Highly diastereoselective desymmetrisation of cyclic meso-anhydrides and derivatisation for use in natural product synthesis

Article abstract of DOI:10.1039/b813494d

A new and efficient desymmetrisation of succinic and glutaric cyclic meso-anhydrides is described, providing excellent yields and diastereoselectivities in most cases. Derivatisation of the desymmetrised products is demonstrated by their conversion into m

Full text of DOI:10.1039/b813494d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Highly diastereoselective desymmetrisation of cyclic meso-anhydrides and
derivatisation for use in natural product synthesis†
Amanda C. Evans,a Deborah A. Longbottom,a Masato Matsuoka,b John E. Davies,a Richard Turner,a
Vilius Franckevicˇiusa and Steven V. Ley*a
Received 4th August 2008, Accepted 10th November 2008
First published as an Advance Article on the web 6th January 2009
DOI: 10.1039/b813494d
A new and efficient desymmetrisation of succinic and glutaric cyclic meso-anhydrides is described,
providing excellent yields and diastereoselectivities in most cases. Derivatisation of the desymmetrised
products is demonstrated by their conversion into mono-protected 1,4-diols. General synthetic utility of
the method is established by its application towards a key fragment in the total synthesis of the
immunosuppressant antitumour natural product, rapamycin.
Introduction
The rapidly increasing need to generate intricate chiral molec-
ular structures in a robust and efficient manner demands the
development of new strategies for the direct assembly of complex
molecular architectures. In order to be synthetically useful reaction
processes, such methods are expected to be high yielding, durable
and readily scalable, generating the desired molecular complexity
in a minimum number of chemical steps and, most importantly,
facilitating the production of multiple stereogenic centres in
a highly selective manner. Desymmetrisation of an achiral or
meso-compound using a chiral species (either a catalyst or an
auxiliary) serves as an efficient means for generating usefully
functionalised chiral building blocks with potential application in
the asymmetric synthesis of biologically active products, allowing
multiple stereocentres to be created in a single symmetry-breaking
transformation. This field has attracted a large amount of interest
over the years and a number of powerful methods for the
desymmetrisation of anhydrides, epoxides, diols, dienes, ketones
and dialdehydes have been developed, among others.1–4 More
specifically, the desymmetrisation of cyclic meso-anhydrides is a
particularly useful transformation, facilitating the production of
one or more stereocentres in a single step and simultaneously
producing two chemically differentiated carbonyl groups that can
be synthetically elaborated further in a number of ways, thus
rapidly and efficiently increasing molecular complexity.
Fig. 1 Examples of cyclic meso-anhydrides.
Fig. 2 Examples of natural products incorporating desymmetrised
anhydride frameworks.
enantiotopic carbonyl groups present in the cyclic anhydride
structure, facilitating diastereo- and enantioselective desymmetri-
sation, respectively. Diastereoselective desymmetrisation in par-
ticular is a practical means for employing cyclic anhydrides
in synthesis, permitting the immediate physical isolation and
characterisation of diastereomerically pure materials by chro-
matography or crystallisation; the appended chiral auxiliaries can
then provide flexibility for further chemical differentiation via
cleavage.
A number of nucleophilic chiral auxiliaries have been studied
over the years for the desymmetrisation of cyclic meso-anhydrides,
including chiral alcohols,5 chiral amines,6 and chiral oxazolines
and oxazolidinones.7 However, despite the indisputable advances
that have been made, existing desymmetrisation methodologies
utilising chiral auxiliaries frequently suffer from one or more of
the following problems: difficulties with auxiliary cleavage and
recovery, extended reaction times at reduced temperature, low
enantio- or diastereoselectivities and/or a limited substrate scope.
Given the experimental precedent for high selectivity induced by
benzopyranoisoxazolidines as asymmetric alkylation auxiliaries
and their facile Weinreb-amide-like cleavage as demonstrated by
Abiko et. al.,9–16 it was recognised that (+)- and (-)-7 might also
There are two commonly used types of cyclic meso-anhydrides:
five-membered succinic and six-membered glutaric anhydrides (1
and 2, Fig. 1). Both provide unique precursor frameworks with
potential for application in natural product synthesis (Fig. 2).
A considerable body of work has been devoted to the
development of diastereo- and enantioselective non-enzymatic
desymmetrisations of meso-anhydrides. Chiral auxiliaries5–7 and
chiral catalysts8 have both been employed to differentiate the
aUniversity of Cambridge, Department of Chemistry, Lensfield Road,
Cambridge, UK, CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: +44 (0)1223
336442
bNippon Shinyaku Co., Ltd., 3-14-1 Sakura, Tsukuba, Ibaraki 305-0003,
Japan
† CCDC reference numbers 704059, 704060 and 704062. For crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b813494d
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have potential application as chiral auxiliaries in the desymmetri-
sation of cyclic meso-anhydrides (Fig. 3).
Initial investigations using 7 as a chiral auxiliary in the desym-
metrisation of cyclic meso-anhydrides required some optimisation
of reaction conditions, but pleasingly the reaction of succinic
meso-anhydride 8a (Table 1) with (+)-auxiliary 7 at -8 ◦C in
dichloromethane and subsequent trapping of the carboxylic acid
thus formed with TMS-diazomethane was found to produce only
1
one diastereomeric product (Scheme 1), as determined by H-
NMR and chiral HPLC.17
Fig. 3 Benzopyranoisoxazolidine chiral auxiliaries (+)- and (-)-7.
Results and discussion
A multi-gram synthesis of racemic auxiliary 7 proved to be
straightforward and isolation of each of the (+)- and (-)-
enantiomers from the racemic reaction mixture was possible
using a simple kinetic resolution using a precedented reciprocal
recrystallisation with (+)-10-camphorsulfonic acid ((+)-CSA).10
Due to the highly crystalline nature of the (+)-7·(+)-CSA salt
and the known absolute stereochemical configuration of (+)-
CSA, X-ray diffraction analysis was performed in order to
confirm which enantiomer of the auxiliary was isolated from
each reciprocal recrystallisation. Abiko had previously assigned
an (R,S)-configuration to the (+)-7·(+)-CSA salt and an (S,R)-
configuration to the (-)-7·(+)-CSA salt;10 however we believe this
assignment to be incorrect, based on our X-ray diffraction analysis
of the (+)-7·(+)-CSA salt‡, and upon analysis of the original pub-
lished structure as deposited at the Cambridge Crystallographic
Data Centre (CCDC) by Abiko et al. Indeed we would assign
the (S,R)-configuration to the (+)-7·(+)-CSA salt and the (R,S)-
configuration to the (-)-7·(+)-CSA salt (Fig. 4). This assignment
has been rigorously corroborated by optical rotation analysis, 1H-
and 13C-NMR spectra, and X-ray diffraction analysis. Having
established the correct configurations of auxiliaries (+)- and (-)-7,
we then proceeded with our investigation of the application of 7
as a desymmetrisation agent.§
Scheme 1 Desymmetrisation of succinic meso-anhydrides.
Upon examination of the scope of this one-pot
desymmetrisation-methylation reaction process, it was found
that the protocol works extremely well on a broad range of
substrates under the standard conditions (Table 1, entry 1).
The majority of bi- (entries 1–5) and tri-cyclic (entries 7–9)
succinic anhydrides screened were generally desymmetrised
and methylated with excellent yields and diastereoselectivities.
Indeed, in most cases a single diastereoisomer was produced,
and the only instance in which the observed diastereoselectivity
was less than optimal, for anhydride 8f (entry 6), the major
diastereoisomer was easily separable from the minor one by
standard column chromatography. In addition, many of the
desymmetrised products were crystalline, thus allowing the
determination of relative stereochemistry by X-ray diffraction
analysis. A representative example of this is the methyl ester
product 9a, the result of desymmetrisation of anhydride 8a with
17
auxiliary (+)-7 (Fig. 5).¶
Fig. 5 X-ray diffraction analysis of 9a.
The excellent results obtained using the one pot
desymmetrisation/TMS-diazomethane methylation of succinic
anhydride examples were unfortunately not reproducible when
applied to glutaric anhydrides and resulted in lower conversion and
only moderate stereoselection. Following further investigation,
it became apparent that use of TMS-diazomethane as the
methylating agent was the problem: the intermediate carboxylate
Fig. 4 X-ray diffraction analysis of (+)-7 (+)-CSA.
‡ Crystal Data for (+)-7·(+)-CSA:◦C20H27NO6S, M = 409.49, orthorhom-
◦
˚
˚
˚
bic, a = 6.53530(10) A, a= 90 , b = 9.87590(10) A, b= 90 , c =
◦
˚
30.2519(5) A, g = 90 , 120(2) K, wavelength 0.71073 A, P2(1)2(1)2(1),
3
-1
˚
U = 1952.52(5) A, Z = 4, 1.393 Mg/m , m(Mo-Ka) = 0.204 mm ,
F(000), crystal size: 0.46 ¥ 0.23 ¥ 0.16 mm3, -8<=h<= 8, -12<=k<= 12,
-34<=l<= 39, 12106 reflections collected, 4392 unique, [R(int) = 0.0295],
completeness to theta = 27.46◦, 98.7%, max. and min. transmission:
0.969 and 0.904, data/restraints/parameters: 4392/0/255, final R indices
[I>2sigma(I)]: R1 = 0.0282, wR2 = 0.0700, R indices (all data): R1 =
0.0297, wR2 = 0.0713, absolute structure parameter: -0.02(5), largest diff.
¶ Crystal Data for 9a: C18H21NO5,M
=
331.36, ◦monoclinic, a
=
◦
˚
˚
˚
9.0302(3) A, a= 90 , b = 8.0096(3) A, b= 109.7370(10) , c = 12.1640(4) A,
◦
3
˚
˚
g = 90 , 180(2) K, wavelength 0.71073 A, P2(1), U = 828.12(5) A ,
Z = 2, 1.329 Mg/m3, m(Mo-Ka) = 0.097 mm-1, F(000)352, crystal
size: 0.46 ¥ 0.46 ¥ 0.07 mm3, theta range for data collection: 3.56
to 27.48◦, 4767 reflections collected, 2025 unique, [R(int) = 0.0285],
completeness to theta = 27.48◦, 99.2%, max. and min. transmission: 0.994
and 0.954, data/restraints/parameters: 2025/2/220, 1.091, final R indices
[I>2sigma(I)]R1 = 0.0385, wR2 = 0.0866, R indices (all data): R1 =
0.0453, wR2 = 0.0913, absolute structure parameter: 0.4(13), largest diff.
-3
˚
peak and hole: 0.232 and -0.352 e.A .
§ It should be noted that our initial communication17 concerning the use
of 7 as a desymmetrising agent was published prior to our re-evaluation
of the X-ray diffraction analysis structure as reported by Abiko et al.10
Therefore all structures depicted therein are the enantiomers of the actual
products obtained.
-3
˚
peak and hole: 0.160 and -0.171 e.A .
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Table 1 Desymmetrisation of succinic meso-anhydrides using (+)-7
Entry
Anhydride
Yield (%)a,b
96d
de (%)c
Product
Entry
Anhydride
Yield (%)a,b
de (%)c
Product
1
> 95
6
100ee
60
2
3
4
90d
74d
> 95
7
8
9
98ee
93ee
98ee
> 95
> 95
> 95
92
98ee
> 95
5
99ee
> 95
a Isolated yield. b All examples were desymmetrised using (+)-7. c Determined by 1H-NMR spectroscopy and LC-MS. d Desymmetrised using both (+)-7
and (-)-7, with matching yields and diastereoselectivities. e Desymmetrised using (+)-7.
anion formed after deprotonation can readily substitute into
the auxiliary amide carbonyl and force the auxiliary to leave,
resulting in generation of the anhydride and a negatively charged
auxiliary (Scheme 2).ꢀ This charged auxiliary would be much
more nucleophilic than the neutral species, and therefore less
likely to discriminate selectively between the two anhydride
carbonyl groups upon further reaction. Hence, it became clear
that a methylation protocol that did not involve carboxylate anion
formation would be required.
Indeed, the use of methyl iodide with silver oxide in dimethyl
formamide gave such a good result (91%, 86% de, Table 2, entry 1)
that these conditions were then taken and applied directly to a
range of other glutaric anhydride examples (Scheme 3, Table 2).
Scheme 3 Desymmetrisation of glutaric meso-anhydrides.
Pleasingly, all subsequent glutaric anhydride examples evalu-
ated provided desymmetrised products in good to excellent yields;
however, the diastereoselectivity of desymmetrisation proved to
be highly dependent upon anhydride structure. Glutaric anhy-
drides with substituents alpha to the carbonyl groups afforded
good yields and high diastereoselectivities (entries 1–3), as did
glutaric anhydrides substituted in the 3-position with groups
such as –OH and –OTBS (entries 4, 5). In contrast, the glutaric
anhydrides substituted in the 3-position with only small alkyl
substituents or aromatic groups that can lie flat and effectively
perpendicular to the anhydride ring provided excellent yields but
no diastereoselectivity (entries 6–9), as auxiliary 7 could no longer
differentiate between the two diastereotopic carbonyl centers
of attack for these examples. All diastereoisomers were easily
Scheme 2 Postulated mechanism for the reduced desymmetrisation
diastereoselectivities of glutaric meso-anhydride 10.
ꢀ This does not occur with the succinic anhydrides as the systems
undergoing desymmetrisation are bicyclic in nature and the regenerated
anhydride would be a five-membered ring attached to another ring system:
assuming this reformation occurs more slowly than methylation due to
strain factors, the initial diastereoselectivity generated by the auxiliary
should be preserved, as was the observed result. Given the lower degree
of strain in six-membered ring glutaric anhydrides, if ring closure occurs
more rapidly than methylation, an overall lower diastereoselectivity would
result, as was observed.
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Table 2 Desymmetrisation of glutaric meso-anhydrides using (+)- and (-)-7
Entry
Anhydride
Yield (%)a,b
91
de (%)c
86
Product
Entry
Anhydride
Yield (%)a,b
100
de (%)c
0
Product
1
6
2
3
87
85
70
75
7
8
100
100
0
0
4
5
75
99
70
80
9
95
0
a Isolated yield. b All examples were desymmetrised using both (+)-7 and (-)-7, with matching yields and diastereoselectivities. c Determined by 1H-NMR
spectroscopy and LC-MS.
separable by chromatography, and isolated yields were found to
reflect the diastereomeric excess observed analytically for all crude
reaction mixtures. In addition, the majority of diastereomeric
products isolated were again crystalline, allowing the use of X-ray
diffraction analysis for determination of relative stereochemistry.
A representative example of this is the methyl ester product 11a,
the result of the desymmetrisation of anhydride 10a using auxiliary
(+)-7 (Fig. 6).**
With the successful desymmetrisation of both succinic and
glutaric meso-anhydrides now accomplished, their derivatisation
and subsequent application in a total synthesis programme was
initiated. At this stage, it was necessary to first investigate whether
the amide and ester moieties present in the desymmetrised prod-
ucts could definitively be successfully differentiated. In theory, the
Weinreb-type amide and ester functionalities should have differing
reactivities: thus it was anticipated that via selective manipulation
of these, chiral mono-protected diols might be generated. Chemo-
differentiation between the ester and the Weinreb-type amide in
9a was indeed successfully achieved using Schwartz reagent under
relatively mild conditions (Scheme 4),18,19 which selectively reduced
the methyl ester moiety in 9a to alcohol 12 at room temperature
in 30 minutes. This reaction was found to be reproducible on scale
in high yield without erosion of diastereomeric excess, and left the
auxiliary portion of the molecule intact.
Fig. 6 X-ray diffraction analysis of 11a.
Protection of the primary alcohol 12 as a TBS- or TBDPS-
ether also proceeded smoothly, and subsequent borohydride
reduction facilitated cleavage of the auxiliary to give 1,4-mono-
protected diols 15 and 16 in quantitative yields and with com-
plete retention of stereochemistry. The diastereoselectivity of the
** Crystal Data for 11a: C18H23NO5, M = 333.37, monoclinic, a =
◦
◦
˚
˚
˚
7.6843(2) A, a= 90 . b = 10.9358(3) A, b= 100.974(2) , c = 10.2015(3) A,
◦
3
˚
˚
g = 90 , 180(2) K, wavelength: 0.71073 A, P2(1), U = 841.60(4) A ,
Z 2, 1.316 Mg/m3, m(Mo-Ka) = 0.096 mm-1, F(000)356, crystal
size: 0.46 ¥ 0.46 ¥ 0.42 mm3, theta range for data collection: 3.58
to 27.49◦, 5141 reflections collected, 2004 unique, [R(int) = 0.0195],
completeness to theta = 27.49◦, 99.0%, max. and min. transmission:
0.968 and 0.922, data/restraints/parameters: 2004/1/220, final R indices
[I>2sigma(I)]R1 = 0.0420, wR2 = 0.1141, R indices (all data): R1 =
0.0596, wR2 = 0.1424, absolute structure parameter: -0.4(11), largest diff.
-3
˚
peak and hole: 0.973 and -0.971 e.A .
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utility of this desymmetrisation and derivatisation methodology
for both succinic and glutaric anhydrides.
In addition, the desymmetrisation method combined with the
derivatisation sequence of 11a has now been shown to provide a
highly robust and scaleable route to mono-protected diol 22.
This compound, originally synthesised by alternative means,
has recently been utilised as a key fragment in our group’s total
synthesis of rapamycin 23,21 a powerful immunosuppressant22
and antitumour agent:23 the syn-deoxypolypropionate moiety 22
was used to construct key intermediate C22-C28 electrophile 24
(Scheme 6).21In the original publication,21 oxidation of 22 using
Parikh-Doering conditions provided aldehyde 25 in excellent yield
(99%) and in just five subsequent steps the C22–C28 electrophile
24 was obtained in 25% overall yield (Scheme 7), which was then
incorporated into the total synthesis of rapamycin. One advantage
of using the desymmetrisation method outlined here to obtain
alcohol precursor 22 is that, not only can the mono-protected diol
be accessed in high yields and with excellent stereocontrol, but
its enantiomer can also be easily obtained with the same degree
of efficiency and enantiopurity, thus providing a readily available
route for analogue synthesis.
Scheme 4 Chemoselective reduction, protection and reductive auxiliary
cleavage for succinic anhydrides. Protection conditions: aTBS-OTf, 2,6-lu-
tidine, CH2Cl2, 1 h, 0 ◦C to rt. bTBDPS-Cl, imidazole, DMAP, TBAI,
CH2Cl2, 16 h, 0 ◦C to rt. cDetermined by Mosher ester formation.
d Determined by chiral HPLC.
original desymmetrisation step was thus maintained throughout
the derivatisation process, as monitored by 1H-NMR. Indeed,
the diastereoselectivity of the original anhydride desymmetrisa-
tion ultimately translated into excellent enantioselectivity upon
auxiliary cleavage, as determined by derivatisation via Mosher
1
ester formation and subsequent H-NMR and/or chiral HPLC
analysis.
Selective manipulation and derivatisation of glutaric meso-
anhydride product 11a was next attempted. This particular
substrate was of interest because the syn-deoxypolypropionate
moiety 17 (Fig. 7) is a structural feature found in many natural
products.20 A new method for the stereoselective formation of this
motif would therefore have significant potential application.
Scheme 6 Rapamycin 23 and C22-C28 electrophile fragment 24.
Fig. 7 Syn-deoxypolypropionate moiety 17.
Using the same conditions as had been applied to derivatisation
of the succinic substrate 9a, reduction of ester 11a was now
attempted (Scheme 5). Pleasingly, under these conditions the ester
moiety was indeed reduced to give alcohol 18 in high yield without
any erosion of diastereoselectivity. Alcohol 18 was then protected
as TBS- and PMB-ethers in high yields and with complete
retention of diastereomeric excess. Reduction of ethers 19 and
20 to mono-protected diols 21 and 22 also proved to be highly
successful (100% yield, >99% ee), thus demonstrating the general
Scheme 7 Oxidation of diol 25 and formation C22–C28 electrophile
fragment 22.21
Conclusion
A general synthetically useful method for the desymmetrisation of
cyclic meso-anhydrides using benzopyranoisoxazolidines as chiral
auxiliaries has thus been developed and successfully applied to
a wide range of both succinic and glutaric anhydrides. Facile
access to both enantiomers of the chiral auxiliary 7 facilitates
the formation of all possible diastereomers, and the highly
crystalline nature of many of the desymmetrised products permits
straightforward isolation of the desired products in excellent
yields and diastereoselectivities. Additionally, the desymmetrised
Scheme 5 Chemoselective reduction, protection and auxiliary cleavage
a
for glutaric anhydrides. Conditions: TBS-OTf, 2,6-lutidine, CH2Cl2, 1 h,
0
◦C to rt. bPMB-TCA, La(OTf)3, toluene, 20 min, rt. cDetemined by
Mosher ester formation. d Determined by chiral HPLC.
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products have been effectively derivatised to 1,4-mono-protected
alcohols, which are precursors to key intermediates in natural
product synthesis. An example of this is alcohol 22, which has been
shown to be a useful component in our group strategy towards the
total synthesis of the biologically active natural product rapamycin
23.
shift d (parts per million, ppm) (multiplicity, number of protons,
coupling constant J, in Hertz, Hz, assignment). Multiplicities are
abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet
(q), multiplet (m), broad (br) or combinations of the preceding.
Carbon nuclear magnetic resonance spectra (13C-NMR) were
recorded on a Bruker DPX 400 spectrometer at 100 MHz using
the central resonance of CDCl3 as the internal standard (dC
77.0, t). Spectra are reported as follows: chemical shift d (parts per
million, ppm), (assignment).
=
Experimental
COSY, HMQC, HMBC and DEPT-135 experiments were used
to aid in the assignment of 1H- and 13C-NMR signals.
All X-ray diffraction analyses were performed by Dr. John
Davies at the Department of Chemistry, University of Cambridge.
General methods
When anhydrous conditions were required, reactions were carried
out under an atmosphere of argon and in oven-dried glassware.
Synthetic intermediates were dried in vacuo before us◦e in non-
aqueous reactions. Molecular sieves were dried at 200 C before
use.
Formation of chiral auxiliary
1,3a,4,9b-Tetrahydro-3H-[1]benzopyrano[4,3-c]isoxazole (( )-7).
Petroleum ether was distilled between 40 and 60 ◦C. Diethyl
ether (Et2O) and tetrahydrofuran (THF) were distilled over
calcium hydride and lithium aluminium hydride. Dichloromethane
(CH2Cl2), toluene, acetonitrile (MeCN) and methanol (MeOH)
were distilled over calcium hydride. Triethylamine was distilled
from calcium hydride and stored over potassium hydride. Other
reagents and solvents were used as supplied or purified using
standard procedures as required. Aqueous solutions are saturated
unless otherwise specified.
Flash column chromatography was carried out using Merck
BDH F254 Kieselgel 60 (230–400 mesh) as the stationary phase
and eluted with positive pressure of compressed air.
Analytical thin layer chromatography was performed using pre-
coated Merck glass-backed silica gel plates (Merck Kieselel 60 F254
and visualised by ultraviolet light (254 nm) and treatment with
acidic potassium permanganate, acidic ammonium molybdate
(IV), Schlittler, or anisaldehyde stains followed by heating as
appropriate.
Mass spectra and accurate mass data were obtained on Mi-
cromass Platform HP1050 LC/MS, Waters Alliance HT2795
LC/MS, Kratos QTOF or Bruker BIOAPEX 4.7 FTICR spec-
trometers by electrospray ionization (+ESI) or electron impact
(EI) at the Department of Chemistry, University of Cambridge.
Chiral HPLC was performed on Agilent 1100 using Chiralcel
columns, HPLC grade solvents and UV detection (l = 215, 254,
280 nm) at room temperature.
Infra-red spectra were recorded on Perkin Elmer Spectrum
One FT-IR 1620 Universal ATR sampling accessory from 4000–
600 cm-1. All samples were run as thin films on a diamond/Se
plate. Absorption maxima are reported in wavenumbers (cm-1).
Optical rotations were measured on a Perkin Elmer Model 343
polarimeter using a sodium lamp (l 589 nm, D-line); [a]D values
are reported in units of 10-1 deg cm2 g-1. All optical rotations were
measured using CHCl3 as solvent and were measured at 25 ◦C;
concentration (c) is reported in g/(100 mL).
Prepared by the literature procedure.9–16
A mixture of 2-
allylhydroxybenzaldehyde (0.50 g, 3.08 mmol), 5-hydroxypentanal
oxime (0.38 g, 3.24 mmol), dibutyl tin oxide (0.08 g, 0.31 mmol),
and toluene (40 mL) was heated under reflux with Dean-Stark
apparatus for 12 h. The reaction mixture was cooled to room
temperature, concentrated in vacuo, and the resulting crude
product ( )-7 was taken up in ethanol (14 mL) and aqueous
hydrochloric acid (3 N, 7 mL) solution. This mixture was stirred
at room temperature for 15 h, at which point the solvent was
removed in vacuo and the remaining aqueous phase was washed
with diethyl ether (2 ¥ 20 mL), neutralized with ammonium
hydroxide (50 mL, 15%), and extracted with dichloromethane
(5 ¥ 20 mL), dried (MgSO4) and concentrated in vacuo to yield
a yellow oil. This oil was dissolved in acetone (1.2 L) and left
to stand at ambient temperature, generating yellowish crystals of
)
◦
◦
( )-7 (0.49 g, 2.74 mmol, 89%). mp 95–96 C (lit.,9–16 95–96 C);
IR nmax (film)/cm-1 3187 (NH), 1607 (aromatic), 1582 (aromatic);
1H-NMR (400 MHz, CDCl3): d 7.41 (d, 1H, J = 7.4 Hz), 7.22 (t,
1H, J = 8.3 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.94 (d, 1H, J = 8.3 Hz),
5.03 (s, 1H), 4.35–4.31 (m, 2H), 4.23 (m, 1H), 3.76–3.72 (m, 2H),
3.11–3.07 (m, 1H); 13C-NMR (100 MHz, CDCl3): d 155.5, 131.3,
129.4, 121.6, 118.5, 117.3, 72.8, 65.2, 57.3, 40.7; MS (+ESI) =
Calcd. for C10H11NO2 (M + Na)+: 200.0691, Found (M + Na)+:
200.0690.
(+)-1,3a,4,9b-Tetrahydro-3H -[1]benzopyrano[4,3-c]isoxazole
((+)-7) and (-)-1,3a,4,9b-tetrahydro-3H-[1]benzopyrano[4,3-c]iso-
xazole ((-)-7). Prepared by the literature procedure.9–16 A mixture
of crude ( )-7 (130 g, 0.73 mol) and (+)-camphorsulfonic acid
((+)-CSA) (194 g, 0.78 mmol) in acetone (1.3 L) was heated until
everything was dissolved and then allowed to cool to room temper-
ature. After being allowed to stand overnight, the first crop of (+)-
7·(+)-CSA (56 g, 0.13 mol, 18%) was collected. The mother liquor
was concentrated to 2/3 of its original volume (800 mL) and left
to stand overnight, yielding the first crop of (-)-7·(+)-CSA (43 g,
0.10 mol, 14%). This protocol was repeated twice to yield a second
crop of (+)-7·(+)-CSA (40 g, 0.09 mol, 13%) and (-)-7·(+)-CSA
(34 g, 0.08 mol, 12%), respectively. After enantiomeric purities
were determined to be >99% ee by chiral HPLC (Chiralcel OD-H,
1.0 mL/min, 30 min, hexane:isopropanol, 95:5; retention time for
(-)-7 = 13.2 min, retention time for (+)-7 = 22.7 min), matching
crystalline crops were combined, neutralised by treatment with
aqueous sodium hydroxide (1 N, 40 mL), extracted twice with
Melting points were measured on a Reichert hot stage appara-
tus, and are uncorrected.
Nuclear magnetic resonance (NMR) spectra were recorded at
27 ◦C in deuterated chloroform (CDCl3) unless otherwise stated.
Proton nuclear magnetic resonance spectra (1H-NMR) were
recorded using a Bruker DPX 400 Fourier transform spectrometer
at 400 MHz with residual protic solvent as the internal standard
(CHCl3, dH = 7.26, s). Spectra are reported as follows: chemical
752 | Org. Biomol. Chem., 2009, 7, 747–760
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dichloromethane (2 ¥ 30 mL), dried (MgSO4) and concentrated
in vacuo to afford white crystals: (+)-7 (96 g, 0.23 mol, 31%) and
(-)-7 (81 g, 0.20 mol, 26%).
All desymmetrisations were performed using (+)-7; in some
cases (-)-7 was also used, as is noted where appropriate.
(+)-(1¢S,2¢R,3aR,9bS)-Methyl-2¢-(3,3a,4,9b-tetrahydro-1H-
chromeno[4,3-c]isoxazole-1¢-yl)cyclohexanecarboxylate (9a). Iso-
lated as a white powder, 166 mg total yield (96%, >95% de). mp =
◦
(+)-7·(+)-CSA. mp 185–187 C (lit.,9 185–187); [a]D25 = + 63
(c = 1.12, CHCl3) (lit.,9: [a]D25 = + 61.5 (c = 1.10, CH3OH)); IR
◦
151–152 C; [a]D25 = + 69 (c = 1.17, CHCl3); IR nmax (film)/cm-1
n
max (film)/cm-1 2954 (CH), 1739 (CO), 1586 (aromatic); 1H-NMR
1
2229 (CH), 2857 (CH), 1711 (CO-ester), 1664 (CO-amide); H-
(CDCl3): d 7.41 (d, 1H, J = 7.5 Hz), 7.38 (t, 1H, J = 8.3 Hz), 7.09
(t, 1 H, J = 7.5 Hz), 7.02 (d, 1H, J = 8.3 Hz), 5.19 (d, 1H, J =
7.2 Hz), 4.62 (s, 2H), 4.40–4.35 (m, 1H), 3.90–3.75 (m, 3H), 3.22–
3.17 (m, 1H), 2.79–2.74 (m, 1H), 2.68–2.64 (m, 1H), 2.35–2.31 (m,
1H), 2.06–2.01 (m, 2H), 1.93–1.88 (m, 1H), 1.62–1.58 (m, 1H),
1.15 (s, 3H), 1.13 (s, 3H); 13C-NMR (100 MHz, CDCl3): d 218.8,
157.6, 133.1, 132.8, 123.7, 119.5, 115.1, 75.3, 65.3, 60.0, 58.9, 48.8,
43.2, 40.5, 29.6, 28.2, 26.8, 26.2, 20.8, 20.6; MS (+ESI) = Calcd.
for C20H28NO6S (M + H)+: 410.1637, Found (M + H)+: 410.1642.
NMR (400 MHz, CDCl3): d 7.60 (d, 1H, J = 7.9 Hz), 7.18 (t, 1H,
J = 7.8 Hz), 6.98 (t, 1H, J = 7.6 Hz), 6.87 (d, 1H, J = 7.8 Hz), 5.40
(d, 1H, J = 7.9 Hz), 4.30 (dd, 1H, J = 11.2 and 4.4 Hz), 3.85–3.75
(m, 1H), 3.62 (dd, 1H, J = 7.3 and 3.7 Hz), 3.37 (dd, 1H, J = 11.2
and 9.4 Hz), 3.68 (s, 3H), 3.54–3.49 (m, 1H), 3.19–3.08 (m, 1H),
2.57–2.53 (m, 1H), 2.35–2.25 (m, 1H), 2.11–2.06 (m, 1H), 1.98–
1.91 (m, 1H), 1.84–1.79 (m, 1H), 1.66–1.57 (m, 1H), 1.51–1.38 (m,
2H), 1.31–1.27 (m, 1H); 13C-NMR (100 MHz, CDCl3): d 179.8,
175.4, 155.4, 131.9, 129.2, 122.5, 122.4, 117.2, 71.9, 65.8, 52.7,
52.0, 43.5, 40.5, 38.9, 28.8, 25.4, 25.2, 22.4; MS (+ESI) = Calcd.
for C19H23NO5 (M + H)+: 346.1954, Found (M + H)+: 346.1957.
Ent 9a: [a]2D5 = - 81 (c = 1.25, CHCl3).
◦
(-)-7·(+)-CSA. mp 186–189 C (lit.,9 186–188); [a]D25= - 11
(c = 1.05, CHCl3) (lit.,9 [a]D25 = - 12 (c = 1.15, CH3OH)); IR nmax
1
(film)/cm-1 2954 (CH), 1739 (CO), 1586 (aromatic); H-NMR
(CDCl3): d 7.40 (d, 1H, J = 7.5 Hz), 7.38 (t, 1H, J = 8.3 Hz), 7.08
(t, 1 H, J = 7.5 Hz), 7.02 (d, 1H, J = 8.3 Hz), 5.19 (d, 1H, J =
7.2 Hz), 4.60 (s, 2H), 4.42–4.35 (m, 1H), 3.90–3.76 (m, 3H), 3.22–
3.15 (m, 1H), 2.80–2.74 (m, 1H), 2.68–2.63 (m, 1H), 2.35–2.30 (m,
1H), 2.07–2.00 (m, 2H), 1.93–1.88 (m, 1H), 1.62–1.58 (m, 1H),
1.15 (s, 3H), 1.10 (s, 3H); 13C-NMR (100 MHz, CDCl3): d 218.7,
157.6, 133.0, 132.8, 123.7, 119.3, 115.2, 75.3, 65.5, 60.0, 59.0, 48.8,
43.0, 40.5, 29.5, 28.2, 26.8, 26.1, 20.8, 20.6; MS (+ESI) = Calcd.
for C20H28NO6S (M + H)+: 410.1637, Found (M + H)+: 410.1645.
(+)-(1¢S,3aR,6¢R,9bS)-Methyl-6¢-(3,3a,4,9b-tetrahydro-1H-
chromeno[4,3-c]isoxazole-1¢-yl)cyclohex-3¢-enecarboxylate (9b).
Isolated as a white powder, 154 mg total yield (90%, >95%
◦
de). mp = 152–153 C; [a]2D5 = + 98 (c = 0.85, CHCl3); IR
nmax (film)/cm-1 2950 (CH), 1729 (CO-ester), 1668 (CO-amide);
1H-NMR (400 MHz, CDCl3): d 7.60 (d, 1H, J = 7.6 Hz), 7.15
(t, 1H, J = 8.0 Hz), 6.98 (t, 1H, J = 7.5 Hz), 6.88 (d, 1H, J =
8.0 Hz), 5.80–5.70 (m, 1H), 5.70–5.60 (m, 1H), 5.43 (d, 1H, J =
8.0 Hz), 4.30 (dd, 1H, J = 11.4 and 4.4 Hz), 4.19–4.15 (m, 1H),
4.10 (dd, 1H, J = 7.3 and 3.7 Hz), 3.93 (dd, 1H, J = 11.4 and 8.0),
3.68 (s, 3H), 3.59–3.53 (m, 1H), 3.22–3.17 (m, 1H), 2.90–2.78 (m,
2H), 2.48–2.39 (m, 3H); 13C-NMR (100 MHz, CDCl3): d 179.0,
175.1, 155.4, 132.0, 129.2, 125.9, 124.3, 122.5, 122.2, 117.2, 72.1,
65.7, 52.9, 52.2, 40.6, 39.8, 36.2, 27.7, 25.9. MS (+ESI) = Calcd.
for C19H21NO5 (M + H)+: 344.1423, Found (M + H)+: 344.1419.
Ent 9b: [a]2D5 = - 104 (c = 0.95, CHCl3).
(+)-1,3a,4,9b-Tetrahydro-3H -[1]benzopyrano[4,3-c]isoxazole
((+)-7). mp 95–96 ◦C (lit.,9 95–96); [a]D25 = + 62 (c = 1.20, CHCl3)
(lit.,9 [a]D25 = + 62.4 (c = 1.11, CHCl3)); IR nmax (film)/cm-1 3187
(CH), 1607 (aromatic), 1582 (aromatic); 1H-NMR (400 MHz,
CDCl3): d 7.41 (d, 1H, J = 7.4 Hz), 7.22 (t, 1H, J = 8.3 Hz), 6.98
(t, 1H, J = 7.4 Hz), 6.94 (d, 1H, J = 8.3 Hz), 5.03 (s, 1H), 4.33
(m, 2H), 4.26–4.19 (m, 1H), 3.75–3.71 (m, 2H), 3.12–3.08 (m, 1H);
13C-NMR (100 MHz, CDCl3): d 155.5, 131.3, 129.4, 121.6, 118.5,
117.3, 72.8, 65.2, 57.3, 40.7; MS (+ESI) = Calcd. for C10H11NO2
(M + H)+: 178.1296, Found (M + H)+: 178.1298.
(+)-(1¢S,2¢R,3aR,9bS)-Methyl-2¢-(3,3a,4,9b-tetrahydro-1H-
chromeno[4,3-c]isoxazole-1¢-yl)cyclopentanecarboxylate(9c). Iso-
lated as a white powder, 123 mg total yield (74%, 92% de). mp =
197–200 ◦C; [a]D25 = + 170 (c = 1.10, CHCl3); IR nmax (film)/cm-1
3074 (CH), 2956 (CH), 1717 (CO-ester), 1669 (CO-amide), 1585
(aromatic); 1H-NMR (400 MHz, CDCl3): d 7.62 (d, 1H, J =
7.4 Hz), 7.17 (t, 1H, J = 8.1 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.81 (d,
1H, J = 8.1 Hz), 5.45 (d, 1H, J = 8.1 Hz), 4.28–4.17 (m, 2H), 4.05–
4.00 (m, 1H), 3.99–3.93 (m, 1H), 3.68 (s, 3H), 3.64–3.59 (m, 1H),
3.23–3.18 (m, 1H), 3.11–3.06 (m, 1H), 2.24 - 2.16 (m, 1H), 2.05–
1.94 (m, 4H), 1.76–1.73 (m, 1H); 13C-NMR (100 MHz, CDCl3):
d 175.2, 173.0, 155.1, 131.3, 128.8, 122.9, 119.9, 117.3, 71.9,
66.1, 53.2, 52.2, 40.8, 39.5, 33.6, 29.9, 28.6, 22.4; MS (+ESI) =
Calcd. for C18H21NO5 (M + H)+: 332.2015, Found (M + H)+:
332.2011. Ent 9c: [a]2D5 = - 164 (c = 1.00, CHCl3).
(+)-(1¢S,2¢R,3aR,9bS)-Methyl-2¢-(3,3a,4,9b-tetrahydro-1H-
chromeno[4,3-c]isoxazole-1¢-yl)cyclobutanecarboxylate (MAJOR
9d) and (+)-(1¢R,2¢S,3aR,9bS)-methyl-2¢-(3,3a,4,9b-tetrahydro-
1H-chromeno[4,3-c]isoxazole-1¢-yl)cyclobutanecarboxylate (MI-
NOR 9d). Isolated as major (126 mg, 80%) and minor (31 mg,
20%) diastereoisomers, as clear oils, 157 mg total yield (100%,
60% de). MAJOR 9d: [a]2D5 = + 234 (c = 1.02, CHCl3); IR nmax
(-)-1,3a,4,9b-Tetrahydro-3H-[1]benzopyrano[4,3-c]isoxazole
((-)-7). [a]2D5 = - 59 (c = 0.92, CHCl3) (lit.,9 [a]2D5 = - 62.4 (c =
1.11, CHCl3)).
General protocol for desymmetrisation of succinic anhydrides
To a stirred solution of cyclic meso-anhydride (0.55 mmol) in
dichloromethane (1.5 mL) at -78 ◦C was added a solution of (+)-
or (-)-7 (89 mg, 0.5 mmol) in dichloromethane (0.5 mL) dropwise
via syringe. The reaction was stirred at -78 ◦C for 30 min, and
trimethylsilyldiazomethane (2.0 M in hexanes, 0.5 mL, 1.0 mmol)
was added dropwise via syringe. The resulting yellow solution was
allowed to stir at -78 ◦C for 24 h, at which point the reaction was
quenched with methanol (4 mL). The reaction mixture was allowed
to stir for 30 min while warming to room temperature and was
then concentrated in vacuo. Crude product was purified by flash
column chromatography (petroleum ether:diethyl ether, 1:1). All
diastereomeric excesses were evaluated by 1H-NMR spectroscopy
of crude reaction mixtures prior to purification; all yields are
isolated yields.
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(film)/cm-1 3074 (CH), 2956 (CH), 1715 (CO-ester), 1668 (CO-
amide), 1585 (aromatic); 1H-NMR (400 MHz, CDCl3): d 7.70 (d,
1H, J = 7.4 Hz), 7.17 (t, 1H, J = 8.1 Hz), 6.98 (t, 1H, J = 7.4 Hz),
6.85 (d, 1H, J = 8.1 Hz), 5.48 (d, 1H, J = 8.1 Hz), 4.25 (dd,
1H, J = 11.4 and 4.4 Hz), 4.23–4.16 (m, 1H), 3.94–3.88 (m, 3H),
3.68 (s, 3H), 3.52–3.48 (m, 1H), 3.20–3.16 (m, 1H), 2.54–2.48 (m,
2H), 2.33–2.27 (m, 1H), 2.22–2.18 (m, 1H); 13C-NMR (100 MHz,
CDCl3): d 176.1, 174.4, 155.2, 132.2, 129.4, 122.4, 121.1, 117.3,
71.3, 65.4, 53.1, 52.1, 41.6, 40.5, 39.0, 23.2, 22.2; MS (+ESI) =
Calcd. for C17H19NO5 (M + H)+: 318.3309, Found (M + H)+:
318.3312. MINOR 9d: [a]2D5 = + 225 (c = 1.04, CHCl3); IR nmax
(film)/cm-1 3074 (CH), 2956 (CH), 1715 (CO-ester), 1668 (CO-
amide), 1585 (aromatic); 1H-NMR (400 MHz, CDCl3): d 7.70 (d,
1H, J = 7.4 Hz), 7.17 (t, 1H, J = 7.3 Hz), 6.98 (t, 1H, J = 7.1 Hz),
6.85 (d, 1H, J = 8.1 Hz), 5.46 (d, 1H, J = 8.1 Hz), 4.25 (dd,
1H, J = 11.4 and 4.4 Hz), 4.23–4.16 (m, 1H), 3.94–3.88 (m, 3H),
3.68 (s, 3H), 3.52–3.48 (m, 1H), 3.20–3.16 (m, 1H), 2.54–2.48 (m,
2H), 2.33–2.27 (m, 1H), 2.22–2.18 (m, 1H); 13C-NMR (100 MHz,
CDCl3): d 176.0, 174.3), 155.1, 132.1, 129.4, 122.3, 121, 117.3, 71.3,
65.3, 53.0, 52.0, 41.4, 40.5, 39.0, 23.1, 22.1. MS (+ESI) = Calcd.
for C17H19NO5 (M + H)+: 318.3424, Found (M + H)+: 318.3428.
7.72 (d, 1H, J = 6.9 Hz), 7.17 (t, 1H, J = 8.2 Hz), 6.98 (t, 1H, J =
6.9 Hz), 6.87 (d, 1H, J = 8.2 Hz), 6.23 (s, 2H), 5.45 (d, 1H, J =
7.9 Hz), 4.33 (dd, 1H, J = 11.2 and 4.7 Hz), 4.18–4.14 (m, 1H),
3.99–3.88 (m, 2H), 3.68 (s, 3H), 3.15–3.07 (m, 4H), 2.71–2.68 (m,
1H), 2.19–2.16 (m, 1H), 1.54–1.51 (m, 1H); 13C-NMR (100 MHz,
CDCl3): d 177.1, 174.5, 155.1, 139.0, 138.1, 132.3, 129.4, 122.5,
122.0, 117.2, 70.9, 65.2, 53.1, 52.2, 48.3, 46.8, 46.1, 46.0, 44.1,
40.5; MS (+ESI) = Calcd. for C20H21NO5 (M + H)+: 356.3213,
Found (M + H)+: 356.3210.
(+)-(2¢S,3¢R,3aR,9bS)-Methyl-3¢-(3,3a,4,9b-tetrahydro-1H-
chromeno[4,3-c]isoxazole-1-carbonyl)oxirane-2¢-carboxylate (9h).
Isolated as a clear oil, 150 mg total yield (98%, >95% de). [a]D25
=
+ 246 (c = 1.10, CHCl3); IR nmax (film)/cm-1 2955 (CH), 1719
1
(CO-ester), 1677 (CO-amide); H-NMR (400 MHz, CDCl3): d
7.65 (d, 1H, J = 7.6 Hz), 7.22 (t, 1H, J = 8.3 Hz), 6.96 (t, 1H, J =
7.6 Hz), 6.82 (d, 1H, J = 8.3 Hz), 5.44 (d, 1H, J = 8.0 Hz), 4.31–
4.28 (m, 1H), 4.09–4.05 (m, 2H), 3.95–3.90 (m, 1H), 3.83–3.76 (m,
4H), 3.73–3.70 (m, 1H), 3.23–3.17 (m, 1H); 13C-NMR (100 MHz,
CDCl3): d 167.3, 166.5, 155.3, 131.9, 129.7, 122.6, 120.8, 117.5,
72.2, 65.2, 53.3, 52.9, 52.5, 52.2, 40.4; MS (+ESI) = Calcd. for
C15H15NO6 (M + H)+: 306.3550, Found (M + H)+: 306.3554.
(+)-(1¢S,2¢Ry,3aR,9bS)-Methyl-2¢-(3,3a,4,9b-tetrahydro-1H-
(+)-(2¢S,3¢R,3aR,9bS)-Methyl-3¢-(3,3a,4,9b-tetrahydro-1H-
chromeno[4,3-c]isoxazole-1-yl)-7¢-oxabicyclo[2.2.1]heptane-2¢-
carboxylate (9i). Isolated as a clear oil, 180 mg total yield (98%,
>95% de). [a]D25 = + 217 (c = 1.10, CHCl3); IR nmax (film)/cm-1
2951 (CH), 1708 (CO-ester), 1610 (CO-amide), 1584 (aromatic);
1H-NMR (400 MHz, CDCl3): d 7.70 (d, 1H, J = 6.9 Hz), 7.15
(t, 1H, J = 7.5 Hz), 6.92 (t, 1H, J = 6.9 Hz), 6.85 (d, 1H, J =
7.5 Hz), 5.45 (d, 1H, J = 7.9 Hz), 4.98–4.93 (m, 1H), 4.88–4.84
(m, 1H), 4.22 (dd, 1H, J = 11.2 and 4.7 Hz), 4.18–4.13 (m, 1H),
3.96–3.92 (m, 2H), 3.68 (s, 3H), 3.34–3.28 (m, 1H), 3.15–3.09 (m,
1H), 3.04–3.00 (m, 1H), 1.84–1.75 (m, 2H), 1.55–1.49 (m, 2H);
13C-NMR (100 MHz, CDCl3): d 174.6, 172.1, 155.1, 132.4, 129.4,
122.4, 121.8, 117.1, 79.1, 78.2, 70.9, 65.1, 53.1, 52.7, 52.0, 49.0,
40.0, 29.3, 28.9; MS (+ESI) = Calcd. for C19H21NO6 (M + H)+:
360.6581, Found (M + H)+: 360.6587.
chromeno[4,3-c]isoxazole-1¢-yl)cyclopropanecarboxylate
(9e).
Isolated as a white powder, 150 mg total yield (99%, >95%
◦
de). mp = 221–222 C; [a]2D5 = + 270 (c = 1.10, CHCl3); IR
nmax (film)/cm-1 2953 (CH), 1709 (CO-ester), 1665 (CO-amide);
1H-NMR (400 MHz, CDCl3): d 7.68 (dd, 1H, J = 7.1 Hz), 7.16
(t, 1H, J = 8.1 Hz), 6.93 (t, 1H, J = 7.1 Hz), 6.85 (d, 1H, J =
8.1 Hz), 5.47 (d, 1H, J = 8.0 Hz), 4.29–4.23 (m, 3H), 3.95 (dd, 1H,
J = 8.1 and 1.5 Hz), 3.65 (s, 3H), 3.13–3.08 (m, 1H), 2.46–2.41
(m, 1H), 2.16–2.12 (m, 1H), 1.78–1.71 (m, 1H), 1.30–1.25 (m,
1H); 13C-NMR (100 MHz, CDCl3): d 173.0, 171.5, 155.3, 132.0,
129.4, 122.5, 121.8, 117.3, 71.7, 65.5, 53.3, 52.5, 40.6, 22.2, 21.0,
11.4; MS (+ESI) = Calcd. for C16H17NO5 (M + H)+: 304.3151,
Found (M + H)+: 304.3147.
(+)-(2¢R,3¢S,3aR,9bS)-Methyl-3¢-(3,3a,4,9b-tetrahydro-1H-
chromeno[4,3-c]isoxazole-1¢-yl)bicyclo[2.2.1]hept-5¢-ene-2¢-car-
boxylate (9f). Isolated as a white powder, 174 mg total yield
General protocol for desymmetrisation of glutaric anhydrides
◦
(98%, >95% de). mp = 152–154 C; [a]2D5 = + 164 (c = 1.05,
To a stirred solution of cyclic meso-anhydride (0.55 mmol) in
dichloromethane (1.5 mL) at -78 ◦C was added a solution of (+)-
or (-)-7 (89 mg, 0.5 mmol) in dichloromethane (0.5 mL) dropwise
via syringe. The reaction mixture was stirred at -78 ◦C for 72 h, at
which point the solvent was removed in vacuo. The resulting crude
product was dissolved in N,N-dimethylformamide (2 mL) and the
flask covered with aluminium foil. Methyl iodide (62 mL, 1.0 mmol)
and freshly prepared silver oxide†† (232 mg, 1.0 mmol) were added
and the resulting mixture was stirred at room temperature for
30 min. The suspension was then filtered through celite and washed
four times with diethyl ether. The resulting filtrate was washed
with lithium bromide (5 mL, 4% aqueous) and brine (5 mL),
CHCl3); IR nmax (film)/cm-1 2975 (CH), 1713 (CO-ester), 1666
1
(CO-amide); H-NMR (400 MHz, CDCl3): d 7.73 (d, 1H, J =
7.4 Hz), 7.15 (t, 1H, J = 8.1 Hz), 6.93 (t, 1H, J = 7.4 Hz), 6.85
(d, 1H, J = 8.1 Hz), 6.52 (dd, 1H, J = 5.2 Hz and 2.8 Hz),
6.10 (dd, 1H, J = 5.2 Hz and 2.8 Hz), 5.43 (d, 1H, J = 7.9 Hz),
4.25 (dd, 1H, J = 11.2 and 4.7 Hz), 4.03–4.00 (m, 1H), 3.94–
3.88 (m, 2H), 3.65 (s, 3H), 3.57–3.53 (m, 1H), 3.40–3.36 (m, 1H),
3.18–3.06 (m, 3H), 1.45 (d, 1H, J = 8.2 Hz), 1.36 (d, 1H, J =
8.2 Hz); 13C-NMR (100 MHz, CDCl3): d 176.2, 173.8, 155.0,
137.6, 133.3, 132.5, 131.6, 129.8, 122.3, 117.7, 70.5, 65.0, 57.7,
53.2, 49.2, 47.2, 47.2, 47.0, 46.9, 40.3; MS (+ESI) = Calcd.
for C20H21NO5 (M + H)+: 356.3126, Found (M + H)+: 356.3125.
(+)-(2¢S,3¢R,3aR,9bS)-Methyl-3¢-(3,3a,4,9b-tetrahydro-1H-
chromeno[4,3-c]isoxazole-1-carbonyl)bicyclo[2.2.1]hept-5¢-ene-2¢-
carboxylate (9g). Isolated as a w◦hite solid, 178 mg total yield
(93%, >95% de). mp = 151–154 C; [a]2D5 = + 183 (c = 1.00,
CHCl3); IR nmax (film)/cm-1 2975 (CH), 1710 (CO-ester), 1659
†† Preparation of silver oxide Ag2OA solution of sodium hydroxide
(345 mg, 8.6 mmol) in water (10 mL) was heated to 85 ◦C and added
to a stirred solution of silver nitrate (1.5 g, 8.8 mmol) in water (10 mL)
at 85 ◦C. The resulting brown precipitate was filtered and washed with
water (10 mL) at 85 ◦C, then with ethanol (2 ¥ 10 mL) at rt. The solid thus
generated was dried in vacuo and kept in the freezer, protected from light
with aluminium foil.
1
(CO-amide), 1584 (aromatic); H-NMR (400 MHz, CDCl3): d
754 | Org. Biomol. Chem., 2009, 7, 747–760
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[a]D25 =+ 146 (c = 0.87, CHCl3); IR nmax (film)/cm-1 2965 (CH),
dried (MgSO4) and concentrated in vacuo. Crude product was then
purified by flash column chromatography (petroleum ether:diethyl
ether, 1:1). All diastereomeric excesses were evaluated by 1H-NMR
spectroscopy of crude reaction mixtures prior to purification; all
yields are isolated yields.
1
1715 (CO-ester), 1665 (CO-amide), 1511 (aromatic); H-NMR
(400 MHz, CDCl3): d 7.65 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J =
8.2 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.45
(d, 1H, J = 8.1 Hz), 4.29 (dd, 1H, J = 11.3 and 4.6 Hz), 4.13–4.08
(m, 2H), 3.88 (dd, 1H, J = 11.2 and 8.6 Hz), 3.66 (s, 3H), 3.23–
3.18 (m, 2H), 2.88–2.84 (m, 1H), 2.25–2.18 (m, 2H), 2.10–1.97 (m,
4H); 13C-NMR (100 MHz, CDCl3): d 175.3, 173.1, 155.1, 131.3,
129.0, 122.2, 121.9, 117.5, 72.2, 65.3, 52.1, 51.8, 44.1, 40.6, 39.7,
35.3, 29.6, 28.4; MS (+ESI) = Calcd. for C18H21NO5 (M + Na)+:
All desymmetrisations were performed using (+)-7 and (-)-7.
(+)-(2¢S,3aR,4¢R,9bS)-Methyl-2¢,4¢-dimethyl-5¢-oxo-5¢-(3,3a,
4,9b-tetrahydro-1H-chromeno[4,3-c]isoxazol-1-yl)pentanoate
(MAJOR 11a) and (+)-(2¢R,3aR,4¢S,9bS)-methyl-2¢,4¢-dimethyl-
5¢-oxo-5¢-(3,3a,4,9b-tetrahydro-1H -chromeno[4,3-c]yisoxazol-
1-yl)pentanoate (MINOR 11a). Isolated as major (141 mg, 85%)
and minor (11 mg, 6%) diastereoisomers, both as white powders,
152 mg total yield (91%, 86% de). MAJOR 11a: mp = 110–113 ◦C;
[a]D25 = + 192 (c = 1.10, CHCl3); IR nmax (film)/cm-1 2965 (CH),
354.2349, Found (M + Na)+: 354.2351. Ent MINOR 11b: [a]2D5
- 138 (c = 0.80, CHCl3).
=
(+)-(1¢R,3¢S,3aR,9bS)-Methyl-3¢-(3,3a,4,9b-tetrahydro-1H-
chromeno[4,3-c]isoxazole-1-yl)cyclohexanecarboxylate (MAJOR
11c) and (+)-(1¢S,3¢R,3aR,9bS)-methyl-3¢-(3,3a,4,9b-tetrahydro-
1H-chromeno[4,3-c]isoxazole-1-yl)cyclohexanecarboxylate (MI-
NOR 11c). Isolated as major (129 mg, 75%) and minor (18 mg,
10%) diastereoisomers, both as white powde◦rs, 147 mg total yield
(85%, 75% de). MAJOR 11c: mp = 122–126 C; [a]2D5 = + 129 (c =
1.00, CHCl3); IR nmax (film)/cm-1 2965 (CH), 1702 (CO-ester),
1663 (CO-amide), 1510 (aromatic); 1H-NMR (400 MHz, CDCl3):
d 7.65 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J = 8.2 Hz), 6.98 (t,
1H, J = 7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.47 (d, 1H, J =
8.1 Hz), 4.29 (dd, 1H, J = 11.2 and 4.6 Hz), 4.09–4.00 (m, 2H),
3.88 (dd, 1H, J = 11.2 and 8.6 Hz), 3.65 (s, 3H), 3.21–3.15
(m, 1H), 2.92–2.82 (m, 1H), 2.48–2.35 (m, 1H), 2.04–1.99 (m,
2H), 1.92–1.88 (m, 2H), 1.78–1.71 (m, 1H), 1.51–1.41 (m, 3H);
13C-NMR (100 MHz, CDCl3): d 175.6, 173.4, 155.3, 131.5, 129.2,
122.3, 121.7, 116.9, 71.2, 65.3, 52.2, 52.0, 42.2, 40.2, 35.2, 31.4,
29.5, 28.5, 13.6; MS (+ESI) = Calcd. for C19H23NO5 (M +
Na)+: 368.4539, Found (M + Na)+: 368.4542. Ent MAJOR 11c:
[a]2D5 = - 120 (c = 0.76, CHCl3). MINOR 11c: mp = 110–114 ◦C;
[a]D25 = + 144 (c = 0.85, CHCl3); IR nmax (film)/cm-1 2965 (CH),
1
1706 (CO-ester), 1663 (CO-amide), 1504 (aromatic); H-NMR
(400 MHz, CDCl3): d 7.65 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J =
8.2 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.45
(d, 1H, J = 8.1 Hz), 4.29 (dd, 1H, J = 11.3 and 4.6 Hz), 4.12–4.03
(m, 2H), 3.88 (dd, 1H, J = 11.3 and 8.6 Hz), 3.65 (s, 3H), 3.20–
3.12 (m, 1H), 3.10–3.02 (m, 1H), 2.59–2.52 (m, 1H), 2.18–2.09 (m,
1H), 1.62–1.51 (m, 1H), 1.18 (d, 3H, J = 6.7 Hz), 1.14 (d, 3H,
J = 6.7 Hz); 13C-NMR (100 MHz, CDCl3): d 174.9, 173.6, 155.4,
131.8, 129.5, 122.6, 122.1, 117.5, 72.1, 65.9, 52.4, 52.0, 40.6, 35.8,
34.4, 30.5, 17.8, 16.2; MS (+ESI) = Calcd. for C18H23NO5 (M +
Na)+: 356.1240, Found (M + Na)+: 356.1242. Ent MAJOR 11a:
[a]2D5 = - 187 (c = 1.02, CHCl3). MINOR 11a: mp = 114–118 ◦C;
[a]D25 = + 206 (c = 0.97, CHCl3); IR nmax (film)/cm-1 2965 (CH),
1
1706 (CO-ester), 1663 (CO-amide), 1504 (aromatic); H-NMR
(400 MHz, CDCl3): d 7.65 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J =
8.2 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.42
(d, 1H, J = 8.1 Hz), 4.29 (dd, 1H, J = 11.3 and 4.6 Hz), 4.12–4.03
(m, 2H), 3.88 (dd, 1H, J = 11.3 and 8.6 Hz), 3.63 (s, 3H), 3.20–
3.12 (m, 1H), 3.10–3.02 (m, 1H), 2.59–2.52 (m, 1H), 2.18–2.09 (m,
1H), 1.62–1.51 (m, 1H), 1.18 (d, 3H, J = 6.7 Hz), 1.14 (d, 3H,
J = 6.7 Hz); 13C-NMR (100 MHz, CDCl3): d 175.1, 173.4, 155.4,
131.9, 129.3, 122.6, 122.0, 117.3, 71.9, 65.6, 52.6, 52.2, 40.5, 35.8,
34.4, 30.4, 17.7, 16.1; MS (+ESI) = Calcd. for C18H23NO5 (M +
Na)+: 356.1240, Found (M + Na)+: 356.1238. Ent MINOR 11a:
[a]2D5 = - 208 (c = 1.00, CHCl3).
1
1702 (CO-ester), 1658 (CO-amide), 1510 (aromatic); H-NMR
(400 MHz, CDCl3): d 7.65 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J =
8.2 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.45 (d,
1H, J = 8.1 Hz), 4.29 (dd, 1H, J = 11.2 and 4.6 Hz), 4.09–4.00 (m,
2H), 3.88 (dd, 1H, J = 11.2 and 8.6 Hz), 3.62 (s, 3H), 3.21–3.15
(m, 1H), 2.92–2.82 (m, 1H), 2.48–2.35 (m, 1H), 2.04–1.99 (m,
2H), 1.92–1.88 (m, 2H), 1.78–1.71 (m, 1H), 1.51–1.41 (m, 3H);
13C-NMR (100 MHz, CDCl3): d 175.5, 173.3, 155.2, 131.4, 129.2,
122.2, 121.7, 116.9, 71.1, 65.2, 52.0, 51.8, 42.1, 40.2, 35.1, 31.3,
29.4, 28.4, 13.5; MS (+ESI) = Calcd. for C19H23NO5 (M + Na)+:
(+)-(1¢R,3¢S,3aR,9bS)-Methyl-3¢-(3,3a,4,9b-tetrahydro-1H-
chromeno[4,3-c]isoxazole-1-yl)cyclopentanecarboxylate (MAJOR
11b) and (+)-(1¢S,3¢R,3aR,9bS)-methyl-3¢-(3,3a,4,9b-tetrahydro-
1H-chromeno[4,3-c]isoxazole-1-yl)cyclopentanecarboxylate (MI-
NOR 11b). Isolated as major (122 mg, 74%) and minor (22 mg,
13%) diastereoisomers, both as white powders, ◦144 mg total yield
(87%, 70% de). MAJOR 11b: mp = 125–129 C; [a]2D5 = + 147
(c = 1.02, CHCl3); IR nmax (film)/cm-1 2965 (CH), 1715 (CO-
368.4539, Found (M + Na)+: 368.4538. Ent MINOR 11c: [a]2D5
- 127 (c = 0.70, CHCl3).
=
(+)-(3¢S,3aR,9bS)-3¢-Hydroxy-3¢-methyl-5¢-oxo-5¢y-(3,3a,4,9b-
tetrahydro-1H-chromeno[4,3-c]isoxazol-1-yl)pentanoate (MAJOR
11d) and (+)-(3¢R,3aR,9bS)-3¢-hydroxy-3¢-methyl-5¢-oxo-5¢-(3,
3a,4,9b-tetrahydro-1H-chromeno[4,3-cy]isoxazol-1-yl)pentanoate
(MINOR 11d). Isolated as major (107 mg, 64%) and minor
(20 mg, 11%) diastereoisomers, both as white powde◦rs, 126 mg
1
ester), 1665 (CO-amide), 1510 (aromatic); H-NMR (400 MHz,
CDCl3): d 7.65 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J = 8.2 Hz),
6.98 (t, 1H, J = 7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.47 (d, 1H,
J = 8.1 Hz), 4.29 (dd, 1H, J = 11.2 and 4.6 Hz), 4.13–4.08 (m,
2H), 3.88 (dd, 1H, J = 11.2 and 8.6 Hz), 3.69 (s, 3H), 3.23–3.18
(m, 2H), 2.88–2.84 (m, 1H), 2.25–2.18 (m, 2H), 2.10–1.97 (m,
4H); 13C-NMR (100 MHz, CDCl3): d 175.4, 173.2, 155.2, 131.4,
129.0, 122.3, 121.9, 117.5, 72.1, 65.4, 52.1, 51.9, 44.2, 40.6, 39.8,
35.4, 29.5, 28.5; MS (+ESI) = Calcd. for C18H21NO5 (M + Na)+:
total yield (75%, 70% de). MAJOR 11d: mp = 89–92 C; [a]D25
=
+ 195 (c = 1.05, CHCl3); IR nmax (film)/cm-1 3311 (OH), 2965
1
(CH), 1709 (CO-ester), 1665 (CO-amide), 1519 (aromatic); H-
NMR (400 MHz, CDCl3): d 7.65 (d, 1H, J = 7.4 Hz), 7.19
(t, 1H, J = 8.2 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.88 (d, 1H,
J = 8.2 Hz), 5.48 (d, 1H, J = 8.1 Hz), 4.29 (dd, 1H, J = 11.2
and 4.6 Hz), 4.25 (m, 2H), 3.88 (dd, 1H, J = 11.2 and 8.6 Hz),
354.2349, Found (M + Na)+: 354.2347. Ent MAJOR 11b: [a]2D5
=
- 140 (c = 0.98, CHCl3). MINOR 11b: mp = 118–122 ◦C;
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3.68 (s, 3H), 3.22–3.16 (m, 1H), 2.65–2.25 (m, 4H), 1.28 (s, 3H,
CH3); 13C-NMR (CDCl3): d 175.2, 173.4, 155.4, 131.8, 129.5,
122.6, 122.0, 117.3, 71.9, 70.1, 65.6, 52.6, 52.2, 41.2, 40.7, 39.7,
25.5; MS (+ESI) = Calcd. for C17H21NO6 (M + Na)+: 358.3531,
Found (M + Na)+: 358.3528. Ent MAJOR 11d: [a]2D5 = - 185
(c = 1.00, CHCl3). MINOR 11d: mp = 97–101 ◦C; [a]D25 = + 213
(c = 0.98, CHCl3); IR nmax (film)/cm-1 3311 (OH), 2965 (CH),
4.29 (dd, 1H, J = 11.2 and 4.6 Hz), 4.05–3.97 (m, 2H), 3.88 (dd,
1H, J = 11.2 and 8.6 Hz), 3.65 (s, 3H), 3.19–3.14 (m, 1H), 2.65–
2.25 (m, 5H), 1.08 (d, 3H, J = 5.5 Hz); 13C-NMR (100 MHz,
CDCl3): d 175.3, 173.4, 155.4, 131.8, 129.4, 122.6, 122.0, 117.3,
71.9, 65.6, 52.6, 52.2, 41.2, 40.7, 39.7, 27.4, 20.5; MS (+ESI) Calcd.
for C17H21NO5 (M + H)+: 320.2939, Found (M + H)+: 320.2941.
Ent MAJOR 11f: [a]2D5 = - 222 (c = 1.10, CHCl3). MINOR 11f:
[a]D25 = + 193 (c = 1.00, CHCl3); IR nmax (film)/cm-1 2965 (CH),
1706 (CO-ester), 1663 (CO-amide); 1H-NMR (400 MHz, CDCl3):
d 7.65 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J = 8.2 Hz), 6.98 (t, 1H, J =
7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.43 (d, 1H, J = 8.1 Hz), 4.29
(dd, 1H, J = 11.2 and 4.6 Hz), 4.05–3.97 (m, 2H), 3.88 (dd, 1H,
J = 11.2 and 8.6 Hz), 3.63 (s, 3H), 3.19–3.14 (m, 1H), 2.65–2.25
(m, 5H), 1.08 (d, 3H, J = 5.5 Hz); 13C-NMR (100 MHz, CDCl3):
d 175.2, 173.3, 155.3, 131.7, 129.4, 122.5, 122.0, 117.3, 71.8, 65.5,
52.5, 52.1, 41.1, 40.7, 39.7, 27.3, 20.4; MS (+ESI) = Calcd. for
C17H21NO5 (M + H)+: 320.2939, Found (M + H)+: 319.3144. Ent
MINOR 11f: [a]2D5 =- 188 (c = 1.10, CHCl3).
1
1709 (CO-ester), 1665 (CO-amide), 1519 (aromatic); H-NMR
(400 MHz, CDCl3): d 7.65 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J =
8.2 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.48
(d, 1H, J = 8.1 Hz), 4.29 (dd, 1H, J = 11.2 and 4.6 Hz), 4.25
(m, 2H), 3.88 (dd, 1H, J = 11.2 and 8.6 Hz), 3.66 (s, 3H), 3.22–
3.16 (m, 1H), 2.65–2.25 (m, 4H), 1.26 (s, 3H, CH3); 13C-NMR
(CDCl3): d 175.1, 173.3, 155.3, 131.7, 129.6, 122.5, 122.0, 117.3,
71.8, 70.0, 65.5, 52.5, 52.2, 41.2, 40.7, 39.8, 25.5; MS (+ESI) =
Calcd. for C17H21NO6 (M + Na)+: 358.3531, Found (M + Na)+:
358.3530. Ent MINOR 11d: [a]2D5 = - 207 (c = 0.93, CHCl3).
(+)-(3¢S,3aR,9bS)-Methyl-3¢-(tert-butyldimethylsilyloxy)-5¢-
oxo-5¢-(3,3a,4,9b-tetrahydro-1H -chromeno[4,3-c]isoxazol-1-
yl)pentanoate (MAJOR 11e) and (+)-(3¢R,3aR,9bS)-methyl-3¢-
(tert-butyldimethylsilyloxy)-5¢-oxo-5¢-(3,3a,4,9b-tetrahydro-1H-
chromeno[4,3-c]isoxazol-1-yl)pentanoate (MINOR 11e). Iso-
lated as major (185 mg, 89%) and minor (33 mg, 10%) diastereoiso-
mers, both as yellow oils, 218 mg total yield (99%, 80% de).
MAJOR 11e: [a]D25 = + 178 (c = 1.00, CHCl3); IR nmax (film)/cm-1
(+)-(3¢S,3aR,9bS)-3¢-Ethyl-3¢-methyl-5¢-oxo-5¢-(3,3a,4,9b-
tetrahydro-1H-chromeno[4,3-c]isoxazol-1-yl)pentanoate (MAJOR
11g) and (+)-(3¢R,3aR,9bS)-3¢-ethyl-3¢-methyl-5¢-oxo-5¢-(3,3a,
4,9b-tetrahydro-1H-chromeno[4,3-c]isoxazol-1-yl)pentanoate (MI-
NOR 11g). Isolated as major (87 mg, 50%) and minor (87 mg,
50%) diastereoisomers, both as yellow oils, 174 mg total yield
(100%, 0% de). MAJOR 11g: [a]2D5 = + 189 (c = 1.00, CHCl3); IR
nmax (film)/cm-1 2936 (CH), 1715 (CO-ester), 1643 (CO-amide),
1
2929 (CH), 2857 (CH), 1711 (CO-ester), 1664 (CO-amide); H-
1
NMR (400 MHz, CDCl3): d 7.65 (d, 1H, J = 7.7 Hz), 7.19 (t, 1H,
J = 8.0 Hz), 6.98 (t, 1H, J = 7.7 Hz), 6.87 (d, 1H, J = 8.0 Hz),
5.49–5.45 (m, 1H), 4.62–4.58 (m, 1H), 4.26 (dd, 1H, J = 11.5 and
4.1 Hz), 4.12–4.08 (m, 2H), 3.99–2.94 (m, 1H), 3.66 (s, 3H), 3.19–
3.15 (m, 1H), 2.95–2.91 (m, 2H), 2.64–2.60 (m, 2H), 0.85 (s, 9H),
0.10 (s, 3H), 0.08 (s, 3H); 13C-NMR (100 MHz, CDCl3): d 175.2,
172.8, 155.0, 131.5, 129.1, 122.2, 121.2, 116.9, 71.5, 65.9, 65.4,
52.4, 52.2, 42.2, 40.2, 39.8, 25.6, 18.4, -4.7, -4.8; MS (+ESI) =
Calcd. for C22H33NO6Si (M + Na)+: 458.5935, Found (M + Na)+:
458.5933. Ent MAJOR 11e: [a]2D5 = - 169 (c = 0.90, CHCl3).
MINOR 11e: [a]D25 = + 190 (c = 1.08, CHCl3); IR nmax (film)/cm-1
1584 (aromatic); H-NMR (400 MHz, CDCl3): d 7.65 (d, 1H,
J = 7.5 Hz), 7.25 (t, 1H, J = 8.0 Hz), 6.98 (t, 1H, J = 7.5 Hz),
6.87 (d, 1H, J = 8.0 Hz), 5.48–5.44 (m, 1H), 4.31 (dd, 1H, J =
11.5 and 4.1 Hz), 4.13–4.04 (m, 2H), 3.97–3.88 (m, 1H), 3.70 (s,
3H), 3.22–3.16 (m, 1H), 2.82–2.78 (m, 1H), 2.54–2.34 (m, 3H),
1.47 (q, 2H, J = 7.5 Hz), 1.06 (s, 3H), 0.91 (t, 3H, J = 7.5 Hz);
13C-NMR (100 MHz, CDCl3): d 175.1, 173.6, 155.4, 131.8, 129.5,
122.6, 122.0, 117.3, 71.9, 65.6, 52.7, 52.2, 41.7, 40.3, 39.7, 27.4,
33.1, 23.6, 6.6; MS (+ESI) = Calcd. for C18H23NO5 (M + Na)+:
356.1496, Found (M + Na)+: 356.1491; Ent MAJOR 11g: [a]2D5
=
- 191 (c = 1.01, CHCl3). MINOR 11g: [a]2D5 = + 211 (c = 1.05,
1
2929 (CH), 2857 (CH), 1711 (CO-ester), 1664 (CO-amide); H-
CHCl3); IR nmax (film)/cm-1 2936 (CH), 1715 (CO-ester), 1643
1
NMR (400 MHz, CDCl3): d 7.65 (d, 1H, J = 7.7 Hz), 7.19 (t, 1H,
J = 8.0 Hz), 6.98 (t, 1H, J = 7.7 Hz), 6.87 (d, 1H, J = 8.0 Hz),
5.49–5.45 (m, 1H), 4.62–4.58 (m, 1H), 4.26 (dd, 1H, J = 11.5 and
4.1 Hz), 4.12–4.08 (m, 2H), 3.99–2.94 (m, 1H), 3.64 (s, 3H), 3.19–
3.15 (m, 1H), 2.95–2.91 (m, 2H), 2.64–2.60 (m, 2H), 0.83 (s, 9H),
0.10 (s, 3H), 0.07 (s, 3H); 13C-NMR (100 MHz, CDCl3): d 175.1,
172.7, 155.1, 131.4, 129.1, 122.1, 121.2, 116.9, 71.4, 65.8, 65.3,
52.3, 52.1, 42.1, 40.2, 39.7, 25.5, 18.3, -4.6, -4.8; MS (+ESI) =
Calcd. for C22H33NO6Si (M + Na)+: 458.5935, Found (M + Na)+:
458.5934. Ent MINOR 11e: [a]2D5 = - 195 (c = 1.20, CHCl3).
(+)-(3¢S,3aR,9bS)-3¢-Methyl-5¢-oxo-5¢-(3,3a,4,9b-tetrahydro-
1H-chromeno[4,3-c]isoxazol-1-yl)pentanoate (MAJOR 11f) and
(+)-(3¢R,3aR,9bS)-3¢-methyl-5¢-oxo-5¢y-(3,3a,4,9b-tetrahydro-
1H-chromeno[4,3-c]isoxazol-1-yl)pentanoate (MINOR 11f). Iso-
lated as major (80 mg, 50%) and minor (80 mg, 50%) diastereoiso-
mers, both as clear oils, 160 mg total yield (100%, 0% de). MAJOR
11f: [a]2D5 = + 221 (c = 1.01, CHCl3); IR nmax (film)/cm-1 2965 (CH),
1706 (CO-ester), 1663 (CO-amide); 1H-NMR (400 MHz, CDCl3):
d 7.65 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J = 8.2 Hz), 6.98 (t, 1H,
J = 7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.45 (d, 1H, J = 8.1 Hz),
(CO-amide), 1583 (aromatic); H-NMR (400 MHz, CDCl3): d
7.65 (d, 1H, J = 7.5 Hz), 7.25 (t, 1H, J = 8.0 Hz), 6.98 (t, 1H, J =
7.5 Hz), 6.87 (d, 1H, J = 8.0 Hz), 5.45–5.42 (m, 1H), 4.31 (dd, 1H,
J = 11.5 and 4.1 Hz), 4.13–4.04 (m, 2H), 3.97–3.88 (m, 1H), 3.68
(s, 3H), 3.22–3.16 (m, 1H), 2.82–2.78 (m, 1H), 2.54–2.34 (m, 3H),
1.47 (q, 2H, J = 7.5 Hz), 1.06 (s, 3H), 0.91 (t, 3H, J = 7.5 Hz);
13C-NMR (100 MHz, CDCl3): d 175.0, 173.5, 155.3, 131.7, 129.5,
122.5, 121.9, 117.3, 71.8, 65.5, 52.6, 52.1, 41.6, 40.3, 39.6, 27.3,
33.1, 23.6, 6.6; MS (+ESI) = Calcd. for C19H25NO5 (M + H)+:
348.3285, Found (M + H)+: 348.3283. Ent MINOR 11g: [a]2D5
- 224 (c = 1.10, CHCl3).
=
(+)-(3¢S,3aR,9bS)-Methyl-3¢-(4¢¢-chlorophenyl)-5¢-oxo-5¢-(3,
3a,4,9b-tetrahydro-1H -chromeno[4,3-c]isoxazol-1-yl)pentano-
ate (MAJOR 11h) and (+)-(3¢R,3aS,9bR)-methyl-3¢-(4¢¢-chloro-
phenyl)-5¢-oxo-5¢-(3,3a,4,9b-tetrahydro-1H-chromeno[4,3-c]isoxa-
zol-1-yl)pentanoate (MINOR 11h). Isolated as major (103 mg,
50%) and minor (103 mg, 50%) diastereoisomers, both as a yellow
oil, 206 mg total yield (100%, 0% de). MAJOR 11h: [a]2D5 = + 156
(c = 1.10, CHCl3); IR nmax (film)/cm-1 2965 (CH), 1706 (CO-ester),
1
1663 (CO-amide); H-NMR (400 MHz, CDCl3): d 7.65 (d, 1H,
756 | Org. Biomol. Chem., 2009, 7, 747–760
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J = 7.4 Hz), 7.26–7.22 (m, 2H), 7.20–7.14 (m, 3H), 6.98 (t, 1H,
J = 7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.48 (d, 1H, J = 8.1 Hz), 4.29
(dd, 1H, J = 11.3 and 4.6 Hz), 4.03–3.90 (m, 2H), 3.88 (dd, 1H, J =
11.2 and 8.6 Hz), 3.80–3.72 (m, 1H), 3.68 (s, 3H), 3.20–3.15 (m,
1H), 2.90–2.70 (m, 3H), 2.65–2.62 (m, 1H); 13C-NMR (100 MHz,
CDCl3): d 175.6, 173.2, 155.4, 141.0, 131.8, 130.5, 129.5, 128.5,
127.5, 122.6, 122.0, 117.3, 71.9, 65.6, 52.6, 52.2, 41.2, 39.7, 38.0,
29.8; MS (+ESI) = Calcd. for C22H22ClNO5 (M + Na)+: 438.1595,
Found (M + Na)+: 438.1598. Ent MAJOR 11h: [a]2D5 = - 149 (c =
1.00, CHCl3). MINOR 11h: [a]2D5 = + 177 (c = 1.04, CHCl3); IR
nmax (film)/cm-1 2965 (CH), 1707 (CO-ester), 1663 (CO-amide);
1H-NMR (400 MHz, CDCl3): d 7.65 (d, 1H, J = 7.4 Hz), 7.26–
7.22 (m, 2H), 7.20–7.14 (m, 3H), 6.98 (t, 1H, J = 7.4 Hz), 6.88 (d,
1H, J = 8.2 Hz), 5.44 (d, 1H, J = 8.1 Hz), 4.29 (dd, 1H, J = 11.3
and 4.6 Hz), 4.03–3.90 (m, 2H), 3.88 (dd, 1H, J = 11.2 and 8.6 Hz),
3.80–3.72 (m, 1H), 3.67 (s, 3H), 3.20–3.15 (m, 1H), 2.90–2.70 (m,
3H), 2.65–2.62 (m, 1H); 13C-NMR (100 MHz, CDCl3): d 175.5,
173.1, 155.1, 141.0, 131.7, 130.3, 129.5, 128.4, 127.4, 122.5, 122.0,
117.3, 71.8, 65.5, 52.5, 52.1, 41.1, 39.7, 38.0, 29.7; MS (+ESI) =
Calcd. for C22H22ClNO5 (M + Na)+: 438.1595, Found (M + Na)+:
438.1598. Ent MINOR 11h: [a]2D5 = - 174 (c = 1.00, CHCl3).
layer was separated, washed with brine (2 ¥ 5 mL), dried (MgSO4)
and concentrated in vacuo. The crude product was purified by flash
column chromatography (dichloromethane:methanol, 99:1) to
afford 12 as a clear oil (34 mg, 0.11 mmol, 77%). [a]2D5 = + 94 (c =
1.22, CHCl3); IR nmax (film)/cm-1 3361 (OH), 2925 (CH), 2864
1
(CH), 1663 (CO-amide); H-NMR (400 MHz, CDCl3): d 7.63
(d, 1H, J = 6.9 Hz), 7.14 (t, 1H, J = 8.2 Hz), 6.98 (t, 1H, J =
6.9 Hz), 6.87 (d, 1H, J = 8.2 Hz), 5.40 (d, 1H, J = 7.9 Hz), 4.29
(dd, 1H, J = 11.2 and 4.7 Hz), 4.18–4.13 (m, 1H), 3.99–3.96 (m,
1H), 3.83–3.77 (m, 1H), 3.53–3.47 (m, 1H), 3.22–3.14 (m, 2H),
2.90 (br s, 1H), 2.13–2.07 (m, 1H), 2.03–1.97 (m, 1H), 1.86–1.77
(m, 3H), 1.70–1.30 (m, 4H); 13C-NMR (100 MHz, CDCl3): d
179.4, 155.3, 131.9, 129.4, 122.5, 122.1, 117.3, 72.0, 65.6, 64.4,
52.1, 41.1, 40.5, 39.8, 26.5, 24.8, 23.3, 22.8; MS (+ESI) = Calcd.
for C18H23NO4 (M + H)+: 318.1422, Found (M + H)+: 318.1419.
((1¢R,2¢S,3aR,9bS)-((3,3a,4,9b-Tetrahydro-1H-chromeno[4,3-
c]isoxazole-1-yl)-2¢-((tert-butyldimethylsilyloxy)methyl)cyclo-
hexyl)methanone (13). To a solution of alcohol 12 (43.0 mg,
0.14 mmol) in dichloromethane (2 mL) was added 2,6-lutidine
(24 mL, 0.21 mmol). This mixture was cooled to 0 ◦C in an ice
bath and tert-butyldimethylsilyl trifluoromethansulfonate (41 mL,
0.18 mmol) was added dropwise via syringe. The resulting solution
(+)-(3¢S,3aR,9bS)-3¢-(1¢¢,3¢¢,5¢¢-Triazin-2¢¢-yl)-methyl-5¢y-oxo-
5¢-(3,3a,4,9b-tetrahydro-1H-chromeno[4,3-c]isoxazol-1-yl)penta-
noate (MAJOR 11i) and (+)-(3¢S,3aR,9bS)-3¢-(1¢¢,3¢¢,5¢¢-triazin-
2¢¢-yl)-methyl-5¢-oxo-5¢-(3,3a,4,9b-tetrahydro-1H-chromeno[4,3-
c]isoxazol-1-yl)pentanoate (MINOR 11i). Isolated as major
(96 mg, 48%) and minor (95 mg, 47%) diastereoisomers, both
◦
was allowed to stir at 0 C for 1.5 h, at which point the reaction
was quenched with aqueous ammonium chloride (2 mL). The
organic layer was separated, washed with dichloromethane (2 mL),
dried (MgSO4) and concentrated in vacuo. The crude product was
purified by flash column chromatography (petroleum ether:diethyl
ether, 5:1) to afford 13 as a clear oil (46 mg, 0.11 mmol, 77%).
[a]2D5 = + 68 (c = 1.00, CHCl3); IR nmax (film)/cm-1 2930 (CH),
as clear oils, 191 mg total yield (95%, 0% de). MAJOR 11i: [a]D25
=
+ 182 (c = 1.14, CHCl3); IR nmax (film)/cm-1 2965 (CH), 1712 (CO-
1
1
ester), 1670 (CO-amide), 1517 (aromatic); H-NMR (400 MHz,
2857 (CH), 1664 (CO-amide); H-NMR (400 MHz, CDCl3): d
CDCl3): d 8.72 (s, 2H), 7.65 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J =
8.2 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.48
(d, 1H, J = 8.1 Hz), 4.29 (dd, 1H, J = 11.2 and 4.6 Hz), 4.28–4.22
(m, 2H), 3.88 (dd, 1H, J = 11.2 and 8.6 Hz), 3.69 (s, 3H), 3.35–
3.31 (m, 1H), 3.19–3.14 (m, 1H), 2.65–2.25 (m, 4H); 13C-NMR
(100 MHz, CDCl3): d 181.0, 175.4, 173.2, 165.9, 155.4, 131.8,
129.5, 122.6, 122.0, 117.3, 71.9, 65.6, 52.6, 52.2, 41.3, 39.8, 30.1,
29.8; MS (+ESI) = Calcd. for C19H20N4O5 (M + Na)+: 407.1225,
Found (M + Na)+: 407.1226. Ent MAJOR 11i: [a]2D5 = - 169 (c =
0.99, CHCl3). MINOR 11i: [a]2D5 = + 164 (c = 1.07, CHCl3); IR
nmax (film)/cm-1 2965 (CH), 1712 (CO-ester), 1670 (CO-amide),
1518 (aromatic); 1H-NMR (400 MHz, CDCl3): d 8.72 (s, 2H), 7.65
(d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J = 8.2 Hz), 6.98 (t, 1H, J =
7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.46 (d, 1H, J = 8.1 Hz), 4.29 (dd,
1H, J = 11.2 and 4.6 Hz), 4.28–4.22 (m, 2H), 3.88 (dd, 1H, J =
11.2 and 8.6 Hz), 3.67 (s, 3H), 3.35–3.31 (m, 1H), 3.19–3.14 (m,
1H), 2.65–2.25 (m, 4H); 13C-NMR (100 MHz, CDCl3): d 180.9,
175.3, 173.1, 165.8, 155.3, 131.7, 129.5, 122.5, 122.0, 117.3, 71.8,
65.5, 52.5, 52.1, 41.1, 39.7, 30.0, 29.7; MS (+ESI) = Calcd. for
C19H20N4O5 (M + Na)+: 407.1225, Found (M + Na)+: 407.1228.
Ent MINOR 11i: [a]2D5 = - 166 (c = 1.05, CHCl3).
7.65 (d, 1H, J = 6.9 Hz), 7.15 (t, 1H, J = 8.2 Hz), 6.98 (t, 1H, J =
6.9 Hz), 6.81 (d, 1H, J = 8.2 Hz), 5.40 (d, 1H, J = 7.9 Hz), 4.31 (dd,
1H, J = 11.2 and 4.7 Hz), 4.06–4.00 (m, 1H), 3.96–3.91 (dd, 1H,
J = 7.3 and 3.7 Hz), 3.83 (dd, 1H, J = 11.2 and 9.4 Hz), 3.76–3.72
(m, 1H), 3.58–3.54 (m, 1H), 3.26–3.21 (m, 1H), 3.12–3.07 (m, 1H),
2.02–1.86 (m, 3H), 1.66–1.59 (m, 2H), 1.53–1.38 (m, 4H), 0.89 (s,
9H), 0.08 (s, 3H), 0.06 (s, 3H); 13C-NMR (100 MHz, CDCl3): d
176.8, 155.1, 131.7, 129.4, 123.0, 121.9, 117.1, 71.8, 65.4, 55.3,
52.2, 41.3, 40.2, 37.8, 27.3, 25.9, 25.4, 25.1, 22.6, 18.1, -5.7, -5.8;
MS (+ESI) = Calcd. for C24H37NO4Si (M + H)+: 432.2516, Found
(M + H)+: 432.2513.
((1¢R,2¢S,3aR,9bS)-((3,3a,4,9b-Tetrahydro-1Hy-chromeno[4,3-
c]isoxazole-1-yl)-2¢-((tert-butyldiphenylsilyloxy)methyl)cyclo-
hexyl)methanone (14). A solution of alcohol 12 (87 mg,
0.27 mmol) in dichloromethane (1 mL) was added drop-
wise via cannula. to
a
cooled (0 ◦C) solution of tert-
butyldiphenylsilyl chloride (73 mL, 0.28 mmol) and imidazole
(38 mg, 0.55 mmol) in dichloromethane (2 mL). Catalytic
amounts of 4-dimethylaminopyridine and tetrabutylammonium
iodide were added, and the resulting mixture was allowed to warm
to room temperature over 10 h. The reaction was then diluted
with dichloromethane (2 mL), filtered, washed with water (5 mL)
and brine (5 mL), dried (MgSO4) and concentrated in vacuo.
The crude product was purified by flash column chromatography
(petroleum ether:diethyl ether, 9:1) to afford 14 as a clear oil
(84 mg, 0.15 mmol, 56%). [a]2D5 = + 53 (c = 1.05, CHCl3); IR
((1¢R,2¢S,3aR,9bS)-((3,3a,4,9b-Tetrahydro-1H-chromeno[4,3-
c]isoxazol-1-yl)-2¢-(hydroxymethyl)cyclohexyl)methanone
(12).
A solution of ester 9a (50 mg, 0.14 mmol) in tetrahydrofuran
(1 mL) was added dropwise via cannula to a flask containing
Schwartz reagent (75 mg, 0.29 mmol) at 0 ◦C. The resulting mixture
was allowed to stir at 0 ◦C for 40 min, at which point the reaction
was quenched with aqueous Rochelle’s salt (5 mL). The organic
1
nmax (film)/cm-1 2955 (CH), 2849 (CH), 1659 (CO-amide); H-
NMR (400 MHz, CDCl3): d 7.70–7.58 (m, 6H), 7.37–7.32 (m,
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5H), 6.96 (t, 1H, J = 8.2 Hz), 6.94 (t, 1H, J = 6.9 Hz), 6.85 (d,
1H, J = 8.2 Hz), 5.35 (d, 1H, J = 7.9 Hz), 4.18 (dd, 1H, J = 11.2
and 4.7 Hz), 3.85–3.65 (m, 5H), 3.34–3.30 (m, 1H), 2.84–2.79 (m,
1H), 2.10–1.88 (m, 3H), 1.70–1.57 (m, 3H), 1.50–1.39 (m, 3H),
1.08 (s, 9H); 13C-NMR (100 MHz, CDCl3): d 178.1, 155.3, 135.9,
135.2, 132.0, 129.5, 128.1, 128.0, 122.6, 122.4, 117.2, 71.8, 65.7,
65.6, 52.1, 40.9, 40.5, 27.4, 27.0, 25.7, 23.6, 25.1, 23.6, 19.8; MS
(+ESI) = Calcd. for C34H41NO4Si (M + H)+: 556.2180, Found
(M + H)+: 556.2177.
brine (30 mL), dried (MgSO4) and concentrated in vacuo. The
crude product was purified by flash column chromatography
(dichloromethane:methanol, 99:1), affording 18 as a clear oil
(282 mg, 0.92 mmol, 70%). [a]2D5 = + 83 (c = 1.20, CHCl3); IR
nmax (film)/cm-1 3345 (OH), 2963 (CH), 1663 (CO-amide), 1509
(aromatic); 1H-NMR (400 MHz, CDCl3): d 7.65 (d, 1H, J =
7.4 Hz), 7.19 (t, 1H, J = 8.2 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.88
(d, 1H, J = 8.2 Hz), 5.48 (d, 1H, J = 8.1 Hz), 4.29 (dd, 1H, J =
11.3 and 4.6 Hz), 3.95–3.82 (m, 2H), 3.80 (dd, 1H, J = 11.2 and
8.6 Hz), 3.47–3.39 (m, 2H), 3.10–3.05 (m, 1H), 2.99–2.91 (m, 1H),
1.97 (br s, 1H), 1.88–1.79 (m, 1H), 1.51–1.45 (m, 1H), 1.22–1.18
(m, 1H), 1.11 (d, 3H, J = 6.7 Hz), 0.85 (d, 3H, J = 6.7 Hz);
13C-NMR (100 MHz, CDCl3): d 175.1, 155.4, 131.8, 129.4, 122.6,
121.9, 117.3, 72.1, 67.4, 65.6, 52.6, 41.2, 35.4, 33.6, 31.1, 17.8, 16.2;
MS (+ESI) = Calcd. for C17H23NO4 (M + Na)+: 328.1292, Found
(M + Na)+: 328.1289.
((1¢R,2¢S)-2¢-((tert-Butyldimethylsilyloxy)methyl)cyclohexyl)-
methanol (15). Ethanol (17.3 mL, 0.3 mmol) and lithium boro-
hydride (2 M in THF, 150 mL, 0.3 mmol) were added dropwise via
syringe to a cooled solution (0 ◦C) of mono-protected alcohol 13
(42.5 mg, 0.10 mmol) in diethyl ether (2 mL). The resulting mixture
was allowed to warm to room temperature over 10 h, at which
point the reaction was quenched with aqueous Rochelle’s salt
(2 mL). The organic layer was separated, washed with brine (5 mL),
dried (MgSO4) and concentrated in vacuo. The crude product was
purified by flash column chromatography (petroleum ether:diethyl
ether, 9:1) and afforded 15 as a clear oil (26 mg, 0.10 mmol, 100%,
>99% ee—evaluated by Mosher ester formation). [a]2D5 = - 25
(c = 1.02, CHCl3); IR nmax (film)/cm-1 3303 (OH), 2929 (CH),
(2¢R,4¢S,3aR,9bS)-1¢-(3,3a,4,9b-Tetrahydro-1H -chromeno-
[4,3c]isoxazol-1-yl)-2¢,4¢–dimethyl-5¢y-(tert-butyldimethylsilyl-
oxy)-pentan-1¢-one (19). To a solution of alcohol 18 (0.60 mmol,
198 mg) in dichloromethane (9 mL) was added 2,6-lutidine
(126 mL, 1.08 mmol). This mixture was cooled to 0 ◦C in
an ice bath and tert-butyldimethylsilyl trifluoromethansulfonate
(216 mL, 0.93 mmol) was added dropwise via syringe. The resulting
1
2857 (CH); H-NMR (400 MHz, CDCl3): d 3.85–3.80 (m, 1H),
◦
solution was allowed to stir at 0 C for 1.5 h, at which point the
3.68–3.61 (m, 1H), 3.58–3.53 (m, 1H), 3.45–3.41 (m, 1H), 3.28–
3.24 (m, 1H), 1.94–1.83 (m, 2H), 1.55–1.32 (m, 8H), 0.91 (s, 9H),
0.11 (s, 6H); 13C-NMR (100 MHz, CDCl3): d 64.9, 64.1, 40.9,
39.9, 27.5, 27.0, 26.1, 25.3, 25.9, 18.1, -5.6; MS (+ESI) = Calcd.
for C14H30O2Si (M + H)+: 259.1340, Found (M + H)+: 259.1342.
reaction was quenched with aqueous ammonium chloride (2 mL).
The organic layer was separated, washed with dichloromethane
(2 mL), dried (MgSO4) and concentrated in vacuo. The crude
product was purified by flash column chromatography (petroleum
ether:diethyl ether, 3:1) to afford 19 as a clear oil (252 mg,
0.60 mmol, 100% yield). [a]2D5 = + 33 (c = 1.00, CHCl3); IR nmax
((1R,2S)-2-((tert-Butyldiphenylsilyloxy)methyl)cyclohexyl)-
methanol (16). Ethanol (16 mL, 0.27 mmol) and lithium boro-
hydride (2 M in THF, 135 mL, 0.27 mmol) were added dropwise
via syringe to a cooled solution (0 ◦C) of mono-protected alcohol
14 (49.0 mg, 0.09 mmol) in diethyl ether (2 mL). The resulting
solution was allowed to warm slowly to room temperature over
10 h, at which point the reaction was quenched with aqueous
Rochelle’s salt (2 mL). The organic layer was separated, washed
with brine (5 mL), dried (MgSO4) and concentrated in vacuo.
The crude product was purified by flash column chromatography
(petroleum ether:diethyl ether, 9:1) to afford 16 as a clear oil
(34 mg, 0.09 mmol, 100%, >99% ee). [a]2D5 = -34 (c = 0.96, CHCl3);
IR nmax (film)/cm-1 3300 (OH), 2941 (CH), 2857 (CH); 1H-NMR
(400 MHz, CDCl3): d 7.68–7.62 (m, 4H), 7.40–7.33 (m, 6H), 3.86–
3.81 (m, 1H), 3.78–3.74 (m, 1H), 3.54–3.50 (m, 2H), 2.87–2.84 (m,
1H), 2.04–1.96 (m, 2H), 1.49–1.44 (m, 4H), 1.35–1.29 (m, 4H),
1.07 (s, 9H); 13C-NMR (100 MHz, CDCl3): d 134.0, 130.0, 128.5,
122.4, 64.9, 64.1, 40.9, 39.9, 27.5, 27.0, 26.8, 25.1, 23.5, 19.2; MS
(+ESI) = Calcd. for C24H34O2Si (M + H)+: 383.2317, Found (M +
H)+: 383.2314. Chiralcel ODH: 1 mL/min, 30 min, hexanes:iso-
propanol (90:10), retention time = 9.3 min.
1
(film)/cm-1 2959 (CH), 1670 (CO-amide); H-NMR (400 MHz,
CDCl3): d 7.65 (d, 1H, J = 7.4 Hz), 7.19 (t, 1H, J = 8.2 Hz), 6.98
(t, 1H, J = 7.4 Hz), 6.88 (d, 1H, J = 8.2 Hz), 5.48 (d, 1H, J =
8.1 Hz), 4.29 (dd, 1H, J = 11.3 and 4.6 Hz), 4.03–3.97 (m, 2H),
3.88 (dd, 1H, J = 11.2 and 8.6 Hz), 3.54–5.48 (m, 1H), 3.39–3.33
(m, 1H), 3.16–3.11 (m, 2H), 1.83–1.79 (m, 1H), 1.61–1.57 (m, 1H),
1.23–1.16 (m, 4H), 0.98–0.85 (m, 12H), 0.05 (s, 3H), 0.04 (s, 3H);
13C-NMR (100 MHz, CDCl3): d 179.8, 155.3, 131.9, 129.3, 122.5,
122.3, 117.2, 71.9, 68.6, 65.6, 52.3, 40.6, 37.0, 34.3, 34.2, 26.3, 19.2,
18.7, 17.6, -5.0; MS (+ESI) = Calcd. for C23H37NO4Si (M + Na)+:
442.6312, Found (M + Na)+: 442.6311.
(2R,4S,3aR,9bS)-1¢-(3,3a,4,9b-Tetrahydro-1H-chromeno[4,3-
c]isoxazole-1-yl)-2¢,4¢-dimethyl-5¢-(4-methoxybenzyloxy)pentan-1-
one (20). To a solution of alcohol 18 (106 mg, 0.35 mmol) in
toluene (4 mL) at room temperature was added p-methoxybenzyl
trichloroacetimidate (147 mg, 0.52 mmol) and lanthanum trifluo-
romethansulfonate (5 mol%, 10 mg, 0.017 mmol), and the resulting
solution was allowed to stir at room temperature for 20 min.
Aqueous ammonium chloride (10 mL) was then added, and the
separated organic phase was washed with brine (10 mL), dried
(MgSO4) and concentrated in vacuo. The crude product was then
purified by flash column chromatography (petroleum ether:diethyl
ether, 1:1) providing 20 as a white powder (135 mg, 0.31 mmol,
(2¢R,4¢S,3aR,9bS)-1¢-(3,3a,4,9b-Tetrahydro-1H-chromeno[4,3-
c]isoxazol-1-yl)-2¢,4¢-dimethyl-5¢-hydroxypentan-1¢-one (18).
A
solution of ester 11a (438 mg, 1.32 mmol) in tetrahydrofuran
(13 mL) was added dropwise via cannula to a flask con-
taining Schwartz reagent (680 mg, 2.63 mmol) at 0 ◦C. The
resulting mixture was allowed to stir at 0 ◦C for 40 min, at
which point the reaction was quenched with aqueous Rochelle’s
salt (20 mL). The organic layer was separated, washed with
◦
91%). mp = 59–61 C; [a]2D5 = + 55 (c = 0.97, CHCl3); IR nmax
1
(film)/cm-1 2980 (CH), 1663 (CO-amide); H-NMR (400 MHz,
CDCl3): d 7.69 (d, 1H, J = 7.4 Hz), 7.35–7.28 (m, 2H), 7.17 (t, 1H,
J = 8.2 Hz), 6.98 (t, 1H, J = 7.4 Hz), 6.92–6.88 (m, 3H), 5.48 (d,
1H, J = 8.1 Hz), 4.43 (s, 2H), 4.26 (dd, 1H, J = 11.3 and 4.6 Hz),
758 | Org. Biomol. Chem., 2009, 7, 747–760
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3.99–3.83 (m, 3H), 3.80 (s, 3H), 3.36–3.31 (m, 1H), 3.23–3.19 (m,
1H), 3.10–2.99 (m, 2H), 1.92–1.88 (m, 1H), 1.78–1.74 (m, 1H),
1.22–1.18 (m, 4H), 0.96 (d, 3H, J = 6.7 Hz); 13C-NMR (100 MHz,
CDCl3): d 179.6, 159.5, 155.3, 131.9, 131.1, 129.5, 122.5, 122.2,
122.6, 117.3, 115.3, 77.5, 73.1, 71.9, 65.6, 55.7, 52.3, 40.5, 37.6,
34.4, 32.3, 19.4, 18.0; MS (+ESI) = Calcd. for C25H31NO5 (M +
Na)+: 448.2350, Found (M + Na)+: 448.2351.
2 A. C. Spivey and B. I. Andrews, Angew. Chem., Int. Ed., 2001, 40, 3131.
3 M. C. Willis, J. Chem. Soc., Perkin Trans. 1, 2001, 1765.
4 I. Atodiresei, I. Schiffers and C. Bolm, Chem. Rev., 2007, 107, 5683.
5 (a) For key papers utilising chiral alcohols as auxiliaries for anhydride
desymmetrisation please refer to: R. Altschul, P. Bernstein and S. G.
Cohen, J. Am. Chem. Soc., 1956, 78, 5091; (b) T. Rosen and C. H.
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(2R,4S)-2,4-Dimethyl-5-(tert-butyldimethylsilyloxy)-pentan-1-
ol (21). Ethanol (3 mL, 0.4 mmol) and lithium borohydride (2 M
in THF, 200 mL, 0.4 mmol) were added dropwise via syringe to
a cooled solution (0 ◦C) of mono-protected alcohol 19 (56.6 mg,
0.13 mmol) in diethyl ether (3 mL). The resulting solution was
allowed to warm slowly to room temperature over 10 h, at which
point the reaction was quenched with aqueous Rochelle’s salt
(2 mL). The organic layer was separated, washed with brine (5 mL),
dried (MgSO4) and concentrated in vacuo. The crude product was
purified by flash column chromatography (petroleum ether:diethyl
ether, 3:1) to afford 21 as a clear oil (32 mg, 0.13 mmol, 100%,
>99% ee—evaluated by Mosher ester formation). [a]2D5 = - 25
(c = 1.25, CHCl3); IR nmax (film)/cm-1 3415 (OH), 2875 (CH);
1H-NMR (400 MHz, CDCl3): d 3.52–3.30 (m, 4H), 1.77–1.69 (m,
2H), 1.47–1.42 (m, 2H), 1.02–0.95 (m, 15H), 0.11–0.07 (m, 6H);
13C-NMR (100 MHz, CDCl3): d 68.1, 65.2, 35.4, 33.6, 33.0, 26.1,
18.7, 18.5, 17.3, -5.4; MS (+ESI) = Calcd. for C13H30O2Si (M +
Na)+: 269.1319, Found (M + Na)+: 269.1322.
7 (a) For key papers utilising chiral oxazolines and oxazolidines as
auxiliaries for anhydride desymmetrisation please refer to: S. D. Real,
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J. Chem. Soc., Perkin Trans. 1, 1999, 265.
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Soc., 2001, 123, 12696; (h) J. Woeltinger, H.-P. Krimmer and K. Drauz,
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Asymmetry, 2007, 18, 1481; (l) Z. Hamersak, M. Roje, A. Avdagic and
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(2R,4Sy)-2,4-Dimethyl-5-(p-methoxybenzyloxy)-pentan-1-ol
(22). Ethanol (18 mL, 0.30 mmol) and lithium borohydride (2 M
in THF, 150 mL, 0.30 mmol) were added dropwise via syringe to
a solution of mono-protected alcohol 20 (43.5 mg, 0.10 mmol) in
◦
diethyl ether (1 mL) at 0 C. The resulting mixture was allowed
to warm slowly to room temperature over 10 h, at which point
the reaction was quenched with aqueous Rochelle’s salt (3 mL).
The organic layer was separated, washed with brine (5 mL),
dried (MgSO4) and concentrated in vacuo. The crude product was
purified by flash column chromatography (petroleum ether:diethyl
ether, 3:1), affording 22 as a clear oil (25 mg, 0.10 mmol, 100%,
◦
>99% ee—evaluated by chiral HPLC). mp 64–67 C; [a]D25
=
+ 10 (c = 0.85, CHCl3); IR nmax (film)/cm-1 3315 (OH), 2980 (CH);
1H-NMR (400 MHz, CDCl3): d 7.26–7.23 (m, 2H), 6.92–6.89 (m,
2H), 4.41 (s, 2H), 3.80 (s, 3H), 3.51–3.41 (m, 2H), 3.27–3.22 (m,
2H), 1.88–1.80 (m, 1H), 1.74–1.69 (m, 1H), 1.50 (br s, 1H), 1.45–
1.40 (m, 2H), 0.98–0.92 (m, 6H); 13C-NMR (100 MHz, CDCl3): d
159.5, 131.1, 129.5, 114.2, 76.0, 73.1, 68.4, 55.6, 38.1, 33.7, 31.4,
18.6, 18.0; MS (+ESI) = Calcd. for C15H24O3 (M + Na)+: 275.1673,
Found (M + Na)+: 275.1672.
Acknowledgements
We wish to thank Glaxo Wellcome (S.V.L., A.C.E.), Organon Ltd.
(A.C.E.), the EPSRC (D.A.L., V.F., R.M.T.), the Isaac Newton
Trust for European Research (V.F.), Trinity College (D.A.L.), and
Novartis (S.V.L.) for financial support. We also wish to thank
Dr. J.E. Davies for determining X-ray diffraction analysis.
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