Asymmetric synthesis of (-)-(1R,7aS)-absouline

Article abstract of DOI:10.1016/j.tet.2012.11.080

The most efficient and concise asymmetric synthesis of (-)-(1R,7aS)- absouline to date, which was accomplished in eight steps and 20% overall yield from commercially available starting materials, is described. The doubly diastereoselective conjugate addit

Full text of DOI:10.1016/j.tet.2012.11.080

Tetrahedron 69 (2013) 1369e1377
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric synthesis of (ꢀ)-(1R,7aS)-absouline
*
ꢀ
ꢀ
Stephen G. Davies , Ai M. Fletcher, Clement Lebee, Paul M. Roberts,
James E. Thomson, Jingda Yin
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:
The most efficient and concise asymmetric synthesis of (ꢀ)-(1R,7aS)-absouline to date, which was
Received 17 September 2012
Received in revised form 26 October 2012
Accepted 13 November 2012
Available online 29 November 2012
accomplished in eight steps and 20% overall yield from commercially available starting materials, is de-
scribed. The doubly diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(
amide to an enantiopure -unsaturated ester derived from -proline was employed as the key step. Sub-
sequent hydrogenolytic N-debenzylation and acid-promoted cyclisation of the resultant -amino ester
a-methylbenzyl)-
a,b
L
b
produced the 1-aminopyrrolizidin-3-one scaffold, then reduction with DIBAL-H was followed by DCC-
mediated coupling with (E)-p-methoxycinnamic acid to complete the synthesis of (ꢀ)-(1R,7aS)-absouline.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
(ꢀ)-(1R,7aS)-Absouline
Lithium amide
Conjugate addition
Asymmetric synthesis
1. Introduction
methyl ester, employing the conjugate addition of benzylamine to
a (Z)-a,b
-unsaturated ester10 (Fig. 1).
The pyrrolizidinering, which consists of two fused five-membered
ringswithanitrogenatomatthebridgehead, isacommonunitwithin
alkaloids, which have been shown to possess various biological
activities.1 For example, SC-53116 12 was reported to be the first
selective agonist at the 5-HT4 receptor, which has shown promise in
the treatment of irritable bowel syndrome, atrial arrhythma, urinary
incontinence and gastrointestinal motility disorders; other examples
of naturally occurring pyrrolizidines include the glycosidase
inhibitors (þ)-hyacinthacine A1 23 and (þ)-broussonetine N 3.4 The
1-aminopyrrolizidine (þ)-absouline 4, its (Z)-stereoisomer isoabsou-
line 5 and their corresponding N-oxide derivatives were isolated from
theCaledonianplantsHugonia oregana and Hugonia penicillanthemum
in 1987.5 Since their isolation, two racemic6,7 and three
asymmetric8e10 syntheses of absouline 4 have been reported. For
example, Huang and co-workers applied a diastereoselective carba-
nionic approach to form a trans-2-subsituted-3-aminopyrrolidine in
their asymmetric synthesis of (þ)-absouline 4, in 14 steps and 0.8%
overall yield from N-Cbz-protected (S)-aspartic anhydride.8,11 Couty
and co-workers showcased the boron trifluouride-mediated rear-
rangement of an enantiopure 2-cyanoazetidine to give the corre-
sponding enantiopure 3-aminopyrrolidine in their asymmetric
synthesis of (ꢀ)-absouline 4, which was accomplished in 12 steps and
6.3% overall yield from (S)-
Scheererand co-workers have reported the synthesis of (ꢀ)-absouline
4 in eight steps and 10% overall yield from N-Boc protected -proline
a
-methylbenzylamine.9 More recently,
L
* Corresponding author. E-mail address: steve.davies@chem.ox.ac.uk (S.G. Davies).
Fig. 1. Pyrrolizidine alkaloids 1e3, (þ)-absouline 4 and isoabsouline 5.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.080

1370
S.G. Davies et al. / Tetrahedron 69 (2013) 1369e1377
We have recently developed a protocol for the efficient parallel
kinetic resolution (PKR) of a range of racemic, acyclic N-protected
-amino-
-unsaturated esters.12 In this procedure, the conjugate
addition of a 50:50 pseudoenantiomeric mixture of lithium (R)-N-
benzyl-N-( -methylbenzyl)amide (R)-7 and lithium (S)-N-3,4-
dimethoxybenzyl-N-( -methylbenzyl)amide (S)-8 to racemic
-amino- -unsaturated esters (RS)-6 (derived from the corre-
sponding racemic -amino acids) furnished, in each case, a 50:50
mixture of enantiopure -amino esters and 10 as single
diastereoisomers (>99:1 dr). The resultant -diamino esters 9
g
a,b
a
a
g
a,b
a
b
9
b,g
were then elaborated by hydrogenolytic N-debenzylation followed
by acid-promoted cyclisation to enantiopure 5-substituted-4-
aminopyrrolidin-2-ones, which were isolated as the correspond-
ing acetate derivatives 11 (Scheme 1).
Fig. 2. Proposed asymmetric synthesis of absouline 4.
Scheme 1. Reagents and conditions: (i) lithium (R)-N-benzyl-N-(
a
-methylbenzyl)am-
ide (R)-7, lithium (S)-N-(3,4-dimethoxybenzyl)-N-(
a-methylbenzyl)amide (S)-8 (50:50
mixture), THF, ꢀ78 ꢁC, 2 h; (ii) H2 (5 atm), Pd(OH)2/C, HCl (1.25 M in MeOH), rt, 48 h;
(iii) HCl (3.0 M aq), 90 ꢁC, 18 h; (iv) Ac2O, pyridine, rt, 12 h.
As an extension of this methodology, we became interested in
the introduction of a cyclic constraint within the
saturated ester and therefore proposed to investigate the compat-
ibility of DL-proline derived -unsaturated ester (RS)-12 within
the PKR protocol. It was envisaged that this methodology would
provide access to the 1-aminopyrrolizidin-3-one scaffold 15 via
sequential N-deprotection and acid-promoted cyclisation. Further
elaboration of 15 would then give the corresponding enantiopure
1-aminopyrrolizidine 16, a precursor to absouline 4 (Fig. 2).
g-amino-a,b-un-
Scheme 2. Reagents and conditions: (i) PhCOCl, NaOH, H2O, 0 ꢁC, 2 h; (ii) LiAlH4, THF,
reflux, 18 h; (iii) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC, 1 h, then Ph3P]CHCO2tBu,
CH2Cl2, rt, 18 h.
a,b
When investigating PKR,14 we have found that it is prudent to
follow a strategy of first evaluating the level of substrate control
offered by the chiral a,b-unsaturated ester upon conjugate addition
of achiral lithium N-benzyl-N-isopropylamide 20.15 In cases where
2. Results and discussion
high levels of substrate control are observed, the conjugate addition
of lithium (RS)-N-benzyl-N-(
a-methylbenzyl)amide (RS)-7 to the
2.1. Evaluation of tert-butyl (RS,E)-3-[N(10)-benzylpyrrolidin-
racemic -unsaturated ester [i.e., a mutual kinetic resolution
a,b
20-yl]propenoate in the proposed PKR protocol
(MKR)] is then performed, allowing the maximum levels of enan-
tiodiscrimination (as quantified by the stereoselectivity factor, E)16
to be determined by analysis of the product distribution by 1H NMR
spectroscopy. For those substrates with high levels of enantior-
ecognition (E>10), PKR employing a 50:50 pseudoenantiomeric
a,b-Unsaturated ester (RS)-12 was prepared in three steps from
racemic proline DL-17. Treatment of DL-17 with benzoyl chloride,
followed by global reduction with LiAlH4 afforded N-benzyl pro-
tected
(RS)-19 and in situ Wittig olefination of the resultant aldehyde gave
racemic
-unsaturated ester (RS,E)-1213 in >95:5 dr, and 42% yield
and >99:1 dr after purification (Scheme 2).
a
-amino alcohol (RS)-19 in 81% yield. Swern oxidation of
mixture of enantiopure lithium (R)-N-benzyl-N-(
amide (R)-7 and lithium (S)-N-3,4-dimethoxybenzyl-N-(
benzyl)amide (S)-8 may be performed. This approach was adopted
to investigate whether -unsaturated ester 12 would be
a
-methylbenzyl)-
a-methyl-
a,b
a,b

S.G. Davies et al. / Tetrahedron 69 (2013) 1369e1377
1371
compatible with the PKR protocol. The conjugate addition of achiral
lithium amide 20 to -unsaturated ester 12 proceeded with
moderate diastereoselectivity, giving an 84:16 mixture of 3,4-anti-
21 and 3,4-syn-22, respectively. Upon purification, the major
product 21 was isolated in 46% yield as a single diastereoisomer
(>99:1 dr), along with an 80:20 mixture of 21 and 22 in 16%
combined yield. Next, the level of enantiorecognition between a,b-
unsaturated ester 12 and the chiral lithium amide reagent 7 was
evaluated in the MKR protocol: conjugate addition of lithium (RS)-
benzyl-N-(a-methylbenzyl)amide (RS)-7] to give the corresponding
a
,b
C(1)-epimer (RS,RS)-30 in 14% yield over three steps. The spectro-
scopic data obtained for this sample of (RS,RS)-30 were distinctly
different to those for (RS,SR)-26. The corresponding acetyl pro-
tected derivatives (RS,SR)-27 and (RS,RS)-31 were prepared in 52%
and 53% yield, respectively. 1H NMR NOE experiments for (RS,SR)-
26 and (RS,SR)-27 were consistent with their assigned relative 1,7a-
anti configurations, while those of (RS,RS)-30 and (RS,RS)-31 were
consistent with their assigned relative 1,7a-syn configurations.
Hydogenolytic N-debenzylation of the major diastereoisomeric
product 21 [arising from the conjugate addition of lithium N-ben-
zyl-N-isopropylamide 20 to (RS)-12] mediated by Pearlman’s cat-
alyst [Pd(OH)2/C] in the presence of acetone promoted concomitant
N-benzyl-N-(
ter (RS)-12 gave an 84:16 mixture of (3RS,20SR,
(3RS,20RS,
SR)-24, which were isolated as single diastereoisomers
a
-methylbenzyl)amide (RS)-7 to
a,
b-unsaturated es-
a
SR)-23 and
a
(>99:1 dr) in 63% and 8% yield, respectively (Scheme 3).
reductive alkylation to give N,N0-diisopropyl substituted
b-amino
ester 28 in 84% yield and >99:1 dr. Hydrogenolysis of 23 [the major
diastereoisomeric product arising from MKR of (RS)-12 upon re-
action with lithium (RS)-N-benzyl-N-(
7] in the presence of acetone also gave N,N0-diisopropyl substituted
-amino ester 28 in 71% yield and >99:1 dr; the spectroscopic data
a-methylbenzyl)amide (RS)-
b
for this sample 28 were identical to those for the sample of 28
derived from 21 (Scheme 4).
Scheme 3. Reagents and conditions: (i) lithium N-benzyl-N-isopropylamide 20, THF,
ꢀ78 ꢁC, 2 h; (ii) lithium (RS)-N-benzyl-N-(
a
-methylbenzyl)amide (RS)-7, THF, ꢀ78 ꢁC,
2 h. [a an 80:20 mixture of 21 and 22 was also isolated in 16% combined yield].
The relative configurations within 21e24 were assigned by
a combination of chemical correlation experiments and 1H NMR
NOE spectroscopic analyses. The relative configurations of the C(a)
and C(3) stereogenic centres within 23 and 24 were initially
assigned by reference to the well established transition state
mnemonic developed by us to rationalise the diastereoselectivity
observed upon conjugate addition of lithium amides derived from
Scheme 4. Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C, HCl (1.25 M in MeOH),
rt, 48 h; (ii) HCl (3.0 M aq), 90 ꢁC, 18 h; (iii) K2CO3, toluene, reflux, 18 h, then CbzCl,
K2CO3, THF, rt, 16 h; (iv) Ac2O, pyridine, rt, 18 h; (v) H2 (1 atm), Pd(OH)2/C, MeOH/
acetone (v/v 10:1), rt, 24 h; (vi) HCl (3.0 M aq), 90 ꢁC, 18 h then DOWEX 50WX8-100;
(vii) CbzCl, K2CO3, THF, rt, 16 h.
a
-methylbenzylamine.17 These assignments were later confirmed
by the syntheses of authentic samples of (3R,20S,
aS)-23 and
(3S,20S,
aR)-24. Hydrogenolytic N-debenzylation of the major di-
astereoisomeric product (RS,SR)-23 followed by cyclisation under
strongly acidic conditions afforded the corresponding 1-
aminopyrrolizidin-3-one hydrochloride salt (RS,SR)-25$HCl. The
N-Cbz-protected derivative (RS,SR)-26 was prepared via treatment
of (RS,SR)-25$HCl with CbzCl to give (RS,SR)-26 in 34% overall yield.
The 1H and 13C NMR spectra of (RS,SR)-26 prepared in this manner
were in agreement with those reported for the 1,7a-anti-di-
astereoisomer in the literature.18,19 An analogous sequence of
transformations was applied to the minor diastereomeric product
(RS,RS)-24 [arising from MKR of (RS)-12 with lithium (RS)-N-
The modest levels of enantiorecognition between (RS)-7 and
a,
b
-unsaturated ester (RS)-12 (as quantified by the stereoselectivity
factor Ez5),16 as well as the product distribution resulting from the
substrate directed conjugate addition of 20 to -unsaturated ester
(RS)-12, suggested that -unsaturated ester (RS)-12 is not a suit-
a,b
a,b
able substrate for PKR using enantiomerically pure lithium amides.
However, as both antipodes of proline are readily available, we
proposed to investigate the doubly diastereoselective conjugate
additions20 of both antipodes of lithium N-benzyl-N-(
a-

1372
S.G. Davies et al. / Tetrahedron 69 (2013) 1369e1377
methylbenzyl)amide 7 to
a
,b
-unsaturated ester (S)-12 as an alter-
S)-23 and
native method to enable the synthesis of (3R,20S,
a
(3S,20S,
aR)-24.
2.2. Asymmetric synthesis of (L)-(1R,7aS)-absouline
Enantiopure
a
,
b-unsaturated ester (S,E)-12 was prepared in
three steps from
L-proline 17, following the same sequence of the
transformations for the corresponding racemate (RS,E)-12, in 55%
yield and >99:1 dr, with only one chromatographic purification.21
As the conjugate addition of lithium (RS)-N-benzyl-N-iso-
propylamide 20 to (RS)-12 gave 3,4-anti-21 as the major product
(84:16 dr), it was anticipated that the combination of enantiopure
a,b-unsaturated ester (S,E)-12 and lithium (S)-N-benzyl-N-(a-
methylbenzyl)amide (S)-7 would be the doubly diastereoselective
‘matched’ pairing.22 This was indeed found to be the case as the
conjugate addition of lithium (S)-N-benzyl-N-(
amide (S)-7 (2.0 equiv) to -unsaturated ester (S)-12 showed very
high diastereoselectivity (>99:1 dr), giving (3R,20S,
S)-23 in 74%
isolated yield. Conjugate addition of lithium (R)-N-benzyl-N-(
methylbenzyl)amide (R)-7 (2.0 equiv) to -unsaturated ester (S)-
12 (which was predicted to be the ‘mismatched’ pairing) under
identical conditions showed only 78% conversion to (3S,20S,
R)-24
(>95:5 dr). However, complete conversion to 24 was achieved by
using 4.0 equiv of (R)-7, affording (3S,20R,
R)-24 in 73% yield and
>99:1 dr after purification. In both cases, the 1H and 13C NMR
a-methylbenzyl)
a,b
a
a
-
a,b
a
a
spectroscopic data for (3R,20S,
identical to those of the samples of (3RS,20SR,
(3RS,20RS,
a
S)-23 and (3S,20S,
a
R)-24 were
SR)-23 and
Scheme 6. Reagents and conditions: (i) H2 (5 atm), Pd(OH)2/C (50% w/w), HCl (1.25 M
in MeOH), rt, 48 h; (ii) HCl (3.0 M aq), 90 ꢁC, 18 h; (ii) DIBAL-H (1.0 M in THF), THF, 0 ꢁ
then rt, 18 h; (iv) trans-4-methoxycinnamic acid, DCC, DMAP, CH2Cl2, 0 ꢁC then rt, 3 h.
a
C
a
SR)-24 prepared in the MKR of (RS)-12, therefore con-
firming the assigned relative configurations within (3RS,20SR,
SR)-
23 and (3RS,20RS,
SR)-24 (Scheme 5).
a
a
Scheme 5. Reagents and conditions: (i) PhCOCl, NaOH, H2O, 0 ꢁC, 2 h; (ii) LiAlH4, THF, reflux, 18 h; (iii) (COCl)2, DMSO, Et3N, CH2Cl2, ꢀ78 ꢁC, 1 h, then Ph3P]CHCO2tBu, CH2Cl2, rt,
18 h; (iv) lithium (S)-N-benzyl-N-(
a
-methylbenzyl)amide (S)-7, THF, ꢀ78 ꢁC, 2 h; (v) lithium (R)-N-benzyl-N-(
a
-methylbenzyl)amide (R)-7, THF, ꢀ78 ꢁC, 2 h.
b
-Amino ester (3R,20S,
a
S)-23 was elaborated to (ꢀ)-(1R,7aS)-
(c 0.4, EtOH); lit.9
½
a 2D0
ꢂ
ꢀ37 (c 1.8, CHCl3); lit.10
[
a]
ꢀ48 (c 0.8,
D
absouline 4 in four steps. Hydrogenolytic N-debenzylation of 23
followed by cyclisation under strongly acidic conditions gave the
corresponding 1-aminopyrrolizidin-3-one hydrochloride salt
25$HCl in quantitative yield. Treatment of 25$HCl with excess
DIBAL-H (10 equiv) at rt for 18 h gave the corresponding pyrroli-
zidine 33, and was followed by DCC-mediated coupling of 33 with
trans-4-methoxycinnamic acid to complete the synthesis of
(ꢀ)-(1R,7aS)-absouline 4 in 49% yield and >99:1 dr from 25$HCl
(Scheme 6). The spectroscopic data obtained for this sample of
(ꢀ)-absouline 4 were in excellent agreement with those previously
EtOH). Overall, the synthesis of (ꢀ)-(1R,7aS)-absouline 4 was ach-
ieved in eight steps and 20% overall yield from commercially
available starting materials. This synthesis therefore constitutes the
most efficient and concise asymmetric synthesis of (ꢀ)-(1R,7aS)-
absouline 4 reported to date.
3. Conclusion
In conclusion, the level of enantiorecognition observed between
tert-butyl (RS,E)-3-[N(10)-benzylpyrrolidin-20-yl]propenoate and
reported in the literature {½a D20
ꢂ
ꢀ49 (c 0.2, EtOH); lit.5 for
lithium (RS)-N-benzyl-N-(
addition was evaluated. This analysis indicated that the racemic
-unsaturated ester is not a viable substrate for our PKR protocol.
However, the doubly diastereoselective ‘matched’ conjugate
a-methylbenzyl)amide upon conjugate
(þ)-absouline isolated from the natural source [ D þ56 (c 1, EtOH);
a
]
lit.6 ½a 2D0
ꢂ
ꢀ34 (c 0.91, CHCl3); lit.6 for enantiomer ½a 2D0
ꢂ
þ26 (c 1.05,
a,b
CHCl3); lit.8 for enantiomer ½a 2D0
ꢂ
þ46.0 (c 1.2, CHCl3)}; lit.9 ½a D20
ꢀ51
ꢂ

S.G. Davies et al. / Tetrahedron 69 (2013) 1369e1377
1373
addition of lithium (S)-N-benzyl-N-(
a
-methylbenzyl)amide to tert-
(3.48 g, 87.0 mmol) in H2O (10 mL) were added simultaneously.
The reaction mixture was stirred at 0 ꢁC for 2 h and washed with
Et2O (2ꢃ50 mL). The aqueous layer was acidified with cold 6.0 M
aq HCl (pH¼2) and extracted with EtOAc (3ꢃ50 mL). The com-
bined organic extracts were washed with brine, then dried and
concentrated in vacuo to give 18 as a colourless oil (17.7 g).
Step 2: A solution of 18 (17.6 g) in THF (17 mL) was added to
a suspension of LiAlH4 (6.00g,158mmol)inTHF(200 mL)dropwiseat
butyl (S,E)-3-[N(10)-benzylpyrrolidin-20-yl]propenoate proceeded
with very high diastereoselectivity (>99:1 dr). Subsequent hydro-
genolysis and acid-mediated cyclisation provided access to the 1-
aminopyrrolizidin-3-one scaffold and enabled the asymmetric
synthesis of (ꢀ)-(1R,7aS)-absouline to be achieved in eight steps
and in 20% overall yield from commercially available starting ma-
terials, requiring only three chromatographic purifications. This
approach therefore represents the most efficient route to enantio-
pure absouline reported to date.
0
ꢁC, and the resultant mixture was stirred at reflux for 18 h. The
reaction mixture was then quenched by slow addition of MeOH
(2.0 mL) and 2.0 M aq NaOH (20 mL) at 0 ꢁC. The resultant white
suspension was filtered through short pad of CeliteÒ (eluent MeOH)
and concentrated in vacuo. Purification via flash column chroma-
tography (eluent 30e40 ꢁC petrol/Et2O, 20:1, increased to 10:1) gave
19 as a colourless oil (13.2 g, 81%);24 dH (400 MHz, CDCl3) 1.65e2.00
(4H, m, C(30)H2, C(40)H2), 2.26e2.34 (1H, m, C(50)HA), 2.71e2.78
(1H, m, C(50)HB), 2.79 (1H, br s, OH), 2.95e3.02 (1H, m, C(20)H), 3.35
(1H, d, J 13.0, NCHACHBPh), 3.44 (1H, dd, J 10.6, 2.1, C(1)HA), 3.67 (1H,
dd, J 10.6, 3.4, C(1)HB), 3.95 (1H, d, J 13.0, NCHACHBPh), 7.24e7.39 (5H,
m, Ph).
4. Experimental
4.1. General experimental
Reactions involving moisture-sensitive reagents were carried out
undera nitrogen atmosphere using standard vacuum line techniques
and glassware that was flame-dried and cooled under nitrogen be-
fore use. Solvents were dried according to the procedure outlined by
Grubbs and co-workers.23 Water was purified by an ElixÒ UV-10
system. n-BuLi was purchased from SigmaeAldrich (as a 1.6 or
2.5 M solution in hexanes) and titrated against diphenylacetic acid
before use. Organic layers were dried over MgSO4 unless otherwise
stated. Thin layer chromatography was performed on aluminium
plates coated with 60 F254 silica. Flash column chromatography was
performed either on Kieselgel 60 silica on a glass column, or on
a Biotage SP4 automated flash column chromatography platform.
Elemental analyses were recorded by the microanalysis service of
London Metropolitan University, U.K. Melting points were recorded
on a Gallenkamp Hot Stage apparatus and are uncorrected. Optical
rotations were recorded on a PerkineElmer 241 polarimeter with
a water-jacketed 10 cm cell. Specific rotations are reported in
10ꢀ1 deg cm2 gꢀ1 and 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 cmꢀ1. NMR
spectra were recorded on Bruker Avance spectrometers in the deu-
terated solvent stated, at rt. The field was locked by external refer-
encing to the relevant deuteron resonance. Low-resolution mass
spectrawere recorded on either a VG MassLab 20-250 or a Micromass
Platform 1 spectrometer. Accurate mass measurements were run on
either a Bruker MicroTOF internally calibrated with polyalanine, or
aMicromassGCTinstrumentfittedwithaScientificGlassInstruments
BPX5 column (15 mꢃ0.25 mm) using amyl acetate as a lock mass.
Step 3: A solution of (COCl)2 (4.25 mL, 50.2 mmol) in CH2Cl2
(250 mL) at ꢀ78 ꢁC was added to a solution of DMSO (3.86 mL,
54.4 mmol) in CH2Cl2 (50 mL). After stirring for 10 min, a solution of
19 (8.00 g, 41.8 mmol) in CH2Cl2 (50 mL) was added. The reaction
mixture was stirred for 1 h before the addition of Et3N (11.7 mL,
83.7 mmol) and the reaction mixture was then allowed to warm to
rt. Ph3P]CHCO2tBu (15.8 g, 41.8 mmol) was added and the resultant
mixture was stirred for 18 h. Satd aq Na2CO3 (50 mL) was then
added and the resultant mixture was extracted with CH2Cl2
(3ꢃ100 mL). The combined organic extracts were washed with brine
(150 mL), then dried and concentrated in vacuo. Purification via
flash column chromatography (eluent 30e40 ꢁC petrol/Et2O, 20:1,
increased to 10:1) gave 12 as a colourless oil (5.05 g, 42%, >99:1 dr);
nmax 2974 (CeH), 1710 (C]O),1655 (C]C); dH (400 MHz, CDCl3) 1.51
(9H, s, CMe3), 1.65e1.88 (3H, m, C(30)HA, C(40)H2), 1.95e2.06 (1H, m,
C(30)HB), 2.18 (1H, dd, J 17.2, 8.3, C(50)HA), 2.95e3.06 (2H, m, C(20)H,
C(50)HB), 3.18 (1H, d, J 12.9, NCHACHBPh), 3.91 (1H, d, J 12.9,
NCHACHBPh), 5.92 (1H, d, J 15.7, C(2)H), 6.81 (1H, dd, J 15.7, 8.1,
C(3)H), 7.21e7.35 (5H, m, Ph); dC (100 MHz, CDCl3) 22.5 (C(40)), 28.2
(CMe3), 31.5 (C(30)), 53.5 (C(50)), 58.6 (NCH2Ph), 65.9 (C(20)), 80.2
(CMe3), 123.8 (C(2)), 126.9, 128.2,128.8 (o,m,p-Ph), 139.2 (i-Ph), 149.3
(C(3)), 165.8 (C(1)); m/z (ESIþ) 288 ([MþH]þ, 100%); HRMS (ESIþ)
þ
C
18H26NO2 ([MþH]þ) requires 288.1958; found 288.1950.
4.2. General procedure for lithium amide conjugate addition
4.2.2. tert-Butyl (S,E)-3-[N(10)-benzylpyrrolidin-20-yl]propenoate 12.
n-BuLi (1.55 equiv) was added dropwise to a solution of the
requisite amine (1.6 equiv) in THF at ꢀ78 ꢁC. The resultant pink
solution was stirred at ꢀ78 ꢁC for 30 min before the addition of
a solution of the requisite
a,
b
-unsaturated ester (1.0 equiv) in THF at
Step 1: L-Proline 17 (5.00 g, 43.4 mmol) was added to a stirred
ꢀ78 ꢁC. The reaction mixture was then stirred at ꢀ78 ꢁC for 2 h
before the addition of satd aq NH4Cl. The reaction mixture was then
allowed to warm to rt and concentrated in vacuo. The residue was
partitioned between H2O and Et2O and the aqueous layer was
extracted with Et2O. The combined organic extracts were then
washed sequentially with 10% aq citric acid, satd aq NaHCO3 and
brine, then dried and concentrated in vacuo.
solution of NaOH (1.74 g, 43.5 mmol) in H2O (75 mL) at 0 ꢁC.
Benzoyl chloride (5.00 mL, 43.4 mmol) and a solution of NaOH
(1.74 g, 43.5 mmol) in H2O (5 mL) were added simultaneously. The
reaction mixture was stirred at 0 ꢁC for 2 h and washed with Et2O
(2ꢃ50 mL). The aqueous layer was acidified with cold 6.0 M aq HCl
(pH¼2) and extracted with EtOAc (3ꢃ50 mL). The combined
organic extracts were washed with brine (400 mL), then dried and
concentrated in vacuo to give 18 as a colourless oil (14.9 g), which
was used without purification.
4.2.1. tert-Butyl (RS,E)-3-[N(10)-benzylpyrrolidin-20-yl]propenoate12.
Step 2: A solution of 18 (14.9 g) in THF (30 mL) was added to
a suspension of LiAlH4 (5.17 g, 136 mmol) in THF (200 mL) at 0 ꢁC.
The resulting suspension was stirred at 0 ꢁC for 1 h, then the
resultant mixture was stirred at reflux for 16 h. The reaction mix-
ture was then quenched by slow addition of MeOH (2.0 mL) and
2.0 M aq NaOH (20 mL) at 0 ꢁC. The resultant white suspension was
filtered through short pad of CeliteÒ (eluent MeOH) and
Step 1: DL-Proline 17 (10.0 g, 86.9 mmol) was added to a stirred
solution of NaOH (3.48 g, 87.0 mmol) in H2O (150 mL) at 0 ꢁC.
Benzoyl chloride (10.1 mL, 86.9 mmol) and a solution of NaOH

1374
S.G. Davies et al. / Tetrahedron 69 (2013) 1369e1377
concentrated in vacuo to give 19 as a yellow oil (6.04 g, 73%), which
was used without purification.
methylbenzyl)amine (8.93 g, 42.2 mmol) in THF (90 mL) was
reacted with (RS)-12 (6.07 g, 21.1 mmol) in THF (60 mL) at ꢀ78 ꢁC to
give an 84:16 mixture of 23 and 24. Purification via flash column
chromatography (gradient elution, 1%/10% Et2O in 30e40 ꢁC
petrol) gave 23 as a colourless oil (6.60 g, 63%, >99:1 dr); nmax 2971
Step 3: DMSO (2.92 mL, 41.1 mmol) was added dropwise to
a stirred solution of (COCl)2 (3.21 mL, 37.9 mmol) in CH2Cl2 at
ꢀ78 ꢁC under nitrogen. After 20 min, a solution of 19 (6.04 g,
31.6 mmol) in CH2Cl2 (10 mL) at ꢀ78 ꢁC was added dropwise via
cannula. The reaction mixture was stirred at ꢀ78 ꢁC for 1 h before
the addition of Et3N (8.02 mL, 57.5 mmol) and subsequent warming
to rt. After 30 min, Ph3P]CHCO2tBu (12.0 g, 31.6 mmol) was added
in one portion to the reaction mixture. The resultant reaction
mixture was allowed to stir for 18 h before the addition of satd aq
NaHCO3 (100 mL). The aqueous layer was extracted with CH2Cl2
(3ꢃ100 mL) and the combined organic extracts were washed with
brine (500 mL), then dried, filtered and concentrated in vacuo.
Purification via flash column chromatography (gradient elution,
1%/10% Et2O in 30e40 ꢁC petrol) gave 12 as a colourless oil (6.92 g,
(CeH), 1720 (C]O); dH (400 MHz, CDCl3) 1.42 (3H, d, J 7.1, C(a)Me),
1.51 (9H, s, CMe3),1.66e1.76 (1H, m, C(40)HA), 1.71 (1H, dd, J 15.8,1.8,
C(2)HA), 1.77e1.95 (2H, m, C(30)HA, C(40)HB), 2.00 (1H, dd, J 15.8, 9.6,
C(2)HB), 2.12e2.19 (1H, m, C(30)HB), 2.42e2.50 (1H, m, C(50)HA),
2.78e2.88 (2H, m, C(20)H, C(50)HB), 3.44 (1H, app td, J 9.6, 1.8,
C(3)H), 3.56 (2H, AB system, J 15.2, NCH2Ph), 3.64 (2H, AB
system, J 12.8, N(10)CH2Ph), 3.78 (1H, q, J 7.1, C(
(15H, m, Ph); dC (100 MHz, CDCl3) 20.2 (C(
)Me), 23.8 (C(40)),
27.7 (C(30)), 28.2 (CMe3), 35.6 (C(2)), 50.7 (NCH2Ph), 53.0 (C(50)),
56.3 (C(3)), 58.3 (C(
)), 62.5 (N(10)CH2Ph), 67.4 (C(20)), 79.3
a)H), 7.21e7.49
a
a
(CMe3), 126.6, 126.8, 127.0, 127.9, 127.9, 128.0, 128.1, 128.3, 129.6
(o,m,p-Ph), 140.0, 141.9, 142.0 (i-Ph), 171.9 (C(1)); m/z (ESIþ) 499
([MþH]þ, 100%); HRMS (ESIþ) C33H43N2Oþ2 ([MþH]þ) requires
499.3319; found 499.3317. Further elution gave 24 as a colour-
less oil (819 mg, 8%, >99:1 dr); nmax 2972 (CeH), 1722 (C]O);
76%, >99:1 dr); ½a D25
ꢀ0.6 (c 0.7, CHCl3).
ꢂ
4.2.3. tert-Butyl (RS,SR)-3-(N-benzyl-N-isopropylamino)-3-[N(10)-
benzylpyrrolidin-20-yl]propanoate 21.
dH (400 MHz, CDCl3) 1.42 (3H, d, J 6.8, C(a)Me), 1.48 (9H, s,
CMe3), 1.54e1.69 (2H, m, C(40)H2), 1.69e1.94 (2H, m, C(30)H2),
2.11 (1H, dd, J 16.4, 8.8, C(50)HA), 2.23 (1H, dd, J 15.3, 7.3, C(2)
HA), 2.59 (1H, dd, J 15.3, 5.1, C(2)HB), 2.74e2.82 (1H, m, C(50)HB),
2.85e2.93 (1H, m, C(20)H), 3.05 (1H, d, J 13.1, N(10)CHACHBPh),
3.74e3.80 (2H, m, C(3)H, N(10)CHACHBPh), 3.88 (2H, AB system,
Following the general procedure, a solution of n-BuLi (2.5 M in
hexanes, 0.45 mL, 1.12 mmol) and N-benzyl-N-isopropylamine
(0.23 mL, 1.40 mmol) in THF (4 mL) was reacted with (RS)-12
(200 mg, 0.70 mmol) in THF (2 mL) at ꢀ78 ꢁC to give an 84:16
mixture of (RS,SR)-21 and (RS,RS)-22. Purification via flash column
chromatography (gradient elution, 1%/10% Et2O in 30e40 ꢁC
petrol) gave (RS,SR)-21 as a colourless oil (141 mg, 46%, >99:1 dr);
nmax 2965 (CeH),1721 (C]O); dH (400 MHz, CDCl3) 1.08 (3H, d, J 6.6,
CHMeA), 1.13 (3H, d, J 6.6, CHMeB), 1.57 (9H, s, CMe3), 1.64e1.89
(3H, m, C(30)HA, C(40)H2), 2.01e2.10 (1H, m, C(30)HB), 2.40e2.52
(3H, m, C(2)H2, C(50)HA), 2.77e2.84 (1H, m, C(20)H), 2.84e2.90 (1H,
m, C(50)HB), 2.93 (1H, app septet, J 6.6, CHMe2), 3.24 (1H, ddd, J 11.4,
7.8, 3.8, C(3)H), 3.60 (1H, d, J 12.9, N(10)CHACHBPh), 3.62 (2H, AB
system, J 15.2, NCH2Ph), 3.69 (1H, d, J 12.9, N(10)CHACHBPh),
7.24e7.44 (10H, m, Ph); dC (100 MHz, CDCl3) 17.7, 22.4 (CHMe2), 23.7
(C(40)), 27.7 (C(30)), 28.2 (CMe3), 37.0 (C(2)), 49.5 (CHMe2), 50.4
(NCH2Ph), 53.0 (C(50)), 56.8 (C(3)), 62.3 (N(10)CH2Ph), 67.6 (C(20)),
79.6 (CMe3), 126.5, 126.8, 128.0, 128.1, 128.3, 129.4 (o,m,p-Ph), 140.2,
142.0 (i-Ph), 172.5 (C(1)); m/z (ESIþ) 437 ([MþH]þ, 100%); HRMS
J 15.4, NCH2Ph), 4.07 (1H, q, J 6.8, C(
Ph); dC (100 MHz, CDCl3) 18.8 (C(
)Me), 23.7 (C(40)), 26.6 (C(30)),
28.2 (CMe3), 33.7 (C(2)), 51.0 (NCH2Ph), 53.4 (C(50)), 56.2 (C(3)),
59.0 (C(
)), 59.4 (N(10)CH2Ph), 66.8 (C(20)), 79.8 (CMe3), 126.4,
a)H), 7.17e7.46 (15H, m,
a
a
126.6, 126.6, 126.8, 127.9, 127.9, 128.0, 128.1, 128.9 (o,m,p-Ph),
140.2, 142.4, 144.1 (i-Ph), 172.8 (C(1)); m/z (ESIþ) 499 ([MþH]þ,
þ
100%); HRMS (ESIþ) C33H43N2O2 ([MþH]þ) requires 499.3319;
found 499.3317.
4.2.5. tert-Butyl (3R,20S,
3-[N(10)-benzylpyrrolidin-20-yl]propanoate 23.
aS)-3-[N-benzyl-N-(a-methylbenzyl)amino]-
Following the general procedure, a solution of n-BuLi (2.5 M in
hexanes, 18.9 mL, 47.3 mmol) and (S)-N-benzyl-N-( -methyl-
a
þ
(ESIþ) C28H41N2O2 ([MþH]þ) requires 437.3163; found 437.3158.
benzyl)amine (9.89 mL, 47.3 mmol) in THF (100 mL) was reacted
with a solution of (S)-12 (6.80 g, 23.7 mmol) in THF (30 mL) at
Further elution gave an 80:20 mixture of (RS,SR)-21 and (RS,RS)-22
as a colourless oil (50 mg, 16%). Data for (RS,RS)-22: dH (400 MHz,
CDCl3) [selected peaks] 1.13 (3H, d, J 6.6, CHMeA), 1.16 (3H, d, J 6.6,
CHMeB), 2.07e2.16 (1H, m, C(30)HB), 3.08 (1H, app septet, J 6.6,
CHMe2), 3.58 (1H, d, J 14.7, NCHACHBPh), 3.64 (2H, AB system, J 12.9,
N(10)CH2Ph), 3.70 (1H, d, J 14.7, NCHACHBPh).
ꢀ78 ꢁC to give (3R,20S,
aS)-23 in >99:1 dr. Purification via flash
column chromatography (gradient elution, 5%/15% Et2O in
30e40 ꢁC petrol) gave (3R,20S,
aS)-23 as a yellow oil (8.76 g, 74%,
>99:1 dr); ½a 2D5
ꢂ
ꢀ1.1 (c 0.9, CHCl3).
4.2.6. tert-Butyl (3S,20S,
a
R)-3-[N-benzyl-N-(
a-methylbenzyl)amino]-
4.2.4. tert-Butyl (3RS,20SR,
amino]-3-[N(10)-benzylpyrrolidin-20-yl]propanoate 23 and tert-butyl
aSR)-3-[N-benzyl-N-(a-methylbenzyl)-
3-[N(10)-benzylpyrrolidin-20-yl]propanoate 24.
(3RS,20RS, -methylbenzyl)amino]-3-[N(10)-
aSR)-3-[N-benzyl-N-(a
benzylpyrrolidin-20-yl]propanoate 24.
Following the general procedure, a solution of n-BuLi (2.5 M in
hexane, 0.72 mL, 1.81 mmol) and (R)-N-benzyl-N-( -methylbenzyl)
a
amine (0.38 mL, 1.81 mmol) in THF (2 mL) was reacted with a -
solution of (S)-12 (130 mg, 0.45 mmol) in THF (2 mL) at ꢀ78 ꢁC to
Following the general procedure, a solution of n-BuLi (2.5 M in
give (3S,20S,
aR)-24 in >95:5 dr. Purification via flash column
hexanes, 13.5 mL, 33.8 mmol) and (RS)-N-benzyl-N-(
a
-
chromatography (gradient elution, 1%/10% Et2O in 30e40 ꢁC

S.G. Davies et al. / Tetrahedron 69 (2013) 1369e1377
1375
petrol) gave (3S,20S,
a 2D5
ꢀ0.6 (c 1.0 in CHCl3).
a
R)-24 as a yellow oil (165 mg, 73%, >99:1 dr);
app quintet, J 8.2, C(1)H); dC (100 MHz, CDCl3) 23.0 (COMe), 26.5
(C(6)), 30.8 (C(7)), 41.2 (C(2)), 41.5 (C(5)), 51.4 (C(1)), 68.4 (C(7a)),
½
ꢂ
170.6 (NCO), 172.1 (C(3)); m/z (ESIþ) 205 ([MþNa]þ, 100%); HRMS
þ
4.2.7. (RS,SR)-1-(N-Carboxybenzylamino)pyrrolizin-3-one 26.
(ESIþ) C9H14N2NaO2
205.0943.
([MþNa]þ) requires 205.0947; found
4.2.9. tert-Butyl (RS,SR)-3-N-isopropylamino-3-[N(10)-isopropylpyr-
rolidin-20-yl]propanoate 28.
Step 1: Pd(OH)2/C (20% w/w, 785 mg) was added to a vigorously
stirred, degassed solution of (RS,SR)-23 (1.57 g, 3.15 mmol) in
1.25 M HCl/MeOH (15 mL) at rt. The resultant suspension was
stirred under hydrogen at 5 atm for 48 h. The reaction mixture was
then filtered through CeliteÒ (eluent, MeOH) and concentrated in
vacuo to give a yellow solid (785 mg).
Step 2: A solution of the residue (500 mg) in 3.0 M aq HCl
(10 mL) was heated at 90 ꢁC for 18 h, then allowed to cool to rt and
concentrated in vacuo to give 25$HCl as a yellow foam (415 mg).
Step 3: K2CO3 (1.10 g, 8.00 mmol) was added to a solution of
25$HCl (415 mg, 2.00 mmol) in PhMe (25 mL) and the resultant
mixture was heated at reflux for 18 h. The resultant suspension was
allowed to cool to rt and filtered [eluent PhMe/MeOH (v/v 3:1)],
then concentrated in vacuo to give a yellow foam (260 mg). The
residue (56 mg, 0.40 mmol) was reacted with benzyl chloroformate
Method A: Pd(OH)2/C (50% w/w, 70 mg) was added to a vigor-
ously stirred, degassed solution of (RS,SR)-23 (140 mg, 0.28 mmol)
in MeOH/acetone (10:1, 3.0 mL) at rt. The resultant suspension was
stirred under hydrogen at 1 atm for 24 h. The reaction mixture was
then filtered through CeliteÒ (eluent, MeOH) and concentrated in
vacuo to give a pale yellow oil. Purification via flash column chro-
matography (eluent CH2Cl2/MeOH, 95:5) gave 28 as a colourless oil
(59 mg, 71%, >99:1 dr); nmax 3217 (NeH), 2964 (CeH), 1725 (C]O);
dH (400 MHz, CDCl3) 0.90 (3H, d, J 6.2, NCHMeAMeB), 1.02 (3H, d,
J 6.2, NCHMeAMeB), 1.07 (3H, d, J 7.2, N0CHMeAMeB),1.09 (3H, d, J 7.2,
N0CHMeAMeB), 1.44 (9H, s, CMe3), 1.59e1.68 (3H, m, C(30)HA,
C(40)H2), 1.79e1.82 (1H, m, C(30)HB), 2.17e2.53 (1H, m, C(2)HA),
2.44e2.53 (2H, m, C(2)HB, C(50)HA), 2.74e2.86 (3H, m, C(20)H,
CHMe2, C(50)HB), 3.00 (1H, q, J 6.2, CHMe2), 3.11e3.16 (1H, m, C(3)H);
dC (100 MHz, CDCl3) 13.6, 22.5 (NCHMe2), 22.6, 23.4 (N0CHMe2), 24.4
(C(40)), 25.2 (C(30)), 28.1 (CMe3), 40.0 (C(2)), 45.4 (C(50)), 46.8, 47.7
(CHMe2), 52.8 (C(3)), 62.3 (C(20)), 80.1 (CMe3), 172.2þ(C(1)); m/z
(ESIþ) 299 ([MþH]þ, 100%); HRMS (ESIþ) C17H35N2O2 ([MþH]þ)
requires 299.2693; found 299.2690.
Method B: Pd(OH)2/C (50% by weight as supplied, 50 mg) was
added to a vigorously stirred solution of (RS,SR)-21 (100 mg,
0.23 mmol) in degassed MeOH/acetone (10:1, 3.0 mL) at rt. The
resultant suspension was stirred under hydrogen at 1 atm for 24 h.
The reaction mixture was filtered through CeliteÒ (eluent, MeOH)
and concentrated in vacuo to give a pale yellow oil. Purification via
flash column chromatography (eluent CH2Cl2/MeOH, 95:5) gave 28
as a colourless oil (68 mg, 84%, >99:1 dr).
(63 mL, 0.44 mmol) and K2CO3 (83 mg, 0.60 mmol) in THF (1 mL) at
rt for 18 h then the reaction mixture was concentrated in vacuo.
Purification via flash column chromatography (eluent CH2Cl2/
MeOH, 99:1, increased to 90:10) gave 26 as a colourless oil (40 mg,
34% from 23, >99:1 dr);18 dH (400 MHz, CDCl3) 1.52e1.68 (1H, m,
C(7)HA), 1.90e2.24 (3H, m, C(7)HB, C(6)H2), 2.62 (1H, dd, J 15.9, 10.6,
C(2)HA), 2.78 (1H, dd, J 15.9, 8.3, C(2)HB), 2.98e3.08 (1H, m, C(5)HA),
3.46e3.61 (1H, m, C(5)HB), 3.61e3.75 (1H, m, C(7a)H), 3.95e4.15
(1H, m, C(1)H), 5.10 (2H, AB system, J 12.0, OCH2Ph), 5.26 (1H, d, J
5.6, NH), 7.29e7.37 (5H, m, Ph); dC (100 MHz, CDCl3) 26.6 (C(6)),
30.7 (C(7)), 41.5 (C(5)), 41.6 (C(2)), 53.3 (C(1)), 67.0 (OCH2Ph), 68.3
(C(7a)),128.2,128.3,128.6 (o,m,p-Ph),136.1 (i-Ph),155.8 (NCO),171.6
(C(3)); m/z (ESIþ) 297 ([MþNa]þ, 100%); HRMS (ESIþ)
þ
C
15H18N2NaO3 ([MþNa]þ) requires 297.1210; found 297.1208.
4.2.8. (RS,SR)-1-Acetylaminopyrrolizin-3-one 27.
4.2.10. (RS,RS)-1-(N-Carboxybenzylamino)pyrrolizin-3-one 30.
Step 1: Pd(OH)2/C (20% w/w, 300 mg) was added to a vigorously
stirred, degassed solution of (RS,SR)-23 (600 mg, 1.20 mmol) in
1.25 M HCl/MeOH (5 mL) at rt. The resultant suspension was stirred
under hydrogen at 5 atm for 48 h. The reaction mixture was then
filtered through CeliteÒ (eluent, MeOH) and concentrated in vacuo
to give a yellow solid (295 mg).
Step 1: Pd(OH)2/C (50% w/w, 125 mg) was added to a vigorously
stirred, degassed solution of (RS,RS)-24 (250 mg, 0.50 mmol) in
1.25 M HCl/MeOH (3 mL) at rt. The resultant suspension was stirred
under hydrogen at 5 atm for 48 h. The reaction mixture was then
filtered through CeliteÒ (eluent, MeOH) and concentrated in vacuo
to give a yellow solid (122 mg).
Step 2: A solution of the residue (122 mg) in 3.0 M aq HCl (5 mL)
was heated at 90 ꢁC for 18 h, then allowed to cool to rt and
concentrated in vacuo to give 29 as a yellow foam (70 mg) after
purification via Dowex 50WX8-100 (eluent 1.0 M NH4OH).
Step 3: The residue (35 mg, 0.25 mmol) was reacted with benzyl
Step 2: A solution of the residue (295 mg) in 3.0 M aq HCl
(10 mL) was heated at 90 ꢁC for 18 h, then allowed to cool to rt and
concentrated in vacuo to give 25$HCl as a yellow foam (210 mg).
Step 3: Ac2O (0.17 mL, 1.80 mmol) was added to a solution of
25$HCl (105 mg, 0.60 mmol) in pyridine (1.36 mL, 16.8 mmol) and
the resultant mixture was stirred at rt for 18 h. The reaction mixture
was cooled to 0 ꢁC and MeOH was added. The resultant mixture was
stirred for 30 min, then concentrated in vacuo. Purification via
flash column chromatography (eluent CH2Cl2/MeOH, 99:1,
increased to 90:10) gave 27 as a colourless oil (57 mg, 52% from 23,
>99:1 dr); nmax 3272 (NeH), 2976 (CeH), 1655 (C]O); dH
(400 MHz, CDCl3) 1.53e1.66 (1H, m, C(7)HA), 1.99 (3H, s, COMe),
1.91e2.21 (3H, m, C(7)HB, C(6)H2), 2.63 (1H, dd, J 16.2, 10.2, C(2)HA),
2.77 (1H, dd, J 16.2, 8.2, C(2)HB), 2.98e3.07 (1H, m, C(5)HA),
3.50e3.59 (1H, m, C(5)HB), 3.64 (1H, app q, J 8.2, C(7a)H), 4.29 (1H,
chloroformate (40 mL, 0.28 mmol) and K2CO3 (52 mg, 0.38 mmol) in
THF (1 mL) at rt for 16 h then the reaction mixture was concentrated
in vacuo. Purification via flash column chromatography (eluent
CH2Cl2/MeOH, 99:1, increased to 90:10) gave 30 as a colourless oil
(9 mg, 14% from 24, >99:1 dr); nmax 3281 (NeH), 2953 (CeH), 1673

1376
S.G. Davies et al. / Tetrahedron 69 (2013) 1369e1377
(C]O); dH (500 MHz, CDCl3) 1.52e1.62 (1H, m, C(7)HA), 1.78e1.88
(1H, m, C(7)HB), 2.00e2.12 (2H, m, C(6)H2), 2.27 (1H, app d, J 17.0,
C(2)HA), 3.00e3.14 (2H, m, C(2)HB, C(5)HA), 3.44e3.52 (1H, m,
C(5)HB), 4.03e4.12 (1H, m, C(7a)H), 4.39e4.47 (1H, m, C(1)H), 5.11
(2H, AB system, J 12.3, OCH2Ph), 5.41 (1H, br s, NH), 7.29e7.40 (5H,
m, Ph); dC (125 MHz, CDCl3) 24.6 (C(7)), 27.0 (C(6)), 41.0 (C(5)), 42.4
(C(2)), 49.1 (C(1)), 65.9 (C(7a)), 67.0 (OCH2Ph), 128.1, 128.2, 128.5
HB), 3.24e3.40 (2H, m, C(5)H2), 3.74e3.82 (1H, m, C(1)H),
3.89e3.94 (1H, m, C(7a)H); dH (100 MHz, D2O) 23.3 (C(6)), 27.9
(C(7)), 34.7 (C(2)), 46.6 (C(5)), 48.7 (C(1)), 60.6 (C(7a)), 172.9 (C(3)).
Step 3: A solution of 25$HCl (100 mg, 0.57 mmol) in THF (3 mL)
at 0 ꢁC was treated with DIBAL-H (1.0 M in THF, 5.7 mL, 5.7 mmol).
The resultant mixture was stirred at rt for 18 h then Rochelle’s salt
(0.2 mL) was added. The resultant white suspension was stirred for
2 h and then filtered through CeliteÒ (eluent MeOH) and concen-
trated in vacuo to give 33 as a white solid (134 mg).
(o,m,p-Ph), 136.2 (i-Ph), 155.9 (NCO), 171.5 (C(3)); m/z (ESIþ) 297
þ
([MþNa]þ, 100%); HRMS (ESIþ) C15H18N2NaO3
([MþNa]þ)
requires 297.1210; found 297.1208.
Step 4: DMAP (35 mg, 0.28 mmol) and trans-4-methoxycin-
namic acid (119 mg, 0.65 mmol) were added to a solution of 33
(134 mg) in CH2Cl2 (3 mL). The resultant mixture was cooled to 0 ꢁC
before DCC (229 mg, 1.11 mmol) was added in one portion. The
resultant mixture was stirred at 0 ꢁC for 15 min, then allowed to
warm to rt and stirred at rt for 3 h. The resultant precipitate was
filtered and the filtrate was diluted with satd aq NaHCO3 (10 mL).
The aqueous layer was then extracted with CH2Cl2 (3ꢃ10 mL) and
the combined organic extracts were dried and concentrated in
vacuo. Purification via flash column chromatography (gradient
elution, 0%/15% MeOH in 1% NH4OH in CH2Cl2) gave (1R,7aS)-4 as
a pale yellow solid (76 mg, 49% from 25$HCl); mp 166e168 ꢁC; {lit.8
mp 170e171 ꢁC; lit.9 mp 165 ꢁC; lit.5 for enantiomer mp 186 ꢁC
4.2.11. (RS,RS)-1-Acetylaminopyrrolizin-3-one 31.
Step 1: Pd(OH)2/C (50% w/w, 125 mg) was added to a vigorously
stirred, degassed solution of (RS,RS)-24 (250 mg, 0.50 mmol) in
1.25 M HCl/MeOH (3 mL) at rt. The resultant suspension was stirred
under hydrogen at 5 atm for 48 h. The reaction mixture was then
filtered through CeliteÒ (eluent, MeOH) and concentrated in vacuo
to give a yellow solid (122 mg).
Step 2: A solution of the residue (122 mg) in 3.0 M aq HCl (5 mL)
was heated at 90 ꢁC for 18 h, then allowed to cool to rt and con-
centrated in vacuo to give 29 as a yellow foam (70 mg) after puri-
fication via Dowex 50WX8-100 (eluent 1.0 M NH4OH).
(acetone)}; ½a 2D0
ꢂ
ꢀ49 (c 0.2, EtOH); {lit.5 for (þ)-absouline isolated
from the natural source [
a]
D þ56 (c 1, EtOH); lit.6 ½a D20
ꢀ34 (c 0.91,
ꢂ
CHCl3); lit.6 for enantiomer ½a 2D0
ꢂ
þ26 (c 1.05, CHCl3); lit.8 for
enantiomer ½a 2D0
ꢂ
þ46.0 (c 1.2, CHCl3); lit.9
½
a 2D0
ꢂ
ꢀ51 (c 0.4, EtOH);
lit.9
½
a 2D0
ꢂ
ꢀ37 (c 1.8 in CHCl3); lit.10
[
a
]
D
ꢀ48 (c 0.8, EtOH)}; nmax
3249 (NeH), 2927 (CeH), 1660 (C]O), 1603 (C]C); dH
(400 MHz, CDCl3) 1.61e1.92 (4H, m, C(2)HA, C(6)H2, C(7)HA),
1.98e2.10 (1H, m, C(7)HB), 2.20e2.31 (1H, m, C(2)HB), 2.59e2.69
(2H, m, C(3)HA, C(5)HA), 3.01e3.09 (1H, m, C(5)HB), 3.21e3.39
(2H, m, C(3)HB, C(7a)H), 3.83 (3H, s, OMe), 4.23e4.30 (1H, m,
C(1)H), 6.08 (1H, br d, NH), 6.29 (1H, d, J 15.6, C(20)H), 6.89
(2H, d, J 8.5, Ar), 7.47 (2H, d, J 8.5, Ar), 7.59 (1H, d, J 15.6, C(30)
H); dC (100 MHz, CDCl3) 25.4 (C(6)), 30.6 (C(7)), 33.0 (C(2)), 53.3
(C(5)), 55.2 (C(1)), 55.3 (C(3), OMe), 71.1 (C(7a)), 114.2 (C(300),
C(500)), 118.1 (C(20)), 127.5 (C(100)), 129.4 (C(200), C(600)), 140þ.8
(C(30)), 160.9 (C(400)), 166.1 (C(10)); m/z (ESIþ) 287 ([MþH] ,
Step 3: Ac2O (70 mL, 0.75 mmol) was added to a solution of 29
(35 mg, 0.25 mmol) in pyridine (0.57 mL, 7.0 mmol) and stirred at rt
for 18 h. The reaction mixture was cooled to 0 ꢁC and MeOH was
added. The resultant mixture was stirred for 30 min, then con-
centrated in vacuo. Purification via flash column chromatography
(eluent CH2Cl2/MeOH, 99:1, increased to 90:10) gave 31 as a col-
ourless oil (24 mg, 53% from 24, >99:1 dr); nmax 3271 (NeH), 2978
(CeH),1649 (C]O); dH (500 MHz, CDCl3) 1.53e1.63 (1H, m, C(7)HA),
1.80e1.88 (1H, m, C(7)HB), 2.02 (3H, s, COMe), 2.04e2.17 (2H, m,
C(6)H2), 2.22 (1H, app d, J 16.7, C(2)HA), 3.02e3.11 (2H, m, C(2)HB,
C(5)HA), 3.37e3.45 (1H, m, C(5)HB), 4.06e4.12 (1H, m, C(7a)H), 4.64
(1H, app q, J 6.9, C(1)H), 7.70e7.81 (1H, m, NH); dC (125 MHz, CDCl3)
22.8 (COMe), 24.8 (C(7)), 27.2 (C(6)), 41.1 (C(5)), 42.5 (C(2)), 47.7
(C(1)), 66.2 (C(7a)), 170.5 (NCO), 172.3 (C(3)); m/z (ESIþ) 205
([MþNa]þ, 100%); HRMS (ESIþ) C9H14N2NaO2þ ([MþNa]þ) requires
205.0947; found 205.0945.
þ
100%); HRMS (ESIþ) C17H23N2O2 ([MþH]þ) requires 287.1754;
found 287.1753.
Acknowledgements
The authors would like to thank the EPSRC and SCI-Ink for
a Dorothy Hodgkin Postgraduate Award (J.Y.).
4.2.12. (1R,7aS)-1-[30-(400-Methoxyphenyl)acrylamido] pyrrolizine
[(ꢀ)-absouline] 4.
References and notes
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chemistry 2001, 56, 265.
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A. A.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1.
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5. Ikhiri, K.; Ahond, A.; Poupat, C.; Potier, P.; Pusset, J.; Sevenet, T. J. Nat. Prod. 1987,
50, 626.
Step 1: Pd(OH2)/C (50% w/w, 1.75 g) was added to a stirred,
degassed solution of (3R,20S,
aS)-23 (3.51 g, 7.04 mmol) in 1.25 M
ꢀ
HCl/MeOH (20 mL). The resulting suspension was stirred under H2
(5 atm) for 48 h. The reaction mixture was then filtered through
CeliteÒ [eluent MeOH] and concentrated in vacuo to give a yellow
solid (2.47 g), which was used without purification.
6. Christine, C.; Ikhiri, K.; Ahond, A.; Al Mourabit, A.; Poupat, C.; Potier, P. Tetra-
hedron 2000, 56, 1837.
7. Muniz, K.; Streuff, J.; Chavez, P.; Hovelmann, C. H. Chem. Asian J. 2008, 3, 1248.
8. Tang, T.; Ruan, Y.-P.; Ye, J.-L.; Huang, P.-Q. Synlett 2005, 231.
~
ꢀ
€
9. Vargas-Sanchez, M.; Couty, F.; Evano, G.; Prim, D.; Marrot, J. Org. Lett. 2005, 7, 5861.
10. Eklund, E. J.; Pike, R. D.; Scheerer, J. R. Tetrahedron Lett. 2012, 53, 4644.
11. Tang, T.; Zhu, C.; Huang, P.-Q. Heterocycles 2004, 64, 121.
Step 2: The residue (2.47 g) was then dissolved in 3.0 M aq HCl
(50 mL) and the resultant solution was heated at 90 ꢁC for 18 h.
The reaction mixture was then allowed to cool to rt and
concentrated in vacuo to give 25$HCl as a white solid [2.07 g,
12. Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; Yin, J. Org. Lett. 2012, 14, 218.
13. The (E)-configuration within 12 was assigned based on the diagnostic value of
the olefinic coupling constant (J2,3¼15.7 Hz).
quant from (3R, 20S, S)-23]; mp 238e239 ꢁC; nmax 3361 (NeH),
a
14. (a) Davies, S. G.; Díez, D.; El Hammouni, M. M.; Garner, A. C.; Garrido, N. M.;
Long, M. J. C.; Morrison, R. M.; Smith, A. D.; Sweet, M. J.; Withey, J. M. Chem.
Commun. 2003, 2410; (b) Davies, S. G.; Garner, A. C.; Long, M. J. C.; Smith, A. D.;
Sweet, M. J.; Withey, J. M. Org. Biomol. Chem. 2004, 2, 3355; (c) Davies, S. G.;
Garner, A. C.; Long, M. J. C.; Morrison, R. M.; Roberts, P. M.; Savory, E. D.; Smith,
1738 (C]O); dH (400 MHz, D2O) 1.71e1.82 (1H, m, C(7)HA),
1.91e2.00 (1H, m, C(6)HA), 2.01e2.09 (1H, m, C(6)HB), 2.20e2.31
(1H, m, C(7)HB), 2.81e2.88 (1H, m, C(2)HA), 2.91e2.98 (1H, m, C(2)

S.G. Davies et al. / Tetrahedron 69 (2013) 1369e1377
1377
A. D.; Sweet, M. J.; Withey, J. M. Org. Biomol. Chem. 2005, 3, 2762; (d) Aye, Y.;
Davies, S. G.; Garner, A. C.; Roberts, P. M.; Smith, A. D.; Thomson, J. E. Org. Bi-
omol. Chem. 2008, 6, 2195; (e) Abraham, E.; Davies, S. G.; Docherty, A. J.; Ling, K.
B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Toms, S. M. Tetrahedron:
Asymmetry 2008, 19, 1356; (f) Davies, S. G.; Durbin, M. J.; Hartman, S. J. S.;
Matsuno, A.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.; Toms, S.
M. Tetrahedron: Asymmetry 2008, 19, 2870.
21. The ee of a,b-unsaturated ester (S)-12 was determined to be >98% ee form 400
MHz 1H NMR spectroscopic analysis in the presence of the chiral solvating
agent (R)-O-acetylmandelic acid, and comparison with an authentic racemic
sample of (RS)-12 under identical conditions.
22. Studies into the ‘matched’ and ‘mismatched’ parings in other doubly diaster-
eoselective lithium amide conjugate addition reactions have also been in-
vestigated, see: (a) Davies, S. G.; Durbin, M. J.; Goddard, E. C.; Kelly, P. M.;
Kurosawa, W.; Lee, J. A.; Nicholson, R. L.; Price, P. M.; Roberts, P. M.; Russell, A.
J.; Scott, P. M.; Smith, A. D. Org. Biomol. Chem. 2009, 7, 761; (b) Davies, S. G.; Lee,
J. A.; Roberts, P. M.; Thomson, J. E.; Yin, J. Tetrahedron 2011, 67, 6382; (c) Davies,
S. G.; Fletcher, A. M.; Hermann, G. J.; Poce, G.; Roberts, P. M.; Smith, A. D.;
Sweet, M. J.; Thomson, J. E. Tetrahedron: Asymmetry 2010, 21, 1635; (d) Davies,
S. G.; Nicholson, R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Savory, E. D.;
Smith, A. D.; Thomson, J. E. Tetrahedron: Asymmetry 2009, 20, 758; (e) Davies, S.
G.; Foster, E. M.; Frost, A. B.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Biomol.
Chem. 2012, 10, 6186.
15. Lithium N-benzyl-N-isopropylamide 20 was employed as it has been previously
shown by us to very closely mimic lithium N-benzyl-N-(a-methyl benzyl)amide
7; for example, see: Ref. 12.
16. Horeau, A. Tetrahedron 1975, 31, 1307.
17. Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1994, 5, 1999.
18. Giri, N.; Petrini, M.; Profeta, R. J. Org. Chem. 2004, 69, 7303.
19. The 13C NMR spectroscopic data showed excellent agreement, with the exception
of the signal corresponding to C(2); the reason for this discrepancy is unclear.
20. The diastereoselective lithium amide conjugate addition reaction has been
reviewed, see: (a) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry
2005, 16, 2833; (b) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E.
Tetrahedron: Asymmetry 2012, 23, 1111.
23. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
24. Deur, C. J.; Miller, M. W.; Hegedus, L. S. J. Org. Chem. 1996, 61, 2871.