Studies towards the enantioselective synthesis of an advanced intermediate of elisabethin A

Article abstract of DOI:10.1007/s00706-016-1858-8

Abstract: A nine-step sequence towards a chiral intermediate of elisabethin A starting from a literature known orthoester is reported. Enantioselective α-alkylation of pseudoephedrine amide applying Myers’ protocol was seen as key step of the synthesis. G

Full text of DOI:10.1007/s00706-016-1858-8

Monatsh Chem
DOI 10.1007/s00706-016-1858-8
ORIGINAL PAPER
Studies towards the enantioselective synthesis of an advanced
intermediate of elisabethin A
1
Maximilian Kaiser1 Peter Gartner Valentin S. Enev1
•
•
¨
Received: 9 August 2016 / Accepted: 10 October 2016
Ó Springer-Verlag Wien 2016
Abstract A nine-step sequence towards a chiral interme-
diate of elisabethin A starting from a literature known
orthoester is reported. Enantioselective a-alkylation of
pseudoephedrine amide applying Myers’ protocol was seen
as key step of the synthesis.
system, a fully substituted enedione functionality, and six
contiguous stereocenters. Single-crystal X-ray diffraction
allowed the clarification of the relative but not the absolute
configuration.
The challenging framework, as well as the possible
biological activity, has attracted synthetic chemists around
the world. The first attempt was reported in 2003 by Mulzer
Graphical abstract
and co-workers, who most probably synthesized
a
stereoisomer of elisabethin A [3]. In the same year, Rawal
and co-workers aimed to synthesise (ent)- elisabethin A,
but did not succeed due to an unsuccessful epimerization
[4]. The last attempt was again reported by the Mulzer
group in 2014, leaving this particular total synthesis an
open chapter [5].
Keywords Michael addition Á Lactone formation Á
a-Alkylation Á Chiral auxiliary
Results and discussion
Introduction
Our retrosynthetic analysis of elisabethin A (1) is outlined
in Scheme 1. We planned to construct compound 1 via
intramolecular Friedel–Crafts reaction of bicyclic com-
pound 2 [6]. Therefore, aromatic aldehyde 3 represents a
useful precursor, which, on the other hand, could be pre-
pared via ring-closing metathesis and minor functional
group manipulations from diene 4 [7]. Introduction of the
C2 chain should be achieved by a Mitsunobu reaction/
Claisen rearrangement sequence of compound 5, whereat
the chiral center on C6 (elisabethin numbering) could be
installed via enantioselective a-alkylation of pseu-
doephedrine amide 6 [8–10]. Literature known orthoester 7
[11] represents a suitable precursor for the desired amide.
Our synthesis commenced with conversion of orthoester
7 to methyl ester 8 followed by acid catalyzed cyclisation
to give lactone 9 in 95% yield over two steps (Scheme 2)
[10]. Protection of 9 (TBS-Cl/imidazole) and subsequent
Elisabethin A (1) was isolated from Pseudopterogorgia
elisabethae, a Caribbean Sea whip of the genus Pseu-
dopterogorgia [1]. Pseudoterosins originating from
specimens of the before mentioned animal found in the
same marine area possess anti-inflammatory and analgesic
beneficial properties [2].
The structure was elucidated by 1D and 2D NMR
studies, as well as HRMS, UV, and IR. Elisabethin A was
eponymous for the novel carbon skeleton elisabethane,
which consists of a tricyclic cis–trans-fused 5,6,6 ring
& Valentin S. Enev
valentin.enev@tuwien.ac.at
1
Institute of Applied Synthetic Chemistry, Vienna University
of Technology, Vienna, Austria
123

M. Kaiser et al.
Scheme 1
hydrolysis of lactone 10 gave acid 11 in excellent yield. In
the next step, phenol and acid functionality in 11 were
simultaneously protected (TIPS-Cl and Hu¨nig’s base) and
the resulting crude mixture was hydrolyzed with K2CO3 to
give acid 12 in 76% yield over two steps [12].
patterns of the geminal protons at C5. For (S,S) isomer 17a,
the methylene protons, each appears as a doublet of dou-
blets at 4.52 and 4.42 ppm (Dd ca. 0.11 ppm); while for the
(R,S)-isomer 17b, the same protons are much closer (Dd ca.
0.01 ppm) to each other.
Following the Myers’ protocol [8], acid 12 was con-
verted into the corresponding pseudoephedrine amide 13
which was subjected to enantioselective a-alkylation
(LDA, dry LiCl, and BOM-Br) to give 14 in 46% yield.
Cleavage of the pseudoephedrine auxiliary to obtain chiral
alcohol 15 was accomplished using in situ generated
LiNH2BH3 (from NH3-BH3 complex and LDA) [13]. The
enantiomeric excess of the resulted alcohol 15 was deter-
mined via the NMR studies of the corresponding Mosher
esters as well as chiral HPLC.
Conclusion
In conclusion, a highly enantioselective nine-step synthesis
of a key intermediate towards the total synthesis of elisa-
bethin A is reported.
Experimental
Accordingly, orthoester 7 was elaborated into racemic
alcohol (rac)- 15 in five steps with an overall yield of 66%
(Scheme 3). Both (rac)-15 and 15 were then converted to
the corresponding (S)-Mosher esters 17a ? 17b and 17a
(Scheme 3).
1H and 13C NMR spectra were recorded on a Bruker AC
200 at 200 and 50 MHz or on a Bruker AC 400 at 400 and
100 MHz, using the solvent peak as reference. 13C NMR
spectra were run in proton-decoupled mode. Multiplicities
Based on 1H and 19F NMR (Fig. 1) analysis of the
crude mixture 17a ? 17b and crude 17a, the ee was
estimated to be [98% which was confirmed by chiral
HPLC (Fig. 2). Finally, the expected (R) configuration of
C6 was confirmed by the Yasuhara method which relies
on a different split pattern of the methylene attached to
of H signals were referred to as s (singlet), d (doublet), t
1
(triplet), q (quartet), quin (quintet), sext (sextet), sept
(septet), and m (multiplet). IR spectra were recorded on a
Perkin Elmer Spectrum 65 FT IR Spectrometer equipped
with a MK II Golden Gate Single Reflection ATR unit. The
TLC analysis was done with precoated aluminium-backed
plates (Silica gel 60 F254, Merck). Compounds were
visualized by submerging in an acidic phosphomolybdic
acid/cerium sulfate solution and heating. Column chro-
matography was carried out with silica gel Merck 60.
1
the ester linkage in the MTPA derivatives in the H NMR
[14, 15].
Hence, the absolute configuration at C6 was proved to
be R on the basis of chemical shift differences and signal
123

Studies towards the enantioselective synthesis of an advanced intermediate of elisabethin A
Scheme 2
(a) MeOH/H2O (4:1) reflux, 4 h; (b) p-TsOH cat., 4 Å molecular sieve, toluene, reflux
3 h; (c) TBS-Cl, imidazole, DMF, 35 °C, 4 h; (d) LiOH cat., DMF/H2O (1:1), 2 h; (e)
TIPS-Cl, Hünig’s base, DMF, 16 h; (f) K2CO3, MeOH, 1 h; (g) oxalyl chloride, DMF
cat., benzene, (1R,2R)-(-)-pseudoephedrine, Et3N, THF; (h) LDA, BOM-Br, LiCl, THF;
(i) LDA, NH3-BH3, THF
Specific rotations were measured on an Anton Parr MCP
500 polarimeter at 20 °C and 589 nm. Chiral HPLC mea-
surements were conducted on a DAICEL CHIRALPAK IB
(250 9 4.60 mm, 5 l) as stationary phase and a 99.5:0.5
mixture of n-heptane/i-PrOH as solvent. Flow rate was
0.7 cm3/min.
HPLC grade, respectively, and refluxed over sodium, and
freshly distilled. Dry DMF and DMSO were used as
purchased.
Methyl 2-(2,5-dihydroxy-4-methoxy-3-methylphenyl)
acetate (8)
Orthoester 7 (3.38 g, 14 mmol, 1.0 equiv) was dissolved in
a mixture of MeOH/H2O (80:20, 125 cm3) and heated
under reflux for 4 h. Subsequently, the solvents were
evaporated in vacuo to give quantitative yield. Spectro-
scopic data were identical to that reported in the literature
[11].
All reagents were purchased from commercial sources
except for [(bromomethoxy)methyl]benzene (BOM-Br),
which was prepared according to literature [16]. The sol-
vents used were purified and dried according to common
procedures as follows. Dry methylene chloride and diethyl
ether were retrieved from an Innovative Technologies
PureSolv system. Dry tetrahydrofuran was pre-dried using
an Innovative Technologies PureSolv system, refluxed over
sodium/benzophenone, and freshly distilled. Dry toluene,
n-hexane, ethyl acetate, and acetonitrile were p.a. and
5-Hydroxy-6-methoxy-7-methylbenzofuran-2(3H)-one
(9, C10H10O4)
Hydroquinone 8 (3.18 g, 14 mmol, 1 equiv) was taken up
in 40 cm3 toluene and para-toluenesulfonic acid (catalytic
123

M. Kaiser et al.
Scheme 3
(a) TBS-Cl, imidazole, DMF; (b) MeOH/H2O (4:1) reflux, 4 h; (c) TIPS-Cl, DIPEA,
DMF; (d) LDA, BOM-Br, THF; e) LiAlH4, THF; f) DCC, DMAP, (S)-Mosher’s acid
amount) was added. The mixture was placed in a round
bottom flask equipped with a Soxhlet extractor filled with
molecular sieve. The reaction was heated to reflux for 3 h.
After TLC confirmed full conversion, the reaction was
quenched by addition of NaHCO3 and washed with
saturated NaHCO3 solution. The organic layer was dried
over Na2SO4 before the solvent was removed in vacuo,
yielding 2.46 g (90%) of product. 1H NMR (400 MHz,
CDCl3): d = 6.66 (1H, s), 5.61 (1H, s), 3.73 (3H, s), 3.60
(2H, s), 2.18 (3H, s) ppm; 13C NMR (100 MHz, CDCl3):
d = 174.7, 146.9, 145.7, 145.4, 118.1, 115.1, 108.7, 61.2,
33.7, 9.5 ppm; IR: vꢀ = 3441, 3007, 2959, 2928, 2837,
1796, 1736, 1634, 1610, 1464, 1447, 1426, 1387, 1363,
1323, 1262, 1237, 1212, 1190, 1140, 1074, 1007, 984, 946,
892, 870, 826, 771, 694, 669, 652, 587, 570, 552,
528 cm-1; and Rf = 0.18 (PE/EA: 2:1).
(0.7 cm3 of 0.1 M solution in DMF, 0.46 mmol, 0.45
equiv) was added and the mixture was stirred overnight.
The reaction mixture was quenched by addition of
saturated NaHCO3 solution and toluene. The aqueous layer
was extracted with Et2O, the combined organic layers were
washed with H2O and dried over Na2SO4, and the solvent
was evaporated in vacuo to yield 311 mg (98%) of desired
1
product. H NMR (400 MHz, CDCl3): d = 6.63 (1H, s),
3.74 (3H, s), 3.66 (2H, s), 2.21 (3H, s), 1.00 (9H, s), 0.16
(6H, s) ppm; 13C NMR (100 MHz, CDCl3): d = 174.8,
150.0, 148.0, 145.6, 117.3, 116.4, 114.3, 60.3, 33.8, 25.8,
18.3, 9.4, -4.6 ppm; IR: vꢀ = 2955, 2929, 2885, 2857,
1804, 1792, 1626, 1606, 1470, 1454, 1417, 1389, 1356,
1280, 1247, 1234, 1201, 1177, 1140, 1086, 1063, 1007,
944, 902 cm-1; HRMS (ESI): m/z calcd. for C16H25O4Si
([M ? H]?) 309.1522, found 309.1515; and Rf = 0.71
(toluene/EA 20:1).
5-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-7-methylbenzo-
furan-2(3H)-one (10, C16H24O4Si)
2-[5-[(tert-Butyldimethylsilyl)oxy]-2-hydroxy-4-methoxy-
3-methylphenyl]acetic acid (11, C16H26O5Si)
A Schlenk flask was charged with 200 mg lactone 9
(1.03 mmol, 1.0 equiv) and 208 mg imidazole (3.06 mmol,
3.0 equiv), and the solids were dissolved in 1.0 cm3 dry
DMF. TBS-Cl (1.86 cm3 of 0.1 M solution in DMF,
1.2 mmol, 1.2 equiv) was added and the mixture was
stirred for 4 h at 35 °C. Another portion of TBS-Cl
A round bottom flask was charged with 202 mg TBS-
protected lactone 10 (0.65 mmol, 1.0 equiv) and dissolved
in a 1:1 mixture of DMF/H2O (6 cm3). Several crystals of
LiOH were added to the reaction mixture and it was stirred
for 2 h. The reaction was quenched by addition of NH4Cl.
123

Studies towards the enantioselective synthesis of an advanced intermediate of elisabethin A
Fig. 1 19F NMR spectra of Mosher ester of crude 17a and 17b, and crude 17a
Fig. 2 Chiral HPLC of (rac)-15 and 15
DMF and H2O were evaporated in vacuo and the residue
was dissolved in ethyl acetate and washed with H2O. The
aqueous layer was extracted with ethyl acetate and the
combined organic layers were dried over Na2SO4 and the
solvent was removed in vacuo. The crude product without
further purification was used for the next step. A yield of
123

M. Kaiser et al.
98% according to NMR was achieved. 1H NMR
(400 MHz, CDCl3): d = 6.49 (1H, s), 3.72 (3H, s), 3.58
(2H, s), 2.17 (3H, s), 1.00 (9H, s), 0.15 (6H, s) ppm.
solution over 20 min. The solution was allowed to warm to
r.t. and stirred overnight. The reaction was quenched by the
addition of H2O, the aqueous layer was extracted with ethyl
acetate, the combined organic layers were washed with
brine and dried over Na2SO4, and the solvent was
evaporated in vacuo. Purification was achieved by column
chromatography (PE/EA 15:1) yielding 404 mg (67%) of
2-[5-[(tert-Butyldimethylsilyl)oxy]-4-methoxy-3-methyl-2-
[(triisopropylsilyl)oxy]phenyl]acetic acid
(12, C25H46O5Si2)
A Schlenk flask was charged with 359 mg crude acid 11
(1.1 mmol, 1.0 equiv), 0.75 cm3 Hu¨nig’s base (4.4 mmol,
4.0 equiv), and 5.0 cm3 dry DMF. Subsequently, 0.47 cm3
TIPS-Cl (2.2 mmol, 2.0 equiv) was added and the reaction
mixture was stirred overnight. The reaction was quenched
by the addition of saturated NaHCO3 solution and toluene.
Layers were separated and the organic layer was washed
with H2O, dried over Na2SO4 and afterwards concentrated
in vacuo. The residue was dissolved in 30 cm3 MeOH and
276 mg K2CO3 (2.0 mmol, 2.0 equiv) was added. After
1 h, the reaction was quenched by the addition of solid
NH4Cl, the solvent was evaporated under reduced pressure,
and the residue was taken up in ethyl acetate and washed
with H2O. The organic layer was dried over Na2SO4 and
the solvent was removed in vacuo to yield 404 mg (76%
over 2 steps). 1H NMR (400 MHz, CDCl3): d = 9.75 (1H,
broad s), 6.46 (1H, s), 3.58 (3H, s), 3.46 (2H, s), 2.03 (3H,
s), 1.08–1.19 (3H, m), 0.94 (18H, d, J = 7.5 Hz), 0.85 (9H,
s), 0.00 (6H, s) ppm; 13C NMR (100 MHz, CDCl3):
d = 177.9, 149.4, 147.9, 142.8, 123.1, 120.0, 119.1, 59.9,
35.8, 25.9, 18.4, 18.1, 14.4, 11.4, -4.6 ppm; IR: vꢀ = 2947,
2927, 2867, 1734, 1709, 1481, 1433, 1390, 1347, 1248,
1220, 1127, 1097, 1058, 1014, 915, 883, 836, 799, 780,
732, 680, 650, 617, 577, 560, 528, 511, 502 cm-1; HRMS
(ESI): m/z calcd. for C25H47O5Si2 ([M ? H]?) 483.2962,
found 483.2957; and Rf = 0.15 (DCM/MeOH 95:5).
1
yellow solid. H NMR (400 MHz, CDCl3; 5.5:4.5 rotamer
ratio, asterisk denotes minor rotamer signal): d = 7.27–
7.34 (5H, m), 6.67* (1H, s), 6.57 (1H, s), 4.57–4.63 (1H,
m), 4.27–4.41 (2H, m), 3.71 (3H, s), 3.66* (3H, s), 3.60
(2H, s), 2.88* (3H, s), 2.65 (3H, s), 2.23* (3H, s), 2.16 (3H,
s), 1.21–1.32 (3H, m), 1.06–1.12 (18H, m), 0.98 (9H, s),
0.96* (9H, s) ppm; 13C NMR (100 MHz, CDCl3; asterisk
denotes minor rotamer signal): d = 174.2, 173.1*, 147.2,
146.5*, 143.7*, 143.2, 142.5, 141.2*, 128.8*, 128.5,
128.4*, 127.8, 127.2*, 126.6, 123.7*, 123.0, 121.2*,
120.2, 118.0, 117.7*, 76.7, 75.4*, 60.0, 59.9*, 58.4, 37.0,
36.6*, 26.6, 25.9, 24.0, 18.1, 18.0* 18.4, 15.2*, 14.4, 14.3,
14.2*, 11.4, -4.5, -4.6* ppm; IR: vꢀ = 3368, 2930, 2867,
1622, 1480, 1431, 1344, 1298, 1235, 1123, 1057, 1014,
917, 883, 837, 805, 781, 731, 700, 681, 649, 620, 587,
541 cm-1; HRMS (ESI): m/z calcd. for C35H60NO5Si2
([M ? H]?) 630.4010, found 630.4005; [a]2D0 = -28.20
(c = 0.30, CH2Cl2); and Rf = 0.61 (PE/EA 2:1).
(S)-3-(Benzyloxy)-2-[5-[(tert-butyldimethylsilyl)oxy]-4-
methoxy-3-methyl-2-[(triisopropylsilyl)oxy]phenyl]-N-
[(1R,2R)-1-hydroxy-1-phenylpropan-2-yl]-N-methyl-
propanamide (14, C43H67NO6Si2)
LiCl (62 mg, 1.47 mmol, 7.0 equiv) was placed in a
Schlenk flask, 1.1 cm3 LDA (0.5 M stock solution,
0.53 mmol, 2.5 equiv) was added, and the resulting
suspension was cooled to -78 °C. Amide 13 (130 mg,
0.21 mmol, 1.0 equiv) was dissolved in 0.4 cm3 THF and
added in two portions via syringe. After 2 h, 0.22 cm3
BOM-Br (1.42 mmol, 3.0 eq) was added via syringe. The
reaction mixture was allowed to warm to r.t. overnight and
was quenched using saturated NH4Cl. Purification was
achieved by column chromatography (toluene/CH3CN
25:1) yielding 72 mg (46%) of pure product. 1H NMR
(400 MHz, CDCl3): d = 7.09–7.29 (10H, m), 6.63 (1H, s),
3.89–4.67 (7H, m), 3.64 (3H, s), 2.55 (3H, s), 2.08 (3H, s),
0.95–1.24 (24H, m), 0.91 (9H, s), 0.08 (6H, d, J = 2.4 Hz)
ppm; 13C NMR (100 MHz, CDCl3): d = 174.9, 149.4,
146.5, 143.3, 142.5, 138.7, 128.4, 128.3, 128.1, 127.6,
127.5, 126.7, 122.7, 121.2, 117.2, 76.7, 73.6, 71.7, 59.9,
43.3, 29.8, 25.9, 18.7, 18.5, 18.4, 14.5, 14.0, 11.8, -4.4,
-4.5 ppm; IR: vꢀ = 2962, 2928, 2867, 1740, 1625, 1472,
1430, 1411, 1361, 1259, 1060, 1016, 921, 882, 838, 799,
735, 699, 683, 570, 561, 550, 540, 529, 520, 516, 509, 506,
502 cm-1; HRMS (ESI): m/z calcd. for C43H68NO6Si2
2-[5-[(tert-Butyldimethylsilyl)oxy]-4-methoxy-3-methyl-2-
[(triisopropylsilyl)oxy]phenyl]-N-[(1R,2R)-1-hydroxy-1-
phenylpropan-2-yl]-N-methylacetamide
(13, C35H59NO5Si2)
Acid 12 (521 mg, 1.08 mmol, 1.0 equiv) was dissolved in
12 cm3 benzene, and the solution was cooled to 5 °C and
0.12 cm3 oxalyl chloride (1.40 mmol, 1.3 equiv) was
added, accompanied by slight gas formation. After stirring
for 10 min, the addition of DMF (1 drop) was followed by
vigorous gas formation. The reaction mixture was stirred
for another 10 min at 5 °C, was then allowed to warm to
r.t., and stirred for one additional hour. Subsequently, the
excess of oxalyl chloride was removed via azeotropic
distillation in vacuo to give acyl chloride. (1R,2R)-(-)-
Pseudoephedrine (158 mg, 0.94 mmol, 1.0 equiv) and
0.17 cm3 Et3N (1.22 mmol, 1.3 equiv) were placed in a
Schlenk flask, dissolved in 6 cm3 THF and cooled to 0 °C.
The freshly prepared acyl chloride was dissolved in 10 cm3
THF and added via syringe to the pseudoephedrine/Et3N
123

Studies towards the enantioselective synthesis of an advanced intermediate of elisabethin A
([M ? H]?) 750.4585, found 750.4580; [a]2D0 = -68.786
(c = 0.70, CH2Cl2); and Rf = 0.67 (PE/EA 2:1).
s), 3.38 (6H, s), 3.15 (2H, s), 2.11 (3H, s), 1.01 (9H, s), 0.15
(6H, s) ppm; 13C NMR (100 MHz, CD2Cl2): d = 150.6,
149.9, 143.5, 125.7, 119.3, 114.7, 60.5, 50.7, 37.9, 26.1,
18.7, 9.5, -4.4 ppm; IR: vꢀ = 2930, 2858, 1611, 1472,
1458, 1390, 1359, 1287, 1252, 1233, 1203, 1118, 1087,
1060, 1023, 1003, 991, 951, 892, 832, 816, 780, 754, 739,
(R)-3-(Benzyloxy)-2-[5-[(tert-butyldimethylsilyl)oxy]-4-
methoxy-3-methyl-2-[(triisopropylsilyl)oxy]phenyl]-
propan-1-ol (15, C33H56O5Si2)
Amide 14 (18 mg, 0.024 mmol, 1.0 equiv) was dissolved
in 0.3 cm3 THF and placed in a flame dried microwave vial
under Ar atmosphere. LiH2NBH3 (0.5 cm3, 0.22 mmol/
cm3 in THF stock solution, 0.11 mmol, 4.6 equiv) was
added via syringe, the vial was closed, and the reaction
mixture was heated in an oil bath (T = 55 °C) overnight.
After TLC confirmed full conversion, the reaction was
cooled to 0 °C and HCl (1 M) was added over a period of
40 min to quench excess of hydride accompanied by gas
formation. The aqueous phase was extracted with Et2O and
the combined organic layers were washed with HCl (1 M)
and Na2CO3 (2 M) before being dried over Na2SO4 and
concentrated under reduced pressure. Purification via
column chromatography (PE/EA 20:1) gave 7 mg (42%)
product as colourless oil. HPLC: [98% ee Daicel Chiral-
pak AD-H, n-hexane/2-propanol = 99.5:0.5, v = 0.7 cm3
681, 577, 548, 518, 505 cm-1
.
Just prepared TBS-protected orthoester (270 mg,
0.76 mmol, 1.0 equiv) was dissolved in a mixture of
MeOH/H2O (80:20, 20 cm3) and heated under reflux for
4 h. Subsequent, the solvents were evaporated in vacuo to
give 238 mg (92%). 1H NMR (400 MHz, CDCl3):
d = 6.45 (1H, s), 3.74 (3H, s), 3.72 (3H, s), 3.56 (2H, s),
2.19 (3H, s), 1.00 (9H, s), 0.15 (6H, s) ppm; 13C NMR
(100 MHz, CDCl3): d = 174.5, 149.6, 147.9, 142.4, 121.1,
119.7, 115.5, 59.9, 52.7, 37.6, 25.7, 18.2, 9.4 ppm; IR:
vꢀ = 3348, 2955, 2930, 2858, 1708, 1606, 1483, 1439,
1389, 1329, 1249, 1165, 1121, 1057, 1006, 939, 880, 830,
815, 780, 748, 705, 670, 634, 548, 522, 510 cm-1; and
Rf = 0.73 (PE/EA: 3:1).
3-(Benzyloxy)-2-[5-[(tert-butyldimethylsilyl)oxy]-4-meth-
oxy-3-methyl-2-[(triisopropylsilyl)oxy]phenyl]propan-1-ol
((rac)-15, C33H56O5Si2)
min-1
, k = 254 nm, t (minor) = 9.83 min, t (ma-
jor) = 10.45 min; 1H NMR (400 MHz, CDCl3):
d = 7.28–7.37 (5H, m), 6.43 (1H, s), 4.56 (1H, d,
J = 12.1 Hz), 4.51 (1H, d, J = 12.1 Hz), 3.95 (1H, dd,
J = 10.9, 7.8 Hz), 3.72–3.81 (2H, m), 3.70 (3H, s), 3.64
(1H, t, J = 8.76 Hz), 3.53–3.60 (1H, m), 2.16 (3H, s),
1.24–1.36 (3H, m), 1.10 (18H, dd, J = 7.4, 1.6 Hz), 0.98
(9H, s), 0.11 (6H, s) ppm; 13C NMR (100 MHz, CDCl3):
d = 148.7, 147.6, 142.8, 138.1, 128.6, 127.9, 127.8, 124.9,
123.1, 116.8, 74.5, 73.7, 66.9, 59.9, 40.0, 25.9, 18.2, 18.1,
14.4, 11.5, -4.5 ppm; IR: vꢀ = 2929, 2866, 1481, 1431,
1362, 1250, 1220, 1063, 1015, 919, 883, 838, 782, 735,
681, 548, 525, 507 cm-1; HRMS (ESI): m/z calcd. for
C33H55O4Si2 ([M ? H-H2O]?) 571.3639, found 571.3633;
[a]2D5 = ? 2.275 (c = 0.40, CH2Cl2); and Rf = 0.67 (PE/
EA 2:1).
A
Schlenk flask charged with 877 mg phenol 16
(2.58 mmol, 1.0 equiv), dissolved in 8.5 cm3 dry DMF,
0.90 cm3 Hu¨nig’s base (5.15 mmol, 2.0 equiv) was added
and the reaction mixture was stirred for 5 min. Subse-
quently, 0.66 cm3 TIPS-Cl (1.20 mmol, 1.2 equiv) was
added and stirred overnight. The reaction mixture was
quenched by the addition of saturated NaHCO3 solution
and toluene. Layers were separated and the organic layer
was dried over Na2SO4 and afterwards concentrated in
vacuo. Purification was achieved by column chromatogra-
phy (toluene) to give 1.12 g (88%) of desired product as a
yellow oil. 1H NMR (400 MHz, CDCl3): d = 6.40 (1H, s),
3.74 (3H, s), 3.72 (3H, s), 3.56 (2H, s), 2.19 (3H, s), 1.32–
1.39 (3H, m) 1.05 (18H, s), 1.00 (9H, s), 0.14 (6H, s) ppm;
13C NMR (100 MHz, CDCl3): d = 174.5, 149.6, 147.9,
142.2, 121.1, 119.7, 115.5, 59.9, 52.7, 37.6, 25.7, 17.7,
12.3, 9.5, -4.6 ppm; IR: vꢀ = 2930, 2867, 1741, 1481,
1434, 1390, 1362, 1324, 1249, 1222, 1152, 1127, 1059,
1015, 917, 883, 837, 781, 746, 681, 652, 545, 528, 513,
cm-1; and Rf = 0.67 (toluene/EA: 20:1).
Methyl
2-[5-[(tert-butyldimethylsilyl)oxy]-2-hydroxy-4-
methoxy-3-methylphenyl]acetate (16, C17H28O5Si)
Orthoester 7 (200 mg, 0.83 mmol, 1.0 equiv), 170 mg
imidazole (2.5 mmol, 3.0 equiv), and 1.0 cm3 dry DMF
were placed in a Schlenk flask. Subsequently, 1.50 cm3
TBS-Cl (0.1 M solution in DMF, 1.2 mmol, 1.2 equiv) was
added and the reaction mixture was stirred overnight. The
next day, another portion of TBS-Cl (0.25 cm3 of 0.1 M
solution in DMF, 0.20 mmol, 0.20 equiv) was added, and
after 2 h, the reaction was quenched by addition of
saturated NaHCO3 solution and toluene. The aqueous layer
was extracted with Et2O, and the combined organic layers
were washed with H2O and dried over Na2SO4. Removal of
the solvent resulted in quantitative yield of desired product.
1H NMR (400 MHz, CD2Cl2): d = 6.53 (1H, s), 3.70 (3H,
A Schlenk flask charged with 35 mm3 freshly distilled
diisopropylamine (0.21 mmol, 1.3 equiv) was cooled to
-10 °C. Subsequently, 130 mm3 n-BuLi (1.6 M in hexane,
0.21 mmol, 1.3 equiv) was added, followed by 0.5 cm3
THF, and the mixture was cooled to -78 °C. Just prepared
ester (79 mg, 0.16 mmol, 1.0 equiv) dissolved in 1.5 cm3
THF was added and stirred for one hour. After addition of
28 mm3 BOM-Br (0.19 mmol, 1.2 equiv), the reaction
mixture was allowed to warm to room temperature
123

M. Kaiser et al.
overnight. TLC confirmed full conversion and the reaction
was quenched by addition of H2O. The aqueous layer was
extracted three times with ethyl acetate and the combined
organic layer was dried over Na2SO4. The product was
directly subjected to the next reaction without purification.
A Schlenk flask charged with 3 mg LiAlH4 (0.07 mmol,
1 equiv) and 1 cm3 THF was cooled to 0 °C. Just prepared
a-alkylated ester (45 mg, 0.07 mmol, 1 equiv) dissolved in
4 cm3 THF was added and the mixture was stirred for
30 min. After TLC confirmed full conversion, the reaction
was quenched by addition of Rochelle’s salt and stirred for
3 h. Then, layers were separated, the aqueous layer was
extracted with ethyl acetate twice, the combined organic
layer was dried over Na2SO4, and the solvent removed in
vacuo. Purification of crude material was achieved by
column chromatography (petroleum ether/ethyl acetate
15:1) giving (rac)-15 (72% over three steps). Spectroscopic
data were identical to primary chiral alcohol 15.
equiv), and 0.5 cm3 CH2Cl2. The turbid mixture was
cooled to 2 °C for 15 min before 10 mg (rac)-15
(0.017 mmol, 1 equiv) and DMAP (analytical amount)
dissolved in 1 cm3 CH2Cl2 were added. The reaction
mixture was stirred overnight and quenched with H2O the
next day. Layers were separated and the aqueous layer was
extracted with CH2Cl2 three times. The organic layer was
dried over Na2SO4 and concentrated in vacuo to give both
Mosher esters.
17b: 1H NMR (400 MHz, CDCl3): d = 7.23–7.46 (10H,
m), 6.64 (1H, s), 4.18 (2H, dd, J = 11.1, 5.3 Hz), 4.34 (1H,
d, J = 12.0 Hz), 4.28 (1H, d, J = 12.0 Hz), 3.70 (3H, s),
3.54–3.50 (3H, m), 3.31 (3H, s), 2.15 (3H, s), 1.18–1.34
(3H, m), 0.93 (18H, dd, J = 7.4, 2.3 Hz), 0.84 (9H, s),
-0.04 (6H, s) ppm; 19F NMR (376 MHz, CDCl3):
d = -71.64 ppm.
Acknowledgements This work is financially supported by the Aus-
trian Science Fund (FWF) (Project No P 25556-N28). We wish to
thank Ass. Prof. Dipl.-Ing. Dr.techn. Christian Hametner (Vienna
University of Technology) for performing the 2D NMR measurements.
(S)-3-(Benzyloxy)-2-[5-[(tert-butyldimethylsilyl)oxy]-4-
methoxy-3-methyl-2-[(triisopropylsilyl)oxy]phenyl]propyl
(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
References
(17a, C43H63F3O7Si2)
A Schlenk flask was equipped with 6 mg (S)-Mosher’s acid
(0.025 mmol, 2.5 equiv), 5 mg DCC (0.025 mmol, 2.5
equiv) and 0.5 cm3 CH2Cl2. The turbid mixture was cooled
to 0 °C for 15 min before 6 mg 15 (0.01 mmol, 1 equiv)
and DMAP (analytical amount) dissolved in 1.3 cm3
CH2Cl2 were added. The reaction mixture was stirred
overnight and quenched with H2O the next day. Layers
were separated and the aqueous layer was extracted with
CH2Cl2 three times. The organic layer was dried over
Na2SO4 and concentrated in vacuo to give Mosher ester
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1
17a. H NMR (400 MHz, CDCl3): d = 7.23–7.46 (10H,
m), 6.65 (1H, s), 4.50 (1H, dd, J = 10.6, 7.2 Hz), 4.42 (1H,
dd, J = 10.6, 6.3 Hz), 4.37 (1H, d, J = 12.0 Hz), 4, 32
(1H, d, J = 12.0 Hz), 3.70 (3H, s), 3.53–3.68 (3H, m), 3.41
(3H, s), 2.15 (3H, s), 1.18–1.34 (3H, m), 1.04 (18H, dd,
J = 7.4, 2.3 Hz), 0.95 (9H, s), -0.07 (6H, s) ppm; 19F
NMR (376 MHz, CDCl3): d = -71.59 ppm.
(S)-3-(Benzyloxy)-2-[5-[(tert-butyldimethylsilyl)oxy]-4-
methoxy-3-methyl-2-[(triisopropylsilyl)oxy]phenyl]propyl
(S)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
(17a, C43H63F3O7Si2) and (R)-3-(benzyloxy)-2-[5-[(tert-
butyldimethylsilyl)oxy]-4-methoxy-3-methyl-2-[(triiso-
propylsilyl)oxy]phenyl]propyl
(S)-3,3,3-trifluoro-2-
methoxy-2-phenylpropanoate (17b, C43H63F3O7Si2)
A Schlenk flask was equipped with 10 mg (S)-Mosher’s
acid (0.042 mmol, 2.5 equiv), 9 mg DCC (0.042 mmol, 2.5
123