Total synthesis of phorboxazole B

Article abstract of DOI:10.1002/chem.200500892

An efficient and highly convergent total synthesis of the potent antitumor agent phorboxazole B has been achieved. The synthetic strategy of this synthesis features: 1) a highly efficient substrate-controlled hydrogenation to construct the functionalized

Full text of DOI:10.1002/chem.200500892

FULL PAPER
DOI: 10.1002/chem.200500892
Total Synthesis of Phorboxazole B
De-Run Li, Dong-Hui Zhang, Cai-Yun Sun, Ji-Wen Zhang, Li Yang, Jian Chen, Bo Liu,
Ce Su, Wei-Shan Zhou,* and Guo-Qiang Lin*[a]
Abstract: An efficient and highly con-
vergent total synthesis of the potent
antitumor agent phorboxazole B has
been achieved. The synthetic strategy
of this synthesis features: 1) a highly
efficient substrate-controlled hydroge-
nation to construct the functionalized
cis-tetrahydropyrane unit; 2) iterative
crotyl addition to synthesize the seg-
ment that contains alternating hydroxyl
and methyl substituents; 3) Hg(OAc)2/
I2-induced cyclization to establish the
cis-tetrahydropyrane moiety; 4) 1,3-
asymmetric induction in the Mukaiya-
ma aldol reaction to afford the stereo-
genic centers at C9 and C3; and 5) the
exploration of the Still–Gennari olefi-
nation reaction to complete the macro-
lide ring of phorboxazoloe B.
Keywords:
antitumor agents
·
natural products · phorboxazole B ·
total synthesis
Introduction
oassayed for 60 human tumor cell strains at the National
Cancer Institute (NCI).[1] Although the exact mechanism of
action of the phorboxazoles remains unknown, studies have
shown that they do not inhibit or promote tubulin polymeri-
zation; a process that is known to play an important role in
the mechanism of action of several antitumor natural prod-
ucts, such as taxol and the epothilones.[3] The unprecedented
structural features and the remarkable antitumor activities
of the phorboxazoles have attracted great attention in the
synthetic community,[4] with excellent total syntheses report-
ed by Forsyth,[5] Evans,[6] Smith,[7] Pattenden,[8] and Wil-
liams.[9] In connection with our previous work on phorboxa-
zole B,[4o–p,q,s] we herein wish to report our total synthesis.
Marine sponges have been extensively investigated as im-
portant sources of architecturally complex, biologically
active natural products. Phorboxazole A (1) and its epimer
phorboxazole B (2) were isolated from the Indian ocean
sponge Phorbas sp. by Molinski and co-workers.[1] The rela-
tive and absolute stereochemistries of the phorboxazoles
have been determined by extensive NMR spectroscopic
analysis, degradation studies, and synthetic correlation.
Phorboxazoles represent a newclass of 21-membered mac-
rolides, accommodating four heavily functionalized oxanes
and two 2,4-disubstituted oxazoles.[2] In addition to their
potent antifungal activity against Candida albicans and Sac-
charomyces carlsbergensis, phorboxazoles have also demon-
strated exceptional inhibition of cell growth.[1] These metab-
olites are ranked among the most cytostatic natural products
ever known, exhibiting extraordinary potency (mean GI50 =
<1.6”10À9 m; GI50: 50% inhibition of cell growth) when bi-
Retrosynthetic analysis: Our retrosynthetic analysis of phor-
boxazole B (Scheme 1) began with the disconnection of the
C2=C3 and C19=C20 double bonds, which led us to the key
building blocks 3 and 4. In the synthetic sense, segments 3
and 4 could be combined by an E-selective Wittig reaction,
as reported by the Evans group.[6] It was desirable to con-
struct the C2=C3 Z-double bond by employing the Still–
Gennari olefination that was reported by Forsyth,[5] Smith,[7]
Pattenden,[8] and Williams,[9] in their synthesis of phorboxa-
zole A. By further continuing with this analysis, disconnec-
[a] Dr. D.-R. Li, Dr. D.-H. Zhang, C.-Y. Sun, Dr. J.-W. Zhang,
Dr. L. Yang, Dr. J. Chen, Dr. B. Liu, Dr. C. Su, Prof. W.-S. Zhou,
Prof. G.-Q. Lin
À
tion of the C32 C33 bond and the C41=C42 double bond
Shanghai Institute of Organic Chemistry
354 Fenglin Rd, Shanghai 200032 (P. R. China)
Fax : (+86)21-6416-6263
E-mail: zhws@mail.sioc.ac.cn
lingq@mail.sioc.ac.cn
Supporting information for this article (copies of H and 13C NMR
would separate 4 into tetrahydropyranyl oxazole 5, lactone
6, and the known sulfone 7.[6] It was envisaged that the cou-
pling of lactone 5 with 6, by using a metalation reaction (nu-
cleophilic addition),[6] followed by Julia olefination with
sulfone 7, would lead to the formation of the C20–C46 seg-
ment 4.
1
spectra) is available on the WWW under http://www.chemeurj.org/ or
from the author.
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1185

lowed by TBS (tert-butyldime-
thylsilyl) ether protection[11] to
furnish compound 10. Exposure
of the chiral building block 10
to Wacker oxidation[12] pro-
duced the methyl ketone 11 in
89% yield. Treatment of the
lithium enolate of 11 with alde-
hyde 12[13] in THF at À788C led
to a mixture of two C15 epimer-
ic isomers of b-hydroxy ketone,
which were transformed to the
b-diketone 13 by the oxidation
with Dess–Martin periodinane
(DMP).[14] 1H NMR spectrosco-
py showed that the b-diketone
13 existed entirely as the enol-
ketone. As was expected, expo-
sure of 13 to a 5% solution of
hydrofluoric acid[15] in acetoni-
trile at room temperature led to
the production of the cyclode-
hydrated product 14 in excel-
Scheme 1. Retrosynthetic analysis of phorboxazole B.
lent yield (90%). The primary
hydroxyl of 14 was then repro-
Results and Discussion
tected with a TBS group to afford 2H-pyranone 15 in 97%
yield.
Synthesis of the C3–C19 bistetrahydropyrane segment 3:
Brown asymmetric allylation[10] of aldehyde 8 produced the
chiral alcohol 9[7d] with 87% ee (ee=enantiomeric excess,
determined by HPLC analysis, Scheme 2), which was fol-
With a quantity of 15 in hand, we focused our attention
on the construction of the C13 and C15 stereogenic centers
by substrate-controlled hydrogenation chemistry.[16] Thus,
stereoselective Luche reduction[17] of 2H-pyranone 15 in
Scheme 2. Synthesis of the C9–C19 segment 18. a) (À)-Ipc2BAllyl, Et2O, À788C, 87% ee, 71%; b) TBSCl, imidazole, DMF, 96%; c) PdCl2 (cat), CuCl,
O2, DMF/H2O, RT, 6 h, 89%; d) 1) LDA, 12, THF, À788C; 2) Dess–Martin periodinane, CH2Cl2, RT, 90% for the two steps; e) 5% HF in CH3CN, RT,
12 h, 90%; f) TBSCl, imidazole, DMF, RT, 97%; g) NaBH4, CeCl3, MeOH, À788C, 95%; h) H2, 10% Pd/C, EtOAc, 8 h, 95%; i) H2, 10% Pd/C, EtOAc
(saturated with 0.1n HCl), 8 h, 65%; j) 1) TBSCl, imidazole, DMF, RT; 2) DDQ, CH2Cl2, RT; 3) Dess–Martin periodinane, CH2Cl2, RT, 82% for the
three steps.
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Phorboxazole B
FULL PAPER
methanol at À788C provided 16 in 95% yield as a single
isomer.
tion[19] (PMB) of the resulting chiral alcohol 20[20] and
Wacker oxidation of the PMB ether 21, furnished the C3–
C8 segment 22 of phorboxazole B. An aldol reaction of alde-
hyde 18 with the silyl enol ether of 22, under Mukaiyamaꢁs
conditions,[21] produced the b-hydroxyl ketone 23 as an in-
separable mixture of C9 epimeric isomers (7.8:1).[22] The
next step in the synthesis was to convert the ketone at C7 to
a methylene moiety. Unfortunately, methylenation of the
ketone in 23 did not result in the desired product, despite
the employment of various reaction conditions, such as
those reported by Petasis,[23] Lombardo,[24] and Takai.[25] This
was probably due to the susceptibility of the b-hydroxyl
ketone moiety to the reaction conditions. Thus, to suppress
undesirable side reactions, 23 was first shielded with a ben-
zoyl group[26] and then methylenated with Nysted reagent
The next step involved the creation of the cis-tetrahydro-
pyrane (C11/C15) ring by means of a stereoselective sub-
strate-controlled hydrogenation of the C14=C15 double
bond. In the presence of a catalytic amount of palladium on
charcoal, compound 16 was readily hydrogenated to give the
cis-tetrahydropyrane 17 in 95% yield as a single isomer. The
NOE effect between H-11, H-13, and H-15 confirmed the
cis-tetrahydropyrane structure of 17. We then decided to ex-
plore the possibility of constructing the C13 and C15 stereo-
centers in one pot. To our delight, direct hydrogenation of
15 in ethyl acetate also delivered the desired cis-tetrahydro-
pyrane 17, although the yield was initially very low. By con-
ducting the reaction in ethyl acetate, saturated with HCl
(0.1n), the yield was optimized to 65% yield. Thus, the C9–
C19 cis-tetrahydropyrane unit was stereoselectively synthe-
sized from 2H-pyranone 15 by a one-pot substrate-directed
hydrogenation. Protection (TBSCl) of the C13 hydroxy
group of compound 17 and subsequent removal of the
PMB-protecting group (PMB=p-methoxybenzyl),[18] fol-
lowed by oxidation of the resulting primary hydroxy, afford-
ed the corresponding aldehyde 18 in 82% yield (overall
yield for the three steps).
(cyclo-dibromodi-m-methylene
[m-(tetrahydrofuran)]tri-
zinc)[27] to give 24 in 66% yield and the C9 epimer 25 in 8%
yield.
These two isomers were conveniently separated by flash-
column chromatography on silica gel. Removal of the ben-
zoyl-protecting group by reduction with DIBAL (diisobutyl-
aluminumhydride) and subsequent mesylation[28] of the re-
sulting hydroxyl, followed by cleavage of the PMB-protect-
ing group, provided 26 in 68% yield (overall yield for the
three steps). Finally, a solution of compound 26 in acetoni-
trile was refluxed for 12 h with excess triethylamine (con-
ducted according to Forsythꢁs method)[5] to produce com-
pound 27 (83% yield) and thus complete the construction of
the desired bistetrahydropyrane moiety. The cis configura-
The next step involved the synthesis of the C3–C19 seg-
ment 3 from the TBDPS-protected propionaldehyde 19
(TBDPS=tert-butyldiphenylsilyl, Scheme 3). Brown asym-
metric allylation[10] of 19 (87% ee, as determined by analysis
of the corresponding Mosherꢁs ester), followed by protec-
Scheme 3. Completion of the C3–C19 segment 3. a) (+)-Ipc2BAllyl, Et2O, À788C, 87% ee, 74%; b) PMBOC(=NH)CCl3, cyclohexane/CH2Cl2, BF3·OEt2,
08C, 87%; c) PdCl2 (cat), CuCl, O2, DMF/H2O, RT, 6 h, 86%; d) 1) LHDMS, TMSCl, THF, À788C; 2) 18, TiCl4, À788C, 68%; e) 1) BzCl, py (pyridine),
RT; 2) Nysted reagent, TiCl4, RT, 30 min, 66% for the two steps; f) 1) DIBAL, CH2Cl2, À788C; 2) MsCl (Ms=mesyl), Et3N, CH2Cl2, 08C; 3) DDQ,
CH2Cl2/H2O, 67% for the three steps; g) Et3N, CH3CN, reflux, 83%; h) NH4F, MeOH, 508C, 81%; i) DIPEA, MsCl, 90%.
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G.-Q. Lin, W.-S. Zhou et al.
Table 1. Construction of the cis-tetrahydropyrane moiety of 5.
tion of the newly formed tetrahydropyrane was confirmed
by 2D NOESY spectroscopic analysis. Selective deprotec-
tion (NH4F/MeOH, 508C)[29] of the TBS ether at C19, fol-
lowed by subsequent mesylation completed the synthesis of
segment 3.
Synthesis of the C20–C32 tetrahydropyrane-oxazole segment
5: As segment 5 contained contiguous stereogenic centers
bearing alternating hydroxyl and methyl substituents, it was
planned to utilize asymmetric crotyl addition reactions for
their construction (Scheme 4). Thus, the asymmetric crotyl
Entry
Conditions
35:36[a]
Yield [%][b]
[c]
1
2
3
4
I2, CH3CN, À35 to 08C
I2, NaHCO3, CH3CN, 08C
NIS, CH2Cl2, 308C
–
–
2.6:1
7.7:1
5:1
46
52[d]
86
Hg(OAc)2, toluene, 08C; I2, 308C
[a] The product ratio was determined by 1H NMR spectral analysis
(300 MHz). [b] Isolated yield. [c] Complex mixture. [d] Based on a 40%
recovery of the starting material.
After screening various solvents and reaction conditions, we
found that the treatment of diol 34 with Hg(OAc)2 in dry
toluene at 08C, followed by the treatment of the resulting
organomercurate with iodine, produced the cis-tetrahydro-
pyrane 35 in 86% yield with a 5:1 dr (dr=diastereomeric
ratio). Isolation of compound 35 was achieved by flash chro-
matography over silica gel, producing 35 in a 71% yield as
the major diastereomer. The configuration of 35 was later
confirmed by 2D NOESY spectroscopic analysis of oxazole
5.
Scheme 4. Iterative crotyl addition reactions. a) (À)-30, 4 Š MS, toluene,
À788C, 7 h, 65%; b) Ac2O, Et3N, DMAP (cat), CH2Cl2, RT, overnight,
95%; c) O3, MeOH, À788C; then PPh3, RT, 85%; d) (+)-30, 4 Š MS, tol-
uene, À788C, 6 h, 70%.
Protection of the hydroxyl group in 35 with p-methoxy-
benzyl trichloroacetimidiate[19] in the presence of BF3·OEt2
produced the PMB ether 37 (Scheme 5). This compound 37
was then converted to the nitrile 38, which was successively
reduced with DIBAL and NaBH4 to give alcohol 39.[36] Pro-
tection of the hydroxyl group in 39 with TBDPSCl[37] provid-
ed the ether 40, which was converted to aldehyde 41 by the
use of periodic acid.[38] Addition of MeLi to aldehyde 41,
followed by Dess–Martin oxidation, afforded methyl ketone
42. To complete the synthesis of oxazole 5, an E-selective
olefination reaction was required to construct the C27=C28
trisubstituted double bond. Although the Wittig[39] and Julia
olefination[40] reactions have been successfully employed in
the construction of E-double bonds, we found that our
methyl ketone reacted sluggishly under these reaction condi-
tions. Ultimately, we resorted to the procedure described by
Pattenden, in which the oxazole phosphonate ester 43 was
employed.[8e] To our delight, when the phosphonate ester 43
was deprotonated with LDA (lithium diisopropylamide) at
À788C, followed by treatment with methyl ketone 42, the
desired THP-oxazole (THP=tetrahydropyran) segment 5
was obtained in 78% yield (based on 20% recovery of the
starting material). The cis configuration of the tetrahydro-
pyrane in compound 5 was confirmed by the NOE effect ob-
served between H22, H24, and H26. The NOE effect be-
tween the C27 methyl group and H30 confirmed the E con-
figuration of the C27=C28 double bond.
addition of chiral boronate (À)-30 to 29 (generated from d-
mannitol),[30] under Roushꢁs conditions,[31] afforded homoal-
lylic alcohol 31.[32] This compound was subsequently trans-
formed to its acetate 32, according to the standard proce-
dure.[33] Asymmetric crotylation of aldehyde 33, obtained
from the ozonolysis of 32, was performed with (+)-30, fol-
lowed by treatment with sodium hydroxide.
1
To our surprise, H NMR spectroscopy of the product in-
À
dicated that the B O bond was not cleaved by the usual
workup procedure.[31] This problem was solved by treating
the product mixture with 10% NaOH in diethyl ether, in-
stead of toluene. This method resulted in the simultaneous
hydrolysis of the acetate to provide diol 34. For the con-
struction of the cis-tetrahydropyrane unit of 5, we first ex-
plored the iodocyclization[34] reaction of 34. However, iodo-
cyclization of diol 34 with iodine in acetonitrile yielded a
complex mixture (Table 1, entry 1), probably due to the la-
bility of the acetonide to the HI generated during the cycli-
zation process. Therefore, NaHCO3 was added to the reac-
tion mixture (entry 2) and, to our delight, the desired cis-tet-
rahydropyrane 35 and minor trans isomer 36 were obtained
in an overall yield of 46% (35:36 2.6:1). To optimize the ste-
reochemical outcome, NIS (N-iodosuccinimide) was em-
ployed (entry 3); however, despite an increase in the ratio
of 35/36 to 7.7:1, the overall yield of the reaction was still
unsatisfactory (52% based on a 40% recovery of the start-
ing material). With this in mind, our attention turned to the
Hg(OAc)2-induced cyclization, which is also known to be a
general method for preparing tetrahydropyrane systems.[35]
Synthesis of the C33–C41 lactone segment 6: Monosilylation
of 1,3-propanediol 44 and subsequent oxidation with PCC
(pyridinium chlorochromate), followed by olefination of the
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Phorboxazole B
FULL PAPER
Scheme 6. Synthesis of the C35–C41 segment. a) 1) NaH, TBSCl, THF,
08C; 2) PCC, CH2Cl2, RT; 3) Ph3P=CHCO2Et, benzene, reflux, 51% for
the three steps; b) AD-mix b, tBuOH/H2O, RT, 86 % ee, 87%;
c) 1) PMBOC(=NH)CCl3,
cyclohexane/CH2Cl2,
BF3·OEt2,
08C;
2) LiAlH4, Et2O, RT, 72% for the two steps; d) 1) (COCl)2, DMSO,
CH2Cl2, À788C; then Et3N; 2) CH3C(PPh3)CO2Et, CH2Cl2, reflux, 84%
for the two steps; e) 1) DIBAL, CH2Cl2, À788C; 2) Ac2O, Et3N, CH2Cl2,
RT, 90% for two steps; f) 1) Bu4NF, THF, RT; 2) Dess–Martin periodi-
nane, CH2Cl2, 86% for the two steps.
Scheme 5. Synthesis of oxazole 5. a) PMBOC(=NH)CCl3, BF3·OEt2, 08C,
79%; b) NaCN, DMSO, 708C, 81%; c) 1) DIBAL, CH2Cl2, 08C; then 1n
HCl; 2) NaBH4, MeOH, 72% for the two steps; d) TBDPSCl, Et3N,
CH2Cl2, 92%; e) HIO4, EtOAc; f) 1) MeLi, THF, À788C; 2) Dess–Martin
periodinane, CH2Cl2, RT, 58% for the three steps; g) LDA, THF, À788C,
78% based on the recovery of 42.
standard conditions (BF3·OEt2, MgBr2·OEt2). The use of
strong Lewis acids, such as TiCl4, did not promote a clean
reaction; however, the use of the mixed titanium species
TiCl2(OiPr)2 (toluene, À788C) delivered a high-yielding,
stereoselective reaction (87%, 4:1 dr)[42] that was consistent
with the results reported by Evans et al.[46] Compound 52
was isolated in 61% yield as the major diastereomer. The
orientation of the C35 hydroxyl group was assigned as b,
based on 2D NOESY spectroscopy of the succeeding lac-
tone 54. Several methylation methods to protect the free hy-
droxyl group in 52 proved unsuccessful; these methods in-
cluded the use of NaH/CH3I[47] and a catalyzed diazome-
thane procedure.[48] However, treatment of 52 with Meer-
weinꢁs salt (Me3OBF4)[6b] and 1,8-bis(dimethylamino)naph-
thalene (proton sponge) produced the desired methyl ether
53 in 85% yield.
Oxidative deprotection of the two vicinal PMB ethers in
53[49] proved difficult with reagents, such as DDQ (2,3-di-
chloro-5,6-dicyano-1,4-benzoquinone)[18] and CAN (ceric
ammonium nitrate).[50] Fortunately, when compound 53 was
treated with 10% CF3CO2H in CH2Cl2,[51] the PMB ethers
were removed and the resultant diol was spontaneously cy-
clized to afford lactone 54 in excellent yield (95%). The
NOE effect between H35 and H37 in lactone 54 convinced
us of the configuration of C35. Protection of the C38 free
hydroxyl as its TIPS (triisopropylsilyl) ether furnished lac-
tone 55.[52] The next step in the synthesis of lactone 6 was to
replace the C41 acetoxyl moiety in 55 with a TBS ether. Un-
fortunately, deprotection of the C41 acetoxy group in 55
resultant aldehyde, produced the unsaturated ester 45[41]
(E/Z >95:5, Scheme 6).[42] Sharpless asymmetric dihydroxy-
lation of 45 set the stereogenic centers at C37 and C38 in
place, affording the diol 46 in 87% yield (86% ee, as deter-
mined by chiral GC analysis).[43] Protection of the hydroxyl
groups of 46 with p-methoxybenzyl trichloroacetimidiate in
the presence of BF3·OEt2,[19] followed by reduction with
LAH (lithium aluminum hydride) afforded the alcohol 47.
As the PMB ether group appeared from the literature to
produce the best 1,3-stereoinduction in the Mukaiyama
aldol reaction, we selected this group for the protection of
the hydroxyl groups at C37 and C38.[21a,b] Swern oxidation[44]
of the hydroxyl group at C39 in 47, followed by Wittig olefi-
nation of the resulting aldehyde with CH3C(PPh3)CO2Et, in-
corporated the E-unsaturated ester in 48.[8a] Ester 48 was
conveniently transformed to the acetate 49 by reduction
with DIBAL and acylation of the resultant C41 hydroxyl
group.[33]
Hydrolysis of the TBS ether of 49, followed by oxidation
of the alcohol under Dess–Martin conditions yielded 50, a
b-OPMB-protected aldehyde suitable for the 1,3-anti Mu-
kaiyama aldol reaction. The aldol condensation of 1-ethoxy-
1-[(trimethylsilyl)oxy]ethane 51[45] with aldehyde 50
(Scheme 7) afforded 52 with modest stereoselectivity under
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G.-Q. Lin, W.-S. Zhou et al.
Scheme 8. Synthesis of sulfone 7. a) AD-mix-a, tBuOH/H2O, RT,
87% ee, 66%; b) 1) HBr, AcOH; 2) K2CO3, MeOH, 88%; c) 1) TMSCꢀ
CH, BuLi, BF3·OEt2, THF, À788C; 2) Me3OBF4, proton sponge, CH2Cl2,
RT, 70% for the two steps; d) CAN, CH3CN/H2O, RT, 91%; e) 2-mer-
captobenzothiazole, PPh3, DEAD (diethyl azodicarboxylate), THF, 08C,
81%; f) TBAF, THF, RT, 99%; g) 1) Cp2ZrHCl, THF; then NBS;
2) (NH4)6Mo7O24·4H2O, 30 % H2O2, EtOH, 56% for the two steps.
Scheme 7. Synthesis of lactone 6. a) TiCl2(OiPr)2, toluene, À788C; then
compound 51, 87%, 4:1 dr; b) Me3OBF4, proton sponge, CH2Cl2, RT,
85%; c) 10% CF3CO2H, CH2Cl2, RT, 95%; d) TIPSCl, imidazole,
DMAP (cat), DMF, RT, 78%; e) K2CO3, EtOH, 97%; f) 10% CF3CO2H,
CH2Cl2; then Et3N, 85%; g) TBSCl, Et3N, CH2Cl2, 75%; h) TIPSCl,
AgNO3, py, 78%.
acetylide in the presence of BF3·OEt2, followed by methyla-
tion of the resulting diol with Meerweinꢁs salt (Me3OBF4),
produced the corresponding methyl ether 63.[6b] Treatment
of 63 with CAN[56] removed the hydroquinone and produced
two equivalents of the known alcohol 64.[7d,8e] Displacement
of the primary alcohol of 64 with 2-mercaptobenzothiazole
and desilylation of the TMS group furnished the alkyne 66.
Finally, introduction of the vinyl bromide by hydrozircona-
tion of the alkyne and treatment with NBS (N-bromosucci-
nimide),[57] followed by oxidation of the sulfide with ammo-
nium molybdate,[6d] afforded the desired sulfone 7.
under basic conditions, such as K2CO3/EtOH[53] or K2CO3/
MeOH, did not afford the desired product 56, possibly as a
result of the susceptibility of the lactone moiety in 55 to
these reaction conditions. Alternatively, deprotection of the
acetoxy group in 53 with K2CO3/EtOH[53] afforded alcohol
57 in 97% yield. When compound 57 was treated with 10%
CF3CO2H in CH2Cl2,[51] the PMB-protecting groups were re-
moved, and the resultant triol concomitantly cyclized to
afford the lactone 58. As lactone 58 was highly soluble in
water, the reaction mixture was directly neutralized with
Et3N, concentrated, and then purified by flash-column chro-
matography without extraction. Selective protection of the
primary hydroxyl group in 58 with TBSCl/Et3N[54] delivered
the mono-TBS ether 59. Whilst protection of 59 with a TIPS
group under routine conditions (TIPSCl, imidazole, DMAP
(4-dimethylaminopyridine, cat), DMF)[52] was unsuccessful,
Completion of the total synthesis of phorboxazole B: With
segments 5, 6, and 7 in hand, the stage was set for the com-
pletion of the synthesis of phorboxazole B (Scheme 9).
Thus, oxazole 5 was deprotonated with lithium diethylamide
at À788C,[6a] and then treated with lactone 6 to produce the
desired cyclic hemiketal 67 in 61% yield as the sole isomer.
Selective deprotection of the TBS ether at C41 in 67 and
spontaneous methyl protection of the hemiketal was accom-
plished with PPTS (pyridinium p-toluene sulfonate)/MeOH
to afford the allylic primary alcohol 68. Careful oxidation of
68 with Dess–Martin periodinane,[14] followed by Julia olefi-
nation of the resulting aldehyde 69 with sulfone 7, furnished
the desired E-diene moiety (E/Z >95:5),[42] thus completing
the synthesis of the C20–C46 segment 70 of phorboxazole B.
Selective deprotection[29] of the TBDPS ether at C20 in 70,
[55]
the use of TIPSCl/AgNO3 afforded the desired lactone 6.
Synthesis of sulfone 7:[6,8,9] Following the procedure reported
by Wang,[56] Sharpless asymmetric dihydroxylation of 60 was
carried out to produce alcohol 61 (87% ee, as determined
by HPLC analysis); this was followed by epoxide formation
to give the optically active bis-3C building block 62
(Scheme 8). Ring opening of 62 by the use of lithium TMS
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Chem. Eur. J. 2006, 12, 1185 – 1204

Phorboxazole B
FULL PAPER
Scheme 9. Synthesis of the C20–C46 segment. a) LiNEt2, THF, À788C; then 6, 61%; b) PPTS, MeOH, 308C, 81%; c) Dess–Martin periodinane, py,
CH2Cl2, RT, 93%; d) NaHMDS, THF, À788C, 78%; e) 1) NH4F, MeOH, 508C; 2) Dess–Martin periodinane, py, CH2Cl2, RT, 71% for the two steps.
followed by subsequent oxidation gave the key aldehyde 4
in an overall 71% yield for the two steps.
COSY (500 MHz), HRMS, and IR spectra; [a]D) of our syn-
thetic material were identical to the corresponding spectral
data reported for phorboxazole B.[1,6d]
By using a strategy similar to that employed by Evans,[6]
Smith,[7] Pattenden,[8] and Williams,[9] we utilized an E-selec-
tive Wittig reaction to construct the C19=C20 double bond
(Scheme 10). Thus, treatment of the mesylate 3 with tributyl
phosphine led to the resulting phosphonium salt, which was
Conclusion
subsequently treated with aldehyde
4
and DBU (1,8-
We have accomplished the total synthesis of the potent anti-
tumor marine natural product phorboxazole B, based on an
efficient and convergent synthetic strategy. This synthesis
features: 1) a highly efficient substrate-controlled hydroge-
nation to construct the functionalized cis-tetrahydropyrane
unit; 2) iterative crotyl addition to synthesize the segment
containing the alternating hydroxyl and methyl substituents;
3) Hg(OAc)2/I2-induced cyclization to establish the cis-tetra-
hydropyrane moiety; 4) 1,3-asymmetric induction in the Mu-
kaiyama aldol reaction to generate the stereogenic centers
at C9 and C35; and 5) Still–Gennari olefination to complete
the macrolide ring of phorboxazoloe B.
diazabicyclo[5.4.0]undec-7-ene to afford the E-alkene 71
(E/Z >95:5).[42]
Following an extensive study, selective deprotection of the
TBDPS ether at C3 was achieved by using NH4F in MeOH
(508C) to afford 72. Oxidation of the alcohol and deprotec-
tion of the PMB ether at C24 with DDQ[18] produced com-
pound 73 in 73% yield. We envisaged using Still–Gennari
olefination[58] to construct the macrolide ring of phorboxazo-
loe B; the same strategy that had been used in the synthesis
of phorboxazole A.[5,7–9] Thus, esterification[59] of the C24 al-
cohol with dimethyl phosphonoacetic acid provided phos-
phonate 74. Intramolecular olefination of 74 in toluene
(K2CO3, [18]crown-6) effected a Z-selective macrolization to
afford a mixture of macrocycles (Z/E 5:1, a similar ratio to
that obtained in the synthesis of phorboxazole A[5,7–9]),
which were easily separated on silica gel to give Z-macrolide
75 in 56% yield.
Experimental Section
Optical rotations were measured by using a Perkin–Elmer 241MC polar-
imeter in the solvent indicated. IR spectra were recorded on an
1
AVATAR-360 spectrophotometer. H and 13C NMR spectra were record-
Finally, cleavage of the silyl ethers and the mixed methyl
acetal by sequential treatment of 75 with TBAF (tetrabuty-
lammonium fluoride)/THF and 6% aqueous HCl/THF[5]
produced phorboxazole B. The spectral data (1H NMR,
ed on MERCURY300, Bruker DRX-400, and Bruker AV-500 spectrome-
ters with TMS as the internal standard. HRMS were recorded by using
either FTMS-7 or IonSpec 4.7 spectrometers. Flash-column chromatogra-
phy was carried out on silica gel (300–400 mesh). Yields refer to chroma-
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G.-Q. Lin, W.-S. Zhou et al.
Scheme 10. Completion of the synthesis of phorboxazole B. a) Bu3P, DMF; then 4, DBU, RT, 70%; b) NH4F, MeOH, 508C, 71%; c) 1) Dess–Martin peri-
odinane, py, CH2Cl2, RT; 2) DDQ, CH2Cl2, buffer (pH 7), 73% for the two steps; d) dimethyl phosphonoacetic acid, DCC, CH2Cl2, 85%; e) K2CO3,
[18]crown-6, toluene, À208C, Z/E 5:1, 67%; f) 1) TBAF, THF, RT; 2) 6% HCl, THF, 51% for the two steps.
tographically and spectroscopically pure compounds, unless otherwise in-
dicated.
(3.88 g, 57.0 mmol) in DMF (12 mL). After stirring at RT for 3 h, the re-
action mixture was poured into water (100 mL) and extracted with Et2O
(3”200 mL). The combined organic extracts were then washed with
brine, dried over Na2SO4, and concentrated in vacuo. Chromatography of
the residue on silica gel (petroleum ether/EtOAc 20:1) provided 10
(7.66 g, 96%) as a colorless oil. Rf =0.60 (petroleum ether/EtOAc 6:1);
[a]2D0 =+15.7 (c=1.65 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.40–
7.36 (m, 2H), 7.02–6.98 (m, 2H), 6.01–5.80 (m, 1H), 5.19–5.17 (m, 1H),
5.15–5.13 (m, 1H), 4.57 (d, J=11.4 Hz, 1H; B of AB), 4.51 (d, J=
11.4 Hz, 1H, A of AB), 4.08–3.95 (m, 1H), 3.91 (s, 3H), 3.66–3.62 (m,
2H), 2.38–2.33 (m, 2H), 1.91–1.81 (m, 2H), 1.03 (s, 9H), 0.18 ppm (d, J=
2.7 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=159.0, 134.9, 130.6, 129.2
(2C), 116.9, 113.7 (2C), 72.6, 68.9, 66.7, 55.2, 42.3, 36.7, 25.8 (3C), 18.0,
À4.4, À4.8 ppm; IR (film): n˜ =3076, 2956, 2930, 2858, 1614, 1515,
1250 cmÀ1; HRMS (ESI): calcd for C20H34O3SiNa: 373.2169 [M+Na]+;
found: 373.2169.
Alcohol 9: A solution of allylmagnesium bromide (46.2 mmol) in Et2O
(80 mL) was added dropwise to a well-stirred solution of (À)-Ipc2BOMe
(15.4 g, 48.5 mmol) in anhydrous Et2O (300 mL). Following completion
of the addition, the reaction mixture was stirred for 1 h at RT, and was
then cooled to À788C. A solution of the aldehyde 8 (8.0 g, 41.0 mmol) in
anhydrous Et2O (80 mL) was added dropwise to this mixture, which was
subsequently stirred for a further 4 h at À788C. After this time, NaOH
(3n, 100 mL) was slowly added, followed by the addition of H2O2 (30%,
5 mL). The completion of the oxidation was ensured by refluxing the re-
action mixture for 2 h. Once the reaction was complete, water (100 mL)
was added and extracted with Et2O (2”200 mL). The combined organic
layers were washed with brine, dried over Na2SO4, and concentrated in
vacuo. Chromatography of the residue on silica gel (petroleum ether/
EtOAc 10:1) provided alcohol 9 (6.91 g, 71%) as a colorless oil. The en-
antiomeric excess was determined as 87% (AS, 230 nm, hexane/2-propa-
Ketone 11: Oxygen was bubbled into
a mixture of PdCl2 (18 mg,
nol 60:40, 0.7 mLminÀ1). Rf =0.46 (petroleum ether/EtOAc 4:1); [a]2D0
=
0.1 mmol), CuCl (99 mg, 1.0 mmol), DMF (7 mL), and water (1 mL) at
RT. The reaction mixture was stirred at RT for 30 min to give a deep-
green mixture, and then compound 10 (350 mg, 1.0 mmol) was added.
After the mixture had been vigorously stirred for a further 6 h under an
atmosphere of oxygen, water (5 mL) was added to quench the reaction,
and the resulting mixture was extracted with Et2O (4”15 mL). The com-
bined organic phases were washed with water (10 mL) and brine, dried
over Na2SO4, and concentrated in vacuo. Chromatography of the residue
on silica gel (petroleum ether/EtOAc 20:1) provided 11 (326 mg, 89%)
as a colorless oil. Rf =0.60 (petroleum ether/EtOAc 4:1); [a]2D0 =À6.9 (c=
0.85 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.23–7.21 (m, 2H),
À5.8 (c=1.37 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.23 (d, J=
8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 5.86–5.77 (m, 1H), 5.11–5.09 (m,
1H), 5.05 (d, J=1.2 Hz, 1H), 4.43 (s, 2H), 3.86–3.82 (m, 1H), 3.77 (s,
3H), 3.70–3.55 (m, 2H), 3.02 (brs, 1H), 2.24–2.20 (m, 2H), 1.75–
1.69 ppm (m, 2H); 13C NMR (75 MHz, CDCl3): d=159.1, 134.7, 129.9,
129.1 (2C), 117.3, 113.6 (2C), 72.7, 70.1, 68.4, 55.0, 41.7, 35.6 ppm; IR
(film): n˜ =3435, 3075, 2973, 2862, 1614, 1515, 1249 cmÀ1; HRMS (ESI):
calcd for C14H20O3Na: 259.1305 [M+Na]+; found: 259.1306.
Compound 10: tert-Butyldimethylsilyl chloride (4.13 g, 27.4 mmol) was
added to a stirred solution of alcohol 9 (5.38 g, 22.8 mmol) and imidazole
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Phorboxazole B
FULL PAPER
6.86–6.83 (m, 2H), 4.38–4.26 (m, 3H), 3.77 (s, 3H), 3.46 (m, 2H), 2.55
(m, 2H), 2.08 (s, 3H), 1.73 (m, 2H), 0.82 (s, 9H), 0.02 (s, 3H), 0.00 ppm
(s, 3H); 13C NMR (75 MHz, CDCl3): d=207.7, 159.0, 139.3, 129.1 (2C),
113.6 (2C), 72.4, 66.5, 66.1, 55.1, 51.1, 37.2, 31.5, 25.7 (3C), 17.8, À4.7,
À4.8 ppm; IR (film): n˜ =3001, 1718, 1614, 1587, 1515, 1250 cmÀ1; HRMS
(ESI): calcd for C20H34O4SiNa: 389.2118 [M+Na]+; found: 389.2117.
102.1, 76.4, 72.1, 64.4, 59.9, 56.4, 41.0, 34.0 ppm; IR (film): n˜ =3379, 1661,
1629, 1587, 1539, 1514 cmÀ1
; HRMS (ESI): calcd for C19H21O6NNa:
382.1244 [M+Na]+; found: 382.1261.
Pyranone 15: Imidazole (802 mg, 11.8 mmol) was added to a solution of
alcohol 14 (2.1 g, 5.9 mmol) in DMF (15 mL) under argon. After the mix-
ture had been stirred for 5 min, TBSCl (1.14 g, 7.6 mmol) was added and
the reaction mixture was stirred for a further 5 h at RT. After this time,
the mixture was quenched with water (10 mL) and extracted with Et2O
(4 ”30 mL). The combined organic extracts were washed with water (2”
10 mL) and brine, dried over Na2SO4, and then concentrated in vacuo.
Chromatography of the residue on silica gel (petroleum ether and
EtOAc 4:1) provided 15 (2.71 g, 97%) as a colorless oil. Rf =0.39 (petro-
leum ether/EtOAc 2:1); [a]2D0 =+98.1 (c=1.47 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.78 (s, 1H), 7.26–7.22 (m, 2H), 6.89–6.85 (m,
2H), 6.11 (s, 1H), 4.76 (s, 2H), 4.74–4.70 (m, 1H), 4.49 (AB, J=11.7 Hz,
1H; B of AB), 4.42 (AB, J=11.7 Hz, 1H; A of AB), 3.80 (s, 3H), 3.69–
3.57 (m, 2H), 2.56 (d, J=3.6 Hz, 1H), 2.54 (s, 1H), 2.16–2.12 (m, 1H),
2.04–1.99 (m, 1H), 0.90 (s, 9H), 0.11 ppm (s, 6H); 13C NMR (75 MHz,
CDCl3): d=192.5, 163.3, 162.9, 159.2, 139.1, 135.4, 129.3 (4C), 113.7,
102.8, 76.6, 72.7, 64.8, 58.1, 55.2, 41.6, 34.6, 25.6 (3C), 18.2, À5.5 ppm
(2C); IR (film): n˜ =3136, 3000, 1667, 1633, 1587 1514 cmÀ1; HRMS
(ESI): calcd for C25H35O6NSiNa: 496.2118 [M+Na]+; found: 496.2126.
Aldehyde 12: DIBAL (10.5 mmol, 1n solution in toluene) was added
dropwise to a solution of ethyl 2-[(tert-butyldimethylsilyloxy)methyl]oxa-
zole-4-carboxylate (2 g, 7.0 mmol) in anhydrous CH2Cl2 (20 mL) at
À788C. After the reaction mixture had been stirred for 30 min, MeOH
(3 mL) was added at À788C. The mixture was then diluted with CH2Cl2
(100 mL), and the organic layer was washed with HCl (1n), saturated
NaHCO3 solution, and brine. Finally, the organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. Purification of the residue
by flash chromatography on silica gel (petroleum ether/EtOAc 10:1) pro-
vided 12 (1.43 g, 85%) as a colorless oil. Rf =0.52 (petroleum ether/
EtOAc 6:1); 1H NMR (300 MHz, CDCl3): d=9.83 (s, 1H), 8.14 (s, 1H),
4.66 (s, 2H), 0.79 (s, 9H), 0.00 ppm (s, 6H); 13C NMR (75 MHz, CDCl3):
d=184.1, 163.9, 144.4, 140.7, 58.1, 25.7, 18.3 (3C), À5.4 ppm (2C); IR
(film): n˜ =3001, 1718, 1614, 1587, 1515, 1250 cmÀ1; HRMS (ESI): calcd
for C11H19O3NSiNa: 264.1026 [M+Na]+; found: 264.1030.
Diketone 13: A solution of ketone 11 (2.48 g, 6.8 mmol) in THF (6 mL)
Compound 16: CeCl3·7H2O (440 mg, 1.2 mmol) was added to a solution
of 15 (1.42 g, 3.0 mmol) in MeOH (20 mL) at RT. The resulting mixture
was then cooled to À788C and sodium borohydride (114 mg, 3.0 mmol)
was added. This mixture was stirred at À788C for 20 min, and was then
quenched with saturated aqueous NH4Cl solution (10 mL). Finally, the
mixture was extracted with EtOAc (2” 20 mL), and the combined organ-
ic layers were dried (MgSO4), filtered, and concentrated in vacuo. Chro-
matography of the residue on silica gel (petroleum ether/EtOAc 4:1) pro-
vided 16 (1.35 g, 95%) as a colorless oil. Rf =0.42 (petroleum ether/
EtOAc 1:1); [a]2D0 =+28.2 (c=1.30 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.51 (m, 1H), 7.26–7.23 (m, 2H), 6.88–6.84 (m, 2H), 5.56 (s,
1H), 4.63 (s, 2H), 4.58–4.52 (m, 1H), 4.44 (AB, J=12.0 Hz, 1H; B of
AB), 4.41 (AB, J=12.0 Hz, 1H; A of AB), 4.30–4.21 (m, 1H), 3.78 (s,
3H), 3.67–3.53 (m, 2H), 2.25–2.18 (m, 1H), 2.17–1.95 (brs, 1H), 1.95–
1.84 (m, 2H), 1.71–1.59 (m, 1H), 0.90 (s, 9H), 0.11 ppm (s, 6H);
13C NMR (75 MHz, CDCl3): d=162.5, 159.1, 146.0, 135.5, 135.3, 130.2
(2C), 129.2 (2C), 113.7, 102.6, 72.6, 72.4, 65.6, 63.2, 58.2, 55.2, 37.6, 35.0,
25.7 (3C), 18.3, À5.4 ppm (2C); IR (film): n˜ =3412, 1687, 1613, 1585,
was added dropwise to
a freshly prepared LDA solution [nBuLi
(5.13 mL, 8.2 mmol, 1.6m solution in hexanes) was added to a solution of
diisopropylamine (1.26 mL, 9 mmol) in THF (8 mL) at À788C under
argon]. The resulting mixture was warmed to 08C for 15 min and then
cooled to À788C. After stirring for 30 min at À788C, a solution of alde-
hyde 12 (1.49 g, 6.2 mmol) in THF (6 mL) was added dropwise. This mix-
ture was stirred for 3 h at À788C, and was then quenched with a phos-
phate buffer solution (10 mL, pH 7). The aqueous phase was extracted
with Et2O (3”100 mL), and the combined organic layers were dried
(MgSO4) and then concentrated in vacuo to give a residue. For the next
step in the synthesis, Dess–Martin periodinane (2.89 g, 6.82 mmol) was
added at RT to a solution of the residue in CH2Cl2 (100 mL), and the re-
sulting reaction mixture was stirred at RT for 30 min. After this time, the
reaction was quenched by the addition of saturated aqueous NaHCO3/
Na2S2O3 (5:1, 30 mL) and stirred for a further 15 min. Finally, the mixture
was extracted with CH2Cl2 (2”20 mL), and the combined organic layers
were washed with brine, dried over Na2SO4, filtered, and concentrated in
vacuo. Purification of the residue by flash chromatography on silica gel
(petroleum ether/EtOAc 20:1) provided ketone 13 (3.36 g, 90% overall
yield for the two steps) as a colorless oil. Rf =0.67 (petroleum ether/
EtOAc 4:1); [a]2D0 =À16.9 (c=1.51 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=8.14 (s, 1H), 7.26 (d, J=10.5 Hz, 2H), 6.87 (d, J=10.5 Hz,
2H), 6.28 (d, J=1.8 Hz, 1H), 4.77 (s, 2H), 4.44 (AB, J=11.4 Hz, 1H; B
of AB), 4.35 (AB, J=11.4 Hz, 1H; A of AB), 4.34–4.29 (m, 1H), 3.80 (s,
3H), 3.53 (t, J=6.6 Hz, 2H), 2.56–2.54 (m, 2H), 1.85–1.80 (m, 2H), 1.60
(brs, 1H), 0.91 (s, 9H), 0.83 (s, 9H), 0.12 (s, 6H), 0.03 ppm (d, J=9.6 Hz,
6H); 13C NMR (75 MHz, CDCl3): d=194.6, 176.3, 163.0, 159.1, 141.5,
137.9, 130.4 (2C), 129.2 (2C), 113.7, 99.0, 72.6, 67.3, 66.1, 58.1, 55.1, 47.4,
37.6, 25.7 (6C), 18.3, 18.0, À4.8 (2C), À5.4 ppm (2C); IR (film): n˜ =3157,
839, 780 cmÀ1
; HRMS (ESI): calcd for C25H37O6NSiNa: 498.2293
[M+Na]+; found: 498.2282.
Pyrane 17
Method A: Palladium on carbon (150 mg, 50% wet weight) was added to
a solution of 16 (521 mg, 1.1 mmol) in EtOAc (30 mL). Hydrogen was
then bubbled into the suspension, which was stirred for 8 h at RT. After
this time, the mixture was filtered through Celite and the resulting filtrate
was concentrated in vacuo. Chromatography of the residue on silica gel
(petroleum ether/EtOAc 4:1) provided 17 (Rf =0.29, petroleum ether/
EtOAc 1:1; 498 mg, 95%) as a colorless oil.
Method B: Palladium on carbon (150 mg, 50% wet weight) was added to
a solution of 15 (300 mg, 0.6 mmol) in EtOAc (30 mL, saturated with
0.1n HCl). Hydrogen was then bubbled into the reaction mixture, which
was stirred for 8 h at RT. After this time, the mixture was filtered
through Celite and the resulting filtrate was extracted with EtOAc (2”
20 mL). The combined organic extracts were washed with brine, dried
over Na2SO4, and concentrated in vacuo. Chromatography of the residue
on silica gel (petroleum ether/EtOAc 4:1) provided 17 (200 mg, 65%) as
a colorless oil. Rf =0.29 (petroleum ether/EtOAc 1:1); [a]2D0 =+29.6 (c=
1614, 1514, 1472, 1464, 1251, 1095 cmÀ1
; HRMS (ESI): calcd for
C31H51O7NSi2Na: 628.3081 [M+Na]+; found: 628.3096.
Alcohol 14: HF (1 mL, 40%) was added to a solution of ketone 13
(1.20 g, 1.98 mmol) in acetonitrile (20 mL) at RT. The resulting mixture
was stirred at RT for 24 h, and was then diluted with EtOAc (60 mL) and
neutralized with saturated aqueous NaHCO3 solution. The aqueous
phase was extracted with Et2O (3”5 mL), and the combined organic
layers were dried (MgSO4) and concentrated in vacuo. Chromatography
of the residue on silica gel (petroleum ether/EtOAc 2:1) provided 14
(640 mg, 90%) as a colorless oil. Rf =0.47 (petroleum ether/EtOAc 1:4);
[a]2D0 =+112.6 (c=1.45 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.77
(s, 1H), 7.45 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.11 (s, 1H),
4.75 (d, J=6.3 Hz, 2H), 4.72–4.71 (m, 1H), 4.49 (AB, J=11.4 Hz, 1H; B
of AB), 4.41 (AB, J=11.4 Hz, 1H; A of AB), 3.80 (s, 3H), 3.70–3.55 (m,
2H), 2.80 (t, J=6.0 Hz, 1H), 2.56 (d, J=4.2 Hz, 1H), 2.54 (s, 1H), 2.19–
2.10 (m, 1H), 2.05–1.96 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=
192.7, 163.9, 162.8, 158.7, 139.1, 134.8, 129.5 (2C), 128.9 (2C), 113.3,
1
0.75 in CHCl3); H NMR (CDCl3, 600 MHz): d=7.51 (s, 1H), 7.14 (d, J=
8.7 Hz, 2H), 6.75 (d, J=8.7 Hz, 2H), 4.73 (s, 2H), 4.42 (s, 2H), 4.36 (d,
J=10.5 Hz, 1H), 3.90–3.85 (m, 1H), 3.80 (s, 3H), 3.67–3.64 (m, 1H),
3.62–3.60 (m, 1H), 3.56–3.53 (m, 1H), 2.28 (dt, J=12.6, 2.4 Hz, 1H), 2.01
(dt, J=12.3, 2.4 Hz, 1H), 1.93–1.88 (m, 1H), 1.83–1.78 (m, 1H), 1.34
(appq, J=11.7 Hz, 1H), 1.28 (appq, J = 10.5 Hz, 1H), 0.92 (s, 9H),
0.10 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=162.5, 159.1, 141.2,
135.2, 130.5 (2C), 129.2 (2C), 113.7, 73.1, 72.5, 71.0, 67.8, 66.1, 58.3, 55.2,
40.9, 40.0, 36.0, 25.7 (3C), 18.3, À5.4 ppm (2C); IR (film): n˜ =3400, 1613,
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G.-Q. Lin, W.-S. Zhou et al.
1586, 1514, 1250, 1095, 839, 780 cmÀ1
;
HRMS (ESI): calcd for
aqueous NaHCO3 solution. The organic extracts were then combined,
washed with brine, dried over Na2SO4, and concentrated in vacuo. Chro-
matography of the residue on silica gel (petroleum ether/EtOAc 40:1)
provided 21 (4.07 g, 87%) as a colorless oil. Rf =0.44 (petroleum ether/
EtOAc 20:1); [a]2D0 =À10.8 (c=0.40 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.68–7.64 (m, 4H), 7.43–7.35 (m, 6H), 7.23–7.19 (m, 2H),
6.85–6.82 (m, 2H), 5.88–5.77 (m, 1H), 5.09 (d, J=6.3 Hz, 1H), 5.05 (t,
J=1.2 Hz, 1H), 4.49 (AB, J=11.1 Hz, 1H; B of AB), 4.38 (AB, J=
11.1 Hz, 1H; A of AB), 3.78 (s, 3H), 3.80–3.72 (m, 3H), 2.34–2.29 (m,
2H), 1.76 (appq, J=6.0 Hz, 2H), 1.05 ppm (s, 9H); 13C NMR (75 MHz,
CDCl3): d=159.0, 135.5 (4C), 134.9, 134.0, 133.9, 131.0, 129.7 (2C), 129.5
(2C), 127.6 (4C), 116.9, 113.7 (2C), 75.1, 70.8, 60.5, 55.2, 38.5, 37.0, 26.9
(3C), 19.2 ppm; IR (film): n˜ =3072, 3000, 1614, 1588, 1514, 1248,
C25H39O6NSiNa: 500.2430 [M+Na]+; found: 500.2439.
Aldehyde 18: Imidazole (355 mg, 5.2 mmol) and DMAP (24 mg,
0.2 mmol) were added sequentially to
a solution of 17 (415 mg,
0.85 mmol) in DMF (5 mL) under argon. After the reaction mixture had
been stirred for 5 min, tert-butyldimethylsilyl chloride (523 mg, 3.5 mmol)
was added, and the resulting mixture was stirred at RT overnight. After
this time, water (5 mL) was added to the mixture, which was subsequent-
ly extracted with Et2O (4”30 mL). The combined organic extracts were
washed with water (10 mL) and brine, dried over Na2SO4, and then con-
centrated in vacuo to give a residue. DDQ (194 mg, 0.85 mmol) was
added to a solution of the dissolved residue in CH2Cl2 (10 mL) and
buffer (0.5 mL, pH 7) at RT. After the reaction mixture had been stirred
for 2 h at RT, the reaction was quenched with saturated aqueous
NaHCO3 (10 mL) and then extracted with CH2Cl2 (2”20 mL). The com-
bined organic extracts were dried over Na2SO4 and concentrated in
1112 cmÀ1
;
HRMS (MALDI): calcd for C30H38O4SiNa: 497.2482
[M+Na]+; found: 497.2500.
Ketone 22: Oxygen was bubbled into
a mixture of PdCl2 (56 mg,
vacuo to give
a
second residue. Dess–Martin periodinane (300 mg,
0.31 mmol), CuCl (312 mg, 3.15 mmol), DMF (56 mL), and distilled
water (8 mL) to activate the reaction mixture. This mixture was then stir-
red for 30 min and was observed to turn black. Compound 21 (1.49 g,
3.14 mmol) was added to this mixture, which was vigorously stirred for
12 h. After this time, water (30 mL) was added to quench the reaction,
and the resulting mixture was extracted with Et2O (4”80 mL). The com-
bined organic phases were washed with water (10 mL) and brine, dried
over Na2SO4, and then concentrated in vacuo. Chromatography of the
residue on silica gel (petroleum ether/EtOAc 20:1) provided 22 (1.33 g,
0.7 mmol) was added to a solution of the dissolved residue in CH2Cl2
(10 mL) at RT. After the mixture had been stirred at RT for 30 min, a
mixture of saturated aqueous NaHCO3/Na2SO3 5:1 was added, and the
resulting mixture was stirred for a further 20 min until the two phases
were clear. Once this had occurred, the mixture was extracted with
CH2Cl2 (2”20 mL), and the combined organic extracts were washed with
brine, dried over Na2SO4, and concentrated in vacuo. Chromatography of
the residue on silica gel (petroleum ether/EtOAc 20:1) provided com-
pound 18 (326 mg, 82% overall yield for the three steps) as a colorless
oil. Rf =0.56 (petroleum ether/EtOAc 4:1); [a]2D0 =+3.7 (c=0.59 in
86%) as a colorless oil. Rf =0.47 (petroleum ether/EtOAc 4:1); [a]D20
=
+4.8 (c=1.49 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.68–7.65 (m,
4H), 7.43–7.38 (m, 6H), 7.15 (d, J=9.0 Hz, 2H), 6.82 (d, J=8.1 Hz, 2H),
4.42 (s, 2H), 4.16 (appq, J=6.0 Hz, 1H), 3.79 (s, 3H), 3.69–3.86 (m, 2H),
2.74 (dd, J=8.1, 16.2 Hz, 1H; B of AB-d), 2.54 (dd, J=4.8, 16.2 Hz, 1H;
A of AB-d), 2.13 (s, 3H), 1.82–1.71 (m, 2H), 1.05 ppm (s, 9H); 13C NMR
(75 MHz, CDCl3): d=207.3, 159.2, 135.6 (4C), 133.8, 133.7, 130.6, 129.6
(2C), 129.3 (2C), 127.6 (4C), 113.7 (2C), 72.6, 71.4, 60.3, 55.2, 48.9, 37.2,
31.0, 26.8 (3C), 19.1 ppm; IR (film): n˜ =3072, 3000, 1718, 1614, 1588,
1515 cmÀ1; HRMS (ESI): calcd for C30H38O4SiNa: 513.2427 [M+Na]+;
found: 513.2432.
1
CHCl3); H NMR (300 MHz, CDCl3): d=9.80 (t, J=2.4 Hz, 1H), 7.51 (s,
1H), 4.71 (s, 2H), 4.42 (dd, J=11.4, 1.2 Hz, 1H), 4.05–4.01 (m, 1H),
3.93–3.89 (m, 1H), 2.73 (ddd, J=18.0, 7.5, 2.4 Hz, 1H), 2.54 (ddd, J=
16.8, 5.1, 1.5 Hz, 1H), 2.17 (dt, J=12.9, 2.1 Hz, 1H), 1.92 (dt, J=10.8,
2.4 Hz, 1H), 1.82 (brs, 1H), 1.58 (appq, J=12.0 Hz, 1H), 1.38 (appq, J=
12.0 Hz, 1H), 0.89 (s, 9H), 0.87 (s, 9H), 0.08 (s, 6H), 0.06 ppm (s, 6H);
13C NMR (75 MHz, CDCl3): d=200.7, 162.5, 141.0, 135.2, 71.5, 71.2, 67.9,
58.3, 49.4, 41.1, 40.1, 25.9 (6C), 18.3, 17.9, À4.5 (2C), À4.6 ppm (2C); IR
(film): n˜ =2728, 1729, 1576, 1473, 1464, 1257, 1096, 838, 778 cmÀ1; HRMS
(ESI): calcd for C23H43O5NSi2Na: 492.2565 [M+Na]+; found: 492.2572.
Compound 23: LiHMDS (lithium hexamethyldisilazide, 0.6 mmol, 1.0m
in THF) and TMSCl (0.075 mL, 0.6 mmol) were added sequentially to a
precooled solution of compound 22 (303 mg, 0.6 mmol) in anhydrous
THF (5 mL) at À788C. The reaction was then quenched with buffer solu-
tion (5 mL, pH 7) and extracted with Et2O (4”80 mL). The combined or-
ganic phases were washed with water (10 mL) and brine, dried over
Na2SO4, and then concentrated in vacuo. For the next step in the synthe-
sis, TiCl4 (0.066 mL, 0.6 mmol) was added to a precooled solution of alde-
hyde 18 (243 mg, 0.5 mmol) in THF (5 mL) at À788C. The resulting mix-
ture was stirred for 30 min at À788C, and then a solution of the TMS
ether (produced above) in THF (3 mL) was added. After the reaction
had been stirred at À788C for 2 h, the reaction was quenched with buffer
solution (5 mL, pH 7), and the aqueous phase was extracted with Et2O
(3”20 mL). The combined organic layers were dried (Na2SO4) and then
concentrated in vacuo. Purification by flash-column chromatography on
silica gel (petroleum ether/EtOAc 10:1) provided 23 (334 mg, 68%) as a
Alcohol 20: A solution of allylmagnesium bromide (46.2 mmol) in Et2O
(80 mL) was added dropwise to a well-stirred solution of (+)-Ipc2BOMe
(15.4 g, 48.5 mmol) in anhydrous Et2O (300 mL) at 08C under argon.
After completion of the addition, the reaction mixture was stirred for 1 h
at RT, and then cooled to À788C and a solution of aldehyde 19 (13.0 g,
41.7 mmol) in anhydrous Et2O (80 mL) was added dropwise to the mix-
ture. The resulting reaction mixture was stirred for 4 h at À788C, and
then NaOH (3n, 100 mL) was slowly added, followed by 30% H2O2
(5 mL). The completion of the oxidation was ensured by refluxing the re-
action mixture for 2 h. After this time, water (100 mL) was added to the
reaction mixture, which was subsequently extracted with Et2O (2”
200 mL), washed with brine, dried over Na2SO4, and then concentrated
in vacuo. Chromatography of the residue on silica gel (petroleum ether/
EtOAc 20:1) provided alcohol 20 (10.9 g, 74%) with 87% ee (determined
by analysis of the corresponding Mosherꢁs ester) as a colorless oil. Rf =
0.51 (petroleum ether/EtOAc 10:1); [a]2D0 =+3.6 (c=2.11 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.71–7.66 (m, 4H), 7.46–7.36 (m, 6H),
5.89–5.80 (m, 1H), 5.14–5.10 (m, 1H), 5.07 (s, 1H), 3.98–3.94 (m, 1H),
3.90–3.83 (m, 2H), 3.31 (d, J=1.5 Hz, 1H), 2.29–2.24 (m, 2H), 1.75–1.67
(m, 2H), 1.05 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=135.5 (4C),
134.9, 133.1, 133.0, 129.8 (2C), 127.7 (4C), 117.4, 70.7, 63.2, 41.9, 37.9,
26.8 (3C), 19.0 ppm; IR (film): n˜ =3352, 3074, 3053, 2935, 2860,
1429 cmÀ1; HRMS (ESI): calcd for C22H30O2SiNa: 377.1907 [M+Na]+;
found: 377.1906.
1
colorless oil. Rf =0.39 (petroleum ether/EtOAc 4:1); H NMR (300 MHz,
CDCl3): d=7.67–7.63 (m, 4H), 7.52 (s, 1H), 7.43–7.37 (m, 6H), 7.13 (d,
J=8.7 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 4.71 (d, J=1.2 Hz, 2H), 4.39
(brs, 2H), 4.40–4.22 (m, 2H), 4.15 (m, 1H), 3.89 (m, 1H), 3.78 (s, 3H),
3.80–3.62 (m, 3H), 3.37 (brs, 1H), 2.71 (dd, J=15.3, 7.5 Hz, 1H), 2.54–
2.49 (m, 3H), 2.17 (m, 1H), 1.81–1.59 (m, 6H), 1.38 (m, 1H), 1.04 (s,
9H), 0.90 (s, 9H), 0.88 (s, 9H), 0.09 (s, 6H), 0.07 ppm (s, 6H); 13C NMR
(125 MHz, CDCl3): d=210.3, 162.4, 159.2, 141.6, 135.5 (4C), 135.0, 133.7,
133.6, 130.4, 129.6 (2C), 129.4 (2C), 127.6 (4C), 113.8 (2C), 72.9, 72.5,
71.5, 71.4, 68.4, 64.5, 60.2, 58.3, 55.2, 50.7, 48.7, 42.3, 41.7, 40.5, 37.1, 26.9
(3C), 25.8 (3C), 25.7(3C), 19.1, 18.3, 18.0, À4.5 (2C), À5.3 ppm (2C); IR
Compound 21: BF3·Et2O (3 mL, 0.1m in CH2Cl2) was added dropwise to
a mixture of the alcohol 20 (3.54 g, 10.0 mmol) and Cl3CC(NH)OPMB
(30 mL, 0.4m in hexane) in dry CH2Cl2 (15 mL) at 08C under a nitrogen
atmosphere. A significant quantity of a white solid immediately precipi-
tated, and the mixture was stirred at 08C for 30 min. After this time, the
suspension was filtered and the solid was washed with a mixture of
CH2Cl2/hexane (1:2, 2”5 mL). The filtrate was washed with saturated
(film): n˜ =3500, 3072, 1710, 1614, 1588, 1515, 1251, 1112, 838, 778 cmÀ1
;
HRMS (ESI): calcd for C53H81O9NSi2Na: 982.5132 [M+Na]+; found:
982.5111.
Compound 24: DMAP (12 mg) and benzoyl chloride (0.14 mL,
1.2 mmol) were added sequentially to a solution of 23 (575 mg, 0.6 mmol)
1194
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 1185 – 1204

Phorboxazole B
FULL PAPER
in dry pyridine (2 mL). After the reaction mixture had been stirred at RT
for 3 h, it was diluted with EtOAc (100 mL), washed with saturated
CuSO4 solution and brine, dried over Na2SO4, and concentrated in vacuo
to give a residue. For the next step in the synthesis, powdered molecular
sieves (400 mg, 4 Š) and a preprepared quantity of the methylenation re-
agent [a solution of TiCl4 (3.8 mL, 1.2 mmol) in anhydrous THF (8 mL)
was stirred at 08C under argon for 10 min and then at RT for 20 min;
Nysted reagent (5.2 mL, 4.2 mmol) was then added at 08C, and the re-
sulting mixture was stirred for a further 30 min at RT to afford the meth-
ylenation reagent as a brown/red mixture] were added sequentially at
08C to a solution of the residue in anhydrous THF (10 mL). The reaction
mixture produced was stirred at 08C for 15 min and then at RT for 3 h;
after which time, the mixture was poured into saturated aqueous
NaHCO3 (30 mL, ice-cold). Finally, the mixture was extracted with
EtOAc (30 mL), and the organic layer was dried (Na2SO4) and concen-
trated in vacuo. Chromatography of the residue on silica gel (petroleum
ether/EtOAc 60:1) provided 24 (411 mg, 66% overall yield for the two
water (5 mL) was added to the reaction mixture, which was then extract-
ed with EtOAc (2”15 mL), washed with brine, dried over Na2SO4, and
finally concentrated in vacuo. Purification of the residue by flash chroma-
tography (petroleum ether 20:1) provided 27 (16 mg, 83%) as a colorless
oil. Rf =0.49 (petroleum ether/EtOAc 10:1); [a]2D5 =À14.2 (c=0.35 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.68–7.65 (m, 4H), 7.47 (s,
1H), 7.40–7.37 (m, 6H), 4.72 (d, J=5.4 Hz, 2H), 4.72 (s, 2H), 4.27 (d, J=
10.8 Hz, 1H), 4.02 (appq, J=6.0 Hz, 1H), 3.93 (appq, J=6.0 Hz, 1H),
3.83–3.67 (m, 3H), 3.55–3.49 (m, 1H), 2.36 (brs, 1H), 2.35 (brs, 1H),
2.16–2.12 (m, 1H), 2.07–1.95 (m, 3H), 1.92–1.88 (m, 1H), 1.85–1.79 (m,
1H), 1.70–1.62 (m, 1H), 1.54–1.48 (m, 2H), 1.33–1.20 (m, 1H), 1.04 (s,
9H), 0.89 (s, 9H), 0.86 (s, 9H), 0.09 (s, 6H), 0.034 (s, 3H), 0.028 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=162.4, 142.2, 141.8, 135.7 (4C),
135.2, 135.0, 134.0, 129.7 (2C), 127.8 (2C), 127.7 (2C), 110.4, 73.0, 71.4,
69.0, 68.7, 68.6, 60.7, 58.5, 41.2, 40.8, 40.0, 39.6, 39.4, 36.5, 27.0 (3C), 25.8
(6C), 19.3, 18.5, 18.1, À4.4 (2C), À5.3 ppm (2C); IR (film): n˜ =3073,
1655, 1429, 1255, 1093, 1112 cmÀ1; HRMS (ESI): calcd for C46H73O6NSi3-
Na: 842.4633 [M+Na]+; found: 842.4638.
steps) as a colorless oil. Rf =0.60 (petroleum ether/EtOAc 7:1); [a]D20
=
+13.3 (c=1.10 in CHCl3); 1H NMR (300 MHz, CDCl3): d=8.01 (d, J=
6.6 Hz, 2H), 7.66–7.62 (m, 4H), 7.52–7.50 (m, 2H), 7.43–7.35 (m, 8H),
7.10 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H), 5.62–5.51 (m, 1H), 4.89
(s, 1H), 4.86 (s, 1H), 4.69 (s, 2H), 4.40 (d, J=10.8 Hz, 1H; B of AB),
4.29 (d, J=10.8 Hz, 1H; A of AB), 4.28 (d, J=11.7 Hz, 1H), 3.86–3.68
(m, 4H), 3.76 (s, 3H), 3.57–3.51 (brt, 1H), 2.49–2.35 (m, 3H), 2.23–2.16
(m, 2H), 2.00–1.62 (m, 5H), 1.51 (appq, J=12.0 Hz, 1H), 1.35 (appq, J=
11.4 Hz, 1H), 1.03 (s, 9H), 0.90 (s, 9H), 0.84 (s, 9H), 0.09 (s, 6H),
0.08 ppm (d, J=3.6 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=166.1,
162.4, 159.2, 142.6, 142.6, 141.7, 135.8 (4C), 135.4, 134.1, 133.0, 131.1,
130.8, 129.8 (2C), 129.7 (2C), 129.6 (2C), 129.5 (2C), 128.5, 127.8 (2C),
115.6, 113.9 (4C), 74.6, 73.2, 71.7, 71.0, 70.5, 68.5, 60.7, 58.6, 55.4, 42.2,
42.1, 41.0, 40.8, 37.4, 27.1 (3C), 26.0 (6C), 19.4, 18.6, 18.2, À4.4 (2C),
À5.2 ppm (2C); IR (film): n˜ =3072, 1717, 1647, 1613, 1587 cmÀ1; HRMS
(ESI): calcd for C61H87O9NSi3Na: 1062.5760 [M+Na]+; found: 1062.5761.
Alcohol 28: NH4F (77 mg, 2.1 mmol) was added to a solution of 27
(107 mg, 0.13 mmol) in MeOH (2.0 mL). The resulting mixture was im-
mediately heated to 508C and then stirred for another 25 min. After this
time, the mixture was quenched with saturated NH4Cl solution and then
diluted with EtOAc (200 mL). The organic layer produced was washed
with brine, dried (Na2SO4), and concentrated in vacuo. Chromatography
of the residue on silica gel (petroleum ether/EtOAc 4:1) provided 28
(74 mg, 81%) as a colorless oil. Rf =0.40 (petroleum ether/EtOAc 2:1);
[a]2D5 =À19.0 (c=0.55 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.70–
7.65 (m, 4H), 7.47 (s, 1H), 7.45–7.27 (m, 6H), 4.74 (s, 2H), 4.70 (s, 2H),
4.28 (d, J=11.7 Hz, 1H), 4.04 (m, 1H), 3.93 (s, 1H), 3.72–3.38 (m, 3H),
3.54–3.50 (m, 1H), 3.15 (brs, 1H), 2.77–2.33 (m, 2H), 2.10–0.80 (m, 6H),
1.80–1.60 (m, 3H), 1.30–1.10 (m, 1H), 1.04 (s, 9H), 0.87 (s, 9H),
0.04 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=163.0, 142.0, 141.7,
135.5 (4C), 135.1, 133.8 (2C), 129.6 (2C), 127.6 (4C), 110.3, 72.9, 71.1,
68.9, 68.6, 68.4, 60.5, 57.5, 41.1, 40.6, 39.7, 39.5, 39.3, 36.4, 26.9 (3C), 25.8
(3C), 19.2, 18.0, À4.5 ppm (2C); IR (film): n˜ =3300, 2952, 2931,
1473 cmÀ1; HRMS (ESI): calcd for C40H59O6NSi2Na: 728.3773 [M+Na]+;
found: 728.3774.
Compound 26: DIBAL (0.25 mL, 0.25 mmol, 1m in toluene) was added
dropwise at À788C to a solution of 24 (56 mg, 0.054 mmol) in dry CH2Cl2
(3 mL). After the reaction mixture had been stirred at À788C for 1 h, the
reaction was quenched with MeOH (0.25 mL), and then MgSO4 (3 g) and
Et2O (100 mL) were added. The resulting suspension was stirred at RT
for 3 h, and then filtered through Celite. This filtrate was concentrated in
vacuo to give a residue. For the next step in the synthesis, triethylamine
(0.3 mL) was added to a solution of the residue in anhydrous CH2Cl2
(3 mL). Methanesulfonyl chloride (0.1 mL, 1.4 mmol) was added to the
mixture above, which had been precooled to 08C, and the mixture was
stirred at 08C for a further 30 min. After this time, the mixture was dilut-
ed with EtOAc (50 mL), washed with water (10 mL) and brine, dried
over Na2SO4, and then concentrated in vacuo to give a second residue.
Buffer (0.5 mL, pH 7) and DDQ (18 mg, 0.08 mmol) were added to a so-
lution of this residue in CH2Cl2 (2 mL) at RT. The mixture was stirred
vigorously for 2 h, and then quenched with saturated aqueous sodium bi-
carbonate (2 mL). The separated aqueous phase was extracted with
CH2Cl2 (20 mL), and the combined organic extracts were dried and then
evaporated to dryness in vacuo. Purification by chromatography (EtOAc/
petroleum ether 10:1) gave 26 (32 mg, 67% yield for three steps) as a
colorless oil. Rf =0.58 (petroleum ether/EtOAc 4:1); [a]2D0 =+13.0 (c=0.3
in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.68–7.65 (m, 4H), 7.56 (s,
1H), 7.44–7.37 (m, 6H), 5.12–5.02 (m, 1H), 4.97 (s, 1H), 4.95 (s, 1H),
4.71 (s, 2H), 4.34 (d, J=12.6 Hz, 1H), 4.11–4.02 (m, 1H), 3.93–3.83 (m,
3H), 3.66 (brt, J=10.2 Hz, 1H), 3.41 (d, J=1.8 Hz, 1H), 3.00 (s, 3H),
2.63 (dd, J=14.1, 5.7 Hz, 1H), 2.48 (dd, J=14.1, 7.2 Hz, 1H), 2.31–2.16
(m, 3H), 1.94–1.64 (m, 5H), 1.58 (appq, J=12.0 Hz, 1H), 1.34 (appq, J=
11.4 Hz, 1H), 1.04 (s, 9H), 0.90 (s, 9H), 0.88 (s, 9H), 0.09 (s, 6H),
0.07 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=162.5, 141.8, 141.4,
135.5 (4C), 135.3, 133.0, 129.8 (2C), 127.7 (4C), 116.3, 78.8, 71.6, 71.2,
71.1, 69.6, 68.2, 63.2, 58.3, 44.1, 42.6, 41.5, 40.5, 40.2, 38.3, 38.1, 26.8 (3C),
25.8 (3C), 25.7 (3C), 19.0, 18.3, 18.0, À4.6 (2C), À5.4 ppm (2C); IR
Segment 3: Diisopropylethylamine (DIPEA, 130 mL, 0.78 mmol) and
methanesulfonyl chloride (36 mL, 0.47 mmol) were added to a solution of
28 (280 mg, 0.39 mmol) in dry CH2Cl2 (8 mL), which had been precooled
in an ice-salt bath. The resulting mixture was stirred for another 1.5 h,
and then run through a short pad of silica gel, eluting with petroleum
ether/EtOAc 10:1, to provide 3 (331 mg, 90%) as a colorless oil. Rf =0.39
1
(petroleum ether/EtOAc 4:1); [a]2D5 =À20.1 (c=0.45 in CHCl3); H NMR
(300 MHz, CDCl3): d=7.69–7.65 (m, 4H), 7.56 (s, 1H), 7.45–7.36 (m,
6H), 5.26 (s, 2H), 4.47 (s, 2H), 4.28 (d, J=10.8 Hz, 1H), 4.06–4.03 (m,
1H), 3.96–3.88 (m, 1H), 3.88–3.71 (m, 3H), 3.61–3.50 (m, 1H), 3.08 (s,
3H), 2.35 (dd, J=13.2, 3.6 Hz, 2H), 2.20–1.80 (m, 6H), 1.78–1.40 (m,
3H), 1.39–1.20 (m, 1H), 1.04 (s, 9H), 0.87 (s, 9H), 0.05 (s, 3H), 0.05 ppm
(s, 3H); 13C NMR (75 MHz, CDCl3): d=156.5, 142.9, 142.0, 136.6, 135.5
(4C), 133.9 (2C), 129.6 (2C), 127.6 (4C), 110.3, 73.0, 71.0, 68.9, 68.6,
68.3, 61.9, 60.5, 41.1, 40.6, 39.7, 39.5, 39.3, 38.4, 36.4, 26.9(3C), 25.8 (3C),
19.2 (2C), À4.4 ppm (2C); IR (film): n˜ =2953, 2931, 2858, 1363 cmÀ1
;
HRMS (ESI): calcd for C41H62O8NSSi2: 784.3729 [M+H]+; found:
784.3728.
Alcohol 31: Compound (À)-30 (158 mL, 158 mmol, 1.0m solution in tolu-
ene) was added dropwise to a slurry of powdered molecular sieves (14 g,
4 Š) in anhydrous toluene (50 mL) under argon at RT. After the result-
ing reaction mixture had been stirred for 30 min at RT, it was cooled to
À788C and a solution of 29 (10.19 g, 78.3 mmol) in toluene (75 mL) was
added dropwise over 1 h. The reaction mixture was stirred at À788C for
10 h, and was then quenched with NaOH (2n, 145 mL). This mixture was
stirred for a further 15 min at RT, before being filtered. The aqueous
layer was extracted with Et2O (3”200 mL), and the resulting organic ex-
tracts were combined and concentrated in vacuo. Chromatography of the
residue on silica gel (petroleum ether/EtOAc 20:1) provided 31 as color-
(film): n˜ =3359, 3073, 1653, 1590 cmÀ1
C47H77O8NSSi3Na: 922.4570 [M+Na]+; found: 922.4575.
Compound 27: solution of 26 (22.0 mg, 0.024 mmol), acetonitrile
(5 mL), and triethylamine (1 mL) was refluxed for 24 h. After this time,
; HRMS (ESI): calcd for
A
less oil (9.46 g, 65%). Rf =0.46 (petroleum ether/EtOAc 10:1); [a]D25
+20.3 (c=0.80 in CHCl3); H NMR (300 MHz, CDCl3): d=5.94–5.82 (m,
=
1
Chem. Eur. J. 2006, 12, 1185 – 1204
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1195

G.-Q. Lin, W.-S. Zhou et al.
1H), 5.10–5.02 (m, 2H), 4.11 (q, J=6.3 Hz, 1H), 4.01 (dd, J=8.1, 6.3 Hz,
1H), 3.74 (dd, J=7.8, 7.2 Hz, 1H), 3.40 (q, J=5.1 Hz, 1H), 2.30–2.22 (m,
1H), 1.43 (s, 3H), 1.37 (s, 3H), 1.11 ppm (d, J=6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=139.5, 115.3, 109.1, 77.1, 75.2, 66.0, 41.2, 26.5, 25.4,
16.7 ppm; IR (film): n˜ =3490, 2986, 1640, 1457, 1372 cmÀ1; HRMS (ESI):
calcd for C10H18O3Na: 209.1148 [M+Na]+; found: 209.1148.
was added. The resulting mixture was then warmed to RT and stirred for
12 h. After this time, the mixture was quenched with a mixture of saturat-
ed aqueous NaHCO3/Na2S2O3 5:1, and the organic and aqueous layers
were separated. The aqueous phase was extracted with EtOAc (100 mL),
and then the organic extracts were combined and washed with brine,
dried over Na2SO4, and concentrated in vacuo. Chromatography of the
residue on silica gel (petroleum ether/EtOAc 4:1) provided 35 (1.06 g,
71%) and 36 (0.212 g, 14%) as colorless oils.
Ester 32: DMAP (0.060 g, 0.049 mmol) and triethylamine (3.0 mL,
21.24 mmol) were added sequentially to
a solution of 31 (0.658 g,
3.54 mmol) in CH2Cl2 (20 mL). The reaction mixture was then cooled to
08C, and acetyl anhydride (1.0 mL, 10.62 mmol) was added dropwise;
this mixture was stirred at RT overnight. After this time, the mixture was
diluted with CH2Cl2 (100 mL) and washed with H2O (3”10 mL), saturat-
ed aqueous NaHCO3 solution (10 mL), and brine (10 mL). Finally, the
mixture was dried over Na2SO4 and then concentrated in vacuo. Chroma-
tography of the residue on silica gel (petroleum ether/EtOAc 20:1) pro-
vided 32 (0.766 g, 95%) as a colorless oil. Rf =0.53 (petroleum ether/
EtOAc 10:1); [a]2D0 =+9.8 (c=1.0 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=5.79–5.67 (m, 1H), 5.08–5.01 (m, 2H), 4.88 (t, J=6.0 Hz,
1H), 4.23 (q, J=6.3 Hz, 1H), 4.01 (dd, J=8.4, 6.6 Hz, 1H), 3.66 (dd, J=
8.1, 6.3 Hz, 1H), 2.50–2.40 (m, 1H), 2.10 (s, 3H), 1.42 (s, 3H), 1.35 (s,
3H), 1.06 ppm (d, J=4.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=170.6,
139.1, 115.7, 109.5, 75.8, 75.2, 65.7, 39.8, 26.1, 25.5, 20.9, 16.8 ppm; IR
(film): n˜ =1742, 1643, 1238, 1065, 1025 cmÀ1; HRMS (ESI): calcd for
C12H20O4Na: 251.1254 [M+Na]+; found: 251.1257.
Compound 35: Rf =0.36 (petroleum ether/EtOAc 2:1); [a]2D0 =+70.3 (c=
0.65 in CHCl3); 1H NMR (300 MHz, CDCl3): d=4.32–4.21 (m, 2H), 4.00
(dd, J=6.9, 6.9 Hz, 1H), 3.59–3.54 (m, 1H), 3.45–3.38 (m, 1H), 3.28 and
3.10 (AB of ABX, JAB =9.9, JAX =9.9, JBX =5.4 Hz), 2.92 (dd, J=10.2,
1.8 Hz, 1H), 2.22–2.14 (m, 1H), 1.94–1.84 (m, 1H), 1.68 (d, J=5.7 Hz,
1H), 1.39 (d, J=5.4 Hz, 6H), 1.01 (d, J=6.3 Hz, 3H), 0.87 ppm (d, J=
6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=109.1, 79.9, 78.8, 76.3, 74.7,
65.3, 38.2, 33.5, 26.1, 25.7, 12.4, 5.8, 5.5 ppm; IR (film): n˜ =3455, 2983,
1458, 1379 cmÀ1
; HRMS (ESI): calcd for C13H23O4NaI: 393.0533
[M+Na]+; found: 393.0535.
Compound 36: Rf =0.34 (petroleum ether/EtOAc 2:1); [a]2D0 =+4.1 (c=
0.97 in CHCl3); 1H NMR (300 MHz, CDCl3): d=4.34–4.31 (m, 1H),
4.13–4.02 (m, 2H), 3.63–3.59 (m, 1H), 3.52–3.44 (m, 2H), 3.30–3.22 (m,
2H), 1.99–1.88 (m, 2H), 1.49 (s, 3H), 1.41 (s, 1H; OH), 1.39 (s, 3H), 1.17
(d, J=7.2 Hz, 3H), 0.96 ppm (d, J=6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=109.8, 77.7, 75.0, 72.8, 72.6, 66.0, 37.0, 35.5, 26.4, 25.5, 17.6,
13.3, 10.7 ppm; IR (film): n˜ =3468, 2982, 2880, 1458, 1380 cmÀ1; HRMS
(ESI): calcd for C13H23O4NaI: 393.0533 [M+Na]+; found: 393.0529.
Aldehyde 33: A solution of 32 (3.0 g, 13.2 mmol) in MeOH (120 mL) was
cooled to À788C, and then a stream of ozone/oxygen was bubbled into
the reaction mixture until it turned light blue. Oxygen was bubbled into
the reaction mixture for 1 h, and then Ph3P (4.2 g, 15.8 mmol) was added
at À788C. This mixture was then warmed to RT and stirred for a further
2 h, before being concentrated in vacuo. Chromatography of the residue
on silica gel (petroleum ether/EtOAc 20:1) provided 33 (2.55 g, 85%) as
a colorless oil. Rf =0.59 (petroleum ether/EtOAc 4:1); [a]2D0 =+41.4 (c=
1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=9.71 (d, J=2.4 Hz, 1H),
5.16 (dd, J=6.6, 3.0 Hz, 1H), 4.33 (m, 1H), 4.03 (dd, J=8.7, 6.9 Hz, 1H),
3.74 (dd, J=8.4, 5.4 Hz, 1H), 2.81 (m, 1H), 2.10 (s, 3H), 1.43 (s, 3H),
1.34 (s, 3H), 1.16 ppm (d, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=201.9, 170.6, 109.8, 75.3, 72.8, 65.5, 48.0, 25.9, 25.3, 20.7, 11.1 ppm; IR
PMB ether 37: A solution of BF3·Et2O (0.42 mL, 1m in CH2Cl2) w as
slowly added to
Cl3CC(NH)OPMB reagent (6 mL, approximately 2.7 mmol) in dry
CH2Cl2 (3 mL) at 08C under nitrogen atmosphere. significant
a mixture of alcohol 35 (716 mg, 1.93 mmol) and
a
A
amount of a white solid was observed to immediately precipitate. After
the mixture had been stirred at 08C for 30 min, the suspension was fil-
tered, the solid was washed with a mixture of CH2Cl2/hexane (1:2, 2”
5 mL), and the filtrate was washed with saturated aqueous NaHCO3 solu-
tion (20 mL). The organic extracts were then combined, washed with
brine, dried over Na2SO4, and concentrated in vacuo. Chromatography of
the residue on silica gel (petroleum ether/EtOAc 20:1) provided 37
(750 mg, 79.3%) as colorless oil. Rf =0.60 (petroleum ether/EtOAc 4:1);
[a]2D0 =+58.4 (c=1.55 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.27
(film): n˜ =2989, 1747, 1695, 1374 cmÀ1
; HRMS (ESI): calcd for
C11H18O5K: 269.0785 [M+K]+; found: 269.0787.
Diol 34: Compound (+)-30 (30 mL, 30 mmol, 1.0m solution in toluene)
was added dropwise to a slurry of powdered molecular sieves (3 g, 4 Š)
in anhydrous toluene (10 mL) under argon at RT. After the reaction mix-
ture had been stirred for 30 min at RT, the mixture was cooled to À788C,
(d, J=7.5 Hz, 2H), 6.88 (d, J=7.5 Hz, 2H), 4.59 and 4.30 (AB, JAB =
10.8 Hz), 4.29–4.19 (m, 2H), 3.98 (dd, J=6.9 Hz, 6.0 Hz, 1H), 3.80 (s,
3H), 3.50 (dd, J=7.2, 1.8 Hz, 1H), 3.29 (dd, J=9.9, 1.5 Hz, 1H), 3.13–
3.08 (m, 2H), 2.90 (d, J=10.2 Hz, 1H), 2.35 (m, 1H), 2.05–1.98 (m, 1H),
1.39 (s, 3H), 1.36 (s, 3H), 0.97 (d, J=6.3 Hz, 3H), 0.86 ppm (d, J=
6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=159.2, 130.6, 129.1 (2C),
113.8 (2C), 109.1, 82.7, 80.4, 78.7, 74.9, 69.7, 65.3, 55.3, 34.0, 32.2, 26.1,
and then
a solution of aldehyde 33 (3.37 g, 14.6 mmol) in toluene
(20 mL) was added dropwise over 30 min at À788C. The reaction mixture
was stirred at À788C for 8 h, and was then warmed to RT overnight.
After this time, the mixture was quenched with NaOH solution (2n,
20 mL) and filtered. The aqueous layer was extracted with Et2O (3”
50 mL), and the combined organic layers were concentrated in vacuo to
give a residue. NaOH solution (2n, 20 mL) was then added to a solution
of the residue in diethyl ether (200 mL), and the resulting mixture was
heated to reflux for 24 h. After this time, the mixture was extracted with
diethyl ether (3”100 mL), washed with brine, dried over Na2SO4, and
then concentrated in vacuo. Chromatography of the residue on silica gel
(petroleum ether/EtOAc 4:1) provided 34 (2.49 g, 70%) as a colorless
oil. Rf =0.40 (petroleum ether/EtOAc 1:1); [a]2D0 =+9.9 (c=0.45 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=5.68–5.80 (m, 1H), 5.11–5.18
(m, 2H), 4.24–4.30 (m, 1H), 4.03 (dd, J=8.1, 6.9 Hz, 1H), 3.80 (dd, J=
8.1, 7.2 Hz, 1H), 3.69 (dt, J=9.6, 1.8 Hz, 1H), 3.52–3.58 (m, 1H), 2.25–
2.28 (m, 1H), 1.73–1.78 (m, 1H), 1.46 (s, 3H), 1.40 (s, 3H), 1.01 (d, J=
7.2 Hz, 3H), 0.95 ppm (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=141.70, 115.77, 109.10, 76.74, 74.54, 73.45, 66.12, 41.83, 36.62, 26.29,
25.17, 16.16, 9.44 ppm; IR (film): n˜ =3457, 1641 cmÀ1; HRMS (ESI):
calcd for C13H24O4Na: 267.1567 [M+Na]+; found: 267.1565.
25.9, 12.8, 6.3, 4.8 ppm; IR (film): n˜ =2982, 1614, 1587, 1514, 1459 cmÀ1
;
HRMS (ESI) calcd for C21H31O5NaI: 513.1108 [M+Na]+; found:
513.1110.
Nitrile 38: NaCN (157 mg, 4.05 mmol) was added to a solution of 37
(750 mg, 1.53 mmol) in DMSO (3 mL). The mixture was then heated to
758C and stirred for 12 h at this temperature. After this time, the mixture
was cooled to RT, diluted with Et2O (200 mL), washed with H2O and
brine, dried over Na2SO4, and then concentrated in vacuo. Chromatogra-
phy of the residue on silica gel (petroleum ether/EtOAc 8:1) provided 38
(482 mg, 81%) as a colorless oil. Rf =0.29 (petroleum ether/EtOAc 4:1);
[a]2D0 =+52.8 (c=0.57 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.27
(d, J=8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 4.58 and 4.29 (AB, JAB
11.1 Hz), 4.27 (m, 1H), 4.08 and 3.97 (AB of ABX, JAB =8.1, JAX =6.6,
BX =8.1 Hz), 3.81 (s, 3H), 3.70–3.65 (m, 1H), 3.15 (dd, J=10.8, 4.8 Hz,
1H), 2.97 (dd, J=10.5, 2.1 Hz, 1H), 2.67 and 2.46 (AB of ABX, JAB
=
J
=
16.2, JAX =7.2, JBX =6.6 Hz), 2.23 (m, 1H), 2.10–1.95 (m, 1H), 1.36 (d, J=
6.6 Hz, 6H), 0.98 (d, J=6.6 Hz, 3H), 0.93 ppm (d, J=6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=159.2, 130.3, 129.2 (2C), 117.5, 113.8
(2C), 109.2, 82.2, 80.6, 74.7, 74.0, 69.7 (2C), 65.2, 55.3, 33.6, 32.1, 25.9,
Alcohol 35: A solution of diol 34 (0.982 g, 4.0 mmol) in dry toluene
(30 mL) was added dropwise to
a
mixture of Hg(OAc)2 (1.91 g,
21.7, 12.8, 5.3 ppm; IR (film): n˜ =2983, 2251, 1614, 1587, 1514 cmÀ1
;
6.0 mmol) in dry toluene (70 mL) at 08C under a nitrogen atmosphere.
After the mixture had been stirred at 08C for 8 h, I2 (2.13 g, 8.4 mmol)
HRMS (ESI): calcd for C22H31O5NaN: 412.2094 [M+Na]+; found:
412.2098.
1196
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 1185 – 1204

Phorboxazole B
FULL PAPER
Alcohol 39: DIBAL (1.65 mL, 1.65 mmol, 1m in toluene) was added
dropwise to a solution of 38 (248 mg, 0.64 mmol) in dry CH2Cl2 (10 mL)
under argon at À788C. After the mixture had been stirred at À788C for
1 h, it was quenched with HCl (1n, 15 mL) and extracted with Et2O (3”
50 mL). The combined organic extracts were then washed with saturated
aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in
vacuo to give a residue. NaBH4 (24 mg, 0.64 mmol) was added to a solu-
tion of the residue in MeOH (2 mL) at 08C, and the mixture was stirred
for 30 min. After this time, the mixture was quenched with saturated
aqueous NH4Cl and extracted with Et2O (3”50 mL). The combined or-
ganic extracts were washed with brine, dried over Na2SO4, and concen-
trated in vacuo. Chromatography of the residue on silica gel (petroleum
ether/EtOAc 4:1) provided 39 (181 mg, 72% overall yield for the two
3H), 1.05 (s, 9H), 0.94 (d, J=6.9 Hz, 3H), 0.89 ppm (d, J=6.6 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=206.9, 158.6, 134.9 (4C), 134.2 (2C),
129.8, 129.1 (2C), 128.8 (2C), 127.1 (4C), 113.2 (2C), 87.2, 82.4, 74.2,
69.1, 59.9, 54.7, 35.3, 33.7, 31.8, 26.3 (3C), 24.8, 18.7, 12.3, 5.5 ppm; IR
(film): n˜ =3072, 2932, 1720, 1614, 1588, 1515 cmÀ1; HRMS (ESI): calcd
for C35H46O5NaSi: 597.3006 [M+Na]+; found: 597.2994.
Oxazole 5: LDA (0.23 mL, 0.138 mmol, 0.6m solution in THF) was added
to a solution of 43 (29 mg, 0.14 mmol) in THF (0.5 mL) at À788C under
argon. The resulting mixture was stirred for 30 min at À788C, and then a
solution of ketone 42 (13 mg, 0.023 mmol) in anhydrous THF (0.3 mL)
was added. After the addition, the reaction mixture was warmed to RT,
quenched with saturated aqueous NH4Cl solution, and extracted with
Et2O (2”50 mL). The combined organic layers were washed with brine,
dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography of
steps) as colorless oil. Rf =0.41 (petroleum ether/EtOAc 1:1); [a]D20
=
+43.7 (c=1.0 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.27 (d, J=
8.6 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 4.57 and 4.27 (AB, JAB =11.3 Hz),
the residue on silica gel (petroleum ether/EtOAc 10:1) provided
5
(8.6 mg, 78% yield, 3.4 mg of 42 was recovered) as a colorless oil. Rf =
0.56 (petroleum ether/EtOAc 4:1); [a]2D0 =+38 (c=0.13 in CHCl3);
1H NMR (300 MHz, CDCl3): d=7.68–7.64 (m, 4H), 7.49 (s, 1H), 7.40–
7.35 (m, 6H), 7.28 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 6.17 (s,
1H), 4.56 and 4.28 (AB, JAB =11.1 Hz), 3.81 (s, 3H), 3.79–3.66 (m, 3H),
3.41 (d, J=10.5 Hz, 1H), 3.20 (dd, J=10.8, 4.8 Hz, 1H), 2.45 (s, 3H),
2.15–2.09 (m, 1H), 1.88 (d, J=1.5 Hz, 3H), 1.86–1.70 (m, 3H), 1.05 (m,
9H), 0.94 (d, J=6.9 Hz, 3H), 0.82 ppm (d, J=6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=160.5, 159.1, 138.2, 137.9, 135.5 (4C), 134.0, 133.9,
130.7, 129.5 (2C), 129.3 (3C), 127.6 (5C), 118.4, 113.8 (2C), 88.9, 83.5,
74.8, 69.6, 60.8, 55.3, 35.8, 34.2, 33.3, 26.9 (3C), 19.2, 14.2, 13.8, 13.7,
6.0 ppm; IR (film): n˜ =3072, 2931, 1614, 1587, 1514, 1462 cmÀ1; HRMS
(ESI): calcd for C40H51O5NSiNa: 676.3428 [M+Na]+; found: 676.3411.
4.26 (m, 1H), 4.07 and 3.97 (AB of ABX, JAB =8.1, JAX =6.6, JBX
=
3.9 Hz), 3.81 (s, 3H), 3.80–3.76 (m, 2H), 3.55 (ddd, J=10.8, 2.7, 2.7 Hz,
1H), 3.32–3.29 (m, 1H), 3.12 (dd, J=10.5, 5.1 Hz, 1H), 2. (dd, J=10.2,
2.4 Hz, 1H), 2.10–1.90 (m, 3H), 1.53 (m, 1H), 1.46 (s, 3H), 1.31 (s, 3H),
0.97 (d, J=2.1 Hz, 3H), 0.94 ppm (d, J=1.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=159.2, 130.7, 129.3 (2C), 113.9 (2C), 110.0, 83.3,
82.8, 80.1, 74.8, 69.6, 66.5, 62.5, 55.4, 35.2, 34.8, 32.1, 26.0, 25.5, 12.9,
6.4 ppm; IR (film): n˜ =3485, 2979, 1614, 1587, 1514 cmÀ1; HRMS (ESI):
calcd for C22H34O6Na 417.2247 [M+Na]+; found: 417.2249.
TBDPS ether 40: Triethylamine (0.107 mL, 0.76 mmol), TBDPSCl
(0.182 mL, 0.663 mmol), and DMAP (6.2 mg, 0.051 mmol) were added to
a solution of 39 (200 mg, 0.51 mmol) in CH2Cl2 (4 mL) under argon. The
reaction mixture was stirred at RT for 3 h and then diluted with Et2O
(150 mL), washed with brine (”2), dried over Na2SO4, and concentrated
in vacuo. Chromatography of the residue on silica gel (petroleum ether/
EtOAc 30:1) provided 40 (296 mg, 92%) as a colorless oil. Rf =0.57 (pe-
troleum ether/EtOAc 10:1); [a]2D0 =+43.6 (c=0.375 in CHCl3); H NMR
(300 MHz, CDCl3): d=7.66 (m, 4H), 7.45–7.36 (m, 6H), 7.27 (d, J=
8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.57 and 4.27 (AB, JAB =11.4 Hz),
4.22 (ddd, J=6.0, 6.0, 1.5 Hz, 1H), 3.92–3.75 (m, 4H), 3.81 (s, 3H), 3.51
(m, 1H), 3.11 (dd, J=10.5, 4.5 Hz, 1H), 2.77 (dd, J=9.9, 1.5 Hz, 1H),
2.02–1.97 (m, 2H), 1.90–1.75 (m, 1H), 1.60–1.55 (m, 1H), 1.33 (s, 6H),
1.05 (s, 9H), 0.95 (d, J=6.6 Hz, 3H), 0.87 ppm (d, J=6.9 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=159.0, 135.4 (4C), 133.9, 133.8, 130.8,
129.5 (2C), 129.0 (2C), 127.6 (4C), 113.6 (2C), 108.9, 83.4, 79.9, 75.1,
74.4, 69.3, 65.1, 60.8, 55.2, 36.1, 34.4, 32.3, 26.8 (3C), 26.0, 25.7, 19.2, 13.0,
5.8 ppm; IR (film): n˜ =3702, 2959, 1614, 1588, 1514 cmÀ1; HRMS (ESI):
calcd for C38H52O6NaSi: 655.3425 [M+Na]+; found: 655.3427.
Ester 45: 1,3-Propanediol (7.6 g, 100 mmol) in THF (50 mL) was added
to a suspension of NaH (4.0 g, 100 mmol, 60% in oil) in THF (100 mL)
at RT. After the mixture had been stirred for 45 min, a solution of
TBSCl (15 g, 100 mmol) in THF (50 mmol) was added dropwise at 08C.
The mixture was stirred for a further 1 h, before being quenched with sa-
turated aqueous NaHCO3 (200 mL). This mixture was extracted with
Et2O (3”300 mL) and the combined organic phases were washed with
brine (”2), dried (Na2SO4), filtered, and concentrated in vacuo to give a
residue. For the next step in the synthesis, PCC (43.2 g, 200 mmol) was
added to a solution of the residue in CH2Cl2 (150 mL) at 08C, and the re-
sulting mixture was stirred at RT overnight. After this time, the CH2Cl2
was removed in vacuo and the residue produced was dissolved in Et2O
(400 mL). The mixture was stirred for 1 h, before being filtered through
netural Al2O3 and concentrated in vacuo to give
a
residue.
Ph3PCHCO2Et (38 g, 100 mmol) was added to a solution of this residue
in freshly distilled benzene (400 mL), and the resulting mixture was re-
fluxed for 24 h. After this time, the solvent was removed under reduced
pressure, and the residue produced was dissolved in CH2Cl2 (20 mL),
before being further diluted with petroleum ether (400 mL). At this point
a substantial quantity of Ph3PO precipitated out of the reaction mixture.
After filtration, the filtrate was concentrated in vacuo, and the resultant
residue was treated as above one more time. Chromatography of the resi-
due on silica gel (petroleum ether/EtOAc 60:1) provided 45 (13.2 g, 51%
overall yield for the three steps) as a colorless oil. Rf =0.63 (petroleum
ether/EtOAc 20:1); 1H NMR (300 MHz, CDCl3): d=6.97 (dt, J=15.3,
7.2 Hz, 1H), 5.87 (dt, J=15.9, 1.5 Hz, 1H), 4.19 (q, J=6.9z, 2H), 3.74 (t,
J=6.9 Hz, 2H), 2.42 (qd, J=6.6, 1.2 Hz, 2H), 1.29 (t, J=6.9 Hz, 3H),
0.89 (s, 9H), 0.06 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=166.4,
145.7, 122.9, 61.5, 60.0, 35.6, 25.8 (3C), 18.2, 14.2, À5.4 ppm (2C); IR
(film): n˜ =2952, 2117, 1650, 1471, 1018 cmÀ1; HRMS (ESI): calcd for
C13H26O3SiNa: 281.1543 [M+Na]+; found: 281.1548.
Ketone 42: HIO4 (71 mg, 0.315 mmol) was added to a solution of 40
(94 mg, 0.15 mmol) in EtOAc (4 mL) at 08C. The resulting solution was
stirred at 08C for 6 h, and was then quenched by the addition of a mix-
ture of saturated aqueous NaHCO3/Na2S2O3 (5:1, 10 mL). The resulting
mixture was then diluted with Et2O (150 mL), and the organic layer was
washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to
give a residue. MeLi (0.2 mL, 0.32 mmol, 1.6m solution in Et2O) was
added to a precooled solution of this residue in THF (4 mL) at À788C
under argon. The resulting mixture was stirred at À788C for 1 h, and was
then quenched with aqueous NH4Cl solution at À788C and extracted
with Et2O (150 mL). The organic layer was washed with brine, dried
(Na2SO4), filtered, and concentrated in vacuo to give a second residue.
Dess–Martin periodinane (83 mg, 0.2 mmol) was added to a solution of
this residue in CH2Cl2 (3 mL) at RT. This reaction mixture was stirred at
RT for 2 h. After this time, the reaction was quenched with saturated
aqueous NaHCO3/Na2S2O3 (10 mL, 5:1) and extracted with Et2O
(150 mL). As above, the organic layer was washed with brine, dried
(Na2SO4), filtered, and concentrated in vacuo. Chromatography of the
residue on silica gel (petroleum ether/EtOAc 20:1) provided 42 (49 mg,
58% overall yield for the three steps) as colorless oil. Rf =0.69 (petro-
leum ether/EtOAc 6:1); [a]2D0 =+53.6 (c=0.55 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.66–7.62 (m, 4H), 7.41–7.36 (m, 6H), 7.27 (d, J=
8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.56 and 4.29 (AB, JAB =11.1 Hz),
3.80 (s, 3H), 3.78–3.73 (m, 2H), 3.64 (m, 1H), 3.31 (d, J=10.5 Hz, 1H),
3.17 (dd, J=9.9, 4.2 Hz, 1H), 2.12 (s, 3H), 2.11 (m, 1H), 1.86–1.68 (m,
Diol 46: (Dihydroquinidine)2-phthalazine [(DHQD)2-PHAL, 290 mg,
0.4 mmol, 1 mol%] and potassium osmate (29 mg, 0.08 mmol, 0.2 mol%)
were added to a solution of potassium ferricyanide (32 g, 120 mmol) and
potassium carbonate (16.6 g, 120 mmol) in a mixture of tBuOH and
water (1:1, 400 mL) at RT. Compound 45 (10.3 g, 40 mmol) was then
added to the mixture, and it was vigorously stirred at RT until the reac-
tion had finished (approximately 12 h). After this time, the reaction was
quenched with sodium sulfite (60 g). The aqueous phase was extracted
with EtOAc (4”300 mL), and the combined organic layers were washed
Chem. Eur. J. 2006, 12, 1185 – 1204
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1197

G.-Q. Lin, W.-S. Zhou et al.
with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Chroma-
tography of the residue on silica gel (petroleum ether/EtOAc 4:1) provid-
ed 46 as a colorless oil (10.2 g, 87% yield, 86% ee as determined by
chiral GC analysis). Rf =0.64 (petroleum ether/EtOAc 2:1); [a]2D0 =À3.5
(c=0.66 in CHCl3); 1H NMR (300 MHz, CDCl3): d=4.28 (q, J=7.5 Hz,
2H), 4.20 (m, 1H), 4.07 (d, J=1.8 Hz, 1H), 3.87 (m, 2H), 3.32 (brs, 2H;
OH), 1.94 (m, 1H), 1.75 (m, 1H), 1.32 (t, J=6.9 Hz, 3H), 0.89 (s, 9H),
0.07 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=173.1, 73.6, 71.9, 61.7,
61.4, 35.2, 25.7 (3C), 18.1, 14.0, À5.6 ppm (2C); IR (film): n˜ =3442, 2937,
2859, 1740, 1256, 1101, 837 cmÀ1; HRMS (ESI): calcd for C13H28O5SiNa:
315.1598 [M+Na]+; found: 315.1614.
After the reaction mixture had been stirred at À788C for 2 h, the mixture
was quenched with H2O (2 mL) and MgSO4 (10 g) was added. The mix-
ture was then vigorously stirred at RT for 10 h. After this time, the mix-
ture was filtered and the resulting filtrate concentrated in vacuo to give a
residue. Triethylamine (5.61 mL, 40 mmol), acetyl anhydride (1.8 mL,
20 mmol), and DMAP (cat) were then added to a solution of the residue
in dry CH2Cl2 (30 mL) at 08C under argon. Once the reaction mixture
had been warmed to RT and stirred for 3 h, it was quenched with saturat-
ed aqueous NaHCO3 solution. This mixture was then extracted with
EtOAc (3”80 mL), and the combined organic phases were washed with
brine, dried over Na2SO4, and concentrated in vacuo. Chromatography of
the residue on silica gel (petroleum ether/EtOAc 8:1) provided 49
(1.18 g, 90% overall yield for the two steps) as a colorless oil. Rf =0.53
(petroleum ether/EtOAc 4:1); [a]2D0 =À4.0 (c=0.66 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.25 (d, J=9.0 Hz, 2H), 7.24 (d, J=9.0 Hz, 2H),
6.85 (d, J=9.0 Hz, 2H), 6.84 (d, J=9.0 Hz, 2H), 5.45 (dd, J=9.3, 1.2 Hz,
1H), 4.68 and 4.30 (AB, JAB =10.5 Hz), 4.52 and 4.48 (AB, JAB =9.9 Hz),
4.49 (brs, 2H), 4.15 (dd, J=9.6, 6.3 Hz, 1H), 3.79 (s, 6H), 3.66–3.60 (m,
3H), 2.09 (s, 3H), 1.70 (m, 1H), 1.63 (d, J=1.2 Hz, 3H), 1.60 (m, 1H),
0.87 (s, 9H), 0.03 (s, 3H), 0.02 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=170.9, 159.2 (2C), 135.1, 131.2, 130.8, 129.8 (2C), 129.5 (2C), 126.1,
113.8 (4C), 77.9, 77.3, 73.6, 70.1, 69.0, 59.7, 55.4 (2C), 34.4, 26.1 (3C),
21.1, 18.4, 14.8, À5.1 ppm (2C); IR (film): n˜ =2955, 1743, 1614, 1515,
1249 cmÀ1; HRMS (ESI): calcd for C32H48O7SiNa: 595.3062 [M+Na]+;
found: 595.3069.
Alcohol 47: BF3·Et2O (1.1 mL, 0.1m in CH2Cl2) was added to a mixture
of diol 46 (1.1 g, 3.76 mmol) and Cl3CC(NH)OPMB reagent (39 mL, ap-
proximately 17.7 mmol) in dry CH2Cl2 (15 mL) at 08C under a nitrogen
atmosphere. A substantial quantity of a white solid was observed to im-
mediately precipitate out of the reaction mixture. After the reaction mix-
ture had been stirred at 08C for 30 min, the suspension was filtered. The
solid was washed with a mixture of CH2Cl2/hexane (1:2, 2”5 mL), and
the filtrate was washed with saturated aqueous NaHCO3 solution
(20 mL). The combined organic extracts were washed with brine, dried
over Na2SO4, and then concentrated in vacuo to give a residue. Finally,
LiAlH4 (571 mg, 15 mmol) was added to a solution of the residue in dry
Et2O (100 mL) at 08C. After the addition, the mixture was stirred at RT
for 1 h, and then the mixture was quenched with H2O (3 mL), filtered,
and the resulting filtrate was concentrated in vacuo. Chromatography of
the residue on silica gel (petroleum ether/EtOAc 6:1) provided 47
(1.33 g, 72% overall yield for the two steps) as a colorless oil. Rf =0.33
(petroleum ether/EtOAc 3:1); [a]2D0 =+5.4 (c=1.45 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.20 (d, J=8.4 Hz, 2H), 7.19 (d, J=9 Hz, 2H),
6.81 (d, J=8.4 Hz, 4H), 4.57–4.43 (m, 4H), 3.75 (s, 6H), 3.74 (m, 2H),
3.60 (m, 4H), 1.79 (m, 1H), 1.60 (m, 1H), 0.89 (s, 9H), 0.06 ppm (s, 6H);
13C NMR (75 MHz, CDCl3): d=159.1 (2C), 130.3, 130.2, 129.5 (2C),
129.4 (2C), 113.7 (4C), 78.9, 75.2, 72.4, 72.0, 61.6, 59.2, 55.1 (2C), 32.9,
25.8 (3C), 18.1, À5.3, À5.4 ppm; IR (film): n˜ =3456, 2955, 1614, 1587,
Aldehyde 50: TBAF (15 mL, 1m in THF) was added to a solution of 49
(5.43 g, 9.49 mmol) in dry THF (10 mL) at RT. The resulting mixture was
then stirred at RT for 24 h, before being quenched with saturated aque-
ous NH4Cl solution and extracted with EtOAc (3”80 mL). The com-
bined organic phases were washed with brine, dried over Na2SO4, and
then concentrated in vacuo to give a residue. Dess–Martin periodinane
(4.2 g, 10.0 mmol) was added to a solution of this residue in CH2Cl2
(50 mL) at RT. The mixture was stirred at RT for 3 h and then quenched
with a mixture of saturated aqueous NaHCO3/Na2S2O3 (5:1, 150 mL),
before being extracted with CH2Cl2 (2”200 mL). The combined organic
phases were washed with brine, dried over Na2SO4, and concentrated in
vacuo. Chromatography of the residue on silica gel (petroleum ether/
EtOAc 10:1) provided 50 (3.76 g, 86.4% overall yield for two steps) as a
colorless oil. Rf =0.50 (petroleum ether/EtOAc 4:1); [a]2D0 =À11.8 (c=
1515, 1250, 835, 777 cmÀ1
; HRMS (ESI): calcd for C27H42O6SiNa:
513.2643 [M+Na]+; found: 513.2636.
Ester 48: A solution of dimethyl sulfoxide (DMSO, 0.24 mL, 3.42 mmol)
in CH2Cl2 (5 mL) was added dropwise to a stirred solution of oxalyl chlo-
ride (0.95 mL, 2.3 mmol) in CH2Cl2 (4 mL) at À788C under a nitrogen at-
mosphere. The mixture was stirred at À788C for 10 min, and then a solu-
tion of the alcohol 47 (560 mg, 1.13 mmol) in CH2Cl2 (3 mL) was added
dropwise. The mixture was stirred at À788C for a further 1 h, and then
triethylamine (0.96 mL) was added dropwise. Once the two additions had
been completed, the mixture was warmed to RT and then quenched with
a solution of saturated aqueous potassium hydrogenphosphate (60 mL).
The aqueous layer was extracted with dichloromethane (2”50 mL), and
the combined organic extracts were dried (Na2SO4) and concentrated in
vacuo to give a residue. For the next step in the synthesis, Ph3PCHCO2Et
(517 mg, 1.42 mmol) was added to a solution of the residue in dry CH2Cl2
(20 mL), and the mixture was refluxed for 4 h. After this time, silica gel
(4 g) was added and the solvent removed in vacuo. Chromatography on
silica gel (the residue produced was directly loaded onto the column and
eluted with petroleum ether/EtOAc 10:1) provided 48 (546 mg, 84%
yield for two steps) as a colorless oil. Rf =0.67 (petroleum ether/EtOAc
4:1); [a]2D0 =À6.6 (c=0.57 in CHCl3); 1H NMR (300 MHz, CDCl3): d=
7.24 (d, J=9 Hz, 2H), 7.23 (d, J=9 Hz, 2H), 6.87 (d, J=9 Hz, 2H), 6.84
1
0.59 in CHCl3); H NMR (300 MHz, CDCl3): d=9.65 (d, J=1.5 Hz, 1H),
7.22 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H),
6.84 (d, J=8.4 Hz, 2H), 5.43 (dd, J=9.6, 1.5 Hz, 1H), 4.63 and 4.53 (AB,
JAB =11.1 Hz), 4.52 and 4.27 (AB, JAB =11.4 Hz), 4.49 (s, 2H), 4.21 (dd,
J=9.6, 5.7 Hz, 1H), 4.05–3.99 (m, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 2.58
(m, 2H), 2.10 (s, 3H), 1.63 ppm (d, J=0.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=201.1, 170.8, 159.5, 159.4, 136.4, 130.3 (2C), 129.8 (2C), 129.6
(2C), 124.9, 113.9 (4C), 76.2, 76.0, 73.2, 70.2, 68.8, 55.4 (2C), 45.5, 21.1,
14.9 ppm; IR (film): n˜ =3000, 2937, 2839, 2731, 1737, 1613 cmÀ1; HRMS
(ESI): calcd for C26H32O7Na: 479.2040 [M+Na]+; found: 479.2051.
Alcohol 52: TiCl4 (0.16 mL, 1.46 mmol) was added to a solution of Ti-
(OiPr)4 (0.475 mL) in dry toluene (15 mL) at RT. After the completion
of addition, the mixture was stirred at RT for 10 min and then cooled to
À788C. A solution of aldehyde 50 (1.2 g, 2.65 mmol) in toluene (7 mL)
was then added to the mixture. After the mixture had been stirred for
10 min, a solution of 1-ethoxy-1-[(trimethylsilyl)oxy]ethane 51 (763 mg,
4.77 mmol) in toluene (3 mL) was added. This mixture was stirred at
À788C for 2 h and then quenched with saturated aqueous NaHCO3 solu-
tion, before being extracted with EtOAc (3”50 mL). The combined or-
ganic phases were washed with brine, dried over Na2SO4, and concentrat-
ed in vacuo. Chromatography of the residue on silica gel (petroleum
ether/EtOAc 6:1) provided 52 (879 mg, 61%) as colorless oil. Rf =0.37
(petroleum ether/EtOAc 3:1); [a]2D0 =À3.6 (c=0.49 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.25 (d, J=9.0 Hz, 2H), 7.24 (d, J=9.0 Hz, 2H),
6.86 (d, J=9.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 5.42 (dd, J=9.9, 1.2 Hz,
1H), 4.73 and 4.53 (AB, JAB =11.1 Hz), 4.53 and 4.30 (AB, JAB =11.7 Hz),
4.49 (s, 2H), 4.20 (dd, J=9.3, 6.0 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.81–
3.78 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.13 (d, J=3.9 Hz, 1H), 2.41 (s;
OH), 2.39 (d, J=2.7 Hz, 1H), 2.09 (s, 3H), 1.65 (d, J=1.2 Hz, 3H), 1.61–
1.51 (m, 2H), 1.25 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
(d, J=9 Hz, 2H), 6.72 (dd, J=9.3, 1.5 Hz, 1H), 4.65 and 4.50 (AB, JAB
=
11.1 Hz), 4.55 and 4.31 (AB, JAB =11.7 Hz), 4.26 (m, 1H), 4.22 (q, J=
6.9 Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.72 (m, 1H), 3.62 (m, 2H), 1.82
(d, J=1.5 Hz, 3H), 1.78–1.63 (m, 2H), 1.32 (t, J=6.9 Hz, 3H), 0.89 (s,
9H), 0.04 (s, 3H), 0.02 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=
167.4, 159.0 (2C), 139.0 (2C), 131.2, 130.6, 130.1, 129.6 (2C), 129.4 (2C),
113.6 (2C), 113.5 (2C), 77.2, 76.9, 73.3, 70.4, 60.7, 59.2, 55.1, 33.9, 25.8
(3C), 18.1, 14.1, 13.2, À5.4 ppm (2C); IR (film): n˜ =2956, 1714, 1614,
1587, 1465, 1249 cmÀ1; HRMS (ESI): calcd for C32H48O7NaSi: 595.3062
[M+Na]+; found: 595.3066.
Ester 49: DIBAL (4.77 mL, 4.77 mmol, 1m in toluene) was added drop-
wise to a solution of 48 (1.3 g, 2.3 mmol) in dry Et2O (30 mL) at À788C.
1198
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 1185 – 1204

Phorboxazole B
FULL PAPER
d=175.2, 173.3, 161.9, 161.8, 138.3, 133.4, 133.2, 132.5 (2C), 132.0 (2C),
128.1, 116.5 (2C), 116.4 (2C), 80.7, 76.3, 72.6, 71.5, 67.7 (2C), 63.2, 57.9
(2C), 44.6, 40.4, 23.6, 17.4, 16.8 ppm; IR (film): n˜ =3506, 2937, 2839,
1737, 1613, 1587 cmÀ1; HRMS (ESI): calcd for C30H40O9Na: 567.2564
[M+Na]+; found: 567.2572.
3H), 1.72 (s, 3H), 1.63–1.48 (m, 1H), 1.10–0.98 ppm (m, 21H); 13C NMR
(75 MHz, CDCl3): d=170.1, 169.6, 134.3, 126.4, 80.0, 72.4, 69.6, 68.7, 55.9,
36.9, 29.2, 20.8, 17.9 (3C), 17.8 (3C), 15.0, 12.2 ppm (3C); IR (film): n˜ =
2945, 2868, 1745, 1231 cmÀ1; HRMS (ESI): calcd for C22H40O6SiNa:
451.2486 [M+Na]+; found: 451.2480.
C35 epimer of 52: Rf =0.36 (petroleum ether/EtOAc 3:1); [a]2D0 =À2.8
(c=0.39 in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.28–7.19 (m, 4H),
6.88–6.82 (m, 4H), 5.43 (dd, J=10.2, 1.8 Hz, 1H), 4.71 (d, J=10.8 Hz,
1H), 4.55–4.48 (m, 3H), 4.27 (d, J=10.8 Hz, 1H), 4.26–4.01 (m, 4H),
3.80 (s, 3H), 3.79 (s, 3H), 3.70–3.65 (m, 2H), 3.56 (d, J=2.4 Hz, 1H),
2.45–2.35 (m, 2H), 2.10 (s, 3H), 1.75–1.55 (m, 2H), 1.65 (d, J=0.9 Hz,
3H), 1.25 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=171.1,
170.7, 159.3 (2C), 135.9, 130.3, 130.1, 129.8 (2C), 129.5 (2C), 125.2, 113.8
(2C), 113.7 (2C), 79.8, 76.2, 72.9, 69.9, 68.8, 66.9, 60.5, 55.2 (2C), 41.7,
37.0, 20.9, 14.7, 14.2 ppm; IR (film): n˜ =3497, 2936, 1735, 1613, 1587,
1514 cmÀ1; HRMS (ESI): calcd for C30H40O9Na: 567.2564 [M+Na]+;
found: 567.2565.
Alcohol 57: K2CO3 (17 mg, 0.12 mmol) was added to a stirred solution of
53 (53 mg, 0.93 mmol) in EtOH (1 mL) at RT. After the reaction mixture
had been stirred for 2 h at RT, the mixture was quenched with saturated
aqueous NH4Cl solution. The mixture was then diluted with EtOAc
(100 mL), washed with brine (”2), dried over Na2SO4, and concentrated
in vacuo. Chromatography of the residue on silica gel (petroleum ether/
EtOAc 4:1) provided 57 (47 mg, 97%) as a colorless oil. Rf =0.43 (petro-
leum ether/EtOAc 2:1); [a]2D0 =+5.5 (c=0.47 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.23(d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H),
6.86 (d, J=8.4 Hz, 4H), 5.41 (d, J=9.3 Hz, 1H), 4.74 and 4.32 (AB, JAB
=
10.5 Hz), 4.52 and 4.48 (AB, JAB =11.4 Hz), 4.20 (dd, J=9.3, 6.0 Hz, 1H),
4.12 (q, J=7.2 Hz, 2H), 4.02 (s, 2H), 3.80 (s, 6H), 3.76–3.68 (m, 2H),
3.26 (s, 3H), 2.51 and 2.41 (AB of ABX, JAB =14.4, JAX =5.4, JBX
=
Ether 53: 1,8-Bis(dimethylamino)naphthalene (599 mg, 2.8 mmol) and
Me3OBF4 (414 mg, 2.8 mmol) were added to a solution of 52 (190 mg,
0.35 mmol) in dry CH2Cl2 (6 mL) at 08C. The mixture was stirred at 08C
for 6 h, and then the reaction was quenched with iPrOH (0.5 mL) at 08C.
The resultant mixture was diluted with Et2O (200 mL), and the organic
phase was washed with HCl (1n), saturated aqueous NaHCO3, and
brine. The organic layer was then dried over Na2SO4 and concentrated in
vacuo. Chromatography of the residue on silica gel (petroleum ether/
EtOAc 6:1) provided 53 (165 mg, 85%) as colorless oil. Rf =0.60 (petro-
leum ether/EtOAc 2:1); [a]2D0 =+4.5 (c=0.48 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.24 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H),
6.85 (d, J=8.4 Hz, 4H), 5.42 (dd, J=9.9, 1.2 Hz, 1H), 4.73 and 4.47 (AB,
5.7 Hz), 2.02 (s, 1H; OH), 1.78–1.50 (m, 2H), 1.65 (s, 3H), 1.27 ppm (t,
J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=171.1, 158.8, 158.6,
140.3, 130.5, 130.4, 129.3 (2C), 128.9 (2C), 122.3, 113.3 (2C), 113.2 (2C),
76.7, 76.2, 74.2, 72.9, 69.5, 67.6, 60.1, 56.4, 54.9 (2C), 39.2, 36.2, 14.1,
13.8 ppm; IR (film): n˜ =3449, 2935, 1734, 1613, 1587, 1515 cmÀ1; HRMS
(ESI): calcd for C29H40O8Na: 539.2615 [M+Na]+; found: 539.2621.
Diol 58: A solution of CF3COOH in CH2Cl2 (4.7 mL, 10%) was added
dropwise to a solution of 57 (191 mg, 0.37 mmol) in CH2Cl2 (0.7 mL) at
08C. The mixture was stirred at 08C for 1 h, before being quenched with
Et3N (0.86 mL) and directly concentrated in vacuo. Chromatography of
the residue on silica gel (petroleum ether/EtOAc 1:1) provided 58
(72 mg, 85%) as colorless oil. Rf =0.28 (petroleum ether/EtOAc 1:2);
[a]2D0 =À27.6 (c=0.61 in CHCl3); 1H NMR (300 MHz, CDCl3): d=5.34
(dd, J=9.0, 1.2 Hz, 1H), 4.47 (dd, J=8.1, 8.1 Hz, 1H), 4.16 (ddd, J=
11.4, 6.3, 3.3 Hz, 1H), 4.09 (d, J=2.2 Hz, 2H), 3.77 (m, 1H), 3.36 (s, 3H),
3.19 (d, J=1.8 Hz, 1H; OH), 2.87 (dd, J=17.1, 5.7 Hz, 1H), 2.57 (dd, J=
17.1, 4.5 Hz, 1H), 2.27 (ddd, J=14.1, 4.5, 4.5 Hz, 1H), 1.98 (s, 1H; OH),
1.74 (s, 3H), 1.68–1.56 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=
170.1, 141.7, 120.7, 80.1, 72.2, 69.9, 67.2, 56.1, 36.3, 30.7, 14.4 ppm; IR
(film): n˜ =3400, 2926, 1728, 1253 cmÀ1; HRMS (ESI): calcd for C11H18O5
Na: 253.1046 [M+Na]+; found: 253.1047.
JAB =10.5 Hz), 4.52 and 4.29 (AB, JAB =11.4 Hz), 4.49 (brs, 2H), 4.17 (dd,
J=9.6, 6.3 Hz, 1H), 4.12 (q, J=7.5 Hz, 2H), 3.81–3.68 (m, 2H), 3.80 (s,
3H), 3.79 (s, 3H), 3.25 (s, 3H), 2.51 and 2.40 (AB of ABX, JAB =15.0,
JAX =6.3, JBX =5.7 Hz), 2.09 (s, 3H), 1.73–1.49 (m, 2H), 1.63 (d, J=
1.2 Hz, 3H), 1.24 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=171.4, 170.7, 159.2, 159.1, 135.4, 130.9, 130.6, 129.6 (2C), 129.3 (2C),
125.8, 113.8 (2C), 113.7 (2C), 77.8, 76.6, 74.6, 73.4, 69.9, 68.9, 60.4, 56.7,
55.3, 55.2, 39.8, 36.7, 20.9, 14.7, 14.2 ppm; IR (film): n˜ =2936, 2838, 1737,
1613, 1587, 1515 cmÀ1; HRMS (ESI): calcd for C31H42O9Na: 581.2721
[M+Na]+; found: 581.2724.
Lactone 54: CF3COOH (10% in CH2Cl2, 8.1 mL) was added dropwise to
a solution of 53 (360 mg, 0.65 mmol) in CH2Cl2 (2 mL) at 08C. The mix-
ture was stirred at 08C for 1 h, and then poured into a mixture of saturat-
ed aqueous NaHCO3 and CH2Cl2 (1:1, 100 mL). The aqueous phase was
extracted with CH2Cl2 (2”50 mL), and then the combined organic
phases were washed with brine, dried over Na2SO4, and concentrated in
vacuo. Chromatography of the residue on silica gel (petroleum ether/
EtOAc 1:1) provided 54 (168 mg, 95%) as colorless oil. Rf =0.40 (petro-
leum ether/EtOAc 1:2); [a]2D0 =À5.2 (c=0.60 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=5.52 (d, J=8.3 Hz, 1H), 4.50 (s, 2H), 4.47 (m,
1H), 4.15 (ddd, J=11.5, 6.2, 3.4 Hz, 1H), 3.77 (m, 1H), 3.37 (s, 3H), 2.86
(dd, J=17.2, 5.6 Hz, 1H), 2. 71 (d, J=3.7 Hz, 1H), 2.56 (dd, J=17.2,
7.2 Hz, 1H), 2.24 (ddd, J=13.7, 4.3, 4.3 Hz, 1H), 2.09 (s, 3H), 1.77 (s,
3H), 1.67–1.55 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=170.7,
169.5, 136.9, 124.1, 79.9, 72.2, 70.1, 68.5, 56.1, 36.3, 30.7, 20.9, 14.8 ppm;
IR (film): n˜ =3446, 2933, 1739, 1668, 1442, 1378 cmÀ1; HRMS (ESI):
calcd for C13H20O6Na: 295.1152 [M+Na]+; found: 295.1157.
TBS ether 59: Triethylamine (194 mL, 1.38 mmol), TBSCl (190 mg,
1.26 mmol), and DMAP (11 mg, 0.088 mmol) were added sequentially to
a solution of 58 (290 mg, 1.26 mmol) in dry CH2Cl2 at RT. The reaction
mixture was stirred at RT for 3 h, and then diluted with ether (150 mL),
washed brine (”2), dried over Na2SO4, and concentrated in vacuo. Chro-
matography of the residue on silica gel (petroleum ether/EtOAc 4:1) pro-
vided 59 (325 mg, 75%) as a colorless oil. Rf =0.50 (petroleum ether/
EtOAc 1:1); [a]2D0 =À9.2 (c=0.48 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=5.50 (d, J=8.7 Hz, 1H), 4.48 (dd, J=7.2, 7.2 Hz, 1H), 4.14
(ddd, J=10.8, 6.9, 3.3 Hz, 1H), 4.04 (brs, 2H), 3.74 (m, 1H), 3.35 (s,
3H), 2.86 and 2.54 (AB of ABX, JAB =17.4, JAX =6.0, JBX =7.2 Hz), 2.26
(ddd, J=13.8, 4.5, 4.5 Hz, 1H), 1.70 (s, 3H), 1.59–1.50 (m, 1H), 0.92 (m,
9H), 0.07 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d=169.6, 141.9,
119.8, 80.2, 72.3, 70.3, 67.3, 56.1, 36.4, 30.7, 25.9 (3C), 18.4, 14.3, À5.2,
À5.3 ppm; IR (film): n˜ =3425, 2956, 1737, 1253 cmÀ1; HRMS (ESI): calcd
for C17H32O5SiNa: 367.1911 [M+Na]+; found: 367.1924.
Lactone 6: TIPSCl (0.256 mL, 1.2 mmol) and AgNO3 (210 mg, 1.2 mmol)
were added to a solution of 59 (142 mg, 0.41 mmol) in dry pyridine
(2 mL). The reaction mixture was kept in darkness and stirred for 24 h at
RT. After this time, the reaction mixture was diluted with Et2O
(200 mL), washed with saturated CuSO4 solution and brine, dried over
Na2SO4, and then concentrated in vacuo. Chromatography of the residue
on silica gel (petroleum ether/EtOAc 15:1) provided 6 as a colorless oil
(159 mg, 78%). Rf =0.67 (petroleum ether/EtOAc 6:1); [a]2D0 =À10.5 (c=
Compound 55: Imidazole (171 mg, 2.4 mmol), TIPSCl (0.25 mL,
1.2 mmol), and DMAP (cat) were added to a solution of 54 (108 mg,
0.39 mmol) in anhydrous DMF (1 mL) at RT. Whilst stirring, the reaction
mixture was heated to 408C and then stirred for 20 h. After this time, the
mixture was cooled to RT and diluted with Et2O (150 mL). This mixture
was then washed with water and brine, dried over Na2SO4, and concen-
trated in vacuo. Chromatography of the residue on silica gel (petroleum
ether/EtOAc 10:1) provided 55 (132 mg, 78%) as a colorless oil. Rf =0.43
(petroleum ether/EtOAc 4:1); [a]2D0 =À6.3 (c=0.49 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=5.46 (d, J=8.7 Hz, 1H), 4.73 (dd, J=8.7, 4.8 Hz,
1H), 4.47 (s, 2H), 4.24 (ddd, J=12.0, 3.3, 3.3 Hz, 1H), 3.71–3.67 (m, 1H),
3.37 (s, 3H), 2.91 (ddd, J=17.4, 5.7, 1.2, 1H), 2.46–2.37 (m, 2H), 2.08 (s,
1
0.25 in CHCl3); H NMR (300 MHz, CDCl3): d=5.45 (dd, J=8.7, 1.5 Hz,
1H), 4.74 (dd, J=9.0, 5.1 Hz, 1H), 4.24 (ddd, J=14.7, 7.5, 2.7 Hz, 1H),
3.99 (s, 2H), 3.69 (m, 1H), 3.36 (s, 3H), 2.91 (m, 1H), 2.39 (m, 1H), 1.64
(s, 3H), 1.53 (m, 1H), 1.04 (m, 22H), 0.90 (s, 9H), 0.05 ppm (m, 6H);
13C NMR (75 MHz, CDCl3): d=169.9, 138.9, 121.7, 80.4, 72.6, 69.9, 67.3,
Chem. Eur. J. 2006, 12, 1185 – 1204
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1199

G.-Q. Lin, W.-S. Zhou et al.
56.0, 37.0, 25.9 (3C), 18.4, 18.1 (3C), 18.0 (4C), 14.5, 12.3 (3C),
À5.2 ppm (2C); IR (film): n˜ =2931, 2866, 1749, 1464, 1386 cmÀ1; HRMS
(ESI): calcd for C26H52O5NaSi2: 523.3245 [M+Na]+; found: 523.3234.
Alcohol 64: CAN (1.2 g, 2.22 mmol) was added to a solution of 63
(328 mg, 0.74 mmol) in a mixture of CH3CN and H2O (2:1, 4.5 mL) at
08C. After the mixture had been stirred at 08C for 20 min, it was
quenched with a mixture of saturated aqueous NaHCO3/Na2SO3 solution
5:1 and diluted with EtOAc (200 mL). The organic extracts were washed
with brine (”2), dried over Na2SO4, and then concentrated in vacuo.
Chromatography of the residue on silica gel (petroleum ether/EtOAc
4:1) provided 64 (248 mg, 91%) as a colorless oil. Rf =0.32 (petroleum
ether/EtOAc 3:1); [a]2D0 =À36.6 (c=0.91 in CHCl3); 1H NMR (300 MHz,
CDCl3): d=3.75 (m, 1H), 3.59 (m, 1H), 3.41 (s, 3H), 3.40 (m, 1H), 2.50
(dd, J=16.5, 5.1 Hz, 1H), 2.34 (dd, J=16.5, 7.5 Hz, 1H), 2.32 (brs, 1H;
OH), 0.10 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=102.6, 86.9,
79.9, 63.7, 57.5, 21.4, 0.0 ppm (3C); IR (film): n˜ =3431, 2960, 2831, 2171,
Diol 61: Allylether 60 (3.8 g, 20 mmol) was added to a well-stirred solu-
tion of (dihydroquinine)2-phthalazine [(DHQ)2-PHAL, 311 mg, 2 mol%],
potassium osmate (19 mg, 0.25 mol%), potassium ferricyanide (39.6 g),
and potassium carbonate (33.2 g) in a mixture of tBuOH and water (1:1,
400 mL) at 08C. The mixture was stirred at 08C until the reaction was
completed (approximately 15 h), and was then quenched with sodium sul-
fite (60 g). This mixture was stirred at RT for 4 h and then filtered. The
solid was dried in vacuo, before being boiled in EtOH (250 mL) for
30 min. After this time, the insoluble material was quickly filtered off,
and the filtrate was concentrated in vacuo. Recrystallization from EtOH/
iPrOH gave 61 as colorless solid (3.4 g, 66%) with 87% de (de=diaster-
eomeric excess, measured after acetylation of the alcohol, AD, Vu214,
hexane/2-propanol 80:20). M.p. 123–1248C; [a]2D0 =À11.6 (c=2.35 in
EtOH); 1H NMR (500 MHz, DMSO): d=6.84 (brs, 4H), 4.88 (brs, 1H),
4.63 (brs, 1H), 3.93–3.90 (m, 2H), 3.80–3.73 (m, 4H), 3.45–3.40 (m, 4H),
3.34 ppm (d, J=11.5 Hz, 2H); 13C NMR (125 MHz, DMSO): d=152.7
(2C), 115.3 (4C), 70.0 (2C), 69.9 (2C), 62.7 ppm (2C); IR (KBr): n˜ =
3492, 3255, 1512, 1462 ppm; HRMS (ESI): calcd for C12H18O6Na:
281.0996 [M+Na]+; found: 281.0995.
1251, 844 cmÀ1
;
HRMS (ESI): calcd for C9H18Si1O2Na: [M+Na]+:
209.0968; found: 209.0969.
Compound 65: Triphenylphosphine (283 mg, 1.08 mmol), 2-mercaptoben-
zothiazole (180 mg, 1.08 mmol), and diisopropyl azodicarboxylate
(0.569 mL, 1.08 mmol, 40% in toluene) were added sequentially to a so-
lution of the alcohol 64 (192 mg, 1.03 mmol) in THF (6 mL). The result-
ing reaction mixture was stirred at RT for 1h, and then loaded onto silica
gel (4 g). Chromatography of the residue on silica gel (petroleum ether/
EtOAc 30:1) provided 65 (280 mg, 81%) as a colorless oil. Rf =0.69 (pe-
troleum ether/EtOAc 10:1); [a]2D0 =À9.0 (c=0.58 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.86 (m, 1H), 7.75 (m, 1H), 7.42 (m, 1H), 7.28
(m, 1H), 3.76–3.68 (m, 2H), 3.60–3.48 (m, 1H), 3.47 (s, 3H), 2.71–2.54
(m, 2H), 0.16 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=166.6, 153.1,
135.2, 125.9, 124.1, 121.4, 120.9, 102.2, 87.4, 78.1, 57.9, 36.6, 24.5, 0.0 ppm
(3C); IR (film): n˜ =3064, 2959, 2178, 1462, 1429, 1249 cmÀ1; HRMS
(ESI): calcd for C16H21NOS2SiNa: 358.0726 [M+Na]+; found: 358.0743.
Compound 62: A solution of HBr in acetic acid (2.2 mL, 30%) was
added dropwise to tetrol 61 (500 mg, 1.94 mmol) at RT, and the reaction
mixture was stirred at 508C for 1 h. After this time, saturated aqueous
NaHCO3 and EtOAc were added, and the resulting mixture was extract-
ed with EtOAc (200 mL). The organic layer was washed with brine, dried
over Na2SO4, and then concentrated in vacuo to give a residue. K2CO3
(580 mg, 4.2 mmol) was added to a solution of this residue in MeOH
(4.5 mL) at RT. The mixture was stirred at RT for 4 h and then filtered.
The filtrate was concentrated in vacuo, and the resulting residue was di-
luted with EtOAc (100 mL). This solution was washed with brine, dried
over Na2SO4, and concentrated in vacuo. Chromatography of the residue
on silica gel (petroleum ether/EtOAc 6:1) provided 62 (390 mg, 88%) as
a colorless solid. Rf =0.30 (petroleum ether/EtOAc 4:1); m.p. 72–738C;
[a]2D0 =À8.1 (c=0.71 in CHCl3); 1H NMR (300 MHz, CDCl3): d=6.85
(brs, 4H), 4.17 (dd, J=10.8, 3.0 Hz, 2H), 3.90 (dd, J=10.8, 5.4 Hz, 2H),
3.36–3.31 (m, 2H), 2.90 (dd, J=5.1, 4.2 Hz, 2H), 2.74 ppm (dd, J=4.5,
2.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=153.1 (2C), 115.7 (4C),
69.4 (2C), 50.2 (2C), 44.6 ppm (2C); IR (KBr): n˜ =3010, 2931, 1510,
1453 cmÀ1; HRMS (ESI): calcd for C12H14O4Na [M+Na]+: 245.0784;
found: 245.0784.
Compound 66: TBAF (2.4 mL, 1.0m in THF) was added to a stirred solu-
tion of the silylethyne 65 (663 mg, 1.98 mmol) in THF (2 mL) at RT. The
mixture was stirred at RT for 1 h, and was then diluted with diethyl ether
(200 mL), washed with brine (”2), dried over Na2SO4, and concentrated
in vacuo. Chromatography of the residue on silica gel (petroleum ether/
EtOAc 15:1) provided 66 (517 mg, 99%) as a colorless oil. Rf =0.60 (pe-
troleum ether/EtOAc 10:1); [a]2D0 =À8.6 (c=2.87 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.85 (m, 1H), 7.75 (m, 1H), 7.41 (m, 1H), 7.29
(m, 1H), 3.77 (m, 1H), 3.64 (d, J=5.7 Hz, 2H), 3.50 (s, 3H), 2.62 (q, J=
2.7 Hz, 2H), 2.07 ppm (t, J=2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d=166.4, 153.1, 135.3, 126.0, 124.2, 121.4, 121.0, 79.8, 77.7, 70.8, 57.8,
36.1, 22.9 ppm; IR (film): n˜ =3298, 3063, 2932, 2121, 1460, 1428 cmÀ1
;
HRMS (ESI): calcd for C13H13NOS2Na: 286.0331 [M+Na]+; found:
286.0342.
Compound 63: nBuLi (13.1 mL, 21.0 mmol, 1.6m solution in hexane) was
added to a solution of trimethylsilylethyne (2.96 mL, 21 mmol) in dry
THF (40 mL) at À788C under argon. The mixture was stirred for 30 min
at À788C, and then BF3·Et2O (2.66 mL, 21 mmol) was added. After the
resulting mixture had been stirred for 20 min at À788C, a solution of 62
(1.59 g, 7.0 mmol) in THF (10 mL) was added dropwise. The reaction
mixture was warmed to RT, quenched with saturated NH4Cl solution,
and extracted with EtOAc (300 mL). The organic phase was washed with
brine, dried over Na2SO4, and concentrated in vacuo to give a residue.
1,8-Bis(dimethylamino)naphthalene (6.06 g, 28.4 mmol) and Me3OBF4
(4.18 g, 28.4 mmol) were then added sequentially to a solution of this res-
idue in dry CH2Cl2 (130 mL) at 08C. After the mixture had been stirred
at 08C for 3 h, it was quenched with iPrOH (13 mL) at 08C and diluted
with EtOAc (800 mL). The organic layer was washed with HCl (1n), sa-
turated aqueous NaHCO3, and brine, and then dried over Na2SO4 and
concentrated in vacuo. Chromatography of the residue on silica gel (pe-
troleum ether/EtOAc 15:1) provided 63 (2.21 g, 70% yield for two steps)
as a colorless oil. Rf =0.60 (petroleum ether/EtOAc 6:1); [a]2D0 =À21.8
(c=0.65 in CHCl3); 1H NMR (300 MHz, CDCl3): d=6.86 (m, 4H), 4.09
(m, 2H), 4.01 (m, 2H), 3.68 (m, 2H), 3.48 (s, 3H), 3.47 (s, 3H), 2.56 (m,
4H), 0.12 ppm (s, 18H); 13C NMR (75 MHz, CDCl3): d=153.0 (2C),
115.5 (4C), 102.8 (2C), 86.8 (2C), 78.0 (2C), 69.5 (2C), 57.9 (2C), 22.2
(2C), 0.0 ppm (6C); IR (film): n˜ =3402, 2949, 2837, 1653, 1451,
1027 cmÀ1; HRMS (ESI): calcd for C24H38Si2O4Na: 469.2201 [M+Na]+;
found: 469.2182.
Sulfone 7: Cp2ZrHCl (Schwartz reagent, 370 mg, 1.36 mmol) was added
to a solution of the alkyne 66 (327 mg, 1.24 mmol) in dry benzene
(15 mL) at RT. The mixture was stirred for 30 min at RT, and then NBS
(243 mg, 1.36 mmol) was added. Once the reaction was complete, the
mixture was diluted with Et2O (100 mL), washed with brine (”2), dried
over Na2SO4, and concentrated in vacuo to give a residue. Ammonium
molybdate (1.07 g, 0.87 mmol) and 30% hydrogen peroxide (3 mL) were
then added sequentially to a solution of the residue in MeOH (20 mL) at
RT. The reaction mixture was stirred for 24 h at RT, and then extracted
with EtOAc (300 mL). The organic phase was washed with brine, dried
over Na2SO4, and concentrated in vacuo. Chromatography of the residue
on silica gel (CH2Cl2/MeOH 1:1) provided 7 (260 mg, 56% yield for the
two steps). Rf =0.50 (petroleum ether/EtOAc 4:1); [a]2D0 =+26.4 (c=0.6
in CHCl3); 1H NMR (300 MHz, CDCl3): d=7.85 (m, 1H), 7.75 (m, 1H),
7.41 (m, 1H), 7.29 (m, 1H), 3.77 (m, 1H), 3.64 (d, J=5.7 Hz, 2H), 3.50
(s, 3H), 2.62 (q, J=2.7 Hz, 2H), 2.07 ppm (t, J=2.4 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=166.3, 153.0, 135.3, 133.1, 126.0, 124.3, 121.5, 121.0,
107.2, 78.6, 57.6, 36.4, 30.1 ppm; IR (film): n˜ =3298, 3063, 2932, 2121,
1460, 1428 cmÀ1
; HRMS (ESI): calcd for C13H15BrNOS2: 375.9671
[M+H]+; found: 375.9671.
Compound 67: LiNEt2 [0.050 mL, prepared at À788C from diethylamine
(0.056 mL, 0.59 mmol), BuLi (0.315 mL, 0.504 mmol, 1.60m in hexane),
and THF (0.6 mL)] was added dropwise to a precooled solution of oxa-
zole 5 (12 mg, 0.018 mmol) in THF (0.4 mL) at À788C. After the result-
ing solution had been stirred for 10 min at À788C, a solution of lactone 6
1200
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 1185 – 1204

Phorboxazole B
FULL PAPER
(12 mg, 0.024 mmol) in THF (0.15 mL) was added dropwise. The reaction
mixture was stirred at À788C for 40 min, and then quenched with satu-
rated aqueous NH4Cl and extracted with EtOAc (3”30 mL). The com-
bined organic extracts were washed with brine, dried over Na2SO4, and
then concentrated in vacuo. Chromatography of the residue on silica gel
(petroleum ether/EtOAc 8:1) provided 67 (12 mg, 61%) as a colorless
oil. Rf =0.52 (petroleum ether/EtOAc 6:1); [a]2D0 =+42 (c=0.09 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.68–7.64 (m, 4H), 7.48 (s,
1H), 7.42–7.33 (m, 6H), 7.27 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H),
6.16 (s, 1H), 5.33 (dd, J=7.5, 1.2 Hz, 1H), 5.29 (d, J=1.8 Hz, 1H), 4.57
and 4.28 (AB, JAB =10.8 Hz), 4.38 (dd, J=9.0, 5.7 Hz, 1H), 3.96 (s, 2H),
3.94–3.87 (m, 1H), 3.80 (s, 3H), 3.79–3.66 (m, 4H), 3.40 (d, J=10.2 Hz,
1H), 3.36 (s, 3H), 3.19 (dd, J=10.2, 4.5 Hz, 1H), 3.04 and 2.96 (AB,
69.1, 60.8, 55.5, 55.2, 47.9, 39.2, 35.8, 35.5, 34.2, 33.3, 31.4, 26.9 (3C), 19.2,
17.9 (3C), 17.8 (3C), 14.2, 13.7, 12.2 (3C), 10.2, 6.0 ppm; IR (film): n˜ =
2867, 1716, 1695, 1514, 1248, 1111 cmÀ1
; HRMS (ESI): calcd for
C61H89NO10Si2Na: 1074.5917 [M+Na]+; found: 1074.5906.
Diene 70: NaHMDS (82 mL, 0.165 mmol, 2m in THF) was added drop-
wise to a precooled mixture of 7 (63 mg, 0.167 mmol) and aldehyde 69
(170 mg, 0.162 mmol) in THF (2.6 mL) at À788C. The reaction mixture
was stirred at À788C for 40 min, and then quenched with buffer solution
(pH 7) and extracted with EtOAc (2”150 mL). The combined organic
extracts were washed with brine, dried over Na2SO4, and concentrated in
vacuo. Chromatography of the residue on silica gel (petroleum ether/
EtOAc 10:1) provided 70 (168 mg, 78%) as a colorless oil. Rf =0.58 (pe-
troleum ether/EtOAc 4:1); [a]2D0 =À4 (c=0.18 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.68–7.63 (m, 4H), 7.51 (s, 1H), 7.40–7.35 (m,
6H), 7.26 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.20–6.06 (m, 4H),
5.43 (dd, J=15.6, 7.8 Hz, 1H), 5.42 (d, J=7.8 Hz, 1H), 4.61 (dd, J=8.7,
6.6 Hz, 1H), 4.56 and 4.28 (AB, JAB =10.8 Hz), 3.80 (s, 3H), 3.77–3.54
JAB =15.0 Hz), 2.27 (dd, J=12.0, 3.6 Hz, 1H), 2.14–2.08 (m, 2H), 1.90 (s,
3H), 1.86–1.62 (m, 3H), 1.44 (s, 3H), 1.32–1.23 (m, 1H), 1.05 (s, 10H),
0.94 (s, 22H), 0.90 (s, 11H), 0.82 (d, J=6.6 Hz, 3H), 0.053 ppm (s, 6H);
13C NMR (100 MHz, CDCl3): d=160.3, 159.2, 138.7, 137.8, 136.7, 135.6
(3C), 135.3, 134.0, 133.9, 130.8, 129.6 (2C), 129.3 (4C), 127.6 (4C), 124.3,
117.9, 113.8 (2C), 96.5, 89.0, 83.5, 75.0, 73.7, 73.6, 70.9, 69.6, 68.0, 60.8,
55.5, 55.3, 40.9, 39.9, 35.9, 34.2, 33.3, 31.6, 26.9 (3C), 25.9 (3C), 19.3, 18.0
(3C), 17.9 (3C), 14.2 (2C), 13.8, 12.7 (3C), 6.0, À5.1, À5.2 ppm; IR
(film): n˜ =2930, 2860, 1614, 1514, 1463 cmÀ1; HRMS (ESI): calcd for
C66H103O10Si3NaN: 1176.6786 [M+Na]+; found: 1176.6744.
(m, 6H), 3.41 (d, J=9.9 Hz, 1H), 3.35 (s, 3H), 3.32 and 2.94 (AB, JAB
=
14.7 Hz), 3.28 (s, 3H), 3.26 (s, 3H), 3.20 (dd, J=10.2, 3.9 Hz, 1H), 2.38–
2.20 (m, 3H), 2.13–2.09 (m, 1H), 2.02–1.94 (m, 1H), 1.88 (s, 3H), 1.85–
1.68 (m, 2H), 1.77 (s, 3H), 1.47–1.33 (m, 2H), 1.05 (s, 31H), 0.94 (d, J=
6.6 Hz, 3H), 0.82 ppm (d, J=6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=159.2, 159.1, 138.4, 138.0, 137.4, 136.0, 135.6 (2C), 135.5 (2C), 134.1,
134.0, 133.9, 133.8, 133.2, 130.8, 129.5 (2C), 129.3 (2C), 127.9, 127.6 (4C),
118.5, 113.8 (2C), 106.2, 99.9, 89.0, 83.5, 81.2, 74.8, 73.9, 73.5, 71.8, 69.6,
60.8, 56.3, 55.5, 55.3, 47.9, 39.2, 39.1, 35.8, 35.6, 34.2, 33.3, 32.2, 26.9 (3C),
19.2, 18.0 (3C), 17.9 (3C), 14.2, 13.8, 13.6, 12.4 (3C), 6.0 ppm; IR (film):
Alcohol 68: PPTS (5 mg) was added to
a solution of 67 (7 mg,
0.006 mmol) in anhydrous MeOH (1 mL). The mixture was stirred at
308C for 12 h, and then quenched with saturated aqueous NaHCO3 solu-
tion and extracted with EtOAc (2”50 mL). The combined organic ex-
tracts were washed with brine, dried over Na2SO4, and then concentrated
in vacuo. Chromatography of the residue on silica gel (petroleum ether/
EtOAc 4:1) provided 68 (5 mg, 81%) as a colorless oil. Rf =0.31 (petro-
leum ether/EtOAc 3:1); [a]2D0 =+5 (c=0.26 in CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.64–7.63 (m, 4H), 7.52 (s, 1H), 7.45–7.33 (m,
6H), 7.28 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.7 Hz, 2H), 6.20 (s, 1H), 5.38
(d, J=8.7 Hz, 1H), 4.57 and 4.28 (AB, JAB =11.1 Hz), 4.57–4.51 (m, 1H),
3.98 (d, J=3.9 Hz, 2H), 3.80 (s, 3H), 3.76–3.54 (m, 5H), 3.41 (d, J=
n˜ =2957, 2930, 1724, 1614, 1514, 1463 cmÀ1
; HRMALDI: calcd for
C67H98NO10Si2BrNa: 1234.5804 [M+Na]+; found: 1234.5802.
Aldehyde 4: NH4F (134 mg, 3.63 mmol) was added to a solution of 70
(127 mg, 0.1 mmol) in MeOH (5 mL) at RT. The resulting mixture was
stirred at 508C for 3 h, and then quenched with saturated NH4Cl solution
and extracted with EtOAc (150 mL). The organic extracts were washed
with brine, dried over Na2SO4, and then concentrated in vacuo to give a
residue. Pyridine (39.5 mL) and Dess–Martin periodinane (51 mg,
0.12 mmol) were then added to a solution of this residue in CH2Cl2
(4 mL) at RT. The mixture was stirred at RT for 1 h, and quenched with
saturated aqueous NaHCO3/Na2S2O3 5:1. This mixture was stirred for
15 min, and then extracted with CH2Cl2 (2”60 mL). The combined or-
ganic layers were washed with brine, dried (Na2SO4), filtered, and con-
centrated in vacuo. Chromatography of the residue on silica gel (petro-
leum ether/EtOAc 4:1) provided 4 (71 mg, 71% overall yield for the two
10.2 Hz, 1H), 3.35 (s, 3H), 3.29 (s, 3H), 3.27 and 2.97 (AB, JAB
=
14.7 Hz), 3.20 (dd, J=10.5, 4.5 Hz, 1H), 2.25–2.19 (m, 1H), 2.12–2.09 (m,
1H), 2.02–1.98 (m, 1H), 1.89 (s, 3H), 1.85–1.72 (m, 3H), 1.68 (s, 3H),
1.43–1.36 (m, 1H), 1.05 (s, 31H), 0.93 (d, J=6.6 Hz, 3H), 0.82 ppm (d,
J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=159.2 (2C), 138.4, 138.1,
135.9, 135.6 (4C), 134.0, 133.9, 130.8, 129.5 (2C), 129.3 (2C), 128.7, 127.6
(4C), 125.7, 118.5, 114.6 (2C), 100.1, 89.0, 83.5, 74.9, 73.8, 73.5, 71.3, 69.6,
68.7, 60.8, 55.5, 55.3, 47.9, 39.3, 35.8, 35.6, 34.2, 33.3, 31.9, 26.9 (3C), 19.3,
18.1 (3C), 18.0 (3C), 17.9, 14.7, 13.8, 12.4 (3C), 6.1 ppm; IR (film): n˜ =
2985, 2857, 1514, 1464, 1287 cmÀ1; HRMS (ESI): calcd for C61H91O10Si2-
NaN: calcd for: 1076.6073 [M+Na]+; found: 1076.6067.
steps) as a colorless oil. Rf =0.66 (petroleum ether/EtOAc 2:1); [a]D20
=
+11.85 (c=0.40 in CHCl3); 1H NMR (300 MHz, CDCl3): d=9.76 (m,
1H), 7.51 (s, 1H), 7.27 (d, J=11.1 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.20
(s, 1H), 6.17–6.06 (m, 3H), 5.43 (dd, J=15.6, 7.8 Hz, 1H), 5.42 (d, J=
7.8 Hz, 1H), 4.63–4.56 (m, 2H), 4.31 (d, J=11.1 Hz, 1H), 4.02 (m, 1H),
3.81 (s, 3H), 3.60–3.49 (m, 4H), 3.34 (s, 3H), 3.33–3.24 (m, 2H), 3.29 (s,
3H), 3.24 (s, 3H), 2.97 (d, J=15 Hz, 1H), 2.80 (ddd, J=15.6, 8.4, 1.8 Hz,
1H), 2.47–2.14 (m, 5H), 1.93 (m, 1H), 1.89 (s, 3H), 1.82 (m, 1H), 1.69 (s,
3H), 1.36 (appt, J=11.1 Hz, 1H), 1.04 (brs, 22H), 0.98 (d, J=6.6 Hz,
3H), 0.83 ppm (d, J=6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
201.1, 159.3, 159.2, 137.8, 137.6, 137.3, 136.1, 134.0, 133.9, 133.8, 133.1,
129.3 (2C), 127.8, 118.9, 113.8 (2C), 106.2, 99.9, 89.1, 82.7, 81.2, 73.9,
73.4, 73.2, 71.7, 69.8, 56.2, 55.5, 55.2, 47.8, 46.9, 39.2, 39.1, 35.5, 34.3, 33.0,
32.1, 18.0 (3C), 17.9 (3C), 14.0, 13.7, 13.6, 12.3 (3C), 6.1 ppm; IR (film):
n˜ =2941, 2867, 1728, 1614, 1514 cmÀ1; HRMALDI: calcd for C51H78NO10-
SiBrNa: 994.4471 [M+Na]+; found: 994.4484.
Aldehyde 69: Pyridine (50 mL, 0.64 mmol) and Dess–Martin periodinane
(70 mg, 0.166 mmol) were added sequentially to a solution of alcohol 68
(135 mg, 0.128 mmol) in CH2Cl2 (6 mL). The resulting solution was stir-
red at RT for 2 h, by which point, none of the starting material was de-
tectable by TLC. After this time, the reaction was quenched by the addi-
tion of saturated aqueous NaHCO3/Na2S2O3 5:1. This mixture was stirred
for 15 min, and was then extracted with CH2Cl2 (2”300 mL). The com-
bined organic layers were washed with brine, dried (Na2SO4), filtered,
and then concentrated in vacuo. Chromatography of the residue on silica
gel (petroleum ether/EtOAc 8:1) provided 69 (126 mg, 93%) as a color-
less oil. Rf =0.61 (petroleum ether/EtOAc 4:1); [a]2D0 =+8.5 (c=1.30 in
CHCl3); 1H NMR (300 MHz, CDCl3): d=9.44 (s, 1H), 7.68–7.64 (m,
4H), 7.48 (s, 1H), 7.42–7.35 (m, 6H), 7.28 (d, J=8.4 Hz, 2H), 6.88 (d, J=
8.4 Hz, 2H), 6.38 (d, J=8.7 Hz, 1H), 6.18 (s, 1H), 4.83 (dd, J=8.4 Hz,
5.4 Hz, 1H), 4.57 (d, J=11.1 Hz, 1H), 4.29 (d, J=11.1 Hz, 1H), 3.80 (s,
3H), 3.80–3.64 (m, 5H), 3.41 (d, J=10.5 Hz, 1H), 3.33 (s, 3H), 3.30 (s,
3H), 3.24 (d, J=15.0 Hz, 1H), 3.20 (dd, J=9.9, 4.8 Hz, 1H), 2.97 (d, J=
15.02 Hz, 1H), 2.23 (dd, J=12.9, 4.2 Hz, 1H), 2.11–2.04 (m, 2H), 1.89 (s,
3H), 1.85–1.64 (m, 5H), 1.67 (m, 1H), 1.38 (appt, J=11.7 Hz, 1H), 1.05
(brs, 31H), 0.94 (d, J=6.6 Hz, 3H), 0.83 ppm (d, J=6.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=194.8, 159.1, 158.8, 152.2, 139.7, 138.5,
138.1, 136.0, 135.9 (2C), 135.6 (2C), 134.0, 133.9, 130.8, 129.5 (2C), 129.3
(2C), 127.6 (4C), 118.3, 113.8 (2C), 100.1, 88.9, 83.5, 74.8, 73.4, 73.1, 71.0,
Compound 71: Bu3P (92 mL, 0.371 mmol) was added to a solution of the
mesylate 3 (83 mg, 0.106 mmol) in dry DMF (2.5 mL) at RT. The result-
ing mixture was stirred for 15 h at this temperature, and then the mixture
was added a solution of aldehyde 4 (89 mg, 0.092 mmol) in dry DMF
(1.5 mL), followed by DBU (28 mL, 0.184 mmol). This mixture was stir-
red at RT for 2 h. Removal of the solvent in vacuo, followed by chroma-
tography of the resulting residue on silica gel (petroleum ether/EtOAc
6:1) provided 71 (137 mg, 91%) as a colorless oil. Rf =0.45 (petroleum
ether/EtOAc 4:1); [a]2D0 =+2.03 (c=0.40 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=7.68–7.65 (m, 4H), 7.51 (s, 1H), 7.42–7.35 (m 7H), 7.31 (d,
Chem. Eur. J. 2006, 12, 1185 – 1204
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1201

G.-Q. Lin, W.-S. Zhou et al.
J=9.7 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 6.63 (ddd, J=15.5, 8.2, 6.4 Hz,
1H), 6.33 (d, J=16.0 Hz, 1H), 6.21–6.07 (m, 4H), 5.43 (dd, J=15.9,
8.2 Hz, 1H), 5.42 (d, J=10.2 Hz, 1H), 4.72 (brs, 2H), 4.60 (dd, J=8.7,
6.2 Hz, 1H), 4.57 (d, J=11.0 Hz, 1H), 4.27 (d, J=10.9 Hz, 2H), 4.03 (m,
1H), 3.92 (m, 1H), 3.79 (s, 3H), 3.78–3.68 (m, 3H), 3.63 (appq, J=
7.4 Hz, 1H), 3.59–3.51 (m, 3H), 3.45 (d, J=10.2 Hz, 1H), 3.34 (s, 3H),
3.31–3.28 (m, 2H), 3.29 (s, 3H), 3.26 (s, 3H), 3.18 (dd, J=10.3, 4.4 Hz,
1H), 2.94 (d, J=14.9 Hz, 1H), 2.47 (m, 1H), 2.40–2.20 (m, 6H), 2.14 (m,
2H), 2.05–1.91 (m, 5H), 1.91 (s, 3H), 1.84–1.79 (m, 2H), 1.77 (s, 3H),
1.68 (m, 1H), 1.56–1.48 (m, 2H), 1.37 (appt, J=11.4 Hz, 1H), 1.20 (m,
1H), 1.05 (brs, 31H), 0.99 (d, J=6.9 Hz, 3H), 0.86 (s, 9H), 0.83 (d, J=
6.4 Hz, 3H), 0.03 (s, 3H), 0.02 ppm (s, 3H); 13C NMR (125 MHz,
CDCl3): d=160.8, 159.1 (2C), 142.6, 142.0, 138.0, 137.9, 137.3, 136.0,
135.6, 135.5 (4C), 134.0 (2C), 133.9 (2C), 133.8, 133.1, 130.6, 129.5 (2C),
129.3 (2C), 127.8, 127.6 (4C), 118.7, 118.6, 113.8 (2C), 110.2, 106.2, 99.9,
89.1, 83.2, 81.2, 77.2, 73.9, 73.4, 72.8, 71.7, 71.3, 69.7, 68.9, 68.5, 68.4, 60.5,
56.2, 55.5, 55.2, 47.8, 41.0, 40.7, 39.6, 39.5, 39.3, 39.2, 39.1 (2C), 36.4, 36.3,
35.5, 33.6, 33.3, 32.1, 26.8 (3C), 25.7 (3C), 19.2, 18.0 (3C), 17.9 (3C),
14.1, 13.7, 13.6, 12.3 (3C), 5.7, À4.5 ppm (2C); IR (film): n˜ =2932, 2859,
(ddd, J=13.6, 8.4, 6.3 Hz, 1H), 6.32 (d, J=16.1 Hz, 1H), 6.21–6.14 (m,
3H), 6.09 (d, J=13.6 Hz, 1H), 5.44 (dd, J=15.7, 8.1 Hz, 1H), 5.43 (d, J=
9.0 Hz, 1H), 4.79 (s, 2H), 4.62 (dd, J=8.9, 6.3 Hz, 1H), 4.40–4.34 (m,
2H), 3.98 (m, 1H), 3.87 (m, 1H), 3.63 (dd, J=14.0, 6.4 Hz, 1H), 3.59–
3.52 (m, 4H), 3.49–3.45 (m, 2H), 3.34 (s, 3H), 3.31–3.28 (m, 2H), 3.29 (s,
3H), 3.26 (s, 3H), 2.96 (d, J=15.0 Hz, 1H), 2.68 (ddd, J=16.2, 8.4,
3.0 Hz, 1H), 2.56 (m, 1H), 2.47 (ddd, J=16.1, 5.1, 1.6 Hz, 1H), 2.40–2.32
(m, 4H), 2.27–2.21 (m, 2H), 2.13–1.97 (m, 3H), 1.96–1.89 (m, 3H), 1.93
(s, 3H), 1.77 (s, 3H), 1.75–1.69 (m, 1H), 1.64–1.50 (m, 4H), 1.37 (dd, J=
12.5, 11.2 Hz, 1H), 1.29 (dd, J=23.4, 11.3 Hz, 1H), 1.12–1.04 (m, 21H),
0.99 (d, J=6.9 Hz, 3H), 0.88 (s, 9H), 0.85 (d, J=6.5 Hz, 3H), 0.08 (s,
3H), 0.07 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=200.6, 160.9,
159.2, 142.6, 140.8, 137.9, 137.8, 137.4, 136.1, 135.7, 134.0, 133.9, 133.8,
133.1, 127.9, 118.8, 118.6, 111.3, 106.2, 99.9, 88.8, 81.2, 77.5, 77.2, 76.5,
73.9, 73.5, 72.9, 71.8, 71.4, 69.4, 68.4, 67.3, 56.3, 55.6, 47.9, 47.6, 41.1, 40.6,
39.5, 39.3, 39.2, 39.1, 39.0, 37.9, 36.1, 35.5, 34.7, 32.1, 25.8 (3C), 18.0 (3C),
17.9 (3C), 14.3, 13.6, 13.4, 12.4 (3C), 5.5, À4.5 ppm (2C); IR (film): n˜ =
2945, 2866, 1716, 1463, 1361, 1253 cmÀ1
; HRMALDI: calcd for
C67H107N2O13Si2BrNa: 1305.6387 [M+Na]+; found: 1305.6390.
1718, 1514, 1463 cmÀ1
: HRMALDI: calcd for C91H135N2O14Si3BrNa:
Compound 74: (EtO)2PCH2COOH (0.18 mL, 0.1m in CH2Cl2) and DCC
(N,N-dicyclohexylcarbodiimide, 0.18 mL, 0.1m in CH2Cl2) were added se-
quentially to a solution of 73 (16 mg, 0.012 mmol) in dry CH2Cl2 (2 mL)
at RT. This mixture was stirred for 1 h, and then quenched with saturated
NaHCO3 solution and extracted with CH2Cl2 (3”30 mL). The combined
organic layers were washed with brine, dried over Na2SO4, and then con-
centrated in vacuo. Chromatography of the residue on silica gel (petro-
leum ether/EtOAc 1:1) provided 74 (15 mg, 85%) as a colorless oil. Rf =
0.30 (petroleum ether/EtOAc 1:2); [a]2D0 =À4.5 (c=0.15 in CHCl3);
1H NMR (500 MHz, CDCl3): d=9.76 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H),
6.59 (ddd, J=8.9, 8.3, 1.5 Hz, 1H), 6.31 (d, J=16.0 Hz, 1H), 6.22–6.08
(m, 3H), 5.44 (dd, J=15.7, 8.1 Hz, 1H), 5.42 (d, J=1.5 Hz, 1H), 4.81 (s,
2H), 4.78 (dd, J=18.5, 13.2 Hz, 1H), 4.62 (dd, J=8.6, 6.2 Hz, 1H), 4.38–
4.33 (m, 2H), 4.19–4.14 (m, 4H), 3.99 (m, 1H), 3.86 (m, 1H), 3.64 (m,
2H), 3.58–3.53 (m, 3H), 3.34 (s, 3H), 3.34–3.31 (m, 2H), 3.29 (s, 3H),
3.26 (s, 3H), 2.98 (d, J=21.6 Hz, 2H), 2.95 (d, J=13.4 Hz, 1H), 2.70–2.66
(m, 1H), 2.60–2.54 (m, 1H), 2.50–2.48 (m, 1H), 2.47–2.22 (m, 6H), 2.15–
1.97 (m, 6H), 1.95 (s, 3H), 1.90–1.84 (m, 1H), 1.77 (s, 3H), 1.68–1.50 (m,
9H), 1.37 (m, 7H), 1.10–0.96 (m, 21H), 0.88 (s, 9H), 0.79 (d, J=6.4 Hz,
3H), 0.08 (s, 3H), 0.07 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=
200.6, 160.8, 159.2, 142.6, 140.8, 137.8, 137.4, 137.1, 136.2, 135.3, 134.0,
133.9, 133.8, 133.2, 132.5, 127.9, 119.0, 118.8, 111.3, 106.3, 99.9, 88.8, 81.3,
80.0, 73.9, 73.5, 72.9, 71.8, 71.4, 69.4, 68.4, 67.3, 62.7, 62.6, 56.3, 55.6, 47.9,
47.6, 41.1, 40.7, 39.5, 39.3, 39.2, 39.1, 39.0, 36.0, 35.6, 35.4, 33.9, 32.2, 32.1,
29.3, 29.2, 25.8 (3C), 18.0 (3C), 17.9(3C), 16.3, 16.2, 14.2, 13.6, 13.2, 12.4
(3C), 6.2, À4.5 ppm (2C); IR (film): n˜ =2929, 2857, 1732, 1464,
1665.8297 [M+Na]+; found: 1665.8304.
Alcohol 72: NH4F (134 mg, 3.62 mmol) was added to a solution of 71
(18 mg, 0.011 mmol) in MeOH (1 mL) at RT. The resulting mixture was
stirred at 508C for another 3.5 h, and then quenched with saturated
NH4Cl solution and extracted with EtOAc (100 mL). The organic ex-
tracts were washed with brine, dried over Na2SO4, and then concentrated
in vacuo. Chromatography of the residue on silica gel (petroleum ether/
EtOAc 2:1) provided 72 (11 mg, 71%) as a colorless oil. Rf =0.49 (petro-
leum ether/EtOAc 1:1); [a]2D0 =+2.89 (c=0.25 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=7.51 (s, 1H), 7.46 (s, 1H), 7.28 (d, J=8.7 Hz, 2H),
6.87 (d, J=8.7 Hz, 2H), 6.65 (ddd, J=15.4, 8.4, 6.3 Hz, 1H), 6.34 (d, J=
16.0 Hz, 1H), 6.22–6.08 (m, 4H), 5.43 (dd, J=15.8, 8.1 Hz, 1H), 5.42 (d,
J=11.0 Hz, 1H), 4.75 (d, J=16.9 Hz, 2H), 4.61 (dd, J=8.8, 6.3 Hz, 1H),
4.57 (d, J=11.0 Hz, 1H), 4.36 (d, J=11.7 Hz, 1H), 4.28 (d, J=11.0 Hz,
1H), 4.09–4.06 (m, 2H), 4.01–3.99 (m, 1H), 3.88 (m, 1H), 3.80 (s, 3H),
3.80–3.70 (m, 2H), 3.64 (dd, J=15.0, 7.5 Hz, 1H), 3.59–3.51 (m, 4H),
3.46 (d, J=10.2 Hz, 1H), 3.34 (s, 3H), 3.31–3.28 (m, 2H), 3.29 (s, 3H),
3.26 (s, 3H), 3.18 (dd, J=10.4, 4.5 Hz, 1H), 2.94 (d, J=15.0 Hz, 1H),
2.58 (ddd, J=13.0, 5.4, 5.4 Hz, 1H), 2.41–2.21 (m, 6H), 2.15–2.10 (m,
3H), 2.08–1.95 (m, 3H), 1.91 (s, 3H), 1.85–1.76 (m, 2H), 1.76 (s, 3H),
1.63–1.58 (m, 2H), 1.52 (m, 1H), 1.37 (m, 2H), 1.09–1.04 (m, 22H), 0.98
(d, J=6.8 Hz, 3H), 0.88 (s, 9H), 0.82 (d, J=6.4 Hz, 3H), 0.08 (s, 3H),
0.07 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=161.0, 159.7, 159.1,
142.3, 141.5, 138.0, 137.9, 137.3, 136.1, 136.0, 134.1, 133.9, 133.8, 133.1,
130.6, 129.3 (2C), 127.8, 118.7, 118.4, 113.8 (2C), 110.5, 106.2, 99.9, 89.1,
83.2, 81.2, 77.2, 73.9, 73.7, 73.4, 71.7, 71.2, 70.9, 69.8, 69.7, 68.4, 60.5, 56.2,
55.5, 55.2, 47.9, 41.4, 40.2, 40.1, 39.2, 39.1 (2C), 38.5, 36.3, 36.2, 35.5, 33.7,
33.3, 32.1, 25.8 (3C), 18.0 (4C), 17.9 (3C), 14.1, 13.7, 13.6, 12.3 (3C), 5.7,
À4.5 ppm (2C); IR (film): n˜ =2944, 2866, 1614, 1514, 1464, 1250,
1259 cmÀ1
; HRMALDI: calcd for C73H118N2O17Si2BrPNa: 1483.6782
[M+Na]+; found: 1483.6745.
Macrolide 75: A mixture of K2CO3 (11.4 mg, 82.6 mmol) and [18]crown-6
(90 mg, 0.34 mmol) in toluene (5 mL) was vigorously stirred at RT for
5 h, before being added a solution of 74 (10 mg, 6.8 mmol) in dry toluene
(3.5 mL) at À208C. The resulting mixture was stirred for 2 h at À208C,
and was then warmed to 08C over 10 h. After this time, the mixture was
extracted with EtOAc (150 mL) and the organic layer was washed with
brine (”2), dried over Na2SO4, and then concentrated in vacuo. Chroma-
tography of the residue on silica gel (petroleum ether/EtOAc 4:1) provid-
ed 75 (5 mg, 56%) as a colorless oil. Rf =0.60 (petroleum ether/EtOAc
2:1); [a]2D0 =+3.7 (c=0.2 in CHCl3); 1H NMR (500 MHz, CDCl3): d=
7.53 (s, 1H), 7.48 (s, 1H), 6.67 (ddd, J=16.0, 9.7, 6.5 Hz, 1H), 6.29 (d,
J=15.9 Hz, 1H), 6.26 (s, 1H), 6.20–6.14 (m, 2H), 6.09 (d, J=13.6 Hz,
1H), 5.91 (s, 2H), 5.46–5.41 (m, 2H), 4.97 (s, 1H), 4.62 (m, 2H), 4.51
(dd, J=11.2, 4.5 Hz, 1H), 4.20 (d, J=12.1 Hz, 1H), 4.18–4.11 (m, 1H),
3.98–3.96 (m, 1H), 3.94–3.88 (m, 1H), 3.64 (dd, J=13.6, 6.2 Hz, 1H),
3.59–3.52 (m, 5H), 3.52–3.43 (m, 1H), 3.34 (s 3H), 3.30 (d, J=14.9 Hz,
1H), 3.29 (s, 3H), 3.26 (s, 3H), 2.96 (d, J=14.9 Hz, 1H), 2.63 (d, J=
12.0 Hz, 1H), 2.60–2.50 (m, 1H), 2.43–2.38 (m, 2H), 2.36–2.31 (m, 2H),
2.26 (m, 1H), 2.24–2.20 (m, 1H), 2.14 (dd, J=7.7, 4.5 Hz, 1H), 2.08–1.93
(m, 6H), 1.98 (s, 3H), 1.84 (m, 2H), 1.77 (s, 3H), 1.68 (m, 1H), 1.45–1.32
(m, 3H), 1.06–1.04 (m, 21H), 0.96 (d, J=6.9 Hz, 3H), 0.9 (s, 9H), 0.77
(d, J=6.4 Hz, 3H), 0.09 ppm (s, 6H); 13C NMR (125 MHz, CDCl3): d=
1091 cmÀ1
; HRMALDI: calcd for C75H117N2O14Si2BrNa: 1427.7119
[M+Na]+; found: 1427.7124.
Aldehyde 73: Pyridine (6.7 mL) and Dess–Martin periodinane (10.8 mg,
0.026 mmol) were added to a solution of 72 (24 mg, 0.017 mmol) in
CH2Cl2 (2.5 mL) at RT. The mixture was stirred at RT for 1 h, and then
quenched with saturated aqueous NaHCO3/Na2S2O3 (5:1, 1 mL). This
mixture was stirred for 5 min, and then extracted with CH2Cl2 (2”
60 mL). The combined organic layers were washed with brine, dried
(Na2SO4), and then filtered through a short pad of silica gel. Finally, the
filtrate was concentrated in vacuo to give a residue. DDQ (16 mg,
0.08 mmol) was then added to a solution of the residue in CH2Cl2
(2.5 mL) and buffer (0.25 mL, pH 7) at RT. The resulting mixture was
stirred vigorously for 2 h, before being quenched with saturated aqueous
NaHCO3 (2 mL). The separated aqueous phase was extracted with
CH2Cl2 (2”30 mL), and the combined organic extracts were washed with
brine, dried over Na2SO4, and then concentrated in vacuo. Chromatogra-
phy of the residue on silica gel (petroleum ether/EtOAc 2:1) provided 73
(15 mg, 73% overall yield for the two steps) as a colorless oil. Rf =0.50
1
(petroleum ether/EtOAc 1:1); [a]2D0 =À0.67 (c=0.75 in CHCl3); H NMR
(500 MHz, CDCl3): d=9.75 (m, 1H), 7.52 (s, 1H), 7.44 (s, 1H), 6.62
1202
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Chem. Eur. J. 2006, 12, 1185 – 1204

Phorboxazole B
FULL PAPER
165.6, 161.2, 159.2, 144.3, 141.7, 137.9, 137.4, 137.2, 136.3, 134.2, 134.0,
133.9, 133.8, 133.2, 127.6, 121.0, 119.3, 119.2, 110.1, 106.3, 99.9, 89.3, 81.2,
79.5, 78.0, 73.9, 73.5, 72.3, 71.8, 70.8, 69.0, 68.6, 56.3, 55.6, 47.9, 42.0, 41.2,
39.2, 39.1, 39.0, 37.7, 36.9, 35.6, 34.3, 33.9, 32.6, 32.2, 31.8, 30.4, 25.8 (3C),
25.6, 24.9, 18.0 (3C), 17.9 (3C), 14.2, 13.6, 13.3, 12.4 (3C), 5.9, À4.5 ppm
[5] a) C. S. Lee, C. J. Forsyth, Tetrahedron Lett. 1996, 37, 6449; b) R. D.
Cink, C. J. Forsyth, J. Org. Chem. 1997, 62, 5672; c) F. Ahmed, C. J.
Forsyth, Tetrahedron Lett. 1998, 39, 183; d) C. J. Forsyth, F. Ahmed,
R. D. Cink, C. S. Lee, J. Am. Chem. Soc. 1998, 120, 5597.
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2533; c) D. A. Evans, D. M. Fitch, Angew. Chem. 2000, 112, 2636;
Angew. Chem. Int. Ed. 2000, 39, 2536; d) D. A. Evans, D. M. Fitch,
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1999, 1, 909; b) A. B. Smith, K. P. Minbiole, P. R. Verhoest, T. Beau-
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Minbiole, M. Schelhaas, J. Am. Chem. Soc. 2001, 123, 4834; d) A. B.
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39, 319; c) G. Pattenden, A. T. Plowright, Tetrahedron Lett. 2000, 41,
983; d) M. A. Gonzµlez, G. Pattenden, Angew. Chem. 2003, 113,
1295; Angew. Chem. Int. Ed. 2003, 42, 1255; e) G. Pattenden, M. A.
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b) D. R. Williams, M. P. Clark, M. A. Berliner, Tetrahedron Lett.
1999, 40, 2287; c) D. R. Williams, A. A. Kiryanov, U. Emde, M. P.
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[12] For a reviewon Wacker oxidation see: J. Tsuji, Synthesis 1984, 369.
[13] The aldehyde 12 was synthesized from the known ethyl 2-hydroxy-
methyloxazole-4-carboxylate (see: J. S. Panek, R. T. Beresis, J. Org.
Chem. 1996, 61, 6496) by silylation of the primary hydroxyl (TBSCl,
imidazole, DMF, RT, 96%), followed by partial reduction of the
ester (DIBAL, CH2Cl2, À788C, 85%).
(2C); IR (film): n˜ =2945, 2865, 1722, 1464, 1188, 1158, 1112, 1091 cmÀ1
;
HRMALDI: calcd for C69H107N2O13Si2BrNa: 1329.6387 [M+Na]+; found:
1329.6392.
Compound 2: TBAF (15 mL, 1.0m solution in THF) was added to a solu-
tion of 75 (5 mg, 0.0038 mmol) in THF (2 mL) at RT. The resulting mix-
ture was stirred at RT for 10 h, and was then filtered through a pad of
silica gel (eluted with EtOAc). The filtrate produced was concentrated in
vacuo to give a residue. Aqueous HCl solution (0.3 mL, 6%) was added
to a solution of the residue in THF (0.8 mL) at RT. The resulting mixture
was stirred at RT for 70 h, and was then quenched with saturated
NaHCO3 solution and extracted with CH2Cl2 (3”30 mL). The combined
organic layers were washed with brine, dried over Na2SO4, and concen-
trated in vacuo. Chromatography of the residue on silica gel (EtOAc/
MeOH 150:1) provided 2 (2 mg, 51%) as an amorphous solid. Rf =0.60
(EtOAc/MeOH 15:1); [a]D20 =+35 (c=0.1 in CH2Cl2; lit.[6d] =+32.0, c=
0.2 in CH2Cl2); 1H NMR (500 MHz, CDCl3): d=7.57 (s, 1H; C30H), 7.47
(s, 1H; C17H), 6.67 (ddd, J=16.3, 9.8, 6.7 Hz, 1H; C20H), 6.29 (d, J=
16.0 Hz, 1H; C19H), 6.24 (s, 1H; C28H), 6.19 (d, J=15.8 Hz, 1H; C41H),
6.19–6.15 (m, 1H; C45H), 6.09 (d, J=13.6 Hz, 1H; C46H), 5.92 (m, 2H;
C2H and C3H), 5.50 (dd, J=15.8, 7.9 Hz, 1H; C42H), 5.36 (d, J=9.2 Hz,
1H; C39H), 5.27 (d, J=2.0 Hz, 1H; C33OH), 4.96 (s, 1H; C51H), 4.62 (s,
1H; C51H), 4.51 (dd, J=11.1, 4.5 Hz, 1H; C24H), 4.31 (dd, J=8.8, 8.8 Hz,
1H; C38H), 4.23 (d, J=11.8 Hz, 1H; C15H), 4.17 (m, 1H; C5H), 4.00–3.94
(m, 2H; C9H and C13H), 3.82–3.74 (m, 2H; C35H and C37H), 3.64 (ddd,
J=6.9, 6.2, 6.2 Hz, 1H; C43H), 3.60–3.43 (m, 3H), 3.58 (d, J=10.1 Hz,
1H; C26H), 3.36 (s, 3H; C35OMe), 3.26 (s, 3H; C43OMe), 3.15 (d, J=
15.5 Hz, 1H; C32H), 3.07 (d, J=15.7 Hz, 1H; C32H), 2.63 (d, J=11.8 Hz,
1H; C8H), 2.54 (m, 1H; C21H), 2.43 (m, 2H), 2.36–2.22 (m, 6H), 2.06
(brd, J=13.6 Hz, 1H; C6H), 2.06–1.95 (m, 4H), 1.98 (s, 3H; C48H3), 1.85
(dd, J=15.7, 11.2 Hz, 1H; C8H), 1.81 (s, 3H, C47H3), 1.64 (appq, J=
11.3 Hz, 1H; C14H), 1.50 (m, 1H), 1.38–1.29 (m, 2H), 1.11 (appq, J=
11.6 Hz, 1H; C36H), 0.96 (d, J=6.9 Hz, 3H; C50H3), 0.77 ppm (d, J=
6.4 Hz, 3H; C49H3); IR (film): n˜ =3409, 2932, 2854, 1718, 1439, 1360,
1194 cmÀ1; HRMALDI: calcd for C53H71N2O13BrNa: 1045.4032 [M+Na]+;
found: 1045.4072.
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[43] Column: Rt-bDEXCSTTM, 30 meter, 0.25 mm ID, 25 mm df.
Received: July 27, 2005
Published online: November 3, 2005
1204
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Chem. Eur. J. 2006, 12, 1185 – 1204