Preparation of TADDOL derivatives for new applications

Article abstract of DOI:10.1021/ol990060d

(equation presented) TADDOL Substitution of one or both TADDOL OH groups by other functional groups X, Y is key to new applications of this cheap chiral auxiliary. The Appel reaction and treatment with SOCl₂ provide the mono-and dichlorides, respectively. The chlorides are, in turn, replaced by various nucleophiles, and further modifications give a large variety of derivatives, including mono-and ditritylated dioxolanes. The new compounds -available in either enantiomeric form - are ready to be used in enantioselective synthesis and as dopants in liquid crystals.

Full text of DOI:10.1021/ol990060d

ORGANIC
LETTERS
1
999
Vol. 1, No. 1
5-58
Preparation of TADDOL Derivatives for
5
New Applications1
2
Dieter Seebach,* Arkadius Pichota, Albert K. Beck, Anthony B. Pinkerton,
3
4
5
Thomas Litz, Jaana Karjalainen, and Volker Gramlich
Laboratorium f u¨ r Organische Chemie, UniVersit a¨ tstrasse 16,
Eidgen o¨ ssische Technische Hochschule, ETH-Zentrum, CH-8092 Z u¨ rich, Switzerland
seebach@org.chem.ethz.ch
Received April 27, 1999
ABSTRACT
Substitution of one or both TADDOL OH groups by other functional groups X, Y is key to new applications of this cheap chiral auxiliary. The
Appel reaction and treatment with SOCl provide the mono- and dichlorides, respectively. The chlorides are, in turn, replaced by various
2
nucleophiles, and further modifications give a large variety of derivatives, including mono- and ditritylated dioxolanes. The new compoundss
available in either enantiomeric formsare ready to be used in enantioselective synthesis and as dopants in liquid crystals.
TADDOLs and their derivatives A have found many ap-
plications, ranging from chiral ligands on metals to chiral
NMR shift reagents, to hosts in inclusion compounds for
a variety of chiral diesters for switching to other ring
systems, but there is also the possibility of modifying or
9
replacing the original OH group(s) on the diarylmethanol
6
10-16
enantiomer separation, to dopants for generating cholesteric
unit(s) by other functionalities Y and Z
(see Figure 1).
7
liquid crystal phases. This multitude of usages is due to the
fact that TADDOLs are subject to simple, highly combina-
torial structural variations: not only is there a large number
of aryl halides for the introduction of different aryl groups
through Grignard reactions,6 an even larger number of
,8
6,8
aldehydes and ketones for forming the dioxolane ring, and
(
(
(
1) Part of the projected Ph.D. Thesis.
2) Fulbright fellow 1995/96.
3) Postdoctoral fellow 1996/97, partially financed by the Deutsche
Pharmazeutische Gesellschaft.
4) Postdoctoral fellow 1998/99, financed by Neste Oy Foundation
Finland).
5) Laboratorium f u¨ r Kristallographie, Sonneggstrasse 5, ETH Z u¨ rich,
CH-8092 Z u¨ rich, Switzerland.
6) Dahinden, R.; Beck, A. K.; Seebach, D. In Encyclopedia of Reagents
(
(
(
(
for Organic Synthesis; Paquette, L., Ed.; J. Wiley & Sons: Chichester, 1995;
Vol. 3, pp 2167-2170.
(
7) Kuball, H.-G.; Weiss, B.; Beck, A. K.; Seebach, D. HelV. Chim. Acta
Figure 1. Combinatorial variation of the TADDOL structure A
by employing five readily available types of precursors.
1
997, 80, 2507.
8) Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner, D.
A.; K u¨ hnle, F. N. M. J. Org. Chem. 1995, 60, 1788.
9) (a) Ito, Y. N.; Ariza, X.; Beck, A. K.; Boh a´ c, A.; Ganter, C.; Gawley,
(
(
R. E.; K u¨ hnle, F. N. M.; Tuleja, J.; Wang, Y. M.; Seebach, D. HelV. Chim.
Acta 1994, 77, 2071. (b) Al-Majid, A. M.; Booth, B. L.; Gomes, J. T. J.
Chem. Res., Synop. 1998, 78. (c) Pagenkopf, B. L.; Carreira, E. M.
Tetrahedron Lett. 1998, 39, 9593.
It is the purpose of this paper to disclose the preparation
and some structures of new compounds 8-18 derived from
the parent TADDOL 1 by the last mentioned variation,
1
0.1021/ol990060d CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/26/1999

through intermediates 2-7 (see Tables 1 and 2 and Figures
and 3). There is no doubt in our minds that these readily
available products, being mono-, di-, tri-, and tetradentate
ligands for metals, will be used for syntheses of enantiopure
compounds (EPC) by us and by others.
2
Table 2. Melting Points and Specific Rotations of the TADDOL
Derivatives (for more details and full characterization, see Supporting
Information)
TADDOL
derivative
yielda
[R]Drt
(c in CHCl3)
(from) [%]
mp [°C]
2b
3
72 (1)
(1)
(2)
63d (3)
(2)
135-137
171-172
210-211
198-200
181-183
130-131
68-70
-18.1
-11.1
-58.1
-45.2
-23.0
-36.4
-83.5
-99.9
-73.6
-50.5
+61.1
+108.3
+7.1
(0.4)
(1.0)
(0.2)
(1.0)
(1.2)
(1.2)
(0.7)
(0.9)
(1.2)
(0.7)
(1.2)
(1.2)
(1.1)
(1.0)
(1.0)
(0.6)
(1.0)
(0.6)
(1.0)
(1.1)
(1.0)
(1.2)
Table 1. Derivatives 2-13 of the Parent TADDOL 1
4
5
c
6
7
8
9
0
1
2
3
e
(6)
f
47 (7)
23 (7)
80 (2)
47 (2)
g
97-98
h
1
1
1
1
1
1
1
1
1
1
1
1
1
1
192-193
154-155
138-140
139-140
223-225
200-202
168-169
209-210
182-183
245-246
232-235
155-157
182-185
186-187
TADDOL
i
derivative
X
Y
ref
k
m
l
59 (1)
2
3
4
5
6
7
8
9
0
1
2
3
Cl
Cl
NH2
NH2
NMe2
NMe2
NMe2
NMe2
NHPh
4-tBuPhO
F
OH
Cl
OH
NH2
OH
Cl
10, 13, this paper
10,13
10,13
10,13,16, this paper
10,13
10, this paper
this paper
this paper
this paper
this paper
this paper
this paper
84 (1)
54 (2)
83 (2)
72 (3)
n
n
4a
4b
-2.1
n
5
-65.4
+41.5
+45.5
+37.9
-10.0
+41.0
+18.3
-10.6
p
p
p
q
6a
6b
6c
54 (5)
q
67 (5)
H
q
37 (5)
PhS
OH
OH
OH
F
r
s
7
8
30 (1)
1
1
1
1
t
58 (1)
39
48
u
u
9a
9b
F
a
After purification. b 1 and 2 equiv of P(Ph)3, 3 equiv of CCl4, 2 equiv
of pyridine in CH2Cl2, rt, 3 d (see footnote 20). c 3 and NH3 (neat), 30
equiv of NH4Cl, autoclave, 85 °C, 2 d (see footnote 21). d In addition, 20%
product of cyclization, see compound 7 in ref 10. e Fully characterized,
Besides the linear (17) and cyclic (crown ether17 18, see
Figures 3 and 4) triethylene glycol derivatives and the
oxazolines18 19 (Figure 3), all other new compounds arise
including X-ray structure. f 7 and 7 equiv of Ph PH, THF reflux, 2 d. g 7
2
and PhSH (neat), 60 °C, 1 d. h 2 and PhNH2 in CH2Cl2, rt, 5 d. i 2 and 5
equiv of 4-tBu-C6H4OH in CH2Cl2, 2 equiv of NEt3, reflux, 12 h. k 1 and
from mono- and disubstitutions of the TADDOL OH group-
(
s). The key intermediates in these transformations are the
previously described C -symmetrical chloro (2) and amino
alcohols (4, 6) and the C -symmetrical dichloride (3) and
diamine (5). We have now greatly improved the transforma-
1
equiv of diethylaminosulfur trifluoride (DAST) in CH2Cl2, -78 f 0 °C,
1
X-ray structure, see Figure 4. 13 as side product (12%). m 1 and 2.5 equiv
of DAST, CH2Cl2, -78 f 0 °C. n 2 or 3 and 10 equiv of of amine in
CH2Cl2, rt, 3-5 d. p 5 and 2 equiv of aldehyde in toluene, reflux,
p-toluenesulfonic acid (PTSA), 3-7 d. In addition, the monocondensation
product is isolated. 1 and triethylenglycol ditosylate in THF, 2 equiv of
l
2
1
9
tion of 1 to the monochloride 2 by using the Appel reaction
q
2
0
which does not proceed to the dichloride at all, and we
found a way around the intermediacy of a diazide by going
r
13
KOtBu, reflux, 9 h. s In addition, 21% of a side product. t 1 and triethyl-
directly from the dichloride 3 to the diamine 5 in NH
4
Cl-
englycol ditosylate in THF, 4 equiv of NaH, reflux, 16 h, X-ray structure,
see Figure 4. u Half-ester of (R,R)-tartaric acid acetonide and 3 equiv of
PhMgBr, then condensation with (R)- or (S)-2-amino-2-phenylethanol.
buffered ammonia (heating the neat components in an
2
1
autoclave), see Tables 1 and 2. Thus, the mono- and
diamines 4-6 are now readily accessible in three simple steps
from commercial tartrate acetonide. One additional step, the
(
10) Seebach, D.; Hayakawa, M.; Sakaki, J.-i.; Schweizer, W. B.
Tetrahedron 1993, 49, 1711.
11) Sakaki, J.-i.; Schweizer, W. B.; Seebach, D. HelV. Chim. Acta 1993,
6, 2654.
12) Seebach, D.; Devaquet, E.; Ernst, A.; Hayakawa, M.; K u¨ hnle, F.
N. M.; Schweizer, W. B.; Weber, B. HelV. Chim. Acta 1995, 78, 1636.
13) Seebach, D.; Beck, A. K.; Hayakawa, M.; Jaeschke, G.; K u¨ hnle, F.
(
7
(
(
N. M.; N a¨ geli, I.; Pinkerton, A. B.; Rheiner, P. B.; Duthaler, R. O.; Rothe,
P. M.; Weigand, W.; W u¨ nsch, R.; Dick, S.; Nesper, R.; W o¨ rle, M.; Gramlich,
V. Bull. Soc. Chim. Fr. 1997, 134, 315.
(
14) Seebach, D.; Jaeschke, G.; Pichota, A.; Audergon, L. HelV Chim.
Acta 1997, 80, 2515.
(
15) Heldmann, D. K.; Seebach, D. HelV. Chim. Acta 1999, 82, in press.
Figure 2.
(16) Rothe, P. M. Ph.D. Dissertation, University of Basel, Switzerland,
994; Bichsel, H.-U. Diplomarbeit, ETH Z u¨ rich, 1998.
1
56
Org. Lett., Vol. 1, No. 1, 1999

Figure 3.
condensation with salicylic aldehydes, converts the diamine
to the tetradentate bis-imines 16.
While substitutions of chloride with aniline (f10), a
phenol (f11), and thiophenol (f9) occurred as expected,
Figure 5. X-ray crystal structures22 of the amino alcohols 10 (a)
and 14b (b) (for details see Supporting Information and CCDC
118718 and 118719).
we were surprised to isolate trityl derivatives 14 and 15 with
N-methylaniline and diphenylamine by simply mixing the
2
4-27
components in CH
structures of 10 and 14b in Figure 5.
We did not succeed, as yet, in replacing TADDOL OH
2
Cl
2
at room temperature;
see the
2
8
by R
leading to the product 8 of reduction
attempt, and the fluoro alcohol 12, as well as the difluoride
2
P groups, inspite of many attempts; the reaction
2
9-30
was one such
3
1-32
1
3, was involved in another one.
(17) For use of analogous BINOL derivatives in enantioselective
reactions, see: Kyba, E. P.; Gokel, G. W.; de Jong, F.; Koga, K.; Sousa, L.
R.; Siegel, M. G.; Kaplan, L.; Sogah, G. D. Y.; Cram, D. J. J. Org. Chem.
1
977, 42, 4173.
18) For the corresponding bis-oxazolines, see: (a) Imai, Y.; Zhang, W.;
Kida, T.; Nakatsuji, Y.; Ikeda, I. Tetrahedron: Asymmetry 1996, 7, 2453.
b) Bedekar, A. V.; Koroleva, E. B.; Andersson, P. G. J. Org. Chem. 1997,
62, 2518.
(
(
Figure 4. X-ray crystal structures22 of the fluoro alcohol 12 (a)
and of the crown ether 18 (for details see Supporting Information
and CCDC 118716 and 118717). As expected,23 there is no
OH‚‚‚F hydrogen-bond-forming conformation of 12 present in the
crystal. Rather, 12 has the rare conformation with the heteroatom
(
19) Appel, R. Angew. Chem. 1975, 87, 863; Angew. Chem., Int. Ed.
Engl. 1975, 14, 801.
(20) Preparation of 2: triphenylphosphine (4.5 g, 17.0 mmol) and 1 (4.0
g, 8.6 mmol) were dissolved in anhydrous dichloromethane (15 mL) under
an argon atmosphere. Pyridine (1.4 mL, 17.0 mmol) and carbon tetrachloride
1.7 mL, 17.0 mmol) were added, and the reaction mixture was stirred for
d at room temperature. After concentration to a volume of 5 mL, the
solution was flash chromatographed (silica gel (250 g), pentane/ether 4:1,
Rf 0.58) and the obtained product recrystallized (pentane/ether 6:1 (20 mL))
to yield 2 (3.0 g, 72%). For analytical data, see Table 2 and Supporting
Information.
(
3
(
(
F) above the dioxolane ring, just like the dichloride and the diazide
ref 13). It is intriguing that this compound, like the difluoro
derivative 13, has the opposite sense of rotation (Table 2), as
compared to all other simple TADDOL derivatives.
Org. Lett., Vol. 1, No. 1, 1999
57

All new compounds have been fully characterized, and
the data not presented in Table 2 are included in the
Supporting Information. Besides the four crystal structures
of 10, 12, 14b, and 18, shown in Figures 4 and 5, that of the
chloro amine 7 has also been determined.
cf. 15) is underway. Thus, 19b (0.02 equiv) catalyzes the
addition of Et Zn to PhCHO (-20 °C, toluene) with
formation of 1-phenylpropanol, (R)/(S) ) 92:8.
2
Acknowledgment. We thank Dr. P. B. Rheiner for
determination of the X-ray structure of 18 and L. Audergon,
H.-U. Bichsel, Ch. M u¨ ller, and Ch. Fischer for carrying out
preliminary experiments. Financial support from the Swiss
National Science Foundation (CHiral2) and from Novartis
Pharma AG (Basel) is gratefully acknowledged.
Work on the use of the TADDOL derivatives described
herein in enantioselective synthesis (and for material studies,
(
21) Preparation of 5: 3 (5.0 g, 10.0 mmol), NH4Cl (30 equiv, 16.0 g,
3
00 mmol), and a magnetic stirring bar were placed in an autoclave (250
mL) under an argon atmosphere. The autoclave was cooled to -78 °C, and
ammonia (44 g) was condensed in. The reaction was stirred for 30 min at
room temperature and then heated to 85 °C (25 bar) and stirred for 2 d.
The autoclave was cooled to room temperature, and the unreacted NH3
was vented. The crude product was dissolved in dichloromethane/water and
neutralized (1 N HCl). The organic phase was washed, dried (MgSO4),
and evaporated. The crude product was flash-chromatographed (silica gel
Supporting Information Available: Experimental details
and full characterization of all new compounds, including
the crystal data of five single crystals used for the X-ray
structure determinations. This material is available free of
charge via the Internet at http://pubs.acs.org.
(
100 g), ether, Rf 0.10) to yield 5 (2.9 g, 63%). For analytical data, see
Table 2 and Supporting Information.
22) The figures have been generated by K. Gademann using MolMol
Koradi, R.; Billeter, M.; W u¨ thrich, K. J. Mol. Graphics 1996, 14, 51).
(
(
(
23) Dunitz, J. D.; Taylor, R. Chem. Eur. J. 1997, 3, 89.
OL990060D
(24) The mild conditions (in the absence of Lewis acid) for this
electrophilic aromatic substitution to occur, even twice (f15), are remark-
able. For analogous reactions, see refs 25-27.
(29) Cf. Bezombes, J.-P.; Carr e´ , F.; Chuit, C.; Corriu, R. J. P.; Mehdi,
A.; Rey e´ , C. J. Organomet. Chem. 1997, 535, 81.
(30) Cf. Lambert, J. B.; So, J.-H. J. Org. Chem. 1991, 56, 5960.
(31) Schaffer, F.; Beckhaus, H.-D.; Rieger, H.-J.; R u¨ chardt, C. Chem.
Ber. 1994, 127, 557.
(32) Tani, K.; Suwa, K.; Yamagata, T.; Otsuka, S. Chem. Lett. 1982,
265.
(
(
(
25) Wieland, H.; Dolgow, B.; Albert, T. J. Chem. Ber. 1919, 52, 893.
26) MacKenzie, C. A.; Chuchani, G. J. Org. Chem. 1955, 20, 336.
27) Siskos, M. G.; Garas, S. K.; Zarkadis, A. K.; Bokaris, E. P. Chem.
Ber. 1992, 125, 2477.
28) For an enumeration of the routes tested so far, see the discussion in
ref 15.
(
58
Org. Lett., Vol. 1, No. 1, 1999