7.13ꢀ7.02 (m,

0.3H), 6.39 (s, 0.7H), 4.32ꢀ4.05 (m, 1H), 3.69ꢀ3.44 (m, 4H), 2.12 (s,

3H), 1.99ꢀ1.93 (m, 4H), 1.90ꢀ1.68 (m, 4H), 1.41 (br s, 9H); ¹³C NMR

(100.6 MHz, CDCl₃) (rotamers) δ 168.8 (C), 167.3 (C), 154.3 (br, CH),

121.0 (C), 79.0 (C), 61.0 (CH), 46.8 (CH₂), 44.1 (CH₂), 40.1 (CH₂),

31.7 (CH₂), 30.7 (CH₂), 28.3 (CH₃), 23.4 (CH₂), 21.9 (CH₃), 21.7

(CH₂), 21.3 (CH₃), 21.1 (CH₂); MS (ESI) m/z 317 [(M + Na)⁺, 100],

295 [(M + H)⁺, 60], 239 (18); HRMS (ESI) m/z calcd for C₁₆H₂₆N₂O₃

(M + Na)⁺317.1836, found 317.1836 (0.0 ppm error); HPLC Chiralpak

AD (90:10 hexaneꢀi-PrOH, 1.0 mL min^ꢀ1) (R)-44 8.1 min, (S)-44 9.8

min. Other Pd catalysts/conditions were explored to improve the yield:

Pd(OAc)₂/t-Bu₃PHBF₄(Et₂O), rt, 16 h gave 29% yield, 94:6 er; Pd-

(OAc)₂/t-Bu₃PHBF₄(TBME), rt, 16 h gave 37% yield, 80:20 er;

Pd(OAc)₂/t-Bu₃PHBF₄(TBME), reflux, 16 h gave 43% yield, 93:7 er;

Pd₂(dba)₃/t-Bu₃PHBF₄(TBME), rt, 16 h gave 40% yield, 92:8 er

1-((R)-5-Pyrrolidin-2-yl-3,4-dihydro-2H-pyridin-1-yl)ethanone

(R)-Maackiamine (Scheme 10). tert-Butyldimethylsilyl triflate

(170 μL, 0.8 mmol) was added dropwise to a stirred solution of

N-Boc maackiamine (R)-44 (200 mg, 0.68 mmol, 95:5 er) and pyridine

(80 μL, 1.0 mmol) in CH₂Cl₂(10 mL) at rt under Ar. The resulting

solution was stirred at rt for 16 h. The solvent was evaporated under

reduced pressure, and the residue was dried thoroughly under high

vacuum. The residue was dissolved in saturated NH₄Cl_(aq)(10 mL), and

the aqueous solution was extracted with Et₂O (5 ꢁ 30 mL). The

combined organic extracts were dried (Na₂SO₄) and evaporated under

reduced pressure. THF (7.5 mL) was added to the residue, and the

resulting solution was added dropwise to a stirred suspension of CsF

(152 mg, 1.0 mmol) in THF (7.5 mL) at rt under Ar. The resulting

mixture was stirred at rt for 16 h. The solvent was evaporated under

reduced pressure, and 1 M NaOH_(aq)(15 mL) was added to the residue. The

resulting aqueous solution was extracted with Et₂O (5 ꢁ 40 mL). The com-

bined organic extracts were dried (Na₂SO₄) and evaporated under reduced

pressure to give the crude product. Purification by preparative TLC on silica

with 7:7:2 EtOAcꢀhexaneꢀEt₂NH as eluent gave (R)-maackiamine (71 mg,

54%, 95:5 er by NMR spectroscopy in the presence of (R)-1-(9-anthryl)-

2,2,2-trifluoroethanol)) as a colorless oil, R_f(7:7:2 EtOAcꢀhexaneꢀ

Et₂NH) 0.3; [R]_D+12.8 (c 1.0 in EtOH) (lit.,⁵²[R]_D+110 (c 0.01 in

added dropwise to a stirred solution of N-Boc maackiamine (R)-44

(77 mg, 0.26 mmol, 95:5 er) in CH₂Cl₂(5 mL) at rt under Ar. The

resulting solution was stirred at rt for 4 h. Then, the solvent and excess

TFA were evaporated under reduced pressure. 1 M NaOH_(aq)(5 mL)

was added to the residue, and the resulting aqueous solution was

extracted with CH₂Cl₂(8 ꢁ 10 mL). The combined organic layers

were dried (MgSO₄) and evaporated under reduced pressure to give

rac-maackiamine (448 mg, 96%, 50:50 er by NMR spectroscopy in the

presence of (R)-1-(9-anthryl)-2,2,2-trifluoroethanol) as a brown oil, R_f

(7:7:2 EtOAcꢀhexaneꢀEt₂NH) 0.3.

Determination of the Enantiomeric Ratio of 1-((R)-5-Pyr-

rolidin-2-yl-3,4-dihydro-2H-pyridin-1-yl)ethanone (R)-Maackia-

mine (Scheme 10). Enantiomeric ratio was determined by high

resolution ¹H NMR spectroscopy (400 MHz, CDCl₃) in the presence

of 4.0 equiv of (R)-2,2,2-trifluoro-1-(9-anthryl)-ethanol. A 0.043 M

solution of maackiamine was prepared by dissolving maackiamine (5 mg,

0.026 mmol) in CDCl₃(0.6 mL). Then, (R)-2,2,2-trifluoro-1-(9-

anthryl)-ethanol (28 mg, 0.10 mmol) was added. Diagnostic signals:

¹H NMR (400 MHz, CDCl₃) δ 6.28 (AcNCHd, major), 6.19

(AcNCHd, minor). Integration of the major and minor AcNCH singals

of each rotamer in the ¹H NMR spectra indicated that (R)-maackiamine

was present in 95:5 er. Enantiomeric ratio was determined by high

resolution ¹H NMR spectroscopy (400 MHz, CDCl₃) in the presence of

4.0 equiv of (R)- or (S)-2,2,2-trifluoro-1-(9-anthryl)-ethanol. A 0.043 M

solution of rac-maackiamine was prepared by dissolving maackiamine

(5 mg, 0.026 mmol) in CDCl₃(0.6 mL). Then, (S)-2,2,2-trifluoro-1-(9-

anthryl)-ethanol (28 mg, 0.10 mmol) was added. Diagnostic signals: ¹H

NMR (400 MHz, CDCl₃) δ 6.23 (AcNCHd), 6.12 (AcNCHd). In a

similar fashion, a 0.043 M solution of maackiamine was prepared by

dissolving rac-maackiamine (5 mg, 0.026 mmol) in CDCl₃(0.6 mL).

Then, (R)-2,2,2-trifluoro-1-(9-anthryl)-ethanol (28 mg, 0.10 mmol)

1

was added. Diagnostic signals: H NMR (400 MHz, CDCl₃) δ 6.23

(AcNCHd), 6.12 (AcNCHd). Integration of the major and minor

AcNCH signals of each rotamer in each of the ¹H NMR spectra

indicated that the sample of maackiamine was racemic.

’ ASSOCIATED CONTENT

Supporting Information. ¹H/¹³C NMR spectra of all

S

b

compounds and CSP-HPLC data. This material is available free

of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION

Corresponding Author

*E-mail: peter.obrien@york.ac.uk; kevin_campos@merck.com.

’ ACKNOWLEDGMENT

We thank the EPSRC, BBSRC, Merck, Lilly, and The Lever-

hulme Trust for funding.

1

EtOH)); H NMR (400 MHz, CDCl₃) (70:30 mixture of rotamers)

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5952

dx.doi.org/10.1021/jo2011347 |J. Org. Chem. 2011, 76, 5936–5953

The Journal of Organic Chemistry

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Article Doi

Enantioselective, palladium-catalyzed α-arylation of N-Boc pyrrolidine: In situ react IR spectroscopic monitoring, scope, and synthetic applications

DOI: 10.1021/jo2011347

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