The total synthesis of (+)-aspicilin using 2,3-butane diacetal protected butane tetrols via a chiral memory protocol

Article abstract of DOI:10.1139/v01-144

The total syntheses of the polyhydroxylated macrolactone (+)-aspicilin and a diastereoisomer have been achieved via a concise route, starting from the spatially desymmetrized (R′,R′,R,S)-2,3-butanediacetal-protected butane tetrol 13. The key steps include a regioselective silyl protection of 13 and a stereoselective Lewis acid mediated addition of allyltributylstannane to the equatorially disposed aldehyde of 4. Macrocyclization is achieved using ring closing metathesis, after which selective hydrogenation and protecting group removal yields the natural product.

Full text of DOI:10.1139/v01-144

1668
The total synthesis of (+)-aspicilin using 2,3-
butane diacetal protected butane tetrols via a
chiral memory protocol
Darren J. Dixon, Alison C. Foster, and Steven V. Ley
Abstract: The total syntheses of the polyhydroxylated macrolactone (+)-aspicilin and a diastereoisomer have been
achieved via a concise route, starting from the spatially desymmetrized (R>,R>,R,S)-2,3-butanediacetal-protected butane
tetrol 13. The key steps include a regioselective silyl protection of 13 and a stereoselective Lewis acid mediated addi-
tion of allyltributylstannane to the equatorially disposed aldehyde of 4. Macrocyclization is achieved using ring closing
metathesis, after which selective hydrogenation and protecting group removal yields the natural product.
Key words: aspicilin, butanediacetal, desymmetrization, macrolactone, metathesis.
Résumé : Les synthèses totales de la macrolactone polyhydroxylée (+)-aspiciline et d’une de ses diastéréoisomères ont
été effectvé par le biais d’une route concise partant d’un butanetétrol désymétrisé d’un point de vue spacial sous la
forme de (R>,R>,R,S)-butanediacétal protégé, 13. Les étapes clés impliquent une protection régiosélective du composé 13
par un silyle et une addition stéréosélective, catalysée par un acide de Lewis, de l’allyltributylstannane sur un aldéhyde
en position équatoriale du composé 4. On réalise la macrocyclisation en exploitant à une réaction de fermeture de cycle
par métathèse, suivie d’une hydrogénation sélective et d’une élimination du groupe protecteur pour conduire au produit
naturel.
Mots clés : aspiciline, butanediacétal, désymétrisation, macrolactone, métathèse.
[Traduit par la Rédaction] Dixon et al. 1680
Introduction
Previous work developed in our group using the homochiral
C2 symmetric bis(dihydropyran) (BDP) unit to protect 1,2-
diols was one solution to the problem, allowing for the
desymmetrization of meso compounds such as glycerol and
myo-inositol (4–7). This protecting group makes use of the
anomeric stabilization effect and the preference for all other
substituents to be placed in equatorial environments. Here
we report in full a cheaper alternative process that relies on
the use of 1,2-butane diacetals operating through a chiral
memory protocol to obtain the desired desymmetrized meso
tartaric acid derivatives and then use of this in the synthesis
of the anti-1,2-diol containing macrolactone natural product
(+)-aspicilin 1.
This 18-membered macrolactone metabolite, was first iso-
lated from Lecanoraceae lichen in 1900 by Hesse (9, 10),
but despite the elucidation of the connective structure in
1973 (8), the relative and absolute stereochemistry remained
unknown until 1985 (11). Although no biological function
for 1 has been reported, its structure, which contains four
stereogenic centres, three of which occur as an anti, syn-triol
unit, consequently makes it an ideal target to explore the use
of our new chiral building blocks in a stereoselective synthe-
sis of 1 (12). Other syntheses of (+)-aspicilin have also been
reported (13–27).
The desymmetrization of meso compounds as a method
for obtaining enantiomerically enriched products has become
a powerful tool for synthetic organic chemists. Enzymes are
frequently used to effect this kind of transformation (1);
however, considerable work has also been carried out using
chiral reagents or catalysts (2).
Tartaric acid is a readily available four-carbon building
block in either the (+)-, (–)-, or meso forms. Terminal group
manipulation of the two homochiral tartrates affords the syn-
1,2-diol motif, whereas elaboration of the meso form pro-
vides anti-1,2-diols but as a racemate. Polyhydroxylated nat-
ural products are important synthetic targets, consequently
several methods have been devised for the introduction of a
1,2-diol. However, the number of ways to prepare anti-1,2-
diols is much less than for the corresponding syn-1,2 unit.
Even the powerful Sharpless asymmetric dihydroxylation
procedure favors syn-1,2-diol formation from trans alkenes
in a higher enantiomeric excess (ee) than when cis alkenes
are used as precursors for the anti-1,2-diol motif (3). Alter-
native methods for the introduction of enantiomerically pure
anti-1,2-diols are therefore crucial to expand the repertoire
of the synthetic organic chemist.
Received March 15, 2001. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on November 20, 2001.
Dedicated to Professor Victor Snieckus for his contributions to chemistry and the training of students worldwide.
D.J. Dixon, A.C. Foster, and S.V. Ley.1 Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.
1Corresponding author (telephone: 44 1233 336 398; fax: 44 1233 336 442; e-mail: svl1000@cam.ac.uk).
Can. J. Chem. 79: 1668–1680 (2001)
© 2001 NRC Canada
DOI: 10.1139/cjc-79-11-1668

Dixon et al.
1669
Scheme 1.
Scheme 2.
TMOF, MeOH, CSA,
butane-2,3-dione
OMe
O
O
LDA (2eq), I2
57%
MeO
MeO
MeO
MeO
OH
OH
O
O
O
61%
O
OMe
10
O
HO
MeO
O
MeO
MeO
OMe
OMe
OMe
O
H2, Rh/Al2O3
97%
LiAlH4
82%
O
O
O
O
O
O
HO
MeO
OMe
OMe
OMe
O
12
11
13
Our general route to aspicilin is shown in Scheme 1. Ring
closing metathesis of 3 to give the large ring olefin 2 suggests
that 3 could be constructed by a stereoselective Masamune–
Roush coupling of the phosphonoacetate 5 and aldehyde 6.
In turn compound 5 should be available from ring opening
of propylene oxide 8 with the Grignard derived from 9, and
finally esterification with 7 (28). The preparation of 6 fol-
lows from an anticipated stereoselective addition of an allyl
side chain to the R,R,R>,R>-butane diacetal protected alde-
hyde derivative 4. Compound 4 would be obtained by chem-
istry already established in our group.
rated diester 11. Upon hydrogenation using rhodium on alu-
mina as the catalyst, the spatially desymmetrized diester 12
was produced. All the compounds in Scheme 2 are highly
crystalline therefore avoiding the need for tedious chromato-
graphic purification. Diester 12 was then reduced to give the
diol 13 where the two hydroxyl groups are in spatially dif-
ferentiated environments, one being axially and the other
equatorially disposed. This efficient four-step protocol was
carried out in multigram quantities.
The two hydroxyl protons of the diol 13 were clearly
1
identified in the H NMR spectrum. The relative chemical
shifts indicate the axial hydroxyl proton to be in a more
electronegative environment and this together with H NMR
The synthesis begins from commercially available dimethyl
L-tartrate, which was transformed to the desymmetrized diol 13
using our recently developed chiral memory protocol (29,
30). Firstly, the enantiopure diester was protected as the bu-
tane diacetal 10 using butane-2,3-dione and catalytic acid.
The resulting diacetal was then oxidized, via double
deprotonation and treatment with iodine, to give the unsatu-
1
studies at varying concentrations revealed the axial hydroxyl
group to be involved in an intramolecular hydrogen bond to
the backbone methoxy group (Fig. 1).
Either hydroxyl group of 13 could be selectively protected
as a tert-butyl dimethyl silyl ether. The two diastereomeric
© 2001 NRC Canada

1670
Can. J. Chem. Vol. 79, 2001
Fig. 1. Effect of concentration on hydroxyl proton chemical shift (᭿ H1, ᭡ H2).
Scheme 3.
HO
TBSO
HO
OMe
OMe
OMe
(a) NaH, TBSCl
O
O
O
O
O
O
or (b) imidazole, TBSCl
HO
HO
TBSO
OMe
OMe
OMe
13
14
15
(a) 14:15, 6:1, 98%
(b) 14:15, 1:17, 74%
Scheme 4.
ethers 14 and 15 are readily separable by column chroma-
tography to afford pure materials. Upon treatment of the diol
with one equivalent of sodium hydride a mono-alkoxide pre-
cipitates, which then reacts with the silylating reagent to
give predominantly the axial ether 14 (7:1), whereas treat-
ment of the diol 13 with imidazole and the silyl chloride
gave the equatorial ether 15 as the major product (17:1)
(Scheme 3).
Thus we can infer that the alkoxide that precipitates upon
treatment with sodium hydride is consistent with deprotonation
of the hydroxyl group on the axial ring substituent, with this
being thermodynamically more stable due to the interactions
with the lone pair electrons on the oxygen atom as shown in
Fig. 1. The equatorial alcohol is preferentially silylated in
the presence of imidazole due to the less sterically hindered
nature of this hydroxyl group.
Swern to give the aldehyde 4 (31). The key stereoselective
addition of an allyl group to this aldehyde using allyltributyls-
tannane as the nucleophile was then investigated. Following
similar conditions for the analogous addition to aldehydes
derived from (R>,R>,S,S)- and (S>,S>,R,R)-2,3-butanediacetal
protected butane tetrols (32), aldehyde 4 was dissolved in di-
ethyl ether and lithium perchlorate was added until the solu-
tion was saturated (~5 M). Allyltributyl stannane (3 equiv.)
was added and the reaction left to stir overnight at room
temperature. On work up, two diastereomeric products 16
and 17 were detected in the ratio of 9:1, respectively. Chro-
matographic purification afforded the diastereomerically
pure homoallylic alcohol 16 in 70% yield. However, even
after extended reaction times a small amount of aldehyde
starting material could still be detected in this reaction.
During the course of investigations to increase the yield as
well as the observed selectivity of this addition reaction we
observed an interesting result. When zinc chloride was used
Once the two alcohols had been differentiated, oxidation
of the free hydroxyl occurred smoothly using the method of
© 2001 NRC Canada

Dixon et al.
Table 1.
1671
tion afforded the isomerically pure E-isomer 21 in 58% yield
as well as the Z-isomer in 8% yield (Scheme 5). The axial na-
ture of the side chain could clearly be seen from the size of
the coupling constant between H-2 and H-3 (J = 4 Hz).
Macrocyclization of triene 21 was possible using standard
ring-closing metathesis (RCM) conditions (35). Thus, a di-
lute solution of 21 in dichloromethane at room temperature
was treated with a catalytic quantity of Grubb’s catalyst
(10%) for 14 h and afforded the desired material 22 in 73%
yield and as a 1.5:1 mixture of Z:E isomers. The product of
RCM across the double bond of the a,b-unsaturated ester,
cyclohexene 23, was also detected in 26% yield (Scheme 5).
Co-elution of the starting material and product meant that
early attempts to reduce only the isolated double bond re-
sulted in formation of the fully saturated system due to over-
reduction. Partial hydrogenation of the isomeric mixture of
alkenes 22, however, occurred smoothly using palladium on
barium sulfate in ethyl acetate under an atmosphere of hy-
drogen, when the reaction time was limited to 40 min, to
give fully protected aspicilin in 100% yield.
Lewis acid
Ratio of 16:17
Reaction yield (%)
ZnCl2
1:9
9:1
1.4:1
13:5
89
70a
87
92
LiClO4
Yb(OTf)3
MgBr2
aIsolated yield of 16 only.
as the Lewis acid, the reaction proceeded to completion in a
shorter time and in improved yield. However, the opposite
sense of stereochemical induction was observed giving prod-
ucts 17 and 16 in a ratio of 9:1 (Scheme 4). In an attempt to
explain this result the reaction was repeated using other
Lewis acids. The use of ytterbium(III) triflate gave essen-
tially a 1:1 ratio of alcohols, whilst magnesium bromide
gave a lower ratio than (but with the same major product)
the reaction with lithium perchlorate. A straightforward ad-
dition of allylmagnesium bromide gave a ratio of 2:1 in fa-
vor of the alcohol 16 (Table 1).
The synthesis of protected 6-epi-aspicilin was carried out
in an analogous manner, the yields at all stages up to this
point being comparable to those of the natural system.
Global deprotection using the standard conditions for BDA
removal, namely treatment with a 90% aqueous solution of
trifluoroacetic acid followed by removal of volatiles in
vacuo was first attempted on the unnatural diastereoisomer.
The reaction proceeded smoothly in this case to give the
triol product 24 in 44% yield (Scheme 7).
Attempts to determine the stereochemistry of the newly
formed secondary alcohols by formation of the Mosher es-
ters were not successful due to the hindered nature of these
alcohols. However, a single crystal X-ray structure of the
diol derived from the major product 16 confirmed that the
sense of the asymmetric induction in the lithium perchlorate
mediated reaction was consistent with addition occurring
through chelation control.2
With these compounds available the synthesis of both nat-
ural and 6-epi aspicilin was investigated (Scheme 5). The
preparation of both these diastereoisomers began with
protection of the corresponding homoallylic alcohol as the
methoxymethyl (MOM) ether. This was possible but required
forcing conditions analogous to those used for the protection
of tertiary alcohols (33). Thus alcohol 16 was treated with in
situ generated methoxymethyliodide and Hünig’s base in DME
at reflux for 13 h affording the desired MOM protected com-
pound 18 in 72% yield after chromatographic purification.
Standard TBS removal and Swern oxidation gave the axially
disposed aldehyde 19 in quantitative yield over 2 steps.
The phosphonate 5 required for the olefination reaction
was obtained in a two step process (Scheme 6). Firstly, the
Grignard reagent was generated in situ from the commer-
cially available 8-bromooct-1-ene (9) and reacted with (S)-
propylene oxide (8) in the presence of CuLi2Cl4 to give the
long chain alcohol 20 in good yield. A transesterification of
the thioester 7 with long chain alcohol 20 was mediated by
silver trifluoroacetate and gave the required phosphonate 5
in 84% yield. To minimize the possibility of epimerization of
the axially disposed aldehyde, the Masamune–Roush condi-
tions were chosen for the subsequent olefination reaction
(34). Accordingly, aldehyde 19 was treated with
phosphonate ester 5, lithium chloride, and Hünig’s base at
room temperature for 14 h to give the corresponding olefin
as a 10:1 mixture of E:Z isomers. Chromatographic purifica-
When these deprotection conditions were applied to the
natural diastereoisomer the reaction gave no desired product.
However, treatment with ethanedithiol and boron trifluoride
1
etherate afforded (+)-aspicilin 1 in 73% yield. The H and
13C NMR, IR, melting point, MS, and specific rotation ([a]2D6
+35.0 (c 0.20, CHCl3) (lit. [a]2D6 +37.5 (c 0.55, CHCl3)) of
the synthesized material were in excellent agreement with
the reported data and that of an authentic sample.3
In summary, a short and efficient stereoselective synthesis
of the polyhydroxylated natural product (+)-aspicilin 1 and
that of its C-6 epimer 24, has been achieved using (R>,R>,R,S)-
2,3-butanediacetal protected butane tetrol 13 as the starting
material. The key step relied on the stereoselective allylation
of the equatorially disposed aldehyde in 4. Terminal group
manipulation and olefination using phosphonate ester 5 fol-
lowed by macrocyclization via ring closing metathesis af-
forded, after partial hydrogenation and global deprotection,
the target compounds. Both diastereoisomers of aspicilin
have been submitted for full biological evaluation.
Experimental
(–)-(2R,3R,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-1,4-
dioxane-2,3-dimethyl dicarboxylate (10)
TMOF (123 mL, 1123 mmol), butane-2,3-dione (54 mL,
617 mmol), and CSA (6.52 g, 28 mmol) were added to a solu-
2 Supplementary material may be purchased from the Depository of Unpublished Data, Document Delivery, CISTI, National Research Council
Canada, Ottawa, ON K1A 0S2, Canada. For information on obtaining material electronically go to http://www.nrc.ca/cisti/irm/unpub_e.shtml.
Crystallographic information has also been deposited with the Cambridge Crystallographic Data Centre (CCDC No. 159 012). Copies of the
data can be obtained, free of charge, on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. (fax: 44-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk).
3 Kindly donated by Professor Hatakeyama.
© 2001 NRC Canada

1672
Can. J. Chem. Vol. 79, 2001
Scheme 5
Scheme 6.
(i) Mg, (CH2Br)2, THF
(ii) CuLi2Cl4,
Br
HO
8
9
86%
O
20
AgOCOCF3, Et3N
O
P
O
EtO
EtO
O
P
O
O
EtO
EtO
7
S
5
84%
Scheme 7.
1
tion of dimethyl L-tartrate (100 g, 561 mmol) in MeOH
(246 mL) and the reaction was heated to reflux for 7 h. After
cooling to room temperature for 1.5 h, NaHCO3 (100 g) was
added and the reaction stirred for 2.5 h. The solid was removed
by filtration and the filtrate concentrated in vacuo. The residue
was taken up in ether (1.6 L) and washed with water (2 ×
1.6 L). Each 1.6 L of water was reextracted with ether (0.8 L).
The combined organic layers were washed with brine (1.6 L),
dried (MgSO4), and concentrated in vacuo. Recrystallization
from ether–petrol (650:750 mL) gave white crystals of diester
10 (100.46 g, 61%); mp 109 to 110°C. [a]2D9 –148° (c 1.00,
CH2Cl2). Rf = 0.28 (petrol–ether, 1:1). H NMR (400 MHz,
CDCl3) d: 4.54 (2H, CHCO2CH3), 3.77 (s, 6H, CO2CH3), 3.33
(s, 6H, OCH3), 1.36 (s, 6H, CH3). 13C NMR (100 MHz,
CDCl3) d: 168.4 (CO2CH3), 99.2 (C-5, C-6), 68.7 (C-2, C-3),
52.5 (CO2CH3), 48.4 (OCH3), 17.3 (CH3). Anal. calcd. for
C12H20O8: C 49.3, H 6.90; found: C 49.3, H 6.87.
(–)-(5R,6R)-5,6-Dimethoxy-5,6-dimethyl-5,6-dihydro-1,4-
dioxin-2,3-dimethyl dicarboxylate (11)
LDA (9.3 mL, 1.0 M in THF) was added via cannula to a
stirred solution of diester 10 (1.29 g, 4.43 mmol) in THF
© 2001 NRC Canada

Dixon et al.
1673
(10 mL) at –78°C. The solution was then stirred at –78°C
for 1 h before iodine (1.12 g, 4.43 mmol), as a solution in
THF (10 mL), was added via cannula. Saturated aqueous
ammonium chloride solution (5 mL) was added to the resul-
tant precipitate and the reaction was warmed to room tem-
perature before being diluted with ether (50 mL) and water
(50 mL). The organic layer was separated and the aqueous
layer reextracted with ether (10 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. The
resulting solid was recrystallized from EtOAc–petrol (1:20)
to give the diester 11 (732 mg, 57%) as white prisms; mp 83–
85°C. [a]3D0 –304° (c 1.00, CHCl3). Rf = 0.41 (petrol–ether,
1:1). FAB-MS m/z (%): 291 ([M + H]+, 68), 116 (100) (anal.
calcd. (+FAB) for C12H19O8: 291.1080 (MH); found:
291.1081 [M + H]+). ꢀmax (thin film) (cm–1): 1739 (s), 1652
(ether) to give diol 13 (361 mg, 82%) as a colorless oil
which crystallized on standing; mp 69°C. [a]2D9 –132° (c 1.0,
CH2Cl2). Rf = 0.17 (ether). FAB-MS m/z (%): 259 ([M +
Na]+, 75), 173 (100) (anal. calcd. (+FAB) for C10H20O6Na:
259.1158 (M + Na); found: 259.1163 ([M + Na]+)). ꢀmax
1
(thin film) (cm–1): 3394 (m), 2950 (m), 2834 (m). H NMR
(400 MHz, CDCl3) d: 4.21–4.25 (m, 1H, 2-H), 4.00–4.05
>>
>>
(m, 1H, 1 -H), 3.90–3.92 (m, 1H, OH ), 3.67–3.89 (m, 4H, 3-
H, 1>-H), 3.34 (s, 3H, OCH3), 3.25 (s, 3H, OCH3), 3.06 (t,
J = 6, 1H, OH>), 1.33 (s, 3H, CH3), 1.31 (s, 3H, CH3). 13C
NMR (100 MHz, CDCl3) d: 99.5, 98.0 (C-5, C-6), 72.7
>>
(C-3), 68.3 (C-2), 63.0 (C–1 ), 61.6 (C-1>), 49.2 (OCH3),
47.9 (OCH3), 18.2 (CH3), 17.8 (CH3). Anal. calcd. for
C10H20O6: C 50.84, H 8.53; found: C 50.86, H 8.40.
1
(s). H NMR (400 MHz, CDCl3) d: 3.79 (s, 6H, CO2CH3),
(–)-(2S,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethanol-
2-methanol-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane (14)
Diol 13 (1.00 g, 4.23 mmol) as a solution in THF (6 +
2 mL washout) was added to a suspension of sodium hy-
dride (186 mg, 60% dispersion in mineral oil, 4.65 mmol) in
THF (2 mL). The reaction was then stirred at room tempera-
ture for 40 min. TBSCl (638 mg, 4.23 mmol) as a solution
in THF (8 mL) was then added to the resultant cream precip-
itate and the reaction was stirred at room temperature for
2.5 h before being poured into ether (150 mL). Water
(150 mL) was added and the layers separated. The aqueous
layer was reextracted with ether (100 mL), and the combined
organic layers were dried (MgSO4) and concentrated in vacuo.
3.35 (s, 6H, OCH3), 1.53 (s, 6H, CH3). 13C NMR (100 MHz,
CDCl3) d: 167.9 (CO2CH3), 130.9 (C-2, C-3), 98.8 (C-5,
C-6), 52.5 (CO2CH3), 49.4 (OCH3), 16.7 (CH3). Anal. calcd.
for C12H18O8: C 49.65, H 6.25 found: C 49.67, H 6.28.
(–)-(2R,3S,5R,6R)-5,6-Dimethoxy-5,6-dimethyl-1,4-
dioxane-2,3-dimethyl dicarboxylate (12)
Rhodium on alumina catalyst (1.00 g, 20 mol%) was
added to a solution of unsaturated diester 11 (5.00 g,
17.0 mmol) in MeOH (25 mL). The reaction tube was in-
serted into a pressure bomb and pressurized with hydrogen
to 80 bar (1 bar = 1 × 105 Pa). The reaction was then stirred
vigorously for 6 days. After this time the pressure was re-
leased and the reaction filtered through celite and washed
through with copious MeOH. The solvent was removed in
vacuo and the residue was chromatographed (petrol–ether,
1:1) to give diester 12 (4.83 g, 97%) as white prisms;
mp 100–102°C. [a]D30 –138° (c 1.03, CH2Cl2). Rf = 0.26
(petrol–ether, 1:1). FAB-MS m/z (%): 315 ([M + Na]+, 100),
261 (45), 101 (28) (anal. calcd. (+FAB) for C12H20O8Na:
315.1056 (M + Na); found: 315.1046 ([M + Na]+). ꢀmax (thin
film) (cm–1): 2982 (m), 2954 (m), 2901 (m), 2838 (m), 1788
1
Crude H NMR indicated a 6:1 ratio of isomeric products.
Purification by flash column chromatography (petrol–ether
(2:1) + 1% Et3N) gave the major isomer of silyl ether sepa-
rately from some mixed fractions in a combined yield of
98% with the major isomer 14, a white crystalline solid
(1.11 g, 75%); mp 79°C. [a]2D9 –119° (c 1.05, CHCl3). Rf =
0.63 (petrol–ether, 1:1). EI-MS m/z (%): 319 ([M – OMe]+,
10), 303 (20), 75 (100) (anal. calcd. (EI) for C15H31O5Si:
319.1941 (M – OMe); found: 319.1939 [M – OMe]+). ꢀmax
(thin film) (cm–1): 3491 (br), 2992 (m), 2952 (m), 2930 (m),
2886 (m), 2857 (m), 2833 (m), 1137 (s). 1H NMR
1
(s), 1741 (s). H NMR (400 MHz, CDCl3) d: 4.69 (d, J = 4,
>>
1H, 2-H or 3-H), 4.50 (d, J = 4, 1H, 2-H or 3-H), 3.77 (s,
3H, CO2CH3), 3.75 (s, 3H, CO2CH3), 3.30 (s, 3H, OCH3),
3.21 (s, 3H, OCH3), 1.38 (s, 3H, CH3), 1.33 (s, 3H, CH3).
13C NMR (100 MHz, CDCl3) d: 169.7 (CO2CH3), 168.8
(CO2CH3), 100.5, 99.3 (C-5, C-6), 69.1, 66.1 (C-2, C-3),
52.2 (CO2CH3), 52.0 (CO2CH3), 50.2 (OCH3), 48.5 (OCH3),
17.9 (CH3), 17.4 (CH3). Anal. calcd. for C12H20O8: C 49.31,
H 6.90; found: C 49.40, H 6.85.
(400 MHz, CDCl3) d: 4.35 (t, J = 10, 1H, 1 -H), 4.23–4.28
(m, 1H, 2-H), 3.74 (dt, J = 10, 2 Hz, 1H, 3-H), 3.65–3.72
>>
(m, 2H, 1>-H), 3.58 (dd, J = 10, 2, 1H, 1 -H), 3.24 (s, 3H,
OCH3), 3.22 (s, 3H, OCH3), 2.92 (t, J = 7, 1H, OH), 1.26 (s,
3H, CH3), 1.25 (s, 3H, CH3), 0.88 (s, 9H, C(CH3)3), 0.082
(s, 3H, SiCH3), 0.081 (s, 3H, SiCH3). 13C NMR (100 MHz,
CDCl3) d: 99.3 (C-6), 98.2 (C-5), 72.8 (C-3), 68.0 (C-2),
>>
62.4 (C-1 ), 61.7 (C-1>), 49.3 (OCH3), 47.9 (OCH3), 25.8
(C(CH3)3), 18.1 (C(CH3)3), 18.1 (CH3), 17.8 (CH3), –5.5,
–5.6 (Si(CH3)2). Anal. calcd. for C16H34O6Si: C 54.80,
H 9.80; found: C 54.96, H 9.64.
(–)-(2S,3R,5R,6R)-2,3-Dimethanol-5,6-dimethoxy-5,6-
dimethyl-1,4-dioxane (13)
LiAlH4 (2.05 mL, 1.0 M solution in THF, 2.05 mmol) was
added dropwise to a solution of diester 12 (545 mg,
1.86 mmol) in ether (15 mL) at 0°C. Upon completion of the
addition the ice bath was removed and the reaction left to
warm to room temperature, ca. 30 min. The reaction was
then cooled back to 0°C before quenching with EtOAc
(1 mL). Sodium sulfate decahydrate (2.0 g) was then added
and the reaction stirred at room temperature for 2 h. The
solid was filtered off under reduced pressure through a pad
of MgSO4 and washed with EtOAc (100 mL). Solvent removal
in vacuo left a colorless oil which was chromatographed
(–)-(2S,3R,5R,6R)-2-tert-Butyldimethylsilyloxymethanol-
3-methanol-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane (15)
Imidazole (22 mg, 0.32 mmol) was added to a stirred so-
lution of diol 13 (50 mg, 0.21 mmol) in THF (1.5 mL) at
room temperature and the resulting solution stirred for
5 min. TBSCl (32 mg, 0.21 mmol) was then added as a
solid. A white precipitate formed immediately and the reac-
tion was stirred for 90 min. The precipitate was filtered off
and washed with ether (10 mL). The organic solution was
then washed with water (10 mL), dried (MgSO4), and con-
© 2001 NRC Canada

1674
Can. J. Chem. Vol. 79, 2001
1
>>
>>
centrated in vacuo. Crude H NMR showed a 17:1 ratio of
isomeric silyl ethers 15 and 14, as well as a small amount of
diprotected product which were chromatographed (petrol–
ether (2:1) +1% Et3N) to give separately: colorless oil
(54.2 mg, 74%); [a]D30 –74° (c 1.35, CHCl3). Rf = 0.42
(petrol–ether, 1:1). EI-MS m/z (%): 373 ([M + Na]+, 1), 332
(5), 117 (100) (anal. calcd. (EI) for C16H34O6SiNa: 373.2017
(M + Na); found: 373.2028 ([M + Na]+). ꢀmax (thin film)
(cm–1): 3480 (br), 2991 (m), 2952 (m), 2930 (m), 2857 (m),
2834 (m), 1132 (s), 1114 (s). 1H NMR (400 MHz, CDCl3) d:
4.15–4.19 (m, 1H, 3-H), 3.94–3.98 (m, 1H, 1>-H), 3.82–3.86
1 -HA), 4.09 (dt, J = 10, 4, 1H, 3-H), 3.62 (dd, J = 10, 4, 1H,
1 -HB), 3.24 (s, 3H, OCH3), 3.18 (s, 3H, OCH3), 1.35 (s, 3H,
CH3), 1.26 (s, 3H, CH3), 0.84 (s, 9H, C(CH3)3), 0.01 (s, 3H,
SiCH3), 0.096 (s, 3H, SiCH3). 13C NMR (100 MHz, CDCl3)
d: 195.8 (C=O), 100.4, 98.6 (C-5, C-6), 74.4 (C-3), 72.0
>>
(C-2), 61.1 (C-1 ), 48.6 (OCH3), 48.2 (OCH3), 25.7
(C(CH3)3), 18.4 (CH3), 18.2 (C(CH3)3), 17.9 (CH3), –5.6, –5.6
(Si(CH3)2). Anal. calcd. for C16H32O6Si: C 55.14, H 9.25;
found: C 55.33, H 9.19.
(–)-(2R,1>R,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethanol-
2-(1>-hydroxy-but-3>-ene-1>-yl)-5,6-dimethoxy-5,6-dimethyl-
1,4-dioxane (16) and (–)-(2R,1>S,3R,5R,6R)-3-tert-
butyldimethylsilyloxymethanol-2-(1>-hydroxy-but-3>-ene-1>-
yl)-5,6-dimethoxy-5,6-dimethyl-1,4-dioxane (17)
>>
>>
(m, 3H, 1 -H, 2 -H), 3.71–3.76 (m, 2H, 1>-H, 2-H), 3.34 (s,
3H, OCH3), 3.25 (s, 3H, OCH3), 1.32 (s, 3H, CH3), 1.28 (s,
3H, CH3), 0.88 (s, 9H, C(CH3)3), 0.08 (s, 3H, SiCH3), 0.07
(s, 3H, SiCH3). 13C NMR (100 MHz, CDCl3) d: 99.3 (C-5),
>>
97.9 (C-6), 72.8 (C-2), 68.6 (C-3), 62.8 (C-1>), 62.4 (C-1 ),
49.1 (OCH3), 47.8 (OCH3), 25.7 (C(CH3)3), 18.2 (CH3),
18.1 (C(CH3)3), 17.8 (CH3), –5.4, –5.5 (Si(CH3)2).
Method 1: zinc(II) chloride mediated allyl addition
ZnCl2 solution (15.5 mL, 0.5 M in THF, 7.75 mmol) was
added to a solution of aldehyde 4 (900 mg, 2.58 mmol) in
ether (8 mL) at 0°C. The reaction was stirred at 0°C for
20 min before allyltributylstannane (2.4 mL, 7.75 mmol)
was added neat. The resulting solution was warmed to room
temperature and left stirring overnight. The reaction was
diluted with ether (50 mL) and washed with water (2 ×
50 mL). The aqueous layer was reextracted with ether
(40 mL) and the combined organic layers were washed with
brine (40 mL), dried (MgSO4), and concentrated in vacuo.
(2S,3R,5R,6R)-2,3-Di-tert-butyldimethylsilyloxymethanol-
5,6-dimethoxy-5,6-dimethyl-1,4-dioxane
Colorless oil (4.7 mg, 4.8%). Rf = 0.87 (petrol–ether, 1:1).
ESI-MS m/z (%): 487 ([M + Na]+, 60), 505 (100) (anal.
calcd. (ESI) for C22H48O6Si2Na: 487.2879 (M + Na); found:
487.2887 ([M + Na]+)). ꢀmax (thin film) (cm–1): 2953 (m),
2920 (m), 2857 (m), 1112 (s), 1085 (s). 1H NMR (400 MHz,
CDCl3) d: 4.13–4.20 (m, 2H), 3.70–3.75 (m, 1H,), 3.58–3.65
(m, 3H), 3.29 (s, 3H, OCH3), 3.24 (s, 3H, OCH3), 1.28 (s,
3H, CH3), 1.26 (s, 3H, CH3), 0.89 (s, 9H, C(CH3)3), 0.88 (s,
9H, C(CH3)3), 0.06 (s, 3H, SiCH3), 0.05 (s, 3H, SiCH3),
0.04 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3). 13C NMR
(100 MHz, CDCl3) d: 99.4, 98.2 (C-5, C-6), 73.1, 70.6 (C-2,
1
Crude H NMR indicated a 9:1 ratio of homoallylic alco-
hols, which were separated by flash column chromatography
(petrol–ether (5:1) + 1% Et3N) to give 17 (802 mg, 80%)
and 16 (96 mg, 9%).
>>
C-3), 62.8, 61.9 (C-1>, C-1 ), 49.2 (OCH3), 47.6 (OCH3),
Method 2: ytterbium(III) triflate mediated allyl addition
Ytterbium(III) triflate (534 mg, 0.86 mmol) was added to
a solution of aldehyde 4 (100 mg, 0.29 mmol) in ether
(2 mL) at 0°C and the reaction stirred for 15 min. Neat
allyltributylstannane (267 L, 0.86 mmol) was then added,
the cooling bath removed, and the reaction stirred at room
temperature for 14 h. Ether (50 mL) and water (50 mL) were
added, the layers separated, and the organic layer dried. Af-
ter concentration in vacuo the residue (crude ratio of prod-
25.9, 25.8 (C(CH3)3), 18.3 (C(CH3)3), 18.2 (CH3), 18.0
(C(CH3)3), 17.9 (CH3), –5.2, –5.4 (Si(CH3)2).
(–)-(2R,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethanol-
5,6-dimethoxy-5,6-dimethyl-1,4-dioxane-2-carbaldehyde
(4)
DMSO (526 L, 7.42 mmol), as a solution in CH2Cl2
(10 mL), was added to a solution of oxalyl chloride (324 L,
3.71 mmol) in CH2Cl2 (10 mL) at –78°C. The reaction was
stirred at –78°C for 30 min before alcohol 14 (1.0 g,
2.85 mmol) was added dropwise as a solution in CH2Cl2
(20 + 5 mL washout) over 30 min. The reaction was then
left stirring at –78°C for 1.5 h before Et3N (1.4 mL,
9.98 mmol) was added over 15 min. The reaction was then
removed from the cooling bath and allowed to warm to room
temperature over 1 h. The reaction was then diluted with
CH2Cl2 (100 mL) and washed with water (2 × 80 mL). The
organic layer was dried (MgSO4) and concentrated in vacuo.
Purification by flash column chromatography (petrol–ether
(1:1) + 1% Et3N) gave aldehyde 4 as an oily liquid, which
solidified on standing to a white crystalline solid (1.00 g,
100%); mp 50°C. [a]D28 –122° (c 1.08, CHCl3). Rf = 0.69
(petrol–ether, 1:1). EI-MS m/z (%): 317 ([M – OMe]+, 10),
291 (30), 259 (50), 245 (50), 101 (100) (anal. calcd. for
C15H29O5Si: 317.1784 (M – OMe); found: 317.1788 ([M –
OMe]+)). ꢀmax (thin film) (cm–1): 2952 (m), 2359 (m),
1
ucts by H NMR 1.4:1) was chromatographed (petrol–ether
(4:1) + 1% Et3N) to give homoallylic alcohols 16 (57 mg,
50%) and 17 (42 mg, 37%).
Method 3: lithium perchlorate mediated allyl addition
Aldehyde 4 (2.0 g, 5.74 mmol) was added to a solution of
lithium perchlorate in ether (30 mL, 5 M) and the reaction
stirred at 0°C for 15 min. The allyltributylstannane was then
added and the reaction warmed to room temperature and
stirred for 14 h. Ether (250 mL) and water (250 mL) were
added, the layers separated, and the organic layer dried (MgSO4)
and concentrated in vacuo. The residue (crude ratio of prod-
ucts by 1H NMR 1:9) was chromatographed (petrol:ether
(4:1) + 1% Et3N) to give the major homoallylic alcohol 16
as a colorless oil (1.56 g, 70%). The minor product co-eluted
with some unreacted starting aldehyde.
Method 4: magnesium(II) bromide mediated allyl addition
Magnesium(II) bromide (225 mg, 0.86 mmol) was added
to a solution of aldehyde 4 (100 mg, 0.29 mmol) in ether
1
2340 (m), 1738 (s). H NMR (400 MHz, CDCl3) d: 9.49 (s,
1H, CHO), 4.49 (d, J = 4, 1H, 2-H), 4.30 (ap t, J = 10, 1H,
© 2001 NRC Canada

Dixon et al.
1675
(2 mL) at 0°C and the reaction stirred for 15 min. The
allyltributylstannane (267 L, 0.86 mmol) was then added,
the cooling bath removed, and the reaction stirred at room
temperature for 14 h. Ether (50 mL) and water (50 mL) were
added, the layers separated, and the organic layer dried
(MgSO4). After concentration in vacuo the residue (crude ra-
tio of products by H NMR, 5:13) was chromatographed
(petrol–ether (4:1) + 1% Et3N) to give homoallylic alcohols
17 (23 mg, 20%) and 16 (81 mg, 72%).
62.4 (CH2OTBS), 49.3 (OCH3), 48.0 (OCH3), 37.0 (C-2>),
25.9 (C(CH3)3), 18.2 (C(CH3)3), 18.2 (CH3), 17.9 (CH3), –5.37
(SiCH3), –5.43 (SiCH3). Anal. calcd. for C19H38O6Si:
C 58.43, H 9.81; found: C 58.90, H 9.78.
(–)-(2R,1>S,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethanol-
5,6-dimethoxy-2-(1>-methoxymethylhydroxy-but-3>-ene-1>-
yl)-5,6-dimethyl-1,4-dioxane
1
MOMCl (0.74 mL, 9.79 mmol) was added to a solution of
sodium iodide (1.15 g, 7.68 mmol) in DME (15 mL). The
reaction was left to stir at room temperature for 1 h before
alcohol 17 (750 mg, 1.92 mmol) and DIPEA (1.84 mL,
10.56 mmol) were added as a solution in DME (15 mL). The
reaction was then stirred for 1 h at room temperature,
warmed to 65°C for 1 h, and then heated to reflux for a fur-
ther 17 h before finally cooling to room temperature. Satu-
rated sodium carbonate solution (10 mL) was added
followed by CH2Cl2 (100 mL) then water (50 mL). After
separation of the layers, the organic layer was washed again
with water (50 mL). The aqueous layer was reextracted with
CH2Cl2 (50 mL), then the combined organic layers washed
with brine (50 mL), dried (MgSO4), and concentrated in
vacuo. Purification by flash column chromatography (petrol–
ether (5:1) + 1% Et3N) gave MOM ether as a colorless oil
(714.6 mg, 86%). [a]D28 –100° (c 0.72, CHCl3). Rf = 0.51
(petrol–ether, 3:1). FAB-MS m/z (%): 457 ([M + Na]+, 5),
403 (10), 327 (10), 101 (100) (anal. calcd. (+FAB) for
C21H42O7SiNa: 457.2598 (M + Na); found: 457.2598 ([M +
Na]+)). ꢀmax (thin film) (cm–1): 2955 (m), 2929 (m), 2895
Method 5: allyl MgBr addition
Allyl MgBr solution (1.0 M THF, 0.72 mmol, 720 L)
was added to a solution of aldehyde 4 (50 mg, 0.14 mmol)
in THF (1 mL) at –78°C and the reaction stirred at –78°C
for 6 h. The reaction was then quenched with water and
warmed to room temperature. The reaction was diluted with
ether and washed with water before the organic layer was
dried (MgSO4) and concentrated in vacuo. The crude 1H
NMR showed a 1:2 ratio of 17 to 16. Purification of the resi-
due by flash column chromatogaphy gave pure homoallylic
alcohols (100%).
(–)-(2R,1>S,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethanol-
2-(1>-hydroxy-but-3>-ene-1>-yl)-5,6-dimethoxy-5,6-dimethyl-
1,4-dioxane (17)
[a]2D9 –126° (c 1.23, CHCl3). Rf = 0.49 (petrol–ether, 3:1).
ESI-MS m/z (%): 413 ([M + Na]+, 100), 217 (10) (anal.
calcd. (+ESI) for C19H38O6SiNa: 413.2335 (M + Na); found:
413.2361 ([M + Na]+)). ꢀmax (thin film) (cm–1): 3490 (br),
3075 (m), 2953 (m), 2931 (m), 2901 (m), 2858 (m), 2831
(m), 1139 (s), 1115 (s), 1058 (s). 1H NMR (400 MHz,
CDCl3) d: 5.91–6.01 (m, 1H, 3>-H), 5.13 (d, J = 17, 1H, 4>-
HA), 5.07 (d, J = 10, 1H, 4>-HB), 4.43 (ap t, J = 10, 1H,
CHHOTBS), 3.91–3.96 (m, 2H, 2-H, 3-H), 3.70–3.76 (m,
2H, 1>-H, OH), 3.62 (d, J = 10, 1H, CHHOTBS), 3.25 (s,
3H, OCH3), 3.24 (s, 3H, OCH3), 2.59–2.64 (m, 1H, 2>-HA),
2.16–2.25 (m, 1H, 2>-HB), 1.27 (s, 3H, CH3), 1.26 (s, 3H,
CH3), 0.91 (s, 9H, C(CH3)3), 0.12 (s, 6H, Si(CH3)2). 13C
NMR (100 MHz, CDCl3) d: 135.3 (C-3>), 116.5 (C-4>), 99.4,
97.94 (C-5, C-6), 72.7 (C-3), 70.5 (C-2), 69.4 (C-1>), 62.9
(CH2OTBS), 49.4 (OCH3), 48.1 (OCH3), 37.1 (C-2>), 25.8
(C(CH3)3), 18.2 (C(CH3)3), 18.0 (CH3), 17.9 (CH3), –5.6
(Si(CH3)2). Anal. calcd. for C19H38O6Si: C 58.43, H 9.81;
found: C 58.61, H 9.89.
1
(m), 2856 (m), 2832 (m), 1139 (s), 1109 (s), 1042 (s). H
NMR (400 MHz, CDCl3) d: 5.86–5.96 (m, 1H, 3>-H), 5.12
(d, J = 17, 1H, 4>-HA), 5.06 (d, J = 10, 1H, 4>-HB), 4.73 (d,
J = 7, 1H, OCHHOCH3), 4.60 (d, J = 7, 1H, OCHHOCH3),
4.17 (dd, J = 6, 11, 1H, CHHOTBS), 3.94 (dd, J = 6, 11,
1H, CHHOTBS), 3.74–3.80 (m, 2H, 1>-H, 3-H), 3.36 (s, 3H,
OCH2OCH3), 3.31 (s, 3H, OCH3), 3.24 (s, 3H, OCH3),
2.39–2.56 (m, 2H, 2>-H), 1.27 (s, 3H, CH3), 1.26 (s, 3H,
CH3), 0.90 (s, 9H, C(CH3)3), 0.063 (s, 6H, Si(CH3)2). 13C
NMR (100 MHz, CDCl3) d: 135.1 (C-3>), 116.9 (C-4>),
100.2, 98.41 (C-5, C-6), 96.7 (OCH2OCH3), 76.6 (C-1>),
73.9, 69.3 (C-2, C-3), 62.2 (CH2OTBS), 55.9 (OCH2OCH3),
49.5 (OCH3), 48.1 (OCH3), 35.6 (C-2>), 26.0 (C(CH3)3), 18.5
(CH3), 18.4 (C(CH3)3), 17.9 (CH3), –5.2 (SiCH3), –5.3
(SiCH3). Anal. calcd. for C21H42O7Si: C 58.03, H 9.74;
found: C 58.25, H 9.73.
(–)-(2R,1>R,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethanol-
2-(1>-hydroxy-but-3>-ene)-5,6-dimethoxy-5,6-dimethyl-1,4-
dioxane (16)
(–)-(1>S,2R,3R,5R,6R)-3-Methanol-5,6-dimethoxy-2-(1>-
methoxymethylhydroxy-but-3>-ene-1>-yl)-5,6-dimethyl-
1,4-dioxane
[a]2D9 –88° (c 0.20, CHCl3). Rf = 0.33 (petrol–ether, 3:1).
FAB-MS m/z (%): 413 ([M + Na]+, 10), 327 (40), 101 (100)
(anal. calcd. (+FAB) for C19H38O6SiNa: 413.2336 (M + Na);
found: 413.2333 ([M + Na]+). ꢀmax (thin film) (cm–1): 3374
TBAF (4.29 mL, 1.0 M solution in THF, 4.29 mmol) was
added to a solution of TBS ether (622 mg, 1.43 mmol) in
THF (20 mL) at room temperature. The reaction was then
stirred at room temperature overnight. After concentration in
vacuo the residue was taken up in ether (50 mL) and washed
with water (2 × 50 mL). The aqueous layer was reextracted
with ether (40 mL) and the combined organic layers were
dried (MgSO4) and concentrated in vacuo. Purification by
flash column chromatography (ether–petrol (4:1) + 1%
Et3N) gave the alcohol as a colorless oil (458 mg, 100%).
[a]2D8 –104° (c 1.08, CHCl3). Rf = 0.45 (ether). FAB-MS m/z
(%): 434 ([M + Na]+, 25), 257 (60), 101 (100) (anal. calcd.
1
(br), 2929 (m), 1113 (s). H NMR (400 MHz, CDCl3) d:
5.85–5.95 (m, 1H, 3>-H), 5.06–5.13 (m, 2H, 4>-H), 4.31–4.37
(m, 1H, CHHOTBS), 3.98–4.01 (m, 1H, 3-H), 3.80–3.85 (m,
1H, 1>-H), 3.65–3.72 (m, 3H, 2-H, CHHOTBS, OH), 3.27 (s,
3H, OCH3), 3.24 (s, 3H, OCH3), 2.41–2.47 (m, 1H, 2>-HA),
2.25–2.35 (m, 1H, 2>-HB), 1.31 (s, 3H, CH3), 1.26 (s, 3H,
CH3), 0.89 (s, 9H, C(CH3)3), 0.08 (s, 6H, Si(CH3)2). 13C
NMR (100 MHz, CDCl3) d: 134.9 (C-3>), 116.9 (C-4>),
100.1, 98.3 (C-5, C-6), 73.5 (C-2), 71.0 (C-3), 68.9 (C-1>),
© 2001 NRC Canada

1676
Can. J. Chem. Vol. 79, 2001
(+FAB) for C15H28O7Na: 343.17328 (M + Na); found:
434.17259 ([M + Na]+)). ꢀmax (CH2Cl2 solution) (cm–1):
3444 (br), 1694 (m), 1644 (m), 1615 (m), 1137 (m), 1111
(m), 1036 (m). 1H NMR (400 MHz, CDCl3) d: 5.83–5.93 (m,
1H, 3>-H), 5.07–5.16 (m, 2H, 4>-HAHB), 4.74 (ABq, J = 7,
28, 2H, OCH2OCH3), 4.02–4.13 (m, 3H, 2-H or 3-H, 1>-H,
CHHOH), 3.85–3.87 (m, 3H, 2-H or 3-H, OH, CHHOH),
3.37 (s, 3H, OCH2OCH3), 3.34 (s, 3H, OCH3), 3.23 (s, 3H,
OCH3), 2.55–2.62 (m, 1H, 2>-HA), 2.37–2.44 (m, 1H, 2>-HB),
1.31 (s, 3H, CH3), 1.27 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3) d: 134.2 (C-3>), 117.7 (C-4>), 100.0, 98.0 (C-5, C-6),
96.7 (OCH2OCH3), 77.2 (C-1>), 72.7, 69.0 (C-2, C-3), 62.7
(CH2OH), 56.1 (OCH2OCH3), 49.2 (OCH3), 48.2 (OCH3),
30.3 (C-2>), 18.3 (CH3), 17 9 (CH3). Anal. calcd. for
C15H28O7: C 56.23, H 8.81; found: C 55.95, H 8.80.
(CH2)6), 1.09 (d, J = 6, 3H, H-11). 13C NMR (100 MHz,
CDCl3) d: 139.0 (C-2), 114.0 (C-1), 67.8 (C-10), 39.2, 33.7,
29.5, 29.4, 29.0, 28.8, 25.7 (C-3–C-9), 23.3 (C-11). Anal. calcd.
for C11H22O: C 77.59, H 13.02; found: C 77.33, H 13.03.
(+)-(S)-10-(Diethylphosphonoacetoxy)-undec-1-ene (5)
Silver trifluoroacetic acid salt (178 mg, 0.80 mmol) was
added to a solution of thioester 6 (183 mg, 0.68 mmol), al-
cohol 20 (126 mg, 0.74 mmol), and Et3N in THF (2 mL).
The reaction was stirred at room temperature for 1 h before
the solvent was removed in vacuo. Purification by flash col-
umn chromatography (ether) afforded ester 5 as a pale yel-
low liquid (198 mg, 84%). [a]2D8 +2.7° (c 1.15, CHCl3). Rf =
0.28 (ether). EI-MS m/z (%): 371 ([M + Na]+, 100), 349
(30), 305 (10) (anal. calcd. for C17H33O5P: 371.1970 (M +
Na); found: 371.1963). ꢀmax (CH2Cl2 solution) (cm–1): 3077
(2R,1>S,3R,5R,6R)-5,6-Dimethoxy-2-(1>-methoxymethyl-
hydroxy-but-3>-ene-1>-yl)-5,6-dimethyl-1,4-dioxane-3-
carbaldehyde
1
(w), 2982 (s), 2931 (s), 2857 (s), 1727 (s), 1281 (s). H
NMR (400 MHz, CDCl3) d: 5.75–5.85 (m, 1H, 2-H), 4.89–
5.00 (m, 3H, 1-HAHB, 10-H), 4.13–4.20 (m, 4H, OCH2CH3 ×
2), 2.93 (d, J = 22, 2H, 14-HAHB), 2.00–2.05 (m, 2H, 3-
HAHB), 1.18–1.80 (m, 18H, -(CH2)6-, OCH2CH3 × 2), 1.23
(d, J = 6, 3H, 11-H). 13C NMR (100 MHz, CDCl3) d: 165.4
(C-13, J = 6), 139.1 (C-2), 114.1 (C-1), 72.6 (C-10), 62.6
(OCH2CH3), 62.5 (OCH2CH3), 35.8 (CH2), 34.6 (C-14, J =
134), 29.3, 29.3, 29.0, 28.9, 25.2 (CH2), 19.8 (C-11), 16.3
(OCH2CH3), 16.3 (OCH2CH3).
DMSO (30 L, 0.42 mmol) as a solution in CH2Cl2
(1 mL) was added to a solution of oxalyl chloride (18 L,
0.20 mmol) in CH2Cl2 (1 mL) at –78°C. The reaction was
stirred at –78°C for 30 min before alcohol (50 mg,
0.16 mmol) was added dropwise as a solution in CH2Cl2
(1 + 0.5 mL washout) over 30 min. The reaction was then
left stirring at –78°C for 1.5 h before Et3N (78 L,
0.56 mmol) was added over 15 min. The reaction was then
removed from the cooling bath and allowed to warm to room
temperature over 1 h. The reaction was diluted with CH2Cl2
(10 mL) and washed with water (2 × 8 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo. Rf =
0.42 (petrol–ether, 1:1). Used crude.
>>
(–)-(E)-(2S,3R,5R,6R,1>S,5 S)-5,6-Dimethoxy-2-(1>-methoxy-
>>
methylhydroxy-but-3>-ene)-5,6-dimethyl-3-(5 -methyl-
>> >>
>>
>>
tetradec-1 ,13 -diene-1 -yl-3 -one)-1,4-dioxane
Aldehyde (0.16 mmol) and DIPEA (28 L, 0.16 mmol) as
a solution in MeCN (1 mL) were added to a stirred suspen-
sion of LiCl (8.1 mg, 0.19 mmol) in MeCN (0.5 mL) at
(+)-(S)-10-Hydroxy-undec-1-ene (20)
Three drops of 1,2-dibromoethane were added to a stirred
suspension of magnesium turnings (837 mg, 34.4 mmol) in
THF (10 mL) at room temperature. A solution of 8-bromo-
oct-1-ene (9) (4.13 mL, 24.6 mmol) in THF (16 mL) was
then added as the solution was warmed to 30°C. The reac-
tion was heated to reflux for 6 h, cooled to room tempera-
ture, and THF (20 mL) was added. CuLi2Cl4 (17.2 mL,
0.1 M in THF, 1.72 mmol) was added to (S)-propylene oxide
8 (1.0 g, 17.2 mmol) in THF (20 mL) at –78°C. The Grig-
nard solution was further cooled to –78°C, added to the
cooled propylene oxide solution, and the reaction stirred for
1 h at –78°C before warming to 0°C over 1 h. The reaction
was quenched by addition of saturated aqueous ammonium
chloride solution (200 mL) and then EtOAc (200 mL) was
added. The layers were separated and the aqueous phase
reextracted with EtOAc (150 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. The
crude product was chromatographed (petrol–EtOAc, 5:1) to
give alcohol 20 as a pale yellow liquid (2.53 g, 86%). [a]D28
+6.9° (c 1.14, CHCl3). Rf = 0.3 (petrol–EtOAc, 5:1). EI-MS
m/z (%): 170 (M+, 25), 152 (40), 137 (20), 124 (60), 45
(100) (anal. calcd. for C11H22O: 170.1671 (M); found:
170.1670). ꢀmax (CH2Cl2 solution) (cm–1): 3073 (s), 2979 (s),
2830 (s), 2856 (s), 1639 (w). 1H NMR (400 MHz, CDCl3) d:
5.66–5.77 (m, 1H, 2-H), 4.90 (dd, J = 1, 17, 1H, 1-HA), 4.83
(dd, J = 1, 10, 1H, 1-HB), 3.64–3.70 (m, 1H, 10-H), 2.28
(br s, 1H, OH), 1.93–1.98 (m, 2H, 3-H), 1.11–1.42 (m, 12H,
room temperature. The phosphonate
5
(61.3 mg,
0.18 mmol), was then added as a solution in MeCN (0.5 mL)
and the reaction stirred at room temperature for 24 h. The
reaction mixture was diluted with ether (20 mL) and water
(20 mL) and the layers separated. The organic phase was
washed again with water (15 mL), the aqueous layers
reextracted with ether (20 mL), and the combined organic
layers dried (MgSO4) and concentrated in vacuo. Purifica-
tion by flash column chromatography (petrol–ether (2:1) +
1% Et3N) gave a,b-unsaturated ester as a colorless oil
(58.4 mg, 71%). [a]D29 –57° (c 0.41, CHCl3). Rf = 0.66
(petrol–ether, 1:1). ꢀmax (CH2Cl2 solution) (cm–1): 3890 (w),
3605 (w), 3078 (w), 2931 (m), 2856 (m), 1710 (s), 1143 (s),
1
1108 (s), 1041 (s). H NMR (400 MHz, CDCl3) d: 7.46 (dd,
>>
>>
J = 10, 16, 1H, 1 -H), 5.75–5.97 (m, 2H, 13 -H, 3>-H), 5.96
>>
>>
>>
(d, J = 16, 1H, 2 -H), 4.91–5.15 (m, 5H, 4>-H, 14 -H, 5 -H),
4.50–4.57 (m, 2H, OCH2OCH3), 4.25 (dd, J = 4, 10, 1H,
3-H), 4.15 (dd, J = 4, 9, 1H, 2-H), 3.50–3.55 (m, 1H, 1>-H),
3.31 (s, 3H, OCH2OCH3), 3.27 (s, 3H, OCH3), 3.11 (s,
3H, OCH3), 2.54–2.62 (m, 1H, 2>-HA), 2.38–2.45 (m, 1H,
>>
2>-HB), 2.01–2.06 (m, 2H, 12 -H), 1.21–1.60 (m, 21H, 3 ×
Me, -(CH2)6-). 13C NMR (100 MHz, CDCl3) d: 165.9 (C-3 ),
>>
>>
>>
144.2 (C-1>>), 139.1 (C-13 ), 134.0 (C-3>), 125.6 (C-2 ),
>>
117.5 (C-4>), 114.1 (C-14 ), 100.0, 98.4 (C-5, C-6), 96.7
(OCH2OCH3), 76.7 (C-1>), 72.2, 71.1 (C-2, C-3), 68.6
>>
(C-5 ), 56.1 (OCH2OCH3), 48.4 (OCH3), 48.4 (OCH3), 36.0,
>>
>>
35.1, 33.7, 29.38, 29.36, 29.0 (C-6 –C-11 ), 20.0, 18.2, 17.8
© 2001 NRC Canada

Dixon et al.
1677
(CH3 × 3). Anal. calcd. for C28H48O8: C 65.60, H 9.44;
found: C 65.43, H 9.39.
as a crystalline white solid (1.4 mg, 44%); mp 116°C. [a]D29
+23.0° (c 0.14, CHCl3). Rf = 0.16 (ether). EI-MS m/z (%):
351 ([M + Na]+, 60), 249 (50) (anal. calcd. for C18H32O5Na:
1
351.2140 (M + Na); found: 351.2147). H NMR (600 MHz,
(4E/Z,16E)-(1S,2S,13S,18R,19aR,19bR)-19a,19b-Dimethoxy-
2-methoxymethylhydroxy-13,19a,19b-trimethyl-14,19,20-
trioxa-bicyclo[16.4.0]doicosa-4,16-diene-15-one
CDCl3) d: 6.99 (dd, J = 6, 16, 1H, 3-H), 6.10 (dd, J = 1, 16,
1H, 2-H), 5.01–5.09 (m, 1H, 17-H), 4.68 (m, 1H, 4-H), 3.72
(m, 1H, 5-H), 3.60 (m, 1H, 6-H), 2.68 (br s, 1H, OH), 2.49
(br s, 1H, OH), 1.66 (br s, 1H, OH), 1.34–1.55 (m, 20H,
(CH2)10), 1.25 (d, J = 6, 3H, CH3). 13C NMR (100 MHz,
CDCl3) d: 165.5 (C-1), 144.5 (C-3), 123.2 (C-2), 76.7, 72.5,
71.8, 71.0 (C-4, C-5, C-6, C-17), 36.0, 32.2, 27.74, 27.70,
27.5, 27.4, 26.6, 26.4, 24.09, 24.08 (C-7–C-16), 20.4 (CH3).
Grubb’s catalyst (18.4 mg, 0.02 mmol) was added to a
stirred solution of triene (107 mg, 0.21 mmol) in CH2Cl2
(140 mL). The reaction was stirred at room temperature
overnight and concentrated in vacuo. Purification by flash
column chromatography (petrol–ether, 4:1) afforded cyclic
lactone, a 6:4 inseparable mixture of double bond isomers,
as a colorless oil (48 mg, 45%). Rf = 0.66 (petrol–ether, 1:1).
ꢀmax (CH2Cl2 solution) (cm–1): 2931 (s), 2864 (s), 1712 (s),
1655 (w), 1602 (w), 1377 (m), 1254 (s), 1215 (m), 1183
(m), 1142 (s), 1107 (s), 1038 (s). 1H NMR (400 MHz,
CDCl3) d: 7.48–7.58 (m, 1HA + 1HB, 17-H), 6.02 (d, J = 16,
1HA, 16-H), 5.97 (d, J = 16, 1HB, 16-H), 5.41–5.56 (m,
1HA + 1HB, 4-H or 5-H), 5.33–5.40 (m, 1HA + 1HB, 4-H or
5-H), 5.14–5.22 (m, 1HA + 1HB, 2-H), 4.52–4.65 (m, 2HA +
2HB, CH2OCH3), 4.32 (dd, 1HA, J = 4, 11, 1-H or 18-H),
4.26 (dd, J = 4, 11, 1HB, 1-H or 18-H), 4.03–4.08 (m, 1HA +
1HB, 1-H or 18-H), 3.37 (s, 3HA, CH2OCH3), 3.36 (s, 3HB,
CH2OCH3), 3.28 (s, 3HB, OCH3), 3.26 (s, 3HA, OCH3), 3.20
(s, 3HA, OCH3), 3.17 (s, 3HB, OCH3), 2.39–2.53 (m, 1HA +
1HB, 3-H), 2.04–2.27 (m, 2HA + 2HB, 3-H), 1.85–1.94 (m,
1HA + 1HB), 1.39–1.54 (m, 2HA + 2HB), 1.15–1.33 (m,
21HA + 21HB, 3 × CH3 and 6 × CH2).
(2R,1>R,3R,5R,6R)-3-tert-Butyldimethylsilyloxymethanol-
5,6-dimethoxy-2-(1>-methoxymethylhydroxy-but-3>-ene-1>-
yl)-5,6-dimethyl-1,4-dioxane (18)
MOMCl (1.55 mL, 20.4 mmol) was added to a solution of
sodium iodide (2.39 g, 16.0 mmol) in DME (30 mL) at room
temperature and the reaction stirred for 1 h. A solution of al-
cohol 16 (1.56 g, 4.0 mmol) and DIPEA (3.83 mL,
22.0 mmol) in DME (30 mL) was then added and the reac-
tion stirred for a further hour at room temperature. The reac-
tion was heated to 65°C for 1 h and then to reflux for 13 h.
After cooling to room temperature, saturated sodium carbon-
ate solution (20 mL) was added followed by CH2Cl2
(200 mL) and water (100 mL). The layers were separated
and the organic layer washed again with water (100 mL).
The combined aqueous layers were reextracted with CH2Cl2
(100 mL), the organic layers washed with brine, dried
(MgSO4), and concentrated in vacuo. Purification by flash
column chromatography (petrol–ether (4:1) + 1% Et3N) gave
homoallylic ether 18 (1.25 g, 72% (85% brsm)) as a color-
less oil. [a]3D0 –74.1° (c 1.09, CHCl3). Rf = 0.51 (petrol–
ether, 3:1). ES-MS m/z (%): 457 ([M + Na]+, 100) (anal.
calcd. (+ES) for C21H42O7SiNa: 457.2597 (M + Na); found:
457.2620 ([M + Na]+)). ꢀmax (neat) (cm–1): 2951 (m), 2930
(m), 2888 (m), 2858 (m), 2833 (m), 1641 (w), 1471 (m),
1373 (m), 1257 (m), 1209 (m), 1134 (s), 1110 (s), 1095 (s).
1H NMR (400 MHz, CDCl3) d: 5.84–5.94 (m, 1H, H-3>),
5.05–5.11 (m, 2H, H-4>), 4.88 (d, J = 7, 1H, OCHHOCH3),
4.70 (d, J = 7, 1H, OCHHOCH3), 4.23 (dd, J = 8, 10, 1H,
CHHOTBS), 4.07 (dd, J = 3, 10, 1H, H-1), 3.68–3.81 (m,
3H, H-2, H-3, CHHOTBS), 3.39 (s, 3H, CH2OCH3), 3.27 (s,
3H, OCH3), 3.25 (s, 3H, OCH3), 2.46–2.53 (m, 1H, H-2>),
2.21–2.29 (m, 1H, H-2>), 1.250 (s, 3H, CH3), 1.248 (s, 3H,
CH3), 0.90 (s, 9H, C(CH3)3), 0.07 (s, 6H, Si(CH3)2). 13C
NMR (100.6 MHz, CDCl3) d: 134.6 (C-3>), 117.1 (C-4>),
99.8, 98.2 (C-5, C-6), 97.5 (OCH2OCH3), 74.9, 73.2 (C-2,
C-3), 72.0 (C-1>), 62.3 (CH2OTBS), 55.7 (CH2OCH3), 49.2
(OCH3), 47.6 (OCH3), 36.1 (C-2>), 26.0 (C(CH3)3), 18.3
(C(CH3)3), 18.26 (CH3), 17.9 (CH3), –5.3 (SiCH3), –5.4
(SiCH3).
(16E)-(1S,2S,13S,18R,19aR,19bR)-19a,19b-Dimethoxy-2-
methoxymethylhydroxy-13,19a,19b-trimethyl-14,19,20-
trioxa-bicyclo[16.4.0]doicosa-16-ene-15-one
Pd-BaSO4 (0.5 mg) was added to a solution of diene
(5 mg, mmol) in EtOAc (0.5 mL). The reaction was stirred
under an atmosphere of hydrogen for 40 min, the catalyst
was removed by filtration and the solvent removed in vacuo
to leave crude product (5 mg, 100%). [a]2D9 –85.6° (c 0.45,
CHCl3). Rf = 0.66 (petrol–ether, 1:1). EI-MS m/z (%): 455
([M – OMe]+, 5), 419 (5), 379 (20), 338 (30), 276 (30), 247
(40), 116 (100). (anal. calcd. (EI) for C24H43O7: 455.3009
(M – OMe); found: 455.2997 ([M – OMe]+). ꢀmax (CH2Cl2
solution) (cm–1): 3692 (w), 3605 (w), 2927 (s), 2930 (s),
2857 (s), 1712 (s), 1653 (w), 1607 (w), 1459 (m), 1376 (m),
1
1264 (s), 1253 (s), 1142 (s), 1109 (s), 1035 (s). H NMR
(400 MHz, CDCl3) d: 7.55 (dd, J = 11, 16, 1H, 17-H), 5.97
(d, J = 16, 1H, 16-H), 5.13–5.17 (m, 1H, 13-H), 4.70 (d, J =
7, 1H, CH2OCH3), 4.56 (d, J = 7, 1H, CH2OCH3), 4.21 (dd,
J = 4, 11, 1H, 18-H), 4.13–4.17 (m, 1H, 1-H), 3.41–3.48 (m,
1H, 2-H), 3.38 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 3.17 (s,
3H, OCH3), 1.15–1.57 (m, 29H, 3 × CH3, (CH2)10). 13C NMR
(100 MHz, CDCl3) d: 166.1 (C-15), 145.4 (C-16), 124.5 (C-
17), 100.1, 98.4 (C-19a, C-19b), 96.6 (CH2OCH3), 76.5, 73.0,
70.9, 70.1 (C-1, C-2, C-13, C-18), 55.9 (CH2OCH3), 48.3,
47.8 (OCH3), 36.2, 29.9, 27.9, 27.8, 27.7, 27.5, 26.6, 26.3,
24.8, 24.0 (C-3–C-12), 20.6, 18.2, 17.7 (CH3).
(2R,1>R,3R,5R,6R)-3-Methanol-5,6-dimethoxy-2-(1>-meth-
oxymethylhydroxy-but-3>-ene-1>-yl)-5,6-dimethyl-1,4-
dioxane
6-epi-Aspicilin (24)
TBAF (8.21 mL, 1.0 M solution in THF, 8.21 mmol) was
added to a solution of TBS ether 18 (1.19 g, 2.74 mmol) in
THF (40 mL) and the reaction stirred for 16 h. The solvent
was removed in vacuo and the residue chromatographed
(petrol–ether (2:1) + 1% Et3N) to give alcohol as a colorless
TFA–water (9:1, 500 L) was added to fully protected 6-
epi-aspicilin (5 mg, 0.01 mmol) and the reaction was stirred
for 30 min. Concentration in vacuo followed by purification
by flash column chromatography (ether) gave 6-epi-aspicilin
© 2001 NRC Canada

1678
Can. J. Chem. Vol. 79, 2001
oil (0.91 g, 100%). [a]D30 –73.0° (c 1.15, CHCl3). Rf = 0.46
(ether). ES-MS m/z (%): 343 ([M + Na]+, 100), 257 (15)
(anal. calcd. (ES+) for C15H28O7Na: 343.1733 (M + Na);
found 343.1757 ([M + Na]+)). ꢀmax (neat) (cm–1): 3472 (br),
2948 (m), 2833 (m), 1641 (w), 1455 (m), 1374 (m), 1209
(m), 1135 (s), 1115 (s), 1035 (s). 1H NMR (400 MHz,
CDCl3) d: 5.88 (m, 1H, H-3>), 5.07–5.12 (m, 2H, H-4>), 4.87
(d, J = 7, 1H, OCHHOCH3), 4.72 (d, J = 7, 1H,
OCHHOCH3), 4.03–4.10 (m, 2H, H-1>, H-2), 3.77–3.90 (m,
2H, CH2OH), 3.59–3.66 (m, 2H, OH, H-3), 3.39 (s, 3H,
OCH3), 3.37 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.33–2.39
(m, 1H, H-2>), 2.13–2.20 (m, 1H, H-2>), 1.32 (s, 3H, CH3),
1.28 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3) d: 134.0
(C-3>), 117.6 (C-4>), 99.3, 97.8 (C-5, C-6), 97.6
(OCH2OCH3), 74.9 (C-1>), 71.9 (C-2), 71.4 (C-3), 63.3
(CH2OH), 55.8 (OCH2OCH3), 49.2 (OCH3), 47.8 (OCH3),
36.5 (C-2>), 18.1 (CH3), 17.9 (CH3). Anal. calcd. for
C22H37O6Si: C 56.23, H 8.81; found: C 56.18, H 8.78.
0.65 (petrol–ether, 1:1). ES-MS m/z (%): 535 ([M + Na]+,
100), 522 (5), 439 (8), 404 (5), 341 (15) (anal. calcd. (ES+)
for C28H48O8Na: 535.3247 (M + Na); found: 535.3275
([M + Na]+)). ꢀmax (neat) (cm–1): 2928 (m), 2856 (m), 1718
(s), 1641 (w), 1454 (m), 1373 (m), 1272 (m), 1248 (m),
1
1208 (m), 1137 (s), 1115 (s), 1023 (s). H NMR (400 MHz,
>>
CDCl3) d: 7.43 (dd, J = 10, 16, 1H, H-1 ), 5.96 (d, J = 16,
>>
>>
1H, H-2 ), 5.75–5.91(m, 2H, H-3>, H-13 ), 4.91–5.11 (m, 5H,
>>
>>
H-5 , H-4>, H-14 ), 4.84 (d, J = 7, 1H, OCH2OCH3), 4.68 (d,
J = 7, 1H, OCH2OCH3), 4.11 (dd, J = 3, 9, 1H, H-2), 4.03
(dd, J = 3, 10, 1H, H-3), 3.45–3.54 (m, 1H, H-1>), 3.39 (s,
3H, OCH2OCH3), 3.29 (s, 3H, OCH3), 3.10 (s, 3H, OCH3),
2.23–2.29 (m, 1H, H-2>), 2.01–2.07 (m, 3H, H-2>, CH2),
1.21–1.63 (m, 21H). 13C NMR (100.6 MHz, CDCl3) d:
165.6 (C-3 ), 143.3 (C-1 ), 139.1 (C-13 ), 133.7 (C-3>), 126.0
(C-2 ), 117.7 (C-4>), 114.1 (C-14 ), 99.6, 98.3 (C-5, C-6),
97.2 (OCH2OCH3), 75.2 (C-1>), 71.6, 71.3 (C-2, C-3, C-5 ),
>>
>>
>>
>>
>>
>>
55.7 (OCH2OCH3), 48.3 (OCH3), 47.8 (OCH3), 36.0, 35.2,
>>
>>
33.7, 29.4, 29.35, 29.0, 28.9, 25.4 (C-6 –C-12 , C-2>), 20.0
(CH3), 18.0 (CH3), 17.7 (CH3 at 5 ).
>>
(2R,1>R,3R,5R,6R)-5,6-Dimethoxy-2-(1>-methoxymethyl-
hydroxy-but-3>-ene-1>-yl)-5,6-dimethyl-1,4-dioxane-3-
carbaldehyde (19)
>>
(Z)-(2S,3R,5R,6R,1>R,5 S)-5,6-Dimethoxy-2-(1>-methoxymethyl-
>>
hydroxy-but-3>-ene)-5,6-dimethyl-3-(5 -methyl-tetradec-
DMSO (335 L, 4.72 mmol) as a solution in CH2Cl2
(6 mL) was added to a solution of oxalyl chloride (206 L,
2.36 mmol) in CH2Cl2 (6 mL) at –78°C. The reaction was
stirred for 30 min at –78°C before alcohol (581 mg,
1.81 mmol) as a solution in CH2Cl2 (6 + 3 mL) was added
over 30 min. The reaction was then stirred at –78°C for 1 h
before Et3N (885 L, 6.35 mmol) was added dropwise over
30 min. The reaction was then allowed to warm to room
temperature over 1 h then diluted with CH2Cl2 (150 mL).
The CH2Cl2 solution was washed with water (2 × 150 mL),
the combined aqueous layers reextracted with CH2Cl2
(100 mL), organics dried (MgSO4), and concentrated in
vacuo. The aldehyde (Rf = 0.36 (petrol–ether, 1:1)) was used
without further purification in the next reaction.
>> >>
>>
>>
1 ,13 -diene-1 -yl-3 one)-1,4-dioxane
86% isolated yield; [a]2D9 –13.0° (c 0.80, CHCl3). Rf =
0.71 (petrol–ether, 1:1). ES-MS m/z (%): 535 ([M + Na]+,
100), 503 (2), 457 (2), 413 (2), 343 (55) (anal. calcd. (ES+)
for C28H48O8Na: 535.3247 (M + Na); found: 535.3253
([M + Na]+)). ꢀmax (neat) (cm–1): 2928 (m), 2856 (m), 1716
(s), 1641 (w), 1451 (w), 1416 (m), 1373 (m), 1189 (s), 1113
1
(s), 1024 (s). H NMR (400 MHz, CDCl3) d: 6.86 (dd, J =
>>
>>
>>
11, 12, 1H, H-1 ), 5.92 (d, J = 12, 1H, H-2 ), 5.75–5.88 (m,
2H, H-3>, H-13 ), 5.35 (dd, J = 3, 11, 1H, H-3), 4.89–5.12
>>
>>
(m, 5H, H-5 , H-4>, H-14 ), 4.86 (d, J = 7, 1H, OCH2OCH3),
4.68 (d, J = 7, 1H, OCH2OCH3), 4.12 (dd, J = 3, 9, 1H,
H-2), 3.49–3.53 (m, 1H, H-1>), 3.39 (s, 3H, OCH2OCH3),
3.29 (s, 3H, OCH3), 3.11 (s, 3H, OCH3), 2.24–2.30 (m, 1H,
H-2>), 2.00–2.08 (m, 3H, H-2>, CH2), 1.21–1.63 (m, 21H).
C NMR (100.6 MHz, CDCl3) d: 165.3 (C-3 ), 142.8 (C-1 ),
>>
(E)-(2S,3R,5R,6R,1>R,5 S)-5,6-Dimethoxy-2-(1>-methoxy-
13
>>
>>
>>
methylhydroxy-but-3>-ene)-5,6-dimethyl-3-(5 -methyl-
>>
>>
139.1 (C-13 ), 133.8 (C-3>), 123.0 (C-2 ), 117.7 (C-4>), 114.1
>> >>
>>
>>
tetradec-1 ,13 -diene-1 -yl-3 one)-1,4-dioxane (21) and
>>
(C-14 ), 99.6, 98.1 (C-5, C-6), 97.1 (OCH2OCH3), 75.2 (C-1>),
71.8, 71.1, 64.8 (C-2, C-3, C-5 ), 55.7 (OCH2OCH3), 48.5
>>
(Z)-(2S,3R,5R,6R,1>R,5 S)-5,6-dimethoxy-2-(1>-methoxy-
>>
>>
methylhydroxy-but-3>-ene)-5,6-dimethyl-3-(5 -methyl-
(OCH3), 47.7 (OCH3), 35.9, 35.0, 33.7, 29.3, 29.35, 29.0,
>> >>
>>
>>
tetradec-1 ,13 -diene-1 -yl-3 one)-1,4-dioxane
>>
>>
28.9, 25.4 (C-6 –C-12 , C-2>), 19.9 (CH3), 18.1 (CH3), 17.7
(CH3 at 5 ).
Phosphonate 5 (758 mg, 2.18 mmol) as a solution in
MeCN (9 mL) was added to a suspension of LiCl (92 mg,
2.18 mmol) in MeCN (3 mL) at room temperature. The alde-
hyde 19 (1.81 mmol, crude) and DIPEA (316 L, 1.81 mmol)
were then added as a solution in MeCN (6 + 3 mL). The re-
action was stirred at room temperature for 16 h before being
diluted with ether (100 mL) and washed with water (60 mL).
The organic layer was washed again with water (60 mL), the
aqueous layers reextracted with ether (100 mL), and the
combined organic layers dried (MgSO4) and concentrated in
vacuo. Purification by flash column chromatography (petrol–
ether (4:1) + 1% Et3N) gave a,b-unsaturated ester as 2 double
bond isomers in a combined yield of 66% from the alcohol.
>>
(4E/Z,16E)-(1S,2R,13S,18R,19aR,19bR)-19a,19b-Dimethoxy-
2-methoxymethylhydroxy-13,19a,19b-trimethyl-14,19,20-
trioxa-bicyclo[16.4.0]doicosa-4,16-diene-15-one (22)
Grubbs’ catalyst (34.3 mg, 0.039 mmol) was added to a
deoxygenated solution of triene 21 (200 mg, 0.39 mmol) in
CH2Cl2 (400 mL) and the reaction stirred for 16 h. The sol-
vent was removed in vacuo and the residue chromatographed
to yield the desired macrocycle as a 2:1 mixture of double
bond isomers 22 (112 mg, 73%) as well as a byproduct,
cyclohexene 23 (29 mg, 26%). Rf = 0.29 (petrol–ether, 2:1).
ES-MS m/z (%): 507 ([M + Na]+, 80), 475 (2), 377 (5) (anal.
calcd. (ES+) for C26H44O8Na: 507.2934 (M + Na); found:
507.2950 ([M + Na]+)). ꢀmax (neat) (cm–1): 2928 (m), 2858
(m), 1720 (s), 1654 (w), 1456 (w), 1373 (m), 1331 (w), 1248
>>
(E)-(2S,3R,5R,6R,1>R,5 S)-5,6-Dimethoxy-2-(1>-methoxymethyl-
hydroxy-but-3>-ene)-5,6-dimethyl-3-(5 -methyl-tetradec-1 ,13 -
>>
>> >>
>>
>>
diene-1 -yl-3 one)-1,4-dioxane (21)
58% isolated yield; [a]2D9 –32.1° (c 1.27, CHCl3). Rf =
1
(s), 1209 (m), 1176 (m), 1136 (s), 1110 (s), 1022 (s). H
© 2001 NRC Canada

Dixon et al.
1679
NMR (400 MHz, CDCl3) d: 7.53 (dd, J = 10, 16, 1HA, H-17),
7.52 (dd, J = 10, 16, 1HB, H-17), 6.05 (d, J = 16, 1HA, H-16),
5.96 (d, J = 16, 1HB, H-16), 5.09–5.44 (m, 2HA + 2HB, H-4,
H-5), 4.91 (d, J = 7, 1HB, OCH2OCH3), 4.87 (d, J = 7, 1HA,
OCH2OCH3), 4.73 (d, J = 7, 1HB, OCH2OCH3), 4.71 (d, J =
7, 1HA, OCH2OCH3), 3.99–4.12 (m, 2HA + 2HB, H-1, H-18),
3.33–3.50 (m, 2HA + 2HB, H-2, H-13), 3.41 (s, 3HA,
OCH2OCH3), 3.38 (s, 3HB, OCH2OCH3), 3.29 (s, 3HA,
OCH3), 3.28 (s, 3HB, OCH3), 3.15 (s, 3HB, OCH3), 3.09 (s,
3HA, OCH3), 1.85–2.19 (m, 3HA + 3HB, H-3, CH2), 1.18–
1.40 (m, 20HA + 20HB). 13C NMR (100.6 MHz, CDCl3) (ma-
jor isomer only) d: 165.6 (C=O), 143.8 (C-17), 132.1, 126.5
(C-4, C-5), 125.4 (C-16), 99.5, 98.2 (19a, 19b), 98.1
(OCH2OCH3), 77.1, 72.5, 72.3, 70.8 (CH), 55.9 (OCH2OCH3),
48.3 (OCH3), 47.8 (OCH3), 36.2, 34.0, 31.3, 27.29, 27.25,
25.2, 23.7 (CH2), 20.6, 18.0, 17.6 (CH3). Anal. calcd. for
C26H44O8: C 64.44, H 9.15; found: C 64.57, H 9.29.
(OCH3), 47.8 (OCH3), 35.3, 30.0, 28.4, 27.5, 27.2, 27.0,
26.6, 25.8, 24.3, 22.8 (CH2), 20.3, 18.0, 17.6 (CH3).
(+)-Aspicilin (1)
Ethanedithiol (121 L, 1.44 mmol) was added to fully
protected aspicilin (78 mg, 0.16 mmol) in CH2Cl2 (10 mL)
and the solution cooled to 0°C. BF3·OEt2 (166 L,
1.28 mmol) was then added and the solution warmed to
room temperature and left stirring for 14 h. The reaction was
diluted with EtOAc, washed with saturated NaHCO3 solu-
tion, and the organic layer was dried (MgSO4). Concentra-
tion in vacuo followed by purification by flash column
chromatography (5% MeOH in ether) gave aspicilin as a
crystalline white solid (38 mg, 73%); mp 150–155°C.
[a]2D9 + 35.0° (c 0.20, CHCl3). Rf = 0.16 (ether) EI-MS m/z
(%): 351 ([M + Na]+, 100), 292 (50), 224 (28) (anal. calcd.
for C18H32O5Na: 351.2148 (M + Na); found: 351.2166). ꢀmax
(CHCl3 solution) (cm–1): 3500 (br), 3016 (s), 2931 (s), 2858
(s), 1773 (w), 1709 (s), 1460 (m), 1379 (m), 1360 (w), 1278
(m), 1232 (m), 1180 (s), 1124 (s), 1082 (s), 1040 (s), 1010
(s), 985 (s). 1H NMR (400 MHz, CDCl3) d: 6.90 (dd, J = 16,
5, 1H, 3-H), 6.12 (dd, J = 16, 2, 1H, 2-H), 5.02–5.08 (m,
1H, 4-H), 4.53–4.59 (m, 1H, 5-H), 3.77–3.80 (m, 1H, 6-H),
3.59 (dd, J = 3, 7 1H,), 3.10 (d, J = 7, 1H, 4-OH), 2.95 (d,
J = 7, 1H, 5-OH), 2.35 (d, J = 3, 1H, 6-OH), 1.08–1.60 (m,
23H, (CH2)10, CH3CH). 13C NMR (100 MHz, CDCl3) d:
165.3 (C-1), 144.4 (C-3), 123.1 (C-2), 74.8, 73.2, 71.1, 69.9
(C-4, C-5, C-6, C-17), 35.7, 32.2, 28.3, 27.8, 27.6, 27.3,
27.1, 26.4, 24.3, 23.6 (C7–C16), 20.5 (CH3).
(4Z)-(1S,2R,6R,7aR,7bR)-7a,7b-Dimethoxy-2-methoxy-
methylhydroxy-7a,7b-dimethyl-7,8-dioxa-bicyclo[4.4.0]-
dec-4-ene (23)
[a]2D9 –216.9° (c 0.54, CHCl3). Rf = 0.19 (petrol–ether,
2:1). ES-MS m/z (%): 311 ([M + Na]+, 100), 295 (5), 224
(5), 158 (8) (anal. calcd. (ES+) for C14H24O6Na: 311.1471
(M + Na); found: 311.1489 ([M + Na]+)). ꢀmax (neat) (cm–1):
1
2946 (m), 1375 (w), 1137 (s), 1110 (s), 1035 (s). H NMR
(400 MHz, CDCl3) d: 5.80 (d, J = 10, 1H, H-5), 5.61 (d, J =
10, 1H, H-4), 4.68 (s, 2H, OCH2OCH3), 4.31 (br s, 1H, H-
6), 4.17 (t, J = 4, 1H, H-1), 3.96 (br s, 1H, H-2), 3.36 (s, 3H,
OCH2OCH3), 3.29 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 2.49
(dt, J = 3, 18, 1H, H-3), 2.07 (dd, J = 3, 18, 1H, H-3), 1.28
(s, 3H, CH3), 1.27 (s, 3H, CH3). 13C NMR (100.6 MHz,
CDCl3) d: 128.3 (C-5), 122.6 (C-4), 99.3, 98.7 (C-7a, C-7b),
95.5 (OCH2OCH3), 73.4 (C-2), 66.0 (C-6), 64.4 (C-1), 55.5
(OCH2OCH3), 48.8 (OCH3), 48.0 (OCH3), 26.6 (C-3), 18.7
(CH3), 17.9 (CH3).
Acknowledgments
We thank the EPSRC (to D.J.D. and A.C.F), Syngenta (to
A.C.F.) and the Novartis Research Fellowship (to S.V.L.) for
financial support. Dr. J.E.Davies is kindly thanked for x-ray
crystallography and Dr M. Turnbull for helpful discussions.
(16E)-(1S,2R,13S,18R,19aR,19bR)-19a,19b-Dimethoxy-2-
methoxymethylhydroxy-13,19a,19b-trimethyl-14,19,20-
trioxa-bicyclo[16.4.0]doicosa-16-ene-15-one
References
1. E. Schoffers, A. Golebiowski, and C.R. Johnson. Tetrahedron,
52, 3769 (1996).
Pd-BaSO4 (10 mg) was added to a solution of diene 22
(37.8 mg, 0.08 mmol) in EtOAc (4 mL). The reaction was
stirred under an atmosphere of hydrogen for 40 min, the cat-
alyst was removed by filtration and the solvent removed in
vacuo to leave crude product. Rf = 0.29 (petrol–ether, 2:1).
ES-MS m/z (%): 509 ([M + Na]+, 100), 435 (5), 413 (3), 365
(2), 313 (10), 292 (8), 224 (5) (anal. calcd. (ES+) for
C26H46O8Na: 509.3091 (M + Na); found: 509.3101 ([M +
Na]+)). ꢀmax (neat) (cm–1): 2929 (m), 2857 (m), 1719 (s),
1654 (w), 1460 (m), 1372 (m), 1331 (w), 1247 (s), 1208
(m), 1176 (m), 1135 (s), 1110 (s), 1036 (s). 1H NMR
(400 MHz, CDCl3) d: 7.52 (dd, J = 10, 16, 1H, H-17), 5.96
(d, J = 6, 1H, H-16), 5.10–5.16 (m, 1H, H-13), 4.96 (d, J =
7, 1H, OCH2OCH3), 4.70 (d, J = 7, 1H, OCH2OCH3), 3.98–
4.03 (m, 2H, H-1, H-18), 3.29–3.41 (m, 1H, H-2), 3.39 (s,
3H, OCH2OCH3), 3.28 (s, 3H, OCH3), 3.12 (s, 3H, OCH3),
1.11–1.59 (m, 29H). 13C NMR (100.6 MHz, CDCl3) (major
isomer only) d: 165.6 (C=O), 144.0 (C-17), 125.3 (C-16),
99.5, 98.2 (19a, 19b), 98.4 (OCH2OCH3), 75.5 (C-2), 73.0
(C-18), 72.1 (C-1), 70.5 (C-13), 56.1 (OCH2OCH3), 48.3
2. M.C. Willis. J.Chem. Soc. Perkin Trans. 1, 1765 (1999).
3. H.C. Kolb, M.S. Vannieuwenhze, and K.B. Sharpless. Chem.
Rev. 94, 2483 (1994).
4. P.J. Edwards and S.V. Ley. Synlett, 898 (1995).
5. S.V. Ley and S. Mi. Synlett, 789 (1996).
6. S.V. Ley, S. Mio, and B. Meseguer. Synlett, 791 (1996).
7. D. Laine, M. Fujita, and S.V. Ley. J. Chem. Soc. Perkin Trans.
1, 1639 (1999).
8. S. Huneck, K. Schreiber, and W. Steglich. Tetrahedron, 29,3697
(1973).
9. O. Hesse. J. Prakt. Chem. 62,430 (1900).
10. O. Hesse. J. Prakt. Chem. 70, 449 (1904).
11. G. Quinkert, N. Heim, J.W. Bats, H. Oschkinat, and H. Kessler.
Angew. Chem. Int. Ed. Eng. 24, 987 (1985).
12. D.J. Dixon, A.C. Foster, and S.V. Ley. Org. Lett. 2, 123 (2000).
13. G. Quinkert, N. Heim, J. Glenneberg, U.M. Billhardt, V. Autze,
J.W. Bats, and G. Durner. Angew. Chem. Int. Ed. Engl. 26,
362 (1987).
14. P.P. Waanders, L. Thijs, and B. Zwanenburg. Tetrahedron Lett.
28, 2409 (1987).
© 2001 NRC Canada

1680
Can. J. Chem. Vol. 79, 2001
15. G. Quinkert, N. Heim, J. Glenneberg, U. Doller, M.
Eichhorn, U.M. Billhardt, C. Schwarz, G. Zimmermann,
J.W. Bats, and G. Durner. Helv. Chim. Acta, 71, 1719
(1988).
16. G. Quinkert, E. Fernholz, P. Eckes, D. Neumann, and G. Durner.
Helv. Chim. Acta, 72, 1753 (1989).
17. G. Quinkert, U. Doller, M. Eichhorn, F. Kuber, H.P. Nestler, H.
Becker, J.W. Bats, G. Zimmermann, and G. Durner. Helv. Chim.
Acta, 73, 1999 (1990).
25. T. Nishioka, Y. Iwabuchi, H. Irie, and S. Hatakeyama. Tetrahe-
dron Lett. 39, 5597 (1998).
26. M.G. Banwell and K.J. McRae. Org. Lett. 2, 3583 (2000).
27. N. Maezaki, Y.X. Li, K. Ohkubo, S. Goda, C. Iwata, and
T. Tanaka. Tetrahedron, 56, 4405 (2000).
28. H.J. Liu, P.A. Rose, and D.J. Sasaki. Can. J. Chem. 69, 934
(1991).
29. D.J. Dixon, A.C. Foster, S.V. Ley, and D.J. Reynolds. J. Chem.
Soc. Perkin Trans. 1, 1635 (1999).
18. G. Quinkert, H. Becker, and G. Durner. Tetrahedron Lett. 32,
7397 (1991).
30. D.J. Dixon, A.C. Foster, S.V. Ley, and D.J. Reynolds. J. Chem.
Soc. Perkin Trans. 1, 1631 (1999).
19. S.C. Sinha and E. Keinan. J. Org. Chem. 59, 949 (1994).
20. D. Enders and O.F. Prokopenko. Liebigs Ann. 1185 (1995).
21. W. Oppolzer, R.N. Radinov, and J. Debrabander. Tetrahedron
Lett. 36, 2607 (1995).
22. R. Chenevert, M. Lavoie, and M. Dasser. Can. J. Chem. 75, 68
(1997).
31. A.J. Mancuso and D. Swern. Synthesis, 165 (1981).
32. J.S. Barlow, D.J. Dixon, A.C. Foster, S.V. Ley, and D.J.
Reynolds. J. Chem. Soc. Perkin Trans. 1, 1627 (1999).
33. D. Askin, R.P. Volante, R.A. Reamer, K.M. Ryan, and I. Shinkai.
Tetrahedron Lett. 29, 277 (1988).
34. M.A. Blanchette, W. Choy, J.T. Davis, A.P. Essenfeld, S.
Masamune, W.R. Roush, and T. Sakai. Tetrahedron Lett. 25,
2183 (1984).
23. Y. Kobayashi, M. Nakano, and H. Okui. Tetrahedron Lett. 38,
8883 (1997).
24. S.C. Sinha and E. Keinan. J. Org. Chem. 62, 377 (1997).
35. R.H. Grubbs and S. Chang. Tetrahedron, 54, 4413 (1998).
© 2001 NRC Canada