Highly stereoselective route toward the synthesis of β- and γ-amino alcohols from homochiral α- and β-amino acylsilanes as synthetic equivalents of α- and β-amino aldehydes

Full text of DOI:10.1021/jo961392o

7242
J . Org. Chem. 1996, 61, 7242-7243
To overcome the problems connected with the use of
R- and â-amino aldehydes, we propose an approach to
1,2- and 1,3-amino alcohols focusing on the use of
homochiral R- and â-amino acylsilanes, obtained from
natural R-amino acids, as synthetic equivalents of R- and
â-amino aldehydes, based on the well-known facility to
replace the silyl group with a proton by means of fluoride
ion. In this way we take advantage of the stability of
amino acylsilanes (vide infra) and of the bulkiness of the
silyl group in increasing the degree of diastereoselectiv-
ity.16
The synthetic equivalence between acylsilanes and
aldehydes has already been exploited by Ohno et al. in
the addition reactions of organometallic reagents to
acylsilanes bearing an R-17 and a â-chiral carbon.18
Our strategy involves the addition of an organometallic
reagent to homochiral, nitrogen-protected R- and â-amino
acylsilanes to give R-hydroxysilanes, followed by ste-
reospecific protiodesilylation and deprotection of the
amino group.
The aminoacylsilanes of choice were the [3-phenyl-2(S)-
phthalimidopropionyl]dimethylphenylsilane (5)19 and the
[4-phenyl-3(S)-phthalimidobutanoyl]dimethylphenyl-
silane (4), both obtained from N-Pht-L-phenylalanine (1).
For the synthesis of 4, N-Pht-L-phenylalanine was
homologated with the Arndt-Eistert reaction which is
known20-22 to give enantiopure â-amino acids from their
R-analogues with retention of configuration at the chiral
carbon. The 4-phenyl-3(S)-phthalimidobutanoic acid (2)
obtained was transformed into the acyl chloride 3, which
in turn was allowed to react with bis(dimethylphenylsi-
lyl)zinc cyanocuprate under the same conditions19 used
for compound 5, giving 4 in 45% yield (Scheme 1).
The (aminoacyl)silanes 5 and 4 were purified on silica
gel and stored in the refrigerator (4-10 °C) for long
periods, without experiencing any chemical degradation
or racemization, thus proving their chemical and optical
stability.
The first step of our synthetic protocol toward 1,2- and
1,3-amino hydroxyl systems was accomplished through
a titanium tetrachloride-mediated addition of allyltri-
methylsilane to both R-5 and (â-aminoacyl)silane 4,
resulting in the formation of the R-hydroxysilanes 6 and
8 in 75% and 80% yield, respectively. The NMR spectra
(H-1 and C-13) of 6 and 8 indicate the presence of a single
diastereoisomer for each R-hydroxysilane, thus suggest-
ing de values equal to or higher than 98%.24 Subsequent
protiodesilylation of 6 and 8 with tetrabutylammonium
fluoride (TBAF) in THF afforded 60% of 6-phenyl-5(S)-
phthalimido-1-hexen-4-ol (7) and 80% of (4R,6R)-7-phen-
High ly Ster eoselective Rou te tow a r d th e
Syn th esis of â- a n d γ-Am in o Alcoh ols fr om
Hom och ir a l r- a n d â-Am in o Acylsila n es a s
Syn th etic Equ iva len ts of r- a n d â-Am in o
Ald eh yd es
Bianca F. Bonini, Mauro Comes-Franchini,
Germana Mazzanti,* Alfredo Ricci, and
Massimiliano Sala
Dipartimento di Chimica Organica “A. Mangini”,
Universita`, Viale Risorgimento 4, Bologna 40136, Italy
Received J uly 23, 1996
In recent years there has been a growing interest in
the synthesis of homochiral 1,2- and 1,3-amino alcohols
with two stereogenic centers bearing the amino and the
hydroxyl groups, which are structural units found in a
number of important bioactive compounds. The 1,2-
amino alcohol unit is, in fact, present in compounds such
as antibiotics,1 among which Taxol2 is certainly the most
famous, and hydroxyethylene dipeptide isosteres acting
as HIV-1 protease inhibitors.1,3 The 1,3-amino alcohol
unit is present in a number of widely prescribed antide-
pressants.4
A variety of different methods have been reported for
the diastereoselective synthesis of 1,2-1,5-7 and 1,3-amino
hydroxyl sistems.4,5,8,9 A general synthetic strategy
toward 1,2-amino hydroxyl compounds consists of the
diastereoselective addition of organometallic reagents to
protected R-amino aldehydes that, in turn, are accessible
from the corresponding amino acids.1,3,10-12 However,
several basic problems are connected with the use of
R-amino aldehydes, such as their chemical and configu-
rational instability, as well as the stereocontrol in the
addition step. Due to their instability, special precau-
tions are necessary for their synthesis, handling, and
storage.1,13 The degree of stereoselectivity in the addition
step, not high enough in many cases,1 has been recently
increased by specific variations of protecting groups and
reagents.10,11
To the best of our knowledge an analogous protocol
toward the diastereoselective synthesis of 1,3-amino
alcohols has never been used. This is probably due to
the difficulty in obtaining the â-amino aldehydes in a
pure state owing to their high instability.14,15
(1) J urczak, J .; Golebiowski, A. Chem. Rev. 1989, 89, 149 and
references therein.
(2) Nicolaou, K. C.; Dai, W.; Guy, R. K. Angew. Chem., Int. Ed. Engl.
1994, 33, 15.
(3) D’Aniello, F.; Mann, A.; Mattii, D.; Taddei, M. J . Org. Chem.
1994, 59, 3762 and references therein.
(4) Carlier, P. R.; Lo, K. M.; Lo, M. M. C.; Williams, I. D. J . Org.
Chem. 1995, 60, 7511.
(16) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199.
(17) Nakada, M.; Urano, Y.; Kobayashi, S.; Ohno, M. J . Am. Chem.
Soc. 1988, 110, 4826.
(5) Ohfune,Y. Acc. Chem. Res. 1992, 25, 360.
(18) Nakada, M.; Urano, Y.; Kobayashi, S.; Ohno, M. Tetrahedron
Lett. 1994, 35, 741.
(19) Bonini, B. F.; Comes-Franchini, M.; Mazzanti, G.; Passamonti,
U.; Ricci, A.; Zani, P. Synthesis 1995, 92.
(6) Sakaitani, M.; Ohfune, Y. J . Am. Chem. Soc. 1990, 112, 1150.
(7) Barrett, A. G. M.; Seefeld, M. A.; White, A. J . P.; Williams, D. J .
J . Org. Chem. 1996, 61, 2677.
(8) Gmeiner, P.; J unge, D.; Ka¨rtner, A. J . Org. Chem. 1994, 59, 6766.
(9) Chesney, A.; Marko`, I. E. Synth. Commun. 1990, 20, 3167.
(10) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531. Reetz,
M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed. Engl. 1987,
26, 1141.
(11) Dondoni, A.; Perrone, D.; Merino, P. J . Org. Chem. 1995, 60,
8074. Dondoni, A.; Perrone, D.; Semola, T. Synthesis 1995, 181.
(12) Prasad, J . V. N. V.; Rich, D. H. Tetrahedron Lett. 1990, 31, 1803.
Prasad, J . V. N. V.; Rich, D. H. Tetrahedron Lett. 1991, 32, 5857.
(13) Rein, T.; Kreuder, R.; von Zezschwitz, P.; Wulff, G.; Reiser, O.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1023.
(20) Cole, D. C. Tetrahedron 1994, 50, 9517.
(21) Plucinska, K.; Liberek, B. Tetrahedron 1987, 43, 3509.
(22) Cassal, J . M.; Fu¨rst, A.; Meier, W. Helv. Chim. Acta 1976, 59,
1917.
(23) Sheehan, J . C.; Chapman, D. W.; Roth, R. W. J . Am. Chem.
Soc. 1952, 74, 3822.
(24) The estimate of the de values assigned to compounds 6-9
derives from a measure of the signal to noise ratio of their NMR
spectra. In addition, in the case of compound 9, the value has been
confirmed by the observation that in the 1H NMR spectrum no signal,
which might be attributed to a possible minor diastereoisomer, was
higher than the pair of C-13 satellites (0.55% each) of the major
diastereoisomer.
(14) Marko`, I. E.; Chesney, A. Synlett 1992, 275.
(15) Davis, S. G.; McCarthy, T. D. Synlett 1995, 700.
S0022-3263(96)01392-8 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 21, 1996 7243
Sch em e 1a
Ta ble 1. Deter m in a tion of th e Absolu te Con figu r a tion
of 9
δH C(2)
δH C(3)
δH C(5)
δH C(6)
(R)-MTPA ester of 9
(S)-MTPA ester of 9
∆δH ) δ(R) - δ(S)
5.464
5.617
-0.153
2.275
2.398
-0.123
1.982
1.965
+0.017
4.521
4.444
+0.077
to predict the absolute configuration at C-4 of the â-amino
alcohol 7, since the differences of chemical shifts in the
1H NMR spectra of the corresponding (R)-MTPA and (S)-
MTPA esters were not significant.27
a
Reaction conditions: (a) ref 23, 90%; (b) CH2N2, Et2O/THF,
rt, 1 h, 93%; (c) Ag2O, MeOH, 50 °C, 40 min, 85%; (d) HCl, H2O,
aceton, reflux, 150 min, 80%; (e) SOCl2, 55 °C, 4 h, 93%; (f)
(PhMe2Si)2CuCN(ZnCl)2 (see ref 19), 45%.
In conclusion, these results describe the possibility of
obtaining 1,2- and 1,3-amino alcohol units by overcoming
the problems associated with the use of R- and â-amino
aldehydes. In fact, we found that R- and â-amino
acylsilanes 4 and 5 are stable and react in a highly
stereoselective fashion (de g98%) with allyltrimethylsi-
lane in the presence of TiCl4. Moreover, the protiodesi-
lylation step is stereospecific, thus proving the synthetic
equivalence of these species with R- and â-amino alde-
hydes.
Sch em e 2a
Further investigations regarding the use of other (R-
aminoacyl)- and (â-aminoacyl)silanes and the improve-
ment of their yields, as well as the use of different
protecting groups and of other organometallic reagents
are currently underway in our laboratory.
a
Reaction conditions: (a) allyltrimethylsilane (1 equiv), CH2Cl2,
TiCl4 1 M in CH2Cl2 (1 equiv), -78 °C, 24 h, 75% for 6, 80% for 8;
(b) TBAF 1 M in THF (1 equiv) diluted with THF to obtain a 0.1
M solution, rt, 72 h, 60% for 7, 72% for 9.
Ack n ow led gm en t. This work was supported by
Progetto Strategico, Tecnologie Chimiche Innovative
(CNR, Italy), and by University of Bologna (funds for
selected research topics). The authors thank Professor
L. Lunazzi of this department for useful discussions.
yl-6-phthalimido-1-epten-4-ol (9), respectively, as single
diastereoisomers, suggesting, also in this case, de values
g98%24 (Scheme 2).
The absolute stereochemistry of the newly formed
stereogenic center in 9 was established by 1H NMR
analysis of the corresponding esters of Mosher’s acids (R)-
MTPA and (S)-MTPA. From the differences in the
chemical shifts, the R configuration was attributed25,26
to the carbon bearing the hydroxylic group (C-4) (Table
1). Unfortunately, Mosher’s method could not be used
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization data (6 pages).
J O961392O
(26) Ohtani, I.; Kusumi, I.; Kashman, Y.; Kakisawa, H. J . Am. Chem.
Soc. 1991, 113, 4092 and references therein.
(27) The spectra, recorded at 300 MHz in CDCl3 and C6D6, displayed
chemical shift differences smaller than 1 Hz. Other examples are
known in which Mosher’s method is inapplicable (see ref 26).
(25) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.