Asymmetric synthesis of cis- and trans-2,5-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates: Synthesis of (+)-preussin and analogs

Article abstract of DOI:10.1021/ol800255r

(Chemical Equation Presented) Pyrrolidine enones, derived from 3-oxo pyrrolidine 2-phosphonates and a HWE reaction with aldehydes, on Luche reduction give pyrrolidine allylic alcohols. The alcohols on hydrogenation (Pd/H ₂) give cis-2,5-disubstituted pyrrolidines and on treatment with TFA-NaBH₃CN undergo a hydroxy directed reduction to trans-2,5-disubstituted pyrrolidines.

Full text of DOI:10.1021/ol800255r

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1433-1436
Asymmetric Synthesis of cis- and
trans-2,5-Disubstituted Pyrrolidines from
3-Oxo Pyrrolidine 2-Phosphonates:
Synthesis of (+)-Preussin and Analogs
Franklin A. Davis,* Junyi Zhang, Hui Qiu, and Yongzhong Wu
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received February 4, 2008
ABSTRACT
Pyrrolidine enones, derived from 3-oxo pyrrolidine 2-phosphonates and a HWE reaction with aldehydes, on Luche reduction give pyrrolidine
allylic alcohols. The alcohols on hydrogenation (Pd/H2) give cis-2,5-disubstituted pyrrolidines and on treatment with TFA-NaBH3CN undergo
a hydroxy directed reduction to trans-2,5-disubstituted pyrrolidines.
Cis- and trans-disubstituted pyrrolidines are found in phar-
maceuticals and in numerous natural products.1 They are also
valuable chiral building blocks for the synthesis of more
complex derivatives, including the pyrrolizidine and indolizi-
dine alkaloids.1 Enantiopure pyrrolidines are also useful chiral
auxiliaries and ligands for asymmetric syntheses.2 Although
many methods have been developed for their preparation,
the continuing challenge is to design more concise methods,
principally enantiopure examples that have ring functionality
that can provide access to more complex derivatives.3 This
is particularly true for trans-2,5-disubstituted pyrrolidines for
which there are few general methods of preparation in
enantiopure form.4 In this context, we describe general
methodology for the asymmetric synthesis of functionalized
cis- and trans-2,5-disubstituted pyrrolidines from a common
intermediate derived from 3-oxo pyrrolidine 2-phosphonate,
a sulfinimine-derived chiral building block.5
Earlier we reported an efficient asymmetric synthesis of
3-oxo pyrrolidine 2-phosphonates such as (2R,5R)-(+)-1,
which involved a highly stereoselective intramolecular metal
carbenoid N-H insertion from a δ-amino R-diazo â-keto-
phosphonate.6 These building blocks undergo the Horner-
Wadsworth-Emmons (HWE) reaction with various alde-
hydes, such as benzaldehyde, to give the corresponding
enones in good yield (Scheme 1).7 Enone (5R)-(-)-2 proved
to be relatively unstable and decomposed on purification.
Hydrogenation of (-)-2 provided a good yield of the cis-
2,5-disubstituted 3-oxo pyrrolidine (-)-3, and this methodol-
(1) (a) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005,
68, 1556. (b) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435 and references
cited therein. (c) Leclercq, S.; Braekman, J. C.; Daloze, D.; Pasteels, J. M.
Prog. Chem. Org. Nat. Prod. 2000, 79, 115. (d) Daly, J. W.; Garraffo, H.
M.; Spende, T. F. In Alkaloids: Chemical and Biological PerspectiVes;
Pelletier, S. W., Ed.; Pergamon: New York, 1999; Vol 13, Chapter 1.
(2) Chiral auxiliaries or ligands: (a) Kim, B. H.; Lee, H. B.; Hwang, J.
K.; Kim, Y. G. Tetrahedron: Asymmetry 2005, 16, 1215. (b) Nyerges, M.;
Bendell, D.; Arany, A.; Hibbs, D. E.; Coles, S. J.; Hursthouse, M. D.;
Groundwater, P. W.; Meth-Cohn, O. Synlet 2003, 947. (c) Fache, F.; Schulz,
E.; Tommasino, M. L.; Lemaire, M. Chem. ReV. 2000, 100, 2159. (d) Sweet,
J. A.; Cavallari, J. M.; Price, W. A.; Ziller, J. W.; McGrath, D. V.
Tetrahedron: Asymmetry 1997, 8, 207. (e) Whitesell, J. K. Chem. ReV.
1989, 89, 1581.
(4) For leading references to the asymmetric synthesis of trans-2,5-
disubstituted pyrrolidines, see: Davis, F. A.; Song, M.; Augustine, A. J.
Org. Chem. 2006, 71, 2779.
(5) Davis, F. A.; Wu, Y.; Xu, H.; Zhang, J. Org. Lett. 2004, 6, 4523.
(6) Davis, F. A.; Xu, H.; Wu, Y.; Zhang, J. Org. Lett. 2006, 8, 2273.
(3) For leading references to the asymmetric synthesis of pyrrolidines,
see: Vasse, J.-L.; Joosten, A.; Denhez, C.; Szymoniak, J. Org. Lett. 2005,
7, 4887.
10.1021/ol800255r CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/11/2008

the rearrangement of (-)-4 to (-)-3 is acid catalyzed is the
fact that hydrogenation in the presence of Et3N gives only
the pyrrolidine alcohol (+)-6 (Scheme 2).
Scheme 1
With the crude allylic alcohol, (-)-4, in hand, we next
explored its reduction with various hydrogenation catalysts.
Disappointingly, hydrogenation in CH2Cl2 at various pres-
sures of H2 (1-3 atm) with Ir(COD)py(PCy3)PF6 (Crabtree)
and Rh[(NBD)(DIPHOS-4)]BF4 catalysts either resulted in
no reaction or decomposition. Gratifyingly, reduction of
crude (-)-4 with sodium cyanoborohydride in the presence
of trifluoroacetic acid (TFA) afforded the trans-2,5-disub-
stituted pyrrolidine (+)-7 in 65% yield as a single isomer
for the two-step sequence (Scheme 3).9 These results are
ogy was employed in the asymmetric synthesis of the
Pharaoh’s ant pheromone pyrrolidine 225C.6
Scheme 3
The utility of these new pyrrolidine enone chiral building
blocks could be greatly expanded if there was a way to
transform them into trans-2,5-disubstituted pyrrolidines. We
reasoned that this might be accomplished via a hydroxy-
directed hydrogenation of the pyrrolidine exocyclic double
bond in (-)-2.8 To this aim, a Luche reduction of (-)-2 with
CeCl3‚7H2O/NaBH4 gave the crude allylic alcohol (-)-4 in
83% yield. Unexpectedly, on standing in CDCl3 over 8 h,
this material rearranged to 3-oxo pyrrolidine (-)-3 (Scheme
2). We suggest that under acidic conditions, protonation of
Scheme 2
consistent with hydride being delivered intramolecularly to
the iminium ion via the hydroxyl group as shown in 8
(Scheme 3).10 To confirm our stereochemical assignments
and to illustrate the utility of this new methodology we report
the concise asymmetric syntheses of (+)-preussin and its
trans and p-methoxyphenyl analogs.
(+)-Preussin and Analogs. The alkaloid (+)-preussin
(17a, Scheme 5) is a powerful antifungal agent,11 which also
exhibits antiviral activity12 as well as inducing apoptosis in
(7) For recent examples of sulfinimine-derived chiral building blocks,
see (a) â-Amino ketones: Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005,
127, 8398. (b) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413. (c) syn-
and anti-2,3-Diamino esters: Davis, F. A.; Deng, J. Org. Lett. 2005, 7,
621. (d) Davis, F. A.; Zhang, Y.; Li, D. Tetrahedron Lett. 2007, 48, 7838.
(e) δ-Amino â-keto esters enaminones: Davis, F. A.; Zhang, J.; Li, Y.;
Xu, H.; DeBrosse, C. J. Org. Chem. 2005, 70, 5413. (f) R-Amino 1,3-
dithioketals (R-amino ketones and aldehydes): Ramachandar, T.; Chai, J.;
Skucas, E. Tetrahedron Lett. 2006, 47, 2743. (g) Davis, F. A.; Ramachandar,
T. Tetrahedron Lett. 2008, 49, 870. (h) δ-Amino â-ketophosphonates: see
reference 5. (i) δ-Amino â-ketoesters: Davis, F. A.; Deng, J. Tetrahedron
2004, 60, 5111. (j) 2H-Aziridne 2-carboxylates: Davis, F. A.; Liu, H.; Zhou,
P.; Fang, T.; Reddy, G. V.; Zhang, Y. J. Org. Chem. 1999, 64, 7559. (k)
Aziridine 2-phosphonates: Davis, F. A.; Ramachandar, T.; Wu, Y. J. Org.
Chem. 2003, 68, 6894. (l) 2H-Azirine 2-carboxylates: Davis, F. A.; Liu,
H.; Liang, C.-H.; Reddy, G. V.; Zhang, Y.; Fang, T.; Titus, D. D. J. Org.
Chem. 1999, 64, 8929. (m) 2H-Azirine 3-Phosphonates: Davis, F. A.; Wu,
Y.; Yan, H.; Prasad, K. R.; McCoull, W. Org. Lett. 2002, 4, 655. (n) 2H-
Azirine 3-carboxylates: Davis, F. A.; Deng, J. Org. Lett. 2007, 9, 1707.
(8) (a) Evans, D. A.; Morrissey, M. M. Tetrahedron Lett. 1984, 25, 4637.
(b) Del Valle, J. R.; Goodman, M. J. Org. Chem. 2003, 68, 3923.
(9) Because of the acid sensitivity of the allylic alcohol it was briefly
dried (Na2SO4) and used immediately in the next step without purification.
(10) (a) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560. (b) Halab, L.; Belec, L.; Lubell, W. D. Tetrahedron
2001, 57, 6439.
(-)-4 results in formation of an iminium ion 5 that rearranges
to the more thermodynamic stable product 3-oxo pyrrolidine
(-)-3. Hydrogenation of (-)-4 (Pd-C/H2) afforded both
(+)-6 (40%) and (-)-3 (30%), indicating that rearrangement
is competing with reduction. Consistent with the idea that
1434
Org. Lett., Vol. 10, No. 7, 2008

Scheme 4
Scheme 5
enones (-)-15a and (+)-15b in 85 and 71% yield, respec-
tively (Scheme 4).
With pyrrolidine enones (-)-15a and (+)-15b in hand,
reduction with Pd-C/H2/Et3N afforded cis-2,5-disubstituted
3-oxo pyrrolidines (+)-16a and (+)-16b in 70 and 78%
isolated yields, respectively (Scheme 5). Reduction of (+)-
15 first with 6 equiv of LiAlH4 in refluxing ether for 16 h
followed by an additional 6 equiv of LiAlH4 and refluxing
for 5 h afforded (2S,3S,5R)-(+)-preussin (17a) and the
p-methoxyphenyl analog (2S,3S,5R)-(+)-17b in 83 and 70%
yields, respectively.7i This one-pot reduction sequence ste-
reoselectively transforms the 3-oxo group into the cis-alcohol
and the N-Boc to an N-methyl group (Scheme 5). Our
asymmetric synthesis of (+)-preussin (17a), 9 steps (7
operations) in 28% overall yield from sulfinimine (-)-9, is
one of the most efficient to date.
certain human cancer cell lines.13 For these reasons, (+)-
17a has been a popular target for methods development with
more than 22 different routes, of varying degrees of
efficiency, reported.14 However, as pointed out by Wolfe,
nearly all of these syntheses use phenylalanine as the source
of the phenyl group in (+)-17a and as such there are no
reported analogues of preussin involving modification of the
aryl moiety.14 Furthermore, the asymmetric synthesis of
trans-preussin analogs have not been described.15
To prepare the trans analogs of preussin, the 3-oxo group
in (5R)-15 was reduced (Luche) to the cis-allylic alcohol 18
Scheme 6
The common intermediate in our synthesis of (+)-preussin
(17a) and its analogs is (+)-3-oxo pyrrolidine 2-phosphonate
(2S,5R)-(+)-14, which was prepared in six steps (five
operations) in 54% overall yield from sulfinimine (R)-
(-)-9 using methodology developed earlier.6 The HWE
reaction of (+)-14 with benzaldehyde or p-methoxybenz-
aldehyde using NaH or DBU-LiCl afforded the crude
(11) (a) Schwartz, R. E.; Liesch, J.; Hensens, O.; Zitano, L.; Honeycutt,
S.; Garrity, G.; Fromtling, R. A.; Onishi, J.; Monaghan, R. J. Antibiot. 1988,
1774. (b) Johnson, J. H.; Phillipson, D. W.; Kahle, A. D. J. Antibiot. 1989,
1184.
(12) Achenbach, T. V.; Slater, P. E.; Brummerhop, H.; Bach, T.; Muller,
R. Antimicrob. Agents Chemother. 2000, 44, 2794.
(13) Kinzy, T. G.; Harger, J. W.; Carr-Schmid, A.; Kwon, J.; Shastry,
M.; Justice, M.; Dinman, J. D. Virology 2002, 300, 60.
(14) Bertrand, M. B.; Wolfe, J. P. Org. Lett. 2006, 8, 2353 and references
cited therein.
(15) A nonstereoselective synthesis of all eight isomers of preussin,
separated by chiral HPLC, has been described. Okue, M.; Watanabe, H.;
Kasahara, K.; Yoshida, M.; Horinouchi, S.; Kitahara, T. Biosci. Biotechnol.
Biochem. 2002, 66, 1093.
Org. Lett., Vol. 10, No. 7, 2008
1435

which was in turn treated with TFA-NaBH3CN to give
corresponding trans-2,5-disubstituted pyrrolidine alcohols
(-)-19 in moderate yields (Scheme 6). Attempts to reduce
the N-Boc groups in (-)-19 to N-Me groups by refluxing
with LiAlH4 were unsuccessful. Increased steric hindrance
at the N-Boc site, as a consequence of the trans relationship
of the 2,5-substitutents, is undoubtedly responsible for this.
Reductive amination solved this problem and afforded the
trans analogs (-)-20a and (-)-20b in 70 and 80% yields,
respectively.
In summary, sulfinimine-derived enantiopure 3-oxo pyr-
rolidine 2-phosphonates undergo the HWE reaction with
aldehydes to give pyrrolidine enones that on Luche reduction
give the pyrrolidine allylic alcohols. Hydrogenation of the
allylic alcohol afforded the cis-2,5-disubstituted pyrrolidines.
Pyrrolidine allylic alcohols on treatment with TFA-NaBH3CN
undergo a novel intramolecular hydroxy directed reduction
resulting in trans-2,5-disubstituted pyrrolidines. This new
methodology was employed in the asymmetric synthesis of
the potent antifungal agent (+)-preussin and in the first
asymmetric syntheses of its trans analogue and analogues
in which the preussin aryl moiety has been structurally
modified.
Acknowledgment. This work was supported by grants
from the National Institute of General Medicinal Sciences
(GM57878 and GM51982) and Boehringer Ingelheim Phar-
maceuticals.
Supporting Information Available: Experimental details
1
and H, 13C, and 31P NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL800255R
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Org. Lett., Vol. 10, No. 7, 2008