Asymmetric synthesis of the carbocyclic nucleoside building block (R)-(+)-4-aminocyclopentenone using δ-amino β-ketophosphonates and ring-closing metathesis (RCM)

Article abstract of DOI:10.1021/ol049795v

Amino keto-2,7-dienes undergo ring-closing metathesis (RCM) to give 4-aminocyclopentenones, valuable intermediates in the asymmetric construction of carbocyclic nucleosides. The key amino ketodienes were prepared using δ-amino β-ketophophonates, a new sul

Full text of DOI:10.1021/ol049795v

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1269-1272
Asymmetric Synthesis of the
Carbocyclic Nucleoside Building Block
(R)-(+)-4-Aminocyclopentenone Using
δ-Amino â-Ketophosphonates and
Ring-Closing Metathesis (RCM)
Franklin A. Davis* and Yongzhong Wu
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received February 4, 2004
ABSTRACT
Amino keto-2,7-dienes undergo ring-closing metathesis (RCM) to give 4-aminocyclopentenones, valuable intermediates in the asymmetric
construction of carbocyclic nucleosides. The key amino ketodienes were prepared using δ-amino â-ketophophonates, a new sulfinimine-
derived chiral building block, and HWE chemistry.
(R)-(+)-4-Aminocyclopentenone 1 is a valuable chiral build-
ing block for the asymmetric synthesis of structurally diverse
antiviral and anticancer carbocyclic nucleosides such as
aristeromycin and noraristeromycin (Scheme 1).1 For ex-
ample, stereoselective reduction of 1 would provide the
(1S,4R)-(+)-4-aminocyclopent-2-enol derivative 2.2 Pal-
ladium(0)-catalyzed coupling reactions, via the π-allylpal-
ladium complex, are available for stereoselective introduction
of a variety of substituents at either the hydroxy or amino
positions in 2.1a For instance, Trost et al. devised methodol-
ogy for conversion of the benzoate of 2 to a carbomethoxy
group using phenylsulfonyl nitro-methane and an oxidative
Nef reaction.3 Miller and co-workers demonstrated that
nitrogen bases such as adenine could be attached with
retention of configuration via the corresponding acetate.4
Miller has also developed a procedure for replacing the
hydroxy with a carbomethoxy group.5 Similarly, the amino
group can also be replaced with a suitable nitrogen base.6
Asymmetric palladium-catalyzed desymmetrization of meso-
Scheme 1
(1) For reviews on carbocyclic nucleosides and their syntheses, see: (a)
Crimmins, M. T. Tetrahedron 1998, 54, 9229. (b) Mansour, T. S.; Storer,
R. Curr. Pharm. Des. 1997, 3, 227. (c) Marquez, V. E. In AdVances in
AntiViral Drug Design; De Clercq, E., Ed.; JAI Press: Greenwich, CT,
1966; Vol. 2, p 89. (d) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.;
Challand, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611. (e)
Borthwick, A. D.; Boggadike, K. Tetrahedron 1992, 48, 571.
(2) For related methods for the synthesis of 2, see: (a) Schaudt, M.;
Blechert, S. J. Org. Chem. 2003, 68, 2913. (b) O’Brien, P.; Towers, T. D.;
Voith, M. Tetrahedron Lett. 1998, 39, 8175.
(3) Trost, B. M.; Stenkamp, D.; Pulley, S. R. Chem. Eur. J. 1995, 1,
568.
10.1021/ol049795v CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/17/2004

3,5-dihydroxy-1-cyclopentene was the key step in Trost’s
synthesis of 2,3 while Miller employed a Diels-Alder
strategy using a chiral auxiliary4,7 or an enzyme kinetic
resolution8 process to obtain enantiomerically pure 2. To date,
the only asymmetric synthesis of 4-aminocyclopentenone (1,
NAc) is that described by Zwanenburg et al., which involved
the pyrolysis of tricyclic[5.2.1.02,6]decenyl enaminones.9 The
tricyclic decadienone system was prepared in a series of steps
and employed a dynamic kinetic resolution to give enan-
tiopure material.9,10 We describe here a new synthesis of (R)-
(+)-1 that is highlighted by a novel olefin-enone ring-closing
metathesis reaction and utilizes δ-amino â-ketophosphonates,
new sulfinimine-derived chiral building blocks.11
Scheme 2
Initially, we envisioned that (+)-1 could be prepared using
ring-closing olefin metathesis (RCM) with an appropriate
amino ketodiene;12 however, we found only a single example
of RCM leading to a cyclic enone with less than six-
carbons.13 We were also aware that the RCM reaction is
sensitive to the electronic and steric properties of the
alkene,12-14 as well as the substituent on nitrogen,12,15 so we
knew our amino ketodiene synthesis had to be flexible
enough to allow a variety of substituents to be easily installed
in the alkenes and at nitrogen. Sulfinimine-derived δ-amino
â-ketophosphonates appeared to meet these synthetic objec-
tives: diversely substituted sulfinimines are readily avail-
able16 and Horner-Wadsworth-Emmons (HWE) chemistry
would provide the R,â-unsaturated keto portion (Scheme 2).
Although â-ketophosphonates are well-known, there are
few examples of enantiomerically pure δ-amino â-ketophos-
phonates.17 Nucleophilic ring opening of â-lactams with
methyl phosphonate anions has generally been employed for
the synthesis of enantiomerically pure samples;18,19 however,
this procedure lacks generality, and â-lactams with diverse
functionality are not easily available. We found that the
reaction of sulfinimine-derived â-amino esters20 with lithium
dimethyl methyl phosphonate produced N-sulfinyl δ-amino
â-ketophosphonates in excellent yield. Thus, treatment of
N-sulfinyl â-amino esters (SS,R)-(+)-4 with 5 equiv of
lithium dimethyl methylphosphonate afforded the corre-
sponding N-sulfinyl δ-amino â-ketophosphonates (SS,R)-
(+)-5 in 81-83% isolated yield (Scheme 2). Lesser amounts
of lithium phosphonate resulted in incomplete reaction.
Workup consisted of flash chromatography followed by
Kugelrohr distillation to remove the excess dimethyl meth-
ylphosphonate. Next (+)-5 was treated with 10 equiv of
acetaldehyde followed by DBU to afford the R,â-unsaturated
amino ketone (+)-6 in nearly quantitative yield. The 16.4
Hz coupling constant suggests that (+)-6 has the E geometry.
The â-amino ester (+)-4 was prepared by reaction of the
sulfinimine (S)-(+)-320 with an excess of the sodium enolate
of methyl acetate, as previously described.21
Initial studies aimed at ring closure using RCM were
performed using amino ketodienes (+)-6a (R ) H) and 6b
(R ) Me) with Grubb’s first-generation catalyst I (Scheme
3). With 2-30 mol % catalyst, for up to 40 h in refluxing
DCM, no reaction was observed and starting material was
quantitatively recovered (Table 1, entries 1 and 3). With the
second-generation catalyst II, 6a and 6b gave (+)-9 in 85
and 25% yields, respectively (Table 1, entries 2 and 4).
Because we believed that the N-sulfinyl group may be
poisoning the catalyst, 6a and 6b were transformed into N-Ts
derivatives (-)-7a and 7b in 83 and 85% yields, respectively,
by m-CPBA oxidation. The N-Boc derivatives (-)-8 were
also prepared in 85-89% yield by reaction of (+)-6 with
(4) Ghosh, A.; Ritter, A. R.; Miller, M. J. J. Org. Chem. 1995, 60, 5808.
(5) Mineno, T.; Miller, M. J. J. Org. Chem. 2003, 68, 6591.
(6) Jung, M. E.; Rhee, H. J. Org. Chem. 1994, 59, 4719.
(7) Vogt, P. F.; Hansel, J.-G.; Miller, M. J. Tetrahedron Lett. 1997, 38,
2803.
(8) Mulvihill, M. J.; Gage, J. L.; Miller, M. J. J. Org. Chem. 1998, 63,
3357.
(9) Ramesh, N. G.; Klunder, A. J. H.; Zwanenburg, B. J. Org. Chem.
1999, 64, 3635.
(10) Bakkeren, F. J. A. D.; Ramesh, N. G.; de Goot, D.; Klunder, A. J.
H.; Zwanenburg, B. Tetrahedron Lett. 1996, 37, 8003.
(11) For leading references to sulfinimine derived chiral building blocks,
see: Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855.
(12) For reviews and leading references on ring-closing metathesis, see:
(a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b) Hanessian,
S.; Margarita, R.; Hall, A.; Johnstone, S.; Tremblay, M.; Parlanti, L. J.
Am. Chem. Soc. 2002, 124, 13342. (c) Felpin, F.-X.; Lebreton, J. Eur. J.
Org. Chem. 2003, 3693. (d) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.;
Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360.
(13) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783.
(14) Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310.
(15) (a) Chippindale, A. M.; Davies, S. G.; Iwamoto, K.; Parkin, R. M.;
Smethurst, C. A. P.; Smith, A. D.; Rodriguez-Solla, H. Tetrahedron 2003,
59, 3253 and references therein. (b) Miller, S. J.; Blackwell, H. E.; Grubbs,
R. H. J. Am. Chem. Soc. 1996, 118, 9606.
(16) For reviews on the chemistry of sulfinimines, see: (a) Zhou, P.;
Chen, B.-C.; Davis, F. A. In AdVances in Sulfur Chemistry; Rayner, C. M.,
Ed.; JAI Press: Stamford, CT, 2000; Vol. 2, pp 249-282. (b) Davis, F.
A.; Zhou, P.; Chen, B.-C. Chem. Soc. ReV. 1998, 27, 13. (c) Ellman, J. A.;
Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984.
(17) For a review, see: McKenna, C. E.; Kashemirov, B. A. Top. Curr.
Chem. 2002, 220, 201.
(18) (a) Baldwin, J. E.; Adlington, R. M.; Russell, A. T.; Smith, M. L.
Tetrahedron 1995, 51, 4733. (b) Lee, H. K.; Kim, E.-K.; Pak, C. S.
Tetrahedron Lett. 2002, 43, 9641.
(19) Rudisill, E. E.; Whitten, J. P. Synthesis 1994, 85.
(20) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, T.; Zhou, P.; Carroll, P. J.
J. Org. Chem. 1997, 62, 2555.
(21) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M. J. Org. Chem. 1995,
60, 7037.
1270
Org. Lett., Vol. 6, No. 8, 2004

reaction was observed with catalyst I (Table 1, entries 3, 7,
and 11), and poor yields of 8-25% were noted for catalyst
II (Table 1, entries 4, 8, and 12). These results suggest a
steric effect in which the methyl group R may hinder
formation of the initial “ruthenacycle” necessary for meta-
thesis. While the poor results with (+)-6 and catalyst I, which
is less reactive than II, suggest mild poisoning of the catalyst
by the N-sulfinyl moiety, additional studies will be necessary
to confirm this.
Scheme 3
The N-Boc group in (R)-(+)-1 was removed by treatment
with 1.5 N HCl to give the hydrochloride (R)-(+)-11 in
quantitative yield (Scheme 4). Luche reduction (NaBH4/
Scheme 4
TFA/MeOH followed by treatment with Boc2O/Et3N and the
catalyst DMAP. Results of RCM cyclization of these amino
ketodienes derivatives with catalysts I and II are summarized
in Table 1. Inspection of Table 1 reveals that in all cases,
with one exception, both catalysts gave good to excellent
yields of the amino cyclopentenones, 1, 9, and 10, when R
) H in amino ketodienes 6a, 7a, and 8a (Table 1, entries 2,
5, 6, 9, and 10). The exception was N-sulfinylamino
ketodiene (+)-6a where there was no reaction with catalyst
I (Table 1, entry 1). When R ) Me in 6b, 7b, and 8b, no
CeCl3) afforded a separable 8:1 mixture of diastereomeric
1,4-amino alcohols and a 76% yield of the major diastereo-
isomer (1S,4R)-(+)-2. These materials had properties con-
sistent with literature values, which further establishes their
structures.8,10 With 2.3 equiv of MeLi at -40 °C, (R)-(+)-1
gave a 10:1 mixture of isomeric alcohol (Scheme 4). The
major isomer (1S,4R)-(+)-12 was isolated in 75% yield, and
NOE studies were used to determine its structure. Methyl-
magnesium bromide resulted in lower ratios (2:3) and
incomplete reaction. The stereochemistry of the methyl-
lithium reaction is consistent with attack of this reagent from
the sterically least hindered direction. Roy and Schneller
reported related results.22
Table 1. Ring-Closing Metathesis of Amino Ketodienes with
Grubb’s Catalysts in DCM at Reflux
products
amino
(% isolated
yields)
entry
ketodiene
catalyst/conditions
Amino ketodiene (SS,R)-(+)-6a was stereoselectively
reduced with LiHBEt3 (Super-Hydride) at -78 °C to give
exclusively (+)-13 in 76% isolated yield (Scheme 5). The
anti stereochemistry was assigned to (+)-14 on the basis of
similar reductions of N-sulfinyl â-amino ketones23 and its
conversion to a product of known absolute configuration (see
below). With catalysts I and II, (+)-13a (R ) H) gave 58
and 93% isolated yields, respectively, of the amino cyclo-
pentenone (+)-14 (Table 1, entries 13 and 14). With (+)-
13b (R ) Me), there was no reaction with catalyst I, but II
afforded (+)-14 in 84% yield (Table 1, entries 15 and 16).
These results may suggest that the metathesis process is
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
(+)-6a (R ) H)
(+)-6b (R ) Me)
(-)-7a (R ) H)
(-)-7b (R ) Me)
(-)-8a (R ) H)
(-)-8b (R ) Me)
(+)-13a (R ) H)
I (2-30 mol %) 40 h NR
II (5 mol %) 16 h
(R)-(+)-9 (85)
I (2-30 mol %) 40 h NR
II (5 mol %) 16 h
I (2 mol %) 18 h
II (5 mol %) 18 h
(R)-(+)-9 (25)
(R)-(+)-10 (94)
(R)-(+)-10 (95)
I (2-30 mol %) 40 h NR
II (5 mol %) 18 h
I (2 mol %) 18 h
II (2 mol %) 16 h
I (2 mol %) 16 h
II (2 mol %) 16 h
I (20 mol %) 18 h
II (5 mol %) 18 h
(R)-(+)-10 (8)
(R)-(+)-1 (97)
(R)-(+)-1 (97)
NR
(R)-(+)-1 (21)
(+)-14 (58)
(+)-14 (93)
NR
(+)-13b (R ) Me) I (10 mol %) 16 h
II (5 mol %) 16 h
(22) Roy, A.; Schneller, S. W. J. Org. Chem. 2003, 68, 9269.
(23) Davis, F. A.; Prasad, K. R.; Nolt, B. M.; Wu, Y. Org. Lett. 2003,
5, 925.
(+)-14 (84)
Org. Lett., Vol. 6, No. 8, 2004
1271

literature values25 and confirms the anti stereochemistry for
the reduction of the â-amino ketones (+)-6. Furthermore,
this result illustrates that it is possible to readily obtain the
trans-1,4-amino alcohol carbocycle (+)-16 by stereoselective
reduction of the amino ketodiene prior to RCM cyclization.
In summary, ring-closing metathesis has been employed
in the asymmetric synthesis of (R)-(+)-aminocyclopentenone
1, a valuable chiral building block for the synthesis of
antiviral and anticancer carbocyclic nucleosides. δ-Amino
â-ketophosphonates, a new sulfinimine-derived chiral build-
ing block, and HWE chemistry were employed in the
synthesis of the key amino ketodienes units.
Scheme 5
Acknowledgment. We thank Seung H. Lee for prelimi-
nary studies. 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.
inhibited to some extent by the electron-deficient nature of
the R,â-unsaturated carbonyl unit (Table 1, compare entries
1 and 2 with entries 13 and 14), but additional studies are
necessary to validate this hypothesis.24
Treatment of the N-Boc 1,4-amino alcohol (-)-15, pre-
pared as before from (+)-13a, with 5 mol % catalyst I
resulted in the 1,4-amino alcohol carbocycle (+)-16 in 91%
yield (Scheme 5). This material had properties consistent with
OL049795V
(24) (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc.
1993, 115, 9856. (b) Rutjes, F. P. J. T.; Schoemaker, H. E. Tetrahedron
Lett. 1997, 38, 677. (c) Krikstolaityte, S.; Hammer, K.; Undheim, K.
Tetrahedron Lett. 1998, 39, 7595. (d) Paquette, L. A.; Efremov, I. J. Am.
Chem. Soc. 2001, 123, 4492.
(25) Wu, Y.; Woster, P. M. J. Med. Chem. 1992, 35, 3196.
1272
Org. Lett., Vol. 6, No. 8, 2004