A convergent and stereoselective synthesis of a seco-precursor of macrolactin A

Article abstract of DOI:10.1016/j.tet.2005.07.106

A seco-precursor of macrolactin A was synthesized by coupling two advanced segments. Wittig reaction and Horner-Emmons reaction were utilized to construct the three characteristic E,Z and E,E dienes. The C₁-C₁₀ segment was synthesize

Full text of DOI:10.1016/j.tet.2005.07.106

Tetrahedron 61 (2005) 11291–11298
A convergent and stereoselective synthesis of a seco-precursor
of macrolactin A
*
Shukun Li, Xiangshu Xiao, Xuebin Yan, Xuejun Liu, Rui Xu and Donglu Bai
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China
Received 24 May 2005; revised 11 July 2005; accepted 12 July 2005
Available online 30 September 2005
Abstract—A seco-precursor of macrolactin A was synthesized by coupling two advanced segments. Wittig reaction and Horner–Emmons
reaction were utilized to construct the three characteristic E,Z and E,E dienes. The C1–C10 segment was synthesized through Horner–
Emmons reaction with phosphonate reagent. The a-alkylation of sulfone stabilized anion with allyl bromide followed by desulfonation gave
the C11–C24 segment.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the coupling of the advanced segments 2 and 3. To assemble
the complex polyene macrolide,6 we envisioned that a
Wittig coupling between C1–C10 segment 2 and C11–C24
segment 3 would provide much better stereoselectivity of
C10–C11 double bond than palladium-catalyzed sp2–sp2
coupling (Scheme 1). Further bond-disconnections revealed
that building blocks 4–9 were required.
Macrolactin A (1) is the parent aglycone of a novel family of
polyene 24-membered macrolides isolated from a taxo-
nomically unidentified deep-sea bacterium.1 In preliminary
biological evaluation, it was showed to inhibit B16–F10
murine melanoma cancer cells and mammalian HSV-I and
HSV-II. More significantly, it was found to inhibit the HIV
replication in T-lymphoblasts1 and to be a neuronal cell
protecting substance against the glutamate toxicity.2
However, macrolactin A is no longer readily available
from the bacterial sources due to the unavailability of this
deep-sea bacterium, and thus further biological studies were
retarded. The significant biological activities combined with
the scarcity of the natural resource of macrolactin A
prompted many synthetic organic chemists to investigate its
total synthesis.3,4 Three total syntheses by Smith, Carreira,
and Marino groups have been reported independently.5
However, they addressed the problem of the E,Z-dienes
stereochemistry when they utilized palladium-catalyzed
sp2–sp2 Stille coupling to install three conjugated dienes.
We have also involved in the synthesis of this molecule with
a totally different approach.4 Herein, we report our
stereoselective synthesis of the seco-precursor 28 of
macrolactin A, which features the judicious use of Wittig
and Horner–Emmons reactions to elaborate all three
stereofined 1,3-diene units in the target molecule.
Our strategy for the asymmetric synthesis of 1 is based on
Keywords: Horner–Emmons reaction; seco-Precursor; Macrolactin A.
*
Corresponding author. Fax: C86 21 64370269;
e-mail: author@institute.edu
Scheme 1. Retrosynthesis of macrolactin A.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.106

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S. Li et al. / Tetrahedron 61 (2005) 11291–11298
2. Results and discussion
K78 8C by Ph3P/NBS12 yielded allyl bromide 22, which
was unstable, and decomposed on a silica gel column. It is
worthy to be pointed out that temperature is critical to the
successful bromination. At temperature over K20 8C, no
desired product could be yielded. With allyl bromide 22 and
sulfone 9 in hand, we embarked on the coupling of the two
subunits on the basis of the previous research.4 Gratifyingly,
sulfone 9 and allyl bromide 22 could be efficiently coupled
by treatment with n-BuLi, giving 23 in 93% yield as a
mixture of two diastereomers. The phenylsulfonyl group
was then removed by 6% Na–Hg in methanol giving 24 as a
single isomer in 66% yield. Fluoride ion catalyzed
hydrolysis of TBDPS group in 24 with TBAF (89%) and
iodination of the corresponding alcohol 25 (92%) followed
by phosphonium salt formation of 26 delivered the requisite
C11–C24 segment 3.
The synthesis of C1–C10 segment 2 (Scheme 2) started with
the known compound 5,4 which was derived from S-malic
acid. Protection of the secondary alcohol in 5 as TBDMS
ether furnished ester 10, which was then reduced with
DIBAL-H to allyl alcohol 11 in 91% yield for two steps.
Swern oxidation of 11 gave aldehyde 12, which afforded the
requisite dienoate 13 via Horner–Emmons reaction with
phosphonate 6.7 At first, phosphonate 6a was adopted and
delivered 13 in 44% yield as a chromatographically
separable mixture of isomers (Z,E/E,EZ12.5:1). Never-
theless, phosphonate 6b provided 13 as a mixture of isomers
(Z,E/E,EZ5:1) in 60% yield for two steps. A Wittig
reaction involving the use of formylmethylene triphenyl-
phosphorane8 for a two-carbon chain elongation was
utilized to accomplish the synthesis of C1–C10 segment 2.
To this end, selective hydrolysis of trityl group in 13 with
formic acid in ether9 followed by Swern oxidation and
subsequent Wittig reaction furnished 2 in 60% overall yield
for three steps.
Scheme 2. Reagents and conditions: (a) TBDMSOTf, Et3N, CH2Cl2, 0 8C,
40 min, 95%; (b) DIBAL-H, CH2Cl2, K78 8C, 1 h, 96.5%; (c) (COCl)2,
DMSO, Et3N, CH2Cl2, K78–0 8C; (d) (o-CH3–C6H4O)2P(O)CH2COOEt
(6b), NaH, and then 12, THF, 60% for two steps; (e) HCOOH, Et2O, 75%;
(f) (COCl)2, DMSO, Et3N, CH2Cl2, K78–0 8C; (g) Ph3P]CHCHO (5),
CHCl3, 80% for two steps.
Scheme 3. Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2,
84%; (b) Me2C(OMe)2, CSA, 97%; (c) Raney Ni, EtOH, 98%; (d) (COCl)2,
DMSO, Et3N, CH2Cl2, K78–0 8C; (e) triethyl phosphonocrotonate (8),
˚
LiOH, 4 A MS, THF, reflux, 10 h, 62% for two steps; (f) DIBAL-H,
CH2Cl2, K78 8C, 1 h, 92%; (g) NBS, PPh3, CH2Cl2, K78 8C, 30 min, 95%;
(h) 9, n-BuLi, and then 22, THF, K78 8C; 93%; (i) 6% Na–Hg, Na2HPO4,
MeOH, 0 8C, 66%; (j) TBAF, THF, 89%; (k) Ph3P, imidazole, I2, benzene,
0 8C, 92%; (l) Ph3P, CH3CN, reflux, 48 h, 97%.
The preparation of C11–C24 phosphonium salt 3 (Scheme 3)
was accomplished by Horner–Emmons reaction as well.
Conversion of triol 1610 to monoprotected silyl compound
17 (84%) followed by protection of the 1,3-anti diol using
2,2-dimethoxypropane in the presence of CSA furnished the
acetonide 18 in 97% yield. Reductive removal of benzyl
group in compound 18 by Raney nickel (98%) followed by
oxidation of the resulting alcohol 19 under Swern conditions
provided the corresponding aldehyde 7, which was unstable
on column chromatography and used directly to the next
step without purification. Referring to our previous work,4
the crude aldehyde 7 underwent Horner–Emmons reaction
with triethyl phosphonocrotonate 8 in the presence of LDA.
But the conjugated dienoate 20 was obtained in low yield
(30%). LiHMDS and n-BuLi were also used instead of
LDA, the yields of dienoate 20 were not improved. To our
delight, the Takacs modified procedure11 led to the
conjugated dienoate 20 as a mixture of E,E- and Z,E-diene
isomers in a ratio of 5:1 in 62% yield for two steps. Selective
reduction of the ester group in 20 by DIBAL-H (92%)
followed by bromination of the corresponding alcohol 21 at
The coupling of two advanced segments 2 and 3 in the
presence of NaHMDS smoothly provided macrocyclization
precursor 27 in 79% yield. The Z:E ratio of the newly
formed double bond is 98:2. Subsequent removal of the
PMB group in 27 proved problematic. Treatment of 27 with
13
a slight excess of DDQ in wet CH2Cl2 gave the seco-
precursor 28 in low yield accompanying by decomposition.
Similar results were encountered in the co-solvent of
CHCl3–H2O, CH2Cl2–t-BuOH-buffer (pHZ6.5) and
C6H6–H2O. All attempted PMB group removal with other
reagents, such as MgBr2$Et2O–Me2S,14 SnCl4–PhSH,15
CAN–CH3CN–H2O,16 TMSCl–SnCl2–anisole,17 SnCl2–
EtSH18 failed to generate the desired product. Failure of
deprotection of PMB ether 27 was attributed to 1,3-diene
and the conjugated allylic alkoxy in the molecule. The same
problem was also reported in literature.14,19 Unfortunately,
dearth of material did not permit us to fully study the
macrocyclization (Scheme 4).

S. Li et al. / Tetrahedron 61 (2005) 11291–11298
11293
35.35 mmol) at 0 8C. The resulting solution was stirred at
0 8C for 40 min. Then a saturated aqueous solution of
NH4Cl (40 mL) was added followed by the addition of Et2O
(400 mL). The organic layer was separated and washed with
saturated aqueous solution of NaHCO3 (40 mL), water
(40 mL!2) and brine (40 mL!2). The organic layer was
dried over Na2SO4 and the solvent was removed in vacuo,
yielding an oily residue, which was purified by flash
chromatography (n-hexane/EtOAc, 20:1) to give 10 (11.8 g,
95%) as a colorless oil; [a]2D0 K2.6 (c 0.8, CHCl3); IR
(film): 3059, 2950, 2936, 1720, 1658, 1491, 1448, 1259,
1087, 837, 706, 632 cmK1; 1H NMR (400 MHz, CDCl3): d
7.45 (ddd, 6H, JZ7.7, 7.5, 1.5 Hz), 7.27 (dd, 6H, JZ7.5,
1.5 Hz), 7.20 (t, 3H, JZ7.7 Hz), 6.89 (dt, 1H, JZ15.6,
1.5 Hz), 5.80 (d, 1H, JZ15.6 Hz), 4.18 (q, 2H, JZ7.0 Hz),
3.87–3.80 (m, 1H), 3.18–2.92 (m, 2H), 2.62–2.54 (m, 1H),
2.44–2.36 (m, 1H), 1.29 (t, 3H, JZ7.0 Hz), 0.86 (s, 9H),
K0.02 (s, 3H), K0.06 (s, 3H); 13C NMR (75 MHz, CDCl3):
d 166.3, 146.0, 144.2!3, 134.5, 128.5!6, 127.8!3,
127.7!3, 127.0!3, 86.6, 70.7, 66.9, 60.5, 38.0, 25.7!3,
18.2, 14.3, K4.6, K4.9; MS (ESI): m/z (%)Z553 (100)
[MCNaC].
Scheme 4. Reagents and conditions: (a) 2 and 3, NaHMDS, THF, K78 8C,
79%; (b) DDQ, CH2Cl2–H2O (17/1), 14.4%.
3. Conclusion
In summary, a synthesis of the seco-precursor of macro-
lactin A was achieved through a highly convergent and
efficient route. In the synthesis, Wittig reaction and Horner–
Emmons reaction with phosphonate reagents 6 were utilized
to construct the three characteristic E,Z- and E,E-dienes. An
a-alkylation of sulfone stabilized anion with allyl bromide
was used for the elongation of C11–C20 segment. Although
the removal of PMB protecting group gave troubles to the
completion of the target molecule, this strategy should still
be applicable to a range of similar polyene compounds.
4.2.2. (5S,2E)-5-tert-Butyldimethylsilyloxy-6-trityloxy-2-
hexenol (11). To a stirred solution of ester 10 (13.1 g,
24.7 mmol) in CH2Cl2 (100 mL) was added DIBAL-H
(74.2 mL, 1.0 M in cyclohexane, 74.2 mmol) slowly at
K78 8C. The resulting solution was stirred at K78 8C for
1 h. Then MeOH (1 mL) was added followed by the
addition of Et2O (500 mL). The mixture was shaked
vigorously with saturated aqueous solution of Rochelle’s
salt (200 mL). The organic layer was separated and the
aqueous layer was extracted with Et2O (100 mL!2) and
EtOAc (100 mL). The combined organic layers were further
washed with water (100 mL!2), brine (100 mL!2), and
dried over Na2SO4. Concentration and flash chromato-
graphy (n-hexane/EtOAc, 5:1) provided 11 (11.7 g, 96.5%)
as a colorless oil; [a]D20 K2.6 (c 4.1, CHCl3); IR (film):
4. Experimental
4.1. General
3446, 2928, 2856, 1597, 1448, 1256, 1078, 775, 706 cmK1
;
Unless otherwise noted, materials were obtained from
commercial sources and used without further purification.
All solvents were purified and dried by the standard
procedures before use. Organic solutions of the products
were dried over anhydrous sodium sulfate. All reactions
involving organometallic reagents were conducted under a
nitrogen or argon atmosphere. Silica gel (200–300 mesh)
from Qingdao Marine Chemical Corporation was used for
column chromatography unless otherwise noted. Solvents
were removed by rotary evaporation under reduced
pressure. Infrared spectra were obtained on a Nicoler
Magna 750. NMR spectra were measured on 400 or
300 MHz spectrometers for 1H and 100 or 75 MHz
spectrometers for 13C, respectively, with tetramethylsilane
as internal standard. J values were given in Hz. Optical
rotations were measured on a Perkin-Elmer 241 MC. Mass
spectra and high-resolution mass spectra were measured on
a Varian MAT-711 and MAT-95, respectively.
1H NMR (300 MHz, CDCl3): d 7.45 (ddd, 6H, JZ7.7, 7.5,
1.3 Hz), 7.27 (dd, 6H, JZ7.5, 1.3 Hz), 7.20 (t, 3H, JZ
7.7 Hz), 5.62–5.59 (m, 2H), 4.08 (br s, 2H), 3.85–3.81 (m,
1H), 3.10–2.98 (m, 2H), 2.48–2.40 (m, 1H), 2.34–2.22 (m,
1H), 0.90 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H); 13C NMR
(75 MHz, CDCl3): d 144.1!3, 131.5, 128.9, 128.7!6,
127.7!6, 126.9!3, 86.4, 71.4, 66.8, 63.6, 37.8, 25.8!3,
18.1, K4.6, K4.8; MS (EI, 70 eV): m/z (%)Z488 (5) [MC],
487 (6), 470 (40), 243 (100).
4.2.3. (5S,2E)-5-tert-Butyldimethylsilyloxy-6-trityloxy-2-
hexenal (12). To a stirred solution of oxalyl chloride
(4.0 mL, 45.94 mmol) in CH2Cl2 (100 mL) was added a
solution of DMSO (6.6 mL, 91.88 mmol) in CH2Cl2
(20 mL) at K78 8C over 40 min. Upon completion of the
addition, a solution of alcohol 11 (11.2 g, 22.97 mmol) in
CH2Cl2 (15 mL) was added to the mixture over 30 min at
K78 8C. The stirring was continued for 1.5 h, and then Et3N
(19.0 mL, 137.82 mmol) was added slowly at K78 8C. The
reaction mixture was allowed to warm to 0 8C and stirred at
this temperature for an additional 1.5 h. A saturated aqueous
solution of NH4Cl (50 mL) was added followed by the
addition of Et2O (500 mL). The organic layer was separated,
washed with water (50 mL!2) and brine (50 mL!2), dried
4.2. Synthesis of segment C1–C10
4.2.1. Ethyl (5S,2E)-5-tert-butyldimethylsilyloxy-6-tri-
tyloxy-2-hexenoate (10). To a stirred solution of alcohol
5 (9.8 g, 23.57 mmol) in CH2Cl2 (60 mL) were added Et3N
(13.0 mL, 94.28 mmol) and TBDMSOTf (8.1 mL,

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S. Li et al. / Tetrahedron 61 (2005) 11291–11298
over Na2SO4. Concentration of the organic layer gave the
crude aldehyde 12, which was used directly in the next
reaction without further purification; [a]2D0 C1.1 (c 1.6,
CHCl3); IR (film): 3060, 2927, 2854, 1691, 1491, 1448,
1.35 (t, 3H, JZ7.0 Hz), 0.90 (s, 9H), 0.1 (s, 6H); 13C NMR
(100 MHz, CDCl3): d 161.3, 144.5, 140.2, 129.2, 116.3,
72.3, 66.1, 59.8, 37.6, 25.8!3, 18.0, 14.2, K4.5, K4.6; MS
(EI, 70 eV): m/z (%)Z314 (16) [MC], 257 (22), 117 (56),
73 (100); HRMS-EI: m/z (%) [MC] calcd for C16H30SiO4:
314.1913; found 314.1919.
1257, 995, 833, 777, 700 cmK1 1H NMR (300 MHz,
;
CDCl3): d 9.44 (d, 1H, JZ7.9 Hz), 7.45 (ddd, 6H, JZ7.7,
7.5, 1.3 Hz), 7.27 (dd, 6H, JZ7.5, 1.3 Hz), 7.20 (t, 3H, JZ
7.7 Hz), 6.82 (dt, 1H, JZ15.4, 8.0 Hz), 6.15 (dd, 1H, JZ
15.4, 7.9 Hz), 4.01–3.97 (m, 1H), 3.12–3.08 (m, 1H), 3.06–
3.02 (m, 1H), 2.81–2.72 (m, 1H), 2.67–2.58 (m, 1H), 0.90
(s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 193.6, 154.8, 143.8!3, 134.9, 128.5!6, 127.9!
3, 127.7!3, 127.0!3, 86.6, 70.3, 66.6, 38.3, 25.7!3, 17.9,
K4.6, K4.9; MS (EI, 70 eV): m/z (%)Z485 (1) [MCK1],
243 (100), 183 (37), 105 (28), 77 (13).
4.2.6. Ethyl (7S,2Z,4E)-7-tert-butyldimethylsilyloxy-8-
oxo-2,4-octadienoate (15). To a stirred solution of oxaly
chloride (1.1 mL, 13.00 mmol) in CH2Cl2 (20 mL) was
added a solution of DMSO (1.9 mL, 25.98 mmol) in CH2Cl2
(15 mL) at K78 8C over 40 min. Upon completion of the
addition, a solution of alcohol 14 (2.04 g, 6.49 mmol) in
CH2Cl2 (10 mL) was added to the mixture over 30 min at
K78 8C. The reaction mixture was further stirred at K78 8C
for 1.5 h, and then Et3N (5.4 mL, 38.96 mmol) was added to
slowly at K78 8C. The reaction mixture was then allowed to
warm to 0 8C, and stirred at this temperature for 1.5 h. A
saturated aqueous solution of NH4Cl (30 mL) was added
followed by the addition of Et2O (300 mL). The organic
layer was separated, which was washed with water
(30 mL!2), brine (30 mL!2), and dried over Na2SO4.
Concentration gave the crude aldehyde 15 (2.14 g), which
was used directly in the next reaction without further
purification. 1H NMR (400 MHz, CDCl3): d 9.58 (d,
1H, JZ7.4 Hz), 7.42 (dd, 1H, JZ15.2, 11.5 Hz), 6.50 (t,
1H, JZ11.3 Hz), 5.99 (dt, 1H, JZ15.2, 7.4 Hz), 5.60 (d,
1H, JZ11.3 Hz), 4.20 (q, 2H, JZ7.0 Hz), 4.06–4.02 (m,
1H), 2.61–2.46 (m, 2H), 1.30 (t, 3H, JZ7.0 Hz), 0.90 (s,
9H), 0.08 (s, 3H), 0.06 (s, 3H).
4.2.4. Ethyl (7S,2Z,4E)-7-tert-butyldimethylsilyloxy-8-
trityloxy-2,4-octadienoate (13). To a stirred solution of
ethyl bis(o-methylphenyl)phosphonoacetate (9.07 g,
26 mmol) in THF (30 mL) was added NaH (1.46 g, 60%
in mineral oil, 36.4 mmol) at 0 8C. The resulting solution
was stirred at this temperature for 15 min. Then the mixture
was cooled to K78 8C, and a solution of the above crude
aldehyde 12 (11.9 g, 24.5 mmol) in THF (30 mL) was added
slowly. The mixture was allowed to stir at K78 8C for 2.5 h.
A saturated aqueous solution of NH4Cl (80 mL) was added
to the reaction mixture. Et2O (500 mL) was added to the
reaction mixture, which was washed with H2O (80 mL!2)
and brine (80 mL!2). The organic layer was dried over
Na2SO4, filtered and concentrated. The residue was
subjected to flash chromatography (n-hexane/ether, 10:1),
providing 13 (8.18 g, 60%) as a colorless oil; [a]2D0C5.7 (c
2.0, CHCl3); IR (film): 3059, 2928, 2856, 1716, 1639, 1598,
1178, 835, 706 cmK1; 1H NMR (300 MHz, CDCl3): d 7.45
(ddd, 6H, JZ7.7, 7.5, 1.4 Hz), 7.27–7.20 (m, 10H), 6.48 (t,
1H, JZ11.3 Hz), 5.99 (dt, 1H, JZ15.3, 7.3 Hz), 5.57 (d,
1H, JZ11.3 Hz), 4.20 (q, 2H, JZ7.2 Hz), 3.84 (q, 1H, JZ
5.8 Hz), 3.12–3.00 (m, 2H), 2.62–2.55 (m, 1H), 2.46–2.39
(m, 1H), 1.23 (t, 3H, JZ7.2 Hz), 0.9 (s, 9H), 0.01 (s, 3H),
K0.02 (s, 3H); 13C NMR (100 MHz, CDCl3): d 166.4,
144.8!3, 144.1, 141.3, 129.0, 128.7!6, 128.2!3, 127.7!
3, 126.7!3, 115.9, 86.5, 71.3, 67.2, 59.8, 38.7, 25.8!3,
18.1, 14.3, K4.5, K4.8; MS (ESI): m/z (%)Z579 (19)
[MCNaC].
4.2.7. C1-C10 segment (2). To a stirred solution of
formylmethylenetriphenylphosphorane (2.17 g, 7.14 mmol)
in CHCl3 (30 mL) was added slowly a solution of the crude
aldehyde 15 (2.14 g) in CHCl3 (20 mL) at 0 8C. The reaction
mixture was stirred at 0 8C for 2 h, then at room temperature
overnight. The solvent was removed in vacuo and the
residue was subjected to flash chromatography (n-hexane/
ethyl acetate, 20:1), yielding 2 (1.75 g, 80% over two steps)
as a colorless oil; [a]D20 C75.5 (c 0.4, CHCl3); IR (film):
3411, 2958, 2856, 1712, 1693, 1639, 1600, 1259, 1178,
1095, 835, 781 cmK1; 1H NMR (300 MHz, CDCl3): d 9.59
(d, 1H, JZ7.9 Hz), 7.43 (ddd, 1H, JZ15.1, 11.3, 1.1 Hz),
6.78 (dd, 1H, JZ15.3, 7.9 Hz), 6.53 (t, 1H, JZ11.2 Hz),
6.28 (ddd, 1H, JZ15.3, 8.0, 1.4 Hz), 6.00 (dt, 1H, JZ15.2,
7.5 Hz), 5.62 (d, 1H, JZ11.6 Hz), 4.55–4.51 (m, 1H), 4.20
(q, 2H, JZ7.1 Hz), 2.53–2.49 (m, 2H), 1.30 (t, 3H, JZ
7.1 Hz), 0.90 (s, 9H), 0.04 (s, 3H), 0.02 (s, 3H); 13C NMR
(100 MHz, CDCl3): d 193.3, 166.2, 158.5, 144.1, 138.4,
131.0, 129.9, 116.9, 71.1, 59.9, 40.7, 25.7!3, 18.1, 14.2,
K4.7, K4.9; MS (EI, 70 eV): m/z (%)Z338 (3) [MC], 281
(53), 199 (100), 73 (90); HRMS-EI: m/z (%) [MC] calcd for
C18H30SiO4: 338.1913; found: 338.1907.
4.2.5. Ethyl (7S,2Z,4E)-7-tert-butyldimethylsilyloxy-8-
hydroxy-2,4-octadienoate (14). To a vigorously stirred
solution of trityl ether 13 (5.82 g, 10.47 mmol) in Et2O
(130 mL) was added freshly distilled formic acid (80 mL) at
room temperature. The reaction mixture was stirred for 1 h,
which was then slowly poured down to a saturated aqueous
solution of NaHCO3 (300 mL) at 0 8C. The mixture was
extracted with Et2O (200 mL!3), and combined organic
layers were washed with saturated aqueous solution of
NaHCO3 (50 mL!2) and brine (50 mL!2). The organic
layer was dried over Na2SO4, filtered, concentrated, and the
residue was subjected to flash chromatography (n-hexane/
ethyl acetate, 4:1), providing 14 (2.47 g, 75%) as a colorless
oil; [a]2D0 C27.3 (c 0.5, CHCl3); 1H NMR (300 MHz,
CDCl3): d 7.43 (dd, 1H, JZ15.2, 11.5 Hz), 6.54 (t, 1H, JZ
11.5 Hz), 6.04 (dt, 1H, JZ15.2, 7.7 Hz), 5.60 (d, 1H, JZ
11.5 Hz), 4.20 (q, 2H, JZ7.0 Hz), 3.84 (q, 1H, JZ3.9 Hz),
3.62–3.56 (m, 1H), 3.51–3.44 (m, 1H), 2.46–2.41 (m, 2H),
4.3. Synthesis of segment C11–C24
4.3.1. (2R,4S)-1-Benzyloxy-6-tert-butyldiphenylsilyloxy-
2,4-hexandiol (17). To a stirred solution of triol 16 (6.38 g,
26.58 mmol), imidazole (3.00 g, 44.12 mmol) in dry DMF
(50 mL) was added t-butyldiphenylchlorosilane (7.76 mL,
29.94 mmol). The mixture was stirred for 15 h at room
temperature. Then ether (400 mL) was added to the mixture.
The organic layer was separated and washed with water

S. Li et al. / Tetrahedron 61 (2005) 11291–11298
11295
(50 mL) and brine (50 mL), dried and concentrated.
Purification of the residue by a column chromatography
on silica gel (ethyl acetate/petroleum ether, 1:2) gave 17
(10.65 g, 84%) as a colorless oil; [a]2D2 C8.7 (c 1.3, CHCl3);
IR (film) 3419, 2951, 2858, 1738, 1454, 1427, 1244, 1113,
chloride (2.12 mL, 24.28 mmol) in dry CH2Cl2 (90 mL) at
K78 8C was added DMSO (3.43 mL, 48.41 mmol) in
CH2Cl2 (10 mL) dropwise over 5 min. The resulting
mixture was stirred for 15 min, then the alcohol 19
(5.18 g, 12.10 mmol) in CH2Cl2 (10 mL) was added. After
stirring for 40 min, triethylamine (8.5 mL, 61.09 mmol) was
added dropwise while the reaction temperature was
maintained at K78 8C. The stirring was continued for
5 min, then the mixture was warmed slowly to room
temperature over 1.5 h. Water (10 mL) was added to the
mixture. The organic layer was separated and washed with
water (10 mL). The aqueous layer was extracted with ether
(100 mL!2). The combined organic layers were washed
with brine (30 mL), dried and concentrated. The residual oil
was dissolved in ether (50 mL). The solution was filtered
and concentrated to give crude aldehyde 7 as a yellow oil,
which was directly used in the next step without further
purification.
1
824 cmK1; H NMR (400 MHz, CDCl3): d 7.66–7.63 (m,
4H), 7.44–7.36 (m, 6H), 7.33–7.27 (m, 5H), 4.55 (s, 2H),
4.24–4.18 (m, 1H), 4.17–4.11 (m, 1H), 3.87–3.84 (m, 2H),
3.50 (dd, 1H, JZ4.1, 9.5 Hz), 3.41 (dd, 1H, JZ7.4, 9.4 Hz),
1.87–1.76 (m, 1H), 1.68–1.57 (m, 3H), 1.03 (s, 9H); MS (EI,
70 eV): m/z (%)Z421 (19.5) [MCKtBu], 403 (25.8), 313
(6.1), 199 (31.7), 91 (100).
4.3.2. Benzyl (2R,4S)-6-tert-butyldiphenylsilyloxy-2,4-di-
O-isopropylidene hexyl ether (18). The diol 17 (10.20 g,
21.34 mmol) and CSA (106 mg, 0.46 mmol) were dissolved
in 2, 2-dimethoxypropane (71 mL). The mixture was stirred
for 2 h at room temperature, then neutralized with NaHCO3,
filtered and concentrated. The residue was extracted with
ether (400 mL), and the organic layer was washed with
aqueous solution of NaHCO3 (50 mL), water (50 mL) and
brine (50 mL) successively, then dried and concentrated.
The residue was purified by column chromatography on
silica gel (ether/petroleum ether, 1:8) to afford 18 (10.15 g,
97% based on partially recovered starting material) as a
colorless oil; [a]2D2 C20.3 (c 0.9, CHCl3); IR (film): 3070,
4.3.5. (E,E)-Conjugated diene ester (20). Triethyl 4-phos-
phonocrotonate (6.06 g, 24.38 mmol), LiOH$H2O (1.02 g,
˚
24.28 mmol), 4 A molecular sieves (18 g) and crude
aldehyde 19 were mixed in THF (121 mL). The mixture
was refluxed for 10 h, then filtered with a short silica gel
column. The filtrate was concentrated, and the residue was
purified by column chromatography (ethyl acetate/
petroleum ether, 1:20) to give 20 (3.85 g, 62% for two
steps) as a colorless oil. The stereoselectivity (E,E/Z,EZ
1
2933, 2858, 1473, 1427, 1379, 1225, 1113, 824 cmK1; H
NMR (400 MHz, CDCl3): d 7.65–7.62 (m, 4H), 7.42–7.32
(m, 6H), 7.35–7.25 (m. 5H), 4.61 (d, 1H, JZ12.3 Hz), 4.54
(d, 1H, JZ12.2 Hz), 4.13–4.00 (m, 2H), 3.80–3.74 (m, 1H),
3.69–3.64 (m, 1H), 3.49 (dd, 1H, JZ6.8, 10.5 Hz), 3.41 (dd,
1H, JZ4.2, 10.5 Hz), 1.73–1.48 (m, 4H), 1.35 (s, 6H), 1.02
(s, 9H); 13C NMR (75 MHz, CDCl3): d 138.3, 135.5!4,
133.9, 133.9, 129.5!3, 128.3!3, 127.7!2, 127.6!3,
100.3, 73.3, 72.8, 66.3, 63.3, 60.0, 38.8, 34.8, 26.8!3,
24.9!2, 19.2; MS (EI, 70 eV): m/z (%)Z503 (0.4) [MCK
CH3], 397 (0.4), 255 (2), 235 (6), 199 (100), 181 (6), 121
(3).
1
5:1) was determined by H NMR; IR (film): 2931, 2858,
1716, 1647, 1620, 1473, 1429, 1379, 1227, 1113 cmK1; 1H
NMR (400 MHz, CDCl3): d 7.65–7.62 (m, 4H), 7.42–7.34
(m, 6H), 7.25 (dd, 1H, JZ11.0, 15.2 Hz), 6.31 (dd, 1H, JZ
11.2, 15.2 Hz), 6.10 (dd, 1H, JZ5.4, 15.4 Hz), 5.86 (d, 1H,
JZ15.4 Hz), 4.46–4.41 (m, 1H), 4.19 (q, 2H, JZ7.1 Hz),
4.15–4.06 (m, 1H), 3.81–3.73 (m, 1H), 3.71–3.65 (m, 1H),
1.81–1.65 (m, 4H), 1.37 (s, 3H), 1.35 (s, 3H), 1.30 (t, 3H,
JZ7.1 Hz), 1.03 (s, 9H); 13C NMR (75 MHz, CDCl3): d
166.9, 143.9, 142.4, 135.5!4, 133.8!2, 129.6!2, 127.6!
4, 121.5, 120.0, 100.5, 66.7, 63.1, 60.3, 59.9, 38.8, 37.6,
26.8!3, 25.5, 24.7, 19.7, 14.2; MS (EI, 70 eV): m/z (%)Z
507 (0.1) [MCKCH3], 407 (6), 255 (84), 225 (27), 199
(100), 183 (20), 117 (18).
4.3.3. (2R,4S)-6-tert-Butyldiphenylsilyloxy-2,4-di-O-iso-
propylidene hexanol (19). To a stirred solution of benzyl
ether 18 (6.34 g, 12.24 mmol) in ethanol (200 mL) was
added the freshly prepared W2 Raney Ni. The mixture was
stirred for 6 h at 60 8C. Then the mixture was cooled to room
temperature and filtered. Concentration of the filtrate and
purification of the residue by column chromatography on
silica gel (ethyl acetate/petroleum ether, 1:8) gave 19
(5.19 g, 98%) as a colorless oil; [a]2D2 C9.0 (c 1.1, CHCl3);
IR (film): 3454, 2933, 1473, 1427, 1381, 1225, 1113,
4.3.6. (E,E)-Conjugated diene alcohol (21). To a stirred
solution of ester 20 (1.07 g, 2.05 mmol) in CH2Cl2 (70 mL)
at K78 8C was added DIBAL-H (6.20 mL, 1 M in hexane,
6.20 mmol). After stirring for 30 min, methanol (3 mL) was
added. The mixture was warmed slowly to 0 8C and a
saturated aqueous solution of sodium potassium tartrate
(10 mL) was added. After stirring for 1 h at 0 8C, the organic
layer was separated, and the aqueous layer was extracted
with CH2Cl2 (50 mL). The combined organic layers were
washed with water (15 mL) and brine (20 mL), dried and
concentrated. The residue was purified by column chroma-
tography (ethyl acetate/petroleum ether, 1:6) to give 21
(0.90 g, 91%) as a colorless oil; [a]2D4 C15.5 (c 1.1, CHCl3);
IR (film): 3419, 3070, 2996, 2931, 2858, 1473, 1427, 1379,
824 cmK1 1H NMR (400 MHz, CDCl3): d 7.66–7.63
;
(m, 4H), 7.43–7.34 (m, 6H), 4.10–4.02 (m, 1H), 3.96–3.90
(m, 1H), 3.80–3.75 (m, 1H), 3.70–3.65 (m, 1H), 3.61–3.55
(m, 1H), 3.54–3.48 (m, 1H), 1.78–1.59 (m, 3H), 1.52–1.44
(m, 1H), 1.35 (s, 3H), 1.34 (s, 3H), 1.03 (s, 9H); 13C NMR
(75 MHz, CDCl3): d 135.4!4, 133.7!2, 129.5!2,
127.5!4, 100.4, 67.5, 65.3, 63.3, 59.9, 38.7, 33.7, 26.8!
3, 24.9, 24.8, 19.1; MS (EI, 70 eV): m/z (%)Z413 (2.6)
[MCKCH3], 313 (40), 255 (20.2), 235 (26.8), 199 (100),
183 (19.1). Anal. Calcd for C25H36O4Si: C, 70.04; H, 8.46.
Found: C, 69.68; H, 8.39.
1
1223, 1113 cmK1; H NMR (400 MHz, CDCl3): d 7.66–
7.62 (m, 4H), 7.42–7.34 (m, 6H), 6.28–6.14 (m, 2H), 5.87–
5.78 (m, 1H), 5.72 (dd, 1H, JZ6.1, 14.5 Hz), 4.40–4.34 (m,
1H), 4.21–4.12 (m, 3H), 3.82–3.75 (m, 1H), 3.71–3.65 (m,
1H), 1.80–1.64 (m, 4H), 1.36 (s, 3H), 1.35 (s, 3H), 1.03 (s,
9H); 13C NMR (75 MHz, CDCl3): d 135.4!4, 133.8!3,
4.3.4. (2R,4S)-6-tert-Butyldiphenylsilyloxy-2,4-di-O-iso-
propylidene hexanal (7). To a stirred solution of oxalyl

11296
S. Li et al. / Tetrahedron 61 (2005) 11291–11298
132.5, 130.5, 129.7, 129.5!2, 127.6!4, 100.3, 67.2, 63.1,
63.0, 59.9, 38.8, 37.8, 26.8!3, 25.5, 24.7, 19.1; MS (EI,
70 eV): m/z (%)Z465 (0.1) [MCKCH3], 347 (3), 255
(100), 225 (30), 199 (26), 183 (20).
Na2HPO4 (7.14 g, 50.3 mmol) and Na/Hg (17.22 g, 6%,
44.9 mmol) at 0 8C. The mixture was stirred for 5 h at room
temperature, filtered through a short silica gel column. The
filtrate was concentrated and purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate, 20:1)
to afford 24 (1.08 g, 66%) as a colorless oil; [a]2D2 K2.2 (c
1.2, CHCl3); IR (film): 3070, 2933, 1612, 1514, 1464, 1427,
4.3.7. (E,E)-Conjugated diene bromide (22). To a stirred
solution of alcohol 21 (2.70 g, 5.62 mmol) in CH2Cl2
(30 mL) was added triphenylphosphine (1.70 g,
6.49 mmol). The solution was cooled to K78 8C, and
NBS (1.17 g, 6.57 mmol) was added in portions. After
stirring for 30 min at K78 8C, methanol (0.58 mL) was
added followed by the addition of ether (50 mL). The
mixture was washed with water (10 mL), saturated aqueous
solution of sodium carbonate (10 mL) and brine (15 mL)
successively. The organic layer was dried and concentrated.
The residue was dissolved in hexane (60 mL) and allowed to
stand in a freezer overnight. The solution was filtered and
the filtrate was concentrated. The residue was treated with
hexane three times as described above to afford bromide 22
(2.95 g, 95%); [a]2D4 C2.8 (c 1.9, CHCl3); IR (film): 3070,
1
1379, 1248, 1113 cmK1; H NMR (400 MHz, CDCl3): d
7.66–7.62 (m, 4H), 7.40–7.34 (m, 6H), 7.24 (d, 2H, JZ
8.2 Hz), 6.85 (d, 2H, JZ8.5 Hz), 6.18–6.11 (m, 1H), 6.02–
5.94 (m, 1H), 5.70–5.64 (m, 1H), 5.60–5.53 (m, 1H), 4.47
(d, 1H, JZ11.5 Hz), 4.35 (d, 1H, JZ11.3 Hz), 4.38–4.30
(m, 1H), 4.17–4.07 (m, 1H), 3.78 (s, 3H), 3.85–3.74 (m,
1H), 3.70–3.65 (m, 1H), 3.49–3.43 (m, 1H), 2.08–2.03 (m,
2H), 1.74–1.62 (m, 4H), 1.61–1.18 (m, 4H), 1.36 (s, 3H),
1.35 (s, 3H), 1.15 (d, 3H, JZ6.1 Hz), 1.02 (s, 9H); MS (EI,
70 eV): m/z (%)Z656 (13.4) [MC], 641 (7.7), 541 (12.8),
339 (18.0), 269 (32.5), 255 (100), 225 (99.8); HRMS-EI:
m/z calcd for C41H56SiO5: 656.3897; found: 656.3911.
1
2931, 2858, 1471, 1427, 1379, 1200, 987 cmK1; H NMR
4.3.10. (E,E)-Conjugated diene alcohol (25). To a solution
of 24 (1.05 g, 1.60 mmol) in THF (40 mL) at 0 8C was
added TBAF (20 mL, 0.1 M solution in THF, 2 mmol). The
mixture was warmed to room temperature and stirred for
10 h. Ether (100 mL) was added to the mixture. The organic
layer was washed with water (10 mL) and brine (15 mL),
dried and concentrated. The residue was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate,
4:1) to give 25 (0.60 g, 89%) as a colorless oil; [a]2D2 C9.2
(c 0.6, CHCl3); IR (film): 3440, 1612, 1514, 1379, 1248,
1171, 991, 822 cmK1; 1H NMR (400 MHz, CDCl3): d 7.24
(d, 2H, JZ8.4 Hz), 6.85 (d, 2H, JZ8.5 Hz), 6.15 (dd, 1H,
JZ15.3, 10.5 Hz), 5.98 (dd, 1H, JZ15.0, 10.5 Hz), 5.67 (dt,
1H, JZ6.9, 14.3 Hz), 5.55 (dd, 1H, JZ15.3, 6.6 Hz), 4.47
(d, 1H, JZ11.3 Hz), 4.38–4.34 (m, 1H), 4.34 (d, 1H, JZ
11.2 Hz), 4.12–4.06 (m, 1H), 3.78 (s, 3H), 3.80–3.72 (m,
2H), 3.47–3.43 (m, 1H), 2.49 (br s, 1H), 2.06–2.02 (m, 2H),
1.78–1.66 (m, 4H), 1.55–1.32 (m, 4H), 1.39 (s, 3H), 1.37 (s,
3H), 1.14 (d, 3H, JZ6.1 Hz); 13C NMR (75 MHz, CDCl3):
d 159.0, 135.5, 131.3, 131.2, 130.6, 129.6, 129.1!2,
113.7!2, 100.4, 74.3, 69.9, 67.5, 66.6, 61.0, 55.2, 37.7!
2, 36.1, 32.6, 25.4, 25.1, 24.8, 19.6; MS (EI, 70 eV): m/z
(%)Z418 (2.65) [MC], 3.60 (11.2), 342 (8.55), 286 (9.23),
260 (6.32), 121 (100); HRMS-EI: m/z calcd for C25H38O5:
418.2719; found: 418.2709.
(400 MHz, CDCl3): d 7.66–7.64 (m, 4H), 7.43–7.34 (m,
6H), 6.28–6.17 (m, 2H), 5.91–5.82 (m, 1H), 5.80–5.67 (m,
1H), 4.42–4.36 (m, 1H), 4.18–4.08 (m, 1H), 4.01 (d, 2H, JZ
7.8 Hz), 3.85–3.76 (m, 1H), 3.68 (dd, 1H, JZ5.3, 10.5 Hz),
1.79–1.62 (m, 4H), 1.36 (s, 3H), 1.35 (s, 3H), 1.03 (s, 9H);
MS (EI, 70 eV): m/z (%)Z527/529 (3.3/3.2) [MCKCH3],
463 (21.5), 311 (19.6), 255 (100), 199 (36.0); HRMS-EI:
m/z [MCKBu–Me2CO] calcd for C22H BrO2Si: 427.0729;
79
24
81
found: 427.0707; calcd for C22H BrO2Si: 429.0709; found:
429.0683.
24
4.3.8. (E,E)-Conjugated diene phenylsulfone (23). To a
solution of 9 (1.00 g, 2.99 mmol) in THF (20 mL) was
added dropwise n-BuLi (1.77 mL, 3.54 mmol, 2 M solution
in hexane) under stirring at K78 8C. After 30 min, the
bromide 22 (1.68 g, 3.09 mmol) in THF (10 mL) was added
rapidly. The reaction mixture was stirred at K78 8C for 1 h,
then warmed up to K40 8C. A saturated aqueous solution of
NH4Cl (5 mL) was added followed by the addition of ether
(100 mL). The organic layer was washed with water
(10 mL) and brine (15 mL), dried and concentrated.
Purification of the residue by column chromatography on
silica gel (petroleum ether/ethyl acetate, 8:1) afforded 23
(2.2 g, 93%) as a mixture of diastereomers. IR (film): 3070,
2931, 2856, 1612, 1514, 1379, 1304, 1248, 1146, 1113 cmK1
;
1H NMR (400 MHz, CDCl3): d 7.75 (d, 2H, JZ7.6 Hz),
7.64–7.60 (m, 5H), 7.53–7.50 (m, 2H), 7.40–7.34 (m, 6H),
7.22 (d, 2H, JZ7.3 Hz), 6.87 (d, 2H, JZ7.4 Hz), 6.13–6.04
(m, 1H), 6.00–5.91 (m, 1H), 5.57–5.47 (m, 2H), 4.47 (d, 1H,
JZ11.2 Hz), 4.36–4.27 (m, 1H), 4.22 (d, 1H, JZ11.3 Hz),
4.17–4.05 (m, 1H), 3.80 (s, 3H), 3.85–3.75 (m, 1H), 3.75–
3.65 (m, 2H), 3.29–3.21 (m, 1H), 2.54–2.46 (m, 1H), 2.29–
2.20 (m, 1H), 2.02–1.92 (m, 1H), 1.78–1.68 (m, 4H), 1.67–
1.57 (m, 1H), 1.35 (s, 3H), 1.34 (s, 3H), 1.11 (d, 3H, JZ
5.9 Hz), 1.02 (s, 9H); MS (EI, 70 eV): m/z (%)Z796 (4.7)
[MC], 781 (4.2), 681 (18.8), 539 (11.6), 397 (16.6), 323
(18.8), 255 (100); HRMS-EI: m/z [MCKBu–Me2CO] calcd
for C40H45O6SSi: 681.2707; found: 681.2711.
4.3.11. (E,E)-Conjugated diene iodide (26). To a stirred
solution of 25 (103 mg, 0.25 mmol) in benzene (51 mL) at
0 8C were added iodine (94 mg, 0.37 mmol), triphenyl
phosphine (98 mg, 0.37 mmol) and imidazole (51 mg,
0.75 mmol) successively. The mixture was stirred at 0 8C
for 1 h. A saturated aqueous solution of NaHCO3 (50 mL)
was added. Stirring was continued for an additional 30 min.
The organic layer was washed with saturated aqueous
solution of Na2S2O3 (50 mL), water (20 mL), and brine
(50 mL) successively, dried and concentrated. The residue
was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate, 15:1) to afford 26 (0.12 g,
92%) as a colorless oil; [a]2D2 K12.8 (c 1.2, CHCl3); IR
(film): 2935, 1612, 1514, 1379, 1248, 1173, 1038, 989,
822 cmK1; 1H NMR (400 MHz, CDCl3): d 7.24 (d, 2H, JZ
8.5 Hz), 6.85 (d, 2H, JZ8.5 Hz), 6.22–6.12 (m, 1H), 6.02–
5.94 (m, 1H), 5.70–5.63 (m, 1H), 5.59–5.47 (m, 1H), 4.47
4.3.9. (E,E)-Conjugated diene tert-butyldiphenylsilyl
ether (24). To a solution of the mixture 23 (1.99 g,
2.5 mmol) in dry methanol (100 mL) were added

S. Li et al. / Tetrahedron 61 (2005) 11291–11298
11297
(d, 1H, JZ11.2 Hz), 4.42–4.32 (m, 1H), 4.35 (d, 1H, JZ
11.2 Hz), 3.99–3.92 (m, 1H), 3.78 (s, 3H), 3.48–3.43 (m,
1H), 3.30–3.22 (m, 2H), 2.07–2.03 (m, 2H), 1.96–1.91 (m,
4H), 1.57–1.31 (m, 4H), 1.39 (s, 3H), 1.36 (s, 3H), 1.15 (d,
3H, JZ5.8 Hz); 13C NMR (75 MHz, CDCl3): d 158.9,
135.4, 131.3, 131.1, 130.5, 129.6, 129.1!2, 113.7!2,
100.4, 74.2, 69.8, 67.4, 66.1, 55.2, 39.2, 37.3, 36.1, 32.5,
25.2, 25.1, 24.9, 19.6, 2.2; MS (EI, 70 eV): m/z (%)Z528
(10.26) [MC], 513 (6.5), 470 (9.83), 349 (32.56), 269
(16.24), 121 (100); HRMS-EI: m/z calcd for C25H37IO4:
528.1737; found: 528.1731.
32.6, 29.7, 25.8!3, 25.5, 25.2, 24.9, 19.6, 18.2, 14.3, K4.4,
K4.8; MS (EI, 70 eV): m/z (%)Z722 (0.3) [MC], 707 (2.4),
583 (10.1), 525 (68.8), 121 (100); HRMS-EI: m/z calcd for
C43H66O7Si: 722.4578; found: 722.4538.
4.4.2. seco-Precursor alcohol (28). To a solution of 27
(25.0 mg, 34.6 mmol) in CH2Cl2/H2O (2.8/0.16 mL) was
added DDQ (11.8 mg, 52.0 mmol) at room temperature in
portions. The mixture was stirred for 2 h at room
temperature and filtered. The filtrate was concentrated and
the residue was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate, 20:1–4:1) to afford
28 (3.0 mg, 14.4%) as a colorless oil; [a]2D0 C5.4 (c 0.5,
CHCl3); IR (film): 3419, 2955, 1714, 1639, 1462, 1377,
4.3.12. C11–C24 segment (3). To a solution of 26 (279 mg,
0.53 mmol) in CH3CN (2 mL) was added Ph3P (277 mg,
1.06 mmol). The resulting mixture was refluxed for 48 h
under N2. Then the mixture was cooled to room
temperature, and washed with petroleum ether. Concen-
tration of the mixture gave 3 (412 mg, 97%) as a white foam
solid; [a]2D4 C6.7 (c 0.8, CHCl3); IR (film): 1587, 1512,
1
1252, 1176, 1067, 837, 777 cmK1; H NMR (400 MHz,
CDCl3): d 7.38 (dd, 1H, JZ15.4, 11.3 Hz), 6.83 (dd, 1H,
JZ15.0, 11.0 Hz), 6.55 (dd, 1H, JZ11.3, 11.0 Hz), 6.42
(dd, 1H, JZ15.4, 11.0 Hz), 6.06 (dd, 1H, JZ15.4, 10.9 Hz),
6.02 (dd, 1H, JZ11.3, 11.0 Hz), 5.68 (dt, 1H, JZ15.4,
7.2 Hz), 5.62 (dd, 1H, JZ15.0, 5.8 Hz), 5.59 (d, 1H, JZ
11.4 Hz), 5.42–5.41 (m, 3H), 4.26–4.21 (m, 1H), 4.18 (q,
2H, JZ7.0 Hz), 4.12–4.06 (m, 1H), 3.92–3.82 (m, 1H),
3.50–3.43 (m, 1H), 2.44–2.38 (m, 4H), 2.10–1.99 (m, 2H),
1.62–1.58 (m, 2H), 1.50–1.41 (m, 2H), 1.42 (s, 3H), 1.39 (s,
3H), 1.36–1.32 (m, 2H), 1.30 (t, 3H, JZ7.0 Hz), 1.19 (d,
3H, JZ6.2 Hz), 0.88 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H),
(hydroxy hydrogen was not observed); 13C NMR (75 MHz,
CDCl3): d 166.4, 144.8, 141.0, 136.5, 132.0, 131.7, 130.0,
129.8, 129.0, 126.9, 124.9, 124.6, 116.2, 100.8, 72.8, 68.9,
68.5, 59.8, 55.3, 42.0, 39.8, 36.1, 34.7, 30.2, 29.7, 27.2,
25.8!3, 23.2, 19.8, 18.2, 14.3, K4.3, K4.8; MS (EI,
70 eV): m/z (%)Z602 (3) [MC], 587 (15), 545 (3), 527 (6),
463 (23), 405 (26), 273 (24), 171 (28), 75 (100); HRMS-EI:
m/z calcd for C35H58O6Si: 602.4003; found: 602.3966.
1
1437, 1379, 1248, 1173, 1113, 1032, 997 cmK1; H NMR
(400 MHz, CDCl3): d 7.82–7.67 (m, 15H), 7.22 (d, 2H, JZ
8.4 Hz), 6.83 (d, 2H, JZ8.3 Hz), 6.14–6.08 (m, 1H), 6.00–
5.91 (m, 1H), 5.67–5.59 (m, 1H), 5.54 (dd, 1H, JZ6.6,
15.5 Hz), 4.45 (d, 1H, JZ11.2 Hz), 4.33 (d, 1H, JZ
11.4 Hz), 4.32–4.27 (m, 1H), 4.21–4.12 (m, 1H), 4.11–4.07
(m, 1H), 3.76 (s, 3H), 3.50–3.40 (m, 2H), 2.03–1.98 (m,
2H), 1.91–1.55 (m, 4H), 1.54–1.34 (m, 4H), 1.40 (s, 3H),
1.38 (s, 3H), 1.13 (d, 3H, JZ6.0 Hz); MS (EI, 70 eV): m/z
(%)Z715 (0.4) [MCKC3H7O2], 664 (0.6), 578 (15.5), 319
(69.2), 262 (100), 121 (93.1).
4.4. Synthesis of seco-precursor
4.4.1. PMB ether of seco-precursor (27). To a solution of 2
(31 mg, 0.913 mmol) and 3 (86.6 mg, 0.110 mmol) in THF
(3 mL) was added dropwise NaHMDS (55 mL, 0.110 mmol,
2 M solution in THF) under stirring at K78 8C. The reaction
mixture was stirred at K78 8C for 2 h. A saturated aqueous
solution of NaHCO3 (3 mL) was added followed by the
addition of ether (50 mL). The organic layer was washed
with water (10 mL) and brine (15 mL), dried and
concentrated. Purification of the residue by column
chromatography on silica gel (petroleum ether/ethyl acetate,
20:1) afforded 27 (52 mg, 79%) as a colorless oil, (Z/EZ
98:2 by HPLC, Waters Spherisorb 4.6!150 mm column
with cyclohexane/isopropanol, 97.5:2.5 as eluents); [a]D20
C9.2 (c 0.6, CHCl3); IR (film): 2928, 2854, 1716, 1514,
Acknowledgements
This work was supported by a grant from the National
Natural Science Foundation of China and a grant from the
State Key Laboratory of Bio-organic and Natural Products
Chemistry.
References and notes
1464, 1377, 1248, 1178, 1070, 1038 cmK1 1H NMR
;
(400 MHz, CDCl3): d 7.36 (dd, 1H, JZ15.4, 11.5 Hz),
7.24 (d, 2H, JZ8.4 Hz), 6.85 (d, 2H, JZ8.4 Hz), 6.51 (dd,
1H, JZ11.3, 11.1 Hz), 6.42 (dd, 1H, JZ14.8, 11.2 Hz),
6.15 (dd, 1H, JZ15.0, 10.2 Hz), 6.06—5.95 (m, 3H), 5.64
(dd, 2H, JZ14.9, 6.2 Hz), 5.56 (d, 1H, JZ11.8 Hz), 5.57–
5.53 (m, 1H), 5.45–5.38 (m, 1H), 4.47 (d, 1H, JZ11.2 Hz),
4.35 (d, 1H, JZ11.3 Hz), 4.36–4.31 (m, 1H), 4.27–4.21 (m,
1H), 4.16 (q, 2H, JZ7.1 Hz), 3.91–3.83 (m, 1H), 3.78 (s,
3H), 3.49–3.43 (m, 1H), 2.47–2.31 (m, 4H), 2.10–1.98 (m,
2H), 1.80–1.60 (m, 6H), 1.37 (s, 3H), 1.36 (s, 3H), 1.28 (t,
3H, JZ7.1 Hz), 1.15 (d, 3H, JZ5.9 Hz), 0.87 (s, 9H), 0.02
(s, 3H), 0.006 (s, 3H); 13C NMR (75 MHz, CDCl3): d 166.4,
159.0, 144.9!2, 141.0, 136.5, 135.3, 131.2, 130.9, 129.8,
129.1, 129.0!2, 126.9, 124.9, 116.1!2, 113.7!2, 100.3,
74.3, 72.7, 69.9, 67.5, 66.3, 59.8, 55.3, 42.0, 37.4, 36.2,
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