Novel enantioselective approach to γ-lactams from chiral enol ethers: Synthesis of (-)-statine

Full text of DOI:10.1021/jo961035d

5210
J . Org. Chem. 1996, 61, 5210-5211
Novel En a n tioselective Ap p r oa ch to
γ-La cta m s fr om Ch ir a l En ol Eth er s:
Syn th esis of (-)-Sta tin e
Pascal Nebois and Andrew E. Greene*
Universite´ J oseph Fourier de Grenoble, Chimie Recherche
(LEDSS), Domaine Universitaire, BP 53X,
38041 Grenoble Cedex, France
Received J une 3, 1996
In previous publications we have shown that chiral
O-alkyl enol ethers undergo clean, diastereofacially selec-
tive 2 + 2 cycloaddition with dichloroketene to provide
R,R-dichlorocyclobutanones.1 These 4-membered car-
bocycles, in transformations driven by inherent ring stain
and favorable electronic effects, can then be converted
rapidly and efficiently with diazomethane and m-chlo-
roperbenzoic acid to R,R-dichlorocyclopentanones and R,R-
dichloro-γ-butyrolactones, respectively (eq 1, X ) CH2,O).2
These in turn have proven to be valuable substrates for
the preparation of several natural products in native
form.1b-e
element. This choice was based on the expectation that
reduction of the intermediate R,R-dichloropyrrolidinones
would occur without concomitant auxiliary elimination,
in parallel with the behavior of most of the R,R-dichloro-
γ-butyrolactones that have been studied to date.1e This
would then give access, through benzylic cleavage, not
only to â-hydroxy-γ-lactams, but potentially to a variety
of others as well.3
Conversion of (R)-1-(2,4,6-triisopropylphenyl)ethanol
(2)5 to ynol ether 3a using our published procedure6 was
initially compromised by the reluctance of the acetylide
to undergo alkylation with isobutyl iodide at low tem-
perature, which was essential to prevent decomposition
of this sensitive intermediate. Fortunately, however, the
corresponding triflate7 was sufficiently reactive at low
temperature and produced the crystalline ynol ether 3a
in 61% yield after dry silica gel chromatography8 (Scheme
1). Semihydrogenation of the triple bond in ynol ether
3a in pyridine with palladium on barium sulfate6b then
smoothly afforded the chiral Z-enol ether 3b in 93% yield.
It is noteworthy that in this conversion the formation of
over-reduced and/or hydrogenolyzed material was not
encountered.
It was felt that these same R,R-dichlorocyclobutanones
might also allow access to γ-lactams (X ) NH) and hence
offer a novel entry to not only enantiopure γ-amino acid,
but also pyrrolidine, pyrrolizidine, and indolizidine natu-
ral products.3,4 The first example of the use of dichlo-
roketene-chiral olefin diastereofacial differentiation for
the enantioselective construction of a γ-lactam and its
conversion to the novel amino acid statine are now
reported (eq 2).
The reaction of dichloroketene9 with 3b was found to
proceed best at 0 °C and resulted in clean, diastereose-
lective cycloaddition to afford the dichlorocyclobutanone
(5) 1-(2,4,6-Triisopropylphenyl)ethanol was conveniently and ef-
ficiently resolved (ca. 39% R, 40% S, 100-g scale) in analogy with a
published procedure (Reyes, A.; J uraristi, E. Synth. Commun. 1995,
With the ultimate goal of a broad approach in mind,
1-(2,4,6-triisopropylphenyl)ethanol (2), a chiral benzylic
alcohol auxiliary recently developed and used effectively
in our laboratory for the synthesis of several natural
â-hydroxy-γ-butyrolactones,1e was selected as the control
25, 1053-1058). R: [R]22 +46.2 (c 1, chloroform); mp 84-85 °C. (The
D
values cited in ref 1e are in error.)
(6) (a) Moyano, A.; Charbonnier, F.; Greene, A. E. J . Org. Chem.
1987, 52, 2919-2922. (b) Kann, N.; Bernardes, V.; Greene, A. E. Org.
Synth., in press.
* To whom correspondence should be addressed. Tel: (33) 76-51-
46-86. Fax: (33) 76-51-43-82. E-mail: Andrew.Greene@ujf-grenoble.fr.
(1) (a) Greene, A. E.; Charbonnier, F. Tetrahedron Lett. 1985, 26,
5525-5528. (b) Greene, A. E.; Charbonnier, F.; Luche, M.-J .; Moyano,
A. J . Am. Chem. Soc. 1987, 109, 4752-4753. (c) B. M. de Azevedo, M.;
Murta, M. M.; Greene, A. E. J . Org. Chem. 1992, 57, 4567-4569. (d)
Murta, M. M.; B. M. de Azevedo, M.; Greene, A. E. J . Org. Chem. 1993,
58, 7537-7541. (e) B. M. de Azevedo; Greene, A. E. J . Org. Chem. 1995,
60, 4940-4942.
(2) Significantly, it has been found that the cycloadducts (or a
subsequent intermediate prior to removal of the chiral auxiliary) as a
rule can be efficiently upgraded to diastereomeric purity by simple
recrystallization.
(3) For recent syntheses of chiral pyrrolidinones, see: (a) Meyers,
A. I.; Snyder, L. J . Org. Chem. 1993, 58, 36-42. (b) Gennari, C.; Pain,
G.; Moresca, D. J . Org. Chem. 1995, 60, 6248-6249. (c) Wei, Z.-Y.;
Knaus, E. E. Tetrahedron Lett. 1993, 34, 4439-4442. (d) Wee, A. G.
H.; Liu, B. Tetrahedron Lett. 1996, 37, 145-148 and references cited
therein.
(7) Salomon, M. F.; Salomon, R. G.; Gleim, R. D. J . Org. Chem. 1976,
41, 3983-3987.
(8) Yields are for purified, chromatographically homogeneous sub-
stances. Physical data for key compounds. Ynol ether 3a : mp 34-36
°C; [R]20D +163 (c 1.0, chloroform); IR 2266, 1608, 1579, 1231 cm-1; 1H
NMR (200 MHz) δ 0.72 (d, J ) 6.5 Hz, 3 H), 0.73 (d, J ) 6.9 Hz, 3 H),
1.16-1.30 (m, 18 H), 1.44-1.63 (m, 1 H), 1.68 (d, J ) 6.9 Hz, 3 H),
1.88 (d, J ) 5.8 Hz, 2 H), 2.84 (hept, J ) 6.9 Hz, 1 H), 3.20-3.47 (m,
2 H), 5.61 (q, J ) 6.9 Hz, 1 H), 6.99 (s, 2 H); mass spectrum (CI) m/z
329 (M+ + 1), 231 (100). Anal. Calcd for C23H36O: C, 84.09; H, 11.04.
Found: C, 83.94; H, 11.05. Enol ether 3b: [R]21 -10 (c 1.0, chloro-
D
form); IR 3032, 1662, 1609, 1573, 1085 cm-1
;
1H NMR (200 MHz) δ
0.888 (d, J ) 6.5 Hz, 3 H), 0.892 (d, J ) 6.8 Hz, 3 H), 1.20-1.27 (m, 18
H), 1.58 (d, J ) 6.5 Hz, 3 H), 1.48-1.71 (m, 1 H), 1.99 (m, 2 H), 2.85
(hept, J ) 6.9 Hz, 1 H), 2.72-2.96 (m, 2 H), 4.28 (q, J ) 7.0 Hz, 1 H),
5.30 (dt, J ) 6.7, 6.7 Hz, 1 H), 5.97 (dt, J ) 6.5, 1.5 Hz, 1 H), 7.00 (s,
2 H); HRMS m/e calcd for C23H38O (M+) 330.2923, found 330.2937.
Lactam 5b: mp 144-146 °C; [R]20 +82 (c 1.0, chloroform); IR 3208,
D
3090, 1709, 1608, 1579, 1113, 1074 cm-1
;
1H NMR (200 MHz) δ 0.82
(4) For reviews on pyrrolidines, see: Attygalle, A. B.; Morgan, D.
E. Chem. Soc. Rev. 1984, 13, 245-278. Massiot, G.; Delaude, C. In
The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1986; Vol.
27, Chapter 3. Numata, A.; Ibuka, T. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1987; Vol. 31, Chapter 6. Pyrrolizidines,
see: Robins, D. J . J . Nat. Prod. 1992, 9, 313-321. Indolizidines, see:
Burgess, K.; Henderson, I. Tetrahedron 1992, 48, 4045-4066. Taka-
hata, H.; Momose, T. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1993; Vol. 44, Chapter 3. Michael, J . P. J . Nat. Prod.
1995, 9, 535-552.
(d, J ) 6.2 Hz, 3 H), 0.93 (d, J ) 6.2 Hz, 3 H),1.15-1.28 (m, 18 H),
1.38-1.54 (m, 3 H), 1.52 (d, J ) 7.0 Hz, 3 H), 2.46 (d, J ) 6.5 Hz, 1 H),
2.47 (d, J ) 6.8 Hz, 1 H), 2.83 (hept, J ) 6.9 Hz,1 H), 3.13 (hept, J )
6.5 Hz,1 H), 3.58-3.63 (m, 1 H), 3.85 (hept, J ) 6.5 Hz,1 H), 4.10 (q,
J ) 7.0 Hz, 1 H), 5.03 (q, J ) 6.7 Hz, 1 H), 6.05 (s, 1 H), 6.93 (s, 1 H),
7.02 (s, 1 H); mass spectrum (EI) m/z 387 (M+), 372, 215, 140, 43 (100).
Anal. Calcd for C25H41NO2: C, 77.47; H, 10.66; N, 3.61. Found: C,
77.80; H, 10.67; N, 3.48.
(9) For a recent review on ketene cycloaddition chemistry, see:
Hyatt, J . A.; Raynolds, P. W. Org. React. 1994, 45, 159-646.
S0022-3263(96)01035-3 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 16, 1996 5211
Sch em e 1a
without concomitant elimination of the inductor to pro-
vide γ-lactam 5b.12 On simple recrystallization from
methanol-water, this substance efficiently yielded highly
crystalline, diastereomerically pure lactam 5b (40% from
3b, 74%/step).
As an initial application of this approach, lactam 5b
was converted to the hydroxy amino acid statine, a key
component of several acid protease inhibitors and thus
of considerable medicinal interest.13 Many of the re-
ported syntheses of this unusual amino acid, however,
fail to yield stereochemically pure material. After some
experimentation, it was found that one-pot inductor
cleavage-ring opening could be effected by simply stir-
ring lactam 5b with trifluoroacetic acid1e at 20 °C for a
short period followed by addition of concentrated hydro-
chloric acid and heating.3b Ion-exchange column chro-
matography of the resulting salt then afforded (3S,4S)-
statine, identified through comparison with the naturally
derived material.
In summary, it has been demonstrated that cycload-
dition of chiral enol ethers with dichloroketene coupled
with the Beckmann ring expansion can provide an
effective, stereocontrolled approach to chiral pyrrolidi-
nones. While in the present instance this method has
been used to prepare a natural â-hydroxy-γ-amino acid,
we expect it will also find application in pyrrolidine,
pyrrolizidine, and indolizidine natural product synthesis.
This possibility is currently under study.
a
Key: (a) (1) KH, THF, 20 °C; Cl2CdCHCl, -50 f 15 °C, 81%;
(2) C4H9Li, THF, -85 f -40 °C; isobutyl triflate, THF, -28 °C,
75%; (b) 10% Pd/BaSO4, H2, C5H5N, 93%; (c) Cl3CCOCl, Zn-Cu,
(C2H5)2O, 0 °C; (d) NH2OSO2C6H2(CH3)3, CH2Cl2, 20 °C; Al2O3;
(e) Zn-Cu, CH3OH-NH4Cl, 20 °C, 40% (three steps); (f) CF3CO2H,
20 °C; concd HCl, 80 °C; Dowex H+, 60%.
4. Proton NMR of the crude reaction product indicated
that a most pleasing 94:6 ratio of diastereomeric cyclo-
adducts had been reached in this reaction. Molecular
mechanics calculations clearly showed that cycloaddition
should in fact take place selectively on the CR-si face to
generate 4 as the major product. The correctness of this
prediction was eventually borne out.
In that all attempts to purify 4 led to unacceptable loss
of material, the diastereomeric upgrading was tempo-
rarily postponed and the key conversion to the γ-lactam
was examined. Remarkably, Beckmann ring expansion
of cyclobutanone 4 with Tamura’s reagent (O-(mesityle-
nesulfonyl)hydroxylamine)10 proceeded without apparent
side reactions, in spite of the dense substitution and
sensitive nature of the molecule, to give regioselectively
crude R,R-dichloro-γ-lactam 5a as an oil. On brief
exposure at ambient temperature to excess zinc-copper
couple in methanol saturated with ammonium chloride,11
this material, as had been predicted, suffered reduction
Ack n ow led gm en t. We thank Prof. J . Lhomme for
his interest in our work, Dr. P. Delair for the large-scale
preparation of 2, and a reviewer for helpful comments.
Financial support from the CNRS (UMR 5616) and a
leave of absence granted by the Universite´ Claude
Bernard de Lyon to P.N. are gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data (6 pages).
J O961035D
(11) J ohnston, B. D.; Slessor, K. N.; Oehlschlager, A. C. J . Org.
Chem. 1985, 50, 114-117.
(12) With menthol as the chiral auxiliary, similar results were
obtained.
(13) For syntheses of statine and leading references concerning its
potential use, see: (a) Rich, D. H.; Sun, E. T.; Boparai, A. S. J . Org.
Chem. 1978, 43, 3624-3626. (b) Rittle, K. E.; Homnick, C. F.;
Ponticello, G. S.; Evans, B. E. J . Org. Chem. 1982, 47, 3016-3018. (c)
Woo, P. W. K. Tetrahedron Lett. 1985, 26, 2973-2976. See also ref 3b
and references cited therein.
(10) Tamura, Y.; Minamikawa, J .; Ikeda, M. Synthesis 1977, 1-17.
See also: Luh, T.-Y.; Chow, H.-F.; Leung, W. Y.; Tam, S. W.
Tetrahedron 1985, 41, 519-525.