Synthesis of fluoroalkene dipeptide isosteres by an intramolecular redox reaction utilizing N-Heteorocyclic carbenes (NHCs)

Article abstract of DOI:10.1021/jo900134k

(Z)-Fluoroalkene dipeptide isosteres (FADIs 16) have served as potential dipeptide mimetics possessing the substitution of fluoroalkenes for parent peptide bonds. Previously, we synthesized FADIs by reduction of γ,γ-difluoro-α,β-enoates with organocoppers

Full text of DOI:10.1021/jo900134k

Synthesis of Fluoroalkene Dipeptide Isosteres by an Intramolecular
Redox Reaction Utilizing N-Heteorocyclic Carbenes (NHCs)
Yoko Yamaki,† Akira Shigenaga,† Kenji Tomita,‡ Tetsuo Narumi,‡ Nobutaka Fujii,‡ and
Akira Otaka*,†
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokushima, 1-78-1 Shomachi,
Tokushima 770-8505, Japan, and Graduate School of Pharmaceutical Sciences, Kyoto UniVersity,
Sakyo-ku, Kyoto 606-8501, Japan
aotaka@ph.tokushima-u.ac.jp
ReceiVed January 21, 2009
(Z)-Fluoroalkene dipeptide isosteres (FADIs 16) have served as potential dipeptide mimetics possessing
the substitution of fluoroalkenes for parent peptide bonds. Previously, we synthesized FADIs by reduction
of γ,γ-difluoro-R,ꢀ-enoates with organocoppers or SmI2, which prompted us to use an intramolecular
redox reaction mediated by N-heterocyclic carbenes (NHCs) for the preparation of FADIs. Instead of the
enoates, γ,γ-difluoro-R,ꢀ-enal 20 and γ,γ-difluoro-R,ꢀ-enoylsilane 34 were converted to FADIs by an
NHC-mediated intramolecular redox reaction, whereby aldehyde components reduced the allylic difluoride
component in an SN2′ manner with accompanying monodefluorination.
Introduction
NHCs to carbonyl compounds such as aldehydes followed by
a 1,2-proton shift allowing the aldehyde carbons to possess a
negative charge (4 or 5 in Scheme 1). The resulting nucleophilic
carbons attack other carbonyls2,8 or the ꢀ-carbon of R,ꢀ-
unsaturated carbonyl compounds3 (6 or 7) to afford benzoin-
type 8 or Stetter-type 9, respectively. Additionally, the formed
negative charge can participate intramolecularly in the reduction
of R,ꢀ-epoxy 10,4a aziridinyl 11,4a or unsaturated aldehydes
12,4c,d followed by nucleophilic attack of the alcohols on the
formed acylated NHCs to give ꢀ-hydroxy 13, amino 14, or
Use of N-heterocyclic carbenes (NHCs, 2) derived from
thiazolium salts 1 as environmentally friendly reagents or
catalysts has been increasing in a wide variety of organic
transformations,1 where benzoin-type condensation,2 a Stetter-
type reaction,3 and an intra/intermolecular redox reaction4,5 are
involved (Scheme 1).6 These types of reactions feature the
umpolung7 of carbonyl carbons, that is, nucleophilic attack of
* Tel: +81-88-633-7283. Fax: +81-88-633-9505.
† The University of Tokushima.
‡ Kyoto University.
(3) Stetter-type reaction: (a) Stetter, H. Angew. Chem., Int. Ed. Engl. 1976,
15, 639–712. (b) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H. HelV. Chim.
Acta 1996, 79, 1899–1902. (c) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004,
126, 8876–8877. (d) Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005, 127,
6284–6289.
(4) Intramolecular redox reaction, oxidation to esters, see: (a) Chow,
Y.-K. K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126–8127. (b) Reynolds,
T. N.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518–9519.
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J. W. Org. Lett. 2005, 7, 3873–3876. (e) Zeitler, K. Org. Lett. 2006, 8, 637–
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J. Am. Chem. Soc. 2007, 129, 13798–13799.
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Chem. Commun. 1986, 858–859. (b) Kageyama, Y.; Murata, S. J. Org. Chem.
2005, 70, 3140–3147. (c) Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt, K. A.
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3272 J. Org. Chem. 2009, 74, 3272–3277
10.1021/jo900134k CCC: $40.75 2009 American Chemical Society
Published on Web 03/30/2009

Synthesis of Fluoroalkene Dipeptide Isosteres
SCHEME 1
SCHEME 2. (a) Synthesis of FADIs Using a SET Reaction;
(b) Envisioned Synthesis of FADIs Using NHCs
saturated esters 15, respectively. In these reactions, the aldehyde
portion reduces the epoxide, aziridine, or alkene component with
the aid of NHCs. Similar intermolecular reduction of a disulfide
compound (lipoate) is involved in the sequence of reactions
required for the formation of the acetyl coenzyme A (acetyl-
CoA).5a,9
These attractive features of NHCs typified by umpolung
prompted us to utilize NHCs for the preparation of fluoroalkene
dipeptide isosteres (FADIs, 16).10-13 Recently, we have engaged
in the synthesis of FADIs as a potential peptidomimetic by the
reduction of γ,γ-difluoro-R,ꢀ-enoates 17 with samarium diiodide
(SmI2) or organocoppers (Scheme 2a).14,15 In our proposed
reaction mechanism including Sm or Cu, successive single-
electron transfers (SETs)14c,d,16 occur from metallic reagents,
and the subsequent transfer of the two electrons into the
π-electron system adjacent to the difluoromethylene group
induces the pushing out of one of the fluorine atoms to give
the fluoroalkene moiety. On the basis of these issues, it is
tempting to envision that the addition of NHCs to the carbonyl
group in γ,γ-difluoro-R,ꢀ-enals 20 triggers the intramolecular
redox reaction between the aldehyde and the allyl difluoro units
to afford γ-fluoro-ꢀ,γ-enoates 16 in the presence of an ap-
propriate alcohol (Scheme 2b). Along these lines, we herein
report the attempt to synthesize FADIs and the synthetic
feasibility of the NHC-mediated preparation of FADIs.
(6) For some recent examples (transesterification and amidation, a-d;
homoenolate formation, e-g; others, h-j) without involving the above categories
(refs 2-5), see: (a) Grasa, G. A.; Kissling, R. M.; Nolan, S. P. Org. Lett. 2002,
4, 3583–3586. (b) Nyce, G. W.; Lamboy, J. A.; Connor, E. F.; Waymouth, R. M.;
Hedrick, J. L. Org. Lett. 2002, 4, 3587–3590. (c) Kano, T.; Sasaki, K.; Maruoka,
K. Org. Lett. 2005, 7, 1347–1349. (d) Movassaghi, M.; Schmidt, M. A. Org.
Lett. 2005, 7, 2453–2456. (e) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed.
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E. J. Am. Chem. Soc. 2006, 128, 8736–8737. (h) Fukuda, Y.; Maeda, Y.; Kondo,
K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 397–398. (i) Kano, T.; Sasaki,
K.; Konishi, T.; Mii, H.; Maruoka, K. Tetrahedron Lett. 2006, 47, 4615–4618.
(j) Suzuki, Y.; Ota, S.; Ueda, Y.; Sato, M. J. Org. Chem. 2008, 73, 2420–2423.
(7) For some representative reviews about umpolung, see: (a) Seebach, D.
Angew. Chem., Int. Ed. Engl. 1979, 18, 239–258. (b) Burstein, C.; Tschan, S.;
Xie, X.; Glorius, F. Synthesis 2006, 14, 2418–2439. (c) Brehme, R.; Enders, D.;
Fernandez, R.; Lassaletta, J. M. Eur. J. Org. Chem. 2007, 5629–5660. (d)
Dickstein, J. S.; Kozlowski, M. C. Chem. Soc. ReV. 2008, 37, 1166–1173.
(8) For some examples of reactions to imine, see: (a) Murry, J. A.; Frantz,
D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. J. Am. Chem.
Soc. 2001, 123, 9696–9697. (b) Mennen, S. M.; Gipson, J. D.; Kim, Y. R.; Miller,
S. J. J. Am. Chem. Soc. 2005, 127, 1654–1655. (c) Chan, A.; Scheidt, A. K.
J. Am. Chem. Soc. 2007, 129, 5334–5335. (d) Zhang, Y.-R.; He, L.; Wu, X.;
Shao, P.-L.; Ye, S. Org. Lett. 2008, 10, 277–280.
(10) For some recent reviews for FADIs, see: (a) Welch, J. T.; Allmendinger,
T. In Peptidomimetics Protocols; Kazmierski, W. M., Ed.; Humana Press:
Totowa, NJ, 1999; pp 357-384. (b) Couve-Bonnaire, S.; Cahard, D.; Pan-
necoucke, X. Org. Biomol. Chem. 2007, 5, 1151–1157.
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S. L. R.; Schonholzer, P.; Thomas, W. A. Tetrahedron 1986, 42, 2101–2110.
(b) Allmendinger, T.; Felder, E.; Hungerbu¨hler, E. Tetrahedron Lett. 1990, 31,
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(9) Rastetter, W. H.; Adams, J. J. Org. Chem. 1981, 46, 1882–1887.
J. Org. Chem. Vol. 74, No. 9, 2009 3273

Yamaki et al.
TABLE 1. NHC-Mediated Synthesis of FADIs Using r,ꢀ-Enal Derivatives
precatalyst
entry substrate (30 mol %)
base (30 mol %)
solvent + (additive, equiv) conditions
rt, 15 h
toluene + (EtOH, 3 equiv) rt, 15 h
product(s) (yield %, NMR)
1
2
3
4
5
6
20a
20a
20a
20b
20a
20b
1a
1a
1a
1a
1a
1b
N,N-diisopropylethylamine (DIPEA) THF + (EtOH, 3 equiv)
16a (36), 31a + 32a (12), 20a (51)a
DIPEA
DIPEA
DBU
DIPEA
DIPEA
16a (26), 31a + 32a (18), 20a (55)a
toluene + (EtOH, 5 equiv) 70 °C, 18 h 16a (12), 31a + 32a (23)b, 20a (-)c
THF + (EtOH, 10 equiv)
70 °C, 3 h
70 °C, 7 h
16b (6), 31b + 32b (8)b, 20b (21)c
16a (66)c
EtOH
EtOH
70 °C, 20 h 16b (70)c
a Yields (product ratio) were determined by NMR measurements. b Obtained as mixtures. c Isolated yield.
Results and Discussion
the reaction of an appropriate aldehyde, 25a or 25b, with chiral
phenyl glycinol derivative 26 in the presence of molecular sieves
was subjected to one-pot Honda-Reformatsky conditions
(BrCF2CO2Et + Et2Zn in the presence of catalytic amount of
RhCl(PPh3)3) to yield the chiral fluorinated ꢀ-amino esters 28.18
Hydrogenolitic removal of the chiral auxiliary with Pd(OH)2/
C-H2 followed by N-Boc protection gave the N-Boc-chiral
ꢀ-amino acid derivatives 29. DIBAL-H reduction of the resulting
ester (29a or 29b) followed by the Wittig reaction with
Ph3PdCHCHO (in benzene, 60 °C) yielded requisite substrate
20a (65%) or 20b (60%) with accompanying dienes 30,
respectively. Having the substrates, we next examined the
feasibility of the NHC-initiated synthesis of FADIs, and the
results are summarized in Table 1.
Reaction of 20a with NHC, derived from precatalyst 1a and
N,N-diisopropylethylamine (DIPEA) (30 mol % each), in THF or
toluene in the presence of EtOH at room temperature afforded
desired FADI 16a, albeit in low chemical yields (Table 1, entries
1 and 2).19 In addition to the starting material, these reactions
accompanied the formation of nonnegligible quantities of side
products including difluoro-R,ꢀ-enoate 31a and saturated ester 32a.
Reactions at elevated temperature (70 °C) did not lead to an increase
in the yield of 16 so much as to the formation of unidentified side
products (Table 1, entries 3 and 4). Yields of desired FADIs were
dramatically improved by a reaction in the presence of 1a or 1b20
in EtOH at 70 °C (Table 1, entries 5 and 6), even though the
conversion remained at a moderate level along with the formation
As requisite substrates for reaction evaluation, we first
selected δ-amino-γ,γ-difluoro-R,ꢀ-enal derivatives 20 (Scheme
3). In the course of previous studies on FADIs, we have already
established the synthetic routes for chiral R,R-difluoro-ꢀ-amino
acid derivatives (28 or 29) utilizing the Honda-Reformatsky
reaction.14d,17 In situ formed chiral imines 27 resulting from
(12) For some literature about the synthesis of FADIs or fluoroalkene units,
see: (a) Allmendinger, T.; Felder, E.; Hungerbu¨hler, E. Tetrahedron Lett. 1990,
31, 7301–7304. (b) Boros, L. G.; De Corte, B.; Gimi, R. H.; Welch, J. T.; Wu,
Y.; Handschumacher, R. E. Tetrahedron Lett. 1994, 35, 6033–6036. (c) Bartlett,
P. A.; Otake, A. J. Org. Chem. 1995, 60, 3107–3111. (d) Welch, J. T.; Lin, J.
Tetrahedron 1996, 52, 291–304. (e) Van der Veken, P.; Senten, K.; Kerte`sz, I.;
Meester, I. D.; Lambeir, A.-M.; Maes, M.-B.; Scharpe´, S.; Haemers, A.;
Augustyns, K. J. Med. Chem. 2005, 48, 1768–1780. (f) Dutheuil, G.; Lei, X.;
Pannecoucke, X.; Quirion, J.-C. J. Org. Chem. 2005, 70, 1911–1914. (g) Sano,
S.; Kuroda, Y.; Saito, K.; Ose, Y.; Nagao, Y. Tetrahedron 2006, 62, 11881–
11890. (h) Dutheuil, G.; Couve-Bonnaire, S.; Pannecoucke, X. Angew. Chem.,
Int. Ed. 2007, 46, 1290–1292. (i) Narumi, T.; Tomita, K.; Inokuchi, E.;
Kobayashi, K.; Oishi, S.; Ohno, H.; Fujii, N. Org. Lett. 2007, 9, 3465–3468. (j)
Lamy, C.; Hofmann, J.; Parrot-Lopez, H.; Goekjian, P. Tetrahedron Lett. 2007,
48, 6177–6180. (k) Wnuk, S. F.; Lalama, J.; Garmendia, C. A.; Robert, J.; Zhu,
J.; Pei, D. Bioorg. Med. Chem. 2008, 16, 5090–5102.
(13) Some recent examples of (E)-alkene-type dipeptide isosteres, see: (a)
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.
(b) Sasaki, Y.; Niida, A.; Tsuji, T.; Shigenaga, A.; Fujii, N.; Otaka, A. J. Org.
Chem. 2006, 71, 4969–4979, and references cited therein.
(14) Synthesis of FADIs using copper- or SmI2-mediated reductive
defluorination: (a) Otaka, A.; Mitsuyama, E.; Watanabe, H.; Oishi, S.; Tamamura,
H.; Fujii, N. Chem. Commun. 2000, 1081–1082. (b) Otaka, A.; Watanabe, H.;
Mitsuyama, E.; Yukimasa, A.; Tamamura, H.; Fujii, N. Tetrahedron Lett. 2001,
42, 285–287. (c) Otaka, A.; Watanabe, H.; Yukimasa, A.; Oishi, S.; Tamamura,
H.; Fujii, N. Tetrahedron Lett. 2001, 42, 5443–5446. (d) Otaka, A.; Watanabe,
J.; Yukimasa, A.; Sasaki, Y.; Watanabe, H.; Kinoshita, T.; Oishi, S.; Tamamura,
H.; Fujii, N. J. Org. Chem. 2004, 69, 1634–1645. (e) Niida, A.; Tomita, K.;
Mizumoto, M.; Tanigaki, H.; Terada, T.; Oishi, S.; Otaka, A.; Inui, K.; Fujii, N.
Org. Lett. 2006, 8, 613–616. (f) Narumi, T.; Niida, A.; Tomita, K.; Oishi, S.;
Otaka, A.; Ohno, H.; Fujii, N. Chem. Commun. 2006, 4720–4722. (g) Tomita,
K.; Narumi, T.; Niida, A.; Oishi, S.; Ohno, H.; Fujii, N. Biopolymers 2007, 88,
272–278. (h) Narumi, T.; Tomita, K.; Inokuchi, E.; Kobayashi, K.; Oishi, S.;
Ohno, H.; Fujii, N. Tetrahedron 2008, 64, 4332–4346.
(15) Taguchi’s group independently developed the reductive defluorination
protocols for the synthesis of FADIs, see: (a) Okada, M.; Nakamura, Y.; Saito,
A.; Sato, A.; Horikawa, H.; Taguchi, T. Chem. Lett. 2002, 28–29. (b) Nakamura,
Y.; Okada, M.; Horikawa, H.; Taguchi, T. J. Fluorine Chem. 2002, 117, 143–
148. (c) Okada, M.; Nakamura, Y.; Saito, A.; Sato, A.; Horikawa, H.; Taguchi,
T. Tetrahedron Lett. 2002, 43, 5845–5847. (d) Nakamura, Y.; Okada, M.; Sato,
A.; Horikawa, H.; Koura, M.; Saito, A.; Taguchi, T. Tetrahedron 2005, 61, 5741–
5753. (e) Nakamura, Y.; Okada, M.; Koura, M.; Tojo, M.; Saito, A.; Sato, A.;
Taguchi, T. J. Fluorine Chem. 2006, 127, 627–636.
(17) Honda-Reformatsky reaction: (a) Honda, T.; Wakabayashi, H.; Kanai,
K. Chem. Pharm. Bull. 2002, 50, 307–308. (b) Kanai, K.; Wakabayashi, H.;
Honda, T. Org. Lett. 2000, 2, 2549–2551. (c) Kanai, K.; Wakabayashi, H.; Honda,
T. Heterocycles 2002, 58, 47–51. (d) Boyer, N.; Gloanec, P.; De Nanteuil, G.;
Jubault, P.; Quirion, J.-C. Tetrahedron 2007, 63, 12352–12366.
(18) The use of isolated imine in Honda-Reformatsky type reaction affords
difluoro-ꢀ-lactam derivatives, see: (a) Sato, K.; Tarui, A.; Matsuda, S.; Omote,
M.; Ando, A.; Kumadaki, I. Tetrahedron Lett. 2005, 46, 7679–7681. (b) Tarui,
A.; Kondo, K.; Taira, H.; Sato, K.; Omote, M.; Kumadaki, I.; Ando, A.
Heterocycles 2007, 73, 203–208. (c) Tarui, A.; Ozaki, D.; Nakajima, N.; Yokota,
Y.; Sokeirik, Y. S.; Sato, K.; Omote, M.; Kumadaki, I.; Ando, A. Tetrahedron
Lett. 2008, 49, 3839–3843.
(19) Fluoroalkene compounds obtained in this study as major isomers have
coupling constants (3JHF ) 35.3-37.0). Those values are very consistent with
those of compounds possessing (Z)-fluoroalkene units. See: Waschu¨sch, R.;
Carran, J.; Savignac, P. Tetrahedron 1996, 52, 14199–14216. (E)-Fluoroalkenes
have smaller coupling constants (3JHF ) 20.0-21.2).12a
(20) Although precatalysts (1a and 1b) were equally effective for the
conversion, column chromatographical purification of the crude obtained by the
reaction with 1b was more easily conducted than that with 1a. Therefore, we
preferentially used NHC precursor 1b at the experiments described later.
(16) (a) Chounan, Y.; Ibuka, T.; Yamamoto, Y. J. Chem. Soc., Chem.
Commun. 1994, 2003–2004. (b) Chounan, Y.; Horino, H.; Ibuka, T.; Yamamoto,
Y. Bull. Chem. Soc. Jpn. 1997, 70, 1953–1959.
3274 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Fluoroalkene Dipeptide Isosteres
SCHEME 3a
TABLE 2. NHC-Mediated Synthesis of FADIs Using
r,ꢀ-Enoylsilanes
solvent +
(additive, equiv)
product(s)
conditions (isolated yield %)
entry substrate
1
2
3
4
5
6
34a
34a
34b
34a
34a
34b
THF + (EtOH, 10 equiv) rt, 24 h
16a (37)a
THF + (EtOH, 10 equiv) 70 °C, 3 h 16a (53)b
THF + (EtOH, 10 equiv) 70 °C, 3 h 16b (41)b
EtOH
EtOH
EtOH
rt, 24 h
70 °C, 3 h 16a (81)
70 °C, 2 h 16b (91)
16a (39), 34a (45)
a Starting materials were recovered. b Unidentified materials were
formed, whereas starting materials disappeared.
have been addressed by the Scheidt group.23 Next, we turned our
attention to the use of γ,γ-difluoro-R,ꢀ-enoylsilanes for the NHC-
mediated preparation of FADIs.
Requisite enoylsilanes 34 was prepared by the DIBAL-H
reduction of the N-Boc-protected difluoro-ꢀ-amino acid ester
29, followed by carbon chain elongation via Horner-Emmons
olefination using dimethyl phosphonoacylsilanes.24 We next
examined the synthesis of FADIs using obtained R,ꢀ-enoylsi-
lanes 34 and summarized the results in Table 2.
a Reagents and conditions: (i) molecular sieves 3 Å, THF; (ii)
BrCF2CO2Et, Et2Zn, RhCl(PPh3)3, THF-hexane; (iii) Pd(OH)2/C, H2, EtOH,
then (Boc)2O, THF; (iv) DIBAL-H, CH2Cl2-toluene, then Ph3PdCHCHO,
benzene.
SCHEME 4
In these examinations, the thiazolium salt 1b and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) were used for generation
of the corresponding NHC catalyst.20,25 First, reactions in THF
containing EtOH (10 equiv) were attempted. Treatment of
enoylsilane 34a with NHC in THF in the presence of EtOH at
room temperature gave the desired FADI 16a in 37% yield with
recovery of the starting material (Table 2, entry 1). Increasing
the temperature (70 °C) for the reaction of enoylsilanes 34
caused the starting materials to be consumed; however, isolated
yields held at a moderate level as a result of the formation of
unidentified compounds (Table 2, entries 2 and 3).26 Next, EtOH
was used as the reaction solvent. Although the reaction at room
temperature was not completed, the efficient conversions to
FADI 16 were achieved by treatments at 70 °C for 2-3 h where
the reactions proceeded in high diastereoselectivity [(Z):(E) )
96:4; Table 2, entries 5 and 6]. Compared with the reaction of
the aldehydes 20, that of the acylsilanes 34 proceeded efficiently
to yield desired FADIs 16 in high yield,27 which could be
attributed to factors shown in Scheme 5 as well as the facile
transformation to the carboanion intermediate 36 as mentioned
in the previous section.
of unidentified side products. One possible explanation for generat-
ing the R,ꢀ-enoate derivatives 31 is that the hydrogen atom present
in aldehyde-NHC adduct 21 formally does not shift on the
oxyanion as a proton (1,2-proton shift, 21 to 22) but moves away
as a hydride anion,21 thereby leading to the formation of R,ꢀ-
enoates (21 to 31 via 33, Scheme 4). We speculated that the
preferential conversion of oxyanion 21 to the corresponding
carboanion species 22 could cause the enoates 31 not to be
generated. On the basis of this assumption, utilization of a 1,2-
Brook rearrangement22 involving the 1,2-migration of a silyl group
alternate to the proton seemed to suppress the formation of side
product 31 by the efficient conversion of oxyanions to carboanions.
Recently, reactions of acylsilanes with NHCs followed by the 1,2-
Brook rearrangement with a wide variety of synthetic applications
(23) For literature about the use of acylsilanes in the presence of NHCs,
see: (a) Mattoson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc.
2004, 126, 2314–2315. (b) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6,
2465–2468. (c) Mattoson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6, 4363–4366.
(d) Mattoson, A. E.; Bharadwaj, A. R.; Zuhl, A. M.; Scheidt, K. A. J. Org.
Chem. 2006, 71, 5715–5724.
(24) Diethylphosphonoacylsilane: (a) Nowick, J. S.; Danheiser, R. L.
Tetrahedron 1988, 44, 4113–4134. (b) Nowick, J. S.; Danheiser, R. L. J. Org.
Chem. 1989, 54, 2798–2802.
(21) Chan, A.; Scheidt, A. K. J. Am. Chem. Soc. 2006, 128, 4558–4559.
(22) For literature for 1,2-Brook rearrangement, see: (a) Moser, W. H.
Tetrahedron 2001, 57, 2065–2084. (b) Takeda, K.; Yamawaki, K.; Hatakeyama,
N. J. Org. Chem. 2002, 67, 1786–1794. (c) Takeda, K.; Sawada, Y.; Sumi, K.
Org. Lett. 2002, 4, 1031–1033. (d) Takeda, K.; Onishi, Y. Tetrahedron Lett.
2000, 41, 4169–4172. (e) Tanaka, K.; Takeda, K. Tetrahedron Lett. 2004, 45,
7859–7861. (f) Koudai, T.; Masu, H.; Yamaguchi, K.; Takeda, K. Tetrahedron
Lett. 2005, 46, 6429–6432.
(25) Mixing of 1b and DBU in THF resulted in facile formation of the
corresponding NHC catalyst compared with that of 1b and DIPEA.
(26) Although the reaction of 34b in the presence of MeOH afforded the
corresponding FADI methyl ester in a slightly higher yield than that using EtOH
as additive, the use of 2-propanol as an additive gave a complex mixture.
(27) Attempted reaction of aldehyde 20b in the presence of 1b and DBU in
EtOH at 70 °C was not completed within 2 h to give FADI 16b in 24% isolated
yield.
J. Org. Chem. Vol. 74, No. 9, 2009 3275

Yamaki et al.
SCHEME 5. Comparison of Reactions Using Enals with
Those of Enoylsilanes
presence of the silyl group. This NHC-mediated redox reaction
oxidizes aldehydes or aldehyde equivalents to carboxylic esters.
Oxidative transformation to other carboxylic derivatives such
as amides should be possible. This possibility will be discussed
in the succeeding paper, where incorporation of R-substitutions
also yet to be achieved in this study will also be mentioned.
Experimental Section
(5R,2E)-5-[N-(tert-Butoxycarbonyl)amino]-4,4-difluoro-6-meth-
ylhept-2-enal (20a). To a solution of ester 29a14d (1.0 g, 3.4 mmol)
in CH2Cl2 (9.0 mL) was added dropwise a solution of DIBAL-H
in toluene (0.99 M, 6.8 mL, 6.8 mmol) at -78 °C under argon,
and the mixture was stirred for 15 min. The reaction was quenched
with saturated citric acid and extracted with Et2O. The extract was
washed with saturated citric acid and brine and dried over MgSO4.
Concentration under reduced pressure gave an oily aldehyde, which
was used immediately in the next step without further purification.
To a solution of Ph3PdCHCHO (1.0 g, 3.4 mmol) in benzene (8.0
mL) was added the above aldehyde in benzene at 40 °C under argon,
and the mixture was stirred for 1.5 h at this temperature. Concentra-
tion under reduced pressure followed by column chromatography
over silica gel with EtOAc-n-hexane (1:10) gave the title
compound 20a (612 mg, 65% yield) and 30a (144 mg, 14% yield).
Compound 20a: white powder, mp 33-35 °C. [R]2D6 + 25.2 (c 1.10,
CHCl3). 1H NMR (400 MHz, CDCl3, δ): 0.98 (d, J ) 7.0 Hz, 3H),
1.03 (d, J ) 7.0 Hz, 3H), 1.42 (s, 9H), 2.19-2.27 (m, 1H), 3.98
(dsept, J ) 4.0 and 22.4 Hz, 1H), 4.68 (d, J ) 10.4 Hz, 1H), 6.48
(dd, J ) 7.6 and 15.6 Hz, 1H), 6.69 (ddd, J ) 9.6, 13.6, and 15.6
Hz, 1H), 9.64 (d, J ) 7.6 Hz, 1H). 13C NMR (75 MHz, CDCl3, δ):
17.0, 20.7, 26.9, 28.1, 57.8 (dd, J ) 23.6 and 29.0 Hz), 80.3, 120.1
(t, J ) 246.0 Hz), 133.9 (t, J ) 7.4 Hz), 145.0 (t, J ) 26.6 Hz),
155.6, 191.9. HRMS (ESI) m/z: (M + H+) calcd for C13H22F2NO3,
278.1568; found, 278.1556. Anal. Calcd for C13H21F2NO3: C, 56.31;
H, 7.63; N, 5.05. Found: C, 56.07; H, 7.63; N, 5.05.
1
Compound 30a: colorless oil. H NMR (400 MHz, CDCl3, δ):
0.96 (d, J ) 6.4 Hz, 3H), 1.01 (d, J ) 7.2 Hz, 3H), 1.42 (s, 9H),
2.16-2.24 (m, 1H), 3.94 (dquint, J ) 2.0 and 8.8 Hz, 1H), 4.78
(d, J ) 10.4 Hz, 1H), 6.21 (dd, J ) 11.0 and 13.6 Hz, 1H), 6.29
(dd, J ) 7.6 and 15.6 Hz, 1H), 6.78 (t, J ) 13.2 Hz, 1H), 7.11 (dd,
J ) 11.2 and 15.2 Hz, 1H), 9.62 (d, J ) 8.0 Hz, 1H). 13C NMR
(75 MHz, CDCl3, δ): 16.8, 20.6, 27.0, 28.1, 58.0 (dd, J ) 23.2
and 29.4 Hz), 79.9, 120.1 (t, J ) 244.2 Hz), 131.5 (t, J ) 9.3 Hz),
134.4 (t, J ) 25.7 Hz), 134.8, 148.2, 155.7, 193.0. HRMS (ESI)
m/z: (M + Na+) calcd for C15H23F2NO3Na, 326.1544; found,
326.1536.
(5S,2E)-5-[N-(tert-Butoxycarbonyl)amino]-4,4-difluoro-6-phenyl-
hex-2-enal (20b). By the use of procedures similar to those employed
for the preparation of enal 20a, ester 29b (500 mg, 1.45 mmol)
was converted into the title compound 20b (285 mg, 60% yield)
and 30b (48.5 mg, 19% yield). Compound 20b: colorless crystal,
mp 93-95 °C (recrystallized from EtOAc-n-hexane). [R]2D6 + 32.9
(c 1.00, CHCl3). 1H NMR (400 MHz, CDCl3, δ): 1.27 (s, 9H), 2.74
(dd, J ) 11.2 and 14.4 Hz, 1H), 3.23 (d, J ) 14.4 Hz, 1H), 4.37
(br s, 1H), 4.53 (d, J ) 8.5 Hz, 1H), 6.51 (dd, J ) 7.0 and 15.6
Hz, 1H), 6.71 (ddd, J ) 9.6, 13.6, and 15.6 Hz, 1H), 7.20-7.33
(m, 5H), 9.62 (d, J ) 7.0 Hz, 1H). 13C NMR (75 MHz, CDCl3, δ):
28.0, 33.8, 55.2 (dd, J ) 24.8 and 30.3 Hz), 80.3, 119.5 (t, J )
244.5 Hz), 126.8, 128.5, 129.1, 134.3 (t, J ) 7.4 Hz), 136.0, 144.2
(t, J ) 26.6 Hz), 156.3, 191.9. HRMS (ESI) m/z: (M + H+) calcd
for C17H22F2NO3, 326.1568; found, 326.1566. Anal. Calcd for
C17H21F2NO3: C, 62.76; H, 6.51; N, 4.31. Found: C, 62.87; H, 6.56;
N, 4.22.
Addition of the NHC to the enoylsilanes 34 or enals 20
followed by 1,2-Brook rearrangement or 1,2-proton shift gave
an allyl anion-like species 36 or 22, respectively. Protonation
on the γ-position adjacent to the CF2 group by EtOH resulted
in the formation of saturated ester 32. Compared with the
γ-position of intermediate 22, that of 36 seems to be robustly
shielded by the bulky TBS group. Therefore, protonation on
the γ-position of 36 is kinetically unfavorable, leading to the
preferential formation of defluorination products 37.14d,28
A trap of silyl enol ether-type compounds 37 with electro-
philes such as alkyl halides or aldehydes in the presence of a
fluoride anion could be applicable to the synthesis of R-sub-
stituted FADIs; however, reaction of the enoylsilanes 34 with
NHC most efficiently proceeded in EtOH, working both as an
electrophilic proton source and as a nucleophilic ethoxide source
for the regeneration of the catalyst. Therefore, various attempts
to prepare R-substituted FADIs, including reactions using alkyl
halides and alkoxides in aprotic solvents, resulted in failure to
yield the desired products.
In conclusion, the NHC-mediated intramolecular redox reac-
tion of γ,γ-difluoro-R,ꢀ-enals 20 or -enoylsilanes 34 was
successfully applied to the synthesis of FADIs 16. The use of
enoylsilanes 34 as a starting material gave more favorable results
than that of enals 20, owing to the formation of allyl anion-like
species 36 and efficient reductive defluorination because of the
Compound 30b (mixture of diastereomers at diene position, 10:
1
1): white powder. H NMR (400 MHz, CDCl3, δ): 1.21 (s, 9H:
major isomer), 1.34 (s, 9H: minor isomer), 2.70 (dd, J ) 11.2 and
14.0 Hz, 1H), 3.17-3.32 (1H), 4.13 (br, 1H), 4.53 (d, J ) 8.8 Hz,
1H), 5.98-6.33 (2H), 6.81 (t, J ) 13.2 Hz, 1H: major isomer),
(28) (a) Yoshida, A.; Mikami, K. Synlett 1997, 1375–1376. (b) Yoshida, A.;
Hanamoto, T.; Inanaga, J.; Mikami, K. Tetrahedron Lett. 1998, 39, 1777–1780.
3276 J. Org. Chem. Vol. 74, No. 9, 2009

Synthesis of Fluoroalkene Dipeptide Isosteres
6.91 (t, J ) 12.4 Hz, 1H: minor isomer), 7.08 (dd, J ) 10.8 and
15.2 Hz, 1H: major isomer), 7.20-7.32 (m, 5H), 7.50-7.54 (m,
1H: minor isomer), 9.62 (d, J ) 7.2 Hz, 1H: major isomer), 10.22
(d, J ) 7.6 Hz, 1H: minor isomer). HRMS (ESI) m/z: (M + Na+)
calcd for C19H23F2NO3Na, 374.1544; found, 374.1558.
matography over silica gel with EtOAc-n-hexane (1:20) gave the
title compound 34a (1.10 g, 83% yield) as yellow crystals with a
mp of 67-68 °C. [R]2D5 + 8.3 (c 1.24, CHCl3). 1H NMR (400 MHz,
CDCl3, δ): 0.24 (s, 3H), 0.26 (s, 3H), 0.92-0.94 (m, 12H), 0.99
(d, J ) 6.8 Hz, 3H), 1.43 (s, 9H), 2.10-2.20 (m, 1H), 3.96 (dquint,
J ) 3.2 and 10.4 Hz, 1H), 4.68 (d, J ) 10.4 Hz, 1H), 6.39 (dt, J
) 11.6 and 15.6 Hz, 1H), 6.75 (d, J ) 15.6 Hz, 1H). 13C NMR (75
MHz, CDCl3, δ): -6.6, 16.7, 20.7, 26.4, 27.4, 28.2, 58.2 (dd, J )
24.2 and 27.2 Hz), 80.1, 120.7 (t, J ) 243.9 Hz), 132.8 (t, J )
28.0 Hz), 135.5 (t, J ) 6.5 Hz), 155.7, 235.6. HRMS (ESI) m/z:
(M + H+) calcd for C19H36F2NO3Si, 392.2433; found, 392.2420.
NHC-Mediated Synthesis of FADIs Using r,ꢀ-Enal at 70 °C
in Toluene (Table 1, entry 3). To a suspension of NHC-precursor
1a (12.2 mg, 0.054 mmol) in toluene (0.5 mL) was added DIPEA
(9.4 µL, 0.054 mmol) at room temperature under argon. After 15
min of stirring, a mixture of 20a (50 mg, 0.18 mmol) and EtOH
(53 µL, 0.90 mmol) in toluene (0.5 mL) was added to the above
mixture. The reaction mixture was stirred at 70 °C until the starting
material was completely consumed. The reaction was quenched with
NH4Cl(aq) and extracted with Et2O. The extract was washed with
1 M HCl, NaHCO3(aq), and brine and dried over MgSO4.
Concentration under reduced pressure followed by column chro-
matography over silica gel with EtOAc-n-hexane (1:8) gave the
FADI 16a (12% yield) and a mixture of 31a and 32a (23%
combined yield) with spectroscopic data identical to those reported
in literature.14d Compound 16a is an enantiomer of authentic sample
([R]2D1 - 31.0 (c 1.02, CHCl3)). Compound 16a: [R]2D5 25.8 (c 1.40,
CHCl3). 1H NMR (400 MHz, CDCl3, δ): 0.94 (d, J ) 3.2 Hz, 3H),
0.96 (d, J ) 3.2 Hz, 3H), 1.45 (s, 9H), 1.26 (t, J ) 6.8 Hz, 3H),
1.90 (sext, J ) 6.8 Hz, 1H), 3.10 (dd, J ) 7.4 and 17.4 Hz, 1H),
3.16 (dd, J ) 7.4 and 17.4 Hz, 1H), 3.99 (dt, J ) 8.2 and 19.2 Hz,
1H), 4.14 (t, J ) 6.8 Hz, 2H), 4.72 (d, J ) 8.2 Hz, 1H), 4.98 (dt,
J ) 7.2 and 36.8 Hz, 1H). HRMS (ESI) m/z: (M + Na+) calcd for
C15H26FNNaO4, 326.1744; found, 326.1746.
(5S,2E)-5-[N-(tert-Butoxycarbonyl)amino]-4,4-difluoro-6-phenyl-
hex-2-enoylsilane (34b). By the use of procedures similar to those
described for the preparation of enoylsilane 34a, ester 29b (500
mg, 1.45 mmol) was converted into the title compound 34b (540
mg, 84% yield) as yellow powder with a mp of 41-44 °C. [R]D26
+
20.3 (c 1.03, CHCl3). 1H NMR (400 MHz, CDCl3, δ): 0.24 (s, 3H),
0.25 (s, 3H), 0.93 (s, 9H), 1.26 (s, 9H), 2.67 (dd, J ) 11.2 and
14.0 Hz, 1H), 3.20 (d, J ) 14.0 Hz, 1H), 4.35 (br s, 1H), 4.52 (d,
J ) 10.4 Hz, 1H), 6.44 (dt, J ) 12.0 and 16.0 Hz, 1H), 6.71 (d, J
) 16.0 Hz, 1H), 7.20-7.33 (m, 5H). 13C NMR (75 MHz, CDCl3,
δ): -6.5, 16.7, 26.4, 28.1, 34.4, 55.4 (dd, J ) 24.7 and 30.3 Hz),
80.1, 120.1 (t, J ) 243.7 Hz), 126.7, 128.5, 129.2, 132.4 (t, J )
26.6 Hz), 136.2, 154.9, 235.7. HRMS (ESI) m/z: (M + H+) calcd
for C23H36F2NO3Si, 440.2433; found, 440.2432; Anal. Calcd for
C23H35F2NO3Si: C, 62.84; H, 8.02; N, 3.19. Found: C, 62.73; H,
7.96; N, 3.22.
NHC-Mediated Synthesis of FADIs Using r,ꢀ-Enoylsilanes in
THF (Table 2, entries 1-3). To a white suspension of the NHC
precursor 1b (9.2 mg, 0.034 mmol) in THF (0.5 mL) was added
DBU (5.1 µL, 0.034 mmol) at room temperature under argon. A
reddish orange suspension was immediately formed. After 15 min
of stirring, a solution of R,ꢀ-enoylsilane 34a or 34b (0.11 mmol)
in THF (0.5 mL) and EtOH (66 µL, 1.13 mmol) was added to the
above mixture. After being stirred at room temperature for 24 h or
at 70 °C for 3 h, the reaction was quenched with NH4Cl(aq) and
extracted with Et2O. The extract was washed with 1 M HCl,
NaHCO3(aq), and brine and dried over MgSO4. Concentration under
reduced pressure followed by column chromatography over silica
gel with EtOAc-n-hexane (1:8) gave the FADIs (entry 1, 16a, 37%;
entry 2, 16a, 53%; entry 3, 16b, 41%).
NHC-Mediated Synthesis of FADIs Using r,ꢀ-Enoylsilanes in
EtOH (Table 2, entries 4-6). To a colorless solution of the NHC
precursor 1b (9.2 mg, 0.034 mmol) in EtOH (0.5 mL) was added
DBU (5.1 µL, 0.034 mmol) at room temperature under argon. A
yellow solution was immediately formed with additional stirring
at this temperature for 15 min. To the resulting yellow solution
was added a solution of R,ꢀ-enoylsilane 34a or 34b (0.11 mmol)
in EtOH (0.5 mL). After being stirred at room temperature for 24 h
or at 70 °C for 2-3 h, the reaction was quenched with NH4Cl(aq)
and extracted with Et2O. The extract was washed with 1 M HCl,
NaHCO3(aq), and brine and dried over MgSO4. Concentration under
reduced pressure followed by column chromatography over silica
gel with EtOAc-n-hexane (1:8) gave the FADIs (entry 3, 16a, 37%
and 34a, 45%; entry 2, 16a, 81%; entry 3, 16b, 91%).
Experimental procedures similar to those employed in entry 3
were used for entries 1 and 2 (reaction temperature: room
temperature) and entry 4 (substrate, 20b; base, DBU; reaction
temperature, 70 °C). In entries 1 and 2, the ratio of compounds
included in the crude materials was determined by NMR measure-
ment in comparison with NMR data of authentic samples. In entry
4, 16b, a mixture of 31b and 32b, and 20a (starting material) were
purified by column chromatography over silica gel with EtOAc-n-
hexane. Obtained materials showed spectroscopic data identical to
those of authentic samples.14d
NHC-Mediated Synthesis of FADIs Using r,ꢀ-Enal at 70 °C
in EtOH (Table 1, entries 5 and 6). To a solution of the NHC
precursor (1a or 1b, 0.034 mmol) in EtOH (0.5 mL) was added
DIPEA (5.9 µL, 0.034 mmol) at room temperature under argon
with additional stirring at this temperature for 15 min. To the
resulting mixture was added a solution of R,ꢀ-enal (20a or 20b to
the 1a or 1b mixture, respectively, 0.114 mmol) in EtOH (0.5 mL)
at room temperature. The reaction mixture was stirred at 70 °C until
the starting material (20a or 20b) was completely consumed. The
reaction was quenched with NH4Cl(aq) and extracted with Et2O.
The extract was washed with 1 M HCl, NaHCO3(aq), and brine
and dried over MgSO4. Concentration under reduced pressure
followed by column chromatography over silica gel with EtOAc-n-
hexane (1:8) gave the FADIs (16a, 66% yield; 16b, 70% yield).
(5R,2E)-5-[N-(tert-Butoxycarbonyl)amino]-4,4-difluoro-6-meth-
ylhept-2-enoylsilane (34a). To a solution of ester 29a (1.0 g, 3.4
mmol) in CH2Cl2 (9.0 mL) was added dropwise a solution of
DIBAL-H in toluene (0.99 M, 6.84 mL, 6.77 mmol) at -78 °C
under argon, and the mixture was stirred for 15 min at this
temperature. The reaction was quenched with saturated citric acid
and extracted with Et2O. The extract was washed with saturated
citric acid and brine and dried over MgSO4. Concentration under
reduced pressure gave an oily aldehyde, which was used im-
mediately in the next step without further purification. To a mixture
of LiCl (201 mg, 4.75 mmol), (MeO)2P(O)CH2COTBS24 (1.26 g,
4.75 mmol), and DIPEA (827 µL, 4.75 mmol) in MeCN (5.0 mL)
was added the resulting aldehyde in MeCN (4.0 mL) under argon
at 0 °C. After being stirred at room temperature for 4 h, the reaction
was quenched with NH4Cl(aq) and extracted with Et2O. The extract
was washed with 0.5 M HCl and brine and dried over MgSO4.
Concentration under reduced pressure followed by column chro-
Acknowledgment. We thank Prof. Yasufumi Ohfune (Osaka
City University) for providing information about the preparation
of dimethyl phosphonoacylsilanes. This research was supported
in part by a Grant-in-Aid for Scientific Research (KAKENHI). A.S.
is grateful for research grants from the Takeda Science Foundation.
Supporting Information Available: Copies of 1H NMR and
13C NMR spectra of compounds 16a, 20a, 20b, 30a, 30b, 34a,
and 34b. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO900134K
J. Org. Chem. Vol. 74, No. 9, 2009 3277