Synthesis of C3-C12 fragment of 24-demethylbafilomycin C1 via anti-selective aldol condensation as the key stereocontrol step

Article abstract of DOI:10.1055/s-2008-1072504

An efficient synthesis of the C3-C12 aldehyde fragment of 24-demethylbafilomycin C₁ was accomplished for assembling the 16-membered plecomacrolide skeleton according to a 1,3-diene-ene ring-closing metathesis (RCM) strategy. A boron-mediated anti-selective aldol condensation of Abiko's chiral propionate was used to secure the C6 and C7 stereogenic centers while the C8 chirality was introduced from a chiral building block. The dithiane alkylation and the methyl ketone Horner-Wittig olefination using allyldiphenylphosphine oxide were employed for construction of the requisite (E)-1,3-diene subunit. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072504

LETTER
1013
Synthesis of C3–C12 Fragment of 24-Demethylbafilomycin C1 via
anti-Selective Aldol Condensation as the Key Stereocontrol Step
S
ynthesis of C3–C12 Fr
e
a
gment of
2
i
4-Dem
-
ethylbaf
M
ilomycin C in Dai,*a,b Gaofeng Feng,a,b Jinlong Wu,a Liang Suna,b
1
a
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87953128; E-mail: chdai@zju.edu.cn
b
Center for Cancer Research and Department of Chemistry, The Hong Kong University of Science and Technology,
Clear Water Bay, Kowloon, Hong Kong SAR, P. R. of China
Fax +85223581594; E-mail: chdai@ust.hk
Received 2 January 2008
with the tetraene in place could not be directly constructed
via 1,3-diene–ene RCM. Therefore, we focused our effort
on alternative solutions to meet this synthetic challenge.15
We have successfully prepared a model macrolactone
Abstract: An efficient synthesis of the C3–C12 aldehyde fragment
of 24-demethylbafilomycin C1 was accomplished for assembling
the 16-membered plecomacrolide skeleton according to a 1,3-di-
ene–ene ring-closing metathesis (RCM) strategy. A boron-mediat-
ed anti-selective aldol condensation of Abiko’s chiral propionate lacking the C6–C8 stereotriad via sequential formation of
was used to secure the C6 and C7 stereogenic centers while the C8
the C2–C3 single bond by aldol condensation, the C12–
chirality was introduced from a chiral building block. The dithiane
C13 double bond by 1,3-diene–ene RCM, and finally the
alkylation and the methyl ketone Horner–Wittig olefination using
C2–C3 double bond by b-elimination.15a,b We have re-
allyldiphenylphosphine oxide were employed for construction of
cently accomplished synthesis of the C13–C25 fragment
the requisite (E)-1,3-diene subunit.
2 by a diastereoselective aldol condensation of the ketone
Key words: anti-selective aldol, 1,3-diene, dithiane, Horner–Wit-
boron enolate as the key step.16 We report here on synthe-
tig olefination, a,b-unsaturated aldehyde
ester hydrolysis
RCM
Me
OMe Me
Me
O
OH
The plecomacrolides are a family of unique secondary
metabolites possessing a 16- or 18-membered ring macro-
lactone and a folding hemiacetal subunit on the side
chain.1,2 24-Demethylbafilomycin C1 (1, Scheme 1)3a is a
new member of the class B subgroup of the plecomac-
rolides. It is produced together with other related com-
pounds by a commensal microbe Streptomyces sp. CS
associated with Maytenus hookeri.3 24-Demethylbafilo-
mycin C1 was reported to exert strong cytotoxicity at 10–6
to 10–8 M concentrations against P388 and A549 tumor
cell lines by ca. 80% and 90% inhibitions, respectively.
The parent antibiotic, bafilomycin A1, does not have the
fumaric acid monoester moiety attached to the oxygen
atom at C21.4 It is the most investigated class B plecomac-
rolide as the specific vacuolar H+-ATPase (V-ATPase) in-
hibitor.5–8 Since Evans and Calter9a reported the first total
synthesis of bafilomycin A1 in 1993, a number of labora-
tories has dedicated efforts to construct this complex and
highly functionalized target.9–11 In general, the palladium-
catalyzed cross-coupling reactions of vinyl boron or tin
derivatives with vinyl iodides were used for installation of
the 1,3-diene functionality via formation of the C11–C12
bond. We designed a different approach toward assem-
bling the tetraene macrolactone embedded in a 16-mem-
bered ring by employing a 1,3-diene–ene ring-closing
metathesis (RCM).12,13 According to the findings by Yang
and co-workers,14 the 16-membered ring macrolactone
12
15
O
21
OH
19
13
O
OH
O
23
O
Me
3
22
Me
HO
O
25
Me
2
Me
Me
OMe
24-demethylbafilomycin C1 (1)
aldol and β-elimination
aldol
OMe Me
Me
Me
22
21
25
Me
15
17
23
18
14
16
13
O
OH
O
O
O
Si
1
t-Bu
t-Bu
O
2
2
OMe
+
Horner–Wittig
olefination
anti aldol
TBSO
3
7
CHO
8
6
12
Me
Me
Me
Me
3
O
Ph
7
Me
Bn
O
5
O
CHO
6
O
12
8
P
Ph
Ph
+
+
Me
N
Me
Me
MesO2S
SYNLETT 2008, No. 7, pp 1013–1016
Advanced online publication: 17.03.2008
x
x.
x
x.
2
0
0
8
4
5
6
DOI: 10.1055/s-2008-1072504; Art ID: W00108ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic bond disconnections of 24-demethylbafi-
lomycin C1 (1) yielding the C13–C25 side chain 2 and the C3–C12 al-
dehyde fragment 3

1014
W.-M. Dai et al.
LETTER
sis of the C3–C12 aldehyde fragment 3 via a highly anti-
selective aldol condensation of a derivative of the keto al-
dehyde 5 with Abiko’s chiral propionate 6.17
S
H
(3 equiv)
S
S
Me
I
OPMB
OPMB
n-BuLi (3 equiv),
–78 °C, THF; then 7
S
The C6–C8 stereotriad18 in the bafilomycin-type pleco-
macrolides has been synthesized in various manners.
Toshima and co-workers9d used the chiral intermediate
obtained from Felkin–Anh-selective Hiyama addition of
crotyl–chromium species to O-protected lactaldehyde19
for installation of the C6/C7 anti stereochemistry. It was
followed by a substrate-controlled hydroboration to se-
cure the C8 stereogenic center. Roush’s total synthesis9f
employed a diastereoselective crotylboration of the chiral
aldehyde derived from methyl (R)-(–)-3-hydroxy-2-meth-
ylpropionate to control the C6–C8 anti/anti stereotriad.
Hanessian’s strategy9g relied on the stereocontrolled cu-
prate additions in a two-directional mode. Marshall’s total
synthesis10b of bafilomycin V1 utilized stereoselective ad-
dition of chiral nonracemic allenylzinc reagent to a chiral
aldehyde for formation of the C7–C8 bond. In addition, an
interesting desymmetrization of a cyclohexanone deriva-
tive was developed for accessing the anti/anti stereotri-
ad.10d According to our synthetic strategy in Scheme 1, the
1,3-diene moiety of 3 could be installed by the Horner–
Wittig olefination of the methyl ketone 5 with allyldi-
phenylphosphine oxide 4.20 The aldehyde functionality in
5 was expected to undergo an anti-selective aldol reaction
with the (E)-boron enolate generated from Abiko’s chiral
propionate 6. Thus, our first task was to search for a suit-
able synthetic equivalent of 5 for easy differentiation of
the two carbonyl groups.
Me
Me
Me
91%
7
8
3
NaHCO
2O
DDQ (1.5 equiv)
CH2Cl2–H2O
(18:1), r.t., 1 h
95%
(4 equiv),
I2
acetone–H
0 °C, 1 h
91%
O
OPMB
S
Me
Me
11
OH
S
Me
Me
9
4, n-BuLi, THF, –90 °C;
78%
then –78 °C
SIBX (1.1 equiv)
DMSO, r.t., 10 h
71%
Me
OR
S
CHO
Me
Me
S
Me
12: R = PMB
13: R = H
X
DDQ
pH 7 buffer
10
Scheme 2 Synthesis of the dithiane aldehyde 10 as the masked 5
Influence of the stereogenic center of the aldehyde 10 on
the stereochemical course of the aldol reaction was not
observed. Reduction of 14 with LiAlH4 gave the diol 15 in
76% isolated yield. Protection of 15 as the bis-TBS ether
16 (97%) and subsequent hydrolysis of the dithianyl moi-
ety afforded the methyl ketone 17 in 89% yield from 16.
The Horner–Wittig olefination of 17 with allyldiphen-
ylphosphine oxide 420 furnished the (E)-1,3-diene 18 in
89% yield. It was found that addition of the reagents at
–90 °C was essential for achieving high diastereoselectiv-
ity for the Horner–Wittig olefination. Selective removal
of the primary TBS ether in 18 by treating with a catalytic
amount of PPTS in MeOH at room temperature gave the
alcohol 19 in 80% yield. DMP oxidation in the presence
of NaHCO3 converted 19 into the corresponding aldehyde
20 (86%)28 whose 1,3-diene moiety remained intact under
the oxidation conditions. The aldehyde 20 was subjected
to the Wittig olefination with the ylide,
Ph3P=C(Me)CO2Et, in toluene at 100 °C for 27 hours to
produce the a,b-unsaturated ester 21 in 85% yield with ex-
clusive E configuration for the newly formed trisubstitut-
ed double bond. Reduction of the ester moiety in 21 by
DIBAL-H afforded the alcohol 22 (97%) which was then
oxidized with DMP to furnish the target C3–C12 aldehyde
fragment 3 in 82% yield.29
As given in Scheme 2, we prepared the dithiane derivative
8 from the known chiral iodide 7 readily available from
methyl (R)-(–)-3-hydroxy-2-methylpropionate.21 Hydro-
lysis of the dithiane 8 by treating with I2 and NaHCO3 in
aqueous acetone afforded the ketone 11 (91%) which was
subjected to the Horner–Wittig olefination with 420 to
form the 1,3-diene 12 in 78% yield. We tried removal of
the PMB group in 12 with DDQ but the desired alcohol 13
was not obtained due to decomposition under the reaction
1
conditions. On checking the crude product by H NMR
spectroscopy, only 4-methoxybenzaldehyde could be as-
signed along with some unidentified materials. We turned
our attention to the dithiane aldehyde 10 as the masked ke-
tone aldehyde 5. Removal of the PMB group in 8 with
DDQ gave a 95% yield of the alcohol 9. It was followed
by a selective oxidation of the primary alcohol in the pres-
ence of the dithiane moiety. After screening for different
oxidants, we managed to obtain 10 in 60–70% yields from
9 by using stabilized IBX22 (1.1 equiv; added in por-
tions),23 Dess–Martin periodinane (DMP),24 or TPAP–
NMO.25 It is worthy mentioning that IBX was reported to
remove a 1,3-dithinyl group in aqueous DMSO.26
In summary, we have developed a concise synthesis of the
C3–C12 fragment 3 of 24-demethylbafilomycin C1 and
the related 16-membered class B plecomacrolides. The
readily available dithiane aldehyde 10 was confirmed to
be an appropriate synthon to the ketone aldehyde 5. The
anti-selective aldol reaction of 10 with the (E)-boron eno-
late derived from Abiko’s chiral propionate 6 afforded the
desired anti/anti stereotriad in high diastereoselectivity
presumably attained via a reagent control process. Finally,
the (E)-1,3-diene functionality was installed at –90 °C by
We performed the anti-selective aldol condensation of the
chiral aldehyde 10 with the (E)-boron enolate derived
from 6 to secure the anti/anti stereotriad in 14 (Scheme 3).
The latter was prepared on a 3 gram scale in high diaste-
reoselectivity of 95:527 and in the desired absolute config-
uration as predicted by the chiral auxiliary in 6.17
Synlett 2008, No. 7, 1013–1016 © Thieme Stuttgart · New York

LETTER
Synthesis of C3–C12 Fragment of 24-Demethylbafilomycin C1
1015
of Education of China. This work is supported in part by the rese-
arch grants from Zhejiang University, Zhejiang University Educati-
on Foundation, and The National Natural Science Foundation of
China (Grant No. 20432020), and by the Department of Chemistry,
HKUST.
the Horner–Wittig olefination of the methyl ketone 17
with allyldiphenylphosphine oxide 4. Therefore, the tar-
get molecule 3 could be prepared from the chiral iodide 7
by a 13-step sequence in an overall yield of 12.3%. More-
over, our findings on selective oxidation of an alcohol
with stabilized IBX, DMP, or TPAP–NMO in the pres-
ence of a dithianyl moiety may be useful for application in
multistep syntheses.
References and Notes
(1) Bindseil, K. U.; Zeeck, A. Liebigs Ann. Chem. 1994, 305.
(2) Dai, W.-M.; Guan, Y.; Jin, J. Curr. Med. Chem. 2005, 12,
1947.
(3) (a) Lu, C.; Shen, Y. J. Antibiot. 2003, 56, 415. (b) Lu, C.;
Shen, Y. J. Antibiot. 2004, 57, 597.
(4) Werner, G.; Hagenmaier, H.; Drautz, H.; Baumgartner, A.;
Zähner, H. J. Antibiot. 1984, 37, 110.
(5) (a) Bowman, E. J.; Siebers, A.; Altendorf, K. Proc. Natl.
Acad. Sci. U. S. A. 1988, 85, 7972. (b) Drose, S.; Altendorf,
K. J. Exp. Biol. 1997, 200, 1.
(6) Yoshimoto, Y.; Jyojima, T.; Arita, T.; Ueda, M.; Imoto, M.;
Matsumura, S.; Toshima, K. Bioorg. Med. Chem. Lett. 2002,
12, 2525.
(7) Bowman, B. J.; McCall, M. E.; Baertsch, R.; Bowman, E. J.
J. Biol. Chem. 2006, 281, 31885.
c-Hex2BOTf, Et3N
CH2Cl2, –78 °C;
OH
O
Ph
S
Me
Bn
6
O
then 10, –78 °C
S
74%
Me
Me
Me
N
MesO2S
14
OR
LiAlH4 (3 equiv)
I2, NaHCO3
S
OR
acetone–H2O
0 °C, 0.5 h
89% from 16
Et2O, 0 °C, 2h
76%
S
Me
Me
15: R = H
16: R = TBS
TBSOTf, 2,6-lutidine
CH2Cl2, 0 °C, 1 h
97%
(8) For a review, see: Beutler, J. A.; McKee, T. C. Curr. Med.
Chem. 2003, 10, 787.
(9) For total synthesis of bafilomycin A1, see: (a) Evans, D. A.;
Calter, M. A. Tetrahedron Lett. 1993, 34, 6871.
OTBS
4, n-BuLi, THF, –90 °C;
O
(b) Toshima, K.; Jyokaaki, T.; Yamaguchi, H.; Murase, H.;
Yoshida, T.; Mastumura, S.; Nakata, M. Tetrahedron Lett.
1996, 37, 1069. (c) Toshima, K.; Yamaguchi, H.; Jyojima,
T.; Noguchi, Y.; Nakata, M.; Mastumura, S. Tetrahedron
Lett. 1996, 37, 1073. (d) Toshima, K.; Jyojima, T.;
Yamaguchi, H.; Noguchi, Y.; Yoshida, T.; Murase, H.;
Nakata, M.; Mastumura, S. J. Org. Chem. 1997, 62, 3271.
(e) Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M.
D.; Roush, W. R. Angew. Chem. Int. Ed. 1999, 38, 1652.
(f) Scheidt, K. A.; Bannister, T. D.; Tasaka, A.; Wendt, M.
D.; Savall, B. M.; Fegley, G. J.; Roush, W. R. J. Am. Chem.
Soc. 2002, 124, 6981. (g) Hanessian, S.; Ma, J.; Wang, W.;
Gai, Y. J. Am. Chem. Soc. 2001, 123, 10200; Correction:
J. Am. Chem. Soc. 2002, 124, 7249. (h) Quéron, E.; Lett, R.
Tetrahedron Lett. 2004, 45, 4539; and references cited
therein.
OTBS
then 17, –78 °C
Me
Me
17
Me
89%
OTBS
DMP, NaHCO3
OR
CH2Cl2, r.t., 0.5 h
Me
Me
Me
86% from 19
18: R = TBS
19: R = H
OTBS
PPTS, MeOH
r.t., 12 h
80%
O
Me
Me
Me
20
Ph3P=C(Me)CO2Et
PhMe, 100 °C, 27 h
85%
(10) (a) Paterson, I.; Bower, S.; McLeod, M. D. Tetrahedron Lett.
1995, 36, 175. (b) Marshall, J. A.; Adams, N. D. J. Org.
Chem. 2002, 67, 733. (c) Eustache, F.; Dalko, P. I.; Cossy, J.
J. Org. Chem. 2003, 68, 9994. (d) Poupon, J.-C.; Demont,
E.; Prunet, J.; Férézou, J.-P. J. Org. Chem. 2003, 68, 4700.
(e) Lopez, R.; Poupon, J.-C.; Prunet, J.; Férézou, J.-P.;
Ricard, L. Synthesis 2005, 644.
OTBS
OEt
O
Me
Me
Me
Me
21
(11) For reviews on total synthesis of plecomacrolides, see:
Toshima, K. Curr. Org. Chem. 2004, 8, 185; and ref. 2.
(12) For selected reviews on RCM, see: (a) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (b) Fürstner, A.
Angew. Chem. Int. Ed. 2000, 39, 3012. (c) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (d) Schrock,
R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42,
4592. (e) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104,
2199. (f) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem. Int. Ed. 2005, 44, 4490. (g) Gradillas, A.; Pérez-
Castells, J. Angew. Chem. Int. Ed. 2006, 45, 6086.
(h) Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 2007, 40,
45. (i) Hoveyda, A. H.; Zhugralin, A. R. Nature (London)
2007, 450, 243. (j) Also see: Handbook of Metathesis, Vol.
1–3; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003.
DIBAL-H, THF,
–78 °C, 4 h
97%
OTBS
DMP, NaHCO3
OH
3
CH2Cl2, r.t., 0.5 h
82%
Me
Me
22
Me
Me
Scheme 3 Synthesis of the C3–C12 aldehyde fragment 3
Acknowledgment
The Laboratory of Asymmetric Catalysis and Synthesis is esta-
blished under the Cheung Kong Scholars Program of The Ministry
Synlett 2008, No. 7, 1013–1016 © Thieme Stuttgart · New York

1016
W.-M. Dai et al.
LETTER
(21) (a) Heckrodt, T. J.; Mulzer, J. Synthesis 2002, 1857.
(13) For selected examples of 1,3-diene–ene RCM in synthesis of
macrocycles, see: (a) Cabrejas, L. M. M.; Rohrbach, S.;
Wagner, D.; Kallen, J.; Zenke, G.; Wagner, J. Angew. Chem.
Int. Ed. 1999, 38, 2443. (b) Dvorak, C. A.; Schmitz, W. D.;
Poon, D. J.; Pryde, D. C.; Lawson, L. P.; Amos, R. A.;
Meyers, A. I. Angew. Chem. Int. Ed. 2000, 39, 1664.
(c) Garbaccio, R. M.; Danishefsky, S. J. Org. Lett. 2000, 2,
3127. (d) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D. K.;
Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 10903.
(e) Biewas, K.; Lin, H.; Njardarson, J. T.; Chappell, M. D.;
Chou, T.-C.; Guan, Y.; Tong, W. P.; He, L.; Horwitz, S. B.;
Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 9825.
(f) Paquette, L. A.; Basu, K.; Eppich, J. C.; Hofferberth, J. E.
Helv. Chim. Acta 2002, 85, 3033. (g) Sedrani, R.; Kallen, J.;
Cabrejas, L. M. M.; Papageorgiou, C. D.; Senia, F.;
Rohrbach, S.; Wagner, D.; Thai, B.; Eme, A.-M. J.; France,
J.; Oberer, L.; Rihs, G.; Zenke, G.; Wagner, J. J. Am. Chem.
Soc. 2003, 125, 3849. (h) Yang, Z.-Q.; Danishefsky, S. J. J.
Am. Chem. Soc. 2003, 125, 9602. (i) Yang, Z.-Q.; Geng, X.;
Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am.
Chem. Soc. 2004, 126, 7881. (j) Barluenga, S.; Lopez, P.;
Moulin, E.; Winssinger, N. Angew. Chem. Int. Ed. 2004, 43,
3467. (k) Wang, X.; Bowman, E. J.; Bowman, B. J.; Porco,
J. A. Jr. Angew. Chem. Int. Ed. 2004, 43, 3601.
(b) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55,
5404.
(22) (a) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994,
35, 8019. (b) More, J. D.; Finney, N. S. Org. Lett. 2002, 4,
3001.
(23) Procedure for Oxidation of the Alcohol 9 with Stabilized
IBX to Form Aldehyde 10
To a solution of the alcohol 9 (1.990 g, 9.66 mmol) in DMSO
(40 mL; without drying) was added stabilized IBX in six
portions (45 wt%, 1.002 × 6 g, 9.66 mmol). After each
addition of stabilized IBX, the resultant mixture was stirred
for 2 h at r.t. The reaction was quenched by aq Na2S2O3
followed by addition of sat. aq NaHCO3. The aqueous
mixture was extracted with EtOAc (100 × 2 mL) and the
combined organic layer was dried over anhyd Na2SO4,
filtrated, and concentrated under reduced pressure. The
residue was purified by flash column chromatography (SiO2,
14% EtOAc in hexane) to provide the aldehyde 10 (1.399 g,
71% yield).
Compound 10: yellow oil; [a]D20 –2.2 (c 1.35, CHCl3). 1H
NMR (300 MHz, CDCl3): d = 9.71 (d, J = 1.8 Hz, 1 H),
2.94–2.60 (m, 6 H), 2.10–1.80 (m, 2 H), 1.70 (dd, J = 14.7,
3.0 Hz, 1 H), 1.56 (s, 3 H), 1.15 (d, J = 7.2 Hz, 3 H). 13
C
(l) Lemarchand, A.; Bach, T. Tetrahedron 2004, 60, 9659.
(m) Krishna, C. V.; Maitra, S.; Dev, R. V.; Mukkanti, K.;
Iqbal, J. Tetrahedron Lett. 2006, 47, 6103. (n) Va, P.;
Roush, W. R. J. Am. Chem. Soc. 2006, 128, 15960. (o) Va,
P.; Roush, W. R. Org. Lett. 2007, 9, 307. (p) Va, P.; Roush,
W. R. Tetrahedron 2007, 63, 5768. (q) Meyer, A.; Brünjes,
M.; Taft, F.; Frenzel, T.; Sasse, F.; Kirschning, A. Org. Lett.
2007, 9, 1489. (r) Fürstner, A.; Nevado, C.; Waser, M.;
Tremblay, M.; Chevrier, C.; Teplý, F.; Aïssa, C.; Moulin, E.;
Müller, O. J. Am. Chem. Soc. 2007, 129, 9150. For diene–
diene RCM used in synthesis of macrocycles, see:
(s) Wang, X.; Porco, J. A. Jr. J. Am. Chem. Soc. 2003, 125,
6040. (t) Evano, G.; Schaus, J. V.; Panek, J. S. Org. Lett.
2004, 6, 525.
NMR (75 MHz, CDCl3): d = 203.4, 48.3, 43.2, 42.5, 28.3,
26.5 (×2), 24.6, 16.2. HRMS (ESI+): m/z calcd for C9H17OS2
[M + H+]: 205.0721; found: 205.0729.
(24) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59,
7549. (c) Boeckman, R. K. Jr.; Shao, P.; Mulins, J. J. Org.
Synth. 2000, 77, 141.
(25) For a review, see: Ley, S. V.; Norman, J.; Griffith, W. P.;
Marsden, S. P. Synthesis 1994, 639.
(26) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am.
Chem. Soc. 2004, 126, 5192.
(27) We checked the diastereomeric ratio of the isolated aldol
products prepared in several runs by 1H NMR spectroscopy
and found that the ratio is about 95:5 in all cases. We did not
obtain any separable minor diastereomers on the 3-gram-
scale reaction, implying that the minor diastereomer is not
separable from the major isomer.
(28) Epimerization of the aldehyde 20 obtained from both the
DMP (aq NaHCO3, CH2Cl2, r.t.) and SIBX (DMSO, r.t.)
oxidation was observed. The diastereomeric ratios are about
95:5. We are not sure whether the epimerization occurred
during the oxidation or over silica gel during column
chromatographic separation.
(14) Lu, K.; Huang, M.; Xiang, Z.; Liu, Y.; Chen, J.; Yang, Z.
Org. Lett. 2006, 8, 1193.
(15) (a) Guan, Y. PhD Thesis; Zhejiang University: P. R. of
China, 2006. (b) Preliminary results on successful formation
of the tetraene core of 1 in a model system via 1,3-diene–ene
RCM were reported at The 9th International Symposium for
Chinese Organic Chemists (ISCOC-9), Singapore,
December 17–21, 2006, 85. For our recent RCM approach to
form E-trisubstituted double bond in amphidinolide Y, see:
(c) Jin, J.; Chen, Y.; Li, Y.; Wu, J.; Dai, W.-M. Org. Lett.
2007, 9, 2585.
(16) Guan, Y.; Wu, J.; Sun, L.; Dai, W.-M. J. Org. Chem. 2007,
72, 4953.
(17) (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem. Soc.
1997, 119, 2586. (b) Inoue, T.; Liu, J.-F.; Buske, D.; Abiko,
A. J. Org. Chem. 2002, 67, 5250. (c) Abiko, A. Acc. Chem.
Res. 2004, 37, 387.
(29) Physical and Spectroscopic Data of 3
Colorless oil; [a]D20 31.9 (c 0.73, CHCl3). 1H NMR (300
MHz, CDCl3): d = 9.40 (s, 1 H), 6.72 (dd, J = 9.9, 1.2 Hz, 1
H), 6.61–6.48 (m, 1 H), 5.81 (d, J = 11.4 Hz, 1 H), 5.09 (dd,
J = 16.8, 1.8 Hz, 1 H), 4.99 (d, J = 10.2 Hz, 1 H), 3.54 (dd,
J = 4.5, 3.0 Hz, 1 H), 2.95–2.85 (m, 1 H), 2.19 (d, J = 8.4 Hz,
1 H), 1.85–1.64 (m, 2 H), 1.76 (s, 3 H), 1.71 (s, 3 H), 1.04 (d,
J = 7.5 Hz, 3 H), 0.92 (s, 9 H), 0.74 (d, J = 6.3 Hz, 3 H), 0.07
(s, 3 H), 0.06 (s, 3 H). 13C NMR (75 MHz, CDCl3): d =
195.6, 157.6, 137.3, 137.2, 133.0, 127.4, 115.0, 79.4, 43.7,
36.9, 35.9, 26.0 (×3), 18.6, 18.3, 16.3, 15.3, 9.3, –3.9, –4.0.
HRMS (ESI+): m/z calcd for C21H39O2Si [M + H+]:
351.2719; found: 351.2729.
(18) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26,
489.
(19) Mulzer, J.; Schulze, T.; Strecker, A.; Denzer, W. J. Org.
Chem. 1988, 53, 4098.
(20) (a) Ikeda, Y.; Ukai, J.; Ikeda, N.; Yamamoto, H.
Tetrahedron 1987, 43, 723. (b) For a review, see: Clayden,
J.; Warren, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 241.
Synlett 2008, No. 7, 1013–1016 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.