Synthesis of Enantiopure Piperazines via Asymmetric Lithiation-Trapping of N-Boc Piperazines: Unexpected Role of the Electrophile and Distal N-Substituent

Article abstract of DOI:10.1021/jacs.5b11288

A new method for the synthesis of enantiopure α-substituted piperazines via direct functionalization of the intact piperazine ring is described. The approach utilizes the asymmetric lithiation-substitution of an α-methylbenzyl-functionalized N-Boc piperaz

Full text of DOI:10.1021/jacs.5b11288

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Article
Synthesis of Enantiopure Piperazines via Asymmetric
Lithiation-Trapping of N-Boc Piperazines: Unexpected
Role of the Electrophile and Distal N-Substituent
James D. Firth, Peter O'Brien, and Leigh Ferris
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b11288 • Publication Date (Web): 18 Dec 2015
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Synthesis of Enantiopure Piperazines via Asymmetric Lithia-
tion-Trapping of N-Boc Piperazines: Unexpected Role of the
Electrophile and Distal N-Substituent
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James D. Firth,† Peter O’Brien*,† and Leigh Ferris‡
†Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K., ‡ AstraZeneca UK, Macclesfield, Chesh-
ire, SK10 2NA, U.K.
Supporting Information Placeholder
ABSTRACT: A new method for the synthesis of enantiopure -substituted piperazines via direct functionalisation of the intact
piperazine ring is described. The approach utilizes the asymmetric lithiation-substitution of an -methylbenzyl-functionalised N-
Boc piperazine using s-BuLi/(–)-sparteine or (+)-sparteine surrogate and provides access to a range of piperazines (as single stereo-
isomers). Optimization of the new methodology required a detailed mechanistic study. Surprisingly, it was found that the main
culprits affecting the yield and enantioselectivity were the electrophile (the last reagent to be added to the reaction flask) and the
distal N-substituent. The mechanistic studies included optimization of lithiation times using in situ IR spectroscopy, identification
of a ring-fragmentation of the lithiated piperazines (that could be minimized with sterically hindered N-alkyl groups) and use of a
novel “diamine-switch” strategy to improve enantioselectivity with certain electrophiles. The methodology was showcased with
the preparation of an intermediate for Indinavir synthesis and the stereoselective synthesis of 2,5-trans- and 2,6-trans-piperazines.
general asymmetric route to α-substituted piperazines via
direct functionalisation of the intact piperazine ring.
Introduction
Piperazines occupy a privileged position in the development
of small-molecule therapeutic agents. The piperazine motif
is the third most frequent nitrogen heterocycle in ~2000
FDA-approved pharmaceuticals1 and the fourth most com-
mon ring in drugs approved by the FDA between 1983 and
2012 (51 out of 1175 drugs contained piperazines).2 There
are examples of α-substituted piperazine drugs – Indinavir,3
an antiretroviral drug used for the treatment of HIV and
Vestipitant,4 a NK-1 antagonist in clinical trials for the
treatment of anxiety and tinnitus. However, such examples
are rare mainly because of the lack of general routes to enan-
tiopure α-substituted piperazines. The most common ap-
proaches are racemic synthesis coupled with classical resolu-
tion5 (used to synthesise Indinavir6 and Vestipitant7) and
synthesis from α-amino acids typically proceeding via
diketopiperazines.8 More recent synthetic approaches have
used a kinetic resolution process9 or have started from α-
amino acids and utilised Pd-catalysed cyclisation onto al-
kenes10 or Mitsunobu chemistry.11 A chiral reagent ap-
proach (RMgX/(–)-sparteine) was adopted in additions to
pyrazine N-oxide,12 and, in selected cases, chiral auxiliary13
and chiral catalysis14-16 have also been successful, although
the methods deliver variable enantioselectivity. The most
recent approaches generated α-substituted piperazines via Au
catalysis,17 SnAP reagents18 and photoredox catalysis,19 but,
in general, racemic products were formed. All of the previ-
ous approaches suffer from one or two limitations: (i) the α-
substituent is introduced at an early stage and (ii) they do not
represent a general approach to enantiopure α-substituted
piperazines. In this paper, we present an approach that
solves both of these limitations and represents a practical,
The enantioselective α-functionalisation of N-Boc-protected
nitrogen heterocycles via lithiation-trapping is one of the
best methods for the synthesis of enantioenriched α-
substituted nitrogen heterocycles.20 Asymmetric α-lithiation-
trapping of N-Boc pyrrolidine21 and N-Boc piperidine22 are
well established and include applications in the synthesis of
pharmaceuticals.23 In contrast, there is only one example of
the asymmetric lithiation of a N-Boc piperazine: McDermott
at AstraZeneca24 reported the α-lithiation-carboxylation of a
N-Boc piperazine using s-BuLi/(–)-sparteine to give a
trapped product (after amide formation) in 48% yield and
89:11 er.25,26 Given the opportunity for the direct introduc-
tion of functionality, we set out to investigate this enantiose-
lective approach to α-substituted piperazines. Lithiation of
N-Boc piperazines 1 using s-BuLi and (–)-sparteine or the
(+)-sparteine surrogate27 would give either enantiomer of
lithiated intermediates 2 which would be trapped to give α-
substituted piperazines 3 (Scheme 1).
Scheme 1. Direct piperazine functionalisation approach
to α-substituted piperazines.
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On paper, such an approach appears to be a simple extension electrophiles: MeO2CCl, Bu3SnCl, MeI, Me2SO4, Me3SiCl,
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of Beak’s methodology. In practice, we discovered a num-
ber of issues to be resolved. Of note, and unexpectedly, the
main culprits that affected the yield and enantioselectivity
were the electrophile, the final reagent to be added to the
reaction flask, and the distal nitrogen substituent (N-R in 1)
which is far away from the lithiation position. Our study
also addresses a key limitation of N-Boc α-lithiation-
trapping examples, namely the inability to deliver products
in ≥99:1 er.21-24,28 In this paper, we describe the mechanistic
nuances of the optimization of the α-lithiation-trapping of N-
Boc piperazines 1 and we exploit them in a new strategy for
the stereoselective synthesis of either antipode of a range of
single stereoisomer α-substituted piperazines 3. This new
strategy is showcased with applications such as preparation
of an advanced intermediate for Indinavir synthesis and the
stereoselective synthesis of 2,5-trans-/2,6-trans-piperazines.
Me3SiOTf and Ph2CO. These initial results are summarised
in Scheme 3 and are, at first site, particularly discouraging –
notably, the outcome of the reactions was strongly depend-
ent on the electrophile, the last reagent to be added.
Scheme 3. Enantioselective lithiation-trapping of N-Boc
piperazine 4.
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Results and Discussion
Preliminary Results for the Enantioselective Lithiation-
trapping of N-Boc Piperazine 4
The starting point in our group for investigating the α-
lithiation of a new N-Boc substrate is the use of in situ IR
spectroscopy to identify the time taken for lithiation (by
monitoring the change in νC=O).22c,29,30 Initially, the orthogo-
nally protected N-Boc-N’-benzyl piperazine 425f was used.
A solution of 4 (1.0 mmol) in Et2O (14 mL) at –78 °C (in the
presence of (–)-sparteine) exhibited a νC=O peak at 1702 cm-
1. On addition of s-BuLi, lithiation of 4 proceeded to give
the organolithium 6 (νC=O peak at 1645 cm-1); formation of a
pre-lithiation complex 5, assigned to a peak at 1681 cm-1,
was also observed (Scheme 2a, 2-D plot of absorbance versus
time). As the reaction progressed, the proportion of both 4
and 5 decreased whilst that of the lithiated species 6 steadily
increased (lithiation time ~60 min, t1/2 ~9.5 min31). As seen
with N-Boc pyrrolidine and N-Boc piperidine,22c,29a lithiation
of 4 with s-BuLi/(+)-sparteine surrogate was an order of
magnitude faster than that with (–)-sparteine: lithiation to
give 6 (via 5) occurred in 2 min (t1/2 ~0.5 min Scheme 2b).
Scheme 2. In situ IR spectroscopic monitoring of the
asymmetric lithiation of N-Boc piperazine 4: (a) s-
BuLi/(–)-sparteine; (b) s-BuLi/(+)-sparteine surrogate.
The yields of the desired α-substituted piperazines 7, 9, 11,
13 and 14 varied considerably (0-88%), and 7 was the only
α-substituted product that was generated in >54% yield
(trapping with MeO2CCl). The low yields could in general
be accounted for by the generation of two distinct types of
alkene-containing by-products. With MeO2CCl, Bu3SnCl,
MeI, Me2SO4, Me3SiCl and Me3SiOTf, vinyl carbamates 8,
10 and 12 were formed (to differing extents) via a piperazine
ring-fragmentation process (with functionalisation of the
nitrogen by the electrophile and, in the cases with silicon- or
tin-based electrophiles, subsequent cleavage of the labile N–
Si and N–Sn bonds to give 10). In contrast, with Ph2CO, the
only by-product generated was unsaturated piperazine 15.
Furthermore, the enantioselectivity was also electrophile-
With suitable lithiation times for 4 (Et2O, –78 °C) in hand,
we investigated a series of reactions, trapping with seven
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dependent. With MeO2CCl, Bu3SnCl and Ph2CO, products
(R)-/(S)-7, 9 and 14 were formed in 75:25-88:12 er whereas
lower enantioselectivity was observed when trapping with
MeI, Me2SO4 or Me3SiCl (50:50-61:39 er). The configura-
tion of 7, 9, 11 and 14 was assigned by analogy with
McDermott’s precedent with s-BuLi/(–)-sparteine.24
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From the results shown in Scheme 3, three key aspects re-
quired explanation: (i) formation of the ring-fragmentation
by-products 8, 10 and 12; (ii) the low enantioselectivity ob-
served using MeI, Me2SO4 and Me3SiCl ( 11/13); (iii)
formation of unsaturated piperazine 15 and the accompany-
ing moderate enantioselectivity in the formation 14 upon
trapping with Ph2CO. To explain each of these, we have
identified three distinct mechanistic processes and address-
ing each of these provided the focus for optimising the α-
lithiation-trapping of N-Boc piperazines and, ultimately, the
development of a new strategy to enantiopure piperazines.
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If our mechanistic conjecture in Scheme 4b was correct then
increasing the steric hindrance around the N-alkyl group
should lead to a reduction in ring-fragmentation and accord-
ingly higher yields of the desired α-substituted piperazines.
To investigate this, N-Boc piperazines 19-22 with four steri-
cally hindered groups (t-butyl, trityl, 9-phenylfluoren-9-yl
(PhFl) and cumyl) were prepared and the lithiation of a rep-
resentative substrate, N-Boc-N’-t-butyl piperazine 19 was
studied using in situ IR spectroscopy (Scheme 5). Since the
N-alkyl group is far from the lithiation site, we expected
similar lithiation times to those with N-Boc-N’-benzyl piper-
azine 4. Surprisingly, the distal N-t-butyl group slowed
down the rate of lithiation considerably. Using s-BuLi/(–)-
sparteine, conversion of N-Boc-N’-t-butyl piperazine 19
(νC=O peak at 1700 cm-1), via pre-lithiation complex 23 (νC=O
peak at 1680 cm-1), to lithiated piperazine 24 (νC=O peak at
1644 cm-1) was almost complete after 5 h with t1/2 ~60 min
(Scheme 5a). The corresponding N-benzyl piperazine 4 was
lithiated in 60 min (see Scheme 2a). Similarly, the s-
BuLi/(+)-sparteine surrogate lithiation of N-Boc-N’-t-butyl
piperazine 19 (lithiation time: 5 min, t1/2 ~1 min Scheme 5b)
took longer than that of N-benzyl piperazine 4 (lithiation
time: 2 min, see Scheme 2a). These differences could per-
haps be due to a change in conformation of the piperazine or
aggregation effects of the s-BuLi/diamine complex.
Addressing piperazine ring-fragmentation: lithiation-
trapping of sterically hindered N-Boc piperazines
Initially, we considered formation of the ring-fragmentation
by-products 8, 10 and 12. A potential mechanism would be
ring-fragmentation via -elimination of the N-alkyl group
from lithiated piperazine 6 to give vinyl carbamate 16 which
could then trap on nitrogen to give the observed products 17
(with N–Sn and N–Si bond cleavage  10 in those exam-
ples) (Scheme 4a). Such a mechanism is precedented with
substituted morpholines32 (alkoxide leaving group) and a N-
Boc-N-phenyl piperazine33 (anilide leaving group).34 How-
ever, the mechanism in Scheme 4a would not explain the
electrophile-dependence of the results presented in Scheme
335 and the fact that ring-fragmentation has not been ob-
served in racemic lithiation-trappings of N-alkyl-N-Boc pi-
perazines with the electrophiles in Scheme 3.25,26 Hence, we
propose an alternative mechanism for ring-fragmentation in
which the order of the two steps is reversed so that the lig-
ands around the lithium can play a key role (Scheme 4b).
Since the lithiated piperazine 6 has a sterically hindered di-
amine ligand ((–)-sparteine or the (+)-sparteine surrogate)
coordinated to the lithium, we wondered whether the nucle-
ophilic N-alkyl substituent could competitively react with
the electrophile. This would generate ammonium ion inter-
mediates 18 which, now equipped with a good leaving
group, would readily -eliminate to give vinyl carbamates
17. Although this mechanism appears speculative, there is
some precedent for amines reacting with electrophiles in
preference to enolates in amine-containing enolates.36
Scheme 5. In situ IR spectroscopic monitoring of the
asymmetric lithiation of N-Boc piperazine 19: (a) s-
BuLi/(–)-sparteine; (b) s-BuLi/(+)-sparteine surrogate.
Scheme 4. Mechanistic proposals for ring-fragmentation
in the enantioselective lithiation-trapping of N-Boc pi-
perazine 4.
The in situ IR spectroscopic study directed us to lithiation
times of 6 h (for (–)-sparteine) and 1 h (for the (+)-sparteine
surrogate) for the α-lithiation-trapping of N-Boc piperazines
containing the sterically hindered groups (Table 1). Using
MeO2CCl, Bu3SnCl and t-BuNCO as electrophiles, no ring-
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1
fragmentation by-products were observed in the H NMR
Addressing low enantioselectivity with certain electro-
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spectra of the crude products and good yields of trapped
products (R)- or (S)-25-31 were obtained. This should be
compared with the results using N-benzyl piperazine 4
(MeO2CCl or Bu3SnCl) where ring-fragmentation occurred
(see Scheme 3), supporting our proposed mechanism for
ring-fragmentation (see Scheme 4b). Of the four N-alkyl
groups investigated, the trityl and PhFl groups gave the low-
est enantioselectivity (entries 3, 4 and 7). The t-butyl and
cumyl groups gave similar yields and ers (compare entries
1/5 and 2/6) but we could not remove the t-butyl group. Our
preferred N-alkyl group is thus cumyl (N-Boc-N-cumyl pi-
perazine 22) as it gave trapped products in high yields and
enantioselectivity with both diamines. For example, using
the (+)-sparteine surrogate, substituted piperazines (S)-28
(83%, 88:12 er, entry 6) and (S)-30 (99%, 86:14 er, entry 9)
were generated. The cumyl group could be readily removed
using transfer hydrogenolysis: reaction of (S)-28 with
Pd(OH)2/C and NH4 HCO2 gave the free amine (97%
yield). Subsequent Cbz protection and ester hydrolysis then
gave a known37 compound and this allowed the absolute
configuration to be confirmed (see Supporting Information).
Thus, elucidation of a mechanism for piperazine ring-
fragmentation highlighted a key role for the distal N-alkyl
group. Ultimately, use of the sterically hindered N-cumyl
group allowed high yielding asymmetric α-lithiation-
trapping of N-Boc piperazines to be developed.
philes: the “diamine switch” strategy
Next, we considered the fact that α-substituted piperazines
11 and 13 were generated in very low ers (50:50-61:39 er)
using MeI, Me2SO4 and Me3SiCl (see Scheme 3). These
results are reminiscent of results with N-Boc pyrrolidine38
and N-Boc piperidine.22c In these cases, sterically hindered
ligands around the lithium (e.g. (–)-sparteine and the (+)-
sparteine surrogate) and slow-trapping electrophiles led to
poor enantioselectivity. This is because trapping of the lithi-
ated N-Boc heterocycle is slow at –78 °C and only took
place at temperatures at which the lithiated N-Boc heterocy-
cle was configurationally unstable. Piperazines appeared to
be particularly prone to this problem and, in order to address
it, we devised a “diamine switch” strategy. The idea was to
switch the sterically hindered chiral diamine for the less ste-
rically hindered TMEDA ligand after the lithiation event. It
was hoped that this would allow a more efficient trapping39
at temperatures where the lithiated N-Boc piperazine was
configurationally stable (typically below –40 °C22c,40). The
results of this study, trapping with MeI or Me2SO4, are
shown in Scheme 6.
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+
–
Scheme 6. Investigation of a “diamine switch” strategy.
Table 1. Enantioselective lithiation-trapping of sterically
hindered N-Boc piperazines 19-22.
Lithiation of N-Boc-N-benzyl piperazine 4 using s-BuLi/(–)-
sparteine in Et2O at –78 °C was followed by addition of 5
eq. TMEDA (–78 °C, 30 min). Then, in the expectation that
TMEDA had displaced the (–)-sparteine, MeI was added.
This delivered methylated piperazine (S)-11 in 48% yield
and 87:13 er. Without the “diamine switch” step, (S)-11 was
formed in 61:39 er and 33% yield (see Scheme 3). Further-
more, no piperazine ring-fragmentation was detected using
the “diamine switch” protocol (without TMEDA, 13% of
ring-fragmentation product 12 was formed). Clearly, adding
TMEDA had a significant effect on the outcome of the reac-
tion, which we believe is due to the sterically hindered (–)-
sparteine being displaced by TMEDA which then allows
trapping to occur at lower temperatures where the organo-
lithium is configurationally stable.41 Disappointingly, a sim-
ilar “diamine switch” with the (+)-sparteine surrogate failed:
trapping with Me2SO4 gave ring-fragmentation product 12
only (34% yield). Presumably, TMEDA did not displace the
(+)-sparteine surrogate from the lithiated piperazine and
ring-fragmentation (via the mechanism outlined in Scheme
4b) ensued. This result is in line with our previous observa-
tion of the better coordinating power of the (+)-sparteine
surrogate compared to (–)-sparteine and THF.42
En- SMa
try
R
Electro-
phile
Prodb
Yield/ Erd
%
c
1
t-Bu
t-Bu
MeO2CCl (R)-25e
MeO2CCl (S)-25f
72
90
81
68
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83
74
61
99
54
89:11
19
2
89:11
81:19
84:16
90:10
88:12
82:18
88:12
86:14
87:13
19
3
CPh3 MeO2CCl (S)-26f
PhFl
MeO2CCl (S)-27f
20
4
21
5
Cumyl MeO2CCl (R)-28e
Cumyl MeO2CCl (S)-28f
CPh3 Bu3SnCl (R)-29f
Cumyl Bu3SnCl (S)-30e
Cumyl Bu3SnCl (R)-30f
Cumyl t-BuNCO (S)-31f
22
6
22
7
20
8
22
9
22
10
22
a
b
c
Starting material. Product. % Yield after chromatog-
raphy. d Enantiomer ratio determined using CSP-HPLC (see
e
Supporting Information). Diamine = (–)-sp, lithiation time
= 6 h. f Diamine = (+)-sp surr, lithiation time = 1 h.
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the cumyl group (N-Boc-N-cumyl piperazine 22) gave the
Investigating the formation of unsaturated piperazine 15
and reduced enantioselectivity with Ph2CO: the SET
mechanism
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3
best results in terms of enantioselectivity (87:13-91:9 er) and
the fact that no alkene by-product was observed (entries 6/7).
Since the SET mechanism is only an issue with Ph2CO as
the electrophile, it was not studied further. However, the
potential for lower ers and alkene by-products should be
appreciated when trapping with Ph2CO.
The results with Ph2CO shown in Scheme 3 gave a different
profile to the other electrophiles: a different alkene by-
product, unsaturated piperazine 15, was formed and the en-
antioselectivity of the trapped product 14 was moderate
(75:25-81:19 er) but definitely lower than that of the
MeO2CCl-trapped ester 7 (85:15-88:12 er). To account for
both of these observations, we believe that a single electron
transfer (SET) mechanism is also operating when trapping
with Ph2CO.43 One electron oxidation of lithiated N-Boc
piperazine 5 by Ph2CO would give an -amino radical and
the radical anion of Ph2CO. The -amino radical could ei-
ther lose a -hydrogen atom to give 15 or trap the Ph2CO
radical anion to give some racemic 14 (ultimately lowering
the er of 14). Based on the appreciable er of 14 observed
(75:25-81:19 er), it appears that the SET Ph2CO trapping
process is only a minor pathway. To investigate the SET
pathway, we explored a range of reactions of different N-
Boc piperazines using (–)-sparteine and the (+)-sparteine
surrogate (Table 2).
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Synthesis of enantiopure α-substituted piperazines: use
of an α-methylbenzyl N-alkyl group
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The remaining issue to be addressed was the stereoselective
preparation of enantiopure -substituted piperazines. With
this in mind, we realised that it was necessary to have a ste-
rically hindered N-alkyl group to stop ring-fragmentation. In
addition, building on the initial work of Guerrini and co-
workers,44 use of a stereogenic -methylbenzyl N-alkyl
group would allow separable, diastereomeric -substituted
piperazines to be generated upon trapping. Our innovation is
the use of a chiral diamine to dictate the major diastereomer
that would be formed. Adapting a literature route,45 pipera-
zine (S)-36 was readily synthesised on a multi-gram scale in
three steps (74% overall yield) from commercial materials
(only one chromatographic purification). To ascertain suita-
ble lithiation times, in situ IR spectroscopy was utilised. A
solution of (S)-36 in Et2O at –78 °C (in the presence of (–)-
sparteine) exhibited a νC=O peak at 1702 cm-1. On addition
of s-BuLi, lithiation of (S)-36 gave organolithium 38 (νC=O
peak at 1645 cm-1) via pre-lithiation complex 37 (νC=O peak
at 1679 cm-1) (Scheme 7a). Lithiation of (S)-36 to give lithi-
ated piperazine 38 neared completion only after 2 h (t1/2 ~26
min). Of note, this lithiation is slower than that of N-Boc-
N’-benzyl piperazine 4 (see Scheme 2a), presumably due to
extra steric hindrance of the distal N-alkyl group. In con-
trast, lithiation of (S)-36 with s-BuLi/(+)-sparteine surrogate
was much faster: (S)-36 gave 38 in 2 min (t1/2 ~0.5 min,
Scheme 7b).
Table 2. Enantioselective lithiation-trapping of N-Boc pi-
perazines 4, 19, 20 and 22 using Ph2CO.
En- SMa
try
R
Prodb
Yield/ Erd
Prod:
c
%
Alkenee
1
Bn
(R)-14f
(S)-14h
(R)-32f
(S)-32h
54
36
74
76
80
53
73
81:19 78:22g
75:25 41:59g
90:10 100:0
86:14 85:15i
73:27 100:0
91:9 100:0
87:13 100:0
4
2
Bn
4
Scheme 7. In situ IR spectroscopic monitoring of the
asymmetric lithiation of N-Boc piperazine (S)-36: (a) s-
BuLi/(–)-sparteine; (b) s-BuLi/(+)-sparteine surrogate.
3
t-Bu
t-Bu
CPh3 (S)-33h
Cumyl (R)-34f
19
4
19
5
20
6
22
7
Cumyl (S)-34h
22
a
b
c
Starting material. Product. % Yield after chromatog-
raphy. d Enantiomer ratio determined using CSP-HPLC (see
e
Supporting Information). Ratio of product:alkene 15 or 35
determined by 1H NMR spectroscopy of the crude product.
f
g
Diamine = (–)-sp, lithiation time = 6 h. By-product = al-
kene 15. Diamine = (+)-sp surr, lithiation time = 1 h. By-
product = alkene 35.
h
i
Some trends emerge from the results shown in Table 2. For
example, for 4 and 19, a higher proportion of alkenes 15 and
35, respectively, were observed with (+)-sparteine surrogate
compared to (–)-sparteine (compare entries 1/2 and 3/4).
This suggests that more of the SET process occurs with the
(+)-sparteine surrogate. In general, a more sterically hin-
dered N-alkyl group led to less alkene by-product and use of
Next, we explored the diastereoselectivity of the lithiation of
(S)-36 using the (+)-sparteine surrogate and (–)-sparteine.
Guided by in situ IR spectroscopy, lithiation of (S)-36 using
s-BuLi/(+)-sparteine surrogate in Et2O at –78 °C was carried
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out for 10 min. Subsequent trapping with MeO2CCl deliv- with previously described results, Ph2CO and MeI gave
1
2
3
4
5
6
7
8
ered a 95:5 mixture of diastereomeric piperazines (S,S)-39
and (R,S)-39 (by H NMR spectroscopy of the crude prod-
problems and these led to lower yields of (S,S)-44 (31%) and
(R,S)-45 (53%) respectively. In the case of Ph2CO, signifi-
cant quantities of a dihydropyrazine alkene by-product were
observed in the crude reaction mixture which is indicative of
a competing SET pathway. The SET pathway can also
probably account for the slightly lower 90:10 dr in this case.
1
uct) (Scheme 8). The diastereomers were readily separable
and, after purification, piperazine (S,S)-39 was obtained in
90% yield ((R,S)-39 isolated in 4% yield). However, the
corresponding reaction of (S)-36 with s-BuLi/(–)-sparteine
(3 h lithiation time) was less satisfactory as a 67:33 mixture
of (R,S)-39 and (S,S)-39 was produced (Scheme 8). Given
that we already knew that steric hindrance at the N-alkyl
group could affect the rate of lithiation (see Schemes 2, 5
and 7), we speculated that a long-range match/mismatch
effect between the α-methylbenzyl group and the Boc-
coordinated s-BuLi/chiral diamine complex could occur to
account for these differing outcomes. Two experiments
were deployed to confirm this: (i) lithiation-trapping of (S)-
36 using s-BuLi/TMEDA gave a 68:32 mixture of (S,S)-39
and (R,S)-39 clearly showing that there was an inherent sub-
strate preference44,46 and (ii) lithiation-trapping of enantio-
meric (R)-36 using s-BuLi/(–)-sparteine gave a >95:5 mix-
ture of (R,R)-39 and (S,R)-39 from which a 91% yield of
(R,R)-39 was obtained (Scheme 8). Thus, by matching the
configuration of the α-methylbenzyl group with that of the
chiral diamine, high yields of piperazines (S,S)-39 (90%) and
(R,R)-39 (91%) (as single stereosiomers) can be obtained by
the direct functionalisation of piperazines (S)-36 or (R)-36.
Of note, no ring-fragmentation products were observed in
these reactions, due to the presence of the sterically hindered
N-alkyl group. The -methylbenzyl in (S,S)-39 could be
readily removed upon treatment with Pd/C and hydrogen–
for further functionalisation; Cbz protection and ester hy-
drolysis gave a known37 piperazine, confirming the configu-
ration.
Scheme 9. Electrophile scope in the lithiation-trapping of
N-Boc piperazine (S)-36.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With MeI, lower diastereoselectivity likely resulted from
slow trapping at –78 °C so that trapping took place at tem-
peratures where the lithiated N-Boc piperazine is configura-
tionally unstable. Two approaches were explored to im-
prove the methylation yield. First, a more reactive electro-
phile, MeOTf, was investigated with the intention that it
would trap at lower temperatures before configurational in-
stability of the lithiated piperazine became an issue. With s-
BuLi/TMEDA and trapping with MeOTf, a 72:28 mixture of
(R,S)-45 and (S,S)-45 was generated which gave a 72% yield
of methylated (R,S)-45 after chromatography (Scheme 10).
However, attempted improvement of the diastereoselectivity
using s-BuLi/(+)-sparteine surrogate failed completely: we
only observed ring-fragmentation and (S)-46 was isolated in
46% yield.47 As noted earlier, use of the more sterically
hindered ligand around the lithium impedes the desired trap-
ping and ring-fragmentation occurs (via methylation of the
N-alkyl amine). Nevertheless, the combination of TMEDA
and MeOTf delivered our best yield of methylated (R,S)-45
(72%). Second, a “diamine switch” strategy was explored.
Based on previous results with N-Boc-N’-benzyl piperazine
4 (see Scheme 6), we focused on (–)-sparteine and started
with its matched piperazine (R)-36. After lithiation of (R)-
36 with s-BuLi/(–)-sparteine, 5 eq. TMEDA was added and
reaction with MeI gave a 90:10 mixture of (S,R)-45 and
(R,R)-45. The major diastereomer, (S,R)-45, was isolated in
70% yield (Scheme 10). Without the “diamine switch”, dia-
stereoselectivity was particularly low (55:45 dr), clearly
highlighting the slower rate of trapping when (–)-sparteine is
complexed to the lithium rather than TMEDA.
Scheme 8. Investigation of the diastereoselectivity in the
lithiation-trapping of N-Boc piperazine (S)-36.
A range of electrophiles (allyl–Br, Weinreb amide, Bu3SnCl,
(pTolS)2, Ph2CO and MeI) was then explored using (S)-36
and lithiating with s-BuLi/(+)-sparteine surrogate (Scheme
9). In general, diastereoselectivity was high (90:10-95:5 dr)
and allowed high isolated yields of single stereoisomeric
piperazines to be obtained: allylated (R,S)-40 (79%), ketone
(S,S)-41 (86%) and sulfide (R,S)-42 (86%). With Bu3SnCl,
an inseparable 93:7 mixture of diastereomeric stannanes
(R,S)-43 and (S,S)-43 was isolated (94%). However, in line
Scheme 10. Investigation of the use of MeOTf and a “di-
amine switch” strategy.
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Journal of the American Chemical Society
readily interconvert at –78 °C as was observed with N-Boc
2-phenyl piperidine.29b Alternatively, translocation of the
Boc group in methylated (R,S)-45 to the other nitrogen (via
LiAlH4 reduction, hydrogenolysis and Boc protection) gave
53 which was α-lithiated and trapped to form 2,5-trans-
disubstituted piperazine 54. The regiochemistry is due to
steric hindrance and the diastereoselectivity arises from an
equatorial methyl group in 19 and equatorial lithia-
tion/retentive trapping.50
1
2
3
4
5
6
7
8
9
Scheme 12. Stereoselective synthesis of enantiopure 2,6-
10
11
12
13
14
15
16
17
18
trans- and 2,5-trans-piperazines.
Synthetic applications of single stereoisomer piperazines
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With readily available piperazines as single stereosiomers in
hand, we set out to demonstrate the synthetic utility of our
new methodology. Methyl ester (S,S)-39 was first converted
into amide 47 by ester hydrolysis and amide formation.
Then, the α-methylbenzyl group was deprotected using α-
chloroethyl chloroformate48 to give 48. Alkylation of 48
then generated piperazine 49, a suitably functionalised build-
ing block equipped for application in the synthesis of Indi-
navir.
Conclusion
In summary, a new, practical method for the stereoselective
synthesis of enantiopure piperazines via direct functionalisa-
tion of the intact piperazine ring is described. Our approach
addresses the two key limitations of previous routes to α-
substituted piperazines. As typical examples, the one-step
functionalisation of piperazines (S)-36 or (R)-36 to give sin-
gle stereoisomers of methyl esters (S,S)-39 (90% yield) or
(R,R)-39 (91% yield) respectively serve to illustrate the po-
tential of the methodology. The success of the strategy re-
lied on the use of a stereogenic α-methylbenzyl group and
the realisation that a sterically hindered N-alkyl group re-
duced the likelihood of ring-fragmentation of the lithiated
piperazine. The optimisation process revealed that the elec-
trophile, the last reagent to be added, affected the yield and
enantio-/diastereoselectivity and mechanisms were proposed
to explain these effects. In addition, our studies have also
implicated the N-alkyl group and the diamine ligand around
the lithium as other factors that affected yield and enantio-
/diastereoselectivity. With (–)-sparteine, the use of a new
“diamine switch” strategy can improve enantio-
/diastereoselectivity with slow trapping electrophiles such as
MeI. Our comprehensive mechanistic study also included
identification of lithiation times using in situ IR spectrosco-
py. Ultimately, the utility of the new methodology was
demonstrated by the concise synthesis of an advanced inter-
mediate for Indinavir synthesis and of 2,5-trans- and 2,6-
trans-disubstituted piperazines.
Scheme 11. Synthesis of an advanced intermediate for
the synthesis of Indinavir.
Finally, we have also used the single stereoisomeric pipera-
zines in the synthesis of functionalized, disubstituted pipera-
zines. Routes from allylated (R,S)-40 and methylated (R,S)-
45 to 2,6-trans- and 2,5-trans-disubstituted piperazines via a
second α-lithiation-trapping were developed (Scheme 12).
Lithiation-allylation of allylated (R,S)-40 delivered 50 in
which the trans-stereochemistry was established by α-
methylbenzyl group removal (see Supporting Information) to
give a chiral amine ([α]D –34.9 (c 0.7, CHCl3)).49 In a simi-
lar way, methylated (R,S)-45 gave methyl ester 51 and oxa-
zolidinone 52 after trapping with MeO2CCl and Ph2CO re-
spectively. Presumably, trans diastereoselectivity to give
50, 51 or 52 results from an axially disposed allyl or methyl
group (to avoid A1,3 strain with the Boc group), equatorial
lithiation and retentive electrophilic trapping.50,51 The high
yield (77%) of 51 suggests that the two N-Boc rotamers
ASSOCIATED CONTENT
Supporting Information. Full experimental procedures and spec-
troscopic data, copies of NMR spectra, in situ IR spectroscopic
data and CSP-HPLC data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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Journal of the American Chemical Society
Page 8 of 9
Morgentin, R.; Guilleux, R.; Kalliokoski, T.; Warriner, S.; Foster, R.;
Marsden, S. P.; Nelson, A. Synthesis 2015, 47, 2391.
18. (a) Luescher, M. U.; Vo, C.-V. T.; Bode, J. W. Org. Lett.
2014, 16, 1236. (b) Luescher, M. U.; Bode, J. W. Angew. Chem. Int.
Ed. 2015, 54, 10884.
AUTHOR INFORMATION
Corresponding Author
* peter.obrien@york.ac.uk
1
2
3
4
5
6
7
8
Notes
19.
(a) McNally, A.; Prier, C. K.; MacMillan, D. W. C. Science
The authors declare no competing financial interest.
2011, 334, 1114. (b) Prier, C. K.; MacMillan, D. W. C. Chem. Sci.
2014, 5, 4173. (c) Noble, A.; MacMillan, D. W. C. J. Am. Chem. Soc.
2014, 136, 11602. (d) Musacchio, A. J.; Nguyen, L. Q.; Beard, G. H.;
Knowles, R. R. J. Am. Chem. Soc. 2014, 136, 12217.
ACKNOWLEDGMENT
We thank Melissa Obiedzinski for initial experiments and Adam
Islip for React IR analysis. This work was supported by EPSRC
(DTA) and AstraZeneca. The University of York funded the Met-
tler Toledo ReactIR ic10 spectrometer and Si-probe and the
equipment has been supported in-part by the EPSRC 'ENERGY'
grant EP/K031589/1.
20.
N.; Meerpoel, L.; Maes, B. U. W. Chem. Eur. J. 2012, 18, 10092.
21. (a) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113,
For a review, see: Mitchell, E. A.; Peschiulli, A.; Lefevre,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
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59
60
9708 (b) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc.
1994, 116, 3231.
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(a) Bailey, W. F.; Beak, P.; Kerrick, S. T.; Ma, S.; Wiberg,
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41.
The added TMEDA (5 eq.) in these examples may exert its
influence in other ways, such as by coordinating to other lithiated
intermediates that are generated (including lithium iodide).
To probe the mechanism proposed in Scheme 4a, we gen-
erated lithiated N-methyl-N-Boc piperazine (a substrate we had found
to be particularly prone to ring-fragmentation) using s-BuLi/THF at –
78 °C for 1 hour and then incubated the organolithium intermediate at
0 °C for 1 hour. After quenching with saturated NH4Cl(aq), only start-
ing material was recovered (quantitatively); no ring-fragmentation
products were detected.
42.
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35.
The effect of excess electrophile on the ring-fragmentation
V.; Ruzza, C.; Cavazzini, A.; Costa, V.; Bertolasi, V.; Reinscheid, R.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
process has been explored in one example: N-Boc-N’-benzyl pipera-
zine 4 was lithiated using s-BuLi/(–)-sparteine and trapped with
MeO2CCl (10 eq.) to give α-substituted piperazine (R)-7 in 40% yield
and ring-fragmentation by-product 8 in 36% yield (see Supporting
Information). This should be compared to the use of 2 eq. MeO2CCl
which gave a 71% yield of (R)-7 and a 12% yield of 8 (see Scheme
3). Clearly, the ring-fragmentation process is favoured by a large
excess of electrophile, a result that is inconsistent with the mechanism
in Scheme 4a and supports our preference for the mechanism depicted
in Scheme 4b. From a synthetic viewpoint, use of large excesses of
electrophile should be avoided if α-substituted products are targeted.
K.; Salvadori, S.; Guerrini, R. J. Med. Chem. 2011, 54, 2738.
45.
Opalka, C. J.; Dambra, T. E.; Faccone, J. J.; Bodson, G.;
Cossement, E. Synthesis 1995, 766.
46.
Lithiation of (S)-39 using s-BuLi/TMEDA and trapping
with MeO2CCl was complicated by formation of a disubstituted
piperazine. This occurs via enolate formation and Claisen reaction
during the trapping step and will likely have affected the ratio of
(S,S)- and (R,S)-39.
47.
Methylation of a lithiated piperazine coordinated by the
(+)-sparteine surrogate appears particularly problematic and ring-
fragmentation is the dominant pathway with MeI, Me2SO4 and
MeOTf (see 12 in Schemes 2 and 6; see (S)-46 in Scheme 10).
36.
(a) Majewski, M.; Lazny, R. Tetrahedron Lett. 1994, 35,
3653. (b) Arnott, G.; Clayden, J.; Hamilton, S. D. Org. Lett. 2006, 8,
5325.
48.
Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Mal-
froot, T. J. Org. Chem. 1984, 49, 2081.
37.
Warshawsky, A. M.; Patel, M. V.; Chen. T.-M. J. Org.
49.
A meso amine would have been produced if the piperazine
Chem. 1997, 62, 6439.
had cis-stereochemistry. This synthesis of 50 and proof of trans-
stereochemistry suggest that a related cis-selective reaction has been
assigned incorrectly (see reference 25a).
38.
(a) Husmann, R.; Jörres, M.; Raabe, G.; Bolm, C. Chem.
Eur. J. 2010, 16, 12549. (b) Bauer, J. O.; Stiller, J.; Marqués-López,
E.; Strohfeldt, K.; Christmann, M.; Strohmann, C. Chem. Eur. J.
2010, 16, 12553.
50.
For related examples with piperidines, see: Beak, P.; Lee,
W. K. J. Org. Chem. 1993, 58, 1109.
39.
Metallinos, C.; Dudding, T.; Zaifman, J.; Chaytor, J. L.;
51.
Schanen, V.; Cherrier, M.; Sebastião, J.; Quirion, J.; Hus-
Taylor, N. J. J Org. Chem. 2007, 72, 957.
son, H. Synthesis 1996, 833.
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