Synthesis of enantiopure 1-arylprop-2-en-1-ols and their tert-butyl carbonates

Article abstract of DOI:10.1021/jo801874r

(Chemical Equation Presented) Enantiomerically pure 1-arylpropenols 8 have been prepared by resolution of the corresponding racemates, using the lipase formulation Novozyme 435. Deprotonation of the latter alcohols with n-BuLi, followed by derivatization with (t- BuO)₂CO, afforded the corresponding carbonates 5. Optimization of the process is presented.

Full text of DOI:10.1021/jo801874r

SCHEME 1. Transition-Metal-Catalyzed Asymmetric
Allylic Substitution
Synthesis of Enantiopure 1-Arylprop-2-en-1-ols
and Their tert-Butyl Carbonates
†
,‡
ˇ
Jan Stambasky´, Andrei V. Malkov,* and Pavel Kocˇovsky´*
Department of Chemistry, WestChem, UniVersity of Glasgow,
Glasgow G12 8QQ, Scotland, U.K.
the more delicate tert-butyl carbonates [R2 ) O-(t-Bu)] are
required for the catalytic substitution reaction to occur ef-
ficiently.6 Herein, we report on the optimized protocol for the
preparation of carbonates 5, derived from 1-arylpropenols.
Branched alcohols ArCH(OH)CHdCH2, where the carbinol
atom is flanked by an aromatic ring on one side and a vinyl
group on the other, are rather acid-sensitive compounds, prone
to the generation of a well-stabilized benzylic/allylic cation.
Therefore, both the alcohols and their esters and carbonates have
to be handled with care, and their large-scale preparation and
storage, especially in a nonracemic form, is not trivial.
a.malkoV@lboro.ac.uk; paVelk@chem.gla.ac.uk
ReceiVed August 22, 2008
The synthesis of branched carbonates (()-5 was intended to
be carried out according the known one-pot procedure (Scheme
2),8in which the starting aryl aldehyde 4 is treated with
vinylmagnesium bromide and the resulting magnesium alkoxide
is directly derivatized with Boc anhydride. A series of aromatic
and heteroaromatic aldehydes 4 were used, but the seemingly
straightforward procedure turned out to be complicated by two
side reactions, producing carbonates 6 and 7 (Table 1, entries
1-6), not mentioned in the original paper.8 While the linear
byproduct 6 is presumably formed from the primarily generated
branched carbonate 5 via a [3,3] sigmatropic rearrangement,
carbonate 7 apparently originates from the competing Canniz-
zaro-like reaction of aldehyde 4, followed by derivatization with
Boc2O. In some cases, the desired product 5 was not formed at
all and only 6 and 7 were detected (entries 8 and 9). Only
nicotinic aldehyde 4j afforded the branched carbonate (5j)
selectively (entry 7). As the mixtures of carbonates are very
difficult to separate, this method was abandoned.9
Enantiomerically pure 1-arylpropenols 8 have been prepared
by resolution of the corresponding racemates, using the lipase
formulation Novozyme 435. Deprotonation of the latter
alcohols with n-BuLi, followed by derivatization with (t-
BuO)2CO, afforded the corresponding carbonates 5. Opti-
mization of the process is presented.
π-Allyl complexes of transition metals are indispensable
intermediates in the stereo- and regiocontrolled allylic substitu-
tion (Scheme 1).1 Nonsymmetrically substituted complexes, such
as 2, which can be generated either from the linear esters 1 or
from their branched isomers 3,2 are inherently chiral. Therefore,
an enantioselective reaction starting with 1 requires the use of
a chiral catalyst (with a chiral ligand L*),3 whereas a nonchiral
catalyst is sufficient when the enantiopure branched isomer 3
is employed.1,4-7 While both ester and carbonate leaving groups
have been employed in numerous examples, in some instances,
(5) In the Mo-catalyzed allylic substitution, the η3-complex 2 has been shown
to arise via retention of configuration: (a) Dvorˇák, D.; Stary´, I.; Kocˇovsky´, P.
J. Am. Chem. Soc. 1995, 117, 6130. (b) Lloyd-Jones, G. C.; Krska, S. W.; Hughes,
D. L.; Gouriou, L.; Bonnet, V. D.; Jack, K.; Sun, Y.; Reamer, R. A. J. Am.
Chem. Soc. 2004, 126, 702.
(6) The Rh- and Ir-catalyzed allylic substitution is known to give products
of overall retention of configuration. However, the stereochemistry of the
individual steps has not been elucidated: (a) Evans, P. A.; Nelson, J. D. J. Am.
Chem. Soc. 1998, 120, 5581. (b) Evans, P. A.; Leahy, D. K.; Andrews, W. J.;
Uraguchi, D. Angew. Chem., Int. Ed. 2004, 43, 4788. (c) Evans, P. A.; Leahy,
D. K.; Slieker, L. M. Tetrahedron: Asymmetry 2003, 14, 3613. (d) Shu, C.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4794. For a featured article,
see: (e) Helmchen, G.; Dahnz, A.; Du¨bon, P.; Schelwies, M.; Weihofen, R. Chem.
Commun. 2007, 675.
† Current address: NovaEnergo, Na Hora´nku 673, 38411, Netolice, Czech
Republic.
‡ Current Address: Department of Chemistry, University of Loughborough,
Leicestershire LE11 3UT, U.K.
(1) For Pd-catalyzed allylic substitution, see: (a) Negishi, E., Ed.; Handbook
of Palladium Chemistry for Organic Synthesis; J. Wiley: New York, 2002; Vol
2, p 1663. For an overview of our contribution to Pd-catalyzed allylic substitution,
see: (b) Kocˇovsky´, P. J. Organomet. Chem. 2003, 687, 256. For an overview of
ˇ
catalysis by other metals, see: (c) Kocˇovsky´, P.; Malkov, A. V.; Vyskocˇil, S.;
Lloyd-Jones, G. C. Pure Appl. Chem. 1999, 71, 1425. (d) Kocˇovsky´, P.; Malkov,
A. V. Pure Appl. Chem. 2008, 80, 953.
(2) In principle, the two isomeric substrates 1 and 3 should produce the same
η3-complex 2 (ref 1). However, this may not always be the case, as known from
the elucidation of the “memory effect”: (a) Lloyd-Jones, G. C.; Stephen, S. C.;
(7) The stereochemistry of the formation of the molybdenum complex 2 (M
) Mo) from a chiral substrate 3, carried out in the presence of a chiral ligand,
is controlled predominantly by the ligand. An isomerization in the case of a
“mismatched” combination of 3 and L* has been demonstrated, so that even a
racemic substrate 3 can be converted into a substitution product with high
enantioselectivity: Malkov, A. V.; Stary´, I.; Gouriou, L.; Lloyd-Jones, G. C.;
Langer, V.; Spoor, P.; Vinader, V.; Kocˇovsky´, P. Chem.sEur. J. 2006, 12, 6910.
(8) Stoner, E. J.; Peterson, M. J.; Allen, M. S.; DeMattei, J. A.; Haight, A. R.;
Leanna, M. R.; Patel, S. R.; Plata, D. J.; Premchandran, R. H.; Rasmussen, M.
J. Org. Chem. 2003, 68, 8847–8852.
ˇ
Murray, M.; Butts, C. P.; Vyskocˇil; S.; Kocˇovsky´, P. Chem.sEur. J. 2000, 6,
ˇ
4348. (b) Fairlamb, I. J. S.; Lloyd-Jones, G. C.; Vyskocˇil, S.; Kocˇovsky´, P.
Chem.sEur. J. 2002, 8, 4443. (c) Gouriou, L.; Lloyd-Jones, G. C.; Vyskocˇil,
ˇ
S.; Kocˇovsky´, P. J. Organomet. Chem. 2003, 687, 525.
(3) For overviews, see ref 1 and the following: (a) Trost, B. M.; Van Vranken,
D. L. Chem. ReV. 1996, 96, 395. (b) Helmchen, G.; Pfaltz, A. Acc. Chem. Res.
2000, 33, 336. (c) Helmchen, G.; Kudis, S.; Sennhenn, P.; Steinhagen, H. Pure
Appl. Chem. 1997, 69, 513.
(4) In the Pd-catalyzed allylic substitution, the η3-complex 2 is formed via
inversion of configuration (ref 1). For the retention pathway, see: (a) Stary´, I.;
Kocˇovsky´, P. J. Am. Chem. Soc. 1989, 111, 4981. (b) Farthing, C. N.; Kocˇovsky´,
P. J. Am. Chem. Soc. 1998, 120, 6661, and refs cited therein.
(9) The published example8 featured the reaction of 3-quinolinecarboxalde-
hyde, which is closely related to 4j, our only successful substrate. As we have
now demonstrated, this method is far from being general.
9148 J. Org. Chem. 2008, 73, 9148–9150
10.1021/jo801874r CCC: $40.75 2008 American Chemical Society
Published on Web 10/08/2008

TABLE 2. Two-Pot synthesis of 1-Arylprop-2-en-1-ols and
tert-Butyl 1-arylprop-2-en-1-yl Carbonates (Scheme 3)
SCHEME 2. One-Pot Sythesis of Racemic Boc Derivatives
(for yields, see Table 1)
(()-8
(()-5 (S)-5 (R)-5
(%)b (%)c (%)c
entry aldehyde
Ar
(%)a
1
2
3
4
5
4a
4d
4e
4f
C6H5
n/ad
95
85
89
90
n/a
96
91
n/a
97
99
92
4-Br-C6H4
4-F-C6H4
3-F-C6H4
95e (74)f
77f
n/a
n/a
98
98e
4i
3,4-(MeO)2C6H3 96e (78)f
n/a
a The reactions were carried out on a 80-125 mmol scale. b Isolated
yield from the NaH method (10-65 mmol scale). c Isolated yield from
the n-BuLi method, using the enantiopure alcohol (S)-8 or (R)-8 (5-30
mmol scale). d Commercial. e Isolated yield of pure product (without
chromatography). f Isolated yield after chromatography.
SCHEME 4. Resolution of 1-Arylpropenols 8 (for Ar and
yields, see Table 3)
TABLE 1. Synthesis of tert-Butyl 1-arylprop-2-en-1-yl Carbonates
(Scheme 2)a
entry
aldehyde
Ar
products ratio in %b5:6:7
1
2
3
4
5
6
7
8
9
4b
4c
4d
4f
4g
4h
4j
4-Me-C6H4
2,4-Me2C6H3
4-Br-C6H4
3-F-C6H4
2,4-F2C6H3
3-MeO-C6H4
3-pyridyl
67:27:6c
29:64:7c
39:0:61
51:0:49
24:0:76
68:0:32
100:0:0
0:97:3
4k
4l
2-furyl
2-thiophenyl
0:74:26
a The reaction was carried out on a 50 mmol scale. b The ratio is
based on isolated yields. c Established by the 1H NMR spectroscopy of
the crude reaction mixture.
TABLE 3. Resolution of Racemic Alcohols 8 by Novozyme 435
(Scheme 4)a
entry
(()-8
(S)-8 (%)
(R)-9 (%)
(R)-8 (%)
1
2
3
4
8a
8d
8f
45
22
40
22
47
43
44
46
44
42
41
45
SCHEME 3. Two-Pot Synthesis of Racemic Boc Derivatives
(for Ar and yields, see Table 2)
8i
a The reactions were carried out on a 40-75 mmol scale.
mulation Novozyme 43511b was added to a suspension of the
corresponding 1-arylpropenol 8, isopropenyl acetate, and 4 Å
molecular sieves powder in dry toluene (Scheme 4) and
incubated at 40 °C for 16-20 h. The reactions produced
mixtures of (S)-alcohol (S)-8 and (R)-acetate (R)-9 in all cases,
which were separated by column chromatography. The acetates
were hydrolyzed by KOH in aqueous methanolic solution to
afford (R)-8 in practically quantitative yields. The enantiopurities
of the (S)-alcohols and the ester-liberated (R)-alcohols were
elucidated by GC and/or HPLC and found to be g99% ee in
each case. The absolute configuration of 8a was determined by
comparison with the commercially available enantiopure (S)-
1-phenylpropenol (S)-8a via chiral GC. The absolute configu-
ration of the remaining members of the series can be assumed
to be the same,11b which was confirmed via their carbonates
5.12
Since the one-pot procedure essentially failed, a two-step
alternative was explored next. The alcohols (()-8, resulting from
the reaction of aldehydes 4 with vinylmagnesium bromide in
THF (Scheme 3), were first isolated and purified.10 Their
subsequent deprotonation with sodium hydride, followed by
treatment with Boc anhydride, proved uneventful and afforded
the desired carbonates (()-5 in 85-95% yields (Table 2, fifth
column). The alternative deprotonation with n-BuLi, employed
for the enantiopure alcohols 8 (vide infra), proved more efficient
(Table 2, last two columns).
The nonracemic 1-arylpropenols 8 were prepared via enzy-
matic resolution as follows (Scheme 4 and Table 3).11 The
highly active, acrylic resin-supported recombinant lipase for-
(10) The products purified by chromatography were obtained in 74-78%
yield. However, when only a small excess of the Grignard reagent (5-7%) was
employed in the reaction, aqueous workup provided products of sufficient purity
in 95-98% yield (Table 2, fourth column). These products were contaminated
by minute amounts of a colored substance, which however could not even be
detected by 1H/13C NMR spectroscopy.
The synthesis of the corresponding nonracemic carbonates 5
was further optimized, namely, by using n-buthyllithium as a
base instead of sodium hydride to generate the corresponding
(11) For a review, see: (a) Ghanem, A.; Aboul-Enein, H. Y. Chirality 2005,
17, 1–15. For more examples see: (b) Ghanem, A.; Schurig, V. Tetrahedron:
Asymmetry 2003, 14, 57–62. (c) Maier, S.; Kazmaier, U. Eur. J. Org. Chem.
2000, 7, 1241–1251.
(12) The configuration was corroborated by the reaction of the carbonates 5
in a transition-metal-catalyzed allylic substitution with an enantiomerically pure
alcohol, whose absolute configuration was known. Details of this chemistry will
be revealed in due course. For a preliminary account, see ref 1d.
J. Org. Chem. Vol. 73, No. 22, 2008 9149

g, 29.6 mmol) was converted into (S)-(-)-5f (a light yellow oil;
7.24 g, 97%) using the n-butyllithium method: [R]D -14.1 (c 3.58,
CHCl3), >99% ee.
alkoxide. High yields and excellent purities of the desired
products were attained without chromatography separation
(Table 2, the last two columns). The main advantage of this
procedure over that using NaH is that it allows an accurate
dosing of the base (1.05 equiv), together with the use of a very
small excess of Boc anhydride (1.01 to 1.02 equiv).
In summary, we have successfully prepared various enan-
tiopure 1-arylpropenols 8 and their carbonates 5. Several
published procedures8,11 were tested, modified, and optimized.
These efforts resulted in the development of a robust synthetic
procedure affording enantiopure carbonates 5 that will be utilized
as the key starting materials for our novel approach to
C-nucleosides.
(()-1-(3′-Fluorophenyl)prop-2-en-1-ol (()-(8f). Vinylmagnesium
bromide (85 mL, 85 mmol, 1.0 M solution in THF) was added
slowly to a cold (-83 °C) solution of 3-fluorobenzaldehyde (9.85
g, 79.4 mmol) in THF (100 mL). The reaction mixture was stirred
for an additional 2 h (while the cooling bath was allowed to warm
up to 0 °C), and the reaction was quenched with saturated aqueous
solution of ammonium chloride (50 mL). The mixture was diluted
with ethyl acetate (400 mL), washed with brine (3 × 100 mL),
and dried (Na2SO4). Evaporation of the organic phase gave crude
(()-8f as a yellow oil (11.93 g, 98%): 1H NMR (400.1 MHz,
CDCl3) δ 2.40 (d, 3JOH,1-H ) 3.9 Hz, 1H, OH), 5.15-5.18 (m, 1H,
1-H), 5.21 (ddd, 3J3-Ha,2-H ) 10.3 Hz, 2J3-Ha,3-Hb ) 1.3 Hz, 4J3-Ha,1-H
3
2
) 1.3 Hz, 1H, 3-Ha), 5.34 (ddd, J3-Hb,2-H ) 17.1 Hz, J3-Hb,3-Ha
)
1.3 Hz, 4J3-Hb,1-H ) 1.3 Hz, 1H, 3-Hb), 5.99 (ddd, 3J2-H,3-Hb ) 17.1
Hz, 3J2-H,3-Ha ) 10.3 Hz, 3J2-H,1-H ) 6.2 Hz, 1H, 2-H), 6.97 (dddd,
Experimental Section
(()-tert-Butyl 1-(3′-Fluorophenyl)prop-2-en-1-yl Carbonate
(()-(5f). 1-(3′-Fluorophenyl)prop-2-en-1-ol (()-8f (1.600 g, 10.25
mmol) was added slowly to a suspension of sodium hydride (382
mg, 15.92 mmol, neat) in THF (25 mL) at room temperature, and
the mixture was stirred for 15 min. The resulting solution was added
slowly to a solution of Boc anhydride (2.460 g, 11.28 mmol) in
THF (60 mL) at room temperature, and the mixture was stirred at
room temperature overnight. The reaction was quenched with brine
(20 mL), the mixture was diluted with ether (250 mL), washed
with brine (3 × 50 mL), dried (Na2SO4), and evaporated. Chro-
matography on a column of silica gel (3 × 10 cm) with a mixture
of hexanes and ethyl acetate (98.5:1.5) gave (()-5f as a colorless
3J4′-H,F ) 8.6 Hz, J4′-H,5′-H ) 8.4 Hz, J4′-H,2′-H ) 2.6 Hz, J4′-H,6′-H
3
4
4
3
4
) 0.9 Hz, 1H, 4′-H), 7.09 (ddd, J2′-H,F ) 9.9 Hz, J2′-H,4′-H ) 2.6
Hz, 4J2′-H,6′-H ) 1.8 Hz, 1H, 2′-H), 7.12 (dddd, 3J6′-H,5′-H ) 7.7 Hz,
4J6′-H,2′-H ) 1.0 Hz, 4J6′-H,4′-H ) 1.0 Hz, 5J6′-H,F ) 0.4 Hz, 1H, 6′-H),
7.30 (ddd, 3J5′-H,4′-H ) 8.0 Hz, 3J5′-H,6′-H ) 7.9 Hz, 4J5′-H,F ) 5.9 Hz,
1H, 5′-H); 13C NMR (100.6 MHz, CDCl3) δ 74.65 (CH-1), 113.14
2
2
(d, JCF ) 22.1 Hz, CH-2′), 114.44 (d, JCF ) 21.2 Hz, CH-4′),
115.73 (CH2-3), 121.79 (d, 4JCF ) 2.9 Hz, CH-6′), 129.95 (d, 3JCF
) 8.2 Hz, CH-5′), 139.63 (CH-2), 145.06 (d, 3JCF ) 6.7 Hz, C-1′),
1
162.89 (d, JCF ) 246.0 Hz, CF-3′).
(R)-(-)-1-(3′-Fluorophenyl)prop-2-en-1-ol (R)-(-)-(8f) and (S)-
(+)-1-(3′-Fluorophenyl)prop-2-en-1-ol (S)-(+)-(8f). Novozyme 435
(2 g) was added to a mixture of a crude (()-8f (11.52 g, 75.7 mmol),
isopropenyl acetate (35 mL, 317 mmol), and activated 4 Å
molecular sieves powder (10 g) in dry toluene (650 mL), and the
resulting suspension was stirred at 40 °C for 20 h. The suspension
was then cooled to ambient temperature, filtered, and evaporated.
Gradient chromatography of the residue on a column of silica gel
(8 × 10 cm) with a mixture of hexanes and ethyl acetate (98:2 to
96:4) gave the corresponding acetate (R)-9f as a colorless liquid
(6.42 g, 44%), followed by (S)-8f (4.57 g, 40%) as a colorless liquid.
The acetate (R)-9f (6.41 g, 33.0 mmol) was placed in a 100 mL
flask and cooled to 0 °C, and a solution of KOH (2.13 g, 38.0
mmol) in MeOH (3.0 mL) was added dropwise. The cooling bath
was removed, and the solution was heated at 50 °C for 2 h. The
mixture was then cooled to ambient temperature, brine (50 mL)
was added, and the resulting solution was extracted with ethyl
acetate (3 × 80 mL) and the extract was dried (Na2SO4) and filtered.
Evaporation of the filtrate furnished (R)-8f as a colorless liquid
(4.76 g, 41%). The combined yield of both enantiomers was 81%.
(R)-(-)-8f: [R]D -12.25 (c 4.57, PhH). Anal. Calcd for C9H9FO:
C, 71.04; H, 5.96. Found: C, 70.98; H, 6.01. (S)-(+)-8f: [R]D
+13.13 (c 4.53, PhH). Anal. Calcd for C9H9FO: C, 71.04; H, 5.96.
Found: C, 70.78; H, 5.91.
1
oil (2.325 g, 90%): H NMR (400.1 MHz, CDCl3) δ 1.48 (s, 9H,
3
t-Bu), 5.25-5.36 (m, 2H, 3-H), 5.99 (ddd, J2-H,3-Ha ) 16.1 Hz,
3
3J2-H,3-Hb ) 10.7 Hz, J2-H,1-H ) 6.2 Hz, 1H, 2-H), 6.05 (m, 1H,
1-H), 6.98 (dddd, 3J4′-H,F ) 8.5 Hz, 3J4′-H,5′-H ) 8.5 Hz, 4J4′-H,2′-H
)
2.6 Hz, 4J4′-H,6′-H ) 1.0 Hz, 1H, 4′-H), 7.08 (ddd, 3J2′-H,F ) 9.6 Hz,
4J2′-H,4′-H ) 2.6 Hz, 4J2′-H,6′-H ) 1.0 Hz, 1H, 2′-H), 7.14 (dddd, 3J6′-
4
4
5
H,5′-H ) 7.6 Hz, J6′-H,2′-H ) 1.0 Hz, J6′-H,4′-H ) 1.0 Hz, J6′-H,F
)
3
3
0.4 Hz, 1H, 6′-H), 7.31 (ddd, J5′-H,4′-H ) 8.5 Hz, J5′-H,6′-H ) 7.6
Hz, 4J5′-H,F ) 5.8 Hz, 1H, 5′-H); 13C NMR (100.6 MHz, CDCl3) δ
27.74 (C(CH3)3), 78.37 (d, 4JCF ) 1.9 Hz, CH-1), 82.59 (C(CH3)3),
2
2
113.89 (d, JCF ) 22.4 Hz, CH-2′), 115.05 (d, JCF ) 21.2 Hz,
CH-4′), 117.65 (CH2-3), 122.52 (d, 4JCF ) 3.0 Hz, CH-6′), 130.07
3
3
(d, JCF ) 8.2 Hz, CH-5′), 135.71 (CH-2), 141.35 (d, JCF ) 7.1
1
Hz, C-1′), 152.60 (CO carbonate), 162.89 (d, JCF ) 246.4 Hz,
CF-3′); 19F NMR (376.5 MHz, CDCl3) δ -113.06.
(R)-(+)-tert-Butyl 1-(3′-Fluorophenyl)prop-2-en-1-yl Carbon-
ate (R)-(+)-(5f). n-Butyllithium (16 mL, 32 mmol, 2.0 M solution
in pentane) was added to a cold (0 °C) solution of 1-(3-
fluorophenyl)prop-2-en-1-ol (R)-(-)-8f (4.679 g, 30.74 mmol) in
THF (30 mL). The resulting solution was stirred at 0 °C for 10
min and then transferred (via cannula) to a solution of Boc
anhydride (7.10 g, 32.5 mmol) in THF (100 mL) at 20 °C, and the
mixture was stirred at this temperature for 3 h (TLC monitoring).
The reaction was quenched with brine (20 mL), the mixture was
diluted with ether (300 mL), washed with brine (3 × 100 mL),
and dried (Na2SO4). Evaporation of the organic phase gave (R)-
(+)-5f as a light yellow oil (7.60 g, 98%): [R]D +14.2 (c 4.43,
CHCl3), >99% ee, chiral HPLC (Chiracel OJ-H, hexane/2-propanol
99:1, 0.500 mL·min-1) tR ) 10.20 min ((R)-5f), tR ) 12.06 min
((S)-5f).
Acknowledgment. We thank the University of Glasgow for
ˇ
a graduate fellowship to J.S.
Supporting Information Available: Full experimental sec-
1
tion and H and 13C NMR spectra for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(S)-(-)-tert-Butyl 1-(3′-Fluorophenyl)prop-2-en-1-yl Carbon-
ate (S)-(-)-(5f). 1-(3-Fluorophenyl)prop-2-en-1-ol (S)-(+)-8f (4.50
JO801874R
9150 J. Org. Chem. Vol. 73, No. 22, 2008