Enolate amination and derivatization of a pyrroloisoquinoline template: Towards novel peptidomimetics

Article abstract of DOI:10.1016/j.tet.2010.10.012

Pyrroloisoquinoline-based peptidomimetics are of significant interest in bioorganic chemistry as these targets are known to exhibit type II′ β-turn activity. In this paper we present a novel approach to such pyrroloisoquinoline templates based on a stereo

Full text of DOI:10.1016/j.tet.2010.10.012

Tetrahedron 66 (2010) 9538e9544
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Enolate amination and derivatization of a pyrroloisoquinoline template:
towards novel peptidomimetics
,
b
b
c
d
Steven M. Allin a , Joannah Towler , Sean N. Gaskell , Basu Saha , William P. Martin ,
*
Philip C. Bulman Page e, Mark Edgar b
a School of Physical and Geographical Sciences, Keele University, Keele, ST5 5BG, UK
b Department of Chemistry, Loughborough University, Loughborough, LE11 3TU, UK
c Department of Chemical Engineering, Loughborough University, Loughborough, LE11 3TU, UK
d GSK Pharmaceuticals, Gunnels Wood Road, Stevenage, Herts., SG1 2NY, UK
e School of Chemistry and Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 June 2010
Received in revised form 14 September 2010
Accepted 4 October 2010
Available online 30 October 2010
Pyrroloisoquinoline-based peptidomimetics are of significant interest in bioorganic chemistry as these
targets are known to exhibit type II0
b-turn activity. In this paper we present a novel approach to such
pyrroloisoquinoline templates based on a stereoselective N-acyliminium-mediated cyclization reaction
to construct the heterocyclic core, coupled with an enolate amination protocol. We have applied both
symmetrical and unsymmetrical electrophilic aminating reagents based on azodicarboxylate function-
ality, and demonstrate the utility of our approach in the synthesis of a peptide target.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pyrroloisoquinoline
Electrophilic amination
Peptidomimetic
1. Introduction
demonstrated that such compounds exhibit type II0 -turn activity.7
b
Routes to similar pyrroloisoquinoline-containing peptidomimetics
have been reported by O’Donnell8 and Meldal.9 All of these ap-
proaches to the key pyrroloisoquinoline system have involved the
application of PicteteSpenglerchemistry to construct the heterocycle
with the required amino acid residues in place courtesy of the cor-
Polycyclic lactam scaffolds have been developed as useful tem-
plates for the introduction of reverse-turn motifs, including b-turn
activity, in the study of conformationally restricted peptide ana-
logues.1 The importance of this subject area to medicinal and bi-
ological chemistry is clear since reverse turns play a significant role
in many biological recognition events. Fairlie and co-workers have
recently suggested that more than 100 GPCR’s are able to recognize,
and bind, ligands containing a turn structure.2 In terms of structural
modification of peptide structures to produce pseudopeptides, the
respondinga-amino acidsubstrates employedin the PicteteSpengler
reaction. With this in mind, we envisaged a new approach to ami-
nated pyrroloisoquinoline targets that involved the synthesis of the
key non-racemic heterocyclic framework using our now well-estab-
lished N-acyliminium cyclization methodology,6 followed by elec-
trophilic amination of the lactam ring to introduce the desired
formation of hydrazinopeptidesdin which an
a-amino acid residue
is replaced by an
a
-hydrazino aciddis of significant interest.3 The
a-amino amide functionality.
hydrazino moiety offers additional opportunities for structural
modification (e.g., at either hydrazino N-atom) and added potential
for the formation of novel H-bonded organization in secondary
protein structures. Several synthetic hydrazinopeptides have been
shown to display turn-mimetic activity4 and also possess
wideeranging biological activities (Fig. 1).5
Our research group has an interest in the synthesis of a wide range
of non-racemic heterocyclic targets,6 including the pyrroloisoquino-
line ring system.6a,b Recently, Silvani and co-workers have prepared
pyrroloisoquinoline-based peptide analogues, such as 1, and have
O
H
N
Me
N
H
O
H
O
HN
Me
1
* Corresponding author. E-mail address: s.m.allin@chem.keele.ac.uk (S.M. Allin).
Fig. 1. A pyrroloisoquinoline-derived b-turn mimetic.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.012

S.M. Allin et al. / Tetrahedron 66 (2010) 9538e9544
9539
2. Results and discussion
as shown in Scheme 2. Gratifyingly, compound 4 shares the same
relative and absolute stereochemistry at the three chiral centres as
2.1. Synthesis and derivatization of the pyrroloisoquinoline
template
Silvani’s pyrroloisoquinoline b
-turn lead, 1.7
2.2. Peptide coupling
Pyrroloisoquinoline template 2 was readily prepared as a single
diastereoisomer,6a,b and converted to the corresponding silyl ether
3, as shown in Scheme 1.
Enolate amination was achieved in a highly diastereoselective
fashion through treatment of 3 with LDA in THF at low temperature
and subsequently reacting the lithium enolate with the electrophilic
aminating reagent di-tert-butyl azodicarboxylate (DBAD) to gener-
From compound 4 we were able to remove the TBS-protection
to generate primary alcohol 5, and subsequently remove both Boc-
protecting groups using standard methodologies to yield the novel
hydrazino alcohol 6 (Scheme 3).
Having successfully developed a highly stereoselective route for
introduction of an amine-based substituent into the a-position of
OTBS
O
OH
OH
(i), (ii)
(iii)
N
N
N
O
O
O
H
H
2
3
Scheme 1. Synthesis of pyrroloisoquinoline template: reagents and conditions: (i) NaBH4 (10 equiv), EtOH, 0 ꢀC, 3 h; (ii) 2 M HCl, EtOH, 20 h; then TiCl4 (1.5 equiv), DCM, ꢁ78 ꢀC,
3 h (52% over 2 steps); (iii) DMAP (0.1 equiv), imidazole (1.3 equiv), TBDMS-Cl, (1.25 equiv), DCM, rt, 20 h (98%).
ate the desired
a
-hydrazino ketone product, 4, in 85% yield as a ca.
the lactam ring of the pyrroloisoquinoline template, and with
a view to the potential application of such a system in biological
chemistry, we have also investigated the further manipulation of
the pyrroloisoquinoline template to prepare a typical peptide de-
rivative. Primary alcohol 5 was oxidised to the corresponding car-
boxylic acid, 7, through a two-step procedure (Scheme 4), and 7 was
subsequently utilized in an EDCI-induced coupling with (S)-phe-
nylalanine methyl ester to form the hydrazino peptoid, 8. Due to
significant broadening of the NMR signals at ambient temperature,
the NMR spectrum of 8 was best obtained in DMSO-d6 at elevated
temperature (100 ꢀC).
15:1 mixture of product diastereoisomers by 400 MHz 1H NMR
spectroscopy (Scheme 2). Due to significant broadening of the NMR
signals at ambient temperature, the NMR spectrum of 4 was best
obtained in DMSO-d6 at elevated temperature (100 ꢀC). The major
product diastereoisomer was isolated by column chromatography
and the relative stereochemistry was confirmed by NOE studies
indicating a cis relationship with respect to the newly added
hydrazino substituent and the TBS-protected hydroxymethyl group,
OTBS
OTBS
O
(i), (ii)
2.3. Application of an unsymmetrical aminating reagent
4
N
N
O
H
H
Although the use of DBAD as the electrophilic aminating reagent
was successful in our work, in some respects this reagent suffers
from the drawback of having the same protecting group (i.e., a Boc
group) on each of the hydrazine nitrogen atoms in the product. It
would be of significant advantage, providing added flexibility, if
a suitable reagent containing orthogonal protection could be ap-
plied. This would potentially allow an operator to deprotect each
H
+ve nOe
3
NBoc
H
H
NHBoc
+ve nOe
Scheme 2. Stereoselective amination using DBAD: reagents and conditions: (i) LDA
(1.4 equiv), ꢁ78 ꢀC, THF, 15 min; (ii) DBAD (1.3 equiv), ꢁ78 ꢀC to rt, 20 h (85%).
OTBS
OH
OH
(i)
(ii)
N
O
N
N
O
O
H
H
H
NBoc
NBoc
NH
5
6
4
NH2
NHBoc
NHBoc
Scheme 3. Deprotection of aminated product: reagents and conditions: (i) TBAF (1 equiv), THF, rt, 5 min (45%); (ii) TFA (50 equiv), rt, 24 h (70%).
Ph
OH
O
CO2H
O
N
H
CO2Me
(i), (ii)
(iii)
N
N
N
O
O
H
H
H
NBoc
5
7
8
NBoc
NBoc
NHBoc
NHBoc
NHBoc
Scheme 4. Derivatization to a peptidic product: reagents and conditions: (i) IBX (1.5 equiv), DMSO, rt, 24 h (61%); (ii) NaClO2 (8 equiv), NaH2PO4 (7 equiv), 1-methyl-1-cyclohexene,
MeCN, t-BuOH, H2O, 0 ꢀC, 17 h (80%); (iii) (S)-phenylalanine methyl ester hydrochloride (1.1 equiv), EDCI (1.1 equiv), HOABt (1.1 equiv), NMM (1.1 equiv), DCM, ꢁ15 ꢀC, 3 h (57%).

9540
S.M. Allin et al. / Tetrahedron 66 (2010) 9538e9544
nitrogen atom of the
the possibility of building up a more complex target structure
through derivatization at either N-centre of the -hydrazino group.
A suitably differentiated azodicarboxylate reagent, 9, has pre-
viously been used by Jùrgensen in the synthesis of aminated
2-naphthols,10 and we were interested to see how this reagent
would perform in our own work. Thus, reagent 9 was prepared
accordingly to the method of MacKay11 and applied to the enolate
amination of pyrroloisoquinoline 3 (Scheme 5).
a
-hydrazine substituent in turn, so opening
amination itself. The 400 MHz 1H NMR of compound 11 shows the
appearance of a new broad singlet peak at 4.35 ppm, integrating
accurately for 1H, and also a 1H signal (NH) for the existing tert-
butyl carbamate functionality at 6.40 ppm. This is evidence that the
a
Cbz protection in 10 is situated on the
a
-N-atom and not the al-
-position the
ternative -position. If the Cbz group were at the
b
b
new amine peak would be expected to integrate to 2, and impor-
tantly there would be an absence of the additional NH signal at
6.4 ppm. It was notable that removal of the Cbz-group resulted in
simplification of NMR analysis, with the NMR spectrum for com-
pound 11 obtained in CDCl3 at ambient temperatures.
OTBS
OTBS
H
Following desilylation of the primary alcohol group with TBAF,
the Boc-protecting group on the primary amine functionality was
(i)
5
then removed on treatment with TFA to yield the
a-hydrazino
N
2
10
N
O
O
pyrroloisoquinoline target, 6, that had also been prepared from the
amination protocol using DBAD (Scheme 3).
H
H
3
CbzN NBoc
9
10b
H
NCbz
3. Conclusion
NHBoc
Scheme 5. Application of an unsymmetrical aminating reagent: reagents and condi-
tions: (i) LDA (1.4 equiv), 9 (1 equiv), THF, ꢁ78 ꢀC to rt, 20 h (41%).
In summary, we have developed a novel approach to aminated
pyrroloisoquinoline systems based on a stereoselective N-acylimi-
nium-mediated cyclization reaction to construct the heterocyclic
template, and an enolate amination protocol to functionalize the
lactam ring. We have applied both symmetrical and unsymmetrical
electrophilic aminating reagents based on azodicarboxylate func-
tionality, and have applied our methodology in the synthesis of
a peptide target. The use of an unsymmetrical electrophilic ami-
nating reagent allows us to apply orthogonal deprotection of our
intermediates, adding additional flexibility to our approach. Future
work will aim to investigate the effects of incorporation of the
aminated templates into novel peptide structures.
We were pleased to find that the desired hydrazino product 10
was formed as the major product of the reaction and could be
obtained in 41% isolated yield following column chromatography.
Other by-products were formed in this reaction (as observed by TLC
analysis and by NMR spectroscopy on the crude reaction mixture),
although we were unable to isolate and characterize these. As
a result we are unable to comment confidently at this stage on the
diastereoselectivity of the amination step, or on the overall regio-
selectivity when using reagent 9 in this enolate amination reaction.
Compound 10 was isolated as a single diastereoisomer (by
400 MHz 1H NMR spectroscopy) with the regiochemistry shown in
Scheme 5 (with regards to the amination using reagent 9). An NOE
study was performed on compound 10 to support the assignment
4. Experimental section
4.1. General
of relative stereochemistry at the newly created a-aminated centre
(position 2), and the result was consistent with that observed for
compound 4. Neither of the protons at positions 5 and 10b, nor the
protons at positions 2 and 10b, shows a positive NOE effect towards
each other. This would suggest a trans relationship between the
protons at positions 5 and 10b, and between those at positions 2
and 10b, respectively. The stereochemistry at position 5 is un-
ambiguous, relating to the original enantiomerically pure amino-
alcohol substrate applied to the synthesis of the heterocyclic
template. Due to significant broadening of the NMR signals at
ambient temperature, the NMR spectrum of 10 was obtained in
DMSO-d6 at elevated temperature (100 ꢀC).
With the unsymmetrical amination product 10 in hand we
found that we were readily able to remove the protecting groups in
an orthogonal fashion (Scheme 6). Following the method reported
by Jùrgensen,10 the Cbz-group was selectively removed from the
secondary amine moiety by catalytic hydrogenation to yield the
mono Boc-protected pyrroloisoquinoline, 11, in 88% yield. This re-
action also provided information on the regiochemistry of the
All infrared spectra were obtained using an FT-IR spectropho-
tometer; thin film spectra were acquired using sodium chloride
plates. All 1H and 13C NMR spectra were obtained at 400 and
100 MHz, respectively, in deuteriochloroform solution unless oth-
erwise stated, using TMS (tetramethylsilane) as the internal refer-
ence. Mass spectra were recorded utilizing either electron-impact
(EI), fast atom bombardment (FAB), or electrospray (ES). Analysis by
GCeMS utilized a 15 mꢂ0.25 mm DB-5 column and an electron-
impact low-resolution mass spectrometer. Melting points are un-
corrected. Optical rotation values were measured operating at
l¼589 nm, corresponding to the sodium D line, at the temperatures
indicated. All chromatographic manipulations used silica gel as the
adsorbent. Reactions were monitored using thin layer chromatog-
raphy (TLC) on aluminium-backed plates coated with F254 silica gel.
TLC plates were visualized by UV radiation at a wavelength of
254 nm, or stained by exposure to an ethanolic solution of phos-
phomolybdic acid (acidified with concentrated sulfuric acid), fol-
lowed by charring where appropriate. Reactions requiring
OTBS
OTBS
OH
(i)
(ii), (iii)
N
N
O
N
O
O
H
H
H
10
11
6
NH
NCbz
NH
NHBoc
NHBoc
NH2
Scheme 6. Orthogonal deprotection of 10: reagents and conditions: (i) NHþ4 HCO2ꢁ, Pd/C, MeOH, 2 h (88%); (ii) TBAF, THF, rt, 5 min (48%); (iii) TFA (20 equiv, 24 h (55%).

S.M. Allin et al. / Tetrahedron 66 (2010) 9538e9544
9541
anhydrous conditions were carried out using flame-dried glassware
under a nitrogen atmosphere unless otherwise stated. Reaction
solvents were used as obtained commercially unless otherwise
stated. Light petroleum (bp 40e60 ꢀC) was distilled from calcium
chloride prior to use. Ethyl acetate was distilled over calcium sulfate
or chloride. Dichloromethane was distilled over calcium hydride.
dissolved in anhydrous dichloromethane (20 ml) under a nitrogen
atmosphere. To this solution, tert-butyldimethylsilylchloride
(0.84 ml, 5.59 mmol) was added and the reaction was stirred at
room temperature for 20 h. After 20 h, the resulting mixture was
filtered to remove the solid phase and concentrated under reduced
pressure. The crude product was adsorbed onto silica gel and
chromatographed using silica gel as absorbent and 10% methanol in
dichloromethane as eluent to isolate the target compound as an oil
4.1.1. (S)-1-(1-Hydroxy-3-phenylpropan-2-yl)pyrrolidine-2,5-dio-
ne6b. Succinic anhydride (1.20 g, 12.0 mmol) and (S)-2-amino-3-
phenyl-1-propanol (1.80 g, 12.0 mmol) were stirred in toluene
(100 ml) under a nitrogen atmosphere. Triethylamine (3 ml) was
added to the resultant solution and the mixture heated under
reflux for 18 h. After 18 h, the reaction was cooled to room tem-
perature and the solvent removed by rotary evaporation. The crude
product was adsorbed onto silica gel and chromatographed using
silica gel as absorbent and ethyl acetate as eluent to produce
a colourless solid (1.70 g, 62%). Mp 130e131 ꢀC. Rf (EtOAc) 0.6. 1H
NMR (400 MHz; CDCl3) 2.50e2.63 (4H, m), 3.07e3.17 (2H, m), 3.84
(1H, dd, J¼3.5, 11.9 Hz), 4.00 (1H, dd, J¼7.6, 11.9 Hz), 4.48e4.55 (1H,
m), 7.18e7.29 (5H, m). 13C NMR (100 MHz; CDCl3) 27.8 (2C), 33.7,
55.7, 62.1,126.8,128.5 (2C),129.1 (2C),137.2,178.2 (2C). IR (thin film,
CH2Cl2, cmꢁ1) 3419, 1763, 1682. MS (EI) m/z 233 [Mþ, 3%] (calcd for
C13H15NO3: 233.1052 (Mþ). Found 233.1055).
(1.45 g, 98%). Rf (10% MeOH/DCM) 0.38. [
a
]
20 þ33 [c 1.12 in CH2Cl2].
D
1H NMR (400 MHz, CDCl3) 0.01 (3H, s), 0.02 (3H, s), 0.84 (9H, s),
1.90e2.00 (1H, m), 2.41e2.49 (1H, m), 2.50e2.68 (3H, m), 2.89 (1H,
dd, J¼3.2, 16.4 Hz), 3.02 (1H, dd, J¼6.8, 16.4 Hz), 3.66 (1H, dd, J¼6.0,
10.4 Hz), 3.76 (1H, dd, J¼6.0,10.4 Hz), 4.46e4.51 (1H, m), 4.81 (1H, t,
J¼8.0 Hz), 7.14e7.25 (4H, m). 13C NMR (100 MHz, CDCl3) ꢁ5.5, ꢁ5.6,
18.0, 25.7 (3C), 26.9, 29.3, 31.7, 48.0, 54.9, 62.7, 124.2, 126.5, 127.0,
129.2, 132.8, 137.1, 173.7. IR (thin film, CH2Cl2, cmꢁ1) 1702. MS (EI)
m/z 331 [Mþ, 22%] (Calcd for C19H29NO2Si: 331.1968 (Mþ). Found:
331.1963).
4.1.4. (2S,5S,10bR)-2-N,N0-Bis-(3,3-tert-butyl ester)-hydrazino-5-(tert-
butyl-dimethyl-silanyloxymethyl-1-5,6,10b-tetrahydro-2H-pyrrolo[2,1-
a]isoquinolin-3-one, (4). n-Butyl lithium (1.9 ml, 4.98 mmol) was
cautiously added to a stirred solution of diisopropylamine (0.71 ml,
4.98 mmol) in anhydrous tetrahydrofuran (20 ml) at 0 ꢀC under
a nitrogen atmosphere. The reaction was stirred at 0 ꢀC for further
15 min, then cooled to ꢁ78 ꢀC. (5S,10bR)-5-((tert-Butyldimethylsilyl-
oxy)methyl)-1,2,5,6-tetrahydropyrrolo[2,1-a]isoquinolin-3(10bH)-
one, 3, (1.20 g, 3.61 mmol) in anhydrous tetrahydrofuran (20 ml)
was added and the reaction was allowed to stir for 15 min at
ꢁ78 ꢀC. Di-tert-butyl azodicarboxylate (1.08 g, 4.69 mmol) in an-
hydrous tetrahydrofuran (15 ml) was then added dropwise via sy-
ringe at ꢁ78 ꢀC and the reaction was then allowed to warm to room
temperature overnight. The reaction was quenched by addition of
saturated ammonium chloride and the product extracted into ethyl
acetate (3ꢂ60 ml). The combined organic phases were then dried
over anhydrous magnesium sulfate and the solvent removed on the
rotary evaporator to yield the target compound as a 15:1 mixture of
diastereoisomers by 1H NMR spectroscopy on the crude reaction
product. The crude product was adsorbed onto silica and purified
by column chromatography using silica gel as absorbent and using
a 2:1 mixture of light petroleum and ethyl acetate as eluent to yield
a yellow solid (1.83 g, 85%). Mp 70e72 ꢀC. Rf (2:1, petroleum ether/
4.1.2. (5S,10bR)-5-(Hydroxymethyl)-1,2,5,6-tetrahydropyrrolo[2,1-a]-
isoquinolin-3(10bH)-one, (2)6b. (S)-1-(1-Hydroxy-3-phenylpropan-
2-yl)pyrrolidine-2,5-dione (5.00 g, 21.4 mmol) was dissolved in
absolute ethanol (100 ml) and cooled to 0 ꢀC. Sodium borohydride
(8.11 g, 214.4 mmol) was then added with stirring. A 2 M solution of
HCl in absolute ethanol (10.7 ml, 21.4 mmol) was then added slowly
via syringe over a 3 h period. The resulting solution was acidified to
pH 1e3 by the addition of a 2 M solution of HCl in absolute ethanol
over a 15 min period. This afforded a white suspension, which was
stirred for a further 20 h. The reaction was quenched with a satu-
rated aqueous solution of sodium hydrogen carbonate and extracted
with dichloromethane (3ꢂ50 ml). The dichloromethane layers were
then combined and dried over anhydrous magnesium sulfate, fil-
tered and the solvent removed by rotary evaporation to yield an
ethoxy lactam intermediate as a colourless oil (4.60 g). Without
purification the intermediate ethoxy lactam (4.60 g, 17.6 mmol) was
dissolved in anhydrous dichloromethane (100 ml) under a nitrogen
atmosphere and cooled to ꢁ78 ꢀC. Titanium tetrachloride (2.89 ml,
26.4 mmol) was then slowly added via syringe over a 30 min period.
The reaction was allowed to reach room temperature and stirred for
a further 20 h. The reaction was quenched with aqueous ammonium
chloride and extracted with dichloromethane (3ꢂ50 ml). The
dichloromethane layers were then combined and dried over anhy-
drous magnesium sulfate, filtered and the solvent removed by ro-
EtOAc) 0.6. [
a
]
20 ꢁ16.3 [c 1.08 in CH2Cl2]. 1H NMR (400 MHz, DMSO,
D
100 ꢀC) 0.01 (3H, s), 0.02 (3H, s), 0.85 (9H, s),1.42 (9H, s),1.45 (9H, s),
2.33e2.34 (1H, m), 2.69e2.73 (1H, m), 2.86e2.99 (2H, m), 3.69 (1H,
dd, J¼6.8, 10.0 Hz,), 3.77 (1H, dd, J¼4.4, 10.0 Hz), 4.16e4.18 (1H, m),
4.55 (1H, dd, J¼6.0, 8.4 Hz), 4.75 (1H, t, J¼7.2 Hz), 7.19e7.24 (4H, m),
8.45 (1H, s). 13C NMR (100 MHz, DMSO, 100 ꢀC) ꢁ6.1 (2C), 17.2, 25.2
(3C), 27.4 (3C), 27.5 (3C), 28.4, 28.9, 48.2, 52.0, 62.9, 78.4, 79.2, 80.1,
123.3, 125.8, 126.3, 128.2, 132.8, 136.8, 153.6, 155.1, 168.2. IR (thin
film, CH2Cl2, cmꢁ1) 3271,1715,1682. MS (FAB) m/z 562 [MþHþ, 22%]
(Calcd for C29H48N3O6Si: 562.3312 (MþHþ). Found: 562.3304).
tary evaporation to yield the target compound as
a single
diastereoisomer, by 400 MHz 1H NMR spectroscopy, which was
purified by column chromatography using silica gel as absorbent
and 10% methanol in dichloromethane as eluent to yield a pale
green solid (2.00 g, 52%). Mp 110e111 ꢀC. Rf (10% MeOH/DCM) 078.
1H NMR (400 MHz; CDCl3) 1.97e2.07 (1H, m), 2.41e2.51 (1H, m),
2.59e2.74 (3H, m), 3.04 (1H, dd, J¼6.4, 16.4 Hz), 3.59e3.73 (2H, m),
4.14 (1H, br s), 4.43e4.49 (1H, m), 4.83 (1H, t, J¼7.6 Hz), 7.09e7.31
(4H, m). 13C NMR (100 MHz, CDCl3) 26.6, 29.6, 31.7, 49.5, 54.5, 62.8,
124.3, 126.9, 127.2, 128.7, 132.3, 136.7, 175.2. IR (thin film, CH2Cl2,
cmꢁ1) 3374, 1643. MS (EI) m/z 217 [Mþ, 8%] (calcd for C13H15NO2:
217.1103 (Mþ). Found: 217.1105.).
4.1.5. Di-tert-butyl-1-((2S,5S,10bR)-5-(hydroxymethyl)-3-oxo-
1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinolin-2-yl)hydrazine-1,2-
dicarboxylate, (5). To a solution of (2S,5S,10bR)-2-N,N0-bis-(3,3-tert-
butyl ester)-hydrazino-5-(tert-butyl-dimethyl-silanyloxymethyl-1-
5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one, 4, (0.33 g,
0.59 mmol) in tetrahydrofuran (20 ml) was added a 1 M solution of
tetra-butyl ammonium fluoride in tetrahydrofuran (0.58 ml,
0.58 mmol) and the reaction was stirred for 5 min at room tem-
perature under a nitrogen atmosphere. The resultant solution was
concentrated and chromatographed through a pad of silica gel
using 2:1 light petroleum/ethyl acetate as eluent to yield the target
compound as a yellow solid (0.12 g, 45%). Mp 92e95 ꢀC. Rf (2:1,
4.1.3. (5S,10bR)-5-((tert-Butyldimethylsilyloxy)methyl)-1,2,5,6-tetra-
hydropyrrolo[2,1-a]isoquinolin-3(10bH)-one, (3). Imidazole (0.39 g,
5.82 mmol) and 4-dimethylaminopyridine (0.05 g, 0.45 mmol) fol-
lowed by (5S,10bR)-5-(hydroxymethyl)-1,2,5,6-tetrahydropyrrolo
[2,1-a]isoquinolin-3(10bH)-one, 2, (0.97 g, 4.47 mmol) were
petroleum ether/EtOAc) 0.45. [
a
]
20 þ16.8 [c 1.00 in CH2Cl2]. 1H NMR
D

9542
S.M. Allin et al. / Tetrahedron 66 (2010) 9538e9544
(400 MHz, DMSO, 100 ꢀC) 1.45 (9H, s), 1.46 (9H, s), 2.31e2.35 (1H,
m), 2.72e2.78 (1H, m), 2.85e3.02 (2H, m), 3.50e3.59 (2H, m),
4.15e4.18 (1H, m), 4.41 (1H, t, J¼6.0 Hz), 4.53 (1H, dd, J¼4.4, 8.4 Hz),
4.79 (1H, t, J¼6.8 Hz), 7.18e7.26 (4H, m), 8.40 (1H, br s). 13C NMR
(100 MHz, DMSO, 100 ꢀC) 28.4 (3C), 28.5 (3C), 29.4, 30.3, 49.9, 52.7,
60.4, 61.7, 80.3, 81.2, 124.3, 126.8, 127.3, 129.4, 133.8, 137.8, 154.6,
156.0, 164.9. IR (thin film, CH2Cl2, cmꢁ1) 3409, 3273, 1697. MS (EI)
m/z 448 [MþHþ, 4%] (Calcd for C23H34N3O6: 448.2449 (MþHþ).
Found: 448.2441.).
period and the reaction stirred at room temperature for 17 h. The
reaction mixture was added to a solution of saturated brine/ethyl
acetate (1:1) (50 ml) and product extracted with ethyl acetate
(3ꢂ50 ml). The organic extracts were combined and washed with
a 1 M solution of sodium hydrosulfite, dried over anhydrous
magnesium sulfate, filtered and evaporated under reduced pres-
sure to a crude brown residue. The crude product was adsorbed
onto silica and chromatographed using silica gel as absorbent and
2:1 light petroleum/ethyl acetate as eluent to produce a yellow
solid (713 mg, 80%). The product still contained some impurities
that we were unable to remove by chromatography. For this
reason, the intermediate carboxylic acid was reacted on in its crude
state.
4.1.6. 2-((2S,5S,10bR)-5-(Hydroxymethyl)-3-oxo-1,2,3,5,6,10b-hexahy-
dropyrrolo[2,1-a]isoquinolin-2-yl)hydrazine, (6). Di-tert-butyl-1-((2S,
5S,10bR)-5-(hydroxymethyl)-3-oxo-1,2,3,5,6,10b-hexahydropyrrolo[2,
1-a]isoquinolin-2-yl)hydrazinocarboxylate, 5, (90 mg, 0.20 mmol)
and trifluoroacetic acid (0.78 ml, 10.1 mmol) were allowed to stir at
room temperature under a nitrogen atmosphere for 24 h. After this
time the mixture was concentrated under reduced pressure, and the
residue treated with an aqueous 3 M solution of HCl (15 ml) and the
solution allowed to stir for further 1 h. After this time the solution
was concentrated under reduced pressure and the residue dissolved
in water (20 ml) and washed with ethyl acetate (3ꢂ20 ml). The
aqueous phase was then evaporated to dryness using a rotary evap-
orator to yield a yellow oil (30 mg, 70%). Rf (10% MeOH/DCM) 0.11.
4.1.9. (2S,5S,10bR,30S)-2-N,N0-Bis-(3,3-tert-butyl ester)-hydrazino-2-
[(3-oxo-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline-5-car-
bonyl)-amino]-3-phenyl-propionic acid methyl ester, (8). (2S,5S,10bR)-
2-N,N0-Bis-(3,3-tert-butyl ester)-hydrazino-3-oxo-1,2,3,5,6,10b-hexa
hydro-pyrrolo[2,1-a]isoquinoline-5-carboxylic acid, 7, (713 mg,
1.55 mmol) was dissolved in anhydrous dichloromethane (30 ml)
and cooled to ꢁ15 ꢀC under nitrogen. 1-Hydroxyazabenzotriazole
(231 mg, 1.70 mmol) and 1-ethyl-3-[(dimethylamino) propyl]carbo-
diimide hydrochloride (326 mg, 1.70 mmol) were added and re-
action stirred for 20 min at ꢁ15 ꢀC. N-Methyl morpholine (172 mg,
0.19 ml, 1.70 mmol) and (S)-phenylalanine methyl ester hydrochlo-
ride (366 mg, 1.70 mmol) were added and the reaction stirred for
a further 3 h at ꢁ15 ꢀC. An ice-cold solution of 1 M HCl (6 ml) was
added and reaction extracted with dichloromethane (3ꢂ30 ml). The
organic phase was washed with saturated sodium bicarbonate, dried
over anhydrous magnesium sulfate, filtered and the solvent removed
by rotary evaporation to yield a crude orange residue. The crude
product was adsorbed onto silica and chromatographed using silica
gel as absorbent and 1:1 ethyl acetate/light petroleum as eluent to
[
a
]
20 þ14.5 [c 0.58 in MeOH]. 1H NMR (400 MHz, D2O) 2.38e2.46 (1H,
D
m), 2.51e2.58 (1H, m), 2.67 (1H, dd, J¼3.2, 16.4 Hz), 2.96 (1H, dd,
J¼6.8, 16.4 Hz), 3.51e3.59 (1H, dd, J¼8.8, 12 Hz), 3.62e3.67 (1H, dd,
J¼5.2, 12 Hz), 3.83e3.86 (1H, dd, J¼4.4, 8.8 Hz), 4.22e4.28 (1H, m),
4.92 (1 t, J¼7.2 Hz), 7.10e7.37 (4H, m). 13C NMR (100 MHz, D2O) 28.5,
29.5, 49.7, 52.7, 59.2, 60.7, 124.3, 126.9, 127.6, 129.2, 132.3, 135.4, 172.0.
IR (thin film, CH2Cl2, cmꢁ1) 3386, 1680. MS (EI) m/z 248 [MþHþ,100%]
(Calcd for C13H18N3O2: 248.1394 (MþHþ). Found: 248.1395).
4.1.7. (2S,5S,10bR)-2-N,N0-Bis-(3,3-tert-butyl
ester)-hydrazino-3-
oxo-1,2,3,5,6,10b-hexa hydro-pyrrolo[2,1-a]isoquinoline-5-carbalde-
hyde. o-Iodoxybenzoic acid (221 mg, 0.794 mmol) was added to
a solution of (2S,5S,10bR)-2-N,N0-bis-(3,3-tert-butyl ester)-hydra-
zino-5-hydroxymethyl-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]iso-
quinolin-3-one, 5, (237 mg, 0.530 mmol) in dimethyl sulfoxide
(20 ml) and the reaction stirred for 24 h at room temperature. The
reaction mixture was added to a solution of ethyl acetate/water
and the organic product extracted with ethyl acetate (3ꢂ30 ml).
The organic layer was washed with water (3ꢂ30 ml), dried over
anhydrous magnesium sulfate, filtered and evaporated to a crude
yellow solid. The crude product was adsorbed onto silica and
chromatographed using silica gel as absorbent and 1:1 ethyl ace-
tate/light petroleum as eluent to isolate the target compound as
a colourless solid (144 mg, 61%). Mp 84e87 ꢀC. Rf (2:1, petroleum
isolate the target compound as a colourless solid (549 mg, 57%). Mp
20
89e92 ꢀC. Rf (EtOAc) 0.75. [
a]
D
ꢁ28.0 [c 1.10 in CH2Cl2]. 1H NMR
(400 MHz, DMSO, 100 ꢀC) 1.48 (18H, s), 2.34 (1H, ddd, J¼6.0, 10.0,
13.6 Hz), 2.76e2.82 (1H, m), 2.91e3.05 (2H, m), 3.07e3.23 (2H, m),
3.60 (3H, s), 4.48 (1H, dd, J¼4.4, 9.6 Hz), 4.59e4.64 (1H, m),
4.67e4.72 (1H, m), 4.76 (1H, dd, J¼3.6, 7.2 Hz), 7.05e7.26 (9H, m),
7.75 (1H, d, J¼8.0 Hz), 8.62 (1H, br s). 13C NMR (100 MHz, DMSO,
100 ꢀC) 28.4 (3C), 28.6 (3C), 29.8, 30.5, 37.4, 50.8, 52.1, 52.9, 54.1, 60.9,
80.4, 81.5, 124.7, 126.8, 126.9, 127.2, 128.5 (2C), 129.0, 129.3 (2C),
132.7, 137.4, 137.6, 154.8, 155.9, 169.6, 169.8, 171.9. IR (thin film,
CH2Cl2, cmꢁ1) 3342, 1738, 1699. MS (ES) m/z 623 [MþHþ, 100%]
(Calcd for C33H43N4O8: 623.3081 (MþHþ). Found 623.3077).
4.1.10. 1-Benzyl 2-tert-butyl hydrazine-1,2-dicarboxylate10,11. A so-
lution of Boc-hydrazine (3.20 g, 24.21 mmol) in dichloromethane
(100 ml) was cooled to ꢁ78 ꢀC under a nitrogen atmosphere. Ben-
zyl chloroformate (4.09 ml, 29.06 mmol) was cautiously added
with stirring, followed by sodium carbonate (2.50 g, 24.21 mmol).
The reaction was then stirred for 24 h. After this time the reaction
mixture was evaporated to dryness and redissolved in hot ethyl
acetate (100 ml, refluxed for 1 h). The hot solution was then filtered
and the solvent removed by evaporation under reduced pressure to
yield a white solid that was used without further purification
(6.31 g, 98%). Mp 252e253 ꢀC. 1H NMR (400 MHz, CDCl3) 1.53 (9H,
s), 5.17 (2H, s), 6.33 (1H, s), 6.53 (1H, s), 7.31e7.37 (5H, m). 13C NMR
(400 MHz, CDCl3) 28.1 (3C), 67.8, 81.9,127.0,128.3, 128.4 (2C), 128.6,
135.6, 155.7, 156.7. IR (thin film, CH2Cl2, cmꢁ1) 3302, 1715. MS (EI)
m/z 266 [MþHþ, 100%] (Calcd for C13H19N2O4: 267.1339 (MþHþ).
Found: 267.13418).
ether/EtOAc) 0.6. [
a
]
20 ꢁ8.80 [c 1.00 in CH2Cl2]. 1H NMR (400 MHz,
D
DMSO, 100 ꢀC) 1.46 (18H, s), 2.31e2.38 (1H, m), 2.83e3.20 (3H, m)
4.65 (1H, dd, J¼3.2, 9.2 Hz), 4.72 (1H, dd, J¼5.2, 7.6 Hz), 4.89 (1H, t,
J¼7.2 Hz), 7.17e7.36 (4H, m), 8.57 (1H, br s), 9.64 (1H, s). 13C NMR
(100 MHz, DMSO, 100 ꢀC) 26.9, 28.4 (3C), 28.5 (3C), 31.2, 53.3, 56.7,
60.0, 80.4, 81.3, 124.7, 127.4, 127.5, 129.1, 132.3, 137.4, 154.5, 156.0,
170.0, 200.0. IR (thin film, CH2Cl2, cmꢁ1) 3281, 1730, 1700. MS (ES)
m/z 446 [MþHþ, 100%] (Calcd for C23H32N3O6: 446.2291 (MþHþ).
Found: 446.2364).
4.1.8. (2S,5S,10bR)-2-N,N0-Bis-(3,3-tert-butyl
ester)-hydrazino-3-
oxo-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline-5-carboxylic
acid, (7). A solution of (2S,5S,10bR)-2-N,N0-bis-(3,3-tert-butyl
ester)-hydrazino-3-oxo-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]iso-
quinoline-5-carbaldehyde (862 mg, 1.94 mmol) in acetonitrile
(28 ml), tert-butanol (80 ml) and 1-methyl-1-cyclohexene (28 ml)
was stirred rapidly as it cooled to 0 ꢀC. A solution of sodium chlorite
(1.68 g, 14.9 mmol) and sodium dihydrogen phosphate (1.63 g,
13.5 mmol) in water (55 ml) was added dropwise over a 10 min
4.1.11. (E)-1-Benzyl 2-tert-butyl diazene-1,2-dicarboxylate, (9)10,11. 1-
Benzyl 2-tert-butyl hydrazine-1,2-dicarboxylate (3.29 g,12.48 mmol)
wasaddedinoneportiontoasolutionofN-bromosuccinimide(1.34 g,

S.M. Allin et al. / Tetrahedron 66 (2010) 9538e9544
9543
11.32 mmol) and pyridine (0.91 ml, 11.32 mmol) in dichloromethane
(150 ml) in a separating funnel. After 30 min, during which time the
funnel was occasionally shaken to ensure dissolution of all the hy-
drazine, the reaction mixture was washed with water (3ꢂ75 ml), and
the organic phase was then dried over anhydrous magnesium sulfate,
filtered and evaporated under reduced pressure to yield an orange oil
(0.66 g, 20%). Rf (3:1, petroleumether/EtOAc) 0.83.1H NMR (400 MHz,
CDCl3) 1.53(9H, s), 5.36(2H, s), 7.32e7.38(5H, m).13C NMR (400 MHz,
CDCl3) 27.3 (3C), 70.7, 87.2, 128.6, 128.8 (2C), 128.9, 129.2, 133.7, 158.9,
160.4. IR (thin film, CH2Cl2, cmꢁ1) 1774.
25.8 (3C), 28.4 (3C), 29.3, 30.1, 49.1, 53.1, 61.0, 63.1, 80.7, 123.7, 126.5,
127.3,129.1,133.6,136.9,156.7,171.9. IR (thin film, CH2Cl2, cmꢁ1) 3286,
1688. MS (EI) m/z 462 [MþHþ, 100%] (Calcd for C24H40N3O4Si:
462.2783 (MþHþ). Found: 462.2780).
4.1.14. tert-Butyl-1-((2S,5S,10bR)-5-(hydroxymethyl)-3-oxo-
1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinolin-2-yl)hydrazino-
carboxylate. To
a
solution of tert-butyl 2-((2S,5S,10bR)-5-
((tert-butyldimethylsilyloxy)methyl)-3-oxo-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-2-yl)hydrazinocarboxylate, 11, (0.15 g,
0.35 mmol) in tetrahydrofuran (20 ml) was added a 1 M solution of
tetra-butyl ammonium fluoride in tetrahydrofuran (0.35 ml,
0.35 mmol) and the reaction stirred for 5 min at room temperature
under a nitrogen atmosphere. The resultant solution was concen-
trated under reduced pressure and chromatographed through a pad
of silica using ethyl acetate as eluent to yield the target compound as
4.1.12. 1-Benzyl 2-tert-butyl 1-((2S,5S,10bR)-5-((tert-butyldimethyl-
silyloxy)methyl)-3-oxo-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]iso-
quinolin-2-yl)hydrazine-1,2-dicarboxylate, (10). n-Butyl lithium
(0.85 ml, 2.14 mmol) was cautiously added to a stirring solution of
diisopropylamine (0.30 ml, 2.14 mmol) in anhydrous tetrahydro-
furan (20 ml) at 0 ꢀC and under a nitrogen atmosphere. The reaction
was stirred at 0 ꢀC for a further 15 min then cooled to ꢁ78 ꢀC.
(5S,10bR)-5-((tert-Butyldimethylsilyloxy)methyl)-1,2,5,6-tetrahy-
dropyrrolo[2,1-a]isoquinolin-3(10bH)-one, 3, (0.52 g, 1.55 mmol)
in anhydrous tetrahydrofuran (20 ml) was added and the reaction
was allowed to stir for 15 min at ꢁ78 ꢀC. (E)-1-benzyl 2-tert-butyl
diazene-1,2-dicarboxylate, 9, (0.41 g, 1.55 mmol) in anhydrous tet-
rahydrofuran (15 ml) was then added dropwise at ꢁ78 ꢀC and the
reaction allowed to warm to room temperature overnight. The re-
action was quenched by addition of saturated ammonium chloride
and the product extracted into ethyl acetate (3ꢂ50 ml). The com-
bined organic phases were then dried over anhydrous magnesium
sulfate and the solvent removed by rotary evaporation. The crude
product was adsorbed onto silica and purified by column chro-
matography using silica gel as absorbent and using a 2:1 mixture of
light petroleum and ethyl acetate as eluent to yield a yellow solid
(0.34 g, 41%). Mp 68e70 ꢀC. Rf (2:1, petroleum ether/EtOAc) 0.55.
a yellow oil (59 mg, 48%). Rf (EtOAc) 0.2. [
a
]
20 þ18.9 [c 0.17 in MeOH].
D
1H NMR (400 MHz, CDCl3) 1.45 (9H, s), 2.24e2.27 (1H, m), 2.69e2.74
(2H, m), 2.99e3.05 (1H, m), 3.40e3.43 (1H, m), 3.61e3.81 (4H, m),
4.37e4.38 (1H, m), 4.95 (1H, t, J¼7.2 Hz), 7.11e7.23 (4H, m). 13C NMR
(100 MHz, CDCl3) 28.4 (3C), 29.5, 50.2, 52.7, 61.5, 62.4, 73.4, 80.8,
124.2, 126.8, 127.3, 129.0, 132.6, 136.4, 156.7, 173.0. IR (thin film,
CH2Cl2, cmꢁ1) 3400, 3284, 1692. MS (EI) m/z 348 [MþHþ, 100%]
(Calcd for C18H26N3O4: 348.1918 (MþHþ). Found: 348.1920).
4.1.15. 2-((2S,5S,10bR)-5-(hydroxymethyl)-3-oxo-1,2,3,5,6,10b-hex-
ahydropyrrolo[2,1-a]isoquinolin-2-yl)hydrazinium, (6). tert-Butyl-2-
((2S,5S,10bR)-5-(hydroxymethyl)-3-oxo-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-2-yl)hydrazinecarboxylate (0.11 g, 0.33
mmol, from Section 4.1.14) and trifluoroacetic acid (0.51 ml,
6.56 mmol) were allowed to stir at room temperature under a nitro-
gen atmosphere for 24 h. After 24 h, the mixture was concentrated
under reduced pressure, and the residue treated with aqueous 3 M
solution of HCl (15 ml) and the solution allowed to stir for further 1 h.
After 1 h, the solution was concentrated under reduced pressure and
the residue dissolved in water (20 ml) and washed with ethyl acetate
(3ꢂ20 ml). The aqueous phase was then evaporated to dryness using
a rotaryevaporator to yield a yellow oil (51 mg, 55%). Spectral analysis
was identical to that reported above (See Section 4.1.6).
[
a]
20 þ9.5 [c 0.38 in MeOH]. 1H NMR (400 MHz, DMSO, 100 ꢀC) 0.03
D
(6H, s), 0.84 (9H, s), 1.43 (9H, s), 2.33e2.45 (1H, m), 2.70e2.85 (1H,
m), 2.85e3.0 (2H, m), 3.66e3.70 (1H, m), 3.78 (1H, dq, J¼4.8,
10.4 Hz), 4.17e4.20 (1H, m), 4.60e4.70 (1H, m), 4.78 (1H, t,
J¼6.8 Hz), 5.09e5.16 (2H, m), 7.18e7.23 (4H, m), 7.34e7.40 (5H),
8.80 (1H, br s). 13C NMR (100 MHz, DMSO, 100 ꢀC) ꢁ5.1 (2C), 18.2,
26.1 (3C), 28.5 (3C), 29.4, 29.5, 49.2, 53.0, 60.5, 63.8, 67.7, 80.5,
124.2, 126.8, 127.3, 127.9 (2C), 128.2, 128.6, 129.2 (2C), 133.7, 136.7
(2C), 155.6 (2C), 168.8. IR (thin film, CH2Cl2, cmꢁ1) 2921, 1756, 1715.
MS (FAB) m/z 595 [MþHþ, 21%] (Calcd for C32H46N3O6Si: 596.31559
(MþHþ). Found: 596.31533).
Acknowledgements
The authors wish to thank the Universities of Keele & Lough-
borough for facilities and financial support, the EPSRC Eng. D.
programme (Loughborough) and Charnwood Molecular for stu-
dentship support to J.M.R.T., and GSK Pharmaceuticals and Lough-
borough University for studentship support to S.N.G. We also thank
Prof. Alessandra Silvani for helpful discussions.
4.1.13. tert-Butyl-2-((2S,5S,10bR)-5-((tert-butyldimethylsilyloxy)
methyl)-3-oxo-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinolin-2-yl)
hydrazinecarboxylate, (11). 1-Benzyl 2-tert-butyl 1-((2S,5S,10bR)-
5-((tert-butyldimethylsilyloxy)methyl)-3-oxo-1,2,3,5,6,10b-hexahy-
dropyrrolo[2,1-a]isoquinolin-2-yl)hydrazine-1,2-dicarboxylate, 10
(0.35 g, 0.58 mmol) was dissolved in methanol (10 ml) and added to
a suspension of palladium on carbon (0.18 g, loading 10% Pd) under
a nitrogen atmosphere. Ammonium formate (3.50 g, 55 mmol) in
methanol (10 ml) was added dropwise and allowed to stir at room
temperature for 2 h. After this time, the solution was filtered through
Celite and the resulting solution was extracted with ethyl acetate
(3ꢂ30 ml) and the combined organic phases were dried over anhy-
drous sodium sulfate and the solvent removed by rotary evaporation
to yield the crude product, which was purified by column chroma-
tography using silica gel as adsorbent and ethyl acetate as eluent to
produce a yellow solid (0.23 g, 88%). Mp 118e120 ꢀC. Rf (EtOAc) 0.47.
Supplementary data
Supplementary data associated with this article can be found in
online version at 10.1016/j.tet.2010.10.012.
References and notes
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]
20 þ4.3 [c 0.28 in MeOH].1H NMR (400 MHz, CDCl3) ꢁ0.045 (6H, s),
D
0.81 (9H, s), 1.44 (9H, s), 2.35e2.36 (1H, m), 2.49e2.52 (1H, m) 2.96
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