Michael Additions to (R)-1-Acetyl-5-isopropoxy-3-pyrrolin-2-one and Subsequent N-Acyliminium Ion Generation: Synthesis of Enantiopure 1-Azabicycles and Preparation of an Intermediate for a Projected Synthesis of Roseophilin

Full text of DOI:10.1021/jo971854d

220
J . Org. Chem. 1998, 63, 220-221
Sch em e 1
Mich a el Ad d ition s to
(R)-1-Acetyl-5-isop r op oxy-3-p yr r olin -2-on e
a n d Su bsequ en t N-Acylim in iu m Ion
Gen er a tion : Syn th esis of En a n tiop u r e
1-Aza bicycles a n d P r ep a r a tion of a n
In ter m ed ia te for a P r ojected Syn th esis of
Roseop h ilin
Tim Luker, Wim-J an Koot, Henk Hiemstra,* and
W. Nico Speckamp*
Laboratory of Organic Chemistry, Amsterdam Institute of
Molecular Studies, University of Amsterdam, Nieuwe
Achtergracht 129, 1018 WS Amsterdam, The Netherlands
Received October 8, 1997
First, the configurational stability of 1 under the conditions
envisaged for the addition reactions was checked. After
being stirred in DMF at rt in the presence of Et3N for 72 h,
the optical purity of 1 remained virtually unchanged (>96%
ee). The Michael additions of a range of stabilized nucleo-
philes are summarized in Table 1. The reactions were
generally performed in DMF containing Et3N (1 equiv). The
final entry shows addition of methyl phenylsulfonyl acetate.
As this nucleophile was of identical polarity to the product
9, only 1 equiv could be used. Thus, a large excess of the
Et3N base was used to achieve complete reaction. In all
cases, only trans-products (6-9) were obtained, as deduced
from the singlets for H5 of the pyrrolin-2-one moiety,10 in
excellent yields. The unsymmetrical nucleophiles afforded
products 6 and 9 as 1:1 diastereomeric mixtures at the side
chain stereocenter. With the more hindered methyl 2-(phen-
ylsulfonyl)hexanoate, no significant addition had taken place
after 30 h, thus precluding the use of nucleophiles “prealkyl-
ated” with π-electrophiles vide supra.
The active methine function in the lactam products could
be further functionalized by alkylation. Such reactions
permitted introduction of potential π-nucleophiles for use
in later iminium ion cyclizations. These alkylation reactions
are also summarized in Table 1. Anions were generated
with NaH in DMF before addition of a suitable alkyl halide
alkylating agent. With bromides and chlorides, LiI was used
to accelerate the reactions and increase yields. A variety of
unsaturated nucleophiles were introduced in good yield.11
With quantities of 10-13 in hand we were now in a
position to examine cyclization reactions between the teth-
ered π-nucleophile and the iminium ion generated by acid-
induced loss of the isopropoxy group. Few examples of this
type of intramolecular cyclization reaction exist,3,12 but
considering the constrained position of the nucleophile above
the planar iminium ion, we were confident that the reaction
would afford the desired cis-fused bicycles. The results are
given in Table 2. The N-acyl group was first deprotected
using excess dimethylamine in either CH2Cl2 or DMF3a
(iminium ion generation is not possible when the nitrogen
atom is flanked by two acyl groups).6c The products obtained
were sensitive to hydrolysis at C5 and so were used im-
mediately following solvent removal without further puri-
fication. The first two entries in Table 2 show cyclization
of the isoprenyl nucleophile. The reaction proceeded in good
yield with either formic acid or titanium tetrachloride. As
expected, only the 5-exo-trig cyclization mode occurred (via
In 1992 we disclosed the synthesis of enantiopure (R)-1-
acetyl-5-isopropoxy-3-pyrrolin-2-one (1) from (S)-malic acid
(Scheme 1).1 More recently, Feringa and Kellogg have
shown that larger quantities of similar building blocks are
available in an efficient manner from elegant enzymatic
resolutions of racemic lactams derived from 5-methoxyfura-
none.2 Importantly, both methods allow access to either
antipode of 1. It was hoped that 1 would be a powerful
building block for organic synthesis by virtue of the fact that
further functionalization should be possible at all of the ring
atoms using well-established methodology.3-5 As part of an
ongoing research program committed to total synthesis via
enantiopure iminium ion intermediates,6 herein we wish to
report that Michael additions to 1 proceed in essentially
quantitative yields, affording building blocks 2 (Scheme 1).
Further transformations indeed allow generation of enan-
tiopure N-acyliminium ions 4, which react intramolecularly
with tethered nucleophiles to afford substituted azabicyles
5 in excellent yields. This flexible strategy toward such
bicycles in enantiopure form should be particularly valuable
considering its recent emergance as a structural unit in
roseophilin, a natural product with promising anticancer
properties.7 Our efforts toward its first enantioselective total
synthesis are also disclosed.
Michael additions to enantiopure 3-pyrrolin-2-ones have
not been extensively studied. Previous attempts used meta-
lated enolate anions.8 We expected the presence of the
N-acetyl group in 1 to enhance the electrophilicity of the
double bond,9 making it a good Michael acceptor and thus
allowing additions to take place under milder conditions.
(1) Koot, W.-J .; Hiemstra, H.; Speckamp, W. N. J . Org. Chem. 1992, 57,
1059.
(2) Van der Deen, H.; Cuiper, A. D.; Hof, R. P.; Van Oeveren, A.; Feringa,
B. L.; Kellogg, R. M. J . Am. Chem. Soc. 1996, 118, 3801.
(3) (a) Koot, W.-J .; Hiemstra, H.; Speckamp, W. N. Tetrahedron: Asym-
metry 1993, 4, 1941. (b) Koot, W.-J .; Hiemstra, H.; Speckamp, W. N.
Tetrahedron Lett. 1992, 33, 7969.
(4) Koot, W.-J .; Hiemstra, H.; Speckamp, W. N. J . Chem. Soc., Chem.
Commun. 1993, 156.
(5) Newcombe, N. J .; Ya, F.; Vijn, R. J .; Hiemstra, H.; Speckamp, W. N.
J . Chem. Soc., Chem. Commun. 1994, 767.
(6) (a) (-)-Peduncularine total synthesis: Klaver, W. J .; Hiemstra, H.;
Speckamp, W. N. J . Am. Chem. Soc. 1989, 111, 2588. (b) Approaches toward
gelsedine: Beyersbergen van Henegouwen, W. G.; Hiemstra, H. J . Org.
Chem. 1997, 62, 8862. (c) For a review see: Hiemstra, H.; Speckamp, W.
N. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds;
Pergamon: Oxford, 1991; Vol. 2, Chapter 4.5.
(7) (a) Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihata, K. Tetrahedron
Lett. 1992, 33, 2701. (b) Nakatani, S.; Kirihara, M.; Yamuda, K.; Terashima,
S. Tetrahedron Lett. 1995, 36, 8461. (c) Fu¨rstner, A.; Weintritt, H. J . Am.
Chem. Soc. 1997, 119, 2944. (d) Kim, S. H.; Figueroa, I.; Fuchs, P. L.
Tetrahedron Lett. 1997, 38, 2601.
(10) Thaning, M.; Wistrand, L.-G. J . Org. Chem. 1990, 55, 1406.
(11) For the synthesis of Me3SiCH2CtCCH2OH: Mastalerz, H. J . Org.
Chem. 1984, 49, 4092. The alcohol was converted into the iodide using MsCl/
KI or Ph3P/I2/imidazole (90%).
(12) (a) Wijnberg, J . B. P. A.; Speckamp, W. N. Tetrahedron 1978, 34,
2579. (b) Gramain, J .; Remuson, R. Tetrahedron Lett. 1985, 26, 4083.
(8) (a) Langlois, N.; Andriamialisoa, R. Z. Tetrahedron Lett. 1991, 32,
3057. (b) Baldwin, J . E.; Moloney, M. G.; Shim, S. B. Tetrahedron Lett. 1991,
32, 1379.
(9) Vedejs, E.; Gadwood, R. C. J . Org. Chem. 1978, 43, 376.
S0022-3263(97)01854-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/06/1998

Communications
J . Org. Chem., Vol. 63, No. 2, 1998 221
Ta ble 1. Mich a el Ad d ition s of 1 a n d Alk yla tion of Ad d u cts
R1
R2
nucleophile (equiv)
product (yield, %)
alkylating agent R3X (equiv)
product (yield, %)
COMe
CO2Me
CO2Me
CO2Me
1.1
2.2
6 (99)
7 (95)
-
-
Me2CdCHCH2Br (2.4)a
PhCH2Cl (3.0)a
10 (50)
11 (76)
12 (77)
13 (80)
CO2Et
CO2Me
CO2Et
SO2Ph
2.2
1.0
8 (90)
9 (100)
TMSCH2CtCCH2I (2.5)
TMSCH2CtCCH2I (2.5)
a
LiI (3 equiv) added.
Ta ble 2. Cycliza tion of N-Dep r otected Alk yla tion
P r od u cts 10-13
Sch em e 2
a
tricyclic core 20, with both Fu¨rstner7c and Fuchs7d achieving
racemic syntheses. Our efforts toward enantiopure 20 are
also given in Scheme 2. Allene 18 was transformed using
standard procedures into enone 25. Addition of a bis-
(isopropyl)magnesiocuprate occurred with complete stereo-
control in the presence of BF3‚Et2O (no addition occurred
in its absence), affording 22 as a single diastereomer. Work
toward a completion of the total synthesis is in progress and
will be reported in due course.
Yields (isolated) are for the two-step N-deprotection-cycliza-
b
tion protocol (2 f 5, Scheme 1). 3:1 mixture of diastereomers.
a tertiary cation intermediate). No traces of the 6-exo-trig
cyclization were detected (via a secondary cation). There
was a preference for the isopropyl group on the concave face
of the molecule. Similar stereoselectivities were obtained
with either a Bro¨nsted or Lewis acid. Fortunately, the
crystals of 14r-H were suitable for X-ray analysis, which
allowed conclusive assignment of absolute stereochemistry.
The benzyl group also proved an excellent nucleophile,
affording 16 in good yield as a single diastereomer. We have
previously obtained an analogous product to 16, but devoid
of the ester groups, by addition of a bis(phenylethyl)cuprate
to 1 followed by a similar cyclization protocol.3b It was
gratifying to note that this new methodology proceeded in
similarly high yields. Finally, the tethered propargyl silanes
allowed the synthesis of allenes 17 and 18 in excellent yields.
With relatively facile access to this range of enantiopure
bicycles, we next considered synthetic applications. Roseo-
philin (19) is a complex synthetic target attracting much
recent interest in view of both its unique structure and
promising anticancer properties (Scheme 2).7 Elegant work
by Terishima established the viability of the retrosynthetic
analysis shown and resulted in the synthesis of the hetero-
biaryl fragment 21.7b Others have focused attention on the
Ack n ow led gm en t. The European Union (TMR fellow-
ship, T.L.) and The Netherlands Foundation for Chemical
Research (in part) (SON, W.-J .K.) with financial aid from
The Netherlands Organization for Scientific Research
(NWO, W.-J .K.) are acknowledged for generous financial
support. We thank M. P. Otero Cabredo (ERASMUS
exchange from University of Santiago de la Compostela)
for the synthesis of 1, R. H. Balk for the preparation of
propargyl silanes, and J . Fraanje and K. Goubitz (Crystal-
lography Department, University of Amsterdam) for de-
termining the X-ray crystal structure of 14r-H.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and 1H NMR spectra of all new compounds (27 pages).
J O971854D