Total Synthesis and Structure Revision of (-)-Avicennone C

Article abstract of DOI:10.1021/acs.joc.0c01792

All four possible stereoisomers of the natural product (-)-avicennone C were synthesized using two different methods for ring closure. The absolute stereochemistry was elucidated unambiguously by comparison of the analytical data with those of the reported natural product and by single X-ray crystal diffraction of synthetic intermediates. The proposed structure needed to be revised with regard to the absolute configuration of the stereogenic center bearing the secondary hydroxyl group. The reported synthesis offers a flexible, selective, and efficient access to all possible stereoisomers and may be of value for the stereoselective synthesis of other epoxyquinone natural products.

Full text of DOI:10.1021/acs.joc.0c01792

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Article
Total Synthesis and Structure Revision of (–)-Avicennone C
Yolanda Kleiner, Peter Hammann, Jonathan Becker, Armin
Bauer, Christoph Pöverlein, and Sören M. M. Schuler
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01792 • Publication Date (Web): 18 Sep 2020
Downloaded from pubs.acs.org on September 21, 2020
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Total Synthesis and Structure Revision of (–)-Avicennone C
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Yolanda Kleiner[a], Peter Hammann[b, c], Jonathan Becker[d], Armin Bauer[b], Christoph Pöverlein[b], and
Sören M. M. Schuler[a,c],

[a] Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for Bioresources, 35392 Giessen, Ger-
many
[b] Sanofi-Aventis Deutschland GmbH, R&D, Industriepark Hoechst, 65926 Frankfurt am Main, Germany
[c] present address: Evotec International GmbH, 37079 Goettingen, Germany
[d] Institute of Inorganic and Analytical Chemistry, Justus Liebig University, 35392 Giessen, Germany
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* Email: christoph.poeverlein@sanofi.com; soeren.schuler@evotec.com
Supporting Information Placeholder
ABSTRACT: All four possible stereoisomers of the natural product (–)-avicennone C were synthesized using two different methods
for ring closure. The absolute stereochemistry was elucidated unambiguously by comparison of the analytical data with those of the
reported natural product and by single X-ray crystal diffraction of synthetic intermediates. The proposed structure needed to be revised
with regard to the absolute configuration of the stereogenic center bearing the secondary hydroxyl group. The reported synthesis
offers a flexible, selective, and efficient access to all possible stereoisomers and may be of value for the stereoselective synthesis of
other epoxyquinone natural products.
INTRODUCTION
For epoxyquinone NPs, elucidation of the absolute stereo-
chemistry has shown no clear preference for one specific stere-
oisomer. Since challenging total syntheses are required in most
cases to unambiguously determine the absolute stereoconfigu-
ration, a flexible, selective, and efficient synthetic pathway to
all possible stereoisomers would be desirable.6 We chose (–)-
Epoxyquinone natural products (NPs)1 such as (+)-ambuic
acid (1), (–)-jesterone (2), and (–)-cycloepoxydon (3) (Figure 1)
display promising biological activities and have attracted inter-
est due to their structural novelty. (+)-Ambuic acid2, which
shows antimicrobial activity3, and (–)-jesterone4, possessing an-
timycotic activity, were isolated from the fungus Pestalotiopsis
spp. (–)-Cycloepoxydon5, inhibiting the activation of the tran-
scription factor NF-kB, was obtained from a Deuteromycete
strain.
,
avicennone C (4)7 8 as model system, because in contrast to the
compounds 1, 2, and 3 neither biological activities nor a total
synthesis have been reported. Avicennone C was isolated from
mangrove tree Avicennia marina and its absolute stereochemis-
try was proposed based on NMR and CD data as well as molec-
ular modeling by Sattler and Lin et al.7
Scheme 1. Retrosynthetic analysis.
Figure 1. Selected epoxyquinone NPs.
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Our retrosynthetic analysis of 4 led to a final disconnection
the TBDPS group of 15 and 18 was achieved in only moderate
yields with ammonium fluoride in methanol since significant
double deprotection occurred.15 The oxidation to aldehydes 17
and 20 worked smoothly with DMP followed by a filtration
over silica.
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between the ketone and the aryl moiety (Scheme 1). For the ring
closure we envisaged a palladium-catalyzed intramolecular cy-
clization similar to a published method of Muratake et al.9 Al-
dehyde 5 should be accessible by addition of a Grignard reagent
derived from 1-bromo-2-iodobenzene (6) to the highly func-
tionalized epoxy aldehyde 710, followed by protecting group
manipulations and oxidation.
Scheme 3. Synthesis of aldehydes 17 and 20.a
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RESULTS AND DISCUSSION
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Synthesis of epoxy aldehyde 7 (Scheme 2) was performed
analogously to a described reaction sequence from Barrett et
al.10 The use of a prenyl cuprate, generated from freshly pre-
pared prenyl Grignard reagent11, represents the significant dif-
ference. Key feature of this sequence is the stereoselective for-
mation of the epoxide via Sharpless epoxidation.12 Both enanti-
omers 7 and ent-7 were obtained in excellent yields and enanti-
omeric excesses (ee) over six steps on a 4–5 gram scale. The
final oxidation was performed either under Swern conditions
without further purification or with Dess–Martin periodinane
(DMP) followed by a filtration over silica.
Scheme 2. Synthesis of the epoxy aldehydes 7 and ent-7.a
aConditions: (a) i-PrMgCl, THF, –40 °C, 45 min; 7, –40 °C, 45 min;
42% for 13, 42% for 14; (b) TIPSOTf, 2,6-lutidine, CH2Cl2; 82%
for 15, 92% for 18; (c) NH4F, MeOH/THF 12:1; (d) DMP, CH2Cl2;
54% for 16, 56% for 19.
Scheme 4. Palladium-catalyzed cyclizationa and thermal ellip-
soid plot of the molecular structure of 4.b
aConditions: (a) TBDPSCl, imidazole, CH2Cl2, 99%; (b) n-BuLi,
THF, –78 °C, 30 min; EtOCOCl, 94%; (c) CuBr∙SMe2, prenyl-
MgCl, THF, –40 °C, 40 min; 9, –78 °C, 90 min, 94%; (d) DIBAL-
H, PhMe, –78 °C, 92%; (e) Ti(Oi-Pr)4, L-(+)-DET, t-BuOOH, 4 Å
MS, CH2Cl2, –20 °C, 3 d, 88%, 93% ee; (f) (COCl)2, DMSO,
CH2Cl2, –78 °C, 15 min; 12, –78 °C, 90 min; DIPEA, –78 °C to
0 °C, 30 min, quant. used as a crude; g) DMP, CH2Cl2, 76%.
The preparation of the two diastereomeric alcohols 13 and 14
was first achieved by using 1,2-dibromobenzene and Knochel’s
turbo Grignard reagent.13 However, the reaction was hampered
by slow formation of the aryl Grignard reagent, incomplete con-
version, side reactions, and low isolated yields. A possible ex-
planation is the tendency of 1,2-dibrombenzene to form ben-
zyne via 1,2-elimination rather than forming the desired Gri-
gnard reagent.13 Switching to 2-bromo-1-iodobenzene (6) ena-
bled complete Grignard formation with i-PrMgCl at low tem-
perature and resulted in full conversion of the epoxy aldehyde
7 (Scheme 3). The resulting diastereomers were separated by
careful flash chromatography and were isolated in good yields
with a ratio of approx. 1:1, which could be expected from sim-
aConditions: (a) PdCl2(PPh3)2 (0.1 eq.), Cs2CO3, toluene, reflux[7];
46% for 21, 48% for 22; (b) TBAF, HOAc, THF; 87%, 94% ee for
4, 83%, 94% ee for 23.16
,
ilar reactions described in literature.14 10 The assignment of the
absolute stereochemistry of 13 and 14 was only possible retro-
spectively by deduction from the crystal structure of 4 (Scheme
4). After TIPS protection, the envisaged selective cleavage of
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bThermal ellipsoid probability set to 50%, only one molecule of the
aConditions: (a) i-PrMgCl, THF, –40 °C, 45 min; ent-7, –40 °C, 45
asymmetric unit shown.
min; 39% for ent-13, 45% for ent-14; (b) Ac2O, pyridine, DMAP
(0.1 eq.), CH2Cl2; 93% for ent-25, quant. for ent-29; (c) TBAF,
HOAc, THF; (d) DBU, CH2Cl2; 91% over two steps for ent-27/ent-
2622, 94% over two steps for ent-31/ent-3022; (e) TIPSOTf, 2,6-
lutidine, CH2Cl2; 74% for ent-28, 74% for ent-32; (f) LiOH,
THF/H2O 5:1, 79% for ent-16, 85% for ent-19.
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The final cyclization of aldehydes 17 and 20 was performed
under the palladium-catalyzed conditions described by Mu-
ratake et al9(Scheme 4). There are only few examples for an
intramolecular palladium-catalyzed ketone synthesis by -ary-
lation with an aldehyde17, whilst intermolecular couplings of
this type have been reported by Xiao et al.18 The conversions of
17 and 20 to the desired products 21 and 22 proceeded relatively
slowly and were accompanied by side product formation. How-
ever, it was possible to isolate 21 and 22 in moderate yields
contaminated with minor amounts of their double bond iso-
mers.19 As a side product 24a was isolated20 and identified as
TIPS protected NP hemitectol (24b).21 Final deprotection of 21
and 22 yielded 4 and its hydroxyl epimer 23 in good yields.
Both stereoisomers showed very similar NOE correlations,
which made it impossible to determine their relative stereo-
chemistry. The absolute stereochemistry of compound 4 was
unambiguously determined by single X-ray crystal diffraction
and exhibited to be the proposed structure for NP (–)-avicen-
none C. However, the reported NMR spectra, aspect and spe-
cific rotation7 of (–)-avicennone C matched with compound 23.
Therefore, our results support a revision of the reported stereo-
chemistry of the NP (–)-avicennone C (Scheme 4).
For the synthesis of the corresponding enantiomers a differ-
ent protecting group strategy was applied in order to obtain im-
proved yields (Scheme 5). The hydroxyl functions of ent-13 and
ent-14, obtained from 6 and ent-7, were acetate protected. Dur-
ing TBDPS deprotection of the primary hydroxyl group a par-
tial acetate migration was observed even though the TBAF so-
lution was buffered with acetic acid. Treatment of the prepuri-
fied mixture of regioisomers with DBU in anhydrous CH2Cl2
resulted in almost full conversion to compounds ent-27 and ent-
31.22 Ent-16 and ent-19 were obtained by TIPS protection fol-
lowed by saponification.
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Besides final product 4, in the entire synthetic pathways we
were only able to obtain single crystals for ent-32.23 The abso-
lute configurations determined were in complete alignment.
For the final cyclization a different method with less side
product formation, shorter reaction times, and no isomerization
of the prenyl double bond would be desirable. An alternative
cyclization strategy could start with a selective lithium-bromine
exchange at low temperature followed by an addition of the lith-
ium-species to a carboxylic acid24, an ester25, or an amide26. This
approach requires mild oxidation of the primary hydroxyl group
to the carboxylic acid and subsequent ester or amide formation.
During our literature search for suitable reaction conditions a
one-pot hydroxyl to nitrile oxidation procedure described by
Vatéte attracted our attention.27 The oxidation of ent-16 and
ent-19 to the corresponding nitriles proceeded smoothly. For
the lithium-bromine exchange a solution of ent-33 or ent-34 in
anhydrous THF was cooled to –100 °C and a stoichiometric
amount of n-BuLi solution was added. Within a few minutes
complete conversion to the desired products was detected via
LCMS and TLC. A slightly acidic aqueous work-up ensured
full hydrolysis of the intermediate imines to liberate ketones
ent-21 and ent-22. The final products ent-4 and ent-23 were
obtained by cleavage of the TIPS protection group (Scheme 6).
Scheme 5. Alternative protecting group strategy.a
Scheme 6. Alternative cyclization for ent-avicennones.a
aConditions: (a) TEMPO (0.2 eq.), NH4OAc, BAIB, MeCN/H2O
9:1; 63% for ent-33, 68% for ent-34; (b) n-BuLi, THF, –100 °C, 5
min; 80% for ent-21, 95% for ent-22; (c) TBAF, HOAc, THF; 79%
for ent-4, 93% ee; 93% for ent-23, 92% ee.
For our goal of an efficient and flexible access to any specific
stereoisomer of the epoxyquinoids, the unselective Grignard ad-
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route towards epoxyquinone NPs in general and provided suffi-
dition remained the final optimization parameter. To circum-
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vent the loss of material due to formation of undesired stereoi-
somers, Mitsunobu inversions were attempted for 13 and 14.
Whilst acetate 29 was obtained in good yields and full inversion
of the stereocenter from 13, the Mitsunobu reaction of 14 re-
sulted in a mixture of both stereoisomers 25 and 29 as well as
side product formation.28 From common intermediate 29, (–)-
avicennone C (23) was finalized in 7 steps with an overall yield
of 31% under optimized conditions. In contrast to the failed in-
version of 14, the Mitsunobu reaction of 23 and 4 worked suc-
cessfully and subsequent saponification of acetates 35 and 36
yielded the fully inverted products in good yields (Scheme 7).
cient amounts of all four avicennone C stereoisomers for fol-
low-up biological and physico-chemical profiling, which is cur-
rently ongoing. Finally, this study demonstrates that even the
structure elucidation of relatively small NPs such as (–)-avicen-
none C bears the risk of misassignments and emphasizes the
importance of total synthesis not only for material supply and
generation of analogs, but also for unambiguous structure de-
termination.
9
EXPERIMENTAL SECTION
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General Information. All chemicals and solvents/anhydrous
solvents were commercially supplied and used without further
purification. For heating of reaction mixtures, aluminium flask
carriers in different sizes from IKA were used. Reactions were
monitored using thin layer chromatography (TLC) or using one
of the following LCMS systems: 1100 HPLC (Agilent) with
DAD and ELSD equipped with MSD (Agilent) ESI quadrupole
MS, 1100 HPLC (Agilent) with DAD equipped with Amazon
(Bruker) ESI trap MS, 1290 UPLC (Agilent) with DAD or
ELSD equipped with micrOTOF (Bruker) ESI TOF MS or 1290
UPLC (Agilent) with DAD and ELSD equipped with maXis II
(Bruker) ESI TOF MS. TLC was performed on pre-coated silica
gel glass plates (Merck TLC Silica gel 60 F254) and compounds
were detected under UV light (254 nm) and/or by staining with
an aqueous solution of KMnO4 with K2CO3 and NaOH fol-
lowed by heating with a heat gun. Products were purified by
flash column chromatography using silica gel 60 M (Macherey-
Nagel) or by using an automated flash column chromatography
system (Biotage® SP4 with ISOLUTE® Flash SI II) equipped
with ISOLUTE® Flash SI II columns of different sizes from Bi-
otage or PF-15SIHC flash columns of different sizes from In-
terchim (eluants are given in parentheses). NMR spectra were
recorded on a Bruker AVANCE II WB spectrometer (400
MHz), a AVANCE III HD spectrometer (400 MHz) or a
AVANCE III HD spectrometer (600 MHz) with CDCl3 or
CD3OD as solvent with chemical shifts (δ) quoted in parts per
million (ppm) and referenced to the solvent signal (δ1H/13C:
CDCl3 7.26/77.1, MeOD 3.31/49.0) or TMS (δ = 0 ppm in
CDCl3). Assignment was confirmed based on COSY, HSQC,
HMBC, and NOESY correlations. The absolute configuration
of compounds 4 and ent-32 was assigned by X-ray diffraction
analysis (for details regarding solvent and method for crystal
growth see experimental section and Supporting Information).
High resolution mass spectrometry was performed on the
maXis II (Bruker) ESI TOF MS. Specific rotation was meas-
ured by a polarimeter (P 3000 series) from Krüss. For SI struc-
tures with complete analytical data see Supporting Information.
Ethyl 4-[tert-butyl(diphenyl)silyl]oxybut-2-ynoate (9). The
synthesis of 9 was performed according to literature known pro-
cedure starting from propargyl alcohol in two steps. The analyt-
ical data are in accordance to the reported data in literature.10
1H-NMR (CDCl3, 400 MHz): 7.71–7.67 (m, 4H, aryl-H), 7.48–
7.37 (m, 6H, aryl-H), 4.40 (s, 2H, alkyne-CH2), 4.23 (q, 2H, J
= 7.1 Hz, Me-CH2), 1.32 (t, 3H, J = 7.1 Hz, CH3), 1.06 (s, 9H,
tBu-CH3); 13C-NMR (CDCl3, 100 MHz): 153.5 (C=O), 135.7
(Ar-C), 132.5 (Ar-Cq), 130.2 (Ar-C), 128.0 (Ar-C), 85.5 (al-
kyne-C), 76.9 (alkyne-C), 62.1 (Me-CH2), 52.4 (alkyne-CH2),
26.8 (tBu-CH3), 19.3 (tBu-Cq), 14.2 (CH3); HRMS (ESI) m/z
Scheme 7. Recycling strategy for undesired hydroxy isomers.a
aConditions: (a) for 13: PPh3, HOAc, DIAD, THF; 70%; (b) for 14:
Ac2O, pyridine, DMAP (0.1 eq.), CH2Cl2; 97%; (c) TBAF, HOAc,
THF; (d) DBU, CH2Cl2; 98% over two steps; (e) TIPSOTf, 2,6-
lutidine, CH2Cl2; 66%; (f) LiOH, THF/H2O 5:1, 85%; (g) TEMPO
(0.2 eq.), NH4OAc, BAIB, MeCN/H2O 9:1; 69%; (h) n-BuLi, THF,
–100 °C, 5 min; 92%; (i) TBAF, HOAc, THF; 89%; (j) PPh3,
HOAc, DIAD, THF; 90% for 35, 73% for 36; (k) LiOH, THF/H2O
5:1, 90% for 4, 93% for 23.
CONCLUSION
We synthesized all four possible stereoisomers of avicennone
C following two different pathways and revised the reported
stereochemistry of (–)-avicennone C (23) unambiguously. Be-
sides elegant protecting group manipulation utilizing an acetate
group, the most significant synthetic achievement was realized
by an alcohol to nitrile oxidation-cyclization sequence provid-
ing high yields as well as avoiding side product formation. Fur-
thermore, a step-neutral Mitsunobu inversion approach enabled
us to also recycle the undesired diastereomer 13. Based on this
concept we established a robust and scalable total synthesis
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calcd. for C22H26O3SiNa: (M+Na)+, 389.1543; found: 389.1544
was purified by flash column chromatography (0–30% ethyl ac-
(M+Na)+; Rf (n-heptane/ethyl acetate 10:1): 0.38.
etate in n-heptane) to give alcohol 11 (4.88 g, 12.4 mmol, 92%)
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Ethyl (2Z)-3-[[tert-butyl(diphenyl)silyl]oxymethyl]-6-me-
thyl-hepta-2,5-dienoate (10). The Grignard formation was per-
formed in oven-dried glassware under argon atmosphere. To a
suspension of Mg turnings (10.6 g, 437 mmol, 4.00 eq.) in an-
hydrous THF (28 mL) a small crystal of I2 was added. Prenyl
chloride (12.3 mL, 109 mmol, 1.00 eq.) was dissolved in anhy-
drous THF (185 mL) and the chloride solution was added drop-
wise over a period of 8 h to the reaction mixture. After 5 min
stirring at room temperature the Grignard solution was cooled
until the end of the addition with an ice-water bath. After com-
plete addition of the chloride, the reaction mixture was allowed
to get to room temperature and it was stirred overnight under
inert atmosphere. The supernatant layer was transferred via can-
nula to an oven-dried two-neck round-bottom flask. The Gri-
gnard-solution was titrated according to a literature known pro-
cedure.29 Cuprate addition was carried out in moisture-free
glassware under inert atmosphere. To a suspension of
CuBr·Me2S (6.13 g, 29.8 mmol, 2.10 eq.) in anhydrous THF
(20 mL) the Grignard solution (3.00 eq.) was added at −40 ºC.
The suspension was stirred for 40 min. After this time, the mix-
ture was cooled to −78 ºC and a solution of alkyne 9 (5.20 g,
14.2 mmol, 1.00 eq.) in anhydrous THF (20 mL) was added
dropwise over a period of 30 min. The resulting mixture was
stirred at −78 °C for 1 h and remaining cuprate was quenched
with saturated aqueous NH4Cl (200 mL). The mixture was ex-
tracted with Et2O (3 x 300 mL) and the combined organic layers
were washed with saturated aqueous NaCl (200 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography
(100% DCM) to give addition product 10 (5.84 g, 13.4 mmol,
94%) as colorless oil.
as colorless oil. H-NMR (CDCl3, 400 MHz): 7.72–7.66 (m,
4H, aryl-H), 7.47–7.36 (m, 6H, aryl-H), 5.46 (t, 1H, J = 6.9 Hz,
alkene-CH), 5.13 (m, 1H, Me2C=CH), 4.17 (s, 2H, TBDPSO-
CH2), 3.95 (d, 2H, J = 7.0 Hz, HO-CH2), 2.84 (d, 2H, J = 7.2
Hz, Me2C=CH-CH2), 1.71 (s, 3H, E-CH3), 1.60 (s, 3H, Z-CH3),
1.40 (s, br, 1H, OH), 1.05 (s, 9H, tBu-CH3); 13C-NMR (CDCl3,
100 MHz): 141.4 (CH=Cq), 135.8 (Ar-C), 133.7 (CqMe2 or Ar-
Cq), 133.5 (CqMe2 or Ar-Cq), 129.9 (Ar-C), 127.8 (Ar-C), 125.7
(CH2-CH=Cq), 121.5 (CH=CMe2), 61.9 (TBDPSO-CH2), 58.9
(HO-CH2), 33.4 (Me2C=CH-CH2), 26.9 (tBu-CH3), 25.9 (E-
CH3), 19.3 (tBu-Cq), 17.8 (Z-CH3); HRMS (ESI) m/z calcd. for
C25H34O2SiNa: (M+Na)+, 417.2220; found: 417.2214 (M+Na)+;
Rf (n-heptane/ethyl acetate 4:1): 0.25.
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[(2S,3R)-3-[[tert-Butyl(diphenyl)silyl]oxymethyl]-3-(3-
methylbut-2-enyl)oxiran-2-yl]methanol (12). The reaction
was carried out in oven-dried glassware under argon atmos-
phere. To a suspension of 4 Å molecular sieve in anhydrous
DCM (25 mL) L-(+)-diethyl tartrate (0.156 mL, 0.910 mmol,
0.12 eq.) and Ti(OiPr)4 (0.225 mL, 0.760 mmol, 0.10 eq.) were
added at −30 °C followed by addition of anhydrous tert-butyl
hydroperoxide in dodecane (5.5 M; 2.22 mL, 12.1 mmol, 1.60
eq.). The resulting mixture was stirred carefully for 40 min. Af-
ter this time, allyl alcohol 11 (3.01 g, 7.62 mmol, 1.00 eq.) dis-
solved in anhydrous DCM (10 mL) was added to the suspension
dropwise. The resulting suspension was allowed to stay at −28
°C in the freezer for 3 days. After this time, 10% aqueous NaOH
solution saturated with NaCl (30 mL) was added at −20 °C and
the suspension was allowed to stir for 1.5 h at 0 °C. After filtra-
tion over a frit with Celite® (4 x 7 cm), which was flushed with
DCM (500 mL), the solvent was reduced in vacuo to a volume
of 250 mL and the residue was washed with saturated aqueous
NaCl (100 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure. The crude product was purified by flash
column chromatography (0–40% ethyl acetate in n-heptane) to
give epoxy alcohol 12 (2.75 g, 5.09 mmol, 88%) as colorless
1H-NMR (CDCl3, 400 MHz): 7.71–7.62 (m, 4H, aryl-H), 7.45–
7.33 (m, 6H, aryl-H), 5.59 (m, 1H, alkene-CH), 5.20 (m, 1H,
Me2C=CH), 4.87 (m, 2H, TBDPSO-CH2), 4.01 (q, 2H, J = 7.1
Hz, Me-CH2), 3.13 (d, 2H, J = 7.4 Hz, CH-CH2), 1.75 (s, 3H,
E-CH3), 1.61 (s, 3H, Z-CH3), 1.16 (t, 3H, J = 7.1 Hz, CH2-CH3),
1
oil. H-NMR (CDCl3, 400 MHz): 7.71–7.61 (m, 4H, aryl-H),
t
1.08 (s, 9H, Bu-CH3); 13C-NMR (CDCl3, 100 MHz): 166.4
7.49–7.35 (m, 6H, aryl-H), 5.07 (m, 1H, Me2C=CH), 3.82 (d,
1H, J = 11.0 Hz, TBDPSO-CH2), 3.65 (t, 2H, J = 6.1 Hz, HO-
CH2), 3.61 (d, 1H, J = 11.1 Hz, TBDPSO-CH2), 3.09 (t, 1H, J
= 5.9 Hz, epoxy-CH), 2.52 (dd, 1H, J = 15.1, 7.5 Hz,
Me2C=CH-CH2), 2.42 (dd, 1H, J = 15.0, 7.2 Hz, Me2C=CH-
CH2), 1.89–1,79 (m, 1H, OH), 1.69 (s, 3H, E-CH3), 1.60 (s, 3H,
(C=O), 162.0 (CH=Cq), 135.8 (Ar-C), 135.1 (CqMe2), 133.7
(Ar-Cq), 129.9 (Ar-C), 127.9 (Ar-C), 120.3 (CH=CMe2), 114.9
(O=C-CH), 63.1 (TBDPSO-CH2), 60.0 (Me-CH2), 32.8 (CH-
CH2), 27.2 (tBu-CH3), 26.1 (E-CH3), 19.6 (tBu-Cq), 18.0 (Z-
CH3), 14.4 (CH2-CH3); HRMS (ESI) m/z calcd. for
C27H37O3Si: (M+H)+, 437.2506; found: 437.2501 (M+H)+; Rf
(n-heptane/ethyl acetate 10:1): 0.44.
(2Z)-3-[[tert-Butyl(diphenyl)silyl]oxymethyl]-6-methyl-
hepta-2,5-dien-1-ol (11). Under inert atmosphere DIBAl-H in
toluene (1.20 M; 43.5 mL, 52.2 mmol, 3.90 eq.) was added
slowly to ester 10 (5.84 g, 13.4 mmol, 1.00 eq.) dissolved in
anhydrous toluene (140 mL) at −78 °C. The resulting mixture
was stirred at this temperature for 1.5 h. Excess of DIBAL-H
was quenched carefully with MeOH (6 mL) and afterwards sat-
urated aqueous Rochelle’s salt solution (140 mL) was added.
The resulting suspension was left to warm up to room tempera-
ture and was stirred vigorously for 4 h. The organic layer was
separated and the aqueous layer was extracted with ethyl acetate
(3 x 100 mL). The combined organic layers were washed with
saturated aqueous NaCl (100 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
t
Z-CH3), 1.07 (s, 9H, Bu-CH3); 13C-NMR (CDCl3, 100 MHz):
135.9/135.7 (Ar-C), 135.4 (CqMe2), 133.0/132.8 (Ar-Cq), 130.1
(Ar-C), 128.0/127.9 (Ar-C), 117.9 (CH=CMe2), 64.7
(TBDPSO-CH2), 63.7 (epoxy-Cq), 61.4 (HO-CH2 or epoxy-
CH), 61.3 (HO-CH2 or epoxy-CH), 32.0 (Me2C=CH-CH2), 27.0
(tBu-CH3), 25.9 (E-CH3), 19.4 (tBu-Cq), 18.1 (Z-CH3); HRMS
(ESI) m/z calcd. for C25H34O3SiNa: (M+Na)+, 433.2169; found:
433.2167 (M+Na)+; Rf (n-heptane/ethyl acetate 2:1): 0.38; Chi-
ral HPLC (Chiralpak IC; hexane:isopropyl alcohol 94:6): 12
(Rt = 7.2 min) : ent-12 (Rt = 6.3 min) 96.3 : 3.7 (93% ee); Spe-
cific rotation [훼]2퐷2.6 = − 7.4 (c = 1.08; CHCl3).
[(2R,3S)-3-[[tert-Butyl(diphenyl)silyl]oxymethyl]-3-(3-
methylbut-2-enyl)oxiran-2-yl]methanol (ent-12). Ent-12
(1.18 g, 2.88 mmol, 91%) was synthesized in analogous manner
with D-(-)-diethyl tartrate instead of L-(+)-diethyl tartrate. The
NMR data are identical to the ones reported for 12. HRMS
(ESI) m/z calcd. for C25H34O3SiNa: (M+Na)+, 433.2169; found:
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The Journal of Organic Chemistry
iodobenzene (6, 0.436 mL, 3.40 mmol, 1.60 eq.) dissolved in
433.2173 (M+Na)+; Rf (n-heptane/ethyl acetate 2:1): 0.38; Chi-
1
2
3
4
5
6
7
8
ral HPLC (Chiralpak IC; hexane:isopropyl alcohol 94:6): ent-
12 (Rt = 6.6 min) : 12 (Rt = 7.7 min) 96.9 : 3.1 (94% ee); Spe-
cific rotation [훼]2퐷2.6 = + 6.0 (c = 1.32; CHCl3).
anhydrous THF (13 mL) i-PrMgCl in THF (2.0 M, 1.59 mL,
3.19 mmol, 1.50 eq.) was added dropwise at −40 °C. After stir-
ring for 45 min, epoxy aldehyde 7 (0.868 g, 2.12 mmol, 1.00
eq.) in anhydrous THF (7 mL) was added. The reaction mixture
was stirred for 45 min at −40 °C and was then diluted with sat-
urated aqueous NH4Cl (30 mL). The mixture was extracted with
ethyl acetate (2 x 100 mL) and the combined organic layers
were washed with saturated aqueous NaCl (50 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography
(0–20% ethyl acetate in n-heptane) to give addition products 14
(0.498 g, 0.880 mmol, 42% over two steps) and 13 (0.500 g,
0.880 mmol, 42% over two steps) as colorless oils. For 14: 1H-
NMR (CDCl3, 400 MHz): 7.72–7.63 (m, 4H, aryl-H), 7.55 (dd,
1H, J = 7.9, 1.7 Hz, Br-aryl-H), 7.50 (dd, 1H, J = 8.1, 1.2 Hz,
Br-aryl-H), 7.48–7.36 (m, 6H, aryl-H), 7.33 (td, 1H, J = 7.5, 1.2
Hz, Br-aryl-H), 7.15 (td, 1H, J = 7.7, 1.7 Hz, Br-aryl-H), 5.02
(m, 1H, Me2C=CH), 4.88 (dd, 1H, J = 6.1, 3.6 Hz, CH-OH),
3.91 (d, 1H, J = 11.5 Hz, TBDPSO-CH2), 3.81 (d, 1H, J = 11.6
Hz, TBDPSO-CH2), 3.11 (d, 1H, J = 6.1 Hz, epoxy-CH), 2.72
(dd, 1H, J = 14.8, 7.9 Hz, Me2C=CH-CH2), 2.59 (d, 1H, J = 4.0
Hz, OH), 2.28 (dd, 1H, J = 14.9, 6.8 Hz, Me2C=CH-CH2), 1.66
(s, 3H, E-CH3), 1.58 (s, 3H, Z-CH3), 1.07 (s, 9H, tBu-CH3); 13C-
NMR (CDCl3, 100 MHz): 140.6 (Br-Ar-Cq), 136.0 (Ar-C),
135.8 (Ar-C), 135.5 (CqMe2), 133.3/133.2 (Ar-Cq), 132.9 (Br-
Ar-C), 130.0/129.9 (Ar-C), 129.6 (Br-Ar-C), 128.2 (Br-Ar-C),
127.9 (Br-Ar-C), 127.9/127.8 (Ar-C), 122.2 (Br-Cq), 117.8
(CH=CMe2), 69.3 (C-OH), 65.5 (epoxy-Cq), 64.7 (epoxy-CH),
64.2 (TBDPSO-CH2), 31.4 (Me2C=CH-CH2), 27.0 (tBu-CH3),
25.9 (E-CH3), 19.4 (tBu-Cq), 18.1 (Z-CH3); HRMS (ESI) m/z
calcd. for C31H36BrO2Si: (M+H-H2O)+, 547.1662; found:
547.1660 (M+H-H2O)+; Rf (n-heptane/ethyl acetate 4:1): 0.34;
Specific rotation [훼]퐷24.0 = − 3.4 (c = 1.46; CHCl3). For 13: 1H-
NMR (CDCl3, 400 MHz): 7.75–7.68 (m, 4H, aryl-H), 7.58 (dd,
1H, J = 7.7, 1.6 Hz, Br-aryl-H), 7.54 (dd, 1H, J = 8.1, 1.1 Hz,
Br-aryl-H), 7.51–7.37 (m, 6H, aryl-H), 7.37–7.32 (m, 1H, Br-
aryl-H), 7.15 (td, 1H, J = 7.8, 1.7 Hz, Br-aryl-H), 5.08 (dd, 1H,
J = 7.8, 2.5 Hz, CH-OH), 5.03 (m, 1H, Me2C=CH), 4.02 (d, 1H,
J = 11.2 Hz, TBDPSO-CH2), 3.84 (d, 1H, J = 10.9 Hz,
TBDPSO-CH2), 3.15 (d, 1H, J = 7.8 Hz, epoxy-CH), 3.02 (d,
1H, J = 2.5 Hz, OH), 2.45 (d, 2H, J = 7.2 Hz, Me2C=CH-CH2),
1.65 (s, 3H, E-CH3), 1.56 (s, 3H, Z-CH3), 1.12 (s, 9H, tBu-CH3);
13C-NMR (CDCl3, 100 MHz): 140.2 (Br-Ar-Cq), 136.0/135.8
(Ar-C), 135.5 (CqMe2), 133.0 (Br-Ar-C), 132.7/132.5 (Ar-Cq),
130.2/130.2 (Ar-C), 129.6 (Br-Ar-C), 128.2 (Br-Ar-C),
128.1/128.0 (Ar-C), 128.0 (Br-Ar-C), 123.0 (Br-Cq), 117.8
(CH=CMe2), 70.8 (C-OH), 65.4 (TBDPSO-CH2), 64.7 (epoxy-
CH), 63.9 (epoxy-Cq), 32.1 (Me2C=CH-CH2), 27.1 (tBu-CH3),
25.9 (E-CH3), 19.4 (tBu-Cq), 18.1 (Z-CH3); HRMS (ESI) m/z
calcd. for C31H36BrO2Si: (M+H-H2O)+, 547.1662; found:
547.1659 (M+H-H2O)+; Rf (n-heptane/ethyl acetate 4:1): 0.37;
Specific rotation [훼]2퐷4.0 = − 16.2 (c = 0.93; CHCl3).
(2R,3R)-3-[[tert-Butyl(diphenyl)silyl]oxymethyl]-3-(3-
methylbut-2-enyl)oxirane-2-carbaldehyde (7). Condition 1:
Epoxy alcohol 12 (2.06 g, 5.01 mmol, 1.00 eq.) was dissolved
in anhydrous DCM (30 mL) and Dess–Martin periodinane
(15% in DCM, 20.8 mL, 10.0 mmol, 2.00 eq.) was added. After
stirring for 4 h at room temperature, the TLC showed complete
conversion of the starting material. The reaction solution was
flash chromatographed (100% DCM) to give epoxy aldehyde 7
(1.56 g, 3.81 mmol, 76%) as colorless oil. Condition 2: The re-
action was carried out in moisture-free glassware under inert
atmosphere. To a solution of (COCl)2 (0.365 mL, 4.26 mmol,
1.60 eq.) in anhydrous DCM (15 mL) anhydrous DMSO (0.605
mL, 8.52 mmol) was added carefully at −78 °C. After stirring
for 15 min, epoxy alcohol 12 (1.09 g, 2.66 mmol, 1.00 eq.) dis-
solved in anhydrous DCM (12 mL) was added. The reaction
mixture was stirred for 1.5 h at −78 °C. Then DIPEA (2.32 mL,
13.3 mmol, 5.00 eq.) was added and the solution was stirred for
30 min at −78 °C and for further 30 min without cooling bath.
A mixture of cooled toluene/saturated aqueous NH4Cl (3:1,
120 mL, pre-cooled to 0 °C) was added to the reaction mixture.
The aqueous layer was separated and the organic layer was
washed again with saturated aqueous NH4Cl (3 x 30 mL, pre-
cooled to 0 °C), with saturated aqueous NaHCO3 (30 mL, pre-
cooled to 0 °C), and with brine (30 mL, pre-cooled to 0 °C). The
organic layer was dried over MgSO4, filtered, and concentrated
under reduced pressure to yield epoxy aldehyde 7 (1.09 g,
1.66 mmol, quant.) as slightly yellow oil which was used in the
9
10
11
12
13
14
15
16
17
18
19
20
21
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23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
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43
44
45
46
47
48
49
50
51
52
53
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55
56
57
58
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60
1
next stage without further purification. H-NMR (CDCl3, 400
MHz): 9.47 (d, 1H, J = 4.9 Hz, CHO), 7.72–7.61 (m, 4H, aryl-
H), 7.49–7.36 (m, 6H, aryl-H), 5.03 (m, 1H, Me2C=CH), 3.82
(q, 2H, J = 12.0 Hz, TBDPSO-CH2), 3.25 (d, 1H, J = 4.6 Hz,
epoxy-CH), 2.52 (dd, 1H, J = 15.1, 7.9 Hz, Me2C=CH-CH2),
2.35 (dd, 1H, J = 15.2, 6.8 Hz, Me2C=CH-CH2), 1.68 (s, 3H, E-
t
CH3), 1.57 (s, 3H, Z-CH3), 1.04 (s, 9H, Bu-CH3); 13C-NMR
(CDCl3, 100 MHz): 198.8 (CHO), 136.6 (CqMe2), 135.7/135.7
(Ar-C), 132.6/132.6 (Ar-Cq), 130.1 (Ar-C), 128.0/128.0 (Ar-C),
116.8 (CH=CMe2), 68.6 (epoxy-Cq), 63.3 (TBDPSO-CH2),
62.4 (epoxy-CH), 31.5 (Me2C=CH-CH2), 26.9 (tBu-CH3), 25.9
(E-CH3), 19.3 (tBu-Cq), 18.1 (Z-CH3); HRMS (ESI) m/z calcd.
for C25H32O3SiNa: (M+Na)+, 431.2013; found: 431.2013
(M+Na)+; Rf (n-heptane/ethyl acetate 10:1): 0.31; Specific ro-
tation [훼]2퐷2.6 = + 18.9 (c = 1.59; CHCl3).
(2S,3S)-3-[[tert-Butyl(diphenyl)silyl]oxymethyl]-3-(3-
methylbut-2-enyl)oxirane-2-carbaldehyde (ent-7). Ent-7
(1.09 g, 2.66 mmol, quant.) was synthesized in analogous man-
ner to condition 2 starting from ent-12 (1.09 g, 2.66 mmol). The
NMR data are identical to the ones reported for 7. Yield for
condition 1: 85%. HRMS (ESI) m/z calcd. for C25H32O3SiNa:
(M+Na)+, 431.2013; found: 431.2016 (M+Na)+; Rf (n-hep-
tane/ethyl acetate 10:1): 0.31; Specific rotation [훼]2퐷2.6 = − 17.3
(c = 1.27; CHCl3).
(S)-(2-Bromophenyl)-[(2R,3S)-3-[[tert-butyl(diphenyl)si-
lyl]oxymethyl]-3-(3-methylbut-2-enyl)oxiran-2-yl]methanol
(ent-14) and (R)-(2-bromophenyl)-[(2R,3S)-3-[[tert-butyl(di-
phenyl)silyl]oxymethyl]-3-(3-methylbut-2-enyl)oxiran-2-
yl]methanol (ent-13). Ent-14 (0.928 g 1.64 mmol, 45% over
two steps) and ent-13 (0.802 g, 1.42 mmol, 39% over two steps)
were synthesized in analogous manner starting from epoxy al-
dehyde ent-7 (1.49 g, 3.65 mmol). The NMR data are identical
(R)-(2-Bromophenyl)-[(2S,3R)-3-[[tert-butyl(diphenyl)si-
lyl]oxymethyl]-3-(3-methylbut-2-enyl)oxiran-2-yl]methanol
(14) and (S)-(2-bromophenyl)-[(2S,3R)-3-[[tert-butyl(diphe-
nyl)silyl]oxymethyl]-3-(3-methylbut-2-enyl)oxiran-2-
yl]methanol (13). The reaction was carried out in moisture-free
glassware under inert atmosphere. To a solution of 1-bromo-2-
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Page 8 of 15
to the ones reported for 14 and 13. For ent-14: HRMS (ESI) (Ar-Cq), 132.5 (Br-Ar-C), 129.8/129.8 (Ar-C), 129.2 (Br-Ar-
m/z calcd. for C31H36BrO2Si: (M+H-H2O)+, 547.1662; found:
547.1660 (M+H-H2O)+; Rf (n-heptane/ethyl acetate 4:1): 0.34;
Specific rotation [훼]퐷22.2 = + 1.8 (c = 1.12; CHCl3). For ent-13:
HRMS (ESI) m/z calcd. for for C31H36BrO2Si: (M+H-H2O)+,
547.1662; found: 547.1659 (M+H-H2O)+; Rf (n-heptane/ethyl
acetate 4:1): 0.37; Specific rotation [훼]2퐷2.2 = + 13.5 (c = 0.82;
CHCl3).
C), 129.1 (Br-Ar-C), 127.8 (Ar-C), 127.7 (Br-Ar-C), 122.4 (Br-
Cq), 118.8 (CH=CMe2), 69.7 (C-OTIPS), 65.9 (epoxy-CH),
65.4 (epoxy-Cq), 64.5 (TBDPSO-CH2), 31.2 (Me2C=CH-CH2),
27.1 (tBu-CH3), 25.9 (E-CH3), 19.5 (tBu-Cq), 18.1 (Z-CH3),
17.9/17.8/12.3 (TIPS-C); HRMS (ESI) m/z calcd. for
C40H57BrO3Si2Na: (M+Na)+, 743.2922; found: 743.2928
(M+Na)+; Rf (n-heptane/ethyl acetate 10:1): 0.59; Specific ro-
tation [훼]2퐷3.0 = − 8.1 (c = 1.30; CHCl3).
1
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4
5
6
7
8
[(R)-(2-Bromophenyl)-[(2S,3R)-3-[[tert-butyl(diphenyl)si-
lyl]oxymethyl]-3-(3-methylbut-2-enyl)oxiran-2-yl]meth-
oxy]-triisopropyl-silane (18). 2,6-Lutidine (0.751 mL, 6.47
mmol, 6.00 eq.) and then TIPS triflate (0.870 mL, 3.24 mmol,
3.00 eq.) were added to a solution of alcohol 14 (0.610 g, 1.08
mmol, 1.00 eq.) in anhydrous DCM (25 mL) at 0 °C. The reac-
tion mixture was allowed to stir at room temperature for 1.5 h.
Because the TLC showed remaining starting material, 2,6-
lutidine (6.00 eq.) and then TIPS triflate (3.00 eq.) were added
a second time at 0 °C. After 2.5 h stirring at room temperature,
the TLC showed complete conversion. Saturated aqueous
NH4Cl (30 mL) was added. The mixture was extracted with
ethyl acetate (2 x 75 mL) and the combined organic layers were
washed with saturated aqueous NaCl (40 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography
(0–4% ethyl acetate in n-heptane) to give 18 (0.714 g, 0.99
[(2R,3S)-3-[(R)-(2-Bromophenyl)-triisopropylsilyloxy-
methyl]-2-(3-methylbut-2-enyl)oxiran-2-yl]methanol (19).
Condition 1: To a solution of 18 (0.714 g, 0.990 mmol, 1.00 eq.)
in MeOH/THF (23.5 mL/1.5 mL) NH4F (0.366 g, 9.89 mmol,
10.00 eq.) was added. The reaction mixture stirred for 5 h at 40
°C. Because the TLC only showed a slow conversion of the
starting material, the reaction was allowed to stir overnight at
room temperature and then saturated aqueous NaHCO3 (50 mL)
was added. The mixture was extracted with ethyl acetate (2 x
100 mL) and the combined organic layers were washed with
saturated aqueous NaCl (75 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. The crude product
was purified by flash column chromatography (0–20% ethyl ac-
etate in n-heptane) to give the desired product 19 (0.267 g,
0.550 mmol, 56%) and side product SI1 (0.080 g, 0.250 mmol,
25%) as colorless oils. Condition 2: To a solution of 32 (0.174
g, 0.330 mmol, 1.00 eq.) in THF/H2O (5:1, 8.0 mL/1.6 mL)
LiOH · H2O (0.028 g, 0.66 mmol, 2.00 eq.) was added. The re-
action mixture stirred over night at room temperature. After the
TLC showed a complete conversion the next day, saturated
aqueous NaHCO3 (20 mL) was added. The mixture was ex-
tracted with ethyl acetate (2 x 30 mL) and the combined organic
layers were washed with saturated aqueous NaCl (20 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure.
The crude product was purified by flash column chromatog-
raphy (0–25% ethyl acetate in n-heptane) to give 19 (0.137 g,
9
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14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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32
33
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35
36
37
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mmol, 92%) as a colorless oil. H-NMR (CDCl3, 400 MHz):
7.73–7.62 (m, 4H, aryl-H), 7.48–7.32 (m, 8H, aryl-H, Br-aryl-
H), 7.30–7.24 (m, 1H, Br-aryl-H), 7.07 (ddd, 1H, J = 8.0, 7.3,
1.7 Hz, Br-aryl-H), 4.83 (m, 1H, Me2C=CH), 4.81 (d, 1H, J =
4.8 Hz, CH-OTIPS), 3.78 (d, 1H, J = 11.5 Hz, TBDPSO-CH2),
3.67 (d, 1H, J = 11.5 Hz, TBDPSO-CH2), 3.17 (d, 1H, J = 7.8
Hz, epoxy-CH), 2.90 (dd, 1H, J = 14.7, 8.2 Hz, Me2C=CH-
CH2), 1.99 (dd, 1H, J = 14.6, 6.5 Hz, Me2C=CH-CH2), 1.56 (s,
3H, E-CH3), 1.48 (s, 3H, Z-CH3), 1.07 (s, 9H, tBu-CH3), 1.04–
0.85 (m, 21H, TIPS-H); 13C-NMR (CDCl3, 100 MHz): 141.3
(Br-Ar-Cq), 135.9/135.8 (Ar-C), 134.6 (CqMe2), 133.8/133.4
(Ar-Cq), 132.7 (Br-Ar-C), 129.7/129.7 (Ar-C), 129.7 (Ar-C),
129.3 (Br-Ar-C), 127.7 (Br-Ar-C), 127.6 (Br-Ar-C), 121.4 (Br-
Cq), 118.7 (CH=CMe2), 72.5 (C-OTIPS), 67.1 (epoxy-CH),
66.1 (TBDPSO-CH2), 65.1 (epoxy-Cq), 31.2 (Me2C=CH-CH2),
27.0 (tBu-CH3), 25.8 (E-CH3), 19.5 (tBu-Cq), 18.1 (Z-CH3),
18.0/17.9/12.3 (TIPS-C); HRMS (ESI) m/z calcd. for
C40H57BrO3Si2Na: (M+Na)+, 743.2922; found: 743.2929
(M+Na)+; Rf (n-heptane/ethyl acetate 10:1): 0.68; Specific ro-
tation [훼]2퐷3.0 = + 13.4 (c = 1.20; CHCl3).
1
0.280 mmol, 85%) as a colorless oil. H-NMR (CDCl3, 400
MHz): 7.60 (dd, 1H, J = 7.7, 1.7 Hz, aryl-H), 7.52 (dd, 1H, J =
8.1, 1.1 Hz, aryl-H), 7.39–7.33 (m, 1H, aryl-H), 7.16 (ddd, 1H,
J = 8.9, 6.5, 1.8 Hz, aryl-H), 5.17 (d, 1H, J = 7.8 Hz, CH-
OTIPS), 4.94 (m, 1H, Me2C=CH), 3.80 (dd, 1H, J = 12.1, 6.5
Hz, CH2-OH), 3.67 (dd, 1H, J = 12.2, 6.7 Hz, CH2-OH), 3.25
(d, 1H, J = 7.9 Hz, epoxy-CH), 2.47 (dd, 1H, J = 14.8, 7.7 Hz,
Me2C=CH-CH2), 2.15 (dd, 1H, J = 14.8, 7.2 Hz, Me2C=CH-
CH2), 1.66 (t, 1H, J = 6.7 Hz, OH), 1.61 (s, 3H, E-CH3), 1.50
(s, 3H, Z-CH3), 1.07–0.92 (m, 21H, TIPS-H); 13C-NMR
(CDCl3, 100 MHz): 141.3 (Ar-Cq), 135.5 (CqMe2), 132.9 (Ar-
C), 129.8 (Ar-C), 129.6 (Ar-C), 128.0 (Ar-C), 121.5 (Br-Cq),
117.9 (CH=CMe2), 72.4 (C-OTIPS), 68.0 (epoxy-CH), 64.9
(epoxy-Cq), 63.3 (CH2-OH), 32.0 (Me2C=CH-CH2), 25.8 (E-
CH3), 18.0 (Z-CH3), 18.0/17.9/12.4 (TIPS-C); HRMS (ESI)
m/z calcd. for C24H38BrO2Si: (M+H-H2O)+, 465.1819; found:
465.1819 (M+H-H2O)+; Rf (n-heptane/ethyl acetate 4:1): 0.42;
Specific rotation [훼]2퐷1.3 = − 15.4 (c = 0.97; CHCl3).
[(2R,3S)-3-[(S)-(2-Bromophenyl)-triisopropylsilyloxy-me-
thyl]-2-(3-methylbut-2-enyl)oxiran-2-yl]methanol (16). 16
(0.223 g, 0.460 mmol, 54%) was synthesized in analogous man-
ner to 19 (condition 1) starting from 15 (0.612 g, 0.850 mmol).
16 and side product SI2 (0.103 g, 0.310 mmol, 37%) were ob-
tained as colorless oils. 1H-NMR (CDCl3, 400 MHz): 7.63 (dd,
1H, J = 7.9, 1.7 Hz, aryl-H), 7.51 (dd, 1H, J = 8.1, 1.6 Hz, aryl-
H), 7.36 (td, 1H, J = 7.6, 0.9 Hz, aryl-H), 7.15 (ddd, 1H, J =
[(S)-(2-Bromophenyl)-[(2S,3R)-3-[[tert-butyl(diphenyl)si-
lyl]oxymethyl]-3-(3-methylbut-2-enyl)oxiran-2-yl]meth-
oxy]-triisopropyl-silane (15). 15 (0.613 g, 0.85 mmol, 82%)
was synthesized in analogous manner to 18 starting from 13
1
(0.584 g, 1.03 mmol) and was obtained as colorless oil. H-
NMR (CDCl3, 400 MHz): 7.75–7.66 (m, 4H, aryl-H), 7.57–
7.48 (m, 1H, Br-aryl-H), 7.48–7.33 (m, 7H, aryl-H, Br-aryl-H),
7.29 (td, 1H, J = 7.6, 0.7 Hz, Br-aryl-H), 7.09 (td, 1H, J = 7.7,
1.5 Hz, Br-aryl-H), 5.09 (m, 1H, Me2C=CH), 5.02 (d, 1H, J =
7.0 Hz, CH-OTIPS), 4.14 (d, 1H, J = 11.2 Hz, TBDPSO-CH2),
3.90 (d, 1H, J = 11.1 Hz, TBDPSO-CH2), 3.00 (d, 1H, J = 8.1
Hz, epoxy-CH), 2.93 (dd, 1H, J = 14.5, 7.9 Hz, Me2C=CH-
CH2), 2.08 (dd, 1H, J = 14.5, 7.0 Hz, Me2C=CH-CH2), 1.66 (s,
3H, E-CH3), 1.59 (s, 3H, Z- CH3), 1.10 (s, 9H, tBu-CH3), 0.91–
0.81 (m, 21H, TIPS-H); 13C-NMR (CDCl3, 100 MHz): 142.0
(Br-Ar-Cq), 136.0/135.9 (Ar-C), 134.7 (CqMe2), 133.7/133.2
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7.9, 7.4, 1.7 Hz, aryl-H), 5.37 (d, 1H, J = 7.0 Hz, CH-OTIPS),
obtained as colorless oil. Starting material 16 (0.021 g,
0.040 mmol, 8%) was also recovered. H-NMR (CDCl3, 400
1
1
2
3
4
5
6
7
8
5.09 (m, 1H, Me2C=CH), 4.03 (dd, 1H, J = 12.0, 5.2 Hz, CH2-
OH), 3.93 (dd, 1H, J = 12.0, 8.1 Hz, CH2-OH), 3.10 (d, 1H, J
= 6.8 Hz, epoxy-CH), 2.67 (dd, 1H, J = 14.6, 8.0 Hz,
Me2C=CH-CH2), 2.06 (dd, 1H, J = 14.5, 6.8 Hz, Me2C=CH-
CH2), 1.81 (dd, 1H, J = 7.9, 5.1 Hz, OH), 1.68 (s, 3H, E-CH3),
1.61 (s, 3H, Z-CH3), 1.03–0.95 (m, 21H, TIPS-H); 13C-NMR
(CDCl3, 100 MHz): 141.9 (Ar-Cq), 135.6 (CqMe2), 132.6 (Ar-
C), 129.5 (Ar-C), 129.0 (Ar-C), 127.9 (Ar-C), 122.3 (Br-Cq),
118.1 (CH=CMe2), 69.8 (C-OTIPS), 67.6 (epoxy-CH), 65.6
(epoxy-Cq), 62.3 (CH2-OH), 32.4 (Me2C=CH-CH2), 25.9 (E-
CH3), 18.0 (Z-CH3), 18.0/17.9/12.3 (TIPS-C); HRMS (ESI)
m/z calcd. for C24H38BrO2Si: (M+H-H2O)+, 465.1819; found:
465.1826 (M+H-H2O)+; Rf (n-heptane/ethyl acetate 4:1): 0.41;
Specific rotation [훼]2퐷7.6 = + 10.1 (c = 0.20; CHCl3).
MHz): 9.84 (s, 1H, CHO), 7.52 (dd, 1H, J = 8.0, 0.9 Hz, aryl-
H), 7.41–7.32 (m, 2H, aryl-H), 7.17 (ddd, 1H, J = 8.0, 7.0, 2.0
Hz, aryl-H), 5.64 (d, 1H, J = 2.9 Hz, CH-OTIPS), 4.98 (m, 1H,
Me2C=CH), 3.29 (d, 1H, J = 2.8 Hz, epoxy-CH), 2.54 (dd, 1H,
J = 15.1, 7.5 Hz, Me2C=CH-CH2), 2.31 (dd, 1H, J = 15.2, 7.4
Hz, Me2C=CH-CH2), 1.62 (s, 3H, E-CH3), 1.43 (s, 3H, Z-CH3),
1.12–0.92 (m, 21H, TIPS-H); 13C-NMR (CDCl3, 100 MHz):
200.5 (C=O), 140.3 (Ar-Cq), 136.4 (CqMe2), 132.6 (Ar-C),
129.8 (Ar-C), 129.1 (Ar-C), 128.3 (Ar-C), 121.8 (Br-Cq), 116.7
(CH=CMe2), 70.1 (C-OTIPS), 67.7 (epoxy-CH), 66.6 (epoxy-
Cq), 29.2 (Me2C=CH-CH2), 25.8 (E-CH3), 17.8 (Z-CH3),
17.9/17.8/12.3 (TIPS-C); HRMS (ESI) m/z calcd. for
C24H37BrO3SiNa: (M+Na)+, 503.1588; found: 503.1583
(M+Na)+; Rf (n-heptane/ethyl acetate 4:1): 0.77; Specific rota-
tion [훼]2퐷5.6 = + 5.8 (c = 0.87; CHCl3).
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15
16
17
18
19
20
21
22
23
24
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34
35
36
37
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43
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45
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[(2S,3R)-3-[(S)-(2-Bromophenyl)-triisopropylsilyloxy-me-
thyl]-2-(3-methylbut-2-enyl)oxiran-2-yl]methanol (ent-19)
and [(2S,3R)-3-[(R)-(2-Bromophenyl)-triisopropylsilyloxy-
methyl]-2-(3-methylbut-2-enyl)oxiran-2-yl]methanol (ent-
16). Ent-19 (0.427 g, 0.880 mmol, 85%) and ent-16 (0.346 g,
0.720 mmol, 79%) were synthesized according to 19 (condition
2) starting from ent-32 (0.542 g, 1.03 mmol) and ent-28 (0.822
g, 1.47 mmol). The NMR data are identical to the ones reported
for 19 and 16. For ent-19: HRMS (ESI) m/z calcd. for
C24H38BrO2Si: (M+H-H2O)+, 465.1819; found: 465.1822
(M+H-H2O)+; Rf (n-heptane/ethyl acetate 4:1): 0.42; Specific
rotation [훼]2퐷2.0 = + 21.7 (c = 0.97; CHCl3). For ent-16: HRMS
(ESI) m/z calcd. for C24H39BrO3SiNa: (M+Na)+, 505.1744;
found: 505.1752 (M+Na)+; Rf (n-heptane/ethyl acetate 4:1):
0.41; Specific rotation [훼]2퐷1.2 = − 35.8 (c = 1.17; CHCl3).
(2S,3S)-3-[(R)-(2-Bromophenyl)-triisopropylsilyloxy-me-
thyl]-2-(3-methylbut-2-enyl)oxirane-2-carbaldehyde (20).
Alcohol 19 (0.259 g, 0.540 mmol, 1.00 eq.) was dissolved in
DCM (10 mL) and Dess–Martin periodinane (15% in DCM,
2.24 mL, 1.07 mmol, 2.00 eq.) was added. After stirring for 4 h
at room temperature, the TLC showed a complete conversion of
the starting material. The reaction solution was filtered through
a short silica column (100% DCM, 20 g silica) and was then
purified via flash column chromatography (0–5% ethyl acetate
in n-heptane) to give epoxy aldehyde 20 (0.200 g, 0.420 mmol,
77%) and recovered starting material 19 (0.019 g, 0.040 mmol,
7%) as colorless oils. 1H-NMR (CDCl3, 400 MHz): 9.55 (s, 1H,
CHO), 7.60 (dd, 1H, J = 7.8, 1.8 Hz, aryl-H), 7.50 (dd, 1H, J =
8.1, 1.2 Hz, aryl-H), 7.36 (td, 1H, J = 7.6, 1.1 Hz, aryl-H), 7.17
(ddd, 1H, J = 8.0, 7.4, 1.7 Hz, aryl-H), 5.38 (d, 1H, J = 6.8 Hz,
CH-OTIPS), 4.95 (m, 1H, Me2C=CH), 3.46 (d, 1H, J = 6.6 Hz,
epoxy-CH), 2.50 (dd, 1H, J = 15.2, 7.4 Hz, Me2C=CH-CH2),
2.40 (dd, 1H, J = 15.3, 7.4 Hz, Me2C=CH-CH2), 1.63 (s, 3H, E-
CH3), 1.51 (s, 3H, Z-CH3), 1.16–0.92 (m, 21H, TIPS-H); 13C-
NMR (CDCl3, 100 MHz): 198.9 (C=O), 140.2 (Ar-Cq), 136.2
(CqMe2), 132.8 (Ar-C), 129.9 (Ar-C), 129.5 (Ar-C), 127.9 (Ar-
C), 121.4 (Br-Cq), 116.6 (CH=CMe2), 71.2 (C-OTIPS), 68.1
(epoxy-CH), 67.4 (epoxy-Cq), 28.3 (Me2C=CH-CH2), 25.8 (E-
CH3), 18.0 (Z-CH3), 18.0/17.9/12.3 (TIPS-C); HRMS (ESI)
m/z calcd. for C24H37BrO3SiNa: (M+Na)+, 503.1588; found:
503.1582 (M+Na)+; Rf (n-heptane/ethyl acetate 4:1): 0.75; Spe-
cific rotation [훼]2퐷5.6 = − 41.9 (c = 0.93; CHCl3).
(1aS,7R,7aS)-1a-(3-Methylbut-2-enyl)-7-triisopropylsi-
lyloxy-7,7a-dihydronaphtho[2,3-b]oxiren-2-one (22). Condi-
tion 1: Aldehyde 20 (0.141 g, 0.293 mmol, 1.00 eq.) was dis-
solved in toluene (15 mL). The solution was degassed with Ar-
gon for 15 min and Cs2CO3 (0.286 g, 0.878 mmol, 3.00 eq.) as
well as PdCl2(PPh3)2 (0.021 g, 0.029 mmol, 0.10 eq.) were
added. The reaction mixture was refluxed for 5 h. As the TLC
showed remaining starting material, further PdCl2(PPh3)2 (0.10
eq.) was added. The reaction mixture was stirred overnight at
100 °C. After the TLC showed a complete conversion of the
starting material the next day, the reaction solution was filtered
through a short silica gel column (n-heptane/ ethyl acetate 10:1,
10 g silica) and was then purified via flash column chromatog-
raphy (0–4% ethyl acetate in n-heptane) to give 22 (0.056 g,
0.139 mmol, 48%) as a yellowish oil. Product 22 was contami-
nated with approx. 20% inseparable isomerization product,
which was characterized after deprotection to 23. The formation
of further side products was observed. TIPS protected natural
product hemitectol21 (0.005 g, 0.013 mmol, 4%) 24a was iso-
lated and fully characterized. Condition 2: The halogen-lithium
exchange was carried out in a moisture-free glassware under ar-
gon atmosphere. To a solution of nitrile 34 (0.053 g, 0.110
mmol, 1.00 eq.) in anhydrous THF (5 mL) prediluted n-BuLi
solution (0.110 mmol, 1.00 eq.) was added at −100 ºC.30 The
obtained yellow solution was stirred for 20 min at −100 ºC and
for 5 min without cooling bath. During this time, the reaction
solution turned from yellow to orange. For hydrolysis of the in-
termediate imine, aqueous citric acid (10%, 15 mL) was added
and the mixture was extracted with ethyl acetate (50 mL). The
organic layer was separated, washed with saturated aqueous
NaHCO3 (15 mL) as well as with saturated aqueous NaCl (20
mL), dried over MgSO4, filtered, and concentrated under re-
duced pressure. The crude product was purified by flash column
chromatography (0–15% ethyl acetate in n-heptane) to give ke-
tone 22 (0.041 g, 0.100 mmol, 92%) as colorless oil. 1H-NMR
(CDCl3, 400 MHz): 7.92 (dd, 1H, J = 7.8, 1.2 Hz, aryl-H), 7.56
(td, 1H, J = 7.5, 1.4 Hz, aryl-H), 7.44 (td, 1H, J = 7.6, 1.1 Hz,
aryl-H), 7.35 (d, br, 1H, J = 7.6 Hz, aryl-H), 5.37 (d, 1H, J =
2.4 Hz, CH-OTIPS), 5.16 (m, 1H, Me2C=CH), 3.77 (d, 1H, J =
2.6 Hz, epoxy-CH), 3.02 (dd, 1H, J = 15.3, 7.8 Hz, Me2C=CH-
CH2), 2.55 (dd, 1H, J = 15.3, 6.8 Hz, Me2C=CH-CH2), 1.72 (s,
3H, E-CH3), 1.68 (s, 3H, Z-CH3), 1.14–0.94 (m, 21H, TIPS-H);
13C-NMR (CDCl3, 100 MHz): 195.3 (C=O), 140.0 (Ar-Cq),
135.8 (CqMe2), 133.6 (Ar-C), 130.5 (Ar-Cq-CO), 129.6 (Ar-C),
(2S,3S)-3-[(S)-(2-Bromophenyl)-triisopropylsilyloxy-me-
thyl]-2-(3-methylbut-2-enyl)oxirane-2-carbaldehyde (17).
17 (0.162 g, 0.340 mmol, 75%) was synthesized in analogous
manner to 20 starting from 16 (0.218 g, 0.450 mmol). It was
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129.2 (Ar-C), 127.6 (Ar-C), 117.2 (CH=CMe2), 68.2 (C- tube TBAF in THF (1 M, 0.245 mL, 0.250 mmol, 1.20 eq.), fol-
1
2
3
4
5
6
7
8
OTIPS), 60.5 (epoxy-Cq), 60.1 (epoxy-CH), 26.9 (Me2C=CH-
CH2), 26.0 (E-CH3), 18.1 (Z-CH3), 18.2/18.1/12.7 (TIPS-C);
HRMS (ESI) m/z calcd. for C24H37O3Si: (M+H)+, 401.2506;
found: 401.2505 (M+H)+; Rf (n-heptane/ethyl acetate 10:1):
0.44; Specific rotation [훼]2퐷4.2 = − 140.4 (c = 0.71; CHCl3).
(2,2-Dimethylbenzo[h]chromen-6-yl)oxy-triisopropyl-
lowed by acetic acid glacial (0.012 mL, 0.200 mmol, 1.00 eq.)
were added to a solution of 22 (0.082 g, 0.200 mmol, 1.00 eq.)
in THF (7 mL). After 2 h reaction time, the TLC showed a com-
plete conversion of the starting material. The reaction mixture
was loaded on silica and filtered through a small silica column
(n-heptane/ ethyl acetate 3:1, 10 g silica) and was then purified
via flash column chromatography (0–40% ethyl acetate in n-
heptane) to give 23 (0.044 mg, 0.180 mmol, 89%) as a colorless
oil. Material 22, which was obtained from condition 1, was con-
taminated with some isomerization product. After complete
deprotection 23 (0.019 g, 0.080 mmol, 83%) was obtained (sum
of collected fractions with different amount of SI3 after two
times careful chromatography; in total the content of SI3 was
estimated to be maximum 16% by analysis of the NMR spec-
tra). An almost pure sample of 23 was obtained for full charac-
terization. SI3 was isolated enriched in a mixture with product
23 (ratio SI3:23 approx. 2:1; analytical data see Supporting In-
formation). 1H-NMR (CDCl3, 600 MHz): 7.94 (dd, 1H, J = 7.8,
1.1 Hz, aryl-H), 7.62 (td, 1H, J = 7.5, 1.3 Hz, aryl-H), 7.47 (td,
1H, J = 7.6, 1.3 Hz, aryl-H), 7.44 (dd, 1H, J = 7.6, 1.2 Hz, aryl-
H), 5.24 (d, br, 1H, J = 3.9 Hz, CH-OH), 5.14 (m, 1H,
Me2C=CH), 3.83 (d, 1H, J = 2.1 Hz, epoxy-CH), 2.95 (dd, 1H,
J = 15.5, 8.0 Hz, Me2C=CH-CH2), 2.64 (dd, 1H, J = 15.3, 6.8
Hz, Me2C=CH-CH2), 2.04 (d, 6.5 Hz, OH), 1.73 (s, 3H, E-CH3),
1.70 (s, 3H, Z-CH3); 13C-NMR (CDCl3, 100 MHz): 194.4
(C=O), 139.6 (Ar-Cq), 136.4 (CqMe2), 134.4 (Ar-C), 129.9 (Ar-
C), 129.8 (Ar-Cq-CO), 129.7 (Ar-C), 127.8 (Ar-C), 116.7
(CH=CMe2), 67.2 (C-OH), 60.6 (epoxy-Cq), 60.1 (epoxy-CH),
26.8 (Me2C=CH-CH2), 26.0 (E-CH3), 18.2 (Z-CH3); HRMS
(ESI) m/z calcd. for C15H17O3: (M+H)+, 245.1172; found:
245.1171 (M+H)+; Rf (n-heptane/ethyl acetate 2:1): 0.31; Chi-
ral HPLC (Chiralpak IC; hexane:isopropyl alcohol 95:5): 23
(Rt = 8.3 min) : ent-23 (Rt = 9.2 min) 96.8 : 2.9 (94% ee); Spe-
cific rotation [훼]2퐷4.7 = − 193.6 (c = 0.70; CHCl3).
1
silane (24a). H-NMR (CDCl3, 400 MHz): 8.14 (m, 2H, H-5,
H-8), 7.42 (m, 2H, H-6, H-7), 6.55 (s, 1H, H-3), 6.35 (d, 1H, J
= 9.7 Hz, H-1’), 5.64 (d, 1H, J = 9.6 Hz, H-2’), 1.49 (s, 6H, H-
4’, H-5’), 1.44–1.31 (m, 3H, H-11), 1.18–1.11 (m, 18H, H-12);
13C-NMR (CDCl3, 100 MHz): 145.5 (C-4), 142.2 (C-1), 130.0
(C-2’), 128.2 (C-9), 126.2 (C-10), 125.7 (C-6), 125.4 (C-7),
123.1 (C-1’), 122.8 (C-5), 121.9 (C-8), 115.1 (C-2), 110.2 (C-
3), 76.3 (C-3’), 27.7 (C-4’, C-5’), 18.3 (C-12), 13.2 (C-11);
HRMS (ESI) m/z calcd. for C24H35O2Si: (M+H)+, 383.2401;
found: 383.2399 (M+H)+; Rf (n-heptane/ethyl acetate 10:1):
0.78.
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17
18
19
20
21
22
23
24
25
26
27
28
29
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31
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33
34
35
36
37
38
39
40
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46
47
48
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(1aS,7S,7aS)-1a-(3-Methylbut-2-enyl)-7-triisopropylsi-
lyloxy-7,7a-dihydronaphtho[2,3-b]oxiren-2-one (21). 21
(0.039 g, 0.100 mmol, 46%) was synthesized in analogous man-
ner to 22 (condition 1) starting from 17 (0.100 g, 0.210 mmol).
It was obtained as colorless oil and contaminated with insepa-
rable isomerization product (approx. 16%), which was charac-
terized after deprotection to 4. Formation of TIPS protected NP
hemitectol 24a was also observed, but the compound was not
1
isolated. H-NMR (CDCl3, 400 MHz): 7.86 (dd, 1H, J = 7.8,
1.2 Hz, aryl-H), 7.68 (d, br, 1H, J = 7.7 Hz, aryl-H), 7.62 (td,
1H, J = 7.5, 1.2 Hz, aryl-H), 7.43–7.35 (m, 1H, aryl-H), 5.31
(s, br, 1H, CH-OTIPS), 5.12 (m, 1H, Me2C=CH), 3.77 (d, 1H,
J = 1.6 Hz, epoxy-CH), 2.93 (dd, 1H, J = 15.3, 8.0 Hz,
Me2C=CH-CH2), 2.62 (dd, 1H, J = 15.3, 6.9 Hz, Me2C=CH-
CH2), 1.73 (s, 3H, E-CH3), 1.68 (s, 3H, Z-CH3), 1.35–1.13 (m,
21H, TIPS-H); 13C-NMR (CDCl3, 100 MHz): 195.2 (C=O),
140.4 (Ar-Cq), 136.3 (CqMe2), 134.0 (Ar-C), 129.3 (Ar-Cq-CO),
128.0 (Ar-C), 127.3 (Ar-C), 126.6 (Ar-C), 117.0 (CH=CMe2),
67.8 (C-OTIPS), 61.8 (epoxy-Cq), 58.7 (epoxy-CH), 26.3
(Me2C=CH-CH2), 25.9 (E-CH3), 18.4/18.3 (TIPS-C), 18.2 (Z-
CH3), 12.9 (TIPS-C); HRMS (ESI) m/z calcd. for
C24H36O3SiNa: (M+Na)+, 423.2326; found: 423.2330 (M+Na)+;
Rf (n-heptane/ethyl acetate 10:1): 0.51; Specific rotation
[훼]2퐷5.8 = − 80.9 (c = 1.04; CHCl3).
(1aS,7S,7aS)-7-Hydroxy-1a-(3-methylbut-2-enyl)-7,7a-di-
hydronaphtho[2,3-b]oxiren-2-one
(4).
4
(0.021 g,
0.080 mmol, 87%) was synthesized in analogous manner to 23
starting from 21 (0.039 g, 0.100 mmol) which was only ob-
tained from condition 1. It was obtained as colorless solid (sum
of collected fractions with different amount of SI4 after two
times careful chromatography; in total the content of SI4 was
estimated to be maximum 12% by analysis of the NMR spec-
tra). A sufficiently pure sample of 4 was obtained for full char-
acterization. SI4 was isolated enriched in a mixture with prod-
uct 4 (ratio SI4:4 approx. 2:1; analytical data see Supporting
Information). In a 4 mL Vial, a small portion of 4 was dissolved
in DCM (1 mL) and n-heptane (1.5 mL) was added. The system
was left at room temperature for one night. A crystal was ob-
tained for determination by single X-ray crystal diffraction (see
(1aR,7S,7aR)-1a-(3-Methylbut-2-enyl)-7-triisopropylsi-
lyloxy-7,7a-dihydronaphtho[2,3-b]oxiren-2-one
(ent-22)
and (1aR,7R,7aR)-1a-(3-Methylbut-2-enyl)-7-triiso-
propylsilyloxy-7,7a-dihydronaphtho[2,3-b]oxiren-2-one
(ent-21). Ent-22 (0.129 g, 0.320 mmol, 95%) and ent-21
(0.053 g, 0.130 mmol, 80%) were synthesized according to 22
(condition 2) starting from ent-34 (0.162 g, 0.340 mmol) and
ent-33 (0.079 g, 0.170 mmol). The NMR data are identical to
the ones reported for 22 and 21. No side product formation was
observed. For ent-22: HRMS (ESI) m/z calcd. for C24H37O3Si:
(M+H)+, 401.2506; found: 401.2509 (M+H)+; Rf (n-hep-
tane/ethyl acetate 10:1): 0.44; Specific rotation [훼]2퐷1.3 = +
138.5 (c = 0.61; CHCl3). For ent-21: HRMS (ESI) m/z calcd.
for C24H37O3Si: (M+H)+, 401.2506; found: 401.2501 (M+H)+;
Rf (n-heptane/ethyl acetate 10:1): 0.51; Specific rotation
[훼]2퐷1.3 = + 139.3 (c = 1.14; CHCl3).
1
Supporting Information for further details). H-NMR (CDCl3,
600 MHz): 7.92 (dd, 1H, J = 7.9, 1.0 Hz, aryl-H), 7.69 (m, 2H,
aryl-H), 7.42 (m, 1H, aryl-H), 5.14–5.05 (m, 2H, Me2C=CH,
CH-OH), 3.86 (d, 1H, J = 2.2 Hz, epoxy-CH), 2.94 (dd, 1H, J
= 15.4, 7.9 Hz, Me2C=CH-CH2), 2.62 (dd, 1H, J = 15.4, 7.0 Hz,
Me2C=CH-CH2), 2.33 (d or s, br., 1H, J = 11.2 Hz, OH), 1.73
(s, 3H, E-CH3), 1.68 (s, 3H, Z-CH3); 13C-NMR (CDCl3, 100
MHz): 194.0 (C=O), 140.0 (Ar- Cq), 136.4 (CqMe2), 134.4 (Ar-
C), 129.1 (Ar-Cq-CO), 128.6 (Ar-C), 127.5 (Ar-C), 127.2 (Ar-
C), 116.6 (CH=CMe2), 66.4 (C-OH), 62.4 (epoxy-Cq), 59.4
(epoxy-CH), 26.7 (Me2C=CH-CH2), 26.0 (E-CH3), 18.2 (Z-
(1aS,7R,7aS)-7-Hydroxy-1a-(3-methylbut-2-enyl)-7,7a-di-
hydronaphtho[2,3-b]oxiren-2-one (23). In a 50 mL falcon
10
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The Journal of Organic Chemistry
(0.766 g, 1.35 mmol). It was obtained as colorless oil. 1H-NMR
CH3); HRMS (ESI) m/z calcd. for C15H17O3: (M+H)+,
245.1172; found: 245.1172 (M+H)+; Rf (n-heptane/ethyl ace-
tate 2:1): 0.36; Chiral HPLC (Chiralpak IC; hexane:isopropyl
alcohol 95:5): 4 (Rt = 12.4 min) : ent-4 (Rt = 10.8 min) 97.0 :
3.0 (94% ee); Specific rotation [훼]2퐷3.7 = − 241.3 (c = 1.18;
CHCl3).
(CDCl3, 400 MHz): 7.73–7.65 (m, 4H, aryl-H), 7.51 (dd, 1H, J
= 8.1, 1.0 Hz, Br-aryl-H), 7.46–7.33 (m, 7H, aryl-H, Br-aryl-
H), 7.30 (td, 1H, J = 7.5, 1.2 Hz, Br-aryl-H), 7.15 (td, 1H, J =
7.7, 1.7 Hz, Br-aryl-H), 5.95 (d, 1H, J = 7.6 Hz, CH-OAc), 5.06
(m, 1H, Me2C=CH), 4.01 (d, 1H, J = 11.2 Hz, TBDPSO-CH2),
3.88 (d, 1H, J = 11.4 Hz, TBDPSO-CH2), 3.20 (d, 1H, J = 7.7
Hz, epoxy-CH), 2.71 (dd, 1H, J = 15.0, 7.6 Hz, Me2C=CH-
CH2), 2.37 (dd, 1H, J = 15.0, 7.0 Hz, Me2C=CH-CH2), 1.98 (s,
3H, CO-CH3), 1.69 (s, 3H, E-CH3), 1.61 (s, 3H, Z-CH3), 1.08
(s, 9H, tBu-CH3); 13C-NMR (CDCl3, 100 MHz): 169.1 (C=O),
1
2
3
4
5
6
7
(1aR,7S,7aR)-7-Hydroxy-1a-(3-methylbut-2-enyl)-7,7a-
dihydronaphtho[2,3-b]oxiren-2-one
(ent-23)
and
(1aR,7R,7aR)-7-Hydroxy-1a-(3-methylbut-2-enyl)-7,7a-di-
hydronaphtho[2,3-b]oxiren-2-one (ent -4). Ent-23 (0.023 g,
0.100 mmol, 93%) and ent-4 (0.027 g, 0.110 mmol, 79%) were
synthesized in analogous manner to 23 starting from ent-22
(0.041 g, 0.100 mmol) and ent-21 (0.055 g, 0.140 mmol). The
NMR data are identical to the ones reported for 23 and 4. For
ent-23: HRMS (ESI) m/z calcd. for C15H17O3: (M+H)+,
245.1172; found: 245.1175 (M+H)+; Rf (n-heptane/ethyl ace-
tate 2:1): 0.31; Chiral HPLC (Chiralpak IC; hexane:isopropyl
alcohol 95:5): ent-23 (Rt = 9.2 min) : 23 (Rt = 8.3 min) 96.2 :
3.8 (92% ee); Specific rotation [훼]2퐷5.1 = + 177.1 (c = 1.10;
CHCl3). For ent-4: HRMS (ESI) m/z calcd. for C15H17O3:
(M+H)+, 245.1172; found: 245.1172 (M+H)+; Rf (n-hep-
tane/ethyl acetate 2:1): 0.36.; Chiral HPLC (Chiralpak IC;
hexane:isopropyl alcohol 95:5): ent-4 (Rt = 10.8 min) : 4 (Rt =
12.4 min) 96.3 : 3.7 (93% ee); Specific rotation [훼]2퐷5.1 = +
218.8 (c = 1.26; CHCl3).
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
137.4
(Br-Ar-Cq),
135.9/135.8
(Ar-C),
135.3
(CqMe2),.133.4/133.2 (Ar-Cq), 133.2 (Br-Ar-C), 129.9 (Br-Ar-
C), 129.8 (Ar-C), 128.8 (Br-Ar-C), 127.9/127.8 (Ar-C), 127.8
(Br-Ar-C), 123.7 (Br-Cq), 118.1 (CH=CMe2), 71.3 (C-OAc),
65.3 (epoxy-Cq), 64.1 (TBDPSO-CH2), 62.4 (epoxy-CH), 31.3
(Me2C=CH-CH2), 27.0 (tBu-CH3), 25.9 (E-CH3), 20.9 (CO-
CH3), 19.4 (tBu-Cq), 18.2 (Z-CH3); HRMS (ESI) m/z calcd. for
C33H40BrO4Si: (M+H)+, 607.1874; found: 607.1879 (M+H)+; Rf
(n-heptane/ethyl acetate 4:1): 0.40; Specific rotation [훼]1퐷8.7
+ 10.0 (c = 1.20; CHCl3).
=
[(2S,3R)-3-[(S)-(2-Bromophenyl)-hydroxy-methyl]-2-(3-
methylbut-2-enyl)oxiran-2-yl]methyl acetate (ent-31). In a
50 mL falcon tube, acetic acid glacial (0.124 mL, 2.16 mmol,
1.40 eq.) followed by TBAF in THF (1 M, 1.85 mL, 1.85 mmol,
1.20 eq.) were added to a solution of TBDPS-protected ent-29
(0.939 g, 1.55 mmol, 1.00 eq.) in THF (19 mL). After 4 h, a
second portion of acetic acid (0.60 eq.) and TBAF (0.50 eq.)
were added to complete conversion which was monitored by
TLC. The reaction mixture was loaded on silica and was then
flash chromatographed (n-heptane / ethyl acetate 3:1) to give a
mixture of ent-30 and ent-31. To complete the acetate migra-
tion, the product mixture was dissolved in anhydrous DCM (25
mL) and DBU (0.204 mL, 1.36 mmol, 0.90 eq.) was added. Af-
ter stirring at room temperature for 2.5 h, the LC-MS showed a
nearly complete migration (a stagnation of migration with re-
maining 5–10% of 30 was observed). Saturated aqueous NH4Cl
(30 mL) was added. The mixture was extracted with ethyl ace-
tate (2 x 75 mL) and the combined organic layers were washed
with saturated aqueous NaCl (75 mL), dried over MgSO4, fil-
tered, and concentrated under reduced pressure to yield ent-31
(0.534 g, 1.45 mmol, 94% over two steps)22 as colorless oil,
which was pure enough to be used in the next stage without fur-
ther purification. 1H-NMR (CDCl3, 400 MHz): 7.60 (dd, 1H, J
= 7.7, 1.6 Hz, aryl-H), 7.57 (dd, 1H, J = 8.0, 1.0 Hz, aryl-H),
7.38 (td, 1H, J = 7.7, 1.1 Hz, aryl-H), 7.20 (td, 1H, J = 7.7, 1.6
Hz, aryl-H), 5.08–5.01 (m, 2H, CH-OH, Me2C=CH), 4.35 (d,
1H, J = 12.0 Hz, CH2-OAc), 4.28 (d, 1H, J = 12.1 Hz, CH2-
OH), 3.19 (d, 1H, J = 6.4 Hz, epoxy-CH), 2.73 (d, br, 1H, J =
3.4 Hz, OH), 2.56 (dd, 1H, J = 14.9, 8.1 Hz, Me2C=CH-CH2),
2.21 (dd, 1H, J = 14.8, 7.1 Hz, Me2C=CH-CH2), 2.06 (s, 3H,
CO-CH3), 1.69 (s, 3H, E-CH3), 1.57 (s, 3H, Z-CH3); 13C-NMR
(CDCl3, 100 MHz): 170.7 (C=O), 140.2 (Ar-Cq), 136.3
(CqMe2), 133.1 (Ar-C), 129.9 (Ar-C), 128.3 (Ar-C), 128.1 (Ar-
C), 122.3 (Br-Cq), 117.0 (CH=CMe2), 69.8 (C-OH), 65.0
(epoxy-CH), 64.3 (CH2-OAc), 63.2 (epoxy-Cq), 32.0
(Me2C=CH-CH2), 25.9 (E-CH3), 20.9 (CO-CH3), 18.0 (Z-CH3);
HRMS (ESI) m/z calcd. for C17H21BrO4Na: (M+Na)+,
391.0515; found: 391.0516 (M+Na)+; Rf (n-heptane/ethyl ace-
tate 2:1): 0.40; Specific rotation [훼]1퐷8.7 = + 7.3 (c = 0.82;
CHCl3).
[(S)-(2-Bromophenyl)-[(2R,3S)-3-[[tert-butyl(diphenyl)si-
lyl]oxymethyl]-3-(3-methylbut-2-enyl)oxiran-2-yl]methyl]
acetate (ent-29). To a solution of alcohol ent-14 (0.900 g,
1.59 mmol, 1.00 eq.) in anhydrous DCM (23 mL) anhydrous
pyridine (0.385 mL, 4.77 mmol, 3.00 eq.), acetic anhydride
(0.451 mL, 4.77 mmol, 3.00 eq.) and 4-dimethylaminopyridine
(0.019 g, 0.160 mmol, 0.10 eq.) were added. The reaction mix-
ture was stirred for 2 h until the TLC showed complete conver-
sion. Toluene (20 mL) was added and the reaction mixture was
concentrated in vacuo. The crude product was purified by flash
column chromatography (0–30% ethyl acetate in n-heptane) to
give ent-29 (0.964 g, 1.59 mmol, quant.) as a colorless oil. 1H-
NMR (CDCl3, 400 MHz): 7.68–7.57 (m, 4H, aryl-H), 7.49 (dd,
1H, J = 8.0, 1.1 Hz, Br-aryl-H), 7.46–7.32 (m, 7H, aryl-H, Br-
aryl-H), 7.28 (td, 1H, J = 4.4, 1.1 Hz, Br-aryl-H), 7.14 (td, 1H,
J = 7.8, 1.7 Hz, Br-aryl-H), 5.87 (d, 1H, J = 7.9 Hz, CH-OAc),
4.92 (m, 1H, Me2C=CH), 3.81 (d, 1H, J = 16.8 Hz, TBDPSO-
CH2), 3.77 (d, 1H, J = 16.8 Hz, TBDPSO-CH2), 3.34 (d, 1H, J
= 7.9 Hz, epoxy-CH), 2.70 (dd, 1H, J = 14.9, 7.9 Hz,
Me2C=CH-CH2), 2.24 (dd, 1H, J = 15.0, 6.8 Hz, Me2C=CH-
CH2), 2.03 (s, 3H, CO-CH3), 1.63 (s, 3H, E-CH3), 1.53 (s, 3H,
t
Z-CH3), 1.04 (s, 9H, Bu-CH3); 13C-NMR (CDCl3, 100 MHz):
169.5 (C=O), 137.0 (Br-Ar-Cq), 135.9/135.8 (Ar-C), 135.4
(CqMe2), 133.5 (Br-Ar-C), 133.5/133.1 (Ar-Cq), 130.1 (Br-Ar-
C), 129.9/129.8 (Ar-C), 129.2 (Br-Ar-C), 127.8/127.8 (Ar-C),
127.7 (Br-Ar-C), 123.0 (Br-Cq), 117.9 (CH=CMe2), 73.5 (C-
OAc), 64.9 (TBDPSO-CH2), 64.8 (epoxy-Cq), 62.5 (epoxy-
CH), 30.9 (Me2C=CH-CH2), 27.0 (tBu-CH3), 25.9 (E-CH3),
21.0 (CO-CH3), 19.4 (tBu-Cq), 18.1 (Z-CH3); HRMS (ESI) m/z
calcd. for C33H40BrO4Si: (M+H)+, 607.1874; found: 607.1861
(M+H)+; Rf (n-heptane/ethyl acetate 4:1): 0.37; Specific rota-
tion [훼]1퐷8.7 = − 8.4 (c = 1.19; CHCl3).
[(R)-(2-Bromophenyl)-[(2R,3S)-3-[[tert-butyl(diphenyl)si-
lyl]oxymethyl]-3-(3-methylbut-2-enyl)oxiran-2-yl]methyl]
acetate (ent-25). Ent-25 (0.762 g, 1.25 mmol, 93%) was syn-
thesized in analogous manner to ent-29 starting from ent-13
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[(2S,3R)-3-[(R)-(2-Bromophenyl)-hydroxy-methyl]-2-(3-
547.1853 (M+Na)+; Rf (n-heptane/ethyl acetate 4:1): 0.52; Spe-
cific rotation [훼]2퐷1.6 = + 15.8 (c = 0.95; CHCl3).
1
2
3
4
5
6
7
8
methylbut-2-enyl)oxiran-2-yl]methyl acetate (ent-27). Ent-
27 (0.411 g, 1.11 mmol, 91% over two steps)22 was synthesized
in analogous manner to ent-31 starting from ent-25 (0.423 g,
1.14 mmol). It was obtained as colorless oil. 1H-NMR (CDCl3,
400 MHz): 7.60 (dd, 1H, J = 7.8, 1.7 Hz, aryl-H), 7.56 (dd, 1H,
J = 8.1, 1.1 Hz, aryl-H), 7.37 (td, 1H, J = 7.5, 1.1 Hz, aryl-H),
7.18 (td, 1H, J = 7.6, 1.7 Hz, aryl-H), 5.22 (dd, 1H, J = 7.6, 1.7
Hz, CH-OH), 5.09 (m, 1H, Me2C=CH), 4.40 (d, 1H, J = 12.1
Hz, CH2-OAc), 4.35 (d, 1H, J = 12.1 Hz, CH2-OH), 3.21 (d,
1H, J = 7.6 Hz, epoxy-CH), 3.19–3.14 (m, 1H, OH), 2.36 (d,
br, 2H, J = 7.6 Hz, Me2C=CH-CH2), 2.13 (s, 3H, CO-CH3),
1.70 (s, 3H, E-CH3), 1.60 (s, 3H, Z-CH3); 13C-NMR (CDCl3,
100 MHz): 171.5 (C=O), 139.9 (Ar-Cq), 136.0 (CqMe2), 133.1
(Ar-C), 129.7 (Ar-C), 128.3 (Ar-C), 128.0 (Ar-C), 122.9 (Br-
Cq), 117.3 (CH=CMe2), 69.8 (C-OH), 65.2 (epoxy-CH), 63.5
(CH2-OAc), 62.0 (epoxy-Cq), 32.2 (Me2C=CH-CH2), 26.0 (E-
CH3), 21.0 (CO-CH3), 18.1 (Z-CH3); HRMS (ESI) m/z calcd.
for C17H21BrO4Na: (M+Na)+, 391.0515; found: 391.0517
(M+Na)+; Rf (n-heptane/ethyl acetate 2:1): 0.43; Specific rota-
tion [훼]1퐷8.7 = − 16.0 (c = 1.03; CHCl3).
[(2S,3R)-3-[(R)-(2-Bromophenyl)-triisopropylsilyloxy-
methyl]-2-(3-methylbut-2-enyl)oxiran-2-yl]methyl acetate
(ent-28). Ent-28 (0.484 g, 0.920 mmol, 74%) was synthesized
in analogous manner to ent-32 starting from ent-27 (0.404 g,
1.09 mmol). It was obtained as colorless oil. 1H-NMR (CDCl3,
400 MHz): 7.59 (dd, 1H, J = 7.8, 1.6 Hz, aryl-H), 7.50 (dd, 1H,
J = 8.0, 1.1 Hz, aryl-H), 7.35 (td, 1H, J = 7.5, 1.0 Hz, aryl-H),
7.15 (td, 1H, J = 7.7, 1.7 Hz, aryl-H), 5.38 (d, 1H, J = 5.9 Hz,
CH-OTIPS), 4.99 (m, 1H, Me2C=CH), 4.53 (d, 1H, J = 11.8
Hz, CH2-OAc), 4.46 (d, 1H, J = 11.8 Hz, CH2-OAc), 3.10 (d,
1H, J = 5.9 Hz, epoxy-CH), 2.57 (dd, 1H, J = 14.6, 8.1 Hz,
Me2C=CH-CH2), 2.12 (s, 3H, CO-CH3), 2.06 (dd, 1H, J = 14.6,
7.1 Hz, Me2C=CH-CH2), 1.64 (s, 3H, E-CH3), 1.52 (s, 3H, Z-
CH3), 1.12–0.94 (m, 21H, TIPS-H); 13C-NMR (CDCl3, 100
MHz): 170.9 (C=O), 141.4 (Ar-Cq), 135.7 (CqMe2), 132.6 (Ar-
C), 129.5 (Ar-C), 128.9 (Ar-C), 127.9 (Ar-C), 122.1 (Br-Cq),
117.7 (CH=CMe2), 69.8 (CH-OTIPS), 65.9 (epoxy-CH), 64.1
(CH2-OAc), 62.7 (epoxy-Cq), 32.1 (Me2C=CH-CH2), 25.9 (E-
CH3), 21.0 (CO-CH3), 17.9 (Z-CH3), 17.9/17.9/12.3 (TIPS-C);
HRMS (ESI) m/z calcd. for C26H41BrO4SiNa: (M+Na)+,
547.1850; found: 547.1832 (M+Na)+; Rf (n-heptane/ethyl ace-
tate 4:1): 0.53; Specific rotation [훼]2퐷1.6 = − 21.0 (c = 1.38;
CHCl3).
(2S,3R)-3-[(S)-(2-Bromophenyl)-triisopropylsilyloxy-me-
thyl]-2-(3-methylbut-2-enyl)oxirane-2-carbonitrile (ent-34).
Alcohol ent-19 (0.409 g, 0.850 mmol, 1.00 eq.) was dissolved
in MeCN/H2O 9:1 (30 mL/3.3 mL) and NH4OAc (0.261 g, 3.39
mmol, 4.00 eq.), BIAB (0.818 g, 2.54 mmol, 3.00 eq.), and
TEMPO (0.027 g, 0.170 mmol, 0.20 eq.) were added. The reac-
tion solution was allowed to stir 8.5 h at room temperature, until
the TLC and the LC-MS showed a complete conversion to the
nitrile (n.b. the starting material is first converted to the inter-
mediate aldehyde and then converted to the nitrile in a two-step
fashion). Saturated aqueous Na2SO3 (30 mL) was added. The
mixture was extracted with ethyl acetate (100 mL) and the sep-
arated organic layer was washed with saturated aqueous NaCl
(30 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude product was purified via flash col-
umn chromatography (0–5% ethyl acetate in n-heptane) to give
nitrile ent-34 (0.277 g, 0.580 mmol, 68%) as a colorless solid.
1H-NMR (CDCl3, 400 MHz): 7.61 (dd, 1H, J = 7.8, 1.7 Hz,
aryl-H), 7.57 (dd, 1H, J = 8.0, 1.0 Hz, aryl-H), 7.34 (td, 1H, J
= 7.5, 1.0 Hz, aryl-H), 7.20 (td, 1H, J = 7.7, 1.7 Hz, aryl-H),
5.19 (d, 1H, J = 7.6 Hz, CH-OTIPS), 5.04 (m, 1H, Me2C=CH),
3.39 (d, 1H, J = 7.6 Hz, epoxy-CH), 2.50 (dd, 1H, J = 14.9, 7.6
Hz, Me2C=CH-CH2), 2.41 (dd, 1H, J = 15.0, 7.4 Hz,
Me2C=CH-CH2), 1.69 (s, 3H, E-CH3), 1.54 (s, 3H, Z-CH3),
1.18–0.94 (m, 21H, TIPS-H); 13C-NMR (CDCl3, 100 MHz):
139.6 (Ar-Cq), 138.7 (CqMe2), 133.4 (Ar-C), 130.2 (Ar-C),
130.0 (Ar-C), 127.8 (Ar-C), 122.0 (Br-Cq), 117.5 (CN), 114.6
(CH=CMe2), 73.6 (CH-OTIPS), 65.9 (epoxy-CH), 53.8 (epoxy-
Cq), 33.1 (Me2C=CH-CH2), 25.9 (E-CH3), 18.2 (Z-CH3),
18.0/17.9/12.4 (TIPS-C); HRMS (ESI) m/z calcd. for
C24H37BrNO2Si: (M+H)+, 478.1771; found: 478.1778 (M+H)+;
Rf (n-heptane/ethyl acetate 10:1): 0.52; Specific rotation
[훼]2퐷1.7 = + 14.6 (c = 1.17; CHCl3).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[(2S,3R)-3-[(S)-(2-Bromophenyl)-triisopropylsilyloxy-me-
thyl]-2-(3-methylbut-2-enyl)oxiran-2-yl]methyl
acetate
(ent-32). 2,6-Lutidine (1.00 mL, 8.56 mmol, 6.00 eq.) followed
by TIPS triflate (1.15 mL, 4.28 mmol, 3.00 eq.)were added to a
solution of alcohol ent-31 (0.527 g, 1.43 mmol, 1.00 eq.) in an-
hydrous DCM (20 mL) at 0 °C. The reaction mixture was al-
lowed to stir at room temperature for 2 h. After this time, the
TLC showed remaining starting material. Therefore a second
portion of 2,6-lutidine (2.00 eq.) and TIPS triflate (1.00 eq.)
were added at 0°C. After stirring at room temperature for addi-
tional 3 h, the TLC showed a complete conversion. Saturated
aqueous NH4Cl (30 mL) was added. The mixture was extracted
with ethyl acetate (2 x 100 mL) and the combined organic layers
were washed with saturated aqueous NaCl (70 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude product was prepurified by flash column chromatography
(0–20% ethyl acetate in n-heptane) and finally purified by flash
column chromatography (0–20% ethyl acetate in n-heptane) to
give ent-32 (0.555 g, 1.06 mmol, 74%) as a colorless solid. In a
4 mL Vial, a small portion of ent-32 was dissolved in DCM (1
mL) and n-heptane (1.5 mL) was added. The system was left at
room temperature for one night. A crystal was obtained for de-
termination by single X-ray crystal diffraction (see Supporting
1
Information for further details). H-NMR (CDCl3, 400 MHz):
7.58 (dd, 1H, J = 7.8, 1.7 Hz, aryl-H), 7.51 (dd, 1H, J = 8.1, 1.1
Hz, aryl-H), 7.36 (td, 1H, J = 7.5, 1.0 Hz, aryl-H), 7.16 (td, 1H,
J = 7.7, 1.7 Hz, aryl-H), 5.06 (d, 1H, J = 7.7 Hz, CH-OTIPS),
4.90 (m, 1H, Me2C=CH), 4.23 (d, 1H, J = 11.9 Hz, CH2-OAc),
4.12 (d, 1H, J = 11.9 Hz, CH2-OAc), 3.24 (d, 1H, J = 7.7 Hz,
epoxy-CH), 2.42 (dd, 1H, J = 14.9, 7.8 Hz, Me2C=CH-CH2),
2.10 (dd, 1H, J = 14.8, 7.2 Hz, Me2C=CH-CH2), 2.01 (s, 3H,
CO-CH3), 1.61 (s, 3H, E-CH3), 1.47 (s, 3H, Z-CH3), 1.16–0.91
(m, 21H, TIPS-H); 13C-NMR (CDCl3, 100 MHz): 170.8 (C=O),
141.4 (Ar-Cq), 135.6 (CqMe2), 132.9 (Ar-C), 129.8 (Ar-C),
129.6 (Ar-C), 127.9 (Ar-C), 121.8 (Br-Cq), 117.5 (CH=CMe2),
72.5 (CH-OTIPS), 67.6 (epoxy-CH), 65.3 (CH2-OAc), 62.2
(epoxy-Cq), 32.1 (Me2C=CH-CH2), 25.8 (E-CH3), 20.9 (CO-
CH3), 17.9 (Z-CH3), 18.0/17.8/12.4 (TIPS-C); HRMS (ESI)
m/z calcd. for C26H41BrO4SiNa: (M+Na)+, 547.1850; found:
(2S,3R)-3-[(R)-(2-Bromophenyl)-triisopropylsilyloxy-me-
thyl]-2-(3-methylbut-2-enyl)oxirane-2-carbonitrile (ent-33).
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g, 0.500 mmol, 98% over two steps)22 was synthesized in anal-
Ent-33 (0.201 g, 0.420 mmol, 63%) was synthesized in analo-
1
2
3
4
5
6
7
8
gous manner to ent-24 starting from ent-16 (0.322 g,
0.670 mmol). It was obtained as a colorless oil. 1H-NMR
(CDCl3, 400 MHz): 7.73 (dd, 1H, J = 7.8, 1.3 Hz, aryl-H), 7.54
(dd, 1H, J = 8.0, 1.0 Hz, aryl-H), 7.39 (td, 1H, J = 7.6, 1.0 Hz,
aryl-H), 7.19 (td, 1H, J = 7.7, 1.7 Hz, aryl-H), 5.50 (d, 1H, J =
5.5 Hz, CH-OTIPS), 5.07 (m, 1H, Me2C=CH), 3.18 (d, 1H, J =
5.4 Hz, epoxy-CH), 2.58 (dd, 1H, J = 14.9, 7.8 Hz, Me2C=CH-
CH2), 2.39 (dd, 1H, J = 15.0, 7.3 Hz, Me2C=CH-CH2), 1.70 (s,
3H, E-CH3), 1.57 (s, 3H, Z-CH3), 1.20–0.98 (m, 21H, TIPS-H);
13C-NMR (CDCl3, 100 MHz): 140.2 (Ar-Cq), 138.7 (CqMe2),
132.8 (Ar-C), 129.9 (Ar-C), 129.1 (Ar-C), 128.0 (Ar-C), 122.2
(Br-Cq), 117.4 (CN), 114.8 (CH=CMe2), 70.2 (CH-OTIPS),
65.5 (epoxy-CH), 53.0 (epoxy-Cq), 33.3 (Me2C=CH-CH2), 25.9
(E-CH3), 18.1 (Z-CH3), 18.0/17.9/12.3 (TIPS-C); HRMS (ESI)
m/z calcd. for C24H37BrNO2Si: (M+H)+, 478.1771; found:
478.1772 (M+H)+; Rf (n-heptane/ethyl acetate 4:1): 0.64; Spe-
cific rotation [훼]2퐷1.4 = + 4.6 (c = 0.88; CHCl3).
ogous manner to ent-31 starting from 29 (0.187 g, 0.510 mmol).
The NMR data are identical to the ones reported for ent-31.
HRMS (ESI) m/z calcd. for C17H21BrO4Na: (M+Na)+,
391.0515; found: 391.0520 (M+Na)+; Rf (n-heptane/ethyl ace-
tate 2:1): 0.40; Specific rotation [훼]2퐷6.6 = − 10.9 (c = 0.69;
CHCl3).
[(2R,3S)-3-[(R)-(2-Bromophenyl)-triisopropylsilyloxy-
methyl]-2-(3-methylbut-2-enyl)oxiran-2-yl]methyl acetate
(32). 32 (0.174 g, 0.330 mmol, 66%) was synthesized in analo-
gous manner to ent-32 starting from 31 (0.185 g, 0.500 mmol).
The NMR data are identical to the ones reported for ent-32.
HRMS (ESI) m/z calcd. for C26H41BrO4SiNa: (M+Na)+,
547.1850; found: 547.1849 (M+Na)+; Rf (n-heptane/ethyl ace-
tate 2:1): 0.67; Specific rotation [훼]2퐷1.6 = − 20.8 (c = 0.48;
CHCl3).
(2R,3S)-3-[(R)-(2-Bromophenyl)-triisopropylsilyloxy-me-
thyl]-2-(3-methylbut-2-enyl)oxirane-2-carbonitrile (34). 34
(0.106 g, 0.220 mmol, 69%) was synthesized in analogous man-
ner to ent-34 starting from 19 (0.157 g, 0.320 mmol). The NMR
data are identical to the ones reported for ent-34. HRMS (ESI)
m/z calcd. for C24H37BrNO2Si: (M+H)+, 478.1771; found:
478.1768 (M+H)+; Rf (n-heptane/ethyl acetate 10:1): 0.52; Spe-
cific rotation [훼]2퐷3.1 = – 11.0 (c = 1.18; CHCl3).
(1aS,7R,7aS)-1a-(3-Methylbut-2-enyl)-7-triisopropylsi-
lyloxy-7,7a-dihydronaphtho[2,3-b]oxiren-2-one (22). See
aforementioned synthetic procedure for 22 (conditions 2).
(1aS,7R,7aS)-7-Hydroxy-1a-(3-methylbut-2-enyl)-7,7a-di-
hydronaphtho[2,3-b]oxiren-2-one (23). See aforementioned
synthetic procedure for 23.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for a Mitsunobu inversion.
Alcohol 13 (0.206 g, 0.370 mmol, 1.00 eq.) was dissolved in
anhydrous THF (8 mL). PPh3 (0.143 g, 0.550 mmol, 1.50 eq.)
and HOAc (0.063 mL, 1.09 mmol, 3.00 eq.) were added. Then
DIAD (0.107 mL, 0.550 mmol, 1.50 eq.) was added at 0 °C. The
reaction solution was allowed to stir at room temperature. Every
1-2 h were added further PPh3 (1.5 eq.), HOAc (3.00 eq.) and
DIAD (1.50 eq.) at 0 °C until the LC-MS showed a complete
conversion (n.b. reaction control by TLC is not possible because
the starting material and the product showed the same Rf value).
In total 6 eq. of DIAD had to be added for a complete conver-
sion. The reaction mixture was loaded on silica and was then
purified via flash column chromatography (0–20% ethyl acetate
in n-heptane) to give 29 (0.154 g, 0.25 mmol, 70%) as colorless
oil. All analytical data matched with the ones of 29 described in
the paragraph “Resynthesis of Avicennone C”.
[(S)-(2-Bromophenyl)-[(2S,3R)-3-[[tert-butyl(diphenyl)si-
lyl]oxymethyl]-3-(3-methylbut-2-enyl)oxiran-2-yl]methyl]
acetate (25). The Mitsunobu reaction of 14 (0.166 g, 0.290
mmol, 1.00 eq.) resulted in a mixture of 25 (0.020 g, 0.030
mmol, 11%), 29 (0.026 g, 0.040 mmol, 15%) and side products
SI5 (0.051 g, 0.080 mmol, 26%) as well as SI6 (0.028 g, 0.090
mmol, 32%). For both side products (SI5 and SI6) NMR spectra
indicated formation of only one specific diastereomer each.
However, from analysis of the 2D NMR data it was not possible
to unambiguously determine the stereochemistry. For analytical
data of 29 see aforementioned synthetic procedure of 29. The
NMR data of 25 are identical to the ones reported for ent-25.
HRMS (ESI) m/z calcd. for C33H40BrO4Si: (M+H)+, 607.1874;
found: 607.1879 (M+H)+; Rf (n-heptane/ethyl acetate 4:1):
0.40; Specific rotation [훼]2퐷4.7 = – 8.7 (c = 0.97; CHCl3).
Resynthesis of Avicennone C under improved conditions.
[(R)-(2-Bromophenyl)-[(2S,3R)-3-[[tert-butyl(diphenyl)si-
lyl]oxymethyl]-3-(3-methylbut-2-enyl)oxiran-2-yl]methyl]
acetate (29). 29 (0.210 g, 0.350 mmol, 97%) was synthesized
in analogous manner to ent-29 starting from 14 (0.201 g,
0.360 mmol). The NMR data are identical to the ones reported
for ent-29. HRMS (ESI) m/z calcd. for C33H40BrO4Si: (M+H)+,
607.1874; found: 607.1880 (M+H)+; Rf (n-heptane/ethyl ace-
tate 4:1): 0.37; Specific rotation [훼]2퐷2.3 = + 6.7 (c = 0.91;
CHCl3).
[(1aS,7S,7aS)-1a-(3-methylbut-2-enyl)-2-oxo-7,7a-dihy-
dronaphtho[2,3-b]oxiren-7-yl] acetate (35). Alcohol 23
(0.044 g, 0.180 mmol, 1.00 eq.) was dissolved in anhydrous
THF (10 mL). PPh3 (0.142 g, 0.540 mmol, 3.00 eq.) and HOAc
(0.062 mL, 1.09 mmol, 6.00 eq.) were added. Then DIAD
(0.107 mL, 0.54 mmol, 3.00 eq.) was added at 0 °C. The reac-
tion solution was allowed to stir at room temperature. The TLC
showed a complete conversion after 1 h reaction time. The re-
action mixture was loaded on silica and purified via flash col-
umn chromatography (0–40% ethyl acetate in n-heptane) to
1
give 35 (0.046 g, 0.16 mmol, 90%) as colorless oil. H-NMR
(CDCl3, 400 MHz): 7.96 (dd, 1H, J = 7.8, 1.2 Hz, aryl-H), 7.61
(td, 1H, J = 7.6, 1.3 Hz, aryl-H), 7.45 (m, 1H, aryl-H), 7.30 (d,
1H, J = 7.8 Hz, aryl-H), 6.34 (s, 1H, CH-OAc), 5.09 (m, 1H,
Me2C=CH,), 3.87 (d, 1H, J = 2.0 Hz, epoxy-CH), 2.95 (dd, 1H,
J = 15.5, 7.9 Hz, Me2C=CH-CH2), 2.64 (dd, 1H, J = 15.5, 6.8
Hz, Me2C=CH-CH2), 2.33 (s, 3H, CO-CH3), 1.73 (s, 3H, E-
CH3), 1.68 (s, 3H, Z-CH3); 13C-NMR (CDCl3, 100 MHz): 193.6
(C=O), 171.1 (CO-CH3), 136.7 (CqMe2), 135.7 (Cq-CHOAc),
134.1 (Ar-CH), 129.7 (epoxy-Cq-CO-Cq), 128.9 (Ar-CH), 127.9
(Ar-CH), 126.3 (Ar-CH), 116.3 (CH=CMe2), 67.8 (CH-OAc),
61.4 (epoxy-Cq), 56.2 (epoxy-CH), 26.5 (Me2C=CH-CH2), 26.0
(E-CH3), 21.2 (CO-CH3), 18.2 (Z-CH3); HRMS (ESI) m/z
calcd. for C17H19O4: (M+H)+, 287.1278; found: 287.1276
(M+H)+; Rf (n-heptane/ethyl acetate 2:1): 0.48; Specific rota-
tion [훼]2퐷3.6 = – 244.5 (c = 1.82; CHCl3).
(1aS,7S,7aS)-7-Hydroxy-1a-(3-methylbut-2-enyl)-7,7a-di-
hydronaphtho[2,3-b]oxiren-2-one (4). To a solution of 35
(0.046 g, 0.160 mmol, 1.00 eq.) in THF/H2O (5:1, 6.0 mL/1.2
mL) LiOH · H2O (0.014 g, 0.32 mmol, 2.00 eq.) was added. The
TLC showed a complete conversion after 1.5 h reaction time.
[(2R,3S)-3-[(R)-(2-Bromophenyl)-hydroxy-methyl]-2-(3-
methylbut-2-enyl)oxiran-2-yl]methyl acetate (31). 31 (0.185
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Saturated aqueous NaHCO3 (20 mL) was added. The mixture extracted with ethyl acetate (2 x 30 mL) and the combined or-
1
2
3
4
5
6
7
8
was extracted with ethyl acetate (2 x 30 mL) and the combined
organic layers were washed with saturated aqueous NaCl (20
mL), dried over MgSO4, filtered, and concentrated under re-
duced pressure. The crude product was purified by flash column
chromatography (0–30% ethyl acetate in n-heptane) to give 4
(0.036 g, 0.150 mmol, 90%) as a colorless solid. For analytical
data see aforementioned synthetic procedure of 4.
ganic layers were washed with saturated aqueous NaCl (20
mL), dried over MgSO4, filtered, and concentrated under re-
duced pressure. The crude product was purified by flash column
chromatography (0–50% ethyl acetate in n-heptane) to give 23
(0.024 g, 0.100 mmol, 93%) as a colorless oil. For analytical
data see aforementioned synthetic procedure of 23.
[(1aS,7R,7aS)-1a-(3-methylbut-2-enyl)-2-oxo-7,7a-dihy-
dronaphtho[2,3-b]oxiren-7-yl] acetate (36). Alcohol
ASSOCIATED CONTENT
Supporting Information
4
9
(0.036 g, 0.150 mmol, 1.00 eq.) was dissolved in anhydrous
THF (8 mL). PPh3 (0.115 g, 0.440 mmol, 3.00 eq.) and HOAc
(0.050 mL, 0.880 mmol, 6.00 eq.) were added. Then DIAD
(0.086 mL, 0.440 mmol, 3.00 eq.) was added at 0 °C. The reac-
tion solution was allowed to stir at room temperature. Since
TLC showed incomplete conversion after 2 h, the addition of
the same portions of the reagents was repeated three times after
1 h each and one time the next day. 1 h after the last addition of
reagents, the reaction mixture was loaded on silica and purified
via flash column chromatography (0–50% ethyl acetate in n-
heptane) to give 36 (0.031 g, 0.110 mmol, 73%) as colorless oil
and recovered starting material 4 (0.006 g, 0.020 mmol, 16%)
as colorless solid.31 1H-NMR (CDCl3, 400 MHz): 7.95 (dd, 1H,
J = 7.7, 1.2 Hz, aryl-H), 7.59 (td, 1H, J = 7.5, 1.5 Hz, aryl-H),
7.50 (dt, 1H, J = 7.6, 1.2 Hz, aryl-H), 7.46 (d, br, 1H, J = 7.6
Hz, aryl-H), 6.46 (d, 1H, J = 2.4 Hz, CH-OAc), 5.12 (m, 1H,
Me2C=CH,), 3.75 (d, 1H, J = 2.4 Hz, epoxy-CH), 2.91 (dd, 1H,
J = 15.5, 7.7 Hz, Me2C=CH-CH2), 2.70 (dd, 1H, J = 15.5, 6.8
Hz, Me2C=CH-CH2), 2.05 (s, 3H, CO-CH3), 1.73 (s, 3H, E-
CH3), 1.68 (s, 3H, Z-CH3); 13C-NMR (CDCl3, 100 MHz): 194.3
(C=O), 170.2 (CO-CH3), 136.4 (CqMe2), 135.5 (Cq-CHOAc),
134.1 (Ar-CH), 131.0 (epoxy-Cq-CO-Cq), 130.6 (Ar-CH), 130.1
(Ar-CH), 127.6 (Ar-CH), 116.5 (CH=CMe2), 67.8 (CH-OAc),
60.4 (epoxy-Cq), 57.1 (epoxy-CH), 26.4 (Me2C=CH-CH2), 26.0
(E-CH3), 21.1 (CO-CH3), 18.1 (Z-CH3); HRMS (ESI) m/z
calcd. for C17H19O4: (M+H)+, 287.1278; found: 287.1280
(M+H)+; Rf (n-heptane/ethyl acetate 2:1): 0.53; Specific rota-
tion [훼]2퐷2.8 = – 239.3 (c = 1.00; CHCl3).
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The Supporting Information is available free of charge on the ACS
Publications website at http://pubs.acs.org. Detailed experimental
procedures including spectroscopic data and crystallographic data
as well as determination of enantiomeric excess (PDF).
AUTHOR INFORMATION
Corresponding Author
* Email: christoph.poeverlein@sanofi.com;
soeren.schuler@evotec.com
ORCID
Christoph Pöverlein: 0000-0003-1264-181X
Sören M. M. Schuler: 0000-0003-1089-88737
ACKNOWLEDGMENT
This study was financially supported by the Hessen State Ministry
of Higher Education, Research, and the Arts (HMWK) via gener-
ous grand for the LOEWE Research Center Insect Biotechnology
and Bioresources. Sanofi and Evotec International contributed in
the framework of Sanofi-Fraunhofer Natural Product Center of Ex-
cellence/Fraunhofer Evotec Natural Products Excellence Center.
We thank Prof. Dr. Andreas Vilcinskas for general support, Prof.
Dr. Till Schäberle, Dr. Michael Kurz, Dr. Cédric Couturier, Dr.
Frédéric Jeannot, and Dr. Eric Bacqué for valuable discussions, the
NMR department of the Justus Liebig University Giessen, Stefan
Bernhardt for chiral HPLC analysis, and Christoph Hartwig for
technical assistance.
(1aS,7R,7aS)-7-Hydroxy-1a-(3-methylbut-2-enyl)-7,7a-di-
hydronaphtho[2,3-b]oxiren-2-one (23). To a solution of 36
(0.031 g, 0.110 mmol, 1.00 eq.) in THF/H2O (5:1, 4.0 mL/0.8
mL) LiOH · H2O (0.009 g, 0.21 mmol, 2.00 eq.) was added. The
TLC showed a complete conversion after 1 h reaction time. Sat-
urated aqueous NaHCO3 (20 mL) was added. The mixture was
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23 Thermal ellipsoid plot of the molecular structure of ent-32 see Sup-
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12
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27 Vatéte, J.-M. One-Pot Oxidative Conversion of Alcohols into Nitriles
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action for the Preparation of Functionalized Aryl- and Heteroaryl Mag-
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28 For detailed product ratios and structure elucidation see Supporting
Information.
29 Love, B. E.; Jones, E. G. The Use of Salicylaldehyde Phenylhydra-
zone as an Indicator for the Titration of Organometallic Reagents. J.
Org. Chem. 1999, 64, 3755–3756.
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of Terreumols A and C from the Mushroom Tricholoma terreum. An-
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30 A 2.5 M solution of n-BuLi in hexane from a commercially supplier
was diluted by a factor of four at −78 °C with anhydrous THF for a
better handling. For the −100 °C cooling bath a mixture of ethanol and
liquid N2 was used.
15 Isolated yields and characterization of the diols see Supporting Infor-
mation.
16
Products 21 and 22 were contaminated with approx. 16–20% insep-
31
arable isomerization side products, which were characterized after
deprotection to 4 and 23 (see experimental section).
No traces of diastereomer 35 were detected, which indicates a full
inversion of stereochemistry. The reaction time of the Mitsunobu in-
version of 4 to 36 was significantly slower than the conversion of 23 to
35 and required more reagents. After 24 h the reaction was stopped
even though traces of starting material were detected via TLC.
17 Examples for formation of different ring sizes: (a) Paul, S.; Samanta,
S.; Ray, J. K. Palladium-Catalyzed One-Pot Suzuki Coupling Followed
by Arylpalladium Addition to Aldehyde: A Convenient Route to Flu-
oren-9-one Derivatives. Tetrahedron Lett. 2010, 51, 5604–5608. (b)
Flores-Gaspar, A.; Gutiérrez-Bonet, Á.; Martin, R. N-Heterocyclic
Carbene Dichotomy in Pd-Catalyzed Acylation of Aryl Chlorides via
C-H Bond Functionalization. Org. Lett. 2012, 14, 5234–5237. (c) Ál-
15
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