Tocopherol side chain synthesis via asymmetric organocatalytic transfer hydrogenation and convenient measurement of stereoselectivity

Article abstract of DOI:10.1016/j.tetlet.2014.08.085

An asymmetric synthetic route for 1-iodofarnesane, a key intermediate for tocopherol side chain synthesis, starting from (+)-(R)-citronellal was developed. 1-Iodofarnesane was prepared through eight steps in about 50% overall yield, and asymmetric transfe

Full text of DOI:10.1016/j.tetlet.2014.08.085

Accepted Manuscript
Tocopherol side chain synthesis via asymmetric organocatalytic transfer hy-
drogenation and convenient measurement of stereoselectivity
Hyunji Lee, You-Kyoung Lee, Dong-Guk Kim, Mi-Sun Son, Tae-gyu Nam,
Byeong-Seon Jeong
PII:
S0040-4039(14)01438-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.085
TETL 45052
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 May 2014
5 August 2014
25 August 2014
Please cite this article as: Lee, H., Lee, Y-K., Kim, D-G., Son, M-S., Nam, T-g., Jeong, B-S., Tocopherol side chain
synthesis via asymmetric organocatalytic transfer hydrogenation and convenient measurement of stereoselectivity,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.08.085
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Tetrahedron Letters
journal homepage: www.els evier.com
Tocopherol side chain synthesis via asymmetric organocatalytic transfer
hydrogenation and convenient measurement of stereoselectivity
Hyunji Leea, You-Kyoung Leea, Dong-Guk Kima, Mi-Sun Sona, Tae-gyu Namb,∗ and Byeong-Seon Jeonga,∗
aCollege of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 712-749, Republic of Korea
bDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
An asymmetric synthetic route for 1-iodofarnesane, a key intermediate for tocopherol side chain
synthesis, starting from (+)-(R)-citronellal was developed. 1-Iodofarnesane was prepared
through eight steps in about 50% overall yield, and asymmetric transfer hydrogenation of the
enal with a chiral organocatalyst was conducted as a stereoinduction step. To measure the
stereoinduction level and optical purity of the product, a convenient analytical method was
developed in which a phenylcarbamate derivative of the C15 alcohol was found to be suitable to
give proper polarity and UV-activity for chiral UV-HPLC analysis.
Received in revised form
Accepted
Available online
Keywords:
tocopherol
2009 Elsevier Ltd. All rights reserved
.
asymmetric synthesis
organocatalyst
stereoselectivity
UV-HPLC
———
∗ Corresponding author (T.-g. Nam). Tel.: +82-31-400-5807; fax: +82-31-400-5958; e-mail: tnam@hanyang.ac.kr
∗ Corresponding author (B.-S. Jeong). Tel.: +82-53-810-2814; fax: +82-53-810-4654; e-mail: jeongb@ynu.ac.kr

2
Tetrahedron
α-Tocopherol (1, α-TOH) has been known as nature’s best
KOH, acetone
CHO
lipophilic chain-breaking antioxidant.1 Its antioxidant activity is
attributed to the ability to donate hydrogen atom from its O–H
bond to chain propagating lipid peroxyl radical.2 Therefore, many
synthetic versions of α-TOH derivatives have been prepared to
show better hydrogen atom donating characteristics and air-
stability.2,3 Among them, 6-aminopyridin-3-ol analogues have
much better antioxidant activities (better H-atom donation) and
air-stabilities (higher ionization potential of aromatic ring
tethering –OH group) than α-TOH.4 One of the best examples is
the N-tocopherol (N-TOH, 2), which has the same side chain as
α-TOH. N-TOH showed excellent antioxidant activity in bulk
solvent as well as in the LDL oxidation system.4d In addition, it
does not promote tocopherol-mediated peroxidation (TMP) even
at increased concentration. Interestingly, N-TOH showed much
better binding affinity to human tocopherol transfer protein
(hTTP).4d TTP is responsible for the transportation of tocopherols
to VLDL particle.5 Differential uptake of (R,R,R)-tocopherol over
(S,R,R)-tocopherol by TTP is attributed to the specific interaction
between tocopherol and the protein.6 The stereochemistry of the
tocopherol side chain is responsible for the uptake and therefore
the in vivo antioxidant activity.6 Mechanically, the tocopherol
side chain has biological implications such that its lipophilicity
renders the tocopherol head group to be incorporated at proper
depth inside the LDL particle where the lipid peroxyl radical
resides.6a,7 The C16 isoprenoid side chain of α-TOH is
biosynthesized through the mevalonate pathway where a farnesyl
moiety is formed as a crucial precursor. Chemically, this chain
can be synthesized in different ways.8
O
reflux, 7 h
90%
(6R)
(+)-(R)-Citronellal (7)
8 (E:Z = 6:1)
(EtO)2P(O)CH2CO2Et (10)
H2, Pd/C
EtOH, rt, 2 h
95%
NaH, CH2Cl2, rt, 10 h
88%
O
9
MnO2
DIBAL-H
R
R
CO2Et
CH2Cl2, 0 oC, 1 h
95%
CH2Cl2, rt, 2 d
92%
OH
11
12
O
EtO2C
CO2Et
N
(R)
t-Bu
14
N
N
H
H2
CF3CO2
15
R
CHO
CHCl3, -30 oC, 2 h
87%
13
DIBAL-H
CHO
R
CH2Cl2, 0 oC, 1 h
97%
OH
(7R)
(3R)
16
17
I2, PPh3, imidazole
R =
I
R
CH2Cl2, 0 oC to rt, 1 h
89%
6
Scheme 1. Synthesis of 1-iodofarnesane (6) from (+)-(R)-citronellal
(7) using organocatalytic transfer hydrogenation as a key step.
As shown in Scheme 1, synthesis began with a Claisen-
Schmidt reaction of commercially available (+)-(R)-citronellal (7)
with acetone to give C13 α,β-unsaturated ketone 8 in 90% yield.8f
Subsequent hydrogenation of the two olefins afforded saturated
C13 ketone 9 in 95% yield which was then subject to a Horner-
Wadsworth-Emmons reaction with triethyl phosphonoacetate (10)
to give C15 α,β-unsaturated ester 11 in 88% yield. 11 was then
smoothly reduced to allyl alcohol 12 with DIBAL-H in 95%
yield. Mild oxidation of the allyl alcohol of 12 with
manganese(IV) oxide afforded C15 α,β-unsaturated aldehyde 13,
a substrate for asymmetric transfer hydrogenation reaction. The
origin of stereoselectivity is suggested to be transient formation
of a chiral iminium function between an α,β-unsaturated
aldehyde substrate and a chiral secondary amine catalyst.9 Then,
hydride from Hantzsch ester is delivered in a stereoselective
manner as NAD(P)H or FADH2.9 In this study, for asymmetric
transfer hydrogenation of the enal 13, we employed MacMillan's
imidazolidinone 14 as a chiral organocatalyst10 and diludine (15),
a commercially available Hantzsch ester, as a hydride source,
which afforded saturated aldehyde 16 in 87% yield. The aldehyde
16 was reduced to primary alcohol 17 in 97% yield, followed by
iodination of the alcohol to give 1-iodofarnesane (6), the final
goal of this synthesis. Synthesis is highly efficient so that the
overall yield was about 50% in eight steps from (+)-(R)-
citronellal (7).
Next, we wanted to check the optical purity of the newly
formed C(3)-methine group in the aldehyde 16 or the alcohol 17
using chiral UV-HPLC analysis, one of the most widely used
analytical tools for determination of stereoselectivity. However,
they were difficult to analyze in UV-HPLC due to their
extremely low polarity and UV-inactivity. Therefore, we
prepared racemic versions of 16 and 17 in order to identify
retention times in HPLC traces of each stereoisomer and to
conduct derivatization for improved UV detection and suitable
polarity. Racemic versions of 16 (aldehyde) and 17 (alcohol)
were prepared according to the literature procedure,8l,11 and then
several derivatives were prepared as shown in Table 1.
Figure 1. Tocopherol side chain and its synthesis.
In this letter, we report a synthetic route for 1-iodofarnesane
(6), a key intermediate for tocopherol side chain synthesis, from
commercially available (+)-(R)-citronellal (7) via asymmetric
transfer hydrogenation as a key step utilizing a Hantzsch ester
and a chiral imidazolidinone organocatalyst. We also present
derivatization of an intermediate by which stereoselectivity of
asymmetric transfer hydrogenation can be measured using UV-
HPLC.

Table 1. Compounds for chiral UV-HPLC analysis.
14.6 min (6R-isomer). The (+)-(R)-citronellal used in this study
was a 9:1 enantiomeric mixture based on this chiral HPLC
analysis. With this analytical information in hand, we finally
determined the stereoselectivity of the organocatalytic transfer
hydrogenation of the enal 13 by a chiral HPLC analysis of 18
prepared from 17. As shown in Table 2, relative area %'s of the
four stereoisomers were observed in approximate ratio of
7(P1):63(P2):27(P3):3(P4). From this data, we envisioned that P1
and P4 peaks originated from the minor enantiomer, (–)-(S)-
citronellal, while P2 and P3 peaks represented (+)-(R)-citronellal
(7), the major enantiomer, because the ratio between the sum of
area of P2 and P3 and that of P1 and P4 was about 9:1. Therefore,
P2 and P3 peaks contain (7R)-configuration while the other peaks
have (7S)-configuration. The chiral imidazolidinone catalyst 14
we used is well known to promote asymmetric transfer
hydrogenation of acyclic enal systems to corresponding
aldehydes with a single stereochemical outcome in a very
consistent manner.10a Or, (R)-configured imidazolidinone catalyst
afforded only one stereochemical outcome in 90-97% ee starting
from various enal substrates. Furthermore, the (S)-configured
MacMillan’s imidazolidinone catalyst, the opposite enantiomer
of our catalyst 14, asymmetrically reduces (E)-citral, an
isoprenoid enal which contains the identical local substitution
environment to our substrate, to (R)-configured aldehydes as
major product (enantiomeric ratio = 70:30).10b Thus, we believe
the major peaks, P1 and P2, are favored products that contain the
(3R)-configuration in the asymmetric transfer hydrogenation over
the (3S)-minor isomers, P4 and P3, respectively. Taken together,
we were able to identify the absolute configuration of the four
peaks (i.e., P1: 3R,7S, P2: 3R,7R, P3: 3S,7R, P4: 3S,7S) as shown
in Table 2.
The derivatives were screened about their polarity and UV-
sensitivity. Diphenylamino analogue (entry 1) and tert-
butyldiphenylsilyl ether (entry 2) were still too non-polar for
HPLC separation. Carbamate derivatives (entries 3–5) of the
alcohol generally showed proper polarities; however, the
tosylcarbamate (entry 3) and the p-chlorophenylcarbamate (entry
5) were still troublesome in a clear separation of the four
stereoisomers. On the other hand, the phenylcarbamate derivative
(entry 4) was a suitable compound for good resolution in chiral
UV-HPLC. Four different stereoisomers of the phenylcarbamate
(rac-18) of the racemic C15 alcohol (rac-17) were clearly
separated, and the data and optimal analytical conditions are
described in Table 2.
From the above assignment, stereoselectivity of the
asymmetric transfer hydrogenation was calculated to be 40% ee
Although the catalyst did show much better stereoselectivity in
the other types of substrate,10a this moderate stereoselectivity is
not an outlier in the chemistry of this catalyst, but, in fact, is in
line with literature value. The catalyst is reported to give only 40%
ee as well when the substrate is (E)-citral which contains very
high degree of homology in local substitution patterns as our
substrate.10b Interestingly, there exists a chiral phosphoric acid
catalyst which seems to be much more stereoselective in transfer
hydrogenation of this type of substrate. It showed very efficient
asymmetric transfer hydrogenation of C10-(E)-citral and C15-
farnesal to the corresponding aldehyde in 90% ee and 92% ee,
respectively.10b Since their local substitution patterns are virtually
identical to that of our substrate, the compound 13, it is highly
likely that the chiral phosphoric acid catalyst would have
afforded much better stereoselectivity than the catalyst used in
this work.
Table 2. Chiral UV-HPLC analysis of 18a
Peak
RT (min)b
Area %
18 from 17
Abs.
config.c
rac-18
P1
P2
P3
P4
28.2
31.3
39.1
48.5
25%
7%
63%
27%
3%
3R,7S
3R,7R
3S,7R
3S,7S
25%
25%
25%
a HPLC conditions; • Column: Chiralpak AD-H chiral column (4.6×250 mm),
• Eluent: 0.2 v/v% 2-propanol in hexanes, • Temperature: 23 °C, • Detection:
233 nm, • Flow rate: 1.0 mL/min.
In summary, we developed an eight-step synthetic route for a
chiral C15 isoprenoidal tocopherol side chain starting from (+)-
(R)-citronellal in which asymmetric organocatalytic transfer
hydrogenation was employed as the key step. We also developed
a convenient chiral UV-HPLC analysis method for measuring the
optical purity of the tocopherol side chain. A facile derivatization
of the C15 alcohol 17 to the corresponding phenylcarbamate 18
provided proper polarity and UV-sensitivity, which led to clear
separation of the four stereoisomers in HPLC.
b Retention time.
c Absolute configuration.
Before the determination of stereoinduction level of the key
step (13→16), we had to check the exact optical purity of the
starting material, (+)-(R)-citronellal (7) because it is known that
commercially available (+)-(R)-citronellal is not entirely optically
pure. The optical purity of 7 was determined by chiral UV-HPLC
analysis of the Claisen-Schmidt product 8. To this end, racemic
version of 8, rac-8, was prepared from racemic citronellal. Two
enantiomers in rac-8 were separated in good resolution in chiral
HPLC analysis under the following conditions: i) chiral column:
Chiralcel OD-H (4.6×250 mm), ii) eluent: 0.2 v/v% 2-propanol in
hexanes, iii) temperature: 23 °C, iv) detection: 254 nm, v) flow
rate: 0.6 mL/min, and vi) retention times: 13.7 min (6S-isomer),
Acknowledgement
This work was supported by the Yeungnam University Research
Grant (Grant No.: 212-A-380-222).

4
Tetrahedron
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Supplementary Data
Supplementary data associated with this article can be found in the
online version, at http://
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5
Graphical Abstract
Leave this area blank for abstract info.
Tocopherol side chain synthesis via
asymmetric organocatalytic transfer
hydrogenation and convenient measurement
of stereoselectivity
Hyunji Leea, You-Kyoung Leea, Dong-Guk Kima, Mi-Sun Sona, Tae-gyu Namb,∗ and Byeong-Seon Jeonga,∗
aCollege of Pharmacy and Institute for Drug Research, Yeungnam University, Gyeongsan 712-749, Korea
bDepartment of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791, Korea

6
Tetrahedron
Highlights
•
•
•
•
An asymmetric synthetic route for 1-iodofarnesane from citronellal was developed.
An asymmetric organocatalytic transfer hydrogenation was employed as the key step.
A convenient chiral UV-HPLC analysis for measuring stereoselectivity was developed.
A phenylcarbamate analog provided proper polarity and UV-sensitivity for analysis.