Organocatalytic tandem reaction to construct six-membered spirocyclic oxindoles with multiple chiral centres through a formal [2+2+2] annulation

Article abstract of DOI:10.1002/chem.200903009

An efficient tandem reaction for the asymmetric synthesis of six-membered spirocyclic oxindoles has been successfully developed through a formal [2+2+2] annulation strategy. The amine-catalysed stereoselective Michael addition of aliphatic aldehydes to electron-deficient olefinic oxindole motifs gave chiral C3 components, which were further combined with diverse electrophiles (activated olefins or imines) to afford spirocyclic oxindoles with versatile molecular complexity (up to six contiguous stereogenic centres, high diastereo- and enantioselectivities).

Full text of DOI:10.1002/chem.200903009

DOI: 10.1002/chem.200903009
Organocatalytic Tandem Reaction to Construct Six-Membered
Spirocyclic Oxindoles with Multiple Chiral Centres through a Formal
[2+2+2] Annulation
Kun Jiang,[a] Zhi-Jun Jia,[a] Shi Chen,[a] Li Wu,[a] and Ying-Chun Chen*[a, b]
Abstract: An efficient tandem reaction for the asymmetric synthesis of six-mem-
bered spirocyclic oxindoles has been successfully developed through a formal [2+
2+2] annulation strategy. The amine-catalysed stereoselective Michael addition of
aliphatic aldehydes to electron-deficient olefinic oxindole motifs gave chiral C3
components, which were further combined with diverse electrophiles (activated
olefins or imines) to afford spirocyclic oxindoles with versatile molecular complex-
ity (up to six contiguous stereogenic centres, high diastereo- and enantioselectivi-
ties).
Keywords: annulation · asymmetric
catalysis · molecular complexity ·
spiro
compounds
·
tandem reactions
Introduction
hibited broad biological activities. Compound 1 (Scheme 1)
is a drug candidate that may be used in female healthcare as
a progesterone receptor antagonist, which has effects in con-
Spirocyclic oxindole structures exist in a large number of
natural products and pharmaceutically important mole-
cules.[1] Therefore, considerable efforts have been devoted
to developing efficient protocols to access these interesting
motifs over the past years.[2] Although great progress has
been made for the synthesis of diversely structured spirocy-
clic oxindoles, new methodologies that can afford ones with
more substitution variants are still in high demand. More-
over, the examples that can produce spirocyclic oxindoles in
a catalytic asymmetric manner are still limited,[3] especially
with the more environmentally friendly organocatalysts.[4]
Recently, we have conducted some research work on the
organocatalytic construction of oxindoles with a quaternary
C3 chiral centre.[5,6] Later, it was recognised that some oxin-
doles incorporating a six-membered spirocyclic moiety ex-
Scheme 1. Some biologically active six-membered spirocyclic oxindoles.
[a] K. Jiang, Z.-J. Jia, S. Chen, L. Wu, Prof. Dr. Y.-C. Chen
Key Laboratory of Drug-Targeting and
Drug Delivery System of Education Ministry
Department of Medicinal Chemistry
West China School of Pharmacy
traception, uterine fibroids, endometriosis or hormone-relat-
ed cancers.[7] SR 121463 A was a potent and selective orally
active vasopressin V2 antagonist. It might be better for use
in the clinic than other well-known diuretic agents, such as
furosemide or hydrochlorothiazide.[8] In addition, spirocyclic
oxindole derivatives with a piperidine structure are of great
significance in pharmacochemistry.[9] For example, com-
pound 2 is a potent non-peptide MDM2 inhibitor, which
may have utility as an antiproliferative agent, especially as
an anticancer agent.[10] Herein, we would like to present an
Sichuan University, Chengdu, 610041 (China)
Fax : (+86)28-85502609
E-mail: ycchenhuaxi@yahoo.com.cn
[b] Prof. Dr. Y.-C. Chen
State Key Laboratory of Biotherapy, West China Hospital
Sichuan University, Chengdu, 610041 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903009.
2852
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Chem. Eur. J. 2010, 16, 2852 – 2856

FULL PAPER
Table 1. Screening studies for the three-component domino reaction to
access spirocyclic oxindoles.[a]
organocatalytic tandem reaction for the synthesis of diverse
spirocyclic oxindoles with multiple chiral centres through a
formal [2+2+2] annulation strategy.
Results and Discussion
Our synthetic approach is outlined in Scheme 2. The asym-
metric Michael addition of aliphatic aldehydes to electron-
deficient olefinic oxindoles could be developed by the en-
Entry
Solvent
t [h]
Yield [%][b] (ee [%][c]
)
1
2
3
4
CH3CN
toluene
CH2Cl2
THF
CH3CN
CH3CN
CH3CN
CH3CN
1
4
4
12
4
18
2
7a: 53 (>99); 8a: 42 (>99)
7a: 59 (>99); 8a: 40 (>99)
7a: 60 (>99); 8a: 38 (>99)
7a: 44 (>99); 8a: 49 (>99)
7a: 41 (>99); 8a: 33 (>99)
7a: 25 (>99); 8a: 52 (>99)
7a: 52 (>99); 8a: 43 (>99)
9a: 88 (99)
5[d]
6[e]
7[f]
8[f,g]
2
[a] Boc: tert-butoxycarbonyl; TFA: trifluoroacetic acid. Unless noted oth-
erwise, reactions were performed with 4a (0.11 mmol), 5a (0.1 mmol), 6a
(0.12 mmol), 3 (0.01 mmol) and benzoic acid (0.01 mmol) in solvent
(0.5 mL) at RT. [b] Yield of isolated product. [c] Determined by chiral
HPLC analysis; dr>99:1. [d] AcOH was used as the acid additive.
[e] Without acid additive. [f] With 5 mol% of
3 and 10 mol% of
PhCOOH. [g] TFA (0.2 mmol) was added for dehydration.
Scheme 2. Tandem reaction to access six-membered spirocyclic oxindoles
through a formal [2+2+2] annulation strategy. PG: protecting group;
TMS: trimethylsilyl.
sluggish in the absence of benzoic acid and the aldol adduct
8a was isolated as the major product (Table 1, entry 6). The
domino reaction proceeded very smoothly when the catalyst
loading was decreased to 5 mol% (Table 1, entry 7). Finally,
we found that the dehydration process could occur upon ad-
dition of some trifluoroacetic acid after the domino reaction.
The N-Boc-deprotected cyclohexenecarboxaldehyde 9a was
then cleanly obtained in high yield (Table 1, entry 8).
amine catalysis of a chiral secondary amine, 3, to afford the
chiral bifunctional intermediate A. Subsequently, a tandem
reaction could be conducted with various electrophiles at
the C3 position of oxindole intermediate A, either in a 1,4-
or 1,2-addition manner. The following intramolecular cycli-
sation process would afford the expected six-membered spi-
rocyclic oxindoles with molecular diversity.
With these results in hand, we investigated the substrate
scope of the three-component domino reaction. In compari-
son with the results with oxindole 5a (Table 2, entry 1),
slightly less reaction was observed if 5b, with an ethyl ester
group, was applied (Table 2, entry 2). We then examined a
number of a,b-unsaturated aldehydes, 6, with propionalde-
hyde (4a) and oxindole 5a. The substrate, 5a, was generally
exhausted within 2 h. Enals bearing various electron-with-
drawing or -donating aryl and heteroaryl groups could be
well tolerated, and the spirocyclic oxindoles 9c–f were ob-
tained with excellent enantioselectivities and in good yields
after treatment with TFA (Table 2, entries 3–6). It should be
noted that N-Boc-protected 7g could be isolated as the
single product when the enal with an o-bromophenyl group
was applied (Table 2, entry 7). Simple acrolein and crotonal-
dehyde could also be successfully utilised (Table 2, entries 8
and 9). Subsequently, other aliphatic aldehydes were tested.
Good results could still be attained, although longer reac-
tion times, higher catalyst loadings and higher temperatures
needed to be applied (Table 2, entries 10–12). On the other
hand, a few different olefinic oxindoles were explored. The
electronic features of the substituents on the aryl ring had
little effect on the reactivity, and good results were obtained
(Table 2, entries 13–15). Nevertheless, the olefinic oxindole
with a b-phenyl group exhibited much lower reactivity, and
Based on these considerations, we initially investigated
the three-component domino reaction of propionaldehyde
(4a), the N-Boc-protected olefinic oxindole 5a and cinna-
maldehyde (6a) with the cascade enamine–iminium–enam-
ine catalysis of chiral amine 3 (10 mol%) and benzoic
acid,[11,12] similar to that reported by Enders and co-work-
ers.[13] To our gratification, the domino reaction proceeded
very smoothly in acetonitrile at ambient temperature. The
desired spirocyclic cyclohexenecarboxaldehyde 7a was iso-
lated with excellent diastereo- and enantioselectivity, albeit
in moderate yield. [During the preparation of this paper,
Melchiorre and co-workers reported a similar three-compo-
nent domino reaction to access spirocyclic oxindoles with
excellent stereocontrol. The free-NH olefinic oxindoles were
used as the Michael acceptors; in general, longer reaction
times and lower yields were observed.[14]] Interestingly, the
aldol intermediate 8a was also isolated as a single enantio-
mer. Intermediate 8a could not be converted into 7a by
simply extending the reaction time under the current cata-
lytic conditions (Table 1, entry 1). Similar results were at-
tained in the other solvents tested (Table 1, entries 2–4). A
slower reaction was observed when acetic acid was used as
the additive (Table 1, entry 5). The reaction became quite
Chem. Eur. J. 2010, 16, 2852 – 2856
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2853

Y.-C. Chen et al.
Table 2. Substrate scope in the three-component domino reaction.[a]
Entry
R1
5
R4
t [h]
Yield [%][b] (ee [%][c]
)
Scheme 3. One-pot, three-component tandem reaction to access spirocy-
clic oxindoles.
1
2
3
4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
PhCH2
PhSCH2
Me
Me
Me
Me
5a
5b
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5c
5d
5e
5 f
Ph
Ph
2
4
1
1
2
1
1
1
2
9a: 88 (99)
9b: 73 (>99)
9c: 78 (>99)
9d: 80 (>99)
9e: 83 (>99)
9 f: 77 (>99)
7g: 86 (>99)
9h: 53 (89)
p-CF3C6H4
m-CNC6H4
p-MeOC6H4
2-thienyl
o-BrC6H4
H
Me
Ph
Ph
Ph
AHCTUNGTREG[NNNU 5.4.0]undec-7-ene (DBU) was the preferable base promoter
5
in the later Michael addition/aldol reaction sequences. The
spirocyclic oxindole 11 with multiple functionalities was also
obtained with excellent stereocontrol (Scheme 4).
6[d]
7[e]
8
9
9i: 73 (99)
10
11[f]
12[f]
13
14
15
16[g]
5
9j: 66 (>99)
7k: 64 (>99)
7l: 50 (95)
9m: 70 (>99)
9n: 80 (99)
19
19
2
2.5
3.5
32
Ph
Ph
Ph
Ph
9o: 83 (>99)
7p: 71 (91)
[a] Unless noted otherwise, reactions were performed with 4 (0.11 mmol),
(0.1 mmol), (0.12 mmol), (0.005 mmol) and benzoic acid
5
6
3
(0.01 mmol) in CH3CN (0.5 mL) at RT. After completion, TFA
(0.2 mmol) was added and the mixture was stirred at RT for 3 h.
[b] Yield of isolated product. [c] Determined by chiral HPLC analysis;
dr>99:1. [d] The absolute configuration of 7 f was determined by X-ray
analysis;[15] see the Supporting Information. [e] The aldol product was
not observed. [f] With 10 mol% of 3 and 10 mol% of PhCOOH in tolu-
ene at 408C. [g] With 10 mol% of 3 and 10 mol% of o-FPhCOOH in tol-
uene at 408C.
Scheme 4. One-pot, three-component tandem reaction to access spirocy-
clic oxindoles with a tetracyclic skeleton. Bn: benzyl.
Furthermore, we developed a tandem process to construct
spirocyclic oxindoles incorporating a piperidine motif, which
might be quite valuable for the design of biologically impor-
tant materials.[10] As depicted in Scheme 5, N-Boc-imines
slightly harsher reaction conditions were required (Table 2,
entry 16).[14]
As a,b-unsaturated aldehydes could proceed in the Mi-
chael addition/aldol reaction sequences with intermediate A
depicted in Scheme 2, we proposed that other electrophiles
could also be used in similar formal [4+2] annulation reac-
tions with intermediate A; thus, spirocyclic oxindoles with
different substitution patterns could be generated. We found
that nitroolefins could act as good candidates.[6g,h] After the
Michael reaction of propionaldehyde (4a) to oxindole 5a
was complete, nitroolefins were added. Better results could
be obtained by using dichloromethane as the solvent and
N,N-diisopropylethylamine (DIPEA) was used as the base
catalyst. The tandem Michael addition/Henry reaction se-
quences were generally accomplished within 4 h, and the de-
sired cyclic products, 10a–d, with six contiguous stereogenic
centres were isolated in high yields with excellent enantiose-
lectivities and good diastereoselectivities (Scheme 3). How-
ever, nitroolefins bearing b-alkyl groups exhibited much
lower reactivity and failed to afford the corresponding spiro-
cyclic oxindoles.
Scheme 5. One-pot, three-component tandem reaction to access spirocy-
clic oxindoles incorporating a piperidine motif. TMG: 1,1,3,3-tetrame-
thylguanidine.
could be used as the electrophiles in the reaction with inter-
mediate A.[5a] A highly diastereoselective Mannich reaction
could be catalysed by TMG. The resultant hemiaminals 12
were directly dehydroxylated to give the piperidine deriva-
tives 13a and 13b with high enantioselectivities and in fair
yields after isolation.[16]
Moreover, the one-pot, three-component tandem reaction
of aldehyde 4a, oxindole 5a and N-benzylmaleimide could
be efficiently conducted. In this case, 1,8-diazabicyclo-
2854
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Chem. Eur. J. 2010, 16, 2852 – 2856

Synthesis of Spirocyclic Oxindoles with Multiple Chiral Centres
FULL PAPER
44.6, 31.9, 28.8, 27.3, 18.4 ppm; ESI-HRMS: m/z calcd for C26H27NO4 +
Na: 440.1838; found: 440.1813.
Conclusion
General procedure for the one-pot, three-component tandem reaction to
access spirocyclic oxindoles: Propionaldehyde (4a; 7.9 mL, 0.11 mmol),
olefinic oxindole 5a (35.0 mg, 0.1 mmol), catalyst 3 (1.6 mg, 5 mol%) and
benzoic acid (1.3 mg, 10 mol%) were stirred in acetonitrile (0.5 mL) at
room temperature for 2 h. The solvent was then removed and CH2Cl2
(0.5 mL), nitrostyrene (18.0 mg, 0.12 mmol) and DIPEA (3.6 mL,
0.02 mmol) were added. The reaction was stirred at room temperature
for 1–4 h. The mixture was concentrated and the residue was purified by
chromatography to afford spirocyclic oxindole 10a. For the synthesis of
compound 11, N-benzylmaleimide (22.5 mg, 0.12 mmol) and DBU
(6.0 mL, 40 mol%) were added instead of the nitroolefin and DIPEA.
We have developed an efficient and convenient one-pot,
three-component tandem reaction for the asymmetric syn-
thesis of a diverse spirocyclic oxindoles with excellent dia-
stereo- and enantioselectivities. This protocol proceeded
through a formal [2+2+2] annulation strategy by sequen-
tial amine-based organocatalytic reactions. A series of spiro
oxindolic carbocyclic and heterocyclic derivatives with ver-
satile molecular complexity have been constructed, which
might find applications in the further synthesis of com-
pounds with potential biological activities. We also believe
that the strategy demonstrated here may be utilised in other
asymmetric reactions to efficiently produce chiral materials
with complex structures. More results will be reported in
due course.
Compound 10a: 85% yield; [a]D20 =+79.67 (c=0.60 in EtOH); dr=8:1,
as determined by 1H NMR analysis; 95% ee, as determined by chiral
HPLC analysis (Daicel chiralpak IC, n-hexane/iPrOH 95:5, 1.0 mLminÀ1
l=254 nm,
,
tmajor =15.68 min, t
minor =33.78 min); 1H NMR (400 MHz,
CDCl3): d=7.46–7.35 (m, 2H), 7.20–6.99 (m, 7H), 6.21 (dd, J=12.0,
2.4 Hz, 1H), 4.58 (s, 1H), 4.06 (d, J=12.4 Hz, 1H), 3.37–3.25 (m, 2H),
2.73 (s, 1H), 1.56 (s, 9H), 1.14 (d, J=6.4 Hz, 3H), 1.05 ppm (s, 9H);
13C NMR (50 MHz, CDCl3): d=174.9, 169.8, 148.4, 139.3, 132.8, 128.8,
127.9, 127.8, 127.7, 124.2, 122.8, 121.6, 114.6, 114.4, 86.7, 83.9, 81.5, 71.9,
54.4, 52.1, 46.6, 32.4, 31.5, 28.0, 27.9, 27.4, 27.2, 15.6, 14.2, 14.0 ppm; ESI-
HRMS: m/z calcd for C30H36N2O8 +Na: 575.2369; found: 575.2366.
Experimental Section
Compound 11: 50% yield; [a]D20 =À98.16 (c=0.38 in EtOH); 90% ee,
dr>99:1, as determined by HPLC analysis (Daicel chiralpak AD-H, n-
General procedure for the three-component domino reaction: Propional-
dehyde (4a; 7.9 mL, 0.11 mmol), activated olefinic oxindole 5a (35.0 mg,
0.1 mmol), cinnamaldehyde (6a; 15.0 mL, 0.12 mmol), catalyst 3 (1.6 mg,
5 mol%) and benzoic acid (1.3 mg, 10 mol%) were stirred in acetonitrile
(0.5 mL) at room temperature for 2 h. After the consumption of oxindole
5a, the solvent was removed. The residue was purified by flash chroma-
tography to give the cyclohexenecarboxaldehyde 7a and aldol product
8a. For the dehydration process, TFA (16.0 mL, 0.2 mmol) was added to
the reaction mixture and stirred at room temperature for 3 h. The N-
Boc-deprotected product 9a was isolated after flash chromatography.
Compound 7a: 52% yield; [a]2D0 =À95.3 (c=1.35 in EtOH); >99% ee, as
determined by chiral HPLC analysis (Daicel chiralcel OD-H, n-hexane/
iPrOH 90:10, 1.0 mLminÀ1, l=254 nm, tmajor =5.45 min, tminor =6.99 min);
1H NMR (400 MHz, CDCl3): d=9.49 (s, 1H), 7.84 (d, J=8.0 Hz, 1H),
7.35–6.99 (m, 6H), 6.68 (td, J=7.6, 0.8 Hz, 1H), 6.53 (d, J=6.8 Hz, 1H),
5.49 (dd, J=7.6, 0.8 Hz, 1H), 3.92 (s, 1H), 3.55–3.49 (m, 1H), 2.84 (d, J=
10.4 Hz, 1H), 1.64 (s, 9H), 1.42 (d, J=7.6 Hz, 3H), 0.99 ppm (s, 9H);
13C NMR (50 MHz, CDCl3): d=192.4, 174.4, 169.9, 155.3, 149.5, 139.6,
138.1, 137.3, 133.3, 128.5, 128.0, 127.7, 127.3, 127.1, 125.8, 122.9, 114.2,
84.1, 81.6, 51.7, 50.9, 45.3, 32.1, 28.1, 27.1, 18.4 ppm; ESI-HRMS: m/z
calcd for C30H29NO5 +Na: 540.2362; found: 540.2391.
Compound 8a: 43% yield; [a]2D0 =À33.3 (c=0.6 in EtOH); >99% ee, as
determined by chiral HPLC analysis (Daicel chiralcel OD-H, n-hexane/
iPrOH 90:10, 1.0 mLminÀ1, l=254 nm, tmajor =7.05 min, tminor =9.83 min);
1H NMR (400 MHz, CDCl3): d=9.41 (s, 1H), 7.81 (d, J=8.0 Hz, 1H),
7.38 (brs, 2H), 7.30–7.27 (m, 1H), 7.16 (t, J=8.0 Hz, 1H), 7.06 (brs,
1H), 6.65 (t, J=7.2 Hz, 1H), 6.44 (brs, 1H), 5.60 (d, J=7.6 Hz, 1H), 4.44
(td, J=10.0, 3.2 Hz, 1H), 4.04–4.00 (m, 1H), 3.65 (d, J=6.4 Hz, 1H),
3.11 (d, J=3.2 Hz, 1H), 3.02–2.95 (m, 1H), 2.85 (d, J=12.4 Hz, 1H), 1.68
(s, 9H), 1.23 (d, J=6.4 Hz, 3H), 1.02 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=204.1, 175.4, 169.4, 149.5, 139.3, 136.7, 133.5, 128.6, 128.3,
126.9, 125.8, 123.1, 114.3, 84.4, 81.5, 71.6, 54.3, 53.6, 51.3, 48.2, 33.4, 28.1,
27.2, 16.1 ppm; ESI-HRMS: m/z calcd for C32H27NO3 +Na: 558.2500;
found: 558.2473.
hexane/iPrOH 90:10, 1.0 mLminÀ1, l=254 nm, tmajor =5.41 min, tminor
=
1
8.64 min); H NMR (400 MHz, CDCl3): d=7.69 (d, J=8.0 Hz, 1H), 7.31–
7.24 (m, 3H), 7.23–7.17 (m, 3H), 6.89 (d, J=7.6 Hz, 1H), 6.67 (t, J=
7.6 Hz, 1H), 4.61 (d, J=14.0 Hz, 1H), 4.47 (d, J=14.0 Hz, 1H), 3.88–3.79
(m, 2H), 3.75 (d, J=10.4 Hz, 1H), 3.30 (d, J=18.8 Hz, 1H), 2.96–2.90
(m, 1H), 2.10 (d, J=19.2 Hz, 1H), 1.64 (s, 9H), 1.52 (d, J=7.2 Hz, 3H),
1.41 ppm (s, 9H); 13C NMR (50 MHz, CDCl3): d=178.7, 178.4, 174.5,
169.5, 148.2, 140.2, 135.1, 129.2, 128.8, 128.6, 128.0, 125.0, 124.5, 123.6,
114.9, 85.4, 83.2, 81.7, 62.5, 60.0, 58.3, 47.1, 42.5, 32.4, 29.7, 28.0, 27.8,
27.5, 18.6 ppm; ESI-HRMS: m/z calcd for C33H38N2O8 +Na: 613.2526;
found: 613.2517.
General procedure for the one-pot, three-component tandem reaction to
access spirocyclic oxindoles incorporating a piperidine motif: Propional-
dehyde (4a; 7.9 mL, 0.11 mmol), olefinic oxindole 5a (35.0 mg,
0.1 mmol), catalyst
3 (1.6 mg, 5 mol%) and benzoic acid (1.3 mg,
10 mol%) were stirred in acetonitrile (0.5 mL) at room temperature for
2 h. The solvent was then removed and CH2Cl2 (0.5 mL), N-Boc-phenyli-
mine (25.0 mg, 0.12 mmol) and TMG (2.5 mL, 0.02 mmol) were added.
The mixture was stirred at room temperature. After completion, the mix-
ture was concentrated and the residue was purified by flash chromatogra-
phy to afford hemiaminal 12. BF3·Et2O (25.0 mL, 0.2 mmol) was added to
a solution of 12 and triethylsilane (46.5 mg, 0.4 mmol) in anhydrous
CH2Cl2 (1.0 mL) with ice cooling. After 2 min, the reaction was quenched
with aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was
dried over Na2SO4 and concentrated. The residue was purified by flash
chromatography on silica gel to give piperidine derivative 13a.
Compound 13a: 41% yield; [a]2D0 =+49.7 (c=0.31 in EtOH); 93% ee,
dr>99:1, as determined by chiral HPLC analysis (Daicel chiralpak IC,
n-hexane/iPrOH 90:10, 1.0 mLminÀ1, l=254 nm, tmajor =6.34 min, tminor
=
1
7.51 min); H NMR (400 MHz, CDCl3): d=7.45 (d, J=7.2 Hz, 1H), 7.23–
7.19 (m, 2H), 7.14–7.02 (m, 3H), 6.72 (d, J=6.8 Hz, 2H), 6.60 (d, J=
7.2 Hz, 1H), 5.25 (s, 1H), 4.60 (q, J=6.8 Hz, 1H), 4.03 (d, J=13.6 Hz,
1H), 2.69–2.60 (m, 1H), 1.29 (s, 9H), 1.21 (d, J=6.8 Hz, 3H), 1.06 ppm
(s, 9H); 13C NMR (50 MHz, CDCl3): d=176.0, 171.2, 155.5, 141.0, 138.6,
131.4, 128.8, 127.8, 127.2, 125.9, 123.9, 122.2, 109.0, 81.1, 80.0, 64.3, 55.5,
54.4, 46.7, 29.9, 28.2, 27.4, 20.5 ppm; ESI-HRMS: m/z calcd for
C29H36N2O5 +H: 493.2702; found: 493.2702.
Compound 9a: 88% yield; [a]2D0 =À76.92 (c=0.66 in EtOH); 99% ee, as
determined by chiral HPLC analysis (Daicel chiralpak AD-H, n-hexane/
iPrOH 70:30, 1.0 mLminÀ1
,
l=254 nm,
tmajor =13.84 min, tminor =
7.63 min); 1H NMR (400 MHz, CDCl3): d=9.45 (s, 1H), 8.09 (d, J=
18.0 Hz, 1H), 7.34–7.23 (m, 2H), 7.10–7.01 (m, 4H), 6.79 (d, J=7.2 Hz,
1H), 6.58–6.54 (m, 2H), 5.47 (d, J=7.6 Hz, 1H), 3.91 (s, 1H), 3.61–3.56
(m, 1H), 2.86 (d, J=10.8 Hz, 1H), 1.39 (d, J=7.6 Hz, 3H), 1.00 ppm (s,
9H); 13C NMR (50 MHz, CDCl3): d=192.5, 178.8, 170.9, 155.3, 140.8,
138.3, 138.0, 133.2, 128.3, 127.9, 127.5, 126.7, 120.8, 109.0, 81.3, 51.5, 50.9,
Chem. Eur. J. 2010, 16, 2852 – 2856
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Acknowledgements
We are grateful for financial support from the National Natural Science
Foundation of China (grant nos. 20772084 and 20972101), PCSIRTC
(grant no. IRT0846) and the National Basic Research Program of China
(973 Program) (grant no. 2010CB833303).
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Received: October 31, 2009
Published online: January 28, 2010
2856
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