Uncatalyzed addition of N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole to activated quinones

Article abstract of DOI:10.1016/S0040-4039(02)00932-2

The uncatalyzed addition of N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 to 1,4-quinones bearing an electron withdrawing group at C-2 is reported. Use of 2-methoxycarbonyl-1,4-benzoquinone 4 and 2-methoxycarbonyl-1,4-naphthoquinone 5 provided an efficient synthesis of the pyrrolidinobenzofuran adduct 9 and the corresponding pyrrolidinonaphthofuran adduct 10, respectively, whereas use of 2-acetyl-1,4-benzoquinone 6, 2-acetyl-1,4-naphthoquinone 7 and 2-acetyl-8-methoxy-1,4-naphthoquinone 8 formed silyloxypyrroles 11, 12, and 13 resulting from direct electrophilic substitution of the silyloxypyrrole by the electrophilic quinone. Addition of PPTs to the reaction of 2-acetyl-8-methoxy-1,4-naphthoquinone 8 with N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 afforded pyrrolidinonaphthofuran adduct 14 which then underwent smooth oxidative rearrangement to pyrrolidino pyranonaphthoquinone 15, thereby providing a novel approach for the synthesis of aza-analogues of the pyranonaphthoquinone antibiotics such as kalafungin 16.

Full text of DOI:10.1016/S0040-4039(02)00932-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4777–4780
Uncatalyzed addition of N-(tert-butoxycarbonyl)-2-tert-
butyldimethylsilyloxypyrrole to activated quinones
Margaret A. Brimble,* Rosliana Halim and Maria Petersson
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Received 2 April 2002; revised 2 May 2002; accepted 13 May 2002
Abstract—The uncatalyzed addition of N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 to 1,4-quinones bearing an
electron withdrawing group at C-2 is reported. Use of 2-methoxycarbonyl-1,4-benzoquinone 4 and 2-methoxycarbonyl-1,4-naph-
thoquinone 5 provided an efficient synthesis of the pyrrolidinobenzofuran adduct 9 and the corresponding pyrrolidinonaphtho-
furan adduct 10, respectively, whereas use of 2-acetyl-1,4-benzoquinone 6, 2-acetyl-1,4-naphthoquinone 7 and 2-acetyl-8-
methoxy-1,4-naphthoquinone 8 formed silyloxypyrroles 11, 12, and 13 resulting from direct electrophilic substitution of the
silyloxypyrrole by the electrophilic quinone. Addition of PPTs to the reaction of 2-acetyl-8-methoxy-1,4-naphthoquinone 8 with
N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 afforded pyrrolidinonaphthofuran adduct 14 which then underwent
smooth oxidative rearrangement to pyrrolidino pyranonaphthoquinone 15, thereby providing a novel approach for the synthesis
of aza-analogues of the pyranonaphthoquinone antibiotics such as kalafungin 16. © 2002 Elsevier Science Ltd. All rights reserved.
The five-membered heterocyclic silyloxy dienes 2-
trimethylsilyloxyfuran (TMSOF) 1, 2-(tert-butyldi-
As part of our synthetic programme directed towards
11
the synthesis of pyranonaphthoquinone antibiotics,
methylsilyloxy)thiophene (TBSOT)
butoxycarbonyl) - 2 - tert - butyldimethylsilyloxypyrrole
2
and N-(tert-
we made use of the addition of 2-trimethylsilyloxy-
furan 1 to activated quinones as an efficient furofuran
annulation to provide adducts that underwent subse-
quent oxidative rearrangement to the desired pyrano-
naphthoquinone skeleton (Scheme 2). Despite the
extensive use of N-(tert-butoxycarbonyl)-2-tert-
4
(
TBSOP) 3 provide a cohort of silyl enolate d syn-
1
thons that undergo vinylogous aldol-like reactions2
with aldehydes, vinylogous imino-aldol reactions
(
Mannich-type addition) with imines and vinylogous
4
addition to heteroatom-stabilized carbenium ions
(
butyldimethylsilyloxypyrrole 3 as a d nucleophilic
3
Scheme 1). These nucleophilic modules afford highly
component in reactions with a range of electrophiles,
the reaction of TBSOP 3 with quinones has not been
reported. We therefore describe herein our synthetic
efforts to extend our previously reported furofuran
annulation of activated quinones using TMSOF 1 to
an analogous pyrrolidinofuran annulation using
TBSOP 3.
functionalized aldol-like products that have provided
synthetic platforms for further conversion to signifi-
cant bioactive molecules such as the Annonaceous ace-
4
,5
6
togenins,
indolizidine
carbasugars,
alkaloids,
densely
hydroxylated
hydroxylated8
7
prolines,
9
10
aminosugars and peptidyl C-glycosides.
Scheme 1.
*
0
Corresponding author.
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00932-2

4
778
M. A. Brimble et al. / Tetrahedron Letters 43 (2002) 4777–4780
Scheme 2.
Table 1. Addition of N-(tert-butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole 3 to 2-substituted 1,4-benzoquinones and
,4-naphthoquinones*
1

M. A. Brimble et al. / Tetrahedron Letters 43 (2002) 4777–4780
4779
Scheme 3.
Uncatalyzed addition of N-(tert-butoxycarbonyl)-2-
tert-butyldimethylsilyloxypyrrole 3 (2.0 equiv.) to 2-
methoxycarbonyl-1,4-benzoquinone 4 and 2-methoxy-
carbonyl-1,4-naphthoquinone 5 in acetonitrile at room
temperature afforded pyrrolidinobenzofuran adduct 9
and pyrrolidinonaphthofuran adduct 10 in 36 and 54%
approach to the basic skeleton required for the synthe-
sis of 1-aza-analogues of the pyranonaphthoquinone
family of antibiotics such as kalafungin 16.
In summary the first study of the addition of N-(tert-
butoxycarbonyl)-2-tert-butyldimethylsilyloxypyrrole
3
1
2–14
to electron deficient quinones is reported. The adducts
formed from these reactions provide novel heterocyclic
ring systems that can be further elaborated to provide
aza analogues of natural products, as demonstrated by
the conversion of adduct 15 to the 1-aza analogue of
isolated yield, respectively (Table 1).
The adducts 9
and 10 decomposed substantially upon purification by
flash chromatography. The magnitude of the bridge-
head coupling constant J3a,8b 5.1–5.4 Hz clearly estab-
lished the cis-fusion of the two five-membered rings.
1
6
the bioreductive alkylating agent kalafungin 16.
Analogous addition of TBSOP 3 to 2-acetyl-1,4-benzo-
quinone 6, 2-acetyl-1,4-naphthoquinone 7 and 2-acetyl-
8
-methoxy-1,4-naphthoquinone
quinone substituted silyloxypyrroles 11, 12 and 13 in
6, 64 and 38% isolated yields, respectively. Thus, the
use of the more electron deficient 2-acetyl substituted
,4-quinones afforded products arising from direct elec-
8
afforded hydro-
5
1
trophilic aromatic substitution of the pyrrole ring. Evi-
dence for formation of similar silyloxypyrroles in the
1
H NMR spectrum of the crude reaction mixtures
obtained from addition of TBSOP 3 to the 2-methoxy-
carbonyl-substituted quinones 4 and 5 was not found.
Acknowledgements
Despite the fact that the subtle electronic differences in
the quinones used afforded different products, it was
hoped that silyloxypyrrole 13 could be converted to
pyrrolidinonaphthofuran 14, which would then
undergo oxidative rearrangement to the desired pyrro-
lidino pyranonaphthoquinone 15. This approach
proved disappointing in that after considerable experi-
mentation involving the use of many acidic-, basic- and
fluoride-containing reagents, silyloxypyrrole 13 could
not be induced to form pyrrolidinonaphthofuran 14.
When the initial addition of TBSOP 3 to 2-acetyl-8-
methoxy-1,4-naphthoquinone 8 was carried out in ace-
tonitrile and pyridinium p-toluenesulfonate (PPTs) then
added directly to the reaction mixture, pyrrolidino-
naphthofuran 14 was afforded albeit in 13% yield. The
low yield was attributed to the inherent instability of
the pyrrolidinonaphthofuran 14.
Financial assistance from The University of Auckland
Research Committee is gratefully acknowledged. We
also thank Mr. Chris Guo and Professor Jayanta Ray
for carrying out preliminary experiments using alterna-
tive quinones and silyloxypyrroles that were not
fruitful.
References
1. For a recent review on the vinylogous aldol reaction, see:
Casiraghi, G.; Zanardi, F. Chem. Rev. 2000, 100, 1929.
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see: Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221.
3. For reviews on the synthetic utility of these 2-silyloxy
dienes, see: (a) Rassu, G.; Zanardi, F.; Battistini, L.;
Casiraghi, G. Chem. Soc. Rev. 2000, 29, 109; (b) Casir-
aghi, G.; Rassu, G. Synthesis 1995, 607; (c) Casiraghi, G.;
Rassu, G.; Zanardi, F.; Battistini, L. In Advances in
Asymmetric Synthesis; Hassner, A., Ed.; JAI Press: Stan-
ford, 1998; Vol. 3, p. 113.
Having encountered considerable difficulty in achieving
conversion of silyloxypyrrole 13 to pyrrolidinonaphtho-
furan 14, it was rewarding then to find that pyrrolidi-
nonaphthofuran 14 underwent smooth oxidative
rearrangement to the desired pyrrolidino pyranonaph-
4
. Zanardi, F.; Battistini, L.; Rassu, G.; Auzzas, L.; Pinna,
L.; Marzocchi, L.; Acquotti, D.; Casiraghi, G. J. Org.
Chem. 2000, 65, 2048.
1
5
thoquinone 15 in good yield (Scheme 3) using ceric
ammonium nitrate (CAN). The successful formation of
pyrrolidino pyranonaphthoquinone 15 provides a novel
5. Pichon, M.; Jullian, J.-C.; Figadere, B.; Cave, A. Tetra-
hedron Lett. 1998, 39, 1755.

4
780
M. A. Brimble et al. / Tetrahedron Letters 43 (2002) 4777–4780
6
7
8
9
. Rassu, G.; Auzzas, L.; Pinna, L.; Battistini, L.; Zanardi, flash chromatography using hexane–ethyl acetate (gradi-
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. Rassu, G.; Carta, P.; Pinna, L.; Battistini, L.; Zanardi,
ent elution 9:1 to 4:6) as eluent to afford the title com-
pound 9 (150 mg, 36%) as colourless crystals, mp
+
114–116°C (found: M , 349.1159, C H NO requires
17
19
7
F.; Acquottit, D.; Casiraghi, G. Eur. J. Org. Chem. 1999,
349.1161).
4. Spectroscopic data for 9: max (film)/cm 3295v (OH),
984m, 1754m (CꢀO), 1728m (CꢀO), 1683m (CꢀO); l
−
1
1
395.
1
. Zanardi, F.; Battistini, L.; Nespi, M.; Rassu, G.; Spanu,
P.; Cornia, M.; Casiraghi, G. Tetrahedron: Asymmetry
2
H
t
(
400 MHz, CDCl ) 1.43 (9H, s, Bu), 2.94 (2H, apparent
3
1
996, 7, 1167.
d, J 5.1 Hz, H-3), 3.95 (3H, s, OMe), 5.14 (1H, t, J3a,8b
. Spanu, P.; Rassu, G.; Ulgheri, F.; Zanardi, F.; Battistini,
L.; Casiraghi, G. Tetrahedron 1996, 52, 4829.
5
6
.1, J3a,3 5.1 Hz, H-3a), 5.81 (1H, d, J3a,8b 5.1 Hz, H-8b),
.93 (2H, apparent s, H-5, H-6), 9.65 (1H, s, OH); lC
1
0. Rassu, G.; Zanardi, F.; Batistini, L.; Casiraghi, G. Tetra-
(
5
100 MHz, CDCl ) 27.8 (CH , CMe ), 38.0 (CH , C-3),
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2.1 (CH , OMe), 64.2 (CH, C-8b), 79.3 (CH, C-3a), 83.7
3
1
1
1. Brimble, M. A. Pure Appl. Chem. 2000, 72, 1635.
2. All new compounds gave satisfactory H, C NMR, IR
(
C, CMe ), 112.7 (C, C-8), 116.5 (CH, C-6), 119.9 (CH,
1
13
3
C-5), 123.7 (C, C-8a), 150.2 (C, C-7), 154.0 (C, C-4a),
and HRMS data.
1
3
7
54.4 (C, NCO ), 170.1 (C, C-2), 170.3 (C, CO Me); m/z
2 2
t
1
3. A representative example of the experimental proce-
+
t
49 (M , 4%), 276 (M−O Bu, 3), 249 (M−O Bu−HCN,
dure—tert-butyl
hydroxy-2-oxo-2,3,3a,8b-tetrahydro-1H-[1]benzofuro[3,2-
b]pyrrole-1-carboxylate 9. To an ice-cooled solution of
(3aS*,8bS*)-8-methoxycarbonyl-7-
t
0), 217 (M−O Bu−COCH , 100).
3
1
1
5. The stereochemistry at the hydroxyl centre in 15 was
assigned by analogy to that observed for similar rear-
rangements of furonaphthofurans to furonaphthopyrans,
see: Brimble, M. A.; Stuart, S. J. J. Chem. Soc., Perkin
Trans. 1 1990, 881.
6. For a review on the isolation and biological activity of
pyranonaphthoquinone antibiotics, see: Brimble, M. A.;
Duncalf, L. J.; Nairn, M. R. Nat. Prod. Rev. 1999, 16,
267.
2
-methoxycarbonyl-1,4-benzoquinone 4 (200 mg, 1.2
mmol) dissolved in acetonitrile (8 mL) was added a
solution of N-(tert-butoxycarbonyl)-2-tert-butyldimethyl-
silyloxypyrrole 3 (700 mg, 2.36 mmol) in acetonitrile (12
mL) dropwise under nitrogen. After being stirred for 2 h,
the solution was warmed to room temperature then
stirred for 18 h. The solvent was removed under reduced
pressure to afford a brown residue that was purified by