Total synthesis of (-)-xyloketal D and its enantiomer - Confirmation of absolute stereochemistry

Article abstract of DOI:10.1139/v04-138

The total synthesis of (-)-xyloketal D and its enantiomer have been achieved by the reaction of an orthoquinone methide with (4R)- and (4S)-4,5-dihydro-2,4-dimethylfuran via a diastereoselective inverse electron demand Diels-Alder reaction. This total syn

Full text of DOI:10.1139/v04-138

1
640
Total synthesis of (–)-xyloketal D and its
enantiomer — Confirmation of absolute
stereochemistry
Jeremy D. Pettigrew, Rebecca P. Freeman, and Peter D. Wilson
Abstract: The total synthesis of (–)-xyloketal D and its enantiomer have been achieved by the reaction of an ortho-
quinone methide with (4R)- and (4S)-4,5-dihydro-2,4-dimethylfuran via a diastereoselective inverse electron demand
Diels–Alder reaction. This total synthesis confirmed the absolute stereochemistry of the natural product. The ortho-
quinone methide was generated by reaction of an appropriately functionalized Mannich base with methyl iodide. The
Mannich base was prepared in one step from 2,4-dihydroxyacetophenone, formaldehyde, and morpholine. The
enantiomeric dihydrofurans were prepared from (2R)- and (2S)-2-methylpent-4-ynoic acid via a three-step reaction se-
quence. These chiral nonracemic synthetic precursors were prepared from the corresponding (R)-phenylglycinol-derived
diastereomeric amides of the readily available racemic carboxylic acid. The absolute stereochemistry of these
carboxylic acids was firmly established by conversion to a known compound that had been previously prepared from a
chiral pool starting material.
Key words: xyloketal D, inverse electron demand Diels–Alder reaction, ortho-quinone methide, dihydrofuran.
Résumé : Faisant appel à une réaction de Diels–Alder diastéréosélective, avec une demande d’électron inversée, on a
réalisé une synthèse totale de (–)-xylocétal D et de son énantiomère par réaction d’une ortho-quinone méthide avec les
(
4R)- et (4S)-4,5-dihydro-2,5-diméthyfurane. Cette synthèse totale confirme la stéréochimie absolue du produit naturel.
L’ortho-quinone méthide a été générée par réaction de l’iodure de méthyle avec une base de Mannich portant une fonc-
tionnalisation appropriée. La base de Mannich a été préparée en une étape à partir de la 2,4-dihydroxyacétophénone, du
formaldéhyde et de la morpholine. On a préparé les dihydrofuranes énantiomères en trois étapes par une série de réac-
tions à partir des acides (2R)- et (2S)-2-méthylpent-4-ynoïque. On a préparé ces précurseurs de synthèse chiraux non
racémiques à partir des amides diastéréomères correspondants dérivés du (R)-phénylglycinol et de l’acide carboxylique
racémique commercialement disponible. La configuration absolue de ces acides carboxyliques a été fermement établie
par conversion en un composé connu qui avait précédemment été préparé à partir d’un produit appartenant à un en-
semble chiral.
Mots clés : xylocétal D, réaction de Diels–Alder avec demande d’électron inversée, ortho-quinone méthide, dihydrofu-
rane.
[
Traduit par la Rédaction] Pettigrew et al. 1648
Introduction
member of this family of natural products. We have previ-
ously reported the synthesis of (±)-11-norxyloketal D, the
first total synthesis of (±)-xyloketal D (±)-4 and model stud-
The natural products xyloketal A (1), B (2), C (3), D (4),
and E (5) were isolated from a mangrove fungus of the
Xylaria species (Fig. 1) (1). The molecular structures of
these novel secondary metabolites were determined by ex-
tensive spectroscopic methods and by X-ray crystallography.
In addition, the absolute stereochemistry of xyloketal A (1)
and D (4) were determined by interpretation of their CD
spectra. Xyloketal A (1) has a unique chiral, C -symmetric
molecular structure and was shown to be an inhibitor of ace-
tylcholine esterase (1, 2). Xyloketal D (4) is the simplest
2
ies towards the total synthesis of xyloketal A (1) (3). These
syntheses featured the cycloaddition reactions of appropri-
ately functionalized ortho-quinone methides and dihydro-
furans as a key step (4).
The synthesis of (±)-11-norxyloketal D (10) (43% yield),
via the ortho-quinone methide 9, was achieved by heating
the Mannich base 7 and commercially available 4,5-dihydro-
2-methylfuran (8) (3 equiv.) with methyl iodide (1.05 equiv.)
in benzene at reflux for 5 days (Fig. 2) (4–6). The Mannich
3
Received 25 May 2004. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 21 December 2004.
1
J.D. Pettigrew, R.P. Freeman, and P.D. Wilson. Department of Chemistry, Simon Fraser University, 8888 University Drive,
Burnaby, BC V5A 1S6, Canada.
1
Corresponding author (e-mail: pwilson@sfu.ca).
The numbering scheme provided for (–)-xyloketal D (4) by Lin and co-workers is employed throughout this paper. See ref. 1.
2
Can. J. Chem. 82: 1640–1648 (2004)
doi: 10.1139/V04-138
© 2004 NRC Canada

Pettigrew et al.
1641
Fig. 3. Total synthesis of (±)-xyloketal D ((±)-4), (±)-2,6-epi-
Fig. 1. Molecular structures of xyloketal A (1), B (2), C (3), D
(
4), and E (5).
xyloketal D ((±)-15), and the diastereomeric spiroacetals (±)-16
and (±)-17 (3).
Fig. 2. Synthesis of (±)-11-norxyloketal D ((±)-10) (3).
conditions described above, afforded (±)-xyloketal D ((±)-4),
(
±)-2,6-epi-xyloketal D ((±)-15), and the diastereomeric
spiroacetals (±)-16 and (±)-17 as a mixture of products
11:1:3:3) in a combined yield of 54%. The spectral data for
(
synthetic (±)-xyloketal D ((±)-4) were in agreement with
those reported for the natural product (1). This diastereo-
selective cycloaddition reaction (11:1 dr) was controlled by
the C4-methyl substituent of the dihydrofuran (±)-14. We at-
tributed the formation of the isomeric spiroacetal reaction
products (±)-16 and (±)-17 to the isomerization and subse-
quent cycloaddition reaction of the corresponding exocyclic
dihydrofuran (±)-13. Of note, related spiroacetal reaction
products were not isolated from the cycloaddition reaction
of the dihydrofuran 8 that was employed in the synthesis of
(
±)-11-norxyloketal D (10). We concluded that the addi-
tional methyl substituent of dihydrofuran (±)-14 decreased
the reactivity of this endocyclic dihydrofuran in the cyclo-
addition reaction.
base 7 was prepared as a single regioisomeric product from
2
,4-dihydroxyacetophenone (6), formaldehyde, and morpho-
line in 83% yield (7).
The total synthesis of (±)-xyloketal D ((±)-4) involved a
new synthesis of the known racemic dihydrofuran (±)-14
The preliminary model studies towards the total synthesis
of (±)-xyloketal A ((±)-1) involved the reaction of the
Mannich base 19, the dihydrofuran 8 (9 equiv.), and methyl
iodide (3 equiv.) (Fig. 4). This afforded a mixture (1:4) of
(
Fig. 3) (8). The racemic carboxylic acid (±)-11 was pre-
pared by alkylation of propionic acid with propargyl bro-
mide, which in turn was reduced with lithium aluminum
hydride to afford the racemic alcohol (±)-12 (9, 10). Heating
this alcohol with a sub-stoichiometric amount of sodium am-
ide afforded the exocyclic dihydrofuran (±)-13, which was
isomerized thermally to afford the required dihydrofuran
the desired C -symmetric xyloketal A analogue (±)-20 and
3
the diastereoisomer (±)-21 in 19% combined yield. This un-
precedented and direct synthetic process involved nine indi-
vidual reactions (three alkylation reactions, three elimination
reactions, and three subsequent cycloaddition reactions). Of
additional note, the Mannich base 19 was prepared in one
step by adaptation of a literature procedure from phloro-
(
±)-14 (8). The cycloaddition reaction of the Mannich base 7
with the dihydrofuran (±)-14 (3 equiv.), under the reaction
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Can. J. Chem. Vol. 82, 2004
Fig. 4. Synthesis of xyloketal A analogues (±)-20 and (±)-21 (3).
Scheme 1. Resolution of (±)-2-methylpent-4-ynoic acid ((±)-11).
Reagents and conditions: (a) (COCl) , CH Cl , DMF (cat.), 0 °C
2
2
2
to room temperature, 2 h; (R)-phenylglycinol (22), NEt , CH Cl ,
3
2
2
0
°C to room temperature, 16 h, 36% (23), 34% (24);
–
1
(
b) 3 mol L H SO , p-dioxane, reflux, 7 h, 76% ((2R)-11),
2 4
8
6% ((2S)-11).
Scheme 2. Synthesis of (2R)-2-methylpent-4-yn-1-ol ((2R)-12)
and (2S)-2-methylpent-4-yn-1-ol ((2S)-12): confirmation of abso-
glucinol (18), N,N-dibenzylamine, and formaldehyde (11,
2).
We have subsequently attempted to prepare (±)-xyloketal
A ((±)-1) from the dihydrofuran (±)-14 and the Mannich
base 19. However, it was not possible to isolate the desired
target compound from a complex mixture of reaction prod-
ucts. Presumably, this process was complicated by the for-
mation of diastereomeric as well as spirocyclic reaction by-
products.
1
lute stereochemistry. Reagents and conditions: (a) LiAlH , THF,
4
0
°C to room temperature, 16 h, 89% ((2R)-12), 85% ((2S)-12);
(
b) NaH, BnBr, DMF, THF, 6 h, 90% ((2R)-25), 90% ((2S)-25).
In this paper, we report an efficient resolution procedure
for the racemic carboxylic acid (±)-11, a proof of the abso-
lute stereochemistry, and the asymmetric synthesis of (–)-
xyloketal D (4) as well as its enantiomer. This study was
also undertaken to confirm the absolute stereochemistry of
the natural product. Recently, Krohn and co-workers (13)
have reported an alternative asymmetric synthesis of (–)-
xyloketal D (4) and the C2,C6-epimer (8.5:1.5 dr) from
(
3R)-3-methylbutyrolactone
(93%
ee)
and
2,4-
graphic methods. The corresponding acid chloride of the
carboxylic acid was also condensed with an extensive series
of chiral nonracemic amines. It was found that the
dihydroxyacetophenone (6), as well as model studies to-
wards the total synthesis of xyloketal A (1).
5
diastereomeric amides 23 and 24 prepared from (R)-
phenylglycinol (22) could be separated readily by flash
chromatography on a multigram scale (Scheme 1) (14,
15). The chiral nonracemic carboxylic acids (2R)-11 and
(2S)-11 were then prepared by hydrolysis of the
diastereomeric amides 23 and 24 under acidic reaction con-
ditions (14, 16).
The chiral nonracemic carboxylic acid (2R)-11 was re-
duced with lithium aluminum hydride to afford the corre-
sponding alcohol (2R)-12 (Scheme 2) (17). A sample of this
alcohol was then converted to the benzyl ether (2R)-25. The
latter compound has been prepared previously from an ex-
pensive chiral pool starting material and the optical rotation
Results and discussion
A variety of methods were investigated to identify an effi-
6
,7
cient resolution procedure for the racemic carboxylic acid
3
(
±)-11 (3). It was not possible to separate the
diastereomeric salts that were formed between the
carboxylic acid and (R)-methylbenzylamine or (R)-(1-
naphthyl)-ethylamine by fractional recrystallization. The
racemic carboxylic acid (±)-11 was also converted to the
corresponding acid chloride and condensed with a series of
commercially available chiral nonracemic alcohols. All of
the diastereomeric esters that were prepared could not be
separated by fractional recrystallization or by chromato-
4
3
A full experimental procedure for the preparation of the racemic carboxylic acid (±)-11 is provided in the supplementary material.10
4
5
For example, the diastereomeric esters prepared from menthol, isomenthol, and (2R)-butan-2-ol were copolar by TLC.
The chiral nonracemic amines that were employed in these reactions included: (R)-methylbenzylamine and (R)-(1-naphthyl)-ethylamine, the
methyl esters of (S)-alanine, isoleucine, leucine, phenylalanine, proline, tryptophan, and (R)-phenylglycine, as well as (S)-valinol and
(
1S,2R)-norephedrine.
6
7
The diastereomeric amides that were prepared from (S)-valinol were also chromatographically separable.
Attempts, albeit unsuccessful, were also made to resolve the racemic alcohol (±)-12 on condensation with a series of commercially available
chiral nonracemic carboxylic acids and sulfonyl chlorides.
©
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Pettigrew et al.
1643
Scheme 4. Synthesis of (–)-xyloketal D (4), 2,6-epi-xyloketal D
Scheme 3. Synthesis of (4R)-4,5-dihydro-2,4-dimethylfuran
(
(4R)-14) and (4S)-4,5-dihydro-2,4-dimethylfuran ((4S)-14). Re-
(15), and the diastereomeric spiroacetals 16 and 17. Reagents
and conditions: (a) dihydrofuran (4R)-14 (3 equiv.), MeI
(1 equiv), benzene, reflux, 8 days, 40% (4, 15, 16, and 17
agents and conditions: (a) NaNH , reflux, 2 h; (b) reflux, 2 h,
4
2
4% (over two steps) ((4R)-14), 36% (over two steps) ((4R)-14).
(
8:1:2:2)) or dihydrofuran (4R)-14 (3 equiv.), Me SO (1 equiv.),
2 4
benzene, reflux, 3 days, 37% (4, 15, 16, and 17 (16:1:4:4)).
has been reported (18). Thus, the absolute stereochemistry
and high optical purity of the resolved carboxylic acid (2R)-
1
1 was firmly established (see Experimental section). To
complete the total synthesis of (–)-xyloketal D (4) and its
nonnatural enantiomer, the carboxylic acid (2S)-11 was re-
duced with lithium aluminum hydride to afford the alcohol
(
2S)-12. A sample of this compound was also converted to
the corresponding benzyl ether (2S)-25, which proved to be
the enantiomer of a known compound (18).
The chiral nonracemic alcohol (2R)-12 was then used to
prepare the dihydrofuran (4R)-14 as described earlier for the
racemic compound (Scheme 3).8 This compound would
serve as the precursor of (–)-xyloketal D (4) and would al-
low for the confirmation of the absolute stereochemistry of
the natural product. In an identical fashion, the alcohol (2S)-
The H NMR spectrum and 13C NMR data of synthetic
1
(–)-xyloketal D (4) were identical to those of the natural
1
0
11
product (1). The sign of the optical rotation of synthetic
(–)-xyloketal D (4) was in agreement with that reported for
the natural product. This confirmed the absolute
stereochemistry of the natural product that had been as-
signed previously by the interpretation of CD data (1, 13).
However, the magnitude of the rotation was slightly lower
than reported for the natural product (92% ee based on the
optical rotation of the natural product) (1). To determine the
enantiomeric purity of synthetic (–)-xyloketal D (4), efforts
were also made to separate the enantiomers of a sample of
racemic xyloketal D ((±)-4) (3). This was not possible by
analytical chiral HPLC (Daicel Chiracel OD column) or by
1
2 was used to prepare the dihydrofuran (4S)-14. This com-
pound would serve as the precursor of the nonnatural enan-
tiomer of xyloketal D.
The chiral nonracemic dihydrofuran (4R)-14 (3 equiv.)
and the Mannich base 7 were heated in benzene at reflux
9
with methyl iodide (1 equiv.) (Scheme 4). This reaction
afforded a mixture (8:1:2:2) of (–)-xyloketal D (4), 2,6-epi-
xyloketal D (15), and the diastereomeric spiroacetals 16 and
1
7 in a combined yield of 40%. The reaction was also re-
1
peated using dimethyl sulfate instead of methyl iodide. This
reaction proceeded at a faster rate and afforded a mixture of
reaction products (16:1:4:4) in a similar combined yield. A
diastereomerically and analytically pure sample of the syn-
thetic natural product, (–)-xyloketal D (4), was obtained by
repeated chromatography and recrystallization. An analyti-
cally pure sample of the diastereomeric spiroacetals 16 and
GC (Cyclosil-B column). Similarly, H NMR spectroscopy
using a chiral shift reagent (Eu(hfc) ) was unsuccessful.
Derivatization of the phenol moiety of racemic xyloketal
D ((±)-4) with (S)-(+)-α-methoxy-α-trifluoromethyl-phenyl-
acetyl chloride afforded the corresponding Mosher’s esters
3
1
(19). The H NMR (600 MHz) signals of the methoxy sub-
1
2
stituents were clearly resolved. Subsequent derivatization
of synthetic (–)-xyloketal D (4) afforded the corresponding
Mosher’s ester as a single diastereoisomer. This confirmed
1
7 was also isolated as a mixture (4:5) by repeated chroma-
tography and recrystallization.
8
The lower yield for the preparation of the chiral nonracemic dihydrofuran (4R)-14 than that reported for the racemic compound is reflective
of the smaller scale that this reaction was performed on. See ref. 3.
9
1
We have previously reported full experimental procedures for the preparation of Mannich base 7. See ref. 3.
0
1
Detailed experimental procedures and complete product characterization data for all of the additional compounds synthesized, as well as H
and 13C NMR spectra for compounds (±)-11, 23, 24, (2R)-12, (2R)-25, (4R)-14, 4, 16, 17, and the Mosher’s ester derivatives of (±)-
xyloketal D ((±)-4) and synthetic (–)-xyloketal D (4) may be purchased from the Directory 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).
11
1
Of note, the H NMR signal of natural (–)-xyloketal D (4) centred at 2.15 ppm should have been reported at 2.08 ppm.
12
19
The F NMR (470 MHz) signals of the Mosher’s ester derivatives were separate but poorly resolved.
©
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1
644
Can. J. Chem. Vol. 82, 2004
Scheme 5. Synthesis of (+)-xyloketal D (ent-4), ent-2,6-epi-
xyloketal D (ent-15), and the diastereomeric spiroacetals ent-16
and ent-17. Reagents and conditions: (a) dihydrofuran (4S)-14
Scheme 6. Attempted synthesis of (–)-xyloketal A (1). Reagents
and conditions: (a) dihydrofuran (4R)-14 (9 equiv.), MeI
(3 equiv.), benzene, reflux, or dihydrofuran (4R)-14 (9 equiv.),
Me SO (3 equiv.), benzene, reflux.
(
3 equiv.), MeI (1 equiv.), benzene, reflux, 6 days, 46% (ent-4,
2
4
ent-15, ent-16 and ent-17 (13:1:3:3)) or dihydrofuran (4S)-14
(
3 equiv.), Me SO (1 equiv.), benzene, reflux, 3 days, 36% (ent-
2 4
4
, ent-15, ent-16, and ent-17 (20:1:3:3)).
The total synthesis of (–)-xyloketal A (1) was also at-
tempted (Scheme 6). The Mannich base 19 and a large ex-
cess of the chiral nonracemic dihydrofuran (4R)-14 were
heated in benzene at reflux with methyl iodide and with
1
4
dimethyl sulfate. The natural product was not isolated from
the complex mixtures of products that were produced in
these reactions.
It was anticipated that the stereochemistry of this at-
tempted cycloaddition reaction would have been directed
efficiently by the C4-methyl substituent of the chiral
nonracemic dihydrofuran (4R)-14. However, it appears that
the competing isomerization reaction of the dihydrofuran
that the synthetic material was enantiomerically pure.10 The
melting point of synthetic (–)-xyloketal D (4) (71–73 °C)
was, however, significantly lower than that reported for the
natural product (111–113 °C). We were unable to increase
the melting point of our synthetic material by repeated
recrystallization from petroleum ether. Krohn et al. (13b)
have reported that synthetic (–)-xyloketal D (4) (93% ee cal-
culated from optical rotation and 93% ee based on the
enantiomeric purity of a synthetic precursor) also had a
lower melting point (87 °C, ether–pentane). They also re-
ported that subsequent recrystallization from ether–pentane
afforded the natural product, which had a melting point of
(
4R)-14 and the subsequent nonstereoselective cycloaddition
reaction of the exocyclic dihydrofuran (4R)-13 is a dominant
complicating factor.
Conclusions
The racemic carboxylic acid (±)-11 was resolved by the
chromatographic
separation
of
the
corresponding
diastereomeric amides 23 and 24 that were prepared from
(R)-phenylglycinol (22). The absolute stereochemistry and
the enantiomeric purity of the chiral nonracemic carboxylic
acid (2R)-11 were determined by conversion to the benzyl
ether (2R)-25, which had been prepared previously from a
chiral pool starting material. The total synthesis of (–)-
xyloketal D (4) and its enantiomer were completed from the
chiral nonracemic dihydrofurans (4R)-14 and (4S)-14. These
dihydrofurans, which were prepared in three steps from the
carboxylic acids (2R)-11 and (2S)-11, were reacted with an
appropriately functionalized ortho-quinone methide 9 that
was generated from the Mannich base 7. These results con-
firmed the absolute stereochemistry of the natural product
that was reported by Lin and co-workers (1, 13). The synthe-
sis of (–)-xyloketal A (1) from the chiral nonracemic
dihydrofuran (4R)-14 and the Mannich base 19 was unsuc-
cessful. Thus, alternative synthetic routes are actively being
1
10 to 111 °C. We have also recrystallized our synthetic ma-
terial from this solvent system. However, in our hands this
procedure did not increase the melting point. We have con-
cluded that our sample is either contaminated with a trace
amount of the enantiomer, which has significantly depressed
the melting point, or that we have isolated the natural prod-
uct in a different crystal form.13
The Mannich base 7 was also reacted with the chiral
nonracemic dihydrofuran (4S)-14 using the two procedures
described previously (Scheme 5). These reactions afforded
mixtures of (+)-xyloketal D (ent-4), ent-2,6-epi-xyloketal D
(
1
ent-15), and the diastereomeric spiroacetals ent-16 and ent-
7. A diastereomerically and analytically pure sample of the
enantiomeric natural product, (+)-xyloketal D (ent-4), was
also prepared and fully characterized following repeated
chromatography and recrystallization.
13Professor Krohn has informed us that he has recently checked the melting point of a sample of natural (–)-xyloketal D (4), which was
kindly provided by Professor Lin, and found it to be 107 to 108 °C (Büchi SMP-20 melting point apparatus).
14
We have previously reported full experimental procedures for the preparation of Mannich base 19. See ref. 3.
©
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Pettigrew et al.
1645
pursued to complete the total synthesis of this unique and bi-
ologically relevant natural product.
(50 mL) and extracted with dichloromethane (3 × 50 mL).
The aqueous layer was acidified to pH ~2 with sulfuric acid
–
1
(
5
3 mol L ) and then extracted with dichloromethane (3 ×
0 mL). The combined organic layers were dried over anhy-
Experimental section
drous sodium sulfate and concentrated in vacuo. Purification
by distillation at reduced pressure afforded the title com-
pound (2R)-11 (2.01 g, 76%) as a colourless oil. Rf = 0.48
For general experimental details refer to the supplemen-
1
0
tary material.
(
(
hexanes – ethyl acetate, 1:2), bp 103–106 °C, 5 mmHg
1 mmHg = 133.322 Pa) (lit. value (9) bp 106.5–109.5 °C,
(
2R)-N-[(1R)-1-Phenyl-2-hydroxyethyl]-2-methyl-4-
1
4–15 mmHg (1 mmHg = 133.322 4 Pa)) for the racemic
pentynamide (23) and (2S)-N-[(1R)-1-phenyl-2-
hydroxyethyl]-2-methyl-4-pentynamide (24)
2
0
carboxylic acid (±)-11)). [α] = +6.5 (c 1.50, CHCl ). All
other spectroscopic data were identical to those reported for
D
3
To a solution of the racemic carboxylic acid (±)-11 (3)
1
0
the racemic carboxylic acid (±)-11.
(
5.40 g, 48.2 mmol) in dichloromethane (100 mL) at 0 °C
were added oxalyl chloride (5.5 mL, 58 mmol) and N,N-
dimethylformamide (2 drops). The resultant solution was al-
lowed to warm to room temperature over 2 h and then was
concentrated in vacuo to afford the corresponding acid chlo-
ride. A solution of this acid chloride in dichloromethane
(2S)-2-Methylpent-4-ynoic acid ((2S)-11)
The title compound (2S)-11 (1.91 g, 86%) as a colourless
oil was also prepared from the corresponding amide 24
2
0
(
4.56 g, 19.7 mmol). [α] = –6.1 (c 1.52, CHCl ). All other
D
3
spectroscopic data were identical to those reported for the
racemic carboxylic acid (±)-11.
(
50 mL) was then added to a stirred solution of (R)-
phenylglycinol (22) (6.60 g, 48.2 mmol) and triethylamine
8.0 mL, 58 mmol) in dichloromethane (150 mL) at 0 °C.
1
0
(
The resultant solution was allowed to warm to room temper-
ature over 16 h and then water (50 mL) was added. The re-
action mixture was extracted with ethyl acetate (3 × 50 mL)
and the combined organic layers were washed with brine
(2R)-2-Methylpent-4-yn-1-ol ((2R)-12)
To a suspension of lithium aluminum hydride (0.79 g,
0.8 mmol) in tetrahydrofuran (35 mL) at 0 °C was added a
2
solution of the carboxylic acid (2R)-11 (1.17 g, 10.4 mmol)
in tetrahydrofuran (10 mL) and the resultant suspension was
stirred at room temperature for 16 h. Water (0.8 mL), an
aqueous solution of sodium hydroxide (2 mol L , 0.8 mL),
and water (2.4 mL) were then added in succession and the
resultant mixture was filtered. The filter cake was rinsed
with ether (100 mL) and the combined organic filtrates were
concentrated in vacuo. Purification by distillation at reduced
pressure afforded the title compound (2R)-12 (0.91 g, 89%)
(
50 mL), dried over anhydrous sodium sulfate, and concen-
trated in vacuo. Purification by flash chromatography using
petroleum ether – ethyl acetate (1:2) as the eluant afforded
the title compounds 23 (4.01 g, 36%) and 24 (3.82 g, 34%)
–
1
as white solids. Amide 23: R = 0.37 (petroleum ether –
f
ethyl acetate, 1:2), mp 78–82 °C, petroleum ether – ethyl ac-
2
4
–1
etate. [α] = –63 (c 1.31, CHCl ). IR (ef, cm ): 3314,
D
3
1
3
286, 2936, 1650, 1544, 1052, 758, 702. H NMR
as a colourless oil. R = 0.55 (hexanes – ethyl acetate, 1:2),
(
2
3
(
(
1
400 MHz, CDCl ) δ: 1.25 (d, J = 6.5 Hz, 3H), 2.07 (t, J =
f
3
bp 61–66 °C, ~20 mmHg (1 mmHg = 133.322 4 Pa) (lit.
value (9) bp 64–64.5 °C, 10 mmHg (1 mmHg =
.6 Hz, 1H), 2.30 (broad s, 1H), 2.38 (m, 1H), 2.51 (m, 2H),
.91 (d, J = 4.6 Hz, 2H), 5.10 (dt, J = 7.0, 4.8 Hz, 1H), 6.32
2
0
1
3
1
+
1
33.322 4 Pa) (for the racemic alcohol (±)-12)). [α]
=
broad d, J = 4.9 Hz, 1H), 7.34 (m, 5H). C NMR
D
–
1
10.9 (c 1.10, CHCl ). IR (ef, cm ): 3409, 2961, 2922,
126 MHz, CDCl ) δ: 17.1, 23.1, 40.4, 55.6, 66.2, 70.2, 82.1,
3
3
1
641, 2117, 1461, 1430, 1037, 651. H NMR (400 MHz,
26.6, 127.7, 128.7, 138.9, 175.0. MS (CI) m/z (rel. inten-
CDCl ) δ: 1.01 (d, J = 6.9 Hz, 3H), 1.56 (broad s, 1H), 1.90
sity): 232 (M + H, 100). Anal. calcd. for C H NO : C
3
1
4
17
2
(
m, 1H), 1.98 (t, J = 2.7 Hz, 1H), 2.21 (ddd, J = 16.8, 6.4,
.7 Hz, 1H), 2.29 (ddd, J = 16.8, 6.2, 2.7 Hz, 1H), 3.59 (d,
7
2.70, H 7.41, N 6.06; found: C 72.86, H 7.35, N 5.87. Am-
2
ide 24: R = 0.27 (petroleum ether – ethyl acetate, 1:2), mp
f
1
3
2
3
J = 6.1 Hz, 2H). C NMR (126 MHz, CDCl ) δ: 16.0, 22.2,
9
0
6
3
0–93 °C, petroleum ether – ethyl acetate. [α] = –33 (c
.80, CHCl ). IR (ef, cm ): 3282, 2938, 1645, 1545, 1038,
99. H NMR (400 MHz, CDCl ) δ: 1.29 (d, J = 6.7 Hz,
3
D
–
1
3
4.8, 66.8, 69.6, 82.6. MS (CI) m/z (rel. intensity): 99 (M +
3
1
H, 100).
3
H), 2.01 (t, J = 2.7 Hz, 1H), 2.25 (broad s, 1H), 2.39 (ddd,
J = 15.8, 6.2, 2.8 Hz, 1H), 2.51 (m, 2H), 3.90 (m, 2H), 5.08
(2R)-Benzyl-(2-methylpent-4-ynyl) ether ((2R)-25)
(
dt, J = 6.8, 4.8 Hz, 1H), 6.37 (d, J = 4.3 Hz, 1H), 7.32 (m,
To a suspension of sodium hydride (60 wt. % in mineral
oil, 81.3 mg, 2.03 mmol, prewashed with hexanes) in N,N-
dimethylformamide (4.0 mL) at 0 °C were added a solution
of the alcohol (2R)-12 (181 mg, 1.85 mmol) in tetrahy-
drofuran (1 mL) and benzyl bromide (230 µL, 1.93 mmol).
The resultant mixture was stirred at room temperature for
1
3
5
6
H). C NMR (126 MHz, CDCl ) δ: 17.2, 23.1, 40.4, 55.8,
3
6.4, 70.4, 82.0, 126.7, 127.8, 128.8, 138.8, 175.1. MS (CI)
m/z (rel. intensity): 232 (M + H, 100). Anal. calcd. for
C H NO : C 72.70, H 7.41, N 6.06; found: C 72.45, H
7
1
4
17
2
.54, N 5.77.
6
h. The reaction mixture was then diluted with ether
(
(
10 mL) and washed with water (3 × 10 mL) and brine
10 mL). The organic layer was dried over anhydrous mag-
(
2R)-2-Methylpent-4-ynoic acid ((2R)-11)
To a solution of the amide 23 (5.44 g, 23.5 mmol) in p-
nesium sulfate and concentrated in vacuo. Purification by
flash chromatography using hexanes–ether (50:1) as the
eluant afforded the title compound (2R)-25 (313 mg, 90%)
as a colourless oil. R = 0.77 (hexanes–ether, 4:1). [α]
+
dioxane (60 mL) at room temperature was added sulfuric
–
1
acid (3 mol L , 60 mL). The resultant solution was heated
at reflux for 7 h and then was cooled to 0 °C. The reaction
mixture was basified to pH ~10 with an aqueous solution of
sodium hydroxide (50 wt. %), then diluted with water
2
0
=
f
D
2
0
16.1 (c 1.40, CHCl ) (lit. value (18a) [α] = +16 (c 1.20,
3
D
©
2004 NRC Canada

1
646
Can. J. Chem. Vol. 82, 2004
2
0
CHCl ) and lit. value (18b) [α] = +16.3 (c 0.95, CHCl )).
added the Mannich base 7 (251 mg, 1.00 mmol) and methyl
iodide (65.0 µL, 1.05 mmol). The resultant solution was then
heated at reflux until the Mannich base 7 had completely re-
acted (8 days, TLC analysis). The reaction mixture was then
cooled to room temperature, filtered, and concentrated in
vacuo. Purification by flash chromatography using dichloro-
methane as the eluant afforded a mixture (8:1:2:2) of
(–)-xyloketal D (4), 2,6-epi-xyloketal D (15), and the
diastereomeric spiroacetals 16 and 17 (105 mg, 40%) as a
yellow solid. Repeated flash chromatography using
hexanes–ether (4:1) as the eluant on TLC grade silica gel
(5–25 µm) afforded a mixture (20:1) of (–)-xyloketal D (4)
and 2,6-epi-xyloketal D (15) as a pale cream solid and a sep-
arate mixture (4:5) of the two diastereomeric spiroacetals 16
and 17 as a pale cream solid. An analytically pure sample of
synthetic (–)-xyloketal D (4), as pale pink prisms, was pre-
pared by recrystallization from petroleum ether. An analyti-
cally pure sample of a mixture (4:5) of the diastereomeric
spiroacetals 16 and 17, as white needles, was also prepared
by recrystallization from petroleum ether.
3
D
3
–
1
IR (ef, cm ): 3289, 3031, 2857, 2117, 1609, 1496, 1454,
112, 749. H NMR (400 MHz, CDCl ) δ: 1.03 (d, J =
.8 Hz, 3H), 1.95 (t, J = 2.6 Hz, 1H), 2.02 (m, 1H), 2.21
ddd, J = 16.7, 6.9, 2.6 Hz, 1H), 2.35 (ddd, J = 16.7, 5.5,
.7 Hz, 1H), 3.39 (d, J = 6.5 Hz, 2H), 4.52 (s, 2H), 7.33 (m,
H). C NMR (126 MHz, CDCl ) δ: 16.3, 22.5, 32.8, 69.3,
3.0, 74.1, 82.7, 127.48, 127.51, 128.3, 138.5. MS (CI) m/z
1
1
6
3
(
2
5
7
1
3
3
(
1
rel. intensity): 189 (M + H, 78), 171 (17), 111 (M – Ph,
00).
(
2S)-2-Methylpent-4-yn-1-ol ((2S)-12)
The title compound (2S)-12 (1.17 g, 85%) as a colourless
oil was also prepared from the corresponding carboxylic
acid (2S)-11 (1.57 g, 14.0 mmol). [α] = –11.1 (c 1.83,
CHCl ). All other spectroscopic data were identical to those
reported for the enantiomeric alcohol (2R)-12.
2
0
D
3
(
2S)-Benzyl-(2-methylpent-4-ynyl) ether ((2S)-25)
The title compound (2S)-25 (248 mg, 90%) as a colour-
less oil was also prepared from the corresponding alcohol
20
(
2S)-12 (144 mg, 1.47 mmol). [α] = –15.9 (c 1.05, CHCl3).
Method B
D
All other spectroscopic data were identical to those reported
To a solution of the dihydrofuran (4R)-14 (121 mg,
1.23 mmol) in benzene (5 mL) at room temperature were
added the Mannich base 7 (103 mg, 0.41 mmol) and
dimethyl sulfate (41 µL, 0.43 mmol). The resultant solution
was heated at reflux until the Mannich base 7 had com-
pletely reacted (3 days, TLC analysis). The reaction mixture
was then cooled to room temperature and decanted. The re-
maining solid residue was extracted with dichloromethane
(3 × 5 mL) and the combined organic extracts were concen-
trated in vacuo. Purification by flash chromatography using
dichloromethane–ether (19:1) as the eluant afforded a mix-
ture (16:1:4:4) of (–)-xyloketal D (4), 2,6-epi-xyloketal D
(15), and the diastereomeric spiroacetals 16 and 17 (40 mg,
for the enantiomeric ether (2R)-25.
(
4R)-4,5-Dihydro-2,4-dimethylfuran ((4R)-14)
The alcohol (2S)-12 (0.91 g, 9.28 mmol) and sodium am-
ide (50 mg, 1.28 mmol) were heated, without solvent, at re-
flux for 2 h. Direct distillation of the reaction mixture at
atmospheric pressure afforded the exocyclic dihydrofuran
(
(
4R)-13 and a small amount of the endocyclic dihydrofuran
4R)-14 as a colourless oil. H NMR (500 MHz, C D ,
1
6
6
~
90% pure) δ: 0.58 (d, J = 6.2 Hz, 3H), 1.80 (m, 2H), 2.27
(
m, 1H), 3.27 (dd, J = 8.1, 6.5 Hz, 1H), 3.77 (dd, J = 8.1,
.0 Hz, 1H), 3.92 (m, 1H), 5.46 (m, 1H). This material was
6
heated at reflux for 2 h and then distilled at atmospheric
pressure to afford the title compound (4R)-14 (0.40 g, 44%)
as a colourless oil, bp 97–103 °C, ~760 mmHg (1 mmHg =
37%) as a yellow solid. (–)-Xyloketal D 4: R = 0.24 (hex-
f
anes–ether, 4:1), mp 71–73 °C as pale pink prisms from pe-
troleum ether (lit. value (1) mp 111–113 °C) and mp 68–
70 °C as white crystals on recrystallization from ether–
pentane (lit. value (13) mp 110 to 111 °C, ether–pentane).
33.322 4 Pa) (lit. value (3) bp ~100 °C, ~760 mmHg
2
4
–1
20
25
4)). [α] = +11.8 (c 0.82, CHCl ). IR (ef, cm ): 2961,
[α] = –110.1 (c 0.102, CHCl ) (lit. value (1) [α] = –119.5
D
3
D
3
D
1
–1
875, 1674, 1453, 1383, 1243, 1043, 1008, 886. H NMR
(c 0.113, CHCl )). IR (ef, cm ): 3399, 2967, 2927, 2884,
3
(
400 MHz, C D ) δ: 0.86 (d, J = 6.6 Hz, 3H), 1.68 (apparent
1620, 1491, 1421, 1382, 1370, 1332, 1272, 1117, 1070,
6
6
1
t, J = 1.5 Hz, 3H), 2.76 (m, 1H), 3.71 (dd, J = 8.7, 6.5 Hz,
1006. H NMR (500 MHz, CDCl ) δ: 1.07 (d, J = 6.5 Hz,
3
1
3
1
H), 4.21 (dd, J = 9.5, 8.6 Hz, 1H), 4.43 (m, 1H). C NMR
3H), 1.53 (s, 3H), 1.98 (ddd, J = 11.3, 6.5, 1.1 Hz, 1H), 2.08
(m, 1H), 2.55 (s, 3H), 2.72 (dd, J = 17.9, 6.5 Hz, 1H), 2.97
(d, J = 18.0, 1H), 3.57 (apparent t, J = 8.4 Hz, 1H), 4.20 (ap-
parent t, J = 8.3 Hz, 1H), 6.36 (d, J = 8.9 Hz, 1H), 7.52 (d,
(
(
101 MHz, C D ) δ: 13.6, 20.9, 37.9, 77.2, 101.4, 155.0. MS
CI) m/z (rel. intensity): 99 (M + H, 100).
6 6
1
3
J = 8.9 Hz, 1H), 13.12 (s, 1H). C NMR (101 MHz, CDCl3)
δ: 15.8, 18.0, 22.7, 26.1, 35.1, 47.0, 74.3, 106.2, 108.3,
(
4S)-4,5-Dihydro-2,4-dimethylfuran ((4S)-14)
The title compound (4S)-14 (0.42 g, 36%) as a colourless
1
08.8, 113.1, 130.0, 159.5, 162.9, 202.6. MS (CI) m/z (rel.
oil was also prepared from the corresponding alcohol (2S)-
2
0
intensity): 263 (M + H, 100). Anal. calcd. for C H O : C
1
2 (1.17 g, 11.9 mmol). [α] = –12 (c 0.44, CHCl ). All
15 18
4
D
3
6
8.68, H 6.92; found: C 68.52, H 6.98. Diastereomeric
other spectroscopic data were identical to those reported for
spiroacetals 16 and 17 (4:5 mixture): R = 0.32 (hexanes–
the enantiomeric dihydrofuran (4R)-14.
f
2
0
ether, 4:1), mp 60 to 61 °C, petroleum ether. [α] = +26.9 (c
0
1
D
–
1
.71, CHCl ). IR (ef, cm ): 3423, 2958, 2878, 1626, 1488,
(
–)-Xyloketal D (4), 2,6-epi-xyloketal D (15), and the
3
1
419, 1369, 1331, 1270, 1247, 1136, 1060, 1018, 853. H
diastereomeric spiroacetals (16) and (17)
NMR (400 MHz, CDCl ) δ: 1.10 (d, J = 6.6 Hz, 3H), 1.18
3
Method A
(d, J = 6.6 Hz, 3H), 1.55 (dd, J = 12.8, 9.5 Hz, 1H), 2.00 (m,
5H), 2.27 (dd, J = 13.4, 9.4, 1H), 2.36 (dd, J = 12.9, 7.3,
1H), 2.46 (m, 1H), 2.54 (s, 3H), 2.55 (s, 3H), 2.78 (m, 5H),
To a solution of the dihydrofuran (4R)-14 (295 mg,
.01 mmol) in benzene (10 mL) at room temperature were
3
©
2004 NRC Canada

Pettigrew et al.
1647
2. R.A. Hill and M.C. Parker. Nat. Prod. Rep. 18, iii (2001).
3. J.D. Pettigrew, J.A. Bexrud, R.P. Freeman, and P.D. Wilson.
Heterocycles, 62, 445 (2004).
4. For a recent review on the chemistry of ortho-quinone
methides, see: R.W. Van De Water and T.R.R. Pettus. Tetrahe-
dron, 58, 5367 (2002).
3
7
1
.54 (t, J = 7.7 Hz, 1H), 3.64 (t, J = 8.4 Hz, 1H), 4.09 (t, J =
.9 Hz, 1H), 4.21 (t, J = 7.9 Hz, 1H), 6.34 (d, J = 8.9 Hz,
H), 6.37 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.51
1
3
(
(
d, J = 8.9 Hz, 1H), 13.01 (s, 1H), 13.02 (s, 1H). C NMR
126 MHz, CDCl ) δ: 16.3, 16.5, 17.6, 18.0, 26.2, 29.3, 29.6,
3
3
1
2
1.9, 33.0, 45.2, 45.3, 75.0, 75.4, 108.1, 108.9, 109.0, 110.0,
10.1, 113.16, 113.24, 129.58, 129.62, 159.6, 162.2, 202.7,
02.8. MS (CI) m/z (rel. intensity): 263 (M + H, 100), 111
5
. Alkylation, oxidation, and photochemical reactions have been
used to generate ortho-quinone methides from the Mannich
bases of phenols. See, for example: (a) E. Modica, R.
Zanaletti, M. Freccero, and M. Mella. J. Org. Chem. 66, 41
(
6
12). Anal. calcd. for C H O : C 68.68, H 6.92; found: C
8.58, H 6.99.
15 18 4
(
2001); (b) P.D. Gardner, H.S. Rafsanjani, and L. Rand. J. Am.
Chem. Soc. 81, 3364 (1959); (c) K. Nakantani, N. Higashida,
and I. Saito. Tetrahedron Lett. 38, 5005 (1997).
ent-Xyloketal D (ent-4), ent-2,6-epi-xyloketal D (ent-15),
and the diastereomeric spiroacetals (ent-16) and (ent-17)
6
. For related examples of this regio- and stereoselective inverse
electron demand Diels–Alder reaction, see: (a) M.
Anniyappan, D. Muralidharan, and P.T. Perumal. Tetrahedron,
Method A
A solution of the dihydrofuran (4S)-14 (237 mg,
.42 mmol), the Mannich base 7 (202 mg, 0.804 mmol), and
5
8, 10 301 (2002); (b) J.S. Yadav, B.V.S. Reddy, M. Aurna, C.
2
Venugopal, T. Ramalingam, S.K. Kumar, and A.C. Kunwar. J.
Chem. Soc. Perkin Trans. 1, 165 (2002); (c) L. Diao, C. Yang,
and P. Wan. J. Am. Chem. Soc. 117, 5369 (1995); (d) J.D.
Chambers, J. Crawford, H.W.R. Williams, C. Dufresne, J.
Scheigetz, M.A. Bernstein, and C.K. Lau. Can. J. Chem. 70,
methyl iodide (52 µL, 0.84 mmol) in benzene (8 mL) was
heated at reflux for 6 days. Isolation and purification of the
reaction products, as described previously, afforded a mix-
ture (13:1:3:3) of ent-xyloketal D (ent-4), ent-2,6-epi-
xyloketal D (ent-15), and the diastereomeric spiroacetals
ent-16 and ent-17 (96 mg, 46%) as a yellow solid. Addi-
tional purification and recrystallization of these reaction
products, as described previously, afforded an analytically
pure sample of ent-xyloketal D (ent-4) as pale pink prisms
and an analytically pure mixture (4:5) of the diastereomeric
spiroacetals ent-16 and ent-17 as white needles.
1
717 (1992).
7
. We also prepared a corresponding Mannich base from N,N-
dibenzylamine, 2,4-dihydroxyacetophenone (6), and formalde-
hyde. However, this substrate proved to be less suitable for
subsequent cycloaddition reactions. The synthesis of a corre-
sponding Mannich base derived from diethylamine, 2,4-
dihydroxyacetophenone (6), and paraformaldehyde has been
previously reported. See: Y. Omura, Y. Taruno, Y. Irisa, M.
Morimoto, H. Saimoto, and Y. Shigesasa. Tetrahedron Lett. 42,
Method B
The procedure described in the previous section was also
used to prepare a mixture (20:1:3:3) of ent-xyloketal D (ent-4),
ent-2,6-epi-xyloketal D (ent-15), and the diastereomeric
spiroacetals ent-16 and ent-17 (64 mg, 36%) as a yellow
solid. ent-Xyloketal D (ent-4): mp 70 to 71 °C as pale pink
crystals from petroleum ether and mp 68–71 °C as white
7
273 (2001).
. (a) J. Colonge and R. Gelin. Bull. Soc. Chim. Fr. 799 (1954);
b) G. Eglinton, E.R.H. Jones, and M.C. Whiting. J. Chem.
8
9
(
Soc. 2873 (1952).
. V.E. Buchta and H. Schlesinger. Liebigs Ann. Chem. 598, 1
(
1955).
2
0
crystals from ether–pentane. [α]
= +113.1 (c 0.122,
D
10. B.B. Snider, A.J. Allentoff, and M.B. Walner. Tetrahedron, 46,
CHCl ). All other spectroscopic data were identical to those
3
8031 (1990).
reported previously for (–)-xyoketal D (4). Diastereomeric
1
1. We also prepared a corresponding Mannich base from
morpholine, phloroglucinol (18), and formaldehyde. However,
this substrate was less suitable for subsequent cycloaddition
reactions. For preparative details, see: F.F. Blicke and F.J.
McCarty. J. Org. Chem. 24, 1061 (1959).
2. A number of related Mannich bases of phloroglucinol 18 have
also been prepared, see: A.P. Terent’ev, E.G. Rukhadze, and
S.F. Zapuskalova. Probl. Org. Sint. 122 (1965); Chem. Abstr.
64, 8065 (1966).
13. (a) K. Krohn and M. Riaz. Tetrahedron Lett. 45, 293 (2004).
Of note, there is an error in the title of this paper as the natural
product, xyloketal D (4), is levorotatory; (b) K. Krohn, M.
Riaz, and U. Flörke. Eur. J. Org. Chem. 1261 (2004).
spiroacetals ent-16 and ent-17 (4:5): mp 59–61 °C, petro-
2
0
leum ether. [α] = –26.7 (c 1.05, CHCl ). All other spectro-
D
3
scopic data were consistent with that reported for the
diastereomeric spiroacetals 16 and 17.
1
Acknowledgments
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC) and Simon Fraser
University (SFU) for financial support. We also wish to ac-
knowledge the Canadian Foundation for Innovation (CFI)
and AstraZeneca Canada Inc. for support of our research
program. J.D.P. thanks SFU for an entrance scholarship and
NSERC for a PGSA award. We thank Mr. Jason A. Bexrud
for preliminary investigations. We are also grateful to Pro-
14. (a) D.J. Baek, S.B. Daniels, P.E. Reed, and J.A. Katzenellen-
bogen. J. Org. Chem. 54, 3963 (1989); (b) G. Helmchen, G.
Nill, D. Flockerzi, and M.S.K. Youssef. Angew. Chem. Int. Ed.
Engl. 18, 63 (1979).
1
fessor Yongcheng Lin for kindly providing a copy of the H
NMR spectrum of xyloketal D (4) for comparison purposes.
15. The racemic carboxylic acid (±)-11 was also condensed with
(
R)-phenylglycinol (22) to afford the corresponding diastereo-
meric oxazolines. See: M.J. Kurth, O.H.W. Decker, H. Hope,
and M.D. Yanuck. J. Am. Chem. Soc. 107, 443 (1985). Unfor-
tunately, these derivatives were chromatographically inseparable.
16. A.G. Myers, B.H. Yang, H. Chen, L. McKinstry, D.J. Kopecky,
and J.L. Gleason. J. Am. Chem. Soc. 119, 6496 (1997).
References
1
. Y. Lin, X. Wu, S. Feng, G. Jiang, J. Luo, S. Zhou, L.L.P.
Vrijmoed, E.B.G. Jones, K. Krohn, K. Steingröver, and F.
Zsila. J. Org. Chem. 66, 6252 (2001).
©
2004 NRC Canada

1
648
Can. J. Chem. Vol. 82, 2004
1
7. The chiral nonracemic alcohol (2R)-12 is a known compound
and has been prepared in six steps from commercially avail-
able (2R)-methyl-3-hydroxy-2-methylpropanoate. However,
the optical rotation of this compound was not reported. See:
from commercially available (2R)-methyl-3-hydroxy-2-
methylpropanoate. See: (a) A. Takle and P. Kocienski. Tetra-
hedron, 46, 4503 (1990); (b) P.J. Kocienski, S.D.A. Street, C.
Yeates, and S.F. Cambell. J. Chem. Soc., Perkin Trans. 1,
2189 (1987).
(
a) M. Christmann, U. Bhatt, M. Quitschalle, E. Claus, and M.
Kalesse. Angew. Chem. Int. Ed. 39, 4364 (2000); (b) R. Baker
and M.A. Brimble. Tetrahedron Lett. 27, 3311 (1986).
8. The chiral nonracemic benzyl ether (2R)-25 has been prepared
19. (a) G.J. Kang and T.H. Chan. J. Org. Chem. 50, 452 (1985);
(b) J.A. Dale, D.L. Dull, and H.S. Mosher. J. Org. Chem. 34,
2543 (1969).
1
©
2004 NRC Canada