The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: The CD-spiroacetal segment

Article abstract of DOI:10.1039/b504148a

Stereocontrolled syntheses of the C16-C28 CD-spiroacetal subunit of altohyrtin A/spongistatin 1 (1), relying on kinetic and thermodynamic control of the spiroacetal formation, are described. The kinetic control approach resulted in a slight preference (60: 40) for the desired spiroacetal isomer. The thermodynamic approach allowed ready access to the desired spiroacetal 2 by acid-promoted equilibration, Chromatographic separation of the C23 epimers and resubjection of the undesired isomer to the equilibration conditions. This scalable synthetic sequence provided multi-gram quantities of 2, thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4 of this series. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b504148a

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A R T I C L E
The stereocontrolled total synthesis of altohyrtin A/spongistatin 1:
the CD-spiroacetal segment†‡
Ian Paterson,* Mark J. Coster,§ David Y.-K. Chen, Karl R. Gibson and Debra J. Wallace
University Chemical Laboratory, Lensfield Road, University of Cambridge, Cambridge, UK
CB2 1EW. E-mail: ip100@cam.ac.uk; Fax: +44 (0)1223 336 362
Received 22nd March 2005, Accepted 3rd May 2005
First published as an Advance Article on the web 24th May 2005
Stereocontrolled syntheses of the C16–C28 CD-spiroacetal subunit of altohyrtin A/spongistatin 1 (1), relying on
kinetic and thermodynamic control of the spiroacetal formation, are described. The kinetic control approach resulted
in a slight preference (60 : 40) for the desired spiroacetal isomer. The thermodynamic approach allowed ready access
to the desired spiroacetal 2 by acid-promoted equilibration, chromatographic separation of the C23 epimers and
resubjection of the undesired isomer to the equilibration conditions. This scalable synthetic sequence provided
multi-gram quantities of 2, thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin
1, as reported in Part 4 of this series.
detailed preclinical development as a lead structure for cancer
Introduction
chemotherapy.1 Our strategy2 for the total synthesis of this
Altohyrtin A/spongistatin 1 (1, Scheme 1) is an extraordinarily
captivating marine natural product involves its disconnection
potent cytotoxic marine macrolide. Unfortunately, the paucity
into three fragments, one of which is the C16–C28 CD-
of material available from the sponge sources has precluded its
spiroacetal subunit 2.3–5 Herein, we provide a full account of the
various strategies that we have explored for achieving a scalable
synthesis of this key segment of the altohyrtins.2d,g
† Part 2 of a series of four papers.1
The CD-spiroacetal 2 exhibits an “axial–equatorial” arrange-
‡ Electronic supplementary information (ESI) available: general exper-
ment of the acetal oxygen atoms and hence, unlike the AB-
imental information and procedures for the synthesis of compounds
spiroacetal system, benefits from only one stabilising anomeric
not detailed in the Experimental section of this paper. See http://
www.rsc.org/suppdata/ob/b5/b504148a/
§ Current address: School of Chemistry, University of Sydney, NSW
2006, Australia. E-mail: m.coster@chem.usyd.edu.au; Fax: +61 2 9351
3329.
effect, as indicated in structure 3, in contrast to the presumably
more stable epimeric acetal 4, which has a double anomeric
effect. Two distinct approaches to assembling this portion of the
spongipyrans were pursued. In a similar manner to that already
Scheme 1 Retrosynthetic analysis involving thermodynamic control of CD-spiroacetal formation in the synthesis of altohyrtin A/spongistatin 1 (1).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 1 0 – 2 4 1 9 T h i s j o u r n a l i s T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
2 4 1 0
©

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Scheme 2 Retrosynthetic analysis involving kinetic control of CD-spiroacetal formation.
employed for the AB-spiroacetal, the thermodynamic control
approach relied on the acid-promoted bis-desilylation of a
suitable linear precursor, such as 5, with concomitant spiroacetal
formation. In particular, it was envisaged that using this strategy,
the desired spiroacetal 3 might be stabilised to some extent,
especially in non-polar solvents, by an intramolecular hydrogen
bond between the axial C25 hydroxyl and an acetal oxygen,
ameliorating the presence of only one stabilising anomeric
effect. In contrast, the undesired spiroacetal isomer 4 cannot
form an intramolecular hydrogen bond of this nature and
would be destabilised by 1,3-diaxial interactions involving the
axially oriented C27 side-chain. In turn, the linear precursor
5 would be available from a stereocontrolled aldol reaction
(aldol #5) between methyl ketone 6 and aldehyde 7. Two
alternative strategies for the assembly of ketone 6, and a C17
ethyl homologue were envisioned, one involving establishment
of the C19 and C21 stereocentres by asymmetric allylations,
the other approach relying on a stereocontrolled aldol reaction
(aldol #4) followed by 1,3-anti reduction.
For the kinetic-control approach to the CD-spiroacetal
subunit, stepwise construction of the C- and D-rings was
prescribed (Scheme 2). Thus, it was proposed that the desired
spiroacetal 8 might be obtained from D-ring dihydropyrone
9 by a kinetically-controlled, intramolecular hetero-Michael
addition. Unravelling 9 to linear precursor 10 reveals an aldol
disconnection to ketone 11 and aldehyde 12. The latter of these
intermediates might, in turn, be obtained as the product of
a chelation controlled addition of allylsilane 13 to chiral b-
methoxy aldehyde 14. This kinetic control approach to the CD-
spiroacetal will be described first.
=
Scheme 3 Reagents and conditions: (a) (−)-Ipc2BOMe, H2C CHCH2-
MgBr, Et2O, −78 ◦C, 4 h, then H2O2, NaOH, H2O, rt, 3 d; (b) NaH, MeI,
THF, rt, 16 h; (c) O3, CH2Cl2, NaHCO3, −78 ◦C, 10 min, then PPh3, 0 ◦C,
◦
=
3 h; (d) H2C C(Et)CH2SiMe3 (13), TiCl4, CH2Cl2, −100 C, 20 min; (e)
TIPSOTf, 2,6-lutidine, CH2Cl2, −78 ◦C, 2 h; (f) CSA, MeOH, CH2Cl2,
rt, 3.5 h.
yield, >95% ee by MTPA ester analysis), which was then
protected as the p-methoxybenzyl (PMB) ether 20 (Scheme 4).
Subjection of this diene to Wacker oxidation11 conditions
provided an ca. 4 : 1 mixture of the desired methyl ketone 11 and
undesired aldehyde 21a, respectively. To simplify purification,
the crude reaction mixture was subjected to oxidation (NaClO2,
NaH2PO4, 2-methyl-2-butene, t-BuOH–H2O)12 to convert 21a to
the corresponding acid 21b, facilitating the isolation of 11 (47%).
Results and discussion
Formation of the CD-spiroacetal under kinetic control
The kinetic approach to the CD-spiroacetal2d required the
synthesis of aldehyde 14 in enantiomerically enriched form
(Scheme 3). Brown asymmetric allylation6 of aldehyde 15, em-
ploying B-allyldiisopinocampheylborane (dIpc2BAll), provided
homoallylic alcohol 16 in 90% yield and 85% ee (MTPA
ester7 analysis). Subsequent O-methylation (NaH, MeI) and
ozonolysis gave the aldehyde 14 in 72% yield. Reaction of 14 with
2-(trimethylsilylmethyl)-1-butene (13)8 under chelation control
conditions (TiCl4, CH2Cl2, 0.01 M, −100 ◦C), afforded the 1,3-
anti isomer 17 in 79% yield as the major diastereomer (96 : 4 dr).
Protection of the C19 hydroxyl as the triisopropylsilyl (TIPS)
ether and selective removal of the tert-butyldimethylsilyl (TBS)
group provided 1◦ alcohol 18.
Scheme 4 Reagents and conditions: (a) 10 mol% Ti(Oi–Pr)4, 14 mol%
˚
diisopropyl L-tartrate, t-BuOOH (0.55 eq.), 4 A mol. sieves, CH2Cl2,
−20 ◦C, 20 h; (b) KH, PMBCl, cat. TBAI, rt, 14 h; (c) 8 mol%
PdCl2, CuCl, O2, DMF–H2O (8 : 1), rt, 16 h, then NaClO2, NaH2PO4,
2-methyl-2-butene, t-BuOH–H2O (1 : 1), rt, 2 h.
Oxidation of alcohol 18 with the Dess–Martin periodinane,13
providing aldehyde 12 in 96% yield, set the stage for the boron
aldol coupling reaction14 with ketone 11 (Scheme 5). Generation
of the corresponding dicyclohexylboron enolate 22 from 11
under standard conditions (Chx2BCl, Et3N),15 and reaction with
aldehyde 12, provided the aldol adduct 23 in a surprisingly
diastereoselective fashion (84 : 16 dr). On the basis of this
work and related model studies, and despite the fact that the
Synthesis of the C24–C28 fragment commenced with the
kinetic resolution of alcohol 199 under Sharpless asymmetric
epoxidation10 conditions, to give enantioenriched (R)-19 (40%
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 1 0 – 2 4 1 9
2 4 1 1

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within our laboratory.17 Similar results have been reported by
Evans and co-workers.18
Oxidation of aldol adduct 23 to b-diketone 10 was achieved in
85% yield using the Dess–Martin periodinane (Scheme 6). Re-
moval of the PMB protecting group was followed by dehydrative
cyclisation (PPTS, CD2Cl2) to give the D-ring dihydropyranone
24 in 72% yield from 10. Desilylation with HF–pyridine, with
concomitant spiroacetalisation, provided only the undesired
spiroacetal 25, where presumably acetal equilibration occurred
under the reaction conditions. Gratifyingly, treatment of 24 with
TMSOTf (CH2Cl2, −78 ◦C, 15 min) allowed isolation of the
intermediate alcohol 9. While strong bases such as KOt–Bu also
led to the exclusive formation of the undesired spiroacetal 25,
under mild, basic conditions (DBU, CH2Cl2, 16 h), 9 underwent
intramolecular hetero-Michael reaction to install the C-ring,
leading to a small preference (60 : 40) for formation of the
desired, less stable,19 spiroacetal 8 over 25. In both these cases,
the stereochemistry was unambiguously determined by extensive
NOE studies.
Scheme 5 Reagents and conditions: (a) Dess–Martin periodinane,
CH2Cl2, rt, 30 min; (b) Chx2BCl, Et3N, Et2O, 0 ◦C, 30 min; (c) 12,
−78 → −20 ◦C, 21 h, then pH 7 buffer, H2O2, MeOH, 0 ◦C → rt, 2 h.
Formation of the CD-spiroacetal under thermodynamic control
C23 stereocentre is destroyed in the subsequent oxidation of 23,
we decided to further investigate this intriguing case of remote
asymmetric induction.
Our first reported synthesis of the CD-spiroacetal subunit of
the spongipyrans was performed under thermodynamic control,
where this involved the use of Brown asymmetric allylations and
a fully matched boron-mediated aldol reaction to establish the
oxygen-bearing stereocentres.2d Minor changes were made to
this previously reported route, in order to maximise convergency.
The improved thermodynamic route to the CD-spiroacetal
started with aldehyde 26, readily available in enantiomerically
pure form in three steps from the biopolymer poly[(R)-3-
hydroxybutyric acid] (PHB).20 Although the C23 stereogenic
centre is lost in a subsequent oxidation step, the use of
enantiomerically pure 26 simplified spectroscopic analysis of
subsequent intermediates retaining the C23 stereocentre and
facilitated separation of minor diastereomeric components of
Careful examination of a range of substrates revealed that
the boron-mediated aldol reaction of b-alkoxy methyl ketones
with simple, achiral aldehydes is highly 1,5-anti diastereose-
lective, particularly when PMB protection of the b-oxygen is
utilised.16 The level of 1,5-induction obtained in these aldol
reactions roughly correlated with the steric demand of the
aldehyde, where an increase in selectivity was observed on going
from acetaldehyde to isobutyraldehyde. Furthermore, enhanced
diastereoselectivities were obtained by the use of matched
aldol reactions, employing Ipc2BCl with the appropriate Ipc
ligand chirality. In contrast, methyl ketones containing a b-
tert-butyldimethylsiloxy substituent provided aldol adducts with
greatly reduced stereoselectivity (42 : 58–77 : 23 dr). The discov-
ery and development of this remarkably stereoselective subset of
methyl ketone aldol reactions proved greatly advantageous in the
spongistatin total synthesis and in other total synthesis efforts
d
mixtures. Brown asymmetric allylation of 26 using Ipc2BAll
provided the desired homoallylic alcohol as the major diastere-
omer (92 : 8 dr), which was converted into the methyl ether 27
(NaH, MeI) in 67% yield over two steps (Scheme 7). Ozonolytic
cleavage of the alkene unit in 27 provided aldehyde 28, which
Scheme 6 Reagents and conditions: (a) Dess–Martin periodinane, CH2Cl2, rt, 30 min; (b) DDQ, 10 : 1 CH2Cl2–pH 7 buffer, rt, 1 h; (c) PPTS, CD2Cl2,
rt, 7 d; (d) TMSOTf, CH2Cl2, −78 ◦C, 15 min; (e) DBU, CH2Cl2, rt, 16 h.
2 4 1 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 1 0 – 2 4 1 9

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influence of all three chiral components (aldehyde, ketone and
boron reagent) are matched. Treatment of 5 with 40% aqueous
HF in MeCN effected bis-desilylation with concomitant spiroac-
etal formation, to yield a ca. 5 : 1 mixture of the undesired and
desired spiroacetals, 4 and 3, respectively (92% combined yield).
Derivatisation of the C25 hydroxyl as the TBS ether (33 and 34)
or acetate (35 and 36), facilitated chromatographic separation
and stereochemical assignment. Extensive NOE studies unam-
biguously demonstrated that the major diastereomer formed in
the HF procedure was the undesired “axial–axial” spiroacetal
4. In particular, NOEs were observed between the equatorial
H24 and the axial H19 and H21 in the derivatives 33 and 35,
obtained from the minor spiroacetal 3. These were absent in the
corresponding derivatives 34 and 36, obtained from the major
spiroacetal 4, which displayed a strong NOE between the axial
H25 and both H28 protons. Diagnostic NOEs were observed
around the C-ring in all cases, confirming the stereochemical
relationship between C19 and C21.
=
Scheme 7 Reagents and conditions: (a) (−)-Ipc2BOMe, H2C CHCH2-
MgBr, Et2O, −78 → 0 ◦C 3 h, then H2O2, NaOH, H2O, reflux, 16 h; (b)
NaH, MeI, THF, 0 ◦C → rt, 16 h; (c) O3, CH2Cl2, −78 ◦C then PPh3,
rt, 16 h; (d) (+)-Ipc2BOMe, H2C CHCH2MgBr, Et2O, −78 → −20 ◦C
=
18 h, then H2O2, NaOH, H2O, reflux, 20 h; (e) TBSOTf, 2,6-lutidine,
CH2Cl2, −78 ◦C, 2 h; (f) LiDBB, THF, −78 ◦C, 1 h; (g) Dess–Martin
periodinane, CH2Cl2, 0 ◦C → rt, 1.5 h.
With the stereochemical assignment of spiroacetals 3 and 4
secure, we next focused our attention on procuring more useful
quantities of the desired isomer 3. Gratifyingly, acid-promoted
equilibration in a less polar, aprotic solvent mixture (CH2Cl2–
Et2O), under carefully-controlled conditions so as to avoid
competing decomposition, resulted in an equimolar mixture of
3 and 4. Although spiroacetals 3 and 4 were separable by HPLC,
purification was more readily achieved on up to a gram scale by
careful, gradient elution column chromatography. Through five
cycles of this equilibration–separation procedure, the desired
spiroacetal 3 was isolated in 69% yield.
l
was subjected to allylboration, this time with Ipc2BAll (92 :
8 dr). Protection of the resultant alcohol as the TBS ether
afforded 29 in 91% yield from 28. Debenzylation with lithium
4,4ꢀ-di(tert-butyl)biphenylide (LiDBB)21 and oxidation of the
resultant alcohol with the Dess–Martin periodinane provided
ketone 6 (88% yield from 29), ready for aldol coupling.
The synthesis of the C25–C28 aldehyde 7 began with the asym-
metric allylboration of 30 (Scheme 8), employing B-allylbis(2-
isocaranyl)borane (2-dIcr2BAll),22 providing homoallylic alcohol
1
31 in 75% yield with high enantiomeric excess (94% ee by H
Further elaboration of the desired TBS protected spiroacetal
33 to the fully functionalised C16–C28 CD-spiroacetal ketone 2
was readily achieved by oxidative cleavage of the alkene moiety
(cat. OsO4, NMO; NaIO4), addition of EtMgBr to the resultant
aldehyde and oxidation with the Dess–Martin periodinane (92%
yield from 33). This synthetic route to the CD-spiroacetal
subunit 2 of the spongipyrans proved robust and readily scalable,
affording multi-gram quantities of 2 in a single campaign.
NMR of the derived MTPA esters). Protection of 31 as the TES
ether and oxidative cleavage of the terminal alkene afforded
aldehyde 7. Treatment of methyl ketone 6 with (−)-Ipc2BCl and
Et3N resulted in regioselective formation of enol borinate 32,
which underwent facile aldol union with aldehyde 7 to give the
adduct 5 in 89% yield and with excellent diastereocontrol (≥97 :
3 dr). This pleasingly high level of diastereoselectivity results
from triple asymmetric induction,23 where the stereodirecting
Scheme 8 Reagents and conditions: (a) 2- Icr2BOMe, H2C CHCH2MgBr, Et2O, −78 ◦C, 4 h, then H2O2, NaOH, H2O, rt, 3 d; (b) TESOTf,
2,6-lutidine, CH2Cl2, −78 ◦C, 2 h; (c) cat. OsO4, NMO, acetone–H2O, rt, 3 d; (d) NaIO4, MeOH, pH 7 buffer, 0 ◦C → rt, 16 h; (e) (−)-Ipc2BCl,
Et3N, Et2O, −78 → 0 ◦C, 1 h; (f) 7, −78 → −20 ◦C, 16 h, then pH 7 buffer, H2O2, MeOH, 0 ◦C → rt, 1 h; (g) 40% aq. HF, MeCN, 0 ◦C, 50 min;
(h) cat. HCl, CH2Cl2, Et2O, rt, 30 min, separation and resubjection (x 5); (i) TBSOTf, 2,6-lutidine, CH2Cl2, −78 ◦C, 1 h; (j) Ac2O, DMAP, pyridine,
rt, 2 h; (k) cat. OsO4, NMO, acetone–H2O, rt, 20 h; (l) NaIO4, MeOH, pH 7 buffer, rt, 1 h; (m) EtMgBr, Et2O, −78 ◦C → rt, 2 h; (n) Dess–Martin
periodinane, CH2Cl2, rt, 1 h.
d
=
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 1 0 – 2 4 1 9
2 4 1 3

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analogous manner to the thermodynamic approach reported
above, via desilylation–spiroacetalisation (aq. HF, MeCN) to
give a ca. 5 : 1 mixture of the undesired and desired spiroacetals,
46 and 47, respectively. As before, treatment with anhydrous
HCl in CH2Cl2–Et2O afforded an equimolar mixture of the
two, separable, spiroacetals. Protection of 47 as the TBS ether
and oxidative cleavage of the alkene moiety (cat. OsO4, NMO;
NaIO4) provided the CD-spiroacetal subunit 2, having identical
spectroscopic properties to material produced by the previous
route.
Conclusions
Scheme 9 Reagents and conditions: (a) (+)-Ipc2BCl, Et3N, Et2O, −78 →
0 ◦C, 1 h; (b) 38, −78 → −20 ◦C, 17 h, then pH 7 buffer, H2O2, MeOH,
0 ◦C → rt, 1 h; (c) cat. SmI2, EtCHO, THF, −20 ◦C, 16 h.
The synthesis of the C16–C28 CD-spiroacetal of the
spongipyrans has been achieved by routes involving kinetic and
thermodynamic control over the spiroacetalisation process. The
thermodynamic control route proved the more practical and
useful of the two approaches, due to the readily separable nature
of the spiroacetal epimers 3 and 4, and the robust, reliable and
highly selective nature of the reactions utilised in this sequence.
The latter route provided gram quantities of 2 for the successful
completion of the total synthesis of altohyrtin A/spongistatin
1, as described in Parts 3 and 4 of this series.28
An alternative route to the CD-spiroacetal
An alternative synthetic strategy2g for building up the linear
CD-spiroacetal precursor arose from our desire to harness the
stereocentre derived from the biopolymer PHB and the new
options for stereocontrolled 1,3-polyol synthesis afforded by the
1,5-anti aldol reaction. This approach began with the boron-
mediated aldol reaction of ketone 37, readily available in four
steps from PHB, with aldehyde 38 (Scheme 9). Enolisation of
37 with (+)-Ipc2BCl and Et3N under standard conditions,24 gave
enol borinate 39 in situ, which underwent smooth aldol reaction
with aldehyde 38 (prepared from 3-ethyl-3-buten-1-ol25 by Dess–
Martin oxidation), to afford the desired 1,5-anti aldol product 40
in 51% yield, with high diastereoselectivity (91 : 9 dr). The sense
and extent of asymmetric induction in this aldol reaction was
Experimental
(4S,6R)-6-Benzyloxy-1-hepten-4-ol
A cooled (−78 ◦C) solution of (−)-Ipc2BOMe (22.8 g,
72.0 mmol, 1.5 eq.) in Et2O (200 mL) was treated with
allylmagnesium bromide (1.0 M in Et2O, 67.2 mL, 67.2 mmol,
1.4 eq.). The cooling bath was removed and the mixture left
to stir at rt for 1 h. The white suspension was re-cooled to
1
assessed by high field H NMR analysis of the derived MTPA
esters.7 With the desired C19 stereochemistry secured, 1,3-anti
selective reduction of the carbonyl group in 40 was required.
To this end, Evans–Tishchenko reduction26 using catalytic SmI2
and propionaldehyde provided monoacylated anti 1,3-diol 41 in
90% yield as the only diastereomer by 1H NMR (>97 : 3 dr).
Methylation of the C21 hydroxyl in 41,◦under mild conditions
◦
−78 C and a solution of (R)-3-benzyloxybutanal (26)29 (48.0
mmol) in Et2O (20 mL + 2 × 5 mL washings) was added
by cannula. The mixture was left to stir at −78 ◦C for 2 h
followed by 1 h at 0 ◦C. To the vigorously stirred mixture
was cautiously added a pre-mixed solution of 10% NaOH (30
mL) and 30% H2O2 (60 mL) by dropping funnel. The resultant
biphasic mixture was refluxed for 16 h. H2O (200 mL) was
added, the layers were separated and the aqueous phase was
extracted with Et2O (3 × 100 mL). The combined organic
extracts were washed with brine (50 mL), dried (MgSO4) and
the solvent removed in vacuo. The residue was purified by flash
chromatography (5 : 95 Et2O–CH2Cl2) to give a colourless oil
(32 g), consisting of the homoallylic alcohol and IpcOH, which
was used directly in the next reaction. In other experiments,
repeated flash chromatography (5 : 95 Et2O–CH2Cl2) gave the
R
(Me3OBF4, Proton-Spongeꢀ, CH2Cl2, 0 C),27 was followed by
a protecting group swap at the C19 oxygen, to give TBS ether
42 (Scheme 10). Debenzylation and oxidation with the Dess–
Martin periodinane provided ketone 43 (96% yield from 42),
homologous with 6.
Conversion of ketone 43 into enol borinate 44, and subsequent
aldol reaction with aldehyde 7, provided 45 in 78% yield and
with similarly high diastereoselectivity (≥97 : 3 dr), as for the
previously-exploited case using ketone 6. The remainder of this
alternative synthesis of the CD-spiroacetal proceeded in an
Scheme 10 Reagents and conditions: (a) Me3OBF4, Proton-SpongeꢀR , CH2Cl2, 0 ◦C, 3 h; (b) K2CO3, MeOH, rt, 16 h; (c) TBSCl, Im., DMF, rt, 16 h;
(d) LiDBB, THF, −78 ◦C, 1 h; (e) Dess–Martin periodinane, pyridine, CH2Cl2, rt, 40 min; (f) (−)-Ipc2BCl, Et3N, Et2O, −78 → 0 ◦C, 1 h; (g) 7,
−78 → −20 ◦C, 16 h, then pH 7 buffer, H2O2, MeOH, 0 ◦C → rt, 1 h; (h) 40% aq. HF, MeCN, 0 ◦C, 40 min; (i) cat. HCl, CH2Cl2, Et2O, rt, 30 min;
(j) TBSOTf, 2,6-lutidine, CH2Cl2, −78 ◦C, 1 h; (k) cat. OsO4, NMO, acetone–H2O, rt, 6 h; (l) NaIO4, MeOH, pH 7 buffer, rt, 1 h.
2 4 1 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 1 0 – 2 4 1 9

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title compound, sufficiently pure for characterisation purposes.
characterisation purposes, by repeated flash chromatography
(30 : 70 EtOAc–hexanes). Major diastereomer: Rf: 0.32 (30 :
70 EtOAc–hexanes); [a]D20 −40.5 (c 2.19, CHCl3); IR (liquid
Major diastereomer: Rf: 0.30 (5 : 95 Et2O–CH2Cl2); [a]2D0 −55.8
1
(c 1.56, CHCl3); IR (liquid film): 3443 (br, s), 1641 cm−1; H
1
NMR: d (500 MHz, CDCl3) 7.26–7.36 (5H, m, Ph), 5.83 (1H,
film): 3389 (br, s), 1641, 1603 cm−1; H NMR: d (500 MHz,
=
m, 19-CH), 5.09 (1H, dd, J = 18.8, 1.6 Hz, trans-CH CHaHb),
CDCl3) 7.25–7.37 (5H, m, Ph), 5.80 (1H, m, 17-CH), 5.10 (1H,
=
=
5.08 (1H, dd, J = 9.3, 0.8 Hz, cis-CH CHaHb), 4.67 (1H, d, J =
d, J = 18.6 Hz, trans-CH CHaHb), 5.08 (1H, d, J = 8.6 Hz,
=
11.4 Hz, OCHaHbPh), 4.44 (1H, d, J = 11.4 Hz, OCHaHbPh),
3.78–3.89 (2H, m, 21-CH + 23-CH), 3.63 (1H, br s, OH), 2.21
(2H, m, 20-CH2), 1.68 (1H, app dt, J = 14.6, 9.5 Hz, 22-CHaHb),
1.61 (1H, app dt, J = 14.6, 3.1 Hz, 22-CHaHb), 1.25 (3H, d,
J = 6.0 Hz, 24-CH3); 13C NMR: d (62.9 MHz, CDCl3) 138.1,
135.0, 128.5, 127.81, 127.77, 117.3, 75.8, 70.9, 70.3, 43.2, 42.1,
19.7; HRMS: (+CI, NH3) Calc. for C14H21O2 [MH]+: 221.1542,
found: 221.1541; m/z: (+CI, NH3) 221 ([MH]+, 100), 179 (7),
130 (68), 108 (100), 106 (69), 91 (57).
cis-CH CHaHb), 4.57 (1H, d, J = 11.7 Hz, OCHaHbPh), 4.41
(1H, d, J = 11.7 Hz, OCHaHbPh), 3.91 (1H, m, 19-CH), 3.68
(1H, m, 23-CH), 3.59 (1H, m, 21-CH), 3.34 (3H, s, OCH3), 2.89
(1H, d, J = 3.2 Hz, OH), 2.19 (2H, m, 18-CH2), 2.04 (1H, m,
20-CHaHb), 1.67 (1H, m, 20-CHaHb), 1.53 (2H, m, 22-CH2),
1.24 (3H, d, J = 6.1 Hz, 24-CH3); 13C NMR: d (100.6 MHz,
CDCl3) 138.7, 134.9, 128.4, 127.8, 127.5, 117.4, 76.5, 71.8, 70.3,
68.0, 56.0, 42.2, 40.2, 38.9, 19.9; HRMS: (+CI, NH3) Calc. for
C17H27O3 [MH]+: 279.1960, found: 279.1960; m/z: (+CI, NH3)
279 ([MH]+, 100), 254 (14), 222 (23), 171 (12), 114 (30), 108 (13),
106 (11), 97 (40).
(4S,6R)-6-Benzyloxy-4-methoxy-1-heptene (27)
NaH (60% in mineral oil, 15.4 g, 0.385 mol) was washed with
n-hexane (3 × 50 mL) and suspended in THF (200 mL). The
suspension was cooled to 0 ◦C and a solution of (4S,6R)-6-
benzyloxy-1-hepten-4-ol (from above procedure, ca. 48.0 mmol)
in THF (30 mL + 2 × 10 mL washings) was added via cannula.
After stirring for 10 min at 0 ◦C, MeI (21.5 mL, 0.346 mol) was
added and the mixture left to warm slowly to rt overnight. The
reaction was quenched by the cautious addition of MeOH (100
mL) at 0 ◦C followed by H2O (150 mL) and Et2O (100 mL).
The layers were separated and the aqueous phase was extracted
with Et2O (3 × 50 mL). The combined organic extracts were
washed with 10% Na2S2O3 (150 mL) then brine (100 mL), dried
over MgSO4 and the solvent removed in vacuo. Purification of
the crude product by flash chromatography (80 : 20 CH2Cl2–
hexanes) removed the IpcOMe. Further flash chromatography
(2 : 78 : 20 Et2O–CH2Cl2–hexanes) allowed separation of the
diastereomeric methyl ethers, providing the undesired 21-epi-27
(0.45 g, 4%) and desired methyl ether 27 (7.10 g, 63% from 26):
Rf: 0.45 (5 : 95 Et2O–CH2Cl2); [a]2D0 −6.3 (c 2.24, CHCl3); IR
(4R,6R,8R)-8-Benzyloxy-4-(t-butyldimethylsiloxy)-6-methoxy-
1-nonene (29)
A cooled (−78 ◦C) solution of the alcohol from the above pro-
cedure (2.05 g, 7.36 mmol), in CH2Cl2 (60 mL) was treated with
2,6-lutidine (2.6 mL, 22.5 mmol, 3.0 eq.) followed by TBSOTf
◦
(3.4 mL, 14.8 mmol, 2.0 eq.). After stirring at −78 C for 2 h
the reaction was quenched by the addition of sat. NaHCO3 (20
mL) and warmed to rt. The mixture was concentrated in vacuo
and Et2O (20 mL) was added. The layers were separated and
the aqueous phase was extracted with Et2O (3 × 10 mL). The
combined organic extracts were washed with brine (10 mL),
dried (MgSO4) and concentrated in vacuo. The crude material
was purified by flash chromatography (8 : 92 EtOAc–hexanes)
to yield silyl ether 29 (2.36 g, 91% over 2 steps from 28) as
a colourless oil. Major diastereomer: Rf: 0.36 (10 : 90 EtOAc–
hexanes); [a]2D0 −46.1 (c 1.39, CHCl3); IR (liquid film): 1640 cm−1;
1H NMR: d (500 MHz, CDCl3) 7.25–7.36 (5H, m, Ph), 5.81 (1H,
=
m, 17-CH), 5.03 (1H, d, J = 15.2 Hz, trans-CH CHaHb), 5.03
1
(liquid film): 1640 cm−1; H NMR: d (500 MHz, CDCl3) 7.25–
(1H, d, J = 12.2 Hz, cis-CH CHaHb), 4.56 (1H, d, J = 11.7 Hz,
=
7.35 (5H, m, Ph), 5.81 (1H, m, 19-CH), 5.06 (2H, app d, J =
OCHaHbPh), 4.45 (1H, d, J = 11.7 Hz, OCHaHbPh), 3.96 (1H,
m, 19-CH), 3.60 (1H, m, 23-CH), 3.57 (1H, m, 21-CH), 3.29
(3H, s, OCH3), 2.23 (2H, m, 18-CH2), 2.00 (1H, ddd, J = 14.1,
7.5, 5.3 Hz, 20-CHaHb), 1.49–1.60 (2H, m, 22-CH2), 1.43 (1H,
ddd, J = 14.1, 7.0, 5.2 Hz, 20-CHaHb), 1.21 (3H, d, J = 6.0 Hz,
24-CH3), 0.88 (9H, s, SiC(CH3)3), 0.08 (3H, s, Si(CH3)a), 0.07
(3H, s, Si(CH3)b); 13C NMR: d (100.6 MHz, CDCl3) 138.9, 134.7,
128.3, 127.6, 127.3, 117.0, 74.4, 71.9, 70.3, 68.4, 55.5, 42.7, 41.9,
40.8, 25.9, 20.0, 18.1, −4.1, −4.6; HRMS: (+CI, NH3) Calc. for
C23H41O3Si [MH]+: 393.2825, found: 393.2825; m/z: (+CI, NH3)
393 ([MH]+, 100), 263 (16), 261 (11), 229 (19), 132 (24), 108 (50),
106 (67), 91 (32).
=
13.4 Hz, CH CH2), 4.57 (1H, d, J = 11.7 Hz, OCHaHbPh),
4.44 (1H, d, J = 11.7 Hz, OCHaHbPh), 3.66 (1H, m, 23-CH),
3.38 (1H, m, 21-CH), 3.33 (3H, s, OCH3), 2.26 (2H, m, 20-CH2),
1.93 (1H, app dt, J = 14.1, 6.7 Hz, 22-CHaHb), 1.53 (1H, app dt,
14.1, 6.2 Hz, 22-CHaHb), 1.23 (3H, d, J = 6.1 Hz, 24-CH3); 13
C
NMR: d (62.9 MHz, CDCl3) 139.0, 134.6, 128.3, 127.7, 127.4,
117.1, 77.5, 72.1, 70.3, 56.4, 40.6, 37.7, 19.7; HRMS: (+CI,
NH3) Calc. for C15H23O2 [MH]+: 235.1698, found: 235.1698;
m/z: (+CI, NH3) 235 ([MH]+, 100), 203 (8), 108 (22), 106 (11),
91 (16).
(4R,6S,8R)-8-Benzyloxy-6-methoxy-1-nonen-4-ol
(2R,4R,6R)-6-(t-Butyldimethylsiloxy)-4-methoxy-8-nonen-2-ol
Acooled(−78 ◦C) solution of (+)-Ipc2BOMe (4.10g, 13.0 mmol,
1.9 eq.) in Et2O (80 mL) was treated with allylmagnesium
bromide (1.0 M in Et2O, 11.5 mL, 11.5 mmol, 1.7 eq.). The
cooling bath was removed and the mixture left to stir at rt
for 1 h. The white suspension was re-cooled to −78 ◦C and
a solution of aldehyde 28 (1.64 g, 6.94 mmol) in Et2O (10 mL +
2 × 5 mL washings) was added by cannula. The mixture was left
to stir at −78 ◦C for 2 h followed by 16 h at −20 ◦C. A solution
of 10% NaOH (10 mL) and 30% H2O2 (20 mL) was added to
To a solution of benzyl◦ether 29 (6.58 g, 16.8 mmol) in degassed
THF (30 mL) at −78 C was added LiDBB21 (0.5 M, 80 mL,
40 mmol, 2.4 eq.) via cannula. The reaction was monitored by
TLC to ensure complete consumption of starting material. After
1 h, the reaction was quenched by the addition of sat. NaHCO3
(50 mL) and warmed to rt. H2O (20 mL) and Et2O (50 mL)
were added, the layers were separated and the aqueous phase
was extracted with Et2O (3 × 30 mL). The combined organic
extracts were washed with brine (30 mL), dried (MgSO4) and
concentrated in vacuo. The crude material was purified by flash
chromatography (5 : 95 → 25 : 75 EtOAc–hexanes) to afford the
title compound (4.83 g, 95%), as a colourless oil: Rf: 0.35 (30 : 70
EtOAc–hexanes); [a]2D0 −12.8 (c 2.30, CHCl3); IR (liquid film):
3442 (br, s), 1641 cm−1; 1H NMR: d (500 MHz, CDCl3) 5.81 (1H,
◦
the stirred solution at 0 C and the resultant biphasic mixture
refluxed for 20 h. H2O (20 mL) was added, the layers were
separated and the aqueous phase was extracted with Et2O (3 ×
20 mL). The combined organic extracts were washed with brine
(15 mL), dried (MgSO4) and concentrated in vacuo. The crude
product was purified by flash chromatography (30 : 70 EtOAc–
hexanes) to produce the title compound (2.15 g, contaminated
with IpcOH) as a colourless oil, used without further purification
in the next reaction. A small portion was further purified, for
=
m, 17-CH), 5.07 (1H, d, J = 15.9 Hz, cis-CH CHaHb), 5.06 (1H,
=
d, J = 11.5 Hz, trans-CH CHaHb), 3.95 (1H, m, 23-CH), 3.85
(1H, m, 19-CH), 3.53 (1H, m, 21-CH), 3.33 (3H, s, OCH3), 3.12
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 1 0 – 2 4 1 9
2 4 1 5

View Article Online
(1H, s, OH), 2.23 (2H, m, 18-CH2), 1.77 (1H, ddd, J = 14.3,
8.4, 6.0 Hz, 20-CHaHb), 1.65 (1H, app dt, J = 15.5, 8.8 Hz,
22-CHaHb), 1.56 (1H, m, 22-CHaHb), 1.50 (1H, ddd, J = 14.3,
8.0, 6.0 Hz, 20-CHaHb), 1.18 (3H, d, J = 6.2 Hz, 24-CH3), 0.89
(9H, s, SiC(CH3)3), 0.08 (3H, s, Si(CH3)a), 0.07 (3H, s, Si(CH3)b);
13C NMR: d (100.6 MHz, CDCl3) 134.4, 117.3, 78.6, 69.2, 67.3,
55.5, 43.2, 42.4, 41.1, 25.9, 23.7, 18.0, −4.2, −4.6; HRMS: (+CI,
NH3) Calc. for C16H35O3Si [MH]+: 303.2355, found: 303.2355;
m/z: (+CI, NH3) 303 ([MH]+, 100), 187 (11), 171 (13), 139 (19),
132 (25), 92 (13).
(2R,4S,8S,10R)-10-(t-Butyldimethylsiloxy)-4-hydroxy-8-
methoxy-1-(p-methoxybenzyloxy)-2-(triethylsiloxy)-12-
tridecen-6-one (5)
A two-necked flask containing (−)-Ipc2BCl (1.48 g, 4.62 mmol,
1.3 eq.) was placed under vacuum for 1 h to remove any traces
of HCl. The flask was charged with argon and Et2O (20 mL) was
added. The solution was cooled to −78 ◦C and Et3N (0.743 mL,
5.33 mmol, 1.5 eq.) was added, followed by a solution of ketone
6 (1.07 g, 3.55 mmol) in Et2O (10 mL + 2 × 5 mL washings) via
cannula. The reaction mixture was allowed to warm to 0 ◦C and
stirred for a further 1 h. The reaction mixture was then cooled
to −78 ◦C before a solution of aldehyde 7 (1.36 g, 4.01 mol, 1.13
eq.) in Et2O (10 mL + 2 × 5 mL washings) was added via cannula.
The reaction was stirred at −78 ◦C for a further 30 min then at
−20 ◦C for 16 h. The reaction was quenched by the addition of
pH 7 buffer (20 mL), MeOH (20 mL) and 30% H2O2 (10 mL) at
(4S,6R)-6-(t-Butyldimethylsiloxy)-4-methoxy-8-nonen-2-one (6)
To a solution of the alcohol from the above procedure (4.50 g,
14.9 mmol) in CH2Cl2 (250 mL) at 0 ◦C was added Dess–Martin
periodinane (7.60 g, 17.9 mmol, 1.2 eq.). The white suspension
was warmed to rt and stirred, open to the atmosphere, for 90 min.
The reaction was quenched by the addition of sat. NaHCO3
(100 mL) followed by 10% Na2S2O3 (100 mL) and the biphasic
mixture allowed to stir vigorously for 1 h. The CH2Cl2 was
removed in vacuo, Et2O (100 mL) was added, the layers were
separated and the aqueous phase was extracted with Et2O (3 × 50
mL). The combined organic extracts were washed with brine (30
mL), dried (MgSO4) and concentrated in vacuo. Purification by
flash chromatography (20 : 80 EtOAc–hexanes) afforded ketone
6 (4.15 g, 93%) as a colourless oil. Major diastereomer: Rf: 0.44
(30 : 70 EtOAc–hexanes); [a]2D0 −34.1 (c 1.40, CHCl3); IR (liquid
film): 1715 (s), 1640 cm−1; 1H NMR: d (500 MHz, CDCl3) 5.79
◦
0 C and allowed to warm to rt and stirred vigorously for 1 h.
The reaction mixture was diluted with water (50 mL) and CH2Cl2
(50 mL). The layers were separated and the aqueous phase was
extracted with CH2Cl2 (3 × 50 mL), combined organics were
washed with brine (50 mL), dried (MgSO4) and concentrated in
vacuo. Flash chromatography (1 : 99 → 10 : 90 Et2O–CH2Cl2)
afforded aldol product 5 (2.01 g, 89%) as colourless oil: Rf: 0.35
(30 : 70 EtOAc–hexanes); [a]2D0 −7.0 (c 0.90, CHCl3); IR (liquid
film):3676 (br), 1734(s), 1639, 1612cm−1; 1H NMR:d (500 MHz,
CDCl3) 7.24 (2H, d, J = 8.6 Hz, ArH), 6.87 (2H, d, J = 8.6 Hz,
ArH), 5.80 (1H, m, 17-CH), 5.03 (1H, d, J = 15.2 Hz, trans-
=
=
CH CHaHb), 5.03 (1H, d, J = 12.1 Hz, cis-CH CHaHb), 4.44
(2H, ab q, J = 12.1 Hz, CH2Ar), 4.23 (1H, m, 25-CH), 4.08
(1H, br dq, J = 7.2, 5.3 Hz, 27-CH), 3.88 (1H, m, 19-CH),
3.84 (1H, m, 21-CH), 3.80 (3H, s, ArOCH3), 3.51 (1H, d, J =
2.1 Hz, OH), 3.40 (1H, dd, J = 9.7, 5.2 Hz, 28-CHaHb), 3.36
(1H, dd, J = 9.7, 5.2 Hz, 28-CHaHb), 3.29 (3H, s, OCH3), 2.70
(1H, dd, J = 15.8, 6.5 Hz, 22-CHaHb), 2.60 (1H, dd, J = 16.7,
7.9 Hz, 24-CHaHb), 2.52 (1H, dd, J = 16.7, 4.3 Hz, 24-CHaHb),
2.49 (1H, dd, J = 15.8, 5.5 Hz, 22-CHaHb), 2.22 (2H, br t, J =
6.1 Hz, 18-CH2), 1.60–1.72 (3H, m, 26-CH2 + 20-CHaHb), 1.42
(1H, ddd, J = 14.2, 8.7, 4.0 Hz, 20-CHaHb), 0.94 (9H, t, J =
8.0 Hz, Si(CH2CH3)3), 0.89 (9H, s, SiC(CH3)3), 0.61 (6H, q,
J = 8.0 Hz, Si(CH2CH3)3), 0.08 (6H, s, Si(CH3)2); 13C NMR:
d (100.6 MHz, CDCl3) 209.0, 159.0, 134.5, 130.0, 129.3, 117.2,
113.8, 76.5, 74.2, 73.9, 73.0, 70.6, 68.6, 66.0, 56.5, 55.3, 50.9,
48.5, 42.5, 41.9, 41.1, 25.9, 18.0, 5.0, −4.1, −4.6; HRMS: (+CI,
NH3) Calc. for C34H63O7Si2 [MH]+: 639.4112, found: 639.4110;
m/z: (+CI, NH3) 639 ([MH]+, 10), 356 (100), 353 (60), 318 (68).
=
(1H, m, 17-CH), 5.03 (2H, app d, 13.3 Hz, CH CH2), 3.92 (1H,
m, 19-CH), 3.83 (1H, m, 21-CH), 3.30 (3H, s, OCH3), 2.70 (1H,
dd, J = 15.6, 6.4 Hz, 22-CHaHb), 2.49 (1H, dd, J = 15.6, 5.8 Hz,
22-CHaHb), 2.24 (2H, br t, J = 6.2 Hz, 18-CH2), 2.16 (3H, s, 24-
CH3), 1.65 (1H, ddd, J = 14.2, 8.6, 3.3 Hz, 20-CHaHb), 1.43 (1H,
ddd, J = 14.2, 8.8, 3.9 Hz, 20-CHaHb), 0.90 (9H, s, SiC(CH3)3),
0.08 (6H, s, Si(CH3)2); 13C NMR: d (100.6 MHz, CDCl3) 207.2,
134.4, 117.2, 74.0, 68.6, 56.3, 48.5, 42.6, 41.9, 30.8, 25.9, 18.0,
−4.1, −4.7; HRMS: (+CI, NH3) Calc. for C16H33O3Si [MH]+:
301.2199, found: 301.2199; m/z: (+CI, NH3) 301 ([MH]+, 100),
169 (37), 154 (34), 138 (40), 137 (40), 121 (100), 52 (80).
(R)-1-(p-Methoxybenzyloxy)-4-penten-2-ol (31)
◦
To a cold (−78 C), stirred solution of 2-dIcr2BOMe22 (3.0 g,
9.48 mmol, 1.7 eq.) in dry Et2O (20 mL) was added, dropwise,
allylmagnesium bromide (1.0 M solution in Et2O, 8.3 mL,
8.30 mmol, 1.5 eq.). The solution was stirred at −78 ◦C for
15 min and then warmed to rt for 75 min. The resultant white
suspension was cooled to −78 ◦C and a solution of the aldehyde
30 (1.0 g, 5.55 mmol, 1.0 eq.) in dry Et2O (2 mL + 2 × 2 mL
washings) was added via cannula. The mixture was stirred at
−78 ◦C for 4 h and then quenched with 3 M aqueous NaOH (8
mL) and 30% aqueous H2O2 (11 mL). The biphasic solution was
stirred at rt for 3 d (reflux conditions were avoided to suppress
the decomposition of the PMB–ether functionality). The layers
were then separated and the aqueous phase extracted with Et2O
(3 × 100 mL). The combined organic extracts were washed with
brine (50 mL), dried (MgSO4) and concentrated in vacuo. The
crude oil thus obtained was flash chromatographed (20 : 80
EtOAc–hexanes) to provide the homoallylic alcohol 31 (928 mg,
75%), as a colourless oil: Rf: 0.35 (30 : 70 EtOAc–hexanes); [a]D20
−3.0 (c 2.06, CHCl3); IR (liquid film): 3443 (br, s), 1641, 1612,
(2R,4S,6R,8R,10S)- and (2R,4S,6S,8R,10S)-8-Allyl-10-
methoxy-2-(p-methoxybenzyloxymethyl)-1,7-
dioxaspiro[5.5]undecan-4-ol (4 and 3)
To a cold (0 ◦C) solution of ketone 5 (2.01 g, 3.15 mmol) in
MeCN (50 mL) was added HF (40% aq., 12.0 mL). The reaction
mixture was stirred at 0 ◦C for 50 min then cautiously quenched
with sat. aq. NaHCO3 (200 mL). EtOAc (100 mL) was added and
the layers were separated. The aqueous phase was extracted with
EtOAc (3 × 50 mL) and combined organics were washed with
brine (50 mL), dried (MgSO4) and concentrated in vacuo. Flash
chromatography (50 : 50 → 80 : 20 EtOAc–light petroleum)
afforded spiroacetals 3 and 4 (1.13 g, 92%) as a 1 : 5 mixture,
respectively.
Minor spiroacetal (desired) 3: Rf: 0.49 (5 : 95 MeOH–CH2Cl2);
HPLC: Rt 35 min (65 : 35 EtOAc–hexane); [a]2D0 −37.4 (c 0.70,
CHCl3); IR (liquid film): 3525 (br, s), 3053, 1612, 1513 cm−1; 1H
NMR: d (500 MHz, CDCl3) 7.27 (2H, d, J = 8.6 Hz, ArH), 6.89
(2H, d, J = 8.6 Hz, ArH), 5.83 (1H, m, 17-CH), 5.17 (1H, d,
1
1513 cm−1; H NMR: d (500 MHz, CDCl3) 7.26 (2H, d, J =
8.5 Hz, ArH), 6.89 (2H, d, J = 8.5 Hz, ArH), 5.78–5.86 (1H,
=
m, 25-CH), 5.08–5.13 (2H, m, C CH2), 4.49 (2H, s, OCH2Ar),
3.83–3.89 (1H, m, 27-CH), 3.81 (3H, s, OCH3), 3.49 (1H, dd,
J = 9.3, 3.3 Hz, 28-CHaHb), 3.35 (1H, dd, J = 9.3, 7.6 Hz, 28-
CHaHb), 2.31 (1H, d, J = 3.1 Hz, OH), 2.25 (2H, t, J = 6.6 Hz,
26-CH2); 13C NMR: d (62.9 MHz, CDCl3) 159.3, 134.3, 130.1,
129.4, 117.6, 113.9, 73.6, 73.0, 69.7, 55.3, 37.2; HRMS: (+CI,
NH3) Calc. for C13H19O3 [MH]+: 223.1334, found: 223.1334.
=
J = 18.0 Hz, trans-CH CHaHb), 5.14 (1H, d, J = 10.9 Hz, cis-
=
CH CHaHb), 4.53 (2H, s, OCH2Ar), 4.43 (1H, m, 27-CH), 4.07
(1H, app dt, J = 8.3, 3.0 Hz, 25-CH), 3.81 (3H, s, ArOCH3), 3.65
(1H, m, 19-CH), 3.50 (2H, m, 28-CH2), 3.45 (1H, m, 21-CH),
3.33 (3H, s, OCH3), 2.36 (1H, m, 18-CHaHb), 2.25–2.32 (2H, m,
2 4 1 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 1 0 – 2 4 1 9

View Article Online
18-CHaHb + 24-CHeq), 2.10 (1H, app dd, J = 12.2, 4.4 Hz, 22-
CHeq), 2.05 (1H, app dt, J = 12.4, 2.0 Hz, 20-CHeq), 1.77 (1H,
dd, J = 13.7, 2.0 Hz, 26-CHeq), 1.66 (1H, dt, J = 13.7, 2.8 Hz,
26-CHax), 1.41–1.48 (2H, m, 22-CHax + 24-CHax), 1.27 (1H, br
q, J = 11.8 Hz, 26-CHax); 13C NMR: d (100.6 MHz, CDCl3)
159.1, 134.0, 130.3, 129.3, 118.8, 113.7, 99.8, 73.6, 72.9, 72.5,
71.0, 64.9, 64.7, 55.5, 55.2, 42.6, 40.6, 36.9, 34.4, 34.1; HRMS:
(+CI, NH3) Calc. for C22H36NO6 [M + NH4]+: 410.2543, found:
410.2543; m/z: (+CI, NH3) 410 ([M + NH4]+, 57), 393 ([MH]+,
5), 378 (12), 361 (30), 343 (26), 154 (32), 138 (50), 121 (100).
Major spiroacetal (undesired) 4: Rf: 0.16 (5 : 95 MeOH–
CH2Cl2); HPLC: Rt 45 min (65 : 35 EtOAc–hexane); [a]2D0 +41.3
(c 0.90, CHCl3); IR (liquid film): 3425 (br, s), 3073, 1641, 1612,
from 33) as a colourless oil: Rf: 0.39 (40 : 60 EtOAc–hexanes);
[a]2D0 −8.2 (c 0.80, CHCl3); IR (liquid film): 1724 (C O), 1612,
=
1
1586, 1513 cm−1; H NMR: d (500 MHz, CDCl3) 9.83 (1H, t,
J = 1.8 Hz, 17-CHO), 7.25 (2H, d, J = 8.5 Hz, ArH), 6.86
(2H, d, J = 8.5 Hz, ArH), 4.50–4.53 (3H, m, OCH2Ar + 27-
CH), 4.15 (1H, m, 25-CH), 4.01 (1H, m, 19-CH), 3.80 (3H, s,
ArOCH3), 3.45–3.51 (3H, m, 28-CH2 and 21-CH), 3.32 (3H, s,
OCH3), 2.74 (1H, ddd, J = 17.1, 6.3, 1,7 Hz, 18-CHaHb), 2.60
(1H, ddd, J = 17.1, 6.5, 1.7 Hz, 18-CHaHb), 2.03–2.20 (3H, m,
20-CHeq + 24-CHeq + 22-CHeq), 1.68 (1H, td, J = 11.4, 3.4 Hz,
26-CHax), 1.59 (1H, m 26-CHeq), 1.51 (1H, dd, J = 14.6, 3.9 Hz,
24-CHax), 1.36 (1H, t, J = 11.9 Hz, 22-CHax), 1.04 (1H, m,
20-CHax), 0.85 (9H, s, SiC(CH3)3), 0.03 (3H, s, Si(CH3)a), 0.01
(3H, s, Si(CH3)b); 13C NMR: d (100.6 MHz, CDCl3) 201.4, 159.1,
130.5, 129.2, 113.7, 98.4, 73.7, 72.9, 72.6, 65.9, 64.9, 64.5, 55.5,
55.2, 49.8, 43.2, 37.2, 35.3, 35.0, 26.0, 18.4, −4.7, −5.0; HRMS:
(+FAB) Calc. for C27H44O7NaSi [M + Na]+: 531.2754, found:
531.2726; m/z: (+FAB) 531 ([M + Na]+, 100), 387 (25), 241 (60),
201 (60).
1
1586, 1513 cm−1; H NMR: d (500 MHz, CDCl3) 7.25 (2H, d,
J = 8.5 Hz, ArH), 6.88 (2H, d, J = 8.5 Hz, ArH), 5.76 (1H, m,
=
17-CH), 5.07 (1H, dd, J = 17.5, 1.4 Hz, trans-CH CHaHb), 5.03
=
(1H, d, J = 9.8 Hz, cis-CH CHaHb), 4.50 (1H, d, J = 11.6 Hz,
OCHaHbAr), 4.43 (1H, d, J = 11.6 Hz, OCHaHbAr), 4.17–4.22
(2H, m, 25-CH + 27-CH), 3.85 (1H, m, 19-CH), 3.81 (3H, s,
ArOCH3), 3.63 (1H, m, 21-CH), 3.58 (1H, dd, J = 9.7, 6.2 Hz,
28-CHaHb), 3.51 (1H, dd, J = 9.7, 4.0 Hz, 28-CHaHb), 3.32
(3H, s, OCH3), 2.32 (1H, ddd, J = 12.7, 4.5, 1.9 Hz, 22-CHeq),
2.26 (1H, m, 18-CHaHb), 2.18 (1H, m, 18-CHaHb), 2.00–2.07
(3H, m, 20-CHeq + 24-CHeq 26-CHeq), 1.57 (1H, dt, J = 8.1,
3.7 Hz, 26-CHax), 1.52 (1H, app dd, J = 13.0, 9.3 Hz, 24-CHax),
1.21 (1H, br t, J = 12.0 Hz, 22-CHax), 1.03 (1H, br q, J = 11.7 Hz,
20-CHax); 13C NMR: d (100.6 MHz, CDCl3) 159.1, 134.4, 130.1,
129.2, 117.2, 113.7, 99.8, 72.7, 72.6, 71.7, 71.4, 68.5, 61.5, 55.4,
55.2, 44.8, 41.5, 40.5, 36.5, 34.7; HRMS: (+CI, NH3) Calc. for
C22H33O6 [MH]+: 393.2277, found: 393.2277; m/z: (+CI, NH3)
410 ([M + NH4]+, 28), 393 ([MH]+, 7), 378 (20), 361 (40), 343
(26), 154 (24), 138 (50) 121 (100).
(2R,4S,6R,8R,10S)-1-[10-(t-Butyldimethylsiloxy)-4-methoxy-8-
(p-methoxybenzyloxymethyl)-1,7-dioxaspiro[5.5]undec-2-yl]-
butan-2-one (2)
To a cold (−78 ◦C) solution of the aldehyde from the above
procedure (1.56 g, 3.07 mmol), in Et2O (40 mL) was added
EtMgBr (2.0 M in THF, 3.07 mL, 6.13 mmol, 2.0 eq.). The
reaction mixture was warmed to rt and stirred for 2 h then
cooled to −78 ◦C before being quenched by addition of sat.
aq. NH4Cl (30 mL). The layers were separated and the aqueous
phase was extracted with Et2O (3 × 50 mL). The combined
organics were washed with brine (50 mL), dried (Na2SO4) and
concentrated in vacuo. The crude alcohol was taken up in CH2Cl2
(30 mL) and Dess–Martin periodinane (2.60 g, 6.13 mmol, 2.0
eq.) was added. The reaction mixture was stirred at rt for 1 h
and quenched by pouring into a sat. aq. Na2S2O3–NaHCO3
solution (1 : 1, 50 mL). The biphasic mixture was stirred for a
further 15 min and the layers were separated. The aqueous phase
was extracted with Et2O (3 × 60 mL), combined organics were
washed with brine (50 mL), dried (Na2SO4) and concentrated
in vacuo. Flash chromatography (5 : 95 → 50 : 50 EtOAc–light
petroleum) afforded CD-spiroacetal ethyl ketone 2 (1.53 g, 93%
over 2 steps) as a white crystalline solid: Rf: 0.45 (40 : 60 EtOAc–
hexanes); [a]2D0 −20.3 (c 1.00, CHCl3); mp 47–49 ◦C; IR (liquid
Equilibration of the CD-spiroacetals (4 and 3)
To a mixture of spiroacetals 4 and 3 (1.69 g, 4.31 mmol) in
CH2Cl2 (35 mL) was added anhydrous HCl (1.0 M in Et2O,
0.216 mL, 0.216 mmol, 0.05 eq.). The reaction mixture was
stirred at rt for 30 min then Et3N (0.06 mL, 0.43 mmol) was
added to neutralise the HCl. The mixture was concentrated
in vacuo and flash chromatography (1.25 : 98.75 → 2.5 : 97.5
MeOH–CH2Cl2) allowed the separation of desired spiroacetal 3
and undesired spiroacetal 4. The undesired spiroacetal 4 was re-
subjected to the above conditions and after 5 cycles the desired
spiroacetal 3 (1.17 g, 69%) was obtained as a colourless oil.
1
film): 1713 (s), 1612, 1586, 1513 cm−1; H NMR: d (500 MHz,
CDCl3) 7.25 (2H, d, J = 8.5 Hz, ArH), 6.86 (2H, d, J = 8.5 Hz,
ArH), 4.51–4.52 (3H, m, OCH2Ar + 28-CH), 4.11 (1H, m, 25-
CH), 3.93 (1H, m, 19-CH), 3.80 (3H, s, ArOCH3), 3.45–3.51
(3H, m, 27-CH2 + 21-CH), 3.32 (3H, s, OCH3), 2.84 (1H, dd,
J = 17.1, 3.7 Hz, 18-CHaHb), 2.66 (1H, dd, J = 17.1, 8.9 Hz,
18-CHaHb), 2.40 (2H, q, J = 7.3 Hz, 16-CH2), 2.21 (1H, m,
20-CHeq), 2.13 (1H, dd, J = 14.3, 3.4 Hz, 24-CHaHb), 2.03
(1H, dd, J = 11.5, 3.8 Hz, 22-CHeq), 1.68 (1H, td, J = 13.7,
3.6 Hz, 26-CHax), 1.59 (1H, m, 26-CHeq), 1.50 (1H, dd, J =
14.3, 3.7 Hz, 24-CHax), 1.36 (1H, t, J = 11.9 Hz, 22-CHax), 1.04
(1H, m, 20-CHax), 1.01 (3H, t, J = 7.3 Hz, CH2CH3), 0.85 (9H,
(2R,4S,6R,8R,10S)-[10-(t-Butyldimethylsiloxy)-4-methoxy-8-
(p-methoxybenzyloxymethyl)-1,7-dioxaspiro[5.5]undecan-2-yl]-
ethanal
A solution of alkene 33 (880 mg, 1.74 mmol) in 2.5 : 1 acetone
(10 mL) and H2O (4 mL) was treated with NMO (347 mg,
2.96 mmol, 1.7 eq.) and OsO4 (0.1 M in t-BuOH, 0.87 mL,
0.087 mmol, 5 mol%) and the resultant mixture stirred at rt for
20 h. The remaining oxidant was quenched by the addition of
10% Na2S2O3 (10 mL) and the mixture stirred for 40 min before
the addition of Et2O (10 mL) and separation of the layers. The
aqueous phase was extracted with EtOAc (3 × 10 mL), the
combined organic extracts were washed with brine (10 mL) and
the brine was back-extracted with EtOAc (5 mL). The combined
organic extracts were dried (Na2SO4) and concentrated in vacuo.
The residue was dissolved in 2 : 1 MeOH (10 mL) and pH 7
buffer (5 mL). The resultant solution was treated with NaIO4
(744 mg, 3.48 mmol, 2 eq.) and the mixture was allowed to
stir at rt for 1 h. The mixture was concentrated in vacuo and
H2O (30 mL) was added to dissolve the precipitate. The solution
was extracted with Et2O (3 × 20 mL), the combined organic
extracts were washed with brine (40 mL), dried (Na2SO4) and
the mixture was filtered through a short pad of silica, washing
with 50 : 50 EtOAc–hexanes (2 × 10 mL). The solvent was
removed in vacuo to provide the title compound (875 mg, 99%
S, SiC(CH3)3), 0.03 (3H, s, Si(CH3)a), 0.01 (3H, s, Si(CH3)b); 13
C
NMR: d (100.6 MHz, CDCl3) 209.3, 159.1, 130.5, 129.2, 113.7,
98.4, 73.9, 72.9, 72.6, 66.6, 65.1, 64.3, 55.6, 55.3, 48.6, 43.2, 37.0,
36.9, 35.5, 35.1, 25.9, 18.1, 7.7, −4.91, −4.95; HRMS: (+CI,
NH3) Calc. for C29H52O7NSi [M + NH4]+: 554.3513, found:
554.3510; m/z: (+CI, NH3) 554 ([M + NH4]+, 48), 138 (60),
121 (100).
3-Ethyl-3-butenal (38)
To a cold (0 ◦C), stirred suspension of Dess–Martin periodinane
(3.73 g, 8.79 mmol, 1.1 eq.) in CH2Cl2 (100 mL) was added a
solution of 3-ethyl-3-buten-1-ol25 (801 mg, 8.00 mmol) in CH2Cl2
(10 mL + 2 × 5 mL washings) via cannula. The cooling bath was
removed and the reaction left at rt, open to the atmosphere
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 1 0 – 2 4 1 9
2 4 1 7

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=
=
for 2.5 h. The mixture was cautiously concentrated in vacuo
(bath temperature 0 ◦C), diluted with Et2O (60 mL) and a
1 : 1 mixture of 10% Na2S2O3 (50 mL) and sat. NaHCO3 (50
mL) added. The biphasic mixture was left to stir vigorously
for 1 h, the layers were separated and the aqueous phase was
extracted with Et2O (2 × 20 mL). The combined organic extracts
were dried (Na2SO4), filtered through a plug of silica and the
solution carefully concentrated in vacuo (bath temperature 0 ◦C).
Aldehyde 38 was obtained as a concentrated solution (ca. 5 mL)
in Et2O, and used without further purification in the subsequent
reaction: 1H NMR: d (250 MHz, CDCl3) 9.65 (1H, t, J = 2.6 Hz,
1.4 Hz, C CHaHb), 4.74 (1H, br s, C CHaHb), 4.62 (1H, d, J =
11.6 Hz, OCHaHbPh), 4.43 (1H, d, J = 11.6 Hz, OCHaHbPh),
3.77 (1H, m, 23-CH), 3.72 (1H, m, 21-CH), 3.57 (1H, d, J =
2.2 Hz, OH), 2.34 (1H, br dd, J = 14.1, 7.7 Hz, 18-CHaHb), 2.31
(2H, q, J = 7.6 Hz, COCH2CH3), 2.22 (1H, br dd, J = 14.1,
6.4 Hz, 18-CHaHb), 2.04 (2H, app q, 16-CH2), 1.80 (1H, dt, J =
14.3, 8.8 Hz, 22-CHaHb), 1.54–1.65 (2H, m, 20-CH2), 1.51 (1H,
m, 22-CHaHb), 1.22 (3H, d, J = 6.1 Hz, 24-CH3), 1.13 (3H, t,
J = 7.6 Hz, COCH2CH3), 1.01 (3H, t, J = 7.4 Hz, CH2CH3); 13
C
NMR: d (100.6 MHz, CDCl3) 174.8, 147.1, 138.4, 128.4, 127.7,
127.6, 111.0, 74.4, 70.2, 69.5, 66.5, 44.0, 42.4, 42.0, 28.6, 27.8,
19.6, 12.2, 9.3; HRMS: (+CI, NH3) Calc. for C21H33O4 [MH]+:
349.2379, found: 349.2386; m/z: (+CI, NH3) 349 ([MH]+, 11),
331 (2), 222 (9), 196 (19), 167 (13), 108 (45), 106 (68), 91 (100),
74 (69), 52 (56).
=
=
19-CHO), 4.89 (1H, m, C CHaHb), 4.84 (1H, m, C CHaHb),
3.10 (2H, br d, J = 2.0 Hz, 18-CH2), 2.09 (2H, br q, J = 7.4 Hz,
16-CH2), 1.05 (3H, t, J = 7.4 Hz, CH2CH3).
(2R,6R)-2-Benzyloxy-8-ethyl-6-hydroxy-8-nonen-4-one (40)
(2R,4S,8S,10R)-10-(t-Butyldimethylsiloxy)-12-ethyl-4-hydroxy-
8-methoxy-1-(p-methoxybenzyloxy)-2-(triethylsiloxy)-12-
tridecen-6-one (45)
A 100 mL, two-necked flask containing (+)-Ipc2BCl (1.88 g,
5.85 mmol, 1.3 eq.) was placed under vacuum for 30 min to
remove any traces of HCl. The flask was charged with argon a◦nd
Et2O (20 mL) was added. The solution was cooled to −78 C
and Et3N (0.94 mL, 6.75 mmol, 1.5 eq.) was added, followed by
a solution of ketone 37 (865 mg, 4.50 mmol) in Et2O (3 mL +
2 × 1 mL washings) via cannula. The reaction was stirred for 1 h
at 0 ◦C then re-cooled to −78 ◦C. Aldehyde 38 (in excess, from
above procedure) in Et2O (3 mL + 2 × 1 mL washings) was added
via cannula and the reaction stirred at −78 ◦C for 90 min. The
mixture was warmed to −20 ◦C and stored at this temperature
for 16 h. The reaction was quenched by the addition of pH 7
buffer solution (3 mL), MeOH (3 mL) and 30% H2O2 solution (3
mL). The reaction was stirred at rt for 1 h, diluted with H2O (30
mL), the layers were separated and the aqueous layer extracted
with Et2O (3 × 10 mL). The combined organic extracts were
washed with brine (10 mL), dried (Na2SO4) and concentrated in
vacuo. The crude material was purified by flash chromatography
(25 : 75 EtOAc–hexanes) to provide hydroxyketone 40 (660 mg,
51%, 91 : 9 dr by MTPA ester analysis) as a colourless oil:
Rf: 0.36 (30 : 70 EtOAc–hexanes); [a]2D0 −38.2 (c 2.28, CHCl3);
A 25 mL flask containing (−)-Ipc2BCl (95 mg, 0.296 mmol,
1.4 eq.) was placed under vacuum for 30 min to remove any
traces of HCl. The flask was charged with argon◦and Et2O (3
mL) was added. The solution was cooled to −78 C and Et3N
(50 lL, 0.359 mmol, 1.7 eq.) was added, followed by a solution
of ketone 43 (69.6 mg, 0.212 mmol) in Et2O (1 mL + 2 × 0.5 mL
◦
washings) via cannula. The mixture was stirred for 1 h at 0 C
then re-cooled to −78 ◦C. Aldehyde 7 (93 g, 0.275 mmol, 1.3 eq.)
in Et2O (1 mL + 2 × 0.5 mL washings) was added via cannula.
The reaction mixture was stirred at −78 ◦C for 90 min then left
at −20 ◦C for 16 h. The reaction was quenched by the addition
of pH 7 buffer solution (4 mL), MeOH (2 mL) and 30% H2O2
solution (2 mL). The resultant mixture was stirred vigorously
at rt for 1 h, and then diluted with H2O (10 mL) and Et2O
(10 mL), the layers were separated and the aqueous layer was
extracted with Et2O (3 × 5 mL). The combined organic extracts
were washed with sat. NaHCO3 (10 mL) and brine (10 mL),
dried (Na2SO4) and concentrated in vacuo. The crude material
was purified by sequential flash chromatography (20 : 80 Et2O–
CH2Cl2 then 20 : 80 EtOAc–hexanes) to provide aldol adduct
45 (110.8 mg, 78%) as a colourless oil: Rf: 0.48 (30 : 70 EtOAc–
hexanes), 0.72 (20 : 80 Et2O–CH2Cl2); [a]2D0 −2.5 (c 1.69, CHCl3);
IR (liquid film): 3507 (br), 1710 (s), 1612, 1514 cm−1; 1H NMR:
d (500 MHz, CDCl3) 7.24 (2H, d, J = 8.6 Hz, ArH), 6.87 (2H,
1
IR (liquid film): 3453 (br, s), 1708 (s), 1645 cm−1; H NMR:
d (500 MHz, CDCl3) 7.26–7.34 (5H, m, Ph), 4.85 (1H, d, J =
=
=
1.5 Hz, C CHaHb), 4.78 (1H, d, J = 0.7 Hz, C CHaHb), 4.56
(1H, d, J = 11.5 Hz, OCHaHbPh), 4.43 (1H, d, J = 11.5 Hz,
OCHaHbPh), 4.20 (1H, m, 19-CH), 4.06 (1H, m, 23-CH), 2.81
(1H, s, OH), 2.80 (1H, dd, J = 15.6, 7.8 Hz, 22-CHaHb), 2.63
(1H, dd, J = 17.4, 3.2 Hz, 20-CHaHb), 2.53 (1H, dd, J = 17.4,
8.7 Hz, 20-CHaHb), 2.47 (1H, dd, J = 15.6, 5.0 Hz, 22-CHaHb),
2.22 (1H, dd, J = 13.9, 7.8 Hz, 18-CHaHb), 2.14 (1H, dd, J =
13.9, 5.6 Hz, 18-CHaHb), 2.04 (2H, app q, 16-CH2), 1.24 (3H,
=
d, J = 8.6 Hz, ArH), 4.77 (1H, d, J = 1.4 Hz, C CHaHb), 4.72
=
(1H, br s, C CHaHb), 4.44 (2H, s, CH2Ar), 4.23 (1H, m, 25-
CH), 4.07 (1H, m, 27-CH), 3.97 (1H, m, 19-CH), 3.87 (1H, m,
21-CH), 3.80 (3H, s, ArOCH3), 3.52 (1H, d, J = 2.2 Hz, OH),
3.41 (1H, dd, J = 9.7, 5.1 Hz, 28-CHaHb), 3.37 (1H, dd, J =
9.7, 5.1 Hz, 28-CHaHb), 3.28 (3H, s, OCH3), 2.72 (1H, dd, J =
15.8, 6.5 Hz, 22-CHaHb), 2.60 (1H, dd, J = 16.7, 7.9 Hz, 24-
CHaHb), 2.53 (1H, dd, J = 16.7, 4.3 Hz, 24-CHaHb), 2.48 (1H,
dd, J = 15.8, 5.5 Hz, 22-CHaHb), 2.30 (1H, dd, J = 13.6, 4.7 Hz,
18-CHaHb), 2.10 (1H, dd, J = 13.6, 4.7 Hz, 18-CHaHb),1.99
(2H, br q, J = 7.3 Hz, 16-CH2), 1.61–1.73 (3H, m, 26-CH2 +
20-CHaHb), 1.34 (1H, ddd, J = 14.2, 8.8, 3.8 Hz, 20-CHaHb),
1.02 (3H, t, J = 7.4 Hz, 16-CH2CH3), 0.93 (9H, t, J = 8.0 Hz,
Si(CH2CH3)3), 0.90 (9H, s, SiC(CH3)3), 0.60 (6H, q, J = 8.0 Hz,
d, J = 6.2 Hz, 24-CH3), 1.03 (3H, t, J = 7.4 Hz, CH2CH3); 13
C
NMR: d (100.6 MHz, CDCl3) 210.1, 147.6, 138.3, 128.4, 127.8,
127.6, 111.1, 71.6, 70.9, 65.5, 50.6, 50.1, 43.6, 28.6, 19.8, 12.2.
(2R,4R,6R)-2-Benzyloxy-8-ethyl-6-propionoxy-8-nonen-4-ol
(41)
EtCHO (3.0 mL, 42 mmol, 20 eq.) in THF (8 mL) at −20 ◦C was
treated with SmI2 (ca. 0.1 M in THF, 6.2 mL, 0.62 mmol, 0.3 eq.).
After stirring for 10 min, a solution of hydroxyketone 40 (600 mg,
2.07 mmol) in THF (5 mL + 2 × 2 mL washings) was added
via cannula, the mixture was allowed to warm to 0 ◦C, then left
at −20 ◦C for 16 h. The reaction was quenched by the addition
of sat. NaHCO3 (10 mL), then diluted with H2O (20 mL) and
Et2O (10 mL). The layers were separated and the aqueous phase
was extracted with Et2O (3 × 10 mL). The combined organic
extracts were washed with brine (10 mL), dried (Na2SO4) and
concentrated in vacuo. Purification of the crude material by flash
chromatography (20 : 80 EtOAc–hexanes) afforded propionate
41 (647 mg, 90%) as a colourless oil: Rf: 0.48 (30 : 70 EtOAc–
hexanes); [a]2D0 −56.7 (c 1.71, CHCl3); IR (liquid film): 3504
Si(CH2CH3)3), 0.08 (3H, s, Si(CH3)a), 0.07 (3H, s, Si(CH3)b); 13
C
NMR: d (100.6 MHz, CDCl3) 209.1, 159.2, 147.9, 130.1, 129.3,
113.7, 110.8, 74.2, 73.9, 73.0, 70.6, 67.9, 66.0, 56.4, 55.2, 50.8,
48.5, 45.4, 42.0, 41.1, 29.0, 25.9, 18.0, 12.2, 6.8, 4.9, −4.1, −4.6;
HRMS: (+ESI) Calc. for C36H66O7Si2Na [M + Na]+: 689.4245,
found: 689.4234.
Acknowledgements
Financial support was provided by the EPSRC (GR/L41646),
Churchill College (Research Fellowship to D.J.W.), Cambridge
Commonwealth Trust (M.J.C.), King’s College and Sim’s Fund,
1
(br, s), 1736 (s), 1646 cm−1; H NMR: d (500 MHz, CDCl3)
7.26–7.34 (5H, m, Ph), 5.24 (1H, m, 19-CH), 4.79 (1H, d, J =
2 4 1 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 1 0 – 2 4 1 9

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Cambridge (D.Y.-K.C.). We thank Merck, AstraZeneca and
Novartis Pharmaceuticals for generous support and Dr Anne
Butlin (AZ) for valuable assistance.
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