Trading N and O. Part 3: Synthesis of 1,2,3,4-tetrahydroisoquinolines from α-hydroxy-β-amino esters

Tetrahedron 72 (2016) 2139e2163

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Trading N and O. Part 3: Synthesis of 1,2,3,4-tetrahydroisoquinolines

from

a-hydroxy-b-amino esters

*

Stephen G. Davies , Ai M. Fletcher, Aileen B. Frost, Matthew S. Kennedy,

Paul M. Roberts, James E. Thomson

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansﬁeld Road, Oxford, OX1 3TA, UK

a r t i c l e i n f o

a b s t r a c t

Article history:

A range of enantiopure 1,2,3,4-tetrahydroisoquinolines have been prepared directly from a-hydroxy-b-

Received 12 January 2016

Received in revised form 17 February 2016

Accepted 1 March 2016

amino esters. Activation of the

a-hydroxy group upon treatment with Tf₂O and 2,6-di-tert-butyl-4-

methylpyridine promotes aziridinium formation, which is then followed by rupture of the C(3)eN

bond and FriedeleCrafts alkylation-type cyclisation of an N-benzyl moiety onto the resultant benzylic

carbenium ion. The nature of the N-protecting group was varied and it was found that superior yields

were obtained for reactions employing two benzylic groups. In the cases where two different N-benzyl

groups were used, the regioselectivity resulting from competitive cyclisation of either N-benzyl group

was addressed by the introduction of a p-triﬂuoromethyl group on one of the N-benzyl moieties, which

retarded the rate of cyclisation via this electron poor aryl ring. This methodology was employed in the

asymmetric synthesis of a range of enantiopure 1,2,3,4-tetrahydroisoquinolines, which were isolated in

good yields as single diastereoisomers.

Available online 2 March 2016

Keywords:

Tetrahydroisoquinoline

a

-Hydroxy-b-amino ester

Aziridinium

Asymmetric synthesis

1. Introduction

for tetrahydroisoquinoline formation have been reported in recent

years, including CeH activation strategies,¹¹acid-catalysed cyclisa-

The tetrahydroisoquinoline (or, more formally, 1,2,3,4-

tetrahydroisoquinoline)¹motif 1 is highly prevalent in many alka-

loids and potential therapeutic agents, which often exhibit signif-

icant biological activity.²For example, (ꢀ)-(S)-cherylline 2, which

was isolated from plants from the Amaryllidaceae family, and

(ꢁ)-nomifensine 3 are representative examples of 4-aryl tetrahy-

droisoquinolines which are known to have central nervous system

activity. (ꢁ)-Nomifensine 3 is a monoamine reuptake inhibitor with

unique dual activity at the norepinephrine and dopamine trans-

porters.³Its maleate salt was marketed as an anti-depressant in the

1970s (Merital)⁴and has also been used in the treatment of ADHD;³

it shows enantioselective pharmacological activity with the (S)-

enantiomer being the eutomer.⁵(ꢀ)-Lycorine 4, another alkaloid

from the Amaryllidaceae family,⁶is a potent anti-cancer agent⁷

known for its anti-proliferative properties as well as being an in-

hibitor of protein synthesis in eukaryotic cells (Fig. 1).⁸Classic syn-

thetic methods to access tetrahydroisoquinoline molecular scaffolds

include the BischlereNapieralski synthesis⁹and PicteteSpengler re-

action,¹⁰but substantial efforts into the development of new methods

tions¹²and Lewis acid promoted FriedeleCrafts type reactions,¹³

amongst others.¹⁴

* Corresponding

(S.G. Davies).

author.

E-mail

address:

steve.davies@chem.ox.ac.uk

Fig. 1. The tetrahydroisoquinoline motif 1 and examples of biologically active tetra-

hydroisoquinolines 2e4.

http://dx.doi.org/10.1016/j.tet.2016.03.008

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S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

As part of our previous studies into the asymmetric synthesis of

substituted anti-

-ﬂuorophenylalanines,¹⁵we developed a reaction

isolated in 15% combined yield (Scheme 2). Herein, we report our

b

attempts to optimise these procedures for the selective formation

of tetrahydroisoquinolines and develop a general asymmetric

protocol for the synthesis of enantiopure tetrahydroisoquinolines

for the rearrangement and deoxoﬂuorination of

a-hydroxy-b-

amino esters. For example, treatment of 5 with XtalFluor-E^Òand

Et₃N$HF promoted formation of the corresponding aziridinium ion

7, which then underwent regioselective ring-opening at the C(3)-

from a-hydroxy-b-amino esters.

position with ﬂuoride to give

b-ﬂuoro-a-amino ester 9 in 81%

yield and >99:1 dr. However, application of this protocol to the p-

methoxy bearing analogue 6 resulted in the formation of an

80:12:8 mixture of b-ﬂuoro-a-amino ester 10 and the regioisomeric

tetrahydroisoquinolines 12 (>99:1 dr) and 13 (>99:1 dr), re-

spectively, from which 10 was isolated in 44% yield and >99:1 dr,

and a 68:32 mixture of 12 and 13 was isolated in 8% combined yield

(Scheme 1). In the latter case, the regioisomeric mixture of tetra-

hydroisoquinolines 12 and 13 is presumably formed as a result of

rupture of the C(3)eN bond within aziridinium intermediate 8 to

give the corresponding benzylic carbenium ion 11 (which is assis-

ted by the presence of the electron donating p-methoxy group),

followed by competitive FriedeleCrafts alkylation-type cyclisation

via either the N-

a-methylbenzyl or N-benzyl groups, respectively.

Scheme 2.

2. Results and discussion

2.1. Preliminary studies

Our initial studies towards the development of an efﬁcient

protocol for the preparation of tetrahydroisoquinolines were con-

ducted using N,N-dibenzyl substituted anti-a-hydroxy-b-amino

esters, as cyclisation of either N-benzyl group would lead to the

same product and avoid mixtures of regioisomers being formed.

Reaction of the known racemic N,N-dibenzyl substituted

a-hy-

droxy-

b

-amino ester anti-15¹⁶with 3.0 equiv of Tf₂O in the pres-

ence of 6.0 equiv of Et₃N gave a complex mixture of products from

which only tetrahydroisoquinoline 16 was isolated in 37% yield and

>99:1 dr. 2,6-Di-tert-butyl-4-methylpyridine (DTBMP) was

employed next, as this base is often used alongside Tf₂O,¹⁷and in

polymerisation reactions as its steric bulk prevents it from reacting

with carbocationic intermediates.¹⁸Reaction of 15 with 3.0 equiv of

Tf₂O and 6.0 equiv of DTBMP enabled the isolation of 16 in 58% yield

and >99:1 dr. However, optimised conditions were found by de-

creasing the equivalents of Tf₂O and DTBMP to 1.5 and 3.0, re-

spectively; this resulted in the exclusive formation of 16 as a single

diastereoisomer (>99:1 dr), which was isolated in 76% yield

(Scheme 3). The relative anti-conﬁguration within 16 was initially

Scheme 1.

In a related study concerning the synthesis of

amino acids from -hydroxy- -amino esters (which also proceeds

via the intermediacy of the corresponding aziridinium ions),¹⁶we

observed that treatment of -hydroxy- -amino ester 6 with Ms₂O

followed by the addition of H₂O after 1 min gave an 89:6:5 mixture

of -hydroxy- -amino ester 14 and tetrahydroisoquinolines 12 and

b-hydroxy-a-

a

b

a

b

a

13, respectively, from which only 14 was isolated in 55% yield and

>99:1 dr. However, treatment of 6 with Ms₂O followed by the ad-

dition of H₂O after 1 h gave a 23:43:34 mixture of 14, 12 and 13,

respectively, from which only a 55:45 mixture of 12 and 13 was

3

established by ¹H NMR J_3,4coupling constant analysis¹⁹

(³J_3,4¼3.0 Hz) and this assignment was then conﬁrmed un-

ambiguously via single crystal X-ray diffraction analysis (Fig. 2).²⁰

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2141

Scheme 3.

Scheme 4.

as the phenyl and ester substituents experience unfavourable steric

interactions. Collapse of conformer 23B to give syn-tetrahy-

droisoquinoline 20 would be accompanied by an increase in steric

strain, so ring-closure in this case is presumably slower than ring-

closure of conformer 23A. This allows rotation around the C(2)‒

C(3) bond to occur at a competitive rate, alleviating the steric strain

and producing conformer 23A, for which trapping with an N-ben-

zyl group is fast. Thus, a 59:41 mixture of anti-16 and syn-20, re-

spectively, is formed upon reaction of syn-19. Upon reaction of anti-

15, cyclisation of 23A presumably occurs faster than C(2)‒C(3) bond

rotation and high diastereoselectivity is therefore observed in this

case (Fig. 3).

Fig. 2. X-ray crystal structure of (RS,RS)-16 (selected H atoms are omitted for clarity).

A sample of the epimeric

a

-hydroxy-

b

-amino ester, syn-19, was

prepared from the known -hydroxy-

a

b-amino ester (2S,3R,a

R)-18²¹

via hydrogenolysis and chemoselective N-benzylation, which gave

an enantiopure sample of syn-19 in 45% yield (from 18) and >99:1

dr.²²Reaction of syn-19 with Tf₂O and DTBMP (i.e., under the

optimised conditions for the formation of tetrahydroisoquinoline

anti-16 from anti-15) gave a 59:41 mixture of anti-16 and syn-20,

respectively, which were isolated in 84% combined yield

(Scheme 4). The relative conﬁguration within syn-20 was assigned

based on the diagnostic value of the ¹H NMR ³J coupling constant

observed between the C(3)H and C(4)H protons (³J_3,4¼6.1 Hz).¹⁹

The results of both of these reactions are consistent with our

proposed mechanism for tetrahydroisoquinoline formation. Upon

activation of the hydroxyl group within a-hydroxy-b-amino ester

anti-15, aziridinium anti-21 is formed [with inversion of conﬁgu-

ration at C(2)]; subsequent rupture of the C(3)eN bond generates

the corresponding benzylic carbenium ion 23 in conformation 23A,

which undergoes rapid ring-closure [with retention of conﬁgura-

tion at C(3)] to give anti-tetrahydroisoquinoline 16 as a single di-

astereoisomer. For syn-19, however, treatment with Tf₂O results in

the formation of aziridinium syn-22. In this case, rupture of the

C(3)eN bond gives the corresponding benzylic carbenium ion in

conformation 23B, which is presumably higher in energy than 23A

Fig. 3. Proposed mechanism for tetrahydroisoquinoline formation.

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S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

The substrate scope of this methodology was investigated next.

The substituents around the C(3)-aryl ring were varied in order to

evaluate their impact on the cyclisation reaction, and to see if these

results corroborate our proposed mechanism.

esters 29e33 were prepared in 37e69% yield and >99:1 dr in each

case upon conjugate addition of lithium N,N-dibenzylamide to a,b-

a-Hydroxy-b-amino

unsaturated esters 24e28,²³followed by oxidation of the in-

termediate lithium (Z)-

b

-amino enolates²⁴with (ꢀ)-camphorsulfo-

nyloxaziridine

[(ꢀ)-CSO]

according

to

our

standard

aminohydroxylation procedure.^25e27The relative anti-conﬁgura-

tions within

a-hydroxy-b-amino esters 29e33 were established

upon inspection of the diagnostic values of their ¹H NMR ³J coupling

constants (³J_2,3¼3.0e4.4 Hz).²⁸Furthermore, in the case of the m-

methoxy substituted a-hydroxy-b-amino ester 31, this assignment

was conﬁrmed unambiguously via single crystal X-ray diffraction

analysis (Fig. 4).²⁰Upon application of the conditions for tetrahy-

droisoquinoline formation (i.e., treatment with Tf₂O and DTBMP at

rt for 6 h), reaction of

a

-hydroxy-

b

-amino esters 31 (R¼m-OMe) and

32 (R¼p-F) promoted full conversion to tetrahydroisoquinolines 36

and 37, respectively, which were isolated in 57 and 73% yield, and

>99:1 dr in both cases. It was found that increasing the electron

withdrawing ability of the substituent on the C(3)-aryl ring also

Scheme 5. [^a>99:1 dr [(E):(Z)]; ^bYield in parentheses corresponds to the reaction that

resulted in formation of a

(R¼m-F) under the standard reaction conditions gave a 73:27 mix-

ture of tetrahydroisoquinoline 35 and -hydroxy- -amino ester 40,

from which 35 was isolated in 58% yield and >99:1 dr. For -hy-

droxy- -hydroxy-

-amino ester 29 (R¼p-CF₃), full conversion to

b-hydroxy-a-amino ester: reaction of 30

c

was heated at 40 ^ꢂC for 6 h; The reaction mixture was cooled to ꢀ20 ^ꢂC for 2.5 h].

b

a

These ﬁndings are again consistent with our proposed reaction

mechanism. Both the formation of b-hydroxy-a-amino esters when

b

a-

amino ester 39 was observed, and 39 was isolated in 35% yield and

>99:1 dr after puriﬁcation. The relative anti-conﬁguration within 39

was tentatively assigned by ¹H NMR ³J coupling constant analysis

(³J_2,3¼9.4 Hz),²⁹and by analogy to the stereochemical outcome

observed in related systems.¹⁶However, upon heating the reaction

of 29 (R¼p-CF₃) at 40 ^ꢂC for 6 h an 80:20 mixture of tetrahy-

an electron withdrawing substituent is present on the C(3)-aryl

ring, and the formation of diastereoisomeric mixtures of tetrahy-

droisoquinolines for substrates incorporating a highly electron

donating substituent, are consistent with reaction via a carbenium

intermediate. If an electron withdrawing group is present then

rupture of the C(3)eN bond to give the corresponding benzylic

carbenium ion may be disfavoured, and the aziridinium in-

termediate may instead be preferentially opened by either adven-

droisoquinoline 34 and b-hydroxy-a-amino ester 39 was recovered,

from which 34 was isolated in 62% yield and >99:1 dr. Increasing the

electron density of the C(3)-aryl ring caused a reduction in diastereo-

selectivity, with the reaction of 33 (R¼p-OMe) with Tf₂O and DTBMP

at rt for 6 h giving tetrahydroisoquinoline 38 in 75:25 dr. Cooling

the reaction mixture to ꢀ20 ^ꢂC and reducing the reaction time to

2.5 h gave 38 in 85:15 dr, and 66% isolated yield and 85:15 dr after

chromatographic puriﬁcation (Scheme 5). In all cases, the ¹H NMR

³J_3,4coupling constants observed for the major tetrahy-

droisoquinoline products 34e38 were diagnostic¹⁹of their relative

anti-conﬁgurations (³J_3,4¼2.3e3.3 Hz).

titious water or upon aqueous work-up, to give a

b-hydroxy-a-

amino ester. As good conversion to tetrahydroisoquinoline prod-

ucts can be achieved upon heating the reaction mixture to 40 ^ꢂC in

these cases, this would be consistent with enabling the energetic

barrier for rupture of the C(3)eN bond to be overcome. The re-

duction in diastereoselectivity observed when a strongly electron

donating group is present is consistent with the rate of C(2)‒C(3)

bond rotation becoming competitive with the rate of ring-closure

due to the increased stabilisation of the benzylic carbenium ion.

2.2. Further mechanistic considerations

It was envisaged that ring-closure onto the carbenium ion 44

could proceed via either: (i) cyclisation via the ipso-carbon, to give

a [6,5]-spirocyclic intermediate 45, followed by a 1,2-alkyl shift and

rearomatisation; or (ii) direct cyclisation via the ortho-carbon to give

a [6,6]-bicyclic intermediate followed by rearomatisation (Fig. 5).

These mechanisms were investigated by replacing the N,N-

dibenzylamino fragment with either an N,N-bis(p-methoxybenzyl)-

amino or an N,N-bis(m-methoxybenzyl)amino substituent. Sub-

strates 47 and 49 were selected as model systems for these

investigations due to the relative neutrality³⁰of the C(3)-aryl

substituent, and the additional possibility of analysing the crude

reaction mixtures by ¹⁹F NMR spectroscopy.

ester 47 was prepared in 70% yield and >99:1 dr upon conjugate

addition of lithium N,N-bis(p-methoxybenzyl)amide to -un-

a-Hydroxy-b-amino

a,b

saturated ester 27 followed by oxidation of the intermediate lithium

(Z)-

b

-amino enolate²⁴with (ꢀ)-CSO. The same tandem conjugate

addition/enolate oxidation procedure was attempted for the syn-

Fig. 4. X-ray crystal structure of (RS,RS)-31 (selected H atoms are omitted for clarity).

thesis of 49 although this only gave returned starting material.

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2143

Fig. 5. Possible mechanisms for cyclisation to give tetrahydroisoquinolines. [R¼aryl].

A

stepwise conjugate addition/enolate oxidation protocol was

therefore adopted for the synthesis of 49: conjugate addition of

lithium N,N-bis(m-methoxybenzyl)amide to 27, followed by treat-

ment with saturated aqueous NH₄Cl, gave 48 in 78% yield. Deproto-

nation of 48 followed by oxidation of the resultant lithium (E)-

b

-

Scheme 7. [PMP¼p-methoxyphenyl; MMP¼m-methoxyphenyl].

amino enolate²⁴with (ꢀ)-CSO gave

a-hydroxy-b-amino ester 49 in

24% yield and >99:1 dr (Scheme 6). The relative anti-conﬁgurations

within 47 and 49 were assigned from the diagnostic values of the ¹H

NMR ³J_2,3coupling constants (³J_2,3¼3.9 and 3.8 Hz, respectively).²⁸

iminium intermediate 56 to give 52 (Fig. 6). The relative (RS,SR)-

conﬁguration within 52 was therefore tentatively assigned based

on this mechanistic rationale. When 49 was reacted to form the

regiomeric tetrahydroisoquinolines 50 and 51, however, the cycli-

sation must go via a [6,6]-bicyclic intermediate: the corresponding

spirocyclic intermediate would be expected to be less stable than

55 (due to the absence of the mesomerically electron-donating p-

methoxy group) and therefore undergo fragmentation more readily

than 55, although a b,b-diaryl-a-amino ester was not observed in

this case. This outcome is also consistent with the well-established

ortho/para-directing effect of the methoxy substituent. In the ab-

sence of b,b-diaryl-a-amino esters derived from the N,N-dibenzyl

substituted analogues 15 and 29e33, direct cyclisation to give

a [6,6]-bicyclic intermediate would be a consistent mechanistic

pathway, although the alternative pathway via a spirocyclic in-

termediate cannot be completely excluded.

Scheme 6. [PMP¼p-methoxyphenyl; MMP¼m-methoxyphenyl].

Treatment of 49 (Ar¼MMP) with Tf₂O and DTBMP in CH₂Cl₂at rt

for 6 h gave a 77:23 mixture of two regioisomeric tetrahy-

droisoquinolines 50 and 51, which were separated by ﬂash column

chromatography and isolated as single diastereoisomers in 32 and

10% yield, respectively. The relative anti-conﬁgurations within 50

and 51 were assigned by analogy to those within 16 and 34e38, and

3

these assignments were supported by ¹H NMR J_3,4coupling con-

stant analyses (³J_3,4¼2.8 and 1.7 Hz for 50 and 51, respectively).¹⁹

Treatment of 47 did not result in the formation of any tetrahy-

droisoquinoline products but instead gave

52, which was isolated in 53% yield and >99:1 dr (Scheme 7).

The formation of -diaryl- -amino ester 52 is consistent with

b,b-diaryl-a-amino ester

b,

b

a

cyclisation of benzylic carbenium ion 54 via the ipso-carbon (as

would be expected from the well-established ortho/para-directing

effect of the methoxy substituent) to form spirocyclic intermediate

55, followed by fragmentation³¹and hydrolysis of the resultant

Fig. 6. Proposed mechanism for the formation of

[PMP¼p-methoxyphenyl; Ar¼p-ﬂuorophenyl].

b,b-diaryl-a-amino ester 52.

2144

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2.3. Asymmetric synthesis of 1-methyl-3-(tert-butoxy-

carbonyl)-4-aryl-tetrahydroisoquinolines

With an optimised procedure for the one-pot, diastereoselective

synthesis of tetrahydroisoquinolines derived from racemic N,N-

dibenzyl substituted a-hydroxy-b-amino esters developed, atten-

tion was turned next towards applying this methodology in the

synthesis of enantiopure tetrahydroisoquinolines. As competitive

cyclisation of both the N-

a

-methylbenzyl and N-benzyl groups was

-hydroxy-

previously observed upon reaction of enantiopure

a

b-

amino ester 6¹⁵(leading to mixtures of regioisomeric tetrahy-

droisoquinolines 12 and 13), an alternative protecting group

strategy was required such that only one of the groups on nitrogen

would be able to participate in the cyclisation step. Thus, both the

N-methyl substituted

analogue 62 were initially evaluated in the tetrahydroisoquinoline

forming reaction manifold. -Hydroxy- -amino ester 57 was pre-

pared in 43% yield and >99:1 dr upon conjugate addition of lithium

(R)-N-methyl-N-( -unsaturated ester

-methylbenzyl)amide³²to

27 followed by oxidation of the intermediate lithium (Z)- -amino

a-hydroxy-b-amino ester 57 and the N-allyl

a

b

a

a,b

b

enolate²⁴with (ꢀ)-CSO. The conﬁgurations of the newly formed

C(2) and C(3) stereogenic centres within 57 were assigned by ref-

erence to our transition state mnemonic³³for the conjugate addi-

tion reaction and by analogy to the many other examples of this

aminohydroxylation already reported.²⁶Treatment of 57 with Tf₂O

and DTBMP in CH₂Cl₂at rt for 6 h (i.e., the standard conditions for

tetrahydroisoquinoline formation) gave b-hydroxy-a-amino ester

58 exclusively, and after puriﬁcation 58 was isolated in 35% yield

and >99:1 dr. However, heating the reaction mixture at 40 ^ꢂC for

6 h gave a 27:30:43 mixture of 58, tetrahydroisoquinoline 59 and

styrene 60, respectively, from which a 97:3 mixture of 59 and 60

was isolated in w15% yield, and 60 was isolated in 30% yield, as

single diastereoisomers in each case (Scheme 8). The relative anti-

conﬁguration within 58 was tentatively assigned by ¹H NMR ³J

coupling constant analysis (³J_2,3¼8.7 Hz),²⁹and by analogy to the

stereochemical outcome observed in related systems.¹⁶The con-

ﬁguration of 59 was assigned by analogy to the stereochemical

outcome observed for the tetrahydroisoquinolines derived from all

other N,N-dibenzyl protected substrates investigated. The structure

of 60 was initially determined by ¹H, ¹³C and ¹⁹F NMR spectroscopic

analyses and its relative conﬁguration, as well as its structure, was

then established unambiguously by single crystal X-ray diffraction

analysis (Fig. 7).²⁰Furthermore, the absolute (S,S)-conﬁguration

within 60 was assigned following the determination of a Flack x

parameter³⁴of ꢀ0.010(14) for the structure of 60. The formation of

Scheme 8. [^a97:3 mixture of 59 and 60, respectively].

the conjugate addition reaction and by analogy to the many other

examples of this aminohydroxylation already reported.²⁶Treat-

ment of 62 with Tf₂O and DTBMP in CH₂Cl₂at rt for 6 h (i.e., the

standard conditions for tetrahydroisoquinoline formation) pro-

moted full conversion to tetrahydroisoquinoline 63 as a single di-

astereoisomer (>99:1 dr); following chromatographic puriﬁcation

of the crude reaction mixture, 63 was isolated in 31% yield and

>99:1 dr (Scheme 9). The relative anti-conﬁguration within 63

b-hydroxy-a-amino ester 58 and tetrahydroisoquinoline 59 is

consistent with rearrangement of 57 via an aziridinium in-

termediate. It was proposed that, in turn, styrene 60 was derived

from tetrahydroisoquinoline 59 via a sequence of N-triﬂation to

give ammonium species 61 and subsequent elimination. In support

of this mechanistic hypothesis, the 97:3 mixture of 59 and 60, re-

spectively, was resubjected to the reaction conditions and full

conversion to styrene 60 was observed; this outcome therefore also

supports both the stereochemical assignment of tetrahy-

droisoquinoline 59 and our proposed mechanistic rationale for

tetrahydroisoquinoline formation. Further attempted reaction op-

timisation by reducing the number of equivalents of Tf₂O and

DTBMP was unsuccessful, resulting instead in the formation of

complex mixtures of products.

The corresponding N-allyl substituted

62 was prepared in 78% yield and >99:1 dr upon conjugate addition

of lithium (R)-N-allyl-N-( -un-

-methylbenzyl)amide³⁵to

a-hydroxy-b-amino ester

a

a,b

saturated ester 27 followed by oxidation of the intermediate lith-

ium (Z)-

b

-amino enolate²⁴with (ꢀ)-CSO. The conﬁgurations of the

newly formed C(2) and C(3) stereogenic centres within 62 were

again assigned by reference to our transition state mnemonic³³for

Fig. 7. X-ray crystal structure of (S,S)-60 (selected H atoms are omitted for clarity).

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2145

Scheme 9.

(³J_3,4¼4.4 Hz) was assigned by ¹H NMR ³J coupling constant

analysis.¹⁹

Scheme 10. [^a>99:1 dr [(E):(Z)]; ^bYields in parentheses correspond to reactions that

were heated at 40 ^ꢂC for 24 h].

The substrate scope of this N-allyl substituted series of com-

pounds was next established in the tetrahydroisoquinoline for-

mation reaction manifold.

were prepared in 69e80% yield and >99:1 dr in each case upon

conjugate addition of lithium (R)-N-allyl-N-( -methylbenzyl)am-

ide³⁵to

-unsaturated esters 24e26, 65 and 28, followed by ox-

idation of the intermediate lithium (Z)-

-amino enolates²⁴with

a

-Hydroxy-

b

-amino esters 66e70³⁶

and 77 (³J_2,3¼8.4 Hz),²⁹and tetrahydroisoquinolines 71e74

(³J_3,4¼3.9e4.5 Hz).¹⁹

a

A change in the nature of the non-participating N-protecting

group clearly inﬂuences the reaction outcome and, in the case of

these N-methyl and N-allyl substrates, is detrimental to the for-

mation of the corresponding tetrahydroisoquinolines. As higher

yields, greater substrate scope and cleaner conversion to tetrahy-

droisoquinoline products were observed when both protecting

groups on nitrogen were benzylic, investigations focussed next on

trying to bias the cyclisation of one benzyl group over the other.

Increasing the electron density of the aryl ring of one of the N-

benzyl groups (e.g., upon the introduction of a p-methoxy group)

a,b

b

(ꢀ)-CSO according to our standard aminohydroxylation

procedure.^25e27The relative anti-conﬁgurations within 66e68 and

70 were assigned by reference to our transition state mnemonic³³

for the conjugate addition reaction and by analogy to the well-

established outcome of this aminohydroxylation process, and

3

these assignments were supported by ¹H NMR J_2,3coupling con-

stant analyses (³J_2,3¼3.5e3.8 Hz).²⁸Subjection of 66 (R¼p-CF₃) and

67 (R¼m-F) to the reaction conditions gave 96:4 and 80:20 mix-

was expected to promote the formation of the corresponding

b,b-

tures of the corresponding

b

-hydroxy-

a

-amino esters 76 and 77,

diaryl- -amino ester (vide supra), and in any case this approach

a

and tetrahydroisoquinolines 71 and 72, respectively, from which 76

and 77 were isolated as single diastereoisomers in 31 and 55%

yield; tetrahydroisoquinolines 71 and 72 were also isolated in 3 and

14% yield, respectively, and >99:1 dr in each case. Subjection of 68

(R¼m-OMe) to the reaction conditions gave a 67:34 mixture of

would be inherently limited to syntheses of C(6)-methoxy

substituted tetrahydroisoquinolines, even if it could be deployed

successfully. Instead, it was envisaged that regioselective cyclisa-

tion may be achieved by adding an electron withdrawing group to

the aryl ring of one of the benzyl groups, thus retarding the rate of

cyclisation via the electron poor aryl ring in favour of cyclisation via

the unsubstituted benzyl group. Furthermore, it was envisaged that

by tuning the electron density of the two different N-benzyl groups

tetrahydroisoquinoline 73 and

b-hydroxy-a-amino ester 78, re-

spectively, whereas reaction of the known

a

-hydroxy- -amino es-

b

ter 69^15,36(R¼H) gave tetrahydroisoquinoline 74 exclusively. After

chromatographic puriﬁcation of the crude reaction mixtures, 73

and 74 were isolated in 20 and 32% yield, respectively, and in >99:1

dr in both cases. Upon reaction of 70 (R¼p-OMe) with Tf₂O and

DTBMP in CH₂Cl₂at e20 ^ꢂC for 2.5 h, a complex mixture was pro-

duced, which did not contain any species consistent with either 75

or 80. Attempts to optimise this reaction to promote formation of

the corresponding tetrahydroisoquinoline 75 from 70 were un-

successful, resulting in complex mixtures in all cases. For the re-

in this way the a-methylbenzyl chiral auxiliary may either be in-

corporated into the tetrahydroisoquinoline scaffold [to generate

stereodeﬁned C(1)-methyl substituted tetrahydroisoquinolines] or

not [to generate C(1)-unsubstituted tetrahydroisoquinolines], as

desired. a-Hydroxy-b-amino ester 83 (which incorporates a p-CF₃

group on the aryl ring of the N-benzyl group), was therefore syn-

thesised and subjected to the conditions for tetrahydroisoquinoline

formation. The requisite enantiopure amine (R)-82 was prepared in

actions where

b-hydroxy-a-amino esters were formed, heating the

96% yield and >99:1 er via reductive alkylation of (R)-a-methyl-

reactions of 66, 67 and 68 at 40 ^ꢂC for 24 h increased conversion to

the corresponding tetrahydroisoquinolines 71, 72 and 73, which

were isolated as single diastereoisomers (>99:1 dr) in increased

yields of 26, 28 and 24%, respectively (Scheme 10). ¹H NMR ³J

coupling constant analyses were used to assign the relative anti-

benzylamine 81 (>99:1 er) with p-(triﬂuoromethyl)benzalde-

hyde.³⁷Conjugate addition of the lithium amide reagent derived

from deprotonation of (R)-82 with BuLi to a,b-unsaturated ester 27,

followed by in situ oxidation of the intermediate lithium (Z)-b-

amino enolate²⁴with (ꢀ)-CSO, gave 83 in 85% isolated yield and

>99:1 dr. The relative anti-conﬁguration within 83 was assigned by

conﬁgurations within

b

-hydroxy-

a

-amino esters 76 (³J_2,3¼8.8 Hz)

2146

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

reference to our transition state mnemonic³³for the conjugate ad-

dition reaction and by analogy to the established stereochemical

outcome of this aminohydroxylation process,³⁸and this assignment

established stereochemical outcome of this aminohydroxylation

3

process,^25e27and this assignment was supported by ¹H NMR J_2,3

coupling constant analyses (³J_2,3¼2.7e3.0 Hz).²⁸Upon reaction of

a-

3

was supported by ¹H NMR J_2,3coupling constant analysis

hydroxy-

b

-amino esters 86 (R¼p-CF₃) and 87 (R¼m-F) with Tf₂O and

(³J_2,3¼3.1 Hz).²⁸Reaction of

a-hydroxy-b-amino ester 83 with Tf₂O

DTBMP, it was necessary to heat the reaction mixture at 40 ^ꢂC for 6 h to

and DTBMP gave N-p-(triﬂuoromethyl)benzyl substituted tetrahy-

droisoquinoline 84 exclusively and, following chromatographic pu-

riﬁcation 84 was isolated in 72% yield and >99:1 dr (Scheme 11). The

relative anti-conﬁguration within 84 (³J_3,4¼3.6 Hz) was assigned by

¹H NMR ³J coupling constant analysis,¹⁹and the regioselectivity of

this transformation was conﬁdently assigned by ¹He¹³C NMR HMBC

analysis. When compared with the corresponding N-allyl analogue

63, the yield of tetrahydroisoquinoline 84 is far superior. In this case,

achieve full conversion: reaction of 86 (R¼p-CF₃) gave a 93:7 mixture of

tetrahydroisoquinoline 91 and

b-hydroxy-a-amino ester 96, re-

spectively, fromwhich 91 was isolated in 66% yield and >99:1 dr. For 87

(R¼m-F) a 96:4 mixture of tetrahydroisoquinoline 92 and -hydroxy-

amino ester 97 was recovered, from which 92 was isolated in 75% yield

and >99:1 dr. -Hydroxy-

b

a-

a

b

-amino esters 88 (R¼m-OMe) and 89 (R¼H)

were found to react cleanly under standard reaction conditions (i.e., at

rt for 6 h) to give full conversion to tetrahydroisoquinolines 93 and 94,

respectively, which were isolated in 81 and 72% yield and in >99:1 dr in

the N-(a-methylbenzyl) chiral auxiliary is retained in the tetrahy-

droisoquinoline product, making this an efﬁcient route to stereo-

deﬁned C(1)-methyl substituted tetrahydroisoquinolines.

both cases. However, for

a

-hydroxy-

b

-amino ester 90 (R¼p-OMe)

a reduction in diastereoselectivity was again observed. Reaction of 90

with Tf₂O and DTBMP at ꢀ20 ^ꢂC for 2.5 h gave an 80:20 mixture of

95 and 101, respectively, from which 95 was isolated in 39% yield

and >99:1 dr (Scheme 12). The regiochemistries of 91e95 and 101

were assigned via ¹He¹³C NMR HMBC analyses, and ¹H NMR ³J

coupling constant analyses were used to assign the relative con-

ﬁgurations within the major 3,4-anti-diastereoisomers 91e95

(³J_3,4¼3.2e3.8 Hz) and 3,4-syn-101 (³J_3,4¼5.5 Hz).¹⁹

Scheme 11.

Scheme 12. [^a>99:1 dr [(E):(Z)]; ^bThe reaction mixture was heated at 40 ^ꢂC for 6 h; ^cThe

reaction mixture was cooled to ꢀ20 ^ꢂC for 2.5 h; ^dthe minor (1R,3S,4R)-diastereoisomer

101 was also isolated in 13% yield and >99:1 dr].

The conditions for tetrahydroisoquinoline formation were next

applied to the range of substituted

Conjugate addition of the lithium amide reagent derived from depro-

tonation of (R)-82 with BuLi to -unsaturated esters 24e26, 65 and 28

-amino eno-

-amino esters 86e90 in

a-hydroxy-b-amino esters 86e90.

a,b

Studies into the hydrogenolytic removal of the N(2)-[p-(tri-

with in situ oxidation of the intermediate lithium (Z)-

b

ﬂuoromethyl)benzyl]

protecting

group

within

tetrahy-

lates²¹with (ꢀ)-CSO, gave

a

-hydroxy-

b

droisoquinolines 84 and 91e95 were undertaken next. Reaction of

94 (R¼H) under H₂(5 atm) in the presence of Pearlman’s catalyst

[Pd(OH)₂/C] at rt for 48 h gave 105 in 59% yield and >99:1 dr.

Deprotection of 93 (R¼m-OMe) and 95 (R¼p-OMe) under identical

67e95% yield and >99:1 dr in each case. The conﬁgurations within

86e90 were again assigned by reference to our transition state mne-

monic³³for the conjugate addition reaction and by analogy to the

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2147

conditions gave 104 and 107, respectively, in 74 and 61% yield.

However, when 84 (R¼p-F) was reacted under this optimised

protocol, N-debenzylation was accompanied by complete

deﬂuorination. Reducing the catalyst loading from 40 to 25% w/w

gave 69% conversion to 106 after 48 h, with full conversion to 106

being observed after 5 days; 106 was then isolated in 72% yield and

>99:1 dr after chromatographic puriﬁcation of the crude reaction

mixture. Deprotection of the remaining ﬂuorinated tetrahy-

droisoquinolines 91 and 92 using this alternative protocol gave 102

and 103 in 43 and 37% yield, respectively (Scheme 13).

Scheme 13. [^aReaction time of 5 days].

Scheme 14.

2.4. Asymmetric synthesis of 3-(tert-butoxycarbonyl)-4-aryl-

tetrahydroisoquinolines

The synthesis of N(2)-[a-methyl-p-(triﬂuoromethyl)benzyl]

substituted tetrahydroisoquinolines was conducted in the racemic

series in the ﬁrst instance. The requisite secondary amine (RS)-109

was synthesised by the reductive alkylation of benzylamine with p-

(triﬂuoromethyl)acetophenone 108, which gave (RS)-109 in 42%

yield. Subsequent conjugate addition of the lithium amide reagent

derived from deprotonation of (RS)-109 with BuLi to tert-butyl cin-

namate 65, with in situ oxidation of the intermediate lithium (Z)-b-

aminoenolate²⁴with(ꢀ)-CSO, gave(ꢁ)-110 in64%yieldandin>99:1

dr. The relative conﬁguration within (ꢁ)-110 was assigned by refer-

ence to our transition state mnemonic³³for the conjugate addition

reactionand byanalogytotheestablished stereochemicaloutcomeof

this aminohydroxylation process,^25e27and this assignment was

supported by ¹H NMR ³J_2,3coupling constant analysis (³J_2,3¼3.1 Hz).²⁶

Reaction of (ꢁ)-110 with Tf₂O and DTBMP at rt for 6 h promoted full

conversion to (ꢁ)-111, which was isolated in 68% yield and >99:1 dr

after chromatographic puriﬁcation (Scheme 14). The regiochemistry

of (ꢁ)-111 was assigned via ¹He¹³C NMR HMBC analysis and the

relative 3,4-anti-conﬁguration within (ꢁ)-111 was initially assigned

based on ¹H NMR ³J coupling constant analysis (³J_3,4¼1.6 Hz),¹⁹and

the relative (3RS,4RS,aSR)-conﬁguration of 111 was subsequently

conﬁrmed by single crystal X-ray diffraction analysis (Fig. 8).²⁰

Complete regioselectivity was again observed in the cyclisation step

as a result of exclusive cyclisation via the unsubstituted phenyl ring.

Investigations into an effective strategy to deprotect the N(2)-

[

a

-methyl-p-(triﬂuoromethyl)benzyl] group within (ꢁ)-111 were

undertaken next. In the ﬁrst instance 111 was reacted under stan-

dard hydrogenolysis conditions: stirring 111 under H₂pressure

(5 atm) in the presence of Pd(OH)₂/C (25% w/w) at rt for 48 h, gave

a 55:20:22:3 mixture of starting material 111, a-amino ester 112

[which presumably results from hydrogenolytic cleavage of the

Fig. 8. X-ray crystal structure of (3RS,4RS,aSR)-111 (selected H atoms are omitted for

C(1)eN(2) bond within 111], tetrahydroisoquinoline 113 and

clarity).

2148

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

20

a

-amino ester 114, respectively. Increasing the catalyst loading to

speciﬁc rotation of this sample of (R)-117 {[

a]

þ22.0 (c 1.0 in

D

40% w/w resulted in a 60:40 mixture of 113 and 114, respectively.

Investigations into alternative debenzylation strategies were un-

dertaken next, in the hope that a protocol may be found that would

MeOH)} with the literature value {lit.⁴⁴

[

a]

²⁰þ20.0 (c 1.0 in MeOH)}

D

showed excellent agreement. Attempts to improve the isolated

yield of either (R)-117 or (S)-117 were not successful. However, it

was found that subjection of the crude reaction mixtures of (R)-117

or (S)-117 to reductive alkylation with benzaldehyde, in the pres-

ence of 1.0 equiv of K₂CO₃, gave (R)-109 or (S)-109 in 48 and 63%

yield (from 118 or 119), respectively, and>99:1 er⁴⁵in each case

(Scheme 16).

favour removal of the N(2)-[a-methyl-p-(triﬂuoromethyl)benzyl]

group over cleavage of the C(1)eN(2) bond. However, treatment of

111 with Na in NH₃at e78 ^ꢂC for 30 min gave returned starting

material. Reaction of 111 with NaBrO₃and Na₂S₂O₄resulted in

oxidation at the C(1) position, giving 116 in 82% yield.³⁹Similarly,

treatment of 111 with CAN^40,41gave 115 as a single diastereoisomer

[of unknown conﬁguration at C(1)] in 94% yield. Reduction of 111

under transfer hydrogenolysis conditions (i.e., treatment with

HCO₂NH₄in the presence of Pd/C for 8 h) gave a 3:70:27 mixture of

112, 113 and 114, respectively. Further optimisation revealed that

3 h was sufﬁcient to achieve full conversion, giving a 3:77:20

mixture of 112, 113 and 114, respectively, from which 113 was iso-

lated in 59% yield and >99:1 dr (Scheme 15).

With samples of both antipodes of N-benzyl-N-[

(triﬂuoromethyl)benzyl]amine 109 in hand, work towards the

synthesis of the corresponding enantiopure N(2)-[ -methyl-p-

(triﬂuoromethyl)benzyl] substituted tetrahydroisoquinoline 111

was undertaken. Conjugate addition of the lithium amide reagent

derived from deprotonation of (S)-109 with BuLi to tert-butyl cin-

a-methyl-p-

a

namate 65, with in situ oxidation of the intermediate lithium (Z)-b-

amino enolate²⁴with (þ)-CSO, gave

a-hydroxy-b-amino ester

Scheme 15.

With a selective cyclisation pathway identiﬁed, and subsequent

deprotection optimised, work could begin on the corresponding

enantiopure system. The resolution of

ﬂuoromethyl)benzylamino 117 was ﬁrst conducted according to

a known procedure.⁴²Racemic

-methyl-p-(triﬂuoromethyl)ben-

a-methyl-p-(tri-

a

zylamine (RS)-117 was synthesised via the reductive amination of

p-(triﬂuoromethyl)acetophenone 108, which gave (RS)-117 in 68%

yield.⁴³Subsequent coupling of (RS)-117 with (R)-O-acetylmandelic

acid gave a 50:50 mixture of enantiopure diastereoisomers 118 and

119, which were separated by column chromatography and isolated

in 33 and 36% yield, respectively, as single diastereoisomers (>99:1

dr). The relative conﬁguration within 118 was established by single

crystal X-ray diffraction analysis (Fig. 9),²⁰and the determination of

a Flack x parameter³⁴of 0.09(12) for the structure of 118 conﬁrmed

the assigned absolute (R,R)-conﬁguration of 118; this analysis

therefore also established the absolute (2R,aS)-conﬁguration of 119.

With diastereoisomerically pure samples of 118 and 119 in hand,

subsequent hydrolysis was required to liberate the corresponding

enantiomerically pure amines (R)-117 and (S)-117. Heating a solu-

tion of 118 in HBr at reﬂux for 24 h was found to effectively cleave

the amide bond, but puriﬁcation of (R)-117 by an acid/base ex-

traction protocol gave (R)-117 in only 38% yield; comparison of the

Fig. 9. X-ray crystal structure of (R,R)-118 (selected H atoms are omitted for clarity).

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2149

Scheme 17.

exclusivecyclisationviatheotherunsubstitutedN-benzylgroup.This

methodology was employed in the asymmetric synthesis of a range

of enantiopure 3,4-anti-3-(tert-butoxycarbonyl)-4-aryl-1,2,3,4-

tetrahydroisoquinolines, which were isolated in good yields as sin-

gle diastereoisomers.

Scheme 16.

4. Experimental

(S,S,S)-110 in 94% yield and >99:1 dr. Subsequent treatment of

(S,S,S)-110 with Tf₂O and DTBMP gave tetrahydroisoquinoline

4.1. General experimental

(3R,4R,

and >99:1 dr. Application of the previously optimised deprotection

conditions to (3R,4R, S)-111 gave a 9:74:17 mixture of 112, 113 and

114, respectively, from which (R,R)-113 was isolated in 50% yield

and >99:1 dr (Scheme 17). All ¹H and ¹³C NMR spectroscopic data

for these species were entirely consistent with the racemic samples

prepared previously (vide supra).

aS)-111 as the sole product, which was isolated in 93% yield

Reactions involving organometallic or other moisture-sensitive

reagents were carried out under a nitrogen or argon atmosphere

using standard vacuum line techniques and glassware that was

ﬂame dried and cooled under nitrogen before use. BuLi was pur-

chased (as a solution in hexanes) and titrated against diphenyl-

acetic acid before use. Solvents were dried according to the

procedure outlined by Grubbs and co-workers.⁴⁶Water was puri-

ﬁed by an Elix^ÒUV-10 system. All other reagents were used as

supplied (analytical or HPLC grade) without prior puriﬁcation. Or-

ganic layers were dried over MgSO₄or NaSO₄. Thin layer chroma-

tography was performed on aluminium plates coated with 60 F₂₅₄

silica. Plates were visualised using UV light (254 nm), iodine, 1% aq

KMnO₄, or 10% ethanolic phosphomolybdic acid. Flash column

chromatography was performed on Kieselgel 60 silica.

Melting points were recorded on a Gallenkamp Hot Stage ap-

paratus. Optical rotations were recorded on a PerkineElmer 241

polarimeter with a water-jacketed 10 cm cell. Speciﬁc rotations are

reported in 10^ꢀ1deg cm²g^ꢀ1and concentrations in g/100 mL. IR

spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer

using an ATR module. Selected characteristic peaks are reported in

cm^ꢀ1. NMR spectra were recorded on Bruker Avance spectrometers

in the deuterated solvent stated. Spectra were recorded at rt. The

ﬁeld was locked by external referencing to the relevant deuteron

resonance. ¹He¹H COSY, ¹He¹³C HMQC, and ¹He¹³C HMBC analyses

were used to establish atom connectivity. Low-resolution mass

spectra were recorded on either a VG MassLab 20e250 or

a Micromass Platform 1 spectrometer. Accurate mass measure-

ments were run on either a Bruker MicroTOF internally calibrated

with polyalanine, or a Micromass GCT instrument ﬁtted with

a

3. Conclusion

In conclusion, a general protocol for the synthesis of a range of

3,4-disubstituted

tetrahydroisoquinolines directly from

has been developed. Treatment of a -aryl substituted

amino ester with Tf₂O and 2,6-di-tert-butyl-4-methylpyridine pro-

moted activation of the -hydroxy group and aziridinium formation

and

1,3,4-trisubstituted

1,2,3,4-

a-hydroxy-b-amino esters

b

a-hydroxy-b-

a

[with inversion of conﬁguration at C(2)], which was followed by

rupture of the C(3)eN bond and rapid FriedeleCrafts alkylation-type

cyclisation of an N-benzyl moiety onto the resultant benzylic carbe-

nium ion [with retention of conﬁguration at C(3)]. The nature of the

N-protecting group was varied and it was found that superior yields

were obtained for reactions employing two benzylic groups on ni-

trogen. In the cases where two different N-benzyl groups were used,

the issue of regioselectivity resulting from the competitive cyclisa-

tion via either N-benzyl group was addressed by the introduction of

a p-triﬂuoromethyl group on one of the N-benzyl moieties; this re-

tarded the rate of cyclisation via the electronpoor aryl ring to such an

extent that complete regioselectivity was observed upon formation

of the corresponding 1,2,3,4-tetrahydroisoquinoline resulting from

2150

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

a Scientiﬁc Glass Instruments BPX5 column (15 mꢃ0.25 mm) using

4.6. tert-Butyl (2S,3R)-2-hydroxy-3-(N,N-dibenzylamino)-3-

phenylpropanoate 19

amyl acetate as a lock mass.

Step 1: Pd(OH)₂/C (35 mg, 25% w/w) was added to a degassed

solution of 18²¹(139 mg, 0.32 mmol, >99:1 dr) in MeOH (5 mL) and

the resultant mixture was stirred under H₂(5 atm) at rt for 15 h. The

reaction mixture was then ﬁltered through Celite^Ò(eluent MeOH)

and concentrated in vacuo to give tert-butyl (2S,3R)-2-hydroxy-3-

4.2. General procedure I: aminohydroxylation of

saturated esters

a,b-un-

BuLi (1.55 equiv) was added dropwise to a stirred solution of

the requisite amine (1.60 equiv) in THF at ꢀ78 ^ꢂC and the re-

sultant mixture was stirred at ꢀ78 ^ꢂC for 30 min. A solution of

amino-3-phenylpropanoate as a colourless oil (77 mg, quant,

20

the requisite a,b

-unsaturated ester (1.0 equiv) in THF at ꢀ78 ^ꢂC

>99:1 dr); [

a]

þ11.4 (c 1.0 in CHCl₃); n_max(ATR) 3363, 3298

D

(NeH), 3165 (OeH), 3086, 3063, 3030, 3003, 2978, 2932 (CeH),

1727 (C]O); d_H(400 MHz, CDCl₃) 1.41 (9H, s, CMe₃), 2.59 (3H, br s,

NH₂, OH), 4.15e4.20 (2H, m, C(2)H, C(3)H), 7.21e7.41 (5H, m, Ph); d_C

(100 MHz, CDCl₃) 27.9 (CMe₃), 58.5, 75.3 (C(2), C(3)), 82.5 (CMe₃),

127.0, 127.5, 128.4 (o,m,p-Ph), 142.2 (i-Ph), 172.6 (C(1)); m/z (ESI^þ)

was then added dropwise via cannula and the resultant mixture

was stirred at ꢀ78 ^ꢂC for 2 h (ꢀ)-CSO (1.6 equiv) was then added

and the reaction mixture was allowed to warm to rt then stirred

at rt for 18 h. Satd aq NH₄Cl was added and the reaction mixture

was stirred at rt for 5 min, then concentrated in vacuo. The

residue was partitioned between CH₂Cl₂and 10% aq citric acid,

and the aqueous layer was extracted with three portions of

CH₂Cl₂. The combined organic extracts were washed sequentially

with satd aq NaHCO₃and brine, then dried and concentrated in

vacuo. The residue was then triturated with cold Et₂O and ﬁl-

tered. The resultant solution was then dried and concentrated in

vacuo.

þ

260 ([MþNa]^þ, 100%); HRMS (ESI^þ) C₁₃H₁₉NNaO₃([MþNa]^þ) re-

quires 260.1257; found 260.1250.

Step 2: BnBr (0.10 mL, 0.84 mmol) and K₂CO₃(290 mg, 2.1 mmol)

were added to a stirred solution of tert-butyl (2S,3R)-2-hydroxy-3-

amino-3-phenylpropanoate (100 mg, 0.42 mmol) in MeCN (2.5 mL)

and the resultant mixture was heated at reﬂux for 24 h. The re-

action mixture was then allowed to cool to rt and ﬁltered. The ﬁlter

cake was washed with EtOAc (3 mL), then the combined organic

washings were concentrated in vacuo. Puriﬁcation via ﬂash column

chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 10:1) gave 19 as

a colourless oil (78 mg, 45%, >99:1 dr); n_max(ATR) 3464 (OeH),

4.3. General procedure II: tetrahydroisoquinoline formation

Tf₂O (1.5 equiv) was added to a stirred solution of the requisite

1724 (C]O); [a]

²⁰e32.4 (c 1.0 in CHCl₃); d_H(400 MHz, CDCl₃) 1.00

D

a

-hydroxy-b-amino ester (1.0 equiv) and DTBMP (3.0 equiv) in

(9H, s, CMe₃), 308 (2H, d, J 13.4, N(CH_AH_BPh)₂), 3.81 (1H, d, J 9.8,

C(3)H), 3.91 (2H, d, J 13.4, N(CH_AH_BPh)₂), 4.14 (1H, br s, OH), 4.55

(1H, d, J 9.8, C(2)H), 7.15e7.39 (15H, m, Ph); d_C(100 MHz, CDCl₃) 27.5

(CMe₃), 53.8 (N(CH₂Ph)₂), 65.6 (C(3)), 70.4 (C(2)), 81.3 (CMe₃), 127.4,

128.1, 128.3, 128.7, 129.1, 130.5 (o,m,p-Ph), 133.1, 138.5 (i-Ph), 171._þ3

(C(1)); m/z (ESI^þ) 418 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₇H₃₂NO₃

([MþH]^þ) requires 418.2377; found 418.2374.

CH₂Cl₂at 0 or e20 ^ꢂC. The resultant mixture was stirred at the

stated temperature for the time stated, then H₂O was added and the

aqueous layer was extracted with portions of CH₂Cl₂. The combined

organic extracts were then dried and concentrated in vacuo. The

residue was dissolved in Et₂O and the resultant solution was ﬁl-

tered, then dried and concentrated in vacuo.

4.4. General procedure III: N-deprotection of N(2)-[p-(tri-

ﬂuoromethyl)benzyl] substituted tetrahydroisoquinolines

4.7. (RS,SR)-N(2)-Benzyl-3-(tert-butoxycarbonyl)-4-phenyl-

1,2,3,4-tetrahydroisoquinoline 20

Pd(OH)₂/C (either 25 or 40% w/w, as stated) was added to

degassed solution of the requisite terahydroisoquinoline

Following general procedure II, Tf₂O (15

mL, 90 mmol) was reacted

a

with 19 (25 mg, 60 mol, >99:1 dr) and DTBMP (36 mg, 0.18 mmol)

m

(1.0 equiv) in MeOH and the resultant mixture was placed under H₂

(5 atm) and stirred at rt for either 48 h or 5 days, as stated. The

reaction mixture was ﬁltered through Celite^Ò(eluent MeOH) and

concentrated in vacuo.

in CH₂Cl₂(0.6 mL) at rt for 6 h. Puriﬁcation via ﬂash column

chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 20:1) gave a 59:41

mixture of 16 and 20, respectively, as a pale yellow oil (20 mg, 84%).

Data for 20: d_H(500 MHz, CDCl₃) 1.21 (9H, s, CMe₃), 3.77 (1H, d, J

13.4, NCH_AH_BPh), 3.79 (1H, d, J 6.1, C(3)H), 3.85 (1H, d, J 15.3,

C(1)H_A), 3.86 (1H, d, J 13.4, NCH_AH_BPh), 4.16 (1H, d, J 15.3, C(1)H_B),

4.57 (1H, d, J 6.1, C(4)H), 6.95e7.48 (14H, m, Ar, Ph); d_C(125 MHz,

CDCl₃) 28.0 (CMe₃), 48.2 (C(4)), 52.0 (C(1)), 60.0 (NCH₂Ph), 66.6

(C(3)), 80.9 (CMe₃), 125.8, 125.8, 125.9 (C(6), C(7), C(8)), 126.9, 127.2

(p-Ph), 127.9, 128.0, 128.3, 128.4 (o,m-Ph), 129.0 (C(5)), 135.0, 138.3,

140.3, 140.6 (C(4a), C(8a), i-Ph), 169.2 (CO₂^tBu).

4.5. (RS,RS)-N(2)-Benzyl-3-(tert-butoxycarbonyl)-4-phenyl-

1,2,3,4-tetrahydroisoquinoline 16

Following general procedure II, Tf₂O (181

mL, 1.08 mmol) was

reacted with 15¹⁶(300 mg, 0.719 mmol, >99:1 dr) and DTBMP

(443 mg, 2.16 mmol) in CH₂Cl₂(9 mL) at rt for 6 h. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 20:1)

gave 16 as a pale yellow solid (219 mg, 76%, >99:1 dr); mp

68e70.5 ^ꢂC; n_max(ATR) 1723 (C]O); d_H(500 MHz, CDCl₃) 1.38 (9H,

s, CMe₃), 3.58 (1H, d, J 3.0, C(3)H), 3.86 (1H, d, J 13.4, NCH_AH_BPh),

3.92 (1H, d, J 15.0, C(1)H_A), 3.96 (1H, d, J 13.4, NCH_AH_BPh), 4.06 (1H,

d, J 15.0, C(1)H_B), 4.50 (1H, d, J 3.0, C(4)H), 6.90e7.42 (14H, m, Ar,

Ph); d_C(125 MHz, CDCl₃) 28.2 (CMe₃), 47.9 (C(4)), 51.0 (C(1)), 59.5

(NCH₂Ph), 67.0 (C(3)), 81.3 (CMe₃), 126.0, 126.1, 126.2, 126.3 (C(5),

C(6), C(7), C(8)), 126.9, 127.8, 128.1, 128.6, 129.1, 129.7 (o,m,p-Ph),

134.7 (C(8a)), 135.2 (C(4a)), 138.6, 144.7 (i-Ph), 171.4 (CO^t₂Bu); m/z

4.8. tert-Butyl (RS,RS)-2-hydroxy-3-(N,N-dibenzylamino)-3-

[4⁰-(triﬂuoromethyl)phenyl]propanoate 29

Following general procedure I, BuLi (2.2 M in hexanes, 2.58 mL,

5.67 mmol) and N,N-dibenzylamine (1.12 mL, 5.85 mmol) were

reacted with 24 (1.00 g, 3.66 mmol, >99:1 dr) and (ꢀ)-CSO (1.43 g,

6.22 mmol) in THF (20 mL). Puriﬁcation via ﬂash column chroma-

tography (eluent 30e40 ^ꢂC petrol/Et₂O 5:1) gave 29 as yellow solid

(930 mg, 53%, >99:1 dr); mp 84e87 ^ꢂC; n_max(ATR) 3479 (OeH),

1723 (C]O); d_H(700 MHz, CDCl₃) 1.30 (9H, s, CMe₃), 2.94 (1H, br s,

OH), 3.52 (2H, d, J 14.0, N(CH_AH_BPh)₂), 3.97 (2H, d, J 14.0,

þ

(ESI^þ) 400 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₇H₃₀NO₂([MþH]^þ)

requires 400.2271; found 400.2273.

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2151

þ

N(CH_AH_BPh)₂), 4.20 (1H, d, J 3.0, C(3)H), 4.81 (1H, app s, C(2)H),

7.23e7.28 (2H, m, Ph), 7.31e7.35 (4H, m, Ph), 7.37e7.40 (4H, m, Ph),

7.50e7.54 (2H, m, C(2⁰)H, C(6⁰)H), 7.58e7.62 (2H, m, C(3⁰)H, C(5⁰)H);

d_C(175 MHz, CDCl₃) 27.7 (CMe₃), 54.8 (N(CH₂Ph)₂), 63.7 (C(3)), 71.9

(C(2)), 83.0 (CMe₃), 124.2 (q, J 272.1, CF₃), 124.8 (q, J 3.8, C(3⁰), C(5⁰)),

127.1 (p-Ph), 128.3, 128.7 (o,m-Ph), 129.7 (q, J 32.4, C(4⁰)), 130.1

(C(2⁰), C(6⁰)), 139.5 (i-Ph), 140.5 (C(1⁰)), 172.9 (C(1)); d_F(377 MHz,

(ESI^þ) 436 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₇H₃₁FNO₃([MþH]^þ)

requires 436.2282; found 436.2286.

4.12. tert-Butyl (RS,RS)-2-hydroxy-3-(N,N-dibenzylamino)-3-

(4⁰-methoxyphenyl)propanoate 33

CDCl₃) ꢀ62.5 (CF₃); m/z (ESI^þ) 486 ([MþH]^þ, 100%); HRMS (ESI^þ)

Following general procedure I, BuLi (2.2 M in hexanes, 4.51 mL,

9.93 mmol) and N,N-dibenzylamine (1.97 mL, 10.3 mmol) were

reacted with 28 (1.50 g, 6.41 mmol, >99:1 dr) and (ꢀ)-CSO (2.50 g,

10.9 mmol) in THF (40 mL). Puriﬁcation via ﬂash column chroma-

tography (eluent 30e40 ^ꢂC petrol/Et₂O, 5:1) gave 33 as a white solid

(1.93 g, 67%, >99:1 dr); mp 100e103 ^ꢂC; n_max(ATR) 3483 (OeH),

1724 (C]O); d_H(500 MHz, CDCl₃) 1.31 (9H, s, CMe₃), 3.44 (2H, d, J

þ

C

₂₈H₃₀F₃NNaO₃([MþNa]^þ) requires 508.2070; found 508.2073.

4.9. tert-Butyl (RS,RS)-2-hydroxy-3-(N,N-dibenzylamino)-3-

(3⁰-ﬂuorophenyl)propanoate 30

Following general procedure I, BuLi (2.2 M in hexanes, 4.76 mL,

10.5 mmol) and N,N-dibenzylamine (2.07 mL, 10.8 mmol) were

reacted with 25 (1.50 g, 6.75 mmol, >99:1 dr) and (ꢀ)-CSO (2.63 g,

11.5 mmol) in THF (42 mL). Puriﬁcation via ﬂash column chroma-

tography (eluent 30e40 ^ꢂC petrol/Et₂O, 5:1) gave 30 as a white solid

(2.00 g, 68%, >99:1 dr); mp 77e80 ^ꢂC; n_max(ATR) 3487 (OeH), 2979

(CeH), 1724 (C]O); d_H(500 MHz, CDCl₃) 1.30 (9H, s, CMe₃), 2.93

(1H, br s, OH), 3.51 (2H, d, J 14.0, N(CH_AH_BPh)₂), 3.98 (2H, d, J 14.0,

N(CH_AH_BPh)₂), 4.12 (1H, d, J 3.9, C(3)H), 4.77 (1H, d, J 3.9, C(2)H),

6.97e7.42 (14H, m, Ar, Ph); d_C(125 MHz, CDCl₃) 27.7 (CMe₃), 54.8

(N(CH₂Ph)₂), 63.7 (C(3)), 72.3 (C(2)), 82.9 (CMe₃),114.4 (d, J 21.0, Ar),

116.8 (d, J 21.9, Ar), 125.5 (d, J 2.9, C(6⁰)), 127.0, 128.2, 128.8 (o,m,p-

Ph), 129.3 (d, J 7.6, C(5⁰)), 138.8 (d, J 6.7, C(1⁰)), 139.5 (i-Ph), 162.5 (d, J

245.1, C(3⁰)), 172.8 (C(1)); d_F(377 MHz, CDCl₃) ꢀ113.2 (C(3⁰)F); m/z

14.0, N(CH_AH_BPh)₂), 3.82 (3H, s, OMe), 3.98 (2H, d,

J 14.0,

N(CH_AH_BPh)₂), 4.07 (1H, d, J 4.4, C(3)H), 4.75 (1H, d, J 4.4, C(2)H),

6.89 (2H, d, J 8.7, C(3⁰)H, C(5⁰)H), 7.21e7.42 (12H, m, Ar, Ph); d_C

(125 MHz, CDCl₃) 27.7 (CMe₃), 54.8 (N(CH₂Ph)₂), 55.2 (OMe), 63.8

(C(3)), 72.9 (C(2)), 82.5 (CMe₃),113.3 (C(3⁰), C(5⁰)),126.8,127.7, 128.1,

128.8 (C(2⁰), C(6⁰), o,m,p-Ph), 131.1 (C(1⁰)), 139.8 (i-Ph), 158.9 (C(4⁰)),

173.0 (C(1)); m/z (ESI^þ) 448 ([MþH]^þ, 100%); HRMS (ESI^þ)

þ

C

₂₈H₃₄NO₄([MþH]^þ) requires 448.2482; found 448.2481.

4.13. (RS,RS)-N(2)-Benzyl-3-(tert-butoxycarbonyl)-4-[4⁰-(tri-

ﬂuoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline 34

Following general procedure II, Tf₂O (0.10 mL, 0.618 mmol) was

reacted with 29 (200 mg, 0.412 mmol, >99:1 dr) and DTBMP

(254 mg, 1.24 mmol) in CH₂Cl₂(5.2 mL) at 40 ^ꢂC for 6 h, which gave

an 80:20 mixture of 34 and 39, respectively. Puriﬁcation by ﬂash

column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 20:1) gave

34 as a colourless viscous oil (120 mg, 62%, >99:1 dr); n_max(ATR)

1724 (C]O); d_H(400 MHz, CDCl₃) 1.39 (9H, s, CMe₃), 3.52 (1H, d, J

2.3, C(3)H), 3.86e3.96 (2H, m, NCH₂Ph), 3.98 (1H, d, J 15.9, C(1)H_A),

4.12 (1H, d, J 15.9, C(1)H_B), 4.56 (1H, app s, C(4)H), 6.91e7.00 (3H, m,

C(5)H, Ar), 7.07e7.25 (8H, m, Ar), 7.51 (2H, d, J 8.1, C(3⁰)H, C(5⁰)H); d_C

(100 MHz, CDCl₃) 28.2 (CMe₃), 47.4 (C(4)), 50.9 (C(1)), 59.3

(NCH₂Ph), 65.7 (C(3)), 81.6 (CMe₃), 124.3 (q, J 271.8, CF₃), 124.7 (q, J

3.7, C(3⁰), C(5⁰)),126.2,126.5,126.5,127.0,128.1 (Ar),128.5 (q, J 210.2,

C(4⁰)), 128.6, 129.4 (Ar), 129.6 (C(5)), 134.1 (C(4a)), 134.8 (C(8a)),

þ

(ESI^þ) 436 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₇H₃₁FNO₃([MþH]^þ)

requires 436.2282; found 436.2279.

4.10. tert-Butyl (RS,RS)-2-hydroxy-3-(N,N-dibenzylamino)-3-

(3⁰-methoxyphenyl)propanoate 31

Following general procedure I, BuLi (2.2 M in hexanes, 4.51 mL,

9.93 mmol) and N,N-dibenzylamine (1.97 mL, 10.25 mmol) were

reacted with 26 (1.50 g, 6.41 mmol, >99:1 dr) and (ꢀ)-CSO (2.50 g,

10.9 mmol) in THF (40 mL). Puriﬁcation via ﬂash column chroma-

tography (eluent 30e40 ^ꢂC petrol/Et₂O, 5:1) gave 31 as a pale yel-

low solid (1.05 g, 37%, >99:1 dr); mp 112e115 ^ꢂC; n_max(ATR) 3487

(OeH), 1724 (C]O); d_H(500 MHz, CDCl₃) 1.33 (9H, s, CMe₃), 3.50

(2H, d, J 14.0, N(CH_AH_BPh)₂), 3.81 (3H, s, OMe), 3.99 (2H, d, J 14.0,

N(CH_AH_BPh)₂), 4.11 (1H, d, J 4.4, C(3)H), 4.77 (1H, d, J 4.4, C(2)H),

6.83e7.44 (14H, m, Ar, Ph); d_C(125 MHz, CDCl₃) 27.8 (CMe₃), 54.8

(N(CH₂Ph)₂), 55.1 (OMe), 64.4 (C(3)), 72.5 (C(2)), 82.6 (CMe₃), 112.8

(C(4⁰)), 115.7 (C(2⁰)), 122.2 (C(6⁰)), 126.8 (C(5⁰)), 128.2, 128.8, 128.9

(o,m,p-Ph), 137.4 (C(1⁰)), 139.7 (i-Ph), 159.4 (C(3⁰)), 172.9 (C(1)); m/z

t

138.2 (i-Ph), 148.9 (C(1⁰)), 170.9 (CO₂Bu); d_F(472 MHz, CDCl₃) ꢀ62.3

þ

(CF₃); m/z (ESI^þ) 468 ([MþH]^þ, 100%), HRMS (ESI^þ) C₂₈H₂₉F₃NO₂

([MþH]^þ) requires 468.2145; found 468.2130.

4.14. (RS,RS)-N(2)-Benzyl-3-(tert-butoxycarbonyl)-4-(3⁰-ﬂuoro-

phenyl)-1,2,3,4-tetrahydroisoquinoline 35

þ

(ESI^þ) 448 ([MþH]^þ, 100%); HRMS (ESI⁺) C₂₈H₃₄NO₄([MþH]^þ)

requires 448.2482; found 448.2485.

Following general procedure II, Tf₂O (60

mL, 0.35 mmol) was

4.11. tert-Butyl (RS,RS)-2-hydroxy-3-(N,N-dibenzylamino)-3-

(4⁰-ﬂuorophenyl)propanoate 32

reacted with 30 (100 mg, 0.23 mmol, >99:1 dr) and DTBMP

(142 mg, 0.69 mmol) in CH₂Cl₂(2.9 mL) at rt for 6 h, which gave

a 77:23 mixture of 35 and 40, respectively. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 10:1) gave

35 as a yellow oil (56 mg, 58%, >99:1 dr); n_max(ATR) 2976 (CeH),

1723 (C]O); d_H(500 MHz, CDCl₃) 1.39 (9H, s, CMe₃), 3.56 (1H, d, J

2.5, C(3)H), 3.90 (1H, d, J 13.4, NCH_AH_BPh), 3.96 (1H, d, J 15.6,

C(1)H_A), 3.97 (1H, d, J 13.4, NCH_AH_BPh), 4.08 (1H, d, J 15.6, C(1)H_B),

4.49 (1H, d, J 2.5, C(4)H), 6.84e7.26 (13H, m, Ar, Ph); d_C(125 MHz,

CDCl₃) 28.2 (CMe₃), 47.4 (C(4)), 50.9 (C(1)), 59.5 (NCH₂Ph), 66.3

(C(3)), 81.5 (CMe₃), 113.1 (d, J 21.0, Ar), 116.2 (d, J 21.9, Ar), 124.6 (d, J

1.9, C(6⁰)), 126.2, 126.4, 127.0, 128.1, 128.1, 128.7, (C(6), C(7), C(8),

o,m,p-Ph), 129.1 (d, J 8.6, C(5⁰)), 129.7 (C(5)), 134.4 (C(4a)), 134.7

(C(8a)), 138.4 (i-Ph), 147.4 (d, J 6.7, C(1⁰)), 162.6 (d, J 245.1, C(3⁰)),

171.0 (CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ114.3 (C(3⁰)F); m/z (ESI^þ) 418

Following general procedure I, BuLi (2.2 M in hexanes, 3.17 mL,

6.98 mmol) and N,N-dibenzylamine (1.38 mL, 7.20 mmol) were

reacted with 27 (1.00 g, 4.50 mmol, >99:1 dr) and (ꢀ)-CSO (1.76 g,

7.65 mmol) in THF (28 mL). Puriﬁcation via ﬂash column chroma-

tography (eluent 30e40 ^ꢂC petrol/Et₂O, 8:1) gave 32 as a white solid

(1.35 g, 69%, >99:1 dr); mp 113e116 ^ꢂC; n_max(ATR) 3483 (OeH),

2978 (CeH), 1723 (C]O); d_H(700 MHz, CDCl₃) 1.29 (9H, s, CMe₃),

2.92 (1H, br s, OH), 3.48 (2H, d, J 14.0, N(CH_AH_BPh)₂), 3.98 (2H, d, J

14.0, N(CH_AH_BPh)₂), 4.12 (1H, d, J 3.9, C(3)H), 4.78 (1H, app s, C(2)H),

7.03 (2H, app t, J 8.7, Ar, Ph), 7.23e7.40 (12H, m, Ar, Ph); d_C(175 MHz,

CDCl₃) 27.7 (CMe₃), 54.8 (N(CH₂Ph)₂), 63.5 (C(3)), 72.5 (C(2)), 82.7

(CMe₃), 114.8 (d, J 21.0, C(3⁰), C(5⁰)), 126.9, 128.2, 128.8 (o,m,p-Ph),

131.5 (d, J 7.6, C(2⁰), C(6⁰)), 131.8 (d, J 3.2, C(1⁰)), 139.7 (i-Ph), 162.2 (d,

J 246.1, C(4⁰)), 172.9 (C(1)); d_F(377 MHz, CDCl₃) ꢀ114.9 (C(4⁰)F); m/z

þ

([MþH]^þ, 100%); HRMS (ESI^þ) C₂₇H₂₉FNO₂([MþH]^þ) requires

418.2177; found 418.2174.

2152

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

4.15. (RS,RS)-N(2)-Benzyl-3-(tert-butoxycarbonyl)-4-(3⁰-meth-

oxyphenyl)-1,2,3,4-tetrahydroisoquinoline 36

(138 mg, 0.67 mmol) in CH₂Cl₂(2.6 mL) at ꢀ20 ^ꢂC for 2.5 h, which

gave 38 in 85:15 dr. Puriﬁcation via ﬂash column chromatography

(30e40 ^ꢂC petrol/Et₂O, 10:1) gave 38 as a pale brown viscous oil

(64 mg, 66%, 85:15 dr).

Following general procedure II, Tf₂O (60

mL, 0.34 mmol) was

reacted with 31 (100 mg, 0.22 mmol, >99:1 dr) and DTBMP

(138 mg, 0.67 mmol) in CH₂Cl₂(2.6 mL) at rt for 6 h. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 10:1)

gave 36 as a pale yellow oil (54 mg, 57%, >99:1 dr); n_max(ATR) 2976

(CeH), 2931 (CeH), 1723 (C]O); d_H(500 MHz, CDCl₃) 1.39 (9H, s,

CMe₃), 3.61 (1H, d, J 3.1, C(3)H), 3.76 (3H, s, OMe), 3.88 (1H, d, J 13.6,

NCH_AH_BPh), 3.92 (1H, d, J 15.6, C(1)H_A), 3.96 (1H, d, J 13.6,

NCH_AH_BPh), 4.05 (1H, d, J 15.6, C(1)H_B), 4.48 (1H, d, J 3.1, C(4)H),

6.71e6.81 (3H, m, Ar), 6.99 (10H, m, Ar, Ph); d_C(125 MHz, CDCl₃)

28.2 (CMe₃), 47.8 (C(4)), 50.9 (C(1)), 55.1 (OMe), 59.6 (NCH₂Ph), 67.0

(C(3)), 81.3 (CMe₃), 111.6 (C(4⁰)), 115.1 (C(2⁰)), 121.7 (C(6⁰)), 126.0

(C(8)), 126.1, 126.2, 128.7, 135.0 (C(6), C(7), C(5⁰), p-Ph), 126.9 (C(5)),

128.1, 128.7 (o,m-Ph), 129.7 (C(1⁰)), 134.6 (C(4a)), 138.7 (i-Ph),

146.3 (C(8a)), 159.3 (C(3⁰)), 171.4 (CO₂^tBu); m/z (ESI^þ) 430 ([MþH]^þ,

4.18. tert-Butyl (RS,RS)-2-(N,N-dibenzylamino)-3-hydroxy-3-

[4⁰-(triﬂuoromethyl)phenyl]propanoate 39

Following general procedure II, Tf₂O (30

mL, 0.16 mmol) was

reacted with 29 (50 mg, 0.10 mmol, >99:1 dr) and DTBMP (63 mg,

0.31 mmol) in CH₂Cl₂(1.5 mL) at rt for 6 h. Puriﬁcation by ﬂash

column chromatography (eluent 30e40 ^ꢂC petrol/EtOAc, 10:1) gave

39 as a colourless viscous oil (18 mg, 35%, >99:1 dr); n_max(ATR)

3448 (OeH), 1722 (C]O); d_H(500 MHz, CDCl₃) 1.66 (9H, s, CMe₃),

2.97 (1H, d, J 3.8, OH), 3.48 (1H, d, J 9.4, C(2)H), 3.51 (2H, d, J 13.9,

N(CH_AH_BPh)₂), 3.90 (2H, d, J 13.9, N(CH_AH_BPh)₂), 5.03 (1H, dd, J 9.4,

3.8, C(3)H), 6.95e7.00 (4H, m, Ph), 7.15e7.23 (8H, m, C(2⁰)H, C(6⁰)H,

Ph), 7.51 (2H, d, J 8.0, C(3⁰)H, C(5⁰)H); d_C(125 MHz, CDCl₃) 28.6

(CMe₃), 55.2 (N(CH₂Ph)₂), 66.6 (C(2)), 72.3 (C(3)), 82.7 (CMe₃), 124.3

(q, J 272.8, CF₃), 124.9 (q, J 2.9, C(3⁰), C(5⁰)), 127.2, 128.0 (o,m,p-Ph),

128.2 (C(2⁰), C(6⁰)), 128.8 (o,m,p-Ph), 129.9 (q, J 32.0, C(4⁰)), 138.2 (i-

Ph), 144.9 (C(1⁰)), 171.7 (CO₂^tBu); d_F(472 MHz, CDCl₃) ꢀ62.4 (CF₃);

þ

100%); HRMS (ESI^þ) C₂₈H₃₂NO₃([MþH]^þ) requires 430.2377;

found 430.2381.

4.16. (RS,RS)-N(2)-Benzyl-3-(tert-butoxycarbonyl)-4-(4⁰-ﬂuoro-

phenyl)-1,2,3,4-tetrahydroisoquinoline 37

þ

m/z (ESI^þ) 486 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₈H₃₁F₃NO₃

([MþH]^þ) requires 486.2251; found 486.2236.

Following general procedure II, Tf₂O (0.12 mL, 0.69 mmol) was

reacted with 32 (200 mg, 0.46 mmol, >99:1 dr) and DTBMP

(283 mg, 1.38 mmol) in CH₂Cl₂(2.9 mL) at rt for 6 h. Puriﬁcation by

ﬂash column chromatography (eluent 30e40 ^ꢂC/Et₂O 20:1) gave 37

as a colourless viscous oil (139 mg, 73%, >99:1 dr); n_max(ATR) 2977

(CeH), 1724 (C]O); d_H(500 MHz, CDCl₃) 1.38 (9H, s, CMe₃), 3.51

(1H, d, J 2.9, C(3)H), 3.87 (1H, d, J 13.4, NCH_AH_BPh), 3.93 (1H, d, J

15.6, C(1)H_A), 3.96 (1H, d, J 13.4, NCH_AH_BPh), 4.07 (1H, d, J 15.6,

C(1)H_B), 4.48 (1H, d, J 2.9, C(4)H), 6.93e6.98 (3H, m, C(3⁰)H, C(5⁰)H,

Ar), 7.03e7.08 (3H, m, Ar, Ph), 7.08e7.13 (3H, m, C(2⁰)H, C(6⁰)H, Ar,

Ph), 7.15 (1H, dd, J 7.5,1.2, Ar), 7.17e7.21 (3H, m, Ar, Ph); d_C(125 MHz,

CDCl₃) 28.2 (CMe₃), 47.0 (C(4)), 51.0 (C(1)), 59.5 (NCH₂Ph), 66.7

(C(3)), 81.4 (CMe₃), 114.5 (d, J 21.0, C(3⁰), C(5⁰)), 126.1, 126.2, 126.3,

127.0, 129.6 (C(5), C(6), C(7), C(8), p-Ph), 128.1, 128.7 (o,m-Ph), 130.5

(d, J 7.6, C(2⁰), C(6⁰)), 134.6 (C(8a)), 135.0 (C(4a)), 138.5 (i-Ph), 140.5

(d, J 2.9, C(1⁰)), 161.6 (d, J 244.1, C(4⁰)), 171.2 (CO₂^tBu); d_F(377 MHz,

4.19. tert-Butyl (RS,RS)-2-hydroxy-3-[N,N-bis(4⁰⁰-methoxy-

benzyl)amino]-3-(4⁰-ﬂuorophenyl)propanoate 47

Following general procedure I, BuLi (2.2 M in hexanes, 3.17 mL,

6.98 mmol) and N,N-bis(p-methoxybenzyl)amine (1.85 g,

7.20 mmol) were reacted with 27 (1.00 g, 4.50 mmol, >99:1 dr) and

(ꢀ)-CSO (1.76 g, 7.65 mmol) in THF (26 mL). Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 3:1) gave 47

as a pale yellow solid (1.56 g, 70%, >99:1 dr); mp 100e102 ^ꢂC; v_max

(ATR) 3487 (OeH), 1725 (C]O); d_H(500 MHz, CDCl₃) 1.31 (9H, s,

CMe₃), 2.88 (1H, br s, OH), 3.39 (2H, d, J 13.8, N(CH_AH_BAr)₂), 3.80

(6H, s, 2ꢃOMe), 3.86 (2H, d, J 13.8, N(CH_AH_BAr)₂), 4.09 (1H, d, J 3.9,

C(3)H), 4.74 (1H, d, J 3.9, C(2)H), 6.86 (4H, d, J 8.7, Ar), 7.02 (2H, t, J

8.7, C(2⁰)H, C(6⁰)H), 7.17 (2H, app s, Ar), 7.24e7.28 (4H, m, Ar); d_C

(125 MHz, CDCl₃) 27.8 (CMe₃), 53.8 (N(CH₂Ar)₂), 55.3 (2ꢃOMe), 63.5

(C(3)), 72.3 (C(2)), 82.7 (CMe₃), 113.5 (C(3⁰⁰), C(5⁰⁰)), 114.8 (d, J 21.0,

C(2⁰), C(6⁰)), 129.8 (C(2⁰⁰), C(6⁰⁰)), 131.4 (d, J 7.6, C(3⁰), C(5⁰)) 131.7

(C(1⁰⁰)), 132.0 (d, J 3.8, C(1⁰)), 158.6 (C(4⁰⁰)), 162.2 (d, J 246.1,_þC(4⁰)),

172.9 (C(1)); d_F(377 MHz, CDCl₃) ꢀ115.0 (C(4⁰)F), m/z (ESI ) 496

CDCl₃) ꢀ117.2 (C(4⁰)F); m/z (ESI^þ) 418 ([MþH]^þ, 100%); HRMS (ESI^þ)

þ

C

₂₇H₂₉FNO₂([MþH]^þ) requires 418.2177; found 418.2181.

4.17. (RS,RS)-N(2)-Benzyl-3-(tert-butoxycarbonyl)-4-(4⁰-meth-

oxyphenyl)-1,2,3,4-tetrahydroisoquinoline 38

þ

([MþH]^þ, 100%), HRMS (ESI^þ) C₂₉H₃₅FNO₅([MþH]^þ) requires

496.2494; found 496.2500.

Method A: Following general procedure II, Tf₂O (60

mL,

0.34 mmol) was reacted 33 (100 mg, 0.22 mmol, >99:1 dr) and

DTBMP (138 mg, 0.67 mmol) in CH₂Cl₂(2.6 mL) at rt for 6 h, which

gave 38 in 75:25 dr. Puriﬁcation via ﬂash column chromatography

(30e40 ^ꢂC petrol/Et₂O, 20:1) gave 38 as a pale brown viscous oil

(32 mg, 34%, 75:25 dr); n_max(ATR) 2976 (CeH), 2930 (CeH), 2835

(CeH), 1723 (C]O); d_H(500 MHz, CDCl₃) 1.38 (9H, s, CMe₃), 3.55

(1H, d, J 3.3, C(3)H), 3.82 (3H, s, OMe), 3.86 (1H, d, J 13.5,

NCH_AH_BPh), 3.90 (1H, d, J 15.6, C(1)H_A), 3.96 (1H, d, J 13.5,

NCH_AH_BPh), 4.04 (1H, d, J 15.6, C(1)H_B), 4.45 (1H, d, J 3.3, C(4)H),

6.81e6.85 (2H, m, C(3⁰)H, C(5⁰)H), 6.97e7.16 (11H, m, C(5)H, C(6)H,

C(7)H, C(8)H, C(2⁰)H, C(6⁰)H, Ph); d_C(125 MHz, CDCl₃) 28.2 (CMe₃),

47.1 (C(4)), 51.0 (C(1)), 55.3 (OMe), 59.6 (NCH₂Ph), 67.3 (C(3)), 81.2

(CMe₃), 113.2 (C(3⁰), C(5⁰)), 126.0, 126.9, 129.6 (C(6), C(7), p-Ph),

126.2 (C(8)), 128.1, 128.7 (o,m-Ph), 130.1 (C(2⁰), C(6⁰)), 131.5 (C(5)),

134.5 (C(8a)), 135.6 (C(4a)), 137.0 (C(1⁰)), 138.7 (i-Ph), 158.2 (C(4⁰)),

4.20. tert-Butyl (RS)-3-[N,N-bis(3⁰⁰-methoxybenzyl)amino]-3-

(4⁰-ﬂuorophenyl)propanoate 48

BuLi (2.2 M in hexanes, 1.58 mL, 3.49 mmol) was added drop-

wise to a stirred solution of N,N-bis(m-methoxybenzyl)amine

(926 mg, 3.60 mmol) in THF (7.5 mL) at ꢀ78 ^ꢂC and the resultant

mixture was stirred at ꢀ78 ^ꢂC for 30 min. A solution of 27 (500 mg,

2.25 mmol, >99:1 dr) in THF (7.5 mL) at ꢀ78 ^ꢂC was added drop-

wise via cannula and the resultant mixture was stirred at ꢀ78 ^ꢂC for

2 h. Satd aq NH₄Cl (5 mL) was added and the resultant mixture was

left to warm to rt then concentrated in vacuo. The residue was

partitioned between CH₂Cl₂(50 mL) and 10% aq citric acid (30 mL),

and the aqueous layer was extracted with CH₂Cl₂(3ꢃ30 mL). The

combined organic extracts were washed sequentially with satd aq

NaHCO₃(30 mL) and brine (30 mL), then dried and concentrated in

vacuo. Puriﬁcation via ﬂash column chromatography (eluent

30e40 ^ꢂC petrol/Et₂O, 10:1) gave 48 as a pale yellow viscous oil

(840 mg, 78%); n_max(ATR) 2976 (CeH), 2835 (CeH), 1726 (C]O); d_H

(500 MHz, CDCl₃) 1.32 (9H, s, CMe₃), 2.71 (1H, dd, J 14.6, 9.3,

171.4 (CO₂^tBu); m/z (ESI^þ) 430 ([MþH]^þ, 100%); HRMS (ESI^þ)

þ

C

₂₈H₃₂NO₃([MþH]^þ) requires 430.2377; found 430.2385.

Method B: Following general procedure II, Tf₂O (60

mL,

0.34 mmol) was reacted 33 (100 mg, 0.22 mmol) and DTBMP

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2153

C(2)H_A), 2.96 (1H, dd, J 14.6, 6.3, C(2)H_B), 3.29 (2H, d, J 13.8,

N(CH_AH_BAr)₂), 3.66 (2H, d, J 13.8, N(CH_AH_BAr)₂), 3.80 (6H, s,

2ꢃOMe), 4.28 (1H, dd, J 9.3, 6.3, C(3)H), 6.75e6.80 (2H, m, Ar),

6.92e6.95 (4H, m, Ar), 7.02e7.08 (2H, m, C(3⁰)H, C(5⁰)H), 7.19e7.29

(4H, m, C(2⁰)H, C(6⁰)H, Ar); d_C(125 MHz, CDCl₃) 27.9 (CMe₃), 37.1

(C(2)), 53.9 (N(CH₂Ar)₂), 55.1 (2ꢃOMe), 58.7 (C(3)), 80.6 (CMe₃),

112.3, 114.3, 121.1 (Ar), 114.8 (d, J 21.0, C(3⁰), C(5⁰)), 129.2 (Ar), 130.1

(d, J 7.6, C(2⁰), C(6⁰)), 134.4 (d, J 2.9, C(1⁰)), 141.3, 159.6 (Ar), 162.0 (d, J

246.1, C(4⁰)), 170.8 (C(1)); d_F(377 MHz, CDCl₃) ꢀ40.1 (C(4⁰)F); m/z

J 21.0, C(3⁰), C(5⁰)), 121.0 (C(6⁰⁰)), 127.1 (C(4a)), 129.0 (C(5⁰⁰)), 130.4 (d,

J 8.6, C(2⁰), C(6⁰)), 130.6 (C(5)), 135.8 (C(8a)), 140.2 (C(1⁰⁰)), 140.9 (d, J

3.8, C(1⁰)), 157.9 (C(7)), 159.6 (C(3⁰⁰)), 161.5 (d, J 244.1, C(4⁰))_þ, 171.3

(CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ117.3 (C(4⁰)F); m/z (ESI ) 478

þ

([MþH]^þ, 100%); HRMS (ESI^þ) C₂₉H₃₃FNO₄([MþH]^þ) requires

478.2388; found 478.2381. Further elution gave 51 as a colourless

oil (7 mg, 10%, >99:1 dr); n_max(ATR) 2918 (CeH), 1724 (C]O); d_H

(500 MHz, CDCl₃) 1.38 (9H, s, CMe₃), 3.52 (1H, d, J 1.7, C(3)H), 3.63

(3H, s, C(5)OMe), 3.67 (3H, s, C(3⁰⁰)OMe), 3.87 (1H, d, J 13.4,

NCH_AH_BAr), 3.92 (1H, d, J 13.4, NCH_AH_BAr), 3.98 (1H, d, J 15.8,

C(1)H_A), 4.06 (1H, d, J 15.8, C(1)H_B), 4.65 (1H, app s, C(4)H),

6.58e6.65 (3H, m, C(6)H, C(2⁰⁰)H, C(6⁰⁰)H), 6.68e6.74 (2H, m, C(8)H,

Ar), 6.88e6.93 (2H, m, C(3⁰)H, C(5⁰)H), 7.06e7.18 (4H, m, C(7)H,

C(2⁰)H, C(6⁰)H, Ar); d_C(125 MHz, CDCl₃) 28.2 (CMe₃), 41.5 (C(4)), 50.4

(C(1)), 55.0 (C(3⁰⁰)OMe), 55.4 (C(5)OMe), 59.2 (NCH₂Ar), 65.9 (C(3)),

81.2 (CMe₃), 107.8 (C(6)), 112.9, 129.0 (C(4⁰⁰), C(5⁰⁰)), 113.6 (C(2⁰⁰)),

114.1 (d, J 21.0, C(3⁰), C(5⁰)), 118.3 (C(8)), 120.9 (C(6⁰⁰)), 123.7 (C(4a)),

127.0 (C(7)), 130.0 (d, J 7.6, C(2⁰), C(6⁰)), 136.1 (C(8a)), 140.4 (C(1⁰⁰)),

140.5 (d, J 2.9, C(1⁰)), 157.2 (C(5)), 159.6 (C(3⁰⁰)), 161.3 (d, J 243.2,

C(4⁰)), 171.4 (CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ118.0 (C(4⁰)F); m/z

þ

(ESI^þ) 480 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₉H₃₅FNO₄([MþH]^þ)

requires 480.2545; found 480.2545.

4.21. tert-Butyl (RS,RS)-2-hydroxy-3-[N,N-bis(3⁰⁰-methoxy-

benzyl)amino]-3-(4⁰-ﬂuorophenyl)propanoate 49

LiHMDS (1.0 M in THF, 1.25 mL, 1.25 mmol) was added to a stir-

red solution of 48 (400 mg, 0.834 mmol, >99:1 dr) in THF (4.2 mL)

at 0 ^ꢂC and the resultant mixture was stirred at 0 ^ꢂC for 30 min. The

reaction mixture was then cooled to ꢀ78 ^ꢂC and (ꢀ)-CSO (383 mg,

1.67 mmol) was added. The reaction mixture was stirred at ꢀ78 ^ꢂC

for 1.5 h then allowed to warm to rt. NH₄Cl (5 mL) was then added

and the reaction mixture was concentrated in vacuo. The residue

was partitioned between CH₂Cl₂(50 mL) and H₂O (30 mL), and the

aqueous layer was extracted with CH₂Cl₂(3ꢃ30 mL). The combined

organic extracts were then dried and concentrated in vacuo. The

residue was then triturated with cold Et₂O (100 mL) and ﬁltered.

The resultant solution was then dried and concentrated in vacuo,

which gave 49 in 83:17 dr. Puriﬁcation via ﬂash column chroma-

tography (toluene/Et₂O, 15:1) gave 49 as colourless oil (98 mg, 24%,

>99:1 dr); n_max(ATR) 3483 (OeH), 1723 (C]O); d_H(500 MHz,

CDCl₃) 1.28 (9H, s, CMe₃), 2.94 (1H, d, J 4.3, OH), 3.47 (2H, d, J 14.0,

N(CH_AH_BAr)₂), 3.81 (6H, s, 2ꢃOMe), 3.96 (2H, d, J 14.0, N(CH_AH-

_BAr)₂), 4.14 (1H, d, J 3.8, C(3)H), 4.77 (1H, app d, J 3.8, C(2)H),

6.77e6.81 (2H, m, Ar), 6.95e6.99 (4H, m, Ar), 7.00e7.05 (2H, m,

C(3⁰)H, C(5⁰)H), 7.21e7.26 (2H, m, Ar), 7.35e7.40 (2H, m, C(2⁰)H,

C(6⁰)H); d_C(125 MHz, CDCl₃) 27.7 (CMe₃), 54.8 (N(CH₂Ar)₂), 55.1

(2ꢃOMe), 63.7 (C(3)), 72.6 (C(2)), 82.8 (CMe₃), 112.2, 114.3, 121.0

(Ar), 114.8 (d, J 21.0, C(3⁰), C(5⁰)), 129.2 (Ar), 131.5 (d, J 7.6, C(2⁰),

C(6⁰)), 131.9 (d, J 3.8, C(1⁰)), 141.4, 159.7 (Ar), 162.2 (d, J 246.1,_þC(4⁰)),

172.8 (C(1)); d_F(377 MHz, CDCl₃) ꢀ114.9 (C(4⁰)F); m/z (ESI ) 496

þ

(ESI^þ) 478 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₉H₃₃FNO₄([MþH]^þ)

requires 478.2388; found 478.2381.

4.23. tert-Butyl (RS,SR)-2-[N-(4⁰⁰⁰-methoxybenzyl)amino]-3-

(4⁰⁰-methoxyphenyl)-3-(4⁰-ﬂuorophenyl)propanoate 52

Following general procedure II, Tf₂O (50

mL, 0.30 mmol) was

reacted with 47 (100 mg, 0.20 mmol, >99:1 dr) and DTBMP

(124 mg, 0.61 mmol) in CH₂Cl₂(2.5 mL) at rt for 6 h. Puriﬁcation via

ﬂash column chromatography (eluent petrol 30e40 ^ꢂC/Et₂O, 3:1)

gave 52 as a white solid (50 mg, 53%, >99:1 dr); mp 85e86 ^ꢂC; n_max

(ATR) 3320 (NeH), 1723 (C]O); d_H(500 MHz, CDCl₃) 1.25 (1H, s,

CMe₃), 1.75 (1H, br s, NH), 3.55 (1H, d, J 13.1, NCH_AH_BAr), 3.75e3.81

(5H, m, NCH_AH_BAr, C(2)H, OMe), 3.82 (3H, s, OMe), 4.08 (1H, d, J 9.6,

C(3)H), 6.78e6.94 (6H, m, Ar), 7.08 (4H, m, Ar), 7.21e7.25 (2H, m,

Ar); d_C(125 MHz, CDCl₃) 27.8 (CMe₃), 51.4 (NCH₂Ar), 53.1 (C(3)),

55.2, 55.3 (2ꢃOMe), 64.6 (C(2)), 81.1 (CMe₃), 113.6, 113.8 (C(3⁰⁰),

C(5⁰⁰), C(3⁰⁰⁰), C(5⁰⁰⁰)), 114.9 (d, J 21.0, C(3⁰), C(5⁰)), 129.3, 129.7 (C(2⁰⁰),

C(6⁰⁰), C(2⁰⁰⁰), C(6⁰⁰⁰)), 130.0 (d, J 8.6, C(2⁰), C(6⁰)), 131.6, 133.1 (C(1⁰⁰),

C(1⁰⁰⁰)), 137.8 (d, J 2.9, C(1⁰)), 158.3, 158.7 (C(4⁰⁰), C(4⁰⁰⁰)), 161.6 (d, J

245.1, C(4⁰)), 173.3 (C(1)); d_F(377 MHz, CDCl₃) ꢀ116.6 (C(4⁰)F); m/z

þ

([MþH]^þ, 100%); HRMS (ESI^þ) C₂₉H₃₅FNO₅([MþH]^þ) requires

þ

496.2494; found 496.2486.

(ESI^þ) 466 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₈H₃₃FNO₄([MþH]^þ)

requires 466.2388; found 466.2375.

4.22. (RS,RS)-N(2)-(3⁰⁰-Methoxybenzyl)-3-(tert-butoxy-

carbonyl)-4-(4⁰-ﬂuorophenyl)-7-methoxy-1,2,3,4-

tetrahydroisoquinoline

4.24. tert-Butyl (R,R,R)-2-hydroxy-3-[N-methyl-N-(

benzyl)amino]-3-(4⁰-ﬂuorophenyl)propanoate 57

a-methyl-

50 and (RS,RS)-N(2)-(3⁰⁰-methoxybenzyl)-3-(tert-butoxy-

carbonyl)-4-(4⁰-ﬂuorophenyl)-5-methoxy-1,2,3,4-

tetrahydroisoquinoline 51

Following general procedure I, BuLi (2.2 M in hexanes, 3.17 mL,

6.98 mmol) and (R)-N-methyl-N-(

-methylbenzyl)amine³²

a

(970 mg, 7.20 mmol, >99:1 er) were reacted with 27 (1.00 g,

4.50 mmol, >99:1 dr) and (ꢀ)-CSO (1.76 g, 7.65 mmol) in THF

(26 mL). Puriﬁcation via ﬂash column chromatography (eluent

Following general procedure II, Tf₂O (30

mL, 0.20 mmol) was

reacted with 49 (65 mg, 0.13 mmol, >99:1 dr) and DTBMP (81 mg,

0.39 mmol) in CH₂Cl₂(1.65 mL) at rt for 6 h, which gave a 77:23

mixture of 50 and 51, respectively. Puriﬁcation via ﬂash column

chromatography (30e40 ^ꢂC petrol/Et₂O, 10:1) gave 50 as a colour-

less oil (21.3 mg, 32%, >99:1 dr); n_max(ATR) 2933 (CeH), 2836

(CeH), 1725 (C]O); d_H(500 MHz, CDCl₃) 1.40 (9H, s, CMe₃), 3.53

(1H, d, J 2.8, C(3)H), 3.69 (3H, s, C(3⁰⁰)OMe), 3.77 (3H, s, C(7)OMe),

3.83 (1H, d, J 13.5, NCH_AH_BAr), 3.91 (1H, d, J 15.7, C(1)H_A), 3.93 (1H,

d, J 13.5, NCH_AH_BAr), 4.05 (1H, d, J 15.7, C(1)H_B), 4.43 (1H, d, J 2.8,

C(4)H), 6.59 (1H, d, J 2.5, C(8)H), 6.63e6.71 (3H, m, C(6)H, C(2⁰⁰)H,

C(6⁰⁰)H), 6.75 (1H, dd, J 8.2, 2.2, C(4⁰⁰)H), 6.88 (1H, d, J 8.5, C(5)H),

6.92e6.97 (2H, m, C(3⁰)H, C(5⁰)H), 7.09e7.13 (3H, m, C(2⁰)H, C(6⁰)H,

C(5⁰⁰)H); d_C(125 MHz, CDCl₃) 28.2 (CMe₃), 46.4 (C(4)), 51.1 (C(1)),

55.0 (C(3⁰⁰)OMe), 55.1 (C(7)OMe). 59.6 (NCH₂Ar), 66.9 (C(3)), 81.4

(CMe₃), 110.3 (C(8)), 112.9 (C(6)), 113.1 (C(4⁰⁰)),113.7 (C(2⁰⁰)),114.5 (d,

30e40 ^ꢂC petrol/Et₂O, 3:1) gave 57 as a pale yellow solid (729 mg,

20

43%, >99:1 dr); mp 81e84 ^ꢂC; [

a

]

þ59.0 (c 1.0 in CHCl₃); n_max

D

(ATR) 3492 (OeH), 2977 (CeH), 1726 (C]O); d_H(500 MHz, CDCl₃)

1.30 (3H, d, J 6.8, C( )Me), 1.32 (9H, s, CMe₃), 2.24 (3H, s, NMe), 3.77

(1H, q, J 6.8, C(

a

)H), 3.98 (1H, d, J 3.9, C(3)H), 4.65 (1H, d, J 3.9,

C(2)H), 6.99e7.05 (2H, m, C(3⁰)H, C(5⁰)H), 7.20e7.25 (1H, m, p-Ph),

7.28e7.39 (4H, m, o,m-Ph), 7.46e7.51 (2H, m, C(2⁰)H, C(6⁰)H); d_C

(125 MHz, CDCl₃) 11.7 (C(

a)Me), 27.9 (CMe₃), 33.0 (NMe), 56.8

(C(

a

)), 67.2 (C(3)), 71.0 (C(2)), 82.5 (CMe₃), 115.0 (d, J 21.0, C(3⁰),

C(5⁰)), 126.7 (p-Ph), 127.5, 128.1 (o,m-Ph), 131.0 (d, J 7.6, C(2⁰), C(6⁰)),

133.0 (d, J 3.8, C(1⁰)), 143.7 (i-Ph), 162.4 (d, J 246.1, C(4⁰)), 171_þ.7

(C(1)); d_F(377 MHz, CDCl₃) ꢀ114.3 (C(4⁰)F); m/z (ESI^þ) 374 ([MþH] ,

þ

100%); HRMS (ESI^þ) C₂₂H₂₉FNO₃([MþH]^þ) requires 374.2126;

found 374.2125.

2154

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

4.25. tert-Butyl (2S,3S,

a

R)-2-[N-methyl-N-(

a

-methylbenzyl)-

Puriﬁcation via ﬂash column chromatography (30e40 ^ꢂC petrol/

amino]-3-hydroxy-3-(4⁰-ﬂuorophenyl)propanoate 58

Et₂O, 5:1) gave 62 as a pale yellow viscous oil (4.18 g, 78%, >99:1

dr); [

a

]

²⁰þ2.0 (c 1.0 in CHCl₃); n_max(ATR) 3495 (OeH), 2978 (CeH),

D

Following general procedure II, Tf₂O (70

m

L, 0.40 mmol) was

1722 (C]O), 1603 (C]C); d_H(700 MHz, CDCl₃) 1.21 (3H, d, J 6.8,

reacted with 57 (100 mg, 0.27 mmol, >99:1 dr) and DTBMP

(165 mg, 0.80 mmol) in CH₂Cl₂(3.4 mL) at rt for 6 h. Puriﬁcation by

C(

15.7, 7.2, CH_AH_BCH]CH₂), 3.45 (1H, dd, J 15.7, 4.9, CH_AH_BCH]CH₂),

4.10 (1H, q, J 6.8, C( )H), 4.21 (1H, d, J 3.2, C(3)H), 4.51 (1H, d, J 3.2,

C(2)H), 5.03 (1H, app d, J 10.2, CH₂CH]CH_AH_B), 5.11 (1H, app d, J

17.2, CH₂CH]CH_AH_B), 5.83e5.91 (1H, m, CH₂CH]CH₂), 7.01 (2H,

app t, J 8.6, C(3⁰)H, C(5⁰)H), 7.22e7.48 (7H, m, C(2⁰)H, C(6⁰)H, Ph); d_C

a)Me), 1.29 (9H, s, CMe₃), 2.89e3.05 (1H, br s, OH), 3.25 (1H, dd, J

ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 5:1)

a

20

gave 58 as a pale brown oil (35 mg, 35%, >99:1 dr); [

a

]

e52.1 (c

D

0.3 in CHCl₃); n_max(ATR) 3469 (OeH), 2976 (CeH), 1723 (C]O); d_H

(500 MHz, CDCl₃) 1.12 (3H, d, J 6.6, C( )Me), 1.54 (9H, s, CMe₃), 2.11

)H), 3.70 (1H,

a

(3H, s, NMe), 3.38 (1H, br s, OH), 3.67 (1H, q, J 6.6, C(

a

(175 MHz, CDCl₃) 13.9 (C(

56.6 (C(a

a)Me), 27.8 (CMe₃), 50.5 (CH₂CH]CH₂),

d, J 8.7, C(2)H), 5.00 (1H, d, J 8.7, C(3)H), 6.86 (2H, d, J 6.0, C(3⁰)H,

)), 65.0 (C(3)), 72.3 (C(2)), 82.4 (CMe₃),114.9 (d, J 21.6, C(3⁰),

C(5⁰)H), 7.04e7.40 (7H, m, C(2⁰)H, C(6⁰)H, Ph); d_C(125 MHz, CDCl₃)

C(5⁰)), 115.7 (CH₂CH]CH₂), 126.7, 127.7, 128.1 (o,m,p-Ph), 131.2 (d, J

8.3, C(2⁰), C(6⁰)), 133.7 (d, J 2.5, C(1⁰)), 138.8 (CH₂CH]CH₂), 144.1 (i-

Ph), 162.3 (d, J 246.7, C(4⁰)), 172.0 (C(1)); d_F(377 MHz, CDCl₃) ꢀ114.6

20.5 (C(a)Me), 28.4 (CMe₃), 35.5 (NMe), 62.9 (C(a)), 67.5 (C(2)), 71.9

(C(3)), 82.2 (CMe₃), 114.7 (d, J 21.3, C(3⁰), C(5⁰)), 126.7, 127.0, 128.1

(o,m,p-Ph), 128.6 (d, J 8.3, C(2⁰), C(6⁰)), 137.4 (d, J 2.8, C(1⁰)), 145.6 (i-

Ph), 162.3 (d, J 24_þ6.0, C(4⁰)), 172.5_þ(C(1)); d_F(377 MHz, CDCl₃) ꢀ115.2

(C(4⁰⁰)F); m/z (ESI^þ) 400 ([MþH]^þ, 100%); HRMS (ESI^þ)

C

₂₄H₃₁FNO₃([MþH]^þ) requires 400.2282; found 400.2290.

þ

(C(4⁰)F); m/z (ESI ) 396 ([MþNa] , 16%), 374 ([MþH]^þ, 100%); HRMS

þ

(ESI^þ) C₂₂H₂₈FNNaO₃

396.1947.

([MþNa]^þ) requires 396.1945; found

4.28. (1R,3S,4S)-1-Methyl-N(2)-allyl-3-(tert-butoxycarbonyl)-

4-(4⁰-ﬂuorophenyl)-1,2,3,4-tetrahydroisoquinoline 63

4.26. (1R,3S,4S)-1,N(2)-Dimethyl-3-(tert-butoxycarbonyl)-4-

(4⁰-ﬂuorophenyl)-1,2,3,4-tetrahydroisoquinoline 59 and tert-

butyl (S,S)-2-(N-methyl-N-trifylamino)-3-(4⁰-ﬂuorophenyl)-3-

(2⁰⁰-vinylphenyl)propanoate 60

Following general procedure II, Tf₂O (0.13 mL, 0.75 mmol) was

reacted with 62 (200 mg, 0.50 mmol, >99:1 dr) and DTBMP

(310 mg, 1.0 mmol) in CH₂Cl₂(6.3 mL) at rt for 6 h. Puriﬁcation by

ﬂash column chromatography (eluent 30e40 ^ꢂC/Et₂O,10:1) gave 63

Following general procedure II, Tf₂O (70

mL, 0.40 mmol) was

as a brown viscous oil (20 mg, 31%, >99:1 dr); [

a

]

²⁰þ19.0 (c 0.5 in

D

reacted with 57 (100 mg, 0.27 mmol, >99:1 dr) and DTBMP

(165 mg, 0.80 mmol) in CH₂Cl₂(3.4 mL) at 40 ^ꢂC for 6 h, which gave

a 27:30:43 mixture of 58, 59 and 60, respectively. Puriﬁcation by

ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 8:1)

CHCl₃); n_max(ATR) 1729 (C]O), 1604 (C]C); d_H(500 MHz, CDCl₃)

1.27 (9H, s, CMe₃), 1.41 (3H, d, J 6.5, C(1)Me), 3.33e3.43 (2H, m,

CH₂CH]CH₂), 3.84 (1H, d, J 4.4, C(3)H), 4.27 (1H, q, J 6.5, C(1)H),

4.43 (1H, d, J 4.4, C(4)H), 4.91e4.99 (2H, m, CH₂CH]CH₂),

5.55e5.65 (1H, m, CH₂CH]CH₂), 6.91e7.23 (8H, m, Ar); d_C

(125 MHz, CDCl₃) 22.7 (C(1)Me), 27.9 (CMe₃), 46.7 (C(4)), 53.9

(CH₂CH]CH₂), 55.4 (C(1)), 64.8 (C(3)), 81.1 (CMe₃), 114.6 (d, J 21.0,

C(3⁰), C(5⁰)), 116.4 (CH₂CH]CH₂), 126.1, 126.7, 127.0, 129.5 (C(5),

C(6), C(7), C(8)), 130.3 (d, J 7.6, C(2⁰), C(6⁰)), 134.1 (C(4a)), 136.4

(CH₂CH]CH₂), 139.6 (d, J 1.9, C(1⁰)), 140.7 (C(8a)), 161.4 (d, J 244.1,

C(4⁰)) 172.0 (CO₂^tBu); d_F(472 MHz, CDCl₃) ꢀ117.2 (C(4⁰)F); m/z

gave 60 as a white solid (39 mg, 30%, >99:1 dr); mp 107e108 ^ꢂC;

20

[

a]

þ12.5 (c 0.3 in CHCl₃); n_max(ATR) 2982 (CeH), 2933 (CeH),

D

1732 (C]O), 1605 (C]C); d_H(700 MHz, CDCl₃) 1.16 (9H, s, CMe₃),

2.96 (3H, s, NMe), 4.72 (1H, d, J 12.1, C(3)H), 5.15 (1H, d, J 12.1,

C(2)H), 5.39 (1H, app d, J 11.0, CH]CH_AH_B), 5.56 (1H, app d, J 17.1,

CH]CH_AH_B), 6.97 (2H, t, J 8.5, Ar), 7.07 (1H, dd, J 17.1, 11.0, CH]

CH_AH_B), 7.24e7.61 (6H, m, Ar); d_C(175 MHz, CDCl₃) 27.4 (CMe₃), 31.4

(NMe), 46.0 (C(3)), 62.6 (C(2)), 83.0 (CMe₃), 115.6 (d, J 20.4, C(3⁰),

C(5⁰)), 118.4 (CH]CH₂), 119.7 (q, J 323.4, CF₃), 126.5, 127.8, 127.9,

128.5 (C(3⁰⁰), C(4⁰⁰), C(5⁰⁰), C(6⁰⁰)), 130.8 (d, J 7.6, C(2⁰), C(6⁰)), 133.7 (d,

J 3.8, C(1⁰)), 134.2 (C(1⁰⁰)), 135.0 (CH]CH₂), 137.4 (C(2⁰⁰)), 162.1 (d,

J 246.7, C(4⁰)), 168.6 (C(1)); d_F(377 MHz, CDCl₃) ꢀ114.6 (C(4⁰)F),

e75.1 (CF₃); m/z (FI^þ) 487 ([M]^þ, 100%); HRMS (FI^þ)

C₂₃H₂₅F₄NO₄S^þ([M]^þ) requires 487.1435; found 487.1302. Further

elution gave a 97:3 mixture of 59 and 60, respectively, as a brown

oil (14 mg, w15%). Data for 59: d_H(500 MHz, CDCl₃) 1.31 (9H, s,

þ

(ESI^þ) 382 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₄H₂₉FNO₂([MþH]^þ)

requires 382.2177; found 382.2180.

4.29. tert-Butyl (R,R,R)-2-hydroxy-3-[N-allyl-N-(a-methyl-

benzyl)amino]-3-[4⁰-(triﬂuoromethyl)phenyl]propanoate 66

Following general procedure I, BuLi (2.2 M in hexanes, 2.59 mL,

6.97 mmol) and (R)-N-allyl-N-(a

-methylbenzyl)amine³⁵(948 mg,

CMe₃), 1.47 (3H, d, J 5.5, C(

m, C(3)H), 4.11 (1H, d, J 5.5, C(

a

)Me), 2.53 (3H, s, NMe), 3.63e3.73 (1H,

)H), 4.38e4.44 (1H, m, C(4)H), 6.68

5.88 mmol, >99:1 er) were reacted with 24 (1.00 g, 3.68 mmol,

>99:1 dr) and (ꢀ)-CSO (1.43 g, 6.25 mmol) in THF (20 mL). Puriﬁ-

cation via ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/

Et₂O, 10:1) gave 66 as a pale yellow viscous oil (1.17 g, 71%, >99:1

a

(1H, d, J 7.6, Ar), 6.93e6.99 (2H, m, C(3⁰)H, C(5⁰)H), 7.06e7.11 (1H,

m, Ar), 7.12e7.21 (4H, m, C(2⁰)H, C(6⁰)H, Ar); d_C(500 MHz, CDCl₃)

21.2 (C(1)Me), 27.9 (CMe₃), 40.2 (NMe), 46.3 (C(4)), 57.5 (C(1)), 67.8

(C(3)), 81.3 (CMe₃), 114.9 (d, J 21.0, C(3⁰)H, C(5⁰)H), 126.1, 126.5,

126.7, 129.4 (C(5), C(6), C(7), C(8)), 130.6 (d, J 8.6, C(2⁰), C(6⁰)), 134.3

(C(8a)), 139.5 (C(4a)), 140.1 (C(1⁰)), 161.5 (d, J 244.1, C(4⁰)), 171.5

(CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ116.9 (C(4⁰)F); m/z (ESI^þ) 356

dr); [

a

]

²⁰þ2.1 (c 1.0 in CHCl₃)_;n_max(ATR) 3485 (OeH), 2978 (CeH),

D

1723 (C]O), 1619 (C]C); d_H(500 MHz, CDCl₃) 1.23 (3H, d, J 6.8,

C(

7.0, CH_AH_BCH]CH₂), 3.45e3.52 (1H, m, CH_AH_BCH]CH₂), 4.10 (1H,

q, J 6.8, C( )H), 4.30 (1H, d, J 3.5, C(3)H), 4.52 (1H, d, J 3.5, C(2)H),

a)Me), 1.30 (9H, s, CMe₃), 2.95 (1H, br s, OH), 3.30 (1H, dd, J 15.7,

a

þ

([MþH]^þ, 100%); HRMS (ESI^þ) C₂₂H₂₇FNO₂([MþH]^þ) requires

5.06 (1H, dd, J 10.2, 1.4, CH₂CH]CH_AH_B), 5.14 (1H, dd, J 17.2, 1.4,

CH₂CH]CH_AH_B), 5.85e5.94 (1H, m, CH₂CH]CH₂), 7.22e7.61 (9H,

356.2020; found 356.2025.

m, Ar, Ph); d_C(125 MHz, CDCl₃) 14.3 (C(a)Me), 27.5 (CMe₃), 50.7

4.27. tert-Butyl (R,R,R)-2-hydroxy-3-[N-allyl-N-(

a

-methyl-

(CH₂CH]CH₂), 57.0 (C( )), 65.1 (C(3)), 72.1 (C(2)), 82.7 (CMe₃),116.0

a

benzyl)amino]-3-(4⁰-ﬂuorophenyl)propanoate 62

(CH₂CH]CH₂), 124.2 (q, J 271.8, CF₃), 124.9 (q, J 3.8, C(3⁰), C(5⁰)),

126.8, 127.7, 128.2 (o,m,p-Ph), 129.8 (q, J 32.4, C(4⁰)), 129.8 (C(2⁰),

C(6⁰)), 138.7 (CH₂CH]CH₂), 142.4 (C(1⁰)), 143.8 (i-Ph), 172.0 (C(1));

d_F(472 MHz, CDCl₃) ꢀ62.5 (CF₃); m/z (ESI^þ) 450 ([MþH]^þ, 100%);

Following general procedure I, BuLi (2.2 M in hexanes, 9.52 mL,

20.9 mmol) and (R)-N-allyl-N-(

-methylbenzyl)amine³⁵(3.48 g,

a

þ

21.6 mmol, >99:1 er) were reacted with 27 (3.00 g, 13.5 mmol,

>99:1 dr) and (ꢀ)-CSO (5.27 g, 23.0 mmol) in THF (80 mL).

HRMS (ESI^þ) C₂₅H₃₁F₃NO₃([MþH]^þ) requires 450.2251; found

450.2249.

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2155

4.30. tert-Butyl (R,R,R)-2-hydroxy-3-[N-allyl-N-(

a

-methyl-

1.3, CH₂CH¼CH_AH_B), 5.87 (1H, dddd, J 17,2, 10.2, 7.2, 5.3, CH₂CH]

CH₂), 7.16e7.50 (10H, m, Ph).

benzyl)amino]-3-(3⁰-ﬂuorophenyl)propanoate 67

Following general procedure I, BuLi (2.2 M in hexanes, 9.52 mL,

20.9 mmol) and (R)-N-allyl-N-(

-methylbenzyl)amine³⁵(3.48 g,

4.33. tert-Butyl (R,R,R)-2-hydroxy-3-[N-allyl-N-(a-methyl-

a

benzyl)amino]-3-(4⁰-methoxyphenyl)propanoate 70

21.6 mmol, >99:1 er) were reacted with 25 (3.00 g, 13.5 mmol,

>99:1 dr) and (ꢀ)-CSO (5.27 g, 23.0 mmol) in THF (80 mL). Puri-

ﬁcation via ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/

Et₂₂O₀, 5:1) gave 67 as pale yellow viscous oil (3.74 g, 69%, >99:1 dr);

Following general procedure I, BuLi (2.2 M in hexanes, 4.51 mL,

9.93 mmol) and (R)-N-allyl-N-(a

-methylbenzyl)amine³⁵(1.65 g,

10.3 mmol, >99:1 er) were reacted with 28 (1.50 g, 6.41 mmol,

>99:1 dr) and (ꢀ)-CSO (2.50 g, 10.9 mmol) in THF (36 mL). Puriﬁ-

cation via ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/

Et₂O, 5:1) gave 70 as a pale yellow oil (2.10 g, 80%, >99:1 dr);

[

a]

þ0.3 (c 1.0 in CHCl₃); n_max(ATR) 3479 (OeH), 2975 (CeH),

D

1724 (C]O), 1588 (C]C); d_H(500 MHz, CDCl₃) 1.23 (3H, d, J 6.9,

C( )Me), 1.31 (9H, s, CMe₃), 2.95 (1H, br s, OH), 3.28 (1H, dd, J 15.7,

7.0, CH_AH_BCH]CH₂), 3.44e3.52 (1H, m, CH_AH_BCH]CH₂), 4.13 (1H,

q, J 6.9, C( )H), 4.22 (1H, d, J 3.5, C(3)H), 4.49 (1H, d, J 3.5, C(2)H),

a

[a

]

²⁰þ16.8 (c 1.0 in CHCl₃); n_max(ATR) 3490 (OeH), 2975 (CeH),

D

a

1724 (C]O), 1610 (C]C); d_H(500 MHz, CDCl₃) 1.20 (3H, d, J 6.8,

5.05 (1H, dd, J 10.2, 1.7, CH₂CH]CH_AH_B), 5.13 (1H, dd, J 17.3, 1.7,

CH₂CH]CH_AH_B), 5.84e5.94 (1H, m, CH₂CH]CH₂), 6.94e7.48 (9H,

C(

7.2, CH_AH_BCH]CH₂), 3.44 (1H, dd, J 15.6, 5.4, CH_AH_BCH]CH₂), 3.79

(3H, s, OMe), 4.11 (1H, q, J 6.8, C( )H), 4.17 (1H, d, J 3.8, C(3)H), 4.50

a)Me), 1.30 (9H, s, CMe₃), 3.02 (1H, br s, OH), 3.22 (1H, dd, J 15.6,

m, Ar, Ph); d_C(125 MHz, CDCl₃) 14.1 (C(

a)Me), 27.8 (CMe₃), 50.6

a

(CH₂CH]CH₂), 56.8 (C( )), 65.1 (C(3)), 72.3 (C(2)), 82.6 (CMe₃),

a

(1H, d, J 3.8, C(2)H), 5.02 (1H, dd, J 10.2, 1.4, CH₂CH]CH_AH_B), 5.11

(1H, dd, J 17.2, 1.4, CH₂CH]CH_AH_B), 5.82e5.92 (1H, m, CH₂CH]

114.5 (d, J 21.0, C(2⁰)), 115.8 (CH₂CH]CH₂), 116.5 (d, J 21.0, C(4⁰)),

125.1 (d, J 2.9, C(6⁰)), 126.7, 127.7, 128.1 (o,m,p-Ph), 129.4 (d, J 7.6,

C(5⁰)), 138.7 (CH₂CH]CH₂), 140.7 (d, J 6.7, C(1⁰)), 144.0 (i-Ph), 162.5

(d, J 245.1, C(3⁰)), 172.0 (C(1)); d_F(472 MHz, CDCl₃) ꢀ113.3 (C(3⁰⁰)F);

CH₂), 6.82e7.46 (9H, m, Ar, Ph); d_C(125 MHz, CDCl₃) 13.6 (C(

a)Me),

27.8 (CMe₃), 50.6 (CH₂CH]CH₂), 55.1 (OMe), 56.4 (C( )), 65.4 (C(3)),

a

72.5 (C(2)), 82.1 (CMe₃), 113.4 (C(3⁰), C(5⁰)), 115.6 (CH₂CH]CH₂),

126.6 (p-Ph), 127.8, 128.0 (o,m-Ph), 129.8 (C(1⁰)) 130.7 (C(2⁰), C(6⁰)),

138.9 (CH₂CH]CH₂), 144.3 (i-Ph), 159.0 (C(4⁰)), 172.2_þ(C(1)); m/z

(ESI^þ) 412 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₅H₃₄NO₄([MþH]^þ)

requires 412.2482; found 412.2478.

þ

m/z (ESI^þ) 400 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₄H₃₁FNO₃

([MþH]^þ) requires 400.2282; found 400.2291.

4.31. tert-Butyl (R,R,R)-2-hydroxy-3-[N-allyl-N-(a-methyl-

benzyl)amino]-3-(3⁰-methoxyphenyl)propanoate 68

4.34. (1R,3S,4S)-1-Methyl-N(2)-allyl-3-(tert-butoxycarbonyl)-

4-[4⁰-(triﬂuoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline

Following general procedure I, BuLi (2.2 M in hexanes, 9.03 mL,

71

19.9 mmol) and (R)-N-allyl-N-(a

-methylbenzyl)amine³⁵(3.30 g,

20.5 mmol, >99:1 er) were reacted with 26 (3.00 g, 12.8 mmol,

>99:1 dr) and (ꢀ)-CSO (4.99 g, 21.8 mmol) in THF (80 mL). Puriﬁ-

cation via ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/

Et₂O, 3:1) gave 68 as a pale yellow viscous oil (3.69 g, 70%, >99:1

Following general procedure II, Tf₂O (0.12 mL, 0.67 mmol) was

reacted with 66 (200 mg, 0.45 mmol, >99:1 dr) and DTBMP

(270 mg, 1.3 mmol) in CH₂Cl₂(5.6 mL) at 40 ^ꢂC for 24 h, which gave

an 82:18 mixture of 71 and 76, respectively. Puriﬁcation by ﬂash

column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 15:1) gave

dr); [

a

]

²⁰þ3.0 (c 1.0 in CHCl₃); n_max(ATR) 3486 (OeH), 2976 (CeH),

D

1723 (C]O), 1599 (C]C); d_H(500 MHz, CDCl₃) 1.23 (3H, d, J 7.0,

71 as a yellow oil (50 mg, 26%, >99:1 dr); [a]

²⁰e12.9 (c 0.5 in CHCl₃);

D

C(

3.43e3.52 (1H, m, CH_AH_BCH]CH₂), 3.80 (3H, s, OMe), 4.14 (1H, q, J

7.0, C( )H), 4.21 (1H, d, J 3.8, C(3)H), 4.51 (1H, d, J 3.8, C(2)H),

a)Me), 1.32 (9H, s, CMe₃), 3.27 (1H, dd, J 15.6, 7.1, CH_AH_BCH]CH₂),

n_max(ATR) 1727 (C]O),1618 (C]C); d_H(500 MHz, CDCl₃) 1.28 (9H, s,

CMe₃), 1.42 (3H, d, J 6.6, C(1)Me), 3.38e3.41 (2H, m, CH₂CH]CH₂),

3.90 (1H, d, J 3.9, C(3)H), 4.30 (1H, q, J 6.6, C(1)H), 4.52 (1H, d,

J 3.9, C(4)H), 4.90e4.99 (2H, m, CH₂CH]CH₂), 5.51e5.61 (1H, m,

CH₂CH]CH₂), 6.93e6.96 (1H, m, C(5)H), 7.10e7.15 (1H, m, C(6)H),

7.17e7.20 (1H, m, C(7)H), 7.23e7.32 (3H, m, C(8)H, C(2⁰)H, C(6⁰)H),

7.50e7.55 (2H, m, C(3⁰)H, C(5⁰)H); d_C(125 MHz, CDCl₃) 22.8 (C(1)Me),

27.9 (CMe₃), 47.4 (C(4)), 54.0 (CH₂CH]CH₂), 55.4 (C(1)), 64.5 (C(3)),

81.2 (CMe₃), 116.6 (CH₂CH]CH₂), 124.3 (q, J 271.8, CF₃), 124.8 (q,

J 3.8, C(3⁰), C(5⁰)), 126.1 (C(6)), 127.0 (C(8)), 127.1 (C(7)), 128.4 (q, J

32.5, C(4⁰)), 129.2 (C(2⁰), C(6⁰)), 129.6 (C(5)), 133.2 (C(4a)), 136.1

(CH₂CH]CH₂), 140.9 (C(8a)), 148.1 (C(1⁰)), 171.8 (CO₂^tBu); d_F

(472 MHz, CDCl₃) ꢀ62.3 (CF₃); m/z (ESI^þ) 432 ([MþH]^þ,100%); HRMS

a

5.04 (1H, dd, J 10.1, 1.4, CH₂CH]CH_AH_B), 5.13 (1H, dd, J 17.3, 1.4,

CH₂CH]CH_AH_B), 5.86e5.95 (1H, m CH₂CH]CH₂), 6.82 (1H, dd, J

8.2, 2.5, C(4⁰)H), 7.02e7.07 (2H, m, C(2⁰)H, C(6⁰)H) 7.20e7.25 (2H, m,

p-Ph, C(5⁰)H), 7.32 (2H, app t, J 7.6, m-Ph), 7.46 (2H, d, J 7.4, o-Ph); d_C

(125 MHz, CDCl₃) 13.9 (C(

a)Me), 27.8 (CMe₃), 50.6 (CH₂CH]CH₂),

55.2 (OMe), 56.6 (C(

a

)), 65.8 (C(3)), 72.4 (C(2)), 82.2 (CMe₃), 113.0

(C(4⁰)), 115.3, 121.9 (C(2⁰), C(6⁰)), 115.6 (CH₂CH]CH₂), 126.6, 129.0

(C(5⁰), p-Ph), 127.7, 128.0 (o,m-Ph), 138.9 (CH₂CH]CH₂), 139.5

(C(1⁰)), 144.2 (i-Ph), 159.3 (C(3⁰)), 172.4 (C(1)); m/z (ESI^þ) 412

þ

([MþH]^þ, 100%); HRMS (ESI^þ) C₂₅H₃₄NO₄([MþH]^þ) requires

412.2482; found 412.2483.

þ

(ESI^þ) C₂₅H₂₉F₃NO₂([MþH]^þ) requires 432.2145; found 432.2133.

4.32. tert-Butyl (R,R,R)-2-hydroxy-3-[N-allyl-N-(

benzyl)amino]-3-phenylpropanoate 69

a

-methyl-

4.35. (1R,3S,4S)-1-Methyl-N(2)-allyl-3-(tert-butoxycarbonyl)-

4-(3⁰-ﬂuorophenyl)-1,2,3,4-tetrahydroisoquinoline 72

Following general procedure I, BuLi (2.3 M in hexanes, 4.95 mL,

11.4 mmol) and (R)-N-allyl-N-(

-methylbenzyl)amine³⁵(1.89 g,

Following general procedure II, Tf₂O (130 mL, 0.75 mmol) was

a

reacted with 67 (200 mg, 0.50 mmol, >99:1 dr) and DTBMP

11.8 mmol, >99:1 er) were reacted with 65 (1.50 g, 7.34 mmol,

>99:1 dr) and (ꢀ)-CSO (2.86 g, 12.5 mmol) in THF (60 mL). Puriﬁ-

cation via ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/

Et₂₂O₀, 10:1) gave 69 as a pale yellow oil (2.03 g, 73%, >99:1 dr);³⁶

(310 mg, 1.50 mmol) in CH₂Cl₂(6.3 mL) at 40 ^ꢂC for 24 h. Puriﬁ-

cation by ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/

20

Et₂O, 20:1) gave 72 as a pale yellow oil (53 mg, 28%, >99:1 dr); [a]

D

þ85.2 (c 0.3 in CHCl₃); n_max(ATR) 1728 (C]O), 1615 (C]C); d_H

(500 MHz, CDCl₃) 1.28 (9H, s, CMe₃), 1.41 (3H, d, J 6.6, C(1)Me),

3.37e3.41 (2H, m, CH₂CH]CH₂), 3.88 (1H, d, J 4.3, C(3)H), 4.27

(1H, q, J 6.6, C(1)H), 4.45 (1H, d, J 4.3, C(4)H), 4.93e4.99 (2H, m,

CH₂CH]CH₂), 5.56e5.65 (1H, m, CH₂CH]CH₂), 6.84e6.92 (2H, m,

C(2⁰)H, C(4⁰)H), 6.94e7.00 (2H, m, C(6)H, C(6⁰)H), 7.09e7.14 (1H, m,

[

a

]

þ4.5 (c 1.0 in CHCl₃); d_H(400 MHz, CDCl₃) 1.18 (3H, d, J 6.8,

D

C(

7.2, CH_AH_BCH]CH₂), 3.44 (1H, dd, J 15.6, 5.3, CH_AH_BCH]CH₂), 4.11

(1H, q, J 6.8, C( )H), 4.21 (1H, d, J 3.4, C(3)H), 4.51 (1H, d, J, 3.4,

C(2)H), 5.01 (1H, dd, J 10.2, 1.3, CH₂CH]CH_AH_B), 5.10 (1H, dd, J 17.2,

a)Me), 1.26 (9H, s, CMe₃), 2.96 (1H, br s, OH), 3.23 (1H, dd, J 15.6,

a

2156

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

C(5)H), 7.15e7.18 (1H, m, C(8)H), 7.20e7.26 (2H, m, C(7)H, C(5⁰)H);

d_C(125 MHz, CDCl₃) 22.8 (C(1)Me), 27.9 (CMe₃), 47.2 (C(4)), 54.0

(CH₂CH]CH₂), 55.4 (C(1)), 64.5 (C(3)), 81.1 (CMe₃), 113.0 (d, J 21.0,

Ar), 115.9 (d, J 21.9, Ar), 116.5 (CH₂CH]CH₂), 124.5 (d, J 2.9, C(6⁰)),

126.0 (C(5)), 126.8 (C(7)), 127.0 (C(8)), 129.2 (d, J 8.6, C(5⁰)), 129.6

(C(6)), 133.5 (C(8a)), 136.3 (CH₂CH]CH₂), 140.8 (C(4a)), 146.7 (d, J

6.7, C(1⁰)), 162.6 (d, J 245.1, C(3⁰)), 171.9 (CO₂^tBu); d_F(472 MHz,

CDCl₃) ꢀ114.0 (C(3⁰)F); m/z (ESI^þ) 382 ([MþH]^þ, 100%); HRMS

a 4:96 mixture of 71 and 76, respectively. Puriﬁcation by ﬂash

column chromatography (30e40 ^ꢂC petrol/Et₂O, 10:1) gave 71 as

a yellow oil (4 mg, 3%, >99:1 dr). Further elution gave 76 as a col-

ourless oil (39 mg, 31%, >99:1 dr); [

a

]

D

²⁰þ83.0 (c 1.0 in CHCl₃); n_max

(ATR) 3447 (OeH), 2978 (CeH), 1723 (C]O), 1620 (C]C); d_H

(500 MHz, CDCl₃) 1.29 (3H, d, J 6.9, C(

3.35 (1H, dd, J 14.9, 8.1, CH_AH_BCH]CH₂), 3.41e3.53 (1H, m,

CH_AH_BCH]CH₂), 3.54 (1H, d, J 8.8, C(2)H), 4.03 (1H, q, J 6.9, C( )H),

a)Me), 1.55 (9H, s, CMe₃),

a

þ

(ESI^þ) C₂₄H₂₉FNO₂([MþH]^þ) requires 382.2177; found 382.2173.

4.91 (1H, d, J 8.8, C(3)H), 5.09 (1H, app d, J 10.1, CH₂CH]CH_AH_B), 5.14

(1H, dd, J 16.7, 1.0, CH₂CH]CH_AH_B), 5.61e5.67 (1H, m, CH₂CH]CH₂),

6.85 (2H, d, J 7.3, C(2⁰)H, C(6⁰)H), 7.07e7.22 (5H, m, Ph), 7.47 (2H, d, J

4.36. (1R,3S,4S)-1-Methyl-N(2)-allyl-3-(tert-butoxycarbonyl)-

4-(3⁰-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline 73

8.2, C(3⁰)H, C(5⁰)H); d_C(125 MHz, CDCl₃) 14.9 (C(

a)Me), 28.1 (CMe₃),

51.4 (CH₂CH]CH₂), 57.2 (C(a)), 65.3 (C(2)), 73.2 (C(3)), 82.0 (CMe₃),

Method A: Following general procedure II, Tf₂O (60

m

L,

117.2 (CH₂CH]CH₂),124.2 (q, J 271.8, CF₃), 124.7 (q, J 3.8, C(3⁰), C(5⁰)),

126.6, 127.4, 127.6 (o,m,p-Ph), 127.9 (C(2⁰), C(6⁰)), 129.6 (q, J 32.4,

C(4⁰)),137.2 (CH₂CH]CH₂), 143.2 (i-Ph), 145.6 (C(1⁰)),173.1 (C(1)); d_F

(377 MHz, CDCl₃) ꢀ62.4 (CF₃); m/z (ESI^þ) 450 ([MþH]^þ, 100%);

0.37 mmol) was reacted with 68 (100 mg, 0.24 mmol, >99:1 dr) and

DTBMP (150 mg, 0.73 mmol) in CH₂Cl₂(3.1 mL) at rt for 6 h, which

gave a 66:34 mixture of 73 and 78, respectively. Puriﬁcation by

ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 20:1)

þ

HRMS (ESI^þ) C₂₅H₃₀F₃NNaO₃([MþNa]^þ) requires 472.2070;

gave 73 as a brown oil (20 mg, 20%, >99:1 dr); [

a

]

D

²⁰þ76.1 (c 0.4 in

found 472.2078.

CHCl₃); n_max(ATR) 1728 (C]O), 1599 (C]C); d_H(500 MHz, CDCl₃)

1.28 (9H, s, CMe₃), 1.43 (3H, d, J 6.5, C(1)Me), 3.37e3.42 (2H, m,

CH₂CH]CH₂), 3.76 (3H, s, OMe), 3.91 (1H, d, J 4.5, C(3)H), 4.27 (1H, q, J

6.5, C(1)H), 4.42 (1H, d, J 4.5, C(4)H), 4.95e5.01 (2H, m, CH₂CH]CH₂),

5.60e5.69 (1H, m, CH₂CH]CH₂), 6.73e6.80 (3H, m, Ar), 6.95e7.00

(1H, m, C(5)H), 7.07e7.13 (4H, m, C(6)H, C(7)H, C(8)H, Ar); d_C

(125 MHz, CDCl₃) 22.7 (C(1)Me), 27.9 (CMe₃), 47.4 (C(4)), 54.0

(CH₂CH]CH₂), 55.1 (OMe), 55.4 (C(1)), 64.7 (C(3)), 80.9 (CMe₃), 111.5,

114.9, 121.5 (Ar), 116.4 (CH₂CH]CH₂), 125.9, 128.8 (C(7), Ar), 126.5

(C(6)), 126.9 (C(8)), 129.6 (C(5)), 134.1 (C(4a)), 136.4 (CH₂CH]CH₂),

140.6 (C(8a)), 145.6 (C(1⁰)), 159.2 (C(3⁰)), 172.2 _þ(CO₂^tBu); m/z (ESI^þ)

394 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₅H₃₂NO₃([MþH]^þ) requires

394.2377; found 394.2372.

4.39. tert-Butyl (2S,3S,

aR)-2-[N-allyl-N-(a-methylbenzyl)

amino]-3-hydroxy-3-(3⁰-ﬂuorophenyl)propanoate 77

Following general procedure II, Tf₂O (60

mL, 0.38 mmol) was

reacted with 67 (100 mg, 0.25 mmol, >99:1 dr) and DTBMP

(154 mg, 0.75 mmol) in CH₂Cl₂(3.2 mL) at rt for 6 h, which gave

a 20:80 mixture of 72 and 77, respectively. Puriﬁcation by ﬂash

column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 8:1) gave

72 as a pale yellow oil (13 mg, 14%, >99:1 dr). Further elution gave

77 as a viscous yellow oil (55 mg, 55%, >99:1 dr); [

in CHCl₃); n_max(ATR) 3479 (OeH), 2977 (CeH), 1723 (C]O), 1592

(C]C); d_H(500 MHz, CDCl₃) 1.30 (3H, d, J 6.8, C( )Me), 1.54 (9H, s,

CMe₃), 3.35 (1H, dd, J 14.8, 7.9, CH_AH_BCH]CH₂), 3.44e3.51 (1H, m,

CH_AH_BCH]CH₂), 3.54 (1H, d, J 8.4, C(2)H), 4.06 (1H, q, J 6.8, C( )H),

a]

²⁰e37.7 (c 1.2

D

a

Method B: Following general procedure II, Tf₂O (0.12 mL,

0.73 mmol) was reacted with 68 (200 mg, 0.486 mmol, >99:1 dr)

and DTBMP (300 mg, 1.46 mmol) in CH₂Cl₂(3.15 mL) at 40 ^ꢂC for

24 h. Puriﬁcation by ﬂash column chromatography (eluent 30e40 ^ꢂC

petrol/Et₂O,15:1) gave 73 as a pale yellow oil (45 mg, 24%, >99:1 dr).

a

4.88 (1H, d, J 8.4, C(3)H), 5.07 (1H, dd, J 10.1, 1.2, CH₂CH]CH_AH_B),

5.12 (1H, dd, J 17.3, 1.2, CH₂CH]CH_AH_B), 5.61e5.61 (1H, m,

CH₂CH]CH₂), 6.79e7.24 (9H, m, Ar, Ph); d_C(125 MHz, CDCl₃) 15.2

(C(a)Me), 28.1 (CMe₃), 51.4 (CH₂CH]CH₂), 57.5 (C(a)), 65.4 (C(2)),

4.37. (1R,3S,4S)-1-Methyl-N(2)-allyl-3-(tert-butoxycarbonyl)-

4-phenyl-1,2,3,4-tetrahydroisoquinoline 74

73.2 (C(3)), 81.9 (CMe₃), 114.0 (d, J 21.9, Ar), 114.3 (d, J 21.0, Ar), 117.0

(CH₂CH]CH₂), 122.9 (d, J 2.9, C(6⁰)), 126.7, 127.7, 128.0, (o,m,p-Ph),

129.2 (d, J 7.6, C(5⁰)), 137.4 (CH₂CH]CH₂), 143.5 (i-Ph), 144.2 (d, J 7.6,

C(1⁰)),162.6 (d, J 245.1, C(3⁰)),173.1 (C(1)); d_F(472 MHz, CDCl₃) ꢀ113.7

Following general procedure II, Tf₂O (53

mL, 0.31 mmol) was

þ

reacted with 69 (100 mg, 0.26 mmol, >99:1 dr) and DTBMP

(129 mg, 0.63 mmol) in CH₂Cl₂(3.3 mL) at rt for 6 h. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 20:1)

(C(3⁰)F); m/z (ESI^þ) 400 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₄H₃₁FNO₃

([MþH]^þ) requires 400.2282; found 400.2292.

gave 74 as a pale red oil (30 mg, 32%, >99:1 dr); n_max(ATR) 1728

4.40. (R)-N-[4-(Triﬂuoromethyl)benzyl]-N-(a-methylbenzyl)

amine 82

20

(C]O), 1149 (C]C); [

a]

þ80.0 (c 0.5 in CHCl₃); d_H(500 MHz,

D

CDCl₃) 1.28 (9H, s, CMe₃), 1.43 (3H, d, J 6.6, C(1)Me), 3.33e3.39 (1H,

m, CH_AH_BCH]CH₂), 3.43 (1H, dd, J 14.8, 6.9, CH_AH_BCH]CH₂), 3.91

(1H, d, J 4.5, C(3)H), 4.28 (1H, q, J 6.6, C(1)H), 4.64 (1H, d, J 4.5,

C(4)H), 4.91e4.98 (2H, m, CH₂CH]CH₂), 5.63 (1H, dddd, J 17.0, 10.7,

6.9, 5.0, CH₂CH]CH₂), 6.96e7.29 (9H, m, Ar, Ph); d_C(125 MHz,

CDCl₃) 22.6 (C(1)Me), 27.9 (CMe₃), 47.3 (C(4)), 53.9 (CH₂CH]CH₂),

55.4 (C(1)), 64.8 (C(3)), 80.9 (CMe₃), 116.3 (CH₂CH]CH₂), 125.9

(C(8)), 126.2, 126.5 (C(6), C(7)), 126.9 (p-Ph), 127.9, 129.0 (o,m-Ph),

129.6 (C(5)), 134.3 (C(4a)), 136.3 (CH₂CH]CH₂), 140.7 (C(8a)), 143.8

p-(Triﬂuoromethyl)benzaldehyde (8.62 g, 49.5 mmol) was

added to stirred solution of (R)- -methylbenzylamine 81

a

(6.00 mL, 47.2 mmol, >99:1 er) in EtOH (30 mL) and the resultant

solution was heated at reﬂux for 3 h. The reaction mixture was

allowed to cool to rt, then cooled to 0 ^ꢂC. NaBH₄(1.78 g, 47.2 mmol)

was added portionwise (maintaining a reaction temperature below

15 ^ꢂC), and the resultant suspension was stirred at rt for 20 h. The

reaction mixture was then concentrated in vacuo and the residue

was partitioned between CH₂Cl₂(500 mL) and H₂O (500 mL). The

aqueous layer was extracted with CH₂Cl₂(2ꢃ200 mL) and the

combined organic extracts were then dried and concentrated in

vacuo to give 82 as a yellow oil (12.6 g, 96%, >99:1 er);³⁷n_max(ATR)

t

(i-Ph), 172.1 (CO₂Bu); m/z (ESI^þ) 364 ([MþH]^þ, 100%); HRMS (ESI^þ)

þ

C

₂₄H₃₁NO₂([MþH]^þ) requires 364.2271; found 364.2276.

4.38. tert-Butyl (2S,3S,aR)-2-[N-allyl-N-(a-methylbenzyl)-

amino]-3-hydroxy-3-[4⁰-(triﬂuoromethyl)phenyl]propanoate

3467 (NeH), 1325 (CeF); [

CDCl₃) 1.30 (3H, d, J 6.6, C(

a

]

²⁰þ39.4 (c 1.0 in CHCl₃); d_H(500 MHz,

D

76

)Me), 1.55 (1H, br s, NH), 3.57 (1H, d, J

13.7, NCH_AH_BAr), 3.62 (1H, d, J 13.7, NCH_AH_BAr), 3.71 (1H, q, J 6.6,

C( )H), 7.16e7.29 (5H, m, Ph), 7.32 (2H, d, J 8.0, C(2)H, C(6)H), 7.48

(2H, d, J 8.0, C(3)H, C(5)H); d_C(125 MHz, CDCl₃) 24.5 (C( )Me), 51.1

(NCH₂Ar), 57.6 (C( )), 124.3 (q, J 271.8, CF₃), 125.3 (q, J 3.8, C(3),

Following general procedure II, Tf₂O (70

reacted with 66 (128 mg, 0.29 mmol, >99:1 dr) and DTBMP

(180 mg, 0.86 mmol) in CH₂Cl₂(3.6 mL) at rt for 6 h, which gave

m

L, 0.43 mmol) was

a

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2157

C(5)), 126.7 (m-Ph), 127.1 (p-Ph), 128.3 (o-Ph), 128.6 (C(2), C(6)),

129.1 (q, J 32,4, C(4)), 144.8 (C(1)), 145.3 (i-Ph); d_F(377 MHz, CDCl₃)

ꢀ62.3 (CF₃); m/z (ESI^þ) 280 ([MþH]^þ, 100%); HRMS (ESI^þ)

J 6.9, C(

7.26e7.64 (13H, m, Ar, Ph); d_C(125 MHz, CDCl₃) 16.1 (C(

(CMe₃), 51.9 (NCH₂Ar), 58.5 (C( )), 64.3 (C(3)), 72.7 (C(2)), 83.0

a

)H), 4.35 (1H, d, J 2.7, C(3)H), 4.48e4.53 (1H, m, C(2)H),

a)Me), 27.7

a

C

₁₆H₁₇F₃N^þ([MþH]^þ) requires 280.1308; found 280.1303.

(CMe₃), 124.0, 124.3 (2ꢃq, J 271.8, 2ꢃCF₃), 124.9, 125.1 (2ꢃq, J 3.5,

C(3⁰), C(5⁰), C(3⁰⁰), C(5⁰⁰)), 127.3 (p-Ph), 127.8, 130.0 (o,m-Ph), 128.0

(C(2⁰⁰), C(6⁰⁰)), 128.4 (C(2⁰), C(6⁰)), 128.9, 129.8 (2ꢃq, J 32.5, C(4⁰),

C(4⁰⁰)), 142.5 (C(1⁰)), 143.4 (i-Ph), 146.2 (C(1⁰⁰)), 172.2 (C(1)); d_F

(377 MHz, CDCl₃) ꢀ62.3, e62.5 (2ꢃCF₃); m/z (ESI^þ) 568 ([MþH]^þ,

4.41. tert-Butyl (R,R,R)-2-hydroxy-3-{N-[4⁰⁰-(triﬂuoromethyl)-

benzyl]-N-(a

-methylbenzyl)amino}-3-(4⁰-ﬂuorophenyl)prop-

anoate 83

þ

100%); HRMS (ESI^þ) C₃₀H₃₂F₆NO₃([MþH]^þ) requires 568.2281;

Following general procedure I, BuLi (2.2 M in hexanes, 1.59 mL,

3.50 mmol) and (R)-82 (1.00 g, 3.60 mmol, >99:1 er) were reacted

with 27 (500 mg, 2.25 mmol, >99:1 dr) and (ꢀ)-CSO (877 mg,

3.83 mmol) in THF (18 mL). Puriﬁcation via ﬂash column chroma-

tography (eluent 30e40 ^ꢂC petrol/Et₂O, 5:1) gave 83 as a pale

found 568.2274.

4.44. tert-Butyl (R,R,R)-2-hydroxy-3-{N-[4⁰⁰-(triﬂuoromethyl)-

benzyl]-N-(a

-methylbenzyl)amino}-3-(3⁰-ﬂuorophenyl)prop-

anoate 87

yellow oil (985 mg, 85%, >99:1 dr); n_max(ATR) 3490 (OeH), 1724

20

(C]O), 1325 (CeF); [

a]

e25.6 (c 1.0 in CHCl₃); d_H(500 MHz,

Following general procedure I, BuLi (2.2 M in hexanes, 1.59 mL,

3.50 mmol) and (R)-82 (1.00 g, 3.60 mmol, >99:1 er) were reacted

with 25 (500 mg, 2.25 mmol, >99:1 dr) and (ꢀ)-CSO (877 mg,

3.83 mmol) in THF (18 mL). Puriﬁcation via ﬂash column chroma-

tography (eluent 30e40 ^ꢂC petrol/Et₂O, 7:1) gave 87 as a pale

D

CDCl₃) 1.23e1.26 (3H, d, J 6.9, C(

br s, OH), 4.05 (1H, d, J 15.6, NCH_AH_BAr), 4.18 (1H, d, J 15.6,

NCH_AH_BAr), 4.23 (1H, q, J 6.9, C( )H) 4.25 (1H, d, J 3.1, C(3)H),

4.48e4.51 (1H, m, C(2)H), 6.00e7.56 (13H, m, Ar, Ph); d_C(125 MHz,

CDCl₃) 15.8 (C( )Me), 27.6 (CMe₃), 51.7 (NCH₂Ar), 58.3 (C( )), 64.0

a)Me), 1.24 (9H, s, CMe₃), 2.94 (1H,

a

yellow oil (775 mg, 67%, >99:1 dr); n_max(ATR) 3482 (OeH), 1724

20

(C(3)), 72.8 (C(2)), 82.6 (CMe₃),114.9 (d, J 21.0, C(3⁰), C(5⁰)),124.3 (q, J

271.8, CF₃), 125.0 (q, J 3.8, C(3⁰⁰), C(5⁰⁰)), 127.1 (p-Ph), 127.9 (C(2⁰⁰),

C(6⁰⁰)), 127.8, 128.3 (o,m-Ph), 129.7 (q, J 32.4, C(4⁰⁰)), 132.4 (d, J 7.6,

C(2⁰), C(6⁰)), 135.0 (C(1⁰)), 144.7 (i-Ph), 147.5 (C(1⁰⁰)), 163.1 (d, J 247.0,

C(4⁰)), 173.2 (C(1)); d_F(377 MHz, CDCl₃) ꢀ62.2 (CF₃), e114.5 (C(4⁰)F);

(C]O), 1325 (CeF); [

a

]

e30.9 (c 1.0 in CHCl₃); d_H(500 MHz,

D

CDCl₃) 1.22 (3H, d, J 6.9, C(

OH), 4.05 (1H, d, J 15.6, NCH_AH_BAr), 4.17e4.25 (3H, m, NCH_AH_BAr,

C( )H, C(3)H), 4.46 (1H, app s, C(2)H), 6.95e7.55 (13H, m, Ar, Ph); d_C

(125 MHz, CDCl₃) 15.8 (C( )Me), 27.7 (CMe₃), 51.9 (NCH₂Ar), 58.3

(C(

)), 64.2 (C(3)), 72.9 (C(2)), 82.9 (CMe₃), 114.6 (d, J 21.0, C(4⁰)),

a)Me), 1.24 (9H, s, CMe₃), 2.94 (1H, br s,

a

þ

m/z (ESI^þ) 540 ([MþNa]^þ, 100%); HRMS (ESI^þ) C₂₉H₃₁F₄NNaO₃

a

([MþNa]^þ) requires 540.2132; found 540.2124.

116.7 (d, J 21.9, C(2⁰)), 124.2 (q, J 271.8, CF₃), 125.1 (q, J 3.8, C(3⁰⁰),

C(5⁰⁰)), 125.4 (C(6⁰)), 127.9 (C(2⁰⁰), C(6⁰⁰)), 127.2 (p-Ph), 128.1, 128.3

(o,m-Ph), 128.8 (q, J 32.4, C(4⁰⁰)), 129.5 (d, J 8.6, C(5⁰)), 140.8 (d, J 4.8,

C(1⁰)),143.6 (i-Ph), 146.3 (C(1⁰⁰)),162.6 (d, J 246.1, C(3⁰)), 172.4 _þ(C(1));

d_F(377 MHz, CDCl₃) ꢀ62.2 (CF₃), e113.1 (C(3⁰)F); m/z (ESI ) 518

4.42. (1R,3S,4S)-1-Methyl-N(2)-[4⁰⁰-(triﬂuoromethyl)benzyl]-

3-(tert-butoxycarbonyl)-4-(4⁰-ﬂuorophenyl)-1,2,3,4-

tetrahydroisoquinoline 84

þ

([MþH]^þ, 100%); HRMS (ESI^þ) C₂₉H₃₂F₄NO₃([MþH]^þ) requires

Following general procedure II, Tf₂O (98

mL, 0.58 mmol) was

518.2313; found 518.2305.

reacted with 83 (200 mg, 0.386 mmol, >99:1 dr) and DTBMP

(238 mg, 1.16 mmol) in CH₂Cl₂(5.5 mL) at rt for 6 h. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 30:1)

4.45. tert-Butyl (R,R,R)-2-hydroxy-3-{N-[4⁰⁰-(triﬂuoromethyl)-

benzyl]-N-(a

-methylbenzyl)amino}-3-(3⁰-methoxyphenyl)-

gave 84 as a red oil (171 mg, 89%, >99:1 dr); n_max(ATR) 1726 (C]O),

propanoate 88

20

1325 (CeF); [

a]

þ10.9 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃) 1.30

D

(9H, s, CMe₃), 1.48 (3H, d, J 6.5, C(1)Me), 3.65 (1H, d, J 3.6, C(3)H),

4.01 (1H, d, J 15.4, NCH_AH_BAr), 4.05 (1H, d, J 15.4, NCH_AH_BAr), 4.40

(1H, q, J 6.5, C(1)H), 4.51 (1H, d, J 3.6, C(4)H), 6.75e7.04 (7H, m, Ar),

7.15e7.30 (3H, m, Ar), 7.36 (2H, d, J 8.3, C(3⁰⁰)H, C(5⁰⁰)H); d_C

(125 MHz, CDCl₃) 23.3 (C(1)Me), 27.9 (CMe₃), 47.9, (C(4)), 54.8

(NCH₂Ar), 55.8 (C(1)), 65.1 (C(3)), 81.4 (CMe₃), 114.5 (d, J 21.9, C(3⁰),

C(5⁰)), 124.2 (q, J 271.8, CF₃), 124.9 (q, J 3.8, C(3⁰⁰), C(5⁰⁰)), 126.2 (C(8)),

127.0, 127.1 (C(6), C(7)), 128.0 (C(2⁰⁰), C(6⁰⁰)), 129.0 (q, J 32.4, C(4⁰⁰)),

129.7 (C(5)), 130.3 (d, J 7.6, C(2⁰), C(6⁰)), 133.4 (C(4a)), 139.5 (d, J

2.9, C(1⁰)), 140.6 (C(8a)), 144.2 (C(1⁰⁰)), 161.5 (d, J 245.1, C(4⁰)), 171.5

(CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ117.1 (C(4⁰)F), ꢀ62.3 (CF₃); m/z

Following general procedure I, BuLi (2.2 M in hexanes, 1.41 mL,

3.10 mmol) and (R)-82 (954 mg, 3.41 mmol, >99:1 er) were reacted

with 26 (500 mg, 2.00 mmol, >99:1 dr) and (ꢀ)-CSO (779 mg,

3.40 mmol) in THF (16 mL). Puriﬁcation via ﬂash column chroma-

tography (eluent 30e40 ^ꢂC petrol/Et₂O, 5:1) gave 88 as a pale yel-

low oil (1.01 g, 95%, >99:1 dr); n_max(ATR) 3487 (OeH), 1725 (C]O),

20

1325 (CeF); [

a

]

e29.0 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃)

D

1.21e1.27 (3H, d, J 6.9, C(

a)Me), 1.24 (9H, s, CMe₃), 2.91 (1H, br s,

OH), 3.79 (3H, s, OMe), 4.04 (1H, d, J 15.6, NCH_AH_BAr), 4.17 (1H, d, J

15.6, NCH_AH_BAr), 4.21 (1H, d, J 2.9, C(3)H), 4.24 (1H, q, J 6.9, C(a)H),

4.42e4.45 (1H, m, C(2)H), 6.82 (1H, d, J 8.2, C(4⁰)H), 7.00e7.08 (2H,

þ

(ESI^þ) 500 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₉H₃₀F₄NO₂([MþH]^þ)

m, C(2⁰⁰)H, C(6⁰⁰)H), 7.20e7.54 (10H, m, Ar, Ph); d_C(125 MHz, CDCl₃)

requires 500.2207; found 500.2195.

15.7 (C(a)Me), 27.7 (CMe₃), 51.9 (NCH₂Ar), 55.2 (OMe), 58.2 (C(a)),

64.9 (C(3)), 73.0 (C(2)), 82.6 (CMe₃), 112.8 (C(4⁰)), 115.8 (C(2⁰)), 122.2

(C(6⁰)), 124.5 (q, J 271.8, CF₃), 125.0 (q, J 3.5, C(3⁰⁰), C(5⁰⁰)), 127.1 (p-

Ph), 127.9 (C(2⁰⁰), C(6⁰⁰)), 128.1, 128.2 (o,m-Ph), 128.7 (q, J 32.1, C(4⁰⁰)),

129.0 (C(5⁰)), 139.6 (C(1⁰)), 143.8 (i-Ph), 146.6 (C(1⁰⁰)), 159.3 (C(3⁰)),

172.4 (C(1)); d_F(377 MHz, CDCl₃) ꢀ62.2 (CF₃); m/z (ESI^þ) 530

4.43. tert-Butyl (R,R,R)-2-hydroxy-3-{N-[4⁰⁰-(triﬂuoromethyl)-

benzyl]-N-(a

-methylbenzyl)amino}-3-[4⁰-(triﬂuoromethyl)-

phenyl]propanoate 86

þ

Following general procedure I, BuLi (2.2 M in hexanes, 1.30 mL,

2.86 mmol) and (R)-82 (821 mg, 2.94 mmol, >99:1 er) were reacted

with 24 (500 mg, 1.84 mmol, >99:1 dr) and (ꢀ)-CSO (717 mg,

3.13 mmol) in THF (15 mL). Puriﬁcation via ﬂash column chroma-

tography (eluent 30e40 ^ꢂC petrol/Et₂O, 7:1) gave 86 as a pale

yellow oil (737 mg, 71%, >99:1 dr); n_max(ATR) 3481 (OeH), 1724

([MþH]^þ, 100%); HRMS (ESI^þ) C₃₀H₃₅F₃NO₄([MþH]^þ) requires

530.2513; found 530.2507.

4.46. tert-Butyl (R,R,R)-2-hydroxy-3-{N-[4⁰-(triﬂuoromethyl)-

benzyl]-N-(a-methylbenzyl)amino}-3-phenylpropanoate 89

(C]O),1325 (CeF); [

1.26 (9H, s, CMe₃), 1.26 (3H, d, J 6.9, C(

(1H, d, J 15.8, NCH_AH_BAr), 4.22 (1H, d, J 15.8, NCH_AH_BAr), 4.22 (1H, q,

a]

²⁰e31.2 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃)

Following general procedure I, BuLi (2.2 M in hexanes, 3.45 mL,

7.59 mmol) and (R)-82 (2.19 g, 7.83 mmol, >99:1 er) were reacted

with 65 (1.00 g, 4.90 mmol, >99:1 dr) and (ꢀ)-CSO (1.91 g,

D

a)Me), 2.97 (1H, br s, OH), 4.09

2158

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

4.90 mmol) in THF (40 mL). Puriﬁcation via ﬂash column chroma-

tography (eluent 30e40 ^ꢂC petrol/Et₂O, 5:1) gave 89 as a colourless

4.49. (1R,3S,4S)-1-Methyl-N(2)-[4⁰⁰-(triﬂuoromethyl)benzyl]-

3-(tert-butoxycarbonyl)-4-(3⁰-ﬂuorophenyl)-1,2,3,4-

tetrahydroisoquinoline 92

oil (1.59 g, 65%, >99:1 dr); n_max(ATR) 3494 (OeH), 1724 (C]O),

20

1325 (CeF); [

a

]

e25.6 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃) 1.20

D

(9H, s, CMe₃), 1.21 (3H, d, J 6.9, C(

d, J 15.6, NCH_AH_BAr), 4.17 (1H, d, J 15.6, NCH_AH_BAr), 4.21 (1H, q, J 6.9,

C( )H), 4.22 (1H, d, J 3.0, C(3)H), 4.45 (1H, d, J 3.0, C(2)H), 7.24e7.52

(14H, m, Ar, Ph); d_C(125 MHz, CDCl₃) 15.5 (C( )Me), 27.7 (CMe₃),

51.9 (NCH₂Ar), 58.2 (C( )), 65.1 (C(3)), 73.1 (C(2)), 82.5 (CMe₃), 124.3

a

)Me), 2.79 (1H, br s, OH), 4.02 (1H,

Following general procedure II, Tf₂O (98 mL, 0.58 mmol) was

reacted with 87 (200 mg, 0.386 mmol, >99:1 dr) and DTBMP

(238 mg, 1.16 mmol) in CH₂Cl₂(5.5 mL) at 40 ^ꢂC for 6 h, which gave

a 96:4 mixture of 92 and 97, respectively. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 30:1) gave

a

(q, J 271.8, CF₃), 125.0 (q, J 3.0, C(3⁰), C(5⁰)), 127.9 (C(2⁰), C(6⁰)), 127.1,

127.7 (p-Ph), 128.0, 128.1, 128.2, 129.8 (o,m-Ph), 128.7 (q, J 32.0,

C(4⁰)), 138.1, 143.9 (i-Ph), 146.6 (C(1⁰)), 172.4 (C(1)); d_F(377 MHz,

92 as a red oil (145 mg, 75%, >99:1 dr); n_max(ATR) 1726 (C]O),

20

1325 (CeF); [

a

]

þ10.2 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃) 1.29

D

(9H, s, CMe₃), 1.47 (3H, d, J 6.5, C(1)Me), 3.67 (1H, d, J 3.4, C(3)H),

4.03 (2H, app t, J 17.7, NCH₂Ar), 4.41 (1H, q, J 6.5, C(1)H), 4.51 (1H, d, J

3.4, C(4)H), 6.71e6.76 (1H, m, C(2⁰)H), 6.85 (1H, d, J 7.7, C(6⁰)H),

6.95e6.99 (3H, m, Ar), 7.02 (1H, d, J 7.4, C(5)H), 7.16e7.31 (4H, m,

Ar), 7.38 (2H, d, J 8.0, C(3⁰⁰)H, C(5⁰⁰)H); d_C(125 MHz, CDCl₃) 23.3

(C(1)Me), 27.9 (CMe₃), 47.5, (C(4)), 54.8 (NCH₂Ar), 55.8 (C(1)), 64.9

(C(3)), 81.4 (CMe₃), 113.0 (d, J 21.9, C(4⁰)),116.0 (d, J 21.0, C(2⁰)),124.2

(q, J 271.8, CF₃), 124.5 (d, J 2.9, C(6⁰)), 124.9 (q, J 3.8, C(3⁰⁰), C(5⁰⁰)),

126.3 (C(8)), 127.1, 127.1 (C(6), C(7)), 128.0 (C(2⁰⁰), C(6⁰⁰)), 128.9 (q, J

32.4, C(4⁰⁰)), 129.2 (d, J 7.6, C(5⁰)), 129.7 (C(5)), 132.9 (C(4a)), 140.7

(C(8a)), 144.2 (C(1⁰⁰)), 146.5 (d, J 6.7, C(1⁰)), 162.6 (d, J 246.1, C(3⁰)),

CDCl₃) ꢀ62.2 (CF₃); m/z (ESI^þ) 500 ([MþH]^þ, 100%); HRMS (ESI^þ)

þ

C

₂₉H₃₃F₃NO₃([MþH]^þ) requires 500.2407; found 500.2401.

4.47. tert-Butyl (R,R,R)-2-hydroxy-3-{N-[4⁰⁰-(triﬂuoromethyl)-

benzyl]-N-(

-methylbenzyl)amino}-3-(4⁰-methoxyphenyl)-

a

propanoate 90

Following general procedure I, BuLi (2.2 M in hexanes, 1.41 mL,

3.10 mmol) and (R)-82 (954 mg, 3.41 mmol, >99:1 er) were

reacted with 28 (500 mg, 2.00 mmol, >99:1 dr) and (ꢀ)-CSO

(779 mg, 3.40 mmol) in THF (16 mL). Puriﬁcation via ﬂash col-

umn chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 5:1) gave 90

t

171.4 (CO₂Bu); d_F(377 MHz, CDCl₃) ꢀ113.9 (C(3⁰)F), ꢀ62.3 (CF₃); m/

þ

z

(ESI^þ) 500 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₉H₃₀F₄NO₂

([MþH]^þ) requires 500.2207; found 500.2195.

as a pale yellow oil (859 mg, 81%, >99:1 dr); n_max(ATR) 3486

20

(OeH), 1724 (C]O), 1325 (CeF); [

a

]

e26.7 (c 1.0 in CHCl₃); d_H

D

4.50. (1R,3S,4S)-1-Methyl-N(2)-[4⁰⁰-(triﬂuoromethyl)benzyl]-

3-(tert-butoxycarbonyl)-4-(3⁰-methoxyphenyl)-1,2,3,4-

tetrahydroisoquinoline 93

(500 MHz, CDCl₃) 1.20e1.23 (3H, d, J 6.6, C(a)Me), 1.22 (9H, s,

CMe₃), 2.88 (1H, br s, OH), 3.79 (3H, s, OMe), 3.98 (1H, d, J 15.6,

NCH_AH_BAr), 4.14 (1H, d, J 15.6, NCH_AH_BAr), 4.15e4.17 (1H, m,

C(3)H), 4.20 (1H, q, J 6.6, C(a)H), 4.42e4.45 (1H, m, C(2)H), 6.83

Following general procedure II, Tf₂O (95

mL, 0.57 mmol) was

(2H, d, J 8.2, C(3⁰)H, C(5⁰)H), 7.23e7.42 (7H, m, Ar, Ph), 7.64 (2H, d,

J 7.4, o-Ph), 7.50 (2H, d, J 7.7, C(2⁰⁰)H, C(6⁰⁰)H); d_C(125 MHz, CDCl₃)

reacted with 88 (200 mg, 0.378 mmol, >99:1 dr) and DTBMP

(233 mg, 1.13 mmol) in CH₂Cl₂(5.4 mL) at rt for 6 h. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 30:1)

15.5 (C(a)Me), 27.7 (CMe₃), 51.8 (NCH₂Ar), 55.2 (OMe), 58.1 (C(a)),

64.6 (C(3)), 73.2 (C(2)), 82.4 (CMe₃), 113.4 (C(3⁰), C(5⁰)), 124.4 (q, J

271.8, CF₃), 125.0 (q, J 3.8, C(3⁰⁰), C(5⁰⁰)), 127.0 (p-Ph), 127.9 (C(2⁰⁰),

C(6⁰⁰)), 128.1, 128.2 (o,m-Ph), 128.6 (q, J 32.4, C(4⁰⁰)), 130.0 (C(1⁰)),

130.9 (C(2⁰), C(6⁰)), 144.0 (i-Ph), 146.7 (C(1⁰⁰)), 159.0 (C(4⁰)), 172.4

(C(1)); d_F(377 MHz, CDCl₃) ꢀ62.2 (CF₃); m/z (ESI^þ) 530 ([MþH]^þ,

gave 93 as a red oil (156 mg, 81%, >99:1 dr); n_max(ATR) 1725 (C]O),

20

1325 (CeF); [

a

]

þ2.4 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃) 1.30

D

(9H, s, CMe₃), 1.48 (3H, d, J 6.5, C(1)Me), 3.70 (1H, d, J 3.4, C(3)H),

3.72 (3H, s, OMe), 4.02 (1H, d, J 15.7, NCH_AH_BAr), 4.06 (1H, d, J 15.7,

NCH_AH_BAr), 4.42 (1H, q, J 6.5, C(1)H), 4.51 (1H, d, J 3.4, C(4)H),

6.59e6.69 (1H, m, C(2⁰)H), 6.64 (1H, d, J 7.6, C(6⁰)H), 6.82e6.86 (1H,

m, C(4⁰)H), 6.96 (2H, d, J 8.0, C(2⁰⁰)H, C(6⁰⁰)H), 7.06 (1H, d, J 7.6,

C(5)H), 7.15e7.30 (4H, m, C(6)H, C(7)H, C(8)H, C(5⁰)H), 7.34 (2H, d, J

8.0, C(3⁰⁰)H, C(5⁰⁰)H); d_C(125 MHz, CDCl₃) 23.3 (C(1)Me), 27.9

(CMe₃), 47.9, (C(4)), 54.8 (NCH₂Ar), 55.0 (OMe), 55.8 (C(1)), 65.2

(C(3)), 81.2 (CMe₃), 111.5 (C(4⁰)), 114.7 (C(2⁰)),121.5 (C(6⁰)), 124.3 (q, J

271.8, CF₃), 124.8 (q, J 3.8, C(3⁰⁰), C(5⁰⁰)), 126.1 (C(8)), 126.9, 126.9

(C(6), C(7)), 128.1 (C(2⁰⁰), C(6⁰⁰)), 128.7 (C(5⁰)), 128.7 (q, J 32.4, C(4⁰⁰)),

129.8 (C(5)), 133.3 (C(4a)), 140.8 (C(8a)), 144.4 (C(1⁰⁰)), 145.4 (C(1⁰)),

159.3 (C(3⁰)), 171.7 (CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ62.3 (CF₃); m/z

þ

100%); HRMS (ESI^þ) C₃₀H₃₅F₃NO₄([MþH]^þ) requires 530.2513;

found 530.2504.

4.48. (1R,3S,4S)-1-Methyl-N(2)-[4⁰⁰-(triﬂuoromethyl)benzyl]-

3-(tert-butoxycarbonyl)-4-[4⁰-(triﬂuoromethyl)phenyl]-

1,2,3,4-tetrahydroisoquinoline 91

Following general procedure II, Tf₂O (89

mL, 0.53 mmol) was

reacted with 86 (200 mg, 0.352 mmol, >99:1 dr) and DTBMP

(217 mg, 1.06 mmol) in CH₂Cl₂(5 mL) at 40 ^ꢂC for 6 h, which gave

a 93:7 mixture of 91 and 96, respectively. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 30:1) gave

91 as a red oil (127 mg, 66%, >99:1 dr); n_max(ATR) 1726 (C]O),1326

þ

(ESI^þ) 512 ([MþH]^þ, 100%); HRMS (ESI^þ) C₃₀H₃₃F₃NO₃([MþH]^þ)

requires 512.2407; found 512.2397.

(CeF); [

a

]

²⁰þ14.4 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃) 1.27 (9H, s,

4.51. (1R,3S,4S)-1-Methyl-N(2)-[4⁰-(triﬂuoromethyl)benzyl]-3-

(tert-butoxycarbonyl)-4-phenyl-1,2,3,4-

tetrahydroisoquinoline 94

D

CMe₃), 1.46 (3H, d, J 6.5, C(1)Me), 3.60 (1H, d, J 3.2, C(3)H), 3.98 (2H,

app s, NCH₂Ar), 4.41 (1H, q, J 6.5, C(1)H), 4.55 (1H, d, J 3.2, C(4)H),

6.85 (2H, d, J 8.0, C(2⁰⁰)H, C(6⁰⁰)H), 6.99 (1H, d, J 7.6, C(5)H), 7.12 (2H,

d, J 8.1, C(2⁰)H, C(6⁰)H), 7.14e7.31 (5H, m, Ar), 7.49 (2H, d, J 8.1, C(3⁰)H,

C(5⁰)H); d_C(125 MHz, CDCl₃) 23.3 (C(1)Me), 27.9 (CMe₃), 47.7 (C(4)),

54.7 (NCH₂Ar), 55.7 (C(1)), 65.0 (C(3)), 81.6 (CMe₃), 124.3 (q, J 271.8,

C(4⁰⁰)CF₃), 124.4 (q, J 271.8, C(4⁰)CF₃), 124.7 (q, J 3.8, C(3⁰), C(5⁰)),

124.8 (q, J 3.8, C(3⁰⁰), C(5⁰⁰)), 126.4 (C(8)), 127.2 (C(6)), 127.3 (C(7)),

128.0 (C(2⁰⁰), C(6⁰⁰)), 128.6 (q, J 32.4, C(4⁰)), 128.9 (q, J 32.4, C(4⁰⁰)),

129.2 (C(2⁰), C(6⁰)), 129.7 (C(5)), 132.6 (C(4a)), 140.8 (C(8a)), 144.0

(C(1⁰⁰)), 148.0 (C(1⁰)), 171.2 (CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ62.5,

Following general procedure II, Tf₂O (150 mL, 0.90 mmol) was

reacted with 89 (300 mg, 0.60 mmol, >99:1 dr) and DTBMP

(370 mg, 1.80 mmol) in CH₂Cl₂(8 mL) at rt for 6 h. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 20:1)

gave 94 as a pale yellow oil (208 mg, 72%, >99:1 dr); n_max(ATR)

20

1724 (C]O), 1323 (CeF); [

a

]

D

þ6.2 (c 1.0 in CHCl₃); d_H(400 MHz,

CDCl₃) 1.26 (9H, s, CMe₃),1.44 (3H, d, J 6.4, C(1)Me), 3.67 (1H, d, J 3.5,

C(3)H), 3.97 (1H, d, J 15.8, NCH_AH_BAr), 4.03 (1H, d, J 15.8, NCH_AH_BAr),

4.38 (1H, q, J 6.4, C(1)H), 4.51 (1H, d, J 3.5, C(4)H), 6.88 (2H, d, J 8.1,

C(2⁰)H, C(6⁰)H), 6.99e7.06 (3H, m, Ar, Ph), 7.12e7.31 (8H, m, Ar, Ph);

ꢀ62.3 (2ꢃCF₃); m/z (ESI^þ) 550 ([MþH]^þ, 100%); HRMS (ESI^þ)

þ

C

₃₀H₃₆F₆NO₂([MþH]^þ) requires 550.2175; found 550.2166.

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2159

d_C(125 MHz, CDCl₃) 23.3 (C(1)Me), 27.9 (CMe₃), 47.8, (C(4)), 55.0

(NCH₂Ar), 55.9 (C(1)), 65.4 (C(3)), 81.2 (CMe₃), 124.3 (q, J 272.8, CF₃),

124.9 (q, J 3.8, C(3⁰), C(5⁰)), 126.1 (p-Ph), 126.2 (C(8)), 126.8, 127.0

(C(6), C(7)), 127.9, 127.9 (C(2⁰), C(6⁰), m-Ph), 128.7 (q, J 32.4, C(4⁰)),

129.0 (o-Ph), 129.8 (C(5)), 133.5 (C(4a)), 140.8 (C(8a)), 143.8 (i-Ph),

144.4 (C(1⁰)), 171.7 (CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ62.2 (CF₃); m/z

129.6 (C(2⁰), C(6⁰)), 129.8 (C(5)), 134.9 (C(4a)), 139.8 (C(8a)), 148.0

(C(1⁰)), 171.8 (CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ62.4 (CF₃); m/z (ESI^þ)

þ

392 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₂H₂₅F₃NO₂([MþH]^þ) re-

quires 392.1832; found 392.1831.

þ

4.54. (1R,3S,4S)-1-Methyl-3-(tert-butoxycarbonyl)-4-(3⁰-ﬂuo-

rophenyl)-1,2,3,4-tetrahydroisoquinoline 103

(ESI^þ) 482 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₉H₃₁F₃NO₂([MþH]^þ)

requires 482.2301; found 482.2290.

Following general procedure III, Pd(OH)₂/C (50 mg, 25% w/w) was

reacted with 92 (200 mg, 0.40 mmol, >99:1 dr) in MeOH (1 mL) for

5 days. Puriﬁcation via ﬂash column chromatography (eluent

30e40 ^ꢂC petrol/Et₂O, 2:1, 1% Et₃N) gave 103 as a colourless oil

(51 mg, 37%, >99:1 dr); n_max(ATR) 3402 (NeH), 1725 (C]O), 1152

4.52. (1R,3S,4S)-1-Methyl-N(2)-[4⁰⁰-(triﬂuoromethyl)benzyl]-

3-(tert-butoxycarbonyl)-4-(4⁰-methoxyphenyl)-1,2,3,4-

tetrahydroisoquinoline 95

Following general procedure II, Tf₂O (74

mL, 0.44 mmol) was

(CeF); [

a]

²⁰þ79.1 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃) 1.32 (9H, s,

D

reacted with 90 (155 mg, 0.293 mmol, >99:1 dr) and DTBMP

(180 mg, 0.88 mmol) in CH₂Cl₂(4.2 mL) at e20 ^ꢂC for 2.5 h, which

gave an 80:20 mixture of 95 and 101, respectively. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 20:1)

CMe₃), 1.55 (3H, d, J 6.6, C(1)Me), 2.03 (1H, br s, NH), 3.82 (1H, d, J

6.6, C(3)H), 4.30 (1H, d, J 6.6, C(4)H), 4.36 (1H, q, J 6.6, C(1)H), 6.85

(1H, d, J 7.7, C(5)H), 6.87e6.91 (1H, m, C(2⁰)H), 6.92e6.97 (1H, m,

C(4⁰)H), 6.98 (1H, d, J 7.7, C(6⁰)H), 7.07e7.11 (1H, m, Ar), 7.15e7.22

(2H, m, Ar), 7.24e7.30 (1H, m, C(5⁰)H); d_C(125 MHz, CDCl₃) 23.8

(C(1)Me), 27.8 (CMe₃), 47.4 (C(4)), 49.4 (C(1)), 60.3 (C(3)), 81.4

(CMe₃), 113.0 (d, J 21.0, C(4⁰)), 116.2 (d, J 21.9, C(2⁰)), 124.9 (d, J 2.9,

C(6⁰)), 126.0 (C(8)), 126.4, 126.6 (C(6), C(7)), 129.7 (d, J 8.6, C(5⁰)),

129.8 (C(5)), 132.2 (C(4a)), 139.8 (C(8a)), 146.3 (d, J 6.7, C(1⁰)), 162.9

(d, J 246.1, C(3⁰)), 171.9 (CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ113.4 (C(3⁰)

gave 95 as a red oil (59 mg, 39%, >99:1 dr); n_max(ATR) 1726 (C]O),

20

1325 (CeF); [

a

]

þ31.3 (c 0.3 in CHCl₃); d_H(500 MHz, CDCl₃) 1.27

D

(9H, s, CMe₃), 1.45 (3H, d, J 6.5, C(1)Me), 3.64 (1H, d, J 3.8, C(3)H),

3.84 (3H, s, OMe), 3.98 (1H, d, J 15.7, NCH_AH_BAr), 4.03 (1H, d, J 15.7,

NCH_AH_BAr), 4.36 (1H, q, J 6.5, C(1)H), 4.45 (1H, d, J 3.8, C(4)H),

6.79e6.99 (6H, m, Ar), 7.01 (1H, d, J 7.4, C(5)H), 7.13e7.27 (3H, m,

Ar), 7.32 (2H, d, J 8.0, C(3⁰⁰)H, C(5⁰⁰)H); d_C(125 MHz, CDCl₃) 23.3

(C(1)Me), 27.9 (CMe₃), 46.8, (C(4)), 54.8 (NCH₂Ar), 55.3 (OMe), 55.8

(C(1)), 65.3 (C(3)), 81.2 (CMe₃), 113.2 (C(3⁰), C(5⁰)), 124.3 (q, J 271.8,

CF₃), 124.8 (q, J 3.8, C(3⁰⁰), C(5⁰⁰)), 126.1 (C(8)), 126.7, 126.9 (C(6),

C(7)), 128.0 (C(2⁰⁰), C(6⁰⁰)), 128.7 (q, J 32.4, C(4⁰⁰)), 129.7 (C(5)), 130.0

(C(2⁰), C(6⁰)), 134.0 (C(4a)), 135.9 (C(1⁰)), 140.6 (C(8a)), 144.4 (C(1⁰⁰)),

158.1 (C(4⁰)), 171.8 (CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ62.3 (CF₃); m/z

þ

F); m/z (ESI^þ) 342 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₁H₂₅FNO₂

([MþH]^þ) requires 342.1864; found 342.1862.

4.55. (1R,3S,4S)-1-Methyl-3-(tert-butoxycarbonyl)-4-(3⁰-meth-

oxyphenyl)-1,2,3,4-tetrahydroisoquinoline 104

þ

(ESI^þ) 512 ([MþH]^þ, 100%); HRMS (ESI^þ) C₃₀H₃₃F₃NO₃([MþH]^þ)

Following general procedure III, Pd(OH)₂/C (40 mg, 40% w/w) was

reacted with 93 (100 mg, 0.20 mmol, >99:1 dr) in MeOH (1 mL) for

48 h. Puriﬁcation via ﬂash column chromatography (eluent

requires 512.2407; found 512.2405. Further elution gave (1R,3S,4R)-

101 as a pale red oil (20 mg, 13%, >99:1 dr); n_max(ATR) 1726 (C]O),

1325 (CeF); [a]

²⁰e28.6 (c 0.5 in CHCl₃); d_H(500 MHz, CDCl₃) 1.26

30e40 ^ꢂC petrol/Et₂O, 2:1, 1% Et₃N) gave 104 as a colourless oil

D

(9H, s, CMe₃), 1.54 (3H, d, J 6.3, C(1)Me), 3.59 (1H, d, J 5.5, C(3)H),

3.64 (1H, d, J 14.8, NCH_AH_BAr), 3.79 (3H, s, OMe), 4.18 (1H, d, J 14.8,

NCH_AH_BAr), 4.32 (1H, q, J 6.3, C(1)H), 4.46 (1H, d, J 5.5, C(4)H), 6.80

(2H, d, J 8.7, C(3⁰)H, C(5⁰)H), 6.91 (1H, d, J 7.7, C(5)H), 7.04e7.11 (3H,

m, Ar), 7.17e7.23 (2H, m, Ar), 7.54 (2H, d, J 8.2, C(3⁰⁰)H, C(5⁰⁰)H), 7.60

(2H, d, J 8.2, C(2⁰⁰)H, C(6⁰⁰)H); d_C(125 MHz, CDCl₃) 23.3 (C(1)Me),

28.1 (CMe₃), 47.8, (C(4)), 55.1 (NCH₂Ar), 55.2 (OMe), 55.8 (C(1)), 64.2

(C(3)), 81.0 (CMe₃), 113.5 (C(3⁰), C(5⁰)), 124.3 (q, J 271.8, CF₃), 125.3

(q, J 3.8, C(3⁰⁰), C(5⁰⁰)), 125.3 (C(8)), 126.0, 126.1 (C(6), C(7)), 127.8

(C(5)), 128.6 (C(2⁰⁰), C(6⁰⁰)), 129.3 (q, J 31.5, C(4⁰⁰)), 131.3 (C(2⁰), C(6⁰)),

131.9 (C(1⁰)), 134.5 (C(4a)), 140.7 (C(8a)), 143.9 (C(1⁰⁰)), 158.6 (C(4⁰)),

170.4 (CO₂^tBu); d_F(377 MHz, CDCl₃) ꢀ62.3 (CF₃); m/z (ESI^þ) 512

20

(51 mg, 74%, >99:1 dr); n_max(ATR) 3405 (NeH), 1725 (C]O); [a]

D

þ67.9 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃) 1.31 (9H, s, CMe₃), 1.55

(3H, d, J 6.8, C(1)Me), 1.95 (1H, br s, NH), 3.77 (3H, s, OMe), 3.85 (1H,

d, J 6.7, C(3)H), 4.26 (1H, d, J 6.7, C(4)H), 4.36 (1H, q, J 6.8, C(1)H),

6.70e6.81 (3H, m, C(2⁰)H, C(4⁰)H, C(6⁰)H), 6.88 (1H, d, J 7.7, C(5)H),

7.04e7.10 (1H, m, Ar), 7.13e7.25 (3H, m, Ar); d_C(125 MHz, CDCl₃)

23.9 (C(1)Me), 27.8 (CMe₃), 47.8 (C(4)), 49.5 (C(1)), 55.1 (OMe), 60.3

(C(3)), 81.2 (CMe₃), 111.7 (C(4⁰)), 115.4 (C(2⁰)), 121.7 (C(6⁰)), 125.9

(C(8)), 126.3, 126.4 (C(6), C(7)), 129.3 (C(5⁰)), 129.8 (C(5)), 135.8

t

(C(4a)), 139.8 (C(8a)), 145.1 (C(1⁰)), 159.5 (C(3⁰)), 172.1 (CO₂Bu); m/z

þ

(ESI^þ) 354 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₂H₂₈NO₃([MþH]^þ)

requires 354.2064; found 354.2062.

þ

([MþH]^þ, 100%); HRMS (ESI^þ) C₃₀H₃₃F₃NO₃([MþH]^þ) requires

512.2407; found 512.2404.

4.56. (1R,3S,4S)-1-Methyl-3-(tert-butoxycarbonyl)-4-phenyl-

1,2,3,4-tetrahydroisoquinoline 105

4.53. (1R,3S,4S)-1-Methyl-3-(tert-butoxycarbonyl)-4-[4⁰-(tri-

ﬂuoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline 102

Following general procedure III, Pd(OH)₂/C (35 mg, 40% w/w) was

reacted with 94 (139 mg, 0.29 mmol, >99:1 dr) in MeOH (1 mL) for

48 h. Puriﬁcation via ﬂash column chromatography (eluent

Following general procedure III, Pd(OH)₂/C (26 mg, 25% w/w) was

reacted with 91 (105 mg, 0.19 mmol, >99:1 dr) in MeOH (1 mL) for

5 days. Puriﬁcation via ﬂash column chromatography (eluent

30e40 ^ꢂC petrol/Et₂O, 2:1, 1% Et₃N) gave 102 as a colourless oil

(32 mg, 43%, >99:1 dr); n_max(ATR) 3322 (NeH), 1729 (C]O), 1369

30e40 ^ꢂC petrol/Et₂O, 2:1, 1% Et₃N) gave 105 as a pale yellow oil

20

(55 mg, 59%, >99:1 dr); n_max(ATR) 3290 (OeH), 1724 (C]O); [a]

D

þ87.7 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃) 1.30 (9H, s, CMe₃), 1.57

(3H, d, J 6.8, C(1)Me), 2.01 (1H, br s, NH), 3.85 (1H, d, J 7.1, C(3)H),

4.28 (1H, d, J 7.1, C(4)H), 4.37 (1H, q, J 6.8, C(1)H), 6.85 (1H, d, J 7.7,

C(5)H), 7.05e7.10 (1H, m, Ar), 7.13e7.34 (7H, m, Ar, Ph); d_C(125 MHz,

CDCl₃) 23.9 (C(1)Me), 27.8 (CMe₃), 47.9 (C(4)), 49.6 (C(1)), 60.3

(C(3)), 81.2 (CMe₃), 125.9 (C(8)), 126.3, 126.3 (C(6), C(7)), 126.6 (p-

Ph), 128.3, 129.3 (o,m-Ph), 129.8 (C(5)), 136.1 (C(4a)), 139.9 (C(8a)),

143.4 (i-Ph), 172.1 (CO₂^tBu); m/z (ESI^þ) 324 ([MþH]^þ, 100%); HRMS

(CeF); [

a

]

²⁰þ44.4 (c 0.5 in CHCl₃); d_H(500 MHz, CDCl₃) 1.31 (9H, s,

D

CMe₃), 1.56 (3H, d, J 6.8, C(1)Me), 1.98 (1H, br s, NH), 3.81 (1H, d, J

6.3, C(3)H), 4.38 (1H, q, J 6.8, C(1)H), 4.39 (1H, d, J 6.3, C(4)H), 6.81

(1H, d, J 7.7, C(5)H), 7.07e7.11 (1H, m, Ar), 7.17e7.23 (2H, m, Ar), 7.31

(2H, d, J 8.1, C(3⁰)H, C(5⁰)H), 7.57 (2H, d, J 8.1, C(2⁰)H, C(6⁰)H); d_C

(125 MHz, CDCl₃) 23.8 (C(1)Me), 27.8 (CMe₃), 47.4 (C(4)), 49.3 (C(1)),

60.3 (C(3)), 81.6 (CMe₃), 124.3 (q, J 271.8, CF₃), 125.2 (q, J 3.8, C(3⁰),

C(5⁰)), 126.1 (C(8)), 126.5, 126.7 (C(6), C(7)), 128.9 (q, J 32.4, C(4⁰)),

þ

(ESI^þ) C₂₁H₂₆NO₂([MþH]^þ) requires 324.1958; found 324.1956.

2160

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

4.57. (1R,3S,4S)-1-Methyl-3-(tert-butoxycarbonyl)-4-(4⁰-ﬂuoro-

phenyl)-1,2,3,4-tetrahydroisoquinoline 106

4.60. tert-Butyl (RS,RS,RS)-2-hydroxy-3-{N-benzyl-N-[

methyl-4⁰-(triﬂuoromethyl)benzyl]amino}-3-

phenylpropanoate (RS,RS,RS)-110

a-

Following general procedure III, Pd(OH)₂/C (29 mg, 25% w/w) was

reacted with 84 (115 mg, 0.23 mmol, >99:1 dr) in MeOH (1 mL) for

5 days. Puriﬁcation via ﬂash column chromatography (eluent

30e40 ^ꢂC petrol/Et₂O, 2:1, 1% Et₃N) gave 106 as a colourless oil

(57 mg, 72%, >99:1 dr); n_max(ATR) 3394 (NeH), 1726 (C]O), 1151

Following general procedure I, BuLi (2.2 M in hexanes, 3.45 mL,

7.60 mmol) and (RS)-109 (2.19 g, 7.84 mmol) were reacted with 65

(1.00 g, 4.90 mmol) and (ꢀ)-CSO (1.91 g, 8.33 mmol) in THF (40 mL).

Puriﬁcation via ﬂash column chromatography (eluent 30e40 ^ꢂC

petrol/Et₂O, 5:1) gave (RS,RS,RS)-110 as a colourless oil (1.08 g, 64%,

>99:1 dr); n_max(ATR) 3491 (OeH), 1722 (C]O), 1325 (CeF); d_H

(CeF); [

a

]

²⁰þ55.3 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃) 1.31 (9H, s,

D

CMe₃), 1.55 (3H, d, J 6.8, C(1)Me), 1.95 (1H, br s, NH), 3.79 (1H, d, J

6.8, C(3)H), 4.28 (1H, d, J 6.8, C(4)H), 4.35 (1H, q, J 6.8, C(1)H), 6.82

(1H, d, J 7.7, C(5)H), 6.97e7.02 (2H, m, C(3⁰)H, C(5⁰)H), 7.06e7.10 (1H,

m, Ar), 7.11e7.21 (4H, m, Ar); d_C(125 MHz, CDCl₃) 23.9 (C(1)Me),

27.9 (CMe₃), 47.0 (C(4)), 49.5 (C(1)), 60.4 (C(3)), 81.4 (CMe₃),115.1 (d,

J 21.0, C(3⁰), C(5⁰)), 126.0 (C(8)), 126.4, 126.4 (C(6), C(7)), 129.7 (C(5)),

130.7 (d, J 7.6, C(2⁰), C(6⁰)), 135.9 (C(4a)), 139.3 (d, J 3.8, C(1⁰)), 139.8

(C(8a)), 161.8 (d, J 244.1, C(4⁰)), 172.1 (CO₂^tBu); d_F(377 MHz, CDCl₃)

(400 MHz, CDCl₃) 1.16 (3H, d, J 6.9, C(

(1H, d, J 4.7, OH), 3.85 (1H, d, J 14.7, NCH_AH_BPh), 4.14 (1H, d, J 3.1,

C(3)H), 4.15 (1H, d, J 14.7, NCH_AH_BPh), 4.32 (1H, q, J 6.9, C( )H), 4.43

a)Me), 1.18 (9H, s, CMe₃), 2.83

a

(1H, dd, J 4.7, 3.1, C(2)H), 7.19e7.35 (8H, m, Ph), 7.44e7.48 (2H, m,

Ph), 7.59 (2H, d, J 8.8, C(3⁰)H, C(5⁰)H), 7.63 (2H, d, J 8.8, C(2⁰)H,

C(6⁰)H); d_C(100 MHz, CDCl₃) 14.0 (C(

a

)Me), 27.6 (CMe₃), 52.2

(NCH₂Ph), 56.8 (C(

a)), 64.8 (C(3)), 74.1 (C(2)), 82.4 (CMe₃), 124.3 (q, J

ꢀ116.4 (C(4⁰)F); m/z (ESI^þ) 342 ([MþH]^þ, 100%); HRMS (ESI^þ)

271.8, CF₃), 124.9 (q, J 4.0, C(3⁰), C(5⁰)), 126.8, 127.7 (p-Ph), 128.1,

128.1, 128.3, 129.8 (o,m-Ph), 128.2 (C(2⁰), C(6⁰)), 129.0 (q, J, 32.6,

C(4⁰)), 137.9, 141.2, 148.7 (C(1⁰), i-Ph), 171.2 (C(1)); d_F(377 MHz,

þ

C

₂₁H₂₅FNO₂([MþH]^þ) requires 342.1864; found 342.1865.

CDCl₃) ꢀ62.3 (CF₃); m/z (ESI^þ) 500 ([MþH]^þ, 100%); HRMS (ESI^þ)

þ

C

₂₉H₃₃F₃NO₃([MþH]^þ) requires 500.2407; found 500.2403.

4.58. (1R,3S,4S)-1-Methyl-3-(tert-butoxycarbonyl)-4-(4⁰-meth-

oxyphenyl)-1,2,3,4-tetrahydroisoquinoline 107

4.61. (3RS,4RS,

benzyl]-3-(tert-butoxycarbonyl)-4-phenyl-1,2,3,4-

tetrahydroisoquinoline (3RS,4RS, SR)-111

aSR)-N(2)-[a

-Methyl-4⁰-(triﬂuoromethyl)-

Following general procedure III, Pd(OH)₂/C (24 mg, 40% w/w) was

reacted with 95 (60 mg, 0.12 mmol, >99:1 dr) in MeOH (1 mL) for

48 h. Puriﬁcation via ﬂash column chromatography (eluent

a

Following general procedure II, Tf₂O (250

mL, 1.50 mmol) was

30e40 ^ꢂC petrol/Et₂O, 2:1, 1% Et₃N) gave 107 as a colourless oil

reacted with (RS,RS,RS)-110 (500 mg, 1.00 mmol, >99:1 dr) and

DTBMP (610 mg, 3.0 mmol) in CH₂Cl₂(15 mL) rt for 6 h. Puriﬁcation

via ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O,

20

(25 mg, 61%, >99:1 dr); n_max(ATR) 3378 (NeH), 1725 (C]O); [a]

D

þ72.0 (c 1.0 in CHCl₃); d_H(500 MHz, CDCl₃) 1.31 (9H, s, CMe₃), 1.56

(3H, d, J 6.9, C(1)Me), 3.88 (3H, s, OMe), 3.81 (1H, d, J 7.1, C(3)H), 4.24

(1H, d, J 7.1, C(4)H), 4.38 (1H, q, J 6.9, C(1)H), 6.83e6.87 (3H, m,

C(5)H, C(3⁰)H, C(5⁰)H), 7.05e7.10 (3H, m, Ar), 7.13e7.20 (2H, m, Ar);

d_C(125 MHz, CDCl₃) 23.8 (C(1)Me), 27.8 (CMe₃), 47.0 (C(4)), 49.6

(C(1)), 55.2 (OMe), 60.4 (C(3)), 81.3 (CMe₃), 113.7 (C(3⁰), C(5⁰)), 125.9

(C(8)),126.3,126.3 (C(6), C(7)),129.8 (C(5)),130.2 (C(2⁰), C(6⁰)),135.4

30:1) gave (3RS,4RS,

dr); mp 123e125 ^ꢂC; n_max(ATR) 1724 (C]O), 1324 (CeF); d_H

(500 MHz, CDCl₃) 1.15 (3H, d, J 6.8, C( )Me), 1.38 (9H, s, CMe₃), 3.71

(1H, d, J 15.8, C(1)H_A), 3.91 (1H, d, J 15.8, C(1)H_B), 4.03 (1H, q, J 6.8,

C( )H), 4.08 (1H, d, J 1.6, C(3)H), 4.62 (1H, d, J 1.6, C(4)H), 6.96 (1H, d,

aSR)-111 as a white solid (328 mg, 68%, >99:1

a

J 7.1, C(8)H), 7.04 (1H, d, J 7.3, C(5)H), 7.08e7.16 (2H, m, C(6)H,

C(7)H), 7.16 (2H, d, J 7.1, Ph), 7.24 (2H, d, J 8.2, C(2⁰)H, C(6⁰)H),

7.25e7.35 (3H, m, Ph), 7.48 (2H, d, J 8.2, C(3⁰)H, C(5⁰)H); d_C(125 MHz,

t

(C(4a)), 136.3 (C(1⁰)), 139.7 (C(8a)), 158.3 (C(4⁰)), 172.1 (CO₂Bu); m/z

þ

(ESI^þ) 354 ([MþH]^þ, 100%); HRMS (ESI^þ) C₂₂H₂₈NO₃([MþH]^þ)

requires 354.2064; found 354.2064.

CDCl₃) 21.0 (C(a)Me), 28.1 (CMe₃), 47.9, (C(4)), 49.9 (C(1)), 61.8

(C(

a

)), 62.7 (C(3)), 81.4 (CMe₃), 124.3 (q, J 262.3, CF₃), 125.3 (q, J 3.8,

C(3⁰), C(5⁰)), 126.0 (C(8)), 126.2, 126.2 (C(6), C(7)), 126.3 (p-Ph), 127.3

(C(2⁰), C(6⁰)), 127.9, 128.9 (o,m-Ph), 129.0 (q, J 32.4, C(4⁰)), 129.7

(C(5)), 134.6 (C(4a)), 134.9 (C(8a)), 145.1 (i-Ph), 150.6 (C(1⁰)), 170.8

4.59. (RS)-N-Benzyl-N-[

amine (RS)-109

a-methyl-4-(triﬂuoromethyl)benzyl]-

t

(CO₂Bu); d_F(377 MHz, CDCl₃) ꢀ62.3 (CF₃); m/z (ESI^þ) 482 ([MþH]^þ,

þ

p-(Triﬂuoromethyl)acetophenone 108 (2.00 g, 10.6 mmol) was

added to a stirred solution of benzylamine (1.10 mL, 10.1 mmol) in

EtOH (6.5 mL) and the resultant mixture was heated at reﬂux for

3 h. The reaction mixture was allowed to cool to rt, then cooled to

100%); HRMS (ESI^þ) C₂₉H₃₁F₃NO₂([MþH]^þ) requires 482.2301;

found 482.2287.

4.62. tert-Butyl (2RS,3RS,

ﬂuoromethyl)benzyl]amino}-3-(2⁰-methylphenyl)-3-

phenylpropanoate (2RS,3RS, SR)-112, (RS,RS)-3-(tert-butoxy-

carbonyl)-4-phenyl-1,2,3,4-tetrahydroisoquinoline (RS,RS)-113

and tert-butyl (RS,RS)-2-amino-3-(2⁰-methylphenyl)-3-

phenylpropanoate (RS,RS)-114

aSR)-2-{N-[a

-methyl-4⁰⁰-(tri-

0

^ꢂC. NaBH₄(382 mg, 10.1 mmol) was added portionwise (main-

taining the reaction temperature below 15 ^ꢂC), and the resultant

mixture was stirred at rt for 20 h. The reaction mixture was then

concentrated in vacuo and the residue was partitioned CH₂Cl₂

(10 mL) and H₂O (10 mL). The aqueous layer was extracted with

CH₂Cl₂(2ꢃ8 mL) and the combined organic extracts were then

dried and concentrated in vacuo to give (RS)-109 as a pale yellow oil

(1.25 g, 42%); n_max(ATR) 3321 (NeH), 1323 (CeF); d_H(400 MHz,

a

Pd/C (100 mg, 100% w/w) and HCO₂NH₄(132 mg, 3.28 mmol)

were added to a stirred, degassed solution of (3RS,4RS,aSR)-111

CDCl₃) 1.35 (3H, d, J 6.6, C(

13.2, NCH_AH_BPh), 3.63 (1H, d, J 13.2, NCH_AH_BPh), 3.87 (1H, q, J 6.6,

C( )H), 6.20e7.34 (5H, m, Ph), 7.48 (2H, d, J 7.8, C(2)H, C(6)H), 7.59

(2H, d, J 7.8, C(3)H, C(5)H); d_C(100 MHz, CDCl₃) 24.2 (C( )Me), 51.3

(NCH₂Ph), 56.9 (C( )), 124.0 (q, J 271.8, CF₃), 125.1 (q, J 4.0, C(3),

a

)Me), 1.70 (1H, br s, NH), 3.56 (1H, d, J

(100 mg, 0.328 mmol, >99:1 dr) in MeOH (4.6 mL) at rt and the

resultant mixture was stirred at rt for 5 min, then heated at reﬂux

for 3 h. The reaction mixture was then allowed to cool to rt, ﬁltered

through Celite^Ò(eluent MeOH), and concentrated in vacuo to give

a

a 3:77:20 mixture of (2RS,3RS,aSR)-112, (RS,RS)-113 and (RS,RS)-114,

C(5)), 126.7 (p-Ph), 126.7 (C(2), C(6)), 127.7, 128.1 (o,m-Ph), 128.9 (q, J

31.8, C(4)),139.9,149.4 (i-Ph, C(1)); d_F(377 MHz, CDCl₃) ꢀ62.2 (CF₃);

m/z (ESI^þ) 280 ([MþH]^þ, 100%); HRMS (ESI^þ) C₁₆H₁₇F₃N^þ([MþH]^þ)

requires 280.1308; found 280.1305.

respectively. Puriﬁcation via ﬂash column chromatography (eluent

30e40 ^ꢂC petrol/acetone, 10:1) gave (RS,RS)-114 as a pale yellow

solid (12 mg,12%, >99:1 dr); mp 57.5e59 ^ꢂC; n_max(ATR) 1735 (C]O);

d_H(500 MHz, CDCl₃) 1.16 (9H, s, CMe₃), 2.00e2.10 (2H, br s, NH₂),

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

2161

2.32 (3H, s, C(2⁰)Me), 4.15 (1H, d, J 9.9, C(2)H), 4.33 (1H, d, J 9.9, C(3)

H), 7.14 (2H, d, J 3.9, Ph), 7.16e7.28 (6H, m, Ar, Ph), 7.59 (1H, d, J 7.7,

Ar); d_C(125 MHz, CDCl₃) 28.7 (CMe₃), 31.9 (C(2⁰)Me), 52.7 (C(3)), 59.6

(C(2)), 81.1 (CMe₃), 125.0 (p-Ph), 126.3 (C(6⁰)), 126.6, 126.6 (C(4⁰),

C(5⁰)), 128.3 (m-Ph), 129.0 (o-Ph), 131.0 (C_þ(3⁰)), 137.4 (C(2⁰)), 139.3

(C(1⁰)), 140.4 (i-Ph), 173.3 (C(1)); m/z (ESI ) 312 ([MþH]^þ, 100%);

(5 mL) and the resultant solution was washed with 1.0 M aq HCl

(3ꢃ4 mL). The combined aqueous layers were concentrated in

vacuo to give (3RS,4RS,aSR)-116 as a yellow oil (49 mg, 82%, >99:1

dr); n_max(ATR) 1726, 1653 (C]O); d_H(500 MHz, CDCl₃) 1.24 (9H, s,

CMe₃), 1.47 (3H, d, J 7.2, C( )Me), 3.89 (1H, d, J 1.9, C(3)H), 4.41e4.44

(1H, m, C(4)H), 6.14 (1H, q, J 7.2, C(

a

a)H), 6.57 (2H, d, J 7.6, o-Ph), 6.86

þ

HRMS (ESI^þ) C₂₀H₂₆NO₂([MþH]^þ) requires 312.1958; found

(2H, d, J 8.0, C(2⁰)H, C(6⁰)H), 6.98 (2H, app t, J 7.7, m-Ph), 7.04e7.14

(4H, m, Ar, Ph), 7.44e7.51 (2H, m, Ar, Ph), 8.26e8.29 (1H, m, C(8)H);

312.1960. Further elution gave (RS,RS)-113 as a pale yellow solid

(38 mg, 59%, >99:1 dr); mp 111.5e113 ^ꢂC; n_max(ATR) 1727 (C]O); d_H

(500 MHz, CDCl₃) 1.26 (9H, s, CMe₃), 1.78 (1H, br s, NH), 3.71 (1H, d, J

9.0, C(3)H), 4.16e4.26 (3H, m, C(1)H₂, C(4)H), 6.82 (1H, d, J 7.7, C(5)H),

7.04e7.09 (2H, m, Ar, Ph), 7.13e7.18 (3H, m, Ar, Ph), 7.22e7.33 (3H, m,

Ar, Ph); d_C(125 MHz, CDCl₃) 27.7 (CMe₃), 47.1 (C(1)), 48.3, (C(4)), 64.2

(C(3)), 81.3 (CMe₃), 125.5 (C(8)), 126.3, 126.4, 126.8 (C(6), C(7), p-Ph),

128.4 (m-Ph), 129.4 (o-Ph), 129.8 (C(5)), 135.0 (C(8a)), 137.3 (C(4a)),

142.6 (i-Ph), 171.9 (CO₂^tBu); m/z (ESI^þ) 310 ([MþH]^þ, 100%); HRMS

d_C(125 MHz, CDCl₃) 14.9 (C(a)Me), 27.5 (CMe₃), 46.8 (C(4)), 50.2

(C( )), 61.6 (C(3)), 82.7 (CMe₃), 124.0 (q, J 271.8, CF₃), 124.9 (q, J 3.8,

a

C(3⁰), C(5⁰)), 127.1 (p-Ph), 127.3 (C(2⁰), C(6⁰)), 127.6 (o-Ph), 128.0

(C(8)), 128.1, 128.8 (C(6), C(7)), 128.4 (m-Ph), 128.9 (q, J 32.4, C(4⁰)),

130.8 (C(8a)), 132.3 (C(5)), 135.3 (C(4a)), 139.8 (i-Ph), 142.9 (C(1⁰)),

164.2 (C(1)), 170.5 (CO₂^tBu); m/z (FI^þ) 495 ([M]^þ, 100%).⁴⁷

4.65. (RS)-N-[a-Methyl-4-(triﬂuoromethyl)benzyl]amine (RS)-

117

(ESI^þ) C₂₀H₂₄NO₂([MþH]^þ) requires 310.1802; found 310.1801.

þ

Data for (2RS,3RS,aSR)-112: d_H(500 MHz, CDCl₃) 0.97 (9H, s, CMe₃),

1.21 (3H, d, J 6.6, C(

a

)Me), 1.89 (1H, br s, NH), 2.28 (3H, s, C(2⁰)Me),

)H), 3.92 (1H, d, J 9.9, C(2)H), 4.36 (1H, d, J 9.9,

Ti(OⁱPr)₄(31.5 mL, 106 mmol) was added to (p-triﬂuoromethyl)

acetophenone 108 (10.0 g, 53.1 mmol) in NH₃(2.0 M in EtOH,

133 mL) and the resultant mixture was stirred at rt for 6 h. NaBH₄

(3.01 g, 79.7 mmol) was added at 0 ^ꢂC, and the resultant suspension

was stirred at rt for 3 h, then poured into 2.0 M aq NH₄OH (200 mL).

The resultant suspension was ﬁltered (eluent EtOAc) and the

aqueous layer was extracted with EtOAc (2ꢃ80 mL). The combined

organic extracts were extracted with 1.0 M aq HCl (3ꢃ50 mL) and

the combined aqueous extracts were washed with EtOAc

(3ꢃ30 mL), treated with 2.0 M aq NaOH until pH>8 was observed,

then extracted with EtOAc (4ꢃ50 mL). The combined organic ex-

tracts were washed with brine (200 mL), then dried and concen-

trated in vacuo to give (RS)-117 as a pale yellow oil (6.84 g, 68%);⁴³

3.60 (1H, q, J 6.6, C(

a

C(3)H), 7.06e7.62 (13H, m, Ar, Ph); d_C(125 MHz, CDCl₃) 20.0 (C(2⁰)

Me), 23.5 (C(a)Me), 27.4 (CMe₃), 50.6 (C(3)), 57.7 (C(a)), 64.9 (C(2)),

80.9 (CMe₃), 124.2 (q, J 271.8, CF₃), 125.2 (q, J 3.8, C(3⁰⁰), C(5⁰⁰)), 125.9

(p-Ph), 126.4 (C(6⁰)), 126.5, 126.5 (C(4⁰), C(5⁰)), 127.2, 128.2 (m-Ph,

C(2⁰⁰), C(6⁰⁰)), 129.4 (o-Ph), 129.2 (q, J 32.4, C(4⁰⁰)), 130.7 (C(3⁰)), 137.2

(C(2⁰)), 139.4 (C(1⁰)), 140.0 (i-Ph), 149.8 (C(1⁰⁰)), 173.3 (C(1)).

4.63. (1RS*,3RS,4RS,aSR)-1-Hydroxy-N(2)-[a

-methyl-4⁰-(tri-

ﬂuoromethyl)benzyl]-3-(tert-butoxycarbonyl)-4-phenyl-

1,2,3,4-tetrahydroisoquinoline 115

CAN (205 mg, 0.347 mmol) was added to a stirred solution of

d_H(400 MHz, CDCl₃) 1.40 (3H, d, J 6.6, C(

a

)Me), 1.59 (2H, br s, NH₂),

(3RS,4RS,

a

SR)-111 (30 mg, 62

m

mol, >99:1 dr) in MeCN/H₂O (2:1,

4.20 (1H, q, J 6.6, C(

7.8, C(3)H, C(5)H).

a)H), 7.48 (2H, d, J 7.8, C(2)H, C(6)H), 7.59 (2H, d, J

0.6 mL) and the resultant solution was stirred at rt for 24 h. Satd aq

NaHCO₃(0.5 mL) was added and the resultant mixture was stirred

at rt for 10 min, then extracted with Et₂O (3ꢃ2 mL). The combined

organic extracts were then dried and concentrated in vacuo to give

4.66. (R)-N-[

a

-Methyl-4⁰-(triﬂuoromethyl)benzyl] (R)-2-

-methyl-4⁰-(tri-

acetoxy-2-phenylethanamide 118 and (S)-N-[

a

(1RS*,3RS,4RS,

(ATR) 3642 (OeH), 1713 (C]O); d_H(500 MHz, CDCl₃) 1.34 (3H, d, J

6.9, C( )Me), 1.41 (9H, s, CMe₃), 3.94 (1H, d, J 1.3, C(3)H), 4.37 (1H,

app s, C(4)H), 4.56 (1H, q, J 6.9, C( )H), 4.85 (1H, d, J 11.0, OH), 5.39

a

SR)-115 as a yellow oil (29 mg, 94%, >99:1 dr); n_max

ﬂuoromethyl)benzyl] (R)-2-acetoxy-2-phenylethanamide 119

a

DCC (2.35 g, 12.1 mmol) and DMAP (50 mg) were added to

a stirred solution of (RS)-117 (2.29 g, 12.1 mmol) and (R)-O-ace-

tylmandelic acid (2.35 g, 12.1 mmol, >99:1 er) in CH₂Cl₂(60 mL) at

a

(1H, d, J 11.0, C(1)H), 6.80 (2H, d, J 6.6, o-Ph), 6.95e7.02 (3H, m,

C(2⁰)-H, C(6⁰)H, p-Ph), 7.12e7.33 (7H, m, Ar, m-Ph), 7.60 (1H, d, J 7.7,

0

^ꢂC and the resultant mixture was stirred at rt for 16 h. The re-

C(5)H); d_C(125 MHz, CDCl₃) 19.4 (C(

56.9 (C(

a

)Me), 27.9 (CMe₃), 48.3 (C(4)),

action mixture was ﬁltered and the ﬁltrate was washed sequen-

tially with 1.0 M aq HCl (40 mL), satd aq NaHCO₃(40 mL) and brine

(40 mL), then dried and concentrated in vacuo. Puriﬁcation via ﬂash

column chromatography (eluent 30e40 ^ꢂC petrol/EtOAc, 2:1, 1%

Et₃N) gave 119 as a white solid (1.58 g, 36%, >99:1 dr); mp

132.5e133.5 ^ꢂC; n_max(ATR) 3292 (NeH), 1742, 1662 (C]O), 1327

a

)), 61.4 (C(3)), 79.9 (C(1)), 82.3 (CMe₃), 124.2 (q, J 271.8,

CF₃), 124.7 (q, J 3.8, C(3⁰), C(5⁰)), 126.6, 127.3 (Ar), 127.4 (C(2⁰), C(6⁰)),

128.0 (o-Ph),128.1 (Ar),128.1 (m-Ph),128.7 (q, J 32.4, C(4⁰)),128.8 (p-

Ph), 128.8 (C(5)), 132.2 (C(4a)), 138.2 (C(8a)), 143.7 (i-Ph), 147.7

(C(1⁰)), 175.8 (CO₂^tBu); m/z (ESI^þ) 480 ([MꢀOH]^þ, 100%); HRMS

þ

(ESI^þ) C₂₉H₂₉F₃NO₂

480.2143.

([MꢀOH]^þ) requires 480.2145; found

(CeF); [

d, J 7.0, C(

7.0, C(

)H), 5.94 (1H, s, C(2)H), 7.33e7.39 (3H, m, C(2⁰)H, C(6⁰)H, Ph),

7.48e7.53 (4H, m, Ph), 7.58 (2H, d, J 8.2, C(3⁰)H, C(5⁰)H); d_C

a]

²⁰e153.0 (c 1.0 in MeOH); d_H(500 MHz, CDCl₃) 1.40 (3H,

D

a

)Me), 2.13 (3H, s, COMe), 4.87 (1H, br s, NH), 5.00 (1H, q, J

a

4.64. (3RS,4RS,aSR)-1-Oxo-N(2)-[a

-methyl-4⁰-(tri-

ﬂuoromethyl)benzyl]-3-(tert-butoxycarbonyl)-4-phenyl-

1,2,3,4-tetrahydroisoquinoline 116

(125 MHz, CDCl₃) 20.8 (COMe), 22.1 (C(a)Me), 50.0 (C(a)), 77.2

(C(2)), 125.9 (q, J 269.9, CF₃), 126.4 (q, J 3.8, C(3⁰), C(5⁰)), 127.9 (C(2⁰),

C(6⁰)), 128.7 (o-Ph), 129.8 (m-Ph), 130.2 (p-Ph), 130.3 (q, J 31.5, C(4⁰)),

136.8 (i-Ph), 149.5 (C(1⁰)), 171.0 (C(1)), 172.1 (COMe); d_F(377 MHz,

A solution of NaBrO₃(56 mg, 0.37 mmol) in H₂O (1.25 mL) was

added to a stirred solution of (3RS,4RS,

aSR)-111 (60 mg, 0.13 mmol,

CDCl₃) ꢀ63.9 (CF₃); m/z (ESI^þ) 388 ([MþNa]^þ, 100%); HRMS (ESI^þ)

þ

>99:1 dr) in EtOAc (1.6 mL) at rt and the resultant mixture was

stirred at rt for 10 min. A solution of Na₂S₂O₄(54 mg, 0.37 mmol) in

H₂O (2.3 mL) was added dropwise at rt over 5 min and the resultant

mixture was stirred at rt for 4 h. EtOAc (4 mL) was then added and

the resultant mixture was washed with satd aq Na₂S₂O₃(4 mL). The

aqueous layer was extracted with EtOAc (2ꢃ3 mL) and the com-

bined organic extracts were washed with brine (5 mL), then dried

and concentrated in vacuo. The residue was dissolved in CH₂Cl₂

C

₁₉H₁₈F₃NNaO₃([MþNa]^þ) requires 388.1131; found 388.1122.

Further elution gave 118 as a white solid (1.46 g, 33%, >99:1 dr); mp

118e120 ^ꢂC; n_max(ATR) 3291 (NeH), 1744, 1663 (C]O), 1327 (CeF);

[a]

²⁰e17.0 (c 1.0 in MeOH); d_H(500 MHz, CDCl₃) 1.47 (3H, d, J 7.0,

D

C(

a

)Me), 2.15 (3H, s, COMe), 4.87 (1H, br s, NH), 5.06 (1H, q, J 7.0,

)H), 5.94 (1H, s, C(2)H), 7.24 (2H, d, J 8.4, C(2⁰)H, C(6⁰)H),

7.34e7.38 (3H, m, Ph), 7.44e7.49 (4H, m, C(3⁰)H, C(5⁰)H, Ph); d_C

(125 MHz, CDCl₃) 20.8 (COMe), 22.0 (C(a)Me), 50.0 (C(a)), 77.1

2162

S.G. Davies et al. / Tetrahedron 72 (2016) 2139e2163

(C(2)), 125.7 (q, J 270.8, CF₃), 126.4 (q, J 3.8, C(3⁰), C(5⁰)), 127.6 (C(2⁰),

C(6⁰)),128.8 (o-Ph),129.8 (m-Ph), 130.2 (p-Ph), 130.3 (q, J 32.4, C(4⁰)),

136.7 (i-Ph), 149.5 (C(1⁰)), 170.9 (C(1)), 172.1 (COMe); d_F(377 MHz,

chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 5:1) gave (S,S,S)-110

20

as a colourless oil (800 mg, 94%, >99:1 dr); [

CHCl₃).

a

]

þ27.8 (c 1.0 in

D

CDCl₃) ꢀ63.7 (CF₃); m/z (ESI^þ) 388 ([MþNa]^þ, 100%); HRMS (ESI^þ)

þ

₁₉H₁₈F₃NNaO₃([MþNa]^þ) requires 388.1131; found 388.1120. A

4.71. (3R,4R,

3-(tert-butoxycarbonyl)-4-phenyl-1,2,3,4-

tetrahydroisoquinoline (3R,4R, S)-111

aS)-N(2)-[a

-Methyl-4⁰-(triﬂuoromethyl)benzyl]-

C

57:43 mixture of 118 and 119, respectively, was also recovered as

a white solid (812 mg, 18%).

a

4.67. (R)-N-[a-Methyl-4-(triﬂuoromethyl)benzyl]amine (R)-117

Following general procedure II, Tf₂O (252

mL, 1.50 mmol) was

reacted with (S,S,S)-110 (500 mg, 1.00 mmol, >99:1 dr) and DTBMP

(620 mg, 3.0 mmol) in CH₂Cl₂(15 mL) at rt for 6 h. Puriﬁcation via

ﬂash column chromatography (eluent 30e40 ^ꢂC petrol/Et₂O, 30:1)

A solution of 118 (100 mg, 0.27 mmol, >99:1 dr) in 4.5 M aq HBr

(2 mL) was heated at reﬂux for 24 h, then allowed to cool to rt and

concentrated in vacuo. The residue was dissolved in CH₂Cl₂(3 mL),

and the resultant solution was extracted with 1.0 M aq HCl

(4ꢃ3 mL). The combined aqueous extracts were treated with 2.0 M

NaOH until pH>8 was observed, and the resultant mixture was

extracted with CH₂Cl₂(4ꢃ5 mL). The combined organic extracts

were then dried and concentrated in vacuo to give (R)-117 as a pale

gave (3R,4R,

aS)-111 as a white solid (449 mg, 93%, >99:1 dr); mp

95e97.5 ^ꢂC; [

a

]

²⁰þ6.8 (c 1.0 in CHCl₃).

D

4.72. (R,R)-3-(tert-Butoxycarbonyl)-4-phenyl-1,2,3,4-

tetrahydroisoquinoline (R,R)-113

20

yellow oil (20 mg, 38%); [

a

]

D

þ22.0 (c 1.0 in MeOH); {lit.⁴⁴

[a]

D

Pd/C (100 mg, 100% w/w) and HCO₂NH₄(132 mg, 3.28 mmol)

were added to a stirred, degassed solution of (3R,4R,aS)-111

þ20.0 (c 1.0 in MeOH)}.

(100 mg, 0.33 mmol, >99:1 dr) in MeOH (4.6 mL) and the resultant

mixture was stirred at rt for 5 min, then heated at reﬂux for 3 h. The

reaction mixture was then allowed to cool to rt, ﬁltered through

Celite^Ò(eluent MeOH) and concentrated in vacuo to give a 9:74:17

4.68. (R)-N-Benzyl-N-[

amine (R)-109

a-methyl-4-(triﬂuoromethyl)benzyl]

A solution of 118 (1.52 g, 4.15 mmol, >99:1 dr) in 4.5 M aq HBr

(10 mL) was heated at reﬂux for 24 h, then allowed to cool to rt and

concentrated in vacuo. The residue was dissolved in EtOH (26 mL),

mixture of (2R,3R,aS)-112, (R,R)-113 and (R,R)-114, respectively.

Puriﬁcation via ﬂash column chromatography (eluent 30e40 ^ꢂC

petrol/acetone, 10:1) gave (R,R)-113 as a pale yellow solid (34 mg,

20

50%, >99:1 dr); mp 78.5e81 ^ꢂC; [

a

]

e30.8 (c 1.0 in CHCl₃).

then PhCHO (461 mL, 4.56 mmol) and K₂CO₃(630 mg, 4.56 mmol)

D

were added to the resultant solution. The resultant mixture was

heated at reﬂux for 3 h, allowed to cool to rt, and then cooled

further to 0 ^ꢂC. NaBH₄(157 mg, 4.15 mmol) was added and the

reaction mixture was stirred at rt for 20 h, then concentrated in

vacuo. The residue was partitioned between CH₂Cl₂(20 mL) and

H₂O (20 mL). The aqueous layer was extracted with CH₂Cl₂

(2ꢃ10 mL) and the combined organic extracts were dried and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatogra-

phy (eluent 30e40 ^ꢂC petrol/EtOAc, 3:1, 1% Et₃N) gave (R)-109 as

Supplementary data

Supplementary data associated with this article can be found in

the online version, at http://dx.doi.org/10.1016/j.tet.2016.03.008.

References and notes

1. The term “tetrahydroisoquinoline” is used throughout this manuscript to mean

“1,2,3,4-tetrahydroisoquinoline”.

2. (a) Scott, J. D.; Willams, R. M. Chem. Rev. 2002 , 102 , 1669; (b) Bru, C.; Guillou, C.

Tetrahedron 2006 , 62 , 9043; (c) Avendano, C.; de la Cuesta, E. Chem.dEur. J.

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Nat. Prod. 2011 , 74 , 411.

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Laws, M.; Kitchen, D. B.; Smith, M. A.; Olson, R. E.; Liu, S.; Molino, B. F. Bioorg.

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Schmitt, K.; Witte, P. U. J. Med. Chem. 1987 , 30 , 798.

a pale yellow oil (554 mg, 48% from 118, >99:1 er);⁴⁵

[

a

]

²⁰þ47.8 (c

D

1.0 in MeOH).

4.69. (S)-N-Benzyl-N-[

amine (S)-109

a-methyl-4-(triﬂuoromethyl)benzyl]

A solution of 119 (1.58 g, 4.33 mmol, >99:1 dr) in 4.5 M aq HBr

(10 mL) was heated at reﬂux for 24 h, then allowed to cool to rt and

concentrated in vacuo. The residue was dissolved in EtOH (27 mL),

6. Evidente, A.; Kornienko, A. Phytochem. Rev. 2009 , 8 , 449.

7. Wang, P.; Yuan, H.-H.; Zhang, X.; Li, Y.-P.; Shang, L.-Q.; Yin, Z. Molecules 2014 , 19 ,

2469.

8. Nair, J. J.; Rarova, L.; Strnad, M.; Bastida, J.; van Staden, J. Bioorg. Med. Chem. Lett.

2012 , 22 , 6195.

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Grunewald, G. L.; Sall, D. J.; Monn, J. A. J. Med. Chem. 1988 , 31 , 433; (c) Uematsu,

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then PhCHO (481 mL, 4.76 mmol) and K₂CO₃(598 mg, 4.37 mmol)

were added to the resultant solution. The resultant mixture was

heated at reﬂux for 3 h, allowed to cool to rt, and then cooled

further to 0 ^ꢂC. NaBH₄(163 mg, 4.33 mmol) was added and the

reaction mixture was stirred at rt for 20 h, then concentrated in

vacuo. The residue was partitioned between CH₂Cl₂(20 mL) and

H₂O (20 mL). The aqueous layer was extracted with CH₂Cl₂

(2ꢃ10 mL) and the combined organic extracts were dried and

concentrated in vacuo. Puriﬁcation via ﬂash column chromatogra-

phy (eluent 30e40 ^ꢂC petrol/EtOAc, 3:1, 1% Et₃N) gave (S)-109 as

ꢀ

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€

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a pale yellow oil (756 mg, 63% from 119, >99:1 er);⁴⁵²⁰e45.7 (c

[a]

D

1.0 in MeOH).

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4.70. tert-Butyl (S,S,S)-2-hydroxy-3-{N-benzyl-N-[a

-methyl-4⁰-

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2003 , 51 , 667; (c) Malhotra, R.; Chakrabarti, S.; Ghosh, A.; Ghosh, R.; Dey, T. K.;

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(triﬂuoromethyl)benzyl]amino}-3-phenylpropanoate (S,S,S)-110

Following general procedure I, BuLi (2.2 M in hexanes, 1.20 mL,

2.65 mmol) and (S)-109 (718 mg, 2.57 mmol, >99:1 er) were

reacted with 65 (350 mg, 1.71 mmol, >99:1 dr) and (þ)-CSO

(667 mg, 8.33 mmol) in THF (14 mL). Puriﬁcation via ﬂash column

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28. For anti-

are usually observed whereas values of w10.0 Hz are indicative of syn-

droxy- -amino esters; see: Refs. 16, 22aec.

29. For anti- -hydroxy-

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are usually observed whereas values of w9.5 Hz are indicative of syn- -hy-

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30. Brown, H. C.; Okamoto, Y. J. Am. Chem. Soc. 1958 , 80 , 4979.

a-hydroxy-b

-amino esters ¹H NMR ³J_2,3coupling constants of w4.0 Hz

a

-hy-

b

a

b

~

ꢀ

14. (a) Teichert, J. F.; Fananas-Mastral, M.; Feringa, B. L. Angew. Chem., Int. Ed. 20 1 1 ,

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a

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Centre as supplementary publication numbers CCDC 1439612e1439616,

respectively.

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22. Attempted epimerisation of anti-16 via our usual oxidation/diastereoselective

reduction protocol produced

a 55:45 mixture of anti-16 and syn-19, re-

spectively. For highly diastereoselective examples of this procedure, see: (a)

Davies, S. G.; Fletcher, A. M.; Foster, E. M.; Lee, J. A.; Roberts, P. M.; Thomson, J.

E. J. Org. Chem. 2013 , 78 , 2500; (b) Brambilla, M.; Davies, S. G.; Fletcher, A. M.;

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Davies, S. G.; Foster, E. M.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. J. Org. Chem.

2014, 79, 9686. See also: Ref. 21.

36.

a

-Hydroxy-

b

-amino ester 69 (R ¼ H) has been prepared previously; see: Davies,

S. G.; Polywka, M. E. C.; Fenwick, D. R.; Reed, F. PCT Int. Appl. 1995 WO 9518134.

23.

a

,

b

-Unsaturated esters 24e28 were synthesised in 25e55% yield and >99:1 dr

Article Doi

Trading N and O. Part 3: Synthesis of 1,2,3,4-tetrahydroisoquinolines from α-hydroxy-β-amino esters

DOI: 10.1016/j.tet.2016.03.008

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