Asymmetric synthesis of cis-5-substituted pyrrolidine 2-phosphonates using metal carbenoid NH insertion and δ-amino β-ketophosphonates

Article abstract of DOI:10.1021/ol048157+

(Chemical equation presented) Cis-5-substituted pyrrolidine phosphonates, proline surrogates, are prepared by a highly stereoselective intramolecular metal carbenoid N-H insertion from a sulfinimine-derived δ-amino α-diazo β-ketophosphonate.

Full text of DOI:10.1021/ol048157+

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4523-4525
Asymmetric Synthesis of
Cis-5-Substituted Pyrrolidine
2-Phosphonates Using Metal Carbenoid
NH Insertion and
δ-Amino
â
-Ketophosphonates
Franklin A. Davis,* Yongzhong Wu, He Xu, and Junyi Zhang
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received September 13, 2004
ABSTRACT
Cis-5-substituted pyrrolidine phosphonates, proline surrogates, are prepared by a highly stereoselective intramolecular metal carbenoid N
−H
insertion from a sulfinimine-derived -amino -diazo -ketophosphonate.
δ
r
â
Recently, we introduced the new sulfinimine-derived chiral
building block N-sulfinyl δ-amino â-ketophosphonate 1 and
reported its utility, using Horner-Wadsworth-Emmons
(HWE) chemistry, for the asymmetric synthesis of â-amino
ketodienes 2 (Scheme 1).1,2 With ring-closing metathesis, the
for the asymmetric synthesis of antiviral and anticancer
carbocyclic nucleosides.2 We describe here the application
of 1 to the highly efficient asymmetric synthesis of cis-5-
substituted pyrrolidine 2-phosphonates 4 and the first ex-
ample of an intramolecular NH carbenoid insertion from an
R-diazophosphonate.
R-Amino phosphonic acids have found widespread use as
surrogates and structural analogues of R-amino acids.3 For
these reasons, and the fact that chirality is a central issue
for biologically active molecules, the enantioselective syn-
thesis of R-amino phosphonic acids and their derivatives is
an important objective. In this regard, the highly diastereo-
selective addition of metal phosphites to sulfinimines (N-
sulfinyl imines) is a particularly attractive method for the
asymmetric synthesis of diversely substituted R-amino phos-
phonates including cyclic examples.4-6 Catalyzed by metals,
intramolecular NH insertion reactions within R-diazoketones
Scheme 1
(1) For reviews on the syntheses and applications of sulfinimine-derived
chiral building blocks, see: Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron
2004, 60, 8003.
(2) Davis, F. A.; Wu, Y. Org. Lett. 2004, 6, 1269.
(3) For reviews, see: (a) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur,
Silicon 1991, 63, 193. (b) Seto, H.; Kuzuyama, T. Nat. Prod. Rep. 1999,
16, 589. (c) Aminophosphonic and Aminophosphinic Acids. Chemistry and
Biological ActiVity; Kukhar, V. P., Hudson, H. R., Eds.; Wiley: Chichester,
UK, 2000.
amino ketodienes were transformed to (R)-(+)-4-amino-
cyclopentenone derivatives 3, which are key building blocks
10.1021/ol048157+ CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/04/2004

and δ-amino R-diazo â-ketoester have been used to prepare
a variety of nitrogen heterocycles, including the asymmetric
synthesis of cis-5-substituted prolines.7-9 However, there is
no comparable report of this protocol being used to prepare
5-substituted pyrrolidine 2-phosphonates.10,11
N-Sulfinyl δ-Amino R-Diazo â-Ketophosphonates. The
requisite enantiopure N-sulfinyl δ-amino â-ketophosphonates
6 were prepared, as previously described, by treatment of
the corresponding N-sulfinyl â-amino esters 5 with 5.0 equiv
of the lithium dimethyl methylphosphonate (Scheme 2).2
Table 1. Isolated Yields of Phosphonatesa
entry
R
6
7
8
9 (cis/trans)b 12 13
4
1
2
3
4
5
a: Ph
84 90 83
68 (81:19)
65 (92:8)
88 (96:4)
79 (95:5)
84 (99:1)
81 93 81
b: CHdCH2 83 87 83
c: Me
d: n-Bu
e: t-Bu
88 80 85
93 83 91
80 87 85
88 90 68
76 85 86
76 85 70
a Isolated yield of isomer mixture. b Determined by 31P and 1H NMR
on the crude reaction mixture.
Scheme 2
benzenesulfonyl azide and Et3N, similar treatment of 7
resulted in a very slow reaction.7-9 With 5 equiv of the
sulfonyl azide, the process required more than 16 h for
completion and the product was extremely tedious to isolate.
With Et3N and 4-acetamido-benzenesulfonyl azide (4-
ABSA),12 the process required only 2 equiv and 16 h for
completion, but again the product was difficult to purify.
The optimum combination of reagents proved to be 0.99
equiv of 4-ABSA (commercially available) with NaH as the
base, which afforded the diazo compounds 8 in 1 h in good
to excellent yields (83-91%, Table 1). The byproduct,
4-acetamidobenzsulfonamide, precipitated from the CHCl3
solution and was removed by filtration. The R-diazo com-
pounds were purified by chromatography (Scheme 2).
With the R-diazophosphonates in hand, treatment with 4
mol % Rh2(OAc)4 in DCM for 16 h at 35 °C afforded the
corresponding 3-oxo pyrrolidine phosphonates 9 in 65-88%
isolated yield (Table 1). The cis:trans ratio, determined by
31P and 1H NMR on the crude reaction mixtures, varied from
a low of 81:19 for (2R,5R)-9a (R ) Ph) to a high of >99:1
for (2R,5R)-9e (R ) t-Bu) (Table 1, entries 1 and 5).
Intramolecular cyclopropanation is often observed in the
metal carbenoid reactions when suitably positioned vinyl
substituent is present.12c The fact that such products were
not detected in the decomposition of diazophosphonate (R)-
8b (R ) CH2dCH) suggests that intramolecular NH insertion
is much faster than cyclopropanation.
Chromatography followed by Kugelrohr distillation to re-
move the excess dimethyl methylphosphonate afforded 6 in
good to excellent yields (80-93%). Next, the sulfinyl group
was removed with TFA/MeOH and replaced with a Boc
group, affording 7 in good to excellent yields (Table 1).
Conversion of 7 to the R-diazo compounds 8 proved to
be more difficult. While δ-amino â-ketoesters were readily
converted to their R-diazo derivatives with 4-carboxy-
The stereochemistry in 9a and 9d was determined by NOE
experiments. The enhanced signals observed between the Ph
and P(O)(OMe)2 protons and between the C-2 (H) and C-5
(H) protons argue strongly for their cis relationship. Similar
results were observed for metal carbenoid NH insertion in
δ-amino R-diazo â-ketoesters.7-9
The mechanisms for metal carbenoid insertion into a CH
bond is generally thought to be concerted.13,14 The situation
for metal carbenoid insertion into polar NH bonds is less
clear, but stepwise mechanisms involving ylides have been
(4) R-Amino Phosphonates. (a) Lefebvre, I. M.; Evans, S. A., Jr. J.
Org. Chem. 1997, 62, 7532. (b) Mikolajczyk, M.; Lyzwa, P.; Drabowicz,
J. Tetrahedron: Asymmetry 1997, 8, 3991. (c) Davis, F. A.; Lee, S.; Yan,
H.; Titus, D. D. Org. Lett. 2001, 3, 1757. (d) Mikolajczyk, M.; Lyzwa, P.;
Drabowicz, J. Tetrahedron: Asymmetry 2002, 13, 2571. (e) Davis, F. A.;
Prasad, K. R. J. Org. Chem. 2003, 68, 7249.
(5) Aziridine 2-Phosphonates. (a) Davis, F. A.; McCoull, W. Tetrahe-
dron Lett. 1999, 40, 249. (b) Davis, F. A.; McCoull, W.; Titus, D. D. Org.
Lett. 1999, 1, 1053. (c) Davis, F. A.; Wu, Y.; Yan, H.; Prasad, K. R.;
McCoull, W. Org. Lett. 2002, 4, 655. (d) Davis, F. A.; Wu, Y.; Yan, H.;
McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68, 2410. (e) Davis, F.
A.; Ramachandar, T.; Wu, Y. J. Org. Chem. 2003, 68, 6894.
(6) Cyclic R-Amino Phosphonates. Davis, F. A.; Lee, S. H.; Xu, H. J.
Org. Chem. 2004, 69, 3774.
(7) For leading references, see: Davis, F. A.; Fang, T.; Goswami, R.
Org. Lett. 2002, 4, 1599.
(8) Davis, F. A.; Yang, B.; Deng, J. J. Org. Chem. 2003, 68, 5147.
(9) Davis, F. A.; Deng, J. Tetrahedron 2004, 60, 5111.
(10) Intramolecular CH insertion has been used to prepare â-lactam
3-phosphonates and γ-lactam 4-phosphonates in low yields as mixtures of
isomers. Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2003, 3798.
(11) Intermolecular N-H insertion using metal carbenoids has been
reported. For leading references, see: (a) Moody, C. J.; Morfitt, C. N.;
Slawin, A. M. Z. Tetrahedron: Asymmetry 2001, 12, 1657. (b) Nakamura,
Y.; Ukita T. Org. Lett 2002, 4, 2317.
(12) (a) Nozaki, H.; Takaya, H.; Moriuti, S.; Noyori, R. Tetrahedron
1968, 24, 3655. (b) Davies, H. M. L.; Cantrell, W. R.; Romines, K. R.;
Baum, J. S. Org. Synth. 1992, 70, 93. (c) Honma, M.; Sawada, T.; Fujisawa,
Y.; Utsugi, M.; Watanabe, H.; Umino, A.; Matsumura, T.; Hagihara, T.;
Takano, M.; Nakada, M. J. Am. Chem. Soc. 2003, 125, 2860.
(13) Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.;
Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115,
958.
(14) (a) Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem. Soc.
1996, 118, 547. (b) Taber, D. F.; Malcolm, S. C. J. Org. Chem. 1998, 63,
3717.
4524
Org. Lett., Vol. 6, No. 24, 2004

would afford the all-cis 2,3,5-trisubstituted pyrrolidine phos-
phonate.9
Scheme 3
Removal of the 3-oxo group in 9 is required to give the
cis-5-substituted pyrrolidines 4. This was efficiently ac-
complished by conversion of 9 into the corresponding enol
phosphonates 12 by treatment with NaH, 18-crown-6, and
diethyl chlorophosphonate (Scheme 5, Table 1). Hydrogena-
proposed (Scheme 3).15 The somewhat lower selectivity
noted for the NH insertion reactions of 8 compared to
δ-amino R-diazo â-ketoesters may be related to the geometry
and much larger size of the phosphonate versus carboxylate.
Here the phosphonate may compete with the metal carbenoid
group for the axial position in TS-1 and TS-2, leading to
the major cis and minor trans products. Alternatively,
epimerization at C-2 could occur if proton transfer in the
metal species is slower in the phosphonate. Another pos-
sibility is epimerization on chromatographic work, but this
was not detected in the purification of 9a.16
Scheme 5
The chemistry of the new 3-oxo pyrrolidine phosphonates
9 was briefly explored. When (2R,5R)-(-)-9e (R ) t-Bu)
was treated with TFA at room temperature and stirred in
DCM with silica gel for 24 h, dimethyl 5-tert-butyl-3-
hydroxy-1H-pyrrole 2-phosphonate (10) was obtained in 61%
isolated yield (Scheme 4). The structure of the 2-phosphono-
tion (Pt/C, H2) gave 13, which on removal of the Boc group
with TFA afforded the cis-5-substituted pyrrolidines 4. The
overall yields were good to excellent (Table 1). The
assignment of a cis relationship for the C-2 and C-5
substituents follows from the method of synthesis (hydro-
genation) and NOE experiments on 4 where H-2 and H-5
showed a strong enhancement.
Scheme 4
In summary, new methodology has been introduced for
the asymmetric synthesis of cis-5-substitiuted pyrrolidine
2-phosphonates 4, important proline surrogates. The intra-
molecular metal carbenoid NH insertion reaction from a
R-diazophosphonate, the first such example, proved to be
highly stereoselective and afforded the cis product. These
R-diazophosphonates are prepared from N-sulfinyl δ-amino
â-ketophosphonates, a new sulfinimine-derived chiral build-
ing block.
pyrrole was supported by its lack of optical activity and the
downfield shifts of carbons in the 13C NMR spectra to δ
149-158 ppm. These compounds may be useful scaffolds
for combinatorial library generation, and our procedure also
represents a novel entry to functionalized derivatives of this
class of aromatic heterocycles.17 Luche reduction (NaBH4/
CeCl3) of (2R,5S)-(-)-9d (R ) n-Bu) gave alcohol (2R,3R,5S)-
(-)-11 in 89% yield as a single isomer. Hydride addition is
expected to add from the least hindered direction, which
Acknowledgment. This work was supported by a grant
from the National Institute of General Medical Sciences
57870.
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.
OL048157+
(15) For a review of the relevant literature, see: Nakamura, E.; Yoshikai,
N.; Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.
(17) (a) Griffin, C. E.; Peller, R. P.; Peters, Joan A. J. Org. Chem. 1965,
30, 91. (b) Quin, L. D.; Marsi, B. G. J. Am. Chem. Soc. 1985, 107, 3389.
(c) Palacios, F.; Ochoa de Retana, A. M.; Martnez de Marigorta, E.;
Rodrguez, M.; Pagalday, J. Tetrahedron 2003, 59, 2617.
(16) When (-)-9d (R ) n-Bu) was treated with DBU in acetonitrile for
16 h, a 55:45 mixture of cis:trans isomers resulted, as determined by 31P
1
and H NMR.
Org. Lett., Vol. 6, No. 24, 2004
4525