Development of Phase-Transfer-Catalyzed Asymmetric Strecker

Downloaded by NORTH CAROLINA STATE UNIV on December 25, 2012 | http://pubs.acs.org Publication Date: June 14, 2009 | doi: 10.1021/bk-2009-1009.ch011

Chapter 11

Development of Phase-Transfer-Catalyzed Asymmetric Strecker Reaction Based on the Molecular Design of Chiral Quaternary Ammonium Salts Takashi Ooi Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Chikusa, Nagoya 464-8603, Japan

Asymmetric Strecker reaction o f aldimines using aqueous potassium cyanide ( K C N ) as a cyanide source has been devised through the molecular design o f chiral phase-transfer catalyst 9 bearing a stereochemically defined tetranaphthyl backbone. Further, highly efficient, enantioselective synthesis o f N-protected α-amino nitriles from the corresponding α– amido sulfones under similar biphasic conditions is also described, featuring its practical advantages.

Cyanation o f imines, the second step in the Strecker reaction, represents one o f the most direct and viable methods for the synthesis o f a-amino acids and their derivatives. Primarily because o f the importance o f optically active otamino acids (/), stereochemical control o f this valuable carbon-carbon bondforming reaction has been the focus o f extensive study. Actually, numerous efforts have been devoted for the last decade to the development o f chiral catalysts to effect the enantioselective Strecker reaction o f aldimines and ketimines (2). However, most o f the previously elaborated catalytic asymmetric Strecker methodologies rely on either alkylmetal cyanide such as trimethylsilyl cyanide or anhydrous hydrogen cyanide generally at low temperature, w h i c h poses an important problem to be addressed particularly when large-scale industrial applications are considered (2,3). In this regard, we have been © 2009 A m e r i c a n Chemical Society

In Asymmetric Synthesis and Application of -Amino Acids; Soloshonok, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

177


178 interested in the possibility o f employing potassium cyanide ( K C N ) as a cyanide source within the context o f our continuous research program toward the development o f new and practical synthetic strategies in the realm o f asymmetric phase-transfer catalysis (4,5). In this chapter, we describe the highly enantioselective Strecker reaction o f iV-arylsulfonyl aldimines under tolueneaqueous K C N biphasic conditions based on the molecular design o f chiral quaternary ammonium salts 2 bearing tetranaphthyl backbone as an efficient phase-transfer catalyst (6). Furthermore, we document that the in situ generation o f the reactive imines from the corresponding a-amido sulfones leads to the improvement o f both chemical yield and stereoselectivity (7,8).

Reaction System and Use of 7V-Spiro-type Catalyst W e initiated our search for an appropriate reaction system with an imine o f cyclohexanecarboxaldehyde (la) as a representative substrate in order to realize its smooth cyanation under biphasic conditions consisting o f organic solvent and K C N aqueous solution. F o r this purpose, a protecting group ( P G ) o f the imine nitrogen was screened i n the cyanation with 2 M K C N aqueous solution (1.2 equiv) in t o l u e n e - H 0 (volume ratio = 1:3) at 0 ° C using tetrabutylammonium bromide ( T B A B , 5 m o l % ) as catalyst. W h i l e none o f the product formation was detected in the reactions with substrates having p-methoxyphenyl or benzhydryl group even after stirring at room temperature (entries 1 and 2 in Table 1), cyanation o f M-/?-toluenesulfonyl imine proceeded to give the desired protected a-amino nitrile 2a ( P G = S 0 T o l ) i n 7 6 % isolated yield (entry 3). The marked decrease o f the yield observed in the control experiment without T B A B suggested the essential role o f the catalyst, extracting a cyanide anion from the aqueous phase as an ammonium cyanide with enhanced nucleophilicity (entry 4). These results led us to examine the possibility o f asymmetric induction by the use o f a series o f iV-spiro chiral quaternary ammonium bromide (3a-3c, 1 m o l % , Figure 1) as catalyst, which were quite effective for the phase-transfer-catalyzed alkylation o f glycine derivatives (4e). Unfortunately, however, it turned out that the observed enantiomeric excesses were less than 10% ee, though 3a-3c were reactive enough to catalyze the cyanation as also included in Table 1 (entries 5-7). 2

2

Design, Synthesis and Evaluation of New Catalysts Based on these initial observations, we decided to design new chiral quaternary ammonium salts that w o u l d exert sufficient reactivity and stereoselectivity. Our prime concern at this stage was to endow the ammonium


179 Table 1. Effect of Nitrogen Protecting Group and Results of Asymmetric Cyanation Using (R,R)-3 as Catalyst /

P

G

N

/

catalyst (xmol%)

H

P

G

N

2MKCN(1.2eq) H

toluene-H 0(1:3) 2

[

T


1a entry

PG PMP

conditions

yield (%)

ee (%/

T B A B (5)

0 °C ~r.t., 24 h

T B A B (5) T B A B (5)

0 °C ~r.t., 24 h 0 °C, 30 m i n 0 °C, 30 m i n

n.r. n.r. 76 15

-

CHPh S0 Tol S0 Tol

5

S0 Tol

6 7

S0 Tol

3b(l)

0 ° C , 10 h 0 °C, 8 h

S0 Tol

3c (1)

0 °C, 7 h

2

2

2

2

2

N

catalyst (x)

1 2 3 4

2

C

2a

-

3a(l)

77

rac.

91 82

3

10

a

Determined by chiral H P L C analysis ( D A I C E L Chiralpak AD-H). P M P = pmethoxyphenyl. T B A B = tetrabutylammonium bromide, n.r. = no reaction. Tol =p-tolyl.

(R,R)-3

3a

3b

3c

Figure 1. Representative N-Spiro-type Chiral Phase-Transfer Catalysts.

cation with an optimal structure for achieving both a facile anion extraction and a precise enantiofacial discrimination o f the prochiral imine. Actual design plan toward this end was first to get rid o f one of the two chiral binaphthyl subunits from the parent structure o f iV-sipro-type 3, and replace it by simple alkyl substituents (R) to impart hydrophilicity to the salt (Figure 2). Second, introduction o f orthosubstituted phenyl groups at 3,3'-positions o f chiral binaphthyl unit was considered with the expectation that the orr/io-substituents caused rotational restriction around the naphthyl-phenyl biaryl axes, which would provide a configurational bias to create a stereochemically defined molecular cavity over the nitrogen. A c c o r d i n g to this molecular design, three diastereomers are conceivable as exemplified in Figure 2 [R = M e , orf/zosubstituent = P h (4)], and two symmetric isomers would offer a suitable binding pocket for the imine substrate, possibly exhibiting expected catalytic and chiral efficiencies.



180

asymmetric 4

symmetric 4

Figure 2. Design Plan of New Chiral Quatrenary Ammonium Salts.

The synthesis o f 4 was then implemented in a six-step sequence starting from (7?)-binaphthyl dicaboxylate 5 as illustrated in Scheme 1. The orthomagnesiation-halogenation technique we developed (9) was effective for the neopentyl ester 5, furnishing 6 in 7 1 % yield. Subsequent reduction o f the ester moieties, bromination and alkylation with methyl amine afforded the key intermediate 7, w h i c h was subjected to the Suzuki-Miyaura cross-coupling conditions with or//?o-phenylphenyl boronic acid. Although we assumed that three diastereomers might be formed after the installment o f the 3,3'-orthophenylphenyl groups, the desired 8 was obtained as a mixture o f two stereoisomers, symmetric and asymmetric ones, in a ratio o f 4:1. W e were fortunately able to obtain 4 in a pure form through the quaternization with methyl iodide and purification with silica gel column chromatography (10). T o unequivocally determine the three-dimensional molecular structure o f 4, the single crystal X - r a y diffraction analysis was conducted after derivatization to the corresponding hexafluorophosphate ( 4 - P F ) and recrystallization from T H F hexane solvent system at 0 °C, revealing its (R,R,R) configuration (Figure 3). A s expected, each phenyl substituent at 3,3'-positions o f the binaphthyl unit is nearly perpendicular to the attached naphthalene ring, sticking over the central cationic nitrogen. Further, the pendant ortho-phenyl group is parallel to the other and contributes to extend the aromatic surface to offer an ample reaction cavity, which could hold the imine functionality within an ideal proximity to the 6


181

Br 1)Mg(TMP) ^C0 R


2

' 0

THF.O'C-r.t

2

/C0 R

2

2)Br

C

DIBAH

2 R

C0 R

CH CI 0°C~r.t.

2

2

2

- 7 8 °C to r.t. Br (R = C H B u O

2

PBr

MeNH

3

CH CI THF 0°Or.t. 0 °Or.t 2

2

6

71%

2

[TMP = 2,2,6,6-tetramethylpiperamide] ,Br ^ NMe

Pd(OAc)

B(OH)

2

PPh

3

2l

DMF, C s C 0 2

Br 64% (3 steps)

7

90 °C, 8 h

NMe

Mel

3

Ar / Ar = 2 - P h - C H 6

8 4

\ s y m . / a s y m . = 4:1

2

6 1 % (2 steps)

Scheme 1, Synthesis of Chiral Quaternary Ammonium Iodide 4.


182 cyanide anion located inside the chiral environment, enabling an efficient and stereoselective bond formation. T o examine this hypothesis, we evaluated the potential o f 4 as a chiral phase-transfer catalyst by performing the asymmetric cyanation o f l a ( P G = S 0 T o l ) under the biphasic conditions in the presence o f 4. Thus, a mixture o f l a ( P G = S 0 T o l ) and 1 m o l % o f 4 in t o l u e n e - K C N aqueous solution (1.2 equiv) was vigorously stirred at 0 ° C . The T L C monitoring indicated the complete consumption o f the substrate after 2 h, and the desired protected amino nitrile 2a ( P G = S 0 T o l ) was isolated in 84% yield with enantiomeric excess o f 2 4 % ee (entry 1 in Table 2). Here, employment o f N-mesitylenesulfonyl imine l a ( P G = S 0 M e s ) enhanced the enantioselectivity to 5 7 % ee, though longer reaction time was required (entry 2). These promising results apparently supported the direction o f the molecular design o f the catalyst, which led us to undertake further structural modification o f 4 by replacing the 3,3'-substituents with 2-phenyl-l-naphthyl group for critical improvement o f the stereoselectivity (9a in Figure 4). The chiral quaternary ammonium iodide 9a possessing stereochemically homogeneous tetranaphthyl backbone was prepared in a manner similar to that o f 4. Subsequent crystallographic analysis uncovered its enlarged chiral molecular cavity as shown in Figure 4, implying the feasibility o f more accurate enantiofacial recognition. Indeed, the catalyst 9a exhibited high chiral efficiency in the reaction o f l a ( P G = S 0 M e s ) with aqueous K C N under similar conditions to afford 2a ( P G = S 0 M e s ) with 8 9 % ee (entry 3). Moreover, the additional phenyl substituents at 4-positions o f the outer naphthyl units (9b in Figure 4) were revealed to be associated with even more rigorous enantiocontrol (90% ee) (entry 4). Finally, we found that the introduction o f electron-withdrawing trifluoromethyl group to all the appended phenyl groups (9c) delivered a beneficial effect on the enantioselectivity (entry 5), and the phase-transfer cyanation o f l a ( P G = S 0 M e s ) with 1.5 equiv o f K C N under the influence o f 9c was completed within 2 h to produce 2a ( P G = S 0 M e s ) in 8 9 % yield with 9 5 % ee (entry 6). 2


2

2

2

2

2

2

2

Other selected examples listed in Table 3 clearly demonstrate the effectiveness o f this asymmetric Strecker protocol for a variety o f aliphatic aldimines. In general, 1 m o l % o f 9c with 1.5 equiv o f K C N was sufficient for the smooth reaction, and the corresponding protected amino nitrile 2 was obtained uniformly in high yield with excellent enantioselectivity. Emphasized is the fact that the present system nicely accommodates the substrates having ottert-a\ky\ substituents such as pivalaldimine (entries 5-7), thereby enabling a facile synthesis o f enantiomerically enriched terf-leucine and its various analogues, a series o f considerably useful chiral building blocks not accessible by the asymmetric alkylation o f glycine derivatives (4). be

The mesitylenesulfonyl moiety o f the optically active Strecker product 2 can readily cleaved by the treatment with methanesulfonic acid in T F A -


183

Table 2. Optimization of the Asymmetric Strecker Reaction of l a with Respect to Arylsu lfonyl Group and Catalyst Structure 4 or 9 (1 mol%) Downloaded by NORTH CAROLINA STATE UNIV on December 25, 2012 | http://pubs.acs.org Publication Date: June 14, 2009 | doi: 10.1021/bk-2009-1009.ch011

N

c IX 1a H

J

entry

PG

2

^

0°C

react, time (h)

2a

y / e W (%)

ee (%)" (config)

b

4

2

84

24 (5)

9a 9b

8 4 4

81 83

57(5) 89 (S)

S0 Mes

9c

4

90 89

90 (S) 94 (S)

S0 Mes

9c

4

89

95 (S)

S0 S0 S0 S0

5 C

t o l u e n e - H 0 (1:3)

4

1 2 3 4 6

catalyst

HN

2MKCN(1.2eq)

2

2

2

2

ToI Mes Mes Mes

2

2

a

b

Determined by chiral H P L C analysis (DAICEL Chiralpak AD-H). Mes = mesityl. For assignment of the absolute configuration, see Scheme 2. With 1.5 equiv of 2 M K C N aqueous solution. c

O R T E P diagram of 9a

1

2

9c (Ar = A r = p - C F - C H ) 3

Figure 4. Modification of 4 to Tetranaphthyl-type 9 and Its Structural Determination by X-ray Analysis.


6

4

184

Table 3. Substrate Scope of the Asymmetric Strecker Reaction /S0 Mes


R

1

9c (1 moI%) 2 M K C N (1.5 eq)

2

jj^

H

1 2 3 4 5 6 7

c-Oct ;-Pr 2

2

2

/-Bu Ph(CH ) C Ad 3

^ C N

2

react, time (h)

Ph(CH ) (CH ) CHCH

1

0°C

1

2

R

2

1 (R )

3

2

t o l u e n e - H 0 (1:3)

1 entry

/S0 Mes Hl^

2

ee (%)"

yield (%)

2 3 2 3 3

88 85 81 82 94

97 93 90 88 94

8 8

95 98

98 97

° Determined by chiral H P L C analysis (DAICEL Chiralpak AD-H).

HN

.S0 Mes

NH

2

err 9 5 % ee

NHBz

2

BzCI, K C 0

MeSQ H

2

3

CN TFA-thioanisole (9:1) r.t.,2h

3

CH Cl2-H 0 2

2

10

r.t. 9 0 % (2 steps) 95% ee

HCI/ether

a

©

NH

0 3

CI

S^CN 12

[ ] tt

29 D

+8.14 (c 1.00, M e O H )

lit.; [a] 2° +8.2 (c 1.05, M e O H ) D

Scheme 2. Deprotection and Assignment of Absolute Configuration.


185 thioanisole at room temperature as exemplified in Scheme 2 (77), and complete preservation of the enantiomeric excess was confirmed by HPLC analysis after derivatization of amino nitrile 10 to its 7V-benzoate 11. The absolute configuration of 2a was assigned to be S by comparing the optical rotation of amino nitrile hydrochloride 12 with the reported value (72).


In Situ Generation of Sulfonyl Imines As described above, the phase-transfer-catalyzed, highly enantioselective cyanation of N-mesitylenesulfonyl aldimines using aqueous KCN as a cyanide source has been devised through the molecular design of a chiral quaternary ammonium iodide 9c as catalyst. Although this practical asymmetric Strecker protocol tolerates a wide range of aliphatic aldimines, the chemical yield and enantioselectivity were still insufficient in the reactions with secondary and, particularly, primary alkyl aldimines compared to tertiary alkyl ones (Table 3). We reasoned that it could be ascribed to the partial imine hydrolysis and uncatalyzed cyanation under biphasic conditions. To overcome these problems associated with the direct use of the reactive sulfonyl imines, we sought to employ N-mesitylenesulfonyl a-amido sulfones as a suitable starting substrate for the in situ generation of the imine under similar liquid-liquid phase-transfer conditions (J3,14). The requisite jV-mesitylenesulfonyl a-amido sulfone, actually a synthetic precursor of the corresponding aldimine, can be readily prepared from aldehydes and mesitylenesulfonamide and easily purified by simple recrystallization (6). With cyclohexanecarboxaldehyde-derived a-amido sulfone 13a as a representative substrate, initial attempt was made by exposure of 13a to the biphasic conditions consisting of toluene and 2 M KCN aqueous solution (2 equiv) in the presence of 4 as catalyst. Complete consumption of 13a was comfirmed after 2 h, and the desired jV-mesitylenesulfonyl a-amino nitrile 2a was produced in a quantitative yield with 60% ee (entry 1 in Table 4). Similar reactivity and selectivity were observed when the reaction was performed with 1.2 equivalents of KCN under otherwise identical condition (entry 2). The considerable improvement of the chemical yield and the enhanced enantioselectivity compared to the case with the imine as substrate clearly indicates that the intervention of imine hydrolysis and background cyanation is minimized, thereby releasing the full potential of the chiral phase-transfer catalysis of 4. It should be noted that the amount of KCN can further be reduced to 1.05 equivalents without any detrimental effect on the reaction efficiency, thus solidifying the practical aspect of this system. Finally, switching the catalyst from 4 to 9c enabled the quantitative isolation of highly enantioenriched 2a as included in Table 4.


186 Table 4. Optimization of Reaction Conditions with Respect to the Amount of KCN H N

.S0 Mes 2

4 or 9c (1 mol%)

.S0 Mes 2

2 M K C N (y equiv) r ^ y


\ ^

entry 1 2" 3 4"

v

s o

2

T o i

13a

Catalyst 4 4 4 9c

toluene-H 0(1:3) 2

0 °C

KCNfy) 2.0 1.2 1.05 1.05

r e a c f . f/me (h)

2 1.5 1.5 1.5

7 [ \ ^

C

N

2a

yield (%) 99 99 (81) 99 99 (89)

ee (%)" 60 61 (57) 63 97 (95)

a

Determined by chiral HPLC analysis (DAICEL Chiralpak AD-H). * The results with the corresponding jV-mesitylenesulfonyl aldimine as a starting substrate are shown in the parentheses.

With the optimized conditions in hand, we conducted experiments to probe the scope of this asymmetric Strecker synthesis from a-amido sulfones, and representative results are summarized in Scheme 3. The reaction proceeded rapidly and cleanly with a variety of a-amido sulfones derived from a-branched and a-unbranched aldehydes including a highly enolizable one in the presence of 1 mol% of 9c and 1.05 equivalents of KCN aqueous solution, and the corresponding a-amino nitriles 2 were obtained in excellent chemical yields and constantly higher enantioselectivities. In particular, this method is quite effective for the asymmetric synthesis of an a-amino nitrile possessing a secondary alkyl a-substituent as represented by the cyanation starting from the substrate with A^-benzyloxycarbonyl-4-piperidinyl group, in which the target product was isolated quantitatively in an essentially enantiopure form.

Conclusion We have achieved the phase-transfer-catalyzed, highly enantioselective cyanation of aldimines using aqueous KCN as an inexpensive and easy-to-handle cyanide source through the development of new chiral quaternary ammonium iodide 9c bearing a stereochemically defined tetranaphthyl backbone. Furthermore, remarkably efficient, high yielding asymmetric synthesis of Nmesitylenesulfonyl a-amino nitrilefromthe corresponding a-amido sulfones has also been accomplished under similar biphasic conditions in the presence of 9c, which obviates the preformation of the reactive aldimines having primary and


187 .SO^es

9c(1mol%) 2 M K C N (1.05 eq)

HN R

toluene-H 0

S0 Tol

1

2

2

(1:3)

HN R

2

CN

1

2

0 °C,

Development of Phase-Transfer-Catalyzed Asymmetric Strecker

Recommend Documents