Stereoselective α,α′-annelation reactions of 1,3-dioxan-5-ones

Article abstract of DOI:10.1021/jo101531b

Pyrrolidine enamines derived from three 1,3-dioxan-5-ones undergo α,α′-annelation reactions with methyl α-(bromomethyl) acrylate to produce bridged 2,4-dioxabicyclo[3.3.1]nonane ring systems with complete stereocontrol. Stereochemical outcomes have been rationalized based on steric and stereoelectronic interactions in intermediate boat-like conformations of the 1,3-dioxane ring and subsequent kinetic protonation to set an axial ester group on the cyclohexanone ring. Base-mediated ester epimerization provides the stereochemical array found in the highly oxygenated cyclohexane ring of phyllaemblic acid and glochicoccins B and D.

Full text of DOI:10.1021/jo101531b

pubs.acs.org/joc
Stereoselective r,r0-Annelation Reactions
of 1,3-Dioxan-5-ones
SCHEME 1. Retrosynthetic Analysis
Tyrone C. Casey,† Julie Carlisle,‡ Patrizia Tisselli,‡
Louise Male,† Neil Spencer,† and Richard S. Grainger*,†,‡
†School of Chemistry, University of Birmingham, Edgbaston,
Birmingham B15 2TT, United Kingdom, and ‡Department of
Chemistry, King’s College London, Strand, London WC2R
2LS, United Kingdom
r.s.grainger@bham.ac.uk
Received August 4, 2010
Despite their potential biological activity, approaches
toward the syntheses of these natural products have yet to
be reported. Although structurally related to the extensively
investigated phyllanthocins,4 the presence of an additional
alcohol functionality in the cyclohexane ring suggests a
unique strategy can be adopted based on the presence of a
latent symmetry element, revealed upon disconnection of the
spiroacetal (Scheme 1). This functionality could conceivably
arise through a plausible biomimetic spiroacetalization reac-
tion, engaging one of the two diastereotopic hydroxyl groups
on the cyclohexane ring of 1.5 The latent symmetry element
can be exploited synthetically by further disconnection of
1 along any of the bonds a-d to two fragments of approxi-
mately equal complexity, only one of which need be chiral.
We have targeted meso-2,4,6-trisubstituted cyclohexanone
2 as a suitable building block to investigate such an ap-
proach, and in this Note we report a concise, stereoselective
synthesis of this system based on an R,R0-annelation reaction
of 1,3-dioxan-5-ones.
The R,R0-annelation of enamines with biselectrophiles such as
ethyl R-(bromomethyl)acrylate has been applied to the synthesis
of a range of cyclic ketones with diverse application in organic
chemistry.6-8 The transformation shown in Scheme 2 is typical:
a bridged bicyclic ring system is formed as a single stereoisomer,
with the axial ester stereochemistry arising through in situ
kinetic protonation from the less-hindered face, either of an
ester enolate or in concert with C-C bond formation. Applica-
tion of this methodology in the synthesis of 2 was envisaged
Pyrrolidine enamines derived from three 1,3-dioxan-5-ones
undergo R,R0-annelation reactions with methyl R-(bromo-
methyl)acrylate to produce bridged 2,4-dioxabicyclo[3.3.1]-
nonane ring systems with complete stereocontrol. Stereo-
chemical outcomes have been rationalized based on steric
and stereoelectronic interactions in intermediate boat-like
conformations of the 1,3-dioxane ring and subsequent
kinetic protonation to set an axial ester group on the
cyclohexanone ring. Base-mediated ester epimerization pro-
vides the stereochemical array found in the highly oxygenated
cyclohexane ring of phyllaemblic acid and glochicoccins
B and D.
Phyllaemblic acid is a highly oxygenated, norbisabolane
sesquiterpene isolated, along with its methyl ester and three
ester glycosides, phyllaemblicins A-C, from the roots of
Phyllanthus emblica L., a plant widely distributed in sub-
tropical and tropical areas of China, India, Indonesia, and
the Malay Peninsula.1,2 The rhizomes of a related genus
Glochiddion coccineum, also widely distributed in China,
were found to contain the structurally similar glochicoccins
B and D (Scheme 1).3 Both these plants have long been used
in traditional folk medicine by the indigenous people of these
regions for the treatment of a range of ailments.
(4) For a review of synthetic approaches toward phyllanthocin and
breynolide see: Smith, A. B.; Empfield, J. R. Chem. Pharm. Bull. 1999, 47,
1671.
(5) For reviews on diastereotopic group selective reactions see: (a) Studer,
A.; Schleth, F. Synlett 2005, 3033. (b) Hoffmann, R. W. Synthesis 2004, 2075.
(6) (a) Nelson, R. P.; Lawton, R. G. J. Am. Chem. Soc. 1966, 88, 3884. (b)
Nelson, R. P.; McEuan, J. M.; Lawton, R, G. J. Org. Chem. 1969, 34, 1225.
(c) McEuan, J. M.; Nelson, R. P.; Lawton, R. G. J. Org. Chem. 1970, 35, 690.
(d) Lawton, R. G.; Dunham, D. J. J. Am. Chem. Soc. 1971, 93, 2074. (e)
Haslander, M.; Zawacky, S.; Lawton, R. G. J. Org. Chem. 1976, 41, 1807. (f)
Weiss, D. S.; Haslanger, M.; Lawton, R. G. J. Am. Chem. Soc. 1976, 98, 1050.
(g) Chen, Y.-S.; Kampf, J. W.; Lawton, R. G. Tetrahedron Lett. 1997, 38,
5781.
(1) Zhang, Y.-J.; Tanaka, T.; Iwamoto, Y.; Yang, C.-R.; Kouno, I.
Tetrahedron Lett. 2000, 41, 1781.
(2) (a) Zhang, Y.-J.; Tanaka, T.; Iwamoto, Y.; Yang, C.-R.; Kouno, I.
J. Nat. Prod. 2000, 63, 1507. See also: (b) Zhang, Y.-J.; Tanaka, T.; Iwamoto,
Y.; Yang, C.-R.; Kouno, I. J. Nat. Prod. 2001, 64, 870.
(7) (a) Stetter, H.; Thomas, H. G. Angew. Chem., Int. Ed. 1967, 6, 554. (b)
Stetter, H.; Thomas, H. G. Chem. Ber. 1968, 101, 1115. (c) Stetter, H.;
Thomas, H. G.; Meyer, K. Chem. Ber. 1970, 103, 863. (d) Stetter, H.;
Komorowski, K. Chem. Ber. 1971, 104, 75. (e) Stetter, H.; Elfert, K. Synthesis
€
1974, 36. (f) Stetter, H.; Ramsch, K.-D.; Elfert, K. Liebigs. Ann. Chem. 1974,
1322.
(3) Xiao, H.-T.; Hao, X.-Y.; Yang, X.-W.; Wang, Y.-H.; Lu, Y.; Zhang,
Y.; Gao, S.; He, H.-P.; Hao, X.-J. Helv. Chim. Acta 2007, 90, 164.
DOI: 10.1021/jo101531b
r
Published on Web 10/11/2010
J. Org. Chem. 2010, 75, 7461–7464 7461
2010 American Chemical Society

Casey et al.
SCHEME 3. R,R0-Annelation of 1,3-Dioxan-5-ones
JOCNote
SCHEME 2. Lawton’s R,R0-Annelation Reaction6b
through employment of a suitably protected dihydroxyacetone
derived enamine, with the use of a cyclic acetal protecting group
removing any ambiguity in enamine geometry9 and hence
ensuring both oxygen substituents reside on the same side of
the resulting cyclohexanone ring.
SCHEME 4. Stereochemical Rationale
Our studies began with the known acetonide 3a, prepared
in three steps from commercially available material.10 The
enamine 4a was formed under standard conditions, and could
be purified by distillation, albeit in a modest 53% yield, reflecting
its thermal instability. Subjecting 4a to standard R,R-annelation
reaction conditions with methyl R-(bromomethyl)acrylate
(refluxing MeCN followed by iminium hydrolysis with aqueous
acetic acid) gave the desired bicyclic ketone 5a in 19% yield.
To increase the yield of 5a a series of modifications to the
standard conditions were undertaken. Isolation of the en-
amine was avoided, and the reaction mixture was directly
subjected to the R,R0-annelation reaction. This reaction in
turn was found to be higher yielding at lower temperatures.
The iminium hydrolysis was affected by simple addition of
water, which avoided potential cleavage of the acetal under
overly acidic conditions. In this manner, the yield of 5a could
be increased to 40% over two steps (Scheme 3).
The structure of 5a was deduced by NMR spectroscopy and
X-ray crystallography (see the Supporting Information).11
A “chair-boat” conformation is adopted in both the solid state
and in solution, with no evidence of ring-flipping from
variable-temperature NMR experiments.12 The ester group is
axially oriented on the cyclohexanone ring, cis to the two
oxygen substituents.
A comparable 41% yield was obtained for the benzylidene
acetal 5b, whereas the ortho acetal 5c was prepared in an
improved 61% yield. In both cases a single stereoisomer was
formed. The relative stereochemistry in 5b was determined
by NOE analysis and X-ray crystallography.11 A chair-boat
conformation is again adopted, with the phenyl substituent
residing pseudoequatorial on the dioxanone ring. The rela-
tive stereochemistry in 5c was tentatively assigned by NOE
analysis, and confirmed by X-ray analysis of 12c after ester
epimerization (vide infra).11
The stereochemical outcome in the R,R0-annelation reac-
tion of enamines 4b and 4c can be rationalized by considering
the reaction mechanism shown in Scheme 4. C-Allylation of
enamine 4b,c gives rise to two possible iminiums, 6b,c and 7b,
c (identical starting from 4a). These are in equilibrium with
enamines 9b,c and 10b,c under the reaction conditions. For
the subsequent C-C bond formation, enamines 9b,c and
10b,c must adopt boat conformations to orient the allylic
ester axial.14 This conformation is disfavored for 10b by a
steric interaction of the flagpole Ph group with the pyrroli-
dine ring, hence 9b is favored and 5b is the observed product.
The corresponding steric interactions for 9c and 10c are less
pronounced, but here the additional anomeric stabilizing
The optimized reaction conditions were applied to the
more readily synthesized 1,3-dioxan-5-ones 3b and 3c.10,13
(8) (a) Speckamp, W. N.; Dijkink, J.; Huisman, H. O. J. Chem. Soc. D
1970, 196. (b) Speckamp, W. N.; Dijkink, J.; Huisman, H. O. J. Chem. Soc. D
1970, 197. (c) Speckamp, W. N.; Dijkink, J.; Dekkers, W. J. D.; Huisman,
H. O. Tetrahedron 1971, 27, 3143. (d) Peters, J. A.; Van Der. Toorn, J. M.;
Van Bekkum, H. Tetrahedron 1974, 30, 633. (e) Gompper, R.; Ulrich, W.-R.
Angew. Chem., Int. Ed. 1976, 15, 299. (f) Peters, J. A.; Van De Graff, B.;
Schuyl, P. J. W.; Wortel, Th. M.; Van Bekkum, H. Tetrahedron 1976, 32,
2735. (g) Momose, T.; Muraoka, O. Chem. Pharm. Bull. 1978, 26, 2217. (h)
Bok, Th. B.; Speckamp, W. N. Tetrahedron 1979, 35, 267. (i) Meeuwissen,
H. J.; Van Der Knaap, T. A.; Bickelhaupt, F. Tetrahedron 1983, 39, 4225. (j)
Anzeveno, P. B.; Matthews, D. P.; Barney, C. L.; Barbuch, R. J. J. Org.
Chem. 1984, 49, 3134. (k) Seebach, D.; Missbach, M.; Calderari, G.; Eberle,
M. J. Am. Chem. Soc. 1990, 112, 7625. (l) Padwa, A.; Kline, D. N.; Murphree,
S. S.; Yeske, P. E. J. Org. Chem. 1992, 57, 298. (m) Nemes, P.; Janke, F.;
Scheiber, P. Liebigs Ann. Chem. 1993, 179. (n) Ayres, F. D.; Khan, S. I.;
Chapman, O. L.; Kaganove, S. N. Tetrahedron Lett. 1994, 35, 7151. (o) Yeh,
V. S. C.; Kurukulasuriya, R.; Madar, D.; Patel, J. R.; Fung, S.; Monzon, K.;
Chiou, W.; Wang, J.; Jacobson, P.; Sham, H. L.; Link, J. T. Bioorg. Med.
Chem. Lett. 2006, 16, 5408. (p) Cao, C.-L.; Zhou, Y.-Y.; Zhou, J.; Sun, X.-L.;
Tang, Y.; Li, Y.-X.; Li, G.-Y.; Sun, J. Chem.;Eur. J. 2009, 15, 11384.
(9) For a review on the synthetic utility of dihydroxyacetone derivatives
see: Enders, D.; Voith, M.; Lenzen, A. Angew. Chem., Int. Ed. 2005, 44, 2.
(10) Forbes, D. C.; Ene, D. G.; Doyle, M. P. Synthesis 1988, 879.
(11) A file in CIF format is available in the Supporting Information.
CCDC 779722 - 779726 contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/datarequest/cif.
(12) For a review on conformational analysis of bicyclo[3.3.1]nonanes
and their heteroanalogues see: Zefirov, N. S.; Palyulin, V. A. Top. Stereo-
chem. 1991, 20, 171.
(14) Peters has proposed that R,R0-annelation reactions can proceed
through an alternative half-chair transition state (ref 8d). Application of
this model to 9b,c and 10b,c fails to predict the observed isomer.
(13) Peukert, S.; Giese, B. J. Org. Chem. 1998, 63, 9045.
7462 J. Org. Chem. Vol. 75, No. 21, 2010

Casey et al.
JOCNote
SCHEME 5. Base-Mediated Ester Epimerization
Anal. Calcd for C11H16O5: C, 57.88; H, 7.07. Found C, 57.77;
H, 7.00.
Methyl 9-Oxo-3r-phenyl-2,4-dioxabicyclo[3.3.1]nonane-7r-car-
boxylate (5b). Procedure A was employed with use of 2-phenyl-1,3-
dioxan-5-one10 (3b) (1.986 g, 11.2 mmol). Column chromatogra-
phy (3:1 hexane:diethyl ether) afforded the title compound as a
white solid (1.270 g, 41%); Rf 0.26 (1:1 hexane:diethyl ether); mp
101-104 °C; υmax (neat)/cm-1 1747, 1718, 1456, 1016, 989; δH (500
MHz, CDCl3) 2.12 (2H, dd, J = 7.6, 15.2 Hz, CH2), 2.68 (1H, t,
J = 7.2 Hz, CHCO2CH3), 3.42-3.50 (2H, m, CH2), 3.58 (3H, s,
CO2CH3), 4.60 (2H, d, J = 3.9 Hz, CHCO), 5.70 (1H, s, PhCH),
7.35-7.51 (5H, m, Ph-H); δc (75.5 MHz, CDCl3) 33.7 (CH), 38.0
(CH2), 52.1 (CH3), 80.7 (CH), 98.5 (CH), 126.2 (CH), 128.2 (CH),
129.3 (CH), 136.3 (C), 173.6 (C), 212.9 (C); m/z (ES) 299.1 [M þ
Na]þ, HRMS (ES) [M þ Na]þ 299.0901, C15H16O5Na requires
299.0895.
Methyl 3β-Methoxy-3r-methyl-9-oxo-2,4-dioxabicyclo[3.3.1]-
nonane-7r-carboxylate (5c). Procedure A was employed with
use of 2-methoxy-2-methyl-1,3-dioxan-5-one13 (3c) (1.500 g,
10.3 mmol). Column chromatography (3:1 hexane:diethyl ether)
afforded the title compound as a viscous pale yellow oil (1.530 g,
61%); Rf 0.51 (1:1 hexane:diethyl ether); υmax (neat)/cm-1 1731,
1441, 1046, 1010; δH (300 MHz, CDCl3) 1.41 (3H, s, CH3), 1.97
(2H, dd, J = 7.1, 14.2 Hz, CH2), 2.62 (1H, t, J = 7.0 Hz,
CHCO2CH3), 3.19-3.25 (5H, m, OCH3, CH2), 3.75 (3H, s,
CO2CH3), 4.16 (2H, d, J = 3.9 Hz, CHCO); δc (100 MHz,
CDCl3) 19.7 (CH3), 33.8 (CH), 36.4 (CH2), 50.9 (CH3), 51.9
(CH3), 75.0 (CH), 111.8 (C), 173.5 (C), 207.8 (C); m/z (ES) 267.1
[M þ Na]þ, HRMS (ES) [M þ Na]þ 267.0842, C11H16O6Na
requires 267.0845.
Ester Epimerization:. Methyl 3,3-Dimethyl-9-oxo-2,4-dioxabi-
cyclo[3.3.1]nonane-7β-carboxylate (12a) Methyl 3,3-dimethyl-9-
oxo-2,4-dioxabicyclo[3.3.1]nonane-7R-carboxylate (5a) (0.053 g,
0.232 mmol) was dissolved in acetonitrile (3 mL) followed by
addition of DBU (0.035 g, 0.230 mmol). The reaction mixture was
heated at 65 °C (external temperature) for 24 h, allowed to cool,
and concentrated to approximately half volume. Column chroma-
tography (4:1 hexane:diethyl ether) afforded the title compound as
a white solid (0.041 g, 77%); Rf 0.47 (1:1 hexane:diethyl ether); mp
79-82 °C; υmax (nujol mull)/cm-1 1754, 1455, 1006, 964; δH (400
MHz, CDCl3) 1.42(3H, s, CH3), 1.50(3H, s, CH3), 1.93 (2H, t, J=
13.4 Hz, CH2), 2.60 (2H, m, CH2), 3.55 (1H, tt, J = 4.6, 12.6 Hz,
CHCO2CH3), 3.67 (3H, s, CO2CH3), 4.28 (2H, d, J = 3.8 Hz,
CHCO); δc (75.5 MHz, CDCl3) 25.0 (CH3), 28.5(CH3), 33.0 (CH),
40.3 (CH2), 52.0 (CH3), 76.0 (CH), 98.7 (C), 174.2 (C), 214.0 (C);
m/z (ES) 251.1 [M þ Na]þ, HRMS (ES) [M þ Na]þ 251.0891,
C11H16O5Na requires 251.0895.
Methyl 9-Oxo-3r-phenyl-2,4-dioxabicyclo[3.3.1]nonane-7β-
carboxylate (12b). Methyl 9-oxo-3R-phenyl-2,4-dioxabicyclo-
[3.3.1]nonane-7R-carboxylate (5b) (0.062 g, 0.526 mmol) was
dissolved in acetonitrile (3 mL) followed by addition of DBU
(0.034 g, 0.526 mmol). The reaction mixture was heated at 65 °C
(external temperature) for 24 h, allowed to cool, and concen-
trated to approximately half volume. Column chromatography (4:1
hexane:diethyl ether) afforded the title compound as a white solid
(0.042 g, 68%); Rf 0.38 (1:1 hexane:diethyl ether); mp 113-116 °C;
υmax (neat)/cm-1 1750, 1722, 1453, 1103, 1071; δH (300 MHz,
CDCl3) 2.08 (2H, t, J = 13.7 Hz, CH2), 2.70-2.85 (2H, m, CH2),
3.70 (3H, s, CO2CH3), 3.73 (1H, tt, J = 4.6, 12.5 Hz, CHCO2CH3),
4.59 (2H, d, J = 3.8 Hz, CHCO), 5.76 (1H, s, PhCH), 7.40-7.60
(5H, m, Ph-H); δc (75.5 MHz, CDCl3) 33.1 (CH), 39.6 (CH2), 52.1
(CH3), 79.8 (CH), 98.0 (CH), 126.1 (CH), 128.4 (CH), 129.6 (CH),
136.4 (C), 174.1 (C), 211.7 (C); m/z (ES) [M þ Na]þ 299.1, HRMS
(ES) [M þ Na]þ 299.0898, C15H16O5Na requires 299.0895.
Methyl 3β-Methoxy-3r-methyl-9-oxo-2,4-dioxabicyclo[3.3.1]-
nonane-7β-carboxylate (12c). Methyl 3β-methoxy-3R-methyl-9-
oxo-2,4-dioxabicyclo[3.3.1]nonane-7R-carboxylate (5c) (1.300 g,
5.328 mmol) was dissolved in acetonitrile (50 mL) followed by
interaction is only present for 9c, ultimately favoring forma-
tion of 5c.
In all cases the axial ester group is consistent with an in
situ kinetic protonation, as is typically observed in other R,
R0-annelation reactions.6-8
Ester epimerization of 5a-c was best achieved by using
DBU in acetonitrile at 65 °C (Scheme 5). Upon epimeriza-
tion, there is a diagnostic downfield shift of the proton
adjacent to the ester group, presumably due to its alignment
with the two axial oxygen substituents on the cyclohexanone
ring,15 suggesting the overall chair-boat conformation is
maintained. This is consistent with NOE and variable-
temperature NMR studies, and X-ray crystal structure analysis,
of 12a-c.11 The resulting stereochemical array in 12a-c
corresponds to that of target compound meso-2.
In summary, the R,R0-annelation reaction of 1,3-dioxan-5-
ones provides a convenient method for the synthesis of
usefully substituted meso-cyclohexanones 5 and 12, em-
bedded within a 2,4-dioxabicyclo[3.3.1]nonane ring system.
Use of these building blocks in target synthesis is currently
under investigation.
Experimental Section
r,r0-Annelation of 1,3-Dioxan-5-ones (Procedure A): Methyl
3,3-Dimethyl-9-oxo-2,4-dioxabicyclo[3.3.1]nonane-7r-carboxy-
late (5a) To an ice-cooled solution of 2,2-dimethyl-1,3-dioxan-5-
one10 (3a) (0.501 g, 3.85 mmol) in anhydrous acetonitrile
(10 mL) was added molecular sieves (4 A, 4.00 g) and pyrrolidine
(0.274 g, 3.85 mmol). The solution was stirred at 0 °C (external
ice-bath temperature) for 5 h under an inert atmosphere.
Triethylamine (0.39 g, 3.86 mmol) was added, followed by a
solution of methyl R-(bromomethyl)acrylate16 (0.69 g, 3.85
mmol) in acetonitrile (30 mL) dropwise under an inert atmo-
sphere. A precipitate quickly formed and redissolved. The
resulting yellow solution was stirred for 16 h with gradual
warming to room temperature. The solution was filtered to
remove the molecular sieves, distilled water (40 mL) was added,
and the resulting mixture was stirred at room temperature for 5
h. The mixture was then extracted with dichloromethane (3 ꢀ 40
mL), dried over anhydrous Na2SO4, and filtered, then the
solvents were removed under vacuum. Purification by column
chromatography (3:1 hexane:diethyl ether) afforded the title
compound as a white solid (0.353 g, 40%): Rf 0.25 (1:1 hexane:
diethyl ether); mp 65-67 °C; υmax (nujol mull)/cm-1 1745, 1456,
1023, 992; δH (300 MHz, CDCl3) 1.35 (3H, s, CH3), 1.36 (3H, s,
CH3), 1.99 (2H, dd, J = 7.2, 14.4 Hz, CH2), 2.58 (1H, t, J = 7.2
Hz, CHCO2CH3), 3.27 (2H, m, CH2), 3.76 (3H, s, CO2CH3),
4.28 (2H, d, J = 3.9 Hz, CHCO); δc (75.5 MHz, CDCl3) 24.9
(CH3), 27.9 (CH3), 33.8 (CH), 38.8 (CH2), 52.2 (CH3), 76.8
(CH), 99.2 (C), 173.8 (C), 215.3 (C); m/z (EI) 229.1 [M þ H]þ.
€
(15) Pretsch, E.; Buhlmann, P.; Badertscher, M. Structure Determination
of Organic Compounds, 4th ed.; Springer-Verlag: Berlin, Germany, 2009; p
176.
ꢀ
(16) Borrell, J. I.; Teixido, J.; Martı
´
nez-Teipel, B.; Matallana, J. L.;
Copete, M. T.; Llimargas, A.; Garcıa, E. J. Med. Chem. 1998, 41, 3539.
´
J. Org. Chem. Vol. 75, No. 21, 2010 7463

Casey et al.
JOCNote
addition ofDBU(0.810 g, 5.329mmol). The reactionmixturewas
heated at 65 °C (external temperature) for 24 h, allowed to cool,
and concentrated to approximately half volume. Column chro-
matography (4:1 hexane:diethyl ether) afforded the title com-
pound as a white solid (1.030 g, 79%); Rf 0.68 (1:1 hexane:diethyl
ether); mp 34-36 °C; υmax (neat)/cm-1 1754, 1731, 1434, 1047,
918; δH (300 MHz, CDCl3) 1.59 (3H, s, CH3), 1.96 (2H, t, J =
13.6 Hz, CH2), 2.62 (2H, m, CH2), 3.27 (3H, s, OCH3), 3.46 (1H,
tt, J = 4.5, 12.5 Hz, CHCO2CH3), 3.71 (3H, s, CO2CH3), 4.20
(2H, d, J = 3.6 Hz, CHCO); δc (100 MHz, CDCl3) 20.2 (CH3),
33.2 (CH), 38.1 (CH2), 50.9 (CH3), 52.0 (CH3), 74.5 (CH), 112.0
(C), 174.1 (C), 206.8 (C); m/z (ES) 267.1 [M þ Na]þ, HRMS (ES)
[M þ Na]þ 267.0850, C11H16O6Na requires 267.0845.
Professor M. B. Hursthouse and Dr. Richard A. Stephenson
(EPSRC National Crystallography Service, University of
Southampton, UK) for X-ray crystal structure determination.
The NMR spectrometers used in this research were obtained
through Birmingham Science City: Innovative Uses for
Advanced Materials in the Modern World (West Midlands
Centre for Advanced Materials Project 2), with support
from Advantage West Midlands (AWM) and part funded
by the European Regional Development Fund (ERDF).
R.S.G. is an EPSRC Advanced Research Fellow 2005-2010
(EP/C543122/1).
1
Supporting Information Available: Copies of H and 13C
Acknowledgment. We thank EPSRC (GR/R20465/01),
University of Birmingham, and King’s College London
for financial support. We thank Dr. Andreas E. Goeta
(Department of Chemistry, Durham University, UK) and
NMR for all new compounds, including NOE and variable
temperature analyses, and X-ray crystal data of 5a, 5b, 12a, 12b,
and 12c as CIF files. This material is available free of charge via
the Internet at http://pubs.acs.org.
7464 J. Org. Chem. Vol. 75, No. 21, 2010