Synthesis of the first chiral, functionalised-bridged resorcinarenes in asymmetric catalysis: Evidence for intracavity asymmetric catalysis

Article abstract of DOI:10.1002/ejoc.200400615

Methodology is presented for synthesis of the first examples of chiral, bridged resorcinarenes with functionality in the bridge as possible sites for intracavity asymmetric catalysis. A preliminary study comparing unfunctionalised with functionalised line

Full text of DOI:10.1002/ejoc.200400615

FULL PAPER
Synthesis of the First Chiral, Functionalised-Bridged Resorcinarenes in
Asymmetric Catalysis: Evidence for Intracavity Asymmetric Catalysis
Gareth Arnott,[a] Harry Heaney,[b] Roger Hunter,*[a] and Philip C. B. Page[b]
Keywords: Bridged resorcinarenes / Chiral resorcinarenes / Diethylzinc addition / Asymmetric catalysis / Intracavity
catalysis
Methodology is presented for synthesis of the first examples
ethylzinc to benzaldehyde as a probe reaction, provides com-
of chiral, bridged resorcinarenes with functionality in the pelling evidence for intracavity catalysis.
bridge as possible sites for intracavity asymmetric catalysis.
A preliminary study comparing unfunctionalised with func-
tionalised lines using the enantioselective addition of di-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
junction with cooperative effects in the bowl. In this paper,
we report on methodology for successful synthesis of the
first examples of chiral bridged resorcinarenes with func-
tionality in the bridge that provides sites for intracavity ca-
talysis, particularly through transition-metal coordination.
The methodology extends the use of Mannich technology
for attaching a line across the cavity,[6,7] and by using the
addition of diethylzinc to benzaldehyde as a probe reaction,
we provide compelling evidence for intracavity reactions in-
volving functionality in the line.
Nature has set a supreme ideal before the synthetic chem-
ist in the form of enzymes that can efficiently, regio- and
stereoselectively catalyse a vast array of organic transform-
ations under mild conditions. A synthetic example has yet
to be produced that can match or even rival enzymes in
their rate acceleration, turnover and specificity.[1] Chiral ca-
lixarenes and resorcinarenes offer intriguing possibilities as
potential enzyme mimics, but these frameworks have been
developed in mainly chiral recognition and discrimination
studies.[2] Although the literature contains examples of ca-
lixarenes and resorcinarenes that are used as catalysts,[3]
very few papers describe asymmetric catalysis. Indeed, an
example of an asymmetric reaction occurring on or in the
bowl of resorcinarenes has yet to be reported. Matt has
shown that a lower-rim, inherently chiral calixarene scaffold
can be used in allylic alkylation (palladium) and hydrogen-
ation (rhodium), though low ees were obtained.[4] Others
have shown that cooperative effects may potentially be pro-
vided by supramolecular interactions involving the concave
bowl.[5] However, a comprehensive picture has yet to em-
erge regarding application of directing effects in the bowl
towards designing superior asymmetric catalysts for carry-
ing out reactions rather than purely for recognition
phenomenon.
Results and Discussion
Our preliminary studies[6] were conducted on bridged re-
sorcinarene tetratosylates 3aϪc involving an unfunc-
tionalised line. These could be synthesized by the double
Mannich reaction between resorcinarene tetratosylates
1aϪc, chiral diamine 2 and excess paraformaldehyde in
moderate to good yields (Scheme 1). Resorcinarene tetrato-
sylates 1aϪc were prepared by modification of the method-
ology reported by Shivanyuk and Böhmer,[8] using tosyl
chloride (4 equiv.) with triethylamine (4 equiv.) in THF.
The mechanism of the catalysed enantioselective addition
reaction of diethylzinc to benzaldehyde (aldehydes) has
been exhaustively studied in recent years, with many cata-
lysts now able to achieve ees in excess of 95%.[9] A compre-
hensive mechanistic picture has emerged in which amino
alcohols are postulated to form zincoxazine intermediates
that act as templates for catalysis.[10] In view of the presence
of hydroxyamine functionality in 3aϪc, we decided to ex-
plore the use of the diethylzinc addition reaction as a pos-
sible mechanistic probe for attempting to develop the
bridged compounds as asymmetric catalysts. Indeed, in our
preliminary communication we established catalytic activity
Our research in the area of asymmetric catalysis has fo-
cused on developing chiral bridged resorcinarenes[6] in con-
[a]
Department of Chemistry, University of Cape Town,
Rondebosch 7701, South Africa
Fax: (internat.) ϩ27-21-689-7499
E-mail: roger@science.uct.ac.za
[b]
Department of Chemistry, Loughborough University,
Leicestershire, LE11 3TU, United Kingdom
Fax: (internat.) ϩ44-1509-222555
E-mail: H.Heaney@lboro.ac.uk
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DOI: 10.1002/ejoc.200400615
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Synthesis of the First Chiral, Functionalised-Bridged Resorcinarenes in Asymmetric Catalysis
FULL PAPER
Scheme 1. General synthesis of bridged resorcinarenes
at a modest level of ee with a 5% loading of catalyst.[6] In amine 4 gave (S)-1-phenylpropanol. Secondly, the enantio-
this paper we now report that varying the length of the selectivity increased with lengthening of the resorcinarene
pendent R group, while keeping the bridge length constant pendant R groups. These initial results drew attention to
(5 carbon atoms), reveals a significant influence on the en- the possible involvement of the cavity in influencing the
1
antioselectivity. Table 1 compares these results with those stereochemical outcome of the reaction. H NMR studies
from 4, an o-hydroxybenzylamine with structural character- on resorcinarenes 3aϪc reveal small (about 0.2 ppm), but
istics similar to our catalysts, that has been investigated by significant upfield shifts of the signals for the central bridge
Palmieri,[11] and which returned only a modest enantiose- methylene protons of 3b and 3c. Such shifts indicate that
lectivity for the same reaction.
the line resides deeper within the cavity for 3b and 3c, and
this results in a change in the available space in the bowl,[12]
which in turn seems likely to have a bearing on the ee values
observed. Encouraged by these results, it was decided to
turn our attention to the synthesis of a more complex
bridged resorcinarene with functionality in the line, for
possible coordination to zinc in the addition reaction.
Initially, a synthetic strategy similar to that for the forma-
tion of the model line 2 was envisaged. It was hoped that
by starting with dimethyl 3-oxopentanedioate, the desired
intermediate 5 would be available in a few, short steps, as
shown in Scheme 2. Protection of the ketone to form a ketal
would provide possible donor sites, hopefully for coordi-
nation of a transition-metal to the bridge in the final prod-
uct.
Table 1. Results for the asymmetric addition of diethylzinc using
bridged resorcinarenes as ligands
Two things were immediately evident from these results.
Firstly, the absolute configuration of the major product was
Protection of dimethyl 3-oxopentanedioate by standard
reversed, i.e. (R,R)-bridged resorcinarenes 3aϪc gave (R)-1- methods,[13] however, failed in our hands. Eventually, ket-
phenylpropanol, whereas Palmieri’s (R)-o-hydroxybenzyl- alisation was realised using Noyori’s powerful protocol[14]
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G. Arnott, H. Heaney, R. Hunter, P. C. B. Page
FULL PAPER
Scheme 2. Envisaged synthesis of protected functionalised diamine
involving neopentyl glycol disilyl ether with TMSOTf (cat)
at low temperature to afford 6 in essentially quantitative
yield, Scheme 3. Unfortunately, the thermal aminolysis of
diester 6 using α-methylbenzylamine failed, giving a pleth-
ora of product spots on the TLC plate.
Scheme 4. Reagents and conditions: i) LiAlH4, THF, 0 °C; ii) TsCl,
Et3N, DCM, room temp.; iii) α-methylbenzylamine, CH3CN, 50 °C
˚
Scheme 5. Reagents and conditions: i) TPAP (5%), NMO, 4-A
sieves, DCM, room temp.
Swern conditions to give the aldehyde, which underwent re-
ductive amination with α-methylbenzylamine and sodium
borohydride to furnish monoamine 12 in a high overall
yield.
With one auxiliary in place, the process needed to be re-
peated at the other end of the molecule. Protection of 12
was carried out because it was anticipated that its second-
Scheme 3. Reagents and conditions: i) neopentylglycol disilyl ether,
TMSOTf (cat), DCM, Ϫ20 °C to room temp.; ii) α-methylbenzyl-
amine, 100 °C
It was hoped that introduction of the chiral auxiliaries ary amino group would cyclize by addition to the aldehyde
could be achieved by a double SN2 reaction on diol 7 with formed. Protection was successfully achieved with benzyl
α-methylbenzylamine (Scheme 4), even though α-methyl- chloroformate, to afford the N-CBz derivative, which was
benzylamine is known to be a poor nucleophile and re- chemoselectively deprotected using potassium hydroxide at
quires vigorous reaction conditions for alkylation.[15] To room temperature to give alcohol 13 (Scheme 6). Oxidation
this end, ketal diester 6 was successfully reduced using lith- of 13 to the aldehyde followed by reductive amination with
ium aluminium hydride, and then converted into its bis-tos- α-methylbenzylamine then gave amine 14, which on hydro-
ylate in the usual manner. Unfortunately, SN2 displacement genolysis of the protecting group over palladium, quantitat-
with excess α-methylbenzylamine resulted in a high yield ively furnished the desired ketal diamine 15 (Scheme 6).
of the cyclized piperidine product 9, with no trace of the
Ketal-protected diamine 15 was now used to bridge the
resorcinarene tetratosylate 1a. Using the same reaction con-
desired product.[16]
We next considered a sequence involving double oxi- ditions developed for the model system gave the desired
dation of diol 7 to the dialdehyde, followed by treatment bridged product 16, albeit in a low overall yield of 22%.
with α-methylbenzylamine under reductive amination con- The reaction yield could be optimised by reducing the tem-
ditions.[17] Unfortunately, this proved to be unsuccessful un- perature to 85 °C and increasing the reaction time to one
der standard Swern conditions, while TPAP oxidation[18] hour to return a best yield of 47% after column chromatog-
gave only lactone 10 (Scheme 5).
raphy. (Scheme 7).
It was therefore necessary to opt for a longer reaction
In view of the large steric bulk of the dioxane ketal, it
sequence, which involved the introduction of the α-methyl- was decided to compare catalysis using the smaller dimeth-
benzylamine in a stepwise fashion. Thus, the diol was pro- oxy ketal group in which the space in the bowl would be
tected as its benzoate to give 11 in moderate yield increased while retaining coordination possibilities. The
(Scheme 6). The resultant alcohol was oxidised under relevant ketal diamine for Mannich coupling could be
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Synthesis of the First Chiral, Functionalised-Bridged Resorcinarenes in Asymmetric Catalysis
FULL PAPER
Scheme 6. Reagents and conditions: i) BzCl, Et3N, DCM, 0 °C to room temp.; ii) DMSO, oxalyl chloride, Et3N, Ϫ78 °C; iii) α-methylben-
˚
zylamine, NaBH4, 3-A sieves, MeOH, 0 °C to room temp.; iv) Benzyl chloroformate, iPr2NEt, DCM, 0 °C; v) KOH, EtOH, room temp.;
˚
vi) oxalyl chloride, DMSO, Et3N, DCM, Ϫ78 °C; vii) α-methylbenzylamine, NaBH4, 3A sieves, MeOH, 0 °C to room temp.; viii) Pd/C,
H2, EtOH, room temp.
Scheme 7. Reagents and conditions: i) diamine 15, (CH2O)n, CH3CN, 85 °C
accessed from the advanced amine intermediate 14
(Scheme 8), by protection of the secondary amino group
with benzyl chloroformate followed by deprotection of the
ketal product under acidic conditions to give ketone 17.
This was reprotected as a dimethoxy ketal using Noyori’s
ketalisation methodology followed by deprotection of the
carboxybenzyl group by hydrogenolysis over palladium to
give the desired diamine 18 in good overall yield.
Exposure of the diamine 18 to the bridging reaction con-
ditions used before resulted in the formation of the desired
bridged resorcinarene 19 in low yield (approximately 20%).
TLC shows a complex mixture of polar products, which
were inseparable and could not be identified, although
NMR spectroscopic evidence suggested resorcinarene de-
Scheme 8. Reagents and conditions: i) benzyl chloroformate,
iPr2NEt, DCM, 0 °C; ii) TsOH (cat), acetone, room temp.; iii)
TMSOMe, TMSOTf (cat.), DCM, Ϫ20 °C; iv) Pd/C (10%), H2,
rivatives. Heating the bridged-product 19 in acetonitrile at EtOH, room temp.
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G. Arnott, H. Heaney, R. Hunter, P. C. B. Page
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Scheme 9. Reagents and conditions: i) diamine 18, (CH2O)n, CH3CN, 85 °C
100 °C, resulted in rapid decomposition to the more polar hence over the middle of the cavity. Secondly, this is con-
spots seen on the reaction TLC. Thus, a detailed study was sidered to provide a platform for transition-metal coordi-
carried out to identify reaction conditions that would op- nation of relevance to catalysis, and this principle is demon-
timise product formation with minimal product degra- strated by the dimethoxy ketal bridged case in the enanti-
dation. Optimal conditions were established that involved oselective addition of diethylzinc to benzaldehyde. This is
heating in acetonitrile at 85 °C for one hour with excess considered to be the first reported example of using the
diamine (1.6 equiv.), to return an acceptable yield of 57%.
bowl of an asymmetrically functionalised resorcinarene for
With the bridged resorcinarene ketals in hand, attention promoting asymmetric catalysis, as suggested recently by
was turned to testing for intracavity catalysis using the di- Iwanek.[19] As such, it establishes a platform for the intro-
ethylzinc reaction as a mechanistic probe. Reactions using duction of many structural modifications that may fine tune
individual bridged ketals as catalysts at a 5% loading and this principle of developing the bowl for processes of en-
under the same conditions of solvent (toluene) and tem- zyme mimicry.
perature (room temperature) as the unfunctionalised
bridged compounds returned an extremely interesting set of
results, which are presented in Table 2.
Experimental Section
Table 2. Results for diethylzinc probe reactions
General Remarks: All reactions were carried out under nitrogen
using dry solvents. Nuclear Magnetic Resonance spectra were re-
Catalyst
Ketal
% Product
ee
R/S
corded with a Varian Unity 400 (100 MHz for 13C) or Varian Mer-
cury 300 MHz (75 MHz for 13C), and were carried out in [D1]chlor-
oform. Optical rotations were obtained using a PerkinϪElmer 141
polarimeter at 20 °C. Melting points were obtained using a Reich-
ert Jung Thermovar hot-stage microscope and are uncorrected. El-
emental analyses were performed using a Fisons EA 1108 CHN
3a
16
19
[none]
dioxane
dimethoxy
91
85
85
12%
34%
51%
R
R
S
elemental analyser. Infrared spectra were recorded with
a
The results are striking in that the smaller dimethoxy ke-
tal 19 brought about a complete reversal in enantioselectiv-
ity bias from 34% (R) to 51% (S). This important result
strongly suggests direct involvement of the ketal group as a
coordination site to the zinc, and this implies intracavity
catalysis in view of the position of the ketal in the middle
of the line. A simplistic model for explaining the reversal of
enantioselectivity bias involves extracavity versus intracav-
ity delivery of the ethyl group in which face selectivity on
the aldehyde is reversed.
PerkinϪElmer Paragon 1000 FT-IR spectrometer in either di-
chloromethane or chloroform. Enantiomeric excesses were deter-
mined by chiral GC with a Hewlett Packard HP 5890 Gas Chroma-
tograph, using a modified β-cyclodextrin glass capillary column
(heptakis-2,3-di-O-acetyl-6-O-TMBMS-β-CD) and helium as a
carrier gas.
General Procedure for the Synthesis of 1-Phenylpropanol: To a pre-
dried Schlenk tube was added catalyst (0.025 mmol) and 1  di-
ethylzinc in toluene (1 mmol, 1 mL) at Ϫ20 °C. The solution was
stirred for 15 minutes followed by the addition of 1  benzaldehyde
in toluene (0.5 mmol, 0.5 mL). The reaction vessel was then sealed
and warmed slowly to room temperature. After 16 h, the reaction
was checked (TLC) for complete consumption of benzaldehyde. On
completion, the reaction was cooled to 0 °C and quenched by the
slow addition of 1  HCl (1 mL), and then extracted from water
(20 mL) with dichloromethane (3 ϫ 20 mL). The organic extracts
were dried with magnesium sulfate and reduced in the usual man-
Conclusion
The results in this paper demonstrate two important fea-
tures of interest to the application of chiral resorcinarenes.
Firstly, methodology is presented for the synthesis of chiral,
bridged resorcinarenes with functionality in the line, and ner. Flash chromatography (5 g SiO2, eluting with ethyl acetate/
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Synthesis of the First Chiral, Functionalised-Bridged Resorcinarenes in Asymmetric Catalysis
FULL PAPER
petroleum ether, 3:17) afforded 1-phenylpropanol as a clear oil. The
enantiomeric excess was determined by chiral GC.
(t, J ϭ 7.7 Hz, 1 H, Ph), 8.02 (d, J ϭ 7.7 Hz, 2 H, Ph). 13C NMR
(100 MHz, CDCl3, ppm): δ ϭ 22.4 (ϪCH3), 22.8 (ϪCH3), 29.6 (C-
5Ј), 30.8 (C-2), 38.6 (C-4), 58.4 (C-5), 60.8 (C-1), 70.2 (C-4Ј, C-6Ј),
100.0 (C-3), 128.3 and 129.5 and 130.1 and 132.9 (Ph), 166.5 (Cϭ
O). HRMS: m/z (rel. int.): ϭ 263.1289 (19) [Mϩ Ϫ CH2CH2OH];
C15H19O4 requires 263.1283;, 159 (100), 141 (68), 105 (59), 77 (23),
69 (43)
Dimethyl 3-(5,5-Dimethyl-1,3-dioxan-2-yl)pentanedioate (6): TMS
triflate (0.1 mL, 0.4 mmol) was added to dry dichloromethane
(5 mL), and then cooled to Ϫ20 °C. 2,2-Dimethyl-1,3-bis(trimethyl-
silyloxy)propane (8.87 g, 36 mmol) was added slowly, followed by
dimethyl acetonedicarboxylate (5.39 g, 30 mmol) in dichlorometh-
ane (5 mL). The reaction was warmed to room temperature, and
stirred for 18 h. On completion (TLC), the reaction was cooled to
0 °C and quenched with pyridine (0.8 mL). The quenched reaction
was then added to saturated sodium carbonate (100 mL) and ex-
tracted three times with ethyl acetate (100 mL). The organic phase
was dried with magnesium sulfate and the solvent removed under
reduced pressure. The crude oil obtained was then subjected to
column chromatography (200 g silica gel, eluting with ethyl acetate/
petroleum ether, 3:7), to give 6 (7.74 g, 99%) as a clear oil. IR
(CH2Cl2, cmϪ1): ν˜ ϭ 2955 s and 2873 s (ϪCH3), 1737 s (CϭO,
ester), 1438 s, 1365 m, 1354 m. 1H NMR (400 MHz, CDCl3, ppm):
δ ϭ 0.93 (s, 6 H, ϪCH3 ϫ 2), 3.05 (s, 4 H, H-2,4), 3.53 (s, 4 H, H-
1Ј), 3.66 (s, 6 H, ϪOCH3). 13C NMR (100 MHz, CDCl3, ppm):
δ ϭ 22.6 (ϪCH3), 29.9 (C-2Ј), 39.4 (C-2,4), 51.8 (ϪOCH3), 70.7
(C-1Ј), 97.0 (C-3), 169.8 (C-1,5). HRMS: m/z (rel. int.) ϭ 261.1335
(0.3) [Mϩ ϩ H]; C12H21O6 requires 261.1338; , 187 (100), 143 (58),
101 (98), 69 (73).
3-(5,5-Dimethyl-1,3-dioxan-2-yl)-5-(1-phenylethylamino)pentyl Ben-
zoate (12): A solution of dimethyl sulfoxide (1.33 mL, 18.7 mmol)
in dry dichloromethane (50 mL) was cooled to Ϫ78 °C. Oxalyl
chloride (0.81 mL, 9.3 mmol) was added slowly and the reagent
formed within 10 min. Then a solution of alcohol 11 (2.4 g,
7.8 mmol) in dichloromethane (10 mL) was added slowly and the
reaction stirred for a further 15 min. Triethylamine (5.4 mL,
38.9 mmol) was added slowly, and then the reaction was allowed
to warm to room temperature. The crude material was then poured
into saturated sodium hydrogen carbonate (100 mL) and extracted
with dichloromethane (3 ϫ 50 mL). The organic phase was dried
with magnesium sulfate, and the solvent was removed under re-
duced pressure to give a yellow oil. The product was purified by
column chromatography (60 g silica gel, eluting with ethyl acetate/
petroleum ether, 3:7) to give the aldehyde (2.32 g, 97%) as a clear
oil. The aldehyde (1.48 g, 4.8 mmol) was dissolved in dry methanol
˚
(25 mL), and activated 3-A molecular sieves (1 g) were added. (R)-
α-methylbenzylamine (1.24 mL, 9.7 mmol) was added, and the re-
action was stirred for two hours at room temperature. The solution
was then cooled to 0 °C, and sodium borohydride (454 mg,
12 mmol) was added in small portions to prevent excessive foam-
ing. The reaction mixture was then warmed to room temperature
and stirred for a further hour until the reaction was complete
(TLC). The molecular sieves were removed by filtration through
Celite, and the solvent evaporated under reduced pressure. The
crude material was then added to a saturated sodium carbonate
solution (50 mL), and the organic material extracted with ethyl
acetate (3 ϫ 30 mL). The organic phase was dried with magnesium
sulfate and the solvent removed under reduced pressure to give a
crude oil. The product was purified by column chromatography
(50 g silica gel, eluting with dichloromethane/methanol, 95:5) to
give 12 (1.68 g, 85%) as a clear oil. [α]D ϭ ϩ23.6 [c ϭ 1.15, CHCl3;
(R,R)-enantiomer], Ϫ22.2 [c ϭ 1.86, CHCl3, (S,S)-enantiomer]. IR
(CH2Cl2, cmϪ1): ν˜ ϭ 2960 m and 2870 m (ϪCH3), 1715 s (CϭO,
ester), 1602 w (CϪH, aromatic), 1365 w, 1353 w. 1H NMR
(300 MHz, CDCl3, ppm): δ ϭ 0.93 (s, 3 H, ϪCH3), 0.94 (s, 3
H,ϪCH3), 1.34 (d, J ϭ 6.6 Hz, 3 H, H-2Ј), 1.78 (br., 1 H, NH),
1.98 (t, J ϭ 7.2 Hz, 2 H, H-4), 2.16 (t, J ϭ 7.2 Hz, 2 H, H-2), 2.59
and 2.69 (dt, JAB ϭ 12.0, 7.2 Hz, 2 H, H-5), 3.49 (s, 4 H, H-4ЈЈ,
H-6ЈЈ), 3.74 (q, J ϭ 6.6 Hz, 1 H, H-1Ј), 4.43 (t, J ϭ 7.2 Hz, 2 H,
H-1), 7.17Ϫ7.58 (m, 8 H, Ph), 8.02 (m, 2 H, Ph). 13C NMR
(75 MHz, CDCl3, ppm): δ ϭ 22.6 (ϪCH3), 24.1 (C-2Ј), 29.6 (C-5Ј),
32.9 (C-2), 34.6 (C-4), 42.6 (C-5), 58.6 (C-1Ј), 61.0 (C-1), 70.1 (C-
4ЈЈ, C-6ЈЈ), 99.0 (C-3), 126.6 and 126.8 and 128.3 and 128.4 and
129.5 and 130.4 and 132.8 and 145.7 (Ph), 166.5 (CϭO). HRMS:
m/z (rel. int.) ϭ 411.2417 (2) [Mϩ]; C25H33NO4 requires 411.2410;
326 (50), 274 (63), 188 (35), 105 (100), 91 (7), 77 (16).
3-(5,5-Dimethyl-1,3-dioxan-2-yl)pentane-1,5-diol (7): Diester
6
(7.59 g, 29 mmol) was dissolved in dry THF (300 mL) and the solu-
tion cooled to 0 °C. Lithium aluminium hydride (2.27 g, 60 mmol)
was then added very slowly so as to prevent excessive foaming.
After five minutes the reaction was quenched by the slow addition
of water (2.3 mL), then 1  sodium hydroxide (4.6 mL) and finally
water (4.6 mL). The mixture was stirred at room temperature for
one hour to completely decompose the lithium salts. The solid ma-
terial was filtered off through Celite and washed with dichloro-
methane (250 mL). The organic solvents were then removed under
reduced pressure to give diol 7 (5.72 g, 97%) as a clear oil. IR
(CH2Cl2, cmϪ1): ν˜ ϭ 3531 s (ϪOϪH), 2961 s, 2874 s (ϪCH3), 1472
s, 1367 m, 1352 m. 1H NMR (400 MHz, CDCl3, ppm): δ ϭ 0.94
(s, 6 H, ϪCH3 ϫ 2), 2.01 (t, J ϭ 5.9 Hz, 4 H, H-2,4), 2.91 (br., 2
H, OH), 3.52 (s, 4 H, H-1Ј), 3.75 (t, J ϭ 5.9 Hz, 4 H, H-1,5). 13C
NMR (100 MHz, CDCl3, ppm): δ ϭ 22.7 (ϪCH3), 29.8 (C-2Ј), 36.2
(C-2,4), 58.5 (C-1,5), 70.3 (C-1Ј), 101.1 (C-3). HRMS: m/z (rel.
int.) ϭ 203.1275 (0.01) [Mϩ Ϫ H]; C10H19O4 requires 203.1283; 159
[Mϩ Ϫ C2H5O] (100), 73 (96), 69 (75).
3-(5,5-Dimethyl-1,3-dioxan-2-yl)-5-hydroxypentyl Benzoate (11):
Diol 7 (3.04 g, 15 mmol) and triethylamine (2.5 mL, 18 mmol) were
added to dichloromethane (100 mL) and the solution cooled to 0
°C. A solution of benzoyl chloride (1.73 mL, 15 mmol) in dichloro-
methane (100 mL) was then added slowly over 3Ϫ4 h. The reaction
was warmed to room temperature and stirred under nitrogen for a
further 12 h. On completion (TLC), the reaction was washed with
water (3 ϫ 75 mL) and dried with magnesium sulfate. The dichloro-
methane was removed under reduced pressure to yield a yellow oil
containing mono- and bis-acylated products. The desired mono-
ester product was obtained by chromatographic separation (100 g
silica gel, eluting with ethyl acetate/petroleum ether, 3:7) resulting
in 11 (2.69 g, 58%) as a clear oil. IR (CH2Cl2, cmϪ1): ν˜ ϭ 3524 m
Benzyl N-[3-(5,5-Dimethyl-1,3-dioxan-2-yl)-5-hydroxypentyl]-NЈ-(1-
phenylethyl)carbamate (13): Amine 12 (1.66 g, 4 mmol) was dis-
(ϪOϪH), 2961 s, 2872 s (ϪCH3), 1715 (CϭO, ester), 1602 w solved in dry dichloromethane (8 mL) with diisopropylethylamine
(CϪH, aromatic), 1368 m, 1353 m. 1H NMR (400 MHz, CDCl3, (2.09 mL, 12 mmol). The solution was cooled to 0 °C, and benzyl
ppm): δ ϭ 0.86 (s, 3 H, ϪCH3), 1.11 (s, 3 H, ϪCH3), 2.02 (t, J ϭ
chloroformate (0.75 mL, 5.2 mmol) dripped in slowly. After 5 mi-
5.5 Hz, 2 H, H-4), 2.32 (t, J ϭ 7.3 Hz, 2 H, H-2), 3.48 and 3.65 (d, nutes the reaction was complete (TLC control). The solution was
JAB ϭ 11.4 Hz, 4 H, H-4Ј, H-6Ј), 3.88 (t, J ϭ 5.5 Hz, 2 H, H-5), then added to a saturated sodium hydrogen carbonate solution
4.40 (t, J ϭ 7.3 Hz, 2 H, H-1), 7.42 (t, J ϭ 7.7 Hz, 2 H, Ph), 7.54 (50 mL), and the product extracted into dichloromethane (3 ϫ
Eur. J. Org. Chem. 2004, 5126Ϫ5134
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5131

G. Arnott, H. Heaney, R. Hunter, P. C. B. Page
FULL PAPER
50 mL). The organic phase was dried with magnesium sulfate, and
the solvents evaporated to afford a crude oil, which was purified by
column chromatography (50 g silica gel, eluting with ethyl acetate/ δ ϭ 16.9 (C-2Ј), 22.3 (Me), 22.7 (Me), 24.0 (C-6Ј), 29.0 (C-5), 31.8
3.67 (q, J ϭ 6.8 Hz,1 H, H-5Ј), 5.18 (s, 2 H, H-4Ј), 5.50 (br., 1 H,
H-1Ј), 7.16Ϫ7.38 (m, 15 H, Ph). 13C NMR (75 MHz, CDCl3, ppm):
˝
petroleum ether, 3:7) to give the protected amine (2.02 g, 92%) as
a clear oil. The amine (1.83 g, 3.3 mmol) was dissolved in absolute
ethanol (10 mL), followed by the addition of solid potassium hy-
droxide (188 mg, 3.3 mmol). The solution was stirred at room tem-
perature for 45 min until hydrolysis was complete (TLC). The solu-
tion was then added to water (50 mL), and the product extracted
(C-2), 35.7 (C-4), 38.8 (C-1), 42.3 (C-5) 53.9 (C-1Ј), 58.4 (C-5Ј),
67.1 (C-4Ј), 69.8 (C-4ЈЈ, C-6), 99.1 (C-3), 126.6 and 126.7 and 127.3
and 127.4 and 127.8 and 128.2 and 128.3 and 128.4 and 136.8 and
141.1 and 145.6 (Ph), 156.2 (CϭO). HRMS: m/z (rel. int.) ϭ
544.3290 (0.5) [Mϩ]; C34H44O2N2 requires 544.3301; , 529.3 [Mϩ
Ϫ CH3] (2), 396.2 [Mϩ Ϫ CH2CH2N(H)CH(CH3)Ph] (45), 134.1
˝
with ethyl acetate (3 ϫ 30 mL). The organic fractions were dried [PhCH(CH3)NHCH2] (30), 120.1 [PhCH(CH3)NH] (39), 105.1
and reduced to give a crude oil, which was purified by column
chromatography (50 g silica gel, eluting with ethyl acetate/petro-
leum ether, 4:6). In this way, alcohol 13 (1.39 g, 95%) was obtained
as a colourless oil. [α]D ϭ ϩ48.2 [c ϭ 1.48, CHCl3, (R,R)-enanti-
omer], Ϫ50.2 [c ϭ 1.61, CHCl3, (S,S)-enantiomer]. IR (CH2Cl2,
cmϪ1): ν˜ ϭ 3518 w, 2960 m and 2873 m (ϪCH3), 1685 s (CϭO,
carbamate), 1602 w (CϪH, aromatic), 1419 s, 1221 s. 1H NMR
(300 MHz, CDCl3, ppm): δ ϭ 0.61 (br. s, 3 H, ϪCH3), 1.04 (br. s,
3 H, ϪCH3), 1.55 (d, J ϭ 7.4 Hz, 3 H, H-2Ј), 1.66Ϫ1.88 (br., 4 H,
H-2, H-4), 2.66 (br., 1 H, ϪOH), 2.86Ϫ3.36 (br. m, 6 H, H-4ЈЈ, H-
6ЈЈ, H-1), 3.66 (br. s, 2 H, H-5), 5.21 (s, 2 H, H-4Ј), 5.54 (br., 1 H,
H-1Ј), 7.22Ϫ7.41 (m, 10 H, Ph). 13C NMR (75 MHz, CDCl3, ppm):
δ ϭ 16.9 (C-2Ј), 22.1 (ϪCH3), 22.9 (ϪCH3), 29.4 (C-5Ј), 30.4 (C-
2), 38.9 (C-1, C-4), 53.9 (C-1Ј), 58.3 (C-5), 67.4 (C-4Ј), 69.9 and
70.0 (C-4ЈЈ C-6ЈЈ), 100.3 (C-3), 127.4 and 127.5 and 127.9 and 128.3
and 136.6 and 140.8 (Ph), 156.0 (C-3Ј). HRMS: m/z (rel. int.) ϭ
441.2526 (1) [Mϩ]; C26H35NO5 requires 441.2515; , 396 (12), 159
(100), 141 (5), 105 (26), 91 (45), 77 (2).
[PhCH(CH3)] (100).
3-(5,5-Dimethyl-1,3-dioxan-2-yl)-N,NЈ-bis(1-phenylethyl)pentane-
1,5-diamine (15): Mono-Cbz-diamine 14 (783 mg, 1.4 mmol) was
dissolved in absolute ethanol (10 mL), and palladium on carbon
(149 mg, 0.14 mmol) was added. The suspension was then stirred
for one hour under positive hydrogen pressure. After the reaction
was complete (TLC control), the solution was filtered through Ce-
lite and washed with ethanol. Removal of the ethanol under re-
duced pressure quantitatively afforded diamine 15 (574 mg). The
product was characterised as the bis-tosylate. M.p. 136Ϫ137 °C
(from ethyl acetate/petroleum ether). [α]D ϭ Ϫ22.5 (c ϭ 1.06,
CHCl3). IR (CHCl3, cmϪ1): ν˜ ϭ 2959 m and 2871 m (ϪCϪH,
aliphatic), 1599 w and 1495 m (CϪH, aromatic), 1328 s and 1162
1
s (ϪSO2ϪN͗), 1220 s, 1214 s, 1086 s (CϪOϪC, ether). H NMR
(400 MHz, CDCl3, ppm): δ ϭ 0.70 (6 H, s, 2 ϫ Me), 1.25 (d, J ϭ
7.0 Hz, 6 H, H-2Ј), 1.30 and 1.69 (2 ϫ ddd, J ϭ 13.6, 12.4, 4.8 Hz,
4 H, H-2, H-4), 2.41 (s, Ts-CH3,6 H), 2.86 and 3.19 (2 ϫ ddd, J ϭ
14.6, 12.4 and 4.8, 4 H, H-1, H-5), 2.92 and 3.07 (2 ϫ d, J ϭ
11.0 Hz, 4 H, H-4ЈЈ, H-6ЈЈ), 5.17 (q, J ϭ 7.0 Hz, 2 H, H-1Ј),
7.17Ϫ7.30 (m, 10 H, Ph), 7.32 and 7.80 (2 ϫ d, J ϭ 8.4 Hz, 8 H,
Ts). 13C NMR (100 MHz, CDCl3, ppm): δ ϭ 15.8 (C-2Ј), 21.6 (Ts-
CH3) 22.6 (Me), 29.5 (C-5ЈЈ), 34.9 (C-2,4), 39.0 (C-1,5), 55.4 (C-
1Ј), 69.6 (C-4ЈЈ,6ЈЈ), 98.0 (C-3), 127.3, 127.7, 127.9, 128.4, 129.8,
138.4, 140.6 and 143.1 (Ph and Ts). HRMS: m/z (rel. int) ϭ
703.2872 (0.5) [Mϩ Ϫ CH3]; C39H47O6N2S2 requires 703.2877;,
563.3 [Mϩ Ϫ Tos] (13), 416.2 [Mϩ Ϫ PhCH(CH3)N(Tos)CH2CH2]
(95), 288.1 [CH2N(Tos)CH(CH3)Ph] (22), 105.1 [PhCH(CH3)]
(100). C40H50N2O6S4 (783.1): calcd. C 66.82, H 7.01, N 3.90, S
8.92; found C 66.74, H 7.06, N 3.91, S 8.84.
Benzyl N-[3-(5,5-Dimethyl-1,3-dioxan-2-yl)-5-(1-phenylethylamino)-
pentyl]-NЈ-(1-phenylethyl)carbamate (14): Dimethyl sulfoxide
(2.41 mL, 34 mmol) was added to dry dichloromethane (120 mL),
and the solution cooled to Ϫ78 °C. Oxalyl chloride (1.48 mmol,
17 mmol) was added slowly, and the reaction mixture was stirred
for 15 min. A solution of alcohol 13 (6.22 g, 14 mmol) in dichloro-
methane (30 mL) was added slowly, and the reaction mixture was
stirred for a further 25 min. Triethylamine (9.8 mL, 70 mmol) was
added and the solution allowed to warm to room temperature. The
reaction was then poured into saturated sodium hydrogen carbon-
ate (100 mL) and extracted with dichloromethane (3 ϫ 75 mL).
The organic phase was dried with magnesium sulfate and the sol-
vent removed under reduced pressure to yield a crude yellow oil.
(R,R)-12,14,112,114-Tetrahydroxy-6-(5,5-dimethyl-1,3-dioxan-2-yl)-
This oil was then dissolved in dry methanol (100 mL) with acti-
12,14,15,17-tetramethyl-3,9-bis(1-phenylethyl)-134,136,164,166-tetra-
˚
vated 3A molecular sieves (4 g). (R)-α-Methylbenzylamine (2.7 mL, (p-tolylsulfonyloxy)-3,9-diaza-1,11(1,3,5),13,16(1,3)-tetrabenzena-
21 mmol) was added, and the reaction mixture was stirred for one
hour at room temperature. The solution was then cooled to 0 °C,
and sodium borohydride (1.32 g, 35 mmol) added in small portions.
The reaction mixture was warmed to room temperature and stirred
bicyclo[9.3.3]heptadecaphane (16): (Tetratosyl)resorcinarene 1a
(580 mg, 0.5 mmol), diamine 15 (320 mg, 0.8 mmol) and paraform-
aldehyde (300 mg, 10 mmol) were added to a high-pressure glass
reaction vessel with a screw top. Acetonitrile (40 mL) was added
for a further hour. The molecular sieves were removed by filtration, and the vessel sealed and placed in an oil bath at 85 °C. After one
and the solvent evaporated under reduced pressure. The crude ma-
terial was then added to a saturated sodium carbonate solution
hour, the reaction was checked by TLC for complete consumption
of 4. Silica gel (2Ϫ3 g) was then added, and the solvent removed
(100 mL), and the organic material extracted with ethyl acetate (3 under reduced pressure. The solid-supported crude material was
ϫ 100 mL). The organic phase was dried with magnesium sulfate,
and the solvent removed under reduced pressure to give a crude
then finely ground and subjected to column chromatography (40 g
silica gel eluting with ethyl acetate/petroleum ether, 2:3). In this
oil. The product was purified by column chromatography (150 g manner, bridged resorcinarene 16 (378 mg, 47%) was obtained as a
silica gel, eluting with ethyl acetate) to give 6.52 g (85%) of 14 as a
clear oil. [α]D ϭ ϩ56.7 [c ϭ 1.02, CHCl3 Ϫ (R,R)-enantiomer],
white powder. M.p. 143Ϫ146 °C (diisopropyl ether/dichlorometh-
ane). [α]D ϭ ϩ6.0 (c ϭ 1.93, CHCl3). IR (CH2Cl2, cmϪ1): ν˜ ϭ 3526
Ϫ59.1 [c ϭ 1.20, CHCl3 Ϫ (S,S)-enantiomer]. IR (CHCl3, cmϪ1): m (OϪH, H-bonded), 2956 m and 2931 m (CϪH, aliphatic), 1599
ν˜ ϭ 2960s and 2871s (ϪCϪH, aliphatic), 1687s (CϭO, carbamate),
1604 w and 1496 m (CϪH, aromatic), 1262 s, 1258 s, 1090 s
s (aryl stretch), 1371 s and 1178 s (ϪSO2ϪOϪ), 1093 s (CϪOϪC,
1
ether). H NMR (300 MHz, CDCl3): δ ϭ 0.78 and 1.28 (2 ϫ s, 6
(CϪOϪC, ether). 1H NMR (300 MHz, CDCl3, ppm): δ ϭ 0.67 (br. H, ϾC(CH3)2], 1.33 (2 ϫ d, J ϭ 7.2 Hz, 12 H, ϪCH3), 1.41 (d,
s, 3 H, Me), 0.91 (br. s, 3 H, Me), 1.31 (d, J ϭ 6.8 Hz, 3 H, H-6Ј),
1.51 (d, J ϭ 7.3 Hz, 3 H, H-2Ј), 1.58Ϫ1.80 (br., 5 H, H-2, H-4,
NH), 2.51 (m, 2 H, H-5), 2.95Ϫ3.38 (m, 6 H, H-1, H-4ЈЈ, H-6ЈЈ),
J ϭ 6.6 Hz, 6 H, NCHCH3), 1.56 (m, 4 H, H-5,7), 2.28 and 2.42
(m, 4 H, H-4,8), 2.48 (2 ϫ s, 12 H, H-7Ј) 2.97 and 3.04 (2 ϫ d,
J ϭ 11.4 Hz, 4 H, H-4ЈЈ, 6ЈЈ), 3.74 (s, 4 H, H-2,10), 3.83 (q, J ϭ
5132
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 5126Ϫ5134

Synthesis of the First Chiral, Functionalised-Bridged Resorcinarenes in Asymmetric Catalysis
6.6 Hz, 2 H, H-α), 4.52 and 4.55 (2 ϫ q, J ϭ 7.2 Hz, 4 H, H- (100 mL) and extracted with dichloromethane (3 ϫ 70 mL). The
FULL PAPER
12,14,15,17), 6.69 (s, 2 H, H-132,162), 6.87 (s, 2 H, H-135,165), 7.08 organic phase was dried with magnesium sulfate, and the solvent
(s, 2 H, H-16,116), 7.18Ϫ7.32 (m, 10 H, Ph), 7.40 (2 ϫ d, J ϭ
removed under reduced pressure. The crude oil obtained was then
subjected to column chromatography (100 g silica gel, eluting with
8.4 Hz, 8 H, H-3Ј,5Ј), 7.96 (2 ϫ d, J ϭ 8.4 Hz, 8 H, H-2Ј,6Ј). 13C
NMR (75 MHz, CDCl3, ppm): δ ϭ 17.9 (NCHCH3), 21.4 and 21.5 ethyl acetate/petroleum ether, 3:17), to give the dimethoxy ketal
˝
(C-7Ј), 21.7 (ϪCHCH3), 22.4 [ϪC(CH3)2], 28.8 (C-5,7), 29.4 (C-5), (7.27 g, 90%) as a clear oil. The dicarbamate (3.4 g, 5.3 mmol) was
29.3 [ϪC(CH3)2], 31.1 (C-12,14,15,17), 44.8 (C-4,8), 48.7 (C-2,10), dissolved in absolute ethanol (50 mL), and palladium on carbon
60.8 (NCHCH3), 69.6 (C-4ЈЈ,6ЈЈ), 98.9 (C-6), 108.6 (C-13,113),
(1.06 g, 0.5 mmol) was added. The suspension was then stirred for
114.9 (C-135,165), 119.1 (C-11,15,111,115), 123.5 (C-16,116), 127.4 one hour under positive hydrogen pressure. After the reaction was
(C-132,162), 128.1 and 128.4 and 128.5 (C-2Ј,6Ј, Ph), 130.1 (C- complete (TLC control), the solution was filtered through Celite
3Ј,5Ј), 133.5 (C-1Ј), 139.7 (C-131,133,161,163), 141.8 (Ph), 144.7 (C-
and washed with ethanol. Removal of the ethanol under reduced
134,136,164,166), 145.5 (C-4Ј), 153.5 (C-12,14,112,114). HRMS: m/z pressure afforded dimethoxy diamine 18 (1.9 g) quantitatively.
(rel. int) ϭ 1595.7 (9) [Mϩ] , 1490.6 (3) [Mϩ Ϫ PhCHCH3], 1441.7 [α]D ϭ ϩ52.0 [c ϭ 1.50, CHCl3, (R,R)-enantiomer], Ϫ53.4 [c ϭ
(3), 1185.3 (4), 1031.4 (2), 875.3 (2), 547.2 (2), 411.3 (23), 276.2
(29), 175.1 (39), 134.2 (100),105.1 [PhCHCH3] (100). (NϪH), 3024 s (aromatic CϪH), 2962 s and 2832 s (aliphatic
1.26, CHCl3, (S,S)-enantiomer]. IR (CHCl3, cmϪ1): ν˜ ϭ 3315 m
C88H94N2O18S4 (1596.0): calcd. C 66.23, H 5.94, N 1.76, S 8.04;
found C 66.33, H 6.06, N 1.76, S 8.17.
CϪH), 1602w (aryl ring), 1192 m (CϪN), 1124 s (CϪOϪC). 1H
NMR (300 MHz, CDCl3): δ ϭ 1.32 (d, J ϭ 6.6 Hz, 6 H, ϪCH3),
1.58 (br s, 2 H, NH ϫ 2), 1.68 (t, J ϭ 7.3 Hz, 4 H, H-2,4), 2.38
and 2.44 (2 ϫ dt, J ϭ 11.7, 7.3 Hz, 4 H, H-1,5), 3.08 (s, 6 H,
OCH3), 3.68 (q, J ϭ 6.6 Hz, 2 H, NCHCH3), 7.12Ϫ7.34 (m, 10 H,
Ph). 13C NMR (75 MHz, CDCl3, ppm): δ ϭ 24.2 (CH3), 33.2 (C-
2,4), 42.7 (C-1,5), 47.5 (OCH3), 58.2 (NCHCH3), 102.1 (C-3),
126.4, 126.7, 128.3 and 145.5 (Ph). MS: m/z (rel. int.) ϭ 371 (49)
[Mϩ ϩ H]; C23H35N2O2 requires 371.
Benzyl {5-[Benzyloxycarbonyl-(1-phenylethyl)amino]-3-oxopentyl}-
(1-phenylethyl)carbamate (17): Amine 14 (4.32 g, 7.9 mmol) was
dissolved in dry dichloromethane (40 mL) with diisopropylethyla-
mine (2.09 mL, 12 mmol). The solution was cooled to 0 °C, and
benzyl chloroformate (1.47 mL, 10.3 mmol) dripped in slowly.
After 5 min, the reaction was complete (TLC control). The solution
was then added to a saturated sodium hydrogen carbonate solution
(50 mL), and the product extracted into dichloromethane (3 ϫ
50 mL). The organic phase was dried with magnesium sulfate, and
the solvents evaporated to afford a crude oil, which was purified by
column chromatography (50 g silica gel, eluting with ethyl acetate/
petroleum ether, 2:8) to give the bis-Cbz protected diamine (5.09 g,
95%) as a clear oil. The protected diamine (3.86 g, 5.7 mmol) was
dissolved in acetone (30 mL), and p-toluenesulfonic acid (100 mg,
0.5 mmol) was added. The reaction mixture was allowed to stir at
room temperature until the hydrolysis was complete (TLC control),
typically overnight. Saturated sodium hydrogen carbonate
(100 mL) was then added, and the acetone removed under reduced
pressure. The product was extracted three times into ethyl acetate
(3 ϫ 75 mL), dried with magnesium sulfate, and the solvent re-
duced. The crude oil formed in this manner was further purified by
column chromatography (100 g silica gel, eluting with ethyl acetate/
petroleum ether, 2:8), to furnish ketone 17 (3.14 g, 93%) as a clear
oil. [α]D ϭ ϩ82.9 [c ϭ 1.01, CHCl3, (R,R)-enantiomer], Ϫ87.9 [c ϭ
1.04, CHCl3, (S,S)-enantiomer]. IR (CH2Cl2, cmϪ1): ν˜ ϭ 2980 m
(CϪH, aliphatic), 1690 s (CϭO, carbamate and ketone), 1496 w
12,14,112,114-Tetrahydroxy-6,6-dimethoxy-12,14,15,17-tetramethyl-
3,9-bis(1-phenylethyl)-134,136,164,166-tetra(p-tolylsulfonyloxy)-3,9-
diaza-1,11(1,3,5),13,16(1,3)tetrabenzena-bicyclo[9.3.3]heptade-
caphane (19): Resorcinarene tetratosylate 1a (580 mg, 0.5 mmol),
diamine 18 (300 mg, 0.8 mmol) and paraformaldehyde (300 mg,
10 mmol) were added to a high-pressure glass reaction vessel with
a screw top. Acetonitrile (40 mL) was added, and the vessel sealed
and placed in an oil bath at 85 °C. After one hour, the reaction
was checked by TLC for complete consumption of 1a. Silica gel
(2Ϫ3 g) was then added, and the solvent removed under reduced
pressure. The solid-supported crude material was then finely
ground and subjected to column chromatography (40 g silica gel
eluting with ethyl acetate/petroleum ether, 2:3) to afford bridged
resorcinarene 19 (450 mg, 57%) as a white powder. M.p. 153Ϫ155
°C (acetone/diethyl ether). [α]D ϭ Ϫ45.4 [c ϭ 2.20, CHCl3, (R,R)
enantiomer], ϩ45.1 [c ϭ 1.46, CHCl3, (S,S) enantiomer). IR
(CHCl3, cmϪ1): ν˜ ϭ 3524 s (OϪH, H-bonded), 2974 m and 2935
m (CϪH, aliphatic), 1598 s (aryl stretch), 1371 s and 1176 s
(ϪSO2ϪOϪ), 1093 s (CϪOϪC, ether). 1H NMR (300 MHz,
CDCl3): δ ϭ 1.35 (m, 18 H, ϪCH3, NCHCH3), 1.59 (m, 4 H, H-
5,7), 2.43 (m, 4 H, H-4,8), 2.45 and 2.50 (2 ϫ s, 12 H, H-7Ј), 2.71
(s, 6 H, OCH3), 3.78 and 3.90 (2 ϫ d, JAB ϭ 16.0 Hz, 4 H, H-2,10),
3.78 (q, J ϭ 6.5 Hz, 2 H, H-α), 4.50 and 4.53 (2 ϫ q, J ϭ 7.3 Hz,
4 H, H-12,14,15,17), 6.54 (s, 2 H, H-132,162), 6.89 (s, 2 H, 135,165),
7.03 (s, 2 H, H-16,116), 7.20Ϫ7.34 (m, 10 H, Ph), 7.38 and 7.42 (2
ϫ d, J ϭ 8.4 Hz, 8 H, H-3Ј,5Ј), 7.98 and 7.99 (2 ϫ d, J ϭ 8.4 Hz,
8 H, H-2Ј,6Ј). 13C NMR (75 MHz, CDCl3, ppm): δ ϭ 19.4
(NCHCH3), 20.9 and 21.0 (C-7Ј), 21.7 (ϪCH3), 26.6 (C-5,7), 31.4
and 31.7 (C-12,14,15,17), 45.7 (C-4,8), 47.4 (OCH3), 49.4 (C-2,10),
61.0 (C-α), 101.7 (C-6), 109.1 (C-13,113), 114.8 (C-135,165), 118.6
and 119.3 (C-11,15,111,115), 123.8 (C-16,116), 127.3 (C-132,162),
1
(CϪH, aromatic). H NMR (400 MHz, CDCl3): δ ϭ 1.48 (d, J ϭ
6.9 Hz, 6 H, H-2Ј ϫ 2), 2.17 and 2.36 (br., 4 H, H-2,4), 3.21 (t,
J ϭ 7.4 Hz, 4 H, H-1,5), 5.14 and 5.19 (AB d, J ϭ 12.2 Hz, 4 H,
ϪCH2Ph), 5.44 (br., 2 H, H-1Ј), 7.19Ϫ7.38 (m, 20 H, Ph). 13C
NMR (100 MHz, CDCl3, ppm): δ ϭ 17.0 (C-2Ј), 37.6 (C-1,5), 42.7
(C-2,4), 53.9 (C-1Ј), 67.2 (C-4Ј), 127.2, 127.5, 127.8, 128.0, 128.4,
128.5, 136.7 and 140.8 (Ph), 156.0 (C-3Ј), 207.4 (C-3). HRMS:
m/z (rel. int.) ϭ 592.2926 (0.1) [Mϩ]; C37H40N2O5 requires
592.2937; 487.2 (9) [Mϩ Ϫ PhCHCH3] , 457.2 (5) [Mϩ
Ϫ
PhCH2OCϭO], 383.2 (6) [Mϩ Ϫ 2 ϫ PhCHCH3], 353.2 (7), 202.1
(26), 120.1 (8), 105.1 [PhCHCH3ϩ] (64), 91.1 [PhCH2ϩ] (100).
3,3-Dimethoxy-N,NЈ-bis(1-phenylethyl)pentane-1,5-diamine
TMS triflate (0.1 mL, 0.4 mmol) was added to dry dichlorometh-
(18): 127.6, 127.8, 128.5, 128.6, 128.7 (C-2Ј,6Ј, Ph), 130.0 and 130.2 (C-
3Ј,5Ј), 133.3 and 133.7 (C-1Ј), 139.4 and 140.0 (C-131,133,161,163),
ane (2 mL), and the solution cooled to Ϫ78 °C. Methoxytrimeth-
141.6 (Ph), 145.0 and 145.4, (C-134,136,164,166), 145.5 and 145.7
ylsilane (4.14 g, 40 mmol) was added slowly, followed by ketone (C-4Ј), 152.4 and 154.4 (C-12,14,112,114). MS: m/z (rel. int.) ϭ
17 (7.47 g, 12.6 mmol) in dichloromethane (8 mL). The reaction
mixture was warmed to Ϫ20 °C and stirred for 6 h. On completion
(TLC), the reaction was quenched with triethylamine (0.5 mL). The
quenched reaction was then added to saturated sodium carbonate
1556.0 (28) [Mϩ], 1525.0 (10) [Mϩ Ϫ OCH3], 1318.7 (49), 1185.5
(52), 1029.5 (25), 875.5 (28), 719.4 (19), 307.2 (31), 204.2 (96), 105.1
[PhCHCH3] (100). C85H90N2O18S4·H2O (1573.9): calcd. C 64.87,
H 5.89, N 1.78, S 8.15; found C 64.85, H 5.91, N 1.84, S 7.96.
Eur. J. Org. Chem. 2004, 5126Ϫ5134
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5133

G. Arnott, H. Heaney, R. Hunter, P. C. B. Page
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Received August 31, 2004
5134
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www.eurjoc.org
Eur. J. Org. Chem. 2004, 5126Ϫ5134