Deacetalisation-bicyclisation routes to novel polycyclic heterocycles using stannous chloride dihydrate

Article abstract of DOI:10.1016/j.tetlet.2007.07.018

The stannous chloride dihydrate-mediated deprotection-bicyclisation of a range of amides possessing a pendant acetal group is reported. These mild reaction conditions have been used to prepare a number of ring-fused heterocyclic compounds, some in enantio

Full text of DOI:10.1016/j.tetlet.2007.07.018

Tetrahedron Letters 48 (2007) 6556–6560
Deacetalisation–bicyclisation routes to novel polycyclic
heterocycles using stannous chloride dihydrate
a
b
a
a
´
´
Alex N. Cayley, Rhona J. Cox, Cecilia Menard-Moyon, Jan Peter Schmidt and
Richard J. K. Taylora,*
aUniversity of York, Department of Chemistry, Heslington, York YO10 5DD, UK
bAstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Road, Loughborough LE11 5RH, UK
Received 11 June 2007; revised 25 June 2007; accepted 5 July 2007
Available online 6 August 2007
Abstract—The stannous chloride dihydrate-mediated deprotection–bicyclisation of a range of amides possessing a pendant acetal
group is reported. These mild reaction conditions have been used to prepare a number of ring-fused heterocyclic compounds, some
in enantiomerically pure form, which should be of interest both in their own right and as building blocks for the production of more
complex target molecules.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Polycyclic heterocycles are considered to be ‘privileged
structures’ in the pharmaceutical and agrochemical
industries.1 For this reason, methods of producing a
diverse range of such compounds with a relatively low
molecular weight are invaluable in the search for bio-
active lead compounds. Herein we report the prepara-
tion of a variety of polycyclic heterocyclic systems using
stannous chloride dihydrate in the key step. Stannous
O
O
O
O
SnCl2.2H2O
DCM, rt, 48 h
66%
OBn
2
1
H
Boc
SnCl2.2H2O
N
H
OTIPS
OTIPS
DCM, rt, 12 h
76%
N
O
BnO
O
H
Boc
3
4
O
SnCl2.2H2O
O
OBn
N
O
DCM, rt, 1 h
96% (1:1)
O
HN
OBn
6
O
OH
5
Scheme 1.
Keywords: Heterocycles; Stannous chloride; Deacetalisation; Bicyclisation.
*
Corresponding author. Fax: +44 (0)1904 43 4523; e-mail: rjkt1@ york.ac.uk
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.018

A. N. Cayley et al. / Tetrahedron Letters 48 (2007) 6556–6560
6557
O
O
O
R2
O
R2
m
R2
m
HX
H2N
HX
X
H
n
n
+
n
N
N
CO2H
R1
10
O
R1
O
R1
7
9
8
O
O
O
R1
O
X
R1
m
HX
R1
m
HX
HO2C
14
H
n
+
n
n
N
N
NH2
m
O
O
11
12
13
Scheme 2. X = O, S, NR3.
chloride is widely used as a reducing agent and Lewis
acid catalyst2 and, as its dihydrate, it has been employed
as a mild reagent for the deprotection of acetals.3 In re-
cent natural product ventures, we discovered that stan-
nous chloride dihydrate can be employed to mediate
several useful deprotection–cyclisation sequences. Thus,
as illustrated in Scheme 1, treatment of acetal 1 with
SnCl2Æ2H2O gave the bicyclic product 2 (the core unit
of the novel HIV-1 integrase inhibitors, integrastatins
A and B) via a presumed acetal deprotection–debenzyla-
SnCl2Æ2H2O cyclisation procedure, with the required
amides in turn being produced by the coupling of
dioxolanes 9 and 13 with corresponding partners 10
and 14 (Scheme 2).
In order to evaluate the feasibility of these processes, the
reaction shown in Scheme 3 was investigated. The read-
ily available acid 9a9 was coupled to L-cysteine deriva-
tive 10a using standard conditions giving amide 8a in
60% isolated yield.10 On treatment of amide 8a with
SnCl2Æ2H2O in dichloromethane (DCM) for 72 h we
were delighted to obtain methyl 5-oxohexahydropyr-
rolo[2,1-b]thiazole-3-carboxylate 7a in 70% yield. This
tion–hemi-acetal
formation–alkene
etherification
sequence.4
In a related manner, on treatment with SnCl2Æ2H2O, the
acetals 3 and 5 undergo a deacetalisation–cyclisation or
deacetalisation–bicyclisation process giving the hetero-
cyclic products 45 and 6,6 respectively. The latter
SnCl2Æ2H2O procedure was subsequently employed by
Han and Ong to prepare compounds related to 6 but
containing iron tricarbonyl-cyclohexadiene fragments,
thus establishing still further its mild nature.7
one-pot deprotection–bicyclisation process produced 7a
23
as a single diastereoisomer f½aꢀD ꢁ250.7 (c 1.25, CHCl3)}
which was tentatively assigned the presumed thermo-
dynamically preferred 3R,7aS-configuration shown on
the basis of NMR studies.
We attempted to condense the two-step sequence into a
one-pot process but this approach proved to be unsuc-
cessful. However, it was possible to carry out the two-
step process with minimal purification of the intermedi-
ate amide 8a prior to treatment with SnCl2Æ2H2O. Thus,
after amide formation using the mixed anhydride meth-
od,11 the reaction was filtered through a pad of silica
and the solvent evaporated in vacuo before the addition
of new solvent and SnCl2Æ2H2O. Using this method,
product 7a was obtained in 68% isolated yield (as com-
pared to a 42% overall yield for the two-step process).12
A number of different acids were then screened in this
The simplicity of the SnCl2Æ2H2O cyclisation proce-
dures, coupled to the novelty of the heterocycles
produced, encouraged us to investigate further applica-
tions of this methodology. In this Letter, we report the
one-pot deprotection–bicyclisation processes outlined
retrosynthetically in Scheme 2.
Thus, polycyclic fused heterocycles such as 78 and 11
should be accessible from amides 8 and 12 using the
ClCO2Bui
-methylpiperidine
O
O
SnCl2.2H2O
SH
H
(2 equiv.)
S
N
HCl.H2N
CO2H
O
SH
O
H
N
N
DCM, -10 oC - rt
2 h, 60%
DCM, rt
72 h, 70%
CO2Me
O
CO2Me
O
CO2Me
7a
9a
8a
10a
i. ClCO2Bui,
ii. Filtration
N
-methylpiperidine, DCM, -10 oC - rt, 2 h
iii. Acid, DCM, rt (see Table 1)
Scheme 3.

6558
A. N. Cayley et al. / Tetrahedron Letters 48 (2007) 6556–6560
Table 1. Variation of the acid used in the one-pot processa
SnCl2Æ2H2O
(2 equiv), 72 h
SnCl2
(2 equiv), 72 h
SnBr2
(2 equiv), 72 h
SnCl4
(2 equiv), 72 h
BF3ÆEt2O
(2 equiv), 24 h
10% aq
HCl 72 h
Cat. TsOHÆH2O
PhMe, D, 2 h
68%
57%
35%
5%
26%
39%
29%
a Complete degradation of starting material observed using TiCl4 and ZnCl2.
telescoped process (Table 1) but the original procedure
using SnCl2Æ2H2O proved to be best. Cyclisation was
successful using hydrochloric acid although the 39%
yield of heterocycle 7a was considerably lower than in
the stannous chloride procedure (and a number of deg-
radation products were also formed).
to the mixed anhydride method for amide formation,
proved to be more general (Scheme 5). Thus, deacetali-
sation–bicyclisation produced the novel15 heterocyclic
products 11a–d in moderate to good yields over
the two-step sequence. In the case of the bicyclo[3.3.0]-
octane adducts 11a and 11b, mixtures of diastereomeric
products were obtained (ratio established by NMR spec-
troscopy), and the major diastereomer was tentatively
assigned by inspection of molecular models (NOE
studies were uninformative). The bicyclo[4.3.0]nonane
adduct 11c was obtained as a single diastereoisomer.
The formation of the benz-annellated product 11d is
noteworthy as all attempts to use aromatic coupling
partners in the first approach (Scheme 4) were
unsuccessful.
Next, three further examples were explored to indicate
the generality of the procedure (Scheme 4). Thus, amide
formation between acid 9a and L-serine derivative 10b
followed by treatment with SnCl2Æ2H2O induced the
desired deacetalisation–bicyclisation reaction to give
23
the novel heterocycle 7b f½aꢀD ꢁ124 (c 1.0, CHCl3)} in
moderate yield over the two-step process. In a similar
manner, amide formation between acid 9a and the
amino alcohols 10c and 10d followed by deacetalisa-
tion–bicyclisation gave the known13 heterocyclic system
7c {hemi-aminal proton: dH 4.94 ppm, 1H, dd, J = 6.5,
2.8 Hz; IR 1690 cmꢁ1. Lit.13 dH 4.94 ppm, 1H, m; IR
1690 cmꢁ1} and the novel homologue 7d in reasonable
yields over the two steps.
In conclusion, a mild, cheap and simple method of pro-
ducing a diverse range of polycyclic heterocycles from
commercially available or easily accessible starting
materials using a stannous chloride-mediated deacetali-
sation–bicyclisation procedure has been developed.
The products, several of which were obtained in diaste-
reoselective processes, should be of interest both in their
own right and as building blocks for the production of
more complex target molecules. We are currently carry-
ing out further optimisation and mechanistic studies16 as
Our attention turned next to the second combination of
coupling partners outlined in Scheme 2, in particular the
use of amine 13a14 with a range of acids 14a–d. This
approach, in which HATU was shown to be preferable
i. ClCO2Bui
N
-methylpiperidine
O
H
DCM, -10 oC - rt, 2 h
O
OH
O
+
HCl .H2N
N
ii. Filtration
iii. SnCl2.2H2O, DCM, rt, 12 h
CO2H
O
CO2Me
CO2Me
10b
34%
9a
7b
i. ClCO2Bui
O
N
-methylpiperidine
HO
H2N
THF, -40 oC - rt, 2 h
O
O
+
N
CO2H
ii. Filtration
iii. SnCl2.2H2O, DCM, rt, 3 h
O
9a
10c
7c
56%
i. ClCO2Bui
O
N
-methylpiperidine
THF, -40 oC - rt, 2 h
O
HO
H2N
O
+
N
7d
CO2H
ii. Filtration
iii. SnCl2.2H2O, DCM, rt, 4 h
O
9a
10d
57%
Scheme 4.

A. N. Cayley et al. / Tetrahedron Letters 48 (2007) 6556–6560
6559
i. HATU, DIPEA
O
H
N
DCM, 0 oC - rt, 2 h
HO
O
O
+
+
Ph
Ph
HO
NH2
ii. Filtration
iii. SnCl2.2H2O, DCM, rt, 12 h
O
O
14a
13a
11a
(α:β = 2:1)
43% (separable)
i. HATU, DIPEA
DCM, 0 oC - rt, 2 h
Boc
H
O
BocHN
HO
N
O
Me
Me
N
NH2
ii. Filtration
iii. SnCl2.2H2O, DCM, rt, 12 h
O
O
13a
14b
11b
(α:β = 1:3)
55% (inseparable)
i. HATU, DIPEA
H
O
O
DCM, 0 oC - rt, 2 h
HO
+
O
HO
N
NHBoc
ii. Filtration
NHBoc
NH2
iii. SnCl2.2H2O, DCM, rt, 24 h
O
O
11c
13a
14c
46%
i. HATU, DIPEA
DCM, 0 oC - rt, 2 h
O
HO
O
O
HO
N
NH2
ii. Filtration
O
iii. SnCl2.2H2O, DCM, rt, 20 h
O
13a
14d
11d
45%
Scheme 5.
65–76, but this employed hydrochloric acid and was far
less efficient; For a related procedure using tosic acid see:
(c) Ijzendoorn, D. R.; Botman, P. N. M.; Blaauw, R. H.
Org. Lett. 2006, 8, 239–242; See also: (d) Armorde, S. M.;
Judd, A. S.; Martin, S. F. Org. Lett. 2005, 7, 2031–2033.
7. Han, J. L.; Ong, C. W. Tetrahedron 2007, 63, 609–614.
8. For similar systems see: Meyers, A. I.; Lefker, B. A.;
Sowin, T. J.; Westrum, L. J. J. Org. Chem. 1989, 54, 4243–
4246.
well as extending the range of the procedure and inves-
tigating its application to complex natural product
targets.
Acknowledgements
We are grateful to the University of York for student-
ship/PDRA support (J.P.S., A.C.), AstraZeneca for
9. Shea, K. J.; Wada, E. J. Am. Chem. Soc. 1982, 104, 5715–
5719.
`
additional funding (J.P.S.) and the French Ministere
10. All novel compounds were fully characterised by their
1H/13C NMR, IR and HRMS or elemental analysis.
11. Other coupling agents were also investigated: with pro-
pane phosphonic acid anhydride (T3Pꢁ) a 41% overall
yield was obtained; when HATU was employed the amide
coupling step was unsuccessful.
`
des Affaires Etrangeres for a Lavoisier Postdoctoral
Fellowship (C.M.M.).
References and notes
12. Representative procedure: Methyl 3R,7aS-5-oxohexahy-
dropyrrolo[2,1-b]thiazole-3-carboxylate (7a). (a) Isobutyl
chloroformate (44 lL, 0.34 mmol) was added dropwise to
a solution of acid 9a9 (50 mg, 0.34 mmol) and N-meth-
ylpiperidine (41 lL, 0.34 mmol) in DCM (4 mL) at
ꢁ10 ꢂC. After 2 min, an ice cold solution of L-cysteine
methyl ester hydrochloride 10a (62 mg, 0.36 mmol) and N-
methylpiperidine (44 lL, 0.36 mmol) in DCM (1 mL) was
added dropwise and stirring continued at ꢁ10 ꢂC for 1 h
and then at rt for a further 1 h. The solution was then
filtered through a short pad of silica gel, washing through
with EtOAc (3 · 5 mL) and the volatiles removed from the
filtrate in vacuo to give the crude amide 8a, which was
used immediately without further purification; (b) Unpu-
rified amide 8a was re-dissolved in DCM (5 mL). Stannous
chloride dihydrate (Aldrich 20803-5, 0.17 g, 0.75 mmol)
1. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893–930, and references cited therein.
2. Faul, M. M. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley: Chichester,
1995; Vol. 7, pp 4892–4896.
3. Ford, K. L.; Roskamp, E. J. Tetrahedron Lett. 1992, 33,
1135–1138.
4. Foot, J. S.; Giblin, G. M. P.; Taylor, R. J. K. Org. Lett.
2003, 5, 4441–4444.
´
5. Menard-Moyon, C.; Taylor, R. J. K. Eur. J. Org. Chem.
2007, 3698–3706.
6. (a) Reid, M.; Taylor, R. J. K. Tetrahedron Lett. 2004, 45,
4181–4183; It should be noted that a similar cyclisation
was first reported by Winterfeld et al.: (b) Winterfeld, K.;
Michael, H. Arch. Pharm. Ber. Dtsch. Pharm. Ges. 1961,

6560
A. N. Cayley et al. / Tetrahedron Letters 48 (2007) 6556–6560
was added to this solution and the reaction mixture stirred
CHHS), 2.73–2.60 (1H, m, CHHC@O), 2.59–2.48 (2H,
m, CHHC@O, CHH), 2.19–2.09 (1H, m, CHH); dC
(100 MHz, CDCl3) 176.3, 170.2, 66.3, 57.6, 52.7, 36.1,
31.0, 24.6; m/z (ESI) 202 (100, MH+), 142 (10%,
MꢁCO2Me); HRMS (ESI) MH+, found 202.0539.
C8H12NO3S requires 202.0532.
at rt for 72 h whereupon it was diluted with CHCl3 (5 mL)
and then treated with K2CO3 (0.25 g, 1.8 mmol) and
stirring continued for a further 0.5 h. The mixture was
filtered through a short pad of a mixture of Celiteꢁ and
silica gel (1:1), washing through with EtOAc (3 · 10 mL).
The filtrate was concentrated in vacuo and the crude
product purified by flash column chromatography, eluting
with a solvent system of petroleum ether–EtOAc (1:1), to
give the title compound 7a (46 mg, 0.23 mmol, 68%) as a
clear colourless oil; Rf (petroleum ether–EtOAc, 1:1) 0.33;
13. Okita, M.; Wakamatsu, T.; Mori, M.; Ban, Y. Hetero-
cycles 1980, 14, 1089–1092.
14. Shimizu, M.; Ishikawa, M.; Komoda, Y.; Nakajima, T.
Chem. Pharm. Bull. 1982, 30, 909–914.
15. For similar systems see: Griot, R. G.; Frey, A. J.
Tetrahedron 1963, 19, 1661–1673, and Ref. 6c.
16. In addition to Lewis acid activation provided by Sn(II), it
is likely that HCl generated during the reaction plays a
vital role (attempts to carry out the reactions in the
presence of potassium carbonate were unsuccessful).
23
½aꢀD ꢁ250.7 (c 1.25, CHCl3); IR mmax (neat) 2954, 1743,
1709, 1437, 1388, 1285, 1218, 1177 cmꢁ1; dH (400 MHz,
CDCl3) 5.19 (1H, dd, J 7.0, 4.0 Hz, NCHS), 5.08 (1H, dd,
J 7.5, 4.5 Hz, CHCO2Me), 3.73 (3H, s, CO2Me), 3.38 (1H,
dd, J 11.5, 7.5 Hz, CHHS), 3.33 (1H, dd, J 11.5, 4.5 Hz,