Total Synthesis of the Resorcyclic Acid Lactone Spiroketal Citreoviranol

Article abstract of DOI:10.1021/acs.joc.6b01503

The first total synthesis of resorcyclic acid lactone spiroketal citreoviranol (1) is described. The synthesis was completed in nine steps and via Sonogashira cross-coupling, gold-catalyzed cyclization, and an unusual base-induced ketalization. The relati

Full text of DOI:10.1021/acs.joc.6b01503

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Article
Total Synthesis of the Resorcyclic Acid Lactone Spiroketal Citreoviranol
Rachelle Quach, Daniel P. Furkert, and Margaret A. Brimble
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01503 • Publication Date (Web): 09 Aug 2016
Downloaded from http://pubs.acs.org on August 10, 2016
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Total Synthesis of the Resorcyclic Acid Lactone Spiroketal Citreoviranol.
Rachelle Quach, Daniel. P. Furkert, and Margaret A. Brimble*
School of Chemical Sciences and Maurice Wilkins Centre for Molecular Biodiscovery,
University of Auckland, 23 Symonds Street,
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Auckland 1142, New Zealand
m.brimble@auckland.ac.nz
ABSTRACT
The first total synthesis of resorcyclic acid lactone spiroketal citreoviranol (1) is described. The
synthesis was completed in nine steps and via Sonogashira cross coupling, goldꢀcatalysed
cyclisation and an unusual baseꢀinduced ketalisation. The relative and absolute stereochemistry
of citreoviranol was unambiguously confirmed using 2D NMR spectroscopy and Xꢀray
crystallography.
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INTRODUCTION
Citreoviranol (1) was isolated from the mycelium of the fungus Penicillium citreoviride in 1988
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by Yamamura et al. It is structurally related to the resorcyclic acid lactone (RAL) family of
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natural products (Figure 1). The RALs are bioactive polyketide metabolites produced by a range
of fungal strains that have been shown to possess potent bioactivity against neurodegenerative
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diseases and cancer. For instance, radicicol (2) is a potent HSP90 inhibitor (IC = 20 nM), 5ꢀ
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(Z)ꢀ7ꢀoxozeaenol (3) inhibits TAKꢀ1 (IC = 8.1 nM) and hypothemycin (4) inhibits MAP kinase
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(IC = 17ꢀ90 nM).
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Aside from the characteristic resorcylic acid lactone motif, citreoviranol (1) also contains a
unique 6,6ꢀspiroketal lactone. This subꢀstructure has only been found in one other natural
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product, dehydrocollatolic acid (5) (Figure 1). While RALs have been shown to have potential
therapeutic value, neither citreoviranol (1) nor dehydrocollatolic acid (5) has been tested for
biological activity. In addition, there have been no previous syntheses of the 6,6ꢀspiroketal
lactone ring system rendering these natural products attractive synthetic targets.
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Figure 1. Resorcyclic acid lactone natural products.
Gold catalysis has emerged as a mild and efficient tool to construct complex heterocycles in the
last decade and its use is often favoured due to its high atom economy and high functional group
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tolerance. We were therefore interested to apply this methodology to the unprecedented
spiroketal lactone ring system present in citreoviranol (1). Consequently, our retrosynthetic
strategy hinged on the goldꢀcatalysed cyclisation of alkynol 6, the product of Sonogashira
coupling of bromide 7 and alkyne 8 (Scheme 1).
Scheme 1. Retrosynthetic analysis of citreoviranol (1).
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RESULTS AND DISCUSSION
Initial attention focused on the preparation of Sonogashira coupling partners, bromide 7 and
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alkyne 8. Following literature procedures, synthesis of bromide 7 was achieved via Vilsmeierꢀ
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Haack formylation of 3,5ꢀdimethoxybromobenzene (9), followed by Pinnick oxidation and
subsequent methylation to afford bromide 7 in 54% yield over 3 steps (Scheme 2).
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Scheme 2. Synthesis of bromide 7 .
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Reagents and conditions: i) POCl , DMF, rt, 30 min, then 100 °C, 4 h, 80%. ii) NaClO ,
3
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NaH PO , 2ꢀmethylꢀ2ꢀbutene, tꢀBuOH/H O (5:1), rt, 15 min. iii) K CO , MeI, DMF, 80 °C, 15
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min, 75% over 2 steps.
Synthesis of alkyne coupling partner 10 was readily achieved over 5 steps (Scheme 3). After
protection of ethyl (S)ꢀ3ꢀhydroxybutyrate (11) as the corresponding ethoxymethyl ether,
treatment with DIBAL afforded the desired aldehyde in 92% yield over 2 steps, which upon
addition of propargyl zinc bromide at 0 °C yielded alkyne 12 in 89% yield as a 2:1
diastereomeric mixture. Disappointingly, despite screening a range of temperatures (0 °C, ꢀ40
°
C, ꢀ78 °C), Lewis acids (BF ·Et O, TiCl , MgBr ) and protecting groups (EOM, PMB),
3 2 4 2
attempts to optimise the diastereoselectivity of this reaction proved fruitless. However,
subsequent benzyl protection of the mixture enabled separation of the anti and syn diastereomers
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3a and 13b. Cleavage of the ethoxymethyl ether in antiꢀisomer 13a then afforded the desired
Sonogashira coupling partner 10.
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Scheme 3. Synthesis of alkyne 10 .
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a
Reagents and conditions: i) EOMCl, DIPEA, CH Cl , 0 °C, 1 h then rt, 16 h, 98%. ii) DIBAL,
2
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CH Cl , –78 °C, 1 h, 95%. iii) propargyl bromide, Zn, THF, 0 °C, 1 h, 75%, anti:syn, 2:1. iv) 12,
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NaH, THF, 0 °C, 40 min then BnBr, TBAI (10 mol%), 60 °C, 1 h, 13a (54%), 13b (38%). v) 13a,
pTSA (20 mol%), EtOH, 60 °C, 5 h, 98%.
Pleasingly, despite the use of an electron rich bromide coupling partner, the Sonogashira crossꢀ
coupling of bromide 7 with alkyne 10 proceeded smoothly, using the copperꢀfree Sonogashira
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conditions previously employed by our group and others (Scheme 4). Optimisation of the
reaction conditions provided alkyne 14 in a reliable 67% yield within 30 min at 80 °C.
Saponification of methyl ester 14 then afforded carboxylic acid 15 in a 78% yield.
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Scheme 4. Sonogashira coupling and saponification for the formation of 15 .
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Reagents and conditions: i) Pd(OAc) (10 mol%), dtbpf (15 mol%), K CO , NMP, 80 °C, 30
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min, 70%. ii) aq. KOH (2 M), MeOH, reflux, 4.5 h, 80%.
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With cyclisation precursor 15 in hand, the key goldꢀcatalysed spirocyclisation was attempted.
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The use of AuClPPh as the catalyst in the presence of a silver coꢀcatalyst (AgSbF ) or base
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(
K CO , Et N) resulted in 5ꢀexoꢀdig cyclisation of alkynol acid 15 to the undesired
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isobenzofuranone 16 (entries 1ꢀ3, Table 1). PdCl ꢀcatalysed cyclisation of alkynol acid 15 also
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resulted in the formation of isobenzofuranone 16 (entry 4, Table 1). Exposure of the alkynol
ester 14 to AuClPPh in the presence of AgSbF yielded the elimination product, dihydropyran
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7 (entry 5, Table 1). Based on the conditions reported by Trost et al. that avoided formation of
elimination products on a similar substrate, we next attempted the cyclisation of 14 using AuCl
in the presence of PPTS, coꢀcatalysed by AgSbF . A trace quantity of the 6ꢀendoꢀdig cyclisation
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product, isocoumarin 18 was observed together with elimination product 17 (entry 6, Table 1).
Changing the gold catalyst to AuClPPh yielded 30% of isocoumarin 18 with no elimination
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product observed (entry 7, Table 1). Disappointingly, despite extensive screening no evidence
for cyclisation to the desired spiroketal 19 was observed. However, further optimisation of the
formation of isocoumarin 18 which constitutes a potential precursor to spiroketal 19 resulted in a
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5% yield using AuCl in the presence of PPTS and AgSbF (entry 8, Table 1).
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Table 1. Metalꢀcatalysed cyclisation of 14 and 15.
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b
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additive
yield
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entry
R
[M]
solvent, T
CH Cl , rt
time (h)
[
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AgSbF6
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CH CN, rt
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THF, rt
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AuClPPh3
AuCl
Et N
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AgSbF PPTS
THF, reflux
THF, 50 °C
THF, 50 °C
THF, 50 °C
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All reactions carried out on racemic starting material with 2:1 dr with stereochemistry retained in all entries. 10 mol
b
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catalyst. 10 mol % [Ag] additive except entry 8 (30 mol %). Isolated yield (%).
Following the successful preparation of isocoumarin 18, we screened conditions for its
conversion to spiroketal lactone 19. A number of Brønsted acids returned either starting material
18 or degradation products. The inability to form the spiroketal product was rationalised as being
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due to the unfavourable electronics associated with the formation of the required oxonium ion
(Scheme 5). It is postulated an oxonium ion is unlikely to form next to a carbonyl carbon which
carries a partial positive charge.
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Scheme 5. Proposal for inability to form an oxonium ion intermediate.
Attempts to reduce the isocoumarin to the dihydrocoumarin and perform an oxidative radical
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cyclisation were also unsuccessful. Surprisingly, however, when isocoumarin 18 was subjected
to 1 M KOH for 1 h followed by acidic workꢀup formation of spiroketal lactone 19 was observed
as a 2:1 mixture of epimers 19a and 19b (suggesting substitution of the OBn) in modest yield
(Scheme 6). Occasionally, trace quantities of 6ʹRꢀspiroketals 19c and 19d were observed upon aq
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citric acid workꢀup.
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Scheme 6. Synthesis of 8ꢀmethylcitreoviranol 19a and its antiꢀepimer 19b .
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Reagents and conditions: i) aq. 1 M KOH, dioxane, rt, 1 h, then 1M HCl, 19a (20%), 19b
(16%).
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The stereochemical assignments of 19a, 19b and 19c were achieved by NMR spectroscopy
(Figures 2ꢀ3). Observation of a 1,3ꢀdiaxial nOe correlation between H2 and H4ʹ in 19a shown in
′
Figure 2 established that the substituents on the tetrahydropyran ring are positioned equatorially,
syn to each other (conversely, the nOe correlation between H2ʹ and H4ʹ for antiꢀepimer 19b is
absent). The nOe correlations of H4b with H5ʹax and H5ʹeq of 19a suggested that the
tetrahydropyran ring adopts the chair conformation represented below (conversely, the nOe
correlation between H4 and H2ʹax, H4ʹ and H5ʹ of 19c suggests it adopts the ringꢀflipped chair
ax
eq
conformation). The requirement that H2ʹ and H4ʹ adopt axial positions on the required chair
conformation established that the spiroketal centre in isomer 19a exhibits the Sꢀconfiguration.
This assignment was also further confirmed by subsequent conversion to the natural product
citreoviranol (1) upon selective demethylation of the 8ꢀmethyl ether
Figure 2. nOe correlations of H4ʹ and 4 in 19a, 19b and 19c.
The absence of a nOe correlation between H2ʹ and H4ʹ in spiroketal 19b suggested that it is the
2ʹ,4ʹꢀanti isomer (also confirmed by chemical shift data discussed later). The NOESY spectrum
of 19b exhibited correlations between H4ʹ and both of the H3ʹ and H5ʹ protons (equatorial and
axial), suggesting that H4ʹ is positioned equatorially. nOe correlations between H4b with H5ʹax
and H5ʹ are also present in 19b suggesting that the tetrahydropyran ring also adopts the same
eq
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chair conformation as 19a represented in Figure 2. This combination of structural features (19b
being the antiꢀepimer, H4ʹ is equatorial and adoption of the required chair conformation) implies
that the spiroketal centre also adopts the transꢀdiaxial Sꢀconfiguration.
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The antiꢀconfiguration of 19b was also confirmed by the changes in chemical shift observed for
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H2ʹ and H4ʹ due to the inversion of C4ʹ relative to 19a. The H NMR spectrum of 19b showed a
characteristic downfield chemical shift for H2ʹ at 4.38 ppm due to the additional 1,3ꢀdiaxial
oxygen interaction with C4ʹꢀOH and a distinctive upfield shift for the H4ʹ at 4.17 ppm due to the
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absence of a 1,3ꢀdiaxial interaction with the lactone oxygen atom (Figure 3).
Figure 3. 1,3ꢀdiaxial interactions in 19a and 19b.
The stereochemical assignment of 19c was also achieved by NMR spectroscopy. A 1,3ꢀdiaxial
nOe correlation between H2′ and H4ʹ of 19c shown in Figure 2 indicates that the substituents on
the tetrahydropyran ring are positioned equatorially, syn to each other. The observed nOe
correlations of H4 with H2ʹax, H4ʹ and H5ʹ suggest that the tetrahydropyran ring adopts a chair
ax
eq
conformation as depicted in Figure 2. These structural features require the R-configuration at the
spiroketal centre.
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A proposed mechanism for the spiroketalisation of 18 to 19 is shown in Scheme 7. During the
cyclisation, the secondary benzyl ether of ketone intermediate (i) is eliminated and conjugate
addition of hydroxide to α,βꢀunsaturated ketone (ii) with poor stereocontrol to affords a mixture
of Cꢀ4ʹ epimeric alcohols (iii). Spirocyclisation of hemiketal (iv) affords spiroketal lactone 19a
and its C4ʹꢀepimer 19b. The spiroketal product 19 was only formed upon acidic workup and
attempts to isolate any intermediates using a neutral workup were unsuccessful.
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Scheme 7. Proposed mechanism for spiroketalisation of isocoumarin 18.
Final selective demethylation of 19a with BCl afforded citreoviranol (1), completing the first
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total synthesis of the natural product. Spectroscopic data ( H NMR, C NMR, IR, HRMS) for
the synthetic sample of citreoviranol (1) were in full agreement with that reported for the natural
product. The key 1,3ꢀdiaxial nOe correlation observed between H2ʹ and H4ʹ supported
assignment of synꢀstereochemistry between these two protons. The NOESY spectrum for
synthetic citreoviranol (1) exhibited correlations between H4b and H5ʹ and H5ʹ suggesting
ax
eq
that the tetrahydropyran ring adopts the chair conformation represented below (Scheme 8).
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Scheme 8. Selective demethylation to citreoviranol (1) .
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Reagents and conditions: i) BCl , CH Cl , ꢀ78 °C then rt, 30 min, 84%.
3
2
2
The relative stereochemistry and chair conformation for synthetic citreoviranol (1) were also
1
3
confirmed by Xꢀray crystallography. Notably while the ꢀꢁꢂ values of synthetic and natural
ꢃ
citreoviranol were not in close agreement (synthetic: ꢁꢄꢅ –78.0 (c 0.20 in CHCl ), lit.: ꢁ –147
1
ꢆꢇ
ꢃ
3
ꢃ
(
c 0.196 in CHCl ), use of chiral HPLC confirmed that the enantiopurity of the synthetic sample
3
was 95% by comparison to a racemic synthetic sample.
In summary the first total synthesis of citreoviranol (1) has been accomplished in 9 steps from
readily available starting materials. The synthesis features a Sonogashira cross coupling, gold
catalysed cyclisation and an unprecedented baseꢀinduced ketalisation. The absolute
stereochemistry of the natural product was confirmed by extensive NMR experiments and Xꢀray
crystallography. Future work will involve biological testing of this unique molecule to probe its
therapeutic value.
EXPERIMENTAL SECTION
General Procedures. Unless otherwise noted, all reactions were performed under an oxygenꢀ
free atmosphere of nitrogen using standard techniques. Tetrahydrofuran (THF) and diethyl ether
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were freshly distilled over sodium/benzophenone ketyl. CH Cl was freshly distilled from
2
2
calcium hydride. All other reagents were used as received unless otherwise noted. Yields refer to
chromatographically and spectroscopically (1H NMR) homogeneous materials, unless otherwise
stated. Reactions were monitored by thinꢀlayer chromatography (TLC) carried out on silica gel
plates using UV light as the visualizing agent and an ethanolic solution of vanillin and
ammonium molybdate and heat as developing agents. Silica gel (60, 230−400 mesh) was used
for flash column chromatography. NMR spectra were recorded at room temperature in CDCl3
solution on either a spectrometer operating at 500 MHz for 1H nuclei and 125 MHz for 13C
nuclei or a spectrometer operating at 400 MHz for 1H nuclei and 100 MHz for 13C nuclei.
Chemical shifts are reported in parts per million on the δ scale, and coupling constants, J, are in
hertz. Multiplicities are reported as “s” (singlet), “br s” (broad singlet), “d” (doublet), “dd”
10
11
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(doublet of doublets), “ddd” (doublet of doublets of doublets), “t” (triplet), and “m” (multiplet).
1
13
NMR spectra are calibrated at 7.26 for H NMR and 77.0 for C NMR. Where distinct from
those due to the major diastereomer, resonances due to minor diastereomers are denoted by an
1
13
asterisk. H and C NMR resonances were assigned using a combination of DEPT 135, COSY,
HSQC, HMBC, and NOESY spectra. Infrared (IR) spectra were recorded using a thin film on a
composite of zinc selenide and diamond crystal on an FTꢀIR system transform spectrometer.
Melting points are uncorrected. High resolution mass spectrometry (HRMS) was performed
using a spectrometer operating at a nominal accelerating voltage of 70 eV or a TOFꢀQ mass
spectrometer.
2ꢀBromoꢀ4,6ꢀdimethoxybenzaldehyde
(S1).
To
a
stirred
solution
of
3,5ꢀ
dimethoxybromobenzene (9) (8.00 g, 36.8 mmol) in DMF (17.2 mL, 221 mmol) at 0 °C was
added POCl (10.3 mL, 110 mmol) dropwise. The resultant mixture was stirred at rt for 30 min
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then heated to 100 °C and continued stirring for 4 h. The reaction mixture was poured onto
crushed ice (100 mL), warmed to rt and left to sit at rt for 16 h. The crystals were collected by
filtration and recrystallised from 3:1 hexanesꢀEtOAc (100 mL) to afford S1 (7.2 g, 80%) as
0
1
2
3
4
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7
8
9
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9
0
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9
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9
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1
yellow crystals: HꢀNMR (400 MHz, CDCl ) δ 10.30 (s, 1H, CHO), 6.77 (d, J = 2.4 Hz, 1H,
3
1
3
ArH), 6.43 (d, J = 2.2 Hz, 1H, ArH), 3.88 (s, 3H, OCH ), 3.86 (s, 3H, OCH ); CꢀNMR (100
3
3
MHz, CDCl ) δ 189.1, 164.4, 163.6, 127.3, 116.9, 111.6, 98.1, 56.1, 55.8; MP 150–152 °C. The
3
5
spectroscopic data were in agreement with those reported in the literature.
Methyl 2ꢀbromoꢀ4,6ꢀdimethoxybenzoate (7). To a stirred mixture of S1 (4.00 g, 16.3 mmol),
NaClO (6.30 g, 65.3 mmol) and NaH PO (2.94 g, 24.5 mmol) was added a solution of tꢀ
2
2
4
BuOH:H O (5:1, 66 mL), followed by 2ꢀmethylꢀ2ꢀbutene (10.4 mL, 97.9 mmol). The resultant
2
mixture was stirred at rt for 15 min and then the reaction was quenched with 2 M HCl (15 mL).
The organic layer was separated and the aq layer was further extracted with EtOAc (2 × 100
mL). The combined organic extracts were washed with sat. aq NaCl (100 mL), dried over
Na SO and concentrated in vacuo yielding acid S2 as a yellow solid (4.46 g), which was used
2
4
directly in the next step. To a stirred mixture of crude acid S2 (4.46 g) and K CO (3.38 g, 24.5
2
3
mmol) in DMF (160 mL) was added MeI (1.52 mL, 24.5 mmol) dropwise. The resultant mixture
was warmed to 80 °C then stirred for 45 min and then the reaction was quenched by the addition
of sat. aq NH Cl (100 mL). The organic layer was separated and the aq layer was further
4
extracted with EtOAc (2 × 200 mL). The combined organic extracts were washed with water
(
100 mL) and then sat. aq NaCl (100 mL), dried over Na SO and concentrated in vacuo.
2 4
Purification by flash column chromatography on silica (10:1 hexanesꢀEtOAc) afforded 7 (3.37 g,
75% over 2 steps) as an off white solid: IR (neat) νmax 2951, 1722, 1597, 1566, 1432, 1265, 1219,
ꢀ1
1
1
145, 1100, 1000, 943 cm ; HꢀNMR (400 MHz, CDCl ) δ 6.67 (d, J = 2.0 Hz, 1H, ArH), 6.40
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(
(
(
d, J = 2.1 Hz, 1H, ArH), 3.91 (s, 3H, OCH ), 3.80 (s, 3H, OCH ), 3.79 (s, 3H, OCH ); CꢀNMR
3 3 3
100 MHz, CDCl ) δ 166.7, 161.6, 158.3, 120.5, 118.9, 108.9, 98.0, 56.0, 55.7, 52.5; HRMS
3
+
ESI+) for C H BrNaO [M+Na] requires 296.9733, found 296.9737; MP 42–43 °C.
1
0
11
4
10
11
12
13
14
15
16
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19
20
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59
60
(
S)ꢀEthyl 3ꢀ(ethoxymethoxy)butanoate (S3). To a stirred solution of ethyl (S)ꢀ3ꢀ
hydroxybutyrate (11) (1.00 g, 7.57 mmol) in CH Cl (15 mL) at 0 °C was added DIPEA (9.84
2
2
mL, 56.8 mmol) followed by dropwise addition of EOMCl (1.54 mL, 16.6 mmol). The resultant
mixture was stirred at 0 °C for 1 h, warmed to rt for 16 h and then the reaction was quenched by
the addition of sat. aq NH Cl (20 mL). The organic layer was separated and the aq layer further
4
extracted with CH Cl (2 × 30 mL). The combined organic extracts were washed with 0.5 M aq
2
2
citric acid solution (3 × 100 mL), dried over Na SO and concentrated in vacuo. Purification by
2
4
flash column chromatography on silica (6:1 pentaneꢀEt O) afforded S3 (1.41 g, 98%) as a
2
colourless oil: ꢁ ꢃꢄ ꢄ +8.0 (c 1.01 in CHCl ); IR (neat) ν 2977, 1735, 1447, 1378, 1298, 1256,
3
max
ꢀ1 1
1
195, 1172, 1096, 1029 cm ; HꢀNMR (400 MHz; CDCl ) δ 4.71 (ABq, ꢁδ = 0.02, JAB = 7.1
3 AB
Hz, 2H, OCH O), 4.20–4.12 (m, 1H, Hꢀ3), 4.13 (q, J = 7.2 Hz, 2H, CH CH ), 3.58 (q, J = 7.1
2
2
3
Hz, 2H, OCH CH ), 2.49 (ABX, ꢁδ = 0.18, J = 15.2, J = 7.6, J = 5.6 Hz, 2H, Hꢀ2), 1.26
2
3
AB
AB
AX
BX
(t, J = 7.1 Hz, 3H, CH CH ), 1.24 (d, J = 6.2 Hz, 3H, Hꢀ4), 1.20 (t, J = 7.1 Hz, 3H, OCH CH );
3
2
2
3
1
3
CꢀNMR (100 MHz, CDCl ) δ 171.3, 93.8, 70.2, 63.2, 60.4, 42.4, 20.5, 15.0, 14.2; HRMS
3
+
(ESI+) for C H NaO [M+Na] requires 213.1097, found 213.1105.
9
18
4
(S)ꢀ3ꢀ(Ethoxymethoxy)butanal (S4). To a stirred solution of S3 (1.32 g, 6.93 mmol) in CH Cl
2 2
(75 mL) at –78 °C was added DIBALꢀH (1 M in toluene, 7.62 mL, 7.62 mmol) dropwise over 1
h. The reaction was quenched by the addition of MeOH (10 mL) at –78 °C followed by sat. aq
potassium sodium tartrate (100 mL). The resultant mixture warmed to rt and continued stirring
vigorously for 1 h. The organic layer was separated and the aq layer further extracted with
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CH Cl (2 × 150 mL). The combined organic extracts were washed with sat. aq NaCl (100 mL),
2
2
dried over Na SO and concentrated in vacuo. Purification by flash column chromatography on
2
4
silica (4:1 pentaneꢀEt O) afforded S4 (957 mg, 95%) as a colourless oil: α ꢄꢈ ꢆ +31.7 (c 1.02 in
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
CHCl ); HꢀNMR (500 MHz, CDCl ) δ 9.79 (dd, J = 2.7, 1.8 Hz, 1H, CHO), 4.71 (ABq, ꢁδ
=
3
3
AB
0.05, J = 7.2 Hz, 2H, OCH O), 4.26 (dqd, J = 12.4, 6.3, 4.9 Hz, 1H, Hꢀ3), 3.58 (ABX , ꢁδ =
AB
2
3
AB
0
.03, J = 9.6, J = 7.1, J = 7.1 Hz, 2H, CH CH ), 2.58 (ABXY, ꢁδ = 0.15, J = 16.4, J
AB AX BX 2 3 AB AB AX
=
7.5, J = 2.7, J = 4.9, J = 1.8 Hz, 2H, Hꢀ2), 1.27 (d, J = 6.3 Hz, 3H, Hꢀ4), 1.20 (t, J = 7.1
AY BX BY
1
3
Hz, 3H, CH CH ); CꢀNMR (125 MHz, CDCl ) δ 201.2, 93.6, 68.5, 63.4, 20.6, 15.0; The
2
3
3
14
spectroscopic data were in agreement with that reported in the literature.
(4S,6S)ꢀ6ꢀ(Ethoxymethoxy)heptꢀ1ꢀynꢀ4ꢀol (12). To a stirred suspension on zinc powder (2.04
g, 31.2 mmol) in THF (10 mL) at 0 °C was added propargyl bromide (2.78 mL, 31.2 mmol). The
mixture was stirred for 1.5 h then a solution of S4 (2.28 g) in THF (6 mL) was added dropwise.
The resultant mixture was stirred at 0 °C for 15 min and then the reaction was quenched with sat.
aq NH Cl (50 mL). The solid residue was removed by filtration and 2 M HCl (5 mL) was added
4
to the filtrate. The filtrate was extracted with EtOAc (3 × 100 mL) and the combined organic
extracts were washed with sat. aq NaCl (100 mL), dried over Na SO and concentrated in vacuo.
2
4
Purification by flash column chromatography on silica (5:1 PEꢀEtOAc) afforded a diastereotopic
mixture of 12 (2.18 g, 75%, dr = 2:1) as a yellow oil: IR (neat) νmax 3451, 3296, 2974, 1378,
ꢀ1 1
1
139, 1097, 1027 cm ; HꢀNMR (400 MHz, CDCl ) δ 4.78–4.66 (m, 2H, OCH O), 4.07–3.90
3
2
(
m, 2H, Hꢀ4, Hꢀ6), 3.68–3.52 (m, 2H, CH CH ), 243–2.31 (m, 2H, Hꢀ3), 2.03–2.01 (m, 1H, Hꢀ
2 3
13
1
), 1.81–1.68 (m, 2H, Hꢀ5), 1.23–1.19 (m, 6H, Hꢀ7, CH CH ); CꢀNMR (100 MHz, CDCl ) δ
2 3 3
93.8, 92.9*, 81.0, 80.9, 73.1*, 71.1, 70.4, 70.3*, 69.5*, 66.5, 63.7*, 63.6, 42.8*, 42.5, 27.1,
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7.1*, 20.3, 20.3*, 15.0*, 15.0; HRMS (ESI+) for C H NaO [M+Na] requires 209.1148,
10 18 3
found 209.1153. *denotes synꢀisomer.
(4S,6S)ꢀ4ꢀBenzyloxyꢀ6ꢀ(ethoxymethoxy)heptꢀ1ꢀyne (13a) and (4R,6S)ꢀ4ꢀBenzyloxyꢀ6ꢀ
ethoxymethoxy)heptꢀ1ꢀyne (13b). NaH (60% in mineral oil, 600 mg, 15.1 mmol) was washed
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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57
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59
60
(
twice with hexanes and dried in vacuo. To a stirred solution of NaH in THF (12 mL) at 0 °C was
added a solution of 12 (936 mg, 5.02 mmol) in THF (5.0 mL). The mixture was stirred for 40
min then BnBr (1.20 mL, 10.0 mmol) was added dropwise followed by TBAI (185 mg, 0.50
mmol). The resultant mixture was heated to 60 °C and stirred for 1 h. The mixture was then
cooled to 0 °C and the reaction was quenched by the addition of water (5 mL) and EtOAc. The
organic layer was separated and then the aq layer was further extracted with EtOAc (2 × 20 mL).
The combined organic extracts were washed with sat. aq NaCl, dried over Na SO and
2
4
concentrated in vacuo. Purification by flash column chromatography on silica (20:1 hexanesꢀ
ꢄꢄ
Et O) afforded 13a (757 mg, 54%) and 13b (526 mg, 38%) as pale yellow oils: 13a: ꢁ +62.8
2
ꢃ
ꢀ1 1
(
c 1.00 in CHCl ); IR (neat) ν 3293, 2973, 1455, 1377, 1111, 1071, 1039 cm ; HꢀNMR (400
3 max
MHz, CDCl ) δ 7.38–7.27 (m, 5H, Bn), 4.64 (ABq, ꢁδAB = 0.11, JAB = 7.0 Hz, 2H, OCH O),
3
2
4
1
=
.59 (ABq, ꢁδAB = 0.21, JAB = 11.2 Hz, 2H, OCH Ar), 3.97–3.89 (m, 1H, Hꢀ6), 3.83–3.77 (m,
2
H, Hꢀ4), 3.59 (ABX , ꢁδ = 0.05, J = 9.5, J = 7.1, J = 7.1 Hz 2H, OCH CH ), 2.49 (d, J
3
AB
AB
AX
BX
2
3
2.7 Hz, 1H, Hꢀ3 ), 2.47 (d, J = 2.7 Hz, 1H, Hꢀ3 ), 2.02 (t, J = 2.7 Hz, 1H, Hꢀ1), 1.77 (ABXY,
a
b
ꢁδAB = 0.06, JAB = 14.5, JAX = 9.4, J = 3.2, J = 9.4, J = 3.3 Hz, 2H, Hꢀ5), 1.20 (d, J = 6.2
AY
BX
BY
13
Hz, 3H, Hꢀ7), 1.18 (t, J = 7.1 Hz, 3H, OCH CH ); CꢀNMR (100 MHz, CDCl ) δ 138.3, 128.4,
2
3
3
+
1
27.9, 127.7, 70.8, 70.3, 63.3, 42.8, 24.0, 21.3, 15.1; HRMS (ESI+) for C H NaO [M+Na]
17 24 3
requires 299.1618, found 299.1621. 13b: ꢁ ꢃꢄ ꢉ –10.6 (c 1.04 in CHCl ); IR (neat) ν 3307, 2973,
3
max
ꢀ1
1
1
455, 1377, 1111, 1071, 1039 cm ; HꢀNMR (400 MHz, CDCl ) δ 7.37–7.27 (m, 5H, Bn), 4.68
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(
ABq, ꢁδAB = 0.05, JAB = 7.1 Hz, 2H, OCH O), 4.59 (ABq, ꢁδ = 0.14, JAB = 11.7 Hz, 2H,
2
AB
OCH Ar), 3.90–3.83 (m, 1H, Hꢀ6), 3.68 (ddt, J = 6.8, 5.7, 5.6 Hz, 1H, Hꢀ4), 3.59–3.54 (m, 2H,
2
OCH CH ), 2.51 (dd, J = 5.4, 2.7 Hz, 2H, Hꢀ3), 2.03–1.96 (m, 1H, Hꢀ5 ), 2.01 (t, J = 2.7 Hz, 1H,
2
3
a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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2
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9
0
Hꢀ1), 1.79–1.72 (m, 1H, Hꢀ5 ), 1.19 (t, J = 7.1 Hz, 3H, OCH CH ), 1.16 (d, J = 6.2 Hz, 3H, Hꢀ
b
2
3
1
3
7); CꢀNMR (100 MHz, CDCl ) δ 138.3, 128.3, 127.8, 127.6, 93.3, 80.9, 74.2, 71.1, 70.2, 70.2,
3
+
6
3.3, 41.2, 23.7, 20.3, 15.1; HRMS (ESI+) for C H NaO [M+Na] requires 299.1618, found
17
24
3
2
99.1624.
(2S,4S)ꢀ4ꢀ(Benzyloxy)heptꢀ6ꢀynꢀ2ꢀol (10). To a stirred solution of 13a (104 mg, 0.37 mmol) in
EtOH (2 mL) was added PTSA (14 mg, 0.75 mmol). The resultant solution was stirred at 60 °C
for 6 h and then diluted by the addition of EtOAc (10 mL) and water (2 mL). The organic layer
was separated and the aq layer was further extracted with EtOAc (2 × 20 mL). The combined
organic extracts were washed with sat. aq NaCl (20 mL), dried over Na SO and concentrated in
2
4
vacuo. Purification by flash column chromatography on silica (5:1 hexanesꢀEtOAc) afforded 10
(81 mg, 98%) as a yellow oil: ꢁ ꢃꢄ ꢄ +67.4 (c 1.02 in CHCl ); IR (neat) ν 3416, 3295, 2965,
3
max
ꢀ1
1
2
4
1
915, 1497, 1455, 1352, 1091, 1072 cm ; HꢀNMR (400 MHz, CDCl ) δ 7.37–7.28 (m, 5H, Bn),
3
.62 (ABq, ꢁδAB = 0.17, JAB = 11.5 Hz, 2H, OCH Ar), 4.12–4.05 (m, 2H, Hꢀ2), 3.90–3.84 (m,
2
H, Hꢀ4), 2.52 (ABXY, ꢁδ = 0.07, J = 16.8, J = 4.9, J = 2.7, J = 7.2, J = 2.6 Hz, 2H,
AB
AB
AX
AY
BX
BY
Hꢀ5), 2.03 (t, J = 2.7 Hz, 1H, Hꢀ7), 1.78 (ABXY, ꢁδAB = 0.07, JAB = 14.5, JAX = 7.8, J = 2.9,
AY
1
3
J = 9.0, J = 3.6 Hz, 2H, Hꢀ3), 1.19 (d, J = 6.3 Hz, 3H, Hꢀ1); CꢀNMR (100 MHz, CDCl ) δ
BX
BY
3
1
38.9, 128.5, 128.0, 127.9, 80.8, 74.7, 71.6, 70.4, 64.4, 42.2, 23.7, 23.5; HRMS (ESI+) for
+
C H NaO [M+Na] requires 241.1199, found 241.1200.
14
18
2
(2S,4S)ꢀHeptaneꢀ2,4ꢀdiol (S5). To a stirred solution of 10 (50 mg, 0.23 mmol) in MeOH (2 mL)
was added Pd/C (10 wt%, 24 mg, 0.023 mmol). Hydrogen gas was bubbled through the mixture
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for 30 min. The reaction mixture was filtered through Celite , washed with MeOH and
concentrated in vacuo to afford S5 (27 mg, 92%) as a colourless oil: ꢁ ꢃꢄ ꢊ +16.7 (80% de, c 1.03
15
ꢄꢄ
in CHCl ), lit. ꢁ –21.7 (c 1.15 in CHCl ); IR (neat) ν 3343, 2961, 2932, 1458, 1376, 1148,
3
ꢃ
3
max
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ
1 1
1
120, 1055, 1023 cm ; HꢀNMR (500 MHz, CDCl ) δ 4.42 (d, J = 4.8 Hz, 1H, Hꢀ2), 3.92 (br s,
3
1H, Hꢀ4), 3.07 (d, J = 2.6 Hz, 1H, OH), 2.96 (d, J = 3.8 Hz, 1H, OH), 1.56 (dd, J = 5.8, 5.5 Hz,
H, Hꢀ3), 1.53ꢀ1.30 (m, 4H, Hꢀ5 and Hꢀ6), 1.21 (d, J = 6.4 Hz, 3H, Hꢀ1), 0.91 (t, J = 7.1 Hz, 3H,
2
1
3
Hꢀ7); CꢀNMR (125 MHz, CDCl ) δ 68.9, 65.3, 44.0, 39.5, 23.4, 18.9, 14.0; HRMS (ESI+) for
3
+
C H NaO [M+Na] requires 155.1043, found 155.1037. The spectroscopic data were in
7
16
2
15
agreement with those reported in the literature.
(
2S,4S)ꢀ4ꢀ(Benzyloxy)ꢀ7ꢀ(3,5ꢀdimethoxyꢀ2ꢀ(methylcarboxy)phenyl)heptꢀ6ꢀynꢀ2ꢀol (14). To a
stirred mixture of 7 (280 mg, 1.02 mmol), Pd(OAc) (21 mg, 0.093 mmol), dtbpf (66 mg, 0.14
2
mmol) and K CO (639 mg, 4.63 mmol) was added NMP (6 mL). The reaction mixture was
2
3
degased over 5 min by bubbling a stream of argon through the mixture. A solution of 10 (202
mg, 0.93 mmol) in NMP (4 mL) was added dropwise, heated to 80 °C then continued stirring for
2
h. The resultant mixture was filtered through a short plug of silica and washed with EtOAc.
The filtrate was washed with water (3 × 100 mL), sat. aq NaCl (100 mL), dried over Na SO and
2
4
concentrated in vacuo. Purification by flash column chromatography on silica (2:1 hexanesꢀ
3
EtOAc) afforded 14 (268 mg, 70%) as a yellow oil: ꢁ ꢃꢄ ꢋ +27.1 (c 1.04 in CHCl ); IR (neat) νmax
ꢀ1 1
3493, 2940, 1729, 1597, 1578, 1455, 1229, 1269, 1204, 1161, 1046 cm ; HꢀNMR (400 MHz,
CDCl ) δ 7.38–7.27 (m, 5H, Bn), 6.53 (d, J = 2.2 Hz, 1H, ArH), 6.42 (d, J = 2.2 Hz, 1H, ArH),
3
4
.64 (ABq, ꢁδAB = 0.15, JAB = 11.6 Hz, 2H, OCH Ar), 4.13–4.05 (m, 1H, Hꢀ2), 3.95–3.89 (m,
2
1
H, Hꢀ4), 3.86 (s, 3H, OCH ), 3.79 (s, 3H, OCH ), 3.79 (s, 3H, OCH ), 2.72 (ABX, ꢁδ = 0.18,
3
3
3
AB
JAB = 16.9, JAX = 4.8, J = 7.8 Hz, 2H, Hꢀ5), 2.38 (br s, 1H, OH), 1.84ꢀ1.81 (m, 2H, Hꢀ3), 1.22
BX
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5
5
5
5
5
5
6
13
(
d, J = 6.3 Hz, 3H, Hꢀ1); CꢀNMR (100 MHz, CDCl ) δ 167.6, 161.3, 157.8, 138.0, 128.5,
3
1
27.9, 123.5, 119.1, 108.1, 99.3, 90.2, 79.8, 75.3, 71.7, 64.6, 56.0, 55.5, 52.4, 42.7, 24.6, 23.9;
+
HRMS (ESI+) for C H NaO [M+Na] requires 435.1778, found 435.1780. dtbpf = 1,1ʹꢀbis-
2
4
28
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
diꢀtertꢀbutylphosphino)ferrocene.
(
2S,4S)ꢀ4ꢀ(Benzyloxy)ꢀ7ꢀ(3,5ꢀdimethoxyꢀ2ꢀ(carboxy)phenyl)heptꢀ6ꢀynꢀ2ꢀol (15). To a stirred
solution of 14 (8 mg, 0.020 mmol) in MeOH (0.50 mL) was added 2M KOH (0.5 mL), stirred
under reflux for 4 hours and quenched with 1 M HCl (1 mL). The aqueous layer was extracted
with Et O (5 mL), washed with sat. aq NaCl (20 mL), dried over Na SO and concentrated in
2
2
4
vacuo. Purification by flash column chromatography on silica (1:2 hexanesꢀEtOAc) afforded 15
6.2 mg, 80%) as a white oil: IR (neat) νmax 3395, 2965, 2928, 1707, 1596, 1577, 1455, 1418,
(
ꢀ1 1
1337, 1228, 1203, 1163, 1110, 1045 cm ; HꢀNMR (300 MHz, CDCl ) δ 7.36–7.27 (m, 5H, Bn),
3
6
.56 (d, J = 2.2 Hz, 1H, ArH), 6.43 (d, J = 2.2 Hz, 1H, ArH), 4.60 (ABq, ꢁδ = 0.13, J = 11.5
AB AB
Hz, 2H, OCH Ar), 4.16–4.06 (m, 1H, Hꢀ2), 3.99–3.91 (m, 1H, Hꢀ4), 3.82 (s, 3H, OCH ), 3.80 (s,
2
3
3H, OCH ), 2.69 (ABX, ꢁδ = 0.37, JAB = 16.8, JAX = 3.9, JBX = 9.2 Hz, 2H, Hꢀ5), 1.90 (2H,
3
AB
ABXY, ꢁδAB = 0.36, JAB = 14.6, JAX = 9.8, J = 2.4, J = 9.1, J = 2.5 Hz, Hꢀ5), 1.25 (d, J =
AY
BX
BY
1
3
6
.3 Hz, 3H, Hꢀ1); CꢀNMR (75 MHz, CDCl ) δ 168.1, 162.3, 161.6, 158.0, 138.2, 128.5, 127.9,
3
1
27.8, 124.8, 108.5, 99.2, 91.6, 80.6, 75.6, 71.8, 65.3, 56.1, 55.6, 43.0, 24.8 23.8; HRMS (ESI+)
+
for C H O [M+H] requires 399.1802, found 399.1801.
2
3
27
6
(
Z)ꢀ3ꢀ(3ꢀ(Benzyloxy)ꢀ5ꢀhydroxyhexylidene)ꢀ5,7ꢀdimethoxyꢀ3Hꢀ2ꢀbenzofuranꢀ1ꢀone (16). To
a stirred solution of 15 (20 mg, 0.050 mmol) in THF (1 mL) was added Et N (25 ꢂL, 0.18 ꢂmol)
3
followed by PdCl (0.89 mg, 5.0 ꢂmol). The reaction mixture was stirred at rt for 1 h and then
2
the solvent was removed in vacuo. Purification by flash column chromatography on silica (1:1
hexanesꢀEtOAc, 1% Et N) afforded 16 (10 mg, 50%) as a yellow oil: IR (neat) νmax 3455, 2925,
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ꢀ1
1
1
751, 1601, 1495, 1455, 1431, 1335, 1207, 1158, 1027 cm ; HꢀNMR (500 MHz, CDCl ) δ*
3
7
.38–7.28 (m, 5H, Bn), 6.63 (d, J = 1.7 Hz, 1H, ArH), 6.44 (d, J = 1.7 Hz, 1H, ArH), 5.60 (dd, J
=
8.3, 7.2 Hz, 1H, Hꢀ1), 4.63 (ABq, ꢁδAB = 0.21, J
= 11.5, 2H, OCH Ar), 4.03–3.97 (m, 1H, Hꢀ
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
), 3.96–3.89 (m, 1H, Hꢀ3), 3.95 (s, 3H, OCH ), 3.91 (s, 3H, OCH ), 2.88–2.68 (m, 2H, Hꢀ2),
3
3
1
1.83–1.54 (m, 2H, Hꢀ4), 1.14 (d, J = 6.2 Hz, 3H, Hꢀ6); HꢀNMR (500 MHz, CDCl ) δ 7.38–7.28
3
(m, 5H, Bn), 6.60 (d, J = 1.7 Hz, 1H, ArH), 6.43 (d, J = 1.7 Hz, 1H, ArH), 5.57 (t, J = 7.85 Hz,
1
H, C=CH), 4.62 (ABq, ꢁδ = 0.12, J = 11.3 Hz, 2H, OCH Ar), 4.16–4.06 (m, 1H, Hꢀ5), 3.96–
AB
2
3.89 (m, 1H, Hꢀ3), 3.95 (s, 3H, OCH ), 3.90 (s, 3H, OCH ), 2.88–2.68 (m, 2H, Hꢀ2), 1.83–1.54
3
3
13
(m, 2H, Hꢀ4), 1.18 (d, J = 6.2 Hz, 3H, Hꢀ6); CꢀNMR (125 MHz, CDCl ) δ 167.0, 166.9, 2 ×
3
1
64.8, 2 ×159.3, 147.1*, 146.8, 143.5, 143.4*, 138.0, 137.5, 2 × 128.6*, 2 × 128.5, 2 × 128.1, 2
×
128.0, 128.0*, 127.9, 2 × 105.7, 104.1, 103.2*, 100.1, 100.0, 94.9, 94.9, 78.4*, 75.4, 71.3,
7
0.9*, 67.5*, 64.7, 2 × 56.1, 56.0*, 56.0*, 42.7*, 42.5, 29.7, 29.3*, 23.7, 23.5*; HRMS (ESI+)
+
for C H NaO [M+Na] requires 421.1622, found 421.1620. *denotes minor isomer.
2
3
26
6
6ꢀ(3,5ꢀDimethoxyꢀ2ꢀ(methylcarboxy)benzylidene)ꢀ2ꢀmethylꢀ3,6ꢀdihydroꢀ2Hꢀpyran (17). To
a stirred solution of 14 (20 mg, 0.050 mmol) in THF (1 mL) was added AuClPPh (2.4 mg, 5.0
3
ꢂmol) followed by AgSbF (1.7 mg, 5.0 ꢂmol). The reaction mixture was stirred at 60 °C for 3.5
6
h and then the solvent was removed in vacuo. Purification by flash column chromatography on
silica (4:1 hexanesꢀEtOAc, 1% Et N) afforded 17 (10 mg, 50%) as a yellow oil: IR (neat) νmax
3
2925, 1726, 1631, 1593, 1578, 1456, 1422, 1394, 1325, 1295, 1269, 1237, 1205, 1156, 1100,
ꢀ1 1
1
050 cm ; HꢀNMR (500 MHz, CDCl ) δ 7.51 (d, J = 2.2 Hz, 1H, ArH), 6.30 (d, J = 2.2 Hz, 1H,
3
ArH), 6.07–6.04 (m, 1H, Hꢀ5), 6.00–5.95 (m, 1H, Hꢀ4), 5.26 (s, 1H, HC=C) 4.18–4.10 (m, 1H,
Hꢀ2), 3.89 (s, 3H, OCH ), 3.82 (s, 3H, OCH ), 3.78 (s, 3H, OCH ), 2.25–2.24 (m, 2H, Hꢀ3), 1.43
3
3
3
13
(d, J = 6.2 Hz, 3H, 2ꢀCH ); CꢀNMR (125 MHz, CDCl ) δ 161.1, 160.9, 157.5, 152.3, 135.7,
3
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1
26.9, 125.6, 110.0, 104.8, 103.5, 96.9, 71.4, 55.9, 55.2, 52.2, 31.7, 21.1; HRMS (ESI+) for
+
C H NaO [M+Na] requires 327.1203, found 327.1213.
17 20
5
3ꢀ((2R,4S)ꢀ2ꢀ(Benzyloxy)ꢀ4ꢀhydroxypentyl)ꢀ6,8ꢀdimethoxyꢀ1Hꢀisochromenꢀ1ꢀone (18). To a
stirred solution of 14 (135 mg, 0.33 mmol) in THF (3.5 mL) was added PPTS (8.22 mg, 0.033
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
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6
7
8
9
0
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7
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0
1
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4
5
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7
8
9
0
mmol) followed by AuCl (9.93 mg, 0.033 mmol) and AgSbF (34 mg, 0.098 mmol). The
3
6
reaction mixture was heated to 50 °C for 1 h and then the solvent was removed in vacuo.
Purification by flash column chromatography on silica (1:2 hexanesꢀEtOAc) afforded 18 (93 mg,
72%) as a yellow oil: ꢁ ꢃꢄ ꢋ –21.0 (c 0.85 in CHCl ); IR (neat) ν 3470, 2930, 1710, 1664, 1600,
3
max
ꢀ1 1
1
570, 1456, 1373, 1166, 1059 cm ; HꢀNMR (500 MHz, CDCl ) δ 7.27–7.21 (m, 5H, Bn), 6.44
3
(d, J = 2.3 Hz, 1H, ArH), 6.31 (d, J = 2.3 Hz, 1H, ArH), 6.16 (s, 1H, Hꢀ4), 4.55 (s, 2H,
OCH Ar), 4.20–4.15 (m, 1H, Hꢀ4ʹ), 4.12–4.06 (m, 1H, Hꢀ2ʹ), 3.95 (s, 3H, OCH ), 3.88 (s, 3H,
2
3
OCH ), 2.73 (ABX, ꢁδ = 0.18, JAB = 14.4, JAX = 7.1, JBX = 5.7 Hz, 2H, Hꢀ1ʹ), 1.70 (ABXY,
3
AB
ꢁ
δAB = 0.08, J = 14.6, J = 9.3, J = 3.7, J = 7.1, J = 2.6 Hz, 2H, Hꢀ3ʹ), 1.18 (d, J = 6.3
AB AX AY BX BY
1
3
Hz, 3H, Hꢀ5ʹ); CꢀNMR (125 MHz, CDCl ) δ 165.4, 163.2, 159.2, 155.4, 142.0, 137.7, 128.4,
3
1
28.0, 127.8, 105.3, 103.0, 99.7, 98.4, 74.5, 72.1, 64.5, 56.2, 55.6, 42.3, 38.5, 23.7; HRMS
+
(ESI+) for C H NaO [M+Na] requires 421.1622, found 421.1607.
2
3
26
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(2ʹS,4ʹR,6ʹS)ꢀSpiro[6,8ꢀdimethoxyisochromanꢀ1ꢀoneꢀ3,6ʹꢀ2ʹꢀmethyloxanꢀ4ʹꢀol] (19a) and
2ʹS,4ʹS,6ʹS)ꢀSpiro[6,8ꢀdimethoxyisochromanꢀ1ꢀoneꢀ3,6ʹꢀ2ʹꢀmethyloxanꢀ4ʹꢀol] (19b). To a
(
stirred solution of 18 (25 mg, 63 ꢂmol) in dioxane (1.0 mL) was added KOH (1 M, 1.0 mL, 1.0
mmol). The resultant solution was stirred at rt for 1 h and then the reaction was quenched with
HCl (1 M, 1.0 mL) and EtOAc (2 mL). The organic layer was separated and the aq layer further
extracted with EtOAc (2 × 2 mL). The combined organic extracts were washed with sat. aq
NaCl, dried over Na SO4 and concentrated in vacuo. Purification by flash column
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chromatography on silica (1:9 hexanesꢀEtOAc) afforded a mixture of 19a (3.0 mg, 20%) and 19b
(2.4 mg, 16%) as colourless oils: 19a: ꢁ ꢃꢄ ꢊ –77.4 (c 0.23 in CHCl ); IR (neat) ν 3428, 2923,
3
max
ꢀ1 1
1
702, 1603, 1582, 1459, 1325, 1263, 1220, 1160, 1068, 1033 cm ; HꢀNMR (500 MHz, CDCl )
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
δ 6.40 (d, J = 2.3 Hz, 1H, ArH), 6.31 (d, J = 2.2 Hz, 1H, ArH), 4.38 (tt, J = 11.2, 4.8 Hz, 1H, Hꢀ
4ʹ), 4.08 (dqd, J = 11.5, 6.3, 2.1, 1H, Hꢀ2ʹ), 3.93 (s, 3H, OCH ), 3.86 (s, 3H, OCH ), 3.08 (ABq,
3
3
ꢁ
δ = 0.19, J = 16.3 Hz, 2H, Hꢀ4), 2.37 (ddd, J = 12.7, 4.8, 1.9 Hz, 1H, Hꢀ5ʹ ), 2.04–1.99 (m,
AB AB a
1
H, Hꢀ3ʹ ), 1.47 (dd, J = 12.7, 11.2 Hz, 1H, Hꢀ5ʹ ), 1.28 (m, 1H, Hꢀ3ʹ ), 1.09 (d, J = 6.3 Hz, 3H,
a b b
13
2ʹꢀCH ); CꢀNMR (125 MHz, CDCl ) δ 164.6, 163.1, 160.9, 141.1, 105.9, 104.9, 102.4, 97.7,
3
3
+
6
6.9, 63.7, 56.2, 55.5, 42.8, 41.8, 40.0, 21.3; HRMS (ESI+) for C H NaO [M+Na] requires
16 20 6
331.1152, found 331.1144. 19b: ꢁ ꢃꢄ ꢊ –76.3 (c 0.097 in CHCl ); IR (neat) ν 3442, 2923, 1716,
3
max
ꢀ1
1
1
604, 1583, 1459, 1324, 1265, 1221, 1159, 1082, 1029 cm ; HꢀNMR (500 MHz, CDCl ) δ 6.40
3
(d, J = 2.3 Hz, 1H, ArH), 6.30 (d, J = 2.0 Hz, 1H, ArH), 4.41–4.35 (m, 1H, Hꢀ2ʹ), 4.18–4.16 (m,
1H, Hꢀ4ʹ), 3.93 (s, 3H, OCH ), 3.86 (s, 3H, OCH ), 3.05 (ABq, ꢁδ = 0.27, J = 16.2 Hz, 2H,
3
3
AB
AB
Hꢀ4), 2.25 (ddd, J = 14.5, 2.2, 2.2 Hz, 1H, Hꢀ5ʹ ), 1.92–1.87 (m, 1H, Hꢀ3ʹ ), 1.81 (dd, J = 14.5,
a
a
3
.9 Hz, 1H, Hꢀ5ʹ ), 1.50–1.45 (ddd, J = 14.0, 12.0, 3.0 Hz, 1H, Hꢀ3ʹ ), 1.09 (d, J = 6.3 Hz, 3H,
b
b
13
2ʹꢀCH ); CꢀNMR (125 MHz, CDCl ) δ 164.7, 163.3, 159.8, 141.2, 105.5, 105.0, 102.7, 97.6,
3
3
+
6
4.3, 62.6, 56.2, 55.5, 40.1, 39.2, 39.1, 21.3; HRMS (ESI+) for C H NaO [M+Na] requires
16 20 6
331.1152, found 331.1148.
(2ʹS,4ʹR,6ʹR)ꢀSpiro[6,8ꢀdimethoxyisochromanꢀ1ꢀoneꢀ3,6ʹꢀ2ʹꢀmethyloxanꢀ4ʹꢀol] (19c). To a
stirred solution of 18 (33 mg, 83 ꢂmol) in dioxane (1.5 mL) was added KOH (1 M, 1.5 mL, 1.5
mmol). The resultant solution was stirred at rt for 1 h and then the reaction was quenched with
citric acid solution (0.5 M, 1.0 mL) and EtOAc (2 mL). The organic layer was separated and the
aq layer further extracted with EtOAc (2 × 2 mL). The combined organic extracts were washed
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6
with sat. aq NaCl, dried over Na SO and concentrated in vacuo. Purification by flash column
2
4
chromatography on silica (1:9 hexanesꢀEtOAc) afforded 19c (1.9 mg, 7.4%) as a colourless oil
and an inseparable mixture of 19a and 19d (2:1, 2.2 mg, 6.7%) as a colourless oil: 19c: ꢁ ꢃꢄ ꢆ
–
0
1
2
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7
8
9
0
1
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4
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9
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
4.3 (c 0.014 in CHCl ); IR (neat) ν 3430, 2924, 1709, 1605, 1459, 1430, 1327, 1262, 1203,
3 max
ꢀ1 1
1163, 1068, 1020 cm ; HꢀNMR (500 MHz, CDCl ) δ 6.41 (d, J = 2.3 Hz, 1H, ArH), 6.27 (d, J =
3
2
.3 Hz, 1H, ArH), 4.05–4.00 (m, 1H, Hꢀ4ʹ), 3.93 (s, 3H, OCH ), 3.86 (s, 3H, OCH ), 3.68–3.62
3 3
(
m, 1H, Hꢀ2ʹ), 3.10 (ABq, ꢁδ = 0.03, J = 16.2 Hz, 2H, Hꢀ4), 2.28 (ddd, J = 13.1, 5.1, 1.2 Hz,
AB AB
1H, Hꢀ5ʹ ), 2.08–2.02 (m, 1H, Hꢀ3ʹ ), 1.81 (dd, J = 13.1, 9.0 Hz, 1H, Hꢀ5ʹ ), 1.50–1.43 (m, 1H,
a
a
b
13
Hꢀ3ʹ ), 1.15 (d, J = 6.2 Hz, 3H, 2ʹꢀCH ); CꢀNMR (125 MHz, CDCl ) δ 164.6, 163.1, 160.4,
b
3
3
106.5, 104.9, 101.9, 97.6, 68.1, 56.2, 55.5, 42.6, 40.9, 36.85, 21.9; HRMS (ESI+) for
+
C H NaO [M+Na] requires 331.1152, found 331.1153. 19d: Tentatively identified as
16
20
6
1
(
2ʹS,4ʹS,6ʹR)ꢀisomer based on H NMR, however, it was not possible to obtain full
characterisation of the trace amount present in the mixture.
(2ʹS,4ʹR,6ʹS)ꢀSpiro[6,8ꢀdimethoxyisochromanꢀ1ꢀoneꢀ3,6ʹꢀ2ʹꢀmethyloxanꢀ4ʹꢀol] (1). To a
stirred solution of 19a (3.0 mg, 9.9 ꢂmol) in CH Cl (0.50 mL) at –78 °C was added BCl (10
2
2
3
ꢂL). The resultant mixture was stirred at rt for 15 min and then the reaction was quenched with
ice (0.5 mL). The organic layer was separated and the aq layer was further extracted with CH Cl2
2
(
2 × 1 mL). The combined organic extracts were washed with sat. aq NaCl, dried over Na SO4
2
and concentrated in vacuo. Purification by flash column chromatography on silica (1:1 hexanesꢀ
EtOAc) afforded 1 (2.4 mg, 84%) as a white solid: ꢁꢄꢅ –78.0 (c 0.20 in CHCl ), lit. ꢁ –147 (c
1
ꢆꢇ
ꢃ
3
ꢃ
0
9
6
.196 in CHCl ); IR (neat) ν
3410, 2926, 1664, 1626, 1584, 1508, 1440, 1363, 1232, 1157,
max
3
ꢀ1 1
85 cm ; HꢀNMR (400 MHz, CDCl ) δ 11.16 (s, 1H, ArOH), 6.36 (d, J = 2.2 Hz, 1H, ArH),
3
.26–6.26 (m, 1H, ArH), 4.40 (tt, J = 11.2, 4.7 Hz, 1H, Hꢀ4ʹ), 4.11–4.05 (m, 1H, Hꢀ2ʹ), 3.82 (s,
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H, OCH ), 3.10 (2H, ABq, ꢁδ = 0.15, JAB = 16.4 Hz, Hꢀ4), 2.41 (ddd, J = 12.9, 4.8, 1.9 Hz,
3
AB
1
H, Hꢀ5ʹ ), 2.07–2.02 (m, 1H, Hꢀ3ʹ ), 1.51 (dd, J = 12.9, 11.1 Hz, 1H, Hꢀ5ʹ ), 1.28 (q, J = 11.4
a
a
b
1
3
Hz, 1H, Hꢀ3ʹ ), 1.13 (d, J = 6.3 Hz, 3H, 2ʹCH ); CꢀNMR (125 MHz, CDCl ) δ 168.2, 166.0,
b
3
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
64.4, 138.9, 107.1, 104.6, 100.9, 99.3, 67.4, 63.6, 55.5, 42.7, 41.7, 38.8, 21.2; HRMS (ESI+)
+
for C H NaO [M+Na] requires 317.0996, found 317.0986; MP 71–73 °C.
1
5
18
6
SUPPORTING INFORMATION
1
13
H and C NMR spectra for all compounds, ORTEP structure for citreoviranol (1) and crystal
data (CIF) are available in the supporting information. This material is available free of charge
via the internet at http://pubs.acs.org.
ACKNOWLEDGEMENTS
We thank the University of Auckland for the award of an Auckland Doctoral Scholarship to R.Q.
and Tanya Groutso for the crystal structure of citreoviranol.
References
(
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(6) Anti isomer was confirmed by conversion to (2S,4S)ꢀheptaneꢀ2,4ꢀdiol (S5)
(7) (a) Atkinson, D. J.; Furkert, D. P.; Brimble, M. A. Tetrahedron 2015, 71, 91; (b) Wang, C.;
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Liu, Y.ꢀC.; Sperry, J.; Rathwell, D. C. K.; Brimble, M. A. Synlett 2009, 2009, 793; (e) Brimble,
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(
11) Epimerisation to the 6ʹSꢀspiroketals 23a and 23b meant that only separation and
characterisation of 23c was achieved and isolation of a pure sample of 23d was unobtainable (see
experimental section).
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11
12
13
14
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16
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19
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J.; Snider, B. B. Org. Lett. 2007, 9, 2071.
13) See supporting information for ORTEP structure and crystallographic data in CIF format for
(
1
.
(14) Hume, P. A. PhD. Thesis, University of Auckland, 2014.
15) Roche, C.; Labeeuw, O.; Haddad, M.; Ayad, T.; Genet, J.ꢀP.; RatovelomananaꢀVidal, V.;
Phansavath, P. Eur. J. Org. Chem. 2009, 2009, 3977.
(
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