Efficient synthesis of trifluoromethyl and related trisubstituted alkene dipeptide isosteres by palladium-catalyzed carbonylation of amino acid derived allylic carbonates

Article abstract of DOI:10.1021/jo702318d

(Chemical Equation Presented) A novel stereoselective synthetic approach to (Z)-trifluoromethylalkene dipeptide isosteres (CF₃-ADIs) is described. Starting from readily available N-Boc-L-phenylalanine, Phe-Gly type CF₃-ADIs were obtained through palladium-catalyzed carbonylation of allylic carbonates under CO. While the reaction of N-Boc derivatives proceeds in excellent yields but lower stereoselectivity (E:Z = 62:38-43:57), the reaction of the N,N-diBoc derivative exclusively affords the desired (Z)-isomer in 61% yield. We also present a highly stereoselective synthesis of several Phe-Gly type trisubstituted alkene dipeptide isosteres by palladium-catalyzed carbonylation.

Full text of DOI:10.1021/jo702318d

Efficient Synthesis of Trifluoromethyl and
Related Trisubstituted Alkene Dipeptide Isosteres
by Palladium-Catalyzed Carbonylation of Amino
Acid Derived Allylic Carbonates
Eriko Inokuchi, Tetsuo Narumi, Ayumu Niida,
Kazuya Kobayashi, Kenji Tomita, Shinya Oishi,
Hiroaki Ohno, and Nobutaka Fujii*
FIGURE 1. Structures of native peptides and corresponding alkene-
type isosteres. Xaa, Yaa ) Amino acid side chains.
Graduate School of Pharmaceutical Sciences, Kyoto
UniVersity, Sakyo-ku, Kyoto 606-8501, Japan
electrostatic nature and the three-dimensional structure of
bioisosteres.3 However, our recent studies on stereoselective
synthesis and evaluation of functionalized (Z)-FADIs have
revealed that the (Z)-FADI of Phe-Gly showed lower binding
affinity for peptide transporter PEPT1 compared with the
corresponding EADI.4 Moreover, when compared to the parent
peptide, the EADI analogue of the GPR54 agonistic peptide
expressed similar agonist activity,5 whereas the (Z)-FADI
analogue showed significantly lower potency. These results
suggest that FADIs are not always effective as dipeptide
mimetics, even though some examples of bioactive compounds
containing FADIs have been reported.3b,c,6
nfujii@pharm.kyoto-u.ac.jp
ReceiVed October 26, 2007
We next turned our attention to trifluoromethylalkene dipep-
tide isosteres (CF3-ADIs, Figure 1) that possess a dipole moment
(2.3 D) closer to a native peptide bond (3.6 D) than do other
alkene-type isosteres (FADI, 1.4 D; EADI, 0.1 D).7 CF3-ADIs
could serve as more favorable dipeptide isosteres than FADIs
due to the presence of fluorine atoms on the sp3 carbon atoms.8
Although several asymmetric syntheses of CF3-ADIs have been
reported,7,9 stereoselective synthesis of optically pure Xaa-Gly
A novel stereoselective synthetic approach to (Z)-trifluo-
romethylalkene dipeptide isosteres (CF3-ADIs) is described.
Starting from readily available N-Boc-L-phenylalanine, Phe-
Gly type CF3-ADIs were obtained through palladium-
catalyzed carbonylation of allylic carbonates under CO.
While the reaction of N-Boc derivatives proceeds in excellent
yields but lower stereoselectivity (E:Z ) 62:38–43:57), the
reaction of the N,N-diBoc derivative exclusively affords the
desired (Z)-isomer in 61% yield. We also present a highly
stereoselective synthesis of several Phe-Gly type trisubsti-
tuted alkene dipeptide isosteres by palladium-catalyzed
carbonylation.
(2) (a) For EADIs and TADIs, see: Christos, T. E.; Arvanitis, A.; Cain, G. A.;
Johnson, A. L.; Pottorf, R. S.; Tam, S. W.; Schmidt, W. K. Bioorg. Med. Chem.
Lett. 1993, 3, 1035-1040. (b) Tamamura, H.; Hiramatsu, K.; Ueda, S.; Wang,
Z.; Kusano, S.; Terakubo, S.; Trent, J. O.; Peiper, S. C.; Yamamoto, N.;
Nakashima, H.; Otaka, A.; Fujii, N. J. Med. Chem. 2005, 48, 380–391. (c) Oishi,
S.; Miyamoto, K.; Niida, A.; Yamamoto, M.; Ajito, K.; Tamamura, H.; Otaka,
A.; Kuroda, Y.; Asai, A.; Fujii, N. Tetrahedron 2006, 62, 1416–1424. (d) Xiao,
J.; Weisblum, B.; Wipf, P. Org. Lett. 2006, 8, 4731–4734.
(3) (a) Abraham, R. J.; Ellison, S. L. R.; Schonholzer, P.; Thomas, W. A.
Tetrahedron 1986, 42, 2101–2110. (b) Allmendinger, T.; Felder, E.; Hunger-
bühler, E. Tetrahedron Lett. 1990, 31, 7301–7304. (c) Lin, J.; Toscano, P. J.;
Welch, J. T. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 14020–14024. (d) Narumi,
T.; Niida, A.; Tomita, K.; Oishi, S.; Otaka, A.; Ohno, H.; Fujii, N. Chem.
Commun. 2006, 4720–4722.
Peptides constitute attractive and useful drug leads because
a large number of bioactive peptides have already been isolated
and identified. However, peptidase-mediated digestion of pep-
tides as well as lower membrane permeability of generally
hydrophilic peptides decrease their bioavailability in clinical use.
The backbone modification of amide bonds in bioactive peptides
is one of the most promising approaches to solving these
problems.1 Among the known isosteric units, (E)-alkene dipep-
tide isosteres (EADIs, Figure 1) have been studied extensively
because the (E)-carbon-carbon double bond closely resembles
the planar structure of the parent amide bond.2 Fluoroalkene
dipeptide isosteres (FADIs) can be considered as more ideal
surrogates than nonpolar EADIs due to the presence of a highly
electronegative fluorine substituent. This substituent mimics a
carbonyl oxygen atom and might contribute to both the
(4) Niida, A.; Tomita, K.; Mizumoto, M.; Tanigaki, H.; Terada, T.; Oishi,
S.; Otaka, A.; Inui, K.; Fujii, N. Org. Lett. 2006, 8, 613–616.
(5) (a) Tomita, K.; Niida, A.; Oishi, S.; Ohno, H.; Cluzeau, J.; Navenot, J.;
Wang, Z.; Peiper, S. C.; Fujii, N. Bioorg. Med. Chem. 2006, 14, 7595–7603. (b)
Tomita, K.; Narumi, T.; Niida, A.; Oishi, S.; Ohno, H.; Fujii, N. Biopolymers
2007, 88, 272–278.
(6) Bartlett, P. A.; Otake, A. J. Org. Chem. 1995, 60, 3107–3111.
(7) Wipf, P.; Henninger, T. C.; Geib, S. J. J. Org. Chem. 1998, 63, 6088–
6089.
(8) Howard, J. A. K.; Hoy, V. J.; O’Hagan, D.; Smith, G. T. Tetrahedron
1996, 52, 12613–12622.
(9) (a) Xiao, J.; Weisblum, B.; Wipf, P. J. Am. Chem. Soc. 2005, 127, 5742–
5743. (b) Wipf, P.; Xiao, J.; Geib, S. J. AdV. Synth. Catal. 2005, 347, 1605–
1613.
(10) (a) For further discussion of palladium-catalyzed carbonylation of allylic
carbonates, see: Tsuji, J.; Sato, K.; Okumoto, H. Tetrahedron Lett. 1982, 23,
5189-5190. (b) Tsuji, J.; Sato, K.; Okumoto, H. J. Org. Chem. 1984, 49, 1341–
1344. (c) Ozawa, F.; Son, T.; Ebina, S.; Osakada, K.; Yamamoto, A.
Organometallics 1992, 11, 171–176. (d) Narumi, T.; Fujii, M.; Adachi, T.;
Shimizu, I. Pept. Sci. 2003, 417–420.
(1) (a) Burgess, K. Acc. Chem. Res. 2001, 34, 826–835. (b) Bursavich, M. G.;
Rich, D. H. J. Med. Chem. 2002, 45, 541–558. (c) Hruby, V. J. J. Med. Chem.
2003, 46, 4215–4231.
3942 J. Org. Chem. 2008, 73, 3942–3945
10.1021/jo702318d CCC: $40.75 2008 American Chemical Society
Published on Web 04/16/2008

SCHEME 1. Palladium-Catalyzed Synthesis of CF3-ADIs A
and TADIs B via a Single Intermediate
SCHEME 2. Synthesis of Carbonate 2 Bearing a CF3
Group
type CF3-ADIs by use of the reported methodologies would be
extremely difficult because the construction of a stereogenic
center at the δ-position relies upon the chirality of the R-carbon.
We proposed that palladium-catalyzed carbonylation of allylic
carbonates 210d derived from R-amino acids would provide a
general and convenient approach to enantiopure Xaa-Gly type
CF3-ADIs A (Scheme 1). This strategy could also be applied
to facile synthesis of trisubstituted alkene dipeptide isosteres
(TADIs) B, which are known as useful hydrolytically stable
structural surrogates of dipeptides2d as well as potent ꢀ-turn
promoters in acyclic sequences.9,11 To evaluate the utility of
CF3-ADIs and TADIs, development of a simple and efficient
methodology for the preparation of both isosteres by way of
the same intermediate is highly desirable. Herein, we describe
a novel synthetic approach to Phe-Gly type CF3-ADIs A and
TADIs B (R ) n-Bu, Me, i-Pr, or Ph) by palladium-catalyzed
carbonylation of allylic carbonates such as 2 and 3. These
approaches enable a facile synthesis of enantiomerically pure
dipeptide isosteres by retention of the asymmetric centers of
the starting amino acids.
TABLE 1. Synthesis of Tributylstannylated Enoate 6 via
Organocopper-Mediated Stannylation of (Z)-1a
entry
reagents
solvent
products (yield)
1
2
3
4
5
(n-Bu3Sn)2, Pd(PPh3)2Cl2
(n-Bu3Sn)2, PdCl2[P(o-tol)3]2
n-Bu3Sn(n-Bu)Cu(CN)Li2
n-Bu3SnCu(CN)Lic
THF
DMF
THF
THF
THF
NDb
NDb
6 (35%)
6 (23%)
6 (80%) 7 (trace)
7 (17%)
7 (62%)
n-Bu3SnCu(CN)Lid
a Catalytic reactions (entries
1 and 2) were carried out with
(n-Bu3Sn)2 (1.2 equiv) in the presence of a palladium catalyst (5 mol %)
and LiCl (6.0 equiv). b Not determined (a complex mixture of uniden-
tified products was obtained). c Prepared by stirring at 0 °C for 10 min.
d Prepared by stirring at 0 °C for 60 min.
Our synthesis started from commercially available N-Boc-
L-phenylalanine 4 as illustrated in Scheme 2. After conversion
to ꢀ-keto ester 5 by the reaction with carbonyldiimidazole and
ethyl acetate lithium enolate,12 treatment with Tf2O in the
presence of (i-Pr)2NH afforded the triflate 1 as a separable
mixture of E- and Z-isomers (E:Z ) 1:4). Next, we investigated
the tributylstannylation of (Z)-1 under various conditions.
Representative results are shown in Table 1. While the reactions
with bis(tributyltin) in the presence of a catalytic amount of
Pd(PPh3)2Cl2 or PdCl2[P(o-tol)3]2 gave a mixture of unidentified
products (entries 1 and 2), the reaction with cyano Gilman
reagent [n-Bu3Sn(n-Bu)Cu(CN)Li2], a well-known stannylating
reagent for cross-coupling reaction,13 afforded the desired
product 6 in 35% yield along with 17% of the butylated enoate
7 (entry 3). The reaction with a lower-order cuprate [n-Bu3-
SnCu(CN)Li] gave 7 as a major product (entry 4). In sharp
contrast, the cyanocuprate with the same constituent of the
reagents with a prolonged reaction time gave the desired
stannylated product 6 in 80% yield (entry 5). Stannyl ester 6
was then reduced with DIBAL-H to the corresponding allylic
alcohol, which was converted to the allylic carbonate 8 under
standard conditions. After treatment of 8 with NIS,9 the resulting
vinyl iodide 9 was subjected to copper-mediated trifluoro-
methylation using FSO2CF2CO2Me/CuI14 as a trifluoromethyl
anion equivalent to give the requisite allylic carbonate 2
containing a CF3-alkene unit in high yield.15
Next, allylic carbonates 3 for the syntheses of several Phe-
Gly type TADIs B, Boc-Phe-Ψ[(E)-CRdCH]-Gly-OR’ (Scheme
1), were prepared from the key intermediate (Z)-1 through
(11) Tyndall, J. D. A.; Pfeiffer, B.; Abbenante, G.; Fairlie, D. P. Chem. ReV.
2005, 105, 793–826.
(12) The ketone 5 with >95% ee (Chiralcel OD-RH, MeCN/H2O ) 53:47)
was obtained according to Hoffman’s protocol: Hoffman, R.V.; Maslouh, N.;
Cervantes-Lee, F J. Org. Chem. 2002, 67, 1045-1056. It should be noted that
a prolonged reaction time for CDI treatment caused serious racemization.
(13) (a) Gilbertson, S. R.; Challener, C. A.; Bos, M. E.; Wulff, W. D.
Tetrahedron Lett. 1988, 29, 4795–4798. (b) Piers, E.; Chong, J. M.; Morton,
H. E. Tetrahedron 1989, 45, 363–380. (c) Lipshutz, B. H.; Sharma, S.; Reuter,
D. C. Tetrahedron Lett. 1990, 31, 7253–7256. (d) Oehlschlager, A. C.; Hutzinger,
M. W.; Aksela, R.; Sharma, S.; Singh, S. M. Tetrahedron Lett. 1990, 31, 165–
168.
(14) (a) Chen, Q. Y.; Wu, S. W. Chem. Commun. 1989, 705–706. (b) Tian,
F.; Kruger, V.; Bautista, O.; Duan, J.; Li, A.; Dolbier, W. R., Jr.; Chen, Q. Y
Org. Lett. 2000, 2, 563–564.
(15) The E/Z stereochemistry of the olefinic compounds was determined by
NOE analyses. With the carbonates 2, 3, and 15 and (Z)-enoates 13, 16, and 17,
NOE correlations were observed between the olefinic proton and the proton on
the carbon bearing a nitrogen atom. On the other hand, this correlation was not
observed with the (E)-enoates 13.
J. Org. Chem. Vol. 73, No. 10, 2008 3943

TABLE 2. Palladium-Catalyzed Carbonylation of CF3-Containing
Allylic Carbonate 2
SCHEME 3. Synthesis of Carbonates 3a-d
Pd cat.
entry (mol %)a
ligand
temp. time
yield (%)b
(h) (E)-13 (Z)-13
(mol %)
ROH
(°C)
1
10
10
10
10
10
10
10
10
10
5
PPh3 (40) EtOH
PPh3 (40) EtOH
PPh3 (40) EtOH
PCy3 (40) EtOH
dppm (40) EtOH
dppe (40) EtOH
dppp (40) EtOH
PPh3 (40) EtOH
PPh3 (40) MeOH
PPh3 (20) MeOH
PPh3 (10) MeOH
rt
12
12
12
12
12
12
12
3
26
61
16
34
37
20
2
50
80
50
50
50
50
50
50
50
50
3c
4
NDd
NDd
5
6
7
8
9
10
11
20
12
27
32
35
29
5
14
38
48
45
25
3
3
3
2.5
organocopper-mediatedalkylation16orPd-catalyzedSuzuki-Miyaura
coupling17 (Scheme 3). Organocopper-mediated alkylation of
(Z)-1 using Gilman reagents (n-Bu2CuLi·LiI or Me2CuLi·LiI)
at -78 °C proceeded smoothly to yield the desired n-butyl- and
methyl-substituted enoates 7 and 10 in 87% and 70% yields,
respectively. Although the reactions of (Z)-1 with some typical
isopropylcopper reagents [i-Pr2CuLi · LiI, i-PrCuI · MgCl,
i-Pr2Cu(CN)Li2, or i-PrCu(CN)MgCl] afforded only a mixture
of unidentified compounds, the reaction with the reagent
prepared from i-PrMgCl (1.6 equiv) and a slight excess of
copper cyanide (2.5 equiv) afforded the desired product 11 in
74% yield.16 Phenylated enoate 12 was prepared in 86% yield
by Suzuki-Miyaura coupling of (Z)-1 using PhB(OH)2 in the
presence of a catalytic amount of Pd(PPh3)4.17 The resulting
substituted enoates 7 and 10-12 were converted to the allylic
carbonates 3a-d by a sequence of reactions similar to the
preparation of 2 (Scheme 3).
a Mol
%
of Pd2(dba)3 ·CHCl3. b Isolated yield. c R,ꢀ-Unsaturated
compound 14 was obtained (26%). d Starting material was recovered.
FIGURE 2. Plausible explanation for the observed stereochemical
outcome with allylic carbonate 2.
Next, we investigated the palladium-catalyzed carbonylation
of allylic carbonate 2 bearing a CF3 group (Table 2).10 Treatment
of 2 with 10 mol % of Pd2(dba)3 ·CHCl3 and 40 mol % of PPh3
in EtOH at room temperature under 3.0 MPa of carbon
monoxide afforded the desired ꢀ,γ-unsaturated ester 13a in 60%
yield with a low E/Z selectivity (entry 1).15 Similarly, the
reaction proceeded smoothly at 50 °C to give 13a in 98%
combined isolated yield (entry 2). In sharp contrast, when the
reaction was carried out at 80 °C, a considerable amount of
R,ꢀ-unsaturated ester 14 was obtained (26% yield, entry 3).
Other palladium sources and ligands were ineffective at improv-
ing the E/Z selectivity (entries 4–7). The reaction in MeOH gave
the desired product 13b in 80% yield within 3 h (compare entries
8 vs 9), but the stereoselectivities were similarly low. Decreased
loading of Pd2(dba)3 ·CHCl3 (5 mol %) gave a comparable result,
while a slightly lower yield of 13b was obtained with 2.5 mol
% of Pd2(dba)3 ·CHCl3 (entries 9–11). Based on these observa-
tions, it was determined that the palladium-catalyzed carbonyl-
ation of 2 produces the desired esters in good yields but that
improvement of E/Z selectivity is difficult.
preference for syn-π-allylpalladium intermediates.10b The ob-
served low E/Z selectivities with the carbonate 2 can be partly
explained by the presence of a sterically demanding CF3 group.
Thus, oxidative addition of 2 to palladium(0) would give
π-allylpalladium intermediate A via decarboxylation (Figure 2),
which is in an equilibrium state with the π-complex B and
σ-complexes C and D via π-σ-π rearrangement. Coordination
of CO to the palladium atom of C, exchange of alkoxide, and
reductive elimination would afford (Z)-13. On the other hand,
carbonylation of D derived from B gives (E)-13 in a similar
manner. The bulky CF3 group would partly destabilize the syn
complex A because of the unfavorable 1,3-repulsion with a
hydrogen atom thus leading to nonselective formation of (Z)-
and (E)-13.
To overcome the effect of the CF3 group and improve the
stereoselectivity, we introduced another N-substituent to increase
unfavorable 1,3-repulsion in the π-complex B, thereby desta-
bilizing B and assisting the selective formation of the desired
(Z)-13 through the intermediate A. Accordingly, we prepared
N,N-diprotected allylic carbonates 15a,b from 2 by the standard
protocols and investigated the palladium-catalyzed carbonylation
reaction. As expected, the reaction proceeded smoothly to afford
the desired (Z)-ꢀ,γ-enoates 16a,b as single isomers in moderate
yields (61% and 60%, respectively) (Scheme 4).
It is worth noting that related palladium-catalyzed allylic
carbonylation favors formation of trans-isomers due to the
(16) (a) Zahn, T. J.; Weinbaum, C.; Gibbs, R. A. Bioorg. Med. Chem. Lett.
2000, 10, 1763–1766. (b) Rawat, D. S.; Gibbs, R. A. Org. Lett. 2002, 4, 3027–
3030.
Next, synthesis of TADIs having a n-Bu, Me, i-Pr, or Ph
group on the double bond was investigated. The carbonylation
(17) (a) Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58, 2201–
2208. (b) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
3944 J. Org. Chem. Vol. 73, No. 10, 2008

SCHEME 4. Carbonylation of N,N-Diprotected Allylic
Carbonates 15
SCHEME 6. Conversion to the Desired CF3-ADI 18 by
Deprotection
Further studies including synthesis and evaluation of bioactive
peptides with these isosteres as well as EADIs are now in
progress.
Experimental Section
SCHEME 5. Pd-Catalyzed Carbonylation of Allylic Carbo-
General Procedure for Palladium-Catalyzed Carbonyla-
tion of Allyl Carbonates: Pd2(dba)3 ·CHCl3 (12.8 mg, 0.0124
mmol), PPh3 (13.1 mg, 0.050 mmol), and EtOH (5 mL) were
introduced to a 100 mL stainless steel pressure bottle containing
the carbonate 2 (50 mg, 0.124 mmol). After evacuating, 3.0 MPa
of CO gas was introduced at room temperature, and the mixture
was stirred at 50 °C for 12 h. After purging, the mixture was
concentrated under reduced pressure followed by flash chromatog-
raphy over silica gel with n-hexane-AcOEt (7:1) to give (Z)-13a
(18.3 mg, 37% yield) and (E)-13a (30.4 mg, 61% yield).
nates 3a-d
Compound (Z)-13a: pale yellow solid; mp 84.0–84.5 °C; [R]24
reaction of 3a-d under the same conditions as those with 2
afforded the desired ꢀ,γ-unsaturated esters 17a-d in good yields
(Scheme 5). In sharp contrast to the reaction of CF3 derivatives
2 (Table 2), all the N-Boc-TADIs, including 17c having a bulky
i-Pr group, were obtained as the sole isolable stereoisomer.
These results suggest that the CF3 group would also exert some
interesting effects on the formation of (E)-13, not only as a
sterically congested substituent (Figure 2).18
Finally, the esters (Z)-13b and 16a were converted to the
desired deprotected CF3-ADI 18 by treatment under acidic
conditions in 85% and 95% yields, respectively (Scheme 6).19
In summary, we have developed a novel synthetic route which
is applicable to the general synthesis of CF3-ADIs and TADIs
starting from commercially available N-Boc-amino acids. This
methodology is useful in that the chiral center at the δ-position
of isosteres is derived from R-amino acids, enabling facile
evaluation of CF3-ADIs and several TADIs as peptidomimetics.
D
1
–10.4 (c 0.930, CHCl3); H NMR (400 MHz, CDCl3) δ 1.25 (t, J
) 7.1 Hz, 3H), 1.36 (s, 9H), 2.82 (m, 1H), 3.02 (dd, J ) 13.6, 5.0
Hz, 1H), 3.28–3.36 (m, 2H), 4.15 (q, J ) 7.1 Hz, 2H), 4.42–4.71
(br, 2H), 6.12 (t, J ) 7.1 Hz, 1H), 7.13–7.33 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ14.1, 28.2 (3C), 33.2, 40.6, 53.5, 61.1, 79.9,
125.1, 126.8, 128.5 (2C), 128.6, 129.3 (2C), 130.4, 136.5, 154.5,
170.1; 19F NMR (376 MHz, CFCl3) δ –59.0 (3F); HRMS (FAB)
calcd for C20H27F3NO4 (MH+) 402.1892; found 402.1895.
Compound (E)-13a: pale yellow oil; [R]24 +47.1 (c 0.950,
D
1
CHCl3); H NMR (400 MHz, CDCl3) δ 1.23 (t, J ) 6.8 Hz, 3H),
1.37 (s, 9H), 2.65–2.75 (m, 1H), 2.88–3.02 (br, 2H), 3.18–3.28 (m,
1H), 4.10 (q, J ) 6.8 Hz, 2H), 4.82 (br s, 2H), 6.45 (t, J ) 6.0 Hz,
1H), 7.18–7.33 (m, 5H); 13C NMR (100 MHz, CDCl3) δ14.1, 28.2
(3C), 32.4, 40.1, 49.8, 61.1, 79.9, 126.9, 128.4, 128.6 (2C), 129.0,
129.3 (2C), 136.8, 143.3, 154.9, 169.8; 19F NMR (376 MHz, CFCl3)
δ –61.6 (3F); HRMS (FAB) calcd for C20H27F3NO4 (MH+)
402.1892; found 402.1894.
Acknowledgment. This research was supported in part by
the 21st Century COE Program “Knowledge Information
Infrastructure for Genome Science”, a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan, the Japan Health Science
Foundation, and Targeted Proteins Research Program. E.I., T.N.,
A.N., and K.T. are grateful for the JSPS Research Fellowships
for Young Scientists.
(18) Nucleophilic substitution of allylic carbonate 2 with sodium malonate
gave the (Z)-γ,δ-malonate 19 as a single isomer.
Other examples of a CF3-containing π-allylpalladium complex with a malonate
anion have been reported to proceed with retention of configuration. See: (a)
Hanzawa, Y.; Ishizawa, S.; Kobayashi, Y. Chem. Pharm. Bull. 1988, 36,
4209-4212. (b) Hanzawa, Y.; Ishizawa, S.; Kobayashi, Y.; Taguchi, T. Chem.
Pharm. Bull. 1990, 38, 1104-1106. These results as well as the significantly
higher stereoselectivity observed with the i-Pr derivative 3c suggest other
important influences of the CF3 group in this reaction system containing carbon
monoxide.
(19) Cragoe, E. J., Jr.; Gould, N. P.; Woltersdorf, O. W., Jr.; Ziegler, C.;
Bourke, R. S.; Nelson, L. R.; Kimelberg, H. K.; Waldman, J. B.; Popp, A. J.;
Sedransk, N. J. Med. Chem. 1982, 25, 567–579.
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO702318D
J. Org. Chem. Vol. 73, No. 10, 2008 3945