Diastereo- and Enantioselective Access to Stereotriads through a Flexible Coupling of Substituted Aldehydes and Alkenes

Article abstract of DOI:10.1002/anie.201900801

A flexible redox-neutral coupling of aldehydes and alkenes enables rapid access to stereotriads starting from a single stereocenter with perfect levels of enantio- and diastereoselectivity under mild conditions. The versatility of the method is highlighted by the installation of heteroatoms along the tether, which enables a route to structurally diverse building blocks. The formal synthesis of (+)-neopeltolide further demonstrates the synthetic utility of this approach.

Full text of DOI:10.1002/anie.201900801

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International Edition: DOI: 10.1002/anie.201900801
German Edition: DOI: 10.1002/ange.201900801
Redox-Neutral Coupling
Diastereo- and Enantioselective Access to Stereotriads through
a Flexible Coupling of Substituted Aldehydes and Alkenes
Jing Li+, Alexander Preinfalk+, and Nuno Maulide*
Abstract: A flexible redox-neutral coupling of aldehydes and
alkenes enables rapid access to stereotriads starting from
a single stereocenter with perfect levels of enantio- and
diastereoselectivity under mild conditions. The versatility of
the method is highlighted by the installation of heteroatoms
along the tether, which enables a route to structurally diverse
building blocks. The formal synthesis of (+)-neopeltolide
further demonstrates the synthetic utility of this approach.
Linear reductive coupling products of aldehydes with
alkenes are common structural motifs in a diverse range of
biologically active natural products (Scheme 1a).[1–3] Tradi-
tional synthetic routes towards these scaffolds involve elab-
orate reagents and multiple-step approaches, thus leading to
long synthetic routes to the target compounds.[4] In a recent
example, the Krauss group elegantly achieved the homocro-
tylation of aldehydes using enantiopure cyclopropylboron
reagents.[5] However, preparation of the key cyclopropylme-
thylboronate reagent A requires auxiliary-based method-
ology and a 5–6 step synthesis (Scheme 1b). Thus, a more
direct synthesis of such products is still in high demand. We
recently disclosed a redox-neutral coupling of aldehydes and
alkenes, which selectively yields linear products B with
perfect levels of enantio- and diastereoselectivity through
a tethering “catch-release” approach. This method enables
for the first time the enantioselective synthesis of these
compounds in a single-step operation (Scheme 1c).[6a,b]
A limitation of this method, however, is the necessary
presence in the coupling products B of a long carbon chain
capped by a (methyl)ketone. Cognizant of this, we became
interested in studying systems carrying a heteroatom in the
bridging chain with a view to employing those heteroatoms as
reactive handles for chain cleavage. To our dismay, reaction of
silicon-tethered 1a or oxygen-tethered 1b under the condi-
tions previously developed never gave the desired products in
synthetically useful yields (Scheme 1d).[6c]
Scheme 1. a) Synthetic utility of the coupling products of linear alde-
hyde and alkenes. b) Classical approaches. c) Our prior work. d) Limi-
tations of our method. e) A flexible access to stereotriads.
Furthermore, we realized that an additional substituent on
the alkene present in the starting material would generate
three contiguous stereogenic centres staring from the lone
chiral-epoxide-derived stereocenter of the precursor. How-
ever, it was not clear whether any selectivity at all would be
observed in this event. Herein, the development of a method
for the synthesis of heteroatom-bridged products that enables
selective cleavage at every position of the bridging chain. This
allows a highly flexible building-block synthesis of compli-
cated natural product scaffolds (Scheme 1e). Additionally, we
describe the flexible and fully stereoselective synthesis of
stereotriads through redox-neutral coupling of trisubstituted
alkenes, culminating in a formal synthesis of the marine
macrolide (+)-neopeltolide.
[*] Dr. J. Li,[+] A. Preinfalk,[+] Prof. Dr. N. Maulide
University of Vienna, Institute of Organic Chemistry
Wꢀhringer Strasse 38, 1090 Vienna (Austria)
E-mail: nuno.maulide@univie.ac.at
Homepage: http://maulide.univie.ac.at
[+] 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:
https://doi.org/10.1002/anie.201900801.
ꢁ 2019 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.
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Experiments with silicon-tethered alcohol 1a and hydro-
cinnamaldehyde (2a) quickly revealed that our previously
optimised conditions employing FeCl3 led only to decom-
position (Table 1, entry 1). Using oxygen-tethered alcohols
1b and 1c under the same conditions resulted in similar
observations (entries 2 and 3). Further optimisation on 1a is
shown in Table 1. Increasing the catalyst loading from 5 to
50% finally gave coupling product 3a but only in 10% yield
(entry 4). However, further increasing the amounts of FeCl3
and the temperature did not lead to any improvement
(entries 5–6). We then investigated other Lewis Acids (e.g.
TMSOTf and TBSOTf; entries 7–8), as well as Brønsted acids
(TFA, TfOH, and Tf2NH; entries 9–11). Unfortunately, none
of these conditions resulted in good yields of the desired
coupling product. Finally, we discovered that cheap BF3·Et2O
effectively promotes the reaction (entries 12–13), with the
best results obtained when one equivalent of Lewis acid was
employed (entry 13). We surmise that the coordinating
heteroatom in the tether is responsible for strong binding to
the Lewis Acid, thus mandating the use of a full equivalent.
With suitable conditions in hand, different heteroatom-
tethered unsaturated alcohols were combined with aldehyde
2a. Vinylsilane-derived substrate 1d reacts smoothly to
product 3d in good yield (Table 2, entry 1). This compound
can then be used for selective cleavage of the bridging chain
to afford syn-1,3-diol 4a through modified Tamao–Fleming
oxidation in excellent yield and perfect enantio- and diaste-
reoselectivity.[7] Oxygen-tethered substrate 1a also reacts to
the desired coupling product 3c and can then be cleaved to
afford 1,4-diol 4b by Baeyer–Villiger oxidation (entry 2).[8]
Alternatively, a thioether linker, such as in 1e, opens the
possibility of reductive desulfuration leading to the syn-
methylpentanol motif (4c).[9] For the sake of completeness,
we also show that coupling product 3 f can be converted into
the corresponding 1,5-diol 4d by Saegusa oxidation[10] and
ozonolysis. Cleavage at either of the ketone positions (a or a’)
Table 1: Optimization of conditions for heteroatom-tethered unsatu-
rated alcohols.[a]
Entry
1
Lewis acid
(%)
Yield
(%)
dr
ee (%)
1
2
3
4
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
FeCl3 (5%)
FeCl3 (5%)
FeCl3 (5%)
FeCl3 (50%)
FeCl3 (100%)
FeCl3 (100%)
TMSOTf (20%)
TBSOTf (20%)
CF3COOH (20%)
TfOH (20%)
Tf2NH (20%)
BF3·Et2O (50%)
BF3·Et2O (100%)
<5
<5
5
10
10
<5
<5
<5
<5
<5
<5
25
nd
nd
nd
>20:1
>20:1
nd
nd
nd
nd
nd
nd
>20:1
>20:1
nd
nd
nd
>99
>99
nd
nd
nd
nd
nd
nd
>99
>99
5
6b
7
8
9
10
11
12
13
50
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol) at rt for 1 h.
[b] DCE was used as solvent at 1008C. DCE=1,2-dichloroethane;
DCM=dichloromethane.
Table 2: Flexible asymmetric synthesis of the addition products of aldehydes with alkenes.
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is easily achieved by Baeyer–Villiger oxidation or Lieben
Naturally, one is not restricted to unsaturated alcohols
haloform reaction to afford the corresponding 1,6-diol 4e or
derived from propylene oxide. In order to unambiguously
determine the absolute configuration of our products, we
prepared a chiral unsaturated alcohol nucleophile from
commercially available (S)-epichlorohydrin. This resulted in
the chlorinated coupling product 6k, which gave crystals
suitable for X-ray diffraction analysis. The advantage of using
cheap and readily available propylene oxide, of which both
enantiomers are commercially available at similar prices, is
expressed in the possibility to rapidly access both enantiomers
of a given coupling product as demonstrated for 6l and ent-6l.
The preparation of 6l was achieved on a gram scale.
To demonstrate the synthetic utility of this coupling
reaction, we first applied it to the stereoselective synthesis of
1,3,5-triol 8 (Scheme 2a), a polyol motif often found in
bioactive compounds.[12] To access this compound, we carried
out ring-opening of propylene oxide with silyl-Grignard 7 to
deliver the nucleophilic partner 1d. Redox-neutral coupling
with the aldol product 2g gives 8, which can be directly
converted into the target skipped triol 9 by Tamao–Fleming
oxidation and benzyl-deprotection. Finally, we sought to test
our approach in the formal synthesis of (+)-neopeltolide
carboxylic acid 4 f, respectively.[11]
We then turned our attention towards using trisubstituted
alkenes as substrates for the coupling reaction. In the event,
we found that FeCl3 is an efficient catalyst to promote these
reactions. As shown in Table 3, dimethyl-substituted alkene
5a resulted in coupling product 6a in good yield and with
perfect levels of enantio- and diastereoselectivity. Interest-
ingly, cyclic systems perform particularly well (6b–6e). On
the aldehyde component, a-branched substrates and other
carbonyls such as esters (cf. 6g) are tolerated. By using readily
available a-chiral aldehydes, it is possible to access products
bearing four stereogenic centres (demonstrated by the stereo-
tetrads 6h,i) with high diastereo- and enantioselectivity even
for the labile 2-phenylpropanal. Additionally, by using
BF3·Et2O as the Lewis acid, aldol products can be employed
as electrophiles with similarly high stereoselectivity (6j).
Table 3: Scope of the redox-neutral coupling of alkene-bearing alcohols
with aldehydes using Lewis acid catalysis.[a]
Scheme 2. A) Stereoselective triol synthesis. Reaction conditions:
a) Grignard reagent, CuCN (10 mol%); b) 1g (1 equiv), 2h (1.2 equiv),
BF3·Et2O (50 mol%) in DCM (0.1m), r.t.; c) 7 ( 1 equiv), m-CPBA
(1.5 equiv), then TBAF and H2O2; d) Pd/C (10%) in MeOH; B) Formal
synthesis of (+)-Neopeltolide: e) 1 f (1 equiv), 2g (1.2 equiv), BF3·Et2O
(50 mol%) in DCM (0.1m), r.t.; f) Me3OBF4 ( 4 equiv.), proton sponge
(5 equiv) in DCM (0.1m), r.t.; g) 9 (1 equiv), TBSOTf (2 equiv), lutidine
(3 equiv), Et2O (0.3m), r.t., then Pd(OAc)2 (10 mol%), O2 (1 atm),
DMSO (0.1m); 808C; h) O3, DCM (0.03m), rt, then DMS.
m-CPBA=m-chloroperoxybenzoic acid, TBAF=tetra-n-butylammonium
fluoride, TBS=tert-butyldimethylsilyl, OTf=triflate, DMS=dimethyl
sulfide.
[a] Reactions were performed with 5 (0.2 mmol), aldehyde 2
(0.24 mmol), FeCl3 (20% mol), r.t., 10 minutes. [b] for 6j the reaction
conducted with BF3·Et2O (50%mol) at r.t. for 30 minutes. [c] (S)-
Epichlorohydrin was used to make starting materials 5j.
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d) M. Ishibashi, H. Ishiyama, J. Kobayashi, Tetrahedron Lett.
1994, 35, 8241 – 8242.
(Scheme 2b), a marine macrolide with potent in vitro cyto-
toxicity towards a range of cancer cell lines.[13] Interestingly,
most of the reported total syntheses proceed through
a common precursor (key fragment 11, Scheme 2b) carrying
different O-protecting groups. Starting from inexpensive,
readily available starting materials, the redox-neutral cou-
pling described herein allows access to intermediate 11[13c] in
only five operations from aldehyde 2h.
In summary, we have presented a flexible method for the
enantioselective redox-neutral coupling of aldehydes and
alkenes. By installing heteroatoms in the bridging carbon
chain, it is possible to access a wide variety of structures for
the synthesis of chiral building blocks. We also showed that
the use of trisubstituted alkenes enables the preparation of
products bearing stereotriads with very high enantio- and
diastereopurity in a single-step operation. Application of this
method to the synthesis of enantiopure triols and to the
formal synthesis of (+)-neopeltolide showcases the utility of
these coupling products.
[3] Examples of racemic linear-selective couplings: a) Y. L. Zheng,
Y. Y. Liu, Y. M. Wu, Y. X. Wang, Y. T. Lin, M. C. Ye, Angew.
Chem. Int. Ed. 2016, 55, 6315 – 6318; Angew. Chem. 2016, 128,
6423 – 6426; b) M. Kimura, A. Ezoe, K. Shibata, Y. Tamaru, J.
Am. Chem. Soc. 1998, 120, 4033 – 4034; c) M. Kimura, H.
Fujimatsu, A. Ezoe, K. Shibata, M. Shimizu, S. Matsumoto, Y.
Tamaru, Angew. Chem. Int. Ed. 1999, 38, 397 – 400; Angew.
Chem. 1999, 111, 410 – 413; d) M. Kimura, A. Ezoe, S. Tanaka, Y.
Tamaru, Angew. Chem. Int. Ed. 2001, 40, 3600 – 3602; Angew.
Chem. 2001, 113, 3712 – 3714; e) A. Bauer, N. Maulide, Org. Lett.
2018, 20, 1461 – 1464.
[4] a) L. Ferriꢀ, S. Reymond, P. Capdevielle, J. Cossy, Org. Lett.
2006, 8, 3441 – 3443; b) G. G. Zhu, E. Negishi, Org. Lett. 2007, 9,
2771 – 2774; c) M. Chen, J. F. Hartwig, Angew. Chem. Int. Ed.
2014, 53, 8691 – 8695; Angew. Chem. 2014, 126, 8835 – 8839;
d) W. Youngsaye, J. T. Lowe, F. Pohlki, P. Ralifo, J. S. Panek,
Angew. Chem. Int. Ed. 2007, 46, 9211 – 9214; Angew. Chem.
2007, 119, 9371 – 9374; e) A. K. Ghosh, X. Xu, Org. Lett. 2004, 6,
2055 – 2058; f) J. Chen, C. J. Forsyth, Angew. Chem. Int. Ed.
2004, 43, 2148 – 2152; Angew. Chem. 2004, 116, 2200 – 2204; g) S.
Chandrasekhar, B. Mahipal, M. Kavitha, J. Org. Chem. 2009, 74,
9531 – 9534; h) A. V. Varela, K. B. Garve, D. Leonori, V. K.
Aggarwal, Angew. Chem. Int. Ed. 2017, 56, 2127 – 2131; Angew.
Chem. 2017, 129, 2159 – 2163; i) L. Lu, W. Zhang, R. G. Carter, J.
Am. Chem. Soc. 2008, 130, 7253 – 7255.
Acknowledgements
Generous support of our research programs by the University
of Vienna is acknowledged. We are grateful for financial
support of this research by the ERC (CoG VINCAT), the
FWF (Project P30226) and the Austrian Academy of Sciences
(DOC Fellowship to A.P.). The invaluable assistance of Ing.
A. Roller (UVienna) for X-ray crystallographic determina-
tion is acknowledged.
[5] a) H. K. Lin, L. M. Tian, I. J. Krauss, J. Am. Chem. Soc. 2015,
137, 13176 – 13182; b) W. B. Pei, I. J. Krauss, J. Am. Chem. Soc.
2011, 133, 18514 – 18517; c) H. K. Lin, W. B. Pei, H. Wang, K. N.
Houk, I. J. Krauss, J. Am. Chem. Soc. 2013, 135, 82 – 85.
[6] a) J. Li, A. Preinfalk, N. Maulide, J. Am. Chem. Soc. 2019, 141,
143 – 147; b) For a general review on hydride-shifts, see: M. C.
Haibach, D. Seidel, Angew. Chem. Int. Ed. 2014, 53, 5010 – 5036;
Angew. Chem. 2014, 126, 5110 – 5137; c) In the case of 1b, this is
likely due to catalyst deactivation via strong binding of the
heteroatom X to the Lewis Acidic FeIII
.
Conflict of interest
[7] a) P. F. Hudrlik, A. M. Hudrlik, G. Nagendrappa, T. Yimenu,
E. T. Zellers, E. Chin, J. Am. Chem. Soc. 1980, 102, 6894 – 6896;
b) Z. H. Peng, K. A. Woerpel, Org. Lett. 2000, 2, 1379 – 1381.
[8] a) G. R. Krow, The Baeyer– Villiger Oxidation of Ketones and
Aldehydes. In Organic Reactions, 2004, pp. 251 – 798, https://doi.
org/10.1002/0471264180.or043.03; b) K. V. Chuang, C. Xu, S. E.
Reisman, Science 2016, 353, 912.
The authors declare no conflict of interest.
Keywords: aldehydes · alkenes · coupling reactions ·
Neopeltolide · redox-neutral reactions
[9] G. R. Pettit, R. E. Kadunce, J. Org. Chem. 1962, 27, 4566 – 4570.
[10] a) Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43, 1011 –
1013; b) R. C. Larock, T. R. Hightower, G. A. Kraus, P. Hahn, D.
Zheng, Tetrahedron Lett. 1995, 36, 2423 – 2426.
[11] A. Lieben, Liebigs Ann. Chem. 1870, 7, 218 – 236.
[1] Recent reviews on the coupling of aldehydes and alkenes:
a) H. K. Lin, K. D. Nguyen, B. Y. Park, T. Luong, H. Sato, V. J.
Garza, M. J. Krische, Science 2016, 354, aah5133; b) M. Holmes,
L. A. Schwartz, M. J. Krische, Chem. Rev. 2018, 118, 6026 – 6052;
c) J. F. Bower, M. J. Krische, Top. Organomet. Chem. 2011, 34,
107 – 138; d) J. M. Ketcham, I. Shin, T. P. Montgomery, M. J.
Krische, Angew. Chem. Int. Ed. 2014, 53, 9142 – 9150; Angew.
Chem. 2014, 126, 9294 – 9302.
[2] a) A. E. Wright, J. C. Botelho, E. Guzman, D. Harmody, P.
Linley, P. J. McCarthy, T. P. Pitts, S. A. Pomponi, J. K. Reed, J.
Nat. Prod. 2007, 70, 412 – 416; b) A. Grassia, I. Bruno, C.
Debitus, S. Marzocco, A. Pinto, L. Gomez-Paloma, R. Riccio,
Tetrahedron 2001, 57, 6257 – 6260; c) P. Mungkornasawakul, S.
Chaiyong, T. Sastraruji, A. Jatisatienr, C. Jatisatienr, S. G. Pyne,
A. T. Ung, J. Korth, W. Lie, J. Nat. Prod. 2009, 72, 848 – 851;
[12] Selected examples of triol-synthesis: a) Y. Hayashi, T. Saitoh, H.
Arase, G. Kawauchi, N. Takeda, Y. Shimasaki, I. Sato, Chem.
Eur. J. 2018, 24, 4909 – 4915; b) T. Bootwicha, J. M. Feilner, E. L.
Myers, V. K. Aggarwal, Nat. Chem. 2017, 9, 896 – 902.
[13] Review on the synthesis of (+)-neopeltolide: a) H. Fuwa, Mar.
Drugs 2016, 14, 65; b) Y. Bai, M. J. Dai, Curr. Org. Chem. 2015,
19, 871 – 885; For selected synthesis of (+)-Neopeltolide, see
c) S. K. Woo, M. S. Kwon, E. Lee, Angew. Chem. Int. Ed. 2008,
47, 3242 – 3244; Angew. Chem. 2008, 120, 3286 – 3288; d) M. Yu,
R. R. Schrock, A. H. Hoveyda, Angew. Chem. Int. Ed. 2015, 54,
215 – 220; Angew. Chem. 2015, 127, 217 – 222.
Manuscript received: January 21, 2019
Version of record online: && &&, &&&&
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Communications
Redox-Neutral Coupling
J. Li, A. Preinfalk,
N. Maulide*
&&&& — &&&&
Diastereo- and Enantioselective Access to
Stereotriads through a Flexible Coupling
of Substituted Aldehydes and Alkenes
Make it three: A flexible redox-neutral
coupling of aldehydes and alkenes gives
rapid access to stereotriads, starting from
a single stereocenter, with perfect levels
of enantio- and diastereoselectivity under
mild conditions. The installation of het-
eroatoms along the tether enables the
synthesis of structurally diverse building
blocks. The formal synthesis of (+)-neo-
peltolide further demonstrates the syn-
thetic utility of this approach.
Angew. Chem. Int. Ed. 2019, 58, 1 – 5
ꢀ 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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