Synthesis of (-)-Cytisine Using a 6- endo aza-Michael Addition

Article abstract of DOI:10.1021/acs.joc.8b01156

An asymmetric synthesis of (-)-cytisine has been achieved. The piperidine C-ring was formed using a stereodivergent intramolecular 6-endo aza-Michael addition. The B-ring was established by intramolecular pyridine N-alkylation. The absolute stereochemistry was established by an Evans acyl oxazolidinone enolate alkylation reaction that proceeded with an unexpected stereochemical outcome due to participation of the pyridine nitrogen lone pair.

Full text of DOI:10.1021/acs.joc.8b01156

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Article
A Synthesis of (-)-Cytisine using a 6-endo aza-Michael Addition
Viktor Barat, Daniel Csokas, and Roderick Wayland Bates
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01156 • Publication Date (Web): 12 Jul 2018
Downloaded from http://pubs.acs.org on July 12, 2018
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A Synthesis of (-)-Cytisine using a 6-endo aza-Michael Addition
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Viktor Barát, Dániel Csókás and Roderick W. Bates*
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Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371.
Eꢀmail: roderick@ntu.edu.sg
ABSTRACT: An asymmetric synthesis of (ꢀ)ꢀcytisine has been achieved. The piperidine Cꢀ
ring was formed using a stereodivergent intramolecular 6ꢀendo azaꢀMichael addition. The Bꢀ
ring was established by intramolecular pyridine Nꢀalkylation. The absolute stereochemistry
was established by an Evans acyl oxazolidinone enolate alkylation reaction that proceeded
with an unexpected stereochemical outcome due to participation of the pyridine nitrogen lone
pair.
Introduction
An asymmetric synthesis of (ꢀ)ꢀcytisine has been achieved. The piperidine Cꢀring was formed
using a stereodivergent intramolecular 6ꢀendo azaꢀMichael addition. The Bꢀring was
established by intramolecular pyridine Nꢀalkylation. The absolute stereochemistry was
established by an Evans acyl oxazolidinone enolate alkylation reaction that proceeded with
an unexpected stereochemical outcome due to participation of the pyridine nitrogen lone pair.
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Amongst the lupin alkaloids, cytisine 1 (Fig. 1) has received the most attention as it has
been known for the longest time and has attracted attention due to its biological activities.
This alkaloid has been the subject of a number of syntheses, the earliest of which is due to
van Tamelen.1 The chemistry of cytisine 1 has also been the subject of two reviews,2 and a
further synthesis has appeared since then.3
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Van Tamelen’s synthesis involved formation of a pyridinium salt to close the Bꢀring, and
an intramolecular azaꢀMichael addition in a 6ꢀendoꢀtrig fashion to generate the Cꢀring by Nꢀ
C2 bond formation. This addition involved the use of a vinyl pyridine as the Michael
acceptor. We were interested in the use of a strategically quite distinct azaꢀMichael addition
to form the NꢀC4 bond.4 This particular disconnection appears underexploited.2 In particular
we were interested to understand the stereochemical outcome of this reaction and to know
whether stereodivergent processes might be possible to form either the cis or trans
disubstituted piperidines. A logical extension is to render this approach asymmetric.
FIGURE 1. Cytisine
Results and Discussion
Commercially available 2ꢀbromoꢀ6ꢀmethyl pyridine 2 was acylated on treatment with diethyl
carbonate in the presence of base to give ester 3 (Scheme 1).5 Alkylation of the
corresponding enolate with 1ꢀbromoꢀ2ꢀiodoꢀ2ꢀpropene 46 could then be easily achieved. The
ester group was then reduced to give alcohol 6 which was converted into the toluene
sulfonamide 8a by a Mitsunobuꢀdeacylation sequence.7 Although the Mitsunobu reaction
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proceeded excellently using diꢀisoꢀpropylazodicarboxylate, separation of the product from
the diacylhydrazine byꢀproduct was difficult and tedious. We, therefore, found it to be more
practical to employ diꢀtꢀbutylazodicarboxylate8 and decompose the byꢀproduct by treatment
with trifluoroacetic acid. We also prepared the corresponding oꢀnitrobenzene sulfonamide
8b.9,10 The only significant difference between the two series of reactions in the sequence was
the unexpected lower reactivity of the nitro compounds in Mitsunobu reaction, converting 6b
to 8b. At this point, the vinyl iodides 8 were converted into the required Michael acceptor.
Palladium catalysed carbonylation at atmospheric pressure and at ambient temperature gave
the acrylate derivatives 9ab with no reaction observed at the bromine position.11 We then
attempted the base catalysed cyclisation (Table 1) of acrylate 9a. While no reaction was
observed using iꢀPr2NEt, treatment with DBU in THF at 60 °C gave a ca. 3:2 mixture of
diastereoisomers of the piperidine products 10a in favour of the cisꢀisomer (entry 1). The
ratio increased to ca. 3:1 when the reaction was conducted in dioxane at reflux (entry 2). As
the cis isomer would be expected to be the thermodynamic product, we were concerned that
we might have reached the equilibrium position and further optimisation would be fruitless.
Indeed, DFT calculations showed that the energy difference between the two isomers is 0.46
kcal/mol. This difference corresponds to the ratio obtained. We also examined the use of
cesium carbonate in THF. At room temperature, an almost 1:1 ratio was obtained (entry 4).
Lowering the temperature to ꢀ5°C gave a ca. 10:1 ratio in favour of the trans isomer of 10a
(entry 5). The intramolecular azaꢀMichael addition is, therefore, genuinely stereodivergent,
giving different diastereoisomers as the major product under different conditions.
Subsequently, however, we encountered difficulties in reproducing the result described in
entry 5. We ascribe this to loss of activity of the cesium carbonate on repeated exposure to
air, presumably due to hydration. Gratifyingly, a stereochemically similar result could be
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obtained using LHMDS in THF at 0°C (entry 6). The nosyl protected compound 9b gave
very similar results to the tosyl protected compound 9a (entries 3 and 7).
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While it is easily understood that the cisꢀisomer of piperidine 10 will be
thermodynamically more stable, the fact that the transꢀisomer is kinetically favoured is less
obvious. This phenomenon has been explained by Zimmerman in terms of protonation of
exoꢀcyclic enols from the less hindered face.12
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TABLE 1. The Intramolecular aza-Michael addition
entry substrate
base
solvent
temperature/ trans: cis
°C
ratio
38:62
27:73c
37:63c
43:57
91:9
1
DBUa
THF
60
100
100
RT
ꢀ5
9a
2
DBUa
dioxane
dioxane
THF
9a
3
DBUa
9b
b
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Cs2CO3
Cs2CO3
9a
9a
9a
9b
b
THF
LiHMDSb
LiHMDSb
THF
0
95:5c
95:5c
THF
0
a. 0.5 equiv.; b. 1 equiv.; c. the products were obtained quantitatively in both cases.
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SCHEME 1. Synthesis of (±)-Cytisine.
The esters 10 were found to be unstable during column chromatography on silica gel. The
corresponding alcohols in the tosyl series, 11a, obtained by LiAlH4 reduction, could be
separated. The cis isomer of 11a was found to be crystalline and we were able to obtain an Xꢀ
ray structure to confirm the stereochemistry.13 To proceed with the synthesis, however,
separation of the alcohols 11 was unnecessary. This has already been shown by van
Tamelen.1 Treatment of the alcohols 11ab with mesyl chloride gave the mesylates. In
contrast to an earlier mesylation of a pyridyl alcohol in this laboratory,14 spontaneous
cyclisation was not observed, presumably due to the bisꢀequatorial conformation. Cyclisation
of only the cis isomer occurred on warming to 60°C in chloroform. The resulting pyridinium
salt was then hydrolysed under mildly basic conditions to generate the pyridone 12.15 The
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unreacted transꢀmesylate and the pyridone 12 were easily separable. Initially working with
the toluene sulfonamide 12a, we now faced the need to deprotect the piperidine nitrogen
atom. Reduction with magnesium in methanol resulted in a complex mixture indicating that
reduction of the pyridone was also occurring. As this deprotection proceeds via an SET
mechanism, we arranged for the measurement of the reduction potentials of a pyridone and a
sulfonamide by cyclic voltametry. NꢀMethylpyridone and Nꢀtosyl piperidine were selected as
model compounds for this study. Both compounds underwent irreversible reduction and to
our disappointment, the reduction potentials differed by a mere 30 mV (see S.I.). We,
therefore, concluded that we would be unable to achieve a selective reduction. The synthesis
of cytisine 1 was completed using the oꢀnitrobenzene sulfonamide protected material 12b.
Deprotection was then achieved in excellent yield by treatment with thiophenol in the
presence of base. The spectroscopic data for the synthetic (±)ꢀcytisine 1 were in excellent
agreement with published data.
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To convert our synthesis into an asymmetric synthesis, we returned to the ester alkylation
step, intending to adapt this step using the methods of Evans (Scheme 2).16 Ester 3 was
hydrolysed using lithium hydroxide followed by precise neutralisation with trifluoroacetic
acid. This careful control of reagent stoichiometry avoided the problems associated with the
amphoteric nature of acid 13. The resulting acid 13 was coupled with the (R)ꢀoxazolidinone
14. As formation of the acid chloride of 13 was challenging due to hydrochloride salt
formation, we used carbonyl diimidazole to activate the acid group, followed by
displacement with the potassium salt of oxazolidinone 14. Pivaloyl chloride may also be
employed and gives a similar yield. We then studied the diastereoselective alkylation of
imide 15 with 1ꢀbromoꢀ2ꢀiodoꢀ2ꢀpropene 4 under various conditions (Table 2). It may be
noted that, due to the presence of the pyridine moiety, weaker bases than those typically used
in Evans chemistry can be used. No conversion to the product 16 was observed using
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LiHMDS or NaHMDS in THF at temperatures from ꢀ78°C to ꢀ60°C (entries 1ꢀ4). When a
reaction using LiHMDS was allowed to warm to room temperature, decomposition was
observed (entry 5). Alkylation was observed at ꢀ40 °C (entries 6ꢀ14). Diastereoselectivity
varied from 58:44 (entry 6) to 82:18 (entries 13, 14). Conversion varied from 33% in
THF/toluene (entry 6) to 93% in DMF (entry 14), showing the importance of a polar solvent.
The optimum result was obtained using KOtꢀBu in DMF at ꢀ40°C (entry 14) giving the major
diastereoisomer 16a in 65% isolated yield. It may be noted that the diastereoselectivity is
eroded when the reaction time is prolonged, indicating some epimerisation occurs under the
reaction conditions.17
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TABLE 2. Diastereoselective Alkylation of Acyl Oxazolidinone 15.
entry base
solvent
temperature/
°C
time/h
conversion dr
/%
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10
LiHMDS
THF
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NaHMDS THF
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0
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NaOtꢀBu
LiHMDS
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KHMDS
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THF
THF
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0
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ꢀ78 to 25
100
33
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70
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88
dec.
58:44
67:33
67:33
69:31
70:30
PhMe/THF ꢀ40
THF
THF
ꢀ40
ꢀ40
NaHMDS DME/THF ꢀ40
KOtꢀBu Pyr/THF ꢀ40
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KOtꢀBu
KOtꢀBu
KOtꢀBu
KOtꢀBu
DME/THF ꢀ40
20
20
44
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81
93
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93
72:28
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70:30
82:18
DMF/THF ꢀ40
DME/THF ꢀ40
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DMF
ꢀ40
SCHEME 2. Asymmetric alkylation chemistry.
These observations are in contrast with the usually highly reliable behavior of Evans’
oxazolidones. Fortunately, the two diastereoisomers were separable and the major product
16a of the alkylation reaction proved to be crystalline. Determination of the Xꢀray structure
of 16a13 resulted in a final surprise, as the major diastereoisomer was found to have
stereochemistry opposite to that predicted by the Evans model. In that model, the enolate
counter ion is chelated between the enolate oxygen and the oxazolidonone carbonyl, as in
chelate 17a.18 In the present case, a second, better donor is present: the pyridine nitrogen.19 If
the counter ion is chelated between the enolate oxygen and the pyridine nitrogen, the
oxazolidone is then free to rotate, as shown in chelates 17b and 17c (Scheme 3). It may be
postulated that rotation will occur to contraꢀalign the carbonyl and enolate dipoles, resulting
in selectivity opposite to the Evans’ model. To the best of our knowledge, there is but a single
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example of the alkylation of a pyridylacetyl oxazolidinone using the methodology of Evans.20
We note that those authors did not report the degree of diastereoselectivity nor provide any
independent confirmation of the sense of diastereoselectivity.
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SCHEME 3. Rationalisation of the unexpected outcome of alkylation.
With the alkylated compound 16a in hand, we were able to carry out reductive cleavage of
the oxazolidinone. This reaction occurred without epimerisation. The stereochemical purity
of the alcohol (S)-6 was determined to be ≥95% e.e. by formation of Mosher’s esters.21 The
enantiomerically enriched material (S)-6 was then carried through the steps described, using
the oꢀnitrobenzene sulfonamide protecting group, to give (ꢀ)ꢀcytisine 1. In addition to the
spectroscopic data, the melting point (151ꢀ153 °C; lit.22 154.5ꢀ155.5 °C) and optical rotation
(ꢀ72 (c 0.5, CHCl3; lit.23 ꢀ76 (c 1.0, CHCl3)) were now also in excellent agreement with those
reported.
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Conclusion
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An asymmetric synthesis of (ꢀ)ꢀcytisine has been completed using a stereodivergent 6ꢀendoꢀ
trig intramolecular azaꢀMichael addition to establish the piperidine. As this is a truly
stereodivergent reaction, it can in future be applied to other members of the lupin family. The
absolute stereochemistry was established by an Evans asymmetric alkylation which proceeds
with selectivity opposite to that expected due to an alternative competing chelation mode.
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Experimental
Reactions requiring anhydrous conditions were carried out under a nitrogen atmosphere using
ovenꢀdried glassware. Anhydrous CH2Cl2was freshly distilled from CaH2 under nitrogen,
anhydrous THF was freshly distilled from sodium metal and benzophenone under nitrogen,
anhydrous toluene was freshly distilled from sodium metal under nitrogen. Anhydrous
ethanol and methanol were distilled from activated magnesium under nitrogen. All other
chemicals were obtained commercially and used as received. Column chromatography was
1
carried out on silica gel, 230ꢀ400 mesh. H NMR spectra were recorded at 300 or 400 MHz
(and the corresponding frequencies for 13C) in CDCl3. Chemical shifts are given in ppm and
1
coupling constants in Hz (CDCl3 H: 7.26 ppm, 13C: 77.23 ppm). Mass spectra were recorded
in ESI+ mode with a TOF mass analyzer. Optical rotations were measured using a 10 mm
pathꢀlength cell at 589 nm.
(ꢀ)ꢀCytisine (-)-1: A mixture of Nꢀnosyl (ꢀ)ꢀcytisine (R,R)-12b (70 mg, 0.186 mmol),
thiophenol (0.057 mL, 0.56 mmol) and K2CO3 (77 mg, 0.56 mmol) in MeCN:DMF 4:1 (5
mL) was heated to 45°C for 30 min. The mixture was cooled to room temperature and
transferred to a silica column and eluted using an eluent of CHCl3:MeOH:NH3(aq) 90:10:1 to
give (ꢀ)ꢀcytisine as a colorless crystalline compound (34 mg, 0.179 mmol, 96%).
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1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 8.8, 6.7 Hz, 1H), 6.45 (d, J = 8.9 Hz, 1H), 6.00
(d, J = 6.8 Hz, 1H), 4.12 (d, J = 15.6 Hz, 1H), 3.90 (dd, J = 15.6, 6.6 Hz, 1H), 3.15 – 2.95 (m,
4H), 2.90 (br, 1H), 2.32 (br, 1H), 1.56 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 163.8, 151.2,
138.9, 116.9, 105.1, 54.2, 53.2, 49.9, 35.8; FTIR (neat, cmꢀ1) υ max 3279, 1643, 1537, 1155;
MS (ESI+) m/z 191 (MH+, 100), 403 (2MNa+, 88); HRMS calcd for C11H15N2O (MH+)
191.1184; found 191.1189; mp: 151ꢀ153 °C (lit.22 154.5ꢀ155.5 °C); [α]D21 ꢀ72 (c 0.5 CHCl3)
(lit.23 [α]D23 ꢀ76 (c 1.0 CHCl3)).
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Ethyl 2ꢀ(6ꢀbromopyridinꢀ2ꢀyl)acetate 3: To a solution of diisopropylamine (15.4 mL, 110
mmol) in THF (30 mL) was added nꢀBuLi (71 mL, 107.5 mmol, 1.52 M) at ꢀ78°C and the
mixture was stirred for 1 h. To the prepared LDA solution was cannulated a chilled solution
of 2ꢀbromoꢀ6ꢀmethylpyridine (5.69 mL, 50 mmol) and diethyl carbonate (12.1 mL, 100
mmol) in THF (100 mL) while maintaining the temperature below ꢀ60°C. The mixture was
stirred at ꢀ40°C for 16 h then quenched with 200 ml sat. aq. NH4Cl solution. The mixture was
extracted with 4x50 mL EtOAc and the combined organic layers were washed with 100 mL
brine and dried over anhydrous MgSO4, then filtered and concentrated in vacuo. The crude
product is contaminated with residual diethyl carbonate which can be removed under vacuum
or via column chromatography using hexane:EtOAc 4:1. The product was obtained as a
yellow liquid (12.1 g, quantitative).24
1H NMR (396 MHz, CDCl3) δ 7.52 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.28 (d, J =
7.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.82 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 170.1, 155.8, 141.6, 139.0, 126.7, 123.0, 61.3, 43.4, 14.3; FTIR (neat, cmꢀ1) υ
max 3084, 2983, 1732, 1581, 1556, 1435, 1176, 1118, 1028; MS (ESI+) m/z 244 (MH+, 100),
246 (MH+, 97); HRMS calcd for C9H1179BrNO2 (MH+) 243.9973; found 243.9982. HRMS
calcd for C9H1181BrNO2 (MH+) 245.9953; found 245.9960.
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Ethyl 2ꢀ(6ꢀbromopyridinꢀ2ꢀyl)ꢀ4ꢀiodopentꢀ4ꢀenoate 5: To a solution of 3 (3.77 g, 15.5 mmol)
in THF (25 mL) at ꢀ78°C was added LiHMDS (16.3 mmol, 1M in THF) and stirred for 15
min. A solution of 3ꢀbromoꢀ2ꢀiodopropꢀ1ꢀene 46 (3.8 g, 15.5 mmol) in THF (14 ml) was
added and the mixture was warmed up to 23°C overnight. It was quenched with sat. aq.
NH4Cl (20 mL) and extracted with 3x15 mL EtOAc. The combined organic layers were dried
over anhydrous MgSO4 then filtered and concentrated in vacuo. The resulting red oil was
purified by column chromatography eluting with hexane:EtOAc 90:10 to give ester 5 (4.25 g,
10.4 mmol, 67%) as a yellow oil.
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1H NMR (400 MHz, CDCl3) δ 7.50 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.27 (d, J =
6.7 Hz, 1H), 6.01 (d, J = 1.4 Hz, 1H), 5.66 (d, J = 1.6 Hz, 1H), 4.20 – 4.13 (m, 2H), 3.18 (dd,
J = 14.7, 7.1 Hz, 1H), 3.06 (dd, J = 14.9, 8.0 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 171.0, 158.2, 141.8, 139.0, 128.8, 127.1, 122.6, 107.1, 61.5, 52.5, 46.8,
14.3 FTIR (neat, cmꢀ1) υ max 2981, 1643, 1556 1435, 1242, 1126, 1018, 900, 769; MS (ESI+)
m/z 410 (MH+, 79Br, 100), 412 (MH+, 95); HRMS calcd for C12H1479BrINO2 409.9253, found
409.9236.
(S)ꢀ2ꢀ(6ꢀBromopyridinꢀ2ꢀyl)ꢀ4ꢀiodopentꢀ4ꢀenꢀ1ꢀol (S)-6: To a solution of 16 (14.9 g, 27.5
mmol) in THF (150 mL) was added LiAlH4 (2.1 g, 55 mmol) portionwise over 2 h at 0°C
under a stream of N2. The mixture was quenched by dropwise addition of sat. aq. NaSO4 then
filtered through celite and concentrated in vacuo. The crude product was purified by column
chromatography eluting with hexane:EtOAc 85:15 to give alcohol 6 as a colourless oil (9.51
g, 26 mmol, 94%).
1H NMR (396 MHz, CDCl3) δ 7.50 (t, J = 7.7 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.19 (d, J =
7.9 Hz, 1H), 5.97 (d, J = 1.2 Hz, 1H), 5.68 (d, J = 1.4 Hz, 1H), 3.99 (dt, J = 11.1, 3.6 Hz,
1H), 3.89 (ddd, J = 11.1, 8.2, 5.4 Hz, 1H), 3.25 – 3.17 (m, 1H), 3.12 (dd, J = 8.2, 4.0 Hz,
1H), 2.84 (ddd, J = 22.2, 14.3, 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 163.6, 141.7,
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139.0, 128.5, 126.6, 123.0, 109.1, 64.2, 47.3, 47.0; FTIR (neat, cmꢀ1) υ max 3062, 2931, 2877,
1612, 1581, 1550, 1435, 1157, 1126, 1064, 1026, 902, 794, 740; MS (ESI+) m/z 367 (MH+,
100), 369 (MH+, 91; HRMS calcd for C10H1279BrINO (MH+) 367.9147; found 367.9149;
[α]D21 +103 (c 0.13, MeOH).
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Methyl (2ꢀ(6ꢀbromopyridinꢀ2ꢀyl)ꢀ4ꢀiodopentꢀ4ꢀenꢀ1ꢀyl)(tosyl)carbamate (7a): A solution of
alcohol 6 (2.86 g, 7.75 mmol), PPh3 (2.33 g, 8.9 mmol), DTAD (2.05 g, 8.9 mmol) and
methyl tosylcarbamate (2.04 g, 8.9 mmol) in THF (95 mL) was stirred at 23°C for 3 h then
concentrated. The residue was dissolved in CH2Cl2 (60 mL) and TFA (30 ml) was added. The
mixture was stirred at 23°C for 3 h, then concentrated and the residue was dissolved in
CH2Cl2. It was washed with sat. aq. Na2CO3, then the organic layer was dried over anhydrous
MgSO4, filtered and concentrated in vacuo. The crude product was purified by column
chromatography using a gradient of hexane:EtOAc 8:2 to 6:4 to give sulfonamide 7a as a
colourless oil which was carried through to the next step without further purification.
1H NMR 400 MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 2H), 7.47 – 7.39 (m, 1H), 7.36 – 7.27 (m,
3H), 7.13 (d, J = 7.4 Hz, 1H), 5.95 (d, J = 1.3 Hz, 1H), 5.62 (d, J = 1.3 Hz, 1H), 4.15 (dd, J =
7.2, 3.2 Hz, 2H), 3.66 – 3.56 (m, 1H), 3.55 (s, 3H), 2.99 (dd, J = 14.2, 9.3 Hz, 1H), 2.82 (dd,
J = 14.2, 4.9 Hz, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 161.1, 152.9, 144.9,
142.1, 138.7, 136.4, 129.5, 128,7, 128.6, 126.7, 123.9, 54.0, 50.8, 47.4, 46.8, 21.8; MS
(ESI+) m/z 601 (MNa+, 100), 603 (MNa+, 90); HRMS calcd for C19H2179BrIN2O4S (MH+)
578.9450; found 578.9447; HRMS calcd for C19H2181BrIN2O4S (MH+) 580.9430; found
580.9443.
Methyl
(R)ꢀ(2ꢀ(6ꢀbromopyridinꢀ2ꢀyl)ꢀ4ꢀiodopentꢀ4ꢀenꢀ1ꢀyl)((2ꢀnitrophenyl)sulfonyl)
carbamate (R)-7b:
A solution of (S)-6 (4.4 g, 12 mmol), PPh3 (3.39 g, 13.2 mmol), DTAD (3.0 g, 13.2 mmol)
and methyl ((2ꢀnitrophenyl)sulfonyl)carbamate (3.37 g, 13.2 mmol) in THF (150 mL) was
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heated at reflux for 16 h then concentrated. The residue was dissolved in CH2Cl2 (50 mL) and
TFA (25 ml) was added. The mixture was stirred until TLC indicated the disappearance of
DTAD/reduced DTAD (about 3 h, TLC visualized with molybdate stain). The mixture was
concentrated and the residue dissolved in CH2Cl2. It was washed with water and 2 M aq.
NaOH, then the organic layer was dried over anhydrous MgSO4, filtered and concentrated in
vacuo. The crude product was purified by column chromatography using gradient elution
with hexane:EtOAc 80:20, 65:35, 50:50. The product was obtained as a yellow oil that was
contaminated with the unreacted nosyl carbamate. A portion of this material was carried
through the next step without further purification.
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1H NMR (396 MHz, CDCl3) δ 8.35 – 8.29 (m, 1H), 7.82 – 7.68 (m, 3H), 7.49 (t, J = 7.7 Hz,
1H), 7.35 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 7.5 Hz, 2H), 6.00 (d, J = 7.2 Hz, 1H), 5.64 (d, J =
1.2 Hz, 1H), 4.22 (dd, J = 14.8, 9.0 Hz, 1H), 4.11 (dd, J = 14.8, 5.7 Hz, 1H), 3.70 – 3.36 (m,
4H), 3.05 (dd, J = 14.3, 9.2 Hz, 1H), 2.86 (dd, J = 14.3, 5.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 160.8, 152.4, 148.2, 142.2, 138.8, 134.9, 134.8, 132.8, 132.0, 128.7, 126.8, 127.7,
124.1, 108.0, 54.3, 51.6, 47.3, 47.0; MS (ESI+) m/z 610 (MH+, 100), 612 (MH+, 92); HRMS
calcd for C18H18N3O6S79BrI (MH+) 609.9144 found 609. 9135, HRMS calcd for
C18H18N3O6S81BrI (MH+) 611.9124 found 611. 9113.
Nꢀ(2ꢀ(6ꢀBromopyridinꢀ2ꢀyl)ꢀ4ꢀiodopentꢀ4ꢀenꢀ1ꢀyl)ꢀ4ꢀmethylbenzenesulfonamide (8a):
A
mixture of 7a (3.5 g, 6.04 mmol) and K2CO3 (1.08 g, 7.85 mmol) in MeOH (61 mL) was
stirred for 16 h at 25°C until the opaque mixture turned clear and TLC indicated the
consumption of starting material. Sat. aq. NH4Cl was added and MeOH was evaporated. The
residue was extracted 4x with chloroform. The combined organic layers were dried over
anhydrous MgSO4, filtered and concentrated to give sulphonamide 8a as a yellow oil (2.93 g,
5.62 mmol, 88%) over 2 steps from 6.
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1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 2H), 7.44 (m, J = 7.7 Hz, 1H), 7.30 (m,
3H), 7.06 (d, J = 7.1 Hz, 1H), 5.91 (d, J = 1.4 Hz, 1H), 5.64 (d, J = 1.4 Hz, 1H), 5.33 (t, J =
6.0 Hz, 1H), 3.36 – 3.15 (m, 3H), 2.79 – 2.62 (m, 2H), 2.41 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 161.9, 143.5, 141.9, 139.1, 136.8, 129.9, 129.0, 127.2, 126.8, 123.3, 107.8, 48.2,
45.3, 44.9, 21.7; FTIR (neat, cmꢀ1) υ max 3284, 1555, 1440, 1327, 1222, 1157, 1091, 900; MS
(ESI+) m/z 521 (MH+, 79Br), 523 (MH+, 81Br); HRMS calcd for C17H1979BrIN2O2S (MH+)
520.9392; found 520.9395; HRMS calcd for C17H1981BrIN2O2S 52(MH+) 2.9368; found
522.9975.
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(R)ꢀNꢀ(2ꢀ(6ꢀBromopyridinꢀ2ꢀyl)ꢀ4ꢀiodopentꢀ4ꢀenꢀ1ꢀyl)ꢀ2ꢀnitrobenzenesulfonamide (R)-8b: A
mixture of (R)-7b (1.6 g, 2.62 mmol) and K2CO3 (0.471 g, 3.4 mmol) in MeOH (25 mL) was
stirred for 2 h at 25°C until the opaque mixture turned clear and TLC indicated the
consumption of starting material. Sat. aq. NH4Cl was added and MeOH was evaporated. The
residue was extracted 4x with EtOAc. The combined organic layers were dried over
anhydrous MgSO4, filtered and concentrated to give sulphonamide 8b was obtained as a
yellow oil (1.4 g, 2.54 mmol, 67%) over 2 steps from (S)-6.
1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 7.4 Hz, 1H), 7.84 (d, J = 7.4 Hz, 1H), 7.80 – 7.69
(m, 2H), 7.43 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 5.94 (d, J
= 1.4 Hz, 1H), 5.89 (t, J = 6.1 Hz, 1H), 5.67 (d, J = 1.4 Hz, 1H), 3.49 (qdd, J = 10.3, 7.1, 5.3
Hz, 2H), 3.31 (ddd, J = 15.0, 7.8, 4.3 Hz, 1H), 2.82 – 2.65 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 161.3, 148.1, 142.3, 139.0, 133.9, 133.7, 133.1, 131.2, 129.1, 127.1, 125.6, 123.2,
107.7, 48.3, 45.9, 45.3; MS (ESI+) m/z 552 (MH+, 100), 554 (MH+, 89); 574 (MNa+, 20),
576 (MNa+, 17); HRMS calcd for C16H1679BrIN3O4S (MH+) 551.9090; found 551.9083;
[α]D21 +34 (c 0.12, MeOH)
Methyl
4ꢀ(6ꢀbromopyridinꢀ2ꢀyl)ꢀ2ꢀmethyleneꢀ5ꢀ((4ꢀmethylphenyl)sulfonamido)pentanoate
(9a): A solution of 8a (2.8 g, 5.37 mmol), Pd(PPh3)2Cl2 (188 mg, 0.26 mmol), and Et3N (1.5
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mL, 10.7 mmol) in MeOH (55 mL) was stirred overnight at 25°C under 1 atm of CO. The
mixture was concentrated and the residue was dissolved in CHCl3 then washed with water.
The organic layer was dried over anhydrous MgSO4, filtered and concentrated is vacuo. The
crude product was purified by column chromatography eluting with hexane:EtOAc 60:40 to
give ester 9a as an orange oil (2.27 g, 5.01 mmol, 93%).
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1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.3 Hz, 2H), 7.44 – 7.37 (m, 1H), 7.27 (m, 3H),
7.00 (d, J = 7.7 Hz, 1H), 6.12 (d, J = 1.1 Hz, 1H), 5.45 (m, 2H), 3.72 (s, 3H), 3.35 – 3.22 (m,
1H), 3.22 – 3.11 (m, 2H), 2.64 (qd, J = 13.7, 6.6 Hz, 2H), 2.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.3, 163.0, 143.4, 141.7, 139.0, 136.9, 136.8, 129.8, 128.6, 127.2, 126.5, 122.9,
52.1, 45.5, 44.6, 35.5, 21.6; FTIR (neat, cmꢀ1) υ
3284, 2951, 1732, 1556, 1454, 1323,
max
1203, 1157, 1091, 952, 813, 659; MS (ESI+) m/z 475 (MNa+, 79Br), 477 (MNa+, 81Br) HRMS
calcd for C19H22N2O4S79Br (MH+) 453.0484 found 453.0483, calcd for C19H22N2O2S81Br
(MH+) 455.0463 found 455.0467.
Methyl (R)ꢀ4ꢀ(6ꢀbromopyridinꢀ2ꢀyl)ꢀ2ꢀmethyleneꢀ5ꢀ((2ꢀnitrophenyl)sulfonamido)pentanoate
(R)-9b: A solution of (R)-8b (3.24 g, 5.87 mmol), Pd(PPh3)2Cl2 (206 mg, 0.29 mmol), and
Et3N (1.65 mL, 11.7 mmol) in MeOH (58 mL) was stirred overnight at 25°C under 1 atm of
CO. The mixture was concentrated and the residue was dissolved in CHCl3 then washed with
water and 2M aq. HCl. The organic layer was dried over anhydrous MgSO4, filtered and
concentrated is vacuo. The crude product was purified by column chromatography using
gradient elution with hexane:EtOAc 80:20, 60:40, 50:50 to give ester 9b as a yellow oil (2.7
g 5.57 mmol, 95%).
1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 7.0 Hz, 1H), 7.84 (d, J = 7.1 Hz, 1H), 7.78 – 7.69
(m, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 7.4 Hz, 1H), 6.15 (s,
1H), 5.94 (t, J = 6.0 Hz, 1H), 5.47 (s, 1H), 3.75 (s, 3H), 3.55 – 3.38 (m, 2H), 3.26 (qd, J =
7.4, 4.4 Hz, 1H), 2.67 (qd, J = 13.8, 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 167.3,
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52.2, 46.3, 45.0, 35.9; FTIR (neat, cmꢀ1) υ
3233, 3097, 3024, 2951, 1714, 1697,1633,
max
1583, 1537, 1435, 1359, 1122, 952, 731, 499; MS (ESI+) m/z 484 (MH+, 100), 486 (MH+,
89); HRMS calcd for C18H1979BrN3O6S (MH+) 484.0178; found 484.0193; [α]D21 +14 (c 0.17,
MeOH).
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Methyl 5ꢀ(6ꢀbromopyridinꢀ2ꢀyl)ꢀ1ꢀtosylpiperidineꢀ3ꢀcarboxylate (cis-10a): A mixture of 9a
(906 mg, 2.0 mmol) and DBU (0.15 mL, 1.0 mmol) in dioxane (20 mL) was heated to reflux
for 2h and quenched with 2 mL of sat. aq. NH4Cl. The mixture was extracted 3x with CHCl3,
then washed with water and brine. The combined organic layers were dried over anhydrous
MgSO4, filtered and concentrated to give piperidine 10a quantitatively as a mixture of
diastereomers (63:37 cis:trans).
1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 7.6 Hz, 1H), 7.33 (m,
3H), 7.12 (d, J = 7.2 Hz, 1H), 4.16 – 4.07 (m, 1H), 4.00 – 3.92 (m, 1H), 3.67 (s, 3H), 3.02
(m, 1H), 2.88 – 2.72 (m, 1H), 2.47ꢀ2.39 (m, 6H), 2.33 – 2.20 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 175.8, 162.2, 144.0, 142.1, 139.2, 133.4, 130.0, 127.7, 126.9, 121.5, 52.2, 50.4,
47.2, 43.1, 41.3, 32.5, 21.7; FTIR (neat, cmꢀ1) υ
3498, 2096, 1635, 1435, 1344, 1165,
max
1089, 985 ; MS (ESI+) m/z 475 (MNa+, 79Br), 477 (MNa+, 81Br); HRMS calcd for
C19H22N2O4S79Br (MH+) 453.0484 found 453.0498, calcd for C19H22N2O4S81Br (MH+)
455.0463 found 453.0482.
methyl 5ꢀ(6ꢀbromopyridinꢀ2ꢀyl)ꢀ1ꢀtosylpiperidineꢀ3ꢀcarboxylate (trans-10a): To a solution of
9a (125 mg, 0.27 mmol) in THF (3 mL) was added LiHMDS (0.27 mmol, 1 M) in THF at 0
°C and stirred for 60 h. The mixture was quenched with sat. aq. NH4Cl, then extracted 3x
with CHCl3, then washed brine. The combined organic layers were dried over anhydrous
MgSO4, filtered and concentrated to give piperidine 10a quantitatively as a mixture of
diastereomers (5:95 cis:trans).
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1H NMR (396 MHz, CDCl3) δ 7.64 (d, J = 8.2 Hz, 2H), 7.50 (m, 1H), 7.38 – 7.29 (m, 4H),
3.76ꢀ3.68 (m, 4H), 3.54 – 3.39 (m, 1H), 3.30 (dq, J = 13.0, 4.3 Hz, 1H), 3.10 – 2.90 (m, 2H),
2.80 – 2.69 (m, 1H), 2.44 (s, 3H), 2.20 – 2.05 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 172.8,
162.2, 143.9, 141.8, 139.1, 133.0, 129.9, 127.8, 126.5, 122.0, 52.3, 49.9, 47.6, 39.8, 38.5,
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max
(ESI+) m/z 475 (MNa+, 79Br), 477 (MNa+, 81Br); HRMS calcd for calcd for C19H22N2O4S79Br
(MH+) 453.0484 found 453.0491, calcd for C19H22N2O4S81Br (MH+) 455.0463 found
455.0473.
Methyl (3S,5R)ꢀ5ꢀ(6ꢀbromopyridinꢀ2ꢀyl)ꢀ1ꢀ((2ꢀnitrophenyl)sulfonyl)piperidineꢀ3ꢀcarboxylate
(cis-(R,S)-10b): A mixture of (R)-9b (1.0 g, 2.06 mmol) and DBU (0.154 mL, 1.03 mmol) in
dioxane (20 mL) was heated to reflux for 2h and quenched with 2 mL of sat. aq. NH4Cl. The
mixture was extracted 3x with CHCl3, then washed with water and brine. The combined
organic layers were dried over anhydrous MgSO4, filtered and concentrated to give piperidine
10b quantitatively as a mixture of diastereomers (63:37 cis:trans).
1H NMR (400 MHz, CDCl3) δ 8.07 – 7.96 (m, 1H), 7.77 – 7.67 (m, 2H), 7.68 – 7.61 (m, 1H),
7.50 (t, J = 7.7 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 4.21 – 4.14 (m,
1H), 4.07 – 4.01 (m, 1H), 3.70 (s, 3H), 3.09 – 2.98 (m, 2H), 2.98 – 2.88 (m, 1H), 2.80 (tt, J =
12.1, 3.8 Hz, 1H), 2.43 – 2.31 (m, 1H), 1.93 (dd, J = 25.2, 12.7 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 172.6, 162.0, 148.3, 142.2, 139.2, 134.0, 132.3, 132.0, 131.1, 127.0, 124.5,
121.6, 52.3, 50.0, 47.0, 43.2, 41.4, 32.9; MS (ESI+) m/z 484 (MH+, 100), 486 (MH+, 80);
HRMS calcd for C18H19BrN3O6S (MH+, 79Br) 484.0178; found 484.0181.
Methyl (3R,5R)ꢀ5ꢀ(6ꢀbromopyridinꢀ2ꢀyl)ꢀ1ꢀ((2ꢀnitrophenyl)sulfonyl)piperidineꢀ3ꢀcarboxylate
(trans-(R,R)-10b): To a solution of (R)-9b (600 mg, 1.24 mmol) in THF (12 mL) was added
LiHMDS (1.24 mmol, 1 M) in THF at 0 °C and stirred for 40 h. The mixture was quenched
with sat. aq. NH4Cl, then extracted 3x with CHCl3, then washed brine. The combined organic
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layers were dried over anhydrous MgSO4, filtered and concentrated to give piperidine 10b
quantitatively as a mixture of diastereomers (5:95 cis:trans).
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1H NMR (400 MHz, CDCl3) δ 8.02 – 7.94 (m, 1H), 7.77 – 7.67 (m, 2H), 7.67 – 7.60 (m, 1H),
7.50 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 4.09 (dd, J = 12.6,
3.5 Hz, 1H), 3.82 (dd, J = 12.1, 3.7 Hz, 1H), 3.67 (s, 3H), 3.44 – 3.19 (m, 3H), 2.93 – 2.77
(m, 1H), 2.31 (dt, J = 13.7, 4.0 Hz, 1H), 2.21 – 2.07 (m, 1H).
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(5ꢀ(6ꢀBromopyridinꢀ2ꢀyl)ꢀ1ꢀtosylpiperidinꢀ3ꢀyl)methanol (cis/trans-11a): A mixture of
cis/trans-10a (0.45 g, 1.0 mmol) was cooled to 0 °C in THF (10 mL) and LiAlH4 (76 mg, 2
mmol) was added portion wise. The mixure was quenched by careful addition of sat. aq.
Na2SO4 solution and concentrated in vacuo. The crude product was purified by column
chromatography eluting with hexane:EtOAc 1:4 to give piperidine 11a as a white foam (286
mg, 0.67 mmol, 67%).
1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.2 Hz, 4H), 7.46 (dd, J = 15.0, 7.5 Hz, 2H), 7.30
(dt, J = 7.4, 3.6 Hz, 8H), 7.11 (d, J = 7.6 Hz, 1H), 3.97 (ddd, J = 15.4, 14.4, 6.0 Hz, 1H), 3.79
(dd, J = 10.7, 8.4 Hz, 1H), 3.64 (dd, J = 10.9, 5.6 Hz, 2H), 3.61 – 3.38 (m, 3H), 3.38 – 3.24
(m, 1H), 3.24 – 3.09 (m, 2H), 3.09 – 2.93 (m, 2H), 2.88 (dd, J = 11.4, 2.9 Hz, 1H), 2.65 (s,
1H), 2.41 (s, 4H), 2.40 (s, 2H), 2.11 – 1.84 (m, 5H), 1.84 – 1.68 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 163.17, 163.06, 143.88, 143.78, 141.98, 141.78, 139.19, 139.14, 133.27,
133.14, 129.94, 129.93, 127.78, 127.73, 126.63, 126.45, 121.59, 121.54, 65.26, 63.13, 50.82,
50.13, 49.02, 47.57, 43.47, 39.39, 38.74, 35.19, 32.57, 30.93, 21.68, 21.67; FTIR (neat, cmꢀ1)
υ max 3489, 2088, 1637, 1435, 1338, 1163, 985MS (ESI+) m/z 447 (MNa+, 79Br), 449 (MNa+,
81Br); HRMS calcd for C18H22N2O3S79Br (MH+) 425.0535 found 425.0569, calcd for
C18H22N2O3S81Br (MH+) 427.0514 found 427.0538.
((3S,5R)ꢀ5ꢀ(6ꢀBromopyridinꢀ2ꢀyl)ꢀ1ꢀ((2ꢀnitrophenyl)sulfonyl)piperidinꢀ3ꢀyl)methanol
cis/trans-11b: A solution of cis/trans-10b (dr 1:1) (1.06 g, 2.19 mmol) in THF (22 mL) was
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cooled to 0 °C and LiAlH4 (0.166 g, 4.38 mmol) was added portion wise over 1 h. The
mixture was quenched by careful addition of sat. aq. Na2SO4 solution and concentrated in
vacuo. The residue was purified by column chromatography eluting with
CH2Cl2:MeOH:NH3(aq) 95:5:1 to give piperidine 11b as a yellow oil (696 mg, 1.52 mmol, dr
1:1, 70%).
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1H NMR (400 MHz, CDCl3) δ 8.05 – 7.93 (m, 2H), 7.75 – 7.66 (m, 4H), 7.66 – 7.60 (m, 2H),
7.49 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 3.6 Hz, 1H), 7.33 (d, J = 3.5 Hz, 1H), 7.21 (d, J = 7.6
Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 4.05 (m, 2H), 3.95 – 3.75 (m, 3H), 3.65 (ddd, J = 18.7,
10.6, 5.2 Hz, 2H), 3.59 – 3.47 (m, 1H), 3.30 (dd, J = 12.5, 10.1 Hz, 1H), 3.17 (ddd, J = 16.4,
9.7, 4.4 Hz, 2H), 3.10 – 2.91 (m, 2H), 2.61 (t, J = 11.9 Hz, 1H), 2.07 (m, 5H), 1.95 – 1.76 (m,
13
1H), 1.59 – 1.42 (m, 2H). C NMR (400 MHz, CDCl3) δ 162.8, 142.1, 142.0, 141.1, 139.2,
133.9, 133.8, 132.9, 132.2, 131.9, 131.2, 131.1, 131.0, 126.8, 126.7, 124.4, 124.3, 121.6.
65.2, 62.4, 50.4, 50.3, 48.8, 46.8, 43.6, 39.5, 38.9, 35.5, 33.0, 31.1; MS (ESI+) m/z 456
(MH+, 100), 458 (MH+, 92); HRMS calcd for C17H1979BrN3O5S (MH+) 456.0229; found
456.0220.
NꢀTosyl cytisine (12a): A solution of cis/trans-11a (0.37 g, 0.87 mmol) and Et3N (0.25 mL,
1.7 mmol) in DCM (16mL) was cooled to 0°C and mesyl chloride (0.1 mL, 1.2 mmol) was
added slowly. After stirring the mixture for 1 h, water was added and extracted three times
with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and
concentrated in vacuo. A white foamy material was obtained (0.42 g, quantitative). The
obtained mixture of mesylates in CHCl3 (25 mL) was heated at reflux for 4 h then cooled to
room temperature. Sat. aq. Na2CO3 (10 mL) was added and the mixture stirred for 0.5 h at
23°C. The aqueous layer was extracted three times with EtOAc, and the combined organic
layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue
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was purified by column chromatography eluting with EtOAc to give Nꢀtosyl cytisine 12a as a
tan solid (115 mg, 0.34 mmol, 54%).
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1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 7.9 Hz, 3H), 6.43 (d, J =
9.1 Hz, 1H), 5.97 (d, J = 6.7 Hz, 1H), 3.89 (dt, J = 15.7, 11.0 Hz, 2H), 3.82 – 3.70 (m, 2H),
3.04 (s, 1H), 2.74 (t, J = 13.2 Hz, 2H), 2.51 (s, 3H), 2.40 (s, 2H), 2.27 – 2.01 (m, 1H), 1.91
(d, J = 13.1 Hz, 1H), 1.72 (d, J = 13.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 163.4, 148.5,
144.0, 138.8, 133.6, 129.9, 127.5, 117.8, 105.3, 52.7, 52.0, 49.0, 34.3, 27.2, 25.3, 21.7; FTIR
(neat, cmꢀ1) υ max 3419, 2115, 1633, 1377, 1165, 1008, 948; MS (ESI+) m/z 455 (MH), 467
(MNa+); HRMS calcd for C18H21N2O3S 345.1273 found 345.1294; mp: 201ꢀ203°C.
The unreacted trans mesylate was recovered from the column (61 mg, 0.12 mmol, 29%).
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.35 (dd, J =
8.0, 4.1 Hz, 2H), 7.26 (d, J = 7.5 Hz, 1H), 4.46 – 4.25 (m, 1H), 3.71 – 3.61 (m, 1H), 3.58 –
3.46 (m, 1H), 2.45 (s, 2H), 2.38 – 2.23 (m, 1H), 2.05 (ddd, J = 15.3, 10.8, 4.8 Hz, 1H), 1.91 –
1.79 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 162.3, 144.2, 142.0, 139.3, 133.0, 130.1, 127.8,
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126.8, 121.8, 70.0, 50.4, 47.0, 39.2, 37.5, 32.8, 30.4, 21.7; FTIR (neat, cmꢀ1) υ
3419,
max
2088, 1643, 1454, 1377, 999; MS (ESI+) m/z 525 (MNa+, 79Br), 527 (MNa+, 81Br); HRMS
calcd for C19H24N2O5S279Br (MH+) 503.0310 found 503.0316, calcd for C19H24N2O5S281Br
(MH+) 505.0290 found 505.0304; mp: 140ꢀ141°C.
NꢀNosyl (ꢀ)ꢀcytisine (R,R)-12b: A 1:1 diastereomeric mixture of cis/trans-11b (0.392 g, 0.86
mmol) and Et3N (0.18 mL, 1.3 mmol) in CH2Cl2 (15mL) was cooled to 0°C and mesyl
chloride (0.08 mL, 1.03 mmol) was added slowly. After stirring the mixture for 1 h, water
was added and extracted three times with CHCl3. The combined organic layers were dried
over anhydrous MgSO4, filtered and concentrated in vacuo. A white foamy material was
obtained (0.308 g, 0.61 mmol, 77%). The obtained mixture of mesylates in CHCl3 (12 mL)
was heated at reflux for 6.5 h then cooled to room temperature. Sat. aq. Na2CO3 (10 mL) was
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added and the mixture stirred for 9 h at 23°C. The aqueous layer was extracted three times
with EtOAc, and the combined organic layers were dried over anhydrous MgSO4, filtered and
concentrated in vacuo. The residue was purified by column chromatography eluting with
CHCl3:MeOH:NH3(aq) 95:5:1 to give Nꢀnosyl cytisine (S)-12b as an orange oil (76 mg, 0.2
mmol, 33% (66% from the cis mesylate).
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1H NMR (400 MHz, CDCl3) δ 7.73 – 7.63 (m, 2H), 7.61 – 7.51 (m, 2H), 7.21 (dd, J = 9.1,
6.8 Hz, 1H), 6.33 (d, J = 9.1 Hz, 1H), 6.02 (d, J = 6.9 Hz, 1H), 4.10 (d, J = 15.8 Hz, 1H),
3.97 (dddd, J = 12.4, 4.8, 3.7, 2.0 Hz, 1H), 3.84 (ddd, J = 15.7, 6.6, 1.0 Hz, 1H), 3.20 (dd, J =
12.3, 2.1 Hz, 1H), 3.18 – 3.08 (m, 2H), 2.56 (brs, 1H), 2.09 – 1.97 (m, 1H), 1.95 – 1.84 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 163.1, 147.9, 138.6, 133.8, 131.8, 131.6, 130.3, 124.0,
117.9, 105.5, 53.0, 51.8, 48.6, 34.4, 27.2, 25.3; FTIR (neat, cmꢀ1) υ
3439, 2292, 1645,
max
1454, 1373, 1056, 956; MS (ESI+) 376 (MH+, 52), 751 (2MH+, 100); HRMS calcd for
C17H18N3O5S (MH+) 376.0967; found 376.0982; [α]D22 ꢀ184 (c 0.95 CHCl3).
The unreacted trans mesylate was recovered from the column (147 mg, 0.29 mmol, 94%).
1H NMR (400 MHz, CDCl3) δ 8.01 – 7.91 (m, 1H), 7.77 – 7.68 (m, 2H), 7.63 (d, J = 7.2 Hz,
1H), 7.50 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 4.46 – 4.29
(m, 2H), 3.87 (d, J = 12.2 Hz, 1H), 3.77 (d, J = 13.0 Hz, 1H), 3.30 – 3.15 (m, 3H), 2.39 (tt, J
= 7.5, 3.9 Hz, 1H), 2.21 – 2.08 (m, 1H), 2.01 – 1.90 (m, 1H) ; 13C NMR (100 MHz, CDCl3) δ
162.0, 148.5, 142.1, 139.3, 134.1, 132.0, 131.5, 131.1, 126.9, 124.4, 121.8; FTIR (neat, cmꢀ1)
υ
max 2852, 2358, 1581, 1519, 1155, 1060, 964, 723; MS (ESI+) m/z 534 (MH+, 100), 536
(MH+, 90); 556 (MNa+, 24), 558 (MNa+, 25); HRMS calcd for C18H21N3O7S279Br (MH+)
534.0004; found 534.9998; [α]D22 ꢀ37 (c 1.08 CHCl3).
2ꢀ(6ꢀBromopyridinꢀ2ꢀyl)acetic acid 13: 3 (47.15 g, 194 mmol) and LiOH•H2O (8.15 g, 194
mmol) was stirred in a 1:1 mixture of dioxane/H2O (250 mL) for 40 min at 25°C.
Trifluoroacetic acid (14.85 mL, 194 mmol) was added and the mixture was stirred for another
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30 min. The solvent was evaporated then H2O (100 ml) was added and extracted with 3x50
ml CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous
MgSO4, then filtered and concentrated in vacuo. The crude product was ground to fine
powder under hexane then filtered, washed with disopropyl ether and hexane. The obtained
yellow solid was dried with suction (35.4 g, 164 mmol, 85%).
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1H NMR (400 MHz, CDCl3) δ 7.62 – 7.56 (m, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 7.5
Hz, 1H), 3.89 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 173.8, 155.1, 141.2, 139.6, 127.2,
123.1, 42.5; FTIR (nujol, cmꢀ1) υ max 3433, 2100, 1643, 1454, 1384, 634; MS (ESI+) m/z 216
(MH+, 68), 218 (MH+, 100); mp 84ꢀ86°C.24
(R)ꢀ4ꢀBenzylꢀ3ꢀ(2ꢀ(6ꢀbromopyridinꢀ2ꢀyl)acetyl)oxazolidinꢀ2ꢀone (15): 13 (4.3 g, 20 mmol)
and CDI (3.24 g, 20 mmol) in THF (50 mL) was stirred for 1.5 h at 25°C. In another flask
(R)ꢀ4ꢀbenzyloxazolidinꢀ2ꢀone (3.54 g, 20 mmol) was cooled to 0°C in THF (100 mL) and
KOtꢀBu25 (20 mmol, 1M in THF) was added slowly and stirred for 1.5 h at 0°C. The solution
of the activated acid was cannulated to the oxazolidinone salt solution at 0°C and warmed up
to 25°C overnight. The mixture was quenched with sat. aq. NH4Cl (100 mL), extracted with
4x50 mL EtOAc and washed with brine (50 mL). The combined organic layers were dried
over anhydrous MgSO4, than filtered and concentrated in vauo. The crude product was
diluted with EtOAc and the unreacted acid residue was filtered off. The filtrate was
concentrated and purified by column chromatography using an eluent gradient of
hexane:EtOAc 85:15 to 73:30. Further elution with 50:50 hexane:EtOAc allowed the
recovery of unreacted oxazolidinone. Oxazolidinone 15 was obtained as a yellow solid (4.95
g, 13.2 mmol, 66%).
1H NMR (396 MHz, CDCl3) δ 7.54 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.37 – 7.17
(m, 6H), 4.71 (ddd, J = 10.5, 6.7, 3.2 Hz, 1H), 4.46 (dd, J = 22.6, 16.6 Hz, 2H), 4.28 – 4.17
(m, 2H), 3.37 (dd, J = 13.4, 3.3 Hz, 1H), 2.79 (dd, J = 13.4, 9.8 Hz, 1H); 13C NMR (100
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MHz, CDCl3) δ 169.3, 155.7, 153.5, 141.7, 139.0, 135.4, 129.6 (2C), 129.1 (2C), 127.5,
126.7, 123.5, 66.6, 55.6, 44.4, 38.0 ; FTIR (neat, cmꢀ1) υ max 2922, 2850, 1645, 1663, 1454,
1377, 530; MS (ESI+) m/z 375 (MH+, 100), 377 (MH+, 96); 397 (MNa+, 32), 399 (MNa+,
29); HRMS calcd for C17H1679BrN2O3 (MH+) 375.0344; found 375.0340. HRMS calcd for
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C17H1681BrN2O3 (MH+) 377.0324; found 374.0326; mp 100ꢀ102 °C; [α]D ꢀ179 (c 0.11,
21
MeOH).
(R)ꢀ4ꢀBenzylꢀ3ꢀ((S)ꢀ2ꢀ(6ꢀbromopyridinꢀ2ꢀyl)ꢀ4ꢀiodopentꢀ4ꢀenoyl)oxazolidinꢀ2ꢀone 16a: To a
solution of 15 (3.25 g, 8.66 mmol) in anhydrous DMF (40 mL) was added KOtꢀBu (8.66
mmol, 1M in DMF) at ꢀ40°C and the mixture was stirred for 30 min. A solution of 3ꢀbromoꢀ
2ꢀiodopropꢀ1ꢀene 4 (2.12 g, 8.66 mmol) in anhydrous DMF (10 mL) was added slowly and
the mixture was stirred at ꢀ40°C for 16 h. The reaction was quenched with sat. aq. NH4Cl
(100 mL), extracted with EtOAc (4x40 mL), washed with H2O (40 mL) and brine (40 mL).
The combined organic layers were dried over anhydrous MgSO4, then filtered and
concentrated in vacuo. The residue (dr 81:19 syn:anti) was purified by column
chromatography eluting with hexane:EtOAc 95:5 to 90:10.
Major diastereomer (16a; S,R): pale yellow crystals (3.06 g, 5.65 mmol, 65%).
1H NMR (396 MHz, CDCl3) δ 7.53 (t, J = 7.7 Hz, 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.33 – 7.21
(m, 3H), 7.16 (d, J = 6.4 Hz, 2H), 6.01 (d, J = 1.2 Hz, 1H), 5.73 (d, J = 1.3 Hz, 1H), 5.30 (t, J
= 7.1 Hz, 1H), 4.78 (ddt, J = 9.8, 7.9, 3.2 Hz, 1H), 4.22 (t, J = 8.5 Hz, 1H), 4.13 (dd, J = 9.1,
3.1 Hz, 1H), 3.43 (dd, J = 13.7, 3.2 Hz, 1H), 3.31 (dd, J = 14.6, 7.1 Hz, 1H), 2.90 (dd, J =
14.6, 7.3 Hz, 1H), 2.69 (dd, J = 13.7, 9.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.8,
158.7, 153.0, 141.5, 138.9, 135.6, 129.6 (2C), 129.3, 129.0 (2C), 127.4, 126.9, 124.1, 107.4,
66.4, 55.4, 51.2, 47.5, 37.6; FTIR (neat, cmꢀ1) υ
2954, 2924, 2063, 1643, 1633, 1359,
max
1124, 1020, 914; MS (ESI+) m/z 541 (MH+, 87), 543 (MH+, 100); 563 (MNa+, 58), 565
(MNa+, 52); HRMS calcd for C20H1979BrIN2O3 (MH+) 540.9624; found 540.9620. HRMS
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calcd for C20H1981BrIN2O3 (MH+) 542.9603; found 542.9609; mp 117ꢀ118 °C; [α]D21 ꢀ42 (c
0.11, MeOH)
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Minor diastereomer 16b (anti alkylated; R,R): yellow oil, (466 mg, 0.86 mmol, 10%).
1H NMR (396 MHz, CDCl3) δ 7.49 (t, J = 7.7 Hz, 1H), 7.39 – 7.31 (m, 4H), 7.31 – 7.20 (m,
3H), 6.05 (d, J = 1.3 Hz, 1H), 5.74 (d, J = 1.5 Hz, 1H), 5.40 (t, J = 7.2 Hz, 1H), 4.72 (dtd, J =
8.5, 5.0, 3.4 Hz, 1H), 4.14 (d, J = 5.0 Hz, 2H), 3.42 – 3.30 (m, 2H), 2.95 (dd, J = 14.2, 7.2
Hz, 1H), 2.83 (dd, J = 13.4, 9.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.8, 158.1, 153.1,
141.7, 138.9, 135.6, 129.7 (2C), 129.3, 129.2 (2C), 127.5, 127.1, 124.0, 107.2, 66.4, 56.0,
51.0, 47.6, 38.0; FTIR (neat, cmꢀ1) υ max 2850, 2104, 1643, 1633, 1462, 1373, 1053, 526; MS
(ESI+) m/z 541 (MH+, 100), 543 (MH+, 93); 563 (MNa+, 23), 565 (MNa+, 21); HRMS calcd
for C20H1979BrIN2O3 (MH+) 540.9624; found 540.9620; HRMS calcd for C20H1981BrIN2O3
(MH+) 542.9603; found 542.9613; [α]D21 ꢀ108 (c 0.09, MeOH).
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Supporting Information
Spectroscopic data for compounds 1, 3, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, Mosher’s esters of
6 and oꢀNsNHCO2Me and Xꢀray structures of compounds cis-11a and 16a; cif files for the Xꢀ
ray data; details of the DFT calculations; CV measurements of model compounds. The
Supporting Information is available free of charge on the ACS Publications website.
Acknowledgments
We thank Professor Richard Webster and Sher Li Gan for the electrochemical study. We
thank Nanyang Technological University and the Singapore Ministry of Education Academic
Research Fund Tier 1 (grant RG62/10) for financial support of this work.
References
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2
3
4
5
6
7
8
1. (a) van Tamelen, E. E.; Baran, J. S. The Synthesis Of dlꢀCytisine J. Am. Chem. Soc.
1955, 77, 4944ꢀ4945; (b) van Tamelen, E. E.; Baran, J. S. Total Synthesis of Oxygenated
Lupin Alkaloids J. Am. Chem. Soc. 1958, 80, 4659ꢀ4670.
9
2. (a) Rouden, J.; Lasne, M.ꢀC.; Blanchet, J.; Baudoux, J. (ꢀ)ꢀCytisine and Derivatives:
Synthesis, Reactivity, and Applications Chem. Rev. 2014, 114, 712ꢀ778; (b) Stead, D.;
O’Brien, P. Total synthesis of the lupin alkaloid cytisine: comparison of synthetic routes and
strategies Tetrahedron 2007, 63, 1885ꢀ1897.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3. Donets, P. A.; Cramer, N. Ligand Controlled Regiodivergent Nickel Catalyzed
Annulation of Pyridones Angew. Chem., Int. Ed. 2015, 54, 633ꢀ637.
4. To the best of our knowledge, only a modest number of examples of 6ꢀendo azaꢀMichael
additions have been reported: (a) Molander, G. A.; Ronn, M. Total Synthesis of (ꢀ)ꢀ
Cylindricine C J. Org. Chem. 1999, 64, 5183ꢀ5187; (b) Lim, J.; Kim, G. Synthetic study of (ꢀ
)ꢀlasubine II via sequential cyclization process Tetrahedron Lett. 2008, 49, 88ꢀ89; (c) Pandey,
G.; Balakrishnan, M.; Swaroop, P. S. A Suzuki CrossꢀCoupling and Intramolecular Azaꢀ
Michael Addition Reaction Sequence Towards the Synthesis of 1,10bꢀepiꢀ7ꢀ
Deoxypancratistatins and Their Cytotoxicity Studies Eur. J. Org. Chem. 2008, 5839ꢀ5847; (d)
Toya, H.; Okano, K.; Takasu, K.; Ihara, M.; Takahashi, A.; Tanaka, H.; Tokuyama, H.
Enantioselective Total Synthesis of (ꢀ)ꢀ and (+)ꢀPetrosin Org. Lett. 2010, 12, 5196ꢀ5199; (e)
Liu, S.; Hsu, H.; Chang, C.; Tsai, H. G.; Hou, D. Asymmetric Synthesis of (–)ꢀLentiginosine
by Double AzaꢀMichael Reaction Eur. J. Org. Chem. 2010, 4771ꢀ4773; (f) Fustero, S.;
Moscardo, J.; SanchezꢀRosello, M.; Flores, S.; Guerola, M.; del Pozo, C. Organocatalytic
enantioselective synthesis of quinolizidine alkaloids (+)ꢀmyrtine, (−)ꢀlupinine, and (+)ꢀ
epiepiquinamide Tetrahedron 2001, 67, 7412ꢀ7417; (g) Kalyva, M.; Zografos, A. L.;
Kapourani, E.; Giambazolias, L. D.; Papakyriakou, A.; Dive, V.; Lazarou, Y. G.; Georgiadis,
D. Probing the Mechanism of Allylic Substitution of Morita–Baylis– Hillman Acetates
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2
3
4
5
6
7
8
9
(MBHAs) by using the Silyl Phosphonite Paradigm: Scope and Applications of a Versatile
Transformation Chem. Eur. J. 2015, 21, 3278ꢀ3289; (h) Bhunia, S.; Chaudhuri, S.; Bisai, A.
Total Syntheses of Pyroclavine, Festuclavine, Lysergol, and Isolysergol via a Catalytic
Asymmetric NitroꢀMichael Reaction Chem. Eur. J. 2017, 23, 11234ꢀ11238.
5. Under the same conditions, 2ꢀmethoxyꢀ6ꢀmethylpyridine gave a mere 16% yield, thus we
were unable to intersect with the Honda synthesis: Honda, T.; Takahashi, R.; Namiki, H.
Syntheses of (+)ꢀCytisine, (−)ꢀKuraramine, (−)ꢀIsokuraramine, and (−)ꢀJussiaeiine A J. Org.
Chem. 2005, 70, 499ꢀ504.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6. Kurosu, M.; Liu, M.; Kishi, Y. Fe/Crꢀ and Co/CrꢀMediated Catalytic Asymmetric 2ꢀ
Haloallylations of Aldehydes J. Am. Chem. Soc. 2004, 126, 12248ꢀ12249.
7. Henry, J. R.; Marcon, L. R.; McIntosh, M. C.; Scola, P. M.; Harris, G. D.; Weinreb, S. M.
Mitsunobu reactions of Nꢀalkyl and Nꢀacyl sulfonamidesꢀan efficient route to protected
amines Tetrahedron Lett. 1989, 30, 5709ꢀ5712.
8. Pelletier, J. C.; Kincaid, S. Mitsunobu reaction modifications allowing product isolation
without chromatography: application to a small parallel library Tetrahedron Lett. 2000, 41,
797ꢀ800.
9. Fukuyama, T.; Jow, C.ꢀK.; Cheung, M. 2ꢀ and 4ꢀNitrobenzenesulfonamides:
Exceptionally Versatile Means for preparation of Secondary Amines and Protection of
Amines Tetrahedron Lett. 1995, 36, 6373ꢀ6374.
10. NsNHCO2Me was prepared according to a modification of the method of Li, X.; Dong,
Y.; Qu, F.; Liu, G. Synthesis of Benzofused FiveꢀRing Sultams via RhꢀCatalyzed C–H
Olefination Directed by an NꢀAcꢀSubstituted Sulfonamide Group J. Org. Chem. 2014, 80,
790ꢀ798 (see S.I.).
11. For an example of selective carbonylation of an iodide in the presence of a bromide, see
Takahashi, T.; Kusaka, S.; Doi, T.; Sunazuka, T.; Omura, S. A Combinatorial Synthesis of a
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5
Macrosphelide Library Utilizing a PalladiumꢀCatalyzed Carbonylation on a Polymer Support
Angew. Chem. Int. Ed. 2003, 42, 5230ꢀ5234.
6
7
8
9
12. Zimmermann, H. E. The Stereochemistry of the Ketonization Reaction of Enols J. Org.
Chem. 1955, 20, 549ꢀ557.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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13. Details of all Xꢀray structure determinations have been deposited with the Cambridge
Crystallographic Data Centre and may be obtained at http://www.ccdc.cam.ac.uk; CCDC
deposition numbers: cis-11a 1576570; 16a 1576602.
14. Bates, R. W.; Boonsombat, J. The pyridinium reduction route to alkaloids: a synthesis of
(±)ꢀtashiromine J. Chem. Soc., Perkin Trans. 1 2001, 654ꢀ656.
15. In contrast, van Tamelen (ref. 1) employed a monosubstituted pyridine and used an
oxidation at this point.
16. Evans, D. A.; Ennis, M. D.; Mathre, D. J. Asymmetric alkylation reactions of chiral
imide enolates. A practical approach to the enantioselective synthesis of αꢀsubstituted
carboxylic acid derivatives J. Am. Chem. Soc. 1982, 104, 1737ꢀ1739.
17. Exposure of the major isomer 16a to KOtꢀBu in THF at ꢀ40°C for 1 hour resulted in
formation of a 56:44 mixture of diastereoisomers. The minor isomer 16b was converted to a
13:87 mixture under the same conditions.
18. Tallmadge, E. H.; Collum, D. B. Evans Enolates: Solution Structures of Lithiated
OxazolidinoneꢀDerived Enolates J. Am. Chem. Soc. 2015, 137, 13087ꢀ13095.
19. For pyridine nitrogen to boron coordination in a boron enolate, see Baringhaus, K.ꢀH.;
Matter, H.; Kurz, M. Solution Structure of a Chiral Dialkylboron Enolate by NMR
Spectroscopy and Simulated Annealing:ꢀ Unusual Stabilization of This Intermediate by a
Boron−Nitrogen Interaction J. Org. Chem. 2000, 65, 5031ꢀ5033.
20. Kim, H. S.; Hong, M.; Lee, S.; Lee, H.; Suh, Y.; Oh, D.; Seo, J. H.; Choi, H.; Kim, J. Y.;
Kim, K.; Kim, J. M.; Kim, J.; Kim, Y.; Park, S.; Park, H.; Lee, J. Ringꢀtruncated deguelin
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5
derivatives as potent Hypoxia Inducible Factorꢀ1α (HIFꢀ1α) inhibitors Eur. J. Med. Chem.
2015, 104, 157ꢀ164.
6
7
8
9
21. We were unable to develop a suitable set of conditions for chiral HPLC.
22. Ing, H. R. Cytisine. Part I J. Chem. Soc. 1931, 2195ꢀ2203.
10
11
12
13
14
15
16
17
18
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50
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53
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23. Marriere, E.; Rouden, J.; Tadino, V.; Lasne, M.ꢀC. Synthesis of Analogues of (−)ꢀ
Cytisine for in Vivo Studies of Nicotinic Receptors Using Positron Emission Tomography
Org. Lett. 2000, 2, 1121ꢀ1124.
24. Badiger, S.; Chebrolu, M.; Hurth, K.; Jacquier, S.; Lueoend, R. M.; Machauer,
R.; Rueeger, H.; TintelnotꢀBlomley, M.; Veenstra, S. J.; Voegtle, M. Novel Heterocyclic
Derivatives As BACE Inhibitors and Their Preparation And Use In The Treatment Of
Neurological Disorders International patent WO2012095469 A1, July 19th, 2012.
25. Commercial KOtBu was dissolved in dry THF and filtered under a nitrogen atmosphere
to remove KOH. The solvent was removed under a stream of nitrogen
(https://chemtips.wordpress.com/tag/potassiumꢀbutoxide/).
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