Chemical variation of natural product-like scaffolds: Design and synthesis of spiroketal derivatives

Article abstract of DOI:10.1039/b603015g

The design and synthesis of spiroketal structures and their chemical modification, leading to a collection of new small molecules for biological evaluation as orally-bioavailable lead compounds is described. Both [6,5]- and [6,6]-membered ring spiroketal units have been prepared in a stereochemically-varying fashion starting from commercially available (R)- or (S)-glycidol, in ten, eleven and twelve linear steps, in overall yields of 45, 40 and 20%, respectively. Further elaboration according to Lipinski's guidelines has given a collection of structurally-diverse, new spiroketal derivatives in high yields and with high purity. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b603015g

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Chemical variation of natural product-like scaffolds: design and synthesis of
spiroketal derivatives†
Giovanna Zinzalla, Lech-Gustav Milroy and Steven V. Ley*
Received 28th February 2006, Accepted 29th March 2006
First published as an Advance Article on the web 21st April 2006
DOI: 10.1039/b603015g
The design and synthesis of spiroketal structures and their chemical modification, leading to a collection
of new small molecules for biological evaluation as orally-bioavailable lead compounds is described.
Both [6,5]- and [6,6]-membered ring spiroketal units have been prepared in a stereochemically-
varying fashion starting from commercially available (R)- or (S)-glycidol, in ten, eleven and twelve
linear steps, in overall yields of 45, 40 and 20%, respectively. Further elaboration according to Lipinski’s
guidelines has given a collection of structurally-diverse, new spiroketal derivatives in high yields and
with high purity.
of identifying molecules with new biological activities, distinct
from those of the original natural product, and to discover novel
Introduction
The successful sequencing of the human genome1 has improved
our understanding of biological pathways, forming a basis for the
development of new classes of therapeutics. As a consequence,
the number of new biological targets for screening has increased
noticeably along with advances in synthetic chemistry tools to
map their function through the design of molecularly diverse
compounds. Recent studies corroborate the intuitive link between
structure and biological activity, where a high degree of molecular
shape change within a collection of small molecules is shown to
increase the collection’s chances of hitting a broader range of
biological targets.2
Natural products are an extraordinarily valuable source of
structural variation.3 They are often identified as lead compounds
in drug discovery programmes, especially in the case of anti-
tumour and anti-infective agents,4 and play an important role
in chemical biology studies.5 Natural products are commonly
employed as small molecule chemical probes for the modulation
of protein–protein interactions, and as specific binding agents to
enzymes and proteins.6
In the past decade, libraries built around natural product
templates have been used to improve the selectivity, pharmaco-
logical properties or potency of the natural compound related to
its original biological target.7,8 For example, compounds based
on natural tubulin inhibitors have afforded new anticancer drugs,
while a collection of paclitaxel analogues has yielded four second-
generation drug candidates which are in clinical trials.9 Finally,
derivatives based on curacin A have generated viable candidates in
the anti-infectives therapeutic area.9 Recently, a growing emphasis
has been placed on the generation and use of natural product-like
or natural product-derived compounds, for discovery screening
processes. Compounds of this kind are screened for the purpose
lead compounds to address known biological targets.10,11 For
example, Shair and co-workers have identified a new secretory
pathway inhibitor of protein trafficking of the Golgi apparatus,
using a library based on the core scaffold of galanthamine
(an acetylcholinesterase inhibitor) in a broad phenotypic screen,
whose activity is unrelated to that of the original natural
product.12
An important feature regarding compounds based on natural
products is that, as substructures or fragments of the parent
molecules, they have been shown to retain significant biologi-
cal activity.13 Moreover, natural product-like molecules possess
readily modifiable structures in terms of skeletal, stereochemical,
and side-chain functionality. In fact, appendage variation is a
central feature for improving or modulating the biological activity
of a compound, and involves coupling of the core structure with
a wide range of small chemical units. Stereochemical variation
implies the generation of different derivative isomers, and can
be achieved through stereoselective synthetic pathways. Skeletal
variation results from a change in the atom connectivity or alter-
ation of the shape/3D geometry of the template’s core structure.
Variation of the appendage, stereochemistry and skeleton of the
natural product-inspired scaffold has the potential to change
significantly its shape/geometry, resulting in a wide collection of
structures that can be used for screening purposes.
The design of compound collections from natural product
templates has already demonstrated that a specific, desirable
biological property of a natural product can be improved on; even
with rather small libraries prepared by simple functional group
manipulation (e.g. natural product-like libraries of purines, curacin
A, vancomycin).14,15 These early successes motivated further work
in skeletal modification of natural product-like compound collec-
tions. Armstrong16 and Bartlett17 generated widely-varying sets of
natural product-like compounds. Schreiber and co-workers18 later
developed a strategy termed diversity-oriented synthesis (DOS).
Also, other groups have proposed related synthetic strategies to
prepare diverse molecules from a common scaffold.19 However,
aside from stereochemical and appendage variation, skeletal
variation has yet to be achieved in an effective manner.
Department of Chemistry, University of Cambridge, Lensfield Road,
Cambridge, UK CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: +44 (0)1223
336442; Tel: +44 (0)1223 336398
† Electronic supplementary information (ESI) available: Full experimental
details for preparation of the ynals 5 and 6 with characterisation data
of each intermediate. Experimental details and characterisation data of
compounds 32, 34a–b, and 46–48. See DOI: 10.1039/b603015g
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Spiroketals, in particular 1,6-dioxaspiro[5.5]decanes and 1,7-
dioxaspiro[4.5]undecanes, are molecular frameworks found in a
variety of complex natural products that possess a wide range
of biological activities.20 The spongistatin family, for example, are
tubulin polymerisation inhibitors;21 okadaic acid is a protein phos-
phatase inhibitor;22 tautomycin and integramycin are HIV-1 pro-
tease inhibitors;23 routiennocin is an antibiotic;24 reveromycins A
and B are epidermal growth factor inhibitors;25 purpuromycin and
rubromacyn are human telomerase inhibitors;26 and bistramide A
is a cell proliferation suppressor,27 amongst many others.20
Our group has been interested in spiroketals for a number
of years developing several useful methods for preparing the
spiroketal framework associated with many complex natural
products.28 Furthermore, in 1995 we showed how it was possible to
use a [6,6]-bis-anomerically stabilised spiroketal as a rigid scaffold
to replace the N-acetylglucosamine–galactose disaccharide in a
sialyl Lewis X mimetic (Fig. 1a).29 We later developed a polymer-
supported synthetic route to spiroketal units (Fig. 1b).30 Other
groups have subsequently recognised the opportunity of using
these concepts for the generation of spiroketal libraries.31
Fig. 2 Unnatural spiroketal derivatives and their associated biological
activities.
undergo stereochemical and skeletal variation. Hypothetically, the
spiroketalisation event can deliver the spiroketal structural unit
in four different arrangements (Scheme 1)34 with the anomeric
effect, steric interactions, intramolecular hydrogen bonding and
other chelation effects governing their relative configuration and
Fig. 1 (a) Spiroketal framework as novel scaffold; (b) a solid-phase
synthesis approach to spiroketals.
Further developments have since been reported which clearly
demonstrate that promising pharmacological effects (such as
phosphatase inhibition, modulation of the tubulin cytoskeleton
of breast cancer cells, and cytotoxicity against tumor cell lines)
can be achieved through the construction and screening of simple
spiroketals (Fig. 2).32
Here, we report the design, synthesis, and elaboration of
spiroketal units leading to a collection of small molecules that
could be used as biological probes in phenotopic assays. Our goal
was to generate a wide range of spiroketal derivatives suitable for
biological screening towards orally bio-available lead compounds,
closely matching the Lipinski rule of five.33
Results and discussion
Scheme 1 (a) Spiroketalisation followed by (b) epimerisation at the spiro-
ketal carbon: sources of stereochemical/configurational variation inherent
to the spiroketal molecular framework; (c) acid-catalysed interconversion
of [6,6]-, [6,5]- and [5,5]-spiroketal systems as a source of skeletal variation.
We began the project by focusing on spiroketals with at least three
sites amenable to appendage change. Furthermore, we recognised
the potential shown by the spiroketal molecular framework to
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stabilities.35 Epimerisation at the spiroketal carbon can also be
considered a source of stereochemical and configurational change
by interconverting between isomers (Scheme 1b). Furthermore, the
acid-catalysed interconversion of [6,6]-, [6,5]- and [5,5]-spiroketal
systems should allow for further structural interconversions
(Scheme 1c).
elaboration of the terminal alkene. Where dihydroxylation would
lead ultimately to the spiroketals 1 to 3, alternatively, epoxidation
and nucleophilic addition of the acetylene group could lead
to the spiroketal 4. The ynals would be readily synthesised
using reaction sequences established previously, starting from
commercially available (R)- or (S)-glycidol.
Our initial synthetic efforts focused on the spiroketal scaffolds
1 to 4, which possess a flexible ketal hinge point and a latent,
electrophilic ring-ketone, beta to the spiro-carbon. The spiroketals
1 and 3 contain one benzylic ether and one free primary alcohol
(Fig. 3), whereas structure 2 combines a p-bromo-substituted
benzylic ether with a primary alcohol. The scaffold 4 substitutes
the free primary alcohol with a methyl acetylene group, retaining
the benzyl-protected alcohol. In principle, 3 also allows for the
interconversion of [6,5]- and [6,6]-spiroketal units as a source of
skeletal change.
The plan for the preparation of the spiroketals 1 to 4 was
based on the spiroketalisation of a b-keto-1,3-dithiane precursor
(Fig. 3), which could be generated from the ynone through
a double-conjugate addition of the requisite dithiol using a
method previously developed by our group.36 The ynone could
be derived from the addition of an appropriate Grignard reagent
into the ynal, followed by Dess–Martin periodinane oxidation and
We envisaged the use of the ynals as flexible chiral building
blocks towards the generation of spiroketals through the addition
of nucleophiles at the aldehyde functionality. Furthermore, as
shown in previous work from our group,37 we anticipated that
the presence of the dithiane group would influence the isomeric
ratio of the resulting spiroketals, slowing the equilibration between
spiroketal isomers through the inductive effect of the two sulfur
atoms and thus destabilising the interaction of the sulfur lone pair
with those on the oxygen of the C–O.
As starting materials for the spiroketals, the ynals 5 and 6 were
prepared efficiently on a multigram scale (40–50 g) starting from
the enantiopure (R)-glycidol (Scheme 2).
In general terms (Scheme 2) the first synthetic step involves
the protection of the primary hydroxyl group of glycidol through
formation of the benzylic ether derivative.38 This is followed by ring
opening of the epoxide with TMS-protected acetylide and silyl-
deprotection, which gives the (S)-alcohol in a straightforward
Fig. 3 Spiroketal units and their retrosynthetic analysis.
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and 2 in near quantitative yields. For each of the scaffolds, a
diastereomeric mixture of the precursor resulted in the formation
of three configurationally different spiroketal isomers 1a–c and
2a–c, respectively, with a ratio of 2 : 1 : 3. In particular, the
10S-diastereomeric precursors would lead, exclusively, to isomers
1c and 2c, whereas the 10R-diastereomers would yield a 2 : 1
mixture of 1a,2a and 1b,2b. The isomers 1a and 2a exhibited
an ‘axial-equatorial’ arrangement of the acetal oxygen atoms
(Fig. 4, C6–O bond in green), resulting in only one stabilising
anomeric effect in combination with diequatorial substituents at
C2 and C10 (Scheme 3). In contrast, isomers 1b and 2b show an
‘axial–axial’ arrangement with a favourable bis-anomeric effect
(Fig. 4, C6–O bonds in green), but with high-energy 1,3-diaxial
interactions (Scheme 3, substituent at C10). Finally, the most
abundant isomers 1c and 2c present the most favourable ther-
modynamic configuration with a double anomeric contribution
(Fig. 4, C6–O bonds in green) and diequatorial substituents. Each
of the three spiroketal isomers of 1 and 2 were easily isolated
by column chromatography. It was possible to determine the
absolute configuration of spiroketals 1a, 1c and 2c, all three
of which were obtained as white, crystalline solids, by X-ray
crystallography experiments (Fig. 5). Looking at the space-filling,
3D impression of isomers 1a and 1c (Fig. 5b), the clear differences
in molecular shape between the two spiroketals give a strong
indication of how such differences could translate into molecular
diversity within a collection of small molecule derivatives. The
absolute configuration of 1b was confirmed by extensive spectro-
scopic studies, most noticeably by analysis of nOe enhance-
ments. NOESY experiments also unequivocally confirmed the
configuration at the C6 anomeric centre in spiroketals 2a and
2b as shown.
Scheme 2 Reagents and conditions: (i) NaH, PhCH2Br or p-BrPhCH2Br,
TBAI, DMF, 0 ◦C, 18 h; (ii) TMSCCH, n-BuLi, −78 ◦C, THF, BF3·THF,
18 h; (iii) K2CO3, MeOH, rt, 2 h; (iv) TESCl, imid., THF, rt, 18 h;
(v) n-BuLi, −78 ◦C, THF, 30 min then N-formylmorpholine, rt, 18 h.
manner. Further silyl-protection and carbonylation of the resul-
tant terminal acetylene affords (S)-ynals 5 and 6 in a 62 and
58% overall yield, respectively, with 99% ee over five linear steps.
Starting from (S)-glycidol, the enantiomer of 5 is also synthesised
in the same yield following a similar procedure.
Initially, ynals 5 and 6 were used as starting materials for the
synthesis of the spiroketal scaffolds 1 and 2, respectively. The route
involved 1,2-carbonyl addition of the Grignard reagent 4-pentenyl
magnesium bromide to ynals 5 or 6, followed by Dess–Martin
periodinane oxidation of the alcohol 7 or 8 to form ynones 9 or 10
(Scheme 3). Dihydroxylation of the terminal olefins with osmium
tetroxide was followed by the smooth conversion of the resultant
diols 11 and 12 into b-keto-1,3-dithiane derivatives 13 and 14
respectively in excellent yields. These precursors were amenable to
acid-catalysed spiroketalisation with dilute, aqueous perchloric
acid (under thermodynamic conditions) to form spiroketals 1
Scheme 3 Reagents and conditions: (i) CH2 CH(CH2)3MgBr, Et2O, 30 ◦C, 4 h; (ii) Dess–Martin periodinane, DCM, rt, 2 h; (iii) OsO4, NMO,
H2O–tBuOH, 0 ◦C, 18 h; (iv) HS(CH2)3SH, NaOMe, MeOH–DCM, −10 ◦C, 18 h; (v) HClO4 10% aq., MeCN–DCM, 0 ◦C, 30 min.
=
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Fig. 4 The anomeric effect in [6,6]-spiroketal units 1a–c and 2a–c.
Fig. 5 3D impressions of the spiroketals 1a and 1c determined by X-ray crystallography experiments.
This synthetic approach achieved the formation of the [6,6]-
membered ring spiroketal units through a series of high yielding
and straightforward transformations, with overall yields of 74 and
72% for 1 and 2 starting from ynals 5 and 6, respectively, in gram
quantities. The spiroketalisation event was shown as a key step to
incorporating stereochemical change into the spiroketal scaffold
with the formation of the three isomers.
Further studies aimed at understanding the stereochemical
outcome of the spiroketal ring formation were also carried out
in the form of asymmetric dihydroxylation of 11 to furnish either
of the diastereomeric products. Sharpless asymmetric dihydroxy-
lation using AD-mix-a and b furnished the diastereomerically-
enriched diols 11a and b with 72 and 73% de, respectively
(Scheme 4). Formation of the dithiane derivative occurred in 90%
◦
Scheme 4 Reagents and conditions: (i) AD-mix-b, H2O–tBuOH, 0 C, 18 h; (iv) AD-mix-a, H2O–tBuOH, 0 ◦C, 18 h; (ii) HS(CH2)3SH, NaOMe,
MeOH–DCM, −10 ◦C, 18 h; (iii) HClO4 10% aq., MeCN–DCM, 0 ◦C, 30 min.
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yield on both diastereoisomers and the spiroketalisation events
proceeded in a quantitative manner: it also confirmed that the 10R-
diastereomer 11a provides a 2 : 1 mixture of 1a and 1b (Scheme 4)
and the 10S-diastereomeric precursor 11b provides, exclusively,
isomer 1c. The spiroketalisation was therefore performed across a
◦
range of temperatures (−30 C to rt) with no observable change
in the configurational outcome.
To investigate the use of stereochemical change within a
collection of spiroketal derivatives, we initially looked at the
ability of 1a–c and 2a–c to epimerise at the spiroketal carbon
C6 under acidic conditions. We found that treating isomers 1a and
1b with dilute, aqueous perchloric acid (under thermodynamic
conditions), led to successful epimerisation of the starting material
as a 2 : 1 mixture of 1a : 1b (Scheme 5).
=
Scheme 6 Reagents and conditions: (i) CH2 CH(CH2)2MgBr, Et2O,
30 ◦C, 4 h; (ii) Dess–Martin periodinane, DCM, rt, 2 h; (iii) AD-mix-b,
H2O–tBuOH, 0 ◦C, 18 h; (iv) TESOTf, py, MeOH–DCM, 0 ◦C, 30 min;
(v) HS(CH2)3SH, NaOMe, MeOH–DCM, rt, 18 h; (vi) HClO4 10% aq.,
MeCN–DCM, 0 ◦C, 30 min.
jected to protection of the vicinal diol allowing for the synthesis of
the b-keto-1,3-dithiane 19 in 95% yield at rt. The spiroketalisation
of the diastereomerically-enriched mixture of b-keto-1,3-dithiane
derivative proceeded under the same conditions described above,
leading to the formation of the [6,5]-membered ring spiroketals
3a and 3b in yields of 65 and 15%, respectively. The two [6,5]-
membered ring spiroketals have been isolated enantiomerically
pure and their structures determined by NOESY experiments. In
the case of both isomers the C6–O bond of the five-membered ring
has a pseudo-axial orientation with respect to the six-membered
ring, maximising the stabilising anomeric contribution (Scheme 6,
C6–O bond in green). The presence of a third spiroketal isomer
Scheme 5 Reagents and conditions: (i) HClO4 10% aq., MeCN–DCM,
0 ◦C, 1 h.
The equilibration was also performed within a range of temper-
atures (−30 to 30 ◦C) and reaction times (10 min to 24 h) giving
the same 1a : 1b isomeric ratio.
Epimerisation at the spiroketal carbon was also performed on
spiroketals 2a and 2b providing the same outcome. These initial
results show the propensity of the compounds derived from [6,6]-
membered ring spiroketal scaffolds to undergo stereochemical
change using simple and mild reaction conditions.
The preparation of the [6,5]-membered ring spiroketals 3 and 4
(Scheme 6) was achieved following a similar route to the [6,6]-
membered ring compounds. It is important to underline that
scaffold 3, due to the presence of the hydroxyl group as the
substituent at C9, is set up for skeletal change by conversion into
the [6,6]-membered ring spiroketal. In the case of 4, the presence
of the terminal alkyne allows for 1,3-dipolar addition of azide
derivatives as an example of click-chemistry.39
The synthesis of the common intermediate 16 came as a result
of the addition of 4-butenyl magnesium bromide to the ynal 5,
followed by oxidation to give the ynone 16 in 93% yield over two
steps. The preparation of the spiroketal 3 involved the formation
of the 1,2-diol, which was performed in an asymmetric fashion
by Sharpless dihydroxylation with AD-mix-b catalyst in 94% yield
and 71% de. The diastereomerically-enriched mixture was sub-
1
was detected by H and 13C NMR analysis of the crude reaction
mixture, but attempts to isolate the compound resulted in its
degradation. Evaluation of alternative separation techniques to
obtain this isomer are under investigation. The synthesis of
spiroketal 4 (Scheme 7) proceeded by epoxidation of the terminal
alkene of ketone 16, in a racemic fashion, to give in 75% yield
the oxirane derivative 20, and this was followed by ring opening
with TMS–acetylide in an unoptimised 50% yield. TES-protection
of the resulting secondary alcohol and subsequent 1,4-conjugate
addition of 1,3-propandithiol afforded the spiroketal precursor 23
in 45% over three steps. Spiroketalisation afforded 4 in quantitative
yield as a mixture of two isomers 4a and 4b, in a 1 : 1 ratio.
In each case NMR studies prove that the six-membered ring
bears the oxygen substituent of the five-membered ring axially.
Synthesis of a collection of new spiroketal derivatives: elaboration
of the spiroketal units
Dithiane removal to unveil the ketone functionality at carbon C4
was the first synthetic modification performed on the spiroketal
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Scheme 9 Reagents and conditions: (i) (CH3)3SiOOSi(CH3)3, BF3·Et2O
or SnCl4 or (CH3)3SiOTf, DCM, −40 to −20 ◦C, 12 h.
Chaykovsky homologative epoxidation conditions (Scheme 10)
the preferential formation of one diastereomeric epoxide (27) was
successfully achieved in good yield. The absolute configuration of
the epoxide was determined by NMR, in particular by NOESY
experiments. We believe that given its specific reactivity, the C4
ketone may convey interesting properties to the compounds in
terms of their activity during bioassay screening.
Scheme 7 Reagents and conditions: (i) mCPBA, NaH2PO4, DCM, rt,
13 h; (ii) TMSCCH, n-BuLi, −78 ◦C, BF3·THF, rt, 30 min (iii) TESCl,
imid., rt, 2 h; (iv) HS(CH2)3SH, NaOMe, MeOH–DCM, rt, 18 h;
(v) HClO4 10% aq., MeCN–DCM, 0 ◦C, 30 min.
scaffolds 1a–c and 2c. This was achieved using a mild, chemoselec-
tive method40 to give ketones 24a–c and 25 in high yield, with no
undesirable oxidation of the primary alcohol and no epimerisation
at spiroketal carbon C6 (Scheme 8).
Scheme 10 Reagents and conditions: (i) Me3S(O)+I−, KOtBu, DMSO, rt,
24 h.
Starting from 24c, silyl-protection (28) followed by debenzy-
lation (29) of the resulting silyloxyethers allowed for efficient
differentiation of the two primary hydroxyl groups for further
elaboration (Scheme 11).
Scheme 8 Reagents and conditions: (i) NaClO2, NaH2PO4, 2-methyl-
2-butene, MeOH–H2O, rt, 45 min.
The carbonyl group at carbon C4 is present in a number of
natural spiroketals.20 In its own right this group could be useful
for biological evaluation if not ideal in terms of drug development.
However it was our intention to explore the reactivity at the ketone
centre in an effort to prepare analogues at C4. The literature
transformations on similar spiroketal substrates involve stereos-
elective reduction to the alcohol, or the addition of Grignard
reagents (i.e. MeMgBr).41 In our case, reductive amination of
24c using methylamine, 2-pyridyl-methylamine and 3-morpholin-
4-yl-propylamine under a variety of different conditions failed.
Efforts to convert 24c to the corresponding endocyclic ester to
form a [7,6]-membered ring spiroketal, under the standard Baeyer–
Villiger oxidative conditions (mCPBA, pH 7.6 buffer at rt) were
also unsuccessful; only starting material was recovered.
Scheme 11 Reagents and conditions: (i) TESOTf, 2,6-lutidine, DCM,
−78 to 0 ◦C, 5 min; (ii) Pd(OH)2, CaCO3, EtOH, 70 ◦C, 18 h.
Spiroketal derivatives 24a and b were also shown to be capable
of epimerising at carbon C6 under the same mild conditions used
for compounds 1a and b (Scheme 12). With the aim of exploring
the chemistry of the substituents of the spiroketal ring, the next
step was the oxidation of the primary hydroxyl group at C11 of
24a–c to the corresponding aldheydes 30a–c. This transformation
was achieved using Dess–Martin periodinane (Scheme 13).
The synthesis of an aldehyde of type 30 (with the carbonyl
alpha to a spiroketal system) has very little literature precedent.43
We successfully managed to isolate the three isomers in good
Interestingly, treatment with a masked form of hydrogen
peroxide,42 in the presence of different Lewis acid catalysts
(Scheme 9), including BF3·Et2O, SnCl4 and (CH3)3SiOTf afforded
dioxirane 26. The use of 26 as a potential chiral epoxidation
catalyst is currently under investigation. Finally, under Corey–
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The chemical variation of the spiroketal scaffolds took into
consideration the synthesis of spiroketal-derived small molecules
as potential lead compounds.
To this end, elaboration of the alcohol functional group at C11
was performed, leading to a collection of potential orally bio-
available lead compounds.46
A rapid and clean synthesis of activated carbonate esters of
the spiroketal isomers starting from 24a, 24c, and 25 (Scheme 15)
enabled straightforward access to the N-substituted carbamate
derivatives 35a–b, 36a–b and 37a–b in good yields. In formation
of both the carbonate and the carbamate derivatives, the desired
products were isolated enantiomerically pure.
Scheme 12 Reagents and conditions: (i) HClO4 10% aq., MeCN–DCM,
◦C, 1 h.
0
Scheme 13 Reagents and conditions: (i) Dess–Martin periodinane,
DCM, rt, 2 h.
yields using specific isolation conditions. With a reliable route
to 30, the target was to install medicinally and synthetically
interesting amines via regioselective reductive amination at the
highly reactive a-alkoxy aldehyde. Initial investigations involved
optimisation of the reaction conditions on a simplified spiroketal
31 synthesised previously by our group.28 Oxidation to aldehyde 32
was performed following the same procedure used for 30, and gave
only the most thermodynamically stable isomer. Condensation
with an appropriate primary amine afforded secondary amines
34a–b, after polymer-supported borohydride reduction44 of the
isolable imine intermediates 33a–b (Scheme 14). The reduction
of the imine 33a was also succesfully achieved by catalytic
hydrogenation in a continuous flow-reactor.45
Scheme 15 Reagents and conditions: (i) p-nitrophenyl chloroformate, py,
THF, rt, 20 min (ii) RNH2, DMF, rt, 10 min.
The primary hydroxyl group of spiroketals 24 and 25 were
then coupled with the carboxylic acid of a series of natural and
unnatural N-Fmoc-protected a-amino acids. First, the coupling
reaction was performed on the double anomeric stabilised iso-
mers 24c and 25, as shown in Table 1. A reaction condition
screen gave the desired products using O-(7-azabenzotriazole-1-
yl)-N,N,NꢀNꢀ-tetramethyluronium hexafluorophosphate (HATU)
as coupling reagent, 1-hydroxy-7-azabenzotriazole (HOAt) as
additive and diisopropylethyl amine (DIEA) as base with the
reaction time between 18–48 h. Furthermore, under the selected
conditions, all the spiroketal derivatives (Table 1) were isolated
enantiomerically pure. Condensation of the primary alcohol with
the carboxylic acid of glycine (38a, 39), (S)-phenylalanine (38c)
and (S)-2-furyl-glycine (38e) gave the desired products in 70–94%
yields. Interestingly, phenyl and 2-furyl-glycine coupled in higher
yields than alanine, which, despite the increasing steric demand
(R2 = H < CH3 < CH2–phenyl-2-furyl), suggests an increase
in reactivity due to favourable p-stacking interactions with the
spiroketal C2 methyloxybenzylic group. Compounds 38c and 38f
were isolated in 50 and 44% yield, respectively, by coupling 1c with
(S)-alanine and (S)-a-cyclobutane glycine. Compound 38d was
formed in a 26% yield as a result of the condensation of the primary
alcohol with the carboxylic acid group of (S)-a-allyl-glycine. In
Scheme 14 Reagents and conditions: (i) Dess–Martin periodinane,
DCM, rt, 2 h; (ii) RNH2, EtOH, rt; (iii) PS–borohydride, THF, rt, 18 h.
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Table 1 Coupling reactions of 24c and 25 with N-Fmoc-protected a-
We therefore prepared a number of selected spiroketal ester
derivatives of the three different isomers. Fmoc-deblocking and
partial scavenging of the fullvene by-product was performed
with polymer-supported piperazine47 using microwave heating at
120 ◦C for 30 min. This procedure afforded complete N-Fmoc
deprotection and avoided the need for a purification step. Instead,
direct addition of ethyl isocyanate to the crude amine mixture
readily provided urea derivatives 42a–e (Scheme 17) and 44b
(Scheme 19) in high yields, as a single diastereoisomer. However,
epimerisation at the C6 centre was observed in the synthesis of
urea derivatives 43a–b and these were isolated as a mixture with
isomers 44a–b in a ca. 3 : 2 product ratio (Scheme 18).
amino acids
Entry
R
R1
R2
Yield (%)a
1
2
3
4
5
6
7
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2Ph
CH2–p-Br–Ph
H
H
H
H
H
R1 R2
H
H
CH2Ph
CH3
CH2CH CH2
2-Furyl
–(CH2)3–
H
38a
38b
38c
38d
38e
38f
39
93
70
50
26
94
44
92
=
=
a All compounds have been isolated with 98% de. Reagents and conditions:
(i) N-Fmoc-protected-a-amino acid, HATU, HOAt, DIEA, DMF, rt, 18–
48 h.
Table 2 Coupling reactions of 24a with N-Fmoc-protected-a-amino
acids
Scheme 17 Reagents and conditions: (i) PS–piperazine, DCM, MW,
120 ◦C, 30 min; (ii) EtNCO, DCM, rt, 30 min.
Furthermore, mesylation of the crude deprotected primary
amines starting from compounds 38a–c and 38f provided access
to a series of sulfonamide derivatives 45a–d in quantitative yields
(Scheme 20).
As a comparison in terms of potential biological activity, the
derivatives 46–48 (Fig. 6) were also prepared quantitatively from
the simple spiroketal 31, using the approaches already described.
Entry
R1
R2
Yield (%)a
1
2
3
H
H
H
H
CH2Ph
2-Furyl
40a
40b
40c
90
65
95
a All compounds have been isolated with 98% de. Reagents and conditions:
(i) N-Fmoc-protected-a-amino acids, HATU, HOAt, DIEA, DMF, rt, 18–
48 h.
some cases the coupling reactions were not high yielding, but our
focus was to synthesise derivatives using a range of diverse a-
amino acids of relevance as medicinal chemistry building blocks.
Using the same reaction conditions, the coupling of the primary
alcohol of spiroketal isomers 24a (Table 2) and 24b (Scheme 16)
was performed. The compounds 40b–c and 41 were prepared in
good to excellent yields and were also isolated enantiomerically
pure. The next synthetic step was the elaboration of the terminal
N-Fmoc a-amino group to achieve spiroketal derivatives suitable
for biological screening.
Fig. 6 Simple spiroketal derivatives.
It is important to highlight that the complete series of
carbamate, urea and sulfonamide derivatives closely match the
Lipinski rule of five.46 Moreover, the primary alcohol of compound
24c was oxidised to the corresponding acid as an intermediate
for amide coupling studies. By way of illustration, the amide
derivative 49 was prepared in an excellent 90% yield over three
steps (Scheme 21). Finally, starting from spiroketal 24c, triazole
derivative 51 was obtained in quantitative yield via formation of
the azide precursor and addition of the requisite alkyne in a click-
chemistry fashion48 (Scheme 22). Both routes to compounds 49
and 51 represent viable procedures for the synthesis of a series of
amide and triazole derivatives.
Scheme 16 Reagents and conditions: (i) N-Fmoc-protected-(S)-2-furyl-
a-glycine, HATU, HOAt, DIEA, DMF, rt, 18 h.
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Scheme 18 Reagents and conditions: (i) PS–piperazine, DCM, MW, 120 ◦C, 30 min; (ii) EtNCO, DCM, rt, 30 min.
Scheme 19 Reagents and conditions: (i) PS–piperazine, DCM, MW,
120 ◦C, 30 min; (ii) EtNCO, DCM, rt, 30 min.
Scheme 22 Reagents and conditions: (i) Tf2O, py, DCM, −78 ◦C to rt,
30 min; (ii) NaN3, DMF, rt, 1 h; (iii) PhCCH, CuSO4·5H2O 1 mol%,
sodium ascorbate 5 mol%, H2O–tBuOH, rt, 3 h.
Conclusions
Scheme 20 Reagents and conditions: (i) PS–piperazine, DCM, MW,
DMF, 120 ◦C, 30 min; (ii) MeSO2Cl, py, DCM, rt, 2 h.
In summary, we have synthesized [6,6]- and [6,5]-membered ring
spiroketal units containing three independent points of variation
geared towards the generation of a collection of natural product-
like compounds.
In particular, the spiroketal units 1–4 were prepared following
an efficient linear route, with the last synthetic steps generating
the stereochemical/configurational change through the synthe-
sis of a series of spiroketal isomers with different molecular
shapes. Preliminary studies have also shown the potential of the
epimerisation event at the spiroketal carbon C6 as a source of
stereochemical variation within the collection of spiroketals. In
order to increase molecular diversity, the possibility of achieving
skeletal change on spiroketal 3 is still under investigation. By
successful elaboration of the units 1, 2 and 31 a collection of
structurally-diverse, new spiroketal derivatives (24a–c, 25a, 34a–
b, 35a–b, 36a–b, 37a–b, 42a, 42e, 43a–b, 44a–b, 45a–d, 46–49,
51) was achieved towards orally-bioavailable lead compounds.
Extensive biological screening of all the compounds is currently
under evaluation and will be reported separately.
Scheme 21 Reagents and conditions: (i) PDC, DMF, rt, 18 h; (ii) p-nitro-
phenyl chloroformate, py, THF, rt, 20 min; (iii) 2-picolyl amine, rt, 10 min.
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but-1-enyl-4-magnesium bromide or pent-1-enyl-5-magnesium
bromide (2.3 eq.) in anhydrous THF (1.0 M), pre-cooled to
−78 ◦C. The reaction mixture was heated at 30 ◦C for 4 h and then
quenched with a saturated, aqueous solution of NH4Cl followed
by aqueous phase extraction using Et2O (×3). The recombinant
organic extracts were washed with distilled water (×2) and brine
(×1), dried over anhydrous MgSO4, filtered, and then concentrated
in vacuo. The resultant crude was then purified by gravimetric
column chromatography on silica, using 1 : 4 Et2O and petroleum
ether as eluent.
Experimental
General experimental details
All melting points were determined on a Reichert hot stage
apparatus, and are uncorrected. Infrared spectra were recorded
using a Perkin-Elmer One FTIR spectrometer fitted with an ATR
sampling accessory as either liquid films or dilute solutions in
1
spectroscopic grade chloroform or dichloromethane. H NMR
spectra were recorded on Bru¨ker DPX-400 (400 MHz) and Bru¨ker
DRX-600 (600 MHz) instruments as dilute solutions in deuterated
chloroform unless otherwise stated. The chemical shifts are
reported relative to tetramethylsilane or residual chloroform as an
internal standard. The multiplicity of the signals is designated by
the following abbreviations: s, singlet; d, doublet; t, triplet; q, quar-
tet; qn, quintet; br, broad; m, multiplet. All coupling constants,
J, are reported in Hertz (Hz). 13C-NMR spectra were recorded
at 100 and 150 MHz on Bruker DPX-400 and Bruker DRX-
600 instruments, respectively. The spectra were recorded as dilute
solutions in deuterated chloroform unless otherwise stated, with
chemical shifts reported relative to the residual chloroform as an
internal standard on a broad band decoupled mode. Mass spectra
were obtained on a Kratos MS890MS instrument using electron
impact (+EI), a Kratos-QTQF spectrometer using electrospray
ionisation (+ESI), or LCT Premier spectrometer by Waters using
Micromass MS software by electrospray ionisation (+ESI) at
the Department of Chemistry, Cambridge. Optical rotations were
measured using a Perkin Elmer Model 343 polarimeter; [a]2D5 values
are reported in 10−1 deg cm2 g−1. All microwave heating was
performed on an Emrys synthesizer Biotage AG, 1725 Discovery
Drive, Charlottesville, Virginia 22911. Chiral HPLC analyses
were performed on an Agilent 1100 series HPLC with a diode
array detection, recording at the specified wavelength and with
(10S)-11-Benzyloxy-10-triethylsilanyloxyundec-1-en-7-yn-6-ol
(7). A clear, colourless oil (93%); Rf 0.16 (1 : 4 Et2O–petroleum
ether); tmax(film)/cm−1: 3387, 2953, 2912, 1641, 1488, 1239, 1010,
910, 727 and 698; dH (400 MHz; CDCl3; Me4Si) 7.26–7.35 (5 H, m,
=
Ar), 5.75–5.86 (1 H, m, R–CH CH2), 5.02 (1 H, dd, J 17.1 and
=
=
1.6, R–CH C(HA)H), 4.95–4.98 (1 H, m, R–CH C(HB)H), 4.55
(2 H, s, –OCH2Ph), 4.32 (1 H, d, J 5.2, H6), 3.95–3.98 (1 H, m, H2),
3.45–3.53 (2 H, m, H1), 2.53 (1 H, ddd, J 16.7, 6.2 and 1.7, H3A),
2.40 (1 H, ddd, J 16.7, 5.6 and 1.8, H3B), 2.06–2.10 (2 H, m, H9),
1.76 (1 H, d, J 5.2, OH), 1.63–1.72 (2 H, m, H7), 1.50–1.60 (2 H,
m, H8), 0.97 (9 H, t, J 7.9, –OSi(CH2CH3)3) and 0.63 (6 H, q, J
7.8, –OSi(CH2CH3)3); dC (100 MHz; CDCl3; Me4Si) 138.4, 138.3,
128.3, 127.6, 127.5, 114.7, 82.8, 82.1, 73.4, 73.3, 70.2, 62.5, 37.4,
33.3, 24.9, 24.4, 6.8 and 4.9; m/z (+ESI) calc. for C24H38NaO3Si
(MNa+) 425.2488, found 425.2498.
(10S)-11-(4-Bromobenzyloxy)-10-triethylsilanyloxyundec-1-en-
7-yn-6-ol (8). A clear, colourless oil (95%); Rf 0.25 (3 : 7 Et2O–
petroleum ether); tmax(film)/cm−1: 3398, 2952, 2912, 1641, 1594,
1488, 1239, 1205, 1092, 1071, 910, 835, 802 and 698; dH (400 MHz;
CDCl3; Me4Si) 7.46 (2 H, d, J 8.3, Ar), 7.21 (2 H, d, J 8.3, Ar), 5.80
R
a Chiracelꢀ OD (25 cm × Ø 0.46 cm), manufactured by Daicel
=
=
(1 H, m, R–CH CH2), 5.02 (1 H, d, J 17.2, R–CH C(HA)H),
Chemical Industry. X-Ray crystal structures were determined on
a Nonius Kappa CCD instrument at the Cambridge University
Chemistry Laboratory (CUCL) X-Ray Laboratory, Lensfield
Road, Cambridge, CB2 1EW.‡ Gravimetric or flash column
chromatography was carried out using Merck Kieselgel 230–400
mesh or Fluka florisil. Analytical thin layer chromatography was
performed using pre-coated glass-backed plates (Merck Kieselgel
F254) and visualised by exposure to ultra-violet radiation (254 nm)
and treatment with acidic ammonium molybdate (VI). All solvents
and chemicals were used as provided by the supplier, or were dried
and/or purified according to the accepted literature procedures.
Petroleum ether refers to the 40–60 ◦C boiling point fraction
unless otherwise stated. All reactions were conducted in oven-
dried glassware at room temperature, under an argon atmosphere
unless otherwise stated. All organic extracts were dried over
anhydrous magnesium sulfate and filtered under gravity. Solvents
were removed from the extracts on a Bu¨chi rotary evaporator
under water pump or oil pressure.
=
4.96 (1 H, d, J 10.2, R–CH C(HB)H), 4.49 (2 H, s, –OCH2Ph),
4.30–4.33 (1 H, m, H6), 3.94–3.97 (1 H, m, H2), 3.45–3.51 (2 H,
m, H1), 2.51 (1 H, ddd, J 16.8, 6.5 and 1.7, H3A), 2.39 (1 H, ddd,
J 16.7, 5.5 and 1.5, H3B), 2.08 (2 H, m, H9), 1.63–1.70 (2 H, m,
H7), 1.52–1.58 (2 H, m, H8), 0.96 (9 H, t, J 7.9, –OSi(CH2CH3)3)
and 0.62 (6 H, q, J 7.8, –OSi(CH2CH3)3); dC (100 MHz; CDCl3;
Me4Si) 138.4, 137.2, 131.4, 129.2, 128.3, 114.7, 90.8, 82.1, 73.3,
72.6, 70.2, 62.6, 37.4, 33.3, 24.9, 24.4, 6.8 and 4.9; m/z (+ESI)
calc. for C24H37BrNaO3Si (MNa+) 503.1593, found 503.1584.
(9S)-10-Benzyloxy-9-triethylsilanyloxydec-1-en-6-yn-5-ol (15).
A clear, colourless oil (96%); Rf 0.18 (1 : 4 Et2O–petroleum
ether); tmax(film)/cm−1: 3439, 2953, 2912, 2876, 1641, 1594, 1488,
1458, 1414, 1361, 1239, 1201, 1094, 1071, 1011, 910, 835, 795,
727, 698 and 673; dH (600 MHz; CDCl3; Me4Si) 7.26–7.36 (5 H,
=
m, Ar), 5.75–5.86 (1 H, m, R–CH CH2), 4.97–5.07 (2 H, m,
=
R–CH CH2), 4.55 (2 H, s, –OCH2Ph), 4.33 (1 H, d, J 5.2, H6),
3.99–4.03 (1 H, m, H2), 3.44–3.52 (2 H, m, H1), 2.53 (1 H, ddd,
J 16.5, 6.3 and 1.7, H3A), 2.40 (1 H, ddd, J 16.5, 5.8 and 1.9, H3B),
2.08–2.12 (2 H, m, H8), 1.68–1.78 (3 H, m, H7 & OH), 0.97 (9 H, t,
J 7.9, –OSi(CH2CH3)3) and 0.63 (6 H, q, J 7.8, –OSi(CH2CH3)3);
dC (150 MHz; CDCl3; Me4Si) 138.1, 136.8, 128.3, 127.6, 127.5,
115.2, 82.5, 81.8, 73.4, 73.2, 70.6, 62.4, 37.3, 25.3, 24.6, 6.8 and
4.8; m/z (+ESI) calc. for C23H36NaO3Si (MNa+) 411.2331, found
411.2303.
General procedure for the synthesis of ynols 7, 8 and 15
A solution of ynal 5 or 6 in anhydrous THF (5 M with rinsing × 2)
was added, dropwise, to a stirred, in situ preparation of either
‡ CCDC reference numbers 600002–600004. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b603015g.
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General procedure for the synthesis of ynones 9, 10 and 16
(+ESI) calc. for C23H35O3Si (MH+) 387.2355, found 387.2356;
calc. for C23H34NaO3Si (MNa+) 409.2175, found 409.2169.
To a stirred solution of ynol 7, 8 or 15 in anhydrous DCM (0.2 M)
was added Dess–Martin periodinane reagent (1.5 eq.) at 0 ◦C. The
reaction mixture was allowed to stir at ambient temperature for
2 h then quenched with a 1 : 1 mixture of saturated, aqueous
Na2S2O3 and NaHCO3 solutions, and left to stir for a further
30 min. The aqueous phase was then extracted with Et2O (×3)
and the recombinant organic extracts washed with distilled water
(×2), and brine (×1). Drying over anhydrous MgSO4, followed by
filtration and in vacuo evaporation yielded a clear, colourless liquid
crude, which was purified by gravimetric column chromatography
on silica, using 1 : 4 Et2O and petroleum ether as eluent.
General procedure for the synthesis of diols 11, 12 and 17
Method A. To a rigorously stirred solution of OsO4 (5 mol%)
and NMO (1.1 eq.) in 1 : 1 distilled water–t-butanol (0.02 M) was
added ynone 9 or 10 at 0 ◦C. The resultant heterogeneous mixture
was then stirred for 18 h. Reductive work-up involved the slow,
portionwise addition of solid Na2SO3 (1.5 g mmol−1 of 9 or 10)
followed by further stirring for 1 h. The reaction mixture was then
diluted with EtOAc and the aqueous phase extracted with EtOAc
(×3). The recombinant organic extracts were washed with distilled
water (×1) and brine (×1), dried over anhydrous MgSO4, filtered
and then concentrated in vacuo. Purification of the resultant crude
oil was performed by gravimetric column chromatography on
silica, using 4 : 1 EtOAc and petroleum ether as eluent.
(10S)-11-Benzyloxy-10-triethylsilanyloxyundec-1-en-7-yn-6-one
(9). A clear, colourless liquid (94%); Rf 0.54 (1 : 4 Et2O–
petroleum ether); [a]2D5 −2.9 (c 0.47, CH2Cl2); tmax(film)/cm−1:
2954, 2912, 2216, 1673, 1642, 1496, 1455, 1413, 1362, 1237, 1093,
1003, 911, 729 and 697; dH (400 MHz; CDCl3; Me4Si) 7.17–7.28
(2S)-1-Benzyloxy-10,11-dihydroxy-2-triethylsilanyloxyundec-4-
yn-6-one (11). A clear, colourless oil (93%); Rf 0.34 (EtOAc);
tmax(film)/cm−1: 3419, 3056, 2954, 2214, 1670, 1455, 1420, 1362,
1238, 1096, 1006, 896, 731 and 698; dH (600 MHz; CDCl3; Me4Si)
7.26–7.34 (5 H, m, Ar), 4.53 (2 H, s, –OCH2Ph), 3.99–4.03 (1 H, m,
H2), 3.63–3.66 (1 H, m, H10), 3.59 (1 H, d, J 11.0, H11A), 3.44–3.49
(2 H, m, H1), 3.39–3.42 (1 H, m, H11B), 2.95 (1 H, br s, OH), 2.78
(1 H, br s, OH), 2.68 (1 H, dd, J 17.2 and 5.6, H3A), 2.53–2.57
(3 H, m, H7 and H3B), 1.76–1.80 (1 H, m, H8A), 1.67–1.71 (1 H, m,
H8B), 1.39–1.43 (2 H, m, H9), 0.94 (9 H, t, J 7.9, –OSi(CH2CH3)3)
and 0.61 (6 H, q, J 7.9, –OSi(CH2CH3)3); dC (150 MHz; CDCl3;
Me4Si) 187.9, 138.0, 128.3, 127.7, 127.6, 91.4, 82.0, 73.4, 73.2, 71.7,
69.4, 66.6, 45.1, 32.2, 25.3, 19.8, 6.7 and 4.8; m/z (+ESI) calc. for
C24H38NaO5Si (MNa+) 457.2386, found 457.2391.
=
(5 H, m, Ar), 5.63–5.73 (1 H, m, R–CH CH2), 4.95–4.96 (1 H,
=
=
m, R–CH C(HA)H), 4.89–4.92 (1 H, m, R–CH C(HB)H), 4.46
(2 H, s, –OCH2Ph), 3.92–3.97 (1 H, m, H2), 3.35–3.43 (2 H, m,
H1), 2.61 (1 H, dd, J 17.2 and 5.5, H3A), 2.47 (1 H, dd, J 17.2
and 5.9, H3B), 2.40–2.44 (2 H, t, J 7.4, H7), 1.97–2.01 (2 H, m,
H9), 1.64–1.68 (2 H, m, H8), 0.88 (9 H, t, J 7.9, –OSi(CH2CH3)3)
and 0.54 (6 H, q, J 7.8, –OSi(CH2CH3)3); dC (100 MHz; CDCl3;
Me4Si) 187.9, 138.0, 137.6, 128.3, 2 × 127.6, 115.4, 90.9, 82.0,
73.4, 73.2, 69.4, 44.6, 32.8, 25.3, 23.1, 6.7 and 4.8; m/z (+ESI)
calc. for C24H36NaO3Si (MNa+) 423.2331, found 423.2322.
(10S)-11-(4-Bromobenzyloxy)-10-triethylsilanyloxyundec-1-en-
7-yn-6-one (10). A clear, colourless oil (96%); Rf 0.48 (3 : 7 Et2O–
petroleum ether); [a]2D5 −0.4 (c 2.50, CH2Cl2); tmax(film)/cm−1:
2954, 2911, 2876, 2214, 1673, 1641, 1593, 1488, 1458, 1412, 1361,
1237, 1161, 1093, 1071, 1011, 914, 835, 803, 795, 741, 727 and 674;
dH (400 MHz; CDCl3; Me4Si) 7.47 (2 H, d, J 8.3, Ar), 7.20 (2 H,
(2S)-1-(4-Bromobenzyloxy)-10,11-dihydroxy-2-triethylsilanyl
oxyundec-4-yn-6-one (12). A clear, colourless oil (89%); Rf 0.24
(EtOAc); tmax(film)/cm−1: 3398, 2954, 2911, 2875, 2213, 1671,
1593, 1488, 1457, 1410, 1361, 1238, 1092, 1070, 1010, 925, 873,
835, 803, 728, 698 and 673; dH (600 MHz; CDCl3; Me4Si) 7.45
(2 H, d, J 8.2, Ar), 7.20 (2 H, d, J 8.2, Ar), 4.48 (2 H, s, –OCH2Ph),
3.98–4.03 (1 H, m, H2), 3.66–3.69 (1 H, m, H10), 3.62–3.64 (1 H, m,
=
d, J 8.2, Ar), 5.71–5.82 (1 H, m, R–CH CH2), 5.03–5.05 (1 H,
=
=
m, R–CH C(HA)H), 5.97–5.01 (1 H, m, R–CH C(HB)H), 4.49
(2 H, s, –OCH2Ph), 4.00–4.04 (1 H, m, H2), 3.43–3.50 (2 H, m,
H1), 2.67 (1 H, dd, J 17.2 and 5.8, H3A), 2.49–2.58 (3 H, m, H3B and
H7), 2.06–2.10 (2 H, m, H9), 1.73–1.77 (2 H, m, H8), 0.95 (9 H, t,
J 7.9, –OSi(CH2CH3)3) and 0.62 (6 H, q, J 7.8, –OSi(CH2CH3)3);
dC (100 MHz; CDCl3; Me4Si) 187.7, 137.6, 137.1, 131.5, 129.2,
121.5, 115.4, 90.7, 82.1, 73.4, 72.7, 69.4, 44.7, 33.8, 25.3, 23.1, 6.7
and 4.8; m/z (+ESI) calc. for C24H35BrNaO3Si (MNa+) 501.1436,
found 501.1407.
H
11A), 3.42–3.48 (3 H, m, H1 and H11B), 2.65–2.69 (1 H, dd, J 17.2
and 6.0, H3A), 2.52–2.57 (3 H, m, H3B and H7), 1.71–1.82 (2 H, m,
H8), 1.41–1.45 (2 H, m, H9), 0.95 (9 H, t, J 8.0, –OSi(CH2CH3)3)
and 0.61 (6 H, q, J 7.9, –OSi(CH2CH3)3); dC (150 MHz; CDCl3;
Me4Si) 187.7, 137.0, 131.5, 129.2, 121.5, 91.1, 82.0, 73.3, 72.7, 71.7,
69.4, 66.6, 45.1, 32.2, 25.3, 19.7, 6.7 and 4.8; m/z (+ESI) calc. for
C24H37BrNaO5Si (MNa+) 535.1491, found 535.1494.
(9S)-10-Benzyloxy-9-triethylsilanyloxydec-1-en-6-yn-5-one (16).
A clear, colourless oil (97%); Rf 0.60 (1 : 4 Et2O–petroleum ether);
[a]D25 −2.2 (c 2.50, CH2Cl2); tmax(film)/cm−1: 2955, 2911, 2876, 2214,
1675, 1641, 1497, 1455, 1412, 1360, 1239, 1206, 1239, 1162, 1093,
1003, 971, 915, 861, 730, 697 and 675; dH (600 MHz; CDCl3; Me4Si)
Method B. To a rigorously stirred solution of either AD-
mix-a or AD-mix-b (1.45 g mmol−1 of 9, 10 or 16) in 1 : 1
distilled water–t-butanol (0.02 M) was added ynone 9, 10 or 16
at 0 ◦C. The resultant heterogeneous mixture was then stirred for
18 h. Reductive work-up involved the slow, portionwise addition
of solid Na2SO3 (1.5 g mmol−1 of 9, 10 or 16), followed by
further stirring for 1 h. The reaction mixture was then diluted
with EtOAc and the aqueous phase extracted with EtOAc (×3).
The recombinant organic extracts were washed with distilled water
(×1) and brine (×1), dried over anhydrous MgSO4, filtered and
then evaporated in vacuo. Purification of the resultant crude oil
was performed by gravimetric column chromatography on silica,
using 4 : 1 EtOAc and petroleum ether as eluent.
=
7.26–7.34 (5 H, m, Ar), 5.75–5.85 (1 H, m, R–CH CH2), 5.05 (1 H,
=
dd, J 17.1 and 1.5, R–CH C(HA)H), 5.00 (1 H, dd, J 10.3 and
=
1.3, R–CH C(HB)H), 4.54 (2 H, s, –OCH2Ph), 3.99–4.04 (1 H, m,
H2), 3.46–3.50 (2 H, m, H1), 2.70 (1 H, dd, J 17.1 and 5.5, H3A),
2.53–2.61 (3 H, m, H3B and H7), 2.38–2.41 (2 H, m, H8), 0.96 (9 H,
t, J 8.1, –OSi(CH2CH3)3) and 0.62 (6 H, q, J 7.9, –OSi(CH2CH3)3);
dC (150 MHz; CDCl3; Me4Si) 187.9, 138.0, 136.4, 128.3, 2 × 127.6,
115.5, 91.2, 81.9, 73.4, 73.2, 69.4, 44.5, 27.9, 25.3, 6.7 and 4.8; m/z
1988 | Org. Biomol. Chem., 2006, 4, 1977–2002
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The Royal Society of Chemistry 2006
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(2S),(10R)-1-Benzyloxy-10,11-dihydroxy-2-triethylsilanyloxy-
undec-4-yn-6-one (11a). A clear, colourless oil (94%), Chiral
2950, 2910, 2874, 1712, 1671, 1552, 1488, 1457, 1414, 1362, 1238,
1166, 1088, 1070, 1010, 908, 838, 803, 728 and 675; dH (600 MHz;
CDCl3; Me4Si) 7.42–7.49 (2 H, m, Ar), 7.17–7.22 (2 H, m, Ar),
4.46–4.48 (2 H, m, –OCH2Ph), 4.21–4.23 (1 H, m, H2), 3.59–3.65
(1 H, m, H10), 3.52–3.58 (1 H, m, H11A), 3.36–3.51 (3 H, m, H1
and H11B), 3.13–3.19 (1 H, m, H5A), 2.98–3.05 (1 H, m, H5B),
2.68–2.85 (4 H, m, –S–CH2–CH2–CH2–S–), 2.41–2.65 (3 H,
m, H3A and H7), 2.28–2.41 (1 H, m, H3B), 1.88–1.94 (2 H, m,
–S–CH2–CH2–CH2–S–), 1.52–1.87 (2 H, m, H8), 1.36–1.50 (2 H,
m, H9), 0.90–0.98 (9 H, m, –OSi(CH2CH3)3) and 0.56–0.64 (6 H,
m, –OSi(CH2CH3)3); dC (150 MHz; CDCl3; Me4Si) 205.6, 137.6,
131.5, 129.3, 121.4, 75.1, 74.5, 71.7, 69.5, 66.6, 51.0, 49.5, 44.4,
42.6, 32.4, 26.6, 26.5, 24.9, 19.1, 6.9 and 5.3; m/z (+ESI) calc. for
C27H45BrNaO5S2Si (MNa+) 643.1559, found 643.1563.
R
HPLC: Chiracelꢀ OD, 9 : 1 hexanes–i-PrOH: 10.5 min (2S, 10S),
11.7 min (2S, 10R) gave 72% de.
(2S),(10S)-1-Benzyloxy-10,11-dihydroxy-2-triethylsilanyloxy-
undec-4-yn-6-one (11b). A clear, colourless oil (96%), Chiral
R
HPLC: Chiracelꢀ OD, 9 : 1 hexanes–i-PrOH: 10.6 min (2S, 10S),
11.6 min (2S, 10R) gave 73% de.
(2S),(9R)-10-Benzyloxy-1,2-dihydroxy-9-triethylsilanyloxydec-
6-yn-5-one (17). A clear, colourless oil (94%); Rf 0.38 (EtOAc);
tmax(film)/cm−1: 3396, 2953, 2911, 2876, 2214, 1670, 1496, 1455,
1412, 1361, 1238, 1206, 1093, 1003, 872, 844, 731, 697 and 674;
dH (600 MHz; CDCl3; Me4Si) 7.25–7.34 (5 H, m, Ar), 4.54 (2 H, s,
–OCH2Ph), 4.10–4.13 (1 H, m, H2), 3.66–3.69 (1 H, m, H9), 3.60–
3.62 (1 H, m, H10A), 3.41–3.51 (3 H, m, H1 and H10B), 2.64–2.72
(3 H, m, H3A and H7), 2.53–2.60 (1 H, m, H3B), 1.71–1.81 (2 H, m,
H8), 0.95 (9 H, t, J 8.0, –OSi(CH2CH3)3) and 0.61 (6 H, q, J 7.8, –
OSi(CH2CH3)3); dC (150 MHz; CDCl3; Me4Si) 187.8, 138.0, 128.4,
128.3, 127.7, 127.6, 91.8, 81.9, 73.4, 73.1, 71.2, 69.4, 66.5, 41.6,
26.9, 25.3, 6.8 and 4.8; m/z (+ESI) calc. for C23H37O5Si (MH+)
(2R),(9S)-10-Benzyloxy-1,2,9-tristriethylsilanyloxydec-6-yn-5-
one (18). A stirred solution of diol 17 (146 mg, 0.35 mmol)
in anhydrous DCM (2 cm3) was cooled to −78 ◦C and treated
sequentially with 2,6-lutidine (230 mg, 1.05 mmol, 3.0 eq.) and
TESOTf (230 mg, 0.87 mmol, 1.5 eq.). The reaction was imme-
diately warmed to 0 ◦C over 5 min, quenched with a saturated,
aqueous solution of NaHCO3 (10 cm3) and then extracted with
Et2O (4 × 10 cm3). The recombinant organic extracts were washed
with distilled water (2 × 10 cm3) and brine (1 × 10 cm3), dried over
anhydrous MgSO4 and then concentrated in vacuo. The subsequent
crude oil was purified by gravimetric column chromatography on
silica, using 1 : 19 Et2O and petroleum ether as eluent to afford
the title compound 18 as a clear, colourless oil (221 mg, 98%):
Rf 0.70 (1 : 9 Et2O–petroleum ether); tmax(film)/cm−1: 2945, 2912,
1672, 1550, 1459, 1420, 1362, 1229, 1087, 1001, 913, 819, 726 and
697; dH (400 MHz; CDCl3; Me4Si) 7.26–7.36 (5 H, m, Ar), 4.55
(2 H, s, –OCH2Ph), 3.95–4.01 (1 H, m, H2), 3.68–3.72 (1 H, m,
H9), 3.45–3.56 (4 H, m, H1 and H10), 2.45–2.70 (2 H, m, H7),
2.31–2.44 (1 H, m, H3A), 2.15–2.30 (1 H, m, H3B), 1.09–1.38 (2 H,
m, H8), 0.90–1.01 (27 H, m, 3 × –OSi(CH2CH3)3) and 0.52–0.66
(18 H, m, 3 × –OSi(CH2CH3)3); dC (100 MHz; CDCl3; Me4Si)
187.6, 138.4, 128.3, 127.5, 89.5, 80.2, 73.8, 73.4, 73.0, 70.2, 67.2,
33.2, 30.7, 25.6, 6.8, 2 × 6.7, 5.1, 4.9 and 4.8; m/z (+ESI) calc. for
C35H64NaO5Si3 (MNa+) 671.3959, found 671.3945.
R
421.2410, found 421.2393; Chiracelꢀ OD, 9 : 1 hexanes–i-PrOH:
29.5 min (2S, 9S), 31.6 min (2S, 9R) gave 71% de.
General procedure for the synthesis of dithianes 13 and 14
To a stirred solution of NaOMe (1.35 eq.) and ynone 11 or 12 in
3 : 1 anhydrous MeOH–DCM (0.08 M) was added propane-1,3-
dithiol (1.25 eq.) at −10 ◦C. The temperature was then maintained
at −10 ◦C and the yellow solution left to stir for 18 h, after which
a 1 : 1 mixture of distilled water and saturated, aqueous NaHCO3
solution was added, dropwise. The reaction mixture was then
diluted with Et2O, the aqueous phase extracted with Et2O (×3)
and the recombinant organic extracts washed with distilled water
(×2) and brine (×1). Drying over anhydrous MgSO4, filtration,
and in vacuo evaporation yielded a yellow, liquid crude, which was
purified by gravimetric column chromatography on silica, using
EtOAc as eluent.
(2ꢀꢀS )-1-[2-(3-Benzyloxy-2-triethylsilanyloxy-propyl)[1,3]-
dithian-2-yl]-6,7-dihydroxy-heptan-2-one (13). A clear, colourless
oil (93%); Rf 0.23 (EtOAc); tmax(film)/cm−1: 3421, 2953, 2876,
1709, 1560, 1455, 1415, 1364, 1265, 1239, 1091, 1005, 908, 872,
731 and 699; dH (600 MHz; CDCl3; Me4Si) 7.22–7.29 (5 H, m, Ar),
4.47 (2 H, s, –OCH2Ph), 4.19–4.21 (1 H, m, H2), 3.58–3.62 (1 H,
m, H10), 3.52–3.54 (1 H, m, H11A), 3.33–3.43 (3 H, m, H1, and
(2ꢀS),(5R)-1-[2-(3-Benzyloxy-2-triethylsilanyloxypropyl)[1,3]-
dithian-2-yl]-5,6-bistriethylsilanyloxy-hexan-2-one (19). To
a
stirred solution of NaOMe (190 mg, 0.35 mmol, 1.35 eq.) and
ynone 18 (169 mg, 0.26 mmol) in 3 : 1 anhydrous MeOH–DCM
(1.3 cm3) was added propane-1,3-dithiol (35 mg, 0.33 mmol,
1.25 eq.) at −10 ◦C. The temperature was then maintained at
−10 ◦C for 1 h and the yellow solution then left to reach ambient
temperature over 18 h, at which point a 1 : 1 mixture of distilled
water and saturated, aqueous NaHCO3 solution (2 cm3) was
added, dropwise. The reaction mixture was then diluted with Et2O
(1 × 5 cm3), the aqueous phase extracted with Et2O (3 × 5 cm3) and
the recombinant organic extracts washed with distilled water (2 ×
5 cm3) and brine (1 × 5 cm3). Drying over anhydrous MgSO4,
filtration, and in vacuo evaporation yielded a clear, colourless
oil, which was purified by gravimetric column chromatography
on silica using 1 : 9 Et2O and petroleum ether as eluent to
afford the title compound 19 as a clear, colourless oil (253 mg,
95%): Rf 0.59 (1 : 9 Et2O–petroleum ether); tmax(film)/cm−1: 2953,
2909, 2875, 1713, 1670, 1547, 1456, 1414, 1364, 1238, 1086, 1003,
909, 814, 725, 697 and 673; dH (600 MHz; CDCl3; Me4Si) 7.26–7.36
H
11B), 3.12 (1 H, d, J 15.3, H5A), 2.98 (1 H, d, J 15.3, H5B), 2.68–
2.84 (4 H, m, –S–CH2–CH2–CH2–S–), 2.49–2.51 (2 H, m, H7),
2.42–2.45 (1 H, m, H3A), 2.28 (1 H, dd, J 15.1 and 7.3, H3B), 1.85–
1.89 (2 H, m, –S–CH2–CH2–CH2–S–), 1.62–1.69 (1 H, m, H8A),
1.53–1.60 (1 H, m, H8B), 1.33–1.37 (2 H, m, H9), 0.89 (9 H, t, J
8.2, –OSi(CH2CH3)3) and 0.57 (6 H, q, J 7.9, –OSi(CH2CH3)3); dC
(150 MHz; CDCl3; Me4Si) 206.8, 138.2, 128.2, 127.6, 127.5, 74.9,
73.2, 71.8, 69.6, 66.5, 51.0, 49.4, 44.5, 42.7, 32.4, 26.5, 26.2, 24.7,
19.4, 7.0 and 5.3; m/z (+ESI) calc. for C27H46NaO5S2Si (MNa+)
565.2454, found 565.2546.
(2ꢀꢀS)-1-{2-[3-(4-Bromobenzyloxy)-2-triethylsilanyloxy-propyl]-
[1,3]dithian-2-yl}-6,7-dihydroxy-heptan-2-one (14).
A
clear,
colourless oil (90%); Rf 0.15 (EtOAc); tmax(film)/cm−1: 3439,
This journal is The Royal Society of Chemistry 2006
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©

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(5 H, m, Ar), 4.50–4.57 (2 H, s, –OCH2Ph), 4.24–4.25 (1 H, m,
H2), 3.67–3.74 (1 H, m, H9), 3.52–3.54 (1 H, m, H10A), 3.33–3.43
(3 H, m, H1 and H10B), 3.12 (1 H, d, J 15.3, H5A), 2.98 (1 H, d, J
15.3, H5B), 2.68–2.84 (4 H, m, –S–CH2–CH2–CH2–S–), 2.49–2.51
(2 H, m, H7), 2.42–2.45 (1 H, m, H3A), 2.28 (1 H, dd, J 15.1 and
7.3, H3B), 1.85–1.89 (2 H, m, –S–CH2–CH2–CH2–S–), 1.62–1.69
(1 H, m, H8A), 1.53–1.60 (1 H, m, H8B), 0.89–1.01 (27 H, m, 3 ×
–OSi(CH2CH3)3) and 0.51–0.65 (18 H, m, 3 × –OSi(CH2CH3)3);
dC (150 MHz; CDCl3; Me4Si) 206.3, 138.3, 128.3, 127.7, 127.6,
127.5, 75.0, 73.2, 72.2, 69.6, 66.9, 51.0, 49.5, 42.5, 40.3, 27.9, 26.3,
24.8, 22.8, 7.0, 6.9, 6.8, 5.4, 5.0, and 4.3; m/z (+ESI) calc. for
C38H72NaO5S2Si3 (MNa+) 779.4027, found 779.4025.
(1 H, m, H9), 3.44–3.51 (2 H, m, H1), 2.67–2.73 (3 H, m, H3A
and H7), 2.56 (1 H, dd, J 17.2 and 5.8, H3B), 2.29–2.33 (2 H, m,
H10), 2.14 (1 H, d, J 4.8, OH), 1.75–1.94 (2 H, m, H8), 0.96 (9 H,
t, J 8.0, –OSi(CH2CH3)3), 0.62 (6 H, q, J 7.9, –OSi(CH2CH3)3)
and 0.16 (9 H, s, –Si(CH3)3); dC (100 MHz; CDCl3; Me4Si) 187.4,
138.0, 128.4, 127.7, 102.6, 92.1, 91.5, 88.0, 73.4, 73.2, 69.4, 69.0,
41.7, 30.0, 29.0, 25.4, 6.7, 4.8 and −0.02; m/z (+ESI) calc. for
C28H44NaO4Si2 (MNa+) 523.2676, found 523.2656.
(2S)-1-Benzyloxy-2,9-bistriethylsilanyloxy-12-trimethylsilanyl-
dodeca-4,11-diyn-6-one (22). To a stirred solution of ynone 21
(145 mg, 0.28 mmol) in anhydrous THF (0.5 cm3) were added,
sequentially, imidazole (92 mg, 1.35 mmol, 4.8 eq.) and TESCl
(89 mg, 0.59 mmol, 2.1 eq.) at ambient temperature. After 2 h
the reaction was quenched with a saturated, aqueous solution of
NaHCO3 (2 cm3) and then extracted with Et2O (4 × 5 cm3). The
recombinant organic extracts were washed with distilled water (2 ×
5 cm3) and brine (1 × 5 cm3), dried over anhydrous MgSO4 and
then concentrated in vacuo. Subsequent purification by gravimetric
column chromatography on silica, using 1 : 9 Et2O and petroleum
ether as eluent, afforded the title compound 22 (170 mg, 98%)
as a clear, colourless oil: Rf 0.39 (1 : 9 Et2O–petroleum ether);
tmax(film)/cm−1: 2955, 2913, 2877, 2360, 2339, 1638, 1459, 1416,
1240, 1097, 1005 and 744; dH (400 MHz; CDCl3; Me4Si) 7.26–7.35
(5 H, m, Ar), 4.52 (2 H, s, –OCH2Ph), 4.01–4.05 (1 H, m, H2), 3.85–
3.89 (1 H, m, H9), 3.47–3.51 (2 H, m, H1), 2.53–2.76 (4 H, m, H3
and H7), 2.28–2.45 (2 H, m, H10), 1.99–2.03 (1 H, m, H8A), 1.81–
1.85 (1 H, m, H8B), 0.90–0.96 (18 H, m, –OSi(CH2CH3)3), 0.55–
0.63 (12 H, m, –OSi(CH2CH3)3) and 0.17 (9 H, s, –Si(CH3)3); dC
(100 MHz; CDCl3; Me4Si) 187.8, 138.2, 128.3, 127.6, 127.5, 103.8,
92.8, 90.8, 87.8, 73.4, 73.3, 69.9, 69.0, 41.0, 30.7, 25.3, 6.8, 6.7,
5.0, 4.8 and −0.004; m/z (+ESI) calc. for C34H58NaO4Si3 (MNa+)
637.3541, found 637.3536.
(7S)-8-Benzyloxy-1-oxiranyl-7-triethylsilanyloxyoct-4-yn-3-one
(20). To a stirred solution of ynone 16 (180 mg, 0.47 mmol)
in anhydrous DCM (5 cm3) were successively added Na2HPO4
(248 mg, 1.40 mmol, 3.0 eq.) and mCPBA (ca. 77% purity, 157 mg,
0.70 mmol, 1.5 eq.). After stirring at ambient temperature for 13 h,
the reaction mixture was then quenched with a saturated aqueous
solution of Na2SO4 (2 cm3) and distilled water (4 cm3) and the mix-
ture extracted with DCM (3 × 10 cm3). The recombinant organic
layers were then dried over anhydrous MgSO4 and concentrated
in vacuo. The resultant crude was purified by column chromato-
graphy on silica, using 1 : 4 Et2O and petroleum ether as eluent
to give the title compound 20 (162 mg, 75%) as a clear, colourless
oil: Rf 0.22 (1 : 4 Et2O–petroleum ether); tmax(film)/cm−1: 2954,
2911, 2876, 2215, 1674, 1455, 1412, 1362, 1239, 1167, 1092, 1004,
976, 910, 857, 840, 824, 739 and 698; dH (600 MHz; CDCl3;
Me4Si) 7.25–7.37 (5 H, m, Ar), 4.54 (2 H, s, –OCH2Ph), 4.00–4.04
(1 H, m, H2), 3.45–3.50 (2 H, m, H1), 2.92–2.96 (1 H, m, H9),
2.73–2.77 (1 H, m, H10A), 2.64–2.72 (3 H, m, H3A and H7), 2.57
(1 H, dd, J 17.2 and 5.9, H3B), 2.48 (1 H, dd, J 4.8 and 2.6, H10B),
1.96–2.02 (1 H, m, H8A), 1.73–1.79 (1 H, m, H8B), 0.95 (9 H, t, J
8.0, –OSi(CH2CH3)3) and 0.62 (6 H, q, J 8.0, –OSi(CH2CH3)3); dC
(150 MHz; CDCl3; Me4Si) 186.3, 138.0, 128.4, 127.7, 127.6, 91.6,
81.8, 73.4, 73.1, 69.3, 51.0, 47.0, 41.3, 26.4, 25.3, 6.7 and 4.8; m/z
(+ESI) calc. for C23H35O4Si (MH+) 403.2305, found 403.2313;
calc. for C23H34NaO4Si (MNa+) 425.2124, found 425.2150.
(2ꢀꢀS)-1-[2-(3-Benzyloxy-2-triethylsilanyloxypropyl)-[1,3] dithian-
2-yl]-5-triethylsilanyloxy-8-trimethylsilanyl-oct-7-yn-2-one (23).
To a stirred solution of NaOMe (14 mg, 0.26 mmol, 1.35 eq.) and
ynone 22 (118 mg, 0.19 mmol) in 3 : 1 anhydrous MeOH–DCM
(3.6 cm3) was added propane-1,3-dithiol (26 mg, 0.24 mmol,
1.25 eq.) at 0 ◦C. The reaction was then warmed to ambient
temperature and the yellow solution left to stir for 18 h, after which
a 1 : 1 mixture of distilled water and saturated, aqueous NaHCO3
solution was added (1.5 cm3), dropwise. The reaction mixture was
then diluted with Et2O (5 cm3), the aqueous phase extracted with
Et2O (3 × 5 cm3) and the recombinant organic extracts washed
with distilled water (2 × 5 cm3) and brine (1 × 5 cm3). Drying over
anhydrous MgSO4, filtration, and in vacuo evaporation yielded a
yellow, liquid crude, which was purified by gravimetric column
chromatography on silica, using EtOAc as eluent to afford the
title compound 23 (125 mg, 90%) as a clear, colourless oil: Rf
0.10 (1 : 9 Et2O–petroleum ether); tmax(film)/cm−1: 2954, 2911,
2876, 2178, 1710, 1455, 1414, 1364, 1249, 1102, 1005, 842, 739
and 699; dH (600 MHz; CDCl3; Me4Si) 7.26–7.35 (5 H, m, Ar),
4.50–4.56 (2 H, s, –OCH2Ph), 4.24–4.26 (1 H, m, H2), 3.84–3.88
(1 H, m, H9), 3.36–3.49 (2 H, m, H1), 3.17 (1 H, dd, J 15.3 and
7.2, H5A), 3.03 (1 H, dd, J 15.3 and 5.3, H5B), 2.81–2.94 (2 H,
m, –S–CH(HA)–CH2–CH2–S– and –S–CH2–CH2–CH(HA)–S–),
2.71–2.80 (2 H, m, –S–CH(HB)–CH2–CH2–S– and –S–CH2–
CH2–CH(HB)–S–), 2.60–2.70 (1 H, m, H7A), 2.46–2.59 (2 H, m,
H3A and H7B), 2.25–2.39 (3 H, m, H3B and H10), 1.87–1.99 (3 H,
(2S)-1-Benzyloxy-9-hydroxy-2-triethylsilanyloxy-12-trimethy-
silanyldodeca-4,11-diyn-6-one (21). To a solution of TMS–
acetylene (20 mg, 0.20 mmol, 2.0 eq.) in anhydrous THF (0.5 cm3)
◦
at −78 C was added n-BuLi (0.13 cm3, 0.20 mmol of a 1.6 M
solution in hexanes, 2.0 eq.). After stirring at −78 ◦C for 30 min,
BF3·THF (28 mg, 0.20 mmol, 2.0 eq.) was added. After stirring at
◦
−78 C for a further 30 min, a pre-prepared solution of oxirane
20 (40 mg, 0.10 mmol) in anhydrous THF (0.3 cm3 with rinsing ×
2) was added, dropwise, and the reaction left to reach ambient
temperature, with stirring, over 30 min, then quenched with a
saturated, aqueous solution of NH4Cl (1 cm3) and extracted with
Et2O (3 × 5 cm3). The recombinant organic extracts were washed
with distilled water (2 × 5 cm3) and brine (1 × 5 cm3), dried over
anhydrous MgSO4, filtered, and then evaporated in vacuo. The re-
sultant crude was purified by gravimetric column chromatography
on silica, using 1 : 4 Et2O and petroleum ether as eluent to afford
the title compound 21 (25 mg, 50%) as a clear colourless oil: Rf
0.15 (1 : 4 Et2O–petroleum ether); tmax(film)/cm−1: 3434, 2956,
2913, 2877, 2216, 2177, 1674, 1455, 1412, 1361, 1249, 1094, 1005,
842, 739 and 698; dH (400 MHz; CDCl3; Me4Si) 7.26–7.37 (5 H,
m, Ar), 4.55 (2 H, s, –OCH2Ph), 4.00–4.04 (1 H, m, H2), 3.70–3.77
1990 | Org. Biomol. Chem., 2006, 4, 1977–2002
This journal is
The Royal Society of Chemistry 2006
©

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m, H8A and –S–CH2–CH2–CH2–S–), 1.72–1.82 (1 H, m, H8B),
0.90–0.98 (18 H, m, 2 × –OSi(CH2CH3)3), 0.58–0.65 (12 H, m,
2 × –OSi(CH2CH3)3) and 0.14 (9 H, s, –Si(CH3)3); dC (150 MHz;
CDCl3; Me4Si) 206.1, 138.2, 128.7, 127.7, 127.5, 91.5, 88.2, 74.9,
73.2, 69.8, 69.6, 51.2, 49.4, 42.6, 40.2, 30.1, 27.3, 26.6, 26.3, 24.8,
7.0, 6.9, 5.4, 4.9 and −0.004; m/z (+ESI) calc. for C37H67O4S2Si3
(MH+) 723.3789, found 723.3823, C37H66NaO4S2Si3 (MNa+)
745.3608, found 745.3622.
CDCl3; Me4Si) 7.26–7.37 (5 H, m, Ar), 4.60 (2 H, s, –OCH2Ph),
4.03–4.06 (2 H, m, H10 and H2), 3.63 (1 H, dd, J 10.0 and 5.7,
H
1A), 3.52–3.56 (2 H, m, H1B and H11A), 3.41–3.44 (1 H, m, H11B),
2.95–3.03 (2 H, m, –S–CH2–CH2–CH2–S–), 2.69–2.77 (2 H, m, –S–
CH2–CH2–CH2–S–), 2.48 (1 H, dd, J 13.8 and 2.0, H3A), 2.27–2.34
(1 H, m, OH), 2.19 (1 H, dd, J 13.8 and 11.2, H3B), 2.08–2.14 (3 H,
m, H5 and H7A), 2.03–2.07 (1H, m, –S–CH2–CH(HA)–CH2–S–),
1.81–1.95 (2H, m, H8A and –S–CH2–CH(HB)–CH2–S–), 1.55–1.62
(1 H, m, H8B), 1.43–1.48 (1 H, m, H9A), 1.33 (1 H, td, J 13.5 and
4.3, H7B) and 1.24 (1 H, td, J 12.9 and 4.3, H9B); dC (150 MHz;
CDCl3; Me4Si) 138.3, 128.4, 2 × 127.6, 97.2, 73.4, 73.0, 70.2, 69.5,
66.2, 47.7, 45.6, 39.0, 33.9, 26.9, 26.7, 26.2, 25.1 and 17.9; m/z
(+ESI) calc. for C21H31O4S2 (MH+) 411.1664 found 411.1671;
calc. for C21H30NaO4S2 (MNa+) 433.1483, found 433.1481.
General procedure for the synthesis of dithiane-protected
spiroketal units 1a–c and 2a–c
To a stirred solution of dithiane precursor 13 in 1 : 1 DCM–
MeCN (0.09 M) at 0 ◦C was added, dropwise, perchloric acid
solution (1 cm3 mmol−1 of 13, 10% v/v in H2O). After 30 min, the
reaction was diluted with Et2O and neutralised using a saturated,
aqueous solution of NaHCO3. The aqueous phase was extracted
with Et2O (×4), and the recombinant organic extracts were washed
with distilled water (×2) and brine (×1). Drying over anhydrous
MgSO4, filtration and in vacuo evaporation yielded a crude oil,
which was purified by gravimetric column chromatography on
florisil, using 3 : 2 EtOAc and petroleum ether as eluent.
(15-Benzyloxymethyl-9,14-dioxa-1,5-dithiadispiro[5.1.5.3]hexadec-
10-yl)methanol isomer (1c). A white crystalline solid (48%,
starting from racemic 13; 16%, starting from diastereomerically-
enriched 13a; 83%, starting from diastereomerically-enriched
13b); Rf 0.53 (3 : 2 EtOAc–petroleum ether); mp 127 ◦C (from
pentane); [a]D25 +65.3 (c 0.17, CH2Cl2); tmax(film)/cm−1 3503, 2944,
2866, 1453, 1438, 1370, 1281, 1216, 1167, 1125, 1091, 1040, 1022,
1006, 992, 947, 910, 827, 802, 739 and 699; dH (600 MHz; CDCl3;
Me4Si) 7.26–7.36 (5 H, m, Ar), 4.59–4.64 (2 H, m, –OCH2Ph),
4.13–4.15 (1 H, m, H2), 3.73–3.77 (1 H, m, H10), 3.54–3.60 (2 H,
m, H1), 3.47–3.51 (1 H, m, H11A), 3.40–3.45 (1 H, m, H11B),
3.09–3.14 (1 H, m, –S–CH(HA)–CH2–CH2–S–), 3.01 (1 H, d,
J 11.2, OH), 2.88–2.93 (1 H, m, –S–CH2–CH2–CH(HA)–S–),
2.65–2.69 (1 H, m, –S–CH2–CH2–CH(HB)–S–), 2.56–2.61 (2 H,
m, H3A and –S–CH2–CH2–CH(HB)–S–), 2.16 (1 H, d, J 14.0,
( 15 - Benzyloxymethyl - 9,14 - dioxa - 1,5 - dithiadispiro[ 5.1.5.3 ] -
hexadec-10-yl)methanol isomer (1a). A white crystalline solid
(34%, starting from racemic 13; 56%, starting from diastereo-
merically-enriched 13a; 11%, starting from diastereomerically-
enriched 13b); Rf 0.24 (3 : 2 EtOAc–petroleum ether); mp 117 ◦C
(from pentane); [a]D25 +16.7 (c 0.12, CH2Cl2); tmax(film)/cm−1 3467,
2941, 2866, 1496, 1453, 1360, 1217, 1096, 1023, 1013, 736 and
697; dH (600 MHz; CDCl3; Me4Si) 7.26–7.35 (5 H, m, Ar), 4.56–
4.61 (2 H, m, –OCH2Ph), 4.49–4.51 (1 H, m, H2), 3.82–3.84 (1 H,
m, H10), 3.50–3.61 (4 H, m, H1 and H11), 3.07 (1 H, t, J 11.9,
–S–CH(HA)–CH2–CH2–S–), 2.88 (1 H, t, J 12.0, –S–CH2–CH2–
CH(HA)–S–), 2.70–2.77(2H, m, H5A and–S–CH(HB)–CH2–CH2–
S–), 2.62–2.64 (2 H, m, –S–CH2–CH2–CH(HA)–S– and OH), 2.54
(1 H, d, J 13.7, H3A), 2.00–2.04 (1 H, m, –S–CH2–CH(HA)–
CH2–S–), 1.85–1.89 (1 H, m, –S–CH2–CH(HB)–CH2–S–), 1.77–
1.82 (2 H, m, H3B and H8A), 1.65–1.67 (1 H, m, H7A), 1.48–
1.60 (4 H, m, H5B, H7B, H8B and H9A) and 1.28–1.35 (1 H, m,
H9B); dH (150 MHz; CDCl3; Me4Si) 138.2, 128.3, 127.7, 127.6,
98.0, 74.2, 73.5, 72.6, 66.8, 66.4, 46.8, 40.8, 39.2, 36.7, 26.4, 26.3,
25.9, 25.3 and 19.0; m/z (+ESI) calc. for C21H30NaO4S2 (MNa+)
433.1483, found 433.1482; Crystal structure determination of
spiroketal unit 1a: Single crystals of 1a were recrystallised from
pentane, mounted in inert oil and transferred to the cold gas stream
of the diffractometer. Crystal data. C21H30O4S2, M = 410.57,
H
5A), 2.04–2.08 (1 H, m, –S–CH2–CH(HA)–CH2–S–), 1.85–1.95
(2 H, m, H8A and –S–CH2–CH(HB)–CH2–S–), 1.80 (1 H, dd, J
13.6 and 11.5, H3B), 1.71 (1 H, d, J 14.1, H5B), 1.64–1.67 (1 H,
m, H7A), 1.58–1.61 (1 H, m, H8B), 1.42–1.48 (2 H, m, H7B and
H
9A) and 1.12–1.16 (1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si)
138.4, 128.3, 127.6, 127.5, 96.8, 73.3, 72.5, 70.4, 66.1, 65.9, 47.3,
46.6, 38.5, 34.6, 26.7, 26.2, 25.7, 25.3 and 18.1; m/z (+ESI) calc.
for C21H30NaO4S2 (MNa+) 433.1483, found 433.1486; Crystal
structure determination of spiroketal unit 1c: Single crystals of
1c were recrystallised from pentane, mounted in inert oil and
transferred to the cold gas stream of the diffractometer. Crystal
data. C21H30O4S2, M = 410.57, orthorhombic, a = 8.13710(10),
3
˚
˚
b = 9.73410(10), c = 26.6319(4) A, U = 2109.44(5) A , T =
180(2) K, space group P212121, Z = 4, l(Mo Ka) = 0.276 mm−1,
17628 reflections measured, 4759 unique (Rint = 0.0471) which
were used in all calculations. The final R1 and wR2 indices were
0.0438 and 0.0821, respectively (all data).
orthorhombic, a = 8.18360(10), b = 11.8557(2), c = 21.3327(4)
[15-(4-Bromobenzyloxymethyl)-9,14-dioxa-1,5-dithiadispiro-
[5.1.5.3]hexadec-10-yl]methanol isomer (2a). A clear, colourless
oil (33%, starting from racemic14); Rf 0.18 (3 : 2 EtOAc–petroleum
ether); [a]2D5 +4.4 (c 0.88, CH2Cl2); tmax(film)/cm−1 3493, 2941,
2866, 1454, 1363, 1217, 1092, 1041, 739 and 699; dH (600 MHz;
CDCl3; Me4Si) 7.44 (2 H, d, J 8.2, Ar), 7.21 (2 H, d, J 8.1, Ar),
4.54–4.59 (2 H, m, –OCH2Ph), 4.48–4.51 (1 H, m, H2), 3.82–3.85
(1 H, m, H10), 3.50–3.63 (4 H, m, H1 and H11), 3.05–3.09 (1 H,
m, –S–CH(HA)–CH2–CH2–S–), 2.85–2.89 (1 H, m, –S–CH2–CH2–
CH(HA)–S–), 2.70–2.77 (2 H, m, H5A and –S–CH(HB)–CH2–CH2–
S–), 2.60–2.63 (2 H, m, –S–CH2–CH2–CH(HB)–S– and OH), 2.52–
2.55 (1 H, m, H3A), 2.00–2.04 (1 H, m, –S–CH2–CH(HA)–CH2–S–),
3
˚
˚
A, U = 2069.75(6) A , T = 180(2) K, space group P212121, Z = 4,
l(Mo Ka) = 0.281 mm−1, 13637 reflections measured, 4721 unique
(Rint = 0.0445) which were used in all calculations. The final R1
and wR2 indices were 0.0489 and 0.1178, respectively (all data).
(15-Benzyloxymethyl-9,14-dioxa-1,5-dithiadispiro[5.1.5.3]hexadec-
10-yl)methanol isomer (1b). A clear, colourless oil (16%, starting
from racemic 13; 28%, starting from diastereomerically-enriched
13a; 6%, starting from diastereome-rically-enriched 13b); Rf 0.34
(3 : 2 EtOAc–petroleum ether); [a]2D5 −25.5 (c 0.11, CH2Cl2);
tmax(film)/cm−1 3467, 2941, 2866, 1423, 1362, 1276, 1238, 1211,
1123, 1091, 1028, 1009, 960, 914, 874, 739 and 699; dH (600 MHz;
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 1977–2002 | 1991
©

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1.84–1.89 (1 H, m, –S–CH2–CH(HB)–CH2–S–), 1.77–1.81 (2 H, m,
H3B and H8A), 1.65–1.67 (1 H, m, H7A), 1.51–1.60 (4 H, m, H5B,
H7B, H8B and H9A) and 1.30–1.35 (1 H, m, H9B); dC (150 MHz;
CDCl3; Me4Si) 137.3, 131.5, 129.3, 128.4, 121.5, 98.0, 74.2, 2 ×
72.7, 66.8, 66.5, 46.8, 40.7, 39.1, 36.7, 26.5, 26.3, 25.9, 25.3
and 19.0; m/z (+ESI) calc. for C21H30BrO4S2 (MH+) 489.0769,
found 489.0783; calc. for C21H29BrNaO4S2 (MNa+) 511.0588,
found 511.0618.
in all calculations. The final R1 and wR2 indices were 0.0601 and
0.1457, respectively (all data).
General procedure for the synthesis of dithiane-protected
spiroketal units 3a,b and 4
To a stirred solution of dithiane precursor 19 or 23 in 1 : 1
◦
DCM–MeCN (0.09 M) at 0 C was added, dropwise, perchloric
acid solution (1 cm3 mmol−1 of 19 or 23, 10% v/v in H2O).
After 30 min, the reaction was diluted with Et2O and neutralised
using a saturated, aqueous solution of NaHCO3. The aqueous
phase was extracted with Et2O (×4), and the recombinant organic
extracts washed with distilled water (×2) and brine (×1). Drying
over anhydrous MgSO4, filtration and in vacuo evaporation
yielded a crude oil, which was purified by gravimetric column
chromatography on florisil using EtOAc and petroleum ether as
eluent.
[15-(4-Bromobenzyloxymethyl)-9,14-dioxa-1,5-dithiadispiro-
[5.1.5.3]hexadec-10-yl]methanol isomer (2b). A clear, colourless
oil (17%, starting from racemic14); Rf 0.25 (3 : 2 EtOAc–petroleum
ether); [a]2D5 −11.3 (c 0.60, CH2Cl2); tmax(film)/cm−1 3493, 2940,
2866, 1454, 1424, 1364, 1274, 1243, 1212, 1169, 1089, 1028, 1009,
960, 910, 872, 739 and 699; dH (600 MHz; CDCl3; Me4Si) 7.44
(2 H, d, J 8.3, Ar), 7.22 (2 H, d, J 8.1, Ar), 4.60 (2 H, s,
–OCH2Ph), 4.03–4.06 (2 H, m, H10 and H2), 3.63 (1 H, dd, J
10.0 and 5.7, H1A), 3.52–3.56 (2 H, m, H1B and H11A), 3.41–3.44
(1 H, m, H11B), 2.95–3.03 (2 H, m, –S–CH2–CH2–CH2–S–), 2.69–
2.77 (2 H, m, –S–CH2–CH2–CH2–S–), 2.48 (1 H, dd, J 13.8 and
2.0, H3A), 2.27–2.34 (1 H, m, OH), 2.19 (1 H, dd, J 13.8 and 11.2,
H3B), 2.08–2.14 (3 H, m, H5 and H7A), 2.03–2.07 (1 H, m, –S–
CH2–CH(HA)–CH2–S–), 1.90–1.95 (1 H, m, –S–CH2–CH(HB)–
CH2–S–), 1.81–1.86 (1 H, m, H8A), 1.55–1.62 (1 H, m, H8B), 1.43–
1.48 (1 H, m, H9A), 1.33 (1 H, td, J 13.5 and 4.3, H7B) and 1.24
(1 H, td, J 12.9 and 4.3, H9B); dC (150 MHz; CDCl3; Me4Si)
137.4, 131.5, 129.2, 128.4, 121.4, 97.2, 73.1, 72.6, 70.2, 69.5, 66.2,
47.6, 45.5, 39.0, 33.9, 26.9, 26.7, 26.2, 25.1 and 17.9; m/z (+ESI)
calc. for C21H30BrO4S2 (MH+) 489.0769, found 489.0782; calc. for
C21H29BrNaO4S2 (MNa+) 511.0588, found 511.0609.
(14-Benzyloxymethyl-1,15-dioxa-8,12-dithiadispiro[4.1.5.3]-
pentadec-2-yl)methanol isomer (3a). A clear, colourless oil
(61%); Rf 0.52 (1 : 4 EtOAc–petroleum ether); [a]2D5 +33.0
(c 0.11, CH2Cl2); tmax(film)/cm−1 3434, 2906, 1454, 1361, 1209,
1091, 868, 738 and 698; dH (600 MHz; CDCl3; Me4Si) 7.26–7.35
(5 H, m, Ar), 4.55–4.61 (2 H, m, –OCH2Ph), 4.37–4.44 (2 H,
m, H2 and H9), 3.78 (1 H, d, J 12.0, H10A), 3.44–3.50 (3 H, m,
H1 and H10B), 3.03–3.08 (1 H, m, –S–CH(HA)–CH2–CH2–S–),
2.84–2.88 (1 H, m, –S–CH(HB)–CH2–CH2–S–), 2.67–2.73 (2 H,
m, –S–CH2–CH2–CH(HA)–S– and OH), 2.58–2.65 (1 H, m, –S–
CH2–CH2–CH(HB)–S–), 2.43 (1 H, d, J 13.6, H8A), 2.20 (1 H, dd,
J 14.2 and 1.7, H7A), 2.08–2.14 (1 H, m, H3A), 2.00–2.07 (3 H,
m, H5 and –S–CH2–CH(HA)–CH2–S–), 1.82–1.88 (2 H, m, H3B
and –S–CH2–CH(HB)–CH2–S–) and 1.67–1.71 (2 H, m, H7B and
H8B); dC (150 MHz; CDCl3; Me4Si) 138.0, 128.4, 127.7, 127.6,
105.7, 82.6, 73.4, 72.4, 67.4, 65.6, 47.0, 45.0, 39.8, 38.4, 26.4, 26.3,
25.1 and 23.3; m/z (+ESI) calc. for C20H29O4S2 (MH+) 397.1507,
found 397.1494; calc. for C20H28NaO4S2 (MNa+) 419.1327, found
419.1313.
[15-(4-Bromobenzyloxymethyl)-9,14-dioxa-1,5-dithiadispiro-
[5.1.5.3]hexadec-10-yl]methanol isomer (2c). A white, crystalline
(49%, starting from racemic 14); Rf 0.40 (3 : 7 EtOAc–petroleum
ether); [a]2D5 +48.2 (c 0.11, CH2Cl2); tmax(film)/cm−1 3499, 2940,
2867, 1453, 1439, 1375, 1280, 1216, 1168, 1125, 1089, 1039, 1023,
1006, 992, 947, 909, 828, 802, 735 and 700; dH (600 MHz; CDCl3;
Me4Si) 7.43 (2 H, d, J 8.2, Ar), 7.23 (2 H, d, J 8.3, Ar), 4.52–
4.57 (2 H, m, –OCH2Ph), 4.11–4.14 (1 H, m, H2), 3.71–3.75
(1 H, m, H10), 3.52–3.57 (2 H, m, H1), 3.46–3.50 (1 H, m, H11A),
3.40–3.44 (1 H, m, H11B), 3.08–3.12 (1 H, m, –S–CH(HA)–CH2–
CH2–S–), 3.01 (1 H, d, J 11.3, OH), 2.86–2.91 (1 H, m, –S–CH2–
CH2–CH(HA)–S–), 2.65–2.69 (1 H, m, –S–CH2–CH2–CH(HB)–S–
), 2.53–2.61 (2 H, m, H3A and –S–CH2–CH2–CH(HB)–S–), 2.15
(1 H, d, J 15.9, H5A), 2.04–2.06 (1 H, m, –S–CH2–CH(HA)–
CH2–S–), 1.83–1.93 (2 H, m, H8A and –S–CH2–CH(HB)–CH2–
S–), 1.78 (1 H, dd, J 13.6 and 11.5, H3B), 1.70 (1 H, d, J 14.1,
H5B), 1.57–1.66 (2 H, m, H7A and H8B), 1.40–1.46 (2 H, m, H7B
and H9A) and 1.12–1.16 (1 H, m, H9B); dC (150 MHz; CDCl3;
Me4Si) 137.4, 131.4, 129.2, 122.2, 96.8, 72.6, 72.5, 70.4, 66.0, 65.9,
47.2, 46.6, 38.4, 34.6, 26.7, 26.2, 25.7, 25.3 and 18.1; m/z (+ESI)
calc. for C21H30BrO4S2 (MH+) 489.0769, found 489.0789; calc.
for C21H29BrNaO4S2 (MNa+) 511.0588, found 511.0610; Crystal
structure determination of spiroketal unit (2c): Single crystals of
2c were recrystallised from pentane, mounted in inert oil and
transferred to the cold gas stream of the diffractometer. Crystal
(14-Benzyloxymethyl-1,15-dioxa-8,12-dithiadispiro[4.1.5.3]-
pentadec-2-yl)methanol isomer (3b). A clear, colourless oil (15%);
Rf 0.48 (1 : 4 EtOAc–petroleum ether); [a]2D5 +14.4 (c 0.13, CH2Cl2);
tmax(film)/cm−1 3434, 2906, 1454, 1361, 1209, 1091, 868, 738 and
698; dH (600 MHz; CDCl3; Me4Si) 7.26–7.35 (5 H, m, Ar), 4.55–
4.62 (2 H, m, –OCH2Ph), 4.30–4.34 (1 H, m, H2), 4.00–4.08 (1 H,
m, H9), 3.67–3.69 (1 H, m, H10A), 3.45–3.54 (3 H, m, H1 and
H
10B), 2.95–3.03 (1 H, m, –S–CH(HA)–CH2–CH2–S–), 2.81–2.92
(2 H, m, –S–CH(HB)–CH2–CH2–S– and –S–CH2–CH2–CH(HA)–
S–), 2.67–2.75 (2 H, m, –S–CH2–CH2–CH(HB)–S– and OH), 2.32–
2.45 (m), 2.18–2.25 (m), 2.10–2.16 (m), 2.00–2.09 (m), 1.82–1.99
(m) and 1.68–1.81 (m); dC (150 MHz; CDCl3; Me4Si) 138.2, 128.4,
2 × 127.7, 106.9, 78.2, 73.6, 72.9, 69.7, 65.0, 47.2, 45.4, 39.2,
35.1, 26.3, 26.2, 25.2 and 24.5; m/z (+ESI) calc. for C20H29O4S2
(MH+) 397.1507, found 397.1494; calc. for C20H28NaO4S2 (MNa+)
419.1327, found 419.1313.
14-Benzyloxymethyl-2-prop-2-ynyl-1,15-dioxa-8,12-dithiadispiro-
[4.1.5.3]pentadecane 1 : 1 diastereomeric mixture (4). A colourless
oil (96%); Rf 0.53 (3 : 7 EtOAc–petroleum ether); tmax(film)/cm−1
3288, 2905, 1423, 1362, 1242, 1094, 846, 738 and 698; dH
(600 MHz; CDCl3; Me4Si) 7.26–7.35 (5 H, m, Ar), 4.55–4.59
(2 H, m, –OCH2Ph), 4.29–4.35 (2 H, m, H2 and H9), 3.47–3.53
data. C21H29BrO4S2, M = 489.47, orthorhombic, a = 13.4354(4),
3
˚
˚
b = 16.5257(6), c = 9.9835(3) A, U = 2216.63(12) A , T = 180(2)
K, space group P21212, Z = 4, l(Mo Ka) = 2.067 mm−1, 13524
reflections measured, 3866 unique (Rint = 0.0547) which were used
1992 | Org. Biomol. Chem., 2006, 4, 1977–2002
This journal is
The Royal Society of Chemistry 2006
©

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(2 H, m, H1), 3.05–3.16 (1 H, m, –S–CH(HA)–CH2–CH2–S–),
2.86–2.91 (1 H, m, –S–CH(HB)–CH2–CH2–S–), 2.67–2.75 (1 H,
m, –S–CH2–CH2–CH(HA)–S–), 2.61–2.65 (m), 2.50–2.55 (m),
2.34–2.49 (m), 2.14–2.25 (m), 1.97–2.24 (m), 1.85–1.96 (m) and
1.67–1.87 (m); dC (150 MHz; CDCl3; Me4Si) 138.4, 138.3, 2 ×
128.3, 127.60, 2 × 127.5, 106.4, 106.1, 81.2, 80.9, 79.4, 77.4,
73.3, 73.2, 2 × 72.6, 69.4, 69.3, 67.1, 66.7, 65.8, 47.2, 47.1, 45.1,
44.9, 39.4, 2 × 38.8, 38.1, 28.6, 27.8, 27.1, 26.5, 26.4, 26.3, 25.4
and 2 × 25.2; m/z (+ESI) calc. for C22H29O3S2 (MH+) 405.1558,
found 405.1553; calc. for C22H28NaO3S2 (MNa+) 427.1378, found
427.1367.
1365, 1310, 1288, 1272, 1248, 1208, 1126, 1090, 1040, 983, 955,
935, 903, 865, 844, 738 and 698; dH (600 MHz; CDCl3; Me4Si)
7.26–7.36 (5 H, m, Ar), 4.57–4.62 (2 H, m, –OCH2Ph), 4.21–4.24
(1 H, m, H2), 4.03–4.10 (1 H, m, H10), 3.57–3.62 (2 H, m, H1),
3.50–3.53 (1 H, m, H11A), 3.40–3.44 (1 H, m, H11B), 2.70 (1 H, dd,
J 16.4 and 11.5, H3A), 2.53–2.60 (2 H, m, H5), 2.41 (1 H, dd, J
16.4 and 3.5, H3B), 1.84–1.91 (2 H, m, H8A and H7A), 1.70–1.74
(1 H, m, H8B), 1.48–1.52 (1 H, m, H9A), 1.39 (1 H, td, J 13.0
and 3.9, H7B) and 1.30–135 (1 H, m, H9B); dC (150 MHz; CDCl3;
Me4Si) 206.1, 137.9, 128.4, 127.8, 127.7, 98.9, 73.4, 72.7, 71.2,
70.9, 65.9, 51.0, 41.6, 33.7, 25.9 and 17.9; m/z (+ESI) calc. for
C18H25O5 (MH+) 321.1702, found 321.1702; calc. for C18H24NaO5
(MNa+) 343.1521, found 343.1526.
General procedure for the epimerisation of dithiane-protected
spiroketal units 1a and 1b
2-Benzyloxymethyl-8-hydroxymethyl-1,7-dioxaspiro[5.5]undecan-
4-one isomer (24c). A clear, colourless oil (quant.); Rf 0.30
(1 : 1 EtOAc–petroleum ether); [a]2D5 +42.7 (c 0.52, CH2Cl2);
tmax(film)/cm−1 3439, 2941, 2870, 1717, 1604, 1497, 1454, 1439,
1405, 1364, 1310, 1277, 1254, 1224, 1208, 1151, 1124, 1079,
1041, 980, 904, 883, 834, 738 and 698; dH (600 MHz; CDCl3;
Me4Si) 7.26–7.35 (5 H, m, Ar), 4.59–4.66 (2 H, m, –OCH2Ph),
4.09–4.14 (1 H, m, H2), 3.68–3.70 (1 H, m, H10), 3.63 (1 H, dd, J
10.9 and 3.6, H1A), 3.58 (1 H, dd, J 9.9 and 4.9, H1B), 3.51–3.55
(1 H, m, H11A), 3.43–3.49 (1 H, m, H11B), 2.48 (1 H, dd, J 11.8
and 11.6, H3A), 2.44 (2 H, s, H5), 2.35 (1 H, dd, J 14.3 and 2.6,
H3B), 1.86–2.03 (2 H, m, H7A and H8A), 1.64–1.73 (1 H, m, H8B),
1.43–1.54 (2 H, m, H7B and H9A) and 1.25–1.32 (1 H, m, H9B); dC
(150 MHz; CDCl3; Me4Si) 205.8, 138.1, 128.4, 127.7, 127.5, 99.5,
73.4, 72.0, 71.0, 68.4, 65.8, 51.7, 43.1, 34.4, 25.6 and 18.3; m/z
(+ESI) calc. for C18H25O5 (MH+) 321.1702, found 321.1707.
To a stirred solution of 1a or 1b in 1 : 1 DCM–MeCN (0.09 M) at
0 ◦C was added, dropwise, perchloric acid solution (1 cm3 mmol−1
of 1a or 1b, 10% v/v in H2O). After 1 h, the reaction was diluted
with Et2O and neutralised using a saturated, aqueous solution of
NaHCO3. The aqueous phase was extracted with Et2O (×4), and
the recombinant organic extracts were washed with distilled water
(×2) and brine (×1). Drying over anhydrous MgSO4, filtration
and in vacuo evaporation yielded a crude oil (quant.): ratio 1a :
1b = 1 : 2 by 1H NMR studies.
General procedure for the formation of spiroketal units 24a–c
and 25
To a stirred solution of spiroketal alcohol 1a–c or 2a in 3 :
1 MeOH–H2O (0.1 M) was added, at ambient temperature, 2-
methyl-2-butene (1.7 eq.) and NaH2PO4 (2.0 eq.). After cooling to
0 ◦C, NaClO2 (6.0 eq.) was added, portionwise, and the resultant
suspension was stirred at ambient temperature for 45 min. The
reaction mixture was then diluted with distilled water and the
aqueous phase extracted with EtOAc (×5). The recombinant
organic extracts were washed with distilled water (×2) and brine
(×1), dried over anhydrous MgSO4 and concentrated in vacuo. Pu-
rification was performed by gravimetric column chromatography
on florisil, using 3 : 2 EtOAc and petroleum ether as eluent.
2-(4-Bromobenzyloxymethyl)-8-hydroxymethyl-1,7-dioxaspiro-
[5.5]undecan-4-one isomer (25). A clear, colourless oil (quant.); Rf
0.25 (1 : 1 EtOAc–petroleum ether); [a]2D5 +29.4 (c 0.14, CH2Cl2);
tmax(film)/cm−1 3493, 2941, 2867, 1735, 1593, 1488, 1424, 1372,
1273, 1240, 1214, 1168, 1086, 1069, 1028, 1009, 960, 909, 871, 840,
804, 739 and 699; dH (600 MHz; CDCl3; Me4Si) 7.43 (2 H, d, J 8.2,
Ar), 7.20 (2 H, d, J 8.3, Ar), 4.52–4.56 (2 H, m, –OCH2Ph), 4.09–
4.13 (1 H, m, H2), 3.67–3.71 (1 H, m, H10), 3.54–3.61 (2 H, m, H1),
3.51–3.54 (1 H, m, H11A), 3.43–3.48 (1 H, m, H11B), 2.41–2.49 (3 H,
m, H3A and H5), 2.33 (1 H, dd, J 14.5 and 2.6, H3B), 2.13 (1 H, bs,
OH), 1.91–1.98 (1 H, m, H8A), 1.85–1.89 (1 H, m, H7A), 1.65–1.69
(1 H, m, H8B), 1.43–1.51 (2 H, m, H7B and H9A) and 1.23–1.32
(1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si) 205.7, 137.1, 131.5,
129.1, 121.5, 99.5, 73.4, 72.1, 71.1, 68.3, 65.7, 51.7, 43.0, 34.4, 25.5
and 18.3; m/z (+ESI) calc. for C18H23BrNaO5 (MNa+) 421.0627,
found 421.0615.
2-Benzyloxymethyl-8-hydroxymethyl-1,7-dioxaspiro[5.5]undecan-
4-one isomer (24a). A clear, colourless oil (quant.); Rf 0.24
(3 : 2 EtOAc–petroleum ether); [a]2D5 +10.8 (c 5.00, CH2Cl2);
tmax(film)/cm−1 3493, 2941, 2866, 1736, 1496, 1453, 1424, 1371,
1275, 1242, 1214, 1177, 1167, 1087, 1025, 1007, 958, 908, 870,
844, 804, 734 and 698; dH (600 MHz; CDCl3; Me4Si) 7.26–7.34
(5 H, m, Ar), 4.59–4.64 (2 H, m, –OCH2Ph), 4.54–4.56 (1 H,
m, H2), 3.71–3.75 (1 H, m, H10), 3.56–3.65 (4 H, m, H1 and
H11), 2.90 (1 H, d, J 14.3, H5A), 2.48 (1 H, dd, J 14.3 and 11.7,
(12-Benzyloxymethyl-1,2,6,11-tetraoxadispiro[2.1.5.3]tridec-7-
yl)methanol (26). A stirred solution of spiroketal 24c (20 mg,
62.5 lmol) in anhydrous DCM (1 cm3) was cooled to −60 ◦C
and treated, sequentially, with bis(trimethylsilyl)peroxide (11 mg,
62.5 lmol, 1.0 eq.) and (CH3)3SiOTf or BF3·Et2O or SnCl4
H
3A), 2.34–2.39 (2 H, m, H3B and H5B), 1.89–1.92 (1 H, m, H8A),
1.76–1.79 (2 H, m, H7), 1.56–1.62 (2 H, m, H8B and H9A) and
1.50–1.53 (1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si) 205.3,
137.8, 128.4, 127.8, 127.7, 100.6, 74.2, 73.5, 72.1, 69.5, 65.7,
47.9, 43.3, 35.2, 25.4 and 18.0; m/z (+ESI) calc. for C18H25O5
(MH+) 321.1702, found 321.1703; calc. for C18H24NaO5 (MNa+)
343.1521, found 343.1522.
◦
(31.2 lmol, 5 mol%). The reaction was warmed to −40 C over
18 h, quenched with a saturated, aqueous solution of NaHCO3
(2 cm3) and then extracted with Et2O (4 × 5 cm3). The recombinant
organic extracts were washed with distilled water (2 × 5 cm3)
and brine (1 × 5 cm3), dried over anhydrous MgSO4 and then
concentrated in vacuo. Gravimetric column chromatography on
florisil, using EtOAc as eluent, afforded the title compound 26
2-Benzyloxymethyl-8-hydroxymethyl-1,7-dioxaspiro[5.5]undecan-
4-one isomer (24b). A clear, colourless oil (quant.); Rf 0.18
(1 : 1 EtOAc–petroleum ether); [a]2D5 −3.8 (c 2.50, CH2Cl2);
tmax(film)/cm−1 3453, 2941, 2867, 1722, 1603, 1497, 1454, 1400,
This journal is
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as a clear, colourless oil (21 mg, quant.): Rf 0.44 (EtOAc); [a]D25
+23.5 (c 0.20, CH2Cl2); tmax(film)/cm−1 3310, 2937, 1454, 1314,
1217, 1088, 1043; CDCl3; Me4Si) 7.25–7.34 (5 H, m, Ar), 4.58–
4.64 (2 H, m, –OCH2Ph), 4.02–4.04 (1 H, m, H2), 3.80–3.84 (1 H,
m, H10), 3.64 (1 H, d, J 11.3, H11A), 3.52–3.56 (3 H, m, H1 and
and 0.55 (6 H, q, J 7.9, –OSi(CH2CH3)3); dC (150 MHz; CDCl3;
Me4Si) 205.5, 138.2, 128.3, 127.6, 127.5, 99.3, 73.3, 72.1, 71.3,
67.9, 66.1, 51.6, 43.0, 34.4, 26.4, 18.7, 6.6 and 4.4; m/z (+EI) calc.
for C24H39O5Si (MH+) 435.3, found 435.3.
2-Hydroxymethyl-8-triethylsilanyloxymethyl-1,7-dioxaspiro-
[5.5]undecan-4-one isomer (29). To a stirred solution of TES-
protected spiroketal 28 (10 mg, 23 lmol) and 2-methylcyclo-
hexadiene (0.5 cm3) in anhydrous EtOH (0.5 cm3) was added
CaCO3 (23 mg, 230 lmol, 10.0 eq.) and Pd(OH)2/C (12 mg, 20
mol%) The reaction was refluxed for 18 h then cooled to ambient
temperature, filtered and evaporated in vacuo. The subsequent
crude oil was purified by gravimetric column chromatography
on florisil, using EtOAc as eluent to afford the title compound
29 as a clear, colourless oil (8 mg, quant.): Rf 0.15 (EtOAc);
tmax(film)/cm−1 3349, 1722, 1500, 1478, 1269, 1078, 1050, 1092,
1060, 1000; dH (600 MHz; CDCl3; Me4Si) 4.06–4.10 (1 H, m, H2),
3.80–3.84 (1 H, m, H1A), 3.55–3.64 (3 H, m, H1B, H10 and H11A),
3.45–3.49 (1 H, m, H11B), 2.48 (1 H, dd, J 14.4 and 11.7, H3A),
2.36–2.44 (2 H, m, H5), 2.26–2.30 (1 H, m, H3B), 1.84–1.95 (3 H,
m, H7A, H8A and OH), 1.64–1.71 (2 H, m, H8B and H9A), 1.48 (1 H,
dd, J 13.3 and 4.7, H7B), 1.18–1.24 (1 H, m, H9B), 0.93 (9 H, t, J
7.9, –OSi(CH2CH3)3) and 0.56 (6 H, q, J 7.9, –OSi(CH2CH3)3); dC
(150 MHz; CDCl3; Me4Si) 205.3, 99.4, 71.4, 68.9, 66.0, 65.0, 51.6,
42.1, 34.3, 26.3, 18.6, 6.7 and 4.4; m/z (+EI) calc. for C17H33O5Si
(MH+) 345.2, found 345.2.
H
11B), 2.41 (1 H, d, J 14.4, H5A), 2.18 (1 H, d, J 13.8, H3A), 1.94–
1.98 (1 H, m, H8A), 1.70–1.74 (1 H, m, H7A), 1.60–1.64 (3 H, m,
H3B, H5B and H8B), 1.46–1.51 (2 H, m, H7B and H9A) and 1.24–1.30
(1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si) 138.1, 128.4, 127.6,
127.5, 108.4, 96.8, 73.4, 72.3, 70.6, 66.9, 65.9, 37.4, 34.9, 32.1, 25.9
and 18.1; m/z (+EI) calc. for C18H25O6 (MH+) 337.2, found 337.1.
(12-Benzyloxymethyl-1,6,11-trioxadispiro[2.1.5.3]tridec-7-yl)-
methanol (27). A stirred solution of spiroketal 24c (58 mg,
181 lmol) in anhydrous DMSO (1 cm3) was treated with a pre-
prepared mixture of trimethylsulfonium oxide (60 mg, 270 lmol,
1.5 eq.) and potassium t-butoxide (30 mg, 270 lmol, 1.5 eq.) at
room temperature. After stirring over 18 h, EtOAc (1 cm3) and
distilled water (1 cm3) were added, and the subsequent aqueous
phase extracted with EtOAc (3 × 1 cm3). The recombinant organic
extracts were washed with distilled water (2 × 1 cm3) and brine (1 ×
1 cm3), dried over anhydrous MgSO4, filtered and then evaporated
in vacuo. Gravimetric column chromatography on florisil, using
EtOAc as eluent, afforded the title compound 27 as a clear,
colourless oil (21 mg, 80%); Rf 0.22 (EtOAc); [a]2D5 +72.7 (c 0.13,
CH2Cl2); tmax(film)/cm−1 3455, 2921, 1720, 1595, 1454, 1364, 1231,
1168, 1086, 1048, 989; dH (600 MHz; CDCl3; Me4Si) 7.26–7.35
(5 H, m, Ar), 4.58–4.64 (2 H, m, –OCH2Ph), 4.20–4.24 (1 H, m,
H2), 3.79–3.83 (1 H, m, H10), 3.51–3.59 (4 H, m, H1 and H11),
2.55–2.59 (2 H, m, epoxide–CH2–), 2.03–2.07 (2 H, m, H3A and
General procedure for the synthesis of aldehydes 30a–c
To a stirred solution of the spiroketal alcohol in anhydrous DCM
(0.13 M) was added Dess–Martin periodinane reagent (2.0 eq.)
at ambient temperature. The resultant reaction suspension was
left stirring under a positive argon atmosphere for 2 h, then
quenched through dropwise addition of a 1 : 1 mixture of
saturated, aqueous NaHCO3 and Na2S2O3 solutions at 0 ◦C,
followed by further stirring at ambient temperature for 20 min.
The aqueous phase was then extracted with Et2O (×3), and the
recombinant organic extracts washed with distilled water (×2) and
brine (×1). Drying over anhydrous MgSO4, filtration, and in vacuo
evaporation afforded a liquid oil, which was purified immediately
by gravimetric, column chromatography on florisil, using Et2O
and petroleum ether as eluent. [For the formation of 30a and 30b,
solid, anhydrous NaHCO3 (10.0 eq.) was added, and the pH of the
solution monitered (pH ca. 8) before the addition of Dess–Martin
periodinane.
H
5A), 1.93–2.03 (1 H, m, H7A), 1.70–1.74 (1 H, m, H8A), 1.60–1.64
(1 H, m, H7B), 1.43–1.53 (2 H, m, H8B and H9A), 1.33 (1 H, dd, J
14.2 and 1.8, H5B) 1.23–1.28 (1 H, m, H9B), and 1.19–1.21 (1 H,
m, H3B); dC (150 MHz; CDCl3; Me4Si) 138.4, 128.4, 127.5, 97.1,
73.3, 72.5, 70.3, 66.3, 66.0, 54.8, 50.6, 41.6, 34.6, 34.1, 26.0 and
18.2; m/z (+ESI) calc. for C19H26NaO5 (MNa+) 357.1678, found
357.1678.
2-Benzyloxymethyl-8-triethylsilanyloxymethyl-1,7-dioxaspiro-
[5.5]undecan-4-one isomer (28). A stirred solution of spiroketal
24c (20 mg, 62.5 lmol) in anhydrous DCM (1 cm3) was cooled
to −78 ◦C and treated, sequentially, with 2,6-lutidine (20 mg,
188 lmol, 3.0 eq.) and TESOTf (25 mg, 93.8 lmol, 1.5 eq.).
The reaction was immediately warmed to 0 ◦C over 5 min,
quenched with a saturated, aqueous solution of NaHCO3 (2 cm3)
and then extracted with Et2O (4 × 5 cm3). The recombinant
organic extracts were washed with distilled water (2 × 5 cm3)
and brine (1 × 5 cm3), dried over anhydrous MgSO4 and then
concentrated in vacuo. The subsequent crude oil was purified by
gravimetric column chromatography on florisil, using Et2O and
petroleum ether as eluent to afford the title compound 28 as a
clear, colourless oil (27 mg, quant.): Rf 0.63 (2 : 3 Et2O–petroleum
ether); tmax(film)/cm−1 2950, 2907, 2873, 1718, 1455, 1274, 1212,
1155, 1092, 1072, 1010, 871, 812, 733, 697; dH (600 MHz; CDCl3;
Me4Si) 7.26–7.36 (5 H, m, Ar), 4.58–4.64 (2 H, m, –OCH2Ph),
4.13–4.17 (1 H, m, H2), 3.60–3.69 (2 H, m, H1A and H10), 3.53–
3.58 (2 H, m, H1B and H11A), 3.44–3.48 (1 H, m, H11B), 2.30–2.46
(4 H, m, H3 and H5), 1.90–1.98 (1 H, m, H8A), 1.80–1.89 (1 H, m,
8-Benzyloxymethyl-10-oxo-1,7-dioxaspiro[5.5]undecane-2-car-
baldehyde isomer (30a). A clear, colourless oil (83%); Rf 0.24 (3 :
7 EtOAc–petroleum ether); dH (600 MHz; CDCl3; Me4Si) 9.80
(1 H, s, H11), 7.26–7.37 (5 H, m, Ar), 4.55–4.61 (3 H, m, H2 and
–OCH2Ph), 4.06–4.10 (1 H, m, H10), 3.54–3.59 (2 H, m, H1), 2.73
(1 H, d, J 15.2, H5A), 2.45–2.53 (3 H, m, H3 and H5B), 2.00–2.05
(1 H, m, H9A), 1.80–1.91 (2 H, m, H8A and H7A), 1.64–1.73 (2 H, m,
H7B and H9B) and 1.51–1.61 (1 H, m, H8B); dC (150 MHz; CDCl3;
Me4Si) 204.9, 202.5, 137.9, 128.4, 127.7, 127.6, 100.2, 78.2, 73.5,
71.8, 70.2, 50.4, 43.1, 35.8, 23.2 and 15.9; m/z (+EI) calc. for
C18H23O5 (MH+) 319.2, found 319.1.
8-Benzyloxymethyl-10-oxo-1,7-dioxaspiro[5.5]undecane-2-car-
baldehyde isomer (30b). A clear, colourless oil (80%); Rf 0.60
(1 : 1 EtOAc–petroleum ether); dH (600 MHz; CDCl3; Me4Si) 9.48
H
7A), 1.60–1.68 (2 H, m, H8B and H9A), 1.36–1.47 (1 H, m, H7B),
1.15–1.25 (1 H, m, H9B), 0.91 (9 H, t, J 8.1, –OSi(CH2CH3)3)
1994 | Org. Biomol. Chem., 2006, 4, 1977–2002
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(1 H, s, H11), 7.26–7.36 (5 H, m, Ar), 4.53–4.61 (2 H, m, –OCH2Ph),
4.43–4.47 (1 H, m, H10), 4.21–4.26 (1 H, m, H2), 3.52–3.62 (2 H,
m, H1), 2.79–2.85 (1 H, m, H3A), 2.60–2.66 (2 H, m, H5), 2.37–2.42
(1 H, m, H3B), 1.82–2.02 (3 H, m, H7A, H8A and H9A), 1.68–1.78
(1 H, m, H8B), 1.40–1.54 (1 H, m, H7B) and 1.26–1.35 (1 H, m,
H9B); dC (150 MHz; CDCl3; Me4Si) 205.5, 201.6, 137.7, 128.5,
127.8, 127.7, 99.0, 75.3, 73.4, 72.2, 71.2, 50.3, 41.3, 33.7, 24.8 and
17.7; m/z (+EI) calc. for C18H23O5 (MH+) 319.2, found 319.1.
8-Benzyloxymethyl-10-oxo-1,7-dioxaspiro[5.5]undecane-2-car-
baldehyde isomer (30c). A clear, colourless oil (90%.); Rf 0.53
(1 : 1 EtOAc–petroleum ether); dH (600 MHz; CDCl3; Me4Si) 9.55
(1 H, s, H11), 7.26–7.37 (5 H, m, Ar), 4.57–4.64 (2 H, m, –OCH2Ph),
4.07–4.11 (1 H, m, H2), 4.01 (1 H, dd, J 12.3 and 2.4, H10), 3.51–
3.63 (2 H, m, H1), 2.49 (1 H, dd, J 14.8 and 1.5, H3A), 2.44–2.50
(2 H, m, H3B and H5A), 2.36–2.43 (1 H, m, H5B), 1.98–2.08 (1 H,
m, H8A), 1.90–1.97 (1 H, m, H7A), 1.83–1.89 (1 H, m, H9A), 1.73–
1.78 (1 H, m, H8B), 1.48–1.58 (1 H, m, H7B) and 1.32–1.42 (1 H,
m, H9B); dC (150 MHz; CDCl3; Me4Si) 208.9, 204.7, 137.9, 128.4,
127.7, 127.5, 99.7, 74.9, 73.5, 71.9, 68.8, 51.2, 42.9, 34.2, 24.7 and
17.9; m/z (+EI) calc. for C18H23O5 (MH+) 319.2, found 319.1.
7.23–7.34 (6 H, m, Ar), 7.16–7.19 (1 H, m, Ar), 5.73 (1 H, s,
–O(CO)NH–), 4.58–4.65 (2 H, m, –OCH2Ph), 4.47 (2 H, d, J 5.0,
H12), 4.09–4.11 (1 H, m, H2), 4.03 (2 H, d, J 4.6, H11), 3.82–3.84
(1 H, m, H10), 3.54–3.58 (1 H, m, H1A), 3.59–3.62 (1 H, m, H1B),
2.32–2.47 (4 H, m, H3 and H5), 1.93–1.98 (1 H, m, H8A), 1.86–1.90
(1 H, m, H7A), 1.66–1.70 (1 H, m, H8B), 1.57–1.61 (1 H, m, H9A),
1.45–1.51 (1 H, m, H7B), 1.25–1.32 (1 H, m, H9B); dC (150 MHz;
CDCl3; Me4Si) 205.5, 156.8, 156.4, 149.1, 138.1, 136.7, 128.4,
127.7, 127.5, 122.3, 121.7, 99.4, 73.4, 72.0, 68.8, 68.2, 67.4, 51.4,
46.0, 42.9, 34.2, 26.1 and 18.4; m/z (+EI) calc. for C25H30N2NaO6
(MNa+) 477.2002, found 477.1989.
(3-Morpholin-4-yl-propyl)carbamic acid 8-(4-bromobenzyloxy-
methyl)-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer
(36a). A colourless oil (80%); Rf 0.25 (EtOAc); [a]2D5 +56.0
(c 0.43, CH2Cl2); tmax(film)/cm−1 3324, 2943, 1719, 1529, 1488,
1457, 1359, 1258, 1117, 1088, 1041, 1011, 984 and 804; dH
(600 MHz; CDCl3; Me4Si) 7.47 (2 H, d, J 8.3, Ar), 7.21 (2 H,
d, J 8.1, Ar), 5.82 (1 H, s, –O(CO)NH–), 4.54–4.59 (2 H, m,
–OCH2Ph), 4.07–4.13 (1 H, m, H2), 3.90–4.00 (2 H, m, H11), 3.76–
3.82 (1 H, m, H10), 3.64–3.68 (4 H, m, –CH2–N(–CH2–CH2–)2O),
3.55–3.62 (2 H, m, H1), 3.20–3.24 (2 H, m, H12), 2.33–2.45 (10 H,
m, H3, H5 and –CH2–N(–CH2–CH2–)2O), 1.92–1.96 (1 H, m,
General procedure for the synthesis of spiroketal-derived
carbamates 35a,b, 36a,b and 37a,b
H
8A), 1.83–1.88 (1 H, m, H7A), 1.62–1.69 (3 H, m, H8B and H13),
1.55–1.59 (1 H, m, H9A), 1.45–1.49 (1 H, m, H7B), 1.22–1.29 (1 H,
m, H9B); dC (150 MHz; CDCl3; Me4Si) 205.2, 162.5, 156.4, 137.2,
131.5, 129.1, 121.5, 99.3, 72.6, 2 × 72.1, 68.7, 68.2, 67.1, 67.0,
2 × 53.6, 51.5, 43.0, 40.5, 34.2, 26.1, 25.6 and 18.4; m/z (+ESI)
calc. for C26H38BrN2O7 (MH+) 569.1862, found 569.1899; calc. for
C26H37BrN2NaO7 (MNa+) 591.1682, found 591.1687.
To an anhydrous DMF solution (0.25 M) of the spiroketal alcohol
derivative was added, sequentially, pyridine (1.5 eq.) and p-
nitrophenylchloroformate (1.5 eq.) in one portion at 0 ◦C. The
reaction was then left to stir at ambient temperature for 20 min,
at which point the requisite amine (1.0 eq.) was added dropwise.
After stirring for 10 min, EtOAc and distilled water were added,
and the subsequent aqueous phase extracted with EtOAc (×3).
The recombinant organic extracts were washed with distilled water
(×1) and brine (×1), dried over anhydrous MgSO4, filtered and
then evaporated in vacuo. The resultant crude was purified by
gravimetric column chromatography on silica gel, using 3 : 7
EtOAc and petroleum ether as eluent.
Pyridin-2-ylmethylcarbamic acid 8-(4-bromobenzyloxymethyl)-
10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer (36b).
A
colourless oil (85%); Rf 0.35 (EtOAc); [a]2D5 +62.0 (c 0.50, CH2Cl2)
tmax(film)/cm−1 3336, 3245, 2987, 1756, 1578, 1495, 1378, 1280,
1120, 1045, 1020, 988 and 810; dH (600 MHz; CDCl3; Me4Si)
8.50–8.51 (1 H, m, Ar), 7.68 (1 H, t, J 7.5, Ar), 7.46 (2 H, d,
J 8.2, Ar), 7.26–7.30 (1 H, m, Ar), 7.19–7.24 (3 H, m, Ar), 5.78
(1 H, s, –O(CO)NH–), 4.51–4.59 (2 H, m, –OCH2Ph), 4.47 (2 H,
d, J 5.2, H12), 4.08–4.14 (1 H, m, H2), 3.98–4.03 (2 H, m, H11),
3.78–3.83 (1 H, m, H10), 3.53–3.60 (2 H, m, H1), 2.33–2.47 (3 H,
m, H3A and H5), 2.33 (1 H, d, J 14.3, H3B), 1.90–1.97 (1 H, m,
(3-Morpholin-4-yl-propyl)carbamic acid 8-benzyloxymethyl-10-
oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer (35a).
A
colourless oil (80%); Rf 0.20 (EtOAc); [a]2D5 +30.0 (c 0.81, CH2Cl2);
tmax(film)/cm−1 3344, 2943, 2857, 1715, 1521, 1454, 1360, 1334,
1255, 1087, 1041, 983, 914, 861, 737 and 698; dH (600 MHz;
CDCl3; Me4Si) 7.23–7.38 (5 H, m, Ar), 5.80 (1 H, s, –O(CO)NH–),
4.59–4.65 (2 H, m, –OCH2Ph), 4.08–4.12 (1 H, m, H2), 3.92–3.98
(2 H, m, H11), 3.80–3.84 (1 H, m, H10), 3.65–3.67 (4 H, m, –CH2–
N(–CH2–CH2–)2O), 3.57–3.63 (2 H, m, H1), 3.20–3.24 (2 H, m,
H12), 2.34–2.46 (10 H, m, H3, H5 and –CH2–N(–CH2–CH2–)2O),
1.93–1.99 (1 H, m, H8A), 1.84–1.88 (1 H, m, H7A), 1.62–1.69 (3 H,
m, H8B and H13), 1.54–1.59 (1 H, m, H9A), 1.42–1.50 (1 H, m, H7B),
1.23–1.30 (1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si) 205.4, 156.4,
138.1, 128.4, 127.7, 127.5, 99.3, 73.4, 2 × 72.1, 68.7, 68.2, 67.1,
67.0, 2 × 53.6, 51.5, 43.1, 40.5, 34.2, 26.1, 25.6 and 18.4; m/z
(+ESI) calc. for C26H39N2O7 (MH+) 491.2757, found 491.2774.
H
8A), 1.84–1.88 (1 H, m, H7A), 1.66–1.70 (1 H, m, H8B), 1.56–1.60
(1 H, m, H9A), 1.45–1.50 (1 H, m, H7B), 1.25–1.30 (1 H, m, H9B);
dC (150 MHz; CDCl3; Me4Si) 205.6, 162.8, 156.8, 148.8, 137.1,
131.5, 129.1, 128.4, 126.2, 122.6, 115.7, 99.4, 72.6, 72.1, 68.7, 68.2,
67.4, 51.4, 45.8, 42.9, 34.2, 26.0 and 18.4; m/z (+ESI) calc. for
C25H29BrN2NaO6 (MNa+) 555.1107, found 555.1091.
(3-Morpholin-4-yl-propyl)carbamic acid 8-benzyloxymethyl-10-
oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer (37a).
A
colourless oil (80%); Rf 0.10 (EtOAc); [a]2D5 +2.0 (c 0.30, CH2Cl2);
tmax(film)/cm−1 3344, 2943, 2857, 1715, 1521, 1454, 1360, 1334,
1255, 1087, 1041, 983, 914, 861, 737 and 698; dH (600 MHz; CDCl3;
Me4Si) 7.26–7.35 (5 H, m, Ar), 5.71–5.75 (1 H, s, –O(CO)NH–),
4.50–4.64 (3 H, m, H2 and –OCH2Ph), 4.10–4.13 (2 H, m, H11),
3.83–3.88 (1 H, m, H10), 3.67–3.71 (4 H, m, –CH2–N(–CH2–CH2–
)2O), 3.56–3.63 (2 H, m, H1), 3.22–3.24 (2 H, m, H12), 2.81–2.88
(1 H, m, H5A), 2.34–2.52 (9 H, m, H3, H5B and –CH2–N(–CH2–
CH2–)2O), 1.86–1.88 (2 H, m, H7A and H8A), 1.76–1.79 (1 H, m,
Pyridin-2-ylmethylcarbamic acid 8-benzyloxymethyl-10-oxo-1,7-
dioxaspiro[5.5]undec-2-ylmethyl ester isomer (35b). A colourless
oil (85%); Rf 0.30 (EtOAc); [a]2D5 +45.0 (c 0.87, CH2Cl2);
tmax(film)/cm−1 2942, 1798, 1720, 1592, 1517, 1500, 1454, 1336,
1290, 1246, 1110, 1043, 993, 851, 754 and 699; dH (600 MHz;
CDCl3; Me4Si) 8.50–8.53 (1 H, m, Ar), 7.64 (1 H, t, J 7.6, Ar),
This journal is
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H7B), 1.58–1.68 (4 H, m, H8B, H9A and H13), 1.24–1.27 (1 H, m,
H9B); dC (150 MHz; CDCl3; Me4Si) 205.5, 156.4, 154.4, 138.0,
128.4, 127.7, 100.5, 73.4, 2 × 72.0, 69.3, 66.9, 66.6, 53.6, 48.1, 43.4,
40.4, 35.0, 25.7, 25.6 and 17.6 m/z (+ESI) calc. for C26H38N2NaO7
(MNa+) 513.2577, found 513.2578.
(150 MHz; CDCl3; Me4Si) 205.3, 166.9, 156.5, 143.8, 141.3, 138.0,
128.4, 127.7, 127.5, 127.1, 125.1, 120.0, 99.4, 73.4, 72.0, 68.5, 68.2,
67.5, 67.2, 51.4, 47.1, 43.0, 42.7, 34.1, 25.6 and 18.4; m/z (+EI)
calc. for C35H38NO8 (MH+) 600.3, found 600.2.
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-phenylpropionic
acid 8-benzyloxymethyl-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl
ester isomer (38b). A clear, colourless oil (70%); Rf 0.44 (2 : 3
EtOAc–petroleum ether); tmax(film)/cm−1 3294, 2916, 2350, 2198,
1985, 1720, 1530, 1451, 1249, 1212, 1078, 988, 759, 741; dH
(600 MHz; CDCl3; Me4Si) 7.77 (2 H, d, J 7.5, Ar), 7.55 (2 H,
t, J 7.2, Ar), 7.40 (2 H, t, J 7.4, Ar), 7.21–7.34 (10 H, m, Ar),
7.07 (2 H, d, J 7.1, Ar), 5.23 (1 H, m, NH), 4.62–4.65 (1 H, m,
H12), 4.56–4.62 (2 H, m, –OCH2Ph), 4.43 (1 H, dd, J 10.4 and 7.3,
Pyridin-2-ylmethylcarbamic acid 8-benzyloxymethyl-10-oxo-1,7-
dioxaspiro[5.5]undec-2-ylmethyl ester isomer (37b). A colourless
oil (85%); Rf 0.15 (EtOAc); [a]2D5 +4.0 (c 0.25, CH2Cl2);
tmax(film)/cm−1 2942, 1798, 1720, 1592, 1517, 1500, 1454, 1336,
1290, 1246, 1110, 1043, 993, 851, 754 and 699; dH (600 MHz;
CDCl3; Me4Si) 8.51–8.54 (1 H, m, Ar), 7.65–7.68 (1 H, t, J 7.5,
Ar), 7.20–7.33 (7 H, m, Ar), 5.82 (1 H, s, –O(CO)NH–), 4.45–4.62
(5 H, m, H2, H12 and –OCH2Ph), 4.11–4.18 (2 H, m, H11), 3.84–
3.88 (1 H, m, H10), 3.53–3.63 (2 H, m, H1), 2.79–2.83 (1 H, m, H5A),
2.49–2.56 (1 H, m, H3A), 2.30–2.41 (2 H, m, H3B and H5B), 1.83–
1.92 (1 H, m, H8A), 1.72–1.82 (2 H, m, H7), 1.52–1.63 (2 H, m, H8B
and H9A), 1.42–1.52 (1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si)
205.5, 157.0, 156.6, 148.8, 138.0, 137.2, 128.4, 127.6, 126.2, 122.6,
121.9, 100.5, 73.4, 72.0, 71.8, 69.3, 67.0, 48.3, 45.9, 43.3, 34.9, 25.6
and 17.5; m/z (+ESI) calc. for C25H30N2NaO6 (MNa+) 477.2002,
found 477.1979.
H
13A), 4.29 (1 H, dd, J 10.4 and 7.1, H13B), 4.19 (1 H, t, J 7.0, H14),
4.11–4.14 (1 H, m, H2), 4.01–4.05 (2 H, m, H11), 3.83–3.87 (1 H,
m, H10), 3.54–3.58 (2 H, m, H1), 3.10 (1 H, dd, J 13.9 and 5.4,
–CH(HA)Ph), 2.98 (1 H, dd, J 13.9 and 6.3, –CH(HB)Ph), 2.39–
2.47 (3 H, m, H3A and H5), 2.31–2.34 (1 H, m, H3B), 1.92–2.02
(1 H, m, H8A), 1.84–1.92 (1 H, m, H7A), 1.67–1.70 (1 H, m, H8B),
1.43–1.56 (2 H, m, H7B and H9A) and 1.20–1.24 (1 H, m, H9);
dC (150 MHz; CDCl3; Me4Si) 205.0, 171.3, 155.5, 143.8, 143.7,
141.3, 138.1, 135.6, 129.3, 128.6, 128.4, 127.7, 127.5, 127.1, 127.0,
125.1, 125.0, 120.0, 119.9, 99.4, 73.4, 72.0, 68.5, 68.1, 67.8, 66.9,
54.7, 51.4, 47.1, 42.9, 38.2, 34.1, 26.1 and 18.3; m/z (+EI) calc.
for C42H44NO8 (MH+) 690.3, found 690.2.
General procedure for the synthesis of spiroketal esters 38a–f, 39,
40a–c and 41
To a stirred, argon-flushed solution of the spiroketal-derived
primary alcohol in anhydrous DMF (12.5 lM) was added at
ambient temperature, in the order written: Hu¨nigs base (5.0 eq.),
the requisite N-Fmoc-protected a-amino acid (1.0 eq.), and HOAt
(3.0eq.). Theresultantyellow solution was then cooled to 0 ◦C, and
treated with HATU (3.0 eq.), through a portion-wise addition, and
left to reach ambient temperature with overnight stirring under a
positive argon atmosphere. After 48 h, the reaction was diluted
with EtOAc and the resultant organic phase extracted with a
saturated, aqueous solution of NaHCO3 (×3) with the combined,
basic, aqueous phases subject to further extraction using EtOAc
(×3). The recombinant organic extracts were then washed with
distilled water (×1) and brine (×1), dried over anhydrous MgSO4,
filtered and evaporated in vacuo. The resultant pale-pellow/light-
brown crude was purified by gravimetric column chromatography
on silica gel, using EtOAc and petroleum ether as eluent. [For
formation of 38a, 39 and 40a 1.25 eq. of HATU and HOAt, as
well as 2.00 eq. of Hu¨nigs base were used with a reaction time of
18 h; all de were verified by Chiral HPLC.]
2-(9H-Fluoren-9-ylmethoxycarbonylamino)propionic acid 8-
benzyloxymethyl-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester
isomer (38c). A clear, colourless oil (50%); Rf 0.37 (2 : 3 EtOAc–
petroleum ether); tmax(film)/cm−1 3290, 2943, 2378, 2203, 1945,
1721, 1530, 1451, 1234, 1212, 997, 743, 688; dH (600 MHz; CDCl3;
Me4Si) 7.76 (2 H, d, J 7.4, Ar), 7.55–7.63 (2 H, m, Ar), 7.40 (2 H,
t, J 7.4, Ar), 7.26–7.36 (7 H, m, Ar), 5.34 (1 H, d, J 7.5, NH),
4.56–4.62 (2 H, m, –OCH2Ph), 4.34–4.41 (3 H, m, H12 and H13),
4.22 (1 H, t, J 7.0, H14), 4.10–4.14 (2 H, m, H2 and H11A), 4.04 (1 H,
d, J 11.2, H11B), 3.85–3.88 (1 H, m, H10), 3.55–3.60 (2 H, m, H1),
2.36–2.50 (3 H, m, H3 and H5A), 2.33 (1 H, d, J 14.4, H5B), 1.95–
2.01 (1 H, m, H8A), 1.85–1.92 (1 H, m, H7A), 1.68–1.71 (1 H, m,
H8B), 1.56–1.60 (1 H, m, H9A), 1.45–1.53 (1 H, m, H7B), 1.36 (3 H,
d, J 6.8, –CH3) and 1.21–1.28 (1 H, m, H9B); dC (150 MHz; CDCl3;
Me4Si) 205.2, 172.7, 155.6, 143.9, 143.8, 141.2, 138.1, 128.4, 127.7,
127.6, 127.5, 127.1, 125.1, 120.0, 99.4, 73.4, 72.0, 68.5, 68.1, 67.5,
66.9, 51.4, 49.6, 47.1, 43.0, 34.1, 26.0, 18.6 and 18.3; m/z (+EI)
calc. for C36H40NO8 (MH+) 614.3, found 614.2.
(9H-Fluoren-9-ylmethoxycarbonylamino)acetic acid 8-benzyloxy-
methyl-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer
(38a). A clear, colourless oil (93%); Rf 0.41 (1 : 1 EtOAc–
petroleum ether); tmax(film)/cm−1 3297, 2918, 2354, 2202, 1953,
1718, 1529, 1451, 1250, 1084, 1031, 740, 669; dH (600 MHz; CDCl3;
Me4Si) 7.76 (2 H, d, J 7.5, Ar), 7.60 (2 H, d, J 7.4, Ar), 7.40 (2 H,
t, J 7.5, Ar), 7.26–7.34 (7 H, m, Ar), 5.25–5.29 (1 H, m, NH),
4.56–4.62 (2 H, m, –OCH2Ph), 4.40 (2 H, d, J 7.1, H13), 4.23 (1 H,
t, J 7.1, H14), 4.12 (1 H, dd, J 11.4 and 6.9, H11A), 4.05–4.08 (2 H,
m, H2 and H11B), 3.99 (1 H, dd, J 18.2 and 5.8, H12A), 3.91 (1 H,
dd, J 18.2 and 5.3, H12B), 3.82–3.87 (1 H, m, H10), 3.56–3.60 (2 H,
m, H1), 2.34–2.46 (4 H, m, H3 and H5), 1.93–2.02 (1 H, m, H8A),
1.84–1.88 (1 H, m, H7A), 1.68–1.72 (1 H, m, H8B), 1.54–1.58 (1 H,
m, H9A), 1.45–1.55 (1 H, m, H7B) and 1.25–1.32 (1 H, m, H9B); dC
2-(9H-Fluoren-9-ylmethoxycarbonylamino)pent-4-enoic acid 8-
benzyloxymethyl-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester
isomer (38d). A clear, yellow oil (26%); Rf 0.32 (7 : 13 EtOAc–
petroleum ether); tmax(film)/cm−1 3298, 2954, 2359, 2192, 2022,
1721, 1524, 1453, 1249, 988, 743, 688; dH (600 MHz; CDCl3; Me4Si)
7.77 (2 H, d, J 7.4, Ar), 7.55 (2 H, d, J 7.1, Ar), 7.39 (2 H, t, J 7.3,
=
Ar), 7.26–7.36 (7 H, m, Ar), 5.61–5.71 (1 H, m, –CH2–CH CH2),
=
5.26–5.35 (1 H, m, NH), 5.07–5.17 (2 H, m, –CH2–CH CH2), 4.59
(2 H, m, –OCH2Ph), 4.37–4.49 (2 H, m, H12 and H13A), 4.30–4.37
(1 H, m, H13B), 4.19–4.26 (1 H, t, J 7.0, H14), 4.02–4.15 (3 H, m, H2
and H11), 3.82–3.92 (1 H, m, H10), 3.53–3.62 (2 H, m, H1), 2.51–
=
2.62 (1 H, m, –CH(HA)–CH CH2), 2.30–2.50 (5 H, m, H3, H5 and
=
–CH(HB)–CH CH2), 1.92–2.03 (1 H, m, H8A), 1.84–1.91 (1 H, m,
H
7A), 1.66–1.73 (1 H, m, H8B), 1.54–1.61 (1 H, m, H9A), 1.43–1.53
1996 | Org. Biomol. Chem., 2006, 4, 1977–2002
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(1 H, m, H7B) and 1.22–1.38 (1 H, m, H9B); dC (150 MHz; CDCl3;
Me4Si) 205.0, 171.7, 156.4, 143.9, 143.8, 141.3, 138.1, 128.4, 127.7,
127.5, 127.1, 125.1, 120.0, 119.9, 119.5, 99.4, 73.4, 72.0, 68.4, 68.1,
67.7, 67.0, 53.3, 51.4, 47.1, 42.9, 36.7, 34.1, 26.1 and 18.3; m/z
(+EI) calc. for C38H42NO8 (MH+) 640.3, found 640.2.
171.1, 156.7, 143.9, 141.3, 137.1, 131.5, 129.1, 127.6, 127.1, 125.1,
121.5, 120.0, 99.5, 73.4, 72.1, 68.4, 68.2, 67.5, 67.2, 51.7, 47.1, 43.0,
42.7, 34.1, 25.5 and 18.3; m/z (+EI) calc. for C35H37BrNO8 (MH+)
678.2, found 678.2.
(9H-Fluoren-9-ylmethoxycarbonylamino)acetic acid 8-benzyl-
oxymethyl-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer
(40a). A clear, colourless oil (90%); Rf 0.24 (1 : 1 EtOAc–
petroleum ether); tmax(film)/cm−1 3290, 2354, 2202, 2158, 2053,
1985, 1953, 1719, 1529, 1451, 1245, 1084, 1031, 743, 668; dH
(600 MHz; CDCl3; Me4Si) 7.76 (2 H, d, J 7.5, Ar), 7.53–7.62
(2 H, m, Ar), 7.40 (2 H, t, J 7.5, Ar), 7.23–7.36 (7 H, m, Ar),
6.25–6.27 (1 H, m, NH), 4.61 (2 H, m, –OCH2Ph), 4.40 (2 H, d, J
7.1, H13), 4,23 (1 H, t, J 7.1, H14), 4.12 (1 H, m, H11A), 4.06 (2 H,
m, H2 and H11B), 3.98 (1 H, dd, J 18.2 and 5.9, H12A), 3.93 (1 H,
dd, J 18.3 and 5.9, H12B), 3.83–3.87 (1 H, m, H10), 3.55–3.59 (2 H,
m, H1), 2.35–2.43 (4 H, m, H3 and H5), 1.96–2.00 (1 H, m, H8A),
1.83–1.86 (1 H, m, H7A), 1.68–1.71 (1 H, m, H8B), 1.57–1.61 (1 H,
m, H9A), 1.45–1.50 (1 H, m, H7B) and 1.30–1.35 (1 H, m, H9B); dC
(150 MHz; CDCl3; Me4Si) 205.3, 169.9, 156.1, 143.8, 141.3, 138.0,
128.4, 127.7, 127.5, 127.1, 125.1, 120.0, 99.4, 73.4, 72.0, 68.5, 68.2,
67.5, 67.2, 51.4, 47.1, 43.0, 42.7, 34.1, 25.6 and 18.4; m/z (+EI)
calc. for C35H38NO8 (M+) 600.3, found 600.2.
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-furan-2-yl-propionic
acid 8-benzyl-oxymethyl-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl
ester isomer (38e). A clear, colourless oil (94%); Rf 0.36 (2 :
3 EtOAc–petroleum ether); tmax(film)/cm−1 3290, 2943, 2323,
2192, 2022, 1719, 1529, 1453, 1212, 988, 743, 668; dH (600 MHz;
CDCl3; Me4Si) 7.76 (2 H, d, J 7.4, Ar), 7.55–7.62 (2 H, m, Ar),
7.39 (2 H. t, J 7.4, Ar), 7.23–7.36 (8 H, m, Ar), 6.21 (1 H, s, Ar),
6.05–6.07 (1 H, m, Ar), 5.40–5.46 (1 H, m, NH), 4.58–4.63 (3 H,
m, H12 and –OCH2Ph), 4.40–4.44 (1 H, m, H13A), 4.28–4.32 (1 H,
m, H13B), 4.19–4.24 (1 H, m, H14), 4.04–4.14 (3 H, m, H2 and
H11), 3.81–3.90 (1 H, m, H10), 3.51–3.61 (2 H, m, H1), 3.05–3.25
(2 H, m, –CH2–furan), 2.30–2.40 (4 H, m, H3 and H5), 1.93–2.03
(1 H, m, H8A), 1.83–1.92 (1 H, m, H7A), 1.67–1.71 (1 H, m, H8B),
1.58–1.62 (1 H, m, H9A), 1.46–1.53 (1 H, m, H7B) and 1.23–1.40
(1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si) 205.2, 170.8, 155.5,
150.1, 143.9, 143.8, 142.2, 141.3, 138.1, 132.5, 130.9, 128.8, 128.4,
127.7, 127.5, 127.1, 125.2, 125.1, 120.0, 110.4, 108.1, 99.4, 73.4,
72.0, 68.5, 68.1, 67.7, 67.1, 53.1, 51.4, 47.1, 42.9, 34.1, 30.8, 26.2
and 18.4; m/z (+ESI) calc. for C40H42NO9 (MH+) 680.2860,
found 680.2882.
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-phenylpropionic
acid 8-benzyloxymethyl-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl
ester isomer (40b). A clear, colourless oil (65%); Rf 0.29 (2 : 3
EtOAc–petroleum ether); tmax(film)/cm−1 3278, 2359, 2196, 2150,
2053, 1945, 1713, 1520, 1478, 1221, 1033, 743, 668; dH (600 MHz;
CDCl3; Me4Si) 7.76 (2 H, d, J 7.3, Ar), 7.53–7.60 (2 H, m, Ar),
7.38–7.42 (2 H, m, Ar), 7.19–7.35 (10 H, m, Ar), 7.13 (2 H, d, J
6.9, Ar), 5.23 (1 H, m, NH), 4.62 (1 H, m, H12), 4.56–4.62 (2 H,
m, –OCH2Ph), 4.41–4.45 (1 H, m, H13A), 4.27–4.31 (1 H, m, H13B),
4.19 (1 H, t, J 7.0, H14), 4.10–4.15 (1 H, m, H2), 4.00–4.05 (2 H,
m, H11), 3.84–3.88 (1 H, m, H10), 3.53–3.59 (2 H, m, H1), 3.10
(1 H, dd, J 13.9 and 5.4, –CH(HA)Ph), 2.98 (1 H, dd, J 13.9 and
6.3, –CH(HB)Ph), 2.36–2.42 (4 H, m, H3 and H5), 1.95–1.99 (1 H,
m, H8A), 1.82–1.88 (1 H, m, H7A), 1.67–1.72 (1 H, m, H8B), 1.57–
1.61 (1 H, m, H9A), 1.45–1.49 (1 H, m, H7B) and 1.30–1.35 (1 H,
m, H9B); dC (150 MHz; CDCl3; Me4Si) 205.0, 171.3, 155.5, 143.8,
143.7, 141.3, 138.1, 135.6, 129.31, 128.6, 128.4, 127.6, 127.5, 127.1,
127.0, 125.1, 125.0, 2 × 120.0, 99.4, 73.4, 72.0, 68.5, 68.1, 67.8,
66.9, 54.7, 51.4, 47.1, 42.9, 38.2, 34.1, 26.1 and 18.3; m/z (+EI)
calc. for C42H44NO8 (MH+) 690.3, found 690.2.
1-(9H -Fluoren-9-ylmethoxycarbonylamino)cyclobutane car-
boxylic acid 8-benzyloxymethyl-10-oxo-1,7-dioxaspiro[5.5]undec-
2-ylmethyl ester (38f). A clear, colourless oil (44%); Rf 0.31 (7 : 13
EtOAc–petroleum ether); tmax(film)/cm−1 3288, 2932, 2356, 2145,
2022, 1720, 1523, 1453, 1212, 1078, 988, 743, 668; dH (600 MHz;
CDCl3; Me4Si) 7.76 (2 H, d, J 7.1, Ar), 7.56–7.64 (2 H, m, Ar),
7.37–7.41 (2 H, m, Ar), 7.26–7.35 (7 H, m, Ar), 5.49 (1 H, s, NH),
4.54–4.61 (2 H, m, –OCH2Ph), 4.34–4.38 (2 H, m, H13), 4.20–4.24
(1 H, m, H14) 4.06–4.15 (3 H, m, H2 and H11), 3.83–3.94 (1 H, m,
H10), 3.54–3.59 (2 H, m, H1), 2.48–2.63 (2 H, m, cyclobutyl–CH2–
), 2.33–2.46 (6 H, m, H3, H5 and cyclobutyl–CH2–), 1.95–2.05
(3 H, m, H8A and cyclobutyl–CH2–), 1.87 (1 H, d, J 13.4, H7A),
1.65–1.71 (1 H, m, H8B), 1.56–1.62 (1 H, m, H9A), 1.44–1.50 (1 H,
m, H7B) and 1.26–1.36 (1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si)
205.3, 171.1, 155.5, 2 × 143.9, 141.3, 138.1, 128.4, 127.7, 127.5,
127.0, 125.1, 2 × 119.9, 99.4, 73.4, 72.0, 68.4, 68.2, 67.6, 66.6,
51.5, 47.2, 43.1, 34.1, 31.2, 26.0, 18.4 and 15.0; m/z (+EI) calc.
for C38H42NO8 (MH+) 640.3, found 640.2.
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-furan-2-yl-propionic
acid 8-benzyl-oxymethyl-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl
ester isomer (40c). A clear colourless oil (95%); Rf 0.40 (2 : 3
EtOAc–petroleum ether); tmax(film)/cm−1 3297, 2355, 2196, 2158,
1953, 1721, 1534, 1465, 1210, 1100, 786, 743, 668; dH (600 MHz;
CDCl3; Me4Si) 7.76 (2 H, d, J 7.4, Ar), 7.55–7.62 (2 H, m, Ar),
7.39 (2 H, t, J 7.4, Ar), 7.23–7.36 (8 H, m, Ar), 6.19–6.23 (1 H, m,
Ar), 6.05–6.07 (1 H, m, Ar), 5.40–5.46 (1 H, m, NH), 4.58–4.63
(3 H, m, H12 and –OCH2Ph), 4.40–4.44 (1 H, m, H13A), 4.28–4.32
(1 H, m, H13B), 4.19–4.24 (1 H, m, H14), 4.04–4.14 (3 H, m, H2 and
H11), 3.81–3.90 (1 H, m, H10), 3.51–3.61 (2 H, m, H1), 3.05–3.25
(2 H, m, –CH2–furan), 2.30–2.40 (4 H, m, H3 and H5), 1.93–2.03
(1 H, m, H8A), 1.83–1.92 (1 H, m, H7A), 1.67–1.71 (1 H, m, H8B),
1.58–1.62 (1 H, m, H9A), 1.46–1.53 (1 H, m, H7B) and 1.23–1.40
(1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si) 205.2, 170.8, 155.5,
(9H-Fluoren-9-ylmethoxycarbonylamino)acetic acid 8-(4-bromo-
benzyloxymethyl)-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester
(39). A clear, colourless oil (92%); Rf 0.27 (1 : 1 EtOAc–
petroleum ether); tmax(film)/cm−1 3327, 2954, 2358, 2192, 1719,
1529, 1453, 1245, 988, 759, 743, 668; dH (600 MHz; CDCl3; Me4Si)
7.76 (2 H, d, J 11.0, Ar), 7.60 (2 H, dd, J 11.1 and 7.8, Ar), 7.44–
7.48 (2 H, m, Ar), 7.39 (2 H, t, J 7.5, Ar), 7.28–7.34 (2 H, m,
Ar), 7.17–7.22 (2 H, m, Ar), 5.30–5.34 (1 H, m, NH), 4.53–4.60
(2 H, m, –OCH2Ph), 4.36–4.40 (2 H, m, H13), 4.23 (1 H, t, J 7.1,
H14), 4.09–4.14 (1 H, m, H11A), 3.96–4.08 (3 H, m, H2, H11B and
H
12A), 3.87–3.94 (1 H, m, H12B), 3.80–3.86 (1 H, m, H10), 3.53–3.64
(2 H, m, H1), 2.32–2.50 (4 H, m, H3 and H5), 1.84–1.95 (1 H, m,
7A), 1.63–1.74 (2 H, m, H8), 1.44–1.51 (2 H, m, H7B and H9A
and 1.28–1.35 (1 H, m, H9B); dC (150 MHz; CDCl3; MeSi4) 205.6,
H
)
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150.1, 143.9, 143.8, 142.2, 141.3, 138.1, 132.5, 130.9, 128.8, 128.4,
127.7, 127.5, 127.1, 125.2, 125.1, 120.0, 110.4, 108.1, 99.4, 73.4,
72.0, 68.5, 68.1, 67.7, 67.1, 53.1, 51.4, 47.1, 42.9, 34.1, 30.8, 26.2
and 18.4; m/z (+ESI) calc. for C40H42NO9 (MH+) 680.2860,
found 680.2882.
2-(3-Ethylureido)-3-phenylpropionic acid 8-benzyloxy methyl-
10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer (42b).
A
clear, colourless oil (quant. over two steps); Rf 0.65 (EtOAc); [a]D25
+10.1 (c 0.15, CH2Cl2); tmax(film)/cm−1 3379, 2950, 2880, 1773,
1724, 1641, 1562, 1498, 1440, 1356, 1300, 1269, 1213, 1178, 1156,
1143, 1078, 1043, 980, 882, 811, 730, 720 and 684; dH (600 MHz;
CDCl3; Me4Si) 7.06–7.40 (10 H, m, Ar), 4.74–4.48 (1 H, m, H12),
4.57–4.68 (3 H, m, –OCH2Ph and NH), 4.44–4.48 (1 H, m, NH),
3.98–4.14 (3 H, m, H2 and H11), 3.78–3.82 (1 H, m, H10), 3.56–3.64
(2 H, m, H1), 2.97–3.18 (4 H, m, H13 and –CH2–Ph), 2.41–2.48
(3 H, m, H3A and H5), 2.29–2.37 (1 H, m, H3B), 1.92–2.04 (1 H,
m, H8A), 1.85–1.91 (1 H, m, H7A), 1.66–1.75 (1 H, m, H8B), 1.52–
1.56 (1 H, m, H9A), 1.43–1.53 (1 H, m, H7B), 1.16–1.24 (1 H, m,
H9B) and 1.08 (3 H, t, J 7.2, H14); dC (150 MHz; CDCl3; Me4Si)
205.7, 171.9, 156.9, 138.0, 136.2, 129.4, 128.5, 128.4, 127.7, 127.6,
127.5, 126.9, 99.6, 73.5, 72.0, 68.6, 68.1, 67.1, 54.1, 51.5, 43.1, 38.6,
35.3, 34.1, 26.0, 18.3 and 15.3; m/z (+ESI) calc. for C30H39N2O7
(MH+) 539.2757, found 539.2733, calc. for C30H38N2NaO7 (MNa+)
561.2577, found 561.2563.
2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-furan-2-yl-propionic
acid 8-benzyl-oxymethyl-10-oxo-1,7-dioxaspiro[5.5]undec-2-yl
methyl ester isomer (41). A clear colourless oil (80%); Rf 0.45
(2 : 3 EtOAc–petroleum ether); tmax(film)/cm−1 3301, 2347, 2187,
2123, 1912, 1717, 1534, 1455, 1210, 1100, 786, 743, 650; dH
(600 MHz; CDCl3; Me4Si) 7.77 (2 H, d, J 7.5, Ar), 7.54–7.61 (2 H,
m, Ar), 7.40 (2 H, t, J 7.4, Ar), 7.24–7.37 (10 H, m, Ar), 6.20–6.22
(1 H, m, Ar), 6.04–6.07 (1 H, m, Ar), 5.39–5.47 (1 H, m, NH),
4.56–4.62 (3 H, m, H12 and –OCH2Ph), 4.39–4.44 (1 H, m, H13A),
4.26–4.32 (1 H, m, H13B), 4.20–4.25 (1 H, m, H14), 4.05–4.15 (3 H,
m, H2 and H11), 3.79–3.88 (1 H, m, H10), 3.51–3.60 (2 H, m, H1),
3.06–3.23 (2 H, m, –CH2–furan), 2.29–2.39 (4 H, m, H3 and H5),
1.94–2.03 (1 H, m, H8A), 1.84–1.91 (1 H, m, H7A), 1.68–1.71 (1 H,
m, H8B), 1.57–1.63 (1 H, m, H9A), 1.45–1.54 (1 H, m, H7B) and
1.22–1.40 (1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si) 204.8,
170.9, 155.2, 150.0, 143.8, 143.7, 142.3, 141.2, 137.9, 132.5, 131.0,
128.9, 128.5, 127.7, 127.5, 127.0, 125.0, 124.9, 120.0, 110.5, 108.2,
99.8, 73.5, 72.0, 68.3, 68.1, 67.8, 67.5, 53.0, 51.4, 47.5, 43.2, 34.2,
30.6, 26.1 and 18.5; m/z (+ESI) calc. for C40H42NO9 (MH+)
680.2860, found 680.2883.
2-(3-Ethylureido)pent-4-enoic acid 8-benzyloxymethyl-10-oxo-
1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer (42c). A clear,
colourless oil (quant. over two steps); Rf 0.60 (EtOAc); [a]2D5 +4.5
(c 0.10, CH2Cl2); tmax(film)/cm−1 3365, 2941, 2870, 1770, 1730,
1642, 1565, 1503, 1452, 1360, 1300, 1281, 1255, 1214, 1190, 1162,
1148, 1094, 1045, 986, 890, 810, 736, 724 and 700; dH (600 MHz;
CDCl3; Me4Si) 7.26–7.37 (5 H, m, Ar), 5.64–5.70 (1 H, m, –CH2–
General procedure for the synthesis of urea derivatives 42a–e, 43a,b
and 44a,b
=
=
CH CH2), 5.09 (2 H, d, J 15.1, –CH2–CH CH2), 4.71 (1 H, d,
J 7.8, NH), 4.59–4.66 (2 H, m, –OCH2Ph), 4.53–4.57 (1 H, m,
H12), 4.48–4.53 (1 H, m, NH), 4.01–4.13 (3 H, m, H2 and H11),
3.80–3.88 (1 H, m, H10), 3.57–3.64 (2 H, m, H1), 3.15–3.21 (2 H, m,
Polymer-bound piperazine (10.0 eq.) was added to a solution of the
spiroketal-derived ester in anhydrous DCM (0.1 M), and subjected
to microwave heating at 120 ◦C for 30 min. Sequestration of
the polymer reagent, followed by evaporation of the resultant
filtrate in vacuo yielded the crude amine intermediate, which
was subsequently re-dissolved in anhydrous DCM (0.1 M) and
treated with ethyl isocyanate (1.0 eq.) at ambient temperature.
The resultant reaction mixture was then left to stir for 30 min at
ambient temperature. Evaporation in vacuo was then followed by
purification of the resultant crude liquid by gravimetric column
chromatography on silica gel, using EtOAc and petroleum ether.
=
H13), 2.42–2.54 (5 H, m, –CH2–CH CH2, H3A and H5), 2.32–2.38
(1 H, m, H3B), 1.95–2.01 (1 H, m, H8A), 1.86–1.92 (1 H, m, H7A),
1.66–1.73 (1 H, m, H8B), 1.54–1.62 (1 H, m, H9A), 1.46–1.50 (1 H,
m, H7B), 1.22–1.31 (1 H, m, H9B) and 1.09–1.13 (3 H, m, H14);
dC (150 MHz; CDCl3; Me4Si) 205.6, 172.3, 157.0, 138.0, 132.6,
128.4, 127.7, 127.5, 127.5, 119.0, 99.5, 73.5, 72.0, 68.6, 68.2, 67.4,
52.6, 51.5, 43.1, 37.1, 35.3, 34.1, 26.0, 18.3 and 15.3; m/z (+ESI)
calc. for C26H37N2O7 (MH+) 489.2601, found 489.2589; calc. for
C26H36N2NaO7 (MNa+) 551.2420, found 551.2408.
2-(3-Ethylureido)propionic acid 8-benzyloxymethyl-10-oxo-1,7-
dioxaspiro[5.5]undec-2-ylmethyl ester isomer (42a). A clear,
colourless oil (quant. over two steps); Rf 0.48 (EtOAc); [a]2D5 +7.8
(c 0.09, CH2Cl2); tmax(film)/cm−1 3380, 2951, 2879, 1776, 1720,
1663, 1564, 1500, 1436, 1348, 1301, 1272, 1212, 1178, 1153, 1144,
1059, 1050, 975, 878, 807, 732, 721 and 680; dH (600 MHz; CDCl3;
Me4Si) 7.26–7.36 (5 H, m, Ar), 4.66–4.73 (1 H, m, NH), 4.59–4.66
(2 H, m, –OCH2Ph), 4.42–4.53 (2 H, m, H12 and NH), 3.97–4.14
(3 H, m, H2 and H11), 3.80–3.88 (1 H, m, H10), 3.58–3.65 (2 H,
m, H1), 3.13–3.26 (2 H, m, H13), 2.42–2.50 (3 H, m, H3A and H5),
2.32–2.38 (1 H, m, H3B), 1.94–2.03 (1 H, m, H8A), 1.89 (1 H, d,
J 11.8, H7A), 1.70 (1 H, d, J 13.2, H8B), 1.55–1.59 (1 H, m, H9A),
1.45–1.50 (1 H, m, H7B), 1.31–1.37 (3 H, m, –CH3), 1.22–1.29 (1 H,
m, H9B) and 1.10–1.14 (3 H, m, H14); dC (150 MHz; CDCl3; Me4Si)
205.6, 171.1, 157.0, 146.5, 138.0, 128.4, 127.7, 127.5, 99.6, 73.4,
72.0, 68.6, 68.1, 67.1, 51.6, 49.0, 43.0, 35.3, 34.1, 26.0, 19.2, 18.3
and 15.3; m/z (+ESI) calc. for C24H34N2NaO7 (MNa+) 485.2264,
found 485.2253.
2-(3-Ethylureido)-3-furan-2-ylpropionic acid 8-benzyloxymethyl-
10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer (42d).
A
clear, colourless oil (quant. over two steps); Rf 0.67 (EtOAc); [a]D25
−0.3 (c 1.52, CH2Cl2); tmax(film)/cm−1 3368, 2943, 2875, 1772,
1726, 1641, 1563, 1505, 1454, 1362, 1303, 1279, 1256, 1213, 1189,
1161, 1146, 1089, 1043, 986, 886, 813, 738, 721 and 699; dH
(600 MHz; CDCl3; Me4Si) 7.25–7.35 (6 H, m, Ar), 6.22–6.24 (1 H,
m, Ar), 6.04–6.06 (1 H, m, Ar), 5.00–5.03 (1 H, m, NH), 4.70–4.76
(2 H, m, H12 and NH), 4.56–4.64 (2 H, m, –OCH2Ph), 3.97–4.09
(3 H, m, H2 and H11), 3.78–3.85 (1 H, m, H10), 3.54–3.63 (2 H,
m, H1), 3.01–3.19 (4 H, m, –CH2–furan and H13), 2.38–2.46 (3 H,
m, H3A and H5), 2.32–2.36 (1 H, m, H3B), 1.90–2.00 (1 H, m,
H
8A), 1.85–1.91 (1 H, m, H7A), 1.66–1.70 (1 H, m, H8B), 1.54–1.59
(1 H, m, H9A), 1.45–1.49 (1 H, m, H7B), 1.24–1.31 (1 H, m, H9B)
and 1.08 (3 H, t, J 7.2, H14); dC (150 MHz; CDCl3; Me4Si) 205.8,
172.0, 168.3, 157.1, 150.8, 138.0, 132.7, 128.4, 127.7, 127.6, 127.5,
110.3, 107.8, 99.5, 73.4, 71.9, 68.5, 68.1, 67.4, 52.4, 51.5, 43.0, 35.3,
34.1, 31.3, 26.1, 18.3 and 15.3; m/z (+ESI) calc. for C28H37N2O8
1998 | Org. Biomol. Chem., 2006, 4, 1977–2002
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(MH+) 529.2550, found 529.2526; calc. for C28H36N2NaO8 (MNa+)
551.2369, found 551.2347.
colourless oil (quant. over two steps); Rf 0.16 (1 : 1 EtOAc–
petroleum ether); [a]D25 +9.2 (c 0.12, CH2Cl2); tmax(film)/cm−1 3295,
2939, 1748, 1721, 1454, 1410, 1323, 1212, 1123, 970, 843, 738 and
699; dH (600 MHz; CDCl3; Me4Si) 7.25–7.39 (5 H, m, Ar), 4.89
(1 H, br s, NH), 4.61–4.65 (2 H, m, –OCH2Ph), 4.16 (1 H, dd, J 11.4
and 7.3, H11A), 4.03–4.09 (2 H, m, H2 and H11B), 3.94 (1 H, d, J 18.3,
1-(3-Ethylureido)cyclobutanecarboxylic acid 8-benzyloxymethyl-
10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer (42e).
A
clear, colourless oil (quant. over two steps); Rf 0.62 (EtOAc); [a]D25
+12.5 (c 0.40, CH2Cl2); tmax(film)/cm−1 3360, 2938, 2875, 1773,
1728, 1663, 1560, 1501, 1450, 1370, 1300, 1252, 1210, 1190, 1160,
1143, 1089, 1038, 989, 887, 805, 730, 725 and 701; dH (600 MHz;
CDCl3; Me4Si) 7.26–7.36 (5 H, m, Ar), 4.82 (1 H, s, NH), 4.59–4.65
(2 H, m, –OCH2Ph), 4.43–4.45 (1 H, m, NH), 4.10–4.15 (2 H, m,
H2 and H11A), 4.01–4.05 (1 H, m, H11B), 3.85–3.90 (1 H, m, H10),
3.59–3.64 (2 H, m, H1), 3.14–3.20 (2 H, m, H13), 2.48–2.58 (2 H,
m, cyclobutyl–CH2–), 2.41–2.47 (3 H, m, H3A and H5), 2.30–2.37
(3 H, m, H3B and cyclobutyl–CH2–), 1.92–2.03 (3 H, m, H8A and
cyclobutyl–CH2–), 1.86–1.92 (1 H, m, H7A), 1.67–1.71 (1 H, m,
H8B), 1.58–1.62 (1 H, m, H9A), 1.45–1.50 (1 H, m, H7B), 1.23–1.32
(1 H, m, H9B) and 1.10 (3 H, t, J 7.2, H14); dC (150 MHz; CDCl3;
Me4Si) 205.6, 174.2, 157.1, 138.0, 128.4, 127.7, 127.5, 99.5, 73.5,
72.1, 68.4, 68.3, 67.4, 58.5, 51.6, 43.2, 35.2, 34.1, 31.6, 26.0, 18.3,
15.3 and 15.1; m/z (+ESI) calc. for C26H37N2O7 (MH+) 489.2601,
found 489.2585; calc. for C26H36N2NaO7 (MNa+) 511.2420, found
511.2404.
H
12A), 3.84–3.88 (2 H, m, H10 and H12B), 3.59–3.64 (2 H, m, H1),
2.99 (3 H, s, –NHSO2CH3), 2.41–2.46 (3 H, m, H3A and H5), 2.38
(1 H, dd, J 14.5 and 2.8, H3B), 1.93–2.04 (1 H, m, H8A), 1.86–1.92
(1 H, m, H7A), 1.68–1.74 (1 H, m, H8B), 1.56–1.60 (1 H, m, H9A),
1.47–1.51 (1 H, m, H7B) and 1.25–1.29 (1 H, m, H9B); dC (150 MHz;
CDCl3; Me4Si) 205.4, 169.4, 138.0, 128.4, 127.8, 127.5, 99.6, 73.5,
72.1, 68.8, 68.1, 67.7, 51.5, 44.3, 43.1, 41.4, 34.0, 25.9 and 18.3; m/z
(+ESI) calc. for C21H30NO8S (MH+) 456.1692, found 456.1723,
C21H29NNaO8S (MNa+) 478.1512, found 478.1530.
2-Methanesulfonylamino-3-phenylpropionic acid 8-benzyloxy-
methyl-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer
(45b). A clear colourless oil (quant. over two steps); Rf 0.25
(1 : 1 EtOAc–petroleum ether); [a]2D5 +12.2 (c 0.10, CH2Cl2);
tmax(film)/cm−1 3296, 2933, 1749, 1723, 1455, 1410, 1325, 1279,
1213, 1106, 981, 841, 739 and 701; dH (600 MHz; CDCl3; Me4Si)
7.08–7.45 (10 H, m, Ar), 4.82 (1 H, d, J 9.2, NH), 4.60–4.65 (2 H,
m, –OCH2Ph), 4.32–4.38 (1 H, m, H12), 4.07–4.13 (3 H, m, H2
and H11), 3.78–3.95 (1 H, m, H10), 3.60–3.64 (2 H, m, H1), 3.05–
3.15 (1 H, m, –CH(HA)Ph), 2.88–2.94 (1 H, m, –CH(HB)Ph), 2.60
(3 H, s, –NHSO2CH3), 2.42–2.48 (3 H, m, H3A and H5), 2.36–
2.41 (1 H, m, H3B), 1.93–2.04 (1 H, m, H8A), 1.86–1.92 (1 H, m,
2-(3-Ethylureido)-3-furan-2-yl-propionic acid 8-benzyloxy methyl-
10-oxo-1,7-dioxaspiro[5.5]undec-2 ylmethyl ester isomer (44b).
A
clear, colourless oil (quant. over two steps); Rf 0.54 (EtOAc);
[a]D25 +10.5 (c 0.05, CH2Cl2); tmax(film)/cm−1 3368, 2943, 2875,
1772, 1726, 1641, 1563, 1505, 1454, 1362, 1303, 1279, 1256, 1213,
1189, 1161, 1146, 1089, 1043, 986, 886, 813, 738, 721 and 699; dH
(600 MHz; CDCl3; Me4Si) 7.25–7.35 (m), 6.23–6.26 (m), 6.04–6.09
(m), 5.32–5.35 (m), 5.27–5.29 (m), 5.08–5.12 (m), 4.94–4.99 (m),
4.72–4.82 (m), 4.53–4.63 (m), 4.34–4.36 (m), 4.15–4.24 (m), 4.06–
4.13 (m), 3.94–4.03 (m), 3.12–3.21 (m), 2.96–3.10 (m), 2.69–2.79
(m), 2.48–2.58 (m), 2.35–2.44 (m), 1.98–2.02 (m), 1.79–1.91 (1 H,
m), 1.50–1.67 (3 H, m), 1.21–1.35 (1 H, m) and 1.05–1.18 (3 H,
m); dC (150 MHz; CDCl3; Me4Si) 206.1, 171.1, 168.1, 157.1, 142.0,
141.5, 129.7, 128.5, 128.4, 127.7, 127.6, 127.5, 110.4, 107.9, 99.3,
73.5, 71.7, 68.2, 68.1, 60.4, 53.4, 49.8, 41.3, 36.9, 35.8, 33.1, 27.7,
18.4 and 15.4; m/z (+ESI) calc. for C28H37N2O8 (MH+) 529.2550,
found 529.2562; calc. for C28H36N2NaO8 (MNa+) 551.2369, found
551.2369.
H
7A), 1.66–1.75 (1 H, m, H8B), 1.45–1.62 (2 H, m, H7B and H9A)
and 1.24–1.30 (1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si) 205.1,
171.2, 138.1, 135.5, 129.5, 128.8, 128.4, 127.7, 127.5, 127.4, 99.5,
73.5, 72.1, 68.7, 68.1, 68.0, 57.2, 51.4, 43.0, 41.3, 39.4, 34.1, 25.9
and 18.3; m/z (+ESI) calc for C28H35NNaO8S (MNa+) 568.1981,
found 568.2030.
2-Methanesulfonylaminopropionic acid 8-benzyloxymethyl-10-
oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer (45c).
A
clear colourless oil (quant. over two steps); Rf 0.20 (1 : 1 EtOAc–
petroleum ether); [a]D25 +3.8 (c 0.15, CH2Cl2); tmax(film)/cm−1 3298,
2940, 1757, 1721, 1465, 1406, 1320, 1265, 1210, 1106, 832, 739 and
678; dH (600 MHz; CDCl3; Me4Si) 7.26–7.36 (5 H, m, Ar), 4.95
(1 H, d, J 8.2, NH), 4.60–4.65 (2 H, m, –OCH2Ph), 4.05–4.17
(4 H, m, H2, H11 and H12), 3.85–3.89 (1 H, m, H10), 3.58–3.64
(2 H, m, H1), 2.94 (3 H, s, –NHSO2CH3), 2.40–2.46 (3 H, m, H3A
and H5), 2.36 (1 H, dd, J 14.5 and 2.9, H3B), 1.94–2.04 (1 H, m,
General procedure for the synthesis of spiroketal-derived
sulfonamides 45a–d
H
8A), 1.86–1.92 (1 H, m, H7A), 1.66–1.75 (1 H, m, H8B), 1.53–1.61
Polymer-supported piperazine (10.0 eq.) was added to a solution
of the spiroketal-derived ester in anhydrous DCM (0.1 M), and
subjected to microwave heating at 120 ◦C for 30 min. Sequestration
of the polymer reagent, followed by evaporation of the resultant
filtrate in vacuo yielded the crude amine intermediate, which was
subsequently re-dissolved in anhydrous DCM (0.1 M) and treated,
first with pyridine (1.05 eq.) at ambient temperature, then with
(1 H, m, H9A), 1.46–1.50 (1 H, m, H7B), 1.40 (3 H, d, J 7.2, –CH3)
and 1.25–1.33 (1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si) 205.1,
171.3, 138.0, 128.4, 2 × 127.7, 127.5, 99.5, 73.5, 72.2, 68.7, 68.1,
67.9, 65.8, 51.7, 43.1, 41.7, 34.0, 25.9, 19.7 and 18.3; m/z (+ESI)
calc for C22H31NNaO8S (MNa+) 492.1668, found 492.1674.
1-Methanesulfonylaminocyclobutanecarboxylic acid 8-benzyl-
oxymethyl-10-oxo-1,7-dioxaspiro[5.5]undec-2-ylmethyl ester (45d).
A clear colourless oil (quant. over two steps); Rf 0.26 (1 : 1 EtOAc–
petroleum ether); [a]D25 −7.6 (c 0.98, CH2Cl2); tmax(film)/cm−1 3298,
2931, 1754, 1721, 1450, 1411, 1321, 1268, 1212, 1106, 978, 831, 721
and 701; dH (600 MHz; CDCl3; Me4Si) 7.26–7.36 (5 H, m, Ar), 5.07
(1 H, s, NH), 4.60–4.64 (2 H, m, –OCH2Ph), 4.07–4.17 (3 H, m,
H2 and H11), 3.90–3.95 (1 H, m, H10), 3.58–3.64 (2 H, m, H1),
◦
MeSO2Cl (1.05 eq.) at 0 C. The resultant reaction mixture was
then left to warm to ambient temperature and stirred for 2 h.
Evaporation in vacuo was then followed by purification of the
resultant crude liquid by gravimetric column chromatography on
silica gel, using EtOAc and petroleum ether.
Methanesulfonylaminoacetic acid 8-benzyloxymethyl-10-oxo-
1,7-dioxaspiro[5.5]undec-2-ylmethyl ester isomer (45a). A clear
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2.98 (3 H, s, –NHSO2CH3), 2.52–2.57 (2 H, m, cyclobutyl–CH2–),
2.34–2.46 (6 H, m, H3, H5 and cyclobutyl–CH2–), 1.96–2.05 (3 H,
m, H8A and cyclobutyl–CH2–), 1.86–1.92 (1 H, m, H7A), 1.68–1.74
(1 H, m, H8B), 1.57–1.62 (1 H, m, H9A), 1.47–1.52 (1 H, m, H7B)
and 1.30–1.35 (1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si) 205.3,
173.1, 138.1, 128.4, 127.7, 127.5, 99.5, 73.4, 72.1, 68.5, 68.3, 68.0,
60.6, 51.5, 43.6, 43.1, 34.1, 32.2, 25.9, 18.3 and 15.3; m/z (+ESI)
calc. for C24H34NO8S (MH+) 496.2005, found 496.2020.
(4 × 2 cm3). The recombinant organic extracts were washed with
distilled water (1 × 2 cm3) and brine (1 × 2 cm3), dried over
anhydrous MgSO4 and then concentrated in vacuo. The resultant
crude was re-dissolved in anhydrous DMF (1 cm3) and treated with
NaN3 (8.5 mg, 131 lmol, 1.1 eq.) stirring at room temperature
for 5 h, then EtOAc (2 cm3) and distilled water (2 cm3) were
added, and the subsequent aqueous phase extracted with EtOAc
(4 × 2 cm3). The recombinant organic extracts were washed
with distilled water (1 × 2 cm3) and brine (1 × 2 cm3), dried
over anhydrous MgSO4, filtered and then evaporated in vacuo.
Gravimetric column chromatography on florisil, using EtOAc as
eluent, afforded the title compound 50 as a clear, colourless oil
(42 mg, quant.); Rf 0.30 (EtOAc); dH (600 MHz; CDCl3; Me4Si)
7.26–7.35 (5 H, m, Ar), 4.60–4.66 (2 H, m, –OCH2Ph), 4.12–4.17
(1 H, m, H2), 3.78–3.81 (1 H, m, H10), 3.57–3.65 (2 H, m, H1),
3.22 (1 H, dd, J 12.8 and 7.4, H11A), 3.06 (1 H, dd, J 12.8 and 3.3,
8 - Benzyloxymethyl - 10 - oxo - 1,7 - dioxaspiro[ 5.5 ]undecane - 2 -
carboxylic acid(pyridine-2-ylmethyl)amide isomer (49). To an
anhydrous DMF solution (2 cm3) of spiroketal-derived alcohol
24c (28 mg, 0.089 mmol) was added solid pyridinium dichromate
salt (334 mg, 0.888 mmol, 10.0 eq.), in one portion, at ambient
temperature. The reaction was then stirred at ambient temperature
for 18 h, at which point the reaction was diluted with EtOAc
(2 cm3) anddistilled water (2cm3), and the aqueous phase extracted
with EtOAc (4 × 5 cm3). The recombinant organic extracts were
then dried over anhydrous MgSO4, filtered and then evaporated
in vacuo to afford the crude carboxylic acid intermediate, which
was immediately redissolved in anhydrous DMF (1 cm3). Pyridine
was then added (11 ll, 0.134 mmol) at ambient temperature
followed by p-nitrophenylchloroformate (27 mg, 0.134 mmol) in
one portion, at 0 ◦C. The reaction was then held at ambient
temperature for 20 min, at which point 2-picolylamine was added,
drop-wise, and the reaction left to stir for a further 10 min. The
reaction mixture was diluted with EtOAc (4 cm3), then distilled
water was added (4 cm3), and the aqueous phase extracted with
EtOAc (3 × 4 cm3). The recombinant organic extracts were washed
with distilled water (1 × 10 cm3) and brine (1 × 10 cm3), dried
over anhydrous MgSO4, filtered and then evaporated in vacuo.
Gravimetric column chromatography of the resultant crude on
silica, using EtOAc as eluent, afforded the title compound 49 as
a clear, faint yellow oil (90% over 3 steps); Rf 0.23 (EtOAc); [a]D25
+47.0 (c 0.42, CH2Cl2); tmax(film)/cm−1 3350, 2932, 1722, 1672,
1592, 1571, 1528, 1477, 1438, 1369, 1310, 1274, 1255, 1213, 1118,
1095, 1074, 1049, 979, 953, 932, 910, 893, 851, 833, 751, 700 and
666; dH (600 MHz; CDCl3; Me4Si) 8.57 (1 H, d, J 4.6, Ar), 7.64
(1 H, t, J 7.7, Ar), 7.47–7.53 (1 H, m, NH), 7.26–7.36 (5 H, m, Ar),
7.17–7.22 (2 H, m, Ar), 4.57–4.64 (3 H, m, H12A and –OCH2Ph),
4.49 (1 H, dd, J 16.2 and 5.3, H12B), 4.15–4.20 (1 H, m, H10),
4.02–4.06 (1 H, m, H2), 3.62 (1 H, dd, J 10.4 and 3.9, H1A), 3.57
(1 H, dd, J 10.4 and 4.6, H1B), 2.48–2.58 (3 H, m, H3A and H5),
2.38–2.42 (1 H, m, H3B), 2.16–2.22 (1 H, m, H9A), 1.99–2.05 (1 H,
m, H8A), 1.93 (1 H, m, H7A), 1.72–1.76 (1 H, m, H8B), 1.50–1.56
(1 H, m, H7B), 1.38–1.43 (1 H, m, H9B); dC (150 MHz; CDCl3;
Me4Si) 204.9, 173.6, 156.3, 149.3, 137.9, 136.7, 128.4, 127.8, 122.3,
121.7, 100.3, 73.5, 71.7, 70.8, 68.9, 51.4, 43.9, 43.0, 34.3, 27.6
and 18.6; m/z (+ESI) calc. for C24H29N2O5 (MH+) 425.2076,
found 425.2074, calc. for C24H28N2NaO5 (MNa+) 447.1896, found
447.1895.
H
11B), 2.34–2.47 (4 H, m, H3 and H5), 1.96–2.00 (1 H, m, H8A),
1.87–1.91 (1 H, m, H7A), 1.66–1.72 (1 H, m, H8B), 1.53–1.62 (1 H,
m, H9A), 1.46–1.50 (1 H, m, H7B) and 1.26–1.32 (1 H, m, H9B); dC
(150 MHz; CDCl3; Me4Si) 205.0, 138.1, 128.4, 127.7, 127.5, 99.7,
73.4, 72.0, 70.4, 68.5, 54.9, 51.4, 42.9, 34.1, 27.1 and 18.4; m/z
(+ESI) calc. for C18H24N3O4 (MH+) 346.1767, found 346.1762,
calc. for C18H23N3NaO4 (MNa+) 368.1586, found 368.1588.
2-Benzyloxymethyl-8-(4-phenyl[1,2,3]triazol-1-ylmethyl)-1,7-
dioxaspiro[5.5]undecan-4-one (51). A stirred solution of azide 50
(54.0 mg, 156 lmol) in 2 : 1 distilled water and t-butanol (1 cm3)
was treated, sequentially, with phenylacetylene (17 ll, 156 lmol,
1.0 eq.), CuSO4·5H2O (0.4 mg, 1.56 lmol, 1 mol%) and sodium
ascorbate (1.5 mg 7.8 lmol, 5 mol%). The reaction was stirred
at room temperature for 3 h, and then the mixture was extracted
with EtOAc (4 × 2 cm3). The recombinant organic extracts were
washed with distilled water (2 × 1 cm3) and brine (1 × 1 cm3),
dried over anhydrous MgSO4 and then concentrated in vacuo.
Gravimetric column chromatography on silica gel, using EtOAc as
eluent, afforded the title compound 51 as a white, crystalline solid
(68 mg, quant.); Rf 0.23 (EtOAc); mp 168 ◦C (from pentane); [a]2D5
+30.0 (c 0.35, CH2Cl2); tmax(film)/cm−1 2998, 1720, 1455, 1364,
1309, 1223, 1127, 1077, 1049, 768, 743 and 698; dH (600 MHz;
CDCl3; Me4Si) 7.77–7.83 (2 H, m, Ar), 7.75–7.77 (1 H, m, Ar),
7.37–7.41 (2 H, m, Ar), 7.23–7.32 (3 H, m, Ar), 7.18–7.23 (3 H,
m, Ar), 4.40–4.52 (3 H, m, H11A and –OCH2Ph), 4.16–4.21 (1 H,
m, H11B), 3.84–3.87 (1 H, m, H10), 3.40–3.43 (1 H, m, H1A), 3.32–
3.35 (1 H, m, H1B), 3.28–3.30 (1 H, m, H2), 2.36–2.48 (3 H, m,
H
H
3A and H5), 1.99–2.05 (1 H, m, H3B), 1.87–1.96 (2 H, m, H7A and
8A), 1.67–1.71 (2 H, m, H8B and H9A), 1.40–1.45 (1 H, m, H7B) and
1.18–1.24 (1 H, m, H9B); dC (150 MHz; CDCl3; Me4Si) 206.1, 147.6,
137.7, 130.2, 128.9, 128.3, 128.1, 127.6, 127.5, 125.7, 121.6, 100.2,
73.2, 71.4, 69.4, 68.7, 54.4, 51.7, 42.8, 33.7, 26.7 and 18.1; m/z
(+ESI) calc. for C26H30N3O4 (MH+) 448.2236, found 448.2210,
calc. for C26H29N3NaO4 (MNa+) 470.2056, found 470.2068.
8-Azidomethyl-2-benzyloxymethyl-1,7-dioxaspiro[5.5]undecan-
4-one (50). A stirred solution of spiroketal-derived alcohol 24c
(40.0 mg, 125 lmol) in anhydrous DCM (0.5 cm3) was cooled
to −78 ◦C and treated, sequentially, with anhydrous pyridine
(22 ll, 273 lmol, 2.2 eq.) and Tf2O (14 ll, 139 lmol, 1.1 eq.).
The reaction was allowed to warm to room temperature over
1 h, then the mixture was quenched with a saturated, aqueous
solution of NaHCO3 (0.2 cm3) and then extracted with Et2O
Acknowledgements
The authors thank Novartis for the Novartis Research Fellowship
(S. V. L.), Marie Curie Fellowship for a postdoctoral fellowship
(G. Z.) and the EPSRC for a studentship (L.-G. M.). We also
thank Dr John Davies at the Cambridge University Chemistry
Laboratory for X-ray crystallography experiments.
2000 | Org. Biomol. Chem., 2006, 4, 1977–2002
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Hamel, P. A. Wender and S. A. Kozmin, Nat. Chem. Biol., 2005, 1,
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