Development of dirhodium(II)-catalyzed generation and enantioselective 1,3-dipolar cycloaddition of carbonyl ylides

Article abstract of DOI:10.1002/1521-3765(20011015)7:20<4465::AID-CHEM4465>3.0.CO;2-W

Catalytic, enantioselective, tandem carbonyl ylide formation/cycloaddition of 2-diazo-3,6-diketoester 2 with the use of dirhodium tetrakiscarboxylate and tetrakisbinaphtholphosphate catalysts to give the cycloadducts 3 in good yields and up to 90% ee is described.

Full text of DOI:10.1002/1521-3765(20011015)7:20<4465::AID-CHEM4465>3.0.CO;2-W

FULL PAPER
Development of Dirhodium(ii)-Catalyzed Generation and Enantioselective
1,3-Dipolar Cycloaddition of Carbonyl Ylides
David M. Hodgson,*[a] Paul A. Stupple,[a] Françoise Y. T. M. Pierard,[a]
AgneÁs H. Labande,[a] and Craig Johnstone[b]
Abstract: Catalytic, enantioselective, tandem carbonyl ylide formation/cycloaddi-
Keywords: asymmetric catalysis
catalysts cycloaddition diazo
compounds ´ rhodium
´
tion of 2-diazo-3,6-diketoester 2 with the use of dirhodium tetrakiscarboxylate and
tetrakisbinaphtholphosphate catalysts to give the cycloadducts 3 in good yields and
up to 90% ee is described.
´
´
preferable to use metal ± carbene complexes 1 (Scheme 2) in
which the metal, and the ligands with which it is usually
associated, can potentially influence the reactivity of the
carbene. Metal ± carbene complexes are themselves often
Introduction
There are currently few methods to achieve catalytic enan-
tioselective 1,3-dipolar cycloadditions, despite the potential
utility of such asymmetric transformations.[1] Carbonyl ylides
are usually non-isolable reactive intermediates whose princi-
pal synthetic uses are in 1,3-dipolar cycloadditions. Of the
various methods for carbonyl ylide formation, the interaction
of a carbene with the oxygen atom of a carbonyl group is
particularly attractive because of its apparent simplicity
(Scheme 1).[2]
X
MLn
O
X
X
-MLn
MLn
-N2
Y
R
R
R
R
O
R2C MLn
R2C N2
Y
Y
B
O
1
-MLn
A
B
A
L = chiral (enantiopure) ligand
A
B
A
B
R
R
X
Y
R
R
X
Y
O
X
O
A
B
X
A
B
R
R
R
R
X
Y
+
R2C:
rac
ee?
Y
O
O
Y
O
[3+2]
Scheme 2. Metal-catalysed carbonyl ylide formation/cycloaddition.
Scheme 1. Carbonyl ylide formation/cycloaddition.
transient intermediates. One good way of generating metal ±
carbene complexes as intermediates is the reaction of a diazo
(often an a-diazocarbonyl) compound with a metal ± ligand
system (the metal is often rhodium or copper).[3] This process
has been extensively examined in the context of tandem
carbonyl ylide formation/cycloaddition by Ibata and, partic-
ularly, Padwa and has become an important method for the
synthesis of oxacycles.[4] The transformation is attractive
because of the rapid increase in molecular complexity, and
good levels of diastereoselectivity can be observed. One
intriguing question relates to the possibility of achieving an
enantioselective cycloaddition by using a chiral catalyst
(Scheme 2).
The synthetic utility of free carbenes in such an ylide-
forming process is limited partly by their methods of
generation (thermally, photochemically or under basic con-
ditions), and also by their high reactivity and lack of
selectivity with functionalised organic compounds. It is often
[a] Dr. D. M. Hodgson, P. A. Stupple, Dr. F. Y. T. M. Pierard,
Dr. A. H. Labande
Dyson Perrins Laboratory, Department of Chemistry
University of Oxford, South Parks Road
Oxford, OX1 3QY (UK)
Fax : (‡44)1865-275674
E-mail: david.hodgson@chem.ox.ac.uk
Although significant progress has been made in trans-
formations of diazocarbonyl compounds involving enantiose-
[b] Dr. C. Johnstone
AstraZeneca, Mereside
Alderly Park, Macclesfield
Cheshire, SK10 4TG (UK)
ˆ
lective C C, C H or X H (X ˆ N, Si) insertions using chiral,
non-racemic transition metal-based catalysts,[3, 5] at the outset
of our studies there were no reported examples of enantio-
selective, tandem carbonyl ylide formation/cycloaddition.
Unlike enantioselective insertion, in which an intermediate
Supporting information for this article is available on the WWW under
http://wiley-vch.de/home/chemistry/ or from the author. Preparation of
22 and spectral characterisation (13C NMR spectra) of 2, 3, 5, 16, 17b,
28, 30 ± 33, 35, 36, 38, and 39 (26 pages).
Chem. Eur. J. 2001, 7, No. 20
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D. M. Hodgson et al.
FULL PAPER
metal carbene complex can directly exert an influence on
selectivity, it could be argued that once an ylide is formed the
catalyst is not involved in the subsequent cycloaddition and
asymmetric induction would be unlikely. However, prior to
our work, Padwa and co-workers had observed rhodium(ii)-
catalyst-dependent changes in regiochemistry during intra-
molecular cycloaddition following carbonyl ylide formation.[6]
Also, there were scattered reports of enantioselective rear-
rangements, based on transition-metal catalysis, involving
other types of ylides from diazo compounds, which could also
be interpreted as implying catalyst association with the ylide
during the rearrangement step.[7] In this paper we detail our
studies on the realisation of enantioselective tandem carbonyl
ylide formation/cycloaddition,[8] which have involved the
synthesis and examination of a number of new chiral
rhodium(ii) catalysts to generate cycloadducts in up to
90% ee in this emerging asymmetric process.
a, b
c
d
O
N2
O
CO2H
O
O
O
O
RO2C
RO2C
4
5a (R = Me)
5b (R = Et)
5c (R = tBu)
2a (R = Me)
2b (R = Et)
2c (R = tBu)
Scheme 4. Synthesis of cycloaddition substrate 2. Reagents and condi-
tions: a) tBuLi, CH2 CH(CH2)3I, THF, 788C to 258C; b) Jonesꢁ reagent,
THF, 258C; c) carbonyldiimidazole, THF, 08C, then Mg(O2CCH2CO2R)2,
THF, 258C, then H3O ; d) 4-(NHAc)C6H4SO2N3, Et3N, MeCN, 258C.
ˆ
‡
ketone followed by ring closure. Due to the inefficiency of this
method, an alternative procedure was devised. A range of
4-ketoalkanoic acids have been prepared by Meyers and co-
workers by alkylation of lithiated 2,3-dihydrofuran followed
by hydrolysis/oxidation with Jonesꢁ reagent.[11] Using 5-iodo-
pent-1-ene as the alkylating agent, this two-step procedure
gave keto acid 4 in an improved 68% yield. Homologation of
the keto acid 4 to 3,6-diketoesters 5 was best achieved by a
modified version of the Masamune procedure (58 ± 92%),[12]
in which the magnesium salts of monoalkyl malonates were
prepared using Bu2Mg rather than Mg(OEt)2.[13] Diazo trans-
fer then afforded the cycloaddition precursors 2 in good to
excellent yields (70 ± 91%).
The viability of the substrates 2 to undergo the desired ylide
formation/cycloaddition process was established by treatment
with rhodium(ii) acetate in CH2Cl2 heated under reflux
(60 ± 80% yields of cycloadducts 3); these racemic cyclo-
adducts were also used for establishing enantiomeric purity
determination assays (vide infra). The use of a copper catalyst
6 ([Cu(MeCN)4]PF6 in combination with a enantiopure
Results and Discussion
Our choice of substrate to examine this chemistry was
influenced by the consideration that asymmetric induction
might depend upon the rate of cycloaddition of a carbonyl
ylide, since a potential requirement for asymmetric induction
could be that cycloaddition is faster than catalyst decomplex-
ation from the ylide. We therefore first examined a 2-diazo-
3,6-diketoester 2 (Scheme 3) designed to undergo intramo-
lecular cycloaddition with a simple terminal alkene, as a
MLn
O
O
RO2C
N2
O
O
O
O
RO2C
RO2C
MLn
2
3a (R = Me)
3b (R = Et)
3c (R = tBu)
CO2Me
Rh
CO2Me
Rh
CO2Me
O
O
Rh
N
N
N
N
N
F
Scheme 3. Intramolecular carbonyl ylide formation/cycloaddition.
F
tBu
tBu
O Rh
4
O Rh
4
O Rh
4
+
[Cu(MeCN)4]PF6
6
8
9
7
closely related system to 2 (with CO2R ˆ H) had previously
been shown to undergo intramolecular cycloaddition faster
than intermolecular cycloaddition of the ylide with the highly
reactive dipolarophile dimethyl acetylenedicarboxylate
(DMAD).[9] Expected advantages of studying an a-diazo-b-
ketoester of this type were ease of synthesis by diazo transfer,
combined with stability, storage and ease of handling of a
doubly stabilised (by ester and keto groups) diazo substrate,
and ability to vary the ester group. Also, cycloaddition regio-
and (exo-, endo-) stereochemistry would be unambiguous, and
related systems could find utility in the synthesis of bio-
logically active natural product classes.[4]
2-Diazo-3,6-diketoesters 2 (R ˆ alkyl) were prepared ac-
cording to Scheme 4. 4-Oxo-8-nonenoic acid (4) was origi-
nally made (41%) following the published procedure of
pentenyl Grignard addition to succinic anhydride;[10] however,
a significant amount (ca. 20%) of 4,4-dipentenyl-g-butyro-
lactone was also observed. The latter compound arose from a
second addition of the Grignard reagent to the intermediate
CF3
HO
MeO
Ph
O Rh
MeO
Ph
O Rh
O Rh
4
O Rh
O Rh
4
Ph
O Rh
4
12
10
11
bisoxazoline ligand), as used by Doyle to affect enantiose-
lective cyclopropanation,[14] and more recently in enantiose-
lective 2,3-sigmatropic rearrangements of oxonium and
iodonium ylides,[15] proceeded only sluggishly in CH2Cl2
heated under reflux overnight to deliver optically inactive
cycloadduct 3c (25% yield, 100% based on recovered 2); the
use of copper-based catalysts was not further pursued. At this
stage, representatives of the known classes of chiral rhodi-
um(ii) catalysts, selected for their varying electronic and steric
properties and ability to induce enantioselectivity in other
diazocarbonyl transformations,[3, 5] were screened with the
cycloaddition substrates 2, generally both in chlorinated and
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Tandem Reactions
4465±4476
(where the catalyst was sufficiently soluble) hydrocarbon
solvents.
In 1990 Hashimoto, Watanabe and Ikegami published their
first examples of enantioselective C H insertion of carbenoid
intermediates derived from a-diazo-b-ketoesters and cata-
lysed by chiral RhII carboxylates, the latter generally prepared
from N-phthaloyl amino acids.[23] Since this initial report, a
series of studies have been described by the Ikegami/
Hashimoto groups developing this approach and demonstrat-
ing the utility of the products.[24] As two of the most impressive
catalysts in terms of enantioselectivity are derived from
phenylalanine and tert-leucine, we selected these catalysts (13
and 14) to be screened in the tandem carbonyl ylide
cyclisation/cycloaddition as representative examples of this
group of RhII complexes; however, they were found to be only
weakly enantioselective (up to 28% ee, Table 1, entries
7 ± 11).
Although carboxamidate catalysts might be anticipated to
be somewhat unreactive towards diazo decomposition with
doubly stabilised diazo compounds such as 2, the well-known
commercially available glutamic-acid-derived catalyst
[Rh2{(R)-mepy}4] (7; mepy ˆ methyl 2-pyrrolidine 5-carbox-
ylate anion),[3, 16] the more reactive azetidine-based catalyst
8[17] and the difluorinated catalyst 9[18] all generated cyclo-
adduct 2, albeit with no optical activity. The mandelic-acid-
derived catalysts 10 and 11, were two of the first reported
examples of chiral RhII catalysts,[19, 20] the former generating
the highest levels of asymmetric induction (45% ee) in a study
by McKervey et al. of enantioselective N H insertion.[21] Of
the range of chiral carboxylate catalysts that were screened
(seven examples) in enantioselective Si H insertion by Moody
and co-workers, the highest level of enantioselectivity (31% ee)
was obtained with RhII catalyst 12, which is derived from
Mosherꢁs acid.[22] All three of these oxygenated carboxylate-
ligand-containing catalysts gave the cycloadduct 3c in gen-
erally high yields, and importantly asymmetric induction was
observed, but at a low level (Table 1, entries 1 ± 6); there was
no significant solvent effect on ee with these catalysts. One
anomalous yield (48%) was obtained from the use of 10 in
hexane (entry 2); this could result from the poor solubility of
the catalyst in this solvent.
Ph
N
tBu
N
H
O Rh
O Rh
O Rh
O Rh
O Rh
O Rh
O
N
O
O
SO2
O
4
4
R
4
15a (R = tBu)
15b (R = C12H25
14
13
)
Proline-derived catalysts, initially studied by McKervey,[25]
were found by Davies and co-workers to deliver excellent ees
(up to 98% ee) in a series of cyclopropanations.[26] Examina-
tion of the tandem carbonyl ylide formation/cycloaddition
process with the prolinate catalyst [Rh2{(S)-dosp}4] (15b;
dosp ˆ N-(p-dodecylphenyl)sulfonylprolinate) gave only a
low level of enantioselection in CH2Cl2 (Table 1, entry 13).
However, in line with other asymmetric transformations with
15b,[26] a significant increase in ee was observed in hydro-
carbon solvent (Table 1 entry 14) relative to CH2Cl2. Unlike
most of the catalyts studied, 15b is fully hydrocarbon soluble,
due to the dodecyl substituent. The partially hydrocarbon
soluble (at 258C) catalyst 15a was not as effective (entry 12).
Davies and co-workers have observed a major effect of ester
group size in asymmetric cyclopropanations that make use of
catalyst 15b with ester-substituted vinyldiazomethanes (meth-
yl esters giving the highest levels of enantioselectivity).[26]
However, similar ees to those of the tBu-substituted ester 2c
in hexane were found with the Me- and Et-substituted
2-diazo-3,6-diketoesters 2a,b (e.g., at room temperature
86% yield, 48% ee and 82% yield, 52% ee, respectively).
Yields of the cycloadduct 3c formed by using catalyst 15b in
hexane steadily improved as the reaction was carried out at
increasing temperatures; however, there was a slight erosion
in ee (entries 15 and 16). Cooling the reaction to 08C resulted
in little change in ee or yield (entry 17); below 08C yield was
eroded (entry 18) and no cycloadduct was obtained at 148C.
The Me- and Et-substituted 2-diazo-3,6-diketoesters 2a,b
showed slightly greater variation of ee with temperature (for
2a at 698C, 96% yield, 48% ee and at 08C, 65% yield,
33% ee; for 2b at 698C, 90% yield, 29% ee and at 08C, 63%
yield, 52% ee), room temperature being optimal for both
substrates. This led to tBu ester 2c, rather than the corre-
Table 1. Effect of Rh ± carboxylate catalysts 10 ± 19 in the cycloaddition of
2c.
Entry
Catalyst
Solvent
T [8C]
3c yield [%]
3c ee [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
10
10
11
11
12
12
13
13
CH2Cl2
hexane
CH2Cl2
hexane
CH2Cl2
hexane
CH2Cl2
hexane
CH2Cl2
hexane
Et2O
hexane
CH2Cl2
hexane
hexane
hexane
hexane
hexane
CH2Cl2
hexane
CH2Cl2
hexane
CH2Cl2
hexane
CH2Cl2
hexane
CH2Cl2
hexane
25
25
25
25
25
25
25
25
25
69[b]
25
25
25
25
43
69
0
93
48
97
92
98
95
87
55
72
86
60
59
86
77
84
89
74
55
81
75
43
60
87
65
71
51
55
65
11
9
16
22
17
9
28
21
23
20
14
38
10
52
48
42
51
48
13
31
17
34
16
32
20
36
22
22
14
14
14
15a
15b
15b
15b
15b
15b
15b
16
7
25
25
25
25
25
25
25
25
25
25
16
17a
17a
17b
17b
18
18
19
19
[a] ees were determined after conversion from the tBu ester 3c to the
methyl ester 3a by hydrolysis/esterification [trifluoroacetic acid (TFA),
CH2Cl2 then MeOH, para-toluenesulfonic acid (p-TSA)] and 1H NMR
analysis of the split methoxy signal using praseodymium tri[3-(heptafluoro-
propylhydroxymethylene)-(‡)-camphorate] [Pr(hfc)3]. Negative values
correspond to enrichment in ( )-cycloadduct 3c. [b] No reaction at 258C.
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D. M. Hodgson et al.
FULL PAPER
sponding Me and Et esters 2a,b, being examined in the bulk of
the studies.
With catalyst 15 as an initial lead, modification of the
prolinate framework was probed by an examination of
catalysts 16,[27] 17,[28] 18[29] and 19.[30] A similar solvent
a, b
O
O
O
19%
tBuO2C
O
O
O
20, single diastereomer
(+)-3c
c
99%
NO2
NO2
O
H
d
H
H
O Rh
O Rh
O Rh
O Rh
O
O
O
O
N
O
O
64%
N
OH
N
N
H
O
SO2
SO2
21
22
Scheme 5. Determination of the absolute configuration of cycloadduct
(‡)-3c. Reagents and conditions: a) TFA, CH2Cl2, 258C, 1 h; b) i) ( )-
borneol, DMAP, DCC, CH2Cl2, 258C, 18 h; ii) recrystallisation from
cyclohexane; c) NH2OH.HCl, NaOAc, MeOH, 258C, 15 h; d) 3,5-dinitro-
benzoyl chloride, pyridine, Et2O, 25 8C, 2 h.
R
4
C12H25
4
17a (R = tBu)
17b (R = C12H25
16
)
2,4,6-iPr3C6H2O2S
SO2(4-tBuC6H4)
N
H
H
O
N
sation of the borneol ester 20 with hydroxylamine gave the
oxime 21 and finally reaction with 3,5-dinitrobenzoyl chloride
gave derivative 22 suitable for crystallographic analysis.[31]
During the course of our studies,[8] research groups led by
Doyle,[32] Ibata[33] and Hashimoto[34] reported conceptually
related (but intermolecular) asymmetric carbonyl ylide cyclo-
additions. The asymmetric induction in these cycloadditions
was low (<30% ee), aside from the work of Hashimoto who
used a-diazoketones with DMAD as the dipolarophile for
which ees up to 92% were reported (Scheme 6, R1 ˆ H, R2 ˆ
Ph, absolute sense of predominant asymmetric induction not
O
O
Rh
Rh
Rh
Rh
O
O
O
O
O
N
H
2
H
N
SO2(2,4,6-iPr3C6H2)
2
4-tBuC6H4O2S
19
18
dependency on ee to that observed with 15b was found with 16
and 17 (Table 1, entries 19 to 24); ees were better in hydro-
carbon solvent. The ligand in catalyst 18 was originally
designed by Davies to form a conformationally constrained
catalyst with an up-down up-down arrangement of the
arylsulfonyl groups, thus allowing the effect of ligand align-
ment in vinyl ± carbenoid cyclopropanations in polar and
nonpolar solvents to be studied.[29] To the extent that the ees
converge slightly in CH2Cl2 and hexane with ligand 18
(entries 25 and 26) relative to 15b (entries 13 and 14), then
favourable ligand aligment using 15b in hexane may also play
a role in the asymmetric dipolar cycloaddition process. Similar
results were obtained in both hexane and CH2Cl2 when 19 was
used as the catalyst (entries 27 and 28). Since the favoured
solvent for 19 in cyclopropanations has been found to be
CH2Cl2,[30] the observation in the present study of identical
enantioselectivities in the two solvents suggests that hexane is
inherently the superior solvent for enantioselective cyclo-
addition with the prolinate-type catalysts, for which 15b gave
the highest ee.
It was considered important to establish that the ee in the
reaction with these catalysts arises entirely due to the
cycloaddition process and is not affected by possible enan-
tiomer-selective destruction of the cycloadduct 3 by the
catalyst. This was proven by stirring enantioenriched 3c with
catalyst 15b in CH2Cl2 or hexane at 258C for 12 hours; this
resulted in essentially quantitative recovery of the cyclo-
adduct 3c, with unchanged ee. The absolute configuration of
the predominant cycloadduct enantiomer (‡)-3c formed by
using a-diazo-b-ketoester 2c and catalyst 15b was also
determined, as shown in Scheme 5. Thus, hydrolysis of
cycloadduct 3c with trifluoroacetic acid (TFA) followed by
esterification with (1S)-endo-( )-borneol and recrystallisa-
tion gave the major diastereomer borneol ester 20. Conden-
MeO2C
PhCF3
CO2Me
R2
O
MeO2C
R2
CO2Me
O
N2
O
O
iPr
Rh
O
O
R1
23
R1
N
O Rh
25
24
O
4
up to 92% ee
R1 = H
R2 = Ar, Alkyl
Scheme 6. Cycloadditions with DMAD.
determined).[34a] Applying the optimised catalyst ± solvent
combination for intermolecular cycloaddition of a-diazoke-
tones with DMAD reported by Hashimoto[34a] (catalyst 24,
PhCF3 as solvent) to 2-diazo-3,6-diketoester 2c at 258C
resulted in only essentially racemic cycloadduct 3c (90%
yield, 1% ee). Furthermore, cycloadduct 25 (R1 ˆ CO2Et,
R2 ˆ Me)[35] was obtained in only 33% ee under the same
conditions in the reaction of 2-diazo-3,6-diketoester 23 (R1 ˆ
CO2Et, R2 ˆ Me)[35] with DMAD [a-diazoketone 23 (R1 ˆ H,
R2 ˆ Me) gave cycloadduct in 80% ee].[34a] These last results
indicate that ee is rather sensitive to variation in the electronic
structure of the dipole.
As a maximum ee of 52% was observed from the screening
of RhII ± carboxylate catalysts (Table 1), it was considered that
an alternative class of catalysts should be investigated. In
seeking to develop more efficient catalysts for asymmetric
carbonyl ylide formation/cycloaddition, we were attracted to
the reports in 1992 by Pirrung[36] and McKervey[37] concerning
binaphtholphosphate (bnp) catalysts [Rh2{(R)-bnp}4] (26) and
[Rh2{(S)-bnp}2(O3CH)2] ´ 5H2O for diazocarbonyl decompo-
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Tandem Reactions
4465±4476
sition. C H insertion and cyclo-
propanation were among the
asymmetric processes investi-
gated (up to 60% ee). More
recently Müller and co-workers
have included catalyst 26 in
studies of asymmetric aziridina-
tion (up to 73% ee) and enan-
Br
Br
O
O
O Rh
O
O
O Rh
O Rh
O
O
O Rh
O Rh
P
P
P
O Rh
4
4
4
[Rh2{(R)-bnp}4] (26)
[Rh2{(R)-dmbnp}4] (27)
[Rh2{(R)-dbbnp}4] (28)
tioselective allylic amination (31% ee).[38]
with 2-diazo-3,6-diketoester 2c led to no cycloadduct in
hexane, a very low ee (7%) of (‡)-3c in CH2Cl2 (Table 2,
entry 5) and a poor result in benzene (entry 6), possibly due to
steric congestion at the axial binding sites on the dirhodium
core; this (in CH2Cl2) might also facilitate catalyst release to
give the free ylide for cycloaddition.
Substitution at the 6,6'-positions has been a successful tactic
to alter asymmetric induction with binaphthyl-based cata-
lysts.[41] [Rh2{(R)-dbbnp}4] (28; dbbnp ˆ dibromobinaphthol-
phosphate), available from 6,6'-dibromobinaphtholhydrogen
phosphate,[42] induced similar ees to 26 (entries 7 ± 9). The
yield of reaction in hexane (entry 7) was most likely low due
to the common problem of poor catalyst solubility in hexane,
which also resulted in a long reaction time (15 h as opposed to
0.5 h in CH2Cl2). With the primary aim of investigating a more
hydrocarbon-soluble catalyst, 33 was synthesised according to
Scheme 7.
Initial investigation of Pirrungꢁs structurally well-defined
D4-symmetric catalyst [Rh2{(R)-bnp}4] (26) with 2-diazo-3,6-
diketoester 2c in hexane at 258C gave an immediate improve-
ment in ee of the cycloadduct (‡)-3c (64% ee, Table 2,
Table 2. Effect of binaphtholphosphate-type catalysts 26 ± 28, 33, 36 and 39
in the cycloaddition of 2c.
Entry
Catalyst
Solvent
T [8C]
3c yield [%]
3c ee [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
26
26
26
26
27
27
28
28
28
33
33
33
33
36
36
36
39
39
39
hexane
CH2Cl2
CH2Cl2
benzene
CH2Cl2
benzene
hexane
CH2Cl2
CH2Cl2
CH2Cl2
hexane
hexane
hexane
CH2Cl2
hexane
hexane
CH2Cl2
hexane
hexane
25
25
0
25
25
25
25
25
0
25
25
0
15
25
25
0
65
83
55
55
50
30
34
67
36
80
76
81
66
47
65
35
60
66
42
64
65
64
33
7
26
66
58
61
68
81
88; 89[b] 88[c]
90[b]
55[c]
75[c]
74[c]
59[c]
77[c]
80[c]
Br
C12H25
a
OBn
OBn
OR
OR
40-75%
25
25
0
Br
C12H25
30 (R = Bn)
31 (R = H)
29
b
[a] ees determined by using the method described in Table 1, footnote [a].
[b] ees determined on the benzyl oxime ether (O-benzyl hydroxylamine
hydrochloride, NaOAc, MeOH) of the methyl ester by HPLC analysis
(Daicel Chiralpak AD, 10% EtOH/hexane) of the major geometric isomer.
[c] ees determined directly on 3c by GC analysis (CP Chirasil Dex-CD and
Cydex-b (entry 12), 1408C isotherm). Negative values correspond to
enrichment in ( )-cycloadduct 3c.
c
89%
C12H25
C12H25
O
d
O
O Rh
O Rh
O
P
P
O
O
OH
69%
C12H25
[Rh2{(R)-ddbnp}4] (33)
C12H25
4
entry 1) compared with [Rh2{(S)-dosp}4] (15b; 52% ee), even
though 26 was only partially soluble in hexane at 258C.
Interestingly, asymmetric induction was maintained in CH2Cl2
at 258C (65% ee, entry 2); this compares with 10% ee
previously obtained by using 15b in CH2Cl2 (Table 1, en-
try 13). Whilst binaphthol catalyst 26 remained soluble in
CH2Cl2 at 08C, no improvement in ee was observed (64%,
Table 2, entry 3). Good solubility was also observed in
benzene at 258C, although ee was poor (33%, entry 4). The
results with binaphthol catalyst 26 prompted a study of the
effects of structural variation of the binaphthyl core on
enantioselectivity.
Substitution at the 3,3'-positions was first examined using
dimethylbinaphthol catalyst 27,[39] which was prepared (79%)
by an analogous procedure[36] to 26 from [Rh2(OAc)4] by
ligand exchange with the known 3,3'-dimethylbinaphtholhy-
drogen phosphate.[40] However, reaction of [Rh2{(R)-
32
Scheme 7. Synthesis of catalyst 33. Reagents and conditions:
a) C12H25MgBr, NiCl2, Ph2P(CH2)3PPh2 (1 mol%), Et2O, reflux, 48 h;
b) TMSCl, NaI, MeCN, PhCH3, 408C, 2 h (89%); c) POCl3, pyridine,
258C, 1 h, then H2O, NaHCO3; d) [Rh2(OAc)4], PhCl, reflux, 6 h.
The known bis-ether 29[43] was cross-coupled[44] with
commercially available dodecylmagnesium bromide (40 ±
75%, Scheme 7). Deprotection of the resultant didodecylbis-
ether 30 using TMSI[45] gave diol 31 (89%). Formation of the
acid 32 (91%) from the diol 31 under standard conditions
followed by ligand exchange[46] gave [Rh2{(R)-ddbnp}4] (33,
69%; ddbnp ˆ didodecylbinaphtholphosphate). Although
only a slight rise in the ee of (‡)-3c was noted with 33 in
CH2Cl2 at 258C (Table 2, entry 10) relative to 26, the new
catalyst was significantly more effective in hexane (81% ee,
entry 11). Moreover, catalyst solubility and activity were
dmbnp}4]
(27;
dmbnp ˆ dimethylbinaphtholphosphate)
Chem. Eur. J. 2001, 7, No. 20
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4469

D. M. Hodgson et al.
FULL PAPER
maintained in hexane at 08C and asymmetric induction rose
to give the cycloadduct (‡)-3c in 81% yield and 89% ee
(entry 12). A similar ee (90%) was observed on conducting
the reaction at 158C (entry 13), whereas reaction at 308C
was very slow and gave a complex product mixture from
which no cycloadduct was isolable.
Me
H
Me
H
O
O
a
OH
OH
P
O
OH
100%
H
H
It was considered important to probe the effect on
enantioselectivity of a smaller ester substituent in the cyclo-
additions with the phosphate catalysts, since they might not
show the same insensitivity to ester variation as the prolinate
catalysts. With [Rh2{(R)-dmbnp}4] (27), reaction with methyl
ester 2a was examined and the enantioselectivities in CH2Cl2
(4% ee, 76% yield) and C6H6 (26% ee, 73% yield) were
found to be very similar to those obtained with 2c (Table 2,
entries 5 and 6). However, reaction of methyl ester 2a under
catalysis by [Rh2{(R)-ddbnp}4] (33) at 258C resulted in a
dramatic decrease in enantioselectivity in both hexane
(20% ee, 72% yield) and CH2Cl2 (7% ee, 77% yield), relative
to that observed when using precursor 2c (81% ee and
68% ee, respectively, Table 2, entries 10 and 11). This was
further emphasised by a reversal in the predominant sense of
asymmetric induction when C6H6 was used as the solvent with
2a and 33 at 258C ( 10% ee, 57% yield); this last result is
consistent with the enantioselectivity obtained with 2a and
the parent catalyst [Rh2{(R)-bnp}4] (26) in C6H6 at 258C
35
34
Me
Me
53%
b
Me
H
O
O
Rh
Rh
O
P
[Rh2{(R,S)-biep}4] (36)
O
H
4
Me
Me
Me
H
H
O
a
OH
OH
H
O
P
O
OH
94%
H
38
37
Me
Me
(
8% ee, 70% yield).
b
80%
Me
H
Workers at Schering AG-Berlin have developed the syn-
thesis of bis-steroidal binaphthols, which when incorporated
into catalysts can lead to interesting, and in some cases
increased, enantioselectivity relative to the analogous binaph-
thol-derived catalysts in certain asymmetric transforma-
tions.[47] Construction of a RhII ± phosphate catalyst derived
from a ligand such as 37 (Scheme 8) would result in a complex
with a more substantial steric wall surrounding the axial
binding site at the metal. This appeared attractive in terms of
the potential for modifying enantiocontrol. Furthermore, it
was considered that the alicyclic component should enhance
the solubility in hexane of such a RhII catalyst, relative to
catalyst 26. Thus, bis-isoequilenine scaffolds 34 and 37
(prepared from estrone)[47d] were converted to the novel
catalysts [Rh2{(R,S)-biep}4] (36; biep ˆ bisisoequileninephos-
phate) and [Rh2{(S,S)-biep}4] (39), respectively (Scheme 8,
note that the first stereochemical descriptor refers to the axial
configuration and the second to that of the methyl-substituted
stereogenic centres).
O
Rh
Rh
O
P
[Rh2{(S,S)-biep}4] (39)
O
O
H
4
Me
Scheme 8. Synthesis of biep catalysts 36 and 39. Reagents and conditions:
a) POCl3, pyridine, 258C, 1 h, then H2O, 25 8C 15 min, then HCl;
b) [Rh2(OAc)4], PhCl, reflux, 5 h.
selectivity depends both on the axial chirality and the
stereogenic centres in the ligand backbone.[47, 48] Also, as in
most (but not all)[47c] previous studies of these ligands, the
predominant sense of asymmetric induction observed in our
work is determined by the element of axial chirality and not
by the stereogenic centres in the ligand structure.
In CH2Cl2, both 36 and 39 provide asymmetric induction
inferior to 26 and 33 (Table 2, entries 14 and 17 compared
with 2 and 10). In hexane, the effectiveness of the bis-steroidal
catalysts lie between those of 26 and 33 (entries 15,16 and
18,19 compared with 1 and 11,12). In this solvent, there was a
noticeable difference in catalytic activity between the two bis-
steroidal catalysts (with 36 reaction was complete within
30 minutes at room temperature, whereas 39 requires it 40 to
50 minutes; this compares with 33 requiring 30 minutes at the
same temperature). This may be due to a slight difference in
solubility in hexane between the two diastereomers. Catalyst
39 gives slightly higher asymmetric induction than 36 (en-
tries 17 ± 19 and 14 ± 16). Therefore, as found in other
asymmetric tranformations with this ligand class, the enantio-
Because the catalyst-free carbonyl ylides in our studies and
the studies by Doyle,[32] Ibata[33] and Hashimoto[34] would be
achiral, the observation of enantioselectivity provides unam-
biguous evidence (assuming no catalyst ± dipolarophile inter-
action) for an enantioselective ylide transformation taking
place via a catalyst-complexed ylide intermediate 40/41 or
dipolar complex 42/43 (for a generalised analysis of the
process see Scheme 9).
In this mechanistic analysis, attack of the metal carbene
complex by the carbonyl group would give initially a catalyst-
complexed ylide species 40/41, in which the catalyst is
attached to the originally carbenic carbon. A recent computa-
tional study by Padwa and co-workers indicates that a
catalyst-complexed carbonyl ylide can be of lower energy
4470
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Chem. Eur. J. 2001, 7, No. 20

Tandem Reactions
4465±4476
catalyst dissociation is reversible and is fast compared with
the rates of catalyst-associated and catalyst-free cycloaddi-
tions then the relative rates of these cycloadditions will also be
an important factor influencing the level of asymmetric
induction observed.
R1
R2
X
RhLn
+
Y
O
R1
X
R1
X
40
41
R2
LnRh
R2
LnRh
Y
Y
O
O
Conclusion
or
or
R1
X
R1
X
In summary, our results indicate that dirhodium tetrakisbi-
naphtholphosphate catalysts can be superior to the more
commonly utilised carboxylates and carboxamidates in asym-
metric transformations of diazocarbonyl compounds and
deserve to be more fully investigated.[50] More generally our
studies provide a significant contribution to the emerging
concept that metal-catalysed dipole formation followed by
cycloaddition can be a powerful method for asymmetric
synthesis. Our work described herein (together with Ibataꢁs
and Hashimotoꢁs results) suggests that efficient catalyst
control over enantioselectivity (and diastereoselectivity) in
carbonyl ylide cycloadditions can eventually be developed,
although major challenges clearly lie ahead in developing
catalysts that are effective with various ylide types and
substitution patterns, and different dipolarophiles.
R2
R2
Y
Y
O
O
42
43
'back' RhLn
or
'front' RhLn
or
R1
X
44 R2
Y
O
A
B
A
B
A
B
R1
R2
X
R2
R1
Y
Y
X
O
O
Scheme 9. Mechanistic analysis.
than its acyclic metal ± carbene complex precursor, and can
also be lower in energy than a free carbonyl ylide and catalyst
([Rh2(O2CH)4] was used in the calculations).[49] Assuming that
during the ensuing cycloaddition the catalyst remains asso-
Experimental Section
‡
ˆ
ciated with the C O
C
part of the ylide, rather than
General techniques: All reactions requiring anhydrous conditions were
conducted in flame-dried apparatus under an atmosphere of argon.
Syringes and needles for the transfer of reagents were dried at 1408C
and allowed to cool in a desiccator over P2O5 before use. Ethers were
distilled from sodium/benzophenone, (chlorinated) hydrocarbons and Et3N
from CaH2. Reactions were monitored by TLC by using commercially
available glass-backed plates, pre-coated with a 0.25 mm layer of silica
containing a fluorescent indicator (Merck). Column chromatography was
carried out on Kieselgel 60 (40 ± 63 mm). Light petroleum refers to the
fraction with b.p. 40 ± 608C. [a] values are given in 10 1 degcm2 g 1. IR
spectra were recorded as thin films unless stated otherwise. Peak intensities
are specified as strong (s), medium (m) or weak (w). 1H and 13C NMR
spectra were recorded in CDCl3 unless stated otherwise with a Bruker
AC200, a Varian Gemini 200, a Bruker DPX400, a Bruker AM500 or a
Bruker AMX500 spectrometer (Cq ˆ quaternary C atom). Chemical shifts
are reported relative to CHCl3 [dH ˆ 7.26, dC(central line of t) ˆ 77.0]. Mass
spectra were obtained by the EPSRC National Mass Spectrometry Service
Centre at the University of Swansea by using a Micromass Quattro II low-
resolution triple quadrupole mass spectrometer or, for accurate masses, by
using a Finnigan MAT 900 XLT high-resolution double-focusing mass
spectrometer with tandem ion trap. Chiral stationary phase HPLC was
performed by using a Daicel Chiralpak AD column (4.6 mm  250 mm) on
a Gilson system with 712 Controller Software and a 118 UV/VIS detector
set at 254 nm. Retention times for major (tRmj) and minor (tRmn)
enantiomers are given in minutes. Chiral gas chromatography was carried
out using a CE Instruments Trace GC (Thermoquest) machine with CP
Chirasil Dex-CD or Cydex-b columns. Retention times for major (tRmj)
and minor (tRmn) enantiomers are given in minutes.
ligation with a carbonyl group or carbonyl groups, then the
chiral catalyst can only be associated with either face of a
single carbonyl ylide, since (with the exception of Doyles
studies)[32] the ylide is part of a ring. Cycloaddition could then
occur on the opposite face of the ylide to the catalyst as the
catalyst dissociates. In the case of substrate 2 the cyclo-
addition is likely to be a concerted process from dipolar
complex 42/43, because the dipolarophile is a simple unpo-
larised alkene (the situation could be different with DMAD).
If one also assumes for the moment that no cycloaddition
occurs competitively from the catalyst-free ylide 44, then two
suggestions for the origin of the enantioselectivity are as
follows. If the two catalyst-associated ylide isomers do not
interconvert within the timescale of the cycloaddition, then
the enantioselectivity is governed by the preference of the
tethered carbonyl to cyclise to the Re or Si face of the metal ±
carbene complex under the influence of the chiral ligands of
the catalyst. Alternatively, interconversion between the two
catalyst-associated ylide isomers through a dissociation/re-
combination mechanism (dissociation to the acyclic metal ±
carbene complex) could be faster than the rate(s) of cyclo-
addition. This last case describes a Curtin ± Hammett situation
with the relative proportions of the two catalyst-associated
ylides being inconsequential and the enantioselectivity being
determined by the difference in the free energies of the
activation barriers (DDG=) of the two catalyst-associated ylide
isomers for cycloaddition. Regardless of which of these two
processes operates, enantioselectivity could be affected if the
catalyst dissociates from the ylide prior to, or competitively
with, cycloaddition from the catalyst-associated ylide. If
4-Oxo-8-nonenoic acid (4):[10]
A stirred solution of 2,3-dihydrofuran
(11.4 mL, 151 mmol) in THF (650 mL) was cooled to 788C before
dropwise addition of tBuLi (109 mL of a 1.7m solution in pentane) through
a cannula over 1 h. The solution was warmed to 08C for 30 min before
being recooled to
788C. A solution of 5-iodo-1-pentene[51] (29.7 g,
151 mmol) in THF (30 mL) was added dropwise through a dropping funnel,
and the resulting solution was warmed to room temperature and then
stirred for 1 h. The reaction mixture was recooled to 08C and quenched by
careful addition of saturated aqueous NH4Cl solution (100 mL). The
Chem. Eur. J. 2001, 7, No. 20
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D. M. Hodgson et al.
FULL PAPER
ˆ
aqueous phase was extracted with pentane/Et2O (3 Â 150 mL, 1:1 v/v) and
the combined organic components were dried (MgSO4) before concen-
tration under reduced pressure until the volume was approximately
500 mL. The solution of alkylated dihydrofuran was stirred and Jonesꢁ
reagent[52] (122 mL of a 2.7m aqueous solution) was added dropwise over
90 min. After 18 h the reaction mixture was diluted with Et2O (300 mL)
and H2O (300 mL), and stirred vigorously for 30 min. The aqueous phase
was separated, extracted with Et2O (4 Â 200 mL) and the combined organic
components were washed with H2O (3 Â 100 mL) and extracted with 10%
aqueous NaOH solution (3 Â 200 mL). The combined basic portions were
cooled to 08C and acidified to pH 1 with HCl (6n). The cloudy aqueous
component was extracted with CH2Cl2 (4 Â 200 mL) and the combined
organic components dried (MgSO4). Concentration under reduced pres-
sure gave the keto acid 4 as a white solid (17.5 g, 68% over 2 steps).
1H NMR (400 MHz, CDCl3, 258C): d ˆ 1.63 ± 1.70 (m, 2H;
2929 (s; CH), 2850 (w; CH), 2132 (s; CN2), 1716 (s; C O), 1652 (s), 1369 (s),
‡
1312 (s), 1133 cm 1 (s); MS (CI ‡ ): m/z (%): 312 (37) [M‡NH4] , 295 (70)
‡
[M‡H] , 286 (37), 284 (35), 256 (100), 239 (48), 230 (31); HRMS: calcd for
‡
C15H23N2O4: 295.1657; found: 295.1658 [M‡H] .
7-Carbo-tert-butoxy-11-oxa-tricyclo[5.3.1.01,5]undecan-8-one (3c): A RhII
catalyst (0.2 ± 1.0 mol%) was added to a stirred solution of cycloaddition
precursor 2c (approx. 70 mg, 0.24 mmol) in degassed[54] solvent (7 mL) at
the desired temperature. When TLC analysis indicated complete con-
sumption of starting material (0.3 h ± 3 h) the solution was concentrated
under reduced pressure and the crude product mixture purified by column
chromatography (light petroleum/Et2O 8:2) to give the cycloadduct 3c as a
colourless oil. Rf ˆ 0.37 (light petroleum/Et2O 1:1); [a]2D0 ˆ ‡12.1 (c ˆ 1.0 in
CHCl3) (Table 2, entry 13); 1H NMR (500 MHz, CDCl3, 258C): d ˆ 1.50 (s,
9H; C(CH3)3), 1.50 ± 1.57 (m, 2H; OCCHaHbCH2CH2CH, OCCH2CH-
CHaHbCH2CH2), 1.67 ± 1.72 (m, 1H; OCCH2CHaHbCH2CH), 1.83 ± 2.02
(m, 4H; OCCH2CHaHbCH2CH, OCCH2CHCHaHb, C(O)CHaHb, OC-
CHaHbCH), 2.10 ± 2.18 (m, 1H; OCCHaHbCH2CH2CH), 2.44 (app. dt,
2J(H,H) ˆ 12.9 Hz, 3J(H,H) ˆ 8.5 Hz, 1H; C(O)CH2CHaHb), 2.47 ± 2.59 (m,
4H; CHCHaHbCC(O)CHaHbCHaHbC); 13C NMR (50 MHz, CDCl3, 258C):
d ˆ 27.9 (C(CH3)3), 25.1, 33.6, 34.0, 34.3, 36.7, 41.7 (6  CH2), 45.1 (CH),
CH2CH2CH CH2), 2.00 ± 2.06 (m, 2H; CH2CH CH2), 2.44 (t, 3J(H,H) ˆ
ˆ
ˆ
ˆ
7.4 Hz, 2H; CH2(CH2)2CH CH2), 2.58 ± 2.70 (m, 4H; C(O)CH2CH2C(O)),
3
ˆ
4.86 ± 4.96 (m, 2H; CH CH2), 5.74 (ddt, J(H,H) ˆ 17.0, 10.0, 7.0 Hz, 1H;
CH CH2), 11.58 (brs, 1H; CO2H); 13C NMR (100 MHz, CDCl3, 258C):
ˆ
ˆ
ˆ
d ˆ 22.7, 27.7, 32.9, 36.8, 41.7 (5  CH2), 115.2 (CH CH2), 137.8 (CH CH2),
ˆ
179.0 (CO2H), 208.8 (C O); IR (KBr): nÄ ˆ 3100 (w, br; OH), 2938 (m; CH),
ˆ
82.5 (C(CH3)3), 91.5, 93.8 (2  Cq), 167.1 (CO2), 205.2 (C O); IR: nÄ ˆ 2956
1
ˆ
1712 (s; C O), 1416 (m), 1248 cm (m).
ˆ
ˆ
(m; CH), 1744 (s; C O), 1724 (s; C O), 1369 (m), 1320 (m), 1151 (m), 1137
(m), 1066 cm 1 (m); MS (EI ‡ ): m/z (%): 266 (3) [M] , 210 (13), 182 (16),
‡
tert-Butyl 3,6-dioxo-10-undecenoate (5c): Carbonyl diimidazole (3.04 g,
18.75 mmol) was added to a stirred solution of keto acid 4 (2.66 g,
15.63 mmol) in THF (30 mL) at 08C. After 15 min at 08C the ice bath was
removed and the reaction mixture was allowed to warm to room
164 (22), 137 (33), 94 (50), 79 (47), 57 (100); HRMS: calcd for C15H22O4:
‡
266.1518; found: 266.1518 [M] .
GC analysis of 3c for ee determination: (CP Chirasil Dex-CD, 1408C
isotherm, 0.5 mLmin 1, 2 mgmL 1), tRmj ˆ 32.4 min; tRmn ˆ 34.8 min.
temperature for 1 h. In
a separate flask, mono-tert-butyl malonate
(6.00 g, 37.46 mmol) was dissolved in THF (100 mL), cooled to 788C
and to this was added Bu2Mg (18.80 mL of a 1.0m solution in heptane) by
syringe. The mixture was stirred for 15 min at 788C and then for 1 h at
room temperature. The solvent was removed, the residue dissolved in THF
(50 mL) and the acyl imidazolide added through a cannula, rinsing the flask
with a second portion of THF (10 mL). After 18 h the reaction was
quenched by the addition of 10% aqueous citric acid solution (30 mL), the
layers separated and the aqueous component extracted with Et2O (2 Â
60 mL). The combined organic components were washed with saturated
aqueous NaHCO3 solution (30 mL) and brine (30 mL), dried (MgSO4) and
concentrated under reduced pressure. The crude product mixture was
purified by column chromatography (light petroleum/Et2O 5:1) to give 3,6-
diketoester 5c as a colourless oil (2.41 g, 58%). Rf ˆ 0.35 (light petroleum/
Transesterification of 3c to 3a for ee determination: A solution of
cycloadduct 3c (10 ± 60 mg) in CH2Cl2/TFA (10 mL, 9:1 v/v) was stirred at
room temperature for 1 h. The reaction mixture was concentrated under
reduced pressure to yield the cycloadduct carboxylic acid as a white solid
(quant.). para-Toluenesulfonic acid (p-TSA, approx. 10 mg, 0.05 mmol)
was added to a solution of the acid in MeOH (10 mL) and the solution was
heated at reflux for 18 h. The reaction mixture was absorbed onto silica and
purified by column chromatography (light petroleum/Et2O 3:1) to give the
methyl ester 3a as a white solid (approx. 85% over 2 steps).
Derivatisation as benzyl oxime ether for ee determination: O-Benzylhy-
droxylamine hydrochloride (219 mg, 1.37 mmol) was added to a stirred
solution of methyl ester 3a (205 mg, 0.92 mmol) and NaOAc (113 mg,
1.37 mmol) in MeOH (5 mL). After 1 h the reaction mixture was absorbed
onto silica and purified by column chromatography (light petroleum/Et2O
1
Et2O 1:1); H NMR (500 MHz, CDCl3, 258C): d ˆ 1.47 (s, 9H; C(CH3)3),
ˆ
ˆ
1.64 ± 1.71 (m, 2H; CH2CH2CH CH2), 2.01 ± 2.10 (m, 2H; CH2CH CH2),
3
ˆ
2.47 (t, J(H,H) ˆ 7.4 Hz, 2H; CH2(CH2)2CH CH2), 2.69 ± 2.72, 2.80 ± 2.83
10:1) to give the trans benzyl oxime ether as a colourless viscous oil
(2 Â m, 2 Â 2H; C(O)CH2CH2C(O)), 3.41 (s, 2H; C(O)CH2C(O)), 4.97 ±
1
5.00 (m, 2H; CH CH2), 5.76 (ddt, 3J(H,H) ˆ 16.9, 10.1, 6.7 Hz, 1H;
(263 mg, 87%). HPLC analysis: (hexane/EtOH 90:10, 0.5 mLmin
2 mgmL 1), tRmj ˆ 11.2 min; tRmn ˆ 14.0 min (derived from (‡)-3c).
,
ˆ
CH CH2); 13C NMR (125 MHz, CDCl3, 258C): d ˆ 27.8 (C(CH3)3), 22.7,
ˆ
32.9, 36.0, 36.2, 41.7 (5 Â CH2), 50.5 (C(O)CH2C(O)), 81.8 (C(CH3)3), 115.1
Tetrakis[(1S,3S,5S)-2-(4-dodecylbenzenesulfonyl)-2-azabicyclo[3.3.0]oc-
tan-3-carboxylato]dirhodium (16): A solution of 4-(n-dodecyl)benzenesul-
fonyl chloride (780 mg, 2.26 mmol, single isomer) in THF (5 mL) was
ˆ
ˆ
ˆ
(CH CH2), 137.8 (CH CH2), 166.3 (CO2), 201.9, 208.8 (2  C O); IR: nÄ ˆ
ˆ
ˆ
ˆ
2979 (m; CH), 2936 (m; CH), 1769 (s; C O), 1737 (s; C O), 1715 (s; C O),
1410 (m), 1394 (m), 1339 (m), 1321 (m), 1258 (m), 1153 cm 1 (m); MS (CI‡):
added to
a stirred solution of (1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-
‡
m/z (%): 286 (38) [M‡NH4] , 240 (38), 230 (100), 186 (70), 109 (20), 52
carboxylic acid hydrochloride salt[55] (334 mg, 1.74 mmol) and Na2CO3
(740 mg, 6.98 mmol) in H2O (10 mL). After 15 h the reaction mixture
was diluted with H2O (100 mL) and Et2O (30 mL), the aqueous phase was
then separated and acidified to pH 1 with conc. HCl. The aqueous solution
was saturated with NaCl and extracted with EtOAc (5 Â 100 mL). The
combined organic components were dried (MgSO4) and concentrated
under reduced pressure to yield a crude product mixture which was purified
by column chromatography (CH2Cl2/MeOH 19:1) to give the N-arylsul-
fonyl acid as a colourless viscous oil (657 mg, 82%) which partially
‡
(56); HRMS: calcd for C15H28O4: 286.2018; found: 286.2018 [M‡NH4] .
tert-Butyl 2-diazo-3,6-dioxo-10-undecenoate (2c): Et3N (1.34 mL,
9.69 mmol) was added to a stirred solution of 3,6-diketoester 5c (2.36 g,
8.81 mmol) and 4-acetamidobenzenesulfonyl azide[53] (2.32 g, 9.69 mmol)
in MeCN (70 mL). After 15 h the reaction mixture was filtered and the
precipitate washed with CH2Cl2 (70 mL). Saturated aqueous NH4Cl
(20 mL) solution was added to the combined organics, the layers were
separated and the aqueous phase extracted with CH2Cl2 (20 mL). The
organic components were washed with brine (20 mL), dried (MgSO4) and
absorbed onto silica. Purification by column chromatography (light
petroleum/Et2O 10:1) gave cycloaddition precursor 2c as a yellow oil
(2.35 g, 91%). Rf ˆ 0.61 (light petroleum/Et2O 1:1); 1H NMR (500 MHz,
solidifed on storage in the freezer. Rf ˆ 0.37 (CH2Cl2/MeOH 9:1); [a]D20
ˆ
18.1 (c ˆ 1.0 in CHCl3); 1H NMR (500 MHz, CDCl3, 258C): d ˆ 0.87 ±
0.92 (m, 3H; CH3), 1.22 ± 1.39 (m, 16H), 1.44 ± 1.88 (m, 9H), 1.95 ± 2.16 (m,
3H), 2.49 ± 2.51 (m, 1H), 2.69 (t, 3J(H,H) ˆ 7.8 Hz, 2H), 4.02 ± 4.10 (m, 1H;
CHN), 4.15 ± 4.24 (m, 1H; CHCO2H), 7.36 (m, 2H; C(Ar, 3/5)H), 7.80 (m,
2H; C(Ar, 2/6)H); 13C NMR (125 MHz, CDCl3, 258C): d ˆ 14.0 (CH3),
22.6, 24.3, 29.2, 29.3, 29.4, 29.5, 29.6, 30.9, 31.3, 31.8, 34.3, 35.2 and 35.8
(15 Â CH2), 43.0 (CH), 63.5 (br, CHN), 67.1 (CHCO2H), 127.9, 129.0 (2 Â
CDCl3, 258C): d ˆ 1.53 (s, 9H; C(CH3)3), 1.67 ± 1.73 (m, 2H;
3
ˆ
ˆ
CH2CH2CH CH2), 2.07 (app. q, J(H,H) ˆ 7.1 Hz, 2H; CH2CH CH2),
3
ˆ
2.49 (t, J(H,H) ˆ 7.4 Hz, 2H; CH2(CH2)2CH CH2), 2.72 ± 2.74, 3.09 ± 3.12
ˆ
(2 Â m, 2 Â 2H; C(O)CH2CH2C(O)), 4.96 ± 5.04 (m, 2H; CH CH2), 5.77
(ddt, J(H,H) ˆ 16.7, 10.2, 6.7 Hz, 1H; CH CH2); 13C NMR (125 MHz,
C(Ar)H), 133.9 and 148.8 (2  Cq(Ar)), 178.0 (br, CO2H); IR: nÄ ˆ 2926 (s;
3
ˆ
1
ˆ
ˆ
CDCl3, 258C): d ˆ 22.7 (CH2CH2CH CH2), 28.2 (C(CH3)3), 29.6, 33.0,
CH), 2955 (m; CH), 1727 (m; C O), 1351 (m), 1162 cm (m); MS
‡
ˆ
34.2, 36.1 (4 Â CH2), 68.0 (CN2), 83.1 (C(CH3)3), 115.1 (CH CH2), 137.9
(APCI ): m/z (%): 463 (23), 462 (100) [M H] , 460 (28), 309 (18), 125
(12); HRMS: calcd for C26H42NO4S: 464.2834; found: 464.2834 [M‡H] .
‡
ˆ
ˆ
(CH CH2), 160.5 (CO2), 191.5, 209.0 (2  C O); IR: nÄ ˆ 2969 (m; CH),
4472
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0720-4472 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 20

Tandem Reactions
4465±4476
[Rh2(OAc)4] (32 mg, 0.07 mmol) was added to a stirred solution of the N-
arylsulfonyl acid (199 mg, 0.43 mmol) in chlorobenzene (50 mL). The
solution was heated under reflux in an apparatus fitted with a soxhlet
extractor containing a thimble of CaCO3 for 6 days, the thimble being
replaced every 2 days. The mixture was concentrated under reduced
pressure and the residue dissolved in CH2Cl2 (20 mL). The solution was
then washed with saturated aqueous NaHCO3 solution (10 mL), dried
(Na2SO4) and concentrated under reduced pressure. The crude product was
purified by column chromatography (light petroleum/Et2O 2:1 ! Et2O) to
give catalyst 16 as a green solid (32 mg, 23%). An analytical sample of the
bis-H2O adduct was prepared by heating (1008C) under vacuum
(0.1 mmHg) for 18 h, after which the sample picked up H2O from the
63 mmol) was added and the solution was heated at reflux. The solvent
1
was distilled from the reaction mixture at a rate of approximately 8 mLh
,
further portions of PhCl (6 mL) were added when an equal volume had
been removed. After 5 h the reaction mixture was concentrated under
reduced pressure and the residue was purified by column chromatography
(CH2Cl2) to give the catalyst 28 as a green solid (144 mg, 100%). The
catalyst could be further purified by recrystallisation from THF/MeOH. An
analytical sample of the bis-H2O adduct was prepared by heating (1008C)
under vacuum (0.1 mmHg) for 18 h, after which the sample picked up H2O
from the laboratory atmosphere. M.p. >3008C (THF/MeOH); [a]D20
ˆ
‡20.0 (c ˆ 0.05 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 7.26
(d, 3J(H,H) ˆ 9.1 Hz, 8H; 8  OCCCCH), 7.41 (dd, 3J(H,H) ˆ 9.1 Hz,
4J(H,H) ˆ 1.7 Hz, 8 H; 8  OCCCCHCHCBr), 7.56 (d, 3J(H,H) ˆ 8.9 Hz,
laboratory atmosphere. M.p. 160 ± 1628C; [a]D20
ˆ
129.0 (c ˆ 0.04 in
CHCl3); 1H NMR (500 MHz, CDCl3, 258C): d ˆ 0.88 (t, 3J(H,H) ˆ
6.9 Hz, 12H; 4 Â CH3), 1.22 ± 1.48 (m, 80H), 1.50 ± 1.68 (m, 16H), 1.68 ±
1.85 (m, 12H), 1.98 ± 2.10 (m, 4H), 2.18 ± 2.38 (m, 4H), 2.60 ± 2.70 (m, 8H),
3.80 ± 3.90 (m, 4H; 4 Â CHN), 4.08 ± 4.22 (m, 4H; 4 Â CHCO2), 7.27 (d,
3J(H,H) ˆ 8.0 Hz, 8H; 4  C(Ar, 3/5)H), 7.74 (d, 8H; 4  C(Ar, 4/6)H);
13C NMR (125 MHz, CDCl3, 258C): d ˆ 14.1 (CH3), 22.7, 24.1, 29.3, 29.3,
29.4, 29.5, 29.6, 30.6, 31.1, 31.9, 33.3, 35.7, 35.8 (60 Â CH2), 42.6 (CH), 64.6,
66.6 (8 Â CHN), 128.0, 128.7 (C(Ar)H), 135.4, 148.0 (Cq(Ar)), 191.9 (CO2);
IR (KBr): nÄ ˆ 2942 (s; CH), 2854 (m; CH), 1605 (s; CO2), 1418 (m), 1353
(m), 1164 cm 1 (s); MS (FAB ‡ , NOBA matrix): m/z (%): 2091 (0.4), 2056
8H; 8  OCCH), 7.77 (d, J(H,H) ˆ 8.9 Hz, 8H; 8  OCCHCHCCHCBr),
3
8.06 (d, 4J(H,H) ˆ 1.7 Hz, 8H; 2  BrCCHC); 13C NMR (100 MHz, CDCl3,
258C): d ˆ 119.8, 121.4 (16  Cq), 122.2, 128.5, 130.1, 130.5, 130.5 (40  CH),
130.7, 132.9, 147.8 (24  Cq); IR (KBr): nÄ ˆ 1585 (w), 1493 (w), 1324 (w),
1
1236 (w), 1061 cm (s); MS (FAB ‡ , NOBA): m/z (%): 2226 (100)
‡
[M‡H] (4  79Br and 4  81Br), 1720 (42), 1215 (32), 1084 (35), data not
available below m/z 800; elemental analysis calcd (%) for
C80H40Br8O16P4Rh2 ´ 2H2O: C 42.48, H 1.96; found: C 42.43, H 2.05.
Tetrakis[(R)-6,6'-didodecyl-1,1'-binaphthyl-2,2'-diylphosphate]dirhodium
[Rh2{(R)-ddbnp}4] (33): [1,3-Bis(diphenylphosphino)propane]NiCl2 (1 mg,
2 mmol) and n-dodecyl magnesium bromide (0.48 mL of a 1.0m solution in
Et2O, 0.48 mmol, Aldrich) was added to a stirred solution of (R)-2,2'-
dibenzyloxy-6,6'-dibromo-1,1'-binaphthyl (29)[43] (100 mg, 0.16 mmol) in
Et2O (5 mL). After heating under reflux for 18 h the solution was cooled to
room temperature. H2O (5 mL) was carefully added followed by HCl (2m,
5 mL); the aqueous phase was then separated and extracted with EtOAc
(3 Â 10 mL). The combined organic components were washed with brine
(10 mL), dried (MgSO4) and concentrated under reduced pressure. The
crude product mixture was purified by column chromatography (1.5%
Et2O in light petroleum) to give didodecylbisether 30 as a colourless
‡
(2.4) [M‡H] , 1781 (0.4), 1746 (6.6), 662 (41), 418 (100); elemental analysis
calcd (%) for C104H164N4O18S4Rh2 ´ 2H2O: C 59.70, H 7.90, N 2.68; found: C
59.15, H 7.36, N 2.68.
Tetrakis[(1S,3R,4R)-2-(4-dodecylbenzenesulfonyl)-2-azabicyclo[2.2.1]-
heptane-3-carboxylato]dirhodium (17b): (1S,3R,4R)-2-Azabicyclo[2.2.1]-
heptane-3-carboxylic acid[28] (91 mg, 0.64 mmol) and Na2CO3 (210 mg,
1.93 mmol) was added to a stirred solution of 4(n-dodecyl)benzenesulfonyl
chloride (290 mg, 0.84 mmol) in H2O (5 mL) and THF (2.5 mL). The
solution was stirred at room temperature for 3 days before dilution with
H2O (20 mL). The reaction mixture was acidified to pH 1.5 with conc. HCl
and carefully saturated with NaCl. The mixture was extracted with CH2Cl2
(Â3), and the combined organic layers were dried (MgSO4) and
concentrated under reduced pressure. The crude residue was purified by
column chromatography (light petroleum/Et2O 1:1) to give the N-
arylsulfonyl acid as a yellow oil (0.132 g, 46%). [a]2D0 ˆ ‡68.6 (c ˆ 0.7 in
CHCl3); 1H NMR (200 MHz, CDCl3, 258C): d ˆ 0.87 (m, 3H; CH3), 1.12 ±
2.08 (m, 26H; ArCH2(CH2)10CH3, NCHCH2CH2CH2CHCHCOOH),
2.60 ± 2.75 (m, 2H; ArCH2), 2.82 (brs, 1H), 3.93 (brs, 1H), 4.11 (brs,
1H), 7.31 (d, 3J(H,H) ˆ 7.6 Hz, 2H), 7.84 (d, 3J(H,H) ˆ 7.6 Hz, 2H), 9.04
(brs, 1H, COOH); 13C NMR (50 MHz, CDCl3, 258C): d ˆ 13.9 (CH3), 22.4,
27.4, 28.4, 28.9 ± 29.4, 30.8, 31.7 (12 Â CH2), 35.6 (CH), 36.2, 43.2 (2 Â CH2),
60.0, 64.4 (2 Â CH), 127.8, 129.0 (4 Â C(Ar)H), 137.0, 148.8 (2 Â Cq(Ar)),
viscous oil (96 mg, 75%). Rf ˆ 0.63 (light petroleum/Et2O 2:1); [a]D20
ˆ
‡205.7 (c ˆ 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 0.90
(t, 3J(H,H) ˆ 6.8 Hz, 6H; 2  CH3), 1.22 ± 1.41 (m, 36H; 2  (CH2)9CH3),
1.65 ± 1.72 (m, 4H; 2  ArCH2CH2), 2.73 (t, 3J(H,H) ˆ 7.7 Hz, 4H; 2 Â
ArCH2), 5.04 (s, 4H; 2 Â OCH2), 6.96 ± 6.98 (m, 4H; 2 Â OCCCCH, 2 Â
C(Ar, benzyl)H), 7.08 ± 7.18 (m, 10H; 2 Â OCCCHCH, 8 Â C(Ar, ben-
zyl)H), 7.39 (d, 3J(H,H) ˆ 9 Hz, 2H; 2  OCCH), 7.66 (brs, 2H; 2 Â
OCCHCHCCH), 7.87 (d, 3J(H,H) ˆ 9 Hz, 2H; 2  OCCHCH); 13C NMR
(100 MHz, CDCl3, 258C): d ˆ 14.1 (2  CH3), 22.7, 29.4, 20.4, 4  29.6, 29.7,
31.4, 31.9, 35.9 (22 Â CH2), 71.3 (2 Â OCH2), 116.2 (2 Â CH), 120.9 (2 Â Cq),
125.5, 126.2, 126.8, 127.2, 127.9, 128.1, 128.6 (18 Â CH), 129.6, 132.6, 137.7,
138.2, 153.5 (10  Cq); IR: nÄ ˆ 2924 (s; CH), 2853 (m; CH), 1596 (w), 1453
‡
(w), 1272 cm 1 (w); MS (EI ‡ ): m/z (%): 803 (5) [M‡H] , 713 (5), 622 (4),
175.7 (COOH); IR: nÄ ˆ 3270 (s; OH), 2923 (s; CH), 2854 (s; CH), 1725 (m;
1
ˆ
ˆ
C O), 1597 (w; arC C), 1466 (w), 1340 (m), 1155 cm (m); MS (CI ‡ ):
283 (8), 93 (8), 92 (100), 58 (8), 44 (14); HRMS: calcd for C58H74O2:
‡
‡
‡
m/z (%): 467 (50) [M‡NH4] , 450 (31) [M‡H] , 420 (2), 404 (9), 364 (9),
802.5688; found: 802.5689 [M] .
362 (23), 294 (15), 278 (30), 246 (25), 142 (3), 113 (3), 96 (100); HRMS:
NaI (2.13 g, 14.21 mmol) and TMSCl (1.80 mL, 14.21 mmol) was added to a
stirred solution of didodecylbisether 30 (1.14g, 1.42 mmol) in PhCH3
(20 mL) and MeCN (40 mL). The reaction mixture was heated at 408C
for 2 h. After cooling to room temperature, H2O (40 mL) was added, the
aqueous phase was then separated and extracted with Et2O (3 Â 40 mL).
The combined organic components were washed with aqueous Na2S2O3
solution (1m, 60 mL) and brine (60 mL), dried (MgSO4) and concentrated
under reduced pressure. The crude product mixture was purified by column
chromatography (light petroleum/Et2O 10:1) to give diol 31 as a colourless
oil (784 mg, 89%) which solidified on standing. A portion of this product
was further purified by crystallisation from MeCN (deposited as an oil
which then solidifed) to give essentially enantiomerically pure diol 31 (as
determined by HPLC, see below); concentration of the supernatant gave
diol 31 of 92% ee. Rf ˆ 0.16 (light petroleum/Et2O 3:1); m.p. 67 ± 688C
‡
calcd for C25H43SN2O4: 467.2944; found: 467.2948 [M‡NH4] .
A stirred solution of the N-arylsulfonyl acid (0.499 g, 1.11 mmol) and
[56]
Na4Rh2(CO3)4 (75 mg, 0.14 mmol) in H2O (7.5 mL) was heated at 908C
for 1 h, during which time the colour changed from blue to green. The
reaction mixture was cooled and the solvent evaporated under reduced
pressure. The residue was purified by column chromatography (EtOAc) to
give the catalyst 17b as a green powder (0.121 g, 43%). M.p. 1138C; [a]D20
ˆ
1
‡175.0 (c ˆ 0.6 in CHCl3); H NMR (400 MHz, CDCl3, 258C): d ˆ 0.87 ±
0.90 (m, 12H; 4 Â CH3), 0.90 ± 1.87 (m, 104H; 4 Â ArCH2(CH2)10CH3, 4 Â
NCHCH2CH2CH2CHCHCOOH), 2.66 ± 2.76 (m, 12H; 4 Â CHCHCOO,
4  ArCH2), 3.73 (brs, 4H), 3.93 (brs, 4H), 7.32 (d, 3J(H,H) ˆ 7.8 Hz, 8H),
7.83 (d, 3J(H,H) ˆ 7.8 Hz, 8H); 13C NMR (100 MHz, CDCl3, 258C): d ˆ
14.6 (4 Â CH3), 23.2, 29.6 ± 30.2 ± 30.3, 31.7, 32.4 (48 Â CH2), 36.4 (4 Â CH),
37.4, 44.4 (8 Â CH2), 59.6, 66.7 (8 Â CH), 128.3, 129.3 (16 Â C(Ar)H), 138.5,
148.4 (8  Cq(Ar)), 191.5 (COO); IR (KBr): nÄ ˆ 2924 (s; CH), 2853 (m;
(MeCN); [a]2D0
ˆ
51.4 (c ˆ 1.0 in CHCl3); 1H NMR (400 MHz, CDCl3,
258C): d ˆ 0.89 (t, 3J(H,H) ˆ 6.8 Hz, 6H; 2  CH3), 1.22 ± 1.41 (m, 36H; 2 Â
1
CH), 1601 (m), 1460 (w), 1328 (m), 1156 cm (m); MS (FAB ‡ , NOBA
(CH2)9CH3), 1.64 ± 1.71 (m, 4H; 2  ArCH2CH2), 2.73 (t, 3J(H,H) ˆ 7.7 Hz,
‡
‡
matrix): m/z (%): 2023 (32) [M‡Na] , 2000 (55) [M] , 1691 (35), 1098 (31),
3
4H; 2  ArCH2), 5.00 (s, 2H; 2  OH), 7.10 (d, J(H,H) ˆ 8.6 Hz, 2H; 2 Â
648 (36), 404 (100).
C12H25CCHCH), 7.17 (dd, 3J(H,H) ˆ 8.6 Hz, 4J(H,H) ˆ 1.5 Hz, 2H; 2 Â
C12H25CCHCH), 7.35 (d, 3J(H,H) ˆ 8.9 Hz, 2H; 2  HOCCH), 7.67 (brs,
2H; 2  C12H25CCHC), 7.91 (d, 3J(H,H) ˆ 8.9 Hz, 2H; HOCCHCH);
13C NMR (100 MHz, CDCl3, 258C): d ˆ 14.1 (2  CH3), 22.7, 29.3, 29.4,
29.5, 29.6, 29.6, 29.6, 29.7, 31.4, 31.9, 35.8 (22 Â CH2), 110.8 (2 Â Cq), 117.6,
Tetrakis[(R)-6,6'-dibromo-1,1'-binaphthyl-2,2'-diylphosphate]dirhodium
(28): A round-bottomed flask (25 mL) fitted with a short path distillation
unit was charged with a solution of (R)-6,6'-dibromobinaphtholphosphoric
acid[42] (191 mg, 0.38 mmol) in PhCl (10 mL). [Rh2(OAc)4] (28 mg,
Chem. Eur. J. 2001, 7, No. 20
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0720-4473 $ 17.50+.50/0
4473

D. M. Hodgson et al.
FULL PAPER
124.1, 126.8, 129.0 (8 Â CH), 129.6 (2 Â Cq), 130.8 (2 Â CH), 131.7, 138.6,
152.0 (6  Cq); IR (KBr): nÄ ˆ 3431 (m, br; OH), 2920 (s; CH), 2850 (s; CH),
1601 (m), 1218 (w), 1174 (m), 1145 cm 1 (m); MS (APCI ): m/z (%): 622
(d, 3J(H,H) ˆ 8.7 Hz, 2H), 8.17 (d, 3J(H,H) ˆ 9.1 Hz, 2H); 13C NMR
(100 MHz, CDCl3, 258C): d ˆ 25.2 (2  CH3), 22.8, 23.6, 31.3, 35.4, 40.9
(10 Â CH2), 39.2 (2 Â Cq), 50.7 (2 Â CH), 119.9 (2 Â C(Ar)H), 122.1 (2 Â
Cq(Ar)), 125.1, 126.2, 129.6 (6 Â C(Ar)H), 130.1, 130.7, 131.2, 137.2, 146.3
(10  Cq(Ar)); IR (KBr): nÄ ˆ 3392 (w, br; OH), 2923 (s; CH), 2864 (m; CH),
1580 (w; arCC), 1505 (w; ArCC), 1473 (w), 1431 (w), 1387 (w), 1235 (s),
‡
(39), 621 (100) [M H] ; elemental analysis calcd (%) for C44H62O2: C
84.83, H 10.03; found: C 84.60, H 10.27; HPLC analysis: (hexane/EtOH
70:30, 0.5 mLmin 1, 0.1 mgmL 1), tRmj ˆ 7.8 min and tRmn ˆ 9.5 min.
‡
1027 cm 1 (s); MS (FAB ‡ , NOBA matrix): m/z (%): 587 (100) [M‡Na] ,
POCl3 (121 mL, 1.30 mmol) was added to a stirred solution of diol 31
(402 mg, 0.65 mmol) in pyridine (3 mL) at room temperature. After 2 h,
H2O (65 mL) and NaHCO3 solution (300 mL) were added in that order,
followed by dropwise addition (due to effervescence) of 5% aqueous
NaHCO3 solution (6.5 mL). The reaction mixture was partitioned between
HCl (2m, 50 mL) and EtOAc (50 mL), the aqueous phase was then
separated and further extracted with EtOAc (2 Â 40 mL). The combined
organic layers were washed with brine (30 mL), dried (MgSO4) and
concentrated under reduced pressure to give acid 32 as a viscous colourless
‡
564 (68) [M] , 309 (7), 291 (12), 152 (41), 135 (36); HRMS: calcd for
‡
C36H41NO4P: 582.2773; found: 582.2773 [M‡NH4] .
A round-bottomed flask (25 mL) fitted with a short path distillation unit
was charged with a solution of acid 35 (0.6 g, 1.06 mmol) in PhCl (15 mL).
[Rh2(OAc)4] (78 mg, 0.18 mmol) was added and the solution was heated to
reflux. The solvent was slowly distilled from the reaction mixture and
further portions of PhCl (ꢀ6 mL) were added when an equal volume had
been removed. After 5 h, the reaction mixture was concentrated under
reduced pressure and the residue was purified by column chromatography
(light petroleum/CH2Cl2 6:5 ! CH2Cl2) to give a green solid, which was
suspended in MeOH (5 mL), filtered and air dried to give the catalyst 36 as
a green powder (0.23 g, 53%). M.p. 3148C; [a]2D0 ˆ ‡118.3 (c ˆ 0.6 in
CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 1.05 (s, 24H; 8  CH3),
1.59 ± 1.85 (m, 56H; 8 Â ArCH2CH2, 8 Â ArCHCHaHb, 8 Â ArCHCH2CH2,
8 Â ArCHCH2CH2CH2), 2.27 ± 2.29 (m, 8H; 8 Â ArCHCHaHb), 2.64 ± 2.68
(m, 8H; 8  ArCH), 2.97 ± 3.11 (m, 16H; 8  ArCH2), 7.02 (d, 3J(H,H) ˆ
9.0 Hz, 8H), 7.28 (d, 3J(H,H) ˆ 9.6 Hz, 8H), 7.54 (d, 3J(H,H) ˆ 9.0 Hz, 8H),
7.96 (d, 3J(H,H) ˆ 9.2 Hz, 8H); 13C NMR (100 MHz, CDCl3, 258C): d ˆ
25.3 (8 Â CH3), 22.8, 23.5, 31.3, 35.4 and 40.9 (40 Â CH2), 39.2 (8 Â Cq), 50.7
(8 Â CH), 120.8 (8 Â C(Ar)H), 122.3 (8 Â Cq(Ar)), 125.3, 125.9, 129.3 (24 Â
C(Ar)H), 130.0, 130.6, 131.2, 136.7 147.2 (40 Â Cq(Ar)); 31P NMR
(200 MHz, CDCl3, 258C): d ˆ 21.5; IR (KBr): nÄ ˆ 2949 (m; CH), 2866
(m; CH), 1475 (w), 1458 (w), 1388 cm 1 (w); MS (FAB ‡ , NOBA matrix):
oil (394 mg, 89%) that required no further purification. [a]D20
ˆ
266.2 (c ˆ
0.7 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 0.89 (t, 3J(H,H) ˆ
6.8 Hz, 6H; 2 Â CH3), 1.21 ± 1.49 (m, 36H; 2 Â (CH2)9CH3), 1.60 ± 1.80 (m,
4H; 2  ArCH2CH2), 2.74 ± 2.78 (m, 4H; 2  ArCH2), 7.16 (d, 3J(H,H) ˆ
8.5 Hz, 2H; 2  C12H25CCHCH), 7.33 (d, 3J(H,H) ˆ 8.5 Hz, 2H; 2 Â
C12H25CCHCH), 7.50 (d, 3J(H,H) ˆ 8.5 Hz, 2H; 2  OCCH), 7.69 (s, 2H;
2  C12H25CCHC), 7.86 (d, 3J(H,H) ˆ 8.5 Hz, 2H; 2  OCCHCH);
13C NMR (100 MHz, CDCl3, 258C): d ˆ 14.1 (2  CH3), 22.7, 29.4, 29.4,
29.5, 29.6, 29.6, 29.7, 29.7, 31.2, 31.9, 35.8 (22 Â CH2), 120.5 (2 Â CH), 121.4
(2 Â Cq), 126.7, 127.0, 128.2, 130.6 (8 Â CH), 130.6, 132.0, 140.3, 146.3 (8 Â
1
Cq); IR: nÄ ˆ 2924 (s; CH), 2853 (m; CH), 1466 (w), 1226 (w), 1028 cm
‡
(m); MS (CI ‡ ): m/z (%): 704 (25), 703 (45), 702 (100) [M‡NH4] , 685 (22)
‡
‡
[M‡H] ; HRMS: calcd for C44H61O4P: 684.4307; found: 684.4303 [M] .
A round-bottomed flask (25 mL, B14) fitted with a short path distillation
unit was charged with a solution of acid 32 (360 mg, 0.53 mmol) in PhCl
(8 mL). [Rh2(OAc)4] (39 mg, 0.09 mmol) was added and the solution
heated under reflux. The solvent was distilled from the reaction mixture at
a rate of approximately 7 mLh 1; further portions of PhCl (6 mL) were
added when an equal volume had been removed. After 5 h the reaction
mixture was concentrated under reduced pressure and the residue was
purified by column chromatography (light petroleum/Et2O 30:1 ! 10:1) to
give 33 as a green solid (237 mg, 92%). The product was further purifed by
deposition from hot THF (ca. 1 mL) on addition of MeOH (ca. 2 mL).
After cooling, the supernatant was removed by pipette, the residue washed
with MeOH (3 mL) and dried under vacuum. This was repeated to give the
catalyst 33 as a green foam (182 mg, 69%). An analytical sample of the bis-
H2O adduct was prepared by heating (1008C) under vacuum (0.1 mmHg)
for 18 h, after which the sample picked up H2O from the laboratory
atmosphere. M.p. 220 ± 2248C; [a]2D0 ˆ ‡60.9 (c ˆ 0.03 in CHCl3); 1H NMR
(400 MHz, CDCl3, 258C): d ˆ 0.89 (t, 3J(H,H) ˆ 6.7 Hz, 24H; 8  CH3),
1.21 ± 1.34 (m, 144H; 8 Â (CH2)9CH3), 1.68 ± 1.71 (m, 16H; 8 Â ArCH2CH2),
2.75 (t, 3J(H,H) ˆ 7.5 Hz, 16H; 8  ArCH2), 7.18 (d, 3J(H,H) ˆ 8.7 Hz, 8H;
8  C12H25CCHCH), 7.43 (d, 3J(H,H) ˆ 8.7 Hz, 8H; 8  C12H25CCHCH),
7.56 (d, 3J(H,H) ˆ 8.9 Hz, 8H; 8  OCCH), 7.65 (s, 8H; 8  C12H25CCHC),
7.77 (d, 3J(H,H) ˆ 8.9 Hz, 8H; 8  OCCHCH); 13C NMR (100 MHz,
CDCl3, 258C): d ˆ 14.1 (8  CH3), 22.7, 29.4, 29.4, 29.5, 29.6, 29.6, 29.7,
29.7, 31.2, 31.9, 35.8 (88 Â CH2), 121.2 (8 Â CH), 121.6 (8 Â Cq), 126.7, 127.1,
128.0, 130.4 (32  CH), 130.7, 132.0, 139.9, 147.2 (32  Cq); IR (KBr): nÄ ˆ
2924 (s; CH), 2853 (m; CH), 1591 (w), 1468 (m), 1233 (m), 1205 (m),
1061 cm 1 (s); elemental analysis calcd (%) for C176H240O16P4Rh2 ´ 2H2O: C
71.00, H 8.26; found: C 71.21, H 8.16.
‡
m/z (%): 2460 (17) [M] , 1896 (43), 1330 (14), 588 (97), 313 (100).
Tetrakis[(S,S)-4,4'-bis(estra-1,3,5(10),6,8-pentaene)-3,3'-diylphosphate]-
dirhodium [Rh2{(S,S)-biep}4] (39): POCl3 (0.113 mL, 1 ˆ 1.645, 1.21 mmol)
was added to
a
stirred solution of (S,S)-bis-steroid 37[47d] (0.300 g,
0.60 mmol) in pyridine (2 mL) at room temperature. After 1 h, H2O
(0.25 mL) was added. After 15 minutes, HCl (6n, 3 mL) was added to the
residue. After a further 15 minutes, the precipitate was isolated by filtration
and washed with H2O. Traces of pyridine were removed by dissolving the
powder in CH2Cl2 and washing with HCl (2m). The organic solution was
then dried (MgSO4), and the solvent was evaporated under reduced
pressure to give acid 38 as a gold solid (317 mg, 94%). M.p. > 3408C;
[a]2D0 ˆ ‡522.7 (c ˆ 1.5 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ
1.15 (s, 6H; 2 Â CH3), 1.50 ± 1.88 (m, 14H; 2 Â ArCH2CH2, 2 Â ArCH-
CHaHb, 2 Â ArCHCH2CH2, 2 Â ArCHCH2CH2CH2), 2.18 ± 2.25 (m, 2H;
2  ArCHCHaHb), 2.75 ± 2.79 (t, 3J(H,H) ˆ 8.8 Hz, 2H; 2  ArCH), 3.08 ±
3.23 (m, 4H; 2  ArCH2), 7.07 (d, 3J(H,H) ˆ 8.8 Hz, 2H), 7.22 (d,
3
3J(H,H) ˆ 8.8 Hz, 2H), 7.57 (d, J(H,H) ˆ 9.0 Hz, 2H), 8.18 (d, 3J(H,H) ˆ
9.2 Hz, 2H), 9.90 (brs, 2H, 2 Â ArOH); 13C NMR (100 MHz, CDCl3,
258C): d ˆ 26.0 (2  CH3), 22.8, 23.2, 31.6, 35.4, 40.4 (10  CH2), 39.3
(2 Â Cq), 50.4 (2 Â CH), 120.0 (2 Â C(Ar)H), 122.0 (2 Â Cq(Ar)), 125.1,
126.2, 129.3 (6 Â C(Ar)H), 130.4, 130.5, 130.9, 137.5 and 146.1 (10 Â
Cq(Ar)); IR (KBr): nÄ ˆ 3389 (w, br; OH), 2945 (s; CH), 2856 (m; CH),
1580 (w; ArCC), 1506 (w; ArCC), 1471 (w), 1447 (w), 1432 (w), 1382 (w),
1
1225 (s), 1023 cm (s); MS (FAB ‡ , NOBA matrix): m/z (%): 588 (100)
‡
‡
[M‡Na] , 566 (41) [M‡H] , 483 (10), 330 (13), 309 (15), 291 (18), 135 (47);
‡
HRMS: calcd for C36H41NO4P: 582.2773; found: 582.2768 [M‡NH4] .
Tetrakis[(R,S)-4,4'-bis(estra-1,3,5(10),6,8-pentaene)-3,3'-diylphosphate]-
dirhodium [Rh2{(R,S)-biep}4] (36): POCl3 (0.113 mL, 1.21 mmol) was
added to a stirred solution of (R,S)-bis-steroid 34[47d] (0.300 g, 0.60 mmol)
in pyridine (2 mL) at room temperature. After 1 h, H2O (0.25 mL) was
added. After 15 minutes, HCl (6n, 3 mL) was added to the residue. After a
further 15 minutes, the precipitate was isolated by filtration and washed
with H2O. Traces of pyridine were removed by dissolving the powder in
CH2Cl2 and washing with Hcl (2m). The organic layer was then dried
(MgSO4), and evaporated under reduced pressure to give acid 35 as a gold
A round-bottomed flask (25 mL) fitted with a short path distillation unit
was charged with a solution of acid 38 (0.285 g, 0.50 mmol) in PhCl
(15 mL). [Rh2(OAc)4] (37 mg, 0.08 mmol) was added and the solution was
heated under reflux. The solvent was slowly distilled from the reaction
mixture and further portions of PhCl (ꢀ6 mL) were added when an equal
volume had been removed. After 5 h, the reaction mixture was concen-
trated under reduced pressure and the residue was purified by column
chromatography (light petroleum/CH2Cl2 6:5 ! CH2Cl2) to give a green
solid which was suspended in MeOH (5 mL), filtered and air dried to give
catalyst 39 as a green powder (0.165 g, 80%). M.p. >3308C; [a]2D0 ˆ ‡111.7
(c ˆ 0.6 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C): d ˆ 1.15 (s, 24H;
8 Â CH3), 1.54 ± 1.72 (m, 48H; 8 Â ArCH2CHaHb, 8 Â ArCHCHaHb, 8 Â
ArCHCH2CH2, 8 Â ArCHCH2CH2CH2), 1.82 ± 1.89 (m, 8H; 8 Â ArCH2-
CHaHb), 2.25 ± 2.29 (m, 8H; 8 Â ArCHCHaHb), 2.77 ± 2.80 (m, 8H; 8 Â
ArCH), 3.02 ± 3.19 (m, 16H; 8  ArCH2), 7.10 (d, 3J(H,H) ˆ 8.8 Hz, 8H),
solid (336 mg, 100%). M.p. >3408C; [a]D20
ˆ
357.1 (c ˆ 0.28 in CHCl3);
1H NMR (400 MHz, CDCl3, 258C): d ˆ 1.05 (s, 6H; 2  CH3), 1.63 ± 1.93
(m, 14H; 2 Â ArCH2CH2, 2 Â ArCHCHaHb, 2 Â ArCHCH2CH2, 2 Â
ArCHCH2CH2CH2), 2.26 ± 2.32 (m, 2H; 2 Â ArCHCHaHb), 2.68 ± 2.70
(m, 2H; 2 Â ArCH), 3.05 ± 3.26 (m, 4H; 2 Â ArCH2), 6.39 (brs, 2H, 2 Â
ArOH), 7.05 (d, 3J(H,H) ˆ 8.7 Hz, 2H), 7.23 (d, 3J(H,H) ˆ 8.7 Hz, 2H), 7.57
4474
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Chem. Eur. J. 2001, 7, No. 20

Tandem Reactions
4465±4476
7.33 (d, 3J(H,H) ˆ 9 Hz, 8H), 7.58 (d, 3J(H,H) ˆ 9 Hz, 8H), 8.04 (d,
3J(H,H) ˆ 9.5 Hz, 8H); 13C NMR (100 MHz, CDCl3, 258C): d ˆ 26.2 (8 Â
CH3), 22.8, 23.2, 31.7, 35.4, 40.4 (40 Â CH2), 39.3 (8 Â Cq), 50.4 (8 Â CH),
120.9 (8 Â C(Ar)H), 122.3 (8 Â Cq(Ar)), 125.2, 125.9, 128.9 (24 Â C(Ar)H),
130.3, 130.4, 131.0, 137.0, 147.1 (40 Â Cq(Ar)); 31P NMR (200 MHz, CDCl3,
258C): d ˆ 20.9 ; IR (KBr): nÄ ˆ 2949 (m, CH), 2865 (w, CH), 1474 (w), 1451
[15] M. P. Doyle, D. C. Forbes, M. M. Vasbinder, C. S. Peterson, J. Am.
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Slawin, Adv. Synth. Catal. 2001, 343, 112 ± 117.
‡
(w), 1387 cm 1 (w); MS (FAB ‡ , NOBA matrix): m/z (%): 2460 (26) [M] ,
1896 (27), 1328 (73), 588 (97), 521 (100).
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Acknowledgement
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1465 ± 1466.
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We thank the EPSRC (research grant GR/L98022 PDRA to F.Y.T.M.P.),
the European Community (programme TMR under contract number
HPMF-CT-2000 ± 00559; Marie Curie Fellowship to A.H.L.), European
COST programme (D12/0014/98) and AstraZeneca for support of this
work, and St. Hughꢁs College for a Jubilee Scholarship (to P.A.S.). We also
thank the EPSRC National Mass Spectrometry Service Centre for mass
spectra, Dr. D. J. Watkin (Chemical Crystallography Laboratory, Univer-
sity of Oxford) and J. Ouzman for assistance with the X-ray structure
analysis and Dr I. Nash (AstraZeneca) for useful discussions. We are also
very grateful to the following for generous samples of the materials
indicated in parentheses: M. P. Doyle, Texas (8); C. J. Moody, Exeter (9); L.
Tietze, Hoechst (benzyl (1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxyl-
ate); P. G. Andersson, Upsalla (17a and (1S,3R,4R)-2-azabicyclo[2.2.1]-
heptane-3-carboxylic acid); H. M. L. Davies, Buffalo (18 and 19); M. C.
Pirrung, Duke (ent-26); M. Schneider, Schering AG-Berlin (34 and 37). A
referee is thanked for suggesting dipolar complex 42/43 in the mechanistic
analysis of cycloaddition.
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[31] Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no.
CCDC-1821422 (22). Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB21EZ, UK (fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.
ac.uk). See also Supporting Information.
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4475

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Received: June 18, 2001 [F3344]
4476
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Chem. Eur. J. 2001, 7, No. 20