Phosphine-catalyzed [3+2] cyclizations: Applications to the enantioselective synthesis of cyclopentene-fused chromanones and dihydroquinolinones

Article abstract of DOI:10.1055/s-0030-1260466

Phosphine-promoted [3+2] cyclizations of allenic esters or phosphonates with coumarin derivatives were used to synthesize functionalized bicyclo[4.3.0]chroman-2-ones. Analogous bicyclo[4.3.0]quinolinones were similarly prepared by a two-step strategy invo

Full text of DOI:10.1055/s-0030-1260466

PAPER
2003
Phosphine-Catalyzed [3+2] Cyclizations: Applications to the Enantioselective
Synthesis of Cyclopentene-Fused Chromanones and Dihydroquinolinones
E
nantioselective Phosp
ahine-Catal
t
h
+2]
C
yclizations lde Neel, Jérôme Gouin, Arnaud Voituriez, Angela Marinetti*
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Centre de Recherche de Gif., 1, av. de la Terrasse, 91198 Gif-sur-Yvette,
France
Fax +33(1)69077247; E-mail: angela.marinetti@icsn.cnrs-gif.fr
Received 15 March 2011
ones,5 palladium-promoted cycloadditions with trimeth-
Abstract: Phosphine-promoted [3+2] cyclizations of allenic esters
ylenemethane fragments,6 or photochemical [2+2] annu-
or phosphonates with coumarin derivatives were used to synthesize
functionalized bicyclo[4.3.0]chroman-2-ones. Analogous bicy-
lations and ring-enlargement reactions.7
clo[4.3.0]quinolinones were similarly prepared by a two-step strat-
Bicyclic chromane and chromanone scaffolds have also
egy involving a phosphine-catalyzed [3+2] cyclization of diethyl
been prepared by phosphine-catalyzed reactions by taking
propadienylphosphonate and 3-(2-nitrophenyl)acrylate as the key
advantage of intramolecular annulation processes. These
step. Enantiomerically enriched compounds, with enantiomeric ex-
involve either ring-forming reactions combining an allylic
cesses in the range 70–86%, were obtained by using (S,S)-Ferro-
PHANE as the chiral catalyst for the cyclization step.
and an olefinic function,8 or intramolecular [3+2] cycliza-
tions between an allene and an olefin function
Key words: catalysis, cyclizations, heterocycles, stereoselective
(Scheme 1).9 Enantioselective variants have been devel-
synthesis, chromanones
oped only for the synthesis of bicyclic chromanes.10
CO2Et
(a)
Cyclopentane-fused chromanones, dihydroquinolinones,
and derived structures are structural features of many nat-
O
Br
ural products and biologically active compounds. Some
relevant examples, shown in Figure 1, include the heber-
tane sesquiterpene hebertenolide (I),1 the estrogen recep-
tor b agonist SERBA-1 (II),2 (+)-meloscine (III),3 and the
nitric oxide synthase (NOS) inhibitors IV.4
from ref. 8
EWG
EWG
EWG
(b)
(c)
from ref. 9
X
O
O
O
O
X = CH2, CO
HO
CO2R
this work
EWG
+
O
O
O
O
OH
hebertenolide (I)
SERBA-1 (II)
Scheme 1 Strategies for building chromane-derived benzobi-
cyclo[4.3.0] units with phosphine catalysis
N
H
As a complement to these established methods, we con-
ceived a [3+2] cyclization strategy involving allenoates
and either chromen-2-ones (Scheme 1, equation c) or
quinolin-2-ones as the substrates in phosphine-promoted
processes. We have examined enantioselective variants of
these annulation reactions with the aim of preparing enan-
tiomerically enriched bicyclic species. The main results of
our studies are summarized below.
F
R
H
N
NH2
N
O
H
(+)-meloscine (III)
n-NOS inhibitors (IV)
Figure 1 Natural products and biologically active compounds con-
taining benzobicyclo[4.3.0] subunits derived from chromanones and
dihydroquinolones
Our synthetic approach is based on the [3+2] cyclization
between allenoates and electron-deficient olefins intro-
duced by Zhang and Lu11 which has been applied to a va-
riety of functionalized substrates,12 including cyclic
alkenes as the two-carbon partners.13 As a new variant on
these reactions, we have investigated the use of coumarins
and quinolin-2-ones as potentially suitable olefinic sub-
strates. In preliminary experiments, mixtures of ethyl
buta-2,3-dienoate and either ethyl 1-methyl-2-oxo-1,2-di-
hydroquinoline-3-carboxylate (1) or ethyl 2-oxo-2H-
Construction of these [4.3.0] bicyclic scaffolds has been
carried out mainly by cyclization methods in which
chromen-2-ones5,6 or quinolin-2-ones7 served as the two-
atom units. The olefinic bonds of these substrates under-
went [3+2] cycloaddition reactions with cyclopropen-
SYNTHESIS 2011, No. 12, pp 2003–2009
x
x.
x
x
.
2
0
1
1
Advanced online publication: 16.05.2011
DOI: 10.1055/s-0030-1260466; Art ID: C29511SS
© Georg Thieme Verlag Stuttgart · New York

2004
M. Neel et al.
PAPER
chromene-3-carboxylate (2a) were subjected to nucleo- been previously demonstrated to give high enantiocontrol
philic phosphine catalysis under the usual annulation con- in [3+2] cyclizations of this class.14 In our experiments,
ditions. With either triphenylphosphine or tributyl- these chiral catalysts afforded the desired cycloadducts in
phosphine as the catalyst, the dihydroquinoline derivative good yields and high regioselectivities. (S,S)-Ferro-
1 failed to react at a 20% catalyst loading and a tempera- PHANE also showed good levels of enantioselectivity
ture of either 25 or 80 °C, whereas the substituted cou- (72% ee), whereas (S)-t-Bu-Binepine afforded an only
marin 2a was efficiently converted into a mixture of the moderate enantiomeric excess (34% ee). We therefore se-
desired cycloadducts 4a and 5a at room temperature when lected (S,S)-FerroPHANE as our preferred catalyst for
triphenylphosphine was used as the catalyst (Table 1, en- further studies.
try 2).
In an attempt to improve the selectivity of these cycliza-
tions, we changed the ester functions in both the allene
Table 1 Phosphine-Promoted [3+2] Cyclizations of a 2-Oxo-2H-
chromene and Attempted Cyclizations of a Quinoline Derivative
and the coumarin. With (S,S)-FerroPHANE as the cata-
lyst, increasing the size of the allene R2 group (entries 1–
CO2Et
3, Table 2) had almost no effect on the regioselectivity,
whereas the enantiomeric excess tended to decrease when
CO2Et
+
X
O
a bulky cyclohexyl group was used (entry 3). On the other
hand, only small modulations of the regioselectivity were
observed on changing the steric bulk of the R1 group of the
coumarin esters 2 (entries 1,4, and 5). The enantiomeric
excesses remained in the range 72–76%.
1, X = N-Me
2a, X = O
3a
R3P (10 mol%)
toluene, r.t., 24 h
EtO2C
CO2Et
CO2Et
Table 2 (S,S)-FerroPHANE-Promoted Enantioselective [3+2] Cy-
clizations of 2-Oxo-2H-chromene-3-carboxylates
+
CO2Et
O
X
X
O
CO2R2
CO2R3
4a, X = O
5a, X = O
R1
+
O
O
Entry Substrate Phosphine
4a:5a
Yield of ee
4a (%) (%)
3a–c, R3 = Et, Bn, C6H11
2a–c, R1 = H; R2 = Et, Me, C6H11
a
2d–g, R1 = 7-OMe, 6-OMe, 6-Br, 6-NO2; R2 = Et
1
2
3
4
1
Ph3P or Bu3P
Ph3P
–
–
–
(S,S)-FerroPHANE
(10 mol%)
toluene, r.t., 24 h
2a
2a
2a
5:1
5:1
5:1
76
77
84
–
R3O2C
(S)-t-Bu-Binepine
34
72
(S,S)-FerroPHANEb
CO2R3
CO2R2
CO2R2
O
R1
R1
a Reactions performed at either r.t. or 80 °C with amounts of catalyst
+
of up to 20 mol%.
O
O
O
b
4a–j
5a–j
Entry R1
R2
R3
Products 4:5
Yield of ee
(%)
TMS
Fe
TMS
P
Cy
ratio 4 (%)
1
2
H
H
H
H
H
H
Et
Et
Bn
Cy
Et
Et
Bn
Et
Et
Et
Et
4a + 5a
4b + 5b
4c + 5c
4d + 5d
4e + 5e
4f + 5f
5:1
4:1
4:1
4:1
4:1
4:1
4:1
84%
75%
72%
59%
61%
50%
45%
53%
71%
53%
72%
76%a
53%
76%
74%
72%
71%
71%
64%
71%
Et
The reaction gave the so-called a-adduct 4a as the major
isomer (5:1 regioisomeric ratio); this was readily separat-
ed from the g-adduct 5a by column chromatography and
isolated in pure form in 76% yield. The regiochemistry
3
Et
4
Me
Cy
Me
1
was unambiguously assigned by H NMR. In the major
5
product 4a, the CH-proton at the ring junction (9b-CH)
4
6
gives JH–H couplings of 2.7 and 1.2 Hz (d = 4.64 ppm),
whereas the same CH-proton of the g-adduct 5a displays
3JH–H couplings of 10.5 and 8.1 Hz (d = 4.02 ppm). The
observed regioselectivity is fully consistent with previous
reports that prevalent or exclusive formation of a-adducts
takes place for annulations of allenoates on cyclic alk-
enes.13
7
7-OMe Et
8-OMe Et
4g + 5gb
8
4h + 5hb 4:1
9
8-Br
Et
Et
4i + 5ib
4j + 5jb
4:1
10
8-NO2
3:1
We then investigated enantioselective variants of the same a The minor isomer 5b was obtained in 54% ee.
b Reactions performed in toluene–CH2Cl2 (5:1).
reaction with either (S)-t-Bu-Binepine or (S,S)-Ferro-
PHANE as the catalyst, since both these phosphines have
Synthesis 2011, No. 12, 2003–2009 © Thieme Stuttgart · New York

PAPER
Enantioselective Phosphine-Catalyzed [3+2] Cyclizations
2005
The significant enantiomeric excesses attained in these promoted [3+2] annulation of the phosphonate 6 and the
cyclization reactions led us to examine the expansion of acrylate 8 as the key step. The nitro group serves as a pre-
the scope of the method to coumarin derivatives with sub- cursor to an amino functionality that is involved in the fi-
stituted aryl groups. As shown in entries 7–10 in Table 2, nal cyclization step.
annulations on both electron-rich and electron-deficient
substrates gave the desired products with comparable lev-
CO2Et
P(O)(OEt)2
P(O)(OEt)2
els of enantioselectivity, with enantiomeric excesses
peaking at about 71%.
(i)
+
CO2Et
NO2
NO2
All the enantiomeric excesses discussed above were mea-
sured by chiral HPLC. Racemic samples of compounds
4b–j were similarly obtained from cyclization reactions
promoted by triphenylphosphine (20 mol%) under analo-
gous conditions (yields: 4b, 81%; 4c, 60%; 4d, 77%; 4e,
71%; 4f, 63%; 4g, 63%; 4h, 61%; 4i, 59%; 4j, 66%).
8
6
9, 72%, 86% ee
(ii)
H
P(O)(OEt)2
H
O
N
H
The minor g-adducts 5 were isolated in pure form and
characterized by means of NMR spectroscopy. Spectral
data are reported in the experimental section for the repre-
sentative compounds 5a and 5b.
10, 90%
Scheme 3 Enantioselective synthesis of a cyclopentane-fused dihy-
droquinolin-2-one by an (S,S)-FerroPHANE-promoted [3+2] cycliza-
tion. Reagents and conditions: (i) (S,S)-FerroPHANE (10 mol%),
toluene, 110 °C, 18 h; (ii) Fe, AcOH, 80 °C, 90%.
As far as we know, these are the first examples of phos-
phine-promoted annulations leading to enantiomerically
enriched coumarin derivatives. They produce highly func-
tionalized benzo-fused bicyclo[4.3.0] scaffolds in syn-
thetically useful yields and selectivities.
With regard to the first step of this reaction sequence, it is
worth noting that b-substituted olefins activated by a sin-
gle ester group do not usually undergo phosphine-promot-
ed [3+2] cyclizations with allenic esters or phosphonates,
and that only b-unsubstituted acrylates11,18 or olefins bear-
ing two activating groups (e.g., fumarates, maleates,11 or
cyano esters19) are suitable as substrates for [3+2] cycliza-
tions of this class. We were therefore pleased to observe
that olefin 8, in which the nitro group was expected to in-
crease the electrophilic character, underwent the desired
annulation reaction with phosphonate 6. The desired cy-
clopentenyl phosphonate was obtained as a single isomer,
i.e. the g-adduct 9, in good yield and 86% ee.
We therefore decided to further expand the scope of the
method by using allenic phosphonates as the annulation
partners. In previous studies, we have shown that diethyl
propa-1,2-dien-1-ylphosphonate (6) and analogous propa-
dienylphosphonates are suitable substrates for phosphine-
promoted [3+2] cyclization reactions,15,16 leading to new
series of phosphonates with unusual molecular structures.
On the basis of these previous studies, we treated phos-
phonate 6 with ethyl 1-methyl-2-oxo-1,2-dihydroquino-
line-3-carboxylate (1) or ethyl 2-oxo-2H-chromene-3-
carboxylate (2a) in the presence of (S,S)-FerroPHANE
(10 mol%) in toluene at 110 °C. The coumarin derivative
2a was converted into the expected bicyclic phosphonate
7 as the major product (6:1 isomers ratio), in 72% isolated
yield and a 60% enantiomeric excess (Scheme 2).
The second step of the reaction sequence shown in
Scheme 3, reduction of the nitro group with iron dust and
subsequent in situ cyclization, was performed under the
usual conditions.20 The targeted cyclopentene-fused dihy-
droquinolinone 10, bearing a phosphonate function, was
obtained in 65% cumulative yield and 86% ee.
(EtO)2(O)P
In summary, we have demonstrated two synthetic ap-
proaches to cyclopentene-fused coumarin and quinoline
derivatives based on phosphine-promoted [3+2] cycliza-
tions. Benzo-fused bicyclo[4.3.0] scaffolds with unprece-
dented substitution schemes and functionalizations are
available by these methods. Moreover, enantiomerically
enriched compounds with enantiomeric excesses in the
range 70–86% have been prepared by using (S,S)-Ferro-
PHANE as the chiral phosphorus catalyst.
P(O)(OEt)2
(i)
CO2Et
+
CO2Et
O
X
O
X
1, X = NMe
2a, X = O
X = NMe, no reaction
7, X = O, 72%, 60% ee
6
Scheme 2 (S,S)-FerroPHANE-promoted enantioselective [3+2] cy-
clizations of diethyl propadienylphosphonate with ethyl 2-oxo-2H-
chromene-3-carboxylate. Reagents and conditions: (i) (S,S)-Ferro-
PHANE (10 mol%), toluene, 110 °C, 18 h.
All reagents and solvents were of commercial quality and were used
without further purification. NMR spectra (1H, 13C, and 31P) were
recorded on Bruker AV 500 or AV 300 spectrometers. Chemical
shifts are reported in ppm relative to residual CHCl3 as the internal
standard (d = 7.27 ppm for 1H NMR and 77.16 ppm for 13C NMR).
IR spectra were recorded with a Perkin-Elmer Fourier-transform IR
The dihydroquinoline derivative 1 failed to react under
analogous conditions. Nevertheless, the initial target of
building
cyclopentane-fused
dihydroquinolinone
moieties17 could be attained by the alternative synthetic
strategy shown in Scheme 3. This is a two-step approach spectrophotometer on neat samples. High-resolution mass spectra
(HRMS-ESI) were obtained on LCT Waters equipment. Optical ro-
tations were determined with a JASCO P-1010 polarimeter. HPLC
involving an initial enantioselective (S,S)-FerroPHANE-
Synthesis 2011, No. 12, 2003–2009 © Thieme Stuttgart · New York

2006
M. Neel et al.
PAPER
was performed at a column temperature of 20 °C on a Waters 2695
Separations Module equipped with a diode array UV detector.
0.9 Hz, 1 H), 6.88 (q, J ≈ 2.5 Hz, 1 H), 5.16 (d, J = 12.3 Hz, 1 H),
5.06 (d, J = 12.3 Hz, 1 H), 4.68 (br s, 1 H), 4.20–4.05 (m, 2 H), 3.52
(ddd, J = 18.0, 2.7, 1.2 Hz, 1 H), 3.32 (dt, J = 18.0, 2.7 Hz, 1 H),
1.09 (t, J = 7.2 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 168.8 (C), 166.8 (C), 163.2 (C),
150.2 (C), 142.6 (CH), 135.3 (C), 135.2 (C), 131.6 (CH), 129.2
(CH), 128.6 (CH × 2), 128.4 (CH × 2), 128.3 (CH), 124.4 (CH),
118.5 (C), 116.6 (CH), 66.6 (CH2), 62.6 (CH2), 59.3 (C), 50.3 (CH),
40.3 (CH2), 13.7 (CH3).
The coumarin-derived esters 2a–c were prepared by esterification
of 1-oxo-1H-isochromene-3-carboxylic acid under acidic condi-
tions (H2SO4). Substrates 2d–g were prepared according to the
literature.21 Ethyl 1-methyl-2-oxo-1,2-dihydroquinoline-3-carbox-
ylate (1) was prepared by alkylation of the ethyl 2-oxo-1,2-dihydro-
quinoline-3-carboxylate22 with MeI in KOH/EtOH. Substrates 623
and 824 were prepared according to the literature methods.
HRMS (ESI+): m/z [M + Na]+ calcd for C23H20NaO6: 415.1158;
found: 415.1154.
Phosphine-Promoted [3+2]-Cyclization Reactions of Buta-2,3-
dienoates 3 with 2-Oxo-2H-chromene-3-carboxylates 2; Gener-
al Procedure
3-Benzyl 3a-Ethyl 4-Oxo-1,9b-dihydrocyclopenta[c]chromene-
3,3a(4H)-dicarboxylate (5b)
Colorless oil; yield: 9 mg (15%); Rf = 0.23 (80% heptane–EtOAc).
1H NMR (500 MHz, CDCl3): d = 7.45–7.05 (m, 10 H), 5.30 (d,
J = 12.5 Hz, 1 H), 5.25 (d, J = 12.5 Hz, 1 H), 4.10–4.00 (m, 2 H),
3.98–3.90 (m, 1 H), 3.07 (ddd, J = 18.0, 8.0, 2.5 Hz, 1 H), 2.54 (dd,
J = 18.0, 10.5 Hz, 1 H), 1.03 (t, J = 7.0 Hz, 3 H).
A mixture of buta-2,3-dienoate 3 (0.30 mmol), 2-oxo-2H-
chromene-3-carboxylate 2 (0.15 mmol), and Ph3P (7.8 mg, 0.030
mmol) or (S,S)-FerroPHANE (7.0 mg, 0.015 mmol) in degassed tol-
uene (0.5 mL) was stirred under argon at r.t. for 24 h. The solvent
was removed in vacuo, and the isomeric ratios of the crude products
4 and 5c were determined by 1H NMR spectroscopy. The final prod-
ucts were purified by column chromatography (silica gel, heptane–
EtOAc), which also allowed efficient separation of the two regio-
isomers 4 and 5.
1-Cyclohexyl 3a-Ethyl 4-Oxo-3,9b-dihydrocyclopen-
ta[c]chromene-1,3a(4H)-dicarboxylate (4c)
Orange oil; yield: 41 mg (72%); 53% ee; Rf = 0.37 (80% heptane–
Diethyl 4-Oxo-3,9b-dihydrocyclopenta[c]chromene-1,3a(4H)-
dicarboxylate (4a)
EtOAc); [a]D25 +208 (c 0.4, CHCl3).
Orange oil; yield: 41 mg (84%); ee 72%; Rf = 0.33 (80% heptane–
HPLC (Daicel CHIRACEL AD-H column, 2% i-PrOH–heptane, 1
mL/min, 205 nm): tR = 4.3 min (major), 4.9 min (minor).
EtOAc); [a]D25 +67 (c 0.8, CHCl3).
HPLC (Daicel CHIRACEL AD-H column, 2% i-PrOH–heptane, 1
mL/min, 205 nm): tR = 4.6 min (major), 5.1 min (minor).
IR: 2981, 1760, 1714, 1456, 1329, 1244, 1152, 1112, 1092, 759 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.55 (dd, J = 7.7, 1.5 Hz, 1 H),
7.29 (dt, J = 7.8, 1.5 Hz, 1 H), 7.14 (dt, J = 7.8, 0.9 Hz, 1 H), 7.04
(dd, J = 8.1, 0.9 Hz, 1 H), 6.81 (m, 1 H), 4.64 (br s, 1 H), 4.20–4.05
(m, 4 H), 3.50 (ddd, J = 18.0, 2.8, 1.4 Hz, 1 H), 3.30 (dt, J = 18.0,
2.8 Hz, 1 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.08 (t, J = 7.1 Hz, 3 H).
IR: 2937, 2859, 2361, 1764, 1737, 1712, 1456, 1336, 1248, 1153,
1114, 771 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.56 (dd, J = 7.5, 1.2 Hz, 1 H),
7.30 (dt, J = 7.5, 1.5 Hz, 1 H), 7.16 (dt, J = 7.8, 1.5 Hz, 1 H), 7.05
(dd, J = 8.4, 1.2 Hz, 1 H), 6.81 (q, J = 2.7 Hz, 1 H), 4.80–4.70 (m,
1 H), 4.66 (br s, 1 H), 4.20–4.06 (m, 2 H), 3.51 (ddd, J = 17.8, 2.7,
1.5 Hz, 1 H), 3.31 (dt, J = 18.0, 2.7 Hz, 1 H), 1.88–1.78 (m, 2 H),
1.76–1.65 (m, 2 H), 1.64–1.15 (m, 6 H), 1.09 (t, J = 7.1 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 169.0 (C), 167.0 (C), 163.1 (C),
150.4 (C), 141.8 (CH), 136.1 (C), 131.7 (CH), 129.3 (CH), 124.5
(CH), 118.8 (C), 116.7 (CH), 73.5 (CH), 62.7 (CH2), 59.5 (C), 50.4
(CH), 40.3 (CH2), 31.7 (CH2), 31.6 (CH2), 25.4 (CH2), 23.9
(CH2 × 2), 13.9 (CH3).
13C NMR (75.5 MHz, CDCl3): d = 168.8 (C), 166.8 (C), 163.5 (C),
150.3 (C), 141.9 (CH), 135.5 (C), 131.5 (CH), 129.2 (CH), 124.4
(CH), 118.6 (C), 116.6 (CH), 62.6 (CH2), 60.8 (CH2), 59.3 (C), 50.3
(CH), 40.2 (CH2), 14.2 (CH3), 14.1 (CH3).
HRMS (ESI+): m/z [M + Na]+ calcd for C18H18NaO6: 353.1001;
found: 353.0994.
HRMS (ESI+): m/z [M + Na]+ calcd for C22H24NaO6: 407.1471;
found: 407.1476.
Diethyl 4-Oxo-1,9b-dihydrocyclopenta[c]chromene-3,3a(4H)-
dicarboxylate (5a)
Orange oil; yield: 4 mg (8%); Rf = 0.17 (80% heptane–EtOAc).
1H NMR (500 MHz, CDCl3): d = 7.35–7.05 (m, 5 H), 4.26 (q,
J = 7.2 Hz, 2 H), 4.15 (q, J = 7.2 Hz, 2 H), 4.02 (dd, J = 10.5, 8.1
Hz, 1 H), 3.03 (ddd, J = 17.7, 8.1, 3.0 Hz, 1 H), 2.48 (ddd, J = 17.7,
10.5, 1.5 Hz, 1 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.13 (t, J = 7.1 Hz, 3 H).
1-Ethyl 3a-Methyl 4-Oxo-3,9b-dihydrocyclopenta[c]chromene-
1,3a(4H)-dicarboxylate (4d)
Orange oil; yield: 28 mg (59%); 76% ee; Rf = 0.22 (80% heptane–
EtOAc); [a]D25 +80 (c 1, CHCl3).
HPLC (Daicel CHIRACEL AD-H column, 0.5% i-PrOH–heptane,
1 mL/min, 205 nm): tR = 10.7 min (major), 12.6 min (minor).
13C NMR (75.5 MHz, CDCl3): d = 168.9 (C), 166.9 (C), 163.6 (C),
150.7 (C), 145.5 (CH), 137.4 (C), 129.4 (CH), 128.6 (CH), 124.8
(CH), 120.8(C), 117.3 (CH), 62.7 (CH2), 62.1 (C), 61.2 (CH2), 48.2
(CH), 39.8 (CH2), 14.2 (CH3), 14.0 (CH3).
IR: 2981, 2358, 1763, 1741, 1715, 1458, 1329, 1252, 1153, 1111,
761 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.58 (dd, J = 7.8, 1.5 Hz, 1 H),
7.31 (dt, J = 7.8, 1.8 Hz, 1 H), 7.16 (dt, J = 7.5, 1.2 Hz, 1 H), 7.05
(dd, J = 8.1, 0.9 Hz, 1 H), 6.82 (q, J = 2.7 Hz, 1 H), 4.70 (br s, 1 H),
4.25–4.05 (m, 2 H), 3.70 (s, 3 H), 3.52 (ddd, J = 18.0, 3.0, 1.5 Hz,
1 H), 3.32 (dt, J = 18.0, 2.4 Hz, 1 H), 1.24 (t, J = 7.2 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 169.5 (C), 166.6 (C), 163.4 (C),
150.1 (C), 141.8 (CH), 135.6 (C), 131.6 (CH), 129.3 (CH), 124.3
(CH), 118.4 (C), 116.7 (CH), 60.8 (CH2), 59.3 (C), 53.6 (CH3), 50.1
(CH), 40.6 (CH2), 14.1 (CH3).
1-Benzyl 3a-Ethyl 4-Oxo-3,9b-dihydrocyclopenta[c]chromene-
1,3a(4H)-dicarboxylate (4b)
Orange oil; yield: 44 mg (75%); 76% ee; Rf = 0.29 (80% heptane–
EtOAc); [a]D25 +371 (c 0.4, CHCl3).
HPLC (Daicel CHIRACEL AD-H column, 2% i-PrOH–heptane, 1
mL/min, 206 nm): tR = 12.3 min (major), 13.7 min (minor).
IR: 2982, 2361, 1760, 1722, 1456, 1330, 1250, 1155, 1114, 758 cm–1.
HRMS (ESI+): m/z [M + Na]+ calcd for C17H16NaO6: 339.0845;
1H NMR (500 MHz, CDCl3): d = 7.50 (dd, J = 7.8, 1.5 Hz, 1 H),
7.40–7.25 (m, 6 H), 7.09 (dt, J = 7.2, 0.9 Hz 1 H), 7.06 (dd, J = 8.1,
found: 339.0841.
Synthesis 2011, No. 12, 2003–2009 © Thieme Stuttgart · New York

PAPER
Enantioselective Phosphine-Catalyzed [3+2] Cyclizations
2007
3a-Cyclohexyl 1-Ethyl 4-oxo-3,9b-dihydrocyclopen-
ta[c]chromene-1,3a(4H)-dicarboxylate (4e)
Diethyl 8-Methoxy-4-oxo-3,9b-dihydrocyclopenta[c]chromene-
1,3a(4H)-dicarboxylate (4h)
White solid; yield: 43 mg (61%); 74% ee; Rf = 0.46 (80% heptane–
Yellow oil; yield: 28 mg (53%); 71% ee; Rf = 0.25 (70% heptane–
EtOAc); [a]D25 +70 (c 0.9, CHCl3).
EtOAc); [a]D27 +73 (c 1.3, CHCl3).
HPLC (Daicel CHIRACEL AD-H column, 0.5% i-PrOH–heptane,
1 mL/min, 210 nm): tR = 8.3 min (major), 10.3 min (minor).
HPLC (Daicel CHIRACEL IC column, 10% i-PrOH–heptane, 1
mL/min, 227 nm): tR = 27.0 min (minor), 36.2 min (major).
IR: 2937, 2860, 1761, 1720, 1456, 1329, 1254, 1151, 1116, 1089,
759 cm–1.
IR: 2981, 2934, 1759, 1714, 1622, 1497, 1465, 1242, 1209, 1156,
1110, 1035 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.55 (d, J = 7.5 Hz, 1 H), 7.29 (t,
J = 7.5 Hz, 1 H), 7.14 (t, J = 7.5 Hz, 1 H), 7.05 (d, J = 8.1 Hz, 1 H),
6.81 (q, J = 2.7 Hz, 1 H), 4.76 (m, 1 H), 4.58 (br s, 1 H), 4.20–4.05
(m, 2 H), 3.51 (ddd, J = 18.0, 2.7, 1.5 Hz, 1 H), 3.31 (dt, J = 18.0,
2.7 Hz, 1 H), 1.70–1.60 (m, 2 H), 1.55–1.20 (m, 8 H), 1.22 (t, J = 7.2
Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 168.0 (C), 167.1 (C), 163.4 (C),
150.5 (C), 142.2 (CH), 135.2 (C), 131.8 (CH), 129.2 (CH), 124.3
(CH), 118.7 (C), 116.5 (CH), 74.7 (CH), 60.7 (CH2), 59.6 (C), 50.7
(CH), 39.9 (CH2), 30.6 (CH2), 30.5 (CH2), 25.1 (CH2), 22.4 (CH2),
22.3 (CH2), 14.1 (CH3).
1H NMR (500 MHz, CDCl3): d = 7.11 (d, J = 2.7 Hz, 1 H), 6.99 (d,
J = 8.9 Hz, 1 H), 6.84 (dd, J = 8.9, 3.1 Hz, 1 H), 6.83 (t, J = 3.1 Hz,
1 H), 4.66 (br s, 1 H), 4.20–4.10 (m, 4 H), 3.82 (s, 3 H), 3.47 (d,
J = 18.0 Hz, 1 H), 3.19 (dt, J = 18.0, 2.4 Hz, 1 H), 1.27 (t, J = 7.0
Hz, 3 H), 1.14 (t, J = 7.0 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 169.0 (C), 166.9 (C), 163.5 (C),
156.0 (C), 144.2 (C), 142.0 (CH), 135.7 (C), 119.4 (C), 117.3 (CH),
115.8 (CH), 115.0 (CH), 62.6 (CH2), 60.8 (CH2), 59.1 (C), 55.7
(CH3), 50.4 (CH), 40.3 (CH2), 14.1 (CH3), 13.8 (CH3).
HRMS (ESI+): m/z [M + Na]+ calcd for C19H20NaO7: 383.1107;
found: 383.1092.
HRMS (ESI+): m/z [M + Na]+ calcd for C22H24NaO6: 407.1471;
found: 407.1467.
Diethyl 8-Bromo-4-oxo-3,9b-dihydrocyclopenta[c]chromene-
1,3a(4H)-dicarboxylate (4i)
1-Benzyl 3a-Methyl 4-Oxo-3,9b-dihydrocyclopen-
ta[c]chromene-1,3a(4H)-dicarboxylate (4f)
Orange oil; yield: 44 mg (71%); 64% ee; Rf = 0.65 (70% heptane–
EtOAc); [a]D27 +104 (c 0.8, CHCl3).
White solid; yield: 28 mg (50%); 72% ee; Rf = 0.27 (80% heptane–
HPLC (Daicel CHIRACEL IC column, 10% i-PrOH–heptane, 1
mL/min, 210 nm): tR = 14.6 min (major), 16.0 min (minor).
EtOAc); [a]D25 +63 (c 0.9, CHCl3).
HPLC (Daicel CHIRACEL AD-H column, 0.5% i-PrOH–heptane,
1 mL/min, 238 nm): tR = 8.5 min (major), 10.2 min (minor).
IR: 2981, 1767, 1739, 1715, 1625, 1480, 1328, 1245, 1190, 1149,
1111, 1034 cm–1.
IR: 3033, 2955, 1760, 1738, 1714, 1456, 1330, 1252, 1154, 1114,
1086, 756 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.72 (d, J = 2.4 Hz, 1 H), 7.43 (dd,
J = 8.7, 2.4 Hz, 1 H), 6.95 (d, J = 8.7 Hz, 1 H), 6.86 (q, J = 2.4 Hz,
1 H), 4.61 (br s, 1 H), 4.25–4.10 (m, 4 H), 3.53 (ddd, J = 18.1, 3.0,
1.5 Hz, 1 H), 3.31 (dt, J = 18.1, 2.6 Hz, 1 H), 1.28 (t, J = 7.1 Hz, 3
H), 1.13 (t, J = 7.1 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 168.5 (C), 166.2 (C), 163.3 (C),
149.5 (C), 142.6 (CH), 135.1 (C), 134.5 (CH), 132.4 (CH), 120.7
(C), 118.4 (CH), 116.9 (C) 62.9 (CH2), 61.1 (CH2), 59.2 (C), 50.1
(CH2), 40.3 (CH), 14.2 (CH3), 13.9 (CH3).
1H NMR (300 MHz, CDCl3): d = 7.52 (dd, J = 7.5, 1.7 Hz, 1 H),
7.40–7.26 (m, 6 H), 7.10 (t, J = 8.0 Hz, 1 H), 7.07 (d, J = 8.5 Hz, 1
H), 6.88 (q, J = 2.5 Hz, 1 H), 5.18 (d, J = 12.0 Hz, 1 H), 5.08 (d,
J = 12.0 Hz, 1 H), 4.72 (br s, 1 H), 3.70 (s, 3 H), 3.54 (ddd, J = 18.0,
2.5, 1.5 Hz, 1 H), 3.34 (dt, J = 18.0, 2.5, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 169.4 (C), 166.6 (C), 163.2 (C),
150.1 (C), 142.4 (CH), 135.3 (C × 2), 131.6 (CH), 129.3 (CH),
128.6 (CH × 2), 128.4 (CH), 128.3 (CH × 2), 124.5 (CH), 118.2
(C), 116.6 (CH), 66.6 (CH2), 59.2 (C), 53.6 (CH3), 50.1 (CH), 40.7
(CH2).
HRMS (ESI+): m/z [M + Na]+ calcd for C18H17BrNaO6: 431.0107;
found: 431.0100.
HRMS (ESI+): m/z [M + Na]+ calcd for C22H18NaO6: 401.1001;
found: 401.0990.
Diethyl 8-Nitro-4-oxo-3,9b-dihydrocyclopenta[c]chromene-
1,3a(4H)-dicarboxylate (4j)
White solid; yield: 30 mg (53%); 71% ee; Rf = 0.64 (70% heptane–
Diethyl 7-Methoxy-4-oxo-3,9b-dihydrocyclopenta[c]chromene-
1,3a(4H)-dicarboxylate (4g)
EtOAc); [a]D27 +104 (c 0.8, CHCl3).
HPLC (Daicel CHIRACEL IC column, 10% i-PrOH–heptane, 1
mL/min, 210 nm): tR = 27.0 min (major), 40.7 min (minor).
Orange oil; yield: 24 mg (45%); 71% ee; Rf = 0.56 (70% heptane–
EtOAc); [a]D27 72 (c 1.1, CHCl3).
IR: 2983, 2923, 2360, 1775, 1716, 1530, 1345, 1248, 1138, 1032,
840 cm–1.
HPLC (Daicel CHIRACEL IC column, 10% i-PrOH–heptane, 1
mL/min, 210 nm): tR = 17.0 min (minor), 21.0 min (major).
1H NMR (500 MHz, CDCl3): d = 8.56 (d, J = 2.4 Hz, 1 H), 8.22 (dd,
J = 8.9, 2.7 Hz, 1 H), 7.21 (d, J = 8.9 Hz, 1 H), 6.92 (q, J = 2.7 Hz,
1 H), 4.73 (br s, 1 H), 4.20–4.10 (m, 4 H), 3.59 (dd, J = 18.0, 1.2 Hz,
1 H), 3.36 (dt, J = 18.0, 2.4 Hz, 1 H), 1.25 (t, J = 7.3 Hz, 3 H), 1.13
(t, J = 7.0 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 167.9 (C), 165.4 (C), 163.0 (C),
154.6 (C), 144.2 (C), 143.0 (CH), 134.5 (C), 128.2 (CH), 125.1 (C),
119.9 (C), 117.7 (CH), 63.2 (CH2), 61.3 (CH2), 59.1 (C), 50.2 (CH),
40.3 (CH2), 14.2 (CH3), 14.1 (CH3).
IR: 2981, 2921, 2851, 1764, 1714, 1627, 1509, 1444, 1327, 1240,
1161, 1111, 1034 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.47 (d, J = 8.5 Hz, 1 H), 6.80 (q,
J = 2.4 Hz, 1 H), 6.73 (dd, J = 8.5, 2.4 Hz, 1 H), 6.59 (d, J = 2.4 Hz,
1 H), 4.61 (br s, 1 H), 4.20–4.10 (m, 4 H), 3.81 (s, 3 H), 3.50 (d,
J = 18 Hz, 1 H), 3.30 (dt, J = 18.0, 2.4 Hz, 1 H), 1.25 (t, J = 7.3 Hz,
3 H), 1.13 (t, J = 7.3 Hz, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 169.0 (C), 166.9 (C), 163.5 (C),
160.2 (C), 151.0 (C), 141.5 (CH), 135.8 (C), 132.2 (CH), 110.8
(CH), 110.4 (C), 101.6 (CH), 62.6 (CH2), 60.7 (CH2), 59.4 (C), 55.5
(CH3), 49.9 (CH), 40.2 (CH2), 14.1 (CH3), 13.8 (CH3).
HRMS (ESI+): m/z [M + Na]+ calcd for C18H17NNaO8: 398.0852;
found: 398.0847.
HRMS (ESI+): m/z [M + Na]+ calcd for C19H20NaO7: 383.1107;
found: 383.1100.
Synthesis 2011, No. 12, 2003–2009 © Thieme Stuttgart · New York

2008
M. Neel et al.
PAPER
Phosphine-Promoted [3 + 2] Cyclization Reactions of Diethyl
Propa-1,2-dien-1-ylphosphonate (6); General Procedure
A mixture of phosphonate 6 (0.30 mmol), carboxylate 2a or acrylate
8 (0.15 mmol), and Ph3P (7.8 mg, 0.030 mmol) or (S,S)-Ferro-
PHANE (7.0 mg, 0.015 mmol) in degassed toluene (0.5 mL) was
heated under argon at 110 °C for 24 h. The products were purified
by column chromatography (silica gel, heptane–EtOAc gradient).
Colorless oil; yield: 28 mg (90%); 86% ee; [a]D25 –186 (c 0.3,
CHCl3).
HPLC (Daicel CHIRACEL IC column, 20% EtOH–heptanes, 1
mL/min, 240 nm): tR = 25.2 min (minor), 35.4 min (major).
IR: 3426, 2924, 1736, 1491, 1345, 1185, 1041, 811 cm–1.
1H NMR (300 MHz, CDCl3) 8.35 (br s, 1 H), 7.23–7.14 (m, 2 H),
7.00 (t, J = 7.8 Hz, 1 H), 6.86 (d, J = 12.0 Hz, 1 H), 6.78 (d, J = 7.8
Hz, 1 H), 4.30–4.10 (m, 4 H), 3.98 (dm, J = 6.5 Hz, 1 H), 3.79 (q,
J = 8.4 Hz, 1 H), 2.96 (dd, J = 16.9, 7.3 Hz, 1 H), 2.70–2.60 (m, 1
H), 1.43–1.25 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 168.8 (C), 149.1 (d, JCP = 13.4 Hz,
CH), 136.0 (C), 128.5 (CH), 128.1 (CH), 128.1 (C), 123.8 (C),
123.4 (CH), 115.7 (CH), 62.6 (d, JC,P = 6.6 Hz, CH2), 62.3 (d,
Ethyl 1-(Diethoxyphosphoryl)-4-oxo-1,9b-dihydrocyclopen-
ta[c]chromene-3a(4H)-carboxylate (7)
Colorless oil; yield: 42 mg (72%); 60% ee; [a]D25 +35.3 (c 1.0,
CHCl3).
HPLC (Daicel CHIRACEL IC column, 20% EtOH–heptane, 1 mL/
min, 210 nm): tR = 11.0 min (minor), 12.3 min (major).
IR: 2984, 1763, 1736, 1493, 1458, 1243, 1149, 1019, 967, 757 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.46 (dd, J = 7.5, 1.8 Hz, 1 H),
7.32 (dt, J = 7.8, 1.8 Hz, 1 H), 7.16 (dt, J = 7.5, 1.5 Hz, 1 H), 7.07
(dd, J = 7.8, 1.5 Hz, 1 H), 6.75 (dm, JH-P = 11.1 Hz, 1 H), 4.59 (br
s, 1 H), 4.25–4.05 (m, 2 H), 3.95–3.72 (m, 4 H), 3.66 (dm, J = 17.7
Hz, 1 H), 3.29 (dm, J = 17.7 Hz, 1 H), 1.15 (t, J = 7.2 Hz, 3 H), 1.06
(t, J = 7.2 Hz, 3 H), 1.03 (t, J = 7.2 Hz, 3 H).
JC,P = 8.8 Hz, CH2), 50.2 (d, JC,P = 9.8 Hz, CH), 42.9 (d, JC,P = 10.7
Hz, CH), 42.0 (d, JC,P = 18.8 Hz, CH2), 16.6 (d, JC,P = 6.4 Hz, CH3),
16.5 (d, JC,P = 7.5 Hz, CH3).
31P NMR (121 MHz, CDCl3): d = 14.4 ppm.
HRMS (ESI): m/z [M + H]+ calcd for C16H21NO4P: 322.1208;
found: 322.1200.
13C NMR (75 MHz, CDCl3): d = 168.7 (C), 167.0 (C), 150.8 (C),
146.8 (JCP = 12.3 Hz, CH), 135.8 (C), 130.8 (CH), 129.6 (CH),
124.7 (CH), 118.6 (C), 116.6 (CH), 62.8 (CH2), 62.1 (JC,P = 5.9 Hz,
CH2), 61.9 (JC,P = 5.8 Hz, CH2), 60.5 (JC,P = 9.8 Hz, C), 52.4
(JC,P = 14.9 Hz, CH), 41.9 (JC,P = 18.2 Hz, CH2), 16.2 (JC,P = 6.5
Hz, CH3), 16.0 (JC,P = 6.2 Hz, CH3), 13.9 (CH3).
31P NMR (121 MHz, CDCl3): d = 11.6 ppm.
HRMS (ESI+): m/z [M + Na]+ calcd for C19H23NaO7P: 417.1079;
References
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Ethyl 2-(Diethoxyphosphoryl)-5-(2-nitrophenyl)cyclopent-2-
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Colorless oil; yield: 43 mg (72%); 86% ee; [a]D25 +33.1 (c 1.0,
CHCl3).
HPLC (Daicel CHIRACEL IC column, 20% EtOH–heptanes, 1
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IR: 2983, 2908, 1732, 1525, 1352, 1248, 1181, 1048, 1024, 963,
787, 748 cm–1.
1H NMR (300 MHz, CDCl3) d = 7.81 (dd, J = 8.1, 1.5 Hz, 1 H), 7.55
(dt, J = 7.5, 1.2 Hz, 1 H), 7.42–7.32 (m, 2 H), 6.93 (dq, JH-P = 11.1
Hz, J = 2.1 Hz, 1 H), 4.30–4.00 (m, 7 H), 3.82 (m, J <3 Hz, 1 H),
3.34 (dddt, J = 18.6, 9.0, 4.5, 2.4 Hz, 1 H), 2.66 (dm, J = 18.6, <3
Hz, 1 H), 1.36–1.23 (m, 9 H).
13C NMR (75 MHz, CDCl3): d = 172.6 (C), 150.1 (JCP = 16.0 Hz,
CH), 149.3 (C), 138.9 (C), 133.5 (CH), 131.5 (JC,P = 192.3 Hz, C),
128.2 (CH), 128.0 (CH), 124.4 (CH), 62.3 (JC,P = 7.2 Hz, CH2), 62.1
(JC,P = 6.6 Hz, CH2), 61.4 (CH2), 60.0 (JC,P = 12.4 Hz, CH), 43.2
(JC,P = 10.4 Hz, CH), 42.7 (JC,P = 20.2 Hz, CH2), 16.5 (JC,P = 5.9
Hz, CH3), 16.3 (JC,P = 7.2 Hz, CH3), 14.2 (CH3).
31P NMR (121 MHz, CDCl3): d = 13.3 ppm.
HRMS (ESI): m/z [M + Na]+ calcd for C18H24NNaO7P: 420.1188;
found: 420.1188.
Diethyl (4-Oxo-3a,4,5,9b-tetrahydro-1H-cyclopenta[c]quino-
lin-3-yl)phosphonate (10)
(13) (a) Kumar, K.; Kapoor, R.; Kapur, A.; Ishar, M. P. S. Org.
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Fe dust (1.0 mmol) was added to a soln of nitro derivative 9 (0.06
mmol) in AcOH (0.5 mL), and the mixture was heated at 80 °C for
3 h. The mixture was then cooled and filtered through Celite, which
was washed with EtOAc. The combined organic phases were con-
centrated to give a crude mixture that was purified by column chro-
matography (5% MeOH–CH2Cl2).
Synthesis 2011, No. 12, 2003–2009 © Thieme Stuttgart · New York

PAPER
Enantioselective Phosphine-Catalyzed [3+2] Cyclizations
2009
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