Probing the stereoselectivity of the Heck arylation of endocyclic enecarbamates with diazonium salts. Concise syntheses of (2S,5R)-phenylproline methyl ester and Schramm's C-azanucleoside.

Article abstract of DOI:10.1021/ol027268a

[reaction: see text] The diastereoselectivity of the Heck arylation of several chiral, nonracemic, five-membered endocyclic enecarbamates with aryldiazonium tetrafluoroborates was evaluated. The cis selectivity observed for some enecarbamates bearing coor

Full text of DOI:10.1021/ol027268a

ORGANIC
LETTERS
2003
Vol. 5, No. 3
305-308
Probing the Stereoselectivity of the
Heck Arylation of Endocyclic
Enecarbamates with Diazonium Salts.
Concise Syntheses of
(2S,5R)-Phenylproline Methyl Ester and
Schramm’s C-Azanucleoside
Elias A. Severino, Edson R. Costenaro, Ariel L. L. Garcia, and
Carlos Roque D. Correia*
Instituto de Qu´ımica, UniVersidade Estadual de Campinas, C. P. 6154,
13084-971, Campinas, SP, Brazil
roque@iqm.unicamp.br
Received November 12, 2002
ABSTRACT
The diastereoselectivity of the Heck arylation of several chiral, nonracemic, five-membered endocyclic enecarbamates with aryldiazonium
tetrafluoroborates was evaluated. The cis selectivity observed for some enecarbamates bearing coordinating groups was explored in the
concise synthesis of the (2S,5R)-(+)-phenylproline methyl ester, a scaffold for the nonpeptide cholecystokinin antagonist (+)-RP 66803, and
in the synthesis of Schramm’s potent antiprotozoan C-azanucleoside.
The palladium-catalyzed Heck reaction is an extremely
valuable reaction in modern organic synthesis. This pivotal
C-C coupling reaction has been attracting considerable
interest in recent decades due to its growing versatility and
still unlimited scope and synthetic potential.1
The phosphine-free Heck arylations employing aryl-
diazonium salts are among the earliest Heck arylations
reported, but its application to organic synthesis has been
rather limited despite its outstanding ability for installating
electron-rich aromatic rings, a major challenge when using
aryl halides.1a Recently, interest in the use of aryldiazonium
salts as electrophiles in the synthesis of complex natural
products resurged, demonstrating the feasibility of these Heck
arylations.2
Our interest in the Heck arylation of electron-rich olefins
stems from the prominent display of an R-aryl heterocyclic
framework in the core structure of several natural and
nonnatural compounds (Figure 1). Many of these heterocyclic
compounds exhibit pharmacological activity and are im-
portant synthetic targets. The natural compounds (-)-
codonopsine 13 and the green tea constituent (-)-epigallo-
(2) (a) Andrus, M. B.; Song, C.; Zhang, J. Org. Lett. 2002, 4, 2079. (b)
Brunner, H.; Le Cousturier de Courcy, N.; Geneˆt, J.-P. Tetrahedron Lett.
1999, 40, 4815. (c) Oliveira, D. F.; Severino, E. A.; Correia, C. R. D.
Tetrahedron Lett. 1999, 40, 2083. (d) Mehta, G.; Sengupta, S. Tetrahedron
Lett. 1996, 37, 8625. (e) Beller, M.; Kuhlein, K. Synlett 1995, 441.
(3) Iida, H.; Yamazaki, N.; Kibayashi, C. Tetrahedron Lett. 1986, 27,
5393.
(1) For recent reviews on the Heck reaction consult: (a) Whitcombe,
N. J.; Hii, M.; Gibson, S. E. Tetrahedron 2001, 57, 7449. (b) Beletskaya,
I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009. (c) Shibasaki, M.;
Vogl, E. M. J. Organomet. Chem. 1999, 576, 1. (d) Crisp, G. Chem. Soc.
ReV. 1998, 27, 427. (e) Shibasaki, M.; Boden, D. J.; Kojima, A. Tetrahedron
1997, 53, 7371.
10.1021/ol027268a CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/10/2003

Table 1. Diastereoselectivity for the Heck Arylation with
Aryldiazonium Tetrafluoroborates
entry
R1
R2
trans:cisa
yield (%)b
1
2c
3
4
5
6
7c
8
9
10c
11
12
13
CH2OTBDPS
CH2OTBDPS
CH2OTr
CH2OTr
CH2OAc
CH2OH
CH2OH
CH2OH
CO2Me
CO2Me
t-Bu
t-Bu
t-Bu
Me
t-Bu
t-Bu
t-Bu
Me
Me
Me
t-Bu
t-Bu
t-Bu
92:08
80:20
90:10
87:13
88:12
48:52
40:60
52:48
75:25
63:37
86:14
49:51
82:18
92
92
96
90
67
95
60
92
93
95
90
82
98
Figure 1. Compounds containing an R-aryl heterocycle.
catechin-3-gallate (EGCG) 24 display hypotensive and cancer
preventive properties, respectively. The nonnatural compound
cis-5-phenylproline forms the basic scaffold for the nonpep-
tide cholecystokinin antagonist (+)-RP 66803 3,5 while the
p-aminophenyl C-azanucleoside 4 described by Schramm and
co-workers6 shows very promising trypanosomal activity.
A few years ago we reported the Heck arylation of five-
membered endocyclic enecarbamates employing aryldia-
zonium tetrafluoroborates as the key step in the total
synthesis of codonopsinine.7 In a follow-up study to deter-
mine the factors controlling the diastereoselectivity of
arylation of chiral five-membered enecarbamates, we noticed
wide fluctuations in the diastereomeric ratio, depending on
the nature of the functional group at the chiral center and,
to a lesser extent, on the reaction conditions. These results
are presented in Table 1.
CO2Me
CONMe(OMe)
CO2t-Bu
a Ratio determined by capillary GC. b Isolated yields. c Using 10 mol %
Pd(OAc)2, di-tert-butylmethylpyridine, EtOH, 55 °C, 15 min.
and 10). It is worthwhile pointing out that a moderate reversal
in diastereoselectivity was observed with enecarbamate 5
when we replaced acetonitrile with NMP, DMF, or DMA
as the reaction solvent (Table 2), although these changes in
Table 2. Effect of the Solvent on the Diastereoselectivity of
the Heck Arylation of Enecarbamate 5
As anticipated, bulky functional groups at C-5 provided
the 2,5-trans Heck adduct as the major product, in ratios that
correlated with the steric bulk of the groups. The highest
trans diastereomeric ratios were those obtained with tert-
butyldiphenylsilane (TBDPS) and triphenylmethyl (trityl)
groups (Table 1, entries 1 and 3). In general, a slightly higher
diastereoselectivity is observed with the t-butoxycarbonyl
(Boc) group on the pyrrolidine nitrogen. Somewhat surprising
was the modest stereoselectivity observed for the methyl and
tert-butyl esters of dehydroprolines (entries 9, 10, and 13).
Replacement of the ester groups by more coordinating groups
such as amide or alcohol led to a sharp decrease in the trans
selectivity, as observed for the Weinreb amide enecarbamate
(entry 12) and for the prolinol enecarbamate bearing a
hydroxymethyl group at C-5 (entries 6-8). Coordinating
effects are evident when we compare the results of entries 5
and 6 of Table 1. A decrease in the expected selectivity
toward the trans adduct was also observed when using an
alternative Heck protocol in ethanol (Table 1, entries 2, 7,
solventa
6a /6b (trans:cis)b
yield (%)c
CH3CN
NMP
DMF
48:52
28:72
34:66
36:64
95
40
50
51
DMA
a Ethanol, acetone, and THF led to low conversions. b Ratio was
determined by capillary GC. c Isolated yields.
the reaction conditions also led to a concurrent decrease in
yields, which is probably related to the decomposition of
the diazonium salts in these solvents.8 The results presented
in Tables 1 and 2 for the esters, amide, and hydroxymethyl
(4) Zaveri, N. T. Org. Lett. 2001, 3, 843.
(8) Diazonium salts are rather unstable in NMP and DMF, which might
explain the low yields. For a previous study of the stability of the diazonium
salts, see: (a) Kikukawa, K.; Nagira, K.; Wada, F.; Matsuda, T. Tetrahedron
1981, 37, 31. (b) Lahoti, R. J.; Parameswaran, V.; Wagle, D. R. Ind. J.
Chem. 1981, 20B, 767.
(5) Manfre´, F.; Pulicani, P. Tetrahedron: Asymmetry 1994, 5, 235.
(6) Miles, R. W.; Tyler, P. C.; Evans, G. B.; Furneaux, R. H.; Parkin,
D. W.; Schramm, V. L. Biochemistry 1999, 38, 13147.
(7) Severino, E. A.; Correia, C. R. D. Org. Lett. 2000, 2, 3039.
306
Org. Lett., Vol. 5, No. 3, 2003

groups at the chiral center seem to suggest some degree of
coordination of the ligand-free cationic palladium intermedi-
ate to the potentially coordinating groups at C-5.9
catalytic hydrogenation to give a ∼1:1 mixture of Boc-5-
phenylprolines 9a,b, which were deprotected with HCl/
MeOH to give the diastereomeric phenylproline methyl esters
in an overall yield of 48%. Flash chromatography provided
the two diastereomers 10a and 10b in pure form. Overall,
the desired (2S,5R)-phenylproline methyl ester 10b was
obtained in three steps with an overall yield of 26% from
enecarbamate 7.11
Despite the present low stereoselectivity, a quick access
to 2,5-cis aryl prolinols and prolines (entries 7, 8, and 12)
by these Heck arylations opens new routes to synthetically
relevant intermediates that are otherwise difficult to prepare.
In the specific case of arylation of endocyclic enecarbam-
ate 7, this opens the way to the synthesis of (2S,5R)-phenyl
proline methyl ester, a known precursor of the nonpeptide
cholecystokinin antagonist (+)-RP 66803 3 in a very concise
manner.10 A straightforward synthesis of the (2S,5R)-
phenylproline methyl ester is presented in Scheme 1. Heck
Another illustrative application of the cis Heck adduct
obtained from the arylation of the hydroxy enecarbamate 5
was the total synthesis of the antiprotozoan C-azanucleo-
side 4. Protozoan parasite infections such as malaria and
trypanosomiasis are among the most important tropical
diseases, causing a heavy toll in lives and productivity in
developing and underdeveloped countries.12 A key charac-
teristic of these parasites is the lack of a de novo pathway
for purine biosynthesis, and as a result, these organisms need
to salvage purines from the host for the synthesis of their
own DNA and RNA.13 For this purpose, the parasites produce
a family of nucleoside N-ribosyl hydrolases that are not found
in mammalian cells, thus making the N-ribosyl hydrolases
suitable targets for inhibition and creating viable therapeutic
control of the disease.14
Scheme 1. Synthesis of the (2S,5R), and (2S,5S)-Phenyl
Proline Methyl Esters from Enecarbamate 7
Recently, Schramm and Tyler reported on 1-arylimino-
ribitols, which bind tightly to nonspecific nucleoside hydro-
lases such as inosine-uridine nucleoside hydrolase (IU-NH)
and to specific nucleoside hydrolases such as the inosine-
adenosine-guanosine nucleoside hydrolase (IAG-NH).15 The
trypanosomal nucleoside hydrolase IU-NH involved in purine
salvage pathways is strongly inhibited by the p-amino-
phenyliminoribitol 4 with a dissociation constant of 30 nM.16
(a) C6H4N2BF4, Pd2dba3 (4 mol %), NaOAc, MeCN, 30 °C, 30
min (85%). (b) H2, 10%-Pd/C, 15 h, rt (100%). (c) HCl/MeOH,
rt, 1 h (61%).
Heck arylation of prolinol enecarbamate 5 provided a new
and concise route to the synthesis of Schramm’s C-
azanucleoside 4. The first stage involved the preparation of
the hydroxy enecarbamate 5 from the silyloxy enecarbamate
11 with TBAF (Scheme 2). Heck arylation of the hydroxy
arylation of enecarbamate 7 using phenyldiazonium tetra-
fluoroborate required 4 mol % Pd2(dba)3 and a reaction
temperature of ∼30 °C to attain good yields of the Heck
adducts. The arylation proceeded with an unexpected low
stereoselectivity (compare with entries 9-11, Table 1)
providing a 45:55 (trans/cis) inseparable mixture of 5-phenyl
dehydroprolines 8a/8b, indicating a further dependence of
the stereoselectivity on the diazonium salt substitution
pattern. The mixture of 3,4-dehydroprolines underwent
Scheme 2. Synthesis of the Arylpyrroline Precursor of
Schramm’s C-Azanucleoside
(9) There are many precedents for the stereocontrolled Heck arylation
of olefins promoted by proximal functional groups. For some representative
examples, see: (a) Olofsson, K.; Sahlin, H.; Larhed, M.; Hallberg, A. J.
Org. Chem. 2001, 66, 544. (b) Nilsson, P.; Larhed, M.; Hallberg, A. J. Am.
Chem. Soc. 2001, 123, 8217. (c) Olofsson, K.; Larhed, M.; Hallberg, A. J.
Org. Chem. 2000, 65, 7235. (d) Itami, K.; Mitsudo, K.; Kamei, T.; Koike,
T.; Nokami, T.; Yoshida, J. J. Am. Chem. Soc. 2000, 122, 12013. (e) Buezo,
N. D.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 1998, 120, 7129. (f)
Kang, S.-K.; Lee, H.-W.; Jang, S.-B.; K. T.-H.; Pyun, S.-J. J. Org. Chem.
1996, 61, 2604. (g) Madin, A.; Overman, L. Tetrahedron Lett. 1992, 33,
4859.
(10) Previous synthesis of the (2S,5R)-phenylproline methyl ester: (a)
ref 5. (b) Haddad, M.; Imogai, H.; Larcheveˆque, M. J. Org. Chem. 1998,
63, 5680. (c) Davis, F. A.; Fang, T.; Goswami, R. Org. Lett. 2002, 4, 1599.
(d) Momotake, A.; Togo, H.; Yokoyama, M. J. Chem. Soc., Perkin Trans.
1 1999, 1193. (e) Betsbrugge, J. V.; Nest, W. V. D.; Verheyden, P.; Tourwe´,
D. Tetrahedron 1998, 54, 1753. (f) Zaluski, M. C. F.; Coric, P.; Thery, V.;
Gonzalez, W.; Meudal, H.; Turcaud, S.; Michel, J. B.; Roques, B. P. J.
Med. Chem. 1996, 39, 2594.
(a) TBAF 1M, THF, 0 °C, 1 h (93%); (b) Pd2(dba)3‚dba (1 mol
%), MeCN, NaOAc, 30 min, rt (80%); (c) chromatographic
separation.
enecarbamate 5 gave the Heck adducts with a modest
stereoselectivity in favor of the cis adduct in good yield (80%
yield; 60:40 diastereomeric ratio).
Org. Lett., Vol. 5, No. 3, 2003
307

The hydroxymethyl arylpyrrolines 12a and 12b were
readily separated by flash chromatography and the cis adduct
12b converted to the C-azanucleoside using the sequence
described in Scheme 3. Sharpless dihydroxylation of 12b
acidic hydrolysis of the aryl carbamate to afford the
nucleoside 4 in 88% yield as the corresponding hydro-
chloride.17
This strategy allowed the synthesis of C-azanucleoside 4
in four steps from enecarbamate 5 in an overall yield of 37%
and is amenable to the synthesis of analogues.
In conclusion, the stereoselectivity of the Heck arylation
of five-membered enecarbamates depends significantly on
the nature of the functional group at C-5. Noncoordinating,
bulky groups favor trans aryl insertion, whereas coordinating
groups such as the Weinreb amide and hydroxymethyl seem
to slightly favor cis aryl insertion, thereby counterbalancing
steric effects.
Scheme 3. Completion of the Synthesis of Azanucleoside 4
Exploration of the synthetic potential of 2,5-cis Heck
adducts permitted the concise synthesis of (2S,5R)-phenyl-
proline methyl ester 10b in three steps in an overall yield of
25% and the synthesis of antiprotozoan C-azanucleoside 4
in four steps in an overall yield of 37% from the respective
endocyclic enecarbamates.
Other chiral five-membered endocyclic enecarbamates
bearing potentially complexing groups are under evaluation,
aimed at increasing the Heck cis selectivity and to further
applications of these intermediates in synthesis. These results
will be reported in due course.
(a) K2OsO4‚2H2O (cat.), NMO, acetone:H2O:t-BuOH; 3:6:1; rt,
30 min-1 h (89%); (b) AcCl, MeOH, 0 °C, 30 min (100%); (c)
HCl, EtOH, reflux, 30 h (88%).
occurred smoothly to provide the triol 13 in 89% yield.
Removal of the Boc group was performed with acetyl
chloride in methanol to give the triol 14, followed by the
Acknowledgment. We thank FAPESP for financial
support and CNPq and CAPES for fellowships.
Supporting Information Available: Experimental pro-
cedure for the Heck arylations and spectroscopic character-
ization of compounds 5, 6a, 6b, 10a, 10b, 12a, 12b, and
13. This material is available free of charge via the Internet
at http://pubs.acs.org.
(11) Yields were not optimized. The synthesis can be accomplished in
two steps by using Cbz instead of Boc as the protecting group.
(12) Morel, C. Parasitol. Today 2000, 16, 2.
(13) (a) Hammond, D. J.; Gutteridge, W. E. Mol. Biochem. Parasitol.
1984, 13, 243. (b) Estupin˜a´n, B.; Schramm, V. L. J. Biol. Chem. 1994,
269, 23068.
(14) (a) Gopaul, D. N.; Meyer, S.; Degane, M.; Sachettini, J. C.;
Schramm, V. L. Biochemistry 1996, 35, 5963. (b) Parkin, D. W.; Limberg,
G.; Tyler, P. C.; Furneaux, R. H.; Chen, X.-Y.; Schramm, V. L. Biochemistry
1997, 36, 3528.
(15) (a) Furneaux, R. H.; Limberg, G.; Tyler, P. C.; Schramm, V. L.
Tetrahedron 1997, 53, 2915. (b) Miles, R. W.; Tyler, P. C.; Evans, G. B.;
Furneaux, R. H.; Parkin, D. W.; Schramm, V. L. Biochemistry 1999, 38,
13147.
OL027268A
(16) Degano, M.; Almo, S.; Sacchettini, J. C.; Schramm, V. L.
Biochemistry 1998, 37, 6277.
(17) Acidic hydrolysis of triol 13 provided 4 (hydrochloride), albeit in
lower yields. Filtration through Dowex gave 4 as a free base, the
spectroscopic data of which were in good agreement with those described
in ref 15. The structure of triol 13 was also confirmed by X-ray diffraction.
308
Org. Lett., Vol. 5, No. 3, 2003