Chiral Amine Synthesis (Methods, Developments and Applications) || Asymmetric Reductive Amination

7Asymmetric Reductive AminationThomas C. Nugent

7.1Introduction

Despite its long history and common usage of the term, reductive amination hasremained underdeveloped. Many studies are available regarding racemic reductiveamination, but only B€orner and Tararov have provided summaries of the asymmetricversion [1]. In this chapter we provide an overview of the available methods andachievements since the first demonstrated enantioselective reductive amination byBlaser in 1999 [2].

Compared to the large volume of reports detailing asymmetric imine reduction,only a small number of publications are available regarding asymmetric reductiveamination. Reductive amination remains less developed than the field of iminereduction due in great part to the incompatibility of transitionmetal hydride catalystsin the presence of ketones (alcohol by-product formation) and/or catalyst inhibitionarising from amine starting material or amine product complexation with a catalyt-ically active transition metal species [3]. Future method development will surelyrequire striking the right balance between these competing nonproductive reactionpathways.

Before discussing the relevant literature, a few qualifiers are mentioned anddiscussed. Reductive amination is sometimes incorrectly associated with the reduc-tion of preformed imines and derivatives thereof. Reductive amination, by definition,is only the one-pot conversion of a ketone to an amine inwhich a reductant coexists inthe presence of a ketone starting material [4]. The term indirect reductive amination isoccasionally used, but can be more tersely and accurately described as iminereduction [5]. The reader will note that depending on the perspective one takes forthe transformation, the term reductive amination is applied when considering thereaction course of the ketone starting material, and the term reductive alkylation isapplied when describing the starting amine�s conversion to the product amine.

Included in this section are procedures that are not classified as reductive amina-tion, but are also not imine reductions in the sense that an imine has been isolated,here isolation means a work-up or distillation has been performed before the

Chiral Amine Synthesis: Methods, Developments and Applications. Edited by Thomas C. NugentCopyright � 2010 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32509-2

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reduction step. As a consequence, we include several one-pot procedures in whichimine formation is performed without the presence of the reductant; once the ketone isfully consumed, no workup is performed, but instead the reductant is added tocomplete the reaction sequence. These two-stage, no workup procedures are bydefinition not considered reductive aminations [4], but importantly they do representa significant improvement in reaction step efficiency versus imine formation,isolation, and reduction thereof, and are therefore included in this section.

The enantioselective reductive amination of ketoacid substrates has been dem-onstrated and provides amino acids that are beyond the scope of this review [6].Enzymatic-based reductive amination is now possible and allows nonamino acidchiral amine synthesis, however, this field of study is also beyond the scope of thismaterial [7]. Finally, much of the material discussed here also appeared in a recentreview of ours on the general subject of chiral amine synthesis.

7.2Transition Metal-Mediated Homogeneous Reductive Amination

The first reported example of enantioselective reductive amination was that of Blaseret al. at Solvias (Scheme 7.7) [2]. At the time, 1999, they were still tweaking theindustrial process for metolachlor, the active ingredient of the herbicide Dual�, andexamined its synthesis via the reductive amination of methoxyacetone with 2-methyl-5-ethyl-aniline (MEA, limiting reagent). Working at the 100mmol scale, they showedthat a very low loading of an Ir–xyliphos complex, under 80bar (1160psi) H2, neat,50 �C, and14h,were optimal. By doing so, a 76%eewith full conversionwas achieved.

FePH

P

OMeO

NH2

N

MeO

ClO

HN

MeO

Xyliphos

+

metolachlor

100 mmol

Ir-Xyliphos(0.01 mol%)

80 bar H2

50 oC, 14 h

76% ee99% conversion

1.20 equiv

Scheme 7.1 The first enantioselective reductive amination: synthesis of metolachlor.

226j 7 Asymmetric Reductive Amination

The reactionwasnot as accommodating as just described and additionally requireda cosolvent (10ml of cyclohexane per 100mmol of MEA) and an acid, whichscreening identified as methanesulfonic acid (0.2ml per 100mmol of MEA). Inaddition, tetrabutylammonium iodide (20mg) was required. The combination ofthese additives enhanced the rate of reaction presumably by aiding solubility in thistwo phase reaction.

Although this was an outstanding first example of enantioselective reductiveamination that achieved the project�s ee target, the final industrial process actuallyemployed the corresponding preformed and isolated imine because of the advantageof reducing by one-hundredth the catalyst loading compared to the reductiveamination process outlined here [8].

In 2003,Zhang investigated the reductive amination of aryl–alkyl ketones (limitingreagent) with p-anisidine (1.2 equiv) [9]. The optimal conditions were noted whenusing 1.0mol% of an Ir–f–Binaphane complex, 69 bar (1000 psi) H2, CH2Cl2, 25 �C,and 10 h (Scheme 7.2). Unique and advantageous to this reductive amination systemwas a >99% yield for every substrate studied, but the ee�s varied. For example,acetophenone, phenyl–ethyl ketone, and phenyl–nbutyl ketone lead to progressivelylower ee: 94%, 85%, and 79%, respectively. A trend was also established for methyl-substituted acetophenones: p-CH3-Ph (96% ee), m-CH3-Ph (89% ee), and o-CH3-Ph (44% ee). In general, para-substitution on the aromatic ring of acetophenone leadto high ee: p-CH3O-Ph (95% ee), p-F-Ph (93% ee), p-Cl-Ph (92% ee), and p-Br-Ph(94% ee).

Importantly, Zhang noted that the reaction did not proceed without the addition ofiodine [10]. Furthermore use of Ti(OiPr)4 was not trivial, and replacement byMgSO4,4A

�MS, or TsOH was not helpful. They additionally noted that replacing the chiral

f-Binaphane ligand with BINAP or BIPHEP resulted in poor ee. The source ofnitrogen is important because of the desire to ultimately provide a chiral primaryamine; screening studies with benzylamine, aniline, o-anisidine, m-anisidine,p-anisidine, and 2,6-dimethylaniline showed p-anisidine to be optimal.

Ar

O

R

Ar

HN

R

OMe

Fe

P

P

f-Binaphane

I2 (10 mol %)69 bar (1000 psi) H2

Ir(f-Binaphane)Ti(OiPr)4 (1.5 equiv)

Scheme 7.2 First Ir-based reductive amination.

7.2 Transition Metal-Mediated Homogeneous Reductive Amination j227

The independent and combined efforts of the industrial group of Kadyrov(Degussa AG, now Evoniks) and the academic group of B€orner have providedimportant advancements in the field of a-chiral amine synthesis [11]. Reporting onthe enantioselective reductive amination of 1- and 2-acetylnaphthalene, phenyl ethylketone, and substituted acetophenone derivatives using Leuckart–Wallach transferhydrogenation conditions, they showed that the corresponding primary amine couldbe isolated in high yield and ee (Scheme 7.3). For example, acetophenone provided a92% yield with 95% ee, and aromatic-substituted derivatives provide similar results:m-CH3-Ph (74% yield, 89% ee), p-CH3-Ph (93% yield, 93% ee), p-CH3O-Ph (83%yield, 95% ee), p-Cl-Ph (93% yield, 92% ee), p-Br-Ph (56% yield, 91% ee), and p-NO2-Ph (92% yield, 95% ee), additional substrates are noted in Scheme 7.3. These resultswere possible when employing 0.5–1.0mol% of a Ru–BINAP (and ligand derivativesof BINAP) complex, excess NH3/HCO2NH4, MeOH, 85 �C, and�20 h in a pressurevessel.

The reaction actually produces amixture of the primary amine and the correspond-ing formyl derivative, but the amine product is exclusively isolated after the crudeproduct is treated withHCl (Scheme 7.3). As of this writing, the method provides lowyields and ee for cyclic aromatic substrates, for example, 1-indanone (6% yield, no eereported, chiral Ru catalyst) [11b]. Regarding aliphatic ketones, for example,2-octanone (44% yield, 24% ee, chiral Ru catalyst [11a] or 37% yield with an achiralRh catalyst [11b]). The same authors have recentlymade inroads concerning the use ofaromatic ketones and molecular hydrogen [12], although the transfer hydrogenationmethod presented here appears to be superior as of now.

The development of thesemethods for alkanone-based substrates would representanother precedent-setting breakthrough by Kadyrov and B€orner. The overall impor-tance of these findings is the exceptional reaction step efficiency (ketone to primaryamine in one pot); unfortunately, this feature of amine synthesis is not openly

R

Ar

O

R Ar

NH2

RNH3/HCO2NH4

85 oC, ~20 h

Ru(tol-BINAP)

Ar

HN

R

H

O

NH2 work-up:EtOH/H2O

HClreflux (1 h)

+

NH2

NH2 NH2

yld, ee (see text)

89 yld, 95% ee

91% yld, 95% ee69% yld, 86% ee

Scheme 7.3 Ru-based reductive amination providing primary amines.


discussed in the literature, but of critical importance regarding the advancement ofchiral amine synthesis in general.

An elegant and refreshing approach was demonstrated in 2009 by Rubio-P�erez.Here, 13 different alkyl–alkyl and aryl–alkyl ketones (limiting reagent) were reduc-tively aminated in the presence of 1.5 equiv of an aniline derivative, most notablypara-methylaniline or meta-trifluoromethylaniline, employing 2.5mol% of Pd cat-alyst 1, 55 bar (800 psi)H2, CHCl3, 70 �C, and 24 h (Figure 7.1) [13]. It was additionallycrucial to add 5A

�molecular sieves (150mg per 1.0mmol of ketone substrate). The

system was very effective for aliphatic ketones, major highlights are displayed inFigure 7.1,which is important because of the severe lack ofmethods applicable to thisclass of ketone substrates. Aryl–alkyl ketones, acetophenone derivatives, and phe-nyl–ethyl ketone performed less convincingly with ee�s ranging from 34–43% andyields ranging from 53–67%. In addition, 2,3-butanedione was selectively mono-aminated in very good yield (85%), but with poor enantioselectivity (20% ee).

In 2009, Xiao employed a half-sandwich Cp�Ir(III) complex with different chiral-monosulfonatedDPEN ligands (Figure 7.2), earlier developed for imine reduction bythe same group, in combination with a BINOL-based chiral phosphate counteranion(TRIP anion), to reductively aminate 24 acetophenone derivatives (1.2 equiv) with p-anisidine (limiting reagent) under the conditions of 1.0mol% of the indicated Ircatalyst (Table 7.1), 5 bar (73 psi) H2, toluene, 35 �C, and 15–24 h [14].

Additionally required were 4A�MS (200mg for 0.5mmol of p-anisidine) and

5.0mol% of the chiral phosphoric acid derivative (Figure 7.1, TRIP or XH), whichwere crucial for allowing complete conversion, suppression of alcohol by-productformation, and high ee. The enantioselectivity for 18 aryl–alkyl ketones are shown in

P

P

Pd

Ph2

Ph2Br

Br

HN HNCF3

95% ee, 51% yld 59% ee, 51% yld

HN

99% ee, 77% yld

HN

96% ee, 74% yld

CF3

HN

90% ee, 73% yld

catalyst 1

Figure 7.1 First Pd-based reductive amination.

7.2 Transition Metal-Mediated Homogeneous Reductive Amination j229

Table 7.1 and in general it can be stated that excellent isolated yields were obtained(>90%), using Xiao�s method. Regarding the �ortho�-substituted acetophenoneexamples (Table 7.1, last row),1-acetylnaphthalene (not shown) was also an excellentsubstrate (90% yield, 87% ee). In addition to these successes with acetophenonederivatives, two aryl–ethyl ketones were examined and provided similar high eevalues.

These results are outstanding when considering that a reductive aminationstrategy has been employed and are evenmore impressive because aliphatic ketones,which are historically avoided because of poor yield and ee, are also acceptable

N

NHPh

Ph

S

CH3

OO

IrX

O

OP

O

OX =

iPr

iPr

iPr

iPr

iPr

iPr

N

NHPh

Ph

S OO

IrX

N

NHPh

Ph

S OO

IrX

XH = TRIPcatalyst 2 catalyst 3 catalyst 4

Figure 7.2 Ir catalysts with TRIP ligands for reductive amination.

Table 7.1 Ee values for Ir-based reductive amination of acetophenone derivatives with p-anisidine.

R substituent on Substrate CH3 iBu CH3O Cl Br F CF3 NO2 CN

Substrate Catalyst

O

R

2a) 97 95 95 95 94 95 91 88 86

OR 2a) 94 — 94 — 94 — 93 81

OR 4a) 91 — 86 83 96b)

a) See Figure 7.2.b) See Figure 7.2, catalyst 3 was used.


substrates. For the eight alkyl–methyl ketones examined (not shown), the Figure 7.2catalysts were sufficient to allow reductive amination, thus the addition of TRIP wasnot required (aryl–alkyl ketones require the addition of TRIP). In summary, the Xiaosubstrate examples are impressive, ranging from aryl-alkyl ketones that can evencontain non-conjugated alkenemoieties; ees are high (generally>90%) with good toexcellent yield (79–91%). Researchers have examined similar reaction conditionsbefore and failed, the key innovations of Xiao would appear to be finding a catalystthat is moisture and acid resilient, preferentially reduces imines or iminium ionsover the starting ketone, and importantly is not �trapped� by the amine product.

7.3Enantioselective Organocatalytic Reductive Amination

Examining a variety of chiral BINOL-based phosphoric acid catalysts in 2005, Listfound TRIP (Scheme 7.4) to be optimal (1.0mol%) for the catalytic protonation ofpreformed imines of p-anisidine [15].

The resulting achiral iminium cations, with chiral phosphate counteranion, werethen enantioselectively reduced using an achiral Hantzsch ester (dihydropyridine)providing enantioenriched amines. During this imine reduction study, one examplewas shown in which acetophenone and p-anisidine [16] were prestirred in thepresence of toluene and 4A

�molecular sieves [17] for 9 h (imine formation), after

which the temperature was raised to 35 �C, and the Hantzsch ester (1.4 equiv) andphosphoric acid (TRIP, 5mol%)were added to give the amine product in 88% ee overan additional 45 h. This is an exciting observation and while not a reductiveamination, it is an operational improvement over simple imine reduction whichrequires imine isolation.

Follow-up studies regarding the further development of the just noted one-pot,two-stage amine synthesis from ketones (Scheme 7.4), or of attempts to examinereductive amination conditions themselves have, to the best of our knowledge, yet tobe elaborated on. Regardless, List did make an additional study in which reductive

O

OP

O

OH

iPr

iPr

iPr

iPr

iPr

iPr

NH

CO2EtEtO2C

Hantzsch ester(dihydropyridine)

phosphoric acidcatalysts (TRIP)

Ph

Op-anisidine, toluene,

4Å MS, 25 oC, 9 h, then

CAN (4.0 equiv) MeOH/H2O0 oC, 81% yield

Ph

HN

OCH3

Ph

NH2

Hantzsch ester (1.4 equiv) TRIP (5.0 mol %)

35 oC, 45 h, 92% yield

Scheme 7.4 TRIP-based two-stage, no workup ketone to amine synthesis.

7.3 Enantioselective Organocatalytic Reductive Amination j231

amination was incorporated into a triple organocatalyzed cascade reaction(Scheme 7.5) allowing the formation of cis-3-substituted cyclohexylamines from2,6-diketones. The reaction conditions called for 1.5 equiv of p-anisidine (or deri-vatives thereof) with the chiral phosphoric acid TRIP (10mol%) in cyclohexane with5A

�MS (250mg per 0.25mmol of diketone) at 50 �C for 72 h. A large number of R

groups were acceptable, ranging from aliphatic (linear, a-branched, and b-branched)to aromatic and provided good yield, good diastereoselectivity, and good to excellentenantioselectivity. While very specialized, it is also a wonderful example of ingenuityand provides products that are of pharmaceutical interest as chiral building blocks.

b-chiral amines are not included in this review, but we remind the reader that Listhas extended his TRIP/p-anisidine system to an elegant dynamic kinetic reductiveamination protocol fora-branched aldehydes, which provides b-chiral amines [18]. Acomputational investigation of the stereochemical pathway for b-chiral amineformation has been reported on and is noteworthy [19].

During an overlapping time frame as the work of List, MacMillan devised the first,and to date only, intermolecular organocatalytic enantioselective reductive amination(reductant and ketone coexisting) with a Hantzsch ester [20]. Where List tookadvantage of TRIP, MacMillan found that an analogous phosphoric acid, albeit withtriphenylsilyl groups, was critical for allowing reductive amination (Figure 7.3).Using p-anisidine as the limiting reagent, in the presence of Hantzsch ester(1.2 equiv), the acid catalyst (10mol%), ketone (3.0 equiv), and 5A

�molecular sieves

(1.0 g per 1.0mmol of p-anisidine) at 40–50 �C in benzene (0.1M), was optimal.When acetophenonewas examined, only 24 hwas required for the complete reaction,but all other substrates required 72–96 h when using p-anisidine. Although we onlyshow the p-anisidine reductive amination products here (Figure 7.3), MacMillanadditionally showed that a diverse set of aryl and heteroaromatic amines servedequally well for the enantioselective reductive amination of aryl–alkyl and alkyl–alkylketones.

In 2007 Ko�covsk�y and Malkov reported an alternative organocatalytic approach,taking advantage of trichlorosilane in combination with a chiral formamide ligand(now referred to as Sigamide) for chloroamine formation (Scheme 7.6) and subse-quent conversion to highly enantioenriched aziridines (not shown) [21].

Using their earlier developed organocatalytic methods for imine reduction, theyapplied similar conditions for the enantioselective reduction of a-chloroimines.Some of the a-chloroimines were unstable or sensitive to purification, prompting

R

X O

O

XR

HN

OCH3

R

X O

HN

OCH3

XR

N

OCH3

H

XR

N

OCH3

H

Scheme 7.5 Organocatalytic cascade featuring reductive amination with TRIP.


O

OP

Si

Si

O

OH

phosphoric acid catalyst

Ph

Ph Ph

Ph

PhPh

HN

OCH3

75% yld, 94% eePh

HN

OCH3

60% yld, 90% ee

HN

OCH3

71% yld, 83% ee

BzO

HN

OCH3

72% yld, 81% ee

HN

OCH3

72% yld, 91% ee

HN

OCH3

49% yld, 86% eeHN

OCH3

R= p-H, 87% yld, 94% eeR= p-CH3, 79%, 91% eeR= p-OMe, 77% yld, 90% eeR= p-NO2, 71% yld, 95% eeR= p-Cl, 75% yld, 95% eeR= p-F, 75% yld, 94% eeR= m-F, 81% yld, 95% ee

HN

OCH3

F

60% yld, 83% ee

HN

OCH3

75% yld, 85% ee

HN

OCH3

70% yld, 88% ee

F

MacMillan's

R

Figure 7.3 Organocatalytic reductive amination – product examples.

N

HO

HN

OCH3

Sigamide ligand

tBu

tBu

RCl

O

RCl

N

R'

RCl

HN

R'

5 Å MSaniline derivative

toluene, 20 oC, 24 h

cool to 0 oC, addSigamide (5 mol%)

Cl3SiH (2.0 equiv)then stir at 20 oC, 24 h

Me

R' = OMe, for the below results

R =Me

Cl

MeO

MeO

F3C

F

94%, 89% ee

71%, 82% ee

65%, 93% ee

86%, 91% ee

88%, 84% ee 92%, 91% ee

84%, 92% ee

80%, 92% ee

54%, 96% ee

R' = H, Cl, F, OMe

Scheme 7.6 Organocatalytic chloroamine synthesis.

7.3 Enantioselective Organocatalytic Reductive Amination j233

them to develop a one-pot, two-stage, no workup, ketone to amine synthesis. Bycombining an aniline derivative (limiting reagent), an a-chloroketone, and 5A

�

molecular sieves (200mg per 0.2mmol of aniline derivative) in toluene (0.1M) for24 h, they were able to form the imine in situ. After confirming full consumptionof the ketone, the reducing agent, Cl3SiH, and Sigamide ligand were added(Scheme 7.6).

7.4Diastereoselective Reductive Amination

Auxiliarymethods can hold current value when the auxiliary is inexpensive, availablein both enantiomeric forms, and, for amine synthesis, can be incorporated withconcomitant generation of the new stereogenic a-chiral amine center. Reductiveamination with chiral ammonia equivalents not only holds this potential but is now aproven and established method that allows chiral primary amine synthesis in tworeaction steps (reductive amination and hydrogenolysis) from prochiral ketones. Theapproach is of interest because of its overall reaction step efficiency.

Regarding the use of chiral amine auxiliaries for reductive amination, only (R)- and(S)-phenylethylamine (also referred to as a-methylbenzylamine) and (R)- and (S)-tert-butylsulfinylamide have gained widespread acceptance as useful chiral ammoniaequivalents. The strategy is therefore to use these chiral amines to induce a newchiral amine stereogenic center on a ketone substrate. An alternative approach is to usea chiral ketonewith anachiral source of nitrogen, for example, benzylamine.This latterapproach is lessoften employed, but nonetheless equally important anddiscussedfirst.

7.4.1Stereoselective Reductive Amination with Chiral Ketones

Substance P receptor antagonists have been extensively sought after for alleviating arange of ailments, for example, gastrointestinal and psychotic disorders and inflam-mation-related diseases, and many of the manufactured drug antagonists share acommon advanced core: (2S,3S)-cis-2-benzhydryl-3-aminoquinuclidine or (2S,3S)-1(Scheme 7.7). In 2004 Nugent reported the first successful stereoselective reductiveamination of an a-chiral stereochemically labile ketone (Scheme 7.7), allowing agreatly improved synthesis of (2S,3S)-1 to come forth [22, 23].

The new reductive amination conditions came from recognizing earlier developedachiral reductive amination conditions employing themild Lewis acid Ti(OiPr)4 [24],this removed the a-chiral ketone racemization problem associated with classicalBrønsted acid reductive amination procedures, and by replacing the previously usedhydride reagents (NaBH3CN and NaBH4) [24, 25] with the more environmentfriendly Pt-C/H2 orPd-C/H2 reducing systems. For the shown chiral ketone substrate(Scheme 7.7), reaction under the conditions of Ti(OiPr)4 (1.2 equiv), BnNH2 (1.1equiv), Pt-C (0.4mol%Pt), 4.1 bar (60 psi)H2, THF, 25 �C, over 12 h provided the bestoverall result in terms of the combined outcome of preservation of ketone stereo-


chemistry, diastereoselectivity, yield, and rate of reaction, culminating in the moststepwise and yield-efficient synthesis of this chiral quinuclidine to date.

Menche recently established an effective two-step strategy for synthesizing chiral1,3-amino alcohols [26]. The first step, an enantioselective aldol reaction, provideschiral b-hydroxy ketones, which are then reductively aminated under the conditionsof p-anisidine (2.0 equiv), Ti(OiPr)4 (1.4 equiv), CH3CN (�20 �C), in the presence ofpolymethylhydrosilane (2.2 equiv) over 48 h. A variety of examples are shown inFigure 7.4.

N

HN

Ph

Ph

Ph

N

O

Ph

Ph

Pd/C, H2 (4.1 bar), 50 oC

CH3OH, HCl or CH3SO3H

1. L-tartaric acid

90% yield, 96% eeN

O

Ph

Ph2. toluene, aq NaOH

1. Ti(OiPr)4, BnNH2, THF Pt/C, H2 (4.1 bar), 12 h

N

NH2

Ph

Ph(2S,3S)-195% yield, 99% ee

2. crystallization: nhexane/toluene 61% yield (from ketone) 99% ee, 99% de

Scheme 7.7 Key quinuclidine intermediate synthesis via stereoselective reductive amination.

83% yld, 72% de

HN

OCH3

81% yld, 78% de 79% yld, 86% de

HO HN

OCH3

HO HN

OCH3

HO

76% yld, 84% de

HN

OCH3

HOHN

OCH3

84% yld, 72% de

HOO

HN

OCH3

89% yld, 76% de

HO

HN

OCH3

84% yld, 80% de

HO

HN

OCH3

77% yld, 80% de

HO

HN

OCH3

87% yld, 72% de

HO HN

OCH3

89% yld, 76% de

HO

Figure 7.4 Examples of aminoalcohol formation via reductive amination.

7.4 Diastereoselective Reductive Amination j235

Lopinavir (Scheme 7.8) and Ritonavir (not shown) areHIV-protease inhibitors thatare often used in combination to treat HIV, and Menche adroitly applied his newmethodology to the core 1,4 chiral diamine building block, which is shared by both ofthese marketed drugs. The synthesis is outlined in Scheme 7.8 and represents theshortest synthesis of this key advanced intermediate to date.

Extending the work of Kim [27], Letourneux and Brunel derivatized 3b-acetoxy-7-keto-5a-cholestane (Scheme 7.9), with ammonia, methylamine, 10 acyclic diamines,and spermine (a tetraamine) forming the corresponding b-aminosteroids [28]. Theamines were tested for their gram-positive bacteria activity versus the known andstructurally related squalamine (not shown).

Optimal conditions required the a-chiral ketone (steroid) to be stirred withTi(OiPr)4 (1.3 equiv) and the amine (3.0 equiv) in a dilute solution of MeOH(0.08 M) over 12 h. The reaction was then cooled to �78 �C, NaBH4 (1.0 equiv)added, and stirred for 2 h [29]. Yields were generally poor (6–45%), except whenmethylamine (77% yield) and 1,2-diethylamine (61% yield) were used. For all13 examples, the diastereoselectivity is reported to be excellent (>95%). No mentionwas made of the lability of the a-chiral stereogenic center adjacent to the ketone,presumably it is resilient to epimerization due to the conformational rigidity affordedby the extended steroid skeleton.

Although the above examples represent a limited breadth of demonstratedapplication, the general methodwould appear to hold promise due to its acceptabilityof labile a-chiral ketones.

O

Ph

1. (+)-Ipc2BCl, Et3N

HBocHN

Ph

O

O

PhBocHN

Ph

OH

p-MeOPhNH2Ti(OiPr)4, PMHS

2.

PhBocHN

Ph

HO HN

OCH3

PhBocHN

Ph

HO NH2

56% overall yld(four steps)

CAN

main building block ofLopinavir

Ph

HN

OHNH

OO

PhLopinavir

(Abbott, HIV-protease inhibitor)

O

NHN

O

Scheme 7.8 Application of aldol/reduction amination strategy – formal synthesis of lopinavir.

MeH

MeRH

HAcO

H O

MeH

MeRH

HAcO

H H

NHR

amine (3.0 equiv)Ti(OiPr)4, 12 h, 25 oC

then cool to -78 oCNaBH4 (1.0 equiv)

Scheme 7.9 Two-stage, no workup ketone to amine synthesis.


7.4.2The Phenylethylamine Auxiliary and Stereoselective Reductive Amination

In 2004 Alexakis independently reported on similar reaction conditions (Ti(OiPr)4/Pd-C/H2) as Nugent [22b, 23], albeit when using chiral amines, for example, phen-ylethylamine (PEA), phenylpropylamine, and so on, to reductively aminate skeletonmatching achiral ketones [30]. By doing so, he synthesized a set of five C2-symmet-rical secondary amines from aryl–alkyl ketones (Figure 7.5). The optimal conditionscalled for neat reaction conditions, equal molar quantities of the achiral ketone andchiral amine, Ti(OiPr)4 (3.0 equiv), Pd-C (0.5mol%), and 1.0 bar (14.5 psi) H2. Noreaction times were reported.

Nugent has published several manuscripts examining a two-step strategy allowingprochiral ketones to be converted into enantioenriched chiral primary amines(Scheme 7.10). The method, initially reported on in 2005 [31], relies on reductiveamination with (R)- or (S)-PEA followed by hydrogenolysis, and has been optimizedfor a large variety of ketone substrate classes. The key innovationwas identification ofthe most efficient Lewis acid/heterogeneous hydrogenation catalyst combination,which in turn allowed the reductive amination of previously unreactive, stericallyhindered ketones in good to excellent yield [31, 32] and led to significantly improvedstereoselectivity for alkyl–methyl ketone substrates [33].

NH

NH

92% yld, 82% de

OMeMeO

NH

N.A. yld, 82% de

NH

90% yld, 88% de

NH

90% yld, 70% de

88% yld, 74% de

Figure 7.5 C2-symmetrical secondary amines via reductive amination.

RL

HN

RS

Ph

RL

HN

RS

Ph

RL

NH2

RS

RL

NH2

RS

(S)-PEA

(R)-PEA

RL RS

O Pd-C,8 bar H2Ti(OR)4 or Yb(OAc)3

Raney Ni, 8 bar (120 psi) H2

(yld and de, see Table 7.2)

H2N Ph

H2N Ph

85–95% yield

Scheme 7.10 Two-step chiral primary amine synthesis – reductive amination followed byhydrogenolysis.


One way of organizing the findings of Nugent is regarding the optimal heteroge-neous hydrogenation catalyst. For example, Raney-Ni, the most broadly applicablecatalyst, allows acyclic alkyl–alkyl0 and aryl–alkyl ketones lacking an sp3-hybridizedquaternary carbon, for example, tert-butylmoiety, attached to the carbonyl carbon, tobereductively aminated with good yield and high diastereoselectivity (Table 7.2). Pt-C isthe optimal hydrogenation catalyst for those alkyl–alkyl0 ketone substrates containingsp3-hybridized quaternary carbons adjacent to the carbonyl moiety (Figure 7.6) [32],while Pd-C is optimal for cyclic aryl–alkyl ketones, for example, tetralone andbenzosuberone (Figure 7.6) [32]. Hydrogenolysis of the reductive amination productprovides the primary amine in very high yielding with uncompromised ee.

When comparing the stereoselectivity of the reductive amination products of (R)-or (S)-PEA, when using Ti(OiPr)4 (1.25 equiv) or Yb(OAc)3 (10mol%) or Y(OAc)3(15mol%) or Ce(OAc)3 (15mol%) or Brønsted acids (catalytic or stoichiometric, e.g.,AcOH), the de of the amine product is the same. Furthermore, taking the ketonesused for these reductive amination studies and intentionally preforming andisolating the (R)- or (S)-PEA ketimines (Dean–Stark trap synthesis) and reducingthem in the same manner, albeit without the presence of the Lewis acid or Brønstedacid, the de is the same as that found for the reductive amination [34].

In stark contrast to these stereochemical trends, 2-alkanones without branching atthe a- or b-carbons, for example, 2-octanone or benzylacetone (Table 7.2), can be

Table 7.2 Raney-Ni substrate classes and optimal acid catalysts for stereoselective reductiveamination with phenylethylamine (Scheme 7.10 – Step 1).

Ketone classes Specific examples Yield (%) de (%) Acid cat.a) Comment

RL CH3

O RL¼ iPr 78 98 Ti(OiPr)4 Viable alternative AcOHb)

RL¼ chexyl 90 98 Ti(OiPr)4 Viable alternative AcOHb)

RL¼Ph 85 95 Ti(OiPr)4 Other catalysts – lower yieldc)

RL RS

O RL¼Ph; RS¼ nPr 92 94 Ti(OiPr)4d) Other catalysts <30%

product yieldRL¼ iPr; RS¼ nPr 75 87 Ti(OiPr)4

e) Other cat <20% product yieldRL¼ iPr; RS¼ nBu 80 88 Ti(OiPr)4

e) Other cat <20% product yield

RM CH3

O

RM¼ iBu 79 93 Ti(OiPr)4 Viable alternative AcOHf)

RM¼ –CH2CH2Ph 87 89 Yb(OAc)3 Other catalysts - low de

RS CH3

ORS¼ nhexyl 86 87 Yb(OAc)3 Other catalysts - low deRS¼ nbutyl 82 85 Yb(OAc)3 Other catalysts - low de

a) Unless otherwise noted, reaction conditions are as follows: Ti(OiPr)4 (1.25 equiv) or Yb(OAc)3(0.80–1.1 equiv), Raney-Ni (100wt% of limiting reagent – ketone), (S)- or (R)-PEA (1.1 equiv),22 �C, 8 bar (120 psi) H2, 12 h.

b) The use of 20mol% AcOH, in MeOH, allows very similar results, but only at 50 �C and 20 bar(290 psi) H2.

c) Optimal conditionswithAcOH (20mol%), 50 �C, 30 bar (435 psi), andMeOHprovide 55%yield,93% de.

d) Reaction conditions: 35 �C, 8 bar (120 psi) H2, and 15 h.e) Reaction conditions: 3.0 equiv Ti(OiPr), 60 �C, 8 bar (120 psi) H2, 36 h.f) The use of 20mol%AcOH inMeOHallows very similar results, but only at elevated temperature

(50 �C).


reductively aminated with significantly higher diastereoselectivity when usingstoichiometric quantities (80–110mol%) of Yb(OAc)3 [33].

Finally, some general observations were noted by Nugent regarding reductiveamination with phenylethylamine that are likely to be general in nature. Failure tohave the optimal Lewis acid or Brønsted acid, or no acid at all, results in gross alcoholby-product formation. For example, regarding 2-alkanones, alcohol by-productformation is suppressed below 3% when employing catalytic quantities of Lewisacids [Yb(OAc)3 (10mol%) or Y(OAc)3 (15mol%) or Ce(OAc)3 (15mol%)] or catalyticor stoichiometric quantities of a weak Brønsted acid, for example, AcOH [33].Application of the above-mentioned Lewis acids or Brønsted acids in catalytic orstoichiometric quantities for the reductive amination of aryl–alkyl ketones or verysterically hindered alkanones, for example, i-propyl n-propyl ketone, results in grossalcohol formation, for these substrates Ti(OiPr)4 is required (Table 7.2) [32].

GlaxoSmithKline chemists Gudmundsson and Xie recently reported on a newdrug candidate for the treatment of human papillomavirus (HPV) associated withinfection of the genitalmucosa, in high-risk scenarios cervical cancer results [35]. Theinitial approach focused on racemic primary amine formation followed by prepar-ative chiral supercritical fluid chromatography (SFC) to separate the enantiomers. Toenable racemic primary amine formation (not shown), the ketone (structure shownin Scheme 7.11) was reductively aminated with NH4OAc/NaBH3CN over 15 h at60 �C, providing the amine in 52% yield. This initial resolution approach failedbecause solubility problems hampered the use of SFC separation, and attempts atclassical chemical resolution with an array of chiral acids failed to provide high eewith high yield recovery.

Moving to asymmetric methods, they found Noyori�s enantioselective transferhydrogenation employing HCO2NH4, Ru(II), and DPEN-based ligands reductivelyaminated (not shown) the same ketone providing the enantioenriched primaryamine in 80% ee and 60% yield. They additionally synthesized the corresponding

O O

O O

Yb(OAc)3 (10 mol%) 77% yld, 92% de Ti(OiPr)4 (1.25 equiv)

79% yld, 92% de

Ti(OiPr)4 (1.25 equiv)76% yld*, 92% ee

Ti(OiPr)4 (1.25 equiv)64% yld*, 76% ee

Ti(OiPr)4 (1.25 equiv) 79% yld, 87% de

* overall yield (ketone to primary amine)

Pt-C substrates

Pd-Csubstrates

Figure 7.6 Substrates requiring Pd-C or Pt-C with phenylethylamine.


imine, from ammonia, and then applied the earlier discussed Kadyrov conditions(Section 7.2).With this imine substrate, themodifiedKadyrov conditions provided an82% ee, but with an unacceptable impurity profile.

Gudmundsson and Xie then turned their attention to the often used industrialchiral ammonia equivalents: (R)- and (S)-1-(phenyl)ethylamine (PEA), which are alsocommonly referred to as (R)- or (S)-a-methylbenzylamine (a-MBA). Reductiveamination with (R)-PEA or the (R)-1-(4-methoxyphenyl)ethylamine derivative re-sulted in the desired major diastereomer, 90% de (Scheme 7.11, R¼H) and 92% de(Scheme 7.11, R¼OMe) respectively. On the kilogram scale, they found it morereliable to use a two-stage, no workup procedure, first forming the imine (toluene/Dean–Stark trap, 10 h) and then without workup for (R)-1-(4-methoxyphenyl)ethy-lamine, added EtOH, cooled to�30 �C, and stirred for 12 hwithNaBH4 (1.0 equiv). Itis typical that process development chemists design and screen workup conditionsallowing the product to be obtained in higher de or ee than the reaction provides. Thiscasewas no different and attention to theworkup allowed the desired diastereomer tobe isolated in multi-kilogram quantities in >99% ee as the HCl salt for both (R)-1-(phenyl)ethylamine (86% yield) and (R)-1-(4-methoxyphenyl)ethylamine (82% yield).The corresponding primary amine was their target, but attempts at N-debenzylationvia the common hydrogenolysis route (Pd, Ru, or Rh/H2) failed due to the sensitivityof the tetrahydrocarbazole moiety. This problem was overcome, at the 13.5 kg scale,by treatmentwith BCl3 (2.5 equiv) inCH2Cl2, resulting in an 81%yield of the primaryamine in >99% ee.

7.4.3The tert-Butylsulfinamide Auxiliary and Stereoselective Reductive Amination

In 1999, the group of Ellman demonstrated a two-stage, no workup ketone to aminesynthesis [36]. This was achieved by adding the (S)- or (R)-tert-butylsulfinamideauxiliary, [t-BuS(O)NH2], limiting reagent, to the ketone (1.2 equiv) and Ti(OEt)4 (2.0equiv) in THF. After heating (60–75 �C, usually 10–19 h), the resulting sulfinyl imine

Cl

NH

NH2

Cl

NH

O

Cl

NH

NH

ON

Cl

NH

NH

imine formation(toluene reflux)

R

then cool to -30 oCNaBH4 (1.0 equiv)

BCl3 (2.5 equiv)CH2Cl2

acylation

Drug candidate forhuman papillomavirus

R= OMe, 82% yld, >99% ee

Scheme 7.11 Reductive amination as a key step in drug development.


(TLC examination) is cooled to�48 �C and then transferred via cannula to a�48 �CTHF suspension of NaBH4 (4 equiv). In 2007, he updated the substrate breadth andreported how the method could be simplified to a stereodivergent method requiringonly one enantiomer of the chiral amine auxiliary, tert-butylsulfinylamide, by usingeither NaBH4 (4.0 equiv) or L-Selectride (3.0 equiv) to provide the epimeric sulfinylamine product (Figure 7.7) [37]. Regardless of the reductant used, �48 �C was theoptimal temperature for reduction. In addition to the shownketone substrates, p-NO2

and p-MeO tetralone substrates (not shown) also provided the sulfinyl amine productin good yield and high de. The corresponding primary amine is easily obtained byremoval of the sulfinyl auxiliary under acid conditions, commonly HCl in dioxane atroom temperature.

It is well established that control of peptide conformation allows the tertiarystructure vital for enzyme activity. Unnatural a- and b-amino acids are particularlyuseful in this regard for designing peptides with controlled conformation and thustargeted function, but amino acid mimics have also been put to good effect in thisregard. This was the goal of Pannecoucke when he successfully synthesized en-antiopure monofluorinated allylic amines as site-specific amino acid mimics inpeptides (Scheme 7.12) [38].

Employing the stereodivergent strategy of Ellman to a-fluoroenones, a one-potketone to amine synthesis (two-stage procedure, no workup) allowed the productionof either diastereomer from only one chiral amine source, (S)-tert-butylsulfinamide(Scheme 7.12) Pannecoucke reported that no benefit came from first isolating thechiral sulfinyl imine, thus the sulfinyl imine was formed (2 h of THF reflux),subsequently cooled (�78 �C), and then reduced using a source of hydride. Thereduction step was complete within 1–2 h, regardless of the chosen reductant. Thisapproach provided moderate to good yield (46–86% yield) with excellent diastereos-electivity (94–98%). In most cases, the diastereomeric excess could be increased viasilica gel chromatography. The reported �R� groups were aromatic (p-MeOPh-) andalkyl (PhCH2CH2- and TBDPSiOCH2CH2- and TBDPSiOCH2CH(CH3)-).

Coordinating reductants, for example, NaBH4, BH3, 9-BBN, and DIBAL-H,provided the same stereochemistry as that of the stereogenic sulfur atom of the

Ph

O

O

tBu iPr

O O O

O O O

N: 100%, 16% de L: 49 %, 76% de

N: 80%, 68% de L: 83%, 98% de

N: 28%, 98% de L: 27%, 96% de

N: 78%, 92% de L: 89%, 94% de

N: 62%, 98% de L: 83%, 92% de

N: 66%, 94% de L: 76%, 92% de

N: 74%, 84% de L: 70%, 92% de

N: 82%, 66% de L: 72%, 72% de

R R

HNS

tBu

iBu nBuO

genric Ellmanproduct

N = NaBH4, major prod = (RS,R)

L= L-Selectridemajor prod = (RS,S)

'

Figure 7.7 Stereodivergent amine synthesis: reductant-directed diastereomeric productformation with the (R)-tert-butylsulfinamide auxiliary.


F RHO

L-S

elec

trid

e(3

.0 e

quiv

)

Ti(O

iPr)

4, T

HF

65 o C

, 2 h

F RHN

SB

u

O

(S)-

tBuS

(O)N

H2

(2.0

equ

iv)

cool

to

DIB

AL-

H(4

.0 e

quiv

)F

R HN H

StB

u

O

FR H

N H

StB

u

O-7

8 oC

F RHNH

2

NR

HNH

2

O

tran

soid (S

)-Z

-am

ino

acid

mim

icpe

ptid

e pr

ecur

sor

4 N

HC

ldi

oxan

e

F RHNH

2

NR

HNH

2

O

tran

soid (R

)-Z

-am

ino

acid

mim

icpe

ptid

e pr

ecur

sor

F HRO

repe

at a

sbe

low

F HRNH

2

NH

RNH

2

O

ciso

id

(S)-

E-a

min

o ac

idm

imic

pept

ide

prec

urso

r

DIB

AL-

H

4 N

HC

ldi

oxan

e

Tw

o-st

age,

no

wor

kup,

ket

one

to a

min

e sy

nthe

sis

E-

-flu

oroe

none

α

Z-

-flu

oroe

none

α F HRO

E-

-flu

oroe

nonere

peat

as

abov

eF H

RNH

2

NH

RNH

2

O

ciso

id

(R)-

E-a

min

o ac

idm

imic

pept

ide

prec

urso

r

L-S

elec

trid

e

α

Scheme7.12

Functio

nalized

chiral

aminesynthesis:am

inoacid

mim

icsforpe

ptides.


tert-butylsulfinamide auxiliary, while �noncoordinating� reductants, for example,LiBHEt3, K-Selectride, and L-Selectride provided the epimeric product. DIBAL-HandL-Selectride were the reductants of choice, allowing, after HCl in dioxane removal ofthe sulfinyl moiety, either enantiomer of the primary amine to be formed.

7.5Conclusions

Two important, but rarely discussed, challenges regarding chiral amine synthesis areevaluation of reaction step efficiency from commodity chemical (startingmaterial) tofinal chiral primary amine product; and, second, the ability to install a nitrogen atomwhile leaving a broad array of coexisting functional groups unchanged. The formerpoint is addressed by using a reductive amination strategy, but the latter still needs tobe explored. Future demonstration of broad functional group compatibility, takenwith the standard concerns of good yield and high enantiomeric excess, will allowasymmetric reductive amination to be considered as a reliable and preparativemethod capable of delivering functional group rich chiral amine building blocksthat are �drug� like.

Questions

7.1. (a) Draw the mechanism for the reductive amination of 2-butane with(R)-phenylethylamine in the presence of acetic acid, Raney-Ni/H2.

(b) What role is Ti(iOPr)4 fulfilling when it replaces a Brønsted acid inreductive amination?

7.2. Provide two features of reductive amination that have stalled progress whenusing transition metals.

7.3. (a) Three main sources of nitrogen are used by the methodologies outlined inthis chapter: aniline and its substituted derivatives, phenylethylamine, andtert-butylsulfinamide. Which is considered genotoxic?

(b) The introduction of chiral amines into advanced building blocks must becompatible with coexisting functional groups on the ketone starting ma-terial. Additionally, a chiral primary amine is often required for furtherelaboration to a chiral amine-based pharmaceutical drugs or natural pro-duct. The reductive amination of ketones with aniline derivatives (e.g.,p-anisidine), phenylethylamine, and tert-butylsulfinamide provides facileaccess to chiral amine products, but these products do not become valuableuntil they are deprotected to the corresponding chiral primary amines.Provide the three different deprotection conditions required for the men-tioned sources of nitrogen.

7.5 Conclusions j243

References

1 (a) Tararov, V.I. and B€orner, A. (2005)Synlett, 203–211; (b) Tararov, V.I., Kadyrov,R., Riermeier, T.H., Fischer, C., andB€orner, A. (2004) Adv. Synth. Catal., 346,561–565.

2 Blaser, H.-U., Buser, H.-P., Jalett, H.-P.,Pugin, B., and Spindler, F. (1999) Synlett,867–868.

3 (a) Pouy, M.J., Leitner, A., Weix, D.J.,Ueno, S., and Hartwig, J.F. (2007) Org.Lett., 9, 3949–3952; (b) Hou, G.-H., Xie,J.-H., Wang, L.-X., and Zhou, Q.-L. (2006)J. Am. Chem. Soc., 128, 11774–11775;(c) Blaser, H.-U., Buser, H.-P., Coers, K.,Hanreich, R., Jalett, H.-P., Jelsch, E.,Pugin, B., Schneider, H.-D., Spindler, F.,and Wegmann, A. (1999) Chimia, 53,275–280; (d)Markó, L. and Bakos, J. (1974)J. Organomet. Chem., 81, 411–414.

4 For literature pertaining to the origins anddefinition of reductive amination, see(a) Emerson, W.S. (1948) Org. React., 4,174; (b) Moore, M.L. (1949) Org. React., 5,301; (c) Smith, M.B. and March, J. (eds.)(2001) March�s Advanced OrganicChemistry, 5th edn, John Wiley & Sons,Inc., New York, pp. 1187–1189.

5 Similarly, direct asymmetric reductiveamination is discouraged and should bereplaced by the shorter and more accuratephrase asymmetric reductive amination orenantioselective reductive amination.

6 (a) Kadyrov, R., Riermeier, T.H.,Dingerdissen, U., Tararov, V.I., andB€orner, A., (2003) J. Org. Chem., 68,4067–4070; (b) Kitamura, M., Lee, D.,Hayashi, S., Tanaka, S., andYoshimura,M.(2002) J. Org. Chem., 67, 8685–8687.

7 (a) Koszelewski, D., Lavandera, I., Clay, D.,Guebitz, G.M., Rozzell, D., andKroutil,W.(2008) Angew. Chem., Int. Ed., 47,9337–9340; (b) H€ohne, M., K€uhl, S.,Robins, K., and Bornscheuer, U.T. (2008)ChemBioChem, 9, 363–365.

8 To fully appreciate a great story ofperseverance and know-how at Solviasregarding the dynamics of developing acatalytic enantioselective process forindustrial scale production, see Blaser,H.-U. (2002) Adv. Synth. Catal., 344,17–31.

9 Chi, Y., Zhou, Y.-G., and Zhang, X. (2003)J. Org. Chem., 68, 4120–4122.

10 The reader is referred to the followingcitations to better appreciate the role ofiodine: (a) Xiao, D. and Zhang, X. (2001)Angew. Chem., Int. Ed., 40, 3425–3428;(b) Spindler, F. and Blaser, H.-U. (1999)Enantiomer, 4, 557–568; (c) Togni, A. (1996)Angew. Chem., Int. Ed. Engl., 35,1475–1477.

11 (a) Kadyrov, R. and Riermeier, T.H. (2003)Angew. Chem., Int. Ed., 42, 5472–5474;(b) B€orner, A., Dingerdissen, U., Kadyrov,R., Riermeier, T.H., and Tararov, V. (2004)Method for the production of amines byreductive amination of carbonylcompounds under transferhydrogenationconditions, U.S. Patent No. 2004267051,Degussa AG, Germany.

12 Riermeier, T., Haack, K.-J., Dingerdissen,U., Boerner, A., Tararov, V., andKadyrov, R.(2005) Method for producing amines byhomogeneously catalyzed reductiveamination of carbonyl compounds, U.S.Patent No. 6884887, Degussa AG,Germany.

13 Rubio-P�erez, L., P�erez-Flores, F.J.,Sharma, P., Velasco, L., and Cabrera, A.(2009) Org. Lett., 11, 265–268.

14 Li, C., Villa-Marcos, B., and Xiao, J. (2009)J. Am. Chem. Soc., 131, 6967–6969.

15 Hoffmann, S., Seayad, A.M., and List, B.(2005) Angew. Chem., Int. Ed., 44,7424–7427.

16 We were unable to locate the number ofequiv used in the text or SupportingInformation.

17 We were unable to locate the wt% of 4 A�

molecular sieves used in the text or theSupporting Information.

18 Hoffmann, S., Nicoletti, M., and List, B.(2006) J. Am. Chem. Soc., 128,13074–13075.

19 Marcelli, T., Hammar, P., and Himo, F.(2009) Adv. Synth. Catal., 351, 525–529.

20 Storer, R.I., Carrera, D.E., Ni, Y., andMacMillan, D.W.C. (2006) J. Am. Chem.Soc, 128, 84–86.

21 Malkov, A.V., Ston�cius, S., and Ko�covsk�y,P. (2007) Angew. Chem., Int. Ed., 46,3722–3724.


22 (a) Nugent, T.C. and Seemayer, R. (2006)Org. Process. Res. Dev., 10, 142–148;(b) Nugent, T.C. and Seemayer, R. (2004)Process for the preparation of (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine,Patent No. WO2004035575, PfizerProducts, Inc. and DSM Pharmaceuticals,Inc.

23 The method was used as a trade secretwithin Catalytica/Pfizer since 1998, seecitation [19] of reference [22a].

24 Mattson, R.J., Pham, K.M., Leuck, D.J.,and Cowen, K.A. (1990) J. Org. Chem., 55,2552–2554.

25 For recent publications by Bhattacharyya,see (a) Bhattacharyya, S. and Kumpaty, H.(2005) J. Synthesis, 2205–2209; (b)Miriyala,B., Bhattacharyya, S., and Williamson, J.S.(2004) Tetrahedron, 60, 1463–1471; (c)Neidigh, K.A., Avery, M.A., Williamson,J.S., and Bhattacharyya, S. (1998) J. Chem.Soc., Perkin Trans.1, 2527–2532.

26 Menche,D., Arikan, F., Li, J., andRudolph,S. (2007) Org. Lett., 9, 267–270.

27 Kim, H.S., Cho, N.J., and Khan, S.N.(2008) 7-alpha-aminosteroid derivatives orpharmaceutically acceptable salts thereof,preparation method thereof andcomposition for anticancer or antibioticscontaining the same as an activeingredient, Patent No. WO038965 A1(South Korea).

28 Loncle, C., Salmi, C., Letourneux, Y., andBrunel, J.M. (2007) Tetrahedron, 63,12968–12974.

29 For an example of another chiral ketonereductively aminated with Ti(OiPr)4 or Al(OiPr)3 with hydride reagents, seeDhainaut, J., Leon, P., Lhermitte, F., andOddon, G.(May 2003) A process which is

useful for converting the carbonylfunction in position 400 of the cladinoseunit of an aza-macrolide into an aminederivative, U.S. Patent No. 6,562,953(Merial, France).

30 Alexakis, A., Gille, S., Prian, F., Rosset, S.,and Ditrich, K. (2004) Tetrahedron Lett., 45,1449–1451.

31 Nugent, T.C., Wakchaure, V.N., Ghosh,A.K., and Mohanty, R.R. (2005) Org. Lett.,7, 4967–4970.

32 Nugent, T.C., Ghosh, A.K., Wakchaure,V.N., andMohanty, R.R. (2006) Adv. Synth.& Catal., 348, 1289–1299.

33 Nugent, T.C., El-Shazly, M., andWakchaure, V.N. (2008) J. Org. Chem., 73,1297–1305.

34 The outlined Nugent reductive aminationprotocol with (R)- or (S)-PEA and prochiralalkyl–alkyl0 and aryl–alkyl ketones (acyclicor cyclic) allows higher yields and shorterreaction times than the previouslypracticed two-step strategy via isolated (R)-or (S)-PEA, see: Moss, N., Gauthier, J., andFerland, J.-M., (1995) Synlett, 142–144;(b) Cimarelli, C. and Palmieri, G. (2000)Tetrahedron: Asymmetry, 11, 2555–2563.

35 Boggs, S.D., Cobb, J.D., Gudmundsson,K.S., Jones, L.A.,Matsuoka, R.T.,Millar, A.,Patterson, D.E., Samano, V., Trone, M.D.,Xie, S., andZhou, X.-M. (2007)Org. ProcessRes. Dev., 11, 539–545.

36 Borg, G., Cogan, D.A., and Ellman, J.A.(1999) Tetrahedron Lett., 40, 6709–6712.

37 Tanuwidjaja, J., Peltier, H.M., and Ellman,J.A. (2007) J. Org. Chem., 72, 626–629.

38 Dutheuil, G., Couve-Bonnaire, S., andPannecoucke, X. (2007) Angew. Chem., Int.Ed., 46, 1290–1292.

References j245

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Chiral Amine Synthesis (Methods, Developments and Applications) || Asymmetric Reductive Amination