Total synthesis of the proposed structure of iriomoteolide-1a

Article abstract of DOI:10.1016/j.tet.2011.07.066

Full details of the total synthesis of the proposed structure of iriomoteolide-1a (1) are described. The key steps include (i) a Sakurai reaction between allylsilane 11 and aldehyde 10 that bears both a tertiary chiral center and vinyl iodide moiety (ii)

Full text of DOI:10.1016/j.tet.2011.07.066

Tetrahedron 67 (2011) 7485e7501
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Tetrahedron
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Total synthesis of the proposed structure of iriomoteolide-1a
*
Jun Xie, Yuelong Ma, David A. Horne
Department of Molecular Medicine, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 May 2011
Received in revised form 17 July 2011
Accepted 20 July 2011
Available online 27 July 2011
Full details of the total synthesis of the proposed structure of iriomoteolide-1a (1) are described. The key
steps include (i) a Sakurai reaction between allylsilane 11 and aldehyde 10 that bears both a tertiary
chiral center and vinyl iodide moiety (ii) an anti-aldol reaction to construct the C18/C19 chiral centers (iii)
a B-alkyl SuzukieMiyaura coupling reaction to assemble the C7eC23 fragment, and (iv) a macrocyclic
ring-closing metathesis to complete the construction of the target molecule. Two different approaches to
access penultimate precursor 2 are delineated. The NMR spectra of the synthetic iriomoteolide-1a (1)
were found not to match those reported for the natural product bringing into question its true structural
identity.
Keywords:
Iriomoteolide-1a
SuzukieMiyaura coupling reaction
Sakurai reaction
Ó 2011 Elsevier Ltd. All rights reserved.
Yamaguchi esterification
Ring-closing metathesis
1. Introduction
intermediate 2 could be obtained from esterification between
C7eC23 fragment 3 and C1eC6 acid fragment 4. The C7eC23
Iriomoteolide-1a (1) was isolated from the Amphidinium sp.
strain HYA024 by Tsuda’s group and its structure was elucidated
through 2D NMR and mass spectral analysis.1 Iriomoteolide-1a
possesses potent cytotoxicity with IC50 values against human B
lymphocyte DG-75 cells and EpsteineBarr virus-infected human B
lymphocytes of 2 and 3 ng/mL, respectively. Iriomoteolide-1a (a) is
a synthetically challenging target characterized by a hemiketal ring
that consists of a tertiary chiral center and an exocyclic methylene
group, three pairs of chiral vicinal methyl/hydroxyl groups, and
a trisubstituted Z-unsaturated ester. Because of its important bi-
ological activity and unique structure, iriomoteolide-1a (1) has
become a target of significant interest for synthetic chemists.2
Herein, we report the full account of the total synthesis of the
proposed structure of iriomoteolide-1a (1) for which synthetic
iriomoteolide-1a (1) was found not to match that of the natural
material isolated from nature.3
fragment 3 can be further dissected into smaller subunits, that is,
comprised of vinyl iodide 5 or 6 and alkyl iodide 7, derived from a B-
alkyl SuzukieMiyaura cross-coupling reaction.5 Vinyl iodides 5 or 6
could be prepared from allylsilane 11 and aldehydes 9 or 10, re-
spectively using Sakurai methodology.6 Alkyl iodide
7 is
approached via an anti-aldol reaction whereas C1eC6 fragment 4
can be generated from known diol 8 that also harbors the two
requisite chiral centers.
2.1.2. Synthesis of 5 with PMB group on tertiary center. The prepa-
ration of allylsilane 11 commenced with ring opening of epoxide
137 with commercially available 12 in the presence of t-BuLi and CuI
to provide allyltrimethylsilane 14 in excellent yield.8 The resulting
alcohol was protected with TES to generate 11 (Scheme 1).
The synthesis of aldehyde 9 began with primary alcohol 152c
which contains the requisite chiral tertiary center. Oxidation of 15
followed by homologation with BestmanneOhira reagent9 pro-
duced alkyne 16. Hydrohalogenation10 of 16 was accomplished in
two steps to afford E-vinyl iodide 17. When E-vinyl iodide 17 was
treated with DIBAL-H, the anticipated primary alcohol, 18, was
formed only as the minor product. The ratio of 18 to 19 is approx-
imately 1:4 in 72% overall yield (Scheme 2).
Because of the disappointing yield of forming primary alcohol
18, an alternative method was pursued (Scheme 3). Acetal substrate
21 was prepared from known diol 20.11 Although DIBAL-H re-
duction of a similar substrate has been reported in the literature12
(ethyl group instead of methyl at the tertiary center) to provide the
desired primary alcohol corresponding to 23, reduction of substrate
2. Results and discussion
2.1. First generation synthesis of key intermediate 2
2.1.1. Retrosynthetic analysis. The retrosynthetic strategy for
iriomoteolide-1a (1) is shown in Fig. 1. The final assembly of 1 by
this route was approached via ring-closing metathesis.4 Key
* Corresponding author. Tel.: þ1 626 256 4673; fax: þ1 626 930 5410; e-mail
address: dhorne@coh.org (D.A. Horne).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.066

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J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
Fig. 1. Retrosynthetic analysis of iriomoteolide-1a (1).
Scheme 1. Synthesis of 11.
Scheme 3. Synthesis of 9.
reaction with CrCl2 and CHI3 yielded vinyl iodide 24.13 The desired
aldehyde, 9, is obtained via deprotection of TBDPS followed by
oxidation of the resulting alcohol with DesseMartin reagent.14
Sakurai reaction6 between aldehyde 9 and allylsilane 11 was
initially attempted with BF3$OEt2. While these conditions were
successfully adopted in our previous model system, only trace
amounts of desired product 5 was observed. Fortunately, when
SnCl4 was used, product 5 was obtained in 51% yield and 2:1 dr
(Scheme 4). To consistently obtain decent yields, this reaction
should be quenched with Et3N before adding satd NaHCO3.
Scheme 2. Synthesis of 18.
21 with DIBAL-H under the same conditions resulted in product 23
as the minor product (ratio of 22 to 23 is approximately 3:1) in 82%
overall yield. Oxidation of the primary alcohol 23 followed by
2.1.3. Synthesis of 6 with TES group on tertiary center. Although the
Sakuraireactionworked wellforaldehyde9, theyieldtoprepare 9was

J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
7487
and excellent yield as well as recovery of the chiral auxiliary after
chromatography. Displacement of tosylate 35 with iodide under
Finkelstein conditions afforded SuzukieMiyaura coupling partner,
alkyl iodide 7 (Scheme 7).
Scheme 4. Synthesis of 5.
too low for scale up. To circumvent this problem, aldehyde 10 bearing
a TES group on the tertiary alcohol instead of PMB group was pursued
(Scheme 5). Conversion of acetal 17 into its bisTES ether 26 was ac-
complished in two steps. Selective deprotection of the primary TES
group and subsequent oxidation yielded aldehyde 10. This versatile
intermediate represents a key structural component to which the
remainder of the fragment can be linked in a bidirectional manner.
Scheme 5. Synthesis of 10.
When SnCl4 was used in the reaction with allylsilane 11 and
aldehyde 10, product 6 was obtained in satisfactory yield and 4:1 dr
(Scheme 6). The configuration of the newly formed chiral center
was not determined at this time; however, a chelation controlled
addition product is presumed. Note that chirality at this center is
removed in subsequent steps via oxidation to the corresponding
ketone functionality. At this point, vinyl iodide 6, which will be
used in SuzukieMiyaura coupling reaction, has been obtained.
Scheme 7. Synthesis of 7.
Scheme 6. Synthesis of 6.
2.1.5. Synthesis of complete C7eC23 fragment 3. With alkyl iodide 7
and vinyl iodide 6 in hand, the B-alkyl SuzukieMiyaura coupling17
reaction was performed (Scheme 8). Treatment of alkyl iodide 7
with t-BuLi and 9-BBN followed by subsequent coupling with vinyl
iodide 6 in the presence of Pd(dppf)Cl2 catalyst afforded coupled
products. Initially, we thought the desired product, 38, was pro-
duced but upon oxidation of this product with DesseMartin re-
agent or SO3$py only trace amounts of product 37 could be
obtained. Based on this result, we reconsidered that the main
product of the SuzukieMiyaura coupling reaction was in fact, 36
not 38. The tertiary TES group undergoes migration to the vicinal
secondary alcohol under the SuzukieMiyaura coupling conditions.
To prevent migration of the TES group in 6 during the Suzu-
kieMiyaura coupling reaction, the alcohol moiety was protected as
2.1.4. Synthesis of alkyl iodide 7. Starting from (3S)-methyl
hydroxybutyrate, allylation provided 27 in good yield with high
dr.15 Reduction of 27 with LiAlH4 followed by treatment with 4-
methoxybenzaldehyde dimethyl acetal afforded acetal 28. Selec-
tive reduction with DIBAL-H generated primary alcohol 29, which
was converted to 30 via mesylation and reduction. Ozonolysis of
the terminal alkene provided aldehyde 31. In the presence of 32 and
(c-Hex)2BOTf, anti-aldol product, 33, was obtained in excellent
yield and good dr.16 The newly formed secondary alcohol was
protected as its TES ether. DIBAL-H reduction of 34 yielded the
corresponding primary alcohol but due to difficulties in separation
of the desired product from the chiral auxiliary, the crude mixture
was treated with excess TsCl. This afforded tosylate 35 in pure form

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J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
Following conditions previously developed in our model study2c
treatment of 42 with HF$py produced 3. Under these conditions,
double bond migration of the -unsaturated ketone to -un-
saturated system was not observed.
b
,g
a,b
Scheme 10. Mechanism vicinal TES group cleavage.
2.1.6. Synthesis of C1eC6 fragment 4. With the C7eC23 fragment in
hand, our attention turned to the preparation of the acid fragment
containing C1eC6. The synthesis of acid fragment 4 starts from
known diol 816 (Scheme 11). Treatment of diol
8 with 4-
Scheme 8. Attempted synthesis of 37.
methoxybenzaldehyde dimethyl acetal followed by selective re-
duction with DIBAL-H afforded primary alcohol 44, which was
oxidized to aldehyde 45 with DesseMartin periodinane. Conver-
sion of 45 to propionate 46 was achieved via two steps. Addition of
propionate 46 with methyllithium in the presence of copper(I) io-
dide18 generated Z-alkenoic ester 47. Ester saponification using 1 M
LiOH in MeOH/THF gave acid fragment 4 in high yield upon acidic
work-up.
the corresponding acetate to furnish 39 in high overall efficiency
(Scheme 9). The new vinyl iodide, 39, and alkyl iodide 7 underwent
smooth coupling in excellent yield to afford the linear C7eC23
fragment 40 of iriomoteolide-1a. Upon LiAlH4 cleavage of the ace-
tate functionality of 40, concomitant deprotection of the vicinal
tertiary TES group was observed producing diol, 41, in excellent
yield. The secondary TES group was untouched during this process.
The likely mechanism is shown in Scheme 10. Interestingly, this
sequence may have general implications for selectively removing
TES groups over others that are not vicinal to acetates. Oxidation of
2.1.7. Synthesis of key intermediate 2. With secondary alcohol 3 and
acid 4 in hand, esterification was accomplished under Yamaguchi
conditions19 (Scheme 12). Treatment of
4
with 2,4,6-
diol 41 produced
-unsaturated ketone 42 is relatively unstable and the double
bond slowly migrates to afford -unsaturated ketone 43 in solu-
tion. Ketone 42 should be used immediately in the next step.
b,g-unsaturated ketone 42. It is worth noting that
trichlorobenzoyl chloride and Et3N followed by addition of DMAP
and alcohol 3 generated desired product 48 in 50e60% yield with
some decomposed material due to instability of the exocyclic
methylene-bearing ketal unit. Application of other conditions such
b,g
a,b
Scheme 9. Synthesis of 3.

J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
7489
formed from 49 through global deprotection of PMB groups and
concominant cyclization. In turn, 49 would be obtained from vinyl
iodide 50, which would be derived from allylsilane 51 and aldehyde
10. This approach involves performing the esterification prior to
hemiketal ring formation for which a possible improvement in the
efficiency of esterification may be realized.
Fig. 2. Retrosynthetic analysis.
Scheme 11. Synthesis of 4.
2.2.2. Synthesis of 51. At first, the preparation of allylsilane 51 di-
rectly from its corresponded alcohol 14 through protection with
PMB (Scheme 13) was attempted. Efforts, however, to obtain 51
failed under both basic and acidic conditions (basic conditions:
NaH, PMBCl or KHMDS, PMBCl; acidic conditions: Sc(OTf)3 or PPTS
or TsOH, and PMBO(C]NH)CCl3).
Scheme 13. Attempted Synthesis of 51.
Since the allylsilane group in 14 is sensitive to acidic and basic
conditions, PMB installation on the chiral hydroxyl moiety needs to
occur prior to formation of the allylsilane (Scheme 14). Epoxide ring
opening of 13 with 1,3-dithiane followed by protection with PMB
provided 52 in good yield.21 The dithiane group was converted into
ester 53 in three steps (i) hydrolysis to the aldehyde, (ii) Pinnick
oxidation22 to the corresponding carboxylic acid, and (iii) methyl-
ation in 80% yield. Treatment of ester 53 with anhydrous CeCl3 and
TMSCH2MgCl generated desired allylsilane 51.23
Scheme 12. Synthesis of 2.
as EDCI, MNBA(2-methyl-6-nitrobenzoic anhydride)20 only pro-
vided trace amounts of product. Deprotection of the PMB group
afforded precursor 2, which is primed for ring-closing metathesis.
2.2. Second generation synthesis of key intermediate 2
2.2.1. Retrosynthetic analysis. Since esterification between 3 and 4
proceeded in relatively low yield coupled to the difficulty in chro-
matographic separation of by-products, an alternative strategy for
preparing penultimate intermediate 2 was pursued. The retro-
synthetic analysis is shown in Fig. 2. Key intermediate 2 could be
Scheme 14. Synthesis of 51.
2.2.3. Synthesis of 50. With allylsilane 51 in hand, Sakurai reaction
with aldehyde 10 gave 54 in satisfactory yield (Scheme 15).

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J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
Protection of the newly formed hydroxyl group gave vinyl iodide
50, the key substrate in the B-alkyl SuzukieMiyaura coupling
reaction.
Scheme 15. Synthesis of 50.
Alternatively, vinyl iodide, 50, also can be obtained from pre-
viously synthesized fragment 6 through exchange of protecting
groups (Scheme 16). Protection of 6 with TBS group and selective
deprotection of secondary TES group produced 56. The hydroxyl
group of 56 was protected with PMB in the presence of catalytic
amount of Sc(OTf)3 to provide 50.
Scheme 17. Synthesis of 59.
order to obtain the desired macrocyclic ring product, it was evi-
dent that the hemiketal unit must be formed prior to olefin
metathesis.
OPMB
OR1
R2O
2nd generation
Grubbs' catalyst
O
OPMB
O
CH2Cl2, rt
OPMB
49 R1=TES, R2=TBS
59 R1=H, R2=H
OPMB
Scheme 16. Alternative synthesis of 50.
OR1
R2O
O
O
2.2.4. Yamaguchi reaction for new substrates. B-Alkyl Suzu-
kieMiyaura coupling reaction between 50 and 7 produced de-
sired fragment 57 in good yield. Selective deprotection of the TES
group afforded substrate 58 for Yamaguchi esterification.19 Since
decomposition of the sensitive hemiketal functionality was
averted (which was prevalent in the conversion of 3e48), es-
terification between 58 and acid 4 provided 49 in 93% yield.
With this gratifying result, removal of the two Si protecting
groups with TBAF produced olefin metathesis precursor 59
(Scheme 17).
PMBO
OPMB
60 R1=TES, R2=TBS 52%
61 R1=H, R2=H 54%
Scheme 18. Attempted synthesis of macrocyclic ring.
2.2.6. Alternative synthesis of key intermediate 2. At this stage, only
two steps remained to key intermediate 2 from diol 59 (Scheme 19).
Diol 59 was oxidized to b,g-unsaturated ketone 62 with SO3$py.
Global deprotection along with concomitant hemiketal cyclization
was observed after treatment of 62 with DDQ to afford key in-
termediate 2 in 67% yield. The C13 stereochemistry of hemiketal 2
2.2.5. Attempted synthesis of macrocyclic ring. As noted, ring-
closing metathesis of 49 and 59 was attempted as a means to
access the macrocyclic ring products; however, when 49 or 59
were treated with second generation Grubbs’ catalyst,24 only five-
member ring products 60 or 61 were formed (Scheme 18). In

J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
7491
was confirmed through an observed ROSEY interaction between H9
and C13eOH.
assignment of the natural product. Based on chemical shift of H4 in
natural product, it is likely that the C2eC3 double bond configu-
ration of natural product is E instead of Z. Recently, Yang’s group2j
reported the synthesis of this iriomoteolide-1a diastereomer,
however, this diastereomer still does not match that of the natural
product. Finally, anti-cancer activity for synthetic 1 was examined
in two different cell lines (Raji and A431) and unfortunately no
significant cytotoxicity was observed at 10 mM concentration.
3. Conclusion
Our group was the first to complete the total synthesis of the
proposed structure of iriomoteolide-1a (1) by applying a late stage
Yamaguchi esterification and ring closing metathesis reaction. The
advanced ring closing metathesis precursor, 2, was obtained from
two different routes, the latter of which proved to be more efficient.
B-Alkyl SuzukieMiyaura cross-coupling reaction was efficiently
utilized in constructing the C7eC23 fragment of iriomoteolide-1a.
The versatile aldehyde intermediate 10, which bears the requisite
tertiary chiral center and vinyl iodide group, possesses bidirectional
functionality, that is, suitable for Sakurai and B-alkyl Suzu-
kieMiyaura coupling reactions. Comparison of the NMR spectra of
synthetic iriomoteolide-1a (1) with those of the natural product
suggests that the original structure of iriomoteolide-1a (1) was
misassigned.25 The actual structure of 1 remains a mystery. The
extremely potent anti-cancer activity displayed by iriomoteolide-
1a warrants further investigation of this active principle and
work in this area is currently in progress.
Scheme 19. Alternative synthesis of key intermediate 2.
2.3. Completion of the total synthesis and NMR spectra
comparison
2.3.1. Completion of the total synthesis of 1. After the successful
preparation of 2 by two different strategies, treatment with second
generation Grubbs’ catalyst yielded E- and Z-products
iriomoteolide-1a (1) and 63 in 2.5:1 ratio, respectively (Scheme
20).24
4. Experimental section
4.1. General information
All reagents and solvents were commercial grade and purified
prior to use when necessary. TLC was performed on Silica Gel 60
F254 from EMD. Visualization was performed by ultraviolet light
and/or by staining with potassium permanganate. Flash Chroma-
tography was performed using Silica Gel 60 (particle size
40e63 m
m). All 1H and 13C NMR spectra were recorded at 400 MHz
and 100 MHz (Varian), respectively, at rt. Optical rotations were
measured on JASCO p-2000 polarimeter. High-resolution mass
spectrometry (HRMS) data were obtained from Thermo Electron
LTQ-FT hybrid linear ion trap and Fourier transform ion cyclotron
resonance mass spectrometer. IR spectra were recorded as thin
films on Thermo Nicolet IR200 and are reported at 23 ꢀC in wave-
numbers (cmꢁ1).
4.2. Experimental procedure
4.2.1. Allylsilane 14. To a stirred solution of 12 (900 mg, 4.68 mmol,
2 equiv) in Et2O (1.5 mL) was added t-BuLi (1.5 M in pentane,
9.83 mmol, 4.2 equiv) at ꢁ78 ꢀC. After 2 h at ꢁ78 ꢀC, the solution
was transferred to suspension of CuI (492 mg, 2.57 mmol, 1.1 equiv)
in Et2O (7 mL) at ꢁ78 ꢀC. After 2 h, the mixture was treated with 13
(197 mg, 2.34 mmol, 1 equiv). After 1 h at ꢁ78 ꢀC, the reaction was
warmed up to at ꢁ40 ꢀC and stirred overnight. The reaction was
quenched with satd NH4Cl and extracted with Et2O. The combined
organic layer was washed with H2O and brine, dried over MgSO4,
and concentrated under reduced pressure. The resulting residue
was purified by silica gel column chromatography (1.5e2% EtOAc/
Scheme 20. Completion of the total synthesis of 1.
2.3.2. Comparison of NMR spectra. 1H and 13C NMR spectral com-
parison of synthetic iriomoteolide-1a (1) did not match those
reported for the natural material.1 While minor inconsistencies are
noted throughout the spectra, the main discrepancies reside with
proton and carbon chemicals shifts at C4 (see Table in
Supplementary data). For synthetic iriomoteolide-1a (1), the H4
hydrogen resonates at 3.95 ppm and the carbon-13 shift occurs at
41.0 ppm compared to 2.46 ppm and 47.9 ppm for natural product,
respectively. Attempts to prepare crystalline derivatives of 1 have
not been successful; however, the significant difference in NMR
spectral data brings into question the original structural
hexane) to afford 14 (389 mg, 84%) as a colorless oil. ½a D20
ꢁ13.2 (c
ꢂ
1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d (ppm): 5.91e5.81 (m, 1H),
5.16e5.11 (m, 2H), 4.70 (d, 1H, J¼1.0 Hz), 4.68 (d, 1H, J¼1.0 Hz),
3.81e3.74 (m, 1H), 2.30e2.20 (m, 2H), 2.17 (ddd, 1H, J¼1.0, 3.9,
13.8 Hz), 2.05 (dd, 1H, J¼9.0 Hz, 13.8 Hz), 1.92 (d, 1H, J¼2.3 Hz),
1.60e1.50 (m, 2H), 0.03 (s, 9H); 13C NMR (400 MHz, CDCl3)
d (ppm):

7492
J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
144.8, 135.1, 117.9, 110.7, 68.2, 46.1, 41.6, 26.8, ꢁ1.1; HRMS calcd for
C11H22OSi [MþNa]þ 221.1332, found 221.1332; IR nmax (film) 3395,
1.5H), 3.81 (s, 1.5H), 3.75 (d, 0.5H, J¼8.4 Hz), 1.48 (s, 1.5H), 1.46 (s,
1.5H); 13C NMR (100 MHz, CDCl3) (data as a 1:1 diastereomeric
3074, 2954,1632, 1423, 1250, 1157, 1041, 854 cmꢁ1
.
mixture) d (ppm): 160.8, 160.7, 148.6, 147.8, 129.7, 129.5, 128.3,
128.2, 114.0, 113.9, 104.3, 104.1, 83.3, 82.9, 77.5, 77.3, 75.8, 75.0, 55.5,
25.2, 23.4; HRMS calcd for C13H15IO3 [MþNa]þ 368.9958, found
368.9966; IR nmax (film) 3069, 2972, 2866, 1714, 1613, 1515, 1249,
4.2.2. Allylsilane 11. To a stirred solution of 14 (80 mg, 0.4 mmol) in
CH2Cl2 (2 mL) were added 2,6-lutidine (103 mg, 0.96 mmol,
2.4 equiv) and TESOTf (127 mg, 0.48 mmol, 1.2 equiv) at 0 ꢀC, after
30 min at 0 ꢀC, the reaction was quenched with satd NaHCO3 and
extracted with CH2Cl2, dried over MgSO4, and concentrated under
reduced pressure. The resulting residue was purified by silica
gel column chromatography (1% EtOAc/hexane) to afford 11
1170, 1068, 1033, 833 cmꢁ1
.
4.2.5. Alcohol 18 and 19. To a stirred solution of 17 (35 mg,
0.1 mmol) in CH2Cl2 (1 mL) was added DIBAL-H (1.2 M in toluene,
0.25 mL, 0.3 mmol, 3 equiv) at ꢁ78 ꢀC. After 1.5 h at ꢁ78 ꢀC, the
reaction was quenched with a solution of Rochelle’s salt and
extracted with CH2Cl2. The combined organic layer was dried over
MgSO4, and concentrated under reduced pressure. The resulting
residue was purified by flash chromatography (10e15% EtOAc/
hexane) to afford 18 (5 mg, 14%) and 19 (20 mg, 58%) as a colorless
oil.
(115 mg, 91%) as a colorless oil. ½a D20
ꢂ
0.56 (c 0.57, CHCl3); 1H NMR
(400 MHz, CDCl3)
d (ppm): 5.90e5.79 (m, 1H), 5.07e5.02 (m, 2H),
4.61 (s, 1H), 4.57 (s, 1H), 3.87e3.81 (m, 1H), 2.32e2.13 (m, 2H), 2.10
(d, 2H, J¼6.5 Hz), 1.52 (s, 2H), 0.96 (t, 9H, J¼7.8 Hz), 0.60 (q, 6H,
J¼7.8 Hz), 0.02 (s, 9H); 13C NMR (400 MHz, CDCl3)
d (ppm): 144.5,
135.7, 117.1, 110.2, 71.2, 46.3, 41.9, 27.3, 7.2, 5.3, ꢁ1.1; HRMS calcd for
C17H36OSi2 [MþNa]þ 335.2197, found 335.2201; IR nmax (film) 3394,
Compound 18: ½a 2D0
ꢂ
ꢁ1.1 (c 0.86, CHCl3); 1H NMR (400 MHz,
3074, 2954, 2918, 1632, 1423, 1249, 1040, 853 cmꢁ1
.
CDCl3)
d
(ppm): 7.21 (d, 2H, J¼8.8 Hz), 6.86 (d, 2H, J¼8.8 Hz), 6.65 (d,
1H, J¼14.8 Hz), 6.42 (d, 1H, J¼14.8 Hz), 4.36e4.29 (m, 2H), 3.79 (s,
4.2.3. Alkyn 16. To a stirred solution of 15 (448 mg, 2 mmol) in
CH2Cl2 (20 mL) were added (i-Pr)2NEt (2.1 g, 16 mmol, 8 equiv),
DMSO (2.4 mL), and SO3$py (950 mg, 6.0 mmol, 3 equiv) at 0 ꢀC. The
reaction was stirred for 30 min and quenched with satd NaHCO3
and the mixture was diluted with Et2O. The organic layer was
washed successively with H2O, brine, and dried over MgSO4. The
resulting residue was used in the next step without further puri-
fication. To a stirred solution of crude product and BestmanneOhira
reagent (518 mg, 2.7 mmol, 1.35 equiv) in MeOH (10 mL) was added
K2CO3 (497 mg, 3.6 mmol, 1.8 equiv) at 0 ꢀC. After 10 min, the
mixture was warmed to rt. The reaction was stirred for 1 h and
quenched with satd NH4Cl. MeOH was removed under reduced
pressure and the residue was extracted with Et2O. The organic layer
was washed with H2O, brine, dried over MgSO4, and concentrated.
The resulting residue was purified by flash chromatography (3e5%
EtOAc/hexane) to afford 16 (344 mg, 80%) as a colorless oil. 1H NMR
3H), 3.51e3.44 (m, 2H), 2.00 (t, 1H, J¼6.6 Hz), 1.34 (s, 3H); 13C NMR
(100 MHz, CDCl3) d (ppm): 159.4, 147.8, 130.7,129.4, 114.1, 80.7, 79.4,
69.2, 65.2, 55.5, 18.8; HRMS calcd for C13H17IO3 [MþNa]þ 371.0115,
found 371.0113; IR nmax (film) 3439, 3069, 2932, 2860, 1615, 1512,
1463, 1383, 1249, 1174, 1107, 1036, 956, 827, 702 cmꢁ1
.
Compound 19: ½a 2D0
ꢂ
10.4 (c 1.2, CHCl3); 1H NMR (400 MHz,
CDCl3)
d
(ppm): 7.24 (d, 2H, J¼8.8 Hz), 6.89 (d, 2H, J¼8.8 Hz), 6.57 (d,
1H, J¼14.4 Hz), 6.39 (d,1H, J¼14.4 Hz), 4.49 (s, 2H), 3.82 (s, 3H), 3.33
(d, 1H, J¼9.0 Hz), 3.28 (d, 1H, J¼9.0 Hz), 2.58 (s, 1H), 1.23 (s, 3H); 13C
NMR (100 MHz, CDCl3)
d (ppm): 159.6, 149.8, 129.9, 129.7, 114.1,
77.5, 76.2, 75.5, 73.4, 55.5, 24.4; HRMS calcd for C13H17IO3 [MþNa]þ
371.0115, found 371.0113; IR nmax (film) 3439, 3069, 2927, 2852,
1610, 1508, 1463, 1383, 1249, 1174, 1089, 1036, 947, 818, 702 cmꢁ1
.
4.2.6. Acetal 21. To a stirred solution of 20 (395 mg, 1.15 mmol) in
CH2Cl2 (10 mL) was added PPTS (14 mg, 0.06 mmol, 0.05 equiv) and
acetal (250 mg, 1.38 mmol, 1.2 equiv). The reaction was stirred
overnight and quenched with Et3N. The solvent was removed un-
der reduced pressure and the resulting residue was purified by
flash chromatography (5.5e6.5% EtOAc/hexane) to afford 21
(400 MHz, CDCl3) (data as a 1:1 diastereomeric mixture)
d (ppm):
7.49 (d, 1H, J¼8.6 Hz), 7.42 (d, 1H, J¼8.6 Hz), 6.90 (d, 2H, J¼8.6 Hz),
5.97 (s, 0.5H), 5.90 (s, 0.5H), 4.37 (d, 0.5H, J¼8.2 Hz), 4.18 (d, 0.5H,
J¼7.6 Hz), 3.94 (d, 0.5H J¼7.6 Hz), 3.81 (s, 3H), 3.80 (d, 0.5H,
J¼8.2 Hz), 2.57 (s, 0.5H), 2.53 (s, 0.5H), 1.68 (s, 1.5H), 1.66 (s, 1.5H);
13C NMR (100 MHz, CDCl3) (data as a 1:1 diastereomeric mixture)
(435 mg, 82%). 1H NMR (400 MHz, CDCl3)
d (ppm): 7.70e7.64 (m,
4H), 7.43e7.32 (m, 8H), 6.89 (d, 1H, J¼8.8 Hz), 6.82 (d, 1H, J¼8.8 Hz),
5.87 (s, 0.5H), 5.81 (s, 0.5H), 4.27 (d, 0.5H, J¼8.4 Hz), 4.15 (d, 0.5H,
J¼8.2 Hz), 3.83e3.52 (m, 3H), 3.80 (s, 1.5H), 3.77 (s, 1.5H), 1.41 (s,
1.5H), 1.38 (s, 1.5H), 1.07 (s, 4.5H), 1.06 (s, 4.5H); 13C NMR (100 MHz,
d
(ppm): 160.8, 160.7, 129.7, 129.0, 128.7, 128.4, 114.0, 113.9, 105.2,
104.3, 85.7, 84.9, 77.1, 74.2, 74.1, 73.2, 72.2, 55.5, 26.6, 25.7; HRMS
calcd for C13H14IO3 [MþNa]þ 241.0835, found 241.0838; IR nmax
(film) 3282, 2937, 2844, 1679, 1600, 1511, 1263, 1161, 1028,
CDCl3)
d (ppm):160.59, 160.57, 135.89, 135.86, 135.8, 133.5, 133.4,
833 cmꢁ1
.
131.9, 130.4, 130.0, 129.96, 129.94, 129.87, 128.33, 128.28, 128.1,
127.97,127.95,127.92,114.0,113.9,113.7, 104.7,103.5, 81.6, 81.3, 73.6,
73.1, 68.6, 68.2, 55.53, 55.50, 27.05, 26.97, 23.1, 21.5, 19.5; HRMS
calcd for C28H34O4Si [MþNa]þ 485.2119, found 485.2114; IR nmax
(film) 2976, 2932, 2869,1614,1516,1472,1387,1249,1156, 1076, 831,
4.2.4. Vinyl iodide 17. To a stirred solution of 16 (790 mg, 3.6 mmol)
and Pd(PPh3)4 (208 mg, 0.18 mmol, 0.05 equiv) in THF (18 mL) was
added n-Bu3SnH (1.26 g, 4.3 mmol,1.2 equiv). After 20 min, THF was
removed under reduced pressure. The resulting residue was puri-
fied by flash chromatography (2e3% EtOAc/hexane) to afford vinyl
tributyltin as a colorless oil, which was used directly in the next
step. To a stirred solution of vinyl tributyltin in CH2Cl2 (30 mL) was
added 1 M I2 in CH2Cl2 solution until the color persisted. The re-
action was quenched with satd Na2SO3 and 1 M KF and extracted
with CH2Cl2, dried over MgSO4, and concentrated under reduced
pressure. The resulting residue was purified by flash chromatog-
raphy (3% EtOAc/hexane) to afford 17 (997 mg, 80% for two steps) as
a colorless oil. 1H NMR (400 MHz, CDCl3) (data as a 1:1 di-
738 cmꢁ1
.
4.2.7. Alcohol 22 and 23. To a stirred solution of 21 (837 mg,
1.8 mmol) in CH2Cl2 (10 mL) was added DIBAL-H (1.2 M in toluene,
4.5 mL, 5.4 mmol, 3 equiv) at ꢁ78 ꢀC. After 1.5 h at ꢁ78 ꢀC, the
reaction was quenched with a solution of Rochelle’s salt and
extracted with CH2Cl2. The combined organic layer was dried over
MgSO4, and concentrated under reduced pressure. The resulting
residue was purified by flash chromatography (5e9% EtOAc/hex-
ane) to afford 22 (510 mg, 61%) and 23 (173 mg, 21%) as a colorless
oil.
astereomeric mixture)
d
(ppm): 7.41 (d, 1H, J¼8.8 Hz), 7.40 (d, 1H,
J¼8.8 Hz), 6.92 (d,1H, J¼8.8 Hz), 6.91 (d,1H, J¼8.8 Hz), 6.69 (d, 0.5H,
J¼14.4 Hz), 6.68 (d, 0.5H, J¼14.4 Hz), 6.54 (d, 0.5H, J¼14.4 Hz), 6.43
(d, 0.5H, J¼14.4 Hz), 5.88 (s, 0.5H), 5.84 (s, 0.5H), 4.05 (d, 0.5H,
J¼8.4 Hz), 3.91 (d, 0.5H, J¼8.4 Hz), 3.87 (d, 0.5H, J¼8.4 Hz), 3.82 (s,
Compound 22: ½a 2D0
ꢂ
0.2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
(ppm): 7.65 (d, 4H, J¼8.8 Hz), 7.44e7.33 (m, 6H), 7.21 (d, 2H,
d
J¼8.6 Hz), 6.86 (d, 2H, J¼8.6 Hz), 4.47 (s, 2H), 3.81 (s, 3H), 3.54e3.57
(m, 2H), 3.47 (d, 1H, J¼8.8 Hz), 3.40 (d, 1H, J¼8.8 Hz), 2.58 (s, 1H),

J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
7493
1.18 (s, 3H), 1.05 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
(ppm):159.4,
(400 MHz, CDCl3) (data for major diastereomer)
d
(ppm): 7.20 (d,
135.83, 135.82, 133.5, 133.4, 130.6, 130.0, 129.4, 127.9, 114.0, 74.0,
73.3, 72.7, 68.0, 55.5, 27.1, 21.6, 19.5; HRMS calcd for C28H36O4Si
[MþNa]þ 487.2275, found 487.2270; IR nmax (film) 3448, 2927,
2H, J¼8.6 Hz), 6.86 (d, 2H, J¼8.6 Hz), 6.54 (d, 1H, J¼14.8 Hz), 6.39 (d,
1H, J¼14.8 Hz), 5.83e5.76 (m, 1H), 5.05e5.00 (m, 2H), 4.92 (s, 1H),
4.88 (s, 1H), 4.37e4.31 (m, 2H), 3.84e3.79 (m, 1H), 3.79 (s, 3H),
3.68e3.62 (m, 1H), 2.53 (d, 1H, J¼1.9 Hz), 2.28e2.14 (m, 5H),
2.03e1.95 (m, 1H), 1.34 (s, 3H), 0.93 (t, 9H, J¼7.8 Hz), 0.57 (q, 6H,
J¼7.8 Hz); 13C NMR (100 MHz, CDCl3) (data for major diastereomer)
2852, 1615, 1512, 1472, 1249, 1112, 827, 702 cmꢁ1
.
Compound 23: ½a D
ꢂ
20 1.2 (c 0.4, CHCl3); 1H NMR (400 MHz, CDCl3)
(ppm): 7.65 (d, 4H, J¼8.8 Hz), 7.42e7.32 (m, 6H), 7.21 (d, 2H,
d
J¼8.2 Hz), 6.83 (d, 2H, J¼8.2 Hz), 4.44e4.41 (m, 2H), 3.77 (s, 3H),
d (ppm): 159.3, 148.0, 143.7, 135.2, 130.9, 129.1, 117.5, 115.3, 114.0,
3.76e3.58 (m, 4H), 2.14 (m, 1H), 1.24 (s, 3H), 1.04 (s, 9H); 13C NMR
83.1, 79.6, 75.2, 71.2, 64.9, 55.5, 43.4, 42.0, 38.4, 16.2, 7.2, 5.2; HRMS
calcd for C27H43IO4Si [MþNa]þ 609.1868, found 609.1869; IR nmax
(film); 3563, 2954, 2909, 2874, 1641, 1614, 1512, 1459, 1249, 1081,
(100 MHz, CDCl3)
d (ppm):159.2, 135.90, 135.86, 133.3, 133.1, 131.3,
130.0, 129.3, 128.0, 127.9, 114.0, 78.0, 67.3, 66.1, 64.4, 55.5, 27.0, 19.5,
17.8; HRMS calcd for C28H36O4Si [MþNa]þ 487.2275, found
487.2272; IR nmax (film) 3461, 2958, 2860, 1615, 1512, 1428, 1249,
911, 747 cmꢁ1
.
1112, 1036, 827, 702 cmꢁ1
.
4.2.11. Diol 25. To a stirred solution of 17 (197 mg, 0.57 mmol) in
MeOH (5 mL) were added PPTS (14 mg, 0.057 mmol, 0.1 equiv) and
TsOH$H2O (11 mg, 0.057 mmol, 0.1 equiv). After 2 h, the reaction
was quenched with Et3N and the solvent was removed under re-
duced pressure. The resulting residue was purified by flash chro-
matography (20e40% EtOAc/hexane) to afford 25 (113 mg, 88%) as
4.2.8. Vinyl iodide 24. To a stirred solution of 23 (170 mg,
0.37 mmol) in CH2Cl2 (4 mL) were added (i-Pr)2NEt (239 mg,
1.85 mmol, 5 equiv), DMSO (0.26 mL), and SO3$py (159 mg,
1.11 mmol, 3 equiv) at 0 ꢀC. The reaction was stirred for 30 min and
quenched with satd NaHCO3 and the mixture was diluted with Et2O.
The organic layer was washed successively with H2O, brine, and
dried over MgSO4. After concentration under reduced pressure, the
resulting residue was used for next step without purification. To
a stirredsolution of slurryof anhydrous chromium chloride (455 mg,
3.7 mmol, 10 equiv) in THF (0.8 mL) was added a solution of crude
aldehyde and iodoform (437 mg, 1.1 mmol, 3 equiv) in dioxane
(6 mL) at rt. The reaction was stirred overnight and quenched with
H2O, the aqueous layer was extracted with Et2O. The combined or-
ganic layer was washed with H2O and brine, dried over MgSO4, and
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (4% EtOAc/hexane) to afford 24
a colorless oil. ½a D20
ꢂ
ꢁ11.8 (c 0.49, CHCl3); 1H NMR (400 MHz, CDCl3)
d
(ppm): 6.59 (d, 1H, J¼14.4 Hz), 6.48 (d, 1H, J¼14.4 Hz), 3.53 (dd,
1H, J¼5.2, 11.0 Hz), 3.43 (dd, 1H, J¼7.2, 11.0 Hz), 2.29 (s, 1H), 1.80 (br,
1H), 1.27 (s, 3H); 13C NMR (100 MHz, CDCl3)
d (ppm): 149.3, 77.7,
76.4, 69.4, 24.0. HRMS calcd for C5H9IO2 [MþNa]þ 250.9539, found
250.9543; IR nmax (film) 3368, 2972, 2866, 1607, 1462, 1376, 1198,
1048, 950 cmꢁ1
.
4.2.12. Vinyl iodide 26. To a stirred solution of 25 (284 mg,
1.26 mmol) in CH2Cl2 (12 mL) was added 2,6-lutidine (607 mg,
5.67 mmol, 4.5 equiv) and TESOTf (995 mg, 3.77 mmol, 3 equiv) at
ꢁ78 ꢀC. After 30 min, the reaction was warmed to rt and allowed to
stir an additional hour. The reaction was quenched with satd
NaHCO3, extracted with CH2Cl2 (3ꢃ40 mL), dried over MgSO4, and
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (hexane) to afford 26 (553 mg,
(188 mg, 88%) as a colorless oil. ½a D20
ꢂ
1.3 (c 0.5, CHCl3); 1H NMR
(400 MHz, CDCl3) d (ppm): 7.65e7.62 (m, 4H), 7.41e7.33(m, 6H), 7.20
(d, 2H, J¼8.8 Hz), 6.83 (d, 2H, J¼8.8 Hz), 6.60 (d, 1H, J¼14.8 Hz), 6.36
(d,1H, J¼14.8 Hz), 4.39e4.34 (m, 2H), 3.78 (s, 3H), 3.57 (s, 2H),1.39 (s,
3H), 1.04 (s, 9H); 13C NMR (100 MHz, CDCl3)
d
(ppm): 159.2, 149.3,
97%) as a colorless oil. ½a D20
ꢂ
ꢁ6.0 (c 0.55, CHCl3); 1H NMR (400 MHz,
136.0, 135.9, 133.5, 133.4, 131.2, 129.92, 129.90, 129.1, 127.92, 127.90,
114.0, 81.1, 78.7, 70.0, 65.1, 55.5, 27.0, 19.8, 19.5; HRMS calcd for
C29H35IO3Si [MþNa]þ 609.1292, found 609.1285; IR nmax (film) 3069,
CDCl3)
d
(ppm): 6.62 (d, 1H, J¼14.4 Hz), 6.26 (d, 1H, J¼14.4 Hz), 3.39
(d, 1H, J¼9.4 Hz), 3.35 (d, 1H, J¼9.4 Hz), 1.28 (s, 3H), 0.97e0.91 (m,
18H), 0.61e0.54 (m, 12H); 13C NMR (100 MHz, CDCl3)
d
(ppm):
2958, 2932, 2860, 1615, 1512, 1428, 1249, 1112, 827, 702 cmꢁ1
.
151.3, 78.8, 76.3, 70.8, 24.3, 7.2, 7.0, 6.8, 4.6; HRMS calcd for
C17H37IO2Si2 [MþNa]þ 479.1269, found 479.1276; IR nmax (film)
4.2.9. Alcohol 18. To a stirred solution of 24 (185 mg, 0.32 mmol) in
THF (3 mL) was added TBAF (1 M in THF, 1.28 mL, 1.28 mmol,
4 equiv). The reaction was stirred overnight and quenched with
satd NaHCO3 and extracted with Et2O. The combined organic layer
was washed with H2O and brine, dried over MgSO4, and concen-
trated under reduced pressure. The resulting residue was purified
by flash chromatography (5e15% EtOAc/hexane) to afford 18
(97 mg, 87%) as a colorless oil.
2950, 2870, 1607, 1462, 1236, 1103, 1010, 736 cmꢁ1
.
4.2.13. Aldehyde 10. To a stirred solution of 26 (210 mg, 0.46 mmol)
in 3:1 MeOH/CH2Cl2 (4.6 mL) was added PPTS (12 mg, 0.046 mmol,
0.1 equiv). After 15 min, the reaction was quenched with satd
NaHCO3 and diluted with Et2O. The organic layer was washed with
H2O, brine, dried over MgSO4, and concentrated under reduced
pressure. The resulting residue was used in the next step without
further purification. To a stirred solution of alcohol in CH2Cl2
(14 mL) was added NaHCO3 (384 mg, 4.6 mmol, 10 equiv) and the
DesseMartin reagent (292 mg, 0.69 mmol, 1.5 equiv). After 1 h, the
reaction was quenched with satd Na2SO3 and satd NaHCO3,
extracted with CH2Cl2, dried over MgSO4, and concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography (5% EtOAc/hexane) to afford 10 (114 mg, 73% for
4.2.10. Alcohol 5. To a stirred solution of 18 (94 mg, 0.27 mmol) in
CH2Cl2 (8 mL) were added NaHCO3 (227 mg, 2.7 mmol, 10 equiv)
and the DesseMartin reagent (117 mg, 0.41 mmol, 1.5 equiv). After
1.5 h, the reaction was quenched with satd Na2SO3 and satd
NaHCO3, extracted with CH2Cl2, The organic layer was washed with
H2O, brine, dried over MgSO4, and concentrated under reduced
pressure. The resulting residue was used in the next step without
further purification. To a stirred solution of 11 in CH2Cl2 (0.6 mL)
was added SnCl4 (22.4 mg, 0.086 mmol, 1.3 equiv) at ꢁ78 ꢀC. After
45 min, crude aldehyde 9 (23 mg, 0.066 mmol) in CH2Cl2 (0.2 mL)
was added and stirred for an additional 3 h at ꢁ78 ꢀC. The reaction
was quenched with Et3N (10 equiv) and satd NaHCO3, warmed to rt,
extracted with CH2Cl2, and dried over MgSO4. The combined or-
ganic extracts were concentrated under reduced pressure. The
resulting residue was purified by flash chromatography (3.2e3.6%
EtOAc/hexane) to afford 5 (20 mg, 51%) as a colorless oil. 1H NMR
two steps) as a colorless oil. ½a D20
ꢂ
139.2 (c 1.2, CHCl3); 1H NMR
(ppm): 9.36 (s, 1H), 6.58 (d, 1H, J¼14.4 Hz), 6.42
(400 MHz, CDCl3)
d
(d, 1H, J¼14.4 Hz), 1.40 (s, 3H), 0.96 (t, 9H, J¼8.0 Hz), 0.63 (q, 6H,
J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm): 199.5, 145.1, 83.4,
80.1, 22.7, 7.1, 6.6; HRMS calcd for C11H21IO2Si [MþNa]þ 363.0248,
found 363.0247; IR nmax (film) 2959, 2874, 1735, 1601, 1460, 1201,
1125, 1010, 938, 738 cmꢁ1
.
4.2.14. Alcohol 6. To a stirred solution of 11 (177 mg, 0.56 mmol,
1.2 equiv) in CH2Cl2 (4 mL) was added SnCl4 (146 mg, 0.56 mmol,

7494
J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
1.2 equiv) at ꢁ78 ꢀC. After 45 min, 10 (161 mg, 0.47 mmol) in CH2Cl2
(1.5 mL) was added and stirred for an additional 3 h at ꢁ78 ꢀC. The
reaction was quenched with Et3N (10 equiv) and satd NaHCO3,
warmed to rt, extracted with CH2Cl2, and dried over MgSO4. The
combined organic extracts were concentrated under reduced
pressure. The resulting residue was purified by flash chromatog-
raphy (1e1.2% EtOAc/hexane) to afford 6 (146 mg, 53%) as a color-
less oil. 1H NMR (400 MHz, CDCl3) (data for major diastereomer)
for the next step without purification. To a stirred solution of crude
product in Et2O (10 mL) was added LiAlH4 (2 M in THF, 1 mL,
2 equiv) at 0 ꢀC, the reaction was stirred at 23 ꢀC for 3 h and
quenched with EtOAc, H2O and 1 M HCl. The aqueous layer was
extracted with Et2O and the combined organic layer was dried over
MgSO4, and concentrated under reduced pressure. The resulting
residue was purified by flash chromatography (3% EtOAc/hexane)
to afford 30 (208 mg, 91% for two steps) as a colorless oil. ½a D20
ꢂ
31.2
d
(ppm): 6.61 (d, 1H, J¼14.6 Hz), 6.32 (d, 1H, J¼14.6 Hz), 5.87e5.77
(c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3)
d (ppm): 7.24 (d, 2H,
(m, 1H), 5.08e5.04 (m, 2H), 4.93 (s, 1H), 4.91 (s, 1H), 3.86e3.80 (m,
1H), 3.50e3.43 (m, 1H), 2.55e2.45 (m, 1H), 2.33e2.14 (m, 5H), 1.90
(dd, 1H, J¼10.6, 14.4 Hz), 1.34 (s, 3H), 0.98e0.93 (m, 18H), 0.64e0.57
(m, 12H); 13C NMR (100 MHz, CDCl3) (data for major diastereomer)
J¼7.4 Hz), 6.85 (d, 2H, J¼7.4 Hz), 5.80e5.69 (m, 1H), 5.00e4.94 (m,
2H), 4.48 (d, 1H J¼11.2 Hz), 4.35 (d, 1H, J¼11.2 Hz), 3.78 (s, 3H),
3.41e3.36 (m, 1H), 2.29e2.23 (m, 1H), 1.89e1.82 (m, 1H), 1.69e1.63
(m, 1H), 1.11 (d, 3H, J¼6.4 Hz), 0.88 (d, 3H, J¼6.8 Hz); 13C NMR
d
(ppm): 149.8, 144.1, 135.2, 117.5, 115.4, 80.5, 77.5, 76.5, 71.4, 43.5,
(100 MHz, CDCl3) d (ppm): 159.2, 138.1, 131.5, 129.3, 115.8, 113.9,
42.1, 38.4, 22.2, 7.3, 7.2, 6.8, 5.2; HRMS calcd for C25H49IO3Si2
77.7, 70.4, 55.5, 38.3, 37.1, 16.4, 15.1; HRMS calcd for C15H22O2
[MþNa]þ 603.2157, found 603.2156; IR nmax (film) 3565, 3074, 2954,
[MþNa]þ 257.1512, found 257.1515; IR nmax (film) 3074, 2977, 2835,
2875, 1644, 1604, 1413, 1192, 1086, 1002, 741 cmꢁ1
.
1614, 1512, 1378, 1249, 1033, 917, 825 cmꢁ1
.
4.2.15. Acetal 28. To a stirred solution of 27 (238 mg, 1.5 mmol) in
THF (15 mL) was added LiAlH4 (2 M in THF, 1.5 mL, 2 equiv) at 0 ꢀC.
After 1.5 h at 0 ꢀC, the reaction was quenched with solution of
Rochelle’s salt and the aqueous layer was extracted with EtOAc,
dried over MgSO4, and concentrated under reduced pressure. The
resulting residue was used for the next step without purification. To
a stirred solution of crude diol in CH2Cl2 (15 mL) were added PPTS
(19 mg, 0.075 mmol, 0.05 equiv) and acetal (328 mg, 1.8 mmol,
1.2 equiv). The reaction was stirred overnight and quenched with
Et3N. The solvent was removed under reduced pressure and the
resulting residue was purified by flash chromatography (5% EtOAc/
hexane) to afford 28 (262 mg, 70% for two steps) as a colorless oil.
4.2.18. Aldehyde 31. To a stirred solution of 30 (47 mg, 0.2 mmol) in
CH2Cl2 (5 mL) was bubbled with O2 for 2 min at ꢁ78 ꢀC after which
O3 was bubbled through the solution until the reaction maintained
a blue color. At this point, O2 was bubbled through the solution
until blue color disappeared. PPh3 (262 mg, 1 mmol, 5 equiv) was
added, the reaction was warmed to rt and stirred overnight. The
solvent was removed under reduced pressure. The resulting residue
was purified by silica gel column chromatography (5%e7.5% EtOAc/
hexane) to afford 31 (33 mg, 70%) as a colorless oil. ½a D
ꢂ
20 25.4 (c 0.63,
(ppm): 9.74 (t, 1H, J¼2.0 Hz),
CHCl3); 1H NMR (400 MHz, CDCl3)
d
7.24 (d, 2H, J¼8.6 Hz), 6.87 (d, 2H, J¼8.6 Hz), 4.48 (d, 1H J¼11.2 Hz),
4.35 (d, 1H, J¼11.2 Hz), 3.80 (s, 3H), 3.62e3.44 (m, 1H), 2.59 (ddd,
1H, J¼2.0, 5.6, 16.0 Hz), 2.41e2.32 (m, 1H), 2.59 (ddd, 1H, J¼2.4, 8.0,
16.0 Hz), 1.12 (d, 3H, J¼6.4 Hz), 0.95 (d, 3H, J¼6.8 Hz); 13C NMR
½
a 2D0
0.45 (c 0.40, CHCl3); 1H NMR (400 MHz, CDCl3)
d (ppm): 7.42
ꢂ
(d, 2H, J¼8.8 Hz), 6.88 (d, 2H, J¼8.8 Hz), 5.80e5.69 (m, 1H), 5.43 (s,
1H) 5.09e5.04 (m, 2H), 4.17 (dd, 1H, J¼4.0, 11.6 Hz), 3.79 (s, 3H),
3.69e3.61 (m, 1H), 3.56e3.51 (m, 1H), 2.22e2.16 (m, 1H), 1.86e1.77
(100 MHz, CDCl3) d (ppm): 203.0,159.3, 131.1, 129.4, 114.0, 77.1, 70.4,
55.5, 46.8, 33.0, 15.8, 15.5; HRMS calcd for C14H20O3 [MþNa]þ
259.1305, found 259.1308; IR nmax (film) 2968, 2835, 2725, 1723,
(m, 2H), 1.33 (d, 3H, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm):
160.1,135.1, 131.4, 127.6, 117.2,113.9, 101.3, 78.1, 71.5, 55.5, 40.4, 32.9,
19.5; HRMS calcd for C15H20O3 [MþNa]þ 271.1305, found 271.1309;
IR nmax (film) 3074, 2977, 2835, 1618, 1516, 1378, 1249, 1170, 1033,
1614, 1512, 1378, 1249, 1033, 825 cmꢁ1
.
4.2.19. Alcohol 33. To a stirred solution of 32 (225 mg, 0.47 mmol,
1.1 equiv) in CH2Cl2 (2.4 mL) at ꢁ78 ꢀC were added Et3N (119 mg,
1.17 mmol, 2.75 equiv) and (c-Hex)2BOTf (1 M in hexane, 1 mL,
2.4 equiv). After 3 h at ꢁ78 ꢀC, 31 (100 mg, 0.43 mmol) in CH2Cl2
(0.4 mL) was added and stirred for additional 2 h. The reaction was
warmed to rt over 1 h and quenched with H2O, MeOH, and 30%
H2O2. The aqueous layer was extracted with CH2Cl2 (3ꢃ40 mL) and
the combined organic extracts were dried over MgSO4 and con-
centrated under reduced pressure. The resulting residue was pu-
rified by flash chromatography (8e12% EtOAc/hexane) to afford 33
917, 825 cmꢁ1
.
4.2.16. Alcohol 29. To a stirred solution of 28 (112 mg, 0.45 mmol)
in CH2Cl2 (4.5 mL) was added DIBAL-H (1.2 M in toluene, 1.1 mL,
1.35 mmol, 3 equiv) at ꢁ78 ꢀC. After the addition, the reaction was
warmed to 0 ꢀC. After 30 min at 0 ꢀC, the reaction was quenched
with MeOH and stirred for 30 min at rt. The solid was removed
through filtration and the filtrate was concentrated under reduced
pressure. The resulting residue was purified by flash chromatog-
raphy (8e12% EtOAc/hexane) to afford 29 (101 mg, 90%) as a col-
(295 mg, 92%). ½a D20
ꢂ
33.0 (c 0.40, CHCl3); 1H NMR (400 MHz, CDCl3)
(ppm): 7.33 (d, 2H, J¼7.0 Hz), 7.25e7.12(m, 8H), 6.88 (s, 2H),
orless oil. ½a 2D0
ꢂ
53.5 (c 0.58, CHCl3); 1H NMR (400 MHz, CDCl3)
(ppm): 7.25 (d, 2H, J¼8.4 Hz), 6.88 (d, 2H, J¼8.4 Hz), 5.82e5.71 (m,
d
d
6.83e6.77 (m, 4H), 5.77 (d, 1H, J¼3.9 Hz), 4.78 (d, 1H, J¼16.6 Hz),
4.58 (d, 1H, J¼16.6 Hz), 4.52 (d, 1H, J¼11.2 Hz), 4.29 (d, 1H,
J¼11.2 Hz), 4.05e4.02 (m, 1H), 3.79e3,77 (m, 1H), 3.76 (s, 3H),
3.54e3.49 (m, 1H), 3.25 (d, 1H, J¼5.6 Hz), 2.51e2.41 (m, 1H), 2.47 (s,
6H), 2.28 (s, 3H), 2.05e2.00 (m, 1H), 1.67e1.61 (m, 1H), 1.29e1.22
(m, 1H), 1.12 (m, 6H), 1.06 (d, 3H, J¼7.2 Hz), 0.89 (d, 3H, J¼6.8 Hz);
1H), 5.05e5.00 (m, 2H), 4.59 (d, 1H, J¼11.2 Hz), 4.31 (d, 1H,
J¼11.2 Hz), 3.85 (ddd, 1H, J¼2.8, 5.6, 11.2 Hz), 3.80 (s, 3H), 3.67e3.55
(m, 2H), 2.89 (t, 1H, J¼5.6 Hz), 2.26e2.10 (m, 2H), 1.63e1.57 (m, 1H),
1.27 (d, 3H, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm): 159.5,
136.9, 130.5, 129.6, 116.8, 114.1, 78.2, 70.9, 63.7, 55.5, 45.9, 33.6, 17.8;
HRMS calcd for C15H22O3 [MþNa]þ 273.1461, found 273.1464; IR
nmax (film) 3439, 3074, 2977, 2835, 1614, 1512, 1378, 1249, 1033, 917,
13C NMR (100 MHz, CDCl3)
d (ppm): 174.9, 159.3, 142.8, 140.6, 139.1,
138.6, 133.7, 132.4, 130.8, 129.4, 128.6, 128.5, 128.0, 127.9, 127.3,
126.1, 114.0, 78.2, 77.3, 71.3, 70.4, 57.0, 55.5, 48.5, 46.4, 37.5, 34.4,
23.1, 21.1, 17.1, 14.8, 14.3, 13.7; HRMS calcd for C42H53NO7S [MþNa]þ
738.3435, found 738.3442; IR nmax (film) 3477, 2968, 2932, 1737,
825 cmꢁ1
.
4.2.17. Alkene 30. To a stirred solution of 29 (243 mg, 0.97 mmol) in
CH2Cl2 (5 mL) were added Et3N (294 mg, 2.91 mmol, 3 equiv),
DMAP (cat.), and MsCl (223 mg, 1.94 mmol, 2 equiv) at 0 ꢀC. The
reaction was stirred overnight and quenched with satd NaHCO3 and
the aqueous layer was extracted with Et2O. The combined organic
layer was washed with H2O, brine, dried over MgSO4, and con-
centrated under reduced pressure. The resulting residue was used
1614, 1515, 1453, 1249, 1153, 1033, 860, 758, 701 cmꢁ1
.
4.2.20. Ester 34. To a stirred solution of 33 (295 mg, 0.41 mmol) in
CH2Cl2 (3 mL) were added 2,6-lutidine (133 mg,1.24 mmol, 3 equiv)
and TESOTf (219 mg, 0.83 mmol, 2 equiv) at 0 ꢀC and stirred
overnight at rt. The mixture was quenched with satd NaHCO3, the

J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
7495
aqueous layer was extracted with CH2Cl2 and the combined organic
layer was dried over MgSO4 and concentrated under reduced
pressure. The resulting residue was purified by flash chromatog-
10 equiv), DMAP (cat.), and Ac2O (128 mg, 1.25 mmol, 5 equiv). The
reaction was stirred for 4 h and quenched with satd NaHCO3. The
aqueous layer was extracted with Et2O, dried over MgSO4, and
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (1% EtOAc/hexane) to afford 39
(150 mg, 96%) as a colorless oil: 1H NMR (400 MHz, CDCl3) (data for
raphy (5e8% EtOAc/hexane) to afford 34 (290 mg, 87%). ½a D
ꢂ
20 17.9 (c
0.70, CHCl3); 1H NMR (400 MHz, CDCl3)
d
(ppm): 7.33 (d, 2H,
J¼7.2 Hz), 7.24e7.08 (m, 8H), 6.89e6.79 (m, 6H), 5.77 (d, 1H,
J¼4.7 Hz), 4.77 (d, 1H, J¼16.6 Hz), 4.53 (d, 1H, J¼16.6 Hz), 4.33 (d,
1H, J¼11.4 Hz), 4.18 (d, 1H, J¼11.4 Hz), 4.09e4.06 (m, 1H), 3.96e3.92
(m, 1H), 3.79 (s, 3H), 3.23e3.21 (m, 1H), 2.48e2.46 (m, 1H), 2.44 (s,
6H), 2.27 (s, 3H), 1.54e1.47 (m, 2H), 1.26e1.19 (m, 1H), 1.16 (d, 3H,
J¼6.8 Hz), 1.11 (d, 3H, J¼7.0 Hz), 0.97 (d, 3H, J¼6.4 Hz), 0.93 (t, 9H,
J¼8.0 Hz), 0.80 (d, 3H, J¼6.4 Hz), 0.57 (q, 6H, J¼8.0 Hz); 13C NMR
major diastereomer)
d
(ppm): 6.57 (d, 1H, J¼14.4 Hz), 6.32 (d, 1H,
J¼14.4 Hz), 5.88e5.77 (m,1H), 5.07e5.01 (m, 2H), 4.92e4.90 (m,1H),
4.79 (s, 2H), 3.81e3.74 (m, 1H), 2.38 (d,1H, J¼14.4 Hz), 2.31e2.03 (m,
5H), 2.01 (s, 3H), 1.28 (s, 3H), 0.98e0.93 (m, 18H), 0.64e0.54 (m,
12H); 13C NMR (100 MHz, CDCl3) (data for major diastereomer)
d
(ppm): 170.5, 148.9, 142.6, 135.3, 117.4, 115.4, 79.4, 77.3, 76.7, 70.8,
(100 MHz, CDCl3)
d
(ppm): 172.2, 159.1, 142.7, 140.5, 138.7, 138.6,
43.9, 42.3, 36.3, 24.3, 21.3, 7.3, 7.2, 6.9, 5.3; HRMS calcd for
133.5, 132.3, 131.6, 129.3, 128.6, 128.4, 128.0, 127.9, 127.4, 126.6,
113.8, 78.3, 77.5, 72.7, 70.5, 57.0, 55.5, 48.3, 45.6, 37.5, 35.3, 23.2,
21.1, 16.6, 15.5, 14.0, 12.2, 7.2, 5.3; HRMS calcd for C48H67NO7SSi
[MþNa]þ 852.4300, found 852.4309; IR nmax (film) 2954, 2875,
C27H51IO4Si2 [MþNa]þ 645.2263, found 645.2258; IR nmax (film)
3074, 2954, 2875, 1746, 1644, 1604, 1413, 1232, 1086, 1002, 741 cmꢁ1
.
4.2.24. Acetate 40. To a stirred solution of 7 (57 mg, 0.11 mmol,
1.1 equiv) in Et2O (1 mL) was added 9-MeO/9-BBN (1 M in hexane,
0.28 mL, 0.28 mmol, 2.8 equiv). The mixture was cooled to ꢁ78 ꢀC
1732, 1608, 1515, 1453, 1249, 1153, 1033, 860, 758, 701 cmꢁ1
.
4.2.21. Sulfonate ester 35. To a stirred solution of 34 (290 mg,
0.35 mmol) in CH2Cl2 (3.5 mL) was added DIBAL-H (1.2 M in tolu-
ene, 0.9 mL,1.05 mmol, 3 equiv) at ꢁ78 ꢀC. After 2.5 h at ꢁ78 ꢀC, the
reaction was quenched with a solution of Rochelle’s salt and
extracted with CH2Cl2. The combined organic layer was dried over
MgSO4, and concentrated under reduced pressure. The resulting
residue was used in the next step without further purification. To
a stirred solution of crude product in CH2Cl2 (3.5 mL) were added
DMAP (cat.), Et3N (350 mg, 3.5 mmol, 10 equiv), and TsCl (334 mg,
1.75 mmol, 5 equiv). After 20 h at rt, the reaction was quenched
with satd NaHCO3 and extracted with Et2O, dried over MgSO4, and
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (4e5% EtOAc/hexane) to afford
and treated with t-BuLi (1.6 M in pentane, 144 mL, 0.23 mmol,
2.3 equiv). After 5 min, THF (1 mL) was added dropwise. The re-
action was warmed to rt and stirred for 1 h. In another flask (dppf)
PdCl2 (5 mg, 0.0061 mmol, 0.05 equiv), AsPh3 (5.5 mg, 0.018 mmol,
0.15 equiv), CsCO3 (130 mg, 0.4 mmol, 4 equiv), and H2O (44 mg,
2.4 mmol, 24 equiv) were added to a solution of 39 (62 mg,
0.1 mmol) in DMF (1.6 mL), the alkyl boronate solution was trans-
ferred to the DMF solution. The reaction was stirred overnight and
quenched with pH 7 buffer and 30% H2O2. After 30 min, the mixture
was diluted with Et2O. The organic layer was washed with H2O,
brine, and dried over MgSO4. After concentration under reduced
pressure, the resulting residue was purified by flash chromatogra-
phy (1.5e2% EtOAc/hexane) to afford 40 (73 mg, 82%) as a colorless
oil. 1H NMR (400 MHz, CDCl3) (data for major diastereomer)
35 (174 mg, 88% for two steps) as a colorless oil. ½a D20
ꢁ27.4 (c 0.21,
ꢂ
CHCl3); 1H NMR (400 MHz, CDCl3)
d
(ppm): 7.75 (d, 2H, J¼8.4 Hz),
d
(ppm): 7.25 (d, 2H, J¼8.4 Hz), 6.86 (d, 2H, J¼8.4 Hz), 5.87e5.77 (m,
7.29 (d, 2H, J¼8.4 Hz), 7.23 (d, 2H, J¼8.4 Hz), 6.87 (d, 2H, J¼8.4 Hz),
4.48 (d, 1H J¼11.2 Hz), 4.31 (d, 1H J¼11.2 Hz), 4.09 (dd, 1H, J¼5.6,
9.6 Hz), 3.81 (s, 3H), 3.83e3.78 (m, 1H), 3.68e3.63 (m, 1H),
3.35e3.32 (m, 1H), 2.42 (s, 3H), 1.98e1.88 (m, 1H), 1.60e1.51 (m,
2H), 1.25e1.18 (m, 1H), 1.08 (d, 3H, J¼6.4 Hz), 0.89 (d, 3H, J¼6.8 Hz),
0.88 (t, 9H, J¼8.0 Hz), 0.86 (d, 3H, J¼6.8 Hz), 0.60 (q, 6H, J¼8.0 Hz);
1H), 5.63e5.54 (m, 1H), 5.46 (d, 1H, J¼15.4 Hz), 5.05e5.00 (m, 2H),
4.91 (d, 1H, J¼9.6 Hz), 4.78 (s, 1H), 4.77 (s, 1H), 4.51 (d, 1H
J¼11.4 Hz), 4.35 (d, 1H, J¼11.4 Hz), 3.79 (s, 3H), 3.79e3.74 (m, 1H),
3.69e3.65 (m, 1H), 3.42e3.36 (m, 1H), 2.37 (d, 1H, J¼14.4 Hz),
2.28e2.05 (m, 6H), 2.03e2.00 (m, 1H), 1.98 (s, 3H), 1.86e1.78 (m,
1H), 1.67e1.60 (m, 2H), 1.26 (s, 3H), 1.25e1.18 (m, 1H), 1.14 (d, 3H,
J¼6.4 Hz), 0.97e0.91 (m, 33H), 0.62e0.54 (m, 18H); 13C NMR
13C NMR (100 MHz, CDCl3)
d (ppm): 159.2, 144.8, 133.3, 131.4, 130.0,
129.4, 128.2, 114.0, 77.1, 72.6, 72.4, 70.4, 55.5, 37.5, 37.3, 35.0, 21.8,
16.4, 15.3, 14.4, 7.2, 5.3; HRMS calcd for C30H48O6SSi [MþNa]þ
587.2833, found 587.2838; IR nmax (film) 2959, 2875, 1613, 1515,
(100 MHz, CDCl3) (data for major diastereomer) d (ppm): 170.6,
159.2, 143.1, 135.4, 134.2, 131.4, 130.1, 129.3, 117.3, 115.2, 113.9, 77.4,
77.0, 76.4, 74.8, 70.8, 70.5, 55.5, 43.9, 42.4, 38.6, 36.5, 36.1, 35.4, 34.6,
24.5, 21.3, 16.6, 15.9, 15.6, 7.3, 7.2, 7.0, 5.5, 5.3, 5.2; HRMS calcd for
C50H92O7Si3 [MþNa]þ 911.6043, found 911.6045; IR nmax (film)
1453, 1360, 1249, 1179, 1095, 971, 820, 740, 701 cmꢁ1
.
4.2.22. Alkyl iodide 7. To
a
stirred solution of 35 (174 mg,
2954, 2871, 1746, 1609, 1516, 1456, 1374, 1245, 1086, 1006, 741 cmꢁ1
.
0.31 mmol) in acetone (6 mL) was added NaI (465 mg, 3.1 mmol,
10 equiv). The mixture was refluxed for 24 h and diluted with Et2O.
The organic layer was washed with H2O, brine, dried over MgSO4,
and concentrated under reduced pressure. The resulting residue
was purified by flash chromatography (2% EtOAc/hexane) to afford
4.2.25. Diol 41. To a stirred solution of 40 (169 mg, 0.19 mmol) in
THF (2 mL) was added LiAlH4 (2 M in THF, 0.66 mL, 7 equiv) at 0 ꢀC.
After 2 h at 0 ꢀC, the reaction was quenched with MeOH, H2O, and
a solution of Rochelle’s salt. The aqueous layer was extracted with
Et2O and the combined organic extracts were dried over MgSO4,
and concentrated under reduced pressure. The resulting residue
was purified by flash chromatography (10e15% EtOAc/hexane) to
afford 41 (125 mg, 90%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
7 (136 mg, 85%) as a colorless oil. ½a D
ꢂ
20 13.4 (c 0.50, CHCl3); 1H NMR
(ppm): 7.27 (d, 2H, J¼8.4 Hz), 6.87 (d, 2H,
(400 MHz, CDCl3)
d
J¼8.4 Hz), 4.51 (d, 1H, J¼11.6 Hz), 4.37 (d, 1H, J¼11.6 Hz), 3.81 (s,
3H), 3.78e3.74 (m, 1H), 3.47e3.40 (m, 1H), 3.19 (dd, 1H, J¼5.3,
9.8 Hz), 2.97 (dd,1H, J¼8.6, 9.8 Hz),1.89e1.82 (m,1H),1.68e1.59 (m,
2H), 1.22e1.17 (m, 1H), 1.14 (d, 3H, J¼6.4 Hz), 1.04 (d, 3H, J¼6.8 Hz),
0.95 (t, 9H, J¼8.0 Hz), 0.91 (d, 3H, J¼6.8 Hz), 0.58 (q, 6H, J¼8.0 Hz);
(data for major diastereomer)
d
(ppm): 7.25 (d, 2H, J¼8.4 Hz), 6.86
(d, 2H, J¼8.4 Hz), 5.85e5.77 (m, 1H), 5.75e5.65 (m, 1H), 5.46 (d, 1H,
J¼15.6 Hz), 5.06e5.03 (m, 2H), 4.95 (s, 1H), 4.93 (s, 1H), 4.51 (d, 1H,
J¼11.4 Hz), 4.34 (d, 1H, J¼11.4 Hz), 3.88e3.82 (m, 1H), 3.79 (s, 3H),
3.68e3.64 (m, 1H), 3.52e3.49 (m, 1H), 3.41e3.36 (m, 1H), 2.46e1.98
(m, 10H), 1.85e1.77 (m, 1H), 1.68e1.63 (m, 2H), 1.22 (s, 3H),
1.25e1.16 (m, 1H), 1.13 (d, 3H, J¼6.4 Hz), 0.97e0.91 (m, 21H), 0.87
(d, 3H, J¼6.8 Hz), 0.62e0.54 (m, 12H); 13C NMR (100 MHz, CDCl3)
13C NMR (100 MHz, CDCl3)
d (ppm): 159.2, 131.5, 129.4, 114.0, 77.5,
73.7, 70.5, 55.5, 41.7, 35.9, 35.0, 17.1, 16.4, 15.8, 11.2, 7.2, 5.5; HRMS
calcd for C23H41IO3Si [MþNa]þ 543.1762, found 543.1768; IR nmax
(film) 2959, 2870, 1613, 1520, 1453, 1369, 1245, 1081, 820, 736 cmꢁ1
.
4.2.23. Vinyl iodide 39. To
a
stirred solution of
6
(146 mg,
(data for major diastereomer)
d (ppm): 159.2, 144.0, 135.4, 135.1,
0.25 mmol) in CH2Cl2 (2.5 mL) was added Et3N (253 mg, 2.5 mmol,
131.5, 129.9, 129.3, 117.5, 115.7, 113.9, 77.4, 75.3, 74.8, 74.6, 71.3, 70.4,

7496
J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
55.5, 43.1, 42.0, 38.7, 38.3, 36.0, 35.3, 34.6, 22.6, 16.5, 15.9, 15.7, 7.3,
7.2, 5.5, 5.2; HRMS calcd for C42H76O6Si2 [MþNa]þ 755.5073, found
755.5074; IR nmax (film) 3457, 2954, 2871, 1641, 1614, 1512, 1459,
0.05 equiv) and 4-methoxybenzaldehyde dimethyl acetal (267 mg,
1.47 mmol, 1.2 equiv). The reaction was stirred overnight and
quenched with Et3N. The solvent was removed under reduced
pressure and the resulting residue was purified by flash chroma-
1374, 1245, 1076, 1009, 742 cmꢁ1
.
tography (4.5% EtOAc/hexane) to afford acetal (283 mg, 93%). ½a D20
ꢂ
4.2.26. Ketone 42. To a stirred solution of 41 (124 mg, 0.17 mmol) in
CH2Cl2 (2 mL) were added (i-Pr)2NEt (175 mg, 1.36 mmol, 8 equiv),
DMSO (0.2 mL) and SO3$Py (108 mg, 0.68 mmol, 4 equiv) at 0 ꢀC.
The reaction was stirred for 30 min and quenched with satd
NaHCO3 and the mixture was diluted with Et2O. The organic layer
was washed successively with H2O, brine, and dried over MgSO4.
After concentration under reduced pressure, the resulting residue
was purified by flash chromatography (4e5% EtOAc/hexane) to
ꢁ44.5 (c 0.80, CHCl3); 1H NMR (400 MHz, CDCl3)
d (ppm): 7.42 (d,
2H, J¼8.7 Hz), 6.87 (d, 2H, J¼8.7 Hz), 5.80 (qd, 1H, J¼6.6, 15.3 Hz),
5.52 (m, 1H), 5.48 (s, 1H), 4.14 (dd, 1H, J¼4.6, 11.4 Hz), 3.82 (m, 1H),
3.79 (s, 3H), 3.51 (t, 1H, J¼11.2 Hz), 1.92e1.83 (m, 1H), 1.73 (dd, 3H,
J¼1.5, 6.4 Hz), 0.75 (d, 3H, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3)
d
(ppm): 160.1, 131.4, 130.5, 129.7, 127.8, 113.8, 101.4, 84.9, 73.3, 55.5,
34.3, 18.1, 12.7; HRMS calcd for C15H20O3 [MþNa]þ 271.1305, found
271.1304; IR nmax (film) 3074, 2977, 2835, 1641, 1516, 1378, 1249,
1170, 1033, 917, 825 cmꢁ1. To a stirred solution of acetal (46 mg,
0.19 mmol) in CH2Cl2 (2 mL) was added DIBAL-H (1.2 M in toluene,
0.47 mL, 0.56 mmol, 3 equiv) at ꢁ78 ꢀC. After the addition, the
reaction was warmed to 0 ꢀC. After 30 min at 0 ꢀC, the reaction was
quenched with MeOH and stirred for 30 min at rt. The solid was
removed through filtration and the filtrate was concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography (10e12% EtOAc/hexane) to afford 5 (43 mg, 92%)
afford 42 (89 mg, 70%) as a colorless oil. ½a D20
ꢁ20.3 (c 0.40, CHCl3);
ꢂ
1H NMR (400 MHz, CDCl3)
d
(ppm): 7.25 (d, 2H, J¼8.4 Hz), 6.86 (d,
2H, J¼8.4 Hz), 5.84e5.76 (m, 2H), 5.48 (d, 1H, J¼15.2 Hz), 5.06e5.02
(m, 2H), 4.99 (s, 1H), 4.87 (s, 1H), 4.51 (d, 1H, J¼11.4 Hz), 4.34 (d, 1H,
J¼11.4 Hz), 3.91 (s, 1H), 3.84e3.78 (m, 1H), 3.79 (s, 3H), 3.67e3.63
(m, 1H), 3.39e3.37 (m, 1H), 3.37e3.25 (m, 2H), 2.27e2.10 (m, 6H),
1.82e1.76 (m, 1H), 1.66e1.60 (m, 2H), 1.43 (s, 3H), 1.22e1.19 (m, 1H),
1.13 (d, 3H, J¼6.4 Hz), 0.96e0.90 (m, 21H), 0.84 (d, 3H, J¼6.8 Hz),
0.61e0.53 (m, 12H); 13C NMR (100 MHz, CDCl3)
d
(ppm): 210.0,
as a colorless oil. ½ ꢂ2D0 72.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
a
159.2, 140.0, 135.0, 132.5, 131.8, 131.5, 129.3, 117.5, 117.3, 113.9, 79.2,
77.4, 74.6, 71.4, 70.4, 55.5, 43.9, 43.5, 42.0, 38.1, 36.2, 35.3, 34.3, 25.1,
16.5, 15.9, 15.8, 7.3, 7.2, 5.5, 5.2; HRMS calcd for C42H74O6Si2
[MþNa]þ 753.4916, found 753.4912; IR nmax (film) 3475, 2954,
d
(ppm): 7.23 (d, 2H, J¼8.6 Hz), 6.87 (d, 2H, J¼8.6 Hz), 5.65 (qd, 1H,
J¼6.4, 15.3 Hz), 5.35 (ddd, 1H, J¼1.6, 8.6, 15.3 Hz), 4.53 (d, 1H,
J¼11.4 Hz), 4.24 (d, 1H, J¼11.4 Hz), 3.80 (s, 3H), 3.64e3.52 (m, 3H),
3.15 (dd, 1H, J¼3.5, 8.2 Hz), 1.86e1.80 (m, 1H), 1.77 (dd, 3H, J¼1.6,
2871, 1712, 1614, 1512, 1463, 1374, 1245, 1076, 1009, 742 cmꢁ1
.
6.4 Hz), 0.77 (d, 3H, J¼7.0 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm):
159.4,130.9,130.6,130.5,129.7,114.1, 86.3, 69.7, 68.0, 55.5, 40.1,18.0,
14.1; HRMS calcd for C15H22O3 [MþNa]þ 273.1461, found 273.1459;
IR nmax (film) 3439, 3074, 2977, 2835, 1614, 1512, 1378, 1249, 1033,
4.2.27. Ketone 43. Compound 42 was completely converted into 43
in 5% EtOAc/hexane after 5 days. ½a D20
ꢂ
ꢁ25.2 (c 1.0, CHCl3); 1H NMR
(400MHz, CDCl3)
d
(ppm): 7.24 (d, 2H, J¼8.4 Hz), 6.86(d, 2H, J¼8.4Hz),
917, 825 cmꢁ1
.
6.19 (s, 1H), 5.84e5.76 (m, 2H), 5.48 (d, 1H, J¼15.4 Hz), 5.09e5.03 (m,
2H), 4.50 (d, 1H, J¼11.4 Hz), 4.38 (s, 1H), 4.34 (d, 1H, J¼11.4 Hz),
3.95e3.92 (m,1H), 3.80 (s, 3H), 3.67e3.60 (m, 1H), 3.39e3.35 (m,1H),
2.40e2.10 (m, 6H), 2.20 (s, 3H), 1.83e1.75 (m, 1H), 1.66e1.60 (m, 2H),
1.39 (s, 3H), 1.22e1.19 (m, 1H), 1.13 (d, 3H, J¼6.4 Hz), 0.96e0.90 (m,
21H), 0.83 (d, 3H, J¼6.8 Hz), 0.61e0.53 (m, 12H); 13C NMR (100 MHz,
4.2.30. Aldehyde 45. To a stirred solution of 44 (40 mg, 0.16 mmol)
in CH2Cl2 (5 mL) were added NaHCO3 (134 mg, 1.6 mmol, 10 equiv)
and the DesseMartin reagent (103 mg, 0.24 mmol, 1.5 equiv). After
1 h, the reaction was quenched with satd Na2SO3 and satd NaHCO3,
extracted with CH2Cl2, dried over MgSO4, and concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography (4% EtOAc/hexane) to afford 45 (114 mg, 86%) as
CDCl3)
d (ppm): 200.7, 160.9, 159.2, 134.6, 132.3, 132.0, 131.5, 129.3,
120.3,117.9,113.9, 77.9, 77.4, 74.6, 70.6, 70.4, 55.5, 49.5, 42.3, 38.3, 36.2,
35.3, 34.4, 25.2, 21.0, 16.6, 15.8, 15.6, 7.3, 7.1, 5.5, 5.2; HRMS calcd for
C42H74O6Si2 [MþNa]þ 753.4916, found 753.4910; IR nmax (film) 3475,
a colorless oil. ½a D20
ꢂ
80.7 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d
(ppm): 9.68 (d, 1H, J¼2.7 Hz), 7.20 (d, 2H, J¼8.6 Hz), 6.87 (d, 2H,
2954, 2871, 1700, 1614, 1512, 1463, 1374, 1245, 1076, 1009, 742 cmꢁ1
.
J¼8.6 Hz), 5.73 (qd, 1H, J¼6.4, 15.3 Hz), 5.36 (ddd, 1H, J¼1.6, 8.6,
15.3 Hz), 4.52 (d, 1H, J¼11.4 Hz), 4.26 (d, 1H, J¼11.4 Hz), 3.86 (t, 1H,
J¼8.6 Hz), 3.80 (s, 3H), 2.55e2.51 (m, 1H), 1.78 (d, 3H, J¼6.4 Hz),
4.2.28. Ketal 3. To a stirred solution of 42 (30 mg, 0.041 mmol) in
THF (2 mL) was added 0.3 mL of an HF$py solution consisting of
1.7 mL 70% HF$py: 4 mL THF: 1.7 mL pyridine. After 15 min, the
reaction was quenched with satd NaHCO3 and extracted with Et2O.
The combined organic layer was dried over MgSO4 and concen-
trated under reduced pressure. The resulting residue was purified
by flash chromatography (20e27% EtOAc/hexane) to afford 3
0.97 (d, 3H, J¼7.0 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm): 204.7,
159.4, 131.8, 130.5, 129.6, 129.1, 114.0, 80.8, 69.7, 55.5, 51.0, 18.0, 11.0;
HRMS calcd for C15H20O3 [MþNa]þ 271.1305, found 271.1308; IR
nmax (film) 2923, 2856, 1726, 1605, 1512, 1454, 1249, 1036, 969,
822 cmꢁ1
.
(14 mg, 68%) as a colorless oil. ½a D20
ꢂ
0.3 (c 0.73, CHCl3); 1H NMR
(ppm): 7.23 (d, 2H, J¼8.4 Hz), 6.86 (d, 2H,
4.2.31. Propionate 46. To a stirred solution of CBr4 (93 mg,
(400 MHz, CDCl3)
d
0.28 mmol, 2 equiv) in CH2Cl2 (0.3 mL) was added Ph3P (147 mg,
0.56 mmol, 4 equiv) in CH2Cl2 (0.3 mL) solution at 0 ꢀC. The mixture
was stirred 10 min at rt and recooled to 0 ꢀC. Aldehyde 45 (35 mg,
0.14 mmol) in CH2Cl2 (0.3 mL) was added. After 2 h, the reaction
was quenched with satd NaHCO3 and extracted with CH2Cl2, dried
over MgSO4, and concentrated under reduced pressure. The
resulting residue was purified by flash chromatography (1e2%
EtOAc/hexane) to afford dibromoalkene (50 mg, 88%) as a colorless
J¼8.4 Hz), 5.83e5.67 (m, 3H), 5.09e5.03 (m, 2H), 4.85 (d, 1H,
J¼1.2 Hz), 4.82 (d, 1H, J¼1.2 Hz), 4.54 (d, 1H, J¼11.6 Hz), 4.35 (d, 1H,
J¼11.6 Hz), 3.93e3.86 (m, 1H), 3.79 (s, 3H), 3.54e3.47 (m, 2H), 3.14
(s, 1H), 2.73 (br, 1H), 2.42 (s, 1H), 2.33e2.22 (m, 6H), 2.03e1.85 (m,
3H), 1.66e1.55 (m, 2H), 1.35e1.25 (m, 1H), 1.28 (s, 3H), 1.13 (d, 3H,
J¼6.4 Hz), 0.91 (d, 3H, J¼6.8 Hz), 0.87 (d, 3H, J¼6.8 Hz); 13C NMR
(100 MHz, CDCl3)
d (ppm): 159.3, 141.8, 134.7, 133.8, 130.8, 129.6,
129.3, 117.3, 114.0, 111.3, 99.4, 78.0, 77.4, 73.2, 70.7, 70.4, 55.5, 40.4,
39.6, 39.0, 38.0, 37.0, 35.6, 34.4, 21.3, 17.6, 15.9, 14.6; HRMS calcd for
C30H46O6 [MþNa]þ 525.3187, found 525.3186; IR nmax (film) 3441,
oil. ½a 2D0
ꢂ
5.6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
d (ppm): 7.23
(d, 2H, J¼8.6 Hz), 6.87 (d, 2H, J¼8.6 Hz), 6.30 (d, 1H, J¼9.4 Hz), 5.64
(qd, 1H, J¼6.4, 15.3 Hz), 5.33 (ddd, 1H, J¼1.4, 8.4, 15.3 Hz), 4.52 (d,
1H, J¼11.6 Hz), 4.22 (d, 1H, J¼11.6 Hz), 3.81 (s, 3H), 3.53 (dd, 1H,
J¼5.7, 8.4 Hz), 2.63e2.58 (m, 1H), 1.76 (dd, 3H, J¼1.4, 6.4 Hz), 0.98
2963, 2928, 1614, 1515, 1463, 1374, 1245, 1033, 1009, 913, 816 cmꢁ1
.
4.2.29. Alcohol 44. To a stirred solution of diol
8
(159 mg,
(d, 3H, J¼7.0 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm): 159.2, 141.4,
1.22 mmol) in CH2Cl2 (12 mL) were added PPTS (15 mg, 0.06 mmol,
131.0, 130.7, 129.7, 129.5, 113.9, 88.5, 82.0, 69.5, 55.5, 43.5, 18.1, 15.5;

J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
7497
HRMS calcd for C16H20Br2O2 [MþNa]þ 424.9722, found 424.9722;
IR nmax (film) 2923, 2856, 1587, 1512, 1454, 1249, 1036, 980,
was purified by flash chromatography (14.5e15% EtOAc/hexane) to
afford 48 (16 mg, 53%). ½a D20
ꢂ
ꢁ4.2 (c 1.3, CHCl3); 1H NMR (400 MHz,
822 cmꢁ1
.
To
a
stirred solution of dibromoalkene (48 mg,
CDCl3)
d
(ppm): 7.25 (d, 2H, J¼8.4 Hz), 7.19 (d, 2H, J¼8.4 Hz), 7.86 (t,
0.12 mmol) in THF (1 mL) was added n-BuLi (2.4 M in hexane,
0.11 mL, 0.26 mmol, 2.2 equiv) at ꢁ78 ꢀC. After 30 min, the reaction
was treated with methyl chloroformate (22 mg, 0.24 mmol, 2 equiv)
and warmed to rt over 2.5 h. The reaction was quenched with satd
NH4Cl and extracted with Et2O, dried over MgSO4, and concen-
trated under reduced pressure. The resulting residue was purified
by flash chromatography (3e5% EtOAc/hexane) to afford 46 (33 mg,
4H, J¼9.0 Hz), 5.82e5.61 (m, 5H), 5.32 (dd, 1H, J¼8.4, 15.3 Hz),
5.09e5.03 (m, 2H), 4.93e4.89 (m, 1H), 4.85 (s, 1H), 4.81 (s, 1H), 4.48
(d, 1H, J¼11.6 Hz), 4.47 (d, 1H, J¼11.6 Hz), 4.34 (d, 1H, J¼11.6 Hz),
4.19 (d, 1H, J¼11.6 Hz), 4.08e4.02 (m, 1H), 3.94e3.86 (m, 1H), 3.79
(s, 6H), 3.59 (t, 1H, J¼8.8 Hz), 3.54e3.47 (m, 1H), 3.13 (s, 1H), 2.42 (s,
1H), 2.31e2.17 (m, 6H),1.91e1.79 (m, 4H),1.76 (d, 3H, J¼6.4 Hz),1.73
(s, 3H), 1.30e1.42 (m, 2H), 1.27 (s, 3H),1.09 (d, 3H, J¼6.2 Hz), 0.93 (d,
3H, J¼7.0 Hz), 0.90 (d, 3H, J¼6.8 Hz), 0.84 (d, 3H, J¼6.6 Hz); 13C NMR
91%) as a colorless oil. ½a D20
ꢂ
38.7 (c 1.0, CHCl3); 1H NMR (400 MHz,
CDCl3)
d
(ppm): 7.27 (d, 2H, J¼8.6 Hz), 6.86 (d, 2H, J¼8.6 Hz), 5.70
(100 MHz, CDCl3) d (ppm): 166.3, 162.4, 159.2, 159.0, 141.9, 134.7,
(qd, 1H, J¼6.4, 15.3 Hz), 5.38 (ddd, 1H, J¼1.6, 8.4, 15.3 Hz), 4.56 (d,
1H, J¼11.6 Hz), 4.31 (d, 1H, J¼11.6 Hz), 3.80 (s, 3H), 3.77 (s, 3H), 3.66
(dd, 1H, J¼6.6, 8.2 Hz), 2.77e2.70 (m, 1H), 1.77 (dd, 3H, J¼1.6,
134.1, 131.5, 131.2, 130.9, 130.7, 129.4, 129.3, 129.1, 117.9, 117.3, 114.0,
113.8, 111.3, 99.4, 82.1, 77.4, 76.6, 75.3, 70.7, 70.5, 69.1, 55.5, 40.4,
39.6, 39.3, 38.0, 37.1, 35.3, 35.1. 33.6, 21.4, 20.4, 18.0, 16.6, 15.9, 15.8,
15.4; HRMS calcd for C48H68O9 [MþNa]þ 811.4756, found 811.8744;
IR nmax (film) 3506, 3074, 2967, 2932, 1708, 1641, 1614, 1512, 1454,
6.4 Hz), 1.16 (d, 3H, J¼7.0 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm):
159.3, 154.5, 131.7, 130.6, 129.6, 128.7, 113.9, 91.7, 81.2, 73.9, 69.8,
55.5, 52.8, 32.0, 18.1, 16.0; HRMS calcd for C18H22O4 [MþNa]þ
325.1410, found 325.1408; IR nmax (film) 2940, 2840, 2238, 1717,
1378, 1245, 1160, 1040, 974, 822 cmꢁ1
.
1610, 1512, 1436, 1254, 1169, 1036, 970, 828 cmꢁ1
.
4.2.35. Alcohol 2. To a stirred solution of 48 (26 mg, 0.033 mmol) in
CH2Cl2 (1 mL)þpH 7 buffer (0.5 mL) was added DDQ (30 mg,
0.13 mmol, 4 equiv) at rt. After 30 min, the reaction was quenched
with satd NaHCO3 solution and extracted with CH2Cl2. The com-
bined organic layer was dried over MgSO4, and concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography (30e33% EtOAc/hexane) to afford 2 (13.5 mg, 75%)
4.2.32. Z-Alkenoic ester 47. To a stirred suspension of CuI (57 mg,
0.3 mmol, 3 equiv) in THF (1 mL) was added MeLi (2.2 M in hexane,
0.27 mL, 0.6 mmol, 6 equiv) at 0 ꢀC. After 15 min, the reaction was
cooled to ꢁ50 ꢀC and treated with 46 (32 mg, 0.1 mmol) in THF
(1 mL) solution. After 1.5 h, the reaction was quenched with AcOH
(33
mL) and satd NH4Cl, extracted with Et2O, dried over MgSO4, and
as a colorless oil. ½a D20
ꢂ
ꢁ38.3 (c 0.85, CHCl3); 1H NMR (400 MHz,
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (3% EtOAc/hexane) to afford 47
CDCl3)
d
(ppm): 5.80e5.64 (m, 5H), 5.32 (dd, 1H, J¼7.6, 15.3 Hz),
5.11e5.03 (m, 2H), 5.01e4.97 (m, 1H), 4.85 (s, 1H), 4.82 (s, 1H),
3.93e3.88 (m, 1H), 3.84e3.78 (m, 2H), 3.74e3.68 (m, 1H), 3.19 (s,
1H), 2.69 (br, 1H), 2.60 (s, 1H), 2.34e2.17 (m, 6H), 1.99e1.74 (m, 4H),
1.88 (s, 3H), 1.71 (d, 3H, J¼6.4 Hz), 1.61e1.33 (m, 2H), 1.29 (s, 3H),
1.12 (d, 3H, J¼6.2 Hz), 0.93 (d, 3H, J¼6.8 Hz), 0.90 (d, 3H, J¼6.8 Hz),
(30 mg, 90%). ½a 2D0
ꢂ
ꢁ25.2 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3)
d
(ppm): 7.19 (d, 2H, J¼8.6 Hz), 6.84 (d, 2H, J¼8.6 Hz), 5.67 (s, 1H),
5.69e5.64 (m, 1H), 5.33 (ddd, 1H, J¼1.6, 8.6, 15.3 Hz), 4.48 (d, 1H,
J¼11.6 Hz), 4.21 (d, 1H, J¼11.6 Hz), 4.06e4.02 (m, 1H), 3.79 (s, 3H),
3.65 (s, 3H), 3.59 (t, 1H, J¼9.0 Hz), 1.77 (dd, 3H, J¼1.6, 6.4 Hz), 1.72
(d, 3H, J¼1.2 Hz), 0.93 (d, 3H, J¼7.0 Hz); 13C NMR (100 MHz, CDCl3)
0.87 (d, 3H, J¼7.0 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm): 167.6,
161.6, 141.9, 134.8, 134.4, 133.2, 128.7, 128.6, 119.0, 117.3, 111.4, 99.4,
77.3, 75.9, 75.8, 70.7, 69.8, 41.4, 40.4, 39.5, 38.0, 36.9, 36.2, 35.5,
33.5, 21.5, 20.3, 20.1, 18.0, 15.8, 15.5, 15.1; HRMS calcd for C32H52O7
[MþNa]þ 571.3605, found 571.3597; IR nmax (film) 3439, 2967, 2923,
d
(ppm): 166.9, 163.1, 159.1, 131.1, 130.9, 130.8, 129.6, 117.1, 113.8,
82.0, 69.2, 55.5, 51.0, 39.3, 20.3, 18.0, 15.8; HRMS calcd for C19H26O4
[MþNa]þ 341.1723, found. 341.1719; IR nmax (film) 2949, 2856, 1717,
1641, 1512, 1454, 1245, 1036, 970, 822 cmꢁ1
.
1694, 1637, 1450, 1374, 1245, 1160, 1009, 969 cmꢁ1
.
4.2.33. Acid 4. To a stirred solution of 47 (64 mg, 0.2 mmol) in
MeOH (1 mL) and THF (1 mL) was added LiOH (1 M, 2 mL, 2 mmol,
10 equiv), after 60 h at rt, the pH value was adjusted to 2e3 with
1 M HCl and the mixture was extracted with Et2O, dried over
MgSO4, and concentrated under reduced pressure. The resulting
residue was purified by flash chromatography (25% EtOAc/hexane)
4.2.36. Alkene 52. Toa stirredsolutionofdithiane(216 mg,1.8mmol,
1.5 equiv) in dry THF (4 mL) was added n-BuLi at ꢁ40 ꢀC. After 1 h at
ꢁ40ꢀC, the epoxide13 (105mg,1.25 mmol,1 equiv)inTHF (3 mL) was
added. After 1 h at ꢁ40 ꢀC, the reaction was warmed to rt and
quenched withsatdNH4Cl. the aqueouslayerwasextractedwithEt2O
and the combined organic layer was washed with H2O and brine,
dried over MgSO4, and concentrated under reduced pressure. The
resulting residue was purified by flash chromatography (8e12%
to afford acid 4 (58 mg, 95%). ½a D20
ꢂ
ꢁ5.2 (c 0.38, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
(ppm): 7.16 (d, 2H, J¼8.6 Hz), 6.86 (d, 2H,
J¼8.6 Hz), 5.79 (s, 1H), 5.70 (qd, 1H, J¼6.4, 15.3 Hz), 5.32 (ddd, 1H,
J¼1.6, 8.6, 15.3 Hz), 4.58 (d, 1H, J¼11.6 Hz), 4.26 (d, 1H, J¼11.6 Hz),
3.80 (s, 3H), 3.54 (t, 1H, J¼9.6 Hz), 3.42e3.32 (m, 1H), 1.80 (dd, 3H,
J¼1.5, 6.4 Hz), 1.64 (d, 3H, J¼1.6 Hz), 0.89 (d, 3H, J¼6.8 Hz); 13C NMR
EtOAc/hexane) to afford (S)-1-(1,3-dithian-2-yl)pent-4-en-2-ol
1
(170 mg, 67%). H NMR (400 MHz, CDCl3)
d (ppm): 5.87e5.76 (m,
1H), 5.17e5.13 (m, 2H), 4.27 (t, 1H, J¼7.0 Hz), 4.01e3.96 (m, 1H),
2.96e2.81 (m, 4H), 2.33e2.18 (m, 2H), 2.16e2.09 (m, 1H), 1.96 (d, 1H,
(100 MHz, CDCl3)
d
(ppm): 169.4, 159.5, 157.9, 132.2, 129.9, 129.7,
J¼4.0 Hz), 1.95e1.84 (m, 3H); 13C NMR (100 MHz, CDCl3)
d (ppm):
129.6, 119.7, 114.0, 81.4, 69.5, 55.5, 40.8, 19.3, 18.1, 15.4; HRMS calcd
134.3, 118.8, 67.7, 44.4, 42.3, 42.2, 30.6, 30.3, 26.2; HRMS calcd for
C9H16OS2 [MþNa]þ 227.0535, found227.0535. To a stirred suspension
of NaH (160 mg, 4 mmol, 2 equiv) in DMF (2.5 mL) was added (S)-1-
(1,3-dithian-2-yl)pent-4-en-2-ol (400 mg, 2 mmol, 1 equiv) in DMF
(1.5 mL) at 0 ꢀC. After 1 h at 0 ꢀC, PMBCl (470 mg, 3 mmol, 1.5 equiv)
was added. The reaction was stirred overnight at rt and quenched
with satd NH4Cl. the aqueous layer was extracted with Et2O and the
combined organic layer was washed with H2O and brine, dried over
MgSO4 and concentrated under reduced pressure. The resulting res-
iduewas purified by flash chromatography (3e4.5%EtOAc/hexane) to
for C18H24O4 [MþNa]þ 327.1567, found 327.1565; IR nmax (film)
2940, 2870, 1686, 1632, 1512, 1454, 1249, 1036, 970, 822 cmꢁ1
.
4.2.34. Ester 48. To a stirred solution of Acid 4 (18 mg, 0.06 mmol,
1.5 equiv) in THF (0.8 mL) were added Et3N (16 mg, 0.16 mmol,
4 equiv) and 2,4,6-trichlorobenzoyl chloride (24 mg, 0.1 mmol,
2.5 equiv) at rt. After 4 h at rt, the solid was removed and the filtrate
was transferred to a solution of 3 (20 mg, 0.04 mmol) and DMAP
(8 mg, 0.064 mmol, 1.6 equiv) in toluene (3 mL). After 18 h at rt, the
mixture was quenched with satd NaHCO3 and diluted with Et2O,
the organic layer was washed with H2O, brine, dried over MgSO4,
and concentrated under reduced pressure. The resulting residue
afford 52 (518 mg, 80%). ½a D20
ꢂ
34.1 (c 1.0, CHCl3); 1H NMR (400 MHz,
(ppm): 7.28 (d, 2H, J¼8.6 Hz), 6.88 (d, 2H, J¼8.6 Hz),
CDCl3)
d
5.87e5.76 (m,1H), 5.13e5.08 (m, 2H), 4.56 (d,1H, J¼11.0 Hz), 4.43 (d,

7498
J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
1H, J¼11.0 Hz), 4.16 (dd,1H, J¼4.9, 9.6 Hz), 3.81 (s, 3H), 3.80e3.75 (m,
1H), 2.90e2.74 (m, 4H), 2.40e2.28 (m, 2H), 2.13e2.08 (m, 1H),
10 (35 mg, 0.1 mmol) in CH2Cl2 (0.3 mL) was added and stirred for
an additional 3 h at ꢁ78 ꢀC. The reaction was quenched with Et3N
(10 equiv) and satd NaHCO3, warmed to rt, extracted with CH2Cl2,
and dried over MgSO4. The combined organic extracts were con-
centrated under reduced pressure. The resulting residue was pu-
rified by flash chromatography (3e4.5% EtOAc/hexane) to afford 54
(36 mg, 60%) as a colorless oil. 1H NMR (400 MHz, CDCl3) (data for
1.99e1.81 (m, 3H); 13C NMR (100 MHz, CDCl3)
d (ppm): 159.4, 134.4,
131.0, 129.7, 117.9, 114.0, 75.0, 71.5, 55.5, 44.2, 40.3, 38.7, 30.6, 30.2,
26.3; HRMS calcd for C17H24O2S2 [MþNa]þ 347.1110, found 347.1111;
IR nmax (film) 2936, 2900, 1614, 1512, 1245, 1076, 911, 818 cmꢁ1
.
4.2.37. Ester 53. To a stirred solution of 52 (106 mg, 0.33 mmol,
1 equiv) in CH3CN (2.5 mL) and H2O (0.7 mL) were added NaHCO3
(277mg, 3.3 mmol,10 equiv)and MeI (465mg, 3.3 mmol,10 equiv)at
rt. After 20 h, the reaction was quenched with satd NaHCO3 and
extracted with Et2O, the combined organic layer was dried over
MgSO4 and concentrated under reduced pressure. The resulting
residue was used for next step without purification. To a stirred
solution of crude product in t-BuOH (4 mL) and 2-methyl-2-butene
(1.2 mL) was added a solution of NaClO2 (362 mg, 3.96 mmol,
12 equiv) and NaH2PO4 (552 mg, 3.96 mmol,12 equiv) in H2O (1 mL)
at 0 ꢀC. After 30 min at rt, the reaction was diluted with H2O and
extracted with EtOAc, the combined organic layer was dried over
MgSO4 and concentrated under reduced pressure. The resulting
residue was used for next step without purification. To a stirred
solution of crude product in DMF (3.3 mL) were added K2CO3 (88 mg,
0.66 mmol, 2 equiv) and MeI (90 mg, 0.66 mmol, 2 equiv) at rt. The
reaction was stirred overnight and quenched with satd NH4Cl, the
aqueous layer was extracted with Et2O and the combined organic
layer was washed with H2O and brine, dried over MgSO4, and con-
centrated under reduced pressure. The resulting residue was puri-
fied by flash chromatography (10% EtOAc/hexane) to afford 53
major diastereomer)
d
(ppm): 7.25 (d, 2H, J¼8.6 Hz), 6.87 (d, 2H,
J¼8.6 Hz), 6.57 (d, 1H, J¼14.8 Hz), 6.27 (d, 1H, J¼14.8 Hz), 5.89e5.78
(m, 1H), 5.11e5.07 (m, 2H), 4.93 (s, 1H), 4.92 (s, 1H), 4.51 (d, 1H,
J¼11.2 Hz), 4.43 (d, 1H, J¼11.2 Hz), 3.80 (s, 3H), 3.62e3.54 (m, 1H),
3.44e3.39 (m, 1H), 2.55 (d, 1H, J¼2.0 Hz), 2.38e2.16 (m, 5H), 1.88
(dd, 1H, J¼10.6, 14.4 Hz), 1.29 (s, 3H), 0.94 (q, 9H, J¼7.8 Hz), 0.60 (t,
6H, J¼7.8 Hz); 13C NMR (100 MHz, CDCl3) (data for major di-
astereomer)
d (ppm):159.4, 149.8, 144.3, 134.9, 130.8, 129.7, 117.6,
115.0,114.0, 80.5, 77.1, 76.5, 76.2, 70.9, 55.5, 40.5, 38.5, 38.4, 22.1, 7.3,
6.8; HRMS calcd for C27H43IO4Si [MþNa]þ 609.1868, found
609.1862; IR nmax (film) 3452, 2954, 2874, 1641, 1610, 1512, 1249,
1085, 1000, 747 cmꢁ1
.
4.2.40. Vinyl iodide 50. To a stirred solution of 54 (29 mg,
0.05 mmol) in CH2Cl2 (0.5 mL) were added 2,6-lutidine (16 mg,
0.15 mmol, 3 equiv) and TBSOTf (26 mg, 0.1 mmol, 2 equiv) at 0 ꢀC.
The reaction was stirred overnight at rt and quenched with satd
NaHCO3, the aqueous layer was extracted with CH2Cl2 and the
combined organic layer was dried over MgSO4 and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography (1.5% EtOAc/hexane) to afford 50 (32 mg, 92%). 1H
(68 mg, 80% for three steps). ½a D20
ꢂ
22.8 (c 0.7, CHCl3); 1H NMR
NMR (400 MHz, CDCl3) (data for major diastereomer) d (ppm): 7.25
(400 MHz, CDCl3)
d
(ppm): 7.24 (d, 2H, J¼8.6 Hz), 6.86 (d, 2H,
(d, 2H, J¼8.6 Hz), 6.86 (d, 2H, J¼8.6 Hz), 6.59 (d, 1H, J¼14.4 Hz), 6.18
(d, 1H, J¼14.4 Hz), 5.91e5.81 (m, 1H), 5.11e5.06 (m, 2H), 4.88 (s,
2H), 4.50e4.43 (m, 2H), 3.80 (s, 3H), 3.56e3.50 (m, 2H), 2.45 (d, 1H,
J¼14.4 Hz), 2.38e2.27 (m, 3H), 2.12 (dd,1H, J¼5.6,14.4 Hz), 1.87 (dd,
1H, J¼8.4, 14.4 Hz), 1.31 (s, 3H), 0.97e0.85 (m, 18H), 0.59 (q, 6H,
J¼8.0 Hz), 0.03 (s, 3H), ꢁ0.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
J¼8.6 Hz), 5.85e5.78 (m, 1H), 5.13e5.08 (m, 2H), 4.53 (d, 1H,
J¼11.0 Hz), 4.47 (d, 1H, J¼11.0 Hz), 3.98e3.93 (m, 1H), 3.80 (s, 3H),
3.67 (s, 3H), 2.57 (dd,1H, J¼7.8,15.4 Hz), 2.50 (dd,1H, J¼5.2,15.4 Hz),
2.41e2.31 (m, 2H); 13C NMR (100 MHz, CDCl3)
d (ppm): 172.4,159.4,
134.2,130.7,129.6,118.1,114.0, 75.3, 71.5, 55.5, 51.9, 39.6, 38.7; HRMS
calcd for C15H20O4 [MþNa]þ 287.1254, found 287.1252; IR nmax (film)
(data for major diastereomer) d (ppm):159.3, 150.0, 143.5, 135.3,
2949, 2838, 1734, 1610, 1512, 1245, 1076, 911, 818 cmꢁ1
.
133.9, 129.5, 117.3, 115.3, 114.1, 81.3, 78.1, 77.9, 76.0, 71.2, 55.5, 41.8,
40.3, 39.0, 26.4, 25.0, 18.4, 7.4, 7.0, ꢁ3.1, ꢁ3.8; HRMS calcd for
C33H57IO4Si2 [MþNa]þ 723.2732, found 723.2746; IR nmax (film)
3070, 2954, 2878, 1641, 1601, 1463, 1249, 1192, 1098, 1005, 836,
4.2.38. Allylsilane 51. The powered CeCl3$7H2O (430 mg,
1.15 mmol, 5 equiv) was heated to 155 ꢀC over 3 h with stirring and
continued to be heated at 155 ꢀC overnight in the high vacuum. The
solid was cooled to rt and filled with N2. THF (2 mL) was added and
the suspension was stirred for 5 h. The mixture was cooled to
ꢁ78 ꢀC and treated with TMSCH2MgCl (1.3 M in THF, 1.1 mL,
6 equiv). After 1 h at ꢁ78 ꢀC, 53 (61 mg, 0.23 mmol, 1 equiv) in
0.3 mL THF was added and the reaction was slowly warmed to rt.
The reaction was stirred overnight and quenched with 1 M HCl at
ꢁ78 ꢀC. The mixture was warmed to rt and diluted with Et2O. The
organic layer was washed with H2O and brine, dried over MgSO4,
and concentrated under reduced pressure. The resulting residue
was dissolved in CH2Cl2 (4 mL) and silica gel (1 g) was added. The
suspension was stirred overnight. The silica was removed and the
filtrate was concentrated under reduced pressure. The resulting
residue was purified by flash chromatography (2% EtOAc/hexane)
738 cmꢁ1
.
4.2.41. Vinyl iodide 55. To
a
stirred solution of 6 (304 mg,
0.52 mmol) in CH2Cl2 (2.6 mL) were added 2,6-lutidine (139 mg,
1.3 mmol, 2.5 equiv) and TBSOTf (206 mg, 0.78 mmol, 1.5 equiv) at
0
ꢀC and stirred 1.5 h at rt. The mixture was quenched with satd
NaHCO3, the aqueous layer was extracted with CH2Cl2 and the
combined organic layer was dried over MgSO4 and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography (0.4% EtOAc/hexane) to afford 55 (319 mg, 90%). 1H
NMR (400 MHz, CDCl3) (data for major diastereomer) d (ppm): 6.59
(d, 1H, J¼14.6 Hz), 6.19 (d, 1H, J¼14.6 Hz), 5.88e5.77 (m, 1H),
5.06e5.03 (m, 2H), 4.84 (s, 1H), 4.83 (s, 1H), 3.82e3.77 (m, 1H),
3.57e3.49 (m, 1H), 2.42 (d, 1H, J¼14.4 Hz), 2.27e2.11 (m, 4H), 1.84
(dd, 1H, J¼8.4, 14.4 Hz), 1.31 (s, 3H), 0.97e0.84 (m, 27H), 0.63e0.55
(m, 12H), 0.03 (s, 3H), ꢁ0.04 (s, 3H); 13C NMR (100 MHz, CDCl3)
to afford 51 (55 mg, 75%). ½a D20
ꢂ
5.2 (c 0.88, CHCl3); 1H NMR
(ppm): 7.24 (d, 2H, J¼8.6 Hz), 6.86 (d, 2H,
(400 MHz, CDCl3)
d
J¼8.6 Hz), 5.92e5.82 (m,1H), 5.11e5.05 (m, 2H), 4.66 (s,1H), 4.60 (s,
1H), 4.49 (s, 2H), 3.80 (s, 3H), 3.62e3.56 (m, 1H), 2.24 (m, 3H), 2.12
(dd,1H, J¼6.2,14.0 Hz),1.53 (s, 2H), 0.02 (s, 9H); 13C NMR (100 MHz,
(data for major diastereomer) d (ppm): 150.0, 143.5, 135.5, 117.2,
115.4, 81.3, 78.4, 75.9, 70.8, 44.9, 42.2, 40.3, 26.4, 25.0, 18.4, 7.4, 7.2,
7.0, 5.3, ꢁ3.1, ꢁ3.8; HRMS calcd for C31H63IO3Si3 [MþNa]þ 717.3022,
found 717.3045; IR nmax (film) 3074, 2954, 2875, 1641, 1605, 1413,
CDCl3)
d (ppm): 159.3, 144.7, 135.4, 131.2, 129.5, 117.1, 113.9, 110.0,
77.3, 71.0, 55.5, 43.1, 38.6, 27.2, ꢁ1.1; HRMS calcd for C19H30O2Si
1254, 1192, 1098, 1000, 836, 741 cmꢁ1
.
[MþNa]þ 241.1907, found 341.1910; IR nmax (film) 2949, 2905, 1734,
1611, 1512, 1245, 1076, 841 cmꢁ1
.
4.2.42. Alcohol 56. To a stirred solution of 55 (319 mg, 0.46 mmol)
in THF (4.6 mL) was added 1.4 mL of an HF$py solution consisting of
1.7 mL 70% HF$py: 4 mL THF: 1.7 mL pyridine. After 30 min, the
reaction was quenched with satd NaHCO3 and extracted with Et2O.
4.2.39. Alcohol 54. To a stirred solution of 51 in CH2Cl2 (0.8 mL) was
added SnCl4 (34 mg, 0.13 mmol, 1.3 equiv) at ꢁ78 ꢀC. After 45 min,

J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
7499
The combined organic layer was washed with H2O and brine, dried
over MgSO4, and concentrated under reduced pressure. The
resulting residue was purified by flash chromatography (1.5%
EtOAc/hexane) to afford 56 (234 mg, 88%). 1H NMR (400 MHz,
(m, 2H), 4.85 (s, 2H), 4.54 (d, 1H, J¼11.6 Hz), 4.45 (s, 2H), 4.36 (d, 1H,
J¼11.6 Hz), 3.79 (s, 6H), 3.60e3.47 (m, 4H), 2.66 (d, 1H, J¼4.8 Hz),
2.52 (d, 1H, J¼14.6 Hz), 2.37e2.28 (m, 4H), 2.16e2.11 (dd, 1H, J¼5.4,
14.2 Hz), 2.05e1.95 (m, 1H), 1.90e1.80 (m, 2H), 1.67e1.56 (m, 2H),
1.30 (s, 3H), 1.25e1.18 (m, 1H), 1.13 (d, 3H, J¼6.2 Hz), 0.95e0.82 (m,
24H), 0.56 (q, 6H, J¼7.8 Hz), 0.03 (s, 3H), ꢁ0.03 (s, 3H); 13C NMR
CDCl3) (data for major diastereomer)
d (ppm): 6.59 (d, 1H,
J¼14.6 Hz), 6.19 (d, 1H, J¼14.6 Hz), 5.89e5.77 (m, 1H), 5.16e5.11 (m,
2H), 4.96 (s, 1H), 4.91 (s, 1H), 3.73e3.68 (m, 1H), 3.50e3.47 (m, 1H),
2.50 (d, 1H, J¼14.4 Hz), 2.27e2.17 (m, 3H), 2.07e2.01 (m, 1H), 1.89
(dd,1H, J¼8.8,14.4 Hz), 1.84 (d,1H, J¼2.2 Hz),1.33 (s, 3H), 0.97e0.85
(m, 18H), 0.59 (q, 6H, J¼8.0 Hz), 0.04 (s, 3H), ꢁ0.02 (s, 3H); 13C NMR
(100 MHz, CDCl3) (data for major diastereomer)
d (ppm): 159.3,
159.2, 144.1, 135.4, 135.1, 131.2, 130.9, 129.5, 129.3, 128.5, 117.2, 114.9,
114.0, 113.9, 78.7, 78.2, 78.1, 77.0, 73.2, 71.2, 70.5, 55.49, 55.46, 41.5,
40.6, 39.5, 39.0, 36.8, 35.8, 34.5, 26.4, 25.6, 18.5, 17.6, 15.8, 14.7, 7.5,
7.1, ꢁ3.1, ꢁ3.7; HRMS calcd for C50H84O7Si2 [MþNa]þ 875.5648,
found 875.5663; IR nmax (film): 3460, 2963, 2932, 2878, 1614, 1512,
(100 MHz, CDCl3) (data for major diastereomer)
d (ppm): 149.7,
143.5, 135.0, 118.0, 116.9, 81.2, 77.7, 75.9, 67.8, 43.7, 41.8, 39.8, 26.3,
25.4, 18.4, 7.4, 7.0, ꢁ2.9, ꢁ3.7; HRMS calcd for C25H49IO3Si2
[MþNa]þ 603.2157, found 603.2168; IR nmax (film) 3457, 3074, 2954,
1463, 1249, 1098, 1005, 836, 742 cmꢁ1
.
2878, 1641, 1601, 1463, 1254, 1192, 1098, 1000, 836, 738 cmꢁ1
.
4.2.46. Ester 49. To a stirred solution of acid 4 (82 mg, 0.27 mmol,
1.5 equiv) in THF (2 mL) were added Et3N (73 mg, 0.72 mmol,
4 equiv) and 2,4,6-trichlorobenzoylchloride (110 mg, 0.45 mmol,
2.5 equiv) at rt. After 4 h at rt, the solid was removed and the filtrate
was transferred to a solution of 58 (154 mg, 0.18 mmol) and DMAP
(35 mg, 0.29 mmol, 1.6 equiv) in toluene (6 mL). After 12 h at rt, the
mixture was quenched with satd NaHCO3 and diluted with Et2O,
the organic layer was washed with H2O, brine, dried over MgSO4,
and concentrated under reduced pressure. The resulting residue
was purified by flash chromatography (4e4.5% EtOAc/hexane) to
afford 49 (191 mg, 93%). 1H NMR (400 MHz, CDCl3) (data for major
4.2.43. Vinyl iodide 50. To a stirred solution of 56 (234 mg,
0.4 mmol) and PMBO(C]NH)CCl3 (226 mg, 0.8 mmol, 2 equiv) in
toluene (4 mL) was added Sc(OTf)3 (16 mg, 0.032 mmol, 0.08 equiv).
After 3 h, the solvent was removed. The resulting residue was pu-
rified by flash chromatography (1% EtOAc/hexane) to afford 50
(206 mg, 73%).
4.2.44. Alkene 57. To a stirred solution of alkyl iodide 7 (41 mg,
0.078 mmol, 1.1 equiv) in Et2O (0.8 mL) was added 9-MeO/9-BBN
(1 M in hexane, 0.2 mL, 0.2 mmol, 2.8 equiv). The mixture was
cooled to ꢁ78 ꢀC and treated with t-BuLi (1.6 M in pentane, 0.1 mL,
0.16 mmol, 2.3 equiv). After 5 min, THF (0.8 mL) was added drop-
wise. The reaction was warmed to rt and stirred for 1 h. In another
flask (dppf)PdCl2 (2.9 mg, 0.0036 mmol, 0.05 equiv), AsPh3 (3.1 mg,
0.01 mmol, 0.15 equiv), CsCO3 (92 mg, 0.28 mmol, 4 equiv), and H2O
(31 mg, 1.7 mmol, 24 equiv) were added to a solution of 50 (50 mg,
0.071 mmol) in DMF (1.3 mL), the alkyl boronate solution was
transferred to the DMF solution. The reaction was stirred overnight
and quenched with pH 7 buffer and 30% H2O2. After 30 min, the
mixture was diluted with Et2O. The organic layer was washed with
H2O, brine, and dried over MgSO4. After concentration under re-
duced pressure, the resulting residue was purified by flash chro-
matography (1e1.8% EtOAc/hexane) to afford 57 (57 mg, 84%) as
a colorless oil. 1H NMR (400 MHz, CDCl3) (data for major di-
diastereomer)
d (ppm): 7.25e7.15 (m, 6H), 6.85e6.82 (m, 6H),
5.90e5.80 (m, 1H), 5.66e5.60 (m, 2H), 5.53e5.43 (m, 2H), 5.32 (dd,
1H, J¼8.4, 15.4 Hz), 5.09e5.04 (m, 2H), 4.97e4.92 (m, 1H), 4.85 (s,
2H), 4.48e4.44 (m, 4H), 4.35 (d, 1H, J¼11.6 Hz), 4.20 (d, 1H,
J¼11.6 Hz), 4.10e4.03 (m, 1H), 3.78 (s, 9H), 3.61e3.45 (m, 4H), 2.51
(d, 1H, J¼14.2 Hz), 2.34e2.17 (m, 4H), 2.12 (dd, 1H, J¼5.4, 14.2 Hz),
1.85 (dd, 1H, J¼8.6, 14.6 Hz), 1.77e1.72 (m, 3H), 1.74 (d, 3H,
J¼6.4 Hz), 1.72 (s, 3H), 1.63e1.58 (m, 1H), 1.40e1.33 (m, 1H), 1.30 (s,
3H), 1.09 (d, 3H, J¼6.2 Hz), 0.95e0.81 (m, 27H), 0.57 (q, 6H,
J¼7.8 Hz), 0.02 (s, 3H), ꢁ0.04 (s, 3H); 13C NMR (100 MHz, CDCl3)
(data for major diastereomer)
d (ppm): 166.3, 162.3, 159.3, 159.2,
159.1, 144.1, 135.4, 135.3, 131.6, 131.22, 131.18, 130.9, 130.6, 129.5,
129.4, 129.3, 128.1, 117.9, 117.2, 114.9, 113.9, 113.7, 82.0, 78.6, 78.1,
77.0, 76.7, 75.7, 71.2, 70.5, 69.2, 55.49, 55.45, 41.5, 40.6, 39.3, 39.1,
37.3, 35.3, 35.2, 33.6, 26.4, 25.8, 20.5, 18.5, 18.0, 16.6, 16.0, 15.8, 15.5,
7.5, 7.1, ꢁ3.0, ꢁ3.7; HRMS calcd for C68H106O10Si2 [MþNa]þ
1161.7217, found 1161.7261; IR nmax (film) 2958, 2932, 2874, 1708,
astereomer)
d (ppm): 7.25e7.23 (m, 4H), 6.86e6.83 (m, 4H),
5.91e5.81 (m, 1H), 5.56e5.44 (m, 2H), 5.10e5.05 (m, 2H), 4.85 (s,
2H), 4.50 (d, 1H J¼11.6 Hz), 4.44 (s, 2H), 4.35 (d, 1H, J¼11.6 Hz), 3.78
(s, 6H), 3.67e3.62 (m, 1H), 3.60e3.51 (m, 2H), 3.42e3.35 (m, 1H),
2.52 (d, 1H, J¼14.4 Hz), 2.37e2.21 (m, 3H), 2.19e2.11 (m, 2H), 1.86
(dd,1H, J¼8.6, 14.4 Hz),1.83e1.76 (m, 1H), 1.65e1.58 (m, 3H), 1.30 (s,
3H), 1.25e1.18 (m, 1H), 1.13 (d, 3H, J¼6.2 Hz), 0.97e0.82 (m, 33H),
0.61e0.544 (m, 12H), 0.03 (s, 3H), ꢁ0.03 (s, 3H); 13C NMR (100 MHz,
1641, 1614, 1512, 1459, 1249, 1089, 1036, 831, 742 cmꢁ1
.
4.2.47. Diol 59. To a stirred solution of 49 (191 mg, 0.17 mmol) in
THF (1.2 mL) was added TBAF (1 M in THF, 0.5 mmol, 3 equiv) at rt.
After 8 h, the reaction was quenched with satd NaHCO3 and
extracted with Et2O. The combined organic layer was washed with
H2O and brine, dried over MgSO4 and concentrated under reduced
pressure. The resulting residue was purified by flash chromatog-
raphy (12e25% EtOAc/hexane) to afford 59 (144 mg, 94%). 1H NMR
CDCl3) (data for major diastereomer)
d (ppm): 159.3, 159.2, 144.1,
135.4, 134.8, 131.5, 131.2, 129.4, 129.3, 128.9, 117.1, 114.9, 113.9, 78.7,
78.1, 77.3, 77.1, 74.9, 71.2, 70.5, 55.48, 55.46, 41.5, 40.6, 39.1, 38.9,
36.2, 35.4, 34.9, 26.4, 25.6, 18.5, 16.7, 15.9, 15.5, 7.5, 7.3, 7.1, 5.5, ꢁ3.1,
ꢁ3.7; HRMS calcd for C56H98O7Si3 [MþNa]þ 989.6513, found
989.6536; IR nmax (film): 2963, 2932, 2878, 1614, 1512, 1463, 1249,
(400 MHz, CDCl3) (data for major diastereomer) d (ppm): 7.25e715
(m, 6H), 6.86e6.82 (m, 6H), 5.90e5.78 (m, 1H), 5.70e5.60 (m, 3H),
5.44 (d, 1H, J¼15.6 Hz), 5.32 (dd, 1H, J¼8.6, 15.4 Hz), 5.10e5.06 (m,
2H), 4.95 (s, 1H), 4.93 (s, 1H), 4.90e4.86 (m, 1H), 4.52e4.40 (m, 4H),
4.33 (d, 1H, J¼11.6 Hz), 4.18 (d, 1H, J¼11.6 Hz), 4.10e4.02 (m, 1H),
3.78 (s, 9H), 3.62e3.56 (m, 2H), 3.53e3.45 (m, 2H), 2.70 (br, 1H),
2.39e2.23 (m, 6H), 2.16e2.11 (m, 1H), 2.07e2.00 (m, 1H), 1.88e1.81
(m, 1H), 1.80e1.74 (m, 1H), 1.75 (d, 3H, J¼6.2 Hz), 1.73 (s, 3H),
1.66e1.57 (m, 1H), 1.34e1.28 (m, 1H), 1.13 (s, 3H), 1.07 (d, 3H,
J¼5.2 Hz), 0.92 (d, 3H, J¼7.6 Hz), 0.89 (d, 3H, J¼6.6 Hz), 0.83 (d, 3H,
J¼6.6 Hz); 13C NMR (100 MHz, CDCl3) (data for major diastereomer)
1098, 1005, 836, 742 cmꢁ1
.
4.2.45. Alcohol 58. To a stirred solution of 57 (202 mg, 0.21 mmol)
in THF (3 mL) was added 1 mL of an HF$py solution consisting of
1.7 mL 70% HF$py: 4 mL THF: 1.7 mL pyridine. After 45 min, the
reaction was quenched with satd NaHCO3 and extracted with Et2O.
The combined organic layer was washed with H2O and brine, dried
over MgSO4, and concentrated under reduced pressure. The
resulting residue was purified by flash chromatography (8e10%
EtOAc/hexane) to afford 58 (154 mg, 86%). 1H NMR (400 MHz,
d
(ppm): 166.3, 162.6, 159.4, 159.2, 144.3, 136.5, 135.0, 131.6, 131.2,
130.9, 130.8, 130.7, 129.7, 129.4, 129.3, 128.2, 117.9, 117.5, 115.0, 114.0,
113.9, 113.8, 82.1, 77.1, 76.6, 75.13, 75.11, 74.9, 70.8, 70.4, 69.2, 55.5,
40.4, 39.3, 38.4, 38.3, 37.1, 35.2, 35.1, 33.7, 22.6, 20.3, 18.0, 16.5, 16.0,
CDCl3) (data for major diastereomer)
d (ppm): 7.25e7.23 (m, 4H),
6.86e6.83 (m, 4H), 5.91e5.81 (m,1H), 5.57e5.46 (m, 2H), 5.10e5.04

7500
J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
15.9, 15.5; HRMS calcd for C56H78O10 [MþNa]þ 933.5487, found
933.5501; IR nmax (film) 3497, 2967, 2927, 2869, 1708, 1641, 1610,
3.78 (s, 9H), 3.61e3.47 (m, 3H), 3.32e3.22 (m, 2H), 2.33e2.23 (m,
4H), 2.20e2.12 (m, 1H), 1.80e1.60 (m, 3H), 1.75 (d, 3H, J¼6.6 Hz),
1.73 (s, 3H), 1.62e1.56 (m, 1H), 1.34 (s, 3H), 1.34e1.28 (m, 1H), 1.08
(d, 3H, J¼6.2 Hz), 0.93 (d, 3H, J¼7.0 Hz), 0.89 (d, 3H, J¼6.4 Hz), 0.79
1512, 1459, 1245, 1169, 1031, 822 cmꢁ1
.
4.2.48. Cyclopentene 60. To a stirred solution of 49 (9 mg, 7.9
in CH2Cl2 (8 mL) was added second generation Grubbs catalyst
(0.7 mg, 0.8 mol) at rt. After 3 h, the solvent was removed. The
mmol)
(d, 3H, J¼6.6 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm): 210.1, 166.2,
162.6, 159.4, 159.2, 159.0, 140.0, 134.8, 132.5, 131.5, 131.4, 131.2,
130.90,130.86,130.75,129.6,129.4,129.29,128.26,117.8,117.5,117.2,
114.0, 113.9, 113.8, 82.1, 79.2, 77.1, 76.6, 75.2, 70.7, 70.4, 69.2, 55.50,
55.48, 43.7, 40.5, 39.3, 38.4, 36.9, 35.2, 34.9, 33.6, 25.0, 20.4, 18.0,
16.5, 15.9, 15.8, 15.5; HRMS calcd for C56H76O10 [MþNa]þ 931.5331,
found: 931.5323; IR nmax (film) 3470, 2954, 2927, 2869, 1715, 1708,
m
resulting residue was purified by flash chromatography (6% EtOAc/
hexane) to afford 60 (5 mg, 57%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) (data for major diastereomer) d (ppm): 7.27e7.18
(m, 6H), 6.87e6.82 (m, 6H), 5.67e5.60 (m, 2H), 5.50e5.43 (m, 2H),
5.36e5.27 (m, 2H), 4.93e4.91 (m, 1H), 4.47 (d, 2H, J¼11.4 Hz), 4.41
(s, 2H), 4.36 (d, 1H J¼11.4 Hz), 4.27e4.25 (m, 1H), 4.20 (d, 1H,
J¼11.6 Hz), 4.09e4.05 (m, 1H), 3.79 (s, 3H), 3.78 (s, 6H), 3.60 (t, 1H
J¼8.6 Hz), 3.52e3.47 (m, 2H), 2.62e2.52 (m, 2H), 2.50e2.35 (m,
2H), 2.30e2.17 (m, 2H), 2.04e1.99 (m, 1H), 1.80e1.72 (m, 8H),
1.66e1.58 (m, 1H), 1.40e1.33 (m, 2H), 1.29 (s, 3H), 1.09 (d, 3H,
J¼6.2 Hz), 0.95e0.81 (m, 27H), 0.57 (q, 6H, J¼7.8 Hz), 0.02 (s, 3H),
ꢁ0.09 (s, 3H); 13C NMR (100 MHz, CDCl3) (data for major di-
1641, 1610, 1512, 1459, 1245, 1169, 1031, 822 cmꢁ1
.
4.2.51. Ketal 2. To a stirred solution of 62 (110 mg, 0.12 mmol) in
CH2Cl2 (6 mL)þpH 7 buffer (3 mL) was added DDQ (158 mg,
0.72 mmol, 6 equiv) at rt. After 20 min, the reaction was quenched
with satd NaHCO3 solution and extracted with CH2Cl2. The com-
bined organic layer was dried over MgSO4, and concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography (30e33% EtOAc/hexane) to afford 2 (44 mg, 67%)
as a colorless oil.
astereomer)
d (ppm): 166.3, 162.2, 159.3, 159.2, 159.1, 140.5, 135.2,
131.6, 131.2, 131.1, 130.9, 130.6, 129.52, 129.46, 129.3, 128.0, 123.8,
118.0, 114.0, 113.9, 113.7, 82.0, 78.6, 78.1, 77.0, 76.7, 75.7, 71.2, 70.5,
69.2, 55.49, 55.45, 41.5, 39.6, 39.3, 39.1, 37.2, 35.3, 35.1, 33.6, 26.3,
25.7, 20.5, 18.4, 18.0, 16.6, 15.9, 15.8, 15.5, 7.5, 7.1, ꢁ3.6, ꢁ3.8; HRMS
calcd for C66H102O10Si2 [MþNa]þ 1133.6904, found 1133.6941; IR
nmax (film): 2958, 2932, 2874, 1708, 1641, 1614, 1512, 1459, 1249,
4.2.52. Iriomoteolide-1a 1. To a stirred solution of 2 (18.8 mg,
0.034 mmol) in CH2Cl2 (34 mL) was added second generation
Grubbs catalyst (3 mg, 0.0034 mmol, 0.1 equiv) at rt. After 3 h, the
solvent was removed under reduced pressure. The resulting residue
was purified by flash chromatography (35e45% EtOAc/hexane) to
afford (E)-isomer 1 (9 mg, 52%) and (Z)-isomer 63 (3.6 mg, 21%).
1089, 1036, 831, 742 cmꢁ1
.
4.2.49. Cyclopentene 61. To a stirred solution of 59 (7 mg, 7.7
in CH2Cl2 (8 mL) was added second generation Grubbs catalyst
(0.7 mg, 0.8 mol) at rt. After 3 h, the solvent was removed. The
mmol)
(E)-Isomer iriomoteolide-1a 1: ½a D20
ꢂ
ꢁ27.8 (c 0.3, CHCl3); 1H NMR
(400 MHz, CDCl3) d (ppm): 5.89e5.79 (m, 3H), 5.77 (s, 1H), 5.67 (dd,
m
1H, J¼6.8 Hz, 15.5 Hz), 5.01e4.95 (m, 1H), 4.85 (s, 1H), 4.83 (s, 1H),
4.06e3.92 (m, 3H), 3.86e3.80 (m, 1H), 3.25 (s, 1H), 2.63 (s, 1H),
2.34e2.09 (m, 7H), 2.02e1.82 (m, 2H), 1.93 (s, 3H), 1.78 (ddd, 1H,
J¼3.4, 7.8,14.2 Hz),1.55e1.42 (m,1H),1.35e1.25 (m,1H),1.31 (s, 3H),
1.09 (d, 3H, J¼6.6 Hz), 1.07 (d, 3H, J¼7.8 Hz), 0.98 (d, 3H, J¼7.0 Hz),
resulting residue was purified by flash chromatography (25e30%
EtOAc/hexane) to afford 61 (4.1 mg, 61%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) (data for major diastereomer) d (ppm): 7.27e7.17
(m, 6H), 6.87e6.82 (m, 6H), 5.70e5.60 (m, 3H), 5.50e5.41 (m, 2H),
5.32 (dd, 1H, J¼8.6, 15.4 Hz), 4.88e4.83 (m, 1H), 4.47 (d, 1H,
J¼11.4 Hz), 4.46 (d, 1H, J¼11.4 Hz), 4.41 (s, 2H), 4.34 (d, 1H
J¼11.4 Hz), 4.29e4.22 (m, 1H), 4.19 (d, 1H, J¼11.6 Hz), 4.08e4.03 (m,
1H), 3.79 (s, 3H), 3.78 (s, 6H), 3.60e3.42 (m, 3H), 2.64e2.57 (m, 2H),
2.46e2.01 (m, 8H), 1.95e1.82 (m, 1H), 1.80e1.76 (m, 1H), 1.75 (d, 1H,
J¼6.4 Hz), 1.73 (s, 3H), 1.66e1.58 (m, 1H), 1.37e1.33 (m, 2H), 1.17 (s,
3H), 1.08 (d, 3H, J¼6.2 Hz), 0.92 (d, 3H, J¼7.0 Hz), 0.89 (d, 3H,
J¼6.8 Hz), 0.85 (d, 3H, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3) (data
0.87 (d, 3H, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm): 166.6
(C), 160.3 (C), 142.0 (C), 135.2 (CH), 133.0 (CH), 129.9 (CH), 127.5
(CH), 119.2 (CH), 111.1 (CH2), 99.4 (C), 77.4 (C), 75.3 (CH), 74.7 (CH),
70.6 (CH), 69.6 (CH), 41.0 (CH), 40.0 (CH2), 38.1 (CH2), 37.7 (CH2),
37.0 (CH), 35.9 (CH), 34.54 (CH2), 34.50 (CH2), 21.1 (CH3), 20.9 (CH3),
20.3 (CH3), 16.2 (CH3), 16.0 (CH3), 15.2 (CH3); HRMS calcd for
C29H46O7 [MþNa]þ 529.3136, found 529.3129; IR nmax (film) 3452,
2963, 2923, 2869, 1694, 1632, 1450, 1383, 1218, 1156, 965 cmꢁ1
.
for major diastereomer)
d
(ppm): 166.3, 162.6, 159.3, 159.2, 159.0,
(Z)-Isomer 63: ½a D20
ꢂ
ꢁ29.1 (c 0.4, CHCl3); 1H NMR (400 MHz,
139.7, 136.7, 131.6, 131.2, 131.0, 130.9, 130.8, 129.5, 129.4, 129.3,
128.0, 124.1, 117.9, 114.0, 113.9, 113.8, 82.1, 78.9, 76.6, 75.01, 74.98,
74.93, 70.6, 70.4, 69.2, 55.5, 41.8, 39.5, 39.2, 37.1, 35.1, 33.8, 33.1,
22.6, 20.3, 18.0, 16.5, 15.92, 15.90, 15.5; HRMS calcd for C54H74O10
[MþNa]þ 905.5174, found 905.5173; IR nmax (film): 3490, 2958,
2932, 2874, 1708, 1641, 1614, 1512, 1459, 1249, 1089, 1036, 831,
CDCl3) d (ppm): 5.87e5.81 (m, 2H), 5.77 (s, 1H), 5.67e5.55 (m, 2H),
4.91e4.85 (m, 1H), 4.86 (s, 1H), 4.84 (s, 1H), 4.38e4.27 (m, 1H),
4.25e4.18 (m, 1H), 3.99e3.90 (m, 1H), 3.82e3.77 (m, 1H), 3.73 (s,
1H), 2.46e2.18 (m, 6H), 2.00e1.87 (m, 3H), 1.95 (s, 3H), 1.78 (dd, 1H,
J¼8.2, 12.4 Hz), 1.50e1.42 (m, 1H), 1.35e1.25 (m, 1H), 1.26 (s, 3H),
1.09 (d, 3H, J¼5.5 Hz), 1.08 (d, 3H, J¼6.2 Hz), 0.95 (d, 3H, J¼6.8 Hz),
742 cmꢁ1
.
0.83 (d, 3H, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3)
d (ppm): 166.3
(C), 162.8 (C), 142.0 (C), 135.5 (CH), 132.7 (CH), 129.8 (CH), 125.7
(CH), 118.4 (CH), 111.2 (CH2), 100.0 (C), 77.7 (C), 73.3 (CH), 71.7 (CH),
70.8 (CH), 69.5 (CH), 40.4 (CH2), 39.7 (CH), 37.7 (CH), 37.0 (CH2),
35.9 (CH), 34.7 (CH2), 34.6 (CH2), 34.2 (CH2), 22.8 (CH3), 22.0 (CH3),
20.3 (CH3), 15.51 (CH3), 15.46 (CH3), 15.42 (CH3); HRMS calcd for
C29H46O7 [MþNa]þ 529.3136, found 529.3135; IR nmax (film) 3439,
4.2.50. Ketone 62. To a stirred solution of 59 (144 mg, 0.16 mmol)
in CH2Cl2 (1.6 mL) was added (i-Pr)2NEt (165 mg, 1.28 mmol,
8 equiv), DMSO (0.18 mL), and SO3$py (102 mg, 0.64 mmol, 4 equiv)
at 0 ꢀC. After 30 min at rt, the reaction was quenched with satd
NaHCO3 and diluted with Et2O. The organic layer was washed
successively with H2O, brine, and dried over MgSO4. After con-
centration under reduced pressure, the resulting residue was pu-
rified by flash chromatography (24e30% Et2O/hexane) to afford 62
2967, 2923, 2869, 1694, 1632, 1450, 1383, 1205, 1160, 965 cmꢁ1
.
Acknowledgements
(110 mg, 70%) as a colorless oil. ½a D20
ꢂ
ꢁ11.8 (c 1.5, CHCl3); 1H NMR
(400 MHz, CDCl3)
d
(ppm): 7.25e7.15 (m, 6H), 6.86e6.82 (m, 6H),
Support from Chugai Pharmaceutical Co. and the Caltech/City of
Hope Medical Research Fund is gratefully acknowledged. Y.M. is
supported by an Irell and Manella Graduate School Merit Fellow-
ship. The authors thank Professor Jiong Yang for kindly sharing his
results on iriomoteolide-1a.
5.85e5.61 (m, 4H), 5.42 (d, 1H, J¼15.2 Hz), 5.32 (dd, 1H, J¼8.6,
15.4 Hz), 5.10e5.05 (m, 2H), 5.01 (s, 1H), 4.87 (s, 1H), 4.92e4.84 (m,
1H), 4.51e4.45 (m, 3H), 4.39 (d, 1H, J¼11.2 Hz), 4.32 (d, 1H
J¼11.6 Hz), 4.19 (d, 1H, J¼11.6 Hz), 4.09e4.01 (m, 1H), 3.86 (s, 1H),

J. Xie et al. / Tetrahedron 67 (2011) 7485e7501
7501
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Supplementary data
Supplementary data associated with this article can be found in
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