Intramolecular Tandem Seleno-Michael/Aldol Reaction: A Simple Route to Hydroxy Cyclo-1-ene-1-carboxylate Esters

Article abstract of DOI:10.1021/acs.joc.8b01853

Intramolecular tandem seleno-Michael/aldol reaction followed by an oxidation-elimination process can be an efficient tool for the construction of hydroxy cyclo-1-ene-1-carboxylate esters from oxo-α,β-unsaturated esters. Generation of lithium selenolate from elemental selenium and n-BuLi provides a simple and efficient one-pot access to cyclic endo-Morita-Baylis-Hillman adducts.

Full text of DOI:10.1021/acs.joc.8b01853

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Article
Intramolecular tandem seleno-Michael/aldol reaction: a
simple route to hydroxy cyclo-1-ene-1-carboxylate esters.
Piotr Banachowicz, Jacek Mlynarski, and Szymon Buda
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01853 • Publication Date (Web): 06 Aug 2018
Downloaded from http://pubs.acs.org on August 7, 2018
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The Journal of Organic Chemistry
Intramolecular tandem seleno-Michael/aldol reaction: a simple route to hydroxy cyclo-1-ene-1-
carboxylate esters.
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Piotr Banachowicz,† Jacek Mlynarski,‡ and Szymon Buda*†
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† Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30ꢀ387 Krakow, Poland.
szym.buda@gmail.com
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‡ Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01ꢀ224 Warsaw, Poꢀ
land.
Supporting Information Placeholder
intramolecular, selenoꢀMichael/aldol,
ABSTRACT: Intramolecular tandem selenoꢀMichael/aldol reaction followed by oxidationꢀelimination
process can be an efficient tool for the construction of hydroxy cycloꢀ1ꢀeneꢀ1ꢀcarboxylate esters from
oxoꢀα,βꢀunsaturated esters. Generation of lithium selenolate from elemental selenium and nꢀBuLi proꢀ
vides a simple and efficient oneꢀpot access to cyclic endoꢀMoritaꢀBaylis–Hillman adducts.
Introduction
The tandem or domino reaction has been of interest for organic synthesis because it offers a convenient
and economical way to prepare desired organic molecules.1,2 The sequenced Michael/aldol tandem reacꢀ
tion is one of the most important processes for constructing carbon skeletons. Intramolecular Moritaꢀ
BaylisꢀHillman (IMBH) of α,βꢀunsaturated esters may lead to two types of products: a) “exo” when
acrylate derivatives are cyclized; b) “endo” when the internal double bond is located in the substrate
(Scheme 1).
Scheme 1. IMBH of α,βꢀunsaturated esters
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Results
It has been previously reported that simple phosphine and tertiary amines are efficient in promoting the
MBH reaction of acrylates but are completely unreactive in the case of linear oxoꢀα,βꢀunsaturated esꢀ
ters. For this purpose, high nucleophilicity and very low basicity of chalcogenols and metallic chalꢀ
cogenolates can be employed as initial nucleophiles in the intermolecular reaction leading to Moritaꢀ
BaylisꢀHillman products.3–10
Several examples of endo type products formed in IMBH reaction have been reported11–17 and the most
common procedures are based on intermolecular MBH followed by ringꢀclosing metathesis (RCM).18
This strategy fails in the presence of more than two double bonds in the molecule. Elegant work involvꢀ
ing use of lithium benzylthiolate was presented by Ono.19 They presented total synthesis of Neplanocin
A and the key intermediate was obtained via thioꢀMichael/aldol cyclization.
A serious drawback of this methodology is the use of alkylchalcogenols as starting material, since these
compound are volatile and have a foul odour. Comasseto et. al. recently described a sequence of interꢀ
molecular Michaelꢀaldol reaction activated by lithium nꢀbutylchalcogenate generated in situ.6
Table 1. Catalyst screening
entry
[equiv] nuc.
0.2 DABCO
1.0 DABCO
0.2 DBU
conditions
yield [%]
1
2
3
CHCl3, rt, 7 d
CHCl3, rt, 7 d
CHCl3, rt, 7 d
0
0
0
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The Journal of Organic Chemistry
4
5
1.0 DBU
0.2 PBu3
CHCl3, rt, 7 d
0
1
2
3
4
5
6
7
8
CDCl3, rt, 24 h
CHCl3, rt, up to 7 d
CHCl3, rt, up to 7 d
THF, rt, 7 d
up to 7015
6
0.2 PBu3
<5
<5
0
7
0.2 PMe3
9
10
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12
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16
17
18
19
20
8
1.0 DABCO
1.0 PBu3
9
THF, rt, 7 d
0
10
11
1.0 PMe3
THF, rt, 7 d
0
1.0 nꢀBuSeLi
THF, 0 °C (0.25 h) to rt (1 h)
38
Our initial attempts to induce cyclization simply by exposure of 1 to common catalysts in chloroform or
THF at room temperature gave mostly no reaction (Table 1, Entries 1ꢀ10). Traces of product have been
detected by crude NMR in phosphine catalyzed reactions (Table 1, Entries 6ꢀ7). Those results are oppoꢀ
site of previously reported yield.15 Treatment of 1 with lithium benzenethiolate gave only acyclic sulꢀ
phaꢀMichael adduct as previously reported.17 Detailed NMR studies on the crude mixture containing
lithium nꢀbutylselenolates and oxoꢀα,βꢀunsaturated ester, clearly suggested the formation of selenoꢀ
Michael adduct and the consumption of aldehyde. We decided to stop the reaction with aqueous ammoꢀ
nium chloride and treated the crude mixture with excess of H2O2/pyridine at 50 °C. This protocol gave
desired product with 38% isolable yield. The best experimental protocol for lithium nꢀbutylselenolates
generation was used to investigate the experimental conditions for the chalcogenation/condensation seꢀ
quence. Several reaction conditions and sequences of addition of the components were tested (Table 2).
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Table 2. Optimization of reaction conditions
entry
solvent (v/v)
THF
nꢀBuSeLi equiv
conditions yield [%]c
1
2
3
4
1.0
1.0
1.0
1.0
A
A
A
A
38
49
0a
THF
Et2O
THF/Et2O (1:6)
40
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5
6
THF/DMF (1:6)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.2
A
22
48
43
0b
1
2
3
4
5
6
7
8
THF/MeCN (1:6)
THF/1,4-dioxane (1:6)
THF/MeOH (1:6)
THF/PhMe (1:6)
THF/PhMe (1:6)
THF/PhMe (1:6)
THF/PhMe (1:6)
THF/PhMe (1:6)
THF/PhMe (1:6)
THF/PhMe (1:6)
A
7
A
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A
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9
A
53
<10d
65
64
0b
10
11
12
13
14
15
A
B
C
D
D (6 h)
B
0b
72
Reaction conditions: A: 0 °C (0.25 h) to rt (1 h); B: ꢀ 20 °C (6 h); C: ꢀ 40 °C (6 h); D: ꢀ 78 °C (1 h); a
b
1
c
Nucleophile not soluble in Et2O. No conversion based on H NMR. The yields refer to the isolate
d
product purified by column chromatography. Opposite sequence of addition (nꢀBuSeLi in THF has
been added to aldehyde solution in anhydrous THF).
Omission of the extraction after reaction quenching increased yield to 49% (Table 2, Entry 2). An atꢀ
tempt to improve reaction by employing Et2O was unsuccessful (Table 2, Entry 3). Reductive cleavage
of elemental selenium under these conditions produced an insoluble mixture which when treated with
substrate 1 did not provide desire product. Much better results were obtained using mixtures of solvents
(Table 2, Entries 4ꢀ9). Protic solvents such as methanol stopped the reaction completely (Table 2, Entry
8). The greatest yield was observed in THF/toluene mixture at 0 °C. Alternative sequence of substrate
addition gave a complex mixture and produced the desired product with a low yield (Table 2, Entry 10).
Optimization of the reaction temperature improved the yield slightly to 65%. A small excess of nucleoꢀ
phile lead to the formation of product with 72% yield. Having identified conditions under which the
desired reaction was high yielding, several other potential substrates for this reaction were prepared and
tested. As presented in Table 3, our methodology provides a route to both single and fused cyclic sysꢀ
tems. Synthesis of the sixꢀmembered carbocycles were very high yielding. Furthermore, the syntheses of
five and sevenꢀmembered rings gave products with moderate (2a and 10a) to very high isolated yields.
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The Journal of Organic Chemistry
Interestingly, formation of bridged bicyclic system (13a) gave a desired product with 68% yield and
good diastereomeric ratio (5:1). The simple sevenꢀmembered ring (3a) was obtained with 27% yield
only. Interestingly, compound 5 did not yield the expected product 5a. Rather, further aromatization was
observed to give ethyl 2ꢀnaphthoate (5b). Surprisingly, compound 6 also did not give desired product
and a complex mixture of degradation products were obtained. For detailed descriptions of substrate
syntheses (1-14) please see supporting information.
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Table 3. Substrate scope
a Cyclization in the presence of 0.2 equiv PBu3, CHCl3, rt, 3h.
At this point we turned our attention to common IMBH substrates such as oxoꢀα,βꢀunsaturated ketones.
(5E)ꢀ7ꢀoxoꢀ7ꢀphenylheptꢀ5ꢀenal (14) was chosen as a model substrate. Treatment of 14 with 0.2 equiv
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of PBu3 in chloroform for 3 h at room temperature gave 14a in 83% yield in comparison to 96% obꢀ
1
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3
tained under our conditions.
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9
In addition, this method has been successfully applied to the synthesis of Cꢀ7 aminocyclitol with pharꢀ
macological properties. For example, Nꢀoctylꢀβꢀ(+)ꢀvalienamine (NOV, 15) has been found as a potenꢀ
tial chemical chaperone for Gaucher disease.20 Fully protected βꢀ(+)ꢀvalienamine (19) can be accessed
from the key intermediate cyclohexꢀ1ꢀeneꢀ1ꢀcarboxylate via seleno induced Michael/aldol tandem reacꢀ
tion (Scheme 2). Compound 18 can be obtained by the oneꢀpot intramolecular lithium selenolateꢀ
induced Michaelꢀaldol tandem reaction with furthered oxidationꢀelimination from simple oxoꢀα,βꢀ
unsaturated ester 17.
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Scheme 2. Retrosynthetic analysis of βꢀ(+)ꢀvalienamine
The synthesis of compound 20 was completed in 5 steps from commercially available
Dꢀxylose in 69%
overall yield.21 Wittig reaction of the partially protected
D
ꢀxylose 20 and ylide 21 gave a primary alcoꢀ
hol as mixture of isomers (E/Z = 1:0.2) in 65% yield. Oxidation of the remaining primary hydroxyl
group gave compound 17 after flash chromatography as a mixture of isomers (E/Z =90:10) in 90%
yield. Both isomers of compound 17 have been isolated and fully characterized (see supporting inforꢀ
mation).
Scheme 3. Total synthesis of βꢀ(+)ꢀvalienamine
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CO2Et
CO2Et
1
2
3
4
O
OH
OH
O
OH
HO
ref. 20
21
Ph3P
HO
BnO
OBn
BnO
OBn
OH
OBn
5
OBn
6
7
D-xylose
20, 69% 3 steps
20a, 65%
DMSO,
(COCl)2
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CO2Et
OH
EtO2C
OBn
OBn
O
OBn
OBn
1. n-BuSeLi
2. H2O2, Py
DIBAl-H
HO
BnO
OBn
HO
OBn
OBn
OBn
anti-18a, 61%
18, 66 %; 4:1 anti/syn
17, 90%
NaH, BnBr
OH
OBn
OH
NH3Cl
OH
OBn
OBn
NH2
ref. 21
HClaq
HO
BnO
HO
OH
OH
OBn
OH
22, 95%
-(+)-valienamine (16),
51% 2 steps, total 8%
-(+)-valienamine
hydrochloride (16a), 99%
With the enoate 17 in hand, the key intramolecular tandem reaction was attempted. Elemental selenium
was suspended in dry THF, cooled and equimolar amount of nꢀBuLi in THF was added to generate lithꢀ
ium nꢀbutylselenolate. Then, compound 17 was subjected to the Michael reaction with lithium
nꢀbutylselenolate followed by trapping of the produced enolate containing an aldehyde group to give a
cyclic product as an inseparable mixture of isomers. The crude mixture of nꢀbutylselenol adducts were
treated with H2O2/pyridine system in THF at 50 °C to give mixture of cyclic MoritaꢀBaylisꢀHillman
type products (18 anti/syn = 65:35) in 38% total yield after 3 steps at first attempt. Short optimization
gave compound 18 with 66% yield (Table 4). For further investigation we chose THF as the best solvent
(Table 4, Entries 7 ꢀ 9). Treatment of 17 with excess of nꢀBuSeLi (1.2 equiv) at ꢀ20 °C gave 18 as mixꢀ
1
ture of anti/syn diastereomers (3:1) in 66% total. Diastereomeric ratio was determined by H NMR
analysis and pure isomers have been isolated by column chromatography. On the basis of aboveꢀ
described results, we decided to examine pure Zꢀ17 and Eꢀ17 isomers in cyclization reactions under best
reaction conditions. As presented in Table 4 (Entries 8 and 9), both isomers reacted to produce the same
diastereomeric ratio, but Eꢀisomer gave much better yield than Zꢀisomer. Simple phosphines gave better
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selectivity (dr = 8:1) but unfortunately yields were very poor even after 14 or 28 days (Table 4, Entries
1
2
3
10 and 11).
4
5
Table 4. Reaction conditions and isolated yields of 18.
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8
9
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entry
1
[equiv] nuc.
1.0
solvent
anti/syn
65:35
67:33
nd
yield [%]
38
THF, 0 °C (0.25 h) to rt (1 h)
THF/PhMe, 0 °C (0.25 h) to rt (1 h)
THF/DMF, 0 °C (0.25 h) to rt (1 h)
THF/MeCN, 0 °C (0.25 h) to rt (1 h)
THF/1,4ꢀdioxane, 0 °C (0.25 h) to rt (1 h)
THF/Et2O, 0 °C (0.25 h) to rt (1 h)
THF, ꢀ 20 °C (6 h)
2
1.0
39
3
1.0
traces
32
4
1.0
54:46
66:34
67:33
74:26
75:25
74:26
87:13
81:19
5
1.0
42
6
1.0
34
7
1.2
66
8a
9b
10c
11c
1.2
THF, ꢀ 20 °C (6 h)
42
1.2
THF, ꢀ 20 °C (6 h)
69
1.0 PBu3
CHCl3, rt, 14 d
10
1.0 PMe3
CHCl3, rt, 28 d
20
a Pure Zꢀisomer of 17. b Pure Eꢀisomer of 17. c PBu3 or PMe3 was used instead of nꢀBuSeLi.
With the antiꢀisomer of compound 18 in hand, the reduction of α,βꢀunsaturated ester reaction was atꢀ
tempted. As presented on Scheme 3, compound 18 was treated with 3.5 equivalents of DIBALꢀH in
DCM at ꢀ10 °C to give corresponding diol and protected with benzyl ethers under standard reaction
conditions. Cyclic product (22) was treated with 3 equivalents of chlorosulfonyl isocyanate (CSI) under
optimal reaction conditions (anhydrous toluene, 0 °C, 15 h) to afford the corresponding 1,2ꢀantiꢀamino
alcohol 19 in good yield (74%).22 Only one single diastereomer was isolated. Protection groups were
removed using BCl3 to provide βꢀ(+)ꢀvalienamine (16).
Conclusions
In conclusion, the tandem Michael/aldol reaction with lithium selenolates and subsequent oxidationꢀ
elimination of the seleno group is a highly efficient method for the construction of sixꢀmembered rings.
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The presented methodology shows some interesting advantages in comparison to the classic IMBH reꢀ
action, such as the short reaction times and the substrate scope. We have developed a fast and high
yielding route to multiꢀfunctionalized IMBH adducts employing in situ generated metallic chalꢀ
cogenolates. This protocol can be a valuable alternative route to obtain IMBH adducts and derivatives.
In this context, the asymmetric version of this reaction is under development in our laboratory.
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Experimental section
General information
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All starting materials and reagents were purchased from commercial sources and used without purificaꢀ
tion. Reactions were controlled using TLC on silica [aluꢀplates (0.2 mm)]. Plates were visualized with
UV light (254 nm) and by treatment with: aqueous cerium(IV) sulfate solution with molybdic and sulfuꢀ
ric acid followed by heating. All organic solutions were dried over anhydrous magnesium sulfate. Reacꢀ
tion products were purified by flash chromatography using silica gel 60 (240ꢀ400 mesh). Optical rotaꢀ
tions were measured at room temperature with a digital polarimeter. CDCl3, D2O were used as NMR
solvents. 1H spectra were recorded with 600, 400 and 300 MHz and referenced relative to: CDCl3 ꢀ tetꢀ
ramethylsilane (δ = 0 ppm). Data are reported as follows: chemical shift in parts per million (ppm) ,
multiplicity (s = singlet, d = doublet, t = triplet, dd = doublet of doublets, ddd = doublet of doublet of
doublets, dddd = doublet of doublet of doublet of doublets, m = multiplet), coupling constants (in hertz)
and integration. 13C NMR spectra were measured at 150, 100 and 75 MHz with complete proton decouꢀ
pling. Chemical shifts were reported in ppm from the residual solvent as an internal standard: CDCl3 (δ
= 77.16 ppm). Highꢀresolution mass spectra were acquired using ESIꢀTOF method.
General procedure for ozonolysis/Wittig reaction (Procedure A).15 Cycloalkene (10 mmol) was disꢀ
solved in anhydrous methylene chloride (50 ml) and cooled to ꢀ78 °C whereupon ozone was bubbled in
the flask until the solution became blue in color and at this point, the reaction was flushed with argon
and triphenylphosphine (1 equiv. to the amount of alkene) was added in one portion. Reaction mixture
was allowed to slowly warm to 0 °C and phosphorane (0.1ꢀ2 equiv., substrate dependent) was added and
the reaction mixture was stirred for 12 h in room temperature. Products were purified by column chroꢀ
matography in Hx/EA gradient.
Ethyl (E)ꢀ6ꢀoxohexꢀ2ꢀenoate (2)15 Procedure A: 1,5ꢀCyclooktadiene (1.40 g, 12.94 mmol), 21 (9.00 g,
1
25.88 mmol) gave product as a colorless oil (1.15 g, 7.36 mmol), 28 %. H NMR (600 MHz, CDCl3) δ
9.80 (s, 1H), 6.94 (dt, J = 15.6, 6.7 Hz, 1H), 5.85 (dt, J = 15.7, 1.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H),
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2.64 (t, J = 7.2 Hz, 2H), 2.57 – 2.50 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H). C NMR (151 MHz, CDCl3) δ
1
2
3
200.3, 166.2, 146.2, 122.4, 60.3, 41.8, 24.4, 14.2.
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5
6
7
8
9
Ethyl (E)ꢀ8ꢀoxooctꢀ2ꢀenoate (3)15 Procedure A: Cyclohexene (2.0 g, 24.35 mmol), 21 (4.24 g, 12.17
mmol) gave product as a colorless oil (1.43 g, 6.53 mmol), 54 %. 1H NMR (600 MHz, CDCl3) δ 9.77 (t,
J = 1.6 Hz, 1H), 6.94 (dt, J = 15.6, 6.9 Hz, 1H), 5.83 (dt, J = 15.6, 1.6 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H),
2.46 (td, J = 7.3, 1.6 Hz, 2H), 2.23 (ddd, J = 14.6, 7.3, 1.6 Hz, 2H), 1.71 – 1.62 (m, 2H), 1.51 (dt, J =
15.2, 7.7 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 202.1, 166.6, 148.2, 121.8,
60.2, 43.6, 31.8, 27.4, 21.5, 14.2.
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Ethyl (E)ꢀ4ꢀ(2ꢀformylphenyl)butꢀ2ꢀenoate (5) Procedure A: Indene (2.00 g, 17.22 mmol), 21 (1.80 g,
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5.17 mmol) gave product as a colorless oil (0.42 g, 1.90 mmol), 37%. H NMR (600 MHz, CDCl3) δ
10.16 (s, 1H), 7.85 (dd, J = 7.6, 1.4 Hz, 1H), 7.56 (td, J = 7.5, 1.5 Hz, 1H), 7.47 (td, J = 7.5, 1.1 Hz,
1H), 7.29 (d, J = 7.6 Hz, 1H), 7.14 (dt, J = 15.6, 6.4 Hz, 1H), 5.72 (dt, J = 15.6, 1.7 Hz, 1H), 4.17 (q, J
= 7.1 Hz, 2H), 3.99 (dd, J = 6.4, 1.6 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
192.5, 166.3, 146.6, 139.7, 134.0, 133.8, 133.6, 131.4, 127.5, 122.6, 60.3, 35.2, 14.2.
Ethyl (E)ꢀ3ꢀ((1R,3S)ꢀ3ꢀformylcyclopentyl)acrylate (13) Procedure A: Norbornene (2.16 g, 22.94 mmol),
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21 (4.00 g, 11.47 mmol) gave product as a colorless oil (1.61 g, 8.21 mmol), 72%. H NMR (600 MHz,
CDCl3) δ 9.64 (d, J = 2.3 Hz, 1H), 6.91 (dd, J = 15.6, 7.7 Hz, 1H), 5.83 (dd, J = 15.6, 1.2 Hz, 1H), 4.19
(q, J = 7.1 Hz, 2H), 2.91 – 2.84 (m, 1H), 2.77 – 2.68 (m, 1H), 2.11 – 2.00 (m, 2H), 1.96 – 1.85 (m, 2H),
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1.72 (ddd, J = 13.1, 9.9, 8.7 Hz, 1H), 1.49 – 1.42 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H). C NMR (151
MHz, CDCl3) δ 202.6, 166.6, 150.8, 120.6, 60.3, 51.2, 42.9, 32.2, 31.8, 25.9, 14.2; HRMS (ESI): calcd.
for C11H16O3Na [M+Na]+ 219.0991, found 219.0991.
(E)ꢀ7ꢀoxoꢀ7ꢀphenylheptꢀ5ꢀenal (14)15 Procedure A: Cyclopentene (7.16 g, 105.15 mmol), 23 (4.00 g,
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10.51 mmol) gave product as colorless oil (1.00 g, 4.94 mmol), 47%. H NMR (600 MHz, CDCl3) δ
9.81 (t, J = 1.4 Hz, 1H), 7.94 (dt, J = 8.4, 1.6 Hz, 2H), 7.59 – 7.55 (m, 1H), 7.51 – 7.46 (m, 2H), 7.03
(dt, J = 15.4, 6.8 Hz, 1H), 6.92 (dt, J = 15.4, 1.4 Hz, 1H), 2.54 (td, J = 7.2, 1.4 Hz, 2H), 2.42 – 2.35 (m,
2H), 1.89 (p, J = 7.3 Hz, 2H). 13C NMR (151 MHz, CDCl3) δ 201.6, 190.5, 148.0, 137.7, 132.7, 128.5,
128.5, 126.6, 43.0, 31.8, 20.5.
General procedure for synthesis salicylic aldehyde derivatives (Procedure B).23 Different substituꢀ
ent salicylic aldehyde (0.5 g), ethyl 4ꢀbromocrotonate (1.2 equiv.) and K2CO3 (2 equiv.) were dissolved
in DMF (15 ml) and heated to 40 °C or 70 °C under argon for 4 h. Reaction mixture was allowed to cool
to room temperature and filtrated. After water addition (20 ml) the mixture was extracted with ethyl
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acetate (3 x 20ml). The combined organic phases were washed with water (2 x 20 ml) and brine (30 ml)
and dried over anhydrous MgSO4. After removal of solvent under reduced pressure, the residue was
purified by column chromatography on silica gel in Hx/EA gradient to give the pure products.
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Ethyl (E)ꢀ4ꢀ(2ꢀformylphenoxy)butꢀ2ꢀenoate (7)23 Procedure B: 70 °C, (0.34 g, 1.43 mmol), 35%, pale
yellow solid mp: 68ꢀ70 (66ꢀ68 °C lit.).23 1H NMR (600 MHz, CDCl3) δ 10.56 (d, J = 0.7 Hz, 1H), 7.86
(dd, J = 7.7, 1.8 Hz, 1H), 7.54 (ddd, J = 8.5, 7.3, 1.8 Hz, 1H), 7.13 – 7.05 (m, 2H), 6.94 (d, J = 8.4 Hz,
1H), 6.22 (dt, J = 15.8, 2.1 Hz, 1H), 4.83 (dd, J = 4.1, 2.1 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 1.31 (t, J =
7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 189.3, 165.8, 160.1, 141.1, 135.9, 128.8, 125.1, 122.5,
121.4, 112.5, 66.8, 60.7, 14.2.
Ethyl (E)ꢀ4ꢀ(2ꢀformylꢀ5ꢀmethoxyphenoxy)butꢀ2ꢀenoate (8)23 Procedure B: 40 °C, (0.72 g, 2.72 mmol)
83%, pale yellow solid, mp: 95ꢀ96 °C (91ꢀ93 °C lit.).23 1H NMR (600 MHz, CDCl3) δ 10.38 (d, J = 0.7
Hz, 1H), 7.84 (d, J = 8.7 Hz, 1H), 7.09 (dt, J = 15.8, 4.0 Hz, 1H), 6.59 (ddd, J = 8.7, 2.2, 0.6 Hz, 1H),
6.40 (d, J = 2.2 Hz, 1H), 6.22 (dt, J = 15.8, 2.1 Hz, 1H), 4.80 (dd, J = 4.0, 2.1 Hz, 2H), 4.23 (q, J = 7.1
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Hz, 2H), 3.87 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). C NMR (151 MHz, CDCl3) δ 187.8, 166.0, 165.8,
161.8, 141.0, 130.9, 122.5, 119.2, 106.3, 99.0, 66.8, 60.7, 55.7, 14.2.
Ethyl (E)ꢀ4ꢀ(2ꢀformylꢀ5ꢀmethylphenoxy)butꢀ2ꢀenoate (9) Procedure B: 40°C, (0.65 g, 2.63 mmol) 72%,
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pale yellow solid, mp: 63ꢀ65 °C. H NMR (600 MHz, CDCl3) δ 10.47 (d, J = 0.6 Hz, 1H), 7.75 (d, J =
7.9 Hz, 1H), 7.10 (dt, J = 15.8, 4.0 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.73 (s, 1H), 6.21 (dt, J = 15.8, 2.1
Hz, 1H), 4.81 (dd, J = 4.0, 2.1 Hz, 2H), 4.23 (q, J = 7.1 Hz, 2H), 2.39 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 188.9, 165.8, 160.2, 147.4, 141.3, 128.8, 122.9, 122.4, 122.3, 113.0,
66.7, 60.7, 22.3, 14.2. HRMS (ESI): calcd. for C14H16O4Na [M+Na]+ 271.0941, found 271.0941.
Ethyl (E)ꢀ4ꢀ(2ꢀformylꢀ4ꢀmethoxyphenoxy)butꢀ2ꢀenoate (10)23 Procedure B: 70 °C, (0.61 g. 2.29 mmol)
70%, pale yellow solid, mp: 83ꢀ84 °C (83ꢀ85 °C lit.).23 1H NMR (600 MHz, CDCl3) δ 10.52 (s, 1H),
7.35 (d, J = 3.3 Hz, 1H), 7.13 – 7.06 (m, 2H), 6.90 (d, J = 9.1 Hz, 1H), 6.20 (dt, J = 15.8, 2.1 Hz, 1H),
4.78 (dd, J = 4.1, 2.1 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR
(151 MHz, CDCl3) δ 189.0, 165.8, 155.0, 154.1, 141.4, 125.4, 123.4, 122.4, 114.4, 110.6, 67.5, 60.7,
55.8, 14.2.
Ethyl (E)ꢀ4ꢀ(2ꢀformylꢀ4ꢀmethylphenoxy)butꢀ2ꢀenoate (11) Procedure B: 70 °C, (0.53 g, 2.11 mmol)
57%, pale yellow solid, mp: 64ꢀ65 °C. 1H NMR (600 MHz, CDCl3) δ 10.52 (s, 1H), 7.65 (d, J = 2.1 Hz,
1H), 7.34 (ddd, J = 8.5, 2.4, 0.6 Hz, 1H), 7.09 (dt, J = 15.8, 4.0 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.20
(dt, J = 15.8, 2.1 Hz, 1H), 4.80 (dd, J = 4.0, 2.1 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 1.30 (t, J
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= 7.1 Hz, 3H). C NMR (151 MHz, CDCl3) δ 189.4, 165.8, 158.3, 141.4, 136.5, 130.9, 128.8, 124.8,
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122.4, 112.5, 66.9, 60.7, 20.2, 14.2. HRMS (ESI): calcd. for C14H16O4Na [M+Na]+ 271.0941, found
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271.0941.
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Ethyl (E)ꢀ4ꢀ(4ꢀchloroꢀ2ꢀformylphenoxy)butꢀ2ꢀenoate (12)23 Procedure B: 70°C, (0.57 g, 2.12 mmol),
66%, pale yellow solid, mp: 66ꢀ67 (64ꢀ66 °C lit.).23 1H NMR (600 MHz, CDCl3) δ 10.48 (s, 1H), 7.82
(d, J = 2.7 Hz, 1H), 7.49 (dd, J = 8.9, 2.8 Hz, 1H), 7.09 (dt, J = 15.8, 4.1 Hz, 1H), 6.91 (d, J = 8.9 Hz,
1H), 6.19 (dt, J = 15.8, 2.0 Hz, 1H), 4.83 (dd, J = 4.1, 2.0 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 1.31 (t, J =
7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 187.9, 165.6, 158.6, 140.6, 135.4, 128.3, 127.2, 125.9,
122.8, 114.2, 67.2, 60.8, 14.2.
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Preparation of other substrates
Ethyl 7ꢀoxoheptꢀ2ꢀenoate (1)15 To solution of tetrahydroꢀ2Hꢀpyranꢀ2ꢀol (7.00 g, 68.54 mmol) in anhyꢀ
drous 1,4ꢀdioxane (100 ml) 21 (29.80 g, 85.68 mmol) was added. After 12 h of continuous stirring reacꢀ
tion mixture was heated up to 45 °C for 2 h. After solvent evaporation crude mixture was purified by
flash chromatography Hx/EA (95:5 to 3:1) to give ethyl 7ꢀhydroxyheptꢀ2ꢀenoate as a mixture of diasterꢀ
eoisomers E/Z >95/5. Ethylꢀ7ꢀhydroxyheptꢀ2ꢀenoate was dissolved in anhydrous methylene chloride (60
ml) and was added to oxidative mixture prepared by addition of anhydrous dimethyl sulfoxide (19.6 ml,
275.93 mmol) to solution of oxalyl chloride (11.8 ml, 137.96 mmol) in anhydrous methylene chloride
(100 ml) cooled to ꢀ78 °C. After 1 h of stirring in ꢀ78 °C triethylamine (58.2 ml, 413.89 mmol) was
added and strirring was continued for next 30 min. After that time reaction mixture was allowed to
slowly warm to room temperature. The reaction was quenched with addition of sat. NH4Cl (100 ml),
followed by addition of water (100 ml). The aqueous layer was extracted with methylene chloride (3 x
100 ml), and combined organic layers were washed with water (2 x 100 ml) and brine (100 ml). The
organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure (below 35
°C). Crude product was purified by flash chromatography Hx/EA (95:5) to (4:1) to give 1 as an almost
pure E diastereoisomer (traces of Zꢀproduct) as colorless oil (6.23 g, 37.01 mmol), 54% after 2 steps. 1H
NMR (600 MHz, CDCl3) δ 9.78 (t, J = 1.4 Hz, 1H), 6.92 (dt, J = 15.6, 6.9 Hz, 1H), 5.84 (dt, J = 15.6,
1.6 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.49 (td, J = 7.3, 1.4 Hz, 2H), 2.26 (ddd, J = 14.7, 7.4, 1.6 Hz,
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2H), 1.81 (p, J = 7.3 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). C NMR (151 MHz, CDCl3) δ 201.6, 166.4,
147.5, 122.3, 60.3, 42.9, 31.2, 20.3, 14.2.
Ethyl (E)ꢀ3ꢀ(2ꢀformylphenyl)acrylate (4)23 To the solution of phthaldialdehyde (1.0 g, 7.45 mmol) in
anhydrous toluene 21 (2.6 g, 7.45 mmol) was added in one portion. The reaction mixture was heated to
50 °C under argon for 2 h. After solvent removal, semisolid residue was purified by column chromatogꢀ
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raphy in Hx/EA gradient which results product as a clear, colorless oil (0.74 g, 3.62 mmol), 47%. H
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NMR (600 MHz, CDCl3) δ 10.24 (s, 1H), 8.45 (d, J = 15.9 Hz, 1H), 7.82 (d, J = 7.1 Hz, 1H), 7.59 –
7.52 (m, 2H), 7.49 (td, J = 7.4, 1.8 Hz, 1H), 6.31 (d, J = 15.9 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 1.29 (t,
J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 191.7, 166.2, 140.9, 136.7, 133.9, 133.8, 132.1, 129.8,
128.0, 123.3, 60.8, 14.3.
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Ethyl (E)ꢀ3ꢀ(2ꢀformylphenoxy)acrylate (6) To the solution of salicylic aldehyde (1.00 g, 8.19 mmol) in
anhydrous methylene chloride (10 ml) ethyl propiolate (0.99 ml, 9.83 mmol) was added in one portion.
After addition catalytic amount of Nꢀmethylmorpholine (0.09 ml, 0.82 mmol) reaction mixture was
stirred under argon for 12 h in room temperature. After that time solvent was removed under reduced
pressure and crude product was purified by column chromatography in Hx/EA gradient (5:1 to 3:1)
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which gave pure product as a colorless oil (1.51 g, 6.86 mmol), 84 %. H NMR (600 MHz, CDCl3) δ
10.39 (d, J = 0.7 Hz, 1H), 7.95 (dd, J = 7.7, 1.7 Hz, 1H), 7.86 (d, J = 12.2 Hz, 1H), 7.67 (ddd, J = 8.3,
7.4, 1.8 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 5.66 (d, J = 12.2 Hz, 1H), 4.23 (q, J
= 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 188.1, 166.5, 158.0, 157.5,
136.0, 128.9, 126.5, 125.4, 118.3, 104.2, 60.4, 14.3.
General procedure for tandem seleno-Michael/aldol-oxidation/elimination reaction (Procedure C).
A suspension of elemental selenium (0.50 g, 0.63 mmol) in anhydrous THF (0.8 ml) was cooled in ice
bath and nꢀBuLi (1.6 M in hexanes, 0.394 ml, 0.63 mmol) was added dropwise (a clear, almost colorꢀ
less, solution was produced) and the mixture was stirred 15 min in 0 °C. After that reaction mixture was
cooled to ꢀ20 °C followed by addition anhydrous toluene (3 ml). Solution of substrate (0.53 mmol in 1.5
ml of anhydrous toluene) was added dropwise and stirring was continued through the next 6 hours. Afꢀ
ter that time, reaction was quenched by addition of aqueous, saturated solution of NH4Cl (0.100 ml)
following by addition of hydrogen peroxide solution (30 % v/v, 0.325 ml, 3.15 mmol) and pyridine
(0.254 ml, 3.15 mmol). Reaction mixture was allowed to slowly back to room temperature and after that
was heated to 50 °C for 1 hour (reaction mixture became almost colorless). The solvent was evaporated
under reduced pressure and resign of pyridine was coꢀevaporated with toluene (2 x 15 ml). Crude prodꢀ
ucts were purified by column chromatography Hx/EA gradient.
Ethyl 6ꢀhydroxycyclohexꢀ1ꢀeneꢀ1ꢀcarboxylate (1a)15 Procedure C: colorless oil (0.065g, 0.38 mmol),
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72%. H NMR (600 MHz, CDCl3) δ 7.10 (t, J = 4.0 Hz, 1H), 4.54 (t, J = 4.4 Hz, 1H), 4.23 (q, J = 7.1
Hz, 2H), 3.15 (s, 1H), 2.33 – 2.23 (m, 1H), 2.18 – 2.10 (m, 1H), 1.87 – 1.72 (m, 3H), 1.65 – 1.55 (m,
1H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 167.3, 142.8, 132.4, 63.5, 60.6, 29.9, 26.1,
17.5, 14.2.
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Ethyl 5ꢀhydroxycyclopentꢀ1ꢀeneꢀ1ꢀcarboxylate (2a)15 Procedure C: colorless oil (0.063 g, 0.40 mmol),
75%. 1H NMR (600 MHz, CDCl3) δ 6.91 (t, J = 2.5 Hz, 1H), 5.12 – 5.06 (m, 1H), 4.25 (q, J = 7.2 Hz,
2H), 2.65 (m, 1H), 2.45 – 2.38 (m, 1H), 2.38 – 2.32 (m, 1H), 1.88 (m, 1H), 1.32 (t, J = 7.1 Hz, 3H). 13C
NMR (151 MHz, CDCl3) δ 165.0, 146.2, 138.0, 75.5, 60.4, 31.8, 30.8, 14.2.
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Ethyl 7ꢀhydroxycycloheptꢀ1ꢀeneꢀ1ꢀcarboxylate (3a)15 Procedure C: colorless oil (0.026 g, 0.14 mmol),
27%. 1H NMR (600 MHz, CDCl3) δ 7.16 (t, J = 6.5 Hz, 1H), 4.81 (dd, J = 7.6, 2.2 Hz, 1H), 4.21 (q, J =
7.1 Hz, 2H), 3.20 (s, 1H), 2.48 – 2.38 (m, 1H), 2.33 – 2.22 (m, 1H), 2.01 – 1.92 (m, 2H), 1.82 – 1.76 (m,
1H), 1.76 – 1.63 (m, 2H), 1.62 – 1.55 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ
168.4, 145.2, 136.8, 68.6, 60.8, 32.3, 27.3, 25.7, 23.5, 14.2.
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Ethyl 1ꢀhydroxyꢀ1Hꢀindeneꢀ2ꢀcarboxylate (4a) Procedure C: colorless oil (0.065 g, 0.32 mmol), 60%.
1H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 7.3 Hz, 1H), 7.56 (s, 1H), 7.41 (dd, J = 6.5, 1.0 Hz, 1H),
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7.40 – 7.33 (m, 2H), 5.43 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 3.19 (s, 1H), 1.38 (t, J = 7.1 Hz, 3H). C
NMR (151 MHz, CDCl3) δ 164.8, 145.8, 141.3, 139.7, 139.3, 128.9, 128.9, 124.3, 123.8, 75.6, 60.7,
14.3.
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Ethyl 2ꢀnaphthoate (5b) Procedure C: colorless oil (0.085 g, 0.42 mmol), 80%. H NMR (600 MHz,
CDCl3) δ 8.63 (d, J = 0.7 Hz, 1H), 8.08 (dd, J = 8.6, 1.7 Hz, 1H), 7.97 (dd, J = 8.1, 0.6 Hz, 1H), 7.89 (d,
J = 8.6 Hz, 2H), 7.60 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.55 (ddd, J = 8.0, 6.9, 1.3 Hz, 1H), 4.46 (q, J =
7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 166.8, 135.5, 132.5, 130.9, 129.3,
128.1, 128.1, 127.7 (2C), 126.6, 125.2, 61.1, 14.4.
Ethyl 5ꢀhydroxyꢀ2,5ꢀdihydrobenzo[b]oxepineꢀ4ꢀcarboxylate (7a) Procedure C: white, amorphous solid
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(0.081 g, 0.34 mmol), 65%. H NMR (600 MHz, CDCl3) δ 7.22 (d, J = 7.4 Hz, 2H), 7.08 – 7.03 (m,
2H), 6.82 (dd, J = 3.8, 2.2 Hz, 1H), 5.49 (d, J = 9.3 Hz, 1H), 4.93 (dd, J = 19.2, 3.9 Hz, 1H), 4.49 (dd, J
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= 19.2, 2.1 Hz, 1H), 4.24 – 4.17 (m, 2H), 3.14 (d, J = 9.6 Hz, 1H), 1.26 (t, J = 7.1 Hz, 3H). C NMR
(151 MHz, CDCl3) δ 166.2, 156.8, 140.3, 136.7, 133.9, 129.9, 128.6, 125.1, 121.7, 70.8, 69.1, 61.4,
14.2. HRMS (ESI): calcd. for C13H14O4Na [M+Na]+ 257.0784, found 257.0784.
Ethyl 5ꢀhydroxyꢀ8ꢀmethoxyꢀ2,5ꢀdihydrobenzo[b]oxepineꢀ4ꢀcarboxylate (8a) Procedure C: white, amorꢀ
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phous solid (0.118 g, 0.45 mmol), 85%. H NMR (600 MHz, CDCl3) δ 7.20 (d, J = 8.3 Hz, 1H), 6.90
(dd, J = 4.0, 2.2 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 8.3, 2.5 Hz, 1H), 5.51 (d, J = 8.5 Hz,
1H), 4.99 (dd, J = 19.1, 4.1 Hz, 1H), 4.57 (dd, J = 19.1, 2.2 Hz, 1H), 4.34 – 4.22 (m, 2H), 3.80 (s, 3H),
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3.00 (d, J = 9.0 Hz, 1H), 1.34 (t, J = 7.1 Hz, 3H). C NMR (151 MHz, CDCl3) δ 166.3, 160.9, 157.9,
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140.0, 134.1, 129.6, 128.7, 109.9, 107.8, 70.6, 68.8, 61.4, 55.5, 14.2; HRMS (ESI): calcd. for
C14H16O5Na [M+Na]+ 287.0890, found 287.0890.
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Ethyl 5ꢀhydroxyꢀ8ꢀmethylꢀ2,5ꢀdihydrobenzo[b]oxepineꢀ4ꢀcarboxylate (9a) Procedure C: white, amorꢀ
phous solid (0.093 g, 0.38 mmol), 71%. 1H NMR (600 MHz, CDCl3) δ 7.17 (d, J = 8.0 Hz, 1H), 6.96 –
6.92 (m, 2H), 6.89 (dd, J = 3.9, 2.2 Hz, 1H), 5.53 (d, J = 9.3 Hz, 1H), 4.99 (dd, J = 19.2, 3.9 Hz, 1H),
4.55 (dd, J = 19.2, 2.2 Hz, 1H), 4.32 – 4.25 (m, 2H), 3.11 (d, J = 9.5 Hz, 1H), 2.34 (s, 3H), 1.34 (t, J =
7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 166.3, 156.7, 140.3, 134.0, 133.6, 128.5, 125.6, 122.3,
70.7, 68.9, 61.4, 21.1, 14.2. HRMS (ESI): calcd. for C14H16O4Na [M+Na]+ 271.0941, found 271.0941.
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Ethyl 5ꢀhydroxyꢀ7ꢀmethoxyꢀ2,5ꢀdihydrobenzo[b]oxepineꢀ4ꢀcarboxylate (10a) Procedure C: white,
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amorphous solid (0.122 g, 0.46 mmol), 87%. H NMR (600 MHz, CDCl3) δ 7.03 (d, J = 8.7 Hz, 1H),
6.88 (dd, J = 3.7, 2.2 Hz, 1H), 6.83 (d, J = 3.0 Hz, 1H), 6.78 (dd, J = 8.7, 3.0 Hz, 1H), 5.51 (d, J = 9.3
Hz, 1H), 4.94 (dd, J = 19.3, 3.8 Hz, 1H), 4.52 (dd, J = 19.3, 2.1 Hz, 1H), 4.31 – 4.24 (m, 2H), 3.78 (s,
13
3H), 3.34 (d, J = 9.8 Hz, 1H), 1.33 (t, J = 7.1 Hz, 3H). C NMR (151 MHz, CDCl3) δ 166.2, 156.5,
150.2, 140.6, 137.7, 133.7, 122.3, 114.4, 113.6, 71.0, 69.1, 61.4, 55.6, 14.2; HRMS (ESI): calcd. for
C14H16O5Na [M+Na]+ 287.0890, found 287.0890.
Ethyl 5ꢀhydroxyꢀ7ꢀmethylꢀ2,5ꢀdihydrobenzo[b]oxepineꢀ4ꢀcarboxylate (11a) Procedure C: white, amorꢀ
phous solid (0.111 g, 0.45 mmol), 85%. 1H NMR (600 MHz, CDCl3) δ 7.12 – 7.08 (m, 2H), 7.01 (d, J =
7.9 Hz, 1H), 6.89 (dd, J = 3.8, 2.1 Hz, 1H), 5.52 (d, J = 9.1 Hz, 1H), 4.98 (dd, J = 19.3, 3.8 Hz, 1H),
4.54 (dd, J = 19.2, 2.1 Hz, 1H), 4.32 – 4.26 (m, 2H), 3.20 (d, J = 9.6 Hz, 1H), 2.32 (s, 3H), 1.34 (t, J =
7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 166.3, 154.6, 140.5, 136.4, 134.8, 134.0, 130.2, 129.2,
121.4, 70.9, 69.2, 61.4, 20.8, 14.3. HRMS (ESI): calcd. for C14H16O4Na [M+Na]+ 271.0941, found
271.0941.
Ethyl 7ꢀchloroꢀ5ꢀhydroxyꢀ2,5ꢀdihydrobenzo[b]oxepineꢀ4ꢀcarboxylate (12a) Procedure C: white, amorꢀ
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phous solid (0.097 g, 0.36 mmol), 68%. H NMR (600 MHz, CDCl3) δ 7.30 (d, J = 2.6 Hz, 1H), 7.25
(dd, J = 8.5, 2.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.88 (dd, J = 3.7, 2.3 Hz, 1H), 5.55 (s, 1H), 4.97 (dd,
J = 19.2, 3.8 Hz, 1H), 4.56 (dd, J = 19.2, 2.7 Hz, 1H), 4.32 – 4.25 (m, 2H), 3.35 (s, 1H), 1.34 (t, J = 7.1
13
Hz, 3H). C NMR (151 MHz, CDCl3) δ 166.1, 155.3, 140.1, 138.3, 133.4, 130.1, 129.6, 128.5, 123.1,
70.8, 68.5, 61.6, 14.2. HRMS (ESI): calcd. for C13H13O4ClNa [M+Na]+ 291.0395, found 291.0395.
Ethyl (1R,4R,5S)ꢀ4ꢀhydroxybicyclo[3.2.1]octꢀ2ꢀeneꢀ3ꢀcarboxylate (exoꢀ13a) and Ethyl (1R,4S,5S)ꢀ4ꢀ
hydroxybicyclo[3.2.1]octꢀ2ꢀeneꢀ3ꢀcarboxylate (endo-13a) Procedure C: colorless oil (0.071 g, 0.36
1
mmol), 68% (5:1 exo/endo); exoꢀ13a: H NMR (600 MHz, CDCl3) δ 7.24 (dd, J = 7.0, 1.1 Hz, 1H),
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4.23 – 4.17 (m, 2H), 4.11 (d, J = 2.8 Hz, 1H), 2.71 (s, 1H), 2.67 (dd, J = 9.8, 6.3 Hz, 1H), 2.55 – 2.49
(m, 1H), 1.93 – 1.87 (m, 1H), 1.85 (d, J = 11.3 Hz, 1H), 1.71ꢀ1.64 (m, 1H), 1.63 – 1.58 (m, 1H), 1.35ꢀ
1.31 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.24 – 1.19 (m, 1H). 13C NMR (151 MHz, CDCl3) δ 167.7,
148.6, 129.1, 70.9, 60.5, 38.7, 35.6, 30.3, 30.2, 24.7, 14.2; HRMS (ESI): calcd. for C11H16O3Na
[M+Na]+ 219.0991, found 219.0992. endoꢀ13a: 1H NMR (600 MHz, CDCl3) δ 7.19 (d, J = 6.7 Hz, 1H),
4.77 (d, J = 4.8 Hz, 1H), 4.24 – 4.17 (m, 2H), 3.71 (s, 1H), 2.62 – 2.56 (m, 2H), 2.21 – 2.14 (m, 1H),
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1.78 – 1.72 (m, 3H), 1.72 – 1.62 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H). C NMR (151 MHz, CDCl3) δ
167.6, 148.2, 129.6, 71.7, 60.6, 39.6, 36.5, 36.3, 32.0, 21.2, 14.2; HRMS (ESI): calcd. for C11H16O3Na
[M+Na]+ 219.0991, found 219.0992.
(6ꢀhydroxycyclohexꢀ1ꢀenꢀ1ꢀyl)(phenyl)methanone (14a)15 Procedure C: colorless oil (0.103 g, 0.51
1
mmol), 96%. H NMR (600 MHz, CDCl3) δ 7.69 – 7.63 (m, 2H), 7.57 – 7.52 (m, 1H), 7.44 (dd, J =
10.7, 4.7 Hz, 2H), 6.77 – 6.71 (m, 1H), 4.74 (dd, J = 6.0, 2.8 Hz, 1H), 3.54 (s, 1H), 2.40 – 2.32 (m, 1H),
2.30 – 2.20 (m, 1H), 1.98 – 1.90 (m, 1H), 1.90 – 1.81 (m, 1H), 1.66 (qd, J = 7.1, 3.8 Hz, 1H). 13C NMR
(151 MHz, CDCl3) δ 199.4, 147.2, 139.9, 137.7, 132.0, 129.3, 128.2, 64.0, 29.7, 26.4, 17.4.
Total Synthesis of β-(+)-valienamine.
2,3,4ꢀTriꢀOꢀbenzylꢀ
D
ꢀxylopyranose (20)24,25 To methanolic solution of 1.2 % HCl (100 ml) (prepared by
ꢀxylose (10 g, 66.6 mmol) was added in one portion
dissolved 2.4 ml SOCl2 in anhydrous methanol)
D
and resulting mixture was refluxed for 4.5 h under argon (reaction was monitored by TLC
CH2Cl2/MeOH 2:1). The reaction mixture was allowed to cool to rt, neutralized by addition of solid
NaHCO3 and concentrated under reduced pressure. The residue was dissolved in EtOH (80 ml) and conꢀ
centrated to the half of the original volume, toluene (2 x 50 ml) was added and the mixture was two
times concentrated to dryness. The residue crude mixture oil was used without further purification in the
next step. The viscous oil from the previous step was dissolved in anhydrous DMF (100 ml) and anhyꢀ
drous THF (100 ml) and in 5 portion was added to 60% NaH suspension in mineral oil (13.6 g, 340
mmol) cooled to 0 °C. After hydrogen evolution was complete the mixture was treated with BnBr (29.6
ml, 244 mmol) and stirred for 30 min in 0 °C and then overnight in rt. The reaction mixture was carefulꢀ
ly quenched with 10 % cold, aqueous solution of NH4Cl (60 ml) followed by addition of water (150 ml).
The aqueous layer was extracted with ethyl acetate (3 x 100 ml) and combined organic layers were
washed with water (2 x 120 ml) and brine (100 ml), then dried over anhydrous MgSO4 and concentrated
under reduced pressure. Flash column chromatography Hx/EA (8:1) to (6:1) allows to remove mayor
impurities before next step. The partially purified mixture of xylosides from previous step was heated
under reflux for 15 h with 1M H2SO4 (90 ml), AcOH (90 ml) and 1,4ꢀdioxane (80 ml). Mixture was
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cooled to rt, hexane (40 ml) and water (200 ml) were added with intense stirring. The precipitate was
collected by filtration, washed with hexane (2 x 50 ml) and dried under vacuo. Recrystallization from
methanol gave product as a white solid (19.48 g, 69 %), mp 137ꢀ139 °C (137ꢀ138 °C lit.), 1H NMR and
13C NMR spectra were compared with lit.25
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Ethyl (4S,5R,6R)ꢀ4,5,6ꢀtriꢀOꢀbenzylꢀ7ꢀhydroxyheptꢀ2ꢀenoate (20a) To solution of 21 (3.65 g, 10.46
mmol) in anhydrous toluene (10 ml), 20 (2.00 g, 4.76 mmol) was added in one portion and mixture was
heated to 95 °C for 8 h (reaction was monitored by TLC CHCl3/Acetone 20:1). The reaction mixture
was concentrated under reduced pressure and pass through thin pad of silica to remove part of triꢀ
phenylphosphine oxide (product was eluted with ca. 200 ml Et2O). After concentration under reduced
pressure crude product was purified by chromatography CHCl3/Acetone (1:0) to (93:7). Product as a
mixture of diastereoisomers (E/Z, 1:0.25) was obtained as a colorless oil (1.52 g, 65%). Eꢀ20a: [α]ꢁꢀꢂ= ꢀ
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5.2 (c 1.0, CH2Cl2); H NMR (600 MHz, CDCl3) δ 7.37 – 7.26 (m, 15H), 6.96 (dd, J = 15.8, 5.9 Hz,
1H), 6.07 (dd, J = 15.8, 1.4 Hz, 1H), 4.72 – 4.67 (m, 2H), 4.65 – 4.56 (m, 3H), 4.40 (d, J = 11.7 Hz,
1H), 4.28 – 4.24 (m, 1H), 4.24 – 4.18 (m, 2H), 3.75 – 3.64 (m, 2H), 3.62 (dd, J = 10.1, 4.5 Hz, 1H), 3.54
(dt, J = 10.0, 4.8 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 165.9, 144.6, 138.1,
137.7, 137.3, 128.5, 128.5, 128.4, 128.0, 127.9, 127.8, 123.3, 80.7, 79.3, 78.2, 74.7, 72.9, 71.8, 61.3,
60.5, 14.2; HRMS (ESI): calcd. for C30H34O6Na [M+Na]+ 513.2248, found 513.2238. Zꢀ20a: [α]ꢀꢁꢃ=
+58.5 (c 0.65, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.39 – 7.24 (m, 15H), 6.37 (dd, J = 11.7, 8.2 Hz,
1H), 5.80 (dd, J = 11.7, 1.3 Hz, 1H), 5.17 (d, J = 11.6 Hz, 1H), 4.76 (d, J = 11.4 Hz, 2H), 4.65 – 4.57
(m, 3H), 4.35 (d, J = 11.8 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.85 – 3.80 (m, 2H), 3.69 – 3.64 (m, 1H),
3.50 – 3.45 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 165.8, 148.9, 138.5,
138.1, 137.5, 128.5, 128.4, 128.2, 127.9, 127.9, 127.7, 127.6, 81.3, 80.3, 75.1, 73.8, 73.2, 71.5, 61.6,
60.4, 14.2; HRMS (ESI): calcd. for C30H34O6Na [M+Na]+ 513.2248, found 513.2248.
Ethyl (4S,5R,6R)ꢀ4,5,6ꢀtriꢀOꢀbenzylꢀ7ꢀoxoheptꢀ2ꢀenoate (17) A solution of oxalyl chloride (0.629 ml,
7.34 mmol) in anhydrous methylene chloride (30 ml) was cooled to ꢀ78 °C, after that DMSO (1.042 ml,
14.68 mmol) was dropwise added and stirred for 30 min. The 20a (1.20 g, 2.45 mmol) was dissolved in
dry CH2Cl2 (15 ml) and slowly added to oxidative mixture and kept in ꢀ78 °C for 30 min. The triethylaꢀ
mine (3.094 ml, 22.01 mmol) was added, and continued stirring for next 30 min, after that reaction
mixture was allowed slowly warm to 0 °C. The reaction was quenched with addition of sat. NH4Cl (20
ml), followed by addition of water (20 ml). The aqueous layer was extracted with CH2Cl2 (3 x 20 ml),
and combined organic layers were washed with water (2 x 20 ml) and brine (20 ml). The organic phase
was dried over anhydrous MgSO4 and concentrated under reduced pressure (below 35 °C). Crude prodꢀ
uct was purified by flash chromatography Hx/EA (1:0) to (85:15) to give the title compound as a mixꢀ
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ture of diastereoisomers (E/Z 1:0.1) as colorless oil (1.080 g, 90 %); Eꢀ17: [α]ꢁꢀꢂ= ꢀ5.4 (c 1.0, CH2Cl2);
1H NMR (600 MHz, CDCl3) δ 9.65 (d, J = 0.5 Hz, 1H), 7.38 – 7.27 (m, 13H), 7.22 (dd, J = 7.4, 1.8 Hz,
2H), 6.88 (dd, J = 15.8, 6.2 Hz, 1H), 6.01 (dd, J = 15.8, 1.3 Hz, 1H), 4.72 (d, J = 11.8 Hz, 1H), 4.62 (d,
J = 11.8 Hz, 1H), 4.57 (d, J = 11.8 Hz, 1H), 4.50 (d, J = 11.7 Hz, 2H), 4.39 (d, J = 11.4 Hz, 1H), 4.28
(ddd, J = 6.0, 4.6, 1.3 Hz, 1H), 4.23 – 4.17 (m, 2H), 3.88 (dd, J = 4.4, 0.4 Hz, 1H), 3.82 (t, J = 4.5 Hz,
1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 201.2, 165.8, 144.2, 137.1, 137.1, 136.9,
128.5, 128.4, 128.4, 128.3, 128.2, 128.2, 128.1, 127.9, 123.6, 81.7, 80.7, 77.4, 74.3, 73.3, 72.0, 60.5,
14.2. HRMS (ESI): calcd. for C30H32O6Na [M+Na]+ 511.2091, found 511.2072. Zꢀ17: [α]ꢀꢁꢃ= +27.1 (c
0.85, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 9.74 (d, J = 0.7 Hz, 1H), 7.42 – 7.21 (m, 15H), 6.35 (dd,
J = 11.8, 8.3 Hz, 1H), 5.84 (dd, J = 11.8, 1.3 Hz, 1H), 5.37 (ddd, J = 8.3, 3.0, 1.3 Hz, 1H), 4.77 (d, J =
12.0 Hz, 1H), 4.66 (d, J = 12.0 Hz, 1H), 4.64 – 4.55 (m, 2H), 4.51 – 4.43 (m, 2H), 4.14 (q, J = 7.1 Hz,
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2H), 4.05 (dd, J = 5.6, 3.0 Hz, 1H), 3.98 (dd, J = 5.6, 0.7 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H); C NMR
(101 MHz, CDCl3) δ 200.3, 165.5, 147.5, 137.4, 137.3, 128.4, 128.4, 128.3, 128.2, 128.0, 128.0, 127.9,
127.7, 122.2, 81.4, 81.1, 74.1, 73.7, 72.9, 72.0, 60.3, 14.1; HRMS (ESI): calcd. for C30H32O6Na
[M+Na]+ 511.2091, found 511.2090.
Ethyl (3S,4R,5R,6S)ꢀ3,4,5ꢀtriꢀOꢀbenzylꢀ6ꢀhydroxycyclohexꢀ1ꢀenecarboxylate (anti-18) and Ethyl
(3S,4R,5R,6R)ꢀ3,4,5ꢀtriꢀOꢀbenzylꢀ6ꢀhydroxycyclohexꢀ1ꢀenecarboxylate (syn-18) A suspension of eleꢀ
mental selenium (0.116 g, 1.47 mmol) in anhydrous THF (20 ml) was cooled in ice bath and nꢀBuLi
(1.6 M in hexanes, 0.918 ml, 1.47 mmol) was added dropwise (a clear solution was produced) and the
mixture was stirred 15 min in 0 °C. After that reaction mixture was cooled to ꢀ20 °C, solution of subꢀ
strate 17 (0.60 g, 1.23 mmol in 3 ml of anhydrous THF) was added dropwise and stirring was continued
through the next 6 hours. After that time, reaction was quenched by addition of aqueous, saturated soluꢀ
tion of NH4Cl (0.500 ml) following by addition of hydrogen peroxide solution (30 % v/v, 0.633 ml, 6.15
mmol) and pyridine (0.495 ml, 6.15 mmol). Reaction mixture was allowed to slowly back to rt and after
that was heated to 50 °C for 1 hour (reaction mixture became almost colorless). The solvent was evapoꢀ
rated under reduced pressure and resign of pyridine was coꢀevaporated with toluene (2 x 30 ml). Crude
products (mixture of diastereoisomers anti/syn 74:26) were purified by column chromatography Hx/EA
(6:1) to (5:1). Pure synꢀ18 (0.101 g, 17%) and antiꢀ18 (0.289 g, 48%) diastereoisomers were obtained as
a colorless syrups. Synꢀ18: [α]ꢁꢀꢂ= +3.4 (c 1.0, CH2Cl2); 1H NMR (600 MHz, CDCl3) δ 7.40 – 7.27 (m,
15H), 6.92 (d, J = 2.4 Hz, 1H), 4.96 (d, J = 10.9 Hz, 1H), 4.85 (d, J = 10.9 Hz, 1H), 4.82 (d, J = 11.6 Hz,
1H), 4.79 (d, J = 11.6 Hz, 1H), 4.76 (d, J = 3.8 Hz, 1H), 4.74 (s, 2H), 4.29 – 4.22 (m, 2H), 4.19 (dd, J =
7.8, 2.4 Hz, 1H), 4.12 (dd, J = 10.3, 7.8 Hz, 1H), 3.52 (dd, J = 10.3, 3.8 Hz, 1H), 2.75 (s, 1H), 1.31 (t, J
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= 7.1 Hz, 3H); C NMR (151 MHz, CDCl3) δ 165.5, 140.1, 138.6, 137.9, 137.8, 130.6, 128.5, 128.4,
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128.3, 128.0, 127.9, 127.8, 127.6, (2C)79.1, 78.9, 75.4, 72.8, 72.4, 64.4, 61.2, 14.2; HRMS (ESI):
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calcd. for C30H32O6Na [M+Na]+ 511.2091, found 511.2086. Antiꢀ18: [α]ꢁꢀꢂ= +23.5 (c 1.0, CH2Cl2); H
NMR (600 MHz, CDCl3) δ 7.39 – 7.25 (m, 15H), 6.78 (dd, J = 2.1, 1.2 Hz, 1H), 4.92 (d, J = 11.2 Hz,
1H), 4.89 (d, J = 11.0 Hz, 1H), 4.86 (d, J = 11.2 Hz, 1H), 4.79 (d, J = 11.0 Hz, 1H), 4.76 – 4.70 (m, 2H),
4.69 – 4.65 (m, J = 5.3 Hz, 1H), 4.28 – 4.25 (m, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.74 – 3.68 (m, 2H), 3.51
(d, J = 1.6 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 166.0, 138.6, 138.3, 137.8,
131.3, 128.5, 128.4, 128.3, 128.0, 127.9, 127.9, 127.7, 127.6, 82.9, 81.7, 78.4, 75.4, 75.3, 73.1, 71.9,
61.3, 14.2. HRMS (ESI): calcd. for C30H32O6Na [M+Na]+ 511.2091, found 511.2096.
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(3S,4R,5R,6S)ꢀ3,4,5ꢀtriꢀOꢀbenzylꢀ6ꢀhydroxyꢀ1ꢀhydroxymethylꢀcyclohexene (antiꢀ18a) A solution of
compound antiꢀ18 (0.250 g, 0.51 mmol) in anhydrous methylene chloride (5 ml) was cooled to ꢀ10 °C
and solution of DIBALꢀH (1 M in hexane, 1.790 ml, 1.79 mmol) was added dropwise. When the addiꢀ
tion was complete, the mixture was stirred at ꢀ10 °C for 3 h. After that time, H2O (0.200 ml) was added
to quench the reaction, and mixture was stirred at ꢀ10 °C for 30 min. Evaporation of the solvent under
reduced pressure gave a crude solid residue. Then, methanol (10 ml) and celite (~1 g) were added and
the mixture was vigorously stirred at room temperature for 30 min and then filtered by suction through
thin pad of celite. Crude product was eluted with methanol (20ꢀ30 ml, TLCꢀcheck) and filtrate was conꢀ
centrated under vacuo to give oily residue. Crude product was purified by column chromatography
Hx/EA (2:1) to (1:1). Pure antiꢀ18a was obtained as a colorless syrup (0.139 g, 61%). [α]ꢁꢀꢃ= +77.1 (c
1
0.8, CHCl3); H NMR (400 MHz, CDCl3) δ 7.39 – 7.27 (m, 15H), 5.69 (s, 1H), 5.00 (d, J = 11.5 Hz,
1H), 4.88 (s, 2H), 4.72 – 4.66 (m, 3H), 4.38 (d, J = 7.7 Hz, 1H), 4.27 – 4.09 (m, 3H), 3.75 (dd, J = 10.1,
7.4 Hz, 1H), 3.59 (dd, J = 10.1, 7.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 138.4, 138.3, 138.2, 138.1,
128.6, 128.4, 128.4, 127.9, 127.9, 127.8, 127.8, 127.7, 123.7, 83.6, 82.9, 79.7, 75.2, 75.1, 73.0, 72.3,
64.2; HRMS (ESI): calcd. for C28H30O5Na [M+Na]+ 469.1985, found 469.1985.
(3S,4R,5R,6S)ꢀ3,4,5,6ꢀpentaꢀOꢀbenzylꢀ1ꢀOꢀbenzylmethylꢀcyclohexene (22) To stirred suspension of NaH
(0.035 g, 0.87 mmol, 60% in mineral oil) in anhydrous DMF (3 ml) was added a solution of antiꢀ18a
(0.130 g, 0.29 mmol) and BnBr (0.104 ml, 0.87 mmol) at 0 °C under argon. After 30 min stirring, ice
bath was removed and stirring was continued overnight in room temperature. The reaction mixture was
carefully quenched with a cold, 10% aqueous solution of NH4Cl (3 ml). The aqueous layer was extractꢀ
ed with ethyl acetate (3 x 5 ml). The organic layer was washed with H2O (7 ml) and brine (7 ml), dried
over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by column
chromatography Hx/EA (9:1) to (8:1). Pure 22 was obtained as an amorphous white solid (0.174 g,
95%). [α]ꢁꢀꢃ= +59.2 (c 0.36, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.26 (m, 25H), 5.82 (s, 1H),
5.02 (d, J = 10.9 Hz, 1H), 4.94 (s, 2H), 4.89 – 4.81 (m, 2H), 4.73 (d, J = 9.2 Hz, 3H), 4.58 – 4.47 (m,
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2H), 4.34 (d, J = 7.0 Hz, 1H), 4.29 – 4.21 (m, 2H), 3.96 (d, J = 12.3 Hz, 1H), 3.90 – 3.77 (m, 2H); C
NMR (101 MHz, CDCl3) δ 138.6, 138.6, 138.4, 138.3, 138.1, 136.4, 128.4, 128.4, 128.3, 128.3, 127.9,
127.9, 127.8, 127.8, 127.6, 127.6, 127.60, 125.17, 84.4, 83.7, 80.0, 79.8, 75.5, 75.5, 74.9, 72.4, 72.2,
69.8; HRMS (ESI): calcd. for C42H42O5Na [M+Na]+ 649.2924, found 649.2924.
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Benzyl ((3S,4R,5R,6S)ꢀ4,5,6ꢀtriꢀOꢀbenzylꢀ3ꢀ((benzyloxy)methyl)cyclohexꢀ2ꢀenꢀ1ꢀyl)carbamate (19) To
stirred solution of 22 (0.170 g, 0.27 mmol) in anhydrous toluene (1.8 ml) was added Na2CO3 (0.316 g,
2.98 mmol) and chlorosulfonyl isocyanate (0.189 ml, 2.17 mmol) at 0 °C under argon. The reaction
mixture was stirred 15 h at 0 °C and quenched with carefully addition H2O (2 ml). The aqueous layer
was extracted with ethyl acetate (3 x 4 ml). The organic layer was added to solution of aqueous 25%
Na2SO3 (12 ml). The reaction mixture was stirred for 24 h at room temperature. The organic layer was
washed with H2O (~6 ml) and brine (~6 ml), dried over anhydrous MgSO4 and concentrated under reꢀ
duced pressure. The solid residue was purified by column chromatography DCM/Acetone (1:0) to
(99:1) to afford 19 (0.135 g, 74%) as a white solid, mp. 117ꢀ118 °C (116ꢀ119 °C for enantiomer lit.).22
[α]ꢁꢀꢃ= +83.2 (c 0.64, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.46 – 7.19 (m, 25H), 5.68 (s, 1H), 5.19 –
5.06 (m, 2H), 4.88 – 4.64 (m, 7H), 4.54 – 4.39 (m, 3H), 4.24 (d, J = 8.6 Hz, 2H), 3.95 – 3.86 (m, 2H),
3.61 – 3.52 (t, J = 7.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 155.9, 138.4, 138.2, 138.2, 136.6, 136.4,
128.6, 128.5, 128.5, 128.3, 128.2, 128.0, 128.0, 127.9, 127.9, 127.8, 127.7, 126.1, 82.3, 79.7, 77.9, 74.7,
74.3, 74.2, 72.6, 70.4, 66.8, 52.1; HRMS (ESI): calcd. for C43H43NO6Na [M+Na]+ 692.2983, found
692.2983. 1H NMR and 13C NMR spectra were compared with enantiomeric form published in lit.22
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βꢀ(+)ꢀvalienamine (16) To stirred solution of 19 (0.050 g, 0.07 mmol) in anhydrous methylene chloride
(1.5 ml) was added BCl3 (7 ml, 7 mmol, 1M in DCM) at ꢀ78 °C. The reaction mixture was stirred for 24
h in ꢀ78 °C and after that time quenched with methanol (1.5 ml) was added and kept in
ꢀ78 °C for next 1 h. The resulting mixture was warmed to room temperature and methylene chloride was
distilled. The resulting mixture of hydrogen chloride in methanol was refluxed for 3 h and then evapoꢀ
rated under reduced pressure. The residue was purified by ionꢀexchange resin DOWEX 50WX8ꢀ100
using 0.5 M NH4OH as eluent to afford free amine 16 (0.009 g, 69%) as a nearly colorless syrup.1H
NMR and 13C NMR spectra were compared with lit.26 [α]ꢀꢁꢃ= +83.5 (c 0.45, D2O); 1H NMR (600 MHz,
D2O) δ 5.48 – 5.45 (m, 1H), 4.13 – 4.08 (m, 2H), 3.99 (d, J = 14.1 Hz, 1H), 3.46 (dd, J = 10.4, 8.1 Hz,
1H), 3.41 (d, J = 8.8 Hz, 1H), 3.31 (dd, J = 10.2, 8.9 Hz, 1H); 13C NMR (151 MHz, D2O) δ 139.0,
123.4, 75.9, 74.5, 71.9, 61.0, 53.0; HRMS (ESI): calcd. for C7H13NO4Na [M+Na]+ 198.0736, found
198.0738, calcd. for C14H26N2O8Na [2M+Na]+ 373.1581, found 373.1587.
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βꢀ(+)ꢀvalienamine hydrochloride (16a) 16 (0.009 g, 0,05 mmol) was dissolved in water (1 ml). After
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addition 3 drops of 1M HCl, water was evaporated under high vacuum. Received syrup was dissolved in
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D2O and H and C NMR spectra were collected. H NMR (300 MHz, D2O) δ 5.61 – 5.56 (m, 1H),
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4.22 – 4.11 (m, 3H), 3.87 (d, J = 7.4 Hz, 1H), 3.67 – 3.52 (m, 2H); C NMR (75 MHz, D2O) δ 143.8,
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117.2, 76.0, 72.2, 71.9, 61.3, 54.1.
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ASSOCIATED CONTENT
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website. H and C
NMR spectra for the synthesized compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: szym.buda@gmail.com.
ORCID
Szymon Buda: 0000ꢀ0003ꢀ3711ꢀ3570
NOTES
There are no conflicts to declare.
ACKNOWLEDGMENT
Financial support from the Polish National Science Centre (Grant No. 2015/17/D/ST5/01334) is grateꢀ
fully acknowledged. The research was carried out with the equipment purchased thanks to the financial
support of the European Regional Development Fund in the framework of the Polish Innovation Econꢀ
omy Operational Program (contract no. POIG.02.01.00ꢀ12ꢀ023/08). JM thanks the Polish National Sciꢀ
ence Centre for financial support (MAESTRO Grant Nr. 2013/10/A/ST5/00233).
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