Studies towards the preparation of sparteine-like diamines for asymmetric synthesis

Article abstract of DOI:10.1039/a906969k

A route for the preparation of sparteine-like diamines starting from naturally occurring amino acids has been explored. Starting from the amino acids (S)-proline and (S)-phenylalanine, two novel sparteine-like diamines 2 and 3 have been prepared. The synthetic route involves Dieckmann condensation followed by a double Mannich reaction to set up the tricyclic structure with control of the relative stereochemistry. During the Dieckmann and Mannich reactions it was found that racemisation occurred either via retro-Michael or retro-Mannich processes. Conditions for preventing racemisation in the Dieckmann reaction were uncovered but it was not possible to prevent racemisation during the double Mannich reaction. Thus, the two novel sparteine-like diamines 2 and 3 have been prepared in racemic form. The Royal Society of Chemistry 1999.

Full text of DOI:10.1039/a906969k

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Studies towards the preparation of sparteine-like diamines for
asymmetric synthesis†
a
a
a
b
Justin R. Harrison, Peter O’Brien,* David W. Porter and Neil M. Smith
a
Department of Chemistry, University of York, Heslington, York, UK YO10 5DD
SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (North), Third Avenue,
Harlow, Essex, UK CM19 5AW
b
Received (in Cambridge, UK) 27th August 1999, Accepted 1st October 1999
A route for the preparation of sparteine-like diamines starting from naturally occurring amino acids has been
explored. Starting from the amino acids (S)-proline and (S)-phenylalanine, two novel sparteine-like diamines 2 and
3
have been prepared. The synthetic route involves Dieckmann condensation followed by a double Mannich reaction
to set up the tricyclic structure with control of the relative stereochemistry. During the Dieckmann and Mannich
reactions it was found that racemisation occurred either via retro-Michael or retro-Mannich processes. Conditions for
preventing racemisation in the Dieckmann reaction were uncovered but it was not possible to prevent racemisation
during the double Mannich reaction. Thus, the two novel sparteine-like diamines 2 and 3 have been prepared in
racemic form.
Introduction
The lupine alkaloid (Ϫ)-sparteine, isolated in large quantities
by extracting certain papilionaceous plants such as Scotch
broom, has found widespread use as a chiral ligand in asym-
1,2
metric synthesis over the last ten years. (ϩ)-Sparteine is
3
also naturally ocurring but is far less easily obtained: it can be
synthesised in a long-winded fashion from (Ϫ)-lupanine, itself
4
obtained by resolution of isolated racemic lupanine. Thus,
sparteine is only readily and commercially available as its
(
Ϫ)-antipode and this is a limitation on the use of sparteine as a
chiral ligand.
Instead, our attention has focused on the preparation of chiral
diamines 1–3 which posses similar chiral architecture (vide
infra) to (ϩ)-sparteine but which we envisaged would be easier
to prepare. In this way, using diamines such as 1–3 we would
be able to address the limitation of sparteine and hopefully
develop chiral ligands capable of functioning as surrogates of
To address this problem, two attempts to find sparteine surro-
(
ϩ)-sparteine.
gates, available in either enantiomeric form, have been reported.
The rationale behind the choice of diamines 1–3 as our
5
Beak et al. screened 17 chiral diamines in the asymmetric
initial targets was guided by some observations from the Beak
laboratory. During work on the effect of ligand structure on the
enantioselective deprotonation of N-Boc pyrrolidine, Beak
et al. noted that the use of (Ϫ)-α-isosparteine reduced the rate
functionalisation of N-Boc pyrrolidine and found that none
outperformed (Ϫ)-sparteine. In a similar way, Hodgson and
Lee have reported that the use of C symmetric bisoxazolines
2
in place of (Ϫ)-sparteine gave lower enantioselectivity for the
of lithiation and gave lower enantioselectivity when compared
6
5
α-deprotonation–rearrangement of cyclooctene oxide. An
Both of these effects were explained by
with (Ϫ)-sparteine.
alternative approach to this problem would be to carry out a
synthesis of (ϩ)-sparteine. Such an approach would be particu-
larly demanding not least because only five separate syntheses
considering the steric hindrance in the lithium complexes with
(Ϫ)-α-isosparteine and (Ϫ)-sparteine. These complexes are
depicted schematically in Fig. 1 and as can be seen, there
is greater steric congestion around the lithium cation in the
9
7
of racemic sparteine have previously been reported. Perhaps
surprisingly, there have been no reports of a total asymmetric
synthesis of sparteine. An approach to the synthesis of
sparteine, described by Wendt and Aubé and which could in
principle have been rendered asymmetric, was unfortunately
(
Ϫ)-α-isosparteine complex since both of the peripheral rings
extend towards the lithium. In contrast, with the (Ϫ)-sparteine
complex, one of the rings is held away from the lithium cation
thus exposing it for reaction. In the same way, we anticipated
that diamine ent-1 would also provide a non-sterically hindered
environment around the lithium but at the same time, most
of the chiral backbone of sparteine is present for high enantio-
selectivity.
8
unsuccessful.
Given the difficulty in the synthesis of sparteine encountered
7,8
by previous workers in the field, we decided not to embark on
a total synthesis of enantiomerically enriched (ϩ)-sparteine.
In this paper, we describe our synthetic work on the
attempted synthesis of enantiomerically enriched diamines 2
†
Full experimental procedures for the reactions in Tables 1–3 are avail-
and
3 starting from the amino acids (S)-proline and
able as supplementary data. For direct electronic access see http://
www.rsc.org/suppdata/p1/1999/3623
(S)-phenylalanine respectively. The strategy is delineated in full
J. Chem. Soc., Perkin Trans. 1, 1999, 3623–3631
This journal is © The Royal Society of Chemistry 1999
3623

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Fig. 1 Lithium chelating conformations of (Ϫ)-sparteine, (Ϫ)-α-iso-
sparteine and sparteine surrogate ent-1.
Scheme
2
Reagents and conditions: i, i-BuOCOCl, Et N, Et O
3 2
Ϫ20 ЊC → 0 ЊC then CH N , Et O, 0 ЊC → rt then 16 h; ii, cat
2
2
2
AgOBz Et N, MeOH, dark, Ϫ25 ЊC → rt over 3 h; iii, TFA, CH Cl ,
3
2
2
0
9
ЊC for 15 min, rt for 1.5 h; iv, methyl acrylate, FeCl , Et N, CH Cl , rt,
6 h.
3 3 2 2
oxylic acid of N-Boc proline 9 was converted into the mixed
anhydride with isobutyl chloroformate and subsequent treat-
ment with excess diazomethane gave diazoketone 10 in high
yield (90%) after chromatography; diazoketone 9 could be
stored in the freezer in the absence of light without noticeable
degradation. In our hands, the best procedure for the Wolff
rearrangement of 10 to methyl ester 11 was that documented by
Podlech and Seebach during work on the synthesis of β-amino
17
acids. This involved reaction of a homogeneous solution of
catalytic silver benzoate in triethylamine with diazoketone 10 in
methanol. Provided light was excluded and the reaction was
initiated at low temperatures (Ϫ25 ЊC), an essentially quanti-
tative crude yield of methyl ester 11, which did not require any
purification before use in the next step, was obtained.
Initially, we carried out Boc deprotection of methyl ester 11
and attempted to isolate the resulting amino ester 7. Unfortu-
nately, only a low (16%) yield of 7 was obtained which presum-
ably reflected either the volatility or water solubility of this
compound. Although the subsequent Michael reaction of 7 in
refluxing excess methyl acrylate gave a quantitative yield of
adduct 6, this approach was too low yielding to be synthetically
useful. Therefore, two changes were made: after the Boc depro-
tection, the amino ester 7 was isolated as its trifluoroacetate salt
Scheme 1
for the proposed preparation of diamine 2 (Scheme 1). These
two targets were selected in preference to diamine 1 since the
amino acids required are commercially available. In contrast,
for the synthesis of diamine 1, either the preparation of (S)-
pipecolic acid or of the 6-ring analogue of β-amino acid 7
requires resolution so it was decided to test the methodology on
the more readily accessible diamines 2 and 3.
Our approach to diamine 2 follows the same strategy as that
adopted by Scheiber and Nemes for the preparation of racemic
diamine 1 (Scheme 1). The key intermediate is bicyclic ketone
10
11
(
in essentially crude quantitative yield) and the Michael reac-
tion was accomplished by treating this salt with a mixture of
12
triethylamine (to free up the amino ester 7 in situ), methyl
18
acrylate and iron() chloride in dichloromethane at room
temperature for 96 hours. In this way, the Michael addition
product 6 was obtained in a much improved 98% yield (after
purification by column chromatography) over the two steps
5
since a double Mannich reaction (to give 4) followed by
Wolff–Kishner reduction should furnish the target molecule in
which the relative stereochemistry is controlled by the inherent
diastereoselectivity of the second intramolecular Mannich
reaction. We envisaged preparing ketone 5 from (S)-proline
via N-protection, Arndt–Eistert homologation, N-deprotection,
Michael addition to methyl acrylate and finally Dieckmann
condensation. A similar retrosynthetic analysis furnishes amino
acid 8 (prepared by Pictet–Spengler cyclisation of (S)-phenyl-
alanine) as the starting material. Herein we describe the use of
this approach for the synthesis of diamines 2 and 3 and the
unanticipated problems encountered along the way.
(
Scheme 2). Essentially the same yield of 6 was obtained if we
refluxed the trifluoroacetate salt of 7 in excess methyl acrylate
containing some triethylamine.
Racemic bicyclic ketone 5 has previously been prepared on
1
9–22
four separate occasions
(including the use of Dieckmann
19–21
routes
). Of the previous approaches, we adopted the
23
Dieckmann route to ketone 5 since it was the only one that
should allow enantiomerically enriched ketone 5 to be pre-
pared. We have carried out the Dieckmann reaction of bis ester
6
using sodium hydride with catalytic sodium methoxide or
Results and discussion
Synthesis of proline-derived diamine 2
LDA as the base followed by two different methods for
subsequent decarboxylation. The full results of this study are
presented in Table 1.
Our approach to sparteine-like diamine 2 required the prepar-
ation of the Dieckmann precursor 6. Its synthesis from
The use of sodium hydride together with catalytic sodium
methoxide in refluxing xylenes (a procedure described by
Leonard et al. for the synthesis of the 6-membered ring
analogue ) or the use of LDA in THF at Ϫ78 ЊC followed
by hydrolysis and decarboxylation using refluxing 6 M hydro-
chloric acid resulted in good yields of ketone 5 after purifi-
cation by Kugelrohr distillation (Table 1, Entries 1–2).
Unfortunately, however, ketone 5 thus obtained was shown to
be racemic by optical rotation measurement and by recording
(
S)-proline is outlined in Scheme 2. First of all, the N-Boc
24
derivative 9 was prepared from (S)-proline in 93% yield using
1
3
the published procedure (Et N, Boc O, CH Cl , 0 ЊC, 2.5 h).
3
2
2
2
14
Next, Arndt–Eistert homologation was required to furnish
methyl ester 11. Such an approach to methyl ester 11 has previ-
16
15
ously been described by O’Neil et al. and by Mahboobi et al.
and we essentially followed their procedures. Thus, the carb-
3
624
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Table 1
Method of
decarboxylation
Yield
(%)
[α]D
(% ee)
a
a
b
c
Entry
1
Base
NaH, NaOMe
xylenes
LDA, THF
NaH, NaOMe
xylenes
6 M HCl
6 M HCl
75
0 (0)
0 (0)
2
3
78
29
KOH(aq), MeOH
ϩ41.4 (90)
Scheme 3 Reagents and conditions: i, MeNH
, (CH O) , AcOH,
2 2 n
MeOH, reflux, 16 h; ii, N ؒH O, KOH, diethylene glycol, reflux, 2 h.
H
2
4
2
4
LDA, THF
KOH(aq), MeOH
34
ϩ36.5 (84)
a
b
For details, see experimental section. Yield of isolated pure ketone 5.
Although we were not able to prepare enantiomerically
enriched tricyclic ketone 4, we have converted this into the tar-
get diamine 2 using Wolff–Kishner reduction. Thus, treatment
of ketone 4 with hydrazine hydrate and potassium hydroxide at
high temperature (according to the method of Scheiber and
c
1
Enantiomeric excess determined using H NMR spectroscopy in the
presence of a chiral shift reagent.
12
Nemes ) afforded a 68% crude yield of the novel diamine rac-2
which was of good purity. Indeed, purification of this diamine
by Kugelrohr distillation did not lead to any improvement in its
1
purity as judged by H NMR spectroscopy.
Fig. 2
Synthesis of phenylalanine-derived diamine 3
1
the H NMR spectrum in the presence of the chiral shift
Concurrently with the previously described research, we also
investigated a similar approach to diamine 3 starting from
25
reagent (R)-2,2,2-trifluoro-1-(9-anthryl)ethanol. Presumably
the racemisation occurs in the harsh decarboxylation step and
can be rationalised by invoking either a retro-Michael reaction
to give 12 or a retro-Mannich reaction to give 13 (Fig. 2). Such
a loss of stereochemical information is not that uncommon in
β-amino ketones and has, for example, been noted previously
(
S)-phenylalanine. In this way, we have established the general-
ity of the racemisation problems encountered in the synthesis
of these types of compounds. The preparation of the Dieck-
mann precursor 18 is outlined in Scheme 4.
11
by Knight et al. during the synthesis of lupinine and Slosse
and Hootelé during the preparation and subsequent epimeris-
26
ation of myrtine. In some recent and elegant synthetic work,
a closely related epimerisation was used to advantage by
27
Heathcock et al. in the synthesis of Petrosins C and D.
In order to prepare enantiomerically enriched ketone 5, we
were encouraged by the fact that Slosse and Hootelé had
observed reduced levels of epimerisation of myrtine using
26
dilute aqueous base. Thus, the conditions for the decarboxyl-
ation were modified to refluxing with aqueous potassium
28
hydroxide in methanol for 2–3 hours. In this way, enantio-
merically enriched ketone (S)-5 (84–90% ee) was obtained
albeit in much reduced yield (Table 1, Entries 3–4). Of particu-
lar note, we had been successful in minimising racemisation and
this is the first time that this ketone has been prepared in
non-racemic form.
29
Initially, the double Mannich reaction of ketone (S)-5 with
methylamine was attempted using the conditions reported by
12
Scheiber and Nemes in their synthesis of diamine 1. However,
we were unable to isolate any of the required tricylcic ketone
using these conditions. We had more success using conditions
Scheme 4 Reagents and conditions i, NaOH, Boc O, t-BuOH–water rt,
2
1
6 h; ii, i-BuOCOCl, Et N, THF, Ϫ20 ЊC → 0 ЊC then CH N , Et O
3
2
2
2
5
reported by Beak for the preparation of bispidines. Thus, a
0 ЊC → rt then 16 h at rt; iii, cat AgOBz, Et N, MeOH, dark,
3
mixture of ketone (S)-5 (90% ee), methylamine, paraformalde-
hyde and acetic acid in methanol were refluxed for 16 hours to
give a 29% yield of ketone 4 after Kugelrohr distillation
Ϫ25 ЊC → rt over 3 h; iv, TFA, CH
reflux, 17 h.
Cl , rt, 1 h; v, methyl acrylate,
2 2
(
Scheme 3). Ketone 4 was isolated as a single diastereoisomer as
Initially, cyclic amino acid 8 was prepared in 65% crude yield
using the known Pictet–Spengler reaction of (S)-phenyl-
alanine with aqueous formaldehyde. Next, N-Boc protection
1
13
30
shown by H and C NMR spectroscopy and, in line with
related double Mannich reactions, we believe it has the relative
stereochemistry depicted. Unfortunately, the tricyclic ketone 4
was accomplished in 74% yield using aqueous sodium hydrox-
1
31
was not optically active and was shown to be racemic by H
ide and Boc O, a procedure reported by McMills. A much
2
NMR spectroscopy in the presence of the chiral shift reagent
lower yield was obtained when the conditions used (Et N,
3
(
R)-2,2,2-trifluoro-1-(9-anthryl)ethanol. Racemisation via 12 or
Boc O, CH Cl ) for the preparation of N-Boc derivative 9 were
2
2
2
1
3 (Fig. 2) is occurring under these acidic conditions and we
employed.
have been unable to find racemisation-free double Mannich
reaction conditions (vide infra).
Essentially the same procedure as that used for the Arndt–
Eistert homologation of proline derivative 9 was employed for
J. Chem. Soc., Perkin Trans. 1, 1999, 3623–3631
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Table 2
Table 3
AcOH
(equiv.)
HCl
(equiv.)
Yield
(%)
ee
(%)
Crude
yield
(%)
a
b
Entry
[α]D
Method of
decarboxylation
[α]D
(% ee)
a
a
b
c
Entry Base
1
2
3
4
1
2
2
—
—
—
1
28
30
30
30
Ϫ3.9 (EtOH)
Ϫ8.4 (CHCl3)
Ϫ15.8 (CHCl3)
Ϫ7.0 (CHCl3)
0–10
0–10
20–30
—
1
2
NaH, NaOMe
xylenes
NaH, NaOMe
6 M HCl
6 M HCl
44
84
0 (0)
0 (0)
2
a
1
,4-dioxane
Yield of pure ketone 20 after purification by Kugelrohr distillation.
Enantiomeric excess determined using H NMR spectroscopy in the
presence of a chiral shift reagent.
t
t
b
1
3
4
5
KO Bu, BuOH 6 M HCl
34
94
0 (0)
0 (0)
LDA, THF
NaH, NaOMe
6 M HCl
12 M HCl
90 (44)
Ϫ33.3 (—)
1
,4-dioxane
6
7
LDA, THF
NaH, NaOMe
xylenes
NaH, NaOMe
xylenes
NaH, NaOMe
xylenes
LDA, THF
12 M HCl
NaCl, DMF
—(35)d
Ϫ46.1 (—)
—(29 ) Ϫ10.8
the optical rotation values, it was clear that in our hands
racemisation was not completely suppressed (Table 2, Entries
5
and 6).
d
8
9
0
LiCl, DMF
—(7 )
Ϫ19.0
Attention was switched to alternative methods for decarb-
33
34
d
oxylation. Halide-mediated approaches gave low yields and
ketone 19 was obtained in low optical purity (Table 2, Entries
7 and 8). The best results (Table 2, Entries 9 and 10) were
obtained using base to perform the hydrolysis and decarboxyl-
ation (as we had found in the previous series). Thus, decarboxyl-
ation of the sodium hydride- or LDA-mediated Dieckmann
condensation products using aqueous potassium hydroxide in
methanol generated ketone (S)-19 of high enantiomeric excess.
The reaction using LDA (Table 2, Entry 10) reproducibly gave a
good crude yield (59%) and ketone (S)-19 was shown to be
KOH(aq), MeOH —(28 ) Ϫ72.2 (—)
1
a
KOH(aq), MeOH 59 (19)
Ϫ89.7 (≥90)
b
For details, see Experimental section. Yield of crude ketone 5 (iso-
lated yield of pure product in brackets). Optical rotations performed
on purified ketone 5; enantiomeric excess determined using H NMR
spectroscopy in the presence of a chiral shift reagent. Yield from isol-
ated intermediate obtained from Dieckmann cyclisation with NaH–
NaOMe in xylenes.
c
1
d
1
the conversion of 14 into 16. However, use of diethyl ether as
solvent for the preparation of diazoketone 15 gave only a
moderate 52% yield of 15. We suspected that this low yield was
due to precipitation of the triethylaminmonium salt of acid 14
during the mixed anydride preparation. Indeed, carrying out
the reaction in THF visibly suppressed salt precipitation and
allowed us to obtain an improved 77% yield of diazoketone 15.
Decomposition of the diazoketone 15 to methyl ester 16 (97%
yield) was accomplished analogously to that described previ-
ously (see Scheme 2). In this series, we found that TFA depro-
tection of N-Boc derivative 16 afforded an isolable amino ester
≥90% ee using H NMR spectroscopy in the presence of the
chiral shift reagent (R)-2,2,2-trifluoro-1-(9-anthryl)ethanol.
We found that only low yields of ketone 19 were obtained
whenever the crude product was purified by column chromato-
graphy (Table 2, Entries 5–10). Thus, for the purposes of assess-
ing the optical and enantiomeric purity of ketone 19 from these
reactions, the crude products were purified. However, for
investigating the degree of racemisation in the subsequent
double Mannich reaction, the crude ketone (S)-19 from the
LDA–potassium hydroxide reaction (Table 2, Entry 10) was
utilised directly.
1
7 in 98% crude yield which was used directly in the next step.
The double Mannich reaction of ketone (S)-19 with methyl-
amine and formaldehyde has been examined under acetic acid
and/or hydrochloric acid conditions (Table 3). Using the condi-
tions used for the synthesis of ketone 4 (see Scheme 3), a 28%
yield of tricyclic ketone 20 was obtained after purification by
Kugelrohr distillation (Table 3, Entry 1). This ketone 20 was
The Michael addition of 17 to methyl acrylate was best carried
out by refluxing 17 in methyl acrylate for 17 hours (98% yield
after purification by column chromatography).
The Dieckmann condensation of the bis ethyl ester analogue
of our compound 18 has previously been reported by Yamada
32
1
and Kunieda. They found that treatment of the bis ethyl ester
with sodium hydride in 1,4-dioxane followed by decarboxyl-
ation using concentrated hydrochloric acid (at reflux for 10
hours) gave ketone 19 in 80% crude yield. Ketone 19 thus pro-
duced exhibited [α]D Ϫ91.0 (c 0.26 in EtOH) and the authors
presumed that no racemisation had occurred in its preparation.
In an attempt to optimise the yield and to minimise any racemis-
ation, we have studied a wide range of conditions for the
Dieckmann cyclisation of bis ester 18 to ketone 19. The results
are collected together in Table 2.
Initially, using refluxing 6 M hydrochloric acid for the
decarboxylation step, the base was varied in an attempt to
optimise the crude yield of ketone 19 (Table 2, Entries 1–4)
from the Dieckmann reactions. It was found that sodium
hydride in 1,4-dioxane and LDA in THF gave the highest yields
of, as expected, racemic ketone 19. Therefore, these successful
conditions were combined with decarboxylation conditions
shown to be essentially racemic by polarimetry and H NMR
spectroscopy in the presence of the chiral shift reagent, a result
which is consistent with that obtained in the proline series.
Attempts to lower the amount of racemisation by changing the
conditions were not very successful (Table 3, Entries 2–4). Use
of 2 equivalents of acetic acid in combination with 1 equivalent
35
of hydrochloric acid generated tricyclic ketone 20 in 20% yield
with 20–30% ee (Table 3, Entry 3). The low yields and gener-
ation of products of low enantiomeric excess in the double
Mannich reaction indicated that we should abandon this
approach to our intial target molecules.
In order to demonstrate that it was possible to generate the
target diamine 3 in racemic form using this approach, we have
completed the synthesis as indicated in Scheme 5. Thus,
Dieckmann cyclisation using LDA followed by 6 M hydro-
chloric acid-mediated decarboxylation gave racemic ketone 19
in an excellent 94% crude yield. The double Mannich reaction
using methylamine, paraformaldehyde and acetic acid in reflux-
ing methanol for 16 hours generated a 47% distilled yield of
racemic ketone 20. Finally, Wolff–Kishner reduction using the
(
12 M hydrochloric acid, 2 hours at reflux) similar to those used
by Yamada and Kunieda. In this way, optically active product
was obtained with both bases but, based on the magnitude of
3
626
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For Kugelrohr distillations, the temperatures quoted corre-
spond to the oven temperatures. Melting points were measured
on an Electrothermal IA 9100 digital melting point apparatus.
Infra red spectra were recorded on an ATI Mattson Genesis FT
IR spectrometer as solutions in chloroform. Chemical ionis-
ation and high resolution mass spectra were recorded on a
Fisons Analytical (VG) Autospec spectrometer. Optical
rotations were recorded on a Jasco DIP-370 polarimeter (using
the sodium D line; 589 nm) at 20 ЊC and [α] values are given in
D
Ϫ1
2
Ϫ1
units of 10 deg cm g . Full experimental procedures for all
of the reactions described in Tables 1, 2 and 3 are available as
supplementary information.
Scheme 5 Reagents and conditions: i, LDA, THF, Ϫ78 ЊC, 20 min then
(
2S)-1-(tert-Butoxycarbonyl)pyrrolidine-2-carboxylic acid 9
6
1
M HCl, reflux, 16 h; ii, MeNH , (CH O) , AcOH, MeOH, reflux,
2 2 n
13
6 h; iii, N H ؒH O, KOH, diethylene glycol, reflux, 2 h.
Using the published procedure, (S)-proline (5.0 g, 43.5 mmol)
gave N-Boc proline 9 (8.7 g, 93%) as white crystals, mp 133–
135 ЊC (from petrol) (lit., 138–140 ЊC), [α]D Ϫ51.2 (c 1.0 in
2
4
2
13
conditions employed previously with ketone 4 produced
racemic diamine 3 in 77% isolated yield (Scheme 5).
CHCl ) and identical spectroscopically to that previously
3
reported.
Conclusion
(
3S)-2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-3-
Starting from the amino acids (S)-proline and (S)-phenyl-
alanine, two novel sparteine-like diamines 2 and 3 have been
prepared (albeit in racemic form) and fully characterised.
Although it was possible to minimise racemisation in the
Dieckmann cyclisation reactions used for their synthesis, we
were unable to find racemisation-free double Mannich reaction
conditions. β-Amino ketones such as 5 and 19 are susceptible to
acid-catalysed racemisation at the elevated temperatures (via
either retro-Michael or retro-Mannich processes) required for
the double Mannich reactions. In addition to racemisation, the
yields of the Mannich adducts 4 and 20 (ca. 30%) from these
reactions are low. Because of these problems, our initial route
for the preparation of enantiomerically enriched sparteine-
like diamines 1, 2 and 3 has been abandoned. Alternative
approaches to such chiral diamines are currently being investi-
gated and will be reported in due course.
carboxylic acid 14
Amino acid 8 (4.98 g, 28.1 mmol) was added to a stirred solu-
tion of sodium hydroxide (1.25 g, 31.0 mmol) in water (120 cm )
at room temperature. Then, tert-butyl alcohol (80 cm ) was
added followed by the dropwise addition of liquid di-tert-butyl
dicarbonate (6.20 g, 28.4 mmol). After stirring the resulting
mixture at room temperature for 16 h, the clear solution was
washed with petrol (2 × 50 cm ). The combined organic layers
were extracted with saturated aqueous potassium carbonate
solution (2 × 50 cm ). Then, the aqueous layers and the aque-
ous reaction mixture were combined and acidified to pH 1 by
addition of solid sodium hydrogen sulfate. The acidic aqueous
solution was extracted with Et O (3 × 100 cm ) and the com-
3
3
3
3
3
2
3
bined organic extracts were washed with brine (50 cm ), dried
(
MgSO ) and evaporated under reduced pressure to give the
4
crude product as a solid. Recrystallisation from EtOAc–hexane
gave N-Boc amino acid 14 (5.75 g, 74%) as white crystals, mp
Experimental
General
1
13–115 ЊC (from EtOAc–hexane); [α]D ϩ3.9 (c 1.4 in CHCl );
3
Ϫ1
νmax(CHCl )/cm 1718 (C᎐O, CO H), 1692 (C᎐O, Boc); δ (270
3
2
H
MHz; CDCl ) (rotamers) 10.03–9.96 (2 H, br s, 2 × CO H),
3
2
THF was dried over sodium–benzophenone and distilled before
7
.18–7.11 (8 H, m, Ar), 5.13–5.10 (1 H, m, CHN), 4.75–4.64
use. CH Cl was dried over calcium hydride and distilled before
2
2
(3 H, m, CHN and 2 × CH H N), 4.48 (1 H, d, J 16.0, CH -
A
B
A
use. Xylene was dried over calcium hydride, distilled and stored
over 4 Å molecular sieves before use. Diisopropylamine was
dried over calcium hydride, distilled and stored over potassium
hydroxide pellets before use. Anhydrous 1,4-dioxane was pur-
H N), 4.44 (1 H, d, J 16.3, CH H N), 3.26–3.08 (4 H, m,
B
A
B
CH Ar), 1.50 (9 H, s, CMe ) and 1.39 (9 H, s, CMe ); δ (67.5
2
3
3
C
MHz; CDCl ) (rotamers) 177.6 (C᎐O, CO H), 177.4 (C᎐O,
3
2
CO H), 155.7 (C᎐O, Boc), 154.8 (C᎐O, Boc), 133.8, 132.7,
2
chased from Aldrich Chemical Company Ltd. NH refers to a
3
131.9, 131.6 (ipso-Ar), 128.5, 127.7, 126.9, 126.7, 126.3, 126.2
3
3% aqueous ammonia solution. n-Butyllithium was titrated
(
Ar), 80.9 (CMe ), 54.1, 52.3 (CHN), 44.5, 43.8 (CH N), 31.3,
3
2
36
against N-benzylbenzamide before use. Petrol refers to the
fraction of petroleum ether boiling in the range 40–60 ЊC and
was redistilled in Winchester quantities before use. (3S)-1,2,3,4-
Tetrahydroisoquinoline-3-carboxylic acid 8 was prepared in
3
0.9 (CH Ar), 28.35 and 28.2 (CMe ); m/z (CI, NH ) 395 [15%,
2 3 3
ϩ
(
(
M ϩ NH ) ], 278 (45, M ϩ H) and 178 (100) [Found:
M ϩ H) , 278.1391. C H NO requires M ϩ H, 278.1392].
4
ϩ
1
5
19
4
30
6
5% yield according to the literature procedure. All non-
(
2S)-tert-Butyl 2-diazoacetylpyrrolidine-1-carboxylate 10
aqueous reactions were carried out under oxygen-free nitrogen
using oven-dried glassware. Flash column chromatography was
carried out using ICN Biomedicals GmbH 33–63 silica (60 Å)
or Fisher Matrex silica 60. Thin layer chromatography was car-
ried out on commercially available Merck 5554 aluminium-
backed silica plates and the plates were visualised using a 1%
ethanolic ninhydrin solution.
Proton (270 MHz) and carbon (67.5 MHz) NMR spectra
were recorded on a Jeol EX-270 spectrometer using an internal
deuterium lock. All samples were recorded as solutions in
deuteriated chloroform and chemical shifts are quoted in parts
per million downfield of tetramethylsilane. Coupling constant
3
Triethylamine (0.66 cm , 4.7 mmol) was added dropwise to a
stirred solution of N-Boc proline 9 (1.0 g, 4.7 mmol) in Et O
2
3
(5.4 cm ) at Ϫ10 ЊC under nitrogen. After 5 min, the solution
3
was cooled to Ϫ20 ЊC and isobutyl chloroformate (0.74 cm , 4.8
mmol) was added dropwise. The mixture was allowed to warm
to 0 ЊC and the precipitate was removed by filtration. To the
resulting filtrate, a solution of excess diazomethane in Et O‡ was
added and the solution was allowed to warm to room temper-
ature. After stirring at room temperature for 16 h, two to three
2
‡
For the preparation of diazoketone 10 starting from 5.0 g of N-Boc
(
J) values are given in Hz. Carbon NMR spectra were recorded
proline 9, diazomethane prepared from 23.9 g of Diazald was used
with broad band proton decoupling and were assigned using
DEPT experiments.
(
for diazoketone 16 starting from 10.0 g of N-Boc amino acid 15,

diazomethane prepared from 26.3 g of Diazald was used).
J. Chem. Soc., Perkin Trans. 1, 1999, 3623–3631
3627

View Article Online
drops of acetic acid were added to destroy excess diazomethane.
Then, the reaction mixture was washed with 10% aqueous citric
acid solution (20 cm ) (CAUTION—vigorous effervescence may
(3S)-tert-Butyl 3-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydro-
isoquinoline-2-carboxylate 16
3
Using the procedure described above, silver benzoate (85 mg,
occur), saturated aqueous sodium hydrogen carbonate solution
3
0
.37 mmol) in triethylamine (1.2 cm , 8.5 mmol) and diazoke-
3
3
(
20 cm ) and brine (20 cm ), dried (MgSO ) and evaporated
4
3
tone 15 (874 mg, 2.90 mmol) in MeOH (20 cm ) gave methyl
under reduced pressure to give the crude product as a yellow oil.
ester 16 (842 mg, 97%) as an oil, R (1:1 petrol–EtOAc) 0.55;
F
Purification by flash column chromatography on silica with
Ϫ1
[
α]D ϩ57.4 (c 1.4 in CHCl ); ν (CHCl )/cm 1733 (C᎐O,
15,16
3 max 3
petrol–EtOAc (1:1) as eluent gave known
diazoketone 10
CO Me) and 1685 (C᎐O, Boc); δ (270 MHz; CDCl ) 7.24–7.17
2
H
3
(
1.0 g, 90%) as a yellow oil, R (1:1 petrol–EtOAc) 0.3; [α]
F
D
(
2 H, m, Ar), 7.15–7.10 (2 H, m, Ar), 4.97–4.83 (1 H, br m,
Ϫ1
Ϫ118.0 (c 1.0 in MeOH); νmax(CHCl )/cm 2111 (CHN ), 1689
3
2
CHN), 4.77 (1 H, d, J 17.0, CH H N), 4.33 (1 H, d, J 17.0,
A
B
(
(
C᎐O, Boc) and 1649 (C᎐O, COCHN ); δ (270 MHz; CDCl )
᎐ ᎐
2 H 3
CH H N), 3.65 (3 H, s, MeO), 3.13 (1 H, dd, J 5.6 and 16.0,
A
B
rotamers) 5.49–5.39 (1 H, m, CHN ), 4.37–4.10 (1 H, m,
2
CH H CO), 2.75 (1 H, br d, J 16.0, CH H CO), 2.49 (1 H, dd,
A
B
A
B
CHN), 3.60–3.32 (2 H, m, CH N), 2.30–1.83 (4 H, m, CH CH )
2
2
2
J 6.8 and 14.8, ArCH H ), 2.29 (1 H, dd, J 7.7 and 14.8,
A
B
and 1.46 (9 H, appearing as two singlets, CMe ); δ (67.5 MHz;
3
C
ArCH H ) and 1.50 (9 H, s, CMe ); δ (67.5 MHz; CDCl )
A
B
3
C
3
CDCl ) (rotamers) 196.3, 195.2 (C᎐O, COCHN ), 154.4, 153.7
3
2
(
rotamers) 172.0 (C᎐O, CO Me), 155.0 (C᎐O, Boc), 133.3,
᎐
2
(
(
C᎐O, Boc), 80.4, 77.5 (CMe ), 64.4, 63.3 (CHN ), 53.3, 52.0
᎐
3
2
1
33.1, 132.6 (ipso-Ar), 129.6, 127.1, 126.8, 126.6 (Ar), 80.5
CHN), 47.1, 46.8 (CH N), 31.3, 29.7 (CH ), 28.4 (CMe ), 24.4
2
2
3
(
CMe ), 52.0 (MeO), 47.9, 46.7 (CHN), 43.6, 43.1 (CH N),
ϩ
3
2
and 23.7 (CH ); m/z (CI, NH ) 240 [100%, (M ϩ H) ] and 212
2
3
3
7.6, 37.2, 33.6 (CH ) and 28.8 (CMe ); m/z (CI, NH ) 306
2 3 3
ϩ ϩ
ϩ
(
41, M Ϫ N2) [Found: (M ϩ H) , 240.1352. C H N O
11 18 3 3
[
75%, (M ϩ H) ] 206 (100) [Found: (M ϩ H) , 306.1709.
requires M ϩ H, 240.1348].
C H NO requires M ϩ H, 306.1705].
17
23
4
(
3S)-tert-Butyl 3-diazoacetyl-1,2,3,4-tetrahydroisoquinoline-2-
(
6
2S)-Methyl 3-[2-(2-methoxy-2-oxoethyl)pyrrolidino]propanoate
carboxylate 15
3
Using the procedure described above, triethylamine (5.0 cm ,
6.0 mmol), N-Boc amino acid 14 (10.4 g, 34.6 mmol) in THF
3
Trifluoroacetic acid (12.4 cm , 161.0 mmol) was added dropwise
to a stirred solution of methyl ester 11 (3.6 g, 14.7 mmol) in
CH Cl (50 cm ) at 0 ЊC under nitrogen. After 15 min, the solu-
tion was allowed to warm to room temperature and stirred for a
further 1.5 h. The solvent was evaporated under reduced pres-
sure and excess trifluoroacetic acid was removed by azeotroping
with CHCl (6 × 15 cm ). Then, the residue was dissolved in
CH Cl (90 cm ) at 0 ЊC under nitrogen and to the stirred solu-
tion, triethylamine (7.2 cm , 50.0 mmol) was added dropwise.
The solution was allowed to warm to room temperature and
iron() chloride (238 mg, 1.5 mmol) and methyl acrylate (1.3
cm , 14.7 mmol) were added. The resulting dark mixture was
stirred at room temperature for 96 h. Then, the organic layer
was washed with saturated aqueous sodium sulfate solution
(
sure to give the crude product as a brown oil. Purification by
flash column chromatography on silica with CHCl –MeOH
3
3
3
(
100 cm ), isobutyl chloroformate (4.7 cm , 36.0 mmol) and
3
2
2
excess diazomethane in Et O gave the crude product as a yellow
2
oil. Purification by flash column chromatography on silica with
EtOAc–petrol (4:1) as eluent gave diazoketone 15 (8.7 g, 77%)
as a yellow oil, R (1:1 petrol–EtOAc) 0.5; [α] Ϫ105.0 (c 1.0 in
CHCl ); ν (CHCl )/cm 2112 (CHN ), 1689 (C᎐O, Boc),
1
7
4
2
1
1
1
1
5
2
2
F
D
3
Ϫ1
3
3
max
3
2
3
2
2
641 (C᎐O, COCHN ); δ (270 MHz; CDCl ) (rotamers) 7.26–
᎐
2 H 3
3
.08 (8 H, m, Ar), 5.34 (1 H, s, CHN ), 5.30 (1 H, s, CHN ),
2 2
.97–4.94 (1 H, m, CHN), 4.73–4.43 (5 H, m, CHN and
× CH N), 3.32–3.02 (4 H, m, CH Ar), 1.53 (9 H, s, CMe ) and
2
2
3
3
.47 (9 H, s, CMe ); δ (67.5 MHz; CDCl ) (rotamers) 195.5,
3 C 3
94.0 (C᎐O, COCHN ), 155.1 (C᎐O, Boc), 154.4 (C᎐O, Boc),
᎐
2
33.7, 132.9, 132.6 (ipso-Ar), 128.4, 127.8, 127.3, 127.0, 126.9,
26.6, 126.1, 125.9 (Ar), 81.1, 80.9 (CMe ), 60.3 (CHN ), 59.5,
3
100 cm ), dried (MgSO ) and evaporated under reduced pres-
4
3
2
7.4 (CHN), 44.8, 44.1 (CH N), 31.5, 30.3 (CH Ar) and
2 2
ϩ
3
8.3 (CMe ); m/z (CI, NH ) 302 [45%, (M ϩ H) ], 274 (90),
3 3
ϩ
(
97:3) as eluent gave diester 6 (3.3 g, 98%) as a pale brown oil,
18 (100) [Found: (M ϩ H) , 302.1505. C H N O requires
16 19 3 3
RF (97:3 CHCl –MeOH) 0.3; [α] Ϫ57.2 (c 1.2 in CHCl );
νmax(CHCl )/cm 1734 (C᎐O, CO Me); δ (270 MHz; CDCl )
3
Ϫ1
D
3
M ϩ H, 302.1505].
3
2
H
3
3
2
.61 (3 H, s, OMe), 3.60 (3 H, s, OMe), 3.14–2.91 (2 H, m),
.78–2.67 (1 H, m, CHN), 2.59 (1 H, dd, J 4.1 and 15.0, CHA-
(
2S)-tert-Butyl 2-(2-methoxy-2-oxoethyl)pyrrolidine-1-carb-
oxylate 11
H CO), 2.46–2.37 (3 H, m), 2.22–2.08 (2 H, m), 2.01–1.88 (1 H,
B
A solution of silver benzoate (106 mg, 0.46 mmol) in triethyl-
m) and 1.72–1.40 (3 H, m); δ (67.5 MHz; CDCl ) 172.8, 172.7
C
3
3
amine (1.7 cm , 12.0 mmol) was added dropwise to a stirred
(C᎐O, CO Me), 60.7 (CHN), 53.4 (CH N), 51.6 (OMe), 51.4
2
2
3
solution of diazoketone 10 (1.0 g, 4.2 mmol) in MeOH (17 cm )
(OMe), 49.5 (CH N), 39.4, 33.7, 30.8 and 22.3 (CH ); m/z (EI)
2 2
ϩ ϩ
at Ϫ25 ЊC under nitrogen with the exclusion of light. The mix-
ture was allowed to warm to room temperature over 3 h. Then,
the solvent was evaporated under reduced pressure and the
229 (58%, M ) [Found: M , 229.1303. C H NO requires M,
11 19 4
229.1314].
3
residue dissolved in EtOAc (20 cm ). The organic layer was
(3S)-Methyl 3-[3-(2-methoxy-2-oxoethyl)-1,2,3,4-tetrahydro-
isoquinolin-2-yl]propanoate 18
washed with saturated aqueous sodium hydrogen carbonate
3
solution (20 cm ), saturated ammonium chloride solution (20
3
Trifluoroacetic acid (9 cm , 120.0 mmol) was added dropwise to
3
3
cm ) and brine (20 cm ), dried (MgSO ) and evaporated under
4
a stirred solution of methyl ester 16 (2.89 g, 9.5 mmol) in
15,16
reduced pressure to give known
methyl ester 11 (1.0 g, 99%)
3
CH Cl (20 cm ) at room temperature under nitrogen. After
2
2
as a pale brown oil, R (5:1 petrol–EtOAc) 0.3; [α] Ϫ43.2 (c
F
D
stirring at room temperature for 1.5 h, the solvent was evapor-
16
1
.0 in MeOH){lit., [α] Ϫ38.8 (c 16 in MeOH)}; ν (CHCl )/
D max 3
Ϫ1
ated under reduced pressure and the residue dissolved in EtOAc
cm 1731 (C᎐O, CO Me) and 1683 (C᎐O, Boc); δ (270 MHz;
2
H
3
(
100 cm ). The organic layer was washed with saturated aque-
CDCl ) 4.19–4.10 (1 H, m, CHN), 3.67 (3 H, s, MeO), 3.35
3
3
ous sodium hydrogen carbonate solution (75 cm ). The aqueous
layer was back-extracted with EtOAc (100 cm ) and the com-
[
2 H, dd (appearing as a triplet), J 6.1 and 6.8, CH N], 2.88
2
3
(
1 H, dd, J 3.5 and 15.0, CH H CO), 2.31 (1 H, dd, J 9.7 and
A B
bined organic extracts were dried (MgSO ) and evaporated
4
1
5.0, CH H CO), 2.10–2.00 (1 H, s, CH), 1.89–1.72 (3 H, m,
A B
under reduced pressure. Then, the residue was dissolved in
CHCH ) and 1.49 (9 H, s, CMe ); δ (67.5 MHz; CDCl ) 171.9
2
3
C
3
3
methyl acrylate (20 cm ) and the resulting mixture was heated
(
C᎐O, CO Me), 154.2 (C᎐O, Boc), 79.4 (CMe ), 54.0 (CHN),
᎐
2
3
under reflux for 17 h. The excess methyl acrylate was evapor-
ated under reduced pressure to give the crude product. Purifi-
cation by flash column chromatography on silica with CH Cl –
5
2
2
1.5 (MeO), 46.3 (CH N), 38.7, 30.9 (CH ), 28.5 (CMe ) and
2 2 3
ϩ ϩ
3.1 (CH ); m/z (EI) 243 [45%, M ] [Found: (M ϩ H) ,
2
2
2
44.1543. C H NO requires M ϩ H, 244.1549].
12
22
4
3
628
J. Chem. Soc., Perkin Trans. 1, 1999, 3623–3631

View Article Online
MeOH–NH (96.5:3.0:0.5) as eluent gave diester 18 (2.69 g,
were basified to pH 8 by addition of saturated aqueous sodium
3
9
8%) as a pale brown oil, R (94.5:5.0:0.5 CH Cl –MeOH–
hydrogen carbonate solution and extracted with Et O (3 × 20
F
2
2
2
Ϫ1
3
NH ) 0.5; [α] ϩ10.7 (c 2.7 in CHCl ); ν (CHCl )/cm 1733
cm ). The combined organic extracts were dried (MgSO ) and
3
D
3
max
3
4
(
(
C᎐O, CO Me), 1483 and 1214; δ (270 MHz; CDCl ) 7.12–7.08
evaporated under reduced pressure. To the oily residue was
᎐
2
H
3
3
4 H, m, Ar), 3.77 (1 H, d, J 16.3, CH H N), 3.63 (1 H, d,
added MeOH (60 cm ) and 2 M aqueous potassium hydroxide
A
B
3
J 16.3, CH H N), 3.60 (6 H, s, 2 × OMe), 3.53 (1 H, td, J 4.3
solution (23 cm ) and the resulting mixture was heated under
A
B
and 13.2), 2.87–2.69 (2 H, m), 2.59–2.46 (4 H, m) and 2.22 (1 H,
dd, J 8.9 and 14.9); δ (67.5 MHz; CDCl ) 173.2, 173.1 (C᎐O,
reflux for 2 h. After cooling to room temperature, the solvent
was evaporated under reduced pressure to give the crude prod-
uct. Purification by Kugelrohr distillation§ gave ketone (S)-5
(511 mg, 29%, 90% ee) as a colourless oil, bp 60–65 ЊC/1 mmHg
C
3
CO Me), 133.8, 133.0 (ipso-Ar), 129.6, 126.8, 126.6, 126.2 (Ar),
2
5
4.1 (OMe), 51.9 (2 signals, CHN and OMe), 50.7, 48.8
22
(
CH N), 33.9 (CH ) and 32.2 (ArCH ); m/z (CI, NH ) 292
(lit., 60–63 ЊC/1 mmHg); R (9:1 CHCl –MeOH) 0.35; [α]
F 3 D
Ϫ1
2
2
2
3
ϩ
ϩ
[100%, (M ϩ H) ] [Found: (M ϩ H) , 292.1548. C H NO
ϩ41.4 (c 0.9 in CHCl ); ν (CHCl )/cm 1713 (C᎐O); δ (270
3 max 3 H
16
21
4
requires M ϩ H, 292.1549].
MHz; CDCl ) 3.36–3.30 (1 H, m), 3.20–3.13 (1 H, m), 2.68–2.51
3
(
(
2 H, m), 2.40–2.18 (5 H, m), 2.06–1.76 (3 H, m) and 1.60–1.43
1 H, m); δ (67.5 MHz; CDCl ) 209.3 (C᎐O), 64.1 (CHN), 53.2,
(
2S)-Methyl pyrrolidin-2-ylacetate 7
C
3
ϩ
3
47.3, 40.6, 31.4 and 22.5 (CH ); m/z (EI) 139 [100%, M ] and 96
2
Trifluoroacetic acid (3.5 cm , 45.6 mmol) was added dropwise
to a stirred solution of methyl ester 11 (1.0 g, 4.2 mmol) in
CH Cl (10 cm ) at 0 ЊC under nitrogen. After 15 min, the solu-
tion was allowed to warm to room temperature and stirred for a
further 1.5 h. Then, CH Cl (50 cm ) was added and the organic
layer was washed with saturated aqueous potassium carbonate
solution (50 cm ). The aqueous layer was back-extracted with
CH Cl (3 × 50 cm ) and the combined organic extracts were
dried (MgSO ) and evaporated under reduced pressure to give
the crude product as a brown oil. Purification by Kugelrohr
distillation gave amino ester 7 (96 mg, 16%) as a colourless oil,
bp 135–145 ЊC/1.0 mmHg; RF (7:3 CHCl –MeOH) 0.2; [α]
ϩ7.0 (c 2.6 in CHCl ); νmax(CHCl )/cm 1730 (C᎐O, CO Me);
δ (270 MHz; CDCl ) 3.68 (3 H, s, OMe), 3.48–3.38 (1 H, m,
CHN), 3.05–2.85 (2 H, m, CH N), 2.56–2.40 (2 H, m, CH CO),
2
δ (67.5 MHz; CDCl ) 172.9 (C᎐O, CO Me), 55.0 (CHN), 51.6
ϩ
(
89) [Found: M , 139.1002. C H NO requires M, 139.0997].
8 13
3
2
2
(
11aRS)-1,3,4,6,11,11a-Hexahydro-2H-pyrido[1,2-b]iso-
3
quinolin-2-one 19 (Table 2, Entry 4)
2
2
3
n-Butyllithium (2.75 cm of a 1.58 M solution in hexanes, 4.35
mmol) was added dropwise to a stirred solution of diisopro-
pylamine (0.65 cm , 5.0 mmol) in THF (6 cm ) at 0 ЊC under
nitrogen. After 10 min, the solution was cooled to Ϫ78 ЊC and a
solution of the diester 18 (560 mg, 1.9 mmol) in THF (12 cm )
was added dropwise over 5 min. The reaction mixture was
stirred at Ϫ78 ЊC for 1.5 h and then 12 M hydrochloric acid
solution (0.4 cm , 5.0 mmol) was added. After being allowed to
warm to room temperature, the solvent was evaporated under
reduced pressure. To the oily residue was added 6 M hydro-
3
3
3
3
2
2
4
3
3
D
Ϫ1
3
3
3
᎐
2
H
3
2
2
3
.40 (1 H, s, NH), 2.01–1.67 (3 H, m) and 1.42–1.29 (1 H, m);
chloric acid (50 cm ). The resulting mixture was heated under
C
3
2
reflux for 16 h. After cooling to room temperature, the solution
was carefully basified by addition of solid potassium carbonate
until saturated. The excess solid was removed by filtration and
washed with Et O. The aqueous filtrate was extracted with Et O
(
OMe), 46.3, 40.7, 31.2 and 25.0 (CH ).
2
(
3S)-Methyl (1,2,3,4-tetrahydroisoquinolin-3-yl)acetate 17
2
2
3
3
(3 × 20 cm ) and the combined organic extracts were dried
K CO ) and evaporated under reduced pressure to give crude
Trifluoroacetic acid (1.3 cm , 17.3 mmol) was added dropwise
to a stirred solution of methyl ester 16 (606 mg, 2.0 mmol) in
CH Cl (8 cm ) at room temperature under nitrogen. After stir-
(
2
3
3
racemic ketone 19 (363 mg, 94%) as a yellow solid.
2
2
ring at room temperature for 2.5 h, the solvent was evaporated
under reduced pressure and the residue dissolved in EtOAc (20
(
11aS)-1,3,4,6,11,11a-Hexahydro-2H-pyrido[1,2-b]isoquinolin-
3
2-one 19 (Table 2, Entry 10)
cm ). The organic layer was washed with saturated aqueous
3
3
sodium hydrogen carbonate solution (15 cm ). The aqueous
of a 1.5 M solution in hexanes, 1.75
n-Butyllithium (1.15 cm
mmol) was added dropwise to a stirred solution of diiso-
propylamine (0.3 cm , 2.1 mmol) in THF (3 cm ) at 0 ЊC under
nitrogen. After 10 min, the solution was cooled to Ϫ78 ЊC and a
solution of the diester 18 (232 mg, 0.8 mmol) in THF (3 cm )
was added dropwise over 5 min. The reaction mixture was
stirred at Ϫ78 ЊC for 20 min and then water (0.1 cm
was added. After being allowed to warm to room temperature,
3
layer was back-extracted with EtOAc (20 cm ) and the com-
3
3
bined organic extracts were dried (MgSO ) and evaporated
4
under reduced pressure to give the crude product. Purification
3
by flash column chromatography on silica with CHCl –MeOH–
3
NH (95.5:4.0:0.5) as eluent gave amino ester 17 (315 mg, 79%)
3
3
as an oil, RF (94.5:5.0:0.5 CHCl –MeOH–NH ) 0.3; [α]
, 5.5 mmol)
3
3
D
Ϫ1
Ϫ53.7 (c 0.9 in CHCl ); νmax(CHCl )/cm 1731 (C᎐O, CO Me);
3
3
᎐
2
δ (270 MHz; CDCl ) 7.15–7.01 (4 H, m, Ar), 4.13 (1 H, d,
H
3
the solvent was evaporated under reduced pressure. To the oily
residue was added MeOH (5 cm
3
J 16.3, CH H N), 4.04 (1 H, d, J 16.3, CH H N), 3.73 (3 H, s,
) and 2 M aqueous potassium
A
B
A
B
3
MeO), 3.38–3.31 (1 H, br m, CHN), 2.83 (1 H, dd, J 4.0 and
6.3), 2.66 (1 H, dd, J 4.1 and 17.0) and 2.55–2.51 (2 H, m);
δ (67.5 MHz; CDCl ) 172.4 (C᎐O, CO Me), 135.1, 133.8 (ipso-
hydroxide solution (2 cm ) and the resulting mixture was heated
under reflux for 3 h. After cooling to room temperature, the
reaction mixture was worked up using the procedure described
previously to give the crude product. Purification by flash
column chromatography on silica with 98:2 CH
eluent gave ketone (S)-19 (31 mg, 19%) as an off-white solid,
1
C
3
2
Ar), 129.0, 126.0, 125.8 (Ar), 51.6 (MeO), 50.4 (CHN), 48.1
(
CH N), 40.6 and 34.8 (CH ); m/z (CI, NH ) 206 [100%,
Cl –MeOH as
2
2
ϩ
3
2
2
ϩ
(
M ϩ H) ] [Found: (M ϩ H) , 206.1181. C H NO requires
12 15 2
32
M ϩ H, 206.1181].
119.5–120.5 ЊC); RF (96.5:3.0:0.5
mp 101–109 ЊC (lit.,
CH Cl –MeOH–NH ) 0.5; [α] Ϫ89.7 (c 1.55 in EtOH){lit.,
32
2
2
3
D
Hexahydroindolizin-7(1H)-one 5 (Table 1, Entry 3)
Ϫ1
[
α]D Ϫ91.0 (c 0.26 in EtOH)}; νmax(CHCl )/cm 1720 (C᎐O);
3
᎐
3
δ (270 MHz; CDCl ) 7.18–7.13 (2 H, m, Ar), 7.11–7.04 (2 H,
m, Ar), 4.04 (1 H, d, J 15.3, CH H N), 3.55 (1 H, d, J 15.3,
CH H N), 3.36 (1 H, ddd, J 2.8, 5.7 and 11.4, CHN), 2.89–2.82
A solution of diester 6 (2.9 g, 12.6 mmol) in xylenes (11 cm )
was added dropwise over 3 h (using a syringe pump) to a stirred
refluxing solution of sodium methoxide (51 mg, 1.0 mmol) and
H
3
A
B
A
B
(
2 H, m), 2.79–2.74 (2 H, m), 2.61–2.35 (4 H, m); δ (67.5 MHz;
sodium hydride (1.27 g of a 60 wt% dispersion in mineral oil,
C
3
CDCl ) 207.8 (C᎐O), 133.2, 132.1 (ipso-Ar), 127.9, 126.4, 126.0,
1
9
.2 mmol) in xylenes (60 cm ) under nitrogen. After stirring for
3
25.9 (Ar), 57.9 (CHN), 56.7, 54.3 (CH N), 47.5, 41.1 and 36.6
a further 2 h at reflux, the reaction mixture was cooled to 0 ЊC
2
and acetic acid (2.1 g, 35.4 mmol) was added. Then, water (10
3
cm ) was added and the organic layer was extracted with 2 M
§
Note that ketone 5 is a relatively volatile compound and care must be
3
hydrochloric acid (3 × 20 cm ). The combined aqueous extracts
taken when isolating it by distillation.
J. Chem. Soc., Perkin Trans. 1, 1999, 3623–3631
3629

View Article Online
ϩ
3
(
(
CH ); m/z (CI, NH3) 202 [100%, (M ϩ H) ] [Found:
(5 × 15 cm ) and the combined organic extracts were washed
2
ϩ
3
M ϩ H) , 202.1229. C H NO requires M ϩ H, 202.1231].
Using the procedure described above, n-butyllithium (1.1 cm
of a 1.6 M solution in hexanes, 1.7 mmol), diisopropylamine
with 20% aqueous sodium hydroxide solution (5 × 15 cm ),
dried (MgSO ) and evaporated under reduced pressure to give
crude racemic diamine 2 (2.12 g, 68%) as a colourless oil which
was of high purity by H NMR spectroscopy.
In a separate experiment, racemic ketone 4 (330 mg, 1.7
mmol), hydrazine hydrate (0.44 cm , 9.0 mmol) and potassium
hydroxide (752 mg, 13.0 mmol) in diethylene glycol (3.4 cm )
gave the crude product. Purification by Kugelrohr distillation
gave racemic diamine 2 (165 mg, 54%) as a colourless oil,
bp 140–150 ЊC/0.5 mmHg; R (4:1 CHCl –MeOH) 0.1;
13
15
3
4
3
1
(
(
0.3 cm , 2.1 mmol) and diester 18 (234 mg, 0.8 mmol) in THF
3
3
7.5 cm ) followed by treatment with MeOH (5 cm ) and 2 M
3
3
aqueous potassium hydroxide solution (2 cm ) gave the crude
ketone (S)-19 (95 mg, 59%) as a yellow solid which was suf-
ficiently pure for direct use in subsequent double Mannich
reactions.
3
F
3
Ϫ1
3,7
νmax(CHCl )/cm 2931 and 2783; δ (270 MHz; CDCl ) 3.25–
1
0-Methyl-3,10-diazatricyclo[6.3.1.0 ]dodecan-12-one 4
3
H
3
1
6
.20 (17 H, m) and 2.17 (3 H, s, NMe); δ (67.5 MHz; CDCl )
7.4 (CHN), 60.4, 57.3, 54.9, 54.3 (CH N), 47.5 (NMe), 33.3
CH ), 31.2, 30.0 (CH), 26.7 and 20.7 (CH ); m/z (EI) 180 [60%,
2 2
ϩ ϩ
M ] and 122 (35) [Found: M , 180.1627. C H N requires M,
C
3
3
Methylamine (1.8 cm of a 2.0 M solution in MeOH, 3.8 mmol)
was added dropwise to a stirred solution of ketone (S)-5 (510
mg, 3.6 mmol, 90% ee), paraformaldehyde (334 mg, 11.2 mmol)
and acetic acid (0.2 cm , 3.5 mmol) in MeOH (4.0 cm ) at room
temperature under nitrogen. The resulting solution was heated
under reflux for 16 h. After cooling to room temperature, the
solvent was evaporated under reduced pressure and 50% aque-
ous potassium hydroxide solution (17 cm ) was added to the
residue. The aqueous mixture was extracted with Et O (3 × 25
cm ) and the combined organic extracts were dried (Na SO )
2
(
11
20
2
3
3
1
80.1626].
Diamine 3
3
Using the procedure described above, racemic ketone 20 (211
mg, 0.8 mmol), hydrazine hydrate (0.2 cm , 4.1 mmol) and
potassium hydroxide (320 mg, 5.7 mmol) in diethylene glycol
(1.7 cm ) gave the crude product. Purification by Kugelrohr
distillation gave racemic diamine 3 (154 mg, 77%) as a colour-
less oil (which solidified on standing overnight at Ϫ20 ЊC), bp
3
2
3
2
4
3
and evaporated under reduced pressure to give the crude
product as a yellow oil. Purification by Kugelrohr distillation
gave racemic ketone 4 (208 mg, 29%) as a colourless oil, bp 135–
Ϫ1
1
45 ЊC/0.8 mmHg; R (4:1 CHCl –MeOH) 0.1; ν (CHCl )/
140–150 ЊC/0.3 mmHg; mp 69–72 ЊC; νmax(CHCl
and 739; δ (270 MHz; CDCl
(1 H, dd, J 2.2 and 6.6, Ar), 3.97 (1 H, d, J 15.5, CH H
A B
3
)/cm 1588
F
3
max
3
Ϫ1
cm 1713 (C᎐O); δ (270 MHz; CDCl ) 3.43–1.55 (15 H, m)
and 2.26 (3 H, s, NMe); δ (67.5 MHz; CDCl ) 215.0 (C᎐O),
H
3
) 7.11–7.02 (3 H, m, Ar), 6.95
N),
H
3
C
3
6
8.5 (NMe), 60.3, 56.55, 55.0, 51.9 (CH N), 49.6, 45.75, 45.4
3.28–3.03 (5 H, m), 2.55 (1 H, q, J 2.9), 2.52 (1 H, dd, J 3.5 and
6.7), 2.45 (1 H, ddd, J 1.7, 3.8 and 11.3), 2.21–2.15 (1 H, m),
2.17 (3 H, s, NMe), 2.04 (1 H, dd, J 2.9 and 11.7), 1.99–1.94
2
ϩ
(
CH), 27.4 and 22.8 (CH ); m/z (EI) 194 [27%, M ] and 84 (100)
2
ϩ
[Found: M , 194.1428. C H N O requires M, 194.1419].
11 18 2
(
1 H, m), 1.79–1.74 (1 H, m) and 1.66–1.62 (2 H, m); δ (67.5
C
MHz; CDCl ) 134.9 (ipso-Ar), 128.1, 125.9, 125.6, 125.3 (Ar),
Tricyclic ketone 20
3
6
3
2
2
1.1 (CHN), 60.7, 60.3, 60.2, 58.7 (CH N), 47.8 (NMe),
2
3
Methylamine (0.9 cm of a 2.0 M solution in MeOH, 1.8 mmol)
was added dropwise to a stirred solution of racemic ketone 19
4.1 (CH ), 33.7 (CH), 33.5 (CH ) and 30.7 (CH); m/z (EI)
2
2
ϩ
ϩ
42 [100%, M ], [Found: M , 242.1783. C H N requires M,
16
22
2
(
350 mg, 1.7 mmol), paraformaldehyde (210 mg, 7.0 mmol) and
42.1783].
3
3
acetic acid (0.12 cm , 2.1 mmol) in MeOH (4.0 cm ) at room
temperature under nitrogen. The resulting solution was heated
under reflux for 16 h. After cooling to room temperature, 2 M
hydrochloric acid (30 cm ) was added and the aqueous layer
was washed with Et O (2 × 20 cm ). The aqueous layer was
Acknowledgements
We thank the EPSRC and SmithKline Beecham Pharma-
ceuticals for the award of a CASE studentship (to D. W. P.) and
The Leverhulme Trust for the award of a fellowship (to J. R. H).
3
3
2
basified to pH 14 by addition of 20% aqueous sodium hydrox-
ide solution (20 cm ) and extracted with Et O (3 × 10 cm ). The
3
3
2
combined organic extracts were dried (K CO ) and evaporated
2
3
under reduced pressure to give the crude product. Purification
References
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3
1
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H
3
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4
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2
3
ϩ
ϩ
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3
,7
1
0-Methyl-3,10-diazatricyclo[6.3.1.0 ]dodecane 2
A solution of racemic ketone 4 (3.33 g, 17.2 mmol), hydrazine
hydrate (4.4 cm , 90.2 mmol) and potassium hydroxide (7.58 g,
35.4 mmol) in diethylene glycol (27 cm ) was heated at reflux
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8
3
3
1
1
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3
3
2
2
3
630
J. Chem. Soc., Perkin Trans. 1, 1999, 3623–3631

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Paper 9/06969K
J. Chem. Soc., Perkin Trans. 1, 1999, 3623–3631
3631