A titanium naphtholate approach for the synthesis of analogues of griseusin A

Article abstract of DOI:10.1039/a909243i

The synthesis of analogues of the spiroketal-containing pyranonaphthoquinone antibiotic griseusin A 1 is described. The key disconnection focused on hydroxyalkylation of naphthol 21 with aldehyde 12. Aldehyde 12 was prepared from oxazolidinone 5 and (R)-aldehyde 6. Aldol condensation of oxazolidinone 5 with aldehyde 6 using tin(II) triflate and tetramethylethylenediamine afforded adduct 8 with the required 2',3'-anti 3',5'-syn stereochemistry as the major product. Aldol adduct 8 was then converted into aldehyde 12. The titanium naphtholate generated from naphthol 21 using TiCl₃OⁱPr then afforded alcohol 26 upon addition of aldehyde 12. Oxidation of alcohol 26 afforded ketone 29 which underwent acetylation to acetate 31. Conversion of naphthol acetate 31 into naphthoquinone 33 followed by addition of 2-(trimethylsilyloxy)furan effected furofuran annulation to a 1: 1 inseparable mixture of adducts 34. Ceric ammonium nitrate oxidative rearrangement of this mixture of adducts produced lactol 35 which underwent cyclization to a 3.2:1 mixture of spiroketals 36a and 36b wherein epimerization at C-3' had occurred.

Full text of DOI:10.1039/a909243i

View Article Online / Journal Homepage / Table of Contents for this issue
A titanium naphtholate approach for the synthesis of analogues of
griseusin A†
Margaret A. Brimble,*‡ Michael R. Nairn and Josephine S. O. Park
1
School of Chemistry, F11, University of Sydney, Camperdown, NSW 2006, Australia
Received (in Cambridge, UK) 23rd November 1999, Accepted 17th January 2000
The synthesis of analogues of the spiroketal-containing pyranonaphthoquinone antibiotic griseusin A 1 is described.
The key disconnection focused on hydroxyalkylation of naphthol 21 with aldehyde 12. Aldehyde 12 was prepared
from oxazolidinone 5 and (R)-aldehyde 6. Aldol condensation of oxazolidinone 5 with aldehyde 6 using tin() triflate
and tetramethylethylenediamine afforded adduct 8 with the required 2Ј,3Ј-anti 3Ј,5Ј-syn stereochemistry as the major
product. Aldol adduct 8 was then converted into aldehyde 12. The titanium naphtholate generated from naphthol 21
using TiCl3OiPr then afforded alcohol 26 upon addition of aldehyde 12. Oxidation of alcohol 26 afforded ketone 29
which underwent acetylation to acetate 31. Conversion of naphthol acetate 31 into naphthoquinone 33 followed by
addition of 2-(trimethylsilyloxy)furan effected furofuran annulation to a 1:1 inseparable mixture of adducts 34.
Ceric ammonium nitrate oxidative rearrangement of this mixture of adducts produced lactol 35 which underwent
cyclization to a 3.2:1 mixture of spiroketals 36a and 36b wherein epimerization at C-3Ј had occurred.
Griseusins A 1 and griseusin B 2 were isolated from a soil
sample collected in Peru which had been inoculated with
Streptomyces griseus K-63.1 They are unique members of the
pyranonaphthoquinone family of antibiotics2 in that they
contain a 1,7-dioxaspiro[5.5]undecane ring system fused to a
juglone ring system and have aroused interest due to their
inhibitory activity against gram-positive bacteria, pathogenic
fungi and yeasts1 together with their proposed bioreductive
alkylating properties.3 The absolute configuration of griseusin
A 1 has been confirmed by X-ray analysis of a 6,8-dibromo
derivative4 and only one total synthesis of griseusin A 1 has
been reported to date.5
the spiroketal ring system via hydroxylation of an unsaturated
spiroketal.6 In this case the final hydroxylation occurred on the
C-5a–C-11a naphthoquinone double bond, necessitating a
rethink of our synthetic strategy. We herein report7 our syn-
thetic studies towards griseusin A 1 wherein the spiroketal oxy-
genated substituents are assembled onto an acyclic naphthalene
precursor at an early stage in the synthesis. The basic griseusin
A 1 framework is assembled via oxidative rearrangement of a
furo[3,2-b]naphtho[2,1-d]furan 34 which in turn is assembled
by addition of 2-(trimethylsilyloxy)furan to a 2-acylated 1,4-
naphthoquinone 33. In turn, the oxygenated substituents on the
side chain of this key naphthoquinone 33 were assembled using
a stereoselective aldol condensation.
Naphthoquinone 33 was assembled from naphthol 21 and
aldehyde 12. Construction of aldehyde 12 with the desired
2Ј,3Ј-anti 3Ј,5Ј-syn stereochemistry was based on a key anti
aldol condensation of acyloxazolidinone 5 with aldehyde 6
(Scheme 1). Acyloxazolidinone 5 was itself prepared by the low-
temperature N-alkylation of the lithiate of 4-benzyloxazolid-
inone 4 with benzyloxyacetyl chloride (Scheme 1). In turn, the
oxazolidinone 4 was prepared by heating (R)-phenylalaninol 3
[obtained via reduction of (R)-phenylalanine8] with diethyl
carbonate.
Aldehyde 6 was synthesized in three steps from commercially
available ethyl (R)-(Ϫ)-3-hydroxybutyrate 13 (Scheme 2).
Reduction of silyl ether 14 with LiBH4 in diethyl ether afforded
alcohol 15 in 89% yield. Treatment of 15 with tetrapropyl-
ammonium perruthenate (TPAP) with 4-methylmorpholine
N-oxide as co-oxidant then afforded aldehyde 6 in 81% yield.
Further purification of the crude aldehyde 6 by flash chromato-
graphy resulted in considerable loss of material due to its ready
oxidation by air.9 Aldehyde 6 was therefore prepared immedi-
ately before use in the subsequent aldol reaction. The optical
rotation recorded for 6 produced using TPAP ([α]D Ϫ17.90§)
was slightly higher than that obtained when using pyridinium
chlorochromate ([α]D Ϫ14.4),10 suggesting that the latter
reagent effected partial racemization of aldehyde 6.
Yoshii and co-workers5 assembled the spiroacetal portion of
the griseusins via cyclization of a δ,δЈ-dihydroxy ketone in
which the oxygenated substituents of the spiroketal ring system
were derived from a carbohydrate precursor. Functionalization
of the initial carbohydrate involved a lengthy process.
Results and discussion
Our initial synthetic approach to griseusin A 1 focused on
assembly of the basic pentacyclic framework of the griseusin A
molecule with introduction of the oxygenated substituents of
† Experimental details for conversion of alcohol 11 to acetonide 20
are available as supplementary data. For direct electronic access see
http://www.rsc.org/suppdata/p1/a9/a909243i
With the oxazolidinone 5 and aldehyde 6 in hand, attention
‡ Present address: Department of Chemistry, University of Auckland,
Private Bag 92019, Auckland, New Zealand. Fax: 64 9 3737422;
email: m.brimble@auckland.ac.nz
§ [α]D-values are given in units of 10Ϫ1 deg cm2 gϪ1 throughout.
DOI: 10.1039/a909243i
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709
This journal is © The Royal Society of Chemistry 2000
697

View Article Online
Scheme 1 Reagents, conditions and yields: (i) (EtO)2CO, K2CO3, 135 ЊC (80%); (ii) nBuLi, THF, Ϫ78 ЊC, 2 h; then BnOCH2COCl (84%);
(iii) Sn(OTf)2, CH2Cl2, Et3N, Ϫ78 ЊC; then 6, TMEDA: 7 (5%), 8 (60%), 9 (15%); (iv) Et3SiCl, imidazole, DMF (84%); (v) LiBH4, THF, 0 ЊC (82%);
(vi) TPAP, NMO, CH2Cl2 (80%).
Scheme 2 Reagents, conditions and yields: (i) SitBuMe2, imidazole,
DMF, 0 ЊC to room temp. (87%); (ii) LiBH4, Et2O (89%); (iii) TPAP,
NMO, CH2Cl2 (81%).
then focused on the subsequent aldol coupling reaction. Evans
et al.11 reported that the addition of isobutyraldehyde to the
tin() enolate of benzyloxyoxazolidinone 5 resulted in 63%
yield of the anti aldol product 16. With this in mind, the stan-
nous enolate of oxazolidinone 5 was generated with 1.5 mol
equiv. of Sn(OTf)2 and Et3N at Ϫ78 ЊC. After stirring of the
reaction mixture at Ϫ78 ЊC for 1 h, addition of tetramethyl-
ethylenediamine (1.5 equiv.) followed by the addition of alde-
hyde 6 and stirring for 2 h at Ϫ78 ЊC afforded an 80% yield of
aldol products 7, 8 and 9 in 1:12:3 proportions (Scheme 1).
The anti configuration of the major aldol product 8 was
assigned based on literature precedent11,12 and was supported
by the magnitude of the 2Ј,3Ј vicinal coupling constant, which
was similar to the coupling constant observed for analogous
protons in related anti aldol products 16, 17 (Table 1). Assign-
ment of proton and carbon NMR spectra was supported by
COSY and DEPT experiments.
Scheme 3 Reagents and conditions: (i) Ac2O, Et3N, DMAP (cat.);
(ii) pyridinium toluene-p-sulfonate (cat.), EtOH; (iii) p-TsOH, acetone,
room temp.
diol 19, which was converted into acetonide 20 using acetone
and toluene-p-sulfonic acid (p-TsOH). The 13C NMR spectrum
for 20 featured methyl carbons at δC 19.6 and δC 30.1 and a
ketal carbon at δC 98.6, which was consistent with a syn-
diol-derived acetonide. It was therefore established that H-3
and H-5 were syn to each other in adduct 8 and, given that the
configuration at C-5Ј in 8 was R, the absolute stereochemistry
at C-3Ј was established to be R. The magnitude of the vicinal
2Ј,3Ј coupling constant suggested that the relationship between
H-2Ј and H-3Ј is anti and allowed assignment of the configur-
ation at C-2Ј in 8 as R.
H-2Ј of the major aldol adduct 8 resonated as a doublet at
δ 5.31 with coupling constant J 7.7 Hz, thus the chemical shift
and coupling constant were similar to the analogous protons in
1611 and 1712 (Table 1) which were formed under essentially the
same reaction conditions. This analysis, however, did not estab-
lish whether the major anti aldol product was 7 or 8. It was
therefore necessary to show whether H-3Ј was syn or anti to
H-5Ј.
The major aldol adduct 8 was converted into triethylsilyl
ether 10 using triethylsilyl chloride and imidazole in view of the
fact that use of trimethylsilyl trifluoromethanesulfonate and
2,6-lutidine resulted in epimerization at C-2. Reductive removal
of the oxazolidinone using lithium borohydride afforded alco-
hol 11 in 82% yield, which was converted into acetate 18 under
standard conditions (Scheme 3). Deprotection of both silyl
ethers using pyridinium toluene-p-sulfonate in ethanol afforded
The second most abundant product from the aldol reaction
was assigned as the 2Ј,3Ј-syn isomer 9 based largely on the
chemical shift (δ 5.17) and coupling constant (J 2.9 Hz)
observed for for H-2Ј (Table 1). In the least polar minor isomer
7, H-2Ј resonated at δ 5.28 with coupling constant J 5.9 Hz,
which was similar to 8 and quite different from 9, suggesting
2Ј,3Ј-anti and 3Ј,5Ј-anti stereochemistry.
The anti product 8 is formed as a major product over the
normal Evans’ syn product 9. Based on the suggestion13 that
there may be a change in the co-ordination pattern of the
divalent tin() enolate upon addition of tetramethylethylene-
diamine to the reaction mixture, together with literature
precedent on anti aldol reactions14,15 and the knowledge of
tin() co-ordination patterns,16,17 it is proposed that this aldol
reaction proceeds via a boat-like transition state B (Fig. 1).
Thus, 8 is produced from boat-like transition state B as the
698
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709

View Article Online
Table 1 Comparison of chemical shifts (δ) and coupling constants (J/Hz) for aldol adducts 7–9, 16, 17
Product
SiMe2
8a
16b
17c
7a
9a
0.08, s
0.08, s
0.10, s
0.90, s
1.21, d, 6.2
0.05, s
0.87, s
tBu
Me
0.86, s
1.18, d, 6.2
2.86, s
(NMe)
4.34, m
1.19, d, 6.2
H-4ЈA
H-4ЈB
CHAPh
CHBPh
3Ј-OH
H-3Ј
1.67, ddd, 14.3, 9.7, 9.7
1.94, ddd, 14.3, 3.8, 1.6
2.60, dd, 13.6, 9.9
3.15, dd, 13.6, 3.3
3.54, d, 2.2
2.12, m
1.58, ddd, 14.3, 7.1, 2.2
1.78–1.94, m
2.72, dd, 13.6, 9.9
3.27, dd, 13.6, 3.3
2.83, d, 6.2
1.68–1.86, m
·
2.62, dd, 13.4, 9.9
3.22, dd, 13.5, 3.2
1.92, d, 9.3
3.70, m
4.17, m
2.94, dd, 13.9, 8.1
3.11, dd, 13.9, 3.7
not listed
4.02, dd, 6.9, 5.2
4.19, dd, 8.9, 3.3
4.28, dd, 8.9, 8.0
A: 3.62, dd, 10.9, 4.6
B: 3.68, dd, 10.9, 8.6
2.65, dd, 13.2, 9.9
3.31, dd, 13.2, 3.3
3.23, d, 4.5
4.14–4.34, m 
4.00–4.14, m 

3.94–4.01, m

H-5

4.09–4.28, m
4.54, d, 11.7
4.75, d, 11.7

4.01–4.17, m
H-5Ј
0.88, d, 6.8
1.00, d, 7.0
4.52, d, 11.5
4.14–4.34, m 



OCHAAr
4.42, d, 11.4


(C6H4OMe)

5.07, d, 12.9 (Ph) 
4.61, s
4.61, s
OCHBAr
4.55, d, 11.5
4.46, d, 11.4
(C6H4OMe)
5.09, d, 12.9 (Ph)
4.64, m
5.35, d, 6.9
6.87, m






H-4
H-2Ј
ArH
4.53–4.69, m
5.31, d, 7.7
7.17–7.41, m
4.70, m
5.36, d, 8.5
7.10–7.40, m
4.48–4.66, m
5.28, d, 5.9
7.21–7.40, m
4.63–4.78, m
5.17, d, 2.9
7.19–7.42, m
7.21–7.36, m
3.22, 3.76, s
OMe
a Data recorded at 200 Hz in CDCl3 and listed as δ, multiplicity and J-values(s) (Hz). b Recorded at 500 MHz in CDCl3.11 c Recorded at 500 MHz in
D6-DMSO at 125 ЊC.12 d See H-5Ј signals.
Fig. 1
Scheme 4 Reagents, conditions and yields: (i) Br2, CCl4, room temp.
(72%); (ii) Me2SO4, THF–DMSO, 0 ЊC; then aq. KOH, 0 ЊC to room
major isomer over 9 which is formed from the chair-like transi-
tion state A.
Oxidation of alcohol 11 to aldehyde 12 was effected without
epimerization using TPAP and N-methylmorpholine N-oxide
temp. (68%); (iii) 22, nBuLi (2.0 equiv.), THF, Ϫ78 ЊC; then 12: 21
(73%), 25 (24%).
(NMO). With aldehyde 12 in hand, our attention focused on its
union with a suitable oxygenated naphthalene fragment en route
to the key naphthoquinone 32. Selective bromination of naph-
thol 21 at C-3 afforded bromonaphthalene 22 in 72% yield,
which underwent methylation with potassium hydroxide and
dimethyl sulfate to give trimethoxynaphthalene 23 in 68% yield
(Scheme 4). Initial efforts to combine naphthalene 23 and alde-
hyde 12 focused on generation of an organolithium reagent
from bromide 23 followed by the addition of aldehyde 12.
Disappointingly, only 1,4,5-trimethoxynaphthalene 24 was
recovered from the reaction. Attempts to reduce the basicity of
the naphthyl anion by transmetallation to a softer organo-
magnesium or organocerium species also proved ineffective.
Generation of the dianion from bromonaphthol 22 with n-butyl-
lithium (2.0 equiv.) followed by addition of aldehyde 12 resulted
in formation of unsaturated aldehyde 25. The three oxygenated
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709
699

View Article Online
Scheme 5 Reagents, conditions and yields: (i) TiCl3(OiPr), CH2Cl2, 0 ЊC, 9 min: 26 (44%), 27 (9%), 28 (6%); (ii) MnO2, CH2Cl2 (62%); (iii) Ac2O,
CH2Cl2, Et3N: 30 (25%), 31 (41%), 32 (20%); (iv) guanidine, KOBut, EtOH, 5 min, room temp. (47%).
substituents on the naphthalene ring resulted in a marked
increase in the basic character of the naphthyl anion18 such that
protonation of anionic species by the aldehyde 12 is occurring.
In light of the difficulties experienced with the above
approach, we next decided to effect C-arylation of aldehyde 12
using a titanium naphtholate generated from naphthol 21. This
strategy was based on work by Bigi and co-workers.19 and
Casiraghi et al.20 who have effected regiospecific ortho-arylation
of α-alkoxy and α-amino carbonyl compounds. In the present
work the desired benzylic alcohols 26 were prepared in mod-
erate yield by addition of a titanium naphtholate generated
from naphthol 21 to aldehyde 12 (Scheme 5).
features consistent with the biarylmethane structure includ-
ing four singlets at δ 3.62, 3.74, 3.83 and 3.90 assigned to the
methoxy groups, and two singlets at δ 9.35 and 9.43 assigned to
the two hydroxy groups. A doublet at δ 5.42 with coupling
constant J1Ј,2Ј 7.6 Hz was assigned to H-1Ј.
With alcohols 26 in hand, oxidation with manganese dioxide
provided ketone 29 (62%), which afforded acetates 31 (41%),
32 (20%) and diacetate 30 (25%) upon treatment with acetic
anhydride and triethylamine. Acetylation of alcohol 29 using
acetic anhydride and triethylamine in the presence of a catalytic
quantity of 4-(dimethylamino)pyridine (DMAP) afforded
solely diacetate 30 in 69% yield. Naphthyl acetate 32 underwent
conversion into alkyl acetate 31 upon treatment with guanidine
in ethanol22 thereby providing more of the desired acetate 31.
Use of TiCl(OiPr)3 and TiCl2(OiPr)2 to generate the titanium
naphtholate species afforded only recovered starting material
whereas use of the more Lewis acidic TiCl3(OiPr) did effect
union of naphthol 21 with aldehyde 12. Precise reaction
conditions were developed for this step in order to minimize
formation of biarylmethane 28.21 A cooled solution (0 ЊC) of
naphthol 21 in dichloromethane was added to a solution of
TiCl3(OiPr) in dichloromethane at 0 ЊC. The resultant titanium
naphtholate was then transferred to a solution of aldehyde 12
in dichloromethane and the reaction mixture stirred at 0 ЊC for
9 min. Purification by flash chromatography afforded benzylic
alcohols 26 in 44% yield along with triethylsilyl ethers 27 and
biarylmethane 28 in 9% and 6% yield, respectively. The order of
addition described and the short reaction time was crucial in
order to minimize formation of the undesired biarylmethane
28.
1
The high-field H and 13C NMR spectra for acetate 31 con-
firmed that epimerization of the stereocentre α to the carbonyl
group had not occurred at this stage of the synthesis.
The key naphthol 31 underwent oxidative demethylation to
unstable naphthoquinone 33 upon treatment with aq. ceric
[cerium()] ammonium nitrate (CAN) in acetonitrile (Scheme
6). Immediate addition of 2-(trimethylsilyloxy)furan to the
naphthoquinone 33 then afforded a 1:1 inseparable mixture of
furonaphthofurans 34a/b in 42% yield. Formation of adduct 34
was confirmed by spectroscopic analysis. High-resolution mass
spectrometry established the molecular formula C36H44O10Si.
The IR spectrum featured three bands at 1778, 1741 and 1668
cmϪ1 due to the carbonyl groups of the γ-lactone, ester and
ketone, respectively, whilst a broad band at 3320 cmϪ1 was
1
Formation of biarylmethane 28 as a by-product was con-
firmed by elemental analysis which established the molecular
characteristic of the hydroxy group. The H NMR spectrum
exhibited a multiplet at δ 5.36–5.56 assigned to the bridgehead
proton H-9a and H-3Ј, whilst two doublets at δ 6.36 and 6.69
1
formula C43O54O9Si. The H NMR spectrum displayed all the
700
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709

View Article Online
Scheme 6 Reagents, conditions and yields: (i) CAN, CH3CN, H2O; then 2-(trimethylsilyloxy)furan (42%); (ii) CAN, CH3CN, H2O; then 5% HF
(48%); (iii) CSA, CH2Cl2, reflux (52%).
(both with coupling constant J6b,9a 5.9 Hz) were assigned to
H-6b. These protons resonated at similar chemical shifts to
those reported for analogous furo[3,2-b]naphthofurans23 and
was consistent with cis fusion of the two furan rings. The chem-
ical shifts of the protons in the side chain of adduct 34 were
similar to the corresponding protons in naphthalene-acetate 31.
The 13C NMR spectrum was also consistent with the proposed
structure with two methine carbons at δC 81.4 and 81.9 being
assigned to the bridgehead carbon C-9a in the two diastereom-
ers and resonances at δC 85.2 and 85.4 being assigned to C-6b of
the individual diastereomers. It was disappointing that the
bulky benzyloxy substituent at C-2Ј on naphthoquinone 33
failed to influence any stereocontrol in the ensuing annulation.
With furonaphthofurans 34 in hand, oxidative rearrange-
ment of this tetracyclic system to the pyranonaphthoquinone
ring system present in griseusin A 1 was then investigated. The
1:1 mixture of furonaphthofurans 34a and 34b were treated
with an excess of CAN (8 equiv.) in acetonitrile at room tem-
perature under nitrogen. After stirring of the mixture for 10
min, formation of baseline material was observed upon analysis
by TLC and attempts to purify the crude product by flash
chromatography resulted in decomposition.
5% hydrofluoric acid and stirring for 2 h at room temperature,
one major product was observed by TLC, together with a sub-
stantial quantity of baseline material. Careful purification by
flash chromatography afforded lactol 35a or 35b in 48% yield.
The 1H and 13C NMR spectra of the lactol isolated, together
with analysis by HPLC, indicated that only one diastereomer of
the lactol (either 35a or 35b) was formed from the 1:1 mixture
of adducts 34a and 34b. Definitive assignment of the exact
structure of the lactol obtained however, proved difficult. It
transpired that subsequent cyclization to a spiroketal allowed a
more detailed analysis of the stereochemistry (vide infra).
High-resolution mass spectrometry established the molecular
formula C30H30O11 for lactol 35. The IR spectrum featured a
hydroxy band at 3446 cmϪ1 and bands at 1783 and 1664 cmϪ1
due to the carbonyl groups of the γ-lactone and quinone,
respectively. The 1H NMR spectrum showed an upfield shift in
the resonances of the bridgehead protons H-3a and H-11b
relative to the bridgehead protons H-6b and H-9a in the initial
adducts 34a and 34b. The coupling constant between the
bridgehead protons was notably reduced from 5.9 Hz to 2.4 Hz,
reflecting the 5,6 ring fusion now in place. The coupling
constant, J3a,11b 2.4 Hz, was similar to that reported for the
analogous protons in griseusin A 11, supporting the presence
of a cis-fused furonaphthopyran ring system.
It was therefore next decided to effect deprotection of the
silyl group and oxidative rearrangement in one step. Towards
this end, 5% hydrofluoric acid was added dropwise to the reac-
tion mixture 45 s after adducts 34a and 34b were treated with
CAN (3.0 equiv.) in acetonitrile. Before the addition of 5%
hydrofluoric acid, TLC analysis indicated the formation of a
complex mixture of products. However, after the addition of
A doublet resonating at δ 2.68 with a large geminal coupling
Jgem 17.6 Hz was assigned to H-3A, whilst a doublet of doublets
at δ 2.99 with a geminal coupling Jgem 17.6 Hz and an additional
coupling to H-3a, J3B,3a 5.0 Hz was assigned to H-3B. The sharp
resonance for the phenolic protons in adducts 34a and 34b were
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709
701

View Article Online
Table 2 Comparison of chemical shifts (δ) and coupling constants (J/Hz) for spiroketals 36a, 36b and griseusin A 1
1a
36ab
36bb
H-3A
2.72, d, 17
2.74, d, 17.6
3.00, dd, 17.6, 4.9
4.68–4.70
7.30–7.36
7.47, t, 8.0, 8.0
7.75, d, 8.0
5.31, d, 2.8
3.47, d, 9.8
4.21–4.28
2.00–2.03
2.10–2.13
5.20–5.25
2.00
2.68, d, 17.6
3.00, dd, 17.6, 4.9
4.94–4.96
7.30–7.36
7.47, t, 8.0, 8.0
7.75, d, 8.0
5.27, d, 2.8
3.52, d, 9.8
4.21–4.28
2.00–2.03
2.10–2.13
5.20–5.25
2.03
H-3B
3.07, dd, 17, 5
4.81, dd, 5, 3
7.10–7.80
7.10–7.80
7.10–7.80
5.31, d, 3
4.95, dd, 12, 4
5.29, q, 4
1.91, td, 11, 4
2.10, ddd, 11, 4
4.18, dqd, 11, 6, 2
2.08
H-3a
H-8
H-9
H-10
H-11b
H-3Ј
H-4Ј
H-5ЈA
H-5ЈB
CHMe
COCH3
OCHAPh
OCHBPh
Ph
4.67, d, 11.3
4.92, d, 11.3
7.30–7.36
1.42, d, 6.1
3.98
4.74, d, 11.1
4.95, d, 11.1
7.30–7.36
1.37, d, 5.8
4.00
Me
1.22, d, 6
OMe
3Ј-OH
7-OH
2.90
11.80
a Data recorded at 60 MHz in CDCl3 and listed as δH, multiplicity and J-value(s) (Hz).1 b Recorded at 400 MHz in CDCl3.
replaced by two broad resonances at δ 4.35 and δ 5.03 due to
hydroxy groups. The 13C NMR spectrum reflected the loss of
the carbonyl group at δC 198.5 and the presence of an addi-
tional resonance at δC 91.1 was consistent with a lactol carbon,
C-5. Two quaternary carbonyl carbons at δ 182.1 and δ 188.3
were assigned to C-11 and C-6 respectively. The vicinal coup-
ling constant J3a,11b 2.4 Hz established that the relative stereo-
chemistry of the bridgehead protons at C-3a and C-11b was
cis. The position of the hydroxy group at C-5, however,
was assigned as axial and cis with respect to the bridgehead
protons H-3a and H-11b based on anomeric and steric effects.
Similar assignments were made in related work focused on the
synthesis of kalafungin23 and model ring systems for griseusin
A 1.6
Having synthesized lactol 35, our final step to construct the
spiroketal ring of griseusin A 1 involved an acid-catalysed cycliz-
ation. Lactol 35 was heated under gentle reflux with a catalytic
quantity of camphor-10-sulfonic acid in dichloromethane for
two days affording a 3.2:1 mixture of epimerized spiroketals
36a and 36b in 52% yield after purification by flash chromato-
graphy.
The two spiroketals 36a and 36b were inseparable by flash
chromatography, therefore the product ratio was established by
the integration of the 1H NMR spectrum. The 1H NMR
spectrum exhibited two doublets at δ 1.37 and 1.42 assigned to
6Ј-Me of the minor and major spiroketals, respectively, whilst
the singlets resonating at δ 3.98 and 4.00 were assigned to the
methoxy group of the major and minor isomers, respectively
(Table 2). Two doublets at δ 2.68 (minor) and 2.74 (major) with
coupling constant Jgem 17.6 Hz were assigned to H-3A. In the
major isomer 36a, H-3A exhibited a similar chemical shift and
coupling constant to that observed for the same proton in gri-
seusin A 1 (δ 2.72, J 17 Hz). Two doublets resonating at δ 5.27
(minor) and 5.31 (major) with coupling constant J11b,3a 2.8 Hz,
were assigned to H-11b. The chemical shift of H-11b in the
major isomer 36a was similar to the analogous proton in gri-
seusin A 1 (δ 5.31), whilst H-11b in the minor isomer 36b
(δ 5.27) appeared further upfield compared with griseusin A 1
since H-11b in the minor isomer 36b is not syn to O-1Ј. Two
doublets at δ 3.47 (major) and 3.52 (minor) with coupling con-
stant J3Ј,4Ј 9.8 Hz were assigned to H-3Ј. A multiplet resonating
at δ 2.00–2.03 (major and minor) was assigned to H-5ЈA, whilst
a multiplet at δ 2.10–2.13 (major and minor) was assigned to
H-5ЈB. The chemical shift of H-5Ј in the major 36a and minor
36b isomers was similar to the analogous protons in griseusin A
1.
Fig. 2
In the present work, the coupling constant between H-3Ј and
H-4Ј observed for both the major and minor isomers of the
isolated spiroketals, was J3Ј,4Ј 9.8 Hz. Cyclization of lactol 35
with the stereochemistry of the side chain as depicted (benzyl-
oxy and acetate groups anti) would not afford a spiroketal with
a large vicinal coupling constant J4Ј,3Ј. The possibility that
epimerization at C-3Ј on the spiroketal ring had taken place was
therefore examined.
The most favoured conformation of the two C-3Ј epimers
of the spiroketal ring system of griseusin A are represented in
Fig. 2. The C-3Ј epimerized spiroketals 36a and 36b exhibit
conformations wherein the two bulky substituents at C-3Ј and
C-4Ј adopt more favourable equatorial positions. Spiroketals
36a and 36b wherein the methylene group of the fused γ-lactone
occupies a pseudoequatorial position at C-3a are also preferred
in that unfavourable steric interactions between the methylene
group of the γ-lactone ring with either the oxygen atom O-1Ј or
C-3Ј on the spiroketal ring are alleviated.
Based on these considerations, it was assumed that the two
spiroketals isolated from the spirocyclization of lactol 35 were
spiroketals 36a and 36b. The thermodynamically more stable
major spiroketal was assigned as 36a where the benzyloxy
group at C-3Ј is directed away from the bridgehead protons,
H-3a and H-11b. In the minor isomer 36b the benzyloxy group
is in close proximity to H-3a and H-11b, thereby exhibiting
unfavourable steric interactions.
The stereochemistry assigned to the two spiroketals 36a and
36b was confirmed by examination of the H NMR spectrum.
1
The magnitude of the vicinal coupling constant between H-3Ј
and H-4Ј (J3Ј,4Ј 9.8 Hz) for the major 36a and minor 36b isomers
was consistent with the benzyloxy and acetate groups being
equatorial. In the major isomer 36a, H-3A is in close proximity
to the benzyloxy group, hence it is deshielded, appearing
further downfield at δ 2.74 relative to the equivalent proton in
the minor isomer 36b where H-3A resonates at δ 2.68. H-11b in
702
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709

View Article Online
the major isomer 36a is syn to O-1Ј, therefore it is deshielded,
appearing further downfield at δ 5.31 compared with δ 5.27 for
H-11b in the minor isomer 36b. In the minor isomer 36b, H-3Ј
resonated as a doublet at δ 3.52, whilst in the major isomer 36a,
H-3Ј resonated as a doublet at δ 3.47. Thus, H-3Ј is more
deshielded in isomer 36b where the BnOC–H bond is anti-
periplanar to the C-5–O-4 bond.
The stereochemistry of the major isomer 36a was further
established by NOE experiments wherein enhancement of the
CHOAc signal was observed when the 6Ј-Me resonance was
irradiated. Irradiation of OCHPh in the minor isomer 36b
resulted in enhancement of H-11b signal, indicating that H-11b
and OCHPh are in close proximity. Given that H-11b and
OCHPh in the major isomer 36a are well removed from each
other, further evidence is provided for assignment of the minor
isomer as spiroketal 36b.
Variation of the reaction conditions to effect cyclization of
lactol 35 to spiroketals 36a and 36b was also investigated. When
acetonitrile or toluene was used as the solvent, formation of
baseline material resulted, and this material decomposed upon
attempted purification by flash chromatography. Employing
anhydrous magnesium sulfate to remove water generated from
the reaction also led to decomposition. Use of alternative acid
catalysts did not offer any improvement. Efforts to prevent
epimerization in the final cyclization step also met with little
success.
In summary, a synthesis of pyranonaphthoquinone spiro-
ketals (36a and 36b) which are closely related to griseusin A 1
has been presented. The synthetic work described herein pro-
vides a non-carbohydrate-based approach to the synthesis of
analogues of this natural product. The epimerization observed
in the final spirocyclization step demonstrates that subtle
stereoelectronic effects provide the driving force for the stereo-
chemistry observed in the final spiroketals.
trometry (LSIMS) using caesium() ions as the primary beam
(10 kV) and m-nitrobenzyl alcohol (NBA) and a 5:1 mix (v/v)
of dithiothreitol–dithioerythritol (DTDE) as a matrix. Optical
rotations were recorded on an Optical Activity POLAAR 2001
polarimeter using a 5 dmϪ3 cell. Samples were prepared at the
concentration (measured in g/100 cm3) in the solvent indicated.
Thin-layer chromatography (TLC) was performed using 0.2
mm thick precoated silica gel plates (Merck Kieselgel 60 F254 or
Riedel-de Haen Kieselgel S F254). Compounds were visualized
by UV fluorescence or by staining with iodine or vanillin
in methanolic sulfuric acid. Flash chromatography was per-
formed using Merck Kieselgel 60 or Riedel-de Haen Kieselgel
S silica gel (both 230–400 mesh) with the indicated solvents.
Concentration ‘in vacuo’ or ‘at reduced pressure’ refers to con-
centration using a rotary evaporator connected to a water
aspirator. Removal of residual solvent or volatile reagents
where desired was achieved by evacuation (0.1–0.01 mmHg)
with a high-stage oil vacuum pump. Ether refers to diethyl
ether, hexane refers to light petroleum with distillation range
40–60 ЊC.
(4R)-4-(Phenylmethyl)oxazolidin-2-one 4
A mixture of (2R)-2-amino-3-phenylpropan-1-ol 38 (5.81 g,
38.4 mmol), potassium carbonate (0.53 g, 3.84 mmol) and
diethyl carbonate (8.84 ml, 73.0 mmol) was carefully heated
to 135–140 ЊC, and ethanol was allowed to distil as it was
formed. After 6 h, the light brown slurry was cooled to room
temperature, diluted with dichloromethane (400 ml), and
filtered through a Celite pad to remove potassium carbonate.
The organic layer was washed with aq. sodium hydrogen
carbonate (2 × 100 ml; 10% w/v), dried over magnesium sulfate
and the solvent was removed under reduced pressure to afford
a pale yellow crystalline solid. Recrystallization from hexane–
ethyl acetate (4:1) gave the title compound 4 (5.45 g, 80%)
as colourless needles, mp 86.5–88.5 ЊC {lit.,8 87.0–88.5 ЊC
[(4S)-enantiomer]}; [α]D Ϫ4.90 (c 2.262, EtOH) {lit.,8 [α]D ϩ4.9
(c 1.10, EtOH) [(4S)-enantiomer]}. The 1H NMR spectrum
was in agreement with that reported in the literature.8
Experimental
Mps were determined using a Kofler hot-stage apparatus and
are uncorrected. IR spectra were recorded using a Perkin-Elmer
1600 Fourier Transform IR spectrophotometer as Nujol mulls,
thin films or solutions in the solvent specified. Absorption
maxima are expressed in wavenumbers (cmϪ1) with the follow-
ing abbreviations: vs = very strong, s = strong, m = medium,
w = weak and br = broad. 1H NMR spectra were recorded on a
Bruker AC 200 (200 MHz) or a Bruker AM 400 (400 MHz)
spectrometer at ambient temperature. All J-values are given in
Hz. Chemical shifts are expressed in parts per million downfield
shift from tetramethylsilane as an internal standard, and
reported as position (δH), relative integral, multiplicity (s =
singlet, br s = broad singlet, d = doublet, dd = double doublet,
ddd = double double doublet, t = triplet, dt = doublet of trip-
lets, q = quartet, qd = quartet doublet, m = multiplet), coupling
constant (J/Hz) and assignment. 13C NMR spectra were
recorded on a Bruker AC 200 (50.3 MHz) or a Bruker AM 400
(100.6 MHz) spectrometer at ambient temperature with com-
plete proton decoupling. Data are expressed in parts per million
downfield shift from tetramethylsilane as an internal standard
and reported as position (δC), multiplicity (aided by DEPT135,
COSY and HETCOR experiments) and assignment. Some
peaks may be coincidental. Low-resolution mass spectra were
recorded on a VG70-250S, a VG70-SD or a AEI model MS902
double-focusing magnetic sector mass spectrometer operating
with an ionization potential of 70 eV (EI, CI). High-resolution
mass spectra were recorded at nominal resolution of 5000 or
10 000 as appropriate. LSIMS spectra were recorded between
200–550 Da. Major fragments are given as percentages relative
to the base peak and assigned where possible. Ionization
methods employed were (i) electron impact (EI), (ii) chemical
ionization with ammonia as reagent gas (CI), (iii) fast-atom
bombardment (FAB), (iv) liquid secondary-ion mass spec-
(4R)-3-[2-(Phenylmethoxy)acetyl]-4-(phenylmethyl)oxazolidin-
2-one 5
To a solution of (4R)-4-(phenylmethyl)oxazolidin-2-one 4 (4.54
g, 25.6 mmol) in dry tetrahydrofuran (THF) (68 ml) cooled to
Ϫ78 ЊC under an atmosphere of nitrogen was added n-butyl-
lithium (1.60 M; 17.6 ml, 28.2 mmol). The temperature was
raised to Ϫ20 ЊC over 1.5 h lowered back to Ϫ78 ЊC and benzyl-
oxyacetyl chloride (5.20 g, 28.2 mmol) as a solution in dry
THF (5 ml) added slowly. The solution was stirred for a
further 0.5 h before being quenched by the addition of satur-
ated aq. ammonium chloride (16 ml). Following extraction with
dichloromethane (73 ml), the organic layer was washed succes-
sively with aq. sodium hydroxide (24 ml; 1 M), water (24 ml)
and brine (24 ml) before being dried over sodium sulfate. The
solvent was removed under reduced pressure to afford a pale
yellow oil, which upon purification by flash chromatography
using hexane–ethyl acetate (7:3) as eluent gave the title com-
pound 5 (7.00 g, 84%) as a colourless crystalline solid (Found: C,
69.9; H, 5.7; N, 4.2. C19H19NO4 requires C, 70.1; H, 5.9; N,
4.3%); [α]D Ϫ69.57 (c 1.638, CH2Cl2); νmax (Nujol)/cmϪ1 1765s
(OC᎐ON) and 1703s (NC᎐OC); δ (200 MHz; CDCl3) 2.80
᎐
᎐
H
(1H, dd, Jgem 13.4 and J 9.3, CHCHAPh), 3.29 (1H, dd, Jgem
13.4 and J 3.1, CHCHBPh), 4.09–4.29 (2H, m, H2-5), 4.57–4.75
(5H, m, H-4, OCH2Ph, H-2Ј) and 7.13–7.49 (10H, m, Ph); δC
(50 MHz; CDCl3) 37.6 (CH2, CHCH2Ph), 54.6 (CH, C-4), 67.1
(CH2, C-2Ј), 69.5 (CH2, C-5), 73.3 (CH2, OCH2Ph), 127.3,
127.9(2), 128.4, 128.9, 129.3 [CH, 2 × Ph (last 4 peaks coinci-
dental)], 134.8 (quat, CHCH2Ph), 137.1 (quat, OCH2Ph),
153.2 (quat, C-2) and 170.0 (quat, C-1Ј); m/z (EI) 326 (MHϩ,
0.5%), 234 (M Ϫ CH2Ph, 3), 219 (MH Ϫ OCH2Ph, 27), 176
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709
703

View Article Online
(MH Ϫ OCH2Ph Ϫ CH3CO, 3), 128 (MH Ϫ OCH2Ph Ϫ CH3-
CO Ϫ CH2Ph, 14), 91 (CH2Ph, 100) and 65 (10).
washed thoroughly with sodium-dried ether (6 × 40 ml). The
product, tin() trifluoromethanesulfonate (20.5 g, 73%), was
dried under reduced pressure at 50 ЊC for 8 h, then stored under
argon in a desiccator until required (Found: C, 5.8; F, 27.05; S,
15.3. Calc. for C2F6O6S2Sn: C, 5.8; F, 27.35; S, 15.4%).
Ethyl-(3R) 3-(tert-butyldimethylsilyloxy)butanoate 14
To a solution of ethyl-(3R) 3-hydroxybutanoate 13 (2.36 g, 17.9
mmol) and N,N-dimethylformamide (DMF) (12.2 ml) at 0 ЊC
under an atmosphere of nitrogen was added tert-butyl-
dimethylsilyl chloride (2.85 g, 18.8 mmol) and imidazole (3.04
g, 44.7 mmol). After 2 h, the reaction mixture was left to warm
to room temperature and was stirred for a further 20 h. The
solution was poured into ether (87 ml), washed successively
with water (3 × 14 ml) and brine (14 ml), then dried over
sodium sulfate. Removal of the solvent under reduced pressure
gave a clear liquid which upon distillation afforded the title
compound 14 (3.82 g, 87%) as a colourless liquid, bp 110–
111 ЊC/13 mmHg (lit.,24 87–88 ЊC/5 mmHg); [α]D Ϫ26.15 (c
4.148, CHCl3) {lit.,24 [α]D Ϫ25.5 (c 1.16, CHCl3)}. The 1H NMR
spectrum was in agreement with that reported in the literature.24
3-[5-(tert-Butyldimethylsilyloxy)-3-hydroxy-2-(phenylmethoxy)-
hexanoyl]-4-(phenylmethyl)oxazolidin-2-one 7–9
To a suspension of stannous [tin()] trifluoromethanesulfonate
(6.90 g, 16.6 mmol) in dry dichloromethane (53.5 ml) under an
atmosphere of nitrogen was added triethylamine (2.31 ml, 16.6
mmol) and the resultant yellow suspension was immediately
cooled to Ϫ78 ЊC. After 5 min, a solution of oxazolidinone 5
(3.59 g, 11.0 mmol) in dry dichloromethane (17.9 ml) was
added and the resultant mixture was stirred at Ϫ78 ЊC for 1 h.
N,N,NЈ,NЈ-Tetramethylethylenediamine (TMEDA) (2.50 ml,
16.6 mmol) was then added, followed after 5 min by a solution
of aldehyde 6 (2.23 g, 11.0 mmol) in dry dichloromethane (3.3
ml). The reaction mixture was stirred at Ϫ78 ЊC for 2 h, then
poured into a vigorously stirred, ice-cooled mixture of 1 M aq.
sodium hydrogen sulfate–dichloromethane (1:1; 1.43 l). After
stirring for 5 min, the layers were separated and the aqueous
layer extracted with dichloromethane (360 ml). The combined
organic fractions were washed successively with saturated aq.
sodium hydrogen carbonate (540 ml) and brine (540 ml), dried
over sodium sulfate, and the solvent removed under reduced
pressure. Purification of the pale yellow oil by flash chroma-
tography using hexane–ethyl acetate (4:1) as eluent gave:
(3R)-3-(tert-Butyldimethylsilyloxy)butan-1-ol 15
To a stirred suspension of lithium borohydride (319 mg, 14.7
mmol) in dry ether (22 ml) under an atmosphere of nitrogen
was added a solution of ethyl-(3R) 3-(tert-butyldimethylsilyl-
oxy)butanoate 14 (2.41 g, 9.78 mmol) and methanol (0.57 ml) in
dry ether (4.85 ml) over a period of 1 h. The reaction mixture
was heated under reflux for 5 h, then cooled in ice and quenched
by the addition of sodium hydroxide (12.9 ml; 2 M). After 20
min, the mixture was poured into ether (58 ml) at room tem-
perature. The layers were separated and the aqueous phase
extracted with ether (3 × 40 ml). The combined organic extracts
were washed with brine (32 ml), dried over sodium sulfate, and
the solvent removed under reduced pressure. The clear liquid
obtained was distilled to give the title compound 15 (1.77 g,
89%) as a colourless liquid, bp 62–63 ЊC/0.1 mmHg (lit.,24 74–
80 ЊC/4 mmHg); [α]D Ϫ30.18 (c 0.280, CHCl3) {lit.,24 [α]D Ϫ30.4
(i) (4R,2ЈS,3ЈS,5ЈR)-aldol adduct 7 (291 mg, 5%); Rf 0.63
[hexane–ethyl acetate (7:3)] as a colourless oil (Found: C, 65.9;
H, 7.55; N, 2.70. C29H41NO6Si requires C, 66.0; H, 7.80; N,
2.65%); [α]D Ϫ50.10 (c 1.562, CHCl3); νmax (film)/cmϪ1 3629–
3363br (m, OH), 1777s (OC᎐ON), 1703s (NC᎐OC), 1395m,
᎐
᎐
1387m (C–N) and 1111br m (C–O); δH (200 MHz; CDCl3) 0.08,
0.10 (6H, s, SiMe2), 0.90 (9H, s, But), 1.21 (3H, d, J 6.2, H3-6Ј),
1.68–1.86 (2H, m, H2-4Ј), 2.65 (1H, dd, Jgem 13.2 and J 9.9,
CHCHAPh), 3.23 (1H, d, J 4.5, OH), 3.31 (1H, dd, Jgem 13.2
and J 3.3, CHCHBPh), 4.00–4.14 (2H, m, H2-5), 4.14–4.34 (2H,
m, H-3Ј, -5Ј), 4.48–4.66 (1H, m, H-4), 4.61 (2H, s, OCH2Ph),
5.28 (1H, d, J2Ј,3Ј 5.9, H-2Ј) and 7.21–7.40 (10H, m, Ph); δC (50
MHz; CDCl3) Ϫ5.1, Ϫ4.5 (CH3, SiMe2), 17.9 (quat, CMe3),
23.3 (CH3, C-6Ј), 25.8 (CH3, CMe3), 37.6 (CH2, CHCH2Ph),
40.8 (CH2, C-4Ј), 55.1 (CH, C-4), 66.4 (CH2, C-5), 66.6 (CH,
C-5Ј), 69.9 (CH, C-3Ј), 73.2 (CH2, OCH2Ph), 79.8 (CH, C-2Ј),
127.2, 127.9, 128.3, 128.5, 128.9, 129.4 [CH, 2 × Ph (last
4 peaks coincidental)], 135.3 (quat, CHCH2Ph), 137.4 (quat,
OCH2Ph), 153.2 (quat, C-2) and 172.0 (quat, C-1Ј); m/z
(LSIMS, NBA matrix) 528 (MHϩ, 17%), 396 (M Ϫ C6H16OSi,
11), 304 (11), 286 (17), 178 (C10H12NO2, 13), 91 (CH2Ph, 100),
75 [(CH3)2SiOH, 14] and 73 (23).
1
(c 1.09, CHCl3)}. The H NMR spectrum was in agreement
with that reported in the literature.24
(3R)-3-(tert-Butyldimethylsilyloxy)butanal 6
To a solution of (3R)-3-(tert-butyldimethylsilyloxy)butan-1-ol
15 (2.82 g, 13.8 mmol) in dichloromethane (57 ml) under an
atmosphere of nitrogen were added NMO (2.43 g, 20.7 mmol)
and powdered 4 Å molecular sieves (5.20 g). After 5 min, TPAP
(170 mg, 3.5 mol%) was added and the reaction mixture stirred
at room temperature for 4 h. Filtration of the reaction mixture
through a silica gel pad, followed by removal of the solvent
under reduced pressure gave the title compound 6 (2.24 g, 81%)
as a clear liquid (Found: MHϩ, 203.1467. Calc. for C10H22OSi:
MHϩ, 203.1430); [α]D Ϫ17.90 (c 0.354, CHCl3) {lit.,10 [α]D
Ϫ14.4 (c 1.05, CHCl3)}; νmax (film)/cmϪ1 2723w (H–C᎐O), 1734s
᎐
(ii) (4R,2ЈR,3ЈR,5ЈR)-aldol adduct 8 (3.48 g, 60%); Rf 0.56
[hexane–ethyl acetate (7:3)] as a colourless oil (Found: C, 66.0;
H, 7.4; N, 2.6%); [α]D Ϫ56.11 (c 1.788, CHCl3); νmax (film)/cmϪ1
(C᎐O), 1134m and 1092m (C–O); δ (50 MHz; CDCl3) Ϫ5.0,
᎐
C
Ϫ4.4 (CH3, SiMe2), 17.9 (C, CMe3), 24.1 (CH3, C-4), 25.7 (CH3,
CMe3), 52.9 (CH2, C-2), 64.5 (CH, C-3) and 202.1 (CH, C-1);
m/z (LSIMS, NBA matrix) 203 (MHϩ, 7%), 187 (16), 159
(MH Ϫ CH2CHOH, 81), 145 (C7H17OSi, 26), 115 (C6H15Si, 38),
103 (23), 89 (C4H9O2, 22), 75 (C3H7O2, 24) and 73 (C3H5O2,
100). The 1H NMR spectrum was in agreement with that
reported in the literature.10 The crude material was used in the
next step without further purification.
3589–3280m (OH), 1784s (OC᎐ON), 1703s (NC᎐OC), 1389m
᎐
᎐
(C–N) and 1105m (C–O); δH (200 MHz; CDCl3) 0.08 (6H, s,
SiMe2), 0.86 (9H, s, But), 1.18 (3H, d, J6Ј,5Ј 6.2, H3-6Ј), 1.67 (1H,
ddd, Jgem 14.3, J4ЈA,3Ј 9.7 and J4ЈA,5Ј 9.7, H-4ЈA), 1.94 (1H, ddd,
Jgem 14.3, J4ЈB,3Ј 3.8 or 1.6 and J4ЈB,5Ј 1.6 or 3.8, H-4ЈB), 2.60 (1H,
dd, Jgem 13.6 and J 9.9, CHCHAPh), 3.15 (1H, dd, Jgem 13.6 and
J 3.3, CHCHBPh), 3.54 (1H, d, J 2.2, OH), 3.94–4.01 (1H, m,
H-3Ј), 4.01–4.17 (3H, m, H-5, -5Ј), 4.53–4.69 (1H, m, H-4),
4.61 (2H, s, OCH2Ph), 5.31 (1H, d, J2Ј,3Ј 7.7, H-2Ј) and 7.17–
7.41 (10H, m, Ph); δC (50 MHz; CDCl3) Ϫ5.0, Ϫ4.2 (CH3,
SiMe2), 17.6 (quat, CMe3), 24.2 (CH3, C-6Ј), 25.6 (CH3, CMe3),
37.7 (CH2, CHCH2Ph), 42.2 (CH2, C-4Ј), 55.2 (CH, C-4), 66.2
(CH2, C-5), 69.6 (CH, C-5Ј), 72.6 (CH, C-3Ј), 72.8 (CH2,
OCH2Ph), 78.8 (CH, C-2Ј), 127.0, 127.8, 128.1, 128.2, 128.6,
129.2 [CH, 2 × Ph (last 4 peaks coincidental)], 135.1 (quat,
CHCH2Ph), 137.1 (quat, OCH2Ph), 153.3 (quat, C-2) and 172.1
Tin(II) trifluoromethanesulfonate
The title compound was prepared by an adaptation of the
method of Mukaiyama et al.25 After addition of the trifluoro-
methanesulfonic acid (18.7 ml, 0.21 mol) to anhydrous tin()
chloride (12.72 g, 0.067 mol) under an atmosphere of nitrogen,
the mixture was heated for 21 h, then extra acid was added
(5 ml, 0.056 mol) and the mixture heated for a further 4 h. The
excess of acid and volatiles was removed in vacuo and the solid
704
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709

View Article Online
(quat, C-1Ј); m/z (LSIMS, NBA matrix) 528 (MHϩ, 18%), 396
(M Ϫ C6H16OSi, 16), 304 (6), 286 (8), 268 (11), 178 (C10H12NO2,
11), 159 (C8H19OSi, 8), 117 (8), 91 (CH2Ph, 100), 75 [(CH3)2-
SiOH, 9], 73 (16), 55 (9) and 43 (CH3CO, 8).
(iii) (4R,2ЈR,3ЈS,5ЈR)-aldol adduct 9 (872 mg, 15%); Rf 0.48
[hexane–ethyl acetate (7:3)] as a colourless oil (Found: C, 65.7;
H, 7.6; N, 2.6%); [α]D Ϫ16.91 (c 5.348, CHCl3); νmax (film)/cmϪ1
THF (185 ml) at 0 ЊC under an atmosphere of nitrogen was
added portionwise, over a period of 2 min, lithium borohydride
(216 mg, 9.82 mmol). The solution was allowed to reach room
temperature and was stirred for 5 h, then quenched by the
addition of water (10 ml). After 10 min the reaction mixture
was poured into ether (346 ml), washed successively with water
(103 ml) and brine (103 ml), and dried over sodium sulfate.
Removal of the solvent at reduced pressure gave a clear oil that
upon purification by flash chromatography, using hexane–ethyl
acetate (4:1) as eluent, gave the title compound 11 (1.79 g,
82%) as a colourless oil (Found: C, 63.8; H, 10.35. C25H48O4Si2
requires C, 64.05; H, 10.3%); [α]D Ϫ10.53 (c 1.906, CHCl3); νmax
(film)/cmϪ1 3659–3167m (OH) and 1087br s (C–O); δH (200
MHz; CDCl3) 0.06 (6H, s, SiMe2), 0.65 [6H, q, J 7.7, Si(CH2-
CH3)3], 0.90 (9H, s, But), 0.98 [9H, t, J 7.7, Si(CH2CH3)3], 1.15
(3H, d, J6,5 6.1, H3-6), 1.58–1.86 (2H, m, H2-4), 2.51–2.69 (1H,
br s, OH), 3.44–3.50 (1H, m, H-2), 3.80 (2H, br s, H-1), 3.89–
4.04 (1H, m, H-5), 4.04–4.19 (1H, m, H-3), 4.62 (1H, d, Jgem
11.5, OCHAPh), 4.70 (1H, d, Jgem 11.5, OCHBPh) and 7.26–
7.46 (5H, m, Ph); δC (50 MHz; CDCl3) Ϫ4.6, Ϫ4.4 (CH3,
SiMe2), 4.9 (CH2, CH3CH2Si), 6.9 (CH3, CH3CH2Si), 18.0
(quat, CMe3), 23.9 (CH3, C-6), 25.9 (CH3, CMe3), 44.6 (CH2,
C-4), 61.1 (CH2, C-1), 65.7 (CH, C-5), 71.0 (CH, C-3), 71.8
(CH2, OCH2Ph), 81.6 (CH, C-2), 127.6, 127.8, 128.3 [CH, Ph
(last 2 peaks coincidental)] and 138.4 (quat, OCH2Ph); m/z
(LSIMS, NBA matrix) 469 (MHϩ, 6%), 411 (M Ϫ C4H9, 2), 337
(MH Ϫ C8H19OSi, 9), 245 (11), 159 (C8H19OSi, 30), 115 (13), 91
(CH2Ph, 100), 73 (31) and 59 (9).
3624–3278m (OH), 1782s (OC᎐ON), 1710s (NC᎐OC), 1390m
᎐
᎐
(C–N) and 1105br m (C–O); δH (200 MHz; CDCl3) 0.05 (6H, s,
SiMe2), 0.87 (9H, s, But), 1.19 (3H, d, J6Ј,5Ј 6.2, H3-6Ј), 1.58 (1H,
ddd, Jgem 14.3, J4ЈA,3Ј 7.1 or 2.2 and J4ЈA,5Ј 2.2 or 7.1, H-4ЈA),
1.78–1.94 (1H, m, H-4ЈB), 2.72 (1H, dd, Jgem 13.6 and J 9.9,
CHCHAPh), 2.83 (1H, d, J 6.2, OH), 3.27 (1H, dd, Jgem 13.6
and J 3.3, CHCHBPh), 4.09–4.28 (4H, m, H2-5, H-3Ј, -5Ј),
4.54 (1H, d, Jgem 11.7, OCHAPh), 4.63–4.78 (1H, m, H-4), 4.75
(1H, d, Jgem 11.7, OCHBPh), 5.17 (1H, d, J2Ј,3Ј 2.9, H-2Ј) and
7.19–7.42 (10H, m, Ph); δC (50 MHz; CDCl3) Ϫ5.2, Ϫ4.5 (CH3,
SiMe2), 17.9 (quat, CMe3), 23.4 (CH3, C-6Ј), 25.7 (CH3, CMe3),
37.5 (CH2, CHCH2Ph), 42.0 (CH2, C-4Ј), 55.6 (CH, C-4), 65.9
(CH, C-5Ј), 66.7 (CH2, C-5), 69.1 (CH, C-3Ј), 72.9 (CH2,
OCH2Ph), 79.9 (CH, C-2Ј), 127.3, 128.0, 128.3(2), 128.9, 129.3
[CH, 2 × Ph (last 4 peaks coincidental)], 135.1 (quat, CHCH2-
Ph), 137.1 (quat, OCH2Ph), 153.2 (quat, C-2) and 170.6 (quat,
C-1Ј); m/z (LSIMS, NBA matrix) 528 (MHϩ, 19%), 470
(M Ϫ C4H9, 5), 396 (M Ϫ C6H16OSi, 15), 286 (13), 268 (8), 178
(C10H12NO2, 11), 159 (C8H19OSi, 7), 117 (9), 91 (CH2Ph, 100),
75 [(CH3)2SiOH, 13] and 73 (21). Upon prolonged refrigeration
at approximately 2 ЊC the oil formed a white solid (needles),
mp 68.0–71.0 ЊC.
Auxiliary 4 (621 mg, 75%) was also recovered from the
reaction.
(4R,2ЈR,3ЈR,5ЈR)-3-[5-(tert-Butyldimethylsilyloxy)-2-(phenyl-
methoxy)-3-(triethylsilyloxy)hexanoyl]-4-(phenylmethyl)oxazol-
idin-2-one 10
(2R,3R,5R)-5-(tert-Butyldimethylsilyloxy)-2-(phenylmethoxy)-
3-(triethylsilyloxy)hexanal 12
To a solution of alcohol 8 (2.71 g, 5.15 mmol) in dry DMF (5.55
ml) at 0 ЊC under an atmosphere of nitrogen were added imid-
azole (1.40 g, 20.6 mmol) and triethylsilyl chloride (1.30 ml,
7.72 mmol). The resultant solution was allowed to reach room
temperature and was stirred overnight. The reaction mixture
was poured into ether (200 ml), washed successively with water
(3 × 50 ml) and brine (50 ml), then dried over sodium sulfate.
Removal of the solvent at reduced pressure afforded a pale
yellow oil that was purified by flash chromatography using
hexane–ethyl acetate (4:1) as eluent to give the title compound
10 (2.74 g, 84%) as a colourless oil (Found: C, 65.4; H, 8.4; N,
2.1. C35H55NO6Si2 requires C, 65.5; H, 8.6; N, 2.2%); [α]D
To a mixture of alcohol 11 (95.7 mg, 0.20 mmol), NMO (35.9
mg, 0.31 mmol) and powdered 4 Å molecular sieves (110 mg) in
dichloromethane (0.54 ml) at 0 ЊC under an atmosphere of
nitrogen was added TPAP (3.60 mg, 5 mol%). The reaction
mixture was allowed to warm to room temperature and stirred
for 4 h. Filtration of the reaction mixture through a silica gel
pad and removal of the solvent at reduced pressure afforded a
clear oil. Purification by flash chromatography using hexane–
ethyl acetate (4:1) as eluent gave the title compound 12 (76.1 mg,
80%) as a colourless oil (Found: C, 64.4; H, 9.7. C25H46O4Si2
requires C, 64.3; H, 9.9%); [α]D ϩ14.64 (c 1.152, CHCl3); νmax
(film)/cmϪ1 2737w, 2703w (H–C᎐O), 1736s (C᎐O) and 1109br s
(C–O); δH (200 MHz; CDCl3) 0.02, 0.03 (6H, s, SiMe2), 0.60
[6H, q, J 7.9, Si(CH2CH3)3], 0.87 (9H, s, But), 0.94 [9H, t, J 7.9,
Si(CH2CH3)3], 1.12 (3H, d, J6,5 6.2, H3-6), 1.58–1.85 (2H, m,
H4-4), 3.73 (1H, dd, J2,1 2.6 and J2,3 2.6, H-2), 3.86–4.01 (1H, m,
H-5), 4.13–4.24 (1H, m, H-3), 4.59 (1H, d, Jgem 11.6, OCHAPh),
4.65 (1H, d, Jgem 11.6, OCHBPh), 7.27–7.39 (5H, m, Ph) and
9.69 (1H, d, J1,2 2.6, H-1); δC (50 MHz; CDCl3) Ϫ4.7, Ϫ4.4
(CH3, SiMe2), 4.9 (CH2, CH3CH2Si), 6.8 (CH3, CH3CH2Si),
18.0 (quat, CMe3), 23.9 (CH3, C-6), 25.8 (CH3, CMe3), 44.1
(CH2, C-4), 65.5 (CH, C-5), 71.5 (CH, C-3), 72.7 (CH2,
OCH2Ph), 86.2 (CH, C-2), 127.9, 128.4 [CH, Ph (2 and 3 peaks
coincidental respectively)], 137.4 (quat, OCH2Ph) and 204.0
(CH, C-1); m/z (CI) 484 (MHϩ ϩ NH3, 1%), 467 (MHϩ, 11),
335 (MH Ϫ C6H16OSi, 100), 235 (15), 215 (11), 203 (24), 159
(C8H19OSi, 75), 132 (C6H16OSi, 63), 120 (13), 108 (20), 91
(CH2Ph, 80) and 74 (12).
᎐
᎐
Ϫ43.75 (c 1.408, CHCl3); νmax (film)/cmϪ1 1784s (OC᎐ON),
᎐
1709s (NC᎐OC), 1388br s (C–N) and 1116br s (C–O); δ (200
᎐
H
MHz; CDCl3) 0.01, 0.06 (6H, s, SiMe2), 0.58 [6H, q, J 7.9,
Si(CH2CH3)3], 0.88 (9H, s, But), 0.92 [9H, t, J 7.9, Si(CH2-
CH3)3], 1.13 (3H, d, J6Ј,5Ј 5.9, H3-6Ј), 1.71–1.93 (2H, m, H2-4Ј),
2.55 (1H, dd, Jgem 13.4 and J 9.9, CHCHAPh), 3.13 (1H, dd,
Jgem 13.4 and J 3.3, CHCHBPh), 4.00–4.16 (4H, m, H2-5, H-3Ј,
-5Ј), 4.51–4.67 (3H, m, H-4, OCH2Ph), 5.40 (1H, d, J2Ј,3Ј 7.0,
H-2Ј) and 7.16–7.43 (10H, m, Ph); δC (50 MHz; CDCl3) Ϫ4.6,
Ϫ4.5 (CH3, SiMe2), 5.0 (CH2, CH3CH2Si), 6.8 (CH3, CH3-
CH2Si), 18.1 (quat, CMe3), 23.5 (CH3, C-6Ј), 25.9 (CH3, CMe3),
37.9 (CH2, CHCH2Ph), 46.0 (CH2, C-4Ј), 55.6 (CH, C-4), 65.7
(CH, C-5Ј), 66.1 (CH2, C-5), 70.9 (CH, C-3Ј), 73.2 (CH2,
OCH2Ph), 80.9 (CH, C-2Ј), 127.3, 127.9, 128.3, 128.5, 129.0,
129.4 [CH, 2 × Ph (last 4 peaks coincidental)], 135.3 (quat,
CHCH2Ph), 137.5 (quat, OCH2Ph), 153.2 (quat, C-2) and 172.2
(quat, C-1Ј); m/z (LSIMS, NBA matrix) 642 (Mϩ, 4%), 612 (7),
584 (M Ϫ C4H10, 5), 510 (M Ϫ C6H16OSi, 9), 418 (5), 286 (6),
268 (8), 185 (7), 159 (C8H19OSi, 35), 115 (22), 91 (CH2Ph, 100),
73 (47) and 59 (13).
2-Bromo-4,8-dimethoxy-1-naphthol 22
A solution of bromine (191 mg, 1.20 mmol) in tetrachloro-
methane (3.7 ml) was added dropwise to a solution of
4,8-dimethoxy-1-naphthol 2123 (243 mg, 1.19 mmol) in tetra-
chloromethane (10.1 ml). After 30 min, aq. sodium thiosulfate
(12.7 ml; 10% w/v) was added and the resultant mixture stirred
for 10 min. The reaction mixture was then poured into aq.
(2S,3R,5R)-5-(tert-Butyldimethylsilyloxy)-2-(phenylmethoxy)-
3-(triethylsilyloxy)hexan-1-ol 11
To a solution of oxazolidinone 10 (2.96 g, 4.67 mmol) in dry
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709
705

View Article Online
sodium thiosulfate (38 ml; 10% w/v) and extracted with
dichloromethane (3 × 25 ml). The combined organic fractions
were washed successively with aq. sodium thiosulfate (25 ml;
10% w/v), water (2 × 50 ml) and brine (50 ml), dried over
sodium sulfate, and the solvent removed under reduced pres-
sure. Purification by flash chromatography using hexane–ethyl
acetate (8:2) as eluent afforded the title compound 22 (243
mg, 72%) as colourless needles, mp 141.0–143.0 ЊC (decomp.)
[lit.,26 141–142 ЊC (decomp.)].
Titanium nachtholate coupling
A solution of 4,8-dimethoxy-1-naphthol 21 (0.39 g, 1.89
mmol) in dichloromethane (4.7 ml) was added to a solution of
trichlorotitanium isopropoxide (0.60 g, 2.83 mmol) in dichloro-
methane (3.9 ml) at 0 ЊC under an atmosphere of nitrogen.
After 5 min, the resultant solution was added to a solution of
aldehyde 12 (0.88 g, 1.89 mmol) in dichloromethane (4.2 ml) at
0 ЊC. The reaction mixture was stirred for 9 min, then quenched
with aq. sodium dihydrogen phosphate (5.5 ml; 10%) and par-
titioned between dichloromethane (110 ml) and water (50 ml).
The aqueous layer was extracted with dichloromethane (2 ×
110 ml). The combined organic layers were dried over
magnesium sulfate. The solvent was removed under reduced
pressure and the residue purified by flash chromatography using
hexane–ethyl acetate (7:3) as eluent to yield:
2-Bromo-1,4,8-trimethoxynaphthalene 23
To 2-bromo-1,4,8-dimethoxy-1-naphthol 22 (300 mg, 1.06
mmol), dimethyl sulfoxide (DMSO) (0.5 ml) and THF (1.0 ml)
at 0 ЊC was added, with stirring, dimethyl sulfate (0.15 ml, 2.12
mmol). After 10 min, aq. potassium hydroxide (238 mg, 4.24
mmol in 0.3 ml) was added dropwise and the resultant purple
solution stirred for 1 h at 0 ЊC, then stirred for a further 2 h
upon reaching room temperature. The mixture was poured into
ethyl acetate (20 ml), washed with water (3 × 4 ml) and dried
over sodium sulfate. Removal of the solvent under reduced
pressure and purification of the residue by flash chromato-
graphy, using hexane–ethyl acetate (95:5) as eluent, gave the
title compound 23 (214 mg, 68%) as a white crystalline solid,
mp 84.0–85.5 ЊC (lit.,27 85–87 ЊC); νmax (CHCl3)/cmϪ1 1074s
(C–O); δC (50 MHz; CDCl3) 56.0, 56.1 (CH3, 1-, 4- or 8-OMe),
61.4 (CH3, 4- or 1-OMe), 107.7, 108.7 (CH, C-3, -7), 113.9
(quat, C-2), 114.7 (CH, C-5), 120.9 (quat, C-8a), 125.8 (CH,
C-6), 127.9 (quat, C-4a), 146.4, 151.5 (quat, C-1, C-4) and 156.1
(quat, C-8); m/z (EI) 298 [Mϩ(81Br), 100%], 296 [Mϩ(79Br), 100],
283 [Mϩ(81Br) Ϫ CH3, 34], 281 [Mϩ(79Br) Ϫ CH3, 34], 202 (92
(i)
(2ЈS,3ЈR,5ЈR)-2-[5-(tert-butyldimethylsilyloxy)-1-
hydroxy-2-(phenylmethoxy)-3-(triethylsilyloxy)hexyl]-4,8-di-
methoxy-1-naphthol 27 (114 mg, 9%) as a yellow oil (Found:
Mϩ, 670.3721. C37H58O7Si2 requires M, 670.3720); [α]D Ϫ5.817
(c 1.090, CHCl3); νmax (film)/cmϪ1 3399br w (OH), 2954s (C–H),
1609m (C᎐C) and 1070s (C–O); δ (400 MHz; CDCl3) 0.11,
᎐
H
0.12 (6H, s, SiMe2), 0.60 [6H, q, J 8.0, Si(CH2CH3)3], 0.91 (9H,
s, But), 0.94 [9H, t, J 8.0, Si(CH2CH3)3], 1.20 (3H, d, J6Ј,5Ј 6.0,
H3-6Ј), 1.92–2.02 (2H, m, H2-4Ј), 3.83 (1H, dd, J2Ј,1Ј 4.0 and J2Ј,3Ј
2.5, H-2Ј), 3.93 (3H, s, OMe), 3.99 (1H, br s, OH), 4.04 (3H, s,
OMe), 4.07–4.12 (2H, m, H-3Ј, -5Ј), 4.21 (1H, d, Jgem 11.0,
H-1ЉA), 4.66 (1H, d, Jgem 11.0, H-1ЉB), 5.47 (1H, d, J1Ј,2Ј 4.0,
H-1Ј), 6.84 (1H, dd, J6,7 7.7 and J5 0.6, H-7), 7.19–7.38 (6H, m,
H-3, Ph), 7.32 (1H, dd, J6,5 8.5 and J7,6 7.7, H-6), 7.88 (1H, dd,
J5,6 8.5 and J5,7 0.6, H-5) and 9.20 (1H, s, OH); δC (100 MHz;
CDCl3) Ϫ3.9, Ϫ3.5 (CH3, SiMe2), 5.6 (CH2, CH3CH2Si),
7.5 (CH3, CH3CH2Si), 18.8 (quat, CMe3), 24.6 (CH3, C-6Ј), 26.6
(CH3, CMe3), 44.7 (CH2, C-4Ј), 56.5, 56.8 (CH3, 2 × OMe),
66.6, 68.2 (CH, C-1Ј, -5Ј), 72.7 (CH, C-3Ј), 74.6 (CH2, C-1Љ),
84.4 (CH, C-2Ј), 105.8 (CH, C-3), 106.3 (CH, C-7), 115.8 (quat,
C-2), 116.7 (CH, C-5), 122.4 (quat, C-8a), 125.3 (CH, C-6),
128.0 (quat, C-4a), 128.5, 128.6, 128.8 [CH, Ph (last 2 peaks
coincidental)], 139.2 (quat, OCH2Ph) and 144.4, 148.6, 156.7
(quat, C-1, -4, -8); m/z (EI) 670 (Mϩ, 10%), 652 (M Ϫ H2O, 2),
540 (C31H44O6Si, 25), 520 (M Ϫ C6H18O2Si, 5), 336 (C21H20O4,
9), 317 (C16H37O2Si2, 15), 275 (C16H19O4, 10), 245 (C14H13O4, 8),
232 (C13H12O4, 48), 159 (C8H19OSi, 24), 145 (CH2OSiMe2But, 9)
and 91 (CH2Ph, 100).
1
and 187 (51). The H NMR spectrum was in agreement with
that reported in the literature.28
Dianion reaction of naphthol 22 with aldehyde 12
To 2-bromo-4,8-dimethoxy-1-naphthol 22 (6.5 mg, 0.0231
mmol) as a solution in dry THF (0.25 ml) at Ϫ78 ЊC under
nitrogen was added n-butyllithium (2.45 M; 22 µl, 0.0462
mmol). After precisely 85 s, a solution of aldehyde 12 (10.8 mg,
0.0231 mmol) in THF (0.1 ml) was added and the solution
stirred at Ϫ78 ЊC for 15 min. The reaction mixture was allowed
to warm to room temperature and was stirred for 72 h, then
quenched by the addition of saturated aq. ammonium chloride
(0.5 ml) and ether (2 ml). The mixture was poured into ether
(20 ml) and washed with water (5 ml). The aqueous phase was
extracted with ether (2 × 10 ml) and the combined extracts were
washed with brine (10 ml) and dried over sodium sulfate. Evap-
oration of the solution under reduced pressure gave a yellow oil
that was purified by flash chromatography, using hexane–ethyl
acetate (4:1) as eluent to afford:
(ii) (2ЈS,3ЈR,5ЈR)-2-[5-(tert-Butyldimethylsilyloxy)-1,3-di-
hydroxy-2-(phenylmethoxy)hexyl]-4,8-dimethoxy-1-naphthol 26
(463 mg, 44%) as a yellow oil (Found: C, 66.6; H, 8.0.
C31H44O7Si requires C, 66.8; H, 8.0%); [α]D Ϫ79.17 (c 0.192,
CHCl3); νmax (film)/cmϪ1 3396br m (OH), 2952m (C–H), 1606m
(C᎐C) and 1068br s (C–O); δ (400 MHz; CDCl3) 0.08, 0.10
᎐
H
(6H, s, SiMe2), 0.89 (9H, s, But), 1.22 (3H, d, J6Ј,5Ј 6.0, H3-6Ј),
1.79–1.86 (1H, m, H-4ЈA), 1.87–2.01 (1H, m, H-4ЈB), 3.71 (1H,
dd, J2Ј,1Ј 3.9 and J2Ј,3Ј 3.9, H-2Ј), 3.86 (1H, br s, 1Ј-OH), 3.89,
3.97 (6H, s, 2 × OMe), 4.00–4.18 (3H, m, H-3Ј, H-5Ј, 3Ј-OH),
4.28 (1H, d, Jgem 11.3, H-1ЉA), 4.52 (1H, d, Jgem 11.3, H-1ЉB),
5.51 (1H, d, J1Ј,2Ј 3.9, H-1Ј), 6.80 (1H, dd, J6,7 7.7 and J6,5 0.7 Hz,
H-7), 7.08–7.18 (6H, m, H-3, Ph), 7.27 (1H, dd, J6,5 8.6 and J7,6
7.7, H-6), 7.82 (1H, dd, J5,6 8.6 and J5,7 0.7, H-5) and 9.21 (1H,
s, OH); δC (100 MHz; CDCl3) Ϫ4.9, Ϫ4.1 (CH3, SiMe2), 17.8
(quat, CMe3), 24.4 (CH3, C-6Ј), 25.7 (CH3, CMe3), 41.7 (CH2,
C-4Ј), 55.7, 55.9 (CH3, 2 × OMe), 67.2, 69.9, 72.3 (CH, C-1Ј,
-5Ј, -3Ј), 74.1 (CH2, C-1Љ), 83.6 (CH, C-2Ј), 104.7, 105.1 (CH,
C-3, -7), 115.0 (quat, C-2), 115.8 (CH, C-5), 121.5 (quat, C-8a),
124.6 (CH, C-6), 127.1 (quat, C-4a), 127.4, 127.9, 128.0 [CH,
Ph (last 2 peaks coincidental)], 138.1 (quat, OCH2Ph) and
143.4, 147.8, 155.8 (quat, C-1, -4, -8); m/z (EI) 556 (Mϩ, 4%),
538 (M Ϫ H2O, 4), 424 (M Ϫ HOSiC6H15, 47), 336 (C21H20O4,
15), 245 (M Ϫ C7H8O Ϫ C10H23O2Si, 50), 232 (M Ϫ C18H32O3-
Si, 58), 217 (C13H13O3, 31), 205 (C12H13O3, 13), 131 (OSiMe2-
But, 5) and 91 (CH2Ph, 100).
(i) 4,8-dimethoxy-1-naphthol 21 (3.4 mg, 73%).
(ii) aldehyde 25 (2.6 mg, 24%) as a clear oil; νmax (film)/cmϪ1
3013–3106br w (Ar–H), 2739, 2718w (H–C᎐O), 1691s (C᎐O)
᎐
᎐
and 1631m (C᎐C); δ (200 MHz; CDCl ) 0.01, 0.02 (each 3H, s,
᎐
H
3
SiMe2), 0.87 (9H, s, But), 1.08 (3H, d, J 6.1, Me), 2.31–2.42 (2H,
m, H3-4), 3.69–3.86 (1H, m, H-5), 5.05 (2H, s, OCH2Ph), 6.10
(1H, dd, J3,4A 7.3 and J3,4B 7.3, H-3), 7.23–7.42 (5H, m, Ph) and
9.26 (1H, s, H-1); m/z (EI) 159 [–CH(Me)(OTBDMS), 29%],
149 [᎐C(CHO)(OCH Ph)H, 30], 91 (CH Ph, 100), 57 (But, 80)
᎐
2
2
and 43 (CH3CO, 83).
Trichlorotitanium isopropoxide29
A solution of isopropyl alcohol (1.09 g, 18.2 mmol) in dichloro-
methane (30 ml) was added to a solution of titanium tetra-
chloride (3.45 g, 18.2 mmol) in dichloromethane (40 ml) at 0 ЊC
under an atmosphere of nitrogen and the reaction mixture was
stirred for 5 min. The solvent was removed under reduced
pressure and the residue sublimed to yield trichlorotitanium
isopropoxide (2.76 g, 71%) as a highly hygroscopic yellow solid.
706
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709

View Article Online
(iii)
(2ЈS,3ЈR,5ЈR)-2,2Љ-[5-(tert-Butyldimethylsilyloxy)-3-
amine (0.1 ml, 0.71 mmol) and the mixture was stirred at
hydroxy-2-(phenylmethoxy)hexane-1,1-diyl]bis-(4,8-dimethoxy-
1-naphthol) 28 (42 mg, 6%) as a pale brown solid (Found: C,
69.3; H, 7.4. C43HϪ54O9Si requires C, 69.5; H, 7.3%); [α]D
Ϫ14.29 (c 0.364, CHCl3); νmax (film)/cmϪ1 3395br s (OH), 2952,
room temperature for 6 h. The solvent was removed at
reduced pressure and the residue purified by flash chromato-
graphy, using hexane–ethyl acetate (9:1) then (4:1) as eluent to
afford:
2930, 2855s (C–H), 1608s (C᎐C), 1070br s (C–O); δ (400 MHz;
(i)
(2ЈR,3ЈR,5ЈR)-2-[3-Acetoxy-5-(tert-butyldimethylsilyl-
᎐
H
CDCl3) Ϫ0.18, Ϫ0.09 (6H, s, SiMe2), 0.71 (9H, s, But), 1.02
(3H, d, J6Ј,5Ј 6.0, H3-6Ј), 1.67–1.73 (1H, m, H-4ЈA), 2.11–2.21
(1H, m, H-4ЈB), 3.62, 3.74, 3.83, 3.90 (12H, s, 4 × OMe), 3.84–
3.87 (1H, m, H-3Ј), 3.88 (1H, br s, OH), 3.91–3.94 (1H, m, H5Ј),
4.29 (1H, d, Jgem 11.6, OCHAPh), 4.39–4.42 (1H, m, H-2Ј), 4.69
(1H, d, Jgem 11.6, OCHBPh), 5.42 (1H, d, J1Ј,2Ј 7.6, H-1Ј), 6.66,
6.68 (2H, d, J6,7 8.0 and J6Љ,7Љ 8.0, H-7, H-7Љ), 6.95 (1H, s, H-3 or
H-3Љ), 6.96–7.17 (5H, m, Ph), 7.13–7.16 (2H, m, H-6 or H-6Љ),
7.40 (1H, s, H-3Љ or -3), 7.65, 7.70 (2H, d, J5,6 8.6 and J5Љ,6Љ 8.6,
H-5, H-5Љ) and 9.35, 9.43 (2H, s, 2 × OH); δC (100 MHz;
CDCl3) Ϫ5.0, Ϫ4.3 (CH3, SiMe2), 17.9 (quat, CMe3), 24.2
(CH3, C-6), 25.8 (CH3, CMe3), 38.4 (CH, C-1Ј), 41.3 (CH2,
C-4Ј), 55.7, 55.8, 55.9, 56.0 (CH3, 4 × OMe), 65.8 (CH, C-5Ј),
73.2 (CH, C-3Ј), 74.4 (CH2, OCH2Ph), 85.3 (CH, C-2Ј), 104.8,
104.9 (CH, C-7, -7Љ), 108.2, 108.9 (CH, C-3, -3Љ), 115.5, 115.6
(quat, C-2, -2Љ), 115.7, 115.8 (CH, C-5, -5Љ), 122.0, 122.4 (quat,
C-8a, -8aЉ), 124.4, 124.5 (CH, C-6, -6Љ), 126.7, 126.8 (quat,
C-4a, -4aЉ), 126.9, 127.3, 127.8 [CH, Ph (last 2 peaks coinci-
dental)], 139.3 (quat, OCH2Ph), 144.6, 145.5 (quat, C-4, -4Љ),
147.3, 147.6 (quat, C-1, -1Љ) and 155.8 (quat, C-8, -8Љ); m/z (EI)
742 (Mϩ, 17%), 710 (M Ϫ CH3OH, 2), 634 (M Ϫ HOC7H7, 2),
538 (M Ϫ C12H12O3, 2), 419 (C25H23O6, 100), 387 (C24H19O5,
10), 159 (C8H19OSi, 6), 145 (CH2OSiMe2But, 5) and 91 (CH2Ph,
29).
oxy)-2-(phenylmethoxy)hexanoyl]-4,8-dimethoxy-1-naphthol
31 (37 mg, 41%) as a fluorescent yellow oil (Found: C, 66.5; H,
7.5. C33H44O8Si requires C, 66.4; H, 7.4%); [α]D Ϫ14.10 (c 0.156,
CHCl3); νmax (film)/cmϪ1 3327br w (OH), 2955, 2855m (C–H),
1732s (C᎐O, acetate), 1626s (C᎐O), 1244br s (C–O, acetate) and
᎐
᎐
1074s (C–O); δH (200 MHz; CDCl3) Ϫ0.20, Ϫ0.09 (6H, s,
SiMe2), 0.68 (9H, s, But), 1.01 (3H, d, J6Ј,5Ј 12.5, H3-6Ј), 1.79
(1H, ddd, Jgem 14.7, J4ЈA,5Ј 6.2 and J4ЈA,3Ј 2.8, H-4ЈA), 2.00 (3H, s,
OCOCH3), 2.03 (1H, ddd, Jgem 14.7, J4ЈB,3Ј 9.2 and J4ЈB,5Ј 2.8,
H-4ЈB), 3.78–3.81 (1H, m, H-5Ј), 3.98, 4.05 (6H, s, 2 × OMe),
4.38 (1H, d, Jgem 12.3, H-1ЉA), 4.84 (1H, d, Jgem 12.3, H-1ЉB),
5.21 (1H, d, J2Ј,3Ј 2.8, H-2Ј), 5.40 (1H, ddd, J3Ј,4ЈB 9.2, J3Ј,2Ј 2.8
and J3Ј,4ЈA 2.8, H-3Ј), 6.97 (1H, dd, J6,7 8.1 and J7,5 0.8, H-7),
7.30–7.36 (6H, m, H-3, Ph), 7.57 (1H, dd, J7,6 8.1 and J6,5 8.1,
H-6), 7.82 (1H, dd, J5,6 8.1 and J5,7 0.8, H-5) and 14.20 (1H, s,
OH); δC (50 MHz; CDCl3) Ϫ5.2, Ϫ4.7 (CH3, SiMe2), 17.8
(quat, CMe3), 21.1 (CH3, COCH3), 23.1 (CH3, C-6Ј), 25.5
(CH3, CMe3), 37.4 (CH2, C-4Ј), 56.1, 56.3 (CH3, 2 × OMe),
65.6 (CH, C-5Ј), 71.8 (CH, C-3Ј), 72.2 (CH2, C-1Љ), 81.2 (CH,
C-2Ј), 101.1 (CH, C-3), 107.5 (CH, C-7), 112.0 (quat, C-2),
114.7 (CH, C-5), 116.6 (quat, C-8a), 127.9, 128.0, 128.3 [CH,
Ph (last 2 peaks coincidental)], 130.8 (CH, C-6), 133.1 (quat,
C-4a), 137.5 (quat, OCH2Ph), 147.2 (quat, C-4), 159.6, 160.0
(quat, C-1, -8), 170.7 (quat, C᎐O) and 200.3 (quat, C-1Ј); m/z
᎐
(CI) 597 (MHϩ, 3%), 566 (MH Ϫ HOCH3, 1), 537 (MH Ϫ
HOCOCH3, 2), 465 (MH Ϫ HOSiMe2But, 2), 431 (MH Ϫ
C9H10O3, 5), 404 (M Ϫ HOCOCH3 Ϫ HOSiMe2But, 4), 378
(C23H21O5, 61), 300 (43), 279 (100), 219 (C13H15O3, 30) and 205
(C12H13O3, 32).
(2ЈR,3ЈR,5ЈR)-2-[5-(tert-Butyldimethylsilyloxy)-3-hydroxy-2-
(phenylmethoxy)hexanoyl]-4,8-dimethoxy-1-naphthol 29
Manganese dioxide (130 mg, 1.50 mmol) was added to a solu-
tion of alcohol 26 (167 mg, 0.30 mmol) in dichloromethane (3
ml) and the reaction mixture was stirred for 5 h at room tem-
perature under an atmosphere of nitrogen. The reaction mix-
ture was filtered through Celite and the solvent removed under
reduced pressure. The residue was purified by flash chromato-
graphy using hexane–ethyl acetate (8:2) as eluent to yield the
title compound 29 (103 mg, 62%) as a bright yellow oil (Found:
C, 66.8; H, 7.6. C31H42O7Si requires C, 67.1; H, 7.6%); [α]D
ϩ21.19 (c 0.800, CHCl3); νmax (film)/cmϪ1 3494br w (OH), 2952,
(ii) (2ЈR,3ЈR,5ЈR)-2-[3-Acetoxy-5-(tert-butyldimethylsilyl-
oxy)-2-(phenylmethoxy)hexanoyl]-4,8-dimethoxy-1-naphthyl
acetate 30 (23 mg, 25%) as a pale yellow oil (Found: Mϩ,
638.2928. C35H46O9Si requires Mϩ, 638.2911); [α]D Ϫ12.75
(c 1.992, CHCl3); νmax (film)/cmϪ1 2930, 2856m (C–H), 1740s
(C᎐O, acetate), 1618s (C᎐O), 1243, 1215br s (C–O, acetate) and
᎐
᎐
1073s (C–O); δH (400 MHz; CDCl3) Ϫ0.08, Ϫ0.02 (6H, s,
SiMe2), 0.79 (9H, s, But), 1.05 (3H, d, J6Ј,5Ј 6.1 Hz, H3-6Ј),
1.70–1.77 (1H, m, H-4ЈA), 1.98 (3H, s, 3Ј-OCOCH3), 2.01–
2.08 (1H, m, H-4ЈB), 2.35 (3H, s, 1-OCOCH3), 3.80–3.82 (1H,
m, H-5Ј), 3.97, 4.01 (6H, s, 2 × OMe), 4.50 (1H, d, Jgem 12.3,
H-1ЉA), 4.85 (1H, d, Jgem 12.3, H-1ЉB), 5.00 (1H, d, J2Ј,3Ј 3.2,
H-2Ј), 5.20–5.27 (1H, m, H-3Ј), 6.95 (1H, dd, J6,7 8.0 and J5,5
0.7, H-7), 7.14 (1H, s, H-3), 7.31–7.38 (5H, m, Ph), 7.51 (1H,
dd, J7,6 8.0 and J6,5 8.0, H-6) and 7.90 (1H, dd, J5,6 8.0 and
J5,7 0.7, H-5); δC (50 MHz; CDCl3) Ϫ5.2, Ϫ4.9 (CH3, SiMe2),
17.8 (quat, CMe3), 20.1, 20.9 (CH3, 2 × COCH3), 23.0 (CH3,
C-6Ј), 25.6 (CH3, CMe3), 38.4 (CH2, C-4Ј), 55.8, 56.1 (CH3,
2 × OMe), 65.6 (CH, C-5Ј), 71.5 (CH, C-3Ј), 72.3 (CH2,
C-1Љ), 81.5 (CH, C-2Ј), 102.4 (CH, C-3), 107.7 (CH, C-7), 114.7
(CH, C-5), 119.6 (quat, C-2), 125.4 (quat, C-8a), 127.8 (quat,
C-4a), 128.0, 128.3, 128.4 [CH, Ph (last 2 peaks coinci-
dental)], 130.2 (CH, C-6), 137.3 (quat, OCH2Ph), 139.8 (quat,
C-4), 152.8, 156.7 (quat, C-1, -8), 170.1, 170.3 (quat,
2850m (C–H), 1616m (C᎐O), 1600m (C᎐C) and 1074s (C–O);
᎐
᎐
δH (400 MHz; CDCl3) 0.02, 0.04 (6H, s, SiMe2), 0.83 (9H, s,
But), 1.15 (3H, d, J6Ј,5Ј 6.0, H3-6Ј), 1.78–1.80 (2H, m, H2-4Ј),
3.90, 4.06 (6H, s, 2 × OMe), 4.00–4.05 (2H, m, H-5Ј, OH),
4.28–4.32 (1H, m, H-3Ј), 4.56 (1H, d, Jgem 11.7, H-1ЉA), 4.75
(1H, d, Jgem 11.7, H-1ЉB), 5.04 (1H, d, J2Ј,3Ј 4.5, H-2Ј), 6.95 (1H,
d, J6,7 8.0, H-7), 7.22 (1H, s, H-3), 7.24–7.38 (5H, m, Ph), 7.54
(1H, dd, J7,6 8.0 and J6,5 8.0, H-6), 7.83 (1H, dd, J5,6 8.0 and J5,7
0.7, H-5) and 12.90 (1H, br s, 1-OH); δC (100 MHz; CDCl3)
Ϫ5.0, Ϫ4.2 (CH3, SiMe2), 17.7 (quat, CMe3), 24.2 (CH3, C-6Ј),
25.7 (CH3, CMe3), 40.9 (CH2, C-4Ј), 55.6, 56.2 (CH3, 2 × OMe),
69.4, 72.1 (CH, C-5Ј, -3Ј), 72.4 (CH2, C-1Љ), 85.7, 102.5, 107.0
(CH, C-2Ј, -3, -7), 114.4 (quat, C-2), 115.0 (CH, C-5), 116.1
(quat, C-8a), 127.6, 127.9, 128.2 [CH, Ph (last 2 peaks coinci-
dental)], 129.8 (CH, C-6), 132.2, 137.7 (quat, C-4a, OCH2Ph),
147.0, 156.9, 158.6 (quat, C-1, -4, -8) and 201.1 (quat, C-1Ј); m/z
(EI) 554 (Mϩ, 3%), 445 (M Ϫ C7H9O, 2), 406 (M Ϫ C6H16O2Si,
3), 352 (C21H20O5, 24), 261 (C14H13O5, 23), 246 (C14H14O4, 11),
231 (C13H11O4, 100), 205 (C12H13O3, 11), 160 (C8H20OSi, 14),
145 (CH2OSiMe2But, 57), 131 (C6H15OSi, 9) and 91 (CH2Ph,
89).
2 × C᎐O) and 197.2 (quat, C-1Ј); m/z (CI) 639 (MHϩ, 19%),
᎐
507 (MH Ϫ C6H16OSi, 23), 337 (C19H33O3Si, 6), 273
(C16H19O4, 55), 231 (C13H11O4, 15), 159 (C8H9OSi, 28), 143
(C7H15OSi, 66) and 107 (C7H7O, 100).
(iii)
(2ЈR,3ЈR,5ЈR)-2-[5-(tert-Butyldimethylsilyloxy)-3-
hydroxy-2-(phenylmethoxy)hexanoyl]-4,8-dimethoxy-1-naph-
thyl acetate 32 (18 mg, 20%) as a pale yellow oil (Found:
Mϩ, 596.2821. C33H44O8Si requires M, 596.2805); [α]D Ϫ13.28
(c 0.256, CHCl3); νmax (film)/cmϪ1 3496br w (OH), 2930, 2855m
Acetylation of diol 29
Without using DMAP as a catalyst. To a solution of diol 29
(79 mg, 0.14 mmol) in dichloromethane (2.8 ml) was added
acetic anhydride (0.067 ml, 0.71 mmol) followed by triethyl-
(C–H), 1766m (C᎐O, acetate), 1600m (C᎐O), 1265br s (C–O,
᎐
᎐
acetate) and 1071s (C–O); δH (400 MHz; CDCl3) 0.02, 0.04 (6H,
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709 707

View Article Online
s, SiMe2), 0.85 (9H, s, But), 1.13 (3H, d, J6Ј,5Ј 5.9, H-6Ј), 1.11–
1.73 (2H, m, H2-4Ј), 2.28 (3H, s, OCOCH3), 3.46 (1H, s, OH),
3.90, 3.91 (6H, s, 2 × OMe), 4.00–4.05 (1H, m, H-5Ј), 4.15–4.18
(1H, m, H-3Ј), 4.56 (1H, d, Jgem 11.8, H-1ЉA), 4.70 (1H, d, J2Ј,3Ј
4.6, H-2Ј), 4.73 (1H, d, Jgem 11.8, H-1ЉB), 6.91 (1H, d, J6,7 8.0,
H-7), 7.04 (1H, s, H-3), 7.23–7.32 (5H, m, Ph), 7.46 (1H, dd, J7,6
8.0 and J6,5 8.0, H-6) and 7.86 (1H, d, J5,6 8.0, H-5); δC (50 MHz;
CDCl3) Ϫ4.9, Ϫ4.0 (CH3, SiMe2), 17.9 (quat, CMe3), 21.0
(CH3, COCH3), 24.3 (CH3, C-6Ј), 25.8 (CH3, CMe3), 40.7 (CH2,
C-4Ј), 55.8, 56.1 (CH3, 2 × OMe), 69.5 (CH, C-5Ј), 71.9 (CH,
C-3Ј), 72.6 (CH2, C-1Љ), 85.9 (CH, C-2Ј), 102.8 (CH, C-3), 107.7
(CH, C-7), 114.9 (CH, C-5), 119.5 (quat, C-2), 127.3 (quat,
C-4a, -8a), 127.8, 128.1, 128.4 [CH, Ph (last 2 peaks coinci-
dental)], 130.1 (CH, C-6), 137.6 (quat, OCH2Ph), 139.5 (quat,
665.2756. C36H44O10Si requires MH, 665.2782); νmax (film)/cmϪ1
3320br w (OH), 2954, 2923m (C–H), 1778s (C᎐O, γ-lactone),
᎐
1741s (C᎐OCH ) and 1668m (C᎐OCHOBn); δ (400 MHz;
᎐
᎐
3
H
CDCl3) Ϫ0.19, Ϫ0.08, Ϫ0.06*, Ϫ0.02* (6H, s, SiMe2), 0.70,
0.78* (9H, s, But), 1.02, 1.05* (3H, d, J6Ј,5Ј 6.1, H3-6Ј), 1.72,
1.87* (1H, m, H-4ЈA), 1.89, 1.98* (3H, s, OCOCH3), 2.04–2.09
(1H, m, H-4ЈB), 3.04–3.11 (2H, m, H2-9), 3.71–3.77 (1H, m,
H-5Ј), 4.11 (3H, s, OMe), 4.52, 4.58* (1H, d, Jgem 7.7,
OCHAPh), 4.83, 4.90* (1H, d, Jgem 7.7, OCHBPh), 5.33, 5.45*
(1H, d, J2Ј,3Ј 4.0, H-2Ј), 5.36–5.56 (2H, m, H-3Ј, H-9a), 6.36,
6.69* (1H, d, J6b,9a 5.9, H-6b), 6.95–7.00 (1H, m, H-3), 7.26–
7.52 (7H, m, H-1, -2, Ph) and 10.14, 10.31* (1H, s, OH); δC (50
MHz; CDCl3) Ϫ4.9, Ϫ4.7, Ϫ4.6, Ϫ3.6 (CH3, SiMe2), 15.2, 18.0
(quat, CMe3), 21.1, 21.2 (CH3, COCH3), 23.1, 23.4 (CH3, C-6Ј),
25.7 (CH3, CMe3), 35.7 (CH2, C-9), 38.5, 39.8 (CH2, C-4Ј), 56.7
(CH3, OMe), 65.9, 66.1 (CH, C-5Ј), 71.1, 71.7 (CH, C-3Ј), 72.4,
72.7 (CH2, OCH2Ph), 81.4, 81.9 (CH, C-9a), 84.5, 84.8 (CH,
C-2Ј), 85.2, 85.4 (CH, C-6b), 107.6 (quat, C-6), 107.7 (quat,
C-6a), 116.2 (CH, C-3), 116.5 (CH, C-1), 124.9 (quat, C-4a),
127.5, 127.8, 128.2 [CH, Ph (last 2 peaks coincidental)], 128.4
(quat, C-10b), 129.4 (CH, C-2), 138.3 (quat, OCH2Ph), 150.9
(quat, C-10a), 152.4, 152.6 (quat, C-5), 157.4, 157.9 (quat, C-4),
170.0, 170.1 (quat, COCH3), 174.2 (quat, C-8) and 198.5 (quat,
C-1Ј); m/z (LSIMS, NBA matrix) 665 (MHϩ, 33%), 619
(MH Ϫ CH2O2, 13), 533 (M Ϫ C6H15OSi, 12), 473 (M Ϫ C8H19-
O3Si, 9), 389 (M Ϫ C12H23O5Si, 15), 299 (MH Ϫ C20H34O4Si,
100) and 255 (M Ϫ C21H33O6Si, 18).
C-4), 152.7, 156.4 (quat, C-1, -8), 170.1 (quat, C᎐O) and 200.2
᎐
(quat, C-1Ј); m/z (EI) 596 (Mϩ, 2%), 554 (C31H42O7Si, 1), 445
(M Ϫ HOC7H7 Ϫ COCH3, 2), 352 (C21H20O5, 3), 337 (C19H33-
O3Si, 3), 273 (C16H17O4, 10), 261 (C14H13O5, 35), 248 (C14H16O4,
18), 231 (C13H11O4, 100), 217 (C13H13O3, 10), 205 (C12H13O3, 9),
159 (C8H19OSi, 19), 145 (CH2OSiMe2But, 54) and 91 (CH2Ph,
72) and 57 (C4H9, 35).
Using DMAP as a catalyst. To a solution of diol 29 (11.5 mg,
0.021 mmol) in dichloromethane (0.42 ml) were added acetic
anhydride (4.1 µl, 0.044 mmol), triethylamine (6.1 µl, 0.044
mmol) and a catalytic quantity of DMAP and the reaction
mixture was stirred at room temperature for 5 min. Removal of
the solvent under reduced pressure afforded a brown oil, which
was purified by flash chromatography using hexane–ethyl
acetate (4:1) as eluent to yield diacetate 30 (9.1 mg, 69%) as a
pale yellow oil for which the 1H NMR data were consistent with
those reported above.
(3aR,5R,11bR,1ЈR,2ЈR,4ЈR)- or (3aS,5S,11bS,1ЈR,2ЈR,4ЈR)-5-
[2-Acetoxy-4-hydroxy-1-(phenylmethoxy)pentyl]-3,3a,5,11b-
tetrahydro-5-hydroxy-7-methoxyfuro[3,2-b]naphtho[2,3-d]-
pyran-2,6,11-trione 35
Deacetylation of acetate 32
A solution of CAN nitrate (39 mg, 0.070 mmol) in water
(0.073 ml) was added dropwise to a solution of furonaphtho-
furan 34 (16 mg, 0.023 mmol) in acetonitrile (1.3 ml) at room
temperature and the mixture was stirred for 45 s. Hydro-
fluoric acid (0.07 ml; 5% w/w) was then added dropwise and
the mixture was stirred for 2 h. The reaction mixture was
poured into ethyl acetate (5 ml), washed with water (2 × 3 ml)
and dried over sodium sulfate. Removal of the solvent under
reduced pressure gave a yellow oil, which was purified by
flash chromatography using hexane–ethyl acetate (75:25) as
eluent to give the title compound 35 (6.5 mg, 48%) as a yellow
oil (Found: MHϩ, 567.1854. C30H30O11 requires MH,
567.1866); νmax (film)/cmϪ1 3446br w (OH), 2957–2924m
To a suspension of guanidine hydrochloride (2.8 mg, 0.029
mmol) in dry ethanol (0.095 ml) was added potassium tert-
butoxide (2.7 mg, 0.024 mmol) and the solution was stirred for
5 min at room temperature. To the mixture was added a solu-
tion of acetate 32 (14.3 mg, 0.024 mmol) in dichloromethane
(0.2 ml). After 5 min, the reaction mixture was partitioned
between water (5 ml) and dichloromethane (5 ml). The aqueous
layer was extracted with dichloromethane (2 × 5 ml), and the
combined organic layers washed with water (2 × 5 ml) and
dried over sodium sulfate. Removal of the solvent under
reduced pressure afforded a yellow oil, which was purified by
flash chromatography using hexane–ethyl acetate (8:2) as elu-
ent to afford acetate 31 (5.8 mg, 47%) as a fluorescent yellow oil
(C–H), 1783s (C᎐O, γ-lactone), 1739s (COCH ) and 1664m
᎐
3
(C᎐O, quinone); δ (400 MHz; CDCl3) 1.37 (3H, d, J5Ј,4Ј 6.2,
1
᎐
H
for which the H NMR spectrum was in agreement with that
H-5Ј), 1.71–1.78 (1H, m, H-3ЈA), 1.92–2.03 (1H, m, H-3ЈB),
1.99 (3H, s, OCOCH3), 2.68 (1H, d, Jgem 17.6, H-3A), 2.99
(1H, dd, Jgem 17.6 and J3B,3a 5.0, H-3B), 3.52 (1H, d, J1Ј,2Ј 10.2,
H-1Ј), 3.99 (3H, s, OMe), 4.22 (1H, ddd, J2Ј,3ЈA, 10.4, J2Ј,1Ј
10.2 and J2Ј,3ЈB 2.4, H-2Ј), 4.35 (1H, br s, OH), 4.73 (1H, d,
Jgem 11.1, H-1ЉA), 4.94 (1H, dd, J3a,3B 5.0 and J3a,11b 2.4,
H-3a), 4.95 (1H, d, Jgem 11.1, H-1ЉB), 5.03 (1H, br s, OH), 5.17–
5.20 (1H, m, H-4Ј), 5.27 (1H, d, J11b,3a 2.4, H-11b), 7.24 (1H,
d, J8,9 8.0, H-8), 7.33–7.39 (5H, m, Ph), 7.49 (1H, dd, J9,8 8.0
and J9,10 8.0, H-9) and 7.77 (1H, dd, J10,9 8.0 and J10,8 0.7, H-10);
δC (100 MHz; CDCl3) 14.8 (CH3, C-5Ј), 19.4 (CH3, COCH3),
37.4 (CH2, C-3), 37.9 (CH2, C-3Ј), 56.9 (CH3, OMe), 66.0 (CH,
C-2Ј), 67.9 (CH, C-3a), 68.7 (CH, C-4Ј), 69.9 (CH, C-11b), 76.7
(CH2, C-1Љ), 83.8 (CH, C-1Ј), 91.1 (quat, C-5), 94.4 (quat,
C-6a), 117.6 (CH, C-8), 119.8 (CH, C-10), 129.0 (quat, C-10a),
129.0, 129.1, 129.3 [CH, Ph (last 2 peaks coincidental)], 130.3
(quat, C-11a), 131.1 (CH, C-9), 137.5 (quat, OCH2Ph), 147.3
(quat, C-5a), 157.4 (quat, C-7), 171.1 (quat, COCH3) and 175.0,
182.1, 188.3 (quat, C-2, -11, -6); m/z (CI) 584 (MHϩ ϩ NH3,
62%), 567 (MHϩ, 16), 549 (MϩNH3 Ϫ OH Ϫ OH, 15), 524
(MHϩNH3 Ϫ HOCOCH3, 3), 479 (MϩNH3 Ϫ C4H8O3, 9),
296 (44) and 148 (100).
reported above.
(6bR,9aR,2ЈR,3ЈR,5ЈR)- and (6bS,9aS,2ЈR,3ЈR,5ЈR)-6-[3-
Acetoxy-5-(tert-butyldimethylsilyloxy)-2-(phenylmethoxy)-
hexanoyl]-9,9a-dihydro-5-hydroxy-4-methoxyfuro[3,2-b]-
naphtho[2,1-d]furan-8(6bH)-one 34
A solution of CAN nitrate (161 mg, 0.29 mmol) in water (1.0
ml) was added dropwise to a vigorously stirred solution of
naphthalene acetate 31 (70 mg, 0.12 mmol) in acetonitrile (7.4
ml) at room temperature and the mixture was stirred for exactly
1 min. Anhydrous magnesium sulfate was added and the result-
ant suspension was immediately cooled to 0 ЊC. After 1 min, a
solution of 2-(trimethylsilyloxy)furan (0.039 ml, 0.23 mmol) in
acetonitrile (1.2 ml) was added dropwise and the mixture was
stirred at 0 ЊC for 15 min, diluted with dichloromethane (30 ml),
washed with water (2 × 15 ml) and dried over magnesium
sulfate. The solvent was removed under reduced pressure to give
an orange oil, which was purified by flash chromatography
using hexane–ethyl acetate (4:1) as eluent to afford the title
compound (33 mg, 42%) as a yellow semi-solid and as a 1:1
(34a:34b) mixture of stereoisomers (1H NMR) (Found: MHϩ,
708
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709

View Article Online
3 H. W. Moore, Science, 1977, 197, 527; H. W. Moore and R.
(3aR,5R,11bR,3ЈS,4ЈR,6ЈR)- and (3aR,5S,11bR,3ЈS,4ЈR,6ЈR)-
4Ј-Acetoxy-3a,11b,3Ј,4Ј,5Ј,6Ј-hexahydro-7-methoxy-3Ј-(phenyl-
methoxy)-6Ј-methylspiro{5H-furo[3,2-b]naphtho[2,3-d]pyran-
5,2Ј-[2H-pyran}-2,6,11(3H)-trione 36a and 36b
Czerniak, Med. Res. Rev., 1981, 1, 249.
4 N. Tsuji, T. Kamagauchi, H. Nakai and M. Shiro, Tetrahedron Lett.,
1983, 24, 389.
5 T. Kometani, Y. Takeuchi and E. Yoshii, J. Org. Chem., 1983, 48,
2311.
To a solution of furonaphthopyrantrione 35 (3.4 mg, 6.0 µmol)
in dichloromethane (1 ml) was added a catalytic quantity of
camphor-10-sulfonic acid (ca. 0.12 mg). The mixture was
heated gently under reflux for 2 days. Removal of the solvent
under reduced pressure gave a yellow oil, which was purified by
flash chromatography using hexane–ethyl acetate (6:4) as elu-
ent to give the title compound (1.7 mg, 52%) as a yellow oil and
as a 3.2:1 (36a:36b¶) mixture of stereoisomers (1H NMR)
(Found: MHϩ, 549.1747. C30H28O10 requires MH, 549.1761);
δH (400 MHz; CDCl3) 1.37* (0.7H, d, J 5.8, Me), 1.42 (2.3H, d,
(Found: MHϩ, 549.1747. C30H28O10 requires MH, 549.1761);
δH (400 MHz; CDCl3) 1.37* (0.7H, d, J 5.8, Me), 1.42 (2.3H, d,
J 6.1, Me), 2.00, 2.03* (3H, s, COCH3), 2.00–2.03 (1H, m,
H-5ЈA), 2.10–2.13 (1H, m, H-5ЈB), 2.68* (0.24H, d, Jgem 17.6,
H-3A), 2.74 (0.76H d, Jgem 17.6, H-3A), 3.00 (1H, dd, Jgem 17.6
and J3B,3a 4.9, H-3B), 3.47 (0.76H, d, J3Ј,4Ј 9.8, H-3Ј), 3.52*
(0.24H, d, J3Ј,4Ј 9.8, H-3Ј), 3.98, 4.00* (3H, s, OMe), 4.21–4.28
(1H, m, H-4Ј), 4.67 (0.76H, d, Jgem 11.3, OCHAPh), 4.68–4.70
(0.76H, m, H-3a), 4.74* (0.24H, d, Jgem 11.1, OCHAPh), 4.92
(0.76H, d, Jgem 11.3, OCHBPh), 4.94–4.96* (0.24H, m, H-3a),
4.95* (0.24H, d, Jgem 11.1, OCHBPh), 5.20–5.25 (1H, m, H-6Ј),
5.27* (0.24H, d, J11b,3a 2.8, H-11b), 5.31 (0.76H, d, J11b,3a 2.8,
H-11b), 7.30–7.36 (6H, m, H-8, Ph), 7.47 (1H, t, J9,8 8.0 and
J9,10 8.0, H-9) and 7.75 (1H, d, J10,9 8.0, H-10); m/z (FAB, NBA
matrix) 549 (MHϩ, 2%), 521 (MH Ϫ CO, 2), 489 (MH Ϫ
HOCOCH3, 2), 419 (9), 155 (73), 138 (100), 91 (CH2Ph, 79), 78
(33).
6 M. A. Brimble and M. R. Nairn, Molecules, 1996, 1, 3.
7 For a preliminary communication see: M. A. Brimble, M. R. Nairn
and J. Park, Org. Lett., 1999, 1459.
8 D. A. Evans and A. E. Weber, J. Am. Chem. Soc., 1986, 108, 6757.
9 E. J. Corey and G. Schmidt, Tetrahedron Lett., 1979, 2317.
10 K. Ohta, O. Miyagawa, H. Tsutsui and O. Mitsunobu, Bull. Chem.
Soc. Jpn., 1993, 66, 523.
11 D. A. Evans, J. R. Gage, J. L. Leighton and A. S. Kim, J. Org.
Chem., 1992, 57, 1961.
12 D. A. Evans, J. R. Gage and J. L. Leighton, J. Am. Chem. Soc., 1992,
114, 9434.
13 T. Mukaiyama and N. Iwasawa, Chem. Lett., 1984, 753.
14 L. N. Pridgen, A. F. Abdel-Magid, I. Lantos, S. Shilcrat and
D. S. Eggleston, J. Org. Chem., 1993, 58, 5107.
15 R. O. Duthaler, P. Herold, S. Wyler-Helfer and M. Riediker,
Helv. Chim. Acta, 1990, 73, 659; R. O. Duthaler and A. Hafner,
Chem. Rev., 1992, 92, 807.
16 D. A. Evans, J. S. Clark, R. Metternich, V. J. Novack and
G. S. Sheppard, J. Am. Chem. Soc., 1990, 112, 866.
17 T. Mukaiyama, S. Kobayashi and T. Sato, Tetrahedron, 1990, 46,
4653.
18 M. E. Jung and J. A. Hagenah, J. Org. Chem., 1987, 52, 1889.
19 F. Bigi, G. Casnati, G. Sartori and G. Araldi, Gazz. Chim. Ital.,
1990, 120, 413; F. Bigi, G. Casnati, G. Sartori, G. Araldi and
G. Bocelli, Tetrahedron Lett., 1989, 30, 1121; F. Bigi, G. Casnati,
G. Sartori, C. Dalprato and R. Bortolini, Tetrahedron: Asymmetry,
1990, 1, 861.
20 G. Casiraghi, M. Cornia and G. Rassu, J. Org. Chem., 1988, 53,
4919; M. Cornia and G. Casiraghi, Tetrahedron, 1989, 45, 2869;
G. Casiraghi, F. Bigi, G. Casnati, G. Sartori, P. Soncini, G. G. Fava
and M. F. Belichi, J. Org. Chem., 1988, 53, 1799.
21 M. A. Brimble and E. Oppen, Synth. Commun., 1997, 27, 989.
22 N. Kunesch, C. Meit and J. Poisson, Tetrahedron Lett., 1987, 28,
3569.
Acknowledgements
23 M. A. Brimble and S. J. Stuart, J. Chem. Soc., Perkin Trans. 1, 1990,
881.
24 K. Mori and S. Maemoto, Liebigs Ann. Chem., 1987, 863.
25 T. Mukaiyama, N. Iwasawa, R. W. Stevens and T. Haga,
Tetrahedron, 1984, 40, 1381.
26 R. L. Hannan, R. B. Barber and H. Rapoport, J. Org. Chem., 1979,
44, 2153.
We thank the Australian Research Council and The University
of Sydney for financial support.
¶ The asterisk denotes resonances assigned to the minor isomer.
27 W. Williams, X. Sun and D. Jeberatnam, J. Org. Chem., 1997, 62,
4364.
28 K. H. Dotz and M. Popall, Chem. Ber., 1988, 121, 665.
29 B. Bachand and J. Wuest, Organometallics, 1991, 10, 2015.
References
1 N. Tsuji, M. Kobayashi, Y. Wakisaka, Y. Kawamura, M. Mayama
and K. Matsumoto, J. Antibiot. (Tokyo), 1976, 29, 7; N. Tsuji,
M. Kobayashi, Y. Terui and K. Tori, Tetrahedron, 1976, 32, 2207.
2 For a review see: M. A. Brimble, L. J. Duncalf and M. R. Nairn,
Nat. Prod. Rep., 1999, 16, 267.
Paper a909243i
J. Chem. Soc., Perkin Trans. 1, 2000, 697–709
709