Asymmetric synthesis of polyfunctionalized pyrrolidines from sulfinimine-derived pyrrolidine 2-phosphonates. Synthesis of pyrrolidine 225C

Article abstract of DOI:10.1021/ol060521c

The Horner-Wadsworth-Emmons reaction of aldehydes with sulfinimine-derived 3-oxo pyrrolidine phosphonates represents a new method for the asymmetric synthesis of ring-functionalized cis-2,5-disubstituted 3-oxo pyrrolidines.

Full text of DOI:10.1021/ol060521c

ORGANIC
LETTERS
2006
Vol. 8, No. 11
2273-2276
Asymmetric Synthesis of
Polyfunctionalized Pyrrolidines from
Sulfinimine-Derived Pyrrolidine
2-Phosphonates. Synthesis of
Pyrrolidine 225C
Franklin A. Davis,* He Xu, Yongzhong Wu, and Junyi Zhang
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received March 2, 2006
ABSTRACT
The Horner−Wadsworth−Emmons reaction of aldehydes with sulfinimine-derived 3-oxo pyrrolidine phosphonates represents a new method
for the asymmetric synthesis of ring-functionalized cis-2,5-disubstituted 3-oxo pyrrolidines.
Enantiopure polyfunctionalized pyrrolidines are found in
pharmaceuticals and in numerous natural products.1 They
are also valuable chiral building blocks for the synthesis of
more complex derivatives, including the pyrrolizidine and
indolizidine alkaloids.1 Enantiopure pyrrolidines are also
useful chiral auxiliaries and ligands for asymmetric synthe-
ses.2 Although many methods have been reported for the
synthesis of pyrrolidines, the continuing challenge is to
design more concise methods, particularly enantiopure
examples that have ring functionality that can provide access
to more complex derivatives.3
and the development of related methods for the enantiose-
lective synthesis of amine derivatives, particularly nitrogen
heterocycles.4,5 We require these building blocks to be easily
prepared in both enantiomerically pure forms and to provide
entry to diverse classes of organonitrogen compounds with
a minimum of chemical manipulation and protecting-group
chemistry. In this context, we wish to report that 3-oxo
pyrrolidine 2-phosphonates and the Horner-Wadsworth-
Emmons (HWE) reaction afford enantiopure cis-2,5-disub-
stituted 3-oxo pyrrolidines that are readily elaborated to
functionalized pyrrolidines suitable for further elaboration.
Earlier, we introduced an efficient asymmetric synthesis
of cis-2,5-disubstituted pyrrolidine phosphonates 4, proline
surrogates, via the highly stereoselective intramolecular metal
Recent efforts in our group have focused on the asym-
metric syntheses of sulfinimine-derived chiral building blocks
(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
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. Synlett 2003, 947. (c) Fache, F.;
Schultz, E.; Tomasino, 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.
(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.
(4) For recent reviews on the chemistry of sulfinimines, see: (a) Zhou,
P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003. (b) Ellman, J.
A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (c)
Senanayake, C. H.; Krishnamurthy, D.; Lu, Z.-H.; Han, Z.; Gallou, I.
Aldrichimica Acta 2005, 38, 93.
(5) For reviews on sulfine-derived chiral building blocks, see: (a) Davis,
F. A.; Yang, B.; Deng, J.; Wu, Y.; Zhang, Y.; Rao, A.; Tang, T.; Goswami,
R.; Prasad, K. R.; Nolt, B. M.; Anilkumar, G. Phosphorus, Sulfur Silicon
2005, 180, 1109.
10.1021/ol060521c CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/29/2006

carbenoid N-H insertion from a δ-amino R-diazo â-keto-
phosphonate 2 (Scheme 1). The resulting 3-oxo pyrrolidine
Scheme 2
Scheme 1
Next, treatment of (+)-5 with NaH followed by benzal-
dehyde produced the 2-benzylidene pyrrolidine (R)-(-)-11a
in over 90% yield following purification by flash chroma-
tography (Scheme 3). It was noted that enone (-)-11a slowly
phosphonates 3 were elaborated in three steps to 4.5e The
R-diazo compounds 2 were readily prepared from the
corresponding sulfinimine-derived δ-amino â-ketophospho-
nates 1, by treatment with 4-acetamidobenzenesulfonyl azide
(4-ABSA).6 The phosphonates 1 are prepared in three steps
from an N-sulfinyl â-amino ester. We reasoned that 3-oxo
pyrrolidine phosphonates 3 would be good substrates for the
asymmetric synthesis of 2,5-disubstituted pyrrolidines pro-
vided that the corresponding C-2 â-ketophosphonate anion
is sufficiently reactive to be alkylated and/or to participate
in the HWE reaction with aldehydes.
Scheme 3
Treatment of dimethyl (2R,5R)-(+)-N-(tert-butoxycarbo-
nyl)-3-oxo-5-pyrrolidine 2-phosphonate (5) with NaH in the
presence of 18-crown-6 followed by reaction with io-
domethane or benzyl bromide resulted in complex mixtures.
However, with allyl bromide, a 35% isolated yield of the
quaternary phosphonate (2R,5R)-(+)-6 was obtained as a
mixture of rotamers (Scheme 2). A single pyrrolidine
phosphonate (+)-7 was obtained on removal of the N-Boc
group with TFA. Hydrogenation, Pd-C/H2, of (+)-7 resulted
in ring opening at the benzylic position to give the stable
acyclic R-amino ketone phosphonate (R)-(-)-8 in 95% yield.
R-Amino ketones are notoriously unstable entities even when
suitably N-protected, so it is likely that steric hindrance,
provided by the large phosphonate group, inhibits undesirable
intermolecular reactions of this moiety in (-)-8.7
decomposed after standing for ca. 6-10 h to uncharacter-
izable materials and was therefore used in subsequent
reactions within this time period. Similar results were
observed for the HWE reaction of 3-oxo pyrrolidine phos-
phonates 9 and 10 (Table 1).
Reaction of (+)-5 with n-butrylaldehyde using NaH or
t-BuOK as the base resulted in low yields of the correspond-
ing enone 11b (Table 1, entries 4 and 5). This is probably
due to the presence of R-protons in the aldehyde, which could
promote aldol-type reactions. The use of weaker bases
such as DBU and Et3N in the presence of lithium salts has
been reported to be an effective system for the HWE
reaction.8 Indeed, the yield of 11b improved from 26-32%
to 69-70% with LiCl in DBU or Et3N (Table 1, entries 6
and 7). Steric factors, caused by the large tert-butyl group
in (+)-10 (R ) t-Bu), are likely responsible for our inability
to effect the HWE reaction with benzaldehyde (Table 1, entry
11).
(6) 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) syn- and anti-2,3-diamino esters: Davis, F. A.; Deng, J.
Org. Lett. 2005, 7, 621. (c) δ-Amino â-keto esters enaminones: Davis, F.
A.; Zhang, J.; Li, Y.; Xu, H.; DeBrosse, C. J. Org. Chem. 2005, 70, 5413.
(d) R-Amino 1,3-dithioketals (R-amino ketones and aldehydes): Ram-
achandar, T.; Chai, J.; Skucas, E. Tetrahedron Lett. 2006, 47, 2743 and ref
11. (e) δ-Amino â-ketophosphonates: Davis, F. A.; Wu, Y.; Xu, H.; Zhang,
J. Org. Lett. 2004, 6, 4523. (f) δ-Amino â-keto esters: Davis, F. A.; Deng,
J. Tetrahedron 2004, 60, 5111. (g) Aziridine 2-phosphonates: Davis, F.
A.; Ramachandar, T.; Wu, Y. J. Org. Chem. 2003, 68, 6894. (h) 2H-Azirine
3-phosphonates: Davis, F. A.; Wu, Y.; Yan, H.; Prasad, K. R.; McCoull,
W. Org. Lett. 2002, 4, 655.
(7) Davis, F. A.; Wu, Y. Org. Lett. 2004, 6, 1269.
(8) For leading references to the chemistry of R-amino ketones, see ref
5d.
2274
Org. Lett., Vol. 8, No. 11, 2006

stereochemistry of (+)-16 is based on the reasonable
assumption that hydride adds from the least hindered
direction and is supported by our earlier studies on the
synthesis of the antifungal 3-hydroxy pyrrolidine (+)-
preussin.9 3-Hydroxy pyrrolidine (+)-17 was prepared in
65% yield and obtained as a single isomer on treatment of
(-)-15 with excess methyl magnesium bromide. It is
assumed that MeMgBr adds to the carbonyl group from the
least hindered direction, and this assumption is supported
by our recent synthesis of the polyoxypeptine amino acid
segment (-)-3-hydroxy-3-methylproline.10 It is worth noting
that the rotamers of the Boc tert-butyl group in (+)-17 appear
as a broad peak between 1.47 and 1.23 ppm in the 1H NMR
and coalesce to a singlet at 50 °C.
Table 1. HWE Reaction of 3-Oxo Pyrrolidine Phosphonates
with Aldehydes
phosphonate
enone
entry
(R))
aldehyde
PhCHO
base
TEA
(% yield)a
1
2
(+)-5 (Ph)
NRb
DBU
NR
3
4
5
NaH
NaH
t-BuOK
11a (93)
11b (32)
11b (26)
n-PrCHO
6
7
8
9
LiCl/DBU 11b (69)
LiCl/Et3N 11b (70)
LiCl/DBU 11c (70)
LiCl/DBU 12a (66)
MeCHO
PhCHO
(-)-9 (n-Bu)
10
11
n-C6H13CHO LiCl/DBU 12b (75)
(+)-10 (t-Bu) PhCHO NaH NR
Having demonstrated the facile functional group manipu-
lations of cis-2,5-disubstituted 3-oxo pyrrolidines, we next
turned our attention to the asymmetric synthesis of pyrro-
lidine 225C (22) to highlight an application of our new
building block. Pyrrolidine 225C and related cis-2,5-disub-
stituted pyrrolidines have been of interest in studies of ant
venom toxins of the genus Solenopisis.11 Although trans-
2,5-disubstituted pyrrolidines are the major components of
the ant venom, their structural elucidation requires prepara-
tion of the cis isomers.12 Furthermore, cis-pyrrolidine isomers
have been detected as trail pheromones of the pharoh’s ant
Monomorium pharonis.13 Only two multistep asymmetric
syntheses of 225C have been reported.14 Hydrogenation of
alkylidene pyrrolidine (-)-12b gave the 3-oxo pyrrolidine
(-)-18, which was reduced with NaBH4 to give the alcohol
(+)-19 as a single isomer (Scheme 5). Dehydration was first
explored with I2/imidazole/Ph3P, and although it gave the
a Isolated yield. b No reaction, starting material recovered.
Hydrogenation, Pd-C/H2, of the 2-alkylidene 3-oxo pyr-
rolidines 11a, 11c, and 12a readily afforded the correspond-
ing cis-2,5-disubstituted 3-oxo pyrrolidines 13, 14, and 15
in good yield as single isomers (Scheme 4). It is reasonable
Scheme 4
1
desired 3,4-dehydropyrrolidine (-)-20 as indicated by H
NMR, it could not be satisfactorily purified. A better
procedure proved to be the conversion of the alcohol into
the mesylate with MeSO2Cl/Et3N followed by treatment with
potassium t-butoxide to give (-)-20 in 52% yield. Hydro-
genation (Pt-C/H2) and removal of the N-Boc group (TFA)
resulted in pyrrolidine 225C (22) in 84% yield for the two
steps (Scheme 5). The specific rotation of (-)-21 was -1.2,
whereas the specific rotation of pyrrolidine 225C (22) was
0. This result has also been reported by others and may be
due to the fact that the compound has nearly a meso
structure.14 All attempts to prepare the MTPA amide of 22
were unsuccessful, as also noted by Shiosaki and Rapoport.14a
In summary, a new method has been introduced for the
(9) (a) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(b) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624.
(10) Davis, F. A.; Deng, J. Tetrahedron 2004, 60, 5111.
(11) Davis, F. A.; Ramachandar, T.; Liu, H. Org. Lett. 2004, 6, 3393.
(12) (a) Leclercq, S.; Braekman, J. C.; Daloze, D.; Pasteels, J. M. The
defensive Chemistry of Ants. Prog. Chem. Org. Nat. Prod. 2000, 79, 115.
(b) See ref 1d, page 2.
(13) (a) Garraffo, H. M.; Simon, L. D.; Daly, J. W.; Spande, T. F.
Tetrahedron 1994, 50, 11329. (b) Pedder, D. J.; Fales, H. M.; Jaouni, T.;
Blum, M.; MacConnell, J.; Crewe, R. M. Tetrahedron 1976, 32, 2275.
(14) (a) Schmitz, E.; Sonenschein, H.; Grundemann, C. J. Prakt. Chem.
1980, 322, 261. (b) Ritter, R. J.; Persoons, C. J. Neth. J. Zool. 1975, 25,
261.
to assume that hydrogen is added from the least hindered
direction affording the cis isomer. This assumption was
confirmed in our synthesis of 225C (22). 3-Oxo pyrrolidines
11-15 have not previously been reported and are expected
to be useful new chiral building blocks and templates for
the asymmetric synthesis of more complex pyrrolidines. To
explore their utility in asymmetric synthesis, we briefly
examined several transformations of the 3-oxo group in these
heterocycles.
(15) (a) Shiosaki, K.; Rapoport, H. J. Org. Chem. 1985, 50, 1229. (b)
Arseniyadis, S.; Huang, P. Q.; Piveteau, D.; Husson, H.-P. Tetrahedron
1988, 44, 2457.
Luche reduction of (-)-14 gave the all cis 2,3,5-trisub-
stituted pyrrolidine (+)-16 in 80% yield (Scheme 4). The
Org. Lett., Vol. 8, No. 11, 2006
2275

Scheme 5
asymmetric synthesis of ring-functionalized pyrrolidines
Acknowledgment. This work was supported by a grant
from the National Institutes of General Medical Sciences
(GM 57870).
employing sulfinimine-derived 3-oxo pyrrolidine phospho-
nates and the Horner-Wadsworth-Emmons reaction. Re-
duction of the resulting 3-oxo alkylidene pyrrolidines affords
stereodefined cis-2,5-disubstituted 3-oxo pyrrolidines, which
are useful new building blocks for the asymmetric construc-
tion of more complex pyrrolidines. A concise asymmetric
synthesis of pyrrolidine 225C, in seven steps (six operations)
and 21% overall yield from (-)-9, illustrates the utility of
the new protocol.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060521C
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Org. Lett., Vol. 8, No. 11, 2006