Aminocatalytic asymmetric Diels-Alder reaction of phosphorus dienophiles and 2,4-dienals

Article abstract of DOI:10.1016/j.tet.2013.10.001

Chiral compounds bearing a phosphorus functional group are valuable because of their wide application in biological studies and asymmetric catalysis. Here we present an asymmetric Diels-Alder cycloaddition between phosphor-containing dienophiles and 2,4-d

Full text of DOI:10.1016/j.tet.2013.10.001

Tetrahedron 69 (2013) 10369e10374
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Aminocatalytic asymmetric DielseAlder reaction of phosphorus
dienophiles and 2,4-dienals
,b,
Qing-Qing Zhou a, Xin Yuan a, You-Cai Xiao a, Lin Dong a, Ying-Chun Chen a
*
a Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education, West China School of Pharmacy, and State Key Laboratory of
Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
b College of Pharmacy, Third Military Medical University, Chongqing 400038, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 August 2013
Received in revised form 29 September 2013
Accepted 3 October 2013
Available online 7 October 2013
Chiral compounds bearing a phosphorus functional group are valuable because of their wide application
in biological studies and asymmetric catalysis. Here we present an asymmetric DielseAlder cycloaddition
between phosphor-containing dienophiles and 2,4-dienals under the catalysis of chiral amine 1 via the
intermediacy of trienamine species (trienamine catalysis). A spectrum of densely functionalized phos-
phonocyclohexene derivatives was efficiently constructed in excellent enantioselectivity (up to 99% ee)
and with good to high diastereoselectivity (up to >19:1).
Keywords:
Phosphonate
Ó 2013 Elsevier Ltd. All rights reserved.
Phosphine oxide
Dienophile
DielseAlder cycloaddition
Trienamine
1. Introduction
knowledge, there are still very scare examples of catalytic Diel-
seAlder reaction with phosphorus dienophiles. Encouraged by our
Phosphorus-containing motifs are the key structural features in
a large number of enzyme inhibitors, antibiotics, antiviral agents,
agrochemicals, and haptens of catalytic antibodies.1 In addition, the
chiral phosphines or their oxides have been extensively used as
ligands for metal catalysts or as catalysts in organocatalysis.2 Thus,
the synthesis of chiral organophosphorus compounds has gener-
ated much interest in synthetic communities.3 Among them, the
enantioselective addition of phosphorus nucleophiles provides
a straightforward protocol to access chiral organophosphorus ma-
terials through a new PeC bond formation.4 Another way to con-
struct these motifs is to employ asymmetric addition reactions with
prochiral phosphorous-containing nucleophiles or electrophiles
used as substrates, through which stereogenic centers adjacent or
remote to the phosphorous atom could be generated.3e,5
Asymmetric DielseAlder cycloaddition is one of the most
powerful methodologies to construct six-membered chiral carbo-
or heterocycles.6 In fact, this tool has also been applied to phos-
phorus dienophiles or dienes to obtain valuable phosphonocyclo-
hexene derivatives.7 Although such asymmetric variants have been
reported by using chiral auxiliary strategy,8 to the best of our
recent success in the asymmetric DielseAlder cycloadditions with
HOMO-activated trienamine species,9 here we would like to pres-
ent the aminocatalytic and highly stereoselective DielseAlder re-
action of phosphorus dienophiles and 2,4-dienals, giving an
efficient and convenient approach to synthesize complex cyclo-
hexenes containing a phosphonate or phosphine oxide moiety.
2. Results and discussion
We initially selected 3-(phosphorylmethylene)-oxindole10 2a as
the model dienophile in the reaction with 2,4-hexadienal 3a under
the catalysis of chiral amine 1 and o-fluorobenzoic acid (OFBA) in
chloroform at room temperature, since the analogous 3-(oxy-
carbonylmethylene)oxindoles9a exhibited high reactivity, and use-
ful spirocyclic oxindoles could be generated.11 To our delight, the
cycloadduct 4a was smoothly obtained as a single regio- and endo-
diastereomer in high yield (94%) in 2 h, and with excellent enan-
tioselectivity (96% ee) (Table 1, entry 1). In this case, oxindole
moiety still showed stronger electron-withdrawing property than
that of phosphonate group. We also briefly screened a series of
solvents, such as toluene, THF, 1,4-dioxane, but generally producing
inferior results.12 Consequently, we investigated the substrate
scope and limitations under the above established catalytic con-
ditions. For the cycloadditions with 2,4-hexadienal 3a, 3-
* Corresponding author. Tel./fax: þ86 28 85502609; e-mail address: ycchen@scu.
edu.cn (Y.-C. Chen).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.001

10370
Q.-Q. Zhou et al. / Tetrahedron 69 (2013) 10369e10374
Table 1
Asymmetric DielseAlder reaction of 3-(phosphorylmethylene)oxindoles 2 and 2,4-
dienals 3a
Scheme 1. Asymmetric DielseAlder reaction of 3-methyleneoxindoles 5 with a phos-
phine oxide moiety.
Entry
R2
R3, R4, R5
Yieldb (%)
drc
eed (%)
1
H
5-F
5-Cl
5-Br
5-CF3O
5-MeO
5,7-Me2
H
H
H
H
H
H
H
H
H, H, H
H, H, H
H, H, H
H, H, H
H, H, H
H, H, H
H, H, H
H, Me, H
Me, H, H
Et, H, H
Ph, H, H
Ph, H, Me
H, (CH2)3
H, H, H
H, H, H
4a, 94
4b, 77
4c, 95
4d, 80
4e, 81
4f, 91
4g, 87
4h, 94
4i, 94
4j, 91
4k, 92
4l, 92
4m, 52
4n, 90
d
>19:1
10:1
>19:1
9:1
>19:1
>19:1
15:1
>19:1
>19:1
10:1
15:1
12:1
8:1
>19:1
d
96
97
90f
94
98
94
96
96
99
99
98
98
94
95
d
2e
3e
4e
5
6e
7
8
9
10
11
12
13e
14e,g
15h
a
Unless noted otherwise, reactions were performed with dienophile 2 (0.1 mmol,
R1¼Boc), 2,4-dienal 3 (0.12 mmol), amine 1 (20 mol %), and o-fluorobenzoic acid
(OFBA, 20 mol %) in chloroform (1.0 mL) at room temperature.
b
Yield of isolated major diastereomer.
c
By 1H NMR analysis of crude mixture.
Scheme 2. Exploration with more phosphono dienophiles.
d
Determined by chiral HPLC analysis after conversion to the corresponding
alcohol.
e
At 45 ꢀC.
f
The absolute configuration of 4c was determined by X-ray analysis after con-
version to 2,4-dinitrobenzenehydrazone, see the SD.13 The other products were
assigned by analogy.
(3-oxo-3-phenylprop-1-en-1-yl)-phosphonate 7 exhibited consid-
erable reactivity with 2,4-hexadienal under the above catalytic
conditions. In contrast to what’s observed using substrate 2, this
reaction is exo-selective with respect to the carbonyl group, prob-
ably due to the bulkiness of benzoyl moiety.15 Cycloadduct 8 was
isolated in a moderate yield, while the enantioselectivity was also
outstanding (95% ee). Unfortunately, much lower or inert reactivity
were observed for dienophiles 9e11 in the reactions with 3a or
other 2,4-dienals.
As outlined in Scheme 3, the multifunctional spirocyclic oxin-
doles 4a and 6a could be used to construct more complex frame-
works. The aldehyde group was firstly oxidized by Jone’s reagent in
DCM with good yield. Then an intramolecular bromolactonization
reaction with the obtained acids 12 was conducted with N-bro-
mosuccinimide (NBS) catalyzed by 1,4-diazabicyclo[2.2.2]octane
(DABCO),16 and the corresponding products 13a and 13b were
isolated in 72% and 83% yield, respectively, both with excellent
diastereo- and enantiopurity.
R1¼Cbz.
g
R1¼Me.
h
(phosphorylmethylene)oxindoles
2
bearing either electron-
withdrawing or donating substituents could be well tolerated,
generally exhibiting high to outstanding diastereo- and enantio-
selectivity. The corresponding cycloadducts 4beg could be isolated
in a diastereopure form in good to excellent yield (entries 2e7). On
the other hand, we explored a variety of 2,4-dienals with diverse
substituted patterns in the reactions with dienophile 2a. As sum-
marized in Table 1, entries 8e12, the similar excellent enantiose-
lectivity and high isolated yields were obtained for products 4hel,
though a small amount of exo-diastereomers were detected in
some cases. Nevertheless, a 2,4-dienal with a cyclopentylene motif
exhibited lower reactivity, and product 4m was obtained in
a moderate yield but still with good stereocontrol (entry 13). A
dienophile with an N-Cbz group could be efficiently used, and re-
markable data was afforded (entry 14). However, an N-methyl 3-
olefinic oxindole demonstrated to be inert in the cycloaddition
due to lower electrophilicity (entry 15).
With the delightful results in hand, we further designed another
type of 3-methyleneoxindoles 5 bearing a phosphine oxide moiety,
and tested their reactions with 2,4-dienal 3a. As outlined in
Scheme 1, all the cycloadditions took place smoothly under the
same catalytic conditions, and products 6aec were produced in
exclusive diastereoselectivity and with high enantioselectivity.
Thus, the chiral phosphine compounds, which might be used as
potential metal ligands or in organocatalysis could be attainable
after reducing P]O bond.14
In order to introduce more structural diversity into phospho-
nocyclohexene derivatives, more dienophiles containing a phos-
phonate group was investigated. As illustrated in Scheme 2, diethyl
Scheme 3. Synthetic transformations to access more complex framework.

Q.-Q. Zhou et al. / Tetrahedron 69 (2013) 10369e10374
10371
3. Conclusion
3.91e3.62 (m, 4H), 3.37 (dd, J¼18.8, 8.0 Hz, 1H), 2.90e2.89 (m, 1H),
2.77e2.69 (m, 3H), 2.39e2.33 (m, 1H), 1.62 (s, 9H), 1.12 (t, J¼7.2 Hz,
3H), 1.01 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
In conclusion, we have developed an asymmetric DielseAlder
cycloaddition of diverse phosphorus dienophiles with 2,4-dienals
under the catalysis of a chiral secondary amine, which provides
an efficient and straightforward approach to construct densely
functionalized phosphonocyclohexene derivatives in excellent
enantioselectivity and with good to high diastereoselectivity. These
chiral frameworks with a phosphonate or phosphine oxide group
might find applications in medicinal chemistry or asymmetric
catalysis.
d
¼199.2, 174.5, 159.5 (d, JC,F¼24.0 Hz), 148.9, 127.8, 125.7 (d,
JC,F¼13.1 Hz), 116.0 (d, JC,F¼8.0 Hz), 114.7, 114.5, 112.3, 112.1, 84.1,
62.3 (d, JCOP¼6.3 Hz), 61.3 (d, JCOP¼7.1 Hz), 45.6, 37.2 (d,
JCP¼11.9 Hz), 34.1, 32.7, 28.0, 22.9 (d, JCCCP¼3.8 Hz), 16.0 (d,
JCCOP¼5.9 Hz), 15.8 (d, JCCOP¼6.6 Hz) ppm; ESIeHRMS: calcd for
C
24H31FNO7PþNaþ 518.1714, found: 518.1721.
4.2.3. (1S,2S,6S)-tert-Butyl-50-chloro-6 (diethoxyphosphoryl)-20-oxo-
2-(2-oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-10
carboxylate
4. Experimental
(4c). 4 h, 95% yield; orange oil; Rf¼0.31 (petroleum ether/ethyl
acetate¼1:1); [
a
]
20 ꢁ19.5 (c 0.42 in CHCl3); 90% ee, determined by
D
4.1. General comments
HPLC analysis after 4c was converted to the corresponding alcohol
[NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath] [Daicel Chiralcel
NMR data were obtained for 1H at 400 MHz, and for 13C at
100 MHz. Chemical shifts were reported in parts per million from
tetramethylsilane with the solvent resonance as the internal stan-
dard in CDCl3 solution. ESIeHRMS was recorded on a Waters
SYNAPT G2. In each case, enantiomeric ratio was determined by
HPLC analysis on a chiral column in comparison with authentic
racemate. UV detection was monitored at 220 or 254 nm. Optical
rotation data were examined at 589 nm in CHCl3 solution at 25 ꢀC.
OD-H Column, n-hexane/i-PrOH¼80:20, 1.0 mL/min, ¼254 nm, t
l
(major)¼5.62 min, t (minor)¼6.53 min]; 1H NMR (400 MHz, CDCl3):
d
¼9.67 (s, 1H), 7.85 (d, J¼8.8 Hz, 1H), 7.30e7.25 (m, 2H), 6.03e6.01
(m, 1H), 5.79e5.75 (m, 1H), 3.86e3.72 (m, 3H), 3.65e3.59 (m, 1H),
3.35 (dd, J¼18.4, 8.4 Hz, 1H), 2.89e2.88 (m, 1H), 2.72e2.68 (m, 3H),
2.35 (dd, J¼18.4, 4.0 Hz,1H),1.62 (s, 9H),1.11 (t, J¼7.2 Hz, 3H),1.02 (t,
J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
¼199.2, 171.8,
d
148.8, 137.5, 129.3, 128.2, 127.8, 125.8, 125.7, 124.8, 116.1, 84.3, 62.3
(d, JCOP¼6.4 Hz), 61.3 (d, JCOP¼6.1 Hz), 45.7, 37.1 (d, JCP¼12.0 Hz),
34.1, 32.7, 28.0, 22.9 (d, JCCCP¼3.7 Hz), 16.0 (d, JCCOP¼6.0 Hz), 15.8 (d,
JCCOP¼6.7 Hz) ppm; ESIeHRMS: calcd for C24H31Cl35NO7PþNaþ
534.1419, found: 534.1424 (Cl35), 536.1431 (Cl37).
4.2. General procedure for asymmetric DielseAlder reaction
of phosphono dienophiles and 2,4-dienals via trienamine
activation
Phosphono dienophile 2 or 5 or 7 (0.1 mmol), 2,4-dienal 3
(0.12 mmol), o-fluorobenzoic acid (0.02 mmol), and secondary
amine catalyst 1 (0.02 mmol) were dissolved in CHCl3 (1.0 mL) and
the solution was stirred at room temperature or at 45 ꢀC. After
completion, the mixture was concentrated and the residue was
purified by flash chromatography on silica gel (petroleum ether/
EtOAc) to give the DielseAlder cycloadduct 4 or 6 or 8.
4.2.4. (1S,2S,6S)-tert-Butyl-50-bromo-6-(diethoxyphosphoryl)-20-
oxo-2-(2-oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-10-carboxylate
(4d). 8 h, 80% yield; orange oil; Rf¼0.33 (petroleum ether/ethyl
acetate¼1:1); [
a
]
D
20 ꢁ24.5 (c 0.29 in CHCl3); 94% ee, determined by
HPLC analysis after 4d was converted to the corresponding alcohol
[NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath] [Chiralpak AS-H
Column, n-hexane/i-PrOH¼80:20, 1.0 mL/min,
l
¼254 nm,
t
(minor)¼4.86 min, t (major)¼6.57 min]; major isomer: 1H NMR
4.2.1. (1S,2S,6S)-tert-Butyl-6-(diethoxyphosphoryl)-20-oxo-2-(2-
oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-10-carboxylate
(4a). 2 h, 94% yield; colorless oil; Rf¼0.32 (petroleum ether/ethyl
(400 MHz, CDCl3):
d
¼9.67 (s, 1H), 7.79 (d, J¼8.4 Hz, 1H), 7.44 (dd,
J¼8.4, 2.0 Hz, 1H), 7.37 (d, J¼2.0 Hz, 1H), 6.03e6.01 (m, 1H),
5.79e5.75 (m, 1H), 3.86e3.64 (m, 3H), 3.62e3.56 (m, 1H), 3.34 (dd,
J¼18.8, 8.4 Hz, 1H), 2.89e2.88 (m, 1H), 2.71e2.67 (m, 3H),
2.38e2.32 (m, 1H), 1.62 (s, 9H), 1.11 (t, J¼7.2 Hz, 3H), 1.03 (t,
acetate¼1:1); [
a
]
20 ꢁ14.3 (c 0.14 in CHCl3); 96% ee, determined by
D
HPLC analysis after 4a was converted to the corresponding alcohol
[NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath] [Chiralpak AS-H
J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
¼199.1, 175.6,
d
Column, n-hexane/i-PrOH¼90:10, 1.0 mL/min,
l¼254 nm,
t
148.9, 138.0, 131.1, 127.8, 127.5, 125.8, 125.7, 116.9, 116.5, 84.3, 62.3
(d, JCOP¼6.4 Hz), 61.3 (d, JCOP¼6.9 Hz), 45.6, 37.1 (d, JCP¼12.0 Hz),
34.2, 32.7, 28.0, 22.9 (d, J¼3.8 Hz), 16.0 (d, JCCOP¼5.9 Hz), 15.8 (d,
JCCOP¼6.8 Hz) ppm; ESIeHRMS: calcd for C24H31Br79NO7PþNaþ
578.0914, found: 578.0920 (Br79), 580.0919 (Br81).
(minor)¼8.16 min, t (major)¼13.48 min]; 1H NMR (400 MHz,
CDCl3):
d
¼9.68 (s,1H), 7.86 (d, J¼8.4 Hz,1H), 7.32e7.29 (m, 2H), 7.08
(dt, J¼7.6, 0.8 Hz, 1H), 6.01e5.99 (m, 1H), 5.78e5.75 (m, 1H),
3.84e3.70 (m, 3H), 3.61e3.55 (m, 1H), 3.36 (dd, J¼18.4, 8 Hz, 1H),
2.78e2.68 (m, 4H), 2.35 (dd, J¼18.4, 4.8 Hz, 1H), 1.63 (s, 9H), 1.10 (t,
J¼7.2 Hz, 3H), 0.98 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz,
4.2.5. (1S,2S,6S)-tert-Butyl-6-(diethoxyphosphoryl)-20-oxo-2-(2-
CDCl3):
d
¼199.4, 176.3, 148.5, 128.3, 128.3, 128.0, 125.7, 125.6, 124.6,
oxoethyl)-50-(trifluoromethoxy)spiro[cyclohex[3]ene-1,30-indoline]-
123.9, 114.8, 83.9, 62.2 (d, JCOP¼6.3 Hz), 61.2 (d, JCOP¼6.8 Hz), 45.8,
37.4 (d, JCP¼12.1 Hz), 34.3, 32.9, 29.6, 23.0 (d, JCCCP¼3.8 Hz), 16.0 (d,
JCCOP¼6.0 Hz), 15.8 (d, JCCOP¼6.6 Hz) ppm; ESIeHRMS: calcd for
10-carboxylate (4e). 4 h, 81% yield; orange oil; Rf¼0.35 (petroleum
20
ether/ethyl acetate¼1:1); [
a
]
D
ꢁ16.7 (c 0.31 in CHCl3); 98% ee,
determined by HPLC analysis after 4e was converted to the corre-
sponding alcohol [NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath]
[Daicel Chiralcel OD-H Column, n-hexane/i-PrOH¼90:10, 1.0 mL/
C
24H32NO7PþNaþ 500.1809, found:500.1814.
4.2.2. (1S,2S,6S)-tert-Butyl-6-(diethoxyphosphoryl)-50-fluoro-20-
oxo-2-(2-oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-10 carboxylate
(4b). 7 h, 77% yield; yellow semisolid; Rf¼0.34 (petroleum ether/
min,
l
¼254 nm, t (major)¼8.86 min, t (minor)¼15.04 min]; 1H NMR
(400 MHz, CDCl3):
d
¼9.68 (s, 1H), 7.93 (d, J¼8.8 Hz, 1H), 7.20e7.17
(m, 2H), 6.04e6.02 (m, 1H), 5.79e5.76 (m, 1H), 3.88e3.72 (m, 3H),
3.68e3.58 (m, 1H), 3.38 (dd, J¼18.8, 8.4 Hz, 1H), 2.91e2.90 (m, 1H),
2.72e2.68 (m, 3H), 2.36 (dd, J¼18.8, 3.6 Hz, 1H), 1.63 (s, 9H), 1.11 (t,
J¼7.2 Hz, 3H), 1.00 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz,
ethyl acetate¼1:1); [
a
]
20 ꢁ9.4 (c 0.13 in CHCl3); 97% ee, determined
D
by HPLC analysis after 4b was converted to the corresponding al-
cohol [NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath] [Chiralpak
AD-H Column, n-hexane/i-PrOH¼90:10, 1.0 mL/min,
l¼254 nm, t
CDCl3):
d
¼199.2, 175.8, 148.8, 145.4, 137.5, 132.4, 127.8, 125.8 (d, d,
(minor)¼9.32 min, t (major)¼13.92 min]; major isomer: 1H NMR
JC,F¼13.3 Hz), 121.0, 118.0, 115.8, 84.4, 62.3 (d, JCOP¼6.5 Hz), 61.3 (d,
JCOP¼7.0 Hz), 45.5, 37.1 (d, JCP¼11.7 Hz), 34.2, 32.8, 29.6, 28.0, 22.9
(d, JCCCP¼3.9 Hz), 15.9 (d, JCCOP¼5.8 Hz), 15.7 (d, JCCOP¼6.5 Hz) ppm;
(400 MHz, CDCl3):
d
¼9.68 (s, 1H), 7.86 (dd, J¼8.4, 4.8 Hz, 1H),
7.04e6.99 (m, 2H), 6.02e6.00 (m, 1H), 5.79e5.75 (m, 1H),

10372
Q.-Q. Zhou et al. / Tetrahedron 69 (2013) 10369e10374
ESIeHRMS: calcd for C25H31F3NO8PþNaþ 584.1632, found:
HPLC analysis after 4i was converted to the corresponding alcohol
[NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath] [Daicel Chiralcel
584.1639.
OD-H Column, n-hexane/i-PrOH¼90:10, 1.0 mL/min, ¼254 nm, t
l
4.2.6. (1S,2S,6S)-tert-Butyl-6-(diethoxyphosphoryl)-50-methoxy-20-
oxo-2-(2-oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-10-carboxylate
(4f). 4 h, 91% yield; orange semisolid; Rf¼0.32 (petroleum ether/
(minor)¼7.67 min, t (major)¼9.65 min]; 1H NMR (400 MHz, CDCl3):
d
¼9.64 (s, 1H), 7.80 (d, J¼8.0 Hz, 1H), 7.24e7.16 (m, 2H), 7.00e6.97
(m,1H), 5.65 (s,1H), 3.79e3.55 (m, 3H), 3.53e3.47 (m,1H), 3.34 (dd,
J¼18.8, 8.8 Hz, 1H), 2.72e2.59 (m, 4H), 2.29e2.24 (m, 1H), 1.58 (s,
3H), 1.55 (s, 9H), 1.03 (t, J¼7.2 Hz, 3H), 0.90 (t, J¼7.2 Hz, 3H) ppm;
20
ethyl acetate¼1:1); [
a
]
ꢁ29.7 (c 0.20 in CHCl3); 94% ee, de-
D
termined by HPLC analysis after 4f was converted to the corre-
sponding alcohol [NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath]
[Daicel Chiralcel OD-H Column, n-hexane/i-PrOH¼90:10, 1.0 mL/
13C NMR (100 MHz, CDCl3):
d
¼199.5,176.5,148.9,138.8,133.7,130.5,
128.2, 124.5, 123.9, 120.9 (d, JCP¼13.2 Hz), 114.8, 83.8, 62.1 (d,
JCOP¼6.3 Hz), 61.2 (d, JCOP¼7.1 Hz), 43.8, 41.4 (d, JCP¼12.5 Hz), 33.4,
32.0, 28.0, 23.2 (d, JCCCP¼3.5 Hz), 22.6,16.0 (d, JCCOP¼5.9 Hz),15.7 (d,
JCCOP¼6.5 Hz) ppm; ESIeHRMS: calcd for C25H34NO7PþNaþ
514.1965, found: 514.1971.
min,
l
¼254 nm, t (major)¼12.87 min, t (minor)¼19.70 min]; 1H
NMR (400 MHz, CDCl3):
d
¼9.68 (s, 1H), 7.79 (d, J¼8.8 Hz, 1H), 6.90
(d, J¼2.4 Hz, 1H), 6.82 (dd, J¼9.2, 2.4 Hz, 1H), 6.00e5.98 (m, 1H),
5.78e5.75 (m, 1H), 3.89e3.85 (m, 1H), 3.77 (s, 3H), 3.74e3.67 (m,
2H), 3.65e3.57 (m, 1H), 3.36 (dd, J¼18.8, 8.0 Hz, 1H), 2.89e2.69 (m,
3H), 2.52e2.32 (m, 2H), 1.62 (s, 9H), 1.11 (t, J¼6.8 Hz, 3H), 1.00 (t,
4.2.10. (1S,2S,6S)-tert-Butyl-6-(diethoxyphosphoryl)-3-ethyl-20-oxo-
2-(2-oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-10-carboxylate
(4j). 6 h, 95% yield; colorless oil; Rf¼0.34 (petroleum ether/ethyl
J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
¼199.4, 156.4,
d
149.0,132.4,132.1, 128.1,125.7, 125.6,115.5,112.1, 111.9, 83.8, 62.2 (d,
JCOP¼6.4 Hz), 61.2 (d, JCOP¼7.0 Hz), 55.6, 45.8, 37.4 (d, JCP¼12.1 Hz),
34.3, 32.9, 28.1, 23.1, 16.0 (d, JCCOP¼6.1 Hz), 15.8 (d,
JCCOP¼6.6 Hz) ppm; ESIeHRMS: calcd for C25H34NO8PþNaþ
530.1914, found: 530.1921.
acetate¼1:1); [
a
]
20 ꢁ41.0 (c 0.23 in CHCl3); 99% ee, determined by
D
HPLC analysis after 4j was converted to the corresponding alcohol
[NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath] [Daicel Chiralcel
OD-H Column, n-hexane/i-PrOH¼90:10, 1.0 mL/min, ¼254 nm, t
l
(minor)¼6.71 min, t (major)¼8.84 min]; major isomer: 1H NMR
4.2.7. (1S,2S,6S)-tert-Butyl-6-(diethoxyphosphoryl)-50,70-
dimethyl-20-oxo-2-(2-oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-
10-carboxylate (4g). 3 h, 87% yield; colorless oil; Rf¼0.33 (petro-
(400 MHz, CDCl3):
d¼9.70 (s, 1H), 7.87 (d, J¼8.4 Hz, 1H), 7.31e7.27
(m, 1H), 7.21 (d, J¼7.6 Hz, 1H), 7.05 (t, J¼7.6 Hz, 1H), 5.71 (s, 1H),
3.84e3.55 (m, 4H), 3.42 (dd, J¼18.8, 9.2 Hz, 1H), 2.86e2.69 (m, 3H),
2.23 (dd, J¼18.8, 1.6 Hz, 1H), 2.06e2.00 (m, 2H), 1.80e1.77 (m, 1H),
1.62 (s, 9H), 1.10 (t, J¼7.2 Hz, 3H), 0.98 (t, J¼7.2 Hz, 3H), 0.89 (t,
20
leum ether/ethyl acetate¼1:1); [
a
]
ꢁ15.4 (c 0.13 in CHCl3); 96%
D
ee, determined by HPLC analysis after 4g was converted to the
corresponding alcohol [NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt
bath] [Chiralpak AS-H Column, n-hexane/i-PrOH¼90:10, 1.0 mL/
J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
¼199.4, 176.7,
d
149.0, 139.4, 138.9, 128.2, 124.8, 123.7, 119.4, 119.2, 114.8, 83.9, 62.1
(d, JCOP¼6.4 Hz), 61.2 (d, JCOP¼7.3 Hz), 44.4, 39.8 (d, J¼12.5 Hz), 33.6,
32.2, 28.3, 28.0, 23.0, 16.1 (d, JCCOP¼5.9 Hz), 15.8 (d, JCCOP¼6.6 Hz),
12.2 ppm; ESIeHRMS: calcd for C26H36NO7PþNaþ 528.2122, found
528.2129.
min,
l
¼254 nm, t (minor)¼6.78 min, t (major)¼8.89 min]; 1H NMR
(400 MHz, CDCl3):
d
¼9.73 (s, 1H), 7.00 (s, 1H), 6.98 (s, 1H),
6.06e6.63 (m, 1H), 5.83e5.80 (m, 1H), 3.93e3.74 (m, 3H),
3.64e3.57 (m, 1H), 3.65e3.61 (m, 1H), 3.39 (dd, J¼18.4, 8.0 Hz, 1H),
2.93e2.84 (m, 1H), 2.80e2.74 (m, 3H), 2.43 (dd, J¼18.4, 4.8 Hz, 1H),
2.33 (s, 3H), 2.27 (s, 3H), 1.67 (s, 9H), 1.15 (t, J¼6.8 Hz, 3H), 1.05 (t,
4.2.11. (1S,2S,3S)-tert-Butyl-1-(diethoxyphosphoryl)-20-oxo-3-(2-
oxoethyl)-4-phenylspiro[cyclohex[4]ene-2,30-indoline]-10-carboxylate
(4k). 3 h, 92% yield; white semisolid; Rf¼0.36 (petroleum ether/
J¼6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
¼199.4, 177.1,
d
148.9133.2, 131.7, 128.2, 125.7, 125.6, 123.0, 122.8, 110.7, 84.0, 62.1
(d, JCOP¼6.3 Hz), 61.1 (d, JCOP¼7.1 Hz), 45.9, 37.3 (d, JCP¼11.8 Hz),
34.4, 32.9, 27.7, 23.1 (d, JCCCP¼3.4 Hz), 21.1, 19.7, 16.0 (d,
JCCOP¼5.7 Hz), 15.7 (d, JCCOP¼6.6 Hz) ppm; ESIeHRMS: calcd for
ethyl acetate¼1:1); [
a
]
20 þ5.1 (c 0.46 in CHCl3); 98% ee, determined
D
by HPLC analysis after 4k was converted to the corresponding al-
cohol [NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath] [Chiralpak
C
26H36NO7PþNaþ 528.2122, found: 528.2126.
AD-H Column, n-hexane/i-PrOH¼80:20, 1.0 mL/min, ¼254 nm, t
l
(major)¼5.45 min, t (minor)¼7.70 min]; major isomer: 1H NMR
4.2.8. (1S,2S,6S)-tert-Butyl-6-(diethoxyphosphoryl)-4-methyl-20-
oxo-2-(2-oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-10-carboxylate
(4h). 3 h, 94% yield; colorless oil; Rf¼0.34 (petroleum ether/ethyl
(400 MHz, CDCl3):
d
¼9.56 (s, 1H), 7.94 (d, J¼8.0 Hz, 1H), 7.35e7.24
(m, 4H), 7.19e7.17 (m, 2H), 7.07e7.03 (m, 1H), 6.25e6.24 (m, 1H),
3.89e3.65 (m, 3H), 3.63e3.52 (m, 2H), 3.41 (dd, J¼18.4, 9.2 Hz, 1H),
3.03e2.85 (m, 3H), 2.18 (d, J¼18.4 Hz, 1H), 1.64 (s, 9H), 1.12 (t,
J¼7.2 Hz, 3H), 1.01 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz,
20
acetate¼1:1); [
a]
ꢁ17.9 (c 0.21 in CHCl3); 96% ee, determined by
D
HPLC analysis after 4h was converted to the corresponding alcohol
[NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath] [Chiralpak AD-H
CDCl3):
d
¼199.0, 176.5, 149.0, 140.0, 139.0, 138.6, 130.5, 128.6, 128.4,
Column, n-hexane i-PrOH¼90:10, 1.0 mL/min,
l¼254 nm,
t
127.7, 126.1, 124.4, 124.1, 123.8 (d, JCP¼13.4 Hz), 115.0, 83.9, 62.2 (d,
JCOP¼6.3 Hz), 61.3 (d, JCOP¼7.1 Hz), 44.4, 39.6 (d, JCP¼12.6 Hz), 33.7,
32.2, 28.0, 24.0 (d, JCCCP¼3.6 Hz), 16.1 (d, JCCOP¼5.9 Hz), 15.8 (d,
JCCOP¼6.5 Hz) ppm; ESIeHRMS: calcd for C30H36NO7PþNaþ
576.2122, found: 576.2129.
(major)¼10.52 min, t (minor)¼11.99 min]; 1H NMR (400 MHz,
CDCl3):
d
¼9.68 (s, 1H), 7.86 (d, J¼8.4 Hz, 1H), 7.31e7.27 (m, 1H),
7.13e7.05 (m, 2H), 5.46e5.45 (m, 1H), 3.86e3.68 (m, 3H), 3.63e3.57
(m, 1H), 3.33 (dd, J¼18.4, 8.0 Hz, 1H), 2.87e2.82 (m, 2H), 2.73e2.48
(m, 2H), 2.37e2.31 (m, 1H), 1.84 (s, 3H), 1.63 (s, 9H), 1.11 (t, J¼7.2 Hz,
3H), 0.98 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
4.2.12. (1S,2S,3S)-tert-Butyl-1-(diethoxyphosphoryl)-6-methyl-20-
oxo-3-(2-oxoethyl)-4-phenylspiro[cyclohex[4]ene-2,30-indoline]-10-
d
¼199.7, 176.5, 148.9, 138.8, 133.0, 132.9, 128.2, 124.4, 123.9, 122.3,
114.8, 84.9, 62.2 (d, JCOP¼6.3 Hz), 61.2 (d, JCOP¼7.3 Hz), 46.0, 37.9 (d,
JCP¼12.7 Hz), 34.9, 33.5, 28.0, 27.6 (d, JCCCP¼3.7 Hz), 23.0, 16.0 (d,
JCCOP¼6.0 Hz), 15.7 (d, JCCOP¼6.6 Hz) ppm; ESIeHRMS: calcd for
carboxylate (4l). 4 h, 92% yield; semisolid; Rf¼0.36 (petroleum
20
ether/ethyl acetate¼1:1); [
a]
ꢁ32.5 (c 0.21 in CHCl3); 98% ee,
D
determined by HPLC analysis after 4l was converted to the corre-
sponding alcohol [NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath]
[Daicel Chiralcel OD-H Column, n-hexane/i-PrOH¼90:10, 1.0 mL/
C
25H34NO7PþNaþ 514.1965, found: 514.1973.
4.2.9. (1S,2S,6S)-tert-Butyl-6-(diethoxyphosphoryl)-3-methyl-20-
oxo-2-(2-oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-10-carboxylate
(4i). 3 h, 94% yield; colorless oil; Rf¼0.34 (petroleum ether/ethyl
min,
l
¼254 nm, t (minor)¼7.72 min, t (major)¼10.06 min]; 1H NMR
(400 MHz, CDCl3):
d
¼9.55 (s, 1H), 7.93 (d, J¼8.4 Hz, 1H), 7.32e7.20
(m, 5H), 7.15e7.13 (m, 2H), 7.01 (t, J¼7.6 Hz, 1H), 6.12e6.10 (m, 1H),
3.87e3.62 (m, 4H), 3.44e3.24 (m, 2H), 2.62 (dd, J¼20.8, 9.6 Hz, 1H),
acetate¼1:1); [
a
]
D
20 ꢁ58.1 (c 0.13 in CHCl3); >99% ee, determined by

Q.-Q. Zhou et al. / Tetrahedron 69 (2013) 10369e10374
10373
2.36e2.32 (m, 1H), 2.17 (dd, J¼18.8, 1.6 Hz, 1H), 1.64 (s, 9H), 1.47 (d,
(6b). 3 h, 81% yield; orange semisolid; Rf¼0.37 (petroleum ether/
J¼6.8 Hz, 3H), 1.13 (t, J¼6.8 Hz, 3H), 1.05 (t, J¼6.8 Hz, 3H) ppm; 13
C
ethyl acetate,1:1); [
a
]
D
20 ꢁ63.3 (c 0.33 in CHCl3); 90% ee, determined
NMR (100 MHz, CDCl3):
d
¼198.7, 177.0, 149.0, 139.6, 139.1, 136.9,
by HPLC analysis after 6b was converted to the corresponding al-
cohol [NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath] [Chiralpak
130.7, 130.6, 128.5, 128.3, 127.7, 126.0, 124.7, 123.8, 114.9, 83.8, 62.0
(d, JCOP¼5.9 Hz), 61.4 (d, JCOP¼7.2 Hz), 53.4, 44.8, 39.9 (d, J¼9.9 Hz),
29.9, 28.0, 22.1, 16.1 (d, JCCOP¼5.9 Hz), 15.8 (d, JCCOP¼6.3 Hz) ppm;
ESIeHRMS: calcd for C31H38NO7PþNaþ 590.2278, found: 590.2286.
IC Column, n-hexane/i-PrOH¼70:30, 1.0 mL/min,
l
¼220 nm, t
(minor)¼16.48 min, t (major)¼19.33 min]; 1H NMR (400 MHz,
CDCl3):
d¼9.55 (s, 1H), 7.87 (d, J¼8.8 Hz, 1H), 7.42e7.41 (m, 2H),
7.30e7.26 (m, 9H), 6.80 (d, J¼2.0 Hz, 1H), 5.93e5.91 (m, 1H),
5.63e5.61 (m, 1H), 3.67 (dt, J¼15.2, 6.4 Hz, 1H), 3.48e3.45 (m, 1H),
2.64e2.41 (m, 2H), 1.97 (dd, J¼17.2, 3.2 Hz, 1H), 1.79 (ddd, J¼17.2,
10.8, 2.0 Hz, 1H), 1.62 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3):
4.2.13. (30S,4S,6S)-tert-Butyl-4-(diethoxyphosphoryl)-20-oxo-6-(2-
oxoethyl)-1,2,3,3a,4,6-hexahydrospiro[indene-5,30-indoline]-10-car-
boxylate (4m). 20 h, 52% yield; orange oil; Rf¼0.35 (petroleum
20
ether/ethyl acetate¼1:1); [
a
]
ꢁ9.8 (c 0.42 in CHCl3); 94% ee,
d
¼199.4, 176.4, 148.4, 139.0, 131.7, 131.6, 131.4, 131.3, 128.9, 128.4,
D
determined by HPLC analysis after 4m was converted to the
corresponding alcohol [NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice
salt bath] [Chiralpak AD-H Column, n-hexane/i-PrOH¼90:10,
128.3, 128.0, 127.9, 127.4, 125.9, 125.8, 125.3, 116.5, 84.5, 50.0 (d,
JCP¼2.9 Hz), 43.1, 40.1, 39.4 (d, JCP¼4.6 Hz), 28.0, 24.4 ppm;
ESIeHRMS: calcd for
C
32H31Cl35NO8PþNaþ 598.1521, found:
1.0 mL/min,
l
¼220 nm,
t
(major)¼10.39 min,
t
(minor)¼
598.1527 (Cl35), 600.1503 (Cl37).
17.30 min]; 1H NMR (400 MHz, CDCl3):
d
¼9.59 (s, 1H), 7.79 (d,
J¼8.0 Hz, 1H), 7.24e7.14 (m, 2H), 7.00 (t, J¼7.6 Hz, 1H), 5.29 (s,
1H), 3.73e3.63 (m, 3H), 3.54e3.44 (m, 1H), 3.14 (dd, J¼18.4,
8.4 Hz, 1H), 2.92e2.71 (m, 2H), 2.34e2.31 (m, 1H), 2.29e2.25 (m,
4H), 1.80e1.68 (m, 3H), 1.56 (s, 9H), 1.01 (t, J¼6.8 Hz, 3H), 0.96 (t,
4.2.17. (1S,2S,6S)-tert-Butyl-6-(diphenylphosphoryl)-50-methoxy-20-
oxo-2-(2-oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-10-carboxylate
(6c). 2 h, 87% yield; white semisolid; Rf¼0.39 (petroleum ether/
20
ethyl acetate¼1:1); [
a]
ꢁ84.4 (c 0.24 in CHCl3); 90% ee, de-
D
J¼6.8 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼200.6, 177.3,
termined by HPLC analysis after 6c was converted to the corre-
sponding alcohol [NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath]
[Chiralpak IC Column, n-hexane/i-PrOH¼70:30, 1.0 mL/min,
149.2, 144.4, 144.2, 139.4, 128.5, 124.7, 124.2, 118.6, 115.2, 84.1,
62.2 (d, JCOP¼6.3 Hz), 61.4 (d, JCOP¼7.6 Hz), 47.1, 41.6, 41.2, 39.6,
38.8, 33.7 (d, JCCCP¼2.7 Hz), 29.6, 28.4, 22.6, 16.4 (d, JCCOP¼5.7 Hz),
16.2 (d, JCCOP¼6.4 Hz) ppm; ESIeHRMS: calcd for C27H36NO7Pþ
Naþ 540.2122, found: 540.2129.
l
¼220 nm, t (minor)¼19.65 min, t (major)¼24.09 min]; 1H NMR
(400 MHz, CDCl3):
d
¼9.63 (s, 1H), 7.68e7.60 (m, 3H), 7.51e7.27 (m,
6H), 7.26e7.21 (m 2H), 6.87e6.80 (m, 2H), 6.00e5.98 (m, 1H),
5.76e5.73 (m, 1H), 3.75 (s, 3H), 3.41e3.39 (m, 1H), 3.14 (dd, J¼18.8,
7.2 Hz, 1H), 2.99e2.85 (m, 2H), 2.43e2.35 (m, 1H), 1.56 (s, 9H) ppm;
4.2.14. (1S,2S,6S)-Benzyl-6-(diethoxyphosphoryl)-20-oxo-2-(2-ox
oethyl)spiro[cyclohex[3]ene-1,30-indoline]-10-carboxylate (4n). 4 h,
90% yield; white semisolid; Rf¼0.37 (petroleum ether/ethyl
13C NMR (100 MHz, CDCl3):
d
¼199.2, 176.7, 156.2, 148.3, 131.8, 131.7,
131.6, 131.5, 131.4, 128.4, 128.3, 127.9, 127.8, 127.7, 126.3, 126.2, 115.5,
113.1, 112.0, 83.5, 55.5, 45.6, 38.7 (d, JCP¼8.0 Hz), 36.1, 35.4, 28.0,
23.2 ppm; ESIeHRMS: calcd for C33H34NO6PþNaþ 594.2016, found:
594.2021.
acetate¼1:1); [
a
]
20 ꢁ27.8 (c 0.26 in CHCl3); 95% ee, determined by
D
HPLC analysis after 4n was converted to the corresponding alcohol
[NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath] [Daicel Chiralcel
OD-H Column, n-hexane/i-PrOH¼80:20, 1.0 mL/min, ¼220 nm, t
l
(minor)¼11.42 min, t (major)¼13.71 min]; 1H NMR (400 MHz,
4.2.18. Diethyl ((1S,5R,6R)-6-benzoyl-5-(2-oxoethyl)cyclohex-3-en-
1-yl)phosphonate (8). 10 h, 63% yield; colorless oil; Rf¼0.31 (pe-
CDCl3):
d
¼9.74 (s, 1H), 8.00 (d, J¼8.4 Hz, 1H), 7.57e7.55 (m, 2H),
20
7.45e7.33 (m, 5H), 7.16 (t, J¼7.6 Hz, 1H), 6.07e6.05 (m, 1H),
5.84e5.81 (m, 1H), 5.50e5.49 (m, 2H), 3.84e3.73 (m, 3H),
3.51e3.41 (m, 2H), 2.94e2.81 (m, 1H), 2.76e2.72 (m, 3H), 2.44 (dd,
J¼18.8, 4.0 Hz, 1H), 1.03 (t, J¼7.2 Hz, 6H) ppm; 13C NMR (100 MHz,
troleum ether/ethyl acetate¼1:1); [
a
]
þ55.2 (c 0.56 in CHCl3);
D
95% ee, determined by HPLC analysis after 8 was converted to the
corresponding alcohol [NaBH4 in DCM and MeOH at 0 ꢀC] Chir-
alpak IC Column, n-hexane/i-PrOH¼70:30, 1.0 mL/min,
CDCl3):
d
¼199.2, 176.0, 150.4, 138.2, 134.9, 128.3, 128.2, 128.0, 127.8,
l
¼254 nm, t (major)¼20.75 min, t (minor)¼28.99 min]; 1H NMR
127.7, 125.5, 124.3, 124.1, 114.9, 68.2, 61.9 (d, JCOP¼6.1 Hz), 61.0 (d,
JCOP¼7.0 Hz), 45.6, 37.1 (d, JCP¼11.8 Hz), 34.5, 33.1, 22.8 (d, J¼3.7 Hz),
15.8 (d, JCCOP¼6.0 Hz), 15.6 (d, JCCOP¼6.3 Hz) ppm; ESIeHRMS:
calcd for C27H30NO7PþNaþ 534.1652, found: 534.1657.
of the corresponding alcohol: (400 MHz, CDCl3):
d
¼8.08 (d,
J¼7.2 Hz, 2H), 7.57 (t, J¼7.2 Hz, 1H), 7.49e7.46 (m, 2H), 5.81e5.73
(m, 2H), 3.92e3.90 (m, 2H), 3.88e3.69 (m, 1H), 3.67e3.59 (m,
3H), 2.78e2.69 (m, 1H), 2.56e2.44 (m, 3H), 1.82e1.70 (m, 1H),
1.54e1.41 (m, 2H), 1.14 (t, J¼7.2 Hz, 3H), 1.05 (t, J¼7.2 Hz,
4.2.15. (1S,2S,6S)-tert-Butyl-6-(diphenylphosphoryl)-20-oxo-2-(2-
oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-10-carboxylate
3H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼203.7, 133.1, 129.4, 128.6,
128.4, 124.5, 124.4, 61.8 (d, JCOP¼6.4 Hz), 61.2 (d, JCOP¼7.1 Hz),
60.0, 45.6, 44.5 (d, JCP¼3.8 Hz), 37.5 (d, JCP¼13.3 Hz), 36.1, 33.9,
24.8 (d, JCP¼3.8 Hz), 15.9 (d, JCCOP¼6.3 Hz), 15.8 (d,
JCCOP¼6.1 Hz) ppm; ESIeHRMS: calcd for C19H25O5PþNaþ
387.1332, found: 387.1354.
(6a). 1.5 h, 86% yield; white semisolid; Rf¼0.38 (petroleum ether/
20
ethyl acetate¼1:1); [
a
]
ꢁ88.9 (c 0.51 in CHCl3); 90% ee, de-
D
termined by HPLC analysis after 6a was converted to the corre-
sponding alcohol [NaBH4 in DCM and EtOH at ꢁ5 ꢀC in ice salt bath]
[Chiralpak AD-H Column, n-hexane/i-PrOH¼70:30, 1.0 mL/min,
l
¼220 nm, t (major)¼7.04 min, t (minor)¼17.28 min]; 1H NMR
4.3. General procedure for the synthetic transformations
(400 MHz, CDCl3):
d
¼9.63 (s, 1H), 7.72e7.51 (m, 3H), 7.49e7.22 (m,
11H), 7.21e7.04 (m, 1H), 6.02e5.99 (m, 1H), 5.76e5.73 (m, 1H),
3.43e3.37 (m, 1H), 3.16 (dd, J¼18.4, 7.2 Hz, 1H), 3.06e2.95 (m, 1H),
2.89e2.78 (m, 1H), 2.40e2.35 (m, 2H), 1.56 (s, 9H) ppm; 13C NMR
To a stirred solution of 4a or 6a (0.1 mmol) in DCM was added
Jone’s reagent (0.1 mmol) at 0 ꢀC. After 2 h, the mixture was stirred
at room temperature for 10 h. After completion, the mixture was
purified by flash chromatography on silica gel (petroleum ether/
EtOAc) to give acid products 12a or 12b in 69% and 80% yield, re-
spectively. To a solution of acid (0.1 mmol) and DBACO (0.02 mmol)
in DCM (1 mL) was added N-bromosuccinimide (0.2 mmol) at room
temperature. After 2 h, the mixture was purified by flash chroma-
tography on silica gel (petroleum ether/EtOAc) to give the products
13a or 13b in 72% and 83% yield, respectively.
(100 MHz, CDCl3):
131.3, 128.5, 128.3, 127.8, 127.7, 125.9, 125.8, 125.3, 114.7, 83.7, 45.7,
d
¼199.2, 176.8, 148.3, 138.7, 131.9, 131.8, 131.4,
38.8 (d, JCP¼8.3 Hz), 35.9, 35.3, 28.0, 23.1 ppm; ESIeHRMS: calcd for
C
32H32NO5PþNaþ 564.1910, found: 564.1917.
4.2.16. (1S,2S,6S)-tert-Butyl-50-chloro-6-(diphenylphosphoryl)-20-
oxo-2-(2-oxoethyl)spiro[cyclohex[3]ene-1,30-indoline]-10-carboxylate

10374
Q.-Q. Zhou et al. / Tetrahedron 69 (2013) 10369e10374
4.3.1. (3aR,30S,5S,7R,7aR)-tert-Butyl-7-bromo-5-(diethox-
yphosphoryl)-2,20-dioxo-3,3a,5,6,7,7a-hexahydro-2H-spiro[benzofu-
2005, 105, 899e932; (c) Ma, J.-A. Chem. Soc. Rev. 2006, 35, 630e636; (d)
Ordonez, M.; Rojas-Cabrera, H.; Cativiela, C. Tetrahedron 2009, 65, 17e49; (e)
Albrecht, q.; Richter, B.; Vila, C.; Krawczyk, H.; Jørgensen, K. A. Chem.dEur. J.
2009, 15, 3093e3102.
ꢀ~
ran-4,30-indoline]-10-carboxylate (13a). White semisolid; Rf¼0.58
20
4. (a) Zhao, D.; Wang, R. Chem. Soc. Rev. 2012, 41, 2095e2108; (b) Merino, P.;
(petroleum ether/ethyl acetate¼1:1); [
a]
ꢁ2.7 (c 0.23 in CHCl3);
D
ꢀ
ꢀ
Marques-Lopez, E.; Herrera, R. P. Adv. Synth. Catal. 2008, 350, 1195e1208; (c)
Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur. J. Org. Chem. 2006,
29e49; (d) Maerten, E.; Cabrera, S.; Kjærsgaard, A.; Jørgensen, K. A. J. Org. Chem.
2007, 72, 8893e8903; (e) Zhao, D.; Wang, Y.; Mao, L.; Wang, R. Chem.dEur. J.
2009, 15, 10983e10987; (f) Zhou, X.; Zhang, Q.; Hui, Y.; Chen, W.; Jiang, J.; Lin,
L.; Liu, X.; Feng, X. Org. Lett. 2010, 12, 4296e4299; (g) Feng, J.-J.; Chen, X.-F.; Shi,
M.; Duan, W.-L. J. Am. Chem. Soc. 2010, 132, 5562e5563; (h) Carlone, A.; Bartoli,
G.; Bosco, M.; Sambri, L.; Melchiorre, P. Angew. Chem., Int. Ed. 2007, 46,
4504e4506; (i) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed. 2010,
49, 153e156; (j) Hayashi, M.; Shiomi, N.; Funahashi, Y.; Nakamura, S. J. Am.
Chem. Soc. 2012, 134, 19366e19369; (k) Hatano, M.; Horibe, T.; Ishihara, K.
Angew. Chem., Int. Ed. 2013, 52, 4549e4553.
>99% ee, determined by HPLC analysis [Chiralpak IA Column, n-
hexane/i-PrOH¼90:10, 1.0 mL/min,
l
¼220 nm,
t
(major)¼
24.41 min, t (minor)¼29.78 min]; 1H NMR (400 MHz, CDCl3):
d
¼7.98 (d, J¼8.4 Hz, 1H), 7.52e7.44 (m, 2H), 7.32e7.26 (m, 1H), 4.97
(dd, J¼9.6, 7.2 Hz, 1H), 4.12e4.08 (m, 1H), 3.89e3.79 (m, 3H),
3.62e3.58 (m, 1H), 3.09 (dd, J¼17.6, 6.4 Hz, 1H), 2.88e2.67 (m, 4H),
2.32 (dd, J¼17.6, 8.4 Hz, 1H), 1.69 (s, 9H), 1.13 (q, J¼6.8 Hz, 6H) ppm;
13C NMR (100 MHz, CDCl3):
d¼173.8, 173.3, 148.4, 139.0, 129.4,
124.3, 124.2, 115.7, 84.9, 81.4, 62.6 (d, JCOP¼6.7 Hz), 61.8 (d,
JCOP¼7.1 Hz), 47.6 (d, JCP¼20.4 Hz), 45.1 (d, JCCP¼15.2 Hz), 38.6, 37.1,
31.6, 29.5 (d, JCP¼20.3 Hz), 28.0, 16.1 (d, JCCOP¼5.5 Hz), 15.9 (d,
JCCOP¼6.5 Hz) ppm; ESIeHRMS: calcd for C24H31Br79NO8PþNaþ
594.0863, found: 594.0869 (Br79), 596.0864 (Br81).
5. (a) Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc. 2006, 128, 7442e7443; (b) Jiang, H.;
~
Paixao, M. W.; Monge, D.; Jørgensen, K. A. J. Am. Chem. Soc. 2010, 132,
2775e2783; (c) Xue, Z.-Y.; Li, Q.-H.; Tao, H.-Y.; Wang, C.-J. J. Am. Chem. Soc. 2011,
133, 11757e11765; (d) Cullen, S. C.; Rovis, T. Org. Lett. 2008, 10, 3141e3144; (e)
ꢀ
Sulzer-Mosse, S.; Alexakis, A.; Mareda, J.; Bollot, G.; Bernardinelli, G.; Filinchuk,
Y. Chem.dEur. J. 2009, 15, 3204e3220; (f) Bera, K.; Namboothiri, I. N. N. Org.
Lett. 2012, 14, 980e983.
6. For selected reviews, see: (a) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92,
1007e1019; (b) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650e1667; (c)
Reymond, S.; Cossy, J. Chem. Rev. 2008, 108, 5359e5406; (d) Moyano, A.; Rios, R.
Chem. Rev. 2011, 111, 4703e4832.
4.3.2. (3aR,30S,5S,7R,7aR)-tert-Butyl-7-bromo-5-(diphenylphos-
phoryl)-2,20-dioxo-3,3a,5,6,7,7a-hexahydro-2H-spiro[benzofuran-4,30-
indoline]-10-carboxylate (13b). White semisolid; Rf¼0.63 (petroleum
20
ether/ethyl acetate¼1:1); [
a
]
ꢁ74.8 (c 0.83 in CHCl3); 97% ee, de-
D
7. For selected examples, see: (a) Chien, C.-F.; Wu, J.-D.; Ly, T. W.; Shia, K.-S.; Liu,
H.-J. Chem. Commun. 2002, 248e249; (b) Ruzziconi, R.; Ricci, G.; Gioiello, A.;
termined by HPLC analysis [Chiralpak IB Column, n-hexane/i-
ꢁ
ꢁ
Couthon-Gourves, H.; Gourves, J.-P. J. Org. Chem. 2003, 68, 736e742; (c) Cheng,
E. W. C.; Mandalia, R. T.; Motevalli, M.; Mothia, B.; Patanwadia, Y.; Wyatt, P. B.
Tetrahedron 2006, 62, 12398e12407; (d) Liao, C.-C.; Zhu, J.-L. J. Org. Chem. 2009,
74, 7873e7884; (e) Villemin, E.; Elias, B.; Robiette, R.; Robeyns, K.; Herent, M.-
F.; Habib-Jiwan, J.-L.; Marchand-Brynaert, J. Tetrahedron Lett. 2011, 52,
5140e5144; (f) Villemin, E.; Robeyns, K.; Robiette, R.; Herent, M.-F.; Marchand-
Brynaert, J. Tetrahedron 2013, 69, 1138e1147.
PrOH¼60:40, 1.0 mL/min,
l
¼220 nm, t (minor)¼10.62 min, t
(major)¼22.05 min]; 1H NMR (400 MHz, CDCl3):
¼7.73e7.63 (m,
d
3H), 7.56e7.53 (m, 1H), 7.47e7.36 (m, 5H), 7.32e7.25 (m, 4H),
7.15e7.11 (m, 1H), 4.84 (dd, J¼10.0, 7.2 Hz, 1H), 4.14e4.07 (m, 1H),
3.47e3.40 (m, 1H), 3.08 (dd, J¼17.6, 14.0 Hz, 1H), 2.92 (dq, J¼20.8,
7.2 Hz, 1H) 2.58e2.50 (m, 2H), 2.32 (dd, J¼17.6, 7.6 Hz, 1H), 1.68 (s,
8. For selected examples, see: (a) Robiette, R.; Cheboub-Benchaba, K.; Peeters, D.;
Marchand-Brynaert, J. J. Org. Chem. 2003, 68, 9809e9812; (b) Monbaliu, J.-C.;
Robiette, R.; Peeters, D.; Marchand-Brynaert, J. Tetrahedron Lett. 2009, 50,
1314e1317; (c) Zhu, J.-L.; Chen, P.-E.; Huang, H.-W. Tetrahedron: Asymmetry
2013, 24, 23e36.
9H) ppm; 13C NMR (100 MHz, CDCl3):
d¼174.3, 173.0, 147.9, 138.8,
132.0, 131.2, 131.1, 129.4, 128.8, 128.7, 128.1, 128.0, 124.8, 115.5, 84.6,
81.2, 47.8 (d, JCP¼12.9 Hz), 46.5 (d, JCCP¼10.6 Hz), 39.5, 38.8, 32.1, 29.9,
28.0 ppm; ESIeHRMS: calcd for C32H31Br79NO6PþNaþ 658.0965,
found: 658.0971 (Br79), 660.0966 (Br81).
9. For selected examples of trienamine catalysis, see: (a) Jia, Z.-J.; Jiang, H.; Li, J.-L.;
Gschwend, B.; Li, Q.-Z.; Yin, X.; Grouleff, J.; Chen, Y.-C.; Jørgensen, K. A. J. Am.
Chem. Soc. 2011, 133, 5053e5061; (b) Jia, Z.-J.; Zhou, Q.; Zhou, Q.-Q.; Chen, P.-Q.;
Chen, Y.-C. Angew. Chem., Int. Ed. 2011, 50, 8638e8641; (c) Jiang, H.; Gschwend,
B.; Albrecht, q.; Hansen, S. G.; Ju˛rgensen, K. A. Chem.dEur. J. 2011, 17,
9032e9036; (d) Liu, Y.; Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am. Chem.
Soc. 2011, 133, 15212e15218; (e) Xiong, X.-F.; Zhou, Q.; Gu, J.; Dong, L.; Liu, T.-Y.;
Chen, Y.-C. Angew. Chem., Int. Ed. 2012, 51, 4401e4404; (f) Halskov, K. S.; Jo-
hansen, T. K.; Davis, R. L.; Steurer, M.; Jensen, F.; Jørgensen, K. A. J. Am. Chem.
Soc. 2012, 134, 12943e12946; (g) Albrecht, q.; Acosta, F. C.; Fraile, A.; Albrecht,
A.; Christensen, J.; Ju˛rgensen, K. A. Angew. Chem., Int. Ed. 2012, 51, 9088e9092;
(h) Ma, C.; Jia, Z.-J.; Liu, J.-X.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C. Angew. Chem., Int.
Ed. 2013, 52, 948e951; (i) For reviews, see: (j) Arceo, E.; Melchiorre, P. Angew.
Chem., Int. Ed. 2012, 51, 5290e5292; (k) Kumar, I.; Ramaraju, P.; Mir, N. A. Org.
Biomol. Chem. 2013, 11, 709e716; (l) Jiang, H.; Albrecht, q.; Ju˛rgensen, K. A.
Chem. Sci. 2013, 4, 2287e2300.
Acknowledgements
We are grateful for financial support from the NSFC (21125206
and 21021001), and the National Basic Research Program of China
(973 Program, 2010CB833300).
Supplementary data
Crystal data for enantiopure 2,4-dinitrobenzenehydrazone of 4c,
NMR spectra, and HPLC chromatograms are provided in the Sup-
plementary data. Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2013.10.001.
10. Gasperi, T.; Loreto, M. A.; Migliorini, A.; Ventura, C. Eur. J. Org. Chem. 2011,
385e391.
11. For a comprehensive review on the synthesis of chiral spirocyclic compounds,
see: Rios, R. Chem. Soc. Rev. 2012, 41, 1060e1074.
12. In toluene, 8 h, 93%, 83% ee; in THF, 7 h, 93%, 93% ee; in 1,4-dioxane, 24 h, <10%
conversion.
References and notes
13. CCDC-960041
(2,4-dinitrobenzenehydrazone
of
4c)
contains
the
Supplementary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
1. (a) Fields, S. C. Tetrahedron 1999, 55, 12237e12273; (b) Mucha, A.; Kafarski, P.;
Berlicki, L. J. Med. Chem. 2011, 54, 5955e5980; (c) Schug, K. A.; Lindner, W.
Chem. Rev. 2005, 105, 67e114; (d) Shie, J.-J.; Fang, J.-M.; Lai, P.-T.; Wen, W.-H.;
Wang, S.-Y.; Cheng, Y.-S. E.; Tsai, K.-C.; Yang, A.-S.; Wong, C.-H. J. Am. Chem. Soc.
2011, 133, 17959e17965.
2. For selected reviews, see: (a) Tang, W.; Zhang, X. Chem. Rev. 2003, 103,
3029e3070; (b) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41, 581e593; (c)
Ding, K.; Han, Z.; Wang, Z. Chem.dAsian J. 2009, 4, 32e41.
14. Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-C.; Chan, A. S. C. J. Am. Chem. Soc. 2000,
122, 11513e11514.
ꢀ
15. Liu, Y.; Nappi, M.; Escudero-Adan, E. C.; Melchiorre, P. Org. Lett. 2012, 14,
1310e1313.
16. Cheng, Y. A.; Chen, T.; Tan, C. K.; Heng, J. J.; Yeung, Y.-Y. J. Am. Chem. Soc. 2012,
134, 16492e16495.
3. For selected reviews, see: (a) Moonen, K.; Laureyn, I.; Stevens, C. V. Chem. Rev.
2004, 104, 6177e6216; (b) Palacios, F.; Alonso, C. J.; de los Santos, M. Chem. Rev.