Synthesis of the tricyclic core of manzamine A

Article abstract of DOI:10.1039/c4ob02582b

An efficient synthetic approach to the core structure of the manzamine alkaloids is reported, particularly in relation to incorporating a one-carbon unit in ring B from which the aldehyde in ircinal A or the beta-carboline unit in manzamine A could potent

Full text of DOI:10.1039/c4ob02582b

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Organicꢀ&ꢀBiomolecularꢀChemistry
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DOI: 10.1039/C4OB02582B
ARTICLEꢀ
Synthesis of the tricyclic core of manzamine A
Ravindra B. Pathak, Benjamin C. Dobson, Nandita Ghosh, Khalid A. Ageel,
Madeha Alshawish, Rungroj Saruengkhanphasit and Iain Coldham*
Citeꢀthis:ꢀDOI:ꢀ10.1039/x0xx00000xꢀ
Receivedꢀ00thꢀDecemberꢀ2014,ꢀ
Acceptedꢀ00thꢀDecemberꢀ2014ꢀ
An efficient synthetic approach to the core structure of the manzamine alkaloids is reported, particularly
in relation to incorporating a one-carbon unit in ring B from which the aldehyde in ircinal A or the beta-
carboline unit in manzamine A could potentially be generated. The key steps involve a Johnson–Claisen
rearrangement, enolate alkylation, dithiane alkylation and a stereoselective intramolecular dipolar
cycloaddition of an azomethine ylide, which provided the desired tricyclic ABC core structure.
DOI:ꢀ10.1039/x0xx00000xꢀ
www.rsc.org/ꢀ
Introductionꢀ
found to be a poor substrate for reaction with other secondary
amines. Fortunately, the aldehyde 10 (Scheme 2) was amenable
The alkaloid manzamine A 1 (Fig. 1) was first reported in 1986
1
and has a complex pentacyclic ABCDE structure. This
2
compound, and related alkaloids, have attracted much attention
to reaction with a variety of secondary amines including N-allyl
glycine ethyl ester, which gave the desired product 11 as the
major diastereomer. Alternatively, reaction with the primary
amine glycine ethyl ester gave the tricyclic product 12,
presumably arising from the W-shaped, rather than S-shaped,
azomethine ylide.
due to their intricate structures and their reported biological
3
activities. Several syntheses of manzamine A 1 and ircinal 2
4
have been published to date. In addition, several approaches to
the synthesis of the core ring system, especially of the ABC
5
ring system, are known.
CO Et
i
2
ii
N
OH
N
N
Boc
Boc
Boc
N
N
H
CHO
H
H
3
4
6
A
B
OH
OH
OH
I
N
N
iii
iv, v
D
C
N
N
N
Boc
H
H
E
5
1
manzamine A
2 ircinal A
S
S
S
vi
Fig.ꢀ1ꢀ
Structuresꢀofꢀsomeꢀmanzamineꢀalkaloidsꢀ
N
N
Boc
Boc
S
CHO
OH
7
8
Our research group has reported the synthesis of the core ring
H
6
7
system of manzamine A, and several simpler analogues. Our
synthetic approach has focused on the formation of rings B and
C of manzamine A by using an intramolecular dipolar
S
vii
N
Boc
S
8
9
N
cycloaddition reaction of an azomethine ylide. The alcohol 3
Me
H
was converted to the ester 4 by using a Johnson–Claisen
rearrangement (Scheme 1). The ester 4 was converted in 5 steps
to the aldehyde 8. Condensation with N-methyl glycine ethyl
CO2Et
9
6
Schemeꢀ1ꢀ Syntheticꢀ studiesꢀ withꢀ aldehydeꢀ 8. ꢀ i,ꢀ MeC(OEt)
a
3
,ꢀ xylene,ꢀ 2,4-
dinitrophenol,ꢀheat,ꢀ63%;ꢀii,ꢀLiAlH ,ꢀTHF,ꢀ89%;ꢀiii,ꢀI ,ꢀPh P,ꢀimidazole,ꢀTHF,ꢀ81%;ꢀiv,ꢀ
4
2
3
ester allowed in situ dipolar cycloaddition to give the tricyclic n-BuLi,ꢀTHF,ꢀHMPA,ꢀethylꢀ1,3-dithiane-2-carboxylate,ꢀ–40ꢀ°Cꢀtoꢀr.t.,ꢀ96%;ꢀv,ꢀLiAlH4,ꢀ
THF,ꢀ94%;ꢀvi,ꢀ(COCl)
i
ethylꢀester·HCl,ꢀ Pr
2
,ꢀDMSO,ꢀCH
NEt,ꢀPhMe,ꢀ110ꢀ°C,ꢀ45%.ꢀ
2 2 3
Cl ,ꢀ–60ꢀ°CꢀthenꢀEt N,ꢀ85%;ꢀvii,ꢀN-methylꢀglycineꢀ
compound 9 as a single stereoisomer (stereochemistry verified
by single crystal X-ray analysis). However, the aldehyde 8 was
2
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CO Et
2
S
i, ii
OMe
OMe
N
N
View Article Online
CO Et
Boc
Boc
i
DOI: 10.1039/C4OB02582B
2
ii
S
CHO
N
N
OH
OH
OH
Boc
Boc
7
10
H
3
13
OR
iii
OMe
OMe
N
1
0
Boc
OH
OH
iii
N
H
N
N
Boc
Boc
EtO2C
11
1
4
15 R = Ac
H
1
1
6 R = TBDPS
7 R = PMB
iv
OMe
OMe
N
Schemeꢀ3ꢀ Studiesꢀusingꢀdiesterꢀ13.ꢀi,ꢀ3,3-diethoxyacrylicꢀacidꢀethylꢀester,ꢀ2,4-
dinitrophenol,ꢀPhMe,ꢀ110ꢀ°C,ꢀ97%:ꢀii,ꢀLiAlH ,ꢀTHF,ꢀ64%;ꢀiii,ꢀAc O,ꢀpyridine,ꢀDMAP,ꢀ
CH Cl ,ꢀ15ꢀ68%,ꢀorꢀNaH,ꢀTHF,ꢀTBDPSCl,ꢀ16ꢀ99%,ꢀorꢀNaH,ꢀTHF,ꢀPMBCl,ꢀ17ꢀ80%.ꢀ
1
0
Boc
4
2
N
2
2
EtO2C
H
H
1
2
6
Schemeꢀ2ꢀ Syntheticꢀstudiesꢀwithꢀaldehydeꢀ10. ꢀi,ꢀNCS,ꢀAgNO
b
3
,ꢀcollidine,ꢀTHF,ꢀ As a possible way to distinguish the hydroxymethyl groups, we
MeOH,ꢀ followedꢀ directlyꢀ by:ꢀ ii,ꢀ (COCl) ,ꢀ DMSO,ꢀ CH Cl ,ꢀ –60ꢀ °Cꢀ thenꢀ Et N,ꢀ 60%ꢀ
2
2
2
3
treated the diol 14 with iodine to give the tetrahydrofuran 18
Scheme 4). This did result in some preference for cyclization
of one of the alcohols, although the selectivity was not high (dr
overꢀtwoꢀsteps;ꢀiii,ꢀN-allylꢀglycineꢀethylꢀester,ꢀPhMe,ꢀ110ꢀ°C,ꢀ43%;ꢀiv,ꢀglycineꢀethylꢀ
ester,ꢀPhMe,ꢀ130ꢀ°C,ꢀ52%.ꢀ
(
1
3
:1 by H NMR spectroscopy) and the diastereomers were
The examples in Schemes 1 and 2 demonstrate that an inseparable by column chromatography. Protection of the
intramolecular dipolar cycloaddition approach to the ABC ring alcohol gave compound 19, but these diastereomers were also
system of the manzamine alkaloids is feasible and can provide inseparable. Despite this result, we treated compound 19 with
the desired relative stereochemistry at four of the five zinc, which promoted ring opening to give the mixture (dr 3:1)
stereocentres. One aspect that we were conscious of relates to of diastereomeric alcohols 17. Therefore this method is able to
1
the need for a strategy that allows the future incorporation of provide the desired compound 17 with some selectivity (by H
the β-carboline moiety. Except for the recent approach by NMR spectroscopy the major isomer was 17a, see below),
Dixon and co-workers, the reported syntheses of manzamine A although this was insufficient for further studies.
4
make use of the alkaloid ircinal A (2). We were therefore
OH
OPMB
interested in developing chemistry that would allow the
incorporation of a one-carbon unit in ring B that could be
suitable for conversion to the aldehyde found in ircinal A (and
hence to manzamine A itself). This paper describes our efforts
in this area.
H
H
i
ii
iii
14
17
N
N
O
O
Boc
Boc
I
I
1
8
19
,ꢀCH
4
Cl,ꢀEtOH,ꢀ30ꢀ°C,ꢀ44%.ꢀ
Schemeꢀ4ꢀ Studiesꢀusingꢀdiolꢀ 14.ꢀi,ꢀiodine,ꢀNaHCO
THF,ꢀPMBCl,ꢀ17ꢀ60%;ꢀiii,ꢀZnꢀdust,ꢀNH
3
2 2
Cl ,ꢀ0ꢀ°C,ꢀ75%:ꢀii,ꢀNaH,ꢀ
Resultsꢀandꢀdiscussionꢀ
Several approaches for the synthesis of a suitable precursor
compound, with an extra carbon atom in ring B were
investigated. Ideally this one-carbon unit would be introduced
as part of the sequence of steps for the preparation of the
aldehyde used in the key intramolecular dipolar cycloaddition
step. One approach studied was to alter the Johnson–Claisen
rearrangement using the alcohol 3. Based on a literature
Two further methods to access a single diastereomer of alcohol
7 were investigated. Following precedent for asymmetric
11
1
hydroxymethylation of aldehydes, we treated the aldehyde
6b
2
0
with proline and aqueous formaldehyde (Scheme 5).
However, this gave rise not to the desired α-hydroxymethyl
aldehyde product but rather the alkene 21 resulting from
elimination. Finally, we performed a simple deprotonation of
the ester 4 with LDA followed by addition of formaldehyde
10
method, the alcohol 3 was heated with 3,3-diethoxyacrylic
acid ethyl ester in toluene for just 90 min to give an almost
quantitative yield of the diester 13 (Scheme 3). Reduction of
the diester 13 gave the diol 14. Treatment of the diol 14 with
acetic anhydride gave the monoester 15 (and 28% diester) as an
inseparable mixture of diastereomers. Reaction of the diol 14
with sodium hydride and TBDPSCl or p-methoxybenzyl
chloride gave the alcohols 16 or 17 respectively, but these also
were a 1:1 inseparable mixture of diastereomers.
(
Scheme 5). This gave a mixture of the alcohols 22 and 23
which we were delighted to find were separable by careful
column chromatography. Taking a mixture of these isomers
through the subsequent chemistry described below gave
diastereomeric products that in all cases were inseparable from
each other, so it was important to separate alcohols 22 and 23 at
this stage.
2
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OH
OPMB
H
H
CHO
CHO
View Article Online
i
CO Et
i
DOI: 10
C
.1
O
03
Et
9/C4OB
i
0
i
2582B
2
2
N
N
Boc
Boc
N
N
Boc
Boc
2
0
21
2
3
26
OH
OH
OPMB
OH
OPMB
I
H
H
H
H
CO Et
CO Et
ii
2
2
4
+
iii
iv
N
N
Boc
Boc
N
N
Boc
Boc
2
2
23
(aq),ꢀproline,ꢀDMF,ꢀr.t.,ꢀ89%:ꢀii,ꢀLDA,ꢀ
1
7a
27
Schemeꢀ5ꢀ Alkylationꢀusingꢀ20ꢀorꢀ4.ꢀi,ꢀCH
THF,ꢀCH O,ꢀ63%,ꢀ22:23ꢀ1:1.ꢀ
2
O
OPMB
OPMB
S
2
H
H
v
vi
S
S
N
N
To determine the relative stereochemistry, we took the less
polar isomer (which turned out to be compound 23, see below)
and treated it with p-bromobenzoyl chloride to obtain the ester
Boc
Boc
S
EtO C
2
OH
28
29
2
4 (Scheme 6). This compound was not crystalline, so the N-
OPMB
OPMB
Boc group was removed with acid and the crude amine product
was protected as the sulfonamide 25. This compound was
amenable to single crystal X-ray analysis, which showed the
relative stereochemistry as depicted (Fig. 2).
H
H
vii
OMe
OMe
OMe
N
N
Boc
Boc
OMe
CHO
OH
3
0
31
Br
Schemeꢀ7ꢀ Synthesisꢀofꢀtheꢀaldehydeꢀ31.ꢀi,ꢀPMBOC(=NH)CCl
ii,ꢀLiAlH ,ꢀTHF,ꢀ–5ꢀ°C,ꢀ69%;ꢀiii,ꢀI ,ꢀPh
ethylꢀ1,3-dithiane-2-carboxylate,ꢀ–78ꢀ°Cꢀtoꢀr.t.,ꢀ80%;ꢀv,ꢀLiAlH
NCS,ꢀAgNO ,ꢀcollidine,ꢀTHF,ꢀMeOH,ꢀ49%;ꢀvii,ꢀ(COCl) ,ꢀDMSO,ꢀCH
Et N,ꢀ80%.ꢀ
3
,ꢀCSA,ꢀCH
2
Cl
2
,ꢀ82%;ꢀ
4
2
3
P,ꢀimidazole,ꢀTHF,ꢀ95%;ꢀiv,ꢀn-BuLi,ꢀTHF,ꢀHMPA,ꢀ
,ꢀTHF,ꢀ–5ꢀ°C,ꢀ93%;ꢀvi,ꢀ
Cl ,ꢀ–60ꢀ°Cꢀthenꢀ
4
OH
O
3
2
2
2
H
H
O
3
CO Et
i
CO Et
2
2
N
N
Boc
Boc
With both single diastereomers 22 and 23 in hand, we selected
one of these for further study. The less polar isomer 23 was
protected to give the ether 26 and reduction gave the alcohol
2
3
24
Br
1
7a (Scheme 7). Conversion of the alcohol to the iodide 27 and
displacement with the anion of ethyl 1,3-dithiane-2-carboxylate
gave the ester 28. This was converted in three steps (reduction,
transacetalisation, and oxidation) to the aldehyde 31.
O
H
O
ii
CO Et
2
The key step in our synthetic route to the manzamine alkaloids
involves an intramolecular dipolar cycloaddition with an
aldehyde tethered to the 4-position of a 3-exomethylene-
N,ꢀ DMAP,ꢀ piperidine. We therefore heated aldehyde 31 with N-allyl
glycine ethyl ester (Scheme 8). This gave the desired tricyclic
product 32 as a single stereoisomer, but only in 20–30% yield.
The yield did improve (to 38%) by using the hydrochloride salt
N
S
O
2
2
5
Schemeꢀ6ꢀ Determinationꢀ ofꢀ stereochemistry.ꢀ i,ꢀ p-BrC H COCl,ꢀ Et
6
4
3
CH Cl ,ꢀr.t.,ꢀ99%:ꢀii,ꢀTFA,ꢀCH Cl ,ꢀr.t.,ꢀthenꢀTsCl,ꢀEt N,ꢀCH Cl ,ꢀr.t.,ꢀ62%.ꢀ
2
2
2
2
3
2
2
i
of N-allyl glycine ethyl ester together with Pr2NEt. Other
conditions (such as using excess amine or higher temperature)
did not improve the yield. In all cases the product isolated was
the enol ether 32, in which the cycloadduct had lost methanol.
It is not clear why this loses methanol in comparison with the
formation of cycloadduct 11 but sterics may play a part. As an
alternative, the aldehyde 31 was heated with glycine ethyl ester
to give the tricyclic product 33. The stereochemistry of these
cycloadducts is assumed to be as shown, based on related
chemistry (see Scheme 2).
Figureꢀ2ꢀ X-rayꢀstructureꢀofꢀ25.ꢀꢀ
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promote epimerization. The resulting 1:1 mixture of esters
OPMB
OPMB
(
chromatography.
quantitative yield) can be separated Vbieyw ArticcloelOunmlinne
H
H
DOI: 10.1039/C4OB02582B
OMe
OMe
i
N
N
Boc
Boc
OMe
OH
OMOM
CHO
N
H
H
H
3
3
1
CO Et
CO Et
EtO2C
2
i
2
ii
3
2
N
N
Boc
Boc
OPMB
H
22
34
ii
OMe
OMe
OMOM
OH
OPMB
N
1
Boc
H
H
OMOM
N
iii
iv
EtO2C
H
1
7a
N
N
H
Boc
Boc
3
3
i
Schemeꢀ8ꢀ Keyꢀ cycloadditionꢀ step.ꢀ i,ꢀ N-allylꢀ glycineꢀ ethylꢀ ester·HCl,ꢀ Pr
2
NEt,ꢀ
35
36
i
PhMe,ꢀ110ꢀ°C,ꢀ38%;ꢀii,ꢀglycineꢀethylꢀester·HCl,ꢀ Pr
2
NEt,,ꢀPhMe,ꢀ110ꢀ°C,ꢀ60%.ꢀ
i
Schemeꢀ9ꢀ Inversionꢀofꢀtheꢀundesiredꢀstereoisomer.ꢀi,ꢀMOMCl,ꢀ Pr
2
NEt,ꢀCH
,ꢀ80%;ꢀiv,ꢀHClꢀ
2 2
Cl ,ꢀ0ꢀ
°
C,ꢀ86%;ꢀii,ꢀLiAlH
4
,ꢀTHF,ꢀ–5ꢀ°C,ꢀ87%;ꢀiii,ꢀPMBOC(=NH)CCl
3
,ꢀCSA,ꢀCH
2
Cl
2
i
2ꢀM),ꢀPrOH,ꢀ60ꢀ°C,ꢀ68%.ꢀ
(
By using the same chemistry as shown in Scheme 7 with a 1:1
unseparated mixture of the diastereomers 22 and 23, resulted in
a 1:1 inseparable mixture of the aldehyde 31 and its
diastereomer. Heating this mixture of stereoisomers with N- Conclusionsꢀ
allyl glycine ethyl ester gave the same product 32 in 18% yield
We have described a short and stereoselective route to prepare
the ABC tricyclic ring system found in the manzamine
alkaloids. This extends our previous work by demonstrating
that a one-carbon unit can be located in ring B. This substituent
could potentially be used to later generate the aldehyde
functional group found in ircinal A and hence the beta-
carboline unit in manzamine A. Although a mixture of
stereoisomers was formed when introducing this one-carbon
unit, the undesired isomer can be isomerised. The key steps in
the chemistry involve a Johnson–Claisen [3,3]-sigmatropic
rearrangement, a dithiane alkylation, and an azomethine ylide
dipolar cycloaddition. The dipolar cycloaddition was successful
with only one diastereomer of the starting material. The yield in
this key step was not particularly high, but the chemistry is
significant as it demonstrates the importance of the choice of
stereochemistry in such intramolecular cycloadditions when
used as part of a synthetic endeavour.
as the only product that could be isolated. This indicates that
the stereoisomer derived from the ester 22 does not undergo the
desired intramolecular dipolar cycloaddition reaction. Analysis
of the conformations of the stereoisomers of the azomethine
ylides suggests that a favourable conformation exists from the
stereoisomer 31 (Fig. 3). The azomethine ylide derived from
the other diastereomer of 31 would suffer from greater steric
interactions. This may explain the preference for cycloaddition
only from diastereomer 31.
OMe
MeO
OMe
O
N
H
3
1
32
O
N
O
O
O
Figureꢀ3ꢀ Conformationalꢀanalysis.ꢀ
Experimentalꢀ
The successful synthesis of the tricyclic product 32 represents a tert-Butoxycarbonyl-3-methylene-piperidin-4-yl-malonic
stereoselective approach to the ABC core ring system of the acid diethyl ester 13
manzamine alkaloids. One of the drawbacks of the chemistry The alcohol 3 (10.0 g, 46.9 mmol), 3,3-diethoxyacrylic acid
discussed above is that a 1:1 mixture of the stereoisomers 22 ethyl ester (17.65 g, 93.8 mmol) and 2,4-dinitrophenol (863 mg,
and 23 is formed and only one of these is suitable for further 4.69 mmol) were heated in toluene (250 mL) at 110 °C. After
elaboration. We have found that the undesired stereoisomer 22 90 min, the solvent was evaporated and the residue was purified
can be converted to the desired compound 17a by the sequence by column chromatography, eluting with petrol–EtOAc (9:1),
of reactions shown in Scheme 9. Protection of the alcohol 22 to give the diester 13 (16.1 g, 97%) as an oil; R 0.33 [petrol–
f
–1
1
with methoxymethyl chloride followed by reduction of the ester EtOAc 7:3]; νmax (neat)/cm 2965, 2925, 2865, 1725, 1695; H
gave the alcohol 35 (Scheme 9). Protection of this alcohol as its NMR (500 MHz, CDCl ) δ = 4.89 (1H, br s), 4.71 (1H, s), 4.15
3
PMB ether and removal of the MOM group selectively with (2H, q, J 7), 4.12–4.08 (2H, m), 3.94 (1H, br d, J 14), 3.76 (1H,
mild acid gave the product 17a. Alternatively, it is possibly to d, J 14), 3.62 (1H, d, J 11), 3.53 (1H, ddd, J 13.5, 7.5, 4), 3.36–
simply treat the undesired isomer 22 with sodium ethoxide to 3.29 (1H, m), 3.02 (1H, ddd, J 11, 7.5, 4), 1.75–1.67 (1H, m),
4
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1
7
7
1
.54–1.46 (1H, m), 1.39 (9H, s), 1.22 (3H, t, J 7), 1.18 (3H, t, J was added and the mixture was extracted with CH2Cl2 (3 × 20
13
); C NMR (126 MHz, CDCl3) δ =167.9, 154.5, 142.7, 111.2, mL), dried (MgSO4) and evaporated. Purification by column
9.6, 61.5, 61.4, 53.6, 49.3 (br), 41.9 (br), 40.8, 29.5, 28.3, chromatography, eluting with petrol–EtOAc (4:1), gave the
View Article Online
DOI: 10.1039/C4OB02582B
4.0; HRMS (ES) Found MNa 378.1882. C18H29NO6Na alcohol 16 (2.59 g, 99%) as a mixture of diastereomers (1:1) as
+
+
–1
requires MNa 378.1893; LRMS m/z (ES) 378 (96%), 356 an oil; Rf 0.33 [petrol–EtOAc 4:1]; νmax (neat)/cm 3450, 3075,
1
(
4%), 256 (100%).
2930, 2855, 1690, 1665, 1590; H NMR (500 MHz, CDCl3) δ =
.68–7.63 (8H, m), 7.46–7.36 (12H, m), 4.92 (1H, s), 4.81 (1H,
s), 4.75 (1H, s), 4.64 (1H, s), 3.96–3.87 (5H, m), 3.77–3.68
7
4-(2-Hydroxy-1-hydroxymethyl-ethyl)-3-methylene-
piperidine-1-carboxylic acid tert-butyl ester 14
(7H, m), 3.57 (1H, d, J 14), 3.45–3.32 (3H, m), 3.21–3.14 (1H,
LiAlH4 (18.5 mL, 18.5 mmol, 1.0 solution in THF) was added m), 2.38–2.30 (2H, m), 2.02–1.95 (2H, m), 1.72–1.65 (1H, m),
dropwise to the diester 13 (1.64 g, 4.63 mmol) in THF (15 mL) 1.62–1.52 (2H, m), 1.43 (9H, s), 1.43 (9H, s), 1.06 (9H, s), 1.06
13
at 0 °C. After 1 h, water (10.8 mL) and NaOH (2.8 mL, 4 M) (9H, s); C NMR (126 MHz, CDCl3) δ =154.7, 143.8, 135.6,
were added and the mixture was filtered through celite. The 132.9, 129.9, 127.8, 111.6, 79.5, 65.9, 64.2, 63.2, 49.0, 41.3,
solvent was evaporated and the residue was purified by column 40.8, 40.3, 38.9, 38.6, 28.4, 28.3, 26.9, 19.2; HRMS (ES)
+
+
chromatography, eluting with EtOAc, to give the diol 14 (0.80 Found MNa 532.2856. C30H43NO4NaSi requires MNa
–1
g, 64%) as an oil; Rf 0.44 [EtOAc]; νmax (neat)/cm 3395, 532.2859; LRMS m/z (ES) 532 (100%), 510 (6%).
2
1
970, 2930, 1670, 1570; H NMR (500 MHz, CDCl3) δ = 4.96
(
1H, br s), 4.82 (1H, s), 3.97–3.86 (2H, m), 3.82–3.64 (4H, m), 4-[2-hydroxy-1-(4-methoxy-benzyloxymethyl)-ethyl]-3-
3
1
.52–3.37 (4H, m), 2.43–2.34 (1H, m), 2.06–1.94 (1H, m), methylene-piperidine-1-carboxylic acid tert-butyl ester 17
13
.79–1.55 (2H, m), 1.42 (9H, s); C NMR (126 MHz, CDCl3) NaH (180 mg, 4.48 mmol, 60% dispersion in mineral oil) was
δ = 154.9, 143.8, 111.6, 79.8, 64.6, 63.2, 41.1 (br), 40.1, 38.6, added to the diol 14 (1.21 g, 4.48 mmol) in THF (20 mL) at 0
+
8.4, 28.3; HRMS (ES) Found MNa 294.1675. C14H25NO4Na °C. After 50 min, 4-methoxybenzyl chloride (0.67 mL, 4.93
2
requires MNa , 294.1681; LRMS m/z (ES) 294 (100%).
+
mmol) and tetrabutylammonium iodide (0.165 g, 4.48 mmol) in
THF (5 mL) were dropwise. After 3 d, the solvent was
evaporated and the residue was purified by column
chromatography, eluting with petrol–EtOAc (1:1), to give the
4-(2-Acetoxy-1-hydroxymethyl-ethyl)-3-methylene-
piperidine-1-carboxylic acid tert-butyl ester 15
The diol 14 (0.20 g, 0.73 mmol), Ac2O (0.10 mL, 0.75 mmol), alcohol 17 (1.39 g, 80%) as a mixture of diastereomers (1:1) as
‒
1
pyridine (0.05 mL, 0.74 mmol) and 4-dimethylaminopyridine an oil; Rf 0.41 [petrol–EtOAc 1:1]; νmax (neat)/cm 3450, 3075,
1
~10 mg) in CH2Cl2 (10 mL) were stirred at room temperature. 2970, 2920, 2860, 1680, 1610, 1585; H NMR (500 MHz,
(
After 24 h, water (5 mL) was added and the solution was CDCl3) δ = 7.23–7.18 (4H, m), 6.88–6.84 (4H, m), 4.94 (2H, br
extracted with CH2Cl2 (3 × 5 mL). The combined organic layers s), 4.81 (1H, s), 4.75 (1H, s), 4.46–4.36 (4H, m), 3.89–3.81
were washed with brine (5 mL), dried (MgSO4), and (4H, m), 3.78 (3H, s), 3.77 (3H, s), 3.74–3.62 (4H, m), 3.58–
evaporated. The residue was purified by column 3.43 (4H, m), 3.42–3.81 (4H, m), 2.47–2.41 (1H, m), 2.41–2.35
chromatography, eluting with EtOAc, to give the acetate 15 (1H, m), 2.11–2.02 (2H, m), 1.74–1.61 (2H, m), 1.61–1.59 (1H,
1
3
(
0.15 g, 68%) as a mixture of diastereomers (1:1) as an oil; Rf m), 1.53–1.45 (1H, m), 1.43 (18H, s); C NMR (126 MHz,
‒
1
.64 [EtOAc]; νmax (neat)/cm 3445, 2950, 1735, 1665; H CDCl3) δ =163.4, 159.2, 154.7, 143.9, 129.8, 129.7, 129.2,
1
0
NMR (400 MHz, CDCl3) δ = 4.99 (2H, br s), 4.85 (1H, s), 4.83 113.8, 111.4, 79.5, 73.2, 72.4, 70.5, 64.5, 63.5, 55.2, 49.5, 48.0,
(
1H, s), 4.38 (1H, d, J 3.5), 4.35 (1H, d, J 3.5), 4.21 (1H, d, J 40.9, 39.3, 38.9, 38.7, 38.5, 28.3, 28.2; HRMS (ES) Found
+
+
4
3
3
.5), 4.18 (1H, d, J 4.5), 4.12 (1H, d, J 6.5), 4.09 (1H, d, J 6.5), MNa , 414.2257. C22H33NO5Na requires MNa , 414.2256;
.96 (1H, d, J 10), 3.93 (1H, d, J 10), 3.80–3.75 (2H, m), 3.74– LRMS m/z (ES) 414 (100%).
.72 (2H, m), 3.66–3.58 (1H, m), 3.54–3.46 (1H, m), 3.43–3.31 Alternatively, compound 17a was prepared from 26 by the
(
2H, m), 2.46–2.36 (2H, m), 2.19–2.08 (4H, m), 2.08 (6H, s), following method:
13
1
.84–1.72 (2H, m), 1.71–1.62 (2H, m), 1.42 (18H, s); C NMR LiAlH4 (96 mg, 2.5 mmol) was added to the ester 26 (1.0 g, 2.3
100 MHz, CDCl3) δ = 171.6, 171.5, 154.7, 154.6, 143.8, 143.5, mmol) in THF (20 mL) at –5 °C. After 40 min, EtOAc (10 mL)
(
1
3
3
3
11.9, 111.6, 79.7, 79.6, 63.6, 62.3, 61.5, 59.8, 40.8, 39.2, 39.0, was added, followed by addition of Na2SO4 until a while salt
+
8.9, 38.7, 28.4, 28.3, 28.2, 20.9; HRMS (ES) found: MH , precipitated. The mixture was filtered through celite. The
+
14.1974. C16H28NO5 requires MH , 314.1967; LRMS m/z (ES) solvent was evaporated and the residue was purified by column
14 (100%).
chromatography, eluting with petrol–EtOAc (1:1), to give the
alcohol 17a (0.63 g, 69%) as an oil; data for single
1
stereoisomer: H NMR (400 MHz, CDCl3) δ = 7.25 (2H, d, J
4
-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-2-hydroxy-
ethyl]-3-methylene-piperidine-1-carboxylic acid tert-butyl 8), 6.90 (2H, d, J 8), 4.97 (1H, s), 4.79 (1H, s), 4.46–4.39 (2H,
ester 16 m), 3.97 (1H, d, J 14), 3.89 (1H, dd, J 11, 2), 3.82 (3H, s),
NaH (220 mg, 5.4 mmol, 60% dispersion in oil) was added to 3.76–3.68 (2H, m), 3.60–3.47 (3H, m), 3.41–3.35 (1H, m),
the diol 14 (1.39 g, 5.2 mmol) in THF (30 mL) at 0 °C. After 50 2.50–2.45 (1H, m), 2.10–2.06 (1H, m), 1.78–1.62 (2H, m), 1.46
13
min, tert-butyldiphenylsilyl chloride (1.47 mL, 5.6 mmol) was (9H, s); C NMR (126 MHz, CDCl3) δ =159.3, 154.8, 143.8,
added dropwise. After 1 h, saturated aqueous NaHCO3 (20 mL)
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Organic & Biomolecular Chemistry
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1
3
1
29.8, 129.3, 113.9, 111.6, 79.6, 73.3, 72.6, 63.8, 55.3, 48.8 (9H, s); C NMR (100 MHz, CDCl3, major diastereomer) δ =
br), 40.9, 38.7, 38.5, 28.5, 28.3.
159.3, 154.7, 130.0, 129.2, 113.9, 80.5, 73.0, 71.0Vi,ew6A9r.t9ic,le 6O9nl.in5e,
Alternatively, compound 17a was prepared from 36 by the 55.3, 47.3, 44.1, 42.1, 41.6, 28.4, 24.4, 14.4; HRMS (ES)
(
DOI: 10.1039/C4OB02582B
+
+
following method:
Found MH 518.1392. C22H32NO5I requires MH 518.1404;
+
Aqueous hydrochloric acid (0.07 mL, 2 M) was added to the LRMS m/z (ES) 540 (100%, MNa ).
ether 36 (1.0 g, 2.30 mmol) in dry isopropyl alcohol (10 mL)
and the mixture was heated at 60 °C. After 7 h, the mixture was tert-Butyl 4-[2-(1-Oxo-propenyl)]-3-methylidenepiperidine-
allowed to cool to room temperature and saturated aqueous 1-carboxylate 21
NaHCO3 solution (20 mL) was added. The mixture was Aqueous formaldehyde (37%) (0.44 mL, 5.4 mmol) was added
6b
extracted with Et2O (3 × 50 mL). The combined organic layers to the aldehyde 20 (1.0 g, 4.2 mmol) and L-proline (48 mg,
were washed with brine (10 mL), dried (MgSO4) and 0.42 mmol) in DMF (5 mL) at room temperature. After 5 h,
evaporated. Purification by column chromatography, eluting brine (10 mL) was added. The mixture was extracted with
with petrol–EtOAc (1:1), gave the alcohol 17a (0.61 g, 68%) as EtOAc (3 × 20 mL), dried (MgSO4) and evaporated. The
an oil; data as above.
residue was purified by column chromatography, eluting with
petrol–EtOAc (4:1), to give the aldehyde 21 (938 mg, 89%) as
–1
tert-Butyl
octahydrofuro[2,3-c]pyridine-6-carboxylate 18
3-(Hydroxymethyl)-7a-(iodomethyl)- an oil; Rf 0.40 [petrol–EtOAc 4:1]; νmax (neat)/cm 2980, 1685;
1
H NMR (500 MHz, CDCl3) δ = 9.46 (1H, s), 6.21 (1H, s), 6.15
Iodine (1.73 g, 6.83 mmol) in CH2Cl2 (30 mL) was added to the (1H, s), 4.76 (1H, s), 4.34 (1H, s), 4.31 (1H, br s), 3.97 (1H, br
diol 14 (1.76 g, 6.50 mmol) in saturated aqueous NaHCO3 (20 s), 3.42 (1H, d, J 13), 3.29 (1H, dd, J 11, 5), 2.97–2.82 (1H, m),
13
mL) at 0 °C. After 2 h, aqueous Na2SO3 (10 mL) was added 1.67–1.56 (2H, m), 1.33 (9H, s); C NMR (126 MHz, CDCl3)
dropwise. The aqueous layer was separated and was extracted δ = 193.4, 154.2, 150.0, 143.4, 135.6, 109.9, 79.4, 49.7 (br),
+
with CH2Cl2 (3 × 30 mL). The organic extracts were washed 43.2, 39.9, 30.5, 28.1; HRMS (ES) Found MH 252.1589.
+
with water (20 mL) and brine (20 mL), dried (MgSO4), C14H22NO3 requires MH 252.1600; LRMS m/z (ES) 252
evaporated and purified by column chromatography, eluting (27%), 196 (100%).
with EtOAc, to give iodide 18 (1.94 g, 75%) as mixture of
4
-(1-Ethoxycarbonyl-2-hydroxy-ethyl)-3-methylene-
diastereoisomers (3:1) as an oil; Rf 0.41 (EtOAc); νmax
–1
1
piperidine-1-carboxylic acid tert-butyl ester 22 and 23
n-BuLi (8.12 mL, 16.2 mmol, 2.0 M in hexanes) was added to
diisopropylamine (2.45 mL, 17.5 mmol) in THF (50 mL) at 0
(
neat)/cm 3450, 3310, 2930, 2850, 1695, 1610; H NMR (400
MHz, CDCl3, peaks for major diastereomer listed) δ = 4.09
1H, t, J 7), 3.98–3.85 (1H, m), 3.79–3.67 (4H, m), 3.43 (1H, d,
J 11), 3.35 (1H, d, J 11), 3.08–2.98 (2H, m), 2.55–2.50 (1H,
(
°
C. After 30 min the mixture was cooled to –78 °C and the ester
13
4 (3.83 g, 13.5 mmol) was added dropwise. After 3.5 h
formaldehyde (1.22 g, 40.5 mmol) was added and the mixture
was allowed to warm to room temperature over 16 h. Saturated
NH4Cl(aq) (50 mL) was added and the mixture was extracted
with Et2O (4 × 50 mL). The organic layers were washed with
water, dried (MgSO4) and evaporated. Purification by column
chromatography, eluting with petrol–EtOAc (3:2), gave a 1:1
separable mixture of alcohols 22 and 23 (2.66 g, 63%) as oils;
Data for 22:
m), 2.13–1.92 (2H, m), 1.83–1.70 (2H, m), 1.48 (9H, s);
NMR (100 MHz, CDCl3, major diastereomer) δ = 154.8, 80.6,
C
6
9.5, 63.5, 60.4, 47.6, 45.0, 43.6, 39.3, 28.4, 24.4, 14.3; HRMS
+
+
(
ES) Found MNa 420.0631. C14H24NO4INa requires MNa
20.0648; LRMS m/z (ES) 420 (100%).
4
tert-Butyl
7a-(Iodomethyl)-3-{[(4-
methoxyphenyl)methoxy]methyl}-octahydrofuro[2,3-
c]pyridine-6-carboxylate 19
–1
Rf 0.38 [petrol–EtOAc 1:1]; νmax (neat)/cm 3455, 2940, 2875,
Alcohol 18 (2.14 g, 5.40 mmol) in THF (10 mL) was added via
cannula to sodium hydride (0.2 g, 8.6 mmol) in THF (20 mL).
After 30 min, the mixture was cooled to 0 °C and 4–
methoxybenzyl chloride (0.84 mL, 6.21 mmol) in THF (10 mL)
was added. After 30 min the mixture was allowed to warm to
room temperature. After 24 h, aqueous sodium chloride
solution (20 mL) was added. The mixture was extracted with
Et2O (3 × 20 mL), dried (MgSO4), evaporated and purified by
column chromatography, eluting with petrol–EtOAc (9:1), to
give the iodide 19 (2.6 g, 60%) as a mixture of diastereomers
1
1
730, 1690, 1675; H NMR (250 MHz, CDCl3) δ = 4.91 (1H, br
s), 4.79 (1H, s), 4.19–4.07 (2H, m), 3.97 (1H, d, J 14), 3.80–
.90 (2H, m), 3.59–3.32 (3H, m), 2.91–2.82 (1H, m), 2.80–2.67
1H, m), 2.30 (1H, br s), 1.84–1.63 (2H, m), 1.43 (9H, s), 1.23
3
(
(
13
3H, t, J 7); C NMR (63 MHz, CDCl3) δ = 174.5, 154.6,
43.1, 111.1, 79.7, 61.0, 60.6, 48.1, 41.4, 40.0, 28.4, 28.3, 14.1;
1
+
+
HRMS (ES) Found MH 314.1964. C16H28NO5 requires MH
14.1967; LRMS m/z (ES) 336 (43%), 314 (13%), 258 (100%).
Data for 23:
3
–1
–1
Rf 0.47 [petrol–EtOAc 1:1]; νmax (neat)/cm 3425, 2980, 2935,
1
1730, 1695; H NMR (500 MHz, CDCl3) δ = 4.91 (1H, br s),
(
3:1) as an oil; Rf 0.51 (petrol–EtOAc 8:2); νmax (neat)/cm
1
850, 1685, 1615, 1595; H NMR (400 MHz, CDCl3, peaks for
2
4
.80 (1H, s), 4.15–4.06 (2H, m), 4.00–3.86 (1H, m), 3.68–3.56
3H, m), 3.55–3.45 (1H, m), 3.33–3.23 (1H, m), 3.03–2.74 (2H,
m), 2.55–2.50 (1H, m), 1.68–1.57 (1H, m), 1.48–1.35 (1H, m),
major diastereomer listed) δ = 7.25 (2H, d, J 8.5), 6.90 (2H, d, J
.5), 4.45 (2H, s), 4.08 (1H, t, J 7.5), 4.10–4.06 (1H, m), 3.83
3H, s), 3.69 (1H, t, J 7.5), 3.57–3.47 (2H, m), 3.42 (1H, d, J
(
8
(
13
1.35 (9H, s), 1.21–1.15 (3H, m); C NMR (126 MHz, CDCl3)
δ = 174.2, 154.6, 142.4, 112.5, 79.7, 62.4, 60.7, 48.8 (br), 47.4,
1
2
1), 3.32 (1H, d, J 11), 3.04–2.93 (2H, m), 2.62–2.57 (1H, m),
.09–2.06 (1H, m), 1.77–1.71 (2H, m), 1.64–1.56 (1H, m), 1.48
6
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+
4
3
0.5, 40.0, 29.6, 28.3, 14.1; HRMS (ES) Found MNa
+
54.65; H, 4.91; N, 2.40; Br, 14.62; S, 5.88, C25H28BrNO6S
36.1785. C16H27NO5Na requires MNa 336.1787; LRMS m/z requires C, 54.55; H, 5.13; N, 2.54; Br, 14.52; S, 5.82. For X-
View Article Online
(
ES) 336 (100%).
ray data, see CCDC 1025236 [Monoclinic, Unit cell
DOI: 10.1039/C4OB02582B
dimensions: a 19.1472(17), b 5.7177(5), c 22.9157(19),
3
Volume 2484.3(4) Å , T = 150 K, P21/n, Z = 4].
4-[2-(4-Bromo-benzoyloxy)-1-ethoxycarbonyl-ethyl]-3-
methylene-piperidine-1-carboxylic acid tert-butyl ester 24
4
-Bromobenzoyl chloride (352 mg, 1.60 mmol), Et3N (0.27 tert-Butyl
4-{1-Hydroxy-3-[(4-
mL, 1.92 mmol) and DMAP (78 mg, 0.64 mmol) were added to methoxyphenyl)methoxy]propan-2-yl}-3-
the alcohol 22 (more polar diastereomer) (200 mg, 0.64 mmol) methylidenepiperidine-1-carboxylate 26
in CH2Cl2 (10 mL). After 3 h, saturated aqueous NaHCO3 (10 p-Methoxybenzyl alcohol (5.57 mL, 20 mmol) was added to a
mL) was added. Extraction with CH2Cl2 (3 × 10 mL), drying suspension of NaH (0.62 g, 20 mmol) in Et2O (15 mL) at room
(
MgSO4), and purification by column chromatography, eluting temperature. After 30 min, the mixture was cooled to 0 °C and
with petrol–EtOAc (4:1), gave the ester 24 (313 mg, 99%) as an Cl3CCN (4.30 mL, 20 mmol) was added. The mixture was
–1
oil; Rf 0.18 [petrol–EtOAc 7:3]; νmax (neat)/cm 3070, 2965, allowed to warm to room temperature. After 4 h, the solvent
1
925, 2865, 1725, 1695, 1590; H NMR (500 MHz, CDCl3) δ = was evaporated. Petrol (30 mL) and MeOH (0.5 mL) were
2
7
.82–7.77 (2H, m), 7.54–7.50 (2H, m), 5.01 (1H, br s), 4.92 added, the mixture was filtered through celite and the solvent
(
(
(
(
1H, br s), 4.48 (1H, dd, J 10.5, 4), 4.29 (1H, t, J 10.5), 4.15 was evaporated to give the crude trichloroacetimidate. To this
2H, q, J 7), 3.70 (1H, d, J 17), 3.65–3.56 (1H, m), 3.36–3.28 was added CH2Cl2 (35 mL), the alcohol 23 (3.1 g, 10 mmol)
1H, m), 3.20–3.14 (1H, m), 2.63 (1H, dt, J 11, 5), 1.77–1.68 and CSA (0.3 g, 1.0 mmol) at room temperature. After 18 h, the
13
1H, m), 1.56–1.49 (1H, m), 1.41 (9H, s), 1.18 (3H, t, J 7);
C
saturated aqueous NaHCO3 (15 mL) was added and the mixture
NMR (126 MHz, CDCl3) δ = 172.7, 165.3, 154.6, 141.9, 131.7, was extracted with Et2O (3 × 30 mL). The organic layers were
1
4
4
31.0, 128.6, 128.3, 113.1, 79.7, 65.1, 60.9, 48.0 (br), 44.7, washed with water and purified by column chromatography on
+
0.5, 39.9 (br), 29.7, 28.3, 14.2; HRMS (ES) Found MH silica, eluting with petrol–EtOAc (9:1), to give the ester 26
96.1313. C23H31 BrNO6 requires MH 496.1335; LRMS m/z (3.51 g, 82%) as an oil; Rf 0.50 [petrol–EtOAc 9:1]; νmax
79
+
–1
1
(
ES) 498 (25%), 496 (28%), 442 (92%), 440 (100%), 398 (neat)/cm 2990, 2935, 1725, 1695, 1610; H NMR (400 MHz,
65%), 396 (68%). CDCl3) δ = 7.21 (2H, d, J 8), 6.89 (2H, d, J 8), 4.96 (1H, s),
.83 (1H, s), 4.44 (1H, d, J 11.5), 4.39 (1H, d, J 11.5), 4.20
-Bromobenzoic acid 2-Ethoxycarbonyl-2-[3-methylene-1- (2H, q, J 7), 3.81 (3H, s), 3.70–3.66 (1H, m), 3.64–3.59 (2H,
toluene-4-sulfonyl)-piperidin-4-yl]-ethyl ester 25 m), 3.50 (1H, dd, J 9, 4.5), 3.40–3.33 (1H, m), 3.09–3.01 (1H,
TFA (0.65, 8.52 mmol) was added to the ester 24 (1.05 g, 2.13 m), 2.59–2.51 (1H, m), 1.76–1.65 (1H, m), 1.57–1.46 (2H, m),
(
4
4
(
13
mmol) in CH2Cl2 (15 mL). After 16 h, further TFA (4.0 mL, 1.45 (9H, s), 1.27 (3H, t, J 7); C NMR (100 MHz, CDCl3,
1.9 mmol) was added. After 2 h, saturated aqueous NaHCO3 some peaks could not be observed) δ = 159.3, 154.8, 144.0,
was added until the solution became basic and the mixture was 129.9, 129.3, 113.9, 111.6, 79.6, 73.3, 72.5, 65.8, 63.7, 55.3,
5
+
extracted with CH2Cl2 (4 × 20 mL). The organic layers were 38.8, 38.6, 28.4, 28.3, 15.3; HRMS (ES) Found MH 434.2538.
+
combined, dried (MgSO4) and evaporated to give the secondary C24H36NO6 requires MH 434.2543; LRMS m/z (ES) 456
+
amine as an oil. To this, in CH2Cl2 (10 mL) with Et3N (0.33 (100%, MNa ).
mL, 2.34 mmol) at room temperature, was added tosyl chloride
(
446 mg, 2.34 mmol). After 19 h, water (20 mL) was added and tert-Butyl 4-{1-Iodo-3-[(4-methoxyphenyl)methoxy]propan-
the mixture was extracted with EtOAc (3 × 15 mL), washed 2-yl}-3-methylidenepiperidine-1-carboxylate 27
with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), Imidazole (0.18 g, 2.8 mmol) and iodine (0.67 g, 2.8 mmol)
dried (MgSO4) and evaporated. Purification by column were added to PPh3 (0.74 g, 2.8 mmol) in CH2Cl2 (15 mL).
chromatography, eluting with petrol–EtOAc (4:1), followed by After 10 min, the alcohol 17a (1.0 g, 2.55 mmol) in CH2Cl2 (5
recrystallisation from EtOAc, gave the ester 25 (729 mg, 62% mL) was added. After 5 min, the mixture was filtered through
over 2 steps) as needles; m.p. 153–154 °C; Rf 0.35 [petrol– celite, washed with EtOAc (3 × 15 mL) and evaporated.
–1
EtOAc 4:1]; νmax (neat)/cm 2955, 2915, 2855, 1725, 1715, Purification by column chromatography, eluting with petrol–
1
1
650, 1585, 1340, 1155; H NMR (250 MHz, CDCl3) δ = 7.77 EtOAc (9:1), gave the iodide 27 (1.24 g, 95%) as an oil; Rf 0.40
–
1
(
2H, d, J 8), 7.63 (2H, d, J 8), 7.52 (2H, d, J 8), 7.30 (2H, d, J (petrol–EtOAc 9:1); νmax (neat)/cm 2970, 2925, 2855, 1695,
1
8
4
3
), 5.12 (1H, br s), 5.02 (1H, br s), 4.40 (1H, dd, J 10.5, 3.5), 1650, 1610, 1585; H NMR (400 MHz, CDCl3) δ = 7.27 (2H, d,
.28–4.07 (3H, m), 3.73 (1H, d, J 12.5), 3.45–3.23 (2H, m), J 8.5), 6.90 (2H, d, J 8.5), 4.99 (1H, m), 4.81 (1H, s), 4.44 (2H,
.07–2.85 (2H, m), 2.64–2.49 (1H, m), 2.42 (3H, s), 1.96–1.74 s), 3.97 (1H, d, J 14), 3.83 (3H, s), 3.82–3.76 (1H, m), 3.67
13
(
1H, m), 1.72–1.51 (1H, m), 1.18 (3H, t, J 7); C NMR (63 (1H, dd, J 10, 2.5), 3.52–3.47 (2H, m), 3.41–3.31 (2H, m), 3.22
MHz, CDCl3, one C not observed) δ = 172.3, 165.2, 143.7, (1H, dd, J 10, 5.5), 2.33–2.28 (1H, m), 1.78–1.71 (2H, m),
13
1
6
39.8, 133.2, 131.8, 131.0, 129.8, 128.4, 127.7, 114.8, 64.7, 1.62–1.55 (1H, m), 1.47 (9H, s); C NMR (100 MHz, CDCl3)
1.1, 50.3, 44.5, 42.7, 39.8, 28.9, 21.5, 14.2; HRMS (ES) δ = 159.2, 154.7, 143.5, 130.3, 129.3, 113.8, 111.9, 79.7, 73.0,
+
79
+
Found MNa 572.0706. C25H28 BrNNaO6S requires MNa
72.0718; LRMS m/z (ES) 574 (96%), 572 (100%); Found C,
70.6, 55.3, 42.0, 40.8 (br), 37.8, 28.4, 27.7, 10.4; HRMS (ES)
5
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Organic & Biomolecular Chemistry
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+
+
Found MNa 524.1262. C22H32NO4INa requires MNa
24.1274; LRMS m/z (ES) 524 (100%).
tert-Butyl
4-{5-Hydroxy-4,4-dimethoxy-1-[(4-
5
methoxyphenyl)methoxy]pentan-2-yl}-3-
methylidenepiperidine-1-carboxylate 30
tert-Butyl 4-{1-[2-(Ethoxycarbonyl)-1,3-dithian-2-yl]-3-[(4- The alcohol 29 (1.15 g, 2.20 mmol) in THF (10 mL) was added
View Article Online
DOI: 10.1039/C4OB02582B
methoxyphenyl)methoxy]propan-2-yl}-3-
methylidenepiperidine-1-carboxylate 28
to AgNO3 (1.70 g, 5.17 mmol), 2,4,6-collidine (2.33 mL, 17.6
mmol) and N-chlorosuccinimide (1.15 g, 8.80 mmol) in THF
To a solution of ethyl 1,3-dithiane-2-carboxylate (0.80 mL, (20 mL) and MeOH (30 mL) at 0 °C. After 1 h, saturated
.08 mmol) in THF (20 mL) at –78 °C was added nBuLi (2.0 aqueous Na2CO3 (15 mL) and brine (15 mL) were added and
5
mL, 5.08 mmol, 2.5 M in hexane) and HMPA (CAUTION, the mixture was filtered through celite, washed with CH2Cl2,
toxic) (3.1 mL, 17.6 mmol). After 10 min, the mixture was dried (MgSO4), evaporated and purified by column
warmed to –40 °C, and the iodide 27 (2.0 g, 4.0 mmol) in THF chromatography, eluting with petrol–EtOAc (6:4), to give
(
10 ml) was added. The mixture was allowed to warm to room alcohol 30 (0.52 g, 49%) as an oil; Rf 0.64 (petrol–EtOAc, 1:1);
1
–1
temperature. After 24 h, water (40 mL) was added and the υmax (neat)/cm 3450, 2970, 2930, 2860, 1690, 1610, 1590; H
mixture was extracted with EtOAc (4 × 40 mL), dried NMR (400 MHz, CDCl3) δ = 7.26–7.24 (2H, m), 6.91–6.88
(
MgSO4), evaporated, and purified by column chromatography, (2H, m), 4.94 (1H, s), 4.86 (1H, s), 4.44–4.38 (2H, m), 4.00–
eluting with petrol–EtOAc (9:1), to give ester 28 (1.8 g, 80%) 3.98 (1H, m), 3.82 (3H, s), 3.73–3.70 (1H, m), 3.65–3.55 (2H,
–1
as an oil; Rf 0.38 (petrol–EtOAc, 8:2); νmax (neat)/cm 3065, m), 3.49–3.45 (2H, m), 3.40–3.34 (1H, m), 3.22 (6H, s), 3.04
1
970, 2865, 1720, 1695, 1610, 1585; H NMR (400 MHz, (1H, s), 2.55 (1H, s), 2.35–2.31 (2H, m), 2.20 (1H, br s), 1.80–
2
CDCl3) δ = 7.25 (2H, d, J 8), 6.88 (2H, d, J 8), 4.97 (1H, s), 1.76 (2H, m), 1.67–1.63 (1H, m), 1.47 (9H, s); C NMR (100
13
4
3
.92 (1H, s), 4.34 (2H, s), 4.21 (2H, q, J 7), 3.95 (1H, d, J 14), MHz, CDCl3) δ = 160.0, 154.8, 143.4, 129.6, 129.3, 113.8,
.82 (3H, s), 3.79–3.75 (2H, m), 3.57–3.50 (1H, m), 3.46–3.41 111.5, 102.4, 79.5, 73.1, 71.9, 70.3, 58.6, 54.3, 48.3, 48.1, 43.9,
+
(2H, m), 3.37–3.30 (1H, m), 3.19–3.12 (1H, m), 2.72–2.67 (2H, 32.7, 31.9, 31.5, 28.4, 27.2; HRMS (ES) Found MNa
+
m), 2.53–2.32 (3H, m), 2.15–2.02 (2H, m), 1.93–1.83 (1H, m), 502.2749, C26H41NO7Na requires MNa 502.2724; LRMS m/z
13
1
.71–1.63 (2H, m), 1.47 (9H, s), 1.31 (3H, t, J 7); C NMR (ES) 502 (100%).
100 MHz, CDCl3) δ = 171.1, 159.1, 154.8, 144.0, 130.6, 129.2,
13.6, 111.7, 79.4, 72.6, 70.7, 69.5, 62.0, 55.3, 53.8, 42.3, 41.3 tert-Butyl 4-{4,4-Dimethoxy-1-[(4-methoxyphenyl)methoxy]-
br), 37.0, 34.4, 28.5, 28.2, 27.3, 24.4, 14.1; HRMS (ES) Found 5-oxopentan-2-yl}-3-methylidenepiperidine-1-carboxylate
(
1
(
+
+
MH 566.2604. C29H44NO6S2 requires MH 566.2610; LRMS 31
m/z (ES) 588 (100%), 566 (92%).
DMSO (0.14 mL, 1.99 mmol) in CH2Cl2 (1 mL) was added to
oxalyl chloride (0.084 mL, 0.99 mmol) in CH2Cl2 (4 mL) at –
tert-Butyl 4-{1-[2-(Hydroxymethyl)-1,3-dithian-2-yl]-3-[(4- 60 °C. After 10 min, alcohol 30 (0.40 g, 0.83 mmol) in CH2Cl2
methoxyphenyl)methoxy]propan-2-yl}-3-
methylidenepiperidine-1-carboxylate 29
(1.5 mL) was added. After 10 min, Et3N (0.52 mL, 3.73 mmol)
was added and the mixture was allowed to warm to room
LiAlH4 (1.40 mL, 2.78 mmol, 2.0 M in THF) was added to the temperature. After 1 h, CH2Cl2 (5 mL) and water (5 mL) were
ester 28 (1.45 g, 2.57 mmol) in THF (40 mL) at –5 °C. After 40 added and the mixture was filtered through celite, washed with
min, the EtOAc (20 mL) and then saturated aqueous Na2SO4 CH2Cl2 (3 × 10 mL), dried (MgSO4), evaporated and purified
were added until a white salt precipitated. After 15 min, the by column chromatography, eluting with petrol–EtOAc (7:3),
mixture was filtered through celite, evaporated and purified by to give aldehyde 31 (0.32 g, 80%) as an oil; Rf 0.79 (petrol–
–1
column chromatography, eluting with petrol–EtOAc (1:1), to EtOAc 1:1); υmax (neat)/cm 2975, 2930, 2860, 2835, 1745,
1
give the alcohol 29 (1.15 g, 85%); alternatively, using LiAlH4 1690, 1645, 1610, 1585; H NMR (400 MHz, CDCl3) δ = 9.33
(37.5 mg, 0.95 mmol) with the ester 28 (500 mg, 0.88 mmol) (1H, s), 7.24 (2H, d, J 8), 6.88 (2H, d, J 8), 4.96 (1H, br s), 4.78
gave the alcohol 29 (440 mg, 93%) as an oil; Rf 0.39 (petrol– (1H, s), 4.26 (2H, s), 4.00–3.92 (1H, m), 3.82 (3H, s), 3.70 (1H,
–1
EtOAc, 1:1); υmax (neat)/cm 3450, 3075, 2930, 2855, 1685, d, J 14), 3.44–3.39 (2H, m), 3.31 (3H, s), 3.25 (3H, s), 2.46–
1
610, 1580; H NMR (400 MHz, CDCl3) δ = 7.25 (2H, d, J 8), 2.42 (1H, m), 1.99–1.87 (3H, m), 1.71–1.59 (4H, m), 1.47 (9H,
1
6
4
13
.88 (2H, d, J 8), 4.95 (1H, br s), 4.86 (1H, s), 4.38 (2H, s), s); C NMR (100 MHz, CDCl3) δ = 198.7, 160.4, 154.6, 143.3,
.10–3.90 (1H, m), 3.83 (3H, s), 3.79 (2H, s), 3.74–3.64 (1H, 129.6, 129.3, 113.9, 111.2, 102.2, 79.4, 72.8, 71.3, 55.5, 54.3,
m), 3.54–3.47 (4H, m), 3.00–2.91 (2H, m), 2.77–2.69 (1H, br 49.7, 49.6, 43.6, 41.3, 32.7, 30.5, 28.5, 27.8; HRMS (ES)
+
+
s), 2.63–2.59 (2H, m), 2.40–2.36 (1H, m), 2.29–2.23 (1H, m), Found MNa 500.2649. C26H39NO7Na requires MNa
2
1
.13–2.07 (1H, m), 2.03–1.98 (1H, m), 1.88–1.75 (3H, m), 500.2624; LRMS m/z (ES) 500 (100%) 478 (10%).
13
.72–1.63 (1H, m), 1.47 (9H, s); C NMR (100 MHz, CDCl3)
δ = 159.2, 154.8, 144.4, 130.2, 129.4, 113.7, 111.8, 79.4, 72.8, 2-tert-Butyl
7
9-Ethyl
2.0, 63.4, 55.3, 54.7, 43.8, 37.2, 33.7, 28.5, 26.0, 25.9, 24.8; methoxyphenyl)methoxy]methyl}-8-(prop-2-en-1-yl)-
7-Methoxy-5-{[(4-
+
+
HRMS (ES) Found MH 524.2484. C27H41NO5S2 requires MH
24.2504; LRMS m/z (ES) 546 (38%), 524 (100%).
1H,2H,3H,4H,5H,7aH,8H,9H,10H,10bH-pyrrolo[2,3-
j]isoquinoline-2,9-dicarboxylate 32
N-Allylglycine ethyl ester hydrochloride salt (0.23 g, 1.26
5
i
mmol), the aldehyde 31 (300 mg, 0.63 mmol) and Pr2NEt (0.22
8
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–1
mL, 1.26 mmol) in toluene (5 mL) were heated under reflux 86%) as an oil; Rf 0.69 (petrol–EtOAc, 3:2); νmax (neat)/cm
1
with a Dean–Stark trap. After 2 d, the solvent was evaporated 2930, 2860, 1735, 1695; H NMR (400 MHz, CDCl3) δ = 4.92
View Article Online
and the residue was purified by column chromatography, (1H, s), 4.79 (1H, s), 4.59 (2H, s), 4.17–4.08 (2H, m), 3.99 (1H,
DOI: 10.1039/C4OB02582B
eluting with petrol–EtOAc (4:1), to give the cycloadduct 32 d, J 14), 3.85–3.76 (2H, m), 3.73–3.68 (1H, m), 3.60–3.53 (1H,
(
(
140 mg, 38%) as an oil; Rf 0.14 (petrol–EtOAc, 4:1); υmax m), 3.42–3.34 (1H, m), 3.33 (3H, s), 2.99 (1H, td, J 7, 4), 2.65–
–
1
1
neat)/cm 2930, 2860, 1730, 1690, 1610, 1590; H NMR (400 2.57 (1H, m), 1.81–1.73 (1H, m), 1.55–1.46 (1H, m), 1.44 (9H,
13
MHz, CDCl3) δ = 7.26 (2H, d, J 8), 6.90 (2H, d, J 8), 5.86–5.73 s), 1.23 (3H, t, J 7); C NMR (100 MHz, CDCl3) δ = 173.4,
1H, m), 5.08 (1H, br d, J 17), 4.96 (1H, br d, J 10), 4.83 (1H, 154.6, 143.4, 111.2, 96.5, 79.6, 66.7, 60.5, 55.3, 46.7, 41.5 (br),
(
br s, vinyl ether CH), 4.52–4.44 (2H, ABq), 4.14 (2H, q, J 7), 40.7, 28.6, 28.4, 14.2; HRMS (ES) Found MH 358.2247.
+
+
.95–3.87 (1H, br m), 3.82 (3H, s), 3.71 (1H, dd, J 9, 4), 3.67– C18H32NO6 requires MH 358.2230; LRMS m/z (ES) 358
3
3
.52 (2H, m), 3.52 (3H, s), 3.38–3.25 (3H, m), 2.90–2.73 (2H, (50%), 302 (100%).
m), 2.62–2.58 (1H, m), 2.19–2.11 (1H, m), 1.90–1.45 (5H, m),
13
1
.43 (9H, s), 1.27 (3H, t, J 7); C NMR (100 MHz, CDCl3, tert-Butyl 4-[1-Hydroxy-3-(methoxymethoxy)propan-2-yl]-
data from JMOD and HSQC) δ = 174.4 (C=O), 159.2 (C), 3-methylidenepiperidine-1-carboxylate 35
55.0 (C=O), 153.2 (Cvinyl ether), 136.7 (CH), 130.4 (C), 129.1 LiAlH4 (2.03 mL, 2.78 mmol, 2.0 M in THF) was added to the
CH), 115.9 (CH2), 113.8 (CH), 97.4 (CHvinyl ether), 79.3 (C), ester 34 (1.45 g, 4.06 mmol) in THF (40 mL) at –5 °C. After 40
4.7 (CH2), 72.8 (CH2), 64.2 (CH), 61.6 (CH), 60.1 (CH2), 55.2 min, the EtOAc (20 mL) and then saturated aqueous Na2SO4
CH3), 54.0 (CH3), 52.6 (CH2), ~49.0 (sometimes could discern were added until a white salt precipitated. After 15 min, the
1
(
7
(
very broad, possible NCH2), 45.0 (C), ~39.0 (sometimes could mixture was filtered through celite, evaporated and purified by
discern very broad, possible NCH2), 38.6 (CH2), 35.7 (CH), column chromatography, eluting with petrol–EtOAc (3:2), to
3
5.5 (CH), 28.4 (CH3), 23.7 (CH2), 14.3 (CH3); HRMS (ES) give the alcohol 35 (1.11 g, 87%) as an oil; Rf 0.23 (petrol–
+
+
–1
1
Found MH 571.3374. C32H47N2O7 requires MH 571.3383; EtOAc, 3:2); υmax (neat)/cm 3430, 2925, 2860, 1690, 1670; H
LRMS m/z (ES) 571 (100%). NMR (400 MHz, CDCl3) δ = 5.02 (1H, s), 4.88 (1H, s), 4.64
2H, ABq), 3.95 (1H, d, J 14), 3.86 (1H, d, J 14), 3.82 (1H, dd,
7,7-Dimethoxy-5-{[(4- J 10, 4), 3.75 (1H, dd, J 10, 4), 3.70 (1H, dd, J 10, 7), 3.65 (1H,
(
2
-tert-Butyl
9-Ethyl
methoxyphenyl)methoxy]methyl}-dodecahydropyrrolo[2,3-
j]isoquinoline-2,9-dicarboxylate 33
The aldehyde 31 (0.25 g, 0.52 mmol), glycine ethyl ester (9H, s); C NMR (100 MHz, CDCl3) δ = 155.0, 144.1, 111.4,
dd, J 10, 7), 3.47 (2H, t, J 6), 3.39 (3H, s), 2.46–2.41 (1H, m),
2.17–2.10 (2H, m), 1.79–1.70 (1H, m), 1.66–1.57 (1H, m), 1.47
13
i
hydrochloride salt (0.15 g, 1.05 mmol) and Pr2NEt (0.18 mL, 96.8, 79.6, 67.8, 64.1, 55.5, 49.3, 41.3, 39.4, 39.1, 28.4, 28.3;
+
+
.05 mmol) were heated in toluene (5 mL) were heated under HRMS (ES) Found MH 316.2112. C16H30NO5 requires MH
1
reflux with a Dean–Stark trap. After 3 d, the solvent was 316.2124; LRMS m/z (ES) 316 (25%), 260 (100%).
evaporated and the residue was purified by column
chromatography, eluting with petrol–EtOAc (3:2), to give the tert-Butyl
cycloadduct 33 (0.17 g, 60%) as an oil; Rf 0.10 (petrol–EtOAc methoxyphenyl)methoxy]propan-2-yl]-3-
4-[1-(Methoxymethoxy)-3-[(4-
–
1
1
3
:2); υmax (neat)/cm 3285, 2930, 1690, 1615; H NMR (400 methylidenepiperidine-1-carboxylate 36
MHz, CDCl3) δ = 7.23 (2H, d, J 8.5), 6.88 (2H, d, J 8.5), 4.41 To a solution of alcohol 35 (450 mg, 1.42 mmol) in CH2Cl2 (10
2H, q, J 7), 4.26–4.10 (2H, m), 4.05–3.78 (2H, m), 3.82 (3H, mL) was added 4-methoxybenzyl 2,2,2-trichloroacetimidate
s), 3.58–3.30 (4H, m), 3.27 (3H, s), 3.21 (3H, s), 3.12–2.87 (722 mg, 2.55 mmol) and CSA (33 mg, 0.14 mmol) at room
1H, m), 2.83–2.61 (1H, m), 2.41–1.95 (4H, m), 1.94–1.51 (4H, temperature. After 24 h, saturated aqueous NaHCO3 (5 mL)
(
(
13
m), 1.46 (9H, s), 1.24 (3H, t, J 7); C NMR (100 MHz, CDCl3) was added and the mixture was extracted with Et2O (3 × 30
δ = 174.5, 159.1, 154.8, 130.5, 129.0, 113.7, 100.4, 79.5, 72.7, mL). The organic layers were combined, washed with water,
7
3
5
2.5, 71.1, 61.3, 56.9, 55.3, 48.0, 47.6, 45.7, 40.9, 36.9, 32.0, dried (MgSO4) and evaporated. Purification by column
+
1.7, 28.5, 23.9, 22.5, 20.8, 14.1; HRMS (ES) Found MH chromatography on silica, eluting with petrol–EtOAc (3:2),
63.3304. C30H47N2O8 requires MH 563.3332; LRMS m/z gave the ether 36 (490 mg, 80%) as an oil; Rf 0.60 (petrol–
+
–1
1
(
ES) 563 (100%).
EtOAc, 3:2); υmax (neat)/cm 2930, 2835, 1615, 1515; H NMR
400 MHz, CDCl3) δ = 7.25 (2H, d, J 8.5), 6.89 (2H, d, J 8.5),
tert-Butyl 4-[1-Ethoxy-3-(methoxymethoxy)-1-oxopropan-2- 4.96 (1H, s), 4.82 (1H, s), 4.61 (2H, s), 4.41 (2H, s), 3.88 (2H,
yl]-3-methylidenepiperidine-1-carboxylate 34 s), 3.82 (3H, s), 3.72 (1H, dd, J 10, 3.5), 3.55 (1H, dd, J 10, 6),
(
Chloromethyl methyl ether (0.44 mL, 5.76 mmol) was added to 3.45–3.52 (2H, m), 3.37–3.45 (2H, m), 3.35 (3H, s), 2.40–2.49
the alcohol 22 (1.50 g, 4.80 mmol) and diisopropyl ethylamine (1H, m), 2.15–2.24 (1H, m), 1.68–1.79 (1H, m), 1.55–1.66 (1H,
13
(6.33 mL, 6.24 mmol) in CH2Cl2 (25 mL) at 0 °C. After 1 h, m), 1.46 (9H, s); C NMR (100 MHz, CDCl3) δ = 159.1,
H2O (20 mL) was added and the mixture was extracted with 154.8, 144.3, 130.6, 129.2, 113.7, 111.0, 96.7, 79.6, 72.8, 69.1,
Et2O (2 × 30 mL). The organic layers were washed with 65.6, 55.3, 48.8, 41.4, 39.4, 38.2, 28.5, 28.1; HRMS (ES)
+
+
aqeuous HCl (10 mL, 1 M) and brine (10 mL), dried (MgSO4) Found MH 436.2692. C24H38NO6 requires MH 436.2699;
and evaporated. Purification by column chromatography, LRMS m/z (ES) 436 (100%).
eluting with petrol–EtOAc (7:3), gave the ester 34 (1.47 g,
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Acknowledgements
Fernàndez, J. D. Moseley and R. Rabot, J. Org. Chem., 2002, 67,
We are grateful for support from the Royal Society, the Libyan
Ministry of Higher Education, the Thai Government and the
University of Sheffield. We are grateful to Steven Pih, Chirag
Patel, Laura Butler and Rungroj Saruengkhanphasit for related
studies.
6181; (c) I. Coldham, S. M. Pih and R. Rabot, Synlett, 2005, 1743.
View Article Online
7
Y. Boursereau and I. Coldham, Bioorg. Med. Chem. Lett., 2004, 14,
DOI: 10.1039/C4OB02582B
5841.
8
I. Coldham and R. Hufton, Chem. Rev., 2005, 105, 2765.
J. D. Winkler, J. Axten, A. H. Hammach, Y.-S. Kwak, U.
Lengweiler, M. J. Lucero and K. N. Houk, Tetrahedron, 1998, 54,
7045.
9
Notes and references
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, 10 S. Raucher, K.-W. Chi and D. S. Jones, Tetrahedron Lett., 1985, 26,
UK S3 7HF; e-mail: i.coldham@sheffield.ac.uk
6261.
1
1 J. Casas, H, Sundén and A. Córdova, Tetrahedron Lett., 2004, 45,
1
2
R. Sakai, T. Higa, C. W. Jefford and G. Bernardinelli, J. Am. Chem.
Soc., 1986, 108, 6404.
6117.
See, for example: (a) A. H. El-Desoky, H. Kato, K. Eguchi, T.
Kawabata, Y. Fujiwara, F. Losung, R. E. P. Mangindaan, N. J. de
Voogd, M. Takeya, H. Yokosawa, S. Tsukamoto, J. Nat. Prod., 2014,
7
7, 1536; (b) M. Yamada, Y. Takahashi, T. Kubota, J. Fromont, A.
Ishiyama, K. Otoguro, H. Yamada, S. Omura, J. Kobayashi,
Tetrahedron, 2009, 65, 2313; (c) K. V. Rao, M. S. Donia, J. Peng, E.
Garcia-Palomero, D. Alonso, A. Martinez, M. Medina, S. G.
Franzblau, B. L. Tekwani, S. I. Khan, S. Wahyuono, K. L. Willett,
M. T. Hamann, J. Nat. Prod., 2006, 69, 1034.
3
For bioactivity, see, for example: (a) K. Eguchi, Y. Fujiwara, A.
Hayashida, H. Horlad, H. Kato, H. Rotinsulu, F. Losung, R. E. P.
Mangindaan, N. J. de Voogd, M. Takeya, S. Tsukamoto, Bioorg.
Med. Chem., 2013, 21, 3831; (b) E. A. Guzmán, J. D. Johnson, P. A.
Linley, S. E. Gunasekera, A. E. Wright, Inv. New Drugs, 2011, 29,
7
77; (c) A. G. Shilabin, N. Kasanah, B. L. Tekwani, M. T. Hamann,
J. Nat. Prod., 2008, 71, 1218; (d) M. Hamann, D. Alonso, E. Martín-
Aparicio, A. Fuertes, M. J. Pérez-Puerto, A. Castro, S. Morales, M.
L. Navarro, M. del Monte-Millán, M. Medina, H. Pennaka, A.
Balaiah, J. Peng, J. Cook, S. Wahyuono, A. Martinez, J. Nat. Prod.,
2
007, 70, 1397.
(a) J. D. Winkler and J. M. Axten, J. Am. Chem. Soc., 1998, 120,
425; (b) S. F. Martin, J. M. Humphrey, A. Ali and M. C. Hillier, J.
4
6
Am. Chem. Soc., 1999, 121, 866; (c) J. M. Humphrey, Y. Liao, A.
Ali, T. Rein, Y.-L. Wong, H.-J. Chen, A. K. Courtney and S. F.
Martin, J. Am. Chem. Soc., 2002, 124, 8584; (d) T. Toma, Y. Kita
and T. Fukuyama, J. Am. Chem. Soc., 2010, 132, 10233; (e) P.
Jakubec, A. Hawkins, W. Felzmann and D. J. Dixon, J. Am. Chem.
Soc., 2012, 134, 17482.
5
For recent examples, see: (a) A. Hawkins, P. Jakubec, A.
Ironmonger, D. J. Dixon, Tetrahedron Lett., 2013, 54, 365; (b) C.-M.
Chau, K.-M. Liu, C.-K. Sha, Tetrahedron Lett., 2011, 52, 5068; (c)
Y. Kita, T. Toma, T. Kan, T. Fukuyama, Org. Lett., 2008, 10, 3251;
(
d) J.-C. Wypych, T. M. Nguyen, P. Nuhant, M. Bénéchie, C.
Marazano, Angew. Chem. Int. Ed., 2008, 47, 5418; (e) K. A. El
Sayed, A. A. Khalil, M. Yousaf, G. Labadie, G. M. Kumar, S. G.
Franzblau, A. M. S. Mayer, M. A. Avery, M. T. Hamann, J. Nat.
Prod., 2008, 71, 300; (f) T. Matsumura, M. Akiba, S. Arai, M.
Nakagawa, A. Nishida, Tetrahedron Lett., 2007, 48, 1265; (g) K.
Tokumaru, S. Arai, A. Nishida, Org. Lett., 2006, 8, 27.
6
(a) I. Coldham, S. J. Coles, K. M. Crapnell, J.-C. Fernàndez, T. F. N.
Haxell, M. B. Hursthouse, J. D. Moseley and A. B. Treacy, Chem.
Commun., 1999, 1757; (b) I. Coldham, K. M. Crapnell, J.-C.
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