Total synthesis of (+)-erogorgiaene using lithiation-borylation methodology, and stereoselective synthesis of each of its diastereoisomers

Article abstract of DOI:10.1021/ja207869f

A short (8 steps) synthesis of (+)-erogorgiaene in 44% overall yield from p-methylacetophenone is described. Key steps include lithiation/borylation- protodeboronation to build up the molecule and control the stereochemistry at C1 and C4. The C11 stereoch

Full text of DOI:10.1021/ja207869f

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Total Synthesis of (+)-Erogorgiaene Using LithiationÀBorylation
Methodology, and Stereoselective Synthesis of Each of Its
Diastereoisomers
Tim G. Elford, Stefan Nave, Ravindra P. Sonawane, and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
S Supporting Information
b
We recently reported the lithiation/borylationÀprotodeboro-
ABSTRACT: A short (8 steps) synthesis of (+)-erogor-
giaene in 44% overall yield from p-methylacetophenone is
described. Key steps include lithiation/borylationÀproto-
deboronation to build up the molecule and control the
stereochemistry at C1 and C4. The C11 stereochemistry
was similarly set up by using lithiation/borylation metho-
dology. The use of a mixed, unhindered borane in the
lithiation/borylation reaction proved critical to success in
the reaction of the tetralone-derived carbamate to control
the C4 stereochemistry. The power of the reagent con-
trolled methodology is illustrated in the stereocontrolled
synthesis of all of the diastereomers of (+)-erogorgiaene.
nation (LBP) of secondary carbamates for the stereocontrolled
synthesis of aryldialkylmethines.6 The lithiation/borylation
methodology involves the reaction of lithiated carbamates with
boronic esters, which occurs with retention of configuration, and
with boranes, which react with inversion (Figure 2).7 Precoordi-
nation of the oxygen of the boronic ester with lithium is believed
to be responsible for the delivery of boron with retention. This
leads to tertiary boranes and boronic esters with high enantio-
selectivity. In this paper, we describe the application of this meth-
odology to a short stereocontrolled synthesis of (+)-erogor-
giaene. Furthermore, by targeting all possible diastereoisomers of
the natural product, we demonstrate the broad synthetic utility of
the lithiationÀborylation methodology and the power of reagent
control.
rogorgiaene (1, Figure 1) is a marine diterpene
(+)-Enatural product isolated from the West Indian
sea whip, psueudopterogorgia elisabethae, which shows promis-
ing activity against Mycobacterium tuberculosis H37Rv.1 It is one
member of a family of related bioactive metabolites that have
been isolated from the same marine organism (Figure 1).2
Although erogorgiaene is not complex, the three stereogenic
centers contained in the molecule coupled with the lack of
functional groups proximal to branch points significantly
amplify the synthetic challenge. Nevertheless, the total synth-
esis of erogorgiaene has been reported by Hoveyda,3 Davies,4
and Yadav5 in 11 to 18 steps. In these approaches, functional
groups are often added to enable key disconnections to be
made, which inevitably leads to additional steps. For step
economy, it would be preferable to disconnect the molecule
directly at branch points, without the addition of functional
groups elsewhere.
Figure 2. Lithiation/borylation with boronic esters and boranes leading
to opposite enantiomers.
In our retrosynthetic analysis, and using the lithiation/
borylationÀprotodeboronation reaction as a key step, disconnec-
tion of the C4ÀC11 bond led us back to the trans carbamate
4 and borane 5 or the cis carbamate 6 and the boronic ester 7
(Figure 3). We were aware that this step would be challenging,
since tetralone-derived carbamates always gave the lowest dia-
stereoselectivity of all of the carbamates we have explored,8 and
we therefore wanted to keep both options open. The required
boron reagent could be obtained directly using our lithiation/
borylation reaction of primary carbamates.9 Carbamates 4 and 6
can both be derived from ketone 8 using Noyori reduction,10
which itself could be obtained from ester 9. Ester 9 could be
accessed through another LBP of carbamate 10 with the com-
mercially available boronic ester 11.
Received: August 19, 2011
Figure 1. Erogorgiaene and other closely related natural products
isolated from the West Indian sea whip.
Published: September 21, 2011
r
2011 American Chemical Society
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Figure 3. Retrosynthetic analysis of (+)-erogorgiaene.
Figure 4. Model studies of tetralone-based carbamates and their
selectivity in lithiation/borylation reactions.
Scheme 1. Synthesis of Key Carbamates 4 and 6
diastereoselectivity (>99:1 er, 98:2 dr in both cases). Finally,
carbamoylation of these two alcohols provided the desired carba-
mate fragments 4 and 6.
Before we embarked on the final LBP reaction, we decided to
investigate a model reaction with simpler isopropyl boron
reagents. Previously, we had found that carbamate 15 reacted
with high er with unhindered ethylboronic acid glycol ester
(9:91) or Et3B (95:5), while ethylboronic acid pinacol ester
gave a 20:80 ratio of enantiomers (Figure 4).7 Unfortunately,
reaction of carbamate 15 with isopropylboronic acid glycol
ester gave a 50:50 ratio of enantiomers. These results high-
lighted the problems associated with tetralone-derived carba-
mates and their reactions with boronic esters bearing hindered
substituents. This was further borne out in our additional model
studies.
Unsurprisingly, reaction of carbamate 6 with isopropylboronic
acid pinacol ester or the less hindered isopropylboronic acid
glycol ester gave an ∼1:1 ratio of diastereomers (Figure 4, eqs 1, 2).11
We therefore turned to boranes where higher selectivity had been
observed (e.g., 15 with Et3B). However, reaction of carbamate 4with
B-iPr-9-BBN gave similarly poor dr (Figure 4, eq 3). We clearly
required a much less hindered borane and considered the use of
iPrBMe2, but the issue of which of the three groups would
migrate was a concern. Although sterically hindered groups
(e.g., thexyl) have been used as nonmigrating groups in reac-
tions of boranes, occasionally very small groups (e.g., Me) have
too.12,13 Furthermore, we had found that in reactions of primary
lithiated carbamates with boronic esters, MeBpin reacted con-
siderably more slowly than EtBpin.13b
Our synthesis began by Noyori reduction of p-methylaceto-
phenone, which gave the alcohol in 99% yield and 99:1 er,
followed by carbamoylation with N,N-diisopropylcarbamoyl
chloride (CbCl) to furnish carbamate 10 (Scheme 1). Treatment
with s-BuLi, followed by addition of boronic ester 11, furnished
tertiary boronic ester 12, which was subsequently treated
with TBAF to give ester 9 with complete retention of stereo-
chemistry in high yield. Treatment with polyphosphoric acid
(PPA) gave ketone 8, which was reduced with either the (S,S)- or
(R,R)-Noyori catalyst to give the corresponding trans and cis
alcohols 13 and 14 in high yield and essentially complete
i
Mixed borane PrBMe2 was therefore prepared as shown in
eq 5, simply by the addition of 2 equiv of MeMgBr to the pinacol
ester,14 and employed in the lithiation/borylation reaction.
Following protodeboronation with TBAF,15 product 17 was
obtained with a 81:19 dr (Figure 4, eq 4). As expected, exclusive
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migration of the isopropyl group over the methyl groups was
observed. Purification led to a 81:19 mixture by 1H NMR of the
trans and cis diastereomers of the natural product, calamenene
(17), which were identical to that reported previously.16 The
synthesis of trans-calamenene as the major diastereomer con-
firmed that reaction of the lithiated carbamate with the borane
occurred with inversion of stereochemistry7 and that protode-
boronation occurred with retention of stereochemistry.15
With this result, we continued in our pursuit of the natural
product (+)-erogorgiaene. The required borane was prepared as
shown in Scheme 2. Thus, lithiation of N,N-diisopropyl ethyl-
carbamate (EtOCb) in the presence of O’Brien’s (+)- sparteine
surrogate17 followed by addition of homoallylboronic ester 18
gave boronic ester (S)-19. The boronic ester was converted into
mixed dimethyl borane (S)-20, as before, by treatment with 2
equiv of MeMgBr.14
Scheme 4. Synthesis of C-4 Epimer 22 and C-4/C-11
Diepimer 23 of Erogorgiane
lithiated carbamate derived from 4 with (R)-20 as before gave
C-11 epi-erogorgiaene 21 as a 9:1 ratio of diastereomers, which, after
purification, provided pure 21 in 78% yield (Scheme 3). In a similar
fashion, reaction of cis carbamate 6 with boranes (S)-20 and (R)-20
gave C-4 epi-erogorgiane18 22 and C-4/C-11 diepi-erogorgiane18
23 as a 14:1 and 19:1 mixture of diastereomers, respectively
(Scheme 4). These results indicate that the stereochemical outcome
of the key lithiation/borylation reaction of the tetralone-derived
carbamate is not significantly affected by the pre-existing stereogenic
centers in either the carbamate (at C1) or the borane (i.e., minimal
matched and mismatched stereochemical effects), only by the
nature and steric hindrance of the boron reagent.
Scheme 2. Synthesis of Mixed Boranes (S)- and (R)-20
In summary, we have described an 8 step synthesis of (+)-
erogorgiaene in 44% overall yield using lithiation/borylation
methodology to control all three stereogenic centers. The use
of mixed, unhindered boranes in the lithiation/borylation reac-
tion proved pivotal to success due to the sometimes low
selectivity of the tetralone-derived carbamates toward boronic
esters. Also noteworthy is the finding that TBAF, which had been
previously used for stereoselective protodeboronation of tertiary
boronic esters, is also suitable for tertiary boranes. In addition,
the utility of the methodology is illustrated in the stereocon-
trolled synthesis of not only (+)-erogorgiaene but also each of
the remaining diastereomers, all of which proceeded with equal
ease and high yield and high selectivity. This illustrates the power
of reagent controlled methodology, especially when it dominates
so completely over substrate control. The brevity of the synthesis
stems from exploiting strategic disconnections at branch points,
which eliminate the need for additional functional group manip-
ulations, redox processes, and protecting groups.
Borane (S)-20 was not isolated but directly added to the
lithiated carbamate derived from 4 (Scheme 3). Again without
isolation, direct treatment of the reaction mixture with TBAF
furnished crude 1 as a 13:1 mixture of diastereomers, as analyzed
by GC/MS. Purification by flash chromatography led to pure
(+)-erogorgiaene (1) in 73% yield. The synthetic material was
identical in all respects to previously reported data for (+)-1. The
asymmetric synthesis of the natural product was thus completed
in just 8 steps from p-methylacetophenone and 44% overall yield,
with high levels of stereocontrol over the three stereogenic
centers.
Scheme 3. Synthesis of (+)-Erogorgiaene (1) and C-11 Epi-
mer 23
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
analytical data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
v.aggarwal@bristol.ac.uk
’ ACKNOWLEDGMENT
The power and potential of this methodology is further illustrated
in the stereoselective preparation of all possible diastereomers of 1.
Thus, borane (R)-20 was prepared using (À)-sparteine in the
lithiationÀborylation reaction (Scheme 2). Treatment of the
We thank EPSRC and the European Research Council (FP7/
2007-2013, ERC Grant No. 246785) for financial support. V.K.A.
thanks the Royal Society for a Wolfson Research Merit Award
16800
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and EPSRC for a Senior Research Fellowship. S.N. thanks the
DFG for a research fellowship. We thank Inochem-Frontier
Scientific for the generous donation of boronic acids and boronic
esters.
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42, 1361–1366. (h) Kim, Y. K.; Cool, L. G.; Zavarin, E. Phytochemistry
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