Stereoselective tetrapyrido[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:10.1039/b303031h

Cyclization under both radical and carbanionic conditions of N-substituted 3-phenylsulfanylisoindolin-1-one 14 containing a chiral N-tether incorporating an enoate ester as the acceptor leads to tetrahydropyrido[2,1-a]isoindolones stereoselectively. The m

Full text of DOI:10.1039/b303031h

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Stereoselective tetrapyrido[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. E-mail: Roger@science.uct.ac.za; Fax: ϩ27(21) 6897499;
Tel: ϩ27(21) 6502544
Received 20th March 2003, Accepted 6th May 2003
First published as an Advance Article on the web 27th May 2003
Cyclization under both radical and carbanionic conditions of N-substituted 3-phenylsulfanylisoindolin-1-one
14 containing a chiral N-tether incorporating an enoate ester as the acceptor leads to tetrahydropyrido[2,1-a]-
isoindolones stereoselectively. The major product 17 from carbanionic cyclization was stereoselectively
desulfurized with nickel boride allowing correlation of cyclization products from both methodologies.
The cyclization stereoselectivities have been rationalised using a transition-state model in which the acceptor
grouping adopts a pseudoaxial configuration. This contrasts with other 6-exo-trig processes in which a
pseudoequatorial configuration is normally adopted, and has been attributed to the steric influence imposed
by the bulky tert-butyldiphenylsilyloxy chiral auxiliary allylic to the enoate ester. The product stereochemistries
provide models for the required cis-stereochemistry of the D/E ring fusion of the Tacaman alkaloid skeleton
via the relatively unexplored C-3-C-14 bond disconnection.
protocol6 or using Pd() chemistry.7 In the second, and
Introduction
arguably more commonly encountered approach, 3-substi-
tution is carried out on an existing five-membered ring such as a
phthalimide8 or phthalimidine derivative. Regarding the latter,
both carbanionic9 and carbocationic10 (acyliminium) inter-
mediates have received widespread attention. By comparison,
radical-based approaches,11 have received far less attention.
Recently we reported12 that a seemingly stable, and thus poorly
reactive benzyl radical with a chiral N-tethered chain bearing
an enoate acceptor chain underwent stereoselective radical
cyclization to afford a substituted tetrahydropyrido[2,1-a]-
isoindolone. The reaction was used as a model for the Tacaman
alkaloid ring system in which the desired cis-D/E ring junction
stereochemistry was achieved using a single allylic stereogenic
centre. The cyclization was also extended to the carbanion
generated from the α-sulfanyl lactam with LDA. In this paper
we disclose details of these reactions as well as the scope for
extending these ideas to construction of benzylic tertiary aza
centres (Fig. 1).
The 3-substituted 2,3-dihydro-1H-isoindol-1-one structural
unit 1 (= 3-substituted isoindolinone or phthalimidine) is a
common motif found in both natural products and synthetic
pharmaceuticals with biological activity, with examples includ-
ing the anxiolytic pazinaclone 2,1 the non-nucleoside HIV-
reverse transcriptase inhibitor 32 and the 5-HT antagonist 4.3
Fig. 1 Tacamonine and the radical cyclization precursor.
Methodologies for the synthesis of 1 generally4 fall into two
categories. The first entails construction of the five-membered
ring from a suitably functionalised benzenoid precursor with
concomitant incorporation of the 3-substituent, and the most
popular strategy for this involves aryl–benzylic connection
via an organometallic intermediate,5 such as in the Parham
Results and discussion
In the original study,13 the chiral tether was derived from
-ribose. The two stereogenic centres were cis-allylic and
homoallylic to the enoate ester in the six-membered pseudo-
chair transition state, and were considered to have opposing
effects in controlling which chair conformation predominated.
It was thus rationalised that a desirable cyclization precursor to
study was one involving a single allylic stereogenic centre in the
tether, and retrosynthetic analysis revealed malic acid to be an
† Electronic supplementary information (ESI) available: Experimental
details for compounds 21–23. See http://www.rsc.org/suppdata/ob/b3/
b303031h/
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 4 8 – 2 3 5 6
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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appropriate starting material for its synthesis. Choice of
starting material was further influenced by the availability of
methodology for elegant chemodifferentiation of the two carb-
oxyl functionalities via an assisted reduction developed by Saito
et al.14 To that end, treatment of dimethyl malate with borane
dimethyl sulfide together with catalytic borohydride furnished a
dihydroxy ester which was protected as its ketal and reduced
with lithium aluminium hydride to the known alcohol 5.14
Mitsunobu reaction of 5 with phthalimide to 6 followed by
conventional ketal hydrolysis to 7 and chemoselective disilyl-
ation gave 9 via the mono tert-butyldimethylsilyl (TBS) ether 8.
Monitoring of enantio-integrity in the series was achieved by
converting alcohol 8 to its Mosher’s ester 8a, which by 1H NMR
analysis relative to the diastereomeric mixture of Mosher’s
esters from racemic 8 proved to be 100% enantiopure. Com-
pound 9 was chemoselectively deprotected (TBS) to 10,
oxidized to 11 and olefinated with ethoxycarbonylmethylene-
triphenylphosphorane in dichloromethane exclusively to the
E-enoate ester 12 with no trace15 of any Z-isomer unlike the
ribose series. Finally, conventional chemoselective imide carb-
onyl reduction with borohydride to 13 followed by promoted
sulfanylation with thiophenol9b,13,16 and boron trifluoride
etherate produced the target α-sulfanyl lactam 14. All steps in
the synthesis were high yielding (> 85% per step), and easy to
carry out so that gram quantities of radical precursor 14 could
be obtained, (Scheme 1).
character in the five-membered ring resulting in a trans ring
junction as established by Beckwith et al.18 for a series of related
compounds. Analysis of the cyclization mixture by TLC
suggested a difficult chromatographic separation. Thus, the
mixture was desilylated with TBAF in THF to produce two
compounds separable by column chromatography. The yield of
the major component (53%) was consistent (approximating the
4 : 8 ratio from NMR) with formation from desilylation of the
major component of the crude cyclization mixture. NMR
analysis established it as the cyclized diastereomer 15 with the
hydroxyl and ethoxycarbonylmethylene groups trans on the
basis of a small vicinal coupling constant for H-1/H-2 indi-
cating a gauche relationship, as well as H-2 being assigned as
equatorial (small vicinal couplings to 2 × H-3). The absolute
stereochemistry and conformation could be established as
shown in Scheme 2. Failure of 15 to form a lactone with TBAF
corroborated the assignment. The minor product 16 (19%) gave
an unexpected result. Its infrared spectrum (νCO = 1785 cmϪ1
)
coupled with a downfield signal (δ = 5.06 ppm) for H-2 (num-
bering shown) indicated a lactone and thus a cis-disposition
between the C-1 and C-2 substituents. The absence of a proton
signal for H-10b and the presence of a hydroxyl group sug-
gested that benzylic (C-10b) hydroxylation had taken place to
an α-hydroxylactam. Finally, the structure was unambiguously
established as 16 by a single crystal X-ray structure determin-
ation, (Scheme 2, Fig. 2).
Scheme 1 Reagents and conditions: i, phthalimide, DEAD, PPh3,
THF; ii, HCl (1 M), THF, ∆; iii, TBSCl, imid, CH2Cl2; iv, TBDPSCl,
imid, CH2Cl2, DMF; v, HF (40%), CH3CN; vi Swern oxidation; vii
PPh3᎐᎐CHCO2Et, CH2Cl2; viii, NaBH4, THF, Ϫ40 ЊC; ix, PhSH (2 eq.),
BF3ؒEt2O (2 eq.), CH2Cl2, Ϫ78 ЊC.
Scheme 2 Reagents and conditions: i, Bu3SnH (3eq.), AIBN (cat),
toluene / ∆; ii, TBAF, THF.
The scene was now set for radical cyclisation studies. α-Acyl-
amino radical cyclizations have proven to be a versatile
methodology for N-heterocycle synthesis following pioneering
work by Hart11 and co-workers in the 1980’s. Exposure of 14 to
standard17 radical cyclization conditions (Bu3SnH–AIBN (cat)
in refluxing toluene) resulted in rapid conversion to a more
polar product in essentially quantitative yield (97%). This result
contrasts with our previous study involving a ribose-derived
tether in which cyclization was much slower and the yield of the
major product much lower (∼60%), presumably as a result of
ring strain imposed by the acetonide protecting group. The
radical cyclization in the present study was relatively insensitive
to concentration effects and no reduced product was ever
observed, indicating a fast cyclization step. Scrutiny of the
crude product by 400 MHz 1H NMR revealed it to be a mixture
of cyclized diastereomers (approximated as 4 : 2 : 1 : 1) based on
the loss of the olefinic resonances as well as the appearance of
four new doublets for H-10b. Furthermore, the vicinal coupling
constants (in order as J = 3.7, 11.1, 11.1, 3.5 Hz) indicated the
major diastereomer to have a cis relationship between the
H-10b and H-1 hydrogens, with the ethoxycarbonylmethylene
substituent consequently axial. This followed as a result of
H-10b being obligatorily axial in view of the high degree of sp2
Fig. 2 X-Ray crystal structure of 16.
Precedence in the literature exists for this type of oxidation in
which tetraalkylammonium salts are known to promote allylic
oxidation with oxygen via catalyzing the breakdown of the
hydroperoxide intermediate.19 In this case, fluoride-promoted
benzylic deprotonation to a dienolate followed by reaction
with oxygen would satisfactorily account for hydroperoxide
formation.
Certain aspects of the stereoselectivity of cyclization are
noteworthy. In keeping with other radical cyclizations, the
initial cyclization product leading to 15 must be that of
kinetic control in view of it being a higher energy diastereomer.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 4 8 – 2 3 5 6
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Its formation is striking in that it implies the radical acceptor to
be in a pseudoaxial configuration in the chair-like transition
state. This is in contrast to the known preference in other 6-exo
cyclizations20 for the side chain to be pseudoequatorial, includ-
ing the major product from our previous research on isoindo-
lone formation using an adjacent isopropylidene ketal as the
stereo-directing auxiliary. A transition-state model based on the
stereoselectivity observed reveals that formation of 15 proceeds
via approach of the sterically unencumbered radical from the
face of the enoate ester proximal to the chiral auxiliary in order
to minimise steric interaction between the ethoxycarbonyl-
methylene and OTBDPS groups.
The observed configuration at C-1 indicates that the enoate
ester grouping adopts an endo orientation with respect to the
isoindolone ring, also in order to minimise steric strain with the
bulky OTBDPS group, resulting in a trans C1/2 relationship in
the product. As the six-membered ring begins to take shape,
the acceptor chain adopts a pseudoaxial configuration, (Fig. 3)
leading to 15.
strong stereo-directing bias imposed by the silyloxy group,21
which can override the preference of the acceptor side chain to
be in a pseudoequatorial configuration.
The diastereoselectivity of the radical cyclization was pleas-
ing in that the cis-relationship between the benzylic H-10b and
the hydrogen at C-1 of 15 corresponds to the correct ring junc-
tion stereochemistry found in the Tacaman alkaloids (see
Tacamonine22 in Fig. 1), suggesting an equivalent study to pre-
pare indolo[2,3-a]quinolizidines is worth pursuing. The desired
outcome would necessitate that expanding the radical-contain-
ing ring to six-members and changing the phenyl to an indolo
group retains the stereochemical preference. Furthermore, this
result contrasts with the trans preference obtained from cycliz-
ation in the ribose-tethered series involving two stereo-directing
centres. Presumably in the latter case, the ketal auxiliary didn’t
exert as powerful a steric influence as the silyloxy group in the
present study.
We next turned our attention to studying carbanionic cycliz-
ation in view of the presence of carbonyl and phenylsulfanyl
stabilizing groups. Precedence for this type of reaction existed
in the work of Luzzio and Zacherl9e who had demonstrated a
similar system to undergo sodium hydride-promoted cycliz-
ation. We were further encouraged when it was discovered that
desilylation of 14 using TBAF indeed promoted cyclization via
Michael addition to the enoate ester, with incorporation of the
phenylsulfanyl group in the product, unlike the radical series. In
order to optimise diastereoselectivity, the conditions were
changed to using LDA (3eq.) at low temperature (Ϫ78Њ), which
produced the two anti diastereomers 17 and 18 in 77% and 18%
yield respectively after column chromatography. Stereochemical
assignment of 17 was made on the basis of vicinal coupling
constants and assignment of H-2 as axial (J2/3 = 11.7 Hz). Once
again, a pseudoaxial configuration for the phenylsulfanyl group
is obligatory in view of the requirement for the N–Ccarbonyl
and Cring–Cring attachment bonds of the five-membered ring
to be virtually coplanar, (Scheme 3). Rationalisation of the
diastereoselectivity is again dominated by the observation that
both products 17 and 18 indicate a pseudoaxial configuration
for the Michael acceptor at C-1 in the transition state via an
endo approach of the enoate ester wrt to the isoindolyl ring. In
this case, in contrast to the radical cyclization, the dominant
product 17 was formed by attacking the enoate ester from the
distal face to the bulky OTBDPS group in order to minimise the
dominant SPh–OTBDPS interaction.
Fig. 3 Transition-state model for cyclization to 15.
Rationalization of formation of the minor product 16 is
more complex in view of the oxidation step, which presumably
occurred during the TBAF deprotection via a dienolate.19
Formation of 16 could have arisen from either of two of
the four diastereomeric products in the crude mixture with
the ethoxycarbonylmethylene group in the α-position. Fig. 4
depicts the transition state for formation of 16 via the cyclized
diastereomer that is desilylated with cyclization to the lactone,
and oxidized with retention of configuration at C-10b. As with
formation of 15, it also implies a pseudoaxial configuration for
the acceptor side chain in the transition state. In this case, the
steric implications of having the C-1/C-2 substituents cis is off-
set by the more favourable placing of the OTBDPS group as
pseudoequatorial, as well as the radical approaching anti to the
silyloxy group, (Fig. 4). However, the isolated yield of 19% sug-
gests that formation of 16 may well have occurred from both of
the diastereomers previously mentioned. These results reveal a
Scheme 3 Reagents and conditions: i, LDA (3 eq.), THF, Ϫ78 ЊC;
17 : 18 = 77 : 18.
This is at the expense of the ethoxycarbonylmethylene–
OTBDPS interaction, which is minimized via an endo approach
of the enoate ester to set up a cis C-1/C-2 relationship, (Fig. 5).
The minor component 18 arises from attack of the double
bond from the more hindered face proximal to the silyloxy
group, with some compensation from the endo orientation of
the enoate ester resulting in a trans C1/2 relationship. Once
Fig. 4 Transition-state model for cyclization to 16.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 4 8 – 2 3 5 6
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followed by reaction with allyl bromide (excess) resulted in
benzylic allylation as well as allylation α to the lactone carbonyl
group at low conversion. Since intermolecular allylation
appeared to be too sterically demanding and that the ester func-
tionality was interfering with some of the methods, it was
decided to allylate prior to cyclization so that an intramolecular
process could be studied. Thus imide 9 (Scheme 1) was reduced
to α-hydroxy lactam 21, which could be sulfanylated as before
and efficiently allylated via its carbanion, generated using
n-butyllithium. Chemoselective removal of the TBS ether to 22
with subsequent elaboration as before provided the enoate ester
cyclization precursor 23. Exposure of 22 to standard radical
cyclization conditions resulted in an inseparable mixture of
1
products. H NMR analysis suggested that reductive cleavage
of the sulfide was one of the reactions that had taken place, via
reduction of the intermediate radical. A similar tendency of a
tertiary radical to prefer reduction over C–C bond formation
has been noted by Hart and co-workers,11a (Scheme 5).
Fig. 5 Transition-state model for carbanionic cyclization to 17.
again, the acceptor adopts a pseudoaxial configuration as a
result of the steric influence imposed by the bulky silyloxy
group in the cyclization.
Several methods were screened for reductive desulfurization
of the major diastereomer 17, with nickel boride23 proving to
be the most efficient. Thus treatment of 17 with nickel boride
derived from treating nickel () chloride with sodium boro-
hydride returned a 92% yield of reduced isoindolone 19 with
retention of configuration at the benzylic centre, presumably so
as to retain the OTBDPS group in an equatorial configuration.
Synthesis of compound 19 thus offers a complementary route
to the radical cyclization approach (to 15) for setting up the C-1
and C-10b hydrogens as cis for the Tacaman D/E ring junction
stereochemistry, and as the alternative diastereoisomer. Desilyl-
ation of 19 with HF in acetonitrile resulted in deprotection and
cyclization to the lactone 20, thus vindicating the configur-
ational assignments of the C-1/2 substituents in compound 17,
(Scheme 4).
ؒ
Scheme 5 Reagents and conditions: i, PhSH (2eq.), BF3 Et2O, CH2Cl2,
Ϫ78 ЊC; ii; n-BuLi, THF, Ϫ78 ЊC; allyl bromide to rt; iii, HF, CH3CN;
iv, Swern oxidation, v, PPh3᎐᎐CHCO2Et, CH2Cl2, vi, Bu3SnH, AIBN
(cat), Tol, 100 ЊC.
Desulfurization of 23 and intramolecular carbanionic cyclis-
ation remained as a possibility but this was not studied.
In conclusion, we have effectively developed model systems
for the cis D/E Tacamonine ring junction stereochemistry, and
uncovered a novel expression of 6-exo-trig radical cyclization
stereoselectivity. Further work is in progress attempting to
translate these ideas to alkaloid synthesis.
Experimental
All solvents were freshly distilled. Tetrahydrofuran, benzene
and toluene were distilled under nitrogen from sodium wire,
while dichloromethane was distilled over phosphorus pent-
oxide. Benzophenone was used as an indicator with THF.
All chromatography was carried out using petroleum ether
and ethyl acetate as eluents. Column chromatography was
performed using silica gel 60 (Merck 7734; 70–230 Mesh
ASTM). Thin layer chromatography (TLC) was carried out on
aluminium-backed Merck silica gel 60 F254 plates. Compounds
were viewed on the plates by using a UV lamp, or by spraying
with a 2.5% solution of anisaldehyde in a mixture of sulfuric
acid and ethanol (1 : 10 v/v) and then heating at 150 ЊC. The
organic layers of reactions subjected to extractive work-up were
dried by stirring with magnesium sulfate followed by filtration.
Infrared spectra were recorded on a Perkin Elmer Paragon
1000 FT-IR spectrometer in dichloromethane. These spectra
were recorded from 4000 to 600 cmϪ1 on sodium chloride plates.
High-resolution nuclear magnetic resonance spectra were
Scheme 4 Reagents and conditions: i, Ni boride, aq. EtOH, rt; ii, HF,
CH3CN, 45 ЊC.
A further aspect explored was to investigate the possibility of
quaternizing the isoindolone benzylic position.6c,7a–e,9a–c,24 To
this end α-sulfanylisoindolone 17 was selected for modification
since it provided opportunity to explore the use of various
sulfur-based methodologies. Disappointingly, none of the stand-
ard methods based on intermolecular allylation methodology
(substitution of sulfur) resulted in efficient benzylic allylation.
The various methods tried included: transmetallation with
lithium di-tert-butylbiphenylide25 followed by quenching with
allyl bromide; Lewis acid (BF3ؒEt2O, SnCl4, TMSOTf, TiCl4) /
allyltrimethylsilane; allyltributyltin.16a,26 In each case, several
products were obtained due to multiple allylation or significant
quantities of starting material was recovered. Similarly, treat-
ment of lactone 20 (Scheme 4) with LDA (1 eq., Ϫ78 ЊC, THF)
1
recorded on a Varian Unity 400 (at 399.951 MHz for H and
100.579 MHz for 13C) and were carried out in CDCl3 unless
otherwise stated. Chemical shifts (δ) were recorded using
1
residual chloroform (δ = 7.24 in H NMR and δ = 77.00 in
13C NMR) or tetramethylsilane as an internal standard. The
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 4 8 – 2 3 5 6
2351

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residual DMSO peak (δ = 39.52 in 13C NMR) was used as an
internal standard for D6-DMSO solutions.
(4.52 g, 12.93 mmol, 97%). [α]D = Ϫ3.9Њ (c = 1.0, CDCl3); νmax/
-
cmϪ1 3597, 3048, 2955, 1775, 1713, 1398; δH (400 MHz, CDCl3)
0.06 (6H, s, CH3), 0.89 (9H, s, t-butyl CH3), 1.80 (2H, m, H-3),
2.65 (1H, br s, OH), 3.49 (1H, dd, J 6.7, 10.0 Hz, H-4), 3.63 (1H,
dd, J 3.9, 10.0 Hz, H-4), 3.68 (1H, m, H-2), 3.88 (2H, m, H-1),
7.70–7.86 (4H, m, aromatic); δC (100 MHz, CDCl3) –5.4
(2 × CH3), 18.3 (C(CH3)3), 25.9 (C(CH3)3), 31.9 (C-3), 34.9 (C-
4), 67.0 (C-2), 69.5 (C-1), 123.2 & 132.2 & 133.9 (aromatic),
Optical rotations were obtained using a Perkin Elmer 141
polarimeter at 20 ЊC. The concentration c refers to g 100 mlϪ1
.
Melting points were obtained using a Reichert Jung hot stage
microscope and are uncorrected. Elemental analyses were per-
formed using a Fisons EA 1108 CHN elemental analyser.
HRMS were recorded on a VG70-SEQ Micromass instrument.
All reagents were purchased from Aldrich or Merck. Low tem-
perature reactions were carried out using dry ice in acetone for
the low temperature cooling baths.
168.5 (C᎐O); m/z 334.1472 (Mϩ-CH C H NO Si requires M,
᎐
3.
18 27
4
334.1474).
Mosher’s ester (S )-1-(tert-butyldimethylsilyl)oxy-4-phthalim-
ido-2-butyl 2-(R)-2-trifluoromethyl-2-methoxy-2-phenylethan-
oate, 8a. For monitoring of enantio-integrity, the alcohol 8
(0.030 g, 0.086 mmol) and (R)-methoxytrifluoromethylphenyl-
acetic acid (0.030 g, 0.13 mmol) were stirred in dichloro-
methane (2 ml) at 0 ЊC. DMAP (5 mg, cat.) and DCC (0.027 g,
0.13 mmol) were added and the reaction was warmed to room
temperature. After 2 hours, TLC indicated completion of reac-
tion, thus solvent was evaporated to leave a residue which was
diluted in ether, filtered, and the residue washed with ether. The
filtrate was concentrated and the residue chromatographed
(20% ethyl acetate–petroleum ether) to give the product as a
colourless oil (0.041 g, 0.073 mmol, 85%, 100% ee by 1H NMR
relative to a sample from racemic 8). [α]D = ϩ9.1Њ (c = 1.0,
CHCl3); νmax/cmϪ1 2955, 2858, 1774, 1748, 1714, 1469, 1398;
δH (400 MHz, CDCl3) 0.01 (6H, s, CH3), 0.83 (9H, s, t-butyl
CH3), 2.07 (1H, m, H-3), 2.18 (1H, m, H-3), 3.59 (3H, s, OCH3),
3.69 (1H, dd, J 4.6, 11.2 Hz, H-1), 3.77 (3H, m, 2 × H-4, H-1),
5.12 (1H, m, H-2), 7.40 (3H, m, aromatic) 7.59 (2H, m, aro-
matic), 7.71 (2H, aromatic), 7.84 (2H, m, aromatic); δC(100
MHz, CDCl3) Ϫ5.7 (2 × CH3), 18.1 (C(CH3)3), 25.7 (C(CH3)3),
29.5 (C-3), 34.3 (C-4), 55.4 (OMe), 63.1 (C-1), 74.9 (C-2), 121.9
(COMe), 123.3 (aromatic), 124.7 (CF3), 127.6 & 128.4 & 129.5
Synthesis of radical precursor 14
(S )-2,2-Dimethyl-4-(2-phthalimidoethyl)-1,3-dioxolane
6.
Alcohol 5 (0.43 g, 2.97 mmol) was dissolved in tetrahydrofuran
(10 ml) with stirring under nitrogen. Phthalimide (0.57 g,
3.9 mmol) and triphenylphosphine (1.03 g, 3.9 mmol) were then
added and the solution cooled to 0 ЊC. Diethyl azodicarb-
oxylate (0.62 ml, 3.9 mmol) was added dropwise. The reaction
was allowed to warm to room temperature and on completion
(TLC), the solvent was evaporated and the residue dissolved in
dichloromethane, which was washed with potassium hydroxide
(1 M). The organic layer was dried, the solvent evaporated and
the residue chromatographed (20% ethyl acetate–petroleum
ether) to afford 6 as a colourless crystalline solid (0.77 g, 2.79
mmol, 94%). Mp 44–46 ЊC (ethyl acetate–hexane); [α]D = ϩ10.6Њ
(c = 1.0, CHCl3) (Found: C, 65.57; H, 6.31; N, 5.28%.
C15H17NO4 requires C, 65.44; H, 6.22; N, 5.09%); νmax/cmϪ1
3057, 2986, 1775, 1716, 1398; δH (400 MHz, CDCl3) 1.28 (3H,
d, isopropylidene-Me), 1.34 (3H, d, isopropylidene-Me), 1.90
(2H, m, H-1Ј), 3.56 (1H, dd, J 6.7, 7.8 Hz, H-5), 3.81 (2H, m,
H-2Ј), 4.07 (1H, dd, J 5.9, 7.8 Hz, H-5), 4.14 (1H, m, H-4), 7.70
(2H, m, aromatic), 7.83 (2H, m, aromatic); δC (100 MHz,
CDCl3) 25.5, 26.8 (2 × isopropylidene-Me), 32.3 (C-1Ј), 35.1
(C-2Ј), 69.1 (C-5), 73.9 (C-4), 109.0 (C-2), 123.1, 132.1, 133.8
& 132.1 & 132.2 & 134.0 (aromatic), 166. 2 & 168.1 (C᎐O); m/z
᎐
566 (Mϩ ϩ H, 3%), 508 (Mϩ–C(CH3)3, 45), 332.2 (100).
(aromatic), 168.2 (C᎐O); m/z 260.092 (Mϩ–CH . C H NO
᎐
3
14 14
4
requires M, 260.0923).
(S )-4-Phthalimido-2-(tert-butyldiphenylsilyl)oxy-1-(tert-butyl-
dimethylsilyl)oxybutane 9. To a solution of alcohol 8 (4.52 g,
12.93 mmol) in dichloromethane (50 ml) under a nitrogen
atmosphere was added dimethylformamide (5 ml), imidazole
(1.00 g, 14.7 mmol) and tert-butyldiphenylsilyl chloride (3.50
ml, 13.5 mmol). The mixture was stirred at room temperature
until TLC indicated that the starting material had been con-
sumed. Water was added and the mixture extracted with 3 por-
tions of dichloromethane. The organic layers were combined
and dried, then evaporated to give a residue that was chromato-
graphed (10% ethyl acetate–petroleum ether) to remove di-
methylformamide. The product fraction was evaporated to a
residue (7.62 g) contaminated with tert-butyldiphenylsilyl alco-
hol (TBDPSOH). The product 9 and this contaminant eluted at
the same Rf. The contaminant could easily be separated from
the product 10 of the next step by chromatography so the mix-
ture was not purified further. For characterisation purposes a
portion of pure 10 was reprotected using the same procedure
that was used to obtain 8 to give compound 9 free of TBDP-
SOH. [α]D = ϩ19.0Њ (c = 1.0, CHCl3); νmax/cmϪ1 3057, 2933,
1771, 1715; δH (400 MHz, CDCl3) Ϫ0.12, and Ϫ0.07 (6H, s,
TBDMS CH3), 0.81 (9H, s, t-butyl CH3), 1.07 (9H, s, t-butyl
CH3), 1.90 (1H, m, H-3), 2.03 (1H, m, H-3), 3.53 (2H, d, J 5.9
Hz, H-1), 3.78 (3H, m, H-2, 2 × H-4), 7.30–7.85 (14H, m,
aromatic); δC (100 MHz, CDCl3) Ϫ5.6 (TBDMS 2 × CH3),
18.2 & 19.3 (C(CH3)3), 25.8 & 27.0 (C(CH3)3), 32.6 (C-3), 34.4
(C-4), 65.6 (C-), 71.8 (C-), 123.0 & 127.5 & 127.6 & 129.5 &
129.6 & 132.4 & 133.7 & 133.8 & 134.3 & 135.8 & 135.9
(S )-4-Phthalimido-1,2-butanediol 7. The imide 6 (0.32 g,
1.16 mmol) was dissolved in a mixture of tetrahydrofuran
(3 ml) and hydrochloric acid (3 ml, 1 M) and heated at 60 ЊC for
30 minutes. Aqueous sodium hydrogen carbonate was added
and the tetrahydrofuran removed on a rotary evaporator. The
aqueous phase was extracted with 3 portions of ethyl acetate,
and the organic layers combined, dried and evaporated to a
residue. This was subjected to flash chromatography (80% ethyl
acetate–petroleum ether) to obtain diol 7 as a colourless solid
(0.23 g, 0.98 mmol, 85%). Mp 105–106 ЊC (ethyl acetate–
petroleum ether); [α]D = Ϫ29.9Њ (c = 1.0, CHCl3) (Found: C,
61.45; H, 5.31; N, 5.86%. C12H13NO4 requires C, 61.23; H, 5.57;
N, 5.95%); νmax/cmϪ1 3581, 3061, 2963, 1775, 1707, 1396;
δH (400 MHz, CDCl3) 1.75 (2H, m, H-3), 2.40 (1H, br s, OH),
3.46 (1H, dd, J 7.2, 11.2 Hz, H-4), 3.58 (1H, dd, J 3.2, 11.2 Hz,
H-4), 3.58 (1H, br s, OH), 3.65 (1H, m, H-2), 3.86 (2H, dd,
J 5.6, 7.6 Hz, H-1), 7.70-7.84 (4H, m, aromatic); δC (100 MHz,
CDCl3) 32.0 (C-3), 34.4 (C-4), 66.4 (C-1), 69.1 (C-2), 123.4 &
132.0 & 134.1 (aromatic), 168.9 (C᎐O); m/z 235.0820 (Mϩ.
C12H13NO4 requires M, 235.0844).
᎐
(S )-4-Phthalimido-1-(tert-butyldimethylsilyloxy)butan-2-ol 8.
The diol 7 (3.14 g, 13.36 mmol) was dissolved in dichloro-
methane (60 ml) with stirring under nitrogen. Imidazole (1.00 g,
14.7 mmol) was added and the solution cooled to 0 ЊC. Tert-
butyldimethylsilyl chloride (2.02 g, 13.4 mmol) was added and
the solution allowed to warm to room temperature overnight.
Water was added and the mixture extracted with three portions
of dichloromethane. The organic layers were combined, dried,
and evaporated to a residue. This was chromatographed (20%
ethyl acetate–petroleum ether) to afford 8 as a colourless oil
(aromatic), 168.2 (C᎐O); m/z (EI) 572 (Mϩ Ϫ CH3, 1%), 530
᎐
(Mϩ Ϫ C(CH3)3, 100%), 271 (31), 209 (42), 135 (19).
(S )-4-Phthalimido-2-(tert-butyldiphenylsilyl)oxy-1-butanol
10. In a polypropylene container was placed a solution of the
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 4 8 – 2 3 5 6
2352

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mixture of the disilyl ether 9 and TBDPSOH in acetonitrile
(12 ml) at room temperature. To this solution was added 40%
hydrofluoric acid (2.5 ml) and the reaction monitored by TLC
until the starting material had been consumed. The mixture was
neutralized with aqueous sodium hydrogen carbonate and
extracted with three portions of dichloromethane. The com-
bined organic layers were dried and evaporated to a residue,
which was chromatographed (20% ethyl acetate–petroleum
ether) to give alcohol 10 (5.45 g, 11.52 mmol, 89% over 2 steps).
[α]D = ϩ51.4Њ (c = 1.0, CHCl3); νmax/cmϪ1 3571, 3056, 2938,
1777, 1715, 1397; δH (400 MHz, CDCl3) 1.08 (9H, s, t-butyl
CH3), 1.85 (1H, br s, OH), 1.94 (2H, m, H-3), 3.67 (4H, m, H-1
and H-4), 3.82 (1H, m, H-2), 7.31–7.79 (14H, m, aromatic);
δC (100 MHz, CDCl3) 19.2 (C(CH3)3), 27.0 (C(CH3)3), 32.6
(C-3), 34.4 (C-4), 65.4 (C-2), 71.7 (C-1), 123.1 & 127.6 &
127.7 & 129.7 & 129.8 & 132.1 & 133.2 & 133.7 & 133.8 & 135.6
& 135.8 (aromatic), 168.1 (C᎐O); m/z 442.1826 (Mϩ Ϫ CH OH.
monitored by TLC. When the starting material had been con-
sumed the reaction was carefully quenched with aqueous
ammonium chloride and the methanol removed by evapor-
ation. The aqueous phase was extracted with three portions of
dichloromethane and the combined organic layers were dried,
and evaporated to give the crude product. This was then chro-
matographed (40% ethyl acetate–petroleum ether) to give 13 as
a foam (3.61 g, 6.64 mmol, 2 epimers, 92.0%). νmax/cmϪ1 3056,
2934, 1706, 1683, 1659, 1422; δH (400 MHz, CDCl3) 1.07 (9H, s,
t-butyl CH3), 1.25, 1.29 (3H, t, CH2CH3, 2 epimers), 1.70 (2H,
m, H-5), 3.23 (2H, m, H-6), 4.12, 4.16 (2H, m, CH2CH3, 2
epimers), 4.33, 4.45 (1H, m, H-4, 2 epimers), 5.20, 5.51 (1H, s,
benzylic H, 2 epimers), 5.99 (1H, dd, J 1.2, 15.8 Hz, H-2), 6.86
(1H, dd, J 5.1, 15.8 Hz, H-3), 7.23–7.68 (14H, m, aromatic);
δC (100 MHz, CDCl3) 14.2 (CH2CH3), 19.3 (C(CH3)3), 27.0
(C(CH3)3), 34.7, 35.3, 35.5, 35.7 (C-5, C-6, 2 epimers), 60.4
(CH2CH3), 70.5, 70.7 (C-4, 2 epimers), 81.3, 82.4 (benzylic C, 2
epimers), 120.9, 121.1 (C-2, 2 epimers), 123–143 (aromatic),
᎐
2
C27H28NO3Si requires M, 442.1838).
148.7, 148.8 (C-3, 2 epimers), 166.4, 166.4 & 167.1, 167.1 (C᎐O,
᎐
(S )-4-Phthalimido-2-(tert-butyldiphenylsilyl)oxy-1-butanal
11. Dimethyl sulfoxide (1.73 ml, 24 mmol) was dissolved in dry
dichloromethane and cooled to Ϫ78 ЊC under nitrogen. Oxalyl
chloride (1.45 ml, 16.6 mmol) was then added, and after
15 minutes the alcohol 10 (5.25 g, 11.08 mmol) was slowly
added in a solution of dichloromethane. After a further 5 min-
utes, triethylamine (7.8 ml, 55 mmol) was added and the mix-
ture was slowly allowed to warm to 0 ЊC. The reaction was
quenched by adding aqueous sodium carbonate and extracted
with three portions of dichloromethane. The combined organic
layers were dried and evaporated to give crude 11, which could
be taken on to the next step. For characterisation purposes a
small portion was chromatographed (20% ethyl acetate–
petroleum ether) and subjected to high vacuum for 24 hours to
remove traces of dimethyl sulfide, to give aldehyde 11 as a
colourless gum. [α]D = ϩ23.9Њ (c = 1.1, CHCl3); νmax/cmϪ1 3061,
2938, 1779, 1716, 1400; δH (400 MHz, CDCl3) 1.13 (9H, s,
t-butyl CH3), 2.05 (2H, m, H-3), 3.76 (2H, m, H-4), 4.13 (1H,
td, J 0.9, 5.6, 5.6 Hz, H-2), 7.38 (6H, m, aromatic), 7.70 (6H, m,
aromatic), 7.84 (2H, m, aromatic), 9.65 (1H, d, J 0.9 Hz, H-1);
δC (100 MHz, CDCl3) 19.3 (C(CH3)3), 26.9 (C(CH3)3), 31.4
(C-3), 33.6 (C-4), 76.1 (C-2), 123.2 & 127.9 & 130.1 & 132.2 &
2 epimers); m/z 486.1726 (Mϩ Ϫ C(CH3)3. C28H28NO5Si
requires M, 486.1737).
Ethyl (2E,4S )-6-(1,3-dihydro-3-phenylsulfanyl-1-oxoisoindol-
2-yl)-4-(tert-butyldiphenylsilyl)oxyhex-2-enoate 14. The α-hydr-
oxylactam 13 (1.00 g, 1.84 mmol) was dissolved in dry
dichloromethane and cooled to Ϫ78 ЊC under nitrogen.
BF3ؒEt2O (0.47 ml, 3.7 mmol) and benzenethiol (0.38 ml, 3.7
mmol) were added and the solution stirred at Ϫ78 ЊC for
2 hours. The reaction was quenched with aqueous sodium
carbonate and extracted with three portions of dichloro-
methane. The combined organic layers were washed with dilute
potassium hydroxide and then dried and evaporated. The crude
product was chromatographed (20% ethyl acetate–petroleum
ether) to give pure 14 as a gum (1.14 g, 1.78 mmol, 2 epimers,
97%). νmax/cmϪ1 3054, 2988, 1710, 1697, 1659, 1426; δH (400
MHz, CDCl3) 1.10, 1.13 (9H, s, t-butyl CH3, 2 epimers),
1.21, 1.30 (3H, t, CH2CH3, 2 epimers), 1.77 (2H, m, H-5), 3.52
(2H, m, H-6), 4.05, 4.20 (2H, m, CH2CH3, 2 epimers), 4.50, 4.41
(1H, m, H-4, 2 epimers), 4.98, 5.46 (1H, s, benzylic H, 2 epi-
mers), 5.92 (1H, dd, J 1.5, 15.7 Hz, H-2), 6.82 (1H, dd, J 5.1,
15.7 Hz, H-3), 6.90–7.75 (19H, m, aromatic); δC (100 MHz,
CDCl3) 14.2, 14.3 (CH2CH3, 2 epimers), 19.3, 19.3 (C(CH3)3, 2
epimers), 27.0 (C(CH3)3), 34.9 (C-5), 35.8 (C-6), 60.3, 60.4
(CH2CH3, 2 epimers), 65.7, 66.7 (benzylic C, 2 epimers), 70.3,
70.9 (C-4, 2 epimers), 120.7, 121.3 (C-2, 2 epimers), 123–143
132.6 & 132.7 & 133.9 & 135.8 (aromatic), 168.0 (C᎐O), 202.6
᎐
(C-1); m/z 414.1172 (Mϩ Ϫ C(CH3)3. C24H20NO4Si requires M,
414.1161).
Ethyl (2E,4S )-4-(tert-butyldiphenylsilyl)oxy-6-phthalimido-
hex-2-enoate 12. The crude aldehyde 11 was dissolved in di-
chloromethane and ethoxycarbonylmethylenetriphenylphos-
phorane (4.2 g, 12 mmol) was added. The mixture was stirred at
room temperature and monitored by TLC. When the reaction
was complete the solvent was evaporated and the residue chro-
matographed directly (20% ethyl acetate–petroleum ether) to
obtain enoate ester 12 (5.78 g, 10.66 mmol, 96% over 2 steps) as
a colourless gum. [α]D = ϩ34.0Њ (c = 1.0, CHCl3); νmax/cmϪ1
3058, 2989, 1777, 1714, 1663, 1398; δH (400 MHz, CDCl3) 1.11
(9H, s, t-butyl CH3), 1.27 (3H, t, CH2CH3), 1.87 (2H, m, H-5),
3.67 (2H, m, H-6), 4.13 (2H, m, CH2CH3), 4.42 (1H, m, H-4),
6.01 (1H, dd, J 1.5, 15.6 Hz, H-2), 6.92 (1H, dd, J 5.3, 15.6 Hz,
H-3), 7.30–7.83 (14H, m, aromatic); δC (100 MHz, CDCl3) 14.2
(CH2CH3), 19.3 (C(CH3)3), 27.0 (C(CH3)3), 33.5 (C-5), 35.3
(C-6), 60.3 (CH2CH3), 70.5 (C-4), 121.3 (C-2), 123.1, 127.6,
127.7, 129.7, 129.8, 132.2, 133.1, 133.4, 133.8, 135.8, 135.8,
(aromatic), 148.5, 148.7 (C-3, 2 epimers), 166.0 & 167.3 (C᎐O);
᎐
m/z 578.1798 (Mϩ Ϫ C(CH3)3). C34H32NO4SSi requires M,
578.1821).
Radical cyclization of 14
To a solution of the sulfide 14 (0.46 g, 0.71 mmol) in dry,
deoxygenated toluene (30 ml) at 90 ЊC was added a solution of
tributyltin hydride (0.60 ml, 2.2 mmol) and AIBN (15 mg) in
toluene (20 ml) dropwise over 30 minutes. The solution was
stirred until TLC indicated that no starting material remained.
Carbon tetrachloride (1 ml) was then added and the solvent
evaporated. The residue was chromatographed (30% ethyl
acetate–petroleum ether) to give a band of products as a gum
1
(0.36 g, 0.69 mmol, 97%). H NMR spectral analysis of this
crude residue indicated that 4 diastereomers were present in a
4:2:1:1 ratio in order of decreasing chemical shift based on the
doublet for H-10b at δ = (5.12, J 3.7 Hz; 4.62, J 11.1 Hz; 4.44,
J 11.1 Hz; 4.28, J 3.5 Hz).
135.8 (aromatic), 148.3 (C-3), 166.2 & 168.0 (C᎐O); m/z
᎐
484.1592 (Mϩ Ϫ C(CH3)3. C28H26NO5Si requires M, 484.1580).
Deprotection of mixture of cyclization products
Ethyl (2E,4S )-6-(1,3-dihydro-3-hydroxy-1-oxoisoindol-2-yl)-
4-(tert-butyldiphenylsilyl)oxyhex-2-enoate 13. To a solution of
12 (3.91 g, 7.22 mmol) in tetrahydrofuran (20 ml) and methanol
(50 ml) at Ϫ40 ЊC was added sodium borohydride (1.13 g,
30.0 mmol). The reaction was kept below Ϫ20 ЊC and was
The mixture of isomers (0.606 g, 1.15 mmol) was dissolved in
tetrahydrofuran (10 ml) and tetrabutylammonium fluoride
(1 M) in tetrahydrofuran (4 ml) was added. The mixture was
stirred at room temperature and water was added when TLC
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 4 8 – 2 3 5 6
2353

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indicated that no starting material remained. The tetrahydro-
furan was evaporated and the aqueous phase was extracted
with three portions of dichloromethane. The combined organic
layers were dried and evaporated and the residue chromato-
graphed (80% ethyl acetate–petroleum ether) to give the lactam
15 (0.177 g, 0.63 mmol, 53%) as a colourless crystalline solid. A
band of mixed products was also isolated. This mixture was
purified by recrystallization (ethyl acetate–petroleum ether) to
give a minor product as a colourless crystalline solid identified
as 16 using X-ray crystallography (0.057 g, 0.22 mmol, 19%).
J 4.5, 4.5, 11.7 Hz, H-2), 6.65–7.83 (19H, m, aromatic); δC(100
MHz, CDCl3) 13.9 (CH2CH3), 19.2 (C(CH3)3), 27.0 (C(CH3)3),
29.2 (C-3), 29.3 (C-1a), 34.2 (C-4), 43.8 (C-1), 60.3 (CH2CH3),
69.0 (C-2), 78.7 (C-10b), 122.8, 124.3, 127.7, 127.9, 128.2,
128.4, 128.5, 129.2, 129.9, 130.1, 130.9, 131.6, 133.0, 133.9,
135.8, 136.0, 136.0, 144.4 (aromatic), 165.9 & 172.5 (C᎐O); m/z
᎐
526.2410 (Mϩ Ϫ SC6H5. C32H36NO4Si requires M, 526.2414).
(1R,2S,10bR)-1,2,3,10b-Tetrahydro-1-ethoxycarbonylmethyl-
10b-phenylsulfanyl-2-(tert-butyldiphenylsilyl)oxypyrido[2,1-a]-
isoindol-6(4H)-one 18. Mp 133–135 ЊC (ethyl acetate–petroleum
ether); [α]D = ϩ40.7Њ (c = 1.0, CHCl3), (Found: C, 71.87; H,
6.66; N, 2.42; S, 4.98. C38H41NO4SSi requires: C, 71.78; H, 6.50;
N, 2.20; S, 5.04%); νmax/cmϪ1 3058, 2984, 2307, 1732, 1696,
1427; δH (400 MHz, CDCl3) 0.94 (3H, t, CH2CH3), 1.22 (9H, s,
t-butyl CH3), 1.45 (2H, m, H-3), 1.55 (1H, dd, J 7.9, 16.1 Hz,
H-1a), 1.75 (1H, dd, J 6.2, 16.1 Hz, H-1a), 3.42 (1H, ddd, J 2.3,
6.2, 7.9 Hz, H-1), 3.77 (2H, m, CH2CH3), 3.90 (1H, m, H-4),
3.99 (1H, q, J 2.6 Hz, H-2), 4.20 (1H, m, H-4), 6.90 (4H, m,
aromatic), 7.05 (1H, m, aromatic), 7.14 (1H, m, aromatic), 7.30
(1H, m, aromatic), 7.42 (7H, m, aromatic), 7.55 (1H, m, aro-
matic), 7.81 (4H, m, aromatic); δC (100 MHz, CDCl3) 13.9
(CH2CH3), 19.4 (C(CH3)3), 27.1 (C(CH3)3), 27.8 (C-3), 31.1
(C-1a), 34.9 (C-4), 44.5 (C-1), 60.6 (CH2CH3), 70.0 (C-2), 76.2
(C-10b), 122.9, 123.9, 127.7, 127.8, 128.0, 128.8, 129.9, 129.9,
130.7, 131.1, 131.4, 133.0, 134.0, 136.0, 136.1, 136.3, 145.5
Major product: (1S,2S,10bS )-1,2,3,10b-tetrahydro-1-ethoxy-
carbonylmethyl-2-hydroxypyrido[2,1-a]isoindol-6(4H)-one 15.
Mp 123–125 ЊC (ethyl acetate–petroleum ether); [α]D = Ϫ15.3Њ
(c = 1.0, CHCl3); νmax/cmϪ1 3608, 3059, 2994, 1732, 1679, 1431;
δH (400 MHz, CDCl3) 1.03 (3H, t, CH2CH3), 1.66 (1H, dd,
J 6.7, 16.3 Hz, H-1a), 1.73 (1H, dd, J 7.0, 16.3 Hz, H-1a), 1.78
(2H, m, H-3), 2.66 (1H, br s, OH), 3.03 (1H, m, H-1), 3.39 (1H,
ddd, J 5.8, 11.6, 13.0 Hz, H-4), 3.81 (2H, m, CH2CH3), 4.19
(1H, m, H-2), 4.27 (1H, ddd, J 2.2, 5.2, 13.0 Hz, H-4), 5.03 (1H,
d, J 4.0 Hz, H-10b), 7.36 (1H, d, J 7.8 Hz, H-10), 7.47 (2H, m,
aromatic), 7.88 (1H, d, J 7.6 Hz, H-7); δC (100 MHz, CDCl3)
13.9 (CH2CH3), 27.0 (C-3), 30.7 (C-1a), 33.9 (C-4), 40.2 (C-1),
55.9 (C-10b), 60.6 (CH2CH3), 67.8 (C-2), 122.8 & 123.9 & 128.2
& 131.0 & 133.4 & 143.2 (aromatic), 166.7 & 172.0 (C᎐O); m/z
᎐
289.1304 (Mϩ. C16H19NO4 requires M, 289.1314).
(aromatic), 165.7 & 171.1 (C᎐O); m/z 526.2435 (Mϩ Ϫ SC6H5.
᎐
C32H36NO4Si requires M, 526.2414).
Minor product: (3aS,11bS,11cR)-3a,4,5,11c-tetrahydro-11b-
hydroxyfuro[3Ј,2Ј:3,4]pyrido[2,1-a]isoindol-2(1H),7(11bH)-
dione 16. Mp decomposes > 140 ЊC; [α]D = Ϫ74.1Њ (c = 0.5,
CHCl3); νmax /cmϪ1 3326, 1785, 1696; δH (400 MHz, CDCl3) 1.52
(1H, dd, J 12.2, 17.6 Hz, H-1), 1.59 (1H, m, H-4), 2.00 (1H, dd,
J 9.0, 17.6 Hz, H-1), 2.37 (1H, m, H-4), 3.08 (1H, ddd, J 4.1,
10.3, 13.5 Hz, H-5), 3.42 (1H, ddd, J 7.5, 8.8, 12.2 Hz, H-11c),
3.78 (1H, dt, J 5.4, 13.7 Hz, H-5), 4.00 (1H, d, J 3.0 Hz, OH),
5.06 (1H, m, H-3a), 7.40–7.61 (4H, m, aromatic); δC (100 MHz,
D6-DMSO) 26.4 (C-4), 29.5 (C-1), 31.8 (C-5), 41.7 (C-11c),
75.3 (C-3a), 86.1 (C-11b), 122.2, 122,6, 129.5, 130.9, 132.2,
146.3 (aromatic), 164.6 (C᎐O), 174.6 (C᎐O); m/z 259.0832 (Mϩ.
(1R,2S,10bR)-1,2,3,10b-Tetrahydro-1-ethoxycarbonylmethyl-
2-(tert-butyldiphenylsilyl)oxypyrido[2,1-a]isoindol-6(4H)-one
19. A two-necked flask was fitted with a condenser, a pressure-
equilibrating dropping funnel and a stirrer bar. The system was
purged with nitrogen and 17 (0.30 g, 0.47 mmol) was added as a
solution in ethanol (150 ml), followed by solid nickel chloride
hexahydrate (2.85 g, 12 mmol). When the solution was homo-
geneous, the dropping funnel was filled with aqueous sodium
borohydride (0.90 g, 24 mmol in 10 cm3 H2O), which was added
dropwise to the green solution of nickel chloride, resulting in an
immediate colour change of solution to black. Once the addi-
tion was complete, the reaction mixture was refluxed until TLC
indicated that no starting material remained. This mixture was
filtered through Celite® and the filter cake was washed thor-
oughly with dichloromethane. The filtrate was evaporated and
the residue extracted with dichloromethane. The organic phase
was then dried, and evaporated. The final product was purified
by flash chromatography (30% ethyl acetate–petroleum ether)
to give 19 (0.23 g, 0.43 mmol, 92%) as a colourless, crystalline
᎐
᎐
C14H13NO4 requires M, 259.0845).
Carbanionic cyclization
Diisopropylamine (0.80 ml, 5.7 mmol) was added to dry tetra-
hydrofuran (10 ml) under nitrogen at 0 ЊC. n-Butyllithium
(2.15 ml of a 2.5 M solution in hexanes, 5.4 mmol) was then
added and the mixture was stirred for 15 minutes. The mixture
was then cooled to Ϫ78ЊC and the sulfide 14 (1.14 g, 1.79 mmol)
was slowly added as a solution in tetrahydrofuran (5 ml), turn-
ing the solution yellow. After 60 minutes the reaction was
quenched by adding aqueous sodium hydrogen carbonate and
extracted with dichloromethane. The organic layer was dried
and evaporated to a residue consisting of 2 products by TLC.
These were separated by chromatography (20% ethyl acetate–
petroleum ether) to give the less polar major product 17 (0.87 g,
1.37 mmol, 77%) as a colourless, crystalline solid and the more
polar minor product 18 (0.20 g, 0.32 mmol, 18%), also as a
colourless, crystalline solid.
solid. Mp 102–104 ЊC (ethyl acetate–petroleum ether); [α]D
=
Ϫ97.8Њ (c = 1.0, CHCl3), (Found: C, 72.70; H, 7.22; N, 2.75.
C32H37NO4Si requires C, 72.83; H, 7.07; N, 2.65%); νmax/cmϪ1
3061, 2990, 2314, 1737, 1698, 1429; δH (400 MHz, CDCl3) 0.97
(3H, t, CH2CH3), 1.08 (9H, s, t-butyl CH3), 1.56 (1H, dd, J 8.8,
16.5 Hz, H-1a), 1.60 (2H, m, H-3), 2.54 (1H, dd, J 2.4, 16.5 Hz,
H-1a), 2.73 (1H, td, J 4.7, 13.4, 13.4 Hz, H-4), 3.19 (1H, m,
H-1), 3.63–3.86 (2H, m, CH2CH3), 4.12 (1H, dt, J 4.8, 4.8, 10.8
Hz, H-2), 4.28 (1H, d, J 3.5 Hz, H-10b), 4.30 (1H, ddd, J 1.5,
5.7, 13.4 Hz, H-4), 7.30–7.80 (14H, m, aromatic); δC (100 MHz,
CDCl3) 13.9 (CH2CH3), 19.1 (C(CH3)3), 26.5 (C-3), 26.9
(C(CH3)3), 29.0 (C-1a), 36.7 (C-4), 40.3 (C-1), 60.2 (C-10b),
60.4 (CH2CH3), 71.7 (C-2), 123.5 & 123.7 & 127.7 & 127.8 &
128.3 & 129.9 & 130.0 & 130.8 & 133.3 & 133.4 & 133.8 & 135.8
(1S,2S,10bS )-1,2,3,10b-Tetrahydro-1-ethoxycarbonylmethyl-
10b-phenylsulfanyl-2-(tert-butyldiphenylsilyl)oxypyrido[2,1-a]-
isoindol-6(4H)-one 17. Mp 126–128 ЊC (ethyl acetate–petroleum
ether); [α]D = Ϫ190.1Њ (c = 1.0, CHCl3) (Found: C, 71.74; H,
6.69; N, 2.43; S, 4.87. C38H41NO4SSi requires C, 71.78; H, 6.50;
N 2.20; S 5.04%); νmax /cmϪ1 3055, 2988, 2306, 1733, 1697, 1432;
δH (400 MHz, CDCl3) 0.99 (3H, t, CH2CH3), 1.11 (9H, s, t-butyl
CH3), 1.54 (1H, m, H-3), 1.57 (1H, dd, J 8.8, 16.7 Hz, H-1a),
1.74 (1H, m, H-3), 2.73 (1H, dd, J 2.1, 16.7 Hz, H-1a), 3.21 (1H,
td, J 4.0, 13.2, 13.3 Hz, H-4), 3.38 (1H, m, H-1), 3.79 (2H, m,
CH2CH3), 4.24 (1H, ddd, J 1.3, 5.5, 13.3 Hz, H-4), 4.79 (1H, dt,
& 135.9 & 141.7 (aromatic), 166.7 & 172.9 (C᎐O); m/z 470.1776
᎐
(Mϩ Ϫ C(CH3)3. C28H28NO4Si requires M, 470.1788).
(3aS,11bR,11cR)-3a,4,5,11c-Tetrahydrofuro[3Ј,2Ј:3,4]pyrido-
[2,1-a]isoindol-2(1H),7(11bH)-dione 20. To a solution of 19
(1.58 g, 2.99 mmol) in acetonitrile (6 ml) in a polypropylene
container was added 40% hydrofluoric acid in acetonitrile
(4 ml) and the mixture stirred for 5 days at 45 ЊC. Solid sodium
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 4 8 – 2 3 5 6
2354

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5 J. Clayden, C. J. Menet and D. J. Mansfield, Org. Lett., 2000, 2, 4229.
hydrogen carbonate was then added until the effervescence
ceased. The mixture was diluted with water and extracted with
dichloromethane. The organic layer was dried with magnesium
sulfate and evaporated. The crude product was chromato-
graphed (80% ethyl acetate–petroleum ether) to obtain pure 20
(0.66 g, 2.71 mmol, 91%) as a colourless, crystalline solid;
Mp 223–226 ЊC (ethyl acetate–petroleum ether); [α]D = ϩ183.0Њ
(c = 1.0, CHCl3); νmax/cmϪ1 3058, 2987, 1780, 1694, 1424;
δH (400 MHz, CDCl3) 1.67 (1H, dd, J 10.6, 18.1 Hz, H-1), 1.89
(1H, m, H-4), 2.03 (1H, dd, J 9.2, 18.1 Hz, H-1), 2.28 (1H, m,
H-4), 3.30 (1H, ddd, J 4.2, 8.4, 13.5 Hz, H-5), 3.42 (1H, m,
H-11c), 4.16 (1H, ddd, J 5.1, 7.0, 13.5 Hz, H-5), 4.75 (1H, d,
J 4.8, H-11b), 5.02 (1H, td, J 5.1, 7.7, 7.7 Hz, H-3a), 7.37–7.87
(4H, m, aromatic); δC (100 MHz, CDCl3) 27.3 (C-4), 27.4 (C-1),
34.9 (C-5), 37.3 (C-11c), 55.7 (C-11b), 75.6 (C-3a), 121.8 &
124.2 & 129.0 & 131.9 & 132.8 & 142.6 (aromatic), 167.2 &
6 W. Oppolzer, M. Wills, M. J. Kelly, M. Signer and J. Blagg,
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174.5 (C᎐O); m/z 243.0888 (Mϩ. C H NO requires 243.0895).
᎐
14 13
3
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X-Ray crystal preparation, data collection, processing and
structure refinement‡
A single crystal of 16 (C14H13NO4, M = 259.08) was covered in
a small amount of paratone oil and mounted on a glass fibre.
X-ray intensity data were collected at 173 K on a Nonius Kappa
CCD with 1.5 kW graphite monochromated MoKα-radiation.
Refined unit cell parameters: a = 8.375(1), b = 7.653(1), c =
9.691(1) Å, β = 100.634(1)Њ, V = 610.5(1) Å3 and Z = 2. The
diffraction patterns were indexed with a primitive monoclinic
cell. The strategy for the data collection was evaluated using the
Collect Software.27 The detector to crystal distance was 40 mm.
Data were collected by a phi scan and several omega scans. The
data were scaled and reduced using Denzo-SMN.28 Unit cell
dimensions were refined on all data. Absorption was negligible
(µ(MoKα) = 0.104 mmϪ1). Of the 5227 reflections measured,
2511 were unique (Rint = 0.014). The space group P21 was
chosen on the basis of systematic absences and intensity stat-
istics. The structure was solved and refined using SHELXL97.29
The absolute structure chosen for the final model was based on
the known absolute configuration of the starting material. (The
Flack parameter value of Ϫ0.5(8) indicated that the diffraction
data could not distinguish the enantiomers). Hydrogen atoms
were placed in calculated positions and included in the model
during later stages of the refinement. Plots of the molecular
structure were obtained with ORTEP30 and PLATON.31 The
programme X-SEED,32 an interface to Shelx, was used during
the structure solution and refinements. Final R-factors were R1
= 0.029, wR2 = 0.068 for 2318 observed data [I > 2σ(I )], and S
(goodness of fit) = 1.032.
16 G. E. Keck and E. J. Enholm, Tetrahedron Lett., 1985, 26, 3311;
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S. L. Krintel, J. Chem. Soc., Perkin Trans. 1, 2001, 2885.
18 A. L. J. Beckwith, S. P. Joseph and R. T. A. Mayadunne, J. Org.
Chem., 1993, 58, 4198; A. L. J. Beckwith, S. P. Joseph, R. T. A.
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19 C. Anselmi, A. Camparini and M. Scotton, J. Heterocycl. Chem.,
1983, 20, 687; L. J. Csanyi, K. Jaky I. Palinko, A. Rockenbauer and
L. Korecz, Phys. Chem. Chem. Phys., 2000, 2, 3801; L. J. Csanyi and
K. Jaky, Phys. Chem. Chem. Phys., 2001, 3, 2018.
Acknowledgements
We thank the National Research Foundation for financial
support, and Dr John Bacsa and Professor Mino Caira for the
X-ray determination.
20 M. Ihara, K. Yasui, N. Taniguchi and K. Fukumoto, J. Chem. Soc.,
Perkin Trans. 1, 1990, 1469; M. Koreeda and L. G. Hamaan, J. Am.
Chem. Soc., 1990, 112, 8175; S. D. Burke and J. Rancourt, J.
Am. Chem. Soc., 1991, 113, 2335; K. Ogura, A. Kayano, T. Fujino,
N. Sumitani and M. Fujita, Tetrahedron Lett., 1993, 34, 8313;
A. L. J. Beckwith, Chem. Soc. Rev., 1993, 143; A. Martinez-Grau
and J. Marco-Contelles, J. Chem. Soc., Perkin Trans. 1, 1998, 155;
X. Sanchez-Ruiz, C. Jaime and J. Marco-Contelles, J. Mol. Struct.,
1998, 471, 209; G. E. Keck, S. F. McHardy and J. A. Murry, J. Org.
Chem., 1999, 64, 4465; N. Hori, H. Matsukura, G. Matsuo and
T. Nakata, Tetrahedron Lett., 1999, 40, 2811; A. C. Durand,
J. Rodriguez and J. P. Dulcère, Synlett, 2000, 731; R. Pedrosa,
C. Andrés, J. M. Iglesias and M. A. Obeso, Tetrahedron, 2001, 57,
4005; S. N. Joshi, V. G. Puranik, A. R. A. S. Deshmukh and
B. M. Bhawal, Tetrahedron: Asymmetry, 2001, 12, 3073.
‡ CCDC reference number 208077. See http://www.rsc.org/suppdata/
ob/b3/b303031h/ for crystallographic data in .cif or other electronic
format.
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2356