Formal total synthesis of enantiopure (-)-anisomycin, antibiotic from streptomyces

Full text of DOI:10.1021/jo981908z

J . Org. Chem. 1999, 64, 1383-1386
1383
To date, the preparation of (-)-anisomycin has almost
invariably relied on chiral pool starting material, such
as L-malic acid, L-tartaric acid, D-glucose, D-ribose, D-
galactose, D-mannitol, D-tyrosine, or L-aspartic acid and
has often proceeded in modest yield.10 Given the sus-
tained interest in this alkaloid, it was felt that it would
be worthwhile to test our dichloroketene-chiral O-alkyl
enol ether cycloaddition methodology11 for potentially
flexible access.12
F or m a l Tota l Syn th esis of En a n tiop u r e
(-)-An isom ycin , An tibiotic fr om
Str eptom yces
Philippe Delair, Elisabeth Brot, Alice Kanazawa, and
Andrew E. Greene*
Universite´ J oseph Fourier de Grenoble Chimie Recherche
(LEDSS), 38041 Grenoble Cedex, France
The approach we hoped to develop is shown retrosyn-
thetically in eq 1. The pyrrolidine derivative correspond-
ing to I (eq 1, R ) H), previously10s,t converted to
anisomycin through formal syn elimination of water,
trans dihydroxylation-monoacetylation, and N-depro-
tection, appeared to be available from I (R ) R*) by
carbonyl reduction and O-R* bond cleavage. This pyr-
rolidinone, it was felt, might be accessed through Beck-
mann ring expansion, dechlorination, and N-protection
of the 2 + 2 cycloadduct derived from dichloroketene
(DCK) and a chiral enol ether II. In this paper, we report
an asymmetric formal synthesis of (-)-anisomycin through
the successful realization of this approach.
Received September 21, 1998
The antibiotic (-)-anisomycin was first isolated from
the fermentation broths of Streptomyces griseolus and
Streptomyces roseochromogenes by Pfizer, Inc., in 19541
and, subsequently, from those of Streptomyces sp. No. 638
and SA 3097 by groups in J apan.2 Some 10 years after
its initial isolation, its structure and relative stereochem-
istry were elucidated by chemical and spectroscopic
means, which were later confirmed by X-ray crystal-
lography.3 The absolute stereochemistry of this alkaloid
has been firmly established as 2R,3S,4S by chemical
correlation with L-tyrosine.4
Anisomycin possesses strong and selective activity
against pathogenic protozoa and fungi5 and has clinically
been used with success in the treatment of vaginitis due
to trichomonas vaginilis6 and for amoebic dysentery.7
Both anisomycin and its deacetyl derivative have been
employed as fungicides in the eradication of bean mildew
and to inhibit other pathogenic fungi in plants.8 Ef-
fectively inhibiting peptide bond formation on eukaryotic
ribosomes, anisomycin has found additional use as a tool
in molecular biology.9
For high face discrimination in the cycloaddition and
the possibility to effect subsequently selective C-O bond
cleavage, the easily available, enantiopure, dual purpose
inductor (S)-1-(2,4,6-triisopropylphenyl)ethanol13 (2,
Scheme 1) appeared to be the one of choice. Both
(10) For approaches to (()-anisomycin, see: (a) Oida, S.; Ohki, E.
Chem. Pharm. Bull. 1969, 17, 1405-1421. (b) Schumacher, D. P.; Hall,
S. S. J . Am. Chem. Soc. 1982, 104, 6076-6080. For chiral pool-based
approaches to (-)-anisomycin, see: (c) Wong, C. M.; Buccini, J .; Chang,
I.; Te Raa, J .; Schwenk, R. Can. J . Chem. 1969, 47, 2421-2424. (d)
Felner, I.; Schenker, K. Hev. Chim. Acta 1970, 53, 754-763. (e)
Verheyden, J . P. H.; Richardson, A. C.; Bhatt, R. S.; Grant, B. D.; Fitch,
W. L.; Moffat, J . G. Pure Appl. Chem. 1978, 50, 1363-1383. (f)
Buchanan, J . G.; MacLean, K. A.; Wightman, R. H.; Paulsen, H. J .
Chem. Soc., Perkin Trans. 1 1985, 1463-1470. (g) Iida, H.; Yamazaki,
N.; Kibayashi, C. J . Org. Chem. 1986, 51, 1069-1073. (h) Shono, T.;
Kise, N. Chem. Lett. 1987, 697-700. (i) Baer, H. H.; Zamkanei, M. J .
Org. Chem. 1988, 53, 4786-4789. (j) J egham, S.; Das, R. C. Tetrahe-
dron Lett. 1988, 29, 4419-4422. (k) Takano, S.; Iwabuchi, Y.;
Ogasawara, K. Heterocycles 1989, 29, 1861-1864. (l) Ballini, R.;
Marcantoni, E.; Petrini, M. J . Org. Chem. 1992, 57, 1316-1318. (m)
Yoda, H.; Nakajima, T.; Yamazaki, H.; Takabe, K. Heterocycles 1995,
41, 2423-2426. (n) Han, G.; LaPorte, M. G.; McIntosh, M. C.; Weinreb,
S. M.; Parvez, M. J . Org. Chem. 1996, 61, 9483-9493. (o) Kang, S. H.;
Choi, H.-w. J . Chem. Soc., Chem. Commun. 1996, 1521-1522. (p)
Veith, U.; Schwardt, O.; J a¨ger, V. Synlett 1996, 1181-1183. (q) Kadota,
I.; Saya, S.; Yamamoto, Y. Heterocycles 1997, 46, 335-348. (r) Huang,
P. Q.; Wang, S. L.; Ruan, Y. P.; Gao, J . X. Nat. Prod. Lett. 1998, 11,
101-106. For other approaches, see: (s) Meyers, A. I.; Dupre, B.
Heterocycles 1987, 25, 113-116. (t) Takahata, H.; Banba, Y.; Tajima,
M.; Momose, T. J . Org. Chem. 1991, 56, 240-245. (u) Shi, Z.-c.; Lin,
G.-q. Tetrahedron: Asymmetry 1995, 6, 2907-2910.
* To whom correspondence should be addressed. Tel: (33) 4-76-51-
46-86. Fax: (33) 4-76-51-43-82. E-mail: Andrew.Greene@ujf.grenoble-
fr.
(1) Sobin, B. A.; Tanner, F. W. J . Am. Chem. Soc. 1954, 76, 4053.
(2) Ishida, S.; Yamada, O.; Futatsuya, F.; Ito, K.; Yamamoto, H.;
Munakata, K. Proc. Int. Congr. IAMS 1st 1974, 3, 641-648. Hosoya,
Y.; Kameyama, T.; Naganawa, H.; Okami, Y.; Takeuchi, T. J . Antibiot.
1993, 46, 1300.
(3) Beereboom, J . J .; Butler, K.; Pennington, F. C.; Solomons, I. A.
J . Org. Chem. 1965, 30, 2334-2342. Schaefer, J . P.; Wheatley, P. J .
Ibid. 1968, 33, 166-169. Butler, K. Ibid. 1968, 33, 2136-2141.
(4) Wong, C. M. Can. J . Chem. 1968, 46, 1101-1104.
(5) J imenez, A.; Vazquez, D. In Antibiotics; Hahn, F. E., Ed.;
Springer-Verlag: Berlin, 1979; pp 1-19. Grollman, A. P. J . Biol. Chem.
1967, 242, 3226-3233.
(6) Frye, W. W.; Mule, J . G.; Swartzwelder, C. Antibiot. Ann. 1955,
820-823. Armstrong, T.; Santa Maria, O. Ibid. 1955, 824-826.
(7) Santander, V. M.; Cue, A. B.; Diaz, J . G. H.; Balmis, F. J .;
Miranda, G.; Urbina, E.; Portilla, J .; Plata, A. A.; Zapata, H. B.; Munoz,
V. A.; Abreu, L. M. Rev. Invest. Biol. Univ. Guadalajara 1961, 1, 94-
96.
(8) Windholz, M., Ed. The Merck Index, 12th ed.; Merck: Whitehouse
Station, NJ , 1996; p 710.
(9) Korzybski, T.; Kowszyk-Gindifer, Z.; Kurytowicz, W. Antibiotics;
American Society of Microbiology: Washington, DC, 1978; Vol. 1, pp
343-346.
10.1021/jo981908z CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/23/1999

1384 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
Sch em e 1
the CR-re face of enol ether 4 would be the more acces-
sible, as required in the projected route to (-)-anisomycin,
and this was eventually borne out.
Thus, this alcohol was transformed with potassium
hydride and trichloroethylene to the E dichloro enol ether
3 (82% yield). The corresponding lithium acetylide,
formed from 3 with n-butyllithium, was then treated with
4-methoxybenzyl bromide in THF-HMPA under care-
fully optimized conditions to yield the somewhat unstable
alkylated acetylenic ether, which was converted without
purification into the Z enol ether 4 in 81% yield for the
two steps.16
In the presence of dichloroketene, generated in situ
from trichloroacetyl chloride and zinc-copper couple,17
enol ether 4 underwent clean and, as expected, face-
selective cycloaddition to produce in high yield the
desired dichlorocyclobutanone 5, contaminated with only
ca. 7% of diastereomeric material (1H NMR). Because it
was anticipated that removal of this contaminant would
be more readily achieved at the pyrolidinone stage, the
crude cycloadduct was converted with O-(mesitylene-
sulfonyl)hydroxylamine,18 and apparently with complete
regioselectivity, into the corresponding dichloropyrroli-
dinone, which was dechlorinated with zinc-copper couple
in methanol saturated with ammonium chloride19 to
F igu r e 1. Global minimum-energy conformation of enol ether
4 (b ) enol oxygen).
molecular modeling of enol ether 414,15 (Figure 1) and
synthetic results previously obtained with other enol
ethers derived from this inductor11e-h clearly indicated
(11) (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, M.; Greene, A. E. J . Org. Chem.
1995, 60, 4940-4942. (f) Kanazawa, A.; Delair, P.; Pourashraf, M.;
Greene, A. E. J . Chem. Soc., Perkin Trans. 1 1997, 1911-1912. (g)
Nebois, P.; Greene, A. E. J . Org. Chem. 1996, 61, 5210-5211. (h)
Kanazawa, A.; Gillet, S.; Delair, P.; Greene, A. E. J . Org. Chem. 1998,
63, 4660-4663.
(15) The solid-state structure is shown below (crystal data for
C27H38O2 , triclinic P-1, a ) 10.492(8) Å, b ) 13.428(3) Å, c ) 17.862(5)
Å, R ) 96.47(2)°, â ) 100.41(4)°, γ ) 90.03(4)°, V ) 2459(2) Å3, Z ) 4,
dcalcd ) 1.066 Mg/M3, F(000) ) 864, 2θ range 2-59.9°, 12928 measured
reflections. 12505 [R(int) ) 0.01] independent reflections, 4896 with I
> 3σ, R ) 0.065, Rw ) 0.057, GOF ) 2.301):
(12) For reviews on the occurrence, biological properties, and
syntheses of 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. O’Hagan, D. J . Nat. Prod.
1997, 14, 637-651.
(13) Delair, P.; Kanazawa, A.; B. M. de Azevedo, M.; Greene, A. E.
Tetrahedron: Asymmetry 1996, 7, 2707-2710.
(14) Molecular modeling was performed on an IBM RS 6000
workstation running Insight II Discover 97.0 (MSI, San Diego). The
structure was energy minimized with the force field cvff.frc. and the
minimization algorithm VA09A. The molecular dynamics was per-
formed at 500 K in vacuo (dielectric constant fixed at 1; 200 000 steps
of 1 fs) and consisted of the generation of 200 structures. The depicted
conformation is lowest in energy by 3.6 kcal/mol. (The next lowest in
energy would also be expected to undergo cycloaddition largely on the
CR-re face.)
(16) Kann, N.; Bernardes, V.; Greene, A. E. Org. Synth. 1997, 74,
13-22.
(17) Hassner, A.; Krepski, L. R. J . Org. Chem. 1978, 43, 3173-3179.
Brady, W. T.; Lloyd, R. M. Ibid. 1979, 44, 2560-2564.
(18) Tamura, Y.; Minamikawa, J .; Ikeda, M. Synthesis 1977, 1-17.

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1385
cold saturated aqueous ammonium chloride. The product was
isolated with pentane in the usual way to give crude 2-((1S)-1-
(3-(4-methoxyphenyl)-1-propynyloxy)ethyl)-1,3,5-triisopropylben-
provide the highly crystalline pyrrolidinone 6. Recrys-
tallization of this material from pentane-dichloromethane
afforded in 68% overall yield from enol ether 4 the
stereochemically pure (1H NMR; chiral HPLC of the free
alcohol) pyrrolidinone 6.
zene: IR 2268 cm-1
.
A mixture of the above crude compound, 8.70 g (62.9 mmol)
of potassium carbonate, and 1.5 g of 10% palladium on barium
sulfate in 200 mL of dry pyridine was stirred under hydrogen
for 48 h at 0 °C, whereupon the hydrogen was replaced with
argon and the reaction mixture was diluted with pentane and
filtered over Celite. The solvents were thoroughly washed with
water, saturated aqueous copper sulfate, water, and saturated
aqueous ammonium chloride, dried over sodium sulfate, and
evaporated under reduced pressure. The resulting crude product
was purified by dry silica gel chromatography (pretreated with
2.5% triethylamine, v/v) with 0-5% ether in pentane to afford
4.45 g (81% from 3) of enol ether 4: mp 51-52 °C (pentane);
To intersect the previous synthesis at the above-
mentioned chiral pyrrolidine, pyrrolidinone 6 was first
treated with benzyl chloroformate (CBZ-Cl), which pro-
vided the expected imide in 98% yield after purification.20
Reduction of the ring carbonyl could now be cleanly
effected in yields of up to 78%, but generally somewhat
lower, by using the excellent procedure recently described
by Pedregal, Ruano, and co-workers,21 namely, sequential
reduction with super hydride and triethylsilane in the
presence of boron trifluoride etherate. The resulting
pyrrolidine 7 on brief treatment with trifluoroacetic acid
gave in 99% yield (27% overall from 2, 87%/step) the
[R]20D +36.5° (c 1.4, chloroform); IR 3034, 1661, 1609, 1244 cm-1
;
1H NMR (250 MHz) δ 1.20-1.40 (m, 18 H), 1.75 (d, J ) 6.7 Hz,
3 H), 2.97 (hept, J ) 6.7 Hz, 1 H), 3.52 (AB of ABX, δa ) 3.44,
δb ) 3.61, J ab ) 15.5 Hz, J ax ) 7.1 Hz, J bx ) 7.9 Hz, 2 H), 3.50-
3.75 (m, 2 H), 3.85 (s, 3 H), 4.57 (pseudo q, 1 H), 5.49 (q, J ) 6.7
Hz, 1 H), 6.17 (dt, J ) 6.3, 1.5 Hz, 1H), 7.08 (ABq, δa ) 6.91, δb
) 7.25, J ab ) 8.5 Hz, 4 H), 7.12 (s, 2 H); 13C NMR (62.8 MHz) δ
22.5, 23.9, 24.6, 29.1, 29.5, 34.0, 55.2, 75.4, 105.4, 113.6, 121.9
(br), 129.1, 132.9, 134.0, 144.2, 146.8 (br), 147.7, 157.6; mass
spectrum (EI) m/z 394 (M+), 231 (100), 147.
enantiopure hydroxy pyrrolidine 8 ([R]25 -6.0° (lit.10t
D
[R]25 -4.99°)), which displayed a high-field 1H NMR
D
spectrum in perfect agreement with that kindly provided
by Professor H. Takahata.10t
This highly enantioselective formal total synthesis,
based on an effective asymmetric 2 + 2 cycloaddition,
produces (-)-anisomycin in approximately 8% overall
yield.
Anal. Calcd for C27H38O2: C, 82.18; H, 9.71. Found: C, 82.00;
H, 9.65.
(-)-(2R,3S)-4,4-Dich lor o-2-(4-m eth oxyben zyl)-3-((1S)-1-
(2,4,6-tr iisop r op ylp h en yl)eth oxy)cyclobu ta n on e (5). To a
stirred mixture of 1.98 g (5.02 mmol) of enol ether 4 and 3.60 g
(ca. 55 mmol) of Zn-Cu couple in 50 mL of ether under argon
was added over 1.5 h 0.910 mL (1.34 g, 7.36 mmol) of freshly
distilled trichloroacetyl chloride in 18 mL of ether. After an
additional 1 h, the ether solution was separated from the excess
couple and added to pentane, and the resulting mixture was
partially concentrated under reduced pressure in order to
precipitate the zinc chloride. The supernatant was decanted and
washed successively with a cold aqueous solution of sodium
bicarbonate, water, and brine and then dried over anhydrous
sodium sulfate. Evaporation of the solvent under reduced
pressure left 2.38 g of crude cyclobutanone 5 (containing ca. 7%
of its diastereomer (δ 4.57 ppm)) as a white solid. Recrystalli-
zation from pentane of comparable material from a previous run
Exp er im en ta l Section
The reaction mixture was generally poured into water, and
the separated aqueous phase was then thoroughly extracted with
the specified solvent. After being washed with 10% aqueous HCl
and/or NaHCO3 (if required), water, and saturated aqueous
NaCl, the combined organic phases were dried over anhyd Na2-
SO4 or MgSO4 and then filtered and concentrated under reduced
pressure on a Bu¨chi Rotovapor to yield the crude reaction
product. Tetrahydrofuran and ether were distilled from sodium-
benzophenone, and methanol was distilled from magnesium.
Pentane, dichloromethane, pyridine, HMPA, and triethylamine
were distilled from calcium hydride.
(+)-2-((1S)-1-((1Z)-3-(4-Meth oxyp h en yl)-1-p r op en yloxy)-
eth yl)-1,3,5-tr iisop r op ylben zen e (4). An argon-flushed flask
was charged with 4.40 g (38.4 mmol) of a 35% suspension of
potassium hydride in mineral oil. The mineral oil was removed
by washing with pentane, and the flask was charged with 50
mL of anhydrous tetrahydrofuran, capped with a rubber septum,
and connected to a Nujol-filled bubbler by means of a syringe
needle. The solid alcohol 213 (4.36 g, 17.6 mmol) was then added
portionwise. The mixture was stirred until hydrogen evolution
was complete (ca. 2 h), cooled to -50 °C, and treated dropwise
over 2 h with a solution of trichloroethylene (1.70 mL, 2.49 g,
19.0 mmol) in 3 mL of anhydrous tetrahydrofuran, after which
the reaction mixture was allowed to warm to 20 °C over 1 h,
whereupon it was poured into cold saturated aqueous am-
monium chloride. The crude product was isolated with pentane
in the usual way and purified by filtration through silica gel
(200 mL, pretreated with 2.5% triethylamine, v/v) with pentane
to afford 4.96 g (82%) of pure 2-((1S)-1-((1E)-1,2-dichloroethe-
nyloxy)ethyl)-1,3,5-triisopropylbenzene (3).11g
gave analytically pure 5: mp 102-103 °C; [R]20 -19.2° (c 1.6,
D
chloroform); IR 3054, 3033, 1804, 1609, 1266, 1248 cm-1
;
1H
NMR (250 MHz) δ 1.13 (d, J ) 6.7 Hz, 3 H), 1.21 (d, J ) 6.7 Hz,
3 H), 1.25-1.31 (m, 9 H), 1.36 (d, J ) 6.7 Hz, 3 H), 1.74 (d, J )
6.7 Hz, 3 H), 2.91 (hept, J ) 6.7 Hz, 1 H), 3.10 (d, J ) 7.9 Hz,
2 H), 3.33 (hept, J ) 6.7 Hz, 1 H), 3.71 (pseudo q, 1 H), 3.79 (s,
3 H), 3.86 (hept, J ) 6.7 Hz, 1 H), 4.40 (d, J ) 9.1 Hz, 1 H), 5.52
(q, J ) 6.7 Hz, 1 H), 6.98 (ABq, δa ) 6.83, δb ) 7.14, J ab ) 8.7
Hz, 4 H), 7.04 (s, 1 H), 7.11 (s, 1 H); 13C NMR (62.8 MHz) δ
22.6, 23.7, 23.9, 24.9, 25.2, 25.4, 28.3, 29.2, 30.7, 34.0, 55.2, 60.6,
73.5, 77.4, 88.3, 113.9, 120.8, 123.3, 129.9, 130.2, 130.4, 147.0,
148.3, 148.9, 158.3, 195.8; mass spectrm (CI) m/z 522 (M+ + 18),
231 (100).
Anal. Calcd for C29H38O3Cl2: C, 68.90; H, 7.58. Found: 68.99;
H, 7.67.
(-)-(4R,5R)-5-(4-Met h oxyb en zyl)-4-((1S)-1-(2,4,6-t r iiso-
p r op ylp h en yl)eth oxy)-2-p yr r olid in on e (6). A solution of the
above crude cyclobutanone 5 in 50 mL of dichloromethane was
treated with 1.30 g (6.04 mmol) of O-mesitylenesulfonylhydroxyl-
amine and stirred at 20 °C for 40 min. The solvent was then
removed under reduced pressure, and the resulting material in
10 mL of toluene was placed on a column of basic alumina (200
g, Merck activity 1) and eluted rapidly with methanol. The
resulting crude (4S,5R)-3,3-dichloro-5-(4-methoxybenzyl)-4-((1S)-
To a solution of 4.80 g (14.0 mmol) of the above compound in
40 mL of anhydrous tetrahydrofuran at -78 °C was added
dropwise 14.1 mL (32.4 mmol) of 2.3 M n-butyllithium in
hexanes. After being stirred for 30 min at -78 °C, the reaction
mixture was warmed to -40 °C over 30 min and treated
dropwise with 8.40 g (41.8 mmol) of 4-methoxybenzyl bromide
followed by 11.4 mL of hexamethylphosphoramide. The solution
was stirred at -30 °C for 20 h, whereupon it was poured into
1-(2,4,6-triisopropylphenyl)ethoxy)-2-pyrrolidinone (IR 1684 cm-1
was used below.
)
The crude dichloro lactam in 65 mL of methanol previously
saturated with ammonium chloride was stirred at 20 °C with
1.2 g (ca. 18 mmol) of zinc-copper couple under argon for 1 h,
whereupon the mixture was filtered to remove the excess couple.
The filtrate was concentrated under reduced pressure, and the
residue was then processed with dichloromethane in the usual
way to give 2.05 g of lactam 6. Recrystallization of this material
(19) J ohnston, B. D.; Slessor, K. N.; Oehlschlager, A. C. J . Org.
Chem. 1985, 50, 114-117.
(20) Attempts to R-hydroxylate 6, as well as several of its derivatives,
led to unsatisfactory results.
(21) Pedregal, C.; Ezquerra, J .; Escribano, A.; Carreno, M. C.; Ruano,
J . L. G. Tetrahedron Lett. 1994, 35, 2053-2056.

1386 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
from pentane-dichloromethane provided 1.54 g (68% overall
yield from 4) of stereochemically pure 6. (HPLC (Chiracel OD-H
column, 5 mm, 2-propanol/hexane 20:80, 0.5 mL/min, tR 19.6 min
(vs 22.2 min)) of the free alcohol (10% trifluoroacetic acid in
dichloromethane) showed an ee of g99%.) Pyrrolidinone 6: mp
by, at -78 °C, 0.030 mL (34 mg, 0.24 mmol) of boron trifluoride
diethyl etherate. The same amounts of these two reagents were
again added to the reaction mixture at -78 °C every 30 min
until TLC (20% ethyl acetate in cyclohexane) showed total
disappearance of starting material (six times). The reaction
mixture was then poured into saturated aqueous sodium bicar-
bonate, and the crude product was isolated with dichloromethane
in the usual way and purified by dry silica gel chromatography
with 5% ethyl acetate in cyclohexane to afford 103 mg (62%) of
190-191 °C (pentane-dichloromethane); [R]20 -22.2° (c 1.5,
D
chloroform); IR 3421, 3200, 3052, 1698, 1609, 1265, 1247 cm-1
;
1H NMR (250 MHz) δ 1.1-1.4 (m, 18 H), 1.58 (d, J ) 6.3 Hz, 3
H), 2.50 (AB of ABX, δa ) 2.47, δb ) 2.52, J ab ) 16.6 Hz, J ax
7.1 Hz, J bx ) 7.1 Hz, 2 H), 2.80 (AB of ABX, δa ) 2.63, δb
)
)
pyrrolidine 7 as a white solid: mp 104-105 °C (pentane); [R]20
D
-48.1° (c 1, chloroform); IR 3061, 3029, 1703, 1607, 1247 cm-1
;
2.97, J ab ) 14.1 Hz, J ax ) 10.7 Hz, J bx ) 3.2 Hz, 2 H), 2.85 (hept,
J ) 6.7 Hz, 1 H), 3.16 (hept, J ) 6.7 Hz, 1 H), 3.65-3.80 (m, 1
H), 3.76 (s, 3 H), 3.90 (hept, J ) 6.7 Hz, 1 H), 4.25 (pseudo q, J
) 7.1 Hz, 1 H), 5.09 (q, J ) 6.3 Hz, 1 H), 5.49 (br s, 1 H), 6.92
(ABq, δa ) 6.80, δb ) 7.03, J ab ) 8.7 Hz, 4 H), 6.96 (s, 1 H), 7.06
(s, 1 H); 13C NMR (50.3 MHz) δ 23.2, 23.9, 24.3, 25.0, 25.1, 28.1,
29.2, 34.0, 35.5, 36.3, 55.2, 59.4, 71.3, 72.4, 114.1, 120.6, 123.3,
130.1, 132.1, 145.9, 147.7, 148.7, 158.3, 174.3; mass spectrum
(EI) m/z 452 (M+), 231 (100).
1H NMR (300 MHz, C6D6, 65 °C) δ 1.19-1.26 (m, 20 H), 1.49
(dd, J ) 11.8, 10.1 Hz, 1 H), 1.57 (d, J ) 5.9 Hz, 3 H), 1.74-1.82
(m, 1 H), 2.82 (hept, J ) 7.0, Hz, 1 H), 2.90-3.30 (m, 4 H), 3.45
(s, 3 H), 3.77 (dt, J ) 10.6, 7.0 Hz, 1 H), 4.20 (br q, J ) 5.9 Hz,
1 H), 5.06 (q, J ) 7.0 Hz, 1 H), 5.10 (ABq, δa ) 5.05, δb ) 5.15,
J ab ) 12.9 Hz, 2 H), 6.77 (A of ABq, J ab ) 9.4 Hz, 2 H), 7.05-
7.25 (m, 9 H); 13C NMR (75.5 MHz, rotamers) δ 24.1, 24.8, 24.9,
25.2, 25.7, 26.0, 28.5, 28.9, 29.4, 29.8, 34.7, 35.2, 35.6, 43.7, 43.9,
55.3, 60.8, 61.3, 67.1, 67.4, 71.7, 72.1, 75.8, 76.9, 114.2, 121.4,
124.4, 129.1, 129.2, 132.3, 132.4, 132.7, 133.7, 134.0, 138.2, 138.5,
146.8, 148.6, 150.0, 150.2, 155.0, 155.2, 159.2; mass spectrum
(CI) m/z 572 (MH+), 342, 231 (100).
Anal. Calcd for C29H41NO3: C, 77.12; H, 9.15; N, 3.10.
Found: C, 77.49; H, 9.16; N, 3.27.
(-)-(2R,3R)-1-(Ben zyloxyca r bon yl)-2-(4-m eth oxyben zyl)-
3-((1S)-1-(2,4,6-tr iisop r op ylp h en yl)eth oxy)p yr r olid in e (7).
To a solution of lactam 6 (268 mg, 0.59 mmol) in 4.5 mL of dry
tetrahydrofuran at -78 °C were added 0.29 mL (0.67 mmol) of
a 2.3 M solution of n-butyllithum in hexane and, after 10 min,
0.205 mL (250 mg, 1.47 mmol) of benzyl chloroformate. The
reaction mixture was then allowed to warm to 0 °C over 1 h.
The crude product was isolated with ether in the usual manner
and purified by dry silica gel chromatography with 5-20% ethyl
acetate in cyclohexane to give 339 mg (98%) of (-)-(4R,5R)-1-
(benzyloxycarbonyl)-5-(4-methoxybenzyl)-4-((1S)-1-(2,4,6-triiso-
propylphenyl)ethoxy)-2-pyrrolidinone: mp 118-119 °C (pen-
tane); [R]20D -99° (c 1.7, chloroform); IR 3053, 1787, 1753, 1719,
1609, 1292, 1265 cm-1; 1H NMR (200 MHz) δ 1.10-1.45 (m, 18
H), 1.65 (d, J ) 6.9 Hz, 3 H), 2.41 (AB of ABX, δa ) 2.25, δb )
2.57, J ab ) 16.8 Hz, J ax ) 10.6 Hz, J bx ) 7.5 Hz, 2 H), 2.85 (hept,
Anal. Calcd for C37H49NO4: C, 77.72; H, 8.64; N, 2.45.
Found: C, 77.89; H, 8.74; N, 2.53.
(-)-(2R,3R)-1-(Ben zyloxyca r bon yl)-2-(4-m eth oxyben zyl)-
3-h yd r oxyp yr r olid in e (8). To a solution of 73 mg (0.128 mmol)
of pyrrolidine 7 in 1.2 mL of dichloromethane was added 0.090
mL (133 mg, 1.17 mmol) of trifluoroacetic acid. The reaction
mixture was stirred at 20 °C for 1 h and then evaporated to
dryness under reduced pressure. The residue was processed with
dichloromethane in the usual way, and the crude product was
purified by dry silica gel chromatography with 40% ethyl acetate
in cyclohexane to give 43 mg (99%) of pyrrolidine 8 as an oil:
[R]25 -6.0° (c 1.3, chloroform) (lit.10t [R]25 -4.99° (c 1.145,
D
D
chloroform)); IR 3440, 3061, 3032, 1693, 1611, 1246 cm-1 1H
;
NMR (300 MHz) δ 1.72-1.83 (m, 1 H), 1.93-2.04 (m, 1 H), 2.84-
2.92 (m, 1 H), 3.0-3.15 (br s, 1 H), 3.40-3.60 (m, 2 H), 3.75 (s,
3 H), 4.10 (br q, J ) 6.3 Hz, 1 H), 4.32 (q, J ) 6.0 Hz, 1 H), 5.10
(deformed ABq, δa ) 5.07, δb) 5.13, J ab ) 12.0 Hz, 2 H), 6.93
(deformed ABq, δa ) 6.77, δb ) 7.09, J ab ) 8.5 Hz, 4 H), 7.30-
7.36 (m, 5 H); 13C NMR (50.3 MHz, C6D6, 65 °C) δ 32.8, 34.3,
44.9, 55.5, 63.6, 67.6, 72.3, 114.9, 129.2, 131.6, 132.6, 138.5,
155.9, 159.5. HPLC (Chiracel OD-H, 5 mm, 2-propanol/hexane
15:85, 0.5 mL/min, tR 20.7 min (vs 24.5 min)) indicated an ee of
g99%; the high-field 1H NMR spectrum was in perfect agree-
ment with that kindly provided by Professor H. Takahata.10t
HRMS (FAB+) m/e calcd for C20H23NO4 (M+) + H 342.1713,
found 342.1705.
J ) 6.9 Hz, 1 H), 3.08 (AB of ABX, δa ) 3.00, δb ) 3.16, J ab
)
14.1 Hz, J ax ) 4.1 Hz, J bx ) 5.8 Hz, 2 H), 3.09-3.20 (m, 1 H),
3.70-3.80 (m, 1 H), 3.78 (s, 3 H), 4.11 (dt, J ) 7.9, 10.6 Hz, 1
H), 4.40-4.50 (m, 1 H), 5.07 (q, J ) 6.9, 1 H), 5.19 (ABq, δa )
5.15, δb ) 5.23, J ab ) 12.3 Hz, 2 H), 6.94 (ABq, δa ) 6.77, δb )
7.11, J ab ) 8.9 Hz, 4 H), 6.98 (s, 1 H), 7.06 (s, 1 H), 7.30-7.45
(m, 5 H); 13C NMR (62.8 MHz) δ 23.1, 23.8, 24.1, 24.8, 25.0, 27.9,
29.0, 33.1, 33.9, 37.8, 55.0, 61.2, 68.0, 69.3, 71.3, 113.4, 120.6,
123.3, 128.2, 128.3, 128.4, 129.1, 131.3, 131.4, 135.0, 145.9, 147.7,
148.6, 150.8, 158.1, 170.5; mass spectrum (CI) m/z 586 (MH+),
542, 231 (100).
Anal. Calcd for C37H47NO5: C, 75.86; H, 8.09; N, 2.39.
Found: C, 75.73; H, 8.24; N, 2.43.
To a stirred solution of this lactam (170 mg, 0.29 mmol) in
2.6 mL of THF at -78 °C under argon was added dropwise 0.45
mL (0.45 mmol) of a 1 M solution of lithium triethylborohydride
in THF. The resulting solution was stirred for 30 min at -78
°C, quenched with saturated aqueous sodium bicarbonate (0.5
mL), and then allowed to warm to 0 °C. Ten drops of a 30%
aqueous solution of hydrogen peroxide were added, and the
mixture was then stirred for 1 h at 20 °C. The crude product
was isolated with ether in the usual way to yield 166 mg of the
corresponding R-hydroxypyrrolidine: IR 3424, 1691.
Ack n ow led gm en t. We thank Prof. J . Lhomme for
his interest in our work, Ms. M.-L. Dheu and Prof. C.
Coulombeau for assistance with the molecular modeling,
Dr. A. Durif and Dr. M.-T. Averbuch for the X-ray
structure determination, and Prof. H. Takahata for the
proton NMR spectrum of the hydroxy pyrrolidine.
Financial support from the CNRS (UMR 5616) is
gratefully acknowledged.
To a solution of this material in dry dichloromethane was
added 0.034 mL (25 mg, 0.21 mmol) of triethylsilane followed
J O981908Z