Highly Enantioselective Approach to Indolizidines: Preparation of (+)-(1S,8aS)-1-Hydroxyindolizidine and (-)-Slaframine

Article abstract of DOI:10.1021/jo0005621

A highly stereoselective approach to (-)-slaframine and its probable biosynthetic precursor (+)-(1S,8aS)-1-hydroxyindolizidine has been developed based on a diastereofacially selective cycloaddition of dichloroketene with a chiral dienol ether.

Full text of DOI:10.1021/jo0005621

6966
J . Org. Chem. 2000, 65, 6966-6972
High ly En a n tioselective Ap p r oa ch to In d olizid in es: P r ep a r a tion
of (+)-(1S,8a S)-1-Hyd r oxyin d olizid in e a n d (-)-Sla fr a m in e†
Mehrnaz Pourashraf, Philippe Delair, Martin O. Rasmussen, and Andrew E. Greene*
Universite´ J oseph Fourier de Grenoble, Chimie Recherche (LEDSS), 38041 Grenoble Cedex, France
Andrew.Greene@ujf-grenoble.fr
Received April 13, 2000
A highly stereoselective approach to (-)-slaframine and its probable biosynthetic precursor (+)-
(1S,8aS)-1-hydroxyindolizidine has been developed based on a diastereofacially selective cycload-
dition of dichloroketene with a chiral dienol ether.
Ch a r t 1
Indolizidine alkaloids, due to their structural diversity,
number, and dynamic, chemoecologically important role
in Nature, have over the last several decades been highly
popular targets for synthesis.1 The common denominator
of the overwhelming majority of the enantioselective
syntheses disclosed to date, however, has been the use
of chiral pool material either to set or to allow eventual
relay access to one or more of the stereocenters of the
natural substances. The less frequent, but potentially
more flexible and arguably more satisfying approach
involving the use of either internal or external auxiliaries
for this purpose has so far been limited, at least in part,
by a paucity of suitable methods.
We have previously described an effective, facially
discriminating cycloaddition methodology that diaste-
reoselectively provides a variety of cyclobutanones and
shown that it can be translated into an efficient, enan-
tioselective means for accessing cyclopentenone, γ-lac-
tone, pyrrolidine, and amino acid natural products.2 For
extension to the indolizidines, it was envisaged that a
central, advanced intermediate I might be obtained
through cyclization of the corresponding pyrrolidinone or
pyrrolidine II, which in turn could be generated by
Beckmann ring expansion, reduction, and side-chain
functionalization from the 2 + 2 cycloadduct of chiral enol
ether IV with dichloroketene (Chart 1). The intermedi-
ates I-IV, each being open to ready modification, would
provide entry to a range of indolizidines1 (and pyrroliz-
idines3). Furthermore, with occurrence of the anticipated
high degree of facial selectivity in the cycloaddition,2,4
excellent enantiopurity would result in the indolizidine
final products. In this paper it is demonstrated that this
chemistry can in fact be so extended to provide poten-
tially flexible access to the indolizidine alkaloids through
the synthesis of hydroxy indolizidine 15 and slaframine
2.6
* To whom correspondence should be addressed. Tel: (33) 4-76-51-
46-86; FAX: (33) 4-76-51-44-94.
Slaframine, an unusual toxin produced by the mold
Rhizoctonia leguminicola, can infect members of the
Leguminosae family and lead to excess salivation (“slob-
ber syndrome”), liver damage, and eventual death in
ruminants that graze on the contaminated feed.7 Elegant
studies by Harris and co-workers on the biosynthesis of
this alkaloid in R. leguminicola have identified (+)-(1S,-
8aS)-1-hydroxyindolizidine (1) as a highly probable in-
termediate, engendered from L-lysine via L-pipecolic acid.8
Potential use to improve ruminant digestion and chemo-
† This paper is dedicated with admiration to Prof. J ames A. Marshall
on the occasion of his 65th birthday.
(1) For reviews on the occurrence, biological properties, and syn-
theses of 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. 1995, 12, 535-552. Michael, J . P. Ibid.
1997, 14, 21-41. Michael, J . P. Ibid. 1997, 14, 619-636. Michael, J .
P. Ibid. 1998, 15, 571-594. Michael, J . P. Ibid. 1999, 16, 675-696.
Broggini, G.; Zucchi, G. Synthesis 1999, 905. Mitchinson, A.; Nadin,
A. J . Chem. Soc., Perkin Trans. 1 1999, 2553-2591.
(2) (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. (f) Kanazawa, A.; Delair, P.; Pourashraf, M.; Greene,
A. E. J . Chem. Soc., Perkin Trans. I 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. (i) Delair, P.; Brot, E.; Kanazawa, A.; Greene, A. E. J . Org. Chem.
1999, 64, 1383.
(3) 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. Numata, A.; Ibuka, T. In The Alkaloids;
Brossi, A., Ed.; Academic Press: New York, 1987; Vol. 31, Chapter 6.
Hartmann, T.; Witte, L. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Elsevier Science, Inc.: New York,
1995; Vol. 9, Chapter 4. O’Hagan, D. Nat. Prod. Rep. 1997, 14, 637-
651. Liddell, J . M. Ibid. 1999, 16, 499-507.
(4) Delair, P.; Kanazawa, A.; B. M. de Azevedo, M.; Greene, A. E.
Tetrahedron: Asymmetry 1996, 7, 2707-2710.
10.1021/jo0005621 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/19/2000

Enantioselective Approach to Indolizidines
J . Org. Chem., Vol. 65, No. 21, 2000 6967
variable, but usually small amounts of over-reduced
material and trans isomer, both of which could be readily
removed later in the synthesis (see Experimental Sec-
tion). In situ generated dichloroketene13 then entered
smoothly into cycloaddition with this dienol ether with
1
high diastereoselectivity (95:5, H NMR) and apparent
total regioselectivity for the more electron-rich double
bond to give R,R-dichlorocyclobutanone 5. The presence
of the chloro substituents and the strain inherent in 5
combined to produce a rapid and highly regioselective
ring expansion reaction under Tamura’s Beckmann
conditions14 and generate 6a , which on dechlorination15
afforded the crystalline lactam 6b in 50% overall yield
from 3b (87%/step). Recrystallization then gave stere-
ochemically pure (g98%) lactam, with suitable crystals
for X-ray crystallography.16 Gratifyingly, the S configu-
ration at C-4 and C-5, as had been predicted on the basis
of molecular modeling and precedent, was indeed found.
1-Hydroxyindolizidine 1 provided a relatively simple
target for examining the key pyrrolidine f indolizidine
transformation (II f I). Toward this end, lactam 6b was
F igu r e 1. The two lowest-energy conformations of dienol
ether 4b (• ) enol oxygen, ∆E ) 0.3 kcal/mol).
Sch em e 1
(6) For syntheses of (()-slaframine, see: (a) Cartwright, D.; Gar-
diner, R. A.; Rinehart, J r., K. L. J . Am. Chem. Soc. 1970, 92, 7615-
7617. (b) Gensler, W. J .; Hu, M. W. J . Org. Chem. 1973, 38, 3848-
3853. (c) Gobao, R. A.; Bremmer, M. L.; Weinreb, S. M. J . Am. Chem.
Soc. 1982, 104, 7065-7068. (d) Schneider, M. J .; Harris, T. M. J . Org.
Chem. 1984, 49, 3681-3684. (e) Dartmann, M.; Flitsch, W.; Krebs, B.;
Pandl, K.; Westfechtel, A. Liebigs Ann. Chem. 1988, 695-704. (f)
Shono, T.; Matsumura, Y.; Katoh, S.; Takeuchi, K.; Sasaki, K.; Kamada,
T.; Shimizu, R. J . Am. Chem. Soc. 1990, 112, 2368-2372. (g) Wasser-
man, H.; Vu, C. B. Tetrahedron Lett. 1994, 35, 9779-9782. For
syntheses of (-)-slaframine, see: (h) Choi, J .-R.; Han, S.; Cha, J . K.
Tetrahedron Lett. 1991, 32, 6469-6472. (i) Pearson, W. H.; Bergmeier,
S. C. Williams, J . P. J . Org. Chem. 1992, 57, 3977-3987. (j) Sibi, M.
P.; Christensen, J . W.; Li, B.; Renhowe, P. A. J . Org. Chem. 1992, 57,
4329-4330. (k) Knapp, S.; Gibson, F. S. J . Org. Chem. 1992, 57, 4802-
4809. (l) Hua, D. H.; Park, J .-G.; Katsuhira, T.; Bharathi, S. N. J . Org.
Chem. 1993, 58, 2144-2150. (m) Gmeiner, P.; J unge, D. J . Org. Chem.,
1995, 60, 3910-3915. (n) Szeto, P.; Lathbury, D. C.; Gallagher, T.
Tetrahedron Lett. 1995, 36, 6957-6960. (o) Knight, D. W.; Sibley, A.
W. J . Chem. Soc., Perkin Trans. 1 1997, 2179-2187. (p) Kang, S. H.;
Kim, J . S.; Youn, J .-H. Tethrahedron Lett. 1998, 39, 9047-9050. (q)
Carretero, J . C.; Arraya`s, R. G. Synlett 1999, 1, 49-52. (r) Sibi, M. P.;
Christensen, J . W. J . Org. Chem. 1999, 64, 6434-6442. (s) Comins,
D. L.; Fulp, A. B. Org. Lett 1999, 1, 1941-1943.
(7) Broquist, H. P. Annu. Rev. Nutr. 1985, 5, 391-409.
(8) Harris, C. M.; Schneider, M. J .; Ungemach, F. S.; Hill, J . E.;
Harris, T. M. J . Am. Chem. Soc. 1988, 110, 940-949.
therapeutic application for the treatment of cholinergic
dysfunction have been suggested for slaframine.9
(9) J acques, K.; Harmon, D. L.; Croom, W. J ., J r.; Hagler, W. M.,
J r. J . Dairy Sci. 1989, 72, 443-452. Froetschel, M. A.; Amos, H. E.;
Evans, J . J .; Croom, W. J ., J r.; Hagler, W. M., J r. J . Anim. Sci. 1989,
67, 827-834. Croom, W. J ., J r.; Hagler, W. M., J r.; Froetschel, M. A.;
J ohnson, A. D. Ibid. 1995, 73, 1499-1508, and references therein.
(10) Molecular modeling was performed on an IBM RS 6000
workstation running Insight II Discover 98.0 (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 a vacuum (dielectric constant fixed at 1; 200000
steps of 1 fs) and consisted of generation of 400 structures. These
depicted conformations are lowest in energy by g1.0 kcal/mol. (The
next lowest in energy would also be expected to undergo cycloaddition
largely on the CR-si face.)
On the basis of antecedent2e-i and conformation analy-
sis (Figure 1),10 the R enantiomer of 1-(triisopropylphe-
nyl)ethanol (3a , Scheme 1), a generally effective inductor
for chiral enol ether-dichloroketene cycloaddition,4 ap-
peared to be the appropriate one for producing (+)-(1S,-
8aS)-1-hydroxyindolizidine and (-)-slaframine. After
conversion of this alcohol into the dichloroenol ether 3b
(81%), treatment with 2.05 equiv of butyllithium and
then excess 3-butenyl triflate produced the sensitive
enynol ether 4a ,11 which was used without purification.
Closely monitored catalytic hydrogenation of 4a with
palladium on barium sulfate in the presence of 1-hexene
in pyridine11,12 provided dienol ether 4b together with
(11) Kann, N.; Bernardes, V.; Greene, A. E. Org. Synth. 1997, 74,
13-22.
(12) Ho, T.-L.; Liu, S.-H. Synth. Commun. 1987, 17, 969-973.
(13) Hassner, A.; Krepski, L. R. J . Org. Chem. 1978, 43, 3173-3179.
Brady, W. T.; Lloyd, R. M. Ibid. 1979, 44, 2560-2564.
(14) Tamura, Y.; Minamikawa, J .; Ikeda, M. Synthesis 1977, 1-17.
(15) J ohnston, B. D.; Slessor, K. N.; Oehlschlager, A. C. J . Org.
Chem. 1985, 50, 114-117.
(5) For syntheses of (1RS,8aRS)-1-hydroxyindolizidine, see: (a)
Aaron, H. S.; Rader, C. P.; Wicks, G. E., J r. J . Org. Chem. 1966, 31,
3502-3507. (b) Clevenstine, E. C.; Walter, P.; Harris, T. M.; Broquist,
H. P. Biochemistry 1979, 18, 3663-3667. (c) Takahata, H.; Takamatsu,
T.; Yamazaki, T. J . Org. Chem. 1989, 54, 4812-4822. For syntheses
of (+)-(1S,8aS)-1-hydroxyindolizidine, see: (d) Harris, C. M.; Harris,
T. M. Tetrahedron Lett. 1987, 28, 2559-2562. (e) Takahata, H.; Banba,
Y.; Momose, T. Tetrahedron: Asymmetry 1990, 1, 763-764. (f) Sibi,
M. P.; Christensen, J . W. Tetrahedron Lett. 1990, 31, 5689-5692. (g)
Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J . Org. Chem. 1995,
60, 398-404. (h) Green, D. L. C.; Kiddle, J . J .; Thompson, C. M.
Tetrahedron 1995, 51, 2865-2874.
(16) Two independent conformers, with slightly different geometries,
coexist in the atomic arrangement. Crystal data for
C25H39N1O2,
monoclinic P21, a ) 6.119(1), b ) 16.871(2), c ) 24.244(2) Å, â ) 90.76-
(1)°, V ) 2502.6(5) Å3, Z ) 4, dcalcd ) 1.023 g/cm3, F(000) ) 848, 2θ
range 3.35-41.9°, 8285 measured reflections. 2381 independent reflec-
tions, with I > 0σ(I), R ) 0.073, Rw ) 0.038, GOF ) 2.05. Two H-bonds
(N-H‚‚‚O) link the two independent conformers of the compound. Full
lists of fractional atomic coordinates, bond lengths and angles, and
thermal parameters have been deposited as Supporting Material with
the Cambridge Crystallographic Data Centre.

6968 J . Org. Chem., Vol. 65, No. 21, 2000
Pourashraf et al.
Sch em e 2
present case cyclization was invariably slow and inductor
elimination significant. Therefore, the lactam reduction
was advanced to this point in the synthetic sequence.
This reduction could best be achieved by using Pedregal
and co-workers’ super hydride-triethylsilane procedure17
(70%), after first converting lactam 6b to its benzyloxy-
carbonyl (Cbz) derivative 9 (92%). Osmium tetraoxide-
mediated dihydroxylation of the double bond and subse-
quent highly selective monotosylation of the in situ
generated dibutylstannoxane derivative18 produced in
87% overall yield the desired cyclization substrate, to-
sylate 10c, as a mixture of hydroxy epimers. Hydrogena-
tion of this material over Pearlman’s catalyst triggered
cyclization through reductive cleavage of the Cbz group
(without any inductor hydrogenolysis!) to give now in
nearly quantitative yield the indolizidinediol derivative
11a . Swern oxidation of this substance then provided the
corresponding ketone in 88% yield.
Sch em e 3
The triisopropylphenylethyl group, having served its
last function, was now cleaved by exposure of ketone 11b
to trifluoroacetic acid at ambient temperature, and the
resulting hydroxy ketone, without purification, was im-
mediately acetylated to generate in 87% overall yield the
known6b,g,m keto acetate 12a . The final steps, oxime
formation and reduction, were effected as described by
Wasserman and Vu6g to provide slaframine 2 as an
unstable oil, with spectral characteristics in complete
accord with those reported in the literature. Furthermore,
N-Cbz and N-acetyl slaframine, prepared from this
synthetic material, provided spectra that were indistin-
guishable from those of samples derived from natural6g
and independently synthesized6i slaframine, respectively.
In conclusion, a new, effective asymmetric approach
to indolizidines based on diastereofacially selective 2 +
2 cycloaddition of dichloroketene with chiral enol ethers
has been demonstrated. This approach, one of few not to
involve chiral pool material, is expected to allow general
access to not only indolizidine, but also pyrrolizidine
natural products.
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 satu-
rated aqueous NaCl, the combined organic phases were dried
over anhyd Na2SO4 or MgSO4 and then filtered and concen-
trated under reduced pressure on a Bu¨chi Rotovapor to yield
the crude reaction product. Tetrahydrofuran and ether were
distilled from sodium-benzophenone and dichloromethane,
dimethylformamide, pyridine, dimethyl sulfoxide, and triethy-
lamine were distilled from calcium hydride.
2-[(R)-1-((E)-1,2-Dich lor ovin yloxy)et h yl]-1,3,5-t r iiso-
p r op ylben zen e (3b). An argon-flushed flask was charged
with 1.43 g (12.5 mmol) of a 35% suspension of potassium
hydride in mineral oil. The mineral oil was removed by
washing with pentane 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 (R)-(+)-1-(2,4,6-triisopropylphe-
nyl)ethanol (3a )4 (1.40 g, 5.64 mmol) in 20 mL of THF was
then added dropwise. The mixture was stirred until hydrogen
evolution was complete (ca 3 h), cooled to -50 °C, and treated
converted by hydroboration followed by oxidation into
alcohol 7a , which was then mesylated conventionally to
produce 7b (Scheme 2). While several base-solvent
combinations failed to generate indolizidinone 8a from
lactam 7b due to competitive inductor elimination, pleas-
ingly, it was found that sodium hydride in THF/DMF at
room temperature for 2 h yielded the desired product
without significant secondary reactions and in high yield.
Indolizidinone 8a was then subjected to acid induced
inductor cleavage, which was followed by lithium alumi-
num hydride reduction to produce smoothly (+)-(1S,8aS)-
1-hydroxyindolizidine (1), the identity of which was
confirmed through direct spectral comparison with in-
dependently prepared material.5d With the feasibility of
the key pyrrolidine f indolizidine transformation dem-
onstrated, the more challenging slaframine synthesis was
addressed (Scheme 3).
(17) Pedregal, C.; Ezquerra, J .; Escribano, A.; Carreno, M. C.; Ruano,
J . L. G. Tetrahedron Lett. 1994, 35, 2053-2056.
(18) For a similar transformation, see: Ley, S. V.; Brown, D. S.;
Clase, J . A.; Fairbanks, A. J .; Lennon, I. C.; Osborn, H. M. I.; Stokes,
E. S. E.; Wadsworth, D. J . J . Chem. Soc., Perkin Trans. 1 1998, 2259-
2276.
In parallel with the approach to hydroxyindolizidine
1, lactam 6b was initially subjected to various olefin
functionalization-cyclization procedures; however, in the

Enantioselective Approach to Indolizidines
J . Org. Chem., Vol. 65, No. 21, 2000 6969
dropwise with trichloroethylene (0.560 mL, 0.819 g, 6.24
mmol), after which the reaction mixture was allowed to warm
to 20 °C over 1 h, whereupon a few drops of methanol were
added. The crude product was isolated with pentane in the
usual way and purified by filtration through silica gel (pre-
treated with 2.5% triethylamine, v/v) with pentane to afford
1.57 g (81%) of pure enol ether 3b: mp 38-41 °C (pentane);
[R]20D +16.0 (c 1.0, chloroform); IR 3086, 1623, 1609, 1078, 1049
cm-1; 1H NMR (200 MHz) δ 1.23-1.30 (m, 18 H), 1.67 (d, J )
6.9 Hz, 3 H), 2.85 (hept, J ) 6.9 Hz, 1 H), 3.32-3.75 (m, 2 H),
5.57 (s, 1 H), 5.96 (q, J ) 6.9 Hz, 1 H), 7.03 (s, 2 H); 13C NMR
(50.3 MHz) δ 21.0 (CH3), 23.9 (CH3), 24.5 (CH3), 24.8 (CH3),
29.5 (CH), 34.1 (CH), 76.5 (CH), 98.3 (CH), 122.1 (C), 131.3
(C), 143.0 (C), 148.5 (C); mass spectrum (EI), m/z 343 and 341
(M+), 231 (100%). Anal. Calcd for C19H28Cl2O: C, 66.47; H,
8.22. Found: C, 66.63; H, 8.36.
2-[(R)-1-((Z)-Hexa -1,5-d ien yloxy)eth yl]-1,3,5-tr iisop r o-
p ylben zen e (4b). To a solution of 8.96 g (26.1 mmol) of
dichloro enol ether 3b in 90 mL of anhydrous THF at -78 °C
was added dropwise 23.2 mL (53.4 mmol) of 2.3 M n-
butyllithium in hexanes. The reaction mixture was allowed
to warm to -40 °C and then treated dropwise over 10 min
with 7.40 g (36.2 mmol) of 3-butenyl trifluoromethane-
sulfonate.19 The solution was stirred at -28 °C for 20 h,
whereupon it was poured into cold saturated aqueous am-
monium chloride. The product was isolated with pentane in
the usual way to give 9.63 g of 2-[(R)-1-(hex-5-en-1-ynyloxy)-
ethyl]-1,3,5-triisopropylbenzene (4a ), which was used below
immediately: IR 3050, 2266, 1640, 1608, 1265 cm-1; 1H NMR
(200 MHz) δ 1.20-1.30 (m, 18 H), 1.69 (d, J ) 6.8 Hz, 3 H),
2.00-2.15 (m, 4 H), 2.86 (hept, J ) 6.9 Hz, 1 H), 3.19-3.45
(m, 2 H), 4.85-4.96 (m, 2 H), 5.52-5.78 (m, 2 H), 7.01 (s, 2
H); 13C NMR (50.3 MHz) δ 17.3 (CH2), 21.6 (CH3), 23.9 (CH3),
24.1 (CH3), 29.3 (CH), 34.0 (CH2), 34.1 (CH), 37.7 (C), 82.8
(CH), 89.8 (C), 115.0 (CH2), 121.9 (C), 131.0 (C), 137.5 (CH),
148.4 (C).
ca. 5% of its diastereomer (δ 4.57 ppm)), as an oil: IR 3050,
1
1807, 1608, 1068 cm-1; H NMR (200 MHz) δ 1.02-1.38 (m,
18 H), 1.64 (d, J ) 6.8 Hz, 3 H), 1.70-2.40 (m, 3 H), 2.86 (hept,
J ) 6.9 Hz, 2 H), 3.15-3.40 (m, 1 H), 3.40-3.60 (m, 1 H), 3.82
(hept, J ) 6.9 Hz, 1 H), 4.29 (d, J ) 9.2 Hz, 1 H), 4.95-5.10
(m, 2 H), 5.43 (q, J ) 6.7 Hz, 1 H), 5.60-5.85 (m, 1 H), 6.98
(d, J ) 1.7 Hz, 1 H), 7.06 (d, J ) 2.0 Hz, 1 H); mass spectrum
(CI) m/z 438 (M+, 0.01%), 231 (100%). HRMS m/e calcd for
C
25H36Cl2O2 (M+) + Li: 445.2252. Found: 445.2304.
(4S,5S)-5-Bu t-3-en yl-4-[(R)-1-(2,4,6-tr iisopr opylph en yl)-
eth oxy]p yr r olid in -2-on e (6b). A solution of 11.03 g of
cyclobutanone 5 in 240 mL of dichloromethane was treated
with 6.50 g (30.2 mmol) of O-mesitylenesulfonylhydroxylamine
and a small amount of sodium sulfate and stirred at 20 °C for
ca. 2 h. After filtration of the mixture over Celite, the solvent
was removed under reduced pressure and the resulting mate-
rial in 10 mL of toluene was placed on a column of basic
alumina (600 g, Merck activity 1) and eluted rapidly with
methanol. Evaporation of the solvents left a yellow solid, which
was triturated with dichloromethane, which was then filtered
over Celite and evaporated under reduced pressure to afford
11.65 g of (4R,5S)-5-but-3-enyl-3,3-dichloro-4-[(R)-1-(2,4,6-
triisopropylphenyl)ethoxy]pyrrolidin-2-one (6a ), used directly
1
below: IR 3404, 3224, 3061, 1731, 1641, 1601 cm-1; H NMR
(200 MHz) δ 1.15-1.40 (m, 18 H), 1.69 (d, J ) 6.8 Hz, 3 H),
2.22-2.38 (m, 1 H), 2.61 (m, 2 H), 2.85 (hept, J ) 6.9 Hz, 2
H), 3.33 (hept, J ) 6.9 Hz, 1 H), 3.42-3.55 (m, 1 H), 3.75-
3.98 (m, 1 H), 4.41 (d, J ) 7.5 Hz, 1 H), 4.92-5.10 (m, 2 H),
5.60-5.85 (m, 2 H), 6.96 (d, J ) 1.7 Hz, 1 H), 7.05 (d, J ) 1.7
Hz, 1 H),7.25-7.45 (br s, 1 H); mass spectrum (CI) m/z 471
(M + NH4+, 27%), 265 (100%), 231 (58%).
The above dichloro lactam 6a in 130 mL of methanol
previously saturated with ammonium chloride was stirred with
3.2 g (ca. 49 mmol) of zinc-copper couple at 20 °C under argon
for 3 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 dichlo-
romethane in the usual way to give crude lactam 6b. Purifica-
tion of this material by dry silica gel chromatography with
ethyl acetate in hexane provided 4.94 g (50% overall yield from
dichloro enol ether 3b, 87%/step) of pyrrolidinone as a yellow
solid. Recrystallization of this material from methanol-water
provided 3.16 g (64% recovery) of stereochemically pure (g98%)
6b, containing, however, a small amount of the saturated
(butyl) compound (subsequently eliminated in the purification
of 7a and 10b) (HPLC: Lichrosorb column, 5 mm, 2-propanol:
hexane ) 5:95, 1 mL/min., tR 10.2 min (versus 9.6 min for the
trans diastereomer and the saturated derivative and 13.8 min
for the cis diastereomer). Pyrrolidinone 6b: mp 126 °C
A mixture of 9.63 g of acetylene 4a , 9.00 mL (6.05 g, 72.0
mmol) of 1-hexene, and 0.400 g of 10% palladium on barium
sulfate in 160 mL of dry pyridine was stirred under hydrogen
(balloon pressure) for 4 h at 0 °C, whereupon the hydrogen
was replaced with argon, and the reaction mixture was diluted
with pentane and filtered over Celite. The filtrate was thor-
oughly washed with water, saturated aqueous copper sulfate,
water, and saturated aqueous ammonium chloride, dried over
sodium sulfate, and concentrated under reduced pressure to
provide 9.18 g of diene ether 4b, which was used below without
1
delay: IR 3050, 1665, 1639, 1608, 1084 cm-1; H NMR (200
MHz) δ 1.17-1.27 (m, 18 H), 1.58 (d, J ) 6.9 Hz, 3 H), 2.00-
2.33 (m, 4 H), 2.84 (hept, J ) 6.8 Hz, 1 H), 3.30-3.62 (m, 2
H), 4.25 (dt, J ) 6.9, 6.5 Hz, 1 H), 4.88-5.07 (m, 2 H), 5.30 (q,
J ) 6.9 Hz, 1 H), 5.70-5.90 (m, 1 H), 5.94 (d, J ) 6.2 Hz, 1
H), 6.99 (s, 2 H); 13C NMR (50.3 MHz) δ 22.5 (CH3), 23.6 (CH2),
23.9 (CH3), 24.6 (CH3), 29.0 (CH), 33.9 (CH2), 34.0 (CH), 75.2
(CH), 105.3 (CH), 114.3 (CH2), 121.9 (C), 133.1 (C), 138.8 (CH),
144.2 (CH), 147.7 (C); mass spectrum (CI), m/z 328 (M+, 0.3%),
231 (80%), 230 (100%). HRMS m/e calcd for C23H36O (M+) +
Li: 335.2926. Found: 335.2914.
(3R,4S)-4-Bu t-3-en yl-2,2-d ich lor o-3-[(R)-1-(2,4,6-tr iiso-
p r op ylp h en yl)eth oxy]cyclobu ta n on e (5). To a stirred mix-
ture of 9.10 g of enol ether 4b and 3.0 g (ca. 46 mmol) of Zn-
Cu couple in 300 mL of ether under argon was added over 1.5
h a solution of 3.80 mL (6.19 g, 34.0 mmol) of freshly distilled
trichloroacetyl chloride in 90 mL of ether. After an additional
1 h, the ether solution was separated from the excess couple
and added to a large volume of 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 11.03 g of cyclobutanone 5 (containing
(methanol-water); [R]20 +73 (c 1.5, chloroform); IR (film)
D
3216, 3053, 1697, 1641, 1608, 1265 cm-1; 1H NMR (500 MHz)
δ 1.10-1.32 (m, 18 H), 1.51 (d, J ) 6.6 Hz, 3 H), 1.54-1.64
(m, 1 H), 1.74-1.82 (m, 1 H), 2.03 (hept, J ) 7.5 Hz, 1 H),
2.14 (hept, J ) 7.2 Hz, 1 H), 2.46 (AB of ABX, δa ) 2.44, δb )
2.48, J ab ) 16.5 Hz, J ax ) 7.1 Hz, J bx ) 7.4 Hz, 2 H), 2.83 (hept,
J ) 6.9 Hz, 1 H), 3.13 (hept, J ) 6.6 Hz, 1 H), 3.54-3.60 (m,
1 H), 3.84 (hept, J ) 6.7 Hz, 1 H), 4.11 (q, J ) 7.0 Hz, 1 H),
4.90-5.09 (m, 3 H), 5.70-5.80 (m, 1 H), 6.48 (br s, N-H), 6.93
(s, 1 H), 7.02 (s, 1 H); 13C NMR (50.3 MHz) δ 23.0 (CH3), 23.8
(CH3), 24.2 (CH3), 24.9 (CH3), 25.1 (CH3), 28.0 (CH), 28.9 (CH2),
29.0 (CH), 30.3 (CH2), 33.9 (CH), 36.5 (CH2), 57.3 (CH), 71.2
(CH), 72.7 (CH), 115.2 (CH2), 120.5 (CH), 123.2 (CH), 132.2
(C), 137.8 (CH), 145.7 (C), 147.5 (C), 148.7 (C), 175.5 (C); mass
spectrum (EI), m/z 385 (M+, 4%), 231 (67%), 230 (74%), 43
(100%). Anal. Calcd for C25H39NO2: C, 77.87; H, 10.19; N, 3.63.
Found: C, 77.61; H, 10.06; N, 3.74.
(4S,5S)-5-(4-Hyd r oxybu tyl)-4-[(R)-1-(2,4,6-tr iisop r op yl-
p h en yl)eth oxy]p yr r olid in -2-on e (7a ). To a stirred solution
of lactam 6b (0.788 g, 2.04 mmol) in 6.8 mL of THF at 0 °C
was added 3.2 mL (8.3 mmol) of a freshly prepared 2.6 M
solution of disiamylborane in THF. The resulting solution was
stirred at 20 °C for 5 h, cooled to 0 °C, and carefully treated
with 4 mL of water, 4 mL of 3 M aqueous sodium hydroxide,
and 4 mL of 30% aqueous hydrogen peroxide. The mixture was
vigorously stirred for 20 h at 20 °C and then filtered through
(19) Prepared from 3-buten-1-ol and triflic anhydride according to
the general procedure described in Salomon, M. F.; Salomon, R. G.;
Gleim, R. D. J . Org. Chem. 1976, 41, 3983-3987.

6970 J . Org. Chem., Vol. 65, No. 21, 2000
Pourashraf et al.
Celite with ethyl acetate. The crude product was isolated with
ethyl acetate in the usual way and purified by dry silica gel
column chromatography with methanol in ethyl acetate to give
1H NMR (300 MHz) δ 1.21-1.47 (m, 2 H), 1.53-1.70 (m, 3 H),
1.93-1.98 (m, 1 H), 2.32 (dd, J ) 17.3, 1.7 Hz, 1 H), 2.37-
2.53 (br s, 1 H), 2.55-2.67 (m, 2 H), 6.78 (ddd, J ) 10.9, 4.9,
4.9 Hz, 1 H), 4.04-4.10 (m, 1 H), 4.33-4.38 (m, 1 H); 13C NMR
(75.5 MHz) δ 23.2 (CH2), 24.0 (CH2), 24.6 (CH2), 40.3 (CH2),
41.0 (CH2), 61.7 (CH), 66.3 (CH), 172.2 (C); mass spectrum
0.622 g (75%) of alcohol 7a : mp 145-147 °C; [R]21 +68.0 (c
D
0.2, chloroform); IR 3432, 3242, 1693, 1608 cm-1; 1H NMR (300
MHz) δ 1.13-1.27 (m, 19 H), 1.52 (d, J ) 6.7 Hz, 3 H), 1.30-
1.78 (m, 5 H), 1.87-2.10 (br s, 1 H), 2.46 (AB of ABX, δa
)
(CI), m/z 156 (MH+, 81%), 134 (1%). HRMS m/e calcd for C8H13
-
2.48, δb ) 2.44, J ab ) 16.5 Hz, J ax ) 7.3 Hz, J bx ) 6.9 Hz, 2 H),
2.83 (hept, J ) 6.9 Hz, 1H), 3.12 (hept, J ) 6.8 Hz, 1H), 3.54-
3.63 (m, 3 H), 3.84 (hept, J ) 6.6 Hz, 1 H), 4.11 (pseudo q, X
of ABX, J ax ) 7.3 Hz, J bx ) 6.9 Hz, 1 H), 5.03 (q, J ) 6.7 Hz,
1 H), 6.65-6.90 (br s, 1 H), 6.93 (s, 1 H), 7.02 (s, 1 H); 13C
NMR (75.5 MHz) δ 22.4 (CH2), 23.3 (CH3), 24.0 (CH3), 24.4
(CH3), 25.0 (CH3), 25.1 (CH3), 25.3 (CH3), 28.2 (CH), 29.2 (CH),
29.3 (CH2), 32.3 (CH2), 34.1 (CH), 36.7 (CH2), 57.9 (CH), 62.4
(CH2), 71.5 (CH), 73.0 (CH), 120.7 (CH), 123.4 (CH), 132.4 (C),
145.9 (C), 147.8 (C), 148.9 (C), 175.6 (C); mass spectrum (CI),
m/z 404 (MH+, 100%), 264 (10%), 231 (44%). Anal. Calcd for
NO2 (M+): 155.0946. Found: 155.0959.
(1S,8a S)-Octa h yd r oin d olizin -1-ol (1). A mixture of alco-
hol 8b (0.130 g 0.84 mmol) and lithium aluminum hydride
(0.255 g, 6.72 mmol) in 18 mL of THF was stirred at 20 °C for
24 h. After being diluted with 13 mL of THF, the mixture was
cooled to 0 °C and carefully treated with 0.255 mL of water,
0.255 mL of 10% aqueous sodium hydroxide, and 0.770 mL
water. The resulting mixture was stirred for 40 min at 20 °C
and then treated with anhydrous sodium sulfate. Filtration
of the mixture and concentration of the filtrate under reduced
pressure gave the crude product, which was purified by column
chromatography on silica gel with 0-15% methanol saturated
with ammonia in chloroform to give 0.090 g (76%) of indolizi-
dine 1, as a clear oil: [R]25D +22.5 (c 1.0, ethanol) (lit. +20.2,5f
C
25H41NO3: C, 74.40; H, 10.24; N, 3.47. Found: C, 74.32; H,
10.08; N, 3.58.
(1S,8a S)-1-[(R)-1-(2,4,6-Tr iisop r op ylp h en yl)et h oxy]-
h exa h yd r oin d olizin -3-on e (8a ). To a stirred solution of
0.622 g (1.54 mmol) of alcohol 7a and 0.500 mL (0.363 g, 3.59
mmol) of triethylamine in 6.2 mL of dichloromethane at 0 °C
was added dropwise 0.275 mL (0.407 g, 3.55 mmol) of meth-
anesulfonyl chloride. The resulting solution was stirred at 0
°C for 1.5 h, diluted with 30 mL dichloromethane, and then
treated with 2 mL of water. The crude product was isolated
in the usual way to afford 0.701 g of crude mesylate 7b, which
was used without further purification: IR 3225, 1696, 1607,
1355 cm-1; 1H NMR (300 MHz) δ 1.14-1.40 (m, 20 H), 1.45-
1.56 (m, 4 H), 1.63-1.78 (m, 3 H), 2.44 (AB of ABX, δa ) 2.46,
δb ) 2.42, J ab ) 16.4 Hz, J ax ) 7.2 Hz, J bx ) 7.2 Hz, 2 H), 2.82
(hept, J ) 6.9 Hz, 1 H), 2.97 (s, 3 H), 3.09-3.15 (m, 1 H), 3.51-
3.57 (m, 1 H), 3.82 (hept, J ) 6.6 Hz, 1 H), 4.11 (pseudo q, X
of ABX, J ax ) 7.2 Hz, J bx ) 7.2 Hz, 1H), 4.19 (t, J ) 6.5 Hz, 2
H), 5.03 (q, J ) 6.7 Hz, 1 H), 6.92 (s, 1 H), 7.01 (s, 1 H), 7.03
(s, 1 H); 13C NMR (75.5 MHz) δ 22.2 (CH2), 23.1 (CH3), 23.9
(CH3), 24.2 (CH3), 24.9 (CH3), 25.1 (CH3), 28.1 (CH), 29.1 (CH2),
29.1 (CH), 29.4 (CH2), 33.9 (CH), 36.4 (CH2), 37.4 (CH3), 57.5
(CH), 69.6 (CH2), 71.4 (CH), 72.7 (CH), 120.6 (CH), 123.2 (CH),
132.1 (C), 145.8 (C), 147.7 (C), 148.7 (C), 175.2 (C); mass
spectrum (CI), m/z 482 (MH+, 100%), 386 (94%), 264 (28%),
231 (90%).
+275d), [R]22 +17.4 (c 0.4, chloroform) (lit.5h +16.4, +18.1);
D
IR 3386 cm-1; 1H NMR (300 MHz) δ 1.21 (m, 1 H), 1.42-1.70
(m, 6 H), 1.80-1.99 (m, 3 H), 2.13 (m, 1 H), 2.26 (m, 1 H),
3.07 (m, 2 H), 4.03 (br s, 1 H); 13C NMR (50.3 MHz) δ 23.9
(CH2), 25.2 (CH2), 25.3 (CH2), 33.3 (CH2), 52.8 (CH2), 53.6
(CH2), 68.8 (CH), 73.0 (CH); mass spectrum (CI), m/z 142
(MH+, 61%), 124 (10%), 110 (100%). The 1H NMR spectrum
was in perfect agreement with that of an independently
prepared5d sample (spectrum kindly provided by Professor C.
Harris). HRMS m/e calcd for C8H15NO (M+): 141.1154. Found:
141.1151.
Ben zyl (2S,3S)-2-Bu t-3-en yl-5-oxo-3-[(R)-1-(2,4,6-tr iiso-
p r op ylp h en yl)eth oxy]p yr r olid in e-1-ca r boxyla te (9). To a
solution of lactam 6b (1.80 g, 4.67 mmol) in 36 mL of dry THF
at -78 °C were added 2.50 mL (5.25 mmol) of a 2.1 M solution
of n-butyllithium in hexane and, after 30 min, 1.40 mL (1.67
g, 9.81 mmol) of benzyl chloroformate. The reaction mixture
was allowed to warm to 0 °C and stirred at this temperature
for 1 h. The crude product was isolated with ether in the usual
manner and purified by dry silica gel chromatography with
15% ethyl acetate in hexane to give 2.22 g (92%) of pyrrolidi-
none 9: mp 73 °C (methanol-water); [R]25 +90 (c 1.5,
D
chloroform); IR 3065, 1788, 1754, 1724, 1607, 1288, 1266 cm-1
;
A solution of 0.701 g (ca. 1.46 mmol) of crude mesylate 7b
in 10 mL of THF was added to a stirred mixture of 0.300 g of
sodium hydride (7.50 mmol, 60% in mineral oil) in 12 mL of
THF and 4 mL of freshly distilled DMF at 20 °C. The resulting
mixture was stirred for 2 h, cooled to 0 °C, and then carefully
treated with water. The crude reaction product was isolated
with ether in the normal way and purified by dry silica gel
column chromatography with ethyl acetate in pentane to afford
1H NMR (300 MHz) δ 1.07-1.33 (m, 18 H), 1.54 (d, J ) 6.5
Hz, 3 H), 1.58-1.72 (m, 2 H), 1.92-2.20 (m, 3 H), 2.66 (AB of
ABX, δa ) 2.63, δb ) 2.70, J ab ) 15.8 Hz, J ax ) 8.7 Hz, J bx
)
6.7 Hz, 2 H), 2.83 (hept, J ) 7.0 Hz, 1 H), 3.02-3.18 (m, 1 H),
3.74-3.88 (m, 1 H), 4.03-4.15 (m, 2 H), 4.18-4.29 (m, 1 H),
4.86-4.97 (m, 2 H), 5.04 (q, J ) 6.7 Hz, 1 H), 5.15-5.30 (m, 2
H), 5.64-5.80 (m, 1 H), 6.93 (br s, 1 H), 7.03 (br s, 1 H), 7.25-
7.40 (m, 5 H); 13C NMR (50.3 MHz) δ 22.9 (CH3), 23.8 (CH3),
24.0 (CH3), 24.9 (CH3), 28.0 (CH), 28.3 (CH2), 29.0 (CH), 30.2
(CH2), 33.8 (CH), 38.0 (CH2), 59.6 (CH), 60.0 (CH), 67.9 (CH2),
69.5 (CH), 69.7 (CH), 71.5 (CH), 114.6 (CH2), 120.5 (CH), 123.2
(CH), 128.0 (CH), 128.2(CH), 128.4 (CH), 131.5 (C), 131.8 (C),
135.0 (C), 137.8 (CH), 145.7 (C), 147.6 (C), 148.5 (C), 151.0
(C), 170.4 (C); mass spectrum (CI) m/z 520 (MH+, 100%), 519
(M+, 10%), 231 (6%). Anal. Calcd for C33H45NO4: C, 76.26; H,
8.73; N, 2.70. Found: C, 76.06; H, 8.65; N, 2.63.
Ben zyl (2S,3S)-2-Bu t-3-en yl-3-[(R)-1-(2,4,6-tr iisop r op y-
lp h en yl)et h oxy]p yr r olid in e-1-ca r b oxyla t e (10a ). To a
stirred solution of lactam 9 (2.20 g, 4.23 mmol) in 14 mL of
THF at -78 °C under argon was added dropwise 7.10 mL (7.10
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 solution
(11 mL), and then allowed to warm to 0 °C. Ten drops of 30%
aqueous hydrogen peroxide were added, and the mixture was
then stirred for 30 min at 0 °C. The crude product was isolated
with dichloromethane in the usual way to yield 2.06 g of the
corresponding R-hydroxypyrrolidine, which was used im-
mediately below.
0.525 g (88%) of indolizidinone 8a : mp 144-145 °C; [R]20
D
+86.3 (c 1.0, chloroform); IR 1682, 1608 cm-1; H NMR (300
1
MHz) δ 1.15-1.26 (m, 19 H), 1.29-1.40 (m, 2 H), 1.49 (d, J )
6.8 Hz, 3 H), 1.54-1.72 (m, 2 H), 1.85-1.96 (m, 1 H), 2.49-
2.59 (m, 3 H), 2.83 (hept, J ) 6.9 Hz, 1 H), 3.14 (hept, J ) 6.9
Hz, 1 H), 3.39-3.45 (m, 1 H), 3.85 (hept, J ) 6.8 Hz, 1 H),
4.01 (m, 1 H), 4.08-4.14 (m, 1 H), 5.06 (q, J ) 6.8 Hz, 1 H),
6.92 (s, 1 H), 7.01 (s, 1 H); 13C NMR (75.5 MHz) δ 23.4 (CH3),
24.0 (CH2), 24.2 (CH3), 24.6 (CH3), 24.8 (CH2), 25.2 (CH3), 25.5
(CH3), 25.5 (CH3), 25.8 (CH2), 28.2 (CH), 29.4 (CH), 34.2 (CH),
37.6 (CH2), 40.6 (CH2), 61.5 (CH), 69.8 (CH), 70.7 (CH), 121.0
(CH), 123.5 (CH), 132.3 (C), 146.4 (C), 147.9 (C), 149.1 (C),
171.4 (C). Anal. Calcd for C25H39NO2: C, 77.87; H, 10.19; N,
3.63. Found: C, 77.92; H, 10.35; N, 3.63.
(1S,8a S)-1-Hyd r oxyh exa h yd r oin d olizin -3-on e (8b). A
0.618-g (1.60 mmol) sample of lactam 8a in 10 mL of dichlo-
romethane was stirred with 1.00 mL (1.48 g, 13.0 mmol) of
trifluoroacetic acid at 20 °C for 2.5 h, whereupon chloroform
was added, and the reaction mixture was concentrated to
dryness under reduced pressure. Purification of the resulting
solid by dry silica gel column chromatography with methanol
in ethyl acetate afforded 0.217 g (87%) of alcohol 8b: mp 149-
A stirred solution of this material and 0.700 mL (0.509 g,
4.38 mmol) of triethylsilane in 60 mL of dry dichloromethane
157 °C (dec); [R]20D +26.9 (c 1.5, acetone); IR 3268, 1651 cm-1
;

Enantioselective Approach to Indolizidines
J . Org. Chem., Vol. 65, No. 21, 2000 6971
at -78 °C was treated with 0.700 mL (0.784 g, 5.52 mmol) of
boron trifluoride diethyl etherate and then, after 30 min, the
same amounts of these two reagents were again added. After
being stirred for an additional 2 h at -78 °C, the reaction
mixture was treated with 6.5 mL of saturated aqueous sodium
bicarbonate solution, and the crude product was isolated with
dichloromethane in the usual way. Purification of this material
by dry silica gel chromatography with 10-15% ethyl acetate
in hexane afforded 1.50 g (70%) of pyrrolidine 10a , as an oil:
[R]25D +38 (c 1.6, chloroform); IR 3061, 1704, 1641, 1608, 1411
cm-1; 1H NMR (200 MHz, C7D8, 80 °C) δ 0.90-1.20 (m, 18 H),
1.29 (d, J ) 6.7 Hz, 3 H), 1.35-1.80 (m, 5 H), 1.85-2.08 (m, 2
H), 2.58 (hept, J ) 6.7 Hz, 1 H), 2.90-3.18 (m, 2 H), 3.56 (q,
J ) 9.0 Hz, 1 H), 3.65-3.88 (m, 1 H), 4.56-4.94 (m, 5 H), 5.40-
5.70 (m, 1 H), 6.75-7.08 (m, 7 H); 13C NMR (50.3 MHz, C7D8,
80 °C) δ 23.5 (CH3), 24.4 (CH3), 25.2 (CH3), 25.5 (CH3), 29.5
(CH2), 31.2 (CH2), 34.7 (CH), 43.4 (CH2), 59.0 (CH), 67.0 (CH2),
72.9 (CH), 77.4 (CH), 114.4 (CH2), 128.1 (CH), 128.4 (CH),
128.7 (CH), 134.0 (C), 137.7 (C), 138.1 (C), 139.5 (CH), 148.1
(C), 155.2 (C); mass spectrum (CI) m/z 506 (MH+, 4%), 505
) 8.5, 2.6 Hz, 2 H); 13C NMR (50.3 MHz, C7D8, 60 °C,
diastereomers) δ 23.4 (CH3), 24.3 (CH3), 25.4 (CH3), 26.0 (CH3),
26.1 (CH3), 29.3 (CH2), 30.5 (CH2), 34.7 (CH2), 43.3 (CH2), 58.5
(CH), 58.9 (CH), 67.1 (CH2), 67.3 (CH2), 69.9 (CH), 70.0 (CH),
72.5 (CH), 74.4 (CH2), 76.8 (CH), 128.4 (CH), 128.5 (CH), 128.8
(CH), 130.1 (CH), 133.8 (C), 134.9 (C), 137.7 (C), 137.9 (C),
144.4 (C), 148.2 (C), 155.4 (C), 155.6 (C); mass spectrum (CI)
m/z 694 (MH+, 0.6%), 522 (2.8%), 231 (72%). Anal. Calcd for
C
40H55NO7S: C, 69.23; H, 7.99; N, 2.02; S, 4.62. Found: C,
69.52; H, 8.14; N, 2.19; S, 4.29.
(1S,8a S)-1-[(R)-1-(2,4,6-Tr iisop r op ylp h en yl)eth oxy]oc-
ta h yd r oin d olizin -6-ol (11a ). A mixture of 1.30 g (1.87 mmol)
of tosylate 10c and 0.130 g of palladium hydroxide in 18 mL
of methanol was stirred under hydrogen overnight at 20 °C,
whereupon the hydrogen was replaced with argon, and the
reaction mixture was diluted with methanol and filtered over
Celite. The residue obtained on evaporation of the methanol
under reduced pressure was dissolved in 32 mL of dichlo-
romethane, treated with 0.560 mL (0.407 g, 4.02 mmol) of
triethylamine, and then refluxed for 2.5 h. After being allowed
to cool to room temperature, the reaction mixture was pro-
cessed in the usual way, and the crude product was purified
by dry silica gel chromatography with 0-25% methanol in
dichloromethane to give 0.700 g (97%) of alcohol 11a , as a
(M+, 2%), 231 (19%), 230 (26%). HRMS m/e calcd for C33H47
NO3 (M+) + Li: 512.3716. Found: 512.3710.
-
Ben zyl (2S,3S)-2-(3,4-Dih yd r oxyb u t yl)-3-[(R)-1-(2,4,
6-t r iis o p r o p y lp h e n y l)e t h o x y ]p y r r o lid in e -1-c a r b o x -
yla te (10b). To a solution of 1.83 g (3.62 mmol) of carbamate
10a in 10.8 mL of tert-butyl alcohol, and 3.2 mL of water were
added 0.400 g (3.60 mmol) of trimethylamine oxide dihydrate
and 2.0 mL (0.16 mmol) of a 2.5% solution of osmium
tetraoxide in tert-butyl alcohol. The reaction mixture was
refluxed, with additional trimethylamine oxide dihydrate
(0.200 g, 1.80 mmol) being added at 1 h intervals over the first
3 h. After being refluxed for 12 h, the reaction mixture was
allowed to cool to 20 °C and was treated with a solution of
2.80 g of sodium hydrogen sulfite in 36 mL of water and then
stirred for 15 min. The crude product was isolated with ethyl
acetate in the usual manner and purified by dry silica gel
chromatography with 10-20% ethyl acetate in hexane (to elute
a small amount of saturated side chain material) and then
mixture of hydroxy epimers: [R]25 +64 (c 1.2, chloroform);
D
IR 3404, 1608 cm-1; 1H NMR (500 MHz, major diastereomer)
δ 1.20-1.29 (m, 18 H), 1.30-1.39 (m, 1 H), 1.47 (d, J ) 6.7
Hz, 3 H), 1.50-1.54 (m, 1 H), 1.63-1.74 (br s, 1 H), 1.83-2.08
(m, 6 H), 2.82 (hept, J ) 6.9 Hz, 2 H), 3.01-3.07 (m, 1 H),
3.11 (d, J ) 11.0 Hz, 1 H), 3.21 (hept, J ) 6.7 Hz, 1 H), 3.76
(m, 1 H), 3.84 (br s, 1 H), 3.93 (hept, J ) 6.7 Hz, 1 H), 5.07 (q,
J ) 6.8 Hz, 1 H), 6.91 (s, 1 H), 7.01 (s, 1 H); 13C NMR (50.3
MHz, major diastereomer) δ 19.7 (CH2), 23.3 (CH3), 23.3 (CH3),
24.2 (CH3), 25.2 (CH3), 25.3 (CH3), 25.6 (CH3), 27.6 (CH), 29.0
(CH), 30.5 (CH2), 30.7 (CH2), 33.9 (CH), 53.3 (CH2), 59.4 (CH2),
65.2 (CH), 68.2 (CH), 69.0 (CH), 76.2 (CH), 120.5 (CH), 123.0
(CH), 132.6 (C), 146.1 (C), 147.2 (C), 149.2 (C); mass spectrum
(CI) m/z 388 (MH+, 69%), 231 (11%), 156 (100%). HRMS m/e
calcd for C25H41NO2 (M+) + H: 388.3215. Found: 388.3229.
(1S,8a S)-1-[(R)-1-(2,4,6-Tr iisop r op ylp h en yl)et h oxy]-
h exa h yd r oin d olizin -6-on e (11b). To a stirred solution of
0.380 mL (0.553 g, 4.36 mmol) of oxalyl chloride in 8.5 mL of
dichloromethane at -60 °C under argon was added 0.570 mL
(0.627 g, 8.03 mmol) of dimethyl sulfoxide. After being stirred
for 10 min at -60 °C, a solution of 0.700 g (1.80 mmol) of 11a
in 8.5 mL of dichloromethane was added dropwise. The
mixture was allowed to warm to -40 °C, stirred for 1.5 h at
this temperature, and then treated with 2.50 mL (1.82 g, 17.9
mmol) of triethylamine. After being stirred for 15 min at -40
°C, the reaction mixture was allowed to warm to room
temperature and was then processed with dichloromethane
in the usual way to give the crude product. Purification of this
material by filtration through silica gel (pretreated with 2.5%
triethylamine, v/v) with 20-100% ethyl acetate in hexane
methanol to afford 1.31 g (67%) of diol 10b: mp 38 °C; [R]25
D
+39 (c 1.6, chloroform); IR 3430, 1701, 1607, 1415 cm-1; H
1
NMR (200 MHz, C7D8, 80 °C, diastereomers) δ 0.98-1.28 (m,
18 H), 1.37 (d, J ) 6.8 Hz, 3 H), 1.30-1.92 (m, 4 H), 2.43 (q,
J ) 7.2 Hz, 1 H), 2.65 (hept, J ) 6.8 Hz, 1 H), 2.90-3.94 (m,
12 H), 4.80-5.20 (m, 3 H), 6.80-7.18 (m, 7 H); 13C NMR (50.3
MHz, C7D8, 80 °C, diastereomers) δ 23.3 (CH3), 24.2 (CH3),
25.0 (CH3), 25.3 (CH3), 26.0 (CH2), 26.2 (CH2), 29.2 (CH2), 30.6
(CH2), 30.8 (CH2), 34.5 (CH), 43.3 (CH2), 46.7 (CH2), 59.0 (CH),
59.2 (CH), 67.2 (CH2), 67.2 (CH2), 72.7 (CH), 72.9 (CH), 76.9
(CH), 77.1 (CH), 128.1 (CH), 128.3 (CH), 128.7 (CH), 133.8 (C),
133.9 (C), 137.6 (C), 137.8 (C), 137.8 (C), 148.1 (C), 155.4 (C),
155.5 (C); mass spectrum (CI) m/z 540 (MH+, 3%), 539 (M+,
0.4%), 231 (71%). Anal. Calcd for C33H49NO5‚0.25 H2O: C,
72.76; H, 9.17; N, 2.57. Found: C, 72.96; H, 9.35; N, 2.62.
Ben zyl (2S,3S)-2-(3-Hyd r oxy-4-(tolu en e-4-su lfon yloxy)-
b u t yl]-3-[(R)-1-(2,4,6-t r iisop r op ylp h en yl)et h oxy]p yr r o-
lid in e-1-ca r boxyla te (10c). A solution of 0.034 g (0.063
mmol) of diol 10b in 0.34 mL of methanol was treated with
0.017 g (0.068 mmol) of dibutyltin oxide and then refluxed for
45 min. After being allowed to cool to 20 °C, the reaction
mixture was treated with 0.068 mL (0.049 g, 0.49 mmol) of
triethylamine and 0.088 g (0.46 mmol) of p-toluenesulfonyl
chloride and stirred for 10 min, whereupon a saturated
solution of aqueous sodium bicarbonate was added. The crude
product was isolated with dichloromethane and then stirred
in 1.25 mL of THF with 0.25 mL of water and 0.25 mL of
triethylamine for 2 h, after which time the product was isolated
with ether in the usual way and purified by dry silica gel
chromatography with 20-30% ethyl acetate in hexane to give
0.041 g (94%) of tosylate 10c: mp 45-46 °C (pentane-
dichloromethane); [R]25D +27 (c 1.5, chloroform); IR 3437, 1697,
afforded 0.610 g (88%) of ketone 11b: mp 79-80 °C (hexane);
1
[R]25 +64 (c 1.5, chloroform); IR 1724, 1608 cm-1; H NMR
D
(500 MHz) δ 1.10-1.30 (m, 18 H), 1.50 (d, J ) 6.8 Hz, 3 H),
1.86-1.95 (m, 1 H), 1.96-2.26 (m, 5 H), 2.52 (d, J ) 13.4 Hz,
1 H), 2.69 (d, J ) 14.9 Hz, 1 H), 2.83 (hept, J ) 6.9 Hz, 2 H),
3.06-3.17 (m, 1 H), 3.22 (hept, J ) 6.8 Hz, 1 H), 3.53 (d, J )
14.9 Hz, 1 H), 3.81-3.96 (m, 2 H), 5.10 (q, J ) 6.8 Hz, 1 H),
6.93 (br s, 1 H), 7.02 (br s, 1 H); 13C NMR (62.5 MHz) δ 22.8
(CH2), 23.4 (CH3), 23.9 (CH3), 24.1 (CH3), 25.3 (CH3), 25.7
(CH3), 27.6 (CH), 29.0 (CH), 31.0 (CH2), 33.9 (CH), 38.1 (CH2),
53.4 (CH2), 64.0 (CH2), 65.7 (CH), 68.8 (CH), 75.0 (CH), 120.6
(CH), 123.0 (CH), 132.1 (C), 146.3 (C), 147.4 (C), 149.1 (C),
206.8 (C); mass spectrum (CI) m/z 386 (MH+, 76%), 231 (100%).
HRMS m/e calcd for
C
25H39NO2 (M+): 385.2981. Found:
385.2986.
(1S,8a S)-6-Oxoocta h yd r oin d olizin -1-yl Aceta te (12a ).
To a stirred solution of 0.610 g (1.58 mmol) of ketone 11b in
10 mL of dichloromethane at 20 °C was added 0.720 mL (1.06
g, 9.35 mmol) of trifluoroacetic acid. After being stirred for 1
h, the reaction mixture was concentrated at 20 °C under
reduced pressure to give the corresponding crude keto alcohol.
1609, 1461, 1360 cm-1 1H NMR (200 MHz, C7D8, 60 °C,
;
diastereomers) δ 1.02-1.34 (m, 20 H), 1.44 (d, J ) 6.8 Hz, 3
H), 1.35-1.85 (m, 6 H), 1.90 (s, 3 H), 2.74 (hept, J ) 6.8 Hz,
1 H), 2.84-3.30 (m, 2 H), 3.52-4.08 (m, 4 H), 4.82-5.10 (m, 5
H), 6.75 (d, J ) 7.9 Hz, 2 H), 6.90-7.22 (m, 7 H), 7.66 (dd, J

6972 J . Org. Chem., Vol. 65, No. 21, 2000
Pourashraf et al.
A solution of the above keto alcohol, 3.30 mL (2.40 g, 23.68
mmol) of triethylamine, 1.20 mL (1.30 g, 12.72 mmol) of acetic
anhydride, and a few crystals of DMAP in 27 mL of dichlo-
romethane was stirred for 4 h at 20 °C. The reaction mixture
was then processed with dichloromethane in the usual manner
to give the crude product, which was purified by dry silica gel
chromatography to afford 0.270 g (87%) of keto acetate 12a :
mp 79-80 °C (hexane); [R]25D +34 (c 1.9, chloroform); IR 1737,
that of an independently synthesized6l sample (spectrum
kindly provided by Professor D. H. Hua). HRMS m/e calcd for
C
10H18N2O2 (M+) + H: 199.1446. Found: 199.1445.
(1S ,6S ,8a S )-6-(B e n zy lo x y c a r b o n y la m in o )o c t a h y -
d r oin d olizin -1-yl Aceta te (N-Cbz-sla fr a m in e). A solution
of 0.005 g (0.025 mmol) of slaframine (2), 0.020 mL (0.015 g,
0.144 mmol) of triethylamine, 0.011 mL (0.013 g, 0.077 mmol)
of benzyl chloroformate, and a small crystal of DMAP in 0.300
mL of dichloromethane at 0 °C was stirred for 2 h. The crude
product was isolated with ether in the usual manner and
purified by dry silica gel chromatography to provide in
quantitative yield N-Cbz-slaframine, which displayed a high-
1
1731, 1246 cm-1; H NMR (250 MHz) δ 1.71-2.55 (m, 8 H),
2.02 (s, 3 H), 2.72 (d, J ) 14.3 Hz, 1 H), 3.15 (td, J ) 8.9, 2.4
Hz, 1H), 3.52 (d, J ) 14.3 Hz, 1 H), 5.22-5.32 (m, 1 H); 13C
NMR (62.5 MHz) δ 21.0 (CH3), 22.9 (CH2), 31.4 (CH2), 37.6
(CH2), 53.1 (CH2), 63.7 (CH2), 64.9 (CH), 73.6 (CH), 170.5 (C),
205.3 (C); mass spectrum (EI) m/z 197 (M+, 12%), 154 (10%).
HRMS m/e calcd for C10H15NO3 (M+): 197.1052. Found:
197.1058.
1
field H NMR spectrum in perfect agreement with that of the
Cbz derivative prepared from natural slaframine (spectrum
kindly provided by Professor H. Wasserman).
(1S,6S,8aS)-6-(Acetylam in o)octah ydr oin dolizin -1-yl Ac-
eta te (N-a cetylsla fr a m in e). A solution of 0.017 g (0.086
mmol) of slaframine (2) in 0.50 mL of pyridine and 0.50 mL of
acetic anhydride was stirred at 20 °C for 4 h, whereupon the
solvents were removed under reduced pressure. The resulting
residue was processed with chloroform in the usual way, and
the crude product was purified by dry silica gel chromatogra-
phy with 100% chloroform to yield 0.014 g (68%) of N-
acetylslaframine: mp 138 °C (ether-pentane) (lit. 136-138
°C,6h 138-140 °C,6o 139-141 °C,6i 140-141 °C6k); [R]20D -11.8
(c 1.3, ethanol) (lit. -10,6s -11.2,6i -12.9,6r -13.5,6q -14.6,6k
(1S,8a S)-6-(Hyd r oxyim in o)octa h yd r oin d olizin -1-yl Ac-
eta te (12b). A solution of 0.034 g (0.17 mmol) of keto acetate
12a and 0.040 g (0.58 mmol) of hydroxylamine hydrochloride
in 0.780 mL of 2:1 ethanol-pyridine was refluxed for 4 h,
whereupon the solvents were evaporated under reduced pres-
sure, and the crude reaction product was isolated with dichlo-
romethane in the usual way. Purification of this material by
dry silica gel chromatography with 0-80% methanol in ether
furnished 0.026 g (71%) of oxime 12b, as a 3:1 mixture of the
syn and anti isomers: IR 3312, 1730, 1676, 1118 cm-1 1H
;
NMR (200 MHz), major isomer: δ 1.45-1.94 (m, 4 H), 2.03 (s,
3 H), 2.08-2.42 (m, 3 H), 2.64 (d, J ) 12.3 Hz, 1 H), 3.19 (t, J
) 8.2 Hz, 1 H), 3.36-3.52 (m, 1 H), 3.65 (d, J ) 12.3 Hz, 1 H),
5.19-5.32 (m, 1 H), 8.00-8.30 (br s, 1 H); minor isomer: δ
1.52-2.72 (m, 9 H), 2.04 (s, 3 H), 3.21 (td, J ) 9.0, 1.3 Hz, 1
H), 4.61 (d, J ) 13.4 Hz, 1 H), 5.20-5.30 (m, 1 H); 13C NMR
(62.5 MHz, major isomer) δ 21.0 (CH3), 21.4 (CH2), 22.9 (CH2),
31.0 (CH2), 52.8 (CH2), 56.4 (CH2), 66.5 (CH), 74.1 (CH), 155.0
(C), 170.9 (C); mass spectrum (FAB) m/z 213 (MH+).
(1S,6S,8a S)-6-Am in oocta h yd r oin d olizin -1-yl Aceta te
(Sla fr a m in e, 2). A mixture of 0.033 g (0.16 mmol) of the
oximes 12b, 0.040 g of platinum oxide, and 0.20 mL of concd
HCl in 3 mL of ethanol was placed under 3 atm of hydrogen
and vigorously stirred for 6 h, after which it was filtered, and
the filtrate was concentrated at 20 °C. The residue was
dissolved in chloroform, which was washed with aqueous
sodium carbonate and brine, dried over anhyd sodium sulfate,
filtered, and then concentrated at 20 °C under reduced
pressure. The resulting crude product was purified rapidly on
silica gel with chloroform to give 0.017 g (55%) of slaframine
1
-15.7,6o -18.86h); IR 3437, 1731, 1658, 1511, 1259 cm-1; H
NMR (250 MHz) δ 1.32-2.32 (m, 9 H), 1.98 (s, 3 H), 2.07 (s, 3
H), 2.90-3.10 (m, 2 H), 4.16 (d, J ) 7.9 Hz, 1 H), 5.22 (t, J )
5.5 Hz, 1 H), 6.30 (br s, 1 H); 13C NMR (75 MHz) δ 20.6 (CH2),
21.1 (CH3), 23.5 (CH3), 29.7 (CH2), 30.5 (CH2), 43.8 (CH), 53.0
(CH2), 57.5 (CH2), 67.4 (CH), 74.8 (CH), 169.2 (C), 170.7 (C);
mass spectrum (CI) m/z 241 (MH+, 100%), 181 (18%), 121
(19%). The 1H NMR spectrum was in excellent agreement with
that of an independently prepared6i sample (spectrum kindly
provided by Professor W. H. Pearson). HRMS m/e calcd for
C
12H20N2O3 (M+) + H: 241.1552. Found: 241.1569.
Ack n ow led gm en t. We are most thankful to Dr. A.
Durif, Dr. M-T. Averbuch, and Dr. C. Philouze for the
X-ray structure determination, Ms. M-L. Dheu-Andries
for the molecular modeling study, Dr. C. Bosso and Ms.
D. Forest for the mass spectra, and Professors C. Harris,
D. H. Hua, W. H. Pearson, and H. Wasserman for
comparison spectra. A fellowship from the Danish
Research Academy to M. O. R. and financial support
from the CNRS (UMR 5616) and the Universite´ J oseph
Fourier are gratefully acknowledged.
2, as an unstable oil that darkens in air: IR 3363, 1737 cm-1
;
1H NMR (500 MHz) δ 1.42-1.62 (m, 1 H), 1.62-1.87 (m, 5 H),
1.94-2.10 (m, 1 H), 2.05 (s, 3 H), 2.12 (dd, J ) 11.4, 1.9 Hz, 1
H), 2.16-2.32 (m, 1 H), 2.87-3.15 (m, 4 H), 3.17 (br s, 1 H),
5.16-5.25 (m, 1 H); mass spectrum (FAB) m/z 199 (MH+), 185,
93. The 1H NMR spectrum was in excellent agreement with
J O0005621