Formal synthesis of cytostatin by a convergent approach

Article abstract of DOI:10.1055/s-2007-970786

A formal synthesis of cytostatin, an antitumor agent, has been achieved according to a convergent approach involving the coupling of a functionalized organolithium (C1-C8 subunit) with an aldehyde (C9-C13 subunit). Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970786

934
LETTER
Formal Synthesis of Cytostatin by a Convergent Approach
S
ynthesis of Cytos
n
tatin ne-Frédérique Salit, Christophe Meyer,* Janine Cossy*
Laboratoire de Chimie Organique, Associé au CNRS, ESPCI, 10 Rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)40794660; E-mail: christophe.meyer@espci.fr; E-mail: janine.cossy@espci.fr
Received 28 December 2006
Herein, we would like to report a formal synthesis of
cytostatin relying on a convergent approach for the prep-
aration of the advanced C1–C13 intermediate previously
reported in the first total synthesis of this natural product.5
Abstract: A formal synthesis of cytostatin, an antitumor agent, has
been achieved according to a convergent approach involving the
coupling of a functionalized organolithium (C1–C8 subunit) with
an aldehyde (C9–C13 subunit).
Key words: cytostatin, natural products, formal synthesis, dia- In our retrosynthetic analysis of cytostatin, the formation
stereoselectivity, metathesis
of the Z,Z,E-conjugated triene was envisaged in a classical
fashion by a palladium-catalyzed cross-coupling between
a Z,E-dienyl organometallic reagent (C14–C18 subunit)
and a (Z)-alkenyl iodide prepared from the alkynyl iodide
of type A (C1–C13 subunit). A further disconnection of
the C8–C9 bond in the fragment of type A was consid-
ered. Indeed, the syn relationship between the methyl
group at C10 and the hydroxyl group at C9, suggested that
the nucleophilic addition of an organometallic species
generated from the alkyl iodide of type B (C1–C8 subunit)
to the aldehyde of type C (C9–C13 subunit), may be ac-
complished with Felkin–Anh diastereoselectivity.8 In the
C1–C8 segment of type B the oxygen heterocycle would
be created by a ring-closing metathesis (RCM), whereas
the installation of the C4 and C5 stereocenters would rely
on a diastereoselective crotylboration applied to the opti-
cally active aldehyde of type D, which incorporates the C6
stereocenter of cytostatin. The retrosynthetic analysis of
the C9–C13 subunit of type C suggested the acetylenic b-
ketoester of type E as a suitable precursor. Indeed, an
enantioselective reduction of the keto group would intro-
duce the first stereocenter at C11, followed by an anti-
diastereoselective alkylation of the resulting b-hydroxy-
ester to introduce the methyl group at C10 (Scheme 1).
The natural product cytostatin, isolated in 1994 from a
strain of Streptomyces,1 is an antitumor agent possessing
cytotoxic and antimetastatic activity.2 Its unique mode of
action derives from the selective inhibition of serine-thre-
onine phosphatase 2A (PP2A), an enzyme involved in the
regulation of many crucial cellular processes.3 The identi-
fication of the key structural elements of molecules of the
cytostatin family, which lead to selective PP2A inhibition,
provides useful information for the development of small
molecule-based therapeutics.4
The eighteen-carbon polyketide-type backbone of cyto-
statin contains several remarkable structural elements
such as an a,b-unsaturated lactone (C1–C5), two syn,anti-
stereotriads (alternate methyl-hydroxyl-methyl arrays at
C4–C6 and C9–C11), a phosphate group at C9 and a con-
jugated triene subunit (C12–C17) of Z,Z,E-configuration
(Scheme 1). Although the basic structure of cytostatin
was readily established, its relative and absolute con-
figurations were initially not assigned.1 By assuming an
analogy with the structurally related natural products,
fostriecin and the phoslactomycins, a first total synthesis
of the 4S,5S,6S,9S,10S,11S-isomer of cytostatin was
achieved in 2002 according to a linear approach.5 The 1H
NMR, 13C NMR and 31P NMR data of this synthetic ma-
terial, which inhibits PP2A at a level comparable to the
natural product, were in perfect agreement with those re-
ported for cytostatin. However, a discrepancy in the mag-
nitude of the optical rotations, presumably due to an
impure authentic sample of the natural product, prevented
a definitive stereochemical assignment.5 An alternative
approach towards a C3–C13 fragment of cytostatin, de-
scribed in the first total synthesis, was also disclosed in
2003.6 Recently, a convergent total synthesis of cytostatin
and its C10–C11 diastereomers, as well as their biological
evaluation, has been reported.7
The synthesis of the C1–C8 fragment of cytostatin was
achieved from the readily available carboxylic acid 1.9
After activation of 1 as a mixed anhydride (EtOCOCl,
Et3N, Et2O, 0 °C), addition of the lithium salt derived
from the commercially available (S)-4-benzyloxazolidin-
2-one I (n-BuLi, THF, –78 °C) afforded the N-acyl-
oxazolidinone 2 (72%). The latter compound underwent
a highly diastereoselective methylation (NaHMDS, THF,
–78 °C, then MeI) that led to 3 (80%, dr > 96:4).10 Subs-
equent reduction of 3 with lithium borohydride (THF–
MeOH, 0 °C to r.t.) provided the corresponding optically
active alcohol 4 (85%) and the chiral auxiliary I could be
recovered (80%). Oxidation of the primary alcohol 4 with
2-iodoxybenzoic acid (IBX; THF–DMSO, 1:1) generated
the aldehyde 5 (quantitative yield) which was used in the
subsequent step without purification to avoid partial race-
mization at C6 (Scheme 2).
SYNLETT 2007, No. 6, pp 0934–0938
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-970786; Art ID: D39606ST
© Georg Thieme Verlag Stuttgart · New York
0
3.
0
4.
2
0
0
7
The next stage involved the installation of the C4 and C5
stereocenters through the use of a (Z)-crotylboronate
addition to control the C4–C5 syn relative configura-

LETTER
Synthesis of Cytostatin
935
O
O
P
afford the optically active secondary alcohol 13 (72%)
with an enantiomeric excess of 92%.17 In order to intro-
duce the methyl group at C10 with the requisite configu-
ration, the b-hydroxyester 13 was dilithiated (LDA, THF,
–78 °C) and alkylated (MeI, HMPA, –78 °C to –25 °C) to
afford the anti-a-methyl-b-hydroxy ester 14 (dr = 93:7,
94%).18 The hydroxyl group at C11 was protected as a
tert-butyldimethylsilyl ether (TBSOTf, 2,6-lutidine,
CH2Cl2, –40 °C) to provide 15 (94%) and subsequent
treatment with N-methoxy-N-methylhydroxylamine hy-
drochloride in the presence of i-PrMgCl (2.5 equiv, THF,
–20 °C) led to the Weinreb amide 16 (70%). The latter
compound was reduced (DIBAL-H, THF, –78 °C) to af-
ford the aldehyde 17 which was used in the subsequent
step without purification to avoid epimerization at C10
(Scheme 3).
NaO
1
14
O
O
OH
18
HO
16
6
10
4
5
13
11
9
12
cytostatin
O
O
PGO
P
PG = protecting group
1
O
O
OH
PGO
6
4
9
11
13
A
I
OPG
O
OPG
1
4
O
I
+
6
9
11
H
13
8
SiMe3
O
B
C
O
O
a,b
OTBDPS
OTBDPS
OTBDPS
c
HO
O
N
80%
72%
O
1
2
O
O
OPG
6
Ph
O
5
O
H
9
11
PGO
8
13
6
OTBDPS
6
d
e
SiMe3
O
N
HO
D
E
8
8
85%
Scheme 1 Retrosynthetic analysis of cytostatin
3
dr > 96:4
4
Ph
OH
O
tion.11,12 The anti relative configuration at C5–C6 implied
an anti-Felkin addition mode.8 Thus, the addition of the
optically active (Z)-crotylboronate reagent II, derived
from (S,S)-diisopropyl tartrate, to the aldehyde 5 afforded
the desired homoallylic alcohol 6 with high diastereose-
lectivity (dr > 96:4) and in 80% isolated yield. The latter
compound was then acylated with acryloyl chloride (i-
Pr2NEt, DMAP, CH2Cl2, –78 °C) and the resulting acry-
late 7 underwent RCM on treatment with Grubbs’ second-
generation catalyst III13 (6% mol, CH2Cl2, reflux) to af-
ford the a,b-unsaturated lactone 8 (95%, 2 steps from 6).
The relative configuration of this compound was ascer-
tained by 1H NMR and comparison with the spectral data
of structurally related diastereomeric lactones.14 As, later
in the synthesis, an organometallic reagent will have to be
generated at C8, the carbonyl group of the lactone was
masked as an acetal. Thus, lactone 8 was reduced to the
corresponding lactol (DIBAL-H, THF, –78 °C) and the
latter compound was subsequently converted to the
methyl acetal 9 (MeOH, cat. PPTS, benzene, reflux, 95%
yield).15 The hydroxyl group at C8 was then deprotected
(n-Bu4NF, THF) and the resulting primary alcohol was
then converted to the alkyl iodide 10 (85%, 2 steps from
9) by treatment with PPh3, I2 and imidazole (THF, 0 °C,
Scheme 2).16
f
6
4
OTBDPS
6
OTBDPS
5
H
80%
(2 steps from 4)
8
8
6
dr > 96:4
5
O
O
g
h
1
4
O
O
6
6
4
OTBDPS
95%
OTBDPS
8
8
(2 steps from 6)
7
8
OMe
OMe
1
1
i,j
95%
k,l
O
O
6
6
4
4
OTBDPS
85%
I
8
8
9
10
O
Mes
N
N
Mes
Ph
B
O
O
O
NH
Cl
Cl
Ru
PCy3
III
i-PrO2C
CO2i-Pr
Ph
I
II
Scheme 2 Reagents and conditions: a) EtOCOCl, Et3N, Et2O, 0 °C;
b) addition of lithiated I (n-BuLi, THF, –78 °C), –78 °C to 0 °C; c)
NaHMDS, THF, –78 °C then MeI; d) LiBH4, THF–MeOH, 0 °C to
r.t.; e) IBX, THF–DMSO (1:1), r.t.; f) reagent II, 4 Å MS, toluene,
–78 °C; g) acryloyl chloride, i-Pr2NEt, DMAP (0.3 equiv), CH2Cl2,
–78 °C; h) catalyst III (6 mol%), CH2Cl2, reflux; i) DIBAL-H, THF,
The preparation of the C9–C13 fragment was then carried –78 °C; j) MeOH, PPTS (0.2 equiv), C6H6, reflux; k) n-Bu4NF, THF;
l) PPh3, I2, imidazole, THF, 0 °C.
out. The Claisen condensation of the lithium enolate of
ethyl acetate (LDA, THF, –78 °C) with ethyl trimethyl-
silylpropiolate 11 (THF, –85 °C) led to the b-ketoester 12
(91%). This compound underwent an enantioselective
reduction on treatment with Saccharomyces cerevisiae
(type II) in the presence of glucose (H2O–EtOH, 30 °C) to
With the C1–C8 and C9–C13 fragments in hand, the
key coupling reaction was attempted. Thus, the primary
alkyl iodide 10 was subjected to lithium–iodine exchange
[t-BuLi (2.2 equiv), Et2O, –78 °C to –30 °C] and the alde-
Synlett 2007, No. 6, 934–938 © Thieme Stuttgart · New York

936
A.-F. Salit et al.
LETTER
O
O
O
O
OH
alkenyl iodide, followed by a palladium-catalyzed Stille
coupling to install the Z,Z,E-triene and deprotection of the
fluorenylmethyl phosphate.5
b
a
91%
9
11
72%
EtO
EtO
EtO
11
12
13
ee = 92%
SiMe3
13
SiMe3
SiMe3
SiMe3
We have therefore completed a convergent formal synthe-
sis of cytostatin that relies on an anionic coupling between
a functionalized organolithium (C1–C8 subunit) that in-
corporates the unsaturated lactone moiety protected as a
mixed acetal and an aldehyde (C9–C13 subunit). The key
steps include a diastereoselective alkylation to introduce
the methyl-substituted stereocenter at C6, the addition of
a tartrate-modified (Z)-crotylboronate to a protected 2-
methyl-4-hydroxybutyraldehyde (proceeding with re-
markably high diastereoselectivity) and a RCM to con-
struct the unsaturated lactone. An enantioselective yeast
reduction of an acetylenic b-ketoester followed by a dia-
stereoselective methylation has also been used to establish
the C11 and C10 stereocenters.
O
OH
O
OTBS
c
d
9
11
9
11
EtO
EtO
94%
SiMe3
94%
13
13
dr = 93:7
14
15
O
OTBS
O
OTBS
f
e
Me
9
11
9
11
H
N
70%
SiMe3
MeO
13 SiMe3
13
17
16
Scheme 3 Reagents and conditions: a) EtOAc, LDA, THF, –78 °C
then add 11, –85 °C then AcOH quench; b) Saccharomyces cerevisiae
type II, glucose, H2O–EtOH, 30 °C; c) LDA, THF, –78 °C, then
MeI, HMPA, –78 °C to –25 °C; d) TBSOTf, 2,6-lutidine, CH2Cl2,
–40 °C; e) Me(MeO)NH·HCl, i-PrMgCl (2.5 equiv), THF, –20 °C;
f) DIBAL-H, THF, –78 °C.
OMe
OMe
1
1
O
O
t-BuLi (2.2 equiv)
4
6
I
Li
4
6
Et2O, –78 °C
8
8
hyde 17 was added to the resulting organolithium reagent
18 (–78 °C to –30 °C). Under these conditions, a mixture
of the secondary alcohol 19 (major diastereomer) and its
epimer at C9 was obtained in 52% unoptimized yield. As
the diastereoselectivity was difficult to evaluate directly,
due to partial equilibration of the C1 stereocenter,15 the
methyl acetal was hydrolyzed (PPTS, acetone–H2O) and
the resulting lactol was chemoselectively oxidized
(MnO2, CH2Cl2). A mixture of lactone 20 (major dia-
stereomer) and its epimer at C9 was obtained in a 75:25
ratio (65%).19,20 The S-configuration of the C9 stereo-
center of the major diastereomer can be interpreted in
terms of a (modest) Felkin–Anh control, exerted by the
methyl-substituted C10 stereocenter of aldehyde 17, dur-
ing the nucleophilic addition of the organolithium reagent
18 (Scheme 4).
10
O
9
18
OMe
OTBS
1
O
OH OTBS
11
H
13
4
SiMe3
9
11
17
6
13
8
SiMe3
Et2O, –78 °C to –30 °C
52%
19
+ epimer at C9
(dr = 75:25)
O
1) PPTS
1
4
O
OH OTBS
acetone–H2O
9
11
6
13
2) MnO2, CH2Cl2, r.t.
65%
8
SiMe3
20
dr = 75:25
O
O
(FmO)2P(Ni-Pr2)
The secondary alcohol at C9 in compound 20 (75:25 dia-
stereomeric mixture at C9) was phosphorylated under the
conditions previously described [(FmO)2P(Ni-Pr2),
Fm = fluoren-9-yl-methyl, tetrazole, MeCN–CH2Cl2
(5:4)]5 but the oxidation of the intermediate phosphite was
best carried out with tert-butylhydroperoxide (TBHP).
The resulting phosphate 21 (70%) was treated with
HF·pyridine (THF, r.t.) to deprotect the hydroxyl group at
C11 and the trimethylsilyl-substituted alkyne was then
converted to the corresponding alkynyl iodide (NIS,
AgNO3, DMF, r.t.). At this stage, the C9 epimers could be
easily separated and the major epimer 22 was isolated in
52% yield (two steps from 21). The spectroscopic data of
compound 22, as well as its optical rotation and melting
point, were in perfect agreement with those reported for
the same intermediate in the first total synthesis of
cytostatin (Scheme 4).5,21 It has been shown that com-
pletion of the total synthesis of the natural product can
be achieved in three steps by reduction of 22 to the (Z)-
FmO
P
1
4
O
O
OTBS
tetrazole, then t-BuOOH
FmO
MeCN–CH2Cl2 (5:4), r.t.
70%
6
9
11
13
8
SiMe3
21
dr = 75:25
O
O
1) HF⋅Py
THF, r.t.
FmO
P
1
ref. 5
(known)
O
O
OH
FmO
cytostatin
2) NIS, AgNO3
DMF, r.t.
52%
4
9
11
6
13
8
I
22
Scheme 4 Formal convergent synthesis of cytostatin; Fm = 9H-
fluoren-9-yl-methyl
Acknowledgment
Financial support from AstraZeneca and the CNRS is gratefully
acknowledged (BDI CNRS grant to A.-F. S.).
Synlett 2007, No. 6, 934–938 © Thieme Stuttgart · New York

LETTER
Synthesis of Cytostatin
937
(15) (a) Acetal 9 was obtained as one major diastereomer
References and Notes
(dr > 90:10) having a 1,4-trans-disubstitution pattern based
on the coupling constant between H3 and H4 (3JH3–H4 = 6.0
Hz), see ref. 15b. However, the diastereomeric ratio varied
with the reaction time due to thermodynamic equilibration of
9. Partial equilibration of the compounds bearing an acetalic
C1 stereocenter was also noticed during purification on
silica gel. This had no consequence since the C1 stereocenter
was removed later in the synthesis. (b) Valverde, S.;
Bernabe, M.; Garcia-Ochoa, S.; Gomez, A. M. J. Org.
Chem. 1990, 55, 2294.
(1) (a) Amemiya, M.; Ueno, M.; Osono, M.; Masuda, T.;
Kinoshita, N.; Nishida, C.; Hamada, M.; Ishisuka, M.;
Takeuchi, T. J. Antibiot. 1994, 47, 536. (b) Amemiya, M.;
Someno, T.; Sawa, R.; Naganawa, H.; Ishizuka, M.;
Takeuchi, T. J. Antibiot. 1994, 47, 541.
(2) (a) Yamazaki, K.; Amemiya, M.; Ishizuka, M.; Takeuchi, T.
J. Antibiot. 1995, 48, 1138. (b) Kawada, M.; Amemiya, M.;
Ishizuka, M.; Takeuchi, T. Jpn. J. Cancer Res. 1999, 90,
219. (c) Masuda, T.; Watanabe, S.; Amemiya, M.; Ishizuka,
M.; Takeuchi, T. J. Antibiot. 1995, 48, 528. (d) Kawada,
M.; Kawatsu, M.; Masuda, T.; Ohba, S.; Amemiya, M.;
Kohama, T.; Ishizuka, M.; Takeuchi, T. Int. Immunopharm.
2003, 3, 179.
(3) Kawada, M.; Amemiya, M.; Ishizuka, M.; Takeuchi, T.
Biochim. Biophys. Acta: Mol. Cell Res. 1999, 1452, 209.
(4) Bialy, L.; Waldmann, H. Angew. Chem. Int. Ed. 2005, 44,
3814; and references therein.
(5) (a) Bialy, L.; Waldmann, H. Angew. Chem. Int. Ed. 2002, 41,
1748. (b) Bialy, L.; Waldmann, H. Chem. Eur. J. 2004, 10,
2759.
(6) Marshall, J. A.; Ellis, K. Tetrahedron Lett. 2004, 45, 1351.
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A.; Gauss, C.-M.; Swingle, M. R.; Amable, L.; Honkanen,
R. E.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 16720.
(8) For a review, see: Mengel, A.; Reiser, O. Chem. Rev. 1999,
99, 1191.
(9) This compound was prepared in two steps from butane-1,4-
diol by silylation (TBDPSCl, Et3N, CH2Cl2, r.t.) followed by
oxidation (PDC, DMF, r.t.), see: (a) Barrett, A. G. M.;
Flygare, J. A. J. Org. Chem. 1991, 56, 638. (b) Zhou, S.;
Chen, H.; Liao, W.; Chen, S.-H.; Li, G.; Ando, R.;
Kuwajima, I. Tetrahedron Lett. 2005, 46, 6341.
(10) (a) Aiguade, J.; Hao, J.; Forsyth, C. J. Tetrahedron Lett.
2001, 42, 817. (b) Lafontaine, J. A.; Provencal, D. P.;
Gardelli, C.; Leahy, J. W. J. Org. Chem. 2003, 68, 4215.
(11) (a) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339.
(b) Roush, W. R.; Parkowitz, A. D.; Ando, K. J. Am. Chem.
Soc. 1990, 112, 6348.
(16) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1
1980, 2866.
(17) Cossy, J.; Schmitt, A.; Cinquin, C.; Buisson, D.; Belotti, D.
Bioorg. Med. Chem. Lett. 1997, 7, 1699.
(18) (a) Seebach, D.; Wasmuth, D. Helv. Chim. Acta 1980, 63,
197. (b) Frater, G.; Müller, U.; Günther, W. Tetrahedron
1984, 40, 1269.
(19) In model studies, the addition of n-BuLi to aldehyde 17
(Et2O, –78 °C to –30 °C) and subsequent desilylation
(n-Bu4NF, THF) provided a 70:30 diastereomeric mixture of
the secondary alcohols 23 and 24 (68%, Scheme 5). To
ascertain that the major diastereomer 23 arose from a
Felkin–Anh control, the directed reduction of the b-hydroxy-
ketone 25 [Me4NBH(OAc)3, MeCN–AcOH, –40 °C to 0 °C]
followed by desilylation (n-Bu4NF, THF) was carried out
and led to a 85:15 mixture of the anti-1,3-diol 23 and the
syn-1,3-diol 24, see: Evans, D. A.; Chapman, K. T.; Carreira,
E. M. J. Am. Chem. Soc. 1988, 110, 3560.
O
OTBS
H
SiMe3
17
1) n-BuLi
Et2O, –78 °C to –30 °C
68% 23/24 = 70:30
2) n-Bu4NF, THF, r.t.
OH OH
OH OH
+
n-Bu
n-Bu
(12) (a) Roush, W. R. In Comprehensive Organic Synthesis, Vol.
2; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
1–54. (b) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93,
2207.
SiMe3
23
24
1) Me4NBH(OAc)3
MeCN–AcOH, –40 °C to 0 °C
2) n-Bu4NF, THF, r.t.
(13) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
31% 23/24 = 85:15
(14) The 1H NMR data of lactone 8, and in particular the coupling
constants JH3–H4, JH4–H5 and JH5–H6 as well as the chemical
shifts of the methyl groups (H19 and H20) compare
favorably well with those reported for structurally related
syn,anti-diastereomeric lactones (Figure 1).5,,7
O
OH
n-Bu
25
1H NMR (400 MHz, CD3OD): d = 7.69–7.99 (m, 4 H), 7.43–
7.37 (m, 6 H), 7.13 (dd, J = 9.6, 6.5 Hz, 1 H, H3), 5.92 (dd,
J = 9.6, 0.7 Hz, 1 H, H2), 4.11 (dd, J = 10.5, 3.1 Hz, 1 H,
H5), 3.86–3.74 (m, 2 H, 2 H8), 2.55 (m, 1 H, H4), 2.18 (m,
1 H, H7), 2.05 (m, 1 H, H6), 1.37 (m, 1 H, H7), 1.03 (s, 9 H),
0.98 (d, J = 7.1 Hz, 3 H, 3H19), 0.84 (d, J = 6.8 Hz, 3 H, 3
H20).
Scheme 5
(20) Compound 20 and its epimer at C9 could be separated by
flash chromatography on silica gel. However, the separation
of the C9 epimers turned out to be easier for the alkynyl
iodide 22.
(21) Bis(9H-fluoren-9-ylmethyl)-{(1S,2S,3R)-3-hydroxy-5-
iodo-2-methyl-1-[(3S)-3-((2S,3S)-3-methyl-6-oxo-3,6-
dihydro-2H-pyran-2-yl)butyl]pent-4-ynyl} phosphate (22):
mp 112 °C; [a]D +46.5 (c 0.4, CHCl3). IR: 3353, 2360, 1714,
1449, 1380, 1250, 1106, 1070, 987, 739 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.75–7.67 (m, 4 H), 7.54–7.41 (m, 4 H),
7.41–7.20 (m, 8 H), 6.95 (dd, J = 9.5, 6.5 Hz, 1 H), 5.93 (d,
J = 9.5 Hz, 1 H), 4.69–4.61 (m, 1 H), 4.36–4.07 (m, 7 H),
O
1
4
2
3
O
7
OTBDPS
6
5
8
8
19
20
Figure 1
Synlett 2007, No. 6, 934–938 © Thieme Stuttgart · New York

938
A.-F. Salit et al.
LETTER
3.86 (dd, J = 10.3, 2.4 Hz, 1 H), 2.40 (m, 1 H), 1.83–1.58 (m,
4 H), 1.51–1.41 (m, 1 H), 1.15–1.05 (m, 1 H), 0.98 (d,
J = 7.0 Hz, 3 H), 0.89 (d, J = 6.9 Hz, 3 H), 0.78 (d, J = 6.6
Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 164.4 (s), 151.6
(d), 143.1 (s, 2 C), 142.9 (s), 142.8 (s), 141.3 (s, 4 C), 127.9
(d), 127.8 (d), 127.7 (d, 2 C), 127.2 (d, 2 C), 127.1 (d, 2 C),
125.0 (d, 4 C), 120.0 (d) and 119.9 (d, 5 C), 94.8 (s), 83.5 (d),
78.4 [d, 2J(13C–31P) = 5.8 Hz], 69.4 [t, 2J(13C–31P) = 4.0 Hz],
69.3 [t, 2J(13C–31P) = 4.3 Hz], 65.1 (d), 47.9 [d, 3J(13C–
31P) = 8.4 Hz], 47.8 [d, 3J(13C–31P) = 8.7 Hz], 43.9 [d,
3J(13C–31P) = 3.6 Hz], 33.8 (d), 30.6 [t, 3J(13C–31P) = 4.1
Hz], 30.3 (d), 28.4 (t), 14.7 (q), 10.7 (q), 9.1 (q), 1.1 (s).
Synlett 2007, No. 6, 934–938 © Thieme Stuttgart · New York

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