An improved synthesis of pyridine-thiazole cores of thiopeptide antibiotics

Article abstract of DOI:10.1021/jo900950x

(Figure Presented) The oxidation of 2-methylthiazoles to 2-formylthiazoles simplifies the implementation of the Bagley variant of the Bohlmann-Rahtz reaction as a key step in a concise new route to pyridine cores of thiopeptide antibiotics.

Full text of DOI:10.1021/jo900950x

pubs.acs.org/joc
3
reduced pyridine. On the other hand, fully aromatic cores
are best obtained either by functionalization of an existing
An Improved Synthesis of Pyridine-Thiazole Cores
of Thiopeptide Antibiotics
4
pyridine or by a de novo construction thereof. Approaches
5
of the latter type that rely on variants of the Hantzch and,
Virender S. Aulakh and Marco A. Ciufolini*
6
especially, the Bohlmann-Rahtz reactions tend to be par-
Department of Chemistry, The University of British
Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1,
Canada
ticularly direct. Still, more than 10 linear steps are needed to
reach the desired objectives. Efforts toward the thiopeptide
antibiotics would surely benefit from the advent of more
concise routes.
Incisive work by Bagley has unveiled a remarkable
variant of the Bohlmann-Rahtz synthesis, wherein an en-
olizable ketone, 1, an ynone, 2, and NH OAc combine in
4
7
ciufi@chem.ubc.ca
Received May 7, 2009
refluxing ethanol to afford a pyridine in excellent yield
(Scheme 1). The transformation presumably involves the
initial formation of enamine 3, which then participates in an
actual Bohlmann-Rahtz reaction with 2, i.e., 1,4-addition to
the ynone and cyclodehydration of the emerging 4 to the
ultimate 5. This chemistry could deliver the complete pyr-
idine-thiazole cluster of thiopeptide antibiotics, if it were to
prove serviceable with variants of 1 and 2 wherein the R
groups are thiazolyl residues. Bagley utilized a similar trans-
8
formation to assemble the core motif of amythiamycin,
The oxidation of 2-methylthiazoles to 2-formylthiazoles
simplifies the implementation of the Bagley variant of the
Bohlmann-Rahtz reaction as a key step in a concise new
route to pyridine cores of thiopeptide antibiotics.
except that an enamine such as 3 was prepared separately
as a discrete intermediate, and subsequently it was caused to
react with a thiazolyl ynone in refluxing EtOH. These
important findings beg the question of whether the union
of thiazolyl analogues of 1 and 2 could be effected by the one-
step method. Herein, we detail a procedure that accom-
plishes such a goal.
1
The biomedical potential of thiopeptide antibiotics and
The first objective of this study was the establishment of a
more direct route to 2-formylthiazoles of the type 7 and 12.
These compounds are crucial building blocks of the pyri-
dine-thiazole core of thiopeptides, but their preparation has
the manifold chemical issues associated with a synthetic
attack on these molecules have elicited considerable activity
2
during the past decade. These efforts have produced note-
9
worthy methods for the assembly of the pyridine-thiazole
core of those antibiotics. Remarkable biomimetic cycloaddi-
tions of azadienes have been key to the expeditious construc-
tion of the core thiostrepton and congeners incorporating a
been fairly laborious. We concentrated on the oxidation of
2
-methylthiazoles as an avenue to the corresponding alde-
hydes (Scheme 2). Curiously, this transformation appears to
be undocumented. We found that commercially available 6
or the derived bis-thiazole 11 were largely immune to the
(
1) Recent reviews: (a) Bagley, M. C.; Dale, J. W.; Merritt, E. A.; Xiong,
action of SeO in refluxing ethanol or dioxane. However,
2
X. Chem. Rev. 2005, 105, 685. (b) Hughes, R. A.; Moody, C. J. Angew. Chem.,
Int. Ed. 2007, 46, 7930.
1
0a
they were smoothly converted into the known 7 and 12,
5
(
2) Major synthetic achievements. Promothiocin A: (a) Moody, C. J.;
upon exposure to SeO in refluxing acetic acid. Conduct of
2
Bagley, M. C. Chem. Commun. 1998, 2049. (b) Bagley, M. C.; Bashford,
K. E.; Hesketh, C. L.; Moody, C. J. J. Am. Chem. Soc. 2000, 122, 3301.
Amythiamycin D: (c) Hughes, R. A.; Thompson, S. P.; Alcaraz, L.; Moody,
C. J. J. Am. Chem. Soc. 2005, 127, 15644. (d) Hughes, R. A.; Thompson, S. P.;
Alcaraz, L.; Moody, C. J. Chem. Commun. 2004, 946. Thiostrepton:
the oxidation of 6 in concentrated solutions (1 M or greater)
as
10b,10c
caused the formation of much carbethoxythiazole 8
a byproduct. The genesis of 8 is attributable to overoxidation
of 7 to the corresponding acid and ensuing decarboxylation.
The problem may be contained by operating at concentrations
(
e) Nicolaou, K. C.; Safina, B. S.; Zak, M.; Lee, S. H.; Nevalainen, M.;
Bella, M.; Estrada, A. A.; Funke, C.; Zecri, F. J.; Bulat, S. J. Am. Chem. Soc.
005, 127, 11159. (f) Nicolaou, K. C.; Zak, M.; Safina, B. S.; Estrada, A. A.;
2
Lee, S. H.; Nevalainen, M. J. Am. Chem. Soc. 2005, 127, 11176. (g) Nicolaou,
K. C.; Safina, B. S.; Zak, M.; Estrada, A. A.; Lee, S. H. Angew. Chem., Int.
Ed. 2004, 43, 5087. (h) Nicolaou, K. C.; Zak, M.; Safina, B. S.; Lee, S. H.;
Estrada, A. A. Angew. Chem., Int. Ed. 2004, 43, 5092. Siomycin A: (i) Mori,
T.; Higashibayashi, S.; Goto, T.; Kohno, M.; Satouchi, Y.; Shinko, K.;
Suzuki, K.; Suzuki, S.; Tohmiya, H.; Hashimoto, K.; Nakata, M. Tetrahe-
dron Lett. 2007, 48, 1331. GE2270A and GE 2270T: (j) Nicolaou, K. C.;
Zou, B.; Dethe, D. H.; Li, D. B.; Chen, D. Y. K. Angew. Chem., Int. Ed. 2006,
(4) Noteworthy in this regard is the Bach approach (refs 2k and 2l). See
ref 1 for a thorough bibliography.
(5) Ciufolini, M. A.; Shen, Y. C. J. Org. Chem. 1997, 62, 3804.
(6) (a) Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265. Review:
(b) Bagley, M. C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459. Moody
introduced the reaction into current synthetic practice during his pioneering
synthesis of promothiocin A (ref 2a).
45, 7786. (k) Muller, H. M.; Delgado, O.; Bach, T. Angew. Chem., Int. Ed.
2007, 46, 4771. (l) Delgado, O.; Muller, H. M.; Bach, T. Chem.;Eur. J. 2008,
14, 2322. Micrococcin P1: (m) Lefranc, D.; Ciufolini, M. A. Angew. Chem.,
(7) Bagley, M. C.; Dale, J. W.; Bower, J. Chem. Commun. 2002, 1682.
(8) Bagley, M. C.; Dale, J. W.; Jenkins, R. L.; Bower, J. Chem. Commun.
2004, 102.
Int. Ed. 2009, 48, 4198.
3) (a) Nicolaou, K. C.; Nevalainen, M.; Safina, B. S.; Zak, M.; Bulat, S.
Angew. Chem., Int. Ed. 2002, 41, 1941. (b) Moody, C. J; Hughes, R. A.;
Thompson, S. P.; Alcaraz, L. Chem. Commun. 2002, 1760. See also ref 2d.
(9) For representative methods see the preparation of compounds 7 and
12 (Scheme 2 herein) as described in ref 5 (12, 8 steps from glycolonitrile,
25%), ref 8, and in the following: Merritt, E. A.; Bagley, M. C. Synlett 2007,
954 (7, 4 steps from diethoxyacetonitrile, 83%).
(
5
750 J. Org. Chem. 2009, 74, 5750–5753
Published on Web 07/02/2009
DOI: 10.1021/jo900950x
r 2009 American Chemical Society

Aulakh and Ciufolini
JOCNote
SCHEME 1. The Bagley Variant of the Bohlmann-Rahtz
Pyridine Synthesis
SCHEME 3. One-Step Bohlmann-Rahtz Assembly of Thio-
peptide Cores
SCHEME 2. SeO Oxidation of 2-Methylthiazoles and Pre-
2
paration of Thiazolyl Ynones
SCHEME 4. Other Pyridines Obtained by the Procedure
of ca. 0.5 M. The desired 7 (55% yield after purification) is
then accompanied by 21% of 8, which is readily separated by
Rahtz reactions proceed best in a 5:1 mixture of toluene and
1
acetic acid as the solvent. This induced us to study the
4
1
0d
chromatography. The oxidation of 11 also proceeded in
5% yield (after chromatography), but no discrete bypro-
combination of 14 and 16 with 17 and NH OAc in progres-
4
5
ducts could be detected in this reaction. Addition of
sively more acidic media. In the event, it transpired that the
reaction is best carried out in refluxing acetic acid, in a manner
1
1
15
ethynylmagnesium bromide to 7 and 12 and oxidation of
2
similar to the Eiden-Herdeis pyridine construction. As seen
in Scheme 3, pyridines 18 and 19 were thus obtained in 63%
and 52% yield, respectively, after chromatographic purifica-
tion. Notice that under the present conditions the TBS
protecting group present in 17 was replaced by an acetate,
probably as a consequence of acid-promoted cleavage and
consequent Fischer-type esterification of the liberated alco-
hol. Compound 19 is recognized as a protected form of the
1
the resulting carbinols (IBX for 13; Dess-Martin for 16)
gave ynones 14 and 16.
8
Initial attempts to induce the union of 14 and 16 with the
2
m,5
known 17
(Scheme 3) in refluxing EtOH (original Bagley
conditions) were unsuccessful. Yet, in our hands the Bagley
reaction performed admirably well when a mixture of, e.g., 1-
1
3
phenyl-2-propyn-1-one and ethyl acetoacetate, was treated
2
m,5,9
with NH OAc under the prescribed conditions. The fact that
4
none of the desired product was obtained from the reaction of
core cluster of micrococcin P1-P2,
YM266183. The same procedure was satisfactory also for
thiocillin I, and
1
6
6
the synthesis of known pyridines 23 and 24 (Scheme 4).
a
10e
17 with 14 or 16 was attributed to the failure of 17 to combine
with NH OAc sufficiently rapidly to furnish a requisite
enamine of the type 3. Perhaps for this reason, the Bagley
1
0f
4
Interestingly, pyridine 25 was isolated as a byproduct in
2% yield from the reaction of 21 with 22, but it was not
detected in the crude reaction mixture obtained from 20.
2
8
synthesis of the core of amythiamycin necessitated the for-
mation of the enamine in question as a separate step. On the
other hand, protonic acids are known to facilitate the forma-
tion of such enamines. Indeed, some modified Bohlmann-
(14) (a) Bagley, M. C.; Chapaneri, K.; Dale, J. W.; Xiong, X.; Bower, J.
J. Org. Chem. 2005, 70, 1389. See also: (b) Bagley, M. C.; Brace, C.; Dale,
J. W.; Ohnesorge, M.; Phillips, N. G.; Xiong, X.; Bower, J. J. Chem. Soc.,
Perkin Trans. I 2002, 1663.
(
11) This reaction forms a black precipitate of Se byproducts. Perhaps
this precipitate entrains byproducts arising from 11.
12) The use of IBX for the oxidation of such carbinols was introduced by
(15) Eiden, F.; Herdeis, C. Arch. Pharm. (Athens) 1977, 310, 744. A
similar reaction may be carried out in ionic liquids: Karthikeyan, G.;
Perumal, P. T. Can. J. Chem. 2005, 83, 1746.
(
Moody (refs 2a and 2b). We found that the Dess-Martin periodinane
performed better than IBX in the oxidation of 15.
(16) Thiocillin, I.; Shoji, J.; Kato, T.; Yoshimura, Y.; Tori, K.
J. Antibiot. 1981, 34, 1126. YM-266183: Nagai, K.; Kamigiri, K.; Arao,
N.; Suzumura, K.-I.; Kawano, Y.; Yamaoka, M.; Zhang, H.; Watanabe, M.;
Suzuki, K. J. Antibiot. 2003, 56, 123.
(13) This known compound was made as detailed in the Supporting
Information.
J. Org. Chem. Vol. 74, No. 15, 2009 5751

Aulakh and Ciufolini
JOCNote
SCHEME 5. Eiden-Herdeis Pyridine Construction
Ynone 14. A solution of 7 (1.7 g, 9.0 mmol) in THF (5 mL) was
added dropwise with good stirring to a commercial 0.5 M solution
of ethynylmagnesium bromide (27.0 mL, 13.5 mmol) at rt. The
mixture was stirred for 30 min at rt, then it was cautiously
4
quenched with aqueous saturated NH Cl solution (20 mL). The
organic layer was separated and the aqueous phase was extracted
with EtOAc (2 ꢀ 20 mL). The combined extracts were dried
(Na SO ) and concentrated. The crude product, a thick oil,
2 4
was directly added to a solution of IBX (2.5 g, 18.0 mmol) in
DMSO (10 mL) and heated at 35 °C for 12 h. The cooled mixture
was diluted with EtOAc (30 mL) and water (40 mL) and stirred
vigorously for 10 min, then it was filtered over Celite. The organic
phase was separated and the aqueous layer was extracted with
ether (3ꢀ30 mL). The combined extracts were sequentially washed
A final aspect of this chemistry is worthy of note. Given
that enediones 26 advance to pyridines 27 upon reaction with
with saturated aqueous NaHCO
NaCl (30 mL) solution, dried (Na
(30 mL) and saturated aqueous
SO ), and concentrated to give a
3
1
NH OAc in refluxing AcOH (Scheme 5), we evaluated a
5
4
2
4
dark solid (1.6 g, 85% over 2 steps). Despite the color, this material
was of sufficiently good quality to be used in the next step without
purification. A purified sample (flash chromatography, 20%
variant of the chemistry of Schemes 3 and 4, in which a
preformed substrate of the type 27 is converted into a
pyridine in a separate step. Thus, treatment of the crude
Michael adduct 28 of ethyl acetoacetate and 22 with
1
EtOAc/hex), white solid, had mp 114-116 °C. H NMR (CDCl
3
)
δ 8.50 (s, 1H), 4.48 (q, 2H, J=7.2 Hz), 3.68 (s, 1H), 1.44 (t, 3H, J=
1
7
NH OAc in refluxing AcOH furnished pyridine 23 in lower
4
13
7.2 Hz). C NMR (CDCl ) δ 169.1, 166.0, 160.5, 149.6, 133.5,
3
þ
þ
yield relative to the direct synthesis (76% vs. 85%). This
suggests that the variant of Bagley protocol detailed herein is
superior to the Eiden-Herdeis method.
84.8, 78.9, 62.1, 14.3. ESIMS 210.2 [MþH] , 232.1 [MþNa] .
þ
HRMS calcd for C H NO S [MþH] 210.0225, found 210.0175.
9
8
3
Alcohol 15. A solution of 12 (3.5 g, 13.0 mmol) in THF (8 mL)
was added dropwise to a commercial 0.5 M solution of ethy-
nylmagnesium bromide in THF (57.6 mL, 28.8 mmol) at rt. The
mixture was stirred for 30 min, then it was quenched with
The preparation of 19 outlined in Scheme 3 (7 linear steps
from 6; 16% overall yield) compares favorably with earlier
5
routes (12 linear steps from glycolonitrile, 9% overall yield;
9
1 linear steps from diethoxyacetonitrile, 15% overall
aqueous saturated NH
was separated and the aqueous phase was extracted with EtOAc
SO ) and
4
Cl solution (30 mL). The organic layer
1
yield). Applications of these findings to the synthesis of
thiopeptide antibiotics are being actively pursued and will
be disclosed in due course.
(
2ꢀ30 mL). The combined extracts were dried (Na
2
4
evaporated. Flash chromatographic purification of the residue
(40% EtOAc/hexanes) gave 15 (2.9 g, 75%) as a white solid, mp
1
1
45-148 °C. H NMR (DMSO-d ) δ 8.54 (s, 1H), 8.35 (s, 1H),
6
1
8
7.08 (d, 1H, J=6.0 Hz), 5.73 (dd, 1H, J=6.0, 2.2 Hz), 4.32
q, 2H, J=7.1 Hz), 3.68 (d, 1H, J=2.2 Hz), 1.31 (t, 3H, J=7.1
Experimental Section
(
Hz). C NMR (DMSO-d
1
3
Aldehyde 7. A solution of compound 6 (4.0 g, 23.6 mmol) and
SeO (7.8 g, 70.8 mmol) in AcOH (95 mL) was refluxed for 12 h,
then it was evaporated. The residue was neutralized with aqu-
6
) δ 174.0, 162.8, 161.1, 147.8, 147.4,
þ
130.0, 119.4, 83.16, 77.3, 61.3, 60.8, 14.7. ESIMS 295.1 [MþH] ,
2
þ
[M þ H]þ
317.1 [M þ Na] . HRMS calcd for C12
11 2 3 2
H N O S
þ
2
95.0211, found 295.0191 [Mþ1] .
eous saturated NaHCO
EtOAc. The combined extracts were dried (Na
porated. Flash chromatographic purification of the residue
30% EtOAc/ hexanes) afforded 7 (2.4 g, 55%) as a white solid,
3
solution (30 mL) and extracted with
Ynone 16. Dess-Martin periodinane (735 mg, 1.8 mmol) was
added in small portions to a suspension of alcohol 15 (435 mg,
.5 mmol) in CH Cl (5 mL) at rt and with good stirring. The
2
SO ) and eva-
4
1
2
2
(
10a
solution became clear after 10 min. After 2 h of stirring, the
reaction was complete (TLC), whereupon it was diluted with
mp 65-66 °C (lit. mp 67-68 °C), and 8 (780 mg, 21%) as a
1
0c
1
pale yellow solid, mp 49-50 °C (lit. mp 52-54 °C). H NMR
10 mL each of aqueous saturated NaHCO
Na S O solutions. The organic layer was separated and further
3
and aqueous saturated
(
(
CDCl ) δ 10.08 (d, 1H, J=1.3 Hz), 8.52 (d, 1H, J=1.3 Hz), 4.50
3
13
q, 2H, J=7.1 Hz), 1.45 (t, 3H, J=7.1 Hz). C NMR (CDCl
3
) δ
2
2
3
washed with aqueous saturated NaHCO solution (10 mL), then
3
1
83.6, 166.1, 160.6, 149.6, 133.0, 62.1, 14.3. IR 1717, 1694. ESI-
NO
86.0225, found 186.0224.
þ
þ
it was dried (Na SO ) and concentrated to give 16 as an orange
2
4
MS 207.9 [M þ Na] . HRMS calcd for C
H
7 8
3
S [M þ H]
solid (415 mg, 96%). A sample purified by flash chromatogra-
phy (40% EtOAc/ hexanes), white solid, had mp 107-109 °C.
1
Aldehyde 12. A solution of compound 11 (4.9 g, 19.2 mmol)
and SeO (6.4 g, 57.8 mmol) in AcOH (40 mL) was refluxed for
2 h. The mixture was filtered through Celite to remove a dark
1
H NMR (CDCl ) δ 8.54 (s, 1H), 8.26 (s, 1H), 4.46 (q, 2H, J=
.0 Hz), 3.66 (s, 1H), 1.44 (t, 3H, J=7.0 Hz). C NMR (CDCl )
3
3
2
1
3
7
1
δ 168.6, 165.7, 161.9, 161.2, 151.1, 148.2, 128.6, 124.7, 84.0, 79.1,
precipitate and the filtrate was evaporated. The residue was
treated with aqueous saturated NaHCO solution (30 mL) and
þ
6
1.7, 14.3. ESIMS 315.1 [M þ Na] . HRMS calcd for
3
þ
C H N O S [MþH] 293.0055, found 293.0067.
1
2
9
2
3 2
extracted with EtOAc. The combined extracts were dried
(
2
m,5
Pyridine 18. A solution of ketone 17 (256 mg, 564 μmol),
ynone 14 (118 mg, 564 μmol), and NH OAc (65 mg, 846 μmol) in
Na
5
1
2
SO
4
) and evaporated to give the known 12
(2.8 g,
5%). A sample recrystallized from EtOAc/heptanes had mp
4
1
AcOH (5 mL) was refluxed for 8 h, then it was concentrated,
neutralized (aqueous saturated NaHCO3 solution), and ex-
tracted with EtOAc (2ꢀ20 mL). The combined extracts were
56-157 °C. H NMR (CDCl ) δ 10.06 (d, 1H, J=1.0 Hz), 8.55
d, 1H, J=1.1 Hz), 8.26 (s, 1H), 4.47 (q, 2H, J=7.1 Hz), 1.45 (t,
3
(
13
3
H, J=7.1 Hz). C NMR (CDCl
3
) δ 183.2, 165.9, 161.9, 161.1,
2 4
dried (Na SO ) and evaporated. Flash chromatographic pur-
1
51.1, 148.2, 128.5, 123.9, 61.7, 14.3. IR 1723, 1702. ESIMS 301
ification of the residue (50% EtOAc/hexanes) afforded 18 (203
mg, 63%) as a light orange solid in >98% purity by HPLC
þ
þ
[
MþMeOHþH] . HRMS calcd for C H N O S Na [MþNa ]
19
1
0
8
2
3 2
2
90.9874, found 290.9865.
25
D
1
with mp 95-98 °C, [R]
þ21.1 (c 0.99, acetone). H NMR
(
(
17) Conduct of the reaction in EtOH again failed to produce pyridines.
18) Experimental protocols are provided as Supporting Information.
(19) Details of the HPLC analysis are provided as Supporting Infor-
mation.
5
752 J. Org. Chem. Vol. 74, No. 15, 2009

Aulakh and Ciufolini
CDCl ) δ 8.42 (d, 1H, J=8.1 Hz), 8.32 (s, 1H), 8.19 (d, 1H, J=
JOCNote
(
(d, 1H, J=8.0 Hz), 8.03 (s, 1H), 7.40 (s, 1H), 5.78 (s, br, 1H), 5.23
(s, 2H), 4.65 (dd, 1H, J=6.0, 1.1 Hz), 4.54 (p, 1H, J=6.1 Hz),
4.47 (q, 2H, J=7.2 Hz), 2.13 (s, 3H), 1.48 (d, 3H, J=6.2 Hz), 1.45
3
8
4
.1 Hz), 8.01 (s, 1H), 7.39 (s, 1H), 5.59 (s, br, 1H), 5.22 (s, 2H),
.65 (dd, 1H, J=6.3, 1.2 Hz), 4.54 (quintet, 1H, J=6.2 Hz), 4.48
1
3
(
q, 2H, J=7.1 Hz), 2.13 (s, 3H), 1.48 (d, 3H, J=6.3 Hz), 1.46 (t,
(t, 3H, J=7.2 Hz). C NMR (CDCl ) δ 170.8, 168.4, 168.3,
3
13
3
1
1
2
H, J=7.1 Hz). C NMR (CDCl
3
) δ 170.8, 168.7, 168.5, 165.3,
61.3, 158.0, 154.1, 151.6, 150.5 (2 overlapping peaks), 148.6,
165.4, 163.1, 161.4, 157.7, 154.2, 151.6, 150.7, 150.6, 149.9,
148.1, 140.0, 129.6, 127.9, 121.5, 120.5, 119.1, 118.8, 79.6,
þ
40.0, 130.1, 129.7, 121.5, 119.23, 119.2, 79.6, 61.7, 61.7, 60.8,
0.9, 19.9, 14.4. ESIMS 572 [MþH] , 594 [MþNa] . HRMS
61.8, 61.6, 60.8, 21.0, 19.9, 14.4. ESIMS 655 [MþH] , 677 [M
þ
þ
þ
þ
þ Na] . HRMS calcd for C H N O S 655.0562 [M þ H] ,
2
7
23
6
6 4
þ
calcd for C24
H
22
N
5
O
6
S
3
[MþH] 572.0732, found 572.0727.
found 655.0558.
Pyridine 19. A solution of ketone 17 (380 mg, 832 μmol),
ynone 12 (248 mg, 832 μmol), and NH OAc (97 mg, 1.2 mmol) in
AcOH (5 mL) was refluxed for 12 h, then it was concentrated,
neutralized (aqueous saturated NaHCO solution), and ex-
3
4
Acknowledgment. Financial support by the University of
British Columbia, the Canada Research Chair Program,
CFI, NSERC, CIHR, and MerckFrosst Canada, Ltd., is
gratefully acknowledged.
tracted with EtOAc (2ꢀ25 mL). The combined extracts were
dried (Na SO ) and evaporated. Flash chromatographic pur-
2
4
ification of the residue (70% EtOAc/hexanes) afforded 19 (285
mg, 52%) as a pale yellow solid in >97% purity by HPLC
1
9
Supporting Information Available: Experimental protocols,
characterization data, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
2
5
1
with mp 210-211 °C, [R]
D
þ5.5 (c 0.91, CHCl
3
). H NMR
(
CDCl ) δ 8.34 (d, 1H, J=8.0 Hz), 8.32 (s, 1H), 8.24 (s, 1H), 8.20
3
J. Org. Chem. Vol. 74, No. 15, 2009 5753