Total Synthesis of C30 Botryococcene and epi-Botryococcene by a Diastereoselective Ring Opening of Alkenylcyclopropanes

Article abstract of DOI:10.1002/anie.201808709

Trialkylaluminum compounds perform a diastereoselective 1,6-ring fragmentation of alkenylcyclopropane. This new tool allows the preparation of hydrocarbon compounds containing two distant stereocenters with a good diastereocontrol. Inspired by the biosynthesis of botryococcene this methodology was applied successfully to the diastereo- and enantioselective preparation of this triterpene and its epimer.

Full text of DOI:10.1002/anie.201808709

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Accepted Article
Title: Total Synthesis of C30 Botryococcene and epi-Botryococcene via
a Diastereoselective Ring Opening of Alkenylcyclopropanes
Authors: Ilan Marek, Morgane Cormier, and Aurelien de la Torre
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808709
Angew. Chem. 10.1002/ange.201808709
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10.1002/anie.201808709
Angewandte Chemie International Edition
COMMUNICATION
Total Synthesis of C30 Botryococcene and epi-Botryococcene via
a Diastereoselective Ring Opening of Alkenylcyclopropanes
Morgan Cormier, Aurélien de la Torre and Ilan Marek*
Dedication ((optionnal))
Abstract: Trialkylaluminum compounds perform a diastereoselective 1,6-
ring fragmentation of alkenylcyclopropane. This new tool allows the
preparation of hydrocarbon compounds containing two distant
stereocenters with a good diastereocontrol. Inspired by the biosynthesis of
botryococcene this methodology was applied successfully to the diastereo-
and enantioselective preparation of this triterpene and its epimer.
The complex structure of bioactive natural products has
constantly stimulated the creativity of organic chemists providing
novel and more efficient strategies to perform synthesis.[1] In this
context, biomimetic-based approaches represent one of the most
powerful strategies to tackle synthetic problems related to
complex natural product synthesis as it tend to follow the model of
Nature.[2] For instance, the biosynthesis of the triterpene
botryococcene 1, isolated from Botryococcus braunii, an ancient
microalgae dating back 500 million years ago, starts with a self-
condensation of farnesyl diphosphate (FPP) to form presqualene
diphophate 2 (PSPP) (Scheme 1a).[3] The key intermediate 2,
Scheme 1. a) Biosynthesis of botryococcene b) Proposed transformation
also involved in the synthesis of squalene, contains a stable
cyclopropyl motif which further undergoes a ring-opening via a
reductive rearrangement initiated by NADPH to yield the natural
product botryococcene 1. The synthesis of this triterpene received
a particular attention from the scientific community due to its
attractive potential to produce renewable petrochemicals and
catalytic steps from an alkyne by an enantioselective Rh-
biofuels,[4] and various total syntheses have been completed,[5]
As far as the easy and straightforward preparation of the
starting material was concerned, we have recently reported the
preparation of cyclopropenylcarbinol 3a (LG = OH) in only two
catalyzed decomposition of diazoester followed by
a
the last one being elegantly achieved by Aggarwal in excellent
diastereo- and enantioselectivity.[6] However, none of the previous
syntheses took inspiration from the biosynthetic pathway of the
natural product. Our research group has been interested in the
diastereo- and enantioselective preparation of polysubstituted
three-membered rings[7] as well as their selective ring opening[8]
as a new tool to prepare stereocontrolled acyclic molecules
possessing quaternary carbon stereocenters.[9] We therefore
hypothesized that a properly substituted alkenylcyclopropane ring
3 could serve as a mimic for the biosynthesis of 1. Although ring-
opening of donor-acceptor cyclopropanes are well developed,[10]
the reaction on non-functionalized alkenylcyclopropane as
described in Scheme 1b had no precedent and required the
development of a new, robust and efficient strategy. The
proposed approach targets the general preparation of 1,4-dienyl
hydrocarbons (only composed of C and H bonds) containing two
stereocenters in a 1,4-relationship, including a quaternary carbon
stereocenter. Although the proposed sequence is very appealing,
the formation of diene 4 from alkenylcyclopropane 3 with a high
diastereoselective Cu-catalyzed carbomagnesiation followed by a
Pd-catalyzed cross-coupling reaction and in-situ reduction
(Scheme 2).[11] By a simple protection of the alcohol, the
substrates bearing a leaving group were easily obtained as single
diastereoisomers. Among all leaving group tested (see Table S1
in the supplementary informations) only phosphonate 3b, known
to have the right balance between reactivity and stability, gave a
result. It should be noted that the use of chiral ligand for the [2+1]-
cycloaddition reaction between the alkyne and diazoester
provides the cyclopropenyl ester in excellent enantiomeric
ratios.[12] Inspired by Miyaura’s report on the 1,6-addition of
alkylcuprate on simple 1-acyl-2-vinylcyclopropanes[13] we started
our study by using organocuprates as a source of nucleophiles.
However, all alkylcuprates tested were not efficient to promote the
ring opening of 3b, the starting material being quantitatively
recovered whatever the reaction conditions used (Scheme 2a),
underlining the large difference of reactivity between
vinylcyclopropyl ketone and 3b. To increase the overall reactivity,
we combined the organocuprate with a Lewis acid (LA, see
supporting information for full details). Under these conditions, the
starting material 3b was totally consumed, but a mixture of
different regioisomers including 4a (yield <10 %, dr = 1:1) was
obtained in various proportions (Scheme 2a). From these
experiments, it became clear that the 1,6-substitution product
could only be formed by using the combination of Lewis acid and
nucleophile. Therefore, we were interested to combine both
diastereoisomeric ratio should promote (i)
a regioselective
nucleophilic displacement at carbon C6, in the presence of two
additional electrophilic carbon centers (namely carbon C1 and C4
as described in Scheme 1); (ii) a diastereoselective process at the
newly created sp3-stereocenter; (iii) an easy and straightforward
preparation
of
the
diastereoisomerically
pure
and
enantiomerically enriched stereodefined alkenylcyclopropanes 3.
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10.1002/anie.201808709
Angewandte Chemie International Edition
COMMUNICATION
properties (nucleophilicity and Lewis acidity) by using a single
organometallic species hoping to further improve the reactivity as
well as the regio- and diastereoselectivity of the whole process.
Organoaluminum compounds (AlR3) possessing a polar C-Al
bond but also high Lewis acidity property was the perfect
candidate to perform this transformation (Scheme 2b).[14,15] In this
case, addition of AliBu3 in non-polar solvent at -40 °C led to the
unique 1,6-nucleophilic displacement product 4a in excellent
isolated yields with a decent diastereoselectivity.
Scheme 2. Metal-mediated 1,6-substitution on 3b.
Higher diastereoisomeric ratios could eventually be
obtained at lower temperature but at the expense of yields.
Different solvents as well as different leaving groups were tested
(for a full description, see supporting information) but the best
experimental condition remained the one summarized in Scheme
2b. Having these conditions in hand, we started to evaluate the
scope of the reaction with the pure (Z)-vinylcyclopropanes
substrates 3a-g. Using first AliBu3 as standard nucleophile, the
results were remarkably constant. The 1,6-ring opening products
4a-g were always obtained selectively in good yields (75% to
89%) with
a
unique (E)-stereoselectivity and with
a
diastereoselectivity ranging from 82:18 to >20:1.[16] It should be
noted that changing the nature of the vinylic substituent R2 (i.e 3d,
R2 = Bu) doesn’t affect the selectivity of the transformation
Scheme 3. Scope of 1,6-substitution with (Z)-vinylcyclopropane derivatives 3a-
a more sterically hindered
g.
(formation of 4d). Remarkably,
quaternary carbon (3c, R1 = Hex, Bu) dramatically enhanced the
diastereoselectivity and only one diastereoisomer of 4c was
When vinylcyclopropanes 3h,i having a (E)-double bond were
detected. Similar results were found with AlEt3 as a nucleophile, evaluated under our optimized conditions (Scheme 4), 4o and 4p
allowing the addition of ethyl group regioselectively (yields from were obtained in 90% and 64% yield respectively, still as a single
75% to 88%) with similar satisfactory diastereocontrol (dr 82:18 to E-isomer, but with a lower diastereoselectivity (dr 74:26 and 1.6:1
>20:1) for the formation of the products 4h-m. Interestingly, the respectively). Moreover, when the reaction was performed on
smallest nucleophile AlMe3 proceeds also efficiently and gave the trisubstituted olefin 3j, 4q possessing two challenging quaternary
product 4n in excellent 80% yield albeit with
a
lower carbon stereocenters in a 1,4-relationship was obtained in good
yield (83%) but still with a poor diastereoselectivity (dr 1.8:1). The
same trend was found when the Z-styrenyl cyclopropane 3k was
treated in our conditions; the product 4r was obtained in good
yield but with a low diastereoselectivity (Scheme 4).
diastereoselectivity (dr 82:18). This last result paves however the
way for the preparation of terpenic structures such as
botryococcene.
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10.1002/anie.201808709
Angewandte Chemie International Edition
COMMUNICATION
4q (Scheme 4), the low diastereoisomeric ratio could be
rationalized by the combination of a low nucleophilic reactivity
(reaction of disubstituted double bond) and formation of a more
stable tertiary and planar carbocationic species (IV into V). To
corroborate our hypothesis, the reaction of 3k, possessing a Z-
styrenyl backbone was tested and as expected, 4r was obtained
with
a
very low diastereoselectivitiy suggesting again a
carbocationic pathway. Having developed this new synthetic
protocol based on our straightforward synthesis of starting
materials, we applied our strategy to the synthesis of
botryococcene and epi-botryococcene. The synthesis of the latter
started by the formation of cyclopropene 6, through a (2+1)
cycloaddition reaction between a-diazo ethylacetate and terminal
alkyne 5, easily obtained from geranyl bromide. Cyclopropene 6
underwent the one-pot copper-catalyzed carbometalation–
transmetallation–palladium-catalyzed cross-coupling reaction with
Scheme 4. Other examples
alkenyl iodide 7.[11]
I
To rationalize the dichotomy between the results from the E and
Z-olefin on the diastereoselectivity of the reaction, we propose the
following mechanistic explanations (Scheme 5). From the two
possible conformers s-trans I and s-cis II, and assuming that both
possess similar reactivity, it is apparent that s-cis II generates
more steric interactions between the alkenyl group and the
CH2OPO(OEt)2 moiety. This equilibrium might even be more
displaced towards s-trans I for the Z-isomer than for the E-isomer,
explaining why the selectivity is better in the former case than in
the latter one.
7
1. NIS, AgNO3
Br
2. BH3.DMS, cyclohexene
Mg, HgCl2
Br
H
5
Rh2(OAc)4
N2CHCO2Et
O
OEt
6
XR = OP(O)OEt2
R4
R3
RX
R2
R1
XR
H
R4
R3
1. MeMgBr, CuI (15 mol%)
then ZnBr2, then 7, Pd(PPh3)4 (10 mol%)
2. DIBAL-H
More carbocationic
behavior
(R5)3Al
R2
R1
3. ClPO(OEt)2, Et3N, DMAP
H
OPO(OEt)2
R3, R4
H
R
X
I
II
Al(R5)3
R4
(R5)3Al
R4 = H
Me
δ+
R2
3l
dr >98:2:0:0
R3
R
Al(R5)3
R1
Me3Al,
pentane, -40 ºC
H
Me
IV
X
R3
R2
R1
R4
+
Me
R3
R5
epi-botryococcene
R5
66%
R1 R2
Observed
H
dr 4:1
R1 R2
III
V
Me
low selectivity
Me3Al,
pentane, -40 ºC
Me
Botryococcene
80%
+
OPO(OEt)2
Ph
dr 3:1
er 91:9
Bu Me
VI
Stable benzylic carbocation
Scheme 5. Proposed mechanism
Me
3m
dr >98:2:0:0
er 91:9
MgBr
1. CuI (15 mol%)
Knowing the absolute configuration of our starting
materials and of the final products (determined during the
synthesis of botryococcene), we could deduce that Al(R5)3 plays
the expected dual role of Lewis acid activation of the
phosphonate, and of the nucleophilic species introducing the alkyl
group from the same face of the phosphonate as described in III.
However, the diastereoselectivity resulting from this subtle
balance of “concerted” mechanism of activation-nucleophilic
displacement depicted in III could be disfavored to more
then ZnBr2, then 7, Pd(PPh3)4 (20 mol%)
2. DIBAL-H
3. ClPO(OEt)2, Et3N, DMAP
CO2Et
Me
8
er 91:9
Scheme 6. Total synthesis of botryococcene and epi-
carbocationic species if the substrate would (i) better stabilize botryococcene.
cationic entities and (ii) react slowly for the nucleophilic addition.
For instance, when the reaction was performed on 3j leading to
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10.1002/anie.201808709
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COMMUNICATION
Devarenne, J. Chappell, J. Biol. Chem. 2012, 287, 8163-8173. h) S. A.
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Reduction of the alkenylcyclopropane using DIBAL-H
followed by the introduction of the phosphonate leaving group,
finally provided the cyclopropane 3l necessary for the key ring
opening reaction. Using our optimized conditions, 3l underwent
the diastereoselective 1,6-nucleophilic fragmentation to afford
epi-botryococcene with a diastereoselectivity of 4;1 in only 6
linear steps. The synthesis of botryococcene 1 required the
preparation of cyclopropane 3m, easily obtained as single
diastereoisomer by the same combined copper-catalyzed
carbometalation reaction followed by the Pd-catalyzed cross
coupling and reduction on the methyl-substituted cyclopropene 8.
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the
alkenylcyclopropane
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underwent
our
diastereoselective ring-opening reaction, affording botryococcene
1 with a diastereoselectivity of 3:1 and enantiomeric ratio of 91:9.
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To conclude, we developed a novel approach for the
preparation of acyclic hydrocarbons bearing one quaternary and
one tertiary stereocenter in a 1,4-relationship. The method is
based on the diastereoselective biomimetic ring-opening of
cyclopropane methanol derivatives by the use of ambiphilic
organoalane nucleophiles. The strategy was then applied to the
total synthesis of botryococcene and epi-botryococcene.
[9]
Acknowledgements
This research was supported by a grant from the European
Research Council (ERC Grant Agreement 338912). IM is holder
of the Sir Michael and Lady Sobell Academic Chair.
Keywords: botryococcene • carbometalation • ring-opening •
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established the configuration though the synthesis f the natural product.
[17] Enantioselectivity measured by chiral HPLC after derivatization of the
cyclopropanol resulting from the carbometallation/coupling/reduction
sequence: e.r = 91:9
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Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
OPO(OEt)2
M. Cormier, A. de la Torre, I. Marek*
Me
Me
Page No. – Page No.
Me3Al,
pentane, -40 ºC
dr >98:2:0:0
er 91:9
Me
Botryococcene
80%
Title
dr 3:1
er 91:9
We developed a novel approach for the preparation of acyclic hydrocarbons
bearing one quaternary and one tertiary stereocenter in a 1,4-relationship. The
method is based on the diastereoselective biomimetic ring-opening of cyclopropane
methanol derivatives by the use of ambiphilic organoalane nucleophiles. The
strategy was applied to the total synthesis of botryococcene and epi-botryococcene
This article is protected by copyright. All rights reserved.