Asymmetric synthesis of fluorinated amino macrolactones through ring-closing metathesis

Article abstract of DOI:10.1021/jo701484w

(Chemical Equation Presented) The synthesis of new chiral fluorinated amino and azamacrolactones of types 1 and 2 is described. A ring-closing metathesis (RCM) reaction constitutes the key step in this methodology, which uses fluorinated amino alcohols 7

Full text of DOI:10.1021/jo701484w

Asymmetric Synthesis of Fluorinated Amino Macrolactones through
Ring-Closing Metathesis
Santos Fustero,*,†,¶ Begon˜a Ferna´ndez,† Juan F. Sanz-Cervera,†,¶ Natalia Mateu,¶
Silvia Mosule´n,‡ Rodrigo J. Carbajo,‡ Antonio Pineda-Lucena,‡ and
Carmen Ram´ırez de Arellano†,§
Departamento de Qu´ımica Orga´nica, UniVersidad de Valencia, E-46100 Burjassot, Spain, and
Laboratorio de Mole´culas Orga´nicas and Laboratorio de Biolog´ıa Estructural, Centro de InVestigacio´n
Pr´ıncipe Felipe, E-46013 Valencia, Spain
santos.fustero@uV.es
ReceiVed July 9, 2007
The synthesis of new chiral fluorinated amino and azamacrolactones of types 1 and 2 is described. A
ring-closing metathesis (RCM) reaction constitutes the key step in this methodology, which uses fluorinated
amino alcohols 7 as starting materials. The influence of the CF2 group, which is located in the R-position
relative to the carbon bearing the amino group, on the efficiency of the RCM reaction is noteworthy.
This method allows for the preparation of the desired fluorinated macrolactones in excellent yields.
Introduction
in the preparation of numerous carbo- and heterocycles with
various ring sizes, including medium-sized rings and macro-
cycles.6 In the case of macrocycle preparation through RCM,
the desired compounds are usually obtained as mixtures of E
and Z isomers when the cycle is 11-membered or larger. The
isomeric proportions are generally hard to predict, and control-
Numerous macrolactones with interesting biological activities
have been isolated and identified from various plants and
microorganisms in recent years.1 Among them, the discovery
of erythromycin as a powerful and versatile antibiotic led to a
tremendous surge in interest in both natural and semisynthetic
macrolides, principally because of their antibacterial effects.
However, these compounds also display other important bio-
logical activities, including antitumoral,2 antifungal, and anti-
biotic3 properties.
Of the several synthetic strategies that have been used in the
synthesis of these compounds to form the lactone ring,4 the ring-
closing metathesis (RCM) of dienes has emerged as a powerful
synthetic tool in the past few years,5 mostly due to its efficacy
(2) (a) Va´zquez, D. Mechanism of Action of Antimicrobial and Antitumor
Agents. In Antibiotics III; Corcoan, J., Hahn, F., Eds.; Springer: New York,
1975; pp 459-479. (b) Hindupur, R. M.; Panicker, B.; Valluri, M.; Avery,
M. A. Tetrahedron Lett. 2001, 42, 7341-7344. (c) Palomo, C.; Oiarbide,
M.; Garc´ıa, J.; Gonza´lez, A.; Pazos, R.; Odriozola, J.; Ban˜uelos, P.; Tello,
P.; Linden, A. J. Org. Chem. 2004, 69, 4126-4134.
(3) Katz, L.; Ashley, G. Chem. ReV. 2005, 105, 499-528 and references
included therein.
(4) (a) Ruppin, C.; Dixneuf, P. H. Tetrahedron Lett. 1986, 27, 6323-
6324. (b) Posner, G. H.; Wang, Q.; Halford, B. A.; Elias, J. S.; Maxwell,
J. P. Tetrahedron Lett. 2000, 41, 9655-9659. (c) Litinas, K. E.; Salteris,
B. E. J. Chem. Soc., Perkin Trans. 1 1997, 2869-2872 and references
included therein. (d) Inanaga, J.; Hirata, H.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989-1993. (e) Yeung,
K.-S.; Paterson, I. Chem. ReV. 2005, 105, 4237-4313.
(5) (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 3800-
3801. (b) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59,
4029-4031.
(6) (a) Gradillas, A.; Pe´rez-Castells, J. Angew. Chem., Int. Ed. 2006,
45, 6086-6101. (b) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-
2238. (c) Nicolaou, K. C.; King, N. P.; He, Y. Top. Organomet. Chem.
1998, 1, 73-104. (d) Hoveyda, A. H. Top. Organomet. Chem. 1998, 1,
105-132. (e) Roxburgh, C. J. Tetrahedron 1995, 51, 9767-9822. (f)
Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942-3943. (g)
Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792-803.
† Universidad de Valencia.
¶ Laboratorio de Mole´culas Orga´nicas, Centro de Investigacio´n Pr´ıncipe Felipe.
‡ Laboratorio de Biolog´ıa Estructural, Centro de Investigacio´n Pr´ıncipe Felipe.
§ Corresponding author for X-ray analysis.
(1) (a) Nakanishi, K.; Goto, T.; Ito, S.; Natori, S.; Nozoe, S. Natural
Products Chemistry; Academic Press: New York, 1974; Vol. 2, pp 299-
480. (b) Rychnovsky, S. D.; Hwang, K. J. Org. Chem. 1994, 59, 5414-
5418. (c) Hanson, K.; O’Neill, J. A.; Simpson, T. J.; Willis, C. L. J. Chem.
Soc., Perkin Trans. 1 1994, 2493-2497. (d) Thomson, R. The Chemistry
of Natural Products; Blackie & Son: Glasgow, 1986. (e) Carnell, A. J.;
Casy, G.; Gorins, G.; Kompany-Saeid, A.; McCague, R.; Olivo, H. F.;
Roberts, S. M.; Willetts, A. J. J. Chem. Soc., Perkin Trans. 1 1994, 3431-
3439.
10.1021/jo701484w CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/10/2007
8716
J. Org. Chem. 2007, 72, 8716-8723

Asymmetric Synthesis of Fluorinated Amino Macrolactones
SCHEME 1
ling them is difficult due to the fact that the reaction results
usually depend on the substrate and catalyst used.7 In contrast,
in the case of 10-membered lactones, the Z isomer is generally
obtained in a stereoselective manner.
The introduction of fluorine atoms, in particular, those of
trifluoromethyl and difluoroalkyl groups, into organic molecules8
is advantageous for the biological activity of potential drugs as
it generally increases bioavailability and often leads to a direct
interaction with active centers in certain processes. For this
reason, fluorinated compounds are increasingly being applied
in fields such as medicine,9 crop management,10 and materials
science.11
SCHEME 2
In sharp contrast with the number of known natural lactones,
there are no examples of natural fluorinated lactones. While
reports on nonfluorinated macrolide syntheses are also abundant,
those for the preparation of their fluorinated counterparts are
still very scarce and have mostly focused on the preparation of
five- and six-membered lactones. To the best of our knowledge,
only two research groups have studied the synthesis of
fluorinated macrolactones to date. Very recently, Danishefsky
and co-workers carried out the synthesis of fludelone, a
fluorinated epothilone.12 In this case, the introduction of a
trifluoromethyl group in the macrolactone system led to
enhancement of the well-known antitumoral properties of this
macrolide. Previously, Haufe and co-workers had also prepared
a monofluorinated derivative of lasiodiploidine, a natural 12-
membered lactone.13
although Langlois and co-workers have described the synthesis
of a related system, a 14-membered lactam that features a
trifluoromethyl group.15
Additionally, a handful of interesting amino and azamacro-
lactones have been described as natural products, such as the
azamacrolides that form the defensive pupal secretion of one
species of Epilachna (the Mexican beetle).14 In contrast with
the few existing syntheses of amino or azalactones, however,
none have been described for their fluorinated analogues to date,
Considering the potential interest of these compounds, we
have decided to undertake their synthesis. In this paper, we
describe an efficient synthesis of new chiral amino macrolac-
tones 1 and azamacrolactones 2 in enantiomerically pure form
and with an RCM as the key reaction (Scheme 1). The fluorine
atoms were introduced into the molecule at the building block
3 stage; this, in turn, was transformed into the fluorinated
â-amino alcohols 7, which then served as precursors of both 1
and 2 (Scheme 1). For comparison purposes, we also decided
to prepare an analogue of system 1 with the CF2 group located
at a different position as well as a nonfluorinated analogue in
order to determine the influence of both the presence and
position of the CF2 group on the preparation of these com-
pounds.
(7) (a) Fu¨rstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc.
1999, 121, 11108-11113 and literature cited therein. (b) Lee, C. W.; Grubbs,
R. H. Org. Lett. 2000, 2, 2145-2147. (c) Fu¨rstner, A.; Thiel, O. R.; Blanda,
G. Org. Lett. 2000, 2, 3731-3734. (d) Murga, J.; Falomir, E.; Garc´ıa-
Fortanet, J.; Carda, M.; Marco, J. A. Org. Lett. 2002, 4, 3447-3449. (e)
Fu¨rstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann, C. W.;
Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061-7069.
(8) (a) Chou, T. S.; Heath, P. C.; Patterson, L. E.; Poteet, L. M.; Lakin,
R. E.; Hunt, A. H. Synthesis 1992, 565-570. (b) Berkowitz, D. B.; Sloss,
D. G. J. Org. Chem. 1995, 60, 7047-7050. (c) Uneyama, K. J. Fluorine
Chem. 1999, 97, 11-25 and references therein. (d) Penning, T. D. J. Med.
Chem. 1997, 40, 1347-1365. (e) Banks, R. E.; Smart, B. E.; Tatlow, J. C.
In Organofluorine Chemistry: Principles and Commercial Applications;
Plenum Press: New York, 1994.
(9) (a) Ojima, I.; McCarthy, J. R.; Welch, J. T. In Biomedical Frontiers
of Fluorine Chemistry; ACS Symposium Series 639; American Chemical
Society: Washington, D.C., 1996. (b) Filler, R.; Kobayashi, Y. In
Biomedicinal Aspects of Fluorine Chemistry; Kodansha Ltd.: Tokyo,
Elsevier Biomedicinal Press: Amsterdam, New York, Oxford, 1982. (c)
Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; John
Wiley & Sons: New York, 1991.
Results and Discussion
Synthesis of Amino Alcohols 7. The preparation of fluori-
nated â-amino alcohols 7a,b starts with the condensation of
fluorinated imidoyl chlorides 3a,b, which function as fluorinated
building blocks in this synthesis, and (-)-(S)-methyl-1-naph-
thylsulfoxide 4, used as a chiral auxiliary, to afford â-imino
sulfoxides 5a,b (Scheme 2).16
(10) (a) Cartwright, D. Recent Developments in Fluorine-Containing
Agrochemicals. In Organofluorine Chemistry: Principles and Commercial
Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum
Press: New York, 1994; pp 237-262. (b) Hiyama, T. Organofluorine
Compounds: Chemistry and Applications; Springer-Verlag: Berlin, Heidel-
berg, 2000; pp 167-272.
The diastereoselective reduction16 of â-imino sulfoxides (S)-
5a,b and the subsequent nonoxidative Pummerer reaction
(11) Kitazume, T.; Ohnogi, T.; Ito, K. J. Am. Chem. Soc. 1990, 112,
6608-6615.
(15) Gille, S.; Ferry, A.; Billard, T.; Langlois, B. J. Org. Chem. 2003,
68, 8932-8935.
(16) Fustero, S.; Navarro, A.; Pina, B.; Garc´ıa, J.; Bartolome´, A.; Asensio,
A.; Simo´n, A.; Bravo, P.; Fronza, G.; Volontiero, A.; Zanda, M. Org. Lett.
2001, 3, 2621-2624.
(17) (a) Crucianelli, M.; Bravo, P.; Arnone, A.; Corradi, E.; Meille, S.;
Vanda, M. J. Org. Chem. 2000, 65, 2965-2971 and references included
therein. (b) Garc´ıa Ruano, J. L.; Alema´n, J.; del Prado, M.; Ferna´ndez, I.
J. Org. Chem. 2004, 69, 4454-4463.
(12) (a) Rivkin, A.; Chou, T.-C.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 2005, 44, 2838-2850. (b) Wilson, R. M.; Danishefsky, S. J. J. Org.
Chem. 2006, 71, 8329-8351.
(13) Haufe, G.; Bruns, S.; Runge, M. J. Fluorine Chem. 2001, 112, 55-
61.
(14) Schroeder, F. C.; Smedley, S. R.; Gibbons, L. K.; Farmer, J. J.;
Attygalle, A. B.; Eisner, T.; Meinwald, J. Proc. Natl. Acad. Sci. U.S.A.
1998, 95, 13387-13391.
J. Org. Chem, Vol. 72, No. 23, 2007 8717

Fustero et al.
TABLE 1. Synthesis of Amino Esters (R)-8
generation (I) and second-generation (II) Grubbs catalysts in
CH2Cl2 (Figure 1 and Table 2).
Table 2 shows that the RCM is quite efficient in forming
10-membered rings (entries 1-5, Table 2), as can be seen from
the short reaction times when catalyst II is used and the excellent
yields of both the difluorinated (R,Z)-1a (95% yield, entry 1,
Table 2) and the tetrafluorinated amino macrolactone (R,Z)-1d
(96% yield at room temperature after just 10 min, entry 10,
Table 2). It is worth noting that in both these cases GC-MS
analysis of the reaction product showed that only one stereoi-
somer was formed in each case, which was determined to be
the Z geometric isomer by means of X-ray diffraction studies
(Figures 2 and 4).7
time
yield
(%)
entry
method
n
R
(h)
product
1
2
3
4
Aa
Bb
Bb
Bb
1
2
3
1
H
H
H
F
8
12
12
12
89
95
95
75
8a
8b
8c
8d
a Method A: (X ) Cl) (R)-7a, Et3N, DMAP CH2Cl2, rt, 8 h. b Method
B: (X ) OH) (R)-7a, DIC, DMAP, CH2Cl2, 0 °C to rt, 12 h.
The structural characterization of macrolactones 1a-d, 14
(Scheme 5), 16 (Scheme 6), and in particular the assignment
of Z,E configuration of the carbon-carbon double bond by
means of standard NMR studies was not a trivial task, as a
significant number of the resonances, including those corre-
sponding to the vinylic moiety, present very broad signals with
1
unresolved couplings in the H, 19F, and 13C NMR spectra
recorded at room temperature. This broadening can be attributed
to a conformational exchange equilibrium within the molecule,
although the fact that the NMR spectra also show sharp signals
under the same conditions indicates that such equilibrium affects
only a localized part of the molecule. The broad resonances
precluded any attempt to measure the coupling constants of the
vinylic protons, which would have allowed a quick assignment
of the double bond configuration. Furthermore, the broadening
of the signals gave 2D correlation experiments with incomplete
information that prevented a full characterization of our mac-
rolactones.
FIGURE 1. Grubbs catalysts used in RCM reactions.
(NOPR)17 of the protected â-amino sulfoxide derivatives 6a,b
afforded the enantiomerically pure fluorinated â-amino alcohols
(R)-7a,b, which were then used as starting materials for the
preparation of macrolactones 1 and 2 (see Supporting Informa-
tion).
Synthesis of Amino Macrolactones 1a-d. While amino
ester (R)-8a was easily prepared through treatment of (R)-7a
with 4-pentenoyl chloride in the presence of Et3N and DMAP
(Table 1, Method A), in the case of compounds (R)-8b-d, the
corresponding acid chlorides are not commercially available.
Therefore, these compounds had to be prepared through reaction
of the corresponding 4-carboxylic acids with (R)-7a and
diisopropylcarbodiimide as a coupling agent in dichloromethane
(Table 1, Method B).
In order to determine the structure of these compounds, a
more detailed spectroscopic study had to be carried out. Thus,
1H and 19F spectra were collected over the temperature range
of 260-360 K. Whereas the NMR spectra acquired at high
temperatures still show broad resonances, a significant improve-
ment was observed in the spectra at low temperatures, showing
the sharpest resonances at 270 K (Figure 3). Therefore, the full
characterization of compounds 1a-1d and 16 was carried out
at this temperature, including the acquisition and analysis of
To complete the synthesis, the di- and tetrafluorinated amino
macrolactones (R)-1a-d were prepared by means of a ring-
closing metathesis reaction on compounds 8 with the aid of first-
1
homonuclear COSY experiments as well as H, 13C HMQC,
TABLE 2. Preparation of Chiral, Nonracemic Amino Macrolactones (R)-1a-d
catalyst
(mol %)
temp
(°C)
time
(h)
yield
(%)
entry
n
precursor
R
product
E:Z ratio
1
2
3
4
5
6
7
1
1
1
1
1
2
2
8a
8a
8a
8a
8d
8b
8b
H
H
H
H
F
H
H
II (5)
II (5)
II (10)
II (15)
II (10)
II (5)
II (5)
25
60
60
60
25
25
60
4
4
6
4
95
1a
1a
1a
1a
1d
1b
1a
1b
1b
1c
1c
0:100
0:100
0:100
0:100
0:100
NR
0:100 (1a)
(1b)a
a
98
76
83
10 min
96
24
8
NR
77 (1a)
19 (1b)
22
8
9
10
2
3
3
8b
8c
8c
H
H
H
I (5)
II (5)
II (5)
60
25
60
8
24
8
4
70
a
a
a For both 1b and 1c, GC-MS showed the presence of only one geometric isomer, but these compounds appeared as a complex mixture of conformers
at low temperature, and thus the double bond configuration could not be determined by means of NMR spectroscopy.
8718 J. Org. Chem., Vol. 72, No. 23, 2007

Asymmetric Synthesis of Fluorinated Amino Macrolactones
SCHEME 3
FIGURE 2. Ten-membered fluorinated lactones prepared by means
of RCM.
SCHEME 4
FIGURE 3. 19F NMR spectra (282.37 MHz) of compound 1a at (a)
300 K and (b) 270 K.
δ 156.3 ppm that is assigned to the carbonyl from the benzyl
moiety and the second at δ 170.7 ppm which corresponds to
the lactone carbonyl carbon. The formation of the ring was
confirmed by means of 1H-1H COSY and 1H,13C heteronuclear
1
correlations, as each H atom in the ring gives through-bond
connections with the successive 1H and/or 13C in the molecule.
The full characterization of the molecule allowed the identifica-
tion of those signals that were broadened at higher temperatures,
and they were finally assigned to the atoms that form part of
the macrolactone ring, which is therefore affected by the
conformational exchange equilibrium. The spectra at low
temperatures also allowed the measurement of several coupling
constants between the ring protons. Especially relevant were
the couplings between the vinylic protons, whose value was
found to be 10-11 Hz and therefore in the expected range for
the Z-configuration isomer.
X-ray diffraction analysis confirmed that the configuration
of the ∆7 double bond was Z in both lactones 1a and 1d (Figure
2). The structures for 1a and 1d show C(3)-C(4)-C(5)-C(6)
torsion angles of 4.4(4) and 4(2)°, respectively, corresponding
to a Z conformation for both 10-membered amino lactones (R,Z)-
1a and (R,Z)-1d (Figure 4).18
We propose that the stereoselective formation of the Z
configuration is probably due to the higher ring strain in the E
isomer. Indeed, a molecular mechanics study performed with
the aid of the program MacroModel19 and MM2 force field on
compounds (R,Z)- and (R,E)-1a showed that the Z isomer is
more stable than the E isomer by 5 kcal/mol, a result which
FIGURE 4. X-ray diffraction analysis of macrolactone 1a.
and HMBC correlation spectra. Taking as a model for the
assignment process the characterization of 1a (the assignment
of 1b-1d and 16 follows similar arguments), the disappearance
of two allylic CH2 carbon signals in the 13C/DEPT spectra from
the starting material 8a indicates that the RCM reaction has
taken place. Additionally, the number of carbon signals observed
agrees with the formation of a 10-membered macrolactone ring
and the presence of a Cbz group. Two carbons in the 13C/DEPT
spectra can be ascribed to a vinylic double bond (δ 123.9 and
129.7 ppm). Also, two carbonyl resonances are found: one at
(18) For the X-ray structure of (R,Z)-1d, see the Supporting Information.
J. Org. Chem, Vol. 72, No. 23, 2007 8719

Fustero et al.
SCHEME 5
SCHEME 6
SCHEME 7
sheds light on the reason for the exclusive formation of the
(R,Z)-1a isomer in these cases.
In contrast with the formation of 10-membered rings, 11-
membered rings are noticeably more difficult to obtain with
our protocol, as can be deduced from the fact that the amino
lactone (R)-1b does not form at room temperature (entry 6, Table
2). Even more significantly, when catalyst II was used (entry
7, Table 2), the desired compound 1b was obtained in only 19%
yield. The major reaction product (77% yield) was again
compound (R)-1a, which in this case may arise from an
isomerization reaction previous to the RCM (Scheme 3)20 as
similar processes have already been observed by Fu¨rstner and
co-workers in the preparation of other macrolactones.21 More-
over, both the position of the double bond at ∆7 and the double
bond configuration in the resulting product coincide with those
of (R,Z)-1a obtained in entry 2 (Table 2) as proven by X-ray
diffraction studies. This indicates that the double bond isomer-
ization takes place exclusively in the ester double bond and not
in the amine moiety. This phenomenon has been previously
observed by our group.22
When we attempted to suppress the isomerization by using
catalyst I instead of II on precursor (R)-8b (entry 8, Table 2),
we found that, although the formation of the 10-membered
lactone did not take place, the yield for 1b was only 22%, with
40% of the starting material being recovered unchanged. In
addition, 20% of a dimer was also isolated from the reaction.
We were unable to improve this yield even after testing several
different reaction conditions, such as longer times and successive
additions of catalyst (Scheme 3).
The fluorinated 12-membered amino macrolactone (R)-1c was
obtained in 70% yield (entry 10, Table 2) when the reaction
was performed at 60 °C in a sealed tube with catalyst II and
CH2Cl2 as solvent (Scheme 4).
Although GC-MS showed the formation of single geometric
isomer as the major product of the RCM reaction, both 1b and
1c appeared as a mixture of conformers at low temperature,
and thus their NMR spectra were much less resolved than for
1a, 1d, and 1b. This precluded the structural assignment of the
double bond configuration in 1b and 1c.
Finally, we attempted the synthesis of the nonfluorinated
aminolactone 14 (Scheme 5) and the fluorinated analogue 16
(Scheme 6). Our intention was to compare the preparation of
these compounds with that of those previously obtained, in
which a CF2 group is always present at C-7, next to the amino
group.
(19) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C.
MacroModel (an integrated software system for modeling organic and
bioorganic molecules using molecular mechanics); J. Comput. Chem. 1990,
11, 440-467.
(20) For example, see: (a) Bourgeois, D.; Pancrazi, A.; Nolan, S. P.;
Prunet, J. J. Organomet. Chem. 2002, 643-644, 247-252. (b) Alcaide,
B.; Almendros, P.; Alonso, J. M. Chem.sEur. J. 2003, 9, 5793-5799. (c)
Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem., Int.
Ed. 2002, 41, 4732-4734.
(21) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S.
P. J. Org. Chem. 2000, 65, 2204-2207.
(22) Fustero, S.; Sa´nchez-Rosello´, M.; Jime´nez, D.; Sanz-Cervera, J. F.;
del Pozo, C.; Acen˜a, J. L. J. Org. Chem. 2006, 71, 2706-2714.
8720 J. Org. Chem., Vol. 72, No. 23, 2007

Asymmetric Synthesis of Fluorinated Amino Macrolactones
SCHEME 8
In the case of nonfluorinated lactone 14, the key intermediate
for the synthesis is the â-amino alcohol (R)-12. To prepare this
compound, commercially available (S)-N-Boc-iodoalanine was
first transformed into its corresponding organozinc derivative
and the resulting intermediate was reacted with allyl chloride
in the presence of catalytic amounts of CuBr‚SMe2 to afford
the allylated derivative (R)-9.23 Replacement of the N-Boc group
with a Cbz group, followed by reduction of (R)-11 with LiBH4,
afforded the nonfluorinated amino alcohol (R)-12 (Scheme 5).
The esterification of 12 with 4-pentenoyl chloride afforded
(R)-13 in 80% yield, which in turn was subjected to an RCM
reaction under the same reaction conditions as those used for
1a (entry 2, Table 2). In stark contrast with the preparation of
1a, the nonfluorinated amino macrolactone (R)-14 was obtained
in only 12% yield, while 80% of the starting material was
recovered unchanged. As for the fluorinated 10-membered
amino lactones 1a and 1d, a single stereoisomer with Z double
bond configuration was obtained (Scheme 5).
SCHEME 9
Finally, we were able to synthesize amino macrolactone (R)-
16 with the CF2 group located at C-2 (Scheme 6). This is in
contrast with lactone 1a, in which this group appears at C-7.
The preparation of (R)-16 from (R)-12 was actually quite
simple: Cbz-protected nonfluorinated amino alcohol (R)-12 and
2,2-difluoropentenoic acid 8a were coupled with the acid of
DIC in the presence of DMAP to afford ester (R)-15, which in
turn was treated with 5 mol % of second-generation Grubbs
catalyst II to cause the RCM reaction, thus yielding the desired
amino macrolactone (R)-16 as a single isomer, albeit in low
yield (18%, Scheme 6).
The yield for the RCM reaction that produces compounds
1a and 1d is noticeably higher than that for the nonfluorinated
analogues 14 and 16, a fact which clearly shows the importance
of the presence of the difluoromethyl group at C-7 for the
reaction to be successful. This is most likely due to the decreased
Lewis basicity of the amino group caused by the presence of
the contiguous CF2 group, as it is well-known that, when free
amino groups are present in a substrate, RCM reactions have
been shown to have lower yields as a result of the chelation of
the ruthenium catalyst.24
SCHEME 10
Synthesis of Chiral Nonracemic Fluorinated Azamacro-
lactones 2. Our second synthetic goal was the preparation of
fluorinated macrolactones with a nitrogen atom as part of the
ring. These are also very appealing synthetic targets, and their
preparation has not yet been described in the literature. With
this in mind, we decided to attempt the synthesis of azamac-
rolactones with a CF3 group as ring substituent. The synthesis
once again started with amino alcohol (R)-7b,16 which was
subjected to N-alkylation followed by O-acylation. This reaction
sequence introduced two unsaturated chains that allowed an
RCM reaction to take place later (Scheme 7).
We first attempted the direct N-alkylation on the O-unpro-
tected â-amino alcohol 7a, but the desired N-alkylation product
could not be obtained because of an intramolecular reaction
between the alkoxylate oxygen and the carbamate. This afforded
a mixture of the corresponding oxazolidinone and N-alkylated
oxazolidinone (Scheme 8).
For this reason, it was necessary to protect the hydroxyl group
in (R)-7b before the N-alkylation. Thus, after hydroxyl group
protection as its tert-butyldimethylsilyl ether to furnish com-
pound (R)-17, treatment with NaH in DMF followed by two
alkenyl bromides with different chain lengths afforded deriva-
tives (R)-18. These were then deprotected with a 9:1 TFA/H2O
mixture. The resulting N-alkylated (R)-â-amino alcohols (R)-
19a,b were treated with 4-pentenoyl chloride in the presence
(23) Rodr´ıguez, A.; Miller, D. D.; Jackson, R. F. W. Org. Biomol. Chem.
2003, 1, 973-977.
(24) (a) Wright, D. L.; Schulte, J. P., II; Page, M. A. Org. Lett. 2000, 2,
1847-1850. (b) Yang, Q.; Xiao, W. J.; Yu, Z. Org. Lett. 2005, 7, 871-
874.
J. Org. Chem, Vol. 72, No. 23, 2007 8721

Fustero et al.
339.1282, found 339.1284. The X-ray data for this compound can
be found in the Supporting Information.
of Et3N and DMAP to afford the dienic precursors (R)-20a,b
in excellent yields (Scheme 9).
(+)-(10R)-10-[(N-Benzyloxycarbonyl)amino]-9,9-difluoro-1-
oxa-6-cycloundecen-2-one (1b). This compound was obtained in
22% yield as a colorless oil when 5 mol % of the first-generation
Grubbs catalyst I was used at 60 °C: [R]D25 +4.34 (c 1.0, CHCl3);
1H NMR (CDCl3, 400 MHz) δ 1.77 (m, 2H), 2.01-2.23 (m, 4H),
2.62 (m, 2H), 4.11 (m, 1H), 4.36 (m, 2H), 5.07 (s, 2H), 5.27-5.46
(m, 2H), 7.31 (5H); HRMS calcd for (M+) C18H21F2NO4 353.1439,
found 353.1353. After purification, this compound showed a single
peak in GC-MS, which seems to indicate that it is either the Z or
the E isomer. The signals for the 19F NMR and 13C NMR spectra
of this compound were so broad at room temperature that they
provided no structural information, but at low temperature (acetone-
d6, 240 K), the NMR spectra of compound 1b show the presence
of two major conformers. However, even at 240 K, we were unable
to assign the double bond configuration because of the lack of
resolution of the 1H spectrum. The listed signals correspond to the
Finally, the cyclization of compounds (R)-20 through an RCM
reaction with second-generation Grubbs catalyst II in CH2Cl2
yielded the 10- and 12-membered azamacrolactones (R)-2a,b
in moderate to good yields (Scheme 10).
Although E:Z mixtures are usually obtained in the preparation
of macrolactones through RCM reactions,7 the 10-membered
azamacrolactone (R)-2a was obtained in 50% yield as a single
isomer, as had been the case with 1a and 1d (Scheme 10). As
with 1a, the double bond configuration was determined by
means of NMR analysis. Thus, the constant for the coupling
between the vinylic protons was J ) 10.7 Hz, a value that once
again falls in the expected range for the Z-configuration isomer.
In contrast, while the 12-membered analogue (R)-2b was
obtained in excellent yield (93%, Scheme 10), it was formed
as an E:Z isomeric mixture in a ratio of 3:1 when 5 mol % of
catalyst II was used (GM-MS, 19F NMR). The use of 15%
molar equiv of catalyst II gave a complex reaction mixture in
which compounds resulting from double bond isomerization
both before and after the RCM reaction were present, in addition
to the desired azamacrolactone 2b.
1
major conformer: H NMR (300.13 MHz, acetone-d6, 240 K) δ
1.45 (m, 1H), 1.65 (m, 1H), 1.90 (m, 1H), 2.00 (m, 1H), 2.21 (m,
2
1H), 2.33 (m, 1H), 2.41 (m, 2H), 4.75 (m, 1H), 4.96 (d, JHH
)
2
12.8 Hz, 1H), 4.99 (d, JHH ) 12.8 Hz, 1H), 5.33 (m, 1H), 5.44
(m, 1H), 7.00 (d, 2JHH ) 9.6 Hz, 1H), 7.20-7.35 (m, 5H); 13C NMR
(75.5 MHz, acetone-d6, 240 K) δ 25.2, 32.6, 35.9, 38.8, 53.5, 62.5,
67.5, 124.8, 126.9, 129.4, 129.5, 129.8, 135.3, 138.6, 157.5, 174.3;
19F NMR (282.4 MHz, acetone-d6, 240 K δ-88.2 (dd, 2JFF ) 247.5
Conclusions
3
2
3
Hz, JHF ) 13.3 Hz, 1F), -106.9 (dd, JFF ) 247.5 Hz, JHF
)
26.0 Hz, 1F).
In conclusion, we have developed a new synthetic method
that can be successfully used in the preparation of nonracemic,
optically active, di- and tetrafluorinated amino macrolactones
1 and trifluoromethyl azamacrolactones 2. The efficiency of the
RCM reaction in the formation of the 10-membered amino
macrolactones as a single stereoisomer and in a practically
quantitative manner is noteworthy since the reaction is successful
under mild conditions and with short reaction times. The poor
results obtained in the synthesis of nonfluorinated lactones 14
and 16 clearly highlight the importance of the presence of the
CF2 group at C-7 for the synthesis of this type of compounds
through RCM.
(-)-(11R)-11-[(N-Benzyloxycarbonyl)amino]-10,10-difluoro-
1-oxa-7-cyclodecen-2-one (1c). This compound was obtained in
70% yield as a colorless oil when 5 mol % of the second-generation
Grubbs catalyst II was used at 60 °C: [R]D25 -2.43 (c 1.03, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 1.5 (s, 6H), 1.9 (br s, 2H), 2.29 (m,
2H), 2.59 (m, 2H), 4.23 (m, 2H), 5.08 (m, 1H), 5.36 (m, 1H), 7.28
(s, 5H); 19F NMR (CDCl3, 285 MHz) δ [(-104.0)-(-107.0)] (m,
2F); HRMS calcd for (M+) C19H23F2NO4 367.1595, found 367.1572.
Like in 1b, this compound showed a single peak in GC-MS after
purification, which seems to indicate that it is either the Z or the E
isomer. The signals for the 19F NMR and 13C NMR spectra of this
compound were also so broad at room temperature that they
provided no structural information, but at low temperature (acetone-
d6, 240 K), the NMR spectra of compound 1c show the presence
of at least four major conformers. Even at 240 K, we were unable
to assign the double bond configuration because of the lack of
Experimental Section
Preparation of Difluorinated Amino Macrolactones (R)-1
through RCM. A solution of either the second-generation Grubbs
catalyst II [(IMes)(PCy3)Cl2RudCHPh] or the first-generation
Grubbs catalyst I [(PCy3)2Cl2RudCHPh] (the catalyst used and its
concentration are indicated in each case) was added under N2
atmosphere to a solution of the corresponding precursor (R)-8 in
dry dichloromethane (2 × 10-2 M). The reaction mixture was heated
at 60 °C in a sealed tube or stirred at room temperature until TLC
showed consumption of the starting material. The volatiles were
then removed under reduced pressure, and the brown residue was
purified by means of flash column chromatography [n-hexane/
AcOEt (8:1)].
1
resolution of the H spectrum caused by the complexity of the
conformer mixture. The listed signals correspond to the major
conformer: 1H NMR (300.13 MHz, acetone-d6, 240 K) δ 1.37 (m,
1H), 1.50 (m, 1H), 1.64 (m, 1H), 1.70 (m, 1H), 1.85 (m, 1H), 2.07
(m, 1H), 2.30 (m, 1H), 2.38 (m, 1H), 2.47 (m, 1H), 3.03 (m, 1H),
4.05 (m, 1H), 4.19 (m, 1H), 4.35 (m, 1H), 4.97 (m, 2H), 5.27 (m,
1H), 5.55 (m, 1H), 7.22 (m, 1H), 7.20-7.40 (m, 5H); 13C NMR
(75.5 MHz, acetone-d6, 240 K) δ 23.4, 25.1, 29.5, 33.6, 38.4, (2JCF
) 23.6 Hz), 53.3 (2JCF ) 22.0 Hz), 63.0, 67.5, 121.9 (3JCF ) 6.2 Hz),
124.7 (1JCF ) 244.0 Hz), 129.5, 129.8, 129.8, 135.9, 138.2, 157.2,
174,0; 19F NMR (282.4 MHz, acetone-d6, 240 K) δ-88.2 (dd, 2JFF
3
2
) 247.8 Hz, JHF ) 12.9 Hz, 1F), -107.1 (m, JFF ) 247.8 Hz,
1F).
(+)-(3R)-3-[(N-Benzyloxycarbonyl)amino]-4,4-difluoro-
3,4,5,8,9,10-hexahydro-2H-10-oxecinone (1a). This compound was
obtained in 98% yield as a white solid when 5 mol % of the second-
generation Grubbs catalyst II was used at 60 °C: [R]D25 +5.92 (c
(+)-(3R)-3-[(N-Benzyloxycarbonyl)amino]-4,4,9,9,-tetrafluoro-
3,4,5,8,9,10-hexahydro-2H-10-oxecinone (1d). This compound
was obtained in 96% yield as a white solid when 10 mol % of the
1
1.03, CHCl3); H NMR (600.1 MHz, toluene-d8) δ 1.31 (m, 1H),
25
1.84 (m, 1H), 1.93 (m, 1H), 2.26 (m, 1H), 2.90 (m, 1H), 2.96 (m,
1H), 3.15 (t, J ) 10.7 Hz, 1H), 4.50 (m, 2H), 4.90 (d, J ) 12.1
Hz, 1H), 4.99 (d, J ) 12.1 Hz, 1H), 5.09 (m, 1H), 5.20 (m, 1H),
6.98-7.11 (m, 5H); 13C NMR (150 MHz, toluene-d8) δ 23.4, 33.8,
35.0 (t, 2JCF ) 24.9 Hz), 51.7 (t, 2JCF ) 22.9 Hz), 60.8, 68.2, 123.9,
124.1 (t, 1JCF ) 246.4 Hz), 126.0, 128.8, 129.7, 132.2, 137.6, 156.3,
170.7; 19F NMR (282 MHz, toluene-d8) δ -99.5 (ddd, 2JFF ) 246.8
Hz, JHF ) 36.2 Hz, JHF ) 14.0 Hz, 1F), -109.5 (dd, 2JFF ) 246.8
Hz, JHF ) 23.8 Hz, 1F); HRMS calcd for (M+) C17H19F2NO4
second-generation Grubbs catalyst II was used at 25 °C: [R]D
1
+7.05 (c 1.05, CHCl3); H NMR (600 MHz, CDCl3) δ 2.7 (br s,
1H), 2.72 (br s, 1H), 3.16 (m, 1H), 3.18 (m, 1H), 4.35 (t, J ) 11.3
Hz, 1H), 4.78 (br s, 1H), 5.05 (br s, 1H), 5.18 (d, J ) 12.4 Hz,
1H), 5.24 (d, J ) 12.4 Hz, 1H), 5.67 (br s, 1H), 5.75 (t, J ) 11.5
Hz, 1H), 7.37 (m, 5H); 13C NMR (150 MHz, CDCl3) δ 33.5 (t,
2JCF ) 23.8 Hz), 34.8 (t, 2JCF ) 24.4 Hz), 50.5 (t, 2JCF ) 20.4 Hz),
62.0, 68.0, 115.1 (t, 1JCF ) 252.9 Hz), 122.5 (t, 1JCF ) 247.0 Hz),
128.7, 128.8, 129.0, 135.8, 155.7, 161.6; 19F NMR (282 MHz,
8722 J. Org. Chem., Vol. 72, No. 23, 2007

Asymmetric Synthesis of Fluorinated Amino Macrolactones
toluene-d8) δ -99.7 (ddd, 2JFF ) 248.2 Hz, JHF ) 36.4 Hz, JHF
)
(+)-(3R)-3-Trifluoromethyl-1-oxa-4-[(N-benzyloxycarbonyl)-
aza]-8-cyclodecen-12-one (2b). This compound was obtained in
93% yield when 5 mol % of second-generation Grubbs catalyst II
was used at 60 °C: [R]D25 +17.9 (c 1.00, CHCl3); 1H NMR (CDCl3,
400 MHz) δ 2.05-2.11 (m, 3H), 2.21-2.30 (m, 2H), 2.35-2.50
(m, 3H), 3.37 (m, 1H), 3.54 (m, 1H), 4.37 (dt, J ) 1.2, 13.4 Hz,
2H), 5.07 (m, 1H), 5.19 (s, 2H), 5.33-5.49 (m, 2H), 7.40 (s, 5H);
13C NMR (CDCl3, 100 MHz) δ 22.4, 25.4, 28.6, 31.2, 34.8, 53.0,
60.6, 67.1, 120.4 (q, 1JCF ) 288.9 Hz), 128.1, 128.4, 128.7, 132.4,
136.1, 157.5, 173.1; 19F NMR (CDCl3, 282 MHz) δ [(-70.2)-(-
71.9)], (m, 3F); HRMS calcd for (M+) C19H22F3NO4 385.1480,
found 385.1500.
13.7 Hz, 1F), -100.3 (d, 2JFF ) 259.1 Hz, 1F), -109.0 (ddd, 2JFF
) 259.1 Hz, JHF ) 33.0 Hz, JHF ) 12.5 Hz, 1F), -109.5 (dd, 2JFF
) 248.2 Hz, JHF ) 23.1 Hz, 1F); HRMS calcd for (M+) C17H17F4-
NO4 375.1093, found 375.1072. The X-ray data for this compound
can be found in the Supporting Information.
General Procedure for the Ring-Closing Metathesis of
Compounds 20a,b: Synthesis of (R)-2a,b. A solution of the
precursor (R)-20 in dry dichloromethane (2 × 10-2 M) was
introduced into a sealable pressure tube under N2 atmosphere,
followed by another solution of second-generation Grubbs catalyst
II [(IMes)(PCy3)Cl2RudCHPh] in the concentrations indicated in
the individual listings below. The tube was sealed and the reaction
mixture was stirred at 60 °C until TLC indicated that the reaction
had been completed. The solvents were then removed under reduced
pressure, and the brown residue was purified by means of flash
column chromatography [n-hexane/AcOEt (8:1)] to give the
products as colorless oils.
Acknowledgment. We thank the Ministerio de Educacio´n
y Ciencia (CTQ2007-61462/BQU, CTQ2006-01317) and the
Generalitat Valenciana of Spain (GRUPOS03/193) for financial
support. B.F. and S.M. thank the Ministerio de Educacio´n y
Cultura of Spain for predoctoral fellowships. R.J.C. is a
researcher from the Ramo´n y Cajal program (MEC).
(R)-Benzyl 3-(trifluoromethyl)-2,3,9,10-tetrahydro-10-oxo-5H-
1,4-oxazecine-4(8H)-carboxylate (2a). This compound was ob-
tained in 54% yield when 5 mol % of second-generation Grubbs
catalyst II was used at 60 °C: [R]D25 +7.4 (c 1.0, CCl3); 1H NMR
(CDCl3, 400 MHz) δ 1.92 (m, 1H), 2.33 (m, 1H), 2.70 (m, 2H),
3.91-4.25 (m, 3H), 4.55 (d, J ) 4.5 Hz, 1H), 5.14 (d, J ) 4.5 Hz,
2H), 5.00-5.15 (m, 1H), 5.43 (dt, J ) 4.8, 10.7 Hz, 1H), 5.67 (dt,
J ) 3.0, 10.7 Hz, 1H), 7.29 (s, 5H); 13C NMR (CDCl3, 100 MHz)
Supporting Information Available: Detailed experimental
procedures and spectroscopic data for compounds 8a-d, 10-17,
18a,b, 19a,b, and 20a,b, and X-ray data for compounds 1a and
1d. This material is available free of charge via the Internet at
http://pubs.acs.org.
2
δ 21.3, 34.5, 41.0, 53.3 (q, JCF ) 31.0 Hz), 60.8, 67.5, 123.7 (q,
1JCF ) 282.7 Hz), 126.9, 127.3, 127.4, 127.6, 128.5, 134.7, 155.9,
170.0; 19F NMR (CDCl3, 282 MHz) δ -79.9 (d, JFH ) 8.6 Hz,
3F); HRMS calcd for (M+) C17H18F3NO4 357.1131, found 357.1187.
JO701484W
J. Org. Chem, Vol. 72, No. 23, 2007 8723