Stereoselective tetrahydropyrido[2,1-a]isoindolone synthesis via carbanionic and radical intermediates: A model study for the Tacaman alkaloid D/E ring fusion

Article abstract of DOI:10.1016/S0040-4039(00)00485-8

Stereoselective cyclisation of malic acid-derived α-sulfanyllactam (1) via radical and carbanionic intermediates affords stereo-defined tetrahydropyrido[2,1-a]isoindolones as model compounds for the D/E cis-ring fusion of the Tacaman indole alkaloid skele

Full text of DOI:10.1016/S0040-4039(00)00485-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3755–3758
Stereoselective tetrahydropyrido[2,1-a]isoindolone synthesis via
carbanionic and radical intermediates: a model study for the
Tacaman alkaloid D/E ring fusion
Roger Hunter ∗ and Philip Richards
Department of Chemistry, University of Cape Town, Rondebosch 7701, Cape Town, South Africa
Received 22 February 2000; accepted 21 March 2000
Abstract
Stereoselective cyclisation of malic acid-derived α-sulfanyllactam (1) via radical and carbanionic intermediates
affords stereo-defined tetrahydropyrido[2,1-a]isoindolones as model compounds for the D/E cis-ring fusion of the
Tacaman indole alkaloid skeleton. A transition-state model to explain the stereoselectivity is presented. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: radical and carbanionic cyclisation; indole alkaloid; isoindolone synthesis.
The isoindolone ring system has featured in recent years as a desirable synthetic target in view of
its presence in both natural products and synthetic pharmaceuticals with biological activity.1 Synthetic
methodology for C–C bond formation at the isoindolone benzylic position has been dominated by
procedures based on the nucleophilic interception of iminium ions,1c,2 while carbanionic and radical
approaches have received far less attention. We recently reported on the stereoselective formation
of a substituted tetrahydropyrido[2,1-a]isoindolone via intramolecular cyclisation of a benzylic α-
benzoylamino radical onto an enoate ester, and this was used as a model for synthesising the Tacaman
indole alkaloid D/E ring system.3 In the latter study, a D-ribose-derived cis-isopropylidene grouping in
the tether was used as the stereo-directing auxiliary to afford an incorrect trans D/E ring fusion for the
Tacaman system.4 We have now extended our original study by synthesising precursor (1) in which the
tether is derived from L-malic acid, and in this communication we report on stereoselective cyclisation
of (1) via both radical and carbanionic intermediates to afford model compounds with the desired cis-
stereochemistry (Fig. 1).
The synthesis of the cyclisation precursor (1) proceeded from L-malic acid as follows. Fischer
esterification followed by chemoselective reduction according to literature procedures5 furnished diol (2),
which was protected as its ketal, and its ester reduced to the known alcohol (3).5,6 Mitsunobu coupling
with phthalimide, hydrolysis (ketal) and chemoselective disilylation gave (4). Routine conversion of (4)
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00485-8
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Fig. 1.
(TBS removal, Swern oxidation, Wittig) yielded exclusively the (E)-enoate ester (5). Chemoselective
reduction of the imide (NaBH4) followed by Lewis acid-promoted sulfenylation with thiophenol at low
temperature afforded (1) in good overall yield for the 13 steps (Scheme 1).
Scheme 1. Reagents and conditions: (iii) (CH3)2C(OMe)2/p-TsOH; (iv) LiAlH4/THF; (v) phthalimide/PPh3/DEAD/THF
(94%); (vi) HCl (1 M)/THF/∆ (85%); (vii) TBSCl/imidazole/CH2Cl2 (97%); (viii) TBDPSCl/imid/CH2Cl2/DMF; (ix) HF
(40%)/CH3CN (89% for two steps); (x) Swern; (xi) Ph3PCHCO2Et/CH2Cl2 (96% for two steps); (xii) NaBH4/THF/−40°C
(92%); (xiii) PhSH (2 equiv.)/BF3·Et2O (2 equiv.)/CH2Cl2/−78°C (92% as two epimers)
Cyclisation of α-acylamino radicals was introduced in the 1980s and pioneered by Hart and co-
workers as a versatile methodology for rapid construction of pyrrolizidine and indolizidine nitracycles.7
Exposure of (1) to standard radical cyclisation8 conditions (Bu3SnH/AIBN (cat.)/toluene/∆) resulted in
rapid conversion to a more polar product which was isolated by chromatography in near quantitative
yield (97%). Scrutiny of this product by 400 MHz 1H NMR revealed it to be an inseparable mixture of
three diastereomers in an approximate ratio of 4:2:1. Treatment of the mixture with tetrabutylammonium
fluoride (TBAF) in THF furnished the desilylated alcohol (6) in 55% yield over the two steps as the
dominant diastereomer and in crystalline form. The stereochemical assignments at the newly formed
asymmetric centres at C-1 and C-10b were made on the basis of the two small vicinal coupling constants
between C-1 and its neighbours, C-2 (3.2 Hz) and C-10b (4 Hz), indicating gauche relationships. Since a
pseudo-axial configuration for the hydrogen at C-10b is obligatory, it followed that the hydrogens at C-1
and C-10b were cis. Failure of (6) to form a lactone under the TBAF conditions (see carbanionic case)
resulted in the ethoxycarbonylmethyl substituent being assigned as β- (Scheme 2).
Scheme 2. Reagents and conditions: (i) Bu3SnH (3 equiv.)/AIBN (cat.)/toluene/∆; (ii) TBAF/THF (55% as major diastereomer)
We next examined carbanionic-promoted cyclisation,9 which was prompted, in part, by the observation
that such a process could be brought about by TBAF. In this case the diastereoselectivity was only

3757
modest so we opted for a lower temperature using a stronger base. Furthermore, during the course of
the present study Luzzio10 published his results on a very similar system to ours that lacked the chiral
auxiliary (OTBDPS group) as well as having phenylsulfonyl in place of phenylsulfanyl. The Luzzio study
utilised NaH/DMSO at rt as the base to afford a modest overall yield (50% for two steps) of product
as a 1:1 mixture of diastereomers following desulfonylation. Gratifyingly, addition of (1) to LDA (3
equiv.) in THF at −78°C promoted a highly diastereoselective closure producing the two anti-isomers
(7) and (8) in 77 and 18% yield, respectively, after column chromatography. Once again, assignment
of stereochemistry was based on vicinal coupling constants and the assumption that the phenylsulfanyl
group adopts a pseudo-axial configuration in view of the requirement for the N–C and C–C attachment
bonds of the five-membered ring to be virtually coplanar (Scheme 3).
Scheme 3. Reagents and conditions: (i) LDA (3 equiv.)/THF/−78°C; (7):(8)=77:18
Reductive desulfurisation of the major diastereomer (7) using nickel boride11 afforded isoindolone (9)
in high yield (92%) and with retention of configuration at C-10b, thus offering a complementary route to
the alternative diastereomer in which the C-1 and C-10b hydrogens are cis. Desilylation of (9) afforded
lactone (10), thus vindicating the configurational assignments of the C-1 substituents in compounds (6)
and (7) (Scheme 4).
Scheme 4. Reagents and conditions: (i) NiCl2/NaBH4/aq. EtOH, 92%; (ii) HF (40%)/CH3CN, 90%
A transition-state model to account for the diastereoselectivity of formation of the major diastereomers
(6) and (7) from the two methodologies identifies two orientational features. Firstly, in both cases the
enoate ester adopts an endo orientation with respect to the new ring being formed. Secondly, the facial
approaches are opposite; in the radical reaction the sterically unencumbered radical at C-10b approaches
the enoate ester from its underneath face proximal to the chiral auxiliary (OTBDPS group and α-),
whereas the more congested carbanion is forced to approach from the top face so as to minimise steric
strain between groups around sulfur and silicon (Fig. 2).
Fig. 2.
Research is in progress on the application of these findings to alkaloid synthesis.

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Acknowledgements
We thank the National Research Foundation, Pretoria for research funding.
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