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

Article abstract of DOI:10.1039/b504146e

The convergent synthesis of the C1-C15 AB-spiroacetal subunit 2 of altohyrtin A/spongistatin 1 (1) is described. This highly stereocontrolled synthesis relies on matched boron aldol reactions of chiral methyl ketones, under Ipc₂BCl mediation, t

Full text of DOI:10.1039/b504146e

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A R T I C L E
The stereocontrolled total synthesis of altohyrtin A/spongistatin 1:
the AB-spiroacetal segment†‡
Ian Paterson,* Mark J. Coster,§ David Y.-K. Chen, Renata M. Oballa, Debra J. Wallace and
Roger D. Norcross
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 11th April 2005, Accepted 3rd May 2005
First published as an Advance Article on the web 24th May 2005
The convergent synthesis of the C1–C15 AB-spiroacetal subunit 2 of altohyrtin A/spongistatin 1 (1) is described. This
highly stereocontrolled synthesis relies on matched boron aldol reactions of chiral methyl ketones, under Ipc2BCl
mediation, to establish the C5, C9 and C11 stereocentres, and formation of the desired thermodynamic spiroacetal
under acidic conditions. The scalable synthetic sequence developed provided access to multi-gram quantities of 2,
thus enabling the successful completion of the total synthesis of altohyrtin A/spongistatin 1, as reported in Part 4.
5-desacetylaltohyrtin A from Hyrtios altum and Fusetani4 re-
Introduction
ported the isolation of cinachyrolide A from Cinachyra sponges
Marine organisms, particularly invertebrates such as sponges,
(Fig. 2). Remarkably, each of these groups reported the same
have become
a key source of novel biologically-active
gross structures on the basis of extensive NMR experiments
performed on extremely small quantities of the natural products
(0.5–13.8 mg). However, several discrepancies were apparent
in the relative stereochemical relationships attributed to these
unprecedented 42-membered macrolides. Furthermore, only
the Kitagawa/Kobayashi group proposed the full relative and
absolute configuration, the validity of which was verified by
subsequent total syntheses (vide infra).
compounds.1 Many of these marine-derived natural products
exhibit exceptional levels of biological activity, combined with
unique modes of action, which may have value as lead structures
for the development of new medicines.
The first members of the spongipyran family of antimi-
totic marine macrolides were reported independently by three
research groups in 1993. Bioassay-guided fractionation by
Pettit and co-workers of extracts of Spongia sp. and Spi-
rastrella spinispirulifera led to the identification and partial
structure elucidation of spongistatins 1–9 (Fig. 1).2 Similarly,
the Kitagawa/Kobayashi group3 reported altohyrtins A–C and
The spongipyrans5 have attracted a great deal of excitement
due to their extraordinary biological activity. They are among
the most potent cancer cell-growth inhibitory antimitotic agents
tested by the US National Cancer Institute (NCI), with alto-
hyrtin A/spongistatin 1 being one of the most active of the series.
Typical of the class, this compound displayed sub-nanomolar
level cytotoxicity in the NCI 60 human carcinoma cell line screen
(mean panel GI50 1.3 × 10−10 M) and enhanced potency against
a subset of highly chemoresistant tumour types (GI50 2.5–3.5 ×
10−11 M).2a Furthermore, in vivo human melanoma and ovarian
carcinoma xenograft experiments with this compound, showed
curative responses at extremely low doses.2g Although little data
is available concerning the mode of action of these compounds,
† Part 1 of a series of four papers.
‡ Electronic supplementary information (ESI) available: general exper-
imental information and procedures for the synthesis of compounds
not detailed in the Experimental section of this paper. See http://
www.rsc.org/suppdata/ob/b5/b504146e/
§ Current address: School of Chemistry, University of Sydney, NSW
2006, Australia. Email: m.coster@chem.usyd.edu.au; Fax: +61 2 9351
3329.
Fig. 1 Structures originally proposed for spongistatins 1–9.
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 O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 9 9 – 2 4 0 9
T h i s j o u r n a l i s
2 3 9 9
©

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Fig. 2 Structures originally proposed for altohyrtins A–C, 5-desacetylaltohyrtin A and cinachyrolide A.
altohyrtin A/spongistatin 1 was shown to inhibit mitosis by
binding to tubulin and blocking microtubule assembly.2h Despite
this enticing biological profile, further biological evaluation
has been severely hampered by the extreme paucity of the
spongipyrans available from the natural source (e.g., 13.8 mg
was isolated by the Pettit group from 400 kg wet sponge).
The spongipyran class of marine macrolides have attracted
considerable synthetic interest due to an enticing combination
of their promising anticancer properties, the paltry supply from
the natural source and, most significantly, their unprecedented
molecular architecture. To date, six research groups have re-
ported successful total syntheses of members of the spongipyran
family. The first reported synthesis of altohyrtin C/spongistatin
2 by Evans6 in 1997 was followed soon after by the synthesis of
altohyrtin A/spongistatin 1 by Kishi,7 and both these elegant
studies served to confirm the full stereochemical assignments of
the Kitagawa/Kobayashi group shown in Fig. 2, and established
that the altohyrtins and spongistatins had identical structures.
Subsequent total syntheses have been reported by the Smith,8
Paterson,9 Crimmins10 and Heathcock11 groups, in addition
to a formal total synthesis by Nakata and co-workers12 and
numerous synthetic approaches by other groups.13 In this series
of four papers, we provide a full account of our studies in
this area leading to a highly stereocontrolled total synthesis of
altohyrtin A/spongistatin 1, as well as access to novel structural
analogues for biological evaluation.
anomeric effects, and a highly oxygenated bis-tetrahydropyran
portion are also present.
Taking all these factors into consideration, our retrosynthetic
analysis for altohyrtin A relied on the disassembly of the
molecule via three principal disconnections (Scheme 1). In a
forward sense, fragment coupling of the AB- and CD-spiroacetal
subunits, 2 and 3 respectively, was planned via formation of the
C15–C16 bond, and the associated stereocentres, by a stere-
oselective aldol reaction, while a challenging Wittig coupling
would then be employed to unite an advanced ABCD aldehyde
subunit with the fully elaborated C29–C51 EF phosphonium salt
4. Finally, macrolactonisation of a suitable seco-acid derivative
at the C41 hydroxyl was anticipated to proceed selectively
to complete the fully functionalised spongipyran framework.
A cornerstone of our synthetic strategy was the late-stage
coupling of highly functionalised subunits, allowing for an
optimum level of convergency and a succinct end-game to the
synthesis. Furthermore, our retrosynthetic analysis revealed 10
potential disconnection sites for the use of stereoselective aldol
methodology to form key C–C bonds and establish oxygen-
bearing stereocentres, as indicated by the labels “aldols #1–10”.
The AB-spiroacetal
The C1–C15 fragment of altohyrtin A (1), comprising the AB-
spiroacetal, benefits from two stabilising anomeric effects arising
from the “axial–axial” disposition of the two acetal oxygen
atoms at C7, as shown in segment 2 (Scheme 2). As such, it was
reasoned that the desired spiroacetal would be obtained under
thermodynamic conditions of acid-catalysed acetal formation
from a linear precursor. The fully functionalised AB-spiroacetal
aldehyde 2 would be obtained from the simpler spiroacetal
system 5 by a series of functional group interconversions
and stereoselective methyl addition to a C9 ketone. In turn,
spiroacetal 5 would be the thermodynamic product of an acid-
mediated, selective bis-desilylation of linear precursor 6 with
concomitant spiroacetal formation. Aldol disconnection of 6
to ketone 7 and aldehyde 8 provides a convergent strategy for
union of the C1–C8 and C9–C15 segments. Examination of
7 and 8 reveals two further aldol disconnections of methyl
ketones. Particular synthetic challenges presented by the C1–
C15 fragment include the development of efficient methods
for the construction of the stereochemically dense, polyacetate
framework and differentiation of the oxygen functionality by
means of selective protection or differences in oxidation state.
Retrosynthetic analysis
At the onset of this project in 1995, our synthetic plan for the
spongipyrans was designed to be highly flexible, due to the initial
uncertainty over the stereochemical assignment as discussed
in the introduction, and to allow for the production of useful
quantities of altohyrtin A/spongistatin 1, along with enabling
access to novel structural analogues for SAR studies.
The spongipyran family present a significant synthetic chal-
lenge, due primarily to the unprecedented array of functionality
and the high level of oxygenation which necessitates careful
attention to chemoselectivity issues and the selection of a work-
able protecting group strategy. The control of stereochemistry
is also essential if a useful amount of the target structure is to
be accessed. Altohyrtin A/spongistatin 1 (1, Scheme 1) bears
24 stereogenic centres distributed around the 42-membered
macrolactone core and the sensitive chlorotrienol side-chain.
Two spiroacetals, only one of which benefits from two stabilising
2 4 0 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 9 9 – 2 4 0 9

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Scheme 1 Retrosynthetic analysis for altohyrtin A/spongistatin 1 (1), showing proposed aldol disconnections.
Scheme 2 Retrosynthetic analysis for the AB-spiroacetal subunit 2.
(93 : 7 dr). By comparison, without the chiral ligands on
boron, i.e., using dicyclohexylboron enolate 13b, derived from B-
chlorodicyclohexylborane (Chx2BCl) and Et3N,18 aldol product
14 was provided with significantly reduced diastereoselectivity
(75 : 25 dr). The mismatched situation, using enolate 13c,
prepared from (+)-Ipc2BCl, resulted in a weak preference for
the corresponding 1,3-anti aldol adduct. Protection of the C5
alcohol as the tert-butyldimethylsilyl (TBS) ether produced C1–
C8 ketone 7, ready for aldol coupling with the C9–C15 aldehyde
subunit.
Results and discussion
The C1–C8 chiral ketone 7
Our synthesis of the C1–C15, AB-spiroacetal-containing sub-
unit 2 began with the Brown asymmetric allylation of
9 (Scheme 3), employing B-allylbis(2-isocaranyl)borane (2-
dIcr2BAll),14 providing homoallylic alcohol 10 in excellent yield
(93%) and high enantiomeric excess (97% ee by 1H NMR
analysis of the derived MTPA esters15). Protection as the
triethylsilyl (TES) ether 11 and subsequent ozonolysis, provided
aldehyde 12, poised for the first boron aldol reaction16 of our
synthetic endeavour.
Enolisation of acetone with (−)-B-chlorodiisopinocampheyl-
borane [(−)-Ipc2BCl] and Et3N, under standard conditions
(0 ◦C, Et2O),17 provided enol borinate 13a, which was used in situ
in a matched aldol reaction with aldehyde 12. The nature of the
Ipc ligands on boron reinforces the inherent diastereofacial bias
of aldehyde 12, providing 1,3-syn 14 as the major diastereomer
The C9–C15 subunit
The synthesis of the C9–C15 fragment commenced with the
triisopropylsilyl (TIPS) protection of methyl (S)-3-hydroxy-2-
methylpropionate 15 (Roche ester), and conversion into the
corresponding methyl ketone 16, via the Weinreb amide19
(Scheme 4). This previously-reported,9c three-step procedure
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 9 9 – 2 4 0 9
2 4 0 1

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more, attempts to methylenate 19 under a variety of conditions
(e.g., Wittig, Petasis), resulted in substantial decomposition via
elimination and retro-aldol pathways. The optimal procedure
required initial protection of 19 as the corresponding TES ether,
followed by methylenation (Scheme 5). In earlier work, the
methylenation was conveniently carried out using the Petasis
reagent Cp2TiMe2 in good yield (79%).9c However, application
of the modified Takai procedure22 (Zn, CH2I2, TiCl4, cat. PbI2)
proved generally superior in terms of yield (≥92%) and ease
of purification, and was particularly amenable to larger scale
operations. Removal of the TES protecting group to give 20 (90%
yield from 19), allowed smooth Mitsunobu inversion to take
place, affording 21 (94%). Saponification of the p-nitrobenzoate
and replacement with a TES ether afforded 22 (94%).
d
=
Scheme 3 Reagents and conditions: (a) 2- Icr2BOMe, H2C CHCH2-
MgBr, Et2O, −78 ◦C, 4 h, then H2O2, NaOH, H2O, reflux, 16 h; (b)
TESOTf, 2,6-lutidine, CH2Cl2, −78 ◦C, 2 h; (c) O3, NaHCO3, CH2Cl2,
−78 ◦C, then PPh3, rt, 3.5 h; (d) L2BCl, Et3N, Et2O, 0 ◦C, 45 min; (e)
12, −78 → −20 ◦C, 20 h, then pH 7 buffer, H2O2, MeOH, 0 ◦C → rt,
1 h; (f) TBSCl, Im, DMF, rt, 16 h.
Scheme 5 Reagents and conditions: (a) TESOTf, 2,6-lutidine, −78 ◦C,
2 h; (b) Zn, CH2I2, TiCl4, cat. PbI2, THF–CH2Cl2, rt, 3 h; (c) cat. PPTS,
CH2Cl2–MeOH, 0 ◦C, 20 min; (d) p-NO2C6H4CO2H, PPh3, DEAD,
PhMe, rt, 30 min; (e) K2CO3, MeOH, rt, 16 h; (f) TESCl, Im., DMF, rt,
16 h.
Aldol coupling of the C1–C8 and C9–C15 subunits, and
spiroacetal formation
Formation of the proposed linear precursor to the AB-
spiroacetal, via aldol union of the C1–C8 and C9–C15 frag-
ments, required conversion of 22 into the corresponding C9
aldehyde8. This was achieved by careful treatmentof 22 with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in the presence
of pH 7 buffer, followed by oxidation of the resultant 1◦
alcohol with the Dess–Martin periodinane23 (Scheme 6). This
two-step procedure illustrates a pair of recurring challenges
faced in our synthesis of altohyrtin A. Firstly, removal of a
Scheme 4 Reagents and conditions: (a) TIPSCl, Im, DMAP, CH2Cl2,
0 ◦C → rt, 16 h; (b) MeONHMe–HCl, i-PrMgCl, THF, −20 → −10 ◦C,
4 h; (c) MeMgBr, THF, −78 → 0 ◦C, 3 h; (d) L2BCl, Et3N, Et2O, −78 →
0 ◦C, 1 h; (e) 18, Et2O, −78 → −20 ◦C, 19 h, then H2O2, MeOH, pH 7
buffer, 0 ◦C → rt, 2 h.
could be performed easily on 40 g of 15, with distillation
of ketone 16 being the only purification step required in the
sequence. Previously, we had demonstrated that the boron-
mediated aldol reactions of certain a-chiral methyl ketones
can proceed with high levels of 1,4-syn diastereoselection,
and that this could be enhanced by the appropriate choice
of Ipc ligand chirality.20 The spongipyrans require a 1,4-anti
relationship between C11 and C14, which was best achieved
by the application of a highly 1,4-syn selective, matched aldol
reaction and subsequent Mitsunobu inversion21 at C11. To this
end, conversion of methyl ketone 16 into enol borinate 17a by
reaction with (−)-Ipc2BCl and Et3N, and in situ reaction with
aldehyde 18, afforded the desired 1,4-syn aldol product 19 (98 :
2 dr) in excellent yield (97%). Reaction under purely substrate
control, using Chx2BCl (enolate 17b), or using the mismatched
(+)-Ipc2BCl reagent (enolate 17c) led to lower levels of 1,4-syn
selectivity.
Scheme 6 Reagents and conditions: (a) DDQ, 10 : 1 CH2Cl2–pH 7
buffer, 0 ◦C, 45 min; (b) Dess–Martin periodinane, pyr, CH2Cl2, rt,
30 min; (c) (−)-Ipc2BCl, Et3N, Et2O, 0 ◦C, 40 min; (d) 8, Et2O, −78 →
−20 ◦C, 19 h, then H2O2, MeOH, pH 7 buffer, 0 ◦C → rt, 2.5 h.
The inversion of configuration at C11 was not possible
directly on 19, as Mitsunobu conditions led only to elimination,
providing the corresponding a,b-unsaturated ketone. Further-
2 4 0 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 9 9 – 2 4 0 9

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Scheme 7 Reagents and conditions: (a) cat. PPTS, CH2Cl2–MeOH, rt, 40 min, then separation and resubjection; (b) Dess–Martin periodinane, pyr,
CH2Cl2, rt, 30 min; (c) MeMgBr, THF, −78 → 0 ◦C, 50 min; (d) LiDBB, THF, −78 ◦C, 1 h; (e) Dess–Martin periodinane, CH2Cl2, rt, 1–2 h; (f)
NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH–H2O, 0 ◦C → rt, 16 h; (g) 2,2,2-trichloroethanol, DCC, cat. DMAP, CH2Cl2, rt, 2 h; (h) 40% aq.
HF, MeCN, rt, 0.75–2 h; (i) TIPSCl, Im., cat. DMAP, CH2Cl2, rt, 6 h; (j) Ac2O, DMAP, CH2Cl2, rt, 3 h; (k) TESOTf, 2,6-lutidine, CH2Cl2, −78 →
0
◦C, 3 h; (l) cat. PPTS, CH2Cl2–MeOH, 0 ◦C, 1 h.
p-methoxybenzyl (PMB) protecting group proved problematic
in several instances where acid-sensitive functional groups are
present in the substrate, e.g., the TES ether in 22 was found
to be somewhat labile under standard DDQ-mediated oxidative
deprotection conditions. Gratifyingly, in most instances the acid-
mediated, unwanted side reactions could be limited by careful
optimisation of reaction conditions. In particular, the use of pH 7
buffer, rapid mixing of the biphasic mixture and portion-wise
addition of an excess of DDQ gave the best results. Secondly,
our synthetic route to 1 required the oxidation of several
complex 1◦ and 2◦ alcohols to the corresponding carbonyl
compounds, in the presence of sensitive functional groups, or
potentially labile a-stereocentres. In most instances, the Dess–
Martin periodinane, sometimes buffered with pyridine, proved
to be the oxidant par excellence.
24 is blocked by the bulky C1–C6 portion of the spiroacetal
(Fig. 3).
Fig. 3 Equatorial attack of Grignard reagent on 24.
With aldehyde 8 and ketone 7 in hand, the aldol union of
these fragments could proceed, exploiting triple asymmetric
induction,24 wherein the stereodirecting influence from all three
chiral components (aldehyde, ketone25 and boron reagent) were
matched. Enolisation of 7 with (–)-Ipc2BCl and Et3N, to give
enol borinate 23 in situ, followed by treatment with aldehyde 8
gave the desired aldol adduct 6 cleanly in near quantitative yield
(97 : 3 dr). In this reaction, the 1,3-syn preference of aldehyde 8,
the 1,5-anti preference26,27 of ketone 7 and the stereodirecting
influence of the boron reagent act in a synergistic fashion,
resulting in an excellent level of stereoselectivity.
Selective bis-desilylation of 6 and concomitant spiroac-
etal formation were achieved by subjection to catalytic pyri-
dinium p-toluenesulfonate (PPTS) in CH2Cl2–MeOH, providing
the desired, thermodynamically favoured, AB-spiroacetal 5
(Scheme 7). The spiroacetal stereochemistry was assigned on
the basis of NOESY results for a closely related system,9a and
confirmed at a later point in the AB-spiroacetal synthesis, vide
infra.
Although 25 embodies the complete carbon skeleton of the
AB-spiroacetal of the spongipyrans, in keeping with our syn-
thetic strategy for altohyrtin A, we required C1 at the acid oxida-
tion state and acetylation of the C5 hydroxyl group. To this end,
debenzylation of 25 with lithium 4,4ꢀ-di(tert-butyl)biphenylide
(LiDBB)28 was followed by two-step oxidation to the carboxylic
acid and esterification with 2,2,2-trichloroethanol to provide
26. The 2,2,2-trichloroethyl (TCE) ester protecting group was
chosen on the basis that it would be readily removed in the
final stages of the synthesis, using mild, reductive conditions,
compatible with the manifold sensitive functionality of the
targeted seco-compound. Earlier model studies with a simple
methyl ester had proven this to be unsuitable, due to inability to
remove it chemoselectively under mild conditions at a late stage,
e.g., by using potassium trimethylsilanolate (KOTMS).
After the investigation of several conditions for the selective
removal of the TBS ether in 26 in the presence of the TIPS
group, a high yielding two-step sequence of bis-desilylation,
mono-silylation was finally employed. This allowed selective
acetylation of the hindered 2◦ alcohol at C5 under carefully
optimised conditions (Ac2O, DMAP, CH2Cl2), to yield 27.
Although our synthetic strategy called for acetylation at this
point, it is envisaged that access to several other spongipyran
congeners, e.g., desacetylaltohyrtin A/spongistatin 3, would be
possible by retaining a silyl protecting group at the C5 hydroxyl,
Further functionalisation of the AB-spiroacetal
Oxidation of 5 to the corresponding C9 ketone 24, with the
Dess–Martin periodinane, was followed by equatorial addition
of MeMgBr to give the 3◦ alcohol 25 as the sole product. In this
Grignard addition reaction, axial attack of the reagent on ketone
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 9 9 – 2 4 0 9
2 4 0 3

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which would ultimately be removed in a global deprotection step
at the conclusion of the synthesis.
127.7, 117.6, 73.3, 70.4, 69.0, 41.9, 35.8; HRMS: (CI, NH3) Calc.
for C13H19O2 (MH+) 207.1385, found 207.1385.
Removal of the TIPS ether from 27 (aq. HF, MeCN) provided
diol 28, the stereochemistry of which was confirmed by NOESY
(Fig. 4). Protection of the 3◦ alcohol at C9 as the TES ether,
chosen for ease of removal in the final step of the synthesis, was
achieved by a two-step sequence, to afford 29.
(4S,6S)-8-Benzyloxy-4-hydroxy-6-(triethylsiloxy)-2-octanone
(14)
Et3N (3.89 mL, 28.0 mmol) and freshly distilled acetone (2.5 mL,
34.2 mmol) were added to a solution of (−)-Ipc2BCl (7.48 g,
23.3mmol, previouslydriedunder high vacuum for 1hto remove
traces of HCl) in Et2O (220 mL) at 0 ◦C. After stirring for
45 min at 0 ◦C, the reaction mixture was cooled to −78 ◦C and
a solution of aldehyde 12 (5.0 g, 15.5 mmol) in Et2O (20 mL and
5 mL washings) was slowly added. The reaction mixture was
stirred 4 h at −78 ◦C before being kept in a freezer (−20 ◦C)
overnight. The reaction was quenched by addition of excess of
pH 7 buffer (200 mL) at 0 ◦C. The layers were separated and the
organic layer was dried (MgSO4) and concentrated in vacuo. The
resulting crude material was dissolved in MeOH (220 mL) and
pH 7 buffer (115 mL) then, H2O2 (75 mL of a 30% aq. sol.) was
added at 0 ◦C and the resulting mixture was stirred for 1 h at rt.
The reaction mixture was partitioned between Et2O and pH 7
buffer. The aqueous layer was extracted with Et2O (2 × 100 mL)
and EtOAc (2 × 100 mL). The combined organic layers were
dried (MgSO4) and the solvents removed in vacuo. Purification
by flash chromatography (20 : 80 EtOAc–hexanes) afforded the
desired aldol 14 (5.31 g, 90%) as a colourless oil: Rf: 0.40 (40 : 60
EtOAc–hexanes); [a]2D0 +16.0 (c 2.06, CHCl3); IR (liquid film):
3482, 1713 cm−1; 1H NMR: d (500 MHz, CDCl3) 7.28–7.36 (5H,
m, Ar), 4.46, 4.50 (2H, ABq, J = 11.9 Hz, –OCH2Ph), 4.20 (1H,
sextet, J = 3.8 Hz, H5), 4.12 (1H, qn, J = 6.2 Hz, H3), 3.53 (2H,
t, J = 6.4 Hz, H1A and H1B), 3.45 (1H, br s, –OH), 2.51–2.60
(2H, m, H6A and H6B), 2.16 (3H, s, C7–CH3), 1.84 (2H, q, J =
6.2 Hz, H2A and H2B), 1.57–1.66 (2H, m), 0.96 (9H, t, J = 8.0 Hz,
Fig. 4 Key NOE interactions for 28.
The success of any multi-step total synthesis endeavour relies
on strategic “stockpiling” of highly stable intermediates at key
points. The synthesis of 29 outlined here proved robust and was
able to be scaled up to the extent that multi-gram quantities
of 29 could be produced in a single campaign. Conversion of
alcohol 29 to the corresponding, fully functionalised, C1–C15
AB-spiroacetal aldehyde 2 was efficiently performed, as needed,
using the Dess–Martin periodinane (93% yield).
Conclusions
The synthesis of the C1–C15 AB-spiroacetal segment reported
herein requires 24 steps in the longest linear sequence from
methyl ketone 16, and gives a 27% overall yield of 2. The
challenge of introducing a number of stereogenic centres on
a largely polyacetate-derived backbone was dealt with by the
application of Brown’s allylation methodology and boron-
mediated aldol reactions of methyl ketones, where substrate con-
trol was matched with appropriate choice of Ipc ligand chirality
to afford high levels of diastereoselectivity. The developed route
allowed access to multi-gram quantities of 2 for completion of
the total synthesis of altohyrtin A, as discussed in Parts 2–4 of
this series of papers.29
–OSi(CH2CH3)3), 0.62 (6H, q, J = 8.0 Hz, –OSi(CH2CH3)3); 13
C
NMR: d (100.6 MHz, CDCl3) 208.9, 138.3, 128.3, 127.7, 127.6,
73.0, 69.1, 66.6, 66.2, 50.6, 43.1, 37.2, 30.8, 6.8, 5.0; HRMS
(+FAB) Calc. for C21H36O4Si (MH+) 381.2461, found 381.2442.
(2S,5S)-5-Hydroxy-7-(p-methoxybenzyloxy)-2-methyl-1-
(triisopropylsiloxy)-heptan-3-one (19)
A two-necked round bottomed flask containing (−)-Ipc2BCl
(5.36 g, 16.71 mmol, 1.8 eq.) was placed under high vacuum
for 1 h to remove any traces of HCl. To this flask was added dry
Et2O (150 mL) and the solution was cooled to 0 ◦C. Dry Et3N
(2.6 mL 18.6 mmol, 2.0 eq.) was added followed by a solution
of ketone 16 (2.40 g, 9.28 mmol, 1.0 eq.) in dry Et2O (2 mL +
2 × 3 mL for washings). The resultant white suspension was
stirred at 0 ◦C for 30 min and then cooled to −78 ◦C. A solution
of the aldehyde 18 (2.77 g, 14.27 mmol, 1.5 eq.) in dry Et2O
(2 mL + 2 × 2 mL for washings) was added, via cannula, and
the suspension was stirred at −78 ◦C for 5 h and then at −20 ◦C
for 16 h. The reaction was quenched by the addition of pH 7
buffer (100 mL) and after warming to room temperature, the
layers were separated. The aqueous phase was extracted with
Et2O (3 × 150 mL) and the combined organic extracts were
concentrated in vacuo. The resultant residue was taken up in
MeOH (125 mL) and pH 7 buffer (60 mL) and cooled to 0 ◦C. A
30% aqueous solution of H2O2 (50 mL) was added and the
mixture was warmed to rt and stirred for 2.5 h. Et2O (150 mL)
andH2O (100 mL) were added andthe layers were separated. The
aqueous phase was extracted with Et2O (2 × 150 mL) and EtOAc
(2 × 150 mL). The combined organic extracts were washed with
brine (2 × 100 mL), dried (MgSO4) and concentrated in vacuo.
The crude oil was flash chromatographed (10 : 90 → 20 : 80
EtOAc–hexanes) to yield a 98 : 2 mixture of the 1,4-syn to 1,4-
anti aldol adducts 19 and 5-epi-19 (4.08 g, 97%), respectively.
Major diastereomer: Rf: 0.30 (20 : 80 EtOAc–hexanes); [a]D20
+38.8 (c 1.80, CHCl3); IR (liquid film): 3508, 1708, 1613, 1513,
Experimental
(R)-1-Benzyloxy-hex-5-en-3-ol (10)
To a cold (−78 ◦C), stirred solution of 2-dIcr2BOMe14 (10.34 g,
32.68 mmol, 1.7 eq.) in dry Et2O (62 mL), was added, dropwise,
allylmagnesium bromide (0.98 M in Et2O, 29.0 mL, 28.4 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 9 (3.15 g,
19.2 mmol, 1.0 eq.) in dry Et2O (5 mL + 2 × 2 mL for washings)
was added via cannula. The mixture was stirred at −78 ◦C for 4 h
and then quenched with 3 M aqueous NaOH (13 mL) and a 30%
aqueous solution of H2O2 (27 mL). The biphasic mixture was
refluxed for 16 h, the layers were then separated and the aqueous
phase extracted with Et2O (3 × 200 mL). The combined organic
extracts were washed with brine (1 × 100 mL), dried (MgSO4)
and concentrated in vacuo. The crude oil thus obtained was
flash chromatographed (10 : 90 EtOAc–hexanes) to provide the
homoallylic alcohol 10 (3.64 g, 93%), as a colourless oil: Rf: 0.20
(20 : 80 EtOAc–hexanes); [a]2D0 −4.8 (c 2.31, CHCl3); IR (liquid
1
film): 3424, 3071, 3029, 1640 cm−1; H NMR: d (400 MHz,
CDCl3) 7.28–7.37 (5H, m, Ara), 5.81–5.88 (1H, m, H5), 5.09,
=
5.12 (2H, s, d, J = 8.2 Hz, –C CH2), 4.53 (2H, s, –OCH2Ph),
3.87–3.90 (1H, m), 3.64–3.74 (2H, m), 2.86 (1H, d, J = 2.9 Hz,
–OH), 2.26 (2H, t, J = 6.3 Hz, H4A and H4B), 1.75–1.80 (2H,
m); 13C NMR: d (100.6 MHz, CDCl3) 137.9, 134.9, 128.4, 127.8,
1
1463 cm−1; H NMR: d (500 MHz, CDCl3) 7.25 (2H, d, J =
8.6 Hz, ArH), 6.87 (2H, br d, J = 8.6 Hz, ArH), 4.44 (2H, s,
2 4 0 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 9 9 – 2 4 0 9

View Article Online
1
OCH2Ar), 4.24 (1H, m, 11-CH), 3.79–3.84 (1H, m, 15-CHaHb),
3.80 (3H, s, OCH3), 3.72 (1H, dd, J = 9.7, 5.2 Hz, 15-CHaHb),
3.62 (2H, br sextet, J = 6.0 Hz, 9-CH2), 3.40 (1H, d, J = 2.9 Hz,
OH), 2.79 (1H, br sextet, J = 7.0 Hz, 14-CH), 2.73 (1H, dd,
J = 17.6, 4.2 Hz, 12-CHaHb), 2.67 (1H, dd, J = 17.6, 8.0 Hz,
12-CHaHb), 1.70–1.80 (2H, m, 10-CH2), 1.01–1.10 (24H, m, 14-
CHCH3 + Si(CH(CH3)2)3); 13C NMR: d (100.6 MHz, CDCl3)
214.4, 159.1, 130.2, 129.2, 113.6, 72.8, 67.5, 66.2, 66.0, 55.2, 49.5,
49.3, 36.1, 17.9, 12.7, 11.8; HRMS (+FAB) Calc. for C25H44O5Si
[M]+ 452.2958, found: 452.2913.
3473, 1641, 1613, 1514, 1463 cm−1; H NMR: d (500 MHz,
CDCl3) 7.25 (2H, d, J = 8.5 Hz, ArH), 6.87 (2H, d, J = 8.5 Hz,
=
=
ArH), 4.91 (1H, s, C CHaHb), 4.92 (1H, s, C CHaHb), 4.45
(2H, ABq, J = 11.6 Hz, OCH2Ar), 3.92–3.99 (1H, m, 11-CH),
3.80 (3H, s, OCH3), 3.53–3.72 (4H, m, 9-CH2 + 15-CH2), 2.94
(1H, d, J = 1.8 Hz, OH), 2.33 (1H, sextet, J = 6.9 Hz, 14-
CH), 2.22 (1H, dd, J = 13.9, 4.6 Hz, 12-CHaHb), 2.16 (1H,
dd, J = 13.9, 8.5 Hz, 12-CHaHb), 1.71–1.82 (2H, m, 10-CH2),
1.05–1.13 (21H, m, Si(CH(CH3)2)3), 1.02 (3H, d, J = 6.9 Hz, 14-
CHCH3); 13C NMR: d (100.6 MHz, CDCl3) 159.1, 149.2, 130.3,
129.3, 113.7, 112.0, 72.8, 68.1, 68.0, 67.8, 55.2, 44.0, 41.6, 36.3,
18.0, 17.1, 11.9; HRMS (+FAB) Calc. for C26H47O4Si [MH]+:
451.3243, found: 451.3207.
(4R)-2-[1-(Triisopropylsiloxy)-prop-2-(R)-yl]-6-(p-
methoxybenzyloxy)-4-(triethylsiloxy)-hex-1-ene (20)
To a cold (−78 ◦C), stirred solution of alcohol 19 (2.13 g, 4.70
mmol) in dry CH2Cl2 (50 mL) was added 2,6-lutidine (1.6 mL,
13.7 mmol, 3 eq.) followed by TESOTf (1.6 mL, 7.1 mmol, 1.5
(4S)-2-[1-(Triisopropylsiloxy)-prop-2-(R)-yl]-6-(p-
methoxybenzyloxy)-4-(p-nitrobenzoyloxy)-hex-1-ene (21)
To a stirred solution of 20 (2.50 g, 5.55 mmol, 1.0 eq.) in
dry benzene (50 mL) was added p-nitrobenzoic acid (4.10 g,
24.5 mmol, 4.4 eq.) followed by Ph3P (7.30 g, 27.45 mmol, 5.0
eq.). To the resultant yellow suspension was added, dropwise
over 10 min, diethylazodicarboxylate (4.4 mL, 27.70 mmol, 5.0
eq.). The resultant homogeneous yellow solution was stirred
at rt for 20 min and the reaction was then concentrated in
vacuo. The residue was first passed through a plug of silica
(5% EtOAc in hexane) and after concentration in vacuo, the
resultant oil was flash chromatographed (20 : 80 Et2O–hexanes)
to provide the desired p-nitrobenzoate 21 (3.12 g, 94%), as a
pale yellow oil: Rf: 0.55 (30 : 70 Et2O–hexanes); [a]2D0 +23.6 (c
1.73, CHCl3); IR (liquid film): 3079, 1725, 1610, 1529 cm−1; 1H
NMR: d (500 MHz, CDCl3) 8.22 (2H, d, J = 8.7 Hz, ArH), 8.10
(2H, d, J = 8.7 Hz, ArH), 7.17 (2H, d, J = 8.5 Hz, ArH), 6.77
(2H, d, J = 8.5 Hz, ArH), 5.49 (1H, septet, J = 4.1 Hz, 11-CH),
◦
eq.). The resultant solution was stirred at −78 C for 2 h and
then EtOH (5 mL) was added to quench the excess TESOTf.
Saturated aqueous NH4Cl (50 mL) was added and the reaction
was allowed to warm to rt. The layers were separated and the
aqueous phase was extracted with Et2O (4 × 150 mL). The
combined organic extracts were washed with pH 7 buffer (2 ×
100 mL), dried (MgSO4) and concentrated in vacuo. The crude
oil was flash chromatographed (10 : 90 Et2O–hexanes) to yield
the desired TES ether (2.62 g, 98%), as a colourless oil: Rf: 0.50
(10 : 90 Et2O–hexanes); [a]2D0 +27.4 (c 1.97, CHCl3); IR (liquid
1
film): 1714, 1613, 1586, 1514 cm−1; H NMR: d (500 MHz,
CDCl3) 7.24 (2H, d, J = 8.6 Hz, ArH), 6.86 (2H, d, J = 8.6 Hz,
ArH), 4.41 (2H, s, OCH2Ar), 4.37 (1H, quin., J = 5.4 Hz, 11-
CH), 3.80–3.84 (1H, m, 15-CHaHb), 3.80 (3H, s, OCH3), 3.71
(1H, dd, J = 9.7, 5.7 Hz, 15-CHaHb), 3.50 (2H, t, J = 6.6 Hz,
9-CH2), 2.71–2.78 (2H, m, 12-CHaHb + 14-CH), 2.62 (1H, dd,
J = 16.7, 5.4 Hz, 12-CHaHb), 1.71–1.83 (2H, m, 10-CH2), 1.03–
1.06 (24H, m, 14-CHCH3 + Si(CH(CH3)2)3), 0.92 (9H, t, J =
7.9 Hz, Si(CH2CH3)3), 0.58 (6H, q, J = 7.9 Hz, Si(CH2CH3)3),
13C NMR: d (100.6 MHz, CDCl3) 211.7, 159.0, 130.5, 129.2,
113.6, 72.5, 66.4, 65.8, 65.6, 55.2, 50.6, 49.6, 37.6, 17.9, 12.7,
11.8, 6.8, 4.8; HRMS (+FAB) Calc. for C29H53O5Si2 [M–Et]+:
537.3431, found: 537.3381.
Diiodomethane (16.3 mL, 0.203 mol, 15 eq.) was added
dropwise to a stirred suspension of activated Zn (30.6 g,
0.468 mol, 34 eq., dried at 140 ◦C under vacuum for 2 h before
use) and PbI2 (2.04 g, 4.43 mmol, 0.325 eq.) in THF (150 mL) and
the resulting mixture was maintained at self-reflux during the
addition. The reaction m◦ixture was stirred for a further 30 min
at rt before cooling to 0 C. TiCl4 (5.59 mL in 30 mL CH2Cl2,
51 mmol, 3.75 eq.) was added dropwise, and the mixture was
allowed to stir at rt for a further 1 h after the addition. A solution
of TES ether from the above procedure (7.71 g, 13.6 mmol) in
THF (20 mL + 2 × 10 mL washings) was added via cannula and
the resultant mixture was stirred at rt for 4.5 h. The reaction was
quenched by slow addition to pH 7 buffer (600 mL) at 0 ◦C and
the layers were separated. The aqueous phase was extracted with
Et2O (4 × 500 mL), combined organics were washed with brine
(500 mL), dried (MgSO4) and concentrated in vacuo. The crude
material was filtered through a plug of silica, eluting with Et2O–
light petroleum (50 : 50, 500 mL) and concentrated in vacuo to
afford a pale yellow oil consisting of the desired alkene and the
corresponding TES deprotected compound 20. This mixture was
routinely carried through to the subsequent desilylation reaction
without any further purification.
=
=
4.85 (1H, s, C CHaHb), 4.83 (1H, s, C CHaHb), 4.37 (2H,
ABq, J = 11.6 Hz, OCH2Ar), 3.75 (3H, s, OCH3), 3.65 (1H,
dd, J = 9.4, 5.9 Hz, 15-CHaHb), 3.49–3.54 (3H, m, 9-CH2 +
15-CHaHb), 2.51 (1H, dd, J = 14.5, 8.1 Hz, 12-CHaHb), 2.46
(1H, dd, J = 14.5, 5.3 Hz, 12-CHaHb), 2.36 (1H, sextet, J =
6.6 Hz, 14-CH), 1.96–2.08 (2H, m, 10-CH2), 1.03–1.08 (24H,
m, 14-CHCH3 + Si(CH(CH3)2)3); 13C NMR: d (100.6 MHz,
CDCl3) 164.1, 159.0, 150.2, 147.7, 136.0, 130.5, 130.1, 129.3,
123.3, 113.6, 112.2, 72.7, 72.0, 68.1, 66.2, 55.1, 41.6, 41.4, 34.4,
18.0, 16.5, 11.7; HRMS (+FAB) Calc. for C33H48NO7Si [M–H]+:
598.3200, found: 598.3177.
(3S,5S,9S,11S)-1-Benzyloxy-5-(t-butyldimethylsiloxy)-9-
hydroxy-13-[1-(triisopropylsiloxy)-prop-2-(R)-yl]-3,11-bis-
(triethylsiloxy)-tetradec-13-en-7-one (6)
A two-necked flask containing (−)-Ipc2BCl (1.38 g, 4.31 mmol,
1.5 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 0 ◦C and Et3N (681 lL,
4.89 mmol, 1.7 eq.) was added, followed by a solution of ketone
7 (1.42 g, 2.88 mmol) in Et2O (5 mL + 2 × 3 mL washings) via
cannula. The reaction mixture was stirred for a further 40 min
at 0 ◦C then cooled to −78 ◦C before a solution of aldehyde
8 (1.98 g, 4.46 mmol, 1.55 eq.) in Et2O (5 mL + 2 × 3 mL
washings) was added via cannula. The reaction was stirred at
−78 ◦C for a further 3 h then at −20 ◦C for 16 h. The reaction
◦
was quenched by the addition of pH 7 buffer (50 mL) at 0 C
and allowed to warm to room temperature. The layers were
separated and the aqueous phase was extracted with Et2O (3 ×
50 mL). The combined organics were concentrated in vacuo and
the resultant residue was taken up in MeOH (50 mL), pH7 buffer
(25 mL) and cooled to 0 ◦C. A 30% solution of H2O2 (5 mL) was
added and the mixture was warmed to rt and stirred for 2.5 h.
CH2Cl2 (50 mL) and H2O (50 mL) were added and the layers
were separated. The aqueous phase was extracted with CH2Cl2
(4 × 100 mL) and combined organics were washed with brine
(2 × 100 mL), dried (MgSO4) and concentrated in vacuo. Flash
To a solution of this TES ether–alcohol mixture in 1.3 : 1
CH2Cl2 (130 mL) and MeOH (100 mL), was added PPTS (cat.).
The reaction was stirred at rt for 30 min before addition of
Et3N (200 lL) to neutralise the PPTS. The reaction mixture was
concentrated in vacuo and purification by flash chromatography
(20 : 80 → 40 : 60 Et2O–light petroleum) afforded alcohol 20
(5.64 g, 92% over two steps) as a colourless oil: Rf: 0.35 (30 :
70 Et2O–hexanes); [a]2D0 +12.8 (c 1.97, CHCl3); IR (liquid film):
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 9 9 – 2 4 0 9
2 4 0 5

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chromatography (2.5 : 97.5 → 25 : 75 Et2O–light petroleum)
afforded recovered aldehyde 8 (608 mg) and aldol product 6
(2.69 g, 100%) as a colourless oil: Rf: 0.80 (20 : 80 EtOAc–
hexanes); [a]2D0 +14.9 (c 1.93, CHCl3); IR (liquid film): 3518,
biphasic mixture was stirred for 15 min, the layers were separated
and the aqueous phase was extracted with Et2O (3 × 100 mL).
The combined organics were washed with brine (100 mL), dried
(MgSO4) and concentrated in vacuo. Flash chromatography (5 :
95 → 25 : 75 Et2O–light petroleum) afforded ketone 24 (4.69 g,
94%) as a colourless oil: Rf: 0.75 (20 : 80 EtOAc–hexanes); [a]20
−48.0 (c 0.98, CHCl3); IR (liquid film): 1728, 1642, 1463 cm−D1;
1H NMR: d (500 MHz, CDCl3) 7.24–7.33 (5H, m, ArH), 4.84
1
3030, 1711, 1641, 1462 cm−1; H NMR: d (500 MHz, CDCl3)
=
7.27–7.33 (5H, m, ArH), 4.84 (1H, s, C CHaHb), 4.80 (1H, s,
C CHaHb), 4.48 (2H, ABq, J = 11.9 Hz, OCH2Ph), 4.26 (1H,
=
quin., J = 6.0 Hz), 4.16–4.20 (1H, m), 4.06–4.11 (1H, m), 3.94
(1H, quin., J = 6.0 Hz), 3.70 (1H, dd, J = 9.5, 5.3 Hz), 3.45–
3.55 (4H, m, one of which is OH), 2.45–2.60 (4H, m), 2.13–2.34
(3H, m), 1.50–1.88 (6H, m), 1.04–1.10 (24H, m, 14-CHCH3 +
Si(CH(CH3)2)3), 0.94 (9H, t, J = 7.9 Hz, Si(CH2CH3)3), 0.99
(9H, t, J = 8.0 Hz, Si(CH2CH3)3), 0.84 (9H, s, SiC(CH3)3), 0.63
(6H, q, J = 8.0 Hz, Si(CH2CH3)3), 0.58 (6H, q, J = 7.9 Hz,
Si(CH2CH3)3), 0.05 (3H, s, SiCH3), 0.00 (3H, s, SiCH3); 13C
NMR: d (100.6 MHz, CDCl3) 209.2, 148.2, 138.5, 128.3, 127.7,
127.4, 111.8, 73.0, 71.4, 67.7, 66.8, 66.6, 66.1, 51.5, 51.3, 45.4,
44.2, 42.7, 42.5, 37.1, 25.8, 18.0, 17.9, 16.7, 12.0, 6.9, 6.8, 5.1, 5.0,
−4.5, −4.6; HRMS (+FAB) Calc. for C51H101O7Si4Na [MH +
Na]+: 960.6522, found: 960.6589.
=
(2H, s, C CH2), 4.45 (2H, ABq, J = 11.9 Hz, OCH2Ar), 4.17–
4.21 (1H, m, 3-CH), 4.12 (1H, br t, J = 3.0 Hz, 5-CH), 4.05–4.10
(1H, m, 11-CH), 3.66 (1H, dd, J = 9.5, 5.7 Hz, 15-CHaHb), 3.45–
3.55 (3H, m, 1-CHaCHb + 15-CHaHb), 2.52 (1H, dd, J = 14.5,
4.5 Hz, 12-CHaHb), 2.43 (1H, br d, J = 14.3 Hz, 10-CHaHb),
2.17–2.40 (4H, m, 8-CHaHb + 12-CHaHb + 14-CH), 2.13 (1H,
dd, J = 14.3, 11.5 Hz, 10-CHaHb), 1.95 (1H, br d, J = 14.0 Hz,
6-CHaHb), 1.73 (2H, br q, J = 7.3 Hz, 2-CH2), 1.56–1.61 (2H,
m, 4-CHaHb + 6-CHaHb), 1.47 (1H, dt, J = 12.5, 3.0 Hz, 4-
CHaHb), 1.01–1.08 (24H, m, 14-CHCH3 + Si(CH(CH3)2)3),
0.91 (9H, s, SiC(CH3)3), 0.04, 0.06 (6H, 2 × s, Si(CH3)2); 13C
NMR: d (100.6 MHz, CDCl3) 206.4, 147.0, 138.4, 128.3, 127.5,
127.4, 111.9, 99.3, 72.8, 68.2, 67.4, 66.8, 64.1, 62.0, 52.4, 46.2,
42.6, 42.6, 41.5, 41.1, 36.1, 35.7, 25.8, 18.0, 16.4, 11.9, −4.8,
−5.0; HRMS (+FAB) Calc. for C39H69O6Si2 [M + H]+: 689.4633,
found: 689.4643.
(2S,4S,6R,8S,10S)-8-(2-Benzyloxyethyl)-10-(t-
butyldimethylsiloxy)-2-{2-[1-(triisopropylsiloxy)-prop-2-
(R)-yl]-allyl}-1,7-dioxaspiro[5.5]undecan-4-ol (5)
To a stirred solution of the aldol adduct 6 (864 mg, 0.921 mmol,
1.0 eq.) in a 1 : 1 mixture of dry CH2Cl2 (20 mL) and dry
MeOH (20 mL) was added a catalytic amount of PPTS. The
solution was stirred at rt for 40 min (TLC analysis indicated
product 5, hemiacetal and a very small amount of the TBS
deprotected diol) and then a few drops of Et3N were added to
neutralise the PPTS. The reaction was concentrated in vacuo and
the residue was subjected to flash chromatography (10 : 90 →
20 : 80 EtOAc–hexanes) to yield the spiroacetal 57 (405 mg,
63%) followed by the hemiacetal (202 mg, Rf: 0.50 (20% EtOAc
in hexane). The hemiacetal (202 mg) was resubjected to the
above conditions (CH2Cl2 (5 mL), MeOH (5 mL) and a catalytic
amount of PPTS) and after flash chromatography (10 : 90 → 20 :
80 EtOAc–hexanes), a further 157 mg of the spiroacetal 5 was
recovered. The total spiroacetal 5 obtained was 562 mg (88%):
Rf: 0.60 (20 : 80 EtOAc–hexanes); [a]20 −33.2 (c 1.20, CHCl3);
IR (liquid film): 3526, 1642, 1463 cm−1D; 1H NMR: d (500 MHz,
(2S,4S,6R,8S,10S)-8-(2-Benzyloxyethyl)-10-(t-
butyldimethylsiloxy)-4-methyl-2-{2-[1-(triisopropylsiloxy)-
prop-2-(R)-yl]-allyl}-1,7-dioxaspiro[5.5]undecan-4-ol (25)
◦
To a cold (−78 C) solution of ketone 24 (3.84 g, 5.57 mmol)
in THF (35 mL) was added MeMgBr (3.0 M in Et2O, 3.72 mL,
11.2 mmol, 2.0 eq.). The reaction mixture was stirred at −78 ◦C
for 20 min then warmed to 0 ◦C for a further 30 min. The reaction
was quenched with sat. aq. NH4Cl (100 mL) and the layers were
separated. The aqueous phase was extracted with Et2O (3 × 100
mL), combined organics were dried (MgSO4) and concentrated
in vacuo. Flash chromatography (5 : 95 → 25 : 75 Et2O–light
petroleum) afforded 3◦ alcohol 25 (3.73 g, 95%) as a colourless
oil: Rf: 0.75 (20 : 80 EtOAc–hexanes); [a]2D0 −34.7 (c 1.69, CHCl3);
IR (liquid film): 3516, 1642, 1462 cm−1; 1H NMR: d (500 MHz,
=
CDCl3) 7.25–7.32 (5H, m, Ph), 4.88, 4.82 (2H, s, s, C CH2),
4.61 (1H, s, OH), 4.51, 4.47 (2H, ABq, J = 12.0 Hz, OCH2Ph),
4.26 (1H, br t, J = 9.2 Hz, 3-CH), 4.02–4.08 (2H, m, 5-CH +
11-CH), 3.70 (1H, dd, J = 9.2, 5.4 Hz, 15-CHaHb), 3.56 (2H, t,
J = 6.4 Hz, 1-CH2), 3.46 (1H, dd, J = 7.9, 9.2 Hz, 15-CHaHb),
2.44 (1H, dd, J = 5.0, 14.7 Hz, 12-CHaHb), 2.27 (1H, sextet,
J = 6.6 Hz, 14-CH), 2.05 (1H, dd, J = 7.9, 14.7 Hz, 12-CHaHb),
1.69–1.85 (5H, m, 2-CH2 + 6-CHaHb + 8-CHaHb + 10-CHaHb),
1.49–1.60 (3H, m, 4-CH2 + 6-CHaHb), 1.44 (1H, d, J = 13.8 Hz,
8-CHaHb), 1.20 (1H, t, J = 12.5 Hz, 10-CHaHb), 1.15 (3H, s, 9-
CCH3), 1.05–1.10 (24H, m, 14-CHCH3 + Si(CH(CH3)2)3), 0.89
(9H, s, SiC(CH3)3), 0.04, 0.02 (6H, s, s, Si(CH3)2); 13C NMR:
d (62.5 MHz, CDCl3) 147.8, 138.4, 128.3, 127.7, 127.4, 111.3,
98.6, 73.1, 68.1, 67.6, 67.5, 65.2, 64.2, 63.2, 46.6, 43.3, 43.0,
41.7, 41.1, 38.8, 35.9, 30.1, 25.8, 18.1, 18.0, 16.4, 12.0, −4.8,
−4.9; HRMS (+FAB) Calc. for C40H71O6Si2 [M–H]+: 703.4789,
found: 703.4744; m/z: (+FAB) 703 ([M–H]+, 1), 687 (2), 555
(28), 305 (16), 231 (43), 145 (100), 115 (88).
=
CDCl3) 7.27–7.33 (5H, m, ArH), 4.88 (1H, s, C CHaHb), 4.82
(1H, s, C CHaHb), 4.50 (2H, ABq, J = 12.1 Hz, OCH2Ph),
=
4.26–4.28 (1H, m, 3-CH), 4.23 (1H, d, J = 10.5 Hz, OH), 4.09–
4.13 (1H, m, 11-CH), 4.07 (1H, br t, J = 3.3 Hz, 5-CH), 4.03
(1H, br d, J = 10.5 Hz, 9-CH), 3.70 (1H, dd, J = 9.4, 5.4 Hz,
15-CHaHb), 3.57 (2H, t, J = 6.3 Hz, 1-CH2), 3.46 (1H, dd,
J = 9.4, 8.0 Hz, 15-CHaHb), 2.42 (1H, dd, J = 14.6, 5.1 Hz, 12-
CHaHb), 2.27 (1H, sextet, J = 6.5 Hz, 14-CH), 2.06 (1H, dd, J =
14.6, 7.9 Hz, 12-CHaHb), 1.69–1.90 (5H, m, 2-CH2 + 4-CH2 +
10-CHaHb), 1.49–1.62 (4H, m, 6-CH2 + 8-CH2), 1.36 (1H, dt,
J = 12.7, 2.6 Hz, 10-CHaHb), 1.01–1.12 (24H, m, 14-CHCH3 +
Si(CH(CH3)2)3), 0.89 (9H, s, SiC(CH3)3), 0.04 (3H, s, SiCH3),
0.02 (3H, s, Si(CH3)2); 13C NMR: d (62.5 MHz, CDCl3) 147.9,
138.3, 128.3, 127.8, 127.5, 111.3, 98.7, 73.1, 67.7, 65.2, 64.2,
63.5, 63.4, 43.0, 41.7, 41.4, 40.9, 38.8, 37.5, 36.0, 25.8, 18.1,
16.4, 12.0, −4.8, −5.0; HRMS (+FAB) Calc. for C39H70O6Si2
[M]+: 690.4711, found: 690.4752.
(2S,4S,6R,8S,10S)-8-(2-Hydroxyethyl)-10-(t-
(2S,4S,6R,8S,10S)-8-(2-Benzyloxyethyl)-10-(t-
butyldimethylsiloxy)-2-{2-[1-(triisopropylsiloxy)-prop-2-
(R)-yl]-allyl}-1,7-dioxaspiro[5.5]undecan-4-ol (24)
To a suspension of Dess–Martin periodinane (6.18 g, 14.6 mmol,
2 eq.) in CH2Cl2 (80 mL) was added pyridine (5.90 mL,
72.9 mmol, 10 eq.) at rt. The resultant mixture was stirred at
rt for a further 15 min before a solution of alcohol 5 (5.03 g,
7.28 mmol) in CH2Cl2 (10 mL + 2 × 5 mL washings) was added.
The reaction mixture was stirred at rt for a further 30 min and
poured into sat. aq. Na2S2O3–NaHCO3 (1 : 1, 100 mL). The
butyldimethylsiloxy)-4-methyl-2-{2-[1-(triisopropylsiloxy)-
prop-2-(R)-yl]-allyl}-1,7-dioxaspiro[5.5]undecan-4-ol
To a cold (−78 ◦C) solution of benzyl ether 25 (2.29 g, 3.25
mmol) in THF (20 mL) was added a solution of LiDBB28 (0.5 M
in THF, 26.0 mL, 13.0 mmol, 4 eq.), dropwise. The reaction
mixture was stirred at −78 ◦C for 1 h then quenched by addition
of sat. aq. NaHCO3 (50 mL). Et2O (40 mL) was added and
the layers were separated. The aqueous phase was extracted
with Et2O (3 × 40 mL) and the combined organics were dried
(MgSO4) and concentrated in vacuo. Flash chromatography
2 4 0 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 9 9 – 2 4 0 9

View Article Online
oil: Rf: 0.28 (40 : 60 EtOAc–hexanes); [a]2D0 −28.9 (c 0.70, CHCl3);
(20 : 80 → 75 : 25 Et2O–light petroleum) afforded the title
compound (1.99 g, 100%) as a colourless oil: Rf: 0.28 (30 : 70
IR (liquid film): 3460 (m, OH), 2800–3200 (br, COOH) 1730 (s,
EtOAc–hexanes); [a]2D0 −39.7 (c 0.70, CHCl3); IR (liquid film):
1
=
=
C O), 1643, (w, C C); H NMR: d (500 MHz, CDCl3) 4.88
1
=
=
=
3404 (br, OH), 1642,(w, C C); H NMR: d (500 MHz, CDCl3)
(1H, s, C CHaHb), 4.77 (1H, s, C CHaHb), 4.52 (1H, m, 3-
CH), 4.11 (1H, m, 5-CH), 4.05 (1H, m, 11-CH), 3.79 (1H, dd,
J = 14.4, 4.4 Hz, 15-CHaHb), 3.46 (1H, m, 15-CHaHb), 2.38–
2.48 (3H, m, 2-CH2 + 12-CHaHb), 2.33 (1H, m, 14-CH), 2.20
(1H, m, 12-CHaHb), 1.71–1.75 (2H, m, 6-CHaHb + 10-CHaHb),
1.70 (1H, d, J = 13.7 Hz, 8-CHaHb), 1.50–1.63 (4H, m, 4-CH2 +
6-CHaHb + 10-CHaHb), 1.45 (1H, d, J = 13.7 Hz, 8-CHaHb),
1.14 (3H, s, 9-CCH3), 1.13 (3H, d, J = 6.7 Hz, 14-CCH3), 1.08–
1.11 (21H, m, Si(CH(CH3)2)3), 0.90 (9H, s, SiC(CH3)3), 0.04
(3H, s, SiCH3), 0.03 (3H, s, SiCH3); 13C NMR: d (100.6 MHz,
CDCl3) 173.2, 147.6, 111.4, 98.7, 68.8, 67.8, 64.8, 63.9, 62.4, 46.3,
42.8, 42.7, 41.8, 41.3, 40.9, 38.5, 29.8, 25.8, 18.1, 18.0, 16.8, 12.0,
−7.4, −4.9; HRMS (+CI, NH3) Calc. for C33H65O7Si2 [MH]+:
629.4269, found: 629.4269; m/z: (+CI, NH3) 629 ([MH]+, 50)
611 (95), 479 (100), 435 (65), 285 (70), 155 (100).
=
=
4.89 (1H, s, C CHaHb), 4.82 (1H, s, C CHaHb), 4.31 (1H, m,
3-CH), 4.13 (1H, br, s, OH), 4.04–4.08 (2H, m, 5-CH + 11-CH),
3.75–3.76 (2H, m, 1-CH2), 3.71 (1H, dd, J = 9.1, 5.0 Hz, 15-
CHaHb), 3.46 (1H, br t, J = 9.1 Hz, 15-CHaHb), 2.47 (1H, dd,
J = 14.1, 4.4 Hz, 12-CHaHb), 2.36 (1H, m, 14-CH), 2.27 (1H,
br s, OH), 2.07 (1H, dd, J = 14.1, 8.4 Hz, 12-CHaHb), 1.67–1.74
(3H, m, 4-CHaHb + 6-CHaHb + 8-CHaHb), 1.52–1.60 (3H, m,
4-CHaHb + 6-CHaHb + 10-CHaHb), 1.43 (1H, d, J = 13.8 Hz,
8-CHaHb), 1.21 (1H, t, J = 12.1 Hz, 10-CHaHb), 1.14 (3H, s, 9-
CCH3), 1.09–1.13 (24H, m, 14-CHCH3 + Si(CH(CH3)2)3), 0.95
(9H, s, SiC(CH3)3), 0.03 (3H, s, SiCH3), 0.02 (3H, s, SiCH3);
13C NMR: d (62.5 MHz, CDCl3) 148.3, 111.3, 98.3, 68.2, 67.8,
64.8, 64.2, 63.3, 60.1, 46.5, 43.2, 42.2, 41.6, 38.9, 38.0, 30.4, 25.8,
18.0, 18.0, 16.9, 12.0, −4.7, −4.9; HRMS (+CI, NH3) Calc. for
C33H67O6Si2 [MH]+ : 615.4476, found : 615.4480; m/z: (+CI,
NH3) 615 ([MH]+, 5), 598 (20), 465 (60), 257 (50), 141 (100).
2,2,2-Trichloroethyl (2R,4S,6S,8S,10S)-(4-(t-
butyldimethylsiloxy)-10-hydroxy-10-methyl-8-{2-[1-
(triisopropylsiloxy)-prop-2-(R)-yl]-allyl}-1,7-
dioxaspiro[5.5]undec-2-yl)-acetate (26)
(2R,4S,6S,8S,10S)-(4-(t-Butyldimethylsiloxy)-10-hydroxy-10-
methyl-8-{2-[1-methyl-2-(triisopropylsiloxy)-ethyl]-allyl}-1,7-
dioxaspiro[5.5]undec-2-yl)-acetaldehyde
To a solution of the acid from the above procedure (3.02 g, 4.81
mmol), 2,2,2-trichloroethanol (0.554 mL, 5.77 mmol, 1.2 eq.)
and DMAP (cat.) in CH2Cl2 (20 mL) at rt was added a solution of
DCC (1.0 M in CH2Cl2, 9.62 mL, 9.62 mmol, 2 eq.). The reaction
mixture was stirred at rt for 2 h and then quenched by addition
of H2O (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 (MgSO4) and
concentrated in vacuo. Flash chromatography (5 : 95 → 20 :
80 Et2O–light petroleum) afforded ester 26 (3.18 g, 87%) as a
colourless oil: Rf: 0.23 (10 : 90 EtOAc–hexanes); [a]2D0 −26.3 (c
To a solution of the alcohol from the above procedure (3.33 g,
5.42 mmol) in CH2Cl2 (30 mL) was added Dess–Martin perio-
dinane (4.60 g, 10.8 mmol, 2 eq.) and the resulting suspension
was stirred at rt for 2 h. The reaction was poured into sat. aq.
Na2S2O3–NaHCO3 (1 : 1, 200 mL) and the biphasic mixture
was stirred for a further 15 min. The layers were separated
and the aqueous phase was extracted with Et2O (3 × 100 mL),
combined organics were dried (MgSO4) and concentrated in
vacuo. Flash chromatography (5 : 95 → 75 : 25 Et2O–light
petroleum) afforded the title compound (3.30 g, 99%) as a
colourless oil: Rf: 0.36 (30 : 70 EtOAc–hexanes); [a]2D0 −34.4
=
1.70, CHCl3); IR (liquid film): 3536 (m, OH), 1760 (s, C O),
1
=
=
(c 0.80, CHCl3); IR (liquid film): 3528 (m, OH), 1729 (s, C O),
1642, (w, C C); H NMR: d (500 MHz, CDCl3) 4.93 (1H, s,
1
=
=
=
1641, (w, C C); H NMR: d (500 MHz, CDCl3) 9.81 (1H, m,
C CHaHb), 4.87 (1H, s, C CHaHb), 4.80 (1H, d, J = 12.0 Hz,
OCHaHbCCl3), 4.70 (1H, d, J = 12.0 Hz, OCHaHbCCl3), 4.58
(1H, m, 3-CH), 4.19–4.23 (2H, m, 11-CH + OH), 4.10 (1H, m,
5-CH), 3.72 (1H, dd, J = 9.5, 5.3 Hz, 15-CHaHb), 3.48 (1H,
dd, J = 9.5, 7.7 Hz, 15-CHaHb), 2.62–2.68 (2H, m, 2-CH2),
2.48 (1H, dd, J = 14.7, 4.9 Hz, 12-CHaHb), 2.31 (1H, m, 14-
CH), 2.02 (1H, dd, J = 14.7, 8.4 Hz, 12-CHaHb), 1.63–1.80
(2H, m, 6-CHaHb + 10-CHaHb), 1.62 (1H, d, J = 13.4 Hz, 8-
CHaHb), 1.51–1.58 (2H, m, 4-CHaHb + 6-CHaHb), 1.42 (1H, d,
J = 13.4 Hz, 8-CHaHb), 1.28 (1H, t, J = 7.2 Hz, 10-CHaHb), 1.13
(3H, s, 9-CCH3), 1.08 (3H, d, J = 8.8 Hz, 14-CHCH3), 1.02–1.05
(21H, m, Si(CH(CH3)2)3), 0.89 (9H, s, SiC(CH3)3), 0.04 (3H, s,
SiCH3), 0.02 (3H, s, SiCH3); 13C NMR: d (62.5 MHz, CDCl3)
169.5, 147.8, 111.3, 98.8, 94.9, 73.9, 68.0, 67.6, 65.2, 63.8, 61.5,
46.5, 43.1, 41.4, 41.1, 40.1, 38.2, 30.2, 25.8, 18.1, 18.0, 16.4, 12.0,
−4.8, −5.0; HRMS (+ESI) Calc. for C35H69NO7Cl3Si2 [M +
NH4]+: 776.3678, found: 776.3676; m/z: (+CI, NH3) 776–780
([M + NH4]+, 20), 740–746 (80), 705–711 (100), 669–675 (40),
609–611 (60), 573–577 (70), 436–438 (50).
=
=
1-CHO), 4.94 (1H, s, C CHaHb), 4.88 (1H, s, C CHaHb), 4.65
(1H, m, 3-CH), 4.12 (2H, m, 5-CH + 11-CH), 4.01 (1H, br, s,
OH), 3.72 (1H, dd, J = 9.4, 5.4 Hz, 15-CHaHb), 3.48 (1H, dd, J =
9.4, 7.7 Hz, 15-CHaHb), 2.61 (1H, ddd, J = 16.5, 8.3, 2.3 Hz, 2-
CHaHb), 2.56 (1H, m, 2-CHaHb), 2.48 (1H, dd, J = 14.6, 4.9 Hz,
12-CHaHb), 2.31 (1H, br sextet, J = 6.4 Hz 14-CH), 2.06 (1H,
dd, J = 14.6, 8.2 Hz, 12-CHaHb), 1.74–1.78 (2H, m, 6-CHaHb +
10-CHaHb), 1.65 (1H, d, J = 14.0 Hz, 8-CHaHb), 1.51–1.62
(3H, m, 4-CH2 + 6-CH), 1.43 (1H, d, J = 14.0 Hz, 8-CHaHb),
1.20 (1H, m, 10-CHaHb), 1.16 (3H, s, 9-CCH3), 1.04–1.10 (24H,
m, Si(CH(CH3)2)3 + 14-CHCH3), 0.89 (9H, s, SiC(CH3)3), 0.04
(3H, s, SiCH3), 0.03 (3H, s, SiCH3); 13C NMR: d (62.5 MHz,
CDCl3) 199.6, 147.8, 111.4, 98.9, 68.0, 67.6, 65.4, 63.8, 60.2,
49.4, 46.5, 43.1, 41.4, 41.1, 38.3, 30.0, 25.8, 18.0, 18.0, 16.4,
12.0, −4.8, −5.0; HRMS (+CI, NH3) Calc. for C33H68NO6Si2
[M + NH4]+: 630.4585, found: 630.4590; m/z: (+CI, NH3) 630
([M + NH4]+, 15), 595 (20), 285 (100), 257 (70), 156 (40).
(2R,4S,6S,8S,10S)-(4-(t-Butyldimethylsiloxy)-10-hydroxy-10-
methyl-8-{2-[1-(triisopropylsiloxy)-prop-2-(R)-yl]-allyl}-1,7-
dioxaspiro[5.5]undec-2-yl)-acetic acid
2,2,2-Trichloroethyl (2R,4S,6S,8S,10S)-(4-acetoxy-8-{2-[1-
oxo-prop-2-(R)-yl]-allyl}-10-methyl-10-(triethylsiloxy)-1,7-
dioxaspiro[5.5]undec-2-yl)-acetate (2)
To a solution of the aldehyde from the above procedure (901 mg,
◦
1.47 mmol) in t-BuOH (18 mL) and H2O (6 mL) at 0 C was
To a solution of alcohol 29 (45.9 mg, 71.3 lmol) in CH2Cl2
(2 mL) at rt was added Dess–Martin periodinane (60.0 mg,
143 lmol, 2 eq.). The reaction mixture was stirred at rt for
1 h and quenched by pouring into sat. aq. Na2S2O3–NaHCO3
(1 : 1, 10 mL). The biphasic mixture was stirred for a further
15 min and the layers were separated. The aqueous phase was
extracted with Et2O (3 × 20 mL), combined organics were
washed with brine (20 mL), dried (MgSO4) and concentrated in
vacuo. Flash chromatography (20 : 80 EtOAc–light petroleum)
afforded aldehyde 2 (42.7 mg, 93%) as a colourless oil: Rf: 0.64
added 2-methyl-2-butene (2.0 M in THF, 4.4 mL, 8.8 mmol,
6 eq.), followed by the dropwise addition of a solution of
NaClO2 (technical grade ca. 80%, 333 mg, 2.94 mmol, 2 eq.) and
NaH2PO4·2H2O (0.92 g, 5.9 mmol, 4 eq.) in H2O (12 mL). The re-
sulting mixture was warmed to rt and stirred for 16 h and then di-
luted with H2O (30 mL) and acidified with AcOH (few drops →
pH 6). The mixture was extracted with EtOAc (4 × 15 mL),
the combined extracts were dried (Na2SO4) and concentrated in
vacuo to yield the title compound (924 mg, 100%), as a colourless
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 3 9 9 – 2 4 0 9
2 4 0 7

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(50 : 50 EtOAc–hexanes); [a]2D0 −69.0 (c 3.00, CHCl3); IR
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1
=
=
(liquid film): 2954, 1760, 1732 (s, C O), 1640 (w, C C); H
NMR: d (500 MHz, CDCl3) 9.57 (1H, s, 15-CHO), 5.19 (1H, s,
=
=
C CHaHb), 5.06 (1H, m, 5-CH), 4.93 (1H, s, C CHaHb), 4.84
(1H, d, J = 12.0 Hz, OCHaHbCCl3), 4.63 (1H, d, J = 12.0 Hz,
OCHaHbCCl3), 4.48 (1H, m, 3-CH), 4.33 (1H, m, 11-CH), 3.26
(1H, q, J = 6.9 Hz, 14-CH), 2.78 (1H, dd, J = 16.6, 6.3 Hz,
2-CHaHb), 2.54 (1H, dd, J = 16.6, 6.8 Hz, 2-CHaHb), 2.67 (1H,
dd, J = 14.2, 6.8 Hz, 12-CHaHb), 2.18 (1H, dd, J = 14.2, 5.9 Hz,
12-CHaHb), 2.02 (3H, s, COCH3), 1.82–1.90 (2H, m, 6-CHaHb +
4-CHaHb), 1.78 (1H, dd, J = 14.2, 1.7 Hz, 8-CHaHb), 1.54–1.60
(3H, m, 6-CHaHb + 4-CHaHb + 10-CHaHb), 1.30 (1H, d, J =
14.2 Hz, 8-CHaHb), 1.23 (3H, d, J = 6.9 Hz, 14-CHCH3), 1.21
(4H, m, 10-CHaHb + 9-CCH3), 0.93 (9H, m, Si(CH2CH3)3), 0.56
(6H, m, Si(CH2CH3)3); 13C NMR: d (100.6 MHz, CDCl3) 201.2,
170.4, 168.8, 143.0, 125.1, 115.0, 96.6, 94.4, 73.4, 69.7, 66.4, 64.4,
60.2, 52.1, 47.0, 44.1, 41.6, 39.5, 37.9, 33.4, 31.5, 29.8, 29.2, 21.0,
12.7, 6.8, 6.3; HRMS (+CI, NH3) Calc. for C28H45O8Cl3Si [M +
Na]+: 665.1847, found: 665.1848.
Acknowledgements
Financial support was provided by the EPSRC (GR/L41646),
Churchill College (Research Fellowship to D.J.W.), NSERC-
Canada (Postdoctoral Fellowship to R.M.O.), Cambridge Com-
monwealth Trust (M.J.C.), King’s College and Sim’s Fund,
Cambridge (D.Y.-K.C.). We thank Merck, AstraZeneca and
Novartis Pharmaceuticals for generous support and Dr Anne
Butlin (A.Z.) for valuable assistance.
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