Asymmetric synthesis of the core structure of leucosceptroids A-D

Article abstract of DOI:10.1021/jo200899v

The asymmetric synthesis of the core structure of leucosceptroids A-D has been achieved. The key steps of the synthesis includes the formation of the cis-2,5-disubstituted THF ring by TPAP catalytic oxidative cyclization followed by a highly diastereosele

Full text of DOI:10.1021/jo200899v

ARTICLE
pubs.acs.org/joc
Asymmetric Synthesis of the Core Structure of Leucosceptroids AÀD
Jun Xie, Yuelong Ma, and David A Horne*
Department of Molecular Medicine, Beckman Research Institute at City of Hope, Duarte, California 91010, United States
S Supporting Information
b
ABSTRACT: The asymmetric synthesis of the core structure of
leucosceptroids AÀD has been achieved. The key steps of the
synthesis includes the formation of the cis-2,5-disubstituted
THF ring by TPAP catalytic oxidative cyclization followed by a
highly diastereoselective intramolecular DielsÀAlder reaction
to fashion the fused tricyclic hydrindane ring system.
’ INTRODUCTION
’ RESULTS AND DISCUSSION
Many secondary metabolites including alkaloids, phenolics,
and terpenoids, produced from glandular trichomes, possess a
wide variety of structures and play an important role in defense
against herbivores. Recently, leucosceptroids A (1) and B (2) were
isolated by Li’s group from glandular trichomes of Leucosceptrum
canum and possess antifeedant and antifungal activities. The struc-
tures of 1 and 2 were initially elucidated by 2D NMR and MS
spectral analysis and subsequently confirmed by X-ray diffraction
methods (Figure 1).1a The central core of 1 and 2 is structurally
unique and embodies a tricyclic ring system in which a highly
substituted tetrahydrofuran moiety is fused onto a hydrindane ring
system. Surrounding this core, is a highly decorated set of appen-
dages that is diverse in nature and distributed among eight stereo-
genic centers. Moreover, the additional two sesterterpenoids,
leucosceptroids C (3) and D (4),1b were isolated by the same
group from the same source. The structure of 3and 4share the same
tricyclic core with 1 and 2 and uncommon antipodal cyclopente-
nones. In this regard, leucosceptroids AÀD represent challenging
synthetic targets for which no synthetic work has been reported.
Herein, we describe an efficient approach to the core structure of
these secondary metabolites.
The retrosynthetic strategy is depicted in Figure 2 and is based
on an intramolecular DielsÀAlder approach. The plan is directed
at the synthesis of core structure 5 via ring-opening of epoxide 6.
Differentiation of the resulting hydroxyl moieties would occur
through selective protection as the acetonide. Diastereoselective
introduction of the epoxide ring in 6 was anticipated via hydro-
xyl-directed epoxidation.2 Because intramolecular DielsÀAlder
reactions3 have proven to be an efficientive method to construct
various fused ring systems in natural products, we pursued this
approach in fashioning core structure 7 in a stereocontrolled
manner. Endo orientation of the approaching dienophile oppo-
site to the larger OTBS group would produce 7 and establish four
of the six ring stereocenters in a single step. Key to this approach
is the development of an efficient diastereoselective synthesis of
the 2,5-disubstituted cis-tetrahydrofuran DielsÀAlder substrate
8. This was envisioned from diol 10 using oxidative cyclization4
and Sonagashira cross-coupling strategies.5
Oxidation of 1,2:5,6-diisopropylidene-D-mannitol with NaIO4
followed by nucleophilic addition with 2-methylallylmagnesium
chloride afforded secondary alcohol 116 with a 7:4 dr in 68%
yield. The stereochemistry at the newly formed center would be
eliminated in subsequent steps. After protection with PMB
group, acetonide deprotection of 12 produced diol 10 in high
yield (Scheme 1). Recently, Stark and co-workers4a reported a
powerful method to construct enantiopure cis-THF-diols with
NMO and catalytic TPAP. Inspired by their findings, diol 10 was
transformed to desired product 13 in 34% yield (entry 1). The
yield of this transformation was further optimized to 55% (entry 3)
with NMO in the presence of 8% H2O. Interestingly, similar yields
were obtained without adding water (entries 4). Under all condi-
tions listed, a single diastereomer at C14 was produced (the original
dr value of 7:4 relative to C5 remained unchanged). Subsequent
protection of diol 13 as its TBS ether provided 14. The preparation
of ketone 9 was achieved in nearly quantitative yield via PMB
deprotection and oxidation with DessÀMartin periodinane.7 The
significant NOE correlation between H and Me confirmed the cis-
THF orientation of these two moieties.
With 9 in hand, the construction of fused tricylic ring system
was pursued (Scheme 2). Treatment of 9 with LiHMDS and
PhNTf2 afforded enol triflate 15. Sonagashira cross-coupling
reaction between 15 and alkyne 168 proceeded efficiently to
afford product 17 in 89% yield for the two steps. Upon careful
monitoring, semihydrogenation of the alkyne functionality using
Lindlar’s catalyst and quinoline afforded cis-alkene 18 in 70À80%
yield. It is important to stop the reduction just prior to the
complete consumption of starting material, otherwise over-
reduction begins to predominate.9 Oxidation of allylic alcohol
18 with MnO2 yielded IMDA10 precusor 8. When 8 was heated
with BHT in toluene for 16 h, desired product 7 was isolated in
58% yield as a single diastereomer. This gratifying result can be
rationalized by a top-face endo approach of the dienophile that is
controlled by nonbonded interactions between substituents on
Received: May 5, 2011
Published: June 06, 2011
r
2011 American Chemical Society
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Figure 1. Structures of leucosceptroids AÀD.
Figure 2. Retrosynthetic analysis.
Scheme 1. Synthesis of Ketone 9
the chiral THF ring. In this single step, four key stereogenic
centers are installed in a highly efficient manner.
Next, the focus was on the diastereoselective construction of
the C5ÀC6 epoxide ring (Scheme 3). Reduction of 7 followed by
protection with benzyl or TBDPS groups provided 19 or 23,
respectively. NOE correlations in 19 further confirmed the
stereochemistry of the newly formed four chiral centers that
resulted from the IMDA cyclization. Selective deprotection of
TBS afforded homoallylic alcohols 20 or 24. At this point, it was
anticipated that hydroxyl-directed epoxidation would take place
from the endo face of the cis-hydrindane ring and overcome any
steric hindrance caused by this ring system. When 20 was treated
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Scheme 2. Synthesis of 7
Scheme 3. Synthesis of Epoxide 6
with m-CPBA, epoxides 21 and 22 were produced in a 1.3:1 dr,
respectively. While the major product is also the desired product,
separation of the two diastereomers by column chromatography
proved difficult. Similarly, related analogues 6 and 25 can be
generated from 24 using m-CPBA in 2:1 dr, but unlike 21 and 22,
these diastereomeric epoxides are readily separable by column
chromatography in 90% isolated yield. From the 1H NMR spectrum
of 6, the C6 hydrogen is coupled to the C7 hydrogen and appears as a
doublet (J = 4.9 Hz) whereas the C6 hydrogen of 25 is a singlet.
Based on this coupling information, the stereochemistry was assigned
as indicated. As an attempt to improve the diastereoselectivity of the
epoxidation, the use of VO(acac)2 and t-BuOOH11 was investigated.
Treatment of 24 under these conditions afforded a 9:1 dr of 6and 25
but in much lower yield (30%). The low yield of this reaction might
be attributed to the oxidation of activated hydrogen at C4.
With 6 in hand, an SN2 epoxide ring-opening at C6 was pursued
(Scheme 4). Despite several attempts at nucleophilic ring-opening at
C6, we were unable to introduce the requisite methyl substituent.
The use of Me2CuLi resulted in a complex mixture of products, and
when MeLi was employed, mostly starting material was recovered
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Scheme 4. Epoxide Ring-Opening
yield.12 Fortunately, ketal 30 can be converted to 29 in high yield
(88%) without loss of the acetonide functionality. An X-ray crystal
structure of 31 was obtained after removal of TBDPS group from 29
which unequivocally confirmed the structure and stereochemical
assignments previously made.
Scheme 5. Synthesis of 29
’ CONCLUSION
In summary, a concise and efficient synthesis of the core
structure of leucosceptroids AÀD (1À4) has been achieved. The
construction of the cis-2,5-disubstituted THF ring was accom-
plished through a TPAP-catalytic cyclization which set the stage
for a Sonagashira cross-coupling reaction followed by an IMDA
reaction to establish the fused tricyclic core ring system in a highly
stereocontrolled manner. Future efforts will focus on introducing
the C6 methyl substituent and completion of the total synthesis.
’ EXPERIMENTAL SECTION
General Information. All reagents and solvents were commercial
grade and purified prior to use when necessary. Visualization was performed
by ultraviolet light and/or by staining with potassium permanganate. All 1H
and 13C NMR spectra were recorded at 400 and 100 MHz, respectively, at
room temperature.
from the reaction. Alternatively, Grignard reagents are another choice
for this transformation because epoxides are well-known to undergo
nucleophilic ring-opening with these reagents. To our surprise, when
6 was treated with MeMgBr (3 M in Et2O), only reduction product
26 was obtained in 52% yield (entry 3). Using MeMgBr (1 M in
THF), the yield of 26 increased to 72% (entry 4). Interestingly, when
MeMgCl was tried, 27 was isolated with Cl substituted on C6 in 40%
yield (entry 5). One possible reason for failure to introduce the
methyl group in 6 is the presence of a dianion that is formed upon
addition of excess MeLi. Such a species may prevent attack of a
methyl carbanion. We plan to retool the synthesis and pursue the
epoxide ring-opening with a fully protected substrate.
Although initial efforts thus far have not succeeded in introdu-
cing the C6 methyl substituent, we continued to pursue differentiat-
ing the two hydroxyl substituents in 26. This was accomplished by
converting 26 into its acetonide 29 (Scheme 5). When the reaction
was carried out with 20% CSA in 2,2-dimethoxypropane, desired
product 29 was obtained in 33% yield in addition to ketal 30 in 54%
Experimental Procedure. (R)-4-(1-(4-Methoxybenzyloxy)-3-
methylbut-3-enyl)-2,2-dimethyl-1,3-dioxolane 12. To a stirred solution
of 1,2:5,6-diisopropylidene-D-mannitol (917 mg, 3.5 mmol) in CH2Cl2
(8 mL) was added sat. NaHCO3 (0.4 mL) and NaIO4 (1.28 g, 6 mmol)
slowly at 0 °C. After 3 h at rt, MgSO4 (0.5 g) was added and the reaction was
stirred for 20 min. The solid was filtered, and the solvent was removed under
reduced pressure. The resulting residue was used for the next step without
purification. To a stirred solution of crude aldehyde in THF (5 mL) was
added 2-methylallylmagnesium chloride (0.3 M in THF, 25 mL, 1.1 equiv)
at À78 °C over 20 min. After addition, the reaction was warmed to rt and
stirred overnight. The reaction was quenched with sat. NH4Cl, and the
aqueous layer was extracted with Et2O. The combined organic layer was
dried over MgSO4 and concentrated under reduced pressure. The resulting
residue was purified by flash chromatography (10À12.5% EtOAc/hexane)
to afford 11 (885 mg, 68% for two steps) as a colorless oil. To a stirred
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solution of 11 (885 mg, 4.75 mmol) in DMF (9 mL) was added NaH (380
mg, 9.5 mmol, 2 equiv) at 0°C. After 30 min atrt, PMBCl (1.15 g, 7.4 mmol,
1.5 equiv) was added at 0 °C. The reaction was stirred for 2 h at rt and
quenched with sat. NH4Cl, and the aqueous layer was 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 (4À5% EtOAc/hexane) to afford 12 (1.2
g, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ(ppm):7.23À7.29
(m, 2H), 6.84À6.89 (m, 2H), 4.79À4.83 (m, 2H), 4.56À4.65 (m, 2H),
3.62À4.20 (m, 7H), 2.18À2.27 (m, 2H), 1.68À1.77 (m, 3H), 1.43 (s, 3H),
1.35 (s, 3H); 13C NMR (100 MHz, CDCl3) δ(ppm): 159.4, 142.54, 142.49,
131.0, 130.9, 129.7, 129.6, 114.0, 113.9, 113.5, 113.3, 109.4, 109.2, 78.1, 77.8,
77.4, 72.9, 72.5, 66.1, 66.0, 55.5, 40.5, 39.3, 26.8, 26.7, 25.6, 25.5, 23.2, 23.1;
HRMS calcd for C18H26O4 [M + Na]+ 329.1723, found 329.1722; IR νmax
À5.25; HRMS calcd for C27H50O5Si2 [M + Na]+ 533.3089, found
533.3088; IR νmax (film) 2932, 2856, 1512, 1249, 1098, 840, 778 cmÀ1
.
Another isomer of 14: [R]D20 = À19.4 (c = 0.8, CHCl3); 1H NMR
(400 MHz, CDCl3) δ (ppm): 7.24 (d, 2H, J = 8.6 Hz), 6.85 (d, 2H, J =
8.6 Hz), 4.50 (d, 1H, J = 11.6 Hz), 4.39 (d, 1H, J = 11.6 Hz), 4.07À4.09
(m, 1H), 3.98À4.01 (m, 1H), 3.89 (dd, 1H, J = 7.4, 9.8 Hz), 3.81 (s, 3H),
3.72 (dd, 1H, J = 5.1, 9.8 Hz), 3.58 (d, 1H, J = 9.2 Hz), 3.41 (d, 1H, J =
9.2 Hz), 2.28 (dd, 1H, J = 1.6, 13.8 Hz), 1.66 (dd, 1H, J = 5.2, 13.8 Hz),
1.22 (s, 3H), 0.89 (s, 18H), 0.05 (s, 6H), 0.02 (s, 6H); 13C NMR (100
MHz, CDCl3) δ (ppm): 159.2, 131.0, 129.2, 113.9, 83.0, 82.5, 79.3, 71.2,
69.8, 61.7, 55.5, 39.9, 26.19, 26.13, 24.9, 18.55, 18.48, À5.06, À5.10,
À5.18; HRMS calcd for C27H50O5Si2 [M + Na]+ 533.3089, found
533.3088; IR νmax (film) 2932, 2856, 1512, 1249, 1098, 840, 778 cmÀ1
.
(2R,5R)-2,5-Bis((tert-butyldimethylsilyloxy)methyl)-5-methyldihy-
(film) 2936, 2856, 1610, 1512, 1245, 1076, 1031 cmÀ1
.
drofuran-3(2H)-one 9. To a stirred solution of 14 (282 mg, 0.55 mmol)
in CH2Cl2 (10 mL) + pH 7 buffer (1 mL) was added DDQ (162 mg,
0.72 mmol, 1.3 equiv) at 0 °C. After 1.5 h at rt, the reaction was
quenched with sat. NaHCO3 solution and extracted with CH2Cl2. The
combined organic layer was 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 product in CH2Cl2
(16 mL) were added NaHCO3 (462 mg, 5.5 mmol, 10 equiv) and
DessÀMartin reagent (466 mg, 1.1 mmol, 2 equiv). After 2 h at rt, the
reaction was quenched with sat. Na2SO3 and sat. NaHCO3, extracted
with CH2Cl2, dried over MgSO4, and concentrated under reduced
pressure. The resulting residue was purified by flash chromatography
(R)-3-(4-Methoxybenzyloxy)-5-methylhex-5-ene-1,2-diol 10. A stir-
red solution of 12 (1.2 g, 4 mmol) in HOAc (12 mL), H2O (4 mL), and
THF (4 mL) was heated to 40 °C. After 15 h at 40 °C, the reaction was
diluted with EtOAc and neutralized with NaHCO3. The aqueous layer
was extracted with EtOAc (3 Â 60 mL), and the combined organic
fraction was dried over MgSO4 and concentrated under reduced
pressure. The resulting residue was purified by flash chromatography
(35À50% EtOAc/hexane) to afford 10 (965 mg, 93%) as a colorless oil.
1H NMR (400 MHz, CDCl3) δ (ppm): 7.23À7.25 (m, 2H), 6.86À6.90
(m, 2H), 4.83À4.86 (m, 2H), 4.60À4.64 (m, 1H), 4.40À4.46 (m, 1H),
3.81 (s, 3H), 3.60À3.79 (m, 4H), 2.10À2.50 (m, 4H), 1.79 (s, 3H); 13
C
20
NMR (100 MHz, CDCl3) δ (ppm): 159.7, 159.6, 142.4, 142.1, 130.3,
130.1, 129.9, 129.8, 114.20, 114.17, 114.0, 113.8, 79.8, 77.5, 72.7, 72.6,
72.0, 64.5, 63.3, 55.5, 39.7, 38.9, 23.2, 23.0; HRMS calcd for C15H22O4
[M + Na]+ 289.1410, found 289.1409; IR νmax (film) 3403, 2932, 1610,
(3.5À4% EtOAc/hexane) to afford 9 (205 mg, 96%). [R]D = 61.7
(c = 0.87, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 4.05 (t, 1H,
J = 3.1 Hz), 3.84 (dd, 1H, J = 3.7, 10.9 Hz), 3.79 (dd, 1H, J = 2.5, 10.9 Hz),
3.69 (d, 1H, J = 9.8 Hz), 3.59 (d, 1H, J = 9.8 Hz), 2.49 (d, 1H, J = 17.8
Hz), 2.27 (d, 1H, J = 17.8 Hz), 1.31 (s, 3H), 0.87À0.89 (m, 18H),
0.03À0.06 (m, 12H); 13C NMR (100 MHz, CDCl3) δ (ppm): 215.0,
81.8, 81.0, 70.3, 63.7, 46.7, 26.12, 26.08, 23.7, 18.6, 18.5, À5.16, À5.18,
À5.24, À5.30; HRMS calcd for C19H40O4Si2 [M + Na]+ 411.2357,
found 411.2355; IR νmax (film) 2927, 2856, 1766, 1472, 1254, 1112, 836,
1512, 1245, 1076, 1031 cmÀ1
.
((2R,5R)-4-(4-Methoxybenzyloxy)-2-methyltetrahydrofuran-2,5-
diyl)dimethanol 13. To a stirred solution of 10 (622 mg, 2.3 mmol) in
CH2Cl2 (45 mL) were added NMO (350 mg, 3 mmol, 1.3 equiv) and
TPAP (40 mg, 0.12 mmol, 0.05 equiv) at rt. After 16 h, the reaction was
quenched with 2-propanol. The solvent was concentrated under re-
duced pressure, and the resulting residue was purified by flash chroma-
778 cmÀ1
.
(E)-8-((2S,5R)-2,5-Bis((tert-butyldimethylsilyloxy)methyl)-5-meth-
yl-2,5-dihydrofuran-3-yl)oct-2-en-7-yn-1-ol 17. To a stirred solution of
9 (434 mg, 1.1 mmol) in THF (2.2 mL) was added LiHMDS (1 M in
THF, 1.7 mmol, 1.5 equiv) at À78 °C. After 30 min, PhNTf2 in THF
(2.2 mL) was added, and the reaction was warmed to rt. After 1 h, the
reaction was quenched with sat. NH4Cl solution 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 (0.8À1% EtOAc/hexane) to afford 15. 1H NMR
(400 MHz, CDCl3) δ (ppm): 5.84 (s, 1H), 4.79À4.82 (m, 1H),
3.71À3.78 (m, 2H), 3.62 (d, 1H, J = 9.6 Hz), 3.52 (d, 1H, J = 9.6
Hz), 1.36 (s, 3H), 0.87À0.89 (m, 18H), 0.03À0.06 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ (ppm): 144.1, 119.0, 88.3, 81.9, 69.9, 63.6, 26.1,
26.0, 23.7, 18.6, 18.4, À5.26, À5.42. A flask was charged with 15 (1.1
mmol), alkyne 16 (154 mg, 1.2 mmol, 1.1 equiv), Pd(PPh3)4 (127 mg,
0.11 mmol, 0.1 equiv), and CuI (105 mg, 0.55 mmol, 0.5 equiv) purged
with N2. DMF (9 mL) and i-Pr2NEt (709 mg, 5.5 mmol, 5 equiv) were
added. After 30 min at rt, the reaction was quenched with sat. NH4Cl
solution and extracted with EtOAc. 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 chroma-
tography (6À9% EtOAc/hexane) to afford 17 (497 mg, 89% for two
steps). [R]D20 = 14.2 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
(ppm): 5.98 (s, 1H), 5.66À5.69 (m, 2H), 4.75À4.78 (m, 1H),
4.08À4.12 (m, 2H), 3.80 (dd, 1H, J = 2.8, 11.0 Hz), 3.69 (dd, 1H, J =
4.4, 11.0 Hz), 3.56 (d, 1H, J = 9.4 Hz), 3.52 (d, 1H, J = 9.4 Hz), 2.33
(t, 2H, J = 7.2 Hz), 2.14À2.20 (m, 2H), 1.57À1.63 (m, 2H), 1.29 (s, 3H),
0.88À0.89 (m, 18H), 0.02À0.07 (m, 12H); 13C NMR (100 MHz,
1
tography (40À75% EtOAc/hexane) to afford 13 (360 mg, 55%). H
NMR (400 MHz, CDCl3) δ (ppm): 7.21À7.27 (m, 2H), 6.86À6.90
(m, 2H), 4.43À4.57 (m, 1H), 4.32À4.42 (m, 1H), 4.17À4.30 (m, 1H),
4.05À4.17 (m, 1H), 3.82À3.90 (m, 1H), 3.81 (s, 3H), 3.57À3.64
(m, 2H), 3.39À3.49 (m, 1H), 2.82 (b, 1H), 2.48 (b, 1H), 2.30À2.40
(m, 1H), 1.78À1.92 (m, 1H), 1.20À1.30 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 159.7, 159.5, 130.4, 129.7, 129.6, 129.5, 114.2, 114.1,
84.5, 84.3, 83.3, 80.72, 80.69, 80.5, 71.7, 71.3, 69.2, 68.7, 63.5, 62.5, 55.5,
39.8, 39.4, 24.5, 24.2; HRMS calcd for C15H22O5 [M + Na]+ 305.1359,
found 305.1359; IR νmax (film) 3420, 2932, 1512, 1245, 1076, 1031 cmÀ1
.
Tetrahydrofuran 14. To a stirred solution of 13 (159 mg, 0.56 mmol)
in CH2Cl2 (2 mL) were added cat. DMAP, Et3N (440 mg, 4.4 mmol, 8
equiv), and TBSCl (405 mg, 2.7 mmol, 4.8 equiv) at 0 °C and stirred
overnight at rt. The mixture was quenched with sat. 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 (1.5À1.8%
EtOAc/hexane) to afford 14 (282 mg, 98%). One isomer of 14:
20
[R]D = 4.8 (c = 1.1, CHCl3); 1H NMR (400 MHz, CDCl3)
δ (ppm): 7.26 (d, 2H, J = 8.6 Hz), 6.87 (d, 2H, J = 8.6 Hz), 4.44
(d, 2H, J = 5.4 Hz), 4.04À4.09 (m, 2H), 3.80 (s, 3H), 3.63 (dd, 1H, J =
4.1, 10.6 Hz), 3.49 (dd, 1H, J = 6.2, 10.6 Hz), 3.42 (d, 1H, J = 10.0 Hz),
3.36 (d, 1H, J = 10.0 Hz), 2.19 (dd, 1H, J = 6.4, 13.1 Hz), 1.75 (dd, 1H,
J = 3.5, 13.1 Hz), 1.29 (s, 3H), 0.885 (s, 9H), 0.884 (s, 9H), 0.042 (s,
3H), 0.040 (s, 3H), 0.032 (s, 3H), 0.030 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 159.3, 130.9, 129.5, 114.0, 84.5, 84.1, 81.1, 71.2, 69.9,
64.2, 55.5, 39.4, 26.18, 26.16, 24.5, 18.57, 18.54, À5.11, À5.15, À5.16,
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CDCl3) δ (ppm): 137.7, 132.1, 130.1, 121.9, 94.2, 90.8, 88.3, 74.2, 70.2,
65.4, 63.9, 31.5, 28.1, 26.2, 26.1, 23.3, 19.1, 18.8, 18.5, À5.0, À5.1,
À5.17, À5.20; HRMS calcd for C27H50O4Si2 [M + Na]+ 517.3140,
found 517.3127; IR νmax (film) 3403, 2927, 2856, 1637, 1472, 1249,
aqueous layer was extracted with Et2O. The combined organic layer was
dried over MgSO4 and concentrated under reduced pressure. The
resulting residue was purified by flash chromatography (1% EtOAc/
hexane) to afford 19 (89 mg, 67% for 2 steps). [R]D20= 30.2 (c = 0.75,
CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.27À7.37 (m, 5H),
5.36 (d, 1H, J = 1.4 Hz), 4.48 (d, 1H, J = 11.9 Hz), 4.41 (d, 1H, J = 11.9
Hz), 4.28À4.38 (m, 1H), 3.68 (dd, 1H, J = 5.2, 9.0 Hz), 3.58À3.65
(m, 3H), 3.49 (dd, 1H, J = 5.4, 10.0 Hz), 3.30 (t, 1H, J = 9.0 Hz), 2.72À
2.78 (m, 1H), 2.54À2.60 (m, 1H), 2.44À2.52 (m, 1H), 2.34À2.40
(m, 1H), 1.74À1.84 (m, 1H), 1.58À1.68 (m, 1H), 1.44À1.56 (m, 2H),
1.34À1.42 (m, 2H), 1.14 (s, 3H), 0.88À0.90 (m, 18H), 0.03À0.05
(m, 12H); 13C NMR (100 MHz, CDCl3) δ (ppm): 139.5, 138.9, 128.5,
127.8, 127.6, 122.4, 84.9, 78.4, 73.2, 71.2, 70.8, 66.8, 43.9, 40.5, 36.6,
35.8, 32.0, 28.8, 26.2, 26.1, 23.6, 20.5, 18.6, 18.5, À5.12, À5.17, À5.27;
HRMS calcd for C34H58O4Si2 [M + Na]+ 609.3766, found 609.3764; IR
1094, 836, 778 cmÀ1
.
(2E,7Z)-8-((2S,5R)-2,5-Bis((tert-butyldimethylsilyloxy)methyl)-5-me-
thyl-2,5-dihydrofuran-3-yl)octa-2,7-dien-1-ol 18. To a stirred solution
of 17 (620 mg, 1.2 mmol) in EtOAc (60 mL) were added Lindlar catalyst
(253 mg) and quinoline (186 μL). The reaction was stirred under
hydrogen atmosphere for 4 h, and the solid was filtered. The solvent was
concentrated under reduced pressure, and the resulting residue was purified
by flash chromatography (7À8% EtOAc/hexane) to afford 18 (500 mg,
20
80%) + recovered starting material (rsm) (30 mg, 5%). [R]D = À46.4
1
(c = 1.0, CHCl3); H NMR (400 MHz, CDCl3) δ (ppm): 5.55À5.76
(m, 5H), 4.78À4.82 (m, 1H), 4.06À4.10 (m, 2H), 3.67 (dd, 1H, J = 4.1,
10.8 Hz), 3.64 (dd, 1H, J= 4.5, 10.8 Hz), 3.54 (d, 2H, J= 1.7 Hz), 2.19À2.23
(m, 2H), 2.05À2.10 (m, 2H), 1.47À1.55 (m, 2H), 1.40 (b, 1H), 1.29
(s, 3H), 0.88À0.89 (m, 18H), 0.02À0.04 (m, 12H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 136.1, 135.0, 133.0, 131.0, 129.6, 120.9, 90.4, 88.2, 70.6,
66.3, 63.9, 32.1, 29.3, 29.2, 26.2, 26.1, 23.8, 18.6, 18.5, À5.11, À5.13, À5.15;
HRMS calcd for C27H52O4Si2 [M + Na]+ 519.3296, found 519.3285; IR
νmax (film) 2927, 2856, 1472, 1254, 1107, 836, 778 cmÀ1
.
((1S,3R,3aR,4R,4aS,7aR)-4-(Benzyloxymethyl)-3-methyl-3,3a,4,4a,
5,6,7,7a-octahydro-1H-indeno[5,6-c]furan-1,3-diyl)dimethanol 20.
To a stirred solution of 19 (65 mg, 0.11 mmol) in THF (1.1 mL) was
added TBAF (1 M in THF, 0.44 mmol, 4 equiv). After 75 min at rt, the
reaction was quenched with sat. NH4Cl, and the aqueous layer was extracted
with EtOAc. 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 (1.5À2% MeOH/CH2Cl2) to
afford 20 (31 mg, 77%). [R]D20 = 61.0 (c = 0.75, CHCl3); 1H NMR (400
MHz, CDCl3) δ (ppm): 7.27À7.37 (m, 5H), 5.38 (d, 1H, J = 1.6 Hz), 4.48
(d, 1H, J = 11.9 Hz), 4.41 (d, 1H, J = 11.9 Hz), 4.40À4.44 (m, 1H),
3.66À3.71 (m, 2H), 3.50À3.62 (m, 3H), 3.30 (dd, 1H, J = 6.2, 9.2 Hz), 3.00
(b, 1H), 2.90À2.95 (m, 1H), 2.68 (b, 1H), 2.50À2.58 (m, 1H), 2.26À2.36
(m, 2H), 1.74À1.84 (m, 1H), 1.62À1.72 (m, 1H), 1.44À1.58 (m, 2H),
1.34À1.42 (m, 2H), 1.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ (ppm):
138.4, 128.6, 127.9, 127.8, 123.0, 85.9, 78.6, 73.2, 71.5, 67.7, 66.3, 41.2, 41.1,
36.4, 36.2, 31.9, 29.1, 23.5, 19.8; HRMS calcd for C22H30O4 [M + Na]+
381.2036, found 381.2036; IR νmax (film) 302, 2927, 2856, 1472, 1254,
νmax (film) 3403, 2927, 2856, 1472, 1254, 1094, 836, 778 cmÀ1
.
(2E,7Z)-8-((2S,5R)-2,5-Bis((tert-butyldimethylsilyloxy)methyl)-5-methyl-
2,5-dihydrofuran-3-yl)octa-2,7-dienal 8. To a stirred solution of 18 (172 mg,
0.34 mmol) in CH2Cl2 (3.4 mL) was added MnO2 (2.4 g, 2.72 mmol, 80
equiv). After 36 h at rt, the solid was filtered. The solvent was concentrated
under reduced pressure, and the resulting residue was purified by flash
chromatography (4À4.5% EtOAc/hexane) to afford 8 (142 mg, 82%).
20
[R]D = À51.6 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
δ (ppm): 9.51 (d, 1H, J = 7.8 Hz), 6.84 (dt, 1H, J = 6.6, 15.6 Hz), 6.12
(dd,1H,J= 7.8, 15.6 Hz), 5.79 (d, 1H, J= 11.6 Hz), 5.66 (s, 1H), 5.58 (dt, 1H,
J = 7.0, 11.6 Hz), 4.79À4.82 (m, 1H), 3.62À3.69 (m, 2H), 3.47À3.57 (m,
2H), 2.26À2.39 (m, 4H), 1.60À1.68 (m, 2H), 1.29 (s, 3H), 0.87À0.89 (m,
18H), 0.03À0.06 (m, 12H); 13C NMR (100 MHz, CDCl3) δ (ppm): 194.1,
158.2, 136.1, 133.9, 133.4, 131.2, 121.6, 90.5, 88.1, 70.5, 66.2, 32.5, 29.1, 28.0,
26.22, 26.18, 26.16, 26.13, 23.8, 18.6, 18.5, À5.12, À5.14, À5.16; HRMS calcd
for C27H50O4Si2 [M + Na]+ 517.3140, found 517.3138; IR νmax (film) 2927,
1107, 836, 778 cmÀ1
.
TBDPS Ether 23. To a stirred solution of 7 (110 mg, 0.22 mmol) in
EtOH (6 mL) was added NaBH4 (15 mg, 0.46 mmol, 2 equiv) at 0 °C.
After 1 h at rt, the reaction was quenched with sat. NH4Cl, and the
aqueous layer was extracted with CH2Cl2, dried over MgSO4, and concen-
trated under reduced pressure. The resulting residue was purified by short
column (9% EtOAc/hexane) and used for the next step. To a stirred solution
of alcohol in CH2Cl2 (2 mL) were added cat. DMAP, imidazole (28 mg, 0.44
mmol, 2 equiv), and TBDPSCl (90 mg, 0.33 mmol, 1.5 equiv) and stirred for
2.5 h at rt. The mixture was quenched with sat. NaHCO3 and diluted with
Et2O, and the organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (1.2À1.5% EtOAc/hexane) to afford 23
2856, 1694, 1637, 1472, 1249, 1089, 836, 778 cmÀ1
.
(1S,3R,3aR,4R,4aS,7aR)-1,3-Bis((tert-butyldimethylsilyloxy)methyl)-
3-methyl-3,3a,4,4a,5,6,7,7a-octahydro-1H-indeno[5,6-c]furan-4-car-
baldehyde 7. To a stirred solution of 8 (142 mg, 0.28 mmol) in toluene
(28 mL) was added BHT (62 mg, 0.28 mmol, 1 equiv). The reaction was
stirred at 140 °C for 15 h, and the solvent was concentrated under reduced
pressure. The resulting residue was purified by flash chromatography (1.8%
to 2.5% EtOAc/hexane) to afford 7 (82 mg, 58%). [R]D20 = 1.7 (c = 0.75,
CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 9.77 (d, 1H, J = 5.6 Hz),
5.58 (d, 1H, J= 1.6 Hz), 4.46À4.49 (m, 1H), 3.66(dd, 1H, J= 4.4, 10.0 Hz),
3.54À3.60 (m, 3H), 2.86À2.90 (m, 1H), 2.72À2.82 (m, 2H), 2.16À2.22
(m, 1H), 1.76À1.90 (m, 2H), 1.42À1.56 (m, 4H), 1.03 (s, 3H), 0.87À0.89
(m, 18H), 0.04À0.06 (m, 12H); 13C NMR (100 MHz, CDCl3) δ (ppm):
205.9, 139.7, 123.1, 84.6, 79.4, 71.0, 66.7, 51.7, 43.2, 41.2, 36.3, 32.6, 30.2,
26.2, 26.1, 23.6, 21.8, 18.6, 18.4, À5.15, À5.17, À5.23, À5.3; HRMS calcd
for C27H50O4Si2 [M + Na]+ 517.3140, found 517.3135; IR νmax (film)
20
1
(160 mg, 95%). [R]D = 25.6 (c = 0.5, CHCl3); H NMR (400 MHz,
CDCl3) δ(ppm): 7.62À7.65 (m, 4H), 7.36À7.48 (m, 6H), 5.31 (d, 1H, J =
1.6 Hz), 4.22À4.25 (m, 1H), 3.88 (dd, 1H, J = 5.1, 10.0 Hz), 3.57 (dd, 1H,
J = 4.9, 10.0 Hz), 3.40À3.56 (m, 4H), 2.70À2.75 (m, 1H), 2.55À2.62 (m,
1H), 2.44À2.52 (m, 1H), 2.22À2.30 (m, 1H), 1.72À1.80 (m, 1H),
1.58À1.64 (m, 1H), 1.44À1.56 (m, 2H), 1.32À1.42 (m, 2H), 1.05
(s, 9H), 0.96 (s, 3H), 0.87À0.90 (m, 18H), 0.02À0.05 (m, 12H);
13C NMR (100 MHz, CDCl3) δ (ppm): 139.3, 135.85, 135.83, 134.32,
134.26, 129.7, 127.8, 122.3, 84.9, 78.4, 70.6, 66.8, 64.1, 43.6, 39.6, 39.1, 35.7,
32.0, 28.9, 27.2, 26.19, 26.18, 23.6, 20.6, 19.5, 18.6, 18.5, À5.1, À5.2, À5.3;
HRMS calcd for C43H70O4Si3 [M + Na]+ 757.4474, found 757.4468; IR
2927, 2856, 1721, 1472, 1254, 1107, 836, 778 cmÀ1
.
Benzyl Ether 19. To a stirred solution of 7 (117 mg, 0.23 mmol) in
EtOH (6 mL) was added NaBH4 (15 mg, 0.46 mmol, 2 equiv) at 0 °C.
After 1 h at rt, the reaction was quenched with sat. NH4Cl, and the
aqueous layer was extracted with CH2Cl2, dried over MgSO4, and
concentrated under reduced pressure. The resulting residue was purified
by short column (9% EtOAc/hexane) and used for the next step. To a
stirred solution of alcohol in DMF (0.9 mL) was added NaH (22 mg,
0.56 mmol, 2.5 equiv) at 0 °C. After 45 min at rt, the reaction was treated
with BnBr (75 mg, 0.46 mmol, 2 equiv) and cat. Bu4NI at 0 °C and
stirred for 3 h at rt. The reaction was quenched with sat. NH4Cl, and the
νmax (film) 2936, 2856, 1472, 1112, 836, 702 cmÀ1
.
((1S,3R,3aR,4R,4aS,7aR)-4-((tert-Butyldiphenylsilyloxy)methyl)-
3-methyl-3,3a,4,4a,5,6,7,7a-octahydro-1H-indeno[5,6-c]furan-1,3-diyl)-
dimethanol 24. To a stirred solution of 23 (36 mg, 0.05 mmol) in
MeOH (0.5 mL) was added CSA (2.3 mg, 0.01 mmol, 0.2 equiv). After
2.5 h at rt, the reaction was quenched with Et3N and MeOH was
6174
dx.doi.org/10.1021/jo200899v |J. Org. Chem. 2011, 76, 6169–6176

The Journal of Organic Chemistry
ARTICLE
concentrated under reduced pressure. The resulting residue was purified
by flash chromatography (1.2À1.6% MeOH/CH2Cl2) to afford 24
(23 mg, 90%). [R]D20 = 51.7 (c = 1.85, CHCl3); 1H NMR (400 MHz,
CDCl3) δ (ppm): 7.62À7.65 (m, 4H), 7.36À7.50 (m, 6H), 5.31 (d, 1H,
J = 1.4 Hz), 4.36À4.40 (m, 1H), 3.78 (dd, 1H, J = 6.0, 10.4 Hz), 3.57À
3.69 (m, 2H), 3.40À3.56 (m, 3H), 2.90À2.95 (m, 1H), 2.44À2.52 (m,
1H), 2.36À2.44 (m, 2H), 2.10À2.18 (m, 1H), 1.82À1.94 (m, 1H),
1.70À1.82 (m, 1H), 1.58À1.65 (m, 1H), 1.44À1.56 (m, 2H), 1.28À
1.38 (m, 2H), 1.05 (s, 9H), 1.01 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ (ppm): 138.1, 135.80, 135.77, 133.9, 129.9, 127.9, 123.1, 85.8, 78.6,
67.5, 66.3, 64.3, 41.0, 40.2, 38.9, 36.0, 32.0, 29.0, 27.1, 23.6, 20.1, 19.4;
HRMS calcd for C31H42O4Si [M + Na]+ 529.2745, found 529.2742; IR
((1R,3R,3aR,4S,4aR,7aR,8R,8aR)-8-((tert-Butyldiphenylsilyloxy)methyl)-
4-chloro-3a-hydroxy-1-methyldecahydro-1H-indeno[5,6-c]furan-1,3-diyl)-
dimethanol 27. To a stirred solution of 6 (14.5 mg, 0.03 mmol) in THF
(0.5 mL) was added MeMgCl (3 M in THF, 1.2 mmol, 40 equiv). After 48 h
at 80 °C, the reaction was quenched with sat. NH4Cl, extracted with Et2O,
dried over MgSO4, and concentrated under reduced pressure. The resulting
residue was purified by flash chromatography (1.2% MeOH/CH2Cl2) to
afford 27 (6.3 mg, 40%) and rsm (2.8 mg, 20%). [R]D20 = 28.1 (c = 0.7,
1
CHCl3); H NMR (400 MHz, CDCl3) δ (ppm): 7.64À7.69 (m, 4H),
7.37À7.48 (m, 6H), 4.47 (b, 1H), 4.02À4.22 (m, 3H), 3.79 (d, 1H, J = 13.3
Hz), 3.58À3.72 (m, 4H), 3.25 (b, 1H), 2.91 (d, 1H, J = 4.9 Hz), 2.86
(b, 1H), 2.20À2.28 (m, 1H), 1.94À2.06 (m, 1H), 1.70À1.84 (m, 2H),
1.54À1.62 (m, 2H), 1.40À1.48 (m, 1H), 1.29 (s, 3H), 1.20À1.28 (m, 1H),
1.08 (s, 9H), 0.60À0.68 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm):
136.0, 135.7, 133.1, 133.0, 130.3, 130.2, 128.08, 128.07, 86.2, 84.2, 78.3, 72.2,
71.4, 64.7, 63.3, 57.0, 42.4, 40.9, 39.8, 34.2, 33.1, 27.1, 25.9, 20.1, 19.4; HRMS
calcd for C31H43ClO5Si [M + Na]+ 581.2460, found 581.2454; IR νmax
νmax (film) 3417, 2936, 2856, 1472, 1112, 822, 702 cmÀ1
.
Epoxides 6 and 25. To a stirred solution of 24 (170 mg, 0.35 mmol)
in CH2Cl2 (4 mL) was added m-CPBA (321 mg, 1.3 mmol, 4 equiv).
After 48 h at rt, the reaction was quenched with sat. Na2SO3, extracted
with CH2Cl2, dried over MgSO4, and concentrated under reduced
pressure. The resulting residue was purified by flash chromatography
(1À1.6% MeOH/CH2Cl2) to afford 6 (100 mg, 60%) and 25 (52 mg,
30%). 6: [R]D20 = 30.6 (c = 0.4, CHCl3); 1H NMR (400 MHz, CDCl3) δ
(ppm): 7.63À7.67 (m, 4H), 7.36À7.48 (m, 6H), 3.83À3.86 (m, 1H),
3.52À3.80 (m, 6H), 3.35 (b, 1H), 3.29 (d, 1H, J = 4.9 Hz), 3.06 (d, 1H, J =
4.9 Hz), 2.61 (b, 1H), 2.22À2.30 (m, 1H), 1.77À1.83 (m, 1H), 1.50À1.58
(m, 2H), 1.35À1.47 (m, 3H), 1.16À1.22 (m, 1H), 1.19 (s, 3H), 1.08 (s,
9H), 0.40À0.48 (m, 1H); 13C NMR (100 MHz, CDCl3) δ (ppm): 136.0,
135.7, 133.1, 132.7, 130.3, 130.2, 128.11, 128.06, 84.4, 74.2, 69.3, 68.2, 64.7,
63.4, 60.4, 39.5, 37.9, 37.8, 32.5, 32.4, 28.4, 27.2, 25.3, 21.6, 19.3; HRMS
calcd for C31H42O5Si [M + Na]+ 545.2694, found 545.2689; IR νmax (film)
(film) 3394, 2927, 2860, 1476, 1472, 1111, 1076, 702 cmÀ1
.
Acetonide 29. To a stirred solution of 26 (32 mg, 0.06 mmol) in 2,
2-dimethoxypropane (1 mL) was added CSA (4.6 mg, 0.02 mmol, 0.3
equiv). After 4 h at rt, the reaction was quenched with Et3N, and 2,
2-dimethoxypropane was concentrated under reduced pressure. The
resulting residue was purified by flash chromatography (12% to 18%
EtOAc/hexane) to afford 30 (22 mg, 54%) and 29 (11.5 mg, 34%). To a
stirred solution of 30 (22 mg, 0.035 mmol) in MeOH (1.5 mL) were
added HOAc (20 μL) and H2O (20 μL). After 3.5 h at rt, the reaction
was quenched with sat. NaHCO3, extracted with CH2Cl2, dried over
MgSO4, and concentrated under reduced pressure. The resulting residue
was purified by flash chromatography (18% EtOAc/hexane) to afford 29
(18 mg, 90%). [R]D20 = 24.6 (c = 0.50, CHCl3); 1H NMR (400 MHz,
CDCl3) δ (ppm): 7.64À7.69 (m, 4H), 7.35À7.46 (m, 6H), 4.08 (dd,
1H, J = 4.1, 12.9 Hz), 3.85 (dd, 1H, J = 3.1, 12.9 Hz), 3.72À3.78 (m,
1H), 3.60À3.68 (m, 4H), 3.14 (b, 1H), 2.80 (d, 1H, J = 5.1 Hz),
1.97À2.05 (m, 1H), 1.92 (dd, 1H, J = 4.1, 13.3 Hz), 1.82À1.86 (m, 1H),
1.72À1.80 (m, 1H), 1.44À1.60 (m, 3H), 1.43 (s, 3H), 1.42 (s, 3H), 1.31
(t, 1H, J = 13.5 Hz), 1.26 (s, 3H), 1.22À1.28 (m, 1H), 1.12À1.18
(m, 1H), 1.07 (s, 9H), 0.60À0.68 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ (ppm): 136.1, 135.8, 133.5, 133.4, 130.1, 130.0, 128.0, 127.9,
98.5, 85.2, 84.2, 72.9, 71.9, 65.3, 60.3, 53.0, 42.5, 39.1, 37.1, 34.5, 33.8,
33.5, 29.3, 27.1, 26.2, 25.8, 20.2, 19.4; HRMS calcd for C34H48O5Si
[M + Na]+ 587.3163, found 587.3157; IR νmax (film) 3452, 2932, 2856,
3363, 2932, 2856, 1472, 1427, 1112, 1067, 702 cmÀ1
.
25: [R]D20 = 10.8 (c = 0.45, CHCl3); 1H NMR (400 MHz, CDCl3) δ
(ppm): 7.61À7.65 (m, 4H), 7.35À7.44 (m, 6H), 3.91 (dd, 1H, J = 4.4,
9.6 Hz), 3.84 (t, 1H, J = 3.3 Hz), 3.71À3.80 (m, 2H), 3.56 (d, 1H, J =
11.7 Hz), 3.50 (dd, 1H, J = 3.6, 11.8 Hz), 3.37 (d, 1H, J = 11.7 Hz), 3.07
(s, 1H), 2.73 (d, 1H, J = 5.1 Hz), 2.32À2.40 (m, 2H), 2.24 (b, 2H),
1.76À1.88 (m, 2H), 1.58À1.75 (m, 2H), 1.36À1.46 (m, 2H), 1.25À1.34
(m, 1H), 1.09 (s, 3H), 1.04 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ (ppm): 135.9, 135.8, 134.29, 134.26, 129.9, 129.8, 127.9, 85.0, 79.0, 67.8,
66.6, 65.4, 63.4, 57.7, 40.4, 39.6, 39.4, 35.2, 33.5, 31.7, 27.2, 26.1, 20.8, 19.4;
HRMS calcd for C31H42O5Si [M + Na]+ 545.2694, found 545.2690; IR
νmax (film) 3363, 2932, 2856, 1472, 1427, 1112, 1067, 702 cmÀ1
.
((1R,3R,3aR,4aS,7aS,8R,8aR)-8-((tert-Butyldiphenylsilyloxy)methyl)-
3a-hydroxy-1-methyldecahydro-1H-indeno[5,6-c]furan-1,3-diyl)di-
methanol 26. To a stirred solution of 6 (15.5 mg, 0.03 mmol) in THF
(0.6 mL) was added MeMgBr (3 M in Et2O, 1.2 mmol, 40 equiv). After 72 h
at 80 °C, the reaction was quenched with sat. NH4Cl and extracted with
Et2O, dried over MgSO4, and concentrated under reduced pressure. The
resulting residue was purified by flash chromatography (1.2À2.5% MeOH/
CH2Cl2) to afford 26 (8.3 mg, 52%). Alternative method: To a stirred
solution of 6 (30.5 mg, 0.06 mmol) in THF (0.2 mL) was added MeMgBr
(1 M in THF, 2.4 mmol, 40 equiv). After 72 h at 80 °C, the reaction was
quenched with sat. NH4Cl, extracted with Et2O, dried over MgSO4, and
concentrated under reduced pressure. The resulting residue was purified by
flash chromatography (1.2À2.5% MeOH/CH2Cl2) to afford 26 (22 mg,
72%). [R]D20 = 34.6 (c = 0.58, CHCl3); 1H NMR (400 MHz, CDCl3) δ
(ppm): 7.64À7.69 (m, 4H), 7.37À7.48 (m, 6H), 3.84À3.96 (m, 2H),
3.62À3.78 (m, 5H), 3.21 (b, 1H), 3.10 (b, 1H), 2.80 (b, 1H), 2.64 (d, 1H,
J = 5.4 Hz), 1.95À2.05 (m, 1H), 1.78À1.86 (m, 2H), 1.74 (dd, 1H,
J = 4.8, 14.0 Hz), 1.44À1.60 (m, 3H), 1.36 (dd, 1H, J = 11.8, 14.0 Hz),
1.26 (s, 3H), 1.20À1.28 (m, 2H), 1.08 (s, 9H), 0.64À0.69 (m, 1H);
13C NMR (100 MHz, CDCl3) δ (ppm): 136.0, 135.7, 133.3, 133.2, 130.3,
130.1, 128.1, 128.0, 84.7, 83.5, 80.6, 71.7, 65.1, 62.1, 52.7, 41.4, 37.8, 36.5,
35.2, 33.1, 32.9, 27.2, 25.3, 20.8, 19.4; HRMS calcd for C31H44O5Si
[M + Na]+ 547.2850, found 547.2846; IR νmax (film) 3394, 2932, 2856,
1472, 1370, 1107, 1071, 702 cmÀ1
.
Diol 31. To a stirred solution of 29 (22 mg, 0.039 mmol) in THF
(0.4 mL) was added TBAF (1 M in THF, 0.08 mmol, 2 equiv). After 3 h
at rt, the reaction was quenched with NH4Cl 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 purified
by flash chromatography (50% to 60% EtOAc/hexane) to afford 31 (10
20
1
mg, 80%). [R]D = 12.3 (c = 0.40, CHCl3); H NMR (400 MHz,
CDCl3) δ (ppm): 4.10 (dd, 1H, J = 4.5, 12.9 Hz), 3.84 (dd, 1H, J = 3.4,
12.9 Hz), 3.72À3.80 (m, 2H), 3.50À3.68 (m, 3H), 2.99 (b, 1H), 2.71
(d, 1H, J = 5.5 Hz), 2.29 (b, 1H), 1.85À2.10 (m, 5H), 1.68À1.75
(m, 3H), 1.42À1.50 (m, 1H), 1.41 (s, 3H), 1.37 (s, 3H), 1.26 (s, 3H),
1.22À1.28 (m, 1H), 1.10À1.18 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ (ppm): 98.5, 85.0, 84.3, 72.5, 71.3, 64.0, 60.2, 52.5, 42.9, 39.0, 37.2,
34.6, 34.0, 33.9, 29.2, 26.1, 20.4; HRMS calcd for C18H30O5 [M + Na]+
349.1985, found 349.1989; IR νmax (film) 3480, 2932, 2856, 1472, 1370,
1112, 1071 cmÀ1
.
’ ASSOCIATED CONTENT
S
Supporting Information. Full spectroscopic data for all
b
new compounds and X-ray crystallographic data of 31. This material
1472, 1107, 1071, 702 cmÀ1
.
is available free of charge via the Internet at http://pubs.acs.org.
6175
dx.doi.org/10.1021/jo200899v |J. Org. Chem. 2011, 76, 6169–6176

The Journal of Organic Chemistry
ARTICLE
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: dhorne@coh.org.
’ ACKNOWLEDGMENT
The authors thank Dr. Lev Zakharov of the Chemistry
Department, University of Oregon, for providing X-ray crystal-
lographic analysis. Support from the Nesvig Foundation, Markel
Foundation, and U.S. Army RDECOM Acquisition Center,
Natick Contracting Division, Natick, MA, under Contract No.
W911QY-10-C-0176 is gratefully acknowledged.
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