Towards the enantioselective synthesis of (-)-euonyminol-preparation of a fully functionalised lower-rim model

Article abstract of DOI:10.1039/c3ob27187k

The development of a stereoselective total synthesis of β-dihydroagarofuran 4 is described. This compound contains the same oxygenation pattern on its 'lower-rim' as found in the natural sesquiterpene (-)-euonyminol (1) and it is expected that the route described should be applicable to the synthesis of that complex natural product. (-)-Euonyminol is found as the core scaffold of a series of complex macrodilactone sesquiterpenoids isolated from the Celastraceae which possess interesting biological activities (e.g. anti-HIV activity). The synthetic route builds upon an epoxidative asymmetric desymmetrisation of meso-diallylic alcohol 10 that we have reported previously. It features a lactate Ireland-Claisen rearrangement to establish the quaternary stereocentre at C11 (27 → 28a) and an unusual dealkylative intramolecular epoxide-opening by the C11 methyl ether to establish the tetrahydrofuranyl C-ring of the β-dihydroagarofuran skeleton (35 → 36). The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob27187k

Organic &
Biomolecular Chemistry
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Towards the enantioselective synthesis of
(−)-euonyminol – preparation of a fully functionalised
lower-rim model†
Cite this: Org. Biomol. Chem., 2013, 11,
2514
Matthew J. Webber,a Sarah A. Warren,a Damian M. Grainger,a Matthew Weston,b
Stacy Clark,a Steven J. Woodhead,b Lyn Powell,c Stephen Stokes,d
Alexander Alanine,e Jeffrey P. Stonehouse,f Christopher S. Frampton,g
Andrew J. P. Whitea and Alan C. Spivey*a
The development of a stereoselective total synthesis of β-dihydroagarofuran 4 is described. This compound
contains the same oxygenation pattern on its ‘lower-rim’ as found in the natural sesquiterpene (−)-euony-
minol (1) and it is expected that the route described should be applicable to the synthesis of that complex
natural product. (−)-Euonyminol is found as the core scaffold of a series of complex macrodilactone sesqui-
terpenoids isolated from the Celastraceae which possess interesting biological activities (e.g. anti-HIV activity).
The synthetic route builds upon an epoxidative asymmetric desymmetrisation of meso-diallylic alcohol 10
that we have reported previously. It features a lactate Ireland–Claisen rearrangement to establish the qua-
ternary stereocentre at C11 (27 → 28a) and an unusual dealkylative intramolecular epoxide-opening by the
C11 methyl ether to establish the tetrahydrofuranyl C-ring of the β-dihydroagarofuran skeleton (35 → 36).
Received 9th November 2012,
Accepted 31st January 2013
DOI: 10.1039/c3ob27187k
www.rsc.org/obc
Introduction
(−)-Euonyminol (1) is a nonahydroxylated β-dihydroagarofuran
sesquiterpene (Fig. 1).1–6 It forms the core structure of a large
family of natural product polyesters found exclusively in her-
baceous perennials of the Celastraceae family.7 Crude extracts
of these plants have been used since antiquity in traditional
medicines and many of the isolated components have been
demonstrated to have activity of significant utility in medicine
and agriculture.7–9 For example, the macrodilactone-contain-
ing Celastraceae constituent hypoglaunine B displays potent
anti-HIV activity.10 There has been one total synthesis of
( )-euonyminol by White which set a high bar against which
aDepartment of Chemistry, South Kensington Campus, Imperial College, London
SW7 2AZ, UK. E-mail: a.c.spivey@imperial.ac.uk; Tel: +44 (0)20 75945841
bDepartment of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
cAstraZeneca Process Research and Development, Charter Way, Silk Road Business
Park, Macclesfield, Cheshire, SK10 2NA, UK
Fig. 1 Structures of β-dihydroagarofuran, (−)-euonyminol (1), previously syn-
thesized intermediate 2, and anti-HIV natural product hypoglaunine B.
dAstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
eLead Generation, PRBC-L.y, F. Hoffmann-La Roche, CH-4070 Basel, Switzerland
fAstraZeneca R and D, Charnwood, Department of Medicinal Chemistry,
Bakewell Road, Loughborough, Leics, LE11 5RH, UK
gPharmorphix® Solid State Services, Member of the Sigma-Aldrich Group,
250 Cambridge Science Park, Milton Road, Cambridge, CB4 0WE, UK
†Electronic supplementary information (ESI) available: Crystallographic analysis
subsequent syntheses should be measured (5.2% overall yield,
20 steps).11–13 There have also been several subsequent reports
of synthetic approaches to less densely oxygenated natural and
unnatural β-dihydroagarofurans.14–38
Previously, we have described an approach towards (−)-euony-
minol (1) and its congeners from naphthalene that features a
for compounds 6, 17, 18c, 28a and 31 including CIF files and NMR spectra for
all new compounds. CCDC 905361–905365. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c3ob27187k
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Scheme 1 Overview of approach to tetrahydroxylated β-dihydroagarofuran
derivative 4.
two-directional synthesis followed by Sharpless-like epoxidative
asymmetric desymmetrisation to deliver enantiomerically highly
enriched epoxy allylic alcohol 2 containing the all-cis tetraol array
found on the ‘upper-rim’ of this natural product core (Fig. 1).39
Scheme 2 Synthesis of diallylic alcohol 10 and its asymmetric desymmetrisa-
tion to give epoxy allylic alcohol 3.39 Reagents and conditions: (a) KCN, MeCN/
H2O, reflux, 80%, or Et2AlCN, CH2Cl2/toluene, rt, 98%; (b) VO(acac)2, t-BuOOH,
CH2Cl2/toluene, 70 °C, 87%; (c) Me3Al, CH2Cl2/hexane, 40 °C, 88%; (d) MsCl,
Et3N, CH2Cl2, rt, 92%; (e) DBU, 110 °C, 92%; (f) Zr(Oi-Pr)4·i-PrOH, L-(+)-DIPT,
t-BuOOH, CH2Cl2, −20 °C, 90%, 92% ee.
Herein, we describe the development of
a synthetic
sequence by which the epoxy allylic alcohol functionality, as
found in intermediate 2, can be used as a platform for the fully
stereoselective installation of the tetrahydrofuranyl C-ring and
the associated oxygenation found on the ‘lower-rim’ of (−)-euo-
nyminol (1). This chemistry has been explored on a model
decalin 3 which contains axial methyl groups at C2 and C8, in
place of the upper-rim all-cis tetraol array required for the
natural product. This has led to the synthesis of the unnatural
tetrahydroxylated β-dihydroagarofuran derivative 4 (Scheme 1).
We envisage that compound 4 will prove useful as a model
compound for the development of the chemistry required for
the introduction of the hydroxy-iso-evoninic acid-containing40
macrodilactone bridge between C3 and C13 which is character-
istic of the anti-HIV natural product hypoglaunine B (Fig. 1).41
Moreover, the chemistry described here starting from epoxy
allylic alcohol 3 should also be applicable to the preparation of
(−)-euonyminol (1) itself (when starting from epoxy allylic
Fig. 2 Molecular structure of cyanohydrin 6 as determined by single crystal
X-ray crystallography.
alcohol 2), and hence the eventual synthesis of the aforemen- Scheme 3 Synthesis of γ-lactone 13a via an Ireland–Claisen [3,3]-sigmatropic
rearrangement/lactonisation cascade of propionate ester 12.43 Reagents and
tioned highly complex bioactive natural products, none of
which have yet been prepared by total synthesis.
conditions: (a) n-BuLi, (EtCO)2O, THF, rt, 88%; (b) TMSCl, LHMDS, THF, −78 °C to
70 °C, 76%; (c) t-BuOK, t-BuOH, 90 °C, 91%.
Results and discussion
As also communicated previously,43 an Ireland–Claisen
[3,3]-sigmatropic rearrangement of the propionate ester 12 of
allylic alcohol 3 can be deployed to access γ-lactone diastereo-
isomer 13a following C11 epimerisation with t-BuOK/t-BuOH
at 90 °C (Scheme 3).
Synthesis of enantiomerically highly enriched epoxy allylic
alcohol 3 proceeds smoothly in 6 steps from isotetralin oxide
(5) as described previously39 (Scheme 2).
The identity of cyanohydrin 6 was confirmed by a single
crystal X-ray structure determination (Fig. 2, see also ESI†).
The epoxidative desymmetrisation of diallylic alcohol 10
was initially performed using VO(acac)2/t-BuOOH in order to
characterize the racemic monoepoxide 3 (34% yield) and the
undesired meso-bis-epoxide 11 (16% yield) for chiral-HPLC
assay purposes (see ESI†). Sharpless-type asymmetric epoxida-
tion (AE), using a stoichiometric amount of Zr(Oi-Pr)4·i-PrOH
complex in place of the usual catalytic Ti(Oi-Pr)4,39,42 was then
shown to deliver the required monoepoxide (−)-3‡ in 90%
yield and 92% ee when using L-(+)-DIPT as the chiral ligand.39
γ-Lactone 13a constituted the starting point for our studies
to introduce the tetrahydrofuranyl C-ring.
The first routes we explored were aimed at retaining the C3
axial alcohol, the C4/C5 alkene and the C6 equatorial alcohol
in γ-lactone 13a whilst introducing a C11/C12 alkene to set the
stage for 1,5-diene oxidative cyclisation to give the tetrahydro-
furanyl C-ring of the target (Scheme 4).
This approach to the construction of the C-ring was
inspired by pioneering work by Klein and Rojahn44 using
KMnO4 to construct 2,5-cis-tetrahydrofurans from 1,5-dienes
and subsequent extensive development and mechanistic work
on this and analogous cyclisations using other oxidants by
Baldwin,45 Walba,46 Brown,47 Sharpless (RuO4),48 Piccialli
(RuO4 and OsO4),49 Sica,50 and Donohoe51 (OsO4) and Stark
(TPAP).52 We envisaged that an appropriate oxidant might
‡The six stereocentres in this levorotatory enantiomer have the
(2R,3S,4S,5R,8S,10R) absolute configurations (i.e. as drawn in Scheme 2), as
established from an anomalous dispersion single crystal X-ray structure determi-
nation on a brominated derivative (ref. 43).
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Fig. 3 Molecular structure of tetrahydrofuran 17 as determined by single
Scheme 4 Proposed 1,5-diene oxidative cyclisation strategy for β-dihydro-
agarofuran formation and precedent for a related cyclisation by Sica.
crystal X-ray crystallography.
effect simultaneous introduction of the C13 hydroxyl group,
the tetrahydrofuranyl C-ring and the equatorial C4 hydroxyl
group in a single operation from the 1,5-diene and that the
correct stereochemistry would be assured at the three new
stereocentres (C11, C5 and C4), provided that initial cis-dihy-
droxylation occurs on the correct face of either the C4/C5 or
the C11/C12 alkene. This selectivity was expected to be
favoured by pre-coordination to either the C3 axial alcohol
allylic to the C4/C5 alkene or the C6 equatorial alcohol homo-
allylic to the C11/C12 alkene. Although the vast majority of lit-
erature examples of this type of reaction employ
conformationally flexible, acyclic 1,5-diene substrates, we con-
sidered that the successful cyclisation of (−)-limonene to the
corresponding cis-tetrahydrofuran in 45% yield by Sica et al.
using RuO2·2H2O (5 mol%)/NaIO4 (2.5 equiv.) represented par-
ticularly encouraging precedent (Scheme 4).50
Our first strategy to access a 1,5-diene containing substrate
on which to attempt this type of cyclisation relied upon intro-
duction of the C11/C12 alkene via lactone α-bromination then
reductive lactone cleavage with concomitant bromohydrin
reductive elimination, a sequence successfully applied in
Fukuyama’s synthesis of (−)-hapalindole G (Scheme 5).53
Synthesis of C3 benzoylated α-bromolactone 15 proved
straightforward,43 but attempted reductive cleavage of this
lactone using NaBH4 in EtOH provided the unexpected and
undesired tetrahydrofurans 16 and 17. These products incor-
porate a tert-hydroxyl group at C11, the configuration of which
is inverted relative to the starting bromide. The molecular
structure of compound 17 was secured by a single crystal X-ray
structure determination (Fig. 3, see also ESI†).
Scheme 6 Proposed pathway for the formation tetrahydrofurans 16 and 17.
Initial reduction of the lactol to the primary alcoholate
could initiate 3-exo-tet ring-closure to give an epoxide with con-
comitant inversion of the stereochemistry at C11. Ring-
opening of this epoxide by the C6 alcohol would then give the
products 16 and 17. Since neither compound 16 nor com-
pound 17 appeared promising for further investigation this
approach to the introduction of the C11/C12 alkene was
abandoned.
Our next strategy to access the requisite 1,5-diene was via
reduction of γ-lactone 13a to the corresponding primary
alcohol and then elimination (Scheme 7).
Direct reduction of γ-lactone 13a with LiAlH4 furnished
triol 19 but upon attempted activation as the corresponding
primary mesylate (MsCl, Et3N, CH2Cl2), rapid ring-closure of
the C6 sec-alcohol to give the tetrahydrofuran 20 ensued; none
of the desired 1,5-diene was formed. Subsequent attempts to
selectively protect the C3 and C6 sec-alcohols as acetates or
A plausible route by which products 16 and 17 could arise
is shown in Scheme 6.
Scheme 7 Synthesis of diprotected 1,5-dienes 21a–c and monoprotected 1,5-
dienes 21 and 21d. Reagents and conditions: (a) RBr, KOH, THF, 60 °C, 95%
(18a), 88% (18b), 65% (18c); (b) LiAlH4, THF, 77% (19), 74% (19a), 100%
(19b), 70% (19c); (c) MsCl, Et3N, CH2Cl2, 50% (20a) or i. MsCl, Et3N, CH2Cl2, ii.
DBN, toluene, 110 °C, 34% (20b), (d) i. n-Bu3P, 2-NO2-C6H4SeCN (Grieco’s
reagent) ii. H2O2, 84% (21a), 91% (21b), 68% (21c), (e) DDQ (2 equiv.), CH2Cl2–
water (10 : 1), 54% (21d), 85% (21).
Scheme 5 Initial approach to the synthesis of the 1,5-diene substrates.
Reagents and conditions: (a) Bz2O, Et3N, DMAP, CH2Cl2, −78 °C to rt, 100%; (b)
i. LDA, TMSCl, ii. NBS, THF, −78 °C to rt, 76%; (c) NaBH4 (2.5 equiv.), EtOH, 16
(26%) + 17 (46%).
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benzoates via selective C13 primary alcohol protection as a
TBS ether, dual C3/C6 sec-alcohol ester protection then C13
silyl ether deprotection were thwarted by facile ester migration
from the C6 to the C13 hydroxyl group concomitant with silyl
ether deprotection. Ether protection of the C3 and C6 alcohols
was therefore undertaken. To this end, saponification and
in situ global alkylation of γ-lactone 13a using KOH in combi-
nation with MeI or BnBr provided the corresponding di-etheri-
fied esters 18a and 18b cleanly. Reduction of these esters with Fig. 4 Molecular structure of ester 18c as determined by single crystal X-ray
crystallography.
LiAlH4 provided the corresponding primary alcohols 19a and
19b with both the C3 and C6 sec-alcohols protected as ethers.
However, upon attempted activation of either the di-methyl or
the di-benzyl ether derivatives as their corresponding mesy-
lates (MsCl, Et3N, CH2Cl2) and attempted E2 elimination with
base, undesired tetrahydrofuran ring-formation ensued (with
concomitant ether dealkylation) to give ethers 20a and 20b
respectively, again with no trace of the required 1,5-diene pro-
ducts. This unwanted dealkylative cyclisation reaction could
however be circumvented by the use of Grieco’s ortho-nitrophe-
nylselenylcyanide reagent54,55 with an oxidative work-up; this
protocol effected the required C11/C13 elimination to give 1,5-
dienes 21a and 21b and was rationalised to be successful
because it proceeds via a concerted syn-elimination and does
not rely on the conversion of the C13 alcohol to a good leaving
group. Selective deprotection of the C3 benzyl ether in deriva-
tive 21b could be accomplished using DDQ to give allylic
alcohol-containing 1,5-diene 21d, but efficient deprotection of
both the C3 and C6 ethers required synthesis of the di-PMB
ether 21c. This compound was prepared via saponification/
Scheme 8 Attempted oxidative cyclisations using 1,5-dienes 21a–d. Reagents
alkylation of γ-lactone 13a with PMB-Cl to give di-etherified
ester 18c which underwent clean LiAlH4 reduction and sub-
sequent oxidative dealkylation to give diallylic alcohol-contain-
and conditions: (a) K2OsO4·2H2O (5 mol%) TFA, Me3NO·3H2O, acetone–water
(9 : 1) (36%); (b) OsO4 (1 equiv.), TMEDA (1 equiv.), CH2Cl2; (c) TFA, MeOH
[21 → 23 (50%)]; (d) AcOH, CH2Cl2.
ing 1,5-diene 21.§ The molecular structure of intermediate 18c
was secured by a single crystal X-ray structure determination
(Fig. 4, see also ESI†).
1
∼1 : 1 mixture of C11 epimers was inferred from H NMR data
With this series of 1,5-dienes in hand, exploration of their and following treatment of this intermediate with HCl in
behavior towards metal catalyzed oxidation was undertaken MeOH (cf. Donohoe57) or AcOH in CH2Cl2 (cf. Piccialli58) no
(Scheme 8).
products of oxidative cyclisation could be detected, only diol
Subjection of 1,5-diene di-methyl ether 21a to the con- 22 resulting from simple hydrolysis was formed. Application of
ditions reported by Donohoe56 for 1,5-diene oxidative cyclisa- Sica’s RuO2(H2O)2/NaIO4 conditions50 to substrate 21a resulted
tion using K2OsO4·2H2O (5 mol%) and TFA resulted in the in numerous products which were not fully characterized but
formation of
a complex mixture of products tentatively appeared to result from over-oxidation at both alkenes. Antici-
assigned as containing as the major component the C11–C13 pating that hydrogen bonding interactions between the OsO4
diol 22 (as a ∼1 : 1 mixture of C11 epimers as judged by 1H and both the C3 and C6 alcohols in 1,5-diene 21 would facili-
NMR). Apparently, the C11–C13 alkene reacted in preference tate initial osmate(VI) ester formation on the β-face of the C4–
to the C4–C5 alkene, there was negligible facial selectivity for C5 alkene (i.e. bottom face as drawn), the Donohoe stoichio-
this initial oxidation and moreover acid-mediated cyclisation metric OsO4/TMEDA protocol57 was applied to this substrate.
of the presumed initial osmate(VI) ester onto the C4–C5 alkene However, formation of the C11–C12 osmate(VI) ester (as seen
did not take place. These conclusions were corroborated when for the dimethyl ester substrate 21a) was observed, this time as
an analogous reaction was performed using a stoichiometric a single C11 epimer, presumably controlled by a hydrogen
quantity of OsO4/TMEDA for the oxidation.57 Although the bonding interaction with the homoallylic C6 alcohol. Upon
osmate(VI) ester could not be isolated, its formation as a treatment with HCl in MeOH, this intermediate cyclised to
give β-dihydroagarofuran 23 in 50% yield as a single epimer at
C11. Cross-peaks between the protons attributable to the
C13 methylene and both the C8 methine and equatorial
C9 methylene hydrogen in the NOESY spectrum of
§Compound 21 could not be obtained directly from triol 19 using Grieco’s
method as tetrahydrofuran 20 formed in preference.
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β-dihydroagarofuran 23 confirmed the undesired relative
stereochemistry at the key C11 quaternary stereocentre.¶ To
evaluate the possibility of directing the initial oxidation onto
the C4–C5 alkene using only the C3 hydroxyl group, the same
oxidation conditions were applied to substrate 21d which has
the C6 alcohol protected as a benzyl ether. The mixture of pro-
1
ducts obtained was consistent from analysis of H NMR data
with initial non-stereoselective osmylation once again at the
C11–C13 alkene then acid-mediated cyclisation to give β-dihy-
droagarofuran 24 as a ∼1 : 1 ratio of C11 epimers.
Scheme 9 Bis-epoxidation of 1,5-diene 21 and attempted ring-C formation.
Reagents and conditions: (a) VO(acac)2, TBHP, 2,6-lutidine, CH2Cl2 (85%); (b)
TFA, CHCl3 (33%).
In view of the strong bias of all the 1,5-diene derivatives
tested to undergo oxidation at the C11–C13 alkene in prefer-
ence to the C4–C5 alkene and the observation that a free
hydroxyl group at C6 effectively directs oxidation to the Re face
of this alkene, we decided at this juncture to explore bis-epoxi-
dation of the 1,5-diene diol 21. Provided that selectivity for
epoxidation on the β-face of the C4–C5 alkene could also be
achieved then we anticipated that the resulting di-epoxide
might be susceptible to a double ring-opening cascade with
inversion of configuration at C11 to form the tetrahydrofuran
C-ring with the correct relative stereochemistry (cf. retention of
configuration via the 1,5-diene oxidative cyclisation approach,
Scheme 9).
In the event, bis-epoxidation of diene 21 using VO(acac)2/
TBHP gave the required bis-epoxide 25 with > 11 : 1 diastereo-
selectivity over all other isomers. Attempted C-ring formation
using TFA in CHCl3,11 perhaps unsurprisingly in the light of
our previous observations (cf. Scheme 7), resulted in closure of
the C6 alcohol onto the C11–C13 epoxide to give tetrahydro-
furan 26 with no trace of the desired cascade product under
any of the conditions we explored. The relative stereochemistry
at C11 in tetrahydrofuran 26 was confirmed by cross-peaks
between the C12 methyl protons and the C8 methine proton in
its NOESY NMR spectrum.
In view of our inability to develop an efficient method of
ring-C construction with control of the quaternary C11 stereo-
centre via either of the above described strategies we opted to
explore approaches in which the C11 stereocentre was ‘pre-
established’ during the Ireland–Claisen rearrangement to form
the axial C7–C11 bond. We envisioned that this could be
achieved by introduction of a lactate ester in place of the pro-
pionate ester in derivative 12 (cf. Scheme 3, above). Esterifica-
tion of tert-alcohol 3 proved challenging with lactic acid
derivatives but eventually it was found that good yields of the
lactate methyl ether derivative 27 could be obtained using the
Yamaguchi method59–61 (Scheme 10).
Scheme 10 Esterification of tert-alcohol 3 and Ireland–Claisen rearrangement.
Reagents and conditions: (a) i. 2,4,6-Cl3C6H2COCl, Et3N, DMAP, ii. (−)-(S)-2-meth-
oxypropionic acid (79%); (b) LiHMDS, TMS-Cl, THF, −78 °C to 60 °C [28a (38%)
+ 28b (20%)].
γ-lactones 28a and 28b. The relative stereochemistry of the
major epimer 28a was established, by a single crystal X-ray
structure determination, to be the epimer which will lead to
the correct stereochemistry at C11 in the natural product
targets provided that ring-closure to form the tetrahydrofura-
nyl C-ring is effected with retention of configuration at this
stereocentre (Fig. 5).
When scalemic tert-alcohol 3 (obtained from incompletely
enantioselective desymmetrisation of diallylic alcohol 10, see
Experimental section) was employed in the esterification with
enantiomerically pure (−)-(S)-lactic acid methyl ether, the two
diastereomeric products (i.e. ester 27 and its diastereoisomer
in which all stereocentres except the lactate stereocentre are
inverted) were inseparable. Interestingly however, when this
mixture was subject to the Ireland–Claisen rearrangement con-
ditions, apparently only the major diastereoisomer underwent
rearrangement to give the ∼2 : 1 mixture of γ-lactone products
28a : 28b and the minor diastereoisomer of the ester substrate
27 was recovered. Although this kinetic resolution pheno-
menon allows enhancement of the enantiomeric purity of the
desired product γ-lactones 28a and 28b this aspect of the
rearrangement was not pursued further at this stage as the
immediate aim was to develop the remaining synthetic steps
Upon treatment with LiHMDS and TMS-chloride under con-
ditions analogous to those employed for the propionate
variant (i.e., cf. Scheme 3: −78 °C to 60 °C in THF over ∼15 h)
lactate derivative 27 was found to undergo an Ireland–Claisen
rearrangement to give a ∼2 : 1 mixture of two epimeric
¶That hydrogen bonding to the C6 homoallylic alcohol directs osmylation to the
Re face of the C11–C13 isopropenyl group (i.e. front face as drawn) is consistent
with White’s experiences of epoxidation of the C11–C13 alkene by TBHP/
VO(acac)2 on a related derivative en route to euonyminol (ref. 11).
Fig. 5 Molecular structure of γ-lactone 28a as determined by single crystal
X-ray crystallography.
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to install the lower-rim functionality; the enantiomeric purity
of the material would only become of interest when applied to
(−)-euonyminol itself. Similarly, no concerted effort was made
to improve the diastereoselectivity of the Ireland–Claisen
rearrangement but rather to postpone the optimization of this
important selectivity until en route to (−)-euonyminol itself.
The levels of diastereoselectivity displayed in previously
reported lactate and closely related Ireland–Claisen rearrange-
ments with α-oxygenated esters62–70 have been shown to reflect
not only the selectivity of initial (E)/(Z)-silylketene acetal for-
mation,71,72 but also the operation of both chair and boat tran-
sition states, particularly for cyclohexenyl systems.73,74
Diastereoselectivity has however proved amenable to tuning by
the use of chiral lithium amide bases.75,76
Fig. 6 Molecular structure of β-dihydroagarofuran 31 as determined by single
crystal X-ray crystallography.
undergone alkylative or reductive ring-opening. Consequently,
Having established but not optimised a route to γ-lactone alkylative ring-opening of γ-lactone 28a with MeI/KOH, in an
28a, in which the key C11 quaternary stereocentre has been analogous fashion to that carried out on γ-lactone 13a (cf.
set, our attention focused on methods for its conversion to a Scheme 7), then epoxidation with m-CPBA of the resulting di-
β-dihydroagarofuran containing the oxygenation pattern found etherified ester 29, gave epoxide 30 as the exclusive product as
on the lower rim of euonyminol. Specifically, we were intrigued expected. Upon treatment of this epoxide with BBr3 and NaI,
to see if we could exploit the type of dealkylative intramolecu- reagents that we envisaged would promote epoxide ring-
lar tetrahydrofuran forming reactions that plagued our initial opening and dealkylation respectively, we were delighted to
approaches to 1,5-dienes (cf. 19a/b → 20a/b, Scheme 7). The find that the requisite β-dihydroagarofuran 31 was formed in
plan was to accomplish the key tetrahydrofuranyl C-ring 44% yield. This desired products was accompanied by
closure by inducing the lactate-derived C11 methoxy oxygen to δ-lactone 32 (30% yield) resulting from competitive ring-
act as a nucleophile towards an epoxide introduced on the opening of the epoxide by the methyl ester. The identity of
α-face (i.e. top face as drawn) of the C4–C5 alkene (Scheme 11). β-dihydroagarofuran 31 was confirmed by a single crystal X-ray
We knew from our prior studies leading to the synthesis of structure determination (Fig. 6).
C4–C5 β-epoxide 25 (cf. Scheme 9) that epoxidation by m-CPBA
In order to circumvent the intervention of the ester as a
of the C4–C5 alkene, in derivatives in which the axial C3 competitive nucleophilic group to the ether oxygen in the de-
alcohol was protected, always led to good levels of α-selectivity alkylative epoxide ring-opening reaction, alkene 29 was subject
irrespective of whether the γ-lactone remained intact or had to reduction (LiAlH4, 63% yield) and the resulting primary
alcohol 33 protected as acetate ester 34 (Ac2O, Et3N, DMAP,
99% yield). Treatment of this derivative with m-CPBA gave
α-epoxide 35 which was successfully converted to the β-dihy-
droagarofuran 36 via clean dealkylative epoxide ring-opening
in 78% yield upon treatment with BBr3/LiI.
This method of ring-closure to form the C5–O bond of the
tetrahydrofuranyl C-ring (i.e. 35 → 36, Scheme 11) in which the
C11 methoxy group ring opens the C4–C5 α-epoxide bears
some resemblance to the methods employed by Barrett (C11
OH
→
C5–C10 β-epoxide),15 Mehta (C11 OH
→
→
C5–C6
C4–C5
α-epoxide) and particularly Ducrot (C11 OH
α-epoxide)26 towards related β-dihydroagarofurans. It is
however unique in having been employed in a fashion that
explicitly controls the key quaternary C11 stereogenic centre in
the product. The only previous methods that also control this
key stereogenic centre were reported by Tu who formed the
C11–O bond of the tetrahydrofuranyl C-ring by addition of a
C5 β-OH group to a C7–C11 alkene mediated by NBS18,23,33,34
or Hg(OAc)2,35 and by White who formed the C11–O bond by
an elegant cascade reaction upon protonation of a C11–C13
epoxide.11–13
Scheme 11 Synthesis of tetrahydroxylated β-dihydroagarofuran derivative 4.
Reagents and conditions: (a) KOH, MeI, THF (96%); (b) m-CPBA, CH2Cl2 (70%);
(c) BBr3, NaI, CH2Cl2 [31 (44%) + 32 (30%)]; (d) LiAlH4, THF (63%); (e) Ac2O,
DMAP, pyridine (99%); (f) m-CPBA, CH2Cl2 (96%); (g) BBr3, LiI, CH2Cl2 (78%); (h)
DMP, CH2Cl2 (92%); (i) MeMgCl (4 equiv.), THF (75%).
The axial C4 alcohol in β-dihydroagarofuran 36 was readily
oxidized by the Dess–Martin periodinane to give ketone 37 in
92% yield. Stereoselective conversion of this ketone to the cor-
responding equatorial tertiary alcohol by 1,2-addition of a
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methyl organometallic reagent from the α-face was expected to required to append the macrodilactone functionality found in
be relatively straightforward as nucleophile approach to the hypoglaunine B (Fig. 1) are ongoing in our laboratory and will
β-face is sterically shielded by the flanking axial oxygen groups be reported in due course.
at C3 and C5. In the event however, this proved to be a delicate
transformation, possibly due to the presence of the acetate
ester which undergoes concomitant deprotection and necessi-
tates the use of excess organometallic reagent. We opted to
For general experimental procedures and the single X-ray
explore the use of methyl Grignard reagents and found that
Experimental
crystal data please see the ESI.†
the outcome of this reaction was strongly dependent on the
precise conditions employed. No identifiable products could
Isotetralin79
be isolated when employing either MeMgBr or MeMgI,
whereas when employing MeMgCl we were able to obtain the
According to a slightly modified method of Vogel,79 a 3 L
round-bottomed flask was fitted with a mechanical stirrer, an
acetone/cardice cold finger and a pressure-equalising dropping
funnel. The flask was cooled to −78 °C and ammonia was con-
densed through a KOH drying tower. Sodium lumps (100 g,
4.35 mmol, 5.6 equiv.) were added over 45 min with vigorous
stirring. A solution of naphthalene (100 g, 0.78 mmol, 1
equiv.) in a mixture of EtOH (230 mL) and Et2O (300 mL), was
added via the dropping funnel over a course of 2.5 h. Residual
naphthalene was washed from the apparatus using Et2O
(30 mL). The reaction mixture was left to stir at −78 °C for a
further 3 h, then the cooling bath was removed and the
mixture was left to stand for 16 h. The residual solid was cau-
tiously quenched with ice-cooled MeOH (300 mL) followed by
water (2 L). The aqueous mixture was extracted with Et2O (3 ×
300 mL), dried (MgSO4) and concentrated in vacuo to leave an
off-white solid. Purification by recrystallisation from MeOH
afforded isotetralin as white plates (92.0 g, 89%). Mp 51–52 °C
(MeOH) [Lit.79 52–53 °C (MeOH)]; 1H NMR (250 MHz, CDCl3) δ
2.52 (s, 8H), 5.70 (s, 4H) ppm; MS (EI+) m/z 132 (M+), 117, 91,
78, 54.
desired equatorial tert-alcohol product 4 in a good yield (75%)
using 4 equivalents of reagent. We obtained another product,
tentatively assigned as the equatorial sec-alcohol formally
arising from axial hydride reduction of ketone 37, when using
8 equivalents of Grignard reagent under otherwise identical
conditions. Since MeMgCl contains no β-hydrogens the
reduced product presumably arises via a single electron trans-
fer (SET) mechanism77 as has previously been observed for
cyclic ketones flanked by two ether groups.78 Unfortunately, we
had insufficient quantities of ketone 37 to explore further the
interplay of factors that favor methylation over suspected
reduction; this will therefore be addressed when applying this
chemistry to the synthesis of (−)-euonyminol itself from epoxy
allylic alcohol 2.
Conclusions
In summary, we have developed a 9 step sequence of reactions
by which the enantiomerically enriched decalin epoxy allylic
alcohol 3 can be stereoselectively converted into unnatural
β-dihydroagarofuran 4 in an unoptimised overall yield of 9.3%.
Exploratory studies into alternative strategies have also been
presented. The successful route features a lactate methyl ether
Ireland–Claisen rearrangement (27 → 28a) to establish the
crucial quaternary C11 stereocentre and an unusual dealkyla-
tive ring-opening of a C4–C5 α-epoxide by the lactate-derived
C11 methyl ether to form the tetrahydrofuranyl ring-C (35 →
36). Although β-dihydroagarofuran 4 is not a natural product
itself, it contains all the stereochemical features found on the
lower-rim of the archetypal nonahydroxylated β-dihydroagaro-
furan sesquiterpene natural product constituent (−)-euonymi-
nol. It is therefore anticipated that the chemistry described
herein will be of particular interest to those engaged in the
synthesis of agarofuran-based sesquiterpenes and should be
applicable to the synthesis of (−)-euonyminol itself (when
starting from epoxy allylic alcohol 2).k Studies towards this
end and also into using compound 4 to develop the chemistry
Isotetralin oxide 580
According to a slightly modified method of Vogel,80 a two-
necked 1 L round-bottomed flask was fitted with a pressure
equalising dropping funnel, a nitrogen line, and a magnetic
stirrer bar. The reaction vessel was charged with isotetralin
(26.13 g, 0.198 mol) and CH2Cl2 (250 mL), and cooled to 0 °C.
To this solution was added NaOAc (24.36 g, 0.297 mol), fol-
lowed by the dropwise addition of peracetic acid (50 mL, 4.75 M
in AcOH, 0.238 mol). The reaction was stirred for 1 h 40 min
before water was added (150 mL). The organic phase was
washed with 5% aqueous NaOH solution (300 mL) and water
(300 mL), dried (MgSO4) and evaporated to dryness to give
epoxide 5 as a white solid (28.55 g, 97%): Mp 59–62 °C
(petrol) [Lit.80 58–61 °C (petrol)]; Rf = 0.15 (petrol–EtOAc,
20 : 1); 1H NMR (250 MHz, CDCl3) δ 2.30–2.55 (m, 8H),
5.30–5.60 (m, 4H) ppm; 13C NMR (63 MHz, CDCl3) δ 30.8
(4 × t), 60.3 (2 × s), 122.6 (4 × d) ppm; MS (EI+) m/z 148 (M+),
120, 94, 91, 79, 66; HRMS calcd for C10H12O (M+) 148.0883,
found 148.0888 (Δ = +3.4 ppm).
kAlthough the presence of two methyl ethers at C3 and C6 in model compound
4 may appear unpromising for eventual deprotection in the context of the syn-
thesis of (−)-euonyminol, there is precedent in the work of Yamada for BCl3 in
CH2Cl2 achieving this en route to the closely related β-dihydroagarofuran core
evoninol (ref. 41).
Cyanohydrin 6
Method 1: a mixture of epoxide 579,80 (80 mg, 0.54 mmol) and
potassium cyanide (78 mg, 1.20 mmol) was dissolved in a
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mixture of CH3CN (2 mL) and water (8 mL). The reaction (2 × d), 52.4 (2 × d), 70.3 (s), 123.0 (s) ppm; MS (EI+) m/z 207
mixture was heated at reflux for 3 days. To the cooled reaction (M+), 189, 178, 153, 136, 125, 118, 106, 79, 71, 57; HRMS (EI+)
mixture, was added CH2Cl2 (40 mL) and water (30 mL). The calcd for
C
11H13NO3 (M+) 207.0895, found 207.0887
aqueous layer was acidified by adding 1 M HCl (10 mL), and (Δ = −3.8 ppm).
the phases were separated. The aqueous layer was extracted
with CH2Cl2 (4 × 30 mL). The combined organic layers were
Triol 8
dried (MgSO4), filtered and concentrated in vacuo. Flash
chromatography eluting with EtOAc–petrol (3 : 7) gave cyanohy- To a solution of bis-epoxide 7 (690 mg, 3.33 mmol) in CH2Cl2
drin 6 as a white solid (75 mg, 80%). Mp 159–161 °C (EtOAc– (25 mL) at room temperature was added Me3Al (2 M solution
petrol); Rf = 0.2 (petrol–EtOAc, 4 : 1); IR (CHCl3) νmax 3532, in hexane, 6.7 mL, 13.32 mmol) and the reaction refluxed at
2911, 2237 cm−1 1H NMR (250 MHz, CDCl3) δ 2.20–2.65 (m, 40 °C for 52.5 hours. The reaction was allowed to cool and par-
;
8H), 5.70 (m, 4H) ppm; 13C NMR (63 MHz, CDCl3) δ 29.7 (s), titioned between CHCl3 (75 mL) and 1 M HCl (75 mL). The
33.2 (2 × t), 37.1 (2 × t), 68.1 (s), 123.3 (2 × d), 124.2 (2 × d), aqueous phase was extracted with CHCl3 (2 × 50 mL) and the
123.4 (s) ppm; MS (EI+) m/z 174 (M+), 157, 121; HRMS (EI+) combined organic fractions dried (MgSO4) and evaporated to
calcd for C11H13NO (M+) 175.0997, found 175.0992 (Δ = dryness to give triol 8 as a white solid (700 mg, 88%):
−2.8 ppm); Anal. calcd for C11H13NO: C, 75.4; H, 7.4; N, 8.0%, Mp 205.1–206.6 °C; Rf = 0.4 (EtOAc–petrol, 7 : 3); IR (CHCl3)
Found: C, 75.3; H, 7.6; N, 7.9%.
νmax 3609, 3403, 3030, 3028, 3013, 2928, 2232, 1463, 1438,
Method 2: to a solution of epoxide 579,80 (10.0 g, 67.6 mmol) 1230, 1217, 1104, 1086 cm−1
;
1H NMR (250 MHz, CD3OD) δ
in CH2Cl2 (40 mL) was added a 1 M solution of diethylalumi- 1.30 (d, J = 7.8 Hz, 6H), 1.55–1.68 (m, 2H), 1.83 (dd, J = 3.1 Hz,
nium cyanide in toluene (81.1 mL, 81.1 mmol) dropwise at 14.1 Hz, 2H), 2.05–2.22 (m, 6H), 3.81–3.88 (m, 2H) ppm; 13C
room temperature and the reaction stirred for 15 min. 5% NMR (63 MHz, CD3OD) δ 19.4 (2 × q), 35.0 (2 × t), 36.8 (2 × t),
aqueous NaOH solution (50 mL) was added and the aqueous 36.9 (2 × d), 37.9 (s), 73.7 (2 × d), 75.4 (s), 127.8 (s) ppm; MS
layer extracted with CH2Cl2 (3 × 40 mL). The combined organic (EI+) 239 (M+), 221, 210, 203, 192, 179, 164, 154, 151, 148, 143,
extracts were then dried (MgSO4), and concentrated in vacuo. 139, 135, 126, 120, 115, 112, 109, 106, 97; HRMS (EI+) calcd for
Purification by flash chromatography eluting with petrol– C13H22NO3 (M+) 240.1600, found 240.1595 (Δ = −2.1 ppm);
EtOAc (4 : 1) afforded cyanohydrin 6 as a white solid (11.6 g, Anal. calcd for C13H21NO3: C, 65.2; H, 8.8; N, 5.8%, Found C,
98%). Analytical data as reported above.
64.5; H, 8.7; N, 5.6%.
Crystal data for 6: C11H13N1O1, M = 175.22, monoclinic,
P21/n (no. 14), a = 7.192(3), b = 14.069(4), c = 9.2117(16) Å,
β = 102.365(19)°, V = 910.4(4) Å3, Z = 4, Dc = 1.278 g cm−3
,
Bis-mesylate 9
μ(Mo-Kα) = 0.082 mm−1, T = 123 K, colourless prism, 0.40 × To a suspension of triol 8 (1.31 g, 5.48 mmol) in CH2Cl2
0.35 × 0.20 mm, Rigaku AFC7R diffractometer; 2137 measured (30 mL) was added Et3N (2.29 mL, 16.4 mmol). The mixture
reflections, 1984 unique, (Rint = 0.0200), F2 refinement, was cooled in an ice-water bath and methanesulfonyl chloride
R1(obs) = 0.0413, wR2(all) = 0.1203, 1664 independent observed (1.27 mL, 16.4 mmol) was added drop-wise while ensuring the
reflections [|Fo| > 4σ(|Fo|), 2θmax = 53.94°], 122 parameters. temperature of the reaction remained below 10 °C. The reac-
CCDC 905361.
tion was left to stir at room temperature for 15 h and parti-
tioned by the addition of saturated aq. NH4Cl (40 mL) and
CHCl3 (30 mL). The organic phase was separated and the
Bis-epoxide 7
To a solution of diene 6 (7.70 g, 44.1 mmol) and VO(acac)2 aqueous phase extracted with CHCl3 (3 × 40 mL). The com-
(584 mg, 2.2 mmol) in CH2Cl2 (65 mL) at room temperature bined organic extracts were dried (MgSO4) and concentrated
was added t-BuOOH (3.8 M in toluene, 58.3 mL, 220 mmol) in vacuo to give a pale brown foaming solid. The crude product
and the reaction mixture heated at reflux with a bath tempera- was purified by flash chromatography eluting with EtOAc–
ture of 70 °C. After stirring at this temperature for 18 hours, petrol (1 : 1) to give bis-mesylate 9 as a white solid (2.00 g,
the reaction mixture was allowed to cool and was partitioned 92%). Mp 123.5–126.4 °C; Rf = 0.5 (EtOAc–petrol, 7 : 3); IR
between CH2Cl2 (200 mL) and 5% aqueous Na2SO3 solution (CHCl3) νmax 3588, 3032, 3014, 2931, 2020, 1464, 1334, 1239,
1
(200 mL). The aqueous layer was extracted with CH2Cl2 (2 × 1226, 1220, 1208, 1200, 1177 cm−1; H NMR (250 MHz, CDCl3)
150 mL) and the combined organic extracts were dried δ 1.35 (d, J = 7.8 Hz, 6H), 1.60 (br s, 1H), 1.70 (dd, J = 3.1 Hz,
(MgSO4) and concentrated in vacuo. The crude product was tri- 14.1 Hz, 2H), 2.15 (d, J = 6.3 Hz, 2H), 2.20 (m, 2H), 2.35 (d, J =
tuated with cold petrol (2 × 60 mL) and concentrated in vacuo. 4.7 Hz, 1H), 2.38–2.50 (m, 3H), 3.05 (s, 6H), 3.17 (br s, 1H),
Flash chromatography, eluting with EtOAc–petrol (1 : 1) gave 4.86 (q, J = 3.1 Hz, 2H) ppm; 13C NMR (63 MHz, CDCl3) δ 18.8
bis-epoxide 7 as a white amorphous powder (7.9 g, 87%). Mp (2 × q), 32.8 (2 × d), 34.4 (2 × t), 35.7 (s), 37.1 (2 × t), 38.8
247–249 °C; Rf = 0.1 (petrol–EtOAc, 3 : 2); IR (CHCl3) νmax 3691, (2 × q), 70.8 (s), 81.4 (2 × d), 126.3 (s) ppm; MS (CI+) 413
3474, 3021, 2930, 2360, 2235, 1602, 1430, 1406, 1213, 1114, (MNH4 ), 317, 239, 221, 203, 52; HRMS (ESI+) calcd for
+
1094 cm−1 1H NMR (250 MHz, CDCl3) δ 2.02–2.20 (m, 4H), C15H29N2O7S2 (M+) 413.1416, found 413.1400 (Δ = −2.6 ppm);
;
2.32–2.48 (m, 4H), 3.30–3.40 (4H, m), 3.45 (s, 1H) ppm; 13C Anal. calcd for C15H25NO7S2: C, 45.6; H, 6.34; N, 3.5; S, 16.2%,
NMR (63 MHz, CDCl3) δ 32.8 (2 × t), 34.8 (2 × t), 36.4 (s), 49.4 Found C, 45.6; H, 6.4; N, 3.6; S 16.5%.
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meso-Diallylic alcohol 10
14.1 Hz, 2H), 1.44 (d, J = 7.8 Hz, 6H), 1.80 (dd, J = 14.1, 7.8 Hz,
2H), 2.35 (app. quin, J = 7.8 Hz, 2H), 3.03 (s, 1H), 3.27 (d, J =
4.7 Hz, 2H), 3.55 (d, J = 4.7 Hz, 2H) ppm; 13C NMR (100 MHz,
CDCl3) δ 19.9 (2 × q), 26.1 (2 × d), 29.7 (s), 30.3 (2 × t), 58.3 (2 ×
d), 58.4 (2 × d), 63.0 (s), 123.4 (s); MS (EI+) 235 (M+), 219, 172,
149, 146, 132, 121, 111, 105, 97, 91, 83, 77, 71, 57; HRMS (EI+)
A suspension of bis-mesylate 9 (4.40 g, 11.1 mmol) in DBU
(12 mL) was heated to 110 °C for 12 h. Upon cooling, the
mixture was partitioned between 1.0 M aq. citric acid (100 mL)
and CH2Cl2 (100 mL). The organic phase was separated and
washed with a further portion of citric acid (100 mL). The
aqueous phase was extracted with CH2Cl2 (3 × 50 mL). The
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo to yield an off-white solid. The crude material
was purified on an alumina plug eluting with EtOAc–petrol
(1 : 9) to give diene 10 as a white solid (2.08 g, 92%). Mp
125.8–129.6 °C; Rf = 0.7 (EtOAc–petrol, 1 : 1); IR (CHCl3) νmax
3691, 3587, 3034, 3012, 2966, 2935, 2879, 2362, 2234, 1734,
1638, 1602, 1458, 1402, 1376, 1338, 1282, 1239, 1225,
calcd for
(Δ = +1.7 ppm).
C
13H17NO3 (M+) 235.1208, found 235.1212
CSP-HPLC conditions for determination of the ee of
monoepoxide 3
Chiralcel-OD (25 × 0.46 cm), 80 : 20 hexane : IPA, 0.5 mL
min−1, thermostatic 10 °C, detect by UV (200 nm). Retention
times (Rt): monoepoxide (−)-3 18.0 min, monoepoxide (+)-3
19.5 min. The meso-bis-epoxide 11 is not detected at this
wavelength.
1208 cm−1 1H NMR (250 MHz, CDCl3) δ 1.35 (d, J = 7.8 Hz,
;
6H), 1.73 (d, J = 14.1 Hz, 2H), 2.22 (dd, J = 9.4 Hz, 14.1 Hz, 2H),
2.48–2.65 (m, 2H), 5.85–6.00 (qd, J = 1.6 Hz, 9.4 Hz, 4H) ppm;
13C NMR (63 MHz, CDCl3) δ 21.3 (2 × q), 28.6 (2 × d), 33.7
(2 × t), 36.3 (s), 65.0 (s), 125.1 (s), 129.7 (2 × d), 137.8 (2 × d)
ppm; MS (EI+) m/z 203 (M+), 188, 185, 176, 170, 159, 156, 146,
137, 130, 120, 109, 105, 95, 91, 81, 77, 71, 67, 58, 55; HRMS
(EI+) calcd for C13H17NO (M+) 203.1310, found 203.1314
(Δ = +2.0 ppm).
Asymmetric epoxidative desymmetrisation of diallylic alcohol
10
To a solution of Zr(Oi-Pr)4 (112 mg, 0.29 mmol) in CH2Cl2
(4.5 mL) over 4 Å MS at −20 °C was added L-(+)-DIPT (68 μL,
0.32 mmol) followed by t-BuOOH (3.8 M in toluene, 91 μL,
0.35 mmol). The reaction mixture was stirred at −20 °C for
15 minutes before a solution of diallylic alcohol 10 (58.8 mg,
0.29 mmol) in CH2Cl2 (3.0 mL) precooled to −20 °C was added
and the reaction stored for 167 hours at −20 °C. The reaction
was partitioned between CH2Cl2 (30 mL) and 5% aqueous
Na2SO3, the aqueous phase extracted with CH2Cl2 (3 × 40 mL),
and the combined organic extracts dried (MgSO4) and concen-
trated in vacuo. Flash chromatography, eluting with EtOAc–
petrol (1 : 9) gave (−)-monoepoxide 3 as a white crystalline
solid (57 mg, 90%). Analytical data as reported above,
[α]D −109.1 (c. 0.42, CH2Cl2) as the earlier eluting enantiomer
(Rt 18.0 min) by CSP-HPLC (conditions as above) in 92% ee.
Racemic epoxidative desymmetrisation of diallylic alcohol 10
To a solution of diallylic alcohol 10 (14.6 mg, 71.8 μmol) in
CH2Cl2 (2 mL) at room temperature was added VO(acac)2
(1.1 mg, 4.1 μmol), followed by addition of t-BuOOH (3.5 M in
toluene, 20.5 μL, 71.8 μmol) and the reaction was stirred for
69 hours. The reaction mixture was then added to 5% aqueous
Na2SO3 (5 mL), the aqueous phase extracted with CH2Cl2 (3 ×
5 mL) and the combined organic fractions dried (Na2SO4) and
concentrated in vacuo. Flash chromatography, eluting with
EtOAc–petrol (3 : 7) gave:
Propionate 12
( )-Monoepoxide 3 as a white crystalline solid (5.3 mg,
34%): Rf = 0.4 (EtOAc–petrol, 3 : 7); IR (CHCl3) νmax 3484, 3032,
3024, 2984, 2937, 2883, 2854, 2233, 1736, 1602, 1462, 1403,
1321, 1300, 1264, 1236 cm−1; 1H NMR (250 MHz, CDCl3) δ 1.20
(m, 2H), 1.28 (d, J = 7.8 Hz, 3H), 1.40 (d, J = 7.8 Hz, 3H), 1.54
(m, 3H), 1.70 (dd, J = 7.8, 14.1 Hz, 1H), 2.10 (dd, J = 7.8,
14.1 Hz, 1H), 2.29–2.58 (m, 2H), 3.00 (s, 1H), 3.25 (d, J =
4.7 Hz, 1H), 3.43 (d, J = 4.7 Hz, 1H), 5.83–6.00 (qd, J = 1.6 Hz,
10.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 20.3 (q),
21.2 (q), 26.1 (d), 28.5 (d), 29.7 (s), 31.0 (d), 32.7 (d), 58.7 (d),
59.6 (d), 63.3 (s), 124.3 (s), 127.6 (d), 138.7 (d) ppm; MS (EI+)
219 [M+], 201, 186, 176, 162, 153, 148, 134, 131, 125, 120, 107,
96, 91, 82, 77, 71, 67, 58, 55; HRMS (EI+) calcd for C13H17NO2
[M+] 219.1259, found 219.1263 (Δ = +1.8 ppm).
To a stirred solution of monoepoxide 3 (472 mg, 2.16 mmol)
in anhydrous THF (15 mL), under an atmosphere of nitrogen,
was added n-BuLi (2.5 M solution in hexanes, 1.04 mL,
2.59 mmol) followed by propionic anhydride (333 μL,
2.59 mmol). The reaction was stirred for 10 min at room temp-
erature. The reaction was then partitioned with water (10 mL)
and CH2Cl2 (4 × 100 mL). The organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography eluting with
petrol–EtOAc (4 : 1) giving the pure ester 12 as a white crystal-
line solid (522 mg, 88%). Mp = 78–83 °C; IR (neat) νmax 2940,
1881, 2237 (CN), 1739 (CvO), 1463, 1187, 1025 cm−1; 1H NMR
(270 MHz, CDCl3) δ 1.10 (t, J = 7.5 Hz, 3H), 1.32 (d, J = 7.5 Hz,
3H), 1.44 (d, J = 8.0 Hz, 3H), 1.64 (d, J = 14.0 Hz, 1H), 1.92 (dd,
J = 14.0 Hz and J = 8.0 Hz, 1H), 2.10–2.62 (m, 6H), 3.18 (d, J =
3.0 Hz, 1H), 3.62 (d, J = 3.0 Hz, 1H), 5.93 (dd, J = 10.0 Hz and
J = 2.5 Hz, 1H), 6.43 (dd, J = 10.0 Hz and J = 2.5 Hz, 1H) ppm;
13C NMR (63 MHz, CDCl3) δ 9.0 (q), 19.7 (q), 21.7 (q), 26.3 (d),
27.2 (t), 27.7 (d), 31.1 (t), 33.2 (t), 36.5 (s), 56.2 (d), 58.2 (d),
70.6 (s), 123.2 (s), 127.4 (d), 138.5 (d), 172.1 (s) ppm; MS (EI+)
meso-Bis-epoxide 11** as a clear film (2.7 mg, 16%): Rf = 0.2
(EtOAc–petrol, 3 : 7); IR (CHCl3) νmax 3695, 3491, 3031, 3025,
3013, 2987, 2928, 2854, 2233, 1602, 1464, 1392, 1301, 1275,
1228, 1222 cm−1 1H NMR (250 MHz, CDCl3) δ 1.25 (d, J =
;
**The 1H and 13C NMR data given for this compound in the ESI to ref. 39 is
incorrect.
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m/z (%): 275 (M+), 57; HRMS (EI+) calcd for C16H21NO3 (M+) 3H), 1.33 (d, J = 7.0 Hz, 3H), 1.74 (m, 1H), 1.87–2.19 (m, 5H),
275.1521, found 275.1509 (Δ = −4.6 ppm).
2.25 (m, 1H), 2.38 (m, 1H), 5.19–5.47 (m, 2H), 6.07 (m, 1H),
7.44 (dd, J = 7.5 Hz and J = 7.5 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H),
8.00 (d, J = 7.5 Hz, 2H) ppm; 13C NMR (68 MHz, CDCl3)
γ-Lactone 13ª
Trimethylsilylchloride (442 μL, 3.49 mmol) was added to a δ 16.0 (q), 17.3 (q), 19.6 (q), 30.3 (d), 30.5 (d), 32.7 (s), 38.2 (d),
flask fitted with a condenser containing ester 12 (533 mg, 39.0 (t), 42.6 (t), 49.9 (d), 73.0 (d), 75.6 (d), 123.3 (s), 124.8 (d),
1.94 mmol), this was then washed down with THF (10 mL). 128.5 (d), 129.7 (d), 129.8 (s), 133.3 (d), 133.4 (d), 166.0 (s),
The solution was cooled to −78 °C and LHMDS (1.0 M solution 178.4 (s) ppm; MS (EI+) m/z (%): 379 (M+), 352, 308, 277, 105;
in hexanes, 3.5 mL, 3.48 mmol) was added. The reaction was HRMS (EI+) calcd for C23H25NO4 (M+) 379.1784, found
stirred at −78 °C for 10 min, allowed to warm to room temp- 379.1793 (Δ = +2.4 ppm).
erature for 10 min then heated to 70 °C for 16 h. The THF was
evaporated in vacuo and the residue was dissolved in CH2Cl2
Bromide 15
(10 mL) then partitioned with a saturated aqueous solution of To a solution of diisopropylamine (181 μL, 1.30 mmol) in THF
NH4CI (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL) cooled to −78 °C was added n-BuLi (583 μL as a 2.5 M
(2 × 10 mL). The combined organic phases were dried solution in hexanes, 1.46 mmol). The reaction was warmed
(MgSO4), filtered, and concentrated in vacuo. Purification by to 0 °C for 1 h then cooled to −78 °C before the addition of
flash chromatography eluting with EtOAc–petrol (1 : 9, then γ-lactone 14 (205 mg, 0.54 mmol) in THF (20 mL). After
1 : 4, then 1 : 1) gave recovered ester 12 (l09 mg, 20%) and 15 min trimethylchlorosilane (178 μL, 1.40 mmol) was added
γ-lactone 13 (380 mg, 74%) as a mixture of epimers at C11 followed by N-bromosuccinimide (250 mg, 1.40 mmol) after a
(3 : 1; major as drawn for 13a) as a white crystalline solid. To a further 15 min. The reaction was allowed to warm to room
portion of this mixture of epimers (178 mg, 0.65 mmol) in temperature overnight. The reaction was partitioned between
t-BuOH (3.8 g) was added t-BuOK (145 mg, 1.30 mmol) and the water (10 mL) and CH2Cl2 (40 mL), the aqueous layer was then
resulting solution heated to 90 °C for 2.25 h. The reaction extracted with further portions of CH2Cl2 (3 × 15 mL). The
mixture was then cooled and saturated aqueous ammonium organics were dried (MgSO4), filtered, and concentrated
chloride (5 mL) was added and the reaction mixture stirred at in vacuo. Purification using flash chromatography eluting with
room temperature for 45 min. A further portion of saturated petrol–EtOAc (3 : 1) gave bromide 15 as an off-white crystalline
aqueous ammonium chloride (5 mL) was added followed by solid (186 mg, 75%). Mp 96.3–97.2 °C (CH2Cl2–hexane); IR
1 N HCl (10 mL). The mixture was partitioned with CH2Cl2 (4 × (neat) νmax 2969, 2933, 2230 (CN), 1787 (CvO), 1717 cm−1
;
50 mL), the combined organic extracts were dried (MgSO4), fil- 1H NMR (270 MHz, CDCl3) δ 1.26 (d, J = 7.0 Hz, 3H), 1.31
tered, and concentrated in vacuo giving a clear oil. The product (d, J = 6.5 Hz, 3H), 1.97 (s, 3H), 2.01–2.36 (m 7H), 5.12–5.53
precipitated after the addition of hexane giving γ-lactone 13a (m, 2H), 6.15 (m, 1H), 7.40 (dd, J = 7.5 Hz and J = 7.5 Hz, 2H),
as a white solid (162 mg, 91%). Mp = 155–158 °C; IR (neat) 7.55 (t, J = 7.5 Hz, 1H), 7.94 (d, J = 7.5 Hz, 2H); 13C NMR
νmax 3682, 3600, 2972, 2934, 2232 (CN), 1778 (CvO), 1459, (68 MHz, CDCl3) δ 17.0 (q), 21.3 (q), 29.3 (q), 30.9 (2 × d),
1422, 1042 cm−1 1H NMR (300 MHz, CDCl3) δ 1.15 (d, J = 31.0 (s), 37.2 (t), 42.2 (t), 53.7 (d), 56.5 (s), 71.1 (d), 74.9 (d),
;
6.5 Hz, 3H), 1.19 (d, J = 7.0 Hz, 3H), 1.33 (d, J = 7.0 Hz, 3H), 123.0 (s), 123.5 (d), 128.5 (d), 129.6 (d), 130.0 (s), 132.5 (s),
1.50–2.06 (m, 6H), 2.22 (m, J = 8.0 Hz, 1H), 2.38 (m, J = 7.5 Hz, 133.2 (d), 166.9 (s), 173.9 (s) ppm; MS (EI+) m/z (%):
1H), 3.90 (m, 1H), 5.34 (m, 1H), 6.02 (m, 1H) ppm; 13C NMR 457 [(79Br)M+)], 432, 352, 255, 105; HRMS (EI+) calculated
(63 MHz, CDCl3) δ 15.7 (q), 17.4 (d), 19.8 (q), 30.0 (d), 32.9 (d), for C23H2479BrNO4 (M+) 457.0889, found 457.0897
33.0 (s), 38.0 (d), 39.2 (t), 42.1 (t), 49.8 (d), 70.8 (d), 75.5 (d), (Δ = +1.8 ppm).
123.6 (s), 128.5 (d), 131.3 (s), 178.8 (s) ppm; MS (FAB+) m/z (%):
Hydroxytetrahydrofuran 16 and benzoyloxytetrahydrofuran 17
276 (MH+), 248, 175; HRMS (CI+) calcd for C16H25N2O3
+
(MNH4 ) 293.1865, found 293.1868 (Δ = +1.0 ppm).
To a solution of bromide 15 (31.9 mg, 0.069 mmol) in ethanol
(2 mL) was added NaBH4 (7.4 mg, 0.195 mmol). The reaction
was stirred for 20 h before partitioning with water (2 mL) and
Benzoate ester 14
To a solution of γ-lactone 13a (149 mg, 0.54 mmol), benzoic CH2Cl2 (10 mL). HCl (1 M, 5 drops) was added and the
anhydride (181 mg, 0.80 mmol) and triethylamine (112 μL, aqueous layer separated and extracted with CH2Cl2 (3 ×
0.80 mmol) in CH2Cl2 (10 mL) was added N,N′-4-dimethyl- 10 mL). The combined organic phases were dried (MgSO4), fil-
amino pyridine (33 mg, 0.27 mmol). The reaction was stirred at tered and concentrated in vacuo. Purification using flash
room temperature for 1 h before partitioning with 5% aqueous chromatography eluting with EtOAc–petrol (1 : 1) gave:
K2CO3 solution (15 mL), the aqueous layer was extracted with
Benzoate 17 as a white crystalline solid (12.2 mg, 46%).
CH2Cl2 (3 × 10 mL). The combined organics were dried over Mp = 192.0–194.2 °C (EtOAc–petrol); Rf = 0.55 (EtOAc–petrol,
(MgSO4), filtered, and concentrated in vacuo. Purification by 1 : 1); IR (neat) νmax 3478 (OH), 2969, 2933, 2227 (CN), 1715
1
flash chromatography eluting with petrol–EtOAc (3 : 1) gave (CvO), 1269, cm−1; H NMR (270 MHz, CDCl3) δ 1.11 (d, J =
benzoate ester 14 as a clear oil (205 mg, 100%). IR (neat) νmax 6.5 Hz, 3H, CH3), 1.23 (s, 3H, CH3CH0), 1.27 (d, J = 7.3 Hz, 3H,
2971, 2932, 2229 (CN), 1782 (CO), 1715 cm−1 1H NMR CH3), 1.46–2.25 (7H, C1, C2, C7, C8, C9), 3.69 (s, 2H, CH2O),
;
(270 MHz, CDCl3) δ 1.15 (d, J = 6.0 Hz, 3H), 1.19 (d, J = 7.0 Hz, 4.93 (dt, J = 10.5 and 2.3 Hz, 1H, CH1OCH2), 5.27 (m, 1H,
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CHOBz), 6.15 (dd, J = 4.0 Hz and 2.1 Hz, 1H, vCH), 7.41–7.47 Methyl ester 18a
(m, 2H, o-Ph), 7.57 (t, J = 7.4 Hz, 1H, p-Ph), 7.97 (d, J = 7.0 Hz,
A suspension of γ-lactone 13a (111 mg, 0.40 mmol), freshly
crushed potassium hydroxide (269 mg, 4.80 mmol), methyl
iodide (259 μL, 4.80 mmol) in THF (10 mL) was refluxed for
19 h. The reaction was then allowed to cool to room tempera-
ture and partitioned with water (2 mL) and CH2Cl2 (10 mL).
The biphasic mixture was filtered through a hydrophobic
filter, extracting the aqueous phase with portions of CH2Cl2
(3 × 15 mL). The combined organic phases were concentrated
in vacuo. Purification using flash chromatography eluting with
EtOAc–petrol (1 : 3) gave ester 18a as a clear oil (127 mg, 95%).
Rf = 0.5 (EtOAc–petrol, 1 : 3); IR (neat) νmax 2933, 2225 (CuN),
1735 (CvO) cm−1; 1H NMR (270 MHz, CDCl3) δ 1.01 (d, J = 6.5
Hz, 3H, CH3), 1.08 (d, J = 6.5 Hz, 3H, CH3), 1.45 (d, J = 7.5 Hz,
3H, CH3), 1.55–2.23 (6H, C1, C2, C8, C9), 2.30–2.51 (2H, C7,
C11), 3.31 (s, 3H, OCH3), 3.41 (s, 3H, OCH3), 3.48 (m, 1H,
CH1O), 3.62 (s, 3H, OCH3), 4.27 (m, 1H, CH1O), 6.02 (m, 1H,
vCH) ppm. 13C NMR (68 MHz, CDCl3) δ 15.8 (q), 17.3 (q),
20.7 (q), 28.3 (d), 30.9 (q), 35.1 (s), 36.1 (q), 39.1 (t), 40.2 (t),
46.4 (d), 51.4 (q), 55.8 (q), 57.5 (q), 77.6 (d), 79.5 (d), 124.4 (d),
2H, m-Ph) ppm; 13C NMR (67.5 MHz, CDCl3) δ 16.9 (q),
19.7 (q), 23.1 (q), 27.1 (d), 31.6 (s), 31.3 (d), 37.1 (t), 45.3 (t),
57.1 (d), 71.5 (d), 76.8 (d), 78.2 (s), 78.8 (t), 120.9 (d), 123.8 (s),
128.5, 129.5 (d), 130.3 (s), 133.2 (d), 137.7 (s), 165.6 (s) ppm;
+
MS (CI+) m/z 399 (MNH4 , 7), 279 (5), 186 (100); HRMS (CI+)
+
calcd for C23H31N2O4 (MNH4 ) 399.2284, found 399.2280
(Δ = −1.0 ppm).
Crystal data for 17: C23H27N1O4, M = 381.46, monoclinic,
P21 (no. 4), a = 6.2151(2), b = 16.8252(5), c = 9.7311(4) Å,
β = 90.176(1)°, V = 1017.58(6) Å3, Z = 2, Dc = 1.245 g cm−3
μ(Mo-Kα)
,
= , T = 120 K, colourless block,
0.085 mm−1
0.36 × 0.12 × 0.10 mm, Nonius KappaCCD diffractometer;
12 036 measured reflections, 4019 unique, (Rint = 0.0658), F2
refinement, R1(obs) = 0.0518, wR2(all) = 0.1216, 3150 indepen-
dent observed [|Fo| > 4σ(|Fo|), 99.8% complete to 2θmax
=
52.74°], 260 parameters. CCDC 905362.
Alcohol 16 as a clear oil (5 mg, 26%). Rf = 0.10 (EtOAc–
petrol, 1 : 1); IR (neat) νmax 3423 (OH), 2970, 2932, 2232 (CN),
1
1457, cm−1; H NMR (400 MHz, CDCl3) δ 1.09 (d, J = 6.5 Hz,
+
124.9 (s), 133.2 (s), 177.3 (s); MS (CI+) m/z 353 (MNH4 ), 304;
3H), 1.16 (d, J = 7.1 Hz, 3H), 1.27 (s, 3H), 1.54–2.04 (6H), 2.11
(t, J = 10.4 Hz, 1H), 3.67 (d, J = 8.6 Hz, 1H), 3.70 (d, J = 8.6 Hz,
1H), 3.92 (m, 1H), 4.92 (dt, J = 10.3 Hz and 2.5 Hz, 1H), 6.01
(dd, J = 3.3 Hz and 2.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
17.2 (q), 19.8 (q), 23.2 (q), 27.3 (d), 31.9 (s), 33.6 (d), 37.8 (t),
45.1 (t), 56.6 (d), 69.8 (d), 76.8 (d), 78.5 (t), 78.5 (s), 123.8 (s),
+
HRMS (CI+) calcd for C19H33N2O4 (MNH4 ) 353.2440, found
353.2435 (Δ = −1.4 ppm).
Benzyl ester 18b
A suspension of γ-lactone 13a (180 mg, 0.65 mmol), freshly
crushed potassium hydroxide (339 mg, 6.05 mmol), benzyl
bromide (931 μL, 7.83 mmol) in THF (10 mL) was refluxed for
20 h. The reaction was then allowed to cool to room tempera-
ture and partitioned with water (2 mL) and CH2Cl2 (10 mL).
The biphasic mixture was filtered through a hydrophobic filter,
extracting the aqueous phase with portions of CH2Cl2 (3 ×
5 mL). The combined organic phases were concentrated
in vacuo followed by purification using flash chromatography
eluting with EtOAc–petrol (1 : 19), giving ester 18b as a clear oil
(325 mg, 88%). Rf = 0.80 (EtOAc–petrol, 1 : 3); IR (neat) νmax
+
124.9 (d), 134.4 (s) ppm; MS (CI+) m/z 295 (MNH4 ), 277 (MH+),
+
260, 242; HRMS (CI+) calcd for C16H27N2O3 295.2022 (MNH4 ),
found 295.2014 (Δ = −2.7 ppm).
Triol 19
A solution of γ-lactone 13a (409 mg, 1.780 mmol) in THF
(10 mL) stirred under an atmosphere of nitrogen was cooled in
an ice bath. To this was added LiAlH4 (131 mg, 3.447 mmol)
and the reaction was stirred at 0 °C for 4 h. To the reaction was
cautiously added 1 M NaOH (5 mL) followed by water (10 mL),
this was then partitioned with EtOAc (3 × 40 mL). The com-
bined organic phases were dried (MgSO4), filtered and concen-
trated in vacuo. Purification using flash chromatography
eluting with EtOAc gave triol 19 as a white amorphous solid
(283 mg, 77%). Mp = 58–60 °C (EtOAc); Rf = 0.4 (EtOAc); IR
2933, 2232 (CuN), 1732 (CvO), 1455 cm−1
;
1H NMR
(270 MHz, CDCl3) δ 1.06 (d, J = 6.5 Hz, 3H, CH3), 1.08 (d, J = 6.0
Hz, 3H, CH3), 1.46 (d, J = 7.5 Hz, 3H, CH3), 1.75–2.00 (5H), 2.26
(1H, m), 2.47–2.65 (2H, H7, H11), 3.66 (m, 1H, CH1O), 4.29 (d,
J = 11.6 Hz, 1H, PhCHH), 4.52 (d, J = 11.6 Hz, 1H, PhCHH), 4.44
(d, J = 5.3 Hz, 1H, PhCHH), 4.48 (d, J = 5.3 Hz, 1H, PhCHH),
4.57 (m, 1H), 4.64 (d, J = 12.4 Hz, 1H, PhCHH), 4.81 (d, J =
12.4 Hz, 1H, PhCHH), 6.20 (m, 1H, vCH), 7.0–7.5 (m, 15H, Ph)
ppm; 13C NMR (75 MHz, CDCl3) δ 16.3 (q), 17.9 (q), 21.1 (q),
28.7 (d), 31.7 (d), 35.5 (s), 36.6 (d), 39.7 (t), 40.6 (t), 47.3 (d),
66.4 (t), 70.5 (t), 72.2 (t), 76.2 (d), 77.1 (d), 125.0 (d), 125.2,
127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.7, 128.7, 127.8 (d),
133.9 (s), 136.7, 138.5, 138.7 (s), 177.2 (s); MS (CI+) m/z 581
(neat) νmax 3328.5 (OH), 2932, 2230 (CuN), 1458, 1045 cm−1
;
1H NMR (250 MHz, CDCl3) δ 0.87 (d, J = 6.5 Hz, 3H, CH3), 1.09
(d, J = 6.5 Hz, 3H, CH3), 1.28 (m, 2H), 1.45 (d, J = 7.5 Hz, 3H,
CH3), 1.57 (m, 1H), 1.76 (m, 2H), 1.89 (d, J = 6.5 Hz, 2H), 2.28
(m, 1H), 3.43 (dd, J = 11.5 and 6.5 Hz, 1H, HCHOH), 3.62 (dd,
J = 11.5 and 2.0 Hz, 1H, HCHOH), 3.87 (dt, J = 7.4 Hz and
2.3 Hz, 1H, CH1OH, C3), 4.89 (m, 1H, CH1OH, C6), 5.9 (t, J =
2.0 Hz, 1H, vCH) ppm; 13C NMR (63 MHz, CDCl3) δ 16.6 (q),
17.2 (q), 20.8 (q), 30.4 (d), 33.8 (d), 34.0 (d), 35.5 (s), 38.6 (t),
40.3 (t), 51.9 (d), 68.5 (d), 68.6 (t), 71.2 (d), 125.1 (s), 126.9 (d),
136.3 (s) ppm; MS (ESI−) m/z 278 (M − H−), 324; HRMS (ESI−)
+
(MNH4 , 44), 456 (100); HRMS (CI+) calcd for C37H45N2O4
+
(MNH4 ) 581.3379, found 581.3380 (Δ = +0.2 ppm).
PMB ester 18c
calcd for C16H24NO3 (M − H−) 278.1756, found 278.1746 A suspension of γ-lactone 13a (100.7 mg, 0.37 mmol), freshly
(Δ = −3.6 ppm).
crushed potassium hydroxide (185 mg, 3.30 mmol), para-
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Paper
methoxybenzyl chloride (596 μL, 4.39 mmol) in THF (5 mL) (7H, C1, C2, C11, C8, C9), 2.14–2.36 (m, 1H, C7), 3.33 (dd, J =
was refluxed for 20 h. The reaction was then allowed to cool to 11.5 Hz and 3.5 Hz, 1H, HCHOH), 3.38 (s, 3H, CH3O), 3.47 (s,
room temperature and partitioned with water (2 mL) and 3H, CH3O), 3.50 (m, 1H, CH1O), 3.85 (dd, J = 11.5 and 3.5 Hz,
CH2Cl2 (10 mL). The biphasic mixture was filtered through a 1H, HCHOH), 4.36 (m, 1H, CH1O), 5.95 (m, 1H, vCH) ppm;
hydrophobic filter, extracting the aqueous phase with portions 13C NMR (68 MHz, CDCl3) δ 17.2 (q), 17.5 (q), 21.1 (q), 30.2 (d),
of CH2Cl2 (3 × 5 mL). The organic phases were concentrated 31.1 (d), 34.0 (d), 35.5, 39.5 (t), 40.2 (t), 48.1 (d), 56.4 (s),
in vacuo and purification using flash chromatography eluting 57.9 (s), 66.7 (t), 79.5 (d), 79.8 (d), 123.1 (d), 124.9 (s), 133.1 (s)
+
with EtOAc–petrol (1 : 4) followed by crystallisation induced by ppm; MS (CI+) m/z 325 (MNH4 ), 275, 258, 243, 226; HRMS
the addition of methanol gave ester 18c as a white crystalline (CI+) calcd for C18H33N2O3 (MNH4 ) 325.2491, found 325.2486
+
solid (150.7 mg, 65%). Mp = 119–122 °C (MeOH–petrol– (Δ = −1.5 ppm).
EtOAc); Rf = 0.76 (EtOAc–petrol, 1 : 1); IR (neat) νmax 2936,
Dibenzyl ether alcohol 19b
2837, 2233 (CuN), 1728 (CvO), 1614, 1515, 1249, 1174, 1035,
820 cm−1; 1H NMR (270 MHz, CDCl3) δ 1.02 (d, J = 8.5 Hz, 3H, To a solution of ester 18b (86 mg, 0.15 mmol) in THF (5 mL)
CH3), 1.04 (d, J = 8.5 Hz, 3H, CH3), 1.44 (d, J = 10.5 Hz, 3H, cooled to −10 °C was added LiAlH4 (22 mg, 0.56 mmol). The
CH3), 1.55–2.23 (6H, C1, C2, C8, C9), 2.41–2.60 (2H, C7, C11), reaction was stirred at −10 °C for 2 h before adding 1 N NaOH
3.62 (m, 1H, CH1O), 3.69 (s, 3H, CH3O), 3.77 (s, 3H, CH3O), (1 mL) followed by CH2Cl2 (5 mL). The biphasic mixture was
3.78 (s, 3H, CH3O), 4.17 (d, J = 11.1 Hz, 1H, ArCHH), 4.39 (d, filtered through a hydrophobic filter, extracting the aqueous
J = 11.1 Hz, 1H, ArCHH), 4.39 (d, J = 10.9 Hz, 2H, ArCHH), 4.47 phase with portions of CH2Cl2 (3 × 15 mL). The combined
(d, J = 10.9 Hz, 2H, ArCHH), 4.57 (m, 1H), 4.62 (d, J = 12.0 Hz, organic phases were then concentrated in vacuo. Purification
1H, ArCHH), 4.76 (d, J = 12.0 Hz, 1H, ArCHH), 6.14 (m, 1H), using flash chromatography eluting with petrol–EtOAc (3 : 1)
6.73 (d, J = 8.3 Hz, 2H, CH1, ortho-OMe, PMB), 6.80 (d, J = gave alcohol 19b as a clear oil (70 mg, 100%). Rf = 0.30 (EtOAc–
8.3 Hz, 2H, o-Ar), 6.88 (d, J = 8.2 Hz, 2H, CH1, o-Ar), 7.03 (d, J = petrol, 1 : 3); IR (neat) νmax 3457 (OH), 2931, 2231 (CuN), 1454,
8.3 Hz, 2H, m-Ar), 7.10 (d, J = 8.2 Hz, 2H, CH1, m-Ar), 7.30 (d, 1070 cm−1 1H NMR (300 MHz, CDCl3) δ 0.96 (d, J = 7.0 Hz,
;
J = 8.3 Hz, 2H, m-Ar) ppm; 13C NMR (100 MHz, CDCl3) 3H, CH3), 1.09 (d, J = 7.0 Hz, 3H, CH3), 1.37 (d, J = 8.0 Hz, 3H,
δ 15.8 (q), 17.4 (q), 20.7 (q), 28.3 (d), 31.2 (d), 35.1 (s), 36.2 (d), CH3), 1.63–2.00 (6H, C1, C2, C8, C9), 2.20 (m, 1H, C11), 2.75
39.2 (t), 40.2 (t), 46.9 (d), 55.1 (q), 55.2 (2 × q), 65.8 (t), 69.6 (t), (m, 1H, C7), 3.36 (d, J = 10.8 Hz, 1H, HCHOH), 3.68 (dt, J =
71.4 (t), 75.5 (d), 76.9 (d), 113.7 (3 × d), 124.6 (d), 124.8 (s), 6.9 Hz and 2.4 Hz, 1H, CH1OBn), 3.91 (dd, J = 11.6 and 3.3 Hz,
129.4, 129.5, 129.9 (d), 130.4 (s), 133.4 (3 × s), 159.1, 159.2, 1H, HCHOH), 4.50 (d, J = 11.7 Hz, 1H, PhCHH), 4.52 (d, J =
+
159.3 (s), 176.9 (s) ppm; MS (CI+) m/z 671 (MNH4 ), 535, 303, 11.6 Hz, 1H, PhCHH), 4.62 (d, J = 11.6 Hz, 1H, PhCHH), 4.64
206, 189, 165, 154, 138, 121; HRMS (CI+) calcd for C40H51N2O7 (m, 1H), 4.72 (d, J = 11.7 Hz, 1H, PhCHH), 6.07 (t, J = 2.1 Hz,
+
(MNH4 ) 671.3696, found 671.3688 (Δ = −1.2 ppm).
1H), 7.22–7.44 (m, 10H, Ph) ppm; 13C NMR (75 MHz, CDCl3)
ˉ
Crystal data for 18c: C40H47N1O7, M = 653.79, triclinic, P1 δ 17.7 (q), 17.9 (q), 21.3 (q), 30.8 (d), 31.9 (d), 34.5 (d), 36.0 (s),
(no. 2), a = 10.6749(8), b = 11.6338(9), c = 17.3660(11) Å, α = 39.8 (t), 40.6 (t), 48.7 (d), 66.9 (t), 71.4 (t), 72.8 (t), 77.6 (d),
108.132(3), β = 103.266(3), γ = 110.833(4)°, V = 1769.5(2) Å3, 78.3 (d), 124.0 (d), 125.3 (s), 127.3, 128.2, 128.3, 128.5, 128.9,
Z = 2, Dc = 1.227 g cm−3, μ(Mo-Kα) = 0.083 mm−1, T = 273 K, 129.1 (d), 133.8 (d), 137.7, 138.5 (s); MS (CI+) m/z 477 (MNH4 ),
+
colourless prism, 0.50 × 0.50 × 0.25 mm, Bruker Nonius Kappa 369, 352, 263, 244, 52; HRMS (CI+) calcd for C30H41N2O3
+
Apex 2 CCD diffractometer; 36 283 measured reflections, 8417 (MNH4 ) 477.3117, found 477.3119 (Δ = +0.4 ppm); Anal. Calcd
unique, (Rint = 0.0248), F2 refinement, R1(obs) = 0.0455, for C30H37NO3: C, 78.4; H, 8.1; N, 3.0. Found: C, 78.5; H, 8.0;
wR2(all) = 0.1277, 7356 independent observed [|Fo| > 4σ(|Fo|), N, 2.9.
98.6% complete to 2θmax = 56.00°], 439 parameters. CCDC
905363.
Di-PMB ether alcohol 19c
To a solution of ester 18c (473 mg, 0.743 mmol) in THF
(50 mL) cooled to −18 °C was added LiAlH4 (113 mg,
Dimethyl ether alcohol 19a
To a solution of ester 18a (111.2 mg, 0.36 mmol) in THF 2.97 mmol). The reaction was stirred at −18 °C for 2.5 h before
(10 mL) cooled to −10 °C was added LiAlH4 (42 mg, cautiously adding 1 N NaOH (50 mL) followed by CH2Cl2
1.09 mmol). The reaction was stirred at −10 °C for 2 h before (50 mL). The organic layer was separated and the aqueous
adding 1 N NaOH (4 mL) followed by CH2Cl2 (10 mL). The extracted with CH2Cl2 (2 × 50 mL). The combined organic
biphasic mixture was filtered through a hydrophobic filter, phases were then dried (Na2SO4), filtered and concentrated
extracting the aqueous phase with portions of CH2Cl2 (3 × in vacuo. Purification using flash chromatography eluting with
15 mL). The combined organic phases were then concentrated petrol–EtOAc (3 : 1) gave alcohol 19c as a clear oil (259 mg,
in vacuo. Purification using flash chromatography eluting with 70%). Rf = 0.36 (MeOH–PhMe, 1 : 20); IR (neat) νmax 3459 (OH),
1
petrol–EtOAc (3 : 1) gave ester 18a (29.7 mg, 25%) and alcohol 2930, 2230 (CuN), 1612, 1514, 1248 cm−1; H NMR (270 MHz,
19a as a clear oil (82.7 mg, 74%). Rf = 0.2 (EtOAc–petrol, 1 : 3); CDCl3) δ 0.95 (d, J = 6.7 Hz, 3H, CH3), 1.08 (d, J = 6.4 Hz, 3H,
IR (neat) νmax 3449 (OH), 2929, 2228 (CuN), 1459, 1101 cm−1
;
CH3), 1.37 (d, J = 7.4 Hz, 3H, CH3), 1.63–1.94 (7H, C1, C2, C8,
1H NMR (270 MHz, CDCl3) δ 0.96 (d, J = 7.0 Hz, 3H, CH3), 1.10 C9, C11), 2.20 (m, 1H, C7), 3.32 (dd, J = 11.4 Hz and 3.2 Hz,
(d, J = 6.5 Hz, 3H, CH3), 1.45 (d, J = 7.5 Hz, 3H, CH3), 1.52–2.07 1H, CH2OH), 3.66 (m, 1H, CH1O), 3.80 (s, 3H, CH3O), 3.81
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(s, 3H, CH3O), 3.88 (dd, J = 11.4 and 2.7 Hz, 1H, CH2OH), 4.44 chromatography eluting with petrol–EtOAc (4 : 1) gave tetra-
(d, J = 11.4 Hz, 2H, ArCHH), 4.44 (d, J = 11.4 Hz, 1H, ArCHH), hydrofuran 20b (2 mg, 43%) as a thin film. Rf = 0.80 (EtOAc–
4.57 (d, J = 11.4 Hz, 2H, ArCHH), 4.62 (m, 1H, CH1O), 4.64 petrol, 1 : 3); IR (neat) νmax 2930, 2230 (CuN), 1454,
1
(d, J = 11.4 Hz, 1H, ArCHH), 6.04 (s, 1H), 6.8 (d, J = 8.6 Hz, 2H, 1099 cm−1; H NMR (270 MHz, CDCl3) δ 1.06–1.10 (m, 9H, 3 ×
o-Ar), 6.91 (d, J = 8.5 Hz, 2H, o-Ar), 7.26 (d, J = 8.5 Hz, 2H, CH3), 1.76–2.01 (m, 8H, C1, C2, C7, C8, C9, C11), 3.36 (t, J =
m-Ar), 7.28 (d, J = 8.9 Hz, 2H, m-Ar) ppm; 13C NMR (67.5 MHz, 8.2 Hz, 1H, HCHO), 3.61 (dt, J = 7.9 Hz and 2.5 Hz, 1H,
CDCl3) δ 17.2 (q), 17.4 (q), 20.8 (q), 30.8 (d), 31.4 (d), 34.0 (d), CH1OBn), 4.02 (t, J = 7.3 Hz, 1H, HCHO), 4.49 (d, J = 11.6 Hz,
35.6 (s), 39.2 (t), 40.2 (t), 48.4 (d), 55.2 (2 × q), 66.4 (t), 70.5 (t), 1H, PhCHH), 4.69 (d, J = 11.6 Hz, 1H, PhCHH), 4.82 (dt, J =
71.9 (t), 76.6 (d), 77.4 (d), 113.8, 114.0 (d), 123.7 (d), 124.9 (s), 7.7 Hz and 3.1 Hz, 1H, CH1O), 6.10 (t, J = 2.3 Hz, 1H, vCH),
129.4, 129.5 (d), 130.1 (s), 133.2 (2 × s), 159.2, 159.4 (s) ppm; 7.28–7.34 (m, 5H, Ph) ppm; 13C NMR (125 MHz, CDCl3) δ 17.4
+
MS (CI+) m/z 537 (MNH4 ), 519; HRMS (CI+) calcd (q), 17.7 (q), 19.5 (q), 30.8 (d), 30.9 (d), 33.5 (s), 38.1 (d), 39.9
+
for C32H45N2O5 (MNH4 ) 537.3328, found 537.3319 (t), 44.0 (t), 53.8 (d), 71.0 (t), 74.1 (t), 77.8 (d), 78.3 (d), 123.5
(Δ = −1.7 ppm).
(d), 124.6 (s), 127.7, 128.0, 128.4 (d), 134.2 (s), 138.3 (s) ppm;
MS (CI+) m/z 369 (MNH4 ), 261, 244; HRMS (CI+) calcd for
+
Tetrahydrofuran methyl ether 20a
+
C23H33N2O2 (MNH4 ) 369.2542, found 369.2548 (Δ
=
To a solution of alcohol 19a (10 mg, 0.033 mmol) in CH2Cl2 +1.6 ppm).
(2.5 mL) was added triethylamine (27 μL, 0.20 mmol) followed
Diene dimethyl ether 21a
by methane sulfonylchloride (8 μL, 0.10 mmol). The reaction
stirred at room temperature for 1d. A saturated solution of To a solution of alcohol 19a (20.2 mg, 0.07 mmol), 2-nitrophe-
NaHCO3 (1 mL) was added and the mixture passed through a nylselenocyanate (18 mg, 0.08 mmol) in THF (3 mL) was
hydrophobic filter before concentrating in vacuo. Purification added tri-n-butylphosphine (21 μL, 0.09 mmol). The reaction
using flash chromatography eluting with EtOAc–petrol (1 : 4) was stirred for 1 h before cooling to 0 °C, H2O2 (16 μL) as a
gave tetrahydrofuran 20a as a colourless oil (4.5 mg, 50%). Rf = 35% solution in water was then added. The reaction was
0.50 (EtOAc–petrol, 1 : 1); IR (neat) νmax 2959, 2930, 2229 warmed to room temperature and stirred for 1 h before the
(CuN), 1459, 1097 cm−1 1H NMR (270 MHz, CDCl3) δ addition of water (1 mL) and CH2Cl2 (5 mL). The biphasic
;
1.05–1.10 (m, 9H, 3 × CH3), 1.48–2.04 (m, 8H, C1, C2, C7, C8, mixture was filtered through a hydrophobic filter, washing the
C9, C11), 3.36 (t, J = 8.3 Hz, 1H, HCHO), 3.39 (s, 4H, CH3O and aqueous phase with portions of CH2Cl2 (3 × 5 mL). The
CH1O), 4.03 (t, J = 8.3 Hz, 1H, HCHO), 4.60 (dt, J = 8.0 Hz, and organic phases were then concentrated in vacuo. Purification
2.4 Hz, 1H, CH1OCH2), 6.02 (t, J = 2.0 Hz, 1H, vCH) ppm; 13C using flash chromatography eluting with petrol–EtOAc (4 : 1)
NMR (125 MHz, CDCl3) δ 17.4 (q), 17.6 (q), 19.5 (q), 30.4 (d), gave diene 21a as a clear oil (16 mg, 84%). Rf = 0.9 (EtOAc–
30.9 (d), 33.4 (s), 38.1 (d), 39.7 (t), 44.0 (t), 53.1 (d), 56.6 (q), petrol, 1 : 3); IR (neat) νmax 2962, 2929, 2228 (CuN), 1458,
1
74.1 (t), 77.8 (d), 80.3 (d), 123.1 (d), 124.5 (s), 134.3 (s) ppm; 1261, 1089 cm−1; H NMR (270 MHz, CDCl3) δ 1.15 (d, J = 6.0
MS (CI+) m/z 293 (MNH4 ), 261, 244; HRMS (CI+) calcd for Hz, 3H, CH3), 1.10 (d, J = 7.0 Hz, 3H, CH3), 1.75 (s, 3H,
+
+
C17H29N2O2 (MNH4 ) 293.2229, found 293.2229 (Δ = 0.0 ppm).
CH2vCCH3), 1.80–2.04 (6H, C1, C2, C8, C9), 2.60 (m, 1H, C7),
3.38 (s, 3H, CH3O), 3.42 (s, 3H, CH3O), 3.46 (m, 1H, CH1O),
4.32 (m, 1H, CH1O), 4.79 (s, 1H, CvHCH), 4.89 (s, 1H,
Tetrahydrofuran benzyl ether 20b
To a solution of alcohol 19b (7.5 mg, 0.016 mmol) in CH2Cl2 CvHCH), 6.04 (m, 1H, CH1vCH0) ppm; 13C NMR (125 MHz,
(1 mL) was added triethylamine (27 μL, 0.196 mmol) followed CDCl3) δ 17.7 (q), 20.9 (q), 23.7 (q), 30.9 (d), 31.1 (d), 33.7 (s),
by methane sulfonyl chloride (15 μL, 0.196 mmol). After 1 h a 38.7 (t), 40.8 (t), 52.9 (d), 56.5 (q), 57.9 (q), 78.2 (d), 79.1 (d),
saturated aqueous solution of NaHCO3 (2 mL) was added the 113.7 (t), 123.2 (d), 124.8 (s), 134.2 (s), 144.8 (s) ppm; MS (CI+)
mixture passed through a hydrophobic filter. Concentration m/z 307 (MNH4 ), 275, 258, 243, 226; HRMS (CI+) calcd
+
+
in vacuo followed by purification using flash chromatography for C18H31N2O2 (MNH4 ) 307.2386, found 307.2391
eluting with petrol–EtOAc (3 : 1) gave the corresponding mesy- (Δ = +1.6 ppm).
late as a colourless oil (7.2 mg, 80%). Rf = 0.40 (EtOAc–petrol,
Diene dibenzyl ether 21b
1 : 3); IR (neat) νmax 2934, 2230 (CuN), 1454, 1354, 1175, 1070,
946 cm−1; 1H NMR (270 MHz, CDCl3) δ 0.98 (d, J = 6.8 Hz, 3H, To a solution of alcohol 20b (70 mg, 0.15 mmol), 2-nitrophe-
CH3), 1.10 (d, J = 6.6 Hz, 3H, CH3), 1.39 (d, J = 7.6 Hz, 3H, nylselenocyanate (40 mg, 0.18 mmol) in THF (6 mL) was
CH3), 1.78–2.07 (7H, C1, C2, C8, C9, C11), 2.24 (m, 1H, C7), added tri-n-butylphosphine (47 μL, 0.19 mmol). The reaction
2.71 (s, 3H, SCH3), 3.68 (dt, J = 7.0 Hz and 2.5 Hz, 1H, was stirred for 1 h before cooling to 0 °C, H2O2 (100 μL) as a
CH1OBn), 4.17 (dd, J = 9.5 Hz and 7.1 Hz, 1H, HCHOMs), 35% solution in water was then added. The reaction was
4.47–4.68 (6H, 2 × PhCH2O and CH1OBn and HCHOMs), 6.07 warmed to room temperature and stirred for 1 h before the
(dd, J = 2.2 Hz and 1.9 Hz, 1H), 7.34–7.39 (m, 10, Ph) ppm. addition of water (3 mL) and CH2Cl2 (10 mL). The biphasic
This compound was unstable and so was dissolved directly in mixture was filtered through a hydrophobic filter, extracting
toluene (3 mL) and DBN (53 μL, 0.428 mmol) added. The reac- the aqueous phase with portions of CH2Cl2 (3 × 5 mL). The
tion mixture was then heated to 110 °C for 1.5 h hours before combined organic phases were then concentrated in vacuo.
concentration
in
vacuo.
Purification
using
flash Purification using flash chromatography eluting with petrol–
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EtOAc (4 : 1) gave diene 21b as a clear oil (61 mg, 91%). Rf = 0.9 (CI+) m/z 369 (MNH4 ), 334; HRMS (CI+) calcd for C16H27N2O2
+
+
(EtOAc–petrol, 1 : 3); IR (neat) νmax 2960, 2929, 2227 (CuN), (MNH4 ) 369.2542, found 369.2529 (Δ = −3.5 ppm).
1951, 1874, 1809, 1726, 1640, 1454, 1068 cm−1 1H NMR
;
(300 MHz, CDCl3) δ 1.15 (d, J = 6.5 Hz, 6H, 2 × CH3), 1.80 (s,
Diene di-PMB ether 21c
3H, CH2vCCH3), 1.82–2.07 (6H, C1, C2, C8, C9), 2.55 (m, 1H, To a solution of alcohol 19c (75 mg, 0.15 mmol), 2-nitrophe-
CH1CvCH2), 3.68 (m, 1H, CH1OBn), 4.24 (dt, J = 7.0 Hz and nylselenocyanate (34 mg, 0.15 mmol) in THF (4 mL) was
1.9 Hz, 1H, CH1OBn), 4.48 (d, J = 11.8 Hz, 1H, PhCHH), 4.52 added tri-n-butylphosphine (39 μL, 0.15 mmol). The reaction
(d, J = 11.7 Hz, 1H, PhCHH), 4.62 (d, J = 11.7 Hz, 1H, PhCHH), was stirred for 1 h before cooling to 0 °C, H2O2 (38 μL) as a
4.72 (d, J = 11.8 Hz, 1H, PhCHH), 4.84 (s, 1H, CvHCH), 4.91 35% solution in water was then added. The reaction was
(s, 1H, CvHCH), 6.15 (m, 1H, CH1vCH0), 7.20–7.40 (m, 10H, warmed to room temperature and stirred for 1 h before the
Ph) ppm; 13C NMR (67.5 MHz, CDCl3) δ 17.8 (q), 20.8 (q), addition of water (3 mL) and CH2Cl2 (10 mL). The biphasic
23.9 (q), 30.8 (d), 31.4 (d), 33.6 (s), 38.5 (t), 41.1 (t), 53.6 (d), mixture was filtered through a hydrophobic filter, extracting
70.9 (t), 71.7 (t), 75.8 (d), 76.9 (d), 113.9 (t), 123.8 (d), 125.0 (s), the aqueous phase with portions of CH2Cl2 (3 × 5 mL). The
127.5, 127.6, 127.7, 127.8, 128.4, 128.5 (d), 134.6 (s), 138.5, combined organic phases were then concentrated in vacuo.
138.6 (s), 144.9 (s) ppm; MS (CI+) m/z 459 (MNH4 ), 391, 334; Purification using flash chromatography eluting with petrol–
+
+
HRMS (CI+) calcd for C30H39N2O2 (MNH4 ) 459.3012, found EtOAc (9 : 1) gave diene 21c as a clear oil (52 mg, 68%). Rf =
459.3016 (Δ = +0.9 ppm).
0.83 (EtOAc–petrol, 1 : 2); IR (neat) νmax 2933, 2226 (CuN),
1613, 1514, 1248, 1035, 820 cm−1; 1H NMR (270 MHz, CDCl3) δ
1.13 (m, 6H, 2 × CH3), 1.78 (s, 3H, CH2vCCH3), 1.83–2.00 (6H,
C1, C2, C8, C9), 2.50 (t, J = 6.0 Hz, 1H, C7), 3.64 (m, 1H,
Diene monobenzyl ether 21d
To a solution of bis-benzyl ether 21b (370 mg, 0.839 mmol) in CH1O), 3.79 (s, 3H, CH3O), 3.80 (s, 3H, CH3O), 4.40–4.59 (5H,
CH2Cl2–water (10 : 1, mL) was added DDQ (350 mg, CH1O and 2 × CH2O), 4.82 (s, 1H, CvHCH), 4.90 (s, 1H,
4
1.54 mmol). The reaction was stirred at room temperature for CvHCH), 6.12 (m, 1H, CH1vCH0), 6.86 (d, J = 8.6 Hz, 2H,
16 h. The reaction was partitioned between CH2Cl2 (4 × 20 mL) o-Ar), 6.88 (d, J = 8.6 Hz, 2H, o-Ar), 7.24 (d, J = 8.6 Hz, 2H,
and a saturated aqueous solution of NaHCO3 (20 mL). The m-Ar), 7.28 (d, J = 8.6 Hz, 2H, m-Ar) ppm; 13C NMR (68 MHz,
combined organic phases were dried (Na2SO4), filtered and CDCl3) δ 17.8 (q), 20.8 (q), 24.0 (q), 30.8 (d), 31.5 (d), 33.7 (s),
then concentrated in vacuo. Purification using flash chromato- 38.6 (t), 41.1 (t), 53.6 (d), 55.3 (2 × q), 70.5 (t), 71.4 (t), 75.4 (d),
graphy eluting with EtOAc–petrol (1 : 19, then 7 : 3) gave:
76.6 (d), 113.8 (2 × d), 113.9 (t), 123.9 (d), 124.9 (s), 129.3,
Diene dibenzyl ether 21b as a clear oil (73 mg, 20%). Spec- 129.4 (d), 130.5, 130.6 (s), 134.5 (s), 144.9 (s), 159.2, 159.3 (s);
MS (CI+) m/z 519 (MNH4 ), 312, 252, 217, 201, 154, 137, 121;
+
troscopic data as above.
+
Diol 21 as a white solid (33 mg, 15%). Mp = 151.7–153.5 °C HRMS (CI+) calcd for C32H43N2O4 (MNH4 ) 519.3223, found
(EtOAc–petrol); Rf = 0.2 (EtOAc–petrol, 1 : 1); IR (neat) νmax 519.3211 (Δ = −2.3 ppm).
3433 (OH), 2928, 2233 (CuN), 1545, 1095, 1044, 892 cm−1; H
NMR (300 MHz, CDCl3) δ 1.13 (d, J = 6.7 Hz, 3H, CH3), 1.27 (d,
1
Diene diol 21
J = 7.2 Hz, 3H, CH3), 1.64–2.11 (6H, C1, C2, C8, C9), 1.76 (s, To a solution of bis-PMB ether 21c (49 mg, 0.1 mmol) in
3H, CH3CvCH2), 2.65 (dd, J = 6.7 Hz and 4.7 Hz, 1H, C7), 4.92 CH2Cl2–water (10 : 1,
4 mL) was added DDQ (50 mg,
(m, 1H, CH1OH), 4.70 (m, 1H, CH1OH), 4.85 (s, 1H, CvHCH), 0.22 mmol). The reaction was stirred at room temperature for
5.04 (t, J = 1.5 Hz, 1H, CvHCH), 6.00 (t, J = 2.5 Hz, 1H, 2 h, a further portion of DDQ was then added (10 mg,
CH1vCH0) ppm; 13C NMR (67.5 MHz, CDCl3) δ 17.5 (q), 0.04 mmol) and the reaction stirred for a further 1 h. The reac-
21.1 (q), 24.3 (q), 30.3 (d), 33.7 (d), 33.8 (s), 39.4 (t), 40.1 (t), tion was partitioned between CH2Cl2 (20 mL) and a saturated
54.1 (d), 66.7 (d), 71.0 (d), 115.6 (t), 124.7 (s), 126.3 (d), aqueous solution of NaHCO3 (5 mL), the organic phase was
+
136.7 (s), 144.0 (s) ppm; MS (CI+) m/z 279 (MNH4 ), 261, 245; separated and the aqueous layer extracted with CH2Cl2 (3 ×
HRMS (CI+) calcd for C16H27N2O2 (MNH4 ) 279.2073, found 10 mL). The combined organic phases were dried (Na2SO4), fil-
+
279.2069 (Δ = −1.4 ppm).
tered and then concentrated in vacuo. Purification using flash
Alcohol 21d as a clear oil (159 mg, 54%). Rf = 0.75 (EtOAc– chromatography eluting with EtOAc–petrol (3 : 7) gave diol 21
petrol, 1 : 1); IR (neat) νmax 3481 (OH), 2872, 2230 (CuN), 1671, as a white crystalline solid (22.5 mg, 85%). Spectroscopic data
1456, 1377, cm−1 1H NMR (270 MHz, CDCl3) δ 1.16 (d, J = as above.
;
6.9 Hz, 3H, CH3), 1.20 (d, J = 7.0 Hz, 3H, CH3), 1.69–2.03 (6H,
C1, C2, C8, C9), 2.56 (dd, J = 6.6 and 5.0 Hz, 1H, C7), 3.93 (dt,
Diol 22
J = 6.2 and 2.6 Hz, 1H, CH1OH), 4.48 (dt, J = 6.8 Hz and 2.1 Hz, To a solution of diene 21a (38 mg, 0.13 mmol) in acetone–H2O
1H, CH1OBn), 4.56 and 4.63 (d, J = 11.9 Hz, 1H, PhCH2), 4.81 (9 : 1)(2.5 mL) was added TFA (14 μL, 0.18 mmol) followed by
(m, 1H, CvHCH), 4.90 (m, 1H, CvHCH), 5.99 (m, 1H, trimethylamine-N-oxide dihydrate (58 mg, 0.52 mmol) then
CH1vCH0, C4) ppm; 13C NMR (67.5 MHz, CDCl3) δ 17.6 (q), K2OsO4·2H2O (5.4 mg, 0.015 mmol). The reaction was stirred
21.1 (q), 24.1 (q), 31.0 (d), 33.9 (d), 34.2 (s), 39.0 (t), 40.9 (t), for 2 h. An aqueous solution of Na2SO3 (10%, 3 mL) was added
53.2 (d), 70.9 (d), 71.8 (t), 75.6 (d), 113.8 (t), 124.8 (s), 126.6 (d), and the reaction stirred for 0.5 h before the removal of acetone
127.4, 127.5, 128.3 (d), 134.1 (s), 138.4 (s), 144.9 (d) ppm; MS in vacuo. The product was extracted with CH2Cl2 (2 × 10 mL),
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the combined organic layers were dried (MgSO4) and concen- immediately turned from colourless to orange and then gradu-
trated in vacuo. Purification using flash chromatography ally to brown over a time period of 2 h. The reaction was then
eluting with EtOAc gave diol 22 as a clear oil (15.5 mg, 36%, an warmed to RT before removal of the solvent. The crude
1
inseparable ∼1 : 1 mixture of epimers at C11 by H NMR). Rf = mixture was dissolved in MeOH (3 mL) and 1 drop of conc.
0.50 (EtOAc); IR (neat) νmax 3444 (OH), 2932, 2227 (CuN), HCl was added. The mixture was stirred for 1 h at room temp-
1455 cm−1 1H NMR (270 MHz, CDCl3) δ 1.09–1.15 (12H, erature (a yellow precipitate began to form after 5 min). After
;
CH0CH3 and CH3), 1.45 (d, J = 7.7 Hz, 6H, CH3), 1.84–2.51 adding a further 2 drops of conc. HCl over the ensuing 2 h the
(14H, C1, C2, C7, C8, C9), 2.71 (m, 1H, HCHOH), 3.18–3.55 (m, reaction mixture was concentrated in vacuo. The residue was
4H, CH2O and 2 × CH1OCH3, C3), 3.39 (s, 3H, CH3O), 3.40 (s, purified using flash chromatography eluting with EtOAc to
3H, CH3O), 3.47 (s, 3H, CH3O), 3.52 (s, 3H, CH3O), 3.70 (dd, J = give β-dihydroagarofurans 24a/24b as a clear oil (12.2 mg, 66%,
11.4 Hz and 2.1 Hz, 1H, HCHOH), 4.40 (dt, J = 5.7 Hz and an inseparable ∼1 : 1 mixture of C11 epimers by 1H NMR). Rf =
1.9 Hz, 1H, CH1OCH3, C6), 4.47 (dt, J = 5.5 Hz and 2.1 Hz, 1H, 0.4 (EtOAc); β-dihydroagarofuran 24a: 1H NMR (270 MHz,
CH1OCH3, C6), 5.97 (dd, J = 2.8 Hz and 1.8 Hz, 1H, CDCl3) δ 1.24 (d, J = 7.3 Hz, 3H, CH3), 1.32 (d, J = 9.7 Hz, 3H,
CH1vCH0), 6.03 (dd, J = 2.7 and 2.0 Hz, 1H, CH1vCH0); 13C CH3), 1.61 (s, 3H, CH0CH3), 1.69 (d, J = 13.9 Hz, 1H, HCH,
NMR (100 MHz, CDCl3) δ 17.4 (q), 17.6 (q), 22.5 (q), 23.2 (q), C1α), 1.80 (m, 1H, CH2, C9), 2.02–2.46 (m, 5H), 3.69 (d, J = 10.6
23.7 (q), 25.1 (q), 28.4 (d), 29.5 (d), 30.7 (d), 30.8 (d), 34.9 (s), Hz, 1H, HCHOH), 3.89 (d, J = 10.6 Hz, 1H, HCHOH), 4.46 (s,
35.0 (s), 39.7 (t), 39.8 (t), 41.0 (t), 41.1 (t), 49.9 (d), 52.8 (d), 1H, CHOBn), 4.64 (d, J = 11.7 Hz, 1H, COHCHPh), 4.68 (d, J =
56.7 (q), 57.0 (q), 58.2 (q), 58.5 (q), 69.5 (t), 70.1 (t), 76.0 (s), 11.7 Hz, 1H, COHCHPh), 6.04 (m, 1H, CH1vCH1), 6.10 (dd, J =
76.3 (s), 79.2 (d), 79.3 (d), 79.5 (d), 79.7 (d), 122.5, 123.0 (d), 10.0 and 2.0 Hz, 1H, CH1vCH1), 7.34–7.39 (m, 5H, Ph) ppm;
124.7 (s), 124.9 (s), 133.2 (d), 134.4 (d) ppm; MS (CI+) m/z 341 β-dihydroagarofuran 24b: 1H NMR (270 MHz, CDCl3) δ 1.23 (d,
(MNH4 ), 309, 292, 260; HRMS (CI+) calcd for C18H33N2O4 J = 7.2 Hz, 3H, CH3), 1.32 (d, J = 7.7 Hz, 3H, CH3), 1.62 (s, 3H,
+
+
(MNH4 ) 341.2440, found 341.2436 (Δ = −1.2 ppm).
CH0CH3), 1.69 (d, J = 14.0 Hz, 1H, HCH, C1α), 1.80 (m, 1H,
CH2, C9), 2.03–2.47 (m, 5H), 3.68 (s, 2H, CH2OH), 4.50 (s, 1H,
CHOBn), 4.65 (s, 2H, COCH2Ph), 6.03 (dd, J = 10.2 and 3.5 Hz,
β-Dihydroagarofuran 23
To a solution of diene 21 (22.5 mg, 0.086 mmol) in CH2Cl2 1H, CH1vCH1), 6.17 (dd, J = 10.2 and 2.2 Hz, 1H, CH1vCH1),
(5 mL) was added TMEDA (14 μL, 0.095 mmol). After cooling 7.33–7.39 (m, 5H, Ph) ppm; MS (CI+) m/z 385 (MNH4 ), 368
+
to −78 °C, OsO4 (s) was added (24 mg, 0.095 mmol), the reac- (MH+); HRMS (CI+) calcd for C23H30NO3 (MH+) 368.2226,
tion immediately turned from colourless to orange and then found 368.2228 (Δ = +0.5 ppm).
gradually to brown over a time period of 2 h. The reaction was
Bis-epoxide 25
then warmed to room temperature before removal of the
solvent. The crude mixture was dissolved in MeOH (4 mL) and To a solution of diene 21 (47 mg, 180 μmol) in CH2Cl2 (7 mL)
2 drops of conc. HCl were added. The mixture was stirred for was added 2,6-lutidine (21 μL, 180 μmol) followed by TBHP
1 h at room temperature (a yellow precipitate began to form (3.73 M solution in toluene, 386 μL, 1.44 mmol) and then VO-
after 15 min). Concentrating in vacuo followed by purification (acac)2 (9.9 mg, 37 μmol). The reaction was stirred at room
using flash chromatography eluting with CH2Cl2–MeOH temperature for 4 h then concentrated in vacuo. Purification
(96 : 4) gave β-dihydroagarofuran 23 as a clear oil (11.5 mg, using flash chromatography (EtOAc–petrol, 1 : 1) gave bis-
50%). Rf = 0.5 (EtOAc); IR (neat) νmax 3418 (OH), 2966, 2935, epoxide 25 as a clear oil (45 mg, 85%, as an inseparable
1
2879, 2237 (CuN), 1456, 1042 cm−1
;
1H NMR (270 MHz, ∼10 : 1 mixture of C11 epimers by H NMR). Data quoted for
CDCl3) δ 1.31 (d, J = 8.6 Hz, 3H, CH3), 1.34 (d, J = 7.5 Hz, 3H, major isomer: Rf = 0.50 (EtOAc); IR (neat) νmax 3443 (OH),
CH3), 1.63 (s, 3H, CH0CH3), 1.68 (d, J = 13.8 Hz, 1H, HCH, 2930, 2242 (CuN), 1456 cm−1 1H NMR (270 MHz, CDCl3)
;
C1α), 1.80 (d, J = 4.7 Hz, 2H, CH2, C9), 2.06 (dd, J = 13.8 and δ 1.07 (d, J = 6.2 Hz, 3 H, CHCH3), 1.43 (d, J = 7.3 Hz, 3 H,
7.9 Hz, 1H, HCH, C1β), 2.21 (d, J = 2.8 Hz, 1H, C7), 2.32 (m, CHCH3), 1.50 (s, 3 H, CCH3), 1.16–2.41 (7 H, 1-H, 2-H, 7-H,
1H, C8), 2.47 (m, 1H, C2), 2.61 (d, J = 3.8 Hz, 1H, CH1OH), 3.67 8-H, 9-H), 2.51 (d, J = 4.1 Hz, 1 H, CHHO), 2.90 (d, J = 4.1 Hz,
(s, 2H, CH2OH), 4.80 (d, J = 2.8 Hz, 1H, CH1OH), 6.04 (dd, J = 1 H, CHHO), 3.51 (d, J = 7.5 Hz, 1 H, 3-H), 3.63 (s, 1 H, 4-H),
10.2 and 2.8 Hz, 1H, CH1vCH1), 6.04 (dd, J = 10.2 and 1.4 Hz, 4.67 (d, J = 5.1 Hz, 1 H, 6-H) ppm; 13C NMR (67.5 MHz, CDCl3)
1H, CH1vCH1) ppm; 13C NMR (100 MHz, CDCl3) δ 20.0 (q), δ 18.5 (q), 21.6 (q), 24.5 (q), 29.9 (d), 32.3 (d), 35.6 (t), 35.8 (s),
20.8 (q), 25.1 (q), 28.6 (d), 30.0 (d), 35.2 (t), 37.9 (t), 38.1 (s), 36.5 (t), 47.3 (d), 52.8 (d), 59.9 (s), 61.7 (t), 62.6 (s), 66.7 (d),
+
54.3 (d), 66.8 (t), 75.9 (s), 82.1 (s), 85.9 (s), 120.8 (d), 125.8 (s), 71.4 (q), 123.7 (s) ppm; MS (CI+) m/z 311 (MNH4 ), 293; HRMS
138.6 (d) ppm; MS (CI+) m/z 295 (MNH4 ); HRMS (CI+) (CI+) calcd for C16H27N2O4 (MNH4 ) 311.1971, found 311.1972
+
+
+
calcd for C16H27N2O3 (MNH4 ) 295.2022, found 295.2018 (Δ = +0.3 ppm).
(Δ = −1.4 ppm).
Tetrahydrofuran 26
β-Dihydroagarofurans 24a and 24b
To a solution of bis-epoxide 25 (15.6 mg, 53 μmol) in CHCl3
To a solution of diene 21d (22.6 mg, 0.06 mmol) in CH2Cl2 (0.8 mL) was added TFA (6 μL, 80 μmol). The reaction was
(3 mL) was added TMEDA (10.7 μL, 0.07 mmol). After cooling stirred at room temperature for 2 h then heated to 60 °C for
to −78 °C, OsO4 (s) was added (18 mg, 0.07 mmol), the reaction 0.5 h (TLC analysis showed mainly starting material). A further
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portion of TFA was added (45 μL, 580 μmol) and the reaction 1 H, 9-H), 2.45 (dd, J = 2.6 and 8.0 Hz, 1 H), 2.55 (m, 1 H), 3.21
heated to 60 °C for 0.5 h (the reaction colour had changed to a (d, J = 3.2 Hz, 1 H, 3-H), 3.37 (s, 3 H, OCH3), 3.67 (d, J = 3.3 Hz,
pale turquoise after 20 min). Triethylamine (147 μL, 1 H, 4-H), 3.83 (q, J = 8.2 Hz, 1 H, CHOCH3), 5.99 (dd, J = 2.9
1.06 mmol) was added and the solvent removed in vacuo. Puri- and 9.9 Hz, 1 H, 6-H), 6.47 (dd, J = 2.6 and 9.9 Hz, 1 H, 7-H)
fication by flash chromatography eluting with EtOAc–petrol ppm; 13C NMR (125 MHz, CDCl3) δ 18.7 (q), 19.7 (q), 21.8 (q),
(1 : 1, then 1 : 0) gave tetrahydrofuran 26 as a clear oil (5.4 mg, 26.5 (d), 27.9 (d), 31.2 (t), 33.4 (t), 36.5 (s), 56.1 (q), 57.6 (d),
33%). Rf = 0.50 (EtOAc); IR (neat) νmax 3419 (OH), 2929, 2935, 58.4 (d), 71.4 (s), 76.5 (d), 123.1 (s), 127.2 (d), 139.1 (d),
1
+
2242 (CuN), 1456 cm−1; H NMR (400 MHz, CDCl3) δ 0.89 (d, 170.8 (s); MS (CI+) m/z 323 (MNH4 ); HRMS (CI+) calcd for
J = 6.4 Hz, 3 H, 15-H), 1.11 (d, J = 6.4 Hz, 3 H, 16-H), 1.30 (s, 3 C17H24NO4 (MH+) 306.1705, found 306.1717 (Δ = +3.9 ppm).
H, C(OH)CH3), 1.53–1.62 (2 H, 2-H and 1α-H), 1.75 (m, 1 H,
γ-Lactones 28a and 28b
1β-H), 1.97–2.09 (2 H, 9-H), 2.36 (m, 1 H, 8-H), 2.85 (dd, J = 8.7
and 11.5 Hz, 1H, 7-H), 3.54 (d, J = 12.2 Hz, 1 H, CHHOH), Ester 27 (50 mg, 164 μmol, 48% dr) was dissolved in THF
3.58 (d, J = 12.2 Hz, 1 H, CHHOH), 3.62 (d, J = 8.9 Hz, 1 H, (0.5 mL) and cooled to −78 °C. TMSCl (46 μL, 360 μmol) was
3-H), 3.76 (s, 1H, 4-H), 4.98 (d, J = 8.7 Hz, 1 H, 6-H) ppm; 13C added followed by LHMDS (1 M solution in THF, 360 μL,
NMR (100 MHz, CDCl3) δ 18.7 (q), 18.7 (q), 19.4 (q), 25.8 (d), 180 μmol). The solution was stirred at −78 °C for 30 min, then
29.7 (d), 31.1 (t), 33.1 (s), 37.1 (t), 44.4 (d), 61.1 (d), 63.2 (s), at room temperature for 30 min, then heated to 60 °C for
69.9 (t), 71.1 (d), 71.7 (d), 88.3 (s), 122.7 (d); MS (CI+) m/z 311 14.5 h. The solution was diluted with Et2O (5 mL) and water
(MNH4 ), 293; HRMS (CI+) calcd for C16H27N2O4 (MNH4 ) (10 mL) was added. The mixture was concentrated in vacuo to
+
+
311.1971, found 311.1978 (Δ = +2.2 ppm).
remove all THF and then extracted with CH2Cl2 (4 × 15 mL).
The combined organic extracts were dried (MgSO4) and con-
centrated in vacuo to leave a pale yellow oil. Purification by
flash chromatography eluting with EtOAc–hexane (1 : 4 to 3 : 7)
afforded:
Lactate ester 27
Triethylamine (67 μL, 239 μmol) was added to a solution of
(−)-(S)-2-methoxypropionic acid (44 μL, 239 μmol) in toluene
(1 mL). 2,4,6-Trichlorobenzoyl chloride (75 μL, 239 μmol) was
added and the solution was left to stir at room temperature for
1.5 h. Allylic alcohol (−)-3 (50 mg, 228 μmol, ee 22%)†† and
4-DMAP (31 mg, 125 μmol) in toluene (1 mL) was added,
turning the solution pale yellow. The solution was heated to
60 °C for 20 h then concentrated in vacuo to leave a yellow
solid. Purification by flash chromatography eluting with
EtOAc–hexane (3 : 17) afforded ester 27 as a clear oil (55 mg,
79%, an inseparable 48% de mixture of diastereoisomers by
1H NMR).‡‡ Rf 0.25 (EtOAc–hexane, 1 : 4); IR (neat) νmax 2984,
Ester 27 as a clear oil (5 mg, 10%, almost exclusively the
minor diastereoisomer). Spectroscopic data as above.
γ-Lactone 28a as white crystalline solid (19 mg, 38%). Mp =
124–125 °C (EtOAc–hexane); Rf 0.30 (EtOAc–hexane, 2 : 3); IR
(neat) νmax 2919, 2232 (CuN), 1784 (CvO) cm−1 1H NMR
;
(400 MHz, CDCl3) δ 1.16 (d, J = 6.8 Hz, 3 H, CHCH3), 1.40 (d,
J = 6.2 Hz, 3 H, CHCH3), 1.41 (s, 3 H, CH3COCH3), 1.59 (bs,
1 H, OH), 1.69 (dt, J = 6.9 and 13 Hz, 1 H, 1-H), 1.87 (dd, J = 4.3
and 13 Hz, 1 H, 9-H), 1.97 (d, J = 2.3 Hz, 1 H, 1-H), 1.99 (s, 1 H,
CHCH3), 2.20 (dd, J = 6.0 and 13 Hz, 1 H, 9-H), 2.31 (dd, J = 3.2
and 7.8 Hz, 1 H, CHCCH3OCH3), 2.35 (m, 1 H, CHCH3), 3.24
(s, 3 H, OCH3), 3.92 (m, 1 H, CHOH), 5.31 (dt, J = 2.4 and
2938, 2237 (CuN), 1742 (CvO), 1459, 1373, 1266, 1190 cm−1
.
1
Major diastereoisomer: H NMR (400 MHz, CDCl3) δ 1.35 (d, J =
7.7 Hz, 3 H, CHCH3), 1.36 (d, J = 6.9 Hz, 3 H, CHCH3),
1.45–1.49 (4 H, CH3 and 1-H), 1.69 (d, J = 14 Hz, 1 H, 9-H), 1.94
(dd, J = 8.4 and 14 Hz, 1 H, 1-H), 2.25 (dd, J = 8.4 and 14 Hz,
1 H, 9-H), 2.45 (dd, J = 2.6 and 8.0 Hz, 1 H), 2.55 (m, 1 H), 3.21
(d, J = 3.2 Hz, 1 H, 3-H), 3.40 (s, 3 H, OCH3), 3.67 (d, J = 3.3 Hz,
1 H, 4-H), 3.83 (q, J = 8.2 Hz, 1 H, CHOCH3), 5.99 (dd, J = 2.9
and 9.9 Hz, 1 H, 6-H), 6.47 (dd, J = 2.6 and 9.9 Hz, 1 H, 7-H)
8.1 Hz, 1 H, CHOC(O)), 5.91 (t, J = 2.4 Hz, 1 H, vCH) ppm; 13
C
NMR (100 MHz, CDCl3) δ 17.3 (q), 18.0 (q), 22.6 (q), 25.5 (d),
33.0 (t), 33.3 (s), 39.3 (t), 42.1 (d), 51.3 (q), 53.8 (d), 71.0 (d),
74.9 (d), 76.5 (s), 123.9 (s), 126.1 (d), 132.8 (s), 174.2 (s) ppm;
MS (CI+) m/z 323 (MNH4 ); HRMS (CI+) calcd for C17H27N2O4
+
+
(MNH4 ) 323.1971, found 323.1964 (Δ = −2.2 ppm).
Crystal data for 28a: C17H23NO4·0.5(C4H8O2), M = 349.42,
tetragonal, P43 (no. 78), a = b = 16.17422(15), c = 7.32793(11) Å,
V = 1917.03(5) Å3, Z = 4, Dc = 1.211 g cm−3, μ(Cu-Kα) =
0.713 mm−1, T = 173 K, colourless needles, Oxford Diffraction
Xcalibur PX Ultra diffractometer; 3400 independent measured
reflections (Rint = 0.0454), F2 refinement, R1(obs) = 0.0374,
wR2(all) = 0.0987, 3022 independent observed absorption-
corrected reflections [|Fo| > 4σ(|Fo|), 2θmax = 143°], 203 para-
meters. The absolute structure of 28a could not be unambigu-
1
ppm. Minor diastereoisomer: H NMR (400 MHz, CDCl3) δ 1.35
(d, J = 7.7 Hz, 3 H, CHCH3), 1.36 (d, J = 6.9 Hz, 3 H, CHCH3),
1.45–1.49 (4 H, CH3 and 1-H), 1.70 (d, J = 14 Hz, 1 H, 9-H), 1.94
(dd, J = 8.4 and 14 Hz, 1 H, 1-H), 2.25 (dd, J = 8.4 and 14 Hz,
††The enantiomeric purity of allylic alcohol (−)-3 obtained from the L-(+)-DIPT
mediated asymmetric epoxidative desymmetrisation of diallylic alcohol 10 is
readily determined by CSP-HPLC (see above) but it is very sensitive to the quality
+
–
of the 4 Å MSs employed and the material used for this series of experiments ously determined either by R-factor tests [R1 = 0.0374, R1
was measured to have an ee of just 22%.
=
=
0.0376] or by use of the Flack parameter [x+ = 0.0(2), x−
‡‡A partial kinetic resolution occurs in this esterification reaction. The de of the
product is readily determined by integration of the methyl ether singlets in the
1H NMR at δ 3.37 (minor) and δ 3.40 ppm. The major diastereoisomer is that
shown for ester 27 in Scheme 10. The minor diastereoisomer is that in which all
stereocentres except the lactate stereocentre are inverted.
1.2(2)], and so was assigned based on the known stereochemis-
tries at C(2), C(3), C(8) and C(10).43 CCDC 905364.
γ-Lactone 28b as a clear oil (10 mg, 20%). Rf 0.15 (EtOAc–
hexane, 2 : 3); IR (neat) νmax 2924, 2283 (CuN), 1783 (CvO),
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1382 cm−1; H NMR (400 MHz, CDCl3) δ 1.23 (d, J = 7.0 Hz, 3 5.6 Hz, 1 H, CHCOCH3), 2.90 (d, J = 9.6 Hz, 1 H, CHOCH3),
H, CHCH3), 1.24 (d, J = 6.7 Hz, 3 H, CHCH3), 1.39 (s, 3 H, 3.20 (s, 3 H, OCH3), 3.30 (s, 3 H, OCH3), 3.33 (s, 3 H, OCH3),
CH3COCH3), 1.88–2.03 (m, 6 H), 2.75 (dd, J = 7.5 and 9.7 Hz, 3.43 (s, 3 H, OCH3), 3.95 (s, 1 H, CHOCH3), 4.16 (d, J = 6.0 Hz,
1 H, 7-H), 3.42 (s, 3 H, OCH3), 4.01 (m, 1 H, CHOH), 5.32 (dt, 1 H, CH(O)) ppm; 13C NMR (100 MHz, CDCl3) δ 18.4 (q),
J = 9.7 and 4.6 Hz, 1 H, CHOC(O)), 5.98 (dd, J = 2.2 and 3.3 Hz, 21.4 (q), 22.2 (q), 27.8, 29.2, 36.2, 36.8, 37.3, 51.4 (d), 51.5 (q),
1 H, vCH) ppm; 13C NMR (100 MHz, CDCl3) δ 17.2 (q), 53.4 (q), 57.4 (q), 59.5 (q), 60.2 (d), 62.6 (s), 74.9 (d), 79.7 (d),
+
20.5 (q), 20.7 (q), 26.3 (d), 32.0 (s), 33.5 (t), 37.1 (t), 42.7 (d), 81.6 (s), 133.7 (s), 175.3 (s) ppm; MS (CI+) m/z 399 (MNH4 ) 382
48.10 (d), 51.7 (q), 69.2 (d), 77.2 (d), 78.7 (s), 123.2 (s), (MH+); HRMS (CI+) calcd for C20H32NO6 (MH+) 382.2230,
126.2 (d), 132.5 (s), 176.2 (s) ppm; MS (CI+) m/z 323 (MNH4 ); found 382.2229 (Δ = −0.3 ppm).
+
+
HRMS (CI+) calcd for C17H27N2O4 (MNH4 ) 323.1971, found
323.1973 (Δ = +0.6 ppm).
β-Dihydroagarofuran 31 and δ-lactone 32
Ester 30 (20 mg, 52.4 μmol) was dissolved in CH2Cl2 (2.5 mL)
and LiI (28 mg, 21.2 μmol) was added. The suspension was
Methyl ester 29
γ-Lactone 28a (20 mg, 65.5 μmol) was dissolved in THF cooled to −78 °C and a solution of BBr3 (1 M solution in
(0.8 mL). KOH (37 mg, 655 μmol) was added, followed by MeI CH2Cl2, 210 μL, 210 μmol) was added. The reaction mixture
(41 μL, 655 μmol) to form a pale yellow solution. The solution was stirred at −78 °C. After 1 h, water (3 mL) was added and
was heated to 60 °C for 3 h then allowed to cool to room temp- the organic phase separated. The aqueous phase was extracted
erature. EtOAc (10 mL) followed by water (10 mL) was added with CH2Cl2 (3 × 3 mL) and the combined organic extracts
and the organic layer was separated. The aqueous layer was were dried (MgSO4) and concentrated in vacuo to leave a brown
further extracted with EtOAc (3 × 10 mL) and the combined oil. Purification by flash chromatography eluting with EtOAc–
organic extracts were dried (MgSO4) and concentrated in vacuo petrol (1 : 4, then 1 : 1) gave:
to afford ester 29 as a pale yellow oil (23 mg, 96%). No further
β-dihydroagarofuran 31 as a white solid (10 mg, 52%). Mp =
purification was required. Mp = 96–97 °C; Rf 0.75 (EtOAc– 131–134 °C; IR (neat) νmax 3450 (br, OH), 2235 (CuN), 1748
hexane, 2 : 3); IR (neat) νmax 2929, 2227 (CuN), 1748 (CvO), (CvO), 1455, 1131, 1101 cm−1
;
1H NMR (400 MHz, CDCl3) δ
1457, 1178, 1101 cm−1; H NMR (400 MHz, CDCl3) δ 1.11 (d, 1.06 (d, J = 6.0 Hz, 3 H, CHCH3), 1.40 (s, 3 H, CH3CCO2Me),
J = 6.5 Hz, 3 H, CHCH3), 1.43 (s, 3 H, H3CCOCH3), 1.45 (d, J = 1.46 (d, J = 7.6 Hz, 3 H, CHCH3), 1.66 (d, J = 14.8 Hz, 1 H,
7.7 Hz, 3 H, CHCH3), 1.73 (d, J = 13 Hz, 1 H, CH2), 1.79–1.93 CH2), 1.75 (dd, J = 3.6 and 13 Hz, 1 H, 2-H), 2.01 (t, J = 13 Hz,
(3 H), 2.30–2.35 (2 H), 2.45 (p, J = 7.5 Hz, 1 H, CHCOCH3), 3.19 1 H), 2.06–2.15 (m, 1 H), 2.56 (dt, J = 15 and 7.6 Hz, 1 H, CHC-
(s, 3 H, OCH3), 3.36 (s, 3 H, OCH3), 3.43 (s, 3 H, OCH3), 3.60 (CH3)OCH3), 2.68–2.72 (m, 2 H, 7-H and 9-H), 2.86 (s, 1 H,
(dt, J = 6.5 and 2.4 Hz, 1 H, CHCOCH3), 3.72 (s, 3 H, OCH3), OH), 3.25, (dd, J = 3.2 and 10 Hz, 1 H, CHOCH3), 3.40 (s, 3 H,
4.21 (dt, J = 5.2 and 1.8 Hz, 1 H, CHOCH3), 5.96 (t, J = 1.8 Hz, OCH3), 3.51 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.83 (d, J =
1 H, vCH) ppm; 13C NMR (100 MHz, CDCl3) δ 17.5 (q), 3.6 Hz, 1 H), 4.53 (d, J = 3.2 Hz, 1 H) ppm; 13C NMR (100 MHz,
21.4 (q), 22.3 (q), 28.6 (d), 30.3 (d), 34.9 (s), 40.4 (t), 41.2 (t), CDCl3) δ 17.3 (q), 20.5 (q), 22.7 (q), 27.1 (d), 27.6 (d), 34.4 (t),
51.3 (d), 51.4 (q), 53.0 (q), 58.0 (q), 77.2 (d), 79.0 (d), 80.4 (s), 38.9 (t), 40.5 (s), 43.2 (d), 52.0 (q), 56.0 (q), 57.3 (q), 67.6 (d),
122.9 (d), 125.6 (s), 133.5 (s), 174.8 (s) ppm; MS (CI+) m/z 388 69.2 (s), 77.9 (s), 78.1 (d), 80.8 (d), 124.3 (s), 174.7 (s) ppm;
1
+
+
+
(MNH4 ); HRMS (CI+) calcd for C20H35N2O5 (MNH4 ) 388.2100, MS (CI+) m/z 385 (MNH4 ); HRMS (CI+) calcd for C19H33N2O6
+
found 388.2085 (Δ = −3.9 ppm).
385.2339 (MNH4 ), found 385.2343 (Δ = +1.0 ppm).
Crystal data for 31: C19H29NO6, M = 367.43, monoclinic,
P21/c (no. 14), a = 10.6847(2), b = 12.1746(3), c = 14.6780(3) Å,
Epoxide 30
Alkene 29 (159 mg, 436 μmol) was dissolved in CH2Cl2 (5 mL) β = 95.328(2)°, V = 1901.09(7) Å3, Z = 4, Dc = 1.284 g cm−3
,
and m-CPBA (301 mg, 1.74 mmol) was added. The reaction μ(Cu-Kα) = 0.784 mm−1, T = 173 K, colourless blocks, Oxford
mixture was stirred at room temperature for 34 h before being Diffraction Xcalibur PX Ultra diffractometer; 3756 independent
evaporated to dryness in vacuo. The residue was dissolved in measured reflections (Rint = 0.0297), F2 refinement, R1(obs) =
EtOAc (5 mL) and saturated aqueous NaHCO3 solution (5 mL). 0.0370, wR2(all) = 0.1021, 3397 independent observed absorp-
The organic phase was separated and subsequently washed tion-corrected reflections [|Fo| > 4σ(|Fo|), 2θmax = 145°], 243
with a saturated aqueous NaHCO3 solution (3 × 3 mL). The parameters. CCDC 905365.
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo to give a white solid. Purification by flash νmax 3496 (br, OH), 2229 (CuN), 1726 (CvO), 1453,
chromatography eluting with EtOAc–petrol (1 : 17) gave 1107 cm−1 1H NMR (400 MHz, CDCl3) δ 1.29 (d, J = 7.6 Hz,
δ-Lactone 32 as a colourless gum (1.5 mg, 8%). IR (neat)
;
epoxide 30 as a white solid (136 mg, 82%). Mp = 135–137 °C; 3 H, CHCH3), 1.39 (d, J = 7.2 Hz, 3 H, CHCH3), 1.45 (s, 3 H,
IR (neat) νmax 2933, 2835, 2234 (CuN), 1730 (CvO), 1458, CH3), 1.73–1.79 (m, 2 H, CH2), 1.90 (m, 2 H, CH2), 2.14 (m,
1
1253, 1184, 1097 cm−1; H NMR (400 MHz, C6D6) δ 0.90 (d, J = 1 H, CHCH3), 2.36 (m, 1 H, CHCH3), 2.90 (d, J = 1.2 Hz, 1 H,
6.4 Hz, 3 H, CHCH3), 1.18 (s, 3 H, CH3), 1.19 (m, 1 H, CHCH3), CHCOCH3), 3.29 (s, 3 H, OCH3), 3.33 (m, 1 H, CHOCH3), 3.54
1.32 (dt, J = 14.0 and 1.2 Hz, 1 H, CH2), 1.46 (d, J = 8.4 Hz, 3 H, (s, 3 H, OCH3), 3.71 (s, 3 H, OCH3), 4.43 (s, 2 H, CHOCH3 and
CHCH3), 1.47–1.54 (m, 1 H, CHCH3), 1.75 (t, J = 13 Hz, 1 H), CHOH) ppm; 13C NMR (100 MHz, CDCl3) δ 18.3 (q), 18.9 (q),
2.13 (m, 1 H), 2.32 (dd, J = 6.0 and 14 Hz, 1 H, 9-H), 2.44 (d, J = 19.7 (q), 28.6 (d), 31.3 (d), 35.1 (s), 37.9 (t), 40.0 (t), 48.6 (d),
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52.2 (q), 55.6 (q), 57.4 (q), 69.7 (d), 83.5 (d), 84.0 (d), 86.4 (s), Epoxide 35
87.4 (s), 125.8 (s) ppm; MS (CI+) m/z 385 (MNH4 ); HRMS (CI+)
calcd for C19H33N2O6 385.2339 (MNH4 ), found 385.2358
+
Alkene 34 (10 mg, 26.4 μmol) was dissolved in CH2Cl2 (1 mL)
and m-CPBA (6 mg, 34.0 μmol) was added. The solution was
stirred at room temperature for 3.5 h, then diluted with
CH2Cl2 and saturated aqueous NaHCO3 solution (10 mL) was
added. The organic layer was separated and the aqueous layer
was further extracted with CH2Cl2 (3 × 10 mL). The combined
organic extracts were dried (MgSO4 then concentrated in vacuo.
Purification by flash chromatography eluting with EtOAc–
hexane (1 : 4) afforded epoxide 35 as a white crystalline solid
(10 mg, 96%). Rf 0.35 (EtOAc–hexane, 1 : 3); Mp 88–89 °C
(CH2Cl2); IR (neat) νmax 2933, 2233 (CuN), 1740 (CvO), 1460,
+
(Δ = +4.9 ppm).
Alcohol 33
Ester 29 (49 mg, 134 μmol) was dissolved in THF (5 mL) and
cooled to −5 °C. LiAlH4 (21 mg, 56.2 μmol) was added in two
portions. The suspension was stirred at 0 °C for 2.5 h then
diluted with EtOAc (15 mL) and washed with water (15 mL).
The aqueous layer was further extracted with EtOAc (3 ×
10 mL) and the combined organic extracts were dried (MgSO4)
then concentrated in vacuo to leave a clear oil. Purification by
flash chromatography eluting with EtOAc–hexane (1 : 4, then
1 : 3) afforded alcohol 33 as a clear oil (28 mg, 63%). Rf 0.25
(EtOAc–hexane, 2 : 3); νmax/cm−1 (neat) 3484 (OH), 2934, 2165
1
1382, 1243, 1096 cm−1; H NMR (400 MHz, CDCl3) δ 0.99 (d,
J = 6.3 Hz, 3 H, CHCH3), 1.29 (s, 3 H, C(CH3)(OCH3)), 1.45 (dd,
J = 9.8 and 3.7 Hz, 1 H, CH2), 1.50 (d, J = 7.6 Hz, 3 H, CHCH3),
1.54 (m, 1 H, CH2), 1.62–1.69 (2 H, CHCH3 and CH2), 2.11 (s,
3 H, C(O)CH3), 2.14 (d, J = 5.3 Hz, 1 H, 2-H), 2.51–2.55 (2 H,
CHCHCOCH3 and 9-H), 2.92 (d, J = 9.6 Hz, 1 H, CHOCH3),
3.22 (s, 3 H, OCH3), 3.42 (s, 3 H, OCH3), 3.50 (4 H, OCH3 and
CHOCH3), 4.08 (d, J = 5.3 Hz, 1 H, CH-(O)), 4.28 (d, J = 11 Hz,
1 H, CHHOAc), 4.50 (d, J = 11 Hz, 1 H, CHHOAc) ppm; 13C
NMR (100 MHz, CDCl3) δ 18.2 (q), 20.5 (q), 21.1 (q), 22.0 (d),
28.8 (d), 29.3 (d), 36.2 (t), 37.1 (s), 37.7 (t), 49.1 (q), 49.7 (q),
57.9 (q), 60.3 (q), 60.4 (d), 62.9 (s), 69.5 (t), 76.4 (d), 78.8 (s),
81.9 (d), 124.6 (s), 170.7 (s) ppm; MS (CI+) m/z 413 ([MNH4]+),
396 (MH+), 369; HRMS (CI+) calcd for C21H34NO6 (MH+)
396.2400, found 396.2396 (Δ = −1.0 ppm).
1
(CuN), 1726, 1458, 1085 (C–O); H NMR (400 MHz, CDCl3) δ
1.12 (d, J = 6.6 Hz, 3 H, CHCH3), 1.27 (s, 3 H, C(OCH3)CH3),
1.44 (d, J = 7.4 Hz, 3 H, CHCH3), 1.71 (d, J = 13 Hz, 1 H,
CHCH3), 1.83–1.94 (3 H, CH2 and CHCH3), 2.05 (d, J = 5.0 Hz,
1 H, 9-H), 2.35–2.45 (2 H, 7-H, 9-H), 3.10 (s, 3 H, OCH3), 3.39
(s, 3 H, OCH3), 3.42 (m, 1 H, CHOCH3), 3.46 (s, 3 H, OCH3),
3.54–3.58 (2 H, CHHOH and CHOCH3), 3.83 (dd, J = 4.4 and
11 Hz, 1 H, CHHOH), 4.29 (m, 1 H, CHOCH3), 5.93 (s, 1 H,
vCH) ppm; 13C NMR (100 MHz, CDCl3) δ 17.7 (q), 20.9 (q),
22.6 (q), 29.2 (d), 30.6 (d), 35.4 (s), 40.4 (t), 41.2 (d), 49.0 (q),
51.5 (q), 55.6 (q), 57.8 (t), 66.3 (d), 79.3 (s), 79.8 (d), 123.4 (d),
125.5 (s), 133.4 (s) ppm; MS (ESI+) m/z 338 (MH+), 339, 360
(MNa+), 363; HRMS (ESI+) 360.2140 calcd for C19H31NNaO4
(MNa+), found 360.2151 (Δ = +3.1 ppm).
β-Dihydroagarofuran 36
Epoxide 35 (8 mg, 20.2 μmol) was dissolved in CH2Cl2 (1 mL)
and LiI (14 mg, 101 μmol) was added. The mixture was cooled
Acetate 34
Alcohol 33 (10 mg, 29.3 μmol) was dissolved in pyridine to −78 °C and BBr3 (1 M solution in CH2Cl2, 61 μL, 60.7 μmol)
(1 mL). 4-DMAP (4 mg, 29.3 μmol) was added followed by Ac2O was added. The mixture was stirred at −78 °C for 3 h then
(8 μL, 87.8 μmol). The solution was stirred at room tempera- quenched with saturated aqueous NaHCO3 solution (5 mL)
ture for 1 h then concentrated in vacuo to leave a yellow oil. and extracted with CH2Cl2 (3 × 10 mL). The combined organic
Purification by flash chromatography eluting with EtOAc– extracts were dried (MgSO4) then concentrated in vacuo to leave
hexane (1 : 3) afforded acetate 34 as a colourless oil (11 mg, a yellow residue. Purification by flash chromatography eluting
99%). Rf 0.40 (1 : 3, EtOAc–hexane); IR (neat) νmax 2934, 2829, with EtOAc–hexane (7 : 13) afforded β-dihydroagarofuran 36 as
2227 (CuN), 1741 (CvO), 1459, 1381, 1241, 1098 cm−1 1H a colourless oil (6 mg, 78%). Rf 0.30 (EtOAc–hexane, 1 : 1); IR
;
NMR (400 MHz, CDCl3) δ 1.16 (d, J = 6.4 Hz, 3 H, CHCH3), 1.28 (neat) νmax 3498 (OH), 2924 (CH), 2230 (CuN), 1740 (CvO),
1
(s, 3 H, C(CH3)(OCH3), 1.44 (d, J = 7.6 Hz, 3 H, CHCH3), 1.75 1462, 1387, 1245, 1109, 1039 cm−1; H NMR (400 MHz, CDCl3)
(d, J = 14 Hz, 1 H, 9-H), 1.78–1.91 (d, 3 H, CH2 and CHCH3), δ 1.27 (d, J = 7.4 Hz, 3 H, CHCH3), 1.36 (s, 3 H, C(CH3)-
2.09 (s, 3 H, C(O)CH3), 2.13 (t, J = 4.2 Hz, 1 H), 2.21 (dd, J = 14 CH2OAc), 1.40 (d, J = 7.2 Hz, 3 H, CHCH3), 1.62 (bs, 1 H, OH),
and 7.1 Hz, 1 H, 9-H), 2.42 (m, 1 H, CHC(CH3)(OCH3)), 3.17 (s, 1.75 (dd, J = 14 and 6.1 Hz, 1 H, 2-H), 1.88–1.99 (s, 3 H, CHCH3
3 H, OCH3), 3.33 (s, 3 H, OCH3), 3.42 (s, 3 H, OCH3), 3.55 (dt, and 9-H), 2.09 (s, 3 H, C(O)CH3), 2.12 (m, 1 H, 2-H), 2.32–2.37
J = 6.4 and 2.1 Hz, 1 H, CHOCH3), 4.10 (d, J = 12 Hz, 1 H, (2 H, 7-H and 9-H), 2.87 (d, J = 3.8 Hz, 1 H, CHOCH3), 3.29
CHHOAc), 4.20 (dt, J = 4.4 and 1.4 Hz, 1 H, CHOCH3), 4.47 (d, (dd, J = 5.6 and 3.4 Hz, 1 H, CHOCH3), 3.39 (s, 3 H, OCH3),
J = 12 Hz, 1 H, CHHOAc), 5.99 (t, J = 1.7 Hz, 1 H, vCH) ppm; 3.45 (s, 3 H, OCH3), 4.16 (d, J = 11 Hz, 1 H, CHHOAc), 4.40 (d,
13C NMR (100 MHz, CDCl3) δ 18.2 (q), 20.1 (q), 21.1 (q), J = 11 Hz, 1 H, CHHOAc), 4.52 (s, 1 H, CHOH) ppm; 13C NMR
22.6 (d), 27.8 (d), 31.3 (t), 34.1 (s), 40.3 (t), 41.1 (d), 49.6 (q), (100 MHz, CDCl3) δ 18.5 (q), 19.5 (q), 20.1 (q), 20.9 (d),
41.1 (d), 49.6 (q), 49.9 (q), 56.5 (q), 57.1 (q), 68.5 (t), 78.6 (d), 29.7 (d), 30.3 (q), 31.0 (d), 36.3 (s), 40.6 (t), 46.0 (t), 55.5 (q),
78.8 (s), 80.1 (d), 125.2 (2C, s), 134.2 (d), 170.9 (s) ppm; 57.7 (q), 70.0 (t), 71.3 (d), 84.0 (d), 85.3 (d), 85.8 (s), 87.2 (s),
MS (CI+) m/z 397 (MNH4 ), 383, 348 (M − MeO+); HRMS (CI+) 126.1 (s), 170.6 (s) ppm; MS (ESI+) m/z 382 (MH+), 404, 405;
+
calcd for C21H37N2O5 (MNH4 ) 397.2702, found 397.2706 HRMS (ESI+) calcd for C20H32NO6 (MH+) 382.2224, found
+
(Δ = +1.0 ppm).
382.2222 (Δ = −0.5 ppm).
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Organic & Biomolecular Chemistry
Ketone 37
Notes and references
Alcohol 36 (6 mg, 15.7 μmol) was dissolved in CH2Cl2 (0.4 mL)
and Dess–Martin periodinane (0.3 M solution in CH2Cl2,
79 μL, 23.6 mmol) was added. The mixture was stirred at room
temperature for 2 h then concentrated in vacuo. The white
solid was dissolved in EtOAc (10 mL) and washed with satu-
rated aqueous NaHCO3 solution (4 × 15 mL), dried over MgSO4
then concentrated in vacuo to leave a white solid. Purification
by flash chromatography eluting with EtOAc afforded ketone
37 as a white crystalline solid (5.5 mg, 92%). Mp 118–119 °C
(EtOAc); Rf 0.55 (EtOAc–hexane, 1 : 1); IR (neat) νmax 2926,
1 M. Beroza, J. Am. Chem. Soc., 1953, 75, 44–49, and refer-
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2856, 2225 (CuN), 1736 (CvO), 1461, 1380, 1247, 1042 cm−1
;
1H NMR (400 MHz, CDCl3) δ 1.37 (s, 3 H, CCH3(CH2OAc)), 1.38
(d, J = 7.4 Hz, 3 H, CHCH3), 1.43 (d, J = 7.3 Hz, 3 H, CHCH3),
1.66 (d, J = 13 Hz, 1 H, CH2), 1.83 (d, J = 14 Hz, 1 H, CH2), 1.94
(dd, J = 15 and 7.1 Hz, 1 H, CH2), 2.10 (s, 3 H, C(O)CH3),
2.14–2.26 (2 H, 8-H and 3-H), 2.34–2.40 (2 H, 7-H and 9-H),
3.37 (s, 3 H, OCH3), 3.50 (s, 3 H, OCH3), 4.21 (d, J = 7.4 Hz,
1 H, CHOCH3), 4.38 (d, J = 11 Hz, 1 H, CHHOAc), 4.48 (s, 1 H,
CHOCH3), 4.59 (d, J = 11 Hz, 1 H, CHHOAc) ppm; 13C NMR
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29.7 (d), 30.4 (d), 34.1 (t), 35.4 (t), 38.3 (d), 42.7 (s), 50.7 (q),
58.1 (q), 58.9 (q), 69.8 (t), 86.0 (s), 86.5 (s), 87.1 (d), 88.6 (s),
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Diol 4
Ketone 37 (3.0 mg, 7.91 μmol) was dissolved in THF (0.5 mL).
MeMgCl (3 M solution in THF, 11 μL, 31.6 μmol) was added at
room temperature and the reaction mixture was left to stir for
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N2. The residue was dissolved in a minimum amount of
CH2Cl2 and passed through a short silica plug. The eluent col-
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(2.4 mg, 75%). IR (neat) νmax 3496 (br, OH), 2925, 2856, 2361,
2231 (CuN), 1727, 1461, 1377, 1263, 1111 cm−1 1H NMR
;
(400 MHz, CDCl3) δ 1.29 (s, 6 H, CH3), 1.36 (d, J = 7.6 Hz, 3 H,
CHCH3), 1.41 (d, J = 8.0 Hz, 3 H, CHCH3), 1.87 (m, 3 H), 1.99
(m, 2 H), 2.18 (d, J = 2.8 Hz, 1 H, 9-H), 2.36 (m, 1 H, CHC(CH3)-
CH2OH), 3.37 (m, 4 H, CHOCH3 and OCH3), 3.54 (d, J = 11 Hz,
1 H, CHHOH), 3.57 (s, 3 H, OCH3), 4.04 (d, J = 11 Hz, 3 H,
CHHOH), 4.71 (s, 1 H, CHOCH3) ppm; 13C NMR (100 MHz,
CDCl3) δ 18.6 (q), 20.2 (q), 20.9 (q), 22.5 (q), 27.2 (d), 29.2 (d),
30.3 (t), 42.1 (t), 43.0 (s), 45.8 (d), 55.4 (q), 60.6 (q), 67.9 (t),
86.0 (d), 87.5 (d), 88.4 (s), 90.9 (s), 124.9 (s) ppm; MS (CI+)
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+
m/z 397 (MNH4 ), 383, 348 (MH − MeOH+); HRMS (CI+)
calcd for C21H37N2O5 (MNH4 ) 397.2702, found 397.2706
+
(Δ = +1.0 ppm).
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Acknowledgements
We thank Sheffield University, Imperial College London, Astra-
Zeneca, F. Hoffmann-La Roche and Pharmorphix for generous
support of this work.
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Paper
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