Regio- and Stereoselective Homologation of 1,2-Bis(Boronic Esters): Stereocontrolled Synthesis of 1,3-Diols and Sch 725674

Article abstract of DOI:10.1002/anie.201608406

1,2-Bis(boronic esters), derived from the enantioselective diboration of terminal alkenes, can be selectively homologated at the primary boronic ester by using enantioenriched primary/secondary lithiated carbamates or benzoates to give 1,3-bis(boronic esters), which can be subsequently oxidized to the corresponding secondary-secondary and secondary-tertiary 1,3-diols with full stereocontrol. The transformation was applied to a concise total synthesis of the 14-membered macrolactone, Sch 725674. The nine-step synthetic route also features a novel desymmetrizing enantioselective diboration of a divinyl carbinol derivative and high-yielding late-stage cross-metathesis and Yamaguchi macrolactonization reactions.

Full text of DOI:10.1002/anie.201608406

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201608406
German Edition: DOI: 10.1002/ange.201608406
Selective Homologation
Regio- and Stereoselective Homologation of 1,2-Bis(Boronic Esters):
Stereocontrolled Synthesis of 1,3-Diols and Sch725674
Alexander Fawcett+, Dominik Nitsch+, Muhammad Ali+, Joseph M. Bateman, Eddie L. Myers,
and Varinder K. Aggarwal*
Abstract: 1,2-Bis(boronic esters), derived from the enantio-
selective diboration of terminal alkenes, can be selectively
homologated at the primary boronic ester by using enantio-
enriched primary/secondary lithiated carbamates or benzoates
to give 1,3-bis(boronic esters), which can be subsequently
oxidized to the corresponding secondary-secondary and sec-
ondary-tertiary 1,3-diols with full stereocontrol. The trans-
formation was applied to a concise total synthesis of the 14-
membered macrolactone, Sch725674. The nine-step synthetic
route also features a novel desymmetrizing enantioselective
diboration of a divinyl carbinol derivative and high-yielding
late-stage cross-metathesis and Yamaguchi macrolactonization
reactions.
D
evelopments in the homologation of boronic esters has
continued unabated for almost 40 years, reaching a point
where iterative homologation (“one pot”) of a simple boronic
ester into a molecule bearing 10 contiguous methyl substitu-
ents with full stereocontrol was recently demonstrated.[1] Its
use in complex natural product synthesis, such as (+)-10-
hydroxyphthioceranic acid, has also been demonstrated
(Scheme 1a).[2] The methodology clearly works well in the
construction of carbon chains rich in non-polar residues, but
these represent a rather small sub-set of natural products.
Most natural products contain polar residues where 1,3-
hydroxy groups are ubiquitous. However, whilst 1,3-hydroxy
groups can be easily prepared from alternative starting
materials (e.g. carbonyl compounds),[3] they cannot be
prepared from boronic esters because the intermediate
boronate complex that would be required to generate this
moiety can either undergo the desired 1,2-migration or
Scheme 1. Homologation of organoboron compounds.
undesired b-elimination (Scheme 1b). When X is a halide
(Matteson homologation) or a carbamate (our work), the
desired 1,2-migration does occur but b-elimination often
competes limiting its efficiency and generality, thus rendering
these common motifs inaccessible to the current method-
ology.[4] To address this problem, we considered masking the
b-alkoxy group with another boron atom (Scheme 1c)
because 1) the b-boronic ester does not undergo elimina-
tion,[5] 2) oxygen functionality can be readily generated, and
3) the required 1,2-bis(boronic esters) are readily available
through Morken/Nishiyama catalytic asymmetric diboration
of terminal alkenes.[6] The new process would require regio-
and stereoselective homologation of the 1,2-bis(boronic
ester).[7,8] By combining Morken/Nishiyama diboration with
lithiation–borylation we now show that powerful new meth-
odology can be generated, enabling incorporation of the 1,3-
diol motif through boronic ester homologation. In addition,
we demonstrate its application in the concise total synthesis of
the 14-membered macrolactone, Sch725674.
[*] A. Fawcett,[+] Dr. D. Nitsch,[+] Prof. Dr. M. Ali,[+] J. M. Bateman,
Dr. E. L. Myers, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
Prof. Dr. M. Ali[+]
Department of Chemistry
COMSATS Institute of Information Technology
University Road, Abbottabad-22060, KPK (Pakistan)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201608406.
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
The key selective homologation of a primary boronic ester
over a secondary boronic ester was initially examined. A 1,2-
bis(boronic ester), (R)-2 (e.r. 95:5, 1.2 equiv), which was
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prepared by Morken asymmetric diboration of 1-octene,[6c]
was added to a solution of preformed sparteine-ligated
lithiated carbamate 1a-Li-(+)-sp (1.0 equiv, > 99:1 e.r.)[9] at
ꢀ788C. Subsequent heating at 358C for 16 h, followed by
oxidation (H2O2/NaOH/H2O), gave the desired 1,3-diol (S,S)-
3 (66% yield) together with only trace amounts of the double-
addition product, that is, that derived from homologation of
both the primary and secondary boronic esters (Scheme 2a,
entry 1). The use of the lithiated triisopropylbenzoate (1b-Li-
(+)-sp 1.0 equiv, 96:4 e.r.)[10] in place of the carbamate gave
similar yields of 3 (69% yield; Scheme 2a, entry 4).
Because the enantioenriched 1,2-bis(boronic ester) can
sometimes be more valuable than the lithium-stabilized
carbenoid, we were keen on identifying conditions where
the latter could be used in excess. However, standard
conditions led to increased amounts of the double-addition
product (Scheme 2a, entry 2). Suspecting that this product
was only generated while the reaction mixture was being
warmed from ꢀ788C to room temperature, we performed an
experiment using excess carbamate and where MeOH was
added to the reaction mixture immediately prior to warming,
thus protonating any remaining lithiated carbamate.[11] Pleas-
ingly, the use of this methanol-quench protocol, for both the
carbamate and the benzoate, gave a good yield of 3 and only
trace amounts of the double-addition product (Scheme 2a,
entries 3 and 5), thus supporting our hypothesis and complet-
ing a suite of conditions for the regio- and stereoselective
homologation of 1,2-bis(boronic esters).
The selectivity of this transformation may seem unre-
markable: the less hindered primary boronic ester reacts in
preference to the secondary boronic ester. However, we have
found that it is critically dependent on the nature of the
nucleophile. For example, the use of the either the TMEDA-
ligated or diamine-free lithiated carbamate 1a, or chloro-
methyl lithium (all less-hindered) gave a mixture of starting
material, mono- and double-addition products (see the
Supporting Information for details). Thus, only by using
suitably hindered diamine-ligated lithiated carbamate 1a or
benzoate 1b can high selectivity for reaction of the primary
boronic ester over the secondary boronic ester be achieved.
With these conditions established, we prepared the
remaining three stereoisomers of 3 by using the appropriate
enantiomer of both 1,2-bis(boronic esters) 2 (1.2 equiv) and
lithiated carbamate 1a-Li (Scheme 2A). In all cases, diols 3
were obtained with the same high diastereoselectivity and
yield showing that there were no matched/mis-matched
effects and that the reactions were dominated by reagent
control. The scope of the selective transformation was also
explored. The 1,2-bis(boronic ester), (R)-2, was treated with
a range of lithiated primary and alkyl-alkyl, alkyl-aryl, and
alkyl-vinyl secondary carbamates/benzoates to give the
corresponding secondary-secondary and secondary-tertiary
1,3-diols in moderate to good yield and with excellent levels
of diastereo- and enantioselectivity (4–12, Scheme 2B). By
using the secondary benzylic carbamate, in combination with
a range of 1,2-bis(boronic esters) of different steric demand
bearing commonly encountered functional groups (ester, silyl
ether, carbamate, alkene), the 1,3-diols were again obtained
with high regio- and stereoselectivity (13–19, Scheme 2C).
The ability to prepare secondary-tertiary 1,3-diols in any
stereoisomeric form with such high selectivity is especially
notable because such a transformation is unprecedented.[12]
Finally, a TBS-protected derivative of the lipid-lowering drug,
atorvastatin, was prepared in good yield and excellent levels
of stereoselectivity by using the corresponding pyrrole-
containing 1,2-bis(boronic ester) and lithiated benzoate
containing the primary TBS ether (20, Scheme 2D), demon-
strating further scope and potential application.
Scheme 2. Selective homologation of 1,2-bis(boronic esters): optimiza-
tion and scope. Yields given are of isolated product, d.r. values were
determined by using 13C NMR spectroscopy. [a] 0.55 mmol of the
limiting reagent was used; 1, s-BuLi, (+)- or (ꢀ)-sparteine, Et2O
(0.2m), ꢀ788C; then 2 (1m in Et2O), ꢀ788C, 1 h; for ODG=OCb:
warm to RT, then 358C overnight; for ODG=OTIB: warm to RT; 3m
aq. NaOH/30% aq. H2O2 (2:1), THF, 08C to RT. [b] Reaction
conditions: entry 4. [c] Reaction conditions: entry 1. [d] Reaction
conditions: entry 2. [e] Reaction conditions: entry 1; sparteine was not
used; MgBr2 in MeOH was added prior to warming. [f] Reaction
conditions: entry 4; TMEDA was used in place of sparteine. [g]
0.28 mmol of the TIB ester (0.33m) and 0.14 mmol of the 1,2-
bis(boronic ester) was used. DG=directing group, Cb=N,N-diiso-
propyl carbamoyl, TIB=triisopropylbenzoate, TMEDA=tetramethyl-
ethylenediamine.
We decided to showcase this methodology in a total
synthesis of Sch725674 (21; Figure 1), a 14-membered macro-
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more coordinating O-protecting groups including the free
alcohol were also tested but they performed less well (see the
Supporting Information for details), so the TBS-protected
derivative 27 (90% yield, > 95:5 d.r.) was taken forward.
ꢀ
Conversion of 1,2-bis(boronic ester) 27 to the known triol (C
B oxidation/TBS deprotection), and then to the tri(p-bromo-
benzoyl ester) confirmed both the identity of the major
diastereomer as being anti and the high levels of enantiose-
lectivity (98:2 e.r.).
With a significant amount of 27 in hand, we moved to the
other coupling partner 24a (X = N(iPr)2, Figure 1). Unfortu-
nately the bis-carbamate did not undergo lithiation under
standard deprotonation conditions (sBuLi, diamine, Et2O,
ꢀ788C), but the corresponding bis(triisopropylbenzoate) 24b
(X = 2,3,5-triisopropylbenzene, Figure 1) did. Thus, enantio-
selective deprotonation of 24b with sBuLi (1.2 equiv) in Et2O
in the presence of (ꢀ)-sparteine (1.3 equiv) at ꢀ788C,
followed by addition of 1,2-bis(boronic ester) 27, warming
to room temperature, an oxidative workup, and TBS protec-
tion of the resulting secondary hydroxy groups gave the tris-
TBS protected 1,2,4-triol 28 in 70% yield on multigram scale
(Scheme 3). The diastereoselectivity of the transformation
was ca. 95:5, which is in line with the levels of enantioselec-
tivity we often obtain for sparteine-mediated deprotonation
of primary triisopropyl-benzoates.[11] The reaction was selec-
tive for transformation of the primary boronic ester; we did
not observe any products arising from homologation of the
secondary boronic ester or homologation of both boronic
esters. The remaining benzoate ester was then reacted with
pentyl boronic ester 23 in another lithiation–borylation–
oxidation to give tris(tert-butylsilyl)-protected tetraol 29,
which was isolated in 85% yield as a 90:5:5 mixture of
diastereomers. The diastereopurity of 29 again is in line with
the expected reagent-controlled ꢁ 95:5 selectivity in the
sparteine-mediated deprotonation of 28, imposed on a 95:5
mixture of diastereomers of 28. This reaction was scaled up to
provide grams of material (2.0 g). The terminal alkene was
then converted into the a,b-unsaturated methyl ester through
ruthenium-catalyzed cross-metathesis with methyl acrylate.
Figure 1. Retrosynthetic analysis of Sch725674. L-B-O: lithiation–bory-
lation–oxidation.
lactone, which was isolated in 2005 from Aspergillus sp.[13] The
molecule exhibits moderate antifungal activity and is a rare
example of a macrocyclic polyketide natural product that
does not contain any methyl-group branching. It is a popular
target that has been frequently used to demonstrate method-
ology,[14,15] as it is a representative of a much larger class of
important macrolactone polyketide-derived enolides.[16] Our
retrosynthesis involves a novel desymmetrizing diboration of
a divinylcarbinol derivative (25!22, Figure 1), setting the C4
ꢀ
and C5 stereocenters, followed by two reagent-controlled C
C bond-forming lithiation–borylation reactions on a dicarbe-
noid precursor, 24, the first being a regioselective trans-
formation of the primary boronic ester of 22 and the second
installing the pentyl-substituted C13 carbinol. Cognizant of
previous syntheses of Sch725674,[14,15] we decided on cross-
metathesis/macrolactonization to incorporate C1 and C2 and
form the ring.
We began by investigating the novel desymmetrizing
asymmetric diboration of divinyl carbinol derivatives. We
found that O-silyl derivatives, such as 25a, gave very high
yields of the single-diboration product (27) using Morkenꢀs
conditions, which were obtained as single diastereomers
(> 95:5 d.r.; Scheme 3). Nishiyamaꢀs conditions and other
Scheme 3. Synthesis of Sch725674. Reaction conditions: a) Pt(dba)3 (1 mol%), 26 (1.2 mol%), B2pin2 (1.1 equiv), THF, 608C, 16 h. b) 24b
(1.3 equiv), sBuLi (1.2 equiv), (ꢀ)-sp. (1.3 equiv), Et2O, ꢀ788C, 2 h; then 27 (1.0 equiv), ꢀ788C, 1 h; then 358C, 16 h. c) 2m aq. NaOH/30% aq.
H2O2 (2:1), THF, RT, 1 h. d) TBSOTf (4.1 equiv), 2,6-lutidine (6.2 equiv), CH2Cl2, RT, 1.5 h. e) 28 (1.0 equiv), sBuLi (1.2 equiv), (+)-sp. (1.3 equiv),
Et2O, ꢀ788C, 2 h; then 23 (1.4 equiv), ꢀ788C, 1 h; then 358C, 16 h. f) Hoveyda–Grubbs 2nd gen cat. (10 mol%), methyl acrylate (3.0 equiv),
EtOAc, 808C, 16 h. g) LiOH (10 equiv), THF/MeOH/H2O (1:1:1), 408C, 16 h. h) trichlorobenzoyl chloride (1.2 equiv), NEt3 (3.0 equiv), toluene,
RT, 4 h; then DMAP (2.0 equiv), 808C, 16 h. i) HF (48 wt%, H2O)/CH2Cl2/CH3CN (1:2:6), RT, 3 h.
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3183; h) M. Burns, S. Essafi, J. R. Bame, S. P. Bull, M. P. Webster,
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This reaction initially proved rather difficult, presumably due
to the steric hindrance surrounding the terminal alkene.
However, by slow dropwise addition of a solution of the
second-generation Hoveyda–Grubbs catalyst (10 mol%) to
the reaction mixture, which was maintained at 808C, over
a period of 19 hours the product was obtained in good yield
(67%).[17] Conducting the reaction at ambient temperature,
having the full amount of the catalyst present at the beginning
of the reaction or by adding it in portions gave poor yields of
the cross-metathesis product. These results were suggestive of
a catalyst decomposition pathway that was at least second
order in catalyst concentration.[18] Following hydrolysis of the
methyl ester, which could be isolated in diastereomerically
pure form, macrolactonization of seco-acid 30 was accom-
plished using Yamaguchi conditions giving the hydroxy-
protected macrocycle in 87% yield.[19] All three TBS groups
were then removed by treatment with aq. HF/MeCN/
CH2Cl2,[20] thus giving the target compound, Sch725674 (21)
in 88% yield.
In conclusion, we have demonstrated that 1,2-bis(boronic
esters) derived from the asymmetric Morken/Nishiyama
diboration of terminal alkenes, undergo regio- and stereose-
lective homologation of the primary boronic ester, in the
presence of enantioenriched lithiated carbamates or ben-
zoates, to give stereodefined 1,3-bis(boronic esters), which
can be oxidized to the corresponding 1,3-diol. This merging of
asymmetric diboration with lithiation–borylation overcomes
the long-standing difficulty in homologating b-alkoxy boronic
esters, thus allowing lithiation–borylation to be used for
preparing highly oxygenated target molecules, including
secondary-tertiary 1,3-diols, for which there have been no
generally applicable synthetic routes. We employed this
methodology in a very short (9 steps LLS), high-yielding
and scalable synthesis of Sch725674. The synthesis was
additionally enabled by a novel desymmetrizing diboration
of divinyl carbinols, the products of which should prove to be
highly useful intermediates in synthesis.
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ꢀ
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Acknowledgements
We thank the DFG (postdoctoral fellowship to D.N.), HEC
Pakistan (fellowship to M.A.), EPSRC (EP/1038071/1) and
Bristol University for financial support. We thank Daniel
Blair for valuable discussions, and Paul Lawrence for NMR
assistance.
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Keywords: 1,3-diols · diboration · homologation · lithiation ·
Sch725674
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2016, 688 – 692; b) “The Acetate Pathway: Fatty Acids and
Polyketides”: P. M. Dewick in Medicinal Natural Products: A
Biosynthetic Approach, 2nd ed., Wiley, Chichester, 2002, chap. 3.
[17] The slow addition of metathesis catalysts is often beneficial; for
selected examples, see: a) R. C. Hughes, C. A. Dvorak, A. I.
Meyers, J. Org. Chem. 2001, 66, 5545 – 5551; b) X. Miao, C.
[20] P. A. Evans, J. Cui, S. J. Gharpure, A. Polosukhin, H.-R. Zhang,
J. Am. Chem. Soc. 2003, 125, 14702 – 14703.
Received: August 28, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Selective Homologation
A. Fawcett, D. Nitsch, M. Ali,
J. M. Bateman, E. L. Myers,
V. K. Aggarwal*
&&&& — &&&&
Regio- and Stereoselective Homologation
of 1,2-Bis(Boronic Esters):
Stereocontrolled Synthesis of 1,3-Diols
and Sch725674
All under control: 1,2-Bis(boronic esters),
derived from the enantioselective dibo-
ration of terminal alkenes, undergo
selective homologation of the primary
boronic ester by using enantioenriched
lithiated primary/secondary carbamates/
benzoates to give secondary-secondary
and secondary-tertiary 1,3-diols with full
stereocontrol. The methodology was
applied to a concise total synthesis of the
14-membered macrolactone Sch725674.
6
www.angewandte.org
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!