First asymmetric synthesis of a differentially silyl-protected tris(alkynyl)methyl methyl ether

Article abstract of DOI:10.1039/b601380e

The stereoselective synthesis of the differentially silyl-protected tris(alkynyl) methyl methyl ether, the first optically active trispropargylic alcohol derivative, was investigated. The asymmetric synthesis began with enantiometrically pure ethyl lactat

Full text of DOI:10.1039/b601380e

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www.rsc.org/obc | Organic & Biomolecular Chemistry
First asymmetric synthesis of a differentially silyl-protected
tris(alkynyl)methyl methyl ether†
Vito Convertino, Peter Manini, W. Bernd Schweizer and Franc¸ois Diederich*
Received 30th January 2006, Accepted 6th February 2006
First published as an Advance Article on the web 20th February 2006
DOI: 10.1039/b601380e
For an improved synthesis of the recently described expanded
octamethoxycubane with a central C56 core, formally ob-
tained by inserting buta-1,3-diynediyl moieties into all C(sp3)–
C(sp3) bonds of octamethoxycubane, the preparation of the
optically pure methyl ether of a differentially silyl-protected
trispropargylic alcohol was required. The key step of the
preparation involved a diastereoselective addition of a lithium
acetylide to an optically active alkynyl ketone under Cram
chelation control.
We envisaged the asymmetric synthesis to begin with enan-
tiomerically pure ethyl lactate (−)-(S)-3 (Scheme 1). Our strategy
hinged on the presence of an a-oxygen donor atom that was
expected to assist, by chelation, the diastereoselective addition of
a metal acetylide to an alkynyl ketone. According to Cram’s cyclic
model, the nucleophile would be expected to attack from the steri-
cally less hindered side, thus leading to the predominant formation
of the anti-diastereoisomer (1,2-asymmetric induction).5
Since the early 1990s, we have pursued the geometrically defined
expansion of molecules by insertion of buta-1,3-diynediyl frag-
ments into all C–C single bonds of polyacetylenes, arenes,
annulenes, radialenes or dendralenes, thereby generating new one-
and two-dimensional carbon-rich chromophores with enhanced
optoelectronic properties.1 The application of this concept to
three-dimensional structures recently led to the synthesis of the
first expanded cubane 1.2,3 However, passing via the sequential
construction of corners, edges and faces, an overall yield of 1 of
only 0.2% was obtained. The main drawback of this first synthesis,
which employed a racemic corner building block as starting
material, was the formation of undesired as well as inseparable
stereoisomers at the stage of the various intermediates. By starting
from optically pure corner modules, the formation and low-
yielding transformations of mixtures of stereoisomers can be
largely avoided and the overall yield of 1 improved. This should
provide sufficient material for desirable investigations such as
the experimental determination of the heat of formation of the
highly strained carbon cage.2,3 Here, we report the stereoselective
synthesis of the differentially silyl-protected tris(alkynyl)methyl
methyl ether (R)-2, the first optically active trispropargylic alcohol
derivative.4
Scheme 1 Synthesis of the optically active bispropargylic alcohols
(R,S)-7a/b. Reagents and conditions: (i) PMB-OC(NH)CCl3, TfOH (cat.),
cyclohexane–CH2Cl2 1 : 1, 0 → 20 ◦C; 86%; (ii) PriMgCl, Me(MeO)NH·
HCl, THF, −20 ◦C; 78%; (iii) RC≡CLi, THF, −78 ◦C; 96% [(S)-6a],
89% [(S)-6b]; (iv) Me3SiC≡CLi, Et2O, −78 ◦C; 83% (7b); for conditions
and yields in the conversion (S)-6a → (S)-7a, see Table 1. PMB =
p-methoxybenzyl, Tf = CF3SO2, THF = tetrahydrofuran.
We chose the p-methoxybenzyl (PMB) residue as a protecting
group for the hydroxy function in (−)-(S)-3, since benzyl ethers
are frequently employed in chelation-controlled nucleophilic
additions6 and since this group can be oxidatively removed without
affecting the alkyne moieties. In order to avoid epimerization,
the introduction of the PMB group under formation of (S)-4
was achieved by employing a non-basic procedure7 using cata-
lytic TfOH and p-methoxybenzyl 2,2,2-trichloroacetimidate.8 The
Weinreb amide (S)-5 was prepared following a protocol reported
by Paterson et al.9 and subsequently transformed into ketone
(S)-6a by reaction with lithium (triisopropylsilyl)acetylide.
The subsequent chelation-controlled addition of (trimethylsi-
lyl)acetylide was investigated under a variety of conditions
summarized in Table 1. The lithium acetylide reacted with good
diastereoselectivity (diastereoisomeric excess, de = 82%) but gave
a moderate yield (64%) only (entry 1). The Grignard reagent
(entry 2) was prepared by transmetallation of the lithium acetylide
with MgBr2·OEt2. Addition did not occur at −78 ◦C and therefore
the temperature was raised slowly to 20 ◦C. The products were
Laboratorium fu¨r Organische Chemie, ETH-Ho¨nggerberg, CH-8093 Zu¨rich,
Switzerland. E-mail: diederich@org.chem.ethz.ch; Fax: +41 44 632 11 09;
Tel: +41 44 632 29 92
† Electronic supplementary information (ESI) available: synthetic proto-
cols and crystal packing of (R)-13. See DOI: 10.1039/b601380e
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Table 1 Diastereoselective addition of acetylide nucleophiles (Me3SiC≡CM) to ketone (S)-6a providing alcohols (R,S)-7a and (S,S)-7a
dr (R,S)-7a : (S,S)-7a (de)
dr (de)
GCb
Entry
M
Conditions
Total yield (%)
1H NMRa
1
2
3
Li
MgBr
CeCl2/TiCl4
−78 ◦C, 1.5 h
64
76
65
91 : 9 (82%)
83 : 17 (66%)
51 : 49 (2%)
91 : 9 (82%)
86 : 14 (72%)
50 : 50 (0%)
−78 → 20 ◦C, 24 h
−78 ◦C, 30 min
a Determined by integrating the HO resonances (d = 3.15 and 3.19 in CDCl3) in the 1H NMR spectrum. b Determined by GC analysis (Column: WCOT
Fused Silica, CP-Sil 8CB, 30 m × 0.32 mm; Detector: FID; Isotherm: 210 ◦C; Carrier gas: Helium).
obtained in good yield (76%) but the diastereoselectivity was lower
than in the previous case. The pre-chelation of ketone (S)-6a with
TiCl4, followed by the addition of Ce(III) (trimethylsilyl)acetylide,
did not improve the yield and, moreover, the diastereoselectivity
was lost (entry 3).10 Extremely high reactivity was observed and
this may account for the lack of diastereoselection. In all cases, the
major diastereoisomer (R,S)-7a, presumed to arise from chelation
control, was not separable from the minor diastereoisomer (S,S)-
7a. The diastereoisomeric ratio (dr) was determined by integrating
the HO resonances [d = 3.19 (R,S) and 3.15 (S,S)] in the 1H NMR
spectrum in CDCl3. Separation of the diastereoisomers by ana-
lytical gas chromatography (GC) supported the 1H NMR results.
Within the context of the synthesis of the expanded cubane
1, the yield (64%) together with the optical purity (de 82%) of
(R,S)-7a obtained in entry 1 were not very satisfactory. Therefore,
we changed from the larger triisopropylsilyl to the smaller
triethylsilyl protecting group. Chelation-controlled addition of
Scheme 2 Synthesis of the optically active mono-protected bispropargyl
lithium (triethylsilyl)acetylide to Weinreb amide (S)-5, as described
methyl ether (R,S)-9. Reagents and conditions: (i) n-BuLi, THF, −78 ◦C,
above, gave ketone (S)-6b in high yield (Scheme 1). The following
then MeI, −78 → 20 ◦C; 91%; (ii) 1 M NaOH, MeOH–THF 1 : 1, 20 ◦C,
addition of lithium (trimethylsilyl)acetylide in Et2O at −78 ◦C
89%.
finally provided the diastereoisomeric mixture (R,S)-7b/(S,S)-7b
in a total yield of 83%. Gratifyingly, the diastereoselectivity had
improved to dr 95 : 5 (de 90%), as determined by integrating the
to the corresponding ketone (R)-11 using the mild Dess-Martin
periodinane (DMP) reagent.11 Finally, the generation of the
targeted tris(alkynyl)methyl methyl ether (R)-2 was accomplished
in two steps, comprising (i) the preparation of an enol triflate and
(ii) elimination of the leaving group from the latter by a strong,
non-nucleophilic base. Trapping of the enolate of (R)-11 with a
triflating agent such as N-(5-chloro-2-pyridyl)triflimide (Comins
reagent)12 afforded enol triflate (R)-12. Subsequent elimination
with LDA provided (R)-2 in 37% yield (from (R)-11).
An unambiguous assignment of the configuration of the in-
duced stereogenic center in 7b was achieved by means of converting
ketone (R)-11 into the corresponding tosylhydrazone (R)-13.
Upon evaporation of a hexane solution, crystals suitable for X-
ray analysis were obtained.‡ The crystal structure (Fig. 1) confirms
the absolute configuration of the major diastereoisomer of 7b to
be (R,S), in accordance with the Cram chelate model. The unit
cell contains six symmetrically independent molecules. The silyl
groups are heavily disordered. Three dimers are formed by pairs
1
HO resonances [d = 5.13 (R,S) and 5.16 (S,S)] in the H NMR
spectrum in (CD3)2CO, with (R,S)-7b being the major product as
predicted by Cram’s cyclic model.
Methylation of (R,S)-7b and (S,S)-7b by deprotonation at
−78 ◦C with n-BuLi, followed by addition of an excess of
iodomethane, led to the stable methyl ethers (R,S)-8 and (S,S)-
8 (Scheme 2). All attempts to separate the diastereoisomeric
mixture of (R,S)-7b/(S,S)-7b or (R,S)-8/(S,S)-8 by either column
chromatography, GC or HPLC were unsuccessful.
The subsequent selective deprotection of the trimethylsily-
lalkyne unit by stirring (R,S)-8 and (S,S)-8 for about1h in MeOH–
THF (1 : 1) containing a few drops of 1 M NaOH afforded (R,S)-
9 and (S,S)-9 in very good yield (89%). Gratifyingly, separation
R
by preparative HPLC (‘Hibarꢀ 250–25’) of the diastereoisomeric
mixture was possible at this stage. Both diastereoisomers were
obtained in pure form and the major isomer (R,S)-9 was used for
the completion of the synthesis.
˚
of N(8)–H · · · O(5) H-bonds (N · · · O distance 2.87 to 2.98 A),
Indeed, treating the semi-protected bispropargyl methyl ether
(R,S)-9 with NaHMDS and trimethylchlorosilane in THF at
−78 ◦C furnished the differentially protected bispropargyl methyl
ether (R,S)-8 as a single diastereoisomer (Scheme 3). Subsequently,
the PMB protecting group was removed by oxidation using 2.2
equivalents of CAN in MeCN/H2O 9:1, providing alcohol (R,S)-
10 in 90% yield after purification by column chromatography
(SiO2; hexane/CH2Cl2 1:2). Alcohol (R,S)-10 was readily oxidized
with a gauche orientation of the phenyl ring and the N–N bond
[dihedral angle N(7)–N(8)–S(1)–C(26) = 57 to 67◦]. All dimers
show a pseudo-centre of symmetry when ignoring the different
silyl substituents. Each dimer combines two molecules with the
C(10)–N(7) bond eclipsed to C(9)–C(17) (dihedral angle = 4 to
10◦) or to C(9)–C(12) (dihedral angle = −5 to −2◦), respectively.
In summary, we accomplished the first synthesis of an optically
pure trispropargylic alcohol derivative, (R)-2, by a stereoselective,
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Scheme 3 Synthesis of the optically active tris(alkynyl)methyl methyl ether (R)-2. Reagents and conditions: (i) NaHMDS, THF, −78 ◦C, then Me3SiCl,
−78 ◦C; 86%; (ii) CAN, MeCN–H2O 9 : 1, 20 ◦C; 90%; (iii) DMP, CH2Cl2, 20 ◦C; 96%; (iv) NaHMDS, THF, −78 ◦C, then Comins reagent, −78 → −40 ◦C;
45%; (v) LDA, THF, −78 → −40 ◦C; 82%; (vi) p-TsNHNH2, EtOH, 20 ◦C; 95%. Ts = toluenesulfonyl, CAN = cerium ammonium nitrate, DMP =
Dess–Martin periodinane, NaHMDS = sodium hexamethyldisilazane, LDA = lithium diisopropylamide.
˚
Kappa-CCD diffractometer, Mo-Ka radiation, k = 0.7107 A. Number of
reflections measured = 24 791. The structure was solved by direct methods
(SIR97)13 and refined by full-matrix least-squares analysis (SHELXL-
97),14 using an isotropic extinction correction. Final R(F) = 0.0724,
wR(F2) = 0.1961 for 1727 parameters and 22370 reflections with I > 2r(I)
and 0.998 < h < 25.028◦ (corresponding R-values based on all 24 791
reflections are 0.0827 and 0.2102 respectively). CCDC reference number
275886. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b601380e
1 F. Diederich, Chem. Commun., 2001, 219–227; F. Mitzel, C. Boudon,
J.-P. Gisselbrecht, P. Seiler, M. Gross and F. Diederich, Helv. Chim.
Acta, 2004, 87, 1130–1157.
2 P. Manini, W. Amrein, V. Gramlich and F. Diederich, Angew. Chem.,
Int. Ed., 2002, 41, 4339–4343.
3 For a theoretical study, see: P. D. Jarowski, F. Diederich and K. N.
Houk, J. Org. Chem., 2005, 70, 1671–1678.
4 Numerous examples of bispropargylic alcohols or their derivatives are
described in the literature, but only a few reports describe optically
active compounds. For instance, during the synthesis of Zaragozic Acid
A, Tomooka et al. prepared an optically active, tertiary bispropargylic
alcohol via a diastereoselective Wittig rearrangement, see: K. Tomooka,
Fig. 1 ORTEP plot of (R)-13, showing one of the six independent
molecules contained in the unit cell. Arbitrary numbering. Atomic
displacement parameters obtained at 172 K are drawn at the 50%
probability level.
M. Kikuchi, K. Igawa, M. Suzuki, P.-H. Keong and T. Nakai, Angew.
Chem., Int. Ed., 2000, 39, 4502–4505.
5 D. J. Cram and K. R. Kopecky, J. Am. Chem. Soc., 1959, 81, 2748–
2755; D. J. Cram and D. R. Wilson, J. Am. Chem. Soc., 1963, 85, 1245–
1249.
6 R. M. Devant and H.-E. Radunz, in Stereoselective Synthesis, G. Helm-
chen, R. W. Hoffmann, J. Mulzer and E. Schaumann, eds., Thieme,
Stuttgart, 1995, vol. E21b, pp. 1196–1235.
7 W. R. Roush, C. E. Bennett and S. E. Roberts, J. Org. Chem., 2001, 66,
6389–6393.
8 For a one-step synthesis of p-methoxybenzyl 2,2,2-trichloroacet-
imidate, see: A. M. Gilbert, R. Miller and W. D. Wulff, Tetrahedron,
1999, 55, 1607–1630.
9 I. Paterson, D. J. Wallace and C. J. Cowden, Synthesis, 1998, 639–
652.
10 M. T. Reetz, Angew. Chem., Int. Ed. Engl., 1984, 23, 556–569.
11 D. B. Dess and J. C. Martin, J. Am. Chem. Soc., 1991, 113, 7277–7287;
J. B. Arterburn, Tetrahedron, 2001, 57, 9765–9788.
12 D. L. Comins and A. Dehghani, Tetrahedron Lett., 1992, 33, 6299–6302.
13 A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla,
G. Polidori and M. Camalli, J. Appl. Crystallogr., 1994, 27, 435.
14 G. M. Sheldrick, SHELXL-97, Program for the Refinement of Crystal
Structures, University of Go¨ttingen, Germany, 1997.
11-step synthesis involving preparative HPLC separation. The
other enantiomer, (S)-2 is readily prepared in the same way,
starting from (+)-lactate. We are now applying the optically active
corner modules to an improved synthesis of expanded cubane 1,
providing sufficient material for a detailed investigation of the
physical properties of this interesting cage compound.
This work was supported by a grant from the ETH Research
Council.
Notes and references
‡ X-Ray data for (R)-13: crystal data at 172 K for (C24H38N2O3SSi2)
(Mr = 490.81): triclinic, space group P1, Z = 6, Dc = 1.095 g cm−3
,
˚
a = 11.2537(2), b = 13.9426(2◦), c = 28.9064(5) A, a = 83.0511(6),
3
˚
b = 88.3274(5), c = 82.8675(9) , V = 4466.96(13) A . Bruker-Nonius
1208 | Org. Biomol. Chem., 2006, 4, 1206–1208
This journal is
The Royal Society of Chemistry 2006
©