Stereocontrolled synthesis of adjacent acyclic quaternary-tertiary motifs: Application to a concise total synthesis of (-)-filiformin

Article abstract of DOI:10.1002/anie.201400944

Lithiation/borylation methodology has been developed for the synthesis of acyclic quaternary-tertiary motifs with full control of relative and absolute stereochemistry, thus leading to all four possible isomers of a stereodiad. A novel intramolecular Zweifel-type olefination enabled acyclic stereocontrol to be transformed into cyclic stereocontrol. These key steps have been applied to the shortest enantioselective synthesis of (-)-filiformin to date (9 steps) with full stereocontrol. True to (fili)form: Lithiation/borylation methodology has been developed for the synthesis of acyclic quaternary-tertiary motifs with full control of relative and absolute stereochemistry, thus leading to all four possible isomers of a stereodiad. A novel intramolecular Zweifel-type olefination enabled acyclic stereocontrol to be transformed into cyclic stereocontrol. These key steps were applied to the enantioselective synthesis of (-)-filiformin.

Full text of DOI:10.1002/anie.201400944

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DOI: 10.1002/anie.201400944
Synthetic Methods
Stereocontrolled Synthesis of Adjacent Acyclic Quaternary-Tertiary
Motifs: Application to a Concise Total Synthesis of (À)-Filiformin**
Daniel J. Blair, Catherine J. Fletcher, Katherine M. P. Wheelhouse, and Varinder K. Aggarwal*
Abstract: Lithiation/borylation methodology has been devel-
oped for the synthesis of acyclic quaternary-tertiary motifs with
full control of relative and absolute stereochemistry, thus
leading to all four possible isomers of a stereodiad. A novel
intramolecular Zweifel-type olefination enabled acyclic ste-
reocontrol to be transformed into cyclic stereocontrol. These
key steps have been applied to the shortest enantioselective
synthesis of (À)-filiformin to date (9 steps) with full stereo-
control.
dialed in. However, whilst acyclic stereocontrol can be
straightforward for many substrates, for molecules bearing
quaternary-tertiary motifs this poses a considerable synthetic
challenge.
Our recent methodology for acyclic stereocontrol[2]
involves the reaction of primary/secondary lithiated carba-
mates with boronic esters and its potential strategic applica-
tion in the synthesis of cyclic quaternary-tertiary motifs is
illustrated in Scheme 1. In this strategy we proposed to carry
N
atural products containing quaternary stereogenic centers
flanked by additional stereogenic centers, often embedded in
fused or bridged ring systems, are ubiquitous in nature
(Figure 1). Their varied structures and complexity have
Scheme 1. Proposed route to all-carbon quaternary stereocenters with
adjacent stereocenters. Cb=CON(iPr)2, pin=pinacolato, (À)-sp=
(À)-sparteine.
out sequential homologations with a secondary carbamate
(step 1)[3] followed by a primary carbamate (step 2)[4] to
construct quaternary-tertiary boronic esters. We then pro-
posed to carry out an intramolecular Zweifel-type olefina-
tion[5] reaction (step 3) to construct the ring. Steps 2 and 3,
which are key to this strategy, had not been previously
reported. Herein we describe our success in developing these
reactions and applying them to a short, stereocontrolled
synthesis of (À)-filiformin.
Figure 1. Natural products featuring adjacent quaternary-tertiary
stereocenters.
Our initial studies began with the homologation of the
tertiary boronic ester rac-1 with lithiated carbamate rac-2
which was generated by deprotonation of ethyl carbamate
with sBuLi at À788C in the presence of TMEDA (Scheme
2a). After oxidation rac-3 was isolated in 53% yield and 2:1
stimulated a range of synthetic strategies for their synthesis.[1]
A common strategy in many syntheses is to initially construct
the ring(s) and then to use the ring system to control
stereochemistry around its periphery. Whilst often efficient,
this strategy can be limiting as it is based on substrate control.
A potentially more flexible, but underutilized strategy
involves constructing an acyclic molecule with control of
stereochemistry through reagent control and then to build the
ring afterwards. In this way, stereocontrol can be essentially
[*] D. J. Blair, Dr. C. J. Fletcher, 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
Dr. K. M. P. Wheelhouse
GlaxoSmithKline UK LtD
Gunnels Wood Road, Stevenage, Herts, SG1 2NY (UK)
[**] We thank the EPSRC, GSK, and the European Research Council
(FP7/2007-2013, ERC grant no. 246785) for financial support.
Scheme 2. a) Racemic homologation of rac-1. b) Homologation of
1 with enantioenriched reaction partners and proposed mechanism for
formation of diastereoisomers.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400944.
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d.r., thus showing that there were no appreciable matched/
mismatched effects.
entry 2). As an alternative, we sought to trap the anion 6 as it
was formed with an electrophile, thus preventing its re-
addition to the boronic ester (Table 1, entries 2–5). Of the
electrophiles tested allyl bromide proved to be highly
effective, thus leading to 5 in high d.r. and e.r. (entry 5). The
relative stereochemistry of 5 was determined by X-ray
crystallography.[7]
However, the yield was only moderate (48%) and fell
further (32%) when we attempted to synthesize the other
diastereoisomer of 5 by using OꢀBrienꢀs (+)-sparteine surro-
gate [(+)-sps][8] in place of (À)-sparteine in the lithiation step
(Table 1, entry 6). We reasoned that the bulky diamine was
inhibiting the addition process and therefore explored
diamine-free conditions [generating the organolithium 10a
by tin–lithium exchange of the corresponding stannane 9a] to
make the carbanion less hindered.[9] This led to a considerably
higher yield (73%; Table 1, entry 7). The stannanes 9a and 9b
were easily obtained in high e.r. as shown in Scheme 3.[10]
When we carried out the reaction with the enantioen-
riched boronic ester 1 and enantioenriched lithiated carba-
mate 2 we were expecting to selectively form a single
diastereomeric ate complex 4 which should then rearrange
to give the single diastereomer 5 (Scheme 2b). However,
when we carried out this reaction we obtained 5 together with
8 in a ratio of 88:12, albeit with perfect e.r. (Table 1, entry 1).
Table 1: Optimization of conditions for the homologation of the tertiary
boronic ester 1 with 2/10a.
Entry Carbamate Quench d.r.[a]
e.r.[b]
Yield [%][c]
1
2
2
2
2
88:12 (5/8)
88:12(5/8)
98:2 (5/ent-8) >99:1 28
98:2(5/ent-8) >99:1 22
>99:1 n.d.
n.d. n.d.
2[d]
3
MeOH
MgBr2/
MeOH
AllylBr
AllylBr
AllylBr
4
5
6
7
2
98:2 (5/ent-8) >99:1 48
1:99 (5/ent-8) >99:1 32[f]
98:2 (5/ent-8) >99:1 73
ent-2[e]
10a
[a] Determined by GCMS. [b] Determined by HPLC using a chiral
stationary phase. [c] Yield of isolated 5. [d] Neopentyl glycol boronic ester
used. [e] (+)-sparteine surrogate used in place of (À)-sparteine. [f] Yield
of isolated ent-8.
Scheme 3. Preparation of diamine-free lithiated carbamates 10a and
10b. OCbx=3,3-dimethyl-1-oxa-4-azaspiro[4.5]decane-4-carboxylate,
(+)-sps=(+)-sparteine surrogate.
It was unclear at this point which of the two stereogenic
centers was epimerizing, and so further experiments were
conducted. Thus, the enantioenriched lithiated carbamate 2
was reacted with rac-1 and vice versa. Oxidation and analysis
of the secondary alcohol products by HPLC using a chiral
stationary phase enabled us to map the fate of each
stereogenic center individually during the homologation
process (see the Supporting Information). From these experi-
ments we determined that partial racemization had occurred,
not in the sensitive organolithium 2 bearing the secondary
center which is undergoing significant transformations, but at
the static quaternary stereogenic center derived from the
boronic ester, thus leading to the minor diastereoisomer 8.
The mechanism for its formation is shown in Scheme 2b.
After formation of the boronate complex 4, 1,2-metallate
rearrangement will give the major isomer 5. If this rearrange-
ment is slow, competing fragmentation to the benzylic
carbanion 6 can occur. Racemization of 6, re-addition to
boronic ester 7, and rearrangement then leads to the minor
diastereoisomer 8. In support of this mechanism, 7 was also
isolated in high e.r..
With these optimum reaction conditions we moved on to
synthesize the remaining three stereoisomers (Scheme 4).
Reaction of the enantiomer of the lithiated carbamate 10b
with 1 gave alcohol ent-8 in 99:1 d.r. and greater than 99:1 e.r.
Reaction of the opposite enantiomer of the boronic ester ent-
1 with the pair of lithiated carbamates 10a and 10b gave the
remaining isomers of the series in good yield and with
essentially perfect stereocontrol (Scheme 4). It is interesting
to note that even in the mismatched cases (forming 5 and ent-
5) very high diastereocontrol (> 97:3) was still observed.
We then sought to apply our methodology to a total
synthesis of the sesquiterpene (À)-filiformin. Disconnecting
the phenol ether of debromofiliformin leads back to 3-
hydroxylaurene (11), which itself could potentially be
obtained from an intramolecular Zweifel-type olefination of
12 (Scheme 5). This key intermediate could be synthesized
using the above methodology through reaction of 10a with
the tertiary boronic ester 13. The boronic ester 13 could in
turn be prepared by a lithiation/borylation of the known
carbamate 14 and primary boronic ester 15.
In an attempt to reduce the undesired fragmentation of 4
the less hindered neopentyl glycol boronic ester was tested,
since related neopentyl boronate complexes have been shown
to be less prone to reversibility than the corresponding
pinacol boronates.[3a,6] However, homologation of neopentyl-
1 gave similar results to that of the pinacol ester (Table 1,
The boronic ester 15 was prepared from bromomethyl
boronic acid pinacol ester and 2,3-dibromo-1-propene to give
15 in 81% yield using a procedure described by Knochel
(Scheme 6).[11] The carbamate 14 was prepared in three steps
starting from 2’-hydroxy-4’-methyl acetophenone as previ-
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Scheme 4. Homologation of tertiary boronic esters with lithiated carbamates under diamine-free conditions to produce adjacent quaternary-
tertiary stereocenters. Reactions were performed on 1 mmol of 1/ent-1 using 1.5 mmol of 10a/10b.
Scheme 5. Retrosynthetic analysis of (À)-filiformin.
ously described.[2d] The lithiation/borylation of 14 with 15
proceeded smoothly to give 13 in 78% yield with complete
enantioselectivity.
The tertiary boronic ester 13 is especially hindered
Scheme 6. Total synthesis of (À)-filiformin. TFA=trifluoroacetic acid.
because of the ortho-methoxy group and the long alkyl
chain so formation of the boron ate complex was expected to
be even more challenging than in the model system. Never-
theless, under our optimized reaction conditions using 10a we
were able to obtain 12 in 45% yield with 98:2 d.r. and in
perfect e.r..[12] Using the reaction conditions shown in entry 5
of Table 1, no product was obtained, thus highlighting the
advantages of the diamine-free conditions with especially
hindered substrates.
steps. Finally, bromination completed the synthesis of (À)-
filiformin in a total of just nine steps, 98:2 d.r., and > 99:1 e.r.
The analytical data was identical to that of the natural (À)-
filiformin in all respects.[14]
In conclusion we have developed lithiation/borylation
methodology for the construction of highly challenging
quaternary-tertiary motifs in acyclic systems with full control
of relative and absolute stereochemistry. Key to its success
was the use of diamine-free lithiated carbamates to promote
the addition step and allyl bromide to quench any benzylic
carbanions formed during the 1,2-metallate rearrangement. A
unique intramolecular Zweifel-type olefination enabled acy-
clic stereocontrol to be transformed into cyclic stereocontrol.
These key steps were applied to the shortest enantioselective
synthesis of (À)-filiformin (9 steps), the previous being 19
steps.[15]
We then sought to perform the intramolecular Zweifel-
type olefination of 12. Addition of tBuLi to a solution of 12 in
THF at À788C and subsequent addition of I2 in MeOH gave
the cyclopentene 16 in 97% yield and 100% enantiospeci-
ficity (Scheme 6). The exceptionally high yield in this reaction
prompted us to explore the more challenging intramolecular
Zweifel-type olefination of 13 as this would lead to a highly
strained exomethylene cyclobutane. We were pleased to find
that application of the same conditions to 13 gave 17 in 63%
yield, again with complete selectivity (Scheme 6).
Deprotection of the methyl ether using NaSEt[13] gave 3-
hydroxylaurene (11) and subsequent addition of catalytic
amounts of TFA[14] led to clean cyclization to give debromo-
filiformin as a single diastereoisomer in 60% yield over two
Received: January 28, 2014
Published online: April 22, 2014
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