Practical asymmetric approach to pyrrolidinones: Efficient synthesis of (+)-preussin and (-)-AHPPA

Article abstract of DOI:10.1021/jo9801162

A novel, dichloroketene-chiral enol ether cycloaddition-based synthesis of enantiopure (+)-preussin and (-)-AHPPA has been realized. The efficient, highly stereoselective approach, which involves a Beckmann ring expansion reaction to access the key pyrrolidinone, proceeds in ca. 16% overall yield for each of the compounds.

Full text of DOI:10.1021/jo9801162

4660
J . Org. Chem. 1998, 63, 4660-4663
P r a ctica l Asym m etr ic Ap p r oa ch to P yr r olid in on es: Efficien t
Syn th esis of (+)-P r eu ssin a n d (-)-AHP P A†
Alice Kanazawa, Sandra Gillet, Philippe Delair, and Andrew E. Greene*
Universite´ J oseph Fourier de Grenoble Chimie Recherche (LEDSS), 38041 Grenoble Cedex, France
Received J anuary 22, 1998
A novel, dichloroketene-chiral enol ether cycloaddition-based synthesis of enantiopure (+)-preussin
and (-)-AHPPA has been realized. The efficient, highly stereoselective approach, which involves
a Beckmann ring expansion reaction to access the key pyrrolidinone, proceeds in ca. 16% overall
yield for each of the compounds.
Pyrrolidines are naturally ubiquitous, biologically im-
portant substances that display diverse structural and
stereochemical features.1 Not surprisingly, these alka-
loids have been accorded considerable attention from
synthetic chemists, and an impressive range of new
methodology has resulted, most recently in the area of
asymmetric synthesis.
Over the past several years, we have developed a
conceptually simple, yet quite effective, asymmetric
approach to cyclopentane and γ-butyrolactone-containing
natural products based on diastereofacially selective 2
+ 2 cycloaddition of dichloroketene (DCK) with chiral
O-alkyl enol ethers, followed by regioselective ring ex-
pansion of the resulting R,R-dichlorocyclobutanones (eq
1).2 In this paper, the potential of this methodology for
(+)-Preussin (L-657,398) was first isolated in 1988 from
fermentation broths of Aspergillus ochraceus4a and shortly
after from those of Preussia sp.4b It has been found to
possess a broad spectrum of potent antifungal activity
(3) For recent syntheses of chiral pyrrolidinones, see: (a) Meyers,
A. I.; Snyder, L. J . Org. Chem. 1993, 58, 36-42. (b) Wei, Z-Y.; Knaus,
E. E. Tetrahedron Lett. 1993, 34, 4439-4442. (c) Gennari, C.; Pain,
G.; Moresca J . Org. Chem. 1995, 60, 6248-6249. (d) Wee, A. G. H.;
Liu, B. Tetrahedron Lett. 1996, 37, 145-148. (e) Nebois, P.; Greene,
A. E. J . Org. Chem. 1996, 61, 5210-5211 and references therein.
(4) (a) Schwartz, R. E.; Liesch, J .; Hensens, O.; Zitano, L.; Honeycutt,
S.; Garrity, G.; Fromtling, R. A.; Onishi, J .; Monaghan, R. J . Antibiot.
1988, 41, 1774-1779. Schwartz, R. E.; Onishi, J . C.; Monaghan, R.
L.; Liesch, J . M.; Hensens, O. D. U.S. Patent 4,847,284, 1989. (b)
J ohnson, J . H.; Philippson, D. W.; Kahle, A. D. J . Antibiot. 1989, 42,
1184-1185. For previous syntheses of (+)-preussin from chiral pool
starting material, see: (c) Pak, C. S.; Lee, G. H. J . Org. Chem. 1991,
56, 1128-1133. (d) Shimazaki, M.; Okazaki, F.; Nakajima, F.; Ish-
ikawa, T.; Ohta, A. Heterocycles 1993, 36, 1823-1836. (e) McGrane,
P. L.; Livinghouse, T. J . Am. Chem. Soc. 1993, 115, 11485-11489. (f)
Deng, W.; Overman, L. E. J . Am. Chem. Soc. 1994, 116, 11241-11250.
(g) Overhand, M.; Hecht, S. M. J . Org. Chem. 1994, 59, 4721-4722.
(h) Yoda, H.; Yamazaki, H.; Takabe, K. Tetrahedron: Asymmetry 1996,
7, 373-374. (i) Beier, C.; Schaumann, E. Synthesis 1997, 1296-1300.
(j) de Armas, P.; Garcia-Tellado, F.; Marrero-Tellado, J . J .; Robles, J .
providing efficient access also to pyrrolidines, by way of
the corresponding pyrrolidinones,3 is illustrated through
a synthesis of (+)-preussin (1).4 In addition, a new chiral
pyrrolidinone-based route to (3S,4S)-4-amino-3-hydroxy-
5-phenylpentanoic acid (AHPPA, 2)5 is described.
Tetrahedron Lett. 1998, 39, 131-134. For
a synthesis based on
desymmetrization of a meso anhydride, see: (k) Ghosh, S. K.; Verma,
R. J . Chem. Soc., Chem. Commun. 1997, 1601-1602.
* 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.
(5) (a) Omura, S.; Imamura, N.; Kawakita, K.; Mori, Y.; Yamazaki,
Y.; Masuma, R.; Takahashi, Y.; Tanaka, H.; Huang, L-Y.; Woodruff,
H. B. J . Antibiot. 1986, 39, 1079-1085. For previous syntheses and
uses of AHPPA, see: (b) Rich, D. H.; Sun, E. T. O.; Ulm, E. J . Med.
Chem. 1980, 23, 27-33. (c) J ouin, P.; Castro, B.; Nisato, D. J . Chem.
Soc., Perkin Trans. 1 1987, 1177-1182. (d) Raddatz, P.; Radunz, H.-
E.; Schneider, G.; Schneider, G.; Schwartz, H. Angew. Chem., Int. Ed.
Engl 1988, 27, 426-427. (e) Reetz, M. T.; Drewes, M. W.; Matthews,
B. R.; Lennick, K. J . Chem. Soc., Chem. Commun. 1989, 1474-1475.
(f) Moore, M. L.; Bryan, W. M.; Fakhoury, S. A.; Magaard, V. W.;
Huffman, W. F.; Dayton, B. D.; Meek, T. D.; Hyland, L.; Dreyer, G. B.;
Metcalf, B. W.; Strickler, J . E.; Gorniak, J . G.; Debouck, C. Biochem.
Biophys. Res. Commun. 1989, 159, 420-425. (g) Nishi, T.; Saito, F.;
Nagahori, H.; Kataoka, M.; Morisawa, Y.; Yabe, Y.; Sakurai, M.;
Higashida, S.; Shoji, M.; Matsushita, Y.; Iijima, Y.; Ohizumi, K.; Koike,
H. Chem. Pharm. Bull. 1990, 38, 103-109. (h) Misiti, D.; Zappia, G.
Tetrahedron Lett. 1990, 31, 7359-7362. (i) McConnell, R. M.; Frizzell,
D.; Camp, A.; Evans, A.; J ones, W.; Cagle, C. J . Med. Chem. 1991, 34,
2298-2300. (j) Shinozaki, K.; Mizuno, K.; Oda, H.; Masaki, Y. Chem.
Lett. 1992, 2265-2268. (k) Kiyooka, S-i.; Suzuki, K.; Shirouchi, M.;
Kaneko, Y.; Tanimori, S. Tetrahedron Lett. 1993, 36, 5729-5732. (l)
Banziger, M.; McGarrity, J . F.; Meul, T. J . Org. Chem. 1993, 58, 4010-
4012. (m) Fugi, K.; Kawabata, T.; Kiryu, Y.; Sugiura, Y.; Heterocycles
1996, 42, 701-722. (n) Palomo, C.; Miranda, J . I.; Linden, A. J . Org.
Chem. 1996, 61, 9196-9201 and references therein.
† Dedicated with appreciation to Professor J ean Lhomme on the
occasion of his 60th birthday.
(1) For reviews on the occurrence, biological properties, and syn-
theses 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. Nat. Prod.
Rep. 1997, 14, 637-651. Pyrrolizidines, see: Robins, D. J . Nat. Prod.
Rep. 1992, 9, 313-321. Liddell, J . R. Ibid. 1997, 14, 653-660.
Indolizidines, see: Burgess, K.; Henderson, I. Tetrahedron 1992, 48,
4045-4066. Takahata, H.; Momose, T. In The Alkaloids; Brossi, A.,
Ed.; Academic Press: New York, 1993; Vol. 44, Chapter 3. Michael,
J . P. Nat. Prod. Rep. 1997, 14, 21-41. Michael, J . P. Ibid. 1997, 14,
619-636.
(2) Greene, A. E.; Charbonnier, F. Tetrahedron Lett. 1985, 26, 5525-
5528. Greene, A. E.; Charbonnier, F.; Luche, M.-J .; Moyano, A. J .
Am. Chem. Soc. 1987, 109, 4752-4753. B. M. de Azevedo, M.; Murta,
M. M.; Greene, A. E. J . Org. Chem. 1992, 57, 4567-4569. Murta, M.
M.; B. M. de Azevedo, M.; Greene, A. E. J . Org. Chem. 1993, 58, 7537-
7541. B. M. de Azevedo; Greene, A. E. J . Org. Chem. 1995, 60, 4940-
4942. Kanazawa, A.; Delair, P.; Pourashraf, M.; Greene, A. E. J . Chem.
Soc., Perkin Trans. 1 1997, 1911-1912.
S0022-3263(98)00116-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/11/1998

Synthesis of (+)-Preussin and (-)-AHPPA
J . Org. Chem., Vol. 63, No. 14, 1998 4661
Sch em e 1
against both filamentous fungi and yeasts, significantly
broader than that displayed by the structurally related
pyrrolidine anisomycin.4a,b Although several approaches
to (+)-preussin have been reported over the past decade,
they almost invariably involve construction of the natural
product from chiral pool starting material, most often (S)-
phenylalanine.4c-j
CR-si face of enol ether 4 to be the more accessible, and
was subsequently confirmed by the preparation of (+)-
preussin.
The desired cyclobutanone-pyrrolidinone conversion
of 5 was readily accomplished and apparently with
complete regiocontrol through application of Tamura’s
Beckmann reagent, O-(mesitylenesulfonyl)hydroxyl-
amine (MSH), to provide the ring-expanded derivative
in high yield.3e,8 Exposure of this material at room
temperature to zinc-copper couple in methanol saturated
with ammonium chloride,9 an excellent, but strangely
seldom-used reducing system, cleanly gave pyrrolidinone
6 in 82% overall yield (90%/step).
The stereoselective installation of the nonyl group, in
place of the carbonyl oxygen, proved to be somewhat
challenging. For example, while the imino methyl ether
could be prepared from 6 with trimethyloxonium tet-
rafluoroborate, clean conversion of this substrate to the
desired imine intermediate with the organomagnesium
or lithium reagent could not be accomplished.10 Simi-
larly, the N-trimethylsilyl derivative of 6 failed to provide
more than trace amounts of the expected imine on
treatment with the organolithium reagent.11 Fortu-
nately, however, the corresponding N-tert-butoxylcarbon-
yl (Boc) derivative underwent smooth addition of nonyl-
magnesium bromide, and in situ the resulting R-hydroxy
carbamate experienced stereoselective reduction with
triethylsilane-boron trifluoride etherate4h to provide the
all-cis pyrrolidine 7 as the unique product in 68% yield.
Pyrrolidine 7 suffered double cleavage in the presence
of trifluoroacetic acid to afford in quantitative yield
norpreussin, which was then N-methylated convention-
ally12 to produce (+)-preussin in 78% yield. The identity
of the synthetic material, enantiopure by HPLC, was
unambiguously confirmed through comparison of its
spectral data with those reported for the naturally
Our approach to this alkaloid is outlined retrosyntheti-
cally in eq 2. We envisioned that (+)-preussin would be
obtained from the pyrrolidinone I by reductive alkylation,
inductor cleavage, and N-methylation and that pyrroli-
dinone I in turn would be derived by reduction of the ring-
expanded 2 + 2 cycloadduct formed from a chiral enol
ether and dichloroketene.3e The successful route based
on this strategy is described below.
Readily available, enantiomerically pure (R)-1-(2,4,6-
triisopropylphenyl)ethanol (3, Scheme 1)6 was converted
in a one-pot procedure to the sensitive benzylated ynol
ether, which was partially reduced with hydrogen in the
presence of palladium on barium sulfate in pyridine7 to
afford the pure Z-enol ether 4 in 50% overall yield (70%/
step). Dichloroketene, generated in situ from trichloro-
acetyl chloride with zinc-copper couple, added smoothly
and with pleasingly high facial selectivity to enol ether
4 to provide the dichlorocyclobutanone 5 as the major
1
diastereomer (94:6 by H NMR) in high yield.2 A single
recrystallization of this material from acetone-water
served to remove efficiently the small amount of diaster-
eomeric contamination and afforded the pure cyclobu-
tanone 5 in 69% yield. The indicated stereochemistry
in this adduct was provisionally assigned on the basis of
molecular modeling studies, which clearly indicated the
(8) Tamura, Y.; Minamikawa, J .; Ikeda, M. Synthesis 1977, 1-17.
(9) J ohnston, B. D.; Slessor, K. N.; Oehlschlager, A. C. J . Org. Chem.
1985, 50, 114-117.
(10) Tilley, J . W.; Clader, J . W.; Wirkus, M.; Blount, J . F. J . Org.
Chem. 1985, 50, 2220-2224. Fristschi, H.; Leutenegger, U.; Pfaltz,
A. Angew. Chem., Int. Ed. Engl. 1986, 25, 1005-1006. The corre-
sponding imidoyl chloride could not be prepared. See: Engel, N.;
Steglich, W. Angew. Chem., Int. Ed. Engl. 1978, 17, 676.
(11) Zegga, C. A.; Smith, M. B.; Ross, B. A.; Arhin, A.; Cronin, P. L.
E. J . Org. Chem. 1984, 49, 4397-4399. Hua, D. H.; Miao, S. W.;
Bharathi, S. N.; Katshuhira, T.; Bravo, A. A. Ibid. 1990, 55, 3682-
3684.
(6) Delair, P.; Kanazawa, A.; B. M. de Azevedo, M; Greene, A. E.
Tetrahedron: Asymmetry 1996, 7, 2707-2710.
(7) Kann, N.; Bernardes, V.; Greene, A. E. Org. Synth. 1997, 74,
13-22.
(12) Borch, R. F.; Hassid, A. I. J . Org. Chem. 1972, 37, 1673-1674.

4662 J . Org. Chem., Vol. 63, No. 14, 1998
Kanazawa et al.
stirred at 20 °C for 2 h, whereupon it was poured into cold
saturated aqueous ammonium chloride. The crude product
was isolated with pentane in the usual way and partially
purified by rapid filtration through silica gel (120 mL, pre-
treated with 2.5% triethylamine, v/v) with pentane containing
1% of triethylamine to afford crude 2-[(1R)-1-[(3-phenyl-1-
propynyl)oxy]ethyl]-1,3,5-triisopropylbenzene: IR 3068, 3028,
derived substance and by direct comparison with a
sample kindly provided by Professor Hecht of indepen-
dently prepared4g synthetic (+)-preussin, previously com-
pared directly with natural preussin.
Pyrrolidinone 6 also proved to be a direct precursor of
(3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AH-
PPA, 2), an unusual amino acid that is found in several
ahpatinin acid protease inhibitors from Streptomyces sp.
WK-1425a and that has been used for a variety of
purposes.5b-n Lactam 6 was treated first with trifluoro-
acetic acid and then, in the same pot, with concentrated
hydrochloric acid to effect inductor cleavage-ring opening
(eq 3).3e Ion-exchange column chromatography of the
2272, 1607 cm-1
.
A mixture of the above crude acetylenic ether and 530 mg
of 10% palladium on barium sulfate in 40 mL of pyridine was
stirred under hydrogen for 5 h, whereupon the hydrogen was
replaced with argon and the reaction mixture was filtered with
the aid of ether. The solvents were washed with saturated
aqueous copper sulfate, water, and saturated aqueous sodium
chloride, dried over sodium sulfate, and evaporated under
reduced pressure. The resulting crude product was purified
by chromatography on silica gel (pretreated with 2.5% tri-
ethylamine, v/v) with pentane to afford 2.22 g (50% overall) of
enol ether 4: mp 41-41.5 °C (pentane); [R]20 -40.2° (c 1.0,
D
chloroform); IR 3051, 1662, 1607, 1384, 1271, 1115, 1077, 742
cm-1; 1H NMR (200 MHz) δ 1.20-1.35 (m, 18 H), 1.63 (d, J )
6.9 Hz, 3 H), 2.86 (hept, J ) 6.9 Hz, 1 H), 3.30-3.60 (m, 4 H),
4.49 (dt, J ) 7.2, 6.5 Hz, 1 H), 5.38 (q, J ) 6.9 Hz, 1 H), 6.07
(dt, J ) 6.2, 1.4 Hz, 1 H), 7.01 (s, 2 H), 7.1-7.3 (m, 5 H); 13C
NMR (50.3 MHz) δ 22.6, 24.0, 24.7, 29.2, 30.5, 34.1, 75.4, 104.9,
121.9, 125.5, 128.2, 128.3, 132.9, 141.9, 144.4, 147.7; mass
spectrum (CI) m/z 382 (M+ + 18), 248, 231 (100).
resulting salt then afforded AHPPA, identified through
comparison of its spectral data with those reported in the
literature and shown to be enantiopure by HPLC.
In summary, enantiopure (+)-preussin and (-)-AHPPA
have been prepared in 15% (ten steps) and 17% (six steps)
overall yields, respectively, through chiral enol ether-
dichloroketene diastereofacially selective 2 + 2 cycload-
dition. The syntheses are competitive with most previ-
ously recorded in the literature of these natural products,
in particular those that eschew chiral pool material, and
bode well for future extension to pyrrolizidine and
indolizidine preparation.
Anal. Calcd for C26H36O: C, 85.65; H, 9.96. Found: C,
85.59; H, 9.96.
(+)-(2S,3R)-2-Ben zyl-4,4-d ich lor o-3-[(1R)-1-(2,4,6-tr iiso-
p r op ylp h en yl)eth oxy]cyclobu ta n on e (5). To a stirred
mixture of 1.67 g (4.58 mmol) of enol ether 4 and 4.30 g (ca.
66 mmol) of Zn-Cu couple in 40 mL of ether under argon was
added over 1.5 h 0.770 mL (1.25 g, 6.90 mmol) of freshly
distilled trichloroacetyl chloride in 16 mL of ether. After an
additional 1 h, the ether solution was separated from the
excess couple and added to hexane, 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 crude cyclobutanone 5 (containing ca.
6% of its diastereomer (δ 5.47 ppm)) as a white solid.
Recrystallization of this material from acetone-water gave
1.50 g (69%) of pure 5: mp 115-116 °C (methanol-water);
[R]20D +41.2° (c 1, chloroform); IR 3092, 3068, 3037, 1808, 1610,
Exp er im en ta l Section
Isolation of the crude product was generally accomplished
by pouring the reaction mixture into water and then thor-
oughly extracting the separated aqueous phase 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, acetonitrile, N,N-
diisopropylethylamine, HMPA, and triethylamine were distilled
from calcium hydride.
1
1382, 1166, 1073 cm-1; H NMR (200 MHz) δ 1.00-1.40 (m,
18 H), 1.70 (d, J ) 6.9 Hz, 3 H), 2.91 (hept, J ) 6.9 Hz, 1
H), 3.11 (d, J ) 7.9 Hz, 2 H), 3.26 (hept, J ) 6.9 Hz, 1 H), 3.65-
3.90 (m, 2 H), 4.37 (d, J ) 9.3 Hz, 1 H), 5.49 (q, J ) 6.9 Hz, 1
H), 7.0-7.4 (m, 7 H); 13C NMR (50.3 MHz) δ 22.2, 23.4, 23.5,
24.5, 24.8, 25.0, 27.9, 28.8, 30.5, 31.0, 33.6, 59.9, 73.1, 77.0,
88.0, 120.5, 123.0, 126.2, 128.1, 128.5, 130.0, 137.9, 146.7,
147.9, 148.5, 195.2; mass spectrum (EI) m/z 492 (M+ + 18),
248, 231 (100).
(-)-2-[(1R)-1-[((1Z)-3-P h en yl-1-pr open yl)oxy)eth yl]-1,3,5-
tr iisopr opylben zen e (4). An argon-flushed flask was charged
with 2.80 g (24.4 mmol) of a 35% suspension of potassium
hydride in mineral oil. The mineral oil was removed by
washing with hexane, and the flask was capped with a rubber
septum and connected to a Nujol-filled bubbler by means of a
syringe needle. A solution of 3.00 g (12.1 mmol) of alcohol 36
in 24 mL of anhydrous tetrahydrofuran was then added
dropwise by syringe. The mixture was stirred until hydrogen
evolution was complete, cooled to -50 °C, and treated dropwise
over 15 min with a solution of trichloroethylene (1.10 mL, 1.62
g, 12.4 mmol) in 15 mL of anhydrous tetrahydrofuran, after
which the reaction mixture was allowed to warm to 20 °C over
1 h. The resulting brown solution was then cooled to -70 °C
and treated dropwise with 12.1 mL (30.2 mmol) of 2.5 M
n-butyllithium in hexanes. After being stirred for 30 min at
-70 °C, the reaction mixture was warmed to -40 °C over 30
min and treated dropwise with a solution of 5.80 mL (8.34 g,
48.8 mmol) of benzyl bromide (filtered over 1:1 Al2O3/P2O5) in
9.2 mL of hexamethylphosphoramide. The solution was
Anal. Calcd for C28H36O2Cl2: C, 70.73; H, 7.63. Found:
70.43; H, 7.70.
(+)-(4S,5S)-5-Ben zyl-4-[(1R)-1-(2,4,6-tr iisopr opylph en yl)-
eth oxy]-2-p yr r olid in on e (6). A solution of 546 mg (1.15
mmol) of cyclobutanone 5 in 5 mL of dichloromethane was
treated with 1.19 g (5.53 mmol) of O-(mesitylenesulfonyl)hy-
droxylamine and stirred at 20 °C for 40 min. The solvent was
then removed under reduced pressure, and the resulting
material in 2 mL of toluene was placed on a column of basic
alumina (20 g, Merck activity 1) and eluted rapidly with
methanol. The resulting crude (4R,5S)-5-benzyl-3,3-dichloro-
4-[(1R)-1-(2,4,6-triisopropylphenyl)ethoxy]-2-pyrrolidinone (IR
1730 cm-1) was used below.
The crude dichloro lactam in 40 mL of methanol previously
saturated with ammonium chloride was stirred at 20 °C with
2.0 g (ca. 30 mmol) of zinc-copper couple under argon for 2
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

Synthesis of (+)-Preussin and (-)-AHPPA
J . Org. Chem., Vol. 63, No. 14, 1998 4663
the usual way and purified by silica gel chromatography with
10% ether in dichloromethane to give 398 mg (82% overall) of
(+)-(2S,3S,5R)-2-Ben zyl-3-h ydr oxy-1-m eth yl-5-n on ylpyr -
r olid in e ((+)-P r eu ssin (1)). A mixture of 52 mg (0.08 mmol)
of 7 and 0.5 mL of trifluoroacetic acid 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 silica gel chroma-
tography with 30% ethyl acetate in hexane containing 2% of
methanol saturated with NH3 to give 25 mg (100%) of (-)-
(2S,3S,5R)-2-benzyl-3-hydroxy-5-nonylpyrrolidine as a white
lactam 6: mp 126-127 °C (pentane-ether); [R]20 +34.4° (c
D
1.0, chloroform); IR 3236, 1707, 1615, 1374, 1115, 1087 cm-1
;
1H NMR (200 MHz) δ 1.1-1.4 (m, 18 H), 1.60 (d, J ) 6.5 Hz,
3 H), 2.50 (dd, J ) 7.2, 1.7 Hz, 2 H), 2.60-2.80 (m, 1 H), 2.86
(hept, J ) 6.9 Hz, 1 H), 3.00-3.25 (m, 2 H), 3.70-4.00 (m, 2
H), 4.23 (pseudo q, J ) 7.2 Hz, 1 H), 5.12 (q, J ) 6.9 Hz, 1 H),
5.78 (br s, 1 H), 6.95-7.35 (m, 7 H); 13C NMR (50.3 MHz) δ
23.1, 23.8, 24.2, 24.9, 25.0, 28.0, 29.1, 33.9, 36.2, 36.3, 59.1,
71.3, 72.4, 120.3, 123.2, 126.4, 128.6, 129.2, 132.0, 138.2, 145.8,
147.7, 148.6, 174.3; mass spectrum (CI) m/z 439 (M+ + 18),
422 (MH+, 100).
solid: mp 101-102 °C; [R]20 -15.6° (c 1, methanol); IR 3425,
D
1
1638, 1340, 1161 cm-1; H NMR (200 MHz) δ 0.85 (t, J ) 6.3
Hz, 3 H), 1.20-1.60 (m, 18 H), 1.90 (br s, 1 H), 2.17-2.34 (ddd,
J ) 14.0, 8.5, 6.1 Hz, 1 H), 2.77-3.07 (m, 4 H), 4.0 (m, 1 H),
7.1-7.3 (m, 5 H); 13C NMR (50.3 MHz) δ 139.8, 128.9, 128.5,
126.1, 72.2, 65.7, 57.0, 42.0, 37.5, 35.6, 31.9, 29.7, 29.6, 29.3,
27.2, 22.6, 14.1; mass spectrum (CI) m/z 304 (MH+), 212 (100).
Anal. Calcd for C20H33NO: C, 79.15; H, 10.96; N, 4.61.
Found: C, 78.99; H, 11.06; N, 4.73.
Anal. Calcd for C28H39NO2: C, 79.76; H, 9.32; N, 3.32.
Found: C, 79.66; H, 9.51; N, 3.56.
(-)-(2S,3S,5R)-2-Ben zyl-1-[(1,1-d im et h ylet h oxy)ca r -
bon yl]-5-n on yl-3-[(1R)-1-(2,4,6-tr iisopr opylph en yl)eth oxy]-
p yr r olid in e (7). To a solution of lactam 6 (217 mg, 0.52
mmol) in 2.8 mL of dry dichloromethane was added 0.450 mL
(334 mg, 2.58 mmol) of N,N-diisopropylethylamine, 0.640 mL
(608 mg, 2.79 mmol) of di-tert-butyl dicarbonate, and 34 mg
(0.28 mmol) of 4-(dimethylamino)pyridine. The resulting
mixture was stirred at 20 °C for 3 h, after which time the crude
product was isolated with dichloromethane in the usual
manner and purified by column chromatography on silica gel
with 10% ethyl acetate in hexane to give 269 mg (100%) of
(+)-(4S,5S)-5-benzyl-1-[(1,1-dimethylethoxy)carbonyl]-4-[(1R)-
1-(2,4,6-triisopropylphenyl)ethoxy]-2-pyrrolidinone: mp 137-
To a solution of 16 mg (0.05 mmol) of the above pyrrolidine
in 0.70 mL of acetonitrile was added 0.23 mL of 37% aqueous
formaldehyde, 17 µL of acetic acid, and 16 mg (0.25 mmol) of
sodium cyanoborohydride. The resulting solution was stirred
at 20 °C for 4 h and then concentrated under reduced pressure.
The crude product was isolated with dichloromethane in the
normal manner and purified by silica gel chromatography with
20% ethyl acetate in hexane to afford 13 mg (78%) of (+)-
preussin (1): [R]25 +32° (c 1.1, chloroform); IR 3454, 3087,
D
3064, 3030, 1615, 1355, 1148, 1038, 923 cm-1; H NMR (300
1
138 °C; [R]20 +91.5° (c 1.5, chloroform); IR 3086, 3062, 3030,
D
MHz) δ 0.87 (t, J ) 6.5 Hz, 3 H), 1.16-1.45 (m, 16 H), 1.70
(m, 1 H), 1.90-2.30 (m, 4 H), 2.32 (s, 3 H), 2.75-2.95 (m, 2
H), 3.79 (m, 1 H), 7.10-7.35 (m, 5 H); 13C NMR (75.5 MHz) δ
139.5, 129.3, 128.3, 126.0, 73.6, 70.5, 65.8, 39.3, 38.6, 34.9, 33.7,
31.9, 29.9, 29.6, 29.5, 29.3, 26.2, 22.6, 14.0; mass spectrum (EI)
m/z 317 (M+), 226 (100); HRMS m/e calcd for C21H35NO (M+)
317.2719, found 317.2701; HPLC (Chiracel OD-H, 5 mm,
2-propanol/hexane ) 2:98, 0.5 mL/min, tR 11.80 min (vs 11.18
min)) indicated an enantiopurity of g99%.
1794, 1764, 1718, 1610, 1257, 1218, 1166, 1114, 1079, 1027
cm-1; 1H NMR (200 MHz) δ 1.0-1.30 (m, 18 H), 1.40 (s, 9 H),
1.57 (d, J ) 6.9 Hz, 3 H), 2.42 (AB of ABX, δa ) 2.29, δb
)
2.55, J ab ) 16.7 Hz, J ax ) 10.4 Hz, J bx ) 7.7 Hz, 2 H), 2.75-
3.25 (m, 4 H), 3.69 (m, 1 H), 4.07 (dt, J ) 10.3, 7.9 Hz, 1 H),
4.40 (dt, J ) 6.9, 5.8 Hz, 1 H), 5.02 (q, J ) 6.8, 1 H), 6.92 (br
s, 1 H), 7.00 (br s, 1 H), 7.16-7.28 (br s, 5 H); 13C NMR (62.5
MHz) δ 170.7, 149.4, 148.8, 147.8, 145.9, 137.7, 131.5, 130.4,
128.1, 126.3, 123.4, 120.6, 82.9, 71.3, 69.6, 61.1, 37.0, 34.6, 33.9,
29.0, 27.8, 25.0, 24.9, 24.2, 23.8, 23.1; mass spectrum (CI) m/z
422 (MH+ - Boc), 231 (100).
(-)-(3S,4S)-4-Am in o-3-h ydr oxy-5-ph en ylpen tan oic Acid
((3S,4S)-AHP P A (2)). A 67-mg (0.16 mmol) sample of lactam
6 was stirred with 0.20 mL of trifluoroacetic acid at 20 °C
under argon for 1.5 h, whereupon 11 mL of 12 N HCl was
added, and the reaction mixture was heated at 80 °C for 3 h.
The mixture was then concentrated under reduced pressure
and the resulting material was passed down a column of 8 g
of Dowex 50W (X8 50/100 mesh, H+ form) ion-exchange resin,
eluting with water (discarded) and then 2 N aqueous am-
monium hydroxide. Evaporation of the latter provided 20 mg
(60%) of (-)-AHPPA (2): IR (Nujol) 3342, 3149, 3045, 1620,
1551, 1407, 1160, 1119 cm-1; 1H NMR (200 MHz, D2O) δ 2.17-
2.47 (m, 2 H), 2.61-2.99 (ABX, J ) 14.3, 9.3, 5.0 Hz, 2 H),
3.32 (m, 1 H), 3.86 (m, 1 H), 7.20 (m, 5 H); 13C NMR (50.3
MHz, D2O) δ 38.3, 44.2, 59.7, 70.5, 130.3, 132.0, 132.1, 138.1,
181.3; mass spectrum (CI) m/z 210 (MH+), 192 (100%). The
N-Boc methyl ester derivative: mp 97 °C (lit.5c mp 97-98 °C);
[R]20 -35° (c 0.8, methanol) (lit.5c [R]20 -36° (c 1.0, metha-
Anal. Calcd for C33H47NO4: C, 75.97; H, 9.08; N, 2.68.
Found: C, 75.89; H, 9.21; N, 2.68.
To a stirred solution of this derivative (90 mg, 0.17 mmol)
in 1.8 mL of THF at -80 °C under argon was added dropwise
1.45 mL (0.42 mmol) of a 0.29 M solution of nonylmagnesium
bromide in THF. The resulting solution was stirred for 30 min
at -80 °C, and then the THF was eliminated under under
reduced pressure while the temperature of the reaction
mixture was maintained below -20 °C. The residue was
dissolved in 2 mL of CH2Cl2 and cooled to -90 °C. To this
solution were added 0.320 mL (233 mg, 2.00 mmol) of trieth-
ylsilane and, after 5 min, 0.380 mL (426 mg, 3.00 mmol) of
boron trifluoride etherate. The reaction mixture was allowed
to warm slowly to -40 °C, stirred for 1 h at this temperature,
and then quenched by the addition of aqueous sodium bicar-
bonate solution. The crude product was isolated with dichlo-
romethane in the normal manner and purified by column
chromatography on silica gel with 2% ethyl acetate in hexane
to afford 74 mg (68%) of pyrrolidine 7 as a white solid: mp
D
D
nol)); IR 3390, 3034, 1724, 1701, 1374, 1259, 1173, 1092, 1058
cm-1; NMR (200 MHz) δ 1.40 (s, 9 H), 1.62 (s, 1 H), 2.3-2.7
(m, 2 H), 2.91 (d, J ) 7.5 Hz, 2 H), 3.45 (s, 1 H), 3.68 (s, 3 H),
4.00 (br d, 1 H), 4.94 (m, 1 H), 7.15-7.25 (m, 5 H); 13C NMR
(50.3 MHz) δ 28.3, 38.4, 38.5, 51.8, 55.4, 67.0, 79.4, 126.3,
128.4, 129.4, 138.1, 155.8, 173.8; HPLC (Chiracel OD-H, 5 mm,
2-propanol/hexane ) 1:99, 0.5 mL/min, tR 13.38 min (vs 11.31
min)) indicated an enantiopurity of g99%.
78-79 °C; [R]20 -3° (c 3, chloroform); IR 3092, 3063, 3035,
D
1700, 1615, 1374, 1184, 1144, 1081 cm-1; 1H NMR (200 MHz,
C6D6, 72 °C) δ 0.90 (deformed t, J ) 6.9 Hz, 3 H), 1.15-1.50
(m, 42 H), 1.56 (d, J ) 6.5 Hz, 3 H), 1.55-1.80 (m, 1 H), 2.15-
2.45 (m, 1 H), 2.32 (dt, J ) 12.0, 7.2 Hz, 1 H), 2.70-2.90 (m,
1 H), 2.97 (AB of ABX, δa ) 3.15, δb ) 2.79, J ab ) 13.5 Hz, J ax
) 5.5 Hz, J bx ) 7.2 Hz, 2 H), 3.20-3.90 (m, 3 H), 3.85 (dt, J )
10.3, 7.2 Hz, 1 H), 4.33 (dt, J ) 6.8, 5.8 Hz, 1 H), 5.11 (q, J )
6.7 Hz, 1 H), 7.0-7.4 (m, 7 H); 13C NMR (50.3 MHz) δ 154.8,
148.8, 147.4, 145.4, 139.9, 133.3, 130.1, 127.9, 125.5, 123.3,
120.5, 78.8, 72.0, 61.1, 55.7, 37.5, 36.5, 35.3, 34.0, 31.9, 29.7,
29.6, 29.3, 29.1, 27.9, 26.6, 24.9, 24.4, 23.9, 23.4, 22.7, 14.1;
mass spectrum (CI) m/z 634 (MH+), 231 (100).
Anal. Calcd for C17H25NO5: C, 62.12; H, 7.49; N, 4.53.
Found: C, 61.98; H, 7.74; N, 4.26.
Ack n ow led gm en t. We thank Prof. J . Lhomme for
his interest in our work, Dr. H. Yoda for useful experi-
mental information, and Prof. S. M. Hecht for a sample
of synthetic (+)-preussin. Financial support from the
CNRS (UMR 5616) is gratefully acknowledged.
Anal. Calcd for C42H67NO3: C, 79.57; H, 10.65; N, 2.21.
Found: C, 79.65; H, 10.82; N, 2.32.
J O9801162