Copper-catalyzed synthesis of a highly hydroxy-functionalized benzo[e]indolizidine by intramolecular N-arylation

Article abstract of DOI:10.1002/ejoc.201300440

The enantiopure (2S,3S,3aS,5S)-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a] quinoline-2,3,5-triol (2,3,5-trihydroxybenzo[e]indolizidine) framework has been synthesized by a straightforward strategy consisting of 1,3-dipolar cycloaddition of a pyrroline N-oxide to

Full text of DOI:10.1002/ejoc.201300440

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FULL PAPER
Copper-Mediated N-Arylation
F. M. Cordero,* B. B. Khairnar,
P. Bonanno, A. Martinelli,
A. Brandi* ........................................ 1–9
Copper-Catalyzed Synthesis of a Highly
Hydroxy-Functionalized Benzo[e]indoliz-
idine by Intramolecular N-Arylation
Highly hydroxy-functionalized hexahydro-
pyrrolo[1,2-a]quinolines that have the same
absolute configuration at stereocenters C-
2, C-3 and C-3a as natural lentiginosine
have been synthesized through a three-step
sequence starting from enantiopure dialk-
oxypyrroline N-oxides derived from l-tart-
aric acid.
Keywords: Azasugars / Fused-ring systems /
Copper catalysis / Cross-coupling / Cyclo-
addition
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F. M. Cordero, A. Brandi et al.
FULL PAPER
DOI: 10.1002/ejoc.201300440
Copper-Catalyzed Synthesis of a Highly Hydroxy-Functionalized
Benzo[e]indolizidine by Intramolecular N-Arylation
Franca M. Cordero,*[a] Bhushan B. Khairnar,[a] Paola Bonanno,[a] Andrea Martinelli,[a] and
Alberto Brandi*[a]
Dedicated to Professor Pierre Vogel on the occasion of his 70th birthday
Keywords: Azasugars / Fused-ring systems / Copper catalysis / Cross-coupling / Cycloaddition
The enantiopure (2S,3S,3aS,5S)-1,2,3,3a,4,5-hexahydropyr- pyrroline N-oxide to 2-bromostyrene followed by isoxazolid-
rolo[1,2-a]quinoline-2,3,5-triol (2,3,5-trihydroxybenzo[e]ind-
olizidine) framework has been synthesized by a straightfor-
ward strategy consisting of 1,3-dipolar cycloaddition of a
ine N–O bond reduction and cyclization by copper-catalyzed
nucleophilic aromatic substitution of the intermediate pyr-
rolidine.
on this idea, the synthesis of benzosubstituted lentiginos-
ines was undertaken, supported by computational studies
that suggested a better interaction of a benzolentiginosine
with the enzymatic cavity. In addition, natural aryl-substi-
tuted polyhydroxylated pyrrolidines, like codonopsine or ra-
dicamine,[7] show interesting biological activities.
As outlined in Scheme 1, we envisioned a direct pathway
to the creation of the benzo[e]indolizidine skeleton con-
sisting of an intramolecular aromatic nucleophilic substitu-
tion of a suitable 2-[2-(2-halophenyl)ethyl]pyrrolidine such
as 2. The requisite intermediate 2 was envisioned to arise
through reductive cleavage of the cycloadduct 3 between a
1-halo-2-ethenylbenzene and an enantiopure pyrroline N-
oxide 4 derived, in turn, from tartaric acid. One particular
advantage of this approach was anticipated to be the con-
trol of the regio- and stereochemistry of the 1,3-dipolar cy-
cloaddition (1,3-DC).
Introduction
Polyhydroxylated alkaloids (iminosugars) have attracted
considerable attention for their remarkable biological ac-
tivity and potential as pharmaceuticals tools.[1] Those with
indolizidine structure, like castanospermine, swainsonine, or
lentiginosine, are among the most studied for their broad
activity. For example, castanospermine was brought to be a
commercial drug against HCV infection.[2]
Lentiginosine [(1S,2S,8aS)-octahydroindolizine-1,2-diol],
despite being one of the least-substituted exemplars, has
shown interesting activity in addition to glycosidase inhibi-
tion. In particular, it was shown to be a potent inhibitor of
HSP90.[3] Moreover, its enantiomer [(1R,2R,8aR)-octa-
hydroindolizine-1,2-diol][4] and the corresponding 7-OH de-
rivative [(1R,2R,7S,8aR)-octahydroindolizine-1,2,7-triol][5]
have low cytotoxicity, but can induce apoptosis in cancer
cell strains.
The search for new, more selective and potent candidates
of this important class of compounds suggested the modifi-
cation of the indolizidine skeleton through its conjugation
with biorelevant substructures, like functionalized chains or
amino acid structures. The six-membered ring of lentiginos-
ine was the target of these functionalizations.[6] Proceeding
[a] Department of Chemistry “Ugo Schiff”, University of
Florence,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax: +39-055-4573531
E-mail: franca.cordero@unifi.it
alberto.brandi@unifi.it
Homepage: http://www.unifi.it/dipchimica/CMpro-v-p-
414.html
Scheme 1. Retrosynthetic analysis of benzo[e]indolizidine 1.
http://www.unifi.it/dipchimica/CMpro-v-p-
382.html
We report here the synthesis of pyrrolidine 2 (R =
TBDMS or tBu; RЈ = H) and its cyclization to the corre-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300440.
2
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Hydroxylated Benzo[e]indolizidine Synthesis
sponding tricyclic derivative 1. The tert-butyl derivatives (R
= tBu) were synthesized in both enantiomeric forms, al-
though only the compounds derived from l-tartaric acid (l-
series) are discussed for the sake of brevity.
Results and Discussion
Figure 1. General structure of the two major diastereomers 9a–11a
and 9b–11b.
Initially, the 1,3-DC of dihydroxylated pyrroline N-ox-
ides 5[8,9] and 6[5] with 1-halo-2-ethenylbenzenes was
studied. The reactions of 2,6-dichlorostyrene (7) and 2-bro-
mostyrene (8) with nitrones 5 and 6 in toluene at 70 °C
under microwave heating (MW) afforded diastereomeric
mixtures of the corresponding cycloadducts 9–11 in high
overall yield (92–99%) (Scheme 2).
The stereochemistry of cycloadducts 9–11 was assigned
by NMR analyses and then confirmed by the analysis of
the corresponding derivatives (see Supporting Information).
The selective reduction of the isoxazolidine N–O bond
was carried out with Zn and acetic acid, and afforded the
corresponding pyrrolidines in good yields (Scheme 3). NOE
experiments on pyrrolidines derived from adducts 9a–11a
and 9b–11b confirmed the assigned configurations (see Sup-
porting Information).
Once the phenethyl pyrrolidines 12–14 were available in
very few steps, the nucleophilic amine substitution of the
halogenated aromatic ring was studied. An analysis of the
literature showed that the unsubstituted 1,2,3,3a,4,5-hexa-
hydropyrrolo[1,2-a]quinoline (15) was obtained by Buch-
wald et al.[11] through a Pd-catalyzed amine aromatic sub-
stitution of the 2-Br-phenethylpyrrolidine (16) in 55% yield,
and by Fort et al.[12] through the corresponding cyclization
Scheme 2. 1,3-DC of nitrones 5 and 6 with dipolarophiles 7 and 8. of the chloro derivative 17 in the presence of a Ni catalyst
(81% yield) (Scheme 4).
In all cases, the exo-(3-OR)-anti diastereomer (9a–11a)
(Figure 1), which was derived from the exo attack of the
alkene on the opposite face of the C-3 substituent of the
nitrone, was the major adduct. The second and third iso-
mers were, respectively, the exo-(3-OR)-syn and the endo-
(3-OR)-anti isomers (9b–11b and 9c–11c).[10] The 1,3-DC of
nitrone 5 with dichlorostyrene 7 was less diastereoselective
than the corresponding reaction with 8 (ca 1:1 vs. 1.6:1 exo-
anti/exo-syn ratio). It is likely that the monosubstituted
bromostyrene 8 can better accommodate the substituted
phenyl ring in an anti approach. The highest stereoselecti-
vity was obtained with the dipolarophile 8 and di-tert-bu-
toxy nitrone 6, which afforded the adduct exo-(3-OR)-anti-
11a in as much as 73% yield (calculated). Diastereomeric
Scheme 4. Previous syntheses of unsubstituted 1,2,3,3a,4,5-hexa-
hydropyrrolo[1,2-a]quinoline (15).
adducts were not easily separable by chromatography on
In our hands, such conditions, thoroughly investigated,
silica gel, and were often obtained as enriched fractions of were not able to afford the expected benzoindolizidine start-
isomers and separated at later steps (see the Exp. Sect.).
ing from derivatives 12 and 13. The lack of reactivity of
Scheme 3. Reductive ring opening of the major adducts 9a–11a.
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F. M. Cordero, A. Brandi et al.
FULL PAPER
these compounds under Buchwald reaction conditions 1H NMR spectra of the crude mixtures showed a large ex-
could be explained by a steric hindrance effect, but most cess of high field signals, suggesting that the TBDMS pro-
probably by the presence of the OH group in a suitable tecting group could be part of the problem. In fact, it has
position to form a strong intramolecular hydrogen bond been reported that the TBDMS group can be removed in
with the NH that, as a result, is no longer available for the presence of copper salts.[14]
the coupling. Another possibility is that under the strongly
The copper-mediated cyclization of the di-tert-butyl de-
alkaline conditions, the alcohol is deprotonated and the re- rivative 14a was studied using the best reaction conditions
sulting alkoxide interferes with the vicinal metal coordi- found, i.e. CuI/Cu/l-Pro as catalyst mixture, K3PO4 as base
nated with the benzene ring, quenching its catalytic effect. and a 1:1 mixture of tBuOH/H2O as the solvent (Table 1).
The presence of an intramolecular hydrogen bond in apolar The replacement of the protecting group led to a significant
solvents was proved by the persistence of the broad band reduction of decomposition products. Preliminary tests on
in the 3100–3550 cm–1 region of the IR spectra of diluted 14a revealed that a higher yield based on converted starting
solutions of 13a (30–5 mm in CDCl3). Attempts to convert material could be achieved when the reaction was run at
the free OH group to a silyl ether with TBDMSCl and lower temperature and for longer time (Table 1, entries 1–2
TMSCl in DMF, or TMSOTf in DCM failed or gave very and 5–7). A half mol equiv. of the CuI/Cu couple was found
small yields of the desired compound. Oxidation of the to be the best compromise between conversion percentage,
benzylic alcohol with MnO2 also failed, in accord with a overall yield and a reasonable reaction time (10–12 h) when
reduced reactivity of the OH group.
the reaction was carried out at 90 °C. Due to the long reac-
To verify these hypotheses, the cyclization under tion time, conventional heating was preferred over micro-
Ullmann reaction conditions[13] was then examined, be- wave irradiation that was only slightly more efficient
cause the highly polar solvents used in CuI catalyzed C–N (Table 1, entries 3, 4 and 9). Finally, the best reaction condi-
coupling should effectively reduce the strength of the in- tions (Table 1, entries 9 and 10) were applied to both the
ternal hydrogen bond in substrates 12–14, and should shield
the reactivity of the hydroxy group.
Table 1. Copper-mediated cyclization of the tBu derivative 14a.
Cyclization of pyrrolidine 13a in the presence of copper
salts was tested using various combinations of catalyst
sources, with or without proline, with an organic or inor-
ganic base, and under anhydrous or aqueous conditions. It
was found that CuI in the presence of metallic Cu was a
more efficient catalyst than CuI alone or the CuSO4/Cu
couple, and that the use of proline as a copper ligand in-
creased the yield. The catalytic effect of copper was proved
by analyzing the thermal cyclization of 13a (DMF, DBU or
K3PO4, 120 °C, 2 h), which afforded only traces of 18a
along with a mixture of decomposition products. DBU and
K3PO4 were more efficient than K2CO3 in DMF, but in
protic solvents a higher yield was obtained when K3PO4
was used as base. Unfortunately, the desired compound 18a
could be isolated in only 30–46% yield at best (Scheme 5).
A significant amount of decomposition products was al-
ways detected in the crude reaction mixtures, even when
conversion was not complete. Generally, with longer reac-
tion times or higher temperatures, decomposition increased
with detrimental effect on the overall yield in accord with
CuI/Cu T [°C][a]
[%]
t [h]
RSM
[%][b]
19a yield
[%][c]
1
2
3
4
5
6
7
8
9
10
30:30
30:30
50:50
50:50
80:80
80:80
80:80
50:50
50:50
50:50
100 (MW)
120
90 (MW)
90
90 (MW)
110
100 (MW)
95
3.5
1.5
10
10
13
2
3.5
10
12
12
61
32
n.d.
n.d.
15
n.d.
30
36 (90)
48 (71)
75
65
62 (73)
21
31 (44)
58 (81)
74
28
90
90
n.d.
7[d]
77 (82)[d]
[a] MW: microwave heating. [b] RSM: recovered starting material
(14a) after chromatography; n.d.: not determined. [c] Isolated yield
after chromatography; values in parentheses refer to yields based
the relative instability of 18a under the reaction conditions. on conversion. [d] The reaction was done on ent-14a.
Scheme 5. Representative examples of copper-mediated cyclization of TBDMS derivative 13a.
4
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Hydroxylated Benzo[e]indolizidine Synthesis
vent reference frequencies. Assignments were made on the basis of
1H–1H COSY, HMQC, HSQC and HMBC experiments. IR spectra
were recorded with a Perkin–Elmer Spectrum BX FT-IR System
spectrophotometer on CDCl3 solutions. Mass spectra were re-
corded with a QP5050 Shimadzu spectrometer with a GC–GC or
direct inlet (70-eV ionizing voltage); relative percentages are shown
in parentheses. Elemental analyses were performed with a Perkin–
Elmer 2400 analyzer. Microwave-assisted reactions were carried out
in a CEM Discover™ single mode microwave reactor with an IR
temperature sensor.
enantiomeric pyrrolidines 14a and ent-14a. The corre-
sponding tricyclic products 19a and ent-19a were obtained
in 74 and 77% yield, respectively, demonstrating no major
effect of the use of the chiral l-proline as catalyst ligand
with different enantiomers.
Under the same conditions, the dichloro derivative 12a
proved to be less reactive than 14a, affording only traces of
the corresponding benzoindolizidine after 48 h at 100 °C.
The known reduced reactivity of chloro aromatic com-
pounds in comparison with the corresponding bromo deriv-
atives and the steric hindrance of the densely functionalized
phenethyl pyrrolidines 12 compared to 13 and 14, seem to
explain the lack of reactivity.
(3S,4S)-3,4-Bis(tert-butyldimethylsilyloxy)-1-pyrroline N-Oxide (5):
A mixture of (3S,4S)-1-benzyl-3,4-bis(tert-butyldimethylsilyloxy)-
pyrrolidine (5.76 g, 13.66 mmol) and 20% Pd(OH)2/C (2.02 g,
1.9 mmol) in MeOH (71 mL) was stirred under an H2 atmosphere
(1 atm) at room temp. overnight, then filtered through a short pad
of Celite® and washed with MeOH. The filtrate was concentrated
under reduced pressure to afford the debenzylated pyrrolidine
(3.83 g, 85%) that was used in the next step without further purifi-
cation. A mixture of crude (3S,4S)-3,4-bis(tert-butyldimethylsily-
loxy)pyrrolidine (1.868 g, 5.633 mmol) in a mixture of CH3CN/
THF (4:1, 10.8 mL) and aqueous Na2EDTA (0.01 m, 8.3 mL) was
stirred and cooled to 0 °C and then treated with NaHCO3 (2.37 g,
28.16 mmol). Oxone®[15] (3.64 g, 5.91 mmol) was added portion-
wise over 2 h. The mixture was stirred at 0 °C for 30 min and then
diluted with EtOAc (10 mL) and deionized H2O (10 mL). The two
phases were separated, and the aqueous solution was extracted with
CH2Cl2 (2ϫ 10 mL). The combined organic layers were dried with
Na2SO4, filtered, and then concentrated under reduced pressure to
afford crude 5 as a yellow oil. Purification by chromatography on
silica gel (eluent: EtOAc/petroleum ether, 1:1) afforded 5 (1.43 g,
70%) as a white waxy solid.
Treatment of 18a with tetrabutylammonium fluoride
(TBAF) provided the deprotected triol 20 in 36% unopti-
mized yield (Scheme 6).
Scheme 6. Deprotection of benzoindolizidine 18a.
Conclusions
1,3-DC of an enantiopure 3,4-dialkoxypyrroline N-oxide
with 1-bromo-2-ethenylbenzene, followed by reduction of
the isoxazolidine N–O bond and copper-catalyzed intramo-
lecular N-arylation provided a convenient method for the
synthesis of highly functionalized benzo[e]indolizidines.
The bromophenylpyrrolidines underwent cyclization under
Ullmann reaction conditions (copper catalyst, protic sol-
vents), whereas Pd and Ni catalysts, which operate in apolar
solvents, failed to give the same reaction. The required reac-
tion conditions involving a high temperature (90 °C), stoi-
chiometric copper, and a base were well tolerated by tert-
butyl ether groups, whereas TBDMS ethers suffered partial
decomposition. The method provided access to benzocon-
densed derivatives of iminosugars valuable as glycosidase
inhibitors and apoptosis inducers.
Spectral properties were identical with those reported in the litera-
ture.[8]
(2S,3aS,4S,5S)-2-(2,6-Dichlorophenyl)-4,5-bis(tert-butyldimethylsil-
yloxy)hexahydropyrrolo[1,2-b][1,2]oxazole (9a): 2,6-Dichlorostyrene
(7, 506 mg, 2.92 mmol) was added to a suspension of nitrone 5
(1.0 g, 2.89 mmol) in toluene (0.2 mL), and the reaction mixture
was heated at 70 °C for 1 h 15 min in a microwave reactor (MW)
using an irradiation power of 100 W. A second portion of nitrone
(310 mg, 0.9 mmol) was added, and the reaction mixture was
heated in the MW at 70 °C for 30 min. The solvent was evaporated
under
a nitrogen stream, and the residue was purified by
chromatography on silica gel [eluent: EtOAc (1% Et3N)/petroleum
ether, 1:10]. Enriched fractions of the diastereoisomeric adducts
were obtained in 94% overall yield (1.43 g, exo-anti:exo-syn:endo-
anti ratio = 6.8:6.4:1). The major exo-anti diastereoisomer 9a was
1
obtained in 46% combined yield (696 mg), calculated by H NMR
of the mixed fractions, as a white solid.
Experimental Section
9a (17:1 mixture with 9b): Rf = 0.43; m.p. 72–73 °C. [α]2D2 = +52.2
(c = 1.0, CHCl3). 1H NMR (400 MHz): δ = 7.29 (pseudo d, J =
8.0 Hz, 2 H, HAr), 7.13 (dd, J = 8.5, 7.5 Hz, 1 H, HAr), 5.91 (pseudo
t, J = 8.8 Hz, 1 H, 2-H), 4.09–4.04 (m, 2 H, 4-H, 5-H), 3.91 (ddd,
J = 10.4, 4.3, 1.8 Hz, 1 H, 3a-H), 3.69 (dd, J = 12.5, 4.6 Hz, 1 H,
6-Ha), 3.12–3.06 (m, 1 H, 6-Hb), 2.83 (ddd, J = 12.2, 10.4, 9.4 Hz,
General Remarks: All the reactions requiring anhydrous conditions
were carried out under nitrogen, and the solvents were appropri-
ately dried before use. Chromatographic purifications were per-
formed with silica gel 60 (0.040–0.063 mm, 230–400 mesh ASTM,
Merk) using the flash-column technique; Rf values refer to TLC on
0.25 mm silica gel plates (Merck F254, Macherey–Nagel precoated 1 H, 3-Ha), 2.52 (ddd, J = 12.2, 8.3, 4.3 Hz, 1 H, 3-Hb), 0.93 [br.
sheets) with the same eluant indicated for column chromatography
unless otherwise stated. Melting points (m.p.) were determined
with a RCH Kofler apparatus. Polarimetric measurements were
performed with a JASCO DIP-370 polarimeter. NMR spectra were
recorded with Varian Gemini (1H, 200 MHz), Varian Mercury (1H,
200 MHz), or Varian Mercuryplus (1H, 400 MHz) instruments
using CDCl3 as the solvent, and were referenced internally to sol-
s, 9 H, C(CH3)3], 0.90 [br. s, 9 H, C(CH3)3], 0.12 (br. s, 6 H, SiCH3),
0.10 (br. s, 6 H, SiCH3) ppm. 13C NMR (50 MHz): δ = 135.7 (s; 2
C, CAr), 132.9 (s; CAr), 129.3 (d; 3 C, CHAr), 83.8 (d; C-4), 77.8 (d;
C-5), 74.7 (d; C-2), 73.2 (d; C-3a), 62.6 (t; C-6), 39.0 (t;C-3), 25.9
[q;
C(CH3)3], 25.8 [q; 3 C, C(CH3)3], 18.2 [s; C(CH3)3], 18.0 [s;
C(CH ) ], –4.5 (q; 2 C, SiCH ), –4.7 (q, 2 C, SiCH ) ppm. IR: ν =
3
C,
˜
3 3
3
3
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2956, 2931, 2857, 1564, 1472, 1439, 1259, 1108 cm–1. 11a (6.7:1 mixture of 11a and 11c): Rf = 0.40. [α]2D5 = +12.8 (c =
1
C24H41Cl2NO3Si2 (518.7): calcd. C 55.58, H 7.97, N 2.70; found C
55.52, H 8.23, N 2.79.
0.51, CHCl3). H NMR (CDCl3, 400 MHz): δ = 7.59 (dd, J = 7.8,
1.7 Hz, 1 H, HAr), 7.50 (dd, J = 8.0, 1.2 Hz, 1 H, HAr), 7.30 (pseudo
dt, J = 1.2, 7.6 Hz, 1 H, HAr), 7.11 (pseudo dt, J = 1.7, 7.7 Hz, 1
H, HAr), 5.51 (pseudo t, J = 7.3 Hz, 1 H, 2-H), 3.97 (pseudo dt, J
= 8.0, 5.6 Hz, 1 H, 5-H), 3.87 (dd, J = 5.3, 4.1 Hz, 1 H, 4-H), 3.57
(dd, J = 10.7, 5.9 Hz, 1 H, 6-Ha), 3.60–3.55 (m, 1 H, 3a-H), 3.02
(dd, J = 10.7, 8.0 Hz, 1 H, 6-Hb), 2.82 (ddd, J = 12.5, 7.1, 5.3 Hz,
1 H, 3-Ha), 2.23 (ddd, J = 12.5, 9.0, 7.5 Hz, 1 H, 3-Hb), 1.22 [s, 9
H, C(CH3)3], 1.19 [s, 9 H, C(CH3)3] ppm. 13C NMR (CDCl3,
100 MHz): δ = 140.1 (s; CAr), 132.4 (d; CHAr), 128.8 (d; CHAr),
127.7 (d; CHAr), 127.3 (d; CHAr), 121.8 (s; CAr), 81.6 (d; C-4), 77.3
(d; C-2), 76.2 (d; C-5), 74.1 (s; Me3CO), 74.0 (s; Me3CO), 70.1 (d;
C-3a), 60.3 (t; C-6), 41.6 (t; C-3), 28.7 (q; 3 C, CH3), 28.5 (q; 3 C,
(2S,3aS,4S,5S)- and (2R,3aR,4S,5S)-2-(2-Bromophenyl)-4,5-bis-
(tert-butyldimethylsilyloxy)hexahydropyrrolo[1,2-b][1,2]oxazole
(10a and 10b): 2-Bromostyrene (8, 609 mg, 3.32 mmol) was added
to a suspension of nitrone 5 (1.147 g, 3.32 mmol) in toluene
(2.5 mL), and the reaction mixture was heated at 70 °C for 3 h in
the MW using an irradiation power of 100 W. The solvent was
coevaporated with MeOH under reduced pressure, and the residue
was purified by chromatography on silica gel (eluent: EtOAc/petro-
leum ether, 1:14). Enriched fractions of the diastereoisomeric ad-
ducts were obtained in 92% overall yield (1.618 g, exo-anti:exo-
syn:endo-anti ≈ 18.4:11.6:1). The exo-anti diastereoisomer 10a was
CH ) ppm. IR (CDCl ): ν = 2977, 2935, 2872, 1472, 1390, 1365,
˜
3
3
1
obtained in 55% combined yield (959 mg), calculated by H NMR
of the mixed fractions, as a white solid.
1190, 1105 cm–1. MS (EI): m/z (%) = 413 (6) [(M + 2)]+, 411 (6)
[M]+, 356 (12), 354 (12), 300 (6), 298 (6), 284 (2), 282 (2), 228 (7),
226 (8), 116 (8), 57 (100), 55 (36). C20H30BrNO3 (412.4): calcd. C
58.25, H 7.33, N 3.40; found C 57.94, H 7.41, N 3.24.
10a (ca 7:1 mixture with two minor isomers): Rf = 0.50; m.p. 52–
53 °C. [α]2D2 = +6.1 (c = 1.0, CHCl3). 1H NMR (400 MHz): δ =
7.62 (dd, J = 7.8, 1.6 Hz, 1 H, HAr), 7.51 (dd, J = 8.0, 1.1 Hz, 1
H, HAr), 7.31 (pseudo dt, J = 1.1, 7.6 Hz, 1 H, HAr), 7.12 (pseudo
dt, J = 1.6, 7.6 Hz, 1 H, HAr), 5.44 (pseudo t, J = 7.4 Hz, 1 H, 2-
H), 4.09 (pseudo dt, J = 4.1, 5.5 Hz, 1 H, 5-H), 4.02 (pseudo t, J
= 3.8 Hz, 1 H, 4-H), 3.64 (dd, J = 12.1, 5.4 Hz, 1 H, 6-Ha), 3.67–
3.61 (m, 1 H, 3a-H), 3.14 (dd, J = 12.1, 5.7 Hz, 1 H, 6-Hb), 2.83
(ddd, J = 12.4, 6.7, 4.2 Hz, 1 H, 3-Ha), 2.21 (ddd, J = 12.4, 9.2,
8.1 Hz, 1 H, 3-Hb), 0.92 [s, 9 H, C(CH3)3], 0.88 [s, 9 H, C(CH3)3],
0.12 (s, 3 H, SiCH3), 0.11 (s, 3 H, SiCH3), 0.10 (s, 3 H, SiCH3),
0.08 (s, 3 H, SiCH3) ppm. 13C NMR (100 MHz): δ = 139.9 (s; CAr),
132.5 (d; CHAr), 128.8 (d; CHAr), 127.7 (d; CHAr), 127.3 (d; CHAr),
121.7 (s; CAr), 83.6 (d; C-4), 78.0 (d; C-5), 77.3 (d; C-2), 71.8 (d;
C-3a), 62.2 (t; C-6), 41.5 (t; C-3), 25.9 [q; 3 C, C(CH3)3], 25.8 [q;
3 C, C(CH3)3], 18.1 [s, C(CH3)3], 17.9 [s, C(CH3)3], –4.4 (q; SiCH3),
11b (6.9:1 mixture of 11b and 11d): Rf = 0.22. [α]2D5 = +58.2 (c =
1
0.9, CHCl3). H NMR (CDCl3, 400 MHz): δ = 7.65 (dd, J = 7.8,
1.7 Hz, 1 H, HAr), 7.50 (dd, J = 8.0, 1.2 Hz, 1 H, HAr), 7.30 (pseudo
dt, J = 1.2, 7.6 Hz, 1 H, HAr), 7.10 (pseudo dt, J = 1.7, 7.7 Hz, 1
H, HAr), 5.29 (pseudo t, J = 7.3 Hz, 1 H, 2-H), 4.11 (pseudo dt, J
= 5.1, 6.5 Hz, 1 H, 5-H), 3.96–3.86 (m, 2 H, 3a-H, 4-H), 3.40 (dd,
J = 13.1, 6.3 Hz, 1 H, 6-Ha), 3.09 (dd, J = 13.1, 6.8 Hz, 1 H, 6-
Hb), 3.02 (ddd, J = 12.4, 6.8, 2.9 Hz, 1 H, 3-Ha), 2.01 (pseudo dt,
J = 12.4, 8.0 Hz, 1 H, 3-Hb), 1.22 (s, 9 H, CH3 ϫ3), 1.20 (s, 9 H,
CH3 ϫ3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 140.9 (s; CAr),
132.4 (d; CHAr), 128.6 (d; CHAr), 127.6 (d; CHAr), 127.2 (d; CHAr),
121.7 (s; CAr), 78.6 (d; C-2), 77.4 (d; C-4), 76.4 (d; C-5), 74.0 (s;
Me3CO), 73.6 (s; Me3CO), 66.6 (d; C-3a), 60.7 (t; C-6), 38.7 (t; C-
3), 28.5 (q; 6 C, CH ) ppm. IR (CDCl ): ν = 2977, 2934, 2907,
˜
3
3
2872, 1568, 1472, 1390, 1365, 1193, 1096, 1020 cm–1. MS (EI): m/z
(%) = 413 (3) [(M + 2)]+, 411 (3) [M]+, 356 (8), 354 (7), 300 (5),
298 (5), 284 (2), 282 (2), 228 (5), 226 (6), 116 (7), 57 (100), 55 (36).
C20H30BrNO3 (412.4): calcd. C 58.25, H 7.33, N 3.40; found C
58.40, H 7.35, N 3.60.
–4.5 (q; SiCH ), –4.6 (q; SiCH ), –4.7 (q, SiCH ) ppm. IR: ν =
˜
3
3
3
2955, 2930, 2858, 1471, 1440, 1361, 1258, 1110 cm–1. MS (EI): m/z
(%) = 529 (6) [(M + 2)]+, 527 (5) [M]+, 286 (3), 241 (5), 212 (3),
187 (3), 185 (3), 171 (19), 147 (25), 133 (10), 128 (10), 115 (11), 73
(100). 55, (76). C24H42BrNO3Si2 (528.7): C 54.52, H 8.01, N 2.65;
found C 54.66, H 8.27, N 2.61.
1
11c: (6.7:1 mixture of 11a and 11c): H NMR (CDCl3, 400 MHz,
1
discernible signals): δ = 7.74 (dd, J = 7.8, 1.7 Hz, 1 H, HAr), 7.49
(dd, J = 7.9, 1.2 Hz, 1 H, HAr), 7.29 (pseudo dt, J = 1.2, 7.5 Hz, 1
H, HAr), 5.28 (dd, J = 9.9, 6.1 Hz, 1 H, 2-H), 4.05 (pseudo dt, J =
4.1, 5.7 Hz, 1 H, 5-H), 3.84 (pseudo t, J = 3.8 Hz, 1 H, 4-H), 3.70
(pseudo dt, J = 3.5, 8.3 Hz, 1 H, 3a-H), 3.53 (dd, J = 11.8, 5.6 Hz,
1 H, 6-Ha), 3.25 (dd, J = 11.8, 5.9 Hz, 1 H, 6-Hb), 3.06 (ddd, J =
12.2, 7.8, 6.1 Hz, 1 H, 3-Ha), 2.01 (ddd, J = 12.2, 9.9, 8.6 Hz, 1 H,
3-Hb), 1.21 [s, 9 H, C(CH3)3], 1.16 [s, 9 H, C(CH3)3] ppm. 13C
NMR (CDCl3, 100 MHz, discernible signals): δ = 82.4 (d; C-4),
80.1 (d; C-2), 79.0 (d; C-5), 73.9 (s; Me3CO), 72.6 (d; C-3a), 61.8
(t; C-6), 41.8 (t; C-3), 28.6 (q; 3 C, CH3), 28.5 (q; 3 C, CH3) ppm.
10b H NMR (400 MHz, 18:1 mixture with 10a): δ = 7.65 (dd, J
= 7.8, 1.7 Hz, 1 H, HAr), 7.50 (dd, J = 8.0, 1.2 Hz, 1 H, HAr), 7.30
(pseudo dt, J = 1.2, 7.8 Hz, 1 H, HAr), 7.11 (pseudo dt, J = 1.7,
7.6 Hz, 1 H, HAr), 5.27 (dd, J = 8.8, 6.4 Hz, 1 H, 2-H), 4.25 (pseudo
dt, J = 3.1, 4.9 Hz, 1 H, 5-H), 4.08–4.00 (m, 2 H, 3a-H, 4-H), 3.37
(dd, J = 12.5, 5.2 Hz, 1 H, 6-Ha), 3.22 (dd, J = 12.5, 4.7 Hz, 1 H,
6-Hb), 2.93 (ddd, J = 12.4, 6.4, 2.0 Hz, 1 H, 3-Ha), 2.03 (pseudo
dt, J = 12.4, 8.7 Hz, 1 H, 3-Hb), 0.95 [s, 9 H, C(CH3)3], 0.90 [s, 9
H, C(CH3)3], 0.14 (s, 3 H, SiCH3), 0.12 (s, 3 H, SiCH3), 0.09 (s, 6
H, SiCH3) ppm.
(2S,3aS,4S,5S)-,
(2R,3aR,4S,5S)-,
(2R,3aS,4S,5S)-,
and
1
11d: (6.9:1 mixture of 11b and 11d): H NMR (CDCl3, 400 MHz,
(2S,3aR,4S,5S)-2-(2-Bromophenyl)-4,5-di-tert-butoxyhexahydropyr-
rolo[1,2-b][1,2]oxazole (11a, 11b, 11c, and 11d): 2-Bromostyrene (8,
595 mg, 3.27 mmol) was added to a suspension of nitrone 6[5]
(0.5 g, 2.18 mmol) in toluene (1.16 mL), and the reaction mixture
was heated at 70 °C for 5 h in the MW using an irradiation power
of 100 W. The solvent was evaporated under a nitrogen stream,
and the residue was purified by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether, 1:4), affording fractions enriched
of diastereoisomers, especially the minor ones in 99% overall yield
(0.889 g). The exo-anti adduct 11a and the exo-syn isomer 11b were
obtained in 73% and 22% yield, respectively (677 and 191 mg),
discernible signals): δ = 7.57 (dd, J = 7.8, 1.7 Hz, 1 H, HAr), 7.13
(pseudo dt, J = 1.7, 7.7 Hz, 1 H, HAr), 5.20 (dd, J = 9.8, 6.2 Hz, 1
H, 2-H), 4.27 (pseudo dt, J = 9.1, 6.2 Hz, 1 H, 5-H), 3.55 (dd, J =
13.9, 6.4 Hz, 1 H, 6-Ha), 2.90 (dd, J = 13.9, 9.1 Hz, 1 H, 6-Hb),
2.65 (ddd, J = 12.4, 8.6, 6.2 Hz, 1 H, 3-Ha), 2.35–2.27 (m, 1 H, 3-
Hb), 1.21 [s, 9 H, C(CH3)3], 1.13 [s, 9 H, C(CH3)3] ppm. 13C NMR
(CDCl3, 100 MHz, discernible signals): δ = 132.5 (d; CHAr), 128.9
(d; CHAr), 127.5 (d; CHAr), 127.3 (d; CHAr), 78.9 (d; C-2), 77.6 (d;
C-4), 76.0 (d; C-5), 66.5 (d; C-3a), 58.9 (t; C-6), 37.9 (t; C-3) ppm.
(1S)-1-(2,6-Dichlorophenyl)-2-[(2S,3S,4S)-3,4-bis(tert-butyldimeth-
ylsilyloxy)pyrrolidin-2-yl]ethanol (12a): A 17:1 mixture of isoxazoli-
1
calculated by H NMR of the mixed fractions, as colourless oils.
6
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Job/Unit: O30440
/KAP1
Date: 17-06-13 16:42:14
Pages: 9
Hydroxylated Benzo[e]indolizidine Synthesis
dines 9a and 9b (63 mg, 0.119 mmol of 9a and 3 mg of 9b) was = 12.4, 4.5 Hz, 1 H, 5-Ha), 2.88 (br. d, J = 12.4 Hz, 1 H, 5-Hb),
mixed with zinc powder (36 mg, 0.56 mmol) in AcOH/H2O [9:1 (v/
v), 1.08 mL], and the suspension was heated in an oil bath at 60 °C
for 4 h and then filtered through cotton wool. The solid residue
was washed with EtOAc, the solution was basified to pH = 9 with
a saturated aq. NaHCO3 solution, and then it was extracted with
EtOAc (5ϫ 10 mL). The combined organic phases were dried with
Na2SO4, filtered and concentrated under reduced pressure.
Chromatography on silica gel (eluent: initially CH2Cl2, then
CH2Cl2/MeOH with 1% NH4OH, 15:1) afforded pyrrolidine 12a
in 72% yield (45 mg) as a white solid. Rf = 0.30 (CH2Cl2/MeOH
with 1% NH4OH, 15:1); m.p. 113–114 °C. [α]2D5 = +14.2 (c = 1.0,
2.61 (pseudo dt, J = 14.6, 11.0 Hz, 1 H, CHHCHOH), 1.72 (pseudo
dt, J = 14.6, 2.8 Hz, 1 H, CHHCHOH) ppm. 13C NMR (50 MHz,
CDCl3, discernible signals): δ = 137.8 (s; CAr), 134.5 (s; 2 C, CAr),
129.2 (d; 2 C, CHAr), 128.4 (d; CHAr), 80.0 (d; C-3), 77.9 (d; C-4),
77.1 (d; CHOH), 61.4 (d; C-2), 52.9 (t; C-5), 32.2 (t; CH2CHOH),
25.8 [q; 6 C, C(CH3)3], 18.1 [s; C(CH3)3], 18.0 [s; C(CH3)3] ppm.
(1S)- and (1R)-1-(2-Bromophenyl)-2-[(2S,3S,4S)-3,4-bis(tert-butyldi-
methylsilyloxy)pyrrolidin-2-yl]ethanol (13a and 13b): Following the
same procedure used to prepare 12a, pyrrolidines 13a and 13b were
obtained starting from a mixture of cycloadducts 10a and 10b.
1
13a: White solid, 88% yield, Rf = 0.34 [eluent: CH2Cl2/MeOH (1%
NH4OH) 20:1]; m.p. 102–103 °C. [α]2D5 = +12.1 (c = 1.0, CHCl3).
1H NMR (400 MHz): δ = 7.65 (dd, J = 7.8, 1.7 Hz, 1 H, HAr), 7.48
(dd, J = 7.9, 1.2 Hz, 1 H, HAr), 7.33 (pseudo dt, J = 1.2, 7.5 Hz, 1
H, HAr), 7.09 (pseudo dt, J = 1.7, 7.6, Hz, 1 H, HAr), 5.28 (dd, J
= 6.4, 3.2 Hz, 1 H, CHOH), 3.98–3.94 (m, 1 H, 4-H), 3.82–3.80
(m, 1 H, 3-H), 3.16 (dd, J = 11.9, 4.9 Hz, 1 H, 5-Ha), 3.02 (pseudo
dt, J = 9.6, 2.7 Hz, 1 H, 2-H), 2.89 (dd, J = 11.9, 2.8 Hz, 1 H, 5-
Hb), 2.14 (ddd, J = 14.6, 9.6, 3.2 Hz, 1 H, CHHCHOH), 1.88 (ddd,
J = 14.6, 6.4, 3.3 Hz, 1 H, CHHCHOH), 0.89 [s, 9 H, C(CH3)3],
0.79 [s, 9 H, C(CH3)3], 0.08 (s, 3 H, SiCH3), 0.06 (s, 3 H, SiCH3),
0.00 (s, 3 H, SiCH3), –0.07 (s, 3 H, SiCH3) ppm. 13C NMR
(100 MHz): δ = 143.7 (s; CAr), 132.5 (d; CHAr), 128.2 (d; CHAr),
127.9 (d; CHAr), 127.3 (d; CHAr), 121.2 (s; CAr), 84.0 (d; C-3),
79.9 (d; C-4), 71.6 (d; CHOH), 64.4 (d; C-2), 53.2 (t; C-5), 36.2 (t;
CH2CHOH), 25.8 [q; 3 C, C(CH3)3], 25.7 [q; 3 C, C(CH3)3], 17.9
[s; C(CH3)3], 17.8 [s; C(CH3)3], –4.6 (q; SiCH3), –4.67 (q; SiCH3),
CHCl3). H NMR (400 MHz): δ = 7.27 (pseudo d, J = 8.0 Hz, 2
H, HAr), 7.10 (dd, J = 8.4, 7.6 Hz, 1 H, HAr), 5.69 (dd, J = 9.7,
3.2 Hz, 1 H, CHOH), 4.00–3.97 (m, 1 H, 4-H), 3.87–3.84 (m, 1 H,
3-H), 3.24 (pseudo dt, J = 8.7, 3.6 Hz, 1 H, 2-H), 3.11 (dd, J =
11.9, 4.6 Hz, 1 H, 5-Ha), 2.84 (dd, J = 11.9, 2.4 Hz, 1 H, 5-Hb),
2.46 (ddd, J = 14.5, 9.7, 3.8 Hz, 1 H, CHHCHOH), 1.80 (ddd, J
= 14.5, 8.6, 3.1 Hz, 1 H, CHHCHOH), 0.87 [s, 9 H, C(CH3)3], 0.86
[s, 9 H, C(CH3)3], 0.07 (s, 3 H, SiCH3), 0.066 (s, 3 H, SiCH3), 0.058
(s, 3 H, SiCH3), 0.04 (s, 3 H, SiCH3) ppm. 13C NMR (50 MHz): δ
= 138.1 (s; CAr), 134.2 (s; 2 C, CAr), 129.3 (d; 2 C, CHAr), 128.4
(d; CHAr), 83.7 (d; C-3), 79.9 (d; C-4), 70.0 (d; CHOH), 64.6 (d;
C-2), 53.4 (t; C-5), 36.3 (t; CH2CHOH), 25.8 [q; 6 C, C(CH3)3],
18.0 [s; 2 C, C(CH3)3], –4.4 (q; SiCH3), –4.5 (q; 2 C, SiCH3), –4.6
(q; SiCH ) ppm. IR: ν = 3600, 3200 (br), 2954, 2923, 2862, 1582,
˜
3
1562, 1472, 1437, 1258, 1089 cm–1. MS (EI): m/z (%) = 521 (2) [M
+ 2]+, 519 (2) [M]+, 504 (1), 484 (1), 462 (2), 352 (2), 330 (5), 276
(5), 171 (63), 73 (88), 56 (100). C24H43Cl2NO3Si2 (520.68): calcd.
C 55.36, H 8.32, N 2.69; found C 55.04, H 8.05, N 2.62.
–4.71 (q; SiCH ), –4.8 (q; SiCH ) ppm. IR: ν = 3661, 3190, 2930,
˜
3
3
2858, 1471, 1463, 1258, 1088, 1082 cm–1. MS (EI): m/z (%) = 531
(1) [(M + 2)]+, 529 (1) [M]+, 450 (2), 432 (5), 171 (54), 97 (44), 83
(45), 71 (59), 57 (100). C24H44BrNO3Si2 (530.69): calcd. C 54.32,
H 8.36, N 2.64; found C 54.32, H 8.28, N 2.68.
(1R)-1-(2,6-Dichlorophenyl)-2-[(2R,3S,4S)-3,4-bis(tert-butyldimeth-
ylsilyloxy)pyrrolidin-2-yl]ethanol (12b), (1R)-1-(2,6-Dichlorophenyl)-
2-[(2S,3S,4S)-3,4-bis(tert-butyldimethylsilyloxy)pyrrolidin-2-yl]eth-
anol (12c), and (1S)-1-(2,6-Dichlorophenyl)-2-[(2R,3S,4S)-3,4-bis-
(tert-butyldimethylsilyloxy)pyrrolidin-2-yl]ethanol (12d): Following
the same procedure used to prepare 12a, the diastereomeric pyrroli-
dines 12b, 12c and 12d were obtained starting from mixtures of
cycloadducts 9. The diastereomeric pyrrolidines could only par-
tially be separated by chromatography on silica gel.
13b: White solid; m.p. 155–156 °C. [α]2D6 = +46.2 (c = 1.0, CHCl3).
1H NMR (400 MHz): δ = 7.65 (dd, J = 7.8, 1.6 Hz, 1 H, HAr), 7.49
(dd, J = 7.9, 1.2 Hz, 1 H, HAr), 7.33 (pseudo dt, J = 1.2, 7.5 Hz, 1
H, HAr), 7.10 (pseudo dt, J = 1.6, 7.6, Hz, 1 H, HAr), 5.31 (pseudo
t, J = 4.6 Hz, 1 H, CHOH), 3.94 (pseudo dt, J = 4.6, 1.6 Hz, 1 H,
4-H), 3.74 (dd, J = 4.1, 1.6 Hz, 1 H, 3-H), 3.24 (dd, J = 12.4,
4.6 Hz, 1 H, 5-Ha), 3.19 (pseudo dt, J = 11.3, 3.6 Hz, 1 H, 2-H),
2.69 (dd, J = 12.4, 1.6 Hz, 1 H, 5-Hb), 2.11 (ddd, J = 14.7, 11.3,
4.2 Hz, 1 H, CHHCHOH), 1.93 (ddd, J = 14.7, 5.0, 3.1 Hz, 1 H,
CHHCHOH), 0.87 [s, 9 H, C(CH3)3], 0.82 [s, 9 H, C(CH3)3], 0.033
(s, 3 H, SiCH3), 0.031 (s, 3 H, SiCH3), 0.02 (s, 3 H, SiCH3), –0.01
(s, 3 H, SiCH3) ppm. 13C NMR (100 MHz): δ = 143.7 (s; CAr),
132.7 (d; CHAr), 128.3 (d; CHAr), 127.8 (d; CHAr), 127.3 (d; CHAr),
121.4 (s; CAr), 80.4 (d; C-3), 78.4 (d; C-4), 71.5 (d; CHOH), 57.4
(d; C-2), 52.9 (t; C-5), 32.8 (t; CH2CHOH), 25.8 [q; 3 C, C(CH3)
3], 25.7 [q; 3 C, C(CH3)3], 18.0 [s; C(CH3)3], 17.8 [s; C(CH3)3], –4.6
(q; SiCH3), –4.67 (q; SiCH3), –4.68 (q; SiCH3), –4.9 (q, SiCH3)
ppm.
12b (48:3:1 mixture with 12d and 12c): M.p. 119–120 °C. [α]2D6
=
1
–0.84 (c = 1.0, CHCl3). H NMR (400 MHz): δ = 7.27 (pseudo d,
J = 8.1 Hz, 2 H, HAr), 7.11 (dd, J = 8.5, 7.6 Hz, 1 H, HAr), 5.64
(dd, J = 8.3, 5.0 Hz, 1 H, CHOH), 4.02 (pseudo dt, J = 4.9, 1.3 Hz,
1 H, 4-H), 3.91 (dd, J = 3.3, 1.3 Hz, 1 H, 3-H), 3.50–3.45 (m, 1 H,
2-H), 3.36 (dd, J = 12.2, 4.9 Hz, 1 H, 5-Ha), 3.38–2.87 (br. s, 2 H,
NH, OH) 2.75 (dd, J = 12.2, 1.3 Hz, 1 H, 5-Hb), 2.32 (ddd, J =
14.3, 8.3, 4.7 Hz, 1 H, CHHCHOH), 2.01 (ddd, J = 14.3, 9.3,
5.0 Hz, 1 H, CHHCHOH), 0.87 [s, 9 H, C(CH3)3], 0.86 [s, 9 H,
C(CH3)3], 0.09 (s, 3 H, SiCH3), 0.06 (s, 6 H, SiCH3), 0.05 (s, 3 H,
SiCH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.0 (s; CAr),
134.4 (s; 2 C, CAr), 129.4 (d; 2 C, CHAr), 128.6 (d; CHAr), 79.8
(d; C-3), 78.2 (d; C-4), 70.0 (d; CHOH), 58.4 (d; C-2), 53.2 (t; C-5),
33.7 (t; CH2CHOH), 25.8 [q; 3 C, C(CH3)3], 25.7 [q; 3 C, C(CH3)3],
18.0 [s; C(CH3)3], 17.9 [s; C(CH3)3], –4.4 (q; SiCH3), –4.6 (q;
SiCH3), –4.7 (q; SiCH3), –4.8 (q; SiCH3) ppm.
(1S)- and (1R)-1-(2-Bromophenyl)-2-[(2S,3S,4S)-3,4-di-tert-butoxy-
pyrrolidin-2-yl]ethanol (14a and 14c): A 6.7:1 mixture of isoxazolid-
ines 11a and 11c (686 mg, 1.66 mmol) and zinc powder (544 mg,
8.32 mmol) in AcOH:H2O = 9:1 (15.9 mL) was heated in an oil
bath at 80 °C for 5 h and then diluted with MeOH and filtered
through cotton wool. The filtrate was concentrated under reduced
pressure, the residue was dissolved in CH2Cl2, and the solution was
basified to pH = 9 with a saturated aq. NaHCO3 solution and
solid Na2CO3 at 0 °C. The resulting suspension was sequentially
extracted with CH2Cl2 (3ϫ 30 mL) and EtOAc (2ϫ 30 mL). The
combined organic phases were washed with brine (50 mL), dried
12c: (1:1.2:0.2 mixture with 12b and 12a): 1H NMR (400 MHz,
discernible signals): δ = 3.79–3.77 (m, 1 H, 3-H), 3.34 (dd, J = 12.4,
5.5 Hz, 1 H, 5-Ha), 2.97 (dd, J = 12.4, 2.9 Hz, 1 H, 5-Hb), 2.64
(pseudo dt, J = 14.4, 11.4 Hz, 1 H, CHHCHOH), 1.65 (pseudo dt,
J = 14.4, 3.0 Hz, 1 H, CHHCHOH) ppm.
12d: (1.3:1 mixture with 12b): 1H NMR (400 MHz, discernible sig-
nals): δ = 5.71 (dd, J = 10.8, J = 2.9 Hz, 1 H, CHOH), 3.37 (dd, J
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O30440
/KAP1
Date: 17-06-13 16:42:14
Pages: 9
F. M. Cordero, A. Brandi et al.
FULL PAPER
with Na2SO4, filtered and concentrated under reduced pressure.
Filtration on silica gel [eluent: CH2Cl2/MeOH (1% NH4OH) 95:5]
afforded a 6.2:1 mixture of pyrrolidines 14a and 14c in 96% yield
(658 mg) as a yellow viscous oil.
pressure. Purification by chromatography on silica gel (eluent: pe-
troleum ether/EtOAc, 20:1) afforded 18a in 30% yield (18 mg) as a
white solid.
Method B: Degassed DMF (0.3 mL) was added to a mixture of 13a
(100 mg, 0.19 mmol), CuI (4.5 mg, 0.024 mmol), copper powder
(14 mg, 0.22 mmol), K3PO4 (81 mg, 0.38 mmol), and l-proline
(4.7 mg, 0.04 mmol) under nitrogen atmosphere. The reaction mix-
ture was heated at 100 °C for 48 h in an oil bath and then concen-
trated. The crude product was dissolved in CH2Cl2, filtered through
a short pad of Celite®/Na2SO4 and concentrated under reduced
pressure. Purification by chromatography on silica gel afforded 18a
in 37% yield (31 mg) as a white solid.
14a: (6.2:1 mixture with 14c): Rf = 0.20. [α]2D5 = –15.1 (c = 0.6,
CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.66 (dd, J = 7.8,
1.7 Hz, 1 H, HAr), 7.48 (dd, J = 7.9, 1.2 Hz, 1 H, HAr), 7.33 (pseudo
dt, J = 1.2, 7.5 Hz, 1 H, HAr), 7.09 (pseudo dt, J = 1.7, 7.6 Hz, 1
H, HAr), 5.31 (dd, J = 5.9, 3.5 Hz, 1 H, CHOH), 4.94–4.15 (br. s,
2 H, NH, OH) 3.85–3.80 (m, 1 H, 4-H), 3.66 (pseudo t, J = 2.2 Hz,
1 H, 3-H), 3.16 (dd, J = 12.1, 5.6 Hz, 1 H, 5-Ha), 3.03 (pseudo dt,
J = 10.2, 2.7 Hz, 1 H, 2-H), 2.92 (dd, J = 12.1, 4.3 Hz, 1 H, 5-Hb),
2.21 (ddd, J = 14.7, 10.2, 3.5 Hz, 1 H, CHHCHOH), 1.96 (ddd, J
= 14.7, 5.9, 3.2 Hz, 1 H, CHHCHOH), 1.18 (s, 9 H, CH3 ϫ3), 1.06
(s, 9 H, CH3 ϫ3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 143.5 (s;
Method C: Degassed tBuOH/H2O (1:1, 0.6 mL) and THF
(0.15 mL) were added to a mixture of 13a (22 mg, 0.04 mmol), CuI
(2.4 mg, 0.013 mmol), copper powder (1.0 mg, 0.015 mmol),
K3PO4 (17 mg, 0.08 mmol), and l-proline (2.8 mg, 0.024 mmol) un-
der nitrogen atmosphere in a microwave vial. The reaction mixture
was heated at 100 °C for 5 h in the MW and then filtered through a
short pad of Celite®/Na2SO4. The solution was concentrated under
reduced pressure. Purification by chromatography on silica gel af-
forded 18a in 46% yield (8 mg) as a white solid.
CAr), 132.5 (d; CHAr), 128.2 (d; CHAr), 128.1 (d; CHAr), 127.3 (d;
CHAr), 121.1 (s; CAr), 83.1 (d; C-3), 79.2 (d; C-4), 73.9 (s; Me3CO),
73.8 (s; Me3CO), 71.8 (d; CHOH), 63.0 (d; C-2), 52.3 (t; C-5), 34.8
(t; CH2CHOH), 28.6 (q; 3 C, CH3), 28.5 (q; 3 C, CH3) ppm. IR
(CDCl ): ν = 3500–2500 (br), 3068, 2979, 2934, 2873, 1464, 1391,
˜
3
1365, 1235, 1191, 1071, 1023 cm–1. MS (EI): m/z (%) = 415 (1) [(M
+ 2)]+, 413 (1) [M]+, 358 (1), 356 (1), 342 (1), 340 (1), 334 (1), 260
(5), 228 (3), 187 (5), 185 (6), 148 (9), 116 (34), 98 (12), 57 (100).
18a: Rf = 0.45 (petroleum ether/EtOAc, 9:1); m.p. 142–144 °C.
[α]2D4 = +67.2 (c = 1.0, CHCl3). 1H NMR (400 MHz): δ = 7.38
(pseudo dt, J = 7.6, 1.2 Hz, 1 H, 6-H), 7.12 (dt, J = 8.1, 7.3, 1.5,
0.6 Hz, 1 H, 8-H), 6.67 (pseudo dt, J = 0.8, 7.4 Hz, 1 H, 7-H), 6.30
(dd, J = 8.1, 0.8 Hz, 1 H, 9-H), 4.86 (br. ddd, J = 11.0, 8.8, 5.5 Hz,
1 H, 5-H), 4.23 (pseudo dt, J = 7.7, 6.7 Hz, 1 H, 2-H), 3.78 (dd, J
= 8.0, 6.7 Hz, 1 H, 3-H), 3.51 (dd, J = 9.4, 7.7 Hz, 1 H, 1-Ha),
3.38 (ddd, J = 11.9, 8.0, 3.0 Hz, 1 H, 3a-H), 3.01 (dd, J = 9.4,
6.7 Hz, 1 H, 1-Hb), 2.47 (ddd, J = 11.5, 5.5, 3.0 Hz, 1 H, 4-Ha),
1.71 (d, J = 8.8 Hz, 1 H, OH), 1.58 (pseudo q, J = 11.5 Hz, 1 H,
4-Hb), 0.92 [s, 9 H, C(CH3)3], 0.91 [s, 9 H, C(CH3)3], 0.14 (s, 3 H,
SiCH3), 0.12 (s, 3 H, SiCH3), 0.11 (s, 3 H, SiCH3), 0.10 (s, 3 H,
SiCH3) ppm. 13C NMR (100 MHz): δ = 143.2 (s; CAr), 128.6 (d;
C-8), 125.3 (d; C-6), 124.7 (s; CAr), 115.9 (d; C-7), 109.4 (d; C-9),
1
14c: (6.2:1 mixture of 14a/14c): H NMR (CDCl3, 400 MHz, dis-
cernible signals): δ = 5.13 (dd, J = 10.2, 1.1 Hz, 1 H, CHOH), 3.87
(pseudo dt, J = 2.3, 5.9 Hz, 1 H, 4-H), 3.60 (pseudo t, J = 2.2 Hz,
1 H, 3-H), 3.35 (pseudo dt, J = 12.1, 2.2 Hz, 1 H, 2-H), 3.24 (dd,
J = 12.6, 6.4 Hz, 1 H, 5-Ha), 2.83 (dd, J = 12.6, 5.5 Hz, 1 H, 5-
Hb), 1.69–1.58 (m, 1 H, CHHCHOH), 1.19 (s, 9 H, CH3 ϫ3), 1.15
(s, 9 H, CH3 ϫ3) ppm. 13C NMR (CDCl3, 100 MHz, discernible
signals): δ = 143.8 (s; CAr), 132.3 (d; CHAr), 128.2 (d; CHAr), 127.6
(d; CHAr), 127.5 (d; CHAr), 121.4 (s; CAr), 84.1 (d; C-3), 79.9 (d;
C-4), 74.1 (s; Me3CO), 73.9 (d; CHOH), 73.6 (s; Me3CO), 66.5 (d;
C-2), 52.2 (t; C-5), 37.0 (t; CH2CHOH), 28.7 (q; 3 C, CH3), 28.5
(q; 3 C, CH3) ppm.
(1R)-1-(2-Bromophenyl)-2-[(2R,3S,4S)-3,4-di-tert-butoxypyrrolidin- 82.2 (d; C-3), 76.6 (d; C-2), 67.1 (d; C-5), 59.5 (d; C-3a), 52.2 (t;
2-yl]ethanol (14b): Following the same procedure used to prepare
14a, the diastereomeric pyrrolidine 14b was obtained starting from
a mixture of cycloadducts 11b and 11d.
C-1), 35.8 (t; C-4), 25.9 [q; 3 C, C(CH3)3], 25.8 [q; 3 C, C(CH3)3],
18.0 [s; C(CH3)3], 17.9 [s; C(CH3)3], –3.8 (q; SiCH3), –4.2 (q;
SiCH ), –4.4 (q; SiCH ), –4.5 (q, SiCH ) ppm. IR: ν = 3586, 2955,
˜
3
3
3
2929, 2857, 1605, 1500, 1472, 1462, 1259, 1156, 1113 cm–1. MS
(EI): m/z (%) = 449 (65) [M]+, 434 (2), 430 (7), 392 (12), 374 (10),
168 (56), 161 (69), 143 (48), 132 (19), 73 (100). C24H43NO3Si2
(449.77): calcd. C 64.09, H 9.64, N 3.11; found C 64.48, H 9.36, N
2.76.
1
14b: H NMR (CDCl3, 400 MHz): δ = 7.64 (dd, J = 7.7, 1.7 Hz, 1
H, HAr), 7.48 (dd, J = 7.9, 1.2 Hz, 1 H, HAr), 7.33 (pseudo dt, J =
1.2, 7.6 Hz, 1 H, HAr), 7.09 (pseudo dt, J = 1.7, 7.7 Hz, 1 H, HAr),
5.29 (pseudo t, J = 4.3 Hz, 1 H, CHOH), 4.20–2.92 (br. s, 2 H,
NH, OH) 3.87 (pseudo dt, J = 6.2, 3.5 Hz, 1 H, 4-H), 3.64 (dd, J
= 5.7, 3.6 Hz, 1 H, 3-H), 3.26 (dd, J = 12.5, 6.2 Hz, 1 H, 5-Ha),
3.06 (pseudo dt, J = 9.4, 5.4 Hz, 1 H, 2-H), 2.66 (dd, J = 12.5,
3.4 Hz, 1 H, 5-Hb), 2.06–2.00 (m, 2 H, CH2CHOH), 1.14 (s, 9 H,
CH3 ϫ 3), 1.08 (s, 9 H, CH3 ϫ 3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 143.8 (s; CAr), 132.6 (d; CHAr), 128.2 (d; CHAr),
(2S,3S,3aS,5S)-2,3-Di-tert-butoxy-1,2,3,3a,4,5-hexahydropyrrolo-
[1,2-a]quinolin-5-ol (19a): The mixed solvent tBuOH/H2O (1:1,
3 mL) was added to a mixture of 14a/14c (103 mg, 0.248 mmol of
14a and 14 mg of 14c), CuI (23.6 mg, 0.124 mmol), copper powder
(7.9 mg, 0.124 mmol), K3PO4 (105.5 mg, 0.497 mmol) and l-pro-
128.0 (d; CHAr), 127.2 (d; CHAr), 121.2 (s; CAr), 80.0 (d; C-3), 77.9 line (28.6 mg, 0.248 mmol) under nitrogen atmosphere in a vial.
(d; C-4), 73.7 (s; Me3CO), 73.5 (s; Me3CO), 72.1 (d; CHOH), 56.8 Nitrogen was bubbled through the reaction mixture to remove oxy-
(d; C-2), 51.8 (t; C-5), 31.8 (t; CH2CHOH), 28.6 (q; 3 C, CH3), gen. The reaction mixture was heated at 90 °C in an oil bath for
28.3 (q; 3 C, CH3) ppm.
12 h and then was filtered through a small pad of Celite®. The
solution was diluted with H2O and sequentially extracted with
CH2Cl2 (3ϫ 20 mL) and EtOAc (2ϫ 20 mL). The combined or-
ganic phases were washed with NH4OH (1% H2O solution) and
brine, dried with Na2SO4, filtered and concentrated under reduced
pressure. Purification by flash chromatography on silica gel [eluent:
CH2Cl2/MeOH (1 % NH4OH) 98:2] afforded 19a in 74 % yield
(61.2 mg) as a white solid.
(2S,3S,3aS,5S)-2,3-Bis(tert-butyldimethylsilyloxy)-1,2,3,3a,4,5-
hexahydropyrrolo[1,2-a]quinolin-5-ol (18a). Method A: DBU (40 μL,
0.267 mmol) and degassed tBuOH (2.6 mL) were added to a mix-
ture of 13a (69.8 mg, 0.132 mmol), CuI (2.5 mg, 0.013 mmol), cop-
per powder (1.0 mg, 0.015 mmol) and l-proline (3.0 mg,
0.026 mmol) under nitrogen atmosphere in a microwave vial. The
reaction mixture was heated at 100 °C for 10 h in the MW and then
concentrated. The crude product was dissolved in CHCl3, filtered
through a short pad of Celite® and concentrated under reduced
19a: Rf = 0.42; m.p. 167–169 °C. [α]2D3 = +151.76 (c = 0.42, CHCl3).
1H NMR (CDCl3, 400 MHz): δ = 7.38 (pseudo dt, J = 7.5, 1.3 Hz,
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O30440
/KAP1
Date: 17-06-13 16:42:14
Pages: 9
Hydroxylated Benzo[e]indolizidine Synthesis
1 H, 6-H); 7.12 (dddd, J = 8.1, 7.4, 1.5, 0.6 Hz, 1 H, 8-H), 6.67
(pseudo dt, J = 0.9, 7.4 Hz, 1 H, 7-H), 6.31 (dd, J = 8.1, 0.9 Hz, 1
H, 9-H), 4.92–4.82 (m, 1 H, 5-H), 4.09–4.03 (m, 1 H, 2-H), 3.74
(dd, J = 8.6, 7.2 Hz, 1 H, 3-H), 3.45 (dd, J = 9.6, 7.9 Hz, 1 H, 1-
Ha), 3.33 (ddd, J = 11.8, 8.6, 2.8 Hz, 1 H, 3a-H), 3.04 (dd, J = 9.6,
6.5 Hz, 1 H, 1-Hb), 2.56 (ddd, J = 11.5, 5.7, 2.8 Hz, 1 H, 4-Ha),
1.73 (br. d, J = 7.9 Hz, 1 H, OH), 1.59 (pseudo q, J = 11.5 Hz, 1
H, 4-Hb) 1.26 (s, 9 H, CH3 ϫ3), 1.24 (s, 9 H, CH3 ϫ3) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 143.4 (s; CAr), 128.6 (d; C-8), 125.5
(d; C-6), 124.8 (s; CAr), 115.9 (d; C-7), 109.5 (d; C-9), 80.3 (d; C-
3), 75.2 (d; C-2), 74.3 (s; Me3CO), 73.9 (s; Me3CO), 67.2 (d; C-5),
57.9 (d; C-3a), 52.1 (t; C-1), 35.9 (t; C-4), 29.4 (q; 3 C, CH3), 28.6
[1]
a) E. Borgesde Melo, A. da Silveira Gomes, I. Carvalho, Tetra-
hedron 2006, 62, 10277–10302; b) N. Asano, Glycobiology 2003,
13, 93R–104R; c) N. Asano, R. J. Nash, R. J. Molyneux,
G. W. J. Fleet, Tetrahedron: Asymmetry 2000, 11, 1645–1680; d)
P. Compain, O. Martin, Iminosugars: From Synthesis to Thera-
peutic Applications; John Wiley & Sons, New York, 2007.
L. A. Sorbera, J. Castañer, L. García-Capdevila, Drugs Future
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F. Dal Piaz, A. Vassallo, M. G. Chini, F. M. Cordero, F. Car-
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a) B. Macchi, A. Minutolo, S. Grelli, F. Cardona, F. M.
Cordero, A. Mastino, A. Brandi, Glycobiology 2010, 20, 500–
506; b) A. Minutolo, S. Grelli, F. Marino-Merlo, F. M.
Cordero, A. Brandi, B. Macchi, A. Mastino, Cell Death Dis-
ease 2012, 3, e358.
F. M. Cordero, P. Bonanno, B. B. Khairnar, F. Cardona, A.
Brandi, B. Macchi, A. Minutolo, S. Grelli, A. Mastino, Chem-
PlusChem 2012, 77, 224–233.
a) F. M. Cordero, P. Bonanno, S. Neudeck, C. Vurchio, A.
Brandi, Adv. Synth. Catal. 2009, 351, 1155–1161; b) F. M.
Cordero, P. Bonanno, M. Chioccioli, P. Gratteri, I. Robina,
A. J. Moreno Vargas, A. Brandi, Tetrahedron 2011, 67, 9555–
9564.
a) A. Kotland, F. Accadbled, K. Robeyns, J.-B. Behr, J. Org.
Chem. 2011, 76, 4094–4098; b) J.-K. Su, Y.-M. Jia, R. He, P.-
X. Rui, N. Han, X. He, J. Xiang, X. Chen, J. Zhu, C.-Y. Yu,
Synlett 2010, 1609–1616.
[2]
[3]
[4]
(q; 3 C, CH ) ppm. IR (CDCl ): ν = 3619, 3587, 3069, 3043, 2934,
˜
3
3
2977, 2934, 1605, 1497, 1462, 1364, 1193, 1091 cm–1. MS (EI): m/z
(%) = 333 (21) [M]+, 314 (1), 276 (12), 258 (5), 220 (2), 202 (22),
186 (4), 161 (13), 130 (10), 71 (14), 69 (15), 57 (100). C20H31NO3
(333.4): calcd. C 72.04, H 9.37, N 4.20; found C 71.79, H 9.75, N
4.40.
[5]
[6]
(2R,3R,3aR,5R)-2,3-Di-tert-butoxy-1,2,3,3a,4,5-hexahydropyrrolo-
[1,2-a]quinolin-5-ol (ent-19a): Following the same procedure as for
19a, the enantiomeric trihydroxy-benzo[e]indolizidine ent-19a was
prepared starting from 8 and nitrone ent-6.
(2S,3S,3aS,5S)-1,2,3,3a,4,5-Hexahydropyrrolo[1,2-a]quinoline-
2,3,5-triol (20): A 1 m solution of tetrabutlyammonium fluoride
(TBAF) in THF (0.26 mL, 0.26 mmol) was added to a solution of
18a (26 mg, 0.057 mmol) in dry THF (3 mL). The reaction mixture
was stirred overnight at room temp. under nitrogen atmosphere and
then concentrated under reduced pressure. Purification of the crude
product by flash chromatography on silica gel [eluent: CH2Cl2/
MeOH (1% NH4OH) 9:1] afforded 20 in 36% yield (5 mg) as a
white solid.
[7]
[8]
A. Goti, F. Cardona, A. Brandi, S. Picasso, P. Vogel, Tetrahe-
dron: Asymmetry 1996, 7, 1659–1674.
[9] Nitrone 5 was synthesized following the procedure reported in
ref.[8] except for the last step, where the more environmentally
friendly Oxone® was used as the oxidant instead of H2O2/SeO2
cat (see the Exp. Sect. and ref.[15]).
20: Rf = 0.25; m.p. 161–163 °C (dec.). [α]2D5 = +85.06 (c = 0.45,
1
MeOH); H NMR (CD3OD, 400 MHz): δ = 7.31 (pseudo dt, J =
[10] Only traces (Ͻ1%) of endo-(3-OtBu)-syn-11d were detected af-
7.6, 1.3 Hz, 1 H, 6-H); 7.05–7.00 (m, 1 H, 8-H), 6.59 (pseudo dt, J
= 0.9, 7.5 Hz, 1 H, 7-H), 6.30 (dd, J = 8.1, 0.9 Hz, 1 H, 9-H), 4.79
(br. dd, J = 11.4, 5.5 Hz, 1 H, 5-H), 4.20 (pseudo dt, J = 7.9,
6.9 Hz, 1 H, 2-H), 3.66 (dd, J = 8.3, 7.1 Hz, 1 H, 3-H), 3.53 (dd,
J = 9.7, 7.9 Hz, 1 H, 1-Ha), 3.56–3.29 (m, 1 H, 3a-H), 3.02 (dd, J
= 9.7, 6.7 Hz, 1 H, 1-Hb), 2.46 (ddd, J = 11.6, 5.5, 2.9 Hz, 1 H, 4-
Ha), 1.58 (pseudo q, J = 11.6 Hz, 1 H, 4-Hb) ppm. 13C NMR
(CD3OD, 100 MHz): δ = 144.8 (s; CAr), 129.2 (d; C-6), 126.6 (d;
C-8), 126.4 (s; CAr), 116.9 (d; C-7), 110.6 (d; C-9), 82.8 (d; C-3),
76.6 (d; C-2), 67.5 (d; C-5), 61.3 (d; C-3a), 52.8 (t; C-1), 36.4 (t; C-
4) ppm.
ter chromatographic separation.
[11] J. P. Wolfe, R. A. Rennels, S. L. Buchwald, Tetrahedron 1996,
52, 7525–7546.
[12] R. Omar-Amrani, A. Thomas, E. Brenner, R. Schneider, Y.
Fort, Org. Lett. 2003, 5, 2311–2314.
[13] For selected reviews, see: a) S. V. Ley, A. W. Thomas, Angew.
Chem. 2003, 115, 5558; Angew. Chem. Int. Ed. 2003, 42, 5400–
5449; b) K. Kunz, U. Scholz, D. Ganzer, Synlett 2003, 15,
2428–2439; c) I. P. Beletskaya, A. V. Cheprakov, Coord. Chem.
Rev. 2004, 248, 2337–2364; d) D. Ma, Q. Cai, Acc. Chem. Res.
2008, 41, 1450–1460; e) F. Monnier, M. Taillefer, Angew. Chem.
2009, 121, 7088; Angew. Chem. Int. Ed. 2009, 48, 6954–6971;
f) G. Evano, M. Toumib, A. Costea, Chem. Commun. 2009,
4166–4175.
Supporting Information (see footnote on the first page of this arti-
cle): Diagnostic NOE interactions in compounds 12a–14a, 12b–14b
1
and 19a; copies of the H NMR and 13C NMR spectra.
[14] Z. P. Tan, L. Wang, J. B. Wang, Chin. Chem. Lett. 2000, 11,
753–756.
[15] C. Gella, È. Ferrer, R. Alibés, F. Busqué, P. de March, M. Fig-
ueredo, J. Font, J. Org. Chem. 2009, 74, 6365–6367.
Received: March 25, 2013
Acknowledgments
The authors thank the Italian Ministry of University and Research
(MIUR) for financial support (PRIN20109Z2XRJ)
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9