Stereoselective additions of α-lithiated alkyl-p-tolylsulfoxides to N-PMP(fluoroalkyl)aldimines. An efficient approach to enantiomerically pure fluoro amino compounds

Full text of DOI:10.1021/jo970004v

3424
J . Org. Chem. 1997, 62, 3424-3425
Sch em e 1
Ster eoselective Ad d ition s of r-Lith ia ted
Alk yl-p-tolylsu lfoxid es to
N-P MP (flu or oa lk yl)a ld im in es. An Efficien t
Ap p r oa ch to En a n tiom er ica lly P u r e F lu or o
Am in o Com p ou n d s
Pierfrancesco Bravo,*,† Alessandra Farina,†
Valery P. Kukhar,‡ Andrey L. Markovsky,‡
Stefano V. Meille,† Vadim A. Soloshonok,*,§
Alexander E. Sorochinsky,‡ Fiorenza Viani,†
Matteo Zanda,*,† and Carmela Zappala`†
while for the reactions of imines derived from aromatic
aldehydes high values of stereoselectivity could be
achieved, aliphatic imines were found to be less suitable
substrates for these additions. Considering our design,
the use of fluorinated imines might produce additional
limitations, arising from the strong electron-withdrawing
nature and steric demands of the fluoroalkyl group in
the starting electrophiles 1.5
For preliminary evaluation of the viability of this
approach, we undertook the investigation of the additions
of Me- and Bn-p-tolylsulfoxides (R)-2a ,b to the imines
bearing CF3, CF2CF3, and CF2CF2H groups 1a-c (Scheme
1). The choice of the N-protecting group was of para-
mount importance. In fact, it was shown that the
substituent on nitrogen has a critical influence in deter-
mining the stereochemical outcome of the reactions of
imines with nucleophiles because it strongly affects the
imine geometry, the reactivity of the CdN bond, and the
coordinative ability of the nitrogen atom.6
After achieving only limited success with the additions
of R-lithiated alkyl-p-tolylsulfoxides to N-(alkoxy-
carbonyl)ketimines,7 we turned our attention to the N-(p-
methoxyphenyl) (PMP) derivatives 1.8 Imines 1a -c were
easily prepared by a direct condensation between p-
anisidine and the appropriate aldehyde in presence of an
acidic catalyst.9 An important feature of these substrates
is that they are geometrically anti-homogeneous.10
The condensations between imines 1a -c and R-lithium
derivatives of Me-p-tolylsulfoxide 2a were run in THF
at -70 °C (Table 1).11 We have found that the additions
occurred with a high reaction rate (15 min) to afford
cleanly the desired FSAs (2S,RS)-3 in an excellent overall
yield (96-98%). Determination of the stereoselection of
the condensation by 19F NMR of the crude reaction
mixture also gave very encouraging results. Thus,
regardless of the nature of the imine fluoroalkyl group,
C.N.R.-Centro di Studio per le Sostanze Organiche
Naturali, Dipartimento di Chimica del Politecnico, via
Mancinelli 7, I-20131 Milano, Italy, The Ukrainian
Academy of Sciences-Institute of Bioorganic Chemistry and
Petrochemistry, Murmanskaya 1, Kiev-94, 253660, Ukraine,
and National Industrial Research Institute of Nagoya,
Hirate-cho 1-1, Kita-ku, Nagoya City,
Aichi Prefecture 462, J apan
Received J anuary 3, 1997
We have recently reported the use of enantiopure
R-(fluoroalkyl) â-sulfinyl amines (FSAs) as starting build-
ing blocks for the asymmetric synthesis of fluorinated
amino compounds of biomedicinal interest. Further, we
have found that, apart from conventional removal of the
sulfinyl auxiliary by substitution with hydrogen, this
group can be displaced, in a highly stereospecific SN2
fashion, by a hydroxy group.2 This disclosure gave us
additional impetus in developing FSAs as versatile
intermediates in the enantiocontrolled synthesis of struc-
turally varied fluorinated amines, amino alcohols, amino
acids, and hydroxy amino acids.3
In this paper, we report our initial studies on the
asymmetric additions of R-lithiated alkylarylsulfoxides
to (fluoroalkyl)aldimines, which provide an efficient,
generalized synthesis of the targeted FSAs. The ef-
fectiveness of this strategy is illustrated in the practical
and highly stereoselective synthesis of (R,R)-trifluo-
ronorephedrine, hitherto unavailable in ep form.
Stereoselective additions to CdN double bonds belong
to one of the less developed classes of asymmetric
reactions. In particular, for the addition of chiral sul-
foxide-stabilized nucleophiles to achiral imines, only a
handful of reports have appeared in the literature.4 It
was shown that the stereochemical outcome of these
additions heavily depends on both the reaction conditions
applied and the nature of the substrates and could be
subject to kinetic or thermodynamic control. Moreover,
(5) For recent discussions on stereochemical properties of fluorine
substituents see: (a) Soloshonok, V. A.; Avilov, D. V.; Kukhar, V. P.
Tetrahedron 1996, 52, 12433 and references cited therein.
(6) Volkman, R. A. Additions to C-X π-bonds. In Comprehensive
Organic Synthesis; Schreiber, S. L., Ed.; Pergamon Press: Oxford,
1991; Part 1, Vol. 1, Chapter 1.12.
* To whom correspondence should be addressed. P.B. and M.Z.:
Fax: (39-2) 2399 3080. E-mail: zanda@dept.chem.polimi.it. V.A.S.:
Fax: (81-52) 911 2428. E-mail: solo@nirin.go.jp.
(7) Bravo, P.; Viani, F.; Zanda, M.; Fokina, N.; Kukhar, V. P.;
Soloshonok, V. A.; Shishkin, O. V.; Struchkov, Y. T. Gazz. Chim. Ital.
1996, 126, 645. Attempts to use (R-fluoroalkyl)N-Cbz-aldimines as
electrophiles were not satisfactory.
(8) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: London: 1991. Unfluorinated N-PMP imines were
shown to exist exclusively in the anti-conformation: (b) Yamamoto,
Y.; Nishii, S.; Maruyama, K.; Komatsu, T.; Ito, W. J . Am. Chem. Soc.
1986, 108, 7778.
† C.N.R.-Centro di Studio per le Sostanze Organiche Naturali.
‡ The Ukrainian Academy of Sciences.
§ National Industrial Research Institute of Nagoya.
(1) Arnone, A.; Bravo, P.; Capelli, S.; Fronza, G.; Meille, S. V.; Zanda,
M.; Cavicchio, G.; Crucianelli, M. J . Org. Chem. 1996, 61, 3375.
(2) Bravo, P.; Zanda, M.; Zappala`, C. Tetrahedron Lett. 1996, 37,
6005.
(3) (a) Filler, R.; Kobayashi, Y.; Yagupolskii, L. M. Biomedical
Aspects of Fluorine Chemistry; Elsevier: Amsterdam, 1993. (b) Resnati,
G. Tetrahedron 1993, 49, 9385. (c) Fluorine-Containing Amino Acids:
Synthesis and Properties; Kukhar, V. P., Soloshonok, V. A., Eds.;
Wiley: Chichester, 1994.
(4) (a) Tsuchihashi, G.; Iriuchijima, S.; Maniwa, K. Tetrahedron Lett.
1973, 14, 3389. (b) Pyne, S. G.; Boche, G. J . Org. Chem. 1989, 54, 2663.
(c) Pyne, S. G.; Dikic, B. J . Chem. Soc., Chem. Commun. 1989, 826.
(d) Pyne, S. G.; Dikic, B. J . Org. Chem. 1990, 55, 1932. (e) Ronan, B.;
Marchalin, S.; Samuel, O.; Kagan, H. B. Tetrahedron Lett. 1989, 29,
6101. (f) For a review see: Risch, N.; Arend, M. In Houben-Weyl:
Methods in Organic Synthesis; Mu¨ller, E., Ed.; Thieme Verlag:
Stuttgart, 1995; Vol. E21b, pp 1920-1924.
(9) Harada, K. In Chemistry of the Carbon-Nitrogen Double Bond;
Patai, S., Ed.; Interscience: London, 1970; pp 69-147.
(10) According to NMR analyses (1H, 19F) imines 1a -c exist as single
geometrical isomers. The anti conformation was confidently assigned
by analogy with the parent unfluorinated derivatives; see ref 8b.
(11) Gen er a l P r oced u r e. To a stirred solution of LDA (1.8 mmol)
in dry THF (4 mL) cooled at -60 °C was added a solution of (R)-Me-
p-tolylsulfoxide (1.5 mmol) in 2 mL of dry THF. After 5 min at the
same temperature, the yellow solution was cooled to -70 °C. Then, a
solution of N-PMP(fluoroalkyl)imine 1 (1.8 mmol) in 2 mL of dry THF
was added. After 15 min, the reaction was quenched at -70 °C with
aqueous NH4Cl and routinely worked up. Crystallization of the crude
reaction mixtures and flash chromatography of the mother liquors
(hexane/ethyl acetate) afforded the desired N-PMP-FSAs 3 and 4.
S0022-3263(97)00004-2 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 11, 1997 3425
Ta ble 1. Ad d ition of En a n tiop u r e r-Lith ia ted
Alk yl-p-tolylsu lfoxid es 2 to r-(F lu or oa lk yl)a ld im in es 1a ,b
Sch em e 2
imine/
major/
minor dr
yield (%)
productc
RF
CF3
CF2CF3
CF2CF2H
CF3
R
(major diast)d
1a /3a
1b/3b
1c/3c
1a /4a
1b/4b
1c/4c
H
H
H
Ph
Ph
Ph
92/8
94/6
>98 (74)
96 (72)
97 (70)
98 (59)
97 (60)
>98 (59)
92/8
Sch em e 3a
85/15e
88/12e
83/17e
CF2CF3
CF2CF2H
a
Only the major diastereoisomeric products are depicted, for
clarity. Imines 1 were added at -70 °C. c R-Lithium sulfoxide
b
d
formed at -60 °C, reaction time 15 min. Overall yield determined
by 19F NMR of the crude. The isolated yield of the major
diastereoisomer is reported in parentheses. e Ratio of major dia-
stereoisomer/sum of the three minor diastereoisomers.
a
Key: (i) CAN (72%); (ii) ClCOOCH2Ph, K2CO3 50%, dioxane,
all reactions proceeded with high diastereoselectivity,
providing the major diastereoisomers (2S,RS)-3 in 84-
88% de. Further purification of the products (2S,RS)-3
to diastereoisomerically pure state was easily achieved
by crystallization of the crude mixtures.
60 °C (80%); (iii) (CF3CO)2O, sym-collidine, CH3CN, 0 °C; (iv)
NaBH4, THF/H2O, 0 °C (75% from 7a ); (v) H2/Pd(OH)2-C (100%).
A series of experiments revealed that treatment of
(2S,RS)-3 with 5 equiv of CAN in acetonitrile at rt are
the conditions of choice to obtain the desired free amino
derivatives (2S,RS)-5 in good chemical yield (Scheme 2).
Oxidation of the sulfinyl to sulfonyl moiety was never
observed, even with a larger excess of CAN.
A wide range of synthetic applications can be readily
envisaged for the present approach. For example, reduc-
tive desulfinylation of the FSAs can produce the corre-
sponding fluoroamines.1 More intriguing is the prepa-
ration of the trifluoro analog of norephedrine (R,R)-10
(Scheme 3), which serves to illustrate the efficient and
straightforward elaboration of the enantiopure FSAs in
a biologically important amino alcohol derivative. This
protocol features an absolute economy and the full
exploitation of the carbon stereocenters formed by action
of the sulfinyl group.
The N-PMP group of (1S,2S,RS)-4a was cleaved with
CAN, the amino group of the free FSA (1S,2S,RS)-6a was
reprotected, affording the N-Cbz derivative (1S,2S,RS)-
7a , which was submitted to the stereoselective “non-
oxidative” Pummerer reaction, recently reported from
these laboratories.1,2 Treatment of (1S,2S,RS)-7a with
TFAA and sym-collidine produced a clean SN2-type
displacement of the sulfinyl by a trifluoroacetoxy group,
stereospecifically affording the R-trifluoroacetoxy
sulfenamide (R,R)-8. NaBH4 reduction of the crude
(R,R)-8 delivered the N-Cbz trifluoro norephedrine (R,R)-9
with diastereoselection >98:2 (the other diastereoisomer
was not detected in the crude reaction mixture). Hydro-
genolysis of the N-Cbz protection afforded in quantitative
yield the ep trifluoronorephedrine (R,R)-10, previously
described in racemic form.13
It is worth noting that the stereoselectivity of the
condensations was not markedly influenced by an in-
crease of the reaction time, suggesting that the additions
occur irreversibly and the stereochemical outcome is
therefore kinetically controlled. Further evidence was
obtained by submitting enantiomerically and chemically
pure minor diasteroisomer (2R,RS)-3a to the exact reac-
tion conditions (LDA, -70 °C) for 90 min, which revealed
neither decomposition of 3a to the starting materials nor
its epimerization to the major diastereoisomer. The
(2S,RS)-absolute configuration of the trifluoromethyl-
containing product 3a was determined by X-ray analysis
of the N-unprotected derivative (2S,RS)-5a , previously
described by us (see below).1
The condensations between imines 1a -c and the
lithium derivative of Bn-p-tolylsulfoxide ((R)-2b) were
quite intriguing due to the more complex mechanism of
stereochemical discrimination involved in the simulta-
neous formation of two new stereogenic centers. Despite
steric shielding and additional stabilization of (R)-2b,
these reactions were found to be fast even at -70 °C in
THF (15 min). The corresponding diastereoisomeric
FSAs (1S,2S,RS)-4 formed in very good yields and, to our
great satisfaction, with a high and synthetically useful
level of stereoselectivity, affording with overwhelming
preference one out of four possible diastereoisomers, as
revealed by 19F NMR of the raw reaction mixtures. Also
in this case, the purification of the main diastereoisomer
to diastereoisomerically pure state could be achieved
merely by crystallization of the crude mixture. Deter-
mination of the absolute configuration of 4a by X-ray
analysis gave rather surprising results.14 In fact, the
(1S,2S,RS)-absolute configuration of the main diastereo-
isomer 4a was found to be opposite to the stereochemistry
of the â-sulfinylamine stereoselectively formed in the
condensation between N-phenylbenzaldimine and the
R-lithium derivative of (R)-Bn-t-Bu-sulfoxide.4c While the
direct comparison of the factors influencing the stereo-
chemical preferences in our study and in the previously
reported reactions is not possible, we assume that in the
condensations studied herein the fluoroalkyl group might
play a key role in determining the observed stereochem-
ical outcome.
The extension of the methodology to the preparation
of more complex targets is under active investigation.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectral data of major diastereoisomers 3-5 and
of compounds 6, 7, 9, 10, including a table of spectroscopic data
and copies of 1H, 19F, and 13C NMR, low-resolution mass
spectra; crystal data and ORTEP drawing of (1S,2S,RS)-4a (48
pages).
J O970004V
The chemoselective oxidative deprotection of the N-
PMP derivatives 3 and 4 to the corresponding compounds
having a free amino function has also been addressed.12
(13) (a) Beck, A. K.; Seebach, D. Chem. Ber. 1991, 124, 2897. (b)
Marti, R. E.; Heinzer, J .; Seebach, D. Liebigs Ann. 1995, 1193. (R,R)-
10: [R]20 -14.0 (c 1.24, CHCl3).
D
(14) The author has deposited atomic coordinates for 4a with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(12) Bravo, P.; Cavicchio, G.; Crucianelli, M.; Markovsky, L. A.;
Volonterio, A.; Zanda, M. Synlett 1996, 887.