Stereoselective first total synthesis of a ten-membered macrolide from L-malic acid and (2R)-2,3-O-cyclohexylideneglyceraldehyde

Article abstract of DOI:10.1055/s-0028-1083531

A convergent stereoselective first total synthesis of a novel ten-membered macrolide from L-malic acid and (2R)-2,3-O-cyclohexylideneglyceraldehyde is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083531

LETTER
2795
Stereoselective First Total Synthesis of a Ten-Membered Macrolide from
L-Malic Acid and (2R)-2,3-O-Cyclohexylideneglyceraldehyde
Synthesis of
a
a
T
en-Mem
b
l
ered
M
a
acrolide fro
k
m
L
-Malic
A
o
cid dety Radha Krishna,* A. Sreeshailam
D-206/B, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500607, India
Fax +91(40)27160387; E-mail: prkgenius@iict.res.in
Received 3 July 2008
O
OMe OMOM
Abstract: A convergent stereoselective first total synthesis of a
novel ten-membered macrolide from L-malic acid and (2R)-2,3-O-
cyclohexylideneglyceraldehyde is reported.
O
9
OH
3
1
6
HO2C
8
4
OMe
OBn
OH
O
Key words: ten-membered macrolide, (2R)-2,3-O-cyclohexylidene-
glyceraldehyde, L-malic acid, 1,2-syn allylation, Yamaguchi macro-
lactonization
2
1
OMe OH
PMBO
OBn
O
O
Much current interest has been focused on the utility of
naturally occurring bifidus factors and growth inhibitors
against harmful bacteria such as Clostridium and E. coli.
The ascomycetous genus Cordyceps is an entamopatho-
genic fungus that has found extensive use in food and
herbal medicine in Asia. Cordyceps genus is a known rich
source of biologically active secondary metabolites.1 In
recent years, these secondary metabolites have received
attention due to their unique structure and specific biolog-
ical activities.
3 (major)
OMe
PMBO
CHO
O
+
O
OBn
H
5
4
Cardicepin (3¢-deoxyadenosine), possessing antifungal,
antiviral, and antitumour activities, is one of a few sec-
ondary metabolites previously isolated from C. millitaris.
A novel ten-membered macrolide 1 (Scheme 1), structur-
ally related to cephalosporolide C, was isolated from
Cordiceps militaris BCC 2816 as one of the biologically
active natural product possessing antimalarial activity
against Plasmodium falsifarum K1 (multidrug-resistant
strain).2 Considering the fact that cyclizations of medium-
ring lactones with n = 8–11 (n = number of carbon atoms
in the lactone ring) are difficult to achieve due to enthalpy
and entropy factors3 and the intrinsic limitation that not all
macrolides could be accessed through the Grubbs catalyst
mediated ring-closing metathesis approach,4 makes the
ten-membered macrolide synthesis more so challenging.
The impressive biological profile of 1 coupled with struc-
tural features, especially the strategically located 6-keto
functionality attracted our attention. This paper describes
the stereoselective first total synthesis of 1.
L-malic acid
(R)-2,3-O-cyclohexylideneglyceraldehyde
Scheme 1 Retrosynthetic analysis of 1
controlled 1,2-syn allylation, acetylenic anion addition
onto a chiral aldehyde, exhaustive reduction, and
Yamaguchi macrolactonization as the key steps. Retro-
synthetic analysis reveals that target compound 1 can be
obtained from seco acid 2 by Yamaguchi macrolactoniza-
tion followed by the selective deprotection of MOM ether,
oxidation of the ensuing free hydroxyl group to its keto
functionality, and subsequent deprotection of the benzyl
group. Accordingly, to garner the requisite cabon chain
with rightly positioned stereocenters, accessing seco acid
2 remains the most important task. Strategically, seco acid
2 could be obtained from chiral propargyl alcohol 3. Com-
pound 3, in turn, could be obtained by coupling of frag-
ments 4 and 5 followed by the functional group
manipulations. Both fragments 4 and 5 are realized from
(2R)-2,3-O-cyclohexylideneglyceraldehyde and L-malic
acid, respectively, by simple chemical transformations.
In accordance with our interest in the natural product syn-
thesis,5 herein we report stereoselective first total synthe-
sis of 1 by a convergent strategy wherein both the
intermediates are drawn from the common, inexpensive
starting materials, L-malic acid and (2R)-2,3-O-cyclohex-
ylideneglyceraldehyde. Our strategy relies on chelation-
Accordingly, the synthesis of 1 starts with the preparation
of alkyne 4 (Scheme 2). Thus, known6a (2R)-2,3-O-cyclo-
hexylideneglyceraldehyde 6 was converted into an acety-
lenic functionality via the conventional vinyl dibromide
(CBr4, Ph3P, THF, r.t.) and its subsequent exposure to
EtMgBr to afford the alkyne 4 (60%).6b
SYNLETT 2008, No. 18, pp 2795–2798
1
4
.1
1
.2
0
0
8
Advanced online publication: 15.10.2008
DOI: 10.1055/s-0028-1083531; Art ID: G21808ST
© Georg Thieme Verlag Stuttgart · New York

2796
P. Radha Krishna, A. Sreeshailam
LETTER
As envisaged, compound 5 was obtained from L-malic
acid (Scheme 2). Thus, L-malic acid was converted into
aldehyde 7 according to the modified literature proce-
dure.5b The thus prepared aldehyde 7 on chelation-con-
trolled allylation [allylSn(Bu)3, MgBr2·2Et2O, CH2Cl2,
–78 to –20 °C] afforded highly stereoselective syn-diol
derivative 8 (95%, de >97%).7 The absolute stereochem-
istry of the newly created compound 8 was assigned based
on literature and the synthesis continued as envisaged.
The terminal olefin in 8 was exploited to generate alde-
hyde 5 (85%) through the conventional dihydroxylation–
oxidative cleavage protocol.
O
O
a
O
O
CHO
H
4
6
OH
ref. 5b
PMBO
CHO
OBn
CO2H
HO2C
7
L-malic acid
PMBO
OH
OMe
In order to prepare propargyl alcohol 3, alkyne 4
(Scheme 3) was treated with n-BuLi in THF at –78 °C and
the resulting acetylenic anion was quenched with alde-
hyde 5 to furnish 3 (92%, de 60%) as a chromatographi-
cally separable diastereomeric mixture.8 The major
diastereomer was taken up for further use so that the ensu-
ing NMR spectra are simplified. Also this particular car-
bon eventually correlates to C-6 ketone in macrolide 1 and
chirality ceases to be of any consequence. Exhaustive re-
duction of the triple bond in 3 under the standard condi-
tions gave 10 in quantitative yield. Subsequently, the
newly generated hydroxy group in 10 was protected
(MOMCl, DIPEA, CH2Cl2, 0 °C to r.t.) to afford 10a
(90%). Later, the cyclohexylidene group of 10a was
c
b
PMBO
OBn
OBn
8
9
OMe
d
PMBO
CHO
OBn
5
Scheme 2 Reagents and conditions: (a) (i) CBr4, TPP, THF, –10 °C,
30 min, then aldehyde; (ii) EtMgBr, THF, 0 °C to r.t., 30 min, 60%
(over two steps); (b) allylSn(Bu)3, MgBr2·2Et2O, CH2Cl2, –78 to
–20 °C, 95%; (c) NaH, MeI, THF, 0 °C to r.t., 98%; (d) (i) cat. OsO4,
NMO, acetone–H2O (4:1), 12 h; (ii) NaIO4, CH2Cl2, 0 °C to r.t., 6 h,
85% (over two steps).
OMe OR
OMe OH
OMe
PMBO
b
PMBO
PMBO
CHO
a
O
OBn
10 R = H
OBn
O
OBn
O
5
3 (major)
O
c
10a R = MOM
O
O
O
OMe OMOM
OMe OMOM
O
OBn
OMe
f
d
g
PMBO
+
HO2C
OMe
OBn
OH
OMOM
OBn
OR
O
OMOM
2
11 R = H
12
12a
e
11a R = TBS
O
O
O
O
OBn
O
OH
OMe
O
OBn
OMe
h
i, j
+
O
+
OMe
OMe
OH
OH
13a
15
13
12b
OH
O
i
O
O
OBn
OMe
j
1
O
14
Scheme 3 Reagents and conditions: (a) 4, n-BuLi, THF, –78 °C, 3 h, 92%; (b) PtO2, H2, EtOAc, NaHCO3, r.t., 1 h, 100%; (c) DIPEA,
MOMCl, CH2Cl2, 0 °C to r.t., 12 h, 90%; (d) (i) PTSA, MeOH, r.t., 12 h; (ii) NaH, TsCl, 0 °C to r.t., 2 h; (iii) LAH, THF, 0 °C to r.t., 1 h, 65%
(over three steps); (e) TBSCl, imidazole, CH2Cl2, r.t., 98%; (f) (i) DDQ, CH2Cl2–H2O (9:1), r.t., 30 min, 95%; (ii) (COCl)2, DMSO, CH2Cl2,
Et3N, –78 °C; (iii) NaClO2, NaH2PNO4⋅H2O2, t-BuOH–2-methyl-2-butene (3:1), 0 °C to r.t., 12 h, 85%; (iv) TBAF, THF, r.t., 24 h, 95%; (g)
2,4,6-trichlorobenzoyl chloride, Et3N, THF, 0 °C, 3 h, then DMAP, toluene, 110 °C, 8 h, 12 (48%) and 12a (12%); (h) for conditions see Table
1; (i) DMP, CH2Cl2, 0 °C to r.t., 4 h, 95%; (j) Pd/C, H2, EtOAc, 4 h, r.t., 95%.
Synlett 2008, No. 18, 2795–2798 © Thieme Stuttgart · New York

LETTER
Synthesis of a Ten-Membered Macrolide from L-Malic Acid
2797
Table 1 Various Reaction Conditions Used for the MOM Deprotec-
tion in 12 and 12aa
deprotected (PTSA, MeOH, r.t.) to afford the correspond-
ing diol, which was selectively monotosylated (TsCl,
NaH, r.t.) and exposed to LAH to transform into the me-
thyl group of 11 (65% over three steps). The next task was
to protect the secondary OH group as its silyl ether (TB-
SCl, imidazole, CH2Cl2, r.t.) and release the PMB group
(DDQ, CH2Cl2–H2O, r.t.) in order to oxidize the ensuing
alcohol into an acid.
Entry Reaction conditions
Time Yield of Yield of Yield of
(h)
24
4
13 (%) 13a (%) 12b (%)
1
2
3
4
5
6
7
8
9
PPTS, t-BuOH, r.t.
PPTS, t-BuOH, reflux
PTSA, t-BuOH, r.t.
PTSA, t-BuOH, reflux
TFA, CH2Cl2, r.t.
n.d.
n.d.
n.d.
n.d.
n.d.
30
n.d.
68
n.d.
17
n.d.
15
16
6
24
4
n.d.
65
Accordingly, the primary alcohol was oxidized to the cor-
responding acid by a two-step process; firstly to an alde-
hyde by Swern oxidation and then on perchlorite
oxidation (NaClO2, NaH2PO4·2H2O, t-BuOH, 2-methyl-
2-butene) to afford the seco acid 2 (85% over two steps).
Yamaguchi macrolactonization9 of 2 gave the required
macrolide 12 (48%), along with the a,b-unsaturated deriv-
ative 12a (12%) as an inseparable mixture. Hence, mac-
rolide 12 was characterized at a later stage. To continue
the synthesis, MOM deprotection (TMSBr, CH2Cl2, –5 to
0 °C, entry 10, Table 1)10 of macrolide mixture 12 and
12a afforded 13 (68%) and 12b (17%), respectively, as
chromatographically separable compounds. Likewise,
compound 13a was the major product when the deprotec-
tion was performed under different reaction conditions
(see Table 1). Interestingly, it may be noted that with the
right choice of reagent system one can alter the product
profile either to 13/12b or 13a/12b as separable mixtures.
0.5
67
1 N HCl, MeOH, r.t.b
1 N HCl, MeOH, r.t.b
1 N HCl, MeOH, r.t.b
1 N HCl, MeOH, r.t.
0.5
1
10
25
25
10
15
17
17
2
10
45
12
n.d.
68
65
10 TMSBr, CH2Cl2, –5 to 0 °C 2
n.d.
a n.d. = not detected.
b Starting material recovered.
methyl protons at d = 1.18 as a doublet (J = 6.2 Hz). Dis-
counting the differences in NMR values, the rest of the
synthesis was continued. Consequently, 13a upon oxida-
tion and debenzylation as applied earlier afforded 15. A
closer inspection at the spectral data revealed that indeed
15 is not 1. For instance, 1H NMR spectra of 15 displayed
the methyl protons at d = 2.1 as a singlet, the protons due
to OMe appeared at d = 3.38 as a singlet, and the ester-
1
Macrolide 12b was characterized by its H NMR spec-
trum, which revealed the characteristic olefinic protons at
d = 6.25 as a double doublet (J = 11.3, 5.8 Hz), the other
one at d = 5.84 also as a double doublet (J = 11.3, 1.8 Hz),
and the methyl protons at d = 1.36 as a doublet (J = 6.2
Hz). Further, oxidation of 13 under Dess–Martin per-
iodinane conditions11 gave 14 (95%), and finally debenzy-
lation (Pd/C, H2, EtOAc, r.t.) gave the target compound 1
(95%). The synthetic 1 was thoroughly characterized by
25
linked methine proton at d = 4.57 as a multiplet. The [a]D
value was –105.3 (c 0.15, CHCl3) much different to the re-
ported value.1 Taking into account all the spectral details,
the structure of the macrolide was unambiguously as-
signed as the heptanolide 15.12
1
its spectral data. Its H NMR spectrum revealed that the
characteristic H-9 at d = 5.04 as a multiplet, the protons
due to OMe appeared at d = 3.43 as a singlet, and the
methyl protons at d = 1.26 as a doublet (J = 6.3 Hz). The
In conclusion, a stereoselective total synthesis of a novel
ten-membered macrolide 1 was accomplished by means
of a versatile strategy, wherein L-malic acid and (2R)-2,3-
O-cyclohexylideneglyceraldehyde were used as the inex-
pensive starting materials for accessing both the advanced
intermediates for use in a convergent synthetic strategy.
Interestingly, synthesis of two artifacts 12b and 15, hith-
erto unknown, was also reported en route.
25
MS peak revealed the 231 [M +1 ]+ ion, [a]D +58.0 (c
0.12, CHCl3) {natural 1; [a]D25 +59.0 (c 0.017, CHCl3)1}.
The physical and spectroscopic data of our synthetic sam-
ple 11,12 were identical to those of the reported natural
product.
In order to obtain a product profile in favor of the required
compound, standardization of MOM-deprotection reac-
tion (see Table 1) was felt necessary. As evident from
Table 1, most of the times 13a (85%, Scheme 3) was the
major product which was tentatively assigned as 13 but
whose structure was clarified in due course of synthesis.
Such acid-catalyzed ring contractions or expansions to af-
ford thermodynamically stable compounds is well known
in the literature.13 Subsequently, when the 1H NMR spec-
trum of 13a was compared with that of the natural prod-
uct, there appeared inadequacies especially the ester-
linked methine proton appeared at d = 4.5 as a multiplet
instead of at d = 5.09 for the natural product and the
Acknowledgment
One of the authors (AS) thanks the CSIR, New Delhi, for financial
support in the form of a fellowship.
References and Notes
(1) Kittakoop, P.; Punya, J.; Kongsaeree, P.; Lertwerawat, Y.;
Jintasirikul, A.; Tanticharoen, M.; Thebtaranonth, Y.
Phytochemistry 1999, 52, 453.
(2) Rukachaisirikul, V.; Pramjit, S.; Pakawatchai, C.; Isaka, M.;
Supothina, S. J. Nat. Prod. 2004, 67, 1953.
(3) Parenty, A.; Moreau, X.; Campagne, J. M. Chem. Rev. 2006,
106, 911.
Synlett 2008, No. 18, 2795–2798 © Thieme Stuttgart · New York

2798
P. Radha Krishna, A. Sreeshailam
LETTER
(4) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.
Int. Ed. 2005, 44, 4490. (b) Grubbs, R. H. Tetrahedron
2004, 60, 7117. (c) Fürstner, A. Angew. Chem. Int. Ed.
2000, 39, 3012.
(5) (a) Radha Krishna, P.; Narsingam, M. Synthesis 2007,
3627. (b) Radha Krishna, P.; Narasimha Reddy, P. V.
Tetrahedron Lett. 2006, 47, 7473. (c) Radha Krishna, P.;
Narasimha Reddy, P. V. Tetrahedron Lett. 2006, 47, 4627.
(d) Radha Krishna, P.; Ramana Reddy, V. V. Tetrahedron
Lett. 2005, 46, 3905. (e) Radha Krishna, P.; Narsingam, M.;
Kannan, V. Tetrahedron Lett. 2004, 45, 4773.
(f) Radha Krishna, P.; Ramana Reddy, V. V.; Sharma, G. V.
M. Synthesis 2004, 2107.
(6) (a) Sugiyama, T.; Sugavara, H.; Watanabe, M.; Yamashita,
K. Agric. Biol. Chem. 1984, 48, 1841. (b) Corey, E. J.;
Fuchs, L. Tetrahedron Lett. 1972, 36, 3769.
19.7. FTIR (neat): 3500, 3150, 2930, 1690, 1120 cm–1. ESI-
MS: m/z = 385 [M + H]+, 407 [M + Na]+. Anal. Calcd for
C20H32O7: C, 62.48; H, 8.39. Found: C, 62.61; H, 8.31.
Compound 12b: colorless syrup; [a]D25 –63.3 (c 0.35,
CHCl3). 1H NMR (200 MHz, CDCl3): d = 6.25 (dd, J = 11.3,
5.8 Hz, 1 H), 5.84 (dd, J = 11.3, 1.8 Hz, 1 H), 4.66–4.52 (m,
1 H), 4.13–3.95 (m, 1 H), 3.77 (t, J = 6.9 Hz, 1 H), 3.25 (s,
3 H), 2.34–1.53 (m, 6 H), 1.36 (d, J = 6.2 Hz, 3 H). ESI-MS:
m/z = 225 [M + Na]+. Anal. Calcd for C11H18O4: C, 61.66; H,
8.47. Found: C, 61.53; H, 8.59.
Compound 13a: colorless syrup; [a]D25 +8.33 (c 0.45,
CHCl3). 1H NMR (200 MHz, CDCl3): d = 7.29 (m, 5 H), 4.81
(d, J = 11.7 Hz, 2 H), 4.67–4.53 (m, 2 H), 4.45 (d, J = 11.7,
1 H), 3.89–3.72 (m, 1 H), 3.46 (m, 1 H), 3.31 (s, 3 H), 3.09
(d, J = 13.5 Hz, 1 H), 2.93 (dd, J = 14.2, 6.6 Hz, 1 H), 2.34–
1.69 (m, 2 H), 1.63–1.42 (m, 4 H), 1.18 (d, J = 6.2 Hz, 3 H).
ESI-MS: m/z = 345 [M + Na]+. Anal. Calcd for C18H26O7: C,
67.06; H, 8.13. Found: C, 67.21; H, 8.02
(7) De Brabander, J.; Vandewalle, M. Synthesis 1994, 855; and
references cited therein.
(8) Guillarme, S.; Plé, K.; Blanchet, A.; Liard, A.; Haudrechy,
Compound 14: colorless syrup; [a]D25 +10.7 (c 0.55, CHCl3).
1H NMR (200 MHz, CDCl3): d = 7.46–7.29 (m, 5 H), 5.18–
4.98 (m, 1 H), 4.82 (d, J = 11.3 Hz, 1 H), 4.59 (d, J = 11.3
Hz, 1 H), 4.11 (ddd, J = 11.7, 8.4, 3.6 Hz, 1 H), 3.56 (s, 3 H),
3.46–3.34 (m, 1 H), 2.95–2.59 (m, 3 H), 2.53–2.12 (m, 4 H),
2.05–1.90 (m, 1 H) 1.32 (d, J = 6.6 Hz, 3 H). 13C NMR (75
MHz, CDCl3): d = 208.2, 169.2, 132.9. 129.5, 128.3, 127.6,
81.9, 79.6, 72.1, 71.3, 58.9, 43.9, 40.2, 39.6, 33.2, 19.7.
FTIR (neat): 3452, 1733, 1726 cm–1. HRMS: m/z calcd for
C18H24O5NaCl [M + Na]+: 343.1521; found: 343.1512.
Compound 1: colorless syrup; [a]D25 +58.0 (c 0.12, CHCl3).
1H NMR (500 MHz, CDCl3): d = 5.04 (m, 1 H), 4.11 (ddd,
J = 11.6, 8.7, 2.9 Hz, 1 H), 3.43 (s, 3 H), 3.35 (ddd, J = 10.2,
8.2, 2.4 Hz, 1 H), 3.09 (br s, 1 H, OH), 2.93 (dd, J = 17.4, 7.7
Hz, 1 H), 2.86 (dd, J = 17.4, 3.4 Hz, 1 H), 2.63 (dd, J = 17.4,
2.9 Hz, 1 H), 2.45 (dd, J = 17.4, 2.4 Hz, 1 H), 2.41 (ddd,
J = 13.6, 7.2. 3.8 Hz, 1 H), 2.32 (ddd, J = 14.0, 10.6, 3.4 Hz,
1 H), 2.11 (m, 1 H), 2.02 (m, 1 H), 1.26 (d, J = 6.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 208.6, 169.2, 81.9, 71.6,
68.3, 57.3, 41.7, 40.4, 39.7, 33.1, 19.6. FTIR (neat): 3458,
1735, 1726 cm–1. HRMS: m/z calcd for C11H18O5NaCl [M +
Na]+: 253.1051; found: 253.1048.
A. Chem. Rev. 2006, 106, 2355.
(9) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(b) Fürstner, A.; Aïssa, C.; Riveiros, R.; Ragot, J. Angew.
Chem. Int. Ed. 2002, 41, 4763. (c) Parenty, A.; Moreau, X.;
Campagne, J.-M. Chem. Rev. 2006, 106, 911.
(10) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett.
1984, 25, 2515.
(11) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(12) Spectral Data of Selected Compounds
Compound 9: colorless syrup; [a]D25 –37.3 (c 2.0, CHCl3).
1H NMR (200 MHz, CDCl3): d = 7.35–7.17 (m, 5 H), 7.13
(d, J = 8.4 Hz, 2 H), 6.79 (d, J = 8.4 Hz, 2 H), 4.61 (d, J = 9.7
Hz, 2 H), 4.55–4.39 (m, 2 H), 4.31 (d, J = 7.1 Hz, 2 H), 4.04
(t, J = 7.7 Hz, 1 H), 3.86–3.77 (m, 1 H), 3.77 (s, 3 H), 3.67–
3.58 (m, 1 H), 3.58–3.41 (m, 2 H), 3.35 (s, 3 H), 3.29–3.02
(m, 1 H), 2.00–1.75 (m, 2 H), 1.75–1.55 (m, 10 H), 1.40–
1.30 (m, 2 H). 13C NMR (75 MHz,CDCl3): d = 159.0, 137.9,
130.4, 129.2, 128.3, 127.9, 127.7, 113.6, 110.8, 86.3, 82.3,
79.6, 75.3, 72.7, 72.4, 69.5, 66.1, 65.1, 61.0, 57.9, 55.1, 37.0,
35.7, 35.3, 29.6, 24.9. FTIR (neat): 3400, 3090, 2910, 2250,
1110 cm–1. ESI-MS: m/z = 539 [M + H]+, 556 [M + NH4]+.
Anal. Calcd for C32H42O7: C, 71.35; H, 7.86. Found: C,
71.41; H, 7.79.
Compound 15: colorless syrup; [a]D25 –105.3 (c 0.15,
CHCl3). 1H NMR (200 MHz, CDCl3): d = 4.57 (m, 1 H),
4.11–4.06 (m, 1 H), 3.47 (m, 1 H), 3.38 (s, 3 H), 3.18 (d,
J = 14.1 Hz, 1 H), 2.79–2.55 (m, 3 H), 2.14 (s, 3 H), 2.04 (dd,
J = 9.1, 2.0 Hz, 1 H), 1.96–1.78 (m, 3 H). FTIR (neat): 3442,
1734, 1728 cm–1. ESI-MS: m/z = 231 [M + H]+. Anal. Calcd
for C11H18O5: C, 57.38; H, 7.88. Found: C, 57.51; H, 7.76.
(13) (a) Ishigami, K.; Wantanabe, H.; Kitahara, T. Tetrahedron
2005, 61, 7546. (b) Fürstner, A.; Nagano, T.; Müller, C.;
Seidel, G.; Müller, O. Chem. Eur. J. 2007, 13, 1452.
Seco acid 2: colorless liquid; [a]D25 –3.8 (c 3.0, CHCl3).
1H NMR (200 MHz, CDCl3): d = 7.28 (m, 5 H), 4.72–4.49
(m, 4 H), 4.15–4.05 (m, 1 H), 3.82–3.69 (m, 1 H), 3.69–3.60
(m, 1 H), 3.43–3.25 (m, 7 H), 2.66 (dd, J = 15.8, 4.1 Hz,
1 H), 2.51 (dd, J = 15.8, 7.9 Hz, 1 H), 1.87–1.71 (m, 1 H),
1.66–1.38 (m, 5 H), 1.16 (d, J = 6.0 Hz, 3 H). 13C NMR (75
MHz, CDCl3): d = 175.7, 138.5, 128.2, 127.9, 127.5, 96.1,
78.2, 74.9, 72.4, 67.7, 58.9, 57.7, 55.5, 34.4, 33.6, 30.0, 24.1,
Synlett 2008, No. 18, 2795–2798 © Thieme Stuttgart · New York

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