Asymmetric synthesis of (+)-galbelgin, (-)-kadangustin J, (-)-cyclogalgravin and (-)-pycnanthulignenes A and B, three structurally distinct lignan classes, using a common chiral precursor

Article abstract of DOI:10.1021/jo200968f

The enantioselective synthesis of three structurally distinct classes of lignan from a single, aza-Claisen-derived, chiral morpholine amide is reported. The class of lignan formed is dependent on the substitution pattern in the aryl rings and choice of pr

Full text of DOI:10.1021/jo200968f

ARTICLE
pubs.acs.org/joc
Asymmetric Synthesis of (+)-Galbelgin, (ꢀ)-Kadangustin J,
(ꢀ)-Cyclogalgravin and (ꢀ)-Pycnanthulignenes A and B,
Three Structurally Distinct Lignan Classes, Using a
Common Chiral Precursor
Claire E. Rye and David Barker*
School of Chemical Sciences, University of Auckland, Auckland, New Zealand
S Supporting Information
b
ABSTRACT: The enantioselective synthesis of three structu-
rally distinct classes of lignan from a single, aza-Claisen-derived,
chiral morpholine amide is reported. The class of lignan formed
is dependent on the substitution pattern in the aryl rings and
choice of protecting group on a key benzylic hydroxyl group.
The methodology has been used to asymmetrically synthesize
and determine the absolute stereochemistry of lignans (+)-
cyclogalgravin 3, (ꢀ)-pycnanthulignene A 4, (ꢀ)-pycnanthu-
lignene B 5, and (ꢀ)-kadangustin J 8.
’ INTRODUCTION
Lignans are secondary plant metabolites formed by the
oxidative dimerization of two phenylpropanoid units and have
been found in roots, stems, leaves, seeds, and fruits in more than
70 plant families.1 Though they may consist of only two
phenylpropane (C6ꢀC3) units, they have extremely diverse
structures, with diversity mainly originating from the various linkage
and oxidation patterns.1 The natural biological function of most
plant lignans is unknown; however, they have been discovered to
have a vast array of interesting biological properties. While anti-
microbial, antifungal, and insecticidal properties may be associated
with plant defense it is their antitumor, anti-inflammatory, cardio-
vascular, and antioxidant properties among others that have spurred
significant biological and synthetic interest.1
Lignans are traditionally classified as either classical lignans,
where the phenylpropane dimers are linked in a βꢀβ0 (8ꢀ80)
fashion, or neolignans, whose dimers have linkages other than
βꢀβ0. Examples of classical lignans include the tetrahydrofuran
lignans (Figure 1) such as (+)-galbelgin 12 and (+)-grandisin 2,3
along with the dihydroarylnapthalenes such as (ꢀ)-cyclogalgra-
Figure 1. Diverse structures of natural lignans and neolignans.
vin 34 and the recently discovered pycnanthulignenes A 4 and
B 5.5 Examples of neolignans include the 30,7-epoxy-8,40-
oxyneolignan6 (more commonly known as 1,4-benzodioxane
lignans) eusiderins E 6 and G 77 and the rearranged 1,1-
diarylbutane lignan, kadangustin J 8.8
the first asymmetric synthesis of cyclogalgravin (3), pycnanthu-
lignene A (4), pycnanthulignene B (5), and kadangustin J (8).
’ RESULTS AND DISCUSSION
We have previously shown9 that racemic, acyl-Claisen-de-
rived, morpholine amide 9 could be converted into ketone 10,
Previously we have reported the racemic synthesis of tetrahy-
drofuran lignans,9 and during that study we discovered that altera-
tion of protecting groups and changes in aryl substitution led to
unexpected products being formed. We herein report our findings in
this area and show how a single precursor can be converted into
three structurally diverse classes of lignan and in the process achieve
Received: May 12, 2011
Published: July 12, 2011
r
2011 American Chemical Society
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Scheme 1. Synthesis of Racemic Tetrahydrofurans
Scheme 2. Synthesis of Chiral Morpholine Amide 9
which after stereoselective reduction gave alcohol 11, which was
then protected as the MOM ether 12 (Scheme 1). Conversion of
the terminal alkene to an aldehyde and addition of an aryllithium
reagent gave alcohol 13. In the key step, mesylation of alcohol 13
resulted in cyclization to give tetrahydrofuran lignans 14 in
excellent yields.9
Tsunoda et al. have reported13 the use of acetoxypivalimides for
the hydrolysis of N-monosubstituted carboxamides of this type,
we found iodolactonization followed by reductive ring opening
using zinc in refluxing acetic acid14 was more successful, giving
acid 20 in 75% yield over two steps. Finally coupling of acid 20
with morpholine using DCC and DMAP gave (R,S)-dimethyl
morpholine amide 9 in 73%.
Addition of lithiated 4-bromoveratrole 21 to (R,S)-9 gave
ketone 22, which was reduced with sodium borohydride at
ꢀ78 °C to give alcohol 23 as a single diastereoisomer in 74%
yield, over two steps (Scheme 3). Alcohol 23 was then protected
as the MOM ether before the terminal alkene was converted, via
dihydroxylation followed by sodium periodinate cleavage, to give
aldehyde 24 in 70% yield over three steps. Addition of lithiated
4-bromoveratrole 21 to aldehyde 24 at ꢀ78 °C gave alcohol 25
as a single diastereoisomer in 71% yield. Mesylation of alcohol 25
with 1.3 equiv of methanesulfonyl chloride along with 1.6 equiv
of triethylamine activated the alcohol, deprotected the MOM
ether, and gave (+)-galbelgin 1 in 59% yield in a single synthetic
step. The spectral data and optical rotation of the synthetic
material [R]D = +81.8 (c 1.5, CHCl3) matched reported litera-
ture values [[R]D = +80.7 (c 0.55, CHCl3)].2a
With this non-enantioselective methodology established we
wished to apply this protocol to the asymmetric synthesis of a
series of tetrahydrofuran lignans and thus required the synthesis
of enantiomerically pure amide 9. The synthesis of amide 9 begin
with preparation of the reported chiral amide 15.10 Thus, (S)-R-
methylbenzylamine 16 was acylated with propionyl chloride to
give amide 17 in 93% yield (Scheme 2), which was then alkylated
with (E)-crotylbromide, using NaH and TBAI in THF, to give
amide 18 in 65% yield. Amide 18, when treated with LiHMDS in
toluene at 140 °C, underwent an aza-Claisen rearrangement10,11
to give syn-dimethylamide 15 in 65% yield, along with 7% of the
other, easily separable diastereoisomer 19. Use of this aza-Claisen
rearrangement was preferred over other chiral Claisen
rearrangement12 variants due to the very high level of stereo-
selectivity for the syn-dimethyl acid derivative 15, with none of
the anti diastereoisomers being observed on any occasion. While
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Scheme 3. Synthesis of (+)-Galbelgin
Figure 2. Proposed synthesis of (ꢀ)-veraguensin 26.
We next wished to explore the synthesis of the related
tetrahydrofuran lignan (ꢀ)-veraguensin 26, which differs from
galbelgin 1 only in that the stereochemistry of the substituents
around the tetrahydrofuran in 26 are trans,trans,cis rather than
the trans,trans,trans found in galbelgin 1. We envisaged this could
be accomplished by cyclizing alcohol 27, which has inverted
stereochemistry at the C-70 (carbons numbered using lignan
nomenclature). Activation of alcohol 27, as the mesylate, fol-
lowed by SN2 attack of the C-7 hydroxyl group would result in
the formation of (ꢀ)-veraguensin 26 (Figure 2).
exclusively in all cases, then one might expect some (ꢀ)-
veraguensin 26 to have been produced from the cyclization of
alcohol 25.
In order to further explore this cyclization step we wished to
determine whether the C-70 mesylates formed retained the
stereochemistry of the original alcohol or epimerization was
occurring during their formation. This required altering the
protecting group of the C-7 hydroxyl group, as the C-7 MOM
ether participated in the cyclization under the mesylate forming
conditions. We began our investigation using racemic alcohol 32,
prepared in 83% yield over 2 steps from racemic amide 9 by
addition of lithiated 4-bromoanisole and reduction of the newly
formed ketone (Scheme 5). We decided upon the TBDMS ether,
as benzylic TBDMS ethers have been shown to be stable to
mesylation conditions.16 Thus, alcohol 32 was converted to ether
33 in 87% yield, which followed by dihydroxylation and oxidative
cleavage gave aldehyde 34 in 69% yield over two steps. Addition
of lithiated 4-bromoanisole at ꢀ78 °C gave alcohol 35 again as a
single diastereoisomer in 92% yield. Mesylation of alcohol 35,
however, unexpectedly gave aldehyde 36 in 85% yield.
We have observed9 that using our optimized cyclization
conditions on similar alcohols, such as 28, where the C-70
hydroxyl group is anti to the adjacent methyl group results in
the formation of both the desired trans,trans,cis product 29 and
the trans,trans,trans product 30, in a 1.6:1 ratio. The unwanted
production of the trans,trans,trans product 30 is believed to occur
by the formation of a planar quinone methide intermediate 31,
where electron donation from the para oxygenated substituent
results in elimination of the C-70 mesylate with subsequent loss of
stereochemistry (Scheme 4).15
Attack of the C-7 hydroxyl group on C-70 is then non-
stereospecific, resulting in mixtures of isomers being formed.
The fact that epimeric products are not formed from the
cyclization of alcohols such as 25 shows that competing mechan-
isms are in place. If a quinoid intermediate, such as 31, is formed
The net result of the reaction is a 1,4-aryl shift along with loss
of tert-butyldimethylsilanol. One plausible mechanism for the
synthesis of 36 involves initial formation of the quinoid inter-
mediate 37; however, in this case the generated HCl does not
cleave the OꢀSi bond leading to the formation of an O-centered
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Scheme 4. Proposed Mechanism for the Isomerization of Tetrahydrofurans
Scheme 5. Synthesis of Aldehyde 36
Figure 4. Comparison of 1H NMR chemical shift (δ ppm) between 8
and 39.
methyl substituents was unreported, and we considered whether
this unexpected rearrangement could be applied to the synthesis
and stereochemical determination of kadangustin J 8.
Initially we wished to see if aldehyde 36 could assist with
determining the relative stereochemistry of kadangustin J 8. Thus
aldehyde 36 was reduced with NaBH4 to give alcohol 39 in 64%
1
yield. Comparison of the reported H NMR spectra of kadan-
gustin J 8 with alcohol 39 showed similarities in both the
chemical shift and coupling constants of protons at C-7, -70, -8,
-80, -9 and -90, strongly suggesting kadangustin J 8 had the same
syn-dimethyl stereochemistry found in alcohol 39 (figure 4).
With this knowledge we turned our attention to the asym-
metric synthesis of kadangustin J 8, which began by protecting
chiral alcohol 23 as the TBDMS ether 40, which was then
converted to aldehyde 41 before addition of lithiated 4-bromo-
veratrole 21 gave the desired alcohol 42 in an overall 41% yield,
over 4 steps from 23 (Scheme 6). With the desired alcohol 42 in
hand we then attempted the mesyl chloride induced rearrange-
ment to form aldehyde 43. However in this case rather than
aldehyde 43 being formed, another class of lignan, dihydroar-
ylnapthalene (ꢀ)-3, also known as (ꢀ)-cyclogalgravin,16 was
generated instead as a single stereoisomer in 95% yield.
Figure 3. Proposed mechanism for the formation of aldehyde 36.
The spectral data and optical rotation, [R]D = ꢀ128.0 (c 0.2,
CHCl3), of the purified synthetic product matched the reported
literature value, [R]D = ꢀ105.9 (c 1.07, CHCl3),17 and was
opposite that of of the previously isolated enantiomer, [R]D =
+135.5 (c 0.28, CHCl3).4b All other syntheses of cyclogalgravin
3 have been semisynthetic, using isolated tetrahydrofuran
lignans as starting materials18 and therefore this work consti-
tutes the first asymmetric total synthesis of either enantiomer of
cyclogalgravin 3.
nucleophile. Instead ipso attack of C-1, via donation from the
p-methoxy group, on C-70 leads to the formation of cyclopentyl
intermediate 38. Cleavage of the OꢀSi bond then results in the
formation of aldehyde 36 with re-aromatization being the driving
force (Figure 3).
It was after this result that we noticed the similarity of the
formed aldehyde 36 to the recently isolated lignan, kadangustin J
8,8 which differed only in the extra methoxy groups on the two
aryl rings. While kadangustin J 8 was reported to be optically
active [R]D = +4.9 (c 0.171, MeOH)] the stereochemistry of the
Mechanistically the synthesis of (ꢀ)-3 can be explained by the
attack of C-6, which in this case is para to the C-3 methoxy group,
at C-70, rather than ipso attack of C-1 seen in formation of
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Scheme 6. Synthesis of (ꢀ)-Cyclogalgravin 3
Figure 5. Proposed mechanism for the formation of (ꢀ)-cyclogalgravin 3.
aldehyde 36. The attack at C-70 could have occurred by direct
displacement of the newly formed mesylate or again by formation
of a quinoid intermediate 44. In either case the resultant
intermediate 45 then rearomatizes to give tetrahydronaphtha-
lene 46, which then undergoes elimination of tert-butyldimethyl-
silanol to form the dihydroarylnaphthalene 3 (Figure 5). During
the course of this work, a biosynthetic study was published19 on
aryltetralone lignans that proposes a similar mechanism for the
formation of the arylnaphthalene ring system. This mechanism
was further supported during our synthesis of pycnanthulignene
B 5 when the equivalent intermediate to 46 was able to be
isolated (see below).
With the discovery that substrates such as 42 containing
electron-donating groups at C-3 undergo this alternative
pathway to form dihydroarylnaphthalenes, we looked for addi-
tional targets that would take advantage of this finding. The
recently isolated5 pycnanthulignene A 4 and pycnanthu-
lignene B 5, which show high levels of antimicrobial activity,
are two such chiral dihydroarylnapthalenes in which the
absolute stereochemistry of the natural products has not been
determined.
aqueous HCl to give pycnanthulignene A 4 in 86% yield. The
optical rotation of the synthetic product 4 was [R]D = ꢀ41.0
(c 0.16, EtOH), opposite in sign to natural product [R]D = +33.8
(c 0.31, EtOH),5 thus determining the absolute stereochemistry
of the natural pycnanthulignene A 4 to be 70S,80R. Similarly
treatment of alcohol 48 with mesyl chloride gave the desired
pycnanthulignene B 5 in 95% yield; however, in this case a small
amount of the unstable intermediate 50 was isolated, which upon
standing in CDCl3 converted to 5 over the period of a few hours.
The optical rotation of the synthetic product 5 was [R]D = ꢀ100
(c 0.58, EtOH), again opposite in sign to that of the isolated
natural product, [R]D = +118.5 (c 0.338, EtOH),5 thus determin-
ing the absolute stereochemistry of the natural pycnanthulignene
B 5 to also be 70S,80R.
With a route to the dihydroarylnaphthalene lignans deter-
mined, we returned to the synthesis of kadangustin J 8. Our
alternative strategy involved addition of a second equivalent of
lithiate 21 to ketone 22 to give tertiary alcohol 51, which could
then be dehydroxylated and the terminal alkene converted into
the desired primary alcohol. Thus, addition of lithiated 21 to
ketone 22 gave alcohol 51 in 68% yield (Scheme 8). With alcohol
51 in hand, methods for the dehydroxylation were then explored.
Conversion of alcohol 51 into a sulfonate ester or chloride
followed by reduction with LiAlH4 were unsuccessful,20 giving
Our synthesis of pycnanthulignenes A 4 and B 5 began from
aldehyde 41. Thus the lithiates of 1-bromo-4-(methoxymethoxy)
benzene and 1-bromo-3,4-methylenedioxybenzene were added
to aldehyde 41 and gave alcohols 47 and 48, in 60% and 59%
yields, respectively (Scheme 7). Treatment of alcohol 47 with
mesyl chloride gave the predicted dihydroarylnaphthalene 49 in
61% yield. Deprotection of the MOM ether was achieved with
only degradation products. Eventually use of Et3SiH and BF3 OEt2
3
in a dilute reaction mixture, using DCM at 0 °C, gave a 20:1
mixture of the desired alkane 52 along with dehydrated alkene
53 in overall 95% yield. The terminal alkene of 52 was then
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converted to the desired primary alcohol by dihydroxyla-
tion and oxidative cleavage followed by NaBH4 reduction
and gave (8S,80R)-kadangustin J 8 in 80% yield over 3 -
’ CONCLUSIONS
In conclusion the asymmetric synthesis of (+)-galbelgin 1
along with the first asymmetric syntheses of (ꢀ)-cyclogalgravin
3, (ꢀ)-pycnanthulignenes A 4 and B 5, and (ꢀ)-kadangustin J 8
has been achieved, with absolute stereochemistry of the natural
pycnanthulignenes A 4 and B 5 and kadangustin J 8 being
determined. A common chiral precursor, aza-Claisen-derived
amide 9, was the starting material for each of these structurally
distinct lignans. Tetrahydrofuran products are formed from the
precyclized intermediates when the C-7 hydroxyl group is
protected as a MOM ether and mesyl chloride is added to
activate the C-70 hydroxyl group. However, when the C-7
hydroxyl group is protected with a TBDMS ether, dihydroar-
ylnapthalenes are formed in the case when the adjacent aryl ring
bears an electron-donating substituent at C-3, or if a donating
substituent is only found at C-4, then a 1,4-aryl shift occurs to
give rearranged products.
1
steps. The H and 13C NMR data for the synthetic com-
pound were identical to the reported data for the natural
product. The optical rotation of the isolated synthetic
product was [R]D = ꢀ20.7 (c 1.19, MeOH), larger in
magnitude and opposite in sign to that of the natural
product,8 [R]D = +4.9 (c 0.171, MeOH) thus suggesting
the absolute stereochemistry of the natural kadangustin J 8
to be (8R,80S).
Scheme 7. Synthesis of (ꢀ)-Pycnanthulignene A (4) and B
(5)
’ EXPERIMENTAL SECTION
All reactions sensitive to air or moisture were carried out under argon
or nitrogen atmosphere in dry, freshly distilled solvents under anhydrous
conditions unless otherwise noted. All NMR spectra were recorded on a
300 or 400 MHz spectrometer. Chemical shifts are reported relative to
the solvent peak of chloroform (δ 7.24 for 1H and δ 77.0 for 13C). Signal
patterns are indicated as s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad peak. NMR peak assignments were performed by
COSY, HSQC, HMBC, and NOESY experiments. High-resolution mass
spectroscopy (HRMS) was carried out in electrospray mode. All optical
rotation measurements were determined at 20 °C on the sodium D line
(λ = 589 nm, 0.1 dm cell).
General Procedure A: Lithiate Addition of Disubstituted
Aromatic Bromides. To a solution of the aromatic bromide (1.1
mmol) in THF (10 mL) under an atmosphere of nitrogen at ꢀ78 °C was
added tert-butyllithium (1.5 M in pentane, 2.2 mmol), and the resultant
solution was stirred for 10 min. A solution of the amide or aldehyde
(1 mmol) in THF (10 mL) was then added dropwise, and the mixture
was stirred at ꢀ78 °C for 1 h before being allowed to warm to room
temperature and stirring overnight. Saturated NH4Cl solution (20 mL)
was added, and the aqueous mixture was extracted with ethyl acetate
(3 ꢁ 20 mL). The combined organic extracts were washed with brine
(40 mL) and dried (MgSO4), and the solvent was removed in vacuo. The
crude product was purified by flash chromatography to afford the
product.
General Procedure B: Ketone or Aldehyde Reduction to
an Alcohol. To a solution of ketone or aldehyde (1 mmol) in methanol
(5 mL) at ꢀ78 °C was added sodium borohydride (4 mmol), and the
resulting suspension was stirred under an atmosphere of nitrogen at
Scheme 8. Synthesis of (ꢀ)-Kadangustin J
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room temperature for 6 h. Water (5 mL) was added, and the methanol
was removed in vacuo. Further water (5 mL) was added to the residue,
and the crude product was extracted with ethyl acetatae (3 ꢁ 15 mL).
The combined organic extracts were dried (MgSO4), the solvent was
removed in vacuo, and the crude product was purified by flash chroma-
tography to afford the alcohol.
General Procedure C: Dihydroxylation of Terminal Al-
kene. To a stirred suspension of N-methylmorpholine-N-oxide (3
mmol) in a 1:1 water/tert-butanol mixture (10 mL) was added the
alkene (1 mmol). Osmium tetroxide (0.01 mmol, as a 2.5 g/100 mL
solution in tert-butanol) was added dropwise and the resulting suspen-
sion was stirred at room temperature for 48 h. Saturated sodium sulphite
solution (20 mL) was added and the mixture stirred for 1 h. The
aqueous mixture was extracted with ethylacetate (3 ꢁ 30 mL) and the
combined organic extracts were washed with 1 M KOH solution
(50 mL) and dried (MgSO4), and the solvent was removed in vacuo.
The crude product was purified by flash chromatography to afford the
corresponding diol.
General Procedure D: Periodate Cleavage of Diol to
Aldehyde. To a stirred solution of diol (1 mmol) in a 3:1 metha-
nol/water mixture (30 mL) was added sodium periodate (1.2 mmol),
and the resultant suspension was stirred for 30 min. Brine (20 mL) was
added, the mixture was extracted with ethyl acetate (3 ꢁ 50 mL), and the
combined organic extracts were washed with water (2 ꢁ 50 mL) and
dried (MgSO4). The solvent was removed in vacuo, and the crude
product was purified by flash chromatography to afford the correspond-
ing aldehyde.
General Procedure E: Cyclization Using Methanesulfonyl
Chloride. To a solution of alcohol (1 mmol) and triethylamine (1.6
mmol) in DCM (25 mL) under an atmosphere of nitrogen was added
methanesulfonyl chloride (1.3 mmol), and the reaction mixture was
stirred for 1ꢀ2 h. Saturated NaHCO3 solution (10 mL) was added, the
layers were separated, and the aqueous layer was further extracted with
DCM (3 ꢁ 15 mL). The combined organic extracts were dried
(Na2SO4), and the solvent was removed in vacuo. The crude product
was purified by flash chromatography to afford the cyclized or alternative
product.
(S)-N-(1-Phenylethyl)propanamide, 17. To a stirred solution
of (S)-(1-phenylethyl) amine (5.0 g, 41 mmol) in DCM (50 mL) under
an atmosphere of nitrogen was added triethylamine (11.4 mL, 82
mmol), and the resulting mixture was stirred for 10 min at 0 °C before
propionyl chloride (3.9 mL, 45 mmol) was added dropwise. The
resulting solution was stirred at room temperature for 18 h. Saturated
NH4Cl solution (20 mL) was added, the layers were separated, and the
aqueous phase was further extracted with DCM (3 ꢁ 20 mL). The
combined organic layers were washed with NaHCO3 solution (30 mL)
and dried (MgSO4). The crude product was purified by flash chroma-
tography (2:1 hexanes/ethyl acetate) to give the title product (6.7 g,
93%) as a white solid: mp 59ꢀ61 °C [lit.21 55ꢀ56 °C]; [R]D = ꢀ170
(c 1.26, CHCl3); δH (400 MHz; CDCl3) 1.15 (3H, t, J = 8.0 Hz, 3-CH3),
1.48 (3H, d, J = 8.0 Hz, 10-CH3), 2.21 (2H, q, J = 8.0 Hz, 2-CH2), 5.13
(1H, q, J = 8.0 Hz, 10-H), 5.79 (1H, br s, NH) and 7.32ꢀ7.33 (5H, m, Ar-
H); δC (100 MHz; CDCl3) 9.8 (CH3, C-3), 21.8 (CH3, C-10), 29.8
(CH2, C-2), 48.6 (CH, C-10), 1262, 127.3, and 128.7 (CH, Ar-C), 143.4
(q, Ar-C) and 172.8 (CdO, C-1). The 1H and 13C NMR data were in
agreement with the literature values.21
(S)-N-(But-2-enyl)-N-(1-phenylethyl)propanamide, 18. To
a stirred suspension of NaH (3.2 g, 80 mmol (60% under kerosene)
washed with pentane) in THF (60 mL) was added TBAI (0.73 g, 50
mmol), and mixture was placed under an atmosphere of nitrogen. Crotyl
bromide (5.4 g, 40 mmol) was then added, and the mixture was cooled to
0 °C before amide 17 (7.0 g, 40 mmol) in THF (10 mL) was added
dropwise. The resulting mixture was stirred at 0 °C for 1 h and then
allowed to warm to room temperature overnight. The resultant solid was
filtered off and washed with DCM (20 mL), the filtrate was concentrated
in vacuo, and the residue was dissolved in ethyl acetate (30 mL). This was
washed with brine (20 mL) and dried (MgSO4). The crude product was
purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the
title product (6.1 g, 65%) as a yellow oil: [R]D = ꢀ9.4 (c 1.06, CHCl3);
νmax(neat)/cmꢀ1 2974 and 2938 (CH), 1643 (CdC), 1449, 1416,
1376, 1205, 1178 and 1072, 964 and 699; δH (300 MHz; CDCl3) 1.17
(3H, t, J = 9.0 Hz, CH2CH3), 1.49 (3H, d, J = 6.0 Hz, N-CHCH3), 1.60
(3H, m, CHCH3), 2.35 (2H, q, J = 9.0 Hz, CH2CH3), 3.38 ꢀ3.68 (2H,
m, N-CH2), 5.14ꢀ5.19 and 5.39ꢀ5.45 (2H, m, CH alkene), 6.08 (1H, q,
J = 9.0 Hz, N-CH) and 7.25ꢀ7.32 (5H, m, Ar-H); δC (100 MHz;
CDCl3) 9.6 (CH3, CH2CH3), 16.7 (CH3, NCHCH3), 17.6 (CH3,
CHCH3), 45.3 (CH2, N-CH2), 50.9 (CH, N-CH), 126.7, 127.4, and
128.3 (CH, Ar-C), 141.3 (q, Ar-C) and 174.4 (CdO, N-CdO); m/z
(EI) 231 (M+, 10%), 176 (94), 120 (92), 105 (100), 70 (60); HRMS
(EI) calcd for C15H21NO, 231.1623; found, 231.1626.
(2R,3S)-2,3-Dimethyl-N-((S)-1-phenylethyl)pent-4-enam-
ide, 15. To a stirred solution of hexamethyldisilazane (0.23 mL, 1.0
mmol) in toluene (2 mL) cooled to 0 °C was added n-butyllithium
(0.69 mL, 1.0 mmol, 1.6 M in n-hexanes), and the solution was stirred for
15 min before amide 18 (0.169 g, 0.7 mmol) in toluene (2 mL) was
added dropwise. The pressure vessel was sealed and heated at 140 °C
for 24 h. Reaction mixture was cooled to rt before water (10 mL) was
added, the layers were separated, and the aqueous phase was further
extracted with ethyl acetate (3 ꢁ 30 mL). The combined organic layers
were dried (MgSO4), and the solvent was removed in vacuo. The crude
product was purified by flash chromatography (2:1 hexanes/ethyl
acetate) to give the title product (0.11 g, 65%) as a yellow oil: [R]D
= ꢀ10.1 (c 0.68, CHCl3); νmax(neat)/cmꢀ1 3287 (NH), 2971 and
2931 (CH), 1638 (CdC), 1540, 1494, 1450, 1376, 1227, 997, 910 and
698; δH (400 MHz; CDCl3) 0.99 (3H, d, J = 8.0 Hz, 3-CH3), 1.06 (3H,
d, J = 8.0 Hz, 2-CH3), 1.42 (3H, d, J = 4.0, NCHCH3), 2.08 (1H, m,
2-H), 2.40 (1H, q, J = 4.0 Hz, 3-H), 4.95ꢀ5.03 (2H, m, 5-CH2), 5.09
(1H, m, NCH), 5.77 (1H, m, 4-H), 6.22 (1H, br s, NH) and 7.22ꢀ7.29
(5H, m, Ar-H); δC (100 MHz; CDCl3) 14.5 (CH3, C-2), 16.4 (CH3,
C-3), 21.6 (CH3, CHCH3), 40.6 (CH, C-3), 46.2 (CH, C-2), 48.1 (CH,
NCH), 113.9 (CH2, C-5), 126.0, 126.9, and 128.3 (CH, Ar-C), 141.7
(q, Ar-C), 143.3 (CH, C-4), and 174.3 (CdO, C-1); m/z (ESI) 254
(MNa+, 50%) 232 (MH+, 100), 128 (55), 105 (10); HRMS (ESI) calcd
for C15H22NO, 232.1696; found, 232.1696. The minor diastereomer
19 was also obtained (0.012 g, 7%) as a yellow oil.
(2R,3S)-2,3-Dimethylpent-4-enoic, 20. To a stirred solution of
(2R,3S)-2,3-dimethyl-N-((S)-1-phenylethyl)pent-4-enamide 15 (0.1 g,
0.45 mmol) in a 1:1 THF/water mixture (2 mL), excluded from light,
was added iodine (0.25 g, 1.0 mmol), and the mixture was stirred at
room temperature for 20 h. The solution was diluted with ether (10 mL),
washed with saturated Na2SO5 solution (2 ꢁ 10 mL), and then dried
(MgSO4), and solvent was removed in vacuo, to afford the intermediate
iodolactone (0.1 g, 91%) as a yellow oil that was used directly in the
following reaction. To a stirred solution of iodolactone (0.1 g, 0.45
mmol) in acetic acid (2 mL) was added zinc dust (0.25 g, 3.9 mmol), and
the mixture was stirred at 60 °C for 18 h. The mixture was quenched with
2 M HCl (5 mL) and diluted with ether (10 mL). The layers were
separated, and the aqueous mixture further extracted with ether (3 ꢁ
10 mL) and dried (MgSO4), and the solvent was removed in vacuo, to
afford the title product (0.4 g, 69%) as a yellow oil. [R]D = ꢀ0.9 (c 1.0,
CHCl3); νmax(neat)/cmꢀ1 3354 (OH), 2968, 2923, and 2852 (CH),
1706 (CdO), 1456, 1229 and 914; δH (300 MHz; CDCl3) 1.08 (3H, d,
J = 9.0 Hz, CH3), 1.14 (3H, J = 9.0 Hz, CH3), 2.33ꢀ2.49 (2H, m, 2-H
and 3-H), 5.03 (2H, m, 5-CH2) and 5.67 (1H, m, 4-CH); δC (100 MHz;
CDCl3) 13.1 and 15.9 (2 ꢁ CH3, C-2 and C-3), 40.0 and 44.5 (2 ꢁ CH,
C-2 and C-3), 114.6 (CH2, C-5), 141.1 (CH, C-4), 181.9 (CdO, C-1);
The 1H and 13C NMR data were in agreement with the literature
values.12
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ARTICLE
(2R,3S)-2,3-Dimethyl-1-morpholinopent-4-en-1-one, (R,S)-9.
To a solution of acid 20 (2.7 g, 21 mmol) in DCM (20 mL) at
0 °C was added morpholine (2.0 mL, 23 mmol), followed by DMAP
(0.64 g, 5.25 mmol) and DCC (4.7 g, 23 mmol). The resulting mixture
was stirred under an atmosphere of nitrogen and allowed to warm to
room temperature over 22 h. The mixture was filtered through a pad of
Celite, washed with DCM (30 mL) followed by aqueous HCl (2M,
20 mL) and aqueous NaOH (1 M, 30 mL), then dried (MgSO4), and
the solvent was removed in vacuo. The crude product was purified by
flash chromatography (2:1 hexanes/ethyl acetate) to afford the title
product (3.1 g, 73%) as a yellow oil. [R]D = ꢀ36.0 (c 1.26, CHCl3); δH
(400 MHz; CDCl3) 1.02 (3H, d, J = 4.0 Hz, 3-CH3), 1.10 (3H, d, J =
4.0 Hz, 2-CH3), 2.46 (1H, m, 3-H), 2.59 (1H, m, 2-H), 3.51ꢀ3.68
(8H, m, O(CH2CH2)2N) and 4.99ꢀ5.04 (2H, m, 5-CH2), 5.74
(1H, m, 4-H); δC (100 MHz; CDCl3) 14.5 and 16.0 (2 ꢁ CH3,
2-CH3 and 3-CH3), 40.1 (CH, C-2 and C-3), 42.0 and 46.3 (CH2,
O(CH2CH2)2N), 66.8 and 67.1 (CH2, O(CH2CH2)2N), 114.0 (CH2,
was added, the layers were separated, and the aqueous mixture was
further extracted with DCM (3 ꢁ 30 mL). The combined organic
fractions were dried (MgSO4), and the solvent was removed in vacuo.
The crude product was purified by flash chromatography (3:1 hexanes/
ethyl acetate) to afford the title product (0.13 g, 91%) as a colorless oil.
[R]D = +93 (c 1.56, CHCl3); νmax(neat)/cmꢀ1 2961 (CH), 1593 and
1516 (CdC), 1464, 1262, 1233, 1139, 1032 (CꢀO), 917; δH (400
MHz; CDCl3) 0.47 (3H, d, J = 4.0 Hz, 2-CH3), 0.98 (3H, d, J = 8.0 Hz,
3-CH3), 1.93 (1H, m, 2-H) 2.84 (1H, m, 3-H), 3.35 (3H, s,
OCH2OCH3), 3.85 (6H, s, 30-OCH3 and 40-OCH3), 4.31 (1H, d, J =
8.0 Hz, 1-H), 4.43ꢀ4.47 (2H, dd, J = 2.4, 8.0 Hz, OCH2O), 5.02 (2H, m,
5-CH2), 5.86 (1H, m, 4-H) and 6.79ꢀ6.82 (3H, m, Ar-H); δC (100
MHz; CDCl3) 10.5 (CH3, C-2), 11.8 (CH3, C-3), 36.3 (CH, C-3), 43.2
(CH, C-2), 55.8 (CH3, 3 ꢁ OCH3), 79.9 (CH, C-1), 93.8 (CH2,
OCH2O), 110.1 and 110.4 (CH, Ar-H), 113.1 (CH2, C-5), 120.7 (CH,
Ar-H) 133.3 (q, C-10), 144.1 (CH, C-4), 148.4 and 148.9 (q, C-30 and
C-40); m/z (ESI) 317 (MNa+, 100%), 233 (50), 151 (71); HRMS (ESI)
calcd for C17H26O4Na, 317.1723; found, 317.1721.
1
C-5), 142.1 (CH, C-4) and 173.3 (q, C-1). The H and 13C NMR
spectra were in agreement with literature values.22
(1R,2R,3S)-1-(3,4-Dimethoxyphenyl)-2,3-dimethyl-1-(metho-
xymethoxy)pentan-4,5-diol. The reaction was carried out accord-
ing to general procedure C, using MOM-23 (0.094 g, 0.32 mmol). A
solvent mixture of 19:1 DCM/methanol was used for flash chromatog-
raphy to give the title product as a mixture of diastereomers (0.09 g,
86%) as a pale yellow oil. νmax(neat)/cmꢀ1 3413 (OH), 2936 and 2838
(CH), 1594 and 1510 (CdC), 1464, 1421, 1260, 1231, 1139, 1025
(CꢀO), 913 and 728; δH (400 MHz; CDCl3) [*denotes minor
diastereomer] 0.51 (3H, m, 2-CH3), 0.84 (3H, d, J = 8.0 Hz, 3-CH3),
1.01* (3H, d, J = 8.0 Hz, 3-CH3), 1.91* (1H, m, 2-H), 2.24* (1H, m,
3-H), 2.32 (1H, m, 3-H), 2.41 (1H, m, 2-H), 3.34 (3H, s, OCH2OCH3),
3.51ꢀ3.84 (3H, m, 4-H and 5-CH2), 3.87 (6H, s, 30-OCH3 and 40-
OCH3), 4.26 (1H, m, 1-H), 4.40ꢀ4.47 (2H, dd, J = 20, 4.0 Hz,
OCH2O), and 6.81ꢀ6.86 (3H, m, Ar-H); δC (100 MHz; CDCl3)
9.3* and 9.7 (CH3,C-3), 10.3 and 11.3* (CH3, C-2), 34.5 and 35.1* (CH,
C-3), 37.9 and 40.4* (CH, C-2), 55.8 and 55.9* (CH3, 3 ꢁ OCH3), 65.1*
and 65.5 (CH2, C-5), 73.9 and 75.4* (CH, C-4), 80.0 and 80.3* (CH,
C-1), 93.7 and 93.8* (CH2, OCH2O), 110.2, 110.5 and 120.7* and 120.8
(CH, Ar-H) 133.1* and 133.4 (q, C-10), 148.5 and 149.0 (q, C-30 and
C-40); m/z (ESI) 351 (MNa+, 100%), 231 (15); HRMS (ESI) calcd for
C17H28NaO6, 351.1778; found, 351.1778.
(2R,3S)-1-(3,4-Dimethoxyphenyl)-2,3-dimethylpent-4-en-1-
one, 22. The reaction was carried out according to general procedure A,
using 4-bromoveratrole (0.52 g, 2.4 mmol) and tert-butyllithium
(3.2 mL, 4.8 mmol, 1.5 M) with amide (R,S)-9 (0.32 g, 1.6 mmol). A
solvent mixture of 2:1 hexanes/ethyl acetate was used for flash chroma-
tography to give the title product (0.32 g, 81%) as a pale yellow oil.
[R]D = ꢀ64 (c 1.4, CHCl3); νmax(neat)/cmꢀ1 2968 and 2862 (CH), 1665
(CdO), 1581 and 1510 (CdC), 1454, 1345, 1257, 1197, 1148, and
1021 (CꢀO ether), 909, 852 and 764; δH (400 MHz; CDCl3) 1.01 (3H,
d, J = 8.0 Hz, 3-CH3), 1.14 (3H, d, J = 4.0 Hz, 2-CH3), 2.65 (1H, ddq, J =
8.0, 8.0, 8.1 Hz 3-H) 3.44 (1H, dq, J = 4.1, 8.0 Hz, 2-H), 3.94 (6H, s, 2 ꢁ
OCH3), 4.95 (2H, m, 5-CH2), 5.81 (1H, m, 4-H), 6.90 (2H, d, J = 8.4
Hz, 50-H), 7.53 (1H, d, J = 1.2 Hz, 20-H) and 7.57 (1H, dd, J = 8.4, 1.6 Hz,
60-H); δC (100 MHz; CDCl3) 13.6 (CH3, C-2), 15.7 (CH3, C-3), 40.1
(CH, C-3), 44.7 (CH, C-2), 56.0 and 56.1 (CH3, 2 ꢁ OCH3), 109.9
(CH, C-20), 110.6 (CH, C-50), 113.9 (CH, C-60), 122.6 (CH, C-4),
130.1 (q, C-10), 142.2 (CH2, C-5), 149.1 and 153.1 (q, C-40 and C-50)
and 202.3 (CdO, C-1); m/z (EI) 248 (M+, 20%), 192 (4), 165 (100),
79 (6), 77 (5); HRMS (EI) calcd for C15H20O3, 248.1412; found,
248.1406.
(1R,2R,3S)-1-(3,4-Dimethoxyphenyl)-2,3-dimethylpent-4-
en-1-o1, 23. The reaction was carried out according to general
procedure B, using ketone 22 (0.42 g, 1.68 mmol), and reaction time
was extended to 18 h. A solvent mixture of 3:1 hexanes/ethyl acetate was
used for flash chromatography to give the title product (0.41 g, 95%) as a
pale yellow oil. [R]D = ꢀ0.7 (c 5.5, CHCl3); νmax(neat)/cmꢀ1 3498
(OH), 2968 (CH), 2325, 1634, 1591, 1510, 1458, 1257, 1229, 1137, and
1025 (CꢀO), 902, 807 and 740; δH (400 MHz; CDCl3) 0.53 (3H, d, J =
4.0 Hz, 2-CH3), 1.01 (3H, d, J = 8.0 Hz, 3-CH3), 1.89 (1H, ddq, J = 7.8,
8.0, 8.0 Hz, 3-H) 2.74 (1H, ddq, J = 4.0, 8.0, 8.0 Hz, 2-H), 3.88 (6H, s,
OCH3), 4.40 (1H, dd, J = 2.0, 8.0 Hz, 1-H), 5.04 (2H, m, 5-CH2), 5.91
(1H, m, 4-H) and 6.83ꢀ6.91 (3H, m, Ar-H); δC (100 MHz; CDCl3)
10.9 (CH3, C-2), 13.0 (CH3, C-3), 37.1 (CH, C-2), 44.2 (CH, C-3),
55.9 (CH3, 2 ꢁ OCH3), 73.9 (CH, C-1), 109.6 (CH, C-20), 110.7 (CH,
C-50), 113.2 (CH2, C-5), 119.3 (CH, C-60), 136.4 (q, C-10), 144.3 (CH
and q, C-4, C-30 and C-40); m/z (EI) 250 (M+, 10%), 167 (100), 151 (3),
139 (54), 124 (11), 108 (6), 77 (6) and 55 (8); HRMS (EI) calcd for
C15H22O3, 250.1569; found, 250.1566.
(1R,2R,3R)-1-(3,4-Dimethoxyphenyl)-2,3-dimethyl-1-(metho-
xymethoxy)-4-butanal, 24. The reaction was carried out according
to general procedure D, using (1R,2R,3S)-3,4-dimethoxyphenyl-2,3-
dimethyl-1-(methoxymethoxy)pentan-4,5-diol (0.09 g, 0.27 mmol). A
solvent mixture of 1:1 hexanes/ethyl acetate was used for flash chroma-
tography to give the title product (0.072 g, 90%) as a pale yellow oil.
[R]D = +62 (c 7.1, CHCl3); νmax(neat)/cmꢀ1 2938 and 2836 (CH),
1721 (CdO), 1515, 1464, 1262, 1140, 1028 (CꢀO), 918; δH (400
MHz; CDCl3) 0.55 (3H, d, J = 8.0 Hz, 2-CH3), 1.11 (3H, d, J = 8.0 Hz,
3-CH3), 2.46 (1H, dq, J = 8.0, 8.0 Hz, 2-H), 2.94 (1H, ddq, J = 4.0, 8.0,
8.0 Hz, 3-H), 3.34 (3H, s, OCH2OCH3), 3.90 (6H, s, 30-OCH3 and 40-
OCH3), 4.25 (1H, d, J = 8.0 Hz, 1-H), 4.40ꢀ4.48 (2H, m, OCH2O),
6.83ꢀ6.84 (3H, m, Ar-H) and 9.70 (1H, s, 4-H); δC (100 MHz; CDCl3)
8.0 (CH3, C-3), 12.2 (CH3, C-2), 38.8 (CH, C-2), 47.7 (CH, C-3), 55.9,
55.9, and 56.1 (CH3, 3 ꢁ OCH3), 80.1 (CH, C-1), 93.8 (CH2,
OCH2O), 110.0 and 110.7 and 120.8 (CH, Ar-H) 132.4 (q, C-10),
148.8 and 149.2 (q, C-30 and C-40) and 205.1 (CdO, C-4); m/z (ESI)
319 (MNa+, 100%), 235 (29), 151 (5); HRMS (ESI) calcd for
C16H24NaO5, 319.1516; found, 319.1519
(1R,2R,3S)-1-(3,4-Dimethoxyphenyl)-2,3-dimethyl-1-(methoxy-
methoxy)pent-4-ene (MOM-23). To a stirred solution of alcohol 23
(0.12 g, 0.48 mmol) in DCM (15 mL) under an atmosphere of nitrogen
at 0 °C was added diisopropylethylamine (0.34 mL, 1.9 mmol), followed
by the dropwise addition of methyl methoxy chloride (0.13 mL,
1.2 mmol). The resulting solution was allowed to warm to room
temperature and stirred for 24 h. Saturated NH4Cl solution (20 mL)
(1R,2R,3S,4S)-1,4-Bis(3,4-dimethoxyphenyl)-2,3-dimethyl-
1-(methoxymethoxy)butan-4-o1, 25. The reaction was carried
out according to general procedure A, using bromide 21 (0.053 g,
0.20 mmol) and tert-butyllithium (0.27 mL, 0.41 mmol, 1.5 M in
pentane) with aldehyde 24 (0.05 g, 0.17 mmol). A solvent mixture of
2:1 ethyl acetate/hexanes was used for flash chromatography to give the
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The Journal of Organic Chemistry
ARTICLE
title product (0.052 g, 71%) as a yellow oil. [R]D = +54 (c 2.0, CHCl3);
νmax(neat)/cmꢀ1 3424 (OH), 2936 and 2837 (CH), 1731, 1703, 1594
and 1514, 1463, 1421, 1262, 1139, 1032 (CꢀO); δH (400 MHz;
CDCl3) 0.53 (3H, d, J = 4.0 Hz, 2-CH3), 1.09 (3H, d, J = 4.0 Hz,
3-CH3) 1.68 (1H, m, 2-H), 1.84 (1H, br s, OH), 2.51 (1H, m, 3-H), 3.37
(3H, s, OCH2OCH3), 3.79 and 3.88 (12H, s, OCH3), 4.26 (1H, d, J =
12.0 Hz, 1-H), 4.39 ꢀ4.47 (2H, m, OCH2O), 4.48 (1H, d, J = 4.0 Hz,
4-H), 6.62ꢀ6.91 (6H, m, Ar-H). δC (100 MHz; CDCl3) 10.1 (CH3,
C-3), 11.4 (CH3, C-2), 39.0 (CH, C-3), 40.0 (CH, C-2), 55.8 and 55.9
(4 ꢁ CH3, OCH3), 78.3 (CH, C-4), 80.5 (CH, C-1), 94.0 (CH2,
OCH2O), 109.6, 110.2, 110.5, and 110.8 (CH, C-20, C-200, C-50 and
C-500), 119.2 and 120.3 (CH, C-60 and C-600), 133.4 and 136.3 (q, C-10
and C-100), 148.3, 148.4, 148.8, and 149.0 (q, C-30, C-300, C-40 and C-400);
m/z (ESI) 435 (MH+, 90%), 426 (100); HRMS (ESI) calcd for
C24H35O7, 435.2377; found, 435.2398.
(+)-Galbelgin, (+)-1. The reaction was carried out according to general
procedure E, using alcohol 25 (68 mg, 0.15 mmol) and extending the
reaction time to 16 h. A solvent mixture of 4:1 hexanes/ethyl acetate was
used for flash chromatography to give the title product (34 mg, 59%) as
white solid. [R]D = +81.8 (c 1.5, CHCl3) [lit.2a [R]D = +80.7 (c 0.55,
CHCl3)]; δH (400 MHz; CDCl3) 1.05 (6H, d, J = 8.0 Hz, 3-CH3 and
4-CH3), 1.80 (2H, m, 3-H and 4-H) 3.88 and 3.92 (12H, s, all OCH3),
4.66 (2H, d, J = 8.0 Hz, 2-H and 5-H), 6.85 (2H, d, J = 8.0 Hz, 50-H and
500-H), 6.91 (2H, dd, J = 4.0, 8.0 Hz, 60-H and 600-H) and 6.97 (2H, d, J =
4.0 Hz, 20-H and 200-H). δC (100 MHz; CDCl3) 13.9 (CH3, C-3 and
C-4), 51.0 (CH, C-3 and C-4), 55.9 and 55.9 (CH3, 4 ꢁ OCH3), 88.3
(CH, C-2 and C-5), 109.2 and 110.8 (CH, C-20, C-200, C-60 and C-600),
118.6 (CH, C-50 and C-500) 134.9 (q, C-10), 148.5 and 149.1 (q, C-30 and
C-300 and C-40 and C-400). The 1H and 13C NMR spectra were in
agreement with literature values.2a
(2R*,3S*)-1-(4-Methoxyphenyl)-2,3-dimethylpent-4-en-1-
one. To a solution of 4-bromoanisole (0.76 g, 4 mmol) in THF (10 mL)
under an atmosphere of nitrogen at ꢀ78 °C was added n-butyllithium
(2.75 mL, 4.4 mmol, 1.6 M in n-hexanes), and the resultant solution was
stirred for 5 min. A solution of (2R*,3S*)-2,3-dimethyl-1-morpholino-
pent-4-en-1-one9 (0.66 g, 3.4 mmol) in THF (10 mL) was then added
dropwise, and the mixture was stirred at room temperature for 1.5 h.
Saturated NH4Cl solution (20 mL) was added, and the aqueous mixture
was extracted with ethyl acetate (3 ꢁ 20 mL). The combined organic
extracts were washed with brine (30 mL) and dried (MgSO4), and the
solvent was removed in vacuo. The crude product was purified by flash
chromatography (3:1 hexanes/ethyl acetate) to give the title product
(0.71 g, 96%) as a pale yellow oil. νmax(neat)/cmꢀ1 3077 and 3069
(CH), 1672 (CdO), 1600 (CdC), 1509, 1256, and 1171 (CꢀO) and
1031 (CH); δH (400 MHz; CDCl3) 1.00 (3H, d, J = 8.0 Hz, 3-CH3),
1.13 (3H, d, J = 4.0 Hz, 2-CH3), 2.64 (1H, m, 3-H), 3.42 (1H, m, 2-H),
3.87 (3H, s, OCH3), 4.92ꢀ5.02 (2H, m, 5-CH2), 5.81 (1H, m, 4-H),
6.94 (2H, d, J = 8.0 Hz, 30-H) and 7.91 (2H, d, J = 8.0 Hz, 20-H); δC (75
MHz; CDCl3) 13.3 (CH3, C-2), 15.5 (CH3, C-3), 39.9 (CH, C-3), 44.8
(CH, C-2), 55.4 (CH3, OCH3), 113.7 (CH, C-30), 113.9 (CH2, C-5),
130.3 (q, C-10), 130.5 (CH, C-20), 142.2 (CH, C-4), 163.3 (CH, C-40)
and 202.3 (q, C-1); m/z (CI) 219 (MH+, 75%), 203 (8), 162 (11),135
(100), 121 (10), 111 (14), 97 (12), 84 (14), 70 (17); HRMS (CI) calcd
for C14H19O2, 219.1385; found, 219.1392.
5-CH2), 5.89 (1H, m, 4-H), 6.87 (2H, d, J = 8.0 Hz, 30-H), 7.25 (2H, d,
J = 8.0 Hz, 20-H); δC (100 MHz; CDCl3) 10.9 (CH3, C-2), 12.9 (CH3,
C-3), 37.0 (CH, C-3), 44.2 (CH, C-2), 55.3 (CH3, OCH3), 76.6 (CH,
C-1), 113.2 (CH2, C-5), 113.7 (CH, C-30), 128.0 (CH, C-20), 133.0 (q,
C-10), 144.3 (CH, C-4), 159.1 (q, C-40); m/z (EI) 220 (M+, 4%), 137
(100), 135 (3), 109 (8), 94 (5), 77 (7), 55 (4), 39 (3); HRMS (EI) calcd
for C14H20O2, 220.1463; found, 220.1466.
(1R*,2R*,3S*)-1-(4-Methoxyphenyl)-2,3-dimethyl-1-(tert-
butyldimethylsiloxy)pent-4-ene, 33. To a stirred solution of
alcohol 32 (0.1 g, 0.45 mmol) in DCM (5 mL) was added imidazole
(0.12 g, 1.8 mmol). The mixture was cooled to 0 °C, and TBS chloride
(0.081 g, 0.54 mmol) was added. The resulting solution stirred under an
atmosphere of nitrogen at room temperature for 48 h. Water (5 mL)
was added, the layers were separated, the aqueous mixture was further
extracted with ethyl acetate (3 ꢁ 20 mL) and then dried (MgSO4), and
the solvent was removed in vacuo. The crude product was purified by
flash chromatography (9:1 hexanes/ethyl acetate) to afford the title
product (0.14 g, 87%) as a colorless oil. νmax(neat)/cmꢀ1 2957 and
2855 (CH), 2346 (CH), 1612 and 1512 (CdC), 1462 1299, 1250,
1172, 1073, and 1035 (CꢀO), 909, 835, and 775 (CH); δH (300 MHz;
CDCl3) ꢀ0.33 and ꢀ0.01 (2 ꢁ 3H, s, Si-CH3), 0.47 (3H, d, J = 6.0 Hz,
2-CH3), 0.83 (9H, s, SiC(CH3)3), 0.91 (3H, d, J = 9.0 Hz, 3-CH3), 1.77
(1H, m, 2-H) 2.70 (1H, m, 3-H), 3.79 (3H, s, OCH3), 4.34 (1H, d, J =
9.0 Hz, 1-H), 4.99 (2H, m, 5-CH2), 5.84 (1H, m, 4-H), 6.81 (2H, d, J =
9.0 Hz, 30-H), 7.21 (2H, d, J = 9.0 Hz, 20-H); δC (75 MHz; CDCl3)
ꢀ5.2 and ꢀ4.5 (2 ꢁ CH3, SiCH3), 10.3 (CH3, C-2), 12.5 (CH3, C-3),
18.1 (q, C(CH3)3), 25.8 (CH3, C(CH3)3), 36.2 (CH, C-3), 45.6 (CH,
C-2), 55.1 (CH3, OCH3), 77.0 (CH, C-1), 112.7 (CH2, C-5), 113.1
(2 ꢁ CH, C-30), 128.2 (2 ꢁ CH, C-20), 136.4 (q, C-1), 144.9 (CH,
C-4) and 158.6 (q, C-40) ; m/z (CI): 335 (MH+, 1%), 277 (6), 251
(100), 202 (10), 93 (4), 187 (7), 135 (3), 121 (19), 73 (21), 70 (21);
HRMS (CI) calcd for C20H35O2Si, 335.2406; found, 335.2416.
(1R*,2R*,3R*)-1-(4-Methoxyphenyl)-2,3-dimethyl-1-(tert-
butyldimethylsiloxy)pentan-4,5-diol. The reaction was carried
out according to general procedure C, using alkene 33 (0.135 g, 0.4
mmol). A solvent mixture of 14:1 DCM/methanol was used for flash
chromatography to give the title product (0.12 g, 81%) as a colorless oil.
νmax(film)/cmꢀ1 3387 (OH), 2956 and 2928 (CH), 2856 (CH), 1611
and 1512 (CdC), 1249, 1173, 1069, and 1039 (CꢀO), 864 835 and
775; δH (400 MHz; CDCl3) [*denotes minor diastereomer] ꢀ0.35*,
ꢀ0.34, ꢀ0.02* and ꢀ0.01 (2 ꢁ 3H, s, Si-CH3), 0.54 (3H, d, J = 8.0 Hz,
2-CH3), 0.79 (3H, d, J = 8.0 Hz, 3-CH3), 0.83 (9H, s, SiC(CH3)3),
0.89ꢀ0.93* (6H, m, 2-CH3 and 3-CH3), 1.72 (2H, br s, 4-OH and
5-OH) 2.14ꢀ2.17 (2H, m, 2-H and 3-H), 3.45ꢀ3.74 (3H, m, 4-H and
5-CH2), 3.79 (3H, s, OCH3), 4.26 (1H, d, J = 12.0 Hz, 1-H), 6.82 (2H, d,
J = 8.0 Hz, 30-H), 7.17 (2H, d, J = 8.0 Hz, 20-H); δC (100 MHz; CDCl3)
ꢀ5.2 and ꢀ4.4 (2 ꢁ CH3, Si-CH3), 9.6* and 10.3 (CH3, C-3), 10.7 and
11.4* (CH3, C-2), 18.1 (q, C(CH3)3), 25.8 (CH3, C(CH3)3), 34.5,
34.8*, 40.4 and 42.7* (CH, C-2 and C-3), 55.2 (CH3, OCH3), 65.6* and
65.7 (CH2, C-5), 74.5 (CH, C-4), 77.7 (CH, C-1), 113.3 (CH, C-30),
128.1 (CH, C-20), 136.6 (q, C-10) and 158.7 (CH, C-40); m/z (FAB):
369 (MH+, 3%), 251 (96), 237 (23), 201 (22), 121 (42), 89 (18) and 73
(100); HRMS (CI/NH3) calcd for C16H30NO5, 316.2124.; found,
316.2119.
(1R*,2R*,3S*)-1-(4-Methoxyphenyl)-2,3-dimethylpent-4-en-
1-ol, 32. The reaction was carried out according to general procedure
B, using (2R*,3S*)-1-(4-methoxyphenyl)-2,3-dimethylpent-4-en-1-one
(0.74 g, 3.4 mmol). A solvent mixture of 4:1 hexanes/ethyl acetate was
used for flash chromatography to give the title product (0.65 g, 86%) as a
pale yellow oil. νmax(neat)/cmꢀ1 3407 (OH), 3079 (CH), 2965, 2818,
1612 (CdC alkene), 1586 (CdC aromatic), 1462, 1377 and 1301,
1249, 1175, and 1036 (CꢀO), 832; δH (400 MHz; CDCl3) 0.52 (3H, d,
J = 8.0 Hz, 3-CH3), 1.00 (3H, d, J = 4.0 Hz, 2-CH3), 1.90 (1H, m, 3-H),
2.72 (1H, m, 2-H), 3.81 (3H, s, OCH3), 4.42 (1H, m, 1-H), 5.04 (2H, m,
(1R*,2R*,3R*)-1-(4-Methoxyphenyl)-2,3-dimethyl-1-(tert-butyl-
dimethylsiloxy)-4-butanal, 34. The reaction was carried out
according to general procedure D, using (1R*,2R*,3R*)-4-methoxyphe-
nyl-2,3-dimethyl-1-(tert-butyldimethylsiloxy)pentan-4,5-diol (1.13 g,
3.1 mmol) extending the reaction time to 6 h. A solvent mixture of
2:1 hexanes/ethyl acetate was used for flash chromatography to give the
title product (0.88 g, 85%) as a colorless oil. νmax(film)/cmꢀ1 2956 and
2930 (CH), 1721 (CdO), 1612 and 1511 (CdC), 1248, 1173, and
1066 (CꢀO), 906, 860, 835 and 728; δH (300 MHz; CDCl3) ꢀ0.34 and
ꢀ0.03 (2 ꢁ 3H, s, SiCH3), 0.50 (3H, d, J = 9.0 Hz, 2-CH3), 0.82 (9H, s,
6644
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ARTICLE
SiC(CH3)3), 1.03 (3H, d, J = 6.0 Hz, 3-CH3), 2.35 (1H, m, 3-H), 2.91
(1H, dq, J = 8.1, 8.9 Hz, 2-H), 3.78 (3H, s, OCH3), 4.29 (1H, d, J = 9.0,
1-H), 6.82 (2H, d, J = 9.0 Hz, 30-H), 7.18 (2H, d, J = 9.0 Hz, 20-H); δC
(75 MHz; CDCl3) ꢀ5.2 and ꢀ4.5 (2 ꢁ CH3, Si-CH3), 7.4 (CH3, C-3),
11.6 (CH3, C-2), 18.0 (q, C(CH3)3), 25.8 (CH3, C(CH3)3), 40.6 (CH,
C-3), 47.0 (CH, C-2), 55.1 (CH3, OCH3), 77.2 (CH, C-1), 113.4 (CH,
C-30), 128.1 (CH, C-20), 135.6 (q, C-10) 159.0 (q, C-40) and 205.6
(CdO, C-4); m/z (CI) 337 (MH+, 24%), 279 (70), 251 (81), 205
(100), 187 (31), 175 (19), 121 (50), 75 (68) and 73 (42); HRMS (CI)
calcd for C19H33O3Si, 337.2199; found, 337.2197.
(1H, m, 2-H), 3.45ꢀ3.50 (2H, m, 4-CH2), 3.55 (1H, d, J = 12.0 Hz, 1-H),
3.76 (6H, s, 2 ꢁ OCH3), 6.79ꢀ6.81 (4H, m, 30-H and 300-H), 7.19ꢀ7.22
(4H, m, 20-H and 200-H); δC (75 MHz; CDCl3) 9.4 (CH3, C-3), 11.8
(CH3, C-2), 36.0 (CH, C-2), 55.0 (CH, C-3), 55.1 (2 ꢁ CH3, OCH3),
67.1 (CH2, CH2OH), 113.8 and 114.0 (CH, C-30 and C-300), 128.6 and
128.7 (CH, C-20 and C-200), 136.8 and 137.3 (q, C-10 and C-100), 157.7
and 157.7 (q, C-40 and C-400); m/z (EI) 314 (M+, 8%), 227 (100), 212
(4), 121 (4), 115 (5); HRMS (EI) calcd for C20H26O3, 314.1882; found,
314.1882.
(1R,2R,3S)-1-(3,4-Dimethoxyphenyl)-2,3-dimethyl-1-(tert-
butyldimethylsiloxy)pent-4-ene, 40. To a stirred solution of
alcohol 23 (0.32 g, 1.3 mmol) in DCM (10 mL) was added imidazole
(0.36 g, 5.2 mmol). The mixture was cooled to 0 °C, and TBS chloride
(0.24 g, 1.6 mmol) was added. The resulting solution stirred under an
atmosphere of nitrogen at room temperature for 14 days. Water (10 mL)
was added, the layers were separated, the aqueous mixture was further
extracted with ethyl acetate (3 ꢁ 20 mL) and then dried (MgSO4), and
the solvent was removed in vacuo. The crude product was purified by
flash chromatography (4:1 hexanes/ethyl acetate) to afford the title
product (0.33 g, 72%) as a colorless oil. [R]D = +23.0 (c 3.1, CHCl3);
νmax(neat)/cmꢀ1 2956 and 2857 (CH), 1514, 1463 (CdC), 1259,
1140, 1073, 1031 (CꢀO), 861, 835, 775 and 669; δH (400 MHz;
CDCl3) ꢀ0.30 and ꢀ0.00 (2 ꢁ 3H, s, Si-CH3), 0.48 (3H, d, J = 4.0 Hz,
2-CH3), 0.84 (9H, s, SiC(CH3)3), 0.92 (3H, d, J = 8.0 Hz, 3-CH3), 1.76
(1H, m, 2-H) 2.71 (1H, m, 3-H), 3.86 (3H, s, 2 ꢁ OCH3), 4.34 (1H, d,
J = 8.0 Hz, 1-H), 5.01 (2H, m, 5-CH2), 5.85 (1H, m, 4-H), 6.75 (2H, s,
50-CH and 60-CH) and 6.86 (1H, s, 20-H); δC (100 MHz; CDCl3) ꢀ5.1
and ꢀ4.5 (2 ꢁ CH3, SiCH3), 10.3 (CH3,C-2), 12.5 (CH3, C-3), 18.1 (q,
C(CH3)3), 25.8 (CH3, C(CH3)3), 36.2 (CH, C-3), 45.6 (CH, C-2), 55.8
(CH3, 2 ꢁ OCH3), 77.2 (CH, C-1), 110.0 (CH, C-20), 110.1 (CH, C-50
or C-60), 112.8 (CH2, C-5), 119.5 (CH, C-50 or C-60), 136.9 (q, C-10),
144.8 (CH, C-4), 148.0 and 148.6 (q, C-30 and C-40); m/z (EI) 364 (M+,
2%), 307 (5), 281 (100), 151 (14), 73 (29) and 55 (4), HRMS (EI)
calcd for C21H36O3Si, 364.2434; found, 364.2433.
(1R,2R,3S)-1-(3,4-Dimethoxyphenyl)-2,3-dimethyl-1-(tert-
butyldimethylsiloxy)pentan-4,5-diol. The reaction was carried
out according to general procedure C, using alkene 40 (0.33 g, 0.9
mmol). A solvent mixture of 19:1 DCM/methanol was used for flash
chromatography to give the title product (0.34 g, 94%) as a pale yellow
oil. νmax(neat)/cmꢀ1 3412 (OH), 2930, 2856, 1593, 1513 (CdC),
1463, 1259, 1139, 1069, and 1030 (CꢀO), 861, 835 and 774; δH (300
MHz; CDCl3) [*denotes minor diastereomer] ꢀ0.31 and ꢀ0.01 (2 ꢁ
3H, s, SiCH3), 0.55 (3H, d, J = 6.0 Hz, 2-CH3), 0.79 (3H, d, J = 6.0 Hz,
3-CH3), 0.84 (9H, s, C(CH3)3), 0.88ꢀ0.91* (6H, m, 2-CH3 and
3-CH3), 1.89ꢀ2.18 (4H, m, 2-H, 3-H and 2 ꢁ OH), 3.46ꢀ3.76 (3H,
m, 4-H and 5-CH2), 3.86 (6H, s, 2 ꢁ OCH3), 4.25 (1H, d, J = 9.0 Hz,
1-H), 6.74ꢀ6.85 (3H, m, Ar-H); δC (100 MHz; CDCl3) ꢀ5.2 and ꢀ4.5
(2 ꢁ CH3, SiCH3), 9.6* and 10.3 (CH3, C-3), 10.7 and 11.5* (CH3,
C-2), 18.1 (q, C(CH3)3), 25.8 (CH3, C(CH3)3), 34.5 and 34.5* (CH,
C-3), 40.3 and 42.7* (CH, C-2), 55.8 (CH3, 2 ꢁ OCH3), 65.6* and 65.7
(CH2, C-5), 74.4 and 76.2* (CH, C-4), 77.9 (CH, C-1), 109.7 (CH,
C-20), 110.2 and 110.2* (CH, C-50), 119.4 and 119.4* (CH, C-60),
136.8* and 137.1 (q, C-10) and 148.1* and 148.7 (2q, C-30 and C-40);
m/z (EI) 398 (M+, 1%), 281 (100), 235 (11), 166 (17), 151 (21), 73
(69) and 71 (26); HRMS (EI) calcd for C21H38O5Si, 398.2489; found,
398.2486.
(1R*,2R*,3S*,4S*)-1,4-Bis(4-methoxyphenyl)-2,3-dimethyl-
1-(tert-butyldimethylsiloxy)butan-4-o1, 35. To a solution of
4-bromoanisole (0.53 g, 2.9 mmol) in THF (5 mL) under an atmo-
sphere of nitrogen at ꢀ78 °C was added n-butyllithium (1.9 mL, 2.9
mmol, 1.5 M in hexanes), and the resultant solution was stirred for 5
min. A solution of aldehyde 34 (0.8 g, 2.4 mmol) in THF (5 mL) was
then added dropwise, and the mixture was stirred at room temperature
for 18 h. Saturated NH4Cl solution (10 mL) was added, and the aqueous
mixture was extracted with ethyl acetate (3 ꢁ 10 mL). The combined
organic extracts were washed with brine (10 mL) and dried (MgSO4),
and the solvent was removed in vacuo. The crude product was purified by
flash chromatography (4:1 hexanes/ethyl acetate) to give the title
product (0.97 g, 92%) as a colorless oil. νmax(film)/cmꢀ1 3458 (OH),
2955, 2928 2855, 1611, 1510 (CdC), 1462, 1379, 1302, 1246, 1173,
1064, 1035, and 1005 (CꢀO), 863, 831 and 774; δH (300 MHz;
CDCl3) ꢀ0.38 and ꢀ0.01 (2 ꢁ 3H, s, Si-CH3), 0.48 (3H, d, J = 9.0 Hz,
2-CH3), 0.86 (9H, s, SiC(CH3)3), 1.03 (3H, d, J = 6.0 Hz, 3-CH3), 1.50
(1H, m, 3-H), 1.72 (1H, br s, OH) 2.46 (1H, m, 2-H), 3.77 and 3.81 (2x
3H, s, OCH3), 4.24 (1H, d, J = 9.0 Hz, 1-H), 4.39 (1H, d, J = 9.0 Hz,
4-H), 6.75 (2H, d, J = 9.0 Hz, 30-H or 300-H), 6.85 (2H, d, J = 9.0 Hz, 30-H
or 300-H), 6.99 (2H, d, J = 6.0 Hz, 20-H or 200-H) and 7.20 (2H, d, J = 6.0
Hz, 20-H or 200-H); δC (100 MHz; CDCl3) ꢀ5.2 and ꢀ4.5 (2x CH3, Si-
CH3), 10.1 (CH3, C-3), 10.9 (CH3, C-2), 18.0 (q, C(CH3)3), 25.8
(CH3, C(CH3)3), 38.3 (CH, C-2), 41.7 (CH, C-3), 55.1 and 55.2 (CH3,
OCH3), 77.5 (CH, C-1), 78.2 (CH, C-4), 113.1 and 113.7 (CH, C-30
and C-300), 127.9 (CH, C-20 and C-200), 135.9 and 136.5 (q, C-10 and
C-100), 158.5 and 158.9 (q, C-40 and C-400); m/z (FAB) 427 (M ꢀ OH+,
10%), 295 (23), 251 (77), 121 (48) and 73 (100); HRMS (FAB) calcd
for C26H39O3Si, 427.2669; found, 427.26703.
(2R*,3R*)-4,4-Bis(4-methoxyphenyl)-2,3-dimethylbutanal,
36. The reaction was carried out according to general procedure E, using
alcohol 35 (0.052 g, 0.12 mmol) and extending the reaction time to 7 h. A
solvent mixture of 9:1 hexanes/ethyl acetate was used for flash chroma-
tography to give the title product (30.6 mg, 85%) as a colorless oil.
νmax(film)/cmꢀ1 2961, 2833, 1718 (CdO), 1605, 1507, 1461, 1299,
1243, 1173, and1032 (CꢀO), 814, 747, 666;δH (300 MHz;CDCl3) 0.70
(3H, d, J = 6.0 Hz, 2-CH3), 1.01 (3H, d, J = 6.0 Hz, 3-CH3), 2.38 (1H, m,
3-H), 3.02 (1H, m, 2-H), 3.59 (1H, d, J = 12.0 Hz, 1-H), 3.75 (6H, s,
OCH3), 6.82 (4H, d, J = 9.0 Hz, 30-H and 300-H), 7.23 (4H, d, J = 9.0 Hz,
20-H and 200-H) and 9.64 (1H, s, 4-H); δC (100 MHz; CDCl3) 6.2 (CH3,
C-3), 13.6 (CH3, C-2), 35.6 (CH, C-2), 47.9 (CH, C-3), 54.6 (CH, C-1),
55.2 (CH3, OCH3), 114.0 and 114.3 (CH, C-30 and C-300), 128.5 and
128.6 (CH, C-20 and C-200), 135.9 (q, C-10 and C-100), 158.0 and 158.1 (q,
OCH3), 205.4 (CdO, C-4); m/z (EI) 312 (M+, 5%), 254 (8), 227 (100),
176 (6) and 115 (4); HRMS (EI) calcd for C20H24O3, 312.1725; found,
312.1723.
(2R*,3R*)-4,4-Bis(4-methoxyphenyl)-2,3-dimethylbutanol,
39. The reaction was carried out according to general procedure B, using
aldehyde 36 (0.017 g, 0.05 mmol) and reducing the reaction time to
3 1/2 h. A solvent mixture of 4:1 hexanes/ethyl acetate was used for flash
chromatography to give the title product (11.7 mg, 64%) as a pale yellow
oil. νmax(film)/cmꢀ1 3399 (OH), 2961 and 2833 (CH), 1605, 1507,
1461, 1243, 1176, 1032, 817, 564; δH (400 MHz; CDCl3) 0.67 (3H, d, J =
4.0 Hz, 2-CH3), 0.75 (3H, d, J = 8.0 Hz, 3-CH3), 1.73 (1H, m, 3-H), 2.61
(1R,2R,3R)-1-(3,4-Dimethoxyphenyl)-2,3-dimethyl-1-(tert-
butyldimethylsiloxy)-4-butanal, 41. The reaction was carried out
according to general procedure D, using (1R,2R,3S)-3,4-dimethoxyphe-
nyl-2,3-dimethyl-1-(tert-butyldimethylsiloxy)pentan-4,5-diol (0.34 g,
0.85 mmol). A solvent mixture of 9:1 hexanes/ethyl acetate was used
for flash chromatography to give the title product (0.28 g, 90%) as a pale
yellow oil. [R]D = ꢀ10.0 (c 4.15, CHCl3); νmax(neat)/cmꢀ1 2955, 2931,
and 2857 (CH), 1723 (CdO), 1594 and 1515 (CdC), 1463, 1259,
6645
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ARTICLE
1142, and 1066 (CꢀO), 1030, 860, 836, 776; δH (400 MHz; CDCl3)
ꢀ0.29 and ꢀ0.00 (2 ꢁ 3H, s, SiCH3), 0.53 (3H, d, J = 4.0 Hz, 2-CH3),
0.85 (9H, s, C(CH3)3), 1.05 (3H, d, J = 8.0 Hz, 3-CH3), 2.36 (1H, m,
3-H), 2.92 (1H, m, 2-H), 3.88 (6H, s, 2 ꢁ OCH3), 4.30 (1H, d, J = 12.0
Hz, 1-H), 6.77ꢀ6.78 (2H, m, 50-H and 20-H or 60-H), 6.88 (1H, d, J = 1.5
Hz, 20-H or 60-H) and 9.66 (1H, s, 4-H); δC (100 MHz; CDCl3) ꢀ5.2
and ꢀ4.5 (2 ꢁ CH3, SiCH3), 7.4 (CH3, C-3), 11.7 (CH3, C-2), 18.1 (q,
C(CH3)3), 25.8 (CH3, C(CH3)3), 40.5 (CH, C-3), 47.0 (CH, C-2), 55.8
(2 ꢁ CH3, OCH3), 77.4 (CH, C-1), 109.6 (CH, C-20 or C-60), 110.3
(CH, C-50), 119.5 (CH, C-20 or C-60), 136.0 (q, C-10), 148.3 and 148.8
(q, C-30 and C-40) and 205.7 (CdO, C-4); m/z (EI) 366 (M+, 2%), 309
(42), 281 (98), 234 (11), 151 (26), 83 (22), 73 (100) and 71 (49);
HRMS (EI) calcd for C20H34O4Si, 366.2226; found, 366.2224.
(1R,2R,3S,4S)-1,4-Bis(3,4-dimethoxyphenyl)-2,3-dimethyl-
1-(tert-butyldimethylsiloxy)butan-4-o1, 42. The reaction was
carried out according to general procedure A, using bromide 21 (0.14 g,
0.66 mmol) and tert-butyllithium (0.87 mL, 1.3 mmol, 1.5 M) with
aldehyde 41 (0.2 g, 0.55 mmol). A solvent mixture of 4:1 hexanes/ethyl
acetate was used for flash chromatography to give the title product (0.15
g, 54%) as a pale yellow oil. [R]D = +65.0 (c 4.1, CHCl3); νmax(neat)/
cmꢀ1 3541, 2955, and 2853 (CH), 1594 and 1512 (CdC), 1464, 1418,
1261, 1138, and 1029 (CꢀO), 859, 836, 776; δH (300 MHz; CDCl3)
ꢀ0.34 and ꢀ0.00 (2 ꢁ 3H, s, SiCH3), 0.56 (3H, d, J = 9.0 Hz, 3-CH3),
0.86 (9H, s, C(CH3)3), 1.04 (3H, d, J = 6.0 Hz, 2-CH3), 1.48 (1H, m,
3-H), 1.62 (1H, br s, 4-OH), 2.38 (1H, m, 2-H), 3.83 and 3.86 (each 6H,
s, OCH3), 4.26 (1H, d, J = 6.0 Hz, 4-H), 4.37 (1H, d, J = 9.0 Hz, 1-H) and
6.61ꢀ6.80 (6H, m, Ar-H); δC (75 MHz; CDCl3) ꢀ5.2 and ꢀ4.5 (2 ꢁ
CH3, SiCH3), 10.2 (CH3, C-2), 11.2 (CH3, C-3), 18.1 (q, C(CH3)3),
25.9 (CH3, C(CH3)3), 38.4 (CH, C-2), 41.8 (CH, C-3), 55.7, 55.7, 55.8,
and 55.9 (4 ꢁ CH3, OCH3), 78.0 (CH, C-4), 78.7 (CH, C-1), 109.2,
109.8, 110.2, and 110.6 (4 ꢁ CH, C-20 and C-50 and C-300 and C-600),
119.1 and 119.3 (2 ꢁ CH, C-200 and C-60), 136.5 and 137.1 (2q, C-10 and
C-100), 147.9, 148.4, and 149.1 (4q, C-30 and C-40 and C-400 and C-500);
m/z (EI) 504 (M+, 2%), 354 (77), 281 (86) and 73 (100); HRMS (EI)
calcd for C28H44O6Si, 504.2907; found, 504.2910.
2930, and 2856 (CH), 1609, 1509 (CdC), 1463, 1256, 1230, 1151,
1073, and 1004 (CꢀO) and 833; δH (400 MHz; CDCl3) ꢀ0.34 and
ꢀ0.01 (2 ꢁ 3H, s, SiCH3), 0.54 (3H, d, J = 7.2 Hz, 2-CH3), 0.87 (9H, s,
C(CH3)3), 1.02 (3H, d, J = 6.8 Hz, 3-CH3), 1.49 (1H, m, 2-H), 2.39
(1H, m, 3-H), 3.46 (3H, s, OCH2OCH3), 3.76 and 3.84 (2 ꢁ CH3, s,
OCH3), 4.24 (1H, d, J = 7.6 Hz, 1-H), 4.37 (1H, d, J = 8.8 Hz, 4-H), 5.15
(2H, s, OCH2O), 6.62ꢀ6.76 (3H, m, 20-H, 50-H and 60-H), 6.95 (2H, d,
J = 8.4 Hz, 300-H) and 7.15 (2H, d, J = 8.8 Hz, 200-H); δC (100 MHz;
CDCl3) ꢀ5.3 and ꢀ4.6 (2 ꢁ CH3, SiCH3), 10.2 (CH3, C-2), 11.1
(CH3, C-3), 18.1 (q, C(CH3)3), 25.8 (CH3, C(CH3)3), 38.3 (CH, C-3),
41.7 (CH, C-2), 55.7 (CH3, OCH3), 77.8 (CH, C-1), 78.2 (CH, C-4),
94.4 (CH2, OCH2O), 109.6 (CH, C-20), 110.1 (CH, C-50), 116.0 (CH,
C-300), 119.1 (CH, C-60), 127.9 (CH, C-200), 137.0 and 137.2 (2q, C-10
and C-100), 147.8 and 148.4 (2q, C-30 and C-40) and 156.5 (q, C-400);
m/z (ESI) 527 (MNa+, 100%), 355 (24), 235 (14); HRMS (ESI) calcd
for C28H44NaO6Si (MNa+), 527.2805; found, 527.2792.
(ꢀ)-Methoxymethyl pycnanthuligene A, 49. The reaction
was carried out according to general procedure E, using alcohol 47
(0.085 g, 0.17 mmol), reaction time was 90 min. A solvent mixture of 9:1
hexanes/ethyl acetate was used for flash chromatography to give the title
product (0.034 g, 61%) as a colorless oil. [R]D = ꢀ55 (c 0.2, CHCl3);
νmax(neat)/cmꢀ1 2957 (CH), 1606, 1506 (CdC), 1463, 1228, 1148,
1120, 1076, and 1002 (CꢀO), 921, 865; δH (400 MHz; CDCl3) 0.98
(3H, d, J = 8.0 Hz, 90-CH3), 1.68 (3H, s, 9-CH3), 2.25 (1H, m, 80-H),
3.35 (3H, s, OCH2OCH3), 3.59 (1H, d, J = 4.0 Hz, 70-H), 3.58 and 3.78
(2 ꢁ 3H, s, OCH3), 5.02 (2H, s, OCH2OCH3), 6.03 (1H, s, 7-H), 6.46
(1H, s, 3-H), 6.52 (1H, s, 6-H), 6.78 (2H, d, J = 8.0 Hz, 30-H and 50-H)
and 6.86 (2H, d, J = 8.0 Hz, 20-H and 60-H); δC (100 MHz; CDCl3) 18.8
(CH3, C-90), 22.2 (CH3, C-9), 42.1 (CH, C-80), 50.4 (CH, C-70), 55.9
and 55.9 (3 xCH3, OCH3), 94.5 (OCH2O), 109.0 (CH, C-6), 112.9
(CH, C-3), 116.0 (CH, C-30 and C-50), 121.1 (CH, C-7), 127.1 and
127.1 (2q, C-2 and C-8), 128.5 (CH, C-20 and C-60), 138.6 and 139.0
(2q, C-1 and C-10), 147.5 and 147.6 (2q, C-4 and C-5) and 155.5 (q,
C-40); m/z (ESI) 355 (MH+, 100%) and 338 (10); HRMS (ESI) calcd
for C22H27O4, 355.1904; found, 355.1913.
Cyclogalgravin, (ꢀ)-3. The reaction was carried out according to
general procedure E, using alcohol 42 (0.028 g, 0.056 mmol) and
extending the reaction time to 16 h. A solvent mixture of 4:1 hexanes/
ethyl acetate was used for flash chromatography to give the title product
(ꢀ)-Pycnanthuligene A, (ꢀ)-4. To a stirred solution of 2 M HCl
(5 mL) was added ether 49 (32 mg, 0.09 mmol) in methanol (5 mL),
and the mixture was stirred for 2 h. The solution was neutralized with 1
M NaOH (10 mL), the aqueous mixture was extracted with diethyl ether
(3 ꢁ 10 mL), the combined organic fractions were dried (MgSO4), and
the solvent was removed in vacuo. The crude product was purified by
flash chromatography (3:1 hexanes/ethyl acetate) to give the title
product (24 mg, 86%) as a colorless oil, which solidified upon standing.
[R]D = ꢀ41.0 (c 0.16, EtOH); [lit.5 [R]D = +33.8 (c 0.31, EtOH)]; δH
(400 MHz; CDCl3) 1.07 (3H, d, J = 8.0 Hz, 90-CH3), 1.77 (3H, s,
9-CH3), 2.34 (1H, dq J = 3.0, 7.1 Hz, 80-H), 3.68 (1H, m, 70-H), 3.77
(3H, s, 5-OCH3), 3.87 (3H, s, 4-OCH3), 4.95 (1H, br s, 40ꢀOH), 6.12
(1H, s, 7-H), 6.54 (1H, s, 3-H), 6.62 (1H, s, 6-H), 6.67 (2H, d, J = 8.0 Hz,
30-H) and 6.89 (2H, d, J = 8.0 Hz, 60-H); δC (100 MHz; CDCl3) 18.7
(CH3, C-90), 22.2 (CH3, C-9), 42.2 (CH, C-80), 50.3 (CH, C-70), 55.9
(2 ꢁ CH3, OCH3), 108.9 (CH, C-3), 112.9 and 115.0 (CH, C-20, C-60
and C-6), 121.1 (CH, C-7), 127.2 and 127.2 (2q, C-2 and C-8), 128.7
(CH, C-30 and C-50), 137.7 and 138.7 (2q, C-1 and C-10), 147.5 and
147.5 (2q, C-4 and C-5) and 153.8 (q, C-40); m/z (ESI) 333 (MNa+,
100%), 311 (MH+, 55) and 130 (15); HRMS (ESI) calcd for C20H23O3,
311.1642; found, 311.1642. All spectral data were in agreement with the
literature values with the exception of assignment of several carbons that
should be interchanged.5
(19 mg, 95%) as a colorless oil that solidified upon standing. [R]D
=
ꢀ128.0 (c 0.2, CHCl3) [lit.17 [R]D = ꢀ105.9 (c 1.07, CHCl3) lit. ent4b
[R]D = +135.5 (c 0.25, CHCl3)]; νmax(neat)/cmꢀ1 2996 and 2957,
2833, 1604, 1509 (CdC), 1463, 1262, 1229, 1141, 1120, 1028 (CꢀO),
869 and 759; δH (300 MHz; CDCl3) 1.08 (3H, d, J = 9.0 Hz, 90-CH3),
1.79 (3H, d, J = 3.0 Hz, 9-CH3), 2.40 (1H, m, 80-H), 3.67 (1H, d, J = 3.0
Hz, 70-H), 3.78 (6H, s, OCH3), 3.82 (3H, s, OCH3), 3.88 (3H, s,
OCH3), 6.14 (1H, s, 7-H), 6.54ꢀ6.57 (2H, m, 3-H and 60-H), 6.62 (1H,
s, 6-H), 6.66 (1H, d, J = 3.0 Hz, 20-H) and 6.72 (1H, d, J = 9.0 Hz, 50-H);
δC (75 MHz; CDCl3) 18.6 (CH3, C-90), 22.1 (CH3, C-9), 42.0 (CH,
C-80), 50.8 (CH, C-70), 55.7, 55.8, 55.9 (4 ꢁ CH3, OCH3), 108.9 (CH,
C-6), 110.9 (CH, C-50), 111.0 (CH, C-20), 112.8 (CH, C-3), 119.6 (CH,
C-60), 121.1 (CH, C-7), 127.1 (q, C-1), 127.3 (q, C-2), 138.1 (q, C-10),
138.8 (q, C-8), 147.3 (q, C-40), 147.5 (q, C-4), 147.6 (q, C-5), 148.6 (q,
C-30); m/z (ESI) 377 (MNa+, 100%), 372 (8), 355 (MH+, 12); HRMS
(ESI) calcd for C22H27O4, 355.1904; found, 355.1904. All spectral data
were in agreement with the literature values.4b
(1R,2R,3S,4S)-1-(3,4-Dimethoxyphenyl)-2,3-dimethyl-4-(4-
methoxymethoxyphenyl)-1-(tert-butyldimethylsiloxy)butan-
4-o1, 47. The reaction was carried out according to general procedure
A, using 1-bromo-4-(methoxymethoxy)benzene (0.1 g, 0.47 mmol) and
tert-butyllithium (0.63 mL, 0.95 mmol, 1.5 M) with aldehyde 41 (0.15 g,
0.40 mmol). A solvent mixture of 3:1 hexanes/ethyl acetate was used for
flash chromatography to give the title product (0.12 g, 60%) as a yellow
oil. [R]D = +53 (c 1.0, CHCl3); νmax(neat)/cmꢀ1 3509 (OH), 2956,
(1R,2R,3S,4S)-1-(3,4-Dimethoxyphenyl)-2,3-dimethyl-
4-(4,5-methylenedioxyphenyl)-1-(tert-butyldimethylsiloxy)
butan-4-o1, 48. The reaction was carried out according to general
procedure A, using 1-bromo-3,4-(methylenedioxy)benzene (0.48 g, 2.3
mmol) and tert-butyllithium (3.1 mL, 4.6 mmol, 1.5 M in pentane) with
aldehyde 41 (0.8 g, 2.1 mmol). A solvent mixture of 4:1 hexanes/ethyl
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ARTICLE
acetate was used for flash chromatography to give the title product
(0.588 g, 59%) as a pale yellow oil. [R]D = +68 (c 1.2, CHCl3);
νmax(neat)/cmꢀ1 3519 (OH), 2956, 2857 (CH), 1721, 1594 (CdC),
1486, 1243, 1137, and 1038 (CꢀO), 935, 835, 734 ;δH (400 MHz;
CDCl3) ꢀ0.33 and ꢀ0.00 (2 ꢁ 3H, s, SiCH3), 0.56 (3H, d, J = 4.0 Hz,
3-CH3), 0.87 (9H, s, C(CH3)3), 1.01 (3H, d, J = 4.0 Hz, 2-CH3), 1.51
(1H, m, 3-H), 2.34 (1H, m, 2-H), 3.78 and 3.85 (2 ꢁ 3H, s, OCH3),
4.26 (1H, d, J = 8.0 Hz, 4-H), 4.33 (1H, d, J = 8.0 Hz, 1-H), 5.93 (2H, m,
OCH2O) and 6.60ꢀ6.86 (6H, m, Ar-H); δC (100 MHz; CDCl3) ꢀ5.2
and ꢀ4.6 (2 ꢁ CH3, SiCH3), 10.4 (CH3, C-2), 11.4 (CH3, C-3), 18.1
(q, C(CH3)3), 25.8 (CH3, C(CH3)3), 38.4 (CH, C-2), 41.7 (CH, C-3),
55.6 and 55.8 (2 ꢁ CH3, OCH3), 77.9 (CH, C-4), 78.5 (CH, C-1),
100.9 (CH2, OCH2O), 107.1, 107.8, 109.6, and 110.2 (4 ꢁ CH, C-20
and C-50 and C-300 and C-600), 119.0 and 120.3 (2 ꢁ CH, C-200 and
C-60), 137.0 and 137.9 (2q, C-10 and C-100), 146.8, 147.7, 147.8, and
148.5 (4q, C-30, C-40, C-400 and C-500); m/z (ESI) 527 (MK+, 25%), 511
(MNa+, 56), 489 (MH+, 10), 357 (100) and 399 (75); HRMS (ESI)
calcd for C27H41O6Si, 489.2667; found, 489.2671.
(ꢀ)-Pycnanthuligene B, (ꢀ)-5. The reaction was carried out
according to general procedure E, using alcohol 48 (0.27 g, 0.55 mmol).
Reaction time was 45 min, and 4:1 hexanes/ethyl acetate was used for
flash chromatography to give initially the title product (0.17 g, 90%) as a
pale yellow oil. [R]D = ꢀ100.0 (c 0.58, EtOH); [lit.5 [R]D = +118.5 (c
0.34, EtOH)]; νmax(neat)/cmꢀ1 2959 and 2902 (CH), 1605, 1503
(CdC), 1484, 1226, 1148, 1120, and 1035 (CꢀO), 935, 868, 810; δH
(400 MHz; CDCl3) 1.07 (3H, d, J = 8.0 Hz, 90-CH3), 1.78 (3H, s,
9-CH3), 2.34 (1H, m, 80-H), 3.65 (1H, d, J = 3.0 Hz, 70-H), 3.79 (3H, s,
4-OCH3), 3.88 (3H, s, 5-OCH3), 5.86 (2H, s, OCH2O), 6.13 (1H, s,
7-H) and 6.50ꢀ6.68 (5H, m, Ar-H); δC (100 MHz; CDCl3) 18.8 (CH3,
C-90), 22.2 (CH3, C-9), 42.2 (CH, C-80), 50.8 (CH, C-70), 55.9 (2 ꢁ
CH3, OCH3), 100.7 (CH2, OCH2O), 107.9 (CH, C-50), 108.1 (2 ꢁ
CH, C-60 and C-20), 109.9 (CH, C-3), 112.8 (CH, C-6), 121.1 (CH,
C-7), 127.0 and 127.0 (q, C-1 and C-2), 138.6 (q, C-10), 139.7 (q, C-8),
145.7 (q, C-40), 147.4 (q, C-30), 147.6 and 147.7 (q, C-4 and C-5); m/z
(ESI) 361 (MNa+, 100%), 339 (M+, 39), 217 (11); HRMS (ESI) calcd
for C21H23O4, requires 339.1591; found, 339.1582. All spectral data
were in agreement with the literature values.5 The unstable intermediate
7-tert-butyldimethylsilyl-pycnanthuligene B 50 (19 mg, 5%) was also
obtained but was converted in quantitative yield to (ꢀ)-5 upon standing
in CDCl3 for 5 h. δH (400 MHz; CDCl3) 0.04 and 0.14 (2 ꢁ 3H, s, Si-
CH3), 0.83 (12H, m, C(CH3)3 and 9 or 90-CH3), 1.01 (3H, d, J = 8.0 Hz,
9 or 90-CH3), 1.56 (1H, m, 8-H), 2.06 (1H, m, 80-H), 3.24 (1H, d, J = 8.0
Hz, 70-H), 3.60ꢀ3.84 (6H, m, 4-OCH3 and 5-OCH3), 4.48 (1H, m,
7-H), 5.86 (2H, s, OCH2O) and 6.57ꢀ6.71 (6H, m, Ar-H); m/z (ESI)
471 (NaH+, 5%), 339 (M+ pycnanthuligene B, 100), 201 (19); HRMS
(ESI) calcd for C27H39O5Si, 471.2561; found, 471.2564.
139.5 and 140.1 (q, C-10 and C-100), 144.8 (CH, C-4), 147.2, 147.3,
148.4, and 148.4 (4q, C-30, C-40, C-300 and C-400); m/z (ESI) 409
(MNa+, 100%), 369 (15), 140 (11); HRMS (ESI) calcd for
C23H30NaO5, 409.1985; found, 409.1987.
(2S,3R)-1,1-Bis(3,4-dimethoxyphenyl)-2,3-dimethyl-4-pen-
tene, 52, and (3R)-1,1-Bis(3,4-dimethoxyphenyl)-2,3-di-
methylpent-1,4-diene, 53. To a solution of alcohol 51 (0.19 g,
0.49 mmol) in DCM (65 mL) under an atmosphere of nitrogen at 0 °C
was added triethylsilane (0.63 mL, 3.9 mmol) followed by BF3 OEt2
3
(0.24mL, 2.0mmol). Theresultant solutionwasstirredat0°Cfor 30min.
NH4Cl solution (30 mL) was added, the layers were separated, the
aqueous layer was further extracted with DCM (3 ꢁ 20 mL) and dried
(MgSO4), and the solvent was removed in vacuo. The crude product was
purified by flash chromatography (2:3 diethyl ether/hexanes) to give 52
(0.18 g, 91%) as a yellow oil. [R]D = ꢀ27 (c 3.0, CHCl3); νmax(neat)/
cmꢀ1 2961 and 2935 (CH), 2254, 1601, 1509 (CdC), 1441, 1245, 1166,
and 1026 (CꢀO), 908, 646; δH (400 MHz; CDCl3) 0.70 (3H, d, J = 8.0
Hz, 2-CH3), 0.87 (3H, d, 8.0Hz, 3-CH3), 2.28 (1H, m, 3-H), 2.39(1H, m,
2-H), 3.56 (1H, d, J = 12.0 Hz, 1-H), 3.82, 3.83, and 3.86 (12H, s, OCH3),
4.95 (2H, m, 5-CH2), 5.84 (1H, m, 4-H), 6.76ꢀ6.86 (6H, m, Ar-H); δC
(100 MHz; CDCl3) 11.1 (CH3, C-2), 12.2 (CH3, C-3), 37.2 (CH, C-3),
40.7 (CH, C-2), 55.7 (4 ꢁ CH3, OCH3), 111.1 and 111.2 (CH, C-50 and
C-500 or C-60 and C-600), 112.5 and 112.9 (CH, C-20 and C-200), 113.4
(CH2, C-5), 119.5 and 119.7 (CH, C-50 and C-500 or C-60 and C-600),
135.9 and 136.3 (q, C-10 and C-100), 137.2 (q, C-1), 144.3 (CH, C-4),
147.1, 147.3, 148.7, and 148.8 (q, C-30, C-40, C-400 and C-500); m/z (ESI)
393 (MNa+, 35%), 391 (100), 369 (18); HRMS (ESI) calcd for
C23H30NaO , 393.2036; found, 393.2027. Diene 53 (8 mg, 4%) as a
4
yellow oil was obtained in a second fraction. δH (400 MHz; CDCl) 1.12
(3H, d, J = 8.0 Hz, 3-CH3), 1.66 (3H, s, 2-CH3), 3.35 (1H, m, 3-H), 3.81
(12H, s, OCH3), 5.02 (2H, m, 5-CH2), 5.91(1H, m, 4-H), 6.59 (1H, d, J=
4.0 Hz, 20-H or 200-H), 6.65ꢀ6.67 (3H, m, 60-H, 600-H and 20-H or 200-H)
and 6.83 (2H, d, J = 8.0 Hz, 50-H and 500-H); δC (100 MHz; CDCl3) 14.9
(CH3, C-2), 17.9 (CH3, C-2), 40.8 (CH, C-3), 55.8 and 55.9 (CH3, all
OCH3), 111.8 and 112.2 (CH, C-50 and C-500 or C-60 and C-600), 113.4,
113.7, and 113.9 (CH and CH2, C-20, C-200 and C-5), 122.2 and 122.7
(CH, C-50 and C-500 or C-60 and C-600), 135.4 and 135.5 (q, C-10 and
C-100), 136.3 and 137.5 (q, C-1 and C-2), 142.4 (CH, C-4), 143.9, 144.0,
145.9, and 146.0 (q, C-30, C-300, C-40 and C-400); m/z (ESI) 391 (NaM+,
100%), 369 (11); HRMS (ESI) calcd for C23H28NaO4, 391.1885; found,
391.1883.
(2R,3S)-1,1-Bis(3,4-dimethoxyphenyl)-2,3-dimethyl-4-bu-
tanal. Beginning from alkene 52 (0.176 g, 0.48 mmol) dihydroxylation
according to general procedure C after flash chromatography using 9:1
DCM/methanol gave the corresponding diol (0.19 g, 94%) as a yellow
oil. The diol then underwent a periodate cleavage reaction, according to
general procedure D. A solvent mixture of 3:1 ethyl acetate/hexanes was
used for flash chromatography to give the title product (0.164 g, 91%) as
a pale yellow oil. [R]D = ꢀ51.0 (c 3.32, CHCl3); νmax(neat)/cmꢀ1 2933
and 2836 (CH), 1720 (CdO), 1590, 1510 (CdC) 1463, 1262, 1143,
1027 (CꢀO), 857, 748; δH (300 MHz; CDCl3) 0.72 (3H, d, J = 8.0 Hz,
2-CH3), 1.05 (3H, J = 8.0 Hz, 3-CH3), 2.39 (1H, m, 3-H), 3.00 (1H, m,
2-H), 3.56 (1H, d, J = 8.0 Hz, 1-H), 3.83, 3.84, 3.86, and 3.88 (12H, s,
OCH3), 6.79ꢀ6.89 (6H, m, Ar-H) and 9.65 (1H, s, 4-H); δC (100 MHz;
CDCl3) 6.5 (CH3, C-3), 13.7 (CH3, C-2), 35.6 (CH, C-2), 47.6 (CH,
C-3), 55.4, 55.8, and 55.9 (4 ꢁ CH3, OCH3), 111.0, 111.2, 111.3, and
111.5 (CH, C-20, C-200, C-50 and C-500), 119.4 and 119.6 (CH, C-60 and
C-600), 136.2 (q, C-10 and C-100), 148.1 and 148.4 (q, C-30 and C-300),
205.4 (CdO, C-4); m/z (ESI) 395 (NaM+, 100%), 373 (MH+, 8), 301
(3), 235 (3); HRMS (ESI) calcd for C22H29O5, 373.2010; found,
373.2013.
(2S,3R)-1,1-Bis(3,4-dimethoxyphenyl)-2,3-dimethylpent-
4-ene-1-ol, 51. The reaction was carried out according to general
procedure A, using 21 (1.93 g, 8.9 mmol) and tert-butyllithium
(11.8 mL, 18 mmol, 1.5 M) with ketone 22 (2.0 g, 8.0 mmol). A solvent
mixture of 4:1 hexanes/ethyl acetate was used for flash chromatography
to give the title product (2.1 g, 68%) as a yellow oil. [R]D = ꢀ17.0 (c 3.5,
CHCl3); νmax(neat)/cmꢀ1 3535 (OH), 2960 and 2936 (CH), 2256,
1591, and 1508 (CdC), 1463, 1252, and 1235 (CꢀO), 1138 and 1025,
911, 852, 805 and 762; δH (400 MHz; CDCl3) 0.96 (3H, d, J = 4.0 Hz,
3-CH3), 1.09 (3H, d, J = 8.0 Hz, 2-CH3), 2.51 (1H, m, 3-H), 2.81 (1H,
dd, J = 2.0, 8.0 Hz, 2-H), 3.95 (12H, m, 4 ꢁ OCH3), 5.03 (2H, m,
5-CH2), 5.97 (1H, m, 4-H), 6.89ꢀ6.93 (2H, m, 50-H and 500-H), 7.10
(1H, t, J = 4.0 Hz, 60-H or 600-H), 7.12 (1H, t, J = 4.0 Hz, 60-H or 600-H),
7.17 (1H, d, J = 2.0 Hz, 20-H or 200-H) and 7.20 (1H, d, J = 2.0 Hz, 20-H or
200-H); δC (100 MHz; CDCl3) 9.1 (CH3, C-3), 14.5 (CH3, C-2), 36.9
(CH, C-3), 43.6 (CH, C-2), 55.6 and 55.7 (4 ꢁ CH3, OCH3), 81.5 (q,
C-1), 109.2 and 109.3 (CH, C-20 and C-200), 110.5 and 110.6 (CH, C-50
and C-500), 112.1 (CH2, C-5), 117.5 and 117.7 (CH, C-60 and C-600),
(ꢀ)-Kadangustin J, (ꢀ)-8. To a solution of (2R,3S)-1,1-bis(3,4-
dimethoxyphenyl)-2,3-dimethyl-4-butanal (0.16 g, 0.43 mmol) in
methanol (5 mL) at ꢀ78 °C was added sodium borohydride (0. 64 mg,
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1.7 mmol), and the resulting suspension was stirred under an atmo-
sphere of nitrogen at room temperature for 3 h. Water (5 mL) was
added, and the methanol was removed in vacuo. Further water (5 mL)
was added to the residue, and the crude product was extracted with ethyl
acetate (3 ꢁ 15 mL). The combined organic extracts were dried
(MgSO4), the solvent was removed in vacuo, and the crude product
was purified by flash chromatography (1:1 ethyl acetate/hexanes) to
give the title product (0.150 g, 93%) as a colorless oil that solidified upon
standing. [R]D = ꢀ20.7 (c 1.19, MeOH); [lit.8 [R]D = +4.9 (c 0.171,
MeOH)]; νmax(neat)/cmꢀ1 3222 (OH), 2959, 2939 (CH), 1591, 1514
(CdC), 1463, 1417, 1262, 1143, 1028 (CꢀO), 747; δH (400 MHz;
CDCl3) 0.68 (3H, d, 8.0 Hz, 9-CH3), 0.74 (3H, d, J = 4.0 Hz, 90-CH3),
1.75 (1H, m, 80-H), 2.60 (1H, m, 8-H), 3.45 (2H, m, 70-CH2), 3.52 (1H,
d, J = 12.0 Hz, 7-H), 3.80 (6H, s, OCH3), 3.84 and 3.85 (6H, s, OCH3),
and 6.74ꢀ6.88 (6H, m, Ar-H); δC (100 MHz; CDCl3) 9.5 (CH3, C-90),
11.7 (CH3, C-9), 35.8 (CH, C-8), 35.9 (CH, C-80), 55.7 and 55.7 (4 ꢁ
CH3, OCH3), 77.2 (CH, C-7), 66.8 (CH2, C-70), 111.1, 111.2, and 111.3
(CH, C-5, C-50, C-6 and C-60), 119.5 and 119.6 (C-2 and C-20), 137.1
and 137.6 (q, C-1 and C-10), 147.1 (q, C-4 and C-40), 148.7 and 148.8 (q,
C-3 and C-30); m/z (ESI) 397 (MNa+, 100%), 287 (2), 255 (3), 237 (6);
HRMS (ESI) calcd for C22H30NaO5, 397.1985; found, 397.1988. All
spectral data were in agreement with the literature values with the
exception of assignment of several carbons that should be interchanged.8
(7) (a) Cavalcante, S. H.; Yoshida, M.; Gottlieb, O. R. Phytochemistry
1985, 24, 1051. (b) Jing, X.-B.; Gu, W. X.; Bie, P. Y.; Ren, X. F.; Pan, X. F.
Chin. Chem. Lett. 2000, 11, 875. (c) Dias, S. M. C.; Fernandes, J. B.; Maia,
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’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
compounds (+)-1, (ꢀ)-3, (ꢀ)-4, (ꢀ)-5, (ꢀ)-8, (R,S)-9, 15, 20,
22ꢀ25, 32ꢀ36, 39ꢀ42, and 47ꢀ52. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: d.barker@auckland.ac.nz.
’ ACKNOWLEDGMENT
The authors wish to thank the Royal Society of New Zealand,
Marsden Fund for funding this research and the University of
Auckland for additional financial assistance and a doctoral
scholarship for C.E.R.
’ REFERENCES
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