Chelation and nonchelation control in the [3 + 4] and [3 + 5] annulation reactions of benzyloxy-substituted dicarbonyl electrophiles with bis(trimethylsilyl) enol ethers

Full text of DOI:10.1021/jo9600060

1910
J . Org. Chem. 1996, 61, 1910-1911
Sch em e 1
Ch ela tion a n d Non ch ela tion Con tr ol in th e
[3 + 4] a n d [3 + 5] An n u la tion Rea ction s of
Ben zyloxy-Su bstitu ted Dica r bon yl
Electr op h iles w ith Bis(tr im eth ylsilyl) En ol
Eth er s
Gary A. Molander* and Paul R. Eastwood
Department of Chemistry and Biochemistry, University of
Colorado, Boulder, Colorado 80309-0215
Received J anuary 4, 1996
Sch em e 2
The Lewis acid-mediated annulation of 1,4- and 1,5-
dicarbonyl compounds with bis(trimethylsilyl) enol ethers
represents an increasingly versatile means to access
seven- and eight-membered carbocycles as well as bicyclic
ethers.1 The regiochemical outcome of such reactions
relies predominantly on the Lewis acid utilized. For
instance, in the reaction of keto aldehydes 1 with 2
promoted by TMSOTf, the exclusive regioisomer isolated
is 3 (Scheme 1). This regiochemistry can be explained
by a process which involves the cyclic oxocarbenium ion
4.
By contrast, the use of TiCl4 as the Lewis acid partner
leads predominantly to products of type 5, which possess
the opposite regiochemistry (Scheme 2).1e Presumably,
in this case the reaction pathway does not involve
intermediates of type 4.
in order to determine annulation regioselectivity without
the presence of the chelating heterosubstituent in the
chain.
The 1,5-dicarbonyl compound 8e was prepared by the
Lewis acid-promoted3 addition of acetone trimethylsilyl
enol ether4 onto the known R,â-unsaturated ketone 9 (eq
2).
The high regioselectivity obtained in either protocol
depends upon initial complexation of the Lewis acid to
the least sterically hindered carbonyl center. We were
intrigued by the possibility of incorporating chelating
alkoxy substituents into the dicarbonyl compounds which
could direct the course of the annulation without reliance
upon this steric factor. Herein we report our findings of
this study.
The 1,4- and 1,5-dicarbonyl substrates required for the
studies were readily prepared by straightforward routes.
For example, reaction of the aldehydes 6 with methyl
vinyl ketone catalyzed by 3-benzyl-5-(2-hydroxyethyl)-4-
methyl-1,3-thiazolium chloride (7) afforded the 1,4-di-
carbonyl compounds 8a -8d in modest to good yield (eq
1).2 Compound 8a was prepared as a control substrate
°
Upon annulation the bicyclic ethers were converted to
the corresponding enol acetates (12 and/or 13) to simplify
structural assignments made difficult by the initial
formation of two epimers. In the TiCl4-mediated annu-
lations endo epimers were obtained, whereas in the
TMSOTf-promoted reactions the exo isomers were fa-
vored. The reactivity of the epimers was reflected in the
ease of formation of the enol acetatessthe endo isomers
were easily acetylated under normal conditions (Ac2O,
pyridine, DMAP) whereas for the exo isomers the use of
an alternative procedure (NaH/Ac2O) was usually neces-
sary for efficient conversion. Structural assignments of
the regioisomeric bicyclic ethers were established by NOE
studies on the enol acetates.
Results of the Lewis acid-mediated annulations of 8a -
8e with 2 (Scheme 3) are presented in Table 1. When
no directing oxygen was present (entries 1 and 6, Table
1) moderate regioselectivity was observed. In this case
the major isomer isolated was dependent on the Lewis
acid utilized. These results can be rationalized on the
basis of the mechanistic discussion presented above.1
Entries 2 and 3 of Table 1 demonstrate that when a
heterosubstituent was suitably placed for five- or six-
membered ring chelation with TiCl4, complete regiose-
lectivity was obtained with initial attack of 2 occurring
(1) (a) Molander, G. A.; Cameron, K. O. J . Org. Chem. 1991, 56,
2617. (b) Molander, G. A.; Cameron, K. O. J . Org. Chem. 1993, 58,
5931. (c) Molander, G. A.; Cameron, K. O. J . Am. Chem. Soc. 1993,
115, 830. (d) Molander, G. A.; Siedem, C. S. J . Org. Chem. 1995, 60,
130. (c) Molander, G. A.; Eastwood, P. R. J . Org. Chem. 1995, 60, 4559.
(d) Molander, G. A.; Carey, J . C. J . Org. Chem. 1995, 60, 4845. (e)
Molander, G. A.; Andrews, S. W. Tetrahedron Lett. 1989, 30, 2351. (f)
Molander, G. A.; Eastwood, P. R. J . Org. Chem. 1995, 60, 8382.
(2) Stetter, H.; Mohrmann, K.-H.; Schlenker, W. Chem. Ber. 1981,
114, 581.
(3) Huffman, J . W.; Potnis, S. M.; Satish, A. V. J . Org. Chem. 1985,
50, 4266.
(4) Walshe, N. D. A.; Goodwin, G. B. T.; Smith, G. C.; Woodward,
F. E. Organic Syntheses; Wiley: New York, 1993; Coll. Vol. III, p 1.
(5) Brown, H. C. Organic Syntheses via Boranes; Wiley: New York,
1975.
0022-3263/96/1961-1910$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 6, 1996 1911
Ta ble 1. Lew is Acid -P r om oted An n u la tion s of Dik eton e
Su bstr a tes 8 w ith 2
Sch em e 3
% isoltd
yield
% isoltd
yield
regio-
selectivity
(12:13)b
sub-
entry strate
Lewis
acid
m
(10 + 11)a (12 + 13)a
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8a
8b
8c
8e
1
1
1
1
2
1
1
1
2
TiCl4
89
76
83
51
65
96
83
98
90
88
90
89
77
54
1:6
>100:1
>100:1
2:1
TiCl4
TiCl4
TiCl4
TiCl4
TMSOTf 72
TMSOTf 70
TMSOTf 37 (46)c
TMSOTf 70
>100:1
4:1
1:>100
1.2:1
1:>100
a
Refers to yields of purified products. All of these compounds
have been fully characterized spectroscopically (1H NMR, 13C
NMR, IR), and elemental composition has been established by
combustion analysis and/or high-resolution mass spectrometry.
b
Regioselectivities were determined either by NMR or fused silica
capillary GC analysis. c Based on recovered starting material.
tivity is poor. The precise manner by which this Lewis
acid activation occurs is under current investigation.
at the chelated, more electrophilic carbonyl center.
Formation of an unfavorable seven-membered chelate
accounts for the poor selectivity obtained with substrate
8d (entry 4, Table 1). Chelation must also account for
the excellent regioselectivity obtained in the [3 + 5]
annulation (entry 5, Table 1).
As TMSOTf is a nonchelating Lewis acid it was
expected that the oxygen substituent would have much
less influence upon the relative selectivities. However,
upon annulation of the 1,4-dicarbonyl compound 8b or
the 1,5-dicarbonyl compound 8e (entries 7 and 9, Table
1) only single regioisomers were obtained. The com-
pounds isolated were isomeric to those generated using
the TiCl4-mediated process. This suggests that the
heterosubstituent is directing the complexation of TM-
SOTf to the carbonyl center. Participation by the re-
maining carbonyl group then ensues, followed by attack
of 2. This directing effect is considerably diminished
when the heterosubstituent is further away from the
carbonyl (entry 8, Table 1) in which case the regioselec-
In conclusion, the incorporation of chelating hetero-
substituents, combined with complementary Lewis acids,
provides yet another means to control the regiochemistry
in these [3 + 4] and [3 + 5] annulation reactions.1
Further studies concerning mechanistic and stereochem-
ical aspects of these reactions are underway, as well as
applications of the method to natural product total
synthesis.
Ack n ow led gm en t. This work was carried out with
generous support from the National Institutes of Health.
We thank Paul J . Nichols for his assistance with the
NOE studies.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C for
spectra of compounds for which no elemental analysis was
obtained (56 pages).
J O9600060