Cornforth–Evans Transition States in Stereocontrolled Allylborations of Epoxy Aldehydes

Article abstract of DOI:10.1002/chem.202001479

Allylboration reactions rank among the most reliable tools in organic synthesis. Herein, we report a general synthesis of trifunctionalized allylboronates and systematic investigations of their stereocontrolled transformations with substituted aldehyde substrates, in order to efficiently access diverse, highly substituted target substrates. A peculiar transition in stereocontrol was observed from the polar Felkin–Anh (PFA) to the Cornforth–Evans (CE) model for alkoxy- and epoxy-substituted aldehydes. CE-type transition states were uniformly identified as minima in advanced, DFT-based computational studies of allylboration reactions of epoxy aldehydes, conforming well to the experimental data, and highlighting the underestimated relevance of this model. Furthermore, a mechanism-based rationale for the substitution pattern of the epoxide was delineated that ensures high levels of stereocontrol and renders α,β-epoxy aldehydes generally applicable substrates for target synthesis.

Full text of DOI:10.1002/chem.202001479

Accepted Article
Accepted Article
Title: Cornforth–Evans transition states in stereocontrolled
allylborations of epoxy aldehydes
Authors: Robert R. A. Freund, Matthias van den Borg, Daniel
Gaissmaier, Robin Schlosser, Timo Jacob, and Hans-Dieter
Arndt
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202001479
Link to VoR: https://doi.org/10.1002/chem.202001479
01/2020

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
Cornforth–Evans transition states in stereocontrolled allylborations of epoxy aldehydes
Robert R. A. Freund,[a] Matthias van den Borg,[b] Daniel Gaissmaier,[b,c,d] Robin Schlosser,[a]Timo Jacob,[b,c,d] and
Hans-Dieter Arndt*[a]
Dedicated to the memory of Prof. Dr. Kilian Muñiz (†)
[a]
R. R. A. Freund, R. Schlosser, Prof. Dr. H.-D. Arndt
Institut für Organische Chemie und Makromolekulare Chemie
Friedrich-Schiller-Universität Jena
Humboldtstr. 10
07743 Jena (Germany)
E-Mail: hd.arndt@uni-jena.de
[b]
[c]
[d]
M. van den Borg, D. Gaissmaier, Prof. Dr. T. Jacob
Institut für Elektrochemie
Universität Ulm
Albert-Einstein-Allee 47
89081 Ulm (Germany)
D. Gaissmaier, Prof. Dr. T. Jacob
Electrochemical Energy Storage
Helmholtz-Institute Ulm (HIU)
Helmholtzstr. 11
89081 Ulm (Germany)
D. Gaissmaier, Prof. Dr. T. Jacob
Karlsruhe Institute of Technology (KIT)
P.O. Box 3640
76021 Karlsruhe (Germany)
Supporting information and the ORCID identification number(s)for the author(s)of this article can be found
under: https://doi.org/...
Abstract: Allylboration reactions rank among the most reliable tools in organic synthesis. Herein, we report a
general synthesis of trifunctionalized allylboronates and systematic investigations of their stereocontrolled
transformations with substituted aldehyde substrates, in order to efficiently access diverse, highly substituted
target substrates. A peculiar transition in stereocontrol was observed from the polar Felkin–Anh (PFA) to the
Cornforth–Evans (CE) model for alkoxy- and epoxy-substituted aldehydes. CE-type transition states were
uniformly identified as minima in advanced, DFT-based computational studies of allylboration reactions of
epoxy aldehydes, conforming well to the experimental data, and highlighting the underestimated relevance of
this model. Furthermore, a mechanism-based rationale for the substitution pattern of the epoxide was delineated
that ensures high levels of stereocontrol and renders α,β-epoxy aldehydes generally applicable substrates for
target synthesis.
- 1 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
Introduction
Complex natural products frequently display contiguous stereogenic substitution which contributes polarity,
induces specific conformations, and allows three-dimensional branching (Fig. 1). While specific biosynthesis is
realized by enzymes,[1] many of these motifs are still a considerable challenge for synthesis. Prominently
occurring chiral motifs in natural products are polyhydroxylated 1,2,3,4-substituted alk(en)yl carbon chains (A,
Figure 1). These are frequently found in polyketides such as the antibiotics erythromycin A and rifamycin S,[2] in
terpenes such as parthenolide and micheliolide,[3] as well as in carbasugars like MK7607.[4] Furthermore, such
structural fragments are important synthetic building blocks, for example as synthetic precursor for the
chlorosulfolipid mytilipin A.[5]
Figure 1. The chiral 1,2,3,4-substituted alkenyl carbon chain (A) as a prevalent motif in natural products.
A broadly useful access to motif A may be provided by nucleophilic ring-opening of α,β-epoxy alcohol B
(Scheme 1). The regio- and stereochemistry of such transformations can be predictably controlled by electronic
and/or steric properties of the substrate, by OH-group coordination, or by specific catalysis.[6] During the work
on terpene natural products we established the fragment-linking allylboration of enantioenriched[6a] α,β-epoxy
aldehydes C by using substituted allylboronates D for a direct, stereocontrolled access to α,β-epoxy alcohols B
(Scheme 1).[7] The configuration of the two stereogenic centers created by addition to the carbonyl group should
be established by 1,2-asymmetric induction of the stereochemically-defined epoxide and the given, stable
configuration of the allylboronate.[8]
However, α,β-epoxy aldehydes (C) do not fit well to the common stereochemical prediction models due
to the sp2 character of the α- and β-carbon atoms and the unique geometry of the three-membered ring.[9] There-
fore substrate-controlled stereoselectivity in the addition to the carbonyl group lacks general understanding with
respect to direction and origin of chirality transfer (electrostatics vs. stereoelectronics) and to the influence of
substitution patterns.[10] 1,2-Asymmetric induction by an α-heteroatom substituent (Cα–X) is typically
- 2 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
rationalized by the polar variant of the Felkin–Anh–Eisenstein model (= polar Felkin–Anh, PFA).[8b,11] This
model favors a transition state (TS) which is stabilized by hyperconjugation, i.e. a favorable interaction of the
nucleophile’s filled non-bonding orbital (nNu) with the mixed empty π*C=O and σ*C–O acceptor orbitals (Scheme
2). Additional consideration of the Bürgi–Dunitz trajectory for productive overlap (αBD = 105±5°)[12] leads to a
transition state with an O=C–C–O dihedral angle of Θ ~ 75±5° and 285±5°, from where nucleophilic addition
occurs from the sterically less encumbered side.[11] Additions to carbonyl compounds featuring moderately
electronegative groups in the α position, such as NR2, SR, or PR2, were shown to be under PFA control.[13]
Scheme 1. 1,2,3,4-substituted alkenyl carbon chains accessible by allylboration.
Alternatively, the Cornforth–Evans (CE) model may operate in case of strongly electronegative substituents in
the α-position.[13,14] In this model, dipole moment minimization outweighs hyperconjugation, leading to an
antiperiplanar orientation of the C=O and Cα–O bond vectors in the transition state (Scheme 2). This
arrangement fits to two possible ground state (GS) conformations displaying a dihedral angle of ΘGS ~ 165±15°
and 195±15°, covering “late” (product-like) to “early” (substrate-like) TS geometries.[14b,15] The re and si face of
the carbonyl group is then discriminated by minimizing steric interactions with the approaching nucleophile.
Scheme 2. Stereocontrolled allylboration of α,β-epoxy aldehydes: polar Felkin–Anh or Cornforth–Evans control in the
context of cyclic, quasi-neutral transition states.[8b,13,14b,17]
- 3 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
While both models are clearly different, their dichotomy may easily go unnoticed because for simple
nucleophiles, both the PFA and the CE model predict the same product E (Scheme 2).[13] As the nucleophile
becomes more complex, energetically distinguishable TSs, namely CE, anti-CE, PFA, and anti-PFA, may
potentially lead to different reaction outcomes.[13,14] This could especially be the case for allylboration reactions
that traverse a six-membered ring TS of the adapted Zimmerman–Traxler model.[16]
We have therefore investigated the allylboration of α,β-epoxy aldehydes experimentally and
computationally for generating a mechanistic rationale and for making this transformation accessible to synthesis
planning also for more complex boronate nucleophiles. To meet the general acid-sensitivity of epoxy aldehydes
we explored reactive, functionalized 2-(silyloxymethyl)allylboronates, recently introduced as an effective tool
for the formation of biologically important α-exo-methylene γ-butyrolactones in the total synthesis of (–)-
parthenolide[7]
Results and Discussion
Initially, a general cis- and trans-selective synthesis of 2-(silyloxymethyl)allylboronates from commercially
available 2-butyne-1,4-diol (1) was developed (Scheme 3). The precursor for the trans-configured boronates,
iodoallyl bromide (E)-4, was accessed in 50% yield over six steps via stannyldiol 2 and vinyliodide 3,[7] allowing
to introduce diverse side chains (Scheme 3, bottom). Allyl (Table in Scheme 3, entry 1) and methallyl groups
(entry 4) were connected to bromide 4 by using Grignard reagents. Phenyl- and 2- naphthyl thioethers (entry 2,
3) were formed by substitution with thiolate, all with high reliability in excellent yield. Additionally, a
methoxymethyl ether side chain (entry 5) was introduced by direct functionalization of alcohol 3.
For the transformation of the vinyl iodides into allylboronates, a cascade of (I) I→Li exchange, (II)
Li→Mg transmetalation[14e] and (III) trapping with ICH2B(pin) was investigated (= method M1).[14e] Electron
poor substrates with all-carbon side chains were smoothly transformed into allylboronates in satisfying yields
(entry 1, 4). Unfortunately, in case of the more electron rich thioethers (→5b and 5c) only minor amounts of the
allylboronate were obtained. The major product was an allene (SI-12), probably formed via a β-elimination
pathway of the electron rich intermediate.[18] Attempts to obtain the more stable vinyl magnesium reagent
directly by I→MgX exchange utilizing different reactive organomagnesium compounds (iPrMgCl×LiCl,[19]
iPr2Mg×LiCl,[20] iPr(nBu)2MgLi×LiCl[21]) were unproductive even at elevated temperatures.
- 4 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
Scheme 3. Stereoselective synthesis of trans- and cis-2-(silyloxymethyl)allylboronates. Reagents and conditions: (a)
[Pd(PPh3)4] (1 mol-%), nBu3SnH, THF, 0 °C, 2 h, 98%; (b) Ac2O, Et3N, CH2Cl2, 5 °C, 24 h, 68%; (c) I2, CH2Cl2, –78 °C, 3 h,
92%; (d) TBSCl, imidazole, 0 °C to rt, 3 h; (e) K2CO3, MeOH, 0 °C to rt, 2 h, 83% (2 steps); (f) NBS, PPh3, CH2Cl2, –40 °C,
3 h, 90%; (g) (→5a): 4 or 6, allylMgBr, THF, –40 °C, 2 h; (→5b): PhSH, NaOMe, MeOH, –20 °C, 10 min, then 4 or 6, –20
to 0 °C, 3 h; (→5c): (2-Naph)SH, NaOMe, MeOH, 0 °C, 30 min, then 4, 0 °C, 5 h; (→5d): methallylMgBr, THF, –40 °C, 2
t
n
h; (h) method M1: BuLi [or BuLi (→5c)], Et2O, –78 °C, 2 h, then MgBr2×OEt2, –78 °C, 1 h, then ICH2B(pin), –78 to –
20 °C, 15 h; method M2: IZnCH2B(pin), [Pd(PPh3)4] (10 mol-%), THF, 60 °C, 2 h; (i) (→5e): MeOCH2Cl, iPr2NEt, CH2Cl2,
0 °C to rt, 18 h; (j) Me3SiCl, NaI, MeCN, rt, 10 min, then 1, 1 h, 88%. Note: The cis-configured allylboronate has nominally
(E) configuration [trans applies to (Z)].
A more general way of stereoselective allylboronate formation was realized by coupling the vinyl iodides under
Negishi conditions with Knochel’s IZnCH2B(pin) reagent,[22] giving reproducible yields for boronates trans-5
including also those which contained the challenging phenyl thioether substituent (method M2, entry 1–2, 4).
Unfortunately, the presence of the 2-naphthyl sulfide or an alkoxide (entry 3, 5) limited the method, probably by
competing π-allyl Pd-mediated pathways or catalyst deactivation.
The corresponding reagent for the preparation of cis-configured boronates was obtained by Me3SiI-
mediated trans-selective hydroiodination of 1 with simultaneous O→I exchange (Scheme 3, top), giving stable
diiodide (Z)-6.[23] Carbon- and sulfur-based side chains were smoothly introduced by nucleophilic substitution.
Allylboronates were formed after O-silylation by Negishi coupling, providing the boronates cis-5a and -5b
(entry 6, 7).
Boronates with more complex side chains cannot be prepared from configurationally unstable[24] allyl
nucleophiles that show [1,3]-metallotropic shifts,[8e] such as used for the synthesis of 5a and 5b. However, any
ω-substituted propargyl alcohol should be a suitable substrate for allylboronate synthesis as described above
- 5 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
(Scheme 4). As an example, the known aldehyde 7[25] was transformed into propargyl alcohol 8 by applying a
Corey–Fuchs sequence, hydroxyl-directed hydrostannylation (→9), and Sn→I exchange to obtain vinyl iodide
10. The latter was O-silylated, subjected to I→Li exchange, and trapped by ICH2B(pin) to provide the complex
allylboronate trans-5f in good yield, suitable for installing relay alkene metathesis handles by allylboration.[26]
Scheme 4. Synthesis of complex boronate trans-5f using hydroxyl directed hydrostannylation. Reagents and conditions: (a)
CBr4, PPh3, CH2Cl2, 0 °C, 1.5 h, 74%; (b) nBuLi, THF, –78 °C, 1 h, then (CH2O)n, –10 °C to rt, 3 h, 64%; (c) [PdCl2(PPh3)2]
n
(5 mol-%), Bu3SnH, PhMe, rt, 1.5 h, 82%; (d) I2, CH2Cl2, –78 °C, 3 h, 99%; (e) TBSCl, imidazole, CH2Cl2, 0 °C, 30 min,
t
94%; (f) BuLi, Et2O, –78 °C, 1 h, then ICH2B(pin), –78 to –20 °C, 15 h, 62% (modified method M1).
The reactivity of cis- and trans-2-(silyloxymethyl)allylboronates toward simple, achiral aldehydes (11a–e, for
structures see Fig. SI-1) was investigated next. Gratifyingly, smooth allylboration was already observed at 0 °C
and without external activation by acids, often needed for related allylation by other allylboronates, making those
novel reagents compatible with acid-sensitive substrates (Scheme 5).[27] The homoallyl alcohol products
featuring aryl (→12a– b, 13a–b), alkyl (→12c, 13c), and alkoxy side chains (→12d, 13d) were efficiently
formed under mild conditions (70–92% yield, 0 to 25 °C) for both cis and trans series. The products were
obtained as single diastereomers, indicating complete translation of the defined boronate stereochemistry into the
product according to the Zimmerman–Traxler model.[8b,17] The allylboration of a very sensitive α,β-unsaturated
aldehyde was buffered by solid NaHCO3 and kept at lower temperature (0–5 °C, 48 h) to obtain the products 12e
and 13e in good yield (80–94%) and excellent diastereoselectivity (17–19:1 dr).
- 6 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
Scheme 5. 2-(Silyloxymethyl)allylboration of achiral aldehydes. Conditions: cis- or trans-5 (1.0 equiv.), aldehyde (1.1–
1.5 equiv.), Et2O (0.2 M); (a) 0 to 25 °C, 24 h; (b) NaHCO3 (0.05 equiv.), 0–5 °C, 48 h. Combined yields are given, major
isomer depicted. dr determined by GC–MS, HPLC, or NMR.
With optimized reaction conditions in hand, the study was extended to chiral aldehyde substrates 14a-g (for
structures see Fig. SI-1) featuring an α-heteroatom substituent (Scheme 6). The trans allylboration of α-
carbamato aldehydes enabled the preparation of homoallyl alcohols 13f–g with high yields (79–94%), excellent
dr’s (22–30:1), and without detectable epimerization. In contrast, cis allylboration of these substrates resulted in
slightly lower yields (58– 83%) and low dr (1.3–2.3:1) of the products 12f–g. Surprisingly, extension to an α,β-
substituted dialkoxy aldehyde reversed the trend, leading to good yield and stereocontrol for the cis variant
(→12h, 15:1 dr) while the trans allylboration lacked diastereocontrol (→13h, 2.7:1 dr). Related findings have
been sporadically reported. Dipole effects were invoked as a possible cause for the eroding stereocontrol in these
cases.[28]
The stereochemistry of the α-aminoalcohol carbamates 12f and 13f was elucidated after cyclization to
the corresponding five-membered oxazolidinones which enabled their stereochemical assignment by determining
3
their JNCH,CHO coupling constants (Scheme SI-1).[29] Homoallyl alcohol 12f, obtained as a separable 1.3:1
diastereomeric mixture, allowed for the assignment of both isomers, namely the major one as the 2,3-syn-3,4-syn
product (anti-PFA TS) and the minor one as the 2,3-anti-3,4-syn product (PFA TS). Similarly, trans
allylboration product 13f (22:1 dr) was assigned as the 2,3-anti-3,4-anti product (PFA TS). These findings
conform to the common model of PFA-type attack on the aldehyde carbonyl (cmp. to Scheme 8).[8b] In contrast,
the stereoselective cis allylboration leading to dialkoxy alcohol (+)-12h was found to be either under PFA or CE
control by analysis of its (R)- and (S)-Mosher esters disclosing a 2,3-anti-3,4-syn configuration (Figure SI-2).[30]
Since anti-PFA control would be expected for cis allylboration, the CE model could be relevant for the reaction
of substrates with strongly electronegative α-substituents.[13-14]
- 7 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
Scheme 6. 2-(Silyloxymethyl)allylboration of chiral α-heteroatom-substituted aldehydes. Conditions: cis- or trans-5
(1.0 equiv.), aldehyde (1.1–1.5 equiv.), Et2O (0.2 M); (a) 0 to 25 °C, 24 h; (b) NaHCO3 (0.05 equiv.), 0–5 °C, 48 h.
Combined yields are given, major isomer being depicted. dr determined by GC–MS, HPLC, or NMR.
Different epoxide substitution patterns were studied for their impact on the asymmetric induction, including
α,β,β’, α,α’,β, and α,β-trans substitution (Scheme 6). Gratifyingly, epoxy aldehydes featuring α,β,β’
trisubstitution lead to high diastereoselectivity in the cis case, enabling the synthesis of homoallyl alcohols
12iα,β,β’ and 12jα,β,β’ in excellent yields (91% and 83%) and dr’s (7:1 and 27:1). The same applied to trans
allylboration of these α,β,β’ trisubstituted substrates resulting in products 13i–jα,β,β’ with dr’s of ~18:1 and high
yields of 92% and 94%, respectively. However, changing the epoxide’s substitution pattern from α,β,β’ to α,α’,β
tri- (→12kα,α’,β, 13kα,α’,β) or α,β-trans disubstitution (→12lα,β, 13lα,β) resulted in loss of asymmetric induction for
both the cis- and trans-configured reagents, although combined yields remained high (84–98%). This strong
effect of a cis-β substituent indicated 1,3- rather than 1,2-asymmetric induction to cause the high
diastereoselection.[31]
The stereochemistry of the enantiomerically-enriched epoxide-containing products (+)-12jα,β,β’ and (+)-
13jα,β,β’ was again assigned by analyzing their Mosher esters (Figure SI-2).[30] The relative stereochemistry of
both carbinols featured 2,3-anti configuration, even though being individually prepared from cis and trans
allylboronates. Since these data would correspond to either PFA or CE control in both cases (cmp. to Scheme 8),
as was also found for the dialkoxy-containing substrate, dipole effects might be involved in the allylboration of
epoxy aldehydes. The stereochemistry was independently validated by NMR and X-ray crystal structure analyses
of the alcohols (±)-13iα,β,β’ and (±)-13jα,β,β’ after derivatization.[7] Interestingly, the presence of a second α-
substituent (= Rα’) decreased the directing influence of the epoxy group leading to a switch in stereochemistry
from 2,3-anti to syn in case of cis allylboration product 12kα,α’,β
.
- 8 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
Scheme 7. Synthesis of α-exo-methylene γ-butyrolactones from allylboration products. Reagents and conditions (isol. yields
over 2 steps): (a) TBAF×3H2O, THF, 0 °C, 1 h; (b) TEMPO (30 mol-%), PhI(OAc)2, rt, 18 h; (c) nPr4NRuO4 (TPAP, 10 mol-
%), NMO, 4 Å molecular sieves, CH2Cl2/MeCN (5:1), rt, 18 h. [b]Major isomer (depicted) used. [c]Decomposition during
purification on silica.
In order to convert the flexible 2-(hydroxyethyl)-allylalcohols into more rigid, ring-closed lactones, an efficient
two-step procedure for the transformation of homoallylic substrates 12 and 13 into also more biologically
relevant[32] α-exo-methylene γ-butyrolactones was established (Scheme 7). Fluoride-mediated silyl ether cleavage
released a diol which was oxidatively lactonized by PhI(OAc)2 and catalytic TEMPO (=step b),[7,33] or evenly
effective by using catalytic TPAP and NMO (=step c).[34] Thereby, aryl (→15a, 16a) and alkyl substituted
substrates (→15b, 16b) were converted into the corresponding lactones in high yields, as well as vinyl
substituted molecules featuring an oxidation labile thioether (→15c, 16c). In addition, substrates derived from α-
heteroatom substituted aldehydes were smoothly transformed, showing that secondary carbamates (→15d, 16d),
an acetal (→15e), and epoxides (→15f, 16f) were well tolerated. Unfortunately, attempts to acquire more
structural information from these derivatives by NMR or X-ray crystallography was met with little success.
Therefore, in order to generate further insight, theoretical modelling was pursued by using
computational methods. The reaction of trans allylboronates with α-chiral aldehydes most often results in 2,3-
anti stereochemistry.[8b] This outcome can be explained by the common (P)FA model and was found also to
match the trans allylboration of α,β-epoxy aldehydes, leading e.g. to product 13jα,β,β’. On the other hand, the
model suggests anti-PFA stereochemistry (= 2,3-syn) for cis-configured allylboron reagents. As 2,3-anti
stereochemistry was found for the polar cis allylboration products 12h and 12jα,β,β’, dipole-minimized CE
transition states could rather account for stereochemical control.[8b,17] In order to scrutinize this issue, DFT
calculations were initiated for elucidating (1) the parameters of stereocontrol, (2) the importance of the epoxide
substitution pattern, and (3) the relevance of dipole-minimized CE pathways for the allylboration of epoxy
aldehydes in general.
- 9 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
Initially ground state (subscript GS) rotational energy profiles were calculated for α,β-epoxy aldehyde substrates,
in order to gain insight into preferred and destabilized conformations. Since allylborations traverse an “early”,
substrate-like transition state regarding the C–C bond to be formed,[35] the aldehyde’s conformational preferences
should be reflected in the transition state structures as well.[13-14] For the calculation, the O=C–C–O dihedral
angle ΘGS of simplified substrates 17α,β,β’, 18α,α’,β, and 19α,β featuring the substitution patterns of interest (see
superscript) was incrementally varied from ΘGS = 0 to 360°, followed by geometry optimization for each step at
the dispersion-corrected B3LYP-D3(BJ)/cc-pVDZ level of theory[36] in the gas phase (Figure 2).
The rotational profiles found displayed a strong conformational minimum for all three epoxy aldehydes
at a dihedral angle ΘGS close to 160°, representing a gauche/anti conformation that almost coincides with a
minimized dipole moment by antiperiplanar orientation of the carbonyl group and the epoxide’s C–O bond.[14a]
Moving the Rα’ substituent out of an eclipsed conformation as well as residual stabilizing hyperconjugative
interactions with the carbonyl group probably lead to the deviation from a ΘGS = 180° minimum.[14a,37]
Orientations of ΘGS = 75±5° and 285±5° (–75±5°), which would correspond to (anti-)PFA TSs, were
considerably disfavored by ~6–7 and 3–4 kcal/mol, respectively. Repelling interactions with the residues at C-α
or C-β and unfavorable bond dipole orientations likely destabilize these conformations.
Figure 2. Computed rotational energy profile of simplified α,β-epoxy aldehydes. Level of theory: B3LYP-D3(BJ)/cc-pVDZ
(vacuum). Grey areas show the possible range of conformations associated with the respective stereoinduction model for
nucleophile addition to the carbonyl (PFA: 285±5°, anti-PFA: 75±5°, CE: 165±15°, anti-CE: 195±15°).
The obtained rotational energy profiles resemble those reported for aldehydes bearing an α substituent based on a
sp3-bound, strongly electronegative heteroatom, like halogens and oxygen.[13,37-38] NMR-based conformational
analysis of the simple oxirane-2-carbaldehyde (Rα’ = Rβ = Rβ’ = H) showed such a gauche/anti orientation to be
favored in solution as a result of dipole–dipole interactions with the carbonyl group.[39] In this early study the
electron withdrawing effect of epoxides was reported to be lower than for 2-alkoxy substituents. On the other
hand, epoxides carry a considerable dipole moment of μ ~ 1.9 D (for oxirane),[37] comparable to fluoroethane
(μ = 1.94 D)[40] and surpassing regular ethers (μ ~ 1.3 D for dimethylether, 1.63 D for THF). Hence, it was
- 10 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
necessary to investigate whether the epoxide would primarily govern asymmetric induction according to the CE
model or whether PFA-type stereoelectronics would significantly contribute to TS geometry.
Furthermore, ground state conformations alone cannot explain the variations in diastereoselectivity for
the allylboration of differently substituted epoxy aldehydes (Scheme 6), as the rotational energy profiles were
almost invariant to changes of the substitution pattern. To approach this issue, we initially applied the commonly
used TS structural analysis to trans allylboration of general α-heteroatom-substituted aldehydes which predicts a
2,3- anti-3,4-anti configuration in the product A for both stereoinduction models (Scheme 8A).[8b,13] Preference
for either the PFA or the CE variant of TS-Atrans would drastically depend on the size and electronegativity of
the substituent X, also in comparison to the size and electronegativity of the second substituent R’, calling for a
computational in-depth analysis of the transition states.
Scheme 8. The general Cornforth–Evans and the (polar) Felkin–Anh model for allylboration of α-chiral aldehydes:
Stereochemical outcome of cis allylboration should depend on the electronegativity of the α-carbon substituent. (The atom
count of product A corresponds to the one used in Scheme 2).[8b,13,14b,d,16b,c]
- 11 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
For cis allylboration, the CE and PFA model each predict different product stereochemistry.[14b] In detail, a
strongly electronegative α substituent X should enforce a CE pathway [TS-Bcis(CE)], resulting in a 2,3-anti-3,4-
syn configured product A (Scheme 10B). For less electronegative groups X a similar minimization of 1,3 syn-
pentane interactions should be realized in the anti-PFA TS [TS-Bcis(a-PFA)] leading to a 2,3-syn-3,4-syn
stereochemistry.[13,14b,17] This divergent interplay between electrostatic, steric and hyperconjugative contributions
could account for the poor stereocontrol sometimes found for allylboration of polar aldehydes.[14c,16a,28b,29]
To identify the factors influencing the stereoselectivity in the cis and trans allylboration of the epoxide-
containing products 12/13iα,β,β’, 12/13jα,β,β’
,
12/13kα,α’,β, and 12/13lα,β, a computational TS analysis of the
allylboration of simplified versions of the experimentally used, differently substituted α,β-epoxy aldehydes
14dα,β,β’, 14eα,β,β’, 14fα,α’,β, and 14gα,β was conducted (for structural formulae see Fig. SI-1). These model
substrates 17α,β,β’, 18α,α’,β, and 19α,β display the three epoxy substitution patterns of interest as indicated by the
respective superscript (for structural formulae see Figure 2) and should allow to deduce transferable trends about
asymmetric induction mechanisms that led to the different diastereoselectivities.
The reaction partners, 2-(silyloxymethyl)allylboronates cis- and trans-5, were simplified to the 2-
(methoxymethyl)allylboronates trans-20 [Scheme 2: D, Rtrans = R2 = Me, BX2 = B(pin)] and cis-20 [Rcis = R2 =
Me, BX2 = B(pin)], allowing for a reasonable computational model. Four cyclic, chair-like TS structures were
generated as input for each of the three substrates,[14d,41] featuring an epoxide orientation associated with the
respective model, being anti to the incoming nucleophile (= PFA-type) or anti to the carbonyl group (= CE-
type). The resulting 24 possible structures were found to give stable TSs with activation energies in between ΔG‡
~12–17 kcal/mol for trans and ~10–17 kcal/mol for cis allylboration. CE-type TSs proved to be energetically
favored over PFA-type ones by 0.9–4.4 kcal/mol for trans and 0.72–2.99 kcal/mol for the cis allylboration, with
the exception of aldehyde 18α,α’,β where the additional α’ substituent induced steric restrictions that render an
anti-CE structure most stable with an energy gap of only 0.28 kcal/mol to the corresponding anti-PFA TS.
The most stable TS for each cis- and trans-2-(methoxymethyl)allylboration of the three aldehydes is
depicted in Figure 3. To rule out the relevance of other TS geometries, additional boat-like variants of the TSs
were generated as input structures.[42] These proved to be unstable during the calculation and transformed into
the corresponding chair-like structures. Indeed, previous computational studies on carbonyl allylborations found
boat and twist-boat conformations to be 4–8 kcal/mol higher in energy than their chair analogs, rendering them
rather unimportant for this kind of reactions.[41]
In line with previous computational studies, all of the calculated structures represent an “early” TS
regarding the C–C bond to be formed (dC–C ~2.2–2.4 Å),[14d,35] show an attack trajectory angle within the Bürgi–
Dunitz range of αC–C–O ~102–104°,[12,14d] and don’t show a short distance between the methoxy oxygen atom and
the aldehyde’s hydrogen atom, previously reported as a strong TS geometry-defining interaction.[42] The relative
energies (ΔΔG‡) of all calculated TSs are given in Table 1. A compilation of all TS structures including detailed
geometrical factors, bond dipole orientations, and critical steric interactions is given in Figures SI-3 and SI-4.
Overall, the DFT-computational TS analysis of epoxy aldehyde’s cis and trans allylboration disclosed a
similar preference for dipole moment minimization as already indicated by the rotational energy profiles in the
ground state. Hence, electrostatics favored CE TS conformations with an anti-orientation of the former carbonyl
group and the epoxide’s C–O bond and thus O–C–C–O dihedral angles of 153° ≤ ΘTS ≤ 179° (Figures 2, SI-3,
and SI-4). Besides missing dipole minimization, PFA-type TSs were additionally destabilized by syn-pentane
and gauche interactions of the epoxide’s substituents with the allylboronate’s residue in position 3, Rtrans or Rcis.
- 12 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
Figure 3. Transition state analysis by DFT calculation: Global minima for cis and trans allylboration α,β-epoxy aldehydes
17α,β,β’, 18α,α’,β, and 19α,β. Calculated at the B3LYP-D3(BJ)/cc-pVDZ level of theory (vacuum). The subscript trans or cis
corresponds to the allylboronate geometry. The assignment to the respective stereoinduction model is shown in bold
parentheses. The energy difference (ΔΔG‡) to the next higher opposite TS (“pro” vs. anti, abbreviated as “a”) is given in
light parentheses. The epoxy aldehyde’s methyl group probe is highlighted in blue.
Regarding the stereochemical outcome of the allylborations, the most stable CE TS geometry would indeed lead
to 2,3-anti-3,4-anti configuration in the product of trans allylboration and 2,3-anti-3,4-syn for the general cis
allylboration, as well as 2,3-syn-3,4-syn for the special cis allylboration case toward α-disubstituted product
12kα,α’,β.These match the experimental findings shown in Scheme 6 and the theoretical analysis depicted in
Scheme 8, again showing the strongly electronegative character of the epoxide group and the competitive effect
of two α-substituents with a similar level of asymmetric induction. Although structural simplifications had to be
adopted for computational reason, the calculated relative energies parallel the experimentally observed trend of
diastereoselectivity being dependent on the epoxide’s substitution pattern (Table 1). Hence, the α,β,β’
- 13 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
trisubstitution which showed a high level of stereoinduction in the experiments also features the biggest TS
energy separation to the next opposite pathway in case of trans allylboration [TS-1trans(CE) vs. (a-PFA)]. The
differences were lower in energy for α,α’,β (TS-2trans) and α,β-trans substitution (TS-3trans; Figure 3, Scheme 6),
in line with the experimental data. While a preference for CE-associated pathways was also found for cis
allylboration, the computational model cannot fully explain the high diastereoselectivity just found for α,β,β’
trisubstitution. This is probably due to the truncation of the side chains and the substitution of the bulky
t
OSiMe2 Bu for the small OCH3 group in the computational model, known to drastically influence TS geometries
in related boron-enolate aldol reactions,[42] as well as the neglected solvent influence.
Table 1. Relative energies (ΔΔG‡) of the calculated transition states.
ΔΔG‡ [kcal/mol]
Structure Allylboronate Substrate
PFA
2.80
4.41
2.12
2.99
3.87
1.66
CE
0
a-PFA
1.27
0.88
2.35
0.72
0.28
0.77
a-CE
1.98
3.26
1.06
0.80
0
TS-1trans
TS-2trans
TS-3trans
TS-4cis
17α,β,β’
18α,α’,β
19α,β
17α,β,β’
18α,α’,β
19α,β
trans-20
trans-20
trans-20
cis-20
0
0
0
cis-20
2.66
0
TS-5cis
cis-20
2.96
TS-6cis
A comparison of the in silico generated TS structures disclosed three factors determining the energy differences
in the TSs, correlating with the experimentally observed stereocontrol: (1) minimization of the dipole moment,
(2) destabilizing syn-pentane and gauche interactions in PFA-type structures, and (3) strong 1,3-asymmetric
induction caused by steric repulsion with the substituent Rβ’, if present (Figure 4).
As clearly shown by the calculations, electrostatics enforced a stabilizing anti orientation of the
carbonyl group and the epoxide’s C–O bond in the allylboration of α,β-epoxy aldehydes. The level of this effect
can be qualitatively deduced from the trans and cis allylboration of α,β-disubstituted aldehyde substrate 19α,β
which shows a comparable level of rather weak repulsive steric interactions in all four TSs (CE, anti-CE, PFA,
anti-PFA). For both allylboration cases, being TS-3trans and TS-6cis, non-dipole minimized PFA-type states are
disfavored by ~0.8–2.4 kcal/mol.
A comparison of all resulting TSs suggests that a high level of dipole moment-minimization can be
realized in the CE cases (153° ≤ ΘTS ≤ 179°), but is significantly lowered in the anti-CE cases due to repelling
interactions of the epoxide with the allylboronate’s substituent in position 3, Rtrans or Rcis. This resulted in
destabilization of anti-CE states with dihedral angles drastically differing from a (–)180° maximum, being –42°
≥ ΘTS ≥ –60° for trans and only –30° ≥ ΘTS ≥ –32° for cis allylboration (Figures 4, SI-3, and SI-4). The reduced
stabilization of anti-CE TSs could account for the energetic similarity with anti-PFA TSs in some cases, which
showed more favorable dihedral angles in the range of 94° ≤ ΘTS ≤ 118° (TS-4cis, TS-5cis).
The distinct energetic differentiation between the four TSs in the reaction with α,β,β’-trisubstituted
epoxy aldehyde 17α,β,β’ resulted from a highly destabilizing allylic 1,3-strain between the substituent Rβ’ and the
carbonyl oxygen in case of the anti-CE, or syn-pentane/gauche strain with the allylboronate’s residue Rtrans in the
anti-PFA or Rcis in the PFA case (Figures 4 and SI-3). This combination of dipole minimization and 1,3-
asymmetric induction by the residue Rβ’ is missing for the allylboration of epoxy aldehydes 18α,α’,β and 19α,β
,
- 14 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
likely compromising stereoselectivity. For aldehyde 18α,α’,β it is even counteracted by a non-productive syn-
pentane strain in both CE-type TSs, caused by the substituent Rα’. In this particular case the steric influence on
the discrimination of “pro” and anti-pathways seems to be slightly higher than the electrostatic effect of the
sterically unimposing epoxy group. This led to a switch in stereochemistry as also found by experiment. The
competition between similarly bulky or electronegative geminal α-substituents on asymmetric induction has been
described as a limiting factor of these stereochemical models (see Scheme 8B, X vs. R’).[8b,13,14b,d,16b,c]In this case
it is the formal interplay between an electronegative oxygen atom and a considerably more bulky CH3 group.
The computational overestimation of this effect for cis allylboration transition states is likely caused by
simplifications adopted for the calculations regarding the chemical structures and computational methods.
Figure 4. Rationale for stereocontrolled allylboration of α,β-epoxy aldehydes according to the Cornforth–Evans model.
Conclusions
Functionalized 2-(silyloxymethyl)allylboronates were designed that combine chemical stability and predictable
transfer of stereochemistry into allylboration products. They smoothly react with aldehydes without (Lewis-)
acid activation.[27] The general trans- and cis-selective synthesis to this reagent class featured a late-stage
construction of the allylboronate by using a Negishi coupling or organomagnesium chemistry.
While the reaction of these reagents with α-carbamato aldehydes proceeded according to the polar
Felkin–Anh (PFA) model, more electronegative α-alkoxy, especially α,β-epoxy aldehydes, conformed to
Cornforth–Evans (CE) stereoinduction. Hence, dipole moment-minimization in the transition state (TS) of
allylborations is a strong directing force, as seen for aldol[14b,43] and Wittig reactions.[44] For simple nucleophiles
both the PFA and the CE model predict the same product stereochemistry. This degeneracy was resolved by cis
allylboration that led to a distinct product fitting to the CE model. The level of stereocontrol for the allylboration
of α,β-epoxy aldehydes was found to be strongly dependent on epoxide substitution, with a β-cis substitution
leading to constantly high diastereoselectivity by the combination of dipole minimization and 1,3 asymmetric
- 15 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
induction. α,α-Disubstitution was found to impede viable asymmetric induction by contributing additional steric
interactions that compete with dipole minimization.
DFT analysis of the ground state conformations of differently substituted α,β-epoxy aldehydes and the
possible allylboration TSs verified the preference of dipole-minimizing conformations. Hyperconjugative
stabilization according to the PFA model clearly seemed overridden by electrostatics in case of α,β-epoxy
aldehydes, classifying epoxides as “strongly electronegative” α-substituents.[13] Additionally, the experimentally
observed dependence of stereocontrol on an epoxide’s β-cis substituent was identified by computation as a
selector for the CE transition state. This substitution reinforces the otherwise weak facial discrimination of the
carbonyl group in the CE transition state by the apparently well ordered, but spatially unimposing epoxide group.
By applying this rationale in a forward sense, α,β-epoxy aldehydes and allylboronates can now be
readily applied for the stereocontrolled synthesis of complex polyhydroxylated target molecules. Further
investigations notwithstanding, it is expected that the consistent results obtained herein will apply to most
addition reactions to epoxy aldehydes. Overall, Cornforth-Evans transition states and the impact of dipole
minimization should always be considered for addition reactions to carbonyl compounds.
Experimental Section
Detailed descriptions of instrumentation, materials, experimental procedures, product characterization (1D and
2D NMR including copies of spectra, HRMS, IR, optical rotation), computational details and primary data, as
well as a list of abbreviations is given in the Supporting Information.
General procedure M1 for 2-(silyloxymethyl)allylboronate synthesis by using Grignard chemistry
A solution of a substituted vinyl iodide (1.0 equiv.) in anhydrous Et2O (0.3 M in substrate) was added dropwise
to a stirred solution of (alkoxide- and hydroxide-free) tBuLi (2.0 equiv., 1.9 M in pentane) in anhydrous Et2O (0.3
M in tBuLi) at –78 °C. A freshly prepared anhydrous MgBr2 × OEt2 solution (1.0 equiv., 0.8 M in 4:1 Et2O/C6H6)
was added after 2 h at this temperature (TLC control). After an additional hour at –78 °C a solution of anhydrous
ICH2B(pin) (1.1 equiv., dehydrated by passing through a plug of activated neutral Al2O3 directly before use) in
anhydrous Et2O (0.7 M in reagent) was slowly added via the cooled inner wall of the reaction vessel. The
resulting suspension was allowed to slowly warm to –20 °C and kept at this temperature for 15 h. The cooling
bath was removed and the mixture was added to stirred phosphate buffer (pH 6, 0.5 M, ~10 ml per mmol of
substrate) at 0 °C. The mixture was extracted with MTBE (~20 ml per mmol substrate) and the extract was
washed with brine (~10 ml per mmol substrate). The organic extract was dried with MgSO4, filtered, and the
solvent was removed in vacuo at 25 °C. Rapid (5–10 min) silica gel column chromatography of the residue
(3  10 cm for 0.6 mmol substrate) provided allylboronate 5.
General procedure M2 for 2-(silyloxymethyl)allylboronate synthesis by using Negishi couplings
To a stirred solution of [Pd(PPh3)4] (0.1 equiv.) in anhydrous, deoxygenated THF (~0.02 M in Pd catalyst) at
20 °C was added a solution of IZnCH2B(pin) (2.0 equiv., 0.6 M in anhydrous THF), followed by a solution of a
substituted vinyl iodide (1.0 equiv.) in anhydrous THF (~0.25 M in substrate). The flask was immersed in a
preheated 60 °C oil bath and the mixture was stirred for 3 h (GC–MS control). The oil bath was removed and the
mixture was cooled to 0 °C whereupon it was added to stirred phosphate buffer (pH 6, 0.5 M, ~30 ml per mmol
of substrate) at 0 °C. After complete addition, the mixture was extracted with MTBE (~30 ml per mmol of
- 16 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
substrate) and the extract was washed with brine (~30 ml per mmol substrate). The organic extract was dried
with MgSO4, filtered, and the solvent was removed in vacuo at 25 °C. Rapid (10 min) silica gel column
chromatography of the residue (4 × 10 cm for 2.4 mmol substrate) provided allylboronate 5.
General procedure (a) for 2-(silyloxymethyl)allylboration of aldehydes
Allylboronate 5 (1.0 equiv.) was added to a stirred solution of aldehyde 11/14 (1.1 equiv.) in anhydrous Et2O
(0.15 M in boronate) at 0 °C. The solution was allowed to reach 20 °C over 4 h. After 24 h at this temperature
(TLC control) the solution was directly subjected to silica gel column chromatography (1.5  25 cm for
~0.05 mmol of substrate) to obtain the homoallylic alcohol product 12/13.
General procedure (b) for 2-(silyloxymethyl)allylboration of aldehydes
Allylboronate 5 (1.0 equiv.) was added to a stirred suspension of aldehyde 11/14 (1.1 equiv.) and NaHCO3
(0.30 mg, 3.55 μmol, 0.05 equiv.) in anhydrous Et2O (0.5 ml) at 0 °C. The mixture was kept at this temperature
for 48 h (TLC control) whereupon it was directly subjected to silica gel column chromatography (1.5  25 cm
for ~0.05 mmol of substrate) to obtain the homoallylic alcohol product 12/13. Alternative workup for larger
scale: Sat. NaHCO3 solution (~9 ml per mmol of substrate) was added and the biphasic mixture was stirred for
5 min. The organic layer was separated and washed with brine (~9 ml per mmol substrate). The organic extract
was dried with MgSO4, filtered, and the solvent was removed in vacuo at 25 °C. The homoallylic alcohol 12/13
was obtained after silica gel column chromatography (3  20 cm for 2.2 mmol boronate) of the residue.
General procedure for the preparation of oxazolidinones SI-1/SI-2/SI-3 from N-Boc α-amino alcohols
To a stirred solution of N-Boc α-amino alcohol 12f/13f (1.0 equiv.) in anhydrous THF (0.07 M in substrate) at 0
°C was added NaH (2.0 equiv., 60 weight% in mineral oil) in one portion. The suspension was allowed to warm
to 20 °C during 2 h and stirred at this temperature for 14 h (TLC control). The mixture was diluted with MTBE
(~3.8 ml per 10 μmol of substrate) and sat. NH4Cl solution (~3.8 ml per 10 μmol of substrate). The organic layer
was then separated and washed with brine (~3.8 ml per 10 μmol substrate). The organic extract was dried with
MgSO4, filtered, and the solvent was removed in vacuo. Silica gel column chromatography (2 × 15 cm for
0.04 mmol of substrate) of the residue delivered the oxazolidinone SI-1/SI-2/SI-3.
General procedure for the preparation of Mosher esters SI-6/SI-7/SI-8 from secondary alcohols
To a solution of a secondary alcohol (1.0 equiv.) and DMAP (4.0 equiv.) in anhydrous THF (0.04 M in
substrate) was added (R)-(–)-MTPA–Cl (1.0–1.6 equiv.) at 0 °C with stirring. The cooling bath was removed
after 10 min and the suspension was allowed to warm to 20 °C. After 16 h at this temperature (TLC control)
MTBE (~1.8 ml per 10 μmol of substrate) and sat. NaHCO3 solution (~0.6 ml per 10 μmol of substrate) were
added to the suspension. After additional 10 min of stirring, the mixture was added to MTBE (~6 ml per 10 μmol
of substrate) and sat. NaHCO3 solution (~6 ml per 10 μmol of substrate). The organic layer was separated,
washed with sat. NaHCO3 solution (~6 ml per 10 μmol of substrate), and brine (~6 ml per 10 μmol of substrate),
dried with MgSO4, filtered, and concentrated in vacuo at 25 °C. Silica gel column chromatography of the residue
(SiO2 15–40 μm, 1.5 × 15 cm for ~16 μmol of substrate) provided the (S)-MTPA ester (S)-SI-6/SI-7/SI-8. The
(R)-MTPA ester (R)-SI-6/SI-7/SI-8 were analogously prepared from the epoxy alcohol using (S)-(+)-MTPA–Cl.
- 17 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
Computational details
All spin polarized density functional theory (DFT) calculations were performed within the Orca program
package version 4.0.1,[45] whereas input structures for transition state geometry optimization were generated with
the Spartan 14v114 software by the semi-empirical parameterized model 6 (PM6) method.[46] For all DFT
calculations the correlation consistent cc-pVDZ basis set according to Dunning was used.[36d] The exchange and
correlation effects were taken into account with the hybrid functional by Becke and Lee–Yang–Parr
(B3LYP)[36c,e] and dispersion interactions were considered via the Becke–Johnson damping scheme
[D3(BJ)].[36a,b] For the energy rotation profiles, constrained geometry optimizations were performed at fixed
dihedral angles, which were spanned by the oxygen atom of the respective epoxide and aldehyde groups. The
transition states were located by calculating the Hesse matrix and fully optimizing their geometries in the gas
phase. By calculating the vibrational frequencies within the harmonic approximation, the optimized structures
were confirmed as transition states through the presence of only one imaginary frequency.
Acknowledgements
Partial support by the TMWWDG (grant no. 43-5572-321-12040-12, to H.-D. A) and the DFG (SFB 1127, to
H.-D. A.) is acknowledged. R. R. A. F. was a recipient of a doctoral fellowship from the Fonds der Chemischen
Industrie (FCI). Computational resources were provided by the state of Baden-Württemberg through bwHPC and
the DFG (INST 40/467-1 FUGG, to T. J.).
Author contributions
H.-D.A. and T.J. designed and supervised research. R.R.A.F synthesized and characterized compounds,
supported by R.S. DFT calculations were conducted by M.v.d.B. and D.G. The manuscript was written by
R.R.A.F and H.-D.A., with contributions of all authors.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Allylation • Allylboronates • Synthetic methods • Stereoinduction models • Cornforth-Evans
References
[1]
(a) P. A. Frey, A. D. Hegeman, Enzymatic reaction mechanisms, Oxford University Press, 2007; (b) M.
E. Glasner, J. A. Gerlt, P. C. Babbitt, Curr. Opin. Chem. Biol. 2006, 10, 492–497.
(a) R. B. Woodward, E. Logusch, K. P. Nambiar, K. Sakan, D. E. Ward, B. W. Au-Yeung, P. Balaram,
L. J. Browne, P. J. Card, C. H. Chen, J. Am. Chem. Soc. 1981, 103, 3210–3213; (b) H. Nagaoka, Y.
Kishi, Tetrahedron 1981, 37, 3873–3888.
[2]
[3]
J.-D. Zhai, D. Li, J. Long, H.-L. Zhang, J.-P. Lin, C.-J. Qiu, Q. Zhang, Y. Chen, J. Org. Chem. 2012,
77, 7103−7107.
[4]
[5]
S. Roscales, J. Plumet, Int. J. Carbohydr. Chem. 2016, Article ID 4760548.
W.-j. Chung, J. S. Carlson, D. K. Bedke, C. D. Vanderwal, Angew. Chem. 2013, 125, 10236–10239;
Angew. Chem. Int. Ed. 2013, 52, 10052–10055.
- 18 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
[6]
(a) T. Sawano, H. Yamamoto, J. Org. Chem. 2018, 83, 4889−4904; (b) A. M. Bailey, S. Wolfrum, E.
M. Carreira, Angew. Chem. 2016, 128, 649–653; Angew. Chem. Int. Ed. 2016, 55, 639–643; (c) Q. Wu,
C. Wu, H. Long, R. Chen, D. Liu, P. Proksch, P. Guo, W. Lin, J. Nat. Prod. 2015, 78, 2461–2470; (d)
M. Sasaki, K. Tanino, A. Hirai, M. Miyashita, Org. Lett. 2003, 5, 1789–1791; (e) R. M. Hanson, Chem.
Rev. 1991, 91, 437–475.
[7]
[8]
R. R. A. Freund, P. Gobrecht, Z. Rao, J. Gerstmeier, R. Schlosser, H. Görls, O. Werz, D. Fischer, H.-D.
Arndt, Chem. Sci. 2019, 10, 7358–7364.
(a) T.-P. Loh, Z. Yin, H.-Y. Song, K.-L. Tan, Tetrahedron Lett. 2003, 44, 911–914; (b) A. Mengel, O.
Reiser, Chem. Rev. 1999, 99, 1191–1223; (c) M. J. Wanner, N. P. Willard, G. J. Koomen, U. K. Pandit,
Tetrahedron 1987, 43, 2549–2556; (d) R. H. Schlessinger, J. L. Wood, J. Org. Chem. 1986, 51, 2623–
2624; (e) D. A. Hutchison, K. R. Beck, R. A. Benkeser, J. B. Grutzner, J. Am. Chem. Soc. 1973, 95,
7075–7082.
[9]
A. D. Walsh, Trans. Faraday Soc. 1949, 45, 179–190.
[10]
(a) N. Bartlett, L. Gross, F. Péron, D. J. Asby, M. D. Selby, A. Tavassoli, B. Linclau, Chem. Eur. J.
2014, 20, 3306–3310; (b) F. Zhang, Y. Liu, L. Xie, X. Xu, RSC Advances 2014, 4, 17218–17221; (c) Y.
Takeda, T. Matsumoto, F. Sato, J. Org. Chem. 1986, 51, 4728–4731; (d) L. A. Paquette, T. M. Mitzel,
J. Am. Chem. Soc. 1996, 118, 1931–1937.
[11]
[12]
(a) N. T. Anh, O. Eisenstein, Nouv. J. Chim. 1977, 1, 61–70; (b) M. Chérest, H. Felkin, N. Prudent,
Tetrahedron Lett. 1968, 9, 2199–2204.
(a) J. D. Dunitz, J. M. Lehn, G. Wipff, Tetrahedron 1974, 30, 1563–1572; (b) H. B. Bürgi, J. D. Dunitz,
E. Shefter, J. Am. Chem. Soc. 1973, 95, 5065–5067.
[13]
[14]
V. J. Cee, C. J. Cramer, D. A. Evans, J. Am. Chem. Soc. 2006, 128, 2920–2930.
(a) R. E. Rosenberg, W. J. Kelly, J. Phys. Org. Chem. 2015, 28, 47–56; (b) D. A. Evans, S. J. Siska, V.
J. Cee, Angew. Chem. 2003, 115, 1803–1807; Angew. Chem. Int. Ed. 2003, 42, 1761–1765; (c) J. A.
Marco, M. Carda, S. Díaz-Oltra, J. Murga, E. Falomir, H. Roeper, J. Org. Chem. 2003, 68, 8577–8582;
(d) B. W. Gung, X. Xue, Tetrahedron: Asym. 2001, 12, 2955–2959; (e) W. R. Roush, M. A. Adam, A.
E. Walts, D. J. Harris, J. Am. Chem. Soc. 1986, 108, 3422–3434.
[15]
[16]
J. W. Cornforth, R. H. Cornforth, K. K. J. Mathew, J. Chem. Soc. 1959, 112–127.
(a) C. Gennari, E. Fioravanzo, A. Bernardi, A. Vulpetti, Tetrahedron 1994, 50, 8815–8826; (b) C.
Gennari, S. Vieth, A. Comotti, A. Vulpetti, J. M. Goodman, I. Paterson, Tetrahedron 1992, 48, 4439–
4458; (c) W. R. Roush, J. Org. Chem. 1991, 56, 4151–4157.
[17]
[18]
I. Fleming, Molecular Orbitals and Organic Chemical Reactions: Reference Edition, John Wiley &
Sons, 2010, 226–229.
(a) Y. Zhang, Y. Wu, Org. Biomol. Chem. 2010, 8, 4744–4752; (b) A. Alexakis, P. Mangeney, J. F.
Normant, Tetrahedron Lett. 1985, 26, 4197–4200.
[19]
[20]
H. Ren, A. Krasovskiy, P. Knochel, Chem. Commun. 2005, 543–545.
A. Krasovskiy, B. F. Straub, P. Knochel, Angew. Chem. 2006, 118, 165–169; Angew. Chem. Int. Ed.
2006, 45, 159–162.
[21]
K. Kitagawa, A. Inoue, H. Shinokubo, K. Oshima, Angew. Chem. 2000, 112, 2594–2596; Angew.
Chem. Int. Ed. 2000, 39, 2481–2483.
- 19 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
[22]
(a) R. W. Hoffmann, T. Sander, A. Hense, Liebigs Ann. Chem. 1993, 771–775; (b) T. Watanabe, N.
Miyaura, A. Suzuki, J. Organomet. Chem. 1993, 444, C1–C3; (c) P. Knochel, J. Am. Chem. Soc. 1990,
112, 7431–7433.
[23]
[24]
[25]
[26]
D. F. Taber, M. I. Sikkander, J. F. Berry, K. J. Frankowski, J. Org. Chem. 2008, 73, 1605–1607.
A. Yanagisawa, S. Habaue, H. Yamamoto, J. Am. Chem. Soc. 1991, 113, 5895–5896.
I. W. Ashworth, J. A. L. Miles, D. J. Nelson, J. M. Percy, K. Singh, Tetrahedron 2009, 65, 9637–9646.
R. R. A. Freund, P. Gobrecht, P. Moser, D. Fischer, H.-D. Arndt, Org. Biomol. Chem. 2019, 17, 9703–
9707.
[27]
[28]
T. G. Elford, D. G. Hall, Synthesis 2010, 893–907.
(a) P. G. M. Wuts, S. S. Bigelow, J. Org. Chem. 1988, 53, 5023–5034; (b) W. R. Roush, M. A. Adam,
D. J. Harris, J. Org. Chem. 1985, 50, 2000–2003.
[29]
G. Niel, F. Roux, Y. Maisonnasse, I. Maugras, J. Poncet, P. Jouin, J. Chem. Soc., Perkin Trans. 1 1994,
1275–1280.
[30]
[31]
[32]
T. R. Hoye, C. S. Jeffrey, F. Shao, Nat. Protoc. 2007, 2, 2451–2458.
M. Chen, W. R. Roush, J. Am. Chem. Soc. 2012, 134, 3925–3931.
A. Ghantous, H. Gali-Muhtasib, H. Vuorela, N. A. Saliba, N. Darwiche, Drug Discov. Today 2010, 15,
668–678.
[33]
[34]
T. M. Hansen, G. F. Florence, P. Lugo-Mas, J. Chen, J. N. Abrams, C. J. Forsyth, Tetrahedron Lett.
2003, 44, 57–59.
(a) R. Bloch, C. Brillet, Synlett 1991, 829−830; (b) R. R. A. Freund, H.-D. Arndt, J. Org. Chem. 2016,
81, 11009−11016.
[35]
[36]
J. J. Gajewski, W. Bocian, N. L. Brichford, J. L. Henderson, J. Org. Chem. 2002, 67, 4236–4240.
(a) S. Grimme, S. Ehrlich, L. Goerigk, J. Comput. Chem. 2011, 32, 1456–1465; (b) S. Grimme, J.
Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010, 132, 154104; (c) A. D. Becke, J. Chem. Phys. 1993,
98, 5648–5652; (d) T. H. Dunning Jr., J. Chem. Phys. 1989, 90, 1007–1023; (e) C. Lee, W. Yang, R. G.
Parr, Phys. Rev. B 1988, 37, 785–789.
[37]
[38]
[39]
[40]
[41]
R. M. Pontes, B. C. Fiorin, E. A. Basso, Chem. Phys. Lett. 2004, 395, 205–209.
G. Frenking, K. F. Köhler, M. T. Reetz, Tetrahedron 1993, 49, 3971–3982.
G. J. Karabatsos, D. J. Fenoglio, J. Am. Chem. Soc. 1969, 91, 3577–3582.
W. M. Haynes, CRC Handbook of Chemistry and Physics, 97 ed., CRC press, 2017, 9-59–9-67.
(a) A. Vulpetti, M. Gardner, C. Gennari, A. Bernardi, J. M. Goodman, I. Paterson, J. Org. Chem. 1993,
58, 1711–1718; (b) Y. Li, K. N. Houk, J. Am. Chem. Soc. 1989, 111, 1236–1240.
R. S. Paton, J. M. Goodman, J. Org. Chem. 2008, 73, 1253–1263.
[42]
[43]
[44]
S. E. Denmark, G. L. Beutner, T. Wynn, M. D. Eastgate, J. Am. Chem. Soc. 2005, 127, 3774–3789.
R. Robiette, J. Richardson, V. K. Aggarwal, J. N. Harvey, J. Am. Chem. Soc. 2005, 127, 13468–13469.
[45]
[46]
F. Neese, Wiley Interdiscip. Rev.: Comput. Mol. Sci. 2012, 2, 73–78.
(a) J. J. P. Stewart, J. Mol. Model. 2007, 13, 1173–1213; (b) Spartan '14, Irvine, 2014.
- 20 -
This article is protected by copyright. All rights reserved.

10.1002/chem.202001479
Chemistry - A European Journal
Freund et al.: Cornforth-Evans transition states in stereocontrolled allylborations of epoxy aldehydes…
Entry for the Table of Contents
Graphics for the Table of Contents
Text for the table of contents:
Felkin–Anh or Cornforth–Evans? The allylboration of epoxy aldehydes provides a stereoselective access to
contiguously functionalized alkyl chains as found in a myriad of natural products. Studying this transformation
in experiment and in silico disclosed high stereoselectivities, the mode of asymmetric induction, and enabled the
predictable application for stereocontrolled synthesis of complex molecules.
ORCID information
Robert R. A. Freund: 0000-0001-5771-3237
Matthias van den Borg: 0000-0002-5364-1675
Daniel Gaissmaier: 0000-0002-7688-1989
Timo Jacob: 0000-0001-7777-2306
Hans-Dieter Arndt: 0000-0002-0792-1422
- 21 -
This article is protected by copyright. All rights reserved.