Studies directed toward the synthesis of reiswigin A: Total synthesis of (±)-epi-reiswigin A

Article abstract of DOI:10.1139/v03-210

As a testing ground for the practical application of asymmetric synthesis, (-)-reiswigin A, a potent antiviral agent, was chosen as a target for total synthesis. Initial studies were undertaken to prove the viability of the key asymmetric step, enantiosel

Full text of DOI:10.1139/v03-210

333
Studies directed toward the synthesis of reiswigin
A: Total synthesis of ( )-epi-reiswigin A1
David I. MaGee and Dean E. Shannon
Abstract: As a testing ground for the practical application of asymmetric synthesis, (–)-reiswigin A, a potent antiviral
agent, was chosen as a target for total synthesis. Initial studies were undertaken to prove the viability of the key asym-
metric step, enantioselective deprotonation of an intermediate meso-bicyclic ketone, using a chiral lithium amide base.
Enantiomeric excesses in the range of 90%–94% were routinely obtained, even on runs as large as 10 g. Unfortunately,
conversion of this key enantio-enriched intermediate to the natural product proved unsuccessful. While these studies
were enroute, a parallel synthesis using the racemic compound was transformed into ( )-epi-reiswigin A.
Key words: asymmetric deprotonation, synthesis, ( )-epi-reiswigin A.
Résumé : Comme méthode d’application pratique de synthèse asymétrique, la cible choisie a été la (–)-reiswigine A,
un agent antiviral puissant. Les études initiales ont été entreprises pour montrer la viabilité de l’étape asymétrique clé,
la déprotonation énantiosélective cétone méso-bicyclique intermédiaire à l’aide d’une base chirale, un amide de lithium.
On a régulièrement obtenu des excès énantiomériques de l’ordre de 90 % à 94 %, même avec des lots allant jusqu’à
10 g. Malheureusement, de cet intermédiaire clé énantiomériquement enrichi en produit naturel n’a pu être réalisée.
Alors que ces travaux progressaient, dans une synthèse parallèle il a été possible de transformer le produit racémique
en ( )-épi-reiswigine A.
Mot clés : déprotonation asymétrique, synthèse, ( )-épi-reiswigine A.
[Traduit par la Rédaction] MaGee and Shannon 343
Introduction
and vesicular stomatitis virus (IC50 2 mg) and partial inhibi-
tion at 20 mg against murine A59 hepatitis virus. The abso-
lute stereochemistry was not established until Snider et al.
(2) developed an asymmetric synthesis of (–)-reiswigin A in
1990. A second synthesis by Kim et al. (3) in 1994 con-
firmed the assignments.
Retrosynthetically (Fig. 1), it was envisaged that reiswigin
A could be generated from an intermediate such as 2 via
some type of intramolecular condensation reaction, i.e.,
dithiane alkylation of 3 with a suitable electrophile derived
from 2 and methylation of the thermodynamic enolate to in-
stall the angular ring methyl (C-11). Compound 2 could be
conveniently generated by oxidative cleavage of the [3.2.1]-
silyl enol ether produced by desymmetrization of the meso
ketone 4 via enantioselective deprotonation (4). Bicyclic ke-
tones like 4 are known and can be easily accessed by [4+3]-
cycloaddition (5) between compounds like 5 and 6 (6).
The development of methods for the preparation of carbo-
cylic natural products with control of relative and absolute
stereochemistries has been a longstanding challenge in or-
ganic synthesis. The problem of controlling the configura-
tion of a stereogenic centre on a pendant side chain relative
to the ring to which it is attached has been particularly trou-
blesome. We report that enantioselective deprotonation can
be used to help address this problem. As a testing ground for
the practical application of this strategy, a biologically and
structurally interesting natural product, (–)-reiswigin A (1)
(Fig. 1), was chosen as a target for total synthesis.
Reiswigin A is a hydroazulenoid diterpene that was ob-
tained from the deepwater marine sponge organism Epipo-
lasis reiswigi collected by submersible at 330 m. Its
isolation and characterization using mass spectrometry, IR,
UV, and one- and two-dimensional NMR techniques was
first reported by Koehn et al. (1). It was found to have in-
triguing biological properties, with complete inhibitory in
vitro activity against herpes simplex type 1 virus (IC50 2 mg)
Results and discussions
Construction of the [3.2.1]-bicyclic ketone became the
first targeted intermediate. Starting with the known keto-
aldehyde 8 (6), obtained as an inseparable 5:1 mixture of
stereoisomers by acid catalyzed hydrolysis of [4+3]-cyclo-
adduct 7, Wittig reaction with acetonyltriphenylphosphorane
(7) afforded, after separation of the endo and exo isomers, E-
and Z-unsaturated diketone 9 in 73% combined yield
(Scheme 1). The E- and Z-isomers of diketone 9 were then
hydrogenated over 10% Pd–C to yield 4 in 95% yield. Selec-
tive ketalization provided ketone 10 in 81% yield. Complete
Received 20 June 2003. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 20 February
2004.
D.I. MaGee2 and D.E. Shannon. Department of Chemistry,
University of New Brunswick, P.O. Box 45222, Fredericton,
NB E3B 6E2, Canada.
1This article is part of a Special Issue dedicated to Professor
Ed Piers.
2Corresponding author (e-mail: dmagee@unb.ca).
Can. J. Chem. 82: 333–343 (2004)
doi: 10.1139/V03-210
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Can. J. Chem. Vol. 82, 2004
Fig. 1. Retrosynthetic analysis of (–)-reiswigin A.
Scheme 1. (a) 10% H2SO4, 1,4-dioxane, ∆; (b) acetonyltriphenylphosphorylidene, THF, ∆; (c) H2, Pd–C, EtOAc; (d) ethylene glycol,
HC(OMe)3, pTSA, CH2Cl2; (e) (–)-12·hydrochloride salt, n-BuLi, TMSCl, THF, –30 °C to –100 °C.
and facile control of all the relative stereochemistries made
this route very appealing.
Ketone 10 was deprotonated using chiral lithium amide
base (CLAMB) 12 (8) and Corey’s internal quench proce-
dure to produce silyl enol ether 11 in 91% yield and 94%
ee.3
At this time the absolute stereochemistry and choice of
base are worthy of comment. Although many studies had
been undertaken on the desymmetrization of meso cyclic ke-
tones, there had not been any previous studies on com-
pounds that had substitution at all positions. However,
examination of the studies on 2,6-dimethyl- (9), 3,5-
dimethyl- (10), and 4-alkyl-cyclohexanones (11) suggested
that Simpkins’ base 12 (11)4 and Koga’s base 13 (12) give
enantio-complimentary results, Fig. 2. Thus, it was believed
that CLAMB 13 or CLAMB 12 would be the chiral base of
choice, depending on which one was found to give the high-
est ee. Another consideration, however, was the fact that the
synthesis of Simpkins’ amine was considerably shorter and
its recovery after reaction with the ketone much easier.
When CLAMBs 12 and 13 were used to deprotonate
meso-ketone 10, they were found to favour removal of the
same enantiotopic proton (i.e., optical rotation of the result-
ing silyl enol ethers had the same sign). This supported the
3 The ee was determined via oxidation of the TMS – enol ether with DMDO, followed by use of chiral shift reagents. Complete separation of
1
the methyl doublets was observed; integration of the H NMR signals gave the enantiomeric ratio. This value was corroborated by conver-
1
sion of another intermediate into its Mosher’s ester, followed by integration of the 19F and H NMR signals of the diastereoisomers.
4 Examples found in the literature used the enantiomer of 12.
© 2004 NRC Canada

MaGee and Shannon
335
Fig. 2. Previous studies on asymmetric deprotonation of various substituted meso-cyclohexanones.
Scheme 2. (a) NaIO4, RuCl3, CCl4, CH3CN, H2O, 15 °C; (b) BH3·SMe2, THF, 0 °C; (c) TBDPSCI, DMAP, TEA, CH2Cl2; (d) (COCl)2,
DMSO, TEA, CH2Cl2, –60 °C; (e) LDA, TMSCl, THF, –78 °C; (f) NBS, THF, 0 °C; (g) P(OMe)3, toluene, ∆; (h) PPTS, CH3CN, ∆;
(i) benzyltrimethylammonium methoxide, CH3CN, 0 °C; (j) LDA, MeI, HMPA, THF, –78 °C to 0 °C.
above conclusion and suggested that these chiral bases act
on ketone 10 in a manner similar to the above-noted substi-
tuted cyclohexanones. The degree of stereoinduction and
isolated yield were found to be higher using CLAMB 12
(90%–94% ee, 91% yield) than 13 (72%–75% ee, 84%
yield). The high ees demonstrated the first known successful
enantioselective deprotonation of a fully substituted meso-
cyclohexanone and verified our earlier assumption that this
technique would be useful for this substrate.5
Sharpless (13) conditions produced a highly unstable keto-
acid, which was immediately reduced to the diol with
BH3·SMe2 (14) in 64% yield over the two steps. Several at-
tempts at selective reduction of the acid functionality gave
either only the starting acid or diol. Following standard con-
ditions, the very polar diastereomeric alcohols were trans-
formed to their tert-butyldiphenylsilyl ethers 14 via selective
protection of the primary alcohol (15) followed by oxidation
to ketone 15 using Swern conditions (16). It was hoped that
protection of the primary alcohol with a very bulky group
would help direct methylation at C-1; however, it was real-
With enantioenriched enol ether 11 in hand, the synthesis
was continued (Scheme 2). Oxidative cleavage using
5 As a means of determining the absolute stereochemistry, attempts were made to obtain crystals that were suitable for X-ray analysis. Unfor-
tunately all derivatives were found to be oils or failed to deliver suitable crystals. Therefore, all structures are shown with the stereo-
chemistry inferred from the above analysis.
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Can. J. Chem. Vol. 82, 2004
Scheme 3. (a) TBAF, THF; (b) ethylene glycol, HC(OMe)3, pTSA, CH2Cl2; (c) PPh3, I2, imidazole, Et2O, CH3CN; (d) 2-isobutyl-1,3-
dithiane, n-BuLi, THF, 0 °C to –90 °C; (e) HgCl2, aq. CH3CN, ∆.
ized that 1,3-stereoinduction must override 1,2-stereo-
induction in order for this to happen. Simple molecular
modeling (MMFF92) on an analogue of 15 supported this
speculation.6 The six most stable conformers were found to
be within 1.5 kcal of one another; of these, the four lowest
energy conformations all had at least one phenyl group
blocking the α-face. In fact, the first conformer that did not
have this arrangement was 1.7 kcal higher in energy than the
global minimum. To this end, valiant efforts were under-
taken to methylate the thermodynamic enolate of ketone 15;
however, they were to no avail. The ineffectiveness of
alkylation was primarily attributed to an inability to effect
quantitative thermodynamic enolate formation.
To alleviate this difficulty, 15 was transformed into cyclo-
heptenone 19 by the following sequence (Scheme 2):
(a) bromination of the kinetic enolate with NBS (17) to give
α-bromo-ketone 16; (b) Arbuzov (18) reaction with tri-
methylphosphite to generate β-keto phosphonate 17;
(c) acid-catalyzed deprotection (19) of the dioxolane; and
(d) intramolecular Horner–Emmons reaction. The intra-
molecular cyclization proved more difficult than expected.
Following the traditional protocol of using DBU (20), very
little desired product was obtained. Extended reaction times
at room temperature or higher led to no improvement, while
use of sodium hydride gave an unacceptable 34% yield. For-
tunately, the use of benzyltrimethylammonium (BTMA)
methoxide (21) led to the desired cycloheptenone in 75%
yield, as an approximate 1:1 mixture of C-1 epimers, pre-
sumably because of the use of excess base. The epimeric
mixture was of no concern, since the fate of that stereocenter
was to be determined in the next step
Treatment of the epimeric cycloheptenones with LDA,
followed by addition of MeI, gave a single alkylated product
in 65% yield (Scheme 2). Extensive NMR investigation
proved inconclusive in determining the structure of this
alkylated product. Preliminary evidence,7 however, sug-
gested that C-11 was trans to C-5 and therefore the unde-
sired product. It was reasoned that if the methylation were
done before cyclization then perhaps the substrate would
adopt a conformation that would allow for the desired
stereochemical addition. Previous studies (22) on a ketone
similar to compound 15 were unsuccessful in obtaining the
thermodynamic methylation product. Ketophosphonate 17
(Scheme 2), on the other hand, had the potential to undergo
a Weiler-type reaction (23). Treatment of 17 with NaH, fol-
lowed by n-BuLi and then MeI gave no reaction. Further-
more, the use of lithium diethylamide as base yielded no
improvement.
Although the nOe studies on compound 19 were disap-
pointing, they were not conclusive. It was therefore decided
6 The calculations were performed on the following structure:
7 A small enhancement was seen in the nOesy experiment between H-11 and H-13, while no cross-peak was observed between H-11 and H-5.
© 2004 NRC Canada

MaGee and Shannon
337
Fig. 3. X-ray crystal structure of epi-reiswigin A.
that this compound should be carried on in an effort to finish
the synthesis, thus allowing for the details of the isovaler-
aldehyde side-chain addition to be established. The spectra
obtained from the final compound could then be compared
to that of the natural product for definitive identification.
This would unequivocally show whether or not the proper
relative stereochemistry had been secured. In addition, ow-
ing to the lack of enantio-enriched material at this time, the
synthesis was continued with racemic material.
a chiral imine (2), similar to Snider’s synthesis of (–)-
reiswigin A, would force methylation from the desired face;
see 26* in Scheme 3. Unfortunately, when cycloheptenone
17* was treated with tert-butyl L-valine ester (28) in
refluxing toluene, only recovered starting material was ob-
tained. Efforts to produce the imine using a variety of meth-
ods failed. Attempts to alter the stereochemical outcome of
alkylation by using bulky chiral Lewis acids (29) also
proved futile.
Given these results, it appears that it is unlikely that any
nucleophilic-, electrophilic-, or radical-type additions to in-
troduce the angular methyl group this late in the synthesis
has any chance of success. Therefore, a revision of the syn-
thetic route will have to be undertaken to account for this
problem.
To promote the desired substitution reaction, it was de-
cided to protect the cyclic ketone as its ketal (Scheme 3).
First, exposure of racemic ketone 19*8 to TBAF (15) gener-
ated the primary alcohol 21*. When this alcohol was sub-
jected to standard ketalization conditions, ketal-alcohol 22*
was obtained in only 58% yield with complete double-bond
migration (24). Unexpectedly, however, a significant amount
of ketal formate (30%) was produced. However, this was
easily converted to the desired alcohol by exposure to aque-
ous base, therefore giving an overall yield of 88% for the
ketalization. The alcohol was then converted to iodide 23* in
62% yield, using conditions developed by Garegg and
Samuelsson (25). When the iodide was treated with the an-
ion of isobutyldithiane (26), dithioketal 24* was produced in
81% yield. To achieve this yield, it was imperative to use
HMPA and low temperatures; failure to do so resulted in sig-
nificant elimination. Completion of the synthesis was ac-
complished by subjecting 24* to HgCl2 (27) in refluxing,
aqueous CH3CN to furnish 25* in 67% yield (Scheme 3).
Summary
In conclusion, epi-reiswigin A was synthesized in 19 steps
from the known keto-aldehyde 8 with an overall yield of
2.2%, with an average 82% yield per step. Efforts are cur-
rently underway to alter the strategy to allow for incorpora-
tion of the C-1 methyl group with the correct configuration.
Although it was unfortunate that all endeavors to introduce
the methyl group with the correct stereochemistry in the fi-
nal stages of the synthesis failed, it was gratifying to see that
the asymmetric deprotonation strategy worked as designed.
Given the ease at which controlling the configuration of a
stereogenic centre on a pendant side chain relative to the
ring to which it is attached was accomplished, this approach
should find use in the synthesis of similar cyclopentanoid
compounds such as cereoplastol II (30) and albolic acid
(31).
1
Close examination of the H and 13C NMR data clearly indi-
cated that our synthetic compound was not identical to the
natural product reiswigin A. Furthermore, suitable crystals
of 25 were obtained, and X-ray diffraction studies9 unequiv-
ocally verified the earlier hypothesis; that is, the C-11
methyl group had unfortunately added incorrectly (Fig. 3),
and this in fact meant that we had synthesized epi-reiswigin
A.
Experimental
Given that the configuration at C-1 was incorrect, efforts
were directed towards finding a solution. It was felt that
perhaps conversion of the cyclic ketone functionality into
All nonaqueous reactions were carried out in flame-dried
round bottom flasks under an inert atmosphere (nitrogen or
argon), unless stated otherwise. Temperatures indicated refer
8 Racemic 19* was generated as outlined in Schemes 1 and 2, except that deprotonation of 10 was performed with LDA.
9 The crystallographic data for this compound has been deposited as supplementary data. Supplementary data may be purchased from the De-
pository of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0S2, Canada
(http://www.nrc.ca/cisti/irm/unpub_e.shtml for information on ordering electronically). CCDC 227050 contain the supplementary data for
this paper. These data can be obtained, free of charge, via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge, U.K.; fax +44 1223 336033; or deposit@ccdc.cam.ac.uk).
© 2004 NRC Canada

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Can. J. Chem. Vol. 82, 2004
to an external bath. All reactions were magnetically stirred.
All organic solvents were distilled and dried following
known procedures (32). Reagents were purchased from vari-
ous commercial suppliers and used without further purifica-
tion. Analytical thin layer chromatography (TLC) was
performed using Merck 60 F-254 silica gel precoated glass
plates (0.25 mm). Visualization was effected by short wave
UV illumination and (or) KMnO4 or PMA dip, followed by
development on a hot plate. Flash column chromatography
was performed using Fisher silica gel (32–63 particle size).
Melting points were measured on a Gallenkamp melting
point apparatus with uncorrected temperatures. Infrared
spectra were recorded on either a PerkinElmer 598 IR spec-
trometer using NaCl cells and CHCl3 as solvent or on a
Bruker IFS 25 IR spectrometer using KBr discs and neat
sample. Peaks are reported in wavenumbers (cm–1). Nuclear
magnetic resonance spectra10 were recorded on a Varian
Unity-400 (400 MHz) NMR spectrometer with CDCl3 as
solvent (unless stated otherwise). Chemical shifts were re-
ported in parts per million (ppm) relative to SiMe4 as inter-
nal standard, and coupling constants were reported in Hz.
Low-and high-resolution electron impact mass spectra were
recorded on a Kratos MS50TC mass spectrometer, with
fragments reported as their m+/z ratio. Optical rotations were
measured on a PerkinElmer 241 polarimeter.
were washed with H2O and brine, dried over MgSO4, and
filtered. Concentration under reduced pressure gave crude
ketoaldehyde 8 in a 5:1 ratio as a brown oil. All spectral
data were identical to that reported by Hoffmann (6). This
crude mixture was used directly in the next step.
Synthesis of unsaturated diketone 9
A crude mixture of aldehyde 8 (5.9 g, 33 mmol) in 15 mL
of THF was added to a mixture of acetonyltriphenylphos-
phorane (12.7 g, 40 mmol) and 115 mL of THF. The reac-
tion mixture was stirred at reflux for 2 days, cooled to room
temperature, diluted with ether, and filtered through a pad of
Celite, and the solvent was removed under reduced pressure.
Purification by SiO2 column chromatography (5:1 Hex:EtOAc
as eluant) afforded 6.1 g of the trans-isomer and 0.61 g of
the cis-isomer (73% combined yield over the two steps) as
colorless oils.
trans-Isomer
1
IR (cm–1): 2925, 1710, 1670, 1625, 1440, 1360. H NMR
δ: 1.06 (6H, d, J = 7.0), 2.23 (3H, s), 2.57 (2H, dq, J = 2.8,
6.9), 2.72 (2H, br. s), 3.02 (1H, d, J = 7.9), 6.07 (2H, dd, J =
0.9, 0.9), 6.13 (1H, dd, J = 16.0, 0.9), 6.78 (1H, dd, J =
16.1, 7.9). 13C NMR δ: 13.9 (2C), 27.0, 50.3 (2C), 51.2
(2C), 57.9, 131.3, 133.9 (2C), 147.8, 198.5, 211.3. HR-EI-
MS: C14H18O2 = 218.13026 ([M]+), C14H18O2 = 218.13068
(calcd.).
Synthesis of [3.2.1]-bicycloheptanone 7
To activated (33) copper powder (14.5 g, 228 mmol) and
oven-dried sodium iodide (51.3 g, 342 mmol) was added
240 mL of CH3CN. To the stirring mixture was slowly
added 2,4-dibromo-3-pentanone 6 (41.7 g, 171 mmol) in
20 mL of CH3CN and 6-acetoxyfulvene 5 (7.8 g, 57 mmol)
in 20 mL of CH3CN, simultaneously. The reaction mixture
was stirred at room temperature for 16 h and then poured
into 900 mL of a 1:1:1 mixture of ether, 30% NH4OH, and
H2O. The layers were separated, and the aqueous layer was
extracted with ether (3 × 180 mL). The combined organic
layers were washed with H2O (until the aqueous layer was
neutral) and brine and then dried over MgSO4, filtered, and
concentrated in vacuo. The crude residue was first flash fil-
tered through a pad of silica gel (8:1 hexanes (Hex) : EtOAc
as eluant) and then more rigorously purified via SiO2 col-
umn chromatography (14:1 Hex:EtOAc as eluant) to give
9.3 g (74% yield) of enol acetate 7 (4) as a colorless oil. IR
cis-Isomer
1
IR (cm–1): 2930, 1710, 1695, 1610, 1450, 1350, 1170. H
NMR δ: 1.03 (6H, d, J = 6.8), 2.24 (3H, s), 2.63 (2H, d, J =
0.9), 2.65–2.69 (2H, m), 4.00 (1H, d, J = 7.7), 6.06 (2H, dd,
J = 1.5, 0.9), 6.07–6.18 (2H, m). 13C NMR δ: 13.8 (2C),
31.7, 50.4 (2C), 52.2 (2C), 54.6, 126.9, 134.6 (2C), 150.1,
199.0, 212.2. HR-EI-MS: C14H18O2 = 218.13002 ([M]+),
C14H18O2 = 218.13068 (calcd.).
Synthesis of diketone 4
The unsaturated E- and Z-mixture of diketone 9 (10.0 g,
45.8 mmol) in 150 mL of EtOAc was placed in a Parr bottle,
followed by a catalytic amount of 10% palladium on acti-
vated carbon (~1 g). The mixture was then shaken at room
temperature on a Parr hydrogenation apparatus under H2 at-
mosphere (~40 psi (1 psi = 6.894 kPa)) for 30 min. Celite
was then added, and the reaction mixture was filtered, and
the solvent was removed in vacuo. Purification by SiO2
column chromatography (5:1 Hex:EtOAc as eluant) afforded
9.70 g (95% yield) of diketone 4 as a colorless oil. IR (cm–1):
1
(cm–1): 2920, 1740, 1705, 1375, 1080. H NMR δ: 1.07 (3H,
d, J = 7.0), 1.11 (3H, d, J = 6.8), 2.18 (3H, s), 2.53–2.64
(2H, m), 3.16 (1H, br.s), 3.57 (1H, br.s), 6.16 (1H, dd, J =
2.6, 6.0), 6.22 (1H, dd, J = 2.67 6.1), 7.02 (1H, s). 13C NMR
δ: 13.8, 13.9, 20.7, 45.5, 47.8, 51.3, 52.9, 121.8, 134.4,
1
2930, 1710, 1360. H NMR δ: 0.96 (6H, d, J = 6.7), 1.38
(2H, d, J = 8.9), 1.52–1.62 (4H, m), 2.02 (2H, br. d, J = 4.1),
2.17–2.21 (1H, m), 2.19 (3H, s), 2.47 (2H, m), 2.54 (2H, t,
J = 7.5). 13C NMR δ: 12.5 (2C), 21.9 (2C), 25.1, 29.9, 42.0,
47.0 (2C), 50.5 (2C), 52.3, 208.6, 213.3. HR-EI-MS:
C14H28O2 = 222.16047 ([M]+), C14H28O2 = 222.16199
(calcd.).
135.2, 135.3, 168.2, 211.2. HR-EI-MS: C11H14O2
=
178.09909 ([M+ – C2H2O]), C11H14O2 = 178.09938 (calcd.).
Synthesis of ketoaldehyde 8
To enol acetate 7 (9.3 g, 42 mmol) was added 180 mL of
1,4-dioxane and 180 mL of 10% H2SO4. The reaction mix-
ture was stirred at reflux for 6 h; the heat source was re-
moved, and ice-cold saturated K2CO3 was immediately but
carefully added until the mixture was neutral. It was then ex-
tracted with ether (5×), and the combined organic extracts
Synthesis of ketoketal 10
To a catalytic amount of pTSA in 70 mL of CH2Cl2 was
added diketone 4 (5.7 g, 25.6 mmol) in 15 mL of CH2Cl2.
To this stirring solution was added ethylene glycol (1.7 mL,
1
10Copies of H and 13C NMR spectra of all compounds are provided as supplemental material (see footnote 9).
© 2004 NRC Canada

MaGee and Shannon
339
30.7 mmol) and 98% trimethylorthoformate (3.4 mL,
30.7 mmol). The reaction mixture was stirred at room tem-
perature for 5 h, diluted with saturated NaHCO3, and ex-
tracted with CH2Cl2 (2×). The combined organics were
washed with H2O and brine and dried over MgSO4. The sol-
vent was removed under reduced pressure, and the residue
was purified by SiO2 column chromatography (5:1
Hex:EtOAc as eluant) to give 5.5 g (81% yield) of ketoketal
10 as a low-melting white solid. Further purification could
be accomplished by recrystallization from hexane; mp 45.0–
by SiO2 column chromatography (hexane followed by 20:1
Hex:EtOAc as eluant) afforded 5.89 g (97% yield) of silyl
enol ether 11* as a colorless oil.
Synthesis of diastereomeric alcohols 14
A mixture of silyl enol ether 11 (2.49 g, 7.36 mmol), so-
dium metaperiodate (6.30 g, 29.44 mmol), a catalytic
amount of ruthenium trichloride, and 52.5 mL of
CCl4:CH3CN:H2O (2:2:3) was vigorously stirred at ~5 °C
for 10 min. It was then diluted with CH2Cl2 and just enough
H2O to dissolve the precipitate. The layers were separated,
and the aqueous phase was extracted with CH2Cl2 (3×) and
dried over Na2SO4. The combined organics were concen-
trated under reduced pressure, diluted with ether, and filtered
through a pad of Celite. Concentration in vacuo afforded
crude ketoacid as a black oil, which was unstable and there-
fore was used immediately for the subsequent reaction.
To a 2.0 mol L–1 THF solution of borane – dimethyl sul-
fide complex (19.9 mL, 39.72 mmol) was added 23 mL of
THF. The solution was cooled to 0 °C, followed by dropwise
addition of the crude ketoacid (1.98 g, 6.62 mmol) in 12 mL
of THF. After complete addition, the ice-water bath was re-
moved, and the reaction mixture was allowed to stir at room
temperature for 2 h. Excess borane was then destroyed at
0 °C by slow dropwise addition of H2O, followed by a few
drops of 5% NaOH, and then stirring at room temperature
for 15 min. The cloudy mixture was concentrated in vacuo,
diluted with EtOAc, dried over MgSO4, and filtered, and the
solvent was removed under reduced pressure. The residue
was taken up in ethyl acetate and filtered through a pad of
SiO2 (EtOAc as eluant) to afford 1.35 g of a 1:1 diastereo-
meric mixture of diols 14 as colorless oils. The diastereo-
isomeric diols 14 (1.80 g, 6.28 mmol) in 10 mL of CH2Cl2
were added quickly to a solution of 4-dimethylaminopy-
ridine (100 mg), triethylamine (3.5 mL, 25.1 mmol), and
98% tert-butylchlorodiphenylsilane (1.83 mL, 6.91 mmol) in
20 mL of CH2Cl2. The reaction mixture was stirred at room
temperature overnight, diluted with saturated NaHCO3, and
extracted with CH2Cl2 (2×). The combined organics were
washed with H2O and brine and dried over MgSO4. It was
then filtered, and the solvent was removed in vacuo. The
product was purified by SiO2 chromatography (2:1
Hex:EtOAc as eluant) to give 2.63 g of the diasteromeric
silyl ethers as colorless oils.
1
46.1 °C. IR (cm–1): 2960, 1705, 1380, 1055. H NMR δ:
0.96 (6H, d, J = 6.7), 1.33 (3H, s), 1.34–1.40 (4H, m), 1.58–
1.62 (2H, m), 1.71–1.78 (2H, m), 2.04 (2H, br.d, J = 4.1),
2.18 (1H, t, J = 7.4), 2.47 (2H, dq, J = 1.6, 6.6), 3.91–3.99
(4H, m). 13C NMR δ: 12.6 (2C), 22.0 (2C), 23.7, 25.6, 37.7,
47.2 (2C), 50.7 (2C), 53.3, 64.6 (2C), 109.9, 213.7. HR-EI-
MS: C16H26O3 = 266.18874 ([M]+), C16H26O3 = 266.18820
(calcd.).
Synthesis of silyl enol ether 11
To a mixture of Simpkins’ (+) chiral amine HCl salt 12
(4.97 g, 18.7 mmol) and 90 mL of THF cooled to –30 °C was
added a 2.5 mol L–1 solution of n-BuLi in hexane (14.5 mL,
36.3 mmol), dropwise. After complete addition, the mixture
was stirred for an additional 20 min at –30 °C and then for
2 h at room temperature. It was cooled to –100 °C, and 98%
chlorotrimethylsilane (5.7 mL, 44.0 mmol) was added
quickly, followed immediately by slow dropwise addition of
ketone 10 (2.93 g, 11.0 mmol) in 20 mL of THF. The reac-
tion mixture was stirred at –100 °C for 1 h, and then
triethylamine (9.2 mL, 66.0 mmol) was added, and stirring
continued at –100 °C for 10 min. Ethyl acetate was added,
and the mixture was concentrated under reduced pressure.
The residue was diluted with ether and filtered through a pad
of Celite, and the solvent was removed in vacuo. Purification
by SiO2 column chromatography (hexane followed by 20:1
Hex:EtOAc as eluant) afforded 3.39 g (91% yield) of silyl
enol ether 11 as a colorless oil in 94% enantiomeric excess.
[α]D –20.5 (c = 1.27, CH2Cl2). IR (cm–1): 2965, 1670, 1380,
1
1110, 1060, 885. H NMR δ: 0.15 (9H, s), 0.97 (3H, d, J =
7.0), 1.20–1.26 (2H, m), 1.32 (3H, s), 1.47–1.56 (1H, m),
1.53, (3H, d, J = 2.2), 1.58–1.78 (6H, m), 1.88–1.91
(2H, m), 2.48–2.52 (1H, m), 3.90–3.98 (4H, m). 13C NMR δ:
0.4 (3C), 15.2, 15.9, 20.7, 23.7, 26.2, 30.1, 37.5, 42.3, 44.2,
45.4, 49.4, 64.6 (2C), 110.1, 120.3, 144.7. HR-EI-MS:
C19H34SiO3 = 338.22751 ([M]+), C19H34SiO3 = 338.22772
(calcd.).
Less polar diastereoisomer
[α]D +6.4 (c = 1.02, CH2Cl2). IR (cm–1): 3460, 3060,
1
2915, 1960, 1890, 1805, 1460, 1375, 1080. H NMR δ: 1.02
(3H, d, J = 6.50), 1.05 (9H, s), 1.14 (3H, d, J = 6.3), 1.26–
1.36 (1H, m), 1.30 (3H, s), 1.38–1.66 (12H, m), 3.43 (1H,
dd, J = 7.0, 9.9), 3.56–3.62 (1H, m), 3.65 (1H, dd, J = 4.2,
10.0), 3.86–3.95 (4H, m), 7.34–7.43 (6H, m), 7.65–7.67
(4H, m). 13C NMR δ: 16.7, 19.2, 22.1, 23.7, 26.0, 26.9 (3C),
28.3, 30.0, 37.1, 39.2, 43.9, 48.1, 52.6, 64.5, 64.5, 67.1,
69.3, 110.1, 127.5 (2C), 129.4 (2C), 134.0 (2C), 135.6 (4C),
Synthesis of racemic silyl enol ether 11*
To a mixture of diisopropylamine (2.82 mL, 20 mmol) and
50 mL of THF cooled to –78 °C was added a 2.5 mol L–1 so-
lution of n-BuLi in hexane (8.0 mL, 20 mmol), dropwise.
After complete addition, the mixture was stirred for 5 min;
then 98% chlorotrimethylsilane (2.85 mL, 22.0 mmol) was
added, followed immediately by dropwise addition of ketone
10 (4.79 g, 18.0 mmol) in 20 mL of THF. The reaction mix-
ture was stirred at –78 °C for 1 h, and then triethylamine
(4.6 mL, 33.0 mmol) was added. After stirring for 10 min,
the mixture was concentrated under reduced pressure. The
residue was diluted with ether and filtered through a pad of
Celite, and the solvent was removed in vacuo. Purification
135.6 (2C). HR-EI-MS: C28H41SiO2 = 437.28564 ([M+
C4H8O2]), C28H41SiO2 = 437.28760 (calcd.).
–
More polar diasteroisomer
[α]D +11.5 (c = 1.1, CH2Cl2). IR (cm–1): 3460, 3080,
1
2915, 1960, 1890, 1825, 1460, 1375, 1090. H NMR δ: 1.04
(3H, d, J = 6.8), 1.05 (9H, s), 1.11 (3H, d, J = 6.2), 1.24–
© 2004 NRC Canada

340
Can. J. Chem. Vol. 82, 2004
1.30 (2H, m), 1.30 (3H, s), 1.33–1.42 (1H, m), 1.45–1.57
(6H, m), 1.63–1.74 (4H, m), 3.42 (1H, dd, J = 7.0, 9.9),
3.46–3.50 (1H, m), 3.63 (1H, dd, J = 4.1, 9.9), 3.88–3.96
(4H, m), 7.35–7.44 (6H, m), 7.65–7.67 (4H, m). 13C NMR δ:
16.7, 19.3, 21.6, 23.7, 26.9 (3C), 28.1, 28.9, 31.3, 37.0, 39.6,
44.4, 48.8, 53.0, 64.4, 64.6, 67.4, 71.4, 110.4, 127.6 (4C),
129.5 (2C), 134.0 (2C), 135.6 (2C), 135.6 (2C). HR-EI-MS:
C28H41SiO2 = 437.28546 ([M+ – C4H8O2]), C28H41SiO2 =
437.28760 (calcd.).
bromoketone 16 as a colorless oil. [α]D +6.4 (c = 1.3,
CH2Cl2). IR (cm–1): 3060, 2910, 1960, 1890, 1825, 1710,
1
1470, 1375, 1250, 1070, 945, 705. H NMR δ: 1.02 (3H, d,
J = 6.8), 1.05 (9H, s), 1.27–1.41 (3H, m), 1.28 (3H, s), 1.55–
1.72 (6H, m), 1.79–1.85 (1H, m), 2.08–2.14 (1H, m), 2.91
(1H, ddd, J = 5.8, 5.8, 8.8), 3.46 (1H, dd, J = 6.4, 10.0),
3.62 (1H, dd, J = 4.5, 10.0), 3.86–3.94 (4H, m), 3.94 (2H, d,
J = 0.9), 7.35–7.43 (6H, m), 7.65–7.67 (4H, m). 13C NMR δ:
16.4, 19.3, 23.8, 26.9 (3C), 29.3, 29.9, 34.2, 37.2, 38.8, 44.4,
48.2, 54.6, 64.6 (3C), 67.0, 109.8, 127.6 (4C), 129.5 (2C),
133.8, 133.9, 135.6 (4C), 203.9. HR-EI-MS: C16H26O379Br =
345.10657 ([M+ – C16H19SiO]), C16H26O379Br = 345.10654
(calcd.).
Synthesis of ketone 15
To a stirring solution of 98% oxalyl chloride (0.51 mL,
5.68 mmol) in 8 mL of CH2Cl2 cooled to –60 °C was added
dimethyl sulfoxide (0.84 mL, 11.82 mmol) in 8 mL of
CH2Cl2, dropwise. This mixture was stirred at –60 °C for
15 min; then the alcohol (2.48 g, 4.73 mmol) in 14 mL of
CH2Cl2 was slowly added. After stirring at –60 °C for
30 min, triethylamine (3.3 mL, 23.6 mmol) was added; the
cold bath was removed, and stirring continued at room tem-
perature for 10 min. The cloudy solution was diluted with
saturated NaHCO3 and extracted with CH2Cl2 (2×). The
combined organics were washed with H2O and brine and
dried over MgSO4 and filtered, and the solvent was evapo-
rated in vacuo. Purification by SiO2 column chromatography
(3:1 Hex:EtOAc as eluant) afforded 2.25 g (91% yield) of
ketone 15 as a colorless oil. [α]D +5.6 (c = 1.10, CH2Cl2). IR
(cm–1): 3070, 2920, 1960, 1890, 1820, 1700, 1465, 1370,
Synthesis of ketophosphonate 17
A mixture of α-bromoketone 16 (1.73 g, 2.88 mmol) and
trimethylphosphite (1.4 mL, 11.5 mmol) in 29 mL of toluene
was stirred at reflux overnight. After cooling to room tem-
perature and concentration in vacuo, the residue was purified
by SiO2 column chromatography (1:3 Hex:EtOAc to EtOAc
as eluant) to give 1.60 g (88% yield) of ketophosphonate 17
as a colorless oil. [α]D +11.5 (c = 1.5, CH2Cl2). IR (cm–1):
3060, 2910, 1960, 1895, 1835, 1710, 1460, 1375, 1265,
1
1050. H NMR δ: 1.02 (3H, d, J = 6.7), 1.04 (9H, s), 1.27–
1.36 (2H, m), 1.29 (3H, s), 1.55–1.73 (7H, m), 1.78–1.84
(1H, m), 2.08–2.14 (1H, m), 2.82 (1H, ddd, J = 5.4, 5.4,
8.6), 3.07 (1H, dd, J = 14.0, 22.6), 3.15 (1H, dd, J = 14.0,
22.6), 3.44 (1H, dd, J = 6.5, 9.9), 3.62 (1H, dd, J = 4.4,
10.0), 3.77 (6H, d, J = 11.3), 3.86–3.95 (4H, m), 7.35–7.43
(6H, m), 7.64–7.67 (4H, m). 13C NMR δ: 16.3, 19.2, 23.7,
26.8 (3C), 28.9, 29.2, 30.0, 37.1, 39.0, 40.0 (d, J = 513.2),
43.3, 48.2, 52.9 (2C, d, J = 41.4), 58.5 (d, J = 6.4), 64.5
(2C), 67.1, 109.8, 127.5 (4C), 129.4 (2C), 133.9 (2C), 135.5
1
1235. H NMR δ: 1.03 (3H, d, J = 6.7), 1.05 (9H, s), 1.27–
1.36 (2H, m), 1.29 (3H, s), 1.54–1.70 (7H, m), 1.72–1.76
(1H, m), 2.04–2.08 (1H, m), 2.11 (3H, s), 2.55 (1H, ddd, J =
5.9, 5.9, 8.3), 3.45 (1H, dd, J = 6.6, 10.0), 3.63 (1H, dd, J =
4.4, 9.9), 3.86–3.95 (4H, m), 7.35–7.43 (6H, m), 7.65–7.67
(4H, m). 13C NMR δ: 16.4, 19.3, 23.8, 26.9 (3C), 28.8, 29.1,
29.3, 30.2, 37.4, 39.0, 43.7, 48.2, 58.5, 64.6 (2C), 67.1,
109.8, 127.5 (4C), 129.5 (2C), 133.9 (2C), 135.6 (4C),
210.9. HR-EI-MS: C28H37SiO4 = 465.24595 ([M+ – C4H9]),
C28H37SiO4 = 465.24612 (calcd.).
(4C), 203.8 (d, J = 25.6). HR-EI-MS: C30H42PSiO7
=
573.24459 ([M+ – C4H9]), C30H42PSiO7 = 573.24377
(calcd.).
Synthesis of diketophosphonate 18
Synthesis of bromoketone 16
To ketophosphonate 17 (1.00 g, 1.59 mmol) in 10 mL of
20% aqueous acetonitrile was added a catalytic amount of
pyridinium p-toluenesulfonate. The reaction mixture was
stirred at reflux for 1 h, cooled to room temperature, and
concentrated in vacuo. The residue was taken up in CH2Cl2
and washed with a small amount of H2O. The aqueous phase
was extracted with CH2Cl2 (2×), and the combined organics
were washed with brine, dried over MgSO4, and filtered, and
the solvent was removed in vacuo. Purification via SiO2 col-
umn chromatography (EtOAc as eluant) afforded 846 mg
(91% yield) of diketophosphonate 18 as a colorless oil. [α]D
+10.4 (c = 1.3, CH2Cl2). IR (cm–1): 3060, 2910, 1970, 1890,
To a solution of diisopropylamine (0.84 mL, 6.38 mmol)
in 14 mL of THF cooled to –78 °C was added a 2.5 mol L–1
solution of n-BuLi in hexane (2.4 mL, 6.06 mmol), drop-
wise. The mixture was stirred at –78 °C for 15 min; then
98% TMSCl (0.83 mL, 6.38 mmol) was added quickly, fol-
lowed immediately by slow addition of a solution of ketone
15 (1.67 g, 3.19 mmol) in 14 mL of THF. The reaction mix-
ture was stirred at –78 °C for 45 min and then at room tem-
perature for 10 min. Triethylamine (1.3 mL, 9.57 mmol) was
then added; the solution was stirred for 10 min, concentrated
in vacuo, diluted with ether, and filtered through a pad of
Celite. Solvent removal under reduced pressure afforded
crude silyl enol ether as a pale yellow oil, which was used
directly for the subsequent reaction.
1
1825, 1720, 1695, 1460, 1375, 1260, 1050. H NMR δ: 1.03
(3H, d, J = 6.7), 1.05 (9H, s), 1.29–1.36 (1H, m), 1.40–1.50
(1H, m), 1.56–1.73 (4H, m), 1.74–1.88 (2H, m), 2.11
(3H, s), 2.11–2.17 (1H, m), 2.41 (2H, t, J = 7.7), 2.81 (1H,
ddd, J = 5.8, 5.8, 9.1), 3.05 (1H, dd, J = 13.9, 22.5), 3.18
(1H, dd, J = 13.9, 22.6), 3.46 (1H, dd, J = 6.3, 10.1), 3.62
(1H, dd, J = 4.5, 10.0), 3.77 (3H, d, J = 11.3), 3.78 (3H, d,
J = 11.3), 7.34–7.43 (6H, m), 7.64–7.67 (4H, m). 13C NMR
δ: 16.2, 19.1, 26.8 (3C), 28.9 (2C), 29.4, 29.8, 38.7, 39.9 (d,
J = 513.2), 41.7, 42.1, 48.1, 52.8 (d, J = 38.2), 52.9 (d, J =
38.2), 58.6 (d, J = 6.4), 66.8, 127.5 (4C), 129.4 (2C), 133.7,
To
a
mixture of N-bromosuccinimide (568 mg,
3.19 mmol) in 13 mL of THF cooled to 0 °C was added the
silyl enol ether (1.90 g, 3.19 mmol) in 12 mL of THF. The
reaction mixture was stirred for 2 h at 0 °C, diluted with
ether, washed with saturated NaHCO3 and brine, and dried
over MgSO4. The solvent was removed in vacuo, and purifi-
cation via SiO2 column chromatography (5:1 Hex:EtOAc as
eluant) afforded 1.65 g (86% yield over the two steps) of α-
© 2004 NRC Canada

MaGee and Shannon
341
133.8, 135.4 (2C), 135.5 (2C), 203.5 (d, J = 25.6), 208.6.
HR-EI-MS: C28H38PSiO6 = 529.21589 ([M+ – C4H9]),
C28H38PSiO6 = 529.21753 (calcd.).
to warm gradually to room temperature and to stir for 6 h; it
was diluted with ether; washed with saturated NH4Cl, H2O
(2×), and brine; dried over MgSO4; and filtered, and the sol-
vent was removed in vacuo. Purification by SiO2 column
chromatography (29:1 Hex:EtOAc as eluant) afforded
308 mg (65% yield) of 20 as a colorless oil. [α]D +9.2 (c =
0.25, CH2Cl2). IR (cm–1): 3080, 2905, 1960, 1890, 1825,
Synthesis of heptenone 19
To
a solution of diketophosphonate 18 (820 mg,
1.40 mmol) in 14 mL of CH3CN cooled to 0 °C was added a
solution of 40% by weight benzyltrimethylammonium meth-
oxide in MeOH (1.2 mL, 2.80 mmol). The reaction mixture
was stirred at 0 °C for 15 min and then at room temperature
for 1.5 h. After neutralization with saturated NH4Cl and ex-
traction with ether (3×), the combined organics were washed
with brine, dried over MgSO4, and filtered, and the solvent
was removed in vacuo. Purification via SiO2 column chro-
matography (29:1 Hex:EtOAc as eluant) gave 482 mg (75%
yield) of cycloheptenone 19 as a separable epimeric mixture
(approximately 1:1) of colorless oils.
1
1660, 1450, 1375, 1100. H NMR δ: 1.02 (3H, d, J = 6.7),
1.06 (9H, s), 1.10 (3H, s), 1.17–1.26 (1H, m), 1.36–1.56
(4H, m), 1.61–1.67 (2H, m), 1.71–1.77 (1H, m), 1.83 (3H, d,
J = 0.5), 2.04 (1H, dt, J = 6.5, 12.8), 2.15–2.33 (2H, m),
3.45 (1H, dd, J = 6.7, 9.9), 3.63 (1H, dd, J = 4.7, 10.0), 5.79
(1H, s), 7.35–7.45 (6H, m), 7.65–7.67 (4H, m). 13C NMR δ:
16.5, 19.3, 25.6, 26.9 (3C), 27.3, 28.0, 32.7, 34.8, 36.6, 40.1,
50.4, 51.6, 61.4, 67.1, 126.6, 127.6 (4C), 129.6 (2C), 133.9
(2C), 135.6 (4C), 151.5, 208.5. HR-EI-MS: C27H33SiO2 =
417.22515 ([M+ – C4H9]), C27H33SiO2 = 417.22498 (calcd.).
Less polar epimer
Synthesis of keto-alcohol 21*
IR (cm–1): 3060, 2910, 1960, 1890, 1825, 1660, 1640,
To a solution of silyl ether 20*11 (175 mg, 0.37 mmol) in
2.5 mL of THF was added a 1 mol L–1 solution of tetrabutyl-
ammonium fluoride in THF (0.56 mL, 0.56 mmol). The re-
action mixture was stirred at room temperature for 2 h,
diluted with EtOAc, and concentrated in vacuo. The residue
was filtered quickly through a pad of silica gel using 1:1
Hex:EtOAc and concentrated in vacuo. A more rigorous pu-
rification via SiO2 column chromatography (2:1 Hex:EtOAc
as eluant) gave 82 mg (94% yield) of alcohol 21 as a color-
less oil. IR (cm–1): 3435, 2915, 1660, 1635, 1440, 1380,
1
1465, 1375, 1200, 1100. H NMR δ: 0.98 (3H, d, J = 6.8),
1.05 (9H, s), 1.16–1.23 (1H, m), 1.27–1.37 (1H, m), 1.45–
1.53 (1H, m), 1.59–1.67 (1H, m), 1.69–1.79 (2H, m), 1.85–
1.92 (1H, m), 1.87 (3H, s), 1.94–2.03 (1H, m), 2.12 (1H, dq,
J = 3.9, 10.0), 2.26–2.30 (2H, m), 3.02 (1H, dt, J = 9.9, 7.2),
3.46 (1H, dd, J = 6.9, 10.0), 3.62 (1H, dd, J = 5.4, 10.0),
5.84 (1H, s), 7.35–7.44 (6H, m), 7.65–7.67 (4H, m). 13C
NMR δ: 16.3, 19.2, 25.9, 26.4, 26.8 (3C), 28.1, 31.9, 35.6,
38.1, 44.4, 48.6, 57.3, 66.7, 127.6 (4C), 128.6, 129.5 (2C),
133.8 (2C), 135.5 (2C), 135.6 (2C), 155.7, 204.4. HR-EI-
MS: C26H31SiO2 = 403.20886 ([M+ – C4H9]), C26H31SiO2 =
403.20932 (calcd.).
1
1030. H NMR δ: 1.03 (3H, d, J = 6.7), 1.17 (3H, s), 1.23–
1.69 (7H, m), 1.73–1.81 (2H, m), 1.85 (3H, d, J = 0.5), 2.08
(1H, dt, J = 6.5, 12.8), 2.23–2.38 (2H, m), 3.45 (1H, dd, J =
7.2, 10.4), 3.68 (1H, dd, J = 4.4, 10.5), 5.81 (1H, s). 13C
NMR δ: 16.2, 25.5, 27.4, 28.0, 32.9, 34.8, 36.7, 40.3, 50.5,
51.7, 61.5, 66.4, 126.6, 151.5, 208.5. HR-EI-MS: C15H24O2 =
236.17802 ([M]+), C15H24O2 = 236.17763 (calcd.).
More polar epimer
[α]D +11.2 (c = 0.25, CH2Cl2). IR (cm–1): 3060, 2910,
1
1960, 1890, 1825, 1660, 1640, 1460, 1375, 1080. H NMR
δ: 0.94 (3H, d, J = 6.8), 1.03 (9H, s), 1.30–1.35 (2H, m),
1.52–1.59 (1H, m), 1.65–1.77 (5H, m), 1.91–2.07 (1H, m),
1.94 (3H, d, J = 1.0), 2.18 (1H, dt, J = 15.7, 5.0), 2.52–2.67
(2H, m), 3.44 (1H, dd, J = 6.5, 10.1), 3.58 (1H, dd, J = 5.5,
10.1), 5.91 (1H, d, J = 1.4), 7.35–7.44 (6H, m), 7.63–7.66
(4H, m). 13C NMR δ: 16.0, 19.2, 24.2, 26.9 (3C), 27.5, 28.1,
29.5, 33.1, 37.8, 43.0, 50.0, 56.5, 66.8, 127.6 (4C), 129.3,
129.5 (2C), 133.8 (2C), 135.6 (4C), 156.3, 203.5. HR-EI-
MS: C26H31SiO2 = 403.20803 ([M+ – C4H9]), C26H31SiO2 =
403.20932 (calcd.).
Synthesis of ketal alcohol 22*
To a solution of cycloheptenone 21 (80 mg, 0.34 mmol) in
1.7 mL of CH2Cl2 was added pTSA (5 mg), ethylene glycol
(38 mL, 0.68 mmol), and trimethylorthoformate (76 mL,
0.68 mmol). The reaction mixture was stirred at room tem-
perature for 5 h, then diluted with NH4OH, and stirred for an
additional 30 min. After separation of the two layers, the
aqueous phase was extracted with CH2Cl2 (2×). The com-
bined organics were washed with H2O and brine, dried over
MgSO4, and filtered. The solvent was removed in vacuo, and
the residue was purified via SiO2 column chromatography
(5:1 Hex:EtOAc as eluant) to give 83 mg (88% yield) of
ketal 22* as a colorless oil. IR (cm–1): 3380, 2925, 1720,
Synthesis of methylated cycloheptenone 20
To a solution of diisopropylamine (0.157 mL, 1.20 mmol)
in 3 mL of THF at –50 °C was added a 2.5 mol L–1 solution
of n-BuLi in hexane (0.44 mL, 1.10 mmol), dropwise. The
solution was stirred at –50 °C for 15 min and then cooled to
–78 °C. A solution of cycloheptenone 19 (461 mg,
1.00 mmol, mixture of epimers) in 2 mL of THF was then
added slowly, and stirring continued at –78 °C for 40 min.
HMPA (0.5 mL) was then added, and the reaction mixture
was warmed to 0 °C, followed by addition of iodomethane
(0.189 mL, 3.00 mmol). The reaction mixture was allowed
1
1690, 1450, 1370, 1285. H NMR δ: 1.00 (3H, d, J = 6.8),
1.08 (3H, s), 1.22–1.38 (3H, m), 1.49–1.58 (2H, m), 1.59–
1.71 (2H, m), 1.66 (3H, s), 1.82–1.90 (1H, m), 1.95–2.05
(1H, m), 2.22 (1H, AB quartet, J = 18.3), 2.37–2.47
(1H, m), 2.54 (1H, AB quartet, J = 17.9), 3.40 (1H, dd, J =
7.6, 10.5), 3.66 (1H, dd, J = 4.4, 10.5), 3.87–4.06 (4H, m),
5.45–5.49 (1H, m). 13C NMR δ: 16.2, 25.8, 25.9, 27.1, 30.6,
33.1, 39.7, 40.8, 49.2, 51.6, 52.6, 64.0, 65.7, 66.4, 113.6,
11The synthesis was continued using racemic material. Racemic keto-alcohol 21* was synthesized following the same steps as for optically
pure 21, with the exception that the deprotonation of 10 was done with LDA and not chiral lithium amide base 12.
© 2004 NRC Canada

342
Can. J. Chem. Vol. 82, 2004
123.5, 132.6. HR-EI-MS: C17H28O3 = 280.20383 ([M]+),
C17H28O3 = 280.20386 (calcd.).
by SiO2 preparative thin layer chromatography (8:1
Hex:EtOAc as eluant) afforded 2.0 mg (67% yield) of epi-
reiswigin A 25*, as a low-melting white solid. Recrystal-
lization from hexane provided crystals that were suitable for
X-ray analysis; mp 35.9–36.8 °C. IR (cm–1): 2915, 1710,
Synthesis of iodoketal 23*
To a solution of triphenylphosphine (37 mg, 0.14 mmol),
imidazole (15 mg, 0.22 mmol), 2 mL of Et2O, and 1 mL of
CH3CN was added iodine (33 mg, 0.13 mmol). After stirring
for 10 min at room temperature, alcohol 22* (30 mg,
0.11 mmol) in 1 mL of Et2O was added. The reaction mix-
ture was stirred at room temperature for 1 h, diluted with
ether, and filtered through a pad of Celite, and then the sol-
vent was removed under reduced pressure. Purification via
SiO2 column chromatography (29:1 Hex:EtOAc as eluant)
afforded 27 mg (62% yield) of iodoketal 23* as a colorless
1
1660, 1450, 1370. H NMR δ: 0.92 (3H, d, J = 6.7), 0.93
(6H, d, J = 6.7), 1.17 (3H, s), 1.20–1.29 (1H, m), 1.41–1.53
(4H, m), 1.67–1.73 (1H, m), 1.77–1.82 (1H, m), 1.85
(3H, s), 2.04–2.23 (5H, m), 2.26–2.33 (3H, m), 2.41 (1H,
dd, J = 3.3, 16.1), 5.81 (1H, s). 13C NMR δ: 19.7, 22.6, 22.7,
24.5, 25.6, 26.6, 28.3, 32.3, 32.4, 34.6, 36.6, 47.3, 52.0,
52.6, 53.5, 61.3, 126.6, 151.7, 208.2, 210.7. HR-EI-MS:
C20H32O2 = 304.24017 ([M]+), C20H32O2 = 304.24023
(calcd.).
1
oil. IR (cm–1): 2910, 1440, 1370, 1110, 835, 670. H NMR
δ: 1.06 (3H, d, J = 6.5), 1.08, (3H, s), 1.19–1.25 (1H, m),
1.26–1.34 (1H, m), 1.40–1.55 (3H, m), 1.66 (3H, s), 1.73
(1H, ddd, J = 6.5, 6.5, 11.9), 1.86–1.94 (2H, m), 2.18 (1H,
AB quartet, J = 18.0), 2.39–2.48 (1H, m), 2.57 (1H, AB
quartet, J = 18.1), 3.08 (1H, dd, J = 7.6, 9.5), 3.34 (1H, dd,
J = 2.8, 9.5), 3.87–4.07 (4H, m), 5.46–5.48 (1H, m). 13C
NMR δ: 16.2, 20.1, 25.8, 25.9, 26.9, 31.0, 32.6, 40.0, 40.8,
51.8 (2C), 52.9, 63.9, 65.8, 113.3, 123.5, 132.6. HR-EI-MS:
C17H27IO2 = 390.10505 ([M]+), C17H27IO2 = 390.10559
(calcd.).
Acknowledgments
Financial support from the Natural Sciences and Engi-
neering Research Council of Canada (NSERC) and the Uni-
versity of New Brunswick (UNB) is gratefully
acknowledged. We also wish to thank Gilles Vautour for re-
cording all mass spectra, Dr. Andreas Decken for solving the
X-ray crystal structure, and Dr. Larry Calhoun for helpful
discussions on the interpretation of some of the NMR spec-
tra. We thank the Harbor Branch Oceanographic Institute,
Ft. Pierce, Fla., U.S.A., for kindly providing us with copies
1
of H and 13C NMR spectra for (–)-reiswigin A.
Synthesis of dithioketal 24*
To a solution of isobutyldithiane (32 mg, 0.18 mmol) in
0.5 mL of THF at 0 °C was added a 2.5 mol L–1 solution of
n-BuLi in hexane (56 mL, 0.14 mmol), dropwise. The mix-
ture was stirred at 0 °C for 1 h; then 100 µL of HMPA was
added, and the solution was cooled to –90 °C. Iodoketal
23* (14 mg, 0.036 mmol), cooled in a separate cooling bath
to –50 °C, in 0.5 mL of THF was added via cannula to the
reaction mixture. After stirring at –90 °C for 30 min, 2 mL
of 0.3% oxalic acid was added, and the organic product was
extracted with ether (2×). The combined organics were
washed with H2O (2×) and brine, dried over MgSO4, and fil-
tered, and the solvent was removed in vacuo. Purification via
SiO2 column chromatography (hexane to 29:1 Hex:EtOAc as
eluant) gave 12.6 mg (81% yield) of dithioketal 24* as a col-
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© 2004 NRC Canada