Regioselectivity in the syntheses of enantiopure 2-benzopyrans through intramolecular cyclization of tethered lactaldehydes. Conformations of the products

Article abstract of DOI:10.1071/CH03027

Using titanium tetraisopropoxide, the enantiopure tethered lactaldehyde (α′S,2S)-2-(3′-hydroxy-α′-methyl-benzyloxy) propanal (6) is cyclized with complete regio- and diastereoselectivity ortho to the phenolic hydroxyl group to give (1S,3S,4R)-3,4-dihydro-1,3,-dimethyl-2-benzopyran-4,5-diol (7). Similar cyclization of the epimeric (α′R,2S)-lactaldehyde (25) yields solely the corresponding (1R,3S,4R)-4,5-diol (34). The 4,5-diacetate (26), but not (35), undergoes conformational inversion of the heterocyclic ring through significant 4,5-peri interactions between the adjacent acetoxy substituents. Spontaneous cyclizations of the corresponding phenoxide ions of the lactaldehydes (6) and (25), generated by fluoride from their silyl ethers, led to the related 4,7-diols with high regioselectivity through ring-closure para to the aromatic oxygen.

Full text of DOI:10.1071/CH03027

CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2003, 56, 489–498
Regioselectivity in the Syntheses of Enantiopure 2-Benzopyrans
through Intramolecular Cyclization of Tethered Lactaldehydes.
Conformations of the Products
Rachna Aggarwal,A Anthony A. Birkbeck,A Robin G. F. Giles,A,C Ivan R. Green,B
Yolanta GruchlikA and Francois J. OosthuizenA
A Chemistry Department, Murdoch University, Murdoch 6150, Australia.
B Department of Chemistry, University of the Western Cape, Bellville 7530, South Africa.
C Author to whom correspondence should be addressed (e-mail: rgiles@chem.murdoch.edu.au).
Using titanium tetraisopropoxide, the enantiopure tethered lactaldehyde (αꢀS,2S)-2-(3ꢀ-hydroxy-αꢀ-methyl-
benzyloxy)propanal (6) is cyclized with complete regio- and diastereoselectivity ortho to the phenolic hydroxyl
group to give (1S,3S,4R)-3,4-dihydro-1,3-dimethyl-2-benzopyran-4,5-diol (7). Similar cyclization of the epimeric
(αꢀR,2S)-lactaldehyde (25) yields solely the corresponding (1R,3S,4R)-4,5-diol (34).The 4,5-diacetate (26), but not
(35), undergoes conformational inversion of the heterocyclic ring through significant 4,5-peri interactions between
the adjacent acetoxy substituents. Spontaneous cyclizations of the corresponding phenoxide ions of the lactalde-
hydes (6) and (25), generated by fluoride from their silyl ethers, led to the related 4,7-diols with high regioselectivity
through ring-closure para to the aromatic oxygen.
Manuscript received: 24 January 2003.
Final version: 24 February 2003.
Introduction
pair of C4 epimeric 2-benzopyran-4,7-diols (5) with low
diastereoselectivity as a model[4] for the synthesis of glu-
coside B.[1] In each of these two cases only one regioisomer
of the 2-benzopyran could be formed, ring closure occurring
ortho to the activating phenolic substituent in the first case
and para in the second, since the aromatic methoxy group
blocked the alternative possibility. This paper describes con-
ditions to promote either regioselectivity preferentially in the
related phenolic lactaldehyde (6), which lacks the blocking
methoxy group, when either the 4,5-diol (7) or the 4,7-diols
(8) might be sought (Scheme 2).
In model studies related to the syntheses of the aphid insect
pigments the protoaphins,[1] we have studied the cyclizations
of two isomeric phenolic lactaldehydes to afford monochiral
2-benzopyrans. In the first of these (Scheme 1),[2] the lac-
taldehyde (1) afforded the 2-benzopyran-4,5-diol (2) with
complete diastereoselectivity, and thence the enantiopure
quinone (3) as a model for the assembly of quinone A.[1,3]
In the second, the structurally isomeric phenol (4) gave the
OMe
OMe
O
a'
Results and Discussion
1
O
O
3
O
e
4
Syntheses of the Phenolic Ethers (21)–(24) of the
Tethered Lactaldehydes
e'
OH
O
OH OH
O
OH
3-Hydroxyacetophenone was chosen as the starting mate-
rial for compound (6), into which it was converted by a
sequence related to that for the syntheses of analogues (1)[2]
(1)
(2)
(3)
OMe
OMe
HO
HO
HO
HO
O
O
O
O
O
OH
OH OH
OH
O
O
(7)
(6)
Scheme 2.
10.1071/CH03027
(8)
(4)
(5)
Scheme 1.
© CSIRO 2003
0004-9425/03/05489

490
R. Aggarwal et al.
and (4).[4] In a series of high-yielding reactions, the known
benzyl ether (9)[5] (see Diagram 1) was reduced to the alcohol
(11) and this was converted,[6] in turn, into the trichloro-
OR2
O
1
acetimidate (13), the H NMR spectrum of which showed
R1O
R1
the characteristic NH proton at δ 8.30 and the benzylic α-
proton at δ 5.95. The latter signal was strongly deshielded
from the corresponding proton (δ 4.80) observed in the pre-
cursor alcohol (11). The imidate (13) was treated[4,6,7] with
ethyl (S)-lactate to form an inseparable mixture of protected
lactates (15) in a 55 : 45 ratio and an overall yield of 52%
over the four steps from 3-hydroxyacetophenone. This mix-
ture was subsequently reduced to the chromatographically
separable mixture of alcohols (17) (52% yield) and (18)
(40%). The stereochemistry of each particular diastereoiso-
mer was assumed at this point but confirmation was obtained
upon examination of the 1H NMR spectra of the cyclization
products obtained later in the synthesis.
RO
(9) R = Bn
R2
___________
(10) R = TBS
(11)
(12)
(13)
(14)
Bn
TBS
Bn
H
H
C(=NH)CCl3
TBS
C(=NH)CCl3
O
O
O
R2
R2
R1
EtO2C
R1O
R1O
(17) Bn
R2
RO
_________
The chiral lanthanide NMR shift reagent [Eu(hfc)3] was
used to determine[8] the enantiomeric purity of each of the
alcohols (17) and (18). The respective enantiomers were
assembled from methyl (R)-lactate in the same manner, and
the specific rotation for each enantiomeric pair agreed closely
(except for the sign of rotation). Upon addition of the shift
reagent, a 60 : 40 mixture of each alcohol and its enantiomer
showed good separation in many of the corresponding sig-
CH2OH
CH2OH
(18)
(20)
(22)
(24)
(25)
(15) R = Bn
(19) TBS
(21) Bn
(16) R = TBS
CHO
CHO
CHO
(23) TBS
(6)
H
Diagram 1.
1
nals for the two components in the H NMR spectrum. On
the other hand, the spectrum for each of the enantiopure
alcohols (17) and (18) showed the absence of the respec-
tive enantiomer. These experiments established that these
diastereoisomeric alcohols were optically pure within the
limits of this NMR technique.[2,4,8]
O
5
4
R1O
OR2
The alcohols were each separately oxidized to lactalde-
hyde (21) (75% yield) and (22) (80%), respectively, using
the Swern procedure.[9] Subsequently, each of these aldehy-
des was individually reduced with lithium aluminium hydride
back to its respective alcohol.Thin-layer chromatography and
1H NMR spectroscopy showed no evidence of more than one
diastereoisomeric alcohol, from which it was inferred that
racemization had not occurred at the carbon atom positioned
α to the aldehyde group during the oxidation step.
The same sequence of transformations converted the tert-
butyldimethylsilyl ether (10), through the alcohol (12) and
the imidate (14), into the inseparable mixture of diastereo-
isomeric silyloxy-protected lactates (16), and thence into the
separated alcohols (19) and (20) (see Diagram 1). The enan-
tiomeric purity of each of these was confirmed as described
above for alcohols (17) and (18). Each of the alcohols were
individually oxidized to the corresponding lactaldehydes (23)
and (24).
R1
R2
___________
(26)
(27)
(28)
Ac
Me
Me
Ac
H
Ac
Diagram 2.
proceeded smoothly on the second batch. This potentially
unstable phenolic lactaldehyde (6) was then cyclized with
complete diastereoselectivity using titanium tetraisopropox-
ide to form the structurally isomeric 2-benzopyran-4,5-diol
(7) (73% yield). The high-resolution mass spectrum of the
crude (7) confirmed its molecular formula, while its 1H NMR
spectrumconfirmedthestereochemistry. Firstly, thechemical
shift of the proton H3 (δ 3.93) for this 1,3-trans-dimethyl-2-
benzopyran was at lower field than that for the corresponding
1,3-cis-dimethyl stereoisomer (34) (δ 3.54, see below).[10]
Secondly, the coupling constant between H3 and H4 was
7.0 Hz, which confirmed a near trans arrangement of these
two protons and indicated that H3 was axial and H4 was
pseudoaxial. Furthermore, these data confirmed that the C3
methyl was equatorial, the C1 methyl was pseudoaxial, and
the C4 hydroxyl was pseudoequatorial.
Regio- and Diastereoselective Cyclizations to Form the
2-Benzopyran-4,5-diols and Their Derivatives
Selective phenolic O-debenzylation of the lactaldehyde (21)
was achieved using palladium on charcoal followed by rapid
chromatography to afford the crude phenol (6) (72% yield).
Adventitious sulfur from the Swern oxidation was diffi-
cult to remove and poisoned the catalyst. Therefore, the
first batch was sacrificed, but the desired hydrogenolysis
This 4,5-diol (7) was characterized as its more stable
diacetate (26) (see Diagram 2), for which the gross struc-
ture was confirmed by high-resolution mass and H NMR
1

Regioselectivity in the Syntheses of Enantiopure 2-Benzopyrans
491
a
a'
Me
O
H
e'
4
a'
H1
e
O
O
O
H1
e'
H3
H4
e'
HO
a'
Me
e'
Me
Me
e
AcO
R1O
R1
R1O
R1O
OR2
R2
R2
R2
a'
O
H
3
a
R1
R2
R1
H
R2
(29)
(30)
(31) Me
(32) Me
(33) Ac
Cl
OH
OAc
(34)
(35) Ac
(36) Me
H
Ac
H
(37) Me
(38) Me
(39) Ac
Cl
OH
OAc
Diagram 3.
Diagram 4.
spectrometry. However, detailed examination of the latter
revealed that the coupling constant between the protons H3
and H4 was only 2.0 Hz, which indicated a dihedral angle
between these two protons that was much smaller than for
the diol (7). This coupling constant was also much smaller
than those for the related diacetates of the diols (2) (4.8 Hz)[2]
and (5) (pseudoequatorial 4-OH, 7.4 Hz).[4] These data sup-
port the conformational inversion of the dihydropyran ring
half-chair (29) of the diol (7) into the alternative half-chair
(30) of the diacetate (26) (see Diagram 3). In this latter
conformation the protons H3 and H4 are equatorial and pseu-
doequatorial, respectively, and the dihedral angle between
them is therefore much smaller giving rise to the observed
value of 2.0 Hz for the coupling constant. While such a con-
formational inversion is reasonable, it is to our knowledge the
first such case reported for a 2-benzopyran or naphtho[2,3-
c]pyran in which the C3 methyl (or alkyl) is axial. The
naturally occurring quinones eleutherin and isoeleutherin are
known to have alternative conformations for the dihydro-
pyran ring, but there the C3 methyl is equatorial in each
case.[11] The reason for the conformational inversion in the
case of the diacetate (26) is ascribed to the fact that in (7) and
(26) the 1,8-peri-interactions are small, unlike other related
molecules for which it is general to have a substituent at
C8 which is larger than hydrogen. In the case of diol (7),
the 4,5-peri-interactions between the two hydroxy groups
are sufficiently small to tolerate a pseudoequatorial orienta-
tion for the alcohol at C4. In the diacetate (26), however, the
4,5-peri-interactions are sufficiently large to achieve a con-
formational inversion at the expense of the C3 methyl and C4
acetoxy being axial and pseudoaxial, respectively, while the
lack of significant 1,8-peri-interactions allows the C1 methyl
to become pseudoequatorial.
A series of nuclear Overhauser enhancement spectra
(NOESY) supported the conformational assignment (30) for
the diacetate (26). In addition to all the expected correlations,
a NOESY spectrum showed a strong correlation between the
C3methylgroupandH1, whileH1showedastrongreciprocal
correlation, as would be expected from their close proxim-
ity as shown in conformation (30). Notably, H3 showed no
correlation with the C1 methyl, as would be expected in the
alternative conformation (29), while the reciprocal correla-
tion between the C1 methyl and H3 was very weak. Similarly,
in NOE difference spectra, irradiation of the C3 methyl group
showed an 8.2% enhancement of the H1 signal, while irradia-
tion of the C1 methyl produced a much weaker enhancement
(3.2%) of the H3 signal. Inspection of the methyl intensities
upon reciprocal irradiation of the individual protons also
supported conformation (30).
Further examples of this conformational inversion were
sought. Selective methylation of the phenolic oxygen of the
crude 4,5-diol (7) afforded the 5-O-methyl ether (27), for
which the H3–H4 coupling constant was 5.4 Hz compared
with7.9 Hzfortheanalogous(racemic)phenolicmethylether
of the 4,5-diol (2).[12] The coupling constants for related
compounds are generally in the range 8–9 Hz.[10c,13] This
reduction in the coupling constant presumably corresponds
to a reduction in the dihedral angle between H3 and H4,
which occurs as a consequence of adopting a conforma-
tion to appropriately reduce the 4,5-peri-interactions, but
these are insufficient to achieve an inversion of the ring.
Dreiding models suggest that, in the initial stages of the
ring inversion, the pseudoequatorial C4 hydroxy group starts
to become more pseudoaxial, and this is accompanied by
a decrease in the H3–H4 dihedral angle. This is promoted,
once again, by the potential for the pseudoaxial C1 methyl
to become pseudoequatorial (see above). Acetylation of the
alcohol in (27) yielded the acetate (28). Once again, the cou-
pling constant between H3 and H4 was small (1.9 Hz), which
suggested the same conformational inversion observed for
the related diacetate (26). Since the H3–H4 coupling con-
stant (5.4 Hz) for alcohol (27) was smaller than that found
in other analogues, alcohol (32) (see Diagram 4), which
is the C4 pseudoaxial epimer of (27), was assembled. This
was achieved through conversion of the pseudoequatorial C4
alcohol in the 2-benzopyran (27) into the pseudoaxial chlo-
ride (31) using thionyl chloride, followed by replacement
of the chlorine with water upon treatment of chloride (31)
with aqueous acetonitrile containing silver nitrate.[13b] The
H3–H4 coupling constant for compound (32) was 1.9 Hz,
which (together with its other physical data) distinguished it
from its C4 epimer (27).
Similar conversion of the lactaldehyde (22) into the 2-
benzopyran-4,5-diol (34) was achieved through cyclization
of the crude phenol (25).This cyclization was notable since it,
too, was completely diastereoselective, as was the cyclization
of lactaldehyde(6)reported above. Incontrast, thecyclization
of the benzyl epimer of (1), which is identical to compound
(25) but for an additional aromatic methoxy substituent para
to the phenolic substituent in (25), afforded the two C4
epimeric 4,5-diols.[2] We had previously ascribed[2] this lack
of diastereoselectivity in that case to the additional methoxy

492
R. Aggarwal et al.
group, and the complete diastereoselectivity in the formation
of 4,5-diol (34) bears this out.
This represented an average yield of 78% for each individ-
ual step. Identification of the components followed from the
1H NMR spectrum of the mixture. Although not all the sig-
nals could be assigned to the individual epimers (42) and
(43) since they were obtained in approximately equal propor-
tions, every resonance for the mixture was readily seen (see
Experimental section). These included aromatic signals for
two 1,2,4-trisubstituted products, together with the expected
signals for the three heterocyclic protons in each compound.
In particular, each H3 signal for these 1,3-trans-dimethyl
compounds resonated at a lower field (δ 4.18 and 4.19) than
did their 1,3-cis-dimethyl analogues (δ 3.74 and 3.90) (see
below). The minor component of the mixture was assigned
thestructureofa4,5-diolsince, althoughthearomaticprotons
H6 and H8 were obscured, all the other signals for (33) were
clear. In particular, the aromatic proton H7 at δ 7.35 appeared
as a sharp triplet (J 7.9 Hz) and confirmed the existence of the
alternative 1,2,3-trisubstituted aromatic ring.The signals that
readily distinguished (33) from its C4 epimer (26) were the
chemical shifts of each of the heterocyclic protons (H1, H3,
H4 for (26): δ 4.91, 4.25, 5.72, respectively; and for (33):
δ 5.16, 4.14, 5.89, respectively) and the C1 methyl groups
(for (26): δ 1.60; and for (33): δ 1.52). The coupling con-
stant between H3 and H4 did not distinguish the two epimers
since they were virtually identical ((26): J 2.0 Hz; (33): J
1.9(4) Hz), the value for (26) arising from the conformational
inversion of its heterocyclic ring.
Diol (34) exhibited a resonance in the 1H NMR spectrum
for the proton H3 at δ 3.54, which confirmed a cis arrange-
ment of the methyl substituents (see above), and an H3–H4
coupling constant of 9.0 Hz. The coupling constant for the
corresponding4,5-diacetate(35)was8.2 Hz.Thustheconfor-
mations of the heterocyclic rings in diol (34) and its diacetate
(35) remained the same, in contrast with the earlier obser-
vation (see above) made for diol (7) and its diacetate (26),
where a conformational inversion occurred on formation of
the latter. In the case of diacetate (35), ring inversion to ease
the peri interactions arising from the 4,5-diacetate does not
occur because all three heterocyclic ring substituents would
need to be axial.
For comparison purposes, the phenolic methyl ether (36)
of the diol (34) was prepared and converted through the
pseudoaxial chloride (37) into the C4 epimeric pseudoaxial
alcohol (38). This completed the assembly of all four pos-
sible stereoisomers (27), (32), (36), and (38) of the methyl
ether based on the 3S stereochemistry. In the 1H NMR spec-
trum of (36) the axial H3–pseudoaxial H4 coupling constant
was 8.8 Hz, a value typical for such protons and significantly
larger than for the C1 epimer (27), where the corresponding
value was 5.4 Hz (see above).
Regioselective Cyclizations to Form the
The silyl-protected aldehyde (24) was similarly desily-
lated and underwent spontaneous cyclization. The resultant
mixture which consisted largely of (44) and (45) was then
acetylated (see Diagram 6). Careful chromatography led to
the isolation of the individual C4 epimeric 4,7-diacetates (46)
(24%) and (47) (27%) (a combined yield of 51% represents
an average yield of 80% for each of the three steps involved).
The 4,5-diacetates (35) and (39), if formed, were lost upon
chromatography owing to the small scale of the reaction.
It was anticipated that this spontaneous cyclization
occurred through the formation of the phenoxide ion upon
desilylation of the silyl ethers as drawn for the starting
aldehyde (23) (Scheme 3).The oxide ion (48) promotes spon-
taneous electrophilic substitution predominantly at the para
position to yield the C4 epimers (40) and (41). This regio-
selectivity may arise, at least in part, through greater steric
compression being caused by the adjacent substituent at the
alternative ortho site, thereby discouraging such ring closure.
Related para cyclizations leading to carbocyclic 4,7-diols
2-Benzopyran-4,7-diols and Their Derivatives
The aldehyde (23) was desilylated using a mixture of sat-
urated aqueous solutions of sodium fluoride and ammo-
nium chloride (1 : 1). Subsequently, spontaneous cyclization
occurred to yield a mixture of 2-benzopyrans, which con-
sisted largely of the two C4 epimeric 4,7-diols (40) and
(41) (see Diagram 5). Acetylation of the derived residue
followed by chromatography afforded an inseparable mix-
ture of diastereoisomeric 4,7-diacetates (42) and (43) as the
major products, together with the 4,5-diacetate (33), which
possesses the alternative regiochemistry, as a minor com-
ponent. Presumably the fourth isomer, diacetate (26), was
also formed as a minor component in this reaction but was
lost after chromatographic purification owing to the small
scale of the reaction. These inseparable compounds were
obtained in a combined overall yield of 47% over three
steps from the silyl-protected aldehyde (23), and in a ratio
1
of about 4.6 : 4.6 : 0.8, as judged by H NMR spectroscopy.
RO
RO
RO
RO
O
O
O
O
OR
OR
OR
OR
(40)
(42)
R ꢀ H
R ꢀ Ac
(41)
(43)
(44)
(46)
R ꢀ H
R ꢀ Ac
(45)
(47)
Diagram 5.
Diagram 6.

Regioselectivity in the Syntheses of Enantiopure 2-Benzopyrans
493
3ꢀ-Benzyloxyacetophenone (9)
O
TBSO
Potassium carbonate (12.68 g, 91.9 mmol) was added to a stirred
solution of benzyl bromide (15.72 g, 91.9 mmol) and 3ꢀ-hydroxyaceto-
phenone (5.0 g, 36.8 mmol) in dry dimethylformamide (50 mL). The
resulting suspension was heated under reflux for 12 h. The reaction
mixture was cooled, filtered through a pad of celite, and the filtrate
concentrated under reduced pressure. The residue was subsequently
chromatographed (10–20% ethyl acetate/hexane) to give compound (9)
(6.81 g, 82%) as cream-coloured plates, mp 29.5–30◦C (hexane) (lit.[5]
O
O
F
(40) ꢁ (41)
O
O
(23)
(48)
Scheme 3.
oil) (Found: M+•, 226.0988. C15H14O2 requires M+•, 226.0993). υmax
/
cm−1 1676 (C O), 1578 and 1484 (C C). δH 2.56 (3 H, s, COCH3),
5.10 (2 H, s, OCH2), 7.16 (1 H, ddd, J 2.6, 3.6 and 8.2, H4ꢀ), 7.31–
7.45 (6 H, m, C6H5 and H5ꢀ), 7.51–7.55 (1 H, m, H6ꢀ), 7.57 (1 H, m,
H2ꢀ). δC 26.7 (COCH3), 70.2 (OCH2), 113.6 (C4ꢀ), 120.3 (C5ꢀ), 121.3
(C6ꢀ), 127.6 (C2ꢀꢀ,6ꢀꢀ), 128.1 (C2ꢀ), 128.7 (C3ꢀꢀ,5ꢀꢀ), 129.6 (C4ꢀꢀ), 136.5
(C1ꢀꢀ), 138.6 (C1ꢀ), 159.0 (C3ꢀ), 197.8 (COCH3). Mass spectrum m/z
226 (14%, M+•), 92 (100), 91 (100), 65 (8).
under basic conditions have been reported previously,[14] but
the use of these conditions was not successful with the sub-
strates in the current study, possibly as a consequence here
of nucleophilic substitution of the benzylic oxygen by base.
Conclusions
1-(3ꢀ-Benzyloxyphenyl)ethanol (11)
Conditionshavebeenidentifiedfortheregioselectivecycliza-
tion of meta-hydroxybenzyl lactaldehydes to afford either
2-benzopyran-4,5- or -4,7-diols through ring closure either
ortho or para to the phenolic hydroxy group, respectively.
The 4,5-diols are obtained with complete diastereoselectivity
using titanium tetraisopropoxide. Peri interactions between
the acetoxy substituents following the conversion of the diol
(7) into the 4,5-diacetate (26) lead to the adoption of the alter-
native half-chair conformation of the heterocyclic ring in the
latter compound, in which the C3 methyl assumes the axial
orientation.A related inversion is observed for the 4-acetoxy-
5-O-methyl ether (28). On the other hand, mild generation
of the corresponding phenoxide ions by treatment of the silyl
ethers with fluoride leads to their spontaneous cyclization to
form the 4,7-diols with high regioselectivity.
To a stirred slurry of lithium aluminium hydride (336 mg, 8.85 mmol)
in dry ether (30 mL) was added dropwise
benzyloxyacetophenone (9) (200 mg, 0.88 mmol) in dry ether (8 mL)
under argon. The mixture was stirred for 1 h under argon after which
saturated ammonium chloride solution was added dropwise, followed
by MgSO4. Filtration through celite and subsequent chromatography
a
solution of 3ꢀ-
(radial, 10–20% ethyl acetate/hexane) yielded the benzyl alcohol (11)
•
(200 mg, 99%) as a light-yellow oil (Found: C, 78.5; H, 7.0%; M+
,
228.1144. C15H16O2 requires C, 78.9; H, 7.1%; M+•, 228.1150). υmax
(film)/cm−1 3392 (OH), 1585 and 1488 (C C). δH 1.44 (3 H, d, J 6.5,
1-CH3), 2.18 (1 H, br s, OH), 4.80 (1 H, q, J 6.5, H1), 5.03 (2 H, s,
OCH2), 6.85 (1 H, dd, J 2.0 and 7.9, H6ꢀ), 6.92 (1 H, dd, J 2.0 and 7.9,
H4ꢀ), 7.00 (1 H, t, J 2.0, H2ꢀ), 7.23 (1 H, t, J 7.9, H5ꢀ), 7.30–7.43 (5 H,
m, C6H5). δC 25.1 (C2), 69.9 (OCH2), 70.2 (C1), 111.9 (C6ꢀ), 113.7
(C4ꢀ), 118.0 (C2ꢀ), 127.5 (C2ꢀꢀ,6ꢀꢀ), 127.9 (C4ꢀꢀ), 128.5 (C3ꢀꢀ,5ꢀꢀ), 129.5
(C5ꢀ), 137.0 (C1ꢀ), 147.6 (C1ꢀꢀ), 158.9 (C3ꢀ). Mass spectrum m/z 228
(6%, M+•), 92 (7), 91 (100), 86 (15), 84 (19), 65 (8), 51 (9).
3ꢀ-Benzyloxy-αꢀ-methylbenzyl-2,2,2-trichloroethanimidate (13)
Experimental
General
The benzyl alcohol (11) (1 g, 4.39 mmol) in dry diethyl ether (4 mL) was
added dropwise to a stirred suspension of sodium hydride (60% disper-
sioninoil)(70 mg, 2.92 mmol)indiethylether(15 mL).Themixturewas
stirred for 10 min under argon at −10◦C. Trichloroacetonitrile (1.27 g,
8.79 mmol) was added dropwise over 10 min, and the reaction mixture
was stirred for a further 30 min at that temperature, after which it was
allowed to reach room temperature. The solution was concentrated and
chromatographed (radial, 10% ethyl acetate/hexane) to afford the imi-
date (13) (1.41 g, 85%) as a white solid, mp 78–79◦C (hexane) (Found:
Melting points were determined on a Reichert hot-stage apparatus and
areuncorrected. OpticalrotationsweremeasuredusinganOpticalActiv-
ity PolAAr 2001 polarimeter for chloroform solutions of c 1.0 at 20◦C.
IR spectra were recorded as Nujol mulls for solids and as thin films
between NaCl plates for oils using a Perkin Elmer 1720-X FourierTrans-
form Spectrometer. The sonication bath used was a Branson B3200-E4
operating at a frequency of 44 kHz. Mass spectra were obtained on a
VG Autospec spectrometer operating in the electron impact mode at
70 eV (at the University of Western Australia). Elemental analyses were
carried out by the Canadian Microanalytical Service Ltd. NMR spec-
tra were recorded using a Bruker AM-300 spectrometer (1H, 300 MHz;
13C, 75.5 MHz). The spectra were run at ambient temperature in deute-
rochloroform (CDCl3) solution with tetramethylsilane (1H, 13C, δ 0.00)
and chloroform (1H, δ 7.27; 13C, δ 77.0) as internal standards. In the
NMR and mass spectra, assignments of signals with the same super-
scripts are interchangeable. All solvents were purified by distillation
and, if necessary, were dried according to standard methods.The amount
of residual water present in solvents was determined using a Metrohm
Karl Fischer Calorimeter 684. The hydrocarbon solvent referred to as
hexane routinely had a bp range of 65–70◦C. Chromatography refers
to dry-packed columns of Merck silica gel 60 (70–230 mesh). Pre-
adsorption was carried out on Merck silica gel 60 (35–70 mesh). The
C, 54.9; H, 4.4; N, 3.7%; M+•, 373.0202. C17H16Cl3NO2 requires C,
•
55.0; H, 4.4; N, 3.8%; M+
(
35Cl327Cl), 373.0217). υmax/cm−1 3340
(NH), 1662 (C N), 1597 and 1499 (C C). δH 1.62 (3 H, d, J 6.6, αꢀ-
CH3), 5.04 (2 H, s, OCH2), 5.95 (1 H, q, J 6.6, Hαꢀ), 6.90 (1 H, dd, J 2.0
and 7.9, H6ꢀ), 7.00 (1 H, dd, J 2.0 and 7.9, H4ꢀ), 7.05 (1 H, t, J 2.0, H2ꢀ),
7.25 (1 H, t, J 7.9, H5ꢀ), 7.28–7.43 (5 H, m, C6H5), 8.30 (1 H, s, NH).
δC 22.1 (αꢀ-CH3), 69.9 (OCH2), 76.9 (Cαꢀ), 91.7 (CCl3), 112.2 (C6ꢀ),
114.2 (C4ꢀ), 118.3 (C2ꢀ) 127.5 (C2ꢀꢀ,6ꢀꢀ), 127.9 (C4ꢀꢀ), 128.5 (C3ꢀꢀ,5ꢀꢀ),
129.5 (C5ꢀ), 136.9 (C1ꢀ), 143.0 (C1ꢀꢀ), 1•58.9 (C3ꢀ), 161.5 (C1). Mass
spectrum m/z 397 (10%, [35Cl237Cl]M+ ), 395 (10, [35Cl3]M+•), 340
(25), 338 (25), 235 (24), 234 (40), 213 (17), 179 (19), 178 (50), 177
(100), 161 (16), 151 (23), 149 (12).
Ethyl (αꢀR or S,2S)-2-(3ꢀ-benzyloxy-αꢀ-methylbenzyloxy)-
propanoate (15)
adsorbent for radial chromatography was Merck silica gel 60 PF254
.
Merck silica gel 60 F254 aluminium-backed sheets were used for thin-
layer chromatography (TLC). Compounds were routinely visualized
under short wavelength (245 nm) ultraviolet light. The phrase ‘residue
obtained upon workup’ refers to the residue when the organic layer
was separated, dried with anhydrous magnesium sulfate (MgSO4), and
concentrated under reduced pressure.
Boron trifluoride diethyl etherate (18 mg, 0.13 mmol) was added drop-
wise to a solution of imidate (13) (470 mg, 1.27 mmol) and ethyl
(S)-lactate (300 mg, 2.54 mmol) in dry hexane and dichloromethane
(15 mL, 2 : 1). The reaction mixture was stirred under nitrogen for
40 min. Solid sodium hydrogen carbonate was added to the mixture
and the resulting suspension was filtered through celite. The clear

494
R. Aggarwal et al.
solution was then concentrated and chromatographed (radial, 10%
ethyl acetate/hexane) to yield (15) as an oily, inseparable mixture of
CHCl3) (Found: M+•, 284.1421. C18H20O3 requires M+•, 284.1412).
υmax (film)/cm−1 1733 (C O), 1586 ꢀand 1486 (C C). δH 1.17 (3 H,
d, J 7.0, 2-CH3), 1.49 (3 H, d, J 6.4, α -CH3), 3.69 (1 H, dq, J 1.8 and
7.0, H2), 4.51 (1 H, q, J 6.4, Hαꢀ), 5.06 (2 H, s, OCH2), 6.86–6.95 (3 H,
m, H2ꢀ,4ꢀ,6ꢀ), 7.25 (1 H, t, J 7.8, H5ꢀ), 7.30–7.45 (5 H, m, C6H5), 9.66
(1 H, d, J 1.8, CHO). δC 15.2 (C3), 23.6 (αꢀ-CH3), 69.3 (OCH2), 76.8
(C2), 77.0 (Cαꢀ), 111.9 (C6ꢀ), 113.5 (C4ꢀ), 118.2 (C2ꢀ), 126.8 (C2ꢀꢀ,6ꢀꢀ),
127.3 (C4ꢀꢀ), 127.9 (C3ꢀꢀ,5ꢀꢀ), 129.0 (C5ꢀ), 136.2 (C1ꢀ), 143.9 (C1ꢀꢀ),
158.4 (C3ꢀ), 203.1 (C1). Mass spectrum m/z 284 (7%, M+•), 212 (12),
211 (55), 92 (11), 91 (100).
diastereoisomers (310 mg, 75%) in a ratio of 55 : 45 (Found: C, 73.5;
•
H, 7.5%; M+•, 328.1662. C20H24O4 requires C, 73.2; H, 7.4%; M+
,
328.1674). υmax (film)/cm−1 1746 (C O), 1599 and 1487 (C C). δH
(major diastereoisomer) 1.28 (3 H, t, J 7.2, CH3CH2), 1.32 (3 H, d,
J 6.9, 2-CH3), 1.47 (3 H, d, J 6.5, αꢀ-CH3), 3.82 (1 H, q, J 6.9, H2),
4.15–4.25 (2 H, m, CH3CH2), 4.49 (1 H, q, J 6.5, αꢀ-H), 5.06 (2 H, s,
OCH2), 6.85–7.30 (4 H, m, H2ꢀ,4ꢀ,5ꢀ,6ꢀ), 7.30–7.46 (5 H, m, C6H5). δH
(minor diastereoisomer) 1.18 (3 H, t, J 7.1, CH3CH2), 1.40 (3 H, d,
J 6.8, 2-CH3), 1.47 (3 H, d, J 6.5, αꢀ-CH3), 4.00 (1 H, q, J 6.8, H2),
3.95–4.09 (2 H, m, CH3CH2), 4.54 (1 H, q, J 6.5, αꢀ-H), 5.05 (2 H, s,
OCH2), 6.85–7.30 (4 H, m, H2ꢀ,4ꢀ,5ꢀ,6ꢀ), 7.30–7.46 (5 H, m, C6H5). δC
(mixture of two diastereoisomers) 14.1 and 14.3 (CH3CH2), 18.3 and
19.0 (C3), 23.2 and 24.4 (αꢀ-CH3), 60.7 and 60.7 (CH3CH2), 69.9 and
70.0 (OCH2), 72.0 and 72.8 (Cαꢀ), 77.0 and 77.3 (C2), 112.6 and 112.9
(C6ꢀ), 114.0 (C4ꢀ), 119.0 and 119.2 (C2ꢀ), 127.6 and 127.5 (C2ꢀꢀ,6ꢀꢀ),
128.0 and 127.9 (C4ꢀꢀ), 128.5 and 128.6 (C3ꢀꢀ,5ꢀꢀ), 129.4 and 129.6 (C5ꢀ),
136.9 and 137.0 (C1ꢀ), 144.7 and 144.0 (C1ꢀꢀ), 158.9 and 159.1 (C3ꢀ),
173.1 and 173.7 (C1). Mass spectrum m/z 328 (8%, M+•), 237 (7), 227
(25), 212 (9), 211 (35), 120 (5), 92 (18), 91 (100), 65 (10).
(αꢀR,2S)-2-(3ꢀ-Benzyloxy-αꢀ-methylbenzyloxy)propanal (22)
According to the method described above for the preparation of aldehyde
(21) from (αꢀS,2S)-alcohol (17), the (αꢀR,2S)-alcohol (18) (200 mg,
0.7 mmol) was converted into the crude aldehyde (22) as a pale-orange
oil. Chromatography (radial, 10–30% ethyl acetate/hexane) afforded a
colourless oil (160 mg, 80%), [α]D +51.6◦ (c 1.0 in CHCl3) (Found: C,
76.1; H, 7.0%; M+•, 284.1422. C18H20O3 requires C, 76.0; H, 7.1%;
M+•, 284.1412). υmax (film)/cm−1 1736(C O), 1586and1486(C C).
δH 1.23 (3 H, d, J 6.9, 2-CH3), 1.48 (3 H, d, J 6.5, αꢀ-CH3), 3.71 (1 H,
dq, J 1.3 and 6.9, H2), 4.52 (1 H, q, J 6.5, Hαꢀ), 5.06 (2 H, s, OCH2),
6.85–7.00 (3 H, m, H2ꢀ,4ꢀ,6ꢀ), 7.23 (1 H, t, J 7.9, H5ꢀ), 7.3ꢀ2–7.44 (5 H,
m, C6H5). 9.41 (1 H, d, J 1.3, CHO). δC 15.9 (C3), 24.7 (α -CH3), 70.9
(OCH2), 76.3 (C2), 78.9 (Cαꢀ), 113.9 (C6ꢀ), 115.2 (C4ꢀ), 120.1 (C2ꢀ),
128.4 (C2ꢀꢀ,6ꢀꢀ), 128.9 (C4ꢀꢀ), 129.5 (C3ꢀꢀ,5ꢀꢀ), 130.6 (C5ꢀ), 137.7 (C1ꢀ),
145.7 (C1ꢀꢀ), 160.0 (C3ꢀ), 204.1 (C1). Mass spectrum m/z 284 (5%,
M+•), 212 (16), 211 (65), 92 (13), 91 (100).
(αꢀS, 2S)- and (αꢀR,2S)-2-(3ꢀ-Benzyloxy-αꢀ-methylbenzyloxy)-
propan-1-ol (17) and (18)
The mixture of diastereoisomeric esters (15) (400 mg, 1.22 mmol) was
reduced with lithium aluminium hydride as described for the reduction
of 3ꢀ-benzyloxyacetophenone (9). The pale-yellow oil was subjected
to chromatography (radial, 5–10% ethyl acetate/hexane) to afford the
two alcohols (17) and (18) as colourless oils. The product of higher Rf
was identified as compound (18) (140 mg, 40%), [α]D +67.2◦ (c 1.0 in
CHCl3) (Found: M+•, 286.1555. C18H22O3 requires M+•, 286.1568).
υmax (film)/cm−1 3435 (OH), 1599 and 1486 (C C). δH 1.10 (3 H, d, J
5.9, 2-CH3), 1.41 (3 H, d, J 6.4, αꢀ-CH3), 2.24 (1 H, br s, OH), 3.35–3.46
(3 H, m, CH2OH and H2), 4.51 (1 H, q, J 6.4, Hαꢀ), 5.02 (2 H, s, OCH2),
6.86–7.43 (9 H, m, H2ꢀ,4ꢀ,5ꢀ,6ꢀ and C6H5). δC 15.6 (C3), 24.5 (αꢀ-CH3),
66.6 (C1), 69.9 (OCH2), 72.7 (C2), 74.9 (Cαꢀ), 112.8 (C6ꢀ), 113.8 (C4ꢀ),
118.8 (C2ꢀ), 127.6 (C2ꢀꢀ,6ꢀꢀ), 127.9 (C4ꢀꢀ), 128.5 (C3ꢀꢀ,5ꢀꢀ), 129.6 (C5ꢀ),
136.9 (C1ꢀ), 145.5 (C1ꢀꢀ), 159.0 (C3ꢀ). Mass spectrum m/z 286 (18%,
M+•), 212 (22), 211 (54), 92 (14), 91 (100). The product of lower Rf
was identified as compound (17) (180 mg, 52%), [α]D −38.1◦ (c 1.0 in
CHCl3) (Found: C, 75.6; H, 7.7%; M+•, 286.1574. C18H22O3 requires
C, 75.5; H, 7.8%; M+•, 286.1568). υmax (film)/cm−1 3436 (OH), 1586
and 1486 (C C). δH 1.00 (3 H, d, J 6.2, 2-CH3), 1.43 (3 H, d, J 6.4 Hz,
αꢀ-CH3), 1.99 (1 H, br s, OH), 3.43–3.69 (3 H, m, CH2OH and H2),
4.56 (1 H, q, J 6.4, Hαꢀ), 5.07 (2 H, s, OCH2), 6.89 (1 H, dd, J 2.0 and
8.0, H6ꢀ), 6.92 (1 H, dd, J 2.0 and 8.0, H4ꢀ), 6.99 (1 H, t, J 2.0, H2ꢀ),
7.25 (1 H, t, J 8.0, H5ꢀ), 7.30–7.46 (5 H, m, C6H5). δC 17.9 (C3), 24.6
(αꢀ-CH3), 66.4 (C1), 70.6 (OCH2), 74.7 (C2), 76.9 (Cαꢀ), 113.2 (C6ꢀ),
114.3 (C4ꢀ), 119.4 (C2ꢀ), 128.1 (C2ꢀꢀ,6ꢀ), 128.6 (C4ꢀꢀ), 129.1 (C3ꢀꢀ, 5ꢀꢀ),
130.0 (C5ꢀ), 137.6 (C1ꢀ), 146.8 (C1ꢀꢀ), 159.5 (C3ꢀ). Mass spectrum m/z
286 (10%, M+•), 212 (25), 211 (54), 92 (14), 91 (100).
3ꢀ-t-Butyldimethylsilyloxyacetophenone (10)
t-Butyldimethylsilyl chloride (16.6 g, 0.11 mol) and imidazole (7.5 g,
0.11 mol) were added to a solution of 3ꢀ-hydroxyacetophenone (10 g,
73.5 mmol) in dry dimethylformamide (150 mL). The mixture was
stirred under argon for 12 h at room temperature, after which water
was added and the mixture exhaustively extracted with ethyl acetate.
The residue obtained upon workup was chromatographed (10% ethyl
acetate/hexane) to afford (10) (17 g, 93%) as a colourless oil (Found:
C, 67.2; H, 8.8%; M+•, 250.1379. C14H22O2Si requires C, 67.2; H,
8.9%; M+•, 250.1389). υmax (film)/cm−1 1688 (C O), 1582 and
1484 (C C). δH 0.23 (6 H, s, OSi(CH3)2C(CH3)3), 1.00 (9 H, s,
OSi(CH3)2C(CH3)3), 2.57 (3 H, s, COCH3), 7.04 (1 H, ddd, J 1.0,
2.0 and 7.8, H4ꢀ), 7.32 (1 H, t, J 7.8, H5ꢀ), 7.42 (1 H, t, J 2.0, H2ꢀ), 7.54
(1 H, ddd, J 1.0, 2.0 and 7.8, H6ꢀ). δC –4.4 (OSi(CH3)2C(CH3)3), 18.2
(OSi(CH3)2C(CH3)3), 25.7 (OSi(CH3)2C(CH3)3), 26.7 (COCH3),
119.5 (C4ꢀ), 121.6 (C5ꢀ), 124.9 (C2ꢀ), 129.5 (C6ꢀ), 138.6 (C1ꢀ), 156.0
(C3ꢀ), 197.8 (COCH3). Mass spectrum m/z 250 (13%, M+•), 194 (21),
193 (100), 165 (12), 151 (19), 121 (12), 105 (11), 86 (11), 84 (17).
1-(3ꢀ-t-Butyldimethylsilyloxyphenyl)ethanol (12)
To a stirred slurry of lithium aluminium hydride (610 mg, 16.1 mmol)
in dry diethyl ether (60 mL) was added dropwise a solution of com-
pound (10) (2 g, 8 mmol) in dry diethyl ether (10 mL) under argon. The
mixture was stirred for 1 h, after which saturated ammonium chloride
solution was added dropwise, followed by MgSO4. Filtration through
filter aid and concentration of the filtrate gave a light-yellow oil. Chro-
(αꢀS,2S)-2-(3ꢀ-Benzyloxy-αꢀ-methylbenzyloxy)propanal (21)
To
a solution of oxalyl chloride (220 mg, 1.74 mmol) in dry
dichloromethane (4 mL) at −70◦C under an atmosphere of argon was
added dropwise a solution of dimethyl sulphoxide (270 mg, 3.5 mmol)
in dry dichloromethane (4 mL), keeping the temperature below −65◦C.
Afterstirringfor15 min, asolutionofthe(αꢀS,2S)-alcohol(17)(100 mg,
0.35 mmol) in dry dichloromethane (4 mL) was added dropwise. The
temperature was kept below –65◦C and the stirring was continued for a
further 15 min at that temperature. Dry diisopropylethylamine (540 mg,
4.19 mmol)wasaddedslowlyandthereactionwasstirredforafurther10
min at −70◦C before being allowed to warm to room temperature over
1 h. The reaction mixture was quenched with water and exhaustively
extracted with dichloromethane. The residue obtained upon workup
was chromatographed (radial, 10–20% ethyl acetate/hexane) to give the
aldehyde (21) (73 mg, 75%) as a colourless oil, [α]D –107.4◦ (c 1.0 in
matography (radial, 10–30% ethyl acetate/hexane) yielded the alcohol
•
(12) (1.85 g, 93%) as a colourless oil (Found: C, 66.6; H, 9.4%; M+
,
252.1543. C14H24O2Si requires C, 66.7; H 9.6%; M+•, 252.1545).
υmax (film)/cm−13350 (OH), 1603 and 1587 (C C). δH 0.21 (6 H, s,
OSi(CH3)2C(CH3)3), 0.99 (9 H, s, OSi(CH3)2C(CH3)3), 1.43 (3 H, d,
J 6.4, 1-CH3), 2.33 (1 H, br s, OH), 4.78 (1 H, q, J 6.4, H1), 6.73 (1 H,
dd, J 2.0 and 7.8, H6ꢀ), 6.85 (1 H, t, J 2.0, H2ꢀ), 6.92 (1 H, br dd, J 2.0
and 7.8, H4ꢀ), 7.18 (1 H, t, J 7.8, H5ꢀ). δC –4.4 (OSi(CH3)2C(CH3)3),
18.2 (OSi(CH3)2C(CH3)3), 25.1 (OSi(CH3)2C(CH3)3), 25.7 (C2),
70.1 (C1), 117.1 (C6ꢀ), 118.3 (C2ꢀ), 118.9 (C4ꢀ) 129.4 (C5ꢀ), 147.6
(C1ꢀ), 155.7 (C3ꢀ). Mass spectrum m/z 252 (20%, M+•), 195 (21), 177
(100), 149 (23), 123 (12), 109 (14), 91 (10), 75 (29), 67 (14).

Regioselectivity in the Syntheses of Enantiopure 2-Benzopyrans
495
3ꢀ-t-Butyldimethylsilyloxy-αꢀ-methylbenzyl-2,2,2-trichloro-
ethanimidate (14)
(6 H, s, OSi(CH3)2C(CH3)3), 0.99 (9 H, s, OSi(CH3)2C(CH3)3), 1.13
(3 H, d, J 5.8, 2-CH3), 1.43 (3 H, d, J 6.5, αꢀ-CH3), 1.97 (1 H, br s, OH),
3.38–3.53 (3 H, m, CH2OH and H2), 4.51 (1 H, q, J 6.5, Hαꢀ), 6.75 (1 H,
dd, J 2.0 and 7.8, H6ꢀ), 6.80 (1 H, t, J 2.0, H2ꢀ), 6.91 (1 H, br dd, J 2.0
and 7.8, H4ꢀ), 7.20 (1 H, t, J 7.8, H5ꢀ). δC –4.4 (OSi(CH3)2C(CH3)3),
15.6 (OSi(CH3)2C(CH3)3), 18.2 (OSi(CH3)2C(CH3)3), 24.5 (C3),
25.7 (αꢀ-CH3), 66.8 (C1), 72.7 (C2), 74.9 (Cαꢀ), 117.9 (C6ꢀ), 119.3
(C2ꢀ), 119.3 (C4ꢀ), 128.9 (C5ꢀ), 145.4 (C1ꢀ), 155.9 (C3ꢀ). Mass spec-
trum m/z 310 (9%, M+•), 236 (28), 235 (100), 177 (14), 133 (19). The
compound of lower Rf was identified as (19) (411 mg, 47%), [α]D −40◦
(c 1.0 in CHCl3) (Found: C, 66.1; H, 9.6%; M+•, 310.1964. C17H30O3Si
requires C, 65.8; H, 9.8%; M+•, 310.1964). υmax (film)/cm−1 3431
(OH), 1603 and 1483 (C C). δH 0.20 (6 H, s, OSi(CH3)2C(CH3)3),
0.99 (9 H, s, OSi(CH3)2C(CH3)3), 1.01 (3 H, d, J 6.3, 2-CH3), 1.43
(3 H, d, J 6.5, αꢀ-CH3), 2.06 (1 H, br s, OH), 3.45 (1 H, dd, J 5.7 and
10.9, H1α), 3.57 (1 H, ddq, J 3.4, 5.7 and 6.3, H2), 3.65 (1 H, dd, J 3.4
and 10.9, H1β), 4.53 (1 H, q, J 6.5, Hαꢀ), 6.75 (1 H, dd, J 2.0 and 7.8,
H6ꢀ), 6.84 (1 H, t, J 2.0, H2ꢀ) 6.91 (1 H, d, J 7.8, H4ꢀ), 7.19 (1 H, t, J
7.8, H5ꢀ). δC –4.4 (OSi(CH3)2C(CH3)3), 17.4 (OSi(CH3)2C(CH3)3),
18.2 (OSi(CH3)2C(CH3)3), 24.1 (C3), 25.7 (αꢀ-CH3), 65.7 (C1), 74.0
(C2), 76.3 (Cαꢀ), 117.8 (C6ꢀ), 119.1 (C2ꢀ), 119.2 (C4ꢀ), 129.3 (C5ꢀ),
145.1 (C1ꢀ), 155.8 (C3ꢀ).Mass spectrum m/z 310 (7%, M+•), 249 (12),
237 (11), 236 (33), 235 (63), 179 (22), 178 (30), 177 (100), 151 (15),
133 (25), 121 (12).
The alcohol (12) (1 g, 3.96 mmol) in dry diethyl ether (10 mL) was added
dropwise to a stirred suspension of sodium hydride (60% dispersion in
oil) (64 mg, 2.67 mmol) in dry diethyl ether (7 mL). The mixture was
stirred for 10 min under argon at −10◦C. Trichloroacetonitrile (1.12 g,
7.93 mmol) was added dropwise over 10 min and the reaction mixture
was stirred for a further 30 min at that temperature, after which it was
allowed to warm to room temperature. The solution was concentrated
and chromatographed (radial, 5% ethyl acetate/hexane) to yield the
imidate (14) (1.41 g, 90%) as a colourless oil (Found: M+•, 395.0644.
•
C16H24Cl3NO2Si requires M+
(
35Cl3), 395.0641). υmax (film)/cm−1
3347 (NH), 1664 (C N), 1606 and 1486 (C C). δH 0.20 (6 H, s,
OSi(CH3)2C(CH3)3), 0.99 (9 H, s, OSi(CH3)2C(CH3)3), 1.64 (3 H, d,
J 6.5, αꢀ-CH3), 5.95 (1 H, q, J 6.5, Hαꢀ), 6.78 (1 H, dd, J 2.0 and 7.8,
H6ꢀ), 6.93 (1 H, t, J 2.0, H2ꢀ), 7.00 (1 H, br dd, J 2.0 and 7.8, H4ꢀ), 7.22
(1 H, t, J 7.8, H5ꢀ), 8.32 (1 H, s, NH). δC –4.0 (OSi(CH3)2C(CH3)3),
18.6 (OSi(CH3)2C(CH3)3), 22.5 (OSi(CH3)2C(CH3)3), 26.1 (αꢀ-
CH3), 77.3 (Cαꢀ), 92.1 (CCl3), 117.8 (C6ꢀ), 119.1 (C2ꢀ), 119.9 (C4ꢀ),
129.8 (C5ꢀ), 143.3 (C1ꢀ), 156.2 (C3ꢀ), 162.0 (C1). Mass spectrum m/z
338 (25%, [M–C(CH3)3]+•), 235 (23), 234 (40), 178 (50), 177 (100),
151 (22), 149 (12).
Ethyl (αꢀR or S,2S)-2-(3ꢀ-t-Butyldimethylsilyloxy-αꢀ-methyl-
(αꢀS,2S)-2-(3ꢀ-t-Butyldimethylsilyloxy-αꢀ-methylbenzyloxy)-
benzyloxy)propanoate (16)
propanal (23)
Boron trifluoride diethyl etherate (37.7 mg, 0.27 mmol) was added drop-
wise to a solution of imidate (14) (500 mg, 1.26 mmol) and ethyl (S)-
lactate (300 mg, 2.54 mmol) in dry hexane and dichloromethane (20 mL,
2 : 1) at ambient temperature. The reaction was stirred under nitrogen
for 40 min. Solid sodium hydrogen carbonate was added to the reaction
mixture and the resulting suspension was filtered through filter aid. The
clear solution was then concentrated and chromatographed (radial, 10–
30%ethylacetate/hexane)toyieldtheproducts (16)(390 mg, 88%)asan
oily, inseparable mixture of diastereoisomers in a ratio of 65 : 35 (Found:
C, 64.7; H, 8.7%; M+•, 352.2065. C19H32O4Si requires C, 64.8; H,
9.2%; M+•, 352.2069). υmax (film)/cm−1 1750 (C O), 1603 and 1484
(C C). δH (major diastereoisomer) 0.20 (6 H, s, OSi(CH3)2C(CH3)3),
0.99 (9 H, s, OSi(CH3)2C(CH3)3), 1.28 (3 H, t, J 7.1, CH3CH2), 1.35
(3 H, d, J 6.9, 2-CH3), 1.46 (3 H, d, J 6.4, αꢀ-CH3), 3.83 (1 H, q, J
6.9, H2), 4.20 and 4.22 (2 × 1 H, dq, J 7.1 and 10.8, CH3CH2), 4.46
(1 H, q, J 6.4, Hαꢀ), 6.76 (1 H, dt, J 2.0 and 7.8, H4ꢀ), 6.80 (1 H, t,
J 2.0, H2ꢀ), 6.86 (1 H, br dd, J 2.0 and 7.8. H6ꢀ), 7.19 (1 H, t, J 7.8,
H5ꢀ). δH (minor diastereoisomer) 0.20 (6 H, s, OSi(CH3)2C(CH3)3),
0.99 (9 H, s, OSi(CH3)2C(CH3)3), 1.19 (3 H, t, J 7.1, CH3CH2),
1.40 (3 H, d, J 6.7, 2-CH3), 1.46 (3 H, d, J 6.4, αꢀ-CH3), 4.02 (1 H,
q, J 6.7, H2), 4.05 (2 H, q, J 7.1, CH3CH2), 4.51 (1 H, q, J 6.4,
Hαꢀ), 6.73 (1 H, d, J 7.8, H4ꢀ), 6.80 (1 H, t, J 2.0, H2ꢀ), 6.94 (1 H,
br dd, J 2.0 and 7.8, H6ꢀ), 7.17 (1 H, t, J 7.8, H5ꢀ). δC (mixture
of two diastereoisomers) −4.1 (OSi(CH3)2C(CH3)3), 14.5 and 14.6
(CH3CH2), 18.6 (C3), 19.4 (OSi(CH3)2C(CH3)3), 23.7 and 24.8 (αꢀ-
CH3), 26.1 (OSi(CH3)2C(CH3)3), 61.0 and 61.1 (CH3CH2), 72.3 and
73.0 (Cαꢀ), 77.1 and 77.5 (C2), 118.1 and 118.5 (C4ꢀ), 119.6 and 119.8
(C2ꢀ), 119.8 and 119.9 (C6ꢀ), 129.6 and 129.8 (C5ꢀ), 145.0 and 145.2
(C1ꢀ), 156.1 and 156.3 (C3ꢀ), 173.4 and 174.1 (C1). Mass spectrum m/z
352 (20%, M+•), 295 (13), 252 (15), 251 (70), 250 (20), 249 (97), 235
(100), 177 (92), 151 (22).
To
a solution of oxalyl chloride (310 mg, 2.44 mmol) in dry
dichloromethane (4 mL) at −70◦C under an atmosphere of argon was
added dropwise a solution of dimethyl sulphoxide (380 mg, 4.86 mmol)
in dry dichloromethane (4 mL), keeping the temperature below −65◦C.
After stirring for 20 min, a solution of the alcohol (19) (150 mg,
0.48 mmol) in dry dichloromethane (4 mL) was added dropwise (keep-
ing the temperature below −65◦C) and the stirring was continued for
a further 15 min. Dry triethylamine (590 mg, 5.83 mmol) was added
slowly and the reaction was stirred for a further 10 min at −70◦C
before being allowed to reach room temperature over 1 h. The reac-
tion mixture was quenched with water and exhaustively extracted with
dichloromethane and the residue obtained upon workup was chromato-
graphed (radial, 10–20% ethyl acetate/hexane) to give the aldehyde (23)
(130 mg, 87%) as a colourless oil, [α]D −108.8◦ (c 1.0 in CHCl3)
(Found: C, 65.9; H, 9.0%; M+•, 308.1794. C17H28O3Si requires C,
66.2; H, 9.2%; M+•, 308.1807). υmax (film)/cm−1 1737 (C O), 1603
and 1484 (C C). δH 0.20 (6 H, s, OSi(CH3)2C(CH3)3), 0.99 (9 H, s,
OSi(CH3)2C(CH3)3), 1.22 (3 H, d, J 7.0, 2-CH3), 1.49 (3 H, d, J 6.4
Hz, αꢀ-CH3), 3.71 (1 H, dq, J 1.9 and 7.0, H2), 4.49 (1 H, q, J 6.4,
Hαꢀ), 6.76 (1 H, dd, J 2.0 and 7.8, H6ꢀ), 6.80 (1 H, t, J 2.0, H2ꢀ), 6.86
(1 H, br dd, J 2.0 and 7.8, H4ꢀ), 7.20 (1 H, t, J 7.8, H5ꢀ), 9.68 (1 H, d, J
1.9, CHO). δC –4.3 (OSi(CH3)2C(CH3)3), 16.0 (OSi(CH3)2C(CH3)3),
18.3 (OSi(CH3)2C(CH3)3), 24.4 (C3), 25.8 (αꢀ-CH3), 77.6 (C2), 77.7
(Cαꢀ) 117.9 (C6), 119.5 (C2ꢀ), 119.7 (C4), 129.7 (C5ꢀ), 144.6 (C1ꢀ),
156.1 (C3ꢀ). 204.0 (C1). Mass spectrum m/z 308 (2%, M+•), 252 (11),
236 (33), 235 (100), 207 (63), 195 (11), 177 (73), 163 (13), 151 (22),
137 (8), 121 (13), 97 (11), 85 (15).
(αꢀR,2S)-2-(3ꢀ-t-Butyldimethylsilyloxy-αꢀ-methylbenzyloxy)-
propanal (24)
According to the method described above for the preparation of alde-
hyde (23) from alcohol (19), the alcohol (20) (150 mg, 0.48 mmol)
was converted into the aldehyde (24) as a crude, pale-yellow oil
which was chromatographed (radial, 10–20% ethyl acetate/hexane) to
give a colourless oil (130 mg, 87%), [α]D + 123.2◦ (c 1.0 in CHCl3)
(Found: M+•, 308.1792. C17H28O3Si requires M+•, 308.1807). υmax
(film)/cm−1 1735 (C O), 1601 and 1486 (C C). δH 0.2 (6 H, s,
OSi(CH3)2C(CH3)3), 0.99 (9 H, s, OSi(CH3)2C(CH3)3), 1.27 (3 H, d,
J 6.8, 2-CH3), 1.49 (3 H, d, J 6.4, αꢀ-CH3), 3.75 (1 H, dq, J 1.5 and
6.8, H2), 4.53 (1 H, q, J 6.4, Hαꢀ), 6.77 (1 H, dd, J 2.0 and 7.8, H6ꢀ),
6.84 (1 H, t, J 2.0, H2ꢀ), 6.92 (1 H, d, J 7.8, H4ꢀ), 7.20 (1 H, t, J 7.8,
H5ꢀ), 9.49 (1 H, d, J 1.5, CHO). δC −4.4 (OSi(CH3)2C(CH3)3), 15.1
(αꢀS,2S)- and (αꢀR,2S)-2-(3ꢀ-t-Butyldimethylsilyloxy-
αꢀ-methylbenzyloxy)propan-1-ol (19) and (20)
The mixture of diastereoisomeric esters (16) (1 g, 2.84 mmol) was
reduced with lithium aluminium hydride (220 mg, 5.79 mmol) as
described for the reduction of 3ꢀ-t-butyldimethylsilyloxyacetophenone
(10). The resulting pale-yellow oil was subjected to chromatography
(radial, 5–15% ethyl acetate/hexane) to afford the two alcohols (19) and
(20) as colourless oils. The compound of higher Rf was identified as
(20) (355 mg, 40%), [α]D +79.4◦ (c 1.0 in CHCl3) (Found: C, 65.7;
H, 9.6%; M+•, 310.1975. C17H30O3Si requires C, 65.8; H, 9.8%; M+
,
•
310.1964). υmax (film)/cm−1 3451(OH), 1595and1479(C C). δH 0.20

496
R. Aggarwal et al.
(OSi(CH3)2C(CH3)3), 18.2 (OSi(CH3)2C(CH3)3), 23.8 (C3), 25.7 (αꢀ-
CH3), 77.0 (C2), 78.0 (Cαꢀ) 118.2 (C6ꢀ), 119.7 (C2ꢀ), 119.8 (C4ꢀ), 129.6
(C5ꢀ), 144.3 (C1ꢀ), 156.0 (C3ꢀ), 203.2 (C1). Mass spectrum m/z 308
(2%, M+•), 251 (8), 236 (36), 235 (100), 233 (14), 208 (17), 207 (97),
179 (21), 178 (20), 177 (12), 163 (12), 151 (17), 149 (11), 86 (10),
84 (18).
saturated sodium chloride solution. The residue obtained upon workup
was chromatographed (radial, 10–20% ethyl acetate/hexane) to afford
the diacetate (26) (42 mg, 74%) as a colourless oil, [α]D −88.8◦ (c 1.0
in CHCl3) (Found: C, 65.1; H, 6.5%; [M – CH3CO2H]+•, 218.0951.
C15H18O5 requires C, 64.7; H, 6.5%; [M – CH3CO2H]+•, 218.0942).
υmax (film)/cm−1 1770 and 1733 (C O), 1612 and 1587 (C C). δH
1.25 (3 H, d, J 6.9, 3-CH3), 1.60 (3 H, d, J 6.5, 1-CH3), 2.09 (3 H,
s, 4-OCOCH3), 2.27 (3 H, s, 5-OCOCH3), 4.25 (1 H, dq, J 2.0 and
6.9, H3), 4.91 (1 H, q, J 6.5, H1), 5.72 (1 H, d, J 2.0, H4), 7.02 (1 H,
d, J 8.0, H8), 7.06 (1 H, d, J 8.0, H6), 7.37 (1 H, t, J 8.0, H7). δC
17.6 (3-CH3), 22.9 (4-OCOCH3), 23.2 (5-OCOCH3), 23.9 (1-CH3),
67.7 (C3),a 67.8 (C4),a 72.9 (C1),a 122.9 (C8), 124.1 (C6), 124.3
(C7), 131.6 (C8a),143.8 (C4a),152.1 (C5), 171.5 (4-OCOCH3), 172.7
(5-OCOCH3). Mass spectrum m/z 278 (11%, M+•), 236 (13), 234 (96),
218 (100), 203 (65), 192 (72).
(αꢀS,2S)-2-(3ꢀ-Hydroxy-αꢀ-methylbenzyloxy)propanal (6)
A suspension of the pure benzyl ether (21) (200 mg, 0.7 mmol) and
10% palladium on carbon catalyst (200 mg, 100%) in dry ethyl acetate
(10 mL) was stirred under a hydrogen atmosphere for 1.5 h. The mix-
ture was filtered through filter aid, subjected to another portion of
10% palladium on carbon catalyst (200 mg, 100%), and exposed to
a hydrogen atmosphere for a further 1.5 h. The reaction mixture was
again filtered through filter aid, concentrated and purified through rapid
chromatography (radial, 35% ethyl acetate/hexane) to afford the poten-
(1S,3S,4R)-3,4-Dihydro-4-hydroxy-1,3-dimethyl-5-methoxy-
2-benzopyran (27)
•
tially unstable phenol (6) (98 mg, 72%) as a light-pink oil. (Found: M+
,
194.0950. C11H14O3 requires M+•, 194.0942). υmax (film)/cm−1 3389
(OH), 1730 (C=O), 1592 and 1484 (C C). δH 1.23 (3 H, d, J 7.0, 2-
CH3), 1.50(3 H, d, J 6.4, αꢀ-CH3), 3.76(1 H, dq, J 1.8and7.0, H2), 4.51
(1 H, q, J 6.4, Hαꢀ), 6.29 (1 H, br s, OH), 6.73–6.95 (3 H, m, H2ꢀ,4ꢀ,6ꢀ),
7.20 (1 H, t, J 7.9, H5ꢀ), 9.68 (1 H, d, J 1.8, CHO). δC 15.8 (C3), 24.2
(αꢀ-CH3), 77.6 (C2), 77.7 (Cαꢀ), 113.0 (C6ꢀ), 115.0 (C4ꢀ), 118.5 (C2ꢀ),
129.9 (C5ꢀ), 144.6 (C1ꢀ), 156.2 (C3ꢀ), 204.3 (C1). Mass spectrum m/z
194 (7%, M+•), 177 (19), 149 (15), 122 (15), 121 (100).
A suspension of the diol (7) (900 mg, 4.64 mmol), potassium carbonate
(320 mg, 2.32 mmol), and methyl iodide (330 mg, 2.32 mmol) in dry
dimethylformamide (8 mL) was stirred at room temperature for 12 h
under nitrogen. The reaction was quenched with water and exhaustively
extracted with ethyl acetate.The combined organic extracts were washed
with water, saturated sodium hydrogen carbonate solution, and saturated
sodium chloride solution. The residue obtained upon workup was then
chromatographed (radial, 15% ethyl acetate/petroleum ether) to give the
methyl ether (27) (850 mg, 88%) as white prisms, mp 78–80◦C (hexane•),
(αꢀR,2S)-2-(3ꢀ-Hydroxy-αꢀ-methylbenzyloxy)propanal (25)
[α]D + 9.6◦ (c 1.0 in CHCl3) (Found: C, 69.4; H, 7.6%; [M – H]+
,
In a similar manner to the hydrogenolysis of benzyl ether (21) described
above, the benzyl ether (22) (100 mg, 0.35 mmol) was deprotected to
give the potentially unstable phenol (25), which was rapidly chromato-
graphed (radial, 30% ethyl acetate/hexane) to afford a light-pink
oil (48 mg, 71%) (Found: [M – H]+•, 193.0853. C11H13O3 requires
[M – H]+•, 193.0864). υmax (film)/cm−1 3378 (OH), 1729 (C O), 1608
and 1589 (C C). δH 1.27 (3 H, d, J 6.8, 2-CH3), 1.48 (3 H, d, J 6.4, αꢀ-
CH3), 2.06 (1 H, br s, OH), 3.79 (1 H, dq, J 1.5 and 6.8, H2), 4.52 (1 H,
q, J 6.4, Hαꢀ), 6.73–6.95 (3 H, m, H2ꢀ,4ꢀ,6ꢀ), 7.17 (1 H, t, J 7.8, H5ꢀ),
9.45 (1 H, d, J 1.5, CHO). δC 15.0 (C3), 23.7 (αꢀ-CH3), 77.1 (C2), 78.1
(Cαꢀ), 113.4 (C6ꢀ), 115.3 (C4ꢀ), 118.7 (C2ꢀ), 129.9 (C5ꢀ), 144.3 (C1ꢀ),
156.4 (C3ꢀ), 203.8 (C1). Mass spectrum m/z 193 (9%, [M – H]+•), 177
(27), 150 (11), 149 (21), 122 (12), 121 (100).
207.1019. C12H16O3 requires C, 69.2; H, 7.8%; [M – H]+•, 207.1021).
υmax/cm−1 3409 (OH), 1588 and 1473 (C C). δH 1.32 (3 H, d, J 6.5,
3-CH3), 1.56 (3 H, d, J 6.7, 1-CH3), 3.38 (1 H, br s, OH), 3.88 (3 H, s,
OCH3), 4.09 (1 H, dq, J 5.4 and 6.5, H3), 4.59 (1 H, d, J 5.4, H4), 4.90
(1 H, q, J 6.7, H1), 6.68 (1 H, d, J 8.0, H6), 6.77 (1 H, d, J 8.0, H8), 7.22
(1 H, t, J 8.0, H7). δC 17.5 (3-CH3), 21.6 (1-CH3), 55.5 (OCH3), 66.9
(C3),a 68.7 (C4),a 69.9 (C1),a 108.3 (C8), 117.4 (C6), 123.4 (C8a),
128.4 (C7), 140.8 (C4a), 157.9 (C5). Mass spectrum m/z 207 (13%,
[M – H]+•), 192 (15), 191 (100), 173 (25), 164 (53).
(1S,3S,4R)-4-Acetoxy-3,4-dihydro-1,3-dimethyl-5-
methoxy-2-benzopyran (28)
Compound (27) (60 mg, 0.29 mmol) was dissolved in dry pyridine
(2 mL) and acetic anhydride (2 mL) and stirred for 24 h at room temper-
ature. The reaction mixture was quenched with water and exhaustively
extracted with ethyl acetate.The combined organic extracts were washed
with dilute hydrochloric acid (5 M), water, and saturated sodium hydro-
gen carbonate solution to afford a crude yellow oil. The residue was
chromatographed (radial, 15% ethyl acetate/hexane) to give the mono-
acetate (28) (55 mg, 76%) as pure white needles, mp 96–97◦C (hexane•),
249.1149. C14H18O4 requires C, 67.2; H, 7.3%; [M – H]+•, 249.1126).
υmax (cm−1) 1719 (C O), 1589 and 1474 (C C). δH 1.25 (3 H, d, J 6.9,
3-CH3), 1.57 (3 H, d, J 6.5, 1-CH3), 2.09 (3 H, s, OCOCH3), 3.81 (3 H,
s, OCH3), 4.31 (1 H, dq, J 1.9 and 6.9, H3), 4.88 (1 H, q, J 6.5, H1), 5.79
(1 H, d, J 1.9, H4), 6.75 and 6.77 (2 × 1 H, d, J 8.0, H6,8), 7.31 (1 H,
t, J 8.0, H7). δC 15.6 (3-CH3), 21.3 (1-CH3), 21.9 (4-OCOCH3), 55.6
(OCH3), 65.7 (C3),a 66.4 (C4),a 70.9 (C1),a 108.3 (C8), 116.5 (C6),
117.7 (C8a), 129.6 (C7), 141.4 (C4a), 158.3 (C5), 170.9 (4-OCOCH3).
Mass spectrum m/z 191 (100%, [M – CH3CO2]+•), 190 (20), 175 (11),
173 (28).
(1S,3S,4R)-4,5-Diacetoxy-3,4-dihydro-1,3-dimethyl-
2-benzopyran (26)
Fresh, neat titanium tetraisopropoxide (120 mg, 0.42 mmol) was added
to a solution of the (αꢀS,2S) phenolic aldehyde (6) (55 mg, 0.28 mmol)
in dry dichloromethane (15 mL) at 0◦C under argon. After standing
for 10 min at 0◦C, the reaction mixture was sonically irradiated at
8–35◦C for 5 h, and dichloromethane (30 mL) and a mixture of sat-
urated aqueous solutions of sodium fluoride and ammonium chloride
(60 mL, 1 : 1)wereadded.Themixturewasstirreduntiltheyellowcolour
disappeared. The aqueous layer was extracted with dichloromethane
and the residue obtained upon workup was chromatographed (radial,
50% ethyl acetate/hexane) to give the potentially unstable (1S,3S,4R)-
3,4-dihydro-1,3-dimethyl-2-benzopyran-4,5-diol (7) (40 mg, 73%) as a
light-yellow oil (Found: [M – H]+•, 193.0852. C11H13O3 requires [M –
H]+•, 193.0864). υmax (film)/cm−1 3319 (OH), 1591 and 1464 (C C).
δH 1.34 (3 H, d, J 6.3, 3-CH3), 1.49 (3 H, d, J 6.7, 1-CH3), 3.52 (1 H,
br s, 4-OH),a 3.93 (1 H, dq, J 6.3 and 7.0, H3), 4.56 (1 H, d, J 7.0, H4),
4.90 (1 H, q, J 6.7, H1), 6.55 (1 H, d, J 7.9, H6), 6.69 (1 H, d, J 7.9,
H8), 7.12 (1 H, t, J 7.9, H7), 7.98 (1 H, br s, 5-OH).a δC 17.7 (3-CH3),
21.5 (1-CH3), 69.0 (C3),a 69.8 (C4),a 70.1 (C1),a 114.2 (C8), 116.8
(C6), 120.3 (C7), 128.9 (C8a), 140.6 (C4a), 155.8 (C5). Mass spectrum
m/z 194 (20%, M+•), 193 (17), 178 (14), 177 (100), 176 (10), 159 (24),
150 (34), 149 (11). The crude diol (7) (40 mg, 0.21 mmol) was immedi-
ately dissolved in dry pyridine (2 mL) and acetic anhydride (2 mL) and
stirred for 24 h at room temperature.The reaction mixture was quenched
and exhaustively extracted with ethyl acetate. The combined organic
extracts were washed with dilute hydrochloric acid (5 M), water, and
[α]D −77.5◦ (c 1.0 in CHCl3) (Found: C, 67.4; H, 7.3%; [M – H]+
,
(1S,3S,4S)-3,4-Dihydro-4-hydroxy-1,3-dimethyl-
5-methoxy-2-benzopyran (32)
Compound (27) (120 mg, 0.58 mmol) was dissolved in dry diethyl
ether (7 mL) and phosphorus pentachloride (240 mg, 1.15 mmol) was
added. The mixture was stirred for 10 min at room temperature then
quenched with water (25 mL). More diethyl ether (25 mL) was added
and the organic phase was washed exhaustively with deionized water.
The residue obtained upon workup was immediately redissolved in

Regioselectivity in the Syntheses of Enantiopure 2-Benzopyrans
497
acetonitrile (9 mL), and then deionized water (2 mL) containing silver
nitrate (540 mg, 3.18 mmol) was added. The mixture was stirred for
4 h at room temperature, during which time a white precipitate formed.
Water was added and the mixture was exhaustively extracted with diethyl
ether to afford the crude pseudoaxial C4 epimeric alcohol (32). This
was chromatographed (radial, 15% ethyl acetate/hexane) to afford first,
regenerated alcohol (27) (46 mg, 38%), followed by its C4 epimeric
alcohol (32) [38 mg, 32%, or 51% based on recovered alcohol (27)] as
white needles, mp 93–94◦C (hexane), [α]D + 18.3◦ (c 1.0 in CHCl3)
(Found: C, 69.4; H, 7.7%; [M – H]+•, 207.1003. C12H16O3 requires C,
69.2; H, 7.8%; [M – H]+•, 207.1021). υmax/cm−1 3522 (OH), 1587 and
1468 (C C). δH 1.39 (3 H, d, J 6.5, 3-CH3), 1.48 (3 H, d, J 6.8, 1-
CH3), 2.20 (1 H, br s, OH), 3.89 (3 H, s, OCH3), 4.03 (1 H, dq, J 1.9
and 6.5, H3), 4.57 (1 H, d, J 1.9, H4), 4.99 (1 H, q, J 6.8, H1), 6.63
(1 H, d, J 8.0, H8), 6.76 (1 H, d, J 8.0, H6), 7.24 (1 H, t, J 8.0, H7). δC
16.8 (3-CH3), 20.8 (1-CH3), 55.6 (OCH3), 62.8 (C3),a 66.8 (C4),a 71.1
(C1),a 108.2 (C8), 117.6 (C6), 124.3 (C8a), 128.8 (C7), 140.1 (C4a),
157.5 (C5). Mass spectrum m/z 207 (18%, [M – H]+•), 192 (16), 191
(100), 173 (25), 164 (41), 163 (13), 149 (20), 117 (11), 111 (11), 109
(19), 105 (11), 97 (22), 95 (26), 93 (11), 85 (15), 83 (32), 81 (31), 79
(13), 69 (66).
55.5 (OCH3), 69.3 (C3),a 72.9 (C4),a 75.0 (C1),a 108.7 (C8), 116.9
(C6), 125.3 (C8a), 128.3 (C7), 141.8 (C4a), 157.5 (C5). Mass spectrum
m/z 207 (28%, [M – H]+•), 192 (14), 191 (100), 173 (30), 164 (68), 163
(15), 161 (12), 97 (11), 95 (15), 83 (16), 81 (18), 69 (22).
(1R,3S,4S)-3,4-Dihydro-4-hydroxy-1,3-dimethyl-
5-methoxy-2-benzopyran-4-ol (38)
Compound (36) (100 mg, 0.48 mmol) was treated with phosphorus
pentachloride (20 mg, 0.96 mmol) followed by silver nitrate (450 mg,
2.65 mmol), as described for the conversion of compound (27) into
epimer (32). This afforded the crude pseudoaxial C4 epimeric alcohol
(38), which was chromatographed (radial, 15% ethyl acetate/hexane)
to afford a light-yellow oil (55 mg, 55%), [α]D + 76.6◦ (c 1.0 in
•
CHCl3) (Found: [M – H]+•, 207.1016. C12H15O3 requires [M – H]+
,
207.1021). υmax (film)/cm−1 3502 (OH), 1586 and 1462 (C C). δH
1.42 (3 H, d, J 6.5, 3-CH3), 1.56 (3 H, d, J 6.5, 1-CH3), 2.04 (1 H, br s,
OH), 3.74 (1 H, dq, J 1.7 and 6.5, H3), 3.86 (3 H, s, OCH3), 4.59 (1 H,
d, J 1.7, H4), 4.78 (1 H, q, J 6.5, H1), 6.75 (1 H, d, J 8.0, H8), 6.79 (1 H,
d, J 8.0, H6), 7.26 (1 H, t, J 8.0, H7). δC 16.9 (3-CH3), 21.8 (1-CH3),
55.6 (OCH3), 63.2 (C3),a 73.3 (C4),a 73.7 (C1),a 108.4 (C8), 116.6
(C6), 125.0 (C8a), 129.0 (C7), 140.7 (C4a), 157.5 (C5). Mass spectrum
m/z 208 (13%, M+•), 207 (42), 192 (16), 191 (100), 173 (23), 164 (50),
163 (13).
(1R,3S,4R)-4,5-Diacetoxy-3,4-dihydro-1,3-dimethyl-
2-benzopyran (35)
The phenolic aldehyde (25) (350 mg, 1.79 mmol) was treated with
titanium tetraisopropoxide, as described above for the phenolic alde-
hyde (6), to afford the potentially unstable 2-benzopyran-4,5-diol (34)
(270 mg, 77%) as a pale-orange oil (Found: [M – H]+•, 193.0865.
C11H13O3 requires[M – H]+•, 193.0864). υmax (film)/cm−1 3338(OH),
1614 and 1588 (C C). δH 1.40 (3 H, d, J 6.1, 3-CH3), 1.47 (3 H, d, J
6.5, 1-CH3), 3.46 (1 H, d, J 6.7, 4-OH), 3.54 (1 H, dq, J 6.1 and 9.0,
H3), 4.62 (1 H, dd, J 6.7 and 9.0, H4), 4.72 (1 H, q, J 6.5, H1), 6.61
(1 H, d, J 7.9, H8), 6.71 (1 H, d, J 7.9, H6), 7.12 (1 H, t, J 7.9, H7),
8.12 (1 H, br s, 5-OH). δC 19.9 (3-CH3), 23.0 (1-CH3), 72.7 (C3),a 74.7
(C4),a 76.5 (C1),a 116.2 (C8), 117.5 (C6), 122.8 (C7), 130.6 (C8a),
142.8 (C4a), 157.0 (C5). Mass spectrum m/z 194 (34%, M+•), 193
(24), 178 (16), 177 (100), 159 (25), 150 (59), 149 (17), 91 (27). Using
the method described above for the conversion of diol (7) into its diac-
(1S,3S,4R)- and (1S,3S,4S)-4,7-Diacetoxy-3,4-dihydro-1,3-dimethyl-
2-benzopyrans (42) and (43), and (1S,3S,4S)-4,5-Diacetoxy-
3,4-dihydro-1,3-dimethyl-2-benzopyran (33)
The aldehyde (23) (300 mg, 0.97 mmol) was dissolved in tetrahydrofu-
ran (25 mL) and a mixture of saturated aqueous solutions of ammonium
chloride and sodium fluoride (40 mL, 1 : 1) was added.The solution was
then stirred for 16 h at room temperature whereupon it was exhaustively
extracted with diethyl ether, dried (MgSO4), and concentrated to afford
a mixture consisting largely of two crude C4 epimeric benzo[c]pyran-
4,7-diols (40) and (41) (91 mg, 50%). This mixture was immediately
dissolved in dry pyridine (2 mL) and acetic anhydride (2 mL) and stirred
for 24 h at room temperature. The reaction mixture was quenched with
water and exhaustively extracted with ethyl acetate. The combined
organic extracts were washed with dilute hydrochloric acid (5 M), water,
and saturated sodium hydrogen carbonate solution, and the residue
obtained upon workup was chromatographed (radial, 10–30% ethyl
acetate/hexane) to give the diastereoisomeric diacetates (42), (43), and
(33)asaninseparableoilymixture(128 mg, 47%overallyieldfromalde-
hyde (23)) (Found: C, 65.1; H, 6.5%; [M – H]+•, 277.1094. C15H18O5
requiresC, 64.8;H, 6.5%;[M – H]+•, 277.1075). υmax (film)/cm−1 1733
(C O), 1615 and 1500 (C C). δH (mixture of diastereoisomers (42)
and (43)) 1.25 (3 H, d, J 6.7, 3-CH3), 1.27 (3 H, d, J 6.4, 3-CH3), 1.50
(3 H, d, J 6.8, 1-CH3), 1.56 (3 H, d, J 6.6, 1-CH3), 2.10 (3 H, s, 4-
OCOCH3), 2.12 (3 H, s, 4-OCOCH3), 2.28 (3 H, s, 7-OCOCH3), 2.29
(3 H, s, 7-OCOCH3), 4.18 (1 H, dq, J 4.0 and 6.4, H3), 4.19 (1 H, dq, J
2.0 and 6.7, H3), 4.93 (1 H, q, J 6.6, H1), 5.11 (1 H, q, J 6.8, H1), 5.63
(1 H, d, J 4.0, H4), 5.78 (1 H, d, J 2.0, H4), 6.81 (1 H, d, J 2.3, H8),
6.84 (1 H, d, J 2.2, H8), 6.96 (1 H, dd, J 2.3 and 8.5, H6), 6.98 (1 H, dd,
J 2.2 and 8.4, H6), 7.30 (1 H, d, J 8.5, H5), 7.40 (1 H, d, J 8.4, H5).
δH (minor diastereoisomer (33)) 1.24 (3 H, d, J 6.4, 3-CH3), 1.52 (3 H,
d, J 6.9, 1-CH3), 2.10 (3 H, s, 4-OCOCH3), 2.27 (3 H, s, 5-OCOCH3),
4.14 (1 H, dq, J 1.9 and 6.4, H3), 5.16 (1 H, q, J 6.9, H1), 5.89 (1 H,
d, J 1.9, H4), 7.35 (1 H, t, J 7.9, H7) (H6,8 were obscured by signals
of the major isomers). δC (mixture of diastereoisomers (42) and (43))
16.65 and 16.73 (3-CH3), 20.1 and 21.2 (4-OCOCH3), 21.3 (1-CH3 for
each isomer), 21.5 and 21.8 (7-OCOCH3), 65.6 and 67.8 (C3),a 68.2
and 69.3 (C4),a 70.8 and 70.9 (C1),a 117.8 and 118.3 (C8), 120.6 (C6),
128.4 and 129.2 (C5), 130.7 and 131.5 (C8a), 141.4 and 141.4 (C4a),
150.7 and 150.8 (C7), 169.4 and 169.5 (4-OCOCH3), 171.1 and 171.2
(7-OCOCH3). Mass spectrum m/z 234 (24%, [M–CH3CHO]+•), 218
(37), 203 (11), 192 (57), 177 (12), 176 (43), 162 (13), 161 (100), 105
(14), 91 (19).
etate (26), the product (34) was acetylated to afford the diacetate (35)
•
as a colourless oil, [α]D + 89.5◦ (c 1.0 in CHCl3) (Found: [M – H]+
,
277.1075. C15H17O5 requires [M – H]+•, 277.1076). υmax (film)/cm−1
1768 and 1737 (C O), 1609 and 1584 (C C). δH 1.33 (3 H, d, J 6.3,
3-CH3), 1.54 (3 H, d, J 6.5, 1-CH3), 2.11 (3 H, s, 4-OCOCH3), 2.25
(3 H, s, 5-OCOCH3), 3.74 (1 H, dq, J 6.3 and 8.2, H3), 4.83 (1 H, q, J
6.5, H1), 5.97 (1 H, d, J 8.2, H4), 7.02 (1 H, d, J 8.0, H8), 7.06 (1 H, d, J
8.0, H6), 7.37 (1 H, t, J 8.0, H7). δC 19.0 (3-CH3), 21.0 (4-OCOCH3),a
21.1 (5-OCOCH3),a 21.2 (1-CH3),a 68.7 (C3),b 71.6 (C4),b 72.7 (C1),b
121.4 (C8), 121.7 (C6), 128.9 (C7), 125.4 (C8a), 143.4 (C4a), 149.2
(C5), 169.2 (4-OCOCH3), 170.5 (5-OCOCH3). Mass spectrum m/z
234 (18%, M+•), 219 (16), 218 (64), 203 (25) 192 (30), 176 (54), 161
(100), 150 (69), 149 (30), 134 (60), 133 (45).
(1R,3S,4R)-3,4-Dihydro-1,3-dimethyl-5-methoxy-
2-benzopyran-4-ol (36)
A portion of the crude diol (34) (200 mg, 1.03 mmol) was immedi-
ately dissolved in dry dimethylformamide (8 mL). Potassium carbonate
(710 mg, 5.15 mmol) and methyl iodide (710 mg, 5.15 mmol) were
added and the resulting suspension was stirred at room temperature for
12 h under nitrogen. The reaction mixture was quenched with water and
exhaustively extracted with ethyl actetate. The residue obtained upon
workup was chromatographed (radial, 15% ethyl acetate/hexane) to
afford the methyl ether (36) (147 mg, 68%) as a clear oil, [α]D + 132.6◦
(c 1.0 in CHCl3) (Found: C, 68.7; H, 7.7%; [M – H]+•, 207.1010.
C12H16O3 requires C, 69.2; H, 7.8%; [M – H]+•, 207.1021). υmax
(film)/cm−1 3557 (OH), 1584 and 1476 (C C). δH 1.48 (3 H, d, J
6.1, 3-CH3), 1.50 (3 H, d, J 6.5, 1-CH3), 3.65 (1 H, dq, J 6.1 and 8.8,
H3), 3.87 (3 H, s, OCH3), 3.98 (1 H, d, J 1.5, OH), 4.66 (1 H, dd, J 1.5
and 8.8, H4), 4.80 (1 H, q, J 6.5, H1), 6.75 (1 H, d, J 8.1, H8), 6.78 (1 H,
d, J 8.1, H6), 7.22 (1 H, t, J 8.1, H7). δC 19.8 (3-CH3), 21.4 (1-CH3),

498
R. Aggarwal et al.
(1R,3S,4R)- and (1R,3S,4S)-4,7-Diacetoxy-3,4-dihydro-
1,3-dimethylisochromane (46) and (47)
References
[1] D. W. Cameron, R. I. T. Cromartie, D. G. I. Kingston, A. R.
Todd, J. Chem. Soc. 1964, 51.
[2] R. G. F. Giles, C. A. Joll, J. Chem. Soc., Perkin Trans. 1 1999,
3039.
[3] R. G. F. Giles, I. R. Green, F. J. Oosthuizen, C. P. Taylor,
Tetrahedron Lett. 2001, 42, 5753.
[4] R. G. F. Giles, I. R. Green, Y. Gruchlik, F. J. Oosthuizen, Aust.
J. Chem. 2000, 53, 341.
[5] (a) W. A. Bolhofer, J. Am. Chem. Soc. 1953, 75, 4469.
(b) R. C. Ronald, J. M. Lansinger, T. S. Lillie, C. J. Wheeler,
J. Org. Chem. 1982, 47, 2541.
[6] H.-P. Wessel, T. Iversen, D. R. Bundle, J. Chem. Soc., Perkin
Trans. 1 1985, 2247.
According to the method described above, the aldehyde (24) (290 mg,
0.94 mmol) was deprotected and cyclized to afford
a mixture
consisting largely of the two crude C4 epimeric benzopyran-4,
7-diols (1R,3S,4R)- and (1R,3S,4S)-3,4-dihydro-4,7-dihydroxy-1,3-
dimethylpyran-4,7-diols (44) and (45) (91 mg, 50%). These were imme-
diately acetylated as above to afford a pale-yellow oil, which was
carefully chromatographed (radial, 10–30% ethyl acetate/hexane) to
give two products.The product of higher Rf was compound (46) (63 mg,
24%), mp 50–51◦C (hexane), [α]D −8.3◦ (c 1.0 in CHCl3) (Found: C,
65.2; H, 6.6%; M+•, 278.1155. C15H18O5 requires C, 64.8; H, 6.5%;
M+•, 278.1154). υmax (film)/cm−1 1741 (C O), 1614 and 1498 (C C).
δH 1.32 (3 H, d, J 6.2, 3-CH3), 1.52 (3 H, d, J 6.5, 1-CH3), 2.18 (3 H,
s, 4-OCOCH3), 2.30 (3 H, s, 7-OCOCH3), 3.74 (1 H, dq, J 6.2 and 9.0,
H3), 4.88 (1 H, q, J 6.5, H1), 5.85 (1 H, d, J 9.0, H4), 6.83 (1 H, d, J
2.2, H8), 6.96 (1 H, dd, J 2.2 and 8.5, H6), 7.16 (1 H, d, J 8.5, H5). δC
17.8 (3-CH3), 20.4 (4-OCOCH3), 20.4 (7-OCOCH3), 20.8 (1-CH3),
70.8 (C3),a 72.2 (C1),a 72.4 (C4),a 116.4 (C8), 119.5 (C6), 126.9 (C5),
130.5 (C8a), 140.9 (C4a), 149.2 (C7), 168.7 (4-OCOCH3), 170.3 (7-
OCOCH3). Mass spectrum m/z 234 (62%, [M – CH3CHO]+•), 218
(34), 193 (15), 192 (100), 176 (43), 161 (74), 151 (11), 150 (92), 149
(35), 133 (16). The compound of lower Rf was identified as compound
(47) (70 mg, 27%), and was obtained as white needles, mp 70–72◦C
[7] U. Widmer, Synthesis 1987, 568.
[8] (a) W. H. Pirkle, D. J. Hoover, Top. Stereochem. 1982, 13, 263.
(b) R. M. Silverstein, G. C. Bassler, T. C. Morril, Spectrometric
Identification of Organic Compounds 5th edn 1991, pp. 198–201
(John Wiley & Sons: New York, NY).
[9] (a) K. Omura, D. Swern, Tetrahedron 1978, 34, 1651. (b)
A. J. Mancuso, D. Swern, Synthesis 1981, 165.
[10] (a) D. W. Cameron, D. G. I. Kingston, N. Sheppard, A. R.
Todd, J. Chem. Soc. 1964, 98. (b) T. Kometani, Y. Takeuchi,
E. Yoshii, J. Chem. Soc., Perkin Trans. 1 1981, 1197. (c) T. A.
Chorn, R. G. F. Giles, I. R. Green, P. R. K. Mitchell, J. Chem.
Soc., Perkin Trans. 1 1983, 1249. (d) R. G. F. Giles, I. R.
Green, V. I. Hugo, P. R. K. Mitchell, S. C. Yorke, J. Chem. Soc.,
Perkin Trans 1. 1983, 2309. (e) R. G. F. Giles, R. W. Rickards,
B. S. Senanayake, J. Chem. Soc., Perkin Trans. 1 1996, 2241.
[11] (a) H. Schmid, A. Ebnöther, Helv. Chim. Acta 1951, 34, 561.
(b) H. Schmid, A. Ebnöther, Helv. Chim. Acta 1951, 34, 1041.
[12] R. G. F. Giles, R. W. Rickards, B. S. Senanayake, J. Chem.
Soc., Perkin Trans. 1 1997, 3361.
[13] (a) R. G. F. Giles, I. R. Green, V. I. Hugo, P. R. K. Mitchell,
S. C. Yorke, J. Chem. Soc., Perkin Trans. 1 1984, 2383. (b)
J. F. Elsworth, R. G. F. Giles, I. R. Green, J. E. Ramdohr,
S. C. Yorke, J. Chem. Soc., Perkin Trans. 1 1988, 2469.
[14] (a) G. Guanti, L. Banfi, E. Narisano, R. Riva, S. Thea,
Tetrahedron Lett. 1992, 33, 3919. (b) G. Guanti, L. Banfi,
R. Riva, Tetrahedron 1994, 50, 11 945.
(hexane), [α]D + 226.9◦ (c 1.0 in CHCl3) (Found: C, 64.9; H, 6.4%;
•
[M–H]+•, 277.1097. C15H18O5 requires C, 64.8; H, 6.5%; [M – H]+
,
277.1075). υmax (cm−1) 1734 (C O), 1612 and 1498 (C C). δH 1.32
(3 H, d, J 6.5, 3-CH3), 1.58 (3 H, d, J 6.5, 1-CH3), 2.11 (3 H, s, 4-
OCOCH3), 2.30 (3 H, s, 7-OCOCH3), 3.90 (1 H, dq, J 1.9 and 6.5,
H3), 4.81 (1 H, q, J 6.5, H1), 5.80 (1 H, d, J 1.9, H4), 6.90 (1 H, d, J
2.2, H8), 7.00 (1 H, dd, J 2.2 and 8.2, H6), 7.42 (1 H, d, J 8.2, H5). δC
16.2 (3-CH3), 20.4 (4-OCOCH3), 20.5 (7-OCOCH3), 20.6 (1-CH3),
67.6 (C3), 71.5 (C1), 72.4 (C4), 116.7 (C8), 119.8 (C6), 129.1 (C8a),
131.0 (C5), 140.1 (C4a), 150.2 (C7), 168.7 (4-OCOCH3), 170.5 (7-
OCOCH3). Mass spectrum m/z 277 (11%, [M – H]+•), 234 (17), 219
(100), 192 (11), 159 (11).
Acknowledgments
Financial support from the Australian Research Council and
the Senate of Murdoch University is gratefully acknowl-
edged, as are Murdoch University Research Scholarships
(R.A., Y.G., and F.J.O.)