Asymmetric synthesis of secondary alcohols from primary alcohols via intramolecular carbenoid C-H insertion catalyzed by rhodium(II) 3-phenylcholestane-2-carboxylate

Article abstract of DOI:10.1039/b316984g

Chiral secondary alcohols may be prepared from primary alcohols via asymmetric C-H insertion reactions of α′-alkoxy-α-diazoketones catalyzed by rhodium(II) (2R,3K)-3-phenylcholestane-2-carboxylate.

Full text of DOI:10.1039/b316984g

Asymmetric synthesis of secondary alcohols from primary alcohols via
intramolecular carbenoid C–H insertion catalyzed by rhodium(II
)
3-phenylcholestane-2-carboxylate
Cheol Hee Hwang, You Hoon Chong, Sue Yeon Song, Hyo Shin Kwak and Eun Lee*
School of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-747, Korea.
E-mail: eunlee@snu.ac.kr; Fax: 82-2-889-1568; Tel: 82-2-880-6646
Received (in Cambridge, UK) 6th January 2004, Accepted 29th January 2004
First published as an Advance Article on the web 23rd February 2004
Chiral secondary alcohols may be prepared from primary
alcohols via asymmetric C–H insertion reactions of aA-alkoxy-a-
diazoketones catalyzed by rhodium(II) (2R,3R)-3-phenylcholes-
tane-2-carboxylate.
relatively low yield (28%),6 and the level of asymmetric induction
was low (13% e.e.).7 Use of Rh2[S-TBSP]4 did not much improve
the chemical yield or the asymmetric induction. Use of Rh2(5S-
MEPY)4 in dichloromethane required heating, which resulted in a
low level of asymmetric induction (8% e.e.) (Table 1).
Rhodium(II)-catalyzed C–H insertion reactions of aA-alkoxy-a-
diazoketones are well known to yield 3(2H)-furanones as the
insertion occurs at the C–H bonds adjacent to the ether oxygens.1–4
The reaction proceeds with retention of configuration, and efficient
conversion of secondary alcohols to tertiary alcohols was realized
via oxidative transformations. This way, chiral tertiary alcohols
may be prepared from chiral secondary alcohols (Scheme 1).2
Preparation of chiral secondary alcohols from achiral primary
alcohols presents a completely different and more difficult
problem. Asymmetric C–H insertion reaction of aA-alkoxy-a-
diazoketones prepared from primary alcohols requires developing
appropriate chiral catalysts capable of discriminating two prochiral
hydrogens on the carbinol carbon (Scheme 2).
There was clearly a need for a new chiral catalyst system. We
considered the chiral trans-2-phenylcyclohexanecarboxylate motif
for construction of chiral rhodium(II) carboxylate, and decided to
investigate the efficacy of rhodium(II) (2R,3R)-3-phenylcholes-
tane-2-carboxylate (12, Rh2(PCC)4).
Synthesis of 12 started from the known alcohol 108 prepared
from cholesterol (9). PCC oxidation afforded the corresponding
ketone, which was mainly converted into the 3S-carboxaldehyde
via methylenation, hydroboration, and oxidation. The requisite 3R-
carboxaldehyde was obtained under basic equilibrating conditions,
and ruthenium catalyzed oxidation provided the carboxylic acid 11.
The catalyst 12 was then synthesized via ligand exchange reaction
with rhodium(II) acetate (Scheme 4).
The substrate aA-octyloxy-a-diazoacetone (3a) was prepared
from octanol (1a) via octyloxyacetic acid (2a). Insertion reactions
were carried out and the product 3(2H)-furanone 4a was converted
into the cyclic acetal 5a by treatment with m-chloroperoxybenzoic
acid.2 Methanolysis of 5a under acidic conditions afforded methyl
3-hydroxydecanoate (6a) as the final product. Enantiomeric excess
was calculated for each reaction by converting 6a into the (S)-(O)-
The insertion reaction of 3a in dichloromethane at room
temperature in the presence of Rh2[PCC]4 (12) proceeded to yield
the product 6a in higher enantiomeric excess (80% yield, 37% e.e.)
(Table 1). Different solvent systems were tested aiming at more
efficient asymmetric induction using the catalyst 12, but the
situation did not improve in dichloromethane–pentane (1 : 10, 278
°C), in fluorobenzene (240 °C), and in pentane (r.t.). The insertion
reaction in pentane at 245 °C was found to yield the product 6a in
71% e.e. Further lowering the temperature was not practical as the
1
acetylmandelate mixture (7a and 8a) and analyzing the H-NMR
spectrum (Scheme 3).
Enantioselective processes for reactive carbenoids derived from
diazoketones have proved to be problematic. Among acceptor-
substituted carbenoids, carbenoids derived from a-diazoketones
are more reactive than those derived from a-diazoacetates and a-
diazoacetamides, and C–H activation reactions with enantiopure
rhodium(II) carboxylate or carboxamidate catalysts were reported
to generate little asymmetric induction.5 In our case, the insertion
reaction of 3a in dichloromethane in the presence of Rh2[S-DOSP]4
at room temperature proceeded to give the final product 6a in
Scheme 1 Chiral tertiary alcohol preparation via C–H insertion reaction.
Scheme 3 Insertion reaction of the substrates. Reagents and conditions: 1)
NaH, THF; ClCH2CO2Na, HMPA, reflux; 2) (COCl)2, benzene; 3) CH2N2,
ether; 4) see Table 1; 5) H2, Pd/C (this step is omitted for 4a and 4d. RA =
R in 5a–8a and 5d–8d, and RA = n-C17H35 in 5b–8b and 5c–8c); 6)
mCPBA, DCM; 7) p-TsOH, MeOH; 8) (S)-(O)-acetylmandeloyl chloride,
pyridine, DCM.
Scheme 2 Chiral secondary alcohols from primary alcohols
C h e m . C o m m u n . , 2 0 0 4 , 8 1 6 – 8 1 7
816
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

Table 1 Results of insertion reactions
Yield
(%)b
Substrate
Catalyst (mol%)
Solventa
Temp.
e.e. (%)
3a
Rh2[S-DOSP]4 (2)
Rh2[S-TBSP]4 (2)
Rh2[5S-MEPY]4 (2)
Rh2[PCC]4 (12) (2)
(1)
(1)
(2)
(2)
Rh2[S-DOSP]4 (1)
Rh2[S-PTPA]4 (1)
Rh2[PCC]2 (12) (1)
(1)
(1)
(1)
DCM
DCM
DCM
DCM
r.t.
r.t.
28
31
84
80
87
65
79
72
31
67
60
62
71
52
13(R)
14(R)
8(R)
reflux
r.t.
278 °C
240 °C
r.t.
37(R)
36(R)
30(R)
33(R)
71(R)
23(R)
16(R)
47(R)
83(R)
80(R)
67(R)
DCM–pentane (1 : 10)
PhF
pentane
pentane
DCM
245 °C
3b
0 °C
0 °C
0 °C
DCM
pentane
pentane
pentane
pentane
278 °C
278 °C
278 °C
3c
3d
a Slow addition of the substrate via syringe pump for 4–6 h into the solution containing the catalyst (1 mol% at 0.2–0.5 mM or 2 mol% at 0.8–0.9 mM).
b Three-step yield of 6a from 3a and 6d from 3d. Yield of 4b from 3b and 4c from 3c.
In the presence of the catalyst 12 in pentane at 278 °C, the
furanone 4c was obtained from the a-diazoketone substrate 3c
(prepared from linoleyl alcohol (1c)) in 80% e.e. The C–H insertion
reaction of the substrate 3d prepared from cyclohexanemethanol
(1d) proceeded in 67% e.e.
The present studies show that Rh2(PCC)4 is an efficient chiral
catalyst in asymmetric C–H insertion reaction of aA-alkoxy-a-
diazoketones. Due to its lipophilic character, we were able to carry
out insertion reactions in non-polar solvents at low temperature.
Further applications of this catalyst in related carbenoid reactions
will be the subject of future communications.
The authors thank the Ministry of Science and Technology,
Republic of Korea, and Korea Institute of Science and Technology
Evaluation and Planning for a National Research Laboratory grant
(1999). Brain Korea 21 graduate fellowship grants to C. H. Hwang
and H. S. Kwak are gratefully acknowledged.
Scheme 4 Synthesis of Rh2(PCC)4. Reagents and conditions: 1) PCC, 4 Å
MS, DCM; 2) Cp2TiMe2, THF, reflux; 3) BH3·THF; H2O2, NaOH; 4) PCC,
4 Å MS, DCM; 5) 2 M NaOH, THF, reflux; 6) 5 mol% RuO2, NaIO4,
Notes and references
1 (a) J. Adams, M.-A. Poupart, L. Grenier, C. Schaller, N. Ouimet and R.
MeCN–CCl4–H2O (2 : 2 : 3); 7) Rh2(OAc)4, PhCl, reflux, 48 h, Soxhlet
Frenette, Tetrahedron Lett., 1989, 30, 1749; (b) J. Adams, M.-A. Poupart
(Na2CO3 trap).
and L. Grenier, Tetrahedron Lett., 1989, 30, 1753; (c) D. M. Spero and J.
Adams, Tetrahedron Lett., 1992, 33, 1143.
2 E. Lee, I. Choi and S. Y. Song, J. Chem. Soc., Chem. Commun., 1995,
321.
substrate diazoketone 3a crystallized out in pentane at lower
temperature.
3 (a) J. S. Clark, A. G. Dossetter, C. A. Russell and W. G. Whittingham, J.
Org. Chem., 1997, 62, 4910; (b) J. S. Clark, Y.-S. Wong and R. J.
Townsend, Tetrahedron Lett., 2001, 42, 6187.
4 (a) D. J. Wardrop, A. I. Velter and R. E. Forslund, Org. Lett., 2001, 3,
2261; (b) D. J. Wardrop and R. E. Forslund, Tetrahedron Lett., 2002, 43,
737.
5 H. M. L. Davies and R. E. J. Beckwith, Chem. Rev., 2003, 103, 2861.
6 In this case, the anomalous vinylic ether acetal product was obtained in
more than 30% yield.
7 For informations on chiral catalysts, see ref. 5. S-DOSP: (S)-(N)-p-
dodecylbenzenesulfonylprolinate; S-TBSP: (S)-(N)-p-tert-butylbenzene-
sulfonylprolinate; S-PTPA: (S)-(N)-phthaloylphenylalanate.
8 D.-L. Huang and R. W. Draper, Tetrahedron Lett., 1994, 35, 661.
A new a-diazoketone substrate 3b was prepared from oleyl
alcohol (1b), and the C–H insertion product 4b was analyzed after
conversion to 6b via hydrogenation, mCPBA oxidation, and
methanolysis. The result obtained from the insertion reaction in the
presence of Rh2[S-DOSP]4 in dichloromethane at 0 °C was
comparable to the result obtained for the reaction of 3a. Insertion
reaction in the presence of Rh2[S-PTPA]4 in dichloromethane at 0
°C gave a higher yield of 4b, but the enantiomeric excess did not
improve. The reaction of 3b in the presence of Rh2[PCC]4 (12) in
pentane at 0 °C proceeded to yield 4b in 47% e.e., and eventually
at 278 °C in 83% e.e.
C h e m . C o m m u n . , 2 0 0 4 , 8 1 6 – 8 1 7
817