Synthesis of the tricyclic core of 5α-capnellenols using asymmetric Heck reaction-carbanion capture process

Article abstract of DOI:10.1055/s-2006-951537

The tricyclic core of 5α-capnellenols was synthesized using an asymmetric Heck reaction-carbanion capture process and an intramolecular nitrile oxide cycloaddition as key ring construction steps. Moreover, the desired C5-α-OH product was obtained through

Full text of DOI:10.1055/s-2006-951537

LETTER
3053
Synthesis of the Tricyclic Core of 5a-Capnellenols Using Asymmetric Heck
Reaction–Carbanion Capture Process
S
ynthesis of the Tricycli
a
c
Core of
5
t
a
-Capn
a
ellenols ru Itano, Takashi Ohshima, Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)56845206; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Received 17 April 2006
Dedicated to Professor Richard Heck
capnellenols 4 and 5. We eventually developed a new syn-
Abstract: The tricyclic core of 5a-capnellenols was synthesized
using an asymmetric Heck reaction–carbanion capture process and
an intramolecular nitrile oxide cycloaddition as key ring construc-
tion steps. Moreover, the desired C5-a-OH product was obtained
thetic strategy to construct a C-ring and simultaneously
introduce a hydroxyl group at C5-position (Scheme 1).
The intramolecular nitrile oxide cycloaddition6 of 10 pro-
through a retroaldol and aldol epimerization process of the C5-b- ceeded smoothly to give the tetracyclic compound 11.7
OH tricyclic compound.
The stereochemistry of 11 was determined by NOESY
1
analysis (cross-peak between H3a and H5) and H NMR
coupling constant analysis (H5–H6: 7.0–7.3 Hz).
Key words: asymmetric synthesis, carbanions, cycloadditions,
isomerizations, Heck reaction
EtO2C
CO2Et
[Pd(allyl)Cl]2 (2.5 mol%)
(S)-BINAP (6.3 mol%)
OTf
H
H
Capnellenols 1–6 are sesquiterpene alcohols, isolated
from sun-dried colonies of the soft coral Capnella imbri-
cate (Figure 1).1 These substances appear to have a pro-
tective role against fish predation and invasion by
microorganisms, larvae, and algae.2 Some capnellenols
have been synthesized by our group (1, 3, 6)3a,b and Pat-
tenden’s group (3).3c,d We also reported the catalytic
asymmetric syntheses of capnellenols 3 and 6.4a,b There
are no reports, however, of total syntheses of 5a-capnelle-
nols 4 and 5. In addition to the fact that 5 exhibits antitu-
mor activities,5 5a-capnellenols 4 and 5 are highly
attractive and challenging synthetic targets. We describe
herein a catalytic asymmetric synthesis of the tricyclic
core of 5a-capnellenols using an asymmetric Heck reac-
tion–carbanion capture process4c and an intramolecular
nitrile oxide cycloaddition as key ring-construction steps.
CO2Et
OTBDPS
OBz
(2 equiv)
Me
EtO2C
OTBDPS
Me
7
8
Na
NaBr (2 equiv), DMSO, r.t.
77%, 87% ee
OBz
H
H
H
H
6 steps4c
b
a
6C
3
5
X
H
Me
N
Me
O
9 (X = I)
11
10 (X = NO2)
Scheme 1 Preliminary result of C-ring formation. Reagents and
conditions: (a) AgNO2, Et2O, 35 °C, 72%; (b) p-Cl-C6H4-NCO, Et3N,
benzene, 85 °C, 88% (dr 3:2).
R1 R2 R3 R4
Considering the efficiency of a tetracyclic compound syn-
thesis, however, as many as 8 steps were required from the
Heck adduct 8. Therefore, for easy access to the substrate
for C-ring formation, we planned to use b-keto ester 15
(Scheme 2) as a nucleophile for an asymmetric Heck re-
action–carbanion capture process.
1
2
3
4
5
6
R1
R2
H
H
H
H
H
H
OH
H
H
H
H
H
Me
HO10
1
OH
OH
H
H
A
C
B
H
OH
OH
H
5
R3
Me
H
OH
H
R4
OH H OH
Our retrosynthetic analysis is shown in Scheme 2. The
bisallylic alcohol moiety on the C-ring3a,b and the dimeth-
yl moiety on the A ring4c would be constructed from the
key intermediate 12. The C-ring would be constructed by
an intramolecular nitrile oxide cycloaddition. The precur-
sor oxime for this cycloaddition would be synthesized
from 14. The optically active bicyclic compound 14
would be constructed from achiral triflate 7 via an asym-
metric Heck reaction–carbanion capture process using b-
keto ester 15 as a nucleophile.
Figure 1 Structures of capnellenols
The results of our previous attempts3a,b,4 suggested that the
optically active bicyclic compound 8, which was obtained
from achiral triflate 7 via an asymmetric Heck reaction–
carbanion capture process using a-substituted malonate as
a nucleophile and successfully converted to (–)-D9(12)-cap-
nellene,4c could be utilized for the total synthesis of 5a-
The synthesis began with the asymmetric Heck reaction–
carbanion capture process using achiral triflate 74c as a
substrate (Scheme 3). b-Keto ester 15 was prepared by the
SYNLETT 2006, No. 18, pp 3053–3056
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951537; Art ID: S09006ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
6

3054
W. Itano et al.
LETTER
CO2Me
MeO2C
Me
R2
Me
HO
H
H
OTBDPS
OPMB
H
H
OH
c, d, e
a, b
A
C
14
B
5
O
Me
H
H
Me
OH
OH
Me
4 (R2 = H)
5 (R2 = OH)
12
17
MeO2C
OTBDPS
H
CO2Me
H
H
CO2Me
H
H
O
MeO2C
nitrile oxide
cycloaddition
H
f
H
OTBDPS
O
C
OTBDPS
H
H
3
6
C
N
5
5
Me
18
H
N
Me
OH
OPMB
H
Me
N
O
Me
13
14
13
asymmetric Heck reaction–
carbanion capture process
Scheme 4 Construction of the C- and isoxazoline rings. Reagents
and conditions: (a) NaBH4, MeOH, –40 °C; (b) TBDPSCl, imidazole,
cat. DMAP, DMF, 40 °C, 95% (two steps); (c) DDQ, CH2Cl2–H2O, 0
°C; (d) (COCl)2, DMSO, Et3N, CH2Cl2, –23 °C to 0 °C, 88% (two
steps); (e) NH2OH–HCl, pyridine, MeOH, r.t., quant.; (f) chloramine-
T, MeOH, reflux, 95%.
O
O
+
7
OPMB
MeO
15
Scheme 2 Retrosynthetic analysis of 4 and 5
chloramine-T (sodium p-toluenesulfonchloramide trihy-
drate)11 as an oxidizing agent. The stereochemistry of 13
was confirmed by NOESY analysis (cross-peak between
H3a and H5) and 1H NMR coupling constant analysis (H5–
H6: 6.9–7.7 Hz).
O
a
OPMB
MeO
15
N
16
Me
MeO2C
O
H
H
[Pd(allyl)Cl]2 (2.5 mol %)
(S)-BINAP (6.3 mol %)
CO2Me
CO2Me
OTf
H
H
H
H
9
9
OTBDPS
OTBDPS
OPMB
O
O
Mo(CO)6
(2 equiv)
OPMB
8
8
Me
5
Me
5
14
MeCN–H2O
MeO
H
Me
7
O
Me
H
N
with NaBr (2 equiv) : 82%, 83% ee
Na
O
OH
without NaBr : 74%, 72% ee
additive, DMSO, r.t.
(8β, 9α)-13
19 α-OH 14%
20 β-OH 34%
Scheme 3 Synthesis of 14 via an asymmetric Heck reaction–
carbanion capture process. Reagents and conditions: (a) LDA, THF,
methyl acetate, then 16, –78 °C to r.t., 80%.
Scheme 5 Preliminary result of the N–O bond cleavage and C5-a-
OH formation
alkylation of Weinreb amide 168 with the lithium enolate
of methyl acetate. Treatment of 7 with [Pd(allyl)Cl]2 (2.5
mol%), (S)-BINAP (6.3 mol%), NaBr (2 equiv), and the
sodium enolate of 15 (2 equiv) in DMSO gave the func-
tionalized bicyclic product 149 in 82% yield and 83% ee.
Without NaBr, the chemical yield and enantiomeric ex-
cess decreased to 74% yield and 72% ee. This interesting
positive effect of NaBr was first observed in the case of 7
→ 8 (Scheme 1).4c The enantiomeric excess and absolute
configuration of 14 were determined by its conversion to
methyl (1S,4R,5R)-4-hydroxy-5-methyl-8-methylenebi-
cyclo[3.3.0]oct-2-ene-2-acetate.10 Intensive examination
of the chiral ligand effects indicated that BINAP gave the
highest enantioselectivity.
We then focused on reductive cleavage of the isoxazoline
ring of 13 (Scheme 5). Examination of the N–O bond
12,13
cleavage of 13 with Mo(CO)6
indicated that epimer-
ization of the C5-position through retro-aldol and aldol re-
actions proceeded to afford the desired C5-a-OH product.
The epimerization, however, occurred only from the
8b,9a-isomer, providing the C5-a-OH product 19 in low
yield. Therefore, we decided to converge four isomers of
13 to a,b-unsaturated ester 21 (Scheme 6) before cleavage
of the isoxazoline ring. In this case, the retro-aldol reac-
tion was expected to proceed faster than that of 13 due to
the stability of the supposed intermediate 23 (Figure 2).
OMe
We then examined the C-ring formation (Scheme 4). Re-
duction of 14 with NaBH4 and protection of the resulting
alcohol as a TBDPS ether gave 17 as a mixture of diaste-
reomers. After removal of the PMB group, Swern oxida-
tion of the resulting hydroxyl group followed by
condensation with hydroxylamine gave the oxime 18. The
C-ring formation was successfully achieved by the in-
tramolecular nitrile oxide cycloaddition of 18 with
O
H
Me
(X = N=Mo, NH or O)
X
H
O
23
Figure 2 The supposed intermediate for a retro-aldol and aldol epi-
merization process from 21
Synlett 2006, No. 18, 3053–3056 © Thieme Stuttgart · New York

LETTER
Synthesis of the Tricyclic Core of 5a-Capnellenols
3055
CO2Me
capture process for the catalytic asymmetric synthesis of
the bicyclic compound 14, (2) the intramolecular nitrile
oxide cycloaddition for the C-ring formation, and (3) a
retro-aldol and aldol epimerization process for C5-a-OH
formation.
H
H
O
a–c
13
5
Me
H
N
21
CO2Me
CO2Me
Acknowledgment
H
H
H
H
d
This work was supported by Grant-in-Aid for Encouragements for
Young Scientists (A), and Grant-in-Aid for Specially Promoted
Research from JSPS and MEXT.
+
5
5
O
O
Me
H
Me
H
OH
OH
e
12
22
References and Notes
Scheme 6 Convergence of diastereomers and C5-a-OH formation.
Reagents and conditions: (a) TBAF, THF, r.t.; (b) MsCl, Et3N,
CH2Cl2; (c) DBU, benzene, r.t., 88% (three steps); (d) Mo(CO)6,
MeCN–H2O, 70 °C, 76% (22:12 = 1:18); (e) NaOMe, MeOH, 0 °C,
(22:12 = 1:3.2).
(1) (a) Kaisin, M.; Sheikh, Y. M.; DurHam, L. J.; Djerassi, C.;
Tursch, B.; Daloze, D.; Braekaman, J. C.; Losman, D.;
Karlsson, R. Tetrahedron Lett. 1974, 15, 2239. (b) Sheikh,
Y. M.; Singy, G.; Kaisin, M.; Eggert, H.; Djerassi, C.;
Tursch, B.; Daloze, D.; Braekman, J. C. Tetrahedron 1976,
32, 1171. (c) Sheikh, Y. M.; Djerassi, C.; Braekman, J. C.;
Daloze, D.; Kaisin, M.; Tursch, B.; Karlsson, R.
Tetrahedron 1977, 33, 2115. (d) Ayanoglu, E.; Gehreyesus,
T.; Beechan, C. T.; Djerassi, C.; Kaisin, M. Tetrahedron
Lett. 1978, 19, 1671. (e) Kaisin, M.; Braekman, J. C.;
Daloze, D.; Tursch, B. Tetrahedron 1979, 35, 1035.
(f) Kaisin, M.; Braekman, J. C.; Daloze, D.; Tursch, B.
Tetrahedron 1985, 41, 1067. (g) Morris, L. A.; Jaspars, M.
Tetrahedron 1998, 54, 12953.
(2) (a) Ciereszko, L. S. Trans. N. Y. Acad. Sci. 1962, 24, 502.
(b) Burkolder, P. R.; Burkolder, L. M. Science 1958, 127,
1174. (c) Ciereszko, L. S.; Karns, T. K. B. In Biology and
Geology of Coral Reefs, Biology 1, Vol. 2; Jones, O. A.;
Endean, R., Eds.; Academic Press: New York, 1972, Chap.
6. (d) Tursch, B.; Braekman, J. C.; Daloze, D.; Kaisin, M. In
Marine Natural Products, Chemical and Biological
Perspective, Vol. 2; Scheyer, P. J., Ed.; Academic Press:
New York, 1978, Chap. 4.
After the removal of the TBDPS group, mesylation fol-
lowed by b-elimination with DBU gave 21.14 With
Mo(CO)6, the reductive N–O bond cleavage and epimer-
ization of the C5-position proceeded in one pot to afford
the potential key intermediate 1215 as the major product
(b-OH/a-OH = 1:18). In addition, 22 and 12 were in equi-
librium under basic conditions (MeONa/MeOH: 22/
12 = 1.0:3.2).16 Theoretical calculations17 offer compel-
ling evidence of the preferential formation of C5-a-OH
isomer 12 (DEcalc = 1.29 kcal/mol: 22/12 = ca. 1:9).
CO2Me
CO2Me
H
H
H
H
a
12
+
5
5
O
O
Me
H
Me
H
(3) (a) Shibasaki, M.; Mase, T.; Ikegami, S. J. Am. Chem. Soc.
1986, 108, 2090. (b) Mase, T.; Shibasaki, M. Tetrahedron
Lett. 1986, 27, 5245. (c) Patterson, G.; Teague, S. J. J.
Chem. Soc., Perkin Trans. 1 1988, 1077. (d) Ladlow, M.;
Patterson, G.; Teague, S. J. Tetrahedron Lett. 1986, 27,
3279.
OH
OH
b
25
24
Scheme 7 Cyclopropanation of 12. Reagents and conditions: (a)
Et2Zn, CH2I2, toluene, 30 °C, 70% (24:25 = 1:1.1); (b) NaOMe,
MeOH, r.t., (24:25 = 1:3.2).
(4) (a) Kagechika, K.; Shibasaki, M. J. Org. Chem. 1991, 56,
4093. (b) Kagechika, K.; Ohshima, T.; Shibasaki, M.
Tetrahedron 1993, 49, 1773. (c) Ohshima, T.; Kagechika,
K.; Adachi, M.; Sodeoka, M.; Shibasaki, M. J. Am. Chem.
Soc. 1996, 118, 7108.
(5) Li, R.; Long, K.; Fang, Z.; Zhao, H.; Zhang, M. Zhongshan
Daxue Xuebao, Ziran Kexueban 1985, 17.
(6) Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82,
5339.
To the key intermediate 12, a C1 unit on an A-ring was in-
troduced to construct the carbon skeletons of 5a-capnelle-
nols 4 and 5 (Scheme 7). Simmons–Smith-type reaction
of 12 successfully converted exocyclic olefin to cyclopro-
pane with 70% yield. Although epimerization of the C5-
position occurred simultaneously to give 24 and 2518 in al-
most the same ratio (b-OH/a-OH = 1:1.1), these two iso-
mers were also in equilibrium under basic conditions
(MeONa/MeOH: 24/25 = 1.0:3.2),16 providing the de-
sired 25 as a major compound. Further transformations
from 25 to 5a-capnellenol 4 and another approach from
the key intermediate 12 to 5 are currently under investiga-
tion.
(7) Analytical Data for 11.
Major isomer: Rf = 0.44 (silica gel, EtOAc–hexane, 2 × 1:3).
1H NMR (500 MHz, CDCl3): d = 8.02–7.98 (m, 2 H), 7.60–
7.55 (m, 1 H), 7.47–7.42 (m, 2 H), 4.96–4.94 (br s, 1 H),
4.88–4.86 (br s, 1 H), 4.60 (dd, J = 11.0, 6.4 Hz, 1 H), 4.51
(d, J = 7.0 Hz, 1 H), 4.39 (dd, J = 11.0, 8.2 Hz, 1 H), 4.16
(dd, J = 7.0, 6.4 Hz, 1 H), 3.31–3.22 (m, 1 H), 2.76 (ddd,
J = 16.8, 11.0, 1.6 Hz, 1 H), 2.49–2.30 (m, 5 H), 1.53–1.45
(m, 2 H), 1.04 (s, 3 H). 13C NMR (126 MHz, CDCl3): d =
167.91, 166.34, 152.81, 133.09, 129.97, 129.56 (2 C),
128.42 (2 C), 109.13, 89.30, 66.08, 64.45, 58.58, 55.36,
47.46, 44.25, 34.93, 28.41, 24.47, 20.24.
In conclusion, we achieved a catalytic asymmetric synthe-
sis of the highly functionalized tricyclic compound 12, the
potential key intermediate for the total synthesis of 5a-
capnellenols 4 and 5. Our synthetic approach was high-
lighted by (1) an asymmetric Heck reaction–b-keto ester
Minor isomer: Rf = 0.49 (EtOAc–hexane 2 × 1:3). 1H NMR
(500 MHz, CDCl3): d = 8.03–8.00 (m, 2 H), 7.60–7.56 (m, 1
Synlett 2006, No. 18, 3053–3056 © Thieme Stuttgart · New York

3056
W. Itano et al.
LETTER
H), 7.48–7.44 (m, 2 H), 4.49–4.48 (br s, 1 H), 4.81–4.79 (br
s, 1 H), 4.56 (d, J = 7.3 Hz, 1 H), 4.34 (dd, J = 11.0, 5.8 Hz,
1 H), 4.28 (dd, J = 11.0, 6.7 Hz, 1 H), 4.20–4.16 (m, 1 H),
3.01–2.95 (m, 1 H), 2.87 (dd, J = 15.5, 8.3 Hz, 1 H), 2.50–
2.34 (m, 3 H), 2.21–2.16 (m, 2 H), 1.55–1.40 (m, 2 H), 1.06
(s, 3 H). 13C NMR (126 MHz, CDCl3): d = 167.83, 166.47,
153.63, 133.21, 129.85, 129.56 (2 C), 128.48 (2 C), 106.72,
90.49, 68.14, 61.78, 61.76, 57.96, 49.98, 45.69, 35.30,
28.92, 25.00, 19.67. FT-IR (neat): 2951, 1718, 1451, 1273,
1117, 713 cm–1. LRMS (ESI, MeOH): m/z = 360.1 [M +
Na+], 697.2 [2 M + Na+]. HRMS-FAB: m/z calcd for
C21H23NO3 [M + H+]: 338.1751; found: 338.1760.
(13) For supposed mechanism of a reductive N–O bond cleavage
with Mo, see: (a) Nitta, M.; Kobayashi, T. J. Chem. Soc.,
Perkin Trans. 1 1984, 2103. (b) Nitta, M.; Yi, A.;
Kobayashi, T. Bull. Chem. Soc. Jpn. 1985, 58, 991.
(c) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; Sarlo, F. D.
Tetrahedron Lett. 1990, 31, 3351.
(14) Analytical Data for 21.
Rf = 0.38 (silica gel, EtOAc–hexane, 1:2). FT-IR (neat):
2958, 2930, 2860, 1719, 1439, 1236, 1076, 831 cm–1. 1H
NMR (500 MHz, CDCl3): d = 7.12 (s, 1 H), 5.03–5.01 (m, 1
H), 5.00–4.98 (m, 1 H), 4.61 (d, J = 7.7 Hz, 1 H), 4.23 (dd,
J = 7.7, 6.8 Hz, 1 H), 3.82 (s, 3 H), 3.17 (dd, J = 6.8, 6.1 Hz,
1 H), 2.47–2.41 (m, 2 H), 2.17 (br d, J = 6.1 Hz, 1 H), 1.61–
1.47 (m, 2 H), 1.03 (s, 3 H). 13C NMR (126 MHZ, CDCl3):
d = 169.72, 164.32, 153.56, 153.08, 128.01, 109.12, 90.47,
66.92, 59.97, 55.75, 52.12, 51.79, 37.51, 31.00, 21.20.
LRMS (ESI, MeOH): m/z = 281.9 [M + Na+]. HRMS-FAB:
m/z calcd for C15H17CsNO3 [M + Cs+]: 392.0257; found:
392.0258. [a]D20 +36.4 (c 0.22, CHCl3).
(8) Stockley, M.; Clegg, W.; Fontana, G.; Golding, B. T.;
Martin, N.; Rigoreau, L. J. M.; Smith, G. C. M.; Griffin, R.
J. Bioorg. Med. Chem. Lett. 2001, 11, 2837.
(9) General Procedure for the Asymmetric Heck Reaction–
Carbanion Capture Process.
[Pd(allyl)Cl]2 (1.99 mg, 5.5 mmol, 2.5 mol%) and (S)-
BINAP (8.55 mg, 13.7 mmol, 6.3 mol%) were added to a
solution of 7 (61.5 mg, 0.218 mmol) in DMSO (1.0 mL,
0.218 M). After degassing, the sodium enolate of 15 (0.33
M, in DMSO, 1.32 mL, 0.436 mmol, 2 equiv) was gradually
added to the mixture. The reaction mixture was stirred at r.t.
for 1 h, diluted with Et2O, washed with 1 N aq HCl and brine,
dried (Na2SO4), and concentrated. The residue was purified
twice by silica gel column chromatography (Et2O–hexane,
1:25) to give 14 (68.5 mg, 82%, 83% ee) as colorless oil
(1:1 mixture of diastereomers). Rf = 0.39 (silica gel, EtOAc–
hexane, 1:3). FT-IR (neat): 2919, 2849, 1722, 1314, 1249,
1035, 821, 760 cm–1. 1H NMR (500 MHz, CDCl3): d = 7.28–
7.24 (m, 2 H), 6.90–6.88 (m, 2 H), 5.54 (dd, J = 5.5, 2.2 Hz,
0.5 H), 5.52–5.48 (m, 1 H), 5.54 (dd, J = 5.5, 2.5 Hz, 0.5 H),
4.91–4.82 (m, 2 H), 4.53–4.49 (m, 2 H), 4.16 (d, J = 17.4 Hz,
0.5 H), 4.14 (d, J = 17.4 Hz, 0.5 H), 4.11 (d, J = 17.4 Hz, 0.5
H), 4.08 (d, J = 17.4 Hz, 0.5 H), 3.81 (s, 3 H), 3.70, 3.66 (s,
1.5 H), 3.63 (d, J = 9.5 Hz, 0.5 H), 3.55 (d, J = 10.4 Hz, 0.5
H), 3.28–3.23 (m, 1 H), 2.38–2.36 (br s, 0.5 H), 2.29–2.17
(m, 2.5 H), 1.72–1.64 (m, 1 H), 1.51–1.41 (m, 1 H), 1.19,
1.15 (s, 1.5 H). 13C NMR (126 MHz, CDCl3): d = 168.64,
168.57, 159.46, 157.52, 157.40, 141.47, 141.14, 129.60 (2
C), 129.24, 128.92, 128.89, 113.82 (2 C), 106.07, 106.04,
74.58, 74.53, 73.00, 72.97, 61.17, 60.73, 57.22, 57.19,
56.51, 56.34, 55.25, 54.63, 54.17, 52.34, 52.20, 38.35,
38.32, 33.19, 27.68, 27.59. LRMS (ESI, MeOH): m/z =
407.1 [M + Na+], 791.2 [2 M + Na+]. HRMS-FAB: m/z calcd
for C23H28CsO5 [M + Cs+]: 517.0986; found: 517.0981. The
allylated product of 14 (Figure 3, 2.5 mg, 3%) was obtained
as the by-product.
(15) (a) Analytical Data for 12.
Rf = 0.28 (silica gel, EtOAc–hexane, 2 × 1:2). FT-IR (neat)
3438, 2953, 2925, 1710, 1437, 1222, 1082, 887 cm–1. 1H
NMR (500 MHz, CDCl3): d = 6.56 (d, J = 2.1 Hz, 1 H),
5.22–5.20 (m, 1 H), 5.03–5.01 (m, 1 H), 3.91–3.89 (m, 1 H),
3.88 (s, 3 H), 3.46 (ddd, J = 6.7, 4.9, 2.1 Hz, 1 H), 3.08 (dd,
J = 6.7, 6.7 Hz, 1 H), 2.61–2.54 (m, 1 H), 2.51–2.43 (m, 2
H), 2.16–2.13 (br s, 1 H), 1.97 (ddd, J = 13.2, 9.3, 9.3 Hz, 1
H), 1.51–1.46 (m, 1 H), 1.03 (s, 3 H). 13C NMR (126 MHz,
CDCl3): d = 209.04, 165.90, 164.46, 155.08, 136.02, 108.31,
81.70, 59.92, 59.01, 57.17, 52.47, 51.12, 31.85, 31.28,
24.25. LRMS (ESI, MeOH): m/z 285.0 [M + Na+]. HRMS-
FAB: m/z calcd for C15H18CsO4 [M + Cs+]: 395.0254; found:
395.0251. [a]D20 +62.5 (c 0.20, CHCl3). (b) The stereo-
chemistry at C5 was confirmed by NOE analysis after
protection of the hydroxyl group with a TBS group
(Scheme 8).
CO2Me
H
H
TBSCl
imidazole
12
6
DMF
5
O
Me
H
H
NOE 1.5%
NOE 3%
OTBS
Scheme 8
(16) Improvement of the C5–OH isomer ratio is still under
investigation.
(17) The DFT calculation was performed on Gaussian03 with
B3LYP/6-31+G(d).
(18) (a) Analytical Data for 25.
MeO2C
O
Rf = 0.33 (silica gel, EtOAc–hexane, 2 × 1:2). FT-IR (neat):
3406, 2924, 2852, 1710, 1438, 1221, 1086, 802 cm–1. 1H
NMR (500 MHz, CDCl3): d = 6.49 (d, J = 2.2 Hz, 1 H), 3.83
(s, 3 H), 3.77 (dd, J = 7.6, 4.6 Hz, 1 H), 3.39 (ddd, J = 7.0,
4.2, 2.2 Hz, 1 H), 2.99 (dd, J = 7.6, 7.0 Hz, 1 H), 2.16–2.10
(m, 1 H), 2.13 (d, J = 4.6 Hz, 1 H), 1.95–1.89 (m, 1 H), 1.61
(d, J = 4.2 Hz, 1 H), 1.51–1.41 (m, 2 H), 1.20 (s, 3 H), 1.03–
0.98 (m, 1 H), 0.64–0.60 (m, 1 H), 0.56–0.52 (m, 1 H), 0.46–
0.42 (m, 1 H). 13C NMR (126 MHz, CDCl3): d = 209.11,
165.87, 164.45, 135.61, 81.70, 59.80, 59.67, 58.79, 52.40,
49.19, 35.06, 31.57, 29.69, 26.35, 15.59, 7.15. LRMS (ESI,
MeOH): m/z = 298.8 [M + Na+]. HRMS-FAB: m/z calcd for
H
H
OPMB
Me
Figure 3
(10) Ohshima, T.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett.
1993, 34, 8509.
(11) Hassener, A.; Rai, K. M. L. Synthesis 1989, 57.
(12) Baraldi, P. G.; Barco, A.; Benetti, S.; Manfredini, S.;
Simoni, D. Synthesis 1987, 276.
C16H20CsO4 [M + Cs+] 409.0410; found: 409.0399. [a]D
+35.8 (c 0.12, CHCl3).
24
Synlett 2006, No. 18, 3053–3056 © Thieme Stuttgart · New York