Asymmetric conjugate addition of alkylzirconium reagents to α,β-unsaturated thioesters: Access to fragrances and acyclic stereochemical arrays

Article abstract of DOI:10.1039/c7cc05433e

Copper-catalyzed asymmetric conjugate addition of alkylzirconium species to α,β-unsaturated thioesters is reported. A variety of functionalized alkyl nucleophiles were introduced with yields around 70% and ee's over 92%. The method was applied to the straightforward syntheses of the commercially important fragrances phenoxanol (both enantiomers 97% ee), and hydroxycitronellal (98% ee). The 1,4-addition products can be converted to enantiomerically enriched linear building blocks bearing a terminal functional group. Formation of further α,β-unsaturated thioesters provides an iterative route for the stereocontrolled synthesis of functionalized acyclic arrays and we demonstrate almost complete catalyst control in the formation of additional stereocentres.

Full text of DOI:10.1039/c7cc05433e

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Z. Gao and S. P.
Fletcher, Chem. Commun., 2017, DOI: 10.1039/C7CC05433E.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 5
View Article Online
DOI: 10.1039/C7CC05433E
Journal Name
COMMUNICATION
Asymmetric Conjugate Addition of Alkylzirconium Reagents to
α,β-Unsaturated Thioesters: Access to fragrances and acyclic
stereochemical arrays
Received 00th January 20xx,
Accepted 00th January 20xx
Zhenbo Gao and Stephen P. Fletcher*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Copper-catalyzed asymmetric conjugate addition of alkylzirconium
Here we report ACA of alkylzirconium species to unsaturated
species to α,β-unsaturated thioesters is reported. A variety of thioesters with high yield and excellent stereocontrol. The
functionalized alkyl nucleophiles were introduced with yields products readily undergo C-S bond cleavage to provide
around 70% and ee’s over 92%. The method was applied to the enantioenriched linear building blocks. The procedure
straightforward syntheses of the commercially important tolerates various functional groups and is applied to the
fragrances phenoxanol (both enantiomers 97% ee), and synthesis of two commercially used fragrances. The method
hydroxycitronellal (98% ee). The 1,4-addition products can be
converted to enantiomerically enriched linear building blocks
bearing a terminal functional group. Formation of further α,β-
unsaturated thioesters provides an iterative route for the
stereocontrolled synthesis of functionalized acyclic arrays and we
demonstrate almost complete catalyst control in the formation of
additional stereocentres.
Intensive research on asymmetric conjugate addition (ACA) of
organometallic reagents has lead to useful procedures for the
addition of alkyl groups1. We have previously described Cu-
catalysed asymmetric addition of alkylzirconium species
generated in situ from terminal or internal olefins2 which
function as primary alkyl nucleophiles3. These procedures
allow asymmetric construction of tertiary stereogenic centres
by addition to cyclic4 and acyclic enones5, the formation of
cyclic6 and acyclic quaternary centres7 by addition to
β-
substituted enones (scheme 1a), and asymmetric allylic
alkylations8 to give enantiomerically enriched cyclic alkenes.
With the exception of one report of addition to unsaturated
lactones9, the products of these ACAs are cyclic or acyclic
ketones which are difficult to differentiate in further
transformations and this limits the building blocks that can be
accessed through these procedures. While it should be
can be used in iterative procedures where further α,β
unsaturated thioesters undergo ACA to give additional
stereogenic centres with almost complete catalyst control.
-
Asymmetric
addition
of
alkyl
nucleophiles
to
α,β−unsaturated aldehydes, esters and thioesters are high
value transformations as enantiopure β-substituted carboxylic
acid derivatives have enormous synthetic utility. While a great
many non-enantioselective procedures have been developed
possible to use intermediate Zr-enolates to differentiate the α-
CH2 groups, we10 and the Šebesta group11 have both found it
difficult to develop high yielding procedures.
and used in synthesis, there are only
a few catalytic
enantioselective methods, and these are limited to the
addition of simple alkyl nucleophiles. The Loh group12 used
Grignard reagents to form stereogenic centres by ACA to
esters, while the Minnaard/Feringa13 and Alexakis14 groups
built tertiary centres from α,β-unsaturated thioesters and
aldehydes respectively.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
View Article Online
DOI: 10.1039/C7CC05433E
COMMUNICATION
Journal Name
In the Cu-catalyzed ACA of alkylzirconium species, cyclic and 91% ee) can give good results and demonstrate (vida infra)
acyclic electrophiles require different ligand families to obtain that preparative scale (~1 g) reactions are easily carried out
high ee, and based on procedures which allowed highly using 10 mol% catalyst.
enantioselective ACAs to linear enones5, 7, we examined a
We examined various β–substituted α,β-unsaturated
variety of α,β-unsaturated carboxylic acid derivatives (not thioesters. n-Pentyl substituted 2b almost performed as well
shown). Esters give excellent enantioselectivities but low yields as model substrate 2a (Table 2, Entries 1 and 2). We found that
(up to 37% yield, 95% ee) due to the intermediate enolate trans-α,β-unsaturated thioesters provided much better results
undergoing subsequent reactions with starting material, a than cis-electrophiles (c.f. 2c and 2d, Entries 3 and 4). It may
process that we were unable to prevent. Additionally, be that the lower ee with cis-2d is partially due to double bond
reactions with α,β−unsaturated aldehydes only gave modest isomerization during ACA as a reaction using cis-2d quenched
results (up to 47% yield and 62% ee). However unsaturated after 15 hours gave R-3d with 25% yield and 78% ee and the
thioesters were found to give good yields and very high ee’s recovered thioester had a trans/cis (2c to 2d) ratio of 1:19. The
after some optimization.
use of (hetero) aromatic β-substituted substrates gave
moderate yields (Entries 5 and 6) with the ee’s decreased
substantially.
Table
1 Reaction conditions for hydrometallation – ACA asymmetric to α,β-
unsaturated thioester 2a
The scope of the reaction was investigated using substrates
2a and 2c with different zirconium species, especially those
containing functional groups. While styrenes are sometimes
difficult substrates in alkyl zirconocene additions here the yield
and enantioselectivity are high (75%, 97% ee, Table 3, Entry 1).
Both 2-bromo styrene and 4-methoxyl styrene performed well
using our method (Entries 2 and 3) giving ee’s over 97%.
Alkenes bearing protected alcohols (Entries
4 and 9),
unsaturated C-C bonds (Entries 5 and 6), halogens (Entries 7
and 8) and bulky vinylcyclohexane, all gave >92% ee and most
products were obtained with >96% ee.
Table 2 Scope of acyclic α, β-unsaturated thioesters
Reaction conditions: Hydrozirconation is performed on alkene before ACA.
alkene (2.5 eq.), [Cp2ZrHCl] (2 eq.), enone (1 eq.), copper (10 mol%), ligand
(10 mol%), silver (11 mol%), TMSCl (5 eq.), room temperature 15 hours [1]
Calculated by HPLC or NMR. [2] Enantiomeric excess was determined by
HPLC [3] ice bath [4] 20 mol% catalyst [5] 40 h reaction [6] 1mmol scale
reaction using 5 mol% catalyst
We found that the combination of copper (I) triflate and
ligand A in the presence of TMSCl afforded 3a with 91% ee
(Table 1, Entry 1). After trialling several similar ligands found
D
gave 3a with better results (Entries 2-4). A combination of
Et2O/DCM (1/1) provided 78% conversion with 97% ee. We
found that the yield and ee can be further increased by cooling
the reaction to 0 °C, increasing the catalyst loading to 20
mol%, and the reaction time from overnight to 40 h (Entries 7-
11). By combining all of these variations, we observe 98%
conversion (85% isolated yield) and 98% ee. Throughout this
work we chose to use 20 mol% of our readily available catalyst
to slightly improve the results, however it is not necessary to
use this catalyst loading (c.f. Table 1, Entries 6 and 8). We also
show that using 5 mol% catalyst (Entry 12, 66% conversion,
Reaction conditions: Hydrozirconation is performed on alkene before ACA.
alkene (2.5 eq.), [Cp2ZrHCl] (2 eq.), enone (1 eq.), copper (20 mol%), ligand
(20 mol%), silver (22 mol%), TMSCl (5 eq.) [1] Yield of isolated product. [2]
Enantiomeric excess was determined by HPLC.[3] But-3-en-1-ylbenzene was
used. [4] Ethylene was used.
We decided to test our approach in the synthesis of some
commercially used fragrances where the enantiomers are known to
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 5
View Article Online
DOI: 10.1039/C7CC05433E
Journal Name
COMMUNICATION
show different characteristics. We first made the phenoxanols,
which have a rosy fragrance and are widely used under various
brand names15 (Scheme 2) from styrene via ACA and then LiAlH4
reduction. This sequence gave overall yields around 70% for each
enantiomer (both 97% ee). We next synthesized (R)-
incorporation of several functional groups, which may open a
door to more complex “deoxypropionate” units and
complement existing methods for iterative synthesis. We
therefore examined an iterative route for the stereocontrolled
synthesis of 1,3-acyclic arrays where nucleophiles containing
important functional groups (an aryl bromide, a protected
alcohol, and a alkyl bromide, Scheme 3) were added in
sequence.
hydroxycitronellal16 (Scheme 2, bottom), which is
a perfume
ingredient and more expensive than the S-enantiomer.
Commercially available 2-methylpent-4-en-2-ol was subjected to
benzyl protection, ACA, DIBAL reduction and then deprotection to
give the fragrance with an overall yield of 62% in 98% ee.
Table 3 Scope of alkenes
Reaction conditions: Hydrozirconation is performed on alkene before ACA.
alkene (2.5 eq.), [Cp2ZrHCl] (2 eq.), enone (1 eq.), copper (20 mol%), ligand
(20 mol%), silver (22 mol%), TMSCl (5 eq.) [1] Yield of isolated product. [2]
Enantiomeric excess was determined by HPLC. [3] α,β-unsaturated thioester
2d was used instead of 2a.
This provided the opportunity to examine the ACA on a
preparative scale. On a gram scale using 10 mol% catalyst,
alkene 1f and α, β-unsaturated thioester 2a, we obtained good
results (1.03 g 3i, 70% yield, 96% ee) similar to those on a
small-scale with 20% catalyst (75% yield, 98% ee). Product 3i
The broad range of deoxypropionate containing natural
products has promoted the development of many methods for
their stereocontrolled synthesis13, 17. However, most of these
are limited to the introduction of simple alkyl groups when
forming stereocentres. The present method allows
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
View Article Online
DOI: 10.1039/C7CC05433E
COMMUNICATION
Journal Name
9
E. E. Maciver, R. M. Maksymowicz, N. Wilkinson, P. M. Roth
and S. P. Fletcher, Org. Lett., 2014, 16, 3288-3291.
was then subjected to DIBAL reduction and a Horner–
Wadsworth–Emmons reaction (HWE) to give α,β-unsaturated
10 Unpublished work
11 R. Šebesta, I. Némethová and Z. Sorádová, Synthesis, 2017,
49, 2461-2469.
12 S. Y. Wang and T. P. Loh, Chem. Commun., 2010, 46, 8694-
8703.
13 R. D. Mazery, M. Pullez, F. Lo´pez, S. R. Harutyunyan, A. J.
thioester 5b. ACA using (S)-
97.5:2.5 mixture of diastereomers and 59% overall yield for
the sequence, while the use of (R)- gave anti-5d with a d.r. of
D gave syn-thioester 5c as a
D
98:2. Further conversion of 5d to Michael acceptor 5e allowed
formation of a third stereogenic centre via the copper
catalysed addition of a Br-containing alkyl chain with a
diastereometric ratio of 98:2. This work demonstrates that the
formation of new stereogenic centres in these acyclic arrays
operates under almost complete ligand control, and that the
method is tolerant to the presence of important functional
groups that could allow the construction even more complex
molecules.
Minnaard and B. L. Feringa, J. Am. Chem. Soc., 2005, 127
9966-9967.
,
14 A. Alexakis, S. Goncalves-Contal, L. Gremaud, L. Palais and L.
Babel, Synthesis, 2016, 48, 3301-3308.
15 W. M. Akhtar, C. B. Cheong, J. R. Frost, K. E. Christensen, N.
G. Stevenson and T. J. Donohoe, J. Am. Chem. Soc., 2017,
139, 2577-2580.
16 T. Yamamoto, in Current Topics in Flavours and Fragrances:
Towards a New Millennium of Discovery, ed. K. A. D. Swift,
Springer Netherlands, Dordrecht, 1999, DOI: 10.1007/978-
94-011-4022-5_3, pp. 33-58.
In conclusion, we have established a new Cu-catalysed ACA to
enantioselectively generate
β-stereogenic centres in acyclic
17 (a) S. Hanessian, Y. Yang, S. Giroux, V. Mascitti, J. Ma and F.
Raeppel, J. Am. Chem. Soc., 2003, 125, 13784-13792; (b) P.
Demel, M. Keller and B. Breit, Chem. Eur. J., 2006, 12, 6669-
6683; (c) B. t. Horst, B. L. Feringa and A. J. Minnaard, Org.
carboxylic acid derivatives.
A
range of α,β-unsaturated
thioesters can be used but the best yields and ee’s are
obtained when forming tri-n-alkyl substituted products. The
method tolerates halides, benzyl and silyl ethers, arenes, as
well as C-C double and triple bonds without compromising
enantioselectivity. The fragrances phenoxanol (97% ee) and
hydroxycitronellal (98% ee) were easily made in good yield and
preliminary experiments show the reaction can be scaled to
1.0 g with 10% catalyst loading. This method also enables a
catalytic asymmetric iterative approach for the synthesis of
acyclic 1,3-stereochemical arrays.
Lett., 2007,
J. Minnaard, Chem. Commun., 2007, DOI: 10.1039/b612593j,
489-491; (e) Y. Schmidt and B. Breit, Org. Lett., 2009, 11
9, 3013-3015; (d) B. ter Horst, B. L. Feringa and A.
,
4767-4769; (f) T. den Hartog, D. Jan van Dijken, A. J.
Minnaard and B. L. Feringa, Tetrahedron: Asymmetry, 2010,
21, 1574-1584; (g) S. Xu, A. Oda, T. Bobinski, H. Li, Y.
Matsueda and E. Negishi, Angew. Chem. Int. Ed. , 2015, 54
9319-9322; (h) S. Drissi-Amraoui, T. E. Schmid, J.
,
Lauberteaux, C. Crévisy, O. Baslé, R. M. de Figueiredo, S.
Halbert, H. Gérard, M. Mauduit and J.-M. Campagne,
Advanced Synthesis & Catalysis, 2016, 358, 2519-2540; (i) S.
Xu, H. Li, M. Komiyama, A. Oda and E. I. Negishi, Chem. Eur.
J., 2017, 23, 149-156.
ZG thanks the China Scholarship Council (CSC) for financial
support. SF acknowledges funding from the EPSRC
(EP/N022246/1).
Notes and references
1
(a) S. R. Harutyunyan, T. d. Hartog, K. Geurts, A. J. Minnaard
and B. L. Feringa, Chem. Rev., 2008, 108, 2824-2852; (b) A.
Alexakis, J. E. Ba¨ckvall, N. Krause, O. Pa`mies and M.
Die´guez, Chem. Rev., 2008, 108, 2796-2823; (c) A. Alexakis,
N. Krause and S. Woodward, Copper-Catalyzed Asymmetric
Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, 2014; (d) S.
R. Harutyunyan, in Progress in Enantioselective Cu(I)-
catalyzed Formation of Stereogenic Centers, Springer,
Switzerland, 2016, vol. 58, pp. 1-2.
2
3
L. Mola, M. Sidera and S. P. Fletcher, Aust. J. Chem., 2015,
68, 401-403.
(a) R. M. Maksymowicz, A. J. Bissette and S. P. Fletcher,
Chem. Eur. J. , 2015, 21, 5668-5678; (b) K. Garrec and S. P.
Fletcher, Org. Lett., 2016, 18, 3814-3817.
4
(a) R. M. Maksymowicz, P. M. Roth and S. P. Fletcher, Nat.
Chem., 2012, 4, 649-654; (b) R. M. Maksymowicz, P. M. Roth,
A. L. Thompson and S. P. Fletcher, Chem. Commun., 2013, 49
4211-4213.
,
5
6
P. M. Roth and S. P. Fletcher, Org. Lett., 2015, 17, 912-915.
(a) M. Sidera, P. M. Roth, R. M. Maksymowicz and S. P.
Fletcher, Angew. Chem. Int. Ed. , 2013, 52, 7995-7999; (b) P.
M. Roth, M. Sidera, R. M. Maksymowicz and S. P. Fletcher,
Nat. Protoc., 2014,
Z. Gao and S. P. Fletcher, Chem. Sci., 2017, 8, 641-646.
(a) H. You, E. Rideau, M. Sidera and S. P. Fletcher, Nature,
2015, 517, 351-355; (b) E. Rideau, H. You, M. Sidera, T. D. W.
9, 104-111.
7
8
Claridge and S. P. Fletcher, J. Am. Chem. Soc., 2017, 139
5614-5624.
,
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/C7CC05433E
Asymmetric Conjugate Addition of Alkylzirconium Reagents to α, β-
Unsaturated Thioesters: Access to fragrances and acyclic
stereochemical arrays
Zhenbo Gao and Stephen P. Fletcher*
Department of Chemistry, University of Oxford. Chemistry Research Laboratory,
12 Mansfield Road, Oxford, OX1 3TA (UK).
An asymmetric iterative route for the synthesis of acyclic stereochemical arrays
is obtained by addition to α, β-unsaturated thioesters.