Partial reduction of annulated heterocycles as a general route to medium rings containing oxygen and nitrogen.

Article abstract of DOI:10.1021/ol007035o

The preparation of annulated furans and pyrroles is described as part of a general strategy for the synthesis of medium ring heterocycles. After Birch reduction, the corresponding dihydro compounds were oxidatively cleaved to produce medium ring ethers an

Full text of DOI:10.1021/ol007035o

ORGANIC
LETTERS
2
001
Vol. 3, No. 6
61-864
Partial Reduction of Annulated
Heterocycles as a General Route to
Medium Rings Containing Oxygen and
Nitrogen
8
,†
†
‡
†,§
Timothy J. Donohoe,* Ali Raoof, Ian D. Linney, and Madeleine Helliwell
Department of Chemistry, UniVersity of Manchester, Oxford Road,
Manchester, M13 9PL, U.K., and The James Black Foundation, 68 Half Moon Lane,
Dulwich, London, SE24 9JE, U.K.
t.j.donohoe@man.ac.uk
Received December 21, 2000
ABSTRACT
The preparation of annulated furans and pyrroles is described as part of a general strategy for the synthesis of medium ring heterocycles.
After Birch reduction, the corresponding dihydro compounds were oxidatively cleaved to produce medium ring ethers and amines in an
efficient manner. This methodology was successfully applied to the formation of eight- and nine-membered cyclic ethers and nine-membered
cyclic amines. Attaching a chiral auxiliary (bismethoxymethylpyrrolidine) to the furan allowed the formation of nine-membered ethers in 95%
ee.
The abundance of medium ring heterocycles, containing
oxygen and nitrogen, in natural products continues to ensure
that they are popular targets for synthetic chemists. Indeed,
the synthesis of medium ring ethers and the elegant solutions
that have been developed in response.
1
Ring enlargement protocols are also popular routes to
medium rings, and one potentially useful variant does not
involve a ring closure reaction but, instead, relies on the
synthesis of a fused ring system which has the potential to
become a medium ring after oxidative cleavage of an internal
some of these compounds, such as the eleutherobins and the
2
sarcodictyins, have impressive and potentially useful bio-
logical activity.
Synthetic routes to medium ring heterocycles which
involve direct ring closure are often slow and are hampered
5
alkene, see 2 (Figure 1). Of course, access to the medium
3
by unfavorable entropies and enthalpies of reaction. One
ring precursor 2 is relatively easy to accomplish providing
only needs to look at the synthesis of brevetoxin B by
4
Nicolaou to appreciate both the challenges associated with
†
University of Manchester.
James Black Foundation.
To whom correspondence regarding the crystal structure should be
‡
§
addressed.
(
1) For recent work in this area, see: Crimmins, M. T.; Choy, A. L. J.
Am. Chem. Soc. 1999, 121, 5653, and references therein.
2) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A. M.;
Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744.
3) For a pertinent discussion of the issues surrounding medium ring
synthesis, see: Eliel, E. L. Stereochemistry of Organic Compounds; John
Wiley: New York, 1994.
(
(
Figure 1.
1
0.1021/ol007035o CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/17/2001

one can achieve a Birch reduction of the appropriate
annulated furans and pyrroles (i.e. 1, X ) O, NBoc). In this
case, the successful implementation of this strategy reveals
three distinct tactics for further functionalization of the
medium rings: (1) we can prepare heterocycles with more
elaborate annulated rings; (2) we can functionalize the
heterocycle during or immediately after the Birch reduction;
With multigram quantities of the two annulated furans 10
and 11 at our disposal, we attempted Birch reductive
alkylation reactions on the n ) 1 series, quenching with two
7
different electrophiles, Scheme 2. Both reactions worked
Scheme 2a
(3) we should be able to derivatize the cyclic diketone
products after oxidative cleavage of the alkene unit. Of
course, it is the combination of all or some of these
opportunities that will give rise to a powerful and versatile
method for medium ring synthesis. In this paper we wish to
communicate the results of our initial studies confirming the
viability of this approach.
Our studies began with the synthesis of cyclic ethers. Their
furan progenitors were prepared from cyclopentanone and
cyclohexanone, respectively, using a modification of an
6
established method, Scheme 1. Initial Claisen condensation
a
3
Reagents and conditions: (a) Li (4.0 equiv), NH (l), THF,
-
78 °C, bis(2-methoxyethyl)amine (20 equiv), then isoprene, then
RI (10 equiv); (b) O /O , CH Cl , -78 °C, 2 h, then DMS; (c)
2
3
2
2
Scheme 1a
toluene, 4Å molecular sieves, Dean-Stark reflux, 36 h; (d) column
chromatography using silica. Yields based on Birch reduced starting
a
materials 12 and 13; compound 15 could not be completely purified.
well (even with isobutyl iodide, a relatively unreactive
electrophile) and show the potential that this method holds
for the introduction of a variety of different groups at the
C-2 position. It was found that reduction of the trisubstituted
furans required relatively long reaction times and that using
the additive bis(2-methoxyethyl)amine reduced nucleophilic
8
attack of amide anion at the ester group. The dihydrofurans
1
2 and 13 were then cleaved with ozone (using DMS
a
Reagents and conditions: (a) NaH (1.0 equiv), HCO
O, 0 °C to reflux, 2 h; (b) EtOH, CH COCl (2 equiv),
MeOH (excess), 0 °C to rt, 16 h; (c) ClCH CO Me (1.6 equiv),
NaOMe (1.5 equiv), Et O, -10 °C to rt, 20 h; (d) CSA (1.0 equiv),
2
Et (2.0
workup) to give eight-membered ring ethers. We found that
the diketones 15 and 16 were each in equilibrium with a
corresponding bicyclic hemiacetal; this equilibrium could be
shifted to either side by chromatography on silica (to hydrate
the ketone) or azeotroping in toluene (to dehydrate the
system). The structure of hydrate 14 was secured by X-ray
equiv), Et
2
3
2
2
2
toluene, reflux, 6-8 h; (e) Ti(OEt)
reflux, 7 h.
4
(1 equiv), i-PrOH (excess),
9
crystallography, Figure 2.
was followed by formation of two dimethylacetals, 4 and 5;
subsequent Darzen’s condensation gave the two epoxides 6
and 7 as a mixture of diastereoisomers. These epoxides are
at the correct oxidation level for furan formation, and this
was accomplished by heating in toluene with CSA. Finally,
the methyl esters 8 and 9 were transformed into isopropyl
analogues 10 and 11 in excellent yield (this was necessary
because hindered esters are less prone to nucleophilic attack
in the Birch reduction, vide infra).
(
4) (a) Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F. P. J. T.; Tiebes,
J.; Sato, M.; Untersteller, E.; Xiao, X.-Y. J. Am. Chem. Soc. 1995, 117,
171. (b) Nicolaou, K. C.; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes,
J.; Sato, M.; Untersteller, E. J. Am. Chem. Soc. 1995, 117, 1173.
5) For related approaches, see: (a) Elliot, M. C.; Moody, C. J.; Mowlem,
1
(
T. J. Synlett 1993, 909. (b) Oishi, T.; Shoji, M.; Maeda, K.; Kumahara, N.;
Hirama, M. Synlett 1996, 1165. (c) Oishi, T.; Maruyama, M.; Shoji, M.;
Maeda, K.; Kumahara, N.; Tanaka, S.-I.; Hirama, M. Tetrahedron 1999,
Figure 2.
5
5, 7471.
6) (a) Burness, D. M. Organic Syntheses; Wiley: New York, 1963;
(
In a similar manner, Birch reduction/alkylation of 11 gave
Collect. Vol. IV, p, 649. (b) Pye, P. J. Ph.D. Thesis, University of Texas at
Austin, 1995. (c) Datta, A.; Pooranchand, D.; Ila, H.; Junjappa, H.
Tetrahedron 1989, 45, 7631.
10
the two 6,5-fused dihydrofurans 17 and 18, Scheme 3.
1
1
Subsequent reaction with ozone and DMS, as before,
862
Org. Lett., Vol. 3, No. 6, 2001

22 was isolated showed that it was formed as a 45:1 mixture
Scheme 3a
of diastereoisomers. After cleavage of the auxiliary, we re-
analyzed the acid 23 and showed it to be of 95% ee (again
using GC and in comparison with a racemic standard). To
complete the sequence, we reattached the isopropyl ester to
allow comparison with the sample shown in Scheme 3. After
ozonolysis, the ester (-)-19 was isolated in good yield;
although we were unable to measure directly the enantio-
meric excess of this material, it seems reasonable to assume
that it is identical with the acid 23 from which it originated
(i.e. 95% ee).
a
Reagents and conditions: (a) Li (4.0 equiv), NH
C, bis(2-methoxyethyl)amine (33 equiv), then isoprene, then RI
20 equiv); (b) O /O , CH Cl , -78 °C, 1.5 h, then DMS, rt, 16 h.
3
(l), THF, -78
°
(
2
3
2
2
The relative stereochemistry of 22 (and therefore the
absolute stereochemistry of 23) was determined by X-ray
crystallographic analysis of a crystalline derivative of 23.
The sense of stereoselectivity thus displayed during the Birch
reductive alkylation of 21 is in accord with the model that
we have previously presented for related systems.
Finally, we applied our methodology to the partial reduc-
generated two nine-membered cyclic ethers in excellent yield,
without any observable formation of hydrates.12
The methodology described herein is also amenable to the
production of enantiopure compounds if an auxiliary (R,R-
bismethoxymethylpyrrolidine) is attached to the C-2 acyl
group of the furan prior to reduction, compound 21, Scheme
12
tion of annulated pyrrole 25 (easily prepared in two quantita-
4. Our earlier work was concerned with the partial reduction
14
tive yielding steps, Scheme 5 ). Birch reductive alkylation
Scheme 4a
Scheme 5a
a
Reagents and conditions: (a) EtO
(l), THF, -78 °C, bis(2-methoxyethy-
l)amine (10 equiv), then isoprene, then (aq.) NH Cl; (d) O /O
CH Cl , -78 °C, then DMS.
2 2
CCHNC, DBU; (b) (Boc) O,
NaH; (c) Li (4 equiv), NH
3
4
2
3
,
2
2
a
Reagents and conditions: (a) MeOH:H
2
O (9:1), KOH, ∆, 3 h;
N (2
(l), THF, -78 °C,
(
b) (R,R)-(+)-2,5-bismethoxymethylpyrrolidine (1 equiv), Et
equiv), CH Cl , BOP-Cl; (c) Li (4 equiv), NH
bis(2-methoxyethyl)amine (20 equiv), then isoprene, then Mel (10
3
2
2
3
of 25, quenching with methyl iodide, proceeded well to give
1
5
2
6 (R ) Me, 83%). However, we found that the alkene
equiv); (d) 2 M HCl (aq.), ∆, 2.5 h; (e) EDCl (1 equiv), DMAP
group within this pyrroline was resistant to ozonolysis at low
temperature and gave multicomponent mixtures at higher
(
2 2 2 3 2 2
cat.), iPrOH, CH Cl , rt; (f) O /O , CH Cl , -78 °C, then DMS.
(
10) Representative experimental procedure: Lithium (27 mg, 3.8
of 2-furoic acids and, using bismethoxymethylpyrrolidine as
an auxiliary, had shown that an ortho methyl substituent was
essential for high levels of stereoselectivity as it sets the
mmol) was added to freshly distilled ammonia (50 mL) and allowed to stir
at -78 °C under an atmosphere of nitrogen for 2 h before the addition of
bis-(2-methoxyethyl)amine (5 mL, 30 mmol). Compound 11 (200 mg, 0.96
mmol) was dissolved in THF (25 mL) and added to the reaction mixture
after 5 min. The resultant solution was allowed to stir at -78 °C for 2.5 h
before the addition of isoprene (50 µL), immediately followed by methyl
iodide (2 mL, 32 mmol). After an additional 1 h, the resultant bright yellow
solution was treated with a saturated ammonium chloride solution (5 mL)
before being allowed to warm to room temperature over 16 h. The reaction
mixture was extracted into diethyl ether (3 × 50 mL), dried over anhydrous
sodium sulfate, and concentrated under reduced pressure to afford a yellow
oil. Purification by chromatography (silica, petroleum ether-diethyl ether,
13
geometry of the enolate formed during the Birch reduction.
Fortunately, in this case, the annulated ring is sufficiently
bulky to allow formation of a single enolate isomer (we
presume it is trans) and we observed high diastereoselectivity
upon reductive alkylation of 21, Scheme 4. In fact, GC
analysis of the crude reaction mixture from which compound
9
:1 v/v) afforded compound 17 (140 mg, 65%) as a colorless oil.
(
7) (a) Coggiola, I. M. Nature 1963, 200, 954. Kinoshita, T.; Miwa, T.
(11) Compound 17 (50 mg, 0.22 mmol) was dissolved in dichloromethane
J. Chem. Soc., Chem. Commun. 1974, 181. (b) Masamune, T.; Ono, M.;
Matsue, H. Bull. Chem. Soc. Jpn. 1975, 48, 491. (c) Birch, A. J.; Slobbe,
J. Tetrahedron Lett. 1975, 627. (d) Birch, A. J.; Slobbe, J. Tetrahedron
Lett. 1976, 2079. (e) Semple, J. E.; Wang, P. C.; Lysenko, Z.; Joullie, M.
M. J. Am. Chem. Soc. 1980, 102, 7505. (f) Ohta, Y.; Tamura, M.; Tanaka,
R.; Moriomoto, Y.; Yoshihara, K.; Kinoshita, T. J. Heterocycl. Chem. 1998,
(15 mL) and cooled to -78 °C under an atmosphere of O2. Ozone was
generated and bubbled through the reaction mixture for 1.5 h. The resultant
blue solution was saturated with O2 for 10 min before the addition of
dimethyl sulfide (0.16 mL, 2.2 mmol). The reaction mixture was allowed
to warm to room temperature over 16 h. The resultant solution was washed
with brine (2 × 5 mL), dried over anhydrous sodium sulfate, and
concentrated under reduced pressure to afford compound 19 (59 mg, 100%)
as a pale yellow oil which did not require further purification.
3
5, 461. See also ref 9.
8) Donohoe, T. J.; Guyo, P. M.; Harji, R. R.; Cousins, R. P. C.
Tetrahedron Lett. 1998, 39, 3075.
9) CCDC deposition number for 14 is 156092.
(
(12) Care must be taken with these compounds as an intramolecular aldol
reaction takes place on exposure to silica.
(
Org. Lett., Vol. 3, No. 6, 2001
863

temperatures. Other methods of bond cleavage (e.g., Lemieux
oxidation) were not successful in producing a nine-membered
ring. A solution to this problem was found via formation of
leads to the formation of cyclic ethers with a very high
enantiomeric excess. Future work will concentrate on de-
rivatization reactions of these medium ring compounds and
application of our methodology to the synthesis of biologi-
cally important targets.
26 (R ) H) by protonation of the Birch reduction (76%).
The alkene could then be cleaved in a standard manner to
furnish the corresponding diketone, which existed entirely
as the enol tautomer, 27.
To conclude, this methodology provides a convenient route
to substituted medium ring ethers and amines which have
ample potential for further functionalization. Moreover,
employing a chiral auxiliary laiden aromatic heterocycle
Acknowledgment. We thank the James Black Foundation
and the EPSRC for funding this work. We also thank
AstraZeneca, GlaxoWellcome, and Pfizer for unrestricted
support which aided this project.
(13) (a) Donohoe, T. J.; Helliwell, M.; Stevenson, C. A.; Ladduwahetty,
T. Tetrahedron Lett. 1998, 39, 3071. (b) Donohoe, T. J.; Calabrese, A. A.;
Stevenson, C. A.; Ladduwahetty, T. J. Chem. Soc., Perkin Trans. 1 2000,
Supporting Information Available: Detailed spectro-
scopic data for new compounds and representative experi-
mental procedures, plus X-ray data for compound 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
3
724. (c) Donohoe, T. J.; Guillermin, J.-B.; Frampton, C.; Walters, D. S.
Chem. Commun. 2000, 465.
14) Barton, D. H. R.; Kervagaret, J.; Zard, S. Z. Tetrahedron 1990, 46,
587.
15) (a) Donohoe T. J.; Guyo, P. M. J. Org. Chem. 1996, 61, 7664. (b)
(
7
(
Donohoe, T. J.; Guyo, P. M.; Beddoes, R. L.; Helliwell, M. J. Chem. Soc.,
Perkin Trans. 1 1998, 667.
OL007035O
864
Org. Lett., Vol. 3, No. 6, 2001