Syntheses of Gymnothespirolignans B and C and Non-natural Isomer 9-Epi-gymnothespirolignan B

Article abstract of DOI:10.1021/acs.joc.1c01159

Syntheses of polycyclic spiro lignans gymnothespirolignans B and C as well as the unnatural isomer 9-epi-gymnothespirolignan B were accomplished using (R)-Roche ester and an appropriately substituted fluorenone. Key features of the convergent syntheses include coupling of the fluorenone and an iodo-alkene intermediate derived from (R)-Roche ester in the presence of the Lewis acid TiCl(OiPr)3, C9-O bond formation via an SN2 reaction with retention of stereochemistry, and diastereoselective hydrogenations of a common alkene intermediate guided by accessibility or positioning by the C8-methoxy.

Full text of DOI:10.1021/acs.joc.1c01159

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Article
Syntheses of Gymnothespirolignans B and C and Non-natural
Isomer 9‑Epi-gymnothespirolignan B
Ghada Ali and Gregory D. Cuny*
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ABSTRACT: Syntheses of polycyclic spiro lignans gymnothespir-
olignans B and C as well as the unnatural isomer 9-epi-
gymnothespirolignan B were accomplished using (R)-Roche ester
and an appropriately substituted fluorenone. Key features of the
convergent syntheses include coupling of the fluorenone and an
iodo-alkene intermediate derived from (R)-Roche ester in the
presence of the Lewis acid TiCl(OiPr)3, C9-O bond formation via
an SN2 reaction with retention of stereochemistry, and diaster-
eoselective hydrogenations of a common alkene intermediate
guided by accessibility or positioning by the C8-methoxy.
in the synthesis of structurally related sacidumlignan D.4−8 In
terms of synthesizing gymnothespirolignans B (1) and C (2),
we envisioned that a different method for late-stage ether
formation would likely be needed in order to maintain
stereochemical integrity at C9. In this study, we report the
syntheses of gymnothespirolignans B (1) and C (2) and the
non-natural isomer 9-epi-gymnothespirolignan B (3) (Figure
1). As depicted in Scheme 1, we anticipated generating 1 and 2
by diastereoselective hydrogenation of intermediate 4a from
INTRODUCTION
Gymnothespirolignans B (1) and C (2), shown in Figure 1, are
members of the polycyclic spiro lignans, a rare family of lignan
■
Scheme 1. Retrosynthetic Analysis of
Gymnothespirolignans B (1) and C (2)
Figure 1. Structures of gymnothespirolignans B (1) and C (2) and
non-natural isomer 9-epi-gymnothespirolignan B (3).
natural products. They were recently isolated by Zhou et al.
from the flowering herbaceous plant Gymnotheca involucrata
Pei (Saururaceae) distributed in southwestern China.1,2
Biological evaluation revealed that gymnothespirolignan B
possesses moderate antiviral activity against respiratory
syncytial virus with an IC50 = 17.51 μM1 and gymnothespir-
olignan C has modest insecticidal activity against the banded
cucumber beetle Diabrotica balteata at 500 ppm in an artificial
diet assay.2 Structurally, gymnothespiolignans B and C are
characterized by a tetracyclic skeleton containing a highly
oxygenated fluorene motif and a spiro oxacyclopentane with
three contiguous asymmetric centers.
Our laboratory recently reported syntheses of two model
substrates of this natural product family.3 In those syntheses,
we employed a late-stage acid-mediated cyclization to
construct the C9-O bond of the spiro oxacyclopentane moiety,
which provided a route to the spiro cyclic ether without
employing butyrolactonesintermediates frequently utilized
Received: May 18, 2021
Published: July 20, 2021
https://doi.org/10.1021/acs.joc.1c01159
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© 2021 American Chemical Society
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the Si and Re faces, respectively. Compound 4a would be
assembled via cyclization of 5a with retention of stereo-
chemistry at C9. Diol 5a would be derived from coupling the
previously prepared fluorenone 63 with iodo-alkene 7. This
latter material would be obtained from commercially available
(R)-Roche ester, 8, through functional group interconversion.
13 was delivered in only 15−33% yield and the undesired
product 13a was formed in 35−60% yield. The low yield of 13
obtained in the absence of the titanium Lewis acid presumably
results from the low electrophilicity of the ketone in the highly
electron-rich fluorenone 12. Next, desilylation of 13 using
tetrabutylammonium fluoride (TBAF) furnished diol 14 in
90% yield, which upon treatment with trifluoroacetic acid
(TFA) at 0 °C delivered cyclic intermediate 15 in 88% yield.
Finally, hydrogenation of 15 in methanol using 10% Pd/C
under an atmosphere of hydrogen furnished the expected
product ( )-9 as a single diastereomer along with the
inseparable isomerized alkene 9a in a 2:1 ratio, respectively.
To mitigate formation of 9a, PtO2 (15 mol %) was used.
Pleasingly, this resulted in formation of the desired
diastereomer ( )-9 in 98% yield and 98:2 diastereoselectivity
with only trace amounts of 9a (<1%). The relative stereo-
chemistry of the two stereocenters in ( )-9 was unambigu-
ously confirmed with X-ray crystallographic analysis (Figure
2A). The formation of this diastereomer presumably results
from hydrogen addition from the least hindered Re face, as the
Si face is blocked by the methoxy at the C8 position (Figure
2B).
RESULTS AND DISCUSSION
■
To assess the feasibility of installing a 3′-methyl via
diastereoselective hydrogenation, synthesis of racemic model
substrate ( )-9 starting from commercially available 3-
bromobut-3-en-1-ol, 10, was first pursued (Scheme 2). The
Scheme 2. Synthesis of the Model Substrate ( )-9
Next, the syntheses of gymnothespirolignans B and C were
pursued starting with generation of the requisite vinyl iodide
7a, as depicted in Scheme 3. Treatment of (R)-Roche ester, 8,
with TBDPSCl and imidazole formed 16a. Methyl ester
reduction using DIBAL-H generated alcohol 17a in 99% yield.
Subsequent Parikh−Doering oxidation followed by a Corey−
Fuchs reaction produced alkyne 18a in 70% yield over three
steps. Finally, regioselective Markovnikov iodoboration of 18a
with B-I-9-BBN followed by protodeboronation with acetic
acid11 furnished vinyl iodide 7a. Notably, attempts to
synthesize the corresponding vinyl iodide or bromide bearing
a TBS protecting group using the same approach encountered
difficulties in the last step. Using B-I-9-BBN/acetic acid or
PPh3/I2/H2O12 resulted in vinyl iodide formation with loss of
the protecting group. Also, Ni-catalyzed α-hydroalumination
followed by halogenation13 (Ni(dppp)Cl2/DIBAL-H and then
NBS or NIS) gave unsatisfactory yields.
approach commenced with TBS protection of alcohol 10 to
generate 11 in 86% yield using a reported procedure.9 Next,
coupling of vinyl bromide 11 and fluorenone 123 (previously
synthesized in 85% yield over four steps) was investigated.
Although Grignard reactions3 failed, 13 was generated in
almost quantitative yield using n-BuLi in the presence of 1
equiv of the Lewis acid TiCl(OiPr)3.10 Interestingly, under a
variety of reaction conditions in the absence of TiCl(OiPr)3,
The next task, as shown in Scheme 4, was to synthesize diols
5a and 5b. Therefore, the coupling of 7a and fluorenone 63
(previously synthesized in 78% yield over three steps) was
studied. Lithiation of 7a with n-BuLi at −78 °C followed by
the addition of a mixture of fluorenone 6 and TiCl(OiPr)3
resulted in full recovery of 6 and exclusive formation of
Figure 2. (A) ORTEP diagram of ( )-9 showing thermal ellipsoids at the 50% equiprobability level. (B) Rationale for diastereoselective
hydrogenation of 15.
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Scheme 3. Syntheses of the Vinyl Iodides 7a and 7b
Scheme 4. Syntheses of Diols 5a and 5b
Scheme 5. Syntheses of 4a and 4b via Cyclization
in Figure 3, we hypothesized that hydrogenation of 4a from the
more accessible Re face, as was observed in the conversion of
15 to ( )-9, would give gymnothespirolignan C (2). However,
hydrogenation from the Si face directed by the C8-methoxy
would generate gymnothespirolignan B (1). Furthermore,
hydrogenation of 4b would occur mainly from the Si face as
the Re face is significantly blocked by both the methoxy at C8
and the pseudo-equatorial methyl at C4′.
vinylsilane 7c via retro-Brook rearrangement.14 Slow addition
of n-BuLi to a mixture of 6, 7a, and TiCl(OiPr)3 at −78 °C
inhibited formation of the rearrangement product 7c.
However, 19a was delivered in only 50% yield (dr = 57:43)
accompanied by formation of 19c (∼30% yield) that resulted
from competing addition of n-BuLi to 6. To overcome these
difficulties, vinyl iodide 7b bearing a TIPS protecting group
was synthesized via the same approach outlined for 7a
(Scheme 3). Fortunately, the coupling of 6 and vinyl iodide
7b using n-BuLi in the presence of TiCl(OiPr)3 afforded the
desired product 19b as a mixture of inseparable C9
diastereomers in a 75:25 ratio. Of note, vinyl iodides 7a and
7b need to be recently prepared (≤4 days) to achieve efficient
coupling. Subsequent TBAF-mediated removal of the TIPS
group from 19b followed by chromatographic separation
afforded 5a and 5b in 73 and 24% yields, respectively.
Cyclization of diol 5a to 4a with retention of stereo-
chemistry at C9 was investigated (Scheme 5). Acid-mediated
cyclization using TFA, as expected, resulted in racemization at
C9 due to carbocation formation via an SN1 mechanism. To
circumvent this issue, cyclization via an SN2 reaction was
adopted. Mitsunobu conditions using PBu3 and DIAD
generated 4a in 90% yield and 97:3 diastereoselectivity.
However, cyclization with triflic anhydride in the presence of
First, conditions were screened favoring hydrogenation from
the more accessible Re face of 4a to form gymnothespirolignan
C (2). Hydrogenation using the optimized condition
employed in the synthesis of ( )-9 furnished diastereomers
2 and 1 in 78:22 ratio and 97% combined yield (Table 1, entry
1). This lower diastereoselectivity compared to the model
substrate is attributed to the presence of the pseudo-axial
methyl at C4′ that partially blocks the Re face. Using a 10%
Pd/C catalyst resulted in inferior diastereoselectivity (entry 2).
On the other hand, conducting the hydrogenation with a 5%
Pt/C catalyst generated a 71% combined yield of 2 and 1 in
81:19 ratio (entry 3). Increasing the solution molarity led to
enhanced diastereoselectivity but lower yield (entries 4−6)
with the best condition highlighted in entry 4. The low yields
encountered with Pt/C were attributed to the formation of
1
four diastereomeric byproducts (as observed via H NMR)
likely resulting from hydrogenolysis of the C9-O bond and
alkene hydrogenation. Several other reduction conditions were
assessed without success. For example, diimide reduction15
gave only 30% conversion and low diastereoselectivity (1:2 =
47:53), whereas one-pot hydroboration followed by proto-
deboronation16 resulted in cleavage of the C9-O bond with no
alkene hydrogenation.
Next, as shown in Scheme 6, hydrogenation of diastereomer
4b using PtO2 occurred smoothly, as expected, from the
accessible Si face to form the non-natural 9-epi-gymnothespir-
olignan B (3) as a single diastereomer in 99% yield.
Hunig’s base at −78 °C proceeded smoothly to give 4a as a
̈
single diastereomer in 97% yield. Similarly, cyclization of 5b
under the latter condition generated 4b as a single
diastereomer in 83% yield.
To complete the syntheses of the natural products and the
unnatural isomer, the diastereoselective hydrogenations of 4a
and 4b were explored (Table 1 and Scheme 6). As illustrated
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Last, the challenging diastereoselective hydrogenation of 4a
from the sterically hindered Si face oriented by the C8-
methoxy to furnish gymnothespirolignan B (1) was explored.
Heterogeneous hydrogenation using Raney nickel, which is
known to have chelating properties,17,18 gave 99% combined
yield of 1 and 2 in 63:37 ratio, respectively (Table 1, entry 7).
Performing the reaction at 10 atm slightly improved the
diastereoselectivity (entry 8), whereas higher pressures (e.g.,
17 and 31 atm) resulted in poorer diastereoselectivity and
formation of many byproducts (entry 9). Next, homogeneous
hydrogenations were investigated. Unfortunately, under a
variety of reaction conditions using several iridium and
rhodium catalysts (e.g., [Rh(Cl)(PPh3)3], (S,S)-[cod]Ir-
[Pcy2ThrePhox]BArF4, [Ir(cod)(PCy3)(py)]PF6, or [Ir(cod)-
(PCy3)(py)]BArF4) at 1 atm, the formation of the desired
product 1 was not observed, likely due to steric hindrance of
the catalysts and 4a. Pleasingly, conducting the reaction at 10
atm using a 15 mol % Crabtree BArF4 catalyst resulted in 65%
conversion of 4a and generation of 1 in excellent
diastereoselectivity (98:2) (entry 10); however, the non-
natural epimer 3 was surprisingly formed as a minor byproduct
(vide infra). Finally, hydrogenation using higher catalyst
loading (entry 11) led to 100% conversion and delivered 1
in 70% yield and 99:1 diastereoselectivity of 1:2 and its C9-
epimer 3 in 28% yield.
Table 1. Conditions Assessed for Hydrogenating 4a to
Gymnothespirolignans B (1) and C (2)
e
To understand how 3 was formed from enantiopure
1
diastereomer 4a, the H NMR spectrum of the crude product
of Table 1, entry 10 was carefully examined. This spectrum
showed peaks corresponding to 4b, indicating that 4a was
hydrogenated to 1 and epimerized at C9 to 4b, which
subsequently underwent hydrogenation to 3. However,
another route for formation of 3 could be epimerization of
C9 in 1. To examine this possibility, 1 was subjected to the
same reaction condition in Table 1, entry 11. Surprisingly, the
epimeric product 3 was formed with 1:3 ratio of 72:28. From
these observations, we concluded that 3 may be formed
directly from 1 via epimerization of C9 and indirectly from 4a
through epimerization to 4b and subsequent hydrogenation.
a
Unless otherwise indicated, reactions were conducted with 1 atm H2
b
at room temperature. Determined via 1H NMR analysis.
c
d
Epimerization of C9 to form 3 occurred. 3 was formed in 28%
e
yield. nd = not determined.
Scheme 6. Synthesis of 3 via Diastereoselective
Hydrogenation of 4b
CONCLUSIONS
■
In summary, the first syntheses of gymnothespirolignans B (1)
and C (2) and non-natural isomer 9-epi-gymnothespirolignan
B (3) were accomplished in 10 steps and overall yields of 34,
31, and 14%, respectively, starting from (R)-Roche ester. The
synthetic routes featured three key steps: (1) efficient coupling
of iodo-alkene 7b and fluorenone 6 using n-BuLi in the
presence of TiCl(OiPr)3; (2) cyclization of diols 5a and 5b
with retention of stereochemistry at C9 using triflic anhydride
in the presence of Hunig’s base; and (3) diastereoselective
̈
hydrogenation of 4a from the more accessible Re face to
furnish 2 and from the more congested Si face directed by the
C8-methoxy to give 1. In addition, 3 was exclusively generated
via diastereoselective hydrogenation of 4b from the accessible
Si face.
EXPERIMENTAL SECTION
■
General Information and Materials. All moisture- or oxygen-
sensitive reactions were conducted under an argon atmosphere with
magnetic stirring in oven-dried glassware with rubber septa unless
otherwise stated. An oil bath was used as the heat source for reactions
that required heating. All commercially available chemicals and
reagent-grade solvents were used directly without further purification.
Reactions were monitored by thin-layer chromatography (TLC) on
Figure 3. (A, B) Rationale for diastereoselective hydrogenation of
substrates 4a and 4b.
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Baker-flex silica gel plates IB2-F. Visualization was accomplished with
UV light (254 nm) or a visualizing agent (phosphomolybdic acid
stain). Flash chromatography was performed on silica gel (40−60
μm) using a Teledyne ISCO CombiFlash Rf. Melting points were
measured using a Thomas Hoover Uni-Melt capillary melting point
apparatus and are uncorrected. Nuclear magnetic resonance (NMR)
spectra were recorded at room temperature on a 600 MHz
spectrometer. Chemical shifts (δ) for all 1H NMR spectra were
measured in parts per million (ppm) relative to the signal of
tetramethylsilane (TMS, 0.0 ppm) or CDCl3 (7.26 ppm). Signal
patterns were reported as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), and br (broad). Coupling constants (J) were
hexane, 10:90) to give fluorenol 13 (802 mg, 99% yield) as a pale
yellow solid; mp: 88−90 °C; H NMR (CDCl3, 600 MHz): 7.37 (s,
1
1H), 7.20 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 7.9
Hz, 1H), 5.76 (s, 1H), 5.16 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.92
(s, 3H), 3.86 (s, 3H), 3.40 (td, J = 9.4, 6.4 Hz, 1H), 3.31 (td, J = 9.6,
5.7 Hz, 1H), 3.06 (s, 1H), 1.95−1.90 (m, 1H), 1.72−1.66 (m, 1H),
0.77 (s, 9H), −0.14 (d, J = 2.1 Hz, 6H); 13C{1H} NMR (CDCl3, 151
MHz): 155.1, 154.9, 150.0, 149.8, 147.8, 141.1, 135.5, 131.5, 128.8,
127.6, 116.0, 111.2, 110.2, 103.7, 84.5, 63.2, 60.9, 60.7, 56.3, 55.4,
34.7, 25.9, 18.2, −5.5, −5.6; HRMS (+ESI) m/z: [M + Na]+ calcd for
C27H38O6SiNa: 509.2330, found: 509.2332.
9-(4-Hydroxybut-1-en-2-yl)-1,2,3,5-tetramethoxy-9H-fluoren-9-
ol (14). To a solution of fluorenol 13 (532 mg, 1.1 mmol, 1 equiv) in
THF (5 mL) at 0 °C was added TBAF (1 M in THF) (2.2 mL, 2.2
mmol, 2 equiv). The resulting mixture was stirred at room
temperature for 2 h before quenching by addition of saturated
aqueous NH4Cl solution (10 mL). The aqueous phase was extracted
with EtOAc (3 × 20 mL), and the combined organic extracts were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified
by flash column chromatography on silica gel (EtOAc/hexane, 40:60
to 80:20) to afford diol 14 (366 mg, 90% yield) as a white solid; mp:
175−176 °C; 1H NMR (CDCl3, 600 MHz): 7.36 (s, 1H), 7.21 (t, J =
7.8 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 5.82
(s, 1H), 5.18 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.94 (s, 3H), 3.85 (s,
3H), 3.36−3.28 (m, 2H), 2.93 (br s, 1H), 1.86 (t, J = 6.4 Hz, 2H),
1.63 (br s, 1H); 13C{1H} NMR (CDCl3, 151 MHz): 155.1, 155.1,
150.0, 149.9, 146.9, 141.2, 135.5, 131.1, 129.0, 127.4, 115.7, 111.3,
111.1, 103.7, 84.4, 61.3, 61.0, 60.9, 56.3, 55.5, 34.7; HRMS (+ESI) m/
z: [M + Na]+ calcd for C21H24O6Na: 395.1465, found: 395.1469.
1,2,3,5-Tetramethoxy-3′-methylene-4′,5′-dihydro-3′H-spiro-
[fluorene-9,2′-furan] (15). To a solution of diol 14 (366 mg, 0.98
mmol, 1 equiv) in CHCl3 (11 mL) at 0 °C was added TFA (150 μL,
1.96 mmol, 2 equiv) in one portion. The reaction mixture was stirred
for 2 min at the same temperature and then quenched by the addition
of saturated aqueous NaHCO3 solution (10 mL). The aqueous phase
was extracted with DCM (3 × 30 mL). The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The resulting
residue was subjected to flash column chromatography on silica gel
(EtOAc/hexane, 10:90) to give 15 (307 mg, 88% yield) as a white
1
given in Hz. Data for H NMR were reported as follows: (chemical
shift, multiplicity, coupling constant, and integration). All 13C NMR
spectra were recorded on a 151 MHz spectrometer and were reported
in ppm relative to solvent peaks: CDCl3 (77.0 ppm) or (CD3)2CO
(29.8 ppm). In the case of inseparable diastereomers, NMR data were
reported as major [minor] if the corresponding peaks were separated
from each other or they were written as a range for both of the major
and minor diastereomers if the peaks were overlapping. High-
resolution mass spectra (HRMS) were obtained by the University of
Texas Mass Spectrometry facility using chemical ionization (CI) or
electrospray ionization (ESI) and were analyzed using a quadrupole
time-of-flight (Q-TOF) mass spectrometer. The spectra were
reported as m/z (relative intensity) for the molecular ion [M].
Preparative high-performance liquid chromatography (HPLC) was
performed on a Waters system equipped with a 2489 UV/visible
detector and Xselect CSH prep column [19 × 100 mm (C18, 5 μm
OBD)]. Optical rotations were measured on a Reichert polar 3
polarimeter, and the specific rotation [α]2D5 values were given in units
of 10−1 deg cm2 g−1. Fluorenones 6 and 12 were previously
synthesized from commercially available methyl 3,4,5-trihydroxyben-
zoate and 2-bromo-3-hydroxybenzaldehyde, respectively.3
Synthetic Procedures. ((3-Bromobut-3-en-1-yl)oxy)(tert-butyl)-
dimethylsilane (11). To a solution of 3-bromobut-3-en-1-ol (10)
(992 μL, 10 mmol, 1 equiv) and imidazole (1.02 g, 15 mmol, 1.5
equiv) in DCM (20 mL) at 0 °C was added a solution of TBSCl (1.96
g, 13 mmol, 1.3 equiv) in DCM (10 mL). The reaction mixture was
stirred at room temperature overnight and then quenched with
saturated aqueous NaHCO3 solution (50 mL). The aqueous phase
was extracted with DCM (3 × 50 mL), and the combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was subjected to flash column chromatography on silica gel (EtOAc/
hexane, 5:95) to furnish 11 (2.28 g, 86% yield) as a colorless liquid;
1H NMR (CDCl3, 600 MHz): 5.63 (s, 1H), 5.45 (d, J = 1.0 Hz, 1H),
1
solid; mp: 99−100 °C; H NMR (CDCl3, 600 MHz): 7.36 (s, 1H),
7.18 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 8.4 Hz,
1H), 4.92 (t, J = 2.1 Hz, 1H), 4.52 (t, J = 2.4 Hz, 1H), 4.39 (q, J = 7.4
Hz, 1H), 4.32 (td, J = 7.8, 5.6 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H),
3.92 (s, 3H), 3.88 (s, 3H), 3.11−3.00 (m, 2H); 13C{1H} NMR
(CDCl3, 151 MHz): 154.8, 154.7, 152.8, 152.4, 149.8, 141.6, 135.6,
132.9, 128.8, 126.6, 115.9, 110.8, 105.8, 103.5, 91.0, 67.8, 60.9, 60.5,
56.2, 55.4, 34.4; HRMS (+ESI) m/z: [M + Na]+ calcd for
C21H22O5Na: 377.1359, found: 377.1362.
3.79 (t, J = 6.4 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 0.89 (s, 9H), 0.07 (s,
6H); 13C{1H} NMR (CDCl3, 151 MHz): 130.8, 118.4, 60.8, 44.8,
25.9, 18.3, −5.3.
Note: It is preferable to store 11 under an atmosphere of argon at
−20 °C to prevent loss of the TBS group.
( )(3′R,9R)-1,2,3,5-Tetramethoxy-3′-methyl-4′,5′-dihydro-3′H-
spiro[fluorene-9,2′-furan] (9). To a solution of 15 (256 mg, 0.722
mmol, 1 equiv) in EtOAc (30 mL) was added PtO2 (24.6 mg, 0.11
mmol, 15 mol %). An additional 1 mL of EtOAc was added to wash
the wall of the flask. The reaction mixture was stirred under an
atmosphere of H2 at room temperature for 7 h. The reaction mixture
was then filtered through celite and concentrated under reduced
pressure. The crude product was purified by flash column
chromatography on silica gel (EtOAc/hexane, 10:90) to furnish
( )-9 (253 mg, 98% yield, dr = 98:2) as a white solid; mp: 97−98 °C;
1H NMR (CDCl3, 600 MHz): 7.40 (s, 1H), 7.21 (t, J = 7.8 Hz, 1H),
7.06 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 7.8, 1H), 4.36 (t, J = 7.8, 1H),
4.24−4.20 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H), 3.90 (s,
3H), 2.83−2.76 (m, 1H), 2.50−2.43 (m, 1H), 2.25−2.21 (m, 1H),
0.69 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 151 MHz): 154.8,
154.2, 153.1, 150.6, 141.3, 135.6, 130.2, 128.4, 126.8, 115.5, 110.5,
103.8, 94.4, 69.7, 61.1, 61.0, 56.1, 55.4, 45.2, 35.6, 14.4; HRMS
(+ESI) m/z: [M + Na]+ calcd for C21H24O5Na: 379.1516, found:
379.1520.
9-(4-((tert-Butyldimethylsilyl)oxy)but-1-en-2-yl)-1,2,3,5-tetrame-
thoxy-9H-fluoren-9-ol (13). In a round-bottom flask, a solution of
bromo vinyl 11 (2.65 g, 10 mmol, 6 equiv) in THF (30 mL) under an
atmosphere of argon was cooled to −78 °C and then n-BuLi (2.5 M
in hexane) (3.33 mL, 8.325 mmol, 5 equiv) was added dropwise. The
resulting mixture was stirred at the same temperature for 1 h. In
another round-bottom flask, a solution of fluorenone 12 (500 mg,
1.665 mmol, 1 equiv) and TiCl(OiPr)3 (434 mg, 1.665 mmol, 1
equiv) in THF (15 mL) was stirred for 10 min at room temperature
and then added dropwise to the lithiated 11 solution at −78 °C. The
resulting mixture was stirred for an additional 10 min at the same
temperature and then quenched by the addition of a saturated
aqueous NH4Cl solution (50 mL). The reaction mixture was then
allowed to warm to room temperature before filtering through a pad
of celite to remove a fine white precipitate. The aqueous phase was
extracted with EtOAc (3 × 50 mL), and the combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was purified by flash column chromatography on silica gel (EtOAc/
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Methyl (R)-3-((tert-Butyldiphenylsilyl)oxy)-2-methylpropanoate
(16a). To a solution of (R)-Roche ester (8) (1.11 mL, 10 mmol, 1
equiv) and imidazole (1.021 g, 15 mmol, 1.5 equiv) in DCM (20 mL)
at 0 °C was added TBDPSCl (3.38 mL, 13 mmol, 1.3 equiv)
dropwise. The reaction mixture was stirred for 2 h at room
temperature and then quenched with saturated aqueous NaHCO3
solution (50 mL). The aqueous phase was extracted with DCM (3 ×
50 mL), and the combined organic extracts were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude product was purified with flash column
chromatography on silica gel (EtOAc/hexane, 4:96) to furnish 16a
(3.53 g, 99% yield) as a colorless viscous liquid; [α]2D5 −16.3 (c 1.1,
CHCl3), [lit.19 value: [α]D25 −18.2 (c 0.88, CHCl3)]; 1H NMR
(CDCl3, 600 MHz): 7.65 (d, J = 7.2 Hz, 4H), 7.44−7.37 (m, 6H),
3.83 (t, J = 8.3 Hz, 1H), 3.72 (dd, J = 9.5, 6.0 Hz, 1H), 3.68 (s, 3H),
2.72 (sextet, J = 6.6 Hz, 1H), 1.16 (d, J = 7.2 Hz, 3H), 1.03 (s, 9H);
13C{1H} NMR (CDCl3, 151 MHz): 175.4, 135.5, 133.5 (d, JC,Si = 8.8
Pyridine (3 equiv). The reaction mixture was allowed to warm to
room temperature and then stirred for 2 h. The resulting mixture was
cooled to 0 °C before quenching with a saturated aqueous solution of
NH4Cl. The organic layer was separated, and the aqueous phase was
extracted with DCM. The combined organic extracts were washed
with brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to form the corresponding aldehydes. The
crude product was used in the next step without purification.
To a solution of the above crude product and PPh3 (4 equiv) in
DCM at 0 °C was added CBr4 (2 equiv) in portions. The resulting
solution was stirred at room temperature for 1 h and then
concentrated in vacuo to about one-fourth of its volume. Hexane
was then added, the resulting suspension was filtered through celite,
and the filter cake was washed with more hexane. The filtrate was
subjected to the above cycle one more time (concentration, hexane
precipitation, and filtration). The resulting filtrate was concentrated to
dryness to give the crude dibromoalkene product, which was used
directly in the next step without purification.
Hz), 129.6, 127.6, 65.9, 51.5, 42.4, 26.7, 19.2, 13.4.
Methyl (R)-2-methyl-3-((triisopropylsilyl)oxy)propanoate (16b).
To a solution of (R)-Roche ester (8) (2.76 mL, 25 mmol, 1 equiv) in
DCM (97 mL) at 0 °C were added 2,6-lutidine (7.26 mL, 62.5 mmol,
2.5 equiv) and then TIPSOTf (7.42 mL, 27.5 mmol, 1.1 equiv)
dropwise. The reaction mixture was stirred at room temperature for 2
h and then quenched with water (400 mL). The aqueous phase was
extracted with DCM (3 × 150 mL), and the combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was subjected to flash column chromatography on silica gel (EtOAc/
hexane, 1:99) to give 16b (6.81 g, 99% yield) as a colorless oil; [α]D25
To a solution of the dibromoalkene product in THF at −78 °C
under an atmosphere of argon was added n-BuLi (2.2 equiv)
dropwise. The resulting solution was stirred at −78 °C for 1 h and
then allowed to warm to 0 °C. The reaction was quenched by the
addition of a saturated aqueous solution of NH4Cl. The organic layer
was separated, and the aqueous phase was extracted with diethyl
ether. The combined organic extracts were washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The resulting residue was purified with flash column
chromatography on silica gel (hexane) to form 18a or 18b.
(S)-tert-Butyl((2-methylbut-3-yn-1-yl)oxy)diphenylsilane (18a).
Prepared according to general procedure 2 using 17a (2.98 g, 9.08
mmol) to give 18a (2.06 g, 70% yield) as a colorless liquid; [α]2D5 −5.5
−18.7 (c 1.0, CHCl3), [lit.20 value [α]D25 −19.6 (c 1.0, CHCl3)]; H
1
NMR (CDCl3, 600 MHz): 3.86 (dd, J = 9.3, 6.9 Hz, 1H), 3.77 (dd, J
= 9.3, 5.9 Hz, 1H), 3.68 (s, 3H), 2.67 (sextet, J = 6.6 Hz, 1H), 1.16
(d, J = 6.9 Hz, 3H), 1.11−0.97 (m, 21H); 13C{1H} NMR (CDCl3,
151 MHz): 175.5, 65.6, 51.5, 42.7, 17.9, 13.4, 11.9.
(c 1.0, CHCl3), [lit.19 value: [α]D25 −4.2 (c 0.94, CHCl3)]; H NMR
1
(CDCl3, 600 MHz): 7.68 (d, J = 7.6 Hz, 4H), 7.44−7.37 (m, 6H),
3.73 (dd, J = 9.6, 5.9 Hz, 1H), 3.54 (t, J = 8.4 Hz, 1H), 2.67−2.64 (m,
1H), 2.02 (d, J = 1.8 Hz, 1H), 1.23 (d, J = 6.6 Hz, 3H), 1.06 (s, 9H) ;
13C{1H} NMR (CDCl3, 151 MHz): 135.6, 133.5, 129.6, 127.6, 86.5,
General Procedure 1 for the Synthesis of 17a and 17b. To a
solution of 16a or 16b (1 equiv) in DCM at −78 °C under an
atmosphere of argon was added DIBAL-H (1 M/hexane) (2 equiv)
dropwise. The reaction mixture was stirred at that temperature for 1 h
and then allowed to warm to 0 °C before quenching by the addition
of saturated aqueous solution of potassium sodium tartrate
(Rochelle’s salt). The reaction mixture was then stirred at room
temperature until two layers separated (2 to 4 h). The organic layer
was separated, and the aqueous phase was extracted with DCM. The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was subjected to flash column
chromatography on silica gel (EtOAc/hexane, 3:97) to form 17a or
17b.
(S)-3-((tert-Butyldiphenylsilyl)oxy)-2-methylpropan-1-ol (17a).
Prepared according to general procedure 1 using 16a (3.27 g, 9.16
mmol) and DIBAL-H (18.32 mL, 18.32 mmol) in 25 mL DCM to
give 17a (2.98 g, 99% yield) as a colorless liquid; [α]2D5 −6 (c 1.0,
CHCl3), [lit.19 value: [α]D25 −7.6 (c 0.66, CHCl3)]; 1H NMR (CDCl3,
600 MHz): 7.68 (d, J = 6.9 Hz, 4H), 7.45−7.37 (m, 6H), 3.72 (dd, J
= 9.9, 4.5 Hz, 1H), 3.69−3.64 (m, 2H), 3.60 (dd, J = 9.8, 7.7 Hz, 1H),
2.73 (br s, 1H), 2.01−1.96 (m, 1H), 1.06 (s, 9H), 0.83 (d, J = 7.2 Hz,
3H); 13C{1H} NMR (CDCl3, 151 MHz): 135.5 (d, JC,Si = 2.8 Hz),
133.1, 129.7, 127.7, 68.5, 67.4, 37.3, 26.8, 19.1, 13.1.
69.0, 67.4, 28.8, 26.8, 19.3, 17.3.
(S)-Triisopropyl((2-methylbut-3-yn-1-yl)oxy)silane (18b). Pre-
pared according to general procedure 2 using 17b (6.11 g, 24.8
mmol) to give 18b (4.35 g, 73% yield) as a colorless liquid; [α]D25
−2.4 (c 3.7, CHCl3); 1H NMR (CDCl3, 600 MHz): 3.80 (dd, J = 9.3,
5.5 Hz, 1H), 3.55 (t, J = 8.6 Hz, 1H), 2.64−2.58 (m, 1H), 2.04 (d, J =
2.4 Hz, 1H), 1.22 (d, J = 6.9 Hz, 3H), 1.17−1.02 (m, 21H); 13C{1H}
NMR (CDCl3, 151 MHz): 86.7, 68.9, 67.3, 29.1, 18.0, 17.3, 11.9;
HRMS (+ESI) m/z: [M + Na]+ calcd for C14H28OSiNa: 263.1802,
found: 263.1804.
General Procedure 3 for the Synthesis of 7a and 7b. To a
solution of 18a or 18b (1 mmol, 1 equiv) in pentane at −78 °C was
added B-I-9-BBN (1 M/hexane) (1.1 equiv) dropwise. The reaction
mixture was then placed into a −10 °C bath (acetone/ice) and
allowed to stir at this temperature for 1 h. Glacial acetic acid (14
equiv) was added at −10 °C, and the resulting mixture was stirred for
an additional 30 min at the same temperature. The reaction mixture
was then diluted by the addition of hexane and neutralized with a
saturated aqueous solution of NaHCO3. The organic layer was
separated, and the aqueous phase was extracted with hexane. The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified with flash column
chromatography on silica gel (hexane) to form 7a or 7b.
(S)-2-Methyl-3-((triisopropylsilyl)oxy)propan-1-ol (17b). Prepared
according to general procedure 1 using 16b (6.81 g, 24.8 mmol) and
DIBAL-H (49.6 mL, 49.6 mmol) in 56 mL DCM to give 17b (6.11 g,
99.9% yield) as a colorless oil; [α]2D5 −6.9 (c 1.4, CHCl3), [lit.20 value:
[α]2D5 −6.8 (c 0.25, CHCl3)]; 1H NMR (CDCl3, 600 MHz): 3.84 (dd,
J = 9.6, 4.1 Hz, 1H), 3.69−3.62 (m, 3H), 3.09 (br dd, J = 3.6, 7.2 Hz,
1H), 2.02−1.97 (m, 1H), 1.18−1.07 (m, 21H), 0.84 (d, J = 7.2 Hz,
3H); 13C{1H} NMR (CDCl3, 151 MHz): 69.5, 68.6, 37.1, 17.9, 13.0,
11.7.
(R)-tert-Butyl((3-iodo-2-methylbut-3-en-1-yl)oxy)diphenylsilane
(7a). Prepared according to general procedure 3 using 18a (968 mg, 3
mmol), B-I-9-BBN (1 M/hexane) (3.3 mL, 3.3 mmol, 1.1 equiv), and
glacial acetic acid (2.52 mL, 42 mmol, 14 equiv) to give 7a (1.34 g,
99% yield) as a colorless oil; [α]2D5 −3.1 (c 4.0, CHCl3); H NMR
1
(CDCl3, 600 MHz): 7.69−7.66 (m, 4H), 7.43−7.37 (m, 6H), 6.18 (s,
1H), 5.82 (d, J = 1.0 Hz, 1H), 3.57 (dd, J = 10.0, 7.2 Hz, 1H), 3.47
(dd, J = 10.0, 5.9 Hz, 1H), 2.17 (sextet, J = 6.6 Hz, 1H), 1.05 (s, 9H),
0.99 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (CDCl3, 151 MHz): 135.7
(d, JC,Si = 15.8 Hz), 133.6 (d, JC,Si = 23.1 Hz), 129.6, 127.6, 125.8,
General Procedure 2 for the Synthesis of 18a and 18b. To a
solution of 17a or 17b (1 equiv) in DCM at 0 °C were added
sequentially DMSO (10 equiv), triethylamine (6 equiv), and SO3
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118.2, 67.2, 48.8, 26.8, 19.3, 17.4; HRMS (+ESI) m/z: [M + Na]+
calcd for C21H27IOSiNa: 473.0768, found: 473.0769.
chromatography on silica gel (EtOAc/hexane, 10:90) to give
fluorenol 19b (872 mg, 99% yield, dr = 75:25) as a colorless very
viscous liquid; 1H NMR (CDCl3, 600 MHz) (Note: data were
reported as major [minor] if the corresponding peaks were separated
from each other or they were written as a range for both of the major
and minor diastereomers if the peaks were overlapping): 7.22 (s, 1H),
[7.21 (s, 1H)], 6.56 (s, 1H), [6.52 (s, 1H)], 5.95 (d, J = 11.7 Hz,
2H), [5.92 (d, J = 25.1 Hz, 2H)], [5.80 (s, 1H)], 5.73 (s, 1H), 5.15
(s, 1H), [5.13 (s, 1H)], 4.12 (s, 3H), [4.11 (s, 3H)], [3.97 (s, 3H)],
3.95 (s, 3H), [3.93 (s, 3H)], 3.92 (s, 3H), 3.82 (s, 3Hmajor and minor),
3.33−3.26 (m, 2H), [3.18−3.13 (m, 2H)], 3.08 (br s, 1H), [2.98 (s,
1H)], 1.65−1.95 (br m, 1H), [1.53−1.47 (br m, 1H)], 1.03−0.78 (m,
24Hmajor and minor); 13C{1H} NMR (CDCl3, 151 MHz) for major
[minor] diastereomers (Note: some carbons of the minor
diastereomer were not resolved): 155.0, [154.9], 153.4, [149.7],
149.6, 149.2, 143.4, [142.9], 140.1, [139.0], 138.9, 136.6, 135.8,
130.8, [130.8], 125.0, 109.1, [108.6], 102.3, [102.2], 101.3, 99.5,
[99.4], 84.3, [84.2], 69.1, [69.0], [60.8], 60.8, 60.7, 59.5, [59.5], 56.1,
37.0, [37.0], 19.0, [18.8], [17.9], [17.9], 17.8, 11.8; HRMS (+ESI)
m/z: [M + Na]+ calcd for C32H46O8SiNa: 609.2854, found: 609.2853.
Procedure for Synthesis of 5a and 5b. To a solution of
fluorenol 19b (dr = 75:25) (587 mg, 1 mmol, 1 equiv) in THF (15
mL) at 0 °C was added TBAF (1 M/THF) (2 mL, 2 mmol, 2 equiv).
The resulting mixture was stirred at room temperature for 2 h before
quenching by the addition of saturated aqueous NH4Cl solution (15
mL). The aqueous phase was extracted with EtOAc (3×30 mL), and
the combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash column
chromatography on silica gel (EtOAc/hexane, 30:70 to 40:60) to
afford a mixture of diols 5a and 5b (430 mg, quant. yield) as a white
solid. The two enantiopure diastereomers 5a and 5b were then
separated by preparative TLC (EtOAc/Hexane 40:60 with 1%
triethylamine to prevent cyclization).
(S)-9-((S)-4-Hydroxy-3-methylbut-1-en-2-yl)-4,6,7,8-tetrame-
thoxy-9H-fluoreno[2,3-d][1,3]dioxol-9-ol (5a). (314 mg, 73% yield);
White solid; mp: 126−128 °C; [α]2D5 −21 (c 0.95, CHCl3); 1H NMR
(CDCl3, 600 MHz): 7.26 (s, 1H), 6.56 (s, 1H), 5.98 (s, 1H), 5.96 (s,
1H), 5.94 (s, 1H), 5.26 (s, 1H), 4.14 (s, 3H), 3.98 (s, 3H), 3.93 (s,
3H), 3.81 (s, 3H), 3.38 (t, J = 9.1 Hz, 1H), 3.21−3.16 (br m, 1H),
2.58 (s, 1H), 2.03 (br s, 1H), 1.57 (hextet, J = 6.6 Hz, 1H), 0.75 (d, J
= 6.9 Hz, 3H); 13C{1H} NMR (CDCl3, 151 MHz): 155.0, 152.2,
149.8, 149.3, 143.1, 140.4, 139.0, 136.7, 135.9, 130.6, 124.7, 109.2,
102.5, 101.3, 99.5, 84.3, 67.7, 61.3, 61.0, 59.6, 56.1, 36.7, 19.6; HRMS
(+ESI) m/z: [M + Na]+ calcd for C23H26O8Na: 453.1520, found:
453.1523.
(R)-9-((S)-4-Hydroxy-3-methylbut-1-en-2-yl)-4,6,7,8-tetrame-
thoxy-9H-fluoreno[2,3-d][1,3]dioxol-9-ol (5b). (103 mg, 24% yield);
White solid; mp: 145−147 °C; [α]2D5 +31.8 (c 1.1, CHCl3); 1H NMR
(CDCl3, 600 MHz): 7.24 (s, 1H), 6.57 (s, 1H), 5.96 (s, 2H), 5.66 (s,
1H), 5.10 (s, 1H), 4.14 (s, 3H), 3.98 (s, 3H), 3.94 (s, 3H), 3.84 (s,
3H), 3.26 (t, J = 6.0 Hz, 2H), 3.20 (s, 1H), 2.05 (sextet, J = 6.6 Hz,
1H), 0.92 (d, J = 6.9 Hz, 3H); 13C{1H} NMR (CDCl3, 151 MHz):
155.0, 153.6, 149.5, 149.4, 143.4, 140.2, 139.2, 136.6, 135.8, 131.2,
124.3, 108.9, 102.3, 101.3, 98.8, 84.1, 68.1, 60.9, 60.8, 59.6, 56.2, 36.5,
18.5; HRMS (+ESI) m/z: [M + Na]+ calcd for C23H26O8Na:
453.1520, found: 453.1520.
(R)-((3-Iodo-2-methylbut-3-en-1-yl)oxy)triisopropylsilane (7b).
Prepared according to general procedure 3 using 18b (1516 mg,
6.33 mmol), B-I-9-BBN (1 M/hexane) (6.93 mL, 6.93 mmol, 1.1
equiv), and glacial acetic acid (5.1 mL, 88.2 mmol, 14 equiv) to give
7b (2.32 g, 99% yield) as a colorless oil; [α]2D5 −1.0 (c 4.2, CHCl3);
1H NMR (CDCl3, 600 MHz): 6.17 (s, 1H), 5.79 (s, 1H), 3.64 (dd, J
= 9.8, 6.7 Hz, 1H), 3.49 (dd, J = 9.6, 6.2 Hz, 1H), 2.15 (sextet, J = 6.6
Hz, 1H), 1.17−1.05 (m, 21H), 1.03 (d, J = 6.6 Hz, 3H); 13C{1H}
NMR (CDCl3, 151 MHz): 125.5, 118.2, 67.1, 49.1, 18.0, 17.4, 12.0;
HRMS (+CI) m/z: [M − H]+ calcd for C14H28IOSi: 367.0954, found:
367.0954.
9-((S)-4-((tert-Butyldiphenylsilyl)oxy)-3-methylbut-1-en-2-yl)-
4,6,7,8-tetramethoxy-9H-fluoreno[2,3-d][1,3]dioxol-9-ol (19a). To
a solution of fluorenone 6 (34.5 mg, 0.1 mmol, 1 equiv), TiCl(OiPr)3
(52.10 mg, 0.2 mmol, 2 equiv), and iodo-alkene 7a (360.35 mg, 0.8
mmol, 8 equiv) in THF (3 mL) at −78 °C under an atmosphere of
argon was added n-BuLi (2.5 M in hexane) (280 μL, 0.7 mmol, 7
equiv) dropwise over 5 min. The resulting mixture was stirred at the
same temperature for 15 min and then quenched by the addition of
saturated aqueous NH4Cl solution (5 mL). The reaction mixture was
then allowed to warm to room temperature and then filtered through
a pad of celite to remove a fine white precipitate. The aqueous phase
was extracted with EtOAc (3 × 5 mL), and the combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The crude product
was purified by flash column chromatography on silica gel (EtOAc/
hexane, 10:90) to give fluorenol 19a (33 mg, 50% yield, dr = 57:43)
1
as a pale yellow very viscous liquid; H NMR (CDCl3, 600 MHz)
(Note: data were reported as major [minor] if the corresponding
peaks were separated from each other or they were written as a range
for both of the major and minor diastereomers if the peaks were
overlapping): 7.55 (d, J = 6.5 Hz, 4H), 7.48−7.28 (m, 6Hmajor and
10Hminor), 7.25 (s, 1H), [7.21 (s, 1H)], [6.57 (s, 1H)], 6.46 (s, 1H),
[5.98 (s, 1H)], [5.96 (s, 1H)], 5.90 (s, 1H), 5.81 (s, 1H), [5.71 (d, J
= 15.5 Hz, 2H)], 5.13 (d, J = 3.8 Hz, 2H), [4.16 (s, 3H)], 4.11 (s,
3H), 3.95 (s, 3H), 3.94 (s, 3H), [3.91 (s, 3H)], 3.83 (s, 3H), [3.68 (s,
3H)], [3.60 (s, 2H)], 3.35−3.33 (m, 1H), [3.31−3.25 (m, 2H)], 3.19
(t, J = 9.0 Hz, 1H), 2.91 (s, 1H, OH), [2.90 (s, 1H, OH)], 1.79−1.72
(m, 1Hmajor and 1Hminor), 0.99 (d, J = 6.6 Hz, 3H), 0.95 (s, 9H), [0.94
(s, 9H)]; 13C{1H} NMR (CDCl3, 151 MHz) (Note: because of
similar intensities, all peaks were written without assignment for major
or minor diastereomer): 154.9, 154.9, 153.4, 153.2, 149.8, 149.6,
149.2, 143.2, 142.9, 140.2, 140.1, 139.0, 136.7, 135.9, 135.8, 135.5,
135.3, 135.3, 133.9, 133.8, 133.7, 130.9, 130.6, 129.4, 129.4, 129.3,
127.5, 127.5, 127.5, 125.0, 124.9, 109.2, 109.0, 102.3, 102.2, 101.3,
101.2, 99.6, 99.5, 84.4, 84.3, 69.3, 69.2, 60.9, 60.8, 60.7, 60.5, 59.6,
59.6, 56.2, 56.1, 36.7, 36.5, 29.7, 26.8, 26.7, 19.5, 19.2, 19.2; HRMS
(+ESI) m/z: [M + Na]+ calcd for C39H44O8SiNa: 691.2698, found:
691.2694.
4,6,7,8-Tetramethoxy-9-((S)-3-methyl-4-((triisopropylsilyl)oxy)-
but-1-en-2-yl)-9H-fluoreno[2,3-d][1,3]dioxol-9-ol (19b). In a round-
bottom flask, a solution of iodo-alkene 7b (4.42 g, 12 mmol, 8 equiv)
in THF (30 mL) under an atmosphere of argon was cooled to −78
°C and then n-BuLi (2.5 M in hexane) (4.20 mL, 10.5 mmol, 7 equiv)
was added dropwise. The resulting mixture was stirred at the same
temperature for 15 min. In another round-bottom flask, a solution of
fluorenone 6 (516.48 mg, 1.5 mmol, 1 equiv) and TiCl(OiPr)3
(781.74 mg, 3 mmol, 2 equiv) in THF (15 mL) was stirred for 10 min
at room temperature and then was added dropwise to the lithiated 7b
solution at −78 °C. The resulting mixture was stirred for an additional
10 min at the same temperature and then quenched by the addition of
saturated aqueous NH4Cl solution (50 mL). The reaction mixture
was then allowed to warm to room temperature and then filtered
through a pad of celite to remove a fine white precipitate. The
aqueous phase was extracted with EtOAc (3 × 50 mL), and the
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash column
General Procedure 4 for the Synthesis of 4a and 4b. To a
solution of diol 5a or 5b (1 equiv) in DCM at −78 °C under an
atmosphere of argon were added sequentially N,N-diisopropylethyl-
amine (DIPEA) (5 equiv) and triflic anhydride (1.5 equiv). The
resulting mixture was stirred at the same temperature for 15 min and
then quenched by the addition of saturated aqueous NaHCO3
solution. The organic phase was separated, and the aqueous phase
was extracted with DCM. The combined organic extracts were
washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The resulting residue was
subjected to flash column chromatography on silica gel (EtOAc/
hexane, 10:90) to furnish cyclic ethers 4a or 4b.
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Article
(4′S,9S)-4,6,7,8-Tetramethoxy-4′-methyl-3′-methylene-4′,5′-di-
hydro-3′H-spiro[fluoreno[2,3-d][1,3]dioxole-9,2′-furan] (4a). Pre-
pared according to general procedure 4 using 5a (91 mg, 0.21
mmol), DIPEA (182 μL, 1.05 mmol), and triflic anhydride (52 μL,
.32 mmol) in 6 mL of DCM to give 4a as a single diastereomer (84
mg, 97% yield) as a white solid; mp: 143−144 °C; [α]2D5 +7.6 (c 1.8,
61.4, 60.9, 59.5, 56.1, 46.4, 37.4, 12.7, 11.4; HRMS (+ESI) m/z: [M +
H]+ calcd for C23H27O7: 415.1751, found: 415.1758.
(3′R,4′S,9S)-4,6,7,8-Tetramethoxy-3′,4′-dimethyl-4′,5′-dihydro-
3′H-spiro[fluoreno[2,3-d][1,3]dioxole-9,2′-furan] (1). Method 1
(Table 1, Entry 10). To a solution of 4a (20.5 mg, 0.05 mmol, 1
equiv) in MeOH (26 mL) in a high-pressure steel autoclave was
added a suspension of Raney nickel in MeOH (1 mL). The autoclave
was then purged with hydrogen three times and finally pressurized to
10 atm with hydrogen, and the resulting suspension was stirred at
room temperature for 18 h. The pressure was released slowly, and the
reaction mixture was filtered through celite and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography on silica gel (EtOAc/hexane, 10:90) to produce 1
(20 mg, 99% yield, dr [1:2] = 73:27) as a white solid. The subsequent
separation of these two diastereomers by preparative HPLC
(acetonitrile/H2O with 0.1% formic acid (65:35), flow rate of 20
mL/min) gave gymnothespirolignan B (1) (10.5 mg, tR = 12.6 min)
and gymnothespirolignan C (2) (3.5 mg, tR = 13.7 min).
1
CHCl3); H NMR (CDCl3, 600 MHz): 7.24 (s, 1H), 6.45 (s, 1H),
5.94 (d, J = 6.6 Hz, 2H), 4.88 (s, 1H), 4.60 (d, J = 2.4 Hz, 1H), 4.49
(t, J = 8.1 Hz, 1H), 4.11 (s, 3H), 3.92 (s, 3H), 3.89 (s, 3H), 3.85 (s,
3H), 3.76 (t, J = 9.0 Hz, 1H), 3.40−3.35 (m, 1H), 1.28 (d, J = 6.6 Hz,
3H); 13C{1H} NMR (CDCl3, 151 MHz): 157.7, 154.7, 149.9, 149.1,
146.1, 141.0, 138.7, 136.5, 135.2, 133.3, 124.3, 105.5, 102.5, 101.2,
99.9, 91.8, 74.9, 60.9, 60.6, 59.5, 56.1, 38.7, 15.7; HRMS (+ESI) m/z:
[M + Na]+ calcd for C23H24O7Na: 435.1414, found: 435.1415.
(4′S,9R)-4,6,7,8-Tetramethoxy-4′-methyl-3′-methylene-4′,5′-di-
hydro-3′H-spiro[fluoreno[2,3-d][1,3]dioxole-9,2′-furan] (4b). Pre-
pared according to general procedure 4 using 5b (27.5 mg, 0.064
mmol), DIPEA (55 μL, 0.32 mmol), and triflic anhydride (27 μL,
0.096 mmol) in 2 mL of DCM to give 4b as a single diastereomer (22
mg, 83% yield) as a white solid; mp: 118−120 °C; [α]2D5 +56.6 (c
Method 2 (Table 1, Entry 13). To a solution of 4a (10.1 mg, 0.025
mmol, 1 equiv) in DCM (3 mL) in a high-pressure steel autoclave was
added a Crabtree BArF4 catalyst (11.4 mg, 0.0075 mmol, 30 mol %).
The autoclave was then purged with hydrogen three times and finally
pressurized to 10 atm with hydrogen, and the resulting suspension
was stirred at room temperature for 48 h. The pressure was released
slowly, and the reaction mixture was concentrated under reduced
pressure and purified by flash column chromatography on silica gel
(EtOAc/hexane, 10:90) to produce a mixture of 1 (dr [1:2] = 99:1)
and 3 (10 mg, 99% combined yield) as a white solid. The subsequent
separation of these two diastereomers (1 and 3) by preparative HPLC
(acetonitrile/H2O with 0.1% formic acid (65:35), flow rate of 20 mL/
min) gave gymnothespirolignan B (1) (5 mg, tR = 12.6 min) and its
C9 epimer diastereomer (3) (1.8 mg, tR = 14.8 min).
1
0.77, CHCl3); H NMR (CDCl3, 600 MHz): 7.24 (s, 1H), 6.51 (s,
1H), 5.92 (d, J = 1.8 Hz, 2H), 4.74 (d, J = 2.4 Hz, 1H), 4.56 (d, J =
2.4 Hz, 1H), 4.39 (t, J = 7.9 Hz, 1H), 4.11 (s, 3H), 3.93 (s, 3H), 3.90
(dd, J = 10.5, 7.7 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.21−3.14 (m,
1H), 1.27 (d, J = 6.5 Hz, 3H); 13C{1H} NMR (CDCl3, 151 MHz):
157.0, 154.8, 149.4, 149.2, 145.9, 141.0, 138.9, 136.5, 135.9, 133.2,
123.0, 103.6, 102.2, 101.2, 99.0, 91.8, 74.3, 60.9, 60.1, 59.6, 56.2, 39.4,
13.8; HRMS (+ESI) m/z: [M + Na]+ calcd for C23H24O7Na:
435.1414, found: 435.1417.
(3′S,4′S,9S)-4,6,7,8-Tetramethoxy-3′,4′-dimethyl-4′,5′-dihydro-
3′H-spiro[fluoreno[2,3-d][1,3]dioxole-9,2′-furan] (2) (Table 1, Entry
4). To a 0.025 M solution of 4a (41 mg, 0.1 mmol, 1 equiv) in EtOAc
(4 mL) was added 5% Pt/C (12 mg, 30 wt %). The reaction mixture
was stirred under an atmosphere of H2 at room temperature for 3 h.
The reaction mixture was then filtered through celite and
concentrated under reduced pressure. The crude product was purified
by flash column chromatography on silica gel (EtOAc/hexane, 10:90)
to produce 2 (29.5 mg, 71% yield, dr [2:1] = 89:11) as a white solid.
The subsequent separation of these two diastereomers by preparative
HPLC (acetonitrile/H2O with 0.1% formic acid (65:35), flow rate of
20 mL/min) gave gymnothespirolignan B (1) (2 mg, tR = 12.6 min)
and gymnothespirolignan C (2) (18 mg, tR = 13.7 min) as a white
solid; mp: 140−141 °C; [α]2D5 −8 (c 0.1, MeOH), [α]2D5 −7 (c 0.1,
MeOH), [lit.2 value: [α]2D5 −3 (c 0.1, MeOH)] (Note: The isolated
natural product 2 showed only 90% purity, which may account for the
White solid; mp: 129−130 °C; [α]2D5 −32 (c 0.16, MeOH), [α]2D5
−35 (c 0.8, MeOH), [α]D25 −38 (c 0.1, MeOH), [lit.1 value: [α]2D5 −69
1
(c 0.16, MeOH)]; H NMR ((CD3)2CO, 600 MHz): 7.31 (s, 1H),
6.69 (s, 1H), 6.02 (d, J = 13.8 Hz, 2H), 4.40 (t, J = 7.5 Hz, 1H), 4.12
(s, 3H), 3.91 (s, 3H), 3.88 (s, 3H), 3.86 (dd, J = 8.4, 4.2 Hz, 1H),
3.80 (s, 3H), 3.14−3.09 (m, 1H), 2.76−2.69 (m, 1H), 1.17 (d, J = 7.2
Hz, 3H), 0.60 (d, J = 7.6 Hz, 3H); 13C{1H} NMR ((CD3)2CO, 151
MHz): 155.4, 150.7, 149.6, 143.9, 142.2, 139.9, 137.0, 135.5, 135.4,
125.1, 103.4, 102.3, 102.1, 95.7, 75.9, 61.5, 60.9, 59.9, 56.4, 44.0, 38.3,
14.5, 12.8; HRMS (+ESI) m/z: [M + H]+ calcd for C23H27O7:
415.1751, found: 415.1760.
ASSOCIATED CONTENT
■
1
lower reported value); H NMR ((CD3)2CO, 600 MHz): 7.32 (s,
sı
* Supporting Information
1H), 6.73 (s, 1H), 6.01 (d, J = 1.2 Hz, 2H), 4.32 (t, J = 7.6 Hz, 1H),
4.12 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 3.80 (s, 3H), 3.76 (dd, J =
10.3, 8.3 Hz, 1H), 2.75−2.69 (m, 1H), 2.21−2.16 (m, 1H), 1.10 (d, J
= 6.6 Hz, 3H), 0.61 (d, J = 6.6 Hz, 3H); 13C{1H} NMR ((CD3)2CO,
151 MHz): 155.3, 151.6, 150.2, 147.7, 142.0, 139.5, 137.2, 136.2,
131.6, 124.3, 103.7, 102.2, 99.7, 95.8, 76.8, 61.3, 60.9, 59.9, 56.3, 53.2,
41.9, 15.1, 12.7; HRMS (+ESI) m/z: [M + H]+ calcd for C23H27O7:
415.1751, found: 415.1756.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01159.
1H and 13C{1H} NMR comparison of natural and
synthetic gymnothespirolignans B and C, X-ray crystal
data for ( )-9, and copies of the 1H and 13C{1H} NMR
spectra (PDF)
(3′R,4′S,9R)-4,6,7,8-Tetramethoxy-3′,4′-dimethyl-4′,5′-dihydro-
3′H-spiro[fluoreno[2,3-d][1,3]dioxole-9,2′-furan] (3). To a solution
of 4b (18 mg, 0.043 mmol, 1 equiv) in EtOAc (1 mL) was added
PtO2 (1.5 mg, 0.0065 mmol, 15 mol %). An additional 0.5 mL of
EtOAc was added to wash the wall of the flask. The reaction mixture
was stirred under an atmosphere of H2 at room temperature for 18 h.
The reaction mixture was then filtered through celite and
concentrated under reduced pressure. The crude product was purified
by flash column chromatography on silica gel (EtOAc/hexane, 10:90)
to form 3 (17.8 mg, 99% yield, dr = 100) as a white solid; mp: 54−56
Accession Codes
CCDC 2060670 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
1
°C; [α]2D5 +6 (c 0.1, CHCl3); H NMR (CDCl3, 600 MHz): 7.29 (s,
AUTHOR INFORMATION
■
1H), 6.68 (s, 1H), 5.93 (d, J = 2.4 Hz, 2H), 4.25 (t, J = 7.6 Hz, 1H),
4.10 (s, 3H), 3.92 (s, 3H), 3.90−3.80 (m, 7H), 2.88−2.80 (m, 1H),
2.50−2.45 (m, 1H), 1.07 (d, J = 6.9 Hz, 3H), 0.83 (d, J = 7.6 Hz,
3H); 13C{1H} NMR (CDCl3, 151 MHz): 154.1, 150.7, 149.2, 148.4,
140.8, 138.8, 136.0, 135.4, 131.7, 122.5, 102.7, 101.1, 98.1, 95.9, 74.3,
Corresponding Author
Gregory D. Cuny − Department of Pharmacological and
Pharmaceutical Sciences, College of Pharmacy, University of
Houston, Houston, Texas 77204, United States;
10524
https://doi.org/10.1021/acs.joc.1c01159
J. Org. Chem. 2021, 86, 10517−10525

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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orcid.org/0000-0002-3188-4748; Email: gdcuny@
central.uh.edu
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Author
Ghada Ali − Department of Chemistry, College of Natural
Sciences and Mathematics, University of Houston, Houston,
Texas 77204, United States
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for the reduction of β-alkylcatecholboranes to alkanes. J. Am. Chem.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01159
(18) Zhou, Q.; Chen, X.; Ma, D. Asymmetric, protecting-group-free
total synthesis of (−)-englerin A. Angew. Chem., Int. Ed. 2010, 49,
3513−3516.
Notes
The authors declare no competing financial interest.
(19) García-Ruiz, C.; Chen, J. L. Y.; Sandford, C.; Feeney, K.;
Lorenzo, P.; Berionni, G.; Mayr, H.; Aggarwal, V. K. Stereospecific
allylic functionalization: The reactions of allylboronate complexes
with electrophiles. J. Am. Chem. Soc. 2017, 139, 15324−15327.
ACKNOWLEDGMENTS
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The authors would like to thank the Welch Foundation (E-
1916-20170325) for generous financial support for this
research.
(20) Bonazzi, S.; Guttinger, S.; Zemp, I.; Kutay, U.; Gademann, K.
̈
Total synthesis, configuration, and biological evaluation of anguino-
mycin C. Angew. Chem., Int. Ed. 2007, 46, 8707−8710.
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