Synthetic studies toward the brasilinolides: Controlled assembly of a protected C1-C38 polyol based on fragment union by complex aldol reactions

Article abstract of DOI:10.1039/c5ob00498e

The brasilinolides are an architecturally complex family of 32-membered macrolides, characterised by potent immunosuppressant and antifungal properties, which represent challenging synthetic targets. By adopting a highly convergent strategy, a range of asymmetric aldol/reduction sequences and catalytic protocols were employed to assemble a series of increasingly elaborate fragments. The controlled preparation of suitable C1-C19 and C20-C38 acyclic fragments 5 and 6, containing seven and 12 stereocentres respectively, was first achieved. An adventurous C19-C20 fragment union was then explored to construct the entire carbon chain of the brasilinolides. This pivotal coupling step could be performed in a complex boron-mediated aldol reaction to install the required C19 hydroxyl stereocentre when alternative Mukaiyama-type aldol protocols proved unrewarding. A protected C1-C38 polyol 93 was subsequently prepared, setting the stage for future late-stage diversification toward the various brasilinolide congeners. Throughout this work, asymmetric boron-mediated aldol reactions of chiral ketones with aldehydes proved effective both for controlled fragment assembly and coupling with predictable stereoinduction from the enolate component.

Full text of DOI:10.1039/c5ob00498e

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Synthetic studies toward the brasilinolides:
controlled assembly of a protected C1–C38
polyol based on fragment union by complex
aldol reactions†
Cite this: DOI: 10.1039/c5ob00498e
Ian Paterson,*a Michael P. Housden,a Christopher J. Cordier,a Paul M. Burton,a
Friedrich A. Mühlthaua and Olivier Loiseleurb
The brasilinolides are an architecturally complex family of 32-membered macrolides, characterised by
potent immunosuppressant and antifungal properties, which represent challenging synthetic targets. By
adopting a highly convergent strategy, a range of asymmetric aldol/reduction sequences and catalytic
protocols were employed to assemble a series of increasingly elaborate fragments. The controlled prepa-
ration of suitable C1–C19 and C20–C38 acyclic fragments 5 and 6, containing seven and 12 stereocentres
respectively, was first achieved. An adventurous C19–C20 fragment union was then explored to construct the
entire carbon chain of the brasilinolides. This pivotal coupling step could be performed in a complex boron-
mediated aldol reaction to install the required C19 hydroxyl stereocentre when alternative Mukaiyama-type
aldol protocols proved unrewarding. A protected C1–C38 polyol 93 was subsequently prepared, setting the
stage for future late-stage diversification toward the various brasilinolide congeners. Throughout this work,
asymmetric boron-mediated aldol reactions of chiral ketones with aldehydes proved effective both for con-
trolled fragment assembly and coupling with predictable stereoinduction from the enolate component.
Received 12th March 2015,
Accepted 12th April 2015
DOI: 10.1039/c5ob00498e
www.rsc.org/obc
of the relative and absolute configuration of brasilinolide A (1),
along with the congeneric brasilinolides B (2) and C (3).3
Introduction
The polyketides represent a diverse array of structurally elabo- Notably, brasilinolide A (1) was reported to exhibit pronounced
rate natural products having a wide range of biological activity, immunosuppressive activity in vivo (IC50 value of 0.625 µg mL−1
,
with many members having important therapeutic utility in mouse mixed lymphocyte assay) with no significant toxicity. In
human and veterinary medicine.1 The brasilinolides (Fig. 1), addition, brasilinolide A showed antifungal activity and brasili-
isolated by Mikami and Kobayashi and co-workers in 1996 nolide B was found to be active against a range of fungi and
from the pathogenic actinomycetes Nocardia brasiliensis, con- bacteria. Altogether, their notable biological activities, along
stitute a unique family of immunosuppressive and antifungal with the low toxicity profile and favourable physicochemical
polyketides based on a highly hydroxylated macrolide scaffold, properties, make further evaluation of the brasilinolides as
which presumably arises in the biosynthesis from a PKS- promising lead structures of interest, with potential therapeutic
mediated cyclisation of a linear 38-carbon chain.2 As X-ray applications to autoimmune diseases and fungal infections,
quality crystals of the brasilinolides proved elusive, and ana- and in the prophylaxis of organ transplant rejection.4
lysis of the 1H and 13C NMR data did not allow a full structural
Each member of the brasilinolide family contains several
assignment, detailed stereochemical information was gleaned distinctive structural features, including some 26 stereocen-
by controlled chemical degradation and spectroscopic studies tres, of which 16 are embedded in the macrocyclic lactone,
of the resulting fragments. This work enabled the elucidation and an elaborate propionate-derived side chain with a glycosyl
appendage at C37. The signature 32-membered macrolide core
itself contains a six-membered hemiacetal ring, an epoxide
and a characteristic 1,3-polyol array, with an acidic 23-O-
aUniversity Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW, UK.
E-mail: ip100@cam.ac.uk
malonyl residue present in brasilinolide A (1). Herein, we
bSyngenta Crop Protection AG, Schaffhauserstrasse, 4332 Stein, Switzerland
report in full on progress to date toward the total synthesis of
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
the brasilinolides, documenting the multiple selectivity and
logistical issues addressed in this eventful journey.
c5ob00498e. All data accompanying this publication are directly available within
the publication and the ESI.
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Fig. 1 Structures of brasilinolides A–C.
logy developed in our group could be exploited in several
situations to construct 5 and 11. As discussed in more detail
later, a suitably flexible strategy to assemble and couple the
Results and discussion
Overview of synthesis plan
Our initially devised synthesis plan for brasilinolide A (1) is five building blocks shown in Scheme 1 was devised to allow
outlined in Scheme 1. Such rich stereochemical features, par- modification based on experimental findings. In two prelimi-
ticularly with the preponderance of secondary hydroxyl groups nary communications,6 we had previously reported synthetic
within the aglycon, inspired the pursuit of a strategy using routes to two major brasilinolide fragments, which now
asymmetric aldol chemistry5 for realising the critical fragment needed to be refined and optimised. This entailed some modi-
assembly steps to configure many of these stereocentres. fication to the protecting groups, and scale up to enable access
Additionally, a carefully planned protecting group regime was to larger quantities of advanced intermediates.
devised for the purposes of achieving predictable stereoinduc-
The C1–C19 southern fragment 5
tion, along with enabling the late-stage introduction of the
defining brasilinolide substituents, and to ensure the neces- Our initial focus was on efficiently assembling the southern
sary control in progressing the synthetic route. Building on our hemisphere fragment 5 in Scheme 1. This contains seven
earlier preliminary studies,6 the highly convergent assembly of oxygen-bearing stereocentres, a ketone at C15, and terminates
a suitably protected C1–C38 linear precursor 4 was initially tar- in an enoate and TBS ether as a latent form of C19 aldehyde.
geted. Further simplification was proposed by the late-stage Configurational analysis of
5 revealed a pivotal 1,5-anti
attachment of the polar C23-O-malonyl substituent and C37-O- relationship between the protected hydroxyl groups at C5 and
glycosylation, following macrolactonisation of the C1–C38 C9, and also between C13 and C17, that would represent inter-
intermediate 4 after liberation of the C31 hydroxyl group. The esting cases for studying long-range asymmetric induction
pivotal linear precursor 4 was therefore designed to allow for using aldol reactions of methyl ketones.7 Disconnection across
precise site-controlled functionalisation. Furthermore, it was the C8–C9 and C13–C14 bonds to afford β-alkoxy methyl
envisaged that a high level of stereoinduction might be lever- ketones 7 and 9 was then anticipated to facilitate a useful
aged in its controlled aldol-based assembly from suitable degree of remote asymmetric induction during fragment
ketone building blocks.
assembly. In order to advance to exploring the projected aldol-
Following this overall plan, 4 was disconnected at the C19– based construction of the C1–C19 fragment 5, an efficient
C20 bond to afford the C1–C19 fragment 5, as the corres- gram-scale preparation of the three chiral building blocks 7, 8
ponding southern hemisphere region, and the methyl ketone and 9 in high enantiomeric purity was first deemed necessary.
6, corresponding to the brasilinolide northern hemisphere. It The preparation of these building blocks is now considered in
was envisaged that these two major fragments would be con- turn.
nected by a strategic aldol coupling between 6 and a suitable
As shown in Scheme 2, our initial approach towards acces-
C19 aldehyde derived from 5. Further analysis of 5 suggested sing the C1–C8 methyl ketone 9 started out with the commer-
that favourable carbon–carbon bond scissions might be made cially available (S)-(+)-epichlorohydrin (12) as a convenient
at C8–C9 and C13–C14 to reveal three chiral building blocks means of installing the C5 stereocentre in high configurational
7–9 of roughly equal complexity. Examination of the C20–C38 purity. In following this route A, epoxide opening of 12 with
fragment 6 suggested that a Horner–Wadsworth–Emmons vinylmagnesium bromide proceeded in the presence of CuBr
(HWE) disconnection would serve to isolate the C23 stereocen- (10 mol%) in Et2O at −40 °C to afford an intermediate chloro-
tre, leading back to the β-ketophosphonate 10 and the alde- hydrin; where KOH-mediated cyclisation then gave the known
hyde 11. Following this synthesis plan, 4 is conveniently epoxide 13 (55%, two steps).8 Reopening of this epoxide with
broken down to give five building blocks: with 7–10 having lithium acetylide ethylene diamine complex proceeded in
only one or two stereocentres along with the more complex DMSO to give the corresponding allylic alcohol, which was
polypropionate array embedded in 11.
converted into its PMB ether 14 (NaH, PMBBr) in 69% overall
With regard to the critical issue of controlling stereo- yield. Next, the two unsaturated moieties attached to the C5
chemistry, it was envisaged that asymmetric aldol methodo- stereocentre were sequentially elaborated. Firstly, controlled
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Scheme 1 Overview of synthesis plan for brasilinolide A (1) leading back to the five chiral building blocks 7–11.
oxymercuration (Hg(OAc)2 (30 mol%), PPTS) of the alkyne in functionality of 9 based on a vinylogous Mukaiyama aldol reac-
wet acetone afforded the methyl ketone 15, which was followed tion10 leads to an opportunity for exploring an alternative con-
by cross-metathesis of the olefin with methyl acrylate using struction of this fragment using asymmetric catalysis.
Grubbs II catalyst (1 mol%) to generate enoate 9 (75%, two Following the work of Kalesse and co-workers, a complemen-
steps).9 This sequence afforded the enantiopure C1–C8 ketone tary route B to prepare 9 was therefore developed using the
9 in 29% yield over six steps from (S)-(+)-epichlorohydrin (12).
D-tryptophan-derived oxazaborolidinone 16.11 In practice, a
Although methyl ketone 9 was available in high enantio- Mukaiyama aldol addition of silyl dienolate 17 to but-3-enal12
meric purity via the foregoing route A, preliminary attempts to (18) in the presence of 16 afforded the required γ-adduct 19
perform this sequence on a suitably large scale encountered a (57%) in >95% ee. Following PMB ether formation to give 20
number of issues. The first three steps generate volatile com- (PMBTCA, Ph3CBF4, 64%),13 a Wacker oxidation14 of the termi-
pounds and the associated handling difficulties depleted nal olefin (PdCl2 (10 mol%), CuCl2, O2) then provided the
yields on a larger scale. Disconnection of the δ-alkoxyenoate methyl ketone 9 (63%). Both the above routes to 9 were then
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scalable synthesis of 8 bearing a masked aldehyde at C9 was
thus completed in three steps from 21 in 87% yield and in
high enantiomeric purity (97% ee).
As shown in Scheme 4, the synthesis of the remaining
chiral building block 7 required for constructing the brasilino-
lide southern fragment 5 relied on asymmetric catalysis. It
commenced with the TBS ether 24 prepared from but-3-en-1-
ol. Ozonolysis and in situ Wittig reaction of the resulting alde-
hyde with Ph3PvCHCOMe gave the corresponding enone 25
(69%), solely as the E-isomer.17 This was then subjected to a
Sharpless asymmetric dihydroxylation,18 where a ligand screen
indicated that (DHQ)2AQN (1 mol%) reliably gave chiral diol
26 with excellent enantioselectivity (91%, 97% ee). By exposure
to PMBTCA in the presence of catalytic Ph3CBF4 (0.5 mol%),13
this diol was then converted into its bis-PMB ether 7 (77%).
This scalable route gave methyl ketone 7 in three steps from
24 in high yield (48%) and enantiomeric purity (97% ee).
In assembling the C1–C19 southern fragment 5, we
planned to use two strategic boron-mediated aldol reactions to
couple together the three fragments 7, 8 and 9. With boron
enolates derived from β-alkoxy methyl ketones such as 9,
remote 1,5-anti stereoinduction is known to be enhanced in
addition to aldehydes by employing a PMB ether.7 This facili-
tates aldol transition state organisation by formyl hydrogen
bonding involving this ether oxygen atom. We first needed to
explore the scope of this reaction to include β-alkoxy methyl
ketones such as 7 that have an additional α-alkoxy stereocen-
tre. In support of this approach, DFT calculations predicted
that these aldol reactions are also likely to proceed preferen-
tially through a bicyclic boat TS-1, where π-facial discrimi-
nation is controlled by a stabilising formyl hydrogen bond
involving only the PMB ether oxygen at the β-centre and mini-
misation of steric interactions.19
Scheme 2 Synthesis of methyl ketone 9 using either a chiral starting
material or by an asymmetric vinylogous Mukaiyama aldol reaction.
Reagents and conditions: (a) H2CvCHMgBr, CuBr (10 mol%) Et2O,
−40 °C, 73%; (b) KOH, 75%; (c) HCCLi·(CH2NH2)2, DMSO; (d) NaH,
PMBBr, THF, 69% (two steps); (e) Hg(OAc)2 (30 mol%), PPTS, H2O,
acetone, 82%; (f) methyl acrylate, Grubbs II catalyst (1 mol%), CH2Cl2,
92%; (g) 16, i-PrOH, i-PrCN, 57%, >95% ee; (h) PMB-2,2,2-trichloroacet-
imidate, Ph3CBF4, THF, 64%; (i) PdCl2 (10 mol%), CuCl2, O2, DMF–H2O
(7 : 1), 63%.
used to generate useful stocks of the planned C1–C19 southern
fragment 5.
As shown in Scheme 3, control over the C12 methyl-bearing
stereocentre in aldehyde 8 was conveniently achieved through
the use of the chiral auxiliary methodology developed by
Myers.15 Alkylation of the lithium enolate derived from propio-
namide 21 with 4-iodobut-1-ene gave the desired amide 22,
which was isolated in high yield (94%) and >95 : 5 dr on multi-
gram scale. The auxiliary was then reductively cleaved with
LDA/NH3·BH3 (88%) and Swern oxidation16 of the resulting
alcohol 23 gave the desired C9–C13 aldehyde 8 (97%). This
After some optimisation, it was found that methyl ketone 7
was best treated with Bu2BOTf/i-Pr2NEt in Et2O and the result-
ing enolate 27 reacted with aldehyde 8 at −78 °C, leading on
work-up to the isolation of adduct 28 with excellent diastereo-
Scheme 4 Synthesis of methyl ketone 7. Reagents and conditions: (a)
O3, CH2Cl2, −78 °C; Ph3PvCHCOMe,
0 °C, 69%, >95 : 5 E : Z; (b)
Scheme 3 Synthesis of aldehyde 8. Reagents and conditions: (a) LDA,
LiCl, THF, −78 °C; 4-iodobut-1-ene, 94%, >95 : 5 dr; (b) LDA, NH3·BH3,
THF, 0 °C, 88%; (c) (COCl)2, DMSO, CH2Cl2; Et3N, −78 to 0 °C, 97%.
K2OsO2(OH)4 (1 mol%), (DHQ)2AQN (1 mol%), K3[Fe(CN)6], K2CO3,
NaHCO3, MeSO2NH2, t-BuOH–H2O (1 : 1), 91%, 97% ee; (c) PMB-2,2,2-
trichloroacetimidate, Ph3CBF4 (0.5 mol%), THF, 77%.
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Scheme 5 Synthesis of aldehyde 31. Reagents and conditions: (a)
Ketone 7, Bu2BOTf, i-Pr2NEt, Et2O, −78 °C; aldehyde 8, Et2O, −78 °C,
98%, >95 : 5 dr; (b) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C, 98%; (c) O3,
NaHCO3, Sudan Red 7B, CH2Cl2–MeOH (1 : 1), −78 °C, 95%.
selectivity and in high yield (>95 : 5 dr, 98%, Scheme 5). The
newly formed stereocentre in 28 was installed with the
required (13R)-configuration20 in the anticipated 1,5-anti sense
relative to C17.21 As predicted in TS-1, this indicated that the
β-alkoxy stereocentre was presumably responsible for control-
ling the π-facial selectivity of the boron enolate in this complex
aldol fragment coupling. A similar aldol reaction of 7 with iso-
butyraldehyde also gave the corresponding 1,5-anti adduct 29
in high diastereoselectivity, suggesting that Felkin–Anh-type
1,2-stereoinduction from the α-chiral aldehyde component 8
was not significantly contributing to the outcome.22
Moving forward, the resulting aldol adduct 28 was next
transformed into the TBS ether 30 (TBSOTf, 2,6-lutidine) and
the olefin oxidatively cleaved via ozonolysis to afford 31 (97%,
two steps). This served to generate the aldehyde functionality
at C9 in readiness for performing the next aldol fragment
coupling with methyl ketone 9 (Scheme 6). In this case, 9 was
treated with c-Hex2BCl/Et3N in Et2O and the resulting boron
enolate 32 added smoothly to aldehyde 31 at −78 °C to give
the β-hydroxyketone 33 (>95 : 5 dr, 95%). This complex aldol
Scheme 6 Assembly of the southern hemisphere fragment 5. Reagents
and conditions: (a) Ketone 9, c-Hex2BCl, Et3N, Et2O, 0 °C; aldehyde 31,
−78 to −23 °C, 95%, >95 : 5 dr; (b) Me4NBH(OAc)3, MeCN, AcOH (4 : 1),
−30 °C, 95%, >95 : 5 dr; (c) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C, 97%.
coupling reaction delivers equally high 1,5-anti diastereo- from a β-positioned PMB ether oxygen in the boron enolate.
selectivity and is considered to preferentially proceed through An Evans–Saksena23 1,3-anti reduction of 33 with Me4NBH
the related boat TS-2, again invoking a formyl hydrogen bond (OAc)3 at −30 °C then served to efficiently configure the
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remaining stereocentre at C7, again proceeding with high controlled installation of a potentially sensitive trans-epoxide
diastereoselectivity (>95 : 5 dr, 95%). While the resulting diol moiety.
34 was protected as its cyclic di-tert-butylsilylene (Si(t-Bu)2)
Strategically, an HWE-type disconnection across C28–C29
derivative in our previous studies,6a to facilitate progression of was proposed, leading back to the β-ketophosphonate (R)-10
material on a larger scale it was decided instead to now deriva- (having a C21 methylene as a latent ketone) and the aldehyde
tise the C7 and C9 hydroxyl groups as the bis-TBS ether 5 11, which contains the extended polypropionate region.
(TBSOTf, 2,6-lutidine, 97%). This revised approach was pre- Detailed configurational analysis of the aldehyde 11 reveals
ferred both in terms of a substantially improved yield and to two similar stereotetrads with an epimeric relationship
ensure that the carbon skeleton was not unduly conformationally between C31 and C35. Two iterative aldol chain extensions of
restricted for the later macrocyclisation step. In earlier acetaldehyde employing the (S)-Roche ester-derived ethyl
work,6a we had also explored the effect of reversing the order ketones 35 and 36 were chosen to install the required stereo-
of the fragment couplings whereby the C8–C9 bond was forged centres associated with the C32–C33 and C36–C37 bonds via
ahead of the C13–C14 bond – however, this longer route gave a substrate-controlled induction based on aldol methodology
lower overall yield so was not pursued further.
developed in our group. The appropriate oxygenated stereocen-
The fully protected C1–C19 southern fragment 5 was tres at C31 and C35 in 11 would then be set by controlled
obtained by this improved route in a satisfying 43% overall reductions of the corresponding ketones.
yield in 10 steps over the longest linear sequence (16 total
Following this plan (Scheme 8), the enantioselective prepa-
steps) from the alcohol precursor to 24. Implementation of ration of the β-ketophosphonate (R)-10 was first targeted. This
this reaction sequence on multi-gram scale served to generate route relied on asymmetric catalysis through use of Jacobsen’s
useful quantities of the pivotal major fragment 5 with all of hydrolytic kinetic resolution of terminal epoxides to configure
the seven stereocentres installed in high configurational the C23 stereocentre.24 In the event, 5-hexen-1-ol (37) was first
purity, as required for advancing synthetic efforts toward the derivatised as the TBS ether and converted into the racemic
brasilinolides.
epoxide with m-CPBA. The hydrolytic resolution of this epoxide
then proceeded with operational ease with (R,R)-Co(salen) pre-
catalyst (0.5 mol%) to give multi-gram quantities of (R)-38
(41%) in >98% ee. Opening the epoxide (R)-38 with iso-pro-
penylmagnesium bromide in the presence of catalytic CuI
(15 mol%) then gave alcohol (R)-39 (99%). The C23 hydroxyl
group was subsequently protected (NaH, DMBCl) as its DMB
ether (R)-40 (82%). TBS ether cleavage of (R)-40 (PPTS, MeOH)
afforded alcohol (R)-41, which was then oxidised to the alde-
hyde (R)-42 with Dess–Martin periodinane (84%, two steps).25
Reaction of (R)-42 with lithiated methyl dimethylphosphonate,
followed by a further Dess–Martin oxidation then provided the
The C20–C38 northern fragment 6
With an efficient synthesis of the C1–C19 fragment 5 in place,
the construction of the C20–C38 fragment 6 was addressed
next, as shown in Scheme 7. The methyl ketone 6, corres-
ponding to the northern hemisphere of the brasilinolides, is
characterised by having 11 contiguous stereocentres together
with a remote oxygenated stereocentre at C23. Suitable differ-
entiation of six hydroxyl groups is required, as well as the
Scheme 8 Synthesis of β-ketophosphonate (R)-10. Reagents and con-
ditions: (a) TBSCl, imidazole, CH2Cl2, 96%; (b) m-CPBA, CH2Cl2, 96%; (c)
(R,R)-Co(salen) (0.5 mol%), AcOH (1 mol%), H2O (55 mol%), THF, 41%,
>98% ee; (d) iso-propenylmagnesium bromide, CuI (15 mol%), THF, −78
to −50 °C, 99%; (e) NaH, DMBCl, DMF, 82%; (f) PPTS, MeOH, 99%; (g)
DMP, CH2Cl2, 85%; (h) MeP(O)(OMe)2, BuLi, THF, −78 °C; (i) DMP,
CH2Cl2, 73% (two steps).
Scheme 7 Retrosynthetic analysis of northern fragment 6.
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required β-ketophosphonate (R)-10 (73%, two steps) in high the aldehyde component. Following our standard conditions,
enantiomeric purity. 36 was treated with c-Hex2BCl/Et3N at 0 °C in Et2O to selec-
With the β-ketophosphonate (R)-10 in hand, attention tively form the E-dicyclohexylboron enolate 43 and addition to
turned to the preparation of the C29–C38 aldehyde 11 for the acetaldehyde at −78 °C gave the expected 1,4-syn aldol adduct
planned assembly of the northern fragment 6. This started out with high diastereoselectivity. This reaction is considered to
with the known ethyl ketone 36 (Scheme 9), readily derived proceed through the preferred formyl hydrogen bonded TS-3,
from (S)-Roche ester.26 We have extensively used such chiral where allylic strain is minimised. Interception of the cyclic
ketones for the aldol-based construction of elaborate polypro- boron intermediate 44 by preferred axial attack of an external
pionate sequences in a variety of complex polyketides,27 where hydride via TS-4 also allowed the C35 stereocentre in 45 to be
inherently high levels of control can be attained over both configured in situ. Thus, a Narasaka-type reduction of inter-
their enolate geometry and π-facial selectivity in addition to mediate 44 with LiBH4 at −78 °C efficiently set the 1,3-syn
relationship between C35 and C37 in diol 45 (88%, >95 : 5
dr).28 This convenient one-pot procedure efficiently installed
three new stereogenic centres in excellent diastereoselectivity
in 45 and proved easily scalable.
A key requirement for constructing the northern fragment 6
was that the hydroxyl stereocentres are appropriately differen-
tiated to facilitate macrocyclisation and the sequential attach-
ment of appendages. With this in mind, oxidation of the PMB
ether 45 with DDQ under anhydrous conditions induced cycli-
sation to give the corresponding PMP acetal 46 (92%).29 The
remaining free hydroxyl group at C37 (the future site for glyco-
sylation) was efficiently converted into the DEIPS (Et2i-PrSi)
ether 47 under standard silylation conditions (DEIPSCl, imida-
zole, 97%). Reductive opening of the PMP acetal, mediated by
DIBAL at −78 °C, then regioselectively generated the secondary
PMB ether 48 and the remaining primary alcohol was sub-
sequently oxidised with Dess–Martin periodinane under
buffered conditions to give aldehyde 49 (86%, two steps).
At this point, another boron aldol reaction was employed
for chain extension to complete the full C29–C38 backbone of
fragment 11 (Scheme 10). Selective E-enolisation (c-Hex2BCl,
Et3N) of ethyl ketone 3530 to give enolate 50 and subsequent
reaction with aldehyde 49 proceeded smoothly to provide
adduct 51 (>95 : 5 dr, 96%). Pleasingly, this reaction was found
to be higher yielding when performed on multi-gram scale
than previously observed during route investigation.6b This
highly selective 1,4-syn aldol reaction is considered to proceed
via TS-5, with a stabilising formyl hydrogen bond and avoid-
ance of allylic strain in the enolate matched with Felkin–Anh
induction from the aldehyde component. It results in the con-
trolled installation of the stereocentres at C32 and C33 with
the requisite 1,2-anti configuration and C30 and C33 in a 1,4-
syn relationship.
Directed reduction of the resulting β-hydroxyketone 51
under Evans–Saksena conditions23 using Me4NBH(OAc)3 then
provided the desired 1,3-anti diol 52 with high diastereo-
selectivity (>95 : 5 dr, 91%). This reduction set the final stereo-
genic centre of the characteristic stereooctet spanning the
C24–C38 region of the brasilinolides. Further protecting group
manipulation was required at this stage to differentiate the
newly formed C31 hydroxyl group, which corresponds to the
site for eventual macrolactonisation. Oxidative cyclisation of
the PMB ether 52 with DDQ in CH2Cl2 under anhydrous con-
ditions proceeded cleanly and afforded the PMP acetal 53
(85%). Conversion into the TES ether 54 (TESOTf, 2,6-lutidine)
Scheme 9 Synthesis of aldehyde 49. Reagents and conditions: (a) c-
Hex2BCl, Et3N, Et2O, 0 °C; MeCHO, −78 to −20 °C; (b) LiBH4, THF,
−78 °C; NaOH, MeOH, H2O2, 88%, >95 : 5 dr; (c) DDQ, 4 Å mol. sieves,
CH2Cl2, −10 °C, 92%; (d) DEIPSCl, imidazole, CH2Cl2, 97%; (e) DIBAL,
CH2Cl2, −78 °C, 93%; (f) DMP, NaHCO3, CH2Cl2, 93%.
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Scheme 10 Synthesis of aldehyde 11. Reagents and conditions: (a) Ketone 35, c-Hex2BCl, Et3N, Et2O, 0 °C; aldehyde 49, Et2O, −78 to −20 °C, 96%,
>95 : 5 dr; (b) Me4NBH(OAc)3, MeCN–AcOH (4 : 1), −30 °C, 91%, >95 : 5 dr; (c) DDQ, 4 Å mol. sieves, CH2Cl2, −10 °C, 85%; (d) TESOTf, 2,6-lutidine,
CH2Cl2, −78 °C, 99%; (e) H2, RANEY-Nickel®, EtOH, 92%; (f) DMP, NaHCO3, CH2Cl2, 92%.
was followed by selective hydrogenolysis of the benzyl ether in Preliminary studies on the aldol coupling of the northern and
the presence of the PMP acetal using RANEY®-Nickel in EtOH southern fragments
to reveal the primary alcohol 55,31 which was oxidised using
With routes to the major fragments 5 and 6 developed, atten-
buffered Dess–Martin periodinane to give aldehyde 11 (85%,
two steps).
tion now turned to exploring the pivotal C19–C20 aldol bond
construction to enable completion of the full carbon skeleton
of the brasilinolides. As outlined in Scheme 12, it was initially
planned that the C19 configuration could be controlled in a
1,3-anti sense relative to C17 via a Mukaiyama-type aldol bond
construction.5a,36 This envisaged addition of the silyl enol
ether 59 (derived from 6) to a suitable aldehyde such as 60 to
be prepared from the available southern fragment 5. The
anticipated β-hydroxyketone 61 resulting from this coupling
would then be expected to undergo in situ hemiacetalisation at
C15 to give 62. The advanced nature of both components dic-
tated that this complex system should first be modelled by
investigating the aldol coupling reactions of suitable truncated
fragments, which could be readily prepared by interception of
intermediates already in hand.
As shown in Scheme 13, the truncated methyl ketone (R)-63
was easily accessed from the previously described intermediate
(R)-40. Thus dihydroxylation of olefin (R)-40 (OsO4, NMO) and
oxidative glycol cleavage with NaIO4–SiO2 provided (R)-63
(86%). The model aldehyde 64 was prepared from the β-hydroxy-
ketone 29 obtained in exploratory studies (Scheme 5) for the
southern fragment synthesis. In this case, the secondary
alcohol was first protected as the TBS ether (TBSOTf, 2,6-luti-
dine) and the ketone reduced (NaBH4). Then, the primary TBS
ether was cleaved (PPTS, MeOH) and both hydroxyl groups oxi-
dised under Swern conditions to give the δ-ketoaldehyde 64
With the β-ketophosphonate (R)-10 and the aldehyde 11 in
hand, fragment union via HWE olefination was examined
(Scheme 11). Following our standard conditions,32 this trans-
formation was mediated by Ba(OH)2 in wet THF to efficiently
afford enone 56 (96%) in excellent selectivity (>95 : 5 E : Z).
Reagent-controlled CBS reduction33 of 56 to generate the
required allylic alcohol 57 was found to be highly diastereo-
selective (88%, >95 : 5 dr) with the use of (R)-Me-CBS catalyst
and BH3·SMe2 at −50 °C. Having installed the requisite (27S)-
hydroxyl-bearing centre, the Sharpless asymmetric epoxidation
of this elaborate allylic alcohol was investigated.34 In this case,
the desired epoxide configuration indicated the deployment of
the Ti(Oi-Pr)4–(+)-DIPT reagent system. On small scale, the
Sharpless epoxidation of 57 was found to proceed to afford 58
in 59% yield, attaining an acceptable 7 : 1 dr, but this proved
to be capricious and difficult to reproduce on a larger scale.
Nevertheless, with some of the desired epoxide in hand, the
synthesis of the planned northern fragment 6 (86%, two steps)
was completed by TBS ether formation (TBSOTf, 2,6-lutidine)
followed by a dihydroxylation–oxidative diol cleavage step
(OsO4; NaIO4–SiO2) to reveal the methyl ketone functionality.35
Following this route, the preparation of the C20–C38 northern
fragment 6 was achieved in 13% overall yield over 16 linear
steps from ethyl ketone 36.
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indicated in Scheme 14, the use of BF3·OEt2, B(C6F5)3,
Me2AlCl, TiCl2(Oi-Pr)2, Sc(OTf)3 or Yb(OTf)3 all led to
decomposition of the δ-ketoaldehyde component 64. Disap-
pointingly, screening further Lewis acids such as MgBr2, ZnCl2
or Zn(OTf)2 also did not affect the desired aldol addition but
served to only cleave the silyl enol ether to afford the corres-
ponding methyl ketone (R)-63. In all of these cases, no
product-derived material was observed in the crude 1H NMR
spectra.
As the Mukaiyama aldol approach failed in this situation
due to the unanticipated sensitivity of 64 to Lewis acids, it was
proposed that the desired construction of the C19–C20 bond
might be realised through the much milder conditions associ-
ated with a boron-mediated aldol reaction (Scheme 16). By
comparison with the known reactivity of such β-alkoxy methyl
ketones, the newly formed C19 hydroxyl centre likely would
preferentially form with the undesired configuration due to
the inherent 1,5-anti induction from the (23R)-stereocentre.
As the stereocentre at C23 was anticipated to control the
installation of the C19 hydroxyl group in a 1,5-anti sense,7,21 it
was decided to consider inverting the configuration of the
enolate component to achieve the requisite diastereoselectivity
in the coupling step and this might help simplify the NMR
analysis. This revised strategy was adopted having noted that a
late-stage installation of an ester appendage at C23 might be
performed with inversion of configuration under Mitsunobu
conditions instead of the previously anticipated direct esterifi-
cation suggested earlier in Scheme 1. Therefore, model studies
using the enantiomeric methyl ketone (S)-63 were pursued
next, where this was easily prepared by changing the enantio-
mer of the Jacobsen catalyst used in the established route
(Scheme 8). In the event, enolisation of methyl ketone (S)-63
under standard conditions (c-Hex2BCl, Et3N) and addition to
64 resulted in, for the first time, evidence of adduct formation
Scheme 11 Synthesis of methyl ketone 6. Reagents and conditions: (a)
Ba(OH)2, THF–H2O (40 : 1), 96%, >95 : 5 E : Z; (b) (R)-Me-CBS catalyst,
BH3·SMe2, THF, −50 °C, 88%, >95 : 5 dr; (c) Ti(Oi-Pr)4, (+)-DIPT, t-
BuOOH, 4 Å mol. sieves, CH2Cl2, −20 °C, 59%, 7 : 1 dr; (d) TBSOTf, 2,6-
lutidine, CH2Cl2, −78 °C; (e) OsO4, NMO, THF–H2O; NaIO4–SiO2,
CH2Cl2, 86% (two steps).
1
in the crude H NMR spectrum. The NMR analysis, however,
was complicated due to the presumed equilibrium formed
between the β-hydroxyketone 72 and the cyclic hemiacetal
(74%, four steps). This sequence served to circumvent deleter- form 73 and diastereomers thereof. These observations were
ious cyclisation–elimination pathways, which can occur in the taken as a promising indication that further investigations of
oxidative manipulation of 1,5-hydroxyketones.37
these types of model systems would yield the desired outcome
Given the β-oxygenation at C17 in the aldehyde component to be deployed in the real fragment coupling.
64, it was anticipated that addition of the silyl enol ether (R)-
It was also apparent from several attempted manipulations
65 derived from (R)-63 would install the C19 hydroxyl stereo-
of the mixture of 72 and 73 that in the full system (cf.
centre in a 1,3-anti sense (Scheme 14). The predicted 1,3- Scheme 12) clean formation of the C15 hemiacetal product
stereoinduction in such Mukaiyama aldol reactions of β-alkox- would be difficult to realise. Faced with these problems, it was
yaldehydes to 66 invokes an acyclic transition state based on
proposed that masking the C15 ketone as an alkene might
the Evans polar model.38 In support of this plan, a similar help attain more control in this critical fragment coupling
Mukaiyama aldol coupling (Scheme 15) of silyl enol ether 67 step. Previously prepared ketone 30 allowed for such explora-
with the δ-ketoaldehyde 68 mediated by BF3·OEt2 at −98 °C
tory investigations to be performed (Scheme 17). It was found
gave the hemiacetal adduct 70 (cyclised version of 69) as a to be possible to methylenate ketone 30 under both Takai–
single diastereomer, which served as a key step in our total Lombardo40 and Nysted reagent41 protocols to give 74 (94%
synthesis of auriside A (71).39
and 74% yields, respectively). Selective cleavage of the primary
However, although the aldol reaction of silyl enol ether (R)- TBS ether (HF·pyr) then gave alcohol 75 (96%), which was oxi-
65 using BF3·OEt2 at −78 °C was found to proceed smoothly dised to give the revised model aldehyde 76 (95%) with Dess–
with simple aldehydes, many attempts to form the requisite
Martin periodinane in readiness for further fragment coupling
C19–C20 bond in the more elaborate aldehyde 64 failed. As studies (Tables 1 and 2).
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Scheme 12 Proposed Mukaiyama-type aldol coupling between 59 and 60 to assemble the advanced C1–C38 intermediate 62.
reagents (Scheme 18, Table 1, entries 1–5). As anticipated,
there was some selectivity for the desired 1,5-anti product 77,
although not as high as previously observed in these types of
reaction. There was a modest increase in diastereoselectivity to
a more promising 4.8 : 1 dr (entry 5), when using 9-BBNCl/i-
Pr2NEt. In this complex aldol coupling, it was conjectured that
the aldehyde component 76 has a π-facial bias in the opposing
sense to that desired and 1,3-syn to the C17 stereogenic centre.
This would appear to violate the bias for 1,3-anti stereoinduc-
tion observed in simple systems according to the Evans polar
model.38 There is, however, some evidence to suggest that
additional stereochemical features and steric bulk in the
γ-position of β-alkoxyaldehydes can disrupt this model by way
of a gearing effect, such as that described by Sulikowski and
co-workers.42
Having achieved a promising level of selectivity for setting
the desired C19 configuration in 77, switching to a chiral
boron reagent ((−)-Ipc2BCl) was expected to help reinforce the
enolate π-facial preference (entries 6–8).43 Unfortunately, the
product 77 was only observed to form with moderate diastereo-
selectivity (2.5 : 1 dr, 77 : 78) and changing the reaction solvent
Scheme 13 Preparation of model fragments (R)-63 and 64. Reagents
and conditions: (a) OsO4, N-morpholine-N-oxide, THF–H2O; NaIO4–SiO2,
86%; (b) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C, 95%; (c) NaBH4, MeOH,
99%; (d) PPTS, MeOH, 85%; (e) (COCl)2, DMSO, CH2Cl2, −78 °C; Et3N, 93%.
Enolisation of methyl ketone (S)-63 (epi-C23 series) and sub- to pentane or CH2Cl2 was also found to give no improvement.
sequent aldol addition to aldehyde 76 was first performed in This reduced diastereoselectivity was further observed by reac-
Et2O at low temperature with a variety of achiral boron tion with the enantiomeric (+)-Ipc2BCl (entry 9), whereby the
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for the effects of stereochemical bias from the enolate, alde-
hyde and boron reagent (Scheme 19, Table 2). Reaction of
aldehyde 76 with the dicyclohexylboron enolate of (R)-63 pro-
ceeded in 5 : 1 dr for the 1,5-anti product 79 corresponding to
the unnatural configuration at C19 (entry 1). Comparison to
the corresponding result with (S)-63 (Table 1, entry 1) shows
an increase in 1,5-anti selectivity, indicating a small matched
effect between the enolate and aldehyde. Indeed, reinforce-
ment of this substrate-based stereoinduction with the appro-
priate (+)-Ipc2BCl reagent (Table 2, entry 2) now achieved
excellent levels of diastereoselectivity (17 : 1 dr, 79 : 80) in
favour of the 1,5-anti product. Unsurprisingly, when the enan-
tiomeric (−)-Ipc2BCl was employed to help favour the 1,5-syn
product 80 with the desired C19 configuration (entry 3), the
diastereoselectivity was poor (1 : 1.5 dr, 79 : 80, 1,5-anti : syn)
as the chiral reagent is tasked with overriding the inherent
substrate reactivity.
This preliminary investigation of the unexpectedly complex
C19–C20 aldol coupling step gave a helpful steer as to how to
best evolve our strategy to advance the synthesis of the brasili-
nolides. It was concluded that it would be highly challenging
to achieve excellent diastereoselectivity for the correct C19 con-
figuration using boron-mediated aldol reactions. The comple-
tely matched reactivity between all components was identified
as the scenario where (R)-63 (natural C23 configuration), alde-
hyde 76 (facial preference 1,3-syn to C17) and (+)-Ipc2BCl were
used to give product 79 with the incorrect C19 configuration
(Table 2, entry 2). Although as discussed previously, the C23
stereocentre could potentially be inverted at a later stage on
esterification, selective inversion of C19 would be considerably
more problematic. Having established a set of workable, albeit
unoptimised, conditions for the formation of the C19–C20
Scheme 14 Attempted Mukaiyama aldol addition between (R)-65 and
64. Reagents and conditions: (a) LiHMDS, THF, −78 °C; TMSCl·Et3N,
90%; (b) Lewis acid, CH2Cl2, −98 to −78 °C.
chiral reagent reversed the sense of stereoinduction to the
undesired C19 configuration.
The unexpected sense of π-facial bias of aldehyde 76
towards boron-mediated aldol additions prompted further
investigation of this reaction. Further studies were performed
with the methyl ketone (R)-63 (natural C23 configuration as in
the brasilinolides). This was anticipated to expand the data set
Scheme 15 Fragment coupling using a Mukaiyama aldol reaction in the synthesis of (−)-auriside A (71). Reagents and conditions: (a) BF3·OEt2,
CaH2, CH2Cl2, −98 °C, 10 min, 66%, single diastereomer.
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bond with the C15-methylene model substrate 76, it was
important in going forward to able to transfer this chemistry
to the real system. Disappointingly, the C15-methylene func-
tionality proved to be unreactive towards standard oxidation
conditions to regenerate the required ketone presumably due
to steric congestion. This shortcoming necessitated a change
in strategy for masking the C15 ketone in the southern frag-
ment as discussed below.
Elaboration of 5 to the advanced southern fragment 81
Based on the foregoing findings, a C15-acetoxy aldehyde 81
(Scheme 20) was proposed as the revised southern fragment to
be used in the pivotal C19–C20 aldol coupling step. It was envi-
saged that the C15 ketone could subsequently be reinstalled
by oxidation after selective cleavage of the acetate. Given the
already high level of molecular complexity of the northern and
southern fragments, it was advantageous that any reduction of
the C15 ketone moiety was performed in a highly stereo-
controlled fashion. In practice, reduction of 5 with Zn(BH4)2 at
low temperature proceeded cleanly to afford alcohol 82 with
high diastereoselectivity (99%, >95 : 5 dr).44 As expected from
the reaction proceeding by a chelation pathway, this was assigned
as the C15,C16-anti stereoisomer with the (15S)-configuration.
Acetylation then gave ester 83 in 97% yield.
Scheme 16 Model boron-mediated aldol reaction between (S)-63 and
64. Reagents and conditions: (a) Ketone (S)-63, c-Hex2BCl, Et3N, Et2O,
0 °C, 1 h; aldehyde 64, −78 to −20 °C.
Selective desilylation of 83 (TBAF, AcOH) at C19 to give 84
was followed by oxidation with Dess–Martin periodinane to
afford aldehyde 81 (89%, two steps). This high yielding
sequence gave the required stereodefined C15-acetoxy alde-
hyde 81 in 37% overall yield over 14 steps from 24.
Revisiting the northern fragment
One of the concerns in our planned synthesis of the brasili-
nolides was the potential reactivity of the C28–C29 epoxide
moiety in the northern hemisphere. In the context of the
structure determination studies performed on brasilinolide
C (3), it was demonstrated that the epoxide was prone to
intramolecular nucleophilic opening by pendant hydroxyl
groups.3b Fortunately, this had not been a problem to date,
where presumably the adjacent protecting groups shielded
the epoxide even towards exposure to Lewis acids such as di-
butylboron triflate. An unexpected hurdle, however, was the
reliable installation of the epoxide itself in acceptable yield,
diastereoselectivity, and on a reasonable scale. At the time,
Sharpless asymmetric epoxidation of the allylic alcohol 57
(Scheme 11) did not appear to satisfy all these requirements
and a screen of reaction conditions and other hydroxyl-
directed electrophilic epoxidation protocols was performed to
no avail.
With the exploration of alternative electrophilic epoxidation
methods on 57 proving unrewarding, it was proposed that the
enone 85 (Scheme 21) could be employed as a substrate for
nucleophilic epoxidation. This enone was prepared by an ana-
logous route to that shown in Scheme 11 for the corresponding
C23-epi compound 56 but now using the (23S)-β-ketophospho-
nate (S)-10 for the HWE step.20 Serendipitously, epoxidation of
Scheme 17 Preparation of aldehyde 76. Reagents and conditions:
(a) Nysted reagent (cyclo-dibromodi-μ-methylene[μ-(tetrahydrofuran)]-
trizinc), TiCl4, THF, 94% or PbI2, CH2I2, Zn, THF, 74%; (b) HF·pyr, pyr,
THF, 96%; (c) DMP, NaHCO3, CH2Cl2, 95%.
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Table 1 Model aldol coupling between (S)-63 and 76
Enolisation
temp. (Time)
Crude dr
77 : 78
Entry
Lewis acid
Base
Reaction temp. (Time)
Solvent
1
2
3
4
5
6
7
8
9
c-Hex2BCl
Bu2BOTf
9-BBNOTf
9-BBNCl
Et3N
−78 °C (1 h)
−78 °C (1 h)
−78 °C (1 h)
−78 °C (1 h)
−78 °C (1 h)
0 °C (1 h)
0 °C (1 h)
0 °C (1 h)
0 °C (1 h)
−78 °C (3 h) → −23 °C (16 h)
−78 °C (3 h)
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Pentane
CH2Cl2
Et2O
3 : 1
3.5 : 1
4 : 1
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
Et3N
Et3N
Et3N
−78 °C (1 h)
−78 °C (3 h)
4 : 1
9-BBNCl
−78 °C (3 h) → −20 °C (1 h)
−78 °C (3 h) → −20 °C (1 h)
−78 °C (3 h) → −20 °C (1 h)
−78 °C (3 h) → −20 °C (1 h)
−78 °C (3 h) → −20 °C (1 h)
4.8 : 1
2.5 : 1
2 : 1
1 : 1
1 : 2
(−)-Ipc2BCl
(−)-Ipc2BCl
(−)-Ipc2BCl
(+)-Ipc2BCl
Et3N
Table 2 Model aldol coupling between (R)-63 and 76
Enolisation
temp. (Time)
Crude dr
79 : 80
Entry
Lewis acid
Base
Reaction temp. (Time)
Solvent
1
2
3
c-Hex2BCl
(+)-Ipc2BCl
(−)-Ipc2BCl
Et3N
Et3N
Et3N
−78 °C (1 h)
−78 °C (1 h)
−78 °C (1 h)
−78 °C (3 h) → −23 °C (16 h)
−78 °C (3 h) → −20 °C (1 h)
−78 °C (3 h) → −20 °C (1 h)
Et2O
Et2O
Et2O
5 : 1
17 : 1
1 : 1.5
Scheme 18 Model aldol coupling between (S)-63 and 76. Reagents and
conditions: (a) Ketone (S)-63, L2BX, R3N; aldehyde 76, conditions in
Table 1.
Scheme 19 Model aldol coupling between (R)-63 and 76. Reagents
and conditions: (a) Ketone (R)-63, L2BX, R3N; aldehyde 76, conditions in
Table 2.
85 with t-BuOOLi was found to be effective at −78 °C to afford opportunity for embarking on this intelligence gathering
86 in both high diastereoselectivity (30 : 1 dr) and yield (91%). exercise.
The configuration at C28 and C29, however, was subsequently
As shown in Scheme 21, stereocontrolled reduction of
determined to be epimeric to that required for the brasilino- ketone 86 was affected by treatment with DIBAL in t-BuOMe at
lides.20 Given this unexpectedly high selectivity and the −98 °C to give the alcohol 87 (83%) with 10 : 1 dr for the
enhanced scalability of the transformation, it was decided at natural C27 configuration (Mosher ester analysis20). Alcohol 87
this stage to go forward to advance the chemistry required for was protected as the TBS ether 88 (TBSOTf, 2,6-lutidine) and
constructing the brasilinolides, chiefly examination of the oxidative cleavage of the alkene (OsO4, NaIO4–SiO2) afforded
major fragment coupling and further manipulation. The the methyl ketone 89 (80%, two steps). With this modified
greater availability of the advanced intermediate 86 with the route established, sufficient quantities of a full northern frag-
opposite epoxide configuration was considered to be a good ment mimic 89 were now generated to develop suitable con-
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Scheme 21 Synthesis of ketone 89. Reagents and conditions: (a) t-
BuOOH, BuLi, THF, −78 to −20 °C, 91%, 30 : 1 dr; (b) DIBAL, t-BuOMe,
−98 °C, 83%, 10 : 1 dr; (c) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C, 91%; (d)
OsO4, N-methylmorpholine-N-oxide, THF–H2O; NaIO4–SiO2, CH2Cl2,
88%.
Scheme 20 Preparation of C1–C19 aldehyde 81. Reagents and con-
ditions: (a) Zn(BH4)2, Et2O, −78 to 0 °C, 99%, >95 : 5 dr; (b) Ac2O, Et3N,
DMAP, CH2Cl2, 97%; (c) TBAF, AcOH, THF, 90% (brsm); (d) DMP,
NaHCO3, CH2Cl2, 98%.
With a view to enhancing the reactivity of the boron
enolate, the Lewis acid was changed to Bu2BOTf (entries 4–8).
Conducting the aldol reaction at −78 °C led to a 32% isolated
yield of a separable 2.5 : 1 mixture of adducts in favour of the
desired C19 configuration in 90 with good recovery of
unreacted ketone 89 and aldehyde 81 (entry 4). Use of the
more reactive dibutylboron enolate was compatible with per-
forming the reaction at a lower temperature (−98 °C), resulting
in both higher diastereoselectivity and isolated yield (entry 5),
with both starting materials also recoverable. This provided
the aldol adducts in 95% yield brsm with a workable 3.5 : 1 dr
in favour of 90. This would prove to be the preferred set of con-
ditions for carrying out this challenging aldol fragment union,
despite varying different reaction parameters (entries 6–8).
ditions for achieving the complex aldol coupling with the full
southern aldehyde 81.
Realising the aldol coupling of the northern and southern
fragments
With useful stocks of the major fragments now in hand, their
planned aldol union to assemble an advanced C1–C38 inter-
mediate for the brasilinolides could be studied and any pitfalls
identified. From experience gained earlier of boron-mediated
aldol reactions using truncated systems, the desired 1,5-anti
selective addition reaction between 81 and 89 was much antici-
pated (Scheme 22). At the outset, preliminary screenings of
standard conditions using c-Hex2BCl/Et3N were found to give a
Further elaboration to a C1–C38 advanced intermediate
modest 2 : 1 dr in favour of the 1,5-anti product 90 (Table 3, With access to the configurationally pure aldol product 90
entry 1). Use of (−)-Ipc2BCl as the matched chiral boron representing the full C1–C38 carbon skeleton, studies into its
reagent proceeded with an improved 3 : 1 dr in favour of the manipulation to afford an advanced brasilinolide intermediate
desired C19 diastereomer (entry 2) but in low conversion. By were commenced (Scheme 23). Hydroxyl-directed reduction of
contrast, use of (+)-Ipc2BCl resulted in negligible diastereo- the ketone 90 under Evans–Saksena conditions23 proceeded
selectivity for this transformation (entry 3). While all of these smoothly to give the 1,3-anti diol 91 (>95 : 5 dr, 85%). This
exploratory reactions gave a disappointingly low conversion, transformation represented the controlled installation of the
both starting materials were recoverable (Table 3).
remaining C21 stereocentre. The hydroxyl groups were then
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Scheme 22 Aldol coupling of fragments 81 and 89. Reagents and conditions: (a) Ketone 89, L2BX, R3N; aldehyde 81, conditions in Table 3.
both derivatised as TBS ethers (TBSOTf, 2,6-lutidine) to give only moderate diastereoselectivity (2 : 1 dr 95 : 87). Nonethe-
the fully protected intermediate 92 (98%).
less, this reproducible transformation now gave ready access to
We now required to saponify the acetate group at C15 in 92 useful amounts of 95 possessing the requisite epoxide con-
with concomitant generation of the free carboxylic acid at C1 figuration. Thus epoxide 95 was converted into TBS ether 96
(Scheme 23). However, a screen of standard reagents (e.g. (TBSOTf, 2,6-lutidine, 86%) and finally to the revised northern
LiOH) led to hydrolysis of the methyl ester but without achiev- fragment 97 by a dihydroxylation–oxidative diol cleavage step
ing the acetate cleavage. Gratifyingly, reduction of 92 with (OsO4; NaIO4–SiO2, 85%), in readiness for repeating the aldol
DIBAL at −78 °C successfully cleaved the acetate and also coupling with aldehyde 81 (cf. Scheme 22).
reduced the ester to an inconsequential mixture of allylic
alcohol and enal. The crude mixture of these products was
subjected to Dess–Martin oxidation to afford solely enal 93
Conclusions and outlook
(90%, two steps), also reintroducing the required ketone oxi-
dation level at C15.45 While this has the wrong configuration
The brasilinolides are an architecturally complex family of
for the epoxide, it is anticipated that this sequence should be
directly applicable to the desired epoxide series.
polyhydroxylated 32-membered macrolides, characterised by
their potent immunosuppressant and antifungal properties. In
work directed toward their total synthesis, a range of asym-
metric aldol/reduction sequences and catalytic protocols were
employed to assemble a series of increasingly elaborate frag-
ments. By adopting the highly convergent strategy outlined in
Scheme 1, the preparation of the required C1–C19 and C20–
C38 acyclic fragments 5 (10 steps, 43%) and 6 (16 steps, 13%
from 36), containing seven and 12 stereocentres respectively,
was first achieved. An adventurous fragment union by con-
trolled C19–C20 bond formation was then extensively explored
As a prelude to these future efforts, we returned to earlier
intermediates to address the incorrectly configured epoxide
(Scheme 24). Reagent-controlled CBS reduction of enone 85 to
generate allylic alcohol 94 proceeded smoothly at −50 °C
(88%, >95 : 5 dr) as had been observed with the epi-C23 com-
pound 56. After some experimentation, it was found that
Sharpless asymmetric epoxidation directed by the (27S)-
hydroxyl-bearing stereocentre could be affected using a Ti(Oi-
Pr)4–(+)-DET reagent system to give 95 in high yield (86%) but
Table 3 Aldol coupling of fragments 81 and 89
Entry
Lewis acid
Base
Enolisation temp. (Time)
Reaction temp. (Time)
Solvent
Isolated yield (%)
dr 1,5-anti : syn
1
2
3
4
5
6
7
8
c-Hex2BCl
(−)-Ipc2BCl
(+)-Ipc2BCl
Bu2BOTf
Bu2BOTf
Bu2BOTf
Bu2BOTf
Bu2BOTf
Et3N
Et3N
Et3N
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
−78 °C (1 h)
0 °C (1 h)
0 °C (1 h)
−78 °C (1 h)
−78 °C (1 h)
−78 °C (0.5 h)
−50 °C (0.5 h)
−78 °C (1 h)
−78 °C (3 h) → −23 °C (16 h)
−78 °C (3 h) → −20 °C (1 h)
−78 °C (3 h) → −20 °C (1 h)
−78 °C (4 h)
−98 °C (1 h) → −78 °C (4 h)
−98 °C (1 h) → −78 °C (4 h)
−98 °C (1 h) → −78 °C (4 h)
−98 °C (1 h) → −78 °C (4 h)
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Pentane
8
5
4
32
2 : 1
3 : 1
1 : 1.2
2.5 : 1
3.5 : 1
3 : 1
48 (95% brsm)
44
<5
23
—
2.5 : 1
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Scheme 23 Preparation of the advanced C1–C38 coupled product 93. Reagents and conditions: (a) Me4NBH(OAc)3, MeCN–AcOH (4 : 1), −30 °C,
85%, >95 : 5 dr; (b) TBSOTf, 2,6-lutidine, CH2Cl2, −78 °C, 98%; (c) DIBAL, CH2Cl2, −78 °C; (d) DMP, NaHCO3, CH2Cl2, 90% (2 steps).
to construct the entire carbon chain of the brasilinolides.
Notably, the use of boron-mediated aldol reactions of chiral
ketones proved efficient on multiple occasions to assemble
and then couple key fragments, with predictable installation of
the required configuration via either 1,4- or 1,5-stereoinduc-
tion from the enolate component. In particular, this chemistry
proved crucial for achieving the complex aldol coupling
between methyl ketone 89 and aldehyde 81 to give adduct 90,
where Mukaiyama-type aldol protocols had earlier proved
unrewarding in model studies. Following the controlled
manipulation of various intermediates derived from 90, the
preparation of the protected C1–C38 polyol 93 (21 steps from
36 in the longest linear sequence) was then achieved, thus
setting the stage for future efforts directed at late-stage diversi-
fication to access the various brasilinolide congeners.
From our perspective, the controlled assembly of the highly
oxygenated and stereochemically elaborate molecular architec-
ture of the brasilinolides serves to test the limits of chemical
synthesis. Moreover, this adventurous endeavour underscores
the multiple logistical and selectivity issues that are regularly
faced in tackling the synthesis of such promising polyketide
natural products of biological and medicinal importance.1b,d,46
In future work, it is anticipated that we can build on the sup-
portive findings reported here to further progress a unified
approach to the construction of the brasilinolides.
Scheme 24 Preparation of C20–C38 methyl ketone 97. Reagents and
conditions: (a) (R)-Me-CBS catalyst, BH3·SMe2, THF, −50 °C, 88%, >95 : 5
dr; (b) Ti(Oi-Pr)4 (10 mol%), (+)-DIPT (15 mol%), t-BuOOH, 4 Å mol.
Experimental
Full experimental and characterisation details are provided in
the ESI.†
sieves, CH2Cl2, −25 °C, 86%, 2 : 1 dr; (c) TBSOTf, 2,6-lutidine, CH2Cl2,
−78 °C, 86%; (d) OsO4, NMO, THF–H2O; NaIO4–SiO2, CH2Cl2, 85%.
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10 For a selection of reviews on the vinylogous aldol reaction,
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Acknowledgements
We thank the EPSRC (EP/F025734/1) and Syngenta for support,
the Isaac Newton–Mays Wild Research Fellowship at Downing
College (M.P.H.), the Herchel Smith Postdoctoral Fellowships
Fund at Cambridge (C.J.C.) and the Deutsche Akademie der
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additional funding, and the EPSRC National Mass Spectro-
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