The stereocontrolled total synthesis of altohyrtin A/spongistatin 1: The southern hemisphere EF segment

Article abstract of DOI:10.1039/b504149j

The fully functionalised C29-C51 southern hemisphere of altohyrtin A/spongistatin 1 (1), incorporating the E- and F-ring tetrahydropyran rings and the unsaturated side chain, has been synthesised in a highly convergent and stereocontrolled manner. Key steps in the synthesis of this phosphonium salt include four highly diastereoselective, substrate-controlled, boron aldol reactions to establish key C-C bonds and accompanying stereocentres, where the introduction of the chlorodiene side chain and the C47 hydroxyl-bearing centre were realised by exploiting remote stereoinduction from the F-ring tetrahydropyran. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b504149j

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A R T I C L E
The stereocontrolled total synthesis of altohyrtin A/spongistatin 1:
the southern hemisphere EF segment†‡
Ian Paterson,* Mark J. Coster,§ David Y.-K. Chen, Jose´ L. Acen˜a, Jordi Bach, Linda E. Keown
and Thomas Trieselmann
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
The fully functionalised C29–C51 southern hemisphere of altohyrtin A/spongistatin 1 (1), incorporating the E- and
F-ring tetrahydropyran rings and the unsaturated side chain, has been synthesised in a highly convergent and
stereocontrolled manner. Key steps in the synthesis of this phosphonium salt include four highly diastereoselective,
substrate-controlled, boron aldol reactions to establish key C–C bonds and accompanying stereocentres, where the
introduction of the chlorodiene side chain and the C47 hydroxyl-bearing centre were realised by exploiting remote
stereoinduction from the F-ring tetrahydropyran.
structurally complex polyketide natural product involves its
Introduction
disconnection into three major fragments, one of which is the
Altohyrtin A/spongistatin 1 (1, Scheme 1) is a remarkably
C29–C51 southern hemisphere EF-subunit 2, incorporating the
cytotoxic marine macrolide that is in limited supply from
sensitive chloro-triene side chain.3–5 Herein, we provide a full
its sponge sources.1 Our strategy2 for the synthesis of this
account of our synthesis of this segment, which proved by far
to be the most challenging part of the spongipyran molecular
architecture that we had to assemble.2b,f Our synthesis of the
fully functionalised C29–C51 phosphonium salt 2 was designed
to minimise functional group manipulations subsequent to late
† Part 3 of a series of four papers.1
‡ Electronic supplementary information (ESI) available: general exper-
imental information and procedures for the synthesis of compounds
stage Wittig coupling with the C1–C28 northern hemisphere
ABCD-subunit. It was planned that 2 would be derived, in the
forward sense, from a stereocontrolled boron aldol reaction6
between complex methyl ketone 3 and aldehyde 4, followed by
hydroxyl protection, ketone methylenation and conversion of the
not detailed in the Experimental section of this paper. See http://
www.rsc.org/suppdata/ob/b5/b504149j/
§ Current address: School of Chemistry, University of Sydney, NSW
2006, Australia. Email: m.coster@chem.usyd.edu.au; Fax: +61 2 9351
3329.
Scheme 1 Retrosynthetic analysis for the C29–C51 southern hemisphere EF-subunit 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 2 0 – 2 4 3 0 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 2 0
©

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primary alkyl chloride to the corresponding phosphonium salt.
The E-ring of 3 would be formed by acetalisation of 5, which
in turn might be obtained by a stereocontrolled aldol reaction
between F-ring methyl ketone 6 and aldehyde 7, the latter of
which is simplified by a further aldol disconnection. It was
proposed that the formation of the F-ring in 6 would be achieved
by intramolecular hetero-Michael addition of 8, which might be
derived from 9 using Sharpless asymmetric dihydroxylation and
chain extension as key steps. Finally, the stereo-tetrad present
in 9 is well suited to the application of an asymmetric aldol-
stereoselective reduction sequence, as previously developed in
our laboratory.
Results and discussion
Synthesis of the C29–C35 segment 7
Our synthesis of C29–C35 aldehyde 7 utilised syn-selective aldol
methodology of a lactate-derived ethyl ketone,7 to establish the
C34 and C35 stereocentres. To this end, (Z)-selective enolisation
of ketone 10 under the standard conditions (Chx2BCl, Et3N,
Et2O)7,8 provided the dicyclohexylboron enolate 11, in situ
(Scheme 2). This underwent a highly diastereoselective aldol
reaction with 5-chloropentanal (12), to provide 13 (>95 : 5 dr),
which was protected as the triethylsilyl (TES) ether 14 (98%
from 10). The stereochemical assignment of aldol adduct 13 was
made by analogy with our extensive previous work with aldol
reactions of such lactate-derived ethyl ketones,7 and by NMR
analysis of a cyclic derivative prepared later in the synthesis, vide
infra. The aldol reaction to form 13 is believed to proceed via TS-
1, where the PMB ether and enolate oxygens are directed away
from each other, and the smaller of the two remaining groups at
the stereogenic centre (H vs. Me), is directed inwards. Removal
of the p-methoxybenzyl (PMB) group from 14 was achieved
using DDQ, providing a-hydroxy ketone 15 in preparation for
conversion to the corresponding C35 aldehyde.
Scheme 3 Reagents and conditions: (a) Chx2BCl, Et3N, Et2O, −78 →
0 ◦C, 2 h; (b) MeCHO, −78 → −20 ◦C, 16 h, then pH 7 buffer, H2O2,
MeOH, 0 ◦C, 3 h; (c) Me4NBH(OAc)3, MeCN–AcOH (1 : 1), 4 ◦C, 60 h.
boron enolate 17, in situ (Scheme 3). Reaction with acetaldehyde
ina substrate-controlledaldol reaction providedthe 1,2-anti-2,4-
anti adduct 18 with excellent diastereocontrol (≥97 : 3 dr) in 93%
yield. While the configuration of 18 was confidently predicted
on the basis of previous work by our group,9 the large vicinal
coupling constant (3J = 6.4 Hz) between protons of the newly
formed stereocentres validated the 1,2-anti stereochemistry and
1H NMR analysis of the derived MTPA esters10 confirmed the
(37R)-configuration. The contra-steric preference for reaction
via TS-2, in which A(1,3) strain is minimised,11 could be a
result of unfavourable repulsion between the oxygen lone pairs
of the boron enolate and ether (PMB) in the diastereomeric
chair-like transition state TS-3. There may also be a favourable
formyl hydrogen bond12 between the aldehydic hydrogen and
the PMB ether oxygen contributing to stabilisation of TS-2.
Next, stereoselective 1,3-anti reduction of b-hydroxy ketone
18 was achieved with tetramethylammonium triacetoxyborohy-
dride {Me4NBH(OAc)3} in MeCN–AcOH,13 to yield the desired
diol 19 as the major diastereomer (80 : 20 dr). Separation of the
unwanted 1,3-syn diastereomer was readily achieved at a later
stage, vide infra.
With the requisite diol 19 in hand, conversion to aldehyde
20 was achieved in three steps by firstly acetonide protection14
{cat. p-toluenesulfonic acid (PTSA), Me2C(OMe)2} and PMB
removal by DDQ to reveal the C41 primary alcohol (Scheme 4).
At this stage, the desired compound and the corresponding,
undesired C39 epimer were readily separable. Oxidation of
the primary alcohol using the Dess–Martin periodinane15 then
provided aldehyde 20 (61% from 19).
Horner–Wadsworth–Emmons (HWE) chain extension of a-
chiral aldehyde 20 to the (E)-alkene 9 was best achieved under
the Masamune–Roush conditions,16 using trimethylphospho-
noacetate, LiCl and i-Pr2NEt in MeCN (96% yield), with no de-
tectable epimerisation at C40. Although sluggish to react under
standard conditions, Sharpless asymmetric dihydroxylation17 of
9 using enriched AD-mix-b,17b with added MeSO2NH2, provided
the desired diol 21 in 98% yield with excellent diastereoselectivity
(≥97 : 3 dr). Protection of the C38 hydroxyl as a benzyl ether
was crucial to obtain good stereoselectivity in this asymmet-
ric dihydroxylation. By comparison, an analogue with tert-
butyldimethylsilyl (TBS) protection of the C38 hydroxy group
Scheme 2 Reagents and conditions: (a) Chx2BCl, Et3N, Et2O, −78 ◦C,
1 h; (b) 12, −78 → −20 ◦C, 17 h, then pH 7 buffer, H2O2, MeOH,
DDQ, CH2Cl2–pH 7 buffer (10 : 1), 0 ◦C, 2 h.
0
◦C → rt, 2 h; (c) TESOTf, 2,6-lutidine, CH2Cl2, −78 ◦C, 1 h; (d)
Synthesis of the C36–C46 F-ring ketone 6
Ketone 16, derived from methyl (R)-3-hydroxy-2-methylpro-
pionate (Roche ester),2b,9b was subjected to (E)-selective eno-
lisation under conditions previously employed with a number
of closely related a-chiral alkoxymethyl ketones,9 to provide the
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 2 0 – 2 4 3 0
2 4 2 1

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Scheme 4 Reagents and conditions: (a) Me2C(OMe)2, cat. PTSA, CH2Cl2, rt, 16 h; separate from starting materials, 5 cycles; (b) DDQ, CH2Cl2–pH 7
buffer (5 : 1), 0 ◦C, 1.5 h; (c) Dess–Martin periodinane, CH2Cl2, rt, 1 h; (d) (MeO)2P(O)CH2CO2Me, LiCl, i-Pr2NEt, MeCN, rt, 16 h; (e) enriched
AD-mix-b, t-BuOH–H2O (1 : 1), MeSO2NH2, rt, 16 h; (f) H2, cat. Pd(OH)2–C, NaHCO3, MeOH, rt, 20 h; (g) PMBOC(NH)CCl3, cat. Ph3CBF4,
THF, 0 ◦C, 0.5 h; (h) DIBAL-H, CH2Cl2, −78 ◦C, 1.5 h; (i) (MeO)2P(O)CH2COCH3, Ba(OH)2, THF–H2O (40 : 1), rt, 16 h; (j) AcOH–THF–H2O
(9 : 1 : 1), rt, 60 h; (k) KOH, MeOH, rt, 20 h; (l) Cp2TiMe2, PhMe, 110 ◦C, 2 h; (m) cat. TPAP, NMO, 4 A mol. sieves, CH2Cl2, 0 ◦C → rt, 2 h.
˚
gave an unsatisfactory ca. 2 : 1 mixture of diastereomers under
the same dihydroxylation conditions.
all-equatorial tetrahydropyran 25 as the major diastereomer
(95 : 5 dr, 86% yield from 24), the stereochemistry of which
was confirmed by analysis of NOESY spectra.
At this juncture, it became necessary to make a judicious
choice of protecting groups for the C41 and C42 hydroxyl
groups and to re-appraise the C38 hydroxyl protecting group.
Our previously reported synthesis of the C36–C46 segment of
altohyrtin A,2b utilised the b-(trimethylsilyl)ethoxymethyl (SEM)
protecting group for the C41 and C42 hydroxyls and a benzyl
(Bn) ether at C38. Through model studies and the results of
experiments on other advanced intermediates, the PMB group
was chosen for protection of the C38, C41 and C42 hydroxyls.
Hence, our synthetic plan for 1 would involve the removal of all
three PMB ethers on a sensitive fully-protected seco-compound,
prior to regioselective macrolactonisation at the C41 hydroxyl
on the resultant triol. Although PMB ethers can be problematic
to remove on sensitive substrates, we were reasonably confident,
on the basis of extensive prior work using this protecting group
(as well as from the Kishi synthesis3f of altohyrtin A, which
involved removal of two PMB ethers), that appropriately mild
deprotection conditions would be developed for the late-stage
tris-PMB removal.
With the protecting group strategy mapped out, debenzyla-
tion of 21 to provide triol 22, was achieved by hydrogenolysis
(H2, Pd(OH)2–C, MeOH) in the presence of NaHCO3, in
order to prevent adventitious acid-promoted removal of the
sensitive acetonide moiety.18 Subjection of triol 22 to an excess
of p-(methoxybenzyl)trichloroacetimidate (PMBTCA)19 and
catalytic trityl tetrafluoroborate (Ph3CBF4)20 in THF effected
smooth protection of all three hydroxyl groups to afford 23 (97%
yield). The excellent yield obtained in this tris-PMB protection
highlights the superior nature of Ph3CBF4 as a catalyst for
etherifications of this type, on delicate acid-sensitive substrates.
Reduction of 23 directly to the corresponding aldehyde using
diisobutylaluminium hydride (DIBAL-H), which is presumably
assisted by chelation of the intermediate aluminium species by
a neighbouring alkoxy group, was followed by HWE chain
extension with (MeO)2P(O)CH2COCH3 to the a,b-unsaturated
methyl ketone 24, this time using activated Ba(OH)2 in aq. THF21
(90% from 23).
At this point, it was possible, in principle, to construct the
remainder of the southern hemisphere fragment 2 by aldol
reactions at either the C36 or C46 terminus. In order to minimise
the number of synthetic operations conducted in the presence
of the sensitive chloro-trienol side-chain, extension via initial
aldol reaction at the C36 terminus was exploited. In preparation
for this aldol reaction, 25 was m◦ethylenated using the Petasis
reagent22 (Cp2TiMe2, PhMe, 110 C). Subsequent oxidation at
C37 (TPAP, NMO)23 provided ketone 6 (76% yield from 25),
ready for aldol reaction with the C29–C35 segment.
Aldol union of the C29–C35 and C36–C46 segments and
formation of the F-ring
In preparation for the aldol reaction to unite the C29–C35
and C36–C46 fragments, a-hydroxy ketone 15 was reduced to a
diastereomeric mixture of vicinal diols with LiAlH4 (Scheme 5),
which were subsequently cleaved oxidatively to the aldehyde 7
as needed, using Pb(OAc)4 (87% from 15). With the requisite
ketone 6 and aldehyde 7 in hand, realisation of the desired aldol
reaction proved to be demanding. In simplified model systems,
the required Felkin–Anh selective aldol reaction was achievable
using Mukaiyama conditions, or by using tin(II), boron and
lithium enolates. However, all attempts to effect the Mukaiyama
aldol reaction of aldehyde 7 with the trimethylsilyl (TMS) enol
ether of 6, under a variety of conditions, were unsuccessful.
Standard conditions for the aldol reaction of 6 with 7 using tin(II)
and boron enolates (Chx2BCl, Et3N) also failed to deliver any
aldol product. Furthermore, the lithium-mediated aldol reaction
provided the undesired anti-Felkin–Anh diastereomer in low
yield.
Success in the aldol union of 6 with 7 was finally achieved by
using a more reactive boron Lewis acid, Chx2BBr, in the enolate
preparation. As such, ketone 6 was transformed into the boron
enolate 26 (Chx2BBr, Et3N, Et2O, −78 ◦C), in situ, followed by
reaction with aldehyde 7 to afford the desired aldol product 5
with good diastereoselectivity (90 : 10 dr). Although 5 could be
separated from the corresponding C35 epimer by careful column
chromatography at this stage, it was more convenient to first
subject 5 to a catalytic amount of pyridinium p-toluenesulfonate
(PPTS) in MeOH–(MeO)3CH to effect TES deprotection and
formation of the E-ring as a methyl acetal 27 (82% from 6), which
was readily separated from its C35 epimer. At this point, analysis
of NOESY spectra obtained for 27 and 35-epi-27 confirmed the
With the stage set for formation of the F-ring of altohyrtin A
(1), 24 was exposed to AcOH–THF–H2O, unmasking the C37
and C39 hydroxyls, with concomitant intramolecular hetero-
Michael addition to give a ca. 1 : 1 mixture of C43 epimeric
tetrahydropyrans. Base-promoted equilibration of this mixture
could be achieved with either Triton methoxide (BnNMe3OMe)
in THF–MeOH or with KOH in MeOH. The latter procedure
proved superior on scaling up, cleanly providing the desired,
2 4 2 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 2 0 – 2 4 3 0

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Scheme 6 Reagents and conditions: (a) (EtO)2P(O)CH2CO2Et, NaH-
MDS, catechol, THF, −78 → −20 ◦C, 19 h; (b) DIBAL-H, CH2Cl2,
−78 ◦C, 2 h; (c) (COCl)2, DMSO, −78 ◦C, 20 min; then Et3N, −78 ◦C,
1 h; (d) Chx2BCl, Et3N, Et2O, −78 → −40 ◦C, 1.5 h; (e) 4, −78 →
−20 ◦C, 16 h, then pH 7 buffer, H2O2, MeOH, 0 ◦C, 2.5 h.
the 1,5-anti stereoinduction typically observed for boron aldol
reactions of simple b-alkoxy methyl ketones,26,27 indicating the
overriding influence, in this more complex case, of the more
remote stereocentres. This serendipitous result was certainly
welcome and greatly simplified the introduction of the C47
stereocentre, particularly relative to the more elaborate strategies
employed by other research groups.3–5
Following on from these promising model studies, the C29–
C46 EF-subunit 28 was converted into the corresponding C45
ketone 3 in 90% yield (Scheme 7). Regioselective enolisation
of 3 provided the boron enolate 32, in situ, which underwent
smooth aldol reaction with 4. After careful oxidative workup,
the desired (47S)-adduct 33 was isolated in 79% yield as the
major diastereomer (95 : 5 dr). The (47S)-configuration was
determined by 1H NMR analysis of the derived MTPA esters.10
The enhanced stereoselectivity in this aldol reaction compared
to the case with F-ring ketone 29, both of which are under
substrate control, illustrates a reinforcing stereodirecting effect
of the E-ring. In both these cases, the corresponding lithium
aldol reaction (LiHMDS) gave no measurable induction.
Towards completion of the fully elaborated southern hemi-
sphere segment 2, the C47 hydroxyl was protected as the
corresponding TBS ether 34 (93% yield), and methylenation
of this highly functionalised compound was achieved in 81%
yield, providing 35, by using a modified Takai procedure
under carefully controlled conditions (Zn, cat. PbI2, TMSCl,
CH2I2, TiCl4).28 Finally, conversion of the chloride 35 to the
corresponding phosphonium salt 2 was readily achieved in 91%
yield by heating with Ph3P in the presence of NaI. Notably,
the selection of a chloride substituent at C29, as opposed to
a protected hydroxyl group, served to streamline the synthetic
sequence.
Scheme 5 Reagents and conditions: (a) LiAlH4, THF, −78 ◦C, 0.5 h;
(b) Pb(OAc)4, Na2CO3, CH2Cl2, 0 ◦C, 40 min; (c) Chx2BBr, Et3N, Et2O,
−78 ◦C, 2.5 h; (d) 7, −78 → −20 ◦C, 17 h, then pH 7 buffer, H2O2,
MeOH, 0 ◦C → rt, 2 h; (e) cat. PPTS, MeOH–(MeO)3CH (10 : 1), rt,
2 h; (f) TBSCl, Et3N, Im, DMF, rt, 48 h.
assigned stereochemistry, established in the aldol reaction of 6
with 7. At this stage, recycling of the undesired diastereomer 35-
epi-27 could be achieved by oxidation (TPAP, NMO) followed by
stereoselective reduction with L-Selectride to give a ca. 4 : 1 ratio
of 27 and 35-epi-27, respectively (63% yield). Finally, the axial
C35 hydroxyl was protected as the TBS ether under carefully
defined conditions (TBSCl, Et3N, Im, DMF), providing 28 in
98% yield.
Installation of the chloro-trienol side-chain and final steps to
construct the southern hemisphere phosphonium salt 2
Model studies for the key aldol reaction to install the C47–
C51 chlorodiene segment were carried out on C36–C46 F-ring
ketone 29 (Scheme 6). The required C47–C51 aldehyde 4 was
synthesised in three steps from 2-chloroacrolein24 by HWE chain
extension, DIBAL-H reduction and Swern oxidation25 in 76%
overall yield. Conversion of ketone 29 into the dicyclohexyl-
boron enolate 30, under the standard conditions, and reaction
with (E)-4-chloro-2,4-pentadienal (4) provided the desired aldol
product 31 with surprisingly good diastereoselectivity (80 : 20
dr). Notably, this outcome is in the 1,5-syn sense, in contrast to
Conclusions
The functionally and stereochemically dense C29–C51 EF
southern hemisphere subunit 2 has been synthesised in a
highly stereoselective manner, providing access to multi-gram
quantities. Key steps include two substrate-controlled boron
aldol reactions of elaborately functionalised methyl ketones, 6
and 3, to install the E-ring linear precursor and chlorodienol
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 2 0 – 2 4 3 0
2 4 2 3

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Scheme 7 Reagents and conditions: (a) cat. OsO4, Me3N→O, acetone–H2O (8 : 1), rt, 16 h; (b) Pb(OAc)4, Na2CO3, CH2Cl2, 0 ◦C, 40 min; (c)
Chx2BCl, Et3N, Et2O, −78 → −40 ◦C, 1.5 h; (d) 4, −78 → −20 ◦C, 16 h, then pH 7 buffer, H2O2, MeOH, 0 ◦C, 2.5 h; (e) TBSCl, Im, DMF, rt, 2 h;
(f) Zn, cat. PbI2, TMSCl, CH2I2, TiCl4, THF–CH2Cl2, rt, 1.75 h, then 34, THF, rt, 4 h; (g) PPh3, NaI, i-Pr2NEt, MeCN–MeOH (9 : 1), D, 19 h.
side-chains, respectively. Notably, the late-stage incorporation of
the C47–C51 side-chain segment and the remote C47 hydroxyl-
bearing stereocentre by a remarkably stereoselective (1,5-syn)
aldol reaction should allow ready access to the C50 protio-
and bromo-altohyrtin/spongistatin congeners, by appropriate
choice of aldehyde coupling partner. At this stage, we had
assembled the three major fragments of altohyrtin A by scalable
routes and were poised to examine their sequential coupling and
elaboration, as described in Part 4 of this series.29
129.4, 129.4, 113.9, 79.2, 71.4, 70.8, 55.3, 45.2, 44.9, 33.2, 32.4,
23.4, 17.3, 10.1; HRMS: (+ES) Calc. for C18H31ClNO4 [M +
NH4]+: 360.1942, found: 360.1944; m/z: (+CI, NH3) 360 ([M +
NH4]+, 5), 240 (40), 138 (40), 121 (100).
(2R,4S,5R)-9-Chloro-5-triethylsiloxy-2-(p-methoxybenzyloxy)-
4-methyl-nonan-3-one (14)
To a cold (−78 ◦C) solution of aldol product 13–ChxOH (2.53 g,
max. 6.64 mmol) in CH2Cl2 (60 mL) was added 2,6-lutidine
(1.72 mL, 14.8 mmol, 2.2 eq.), followed by TESOTf (2.50 mL,
11.1 mmol, 1.67 eq.). The reaction mixture was stirred at −78 ◦C
for 1 h then quenched by the addition of sat. aq. K2CO3
(50 mL). The mixture was allowed to warm to rt 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 → 20 :
80 EtOAc–light petroleum) afforded TES ether 14 (2.97 g, 98%
over two steps from 10) as a colourless oil: Rf: 0.37 (15 : 85
EtOAc–hexanes); [a]2D0 +31.5 (c 1.80, CHCl3); IR (film): 2952,
Experimental
(2R,4S,5R)-9-Chloro-5-hydroxy-2-(p-methoxybenzyloxy)-4-
methyl-nonan-3-one (13)
To a cold (−78 ◦C) solution of Chx2BCl (1.89 mL, 8.62 mmol,
1.3 eq.) in Et2O (30 mL) was added Et3N (1.39 mL, 9.97 mmol,
1.5 eq.) followed by a solution of ketone 10 (1.48 g, 6.64 mmol)
in Et2O (5 mL + 2 × 2 mL washings) via cannula. The reaction
mixture was stirred at −78 ◦C for 1 h before a solution of
aldehyde 12 (ca. 1.3 eq.) in PhMe was added. The ◦mixture was
−1
1
=
2875, 1716 (C O) cm ; H NMR: d (500 MHz, CDCl3) 7.27
(2H, d, J = 8.5 Hz, ArH), 6.88 (2H, d, J = 8.6 Hz, ArH), 4.47
(2H, s, OCH2Ar), 4.04 (1H, q, J = 6.7 Hz, 36-CH), 3.96–4.00
(1H, m, 33-CH), 3.80 (3H, s, ArOCH3), 3.46 (2H, t, J = 6.6 Hz,
29-CH2), 3.05 (1H, quin., J = 6.8 Hz, 34-CH), 1.64–1.76 (2H,
m, 30-CH2), 1.36–1.43 (4H, m, 31-CH2 + 32-CH2), 1.33 (3H, d,
J = 6.7 Hz, 36-CHCH3), 1.07 (3H, d, J = 7.0 Hz, 34-CHCH3),
0.94 (9H, t, J = 8.0 Hz, Si(CH2CH3)3), 0.58 (6H, q, J = 8.0 Hz,
Si(CH2CH3)3); 13C NMR: d (100.6 MHz, CDCl3) 213.6, 159.4,
129.8, 129.5, 113.9, 78.9, 72.6, 70.9, 55.3, 47.1, 44.9, 35.0, 32.7,
22.4, 16.4, 12.9, 6.9, 5.2; HRMS: (+ES) Calc. for C24H42ClO4Si
[M + H]+: 457.2541, found: 457.2538; m/z: (+CI, NH3) 474
([M + NH4]+, 5), 240 (40), 138 (35), 121 (100).
◦
stirred at −78 C for a further 1.5 h then at −20 C for 16 h.
The reaction was quenched at 0 ◦C by the addition of pH 7
buffer (15 mL) and MeOH (60 mL), followed by 30% H2O2
solution (10 mL). The reaction mixture was allowed to warm to
rt and stirred for a further 2 h before being diluted with H2O
(50 mL) and CH2Cl2 (100 mL). The layers were separated and
the aqueous phase was extracted with CH2Cl2 (3 × 100 mL).
The combined organics were washed with sat. aq. NaHCO3
(80 mL) and brine (80 mL), dried (MgSO4) and concentrated in
vacuo. Flash chromatography (10 : 90 → 50 : 50 EtOAc–light
petroleum) afforded aldol product 13 (2.53 g) as a colourless oil
which contained a small amount of ChxOH and was carried
to the subsequent step without further purification. Further
purification by column chromatography allowed production of
analytically pure material for characterisation purposes: Rf: 0.25
(2R,4R,5R)-4-Benzyloxy-5-hydroxy-1-(p-methoxybenzyloxy)-2-
methyl-3-hexanone (18)
(30 : 70 EtOAc–hexanes); [a]2D0 +16.3 (c 1.50, CHCl3); IR (film):
To a cold (−78 ◦C) solution of Chx2BCl (10.6 mL, 48.4 mmol,
1.2 eq.) in Et2O (200 mL) was added Et3N (8.4 mL, 60.3 mmol,
1.5 eq.) followed by a solution of ketone 16 (13.2 g, 40.2 mmol)
in Et2O (10 mL + 2 × 5 mL washings) via cannula. The reaction
−1
3493 (br, OH), 2937, 2867, 1713 (C O) cm ; 1H NMR: d
=
(400 MHz, CDCl3) 7.26 (2H, d, J = 8.6 Hz, ArH), 6.89 (2H,
d, J = 8.6 Hz, ArH), 4.47 (2H, s, OCH2Ar), 4.02 (1H, q, J =
6.9 Hz, 36-CH), 3.81 (3H, s, ArOCH3), 3.80–3.83 (1H, m, 33-
CH), 3.52 (2H, t, J = 6.7 Hz, 29-CH2), 2.98 (1H, qd, J = 7.2,
2.9 Hz, 34-CH), 2.83 (1H, d, J = 2.7 Hz, OH), 1.77 (2H, qn,
J = 6.9 Hz, 30-CH2), 1.45–1.60 (4H, m, 31-CH2 + 32-CH2),
1.36 (3H, d, J = 6.9 Hz, 36-CHCH3), 1.11 (3H, d, J = 7.2 Hz,
34-CHCH3); 13C NMR: d (100.6 MHz, CDCl3) 217.2, 159.5,
◦
◦
mixture was stirred for 2 h at 0 C and then cooled to −78 C
before MeCHO (9.0 mL, 161 mmol, 4 eq.) was added. The
mixture 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 (200 mL) and the layers were separated. The
aqueous layer was extracted with Et2O (3 × 150 mL) and the
2 4 2 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 2 0 – 2 4 3 0

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combined organics were concentrated in vacuo. The residue was
taken up in◦MeOH (150 mL) and pH 7 buffer (50 mL) and
cooled to 0 C. A 30% H2O2 solution (50 mL◦) was added and
the mixture was stirred for a further 3 h at 0 C. The reaction
mixture was diluted with H2O (200 mL) and CH2Cl2 (100 mL).
Layers were separated and the aqueous layer was extracted with
CH2Cl2 (3 × 150 mL). The combined organics were washed with
sat. aq. NaHCO3 (100 mL) and brine (100 mL), dried (MgSO4)
and concentrated in vacuo. Removal of the ChxOH by Kugelrohr
short-path distillation (50 ◦C, 0.2 mmHg) for 16 h afforded aldol
adduct 18 (13.9 g, 93%) as a slightly yellow oil, which was carried
to the subsequent step without further purification: Rf: 0.23 (50 :
50 Et2O–hexane); [a]2D0] +28.6 (c 0.90, CHCl3); IR (liquid film):
3452 (s, br), 1717 (s), 1612 (s), 1586 (m), 1513 (s), 1454 cm−1 (s);
1H NMR: d (400 MHz, CDCl3) 7.27–7.36 (5H, m, ArH), 7.19
(2H, d, J = 8.6 Hz, ArH), 6.86 (2H, d, J = 8.6 Hz, ArH), 4.59
(1H, d, J = 11.6 Hz, OCHaHbAr), 4.35–4.43 (3H, m, OCH2Ar +
OCHaHbAr), 4.02–4.09 (1H, m, 37-CH), 3.79 (3H, s, ArOCH3),
3.73 (1H, d, J = 6.4 Hz, 38-CH), 3.65 (1H, m, 40-CH), 3.43
(2H, m, 41-CH2), 3.04 (1H, d, J = 6.3 Hz, OH), 1.20 (3H, d,
J = 6.4 Hz, 36-CH3), 1.00 (3H, d, J = 6.6 Hz, 40-CHCH3);
13C NMR: d (100.6 MHz, CDCl3) 214.3, 159.4, 137.3, 129.5,
129.0, 128.4, 127.9, 127.8, 113.8, 89.8, 73.3, 73.1, 72.9, 67.1,
55.2, 41.1, 19.1, 13.8; HRMS: (+FAB) Calc. for C22H29O5 [M +
H]+: 373.2015, found: 373.2026; m/z: (+CI, NH3) 373 ([M +
H]+, 47), 307 (100).
in MeCN (5 mL + 2 × 2 mL washings) was added via cannula.
The resultant mixture was then stirred at rt for 16 h before
being quenched by addition of sat. aq. NH4Cl (50 mL). The
mixture was diluted with Et2O and the layers were separated. The
aqueous phase was extracted with Et2O (3 × 100 mL), combined
organics were washed with brine (100 mL), dried (Na2SO4) and
concentrated in vacuo. Flash chromatography (2.5 : 97.5 → 50 :
50 Et2O–light petroleum) afforded enoate 9 (5.99 g, 96%) as
a colourless oil: Rf: 0.57 (30 : 70 EtOAc–hexanes); [a]20 −12.2
(c 1.05, CHCl3); IR (liquid film): 1718 (m), 1660 (w), 1D454 (w),
1436 (w), 1380 (w), 1265 cm−1 (s); 1H NMR: d (500 MHz, CDCl3)
7.28–7.36 (5H, m, Ph), 7.05 (1H, dd, J = 15.8, 7.6 Hz, 41-CH),
5.85 (1H, d, J = 15.8 Hz, 42-CH), 4.65 (1H, d, J = 11.5 Hz,
OCHaHbPh), 4.47 (1H, d, J = 11.5 Hz, OCHaHbPh), 3.86–3.93
(1H, m, 37-CH), 3.71 (3H, s, OCH3), 3.59 (1H, dd, J = 9.3,
3.2 Hz, 39-CH), 3.39 (1H, dd, J = 5.5, 3.2 Hz, 38-CH), 2.80–
2.87 (1H, m, 40-CH), 1.39 (3H, s, CMeaMeb), 1.32 (3H, d, J =
6.4 Hz, 36-CH3), 1.28 (3H, s, CMeaMeb), 0.99 (3H, d, J = 6.8 Hz,
40-CHCH3); 13C NMR: d (62.5 MHz, CDCl3) 167.3, 152.3,
138.0, 128.4, 127.8, 127.7, 120.3, 100.8, 82.2, 73.7, 72.9, 69.7,
51.3, 35.4, 24.9, 23.8, 21.2, 15.6; HRMS: (+CI, NH3) Calc. for
C20H29O5 [MH]+: 349.2015, found: 349.2015; m/z: (+CI, NH3)
349 ([MH]+, 14), 308 (18), 291 (28).
Methyl (2S,3R,4R)-4-[5-(R)-benzyloxy-2,2,6-(6R)-trimethyl-
1,3-dioxan-4-(R)-yl]-2,3-dihydroxy-pentanoate (21)
To a cold (0 ◦C) solution of enoate 9 (8.58 g, 24.6 mmol)
in BuOH–H2O (1 : 1, 250 mL) was added freshly prepared,
(2R,3R,4R,5R)- and (2R,3R,4S,5R)-3-Benzyloxy-6-(p-
methoxybenzyloxy)-5-methyl-hexane-2,4-diol (19 and
39-epi-19)
t
enriched AD-mix-b (36.9 g, 1.5 g mmol−1 substrate) and
MeSO2NH2 (4.68 g, 49.2 mmol, 2 eq.). The reaction mixture was
allowed to warm to rt and stirred vigorously for 16 h. Sodium
sulfite (37.0 g, 294 mmol, 12 eq.) was added and the reaction
stirred for a further 1 h. The mixture was diluted with water
(200 mL) and EtOAc (200 mL), and the layers were separated.
The aqueous phase was extracted with EtOAc (3 × 200 mL),
combined organics were dried (Na2SO4) and concentrated in
vacuo. Flash chromatography (20 : 80 → 80 : 20 EtOAc–light
petroleum) afforded diol 21 (9.20 g, 98%) as a colourless oil:
Rf: 0.25 (40 : 60 EtOAc–hexanes); [a]2D0 −17.8 (c 0.39, CHCl3);
IR (liquid film): 3464 (s, br), 1739 (s), 1454 (m), 1380 (m) cm−1;
1H NMR: d (500 MHz, CDCl3) 7.28–7.36 (5H, m, ArH), 4.68
(1H, d, J = 11.4 Hz, OCHaHbAr), 4.45 (1H, d, J = 11.4 Hz,
OCHaHbAr), 4.26–4.28 (1H, m, 42-CH), 4.07–4.10 (1H, m, 41-
CH), 4.04 (1H, dd, J = 9.9, 3.0 Hz, 39-CH), 3.92–3.97 (1H,
m, 37-CH), 3.79 (3H, s, OCH3), 3.36 (1H, dd, J = 5.0, 3.1 Hz,
38-CH), 3.28 (1H, d, J = 7.8 Hz, OH), 3.09 (1H, d, J = 6.2 Hz,
OH), 2.37–2.44 (1H, m, 40-CH), 1.41 (3H, s, CMeaMeb), 1.38
(3H, s, CMeaMeb), 1.34 (3H, d, J = 6.5 Hz, 36-CH3), 0.93 (3H,
d, J = 6.9 Hz, 40-CHCH3); 13C NMR: d (100.6 MHz, CDCl3)
174.3, 138.1, 128.4, 127.8, 127.6, 100.9, 81.9, 73.5, 72.8, 72.7,
72.5, 69.8, 52.7, 35.2, 25.5, 24.0, 21.4, 11.2; HRMS: (+CI, NH3)
Calc. for C20H31O7 [M + H]+: 383.2070, found: 383.2070; m/z:
(+CI, NH3) 383 ([M + H]+, 7), 235 (38), 217 (100).
To a solution of Me4NBH(OAc)3 (53.5 g, 203 mmol, 3 eq.) in
MeCN (80 mL) was added AcOH (80 mL) and the resultant
mixture was stirred at rt for 1 h. The mixture was then cooled to
−20 ◦C and a solution of hydroxyketone 18 (25.3 g, 67.8 mmol)
in MeCN (20 mL + 2 × 5 mL washings) was added via cannula.
The reaction mixture was stirred at −20 ◦C for 1 h and then
at 4 ◦C for 60 h. The reaction was quenched by pouring into
a sodium potassium tartrate solution (0.5 M, 500 mL) and
vigorously stirred for 1 h. The resultant mixture was diluted with
CH2Cl2 (100 mL) and the layers were separated. The aqueous
layer was extracted with CH2Cl2 (3 × 250 mL) and the combined
organics were washed with sat. aq. NaHCO3 until aqueous
washing attained a neutral pH. The organic extracts were dried
(Na2SO4) and concentrated in vacuo. Flash chromatography (5 :
95 → 25 : 75 EtOAc–light petroleum) afforded a ca. 4 : 1 mixture
of diols 19 and 39-epi-19 (23.0 g, 91% over 2 steps from 16) as a
colourless oil: Rf: 0.29 (50 : 50 EtOAc–hexanes); IR (liquid film):
3442 (m, br), 1612 (m), 1513 (s), 1455 cm−1 (m); The following
NMR data corresponds to the major (anti) diastereomer 19:
1H NMR: d (400 MHz, CDCl3) 7.26–7.38 (5H, m, ArH), 7.24
(2H, d, J = 8.6 Hz, ArH), 6.87 (2H, d, J = 8.6 Hz, ArH), 4.79
(1H, d, J = 11.5 Hz, OCHaCHbAr), 4.53 (1H, d, J = 11.5 Hz,
OCHaHbAr), 4.44 (2H, s, OCH2Ar), 4.18–4.27 (1H, m, 37-CH),
3.84 (1H, br s, 39-CH), 3.79 (3H, s, ArOCH3), 3.53 (2H, d, J =
6.0 Hz, 41-CH2), 3.40 (1H, br s, OH), 3.27–3.30 (1H, m, 38-CH),
2.17–2.27 (1H, m, 40-CH), 1.27 (3H, d, J = 6.5 Hz, 36-CH3),
0.78 (3H, d, J = 6.9 Hz, 40-CHCH3); 13C NMR: d (100.6 MHz,
CDCl3) 159.3, 138.2, 130.0, 129.2, 128.4, 128.0, 127.8, 113.9,
80.4, 75.5, 74.3, 73.1, 72.1, 67.3, 55.3, 35.5, 19.8, 13.9; HRMS:
(+CI, NH3) Calc. for C22H31O5 [M + H]+: 375.21715, found:
375.2171: m/z: (+CI, NH3) 375 ([M + H]+, 14), 121 (100).
Methyl (2S,3R,4R)-2,3-dihydroxy-4-[5-(R)-hydroxy-2,2,6-(6R)-
trimethyl-1,3-dioxan-4-(R)-yl]-pentanoate (22)
To a solution of diol 21 (4.23 g, 11.1 mmol) in MeOH (70 mL)
was added NaHCO3 (1.86 g, 22.1 mmol, 2 eq.) and Pd(OH)2/C
(20% w/w on carbon, 3.86 g, 5.54 mmol, 0.5 eq.). The system was
evacuated and then filled with H2. The procedure was repeated
twice more and then the reaction was left under an atmosphere of
H2 for 20 h. The reaction mixture was filtered through celite, and
the filtrate was concentrated in vacuo. Flash chromatography
(80 : 20 EtOAc–light petroleum → 100% EtOAc) afforded triol
22 (3.28 g, 100%) as a colourless oil: Rf: 0.09 (65 : 35 EtOAc–
Methyl (2E,4R)-4-[5-(R)-benzyloxy-2,2,6-(6R)-trimethyl-1,3-
dioxan-4-(R)-yl]-pent-2-enoate (9)
To a suspension of LiCl (dried at 140 ◦C under vacuum for
5 h, 1.89 g, 44.6 mmol, 2.5 eq.) in MeCN (40 mL) was added
trimethyl phosphonoacetate (4.35 mL, 26.9 mmol, 1.5 eq.) and
iPr2NEt (4.06 mL, 23.3 mmol, 1.3 eq.). The mixture was stirred at
rt for 10 min before a solution of aldehyde 20 (5.24 g, 17.9 mmol)
hexanes); [a]2D0 −23.9 (c 0.90, CHCl3); IR (liquid film): 3435
−1
=
(broad, OH), 2985, 2935, 1738 (C O), 1440, 1381, 1225 cm ;
1H NMR: d (500 MHz, CDCl3) 4.30–4.32 (1H, m, 42-CH),
3.96–4.00 (2H, m, 39-CH + 41-CH), 3.79 (3H, s, OCH3),
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 2 0 – 2 4 3 0
2 4 2 5

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3.59–3.64 (1H, m, 37-CH), 3.42–3.45 (2H, m, 38-CH + 41-
CHOH), 3.33–3.37 (1H, m, 42-CHOH), 2.18–2.23 (1H, m, 40-
CH), 1.36 (3H, s, CMeaMeb), 1.35 (3H, s, CMeaMeb), 1.29 (3H,
d, J = 6.4 Hz, 36-CH3), 0.99 (3H, d, J = 6.9 Hz, 40-CHCH3);
13C NMR: d (100.6 MHz, CDCl3) 174.2, 101.1, 74.6, 73.6, 72.8,
72.4, 71.9, 52.8, 35.3, 25.0, 24.4, 19.6, 11.3; HRMS: (+CI, NH3)
Calc. for C13H25O7 [M + H]+: 293.1600, found: 293.1609; m/z:
(+CI, NH3) 310 ([M + NH4]+, 80), 293 ([M + H]+, 20), 218 (70),
202 (100).
OCHaHbAr), 4.51 (2H, m, 2 × OCHaHbAr), 4.38 (1H, d, J =
11.1 Hz, OCHaHbAr), 4.24 (1H, dd, J = 6.7, 2.0 Hz, 41-CH),
3.99 (1H, dd, J = 6.7, 3.0 Hz, 42-CH), 3.85–3.92 (1H, m,
37-CH), 3.81 (3H, s, ArOCH3), 3.80 (3H, s, ArOCH3), 3.79
(3H, s, ArOCH3), 3.78–3.80 (1H, m, 39-CH), 3.35 (1H, dd, J =
5.1, 3.1 Hz, 38-CH), 2.16–2.24 (1H, m, 40-CH), 1.39 (3H, s,
CMeaMeb), 1.32 (3H, d, J = 6.5 Hz, 36-CH3), 1.29 (3H, s,
CMeaMeb), 0.91 (3H, d, J = 6.8 Hz, 40-CHCH3); 13C NMR:
d (100.6 MHz, CDCl3) 202.2, 159.5, 159.3, 159.0, 131.2, 130.3,
129.8, 129.4, 129.3, 128.6, 113.9, 113.8, 113.7, 100.7, 87.0, 81.4,
77.3, 73.9, 72.8, 72.4, 71.2, 69.9, 55.3, 55.2, 34.2, 25.7, 24.1, 21.4,
9.7; HRMS: (+CI, NH3) Calc. for C36H50NO9 [M + NH4]+:
640.3486, found: 640.3485; m/z: (+CI, NH3) 640 ([M + NH4]+,
20), 571 (100).
Methyl (2S,3R,4R)-2,3-bis-(p-methoxybenzyloxy)-4-[5-(R)-(p-
methoxybenzyloxy)-2,2,6-(6R)-trimethyl-1,3-dioxan-4-(R)-yl]-
pentanoate (23)
To a cold (0 ◦C) solution of triol 22 (3.56 g, 12.2 mmol) in THF
(120 mL) was added PMBTCA19 (20.7 g, 73.3 mmol, 6 eq.),
followed by a solution of Ph3CBF4 (weighed into a dry flask in
the glovebox, 80 mg, 0.242 mmol, 2.0 mol%) in THF (2 mL) via
cannula. The reaction mixture was stirred at 0 ◦C for a further
30 min before being quenched by addition of sat. aq. NaHCO3
(100 mL) and Et2O (50 mL). The layers were separated and the
aqueous phase was extracted with Et2O (3 × 100 mL). Combined
organics were washed with brine (100 mL), dried (Na2SO4) and
concentrated in vacuo. The resulting crude was dissolved in
the minimum amount of CH2Cl2 and then hexane was added
slowly until precipitation of the trichloroacetamide occurred.
After filtration, the filtrate was concentrated in vacuo. Flash
chromatography (15 : 85 → 30 : 70 EtOAc–light petroleum)
afforded the tris-PMB ether 23 (7.73 g, 97%) as a colourless oil:
Rf: 0.31 (30 : 70 EtOAc–hexanes); [a]2D0 −28.5 (c 1.10, CHCl3);
(3E,5R,6R,7R)-5,6-Bis-(p-methoxybenzyloxy)-7-[5-(R)-(p-
methoxybenzyloxy)-2,2,6-(6R)-trimethyl-1,3-dioxan-4-(R)-yl]-
oct-3-en-2-one (24)
Ba(OH)2·8H2O (dried at 140 ◦C under vacuum for 4 h be-
fore the reaction) was added to a solution of dimethyl(2-
oxopropyl)phosphonate (87 lL, 0.63 mmol) in THF (7.5 mL)
and the resulting mixture was stirred for 30 min at rt. A solution
of the aldehyde from the above procedure (196 mg, 0.315 mmol)
in THF (7.3 mL) and water (0.4 mL) was then added via cannula
and the resulting mixture was stirred for 4 h before quenching
the reaction by addition of excess of NaHCO3 solution (20 mL).
The mixture was partitioned between aqueous NaHCO3 sol.
and Et2O (20 mL) and the aqueous layer was washed with
Et2O (50 mL). The combined organic layers were dried (MgSO4)
and concentrated in vacuo. Purification by flash chromatography
(20 : 80 EtOAc–hexanes) afforded enone 24 (199 mg, 96%) as
a colourless oil: Rf: 0.24 (35 : 65 EtOAc–hexanes); [a]2D0 −7.3 (c
−1
1
=
IR (liquid film): 2935, 1733 (C O), 1613, 1514, 1248 cm ; H
NMR: d (500 MHz, CDCl3) 7.18–7.27 (6H, m, ArH), 6.78–6.88
(6H, m, ArH), 4.92 (1H, d, J = 11.1 Hz, OCHaHbAr), 4.57
(1H, d, J = 11.3 Hz, OCHaHbAr), 4.54 (1H, d, J = 11.9 Hz,
OCHaHbAr), 4.51 (1H, d, J = 11.4 Hz, OCHaHbAr), 4.40
(1H, d, J = 11.1 Hz, OCHaHbAr), 4.34 (1H, d, J = 10.9 Hz,
OCHaHbAr), 4.21 (1H, d, J = 7.2 Hz, 42-CH), 4.17 (1H, dd, J =
7.2, 1.7 Hz, 41-CH), 3.84–3.90 (1H, m, 37-CH), 3.80 (6H, s, 2 ×
ArOCH3), 3.79 (3H, s, ArOCH3), 3.76–3.79 (1H, m, 39-CH),
3.64 (3H, s, CO2CH3), 3.34 (1H, dd, J = 5.4, 3.2 Hz, 38-CH),
1.98–2.08 (1H, m, 40-CH), 1.34 (3H, s, CMeaMeb), 1.32 (3H,
d, J = 6.4 Hz, 36-CH3), 1.26 (3H, s, CMeaMeb), 0.94 (3H, d,
J = 6.8 Hz, 40-CHCH3); 13C NMR: d (100.6 MHz, CDCl3)
171.6, 159.4, 159.2, 158.8, 131.7, 130.5, 129.9, 129.5, 129.1,
128.5, 113.8, 113.7, 113.6, 100.6, 83.5, 81.8, 78.5, 74.1, 72.7,
72.5, 71.7, 69.7, 55.3, 55.3, 55.2, 51.8, 34.5, 25.6, 24.1, 21.4,
9.9; HRMS: (+CI, NH3) Calc. for C37H52NO10 [M + NH4]+:
670.3591, found: 670.3579; m/z: (+CI, NH3) 670 ([M + NH4]+,
20), 396 (40), 275 (100).
=
1.40, CHCl3); IR (liquid film): 2984, 2936, 2835, 1678 (C O),
1
1612, 1514, 1248, 1034 cm−1; H NMR: d (400 MHz, CDCl3)
7.13–7.27 (6H, m, ArH), 6.80–6.88 (6H, m, ArH), 6.60 (1H,
dd, J = 16.2, 7.5 Hz, 43-CH), 6.24 (1H, d, J = 16.2 Hz, 44-
CH), 4.99 (1H, d, J = 11.2 Hz, OCHaHbAr), 4.58 (1H, d, J =
11.0 Hz, OCHaHbAr), 4.52 (1H, d, J = 11.2 Hz, OCHaHbAr),
4.47 (1H, d, J = 11.0 Hz, OCHaHbAr), 4.35 (1H, d, J = 11.0 Hz,
OCHaHbAr), 4.31 (1H, d, J = 11.0 Hz, OCHaHbAr), 4.19 (1H,
t, J = 7.5, Hz, 42-CH), 4.02 (1H, dd, J = 7.5, 1.4 Hz, 41-CH),
3.85–3.91 (1H, m, 37-CH), 3.80 (6H, s, 2 × ArOCH3), 3.79
(3H, s, ArOCH3), 3.75–3.80 (1H, m, 39-CH), 3.34 (1H, dd, J =
5.2, 3.2 Hz, 38-CH), 2.22 (3H, s, 46-CH3), 2.04–2.12 (1H, m, 40-
CH), 1.38 (3H, s, CMeaMeb), 1.33 (3H, d, J = 6.5 Hz, 36-CH3),
1.27 (3H, s, CMeaMeb), 0.82 (3H, d, J = 6.8 Hz, 40-CHCH3); 13C
NMR: d (100.6 MHz, CDCl3) 198.5, 159.3, 159.3, 158.8, 143.5,
132.6, 131.8, 130.3, 130.0, 129.6, 129.0, 128.3, 113.8, 113.7,
113.6, 100.7, 83.5, 81.6, 79.3, 73.9, 72.5, 71.3, 70.9, 69.8, 55.3,
55.3, 55.2, 34.3, 26.9, 25.7, 24.2, 21.4, 9.3; HRMS: (+CI, NH3)
Calc. for C39H54NO9 [M + NH4]+: 680.3799, found: 680.3795;
m/z: (+CI, NH3) 680 ([M + NH4]+, 50), 287 (50), 274 (100).
(2S,3R,4R)-2,3-Bis-(p-methoxybenzyloxy)-4-[5-(R)-(p-
methoxybenzyloxy)-2,2,6-(6R)-trimethyl-1,3-dioxan-4-(R)-yl]-
pentanal
To a cold (−78 ◦C) solution of ester 23 (4.16 g, 6.38 mmol)
in CH2Cl2 (50 mL) was added DIBAL-H (1.0 M in CH2Cl2,
16.0 mL, 16.0 mmol, 2.5 eq.) dropwise. The reaction mixture was
(2S,3S,4R,5R,6R)- and (2R,3S,4R,5R,6R)-6-(2-(R)-Hydroxy-
1-(R)-[p-methoxybenzyloxy)-prop-1-yl]-3,4-bis(p-
methoxybenzyloxy)-5-methyl-2-(propanone)-tetrahydropyran
(25 and 43-epi-25)
◦
stirred at −78 C for 1.5 h before being quenched by addition
of a solution of sat. aq. potassium sodium tartrate (150 mL).
The resultant mixture was stirred vigorously for 30 min and the
layers were separated. The aqueous phase was extracted with
Et2O (3 × 150 mL), combined organics were dried (Na2SO4)
and concentrated in vacuo. Flash chromatography (5 : 95 → 40 :
60 EtOAc–light petroleum) afforded the title aldehyde (3.73 g,
94%) as a colourless oil: Rf: 0.29 (35 : 65 EtOAc–hexanes); [a]D20
To a solution of enone 24 (5.38 g, 8.12 mmol) in THF–H2O
(1 : 1, 20 mL) was added AcOH (90 mL) and the resultant
mixture was stirred at rt for 60 h. The reaction was quenched by
careful addition to sat. aq. NaHCO3 (500 mL) and diluted with
EtOAc (300 mL). The layers were separated and the aqueous
phase was extracted with EtOAc (3 × 250 mL). The combined
organics were washed with brine (250 mL), dried (Na2SO4) and
concentrated in vacuo. Flash chromatography (30 : 70 → 80 : 20
EtOAc–light petroleum) afforded a mixture of tetrahydropyrans
25 and 43-epi-25 (ca. 1 : 1, 4.58 g, 91%) as a colourless oil.
=
−26.4 (c 1.00, CHCl3); IR (liquid film): 2984, 1729 (C O), 1612,
1514, 1248, 1032 cm−1; 1H NMR: d (400 MHz, CDCl3) 9.64 (1H,
d, J = 3.0 Hz, 43-CHO), 7.18–7.27 (6H, m, ArH), 6.81–6.89
(6H, m, ArH), 4.78 (1H, d, J = 10.9 Hz, OCHaHbAr), 4.58
(1H, d, J = 11.1 Hz, OCHaHbAr), 4.57 (1H, d, J = 11.3 Hz,
2 4 2 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 2 0 – 2 4 3 0

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Equilibration of the mixture of tetrahydropyrans (25 and
43-epi-25)
(+CI, NH3) Calc. for C37H52NO8 [M + NH4]+: 638.3693, found:
638.3689; m/z: (+CI, NH3) 638 [M + NH4]+, 1), 154 (100), 137
(50), 121 (70).
The mixture of tetrahydropyran epimers 25 and 43-epi-25
(181 mg, 0.291 mmol) was dissolved in dry MeOH (14 mL).
Separately, KOH (2.00 g, 35.6 mmol) was dissolved in dry MeOH
(5 mL) to make a ca. 7 M solution. Of this KOH solution, 3 mL
(ca. 21 mmol) was added to the stirred solution of substrate, and
the reaction left at rt for 20 h. The mixture was cooled (0 ◦C) and
H2O (100 mL) was slowly added, followed by EtOAc (20 mL).
The layers were separated and the aqueous phase was extracted
with EtOAc (2 × 20 mL). The combined organic extracts were
washed with brine (10 mL), dried (Na2SO4), filtered through a
short pad of silica and concentrated in vacuo to yield a ca. 95 :
5 ratio of desired and undesired THPs (170 mg, 94%), 25 and
43-epi-25, respectively, as a colourless oil. Major diastereomer:
Rf: 0.05 (30 : 70 EtOAc–hexanes); [a]2D0 +8.8 (c 1.13, CHCl3);
(2R,3R,4R,5R,6R)-6-[1-(S)-(p-Methoxybenzyloxy)-propanone]-
3,4-bis(p-methoxybenzyloxy)-5-methyl-2-(2-methylallyl)-
tetrahydropyran (6)
To a cold (0 ◦C) solution of the 2◦ alcohol from the above
procedure (1.17 g, 1.88 mmol), in CH2Cl2 (23.0 mL) was added
˚
activated (heated under vacuum) powdered 4 A molecular sieves
(1.64 g), NMO (663 mg, 5.66 mmol, 3.0 eq.) and TPAP (65 mg,
0.19 mmol, 10 mol%). The reaction mixture was stirred at rt for
2 h, filtered through a pad of silica, eluted with EtOAc (100 mL)
and concentrated in vacuo. Flash chromatography (5 : 95 →
70 : 30 Et2O–light petroleum) afforded ketone 6 (1.10 g, 94%)
as a colourless oil: Rf: 0.31 (30 : 70 EtOAc–hexanes); [a]2D0 −15.7
−1
1
=
=
IR (liquid film): 3518 (br), 2964, 2909, 2836, 1712 (C O),
(c 1.00, CHCl3); IR (liquid film): 2932, 1710 (C O) cm ; H
NMR: d (500 MHz, CDCl3) 7.27 (2H, d, J = 8.6 Hz, ArH), 7.24
(2H, d, J = 8.5 Hz, ArH), 7.23 (2H, d, J = 8.5 Hz, ArH), 6.89
(2H, d, J = 8.2 Hz, ArH), 6.87 (2H, d, J = 8.4 Hz, ArH), 6.86
(2H, d, J = 8.7 Hz, ArH), 4.83 (1H, d, J = 10.6 Hz, OCHaHbAr),
1
1612, 1514, 1249, 1082, 1034 cm−1; H NMR: d (400 MHz,
CDCl3) 7.21–7.32 (6H, m, ArH), 6.82–6.92 (6H, m, ArH), 4.86
(1H, d, J = 11.1 Hz, OCHaHbAr), 4.85 (1H, d, J = 10.5 Hz,
OCHaHbAr), 4.61 (1H, d, J = 11.1 Hz, OCHaHbAr), 4.59
(1H, d, J = 10.5 Hz, OCHaHbAr), 4.54 (1H, d, J = 11.1 Hz,
OCHaHbAr), 4.47 (1H, d, J = 11.1 Hz, OCHaHbAr), 3.93–
4.01 (1H, m, 37-CH), 3.81 (6H, s, 2 × ArOCH3), 3.79 (3H, s,
ArOCH3), 3.60–3.69 (1H, m, 43-CH), 3.48 (1H, dd, J = 10.3,
2.2 Hz, 39-CH), 3.18–3.32 (4H, m, 38-CH + 41-CH + 42-
CH + OH), 2.71 (1H, dd, J = 17.8, 2.0 Hz, 44-CHaHb), 2.49
(1H, dd, J = 17.8, 10.2 Hz, 44-CHaHb), 2.10–2.18 (1H, m, 40-
CH), 2.06 (3H, s, 46-CH), 1.27 (3H, d, J = 6.4 Hz, 36-CH3),
0.88 (3H, d, J = 6.5 Hz, 40-CHCH3); 13C NMR: d (100.6 MHz,
CDCl3) 207.2, 159.5, 159.4, 159.3, 130.5, 130.3, 130.2, 129.8,
129.7, 129.6, 113.9, 113.8, 86.9, 81.4, 81.2, 80.3, 75.3, 75.1, 74.5,
72.6, 66.8, 55.3, 44.8, 37.9. 30.5, 20.4, 12.8; HRMS: (+CI, NH3)
Calc. for C36H50NO9 [M + NH4]+: 640.3486, found: 640.3488;
m/z: (+CI, NH3) 640 ([M + NH4]+, 100), 520 (30).
=
4.80 (1H, d, J = 10.6 Hz, OCHaHbAr), 4.72 (1H, s, C CHaHb),
=
4.71 (1H, d, J = 11.6 Hz, OCHaHbAr), 4.67 (1H, s, C CHaHb),
4.57 (1H, d, J = 10.6 Hz, OCHaHbAr), 4.54 (1H, d, J = 10.6 Hz,
OCHaHbAr), 4.25 (1H, d, J = 11.6 Hz, OCHaHbAr), 3.81 (3H, s,
ArOCH3), 3.80 (3H, s, ArOCH3), 3.79 (3H, s, ArOCH3), 3.71
(1H, d, J = 2.2 Hz, 38-CH), 3.22–3.28 (3H, m, 39-CH + 42-
CH + 43-CH), 3.14 (1H, dd, J = 10.3, 8.4 Hz, 41-CH), 2.49 (1H,
d, J = 14.6 Hz, 44-CHaHb), 2.20 (3H, s, 36-CH3), 2.17 (1H, dd,
J = 14.5, 10.0 Hz, 44-CHaHb), 2.02–2.05 (1H, m, 40-CH), 1.63
(3H, s, 46-CH3), 0.61 (3H, d, J = 6.5 Hz, 40-CHCH3); 13C NMR:
d (100.6 MHz, CDCl3) 213.4, 159.7, 159.3, 159.3, 142.5, 130.6,
130.4, 130.3, 129.6, 129.6, 128.7, 113.9, 113.9, 113.9, 112.3, 86.2,
83.1, 83.0, 82.6, 78.1, 75.1, 74.7, 73.1, 55.3, 55.3, 55.3, 39.7, 37.9,
27.8, 22.0, 12.2; HRMS: (+CI, NH3) Calc. for C37H50NO8 [M +
NH4]+: 636.3536, found: 636.3544; m/z: (+CI, NH3) 636 ([M +
NH4]+, 5), 154 (100), 137 (60), 121 (75).
(2R,3R,4R,5R,6R)-6-[2-(R)-Hydroxy-1-(R)-(p-
methoxybenzyloxy)-prop-1-yl]-3,4-bis(p-methoxybenzyloxy)-5-
methyl-2-(2-methylallyl)-tetrahydropyran
(1S,4S,5R,6R)- and (1S,4R,5R,6R)-10-chloro-4-hydroxy-1-(p-
methoxybenzyloxy)-1-[4,5-(R,R)-bis(p-methoxybenzyloxy)-3-
(R)-methyl-6-(R)-(2-methylallyl)-tetrahydropyran-2-(R)-yl]-5-
methyl-6-(triethylsiloxy)-decan-2-one (5 and 35-epi-5)
To a solution of hydroxyketone 25 (140 mg, 0.225 mmol) in
PhMe (1.8 mL), Cp2TiMe2 (10 wt% in 1 : 1 PhMe–THF, 1.4 mL,
0.67 mmol, 3 eq.) was added. The mixture was heated at 120 ◦C
for 2 h, shielded from light, before being cooled to rt and
concentrated in vacuo. The crude was dissolved in CH2Cl2 and
adsorbed onto silica. Flash chromatography (10 : 90 → 60 :
40 EtOAc–hexanes) yielded the title compound (98.5 mg, 71%).
The same procedure was repeated on a larger scale (194 mg,
0.312 mmol of 25) to afford a further batch of the title compound
(172 mg, 89%). The two batches were combined to yield the
title compound (270 mg, 81%) as a yellow oil: Rf: 0.16 (30 : 70
EtOAc–hexanes); [a]2D0 −4.5 (c 1.00, CHCl3); IR (liquid film):
3514 (br, OH), 2965, 2933 cm−1; 1H NMR: d (500 MHz, CDCl3)
7.29 (2H, d, J = 8.6 Hz, ArH), 7.26 (2H, d, J = 8.4 Hz, ArH),
7.25 (2H, d, J = 8.3 Hz, ArH), 6.89 (2H, d, J = 8.9 Hz, ArH),
6.87 (2H, d, J = 8.7 Hz, ArH), 6.86 (2H, d, J = 8.4 Hz, ArH),
To a cold (−78 ◦C) solution of Chx2BBr (1.14 mL, 5.23 mmol,
3.5 eq.) in Et2O (20 mL) was added Et3N (1.25 mL, 8.97 mmol,
6 eq.) followed by a solution of ketone 6 (921 mg, 1.49 mmol)
in Et2O (5 mL + 2 × 2 mL washings) via cannula. The reaction
mixture was stirred at −78 ◦C for 2.5 h before a solution of
aldehyde 7 (1.75 g, 5.96 mmol, 4 eq.) in Et2O (2 mL + 2 ×
1 mL washings) was added via cannula. The reaction was stirred
at −78 ◦C for a further 1 h and then at −20 ◦C for 16 h.
The reaction was quenched at 0 ◦C by the addition of pH 7
buffer (30 mL) and allowed to warm to rt. 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–pH7 buffer (3 : 1,
100 mL) and cooled to 0 ◦C. A 30% solution of H2O2 (5.5 mL)
was added and the mixture was warmed to rt and stirred for
2 h. Et2O (100 mL) and H2O (100 mL) were added and the
layers were separated. The aqueous phase was extracted with
Et2O (3 × 100 mL), combined organics were washed with sat.
aq. NaHCO3 (100 mL) and brine (100 mL), dried (Na2SO4)
and concentrated in vacuo. Flash chromatography (5 : 95 →
50 : 50 EtOAc–light petroleum) afforded aldol product 5 and
diastereomer 35-epi-5 contaminated with ChxOH. The mixture
was used in the subsequent step without further purification.
Major diastereomer 5: Rf: 0.34 (30 : 70 EtOAc–hexanes);
[a]2D0 −23.8 (c 1.30, CHCl3); IR (liquid film): 3530 (br, OH),
=
4.87 (1H, s, C CHaHb), 4.86 (1H, d, J = 10.4 Hz, OCHaHbAr),
=
4.82 (1H, d, J = 10.4 Hz, OCHaHbAr), 4.81 (1H, s, C CHaHb),
4.73 (1H, d, J = 11.7 Hz, OCHaHbAr), 4.58 (1H, d, J = 10.6 Hz,
OCHaHbAr), 4.57 (1H, d, J = 10.6 Hz, OCHaHbAr), 4.42 (1H,
d, J = 11.7 Hz, OCHaHbAr), 4.15–4.17 (1H, m, 37-CH), 3.81
(3H, s, ArOCH3), 3.80 (6H, s, 2 × ArOCH3), 3.33–3.38 (2H, m,
39-CH + 43-CH), 3.27 (1H, t, J = 9.0 Hz, 42-CH), 3.15–3.21
(3H, m, 38-CH + 41-CH + OH), 2.54 (1H, d, J = 14.0 Hz, 44-
CHaHb), 2.16–2.21 (2H, m, 40-CH + 44-CHaHb), 1.73 (3H, s,
46-CH3), 1.16 (3H, d, J = 6.5 Hz, 36-CH3), 0.74 (3H, d, J =
6.5 Hz, 40-CHCH3); 13C NMR: d (100.6 MHz, CDCl3) 159.4,
159.3, 159.3, 142.1, 130.7, 130.3, 130.1, 129.8, 129.6, 129.6,
113.9, 113.9, 113.7, 113.7, 86.5, 82.9, 81.6, 77.7, 77.1, 75.0, 74.8,
70.4, 66.1, 55.3, 55.3, 55.3, 40.2, 37.7, 21.8, 20.4, 12.5; HRMS:
−1
1
=
2954, 1712 (C O) cm ; H NMR: d (500 MHz, CDCl3) 7.22–
7.26 (6H, m, ArH), 6.85–6.89 (6H,m, ArH), 4.82 (1H, d,
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 2 0 – 2 4 3 0
2 4 2 7

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J = 11.7 Hz, OCHaHbAr), 4.80 (1H, d, J = 11.4 Hz,
OCHaHbAr), 4.78 (1H, d, J = 11.7 Hz, OCHaHbAr), 4.63 (2H, s,
3.75 (1H, d, J = 8.0 Hz, OH), 3.66–3.71 (1H, m, 35-CH), 3.61
(2H, t, J = 6.3 Hz, 29-CH2), 3.48 (1H, s, 38-CH), 3.35 (1H, t,
J = 9.5 Hz, 43-CH), 3.22 (1H, t, J = 8.8 Hz, 42-CH), 3.19 (3H, s,
37-COCH3), 3.10 (1H, t, J = 9.5 Hz, 41-CH), 3.06 (1H, d, J =
10.3 Hz, 39-CH), 2.51 (1H, d, J = 14.3 Hz, 44-CHaHb), 2.26
(1H, dd, J = 14.5, 10.3 Hz, 44-CHaHb), 2.17 (2H, d, J = 2.5 Hz,
36-CH2), 1.88 (2H, quin., J = 6.8 Hz, 30-CH2), 1.78–1.88 (2H,
m, 31-CHaHb + 40-CH), 1.74 (3H, s, 46-CH3), 1.66–1.76 (2H,
m, 32-CHaHb + 34-CH), 1.52–1.60 (1H, m, 31-CHaHb), 1.40–
1.48 (1H, m, 32-CHaHb), 0.89 (3H, d, J = 7.1 Hz, 34-CHCH3),
0.42 (3H, d, J = 6.4 Hz, 40-CHCH3); 13C NMR: d (100.6 MHz,
CDCl3) 159.4, 159.3, 159.2, 142.7, 131.1, 130.7, 130.5, 130.1,
129.7, 129.5, 113.9, 113.9, 113.7, 112.8, 104.2, 86.8, 82.8, 80.2,
78.1, 74.7, 74.6, 73.9, 72.8, 70.5, 67.6, 55.3, 55.3, 55.3, 47.6, 45.0,
39.7, 38.3, 37.3, 32.7, 32.3, 29.1, 23.6, 22.1, 12.4, 10.7; HRMS:
(+ESI) Calc. for C46H63O10ClNa [M + Na]+: 833.4007, found:
833.4037.
=
C CH2), 4.56 (1H, d, J = 11.0 Hz, OCHaHbAr), 4.53 (1H, d,
J = 11.0 Hz, OCHaHbAr), 4.34 (1H, d, J = 9.5 Hz, 35-CH), 4.28
(1H, d, J = 11.4 Hz, OCHaHbAr), 3.90–3.95 (1H, m, 33-CH),
3.80 (6H, s, 2 × ArOCH3), 3.79 (3H, s, ArOCH3), 3.75 (1H, s,
38-CH), 3.54 (2H, t, J = 6.5 Hz, 29-CH2), 3.19–3.27 (3H, m,
39-CH + 42-CH + 43-CH), 3.05–3.15 (3H, m, 36-CHaHb +
41-CH + OH), 2.44–2.50 (2H, m, 36-CHaHb + 44-CHaHb),
2.15 (1H, dd, J = 14.4, 10.2 Hz, 44-CHaHb), 1.98–2.05 (1H,
m, 40-CH), 1.78 (2H, quin., J = 6.9 Hz, 30-CH2), 1.61 (3H, s,
46-CH3), 1.46–1.59 (3H, m, 32-CH2 + 34-CH), 1.36–1.44 (2H,
m, 31-CH2), 0.98 (9H, t, J = 7.7 Hz, Si(CH2CH3)3), 0.90 (3H, d,
J = 6.9 Hz, 34-CHCH3), 0.64 (6H, q, J = 7.8 Hz, Si(CH2CH3)3),
0.59 (3H, d, J = 6.5 Hz, 40-CHCH3); 13C NMR: d (100.6 MHz,
CDCl3) 214.3, 159.7, 159.3, 159.3, 142.9, 130.6, 130.5, 130.4,
130.3, 129.8, 129.6, 129.6, 128.8, 113.9, 113.9, 113.7, 111.9, 86.2,
82.8, 82.8, 82.5, 77.9, 77.7, 75.1, 74.7, 72.8, 69.8, 55.3, 55.3,
55.3, 45.3, 44.8, 40.4, 39.5, 37.9, 33.9, 32.7, 22.8, 22.3, 12.2, 6.9,
6.7, 5.4; HRMS: (+ESI) Calc. for C51H75O10ClSiNa [M + Na]+:
933.4716, found: 933.4749.
Minor diastereomer 35-epi-27: Rf: 0.12 (30 : 70 EtOAc–
1
hexanes); H NMR: d (500 MHz, CDCl3) 7.30 (2H, d, J =
8.4 Hz, ArH), 7.25 (2H, d, J = 8.1 Hz, ArH), 7.24 (2H, d,
J = 8.5 Hz, ArH), 6.85–6.90 (6H, m, ArH), 4.77–4.81 (5H, m,
=
Minor diastereomer 35-epi-5: Rf: 0.42 (30 : 70 EtOAc–
C CH2 + 2 × OCHaHbAr + OCHaHbAr), 4.67 (1H, d, J =
1
hexanes); H NMR: d (500 MHz, CDCl3) 7.20–7.25 (6H, m,
11.4 Hz, OCHaHbAr), 4.57 (1H, d, J = 10.6 Hz, OCHaHbAr),
4.51 (1H, d, J = 10.6 Hz, OCHaHbAr), 4.03–4.07 (1H, m, 35-
CH), 3.81 (3H, s, ArOCH3), 3.80 (3H, s, ArOCH3), 3.80 (3H, s,
ArOCH3), 3.57–3.61 (3H, m, 29-CH2 + 33-CH), 3.55 (1H, s,
38-CH), 3.35 (1H, td, J = 9.2, 2.0 Hz, 43-CH), 3.21 (1H, t,
J = 9.0 Hz, 42-CH), 3.12 (3H, s, 37-COCH3), 3.04–3.15 (2H,
m, 39-CH + 41-CH), 2.50 (1H, d, J = 14.1 Hz, 44-CHaHb),
2.27 (1H, dd, J = 14.2, 10.1 Hz, 44-CHaHb), 2.12 (1H, dd, J =
13.7, 4.7 Hz, 36-CHaHb), 1.93 (1H, t, J = 13.5 Hz, 36-CHaHb),
1.80–1.90 (4H, m, 30-CH2 + 34-CH + 40-CH), 1.74 (3H, s, 46-
CH3), 1.68–1.78 (2H, m, 31-CHaHb + 32-CHaHb), 1.50–1.58
(1H, m, 31-CHaHb), 1.44–1.50 (1H, m, 32-CHaHb), 1.08 (1H,
d, J = 4.9 Hz, OH), 0.88 (3H, d, J = 6.8 Hz, 34-CHCH3), 0.43
(3H, d, J = 6.4 Hz, 40-CHCH3).
ArH), 6.84–6.89 (6H, m, ArH), 4.83 (1H, d, J = 10.7 Hz,
OCHaHbAr), 4.79 (1H, d, J = 11.0 Hz, OCHaHbAr), 4.76 (1H,
=
d, J = 11.9 Hz, OCHaHbAr), 4.71 (1H, s, C CHaHb), 4.69
=
(1H, s, C CHaHb), 4.56 (1H, d, J = 11.0 Hz, OCHaHbAr), 4.54
(1H, d, J = 10.7 Hz, OCHaHbAr), 4.28 (1H, d, J = 11.9 Hz,
OCHaHbAr), 3.99 (1H, t, J = 9.0 Hz, 35-CH), 3.92–3.96 (1H,
m, 33-CH), 3.85–3.91 (2H, m, 38-CH + OH), 3.81 (3H, s,
ArOCH3), 3.80 (3H, s, ArOCH3), 3.79 (3H, s, ArOCH3), 3.54
(2H, t, J = 6.7 Hz, 29-CH2), 3.33 (1H, d, J = 11.4 Hz, 39-CH),
3.20–3.29 (2H, m, 42-CH + 43-CH), 3.14 (1H, dd, J = 9.7,
8.3 Hz, 41-CH), 2.75 (1H, d, J = 16.1 Hz, 36-CHaHb), 2.43–
2.53 (2H, m, 36-CHaHb + 44-CHaHb), 2.14 (1H, dd, J = 14.2,
9.8 Hz, 44-CHaHb), 2.00–2.08 (1H, m, 40-CH), 1.78 (2H, quin.,
J = 6.9 Hz, 30-CH2), 1.65–1.72 (1H, m, 34-CH), 1.64 (3H, s,
46-CH3), 1.46–1.58 (3H, m, 31-CHaHb + 32-CH2), 1.35–1.44
(1H, m, 31-CHaHb), 0.98 (9H, t, J = 7.7 Hz, Si(CH2CH3)3),
0.75 (3H, d, J = 6.8 Hz, 34-CHCH3), 0.60–0.66 (9H, m, 40-
CHCH3 + Si(CH2CH3)3).
(4S)-1-[6-[[4-(S)-(t-Butyldimethylsiloxy)-6-(R)-(4-chlorobutyl)-
2-(R)-methoxy-5-(S)-methyl-tetrahydropyran-2-yl]-(S)-(p-
methoxybenzyloxy)-methyl]-(6R)-3,4-(R,R)-bis-(p-
methoxybenzyloxy)-5-(R)-methyl-tetrahydropyran-2-(R)-yl]-7-
chloro-4-hydroxy-octa-5,7-dien-2-one (33)
(2R,4S,5R,6R)- and (2R,4R,5R,6R)-6-(4-chlorobutyl)-2-
methoxy-2-[[4,5-(R,R)-bis-(p-methoxybenzyloxy)-3-(R)-methyl-
6-(R)-(2-methylallyl)-tetrahydropyran-2-(R)-yl]-((S)-p-
methoxybenzyloxy)-methyl]-5-methyl-tetrahydropyran-4-ol (27
and 35-epi-27)
To a cooled (−78 ◦C) solution of ketone 3 (23.8 mg, 25.7 lmol)
in Et2O (500 lL) were added Et3N (29 lL, 208 lmol, 8 eq.)
followed by Chx2BCl (23 lL, 105 lmol, 4 eq.). The resultant
mixture was stirred at −78 ◦C for 30 min before warming to
−40 ◦C. After stirring at −40 ◦C for 1 h, the mixture was cooled
back to −78 ◦C and a solution of aldehyde 4 (22.4 mg, 192
lmol, 7.5 eq.) in Et2O (250 lL + 2 × 125 lL) was added via
cannula. The reaction was stirred at −78 ◦C for 2 h before
being warmed to −20 ◦C and was ◦stored at this temperature
for 14 h. To the cooled solution (0 C) was added a premixed
solution of 3 : 1 MeOH (900 lL) and pH 7 buffer (300 lL). The
mixture was stirred for 10 min before the dropwise addition of a
premixed solution of 2 : 1 pH 7 buffer (800 lL) and 30% H2O2
To a solution of aldol products 5 and 35-epi-5 (from above
procedure, max. 1.49 mmol) in MeOH–(MeO)3CH (10 : 1,
33 mL) was added PPTS (cat.). The reaction mixture was stirred
at rt for 2 h then quenched by the addition of sat. aq. NaHCO3
(30 mL) and CH2Cl2 (30 mL). The layers were separated and
the aqueous phase was extracted with CH2Cl2 (3 × 50 mL).
The combined organics were washed with brine (20 mL), dried
(Na2SO4) and concentrated in vacuo. Flash chromatography (5 :
95 → 50 : 50 EtOAc–light petroleum) afforded methyl acetal 27
(849 mg, 70%) and the diastereomer 35-epi-27 (142 mg, 12%) as
colourless oils. The combined yield was 991 mg, 82% over two
steps from ketone 6.
◦
(400 lL). The resultant mixture was stirred vigorously at 0 C
for 2.5 h before dilution with H2O (5 mL). Et2O (3 mL) was
added and the layers were separated. The aqueous phase was
extracted with Et2O (3 × 2 mL), the combined organic extracts
were washed with NaHCO3 (2 × 2 mL) and brine (2 mL), dried
(Na2SO4) and the solvent removed in vacuo. Purification by flash
chromatography (20 : 80 → 35 : 65 EtOAc–hexanes) gave the
aldol adduct 33 (21.2 mg, 79%) as a colourless oil, which was
found to decompose over time (noticeable decomposition after
1 week at −20 ◦C): Rf: 0.25 (30 : 70 EtOAc–hexanes); 1H NMR:
d (500 MHz, CDCl3) 7.28 (2H, d, J = 8.5 Hz, ArH), 7.25 (2H,
d, J = 8.5 Hz, ArH), 7.23 (2H, d, J = 8.5 Hz, ArH), 6.86 (6H,
d, J = 8.3 Hz, ArH), 6.29 (1H, d, J = 14.9 Hz, 49-CH), 5.94
(1H, dd, J = 14.9, 4.6 Hz, 48-CH), 5.33 (1H, s, 51-CHaHb), 5.31
Major diastereomer 27: Rf: 0.24 (30 : 70 EtOAc–hexanes);
[a]2D0 +14.7 (c 0.80, CHCl3); IR (liquid film): 3531 (br, OH),
−1
1
=
2935, 1612 (C C) cm ; H NMR: d (500 MHz, CDCl3) 7.29
(2H, d, J = 8.5 Hz, ArH), 7.25 (2H, d, J = 7.9 Hz, ArH), 7.25
(2H, d, J = 8.6 Hz, ArH), 6.88 (2H, d, J = 8.6 Hz, ArH), 6.86
=
(4H, d, J = 8.2 Hz, ArH), 4.80 (2H, s, C CH2), 4.77–4.82 (3H,
m, 2 × OCHaHbAr + OCHaHbAr), 4.66 (1H, d, J = 11.4 Hz,
OCHaHbAr), 4.57 (1H, d, J = 10.6 Hz, OCHaHbAr), 4.52 (1H,
d, J = 10.6 Hz, OCHaHbAr), 4.02–4.06 (1H, m, 33-CH), 3.81
(3H, s, ArOCH3), 3.80 (3H, s, ArOCH3), 3.80 (3H, s, ArOCH3),
2 4 2 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 2 0 – 2 4 3 0

View Article Online
(1H, s, 51-CHaHb), 4.84 (1H, d, J = 10.9 Hz, OCHaHbAr), 4.78
(1H, d, J = 11.2 Hz, OCHaHbAr), 4.77 (1H, d, J = 10.4 Hz,
OCHaHbAr), 4.66 (1H, d, J = 11.2 Hz, OCHaHbAr), 4.61 (1H,
d, J = 10.9 Hz, OCHaHbAr), 4.54–4.58 (1H, m, 47-CH), 4.52
(1H, d, J = 10.4 Hz, OCHaHbAr), 4.10–4.14 (1H, m, 33-CH),
3.80 (3H, s, ArOCH3), 3.79 (6H, s, 2 × ArOCH3), 3.76–3.80 (1H,
m, 35-CH), 3.66–3.73 (1H, m, 43-CH), 3.60 (2H, t, J = 6.3 Hz,
29-CH2), 3.49 (1H, s, 38-CH), 3.37 (1H, d, J = 2.7 Hz, OH),
3.22–3.28 (2H, m, 39-CH + 42-CH), 3.12 (3H, s, 37-COCH3),
3.10–3.13 (1H, m, 41-CH), 2.70 (1H, dd, J = 15.1, 5.0 Hz, 44-
CHaHb), 2.58–2.63 (2H, m, 44-CHaHb + 46-CHaHb), 2.48 (1H,
dd, J = 17.1, 9.7 Hz, 46-CHaHb), 2.08 (1H, dd, J = 15.1, 3.5 Hz,
36-CHaHb), 1.87 (2H, qn, J = 6.8 Hz, 30-CH2), 1.68–1.78 (2H,
m, 31-CHaHb + 40-CH), 1.46–1.66 (4H, m, 31-CHaHb + 32-
CHaHb + 34-CH + 36-CHaHb), 1.36–1.42 (1H, m, 32-CHaHb),
0.89 (9H, s, SiC(CH3)3), 0.86 (3H, d, J = 7.2 Hz, 34-CHCH3),
0.51 (3H, d, J = 6.3 Hz, 40-CHCH3), 0.07 (3H, s, Si(CH3)a), 0.01
(3H, s, Si(CH3)b); HRMS: (+ESI) Calc. for C56H80O12Cl2SiNa
[M + Na]+: 1065.4688, found: 1065.4654.
115.0, 114.2, 114.2, 114.2, 114.0, 102.9, 87.2, 83.0, 80.0, 78.8,
74.9, 74.7, 74.3, 73.4, 71.3, 70.6, 67.1, 55.6, 55.6, 55.6, 47.5,
45.7, 45.4, 38.8, 38.5, 38.4, 33.1, 32.6, 31.1, 26.2, 26.1, 23.9,
18.6, 18.2, 12.9, 10.5, −4.2, −4.2, −4.4, −4.4; HRMS: (+ESI)
Calc. for C63H96O11Cl2Si2Na [M + Na]+: 1177.5760, found:
1177.5694.
(4S)-1-[6-[[4-(S)-(t-Butyldimethylsiloxy)-6-(R)-(4-
(triphenylphosphonium)-butyl)-2-(R)-methoxy-5-(S)-methyl-
tetrahydropyran-2-yl]-(S)-(p-methoxybenzyloxy)-methyl]-(6R)-
3,4-(R,R)-bis-(p-methoxybenzyloxy)-5-(R)-methyl-
tetrahydropyran-2-(R)-yl]-4-(t-butyldimethylsiloxy)-7-chloro-2-
methylene-octa-5,7-diene iodide (2)
To a solution of 35 (9.7 mg, 8.39 lmol) in 9 : 1 MeCN (450 lL)
and MeOH (50 lL) were added i-Pr2NEt (3 lL, 17.2 lmol,
2 eq.), NaI (19 mg, 127 lmol, 15 eq.) and PPh3 (88 mg, 336
lmol, 40 eq.). The resultant mixture was heated at reflux for
11 h at which point TLC analysis showed that a small amount
of starting material 35 remained. A further portion of PPh3
(44 mg, 118 lmol, 20 eq.) was added and the mixture heated at
reflux for an additional 8 h. The mixture was cooled to rt and
the solvent was removed in vacuo before the addition of CH2Cl2
(1 mL) and the resultant suspension was filtered through cotton
wool, washing with CH2Cl2 (3 × 0.5 mL). The resultant filtrate
was concentrated in vacuo and the crude material was purified by
flash chromatography (10 : 90 → 60 : 40 MeCN–EtOAc). The
residue was dissolved in CH2Cl2 and filtered through cotton
wool. The filtrate was concentrated in vacuo to afford a glassy
solid. Lyophilisation with C6H6 (2x) provided phosphonium salt
2 (11.5 mg, 91%) as a white powder: Rf: 0.54 (70 : 30 MeCN–
EtOAc); [a]2D0 +12.2 (c 1.15, CHCl3); IR: (neat) 2929, 2855, 1612,
1513, 1438 cm−1; 1H NMR: d (500 MHz, C6D6) 7.83–7.85 (6H,
m, ArH), 7.74 (3H, dd, J = 11.6, 7.3 Hz, ArH), 7.57 (2H, d,
J = 8.3 Hz, ArH), 7.34 (2H, d, J = 8.4 Hz, ArH), 7.27 (2H, d,
J = 8.4 Hz, ArH), 7.14–7.20 (2H, m, ArH), 7.03 (2H, d, J =
6.1 Hz, ArH), 6.97–7.01 (2H, m, ArH), 6.96 (2H, d, J = 8.3 Hz,
ArH), 6.84 (2H, d, J = 8.1 Hz, ArH), 6.83 (2H, d, J = 8.1 Hz,
ArH), 6.45 (1H, dd, J = 14.9, 5.0 Hz, 48-CH), 6.37 (1H, d, J =
14.9 Hz, 49-CH), 5.10–5.13 (4H, m, OCHaHbAr + 51-CHaHb +
(4S)-1-[6-[[4-(S)-(t-Butyldimethylsiloxy)-6-(R)-(4-chlorobutyl)-
2-(R)-methoxy-5-(S)-methyl-tetrahydropyran-2-yl]-(S)-(p-
methoxybenzyloxy)-methyl]-(6R)-3,4-(R,R)-bis-(p-
methoxybenzyloxy)-5-(R)-methyl-tetrahydropyran-2-(R)-yl]-4-
(t-butyldimethylsiloxy)-7-chloro-2-methylene-octa-5,7-diene (35)
To a stirred suspension of Zn (4.27 g, 65.3 mmol, 180 eq.) and
PbI2 (300 mg, 0.65 mmol, 1.8 eq.) in THF (25 mL) was added
TMSCl (0.42 mL, 3.31 mmol, 9.0 eq.). The resulting suspension
was stirred at rt for 15 min before diiodomethane (2.92 mL,
36.2 mmol, 100 eq.) was added dropwise. The reaction was
maintained at self-reflux during the addition and stirred for a
further 30 min at rt before cooling to 0 ◦C. TiCl4 (1 M in CH2Cl2,
7.25 mL, 7.25 mmol, 20 eq.) was added dropwise and the reaction
mixture was warmed to rt and stirred for a further 1 h. A solution
of TBS ether 34 (420 mg, 0.36 mmol) in THF (10 mL + 2 × 5 mL
washings) was added via cannula and the resultant mixture was
stirred at rt for 4 h. The reaction was quenched by slow addition
to a cold (0 ◦C) sodium potassium tartrate solution. It was
allowed to warm to rt and vigorously stirred for 30 min. The
layers were separated and the aqueous phase was extracted with
Et2O (4 × 150 mL), combined organics were dried (MgSO4) and
concentrated in vacuo. Flash chromatography (5 : 95 → 40 :
60 EtOAc–light petroleum) afforded triene 35 (342 mg, 81%)
as a colourless oil: Rf: 0.26 (7 : 30 : 63 Et2O–CH2Cl2–hexanes);
[a]2D0 +16.8 (c 1.03, CHCl3); IR (liquid film): 2931, 2856, 1612,
=
45-C CH2), 5.02(1H, br s, 51-CHaHb), 4.94 (1H, d, J = 12.4 Hz,
OCHaHbAr), 4.93 (1H, d, J = 10.8 Hz, OCHaHbAr), 4.91 (1H,
d, J = 11.1 Hz, OCHaHbAr), 4.63–4.68 (1H, m, 29-CHaHb), 4.61
(1H, d, J = 10.8 Hz, OCHaHbAr), 4.54 (1H, d, J = 11.1 Hz,
OCHaHbAr), 4.50 (1H, app. q, J = 6.2 Hz, 47-CH), 4.30 (1H,
br d, J = 9.7 Hz, 33-CH), 4.22–4.25 (1H, m, 29-CHaHb), 4.05
(1H, br s, 38-CH), 3.95 (1H, br d, J = 1.9 Hz, 35-CH), 3.56
(1H, br t, J = 8.9 Hz, 43-CH), 3.42 (1H, m, 39-CH), 3.42 (3H, s,
OCH3), 3.39 (3H, s, OCH3), 3.34 (1H, m, 42-CH), 3.33 (3H, s,
OCH3), 3.31 (3H, s, OCH3), 3.19 (1H, br t, J = 9.5, 41-CH),
2.74 (1H, br d, J = 14.6 Hz, 44-CHaHb), 2.66 (1H, dd, J =
13.5, 6.7 Hz, 46-CHaHb), 2.56 (1H, dd, J = 15.3, 3.4 Hz, 36-
CHaHb), 2.52 (1H, dd, J = 13.5, 6.9 Hz, 46-CHaHb), 2.44 (1H,
m, 30-CHaHb), 2.30 (1H, dd, J = 14.6, 9.1 Hz, 44-CHaHb),
2.19 (1H, m, 40-CH), 1.99 (1H, br d, J = 15.3 Hz, 36-CHaHb),
1.90 (1H, m, 30-CHaHb), 1.72 (1H, m, 32-CHaHb), 1.55–1.64
(3H, 31-CH2 + 34-CH), 1.20 (1H, m, 32-CHaHb), 1.08 (9H, s,
SiC(CH3)3), 1.05 (3H, d, J = 6.2 Hz, 40-CHCH3), 1.02 (3H, d,
J = 7.1 Hz, 34-CHCH3), 1.01 (9H, s, SiC(CH3)3), 0.25 (3H, s,
SiCH3), 0.15 (3H, s, SiCH3), 0.13 (3H, s, SiCH3), 0.09 (3H, s,
SiCH3); 13C NMR: d (125.7 MHz, C6D6) 159.7, 159.6, 143.3,
1
1514 cm−1; H NMR: d (500 MHz, CDCl3) 7.31 (2H, d, J =
8.4 Hz, ArH), 7.23 (4H, d, J = 7.8 Hz, ArH), 6.83–6.87 (6H,
m, ArH), 6.21 (1H, d, J = 14.9 Hz, 49-CH), 6.10 (1H, dd, J =
14.9, 5.2 Hz, 48-CH), 5.29 (1H, br s, 51-CHaHb), 5.24 (1H, br s,
=
51-CHaHb), 4.92 (1H, br s, 45-C CHaHb), 4.83 (1H, br s, 45-
C CHaHb), 4.81 (2H, app. d, J = 11 Hz, 2 × OCHaHbAr), 4.76
=
(1H, d, J = 10.6 Hz, OCHaHbAr), 4.72 (1H, d, J = 11.4 Hz,
OCHaHbAr), 4.55 (1H, d, J = 10.8 Hz, OCHaHbAr), 4.50 (1H,
d, J = 10.6 Hz, OCHaHbAr), 4.32 (1H, td, J = 6.2, 5.2 Hz,
47-CH), 4.13 (1H, br t, J = 6.9 Hz, 33-CH), 3.80 (6H, s, 2 ×
ArOCH3), 3.79 (3H, s, ArOCH3), 3.73 (1H, m, 35-CH), 3.59
(2H, t, J = 6.3 Hz, 29-CH2), 3.45 (1H, s, 38-CH), 3.30 (1H,
br t, J = 8.7 Hz, 43-CH), 3.16 (1H, t, J = 9.0 Hz, 42-CH),
3.10 (3H, s, 37-COCH3), 3.02–3.13 (2H, m, 39-CH + 41-CH),
2.51 (1H, br d, J = 14.8 Hz, 44-CHaHb), 2.32 (1H, dd, J =
13.6, 6.5 Hz, 46-CHaHb), 2.15–2.22 (2H, m, 44-CHaHb + 46-
CHaHb), 2.12 (1H, dd, J = 15.5, 3.7 Hz, 36-CHaHb), 1.85 (2H,
m, 30-CH2), 1.72–1.77 (2H, m, 31-CHaHb + 40-CH), 1.60–1.69
(3H, m, 31-CHaHb + 32-CHaHb + 36-CHaHb), 1.34–1.46 (2H,
m, 32-CHaHb + 34-CH), 0.86–0.88 (21H, m, 34-CHCH3 + 2 ×
SiC(CH3)3), 0.41 (3H, d, J = 6.4 Hz, 40-CHCH3), 0.02 (3H, s,
SiCH3), 0.01 (3H, s, SiCH3), −;0.01 (6H, 2 × s, 2 × SiCH3);
13C NMR: d (100.6 MHz, CDCl3) 159.7, 159.6, 159.5, 142.7,
138.8, 138.4, 131.5, 131.1, 131.0, 129.9, 129.6, 126.2, 115.5,
2
138.9, 138.8, 134.4, 134.4, 132.4 (d, JP–C = 9.7 Hz, C ortho to
P+), 131.5, 131.0, 130.2 (d, 3JP–C = 12.2 Hz, C meta to P+), 129.5,
1
129.3, 126.4, 119.1 (d, JP–C = 85.2 Hz, C ipso to P+), 115.0,
114.3, 114.1, 102.9, 87.5, 83.2, 80.1, 78.6, 76.5, 75.1, 74.7, 74.5,
71.4, 71.3, 66.6, 55.0, 54.8, 54.7, 48.7, 46.2, 39.4, 39.4, 39.0, 33.7,
3
31.7, 27.4 (d, JP–C = 16.2 Hz, 31-C), 26.2, 26.2, 23.4, 23.1 (d,
1JP–C = 48.8 Hz, 29-C), 18.5, 18.4, 14.0, 10.9, −4.1, −4.3, −4.4;
31P NMR: d (162 MHz, C6D6) 25.6; HRMS: (+ESI) Calc. for
C81H111O11ClPSi2 [M]+: 1381.7076, found: 1381.7173.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 2 0 – 2 4 3 0
2 4 2 9

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E. Fernandez-Megia, N. Gourlaouen, S. V. Ley and G. J. Rowlands,
Synlett, 1998, 991–994; I. H. Cho and L. A. Paquette, Heterocycles,
2002, 58, 43–46; S. A. Hermitage, S. M. Roberts and D. J. Watson,
Tetrahedron Lett., 1998, 39, 3567–3570; P. D. Kary, S. M. Roberts and
D. J. Watson, Tetrahedron: Asymmetry, 1999, 10, 213–216; P. D. Kary
and S. M. Roberts, Tetrahedron: Asymmetry, 1999, 10, 217–219; G. C.
Micalizio and W. R. Roush, Tetrahedron Lett., 1999, 40, 3351–3354;
G. C. Micalizio, A. N. Pinchuk and W. R. Roush, J. Org. Chem., 2000,
65, 8730–8736; M. Samadi, C. Munoz-Letelier, S. Poigny and M.
Guyot, Tetrahedron Lett., 2000, 41, 3349–3353; S. Lemaire-Audoire
and P. Vogel, Tetrahedron Lett., 1998, 39, 1345–1348.
Acknowledgements
Financial support was provided by the EPSRC (GR/L41646),
EC (Marie Curie Fellowship to J.L.A.), DFG (Postdoctoral
Fellowship to T.T.), Cambridge Commonwealth 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 (AZ) for valuable
assistance.
6 C. J. Cowden and I. Paterson, Org. React., 1997, 51, 1–200; I.
Paterson, C. J. Cowden, and D. J. Wallace, in Modern Carbonyl
Chemistry, ed. J. Otera, Wiley-VCH, Weinheim, 2000, pp. 249–297.
7 I. Paterson, D. J. Wallace and S. M. Velazquez, Tetrahedron Lett.,
1994, 35, 9083–9086; I. Paterson and D. J. Wallace, Tetrahedron Lett.,
1994, 35, 9087–9090; I. Paterson and D. J. Wallace, Tetrahedron Lett.,
1994, 35, 9477–9480; I. Paterson, D. J. Wallace and C. J. Cowden,
Synthesis, 1998, 639–652.
References
1 For a full introduction and background, see the preceding papers in
this series: I. Paterson, M. J. Coster, D. Y.-K. Chen, R. M. Oballa,
D. J. Wallace and R. D. Norcross, Org. Biomol. Chem., 2005, 3,
DOI: 10.1039/b504146e; I. Paterson, M. J. Coster, D. Y.-K. Chen,
K. R. Gibson and D. J. Wallace, Org. Biomol. Chem., 2005, 3,
DOI: 10.1039/b504148a.
8 H. C. Brown, R. K. Dhar, K. Ganesan and B. Singaram, J. Org.
Chem., 1992, 57, 499–504.
2 For previous communications of our work, see: (a) I. Paterson, R. M.
Oballa and R. D. Norcross, Tetrahedron Lett., 1996, 37, 8581–8584;
(b) I. Paterson and L. E. Keown, Tetrahedron Lett., 1997, 38, 5727–
5730; (c) I. Paterson and R. M. Oballa, Tetrahedron Lett., 1997,
38, 8241–8244; (d) I. Paterson, D. J. Wallace and K. R. Gibson,
Tetrahedron Lett., 1997, 38, 8911–8914; (e) I. Paterson, D. J. Wallace
and R. M. Oballa, Tetrahedron Lett., 1998, 39, 8545–8548; (f) I.
Paterson, D. Y.-K. Chen, M. J. Coster, J. L. Acena, J. Bach, K. R.
Gibson, L. E. Keown, R. M. Oballa, T. Trieselmann, D. J. Wallace,
A. P. Hodgson and R. D. Norcross, Angew. Chem., Int. Ed., 2001, 40,
4055–4060; (g) I. Paterson and M. J. Coster, Tetrahedron Lett., 2002,
43, 3285–3289; (h) I. Paterson, J. L. Acena, J. Bach, D. Y.-K. Chen
and M. J. Coster, Chem. Commun., 2003, 462–463; (i) I. Paterson
and M. J. Coster, in Strategy and Tactics in Organic Synthesis, ed.
M. Harmata, Elsevier, Oxford, 2004, vol. 4, ch. 8, pp. 211–245.
3 Completed altohyrtin/spongistatin total syntheses: (a) D. A. Evans,
P. J. Coleman and L. C. Dias, Angew. Chem., Int. Ed., 1997, 36, 2738–
2741; (b) D. A. Evans, B. W. Trotter, B. Cote and P. J. Coleman, Angew.
Chem., Int. Ed., 1997, 36, 2741–2744; (c) D. A. Evans, B. W. Trotter,
B. Cote, P. J. Coleman, L. C. Dias and A. N. Tyler, Angew. Chem., Int.
Ed., 1997, 36, 2744–2747; (d) D. A. Evans, B. W. Trotter, P. J. Coleman,
B. Cote, L. C. Dias, H. A. Rajapakse and A. N. Tyler, Tetrahedron,
1999, 55, 8671–8726; (e) J. Guo, K. J. Duffy, K. L. Stevens, P. I.
Dalko, R. M. Roth, M. M. Hayward and Y. Kishi, Angew. Chem.,
Int. Ed., 1998, 37, 187–192; (f) M. M. Hayward, R. M. Roth, K. J.
Duffy, P. I. Dalko, K. L. Stevens, J. Guo and Y. Kishi, Angew. Chem.,
Int. Ed., 1998, 37, 192–196; (g) A. B. Smith, III, V. A. Doughty,
Q. Lin, L. Zhuang, M. D. McBriar, A. M. Boldi, W. H. Moser, N.
Murase, K. Nakayama and M. Sobukawa, Angew. Chem., Int. Ed.,
2001, 40, 191–195; (h) A. B. Smith, III, Q. Lin, V. A. Doughty, L.
Zhuang, M. D. McBriar, J. K. Kerns, C. S. Brook, N. Murase and
K. Nakayama, Angew. Chem., Int. Ed., 2001, 40, 196–199; (i) A. B.
Smith, III, V. A. Doughty, C. Sfouggatakis, C. S. Bennett, J. Koyanagi
and M. Takeuchi, Org. Lett., 2002, 4, 783–786; (j) A. B. Smith, III, W.
Zhu, S. Shirakami, C. Sfouggatakis, V. A. Doughty, C. S. Bennett and
Y. Sakamoto, Org. Lett., 2003, 5, 761–764; (k) M. T. Crimmin and
D. G. Washburn, Tetrahedron Lett., 1998, 39, 7487–7490; (l) M. T.
Crimmin, J. D. Katz, L. C. McAtee, E. A. Tabet and S. J. Kirincich,
Org. Lett., 2001, 3, 949–952; (m) M. T. Crimmin and J. D. Katz,
Org. Lett., 2000, 2, 957–960; (n) M. T. Crimmin, J. D. Katz, D. G.
Washburn, S. P. Allwein and L. F. McAtee, J. Am. Chem. Soc., 2002,
124, 5661–5663; (o) J. L. Hubbs and C. H. Heathcock, J. Am. Chem.
Soc., 2003, 125, 12836–12843; (p) C. H. Heathcock, M. McLaughlin,
J. Medina, J. L. Hubbs, G. A. Wallace, R. Scott, M. M. Claffey, C. J.
Hayes and G. R. Ott, J. Am. Chem. Soc., 2003, 125, 12844–12849.
4 Formal total synthesis of altohyrtin C/spongistatin 2 by Nakata and
co-workers: T. Terauchi, T. Terauchi, I. Sato, W. Shoji, T. Tsukada,
T. Tsunoda, N. Kanoh and M. Nakata, Tetrahedron Lett., 2003,
44, 7741–7745; T. Terauchi, T. Tanaka, T. Terauchi, M. Morita, K.
Kimijima, I. Sato, W. Shoji, Y. Nakamura, T. Tsukada, T. Tsunoda,
G. Hayashi, N. Kanoh and M. Nakata, Tetrahedron Lett., 2003, 44,
7747–7751.
9 (a) I. Paterson and R. D. Tillyer, J. Org. Chem., 1993, 58, 4182–4184;
(b) I. Paterson and T. Nowak, Tetrahedron Lett., 1996, 37, 8243–8246.
10 J. A. Dale, D. L. Dull and H. S. Mosher, J. Org. Chem., 1969, 34,
2543–2549; J. A. Dale and H. S. Mosher, J. Am. Chem. Soc., 1973,
95, 512–519; I. Ohtani, T. Kusumi, Y. Kashman and H. Kakisawa,
J. Am. Chem. Soc., 1991, 113, 4092–4096.
11 R. W. Hoffmann, Chem. Rev., 1989, 89, 1841–1860.
12 E. J. Corey, D. Barnes-Seeman and T. W. Lee, Tetrahedron Lett.,
1997, 38, 4351–4354, and references cited therein.
13 D. A. Evans and K. T. Chapman, Tetrahedron Lett., 1986, 27, 5939–
5942; D. A. Evans, K. T. Chapman and E. M. Carreira, J. Am. Chem.
Soc., 1988, 110, 3560–3578.
14 Analysis of these acetonides by 13C NMR confirmed the 1,3-anti
selectivity in the Me4NBH(OAc)3 reduction step: S. D. Rychnovsky
and D. J. Skalitzky, Tetrahedron Lett., 1990, 31, 945–948; S. D.
Rychnovsky, B. Rogers and G. Yang, J. Org. Chem., 1993, 58, 3511–
3515; D. A. Evans, D. L. Rieger and J. R. Gage, Tetrahedron Lett.,
1990, 31, 7099–7100.
15 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155–4156; D. B.
Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277–7287.
16 M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune,
W. R. Roush and T. Sakai, Tetrahedron Lett., 1984, 25, 2183–2186.
17 (a) K. B. Sharpless, W. Amberg, Y. L. Bennani, G. A. Crispino, J.
Hartung, K.-S. Jeong, H.-L. Kwong, K. Morikawa, Z.-M. Wang, D.
Xu and X.-L. Zhang, J. Org. Chem., 1992, 57, 2768–2771; (b) Z. M.
Wang and K. B. Sharpless, Tetrahedron Lett., 1993, 34, 8225–8228;
(c) H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Chem.
Rev, 1994, 94, 2483–2547.
18 All compounds in this series bearing an acetonide protecting group
were found to be sensitive to even mildly acidic conditions, presum-
ably due to the sterically unfavourable 1,2-cis-1,3-trans- nature of the
substituents on the 1,3-dioxane ring.
19 N. Nakajima, K. Horita, R. Abe and O. Yonemitsu, Tetrahedron
Lett., 1988, 29, 4139–4142.
20 R. E. Ireland, L. Liu and T. D. Roper, Tetrahedron, 1997, 53, 13221–
13256.
21 C. Alvarez-Ibarra, S. Arias, G. Banon, M. J. Fernandez, M.
Rodriguez and V. Sinisterra, J. Chem. Soc., Chem. Commun., 1987,
1509–1511; I. Paterson, K. S. Yeung and J. B. Smaill, Synlett, 1993,
774–776.
22 N. A. Petasis and E. I. Bzowej, J. Am. Chem. Soc., 1990, 112, 6392–
6394.
23 S. V. Ley, J. Norman, W. P. Griffith and S. P. Marsden, Synthesis,
1994, 639–666.
24 K. Griesbaum, A. R. Bandyopadhyay and M. Meister, Can. J. Chem.,
1986, 64, 1553–1559.
25 A. J. Mancuso and D. Swern, Synthesis, 1981, 165–185.
26 I. Paterson, K. R. Gibson and R. M. Oballa, Tetrahedron Lett., 1996,
37, 8585–8588; I. Paterson and L. A. Collett, Tetrahedron Lett., 2001,
42, 1187–1191.
27 D. A. Evans, P. J. Coleman and B. Coˆte´, J. Org. Chem., 1997, 62,
788–789; D. A. Evans, B. Cote, P. J. Coleman and B. T. Connell,
J. Am. Chem. Soc., 2003, 125, 10893–10898.
28 K. Takai, T. Kakiuchi, Y. Kataoka and K. Utimoto, J. Org. Chem.,
1994, 59, 2668–2670.
29 I. Paterson, D. Y.-K. Chen, M. J. Coster, J. L. Acen˜a, J. Bach and
D. J. Wallace, Org. Biomol. Chem., 2005, 3, DOI: 10.1039/b504151a.
5 Syntheses of E- and/or F-ring subunits by other groups: J. C.
Anderson and B. P. McDermott, Tetrahedron Lett., 1999, 40,
7135–7138; J. C. Anderson, B. P. McDermott and E. J. Griffin,
Tetrahedron, 2000, 56, 8747–8767; R. Dunkel, J. Treu, H. Martin
and R. Hoffmann, Tetrahedron: Asymmetry, 1999, 10, 1539–1549; H.
Kim and H. M. R. Hoffmann, Eur. J. Org. Chem., 2000, 2195–2201;
2 4 3 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 2 0 – 2 4 3 0