Synthesis of Conformationally Restricted Symmetric Macrodiolides via Carbonyl Ylides

Article abstract of DOI:10.1055/s-0033-1338801

Reaction of bis-diazocarbonyl compounds and dicarbaldehyde/divinyl derivatives in the presence of rhodium(II) acetate dimer as the catalyst led to the facile synthesis of conformationally restricted symmetric macrodiolides incorporating oxa/dioxa-bridged bicyclic systems. The structure and configuration of a representative macrodiolide were unequivocally confirmed using single-crystal X-ray analysis. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338801

2034▌
PAPER
paper
Synthesis of Conformationally Restricted Symmetric Macrodiolides via
Carbonyl Ylides
Synthesis of Conformationally Restricted Macrodiolides
Sengodagounder Muthusamy,*a Manickasamy Sivaguru,a Eringathodi Sureshb
a
School of Chemistry, Bharathidasan University, Tiruchirappalli 620024, India
Fax +91(431)2407045; E-mail: muthu@bdu.ac.in
b
Central Salt & Marine Chemicals Research Institute, Bhavnagar 364002, India
Received: 15.01.2013; Accepted after revision: 18.04.2013
This paper is dedicated with best wishes to Professor Goverdhan Mehta on the occasion of his 70th birthday.
tions, the synthesis of a series of bis-diazocarbonyl com-
pounds 3a–d (Scheme 1) was planned. Thus, diazo
Abstract: Reaction of bis-diazocarbonyl compounds and dicarbal-
dehyde/divinyl derivatives in the presence of rhodium(II) acetate
dimer as the catalyst led to the facile synthesis of conformationally
restricted symmetric macrodiolides incorporating oxa/dioxa-
compounds
3a–d
were
synthesized
via
transesterification10 of active methylene11 compound 1
bridged bicyclic systems. The structure and configuration of a with diols to afford the corresponding diester derivatives
2a–d (Table 1). Subsequent diazo-transfer12 reaction of
compounds 2a–d afforded the corresponding bis-diazo-
representative macrodiolide were unequivocally confirmed using
single-crystal X-ray analysis.
Key words: cycloaddition, diazo compounds, macrocycles, rhodi-
um, ylides
carbonyl compounds 3a–d in very good yields. These
compounds have a lower number of carbon signals than
expected in their 13C NMR spectra due to their symmetry.
Diazocarbonyl compounds1 are excellent precursors for
carbenoids and hence they have been employed in cyclo-
propanation, insertion, and ylide formation. The reaction
of metallocarbenoids with carbonyl groups is one of the
most effective methods to generate carbonyl ylides, and
their use in 1,3-dipolar cycloadditions2 with π-bonds of
C=C or C=O groups to construct carbo/heterocyclic ring
systems are well documented. As a result, there has been
growing interest in the use of rhodium(II)-generated car-
bonyl ylides as 1,3-dipoles for the synthesis of many bio-
active natural products.3 In order to synthesize
macrocycles via [3+2]-cycloaddition reactions, the selec-
tion of dipolarophile and diazocarbonyl compound is of
considerable interest. Synthesis4 and application studies5
of macrodiolides are valuable in organic synthesis due to
their biological as well as ion-selective properties and ap-
plication in the perfume industry. The synthesis of macro-
cycles generally results in low yields and requires high
dilution techniques. The physicochemical advantages of
conformationally restricted macrocycles result from their
shape6 and lower rotatable bond count.7 However, there is
no literature available for the synthesis of macrocycles via
carbonyl ylides. As a part of our ongoing research8 on car-
bonyl ylides and supramolecular systems,9 we herein re-
port the reactions of bis-diazo ketones with
dicarbaldehyde and divinyl compounds in the presence of
rhodium(II) acetate dimer as the catalyst to synthesize
conformationally restricted symmetric macrodiolides in a
tandem manner.
HO
OH
O
( )n
toluene, reflux
O
O
O
1
O
O
( )n
O
O
O
O
O
O
O
2a–d
MsN3 Et3N, CH2Cl2
N2
N2
O
O
( )n
O
O
O
O
O
3a–d n = 2–4
Scheme 1
Table 1 Synthesis of Bis-diazocarbonyl Compounds 3a–d
Entry
n
Linked diesters
Bis-diazocarbonyl compounds
2
Yielda (%) 3 Yielda (%)
1
2
3
4
2
3
4
8
2a
2b
2c
2d
41
51
39
38
3a
3b
3c
3d
96
88
89
92
a Isolated yields.
With an aim to develop new macrocyclic compounds via
carbonyl ylide mediated 1,3-dipolar cycloaddition reac-
Initially, it was planned to study the rhodium(II) acetate
dimer catalyzed reaction of bis-diazocarbonyl compounds
3 in the presence of excess alkene or alkyne as a dipolaro-
phile. Thus, for the reaction of 3a, 2.5 equivalents of di-
methyl acetylenedicarboxylate (DMAD) and 1 mol% of
SYNTHESIS 2013, 45, 2034–2042
Advanced online publication: 29.05.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338801; Art ID: SS-2013-T0042-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Conformationally Restricted Macrodiolides
2035
rhodium(II) acetate dimer in dry benzene was refluxed to (6a) in the presence of rhodium(II) acetate dimer was re-
afford the bis-cycloadduct 4a in 72% yield (Scheme 2).
fluxed in benzene to furnish the corresponding bis-cyclo-
adduct 7a in 76% yield. The 1H NMR spectrum of product
7a exhibited a characteristic signal at δ = 4.95 and 4.97 as
two separate singlets for the H* protons, which clearly in-
dicates the presence of diastereomers in the ratio of 51:49
(Scheme 3, Table 3). Similar reaction of bis-diazocarbon-
yl compounds 3b,c with substituted benzaldehydes 6b–e
afforded bis-cycloadducts 7b–g as mixtures of diastereo-
mers that were inseparable by column chromatography.
Similarly, diazocarbonyl compounds 3b,c were treated
with dimethyl acetylenedicarboxylate to furnish the corre-
sponding bis-cycloadducts 4b,c in moderate yields
(Scheme 2, Table 2). Treatment of 3a with 2.5 equivalents
of N-phenylmaleimide (NPM) in the presence of rhodi-
um(II) acetate catalyst for 60 minutes in benzene under re-
flux conditions furnished the corresponding bis-
cycloadduct 5a in 86% yield as a mixture of diastereomers
(Scheme 2). The 1H NMR spectrum of the crude reaction
mixture of compound 5a exhibited four characteristic sig-
nals as a doublet for each C–H* proton. Similarly, the rho-
dium(II) acetate catalyzed reaction of bis-diazocarbonyl
compounds 3b and 3c with N-phenylmaleimide furnished
bis-cycloadducts 5b and 5c as white solids in excellent
yield, respectively. Based on the NMR of crude reaction
mixtures, we observe that products 4 and 5 exist as a mix-
ture of meso and dl compounds that was inseparable by
column chromatography.
1
Although the H NMR did not exhibit a mixture of iso-
mers based on H* protons, 13C NMR indicated a mixture
isomers for the crude reaction mixture of 7g.
O
O
O
H*
H
O
O
Rh2(OAc)4
(1 mol%)
O
( )n
R
R
+
3a–c
benzene
reflux
O
O
R
O
H*
O
H*
6a–e
(2.5 equiv)
O
CO2Me
n = 2–4
O
O
Ph
N
O
CO2Me
O
O
H*
H*
O
O
O
NPM
DMAD
7a–g
O
O
( )n
Rh2(OAc)4
Rh2(OAc)4
3a–c
( )n
Scheme 3
benzene
reflux
benzene
reflux
O
O
O
O
O
Table 3 Synthesis of Bis-cycloadducts 7
O
O
CO2Me
CO2Me
O
Ph
N
O
n = 2–4
Entry
n
Substrate
R
Product Yielda (%) drb
H*
O
1
2
3
4
5
6
7
2
4
3
4
4
4
3
6a
6a
6b
6b
6c
6d
6e
H
7a
7b
7c
7d
7e
7f
76
80
85
88
84
79
68
51:49
51:49
50:50
5a–c
4a–c
H
Scheme 2
Table 2 Synthesis of Bis-cycloadducts 4,5
3-OMe
3-OMe
3-F
c
–
Entry
n
Product
Yielda (%) drb
c
–
c
c
1
2
3
4
5
6
2
3
4
2
3
4
4a
4b
4c
5a
5b
5c
72
62
65
86
94
95
–
–
–
3-NO2
2-OH
–
c
c
c
7g
–
a Isolated yields.
b Diastereomeric ratio based on NMR spectra of crude reaction mix-
50:50
55:45
53:47
ture.
c Diastereomeric ratio could not be determined.
After the successful intermolecular bis-cycloaddition re-
action of carbonyl ylides, generated from compounds 3,
with π-bonds of C=O and C=C functional groups, we
were further interested in elaborating the scope and syn-
thetic utility of the tandem cyclization–cycloaddition re-
action toward the synthesis of conformationally restricted
macrocycles.
a Isolated yields.
b Diastereomeric ratio based on NMR spectra of crude reaction mix-
ture.
c Diastereomeric ratio could not be determined.
Optimistic from the above results, we extended the above
bis-carbonyl ylide reactions with an excess amount of ar-
omatic aldehydes to furnish the substituted dioxolane8d,13
ring systems. For this purpose, a mixture of bis-diazocar-
bonyl compound 3a and 2.5 equivalents of benzaldehyde
For this purpose, Wittig reaction of dicarbaldehydes 8,
prepared by O-alkylation of salicylaldehyde with dialkyl
halides using potassium carbonate as base in dry N,N-di-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2034–2042

2036
S. Muthusamy et al.
PAPER
methylformamide, was carried out to afford the corre- 1,3-dibromopropane. The 1H and 13C NMR spectra of the
sponding divinyl compound 9 in good yield (Scheme 4).
crude reaction mixture of 10c did not reveal a mixture of
isomers. Further, products 10a–c were tested using ana-
lytical HPLC (C18 column) and the results unfortunately
did not show the presence of isomers.
O
O
Ph3PMeBr
O
O
O
O
( )m
( )m
n-BuLi,THF
8a m = 3
8b m = 6
9a m = 3
9b m = 6
Scheme 4 Synthesis of divinyl compounds 9
Next, we planned to investigate the reaction of bis-diazo-
carbonyl compounds 3 with dicarbaldehyde derivatives 8.
A mixture of bis-diazocarbonyl compound 3c with dicarb-
aldehyde 8a in benzene was refluxed in the presence of
rhodium(II) acetate dimer to furnish the conformationally
restricted symmetric macrodiolide 10a (Scheme 5) incor-
porating the dioxa-bridged units in 53% yield as a single
product based on the NMR spectrum of crude reaction
mixture. The FT-IR spectrum of compound 10a exhibited
strong bands at 1778 and 1752 cm–1. The presence of a
singlet at δ = 5.53 for H* proton and a singlet at δ = 1.67
corresponding to the bridgehead methyl group was re-
Figure 1 ORTEP diagram for one of the isomers of 10a; atom num-
bers are removed for better clarity
Based on these studies, the products 10a–c might be a
mixture of meso and dl compounds and on crystallization
of 10a might have produced a single isomer.
1
corded by H NMR. An oxygen attached carbon (CHa)
signal appeared at δ = 71.4 in 13C NMR. DEPT spectral
analyses of product 10a showed peaks for three CH3 car-
bons, four CH2 carbons, five CH carbons, and seven qua-
ternary carbons including two carbonyl groups, which
clearly confirmed the proposed structure as a bis-cycload-
duct having the macrocyclic ring system.
After obtaining various macrodiolides 10 incorporating
dioxa-bridged bicyclic systems, we were further interest-
ed in illustrating the scope and synthetic utility of the tan-
dem cyclization–cycloaddition sequence with the π-bond
of a C=C group. Towards this, a mixture of bis-diazocar-
bonyl compound 3b and divinyl compound 9a in benzene
was refluxed in the presence of rhodium(II) acetate dimer
as catalyst to furnish the conformationally restricted sym-
metric macrodiolide 11a in 58% yield (Scheme 5). The 1H
NMR spectrum of product 11a exhibited a characteristic
doublet of doublet at δ = 1.70, 2.63, and 3.96. 13C NMR
and DEPT-135 spectral analyses of product 11a showed
peaks for three CH3 carbons, five CH2 carbons, five CH
carbons, and seven quaternary carbons including two car-
bonyl groups. The product assignment was further sup-
ported by using COSY and HSQC experiments. Similar
reaction of bis-diazocarbonyl compounds 3a,d and divi-
nyl derivatives 9a,b afforded macrodiolides 11b,c in
moderate yields, respectively. In line with products 10,
the compounds 11 might also be a mixture of isomers.
( )n
O
O
O
O
O
O
Rh2(OAc)4
(1 mol%)
Rh2(OAc)4
(1 mol%)
O
O
3a–c
+
8
3a, b, d
+
9a, b
H*
*H
X
X
benzene
reflux
benzene
reflux
O
O
( )m
with X = O
with X = CH2
10a n = 4; m = 3; 53%
10b n = 2; m = 3; 56%
10c n = 3; m = 3; 50%
11a n = 3; m = 3; 58%
11b n = 2; m = 3; 55%
11c n = 8; m = 6; 60%
Scheme 5 Synthesis of macrodiolides 10 and 11
In order to characterize the regio- and stereochemical as-
signments of the products precisely, we studied the prod-
uct by single-crystal X-ray analysis. Compound 10a was
recrystallized in chloroform–hexane to provide colorless
crystals and these were subjected to low temperature X-
ray crystallographic analysis.14 The X-ray structure of
compound 10a (Figure 1) exhibits two asymmetric units
present in a unit cell. No other notable byproducts were
observed in the above reaction. Similar reaction of bis-di-
azocarbonyl compounds 3a,b with dicarbaldehyde deriv-
ative 8a afforded the corresponding macrodiolides 10b,c.
From the NMR and X-ray studies one might think that the
products 10 might be formed as single stereoisomers. To
understand the presence of stereoselectivity issues in 10,
product 10c was synthesized via dialkylation of 7g using
The above results show that the carbonyl ylide dipoles in-
volved in the mechanism while furnishing symmetric
macrodiolides 10 and 11. This process involves rapid cy-
clization of the transient rhodium carbenoid 12 onto the
neighboring ring carbonyl group to give intramolecular
five-membered-ring bis-carbonyl ylide 13. Subsequent
intermolecular 1,3-dipolar cycloaddition of ylide 13 with
the π-bond of 8/9 affording mono-cycloadduct 14 and
their successive cyclization–cycloaddition afforded sym-
metric macrodiolide (Scheme 6) in a tandem manner. This
protocol demonstrates the tandem intermolecular 1,3-di-
polar cycloaddition of bis-diazocarbonyl compounds with
dicarbaldehyde or divinyl compounds affording macrocy-
cles 10 or 11.
Synthesis 2013, 45, 2034–2042
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Conformationally Restricted Macrodiolides
2037
1
mined using 400 MHz H NMR spectrum of the corresponding
crude mixture.
In conclusion, we have demonstrated that the rhodium(II)
acetate catalyzed 1,3-dipolar cycloaddition reaction of
bis-five-membered-ring carbonyl ylides across π-bonds of
vinyl and carbaldehyde functionalities provides novel
conformationally restricted symmetric macrodiolides in-
corporating aryl, oxa/dioxa-bridged units. This tandem in-
tramolecular cyclization–intermolecular cycloaddition
sequence is particularly attractive as it forms carbon–car-
bon and carbon–oxygen bonds concomitantly in a single
step under mild experimental conditions. These confor-
mationally restricted macrodiolides were assembled effi-
ciently from simple starting materials without using
dilution methods.
Methyl 4,4-Dimethyl-3,5-dioxohexanoate (1)
A soln of i-PrMgBr (49.5 mmol) in anhyd THF (50 mL) was added
dropwise to a soln of freshly prepared monomethyl malonate (3.2 g,
27.1 mmol) in anhyd CH2Cl2 (10 mL) until propane was evolved.
To this mixture was added a freshly prepared soln of 2,2-dimethyl-
3-oxobutyryl chloride (2.95 g, 19.9 mmol) in anhyd CH2Cl2 (10
mL) dropwise with efficient stirring over 1 h. Subsequent workup
as described in the literature11 and purification using column chro-
matography (hexane–EtOAc, 60:40) afforded 1 (1.57 g, 42%) as a
colorless thin oil.
IR (neat): 2989, 2131, 1924, 1701, 1623, 1327 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.38 (s, 6 H, CH3), 2.17 (s, 3 H,
CH3), 3.52 (s, 2 H, CH2), 3.72 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3): δ = 20.8 (CH3), 25.2 (CH3), 44.7
(CH2), 52.1 (OCH3), 63.2 (Cq), 167.1 (CO2Me), 202.1 (C=O), 206.9
(C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C9H14O4: 209.0790; found:
209.0786.
O
O
O
O
Rh2L4
O
O
O
( )n
O
( )n
Rh2L4
– N2
Ethane-1,2-diyl Bis(4,4-dimethyl-3,5-dioxohexanoate) (2a);
Typical Procedure
3
O
O
To a round-bottomed flask attached to a reflux condenser contain-
ing a soln of 1 (500 mg, 2.7 mmol) in toluene (10 mL) was added a
soln of ethane-1,2-diol (80 mg, 1.3 mmol) in toluene (2 mL) drop-
wise and the mixture was refluxed for 24 h (TLC monitoring). The
reaction was quenched with H2O (10 mL) and then it was extracted
with CH2Cl2 (2 × 10 mL). The combined organic layer was washed
with H2O (15 mL), dried over anhyd Na2SO4, concentrated and
purified by column chromatography (silica gel, 100–200 mesh,
hexane–EtOAc, 80:20) to afford 2a (410 mg, 41%) as a colorless
oil.
O
O
O
O
O
Rh2L4
O
13
12
8 or 9
X
IR (neat): 2941, 2867, 1720, 1624, 1576, 1472, 1264, 1161, 733
cm–1.
O
O
X
O
O
1H NMR (400 MHz, CDCl3): δ = 1.32 (s, 12 H, CH3), 2.10 (s, 6 H,
CH3), 3.46 (s, 4 H, CH2), 4.27 (s, 4 H, OCH2).
13C NMR (100 MHz, CDCl3): δ = 21.1 (CH3), 26.2 (CH3), 45.0
(CH2), 53.7 (Cq), 62.7 (OCH2), 166.7 (COO), 202.1 (C=O), 207.2
(C=O).
O
O
O
O
( )n
O
O
O
( )m
10/11
( )n
( )m
O
O
O
O
O
O
O
HRMS (ESI): m/z [M + Na]+ calcd for C18H26O8: 393.1525; found:
393.1522.
O
O
X
X
Propane-1,3-diyl Bis(4,4-dimethyl-3,5-dioxohexanoate) (2b)
Following the typical procedure for 2a from 1 gave 2b as a colorless
oil; yield: 526 mg (51%).
IR (neat): 2987, 1746, 1724, 1702, 1265, 1042, 743 cm–1.
15
X = O or CH2
14
Scheme 6 Mechanistic pathway
1H NMR (200 MHz, CDCl3): δ = 1.29 (s, 12 H, CH3), 1.94 (q, J =
6.2 Hz, 2 H, CH2), 2.08 (s, 6 H, CH3), 3.42 (s, 4 H, CH2), 4.17 (q,
J = 6.4 Hz, 4 H, OCH2).
13C NMR (50.3 MHz, CDCl3): δ = 20.9 (CH3), 25.9 (CH3), 27.5
(CH2), 44.9 (OCH2), 61.7 (OCH2), 62.5 (Cq), 166.7 (COO), 202.1
(C=O), 206.9 (C=O).
Melting points were determined on a capillary melting point appa-
ratus and are uncorrected. IR spectra were recorded using ATR
technique on a Bruker Alpha FT-IR spectrophotometer. H NMR
1
spectra were recorded on a Bruker DPX 200 and Bruker Avance
400 using CDCl3 relative to TMS as an internal standard. 13C NMR
spectra were recorded at 100 MHz in CDCl3 relative to the center of
the triplet δ = 77.7 for CDCl3. Carbon types were determined using
DEPT experiments. HRMS analyses were performed using electro-
spray ionization technique on a Waters QTof-micromass spectrom-
eter. All solvents were purified by distillation following standard
procedures. TLC was performed on silica gel or alumina plates and
components visualized by observation under I2/UV light at 254 nm.
Column chromatography was performed on silica gel (100–200,
230–400 mesh). Analytical HPLC was performed on an Agilent
1200 infinity series. All the reactions were conducted in oven-dried
glassware under a positive pressure of argon with magnetic stirring.
Reagents were added via syringes through septa. The dr was deter-
HRMS (ESI): m/z [M + Na]+ calcd for C19H28O8: 407.1682; found:
407.1689.
Butane-1,4-diyl Bis(4,4-dimethyl-3,5-dioxohexanoate) (2c)
Following the typical procedure for 2a from 1 gave 2c as a colorless
oil; yield: 100 mg (39%).
IR (neat): 2984, 1744, 1715, 1702, 1618, 1266, 948, 610 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.25 (s, 12 H, CH3), 1.60 (t, J =
4.6 Hz, 4 H, CH2), 2.04 (s, 6 H, CH3), 3.38 (s, 4 H, CH2), 4.03 (t, J =
4.0 Hz, 4 H, OCH2).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2034–2042

2038
S. Muthusamy et al.
PAPER
13C NMR (50.3 MHz, CDCl3): δ = 20.8 (CH3), 24.8 (CH2), 25.8
(CH3), 44.9 (CH2), 62.4 (Cq), 64.8 (OCH2), 166.7 (COO), 202.2
(C=O), 206.9 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C20H30O8: 421.1838; found:
421.1841.
Octane-1,8-diyl Bis(2-diazo-4,4-dimethyl-3,5-dioxohexanoate)
(3d)
Following the typical procedure for 3a from 2d gave 3d as a yellow-
ish green solid; yield: 410 mg (92%); mp 65–67 °C.
IR (neat): 2932, 2858, 2137, 1701, 1653, 1469, 1314, 1122, 1011,
968, 747 cm–1.
Octane-1,8-diyl Bis(4,4-dimethyl-3,5-dioxohexanoate) (2d)
Following the typical procedure for 2a from 1 gave 2d as a colorless
oil; yield: 466 mg (38%).
IR (neat): 2984, 1899, 1744, 1715, 1702, 1618, 1266, 948 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.24 (s, 8 H, CH2), 1.31 (s, 12 H,
CH3), 1.53–1.59 (m, 4 H, CH2), 2.09 (s, 6 H, CH3), 3.41 (s, 4 H,
CH2), 4.04 (t, J = 6.8 Hz, 4 H, OCH2).
13C NMR (100 MHz, CDCl3): δ = 20.1 (CH3), 21.1 (CH2), 24.6
(CH2), 25.2 (CH3), 27.4 (CH2), 28.0 (CH2), 44.2 (CH2), 61.8 (Cq),
64.5 (OCH2), 166.0 (COO), 201.4 (C=O), 206.1 (C=O).
1H NMR (400 MHz, CDCl3): δ = 1.25 (s, 8 H, CH2), 1.34 (s, 12 H,
CH3), 1.56–1.59 (m, 4 H, CH2), 2.19 (s, 6 H, CH3), 4.08 (t, J = 6.8
Hz, 4 H, OCH2).
13C NMR (100 MHz, CDCl3): δ = 22.5 (CH3), 25.4 (CH3), 25.6
(CH2), 28.5 (CH2), 29.0 (CH2), 59.9 (Cq), 65.4 (OCH2), 75.6 (Cq),
161.2 (COO), 192.3 (C=O), 208.7 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C24H34N4O8: 529.2274;
found: 529.2270.
Ethane-1,2-diyl Bis[5,6-Bis(methoxycarbonyl)-3,3,4-trimethyl-
2-oxo-7-oxabicyclo[2.2.1]hept-5-ene-1-carboxylate] (4a); Typi-
cal Procedure
HRMS (ESI):m/z [M + Na]+ calcd for C24H38O8: 477.2464; found:
477.2461.
To a soln containing DMAD (84 mg, 0.6 mmol) and Rh2(OAc)4 (1.0
mol%) in anhyd benzene (5 mL) was added dropwise a soln of bis-
diazo 3a (100 mg, 0.2 mmol) in anhyd benzene (5 mL). The mixture
was refluxed for 1 h and evaporated to obtain the crude mixture,
which was purified by column chromatography (silica gel, 100–200
or 200–400 mesh, hexane–EtOAc, 60:40) to furnish the desired bis-
cycloadduct 4a (150 mg, 72%, mixture of two inseparable diaste-
reomers) as a viscous oil.
Ethane-1,2-diyl Bis(2-diazo-4,4-dimethyl-3,5-dioxohexanoate)
(3a); Typical Procedure
To a soln containing 2a (400 mg, 1.0 mmol) in anhyd CH2Cl2 (5
mL) at 0 °C under argon atmosphere was added freshly distilled
Et3N (273 mg, 2.7 mmol), then, methanesulfonyl azide (392 mg,
3.24 mmol) was added dropwise. After completion (TLC monitor-
ing), the mixture was washed with H2O (2 × 10 mL). The solvent
was removed under reduced pressure at r.t. and the residue subject-
ed to column chromatography (alumina, hexane–EtOAc, 70:30) to
afford bis-diazo ketone 3a (438 mg, 96%) as a greenish viscous oil.
IR (neat): 2954, 1749, 1739, 1716, 1657, 1441, 1266, 1202, 739
cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.02 (s, 6 H, CH3), 1.17 (s, 6 H,
CH3), 1.65 (s, 6 H, CH3), 3.71 (s, 6 H, OCH3), 3.77 (s, 6 H, OCH3),
4.43 (s, 4 H, OCH2).
IR (neat): 2941, 2124, 1682, 1588, 1526, 1365, 1159, 1086, 746
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.32 (s, 12 H, CH3), 2.17 (s, 6 H,
CH3), 4.33 (s, 4 H, OCH2).
13C NMR (100 MHz, CDCl3): δ = 22.3 (CH3), 25.3 (CH3), 59.8 (Cq),
62.6 (OCH2), 75.5 (Cq), 160.8 (Cq), 191.8 (C=O), 208.5 (C=O).
13C NMR (50.3 MHz, CDCl3): δ = 13.5 (CH3), 20.8 (CH3), 22.4
(CH3), 43.0 (Cq), 52.5 (OCH3), 52.8 (OCH3), 63.1 (OCH2), 91.7
(Cq), 144.1 (Cq), 161.3 (COO), 162.0 (COO), 203.1 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C30H34O16: 673.1745; found:
673.1738.
HRMS (ESI): m/z [M + Na]+ calcd for C18H22N4O8: 445.1335;
found: 445.1332.
Propane-1,3-diyl Bis[5,6-bis(methoxycarbonyl)-3,3,4-trimeth-
yl-2-oxo-7-oxabicyclo[2.2.1]hept-5-ene-1-carboxylate] (4b)
Following the typical procedure for 4a from 3b gave 4b as a viscous
oil; yield: 94 mg (62%).
Propane-1,3-diylBis(2-diazo-4,4-dimethyl-3,5-dioxohexanoate)
(3b)
Following the typical procedure for 3a from 2b gave 3b as a yellow-
ish green solid; yield: 400 mg (88%); mp 56–58 °C.
IR (neat): 2979, 1715, 1655 1440, 1204, 1026 cm–1.
IR (neat): 2931, 2146, 1715, 1653, 1312, 1027, 838 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.28 (s, 12 H, CH3), 1.93 (m, 2 H),
2.13 (s, 6 H, CH3), 4.12 (t, J = 6.0 Hz, 4 H, OCH2).
13C NMR (50.3 MHz, CDCl3): δ = 22.1 (CH3), 25.0 (CH3), 27.8
(CH2), 59.6 (Cq), 61.3 (OCH2), 75.7 (Cq), 160.7 (COO), 191.7
(C=O), 208.3 (C=O).
1H NMR (200 MHz, CDCl3): δ = 1.03 (s, 6 H, CH3), 1.17 (s, 6 H,
CH3), 1.66 (s, 6 H, CH3), 1.99–2.04 (m, 2 H, CH2), 3.72 (s, 6 H,
OCH3), 3.78 (s, 6 H, OCH3), 4.29 (m, 4 H, OCH2).
13C NMR (50.3 MHz, CDCl3): δ = 13.7 (CH3), 20.9 (CH3), 22.6
(CH3), 27.8 (CH2), 43.2 (Cq), 52.6 (OCH3), 52.9 (OCH3), 62.6
(OCH2), 91.7 (Cq), 91.8 (Cq), 142.6 (Cq), 144.1 (Cq), 162.1 (COO),
162.4 (COO), 203.7 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C19H24N4O8: 459.1492
found: 459.1490.
HRMS (ESI): m/z [M + Na]+ calcd for C31H36O16: 687.1901; found:
687.1897.
Butane-1,4-diyl Bis(2-diazo-4,4-dimethyl-3,5-dioxohexanoate)
(3c)
Following the typical procedure for 3a from 2c gave 3c as a yellow-
ish green solid; yield: 402 mg (89%); mp 59–61 °C.
Butane-1,4-diyl Bis[5,6-bis(methoxycarbonyl)-3,3,4-trimethyl-
2-oxo-7-oxabicyclo[2.2.1]hept-5-ene-1-carboxylate] (4c)
Following the typical procedure for 4a from 3c gave 4c as a viscous
oil; yield: 98 mg (65%).
IR (neat): 2977, 2138, 1707, 1644, 1392, 1331, 1309, 1162, 1008,
968 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.40 (s, 12 H, CH3), 1.73 (s, 4 H,
IR (neat): 2957, 1743, 1712, 1701, 1658, 1441, 1201, 737 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.02 (s, 6 H, CH3), 1.17 (s, 6 H,
CH3), 1.66 (s, 6 H, CH3), 1.71 (s, 4 H, CH2), 3.72 (s, 6 H, OCH3),
3.77 (s, 6 H, OCH3), 4.25 (br s, 4 H, OCH2).
13C NMR (50.3 MHz, CDCl3): δ = 13.7 (CH3), 20.9 (CH3), 22.5
(CH3), 24.7 (CH2), 43.2 (Cq), 52.5 (OCH3), 52.8 (OCH3), 65.7
(OCH2), 91.1 (Cq), 91.7 (Cq), 142.8 (Cq), 144.0 (Cq), 161.4 (COO),
162.3 (COO), 162.5 (COO), 203.7 (C=O).
CH2), 2.26 (s, 6 H, CH3), 4.20 (s, 4 H, OCH2).
13C NMR (50.3 MHz, CDCl3): δ = 22.2 (CH3), 24.9 (CH2), 25.1
(CH3), 59.7 (Cq), 64.3 (OCH2), 75.5 (Cq), 160.9 (COO), 191.9
(C=O), 208.4 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C20H26N4O8: 473.1648;
found: 473.1644.
Synthesis 2013, 45, 2034–2042
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Conformationally Restricted Macrodiolides
2039
HRMS (ESI): m/z [M + Na]+ calcd for C32H38O16: 701.2058; found:
701.2054.
Ethane-1,2-diyl Bis(1,6,6-trimethyl-5-oxo-3-phenyl-2,7-dioxa-
bicyclo[2.2.1]heptane-4-carboxylate) (7a); Typical Procedure
To a soln containing benzaldehyde 6a (63 mg, 0.6 mmol) and
Rh2(OAc)4 (1.0 mol%) in anhyd benzene (5 mL) was added drop-
wise a soln of bis-diazo compound 3a (100 mg, 0.2 mmol) in anhyd
benzene (4 mL). The mixture was refluxed for 1 h and the solvent
was removed under reduced pressure. Further chromatographic pu-
rification (hexane–EtOAc, 60:40) afforded 7a (104 mg, 76%) as a
white solid; mp 195–197 °C.
Ethane-1,2-diyl Bis(6,6,7-trimethyl-1,3,5-trioxo-2-phenylocta-
hydro-1H-4,7-epoxyisoindole-4-carboxylate) (5a)
Following the typical procedure for 4a from 3a gave 5a as a white
solid; yield: 145 mg (86%); mp 216–218 °C.
IR (neat): 2985, 1756, 1718, 1598, 1456, 1391 cm–1.
1H NMR (400 MHz, CDCl3): δ (mixture of two diastereomers) =
1.04 (s, 3 H, CH3), 1.06 (s, 3 H, CH3), 1.10 (s, 3 H, CH3), 1.13 (s, 3
H, CH3), 1.52 (s, 6 H, CH3), 3.26 (d, J = 7.2 Hz, 1 H, CH), 3.29 (d,
J = 7.6 Hz, 1 H, CH), 3.55 (d, J = 7.6 Hz, 1 H, CH), 3.62 (d, J = 7.6
Hz, 1 H, CH), 4.43–4.73 (m, 4 H, OCH2), 7.15–7.19 (m, 4 H, HAr),
7.31–7.36 (m, 6 H, HAr).
IR (neat): 2930, 1786, 1743, 1659, 1400, 1150, 893 cm–1.
1H NMR (200 MHz, CDCl3): δ (mixture of two diastereomers) =
1.21 (s, 6 H, CH3), 1.26 (s, 6 H, CH3), 1.79 (s, 6 H, CH3), 3.76–3.94
(m, 4 H, OCH2), 4.95 (s, 1 H, OCH), 4.97 (s, 1 H, OCH), 7.27–7.37
(m, 10 H, HAr).
13C NMR (100 MHz, CDCl3): δ (mixture of two diastereomers) =
13.38 (CH3), 13.40 (CH3), 19.2 (CH3), 20.76 (CH3), 20.84 (CH3),
48.1 (CH), 48.2 (CH), 49.2 (CH), 49.3 (CH), 51.15 (Cq), 51.20 (Cq),
63.25 (OCH2), 63.33 (OCH2), 88.79 (Cq), 88.85 (Cq), 90.2 (Cq), 90.3
(Cq), 126.4 (CH), 129.05 (CH), 129.08 (Cq), 129.2 (CH), 134.2 (Cq),
162.4 (COO), 162.5 (COO), 171.7 (CON), 171.8 (CON), 173.50
(CON), 173.53 (CON), 206.7 (C=O).
13C NMR (50.3 MHz, CDCl3): δ (mixture of two diastereomers) =
14.7 (CH3), 19.3 (CH3), 21.0 (CH3), 53.1 (Cq), 62.3 (OCH2), 79.3
(OCH), 92.0 (Cq), 113.5 (Cq), 127.6 (=CH), 128.3 (=CH), 129.2
(=CH), 135.8 (Cq), 161.9 (COO), 206.2 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C32H34O10:601.2050; found:
601.2047.
HRMS (ESI): m/z [M + Na]+ calcd for C38H36N2O12: 735.2166;
found: 735.2162.
Butane-1,4-diyl Bis(1,6,6-trimethyl-5-oxo-3-phenyl-2,7-dioxa-
bicyclo[2.2.1]heptane-4-carboxylate) (7b)
Following the typical procedure for 7a from 3c gave 7b as a yellow
solid; yield: 108 mg (80%); mp 198–200 °C.
Propane-1,3-diyl Bis(6,6,7-trimethyl-1,3,5-trioxo-2-phenylocta-
hydro-1H-4,7-epoxyisoindole-4-carboxylate) (5b)
Following the typical procedure for 4a from 3b gave 5b as a white
solid; yield: 156 mg (94%); mp 205–207 °C.
IR (neat): 2972, 1782, 1751, 1730, 1451, 1404, 1342, 1128, 1061,
699 cm–1.
1H NMR (400 MHz, CDCl3): δ (mixture of two diastereomers) =
1.10–1.14 (m, 4 H, CH2), 1.13 (s, 6 H, CH3), 1.17 (s, 6 H, CH3), 1.70
(s, 6 H, CH3), 3.68–3.73 (m, 2 H, OCH2), 3.86–3.92 (m, 2 H,
OCH2), 4.85 (s, 1 H, OCH), 4.86 (s, 1 H, OCH), 7.22–7.25 (m, 6 H,
HAr), 7.29–7.31 (m, 4 H, HAr).
13C NMR (100 MHz, CDCl3): δ (mixture of two diastereomers) =
14.8 (CH3), 19.3 (CH3), 21.0 (CH3), 24.6 (CH2), 53.1 (Cq), 64.9
(OCH2), 79.3 (OCH), 92.3 (Cq), 113.4 (Cq), 127.7 (=CH), 128.3
(=CH), 129.2 (=CH), 136.01 (Cq), 136.03 (Cq), 162.2 (COO), 206.7
(C=O).
IR (neat): 2360, 1773, 1742, 1718, 1387, 1138 cm–1.
1H NMR (400 MHz, CDCl3): δ (mixture of two diastereomers) =
1.06 (s, 3 H, CH3), 1.08 (s, 3 H, CH3), 1.10 (s, 3 H, CH3), 1.15 (s, 3
H, CH3), 1.53 (s, 3 H, CH3), 1.54 (s, 3 H, CH3), 2.16–2.19 (m, 2 H,
CH2), 3.30 (d, J = 5.6 Hz, 1 H, CH), 3.32 (d, J = 5.6 Hz, 1 H, CH),
3.51 (d, J = 7.2 Hz, 1 H, CH), 3.56 (d, J = 7.2 Hz, 1 H, CH), 4.47–
4.52 (m, 4 H, OCH2), 7.16–7.18 (m, 4 H, HAr), 7.31–7.41 (m, 6 H,
HAr).
13C NMR (100 MHz, CDCl3): δ (mixture of two diastereomers) =
13.1 (CH3), 18.9 (CH3), 20.5 (CH3), 27.4 (CH2), 48.1 (CH), 49.1
(CH), 50.9 (Cq), 62.4 (OCH2), 88.5 (Cq), 89.8 (Cq), 125.9 (CH),
128.8 (CH), 129.0 (CH), 131.3 (Cq), 162.4 (COO), 171.7 (CON),
173.3 (CON), 206.9 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C34H38O10: 629.2363; found:
629.2354.
Propane-1,3-diyl Bis[3-(3-methoxyphenyl)-1,6,6-trimethyl-5-
oxo-2,7-dioxabicyclo[2.2.1]heptane-4-carboxylate] (7c)
Following the typical procedure for 7a from 3b gave 7c as a white
solid; yield: 127 mg (85%); mp 226–228 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C39H38N2O12: 749.2322;
found: 749.2319.
Butane-1,4-diyl Bis(6,6,7-trimethyl-1,3,5-trioxo-2-phenylocta-
hydro-1H-4,7-epoxyisoindole-4-carboxylate) (5c)
Following the typical procedure for 4a from 3c gave 5c as a white
solid; yield: 156 mg (95%); mp 230–232 °C.
IR (neat): 2924, 1749, 1604, 1459, 1336, 1154, 1053, 864, 693 cm–1.
1H NMR (200 MHz, CDCl3): δ (mixture of two diastereomers) =
1.19 (s, 6 H, CH3), 1.22 (s, 6 H, CH3), 1.41–1.47 (m, 2 H, CH2), 1.76
(s, 6 H, CH3), 3.77 (s, 6 H, OCH3), 3.86–3.99 (m, 4 H, OCH2), 4.88
(s, 1 H, OCH), 4.90 (s, 1 H, OCH), 6.82–6.93 (m, 6 H, HAr), 7.16–
7.29 (m, 2 H, HAr).
13C NMR (50.3 MHz, CDCl3): δ (mixture of two diastereomers) =
14.6 (CH3), 19.2 (CH3), 20.8 (CH3), 27.5 (CH2), 52.9 (Cq), 55.1
(OCH3), 61.7 (OCH2), 79.0 (OCH), 92.1 (Cq), 113.1 (Cq), 113.2
(=CH), 114.6 (=CH), 119.9 (=CH), 129.2 (=CH), 137.4 (Cq), 159.4
(Cq), 161.9 (COO), 206.4 (C=O).
IR (neat): 2977, 1774, 1745, 1719, 1500, 1385 cm–1.
1H NMR (400 MHz, CDCl3): δ (mixture of two diastereomers) =
1.06 (s, 3 H, CH3), 1.08 (s, 3 H, CH3), 1.15 (s, 6 H, CH3), 1.54 (s, 3
H, CH3), 1.55 (s, 3 H, CH3), 1.90–1.92 (s, 4 H, CH2), 3.28 (d, J =
7.2 Hz, 1 H, CH), 3.32 (d, J = 7.2 Hz, 1 H, CH), 3.53 (d, J = 7.2 Hz,
1 H, CH), 3.63 (d, J = 7.2 Hz, 1 H, CH), 4.37–4.38 (m, 4 H, OCH2),
7.16–7.18 (m, 4 H, HAr), 7.31–7.41 (m, 6 H, HAr).
13C NMR (100 MHz, CDCl3): δ (mixture of two diastereomers) =
13.4 (CH3), 19.2 (CH3), 19.3 (CH3), 20.9 (CH3), 25.08 (CH2), 25.12
(CH2), 48.26 (CH), 48.29 (CH), 49.1 (CH), 51.2 (Cq), 66.0 (OCH2),
88.9 (Cq), 89.0 (Cq), 90.0 (Cq), 90.1 (Cq), 126.39 (CH), 126.42 (CH),
129.1 (CH), 129.3 (CH), 131.4 (Cq), 162.7 (COO), 171.8 (CON),
173.5 (CON), 207.3 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C35H40O12: 675.2417; found:
675.2411.
Butane-1,4-diyl Bis[3-(3-methoxyphenyl)-1,6,6-trimethyl-5-
oxo-2,7-dioxabicyclo[2.2.1]heptane-4-carboxylate] (7d)
Following the typical procedure for 7a from 3c gave 7d as a white
solid; yield: 130 mg (88%); mp 233–235 °C.
HRMS (ESI):m/z [M + Na]+ calcd for C40H40N2O12: 763.2479;
found: 763.2477.
IR (neat): 2926, 1753, 1603, 1466, 1401, 1336, 1153, 1058, 857,
781 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2034–2042

2040
S. Muthusamy et al.
PAPER
1H NMR (200 MHz, CDCl3): δ (mixture of two diastereomers) =
1.18 (s, 6 H, CH3), 1.22 (s, 6 H, CH3), 1.37–1.46 (m, 4 H, CH2), 1.76
(s, 6 H, CH3), 3.76 (s, 6 H, OCH3), 3.89–4.17 (m, 4 H, OCH2), 4.90
(s, 2 H, OCH), 6.82–6.96 (m, 6 H, HAr), 7.17–7.25 (m, 2 H, HAr).
(Cq), 113.8 (Cq), 113.9 (Cq), 116.6 (=CH), 117.0 (=CH), 120.7
(=CH), 120.8 (=CH), 129.89 (=CH), 129.93 (=CH), 130.68 (=CH),
130.73 (=CH), 154.0 (Cq), 162.5 (COO), 162.6 (COO), 206.5 (CO),
206.8 (CO).
13C NMR (50.3 MHz, CDCl3): δ (mixture of two diastereomers) =
14.6 (CH3), 19.2 (CH3), 20.8 (CH3), 24.5 (CH2), 52.9 (Cq), 55.1
(OCH3), 64.8 (OCH2), 79.0 (OCH), 92.1 (Cq), 113.2 (=CH), 114.4
(=CH), 119.9 (=CH), 129.2 (=CH), 137.4 (Cq), 159.4 (Cq), 162.0
(COO), 206.5 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C36H42O12: 689.2574; found:
689.2567.
HRMS (ESI): m/z [M + Na]+ calcd for C33H36O12: 647.2104; found:
647.2097.
1,3-Bis(2-vinylphenoxy)propane (9a); Typical Procedure
To a soln of Wittig salt (1.88 g, 5.2 mmol) in anhyd THF (20 mL)
at –10 °C was added a soln of BuLi (15%, 2.5 mL, 5.6 mmol) and
the mixture was stirred for 15 min. Then, a soln of dicarbaldehyde
8a (500 mg, 1.7 mmol) in anhyd THF (10 mL) was added and the
mixture was stirred for 1 h. The mixture was quenched with sat.
NH4Cl (20 mL) and extracted with EtOAc (2 × 20 mL). The com-
bined organic layer was washed with H2O (15 mL), dried over an-
hyd Na2SO4 and concentrated. The residue was purified by column
chromatography (silica gel, 100–200 mesh, hexane–EtOAc, 90:10)
to afford 9a (417 mg, 84%) as a white solid; mp 149–151 °C.
Butane-1,4-diyl Bis[3-(3-fluorophenyl)-1,6,6-trimethyl-5-oxo-
2,7-dioxabicyclo[2.2.1]heptane-4-carboxylate] (7e)
Following the typical procedure for 7a using 3c gave 7e as a yellow
solid; yield: 120 mg (84%); mp 227–229 °C.
IR (neat): 2969, 1787, 1749, 1731, 1606, 1512, 1405, 1343, 1230,
1127, 1062, 892, 840 cm–1.
IR (neat): 3013, 2944, 2875, 1592, 1450, 1233, 1107, 984, 900, 738
cm–1.
1H NMR (400 MHz, CDCl3): δ (mixture of two diastereomers) =
1.13 (s, 6 H, CH3), 1.16 (s, 6 H, CH3), 1.23–1.26 (m, 4 H, CH2), 1.69
(s, 6 H, CH3), 3.73–3.78 (m, 2 H, OCH2), 3.95–4.00 (m, 2 H,
OCH2), 4.86 (s, 2 H, OCH), 6.95 (t, J = 8.4 Hz, 3 H, HAr), 7.08 (t,
J = 8.8 Hz, 1 H, HAr), 7.23 (m, 3 H, HAr), 8.05 (dd, J1 = 8.8 Hz, J2 =
5.6 Hz, 1 H, HAr).
13C NMR (100 MHz, CDCl3): δ (mixture of two diastereomers) =
14.8 (CH3), 19.3 (CH3), 21.0 (CH3), 24.7 (CH2), 53.1 (Cq), 65.0
(OCH2), 78.6 (OCH), 92.2 (Cq), 113.5 (Cq), 115.2 (=CH), 115.4
(=CH), 115.6 (=CH), 115.9 (=CH), 129.5 (=CH), 129.6 (=CH),
162.01 (Cq), 162.03 (Cq), 164.5 (COO), 206.5 (C=O).
1H NMR (400 MHz, CDCl3): δ = 2.22–2.28 (m, 2 H, CH2), 4.12 (t,
J = 6.0 Hz, 4 H, OCH2), 5.16 (dt, J1 = 11.2 Hz, J2 = 1.6 Hz, 2 H,
=CH2), 5.65 (dt, J1 = 11.2 Hz, J2 = 1.6 Hz, 2 H, =CH2), 6.79–6.87
(m, 4 H, HAr), 6.94–7.02 (m, 2 H, HAr), 7.13 (td, J1 = 8.4 Hz, J2 =
1.6 Hz, 2 H, ArCH), 7.39 (dd, J1 = 7.6 Hz, J2 = 1.2 Hz, 2 H, =CH).
13C NMR (100 MHz, CDCl3): δ = 29.5 (CH2), 64.9 (OCH2), 112.0
(=CH), 114.4 (=CH2), 120.8 (=CH), 126.5 (=CH), 126.8 (Cq), 128.9
(=CH), 131.6 (=CH), 155.9 (Cq).
HRMS (ESI): m/z [M + Na]+ calcd for C19H20O2: 303.1361; found:
HRMS (ESI): m/z [M + Na]+ calcd for C34H36F2O10: 665.2174;
303.1359.
found: 665.2166.
1,6-Bis(2-vinylphenoxy)hexane (9b)
Following the typical procedure for 9a from 8b gave 9b as a white
solid; yield: (357 mg, 72%); mp 157–159 °C.
Butane-1,4-diyl Bis[1,6,6-trimethyl-3-(3-nitrophenyl)-5-oxo-
2,7-dioxabicyclo[2.2.1]heptane-4-carboxylate] (7f)
Following the typical procedure for 7a from 3c gave 7f as a yellow
solid; yield: 122 mg (79%); mp 240–242 °C.
IR (neat): 3066, 3010, 2942, 2877, 1594, 1450, 1230, 1109, 9823,
740 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.52 (s, 4 H, CH2), 1.81 (s, 4 H,
CH2), 3.93 (t, J = 6.0 Hz, 4 H, OCH2), 5.15–5.18 (m, 2 H, =CH2),
5.65–5.75 (m, 2 H, =CH2), 6.77–6.86 (m, 4 H, HAr), 6.95–7.03 (m,
2 H, HAr), 7.12–7.18 (m, 2 H, HAr), 7.39–7.41 (m, 2 H, HAr).
13C NMR (100 MHz, CDCl3): δ = 26.0 (CH2), 29.3 (CH2), 68.1
(OCH2), 111.9 (=CH), 114.2 (=CH2), 120.5 (=CH), 126.5 (=CH),
126.8 (Cq), 128.8 (=CH), 131.7 (=CH), 156.3 (Cq).
IR (neat): 2926, 1784, 1754, 1704, 1605, 1534, 1402, 1352, 1262,
1154, 1061, 891, 735 cm–1.
1H NMR (200 MHz, CDCl3): δ (mixture of two diastereomers) =
1.22 (s, 6 H, CH3), 1.26 (s, 6 H, CH3), 1.45 (s, 4 H, CH2), 1.83 (s, 6
H, CH3), 3.84–3.89 (m, 2 H, OCH2), 4.05–4.09 (m, 2 H, OCH2),
5.10 (s, 2 H, OCH), 7.50–7.58 (m, 2 H, HAr), 7.73–7.77 (m, 2 H,
HAr), 8.18–8.26 (m, 4 H, HAr).
13C NMR (50.3 MHz, CDCl3): δ (mixture of two diastereomers) =
14.5 (CH3), 19.0 (CH3), 20.8 (CH3), 24.5 (CH2), 53.1 (Cq), 65.1
(OCH2), 77.8 (OCH), 92.0 (Cq), 114.0 (Cq), 122.5 (=CH), 123.8
(=CH), 129.2 (=CH), 133.5 (=CH), 138.2 (Cq), 148.0 (Cq), 161.7
(COO), 205.3 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C34H36N2O14: 719.2064;
found: 719.2060.
HRMS (ESI): m/z [M + Na]+ calcd for C22H26O2: 345.1830; found:
345.1828.
(4bR,6S,8aS,16aS,19S,20aR)-6,7,7,18,18,19-Hexamethyl-
6,7,11,12,13,14,18,19,27,28-decahydro-4bH-6,8a:16a,19-
diepoxydibenzo[f,t]dipyrano[2,3-h:3′,2′-r][1,5,11,16]tetraoxa-
cyclohenicosine-8,9,16,17(20aH,26H)-tetraone (10a); Typical
Procedure
To a soln of 8a (63 mg, 0.2 mmol) and Rh2(OAc)4 (1.0 mol%) in an-
hyd benzene (5 mL) was added dropwise a soln of bis-diazo com-
pound 3c (100 mg, 0.2 mmol) in anhyd benzene (5 mL). The
mixture was refluxed for 1 h and the solvent was removed under re-
duced pressure. Further chromatographic purification (hexane–
EtOAc, 60:40) afforded 10a (80 mg, 53%) as a white solid; mp 215–
217 °C.
Propane-1,3-diyl Bis(3-(2-hydroxyphenyl)-1,6,6-trimethyl-5-
oxo-2,7-dioxabicyclo[2.2.1]heptane-4-carboxylate) (7g)
Following the typical procedure for 7a from 3b gave 7g as a brown
gel; yield: 98 mg (68%).
IR (neat): 3326, 1786, 1748, 1702, 1608, 1527, 1359, 1260, 1151,
1056, 889, 730 cm–1.
1H NMR (400 MHz, CDCl3): δ (mixture of two diastereomers) =
0.86–0.88 (m, 2 H, CH2), 1.19 (s, 6 H, CH3), 1.24 (s, 6 H, CH3), 1.77
(s, 6 H, CH3), 3.83–3.95 (m, 2 H, OCH2), 4.02–4.03 (m, 1 H,
OCH2), 4.11–4.13 (m, 2 H, OCH2), 5.34 (s, 2 H, OCH), 6.76–6.89
(m, 4 H, HAr), 7.15–7.20 (m, 2 H, HAr), 7.30–7.33 (m, 2 H, HAr).
13C NMR (100 MHz, CDCl3): δ (mixture of two diastereomers) =
14.7 (CH3), 19.4 (CH3), 21.0 (CH3), 52.9 (Cq), 53.0 (Cq), 62.0
(OCH2), 62.2 (OCH2), 75.2 (OCH), 75.4 (OCH), 91.6 (Cq), 91.7
IR (neat): 2931, 1778, 1752, 1683, 1601, 1464, 1399, 1335, 1246,
1147, 1058, 759 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.70–0.74 (m, 4 H, CH2), 1.14 (s,
6 H, CH3), 1.20 (s, 6 H, CH3), 1.67 (s, 6 H, CH3), 2.18–2.20 (m, 2
H, CH2), 3.38–3.44 (m, 2 H, OCH2), 3.90–3.93 (m, 2 H, OCH2),
4.05–4.09 (m, 2 H, OCH2), 4.34–4.40 (m, 2 H, OCH2), 5.53 (s, 2 H,
OCH), 6.86–6.93 (m, 4 H, HAr), 7.22–7.26 (m, 2 H, HAr), 7.51 (dd,
J1 = 8.0 Hz, J2 = 2.0 Hz, 2 H, HAr).
Synthesis 2013, 45, 2034–2042
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Conformationally Restricted Macrodiolides
2041
13C NMR (50.3 MHz, CDCl3): δ = 14.8 (CH3), 19.4 (CH3), 20.9
(CH3), 24.9 (CH2), 29.5 (CH2), 53.1 (Cq), 63.2 (OCH2), 64.7
(OCH2), 71.4 (OCH), 92.0 (Cq), 111.1 (=CH), 112.7 (Cq), 121.1
(=CH), 124.2 (Cq), 128.9 (=CH), 130.3 (=CH), 156.1 (Cq), 162.4
(COO), 206.9 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C37H42O12: 701.2574; found:
701.2571.
(2R,4aS,11aS,14R,15aR,28bR)-2,3,3,13,13,14-Hexamethyl-
1,2,3,8,9,13,14,15,15a,22,23,28b-dodecahydro-2,4a:11a,14-
diepoxytetrabenzo[f,h,q,s][1,5,11,15]tetraoxacycloicosine-
4,5,11,12(7H,21H)-tetraone (11a)
Following the typical procedure for 10a from 3b and 9a gave 11a
as a white solid; yield: 88 mg (58%); mp 202–204 °C.
IR (neat): 2973, 1767, 1742, 1495, 1454, 1333, 1243, 1130, 1054,
842, 731 cm–1.
Crystal data for 10a: (CCDC 900352) C37H42O12, M = 678.71, 0.17
× 0.11 × 0.08 mm, triclinic, space group P-1 with a = 9.2900(9) Å,
b = 12.2162(11) Å, c = 31.952(3) Å, α = 99.062(2), β = 95.660(2),
γ = 99.688(2), V = 3500.5(6) Å3, T = 100(2) K, R1 = 0.0579, wR2 =
0.1393 on observed data, z = 4, Dcalcd = 1.288 mg cm–3, F(000) =
1440, absorption coefficient = 0.096 mm–1, λ = 0.71073 Å, 12084
reflections were collected on a smart apex CCD single crystal dif-
fractometer 9283 observed reflections [I ≥ 2σ (I)]. The largest dif-
ference peak and hole = 1.024 and –0.319 eÅ–3, respectively. The
structure was solved by direct methods and refined by full-matrix
least squares on F2 using SHELXL–97 software.
1H NMR (400 MHz, CDCl3): δ = 0.88–0.91 (m, 2 H, CH2), 1.10 (s,
6 H, CH3), 1.12 (s, 6 H, CH3), 1.48 (s, 6 H, CH3), 1.70 (dd, J1 = 13.1
Hz, J2 = 6.2 Hz, 2 H, CH2), 2.17–2.26 (m, 2 H, CH2), 2.63 (dd, J1 =
13.1 Hz, J2 = 9.1 Hz, 2 H, CH2), 2.73 (dt, J1 = 13.1 Hz, J2 = 6.6 Hz,
2 H, OCH2), 3.70 (dt, J1 = 13.7 Hz, J2 = 6.9 Hz, 2 H, OCH2), 3.96
(dd, J1 = 9.1 Hz, J2 = 6.2 Hz, 2 H, CH), 4.01 (dt, J1 = 8.7 Hz, J2 =
3.2 Hz, 2 H, OCH2), 4.21–4.27 (m, 2 H, OCH2), 6.81 (td, J1 = 7.6
Hz, J2= 0.8 Hz, 2 H, HAr), 6.90 (dd, J1 = 8.4 Hz, J2 = 0.8 Hz, 2 H,
HAr), 7.14 (td, J1 = 8.4 Hz, J2 = 1.6 Hz, 2 H, HAr), 7.37 (dd, J1 = 8.0
Hz, J2 = 1.6 Hz, 2 H, HAr).
13C NMR (100 MHz, CDCl3): δ = 16.7 (CH3), 20.0 (CH3), 20.7
(CH3), 26.3 (CH2), 29.7 (CH2), 38.7 (CH), 44.0 (CH2), 50.4 (Cq),
61.2 (OCH2), 63.3 (OCH2), 87.2 (Cq), 93.8 (Cq), 111.0 (=CH), 121.3
(=CH), 127.3 (=CH), 128.4 (=CH), 129.9 (Cq), 155.5 (Cq), 164.9
(COO), 210.9 (C=O).
(3S,4aR,17bR,19S,21aS,27aS)-2,2,3,19,20,20-Hexamethyl-
2,3,11,12,19,20,24,25-octahydro-1H-3,27a:19,21a-
diepoxydibenzo[h,o]dipyrano[3,2-f:2′,3′-q][1,4,10,14]tetraoxa-
cyclononadecine-1,21,22,27(4aH,10H,17bH)-tetraone (10b)
Following the typical procedure for 10a from 3a and 8a gave 11b
as a white solid; yield: 86 mg (56%); mp 205–207 °C.
HRMS (ESI): m/z [M + Na]+ calcd for C38H44O10: 683.2832; found:
683.2834.
IR (neat): 2972, 1782, 1755, 1689, 1600, 1459, 1288, 1244, 756
cm–1.
(3R,4aR,17bR,19R,21aS,27aS)-2,2,3,19,20,20-Hexamethyl-
2,3,4,4a,11,12,17b,18,19,20,24,25-dodecahydro-1H-
3,27a:19,21a-diepoxytetrabenzo[f,h,o,q][1,4,10,14]tetraoxacy-
clononadecine-1,21,22,27(10H)-tetraone (11b)
Following the typical procedure for 11a from 3a and 9a gave 11b
as a white solid; yield: 84 mg (55%); mp 191–193 °C.
1H NMR (400 MHz, CDCl3): δ = 1.11 (s, 6 H, CH3), 1.20 (s, 6 H,
CH3), 1.68 (s, 6 H, CH3), 2.20–2.30 (m, 4 H, CH2), 2.32–2.34 (m, 2
H, OCH2), 3.97–4.01 (m, 2 H, OCH2), 4.29–4.40 (m, 2 H, OCH2),
5.55 (s, 2 H, OCH), 6.90 (q, J = 7.6 Hz, 4 H, HAr), 7.27 (dt, J1 = 7.6
Hz, J2 = 1.6 Hz, 2 H, HAr), 7.45 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 2 H,
HAr).
13C NMR (100 MHz, CDCl3): δ = 14.7 (CH3), 19.5 (CH3), 21.0
(CH3), 29.5 (CH2), 53.2 (Cq), 62.8 (OCH2), 64.8 (OCH2), 72.0
(OCH), 91.8 (Cq), 110.6 (=CH), 112.9 (Cq), 121.0 (=CH), 123.4
(Cq), 128.7 (=CH), 130.6 (=CH), 155.8 (Cq), 162.4 (COO), 206.5
(C=O).
IR (neat): 2978, 2931, 2361, 1743, 1455, 1377, 1284, 1114, 1052,
863, 733 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.10 (s, 12 H, CH3), 1.48 (s, 6 H,
CH3), 1.67 (dt, J1 = 12.2 Hz, J2 = 2.4 Hz, 2 H, OCH2), 1.75 (dd, J1 =
13.0 Hz, J2 = 6.4 Hz, 2 H, CH2), 2.20–2.23 (m, 2 H, CH2), 2.63 (dd,
J1 = 13.0 Hz, J2 = 9.2 Hz, 2 H, CH2), 4.01–4.02 (m, 2 H, OCH2),
4.04 (dd, J1 = 9.24 Hz, J2 = 6.4 Hz, 2 H, CH2), 4.25–4.34 (m, 2 H,
OCH2), 4.32 (dd, J1 = 10.0 Hz, J2 = 2.4 Hz, 2 H, OCH2), 6.81 (td,
J1 = 7.6 Hz, J2 = 0.8 Hz, 2 H, HAr), 6.90 (dd, J1 = 8.4 Hz, J2 = 0.8
Hz, 2 H, HAr), 7.17 (td, J1 = 8.4 Hz, J2 = 1.6 Hz, 2 H, HAr), 7.33 (dd,
J1 = 7.6 Hz, J2 = 1.6 Hz, 2 H, HAr).
13C NMR (100 MHz, CDCl3): δ = 16.7 (CH3), 20.1 (CH3), 20.6
(CH3), 29.6 (CH2), 39.3 (CH), 43.6 (CH2), 50.4 (Cq), 62.7 (OCH2),
64.2 (OCH2), 87.1 (Cq), 93.1 (Cq), 110.7 (=CH), 121.0 (=CH), 127.4
(=CH), 128.57 (Cq), 128.64 (=CH), 155.6 (Cq), 164.7 (COO), 210.0
(C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C35H38O12: 673.2261; found:
673.2258.
(2S,4aS,11aS,14S,15aR,28bR)-2,3,3,13,13,14-Hexamethyl-
2,3,8,9,13,14,22,23-octahydro-2,4a:11a,14-diepoxydiben-
zo[f,s]dipyrano[2,3-h:3′,2′-q][1,5,11,15]tetraoxacycloicosine-
4,5,11,12(7H,15aH,21H,28bH)-tetraone (10c)
Following the typical procedure for 10a from 3b and 8a gave 10c as
a white solid; yield: 75 mg (50%); mp 210–212 °C.
IR (neat): 2965, 2926, 1780, 1750, 1689, 1601, 1400, 1334, 1262,
1056, 802, 750 cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C37H42O10: 669.2676; found:
669.2673.
1H NMR (400 MHz, CDCl3): δ = 0.78–0.83 (m, 2 H, CH2), 1.13 (s,
6 H, CH3), 1.20 (s, 6 H, CH3), 1.67 (s, 6 H, CH3), 2.21–2.22 (m, 2
H, CH2), 2.91–2.97 (m, 2 H, OCH2), 3.74–3.80 (m, 2 H, OCH2),
3.95–3.98 (m, 2 H, OCH2), 4.30–4.36 (m, 2 H, OCH2), 5.50 (s, 2 H,
OCH), 6.87 (t, J = 7.6 Hz, 2 H, HAr), 6.93 (d, J = 8.0 Hz, 2 H, HAr),
7.26 (dt, J1 = 8.4 Hz, J2 = 1.6 Hz, 2 H, HAr), 7.47 (dd, J1 = 7.6 Hz,
J2 = 1.6 Hz, 2 H, HAr).
13C NMR (100 MHz, CDCl3): δ = 14.8 (CH3), 19.5 (CH3), 21.0
(CH3), 26.6 (CH2), 29.4 (CH2), 53.1 (Cq), 61.6 (OCH2), 63.1
(OCH2), 71.4 (OCH), 92.2 (Cq), 111.2 (=CH), 112.9 (Cq), 121.1
(=CH), 124.3 (Cq), 128.7 (=CH), 130.5 (=CH), 156.1 (Cq), 162.6
(COO), 207.4 (C=O).
(4bR,6R,8aS,20aS,23R,24aR)-6,7,7,22,22,23-Hexamethyl-
4b,5,6,7,11,12,13,14,15,16,17,18,22,23,24,24a,30,31,32,33,34,35-
docosahydro-6,8a:20a,23-diepoxytetraben-
zo[c,e,o,q][1,7,14,20]tetraoxacyclooctacosine-8,9,20,21-tetra-
one (11c)
Following the typical procedure for 11a from 3d and 9b gave 11c
as a white solid; yield: 91 mg (60%); mp 215–217 °C.
IR (neat): 2929, 2856, 1769, 1745, 1493, 1454, 1333, 1245, 1110,
1086, 754 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.00–1.20 (m, 24 H), 1.48 (s, 6 H,
CH3), 1.67 (dd, J1 = 13.2 Hz, J2 = 6.0 Hz, 4 H, CH2), 1.79 (s, 6 H,
CH2), 2.63 (dd, J1 = 12.8 Hz, J2 = 10.0 Hz, 2 H, CH), 3.63–3.65 (m,
2 H, CH2), 3.84–3.97 (m, 8 H, OCH2), 6.81 (dd, J1 = 16 Hz, J2 = 7.2
Hz, 4 H, HAr), 7.07–7.10 (m, 2 H, HAr), 7.42 (d, J = 7.2 Hz, 2 H,
HAr).
HRMS (ESI): m/z [M + Na]+ calcd for C36H40O12: 687.2417; found:
687.2412.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2034–2042

2042
S. Muthusamy et al.
PAPER
13C NMR (100 MHz, CDCl3): δ = 16.7 (CH3), 20.0 (CH3), 20.7
(CH3), 23.4 (CH2), 26.0 (CH2), 26.3 (CH2), 28.7 (CH2), 29.7 (CH2),
38.7 (CH), 44.1 (CH2), 50.4 (Cq), 61.2 (OCH2), 63.3 (OCH2), 87.6
(Cq), 93.8 (Cq), 110.3 (=CH), 120.5 (=CH), 126.3 (=CH), 127.5
(=CH), 128.5 (Cq), 155.0 (Cq), 165.5 (COO), 209.5 (C=O).
HRMS (ESI): m/z [M + Na]+ calcd for C46H60O10: 795.4084; found:
795.4081.
Podesta, J. C. Organometallics 2012, 31, 662. (c) Salunke,
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Acknowledgment
This research was supported by Department of Science and Techno-
logy (DST), New Delhi. MS thanks CSIR-SRF, for a research fel-
lowship. We thank DST, New Delhi for providing 400 MHz NMR
facility under FIST program.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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Synthesis 2013, 45, 2034–2042
© Georg Thieme Verlag Stuttgart · New York