Ferrocene derivatives of liquid chiral molecules allow assignment of absolute configuration by X-ray crystallography

Article abstract of DOI:10.1016/j.tetasy.2017.09.002

The present study investigates a synthetically simple ferrocene derivatization of natural products and active pharmaceutical ingredients. Seven new crystal structures are analyzed together with 16 structures of ferrocene derivatives reported previously. In all cases, the unambiguous determination of the absolute structure was established from anomalous dispersion using the methods of Flack and Parsons. A comparison with other derivatization approaches shows the advantage of the described ferrocene derivatization for establishing the absolute configuration of novel compounds.

Full text of DOI:10.1016/j.tetasy.2017.09.002

Tetrahedron: Asymmetry 28 (2017) 1321–1329
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Ferrocene derivatives of liquid chiral molecules allow assignment
of absolute configuration by X-ray crystallography
Philipp M. Holstein a, , Julian J. Holstein , Eduardo C. Escudero-Adán , Olivier Baudoin ,
⇑
b,
⇑
a
c
a,d
Antonio M. Echavarren
a
Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Av. Països Catalans 16, 43007 Tarragona, Spain
Faculty of Chemistry and Chemical Biology, TU Dortmund, Otto-Hahn-Str. 6, 44227 Dortmund, Germany
University of Basel, Department of Chemistry, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/ MarcelÁli Domingo s/n, 43007 Tarragona, Spain
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
The present study investigates a synthetically simple ferrocene derivatization of natural products and
active pharmaceutical ingredients. Seven new crystal structures are analyzed together with 16 structures
of ferrocene derivatives reported previously. In all cases, the unambiguous determination of the absolute
structure was established from anomalous dispersion using the methods of Flack and Parsons. A compar-
ison with other derivatization approaches shows the advantage of the described ferrocene derivatization
for establishing the absolute configuration of novel compounds.
Received 15 August 2017
Revised 21 August 2017
Accepted 1 September 2017
Available online 6 October 2017
Dedicated to the memory of Dr. Howard
Flack
Ó 2017 Elsevier Ltd. All rights reserved.
1
. Introduction
the absolute structure of a crystal on a routine basis.11–14 This in
turn allows the assignment of the absolute configuration of the chi-
15
Chirality plays a central role in biological recognition processes.
ral molecules contained in the crystal structure. Hooft et al. and
1
6
Therefore, the vast majority of molecules addressing biological
receptors such as natural products, active pharmaceutical ingredi-
ents and fragrances are chiral. Asymmetric syntheses and enan-
tioselective total syntheses have seen recent major advances.
Unfortunately, we are facing deficits in the analysis of unknown
compounds as witnessed by the considerable number of wrongly
assigned natural products in the literature.1 As a consequence,
the correction of structural assignments for natural products is a
common outcome of total syntheses. Although these efforts correct
wrongly assigned structures in the literature, it is a very costly way
to do so. New methods for better and easier determination of the
absolute configuration are still necessary. Currently a general
Parsons et al. have further optimized this approach which even
allows the absolute structure determination of molecules contain-
1
7
ing only light atoms.
With advances in primary beam intensity, computational power
and X-ray detectors, the measurement as well as the refinement
have become fast processes, which make crystallography a rapid
technique to determine previously unknown molecular structures.
However, the route from a pure compound to a suitable single
crystal is often tedious and the bottle neck of the process.10 Sam-
ples which are liquid at room temperature represent a particular
challenge. Although crystallization under cryogenic conditions is
possible, it requires specialized equipment and takes considerable
,2
3
,4
18
approach for the absolute structure determination does not exist
effort. Even solid samples can require crystallization to give a sin-
5–7
19
and different methods are available including NMR,
chiroptical
gle crystal of good quality. It is therefore not surprising that the
spectroscopic methods8 and X-ray diffraction. When crystals of
a molecule of interest are obtained, single-crystal X-ray crystallog-
raphy is the method of choice for structure elucidation.9 It gives
access to the three dimensional structure of a molecule and, with
the method introduced by Flack, also allows the determination of
5,9
discussion about crystal size and quality can lead to incomprehen-
sion between crystallographer and synthetic chemist. In some
cases special equipment or sophisticated methods can help. Tiny
,10
3
crystals with dimensions below 0.1 Â 0.1 Â 0.1 mm can nowadays
be measured on modern in-house diffractometers and more pri-
mary beam intensity is available at modern synchrotron X-ray
diffraction beamlines. Fujita et al. presented the crystalline sponge
method, a supramolecular approach, which is based on soaking
⇑
Corresponding authors at present address: Edelris, 115, Av. Lacassagne, 69003
Lyon, France (P.M. Holstein). Tel.: +33 4 3756 16 63 (P.M.H.); tel.: +49 231 755
2
0
3
426; fax: +49 231 755 8138 (J.J.H.).
small molecules into MOF crystals. Its procedure has been criti-
2
1
22
E-mail addresses: pholstein@iciq.es (P.M. Holstein), julian.holstein@tu-dort-
cally assessed, further optimized and successfully applied for
mund.de (J.J. Holstein).
https://doi.org/10.1016/j.tetasy.2017.09.002
0
957-4166/Ó 2017 Elsevier Ltd. All rights reserved.

1
322
P. M. Holstein et al. / Tetrahedron: Asymmetry 28 (2017) 1321–1329
assigning the absolute configuration of natural products.23,24 Nev-
ertheless, establishing the absolute configuration of liquid or non-
crystalline compounds remains a challenge frequently encoun-
tered in the synthetic laboratory. Historically organic chemists
solve this problem by derivatization. Before the arrival of powerful
spectroscopic methods, crystallization and determination of melt-
ing points were of central importance as purification and analytical
2. Concept
With the aim of establishing the absolute configuration of a sca-
lemic, liquid sample we searched for an operationally simple way
to solve this problem. We sought to render oily organic substrates
crystalline by covalently linking them to an organometallic com-
pound with high melting point and good crystallinity. For this pur-
pose ferrocene carboxylic acid seems to be the ideal candidate as it
combines several attractive properties:
th
methods, respectively. From the late 19 century, alcohols were
converted into the corresponding nitrobenzoates (4-NO
NO benzoates), and aldehydes and ketones into the correspond-
ing 3,5-(NO
2
or 3,5-
(
2 2
)
-phenyl hydrazones2
5,26
which are characterized by
2
)
2
ꢀ Highly crystalline
high crystallinity and sharp melting points. Comparison of the
obtained melting points allowed the structural identity of products
to be proved. Milestones such as Fischer’s ground breaking work on
sugars and the asymmetric carbon atom itself were based on
ꢀ Contains a heavy atom for increased diffraction intensity
ꢀ Intense anomalous scattering effect allowing for the determina-
tion of the absolute structure
ꢀ Chemically and thermally stable
2
7,28
chemical derivatization.
The conversion of different sugars into
ꢀ Characteristic orange color
their corresponding osazones29 (Scheme 1a), which have sharp
melting points and stable optical rotations enabled Fischer’s funda-
mental work with which the concept of the chiral carbon atom was
37–39
ꢀ High sensitivity to electrospray mass spectrometry
40
ꢀ Relatively inexpensive or easily synthesized from ferrocene
30
Based on seminal work by Shibata et al. (vide infra),41–43 we
identified ferrocene carboxylic acid as an ideal auxiliary that could
be easily reacted under mild conditions with liquid chiral mole-
cules containing either an alcohol and/or amine functionality
(Scheme 2). Either one of these two functional groups is found in
most natural products, active pharmaceutical ingredients and in
many synthetic intermediates. Therefore, we reasoned that this
method should be broadly applicable.
introduced into sugar chemistry. The characterization and the
3
1
first industrial synthesis of vitamin A involved esterification into
32
the corresponding anthraquinone ester 4 for the purpose of
recrystallization (Scheme 1b).33 After purification at this stage,
saponification liberates the desired vitamin A in its pure, high
3
4
melting form.
Of those important derivatization techniques,35 only the
nitrobenzoate derivatization remained and is still routinely used
to facilitate the crystallization of difficult samples.36 Unfortunately,
this auxiliary does not introduce a heavy atom or a stereogenic ref-
erence center, which would help assigning the absolute configura-
tion by means of X-ray crystallography.
We have identified ferrocene derivatization as a simple and effi-
cient technique for obtaining single crystals. We have found it very
useful for establishing the absolute configuration and will start by
introducing the rationale behind this idea.
O
R* OH
or
5
6
FcCO
H
R*
2
R*
X
Fe
Absolute structure
R* NH2
7
(X = O)
8
(X = NR')
liquid
solid
single crystal
a)
H
N
Scheme 2. Concept of ferrocene derivatization to transfer liquid, chiral substrates
into crystalline solids.
H
O
H
N
Ph
Ph
H
H
HO
H
OH
H
OH
OH
N
H
OH
OH
N
Fischer (1884)
Herein, we will (a) analyze the synthetic scope; (b) discuss the
capacities of the method to increase the melting point and yield high
quality crystallographic data suitable for unequivocal assignment of
the absolute configuration; and (c) comment on its limitations.
HO
H
H
H
CH OH
CH OH
2
2
Glucose (1)
Glucosazone (2)
3. Results and discussion
3
3
.1. Synthetic part
b)
O
.1.1. Initial proof of concept
O
With the above detailed considerations in mind, we set out to
test our idea for the first time on indane 6a (Scheme 3). The correct
analysis of its precursor 9 was a center piece to our report on cat-
alytic asymmetric C(sp )AH activation and allowed us to resolve a
3
OH
O
O
Hamano (1935)
and
Isler (1947)
contradiction between a previous assignment of the absolute con-
4
4
figuration and a DFT study. The liquid nitrile 9 was reduced to the
liquid amine 6a, which was finally converted into the solid ferro-
cenyl amide 8a by reaction with commercially available ferrocene
carboxylic acid. The large (0.60 Â 0.48 Â 0.34 mm) single crystal
obtained gave excellent diffraction data and allowed us to establish
the (R,R)-configuration of indane 8a with high certainty (Flack
x = 0.006(12)). The corresponding amide derived from 3-bromo
benzoic acid remained a liquid and did not allow for crystallo-
Vitamine A (3)
Vitamine A anthraquinone ester (4)
4
5
graphic analysis.
Encouraged by our first example which enabled facile
crystallization and resulted in high quality X-ray diffraction data,
Scheme 1. Prominent historical examples of derivatizations which improve
crystallinity.

P. M. Holstein et al. / Tetrahedron: Asymmetry 28 (2017) 1321–1329
1323
NH2
i-Pr
Me
alcohols, nerol 5c and geraniol 5d, were converted into the cor-
NC
responding ferrocene carboxylates 7c and 7d. The reaction can
i-Pr
Me
LiAlH4
49
be easily carried out on a small scale (65 lmol scale for 7d).
THF, 80 °C
The characteristic orange color is a particular advantage during
chromatographic purification of small amounts because it facili-
tates product detection. Eugenol, a phenolic fragrance molecule
found in cloves, was converted efficiently into the corresponding
ferrocene carboxylate 7e. Recovery of the natural product from
ferrocene carboxylates 7 is possible. After saponification of 7e
using lithium hydroxide, we isolated pure eugenol 5e in 75%
FcCO H
PyBOP
2
9
97%
6a
(
iPr) NEt
2
CH Cl , r.t.
2
2
O
98%
iPr
NH
Me
Fe
4
9
yield. The ferrocenyl esters of the secondary alcohols choles-
5
0,51
52
terol 5f
and cholestanol 5g were prepared through reaction
with ferrocenoyl chloride at room temperature. Esters of more
8
a
50
hindered secondary alcohols, such as testosterone
or men-
Scheme 3. Ferrocene derivatization and crystallization of a chiral indane.44
53
thol, could not be obtained at room temperature. Moreover,
the esterification of tertiary alcohols was unsuccessful, e.g., (R)-
linalool 5h did not react at all. In the literature, the only fer-
rocene carboxylate issued from a tertiary alcohol was obtained
the ferrocene derivatization was applied in the total synthesis of
4
6,47
aeruginosins.
The preparation of the octahydroindole core of
54
by refluxing ferrocenoyl chloride in tert-butanol. These results
these molecules involved a nucleophilic substitution step on dibro-
mocyclohexenol 10 to give intermediate 13 (Scheme 4). Although
this reaction had been reported previously to proceed with high
cis-selectivity with sodium azide as the nucleophile,48 the nucle-
show that esterification of sterically hindered alcohols is a limi-
tation of our current synthetic strategy. Additionally, it should be
mentioned that
remained liquid.
a small number of ferrocene derivatives
3
ophilic substitution with an aliphatic amine followed by C(sp )A
The liquid thiophene building block 6b was converted into the
solid amide 8b by reacting with ferrocene carboxylic acid. As
expected, the secondary amine ephedrine reacted selectively at
the nitrogen atom in the presence of a free hydroxyl group when
using peptide coupling conditions.
H activation led to an aeruginosin fragment with a trans-configura-
tion. To clarify the outcome of the substitution step, compounds 11
and 12 were prepared. Structural elucidation by NOE NMR would
have been particular challenging and so ferrocene derivatization
was applied. After deprotection of the alcohol, Steglich esterifica-
tion with ferrocene carboxylic acid gave 7a and 7b as orange solids.
Crystals suitable for X-ray crystallography were obtained in the
first recrystallization attempt. The crystal structures of 7a and 7b
allowed us to establish the stereodivergent behavior for the nucle-
ophilic substitution of 10 with different nucleophiles.
The derivatization of two sterically hindered amines was
55
recently described by one of us (Scheme 6). Chiral indoline carba-
3
mates 14, obtained from asymmetric C(sp )AH activation are liq-
uid substances. Therefore, 14d–e were deprotected to the NAH
indolines 6d–e and converted into the corresponding ferrocene
carboxamides. Whereas 8d could be prepared using classical con-
ditions, 8e required the generation of the lithium amide which
was then reacted with ferrocenoyl chloride.
For all of the above described liquid molecules, we were able to
obtain good single crystals through ferrocene derivatization. Crys-
tal structures obtained were of high quality and allowed to assign
the absolute configuration for all chiral molecules (vide infra).
3
.1.2. New ferrocenyl ester and amides
After the success of these two initial applications, we investi-
gated the scope of the ferrocene derivatization by applying it to
other chiral or liquid molecules, with a focus on natural products
Scheme 5). Ferrocenyl esters and amides were prepared via fer-
rocenoyl chloride (method A) or using the activating agent
PyBOP (method B). Both protocols were operationally simple
and without any optimization, the desired products were
obtained in moderate to high yield. The oily monoterpene
(
3
.1.3. Structures published by other groups
Shibata et al. used ferrocene derivatization with the aim of
obtaining single crystals already in 2006. They described the first
1
) TBAF, THF
Br
Br
O
O
cis pathway
TBDPSO
0 °C to r.t., 16h
N3
N3
2) FcCO H, EDCI, DMAP
Fe
2
CH Cl , 0 °C to r.t., 16h
(
±)-11
2
2
Br
Br
d.r. 15:1
Nu
(
±)-7a
5% over 2 steps
3
TBDPSO
1) TBAF, THF
Br
Br
0
°C to r.t., 16h
O
(
±)-10
d.r. 6:1
trans pathway
O
N
H
TBDPSO
N
H
2) FcCO H, EDCI, DMAP
2
Fe
CH Cl , 0 °C to r.t., 16h
2
2
(
±)-12
d.r. 11:1
(
±)-7b
1% over 2 steps
1
H
Br
R
C-H activation
OTBS
TBDPSO
N
H
N
O
RO
H H
13
Aeruginosin fragment
Scheme 4. Investigation of the stereochemistry of a nucleophilic substitution in the context of the total synthesis of aeruginosins.47

1
324
P. M. Holstein et al. / Tetrahedron: Asymmetry 28 (2017) 1321–1329
method A
method B
O
O
O
O
(
COCl)2
RXH
RXH
DMF (cat.)
OH
Cl
XR
OH
Fe
Fe
Fe
Fe
CH Cl2
2
DMAP
PyBOP, (iPr)
2
NEt
CH Cl 23 °C
CH Cl 23 °C
2
2,
2
2,
prepared in situ
X = O (5)
X = NHR' (6)
7
8
X = O (5)
X = NHR' (6)
commercially available
or
isolated
alcohol derivatization
amine derivatization
H
O
O
N
H
H
O
Fe
O
O
H
H
Fe
H
S
c (40%)b
Fe
7
8b (70%)a
f (40%)a
7
O
O
O
H
Fe
Fe
H
Fe
N
Ph
O
O
H
HO
8c (85%)b
7
d (51%)b
Fe
Fe
7
g (82%)a
O
O
O
O
O
7
h (0%)a
7
e (97%)a
Scheme 5. Ferrocene derivatization of representative liquid or chiral alcohol and amine substrates, reaction conditions: amethod A, bmethod B.
assigned the absolute configuration of 5t, an intermediate in the
6
0
total synthesis of (À)-cyclosmenospongine, via crystallization of
the ferrocene carboxylate 7t. The latter demonstrates that a steri-
cally hindered neopentylic alcohol can be efficiently converted
N
O
conditions a or b
R
(
70%) at room temperature.
R
N
Fe
The independent applications by different international
R'
research groups underline that a powerful and operationally sim-
ple method to introduce a heavy atom containing moiety has been
found.
1
4 (R' = CO Me)
2
8d R = H (83%)
e R = CO Me (80%)
8
2
6
(R' = H)
5
5
3.2. Physical properties
Scheme 6. Preparation of tertiary ferrocenyl amides, reaction conditions: (a)
i
DMAP, Pr
2
NEt, FcCOCl, CH
2
Cl
2
, (b) LiHMDS, THF, À78 °C, then FcCOCl, À10 °C.
3
.2.1. Melting point
As discussed before, derivatization with p-nitrobenzoic acid has
two examples of ferrocene carboxylates which allowed X-ray
diffraction analysis and established the absolute configurations of
been used for a long time to deliver solids with sharp melting
points from samples of poor crystallinity. A related, measureable
effect is the increase in melting point that the p-nitrobenzoyl
derivatization often induces. As a consequence it converts certain
liquid samples into solids and thus allow for crystallization. In
order to critically assess the utility of the ferrocene derivatization
for liquid samples, we wanted to compare the melting points of
ferrocene and p-nitrobenzoate derivatives of the same compound.
Herein we have included the described compounds 5c–5f, 6b–c as
4
1
7
i–k (Fig. 1). In the following years, this process was applied to
the chiral alcohols 7l–m and the determination of their absolute
configuration was reported.4
2,43
Although some structures already
contained a heavy atom, the ferrocene moiety helped in the recrys-
tallization process. Burns et al. have applied the ferrocene deriva-
tization to synthetic intermediates of the halogenated terpene
(
+)-halomon and found the ferrocene carboxylates ‘‘as being partic-
4
9
ularly valuable in cases where common benzoate and sulfonate
derivatives fail to induce adequate crystallinity.”56 The same group
also prepared the polyhalogenated structures 7p–q and studied
their conformation in the solid state.57 In both cases, the primary
alcohol reacted selectively in the presence of a secondary alcohol.
well as the literature known derivatives 5u–z, 6f–l.
In general, the melting points of both derivatives are relatively
similar (Fig. 2). Geraniol 5d, a component of essential oils, was con-
verted from liquid to solid state by both derivatization approaches.
Only sporadically, e.g., 5e, 5v or 6c, marked differences between
both derivatives can be noted. Although the comparison is of lim-
ited significance, it shows that ferrocene derivatization is as pow-
5
8
Brown et al. determined the absolute configuration of 7r.
5
9
Magauer et al. determined the constitution of racemic 7s and

P. M. Holstein et al. / Tetrahedron: Asymmetry 28 (2017) 1321–1329
1325
Fe
O
O
NMeTs
TsN
O
O
Fe
O
O
O
7k
Fe
7i
O
O
O
O
Fe
CF3
Fe
7m
7l
Br
Cl
Cl Me
Br
O
O
O
Cl
Cl
O
Fe
Fe
Cl
Cl
Br
7
n
7o
OH Cl
Cl
Br OH Br
O
O
O
Me
O
Me
Fe
Fe
Fe
Cl
Cl
Br
Br
Br
7p
7q
O
O
OCH3
N
7
r
O
O
Figure 2. Comparison of the melting points of (a) ester derived from alcohols 5 and
(b) amides derived from amines 6 (orange: ferrocene derivatives, blue: p-
SPh
H C
3
O
O
H C
3
CH3
nitrobenzoyl derivatives; average values are plotted for melting points which were
O
49
O
reported as temperature ranges).
Fe
O
O
Fe
H
7t
OBoc
(
±)-7s
3
H C
Figure 1. Further examples of successful utilization of ferrocene derivatization for
crystallization.
erful as p-nitrobenzoyl for the conversion of liquid samples 5c–e,v,
w,z and 6b,f–h,k into solids.
3
.2.2. Crystallographic data
Single crystals suitable for X-ray diffraction analysis of 7c, 7e–g
and 8b–c were obtained by recrystallization. The ability to obtain
crystal structure of 7c and 7e (Fig. 3) is particularly remarkable
since the original compounds are oily liquids. Crystal structures
of the steroid derivatives 7f–g and ephedrine derivative 8c are
good examples of absolute configuration determination for com-
pounds possessing only light atoms Recrystallization was mostly
carried out by vapor diffusion (for crystal structures in Fig. 3)
and crystals with edge length ꢁ0.5 mm are not rare (Table 1). In
some cases the crystal obtained was too large for a modern rotat-
ing anode with focusing mirrors and had to be cut to conduct the
X-ray experiment.
The crystallographic data of the above described ferrocene
derivatives are listed in Table 1. When structure factors of com-
pounds previously reported in the literature were available, the
61
structures were re-refined using SHELXL. Since the methods of
Parsons and Hooft improve the precision of the enantiopure distin-
guishing parameter in a similar way,62 we calculated it using Par-
sons quotients here. Most crystal structures had excellent R
ꢁ0.05) with exception of 7m (Table 1).
All crystal structures in Table 1 were measured on either MoK
or GaK radiation and are characterized of excellent absolute
structure parameters (Fig. 4). The limit for enantiopure compounds
1
values
(
a
a
Figure 3. Crystal structures of 7c, 7e, 7f, 7g, 8b, 8c (Ortep representation with
thermal ellipsoids at 50% probability).

1
326
P. M. Holstein et al. / Tetrahedron: Asymmetry 28 (2017) 1321–1329
Table 1
Crystal data obtained from new or previously reported ferrocene derivatives
No.
R1
wR2
GooF
Radiation type
Crystal system, space group
Crystal dimensions (mm3)
Flack xa
7
(
(
±)-7a4
0.0499
0.0468
0.0323
0.0532
0.0478
0.0761
0.0435
0.0856
0.0317
0.1672
0.0533
0.0187
0.0228
0.0301
0.0412
0.0447
0.0327
0.0309
0.0225
0.0450
0.0380
0.0471
0.1038
0.0799
0.1358
0.1283
0.1870
0.1136
0.2138
0.0745
0.3666
0.1103
0.0478
0.0481
0.0671
0.0892
0.0792
0.0818
0.0809
0.0632
0.1192
0.1098
1.0423
1.005
1.080
1.088
1.059
1.014
0.986
0.914
1.019
1.001
1.051
1.032
0.994
1.111
1.070
1.039
1.109
1.039
1.062
1.096
1.040
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
MoK
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
Triclinic, P1ꢀ
Monoclinic, P2
Monoclinic, P2
Triclinic, P1ꢀ
Monoclinic, C2
Triclinic, P1
0.47 Â 0.38 Â 0.12
0.55 Â 0.27 Â 0.20
0.40 Â 0.04 Â 0.02
0.35 Â 0.25 Â 0.15
0.10 Â 0.05 Â 0.03
0.10 Â 0.05 Â 0.05
0.60 Â 0.20 Â 0.20
0.40 Â 0.40 Â 0.10
0.80 Â 0.50 Â 0.40
0.75 Â 0.29 Â 0.18
0.16 Â 0.15 Â 0.06
0.27 Â 0.18 Â 0.08
0.29 Â 0.09 Â 0.04
0.08 Â 0.07 Â 0.04
0.10 Â 0.06 Â 0.02
0.10 Â 0.03 Â 0.01
0.60 Â 0.48 Â 0.34
0.20 Â 0.15 Â 0.10
0.20 Â 0.15 Â 0.10
0.70 Â 0.30 Â 0.20
0.11 Â 0.07 Â 0.03
—
±)-7b47
0.017(16)b
—
1
1
7
7
7
7
7
7
7
7
7
7
7
7
c
e
f
/n
—
0.026(16)
À0.001(14)
g
i
4
1
c
Monoclinic, P2
Orthorhombic, P2
1
0.000(12)
4
1
0.06(4)c
k
1
2
1
2
1
4
2
c
l
Monoclinic, P2
Monoclinic, P2
Monoclinic, P2
Monoclinic, P2
Triclinic, P1
Monoclinic, P2
Triclinic, P1ꢀ
Monoclinic, P2
Orthorhombic, P2
Monoclinic, P2
Monoclinic, P2
Orthorhombic, P2
Trigonal, P3
1
1
1
1
0.011(13)
4
3
c
m
n
o
p
q
À0.01(4)
5
6
0.053(5)
0.025(3)
0.006(5)
5
5
5
6
7
7
d
1
/n
—
—
5
9
(
±)-7s
6
0
7
8
8
8
8
8
t
1
0.008(10)
0.006(12)c
—
0.007(7)
0.000(12)
0.026 (9)
4
4
a
1
2
1
1
2
1
1
b
c
1
/c
1
5
5
d
GaKa
1
2
2
5
5
e
GaKa
2
a
b
c
Recalculated Flack parameter using the quotient method according to Parsons.
The racemic compound crystalized as conglomerate yielding an enantiopure crystal.
Originally published Flack parameter, see reference in column 1.
d
The compound with an optical purity of 80% ee57 crystalized as racemate.
for X-ray diffraction analysis. Seven new crystal structures of ferro-
cenyl ester and amides containing natural products and synthetic
building blocks are reported. Together with previous applications
in total syntheses and asymmetric catalysis, these examples under-
line that the derivatization of small molecules with ferrocene car-
boxylic acid is an operationally simple method to obtain crystals of
good quality. The strength of this technique lies in the ability to
convert liquid samples into solids and to introduce a heavy atom
for absolute structure determination. The crystallographic data
sets obtained are of high quality and all absolute structures were
unambiguously determined using MoKa or GaKa radiation.
This method has been successful applied in 23 cases, but we
also experienced some limitations, as the derivatization of tertiary
alcohols did not succeed in our hands. That said, the method was
found to be superior to other derivatizations in some examples.
It is based on a simple manipulation, standard equipment and a
commercial reagent which makes it easily accessible for synthetic
chemists. Further application in total synthesis and asymmetric
synthesis are expected in the future.
5
5
. Experimental
.1. General
Figure 4. Flack parameter using quotient method according to Parsons with 1
r
uncertainty.
Ferrocene carboxylic acid (CAS: 1271-42-7) was purchased
6
3
from Sigma Aldrich. Ferrocenoyl chloride was prepared following
standard protocol using oxalyl chloride in dichloromethane with a
catalytic amount of DMF and stored in the glovebox. Alternatively,
Ferrocenoyl chloride can be purchased from Sigma Aldrich (CAS:
defined by Flack of x(u) ꢂ 0.1(1) was easily met and in most cases
the parameter and its standard deviation were significantly smaller
than the strong inversion-distinguishing power x ꢂ 0.04(4) defined
1
293-79-4). The reactions were carried out under argon atmo-
1
3
by Flack. In summary, the ferrocene derivatization of a variety of
liquid chiral molecules allowed us to obtain single crystals suitable
for X-ray crystallography, which enabled us to unambiguously
assign the absolute configuration.
sphere in solvents dried by passing through an activated alumina
TM
column on a PureSolv solvent purification system (Innovative
Technologies, Inc., MA). Purifications were carried out on a Combi-
Ò
+
Flash Rf apparatus. Organic solutions were concentrated under
reduced pressure on a Büchi rotary evaporator. NMR spectra were
recorded at 23 °C on a Bruker Avance 400 Ultrashield and Bruker
Avance 500 Ultrashield apparatus. Mass spectra were recorded
on a Waters LCT Premier Spectrometer. Melting points were deter-
mined using a Büchi melting point apparatus. Crystal structure
4
. Conclusion
We have outlined the concept of derivatizing small molecules
with ferrocene carboxylic acid in order to obtain suitable crystals

P. M. Holstein et al. / Tetrahedron: Asymmetry 28 (2017) 1321–1329
1327
determination for compounds 7e, 7f, 7g, 8b and 8c was carried out
using a Rigaku diffractometer equipped with a Pilatus 200 K area
detector, a Rigaku MicroMax-007HF microfocus rotating anode
39.6, 26.3, 25.7, 17.7, 16.6; mp: 39–41 °C; HRMS-ESI: calculated
+
for C21
5.4. Eugenyl ferrocene carboxylate 7e
To suspension of ferrocenecarboxylic acid (57.4 mg,
2
H26FeNaO [M+Na] : 389.1175; found: 389.1171.
a
with MoK radiation, Confocal Max Flux optics and an Oxford
Cryosystems low temperature device Cryostream 700 plus
(
T = À173 °C). Crystal structure determination for compound 7c
a
were carried out using a Apex DUO diffractometer equipped with
a Kappa 4-axis goniometer, an APEX II 4K CCD area detector, a
0.250 mmol, 1.4 equiv) in DCM (1 mL) were added oxalyl chloride
(0.021 mL, 0.245 mmol, 1.3 equiv) and three drops of dry DMF at
0 °C. After the gas evolution ceased and the reaction mixture
turned into a clear solution, it was stirred for 0.5 h at rt. Next, a
solution of eugenol (30 mg, 0.183 mmol, 1.0 equiv) and DMAP
(61 mg, 0.499 mmol, 2.7 equiv) in DCM (1 mL) was added and
the reaction mixture was stirred for 16 h at rt. The reaction mixture
was quenched by adding a small amount of silica gel and concen-
trating to dryness. The crude product was purified by flash chro-
a
Microfocus Source E025 IuS using MoK radiation, Quazar MX mul-
tilayer Optics as monochromator and an Oxford Cryosystems low
temperature device Cryostream 700 plus (T = À173 °C). Crystal
structures 7a–b, 7i–t and 8a were reported previously and mea-
sured using MoKa radiation from various sources. Amides 8d-e
were also reported previously and measured on a Stoe StadiVari
diffractometer equipped with a MetalJet D2+ 70 and a Pilatus
3
00K area detector using GaK
a
radiation. More detailed informa-
matography (12 g SiO
affording 67 mg (0.178 mmol, 97%) of an orange solid. Single crys-
tals were obtained by vapor diffusion using CH Cl (solvent) and
pentane (anti-solvent). H NMR (400 MHz, CDCl ) d 7.03 (d,
2
, gradient: 0–10% EtOAc in CyHex)
tion on the X-ray experiments of all previously reported structures
can be found in the references given in column 1 of Table 1. Crystal
structures of 7c, 7e–g and 8b–c, which are reported here for the
first time, can be obtained free of charge from the Cambridge Crys-
tallographic Data Centre under the deposit numbers 1568685–
2
2
1
3
J = 8.0 Hz, 1H), 6.89–6.80 (m, 2H), 6.02 (ddt, J = 16.8, 10.1, 6.7 Hz,
1H), 5.19–5.10 (m, 2H), 5.01–4.97 (m, 2H), 4.53–4.48 (m, 2H),
13
1
568690.
4.37 (s, 5H), 3.90 (s, 3H), 3.43 (d, J = 6.7 Hz, 2H);
101 MHz, CDCl ) d 169.9, 151.4, 138.9, 138.1, 137.3, 123.1,
120.9, 116.2, 112.9, 71.8 (2C), 70.8 (2C), 70.3, 70.2 (5C), 55.8,
0.2; mp: 136–137 °C; HRMS-ESI: calculated for C21 20FeNaO
3
C NMR
(
3
5
.2. Neryl ferrocene carboxylate 7c
4
H
+
To
a
suspension of ferrocenecarboxylic acid (82 mg,
[M+Na] : 399.0654; found: 399.0652.
0
.357 mmol, 1.1 equiv), nerol (50 mg, 0.324 mmol, 1.0 equiv),
DMAP (7.9 mg, 0.065 mmol, 0.2 equiv) and DIPEA (0.113 mL,
.648 mmol, 2.0 equiv) in DCM (2 mL) was added PyBOP
186 mg, 0.357 mmol, 1.1 equiv). The reactions mixture turned
into an orange solution and was stirred at r.t. for 16 h. The reaction
mixture was quenched with brine, diluted with EtOAc and the
phases were separated. The aq. layer was extracted with EtOAc
twice and the combined organic extracts were concentrated under
reduced pressure. The crude product was purified by flash chro-
5.5. Recovery of eugenol 5d by saponification of 7d
0
(
Eugenyl ferrocene carboxylate (25 mg, 0.066 mmol, 1.0 equiv)
was added to test tube, dissolved in THF/ MeOH (0.7 mL, ratio
3:1) and cooled to 0 °C. At that temperature, an aqueous solution
of lithium hydroxide (c 1 M, 0.4 mL, 0.396 mmol, 6.0 equiv) was
added. The reaction mixture was allowed to warm up and stirred
for 16 h at rt 600 mg silica were added and all volatiles were evap-
orated. The solid was loaded directly onto a column and purifica-
matography (12 g SiO
7 mg (0.128 mmol, 40%) of an orange oil, which could be crystal-
ized. Single crystals were obtained by vapor diffusion using Et
solvent) and ethanol (anti-solvent). 1H NMR (500 MHz, CDCl
) d
.49–5.43 (m, 1H), 5.17–5.12 (m, 1H), 4.82–4.79 (m, 2H), 4.71
2
, gradient: 0–3% EtOAc in CyHex) affording
4
2
tion by flash chromatography (12 g SiO , 5–10% EtOAc in CyHex)
gave 8.2 mg (0.050 mmol, 75%) of a pale yellow oil. Spectroscopic
2
O
64
(
3
data are were in agreement with the ones previously reported.
1
5
3
H NMR (500 MHz, CDCl ) d = 6.88–6.81 (m, 1H), 6.72–6.64 (m,
(
(
dd, J = 7.2, 0.8 Hz, 2H), 4.39–4.35 (m, 2H), 4.19 (s, 5H), 2.23–2.17
m, 2H), 2.16–2.10 (m, 2H), 1.79 (d, J = 1.2 Hz, 3H), 1.70 (d,
2H), 5.95 (ddt, J = 16.8, 10.0, 6.7 Hz, 1H), 5.47 (s, 1H), 5.12–5.01
(m, 2H), 3.87 (s, 3H), 3.32 (dt, J = 6.6, 1.2 Hz, 2H).
13
J = 0.9 Hz, 3H), 1.63 (s, 3H); C NMR (126 MHz, CDCl
1
6
3
) d 171.6,
42.3, 132.2, 123.7, 119.8, 71.5, 71.2 (2C), 70.2 (2C), 69.7 (5C),
0.8, 32.3, 26.8, 25.7, 23.6, 17.7; mp: 50–51 °C; HRMS-ESI: calcu-
5.6. Cholesteryl ferrocene carboxylate 7f50,51
+
lated for C21
H
26FeNaO
2
[M+Na] : 389.1175; found: 389.1170.
Cholesterol (60.1 mg, 0.155 mmol, 1.0 equiv) and DMAP
(
22.0 mg, 0.180 mmol, 1.2 equiv) were weight in a small vial and
5
.3. Geranyl ferrocene carboxylate 7d
a solution of ferrocenoyl chloride (56.0 mg, 0.225 mmol, 1.5 equiv)
in 2 mL DCM was added dropwise and resulted in a deep red solu-
tion which was stirred at rt for 16 h. The reaction mixture was
quenched by adding a small amount of silica gel and all volatiles
were evaporated under reduced pressure. The crude product was
To
.071 mmol, 1.1 equiv), geraniol (10 mg, 0.065 mmol, 1.0 equiv),
(0.018 mL,
.130 mmol, 2.0 equiv) in DCM (1 mL) was added PyBOP (37 mg,
.071 mmol, 1.1 equiv). The reactions mixture turned into an
a
suspension of ferrocenecarboxylic acid (16 mg,
0
3
DMAP (1 mg, 0.008 mmol, 0.1 equiv) and Et N
0
0
2
purified by flash chromatography (12 g SiO , gradient: 0–10%
EtOAc in CyHex, flushing with 50% EtOAc in CyHex to recovered
unreacted cholesterol) affording 36.5 mg (0.061 mmol, 40%) of an
orange solid. 26.5 mg (0.069 mmol, 44%) of unreacted cholesterol
were recovered. Single crystals were obtained by vapor diffusion
orange solution and was stirred at rt for 16 h. The reaction mixture
was quenched with brine, diluted with EtOAc and the phases were
separated. The aq. layer was extracted with EtOAc twice and the
combined organic extracts were concentrated under reduced pres-
sure. The crude product was purified by flash chromatography
1
using acetone (solvent) and pentane (anti-solvent). H NMR
3
(500 MHz, CDCl ) d 5.42 (d, J = 3.7 Hz, 1H), 4.83–4.79 (m, 2H),
(
12 g SiO
2
, gradient: 0–4% EtOAc in CyHex) affording 12 mg
4.79–4.73 (m, 1H), 4.39–4.35 (m, 2H), 4.20 (s, 5H), 2.42 (m, 2H),
2.01 (m, 5H), 1.75–1.64 (m, 1H), 1.52 (m, 6H), 1.41–0.96 (m,
14H), 1.08 (s, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 2.3 Hz, 3H),
(
0.033 mmol, 51%) of an orange oil which solidifies upon standing.
1
H NMR (400 MHz, CDCl
3
) d 5.48 (m, 1H), 5.16–5.10 (m, 1H), 4.83
1
3
(
t, J = 1.9 Hz, 2H), 4.76 (d, J = 7.0 Hz, 2H), 4.40 (t, J = 1.9 Hz, 2H),
3
0.86 (d, J = 2.2 Hz, 3H), 0.69 (s, 3H); C NMR (126 MHz, CDCl ) d
4
3
1
.22 (s, 5H), 2.21–2.06 (m, 4H), 1.81 (s, 3H), 1.71 (d, J = 0.7 Hz,
171.2, 139.9, 122.8, 73.7, 71.9, 71.3 (2C), 70.3 (2C), 69.9 (5C),
56.9, 56.3, 50.2, 42.5, 39.9, 39.7, 38.6, 37.2, 36.8, 36.3, 36.0, 32.1,
32.1, 28.4, 28.3, 28.2, 24.5, 24.0, 23.0, 22.7, 21.2, 19.6, 18.9, 12.0;
H), 1.63 (s, 3H); 1 C NMR (126 MHz, CDCl
3
3
) d 171.7, 142.0,
31.8, 123.8, 118.9, 71.4, 71.2 (2C), 70.2 (2C), 69.7 (5C), 61.1,

1
328
P. M. Holstein et al. / Tetrahedron: Asymmetry 28 (2017) 1321–1329
mp: 186–187 °C; HRMS-ESI: calculated for C38
H
54FeNaO
2
[M+Na]+:
EtOAc in CyHex) affording 68 mg (0.180 mmol, 85%) of an orange
solid. Single crystals were obtained by vapor diffusion using THF
26
6
21.3366; found: 621.3367; [
a
]
D
= +4.7 (c 0.5, CHCl ).
3
(
solvent) and cyclohexane (anti-solvent). Due to the presence of
5
.7. Cholestanyl ferrocene carboxylate 7g52
conformers, the NMR analysis had to be carried out at 393 Kelvin.
Due the conformational effects, some C NMR signals contain
shoulders, others are of weak intensity. H NMR (500 MHz,
1
3
1
To
a
suspension of ferrocenecarboxylic acid (29.8 mg,
0
.130 mmol, 2.0 equiv) in DCM (1 mL) were added oxalyl chloride
6
DMSO-d , 393 K) d 7.32 (m, 4H), 7.24 (m, 1H), 5.02 (d, J = 4.3 Hz,
(
0.011 mL, 0.130 mmol, 2.0 equiv) and two drops of dry DMF at
1H), 4.71 (m, 1H), 4.50 (m, 1H), 4.45 (br s, 1H), 4.40 (br s, 1H),
0
°C. After the gas evolution ceased and the reaction mixture
4.28 (br s, 2H), 4.12 (s, 5H), 2.95 (s, 3H), 1.24 (d, J = 6.7 Hz, 3H);
1
3
turned into a clear solution, it was stirred for 0.5 h at rt. Then, a
solution of cholestanol (25.2 mg, 0.065 mmol, 1.0 equiv) and DMAP
C NMR (126 MHz, DMSO-d
6
, 393 K) d 168.7, 143.1, 127.0, 126.2,
125.8, 79.6, 74.4, 70.0, 68.7, 67.9, 56.2, 31.0, 12.3; mp: 140–
+
(
39.6 mg, 0.650 mmol, 5.0 equiv) in DCM (1 mL) was added and the
141 °C; HRMS-ESI: calculated for C21
H
24FeNO
2
[M+H] : 378.1151;
2
6
reaction mixture was stirred for 16 h at rt. The reaction mixture
was quenched by adding a small amount of silica gel and all vola-
tiles were evaporated under reduced pressure. The crude product
found: 378.1157; [
a
]
D
= À89.4 (c 1.0, CHCl ).
3
Acknowledgements
was purified by flash chromatography (40 g SiO
Et O in Pentane) affording 32 mg (0.178 mmol, 80%) of an orange
solid. Single crystals were obtained by slow evaporation of a solu-
tion of CH Cl ) 4.86 (tt,
and ethanol. 1H NMR (500 MHz, CDCl
J = 11.2, 4.9 Hz, 1H), 4.81–4.77 (m, 2H), 4.38–4.34 (m, 2H), 4.19
s, 5H), 2.01–1.94 (m, 1H), 1.94–1.87 (m, 1H), 1.87–1.74 (m, 2H),
.72–1.42 (m, 7H), 1.41–1.19 (m, 10H), 1.17–0.96 (m, 9H), 0.91
d, J = 6.8 Hz, 3H), 0.89–0.87 (m, 6H), 0.86 (d, J = 2.3 Hz, 3H), 0.66
s, 3H), 0.71–0.65 (m, 1H); 13C NMR (126 MHz, CDCl
) d 171.3,
3.4, 72.1, 71.2 (2C), 70.3, 70.2, 69.9 (5C), 56.6, 56.4, 54.4, 44.9,
2
, gradient: 0–10%
2
This work was supported by MINECO/FEDER, UE (Grant
CTQ2016-75960-P to A.M.E.), MINECO-Severo Ochoa Excellence
Accreditation 2014–2018 (Grant SEV-2013-0319 to A.M.E.), and
the CERCA Program/Generalitat de Catalunya. We thank Imma
Escofet (ICIQ) for determining optical rotations and for additional
experiments. Guillaume Pilet (Université Claude Bernard Lyon 1)
and Markus Neuburger (University of Basel) are gratefully
acknowledged for providing X-ray structure factors of 8a, 7a–b
and 8d–8e, respectively.
2
2
3
(
1
(
(
7
4
2
1
6
3
2.8, 40.2, 39.7, 37.0, 36.3, 36.0, 35.7, 35.7, 34.5, 32.2, 28.9, 28.4,
8.2, 28.0, 24.4, 24.0, 23.0, 22.7, 21.4, 18.8, 12.5, 12.2; mp:
+
A. Supplementary data
91–192 °C; HRMS-ESI: calculated for C38
H
56FeNaO
2
[M+Na] :
26
23.3523; found: 623.3531; [
a
]
D
= +22.0 (c 0.5, CHCl
3
).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.09.
5
.8. N-(Thiophen-2-ylmethyl)ferrocenyl amide 8b
0
02.
To
a
suspension of ferrocenecarboxylic acid (73 mg,
References
0
.319 mmol, 1.1 equiv) in DCM (1 mL) were added oxalyl chloride
(
0
0.027 mL, 0.319 mmol, 1.1 equiv) and three drops of dry DMF at
°C. After the gas evolution ceased and the reaction mixture
1
2
.
.
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4.
5.
6.
Kong, L.-Y.; Wang, P. Chin. J. Nat. Med. 2013, 11, 193–198.
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1
2
1
.0 equiv) in DCM (0.5 mL) and DIPEA (0.101 mL, 0.580 mmol,
.0 equiv) were added and the reaction mixture was stirred for
6 h at rt. The reaction mixture was quenched by adding a small
7. Seco, J. M.; Quiñoá, E.; Riguera, R. Chem. Rev. 2012, 112, 4603–4641.
8
.
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1
amount of silica gel and concentrating to dryness. The crude pro-
duct was purified by flash chromatography (12 g SiO , gradient:
–30% EtOAc in CyHex) affording 66 mg (0.203 mmol, 70%) of a
brown solid. Single crystals were obtained by vapor diffusion using
CH Cl
(solvent) and pentane (anti-solvent). 1H NMR (500 MHz,
CDCl ) d = 7.25–7.28 (m, 1H), 7.06 (m, 1H), 6.99 (dd, J = 5.3,
.5 Hz, 1H), 5.98 (br s, 1H), 4.76 (d, J = 5.8 Hz, 2H), 4.64–4.71 (m,
H), 4.33–4.39 (m, 2H), 4.19 (s, 5H); 13C NMR (126 MHz, CDCl
) d
70.3, 141.7, 127.0, 126.0, 125.2, 75.7, 70.7 (2C), 69.8 (5C), 68.3
9
.
2
10. Deschamps, J. R. Life Sci. 2010, 86, 585–589.
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2
2
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1
1
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2
2
2
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C
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+
16
H15FeNNaOS [M+Na] : 348.0116; found: 348.0123.
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1
To
a
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2
0
1
.212 mmol, 1.0 equiv), (À)-ephedrine (35 mg, 0.212 mmol,
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2
2
2
(
2 mL) was added PyBOP (110 mg, 0.212 mmol, 1.0 equiv). The
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3
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