Cryptophycin-39 unit a precursor synthesis by a tandem Shi epoxidation and lactonization reaction of trans-styryl acetic acid

Article abstract of DOI:10.1055/s-0028-1087541

Unit A of cryptophycins is a δ-hydroxy acid with two or four stereogenic centers. The first synthesis of the unit A building block of cryptophycin-39 is based on a catalytic asymmetric Shi epoxidation of trans-styryl acetic acid followed by an in situ lac

Full text of DOI:10.1055/s-0028-1087541

LETTER
417
Cryptophycin-39 Unit A Precursor Synthesis by a Tandem Shi Epoxidation
and Lactonization Reaction of trans-Styryl Acetic Acid
S
ynthesis of Cryp
e
tophycin-3
n
9 Unit A Pre
e
c
ursor dikt Sammet,a Hanna Radzey,a Beate Neumann,b Hans-Georg Stammler,b Norbert Sewald*a
a
Department of Chemistry, Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstr. 25, 33615 Bielefeld, Germany
Fax +49(521)106 8094; E-mail: norbert.sewald@uni-bielefeld.de
b
Department of Chemistry, Inorganic Chemistry, Bielefeld University, Universitätsstr. 25, 33615 Bielefeld, Germany
Received 13 October 2008
Retrosynthetically, cryptophycins can be divided into the
respective hydroxy and amino acid building blocks, that
is, units A–D (Figure 1). From a synthetic point of view
cryptophycin-39 (2) is one of the most interesting crypto-
Abstract: Unit A of cryptophycins is a d-hydroxy acid with two or
four stereogenic centers. The first synthesis of the unit A building
block of cryptophycin-39 is based on a catalytic asymmetric Shi ep-
oxidation of trans-styryl acetic acid followed by an in situ lacton-
ization. The scope of this reaction has been investigated with phycin analogues. It contains a cis-epoxide in its unit A
respect to various b,g-unsaturated carboxylic acids as substrates for
the asymmetric synthesis of 4-hydroxy-5-phenyl-tetrahydrofuran-
2-ones under Shi conditions.
and was obtained by Chaganty et al. through a semisyn-
thetic approach. Opening of the epoxide in cryptophycin-
1 (1) under acidic conditions gives the corresponding
chlorohydrin.3 The chloro-substituted stereogenic center
in the benzylic position was then partly epimerized by the
addition of excess lithium chloride. After HPLC separa-
tion of the diastereomers the epimeric chlorohydrin was
converted back to an epoxide function under basic condi-
tions yielding cryptophycin-39 (2) on a single-digit milli-
gram scale. It showed moderate bioactivity (IC50 72 nM)
against the human upper throat tumor cell line KB.3
Key words: asymmetric synthesis, bioorganic chemistry, epoxida-
tions, lactones, natural products
Cryptophycins are a group of 16-membered macrocyclic
depsipeptides which have been isolated from cyanobac-
teria of the genus Nostoc and from the marine sponge
Dysidea arenaria.1 This family of natural products with
its main member cryptophycin-1 (1) is attracting much at-
tention due to their superb cytotoxicity and antitumor ac-
tivity even against multidrug-resistant tumor cell lines. It
often exceeds the activity of vinblastine and paclitaxel.2
Numerous cryptophycin analogues have been synthesized
and their biological activity has been evaluated.1f,2a
Several recent papers address the synthesis of cryptophy-
cin-1 unit A precursors containing four stereogenic cen-
ters. In many cases the configuration of the future syn-
epoxide is established by conversion of a syn-diol under
retention of the configuration.4 Following this strategy, a
six- or seven-step synthesis of a cryptophycin-1 unit A
building block was recently published.5
unit A
O
However, it had not been known so far, whether the unit
A building block of cryptophycin-39 could be obtained
following a similar route. Our retrosynthetic analysis sug-
gested to start from (4R,5S)-4-hydroxy-5-phenyl-tetrahy-
drofuran-2-one (5) as a key intermediate in the synthesis
(Scheme 1).
unit B
O
O
O
O
HN
Cl
O
N
H
O
OMe
unit D
unit C
1
An asymmetric three-step synthetic approach to ent-5 had
been published by Kino et al.6 The first step was based on
the enantioselective epoxidation of trans-ethyl-3-
benzoylacrylate with cumene hydroperoxide and a cata-
lyst derived from lanthanum isopropoxide, tris(4-fluoro-
phenyl)phosphine oxide and BINOL. This was followed
by a diastereoselective reduction of the ketone with
Zn(BH4)2, reductive opening, and in situ lactonization
with diphenyl diselenide and NaBH4.
O
O
O
O
O
HN
Cl
O
N
H
O
OMe
2
In addition, Burrows and Van Horn published a one-step
synthesis of rac-5 from commercially available trans-
styryl acetic acid (4) by oxidation with Oxone (potassium
monopersulfate triple salt) and in situ lactonization in
aqueous acetonitrile solution in very good yield.7
Figure 1 Structures of cryptophycin-1 (1) and cryptophycin-39 (2)
SYNLETT 2009, No. 3, pp 0417–0420
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087541; Art ID: G30508ST
x
x.
x
x.
2
0
0
9
Those reaction conditions employed are similar to the
ones used in the Shi epoxidation of olefines, a method
© Georg Thieme Verlag Stuttgart · New York

418
B. Sammet et al.
LETTER
developed by Shi et al. mediated by the D-fructose-de- racemic epoxidation of trans-cinnamic acid and p-vinyl-
rived ketone catalyst 3.8 This epoxidation method was benzoic acid with Oxone gave the corresponding epoxides
also used by Hoard et al. on a late stage to synthesize a in only 5% and 30% yield, respectively.7
cryptophycin derivative.9 Reports of unsaturated carbox-
ylic acids as starting materials for such an asymmetric in
situ lactonization are very rare. To the best of our knowl-
Hydroxy lactone 5 was chemoselectively methylated in
the anti-position to the hydroxyl group using LDA/methyl
iodide and DMPU.
edge, only one Shi epoxidation from the g,d-unsaturated
The stereochemical purity of the crude a-methylated lac-
potassium trans-6-(3-fluorophenyl)-4-hexenoate yielding
tone 6 (90% ee, 85% de) was increased by recrystalliza-
the corresponding lactone has been published so far.10
After careful optimization the reaction conditions for sub-
strate 4, the asymmetric epoxidation gave the desired
hydroxy lactone 5. The enantiomeric excess of the reac-
tion (determined by chiral HPLC) was increased by re-
crystallization from 82% ee to 90% ee in 44% yield
(Table 1, entry 1).11 For comparison, application of the
Shi catalyst 3 under the reaction conditions reported for
the racemic synthesis7 led to an improved yield of 81%
but only 50% ee.
Table 1 Asymmetric and Racemic Tandem Epoxidation and Lac-
tonization Reaction of b,g-Unsaturated Acids
Entry
1
Acid
Yield (%)
ee (%)
44
82 (rac.)
90a
–
4
MeO
Br
33
77 (rac.)
45
–
O
2
OH
The scope of the reaction was further examined. The
asymmetric and racemic lactonization of substituted
trans-styryl acetic acids12 (Table 1, entries 2 and 3), such
as trans-p-methoxystyryl acetic acid (33% yield, 45% ee)
and trans-p-bromostyryl acetic acid (15% yield, 82% ee)
were performed. The reaction of aliphatic b,g-unsaturated
carboxylic acids, such as trans-n-pent-3-enoic acid and 1-
cyclohexene-1-acetic acid (Table 1, entries 4 and 5) did
not yield any lactone at all. The limited substrate range is
in agreement with the results published by Burrows.7 The
15
51 (rac.)
82
–
O
3
4
5
OH
O
O
0
–
–
0 (rac.)
OH
0
–
–
0 (rac.)
OH
a After recrystallization.
1. Oxone, Shi catalyst (3),
1. LDA, DMPU, MeI,
THF
2. recrystallization
MeCN–H2O
O
O
O
O
2. recrystallization
O
OH
65%, >99% ee, 92% de
44%, 90% ee
HO
HO
4
5
6
Amberlyst-15, MeOH,
Me2C(OMe)2
DIBAL-H, CH2Cl2,
–78 °C
OMe
H
O
O
64%
89%
O
O
O
O
7
8
AllylSn(n-Bu)3,
MgBr2⋅OEt2, CH2Cl2
CH2=CHCO2t-Bu,
Grubbs II, CH2Cl2
O
O
O
73%
72%
OH
Ot-Bu
O
O
OH
9
10
HCl, MeOH,
H2O
66%
O
O
O
O
O
OH
O
OH
11
OH
Shi catalyst (3)
Scheme 1 Synthesis of cryptophycin-39 unit A building blocks 9 and 10
Synlett 2009, No. 3, 417–420 © Thieme Stuttgart · New York

LETTER
Synthesis of Cryptophycin-39 Unit A Precursor
J.; Heltzel, C. E.; Husebo, T. L.; Jensen, C. M.; Larsen,
419
tion to more than 99% ee (determined by chiral HPLC)
and 92% de in 65% yield. The addition of DMPU acceler-
ated the reaction and the directing power of the hydroxy
group sufficiently outweighed the detrimental influence
of the phenyl substituent. While the absolute configura-
tion in b- and g-position of 5 was defined by the known
enantioselectivity of the Shi epoxidation,8,10 the X-ray
crystal-structure analysis gave proof of the relative con-
L. K.; Patterson, G. M. L.; Moore, R. E.; Mooberry, S. L.;
Corbett, T. H.; Valeriote, F. A. J. Am. Chem. Soc. 1995, 117,
12030. (d) Kobayashi, M.; Kurosu, M.; Ohyabu, N.; Wang,
W.; Fujii, S.; Kitagawa, I. Chem. Pharm. Bull. 1994, 42,
2196. (e) Kobayashi, M.; Aoki, S.; Ohyabu, N.; Kurosu, M.;
Wang, W.; Kitagawa, I. Tetrahedron Lett. 1994, 35, 7969.
For reviews, see: (f) Eißler, S.; Stončius, A.; Nahrwold, M.;
Sewald, N. Synthesis 2006, 3747. (g) Eggen, M.; Georg,
G. I. Med. Res. Rev. 2002, 22, 85. (h) Tius, M. A.
Tetrahedron 2002, 58, 4343.
1
figuration of the methyl group in 6. The observed H
NMR coupling constant (3J = 9.5 Hz) between Ha and Hb
in 6 was furthermore in accordance with published data
for a similar system.13
(2) (a) Al-awar, R. S.; Corbett, T. H.; Ray, J. E.; Polin, L.;
Kennedy, J. H.; Wagner, M. M.; Williams, D. C. Mol.
Cancer Ther. 2004, 9, 1061. (b) Smith, C. D.; Zhang, X.;
Mooberry, S. L.; Patterson, G. M.; Moore, R. E. Cancer Res.
1994, 54, 3779.
(3) Chaganty, S.; Golakoti, T.; Heltzel, C.; Moore, R. E.;
Yoshida, W. Y. J. Nat. Prod. 2004, 67, 1403.
(4) (a) Gardinier, K. M.; Leahy, J. W. J. Org. Chem. 1997, 62,
7098. (b) Liang, J.; Moher, E. D.; Moore, R. E.; Hoard,
D. W. J. Org. Chem. 2000, 65, 3143. (c) Pousset, C.;
Haddad, M.; Larchevêque, M. Tetrahedron 2001, 57, 7163.
(d) Li, L.-H.; Tius, M. A. Org. Lett. 2002, 4, 1637.
(e) Mast, C. A.; Eißler, S.; Stončius, A.; Stammler, H.-G.;
Neumann, B.; Sewald, N. Chem. Eur. J. 2005, 11, 4667.
(5) Eißler, S.; Nahrwold, M.; Neumann, B.; Stammler, H.-G.;
Sewald, N. Org. Lett. 2007, 9, 817.
Opening of lactone 6 by reaction with 2,2-dimethoxypro-
pane, methanol, and Amberlyst-155,14 provided the methyl
ester 7 with the sterically hindered cis-diol being concom-
itantly protected as an acetonide in 64% overall yield. Re-
covered starting material and intermediate products were
subjected to the same reaction for a second time. Reduc-
tion of 7 with diisobutylaluminium hydride gave aldehyde
8 in 89% yield without any epimerization.
Diastereoselective allylation with allyltributylstannane
under chelation by addition of MgBr2·OEt2 was per-
formed according to a protocol15 published by Lee et al.
and yielded homoallyl alcohol 9 in 73%. In fact, this com-
pound is already a potential unit A precursor for an RCM
approach.5,16 A metathesis reaction with tert-butylacrylate
gave rise to the more traditional unit A precursor 10 in
72% yield after six steps.17 This six-step synthesis repre-
sents the shortest route to a cryptophycin unit A precursor
with four stereogenic centers, so far.
(6) Kino, R.; Daikai, K.; Kawanami, T.; Furuno, H.; Inanaga, J.
Org. Biomol. Chem. 2004, 2, 1822.
(7) van Horn, J. D.; Burrows, C. J. Tetrahedron Lett. 1999, 40,
2069.
(8) (a) Wang, Z. X.; Tu, Y.; Frohn, M.; Zhang, J. R.; Shi, Y.
J. Am. Chem. Soc. 1997, 119, 11224. (b) Wang, Z. X.; Tu,
Y.; Frohn, M.; Shi, Y. J. Org. Chem. 1997, 62, 2328.
(c) Shi, Y. Acc. Chem. Res. 2004, 37, 488. (d) Wong, O. A.;
Shi, Y. Chem. Rev. 2008, 108, 3958.
To prove the diastereoselectivity of the allylation, homo-
allyl alcohol 9 was deprotected with aqueous hydrochloric
acid in methanol in 66% yield to provide the crystalline
triol 11, which was subjected to X-ray crystal-structure
analysis.18
(9) Hoard, D. W.; Moher, E. D.; Martinelli, M. J.; Norman,
B. H. Org. Lett. 2002, 4, 1813.
(10) Ager, D. J.; Anderson, K.; Oblinger, E.; Shi, Y.;
VanderRoest, J. Org. Process Res. Dev. 2007, 11, 44.
(11) Synthesis of (4R,5S)-4-hydroxy-5-phenyl-tetrahydro-
furan-2-one (5)
In summary, a synthesis of the cryptophycin-39 unit A
building blocks 9 and 10 was developed in five and six
steps, respectively. Furthermore, it was shown that the Shi
epoxidation can be used for the very efficient and straight-
forward synthesis of a versatile lactone, which served as
key building block in an economical asymmetric synthe-
sis.
trans-Styryl acetic acid (4, 21.8 mmol, 3.54 g) was dissolved
in MeCN (210 mL). Aqueous KOH soln (1 M, 21.8 mmol,
21.8 mL), acetate buffer (150 mL, prepared by adding 5.00
mL AcOH to 13.82 g K2CO3 in 1000 mL H2O and pH
adjusted to 9.3 by the dropwise addition of concd aq NaOH
soln) and n-Bu4NHSO4 (0.954 mmol, 324 mg) were added.
The solution was cooled to 0 °C and Shi catalyst (3, 7.16
mmol, 1.85 g) was added. Freshly prepared Oxone (29.90
mmol, 18.36 g) in aq Na2EDTA solution (0.4 mM, 0.0432
mmol, 108 mL) and aq K2CO3 soln (108 mL, prepared by
dissolving 32.00 g K2CO3 in 200 mL H2O) were separately
added within 120 min at 0 °C. The cooling bath was
removed, and the mixture was stirred for 180 min. Aqueous
HCl (6 M, 0.36 mol, 60 mL) was carefully added. The
solution was extracted with Et2O (1 × 600 mL and 2 × 500
mL). The combined organic layers were washed with sat. aq
NaHCO3 solution (200 mL) and brine (30 mL). After drying
over Na2SO4 the solvent was removed in vacuo (40 °C) and
the crude material was purified by flash chromatography
(hexane–EtOAc 3:2) giving a crystalline solid (10.78 mmol,
1.920 g, 82% ee), which was recrystallized from EtOAc (3.5
mL) at 2 °C overnight yielding (4R,5S)-4-hydroxy-5-
phenyl-tetrahydrofuran-2-one (5, 9.58 mmol, 1.708 g, 44%,
90% ee) as a colorless solid; [a]D24 2.57 (c 1.38, CHCl3).
HPLC [Chiralpak AD, 2-PrOH–hexane (1:9), 1 mL/min]:
Acknowledgment
This work has been supported by the DFG (German Research Foun-
dation). B.S. would like to thank the German National Academic
Foundation (Studienstiftung des deutschen Volkes) for a scholar-
ship and expresses his gratitude to Dr. S. Eißler and M. Nahrwold
for helpful discussions.
References and Notes
(1) (a) Schwartz, R. E.; Hirsch, C. F.; Sesin, D. F.; Flor, J. E.;
Chartrain, M.; Fromtling, R. E.; Harris, G. H.; Salvatore,
M. J.; Liesch, J. M.; Yudin, K. J. Ind. Microbiol. 1990, 5,
113. (b) Trimurtulu, G.; Ohtani, I.; Patterson, G. M. L.;
Moore, R. E.; Corbett, T. H.; Valeriote, F. A.; Demchik, L.
J. Am. Chem. Soc. 1994, 116, 4729. (c) Golakoti, T.; Ogino,
Synlett 2009, No. 3, 417–420 © Thieme Stuttgart · New York

420
B. Sammet et al.
LETTER
(ent-6). Anal. Calcd (%) for C11H12O3: C, 68.74; H, 6.29.
Found: C, 68.67; H, 6.24. (b) Chen, S. Y.; Joullie, M. M.
J. Org. Chem. 1984, 49, 2168. (c) CCDC 703492 contains
the crystallographic data of 6. They can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
tR = 16.6 min (5), 12.2 min (ent-5). Anal. Calcd (%) for
C10H10O3: C, 67.41; H, 5.66. Found: C, 67.39; H, 5.67.
Further analytical data are in accordance with ref. 7.
(12) General Procedure for the Synthesis of Substituted
trans-Styryl Acetic Acids (Table 1, Entries 2 and 3)
KOt-Bu (13 mmol, 1.469 g) in THF (14 mL) was added to a
solution of the substituted benzaldehyde (9 mmol) and
(2-carboxyethyl)triphenylphosphonium bromide (6 mmol,
2.494 g) in THF (12 mL) at 0 °C over 15 min. After stirring
for additional 15 min at 0 °C and overnight at r.t., H2O (10
mL) and Et2O (50 mL) were added. The phases were
acidified with 6 M aq HCl soln to pH 1 and separated. The
aqueous phase was extracted with Et2O (50 mL). The
combined organic phases were extracted with sat. aq
NaHCO3 soln (2 × 60 mL). The sat. aq NaHCO3 phases were
washed with EtOAc (3 × 90 mL), acidified with concd aq
HCl to pH 1 and extracted with Et2O (2 × 75 mL). The
organic extracts were washed with H2O (20 mL) and brine
(10 mL). After drying over Na2SO4 the solvent was removed
in vacuo (40 °C) yielding the corresponding substituted
trans-styryl acetic acid in 70–74% yield.
(14) Harcken, C.; Brückner, R. Synlett 2001, 718.
(15) Lee, E.; Jeong, E. J.; Kang, E. J.; Sung, L. T.; Hong, S. K.
J. Am. Chem. Soc. 2001, 123, 10131.
(16) Tripathy, N. K.; Georg, G. I. Tetrahedron Lett. 2004, 45,
5309.
(17) Synthesis of (5S,6S,E)-tert-Butyl-6-[(4R,5S)-2,2-
dimethyl-5-phenyl-1,3-dioxolan-4-yl]-5-hydroxyhept-2-
enoate (10)
Homoallyl alcohol 9 (0.615 mmol, 170 mg) in CH2Cl2 (0.85
mL) was added to a solution of Grubbs II catalyst (0.026
mmol, 22.1 mg) and tert-butylacrylate (0.513 mmol, 74.4
mL) in CH2Cl2 (3.4 mL). The solution was refluxed in the
dark overnight. The solvent was removed in vacuo (30 °C),
and the residue was purified by flash chromatography
(hexane–EtOAc, 8:2) yielding 10 (0.369 mmol, 138.8 mg,
72%) as a colorless oil; [a]D24 –7.50 (c 1.10, CHCl3). 1H
NMR (500 MHz, CDCl3): d = 7.28–7.40 (m, 5 H), 6.77 (m,
1 H), 5.80 (d, J = 15.7 Hz, 1 H), 5.38 (d, J = 7.5 Hz, 1 H),
4.70 (dd, J = 3.8, 7.5 Hz, 1 H), 3.50 (m, 1 H), 2.37 (m, 1 H),
2.22 (m, 1 H), 1.58–1.72 (m, 4 H), 1.41–1.56 (m, 12 H), 0.71
(d, J = 6.9 Hz, 3 H). 13C NMR (126 MHz, CDCl3):
d = 165.5, 144.0, 138.0, 128.2, 127.5, 126.6 125.7, 108.2,
80.3, 79.4, 78.1, 73.5, 38.3, 37.4, 28.2, 26.3 24.7, 11.2. IR
(neat): 3453, 2979, 2934, 2360, 1709, 1651, 1494, 1454,
1379, 1367, 1326, 1253, 1210, 1086, 1044, 1029, 1006, 980,
917, 879, 850, 730, 700, 647, 512, 466 cm–1. ESI-MS: m/z =
399.2 [M + Na+]. ESI-HRMS: m/z calcd for C22H32O5Na+ [M
+ Na+]: 399.21420; found: 399.21373.
(13) (a) Synthesis of (3R,4R,5S)-4-Hydroxy-3-methyl-5-
phenyl-tetrahydrofuran-2-one (6)
Diisopropylamine (11.56 mmol, 1.6 mL) in THF (28 mL)
was cooled to –78 °C, then n-BuLi (1.6 M in hexane, 11.49
mmol, 7.2 mL) was added dropwise over 15 min. The
solution was stirred for 15 min at –78 °C and for 30 min at
r.t. The LDA solution was cooled to –78 °C again and
DMPU (34.87 mmol, 4.2 mL) was added. After 45 min
lactone (5, 4.60 mmol, 819 mg) in THF (19.2 mL) was added
during 90 min. After stirring for 45 min and addition of THF
(16 mL), MeI (46.6 mmol, 2.9 mL) in THF (8.6 mL) was
added during 150 min. The solution was stirred overnight at
–78 °C. Acetic acid (0.6 mL) in THF (1.0 mL) was added,
and the suspension was warmed to r.t. Then, 5% aq Na2SO3
soln (8.8 mL) was added, and after 5 min the solvent was
removed in vacuo (40 °C), until a pink suspension remained,
which was partitioned between Et2O (40 mL) and H2O (20
mL). The aqueous layer was extracted with Et2O (4 × 60
mL), and the combined organic phases were washed with
5% aq KHSO4 soln (30 mL) and brine (15 mL). After drying
over Na2SO4 the solvent was removed in vacuo (40 °C), and
the residue was purified by flash chromatography (hexane–
EtOAc, 7:3). The product (3.80 mmol, 731 mg, 90% ee, 85%
de) was recrystallized in EtOAc (1 mL) at –22 °C overnight.
A colorless solid (6, 3.00 mmol, 576 mg, 65%, >99% ee,
92% de) was obtained; [a]D24 6.21 (c 1.18, CHCl3); mp
90 °C. 1H NMR (500 MHz, CDCl3): d = 7.30–7.50 (m, 5 H),
5.06 (d, J = 7.5 Hz, 1 H), 3.98 (m, 1 H), 2.77 (dq, J = 9.4, 6.9
Hz, 1 H), 2.61 (d, J = 5.0 Hz, 1 H), 1.36 (d, J = 6.9 Hz, 3 H).
13C NMR (126 MHz, CDCl3): d = 176.0, 136.6, 128.9,
128.8, 125.7, 84.2, 81.4, 43.6, 12.3. IR (neat): 3409, 3069,
3035, 2974, 2935, 2886, 1732, 1499, 1458, 1363, 1312,
1254, 1184, 1135, 1092, 971, 921, 854, 834, 765, 715, 695,
653 cm–1. MS (EI): m/z = 192.1 [M+], 174.1 [M+ – H2O],
(18) (a) Synthesis of (1S,2R,3S,4S)-3-Methyl-1-phenylhept-6-
ene-1,2,4-triol (11)
A 5% aq HCl soln (4 mL) was added to a solution of
homoallyl alcohol 9 (0.615 mmol, 170.0 mg) in MeOH (6
mL). After refluxing the solution for 90 min MeOH was
removed in vacuo (40 °C), and the aqueous phase was
extracted with Et2O (5 × 30 mL), dried over MgSO4, and
purified by flash chromatography (hexane–EtOAc, 7:3). A
colorless crystalline solid (11, 0.405 mmol, 95.7 mg, 66%)
was obtained; [a]D24 43.59 (c 1.22, CHCl3); mp 77 °C. 1H
NMR (500 MHz, CDCl3): d = 7.26–7.49 (m, 5 H), 5.80 (m,
1 H), 5.13–5.20 (m, 2 H), 4.70 (d, J = 7.5 Hz, 1 H), 4.15 (d,
J = 7.5 Hz, 1 H), 3.70 (m, 1 H), 2.60 (d, J = 2.5 Hz, 1 H),
2.27–2.44 (m, 3 H), 2.21 (s, 1 H), 1.98 (m, 1 H), 1.16 (d,
J = 6.9 Hz, 3 H). 13C NMR (126 MHz, CDCl3): d = 141.8,
134.8, 128.6, 128.1, 126.8, 118.4, 75.1 75.0, 74.1, 40.0, 37.2,
11.2. IR (neat): 3545, 3345, 3063, 3030, 2970, 2923, 2360,
2341, 1639, 1493, 1455, 1431, 1404, 1382, 1340, 1269,
1212, 1135, 1071, 1023, 1000, 989, 974, 917, 870, 842, 786,
697, 639, 604, 544, 475, 419 cm–1. ESI-MS: m/z = 259.2 [M
+ Na+]. ESI-HRMS: m/z calcd for C14H20O3Na+ [M + Na+]
259.13047; found: 259.13030. Anal. Calcd (%) for
C14H20O3: C, 71.16; H, 8.53. Found: C, 71.00; H, 8.60.
(b) CCDC 703493 contains the crystallographic data of 11.
They can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
107.0 [Ph – CHOH+]. HRMS (EI): m/z calcd for C11H12O3
+
[M+]: 192.07864; found: 192.07934. HPLC [Chiralpak AD,
2-PrOH–hexane (1:9), 1 mL/min]: tR = 13.4 min (6), 9.2 min
Synlett 2009, No. 3, 417–420 © Thieme Stuttgart · New York

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