Oxidative spirocyclisation routes towards the sawaranospirolides. Synthesis of ent-sawaranospirolides C and D

Article abstract of DOI:10.1039/b918091e

Two routes are described for the synthesis of the sawaranospirolides, stereoisomeric spirolactone ascorbigenins isolated from Chamaecyparis pisifera. Trapping of the keto enal formed by oxidation of a functionalised 2-(4-hydroxybutyl)furan affords a potential butenolide spiroacetal precursor to sawaranospirolides A and C. Alternatively, epoxidation of protected 3-(dihydropyran-2-yl)3-arylpropanoic acids results in spirolactonisation to generate ent-sawaranospirolide C; a related acid-mediated spirocyclisation gave access to ent-sawaranospirolide D. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b918091e

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Oxidative spirocyclisation routes towards the sawaranospirolides. Synthesis
of ent-sawaranospirolides C and D†
Jeremy Robertson,* Praful T. Chovatia, Thomas G. Fowler, Jonathan M. Withey and Daniel J. Woollaston
Received 3rd September 2009, Accepted 7th October 2009
First published as an Advance Article on the web 4th November 2009
DOI: 10.1039/b918091e
Two routes are described for the synthesis of the sawaranospirolides, stereoisomeric spirolactone
ascorbigenins isolated from Chamaecyparis pisifera. Trapping of the keto enal formed by oxidation of a
functionalised 2-(4-hydroxybutyl)furan affords a potential butenolide spiroacetal precursor to
sawaranospirolides A and C. Alternatively, epoxidation of protected 3-(dihydropyran-2-yl)-
3-arylpropanoic acids results in spirolactonisation to generate ent-sawaranospirolide C; a related
acid-mediated spirocyclisation gave access to ent-sawaranospirolide D.
Introduction
The sawaranospirolides are spiroacetal butyrolactones, isolated
from the acetone-soluble components of the heartwood of the
Japanese tree ‘Sawara’, Chamaecyparis pisifera, and shown to
differ merely in the configurations at C-3 and C-5 (Fig. 1).1
In a plausible biosynthesis, outlined in Scheme 1,2 the C-6 and
C-7 stereogenic centres derive from C-4 and C-5 of ascorbic
acid, respectively, the C-3 centre arises on introduction of a
tyrosine-derived fragment, and the C-5 configuration is established
after protonation of a putative ene-diol intermediate (1). Double
cyclisation initiated by the 1◦-hydroxy group affords the natural
products with the expected3 configuration at the spiro-centre.
Scheme 1 Outline biosynthesis of sawaranospirolides A–D.
Fig. 1 Sawaranospirolides A–D (Ar = p-HO–C6H4–).
Furan oxidative spirocyclisation
Scheme 2 Access to the sawaranospirolide system by furan oxidation
(Ar = p-HO–C6H4–, [P] = protecting group).
Scheme 2 summarises, in retrosynthetic terms, an approach to
the sawaranospirolides based on formation of the pyranose ring
with installation of the aromatic group by conjugate addition to
by cyclisation onto a keto enal (3) exposed by furan oxidation,
butenolide 2.4,5 This approach is conceptually related to the outline
biosynthesis (Scheme 1) in which the C-8 hydroxy group and a C-4
Department of Chemistry, Chemistry Research Laboratory, University of
Oxford, Mansfield Road, Oxford, UK OX1 3TA. E-mail: jeremy.robertson@
chem.ox.ac.uk; Fax: 44 1865 285002; Tel: 44 1865 275660
† Electronic supplementary information (ESI) available: Experimental
details for Schemes 3, 4 and 6; copies of selected 1H and 13C NMR spectra
for the compounds in Schemes 7 and 8. See DOI:10.1039/b918091e
carbonyl participate in a tandem cyclisation event to achieve the
spirocyclic ring system present in the sawaranospirolides.
We sought a synthesis of the tri-protected tetraol 4 that was
efficient, convergent, and flexible in terms of the relative and
absolute stereochemistry at the hydroxylated positions. Therefore,
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furfuraldehyde was olefinated with phosphonate 66 (Scheme 3),
and the alkene (7) dihydroxylated with AD-mix-b to yield diol 8
with an ee > 98% (as inferred by Mosher’s ester analysis of alcohol
12).7 After di-benzoylation (→ 9), reduction of the carbonyl
group afforded alcohol 10 as a mixture of diastereomers.8 Direct
benzoylation of the desired stereoisomer (10a) and benzoylation
under Mitsunobu conditions of the undesired stereoisomer (10b),9
followed by deprotection of the primary hydroxy group, provided
oxidative cyclisation substrate 12 (Scheme 4).
Fig. 2 Diagnostic 1H NMR coupling constants for spirolactone 13.
Oxidative spirocyclisation of this substrate with mCPBA alone4a
could not be driven to the butenolide (13); however, direct
treatment of the crude lactol mixture with TPAP/NMO completed
the oxidation to give a high overall yield of the spirocycle as a
additions were also unproductive.10 Ultimately, this had to be
abandoned and we anticipate an eventual solution to this problem
to be based on oxidative spirocyclisation of a furan substrate
already bearing the phenol substituent.11
1
single diastereomer. Fig. 2 summarises key H NMR resonances
supporting the all-equatorial substitution pattern around the
THP-ring.
Dihydropyran oxidative spirocyclisation
Our second approach was based on the construction of the C-3–C-
4 bond by conjugate addition of a metallated glycal (14, Scheme 5)
to a chiral 4-coumaric acid equivalent12 (15) in order to control
the C-3 configuration (pathway a). Subsequent epoxidation of
the enol ether anti to the allylic alkoxy substituent (→ 17), and
cyclisation13 to the spirolactone (18) in situ, would lead directly to
sawaranospirolides A and C following deprotection. Alternatively,
acidic treatment of enol ether 16 with loss of the C-6 hydroxy
group, then lactonisation14 (→ 20) and dihydroxylation (→ 21)
would lead to sawaranospirolides B and D. Attractions in this
approach included the ready availability of suitably protected
glycals, the possibility of total control of the C-3 centre (by the
chiral auxiliary in A*) and the divergent entry to the four natural
product configurations towards the end of the synthesis.
Scheme 3 Reagents and conditions: (i) TBSCl, imidazole, DMF, 20 ◦C,
16 h; (ii) MePO(OMe)2, BuLi, THF, -78 ◦C, 2 h.
Expecting that dihydropyran-2-yl cuprate reagents would be
insufficiently reactive to form conjugate adducts with coumarate-
type electrophiles, we assessed Meyers’ 2-alkenyl-1,3-oxazolines
as the chiral conjugate acceptor because these react with organo-
lithium reagents with a predictable sense of stereoselectivity (anti
addition with respect to the oxazoline substituent in an s-cis diene
conformation).15 Preliminary experiments16 with model oxazoline
22 (Scheme 6) showed that 2-lithiodihydropyran was unable to
generate 1,4-adducts under a variety of conditions. This led to
an early revision of the strategy; viz., introduction of the p-
hydroxyphenyl substituent to a pre-formed (C-1)–(C-8) system
(19, pathway b, Scheme 5) to link up with the first strategy at key
intermediate 16.
Scheme 4 Reagents and conditions: (i) add to 6/NaH, THF, 0 ◦C, 2 h;
(ii) AD-mix-b, MsNH2, aq. t-BuOH, 20 ◦C, 16 h; (iii) BzCl, DMAP,
pyridine, CH2Cl2, 20 ◦C, 16 h; (iv) Zn(BH4)2, Et2O, -25 ◦C, 2 h; (v) BzCl,
DMAP, pyridine, CH2Cl2, 20 ◦C, 16 h (88% from 10a); (vi) BzOH, DEAD,
PPh3, C6H6, 20 ◦C, 48 h (57% from 10b); (vii) H2SiF6, aq. CH3CN, 20 ◦C,
5 min; (viii) mCPBA, CH2Cl2, 0→20 ◦C, 18 h then TPAP, NMO, CH2Cl2,
20 ◦C, 18 h.
Following
a
preliminary feasibility study,17 the sawara-
nospirolide synthesis was initiated by formylation and Horner–
Wadsworth–Emmons reaction of dihydropyran derivative 2418
with phosphonate 3119 to give dienyloxazoline 26 in good
overall yield (Scheme 7). Treatment of this acceptor with p-
(benzyloxy)phenyllithium at -48 ◦C resulted in the formation
of a single diastereomer (27)20 along with a second component,
tentatively assigned as an oxidation product of the intermediate a-
lithio-oxazoline. Other p-hydroxyphenyllithium equivalents (32–
34, Fig. 3) also gave acceptable results in this reaction but
the phenolic protecting groups were either incompatible with
subsequent steps (32, 33) or did not allow release of the free phenol
at the end of the synthesis (34).
In order to complete syntheses of sawaranospirolides A and C,
all that remained at this point was to effect conjugate addition of
a p-hydroxyphenyl equivalent for which various approaches were
screened. We had been successful in effecting such transformations
in the context of our work on the lituarines4b but substrate 13
proved to be remarkably unreactive towards conjugate addition
under the mild conditions necessary to prevent degradation of the
starting material, and variants of the Heck reaction and radical
Conditions for the overall hydrolysis of the oxazoline and
subsequent oxidative spirocyclisation were optimised on a model
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Scheme 5 Synthetic strategies based on dihydropyran oxidative or acid-mediated spirolactonisation ([M] = metal, [P] = protecting group, Ar =
p-hydroxyphenyl equivalent, A* = chiral carboxylic acid equivalent).
Scheme 6 Reagents and conditions: (i) HOCH2CH2NH2, CHCl3, 0 ◦C,
30 min; (ii) PPh3, DIAD, THF, 0 → 20 ◦C, 4.5 h; (iii) DHP-Li.
substrate (35, Fig. 3) and, after extensive experimentation, a
sequence of methyl triflate activation of the oxazoline, followed by
partial hydrolysis with LiOH in warm aq. THF, gave amide 36.21
More forcing alkaline conditions completed amide hydrolysis, and
acid 37 was obtained without apparent loss of stereochemical
integrity, on protonation at pH 5. Pleasingly, the crucial oxidative
spirocyclisation step progressed smoothly on treatment with
mCPBA at 0 ◦C, the spirolactone (38) being isolated in 72% yield.
The relative stereochemistry in this molecule was supported by
1H–1H coupling constants—all CHOH and CHOTIPS methine
protons are axial, showing 3J 9.1 Hz—and the NOE interactions
shown.
Application of these conditions to adduct 27 provided spiro-
lactone 29 in 25% overall yield, somewhat down on the optimised
yield obtained for the equivalent transformation in 35 → 38 (63%).
Although we could not improve upon this yield, it was gratifying
that the subsequent TIPS-deprotection and hydrogenolysis of the
phenolic O-benzyl substituent proceeded efficiently to produce
ent-sawaranospirolide C (30). Both 1H and 13C NMR data were in
excellent agreement with those reported1 for the natural product,
Scheme 7 (i) t-BuLi, THF, -78 → 0 ◦C, 40 min then DMF, -78 ◦C, 10 h;
and the specific rotation for the synthetic material was, as expected,
opposite in sign and of comparable magnitude to that reported for
the natural enantiomer.
(ii) add to 31, DBU, LiCl, CH3CN, 20 ◦C, 38 h; (iii) add to p-BnO–C6H4Li,
THF, -48 ◦C, 30 min; (iv) a. MeOTf, CH2Cl2, 20 ◦C, 5 min; b. LiOH, aq.
THF, 45 ◦C, 6 h; c. KOH, aq. MeOH/t-BuOH, reflux, 30 h; d. buffer
(pH = 5); (v) mCPBA, CH2Cl2, 0 ◦C, 30 min; (vi) H2SiF6, aq. CH3CN,
20 ◦C, 20 h; (vii) H2, Pd/C, EtOH, 20 ◦C, 18 h. (Ar = p-BnO–C6H4–).
We also examined the possibility of extending this general
methodology to encompass the synthesis of ent-sawaranospirolide
D, the C-5 epimer of sawaranospirolide C (Scheme 8). An
attempted Mitsunobu inversion at the C-5 centre (29 → 40) was
unsuccessful; therefore, spirolactone 29 was oxidised efficiently to
ketone 39 with Dess–Martin periodinane, with the intention of
reducing it to the epimer (40). However, reduction of this ketone
led either to return of the original alcohol (29) (with NaBH4)
or non-productive reactions (with L-Selectride, Luche reduction,
‘kinetic’ Meerwein–Pondorff–Verley conditions22) and this idea
was abandoned.
Alternatively, acid-mediated spirocyclisation of acid 28 could
be achieved, albeit in only moderate yield.23 Problems in this
approach included simple enol ether protonation and cyclisation,
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Scheme 8 Reagents and conditions: (i) Dess–Martin periodinane, CH2Cl2,
20 ◦C, 18 h; (ii) PPTS, CH2Cl2, 20 ◦C, 6 h; (iii) a. OsO4, TMEDA, CH2Cl2,
-78 ◦C, 3 h then 20 ◦C, 12 h; b. H2S (g), THF, 0 ◦C, 30 min; (iv) H2SiF6,
aq. CH3CN, 20 ◦C, 24 h; (v) H2, Pd/C, EtOH, 20 ◦C, 18 h.
Fig. 3 Reference structures and NOE data from model studies.
giving 5-deoxyspirolactones, or slow reactions which offered
opportunities for loss of stereochemical integrity at the benzylic
(C-3) position. Fortunately, both ‘anomers’ (41a,b) of the spiro-
cyclic product could be dihydroxylated to give diols 42a,b in high
yield, with the stereochemistry apparently being dictated in both
cases by the bulky C-7 silyloxy substituent. The stereochemistry
in these two series converged during the silyl ether deprotection
and the enantiomer of the second natural product isomer, ent-
sawaranospirolide D (43), was obtained after hydrogenolysis.
There was again complete correspondence between the NMR
data for synthetic and natural material and the respective specific
rotations were of opposite signs as expected, although their
magnitude differed somewhat.
were washed successively with water and brine before being dried
over MgSO4 and concentrated in vacuo. Purification by column
chromatography (petrol/ether, 30 : 1) afforded starting material
(24, 102 mg, 11%) and aldehyde 25 (693 mg, 71%) as a colourless
oil. Rf 0.64 (petrol/ether, 4 : 1); [a]2D3 -116.5 (c 1.3, CHCl3); nmax
(thin film)/cm-1 1718 s, 1638 s, 1464 s, 1344 m, 1245 s, 1176 s,
1141 s, 1070 s, 923 s, 882 s, 738 s, 681 s; dH (400 MHz, CDCl3)
0.95–1.15 (42 H, m, 2 ¥ TIPS), 3.96–3.97 (1 H, m, H-3), 4.07 (1 H,
d, J 11.2, H-2), 4.16–4.19 (1 H, m, H-4), 4.21–4.25 (1 H, m, H-2¢),
5.84 (1 H, dd, J 5.3, 1.5, H-5), 9.19 (1 H, s, CHO); dC (100 MHz,
CDCl3) 12.3 (complex), 18.0 (complex), 64.3, 66.4, 68.8, 118.7,
+
151.7, 187.6; m/z (CI) 474 (MNH4 , 23%), 300 (38), 283 (100),
241 (22), 213 (17); HRMS (CI) found 474.3439, C24H52NO4Si2
+
In summary, we have described the first total syntheses of
sawaranospirolides C and D, as their enantiomers, in 7 and 9
steps, respectively, from known glycal derivative 24.
(MNH4 ) requires 474.3429.
(S)-2-{(E)-2-[(3R,4R)-3,4-Bis(triisopropylsilyloxy)-3,4-dihydro-
2H-pyran-6-yl]vinyl}-4-isopropyl-4,5-dihydrooxazole 26
Experimental
To stirred a solution of diisopropylamine (6.20 mL, 43.9 mmol) in
THF (25 mL) at 0 ◦C was added dropwise butyllithium (25.5 mL of
a 1.7 M solution in hexanes, 43.4 mmol). After 15 min the solution
was cooled to -78 ◦C and a solution of (S)-4-isopropyl-2-methyl-
4,5-dihydrooxazole24 (1.06 g, 8.35 mmol) in THF (8 mL) was
added. After 1 h diethylphosphochloridate (1.51 mL, 10.5 mmol)
was added; stirring was continued for 1 h at -78 ◦C then warmed
to 0 ◦C and quenched with saturated NH4Cl solution (50 mL).
The mixture was poured onto water (15 mL) and extracted with
ether (3 ¥ 25 mL), dried over MgSO4, and concentrated in vacuo
to give the crude phosphonate (31),19 as a yellow oil, that was
used directly in the next step. The phosphonate (31, 8.35 mmol
(3R,4R)-3,4-Bis(triisopropylsilyloxy)-3,4-dihydro-2H-pyran-6-
carbaldehyde 25
To a stirred solution of dihydropyran derivative 24 (911 mg,
2.13 mmol) in THF (1 mL) at -78 C was added dropwise tert-
butyllithium (1.25 mL of a 1.8 M solution in pentane, 2.25 mmol).
After 10 min the reaction was warmed to 0 ◦C for 30 min then
re-cooled to -78 ◦C and a solution of DMF (0.17 mL, 2.19 mmol)
in THF (5 mL) added dropwise. After a further 10 h at -78 C
the reaction mixture was then poured into water (30 mL) and
extracted with ether (3 ¥ 30 mL). The combined organic extracts
◦
◦
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assumed) was dissolved in acetonitrile (30 mL), and LiCl (416 mg,
9.82 mmol) and DBU (1.43 mL, 9.58 mmol) were then added to
this stirred solution. A solution of aldehyde 25 (3.65 g, 8.00 mmol)
in acetonitrile (20 mL) was added dropwise and, after 38 h, the
mixture was poured onto water (100 mL) and extracted with ether
(3 ¥ 50 mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo to give a residue that was purified by
column chromatography (petrol/ether, 9 : 1) to give the oxazoline
26 (3.43 g, 76%) as a viscous clear light yellow oil. Rf 0.39
(petrol/ether, 9 : 1); nmax (thin film)/cm-1 2867 s, 1640 s, 1464 s,
1385 s, 1248 s, 1143 s, 1060 s, 995 s, 921 s, 682 s; dH (400 MHz,
CDCl3) 0.89 and 0.97 (2 ¥ 3 H, 2 ¥ d, J 6.8, oxazoline-CH(CH3)2),
0.99–1.10 (42 H, m, 2 ¥ TIPS), 1.72–1.85 (1 H, m, oxazoline-
CH(CH3)2), 3.82–3.91 (1 H, m, CH(OTIPS)CH2), 3.95–4.01 (2
H, m, OCHH¢CHN), 4.02–4.06 (2 H, m, CHH¢CHOTIPS and
CH(OTIPS)CH=), 4.10 (1 H, br d, J 11.3, CHH¢CHOTIPS),
4.22–4.32 (1 H, m, OCHH¢CHN), 5.09 (1 H, d, J 4.3, =CH),
The combined organic layers were then dried over MgSO4 and
concentrated in vacuo. This material was then dissolved in THF
(5 mL), treated with LiOH solution (0.97 mL of a 1 M solution,
0.97 mmol), and the mixture warmed to 45 ◦C for 6 h. The mixture
was cooled to RT, most of the THF evaporated in vacuo, the residue
diluted with B(OH)3 solution (0.033 M, 25 mL), and extracted with
dichloromethane (3 ¥ 50 mL). The combined organic portions
were dried over MgSO4 and concentrated in vacuo. Purification
by column chromatography (dichloromethane/methanol, 50 : 1)
afforded a mixture of amide and ester products of oxazoline
hydrolysis (595 mg, 98%) as a viscous, colourless oil. A portion of
this amide/ester mixture (356 mg, 0.456 mmol) was dissolved in
methanol (2.5 mL) and tert-butanol (2.5 mL) then KOH solution
(4.60 mL, 2 M, 9.20 mmol) was added. The mixture was heated at
reflux for 30 h then, after cooling to RT, was concentrated in vacuo,
diluted with B(OH)3 solution (0.033 M, 20 mL) and extracted with
dichloromethane (3 ¥ 100 mL). The combined organic layers were
dried over MgSO4 and concentrated in vacuo. This crude material
was then re-dissolved in ether (50 mL) and washed with B(OH)3
solution (0.033 M, 3 ¥ 20 mL) and brine (10 mL). The organic
solution was dried over MgSO4 and concentrated in vacuo to give
acid 28 as a gluey oil (256 mg, 82%) that was used in this crude
form. nmax (thin film)/cm-1 3500–2500 br m, 2866 s, 1713 s, 1663 s,
1612 m, 1511 s, 1463 s, 1245 m, 883 m, 681 m; dH (400 MHz,
CDCl3) 0.95–1.10 (42 H, m, 2 ¥ TIPS), 2.79 (1 H, dd, J 16.3, 8.5)
and 2.92 (1 H, dd, J 16.3, 6.7, CHCO2H), 3.75–3.88 (2 H, m) and
3.91–4.07 (3 H, m, CH2CH(OTIPS)CH(OTIPS) and CHAr), 4.76
=
6.46 and 6.64 (2 ¥ 1 H, 2 ¥ d, J 15.7, CH CH); dC (100 MHz,
CDCl3) 12.4–12.7 and 17.9–18.8 (complex), 32.8, 65.2, 66.0, 69.1,
69.7, 72.6, 106.8, 115.6, 135.0, 150.3, 163.0; HRMS (ESI+) found
566.4041, C31H60NO4Si2 (MH+) requires 566.4055.
(S)-2-{(S)-2-[4-(Benzyloxy)phenyl]-2-[(3R,4R)-3,4-
bis(triisopropylsilyloxy)-3,4-dihydro-2H-pyran-6-yl]ethyl}-4-
isopropyl-4,5-dihydrooxazole 27
To a stirred solution of 4-(benzyloxy)bromobenzene (827 mg,
3.14 mmol) in dry THF (10 mL) at -78 ◦C was added dropwise tert-
butyllithium (1.89 mL of a 1.7 M solution in pentane, 3.21 mmol).
After 30 min the solution was warmed up to -48 ◦C and a
solution of oxazoline 26 (890 mg, 1.58 mmol) in THF (10 mL)
was added over 30 min. After a further 10 min, the reaction was
quenched with methanol (2 mL) and allowed to warm to RT.
The mixture was poured onto water (50 mL) and extracted with
ether (3 ¥ 50 mL). The combined organic extracts were dried
over MgSO4 and concentrated in vacuo. Purification by column
chromatography (petrol/ether, 9 : 1) gave the title compound (27)
as a colourless oil (980 mg, 86%). Rf 0.4 (petrol/ether, 4 : 1); nmax
(thin film)/cm-1 2943 s, 2866 s, 1668 s, 1611 m, 1511 s, 1464 s, 1384
m, 1244 s, 1058 s, 883 s, 681 s; dH (400 MHz, CDCl3) 0.65 and
0.73 (2 ¥ 3 H, 2 ¥ d, J 6.7, oxazoline-CH(CH3)2), 0.95–1.10 (42
H, m, 2 ¥ TIPS), 1.45–1.55 (1 H, m, oxazoline-CH(CH3)2), 2.76 (1
H, dd, J 14.7, 6.0) and 2.84 (1 H, dd, J 14.7, 10.2, CH2C(=N)O),
3.71–3.80 (4 H, m), 3.90–4.01 (3 H, m) and 4.05–4.12 (1 H, m,
CH2CH(OTIPS)CH(OTIPS), CH2CHN and CHAr), 4.77 (1 H,
d, J 5.2, =CH), 5.03 (2 H, s, CH2Ph), 6.85 and 7.20 (2 ¥ 2 H, 2 ¥
d, J 8.6, Ar), 7.29–7.46 (5 H, m, Ph); dC (100 MHz, CDCl3) 12.0–
12.5 and 17.9–18.3 (complex), 32.2 (2 peaks), 46.1, 65.3, 66.3, 69.0,
69.7, 70.0, 71.8, 96.7, 114.4, 127.4, 127.8, 128.5, 129.2, 132.9, 137.3,
156.7, 157.5, 165.4; HRMS (ESI+) found 750.4944, C44H72NO5Si2
(MH+) requires 750.4944.
=
(1 H, d, J 5.1, CH), 5.04 (2H, s, CH2Ph), 6.90 and 7.21 (2 ¥ 1 H,
2 ¥ d, J 8.6, Ar), 7.31–7.48 (5 H, m, Ph); dC (100 MHz, CDCl3)
12.2–12.5 and 17.7–18.1 (complex), 29.7, 44.9, 65.0, 66.3, 68.9,
70.0, 96.9, 114.5, 127.5, 127.9, 128.6, 128.9, 133.2, 137.2, 156.3,
157.6, 177.7; HRMS (ESI+) found 683.4149, C39H63O6Si2 (MH+)
requires 683.4158.
(4S,5R,8R,9R,10R)-4-[4-(Benzyloxy)phenyl]-10-hydroxy-8,9-
bis(triisopropylsilyloxy)-1,6-dioxaspiro[4.5]decan-2-one 29
To a stirred solution of crude acid 28 (256 mg, 0.375 mmol)
in dichloromethane (5 mL) at 0 ◦C was added dropwise a
solution of mCPBA (101 mg, ca. 75% by weight, 0.439 mmol)
in dichloromethane (4 mL). After 30 min the reaction mixture was
mixed with saturated NaHCO3 solution (25 mL) and extracted
with dichloromethane (3 ¥ 25 mL). The combined organic extracts
were dried over MgSO4, concentrated in vacuo, and purified by
column chromatography (petrol/ether, 7 : 3) to afford spirocycle
29 (82 mg, 31%) as an oil. Rf 0.5 (petrol/ether, 6 : 4); nmax (thin
film)/cm-1 3480 br m, 2945 s, 2867 s, 1785 s, 1613 m, 1514 s, 1465
m, 1383 m, 1241 m, 1090 m, 1016 m, 916 s, 884 s, 735 s, 682 s;
dH (400 MHz, CDCl3) 1.02–1.20 (42 H, m, 2 ¥ TIPS), 1.88 (1 H,
d, J 9.1, OH), 2.79 (1 H, dd, J 17.1, 8.3) and 3.01 (1 H, dd, J
17.1, 12.5, CH2CO), 3.31 (1 H, t, J 9.1, CHOH), 3.57–3.66 (2 H,
m, CHH¢CHOTIPS), 3.69–3.76 (1 H, m, CHH¢CHOTIPS), 3.85
(1H, app. t, J 8.1, CH(OTIPS)CHOH), 4.00 (1 H, dd, J 12.5, 8.3,
CHAr), 5.07 (2 H, s, CH2Ph), 6.97 and 7.24 (2 ¥ 2 H, 2 ¥ d, J
8.8, Ar), 7.32–7.48 (5 H, m, Ph); dC (100 MHz, CDCl3) 13.4–13.6
and 18.2–18.4 (complex), 34.1, 44.6, 64.8, 70.0, 71.7, 71.8, 78.2,
108.6, 114.6, 126.1, 127.5, 128.1, 128.6, 130.5, 136.8, 158.5, 174.9;
HRMS (ESI+) found 721.3929, C39H62NaO7Si2 (MNa+) requires
721.3926.
(S)-3-[4-(Benzyloxy)phenyl]-3-[(3R,4R)-3,4-bis(triisopropyl-
silyloxy)-3,4-dihydro-2H-pyran-6-yl]propanoic acid 28
To stirred a solution of oxazoline 27 (558 mg, 0.774 mmol)
in dichloromethane (5 mL) at RT was added methyl triflate
(93 mL, 0.82 mmol). After 5 min the mixture was poured onto
water (50 mL) and extracted with dichloromethane (3 ¥ 50 mL).
230 | Org. Biomol. Chem., 2010, 8, 226–233
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(4S,5R,8R,9S,10R)-4-[4-(Benzyloxy)phenyl]-8,9,10-trihydroxy-
1,6-dioxaspiro[4.5]decan-2-one (30-OBn)
CH2CO), 3.87–4.02 (3 H, m, CH2CHO), 4.31 (1 H, dd, J 11.8, 8.7,
CHAr), 4.82 (1 H, dd, J 4.8, 3.7, CHCO),25 5.06 (2 H, s, CH2Ph),
6.94 and 7.26 (2 ¥ 2 H, 2 ¥ d, J 8.8, Ar), 7.31–7.47 (5 H, m, Ph);
dC (100 MHz, CDCl3) 12.9–13.1 and 18.0–18.2 (complex), 33.9,
42.7, 65.4, 70.0, 75.1, 81.4, 105.4, 114.5, 125.9, 127.5, 128.0, 128.6,
130.6, 136.8, 158.3, 173.4, 196.5; HRMS (ESI+) found 787.4747,
Aqueous H2SiF6 solution (7.0 mL, 25% by weight, 0.011 mmol) was
added to a stirred solution of spirocycle 29 (39 mg, 0.056 mmol)
in acetonitrile (2 mL) at RT. After 2 h a further portion
of H2SiF6 solution (7 mL, 25% by weight, 0.011 mmol) was
added and the mixture stirred for 18 h. The solution was then
concentrated in vacuo and purified by column chromatography
(dichloromethane/methanol, 49 : 1) to provide the title compound
(18 mg, 83%). Rf 0.2 (dichloromethane/methanol, 95 : 5); nmax (thin
film)/cm-1 3600–3400 br m, 2943 s, 2866 s, 1784 s, 1514 s, 1240 m,
1109 s, 915 s; dH (400 MHz, CDCl3) 2.74 (1 H, dd, J 17.3, 8.6) and
2.97 (1 H, dd, J 17.3, 12.2, CH2CO), 3.35–3.42 (1 H, m, CH(OH)-
spiro), 3.43–3.51 (1 H, m, CH2CHOH), 3.56 (1 H, app. t, J 10.8,
CHH¢CHOH), 3.71–3.83 (2 H, m, CHH¢CH(OH)CHOH), 4.00
(1 H, dd, J 12.2, 8.6, CHAr), 4.59 (1 H, bs, OH), 4.96 (2 H, app. s,
CH2Ph), 5.04 (1 H, bs, OH), 5.40 (1 H, bs, OH), 6.90 and 7.23 (2 ¥
2 H, J 8.5, Ar), 7.31–7.42 (5 H, m, Ph); dC (100 MHz, CDCl3) 33.9,
44.2, 64.1, 69.3, 69.9, 70.3, 75.2, 108.9, 114.6, 125.9, 127.5, 128.0,
128.6, 130.5, 136.8, 158.5, 176.1; HRMS (ESI+) found 409.1257,
C21H22NaO7 (MNa+) requires 409.1258.
+
C42H71N2O8Si2 (M·CH3CN·MeOH·NH4 ) requires 787.4743.
(4S,5S,8S)- and (4S,5R,8S)-4-[4-(Benzyloxy)phenyl]-8-
(triisopropylsilyloxy)-1,6-dioxaspiro[4.5]dec-9-en-2-one 41a,b
To a stirred solution of acid 28 (121 mg, 0.177 mmol) in
dichloromethane (4 mL) at RT was added a solution of PPTS
(30 mg, 0.12 mmol) in dichloromethane (2 mL). Stirring was
continued for 6 h, then the mixture was mixed with water
(20 mL) and the separated aqueous layer was extracted with
dichloromethane (3 ¥ 20 mL). The combined organic portions
were dried over MgSO4, filtered and concentrated in vacuo.
Purification by flash chromatography (petrol/ether, 4 : 1) afforded
spirocycles 41a (22 mg, 24%) and 41b (12 mg, 13%) as oils. Data
for 41a: Rf 0.53 (petrol/ether, 7 : 3); nmax (thin film)/cm-1 2942 s,
2890 s, 1784 s, 1659 m, 1612 m, 1583 m, 1514 s, 1463 m, 1427 m,
1400 m, 1383 m, 1245 s, 781 s; dH (400 MHz, CDCl3) 1.04–1.12
(21 H, m, TIPS), 2.77 (1 H, dd, J 17.5, 5.1) and 3.25 (1 H, dd,
J 17.5, 8.6, CH2CO), 3.73 (1 H, dd, J 8.6, 5.1, CHAr), 3.98 (1
H, d, J 12.1, CHH¢O), 4.04–4.07 (1 H, m, CHOTIPS), 4.15 (1
H, dd, J 12.1, 2.6, CHH¢O), 5.05 (2 H, s, CH2Ph), 5.30 (1 H,
(4S,5R,8R,9S,10R)-8,9,10-Trihydroxy-4-(4-hydroxyphenyl)-1,6-
dioxaspiro[4.5]decan-2-one (ent-sawaranospirolide C 30)
A solution of the spirocycle obtained by TIPS-deprotection of
precursor 29 (18 mg, 46.6 mmol) and 5% Pd/C (20 mg) in ethanol
(2 mL) was purged with argon and then stirred under hydrogen
at RT for 18 h. After flushing with argon, the reaction mixture
was filtered though Celite and concentrated in vacuo to give
ent-sawaranospirolide C (13 mg, 94%) as a viscous oil. Rf 0.28
(dichloromethane/methanol, 9 : 1); [a]2D3 +40.5 (c 1.4, MeOH), lit.1
(for enantiomer) -36 (c 2.25, MeOH); nmax (thin film)/cm-1 3600–
3000 br s, 2926 m, 1769 s, 1700 m, 1651 m, 1519 s, 1367 m, 1260 m,
1105 m, 1047 m, 917 m; dH (500 MHz, d6-DMSO) 2.73 (1 H, dd,
J 17.1, 8.4) and 3.01 (1 H, dd, J 17.1, 12.9, CH2CO), 3.07–3.15
(2 H, m, CH(OH)CH(OH)-spiro), 3.30 (1 H, t, J 11.3, CHH¢O),
overlaying 3.28–3.35 (1 H, m, CH(OH)CH2O), 3.53 (1 H, dd, J
11.3, 6.4, CHH¢O), 3.89 (1 H, dd, J 12.9, 8.4, CHAr), 5.01 (1
H, d, J 6.0, one of CH(OH)CH(OH)-spiro), 5.13 (1 H, d, J 6.0,
CH(OH)CH2O), 5.74 (1 H, d, J 6.0, one of CH(OH)CH(OH)-
spiro), 6.70 and 7.12 (2 ¥ 2H, 2 ¥ d, J 8.5, Ar), 9.40 (1 H, br s,
ArOH); dC (125 MHz, d6-DMSO) 32.6, 43.3, 64.2, 69.0, 69.7,
74.3, 108.7, 114.8, 124.8, 130.2, 156.6, 175.1; HRMS (FI+) found
296.0901, C14H16O7 (M+) 296.0891.
=
d, J 10.2) and 6.02 (1 H, ddd, J 10.2, 5.2, 1.0, CH CH), 6.94
and 7.13 (2 ¥ 2 H, 2 ¥ d, J 8.7, Ar), 7.32–7.47 (5 H, m, Ph); dC
(100 MHz, CDCl3) 12.3, 18.0 (2 peaks), 35.2, 49.7, 61.0, 68.4, 70.0,
106.0, 115.0, 125.3, 127.5, 128.1, 128.6, 128.9, 129.4, 131.0, 136.8,
158.3, 175.6; HRMS (ESI+) found 509.2717, C30H41O5Si (MH+)
requires 509.2718. Data for 41b: Rf 0.45 (petrol/ether, 7 : 3); nmax
(thin film)/cm-1 2943 s, 2867 s, 1799 s, 1514 s, 1463 m, 1395 m,
1221 s, 1181 s, 1125 m, 899 m, 688 m; dH (400 MHz, CDCl3) 0.98–
1.10 (21 H, m, TIPS), 2.78 (1 H, dd, J 16.9, 7.9) and 3.13 (1 H, dd,
J 16.9, 12.9, CH2CO), 3.57 (1 H, dd, J 12.9, 7.9, CHAr), 3.69 (1 H,
t, J 10.3) and 3.80 (1 H, dd, J 10.3, 5.7, CH2O), 3.99–4.07 (1 H, m,
CHOTIPS), 5.06 (2 H, s, CH2Ph), 5.78 (1 H, dd, J 10.2, 1.9) and
=
6.14 (1 H, d, J 10.2, CH CH), 6.94 and 7.18 (2 ¥ 2 H, 2 ¥ d, J 8.7,
Ar), 7.32–7.46 (5 H, m, Ph); dC (100 MHz, CDCl3) 12.1–12.3 and
17.9–18.0, 33.5, 50.1, 62.9, 65.5, 70.0, 104.5, 114.5, 124.7, 126.7,
127.5, 128.1, 128.6, 129.6, 136.8, 139.1, 158.3, 175.1; HRMS (ESI)
found 509.2723, C30H41O5Si (MH+) requires 509.2718.
(4S,5R,8R,9R,10S)- and (4S,5S,8R,9R,10S)-4-[4-
(Benzyloxy)phenyl]-9,10-dihydroxy-8-(triisopropylsilyloxy)-
1,6-dioxaspiro[4.5]decan-2-one 42a,b
(4S,5R,8R,9S)-4-[4-(Benzyloxy)phenyl]-8,9-bis(triisopropyl-
silyloxy)-1,6-dioxaspiro[4.5]decane-2,10-dione 39
Dess–Martin periodinane (44 mg, 0.10 mmol) was added to a
solution of spirocycle 29 (36 mg, 0.052 mmol) in dichloromethane
(5 mL) at RT and the mixture was stirred for 18 h. The mixture was
diluted with ether (20 mL) then filtered through Celite; the filtrate
was concentrated in vacuo and the residue purified by column
chromatography (petrol/ether, 9 : 1) to give ketone 39 (29 mg,
83%) as a colourless oil. Rf 0.82 (petrol/ether, 4 : 1); nmax (thin
film)/cm-1 2947 s, 1814 s, 1752 s, 1614 m, 1514 s, 1464 s, 1383 m,
1124 s, 899 m, 793 m; dH (400 MHz, CDCl3) 1.03–1.12 (42 H, m,
2 ¥ TIPS), 2.88 (1 H, dd, J 17.5, 8.7) and 3.00 (1 H, dd, J 17.5, 11.8,
A solution of spirocycle 41a (39 mg, 76.7 mmol) and TMEDA
(13 mL, 0.084 mmol) in dichloromethane (3 mL) was cooled to
-78 ◦C under argon. A solution of OsO4 (21 mg, 0.084 mmol)
in dichloromethane (2 mL) was added and the solution was
stirred at -78 ◦C for 3 h then allowed to warm up to RT.
The reaction mixture was stirred for a further 12 h and then
concentrated in vacuo to give a residue that was subsequently
dissolved in THF (5 mL). H2S (g) was bubbled through the
solution at 0 ◦C for 30 min then the reaction mixture was
concentrated in vacuo and the residue purified by chromatography
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(dichloromethane/methanol, 9 : 1); [a]2D3 +28.7 (c 0.4, MeOH),
lit.1 (for enantiomer) -54 (c 0.74, MeOH); nmax (thin film)/cm-1
3650–3100 br s, 2925 m, 1771 s, 1615 m, 1519 s, 1260 s, 1024 m,
960 m; dH (400 MHz, d6-DMSO) 2.75 (1 H, dd, J 17.7, 9.8) and
2.90 (1 H, dd, J 17.7, 9.2, CH2CO), 3.25 (1 H, t, J 10.1, CHH¢O),
3.47–3.61 (3 H, m, CHH¢CH(OH)CH(OH)), 3.70–3.82 (2 H, m,
CH(OH)-spiro and CHAr), 4.36, 4.88 and 5.01 (3 ¥ 1 H, 3 ¥ br s,
3 ¥ OH), 6.62 and 7.10 (2 ¥ 2 H, 2 ¥ d, J 8.6, Ar); dC (100 MHz,
d6-DMSO) 35.8, 46.3, 65.1, 65.4, 71.3, 72.9, 108.3, 114.2, 127.8,
130.7, 156.0, 174.3; HRMS (FI+) found 296.0888, C14H16O7 (M+)
requires 296.0896.
(dichloromethane/methanol, 98 : 2) to give diol 42a (35 mg, 85%)
as an oil. Rf 0.67 (dichloromethane/methanol, 95 : 5); nmax (thin
film)/cm-1 3600–3300 br m, 2941 s, 2865 s, 1774 s, 1513 s, 1456 s,
1238 s, 1124 s, 1054 s, 845 s; dH (500 MHz, CDCl3) 0.95–1.05 (21
H, m, TIPS), 2.31 (1 H, br s, OH), 2.55 (1 H, br s, OH), 2.85 (1 H,
dd, J 17.1, 9.2) and 3.32 (1 H, dd, J 17.1, 12.8, CH2CO), 3.71 (1 H,
dd, J 12.8, 9.2, CHAr), 3.73 (1 H, br s, CH(OH)-spiro) overlaying
3.78 (1 H, d, J 12.6, CHH¢O), 3.80 (1 H, br s, CH(OH)CHOTIPS),
3.99 (1 H, d, J 3.6, CHOTIPS), 4.21 (1 H, d, J 12.6, CHH¢O),
5.06 (2 H, AB q, J 11.8, CH2Ph), 6.96 and 7.33 (2 ¥ 2 H, 2 ¥ d, J
8.7, Ar), 7.30–7.46 (5 H, m, Ph); dC (125 MHz, CDCl3) 12.1–12.2
and 17.9 (2 peaks), 34.3, 50.8, 64.0, 64.6, 70.0, 70.1, 71.7, 110.7,
115.0, 126.6, 127.4, 128.0, 128.6, 129.1, 136.9, 158.5, 173.4; HRMS
(ESI+) found 565.2580, C30H42NaO7Si (MNa+) requires 565.2592.
Analogously, from 41b (28 mg, 55.1 mmol), diol 42b was obtained
(25 mg, 84%). Rf 0.79 (dichloromethane/methanol, 95 : 5); nmax
(thin film)/cm-1 3500–3100 br m, 2926 s, 1773 s, 1513 s, 1245 m,
1038 m; dH (400 MHz, CDCl3) 1.02–1.06 (21 H, m, TIPS), 2.29
and 2.50 (2 ¥ 1 H, 2 ¥ br s, 2 ¥ OH), 2.85–2.95 (2 H, m, CH2CO),
3.63 (1 H, t, J 10.3, CHH¢O), 3.75–3.85 (2 H, m, CHAr and
CHH¢O), 3.88–3.97 (2 H, m, 2 ¥ CHOH), 4.08 (1 H, d, J 2.3,
CHOTIPS), 5.05 (2 H, s, CH2Ph), 6.94 and 7.32 (2 ¥ 2 H, 2 ¥ d,
J 8.7, Ar), 7.34–7.46 (5 H, m, Ph); dC (100 MHz, CDCl3) 12.1 (2
peaks) and 17.9 (3 peaks), 36.3, 48.2, 65.1, 67.8, 69.9, 73.0, 73.7,
106.8, 114.3, 127.5, 128.0, 128.6, 130.8, 136.9, 158.2, 174.3; HRMS
(ESI+) found 543.2789, C30H43O7Si (MH+) requires 543.2773.
Acknowledgements
We thank the University of Oxford and the Engineering and
Physical Sciences Research Council for funding. We also thank
Drs Tim Claridge and Barbara Odell, University of Oxford, for
supporting NMR studies.
Notes and references
1 S. Hasegawa, H. Koyanagi and Y. Hirose, Phytochemistry, 1990, 29,
261–266.
2 This is based on the proposed biosynthesis described in ref. 1, and
references cited therein.
3 Spirolactones of this type show a strong thermodynamic preference for
an axially-disposed acyl oxygen–carbon bond. For a general discussion
of the axial preference of anomeric acyloxy functionality see: A. J.
Kirby, The Anomeric Effect and Related Stereoelectronic Effects at
Oxygen, Springer-Verlag, Berlin, 1983, pp. 60–61.
(4S,5R,8R,9S,10S)-4-[4-(Benzyloxy)phenyl]-8,9,10-trihydroxy-
4 For our recent applications of this approach in the context of natural
product synthesis see: (a) J. Robertson, P. Meo, J. W. P. Dallimore,
B. M. Doyle and C. Hoarau, Org. Lett., 2004, 6, 3861–3863; (b) J.
Robertson and J. W. P. Dallimore, Org. Lett., 2005, 7, 5007–5010; (c) J.
Robertson, K. Stevens and S. Naud, Synlett, 2008, 2083–2086; see also:
(d) J. Robertson and S. Naud, Org. Lett., 2008, 10, 5445–5448.
5 H. Fukuda, M. Takeda, Y. Sato and O. Mitsunobu, Synthesis, 1979,
368–370.
1,6-dioxaspiro[4.5]decan-2-one (43-OBn)
To stirred a solution of diol 42a (35 mg, 64.6 mmol) in acetonitrile
(2 mL) at RT was added H2SiF6 (28 mL, 22% by weight, 42.8 mmol)
in three portions (8, 10 and 10 mL). The mixture was stirred for
24 h in total then the volatiles were evaporated and the residue
purified by column chromatography (dichloromethane/methanol,
98 : 2) to give the title compound (11 mg, 44%) as an oil.
[The same compound was obtained in similar yield by the
analogous reaction of diol 42b (25 mg, 46.1 mmol).] Rf 0.36
(dichloromethane/methanol, 95 : 5); nmax (thin film)/cm-1 3700–
3100 br m, 3079 s, 1784 m, 1616 s, 1543 s, 1229 s, 1035 m, 1012
m, 816 m, 682 m; dH (400 MHz, CD3OD) 2.90 (2 H, app. d, J 9.8,
CH2CO), 3.49 (1 H, app. ddd, J 14.9, 7.4, 2.9, CHH¢O), 3.66–3.81
(3 H, m, CHH¢O and CH(OH)CH(OH)-spiro), 3.83 (1 H, t, J 9.8,
CHAr), 3.95 (1 H, d, J 3.2, CH2CHOH), 5.07 (2 H, s, CH2Ph),
6.90 and 7.31 (2 ¥ 2 H, 2 ¥ d, J 8.6, Ar), 7.34–7.46 (5 H, m, Ph);
dC (100 MHz, CD3OD) 36.2, 48.0, 65.3, 65.9, 69.9, 72.2, 73.9,
108.6, 114.2, 127.5, 127.8, 128.5, 129.6, 131.0, 137.9, 158.3, 175.6;
HRMS (FI+) found 386.1359, C21H22O7 (M+) requires 386.1366.
6 P. Angehrn, P. Hebeisen, I. Heinze-Krauss, M. Page, Eur. Pat. Appl.,
1998, EP0831093 (A1).
7 Products of the type 8 show a tendency to fragment by retro-aldol
reaction under the dihydroxylation conditions. For this reason, the
reaction was terminated before complete consumption of the starting
alkene and the latter could be recycled.
8 Although reduction with L-Selectride favoured the formation of isomer
10a, benzoyl migration complicated product isolation which resulted
in a lower overall yield.
9 The stereochemistry of 10a/10b was assigned retrospectively following
spirocyclisation.
10 D. Woollaston, D.Phil. Thesis, Oxford, 2007..
11 In another approach (see ref. 10) we prepared the 3,5-dibromofuryl
variant of substrate 12 in order to provide a handle for introducing the
p-hydroxyphenyl group by cross-coupling. However, the two bromine
substituents deactivated the furan and we were unable to effect
oxidation.
12 B. E. Rossiter and N. M. Swingle, Chem. Rev., 1992, 92, 771–806.
13 R. M. Boyce and R. M. Kennedy, Tetrahedron Lett., 1994, 35, 5133–
5136.
(4S,5R,8R,9S,10S)-8,9,10-Trihydroxy-4-(4-hydroxyphenyl)-1,6-
dioxaspiro[4.5]decan-2-one (ent-sawaranospirolide D 43)
14 S. J. Danishefsky and W. H. Pearson, J. Org. Chem., 1983, 48, 3865–
3866.
15 A. I. Meyers and M. Shipman, J. Org. Chem., 1991, 56, 7098–7102.
16 J. M. Withey, Chemistry Part II Thesis, Oxford, 2000.
17 T. Fowler, Chemistry Part II Thesis, Oxford, 2001.
18 L. A. Paquette, M. J. Kinney and U. Dullweber, J. Org. Chem., 1997,
62, 1713–1722.
19 A. Chesney, M. R. Bryce, A. S. Batsanov, J. A. K. Howard and L. M.
Goldenberg, Chem. Commun., 1998, 677–678.
A stirred suspension of the triol obtained from TIPS deprotection
of 42a,b (11 mg, 28.5 mmol) and 5% Pd/C (15 mg) in ethanol
(2 mL) was purged with argon then stirred under hydrogen
at RT for 29 h. The reaction vessel was then flushed with
argon and the mixture filtered through Celite, washing through
with more ethanol; the filtrate was concentrated in vacuo to
give ent-sawaranospirolide D (8 mg, 95%) as a gum. Rf 0.17
20 We note that this represents the stereochemically matched case;
repetition of this sequence starting with ent-31 gave a mixture of
232 | Org. Biomol. Chem., 2010, 8, 226–233
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diastereomers in the conjugate addition. Thus, although the cheaper
valinol-derived auxiliary serves for some purposes, the tert-leucinol-
analogue (ref. 15) still remains the most generally useful.
21 This amide was examined as an oxidative cyclisation substrate but
under a variety of conditions satisfactory results were not achieved;
instead, recovered starting material, eliminated material, and over-
oxidised products were obtained.
23 The use of BF3·OEt2 (1.1 equiv.) in THF at RT gave a similar
yield of spirocycles 41a,b, essentially free of the simple acid-catalysed
spirocyclisation products.
24 M. J. Kurth and O. H. W. Decker, J. Org. Chem., 1985, 50, 5769–
5775.
25 This coupling pattern suggests that a significant proportion of the
conformers bear a 1,2-diaxial arrangement of the silyloxy substituents,
which was supported by preliminary molecular mechanics calculations
(Monte Carlo conformational search, MMFF).
22 A. K. Dilger, V. Gopalsamuthiram and S. D. Burke, J. Am. Chem. Soc.,
2007, 129, 16273–16277.
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