A novel aryl migration from silicon to carbon: An efficient approach to asymmetric synthesis of α-aryl β-hydroxy cyclic amines and silanols

Full text of DOI:10.1021/ja993295t

408
J. Am. Chem. Soc. 2000, 122, 408-409
A Novel Aryl Migration from Silicon to Carbon: An
Efficient Approach to Asymmetric Synthesis of
r-Aryl â-Hydroxy Cyclic Amines and Silanols
Katsuhiko Tomooka,* Atsuo Nakazaki, and Takeshi Nakai*
Department of Applied Chemistry
Tokyo Institute of Technology
Meguro-ku, Tokyo 152-8552, Japan
ReceiVed September 13, 1999
Currently much attention has been focused on stereochemically
defined R-substituted cyclic amines because of their diverse physi-
ological activities1 and hence several stereoselective methods for
their syntheses have been developed, including organometallic
additions to cyclic N-acyliminium ions,2 electrophilic substitutions
of R-metallo cyclic amines,3 and cyclizations of R-substituted
acyclic amines.4 Herein we wish to report a new, efficient entry
to R-aryl â-hydroxy cyclic amines C via the novel 1,4-aryl migra-
tion from silicon to carbon which was discovered by chance in
the reaction of â-tert-butyldiarylsiloxy cyclic hemiaminal A with
an alcohol promoted by montmorillonite K10 clay (eq 1). The
(K10) and molecular sieves 4A (MS 4A) which has worked well
for the preparation of O-glycoside from the hemiacetals.7,8 To
our surprise, the reaction was found to yield the unexpected phenyl
migration product 3a9 in moderate yield as the almost single
diastereomer, along with a small amount of the expected benzyl
aminal 2a (eq 3).10 Aminal 2a thus obtained was also converted
to R-phenylpyrrolidine 3a under similar reaction conditions. This
result indicates that one of the phenyl groups in TBDPS migrates
from the silicon to the R-amino carbon in a cis fashion, and at
the same time benzyl alcohol attacks the silicon in a highly dia-
stereoselective manner to create the single configuration at both
the R-amino carbon and the silicon center. Indeed, treatment of 3a
with n-BuLi (3 equiv) in THF at -78 to 0 °C was found to liberate
the chiral benzyloxysilanol (S)-4a with extremely high enantio-
meric excess (95% ee) in 87% yield,11 together with the formation
of the R-phenyldihydropyrrole 5 (eq 4). On the other hand,
most striking feature of the aryl migration process is that the dis-
placement at the silicon proceeds in a highly diastereoselective
fashion to create the single configuration at the Si-centered chiral
center, thereby permitting ready access to enantio-enriched
alkoxysilanols D.
The details of the discovery of the novel aryl migration are as
follows. Recently, we have developed the acetal [1,2]-Wittig
rearrangement protocol by which O-glycosides (cyclic acetals)
can be converted to the C-glycosides with high diastereoselectivity
(eq 2, X ) O).5 Thus, we envisioned that application of the [1,2]-
desilylation of 3a by tetrabutylammonium fluoride (TBAF) gave
the cis-R-phenyl-â-hydroxypyrrolidine 6 (>95% dr) in good yield.
A similar reaction of 1 with allyl alcohol gave the Si-allyloxy
phenyl migration product 3b (62%), in comparably high stereo-
selectivities, and 3b was also converted to the chiral allyloxysi-
lanol (S)-4b (82%, 97% ee)11 or pyrrolidine 6 (87%, >95% cis).
(6) This compound was derived from (S)-3-hydroxypyrrolidin-2-one in three
steps: (i) TBDPSCl, imidazole; (ii) (Boc)2O, Et3N; (iii) NaBH4/MeOH. (S)-
3-Hydroxypyrrolidin-2-one was prepared according to the literature procedure:
Sarairi, D.; Maurey, G. Bull. Soc. Chim. Fr. 1987, 297-301. The details are
described in the Supporting Information.
Wittig protocol to aminals (cyclic N,O-acetal) could provide the
R-substituted cyclic amines of synthetic interest (X ) NR′). To
this end, we first attempted the preparation of the requisite aminal
2a from the â-tert-butyldiphenylsiloxy cyclic hemiaminal (S)-1
(98% ee)6 and benzyl alcohol using montmorillonite K10 clay
(7) (a) Trost, B. M.; Edstrom, E. D. Angew. Chem., Int. Ed. Engl. 1990, 29,
520-522. (b) Tomooka, K.; Nakamura, Y.; Nakai, T. Synlett 1995, 321-322.
(8) The general procedure is as follows: Cyclic hemiaminal 1 (369 mg,
0.835 mmol) and benzyl alcohol (0.173 mL, 1.67 mmol) in CH2Cl2 (11 mL)
was added to flame-dried MS 4A (2.0 g) in a two-necked flask. The resulting
mixture was stirred at room temperature for 0.5 h. Flame-dried montmorillonite
K10 (1.5 g) was added to the suspension and stirred vigorously at that
temperature for 1 h. Then the resulting mixture was filtrated through a pad of
Celite. Evaporation of the filtrate gave the crude product. Purification by silica
gel chromatography gave 116 mg (26%) of benzyl aminal 2a and 165 mg
(36%) of R-phenylpyrrolidine 3a. The diastereomeric ratio of these compounds
* To whom correspondence should be addressed. Fax: +81-3-5734-3931.
E-mail: ktomooka@o.cc.titech.ac.jp.
(1) The Alkaloids, Chemistry and Biology; Cordell, G. A., Ed.; Academic:
San Diego, 1998; Vol. 50.
(2) For a recent example, see: Batey, R. A.; MacKay, D. B.; Santhakumar,
V. J. Am. Chem. Soc. 1999, 121, 5075-5076 and references therein.
(3) (a) Beak, P.; Zajdel, W. J. Chem. ReV. 1984, 84, 471-523. (b) Meyers,
A. I. Aldrichim. Acta 1985, 18, 59-68.
(4) (a) Bringmann, G.; Ewers, C. J.; Walter, R. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon:
Oxford, 1991; Vol. 6, pp 733-762. (b) Nadin, A. Contemp. Org. Synth. 1997,
387-414. (c) Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem. Commun.
1998, 633-640.
(5) Tomooka, K.; Yamamoto, H.; Nakai, T. J. Am. Chem. Soc. 1996, 118,
3317-3318.
1
was determined by H NMR analysis.
(9) The structure of 3a was determined by X-ray crystallography, see the
Supporting Information.
(10) The product ratio depended upon the reaction time: aminal 2a (26%
for 1 h, and 13% for 12 h) and R-phenylpyrrolidine 3a (36% for 1 h and 46%
for 12 h). Obviously, aminal 2a initially formed is gradually converted to 3a
under the reaction conditions.
10.1021/ja993295t CCC: $19.00 © 2000 American Chemical Society
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Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 2, 2000 409
Next, we examined the reaction of piperidine hemiaminal 7
(racemic) with various alcohols in a similar way (eq 5). These
1214 gave p-tolyl substituted pyrrolidine 13 as the sole product,
indicating that the aryl migration occurrs at the ipso position (eq
7).
A plausible mechanism of this 1,4-migration is shown in eq 8.
The mechanism most likely involves the N-acyliminium ion i
which should be in equilibrium with either the hemiaminal or
the aminal once formed from i and the alcohol added. Then,
species i undergoes an intramolecular Friedel-Crafts reaction15
onto one of the aryl groups on the silicon in a highly diastereo-
selective manner to form the â-silyl cation ii which is then
collapsed by alcohol attack onto the silicon to give the 1,4-phenyl
migration product.16,17
reactions resulted in the exclusive formation of the corresponding
phenyl migration product 8a-d in a highly diastereoselective
fashion to provide >95% cis at the R-carbon and >80% dr at
the silicon center; none of aminal 9 was formed.12 Treatment of
8a (R ) benzyl) with TBAF gave cis-R-phenyl-â-hydroxypip-
eridine 10 which was then converted to the known antagonist 11
of the neurokinine substance P (eq 6).13 This is one example to
In summary, we have described a novel 1,4-aryl migration that
occurs on â-tert-butyldiarylsiloxy pyrrolidine and piperidine hemi-
aminals under the action of K10/MS 4A in a highly stereoselective
manner. This new reaction provides a novel, efficient entry to
R-aryl â-hydroxy cyclic amines of synthetic value as well as
enantio-enriched alkoxysilanols which are otherwise difficult to
obtain.18 Further work is in progress to elucidate the mechanism
of this process and enhance the synthetic potential thereof.
demonstrate the synthetic potential of the present novel reaction
as a method for the synthesis of R-aryl â-hydroxy cyclic amines,
a class of compounds of biological importance.
Acknowledgment. This work was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science, and Culture,
Japan, and by the Research for the Future Program, administered by the
Japan Society for the Promotion of Science. We thank Prof. Shigeru
Nishiyama (Keio University) for giving us the 3-hydroxypiperidin-2-one,
Prof. Keiji Tanino (Hokkaido University) and Prof. Atsunori Mori (Tokyo
Institute of Technology) for their helpful discussions, and Dr. Masato
Oshima of our department for technical assistance with the X-ray analysis.
Further experimentation was undertaken to elucidate the mech-
anism of this novel phenyl migration process. First, the unique
character of the K10/MS 4A system was evaluated in the reaction
of 7 with benzyl alcohol. While the absence of MS 4A led to the
formation of a mixture of 8a and its Si-hydroxy analogue 8e (R
) H), the use of PPTS (0.1 equiv), p-TsOH (0.1 equiv), and BF3‚
OEt2 (2.0 equiv) all resulted in the exclusive formation of benzyl
aminal 9 (R ) Bn) in 90-98% yields; none of 8a was formed.
Thus, these observations reveal that the present phenyl migration
can effectively occur only under the unique action of K10/MS
4A. Second, a similar K10-promoted reaction of benzyl aminal
9 with allyl alcohol (1.0 equiv) was found to result in the
formation of a mixture of 8b (R ) allyl) and 8a (R ) benzyl) in
70:30 ratio. Furthermore, when the K10-promoted reaction of
benzyl aminal 9 was carried out in the absence of any alcohol,
only a trace of 8a was formed. These results suggest that addition
of an alcohol substantially facilitates the phenyl migration process.
Third, a similar reaction of tert-butylbis(p-tolyl)silyloxy analogue
Supporting Information Available: Experimental procedures with
spectroscopic data for compounds 1-13 and crystallographic data of 3a
and 8e (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
JA993295T
(15) Related example of intramoleculer Friedel-Crafts reaction, see:
Martin, O. R.; Rao, S. P.; Kurz, K. G.; El-Shenawy, H. A. J. Am. Chem. Soc.
1988, 110, 8698-8700.
(16) Related examples of phenyl migration reaction from silicon to carbon
have been reported. For 1,4- or 1,5-phenyl or vinyl migration promoted by
Lewis acids, see: (a) Archibald, S. C.; Fleming, I. Tetrahedron Lett. 1993,
34, 2387-2390. (b) Hioki, H.; Izawa, T.; Yoshizuka, M.; Kunitake, R.; Ito,
S. Tetrahedron Lett. 1995, 36, 2289-2992. For 1,2-phenyl migration promoted
by fluoride ion, see: (c) Morihata, K.; Horiuchi, Y.; Taniguchi, M.; Oshima,
K.; Utimoto, K. Tetrahedron Lett. 1995, 36, 5555-5558.
(11) The absolute configuration of (S)-4a was assigned from the stereo-
chemistry of 3a, based on the reasonable postulate that the â-elimination
proceeds without loss of the configurational integrity at the silicon. The
enantiomeric excess of 4a and 4b was determined by HPLC analysis using a
Daicel CHIRACEL OD column with hexane/2-propanol as a solvent.
(12) The diastereomeric ratios at the silicon were determined by 1H NMR
analysis. The cis stereochemistry of 8a was established by X-ray analysis
after conversion (H2/Pd-C) to 8e (eq 5, R ) H).
(13) (a) Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg.
Med. Chem. Lett. 1994, 4, 2545-2550. (b) Lowe, J. A., III; McLean, S. Curr.
Pharm. Des. 1995, 1, 269-278.
(14) This compound was prepared from (S)-hydroxypyrrolidin-2-one in a
manner similar to 1. The corresponding silyl ether was derived from tert-
butylbis(4-methylphenyl)silanol and (S)-hydroxypyrrolidin-2-one in the pres-
ence of oxalyl chloride according to the literature procedure: Tanino, K.;
Yoshitani, N.; Moriyama, F.; Kuwajima, I. J. Org. Chem. 1997, 62, 4206-
4207. Lennon, P. J.; Mack, D. P.; Thompson, Q. E. Organometallics 1989, 8,
1121-1122.
(17) Obviously, more detailed studies are needed to elucidate the exact
mechanism, particularly concerning the specific role of K10 and the steric
course of the substitution on the silicon. Semiempirical calculations on the
transition states are underway.
(18) A few synthetic methods for enantio-enriched silanol have been
reported. For resolution or separation of racemic or diastereomeric silanols,
see: (a) Tacke, R.; Linoh, H.; Ernst, L.; Moser, U.; Mutschler, E.; Sarge, S.;
Cammenga, H. K.; Lambrecht, G. Chem. Ber. 1987, 120, 1229-1237. (b)
Yamamoto, K.; Kawanami, Y.; Miyazawa, M. J. Chem. Soc., Chem. Commun.
1993, 436-437. (c) Feibush, B.; Woolley, C. L.; Mani, V. Anal. Chem. 1993,
65, 1130-1133. (d) Mori, A.; Toriyama, F.; Kajiro, H.; Hirabayashi, K.;
Nishihara, Y.; Hiyama, T. Chem. Lett. 1999, 549-550. For stereospecific
oxidation of enantio-enriched silanes or halosilanes, see: (e) Cavicchioli, M.;
Montanari, V.; Resnati, G. Tetrahedron Lett. 1994, 35, 6329-6330. (f) Adam,
W.; Mitchell, C. M.; Saha-Mo¨ller, C. R.; Weichold, O. J. Am. Chem. Soc.
1999, 121, 2097-2103 and references therein.