A symmetry-based synthesis of the heterobicyclic core of the zaragozic acids/squalestatins

Article abstract of DOI:10.1002/adsc.200900295

The pseudo C₂-symmetrical diketone 22 was efficiently constructed from furan-3,4-dimethanol (7) using a two-directional route featuring a double asymmetric dihydroxylation. Acidic hydrolysis of the cyclopentylidene acetais of 22 triggered a sel

Full text of DOI:10.1002/adsc.200900295

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DOI: 10.1002/adsc.200900295
A Symmetry-Based Synthesis of the Heterobicyclic Core of the
Zaragozic Acids/Squalestatins
Yuzhou Wang,a Olga Kataeva,a,b and Peter Metza,*
a
Department of Chemistry, Technische Universitꢀt Dresden, Bergstr. 66, 01069 Dresden, Germany
Fax : (+49)-351-463-33162; e-mail: peter.metz@chemie.tu-dresden.de
Author responsible for X-ray diffraction analysis
b
Received: April 26, 2009; Published online: September 8, 2009
Dedicated to Professor Hans-Ulrich Reißig on the occasion of his 60th birthday.
Abstract: The pseudo C2-symmetrical diketone 22
was efficiently constructed from furan-3,4-dimetha-
nol (7) using a two-directional route featuring a
double asymmetric dihydroxylation. Acidic hydroly-
sis of the cyclopentylidene acetals of 22 triggered a
selective cyclization of the resulting hexaol dike-
as well as detailed investigations on structure-activity
relationships have been carried out.[1,4,5]
Here we report the enantioselective synthesis of a
heterobicyclic system of type A, which rests on the
symmetry-based concept depicted in Scheme 1.[5,6]
A
retrosynthetic disconnection of the acetal of A leads
to polyhydroxy ketone B that exhibits regions with
local meso and C2 symmetry. Expansion of the C2
region in B by addition of a two-carbon unit to the
ester terminus enhances the molecular complexity,
however, a pseudo C2-symmetric diketone C is at-
tained that should be rapidly accessible by two-direc-
tional synthesis.[7] Synthetically, diketone C might
serve as a surrogate for B, provided its intramolecular
acetalization would lead to D in a chemoselective
fashion and with simultaneous differentiation of the
two diastereotopic g,e-dihydroxy ketone moieties. Fi-
nally, the superfluous appendage in D can be re-
moved via a chemoselective oxidative cleavage[8] to
generate A. Due to its functionality, A can be regard-
ed as a general building block for zaragozic acids/
squalestatins and non-natural analogues. In this re-
spect, the protected hydroxymethyl group at C-1 of A
tone to generate the 2,8-dioxabicycloACTHUNRTGNEUNG[3.2.1]octane
core of the zaragozic acids/squalestatins. Chemose-
lective oxidative cleavage of a superfluous two-
carbon appendage and further functional group ma-
nipulations yielded the enantiomerically pure tri-
ACHTUNGTRENNUNGester 30, which offers itself as a general heterobicy-
clic building block for naturally occurring zaragozic
acids/squalestatins and unnatural analogues.
Keywords: aldol reaction; asymmetric catalysis;
chemoselectivity; cyclization; dihydroxylation; two-
directional synthesis
The zaragozic acids/squalestatins isolated from vari- offers the possibility to attach different alkyl side
ous fungi are potent inhibitors of squalene synthase chains, while the hydroxy group at C-6 allows the con-
and in part ras-farnesyl protein transferase, too.[1] nection of diverse ester side chains by position-selec-
More recent studies show that these natural products tive acylation.[9]
can also cure prion-infected neurons and protect
Previous model studies relevant to the present
against prion neurotoxicity[2] as well as sensitize acute work are summarized in Scheme 2. Thus, we recently
myeloid leukemia cells (AML) to radiochemothera- communicated a concise synthesis of the C2-symmet-
py.[3] Almost all of these compounds feature the 2,8- ric linear model compound 2 from the diethyl tartrate
dioxabicycloACHTUNGTRENNUNG
[3.2.1]octane core with an unusually high derivative 1.[5a] Under suitable conditions, the hexahy-
density of polar oxygen functions, while structural dif- droxy diketone 2 cyclized with completely chemose-
ferences reside in the alkyl side chain at C-1 and the lective participation of the g,e-hydroxy groups to
ester side chain at C-6. Due to their strong physiologi- afford the 2,8-dioxabicycloACTHUNRTGNEUNG[3.2.1]octane derivative 3,
cal effects and complex molecular structure, the zara- which is epimeric at C-4 to the heterobicyclic core of
gozic acids/squalestatins have stimulated enormous the zaragozic acids/squalestatins in high yield after
synthetic efforts. Thus, the total synthesis of several of peracetylation. More advanced model studies showed
these natural products has been accomplished, and that the pseudo C2-symmetric tetrabenzyl ether 5
many synthetic studies toward the heterobicyclic core could be readily accessed from alkyne 4 through
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Scheme 1. Concept for the synthesis of the heterobicyclic
core of the zaragozic acids/squalestatins.
Sharpless AD methodology.[5b] Under optimized con-
ditions, the derived hexahydroxy diketone smoothly
underwent a chemoselective intramolecular acetaliza-
tion to give the desired g,e-cyclization product 6 as a
Scheme 2. Model studies.
model for the heterobicyclic core upon treatment AD reaction as well as to ensure high catalyst control
with acetic anhydride. for the second AD process. The smooth two-fold AD
The successful execution of a symmetry-based transformation fortunately observed for 9 in contrast
route according to Scheme 1 to a fully substituted to the model substrate[5b] can probably be rationalized
compound of type A is illustrated in Scheme 3, with a better solubility of the diol intermediate pro-
Scheme 4, Scheme 5, and Scheme 6.
duced from 9 in the organic layer. Use of isopropyl-
A two-directional, sequential Swern oxidation/ magnesium chloride[14] allowed a chemoselective ex-
Wittig reaction[10] converted the disubstituted furan change of the ester functions against Weinreb amides,
7[11] into the (E,E) configured bis-isopropyl ester 9 in whereupon the resulting product 12 was converted
a one-pot process. Double asymmetric dihydroxyla- into diketone 14 with the lithium species[15] derived
tion[12] of 9 with a modified “AD-mix-a”[13] furnished from 13. At this point, it proved advisable to mask
a tetraol that was subsequently derivatized to give the the two carbonyl groups temporarily as protected al-
bis-cyclopentylidene acetal 11 (Scheme 3). The furan cohols in order to prevent undesired cyclizations in
nucleus of 9, which introduces two latent carboxylic the course of the furan oxidation. Diacetate 15 ob-
acids into the system with C-2 and C-5, also assumes tained with complete diastereoselectivity[16] was then
the role of the alkyne spacer utilized in the model ser- transformed to the two lactol lactone epimers 16 (4:1
1
ies[5b] to avoid an undesired cyclization after the first according to H NMR integration) uneventfully.[17]
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A Symmetry-Based Synthesis of the Heterobicyclic Core of the Zaragozic Acids
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Scheme 4. Alternative preparation of bis-Weinreb amide 12.
Reagents and conditions: a) (i) Et2BOTf, Et3N, CH2Cl2,
À788C, (ii) 18, À788C to 08C, (iii) buffer pH 7, MeOH,
H2O2, 08C, 95%; b) MeONHMe·HCl, Me3Al, THF, 08C to
room temperature, 77%; c) H2, 10% Pd/C, HOAc, dioxane,
room temperature; d) 10, TsOH, CH2Cl2, 08C to room tem-
perature, 61% from 20.
the bis-tert-butyldiphenylsilyl ether 21, Dess–Martin
oxidation[21] of which yielded the pseudo C2-symmetri-
cal diketone 22 (Scheme 5). In the following key step,
22 was indeed selectively cyclized to give the desired
heterobicyclic acetal, whereby a partial desilylation
occurred. After resilylation, 23 was isolated in good
yield as two epimeric hemi-acetals (3:1 according to
1H NMR integration).[22] Reduction of the masked
ketone within 23 to provide two diastereomeric pen-
1
Scheme 3. Two-directional synthesis of lactol lactone 16. Re-
agents and conditions: a) (i) DMSO, (COCl)2, Et3N, CH2Cl2,
À788C to 08C, (ii) 8, 08C to room temperature, 86%; b)
taols 24 (5:1 according to H NMR integration) set
the stage for a chemoselective[8] oxidative cleavage of
the superfluous two-carbon appendage with sodium
periodate that led to aldehyde 25 with high efficacy.
Due to its sensitivity, aldehyde 25 was directly con-
verted to tert-butyl ester 27 by chlorite oxidation[23]
2.5 mol%
K2OsO2(OH)4,
K3[Fe(CN)6],
5 mol%
(DHQ)2PHAL, K2CO3, NaHCO3, MeSO2NH2, t-BuOH,
H2O, 0 8C; c) 10, TsOH, CH2Cl2, 08C to room temperature,
92% from 9; d) MeONHMe·HCl, i-PrMgCl, THF, À208C,
and
esterification
with
O-alkylisourea
26[24]
98%; e) 13, BuLi, THF, À788C, 100%; f) Li
ACHTUNGTERNN(UNG s-Bu)3BH,
(Scheme 6). An X-ray diffraction analysis of 27 with
anomalous X-ray scattering provided an independent
proof of the absolute configuration.[25] After chemose-
lective O-benzoylation of the two secondary alcohols
THF, À1008C to À788C; g) Ac2O, DMAP, Et3N, CH2Cl2,
08C to room temperature, 97% from 14; h) Br2, K2HPO4,
THF, H2O, 0 8C; i) CrO3, H2SO4, acetone, 08C, 93% from 15.
The high enantioselectivity of the double AD reac- to give 28, desilylation to furnish 29 proceeded with-
tion in Scheme 3 was proven by an alternative prepa- out competing acyl shift.[26] Finally, the reaction se-
ration of bis-Weinreb amide 12 via an Evans aldol re- quence double Swern oxidation, double chlorite oxi-
action[18] of the enantiomerically pure glycolic acid de- dation and double esterification with 26 resulted in
rivative 17[19] with dialdehyde 18,[20] which succeeded tri-tert-butyl ester 30, which represents a largely or-
efficiently in a two-directional fashion (Scheme 4). thogonally protected derivative of the desired hetero-
The resultant C2-symmetrical product 19 was trans- bicyclic building block A for zaragozic acids/squale-
formed to 12 by cleavage of the auxiliaries[19] to give statins and, thus, warrants high flexibility regarding an
20 followed by debenzylation and acetalization {12 elaboration to these natural products or analogues
from 9: [a]2D2: À39.9 (c 0.96, CHCl3); 12 from 17: [a]2D2: thereof. Differentiation between the C-6 and C-7 hy-
À39.1 (c 0.98, CHCl3)}.
droxy groups can be achieved according to the
A sequence consisting of dihydroxylation, global re- method developed by Carreira,[9] and attachment of
duction of all carbonyl groups and chemoselective several C-1 alkyl side chains proceeds readily after
blocking of the two primary alcohols converted 16 to debenzylation of 30 followed by Swern oxidation.
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Scheme 6. Completion of the synthesis of tri-tert-butyl ester
30. Reagents and conditions: a) NaClO2, KH2PO4, isoprene,
t-BuOH, H2O, 0 8C to room temperature; b) 26, CH2Cl2,
room temperature, 80% 27 from 25, 50% 30 from 29; c)
PhCOCl, DMAP, CH2Cl2, 08C to room temperature, 100%;
d) HF·pyridine, THF, pyridine, room temperature, 94%; e)
DMSO, (COCl)2, Et3N, CH2Cl2, À788C.
(70 mL) was stirred for 1 h at room temperature. After cool-
ing to 08C, methanesulfonamide (1.53 g, 16 mmol) was
added followed by a solution of bis-enoate 9 (2.336 g,
8 mmol) in t-BuOH (30 mL). Stirring at 08C was continued
for 24 h, sodium sulfite (23 g) was added, and the mixture
was stirred for 1 h at 08C. The layers were separated, and
the aqueous layer was extracted with ethyl acetate (4ꢂ
50 mL). After drying the combined organic layers with
Na2SO4 and concentration under vacuum, the oily residue
was passed through a short silica gel column (ethyl acetate).
The crude tetraol obtained was dissolved in dry CH2Cl2
(20 mL), and the resultant solution was cooled to 08C. 1,1-
Dimethoxycyclopentane (21 g) and TsOH (152 mg,
0.8 mmol) was added, and stirring was continued overnight
while allowing the mixture to warm to room temperature.
The mixture was diluted with diethyl ether (80 mL), washed
with semi-saturated NaHCO3 solution (10 mL) and water
(10 mL), dried with MgSO4, and concentrated under
vacuum. Purification of the residue by flash chromatography
on silica gel (diethyl ether/pentane, 1:3) gave the bis-acetal
11 as a colorless oil; yield: 3.638 g (92%). Rf =0.37 (diethyl
ether/pentane, 1:3); [a]2D2: À23.13 (c 0.83, CHCl3); IR
(ATR): n=2978 (m), 2876 (w), 1746 (s), 1727 (s), 1554 (w),
1468 (w), 1454 (w), 1434 (w), 1375 (m), 1337 (m), 1279 (m),
1194 (s), 1098 (s), 1039 (m), 969 (s), 877 (m), 820 (m), 821
Scheme 5. Construction of the heterobicyclic aldehyde 25.
Reagents and conditions: a) OsO4, pyridine, toluene, 08C; b)
LiAlH4, Et3N, THF, CH2Cl2, 08C to 658C; c) TBDPSCl,
DMAP, Et3N, CH2Cl2, room temperature, 43% 21 from 16,
66% 23 from 22; d) Dess–Martin periodinane, pyridine,
CH2Cl2, room temperature, 91%; e) TFA, CH2Cl2, H2O, 0 8C
to room temperature; f) LiBH4, Et3N, THF, 0 8C, 94%; g)
NaIO4, pyridine, MeOH, H2O, room temperature, 93%.
Due to the two-directional strategy employed, the
24-steps route from 7 to 30 compares well to previous
syntheses of the fully functionalized heterobicyclic
core in terms of efficiency and stereoselectivity. Ap-
plication of 30 toward the total synthesis of naturally
occurring zaragozic acids/squalestatins is the subject
of ongoing work.
(m), 752 (m), 604 (m) cmÀ1 1H NMR (300 MHz, CDCl3):
;
Experimental Section
d=1.24 (d, J=5.9 Hz, 6H), 1.26 (d, J=5.9 Hz, 6H), 1.65–
1.83 (m, 10H), 1.95–2.06 (m, 6H), 4.62 (d, J=7.4 Hz, 2H),
5.02–5.14 (m, 4H), 7.51 (s, 2H); 13C NMR (75.5 MHz,
CDCl3): d=21.65 (q), 21.71 (q), 23.13 (t), 24.00 (t), 36.19 (t),
36.43 (t), 69.08 (d), 73.30 (d), 78.75 (d), 121.18 (s), 121.38
(s), 143.03 (d), 170.43 (s); MS (ESI): m/z=510.2 [M+
Double AD Reaction of 9 and Acetalization to Give
Diester 11
A
mixture of K3Fe(CN)6 (15.804 g, 48 mmol), K2CO3
(6.624 g, 48 mmol), NaHCO3 (4.032 g, 48 mmol),
K2OsO2(OH)4 (73.6 mg, 0.2 mmol) and (DHQ)2PHAL
+
NH4 ]; anal. calcd. for C26H36O9: C 63.40, H 7.37; found: C
(311.6 mg, 0.4 mmol) in water (100 mL) and t-BuOH
63.41, H 7.56.
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A Symmetry-Based Synthesis of the Heterobicyclic Core of the Zaragozic Acids
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1H NMR (500 MHz, CDCl3): d=0.96 (s, 9H), 1.04 (s, 9H),
2.56 (d, J=2.6 Hz, 1H), 3.49 (s, 1H), 3.58 (d, J=11.6 Hz,
1H), 3.66 (d, J=10.1 Hz, 1H), 3.85 (d, J=11.6 Hz, 1H),
3.86 (d, J=10.1 Hz, 1H), 3.87 (d, J=11.7 Hz, 1H), 3.93 (d,
J=8.3 Hz, 1H), 4.06 (d, J=11.7 Hz, 1H), 4.53 (apparent t
with J=2.7 Hz, 1H), 4.60 (d, J=11.9 Hz, 1H), 4.69 (d, J=
11.9 Hz, 1H), 4.71 (d, J=0.8 Hz, 1H), 4.86 (dd, J=2.9 Hz,
J=8.3 Hz, 1H), 7.28–7.44 (m, 17H), 7.56–7.58 (m, 4H),
7.60–7.62 (m, 2H), 7.66–7.68 (m, 2H), 9.54 (d, J=0.8 Hz,
1H, CHO); 13C NMR (125.8 MHz, CDCl3): d=19.07 (s),
26.69 (q), 26.74 (q), 62.39 (t), 62.85 (t), 72.29 (t), 73.18 (s,
C4), 74.03 (t), 77.69 (d), 79.13 (d), 84.38 (d), 87.21 (s),
103.00 (s), 127.74 (d), 127.84 (d), 127.86 (d), 128.05 (d),
128.58 (d), 130.03 (d), 130.12 (d), 131.63 (s), 131.72 (s),
131.92 (s), 132.21 (s), 135.49 (d), 135.66 (d), 135.74 (d),
135.81 (d), 137.27 (s), 199.20 (d); MS (ESI): m/z=864.4
Preparation of Aldehyde 25 from Diketone 22 via
Selective Cyclization, Resilylation, Reduction and
Oxidative Cleavage
A solution of diketone 22 (2.95 g, 2.57 mmol) in CH2Cl2
(52 mL) cooled to 08C was treated with water (0.463 g,
25.72 mmol) and TFA (2.932 g, 25.72 mmol). After stirring
for 1 h at 08C and 24 h at room temperature, the reaction
was quenched by addition of saturated NaHCO3 solution
(36 mL). The layers were separated, the aqueous layer was
extracted with CH2Cl2 (3ꢂ60 mL), and the solvent was re-
moved under vacuum. Purification by flash chromatography
on silica gel (diethyl ether/CH2Cl2, 1:6) gave hemi-acetal 23
(yield: 1.17 g, 46%) and partially desilylated material (yield:
0.724 g, 37%) as white solids. The latter material was dis-
solved in dry CH2Cl2 (19 mL) and treated with triethylamine
(241 mg, 2.31 mmol), DMAP (5.8 mg, 0.05 mmol) and
TBDPSCl (315.5 mg, 1.15 mmol). After stirring for 50 h at
room temperature, the mixture was filtered through a pad
of silica gel (diethyl ether). Concentration under vacuum
and purification by flash chromatography on silica gel (di-
+
+
[M+NH4 ], 896.4 [M+MeOH+NH4 ], 901.4 [M+
MeOH+Na+]; anal. calcd. for C49H58O9Si2: C 69.47, H 6.90;
found: C 69.55, H 6.80.
ethyl ether/CH2Cl2, 1:6) gave additional (520 mg) 23 as a Preparation of Tri-tert-butyl Ester 30 from Triol 29
white solid; total yield from 22: 1.69 g (66%). Rf =0.26 (di-
A solution of dry DMSO (135 mg, 1.726 mmol) in dry
ethyl ether/CH2Cl2, 1:6); IR (ATR): n=3452 (br., w), 3070
CH2Cl2 (1 mL) was added dropwise to a solution of oxalyl
(w), 2931 (w), 2857 (w), 1469 (m), 1457 (m), 1427 (m), 1391
dichloride (109.6 mg, 0.863 mmol) in dry CH2Cl2 (4 mL)
(w), 1363 (w), 1184 (w), 1106 (s), 1072 (s), 1043 (s), 1000
cooled to À788C under argon. After stirring for 10 min, a
(m), 939 (m), 820 (m), 793 (m), 738 (s), 783 (m), 697 (s), 609
solution of triol 29 (216 mg, 0.332 mmol) in dry CH2Cl2
+
(m) cmÀ1; MS (ESI): m/z=1014.5 [M+NH4 ], 1019.4 [M+
(3.4 mL) was added dropwise, and stirring was continued at
Na+], 1035.4 [M+K+].
À788C for 45 min. Dry triethylamine (262 mg, 2.59 mmol)
A solution of hemi-acetal 23 (1.061 g, 1.064 mmol) in dry
was added, and the mixture was stirred for 30 min at
THF (32 mL) was treated with triethylamine (129 mg,
À788C. The reaction was quenched by addition of 1M
1.277 mmol). After stirring for 30 min at room temperature,
KH2PO4 (3.4 mL). The mixture was extracted with CH2Cl2
the mixture was cooled to 08C, lithium borohydride
(81.44 mg, 3.724 mmol) was added, and stirring at 08C was
continued for 4 h. The reaction was quenched by dropwise
addition of 2N NaOH (10 mL) followed by stirring for
30 min. Extraction with ethyl acetate (3ꢂ20 mL), drying of
the organic layer with Na2SO4 and removal of the solvent
under vacuum left a residue, which was purified by flash
chromatography on silica gel (diethyl ether/CH2Cl2, 1:6) to
(3ꢂ10 mL), and the combined organic layers were dried
with Na2SO4. The crude dialdehyde obtained after removal
of the solvent under vacuum was dissolved in a mixture of t-
BuOH (31 mL) and isoprene (7.7 mL). The resultant solu-
tion was cooled to 08C, and a 1M solution of NaClO2 in 1M
KH2PO4 (3.3 mL, 3.3 mmol) was added dropwise. After stir-
ring the reaction mixture for 1 h at 08C and 4 h at room
temperature, another portion of the 1M solution of NaClO2
give pentaol 24 as a white solid; yield: 1.002 g (94%). Rf =
0.23 (diethyl ether/CH2Cl2, 1:6); IR (ATR): n=3410 (br.,
in 1M KH2PO4 (3.3 mL, 3.3 mmol) was added dropwise, and
stirring was continued for further 19 h. The mixture was
w), 3071 (w), 2931 (w), 2858 (w), 1457 (m), 1427 (m), 1363
treated with brine (5 mL) and a pH 2 KH2PO4 buffer
(w), 1108 (s), 1072 (s), 936 (w), 821 (m), 783 (m), 698 (s),
(5 mL) followed by extraction with ethyl acetate (5ꢂ
15 mL). The combined organic layers were dried with
Na2SO4, and the solvent was removed under vacuum to give
610 (m) cmÀ1; MS (ESI): m/z=1016.5 [M+NH4 ], 1021.4
+
[M+Na+]; anal. calcd. for C58H70O11Si2: C 69.71, H 7.06;
found: C 69.85, H 6.96.
a crude diacid, which was dissolved in dry CH2Cl2 (15 mL)
and treated with N,N’-diisopropyl-O-tert-butylisourea
(664 mg, 3.32 mmol) under argon. After stirring for 24 h at
room temperature, another portion of N,N’-diisopropyl-O-
tert-butylisourea (664 mg, 3.32 mmol) was added, and stir-
ring was continued for further 24 h. The white precipitate
formed was filtered off, and the solvent was removed under
vacuum. Purification of the residue by flash chromatography
on silica gel (diethyl ether/CH2Cl2, 1:20) furnished tri-tert-
butylester 30 as a white foam; yield: 131 mg (50%). Rf =
0.20 (diethyl ether/CH2Cl2, 1:20); [a]2D2: +68.01 (c 1.31,
CH2Cl2); IR (ATR): n=3447 (br., w), 2981 (w), 2935 (w),
2876 (w), 1727 (s), 1454 (m), 1369 (m), 1315 (m), 1252 (s),
1150 (s), 1108 (s), 1063 (s), 1026 (m), 998 (m), 968 (w), 911
A solution of sodium periodate (343.5 mg, 1.61 mmol) in
water (4 mL) was added dropwise to a solution of pentaol
24 (802 mg, 0.803 mmol) and pyridine (190 mg, 2.41 mmol)
in methanol (28 mL). After stirring for 20 h at room temper-
ature, additional sodium periodate (86 mg, 0.402 mmol) in a
mixture of water (0.5 mL) and methanol (3 mL) was added,
and stirring was continued for 6 h. Dilution with ethyl ace-
tate, drying with Na2SO4, and removal of the solvent under
vacuum left a residue, which was purified by flash chroma-
tography on silica gel (diethyl ether/CH2Cl2, 1:15) to give al-
dehyde 25 as a white solid; yield: 786 mg (93%). Rf =0.24
(CH2Cl2/ethyl acetate, 15:1); mp 57.5–58.68C; [a]2D2: +6.63
(c 1.19, CH2Cl2); IR (ATR): n=3436 (br., w), 3068 (w),
2931 (m), 2858 (m), 1739 (m), 1457 (m), 1427 (m), 1390 (w),
(w), 838 (m), 708 (s), 602 (m) cmÀ1
;
1H NMR (500 MHz,
1108 (s), 1073 (s), 820 (m), 739 (m), 699 (s), 610 (m) cmÀ1
;
CDCl3): d=1.29 (s, 9H), 1.47 (s, 9H), 1.62 (s, 9H), 3.97 (d,
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J=12.1 Hz, 1H), 4.02 (d, J=12.1 Hz, 1H), 4.20 (s, 1H), 4.71
(d, J=11.5 Hz, 1H), 4.96 (d, J=11.5 Hz, 1H), 5.16 (s, 1H),
5.86 (d, J=1.7 Hz, 1H), 6.86 (d, J=1.7 Hz, 1H), 7.24–7.29
(m, 3H), 7.38–7.46 (m, 6H), 7.54–7.60 (m, 2H), 7.99–8.03
(m, 4H); 13C NMR (125.8 MHz, CDCl3): d=27.81 (q), 27.95
(q), 28.09 (q), 68.86 (t), 74.13 (t), 74.23 (s), 75.49 (d), 76.20
(d), 78.48 (d), 83.92 (s), 84.28 (s), 86.50 (s), 90.72 (s), 104.30
(s), 127.46 (d), 127.84 (d), 128.22 (d), 128.35 (d), 128.53 (d),
128.97 (s), 129.04 (s), 129.81 (d), 130.05 (d), 133.44 (d),
133.54 (d), 138.22 (s), 163.51 (s), 164.22 (s), 164.99 (s),
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Financial support of this work by the Deutsche Forschungs-
gemeinschaft (ME 776/13-3, ME 776/18-1) is gratefully ac-
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Adv. Synth. Catal. 2009, 351, 2075 – 2080