Laboratory emulation of polyketide biosynthesis: An iterative, aldol-based, synthetic entry to polyketide libraries using (R)- And (S)-l-(benzyloxy)-2-methylpentan-3-one, and conformational aspects of extended polypropionates

Article abstract of DOI:10.1039/a809818b

Iterative, one-directional, boron-mediated aldol chain extensions, using the dipropionyl reagent (A)-l-(benzyloxy)-2methyIpentan-3-one 7, have enabled the highly diastereoselective assembly of the stereoregular heptapropionates 5 and 6. The synthetic sequence developed permits structural diversity through variation in the stereochemical nature of the aldolisation and reduction steps, together with the choice of the chiral ketone employed at each iteration. The heptapropionate 5 has been shown to represent an example of a fully flexible molecule, whose backbone nevertheless adopts a single preferred conformation. It forms part of a family of conformationally controlled polyols, exploiting the avoidance of , s)v;-pentane interactions and the preference for preorganisation through intramolecular hydrogen bonding.

Full text of DOI:10.1039/a809818b

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Laboratory emulation of polyketide biosynthesis: an iterative,
aldol-based, synthetic entry to polyketide libraries using (R)- and
(S)-1-(benzyloxy)-2-methylpentan-3-one, and conformational
aspects of extended polypropionates
Ian Paterson* and Jeremy P. Scott
University Chemical Laboratory, Lensfield Road, Cambridge, UK CB2 1EW
Received (in Cambridge) 10th December 1998, Accepted 5th January 1999
Iterative, one-directional, boron-mediated aldol chain extensions, using the dipropionyl reagent (R)-1-(benzyloxy)-2-
methylpentan-3-one 7, have enabled the highly diastereoselective assembly of the stereoregular heptapropionates 5
and 6. The synthetic sequence developed permits structural diversity through variation in the stereochemical nature
of the aldolisation and reduction steps, together with the choice of the chiral ketone employed at each iteration. The
heptapropionate 5 has been shown to represent an example of a fully flexible molecule, whose backbone nevertheless
adopts a single preferred conformation. It forms part of a family of conformationally controlled polyols, exploiting
the avoidance of syn-pentane interactions and the preference for preorganisation through intramolecular hydrogen
bonding.
the synthesis of polypropionate-derived natural products and
Introduction
their value has been illustrated in a number of target-oriented
In these modern times, the perceived diminishing returns from
synthetic ventures.6,7 By appropriate choice of preformed enol-
natural product screening are driving the development and
application of combinatorial strategies to identify and optimise
ate, three out of the four possible aldol diastereomers, viz. 8,7a
9
7b and 10,7c are readily accessible (Fig. 1) and this has enabled
drug discovery leads. Consequently, there is a continuing inter-
est in the construction of libraries based on the known classes
of biopolymer.1 The polyketides represent an important class
of natural products associated with a broad spectrum of bio-
logical activity and whose structures encompass a rich array
of molecular architecture.2 Recently, the polyketides have come
under scrutiny as a potential source of molecular diversity. The
salient motifs of this biopolymer class, such as hydrocarbon
backbones, polyoxygenation and multiple contiguous stereo-
genic centres, contrast with those of the more conventional
peptidic and peptidomimetic libraries already available.1
Indeed biosynthetic approaches to the generation of poly-
ketide diversity, entailing the combinatorial reconstruction of
existing biosynthetic pathways, are now well under way.3 As a
complementary approach, we envisaged the rational construc-
tion of libraries of novel, unnatural polyketides by exploiting
aldol-based methodology previously developed within our
laboratory. In this article, we present our synthetic studies high-
lighting the power of this approach to the iterative assembly of
polyketide libraries. We also discuss the conformational prefer-
ences of some representative extended polypropionates having
up to 12 contiguous stereogenic centres.
the development of a general protocol for the selective synthesis
of all 32 stereoisomers of the stereopentad 11.7d In this way,
the synthesis of a large variety of natural and unnatural poly-
propionate subunits can be realised.
Using propionaldehyde as our starter unit, three iterative
aldol chain extension cycles with (R)-7 were planned to enable
access to the hexols 5 and 6. First, we required to establish
protocols by which a common intermediate functionality could
be efficiently regenerated. In previous studies, we had shown
that selective generation of the (E)-enol dicyclohexylborinate
of the ethyl ketones (R)- and (S)-7 and aldol addition,7a fol-
lowed by reduction8 in situ, proceeds with excellent diastereo-
selection for the 1,3-syn diol. Using our standard enolisation
procedure (Scheme 2),6e,7a anti aldol addition of (R)-7 to prop-
ionaldehyde gave the intermediate aldolate 12, which was
reduced in situ with LiBH4 to give the 1,3-syn diol 13 in 99%
yield with 94% diastereoselection (ds).9 Protection as its
acetonide 14 (95%) enabled the stereochemistry of the aldol
bond construction and reduction to be confirmed.† With the
required stereotetrad so configured, the iterative protocol was
completed by hydrogenolysis of the benzyl ether and Swern
oxidation10 to give the aldehyde 15 (93%), thereby regener-
ating the common aldehyde functionality. In this way, the
tripropionate building block 15 was obtained in four steps from
(R)-7 in 88% yield with 94% ds.
Results and discussion
Iterative assembly of extended polypropionates
With these optimum reaction conditions, we applied this syn-
reduction iterative sequence twice successively. The boron-
mediated aldol reaction of aldehyde 15 with the (E)-enolate of
(R)-7, followed by in situ reduction with external hydride
(LiBH4), gave the 1,3-syn diol 16 in 78% yield with >97% ds. In
this second iteration, the enhanced stereochemical fidelity is
ascribed to a matched relationship of the coupling partners in
the aldol bond construction.11 Using the standard 3-step
Our initial studies (Scheme 1) sought to emulate the processive
mechanism of biosynthesis of bacterial polyketides, in which
each chain extension unit introduced is correctly function-
alised prior to addition of the next.4 In the case of 6-deoxy-
erythronolide B (1), the primary heptapropionate framework in
2 is assembled by the appropriate polyketide synthase from a
propionate starter unit 3 and 6 methyl malonyl extender units
4.5 We identified heptapropionates 5 and 6 as ideal targets
by which to demonstrate biomimetic iterative chain extension
utilising stereoselective aldol methodology.
†
13C NMR resonances at 19.0, 30.2 and 98.3 ppm are characteristic of
a syn acetonide and the large 1H NMR vicinal coupling constants,
J3,4 = J4,5 = 10.4 Hz are consistent with the preferred chair conform-
ation. See reference 12.
Previously, we have introduced the ethyl ketone (R)-7 and its
enantiomer as versatile and powerful dipropionyl reagents for
J. Chem. Soc., Perkin Trans. 1, 1999, 1003–1014
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O
13
S
CoA
13
S
ACP
1
O
3
2
OH
OH
O
OH
OH
O
OH
+
Iterative propionate chain extension
13
O
OH
OH
1
S
CoA
OH
HO2C
O
O
6 x
4
[O]
[O]
[O]
[O]
[O]
[O]
[O]
6-deoxyerythronolide B (1)
propionyl reagent
1
OBn
OBn
H
13
11
9
7
5
3
13
OBn
OH
13
1
+
OH
OH
OH
OH
OH
OH
O
OH
OH
OH OH
OH
OH
5
6
and
Iterative dipropionate chain extension
OBn
3 x (R)-7
dipropionyl reagent
13
11
9
7
5
3
1
O
OH
OH
OH
OH
OH
OH
[O]
[O]
[O]
[O]
[O]
[O]
[O]
Scheme 1 Iterative biosynthetic and synthetic polyketide construction.
anti-anti 7a
syn-anti 7b
ds). Previously we had exploited the acetonide group as both
protection for the 1,3-syn diol and as an endogenous stereo-
chemical reporter in the H and 13C NMR spectra.12 However,
1
R
OBn
R
OBn
here we found it to be too labile under all hydrogenolysis con-
ditions studied. Silylene protection of diol 21 alleviated this
problem, with debenzylation then uneventfully providing the
new tripropionate building block 22 (81%).
OH
O
OH
O
8
9
general stereopentad 7d
syn-syn 7c
Following Swern oxidation, a second chain extension with
(R)-7 was performed to give the ketone 23 (72%, >97% ds).
Application of the standard 3-step sequence (cf. 20→22) then
gave 24, in readiness for a third dipropionate extension.§ As
before, the anti aldol reaction of (R)-7 with the aldehyde
derived from 24 was followed by anti reduction, leading to diol
25 (60%). At this stage, silylene deprotection was carried out
(HFؒpy) to give the hexol 6 (79%). In this sequence, the inter-
mediate aldehydes were found to be prone to elimination if
handled extensively and were, therefore, not isolated but sub-
jected immediately to aldol chain extension.
We now looked to introduce further diversity by variation of
the ketone chain extension unit with regard to substitution and
absolute configuration (Scheme 4). For example, an anti aldol
reaction of the aldehyde 15 with the enantiomeric ketone (S)-7
gave adduct 26 (79%) as the major isomer with 85% ds. In this
more demanding mismatched case,11 the high level of π-face
selectivity from the (E)-enolate overrides any Felkin–Anh type
influence from the aldehyde. Selecting (R)-278a in the aldol
reaction with 15 gave ketone 28 with high diastereoselectivity
(>97% ds), as expected from the matched relationship of the
coupling partners, demonstrating the potential for introducing
substituents other than methyl in these extended polyketide
systems. In previous work, we have demonstrated that alkoxy
substituents (e.g. BnO, MeO) can also be employed without
impairment of the reaction stereoselectivity.16
R
OBn
OBn
11
OH
O
OH OH
OH
10
Fig. 1 Aldol diastereomers accessible from dipropionyl reagent (R)-7.
sequence (cf. 13→15), this was elaborated into aldehyde 17
(88%) in readiness for a further chain extension. The third iter-
ation again proceeded with matched induction to give the diol
18 (74%, >97% ds). Protection of 18 as its triacetonide 19 (97%)
led to diagnostic 13C NMR acetal resonances at 97.2, 97.1 and
96.8 ppm.12 Overall, the protected 1,3-polyol 19 was obtained in
44% yield (10 steps) from the starting ketone (R)-7, with >88%
ds for introduction of the 12 contiguous stereogenic centres.
Finally, acetonide hydrolysis was effected with activated
Dowex-50 resin to give the hexol 5 (89%) in which the hydroxys
have an all-syn arrangement, combined with 1,3-anti methyl-
ation along the hydrocarbon backbone. The effective regener-
ation of a common intermediate functionality and high stereo-
chemical and material efficiency of this sequence has led to its
application on solid support, subject to appropriate modifi-
cations,13 where the aldehyde starter unit is attached to a resin.
Introducing diversity by stereochemical and structural changes
Next we sought to demonstrate that library diversity could be
introduced through stereochemical changes, in both the aldol
bond construction and β-hydroxyketone reduction steps, as
well as the introduction of substituents other than methyl into
the backbone. First, the ketone reduction stereochemistry
was reversed (Scheme 3). Using Me4NBH(OAc)3 for hydroxy-
directed reduction14 of 20‡ gave the 1,3-anti diol 21 (91%, >97%
A family of conformationally controlled polyols
The heptapropionates 5 and 6 can be regarded as long chain n-
alkanes upon which methyl and hydroxy substituents have been
appended in a stereoregular manner. Both possess a 1,3-anti
methylation pattern, the preferred conformation of which has
been known from polymer chemistry for many years. Syndio-
‡ In all new aldol products, the anti relative configuration of the aldol
bond was supported by the large vicinal coupling constant (J = 7.0–9.6
Hz) observed; the configuration of the new hydroxy-bearing centre was
also established, in several cases, by 1H NMR Mosher ester analysis. See
reference 15.
§ The anti relative stereochemistry of the 1,3-diol was confirmed, at
each iteration, by acetonide formation and 13C NMR analysis. See
reference 12.
1004
J. Chem. Soc., Perkin Trans. 1, 1999, 1003–1014

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1st iteration
i
iii, iv
OBn
H
+
OBn
OBn
H
(99%)
(93%)
+
O
O
O
–
B
O
OP
OP
O
O
O
15
13, P = H 94% ds
14, P–P = CMe2
cHex
cHex
(R)-7
2nd iteration
12
ii
(95%)
v
ii-iv
H
OBn
H
+
(R)-7
(78%)
(88%)
O
O
O
O
O
OH
16
OH
O
O
O
O
O
15
3rd iteration
> 97% ds
17
anti
H
i
OBn
v
OBn
+
(R)-7
(74%)
(89%)
O
O
O
O
OP
OP
O
O
O
2
OH
OH
syn
3
18, P = H > 97% ds
19, P–P = CMe2
ii
(97%)
17
5
Scheme 2 Reagents and conditions: (i) (c-Hex)2BCl, Et3N, Et2O, 0 ЊC, 1.5 h; RCHO, Ϫ78→Ϫ15 ЊC, 3.5 h; LiBH4, Ϫ78 ЊC, 2 h; H2O2, 10% NaOH,
MeOH, 2 h; (ii) Me2C(OMe)2, PPTS, CH2Cl2, 5–18 h; (iii) Pd(OH)2/C, H2, EtOH, 1–4 h; (iv) (COCl)2, DMSO, CH2Cl2, Ϫ78 ЊC, 0.5 h; Et3N,
Ϫ78→Ϫ40 ЊC, 0.25 h; (v) Dowex-50, MeOH–H2O (9:1), ∆, 4 h.
i
ii
iii, iv
OBn
OH
H
OBn
(90%)
(91%)
(81%)
OH
OH
O
O
O
OH
20
O
Si
But
But
94% ds
> 97% ds
21
22
ii-iv
v, i
OH
OBn
(42%)
(72%)
O
O
O
O
O
O
OH
23
O
Si
Si
Si
But
But But
But
But
But
24
> 97% ds
anti
v, i, ii
vii
OBn
OBn
(60%)
(79%)
O
O
O
O
OH
25
OH
OH
anti
OH
Si
Si
3
But
But But
But
> 94% ds
6
Scheme 3 Reagents and conditions: (i) (R)-7, (c-Hex)2BCl, Et3N, Et2O, 0 ЊC, 1.5 h; RCHO, Ϫ78→Ϫ15 ЊC, 3.5 h; H2O2, pH 7 buffer, MeOH, 2 h; (ii)
Me4NBH(OAc)3, AcOH–MeCN, Ϫ20 ЊC, 13–44 h; (iii) (t-Bu)2Si(OTf)2, 2,6-lutidine, CH2Cl2, 20 ЊC, 21–44 h; (iv) 10% Pd/C, H2, EtOH, 1.5–3 h; (v)
(COCl)2, DMSO, CH2Cl2, Ϫ78 ЊC, 0.5 h; Et3N, Ϫ78→Ϫ40 ЊC, 0.25 h; (vi) HFؒpyridine–pyridine, THF, 14 h, 20 ЊC.
tactic polypropylene, for example, exists in either extended
chain17a or helical17b conformations in which destabilising syn-
pentane interactions are avoided. With the additional presence
of 1,3-related hydroxy groups in 5 and 6, it was suspected that
the polypropionate sequences generated might demonstrate
pronounced conformational biases in solution. In general
terms, it is of interest to identify structural units within mole-
cules that can be exploited as ‘conformational building
blocks’.18 Moreover, an understanding of the principles which
render them conformationally restricted is important for the
design of novel drugs and host molecules.19
Initially, we examined the monomeric syn-diol 13 (≡29, with
n = 1, Fig. 2). The calculated global minimum conformer 30
(MM2, MacroModel, ver. 4.5)20 shows that the 2-Me and
4-Me are oriented to avoid syn-pentane interactions whilst
the hydroxy groups form an intramolecular hydrogen bonding
network. To obtain experimental evidence for this population
bias, we related the observed vicinal coupling constants to those
predicted by MacroModel, using the Karplus-type routine21
included in this package. For 3-H, the experimental J values
3
(1.4 and 9.5 Hz) compare favourably with those calculated
(1.7 and 9.2 Hz) reflecting the gauche 2-H/3-H and trans 3-H/4-
H relative orientations in 30. The strong divergence of these
two diagnostic coupling constants indicates a substantial
population in solution of the calculated conformation.
Next, we examined the longer chain homologue 5 (≡29,
n = 3, Fig. 3). Monte Carlo exploration of the accessible con-
formational space of hexol 5 gave 31 as the global minimum
conformer. In an analogous manner to 13, the alkane backbone
adopts an extended all trans conformation (mean dihedral
angle 168Њ) with an intramolecular hydrogen bonding network
terminating on the benzyl ether oxygen. Vicinal 1H NMR coup-
ling constants again provided evidence for the solution phase
conformation. For the methine protons of the hydroxy bearing
J. Chem. Soc., Perkin Trans. 1, 1999, 1003–1014
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Fig. 4 Part of the 1H NMR spectrum of hexol 5 (6.3 to 4.4 ppm,
300 K, C6D6 solution).
Fig. 2 Chem3D representation of the global minimum conformer 30
of diol 13.
ing in concert with the constraint provided by the 1,3-anti
methylation, was predicted by the preceding modelling results.
By 1H NMR spectroscopy, the hydroxy protons of 5 are mark-
edly downfield in chemical shift (δH range 4.47–6.07 ppm in
C6D6) and appear as six distinct singlets (Fig. 4). Over the
concentration range of 0.5 mM to 77 mM, these chemical
shifts have essentially constant values [∆(δH) ≤ 0.08 ppm, CDCl3
(s)], supporting the existence of well-defined intramolecular
hydrogen bonding networks (Fig. 5).
The molecular modelling also predicted that the methyl
groups of the main chain (excluding the ethyl terminus) should
split into two distinct chemical shift groupings, due to their
distinct chemical environments in 31. NOESY spectroscopy
(500 MHz; C6D6) permitted assignment and the expected
separation was observed: 1.15, 1.10, 1.04 ppm for the 1,5-syn
methyl groups behind the plane (2-Me, 6-Me and 10-Me),
whereas those in front (4-Me, 8-Me, 12-Me) appeared at 0.70,
0.60 and 0.55 ppm. Furthermore, these methyl groups exhibited
quite distinct NOE patterns (Fig. 6) as expected from the pre-
ferred conformation 31. This is most readily understood by
considering the 6-Me and 8-Me groups. The modelling results
predicted the 8-Me would show the observed NOE contacts
with 7-H, 8-H, 9-H, and with 6-H and 10-H. Contrastingly,
the 6-Me shows NOEs to 4-H, 6-H and 8-H but there are no
observable NOEs to either 5-H or 7-H. In the global minimum
conformer 31, 5-H and 7-H adopt trans relationships (dihedral
angles 165 and 177Њ) with respect to the 6-Me. Whilst absence
of an NOE is a negative result, this is supportive of the local
conformation in this subunit of the molecule. Moreover, neither
the 2-Me (dihedral angle to 3-H, 164Њ) nor the 10-Me (dihedral
angles to 9-H and 11-H, 165 and 177Њ) show NOE contacts to
the methines of the adjacent hydroxy bearing carbons.
To complete the sequence, the shorter chain tetrol 32
(Scheme 5) was examined (≡29, n = 2). Acidic cleavage of the
acetonide protecting group present in diol 16 afforded the tetrol
32 (76%). An entirely analogous pattern of behaviour was
observed: well-defined downfield hydroxy chemical shifts (δH
range 4.13–5.63 ppm in C6D6), correlation between the cal-
culated20,21 and observable 3J values for the diagnostic methine
protons (calculated ranges: 0.7–1.5 and 9.5–10.2 Hz; values
observed: <1.0, 1.3, 1.8, 9.0, 9.4, 9.4 Hz) and distinctive
chemical shift separation of the methyl groups in two different
environments.
Fig. 3 Chem3D representations of the global minimum conformer 31
of hexol 5 (only selected H shown for clarity).
Mismatched chain extension
i
+
15
(79%)
O
OBn
(S)-7
O
O
OH
O
OBn
26
85% ds
Matched chain extension
i
+
15
(93%)
O
OBn
(R)-27
O
O
OH
O
OBn
28 > 97% ds
Scheme 4 Reagents and conditions: (i) (c-Hex)2BCl, Et3N, Et2O, 0 ЊC,
1.5 h; 15, Ϫ78→Ϫ15 ЊC, 3.5 h; H2O2, pH 7 buffer, MeOH, 2 h.
Seeking further evidence for the specific nature of the hydro-
gen bonding observed in hexol 5, the diastereomeric hexol 6,
where the configurations at three of the six hydroxy bearing
carbons (C3, C7 and C11) had been inverted, was studied. In
contrast to 5, molecular modelling20 of hexol 6 did not provide
any distinct global minimum conformer. The calculated low
energy conformers avoided unfavourable syn-pentane inter-
actions, but no distinctive hydrogen bonding pattern emerged.
Experimentally, the hydroxy groups of 6 are collapsed into a
carbons in 5, the calculated values fell into two distinct ranges,
0.6–1.7 Hz and 10.1–10.6 Hz, reflecting the dihedral angles
associated with the trans conformations for the main chain.
Although signal overlap prevented determination of all of the
pertinent coupling constants, the observed 3J values of 1.2, 1.3,
1.5, 1.7 and 9.1, 9.3, 9.4 Hz (500 MHz; C6D6) provide support
for a strong bias in the conformer population in solution,
toward that calculated in vacuo.
1
An extended intramolecular hydrogen bonding network, act-
broad envelope in the H NMR spectrum (500 MHz; CDCl3),
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J. Chem. Soc., Perkin Trans. 1, 1999, 1003–1014

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anti
OH
OBn
n = 1, 13
n = 2, 32
n = 3, 5
OH
OH
OH
syn
OR
n
33
Fig. 7 A family of conformationally controlled propionates.
1st iteration, 5 different R1 substituents
R1
Me
OBn
OH
OH
24 x 5 = 80 sequences
2nd iteration, 5 different R2 substituents
Fig. 5 1H NMR chemical shift (δOH) of the hydroxy protons at 300 K
as a function of the logarithm of concentration for hexol 5 (CDCl3
solution).
R1
Me
R2
Me
OBn
OH
OH
OH
OH
(24 x 5)2 = 6400 sequences
3rd iteration, 5 different R3 substituents
R1
Me
R2
Me
R3
Me
OBn
OH
OH
OH
OH
OH OH
(24 x 5)3 = 512000 sequences
Fig. 8 Potential numbers of library components accessible at 1st, 2nd
and 3rd iterations through stereochemical and substituent variation.
and (S)-7 provide a practical method for the laboratory emu-
lation of the iterative construction of extended polypropionate
sequences.22 However, the pressing question for polyketide
libraries remains whether they can be made sufficiently diverse.
Fortunately, further structural diversity is accessible by chain
extending using other chiral enolate reagents developed within
our laboratory. In a combinatorial context (Fig. 8), 5 different
R substituents (e.g. Me,7a Et,8a Pr, OMe16 and OBn16) together
with the 24 accessible stereoisomers for each R, allows 80
possible sequences. As the chain length grows, the number of
potential sequences rapidly escalates, with 6400 at the second
iteration and 512000 at the third iteration. In principle, parallel
synthesis (possibly on solid support13) should provide access
to large libraries of stereochemically defined polyols, which
might be further modified by appropriate functional group
manipulation. Furthermore, such polyol structures are attract-
ive in that they have directional hydrogen-bonding capability
and provide quite subtle variability at a series of closely-
spaced centres, complementary to the larger-scale repeat units
present in peptidic and peptidomimetic sequences. Moreover,
the readily attainable structural diversity, combined with the
inherent conformational preferences of these flexible polyol
structures, permits a high level of sampling of 3-dimensional
space.
Fig. 6 Molecular fragment of hexol 5, excised from the global
minimum conformer 31, with observed NOESY correlations (C6D6
solution).
i
OBn
OBn
(76%)
O
O
OH
OH
OH
OH
16
32
2
Scheme 5 Reagents and conditions: (i) Dowex-50, MeOH–H2O (9:1),
∆, 20 h.
preventing the observation of the vicinal coupling constants of
the methines on the hydroxy bearing carbons. In this case, the
1,3-anti related hydroxy groups are presumably no longer all in
an appropriate spatial arrangement to collectively hydrogen
bond in solution. It can be concluded that the avoidance of syn-
pentane interactions and intramolecular hydrogen bonding
act in a synergistic manner in 5 leading to the population of
essentially a single conformer in solution. These same two con-
formational determinants appear to be non-reinforcing in the
diastereomeric hexol 6. Notably, these two polyols have con-
trasting polarities (TLC) and solubility properties, e.g. 5 is
readily soluble in benzene with Rf 0.37 (50% EtOAc–hexane)
whilst in comparison, 6 is insoluble in this solvent exhibiting an
Rf of 0.25 (10% MeOH–CH2Cl2). Diol 13, tetrol 32 and hexol 5
can be considered to form part of a family of conformationally
controlled polyols based on the structural subunit 33 (Fig. 7).
In closing, we note that modular polyketide synthases have
remarkable scope3 in their substrate specificity and this should
allow for a variety of non-natural polyols to be elaborated by
directed biosynthesis. In this way, a library of low molecular
weight polyols, obtained by combinatorial synthesis, could
potentially be translated to the higher levels of diversity typical
of the clinically significant polyketide natural products. Such
integration may prove beneficial in combinatorial approaches
to even more diverse polyketide libraries.
Achieving further structural diversity in polyketide libraries
These results demonstrate that the dipropionate reagents (R)-
J. Chem. Soc., Perkin Trans. 1, 1999, 1003–1014
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gram (ver. 4.5) developed by Still and co-workers.20 Structures
were subjected to a minimisation procedure into the nearest
local minimum prior to the generation of new low energy con-
formers by Monte Carlo searching. A 20 kJ molϪ1 cut off was
employed, with experiments generally sampling batches of 2000
structures. Calculations were performed in vacuo.
General procedure A. The isolated aldolate was taken up in
MeOH and pH 7 buffer (1:1, 10 cm3 per mmol of aldolate) and
stirred at 0 ЊC. Hydrogen peroxide (30% aqueous; 1.0 cm3 per
mmol of boron) was added dropwise and the mixture stirred at
RT for 1–2 h. Dilution with H2O, extraction with CH2Cl2, dry-
ing of the combined organics (MgSO4) and evaporation in
vacuo gave the crude aldol products which were, in general,
purified by flash chromatography. For large scale preparations,
a reductive wash of the combined organics (NaSO3) was gener-
ally employed.
General procedure B. The isolated boronate was taken up in
MeOH and 10% NaOH (2:1, 4 cm3 per mmol of boronate)
and stirred at 0 ЊC. Hydrogen peroxide (30% aqueous; 1.1 cm3
per mmol of boron) was added dropwise and the mixture
stirred at RT for 1–2 h. Dilution with H2O, extraction with
CH2Cl2, drying of the combined organics (MgSO4) and evapor-
ation in vacuo gave the crude diol products which were, in
general, purified by flash chromatography.
(R)- and (S)-1-Benzyloxy-2-methylpentan-3-one 7
These were prepared according to our previously reported
three-step procedure from (R)- and (S)-methyl 3-hydroxy-2-
methylpropionate, respectively.6e
(R)-1-Benzyloxy-2-methylhexan-3-one 27
Fig. 9
This was prepared by a modification of our existing 3-step pro-
cedure for the synthesis of (R)-7.6e Substitution of PrMgCl in
place of EtMgBr in the third step gave (R)-27 as a colourless
Experimental
General
1H NMR: 250, 400 or 500 MHz on Bruker DPX250, AM400,
DRX400 or DRX500. 13C NMR: 50.0, 62.9 or 100.6 MHz on
Bruker AM200, DPX250, AM400 or DRX400. Spectra
oil; [α]D20 Ϫ19.9 (c 2.0, CHCl3); νmax (film)/cmϪ1 1730s (C᎐O),
᎐
1604m; δH (500 MHz; CDCl3) 7.35–7.22 (5H, m, ArH), 4.50 and
4.47 (2H, ABq, J 12.0, CH2Ph), 3.64 (1H, dd, J 9.0, 7.9, 1-HA),
3.46 (1H, dd, J 9.0, 5.5, 1-HB), 2.91–2.83 (1H, m, 2-H), 2.47
(1H, t, J 7.3, 4-HA), 2.46 (1H, t, J 7.3, 4-HB), 1.64–1.56 (2H,
ddq, J 7.3, 7.3, 7.3, 5-H), 1.07 (3H, d, J 7.1, 2-Me), 0.90 (3H, t,
J 7.4, CH2CH3); δC (50.3 MHz; CDCl3) 213.1, 138.1, 128.3,
128.0, 127.5, 73.2, 72.3, 46.3, 44.0, 16.6, 13.7, 13.5; m/z (FAB)
221 (MHϩ, 93%), 219 (100), 181 (26), 143 (12), 137 (12), 123
(42), 113 (55), 107 (22), 105 (15); HRMS (FAB) Calc. for
C14H21O2 (MHϩ) 221.1541. Found 221.1536.
1
obtained in CDCl3 were referenced to CHCl3 (δ = 7.26) for H
NMR and CDCl3 (δ = 77.0) for 13C NMR. J values are given in
Hz. NOESY correlations were determined with a mixing time
of 1.5 s. The numbering of protons for assignment refers to the
numbering of the carbon skeleton from the nascent terminus
(see Scheme 1). [α]D values are given in 10Ϫ1 deg cm2 gϪ1 and
were measured at 20 ЊC on a Perkin Elmer 241 polarimeter.
HPLC was carried out using a Rainan Instrument Co. Inc.
DYNAMAX Macro-HPLC column with a flow rate of 10 cm3
minϪ1. GC analysis used a Hewlett Packard 5890 Series II GC
with an HP5 capillary column. IR spectra were recorded on a
Perkin Elmer 1620 FT-IR instrument. Melting points are
uncorrected. Mass spectra were recorded by the EPSRC Mass
Spectrometry Centre, Swansea. Microanalyses were carried out
by the staff of the University Chemical Laboratory Micro-
analytical Department. Analytical TLC: precoated 0.25 mm
Merck 60 F254 silica plates. Flash chromatography: Merck
Kieselgel 60 (230–400 mesh). All experiments were carried
out under an argon atmosphere with anhydrous solvents unless
otherwise stated. Solvents and reagents were purified and
dried according to standard procedures. Diastereoselectivities
were determined by a combination of 1H NMR, GC (following
silylation with TMS imidazole–pyridine) and/or HPLC
analysis.
(2R,4R,5R)-1-(Benzyloxy)-5-hydroxy-2,4-dimethylheptan-3-one
20
To a stirred solution of (c-Hex)2BCl (0.31 cm3, 1.45 mmol) in
Et2O (4 cm3) was added Et3N (0.22 cm3, 1.55 mmol) and the
mixture was cooled to Ϫ15 ЊC. The ketone (R)-7 (0.20 g, 0.97
mmol) in Et2O (1.5 cm3) was added via cannula and the reaction
mixture stirred for 2 h at Ϫ15 ЊC. A solution of EtCHO (0.10
cm3, 1.45 mmol) in Et2O (5 cm3) was added via cannula and
stirring continued for 2 h. The reaction mixture was then par-
titioned between Et2O (3 × 15 cm3) and pH 7 buffer (10 cm3).
The organic extracts were concentrated in vacuo to give an oil
which was oxidised according to procedure A. Flash chrom-
atography (10% Et2O–CH2Cl2) gave the aldol product 20
(0.23 g, 90%) as a colourless oil (Found C 72.7, H 9.2. Calc.
for C16H24O3: C 72.7, H 9.15%); [α]D20 Ϫ0.3 (c 2.4, CHCl3);
νmax (film)/cmϪ1 3463br (OH), 2971s, 2935s, 2877s, 1710s (C᎐O);
᎐
δH (500 MHz; CDCl3) 7.37–7.24 (5H, m, ArH), 4.46 and 4.50
(2H, ABq, J 10.6, CH2Ph), 3.69 (1H, dd, J 8.8, 8.8, 1-HA), 3.67–
3.58 (1H, m, 5-H), 3.44 (1H, dd, J 8.8, 4.9, 1-HB), 3.13–3.03
(1H, m, 2-H), 2.78 (1H, d, J 6.3, OH), 2.73 (1H, dq, J 7.0, 7.0,
Molecular modelling
Molecular modelling studies were performed on a Silicon
Graphics Iris and Indigo cluster using the MacroModel pro-
1008
J. Chem. Soc., Perkin Trans. 1, 1999, 1003–1014

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4-H), 1.62–1.54 (1H, m, 6-HA), 1.44–1.34 (1H, m, 6-HB), 1.13
(3H, d, J 7.2, CHCH3), 1.05 (3H, d, J 7.0, CHCH3), 0.96 (3H, t,
J 7.4, 6-Me); δC (100 MHz; CDCl3) 218.0, 137.7, 128.3, 127.6,
127.6, 74.8, 73.3, 72.2, 51.5, 45.3, 27.3, 13.7, 13.5, 9.9; m/z (CI)
282 (M ϩ NH4ϩ, 16%), 265 (MHϩ, 4), 247 (MHϩ Ϫ H2O, 3),
224 (100), 207 (65), 108 (16); HRMS (CI) Calc. for C16H25O3
(MHϩ) 265.1804. Found 265.1799.
vent concentrated in vacuo to give a colourless oil. Purification
by flash chromatography (15% EtOAc–hexane) yielded the
product 34 (see Fig. 9) (1.04 g, 95%) and allowed separation of
the minor diastereomer (р6% by weight); [α]D20 Ϫ6.9 (c 1.8,
CHCl3); νmax (film)/cmϪ1 3407br (OH), 2967vs, 2937vs, 2878s;
δH (500 MHz; CDCl3) 3.74 (1H, dd, J 10.2, 2.4, 3-H), 3.78–3.71
(1H, m, 1-HA), 3.68–3.59 (1H, m, 1-HB), 3.46 (1H, ddd, J 10.2,
8.6, 2.6, 5-H), 2.44 (1H, d, J 7.9, OH), 1.92–1.84 (1H, m, 2-H),
1.73–1.64 (1H, m, 6-HA), 1.50 (1H, ddq, J 10.2, 10.2, 6.6, 4-H),
1.44 (3H, s, C(CH3)CH3), 1.42–1.32 (1H, m, 6-HB (Part. obs.)),
1.36 (3H, s, C(CH3)CH3), 0.98 (3H, d, J 7.1, CHCH3), 0.92 (3H,
t, J 7.4, 6-Me), 0.74 (3H, d, J 6.6, CHCH3); δC (50 MHz;
CDCl3) 97.6, 77.4, 75.4, 67.9, 34.8, 34.8, 30.1, 25.8, 19.8, 11.6,
9.4, 9.0; m/z (CI) 217 (MHϩ, 62%), 201 (12), 176 (40), 159 (100),
139 (27), 108 (46); HRMS (CI) Calc. for C12H25O3 (MHϩ)
217.1803. Found 217.1804.
(2R,3S,4R,5R)-1-Benzyloxy-2,4-dimethylheptane-3,5-diol 13
To a stirred solution of (c-Hex)2BCl (4.9 cm3, 22.5 mmol) in
Et2O (30 cm3) was added Et3N (3.4 cm3, 24.0 mmol) and the
mixture was cooled to Ϫ78 ЊC. A solution of the ketone (R)-7
(3.09 g, 15.0 mmol) in Et2O (16.5 cm3) was added via cannula
and the mixture stirred 30 min at Ϫ78 ЊC then at 0 ЊC for 1.5 h.
After recooling to Ϫ78 ЊC, a solution of EtCHO (1.45 g, 26.3
mmol) in Et2O (10.5 cm3) was added via cannula and stirring
continued at Ϫ78 ЊC for 30 min before warming to Ϫ15 ЊC for
3.5 h. The resultant solution was then recooled to Ϫ78 ЊC and
precooled (Ϫ78 ЊC) before LiBH4 (37.5 cm3 of a 2 M THF solu-
tion, 75.0 mmol) was added. After 2 h, the reaction mixture was
partitioned between Et2O (3 × 150 cm3) and NH4Cl solution
(200 cm3), the organic extracts combined, concentrated in vacuo
and the residue oxidised according to procedure B. Flash
chromatography (25% EtOAc–hexane) and high vacuum dry-
ing (8 h/0.4 mmHg) gave the diol 13 (3.98 g, 99%) as a colour-
(2S,3R,4R,5R)-3,5-Isopropylidenedioxy-2,4-dimethylheptanal
15
To a stirred solution of oxalyl chloride (0.67 cm3, 7.7 mmol) in
CH2Cl2 (28 cm3) at Ϫ78 ЊC was added via cannula a solution of
DMSO (0.96 cm3, 13.5 mmol) in CH2Cl2 (6.2 cm3) and the
mixture stirred for 5 min. The alcohol 34 (0.43 g, 2.0 mmol) was
added via cannula in CH2Cl2 (6 cm3) and the resultant solution
stirred at Ϫ78 ЊC for 45 min. Et3N (3.6 cm3, 25.8 mmol) was
added and stirring continued at Ϫ78 ЊC for 15 min and at
Ϫ41 ЊC for 15 min. The reaction was partitioned between
NH4Cl solution (30 cm3) and CH2Cl2 (3 × 60 cm3). The com-
bined organic extracts were washed with brine (100 cm3), dried
(MgSO4) and concentrated in vacuo. The resultant yellow oil
was triturated with cold hexane (3 × 10 cm3), filtered through
Celite and concentrated in vacuo to give the product 15 as a pale
yellow oil (0.41 g, 98%). The product was stable to flash chrom-
1
less oil. 400 MHz H NMR analysis of the crude indicated
у94% ds. The major isomer was isolated diastereomerically
pure by HPLC; Rt 24.0 min (40% EtOAc–hexane); [α]D20 ϩ5.6
(c 1.4, CHCl3); νmax (film)/cmϪ1 3374br (OH), 2966vs, 2931s,
2876s; δH (500 MHz; CDCl3) 7.38–7.27 (5H, m, ArH), 4.54 and
4.52 (2H, ABq, J 12.0, CH2Ph), 3.97 (1H, s br, OH), 3.81 (1H,
dd, J 9.5, 1.4, 3-H), 3.74 (1H, s br, OH), 3.64–3.55 (3H, m, 5-H,
1-HA, 1-HB), 1.97–1.90 (1H, m, 2-H), 1.70–1.60 (2H, m, 4-H,
6-HA), 1.46–1.37 (1H, m, 6-HB), 0.99 (3H, d, J 6.7, CHCH3),
0.97 (3H, t, J 7.3, 6-Me), 0.74 (3H, d, J 6.9, CHCH3); δC (100
MHz; CDCl3) 137.6, 128.5, 127.8, 127.6, 79.6, 77.3, 75.6, 73.5,
40.2, 35.0, 27.1, 12.6, 9.3, 9.1; m/z (CI) 267 (MHϩ, 100%), 249
(MHϩ Ϫ H2O, 3); HRMS (CI) Calc. for C16H27O3 (MHϩ)
267.1960. Found 267.1960.
1
atography but in practice could be shown to be pure by H
NMR and was used directly; [α]D20 ϩ30.4 (c 1.9, CHCl3); νmax
(film)/cmϪ1 2984s, 2940s, 2851m, 2716w (CHO), 1732s (C᎐O),
᎐
1456m; δH (400 MHz; CDCl3) 9.63 (1H, s, CHO), 4.09 (1H, dd,
J 10.4, 2.5, 3-H), 3.45 (1H, ddd, J 10.4, 8.2, 2.6, 5-H), 2.47 (1H,
dq, J 7.0, 2.5, 2-H), 1.68 (1H, ddq, J 10.4, 7.4, 2.6, 6-HA), 1.53–
1.44 (1H, m, 4-H), 1.40 (3H, s, C(CH3)CH3), 1.42–1.32 (1H, m,
6-HB (Part. obs.)), 1.30 (3H, s, C(CH3)CH3), 1.10 (3H, d, J 7.0,
CHCH3), 0.92 (3H, t, J 7.4, 6-Me), 0.78 (3H, d, J 6.7, CHCH3);
δC (100 MHz; CDCl3) 204.8, 98.0, 75.2, 73.4, 47.2, 34.4, 29.8,
25.8, 19.5, 11.6, 9.3, 6.2.
(2R,3S,4R,5R)-1-Benzyloxy-3,5-isopropylidenedioxy-2,4-
dimethylheptane 14
To a stirred solution of diol 13 (3.48 g, 13.1 mmol) in CH2Cl2
(20 cm3) was added 2,2-dimethoxypropane (40.1 cm3), followed
by PPTS (5 crystals) and stirring was continued for 8 h.
Solid NaHCO3 (30 mg) was then added, the solvent removed
in vacuo, and the residue purified by flash chromatography (5%
Et2O–hexane) to give the acetonide 14 as a colourless oil (3.84
g, 95%); [α]D20 Ϫ15.8 (c 2.0, CHCl3); νmax (film)/cmϪ1 2966s, 2935s,
2852s, 1453m; δH (500 MHz; CDCl3) 7.36–7.26 (5H, m, ArH),
4.53 and 4.49 (2H, ABq, J 12.0, CH2Ph), 3.68 (1H, dd, J 10.4,
2.0, 3-H), 3.48 (1H, dd, J 8.8, 8.6, 1-HA), 3.37 (1H, ddd, J 10.4,
8.2, 2.6, 5-H), 3.31 (1H, dd, J 8.8, 6.3, 1-HB), 2.10–2.03 (1H, m,
2-H), 1.68 (1H, m, 6-HA), 1.46 (1H, ddq, J 10.4, 10.4, 6.9, 4-H),
1.38 (3H, s, C(CH3)CH3), 1.41–1.34 (1H, m, 6-HB (Part. obs.)),
1.33 (3H, s, C(CH3)CH3), 0.92 (3H, t, J 7.4, 6-Me), 0.86 (3H, d,
J 6.9, CHCH3), 0.74 (3H, d, J 6.6, CHCH3); δC (100 MHz;
CDCl3) 138.8, 128.3, 127.5, 127.4, 97.6, 75.5, 73.3, 73.1, 73.0,
34.6, 34.0, 30.1, 25.9, 19.7, 11.6, 9.5, 9.4; m/z (CI) 307 (MHϩ,
82%), 291 (18), 266 (20), 249 (100), 141 (12), 108 (18), 99 (25),
91 (15); HRMS (CI) Calc. for C19H31O3 (MHϩ) 307.2273.
Found 307.2273.
(2R,3S,4S,5S,6R,7S,8R,9R)-1-Benzyloxy-7,9-isopropylidene-
dioxy-2,4,6,8-tetramethylundecane-3,5-diol 16
To a stirred solution of (c-Hex)2BCl (0.43 g, 2.0 mmol) and
Et3N (0.20 g, 2.0 mmol) in Et2O (11 cm3) at Ϫ78 ЊC was added,
via cannula, a solution of ketone (R)-7 (0.31 g, 1.5 mmol) in
Et2O (6 cm3). The resultant solution was stirred for 0.5 h at
Ϫ78 ЊC and 1 h at 0 ЊC. After recooling to Ϫ78 ЊC, a solution of
aldehyde 15 (0.21 g, 1.0 mmol) in Et2O (2.1 cm3) was added via
cannula and stirring continued at this temperature for 0.5 h and
at 0 ЊC for 1 h. Recooling to Ϫ78 ЊC was followed by addition
of a precooled (Ϫ78 ЊC) solution of LiBH4 (2.5 cm3 of a 2 M
THF solution, 5.0 mmol). After 2 h at this temperature, the
solution was partitioned between NH4Cl solution (100 cm3)
and Et2O (3 × 100 cm3). The combined organics were concen-
trated in vacuo and oxidised according to procedure B. Flash
chromatography (10% EtOAc–hexane) and HPLC (10%
EtOAc–hexane) yielded the diol 16 (0.33 g, 78%) as colourless
crystals (Found C 71.1, H 10.0. Calc. for C25H42O5: C 71.0, H
10.0; mp 59–60 ЊC (pentane); [α]D20 Ϫ3.0 (c 3.4, CHCl3); νmax
(film)/cmϪ1 3444br (OH), 2971vs, 2937s, 2855s; δH (500 MHz;
CDCl3) 7.33–7.24 (5H, m, ArH), 4.84 (1H, s, OH), 4.52 and
4.57 (2H, ABq, J 12.0, CH2Ph), 4.25 (1H, s, OH), 3.78–3.71
(3H, m, OCH), 3.62 (1H, dd, J 8.9, 6.8, OCH), 3.42–3.38 (2H,
m, OCH), 2.03–1.92 (2H, m, 6-H, 4-H), 1.78–1.63 (2H, m,
(2R,3S,4R,5R)-3,5-Isopropylidenedioxy-2,4-dimethylheptan-1-
ol 34
To a stirred solution of the benzyl ether 14 (1.48 g, 4.8 mmol) in
EtOH (21 cm3) was added 20% Pd(OH)2/C (0.2 g) and the mix-
ture stirred under a hydrogen atmosphere for 4.25 h at RT. The
catalyst was removed by filtration through Celite and the sol-
J. Chem. Soc., Perkin Trans. 1, 1999, 1003–1014
1009

View Article Online
10-HA, 8-H), 1.47 (3H, s, C(CH3)CH3), 1.43–1.35 (1H, m,
10-HB (Obscured)), 1.37 (3H, s, C(CH3)CH3), 0.93 (3H, d, J 7.4,
CHCH3), 0.92 (3H, t, J 7.4, 10-Me), 0.91 (3H, d, J 7.4, CH-
CH3), 0.74 (3H, d, J 6.6, CHCH3), 0.72 (3H, d, J 6.9, CHCH3);
δC (100 MHz; CDCl3) 138.9, 128.2, 127.6, 127.3, 98.1, 83.5,
81.1, 76.0, 75.3, 74.3, 73.2, 38.1, 35.9, 34.7, 34.0, 30.0, 25.7,
19.8, 13.1, 11.6, 9.4, 9.3, 4.7; m/z (CI) 423 (MHϩ, 100%), 366 (8),
365 (35), 347 (15); HRMS (CI) Calc. for C25H43O5 (MHϩ)
423.3110. Found 423.3110.
cm3). The combined organic extracts were washed with brine
(100 cm3), dried (MgSO4) and concentrated in vacuo. Flash
chromatography (15% EtOAc–hexane) gave the aldehyde 17
(58.4 mg, 98%) as a colourless oil; [α]D20 ϩ16.1 (c 3.8, CHCl3);
νmax (film)/cmϪ1 2989vs, 2938vs, 2878s, 2851m, 2714w (CHO),
1734vs (C᎐O); δ (400 MHz; CDCl3) 9.63 (1H, s, CHO), 4.09
᎐
H
(1H, dd, J 10.3, 2.6, 3-H), 3.62 (1H, dd, J 10.2, 2.0, 5-H or 7-H),
3.59 (1H, dd, J 10.3, 1.7, 5-H or 7-H), 3.37 (1H, ddd, J 10.2, 8.0,
2.6, 9-H), 2.50 (1H, dq, J 7.0, 2.6, 2-H), 1.94–1.86 (1H, m, 6-H),
1.74 (1H, ddq, J 10.3, 10.3, 6.6, 4-H), 1.72–1.63 (1H, m, 10-HA),
1.46 (1H, ddq, J 10.2, 10.2, 6.7, 8-H (Part. obs.)), 1.41 (3H,
s, C(CH3)CH3), 1.39 (3H, s, C(CH3)CH3), 1.41–1.33 (1H, m,
10-HB (Part. obs.)), 1.33 (3H, s, C(CH3)CH3), 1.25 (3H, s,
C(CH3)CH3), 1.09 (3H, d, J 7.0, CHCH3), 0.99 (3H, d, J 7.6,
CHCH3), 0.91 (3H, t, J 7.4, 10-Me), 0.80 (3H, d, J 6.6,
CHCH3), 0.75 (3H, d, J 6.5, CHCH3); δC (100 MHz; CDCl3)
204.8, 97.5, 97.2, 76.1, 75.5, 75.3, 73.7, 47.2, 38.4, 35.2, 32.4,
30.1, 29.7, 25.9, 19.7, 19.5, 12.5, 12.0, 10.8, 9.4, 6.2.
(2R,3S,4S,5S,6S,7R,8R,9R)-1-Benzyloxy-3,5:7,9-bis(isopropyl-
idenedioxy)-2,4,6,8-tetramethylundecane 35
Diol 16 (86.4 mg, 0.20 mmol) was stirred in dimethoxypropane
(1.25 cm3, 10.2 mmol) and CH2Cl2 (0.5 cm3). PPTS (3 mg)
was added and the mixture stirred for 18 h. Concentration
in vacuo and flash chromatography (5% EtOAc–hexane) gave
the diacetonide 35 (88.7 mg, 94%) as a colourless oil; [α]D20 Ϫ10.7
(c 1.6, CHCl3); νmax (film)/cmϪ1 2965s, 2936s, 2877s, 1728w;
δH (500 MHz; CDCl3) 7.34–7.26 (5H, m, ArH), 4.49 and 4.51
(2H, ABq, J 12.0, CH2Ph), 3.66 (1H, dd, J 10.4, 2.1, 3-H), 3.57
(1H, dd, J 9.9, 1.9, 5-H), 3.55 (1H, dd, J 10.1, 1.7, 7-H), 3.48
(1H, dd, J 8.9, 8.2, 1-HA), 3.37 (1H, ddd, J 10.1, 7.9, 2.7, 9-H),
3.31 (1H, dd, J 8.9, 6.4, 1-HB), 2.14–2.06 (1H, m, 2-H), 1.93–
1.86 (1H, m, 6-H), 1.62–1.74 (2H, m, 4-H, 10-HA), 1.47 (1H,
ddq, J 10.1, 10.1, 6.6, 8-H), 1.41 (3H, s, C(CH3)CH3), 1.43–1.34
(1H, m, 10-HB (Obscured)), 1.37 (3H, s, C(CH3)CH3), 1.34 (3H,
s, C(CH3)CH3), 1.27 (3H, s, C(CH3)CH3), 0.98 (3H, d, J 7.5,
6-Me), 0.92 (3H, t, J 7.4, 10-Me), 0.84 (3H, d, J 6.9, 2-Me), 0.77
(3H, d, J 6.6, 8-Me), 0.75 (3H, d, J 6.8, 4-Me); δC (100 MHz;
CDCl3) 138.8, 128.3, 127.5, 127.4, 97.2, 97.1, 76.3, 75.6, 73.4,
73.2, 73.1, 38.2, 35.9, 35.3, 33.9, 32.5, 30.2, 30.0, 25.9, 19.7,
19.7, 12.5, 11.9, 10.7, 9.6, 9.4; m/z (CI) 463 (MHϩ, 65%), 405
(61), 347 (100), 329 (90), 239 (34), 157 (61), 139 (28); HRMS
(CI) Calc. for C28H47O5 (MHϩ) 463.3423. Found 463.3423.
(2R,3S,4S,5S,6R,7S,8S,9S,10S,11R,12R,13R)-1-Benzyloxy-
7,9:11,13-bis(isopropylidenedioxy)-2,4,6,8,10,12-hexamethyl-
pentadecane-3,5-diol 18
To a stirred solution of (c-Hex)2BCl (0.11 cm3, 0.49 mmol) and
Et3N (68 µL, 0.49 mmol) in Et2O (2.7 cm3) at Ϫ78 ЊC was added
via cannula a solution of ketone (R)-7 (75.5 mg, 0.37 mmol) in
Et2O (1.5 cm3). The resultant solution was stirred for 0.5 h at
Ϫ78 ЊC and 1 h at 0 ЊC. After recooling to Ϫ78 ЊC, a solution of
aldehyde 17 (83.5 mg, 0.23 mmol) in Et2O (0.5 cm3) was added
via cannula and stirring continued at this temperature for 0.5 h
and at 0 ЊC for 1 h. The solution was then recooled to Ϫ78 ЊC
and a precooled (Ϫ78 ЊC) solution of LiBH4 (0.7 cm3 of a 2 M
THF solution, 1.35 mmol) added via cannula. After 2 h at this
temperature, the solution was partitioned between NH4Cl solu-
tion (30 cm3) and Et2O (3 × 40 cm3). The combined organics
were washed with H2O (20 cm3), concentrated in vacuo and
oxidised according to procedure B. Flash chromatography (8%
EtOAc–hexane) yielded the diol 18 as an oil (96.2 mg, 74%); [α]D20
Ϫ2.8 (c 3.5, CHCl3); νmax (film)/cmϪ1 3461br (OH), 2968vs,
2937vs, 2855s; δH (500 MHz; CDCl3) 7.38–7.24 (5H, m, ArH),
4.87 (1H, s, OH), 4.57 and 4.51 (2H, ABq, J 12.0, CH2Ph), 4.29
(1H, s, OH), 3.78–3.70 (3H, m, 3-H, 5-H, 7-H), 3.64–3.55 (3H,
m, 9-H, 11-H, 1-HA), 3.41 (1H, dd, J 8.9, 6.9, 1-HB), 3.37 (1H,
ddd, J 10.1, 7.9, 2.6, 13-H), 2.03–1.95 (2H, m, 2-H, 6-H), 1.93–
1.87 (1H, m, 10-H), 1.80–1.63 (3H, m, 4-H, 8-H, 14-HA), 1.46
(3H, s, C(CH3)CH3), 1.48–1.43 (1H, m, 12-H (Obscured)), 1.42
(3H, s, C(CH3)CH3), 1.42–1.34 (1H, m, 14-HB (Part. obs.)), 1.34
(3H, s, C(CH3)CH3), 1.33 (3H, s, C(CH3)CH3), 0.99 (3H, d,
J 7.5, 10-Me), 0.93–0.90 (9H, m, 2-Me, 6-Me, 14-Me), 0.77 (6H,
d, J 6.4, 8-Me, 12-Me), 0.73 (3H, d, J 6.8, 4-Me); δC (100 MHz;
CDCl3) 138.8, 128.2, 127.6, 127.3, 97.6, 97.2, 83.5, 81.3, 76.1,
76.0, 75.4, 75.4, 74.3, 73.2, 38.2, 38.1, 35.9, 35.2, 33.8, 32.7,
30.1, 30.0, 25.8, 19.7, 19.6, 13.1, 12.4, 11.9, 10.7, 9.3, 9.3, 4.8;
m/z (CI) 579 (MHϩ, 11%), 521 (12), 371 (15), 196 (58), 157 (55),
139 (57), 111 (55), 108 (100); HRMS (CI) Calc. for C34H59O7
(MHϩ) 579.4261. Found 579.4260.
(2R,3S,4S,5S,6S,7R,8R,9R)-3,5:7,9-Bis(isopropylidenedioxy)-
2,4,6,8-tetramethylundecan-1-ol 36
To a stirred solution of the diacetonide 35 (31.2 mg, 0.067
mmol) in EtOH (1.0 cm3) was added 20% Pd(OH)2/C (5 mg)
and the mixture stirred under a hydrogen atmosphere for 1 h.
The catalyst was removed by filtration through Celite and the
solvent concentrated in vacuo. Purification by flash chrom-
atography (25% Et2O–hexanes) yielded the product 36 (24.2
mg, 96%) as a colourless oil; [α]D20 Ϫ6.0 (c 2.2, CHCl3); νmax
(film)/cmϪ1 3408br (OH), 2966s, 2878s; δH (500 MHz; CDCl3)
3.73 (2H, dd, J 10.4, 2.4, 1-HA, 3-H), 3.65–3.59 (1H, m, 1-HB),
3.57 (2H, dd, J 10.1, 1.9, 5-H, 7-H), 3.36 (1H, ddd, J 10.1, 7.6,
2.3, 9-H), 2.54 (1H, br s, OH), 1.93–1.86 (2H, m, 2-H, 6-H),
1.74–1.63 (2H, m, 4-H, 10-HA), 1.46 (1H, ddq, J 10.1, 10.1, 6.5,
8-H), 1.43 (3H, s, C(CH3)CH3), 1.41 (3H, s, C(CH3)CH3), 1.42–
1.33 (1H, m, 10-HB), 1.33 (3H, s, C(CH3)CH3), 1.31 (3H, s,
C(CH3)CH3), 0.99 (3H, d, J 7.6, 6-Me), 0.97 (3H, d, J 7.1,
2-Me), 0.91 (3H, t, J 7.4, 10-Me), 0.76 (3H, d, J 6.5, 4-Me), 0.75
(3H, d, J 6.5, 8-Me); δC (100 MHz; CDCl3) 97.3, 97.2, 77.9,
76.2, 75.5, 75.5, 68.1, 38.2, 35.2, 34.6, 32.8, 30.1, 30.1, 25.9,
19.7, 19.7, 12.5, 11.9, 10.7, 9.4, 9.0; m/z (CI) 373 (MHϩ, 80%),
315 (100), 257 (92), 157 (69); HRMS (CI) Calc. for C21H41O5
(MHϩ) 373.2954. Found 373.2954.
(2R,3S,4S,5S,6R,7S,8R,9R,10S,11R,12R,13R)-1-Benzyloxy-
3,5:7,9:11,13-tris(isopropylidenedioxy)-2,4,6,8,10,12-hexa-
methylpentadecane 19
(2S,3R,4R,5R,6S,7R,8R,9R)-3,5:7,9-Bis(isopropylidenedioxy)-
2,4,6,8-tetramethylundecanal 17
Diol 18 (70.1 mg, 0.12 mmol) was stirred in dimethoxypropane
(0.74 cm3, 6.1 mmol) and CH2Cl2 (0.74 cm3). PPTS (5 mg)
was added and the mixture stirred for 5 h. Addition of
solid NaHCO3 (5 mg), concentration in vacuo and flash
chromatography (5% Et2O–hexane) gave the triacetonide 19
(72.3 mg, 97%) as a colourless oil; [α]D20 Ϫ7.7 (c 4.6, CHCl3); νmax
(film)/cmϪ1 2988s, 2936s, 2877s, 1733w; δH (500 MHz; CDCl3)
7.35–7.25 (5H, m, ArH), 4.52 and 4.48 (2H, ABq, J 12.1,
CH2Ph), 3.66 (1H, dd, J 10.3, 1.7, 3-H), 3.56–3.53 (4H, m, 5-H,
7-H, 9-H, 11-H), 3.47 (1H, dd, J 8.6, 8.6, 1-HA), 3.38–3.33 (1H,
To a stirred solution of oxalyl chloride (55 µL, 0.63 mmol) in
CH2Cl2 (1.1 cm3) at Ϫ78 ЊC was added DMSO (78 µL, 1.10
mmol) and the mixture stirred for 15 min. The alcohol 36 (60.0
mg, 0.16 mmol) was added via cannula in CH2Cl2 (1.1 cm3) and
the resultant solution stirred at Ϫ78 ЊC for 30 min. Et3N (0.29
cm3, 2.09 mmol) was added and stirring continued at Ϫ78 ЊC
for 30 min and at Ϫ41 ЊC for 15 min. The reaction was par-
titioned between NH4Cl solution (20 cm3) and CH2Cl2 (3 × 40
1010
J. Chem. Soc., Perkin Trans. 1, 1999, 1003–1014

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m, 13-H), 3.30 (1H, dd, J 8.6, 6.4, 1-HB), 2.12–2.06 (1H, m,
2-H), 1.94–1.87 (2H, m, 6-H, 10-H), 1.72–1.63 (3H, m, 4-H,
8-H, 14-HA), 1.52–1.44 (1H, m, 12-H), 1.40 (3H, s, C(CH3)-
CH3), 1.41–1.33(1H, m, 14-HB (Obscured)), 1.39(3H, s, C(CH3)-
CH3), 1.36 (3H, s, C(CH3)CH3), 1.34 (3H, s, C(CH3)CH3), 1.29
(3H, s, C(CH3)CH3), 1.28 (3H, s, C(CH3)CH3), 0.98 (6H, d,
J 7.4, 2 × CHCH3), 0.92 (3H, t, J 7.3, 14-Me), 0.85 (3H, d,
J 6.9, 2-Me), 0.79 (3H, d, J 6.5, CHCH3), 0.77 (3H, d, J 7.0,
CHCH3), 0.75 (3H, d, J 6.6, CHCH3); δC (100 MHz; CDCl3)
138.8, 128.2, 127.5, 127.3, 97.2, 97.1, 96.8, 76.4, 76.1, 76.0, 75.9,
75.5, 73.3, 73.2, 73.0, 38.2, 38.1, 35.3, 33.9, 32.7, 32.5, 30.1,
30.1, 30.0, 25.8, 20.0, 19.6, 19.6, 13.4, 12.5, 11.8, 10.3, 10.3, 9.5,
9.3; m/z (CI) 619 (MHϩ, 16%), 603 (15), 503 (52), 486 (26), 446
(43), 428 (39); HRMS (CI) Calc. for C37H63O7 (MHϩ) 619.4574.
Found 619.4570.
13.2, 12.9, 9.4, 9.1, 4.2; m/z (FAB) 383 (MHϩ, 82%), 307 (21);
HRMS (FAB) Calc. for C22H39O5 (MHϩ) 383.2797. Found
383.2791.
(2R,3R,4R,5R)-1-Benzyloxy-2,4-dimethylheptane-3,5-diol 21
To a stirred solution of Me4NBH(OAc)3 (4.70 g, 17.9 mmol) in
CH3CN (15 cm3) at RT was added AcOH (15 cm3) and the
mixture stirred for 30 min. Following cooling to Ϫ25 ЊC, a solu-
tion of aldol product 20 (483 mg, 1.83 mmol) in CH3CN (7 cm3)
was added via cannula. After 30 min at this temperature the
reaction was transferred to the freezer for 13 h. The solution
was poured into potassium sodium tartrate solution (100 cm3;
0.5 M aq.), stirred for 30 min and extracted with CH2Cl2
(3 × 100 cm3). The combined organics were washed with
NaHCO3 solution (50 cm3) and dried (MgSO4). Evaporation
in vacuo and flash chromatography (10% Et2O–hexane) gave
the product 21 (443 mg, 91%) as a white solid; mp 48–50 ЊC
(pentane); Rt 26.7 min (35% EtOAc–hexane); [α]D20 Ϫ37.6 (c 1.8,
CHCl3); νmax (CHCl3)/cmϪ1 3455br (OH); δH (400 MHz; CDCl3)
7.39–7.25 (5H, m, ArH), 4.57 and 4.51 (2H, ABq, J 11.8,
CH2Ph), 4.14 (1H, s, OH), 3.92–3.87 (1H, m, CHOH), 3.63
(1H, dd, J 9.0, 4.2, 1-HA), 3.51 (1H, dd, J 9.0, 9.0, 1-HB), 3.51–
3.45 (1H, m, CHOH), 3.24 (1H, s, OH), 2.08–1.96 (1H, m,
CHCH3), 1.68–1.50 (3H, m, 3 × CHCH3), 1.02 (3H, d, J 7.0,
CHCH3), 0.97 (3H, t, J 7.4, 6-Me), 0.75 (3H, d, J 6.9, CHCH3);
δC (100 MHz; CDCl3) 137.4, 128.4, 127.9, 127.7, 77.5, 76.8,
76.4, 73.5, 37.6, 35.7, 28.5, 12.9, 10.6, 10.4; m/z (CI) 267 (MHϩ,
100%), 196 (43); HRMS (CI) Calc. for C16H27O3 (MHϩ)
267.1960. Found 267.1960.
(2R,3S,4S,5S,6R,7S,8R,9R,10S,11R,12R,13R)-1-Benzyloxy-
2,4,6,8,10,12-hexamethylpentadecane-3,5,7,9,11,13-hexol 5
Triacetonide 19 (69.0 mg, 0.11 mmol) was heated under reflux
with Dowex-50 [85 mg moist, washed with HCl (1 M, 3 × 2
cm3), H2O (3 × 2 cm3) and MeOH (4 × 2 cm3)] in MeOH (1.1
cm3) and H2O (0.12 cm3). After 4 h the resultant white solid was
dissolved and filtered through Celite with the aid of MeOH (30
cm3) and azeotroped with toluene (3 × 5 cm3). Flash chrom-
atography (40% EtOAc–hexane) yielded the hexol 5 as a white
solid (49.4 mg, 89%); [α]D20 ϩ7.7 (c 2.5, CHCl3); νmax (CHCl3)/
cmϪ1 3374br (OH), 2959vs, 2928s, 2872s; δH (500 MHz; C6D6)
7.35–7.15 (5H, m, ArH), 6.07 (1H, s, C7- or C9-OH), 5.85 (1H,
s, C5-OH), 5.82 (1H, s, C7- or C9-OH), 5.72 (1H, s, C11-OH),
4.50 (1H, s br, C13-OH), 4.48 (1H, s br, C3-OH), 4.34 and 4.30
(2H, ABq, J 12.0, CH2Ph), 4.00–3.96 (1H, app dd, J Obs, 1.5,
7-H or 9-H), 3.97–3.95 (1H, app dd, J Obs, 1.3, 11-H), 3.92
(1H, app dd, J 9.4, 1.2, 7-H or 9-H), 3.89 (1H, app dd, J 9.3,
1.7, 5-H), 3.88–3.85 (1H, m, 3-H), 3.77–3.75 (1H, m, 13-H),
3.47 (1H, dd, J 8.9, 5.3, 1-HA), 3.47 (1H, dd, J 8.9, 4.5, 1-HB),
1.93 (1H, ddq, J 9.1, 9.1, 6.8, 8-H), 1.90–1.72 (6H, m, 12-H,
4-H, 10-H, 2-H, 6-H, 14-HA), 1.60–1.51 (1H, m, 14-HB), 1.22
(3H, t, J 7.3, 14-Me), 1.15 (3H, d, J 7.0, 10-Me), 1.10 (3H,
d, J 6.9, 6-Me), 1.04 (3H, d, J 7.0, 2-Me), 0.70 (3H, d, J 6.9,
12-Me), 0.60 (3H, d, J 6.8, 8-Me), 0.55 (3H, d, J 6.9, 4-Me);
δC (62.5 MHz; CDCl3) 137.7, 128.5, 127.9, 127.6, 83.7, 83.1,
83.0, 83.0, 80.4, 77.5, 75.9, 73.6, 40.1, 38.0, 38.0, 35.1, 35.1,
35.1, 27.3, 13.2, 13.1, 12.8, 9.4, 9.1, 4.3, 4.2; m/z (FAB) 521
(MNaϩ, 35%), 499 (MHϩ, 100); HRMS (FAB) Calc. for C28H51-
O7 (MHϩ) 499.3635. Found 499.3672.
(2R,3R,4R,5R)-1-Benzyloxy-3,5-{[bis(1,1-dimethylethyl)-
silylene]dioxy}-2,4-dimethylheptane 37
To a stirred solution of diol 21 (67.8 mg, 0.25 mmol) and 2,6-
lutidine (0.12 cm3, 109 mg, 1.02 mmol) in CH2Cl2 (0.5 cm3) was
added (But)2Si(OTf)2 (0.12 cm3, 0.38 mmol). After 21 h the
resultant solution was quenched with NaHCO3 solution (10
cm3) and extracted with CH2Cl2 (4 × 30 cm3). The combined
organics were dried (MgSO4), concentrated in vacuo and puri-
fied by flash chromatography (3% EtOAc–hexane) to yield the
product 37 as a colourless oil (85.8 mg, 83%); [α]D20 ϩ37.1 (c 2.2,
CHCl3); νmax (CHCl3)/cmϪ1 2969s, 2934s, 2859s, 1476s; δH (400
MHz; CDCl3) 7.39–7.25 (5H, m, ArH), 4.56 and 4.50 (2H, ABq,
J 11.9, CH2Ph), 4.04 (1H, dd, J 9.7, 2.5, 3-H), 3.78–3.73 (1H, m,
5-H), 3.70 (1H, dd, J 8.6, 3.0, 1-HA), 3.57 (1H, dd, J 8.6, 6.3,
1-HB), 1.93–1.82 (1H, m, CHCH3), 1.76–1.64 (2H, m, 2 ×
CHCH3), 1.62–1.48 (1H, m, CHCH3), 1.11 (3H, d, J 7.4,
CHCH3), 1.06 (9H, s, Si(C(CH3)3), 1.03 (9H, s, Si(C(CH3)3),
0.97 (3H, t, J 7.3, 6-Me), 0.92 (3H, d, J 6.8, CHCH3); δC (100
MHz; CDCl3) 138.9, 128.2, 127.6, 127.3, 81.7, 73.1, 72.6, 72.3,
37.3, 37.1, 31.3, 28.2, 27.9, 22.0, 21.4, 13.6, 13.5, 10.4; m/z (CI)
407 (MHϩ, 91%), 317 (40), 299 (23); HRMS (CI) Calc. for
C24H43O3Si (MHϩ) 407.2981. Found 407.2981.
(2R,3S,4S,5S,6R,7S,8R,9R)-1-Benzyloxy-2,4,6,8-tetramethyl-
undecane-3,5,7,9-tetrol 32
Diol 16 (32.0 mg, 0.076 mmol) was heated to reflux with
Dowex-50 [40 mg moist, washed with HCl (1 M, 3 × 2 cm3),
H2O (3 × 2 cm3) and MeOH (4 × 2 cm3)] in MeOH (1.1 cm3)
and H2O (0.12 cm3). After 1 h further MeOH (1.0 cm3), H2O
(0.1 cm3) and Dowex-50 (40 mg) were added and reflux con-
tinued for a total of 20 h. The resultant solution was filtered
through Celite with the aid of MeOH (45 cm3) and azeotroped
with toluene (3 × 4 cm3). Flash chromatography (45% EtOAc–
hexane) yielded the tetrol 32 as a white solid (22.0 mg, 76%); [α]D20
ϩ9.2 (c 1.4, CHCl3); νmax (CHCl3)/cmϪ1 3387br (OH), 2434s,
2400s, 1522s; δH (500 MHz; C6D6) 7.35–7.28 (5H, m, ArH),
5.63 (1H, s, OH), 5.42 (1H, s, OH), 4.32 and 4.28 (2H, ABq,
J 12.0, CH2Ph), 4.22 (1H, s, OH), 4.13 (1H, s, OH), 3.88 (1H,
app dd, J 9.4, 1.3, CHOH), 3.84 (1H, app dd, J 9.0, 1.8,
CHOH), 3.80 (1H, app dd, J 9.4, <1.0, CHOH), 3.75–3.70
(1H, m, CHOH), 3.43–3.37 (2H, m, CH2OBn), 1.89–1.70 (5H,
m, 5 × CHCH3), 1.58–1.48 (1H, m, 10-HB), 1.20 (3H, t, J 7.4,
10-Me), 1.12 (3H, d, J 7.0, CHCH3), 1.03 (3H, d, J 7.0,
CHCH3), 0.68 (3H, d, J 6.9, CHCH3), 0.53 (3H, d, J 6.6,
CHCH3); δC (62.5 MHz; CDCl3) 137.7, 128.5, 127.9, 127.6,
83.1, 83.0, 80.7, 77.4, 76.0, 73.7, 40.2, 38.0, 35.2, 35.1, 27.3,
(2R,3R,4R,5R)-3,5-{[Bis(1,1-dimethylethyl)silylene]dioxy}-2,4-
dimethylheptan-1-ol 22
To a stirred solution of the benzyl ether 37 (481 mg, 1.18 mmol)
in EtOH (15 cm3) was added 10% Pd/C (0.24 g) and the mixture
stirred under a hydrogen atmosphere for 3 h. The catalyst was
removed by filtration through Celite and the solvent concen-
trated in vacuo. Purification by flash chromatography (15%
EtOAc–hexane) yielded the product 22 (364 mg, 97%) as a
colourless oil; [α]D20 ϩ19.3 (c 1.6, CHCl3); νmax (CHCl3)/cmϪ1
3479br (OH), 3016s, 3009s, 2971vs, 2935vs; δH (400 MHz;
CDCl3) 4.10 (1H, dd, J 9.8, 2.5, 3-H), 3.78–3.70 (3H, m, 1-HA,
1-HB, OH), 3.63–3.55 (1H, m, 5-H), 2.03–1.92 (1H, m,
CHCH3), 1.71–1.62 (2H, m, 2 × CHCH3), 1.58–1.45 (1H,
m, CHCH3), 1.14 (3H, d, J 7.4, CHCH3), 1.08–1.02 (18H, m,
2 × Si(C(CH3)2), 0.96 (3H, t, J 7.3, 6-Me), 0.71 (3H, d, J 6.9,
J. Chem. Soc., Perkin Trans. 1, 1999, 1003–1014
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CHCH3); δC (100 MHz; CDCl3) 81.4, 79.1, 69.5, 37.6, 37.5,
31.3, 28.1, 27.9, 22.1, 21.4, 13.7, 13.1, 10.3; m/z (CI) 317 (MHϩ,
53%); HRMS (CI) Calc. for C17H37O3Si (MHϩ) 317.2510.
Found 317.2512.
39 as a colourless oil (136 mg, 75%); [α]D20 ϩ2.5 (c 1.4, CHCl3);
νmax (CHCl3)/cmϪ1 3474br (OH); δH (500 MHz; CDCl3) 7.38–
7.26 (5H, m, ArH), 4.56 and 4.52 (2H, ABq, J 11.9, CH2Ph),
4.19 (1H, dd, J 8.8, 2.4, OCH), 4.15–4.10 (1H, m, OCH), 3.94–
3.87 (1H, m, OCH), 3.82 (1H, s, OH), 3.79–3.75 (1H, m,
OCH), 3.62 (1H, dd, J 8.8, 4.3, 1-HA), 3.58 (1H, dd, J 8.8, 8.8,
1-HB), 2.73 (1H, d, J 4.8, OH), 2.10–1.98 (1H, m, CHCH3),
1.80–1.64 (4H, m, 4 × CHCH3), 1.61–1.49 (1H, m, CHCH3),
1.11 (3H, d, J 7.3, CHCH3), 1.08–1.02 (18H, m, Si(C(CH3)3)2),
0.96 (3H, t, J 7.3, 10-Me), 0.86 (3H, d, J 6.9, CHCH3), 0.81
(3H, d, J 7.0, CHCH3), 0.80 (3H, d, J 6.9, CHCH3); δC (100
MHz; CDCl3) 137.6, 128.5, 127.8, 127.7, 82.0, 76.7, 76.3, 73.5,
73.2, 71.9, 38.5, 37.9, 37.7, 35.9, 31.2, 28.3, 27.9, 22.1, 21.4,
13.8, 13.2, 10.5, 9.9, 9.5; m/z (CI) 523 (MHϩ, 100%); HRMS
(CI) Calc. for C30H55O5Si (MHϩ) 523.3819. Found 523.3820.
(2S,3S,4R,5R)-3,5-{[Bis(1,1-dimethylethyl)silylene]dioxy}-2,4-
dimethylheptanal 38
To a stirred solution of oxalyl chloride (70 µL, 0.80 mmol) in
CH2Cl2 (1.4 cm3) at Ϫ78 ЊC was added DMSO (0.10 cm3, 1.40
mmol). After 5 min the alcohol 22 (65.2 mg, 0.21 mmol) was
added via cannula in CH2Cl2 (1.4 cm3) and stirring continued
for 30 min. Et3N (0.37 cm3, 2.68 mmol) was added dropwise
and the mixture stirred for 15 min at Ϫ78 ЊC and at Ϫ41 ЊC for
15 min. The reaction was quenched with NH4Cl solution (10
cm3) and extracted with CH2Cl2 (3 × 20 cm3). The combined
organics were dried (MgSO4), concentrated in vacuo and tritur-
ated with cold pentane. Filtration through Celite with hexane
(30 cm3) and evaporation in vacuo gave the semi-crude aldehyde
as a pale yellow oil (65.9 mg): Rf 0.57 (20% EtOAc–hexane).
This compound was prone to elimination and was used immedi-
ately and without purification in subsequent aldol reactions.
(2R,3R,4S,5S,6R,7S,8R,9R)-1-Benzyloxy-3,5:7,9-bis{[bis(1,1-
dimethylethyl)silylene]dioxy}-2,4,6,8-tetramethylundecane 40
To a stirred solution of diol 39 (95.3 mg, 0.18 mmol) and 2,6-
lutidine (0.10 cm3, 88.0 mg, 0.82 mmol) in CH2Cl2 (0.4 cm3) was
added (But)2Si(OTf)2 (0.11 cm3, 0.33 mmol). After 22 h, further
2,6-lutidine (44 µL, 0.36 mmol) and (But)2Si(OTf)2 (61 µL, 0.18
mmol) were added. Following 22 h at RT, the resultant solution
was quenched with NaHCO3 solution (10 cm3) and extracted
with CH2Cl2 (3 × 30 cm3). The combined organics were dried
(MgSO4), concentrated in vacuo and purified by flash chrom-
atography (8% Et2O–hexane) to yield the product 40 (71.7 mg,
59%) as a white solid; mp 97–98 ЊC (pentane); [α]D20 ϩ40.7 (c 4.2,
CHCl3); νmax (CHCl3)/cmϪ1 2968vs, 2935vs, 2959vs, 1477vs;
δH (500 MHz; CDCl3) 7.36–7.22 (5H, m, ArH), 4.53 and 4.48
(2H, ABq, J 12.0, CH2Ph), 4.36–4.34 (1H, m, OCH), 4.20 (1H,
dd, J 9.7, 1.8, OCH), 3.95 (1H, dd, J 10.1, 2.9, OCH), 3.77 (1H,
app t, J 6.9, OCH), 3.73 (1H, dd, J 8.8, 3.0, OCH), 3.53–3.48
(1H, m, OCH), 1.95–1.85 (1H, m, CHCH3), 1.84–1.70 (2H,
m, 2 × CHCH3), 1.67–1.60 (1H, m, CHCH3), 1.59–1.51 (1H,
m, CHCH3), 1.49–1.40 (1H, m, CHCH3), 1.12 (3H, d, J 7.4,
CHCH3), 1.10–0.92 (45H, m, 3 × CHCH3, 2 × Si(C(CH3)3)2),
0.83 (3H, d, J 6.8, CHCH3); δC (100 MHz; CDCl3) 138.9, 128.2,
127.6, 127.3, 82.4, 76.5, 73.7, 73.0, 72.6, 71.0, 45.7, 37.9, 37.1,
36.3, 31.2, 28.2, 27.9, 27.9, 27.7, 22.4, 22.4, 22.1, 21.3, 13.7,
13.7, 13.7, 10.8, 8.9; m/z (ϩFAB, NOBA) 663 (MHϩ, 70%), 605
(23), 513 (20), 487 (30), 460 (100); HRMS (ϩFAB) Calc. for
C38H71O5Si2 (MHϩ) 663.4840. Found 663.4785.
(2R,4R,5R,6R,7R,8R,9R)-1-Benzyloxy-5-hydroxy-7,9-{[bis(1,1-
dimethylethyl)silylene]dioxy}-2,4,6,8-tetramethylundecan-2-one
23
To a stirred solution of (c-Hex)2BCl (0.13 cm3, 0.62 mmol) in
Et2O (2.5 cm3) was added Et3N (86 µL, 0.62 mmol) and the
mixture was cooled to 0 ЊC. The ketone (R)-7 (128 mg, 0.62
mmol) in Et2O (1.6 cm3) was added via cannula and the reaction
mixture stirred for 2 h at 0 ЊC. After cooling to Ϫ78 ЊC a solu-
tion of aldehyde 38 (65.9 mg, 0.21 mmol) in Et2O (0.9 cm3) was
added via cannula and stirring continued for 0.45 h before
warming to 0 ЊC. The reaction mixture was partitioned between
Et2O (3 × 15 cm3) and pH 7 buffer solution (10 cm3), the
organic extracts were combined and concentrated in vacuo to
give an oil. This residue was oxidised according to procedure
A. Flash chromatography (8% EtOAc–hexane) gave the
aldol product 23 (77.0 mg, 72%) as a colourless oil; [α]D20 ϩ31.2
(c 5.2, CHCl3); νmax (CHCl3)/cmϪ1 3450br (OH), 1707vs (C᎐O);
᎐
δH (400 MHz; CDCl3) 7.37–7.25 (5H, m, ArH), 4.53 and 4.47
(2H, ABq, J 12.3, CH2Ph), 4.43–4.38 (1H, m, 5-H), 4.21 (1H,
dd, J 9.3, 2.3, 7-H), 3.79–3.75 (1H, m, 9-H), 3.70 (1H, dd, J 8.8,
8.8, 1-HA), 3.40 (1H, dd, J 8.8, 4.7, 1-HB), 3.19–3.10 (1H, m,
2-H), 2.94 (1H, d, J 4.6, OH), 2.85 (1H, dq, J 9.6, 7.0, 4-H),
1.79–1.63 (3H, m, 3 × CHCH3), 1.59–1.48 (1H, m, CHCH3),
1.10 (3H, d, J 7.4, CHCH3), 1.08–1.00 (24H, m, 2 × CHCH3,
Si(C(CH3)3)2), 0.97 (3H, t, J 7.3, 10-Me), 0.77 (3H, d, J 7.0,
CHCH3); δC (100 MHz; CDCl3) 217.4, 137.5, 128.4, 127.7,
127.6, 82.0, 73.3, 72.2, 71.8, 70.7, 50.8, 44.2, 37.5, 37.2, 31.2,
28.3, 27.8, 22.0, 21.3, 14.3, 13.6, 13.0, 10.5, 8.5; m/z (CI) 521
(MHϩ, 4%), 315 (91), 257 (28), 224 (100), 207 (58); HRMS (CI)
Calc. for C30H53O5Si (MHϩ) 521.3662. Found 521.3660.
(2R,3R,4S,5S,6R,7S,8R,9R)-3,5:7,9-Bis{[bis(1,1-dimethyl-
ethyl)silylene]dioxy}-2,4,6,8-tetramethylundecan-1-ol 24
To a stirred solution of the benzyl ether 40 (43.1 mg, 0.065
mmol) in EtOH (2.0 cm3) was added 10% Pd/C (20 mg) and the
mixture stirred under a hydrogen atmosphere for 1.5 h. The
catalyst was removed by filtration through Celite and the sol-
vent concentrated in vacuo to give a colourless oil. Purification
by flash chromatography (15% EtOAc–hexane) yielded the
product 24 (35.4 mg, 95%) as a white crystalline solid; mp 167–
168 ЊC (pentane); [α]D20 ϩ29.8 (c 2.8, CHCl3); νmax (CHCl3)/cmϪ1
3474br (OH), 2976vs, 2936vs, 2860vs, 1477vs; δH (500 MHz;
CDCl3) 4.38 (1H, app d, J 1.4, OCH), 4.20 (1H, dd, J 9.7, 2.0,
OCH), 4.11 (1H, dd, J 9.9, 3.0, OCH), 3.81–3.73 (3H, m,
CH2OH and CH2OH), 3.59 (1H, ddd, J 10.5, 10.5, 3.0, 9-H),
2.06–1.97 (1H, m, CHCH3), 1.84–1.71 (2H, m, 2 × CHCH3),
1.66–1.60 (1H, m, CHCH3), 1.60–1.50 (1H, m, CHCH3), 1.49–
1.40 (1H, m, CHCH3), 1.12 (3H, d, J 7.5, CHCH3), 1.10 (3H, d,
J 7.5, CHCH3), 1.08–1.02 (36H, m, 2 × Si(C(CH3)3)2), 0.98 (3H,
t, J 7.3, 10-Me), 0.82 (3H, d, J 6.8, CHCH3), 0.77 (3H, d, J 6.9,
CHCH3); δC (100 MHz; CDCl3) 82.3, 80.7, 76.4, 70.9, 69.7,
45.7, 38.3, 37.3, 36.3, 31.2, 28.2, 27.9, 27.7, 27.7, 22.5, 22.4,
22.1, 21.3, 13.9, 13.7, 13.2, 10.8, 8.8; m/z (FAB) 573 (MHϩ,
80%), 515 (25), 397 (62); HRMS (FAB) Calc. for C31H65O5Si2
(MHϩ) 573.4370. Found 573.4314.
(2R,3R,4S,5S,6R,7R,8R,9R)-1-Benzyloxy-7,9-{[bis(1,1-di-
methylethyl)silylene]dioxy}-2,4,6,8-tetramethylundecane-3,5-
diol 39
To a stirred solution of Me4NBH(OAc)3 (81.9 mg, 3.1 mmol) in
CH3CN (3.0 cm3) at RT was added AcOH (3.0 cm3) and the
mixture stirred for 30 min. Following cooling to Ϫ25 ЊC, a solu-
tion of aldol product 23 (180 mg, 0.35 mmol) in CH3CN (2.7
cm3) was added via cannula. After 30 min at this temperature
the reaction was transferred to the freezer for 43 h. The solution
was poured into potassium sodium tartrate solution (35 cm3;
0.5 M aq.), stirred for 30 min and extracted with CH2Cl2 (4 × 30
cm3). The combined organics were washed with NaHCO3 solu-
tion (30 cm3) and dried (MgSO4). Evaporation in vacuo and
flash chromatography (10% EtOAc–hexane) gave the product
1012
J. Chem. Soc., Perkin Trans. 1, 1999, 1003–1014

View Article Online
(2S,3S,4R,5R,6S,7S,8R,9R)-3,5:7,9-Bis{[bis(1,1-dimethylethyl)-
silylene]dioxy}-2,4,6,8-tetramethylundecanal 41
mg, 90%); [α]D20 ϩ15.5 (c 1.9, CHCl3); νmax (CHCl3)/cmϪ1 3469br
(OH), 3010s, 2973vs, 2934vs, 2859vs, 1477vs; δH (500 MHz;
CDCl3) 7.39–7.23 (5H, m, ArH), 4.56 and 4.52 (2H, ABq,
J 11.9, CH2Ph), 4.37 (1H, app s, OCH), 4.21 (1H, app d, J 8.5,
OCH), 4.18–4.11 (2H, m, 2 × OCH), 3.88 (1H, app d, J 9.2,
OCH), 3.80–3.74 (2H, m, OCH, OH), 3.62 (1H, dd, J 8.9, 4.2,
1-HA), 3.54 (1H, dd, J 8.9, 8.9, 1-HB), 2.73 (1H, dd, J 4.3, OH),
2.08–1.98 (1H, m, CHCH3), 1.83–1.71 (4H, m, 4 × CHCH3),
1.67–1.60 (1H, m, CHCH3), 1.59–1.52 (1H, m, CHCH3), 1.46–
1.40 (1H, m, CHCH3), 1.12 (3H, d, J 7.3, CHCH3), 1.07–1.03
(39H, m, 4 × Si(C(CH3)3) and CHCH3), 0.97 (3H, t, J 7.3,
14-Me), 0.88 (3H, d, J 6.5, CHCH3), 0.86 (3H, d, J 6.8,
CHCH3), 0.84 (3H, d, J 7.0, CHCH3), 0.81 (3H, d, J 6.9,
CHCH3); δC (100 MHz; CDCl3) 137.6, 128.5, 127.8, 127.7, 82.4,
77.2, 77.1, 76.4, 74.6, 73.5, 71.8, 71.1, 45.7, 38.8, 38.3, 37.9,
36.3, 35.9, 31.2, 28.2, 28.0, 27.9, 27.8, 22.5, 22.4, 22.2, 21.3,
14.1, 13.7, 13.2, 10.8, 10.1, 9.8, 9.0; m/z (FAB) 779 (MHϩ, 27%),
585 (14), 513 (67), 473 (33); HRMS (FAB) Calc. for C44H83-
O7Si2 (MHϩ) 779.5677. Found 779.5695.
To a stirred solution of oxalyl chloride (32 µL, 0.36 mmol) in
CH2Cl2 (0.7 cm3) at Ϫ78 ЊC was added DMSO (45 µL, 0.63
mmol). After 5 min the alcohol 24 (50.8 mg, 0.09 mmol) was
added via cannula in CH2Cl2 (0.8 cm3) and stirring continued
for 30 min. Et3N (0.17 cm3, 1.21 mmol) was added dropwise
and the mixture stirred for 15 min at Ϫ78 ЊC and at Ϫ41 ЊC for
15 min. The reaction was quenched with NH4Cl solution (20
cm3) and extracted with CH2Cl2 (3 × 30 cm3). The combined
organics were dried (MgSO4), concentrated in vacuo and tritur-
ated with cold pentane. Filtration through Celite with hexane
(40 cm3) gave the semi-crude product aldehyde 41 as a crystal-
line white solid (54.2 mg): Rf 0.48 (10% EtOAc–hexane). This
compound was prone to elimination and was used immediately
and without purification in subsequent aldol reactions.
(2R,4R,5R,6R,7R,8S,9R,10S,11S,12R,13R)-1-Benzyloxy-5-
hydroxy-7,9:11,13-bis{[bis(1,1-dimethylethyl)silylene]dioxy}-
2,4,6,8,10,12-hexamethylpentadecan-3-one 42
(2R,3R,4S,5S,6R,7R,8R,9R,10S,11S,12R,13R)-1-Benzyloxy-
2,4,6,8,10,12-hexamethylpentadecane-3,5,7,9,11,13-hexol 6
To a stirred solution of (c-Hex)2BCl (59 µL, 0.27 mmol) in Et2O
(1.1 cm3) was added Et3N (38 µL, 0.27 mmol) and the mixture
was cooled to 0 ЊC. The ketone (R)-7 (56.0 mg, 0.27 mmol) in
Et2O (0.8 cm3) was added via cannula and the reaction mixture
stirred for 1 h at 0 ЊC. After cooling to Ϫ78 ЊC a solution of
aldehyde 41 (49.1 mg, 0.086 mmol) in Et2O (0.9 cm3) was added
via cannula and stirring continued for 1 h before warming to
0 ЊC for 1.5 h. The reaction mixture was partitioned between
Et2O (3 × 40 cm3) and pH 7 buffer (20 cm3), the organic extracts
were combined and concentrated in vacuo to give an oil. This
residue was oxidised according to procedure A. Flash chrom-
atography (8% EtOAc–hexane) gave the aldol 42 (45.0 mg,
67%) as a white solid; Rt 29.7 min (10% EtOAc–hexane); [α]D20
ϩ20.3 (c 0.7, CHCl3); νmax (CHCl3)/cmϪ1 3448br (OH), 2974vs,
To a stirred solution of diol 25 (20.0 mg, 0.026 mmol) in THF
(0.5 cm3) was added HFؒpyridine–pyridine solution (150 µL of
stock solution¶). After 14 h at RT, NaHCO3 (40 mg) and silica
gel (50 mg) were added and the slurry concentrated in vacuo.
Flash chromatography (10% MeOH–CH2Cl2) gave the hexol 6
as a white solid (10.1 mg, 79%); [α]D20 Ϫ6.3 (c 0.7, CHCl3); νmax
(CHCl3)/cmϪ1 3420br (OH), 2985vs, 2940s, 2881m; δH (500
MHz; CD3OD) 7.37–7.20 (5H, m, ArH), 4.52 (2H, s, CH2Ph),
4.05–3.95 (4H, m, 4 × CHOH), 3.88 (1H, app dd, J 9.8, 1.2,
CHOH), 3.70 (1H, dd, J 9.0, 4.5, 1-HA), 3.56 (1H, dd, J 9.0, 6.4,
1-HB), 3.51–3.48 (1H, m, CHOH), 1.94–1.86 (1H, m, CHCH3),
1.79–1.56 (6H, m, 6 × CHCH3), 1.53–1.43 (1H, m, CHCH3),
0.98 (3H, t, J 7.4, 14-Me), 0.92 (3H, d, J 6.8, CHCH3), 0.92
(3H, d, J 7.0, CHCH3), 0.81–0.73 (12H, m, 4 × CHCH3);
δC (62.5 MHz; CD3OD) 137.0, 126.4, 125.9, 125.7, 74.3, 72.7,
71.4, 70.7, 70.2, 69.5, 69.1, 69.1, 37.2, 36.1, 36.1, 36.1, 35.7,
35.4, 25.6, 11.5, 7.8, 7.3, 6.4, 6.4, 6.4, 6.2; m/z (FAB) 521
(MNaϩ, 47%), 499 (MHϩ, 100); HRMS (FAB) Calc. for
C28H51O7 (MHϩ) 499.3635. Found 499.3670.
2936vs, 2859vs, 1707m (C᎐O); δ (500 MHz; C6D6) 7.30–7.25
᎐
H
(5H, m, ArH), 4.80–4.73 (1H, m, 5-H), 4.70–4.66 (1H, m,
OCH), 4.55–4.49 (2H, m, 2 × OCH), 4.37 and 4.32 (2H, ABq,
J 12.3, CH2Ph), 3.86 (1H, dd, J 8.4, 5.4, OCH), 3.74 (1H, dd,
J 8.7, 8.7, 1-HA), 3.24 (1H, dd, J 8.7, 4.0, 1-HB), 3.21 (1H, d,
J 4.3, OH), 3.12–3.03 (1H, m, 2-H), 2.97 (1H, dq, J 9.2, 7.3,
4-H), 1.97–1.81 (3H, m, 3 × CHCH3), 1.67–1.61 (2H, m, 2 ×
CHCH3), 1.48–1.40 (1H, m, CHCH3), 1.36 (9H, s, Si(C-
(CH3)3)), 1.35 (9H, s, Si(C(CH3)3)), 1.32 (9H, s, Si(C(CH3)3)),
1.31 (9H, s, Si(C(CH3)3)), 1.24 (3H, d, J 7.2, CHCH3), 1.20 (3H,
d, J 7.3, CHCH3), 1.08–1.06 (6H, m, 2 × CHCH3), 1.02 (3H, d,
J 6.8, CHCH3), 0.97 (3H, d, J 6.9, CHCH3), 0.93 (3H, d, J 7.0,
CHCH3); δC (100 MHz; CDCl3) 217.6, 137.6, 128.4, 127.7,
127.7, 82.4, 76.7, 73.3, 73.2, 72.1, 71.0, 70.6, 50.9, 45.7, 44.1,
38.3, 37.3, 36.3, 31.2, 28.2, 28.0, 27.9, 27.7, 22.4, 22.3, 22.2,
21.3, 14.3, 13.9, 13.7, 13.1, 10.8, 9.0, 8.7; m/z (FAB) 777 (MHϩ,
26%), 759 (8), 719 (15), 601 (30), 513 (74); HRMS (FAB) Calc.
for C44H81O7Si2 (MHϩ) 777.5521. Found 777.5538.
(2S,4S,5S,6R,7S,8R,9R)-1-Benzyloxy-5-hydroxy-7,9-isopropyl-
idenedioxy-2,4,6,8-tetramethylundecan-3-one 26
To a stirred solution of (c-Hex)2BCl (0.65 cm3, 3.0 mmol) in
Et2O (12 cm3) was added Et3N (0.42 cm3, 3.0 mmol) and the
mixture was cooled to Ϫ78 ЊC. The ketone (S)-7 (0.62 g, 3.0
mmol) in Et2O (5 cm3) was added via cannula and the reaction
mixture stirred for 1.5 h at Ϫ78 ЊC and at Ϫ5 ЊC for 30 min.
After recooling to Ϫ78 ЊC, a solution of the aldehyde 15 (0.21 g,
1.0 mmol) in Et2O (2.4 cm3) was added via cannula and stirring
continued at Ϫ78 ЊC for 0.75 h at Ϫ5 ЊC for 1.5 h. The reaction
mixture was partitioned between Et2O (3 × 50 cm3) and pH 7
buffer solution (35 cm3), the organic extracts were combined,
washed with H2O (50 cm3) and concentrated in vacuo to give an
oil. This residue was oxidised according to procedure A. Flash
chromatography (15% EtOAc–hexane) yielded the aldol prod-
ucts (0.33 g, 79%). HPLC (15% EtOAc–hexane) of a portion of
this material yielded the minor diastereomers (17.6 mg) and
major isomer 26 (96.9 mg) as a colourless oil (85% diastereo-
selection); Rt 25.2 min (15% EtOAc–hexane); [α]D20 ϩ46.9 (c 2.3,
CHCl3); νmax (CHCl3)/cmϪ1 3499br (OH), 2972s, 2877s, 1714s
(2R,3R,4S,5S,6S,7R,8S,9S,10S,11S,12R,13R)-1-Benzyloxy-
7,9:11,13-bis{[bis(1,1-dimethylethyl)silylene]dioxy}-2,4,6,8,10,
12-hexamethylpentadecane-3,5-diol 25
To a stirred solution of Me4NBH(OAc)3 (81.6 mg, 0.31 mmol)
in CH3CN (0.3 cm3) at RT was added AcOH (0.3 cm3) and the
mixture stirred for 30 min. Following cooling to Ϫ30 ЊC, a solu-
tion of aldol product 42 (26.3 mg, 0.035 mmol) in CH3CN (0.6
cm3) and AcOH (0.6 cm3) was added via cannula. After 15 min
at this temperature the reaction was transferred to the freezer
for 44 h. The solution was poured into potassium sodium tar-
trate solution (15 cm3; 0.5 M aq.), stirred for 30 min and
extracted with CH2Cl2 (4 × 30 cm3). The combined organics
were washed with NaHCO3 solution (30 cm3) and dried
(MgSO4). Evaporation in vacuo and flash chromatography (12%
EtOAc–hexane) gave the product 25 as a colourless oil (24.1
(C᎐O); δH (500 MHz; C6D6) 7.34–7.10 (5H, m, ArH), 4.38 and
᎐
4.32 (2H, ABq, J 12.0, CH2Ph), 3.97 (1H, dd, J 10.2, 1.9, 7-H),
3.90 (1H, m, 5-H), 3.69 (1H, dd, J 8.6, 8.6, 1-HA), 3.69 (1H, d,
J 9.6, OH), 3.41 (1H, dd, J 8.6, 5.3, 1-HB), 3.33–3.26 (1H, m,
¶ Stock solution prepared from pyridinium hydrofluoride (2.1 g) in
THF (20 ml) and pyridine (7.0 ml).
J. Chem. Soc., Perkin Trans. 1, 1999, 1003–1014
1013

View Article Online
pp. 1–81, eds. W. Herz, G. W. Kirby, W. Steglich and C. Tamm,
Springer-Verlag, Wien, New York, 1991; (c) D. E. Cane, Science,
1994, 263, 338.
5 (a) M. J. B. Brown, J. Cortes, A. L. Cutter, P. F. Leadlay and
J. Staunton, J. Chem. Soc., Chem. Commun., 1995, 1517; (b) J.
Cortes, K. E. H. Wiesmann, G. A. Roberts, M. J. B. Brown,
J. Staunton and P. F. Leadlay, Science, 1995, 268, 1487; (c) R.
Pieper, G. Luo, D. E. Cane and C. Khosla, J. Am. Chem. Soc.,
1995, 117, 11373; (d) C. M. Kao, G. Luo, L. Katz, D. E. Cane and
C. Khosla, J. Am. Chem. Soc., 1996, 118, 9184.
6 (a) Aplyronines: I. Paterson, C. J. Cowden and M. D. Woodrow,
Tetrahedron Lett., 1998, 39, 6037; (b) Scytophycin C: I. Paterson,
C. Watson, K.-S. Yeung, P. A. Wallace and R. A. Ward, J. Org.
Chem., 1997, 62, 452; (c) Restricticin: I. Paterson and T. Nowak,
Tetrahedron Lett., 1996, 37, 8243; (d) Swinholide A: I. Paterson,
K.-S. Yeung, R. A. Ward, J. G. Cumming and J. D. Smith, J. Am.
Chem. Soc., 1994, 116, 9391; (e) Oleandolide: I. Paterson, R. D.
Norcross, R. A. Ward, P. Romea and M. A. Lister, J. Am. Chem.
Soc., 1994, 116, 11287; ( f ) Muamvatin: I. Paterson and M. V.
Perkins, J. Am. Chem. Soc., 1993, 115, 1608.
7 (a) I. Paterson, J. M. Goodman and M. Isaka, Tetrahedron Lett.,
1989, 30, 7121; (b) I. Paterson and M. A. Lister, Tetrahedron Lett.,
1988, 29, 585; (c) I. Paterson and R. D. Tillyer, Tetrahedron Lett.,
1992, 33, 4233; (d) I. Paterson and J. A. Channon, Tetrahedron Lett.,
1992, 33, 797.
9-H), 3.20–3.10 (1H, m, 2-H), 3.13 (1H, dq, J 7.1, 7.1, 4-H),
1.84–1.80 (1H, m, 6-H), 1.64–1.58 (1H, m, 10-HA), 1.56 (1H,
ddq, J 10.2, 10.2, 6.6, 8-H), 1.46 (3H, s, C(CH3)CH3), 1.44 (3H,
s, C(CH3)CH3), 1.45–1.36 (1H, m, 10-HB (Part. obs.)), 1.21 (3H,
d, J 6.9, 2-Me), 1.17 (3H, d, J 7.1, 4-Me), 1.12 (3H, d, J 7.1,
6-Me), 1.07 (3H, t, J 7.4, 10-Me), 0.47 (3H, d, J 6.6, 8-Me);
δC (100 MHz; CDCl3) 217.4, 138.1, 128.2, 127.5, 127.5, 97.8,
78.7, 75.4, 74.2, 73.2, 72.6, 49.2, 47.8, 34.4, 33.4, 30.1, 25.7,
19.7, 13.5, 12.9, 11.4, 10.5, 9.2; m/z (CI) 438 (M ϩ NH4ϩ, 6%),
421 (MHϩ, 13), 345 (11), 224 (78), 215 (28), 207 (33), 157 (32),
139 (100), 108 (15); HRMS (CI) Calc. for C25H41O5 (MHϩ)
421.2954. Found 421.2954.
(2R,4R,5R,6R,7S,8R,9R)-1-Benzyloxy-4-ethyl-5-hydroxy-7,9-
isopropylidenedioxy-2,6,8-trimethylundecan-3-one 28
To a stirred solution of (c-Hex)2BCl (0.94 cm3, 4.36 mmol) in
Et2O (17 cm3) was added Et3N (0.61 cm3, 4.36 mmol) and the
mixture was cooled to 0 ЊC. The ketone (R)-27 (0.96 g, 4.36
mmol) in Et2O (6.3 cm3) was added via cannula and the reaction
mixture stirred for 1.5 h at 0 ЊC for 30 min. After cooling to
Ϫ78 ЊC a solution of the aldehyde 15 (0.34 g, 1.45 mmol) in
Et2O (4.7 cm3) was added via cannula and stirring continued at
Ϫ78 ЊC for 0.75 h and at 0 ЊC for 1.5 h. The reaction mixture
was partitioned between Et2O (3 × 50 cm3) and pH 7 buffer
solution (30 cm3), the organic extracts were combined and con-
centrated in vacuo to give an oil. This residue was oxidised
according to procedure A. Flash chromatography (10% EtOAc–
hexane) gave the aldol 28 (0.59 g, 93%) as a colourless oil; [α]D20
Ϫ15.3 (c 2.3, CHCl3); νmax (CHCl3)/cmϪ1 3488br (OH), 3024vs,
8 (a) I. Paterson and M. D. McLeod, Tetrahedron Lett., 1997, 38,
4183; (b) I. Paterson and M. V. Perkins, Tetrahedron, 1996, 52, 1811;
(c) I. Paterson and S. P. Wren, J. Chem. Soc., Chem. Commun., 1993,
1790.
9 Part of this work has appeared as preliminary communications:
(a) I. Paterson and J. P. Scott, Tetrahedron Lett., 1997, 38, 7441;
(b) I. Paterson and J. P. Scott, Tetrahedron Lett., 1997, 38, 7445.
10 A. J. Mancuso and D. Swern, Synthesis, 1981, 165.
11 (a) W. Roush, J. Org. Chem., 1991, 56, 4151; (b) C. Gennari, A.
Comotti, A. Vulpetti, J. M. Goodman and I. Paterson, Tetrahedron,
1992, 48, 4439.
2937vs, 2877vs, 1708vs (C᎐O); δH (500 MHz; CDCl3) 7.33–7.23
᎐
(5H, m, ArH), 4.51 and 4.47 (2H, ABq, J 12.0, CH2Ph), 3.89
(1H, app d, J 9.1, 5-H), 3.73–3.68 (2H, m, 1-HA, 7-H), 3.46 (1H,
dd, J 9.2, 5.7, 1-HB), 3.43 (1H, d, J 1.0, OH), 3.42–3.36 (1H, m,
9-H), 3.05–2.95 (1H, m, 2-H), 2.83 (1H, ddd, J 9.1, 9.1, 4.1,
4-H), 1.86–1.80 (1H, m, 6-H), 1.71–1.63 (1H, m, 10-HA), 1.62–
1.48 (2H, m, 8-H, C4-CHAHBCH3), 1.43 (3H, s, C(CH3)CH3),
1.43–1.33 (2H, m, 10-HB, C4-CHAHBCH3), 1.33 (3H, s, C(CH3)-
CH3), 1.12 (3H, d, J 7.0, 2-Me), 0.94 (3H, d, J 6.9, 6-Me), 0.92
(3H, t, J 7.4, 10-Me), 0.83 (3H, t, J 7.5, C4-CH2CH3), 0.73 (3H,
d, J 6.7, 8-Me); δC (100 MHz; CDCl3) 216.8, 138.1, 128.2, 127.5,
127.4, 98.0, 80.2, 78.2, 75.1, 73.1, 71.6, 54.9, 48.4, 34.7, 33.8,
29.9, 25.7, 21.6, 19.7, 13.0, 11.6, 11.4, 9.3, 5.0; m/z (CI) 452
(M ϩ NH4ϩ, 13%), 435 (MHϩ, 23), 238 (100), 221 (33); HRMS
(CI) Calc. for C26H43O5 (MHϩ) 435.3111. Found 435.3110.
12 (a) S. D. Rychnovsky and D. J. Skalitzky, Tetrahedron Lett., 1990,
31, 945; (b) D. A. Evans, D. L. Rieger and J. R. Gage, Tetrahedron
Lett., 1990, 31, 7099; (c) S. D. Rychnovsky, B. N. Rogers and
T. I. Richardson, Acc. Chem. Res., 1998, 31, 9.
13 C. Gennari, S. Ceccarelli, U. Piarulli, K. Aboutayab, M. Donghi
and I. Paterson, Tetrahedron, 1998, 54, 14999. For an approach
using the Evans oxazolidinone auxiliary, see: (a) M. Reggelin and
V. Brenig, Tetrahedron Lett., 1996, 38, 6851; (b) M. Reggelin, V.
Brenig and R. Welcker, Tetrahedron Lett., 1998, 39, 4801.
14 D. A. Evans, K. T. Chapman and E. M. Carreira, J. Am. Chem. Soc.,
1988, 110, 3560.
15 I. Ohtani, T. Kusumi, Y. Kashman and H. Kakisawa, J. Am. Chem.
Soc., 1991, 113, 4092.
16 I. Paterson and R. D. Tillyer, J. Org. Chem., 1993, 58, 4182.
17 (a) G. Natta, Angew. Chem., 1956, 68, 393; (b) G. Natta, M. Peraldo
and G. Allegra, Makromol. Chem., 1964, 75, 215.
18 R. W. Hoffmann, Angew. Chem., Int. Ed. Engl., 1992, 31, 1124.
19 For recent examples of conformational design, see: (a) R. Göttlich,
B. Colin Kahrs, J. Krüger and R. W. Hoffmann, Chem. Commun.,
1997, 247; (b) U. Schopfer, M. Stahl, T. Brandl and R. W.
Hoffmann, Angew. Chem., Int. Ed. Engl., 1997, 36, 1745; (c) M. T.
Burger, A. Armstrong, F. Guarnieri, D. Q. McDonald and W. C.
Still, J. Am. Chem. Soc., 1994, 116, 3593.
20 F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp,
M. Lipton, C. Caufield, G. Chang, T. Hendrickson and W. C. Still,
J. Comput. Chem., 1990, 11, 440.
21 (a) C. A. G. Haasnoot, F. A. A. M. de Leeuw and C. Altona,
Tetrahedron, 1980, 36, 2783; (b) C. A. G. Haasnoot, F. A. A. M. de
Leeuw, H. P. M. de Leeuw and C. Altona, Org. Magn. Reson., 1981,
15, 43.
22 Evans and co-workers have developed a complementary approach
to the aldol-based construction of polypropionates using their
β-keto imide dipropionyl building block. See, for example: (a) D. A.
Evans, A. S. Kim, R. Metternich and V. J. Novack, J. Am. Chem.
Soc., 1998, 120, 5921; (b) D. A. Evans, H. P. Ng, J. S. Clark and
D. L. Rieger, Tetrahedron, 1992, 48, 2127; (c) D. A. Evans, J. S.
Clark, R. Metternich, V. J. Novack and G. S. Sheppard, J. Am.
Chem. Soc., 1990, 112, 866.
Acknowledgements
This paper is dedicated to the memory of Professor Ralph A.
Raphael—mentor, colleague and friend. We thank Professor
R. W. Hoffmann (Marburg) for helpful discussions. This work
was supported by the EPSRC (GR/L22560, Quota Studentship
to J. P. S.), the EU TMR programme (ERB-FMRX-CT96-
0011), Novartis AG (Basel), Merck Sharp & Dohme, Pfizer
Central Research and the Newton Trust (Cambridge).
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