Ambient-Pressure Asymmetric Preparation of S,S -DICHED, a C 2 -Symmetrical Director for Matteson Reactions

Article abstract of DOI:10.1055/s-0036-1591530

A synthesis of S, S -DICHED (dicyclohexylethane-1,2-diol), a C ₂ -symmetrical chiral director for Matteson homologations, is described. It relies on the insertion of lithiated S -2-cyclohexyloxirane into cyclohexylboronic acid pinacol ester and proceeds in three linear steps from readily available starting materials. No step requires chromatography or any specialized equipment.

Full text of DOI:10.1055/s-0036-1591530

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–C
letter
A
en
K. Bojaryn et al.
Letter
Synlett
Ambient-Pressure Asymmetric Preparation of S,S-DICHED,
a C2-Symmetrical Director for Matteson Reactions
Kevin Bojaryn◊
O
Chris Hoffmann◊
LiTMP,
c-Hex-B(Pin)
CBS-type
reduction
O
HO
OH
c-Hex
Felix R. Struth
c-Hex
cyclization
H2O2
c-Hex
c-Hex
Br
Christoph Hirschhäuser*
0
0
0
0
0-
0
0
2
9-
4
0
9
1-
5
5
0
S,S-DICHED
2nd gen. chiral director
for Matteson reactions
Ambient pressure
Cheap precursors
No chromatography
No transition metals
Institut für Organische Chemie, Universität Duisburg-Essen,
Universitätsstraße 7, 45141 Essen, Germany
Christoph.Hirschhaeuser@uni-due.de
◊ These authors contributed equally to this work.
Received: 15.11.2017
Accepted after revision: 19.12.2017
Published online: 19.01.2018
(A) S,S-DICHED Synthesis
Ph
Ph
DOI: 10.1055/s-0036-1591530; Art ID: st-2017-d0837-l
1. (Pin)B-c-Hex (6, 2 equiv),
LiTMP, THF,
O
O
N
O
B
H
Abstract A synthesis of S,S-DICHED (dicyclohexylethane-1,2-diol), a
C2-symmetrical chiral director for Matteson homologations, is de-
scribed. It relies on the insertion of lithiated S-2-cyclohexyloxirane into
cyclohexylboronic acid pinacol ester and proceeds in three linear steps
from readily available starting materials. No step requires chromatogra-
phy or any specialized equipment.
0 to 13 °C
2. H2O2, NaOH, 0°C
O
O
HO
OR
BH3,
4
X
c-Hex
68%
55–60%
c-Hex
c-Hex
c-Hex
Ph
O
Br2, MeOH
0 °C, 2 h
2 X = H
3 X = Br
5
SS-1 (R = H)
Steglich
esterification
97%
7 (R =
)
OAc
Key words DICHED, DIPED, Matteson reaction, lithiated epoxide,
chiral director
(B) Epoxide Insertion
c-Hex
O
O
(Pin)B
O
B(Pin)
c-Hex
O
c-Hex B(Pin)
c-Hex B(Pin)
c-Hex
c-Hex
B
c-Hex
Li
DICHED (dicyclohexylethane-1,2-diol, 1) and DIPED (di-
isopropylethane-1,2-diol) are C2-symmetrical, highly effec-
tive chiral directors for Matteson's diastereoselective homo-
logation of corresponding boronic esters.1 S,S-DICHED
(SS-1) is commercially available in enantiomerically pure
form but rather expensive. Preparation of scalemic DICHED
was first described by Hoffmann and co-workers.2 It re-
quires Sharpless bishydroxylation of trans-stilbene and
subsequent hydrogenation, which was achieved with
Rh/Al2O3 at 60–70 atm H2. Matteson et al. developed a re-
duction protocol that proceeds via a concentrated solution
of the corresponding methoxy borate, which only requires
10–11 atm H2.3 The high cost of RhCl3, as well as the incon-
venience of the high-pressure hydrogenation procedures4
led us to explore alternative routes, the best of which is
shown in Scheme 1. It was based on the work of Aggarwal
et al., who first described the insertion of lithiated epoxides
(similar to 8) into pinacol boronates.5
c-Hex
O
8
9
10
(C) Matteson Sequence with the Chiral Director
1. LiCHCl2,
THF, –100 °C
then ZnCl2
3. H2C=CH2MgBr,
OBn
OBn
OBn
B
THF, –78 °C
ref. 9
O
O
B
O
O
O
63%
AcO
c-Hex
from SS-1
c-Hex
O
c-Hex
c-Hex
Ph
(ee > 95%)
11
12
13 de 80%
Scheme 1 (A) Synthesis of S,S-DICHED (SS-1). (B) Mechanism of
Aggarwal homologation with lithiated epoxides and suggested explana-
tion for the need for two equivalents of 6.7 (C) Application of SS-1 in a
short Matteson sequence showed no double stereodifferentiation, but
confirmed the absolute configuration of SS-1.
multigram levels was straightforward, as bromide 3 could
be used directly after aqueous workup and oxirane 5 was
distilled at 56–65 °C at 14 mbar.
To convert oxirane 5 into DICHED, lithiation with LiTMP
in the presence of two equivalents of cyclohexylpinacol bo-
ronate 6 had to be carried out at 0 °C for two hours. The
For our synthesis of S,S-DICHED (SS-1), enantiomerical-
ly pure cyclohexyloxirane 5 was prepared as reported by
Ortiz-Marciales et al.6 by brominating ketone 2 and submit-
ting the crude product 3 to a CBS-type reduction and cy-
clization using catalyst 4. Scale up of the procedure to
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

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K. Bojaryn et al.
Letter
Synlett
chiral carbenoid 8 and boronate 6 form ate complex 9 that
undergoes a 1,2-rearrangement to α-alkoxyboronate 10.
Aggarwal's original procedure for this type of reaction5 em-
ployed –30 °C, but 5 did not react with LiTMP under these
conditions (as confirmed by in situ quench with TMSCl).
Initially we allowed the reaction mixture to reach room
temperature to facilitate the 1,2-rearrangement. However,
on warmer days competing β-elimination (of 10 to 1,2-
dicyclohexylethylene) was observed. This problem was
completely avoided by using a p-xylene/solid CO2 cooling
bath (13 °C). The reaction was then completed by
H2O2/NaOH oxidation at 0 °C. Attempts to reduce the re-
quired amount of boronate 6 led to significant losses in
yield.7 However, as 6 can be readily made on a large scale
(see Supporting Information), the need for two equivalents
of 6 is of little preparative concern.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591530.
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References and Notes
(1) Recent reviews: (a) Matteson, D. S. J. Org. Chem. 2013, 78,
10009. (b) Thomas, S. P.; French, R. M.; Jheengut, V.; Aggarwal,
V. K. Chem. Rec. 2009, 9, 24. Original articles: (c) Matteson, D. S.;
Majumdar, D. J. Am. Chem. Soc. 1980, 102, 7588. (d) Matteson, D.
S.; Ray, R. J. Am. Chem. Soc. 1980, 102, 7590. (e) Tripathy, P. B.;
Matteson, D. S. Synthesis 1990, 200.
(2) (a) Hoffmann, R. W.; Ditrich, K.; Köster, G.; Stürmer, R. Chem.
Ber. 1989, 122, 1783. (b) Sharpless, K. B.; Amberg, W.; Bennani,
Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K. S.; Kwong, H. L.;
Morikawa, K.; Wang, Z. M. J. Org. Chem. 1992, 57, 2768.
(3) Hiscox, W. C.; Matteson, D. S. J. Org. Chem. 1996, 61, 8315.
(4) Ref. 3 reports problems with overreduction when using the pro-
cedure described in ref. 2. Our attempts to run the procedure in
ref. 3 on 0.5–2 g scales required some dilution, leading to mix-
tures of starting material and (partially) hydrogenated product.
Ref. (3) also describes RhCl3 recovery.
(5) (a) Vedrenne, E.; Wallner, O. A.; Vitale, M.; Schmidt, F.;
Aggarwal, V. K. Org. Lett. 2009, 11, 165. Also see: (b) Alwedi, E.;
Zakharov, L. N.; Blakemore, P. R. Eur. J. Org. Chem. 2014, 6643.
(6) Huang, K.; Wang, H.; Stepanenko, V.; De Jesús, M.; Torruellas, C.;
Correa, W.; Ortiz-Marciales, M. J. Org. Chem. 2011, 76, 1883.
(7) We initially thought that the 1,2-rearrangement/epoxide
opening had to be facilitated by a Lewis acid, the role of which
could be fulfilled by excess boronate. However, attempts to
replace it with ZnCl2 or TMSCl (added after LiTMP) resulted in
lower conversions of 5 and thus lower yields. The formation of
an ate complex of type 10 after the 1,2-rearrangement would
explain this observation if the rearrangement occurs as
fast/faster than the formation of 9.
(8) Singh, R. P.; Matteson, D. S. J. Org. Chem. 2000, 65, 6650.
(9) Struth, F. R.; Hirschhäuser, C. Eur. J. Org. Chem. 2016, 958.
(10) Based on our previous studies (ref. 9) we expected a de of 80%
for the homologation of 11 with LiCHX2 under the employed
conditions. However, we did expect the de to increase again
after substitution with vinyl Grignard (→ 12) due to the double
stereodifferentiation discovered by Matteson for this type of
chiral director (ref. 1e). See Supporting Information for further
discussion.
The de of the reaction was excellent and no formation of
1
the undesired meso-diol was observed by H NMR analysis
of the crude product. The enantiomeric purity of the prod-
uct was assessed after derivatization with (S)-OAc-mandel-
ic acid (SS-1 → 7) and was usually >95% ee. On occasions
when slightly less pure batches of catalyst 4 were used, the
ee dropped to 89–91%. Such material could, however, be en-
antiomerically enriched afterwards by recrystallization
from EtOH (0.75 g/mL) or by column chromatography after
conversion into 7 (see Supporting Information). The abso-
lute configuration of SS-1was confirmed after using its bo-
ronic ester derivative 118 in a short homologation sequence
to yield 12 (Scheme 1, C). Conversion into 13 delivered a
product of which both diastereomers are known.9 Interest-
ingly 13 had a de of only 80%, although the sequence started
with highly pure material (>95% ee). This could indicate that
the double stereodifferentiation discovered by Matteson1
did not occur in this case, probably due to the high migra-
tion tendency of the newly introduced vinyl group.10
In the context of this work, we also looked at Matteson's
synthesis of DIPED from tartaric acid,11 which we were able
to modify, so that the use of a pyrolysis oven was avoided
and the expensive rhodium catalyst could be replaced by
Raney nickel (see Supporting Information). Nevertheless
the enantioselective synthesis of S,S-DICHED12 (Scheme 1),
emerged as advantageous, as it creates a nonvolatile prod-
uct (unlike DIPED), does not require expensive transition
metals or chromatography and can be conducted without
the use of high pressure or other specialized equipment. Its
disadvantage is the need for the potentially toxic interme-
diates 3 and 5, for which we recommend careful handling.
Accordingly annotated procedures are given in the Support-
ing Information.
(11) Matteson, D. S.; Beedle, E. C.; Kandil, A. A. J. Org. Chem. 1987, 52,
5034.
(12) Procedure for the Preparation of SS-1
Immediately before the reaction, LiTMP was prepared in a sepa-
rate flask by addition of n-BuLi (2 equiv, 1.6 M in hexanes) to a
solution of dry tetramethylpiperidine (2 equiv) in dry THF (1
L/mol of LiTMP) at 0 °C. The LiTMP solution was stirred for 0.5 h
at r.t., transferred into a dropping funnel and added dropwise to
a solution of epoxide 5 (1 equiv) and boronate 6 (2 equiv) in THF
(1 L/mol of 6) with cooling in an ice bath (0 °C). Afterwards the
reaction mixture was stirred for 0.5 h at 0 °C and 1.5 h at 13–14 °C
(p-xylene/dry ice bath). The reaction mixture was cooled to 0 °C
before aq. NaOH (2 M, 3.5 equiv) and aq. H2O2 (30%, 10 equiv)
were added simultaneously. After stirring for 30 min aq.
Na2S2O5 (2 M) was added over the course of 15 min at the same
temperature. Stirring was continued for 5 min before Et2O and
H2O were added and the phases were separated. The aqueous
Acknowledgment
We thank the Science Support Center of the University of Duisburg
and Essen for financial support and Prof. Dr. C. Schmuck for fruitful
discussions.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

C
K. Bojaryn et al.
Letter
Synlett
layer was re-extracted with Et2O, and the combined organic
layers were washed with sat. aq. NH4Cl, brine and aq. NaOH (1
M). The organic phase was dried over MgSO4, filtered, and the
solvent was removed in vacuo to yield a yellow solid. Recrystal-
lization from EtOH or chromatography on silica (CyHex/EtOAc,
9:1) yielded SS-1 in 55–60% yield. Rf = 0.28 (CyHex/EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): δ = 3.45–3.25 (m, 2 H), 1.95–1.42 (m,
12 H), 1.34–0.95 (m, 10 H). 13C NMR (75 MHz, CDCl3): δ = 75.1,
40.4, 29.6, 28.2, 26.4, 26.2, 26.1. 1H NMR and 13C NMR data were
consistent with those previously reported by: Scott, M. S.;
Lucas, A. C.; Luckhurst, C. A.; Prodger, J. C.; Dixon, D. J. Org.
Biomol. Chem. 2006, 4, 1313.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C