3-Alkyl-1,2-cyclopentanediones by Negishi cross-coupling of a 3-bromo-1,2-cyclopentanedione silyl enol ether with alkylzinc reagents: An approach to 2-substituted carboxylic acid γ-lactones, homocitric and lycoperdic acids

Article abstract of DOI:10.1016/j.tet.2015.10.014

Negishi cross-coupling of the silyl-protected 3-bromoenol of 1,2-cyclopentanedione with primary and secondary alkylzinc reagents using Pd-catalysts affords 3-alkyl substituted 1,2-cyclopentanediones in good yield. The method was applied to obtain 3-methyl

Full text of DOI:10.1016/j.tet.2015.10.014

Tetrahedron 71 (2015) 9313e9320
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
3-Alkyl-1,2-cyclopentanediones by Negishi cross-coupling of
a 3-bromo-1,2-cyclopentanedione silyl enol ether with alkylzinc
reagents: an approach to 2-substituted carboxylic acid
homocitric and lycoperdic acids
g
-lactones,
a
a
a
b
ꢀa
~
Anne Paju , Diana Kostomarova , Katharina Matkevits , Marit Laos , Tonis Pehk ,
a
a,
*
~
Tonis Kanger , Margus Lopp
a Department of Chemistry, Tallinn University of Technology, Akadeemia tee 15, 12618, Tallinn, Estonia
b National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618, Tallinn, Estonia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2015
Received in revised form 22 September 2015
Accepted 5 October 2015
Available online 22 October 2015
Negishi cross-coupling of the silyl-protected 3-bromoenol of 1,2-cyclopentanedione with primary and
secondary alkylzinc reagents using Pd-catalysts affords 3-alkyl substituted 1,2-cyclopentanediones in
good yield. The method was applied to obtain 3-methylalkoxycarbonyl- and 3(2-Boc-aminoethyl)-al-
koxycarbonyl-1,2-cyclopentanedionesdhomocitric and lycoperdic acid precursors. Homocitric and ly-
coperdic acids were synthesized using asymmetric oxidation with the Ti(OiPr)4/tartaric ester/tBuOOH
complex in two steps from the obtained precursors.
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Negishi coupling
3-Bromo-1,2-diketones
3-Alkyl-1,2-diketones
Homocitric acid
Lycoperdic acid
1. Introduction
Cross-coupling reactions are widely used tools for constructing
CeC bonds of organic molecules from vinyl halides and other
functionalized alkenes.1,2 There are some examples in the literature
of the replacement of leaving groups (LG) at the enol double
bond.3e7 The substitution of 3-bromine at a 1,2-diketone enol
double bond was recently demonstrated in our group: the Sono-
gashira coupling of 2-silylprotected 1,2-cyclopentanedione enol 3
(LG¼Br) afforded 3-alkynylsubstituted 1,2-diketones 2.8 We pro-
posed that the enol derivatives 3 like many similar vinylic com-
pounds undergo a Negishi cross-coupling reaction affording 3-
Scheme 1. Retrosynthetic sequence to lactone carboxylic acid derivatives.
In the present study the Negishi cross-coupling reaction of
silylprotected 3-bromo-1,2-cyclopentenedione silyl enol ether 5
with primary and secondary alkylzinc reagents 7 by using Pd-
catalysts was investigated. The obtained substituted 1,2-
cyclopentenediones 2f and 2i were used as key intermediates for
the synthesis of natural compounds homocitric acid 1a9 (previous
syntheses10) and lycoperdic acid 1b11 (previous syntheses12) by
using an asymmetric oxidation cascade of 3-substituted 1,2-
cyclopentanediones 2.13 We have used this asymmetric oxidation
alkylsubstituted diketones
2
(R¼alkyl). The resulting 3-
alkylsubstituted 1,2-diones are common substrates for an asym-
metric oxidation reaction leading to lactone carboxylic acids 1.13 In
Scheme
1
a
simple retrosynthetic pathway from 1,2-
cyclopentanedione 4 to lactone carboxylic acids 1 is outlined.
reaction before for the synthesis of
g
-lactone carboxylic acids14 and
several other biologically active compounds.15
* Corresponding author. E-mail address: margus.lopp@ttu.ee (M. Lopp).
http://dx.doi.org/10.1016/j.tet.2015.10.014
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

9314
A. Paju et al. / Tetrahedron 71 (2015) 9313e9320
2. Results and discussion
Also, with the unprotected 3-bromoenol 3 several minor side-
products form, making purification of 2d more complicated than
that of 6d. Therefore, in the following experiments only the pro-
tected substrate 5 was used.
2.1. Synthesis of 3-alkylsubstituted cyclopentane-1,2-diones
In Negishi cross-coupling reactions with differently functional-
ized zinc reagents, a number of Pd-catalyst/ligand combinations
have been studied.16 We initially investigated the coupling re-
actions of bromoenol ether 5 (prepared from cyclopentane-1,2-
dione 4 by direct bromination with NBS8 followed by silylation;
Scheme 2) with butylzinc reagent (7d) using Pd(tBu3P)2 as a cata-
lyst,17 and obtained the product (6d) in 69% yield (Table 1, entry 3).
Zn reagent 7d was prepared from equimolar amounts of nBuLi and
ZnBr2. Zn reagents with Me (7c) and Bn (7e) groups were prepared
from the corresponding alkyl halides and activated zinc dust.18 In
these cases the products 6c and 6e were obtained in low yield (35%
and 40%, respectively, Table 1, No 1 and 5). Using a higher reaction
temperature (50 ꢀC) increases the yield to 70e90% (Table 1, entries
2 and 6).
We carried out a number of preliminary experiments with
functionalized Zn reagent 7f-tBu (Reformatsky reagent from tBu
bromoacetate). This Zn reagent,19 bearing a primary carbon affords
1,2-addition product 8f-tBu and disubstituted addition/cross-
coupling product 9f-tBu with Pd(tBu3P)2 catalyst (2 mol %) in
a 8:1 ratio according to the NMR spectrum. No formation of the
cross-coupling product 6f was observed. It is well known that in
several cases an additional phosphorus ligand is necessary to ach-
ieve the coupling reaction.16e,f,20 When we used Zn reagent 7f-tBu
(5 equiv)21 with Pd2(dba)3 (2 mol %) and with ligand X-Phos (8 mol
%), only 1,2-addition product 8f-tBu was isolated in 84% yield (Table
1, entry 8). The system Pd(OAc)2 (2 mol %)/X-Phos (8 mol %) was less
active, resulting in 20% yield of 8f-tBu with the main amount of
substrate 5 unreacted (Table 1, entry 9). For the coupling of zinc
Scheme 2. Negishi coupling of 3-bromo-cyclopentane-1,2-dione silyl ether 5.
Scheme 3. A general sequences for homocitric acid 1a and lycoperdic acid 1b synthesis.
The unprotected 3-bromoenol 3 also underwent the cross-
ester enolates with haloarenes, sterically hindered ferrocenyl li-
gand Q-phos has been used in the synthesis of
-aryl esters.22
However, in our case, use of the same system, Pd2dba3/Q-Phos
(5 mol %/5 mol %), in the same substrate/reagent ratio (1:5) mainly
coupling reaction with nBuZnBr, using Pd(tBu3P)2 catalyst (2 mol
%), resulting in nBu-substituted product 2d in 60% yield (Table 1, No
4). The obtained yield is lower than that for 6d (69%, Table 1, No 3).
a

A. Paju et al. / Tetrahedron 71 (2015) 9313e9320
9315
Table 1
For the asymmetric oxidation, substituted unprotected enols 2
have to be used. Thus, the silyl protecting groups of compounds 6f-
Et and 6f-tBu were removed. Desilylation with TBAF in THF at room
temperature was fast (10 min) and resulted in substituted enols 2f-
Et and 2f-tBu in 53% and 68% isolated yields, respectively. For
homocitric acid synthesis, enols 2f-Et and 2f-tBu were subjected to
asymmetric oxidation.14
Negishi cross-coupling of 3-bromo-cyclopentane-1,2-dione silyl enolate 5 with alkyl
Zn reagents 7a
No Hal-Zn-R 7
Catalyst: Ligand (mol %)
Product/yield%
6c/35b
1
2
3
4
5
6
7
IZnMe
IZnMe
BrZnnBu
BrZnnBu
BrZnBn
Pd(tBu3P)2 (5)
Pd(tBu3P)2, (5)
Pd(tBu3P)2, (2)
Pd(tBu3P)2, (2)
Pd(tBu3P)2, (5)
Pd(tBu3P)2, (5)
Pd(tBu3P)2, (2)
6c/68
6d/69b
2d/60c
6e/40b
The asymmetric oxidation of substituted enol 2f-Et with
Ti(OiPr)4/diethyl tartrate/tBuOOH complex (1:1.6:2.5; ꢁ20 ꢀC for
64 h14) proceeded smoothly with no starting compound 2f-Et left.
However, the common basic treatment of the reaction mixture with
30% NaOH solution also caused hydrolysis of the ethyl ester func-
tion, making the extraction of the resulted product 10a from the
reaction mixture complicated. To separate the reaction product, the
triacid 10a was lactonized by evaporating the reaction mixture to
dryness and by subsequent treatment of the residue with 0.1 M
hydrochloric acid. After extraction, the product was finally isolated
by chromatography on silica gel. By this procedure, homocitric acid
1a was obtained in 52% overall yield from enol 2f-Et. When t-Bu
ester 2f-tBu was used in asymmetric oxidation instead of alkali
labile ethyl ester 2f-Et, which is stable at these conditions, the
extraction of the reaction productdmono tBu ester 10f-tBu suc-
ceeded: after alkali work-up and neutralization with 1M HCl, the
product 10f-tBu was extracted with ethyl acetate. The extract was
subjected to acidic simultaneous hydrolysis and lactonization with
conc. HCl. The product was purified on silica gel to afford homo-
citric acid 1a in slightly better yield (53%) than that from the use of
ester 2f-Et. Therefore, the use of t-butyl ester 2f-tBu, which made
the isolation and purification of the final product easier and more
convenient, was considered preferable. Asymmetric oxidation of
enol 2f-tBu proceeded with high enantioselectivity: compound 1a
was obtained with 97% ee, as determined by chiral HPLC analysis.
For the synthesis of lycoperdic acid 1b, the precursor 14-tBu for
the Zn reagent IZnCH2CH(NHBoc)COOtBu 7i-tBu was synthesized
BrZnBn
IZnCH2COOtBu
6e/88
8f-tBu:9f-tBu
(ratio 8:1)d
8f-tBu/84
8f-tBu/20
5/67
6f-Me/44
6f-Et/60
6f-tBu/77
6f-tBu/15
9f-tBu/65
6g/0
8
9
IZnCH2COOtBu
IZnCH2COOtBu
Pd2(dba)3: X-Phos, (2:8)
Pd(OAc)2: X-Phos, (2:8)
10 IZnCH2COOMe
11 IZnCH2COOEt
12 IZnCH2COOtBu
13 IZnCH2COOtBud
Pd2(dba)3: Q-Phos, (5:5)
Pd2(dba)3: Q-Phos, (5:5)
Pd2(dba)3: Q-Phos, (5:5)
Pd2(dba)3: Q-Phos, (5:5)
14 BrZncHex
15 BrZncHex
16 BrZncPent
17 IZnCH2CH(NHBoc)COOMe
18 IZnCH2CH(NHBoc)COOtBu
Pd(tBu3P)2, (5)
Pd2(dba)3: Q-Phos, (1:2)
Pd2(dba)3: Q-Phos, (1:2)
Pd2(dba)3: Q-Phos, (5:5)
6g/82
6h/83
6i-Me/64
Pd2(dba)3: Q-Phos, (7.5:7.5) 6i-tBu/88e
19 IZn(CH2)2CH(NHBoc)COOtBu Pd2(dba)3: Q-Phos, (5:5)
6j/61f
a
Conditions: THF, 50 ꢀC, 21e24 h, substrate/reagent ratio 1:3.
b
Reaction at 23 ꢀC.
c
Unprotected substrate 3.
Substrate/reagent ratio 1:5.
d
e
Reaction time 44 h.
f
Solvent DMF, reaction time 48 h.25
lead to dialkylated product 9f-tBu in 65% yield, while the mono-
substituted product 6f-tBu was isolated in only 15% yield (Table 1,
No 13).
Reducing the amount of Zn reagent 7f-tBu to 1.5 equiv (towards
substrate 5) using Pd2(dba)3 catalyst (5 mol %) and ligand Q-Phos
(5 mol %), the cross-coupling product 6f-tBu was isolated in only 5%
yield without formation of the double addition product and with
a considerable amount of recovered unreacted starting compound
5. By using substrate 5/Zn reagent 7f-tBu in a 1:3 ratio and by using
the same catalytic system (Pd2(dba)3 5 mol %, Q-Phos 5 mol %), we
finally obtained the cross-coupling product 6f-tBu in 77% isolated
yield (Table 1, entry 12). As such the substrate 5/reagent 7 ratio
(1:3) was used later in the following experiments. With these
conditions, Zn reagents 7f-Me, 7f-Et and 7f-tBu after reacting with
5 afforded the coupling products 6f-Me, 6f-Et and 6f-tBu in 44%,
60% and 77% yield, respectively (Table 1, Nos 10e12). In these cases,
when the Zn reagents were prepared directly from metallic Zn and
the corresponding halide (all cases except reagent 7d), activation
with TMSCl21 or with 1,2-dibromoethane/TMSCl18 was applied.
With cHexZnBr (7g) when using only the Pd(tBu3P)2 catalyst the
coupling reaction did not proceed either(Table 1, No 14). So we
turned to the combination of Pd2(dba)3/ligand Q-Phos system for
secondary zinc reagents, also. Thus, with cHex and cPent Zn re-
agents 7g and 7h with substrate 5, using Pd2(dba)3 and Q-Phos
system, afforded substitution products 6g and 6h, respectively, in
82% and 83% isolated yield (Table 1, entries 15 and 16).
from
commercial
N-Boc-O-Bn-L-serine
1123,24
(see
Supplementary). By converting it to tert-Bu ester 12-tBu with TBTA
in the presence of BF3$Et2O which was then debenzylated with H2
in the presence of Pd(OH)2/C to afford aminoalcohol 13-tBu, con-
version to iodide 14-tBu with I2 in the presence of PPh3 and im-
idazole was achieved in more than 80% overall yield from 11
(Scheme 4).
Zn reagent 7i-tBu was prepared from activated metallic Zn
(analogous to 7feh) affording the coupling products 6i-tBu in 88%
yield in their reaction with 5 (Table 1, No 18). Silyl enol ether 6i-tBu
was desilylated with TBAF, resulting in the oxidation substrate enol
2i-tBu in 87% yield. Lycoperdic acid 1b was synthesized directly
from substituted enol 2i-tBu by using an asymmetric oxidation
procedure with Ti(OiPr)4/diethyl tartrate/tBuOOH complex
(1:1.6:2.5; ꢁ20 ꢀC; 20 h). Removal of the protecting groups and
lactonization of the intermediate 10-tBu were carried out in one
step by refluxing with 6M hydrochloric acid12 (Scheme 3). Lyco-
perdic acid 1b was obtained after ion exchange chromatography in
48% yield from 2i-tBu. By using the conditions suitable for homo-
citric acid (concentrated hydrochloric acid in CH2Cl2), incomplete
cyclization occurred (lactone/hydroxy-triacid ratio 2:1). Asym-
metric oxidation of enol 2i-tBu (prepared from optically pure ser-
ine derivative 11) proceeded with satisfactory selectivity affording
1b and its epimer12b in 8:1 diastereomeric ratio, as determined by
1H NMR.
Zn reagents with a more complex nature 7i-Me, 7i-tBu and 7j
bearing a Boc-protected amino group afforded products 6i-Me, 6i-
tBu and 6j in 64%, 88% and 61% isolated yield with the same cata-
lytic system (Table 1, entries 17e19).
3. Summary
2.2. Synthesis of homocitric and lycoperdic acids
The scope of the Negishi cross-coupling reaction is broadened to
3-halides of 1,2-cyclopentane diones, affording coupling products
with primary and secondary alkyl Zn reagents and Reformatsky
reagent. This reaction is an ideal tool to get 3-substituted 1,2-
Homocitric and lycoperdic acids were synthesized, using a sim-
ilar general sequence of the main steps: Negishi cross-coupling,
asymmetric oxidation, cyclization (Scheme 2).

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A. Paju et al. / Tetrahedron 71 (2015) 9313e9320
Scheme 4. Synthesis of lycoperdic acid 1b amino acid precursor 14-tBu.
cyclopentanediones, which are substrates of the asymmetric oxi-
dation reaction. Thus, natural lactone carboxylic acids, homocitric
acid and lycoperdic acid in pure enantiomeric form, were prepared
in a very small number of simple steps from cyclopentanedione
with reasonable yield.
4.2.1. 2-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-cyclopent-2-
enone (6c). Obtained as a colorless oil (77 mg, 68%) after purifica-
tion by flash chromatography (heptanes/EtOAc 60:1 to 30:1);
[Found: C, 63.55; H, 9.72. C12H22O2Si requires C, 63.55; H, 9.80];
Rf¼0.41 (heptanes/EtOAc 10:1); nmax (neat, cmꢁ1): 2928, 1712, 1638,
1471, 1390, 1342, 1247, 1218, 1116, 862, 783. dH (400 MHz, CDCl3):
2.42e2.39 (m, 2H, H-4), 2.33e2.31 (m, 2H, H-5), 1.95 (s, 3H, CH3),
0.95 (s, 9H, C(CH3)3), 0.18 (s, 6H, Si(CH3)2); dC (101 MHz, CDCl3):
203.0 (C-1), 151.6 (C-2), 149.7 (C-3), 32.3 (C-5), 27.1 (C-4), 25.9
(C(CH3)3), 18.5 (C(CH3)3), 15.0 (CH3), ꢁ3.9 (Si(CH3)2). m/z (EI) 211
(Mþꢁ15, 3.5), 169 (Mþꢁ57, 100), 95 (15.1), 75 (23.3).
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded in deuterated solvents
on Bruker Avance II 400 and Avance III 800 spectrometers. Deu-
terated solvent peaks were used as reference. 2D FT methods were
used for the full assignment of 1H and 13C chemical shifts. Mass
spectra were measured on a GCeMS spectrometer using EI (70 eV).
TLC was performed using 60 F254 silica gel plates. IR spectra were
recorded on a Bruker PMA 50 spectrometer. Elemental analyses
were performed on a varioMicro Analyzer. For column chroma-
4.2.2. 3-Benzyl-2-(tert-Butyl-dimethyl-silanyloxy)-cyclopent-2-
enone (6e). Obtained as a white solid (134 mg, 88%) after purifi-
cation by flash chromatography (heptanes/EtOAc 60:1) mp
42e44 ꢀC; [Found: C, 71.37; H, 8.68. C18H26O2Si requires C, 71.47; H,
8.66]; Rf¼0.45 (heptanes/EtOAc 10:1); nmax (KBr, cmꢁ1): 2928, 1709,
1637, 1493, 1408, 1362, 1249, 1109, 861, 783, 754, 694. dH (400 MHz,
CDCl3): 7.32e7.28 (m, 2H, m-Ph), 7.25e7.17 (m, 3H, o,p-Ph), 3.70 (s,
2H, Ph-CH2e), 2.31e2.27 (m, 4H, H-4, H-5), 0.99 (s, 9H, C(CH3)3),
0.25 (s, 6H, Si(CH3)2); dC (101 MHz, CDCl3): 203.3 (C-1), 152.7 (C-2),
149.4 (C-3), 138.0 (s-Ph), 129.0 (2C, o-Ph), 128.8 (2C, m-Ph), 126.7
(1C, p-Ph), 35.2 (Ph-CH2e), 32.3 (C-5), 26.0 (C(CH3)3), 24.5 (C-4),
18.5 (C(CH3)3), ꢁ3.8 (Si(CH3)2). m/z (EI) 245 (Mþꢁ57, 100), 167 (8.1),
91 (13.2), 75 (18.2).
tography 40e63 mm and 100e160 mm silica gel was used. All re-
actions sensitive to oxygen or moisture were conducted under
argon atmosphere in oven-dried glassware. Commercial reagents
were generally used as received. THF was distilled from LiAlH4
before use. CH2Cl2 and DMF were distilled from CaH2.
4.2. Procedure for the coupling of bromo-diketone 5 with
alkylzinc reagents 7c, 7e and 7ge7h
4.2.3. 2-(tert-Butyl-dimethyl-silanyloxy)-3-cyclohexyl-cyclopent-2-
enone (6g). Obtained as a white solid (120 mg, 82%) after purifi-
cation by flash chromatography (heptanes/toluene 1:1 to toluene);
mp 57e59 ꢀC; [Found: C, 69.20; H, 10.25. C17H30O2Si requires C,
69.33; H, 10.27]; Rf¼0.47 (toluene); nmax (KBr, cmꢁ1): 2931, 2854,
1700, 1633, 1472, 1407, 1247, 1202, 1112, 973, 864, 785. dH (400 MHz,
CDCl3): 2.73 (tt, J¼8.1, 3.6 Hz, 1H, H-10), 2.39e2.37 (m, 2H, H-4),
2.30e2.28 (m, 2H, H-5), 1.83e1.78 (m, 2H, H-30,50), 1.75e1.69 (m,
1H, H-40), 1.68e1.63 (m, 2H, H-20,60), 1.39e1.17 (m, 5H, H-
20,30,40,50,60), 0.95 (s, 9H, C(CH3)3), 0.19 (s, 6H, Si(CH3)2); dC
(101 MHz, CDCl3): 203.5 (C-1), 159.8 (C-3), 148.1 (C-2), 37.7 (C-10),
32.2 (C-5), 30.3 (2C, C-20,60), 26.3 (2C, C-30,50), 26.1 (C-40), 25.9
(C(CH3)3), 21.9 (C-4), 18.5 (C(CH3)3), ꢁ4.0 (Si(CH3)2). m/z (EI) 279
(Mþꢁ15, 3.2), 237 (Mþꢁ57, 100), 155 (23.8), 75 (12.5).
To a stirred suspension of zinc dust (131 mg, 2 mmol) in THF
(1 mL), one drop of 1,2-dibromoethane was added. The mixture was
heated to reflux, then two drops of Me3SiCl were added and the
mixture was stirred for 15 min at 60 ꢀC. The formation of gas was
observed and the zinc dust changed into dark grey fuzzy material.
The alkyl halide (1 mmol, iodomethane for 6c, benzyl bromide for
6e, bromocyclohexane for 6g and bromocyclopentane for 6h) was
added dropwise to the cooled mixture, stirred overnight at 50 ꢀC
and unreacted zinc was allowed to settle down for 30 min. The
solution of zinc reagent was syringed away from the excess zinc and
was added to a separate flask containing 5 (146 mg, 0.5 mmol),
Pd(tBu3P)2 (12.8 mg, 0.025 mmol) for 6c and 6e or Pd2(dba)3
(4.6 mg, 0.005 mmol)/Q-PHOS (7.1 mg, 0.01 mmol) for 6g and 6h in
THF (0.5 mL). The resulting mixture was stirred at 50 ꢀC for
21e24 h. Subsequently, saturated NH4Cl solution (10 mL) was
added to the cooled mixture and extracted with EtOAc (2ꢂ10 mL).
The extracts were dried (Na2SO4) and the solvents were evapo-
rated. The residue was purified by flash chromatography (silica gel,
heptanes/EtOAc or heptanes/toluene) to give target compounds.
4.2.4. 2-(tert-Butyl-dimethyl-silanyloxy)-bicyclopentyl-1-en-3-one
(6h). Obtained as a white solid (116 mg, 83%) after purification by
flash chromatography (heptanes/toluene 1:1 to toluene); mp
38e39 ꢀC; [Found: C, 68.97; H, 10.02. C16H28O2Si requires C, 68.52;
H, 10.06]; Rf¼0.47 (toluene); nmax (KBr, cmꢁ1): 2953, 2857, 1706,

A. Paju et al. / Tetrahedron 71 (2015) 9313e9320
9317
1634,1471,1380,1248,1224,1113,1006, 938, 843, 788. dH (400 MHz,
CDCl3): 3.16 (p, J¼8.7 Hz, 1H, H-10), 2.41e2.37 (m, 2H, H-5),
2.33e2.28 (m, 2H, H-4), 1.87e1.80 (m, 2H, H-20,50), 1.75e1.60 (m,
4H, H-30,40), 1.54e1.45 (m, 2H, H-20,50), 0.95 (s, 9H, C(CH3)3), 0.19 (s,
6H, Si(CH3)2); dC (101 MHz, CDCl3): 203.3 (C-3), 158.6 (C-1), 148.9
(C-2), 38.6 (C-10), 32.2 (C-4), 30.9 (2C, C-20,50), 26.0 (2C, C-30,40), 25.9
(C(CH3)3), 21.7 (C-5), 18.6 (C(CH3)3), ꢁ3.9 (Si(CH3)2). m/z (EI) 265
(Mþꢁ15, 3.2), 223 (Mþꢁ57, 100), 155 (10.8), 129 (5.0), 75 (18.5).
59.12; H, 8.51]; Rf¼0.18 (heptanes/EtOAc 10:1); nmax (neat, cmꢁ1):
2955, 1744, 1650, 1472, 1253, 1111, 856, 787. dH (400 MHz, CDCl3):
3.69 (s, 3H, OMe), 3.39 (s, 2H, CH2CO), 2.53e2.51 (m, 2H, H-5),
2.36e2.34 (m, 2H, H-4), 0.92 (s, 9H, C(CH3)3), 0.18 (s, 6H, Si(CH3)2);
dC (101 MHz, CDCl3): 202.9 (C-3), 170.0 (COO), 151.0 (C-2), 145.0 (C-
1), 52.2 (OMe), 34.1 CH2CO), 32.4 (C-4), 25.8 (C(CH3)3), 25.1 (C-5),
18.4 (C(CH3)3), ꢁ4.0 (Si(CH3)2). m/z (EI) 227 (Mþꢁ57, 100), 195
(13.9), 167 (41.1), 89 (27.6), 73 (24.9).
4.3. Procedure for the coupling of bromo-diketone 5 and 3
with alkylzinc reagent 7d
4.4.2. [2-(tert-Butyl-dimethyl-silanyloxy)-3-oxo-cyclopent-1-enyl]-
acetic acid ethyl ester (6f-Et). Obtained as a colorless oil (89 mg,
60%) after purification by flash chromatography (heptanes/EtOAc
50:1 to 20:1); [Found: C, 60.52; H, 8.74. C15H26O4Si requires C,
60.37; H, 8.78]; Rf¼0.21 (heptanes/EtOAc 10:1); nmax (neat, cmꢁ1):
2956, 1739, 1716, 1650, 1472, 1369, 1253, 1111, 855, 787. dH
(400 MHz, CDCl3): 4.14 (q, J¼7.1 Hz, 2H, OCH2CH3), 3.37 (s, 2H,
CH2CO), 2.53e2.51 (m, 2H, H-5), 2.36e2.34 (m, 2H, H-4), 1.24 (t,
J¼7.1 Hz, 3H, OCH2CH3), 0.92 (s, 9H, C(CH3)3), 0.18 (s, 6H, Si(CH3)2);
dC (101 MHz, CDCl3): 202.9 (C-3), 169.5 (COO), 150.9 (C-2), 145.3 (C-
1), 61.2 (OCH2CH3), 34.4 CH2CO), 32.4 (C-4), 25.8 (C(CH3)3), 25.1 (C-
5), 18.4 (C(CH3)3), 14.3 (CH2CH3), ꢁ4.0 (Si(CH3)2). m/z (EI) 241
(Mþꢁ57, 100), 213 (21.3), 195 (7.5), 167 (33.9), 75 (24.9).
Butyl-lithium (0.32 mL, 2.5 M in hexane, 0.8 mmol) was added
to a solution of dried ZnBr2 (180 mg, 0.8 mmol) in THF (2 mL) at
0 ꢀC. The mixture was stirred at room temperature for 30 min. Then
Pd(tBu3P)2 (6 mg, 0.01 mmol) and a solution of diketone 5 or 3
(0.5 mmol) was added. After stirring overnight at room tempera-
ture, saturated NH4Cl solution (10 mL) was added and the mixture
was extracted with EtOAc (2ꢂ10 mL). The extracts were dried
(Na2SO4) and the solvents were evaporated. The residue was pu-
rified by flash chromatography (silica gel, heptanes/EtOAc or hep-
tanes/toluene) to give target compounds.
4.3.1. 3-Butyl-2-(tert-butyl-dimethyl-silanyloxy)-cyclopent-2-enone
(6d). Obtained as a colorless oil (92 mg, 69%) after purification by
flash chromatography (heptanes/toluene 1:1 to toluene); [Found: C,
67.22; H, 10.47. C15H28O2Si requires C, 67.11; H, 10.51]; Rf¼0.42
(toluene); nmax (neat, cmꢁ1): 2931,1713,1641,1464, 1375,1251,1116,
860, 785. dH (400 MHz, CDCl3): 2.42e2.30 (m, 6H, H-4,5 and H-10),
1.52e1.44 (m, 2H, H-20), 1.39e1.30 (m, 2H, H-30), 0.94e0.90 (m, 12H,
C(CH3)3 and H-40), 0.18 (s, 6H, Si(CH3)2); dC (101 MHz, CDCl3): 203.3
(C-1), 155.5 (C-3), 149.3 (C-2), 32.3 (C-5), 29.3 (C-20), 28.6 (C-10),
25.9 (C(CH3)3), 24.9 (C-4), 22.9 (C-30), 18.5 (C(CH3)3), 14.0 (C-40),
ꢁ3.9 (Si(CH3)2). m/z (EI) 211 (Mþꢁ57, 100), 168 (9.3), 75 (10.8).
4.4.3. [2-(tert-Butyl-dimethyl-silanyloxy)-3-oxo-cyclopent-1-enyl]-
acetic acid tert-butyl ester (6f-tBu). Obtained as a white solid
(125 mg, 77%) after purification by flash chromatography (hep-
tanes/EtOAc 60:1 to 20:1); mp 87e88 ꢀC; [Found: C, 62.71; H, 9.26.
C17H30O4Si requires C, 62.54; H, 9.26]; Rf¼0.29 (heptanes/EtOAc
10:1); nmax (KBr, cmꢁ1): 2955, 1732, 1709, 1655, 1465, 1261, 1150,
843, 788. dH (400 MHz, CDCl3): 3.32 (s, 2H, CH2CO), 2.55e2.52 (m,
2H, H-5), 2.38e2.36 (m, 2H, H-4), 1.45 (s, 9H, C(CH3)3), 0.95 (s, 9H,
SiC(CH3)3), 0.20 (s, 6H, Si(CH3)2); dC (101 MHz, CDCl3): 203.1 (C-3),
168.8 (COO), 150.8 (C-2), 146.3 (C-1), 81.6 (OC(CH3)3), 35.8 CH2CO),
32.5 (C-4), 28.2 (C-5), 25.9 (C(CH3)3), 25.2 (SiC(CH3)3) 18.5
(SiC(CH3)3), ꢁ4.0 (Si(CH3)2). m/z (EI) 311 (Mþꢁ15, 0.5), 269 (Mþꢁ57,
48.9), 213 (Mþꢁ113, 100), 185 (3.6), 169 (14.2), 167 (23.0), 75 (18.0).
4.3.2. 3-Butyl-2-hydroxy-cyclopent-2-enone
(2d). Obtained as
a colorless oil (46 mg, 60%) after purification by flash chromatog-
raphy (heptanes/EtOAc 10:1 to 10:2); Rf¼0.30 (heptanes/EtOAc
10:3); dH (400 MHz, CDCl3): 6.41 (s, 1H, OH), 2.44e2.38 (m, 6H, H-
4,5 and H-10), 1.56e1.49 (m, 2H, H-20), 1.39e1.30 (m, 2H, H-30), 0.91
(t, J¼7.3 Hz, 3H, H-40); dC (101 MHz, CDCl3): 203.9 (C-1), 149.5 (C-2),
148.9 (C-3), 32.1 (C-5), 29.1 (C-20), 28.5 (C-10), 25.3 (C-4), 22.8 (C-30),
13.9 (C-40).
4.4.4. [3-Bromo-2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-cyclo-
pent-2-enyl]-acetic acid tert-butyl ester (8f-tBu). Obtained as a col-
orless oil (207 mg, containing succinic acid di-tert-butyl ester w4:1
molar ratio:172 mg of 8f-tBu¼84%) according to the general pro-
cedure using 2.5 mmol of zinc reagent 7f-tBu and Pd2(dba)3 (8 mg,
0.01 mmol)/X-Phos (19 mg (0.04 mmol) catalytic system after pu-
rification by flash chromatography (heptanes/EtOAc 60:1 to 20:1);
Rf¼0.43 (heptanes/EtOAc 10:1); dH (400 MHz, CDCl3): 3.87 (s, 1H,
OH), 2.70e2.57 (m, 2H, CH2CO and H-4), 2.43e2.34 (m, 2H, H-4 and
CH2CO), 2.19e2.13 (m, 1H, H-5), 2.07e2.00 (m, 1H, H-5), 1.47 (s, 9H,
OC(CH3)3), 0.98 (s, 9H, SiC(CH3)3), 0.27 (s, 3H, Si(CH3)2), 0.26 (s, 3H,
Si(CH3)2); dC (101 MHz, CDCl3): 172.2 (COO), 151.8 (C-2), 100.1 (C-3),
82.0 (OC(CH3)3), 79.0 (C-1), 43.1 (CH2CO), 35.8 (C-5), 31.8 (C-4), 28.2
(C(CH3)3), 26.1 (SiC(CH3)3), 18.7 (SiC(CH3)3), ꢁ3.3 (Si(CH3)2), ꢁ3.8
(Si(CH3)2).
4.4. Procedure for the coupling of bromo-diketone 5 with
alkylzinc reagents 7f-Me, 7f-Et and 7f-tBu
To a stirred suspension of zinc dust (196 mg, 3 mmol) in THF
(1.2 mL), one drop of Me3SiCl and alkyl bromoacetate (1.5 mmol,
methyl bromoacetate for 7f-Me, ethyl bromoacetate for 7f-Et and
tert-butyl bromoacetate for 7f-tBu) were sequentially added and
the mixture was stirred for 1 h at room temperature. The zinc was
allowed to settle, and the solution of zinc reagent was syringed
from the excess zinc and was added to a separate flask containing 5
(146 mg, 0.5 mmol), Pd2(dba)3 (23 mg, 0.025 mmol) and Q-PHOS
(18 mg, 0.025 mmol) in THF (1 mL). The resulting mixture was
stirred overnight at room temperature. Subsequently, saturated
NH4Cl solution (40 mL) was added to the mixture and extracted
with CH2Cl2 (3ꢂ30 mL). The extracts were dried (Na2SO4) and the
solvents were evaporated. The residue was purified by flash chro-
matography (silica gel, heptanes/EtOAc) to give target compounds.
4.4.5. [3-tert-Butoxycarbonylmethyl-2-(tert-butyl-dimethyl-silany-
loxy)-1-hydroxy-cyclo-pent-2-enyl]-acetic acid tert-butyl ester (9f-
tBu). Obtained as a colorless oil (144 mg, 65%) according to the
general procedure using 2.5 mmol of zinc reagent 7f-tBu after
purification by flash chromatography (heptanes/EtOAc 60:1 to
20:1); Rf¼0.27 (heptanes/EtOAc 10:1); dH (400 MHz, CDCl3): 3.84 (s,
1H, OH), 3.01 and 2.94 (2d, J¼15.6 Hz, 2H, CH2CO), 2.65 (d,
J¼15.4 Hz, 1H, 1-CH2CO), 2.41e2.34 (m, 1H, H-4), 2.32 (d, J¼15.4 Hz,
1H, 1-CH2CO), 2.17e2.30 (m, 2H, H-4 and H-5), 1.95e1.88 (m, 1H, H-
5), 1.46 (s, 9H, C(CH3)3), 1.43 (s, 9H, C(CH3)3), 0.96 (s, 9H, SiC(CH3)3),
0.22 (s, 3H, Si(CH3)2), 0.15 (s, 3H, Si(CH3)2); dC (101 MHz, CDCl3):
172.8 (COO), 170.5 (COO), 150.8 (C-2), 113.0 (C-3), 81.7 (OC(CH3)3),
80.6 (C-1), 80.4 (OC(CH3)3), 43.0 (CH2CO), 35.3 (C-5), 34.3 (CH2CO),
4.4.1. [2-(tert-Butyl-dimethyl-silanyloxy)-3-oxo-cyclopent-1-enyl]-
acetic acid methyl ester (6f-Me). Obtained as a colorless oil (62 mg,
44%) after purification by flash chromatography (heptanes/EtOAc
50:1 to 15:1); [Found: C, 59.25; H, 8.42. C14H24O4Si requires C,

9318
A. Paju et al. / Tetrahedron 71 (2015) 9313e9320
28.3 (C(CH3)3), 28.2 (C(CH3)3), 27.7 (C-4), 26.1 (SiC(CH3)3), 18.5
(SiC(CH3)3), ꢁ3.1 (Si(CH3)2), ꢁ4.0 (Si(CH3)2).
OC(CH3)3), 79.8 (Boc OC(CH3)3), 52.2 (C-2), 32.2 (C-40), 32.1 (C-3),
28.1 (Boc C(CH3)3), 27.8 (ester C(CH3)3), 25.7 (SiC(CH3)3), 24.5 (C-50),
18.3 (SiC(CH3)3), ꢁ3.9 and ꢁ4.1 (Si(CH3)2). Z-conformer dH: 4.87 (d,
J¼7.5 Hz, 1H, NH), 4.20 (ddd, J¼6.8, 7.5 and 8.4 Hz, 1H, H-2), 2.80
(dd, J¼13.8 and 6.8 Hz, 1H, H-3), 2.61 (dd, J¼13.8 and 8.4 Hz, 1H, H-
3), 2.53 (m, 1H, H-50), 2.44 (m, 1H, H-50), 2.36 (m, 2H, H-40), 1.43 (s,
9H, Boc (CH3)3, 1.42 (s, 9H, ester (CH3)3), 0.93 (s, 9H, SiC(CH3)3), 0.20
and 0.18 (2s, 2ꢂ3H, Si(CH3)2); dC 202.7 (C-30), 170.7 (COO), 154.3
(Boc CO), 150.9 (C-10), 148.6 (C-20), 82.2 (ester OC(CH3)3), 80.5 (Boc
OC(CH3)3), 53.4 (C-2), 32.2 (C-40), 32.0 (C-3), 28.1 (Boc C(CH3)3), 27.8
(ester C(CH3)3), 25.7 (SiC(CH3)3), 24.8 (C-50), 18.3 (SiC(CH3)3), ꢁ3.9
and ꢁ4.2 (Si(CH3)2). m/z (EI) 342 (Mþꢁ113,14.9), 326 (7.6), 310(5.7),
286 (100), 268 (21.6), 242 (13.1), 225 (42.5), 169 (19.4), 114 (9.8).
4.5. Procedure for the coupling of bromo-diketone 5 with
alkylzinc reagents 7i-Me and 7i-tBu
To a stirred suspension of zinc dust (131 mg, 2 mmol, dried
under vacuum using a heat gun), THF (0.8 mL) and one drop of
Me3SiCl were added. Protected 3-iodopropionic ester (1 mmol,
methyl 2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate for 6i-
Me
and
tert-butyl
2-[(tert-butoxycarbonyl)amino]-3-
iodopropanoate for 6i-tBu) in THF (1.4 mL) and an additional
drop of Me3SiCl were sequentially added and the mixture was
stirred for 1 h at room temperature. The zinc was allowed to settle
and the solution of zinc reagent was syringed from the excess zinc
and was added to a separate flask containing 5 (146 mg, 0.5 mmol),
Pd2(dba)3 (23 mg, 0.025 mmol) and Q-PHOS (18 mg, 0.025 mmol)
in THF (0.8 mL). The resulting mixture was stirred for 20 h at 50 ꢀC.
Subsequently, saturated NH4Cl solution (20 mL) was added to the
mixture and extracted with EtOAc (2ꢂ20 mL). The extracts were
dried (Na2SO4) and the solvents were evaporated. The residue was
purified by flash chromatography (silica gel, heptanes/EtOAc) to
give target compounds.
4.6. Procedure for the coupling of bromo-diketone 5 with
alkylzinc reagents 7j
To a stirred suspension of zinc dust (393 mg, 6 mmol) in DMF
(0.45 mL), 1,2-dibromoethane (26 mL, 0.3 mmol) was added. The
mixture was heated at 60 ꢀC for 30 min and cooled to room tem-
perature. A drop of Me3SiCl was added and the mixture was stirred
for 30 min. Then a solution of tert-butyl 2-[(tert-butoxycarbonyl)
amino]-4-iodobutanoate (385 mg, 1 mmol) in DMF 0.45 mL) was
added and the mixture was stirred at 35 ꢀC for 30 min, cooled and
unreacted zinc was allowed to settle down. The solution of zinc
reagent was syringed from the excess zinc and was added to
a separate flask containing 5 (146 mg, 0.5 mmol), Pd2(dba)3 (23 mg,
0.025 mmol) and Q-PHOS (18 mg, 0.025 mmol) in DMF (0.2 mL).
The resulting mixture was stirred for 48 h at 50 ꢀC. Subsequently,
saturated NH4Cl solution (20 mL) was added to the mixture and
extracted with EtOAc (2ꢂ20 mL). The extracts were dried (Na2SO4)
and the solvents were evaporated. The residue was purified by flash
chromatography (silica gel, heptanes/EtOAc) to give 2-tert-butox-
ycarbonylamino-4-[2-(tert-butyl-dimethyl-silanyloxy)-3-oxo-
cyclopent-1-enyl]-butyric acid tert-butyl ester (6j) as a colorless oil
(138 mg, 59%) after purification by flash chromatography (hep-
tanes/EtOAc 30:1 to 10:1); [Found: C, 61.16; H, 9.21; N, 2.84.
4.5.1. 2-tert-Butoxycarbonylamino-3-[2-(tert-butyl-dimethyl-silany-
loxy)-3-oxo-cyclopent-1-enyl]-propionic acid methyl ester (6i-Me).-
Obtained as a white solid (133 mg, 64%) after purification by flash
chromatography (heptanes/EtOAc 10:1 to 10:2); mp 88e90 ꢀC;
[Found: C, 58.23; H, 8.52; N, 3.35. C20H35NO6Si requires C, 58.08; H,
8.53; N, 3.39]; Rf¼0.20 (heptanes/EtOAc 10:2); nmax (KBr, cmꢁ1):
3401, 2956, 1710, 1511, 1377, 1247, 1214, 1163, 1120, 846, 787. dH
(800 MHz, CDCl3, 258 K), 12 to 1 mixture of E-and Z-conformers
from urethane bond, E-conformer: 5.17 (d, J¼8.3 Hz, 1H, NH), 4.49
(td, J¼2ꢂ7.2 and 8.3 Hz, 1H, H-2), 3.75 (s, 3H, OCH3), 2.78 (d,
J¼7.2 Hz, 2H, H-3), 2.55 (m, 1H, H-50), 2.40 (m, 1H, H-50), 2.36 (m,
2H, H-40), 1.39 (s, 9H, Boc (CH3)3, 0.93 (s, 9H, SiC(CH3)3, 0.20 and
0.19 (2s, 2ꢂ3H, (Si(CH3)2); dC (201 MHz, CDCl3): 203.0 (C-30), 172.4
(COO), 155.1 (Boc CO), 151.3 (C-10), 148.2 (C-20), 80.1 (OC(CH3)3),
52.7 (OCH3), 51.7 (C-2), 32.2 (C-40), 31.6 (C-3), 28.1 (Boc C(CH3)3),
25.6 (SiC(CH3)3), 24.6 (C-50), 18.2 (SiC(CH3)3), ꢁ4.0 and ꢁ4.1
(Si(CH3)2). Z-conformer dH: 4.90 (d, J¼7.5 Hz, 1H, NH), 4.32 (ddd,
J¼5.3, 7.5 and 8.9 Hz, 1H, H-2), 3.74 (s, 3H, OCH3), 2.77 (dd, J¼13.4
and 5.3 Hz, 1H, H-3), 2.70 (dd, J¼13.4 and 8.9 Hz, 1H, H-3), 2.46 (m,
2H, H-50), 2.38 (m, 2H, H-40), 1.41 (s, 9H, Boc (CH3)3, 0.93 (s, 9H,
SiC(CH3)3; dC 202.7 (C-3), 172.3 (COO), 154.2 (Boc CO), 151.3 (C-10),
147.7 (C-20), 80.7 (OC(CH3)3), 52.6 (OCH3), 51.6 (C-2), 32.2 (C-40),
31.6 (C-3), 28.1 (Boc C(CH3)3), 25.6 (SiC(CH3)3), 24.6 (C-50), 18.2
(SiC(CH3)3), ꢁ4.0 and ꢁ4.1 (Si(CH3)2). m/z (EI) 340 (5.1), 300
(Mþꢁ113, 67.4), 282 (9.5), 256 (22.0), 239 (60.0), 169 (100).
C24H43NO6Si requires C, 61.37; H, 9.23; N, 2.98]; Rf¼0.27 (heptanes/
EtOAc 10:2); nmax (neat, cmꢁ1): 3435, 3350, 2930, 1714, 1641, 1498,
1368, 1251, 1155, 859, 785. dH (800 MHz, CDCl3, 268 K), 10 to 1
mixture of E- and Z-conformers from urethane bond, E-conformer:
5.14 (d, J¼8.4 Hz, 1H, NH), 4.24 (ddd, J¼4.6, 7.6 and 8.4 Hz, 1H, H-2),
2.45e2.33 (m, 6H, H-4, H-40, H-50), 2.00 (m, 1H, H-3), 1.77 (m, 1H, H-
3), 1.46 (s, 9H, ester (CH3)3), 1.44 (s, 9H, Boc (CH3)3), 0.94 (s, 9H,
SiC(CH3)3), 0.19 and 0.17 (2s, 2ꢂ3H, Si(CH3)2); dC (201 MHz, CDCl3):
203.2 (C-30), 171.4 (COO), 155.3 (Boc CO), 153.4 (C-10), 149.4 (C-20),
82.2 (ester OC(CH3)3), 79.7 (Boc OC(CH3)3), 53.6 (C-2), 32.1 (C-40),
30.1 (C-3), 28.2 (Boc C(CH3)3), 27.9 (ester C(CH3)3), 25.7 (SiC(CH3)3),
24.7 (C-50), 24.4 (C-4), 18.3 (SiC(CH3)3), ꢁ4.0 and ꢁ4.1 (Si(CH3)2). Z-
conformer dH: 4.85 (d, J¼7.9 Hz, 1H, NH), 4.04 (ddd, J¼5.3, 7.3 and
7.9 Hz, 1H, H-2), 2.45e2.33 (m, 6H, H-4, H-40, H-50), 1.94 (m, 1H, H-
3), 1.76 (m, 1H, H-3), 1.46 (s, 9H, ester (CH3)3), 1.44 (s, 9H, Boc
(CH3)3), 0.94 (s, 9H, SiC(CH3)3), 0.19 and 0.17 (2s, 2ꢂ3H, Si(CH3)2); dC
203.2 (C-3), 171.9 (COO), 155.3 (Boc CO), 152.9 (C-3), 149.6 (C-20),
81.8 (ester OC(CH3)3), 80.4 (Boc OC(CH3)3), 55.0 (C-2), 32.0 (C-40),
30.2 (C-3), 28.2 (Boc C(CH3)3), 27.9 (ester C(CH3)3), 25.7 (SiC(CH3)3),
24.8 (C-50), 24.5 (C-4), 18.3 (SiC(CH3)3), ꢁ4.0 and ꢁ4.1 (Si(CH3)2). m/
z (EI) 470 (Mþþ1, 0.5) 356 (Mþꢁ113, 7.2), 340 (11.0), 324 (11.9), 312
(10.8), 300 (97.7), 282 (53.9), 239 (11.2), 223 (13.7), 210 (32.2), 167
(36.9), 57 (100).
4.5.2. 2-tert-Butoxycarbonylamino-3-[2-(tert-butyl-dimethyl-silany-
loxy)-3-oxo-cyclopent-1-enyl]-propionic acid tert-butyl ester (6i-
tBu). Obtained as a colorless oil (200 mg, 88%); %) after purification
by flash chromatography (heptanes/EtOAc 30:1 to 10:1); [Found: C,
60.50; H, 9.02; N, 3.08. C23H41NO6Si requires C, 60.63; H, 9.07; N,
25
3.07]; Rf¼0.33 (heptanes/EtOAc 10:2); [
a
]
D
þ14.5 (c 1.14, CHCl3);
nmax (neat, cmꢁ1): 3443, 2932, 2859, 1714, 1643, 1502, 1368, 1251,
1154, 1113, 859, 786. dH (800 MHz, CDCl3, 268 K), 10 to 1 mixture of
E- and Z-conformers from urethane bond, E-conformer: 5.18 (d,
J¼8.2 Hz, 1H, NH), 4.36 (ddd, J¼6.4, 8.2 and 8.3 Hz, 1H, H-2), 2.78
(dd, J¼6.4 and 13.6 Hz, 1H, H-3), 2.71 (dd, J¼8.3 and 13.6 Hz, 1H, H-
3), 2.54 (dt, J¼17.8 and 2ꢂ4.3 Hz, 1H, H-50), 2.48 (dt, J¼17.8 and
2ꢂ4.3 Hz, 1H, H-50), 2.35 (t, J¼4.3 Hz, 2H, H-40), 1.42 (s, 9H, ester
C(CH3)3, 1.40 (s, 9H, Boc C(CH3)3, 0.93 (s, 9H, SiC(CH3)3), 0.20 and
0.18 (2s, 2ꢂ3H, Si(CH3)2); dC (201 MHz, CDCl3): 203.1 (C-30), 170.8
(COO), 155.0 (Boc CO), 150.8 (C-10), 149.2 (C-20), 82.3 (ester
4.7. Procedure for deprotection of silyl enol ethers 6f-tBu and
6i-tBu
A solution of (2-(tert-butyl-dimethyl-silanyloxy)-3-oxo-cyclo-
pent-1-enyl)-acetic acid tert-butyl ester 6f-tBu (48 mg,

A. Paju et al. / Tetrahedron 71 (2015) 9313e9320
9319
23
21
0.147 mmol) in THF (2 mL) was treated with TBAF (0.162 mL,
0.162 mmol, 1M solution in THF). After 10 min of stirring the re-
action was quenched with saturated NH4Cl solution (3 mL), the
phases were separated and the aqueous phase was extracted with
EtOAc (2ꢂ2 mL). The organic phases were combined, dried over
MgSO4, the solvent was evaporated and the residue was purified by
flash chromatography (silica gel, heptanes/EtOAc) to give target
compound.
(lit. [a
]
ꢁ50.5 (c 0.33, H2O),10b
[
a]
ꢁ50.0 (c 0.35, H2O),10d
[
a
]
D
D
D
ꢁ57.0 (c 1, H2O),10j); nmax (KBr, cmꢁ1): 3129, 2982, 2936, 1755, 1722,
1674, 1386, 1185, 1061. dH (800 MHz, (CD3)2CO, 2.05): 3.14 and 2.94
(both d, 2H, J¼17.2 Hz, CH2COOH), 2.61 (ddd, J¼9.7, 10.1 and 17.8 Hz,
1H, H-4), 2.57 (ddd, J¼3.6, 9.8 and 17.8 Hz, 1H, H-4), 2.48 (ddd,
J¼3.6, 9.7 and 13.4 Hz, 1H, H-3), 2.42 (ddd, J¼9.8, 10.1 and 13.4 Hz,
1H, H-3); dC (125 MHz, (CD3)2CO, 29.80): 176.8 (C-5), 172.7 (2-
COOH), 170.8 (CH2COOH), 83.6 (C-2), 41.7 (CH2CO), 31.7 (C-3),
28.3 (C-4).
4.7.1. (2-Hydroxy-3-oxo-cyclopent-1-enyl)-acetic acid tert-butyl
ester (2f-tBu). Obtained as white crystals (21 mg, 68%) after puri-
fication by flash chromatography (heptanes/EtOAc 10:1.5 to 10:3);
mp 84e86 ꢀC; [Found: C, 62.21; H, 7.61. C11H16O4 requires C, 62.25;
H, 7.60]; Rf¼0.20 (heptanes/EtOAc 10:3); nmax (KBr, cmꢁ1): 3307,
2999, 2973, 1728, 1699, 1665, 1415, 1384, 1366, 1151, 699. dH
(400 MHz, CDCl3): 6.35 (s, 1H, OH), 3.37 (s, 2H, CH2CO), 2.56e2.53
(m, 2H, H-5), 2.46e2.43 (m, 2H, H-4), 1.44 (s, 9H, C(CH3)3); dC
(125 MHz, CDCl3): 203.1 (C-3), 169.1 (COO), 150.1 (C-2), 138.3 (C-1),
82.1 (OC(CH3)3)), 35.8 (CH2CO), 32.2 (C-4), 28.2 (OC(CH3)3), 25.6 (C-
5). m/z (EI) 156 (Mþꢁ56, 34.9), 139 (27.7), 111 (28.3), 57 (100).
4.9. (S)-(D)-Lycoperdic acid (1b) [2-(2-amino-2-
carboxyethyl)-5-oxo-tetrahydrofuran-2-carboxylic acid]
ꢁ
To a solution of Ti(OiPr)4 (0.28 mL, 0.93 mmol) and 4 A pow-
dered molecular sieves (93 mg) in CH2Cl2 (5.5 mL), (þ)-DET
(0.26 mL, 1.49 mmol) was added at ꢁ20 ꢀC and the mixture was
stirred for 15 min. Next diketone 2i-tBu (0.93 mmol) in CH2Cl2
(2.0 mL) was added and the reaction mixture was stirred for 30 min.
Next tBuOOH (0.41 mL, 2.5 mmol, 5.68M solution in decane) was
added and the reaction was kept at ꢁ20 ꢀC for 21 h. Water (5.6 mL)
was added and the mixture was stirred for 1 h at room temperature,
then 30%NaOH in saturated NaCl solution (1.12 mL) was added and
the mixture was again stirred at room temperature for an addi-
tional 1 h. The reaction mixture was filtered through a pad of Celite,
washing with water. Then CH2Cl2 layer was removed and the
mixture was acidified with 6M HCl solution (pH¼2e3) and
extracted with several portions of EtOAc. The combined extracts
were dried over MgSO4 and the solvent was evaporated to give
crude diacid 10 as a slightly yellow solid (265 mg, 73%). A solution
of 10 (237 mg, 0.606 mmol) in 6M HCl (10.5 mL) was refluxed for
8 h, then concentrated under reduced pressure. Purification the
residue by ion-exchange chromatography (Dowex 1ꢂ8,
200e400 mesh, acetate form) eluting with 2M aqueous acetic acid
gave 8:1 mixture of 1b and its epimer (87 mg, 66%) as a white solid
which was recrystallized from water to afford pure lycoperdic acid
as colorless needles; mp 202e203 ꢀC (lit. 200e201 ꢀC,12b lit.
4.7.2. 2-tert-Butoxycarbonylamino-3-(2-hydroxy-3-oxo-cyclopent-
1-enyl)-propionic acid tert-butyl ester (2i-tBu). Obtained from 6i-
tBu (382 mg, 0.84 mmol) and TBAF (0.92 mL, 0.92 mmol, 1M so-
lution in THF) in THF (8.4 mL) as a colorless viscous mass (249 mg,
87%) after purification by flash chromatography (heptanes/EtOAc
10:2 to 10:4); [Found: C, 59.58; H, 8.06; N, 4.03. C17H27NO6 requires
25
C, 58.81; H, 7.97; N, 4.10]; Rf¼0.14 (heptanes/EtOAc 10:3); [
a]
D
þ26.0 (c 1.39, CHCl3); nmax (neat, cmꢁ1): 3383, 2980, 2933, 1711,
1661, 1509, 1394, 1368, 1252, 1155. dH (400 MHz, CDCl3), main E-
conformer: 5.97 (s, 1H, OH), 5.24 (d, J¼8.2 Hz, 1H, NH), 4.43 (td,
J¼2ꢂ6.9, 8.2 Hz), 2.82 (d, J¼6.9 Hz, 2H, H-3), 2.59e2.44 (m, 2H, H-
50), 2.46e2.40 (m, 2H, H-40), 1.44 (s, 9H, ester OC(CH3)3), 1.41 (s, 9H,
Boc OC(CH3)3); dC (101 MHz, CDCl3): 203.0 (C-30), 170.9 (COO), 155.4
(COO), 150.3 (C-20), 141.8 (C-10), 82.6 ester (OC(CH3)3), 80.1 Boc
(OC(CH3)3), 52.5 (C-2), 32.3 (C-40), 32.1 (C-3), 28.4 Boc (OC(CH3)3),
28.0 ester (OC(CH3)3), 25.4 (C-50). m/z (EI) 285 (Mþꢁ56, 1.8), 229
(Mþꢁ112, 12.2), 212 (9.7), 185 (15.0), 168 (8.2), 140 (17.0), 130 (6.3),
112 (42.2) 74 (14.9), 57 (100).
200e202 ꢀC,12c,d); [Found: C, 44.19; H, 5.06; N, 6.44. C8H11NO6 re-
21
quires C, 44.24; H, 5.11; N, 6.45]; [
a
]
22 þ12.6 (c 0.32, H2O) (lit. [
a]
D
D
28
24
þ14.2 (c 0.46, H2O),12b; [
a
]
þ12.7 (c 0.21, H2O),12c
[
a]
þ14.4 (c
D
D
0.47, H2O),12f); nmax (KBr, cmꢁ1): 3440, 3239, 2940, 2590,1770,1732,
1634, 1522, 1277, 1210. dH (400 MHz, D2O): 4.03 (dd, J¼3.4, 10.1 Hz,
1H, H-20), 2.92 (dd, J¼3.4,15.6 Hz,1H, H-10), 2.75e2.70 (m, 2H, H-4),
2.67e2.59 (m, 1H, H-3), 2.40e2.32 (m, 1H, H-3), 2.33 (dd, J¼10.1,
15.6 Hz, 1H, H-10); dC (101 MHz, D2O): 179.7(C-5), 175.3 (COOH),
171.9 (COOH), 87.6 (C-2), 51.4 (C-20), 37.6 (C-10), 32.3 (C-3), 27.7
(C-4).
4.8. (R)-(L)-Homocitric acid lactone 1a (2-carboxymethyl-5-
oxo-tetrahydrofuran-2-carboxylic acid)
ꢁ
To a solution of Ti(OiPr)4 (0.3 mL, 1 mmol) and 4 A powdered
molecular sieves (100 mg) in CH2Cl2 (6 mL), (þ)-DET (0.27 mL,
1.6 mmol) was added at ꢁ20 ꢀC and the mixture was stirred for
15 min. Next diketone 2f-tBu (1 mmol) in CH2Cl2 (2.0 mL) was
added and the reaction mixture was stirred for 30 min. Next
tBuOOH (0.38 mL, 2.5 mmol, 6.6M solution in decane) was added
and the reaction was kept at ꢁ20 ꢀC for 63 h. Water (6.0 mL) was
added and the mixture was stirred for 1 h at room temperature,
then 30%NaOH in saturated NaCl solution (1.2 mL) was added and
the mixture was again stirred at room temperature for an addi-
tional 1 h. Then CH2Cl2 layer was removed and the mixture was
acidified with 1M HCl solution (pH¼1e2) and extracted with EtOAc
(6ꢂ20 mL). The combined extracts were dried over MgSO4 and the
solvent was evaporated. The residue was dissolved in CH2Cl2
(40 mL) and concentrated HCl solution (0.4 mL) was added. The
mixture was stirred for 2 h at room temperature, concentrated in
vacuum and treated with EtOAc: toluene (2:1). The product purified
by flash chromatography (silica gel, petroleum ethereacetone) to
give 1a as a white solid (100 mg, 53%); mp 152e154 ꢀC (lit.
154e156 ꢀC,10b 146e148 ꢀC,10c); 97% ee (HPLC: Chiralpak AS-H,
250ꢂ4.6 mm, hexane/EtOH¼85/15 þ0.1% TFA, 0.8 mL/min,
Acknowledgements
The authors thank the Estonian Ministry of Education and Re-
search (Grants IUT19-32, IUT23-7) and EU European Regional De-
velopment Fund (Grant 3.2.0101.08-0017) for financial support;
Tiina Aid for performing IR spectra and elemental analysis, and
€€
Aleksander-Mati Muurisepp for MS measurements.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.10.014.
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