Approaches to the quaternary stereocentre and to the heterocyclic core in diazonamide A using the Heck reaction and related coupling reactions

Article abstract of DOI:10.1039/b609604b

In model studies towards the quaternary centre at the heart of diazonamide A (early structure 2; revised structure 1), cyclisations of the alkene-substituted iodoaryls 4, 13, 18 and 23, under Heck reaction conditions, were shown to lead to the corresponding benzodihydrofuran 5, benzofuranone 14 and the oxindoles 19 and 24 respectively, in 50-80% yield. Further manipulation of the benzodihydrofuran 5 then led to the intermediates 30, 33 and 39, which make up parts of the oxazole-indole heterocyclic core in diazonamide A. Attempts to perform a corresponding 13-exo-trig Heck cyclisation from the precursor 46a, prepared from 44 and 45, leading to 47 were not successful. A similar outcome was obtained during attempts to effect Heck cyclisations from the ester 57 and the related ether 59. Treatment of the chromene-substituted iodoaryl 62 with Pd(OAc)₂, PPh₃ and Ag₂CO₃ led to the spirocycle 64 as a crystalline solid. X-Ray crystal structure analysis established that the quaternary centre in 64 had the same configuration as that present in diazonamide A (1). The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b609604b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Approaches to the quaternary stereocentre and to the heterocyclic core in
diazonamide A using the Heck reaction and related coupling reactions†
James E. M. Booker, Alicia Boto, Gwydion H. Churchill, Clive P. Green, Matthew Ling, Graham Meek,
Jaya Prabhakaran, David Sinclair, Alexander J. Blake and Gerald Pattenden*
Received 5th July 2006, Accepted 29th August 2006
First published as an Advance Article on the web 13th October 2006
DOI: 10.1039/b609604b
In model studies towards the quaternary centre at the heart of diazonamide A (early structure 2; revised
structure 1), cyclisations of the alkene-substituted iodoaryls 4, 13, 18 and 23, under Heck reaction
conditions, were shown to lead to the corresponding benzodihydrofuran 5, benzofuranone 14 and the
oxindoles 19 and 24 respectively, in 50–80% yield. Further manipulation of the benzodihydrofuran 5
then led to the intermediates 30, 33 and 39, which make up parts of the oxazole–indole heterocyclic
core in diazonamide A. Attempts to perform a corresponding 13-exo-trig Heck cyclisation from the
precursor 46a, prepared from 44 and 45, leading to 47 were not successful. A similar outcome was
obtained during attempts to effect Heck cyclisations from the ester 57 and the related ether 59.
Treatment of the chromene-substituted iodoaryl 62 with Pd(OAc)2, PPh3 and Ag2CO3 led to the
spirocycle 64 as a crystalline solid. X-Ray crystal structure analysis established that the quaternary
centre in 64 had the same configuration as that present in diazonamide A (1).
Introduction
The indole–oxazole-based cyclopeptide diazonamide A (1), iso-
lated from the ascidian (“sea squirt”) Diazona angulata, has been
a natural product of intrigue, structural controversy and, above
all, synthetic challenge ever since it was reported in the literature
in 1991.1 Diazonamide A displays potent cytotoxicity towards
human colon carcinoma and B-16 murine melanoma cells in vitro,
with IC50 < 15 ng mL−1.2 In 1991, diazonamide A was originally
assigned as structure 2.1 However, almost exactly ten years later,
Harran et al. synthesised this compound only to find that the
assigned structure was incorrect.3 A reinterpretation of the X-
ray and spectroscopic data led to the newly assigned structure 1.4
In contemporaneous studies, first Nicolaou,5 and then Harran6
and their respective collaborators described elegant solutions to
the total synthesis of this intriguing and formidable secondary
metabolite.
Since it was first described, diazonamide A has enticed a number
of synthetic chemists, challenged by its fascinating and unusual
structure.7 We were one such group, perhaps influenced at the
Results and discussion
time by our contemporaneous synthetic studies towards other
oxazole-based natural products8 and our interests in applications
Analytical disconnections based on the Heck and related coupling
reactions
of transition-metal-mediated sp2–sp2 alkene coupling reactions in
synthesis.9 In this paper, we draw together, and describe, some
In other, earlier, studies we developed the scope for cobalt(I)-
mediated oxidative carbon-to-carbon bond coupling reactions,11
and also the Stille reaction, in the synthesis of a range of
natural products, e.g. thienamycin,12a forskolin,12b rhizoxin D,8b
deoxylophotoxin,12c anhydropristinamycin,12d and amphidinolide
A.12e We also examined, and compared, the scope for cobalt(I)-
and Pd(0)-mediated (i.e., Heck reaction), and the Heck and Stille
reactions in sp2–sp2 alkene coupling reactions in synthesis, includ-
ing natural product synthesis.13 With this background, we felt that
a useful approach to both the quaternary centre and to the hetero-
cyclic core in diazonamide A could be developed based on the key
studies we have made to develop a route to the quaternary centre
linking the two aryl rings and one of the oxazoles to the aminal-
bearing carbon centre in diazonamide A, based specifically on
the ubiquitous Heck reaction. We also summarise studies we have
made to elaborate the heterocyclic core in diazonamide A using
related Pd(0)-mediated alkene coupling reactions.10
School of Chemistry, The University of Nottingham, Nottingham, NG7 2RD,
UK
† Electronic supplementary information (ESI) available: Additional exper-
imental procedures and crystal data. See DOI: 10.1039/b609604b
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disconnections highlighted on structure 3.14 In broad terms, the
disconnections focused on the quaternary centre in diazonamide A
translate to: (i) two similar Heck reactions, i.e., disconnections (b)
and (c) involving aryl rings B or C, and (ii) a Heck, or similar
coupling reaction with the oxazole ring A, disconnection (a),
and appropriate alkene substrates. The other oxazole/indole/aryl
disconnections are more obvious. We have focussed on most
of these key disconnections using both structure 2, the earlier
proposed structure for diazonamide A, and the correct structure 1.
The Pd(0)-mediated coupling reaction of an aryl or vinyl iodide
with an alkene, to create a new carbon-to-carbon bond, described
by Heck in 1968, has become one of the most revered reactions
in contemporary organic synthesis.15–17 There is no doubt that
the pioneering work of Heck16 laid the platform for other related
Pd(0)-mediated coupling reactions, including Stille (organostan-
nanes), Suzuki (organoboronic acids), Hiyama (organosilanes),
Kumada (organonickels) and Negishi (organozincs) couplings.
The outstanding potential for the Heck reaction is perhaps
nowhere better illustrated than its use in an intramolecular fashion
in the construction of quaternary carbon centres. Furthermore,
this feature of the reaction is nowhere better demonstrated than in
the elegant work of Overman and his co-workers,17 particularly in
target natural product synthesis. The regioselectivity of simple, in-
termolecular Heck reactions is controlled by steric factors, with the
new carbon-to-carbon bond being formed at the least-substituted
end of the alkene bond.16 However, in the formation of small rings
via the Heck reaction, conformational constraints override steric
factors and, in the cases of 5-, 6- and 7-ring constructions, exo-
modes of cyclisation predominate.15d With the quaternary centre
in diazonamide A as our focus, we have designed a number of
substrates and used several Heck reaction conditions to access
products from both exo- and endo-modes of macrocyclisation for
further possible elaboration to more advanced precursors to the
natural product.
5-Exo-trig cyclisations of the substituted iodoaryls 4, 13, 18 and
23, under Heck reaction conditions, leading to to 5, 14, 19 and 24
respectively
In our earliest investigations, with the diazonamide A structure 2
in mind, we examined the intramolecular Heck reaction from the
alkene-substituted iodobenzene 4, i.e., disconnection (b) in struc-
ture 3. We anticipated that this reaction would lead largely to the
benzodihydrofuran product 5, via a 5-exo mode of cyclisation.14
Furthermore, we expected to be able to elaborate the alkene unit
in 5 to an oxazole, and also carry out sp2–sp2 coupling reactions
of 5 to 5-substituted indoles, allowing access to an advanced
model compound, i.e. 6, towards the diazonamide A structure
2. We therefore prepared the alkene-substituted iodobenzene 4
from 2,6-dibromophenol in four straightforward steps, shown
in Scheme 1. Lithium–bromide exchange in 2,6-dibromophenol,
followed by a quench with TMSCl, first gave the arylsilane 7.
Alkylation of 7 with 2-bromoacetophenone in the presence of
Na2CO3 next gave 8a, which was then converted into the iodide
8b using AgBF4 and iodine. Finally, a Wittig reaction between the
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Scheme 1 Reagents and conditions: i) NaH, ClSiMe3, 0 ◦C, then nBuLi,
THF, −78 ◦C, 99%; ii) PhCOCH2Br, Na2CO3, MeCN, 64% (recovered 7,
27%); iii) AgBF4, I2, MeOH, 95%; iv) nBuLi, EtP+Ph3 Br−, then 8b, 98%
3 : 1 E/Z; v) Pd(OAc)2, PPh3, Ag2CO3, 80 ◦C, 4 days, 72%.
Scheme 3 Reagents and conditions: i) LDA, THF, −78 ◦C, then CH3CHO,
92%; ii) CH3COCl, MeOH, 84%; iii) MeSO2Cl, DBU, 97% 2 : 1 E/Z;
iv) AlMe3, 2-iodoaniline, 0–40 ◦C, 70%; v) (Boc)2O, DMAP, iPr2NEt,
83%; vi) Pd2(dba)3, PPh3, Ag3PO4, DMA, 90 ◦C, 66%.
ketone 8b and the ylide, derived from ethyltriphenylphosphonium
bromide, gave the alkene 4 as a 3 : 1 mixture of Z- and E-isomers.
When the iodoalkene 4 was treated with Pd(OAc)2 in DMF at
80 ◦C, in the presence of Ag2CO3 and PPh3, for 4 days (i.e.
under Heck conditions)15 a facile 5-exo-trig cyclisation ensued,
producing the expected benzodihydrofuran 5 in 72% yield. In a
similar manner, the more elaborate tyrosine-substituted substrate
13, derived from the vinylstannane 10 and the aryl iodide 11 via
the carboxylic acid 12b (Scheme 2), underwent an intramolecular
5-exo-trig Heck cyclisation, using Pd2(dba)3 and Ag3PO4, leading
to the corresponding benzofuranone 14, albeit in a more modest
yield of 49%. Finally, with the correct diazonamide A structure
1 in mind, we showed that the amide analogues 18 and 23 of
the ester 13 underwent similar Heck cyclisations leading to the
corresponding oxindoles 19 and 24 respectively, in reasonable
yields. The amide 18 was prepared from 2-benzyloxyphenylacetic
acid 15 following deprotonation and alkylation with acetaldehyde
to 16a, esterification and dehydration to 17 and, finally, coupling
with 2-iodoaniline (Scheme 3). The chiral oxazolidine anilide
23 was elaborated from the aryl iodide 21, prepared from the
substituted tyrosine 20b, following a Stille coupling reaction with
methyl E-2-(trimethylstannyl)but-2-enoate, leading to 22, and an
amide bond forming reaction with 2-iodoaniline in the presence
of trimethylaluminium (Scheme 4). Interestingly, the free amine
18a corresponding to 18b failed to undergo a Heck cyclisation,
and only one diastereomer of the oxindole 24 was produced in the
cyclisation of 23 (76%).
Although we were not able to achieve an enantioselective Heck
cyclisation of the substrate 4,14 we did separate the enantiomers
of the racemic acid 25b, produced after ozonisation of the alkene
5. Thus, the racemic acid was converted into a mixture of the
corresponding diastereoisomeric a-methylbenzylamides 26, one
of which was obtained as colourless crystals (Scheme 5). X-Ray
crystallographic analysis established that the quaternary centre in
the more polar, crystalline benzylamide (Fig. 1) had the opposite
configuration to that present in diazonamide A. Hydrolysis of the
less polar benzylamide 26 gave the S-carboxylic acid 27, having
the same configuration present in natural diazonamide A (1).
Elaboration of 5 to the heterocyclic units 30, 33 and 39 in
diazonamide A
Having secured a satisfactory synthesis of the substituted ben-
zodihydrofuran 5, the feasibility of converting it into parts of
the heterocyclic core, i.e. 6, in the diazonamide A structure 2
was then explored. Thus, we first examined the conversion of 5
Scheme 2 Reagents and conditions: i) Me3SiCH2CH2OH, DCC, DMAP; ii) Pd(OAc)2, PPh3, Bu3SnH, 85% (over 2 steps); iii) 10, Ph3As, CuI, NMP,
Pd/C, 55%; iv) TBAF, THF, 0–5 ◦C, 63%; v) EDCI, then 2-bromo-6-iodophenol, DMAP, 60%; vi) Pd2(dba)3, dppp, Ag3PO4, Bu4NBr, 90–95 ◦C, 49%.
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Scheme 4 Reagents and conditions: i) K2CO3, PhCH2Br, DMF, 90%; ii) LiBH4, THF, 93%; iii) BF3·OEt2, Me2C(OMe)2, 90%; iv) Ph3As, Pd2(dba)3,
CuI, E-MeCH C(SnBu3)CO2Me, NMP, 76%; v) AlMe3, 2-iodoaniline, CH2Cl2, 0–40 ◦C, 74%; vi) NaHMDS, Me3SiCH2CH2OCH2Cl, THF, 90%;
=
vii) Pd2(dba)3, PPh3, Ag3PO4, DMA, 90 ◦C, 77%.
also be produced from 28, via a more lengthy procedure following:
i) deprotonation and bromination, leading to 29d, followed by
ii) azide 29e formation and reduction to the amine 29b, using
triphenylphosphine, and finally iii) acylation of 29b, using acetyl
chloride. Cyclodehydration of 29c, using Ph3P–I2–NEt3,20 then
gave the oxazole benzodihydrofuran 30a in 89% yield. Hydrolysis
of 30a to the corresponding carboxylic acid 30b, followed by acid
chloride formation and reaction with the substituted 5-iodoindole
31, gave the keto amide 32. The keto amide 32 was then con-
verted into the benzodihydrofuran–indole-substituted bis-oxazole
intermediate 33 by straightforward treatment with Et3N–Ph3P
in hexachloroethane (Scheme 6). Disappointingly, in spite of a
number of attempts we were not able to achieve the intramolecular
Scheme 5 Reagents and conditions: i) O3, PPh3, 84%; ii) NaClO2, K2HPO4,
Ullmann coupling of 33 to the aromatic core 34 of diazonamide
=
Me2C CHCH3, 85%; iii) SOCl2, D, 93%; iv) S-(−)-a-methylbenzylamine,
A under a range of conditions, e.g. Stille, nickel catalysis. Either
the starting material or the product of reduction of the carbon-to-
iodine bond in the indole ring of 33 was recovered. We therefore
turned to the use of the corresponding Suzuki reaction, and found
that the coupling reaction of the boronic acid 35, derived from
5, with the substituted 5-bromoindole 36,21 gave a satisfactory
80% yield of the benzodihydrofuran–indole 37a (Scheme 7).
Cleavage of the TIPS ether group in 37a, followed by oxidation
of the resulting alcohol then gave the corresponding aldehyde.
A Still–Gennari olefination22 reaction between this aldehyde
and bis(2,2,2-trifluoroethylmethoxycarbonylmethyl)phosphonate
then produced the Z-alkenoate 38. Hydrolysis of the ester group
and deprotection of the Boc group in 38, followed by macrolac-
tamisation of the resulting amino acid in the presence of DPPA–
iPr2NEt gave the macrolactam 39. Frustratingly, however, we were
not able to oxidise the benzylic methylene unit in 39 to the corre-
sponding keto amide precursor en route to the oxazole–indole 40.
Et3N, chromatography, 92% (S : R, 1 : 1); v) 26b, pTSA, toluene, D, 83%;
vi) aq. KOH, 84% (70% over two steps).
Fig. 1 X-Ray crystal structure of the a-methylbenzylamide 26b.
Examination of the 13-exo-trig Heck cyclisation of 46a to the
macrolactam 47
into the oxazole-substituted benzodihydrofuran 30 as a prelude to
preparing the macrocyclic bis-oxazole indole 34. Oxidative cleav-
age of 5 first gave the aldehyde 25a which, on treatment with ethyl
diazoacetate in the presence of ZrCl418 at 0 ◦C, was converted into
the corresponding b-keto ester 28 in 84% yield. In an alternative
sequence, the b-keto ester 28 was produced from the carboxylic
acid 25b following reaction of the corresponding imidazolide with
magnesium ethoxycarboxylacetate.19 The b-keto ester 28 was then
converted into the oxime 29a which, on reduction with zinc dust
in acetic acid, produced the a-amino b-keto ester derivative 29b,
the precursor to the acetamide 29c. The same amide 29c could
Encouraged by the outcome of the aforementioned 5-exo-trig
Heck cyclisations, leading to the products 5, 14, 19 and 24,
we next decided to examine the more ambitious Heck reaction
from the precursor 46a i.e. disconnection (c) on structure 3. In
contemporaneous work, Harran et al.23 had studied the Heck
cyclisation of the lower homologue 46b and showed that it gave the
product 48b, resulting from a 13-endo-trig cyclisation. However,
we felt that the presence of the additional methyl group on
the alkene bond in 46a, in combination with the electronically
controlled Heck reaction conditions developed by Cabri et al.24
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Scheme 6 Reagents and conditions: i) O3, PPh3, 84%; ii) EtO2CCHN2, ZrCl4, 84%; iii) NaNO2, HOAc, 28 → 29a, 94%; iv) Zn, HOAc; v) AcCl, Et3N,
0 ◦C → rt, 29a → 29b → 29c, 71%; vi) NaH, Br2, 28 → 29d, 99%; vii) NaN3, DMF, 0 ◦C, 79%; viii) PPh3, THF, 75%; ix) Et3N, PPh3, I2, 86%; x) LiOH,
MeOH, H2O, 98%; xi) (COCl)2, then 31, 60%; xii) Et3N, PPh3, 81%.
bromooxazole 43, leading to 44a, followed by a coupling reaction
of the amine 44b with the carboxylic acid 45, as the key steps.23
Treatment of 46a under the conditions of Cabri et al.,24 however,
failed to produce any product resulting from an intramolecular
Heck reaction. We tried using a range of alternative conditions
and cocktails, including the use of silver phosphate and carbonate,
the addition of sodium formate and different temperatures, but all
to no avail. However, we were able to repeat the Heck cyclisation of
46b, described by Harran et al.,23 and obtained the same result, i.e.
the formation of the product 48b from a 13-endo-trig cyclisation. It
therefore seems likely that the additional steric requirements of the
bidentate ligand, used in the Cabri conditions, and the additional
methyl substitution on the alkene bond in the substrate conspire
to inhibit a Heck cyclisation from 46a in either the 12-exo or the
13-endo modes.
Synthesis of the tethered Heck reaction precursors 57 and 59, and
the chromene 63. Cyclisation of 63 to the spirocycle 64 under Heck
conditions
After the disappointment of not being able to achieve an
intramolecular Heck cyclisation from the substrate 46a, we
decided to examine corresponding Heck reactions from “tethered”
substrates akin to 49. The idea behind this proposal was that if
Scheme
7
Reagents and conditions: i) O3, CH2Cl2, −78 ◦C,
then O2–MeOH, then NaBH4, 61%; ii) iPr3SiCl, Im, DMF, 83%;
iii) BuLi, B(OMe)3, THF, 99%; iv) Pd(PPh3)4, K2CO3, 36, 80%;
v) TBAF, THF, rt → 60 ◦C, 91%; vi) PySO3, Et3N, DMSO, 82%;
vii) MeO2CCH2PO(OCH2CF3)2, KHMDS, 18-crown-6, THF, −78 ◦C,
96%; viii) LiOH, DME; ix) TFA, CH2Cl2; x) DPPA, iPr2NEt, CH2Cl2,
49% (over 3 steps).
we could achieve the cyclisation of 49 to 50, with simultaneous
introduction of the correct stereochemistry at the newly introduced
quaternary carbon centre, following elaboration via 51 we would
have a reasonably advanced intermediate, viz. 52, cf. 47, en route to
diazonamide A. However, before embarking on such an ambitious
program, we investigated the feasibility of the overall proposal
using the less substituted precursor 57, synthesised from the
vinylstannane 4225 as shown in Scheme 9. Thus, conversion of
42 into the vinyl iodide 53, followed by lithium–iodine exchange,
(i.e. Pd(dppp), TlOAc, DMF, 80 ◦C), might promote cyclisation at
the more electron-deficient end of the alkene bond in 46a, leading
to the product of exo-cyclisation, i.e. 47. We therefore prepared
the substrate 46a, as shown in Scheme 8; this involved an initial
Stille coupling reaction between the vinylstannane 42 and the
26
transmetallation with MgBr2 and finally reaction with Garner’s
aldehyde27 gave the secondary alcohol 54 as a mixture of syn and
anti-diastereoisomers.
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Scheme 8 Reagents and conditions: i) (PPh3)2PdCl2, Bu3SnH, 73%; ii) 42, PdCl2(MeCN)2, DMF, 25 ◦C, 81%; iii) BBr3, CH2Cl2, −78 ◦C, 79%; iv) 44b,
DIPEA, TBTU, DMF, 0 ◦C, 60%.
to 55, and functional group manipulation gave the carboxylic
acid 56. Finally, a straightforward esterification of 56 with 2-
bromo-6-iodophenol gave the substrate 57 for the attempted Heck
cyclisation to 58. Frustratingly, all attempts to effect a 7-exo-
trig Heck cyclisation from the alkene 57 met with failure. A
similar outcome was obtained with the analogous ‘ether’-tethered
precursors 59, produced from the syn and anti-alcohols 54a and
54b.
The diastereomers were separated by chromatography, and
the X-ray crystal structure confirmed the syn-stereochemistry
assigned to 54a (Fig. 2). Benzylation of the anti-diastereomer 54b
followed by cleavage of the oxazolidine in the product, leading
Scheme 9 Reagents and conditions: i) I2, THF, 0 ◦C, 81%; ii) nBuLi,
MgBr2, −78 ◦C, Garner’s aldehyde, 74%; iii) NaH, BnBr, THF, rt →
65 ◦C, 92%; iv) BF3–HOAc, 98%; v) NaHCO3, periodinane, then
NaClO2, KH2PO4, tBuOH, 39% over
2 steps; vi) EDC, DMAP,
2-iodo-6-bromophenol, 55%.
Somewhat perplexed by the lack of reactivity of the substrates 57
and 59 towards Heck cyclisations, we examined the X-ray crystal
Fig. 2 X-Ray crystal structure of the secondary alcohol 54a.
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structures of the syn-precursors 54a and 59a and, to our surprise,
found that the alkene units and the aryl rings to which they are
attached are essentially orthogonal; presumably due to the severe
steric interactions involving the ortho benzyl ether substituent
and the methyl groups of the propenyl units (see Fig. 2 and
Fig. 3). This structural feature could preclude coordination of
the metallated aryl rings in both 57 and 59 to their respective
alkene bonds, thereby preventing any attempted Heck reactions
with these substrates. In order to add credence to this supposition,
we decided to then examine the corresponding Heck reactions
with the chromene substrates 62 and 63, which are devoid of any
of the steric interactions present in the benzyl ether-aryl propenyl
compounds 57 and 59.
method employed in the synthesis of the analogous benzyl
ethers 59 (Scheme 10). Much to our satisfaction, when the syn-
diastereoisomer 62 was treated with Pd(OAc)2, PPh3 and Ag2CO3
in tetrahydrofuran at 60 ◦C for 2 days, a single product 64, resulting
from a 6-exo-trig cyclisation, was obtained in 42% yield. The
product was obtained as a crystalline solid whose X-ray structure
(Fig. 4) established that the quaternary centre had the same
absolute configuration as the same centre in natural diazonamide
A. Interestingly, when the same Heck reaction was carried out
in N,N-dimethylacetamide at higher temperature (85–90 ◦C), a
small amount (∼8%) of the corresponding isomeric ether 65,
resulting from a competing 7-endo-trig cyclisation, was produced
concurrently. A similar outcome was obtained when the anti-
diastereoisomer 63, corresponding to 62, was subjected to Heck
cyclisation i.e., the major product was the spiro-chromene 66.
Fig. 3 X-Ray crystal structure of the iodide 59a.
Fig. 4 X-Ray crystal structure of the spirocyclic system 64.
Having eventually achieved a route to the quaternary centre, and
investigated routes to the heterocyclic core, viz. 6 in diazonamide A
(1), using the Heck and related Pd(0)-mediated coupling reactions,
the spirocyclic system 64 remained a daunting distance from
the ultimate synthetic target. Thus, significant manipulations of
the structure 64, including oxidative cleavage of the vinyl ether
The substituted chromenes 62 and 63 were prepared start-
ing from the known 4-bromo-2H-chromene 6028 using the
Scheme 10 Reagents and conditions: i) nBuLi, MgBr2, −78 ◦C, Garner’s aldehyde, 65%; ii) NaHMDS, 0 ◦C, then 2-iodobenzyl bromide, Bu4NI, 53%;
iii) PPh3, Ag2CO3, Pd(OAc)2, 41–54%.
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moiety, and insertion of nitrogen at the benzylic ether carbon,
would be required to approach a precursor akin to 67, for
further extensive development. Although some of these synthetic
conversions were investigated,29 the re-assignment of the structure
of diazonamide A (2) mid-way through our studies, together
with the decisive synthetic investigations of Harran and Nicolaou
and their respective collaborators discouraged us from further
pursuing our own particular approach to 2 based broadly on the
Heck and related reactions. We therefore abandoned our studies
towards a synthesis of diazonamide A at this point.
band decoupled mode, and the multiplicities were determined
1
using a DEPT sequence. When required, H–1H COSY spectra
were recorded on a Bruker DPX 360 (360 MHz) instrument
and standard Bruker software with no modifications. 1H–13C
HMQC/HMBC and NOE spectra were recorded on a Bruker
AV 400 (400 MHz) spectrometer. Mass spectra were recorded on
either a VG Autospec, an MM-701CF, a VG Micromass 7070E
or a Micromass LCT spectrometer, using electron ionisation (EI),
electrospray (ESI) or fast atom bombardment (FAB) techniques.
Microanalytical data were obtained on a Perkin-Elmer 240B
elemental analyser. All crystals for crystallography were mounted
on dual-stage glass fibres using RS3000 perfluoropolyether oil,
and flash-frozen in the cold stream of the diffractometer’s low-
temperature device.
Flash chromatography was performed using Merck silica gel
60 as the stationary phase and the solvents employed were of
analytical grade. “Petrol” used in chromatography refers to light
petroleum, bp 60–80 ◦C. All reactions were monitored by thin layer
chromatography using aluminium plates precoated with Merck
silica gel 60 F254, which were visualised with ultraviolet light and
then with either acidic alcoholic vanillin solution, basic potassium
permanganate solution, or acidic anisaldehyde solution.
Dry organic solvents were routinely stored under a nitro-
gen atmosphere and/or dried over sodium wire. Benzene and
dichloromethane were distilled from calcium hydride. Dry tetrahy-
drofuran was obtained from a solvent drying tower. Other organic
solvents and reagent were purified by the accepted literature
procedures. Solvent was removed in vacuo using a Bu¨chi rotary
evaporator. Where necessary, reactions requiring anhydrous con-
ditions were performed in dry solvents in flame-dried or oven-dried
apparatus under a dry nitrogen atmosphere.
Summary
In summary, our studies of the scope for the Heck and related
coupling reactions in forming the quaternary stereocentre and
the heterocyclic core in diazonamide A have allowed access to
compounds 5, 14, 19, 24, 64 [cf. disconnection (b) on structure
3] and also to compounds 30, 33 and 39. Unfortunately, we were
not able to realise a 13-exo-trig Heck cyclisation of 46a to the
macrolactam 47 [cf. disconnection (c) on structure 3]. We did not
examine cross-coupling reactions involving 2-substituted oxazoles
in this particular study [cf. disconnection (a) on structure 3].
Nevertheless, there is ample precedent for this type of chemistry,
using a range of substituted oxazoles, in the literature,30 some
of which we have exploited in other research programs in our
laboratory involving polyoxazole-based natural products. These
other studies will be presented at a later date.
E- and Z-1-(2-Bromo-6-iodophenoxy)-2-phenylbut-2-ene (4).
A solution of n-butyllithium (1.6 M) in hexanes (56 mL,
90.0 mmol) was added dropwise over 20 min to a stirred suspension
of ethyltriphenylphosphonium ◦bromide (33.5 g, 90.0 mmol) in
tetrahydrofuran (600 mL) at 0 C under a nitrogen atmosphere;
the mixture was then stirred at 0 ◦C for 20 min. A solution of
the ketone 8b (31.4 g, 75.0 mmol) in tetrahydrofuran (600 mL)
was added dropwise over 15 min, and the mixture was then
stirred at room temperature for 3 h. The mixture was quenched
with saturated aqueous ammonium chloride (500 mL) and water
(300 mL) and then extracted with diethyl ether (3 × 500 mL).
The combined organic extracts were dried and concentrated in
vacuo. Diethyl ether (200 mL) was added to the residue and the
Experimental
General details
All melting points were determined using a Kofler hot-stage
apparatus and are uncorrected. Optical rotations were recorded in
spectroscopic grade chloroform on a Jasco DIP-370 polarimeter,
and [a]D values were recorded in units of 10−1 deg cm2 g−1. Infrared
spectra were obtained on a Perkin–Elmer 1600 series FT-IR
instrument as dilute solutions in spectroscopic grade chloroform.
Proton NMR spectra were recorded on a Bruker DPX 360 (360
MHz) spectrometer as dilute solutions in deuterochloroform at
ambient temperature, unless otherwise stated. The chemical shifts
are quoted in parts per million (ppm) relative to residual solvent
peaks, and the multiplicity of each signal is designated by the
following abbreviations: s, singlet; d, doublet; t, triplet; q, quartet;
sx, sextet; br, broad; m, multiplet; app., apparent. All coupling
constants are quoted in Hertz. Carbon-13 NMR spectra were
recorded using a Bruker DPX 360 (90 MHz) instrument as dilute
solutions in deuterochloroform, unless otherwise stated. Chemical
shifts are reported relative to residual solvent peaks using a broad-
◦
solution was then cooled to 0 C. Pentane (400 mL) was added
◦
to the rapidly stirred solution, and the mixture was kept at 0 C
for 30 min. The precipitated solid was removed by filtration, and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography, eluting with 5% ethyl acetate in petroleum ether,
to give a 3 : 1 mixture of Z- and E-isomers of the olefin (31.5 g, 98%)
as an oil; mmax (CHCl3)/cm−1 1600, 1551; dH (270 MHz, CDCl3) 7.71
(1 H, dd, J 7.9 and 1.5, E ArH), 7.69 (1 H, dd, J 7.9 and 1.5, Z
ArH), 7.57 (2 H, dd, J 8.0 and 1.2, E ArH), 7.50 (1 H, dd, J 7.9
and 1.5, E ArH), 7.49 (1 H, dd, J 7.9 and 1.5, Z ArH), 7.37–7.21
(5 H + 3 H, m, ArH), 6.67 (2 H, t, J 7.9, ArH), 6.19 (1 H, q,
J 6.9, Z-CHCH3), 6.07 (1 H, q, J 7.1, E-CHCH3), 4.98 (2 H, s,
E-OCH2), 4.65 (2 H, s, Z-OCH2), 1.96 (3 H, d, J 7.1, E-CHCH3),
1.73 (3 H, d, J 6.9, Z-CHCH3); dC (67.8 MHz, CDCl3) 155.7 (E
4200 | Org. Biomol. Chem., 2006, 4, 4193–4205
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s), 155.2 (Z s), 141.2 (E s), 138.7 (E d), 138.6 (Z d), 138.0 (Z s),
136.6 (Z s), 136.2 (E s), 133.8 (E d), 133.7 (Z d), 129.5 (E d), 129.0
(d), 127.9 (d), 127.0 (6 × d), 117.1 (s), 92.9 (s), 92.8 (s), 77.0 (Z
t), 69.8 (E t), 14.8 (E q), 14.6 (Z q); m/z (FAB) Found: 427.9279
(M+, 1%, C16H14BrIO requires 427.9275), 349 (1), 285 (1), 91 (91).
127.7 (d), 127.0 (d), 125.3 (d), 123.8 (s), 121.5 (d), 120.9 (d), 113.1
(d), 88.9 (s), 70.0 (t), 15.5 (q); m/z (ESI) Found: 492.0478 ([M +
Na]+, C23H20INO2Na requires 492.0436), 470 (62), 380 (6), 337
(12), 310 (22).
tert-Butyl-(2E)-2-[2-(benzyloxy)phenyl]-N-(2-iodophenyl)carba-
mate (18b). Di-tert-butyl dicarbonate (225 mg, 1.02 mmol)
and 4-dimethylaminopyridine (11 mg, 0.09 mmol), followed
by diisopropylethylamine (0.15 mL, 0.85 mmol) were added in
single portions to a stirred solution of the anilide 18a (400 mg,
0.85 mmol) in acetonitrile (10 mL). The mixture was stirred
at room temperature for 3 h, then water (5 mL) was added
and the solvent was removed in vacuo. Diethyl ether (20 mL)
was added to the residue and the separated aqueous layer was
then extracted with diethyl ether (3 × 30 mL). The combined
organic extracts were washed with brine (30 mL), then dried
over MgSO4 and concentrated in vacuo. The residue was purified
by chromatography, eluting with 5% ethyl acetate in petroleum
ether, to give the carbamate (400 mg, 83%) as pale yellow crystals;
mp 118–120 ◦C (from petroleum ether (bp 60–80 ◦C)–acetone);
(Found: C, 58.7; H, 4.9; N, 2.2; C28H28NO4I requires: C, 59.1; H,
5.0; N, 2.2%); mmax (CHCl3)/cm−1 1734, 1688, 1152; dH (360 MHz,
CDCl3) 7.74 (1 H, d, J 7.9, ArH), 7.40 (2 H, d, J 7.5, ArH),
7.33 (2 H, dt, J 6.9 and 2.0, ArH), 7.29–7.21 (2 H, m, ArH and
( )-3-Ethenyl-7-bromo-3-phenyl-2,3-dihydrobenzofuran (5).
A
solution of palladium(II) acetate (210 mg, 0.93 mmol) in DMF
(10 mL) was added to a mixture of the bromoiodo olefin 4
(20.0 g, 46.7 mmol), triphenylphosphine (490 mg, 1.89 mmol)
and silver carbonate (27.1 g, 98.1 mmol) in DMF (590 mL) at
room temperature under a nitrogen atmosphere and the mixture
was then heated at 80 ◦C for 4 days. Additional palladium(II)
acetate (105 mg, 0.47 mmol) in a DMF solution (5 mL) was
added after the first and third days. The mixture was cooled to
R
room temperature, filtered through Celiteꢀ, diluted with water
(3000 mL) and then extracted with diethyl ether (3 × 1000 mL).
The combined organic extracts were washed with water (1500 mL)
then dried and concentrated in vacuo. The residue was purified by
chromatography, eluting with 10% ethyl acetate in petroleum ether,
to give the dihydrobenzofuran (10.1 g, 72%) as a colourless oil; mmax
(CHCl3)/cm−1 1634, 1598; dH (270 MHz, CDCl3) 7.36 (1 H, dd,
J 7.9 and 1.3, ArH), 7.32–7.22 (5 H, m, ArH), 7.00 (1 H, dd, J
7.3 and 1.3, ArH), 6.72 (1 H, t, J 7.7, ArH), 6.27 (1 H, dd, J 17.2
=
=
=
and 10.6, CH CH2), 5.31 (1 H, d, J 10.6, CH CHH), 5.07 (1 H,
CHCH3), 7.15–7.05 (2 H, m, ArH), 6.97–6.81 (5 H, m, ArH),
=
=
d, J 17.2, C CHH), 4.86 (1 H, d, J 9.2, CHHO), 4.72 (1 H, d,
5.10 (2 H, s, PhCH2OAr), 1.80 (3 H, d, J 7.1, CHCH3), 1.26 (9
J 9.2, CHHO); dC (67.8 MHz, CDCl3) 156.9 (s), 143.4 (s), 140.7
(d), 133.5 (s), 131.8 (d), 128.5 (d), 127.3 (d), 127.1 (d), 124.5 (d),
122.2 (d), 115.5 (t), 103.3 (s), 83.3 (t), 58.4 (s); m/z (ESI) Found:
300.0173 (M+, 91%, C16H13BrO requires 300.0150), 221 (46), 205
(13), 194 (95), 178 (21), 118 (6), 77 (28).
H, s, COOC(CH3)3); dC (90.6 MHz, CDCl3) 171.2 (s), 156.2 (s),
151.5 (s), 141.8 (s), 139.2 (d), 137.6 (d), 136.9 (s), 136.4 (s), 133.0
(d), 129.8 (d), 129.0 (d), 128.9 (d), 128.5 (d), 128.3 (d), 127.6 (d),
127.1 (d), 124.5 (s), 120.6 (d), 113.3 (d), 99.8 (s), 82.7 (s), 70.8
(t), 27.7 (q), 15.5 (q); m/z (ESI) Found: 592.0933 ([M + Na]+,
C28H28INO4Na requires 592.0961), 576 (9), 492 (23), 470 (94), 452
(6).
(2E)-2-[2-(Benzyloxy)phenyl]-N-(2-iodophenyl)but-2-enamide
(18a). A solution of 2-iodoaniline (1.0 g, 4.5 mmol) in
dichloromethane (10 mL) was added dropwise over 10 min to a
stirred solution of trimethylaluminium (2 M) in hexane (2.3 mL,
4.5 mmol) at 0 ◦C under a nitrogen atmosphere. After 10 min,
the solution was allowed to warm to room temperature and
stirred for 30 min giving a clear red–brown solution. A solution
of the unsaturated ester 17 (0.5 g, 1.8 mmol) in dichloromethane
(10 mL) was added dropwise over 10 min, and the mixture was
tert-Butyl 3-(2-(benzyloxy)phenyl)-2-oxo-3-vinylindoline-1-carb-
oxylate (19). A mixture of triphenylphosphine (6 mg, 22.0 lmol),
silver phosphate (46 mg, 110 lmol) and tris(dibenzyl-
ideneacetone)dipalladium(0) (6 mg, 5.50 lmol) in dimethylac-
etamide (0.5 mL) was stirred at room temperature under a nitrogen
atmosphere for 2 h. A solution of the anilide 18b (31 mg, 55.0 lmol)
in dimethylacetamide (1 mL) was added in one portion and the
solution was then degassed with nitrogen for 1 h. The solution was
heated at 90 ◦C for 24 h, then cooled to room temperature, filtered
◦
then heated at reflux for 20 h. The mixture was cooled to 0 C,
then water (5 mL) was added over 15 min, followed by saturated
aqueous Rochelle’s solution (10 mL), and the mixture was stirred
at room temperature for 15 min. After removal of the solvent
in vacuo, diethyl ether (20 mL) was added to the residue and
the separated aqueous layer was extracted with diethyl ether
(3 × 15 mL). The combined organic extracts were washed with
brine (50 mL), dried over MgSO4 and concentrated in vacuo. The
residue was purified by chromatography, eluting with 10% ethyl
acetate in petroleum ether, to give the anilide (0.57 g, 70%) as a
yellow oil; (Found: C, 58.7; H, 4.4; N, 2.9; C23H20NO2I requires:
C, 58.9; H, 4.3; N, 3.0%); mmax (CHCl3)/cm−1 3697, 3347, 2914,
1682; dH (360 MHz, CDCl3) 8.52 (1 H, dd, J 8.2 and 1.5, ArH),
7.70 (1 H, br s, NH), 7.66 (1 H, dd, J 8.2 and 1.5, ArH), 7.41–7.33
R
through Celiteꢀ and washed with diethyl ether (10 mL). Water
(5 mL) was added to the filtrate and the separated aqueous layer
was then extracted with diethyl ether (3 × 10 mL). The combined
organic extracts were washed with brine (15 mL), then dried
over MgSO4 and concentrated in vacuo. The residue was purified
by chromatography, eluting with 5% ethyl acetate in petroleum
ether, to give the oxindole (15 mg, 66%) as a colourless oil; mmax
(CHCl3)/cm−1 2931, 1791, 1725, 1606; dH (360 MHz, CDCl3) 7.72
(1 H, d, J 8.1, ArH), 7.51 (1 H, dd, J 7.5 and 1.6, ArH), 7.31–7.19
(5 H, m, ArH), 7.10 (1 H, dt, J 7.5 and 1.0, ArH), 7.01 (1 H, dt,
J 7.5 and 1.0, ArH), 6.87–6.80 (4 H, m, ArH), 6.33 (1 H, dd, J
17.2 and 10.2, CH CH2), 5.42 (1 H, d, J 10.2, CH CHH), 4.96
(1 H, d, J 17.2, CH CHH), 4.84 (1 H, d, J 11.7, PhCHHOAr),
4.71 (1 H, d, J 11.7, PhCHHOAr), 1.51 (9 H, s, COOC(CH3)3);
dC (90.6 MHz, CDCl3) 175.5 (s), 155.4 (s), 149.5 (s), 140.1 (s),
137.3 (d), 136.0 (s), 129.8 (s), 129.5 (d), 129.2 (d), 128.9 (s), 128.4
(d), 127.9 (d), 127.8 (d), 127.4 (d), 124.6 (d), 123.8 (d), 120.7 (d),
=
=
=
=
(2 H, m, ArH and CHCH3 obs), 7.32–7.21 (7 H, m, ArH),
7.12–7.07 (2 H, m, ArH), 6.77 (1 H, dt, J 7.8 and 1.6, ArH),
5.13 (2 H, s, PhCH2OAr), 1.74 (3 H, d, J 7.1, CHCH3); dC
(90.6 MHz, CDCl3) 165.0 (s), 156.6 (s), 138.9 (s), 138.7 (d), 138.1
(d), 136.7 (s), 134.1 (s), 132.2 (d), 130.3 (d), 129.2 (d), 128.5 (d),
=
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119.0 (t), 115.2 (d), 112.2 (d), 83.6 (s), 70.1 (t), 58.8 (s), 28.1 (q);
m/z (ESI) Found: 464.1867 ([M + Na]+, C28H27NO4Na requires
464.1838), 386 (13), 364 (41), 343 (22), 342 (85).
(10 mL), then dried, and concentrated to leave a sticky colourless
solid. The solid was purified by chromatography, eluting with
ethyl acetate–petrol (16 : 84), to give (i) the anti-allylic alcohol
54b (66 mg, 51%) as colourless crystals; mp 112.5–114.0 ◦C (from
ethyl acetate–petroleum ether); (Found: C, 71.3; H, 7.8; N, 2.9;
C27H35NO5 requires: C, 71.5; H, 7.8; N, 3.1%); [a]1D8 +16.0 (c 1.02
in CDCl3); mmax/cm−1 (CDCl3) 3686, 3563, 2936 and 1694; dH
(250 MHz, d6-DMSO, 353 K) 7.42–7.23 (6 H, m, ArH), 7.06 (1
H, app. d, J 7.9, ArH), 6.97–6.92 (2 H, m, ArH), 5.95 (1 H, q,
tert-Butyl (4S)-4-{4-benzyloxy-3-[2-oxo-1-((2-trimethylsilyl)-
ethoxy)methyl)-3-vinyl-2,3-dihydro-1H-indol-3-yl]benzyl}-2,2-di-
methyl-1,3-oxazolidine-3-carboxylate (24). A mixture of tri-
phenylphosphine (56 mg, 0.21 mmol), silver phosphate (440 mg,
1.10 mmol) and tris(dibenzylideneacetone)dipalladium(0) (55 mg,
0.05 mmol) in dimethylacetamide (1 mL) was stirred at room
temperature under a nitrogen atmosphere for 2 h. A solution of
the anilide 23b (430 mg, 0.53 mmol) in dimethylacetamide (7 mL)
was added, in one portion, and the mixture was then degassed
with nitrogen for 1 h. The solution was heated to 90 ◦C for 36 h,
=
J 6.8, [rotamer 1 + rotamer 2] CHCH3), 5.08 (1 H, d, J 14.1,
ArCHHO), 5.03 (1 H, d, J 14.1, ArCHHO), 4.75 (1 H, br s,
CHOH), 4.45 (1 H, br s, OH), 3.84 (1 H, dd, J 8.5 and 3.3,
CHHO), 3.67–3.64 (1 H, m, CHN), 3.56–3.49 (1 H, m, CHHO),
1.47 (3 H, s, CCH3), 1.39 (3 H, d, J 6.8, [rotamer 1 + rotamer
R
then cooled to room temperature, filtered through Celiteꢀ and
=
2] CHCH3), 1.36 (3 H, s, CCH3), 1.27 (9 H, s, C(CH3)3); dC
washed with diethyl ether (20 mL). Water (20 mL) was added
and the separated aqueous layer was then extracted with diethyl
ether (3 × 30 mL). The combined organic extracts were washed
with brine (50 mL), then dried over MgSO4 and concentrated
in vacuo. The residue was purified by chromatography, eluting
with 10% ethyl acetate in petroleum ether, to give the oxindole
(280 mg, 77%) as a pale yellow oil; [a]2D0 −19.0 (c 1.5 in CHCl3);
mmax (CHCl3)/cm−1 2955, 1719, 1691; dH (360 MHz at 318 K,
CDCl3) 7.37–7.21 (5 H, m, ArH), 7.09 (1 H, br s, ArH), 7.00 (1
H, t, J 7.5, ArH), 6.89 (2 H, d, J 7.5, ArH), 6.84–6.76 (3 H, m,
(90 MHz, CDCl3, 330 K) 156.0 (s), 152.2 (s), 138.0 (s), 137.2 (s),
131.0 (d), 128.6 (d), 128.1 (s), 127.9 (d), 127.2 (d), 123.5 (d), 121.3
(d), 112.6 (d), 94.3 (s), 79.8 (s), 74.7 (d), 70.5 (t), 63.0 (t), 59.7 (d),
28.4 (q), 26.4 (q), 23.4 (q), 14.2 (q); m/z (ESI) Found: 476.2375
([M + Na]+, C27H35NO5Na requires 476.2413), 476 ([M + Na]+,
100%), 296 (80); and (ii) the syn-allylic alcohol 54a (32 mg, 23%)
as a colourless oil which crystallised on standing at 4 ◦C for
one week; (Found: C, 71.5; H, 7.8; N, 2.5; C27H35NO5 requires: C,
71.5; H, 7.8; N, 3.1%). [a]2D0 +21.2 (c 1.02 in CDCl3); mmax/cm−1
(CDCl3) 3687, 3549, 2957 and 1694; dH (360 MHz, CDCl3, 333
K) 7.42–7.26 (6 H, m, ArH), 7.26–7.22 (1 H, m, ArH), 6.99–6.96
=
ArH), 6.35 (1 H, dd, J 17.2 and 10.2, CH CH2), 5.31 (1 H, d, J
=
=
10.2, CH CHH), 4.98 (1 H, d, J 17.2, CH CHH), 4.92 (1 H,
d J 11.1, NCHHO), 4.69 (1 H, d, J 10.6, PhCHHOAr), 4.59 (1
H, d, J 10.6, PhCHHOAr), 4.20–3.95 (1 H, m, NCHCH2Ar),
3.89–3.81 (3 H, m, NCHHO and NCHCH2O), 3.45–3.40 (2
H, m, SiCH2CH2O), 3.30–3.08 (1 H, m, ArCHHCH), 2.67 (1
H, dd, J 12.9, ArCHHCH), 1.64–1.51 (15 H, m, COOC(CH3)3
and C(CH3)2), 0.89–0.74 (2 H, m, (CH3)3SiCH2), 0.08 (9 H, s,
(CH3)3SiCH2); dC (90.6 MHz at 318 K, CDCl3) 177.7 (s), 154.6
(s), 151.7 (s), 142.5 (s), 137.7 (d), 137.6 (d), 136.0 (s), 130.6 (d),
130.5 (d), 129.5 (d), 128.4 (d), 128.3 (d), 128.1 (d), 127.6 (d), 124.4
(d), 122.2 (d), 117.8 (t), 112.0 (d), 109.5 (d), 94.1 (s), 79.6 (s), 70.3
(t), 69.0 (t), 66.1 (t), 65.3 (t), 59.4 (d), 58.6 (s), 39.9 (t), 28.6 (q),
26.9 (q), 23.3 (q), 17.7 (t), −1.5 (q); m/z (ESI) Found: 707.3516
([M + Na]+, 27%, C40H52N2O6SiNa requires 707.3492), 511 (100),
467 (11), 217 (17).
=
(2 H, m, ArH), 5.88 (1 H, q, J 6.7, CHCH3), 5.27 (2 H, s,
ArCH2O), 4.28 (1 H, dd, J 9.8 and 5.1, CHOH), 3.85 (1 H, app
br s, CHN), 3.82 (1 H, app d, J 9.4, CHHO), 3.50 (1 H, dd, J
8.8 and 6.0, CHHO), 1.61 (3 H, s, CCH3), 1.50 (3 H, d, J 6.7,
=
CHCH3), 1.43 (9 H, s, C(CH3)3); dC (90 MHz, CDCl3, 333 K)
156.0 (s), 138.7 (s), 137.2 (s), 132.5 (d), 128.6 (d), 128.5 (d), 128.0
(d), 127.5 (d), 126.5 (s), 124.0 (s), 121.1 (d), 112.1 (d), 94.2 (s),
80.9 (s), 70.5 (t), 65.8 (t), 60.9 (d), 28.4 (q), 27.6 (q), 24.0 (q),
14.5 (q); m/z (ESI) Found: 476.2372 ([M + Na]+, C27H35NO5Na
requires 476.2413), 476 ([M + Na]+, 100%).
X-Ray crystal structure for (+)-syn-allyl alcohol 54a.
C27H35NO5, M = 453.56, orthorhombic, a = 9.5722(11), b =
3
˚
˚
11.5881(13), c = 23.044(3) A, U = 2556.1(9) A , T = 150(2)
K, space group P212121 (No. 19), Z = 4, Dc = 1.179 g cm−3,
l(Mo-Ka) = 0.081 mm−1, 22 674 reflections collected, 3463
unique (Rint 0.038) which were used in all calculations. Final R1
[3045 F > 4r(F)] = 0.0297 and wR(all F2) was 0.0787. CCDC
reference number 613517. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b609604b
(S)-4-[(E),(R)-2-(2-Benzyloxyphenyl)-1-hydroxybut-2-enyl]-2,2-
dimethyloxazolidine-3-carboxylic acid tert-butyl ester (54b) and
(S) - 4 - [(E) - (S) - 2-(2-benzyloxyphenyl)-1-hydroxybut-2-enyl]-2,2-
dimethyloxazolidine-3-carboxylic acid tert-butyl ester (54a).
A solution of tert-butyllithium (1.5 M) in hexanes (0.66 mL,
0.99 mmol) was added dropwise over 0.25 h to a stirred solution of
the vinyl iodide 53 (157 mg, 0.449 mmol) in diethyl ether (5 mL) at
−78 ◦C, and the mixture was then stirred at −78 ◦C for a further
0.75 h. A solution of MgBr2 (1 M in diethyl ether and benzene,
1.00 mL, 1.00 mmol)26 was added rapidly using a syringe, and the
mixture was then stirred at −78 ◦C for a further 0.5 h. A solution
of Garner’s aldehyde (64 mg, 0.28 mmol) in tetrahydrofuran
(2 mL) was added over 0.5 h, and the mixture was stirred for 1 h
at −78 ◦C then warmed to room temperature and stirred for a
further 16 h. The mixture was quenched with 2 M hydrochloric
acid (10 mL) and the aqueous layer was extracted with ethyl
acetate (3 × 10 mL). The combined organic extracts were washed
with sat. aqueous sodium bicarbonate solution (10 mL) and brine
(S)-4-[(E)-(S)-2-(2-Benzyloxyphenyl)-1-(2-iodobenzyloxy)but-2-
enyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
(59a). Sodium hydride (60% dispersion in oil, 53 mg, 1.33 mmol)
was added portion-wise to a stirred solution of the syn-allylic
alcohol 54a (500 mg, 1.10 mmol) in tetrahydrofuran (5 mL) at
0 ◦C, and the mixture was stirred at 0 ◦C for 15 min. 2-Iodobenzyl
bromide (448 mg, 1.43 mmol) was added, the mixture was heated
to 55 ◦C for 20 h and then concentrated in vacuo. The residue was
quenched with saturated aqueous ammonium chloride (5 mL)
and extracted with diethyl ether (3 × 5 mL). The combined
organic extracts were washed with saturated aqueous sodium
bicarbonate solution (5 mL), washed with brine (5 mL) then
dried and concentrated in vacuo. The residue was purified by
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chromatography, eluting with ethyl acetate–petrol (5 : 95 to 20 :
80), to give (i) the syn-ether (580 mg, 79%) as colourless crystals;
mp 81.5–84.0 ◦C; (Found: C, 60.6; H, 5.9; N, 1.7; C34H40NO5I
requires: C, 61.0; H, 6.0; N, 2.1; I, 19.0%); [a]2D0 +25.6 (c 2.33
in CDCl3); mmax/cm−1 (CDCl3) 2935 and 1681; dH (360 MHz,
CDCl3, 333 K) 7.80 (1 H, app d, J 6.5, ArH), 7.63 (1 H, app d,
J 7.6, ArH), 7.40–7.28 (6 H, m, ArH), 7.26–7.18 (2 H, m, ArH),
a further 1 h. The mixture was cooled to 0 ◦C, then quenched
with 2 M hydrochloric acid (150 mL) and extracted with diethyl
ether (3 × 100 mL). The combined organic extracts were washed
with saturated aqueous sodium bicarbonate solution (250 mL)
and brine (250 mL), dried and concentrated in vacuo. The residue
was purified by chromatography, eluting with ethyl acetate–petrol
(10 : 90 to 30 : 70), to give (i) the anti-alcohol 61a (3.65 g, 37%) as
a foam; [a]2D2 +17.6 (c 0.34 in CDCl3); mmax/cm−1 (CDCl3) 3682,
3524 and 1693; dH (360 MHz, C6D6, 320 K) 7.80 (1 H, br s,
ArH), 7.10–7.05 (1 H, m, ArH), 6.97–6.92 (2 H, m, ArH), 5.95
=
6.97–6.91 (3 H, m, ArH), 6.03 (1 H, q, J 6.8, CH), 5.05 (2
H, s, ArCH2O), 4.74 (1 H, d, J 13.3, ArCHHO), 4.46 (1 H, d,
J 13.3, ArCHHO), 4.07 (2 H, app s, CHO and CHN), 3.82 (1
H, app d, J 9.1, CHHO), 3.59 (1 H, m, CHHO), 1.59 (3 H, d,
=
(1 H, t, J 3.6, [rotamer 1 + rotamer 2] CHCH2), 5.40 (1 H,
=
J 6.8, CHCH3), 1.53 (3 H, br s, C(CH3)(CH3)), 1.46 (3 H, s,
br s, CHOH), 4.64–4.63 (2 H, d, J 3.6, [rotamer 1 + rotamer 2]
ArOCH2), 4.25–4.23 (1 H, m, CHN), 4.10 (1 H, dd, J 9.2 and 2.8
CHHO), 3.53 (1 H, dd, J 9.2 and 7.2 CHHO), 2.38 (1 H, br s,
OH), 1.78 (3 H, s, C(CH3)(CH3)), 1.55 (3 H, s, C(CH3)(CH3)),
1.52 (9 H, s, C(CH3)3); dC (90 MHz, C6D6, 320 K) 154.4 (s), 152.3
(s), 134.2 (s), 128.9 (d), 123.8 (d), 121.55 (s), 121.0 (d), 118.55
(d), 116.1 (d), 94.25 (s), 79.8 (s), 68.4 (d), 65.1 (t), 62.05 (t), 59.6
(d), 28.0 (q), 26.7 (q), 26.2 (q); m/z (ESI) Found: 384.1750 (M+
+ Na, C20H27NO5Na requires 384.1786), 384 ([M + Na]+, 100%),
285 (80); and (ii) the syn-alcohol 61b (2.75 g, 28%) as a foam; [a]D20
+12.3 (c 1.30 in CDCl3); mmax/cm−1 (CDCl3) 3680, 3359 (br), 2937,
1731, 1694 and 1604; dH (360 MHz, CDCl3, 325 K): 7.58 (1 H, d,
J 7.7, ArH), 7.12 (1 H, dt, J 7.7 and 1.4 ArH), 6.91 (1 H, dt, J
7.6 and 1.1 ArH), 6.82 (1 H, dd, J 8.0 and 1.1, ArH), 5.92 (1 H, t,
C(CH3)(CH3)), 1.32 (9 H, br s, C(CH3)3); dC (90 MHz, CDCl3,
333 K) 156.2 (s), 153.1 (s), 141.5 (s), 138.8 (d), 137.4 (s), 135.0
(s), 131.8 (d), 129.9 (d), 128.7 (d), 128.5 (d), 128.2 (d), 128.0 (d),
127.4 (d), 126.8 (s), 121.0 (d), 112.0 (d), 94.1 (s), 86.2 (d), 79.3
(s), 74.8 (t), 70.5 (t), 65.8 (t), 59.4 (d), 28.5 (q), 28.0 (q), 24.1 (q),
14.8 (q); m/z (ESI) Found: 692.1841 ([M + Na]+, C34H40NO5INa
requires 692.1849), 692 ([M + Na]+, 100%), 570 (25), 319 (15);
(1S,7aS)-1-{(1E)-1-[2-(benzyloxy)phenyl]prop-1-en-1-yl}-5,5-di-
methyldihydro-1H-[1,3]oxazolo[3,4-c][1,3]oxazol-3-one was also
obtained as a colourless oil (61 mg, 14.5%); [a]2D0 −7.5 (c 1.87 in
CDCl3); mmax/cm−1 (CDCl3) 2938, 1738, 1598, 1578 and 1499; dH
(360 MHz, CDCl3, 298 K) 7.50–7.29 (6 H, m, ArH), 7.16–7.14
(1 H, m, ArH), 7.03–6.99 (2 H, m, ArH), 6.07 (1 H, q, J 6.8,
=
=
[rotamer 1 + rotamer 2] CHCH3), 5.08 (2 H, s, ArCH2O), 4.96
J 3.9, CHCH2), 4.76 (2 H, d, J 3.9, CH2O), 4.69 1 H, (d, J 8.6,
(1 H, app d, J 6.3, CHO), 4.09 (1 H, app dd, J 6.3 and 6.5, CHN),
3.68 (1 H, dd, J 6.5 and 2.1, CHHO), 3.45 (1 H, dd, J 6.5 and
1.1, CHHO), 1.67 (3 H, s, C(CH3)(CH3)), 1.56 (3 H, d, J 6.8,
CHOH), 4.35–4.30 (1 H, m, CHN), 3.79–3.75 (2 H, m, OCH2),
1.58 (3 H, s, C(CH3)(CH3)), 1.54 (9 H, s, C(CH3)3), 1.50 (3 H, s,
C(CH3)(CH3)); dC (90 MHz, CDCl3, 325 K): 154.4 (s), 134.8 (s),
129.0 (d), 124.3 (d), 122.0 (s), 121.3 (d), 121.2 (d), 116.1 (d), 94.4
(s), 81.6 (s), 76.0 (d), 64.9 (t), 64.8 (t), 62.1 (d), 28.3 (q), 27.0 (q),
24.0 (q); m/z (ESI) Found: 384.1775 ([M + Na]+, C20H27NO5Na
requires 384.1786), 384 ([M + Na]+, 100%), 285 (73).
=
[rotamer 1 + rotamer 2] CHCH3), 1.29 (3 H, s, C(CH3)(CH3));
dC (90 MHz, CDCl3, 298 K) 156.8 (s), 155.9 (s), 136.8 (s), 134.2 (s),
131.8 (d), 129.4 (d), 128.6 (d), 128.0 (d), 127.3 (s), 127.0 (d), 124.7
(d), 121.3 (d), 112.3 (d), 94.4 (s), 81.9 (d), 70.1 (t), 67.9 (t), 63.0
(d), 27.2 (q), 23.4 (q), 14.5 (q); m/z (ESI) Found: 402.1655 ([M +
Na]+, C23H25NO4Na requires 402.1681), 402 ([M + Na]+, 100%).
(S)-4-[(S)-(2H -1-Benzopyran-4-yl)-(2-iodobenzyloxy)methyl]-
2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (62).
Sodium bis(trimethylsilyl)amide (1
X-Ray crystal structure of the syn-ether 59a. C30H40INO5,
M = 669.57, monoclinic, a = 11.7081(8), b = 10.0539(7), c =
M in tetrahydrofuran,
◦
3
7.60 mL, 7.60 mmol) was added using a syringe, in one portion, to
a stirred solution of the syn-allylic alcohol 61b (2.11 g, 5.86 mmol)
in tetrahydrofuran (250 mL) at 0 ◦C, and the mixture was
then stirred at 0 ◦C for 15 min. 2-Iodobenzyl bromide (18.3 g,
58.6 mmol) and tetrabutylammonium iodide (11.0 g, 29.3 mmol)
were added, and the mixture was then heated to reflux for 20 h and
concentrated in vacuo. The residue was quenched with saturated
aqueous ammonium chloride and extracted with diethyl ether
(3 × 40 mL). The combined organic extracts were washed with
saturated aqueous sodium bicarbonate solution (40 mL) and brine
(40 mL), dried and concentrated in vacuo. The residue was purified
by chromatography, eluting with diethyl ether–pentane (100 : 0 to
50 : 50), to give the corresponding iodobenzyl ether (1.81 g, 53%)
as a colourless viscous oil; [a]1D7 +7.13 (c 3.40 in CDCl3); mmax/cm−1
(CDCl3) 2974, 1687 and 1604; dH (360 MHz, CDCl3, 325 K) 7.81
(1 H, dd, J 7.9 and 1.0, ArH), 7.62 (1 H, d, J 7.6, ArH), 7.51–7.47
(1 H, m, ArH), 7.32 (1 H, dd, J 7.5 and 1.0, ArH), 7.12 (1 H, dd,
J 7.7 and 1.4, ArH), 6.95 (1 H, dd, J 7.6 and 1.4, ArH), 6.85 (2
˚
˚
13.8008(10) A, b = 97.039(2) , U = 1612.3(3) A , T = 150(2) K,
space group P21 (No. 4), Z = 2, Dc = 1.379 g cm−3, l(Mo-Ka) =
1.033 mm−1, 8763 reflections collected, 6911 unique (Rint 0.016)
which were used in all calculations. Final R1 [6129 F > 4r(F)] =
0.0286 and wR(all F2) was 0.0675. The absolute structure param-
eter refined to −0.043(10). CCDC reference number 613518. For
crystallographic data in CIF or other electronic format see DOI:
10.1039/b609604b
(S)-4-[(S)-(2H-1-Benzopyran-4-yl)hydroxymethyl]-2,2-dimethyl-
oxazolidine-3-carboxylic acid tert-butyl ester (61a) and (S)-4-[(R)-
(2H -1-benzopyran-4-yl)hydroxymethyl]-2,2-dimethyloxazolidine-
3-carboxylic acid tert-butyl ester (61b). A solution of n-
butyllithium (2.5 M) in tetrahydrofuran (17.3 mL, 43.3 mmol)
was added over 0.5 h to a stirred solution of 4-bromo-2H-
chromene 60 (9.60 g, 43.3 mmol) in diethyl ether (90 mL) and
◦
the mixture was stirred at −40 C for 10–15 min. A solution of
magnesium bromide (1 M in diethyl ether and benzene, 90.0 mL,
90.0 mmol) was added rapidly, and the solution was then stirred
=
H, m, ArH), 6.00 (1 H, t, J 3.7, CH), 4.85 (1 H, dd, J 15.0 and
◦
at −40 C for a further 45 min. A solution of Garner’s aldehyde
3.8, CHHO), 4.80 (1 H, dd, J 15.0 and 3.8, CHHO), 4.72–4.64
(1 H, m, CHO), 4.63 (1 H, d, J 12.6, ArCHHO), 4.50 (1 H, d,
J 12.6, CHHO), 4.50–4.45 (1 H, m, CHN), 4.05 (1 H, app t, J
(6.20 g, 27.1 mmol) in diethyl ether (20 mL) was added over
0.75 h, and the mixture was then stirred at room temperature for
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11.4 CHHO), 3.86 (1 H, dd, J 9.5 and 6.0, CHHO) 1.51 (9 H, s,
C(CH3)3), 1.48 (3 H, s, C(CH3)(CH3)), 1.32 (3 H, s, C(CH3)(CH3));
dC (90 MHz, CDCl3, 325 K) 154.6 (s), 153.0 (s), 140.8 (s), 139.2
(d), 132.0 (s), 129.4 (d), 129.2 (d), 128.5 (s), 128.3 (d), 124.7 (d),
122.6 (d), 121.3 (d), 116.3 (d), 97.8 (s), 94.5 (s), 80.1 (s), 75.4 (t),
69.4 (t), 65.3 (t), 64.2 (d), 59.8 (d), 28.6 (q), 26.6 (q), 23.8 (q);
m/z (ESI) Found: 600.1227 ([M + Na]+, C27H32NO5INa requires
600.1223), 600 ([M + Na]+, 100%); (1S,7aS)-1-(2H-chromen-4-yl)-
5,5-dimethyldihydro-1H-[1,3]oxazolo[3,4-c][1,3]oxazol-3-one was
also obtained: [a]D20 +60.3 (c 5.97 in CDCl3); mmax/cm−1 (CDCl3)
2939, 2846, 1732, 1660, 1606, 1576 and 1495; dH (360 MHz, CDCl3,
298 K) 7.18 (1 H, app dt, J 7.7 and 1.4 ArH), 6.94–6.87 (2 H, m,
ArH), 6.78 (1 H, dd, J 7.6 and 1.5, ArH), 6.05 (1 H, t, J 3.8,
(1.81 g, 3.14 mmol) and palladium acetate (178 mg, 0.784 mmol)
was heated under reflux in a nitrogen atmosphere in tetrahydro-
furan (100 mL) for 2 days, then cooled to room temperature. The
mixture was refluxed for 2 days, cooled to room temperature and
R
filtered through Celiteꢀ. The filter cake was washed with ethyl
acetate portion-wise (5 × 10 mL), and the combined filtrates
were washed with brine (50 mL), dried and concentrated in vacuo.
The residue was purified by chromatography, eluting with diethyl
ether–petrol (20 : 80), to give the spiro-benzpyran (460 mg, 41%).
Method 2. The procedure already described was followed except
that the mixture was heated in DMA at 90 ◦C for 4 days. The
crude product was purified by chromatography on silica, eluting
with diethyl ether–petrol (2 : 98 to 20 : 80) to give the spiro-
benzpyran (340 mg, 54%) as a colourless solid; mp 179–180 ◦C;
(Found: C, 71.2; H, 6.9; N, 3.0; C27H31NO5·H2O requires: C, 71.2;
H, 7.0; N, 3.1%); [a]D18 +101.0 (c 1.64 in CDCl3); mmax/cm−1 (CDCl3)
2978, 1682 and 1580; dH (360 MHz, C6D6, 333 K) 7.09–6.99 (5 H,
m, ArH), 6.82–6.79 (1 H, m, ArH), 6.76–6.71 (2 H, m, ArH),
=
[rotamer 1 + rotamer 2] CH), 5.21–5.20 (1 H, m, CHO), 4.85–
4.82 (2 H, m, CH2O), 4.20 (1 H, dd, J 8.0 and 6.4, CHHO), 4.11
(1 H, ddd, J 7.8, 6.3 and 5.3, CHN), 3.84 (1 H, app t, J 8.0,
CHHO), 1.77 (3 H, s, C(CH3)(CH3)), 1.41 (3 H, s, C(CH3)(CH3));
dC (90 MHz, CDCl3, 330 K) 156.1 (s), 154.8 (s), 131.4 (s), 130.0
(d), 122.0 (d), 121.5 (d), 120.1 (s), 119.1 (d), 116.9 (d), 95.2 (s),
76.2 (d), 68.7 (t), 65.1 (t), 64.0 (d), 27.6 (q), 23.3 (q); m/z (ESI)
Found: 288.1239 ([M + H]+, C16H18NO4 requires 288.1237), 288
([M + Na]+, 100%), 244 (85).
=
=
6.59 (1 H, d, J 6.3, CHO), 5.24 (1 H, d, J 6.3, CH), 4.84 (2
H, s, ArCH2O), 4.67 (1 H, dd, J 9.0 and 4.7, CHN), 3.81 (1 H,
d, J 9.0, CHO), 3.47 (1 H, dd, J 9.0 and 4.8, CHHO), 2.72 (1 H,
app t, J 9.0, CHHO), 1.86 (3 H, s, C(CH3)(CH3)), 1.65 (3 H, s,
C(CH3)(CH3)), 1.62 (9 H, s, C(CH3)3); dC (90 MHz, C6D6, 333 K)
152.2 (s), 143.9 (s), 137.8 (d), 133.6 (s), 131.0 (d), 129.6 (d), 128.1
(d), 126.8 (d), 125.9 (d), 123.9 (s), 123.4 (d), 123.2 (d), 116.25 (d),
106.5 (d), 92.95 (s), 82.8 (d), 78.3 (s), 69.1 (t), 66.2 (t), 58.2 (d),
42.4 (s), 28.2 (q), 27.05 (q), 23.8 (q); m/z (ESI) Found: 472.2081
([M + Na]+, C27H31NO5Na requires 472.2100), 513 ([M + CH3CN
+ Na]+, 100%), 472 (65). A small amount (8%) of the 7-ring ether
65 was also isolated; [a]1D7 +112.7 (c 0.60 in CDCl3); mmax/cm−1
(CDCl3) 2934, 1682 and 1600; dH (360 MHz, CDCl3, 328 K) 7.53–
7.50 (2 H, m, ArH), 7.43–7.36 (2 H, m, ArH), 7.27–7.25 (2 H, m,
ArH), 7.20–7.16 (1 H, m, ArH), 6.94–6.90 (1 H, m, ArH), 5.79 (1
H, d, J 4.0, CHO), 5.19 (1 H, d, J 14.1, ArCHHO), 4.67 (1 H, d,
J 12.4, CHHO), 4.60 (1 H, d, J 14.1, ArCHHO), 4.46 (1 H, d, J
12.4, CHHO), 4.17 (1 H, dd, J 7.5 and 4.1, CHN), 3.64–3.63 (2 H,
m, CHCH2O), 1.49 (9 H, s, C(CH3)3), 1.29 (3 H, s, C(CH3)(CH3)),
0.91 (3 H, s, C(CH3)(CH3)); dC (90 MHz, CDCl3, 328 K) 157.4 (s),
152.9 (s), 141.0 (s), 136.9 (s), 132.3 (s), 132.1 (s), 129.2 (d), 128.5
(d), 128.0 (d), 127.7 (d), 127.6 (d), 125.8 (s), 124.2 (d), 121.8 (d),
116.5 (d), 94.4 (s), 80.1 (s), 78.0 (d), 68.7 (t), 68.5 (t), 64.2 (t), 61.7
(d), 28.7 (q), 25.3 (q) 23.7 (q); m/z (ESI) Found: 472.2067 ([M +
Na]+, C27H31NO5Na requires 472.2100), 472 ([M + Na]+, 100%),
350 (75), 336 (31), 257 (18).
(S)-4-[(R)-(2H-1-Benzopyran-4-yl)-(2-iodobenzyloxy)methyl]-2,
2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (63).
The anti-ether was prepared from the anti-allylic alcohol 61a
using an identical procedure to that described for the preparation
of 62: [a]1D9 −15.6 (c 7.60 in CDCl3); mmax/cm−1 (CDCl3) 2976,
2279, 1746 and 1682; dH (360 MHz, CDCl3, 332 K) 7.82 (1 H, dd,
J 7.9 and 1.0, ArH), 7.70–7.50 (2 H, m, ArH), 7.36–7.34 (1 H, m,
ArH), 7.15–7.12 (1 H, m, ArH), 7.00–6.95 (1 H, m, ArH), 6.83 (2
=
H, dd, J 8.0 and 1.0, ArH), 6.00–5.95 (1 H, m, CH), 5.30–4.95
(1 H, br s, CHO), 4.86–4.78 (2 H, m, CH2O), 4.63 (1 H, d, J
12.8, ArCHHO), 4.51 (1 H, d, J 12.8, ArCHHO), 4.27 (1 H, dd,
J 8.9 and 3.4, CHHO), 4.21 (1 H, app qn, J 3.4, CHN), 3.04 (1
H, dd, J 8.9 and 6.0, CHHO), 1.62 (3 H, s, C(CH3)(CH3)), 1.51
(12 H, br s, C(CH3)(CH3) and C(CH3)3); dC (90 MHz, CDCl3,
332 K) 154.5 (s), 152.9 (s), 140.8 (s), 139.2 (d), 132.0 (s), 129.3
(d), 129.1 (d), 128.3 (d), 124.2 (d), 121.7 (s), 121.4 (s), 116.2 (d),
97.5 (s), 95.0 (s), 80.4 (s), 76.05 (t), 76.0 (d), 65.5 (t), 63.3 (t),
59.4 (d), 28.7 (q), 26.4 (q), 25.1 (q); m/z (ESI) Found: 600.1267
([M + Na]+, C27H32NO5INa requires 600.1223), 600 ([M + Na]+,
100%);
(1R,7aS)-1-(2H-chromen-4-yl)-5,5-dimethyldihydro-
1H-[1,3]oxazolo[3,4-c][1,3]oxazol-3-one (0.27 g, 16%) was also
obtained as an oil; dH (360 MHz, C6D6, 325 K) 7.03–7.00 (1 H, m,
ArH), 6.88 (1 H, dd, J 8.1 and 1.1, ArH), 6.75 (1 H, dd, J 7.6 and
1.2, ArH), 6.49 (1 H, dd, J 7.6 and 1.4, ArH), 5.80 (1 H, t, J 3.7,
X-Ray crystal structure of the spiro-benzpyran 64. C27H31NO5,
M = 449.53, monoclinic, a = 9.4857(10), b = 9.8441(10), c =
◦
3
˚
˚
13.0354(14) A, b = 100.138(2) , U = 1198.2(4) A , T = 150(2) K,
space group P21 (No. 4), Z = 2, Dc = 1.246 g cm−3, l(Mo-Ka) =
0.080 mm−1, 7124 reflections collected, 2980 unique (Rint 0.033)
which were used in all calculations. Final R1 [2238 F > 4r(F)] =
0.0376 and wR(all F2) was 0.0739. CCDC reference number
613519. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b609604b
=
[rotamer 1 + rotamer 2] CH), 5.13 (1 H, m, CHO), 4.47–4.45 (2
H, m, CH2O), 4.18 (1 H, app q, J 7.6, CHN), 3.35 (2 H, d, J 7.6,
CH2O), 1.79 (3 H, s, C(CH3)(CH3)), 1.42 (3 H, s, C(CH3)(CH3));
dC (90 MHz, C6D6, 325 K) 155.1 (s), 154.3 (s), 129.7 (d), 129.0 (s),
121.6 (d), 120.8 (d), 119.6 (s), 118.5 (d), 116.5 (d), 94.2 (s), 71.3
(d), 67.7 (2 × CH2), 60.8 (d), 27.4 (q), 22.9 (q); m/z (ESI) Found:
288.1211 ([M + H]+, C16H18NO4 requires 288.1237), 288 ([M +
H]+, 100%).
Acknowledgements
tert-Butyl (4S)-2,2-dimethyl-4-[(3ꢀS,4R)-1ꢀH-spiro[chromene-
4,4ꢀ-isochromen]-3ꢀ-yl]-1,3-oxazolidine-3-carboxylate (64).
Method 1. A slurry of triphenylphosphine (839 mg, 3.14 mmol),
silver carbonate (1.75 g, 6.28 mmol), the 2-iodobenzyl ether 62
We thank the Spanish Ministry of Education (fellowship
to A.B.), the EPSRC (fellowships to G.M. and D.S.; stu-
dentships to J.E.M.B. and C.P.G.), The University of Nottingham
4204 | Org. Biomol. Chem., 2006, 4, 4193–4205
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(studentship to M. L.), and GlaxoSmithKline (CASE awards
to J.E.M.B. and C.P.G.) for financial support. We also thank Drs
Dean Edney, Peter O’Hanlon and David Witty (GlaxoSmithKline)
for their interest in this study.
P. L. Myers and G. Pattenden, Tetrahedron, 1989, 45, 5215–5246;
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