Catalytic enantioselective tautomerization of isolated enols

Article abstract of DOI:10.1002/anie.200701428

(Figure Presented) Smells like roses: The catalytic enantioselective ketonization of two isolated enols was successful and made possible the discussion of the important mechanistic implications of these findings. The indirect enolate protonation occurs vi

Full text of DOI:10.1002/anie.200701428

Angewandte
Chemie
DOI: 10.1002/anie.200701428
Enantioselective Protonation
Catalytic Enantioselective Tautomerization of Isolated Enols
Charles Fehr*
In recent years, the enantioselective protonation of enolates
(or enol equivalents) has emerged as a powerful method for
the synthesis of chiral ketones and esters.[1,2] We have
successfully applied it to the synthesis of several important
fragrance compounds[3] and were the first to extend this
reaction to catalytic enantioselective protonation.[3g,h]
As exemplified in Scheme 1 for the synthesis of the rose-
smelling fragrance compound (S)-a-damascone ((S)-6) by
protonation of lithium enolate 2(Li) by using (ꢀ)-N-isopro-
aniline does not occur by direct C-protonation, but takes
place via en enol intermediate and/or an aggregate with the
generated lithiated chiral aniline. This result supports our
proposal of an indirect enantioselective protonation via a
mixed chiral enol/enolate aggregate; however, the best
confirmation of this reaction course would be the aforemen-
tioned (ꢀ)-3(Li)-catalyzed tautomerization of enol 7.[5]
In general, enols tautomerize very rapidly into ketones
and cannot be isolated. Notable exceptions are highly steri-
cally hindered enols.[6] We felt that it might be possible to
isolate 7 because we had obtained some indirect evidence for
its presence in the reaction medium. Indeed, although the
enantioselective protonation of 2(Li) with (ꢀ)-3 is rapid,
protonation of 2(MgCl) is very slow and inefficient.[3a]
Successive treatment of 2(MgCl) with (ꢀ)-3 and aqueous
HCl immediately afforded a 1:1 mixture of 5 and its isomer
resulting from g-protonation, whereas prolonged treatment
with aqueous acetic acid (AcOH) or aqueous LiOH afforded
5 exclusively.
First attempts to generate enol 7 by protonation of
2(MgCl) by using AcOH, MeOH, or water (1 or 2 equiv)
either gave rise to mixtures of 5 and 7 or incomplete
protonation (loss of material in the filter cake). In addition,
failure to rigorously exclude oxygen resulted in rapid
formation of autoxidation products. After some experimen-
tation, we found that addition of allyl-MgCl to ketene 1 in
toluene/THF (2:1) at ꢀ788C, followed by slow addition
(15 min) of H2O (7.5 equiv) in THF to the resultant enolate
2(MgCl) (ꢀ708C then ꢀ508C) and filtration through Celite
afforded pure enol 7 containing trace amounts of water
(Scheme 2).[7] This solution was used directly for tautomeri-
zation experiments but could also be stored in the freezer
without noticeable ketonization (< 5% in 24 h). All analytical
data are consistent with the postulated enol structure.
For the enantioselective tautomerization of enol 7, we
added the solution of 7 to (ꢀ)-3(Li) at such a rate that 7 would
ketonize continually, thus keeping the risk of a noncatalytic
pathway as low as possible. Under our optimized conditions,
the toluene/THF solution of 7 (1 equiv, ꢁ 0.2m) was added
slowly to a cooled (ꢀ788C) solution of (ꢀ)-3(Li) (0.33 equiv)
in THF. After addition of one third of the solution (stoichio-
metric conditions), the formed (S)-5 showed an ee value of
92%, after addition of two thirds of the solution there was
83% ee, and after complete addition there was 76% ee
(Scheme 2).The reduction in ee values when adding excess
enol may be due to the presence of residual water in 7, leading
to less-efficient aggregates or to a competing LiOH-catalyzed
tautomerization.
Scheme 1. The postulated enol/enolate complex 4, which is formed
prior to irreversible stereocontrolled C-protonation.
pylephedrine ((ꢀ)-3), we postulated that prior to the irrever-
sible stereocontrolled C-protonation, a tight transition-state-
like complex 4 would be formed, which may be further
aggregated with chiral or achiral ligands. If this mechanistic
hypothesis is correct, the “inverse” process, the tautomeriza-
tion of the unknown enol 7 by using the deprotonated chiral
reagent (ꢀ)-3(Li), should also lead to the same hypothetical
species 4 and thus to (S)-a-damascone.
Recently, Vedejs et al.[4] designed an ingenious experi-
ment that demonstrated, contrary to expectations, that the
enantioselective protonation of an amide enolate with a chiral
[*] Dr. C. Fehr
Firmenich SA
Interestingly, by using (ꢀ)-3(Li) of 50% ee, a distinct
nonlinear effect was observed. Continual introduction of 7
(0.25, 0.5, 1.0, 1.5 equiv) to (ꢀ)-3(Li) (50% ee) afforded (S)-5
with 69, 65, 57, and 50% ee respectively. This experiment
Corporate R&D Division
P. O. Box 239, 1211 Geneva 8 (Switzerland)
Fax : (+41)22-780-3334
E-mail: charles.fehr@firmenich.com
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chosen. As shown in the first example, the enantioselectivity
is very high at the beginning of the addition of 9 to (ꢀ)-3(Li)
and decreases upon further addition of 9 (97% ee with
2 equivalents of (ꢀ)-3(Li); 71% ee with 0.33 equivalents of
(ꢀ)-3(Li)).
Alternatively, enantioselective protonation of the E-rich
lithium enolate 8(Li) (E/Z ꢁ 94:6), which was obtained
indirectly via enol silyl ether 11[9] by its addition to a 1:1
mixture of (ꢀ)-3 (1.2 equiv) and (ꢀ)-3(Li) (1.2 equiv)[10] in
THF at 28C, afforded (S)-10 with 90% ee in 95% yield.[11]
In conclusion, we have developed a procedure for the
stereoselective generation and isolation of (E)-enols.
Employing these enols, we have achieved their catalytic
enantioselective ketonization and validated the postulate of
indirect enolate protonation, which occurs via enols and
higher-order mixed aggregates.
Scheme 2. Preparation and reactivity of enol 7. a) Allyl magnesium
chloride (1.04 equiv), THF, toluene, ꢀ708C!RT; b) H2O (7.5 equiv),
THF, toluene, ꢀ70!ꢀ508C, 15 min, ca. 95% crude yield; c) addition
of 7, THF, toluene to (ꢀ)-3(Li), THF, toluene, ꢀ788C; [a] 12-mmol
scale, total addition time: 45 min; [b] 24-mmol scale, total addition
time: 2 h.
Experimental Section
7: A solution of allyl magnesium chloride in THF (1.80m, 13.9 mL,
25.0 mmol) was added at ꢀ708C over 10 min to a stirred solution of 1
(3.60 g, 24.0 mmol) in THF/toluene (1:1, 60 mL). The pale-colored
reaction mixture was allowed to warm to 258C (over 30 min) and was
then cooled at ꢀ788C. By means of a syringe pump, a solution of H2O
(3.24 mL; 180.0 mmol) in THF (15 mL) was added over 15 min to the
cooled reaction mixture. The suspension was allowed to reach ꢀ508C
and a clear liquid phase was formed, which could be easily separated
from the heavy material sticking to the walls of the flask by filtration
over Celite (under N2). MgSO4·H2O (approximately 4 g) was added
and the mixture was swirled under N2. After 2 min, the suspension
was filtered and rinsed with THF/toluene (1:2, 60 mL) to obtain a
volume of 115 mL (containing a maximum of 24.0 mmol of 7).
For the preparation of 7 in deuterated solvents (for NMR
spectroscopic measurements), the above solution of allyl magnesium
chloride was concentrated to dryness and treated at ꢀ788C with a
solution of 1 in [D8]THF/[D8]toluene. The addition of water was
performed as described above. The solution obtained after filtration
over Celite was used as such.
demonstrates that higher-order mixed aggregates are
involved in the enantioselective transformation of enols into
ketones.
In the context of taiwaniaquinoids[8] and to demonstrate
the broader applicability of enantioselective enol tautomeri-
zation, we prepared the phenyl ketone (S)-10 by tautomeri-
zation of enol 9, which is readily isolated as a solution in THF
(95% crude yield, purity > 90%; Scheme 3). To ensure rapid
tautomerization, a reaction temperature of ꢀ308C was
Analytical data of 7 (E/Z ꢁ 9:1) (prepared in [D8]toluene/
[D8]THF (2:1)): IR (THF): 1620, 3000–3700 cmꢀ1 (br). 1H NMR
((E)-7; [D8]THF/[D8]toluene (1:2)): d = 1.46 (s, 6H), 1.47 (dd, J = 6,
6 Hz, 2H), 1.96 (split s, 3H), 2.00 (m, 2H), 3.06 (br d, J = 5 Hz, 2H),
5.05 (m, 1H), 5.15 (m, 1H), 5.59 (m, 1H), 5.82 (m, 1H), 6.24 (s, 1H;
disappears with D2O); characteristic signals of (Z)-7: 1.20 (s, 6H),
3.15 ppm (br d, J = 5 Hz, 2H). 13C NMR ([D8]THF/[D8]toluene (1:2)):
d = 23.7 (t), 25.7 (q), 28.0 (2q), 36.2 (s), 40.4 (t), 42.8 (t), 116.4 (t),
121.1 (s), 127.8 (d), 133.0 (s), 135.8 (d), 147.0 ppm (s).
(S)-5: The solution of 7 in toluene/THF ( ꢁ 1:1, 115 mL) was
added by means of a syringe pump (over 2 h) to a cooled (ꢀ788C)
solution of (ꢀ)-3(Li) (12.0 mmol; prepared form (ꢀ)-3 (2.49 g;
12.0 mmol), BuLi (1.45m in hexane, 8.28 mL, 12.0 mmol), and THF
(15 mL) in the presence of a trace of o-phenanthroline (indicator).
After complete addition, the reaction mixture was allowed to reach
ꢀ408C and was then poured into 5% HCl (250 mL) and extracted
with Et2O (2x). The organic phases were washed successively with
H2O, saturated aqueous NaHCO3, and saturated aqueous NaCl and
then dried (Na2SO4) and evaporated. Bulb-to-bulb distillation (oven
Scheme 3. Preparation and reactivity of enol 9. a) PhMgCl (1.07 equiv
+ 0.16 equiv (after5 h)), THF, 55 8C, 7 h; b) H2O (7.5 equiv), THF,
ꢀ70!ꢀ358C, 15 min, ca. 95% crude yield; c) addition of 9, THF to
(ꢀ)-3(Li), THF, ꢀ308C; [a] 3-mmol scale, THF, total addition time:
70 min; d) Me3SiCl (1.6 equiv), ꢀ508C!RT, 1 h; e) MeLi (1.15 equiv),
THF (Et2O), 408C, 15 min; f) addition of 8(Li), THF to (ꢀ)-3(Li)
(1.2 equiv)/(ꢀ)-3 (1.2 equiv), THF, 28C in 1 h.
temperature 75–1008C/10 mbar, then 2 mbar) afforded a head
fraction of volatile materials (mainly 1,5-hexadiene) and a second
fraction of (S)-5 (3.71 g, 96% pure, 77% from 1; 76% ee (chiral GC:
CP-Chirasil-DEX CB, 25 m ” 0.25 mm)).
(E)-9: 1H NMR([D8]THF): d = 1.12 (split s, 3H), 1.39 (s, 6H),
1.48 (dd, J = 6, 6 Hz, 2H), 2.03 (m, 2H), 5.43 (m, 1H), 7.17 (s, 1H),
7.20–7.33 ppm (m, 5H). 13C NMR ([D8]THF): d = 24.0 (t), 25.6 (q),
7120
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27.8 (2q), 36.2 (s), 42.4 (t), 121.7 (s), 127.3 (d), 128.5 (2d), 128.5 (d),
130.3 (2d), 133.7 (s), 143.2 (s), 150.2 ppm (s).
Angew. Chem. 1994, 106, 1967; Angew. Chem. Int. Ed. Engl.
1994, 33, 1888.
[4] E. Vedejs, A. W. Kruger, N. Lee, S. T. Sakata, M. Stec, E. Suna,J.
Am. Chem. Soc. 2000, 122, 4602.
13C NMR signals for 7 and 9 are assigned as shown.
[5] a) For a unique case of enantioselective tautomerization of an
aldehyde enol obtained in solution at ꢀ788C, see: R. Henze, L.
Duhamel, M.-C. Lasne, Tetrahedron: Asymmetry 1997, 8, 3363;
b) For enantioselective protonation reactions of enols generated
in situ, see: F. HØnin, A. Mꢀboungou-Mꢀpassi, J. Muzart, J.-P.
P›te, Tetrahedron 1994, 50, 2849; F. HØnin, J. Muzart, J.-P. P›te,
A. Mꢀboungou-Mꢀpassi, H. Rau, Angew. Chem. 1991, 103, 460;
Angew. Chem. Int. Ed. Engl. 1991, 30, 416; c) see also: S. H.
Bergens, B. Bosnich, J. Am. Chem. Soc. 1991, 113, 958; d) for the
indirect proof of an enediol intermediacy during enolate
protonation, see: L. Duhamel, J.-C. Launay, Tetrahedron Lett.
1983, 24, 4209.
(S)-10: [a][a]2D0 (CHCl3; c = 2.3) ꢀ256 (63% ee by chiral GC (CP-
Chirasil-DEX CB, 25 m ” 0.25 mm; major enantiomer: first peak)).
Received: April 2, 2007
[6] a) A. Kresge, Chem. Soc. Rev.1996, 25, 275; H. R. Seikaly, T. T.
Tidwell, Tetrahedron 1986, 42, 2587; S. Patai, The Chemistryof
Enols (Ed.: Z. Rappoport), Wiley, Chichester, 1990; b) H. E.
Zimmerman, Acc. Chem. Res. 1987, 20, 263; c) D. A. Nugiel, Z.
Rappoport, J. Am. Chem. Soc. 1985, 107, 3669; d) R. C. Fuson,
L. J. Armstrong, D. H. Chadwick, J. W. Kneisley, S. P. Rowland,
W. J. Shenk, Jr., Q. F. Soper, J. Am. Chem. Soc. 1945, 67, 386.
[7] The different qualities of enol 7 were shown to contain 0.1–
0.2 equivalents of H2O (“Karl Fischer” method). It was not
possible to rigorously dry 7 in toluene/THF in the presence of 4A
molecular sieves as these conditions resulted in rapid ketoniza-
tion. For determination of the enol content, air was bubbled
through a sample of enol solution (room temperature for 5 min),
thus affording g-oxygenated products (primarily the hydroper-
oxide). These represent 97–98% by GC and ketone 4 amounts to
2–3%. Nonvolatile by-products: approximately 5%.
[8] a) G. Liang, Y. Xu, I. B. Seiple, D. Trauner, J. Am. Chem. Soc.
2006, 128, 11022; b) R. M. McFadden, B. M. Stoltz, J. Am. Chem.
Soc. 2006, 128, 7738.
[9] The addition of PhLi in Bu2O to 1 in THFat ꢀ708C affords a 3:1
mixture of (E/Z)-8(Li) which is unsuitable for enantioselective
protonation (74% ee!).
[10] Under these conditions, accumulation of transient 9 is avoided;
see reference [3e].
[11] The absolute configuration of (S)-10 was determined by
independent synthesis (PhLi + p-chlorothiophenylester of (S)-
a-cyclogeranic acid (Ref. [3g]).
Published online: June 26, 2007
Keywords: enantioselective protonation · enols ·
.
Grignard reagents · ketenes · odoriferous compounds
[1] Reviews: a) C. Fehr, Angew. Chem. 1996, 108, 2726; Angew.
Chem. Int. Ed. Engl. 1996, 35, 2566; b) C. Fehr, Chiralityin
IndustryII (Eds.: A. N. Collins, G. N. Sheldrake, J. Crosby),
Wiley, Chichester, 1997, p. 335; c) J. Eames, N. Weerasooriya,
Tetrahedron: Asymmetry 2001, 12, 1; d) B. Schäfer, Chem.
Unserer Zeit 2002, 36, 382; e) L. Duhamel, P. Duhamel, J.-C.
Plaquevent, Tetrahedron: Asymmetry 2004, 15, 3653.
[2] Selected recent examples: a) J. T. Mohr, T. Nishimata, D. C.
Behenna, B. M. Stoltz, J. Am. Chem. Soc. 2006, 128, 11348; b) K.
Mitsuhashi, R. Ito, T. Arai, A. Yanagisawa, Org. Lett. 2006, 8,
1721; c) C. Schaefer, G. Fu, Angew. Chem. 2005, 117, 4682;
Angew. Chem. Int. Ed. 2005, 44, 4606.
[3] a) C. Fehr, J. Galindo, J. Am. Chem. Soc. 1988, 110, 6909; b) C.
Fehr, O. Guntern, Helv. Chim. Acta 1992, 75, 1023; c) C. Fehr, I.
Stempf, J. Galindo, Angew. Chem. 1993, 105, 1091; Angew.
Chem. Int. Ed. Engl. 1993, 32, 1042; d) C. Fehr, J. Galindo, Helv.
Chim. Acta 1995, 78, 539; e) C. Fehr, N. Chaptal-Gradoz, J.
Galindo, Chem. Eur. J. 2002, 8, 853; f) C. Fehr, J. Galindo, I.
Farris, A. Cuenca, Helv. Chim. Acta 2004, 87, 1737; g) C. Fehr, J.
Galindo, I. Stempf, Angew. Chem. 1993, 105, 1093; Angew.
Chem. Int. Ed. Engl. 1993, 32, 1044; h) C. Fehr, J. Galindo,
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