Synthesis of (+)-myrtopsine, (+)-7,8-dimethoxymyrtopsine, and related 2,3-dihydro-3-hydroxy-2-(1-hydroxy-1-methyl-ethyl)benzofuran natural products

Article abstract of DOI:10.3987/com-06-s(w)20

The first syntheses of myrtopsine (8t) and 7,8-dimethoxymyrtopsine (9t) have been carried out by halogen-metal exchange of 3-iodo-4-methoxy-quinolin-2(1H)-ones (15) and (21) with i-PrMgCl followed by addition of 3,3-dimethyloxirane-2-carboxaldehyde (1). A two-step sequence leads selectively to trans-2,3-dihydro-3-hydroxy-2-(1-hydroxy-1-methylethyl)benzofurans (7t), (8t), (9t), (28), and (32) by conversion of a 2-iodophenol or a 3-iodo-4-methoxyquinolin-2(1H)-one to an aryl Grignard reagent and addition of 3-methyl-2-butenal, followed by threo selective epoxidation of the resulting allylic alcohol and cyclization with inversion.

Full text of DOI:10.3987/com-06-s(w)20

HETEROCYCLES, Vol. 70, 2006
279
HETEROCYCLES, Vol. 70, 2006, pp. 279 - 294. © The Japan Institute of Heterocyclic Chemistry
Received, 28th July, 2006, Accepted, 12th September, 2006, Published online, 15th September, 2006. COM-06-S(W)20
SYNTHESIS OF (+)-MYRTOPSINE, (+)-7,8-DIMETHOXYMYRTOPSINE,
AND RELATED 2,3-DIHYDRO-3-HYDROXY-2-(1-HYDROXY-1-METHYL-
ETHYL)BENZOFURAN NATURAL PRODUCTS
Barry B. Snider* and Xiaoxing Wu
Department of Chemistry MS 015, Brandeis University, Waltham, MA
02454-9110, USA. e-mail: snider@brandeis.edu
Abstract – The first syntheses of myrtopsine (8t) and 7,8-dimethoxymyrtopsine
(9t) have been carried out by halogen-metal exchange of 3-iodo-4-methoxy-
quinolin-2(1H)-ones (15) and (21) with i-PrMgCl followed by addition of 3,3-
dimethyloxirane-2-carboxaldehyde (1). A two-step sequence leads selectively
to trans-2,3-dihydro-3-hydroxy-2-(1-hydroxy-1-methylethyl)benzofurans (7t),
(8t), (9t), (28), and (32) by conversion of a 2-iodophenol or a 3-iodo-4-
methoxyquinolin-2(1H)-one to an aryl Grignard reagent and addition of
3-methyl-2-butenal, followed by threo selective epoxidation of the resulting
allylic alcohol and cyclization with inversion.
INTRODUCTION
We recently reported two practical one-step syntheses of 2,3-dihydro-3-hydroxy-2-(1-hydroxy-1-
methylethyl)benzofurans from readily available α,β-epoxy aldehyde (1).1 The first route involves the
reaction of electron-deficient resorcinols with epoxy aldehydes using either Cs2CO3 in DMF or
KOH/CaCl2 in MeOH. For instance, reaction of epoxy aldehyde (S)-(1) with resorcinol (2), CaCl2, and
KOH in MeOH for 1 d afforded epoxy alcohol (3), which cyclized to brosimacutin G (4t) in 47% yield
and the cis isomer (4c) in 43% yield (see Scheme 1). The second route involves the reaction of 1 with a
2-acetoxyaryl Grignard reagent. For instance, halogen-metal exchange of iodoacetoxy coumarin (5)
with i-PrMgCl in THF at -100 °C by Knochel’s procedure2 gave the Grignard reagent, which was treated
with (S)-1 and warmed to 25 °C to complete the first synthesis of vaginol (7t) in 19% yield and vaginidiol
(7c) in 21% yield via epoxy alcohol (6). Smyrindiol, xanthoarnol and avicenol A were prepared
similarly.1
____________________________________________________________________________________
This paper is dedicated to Prof. Steven M. Weinreb on the occasion of his 65th birthday.

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HETEROCYCLES, Vol. 70, 2006
OH
OH
OH
CaCl2/KOH
MeOH, 1 d
O
HO
HO
CHO
O
O
HO
HO
O
(S)-1
OH
O
HO
OH
O
2
H
OH
3
4c, α-OH (43%)
4t, β-OH (47%)
(brosimacutin G)
i-PrMgCl
THF, -100 °C
40 min
O
O
HO
O
O
O
AcO
O
O
OH
I
O
OH
(S)-1
HO
CHO
O
5
7c, β-OH (vaginidiol, 21%)
7t, α-OH (vaginol, 19%)
warm to 25 °C
6
Scheme 1. Synthesis of brosimacutin G (4t), vaginidiol (7c), and vaginol (7t)
Two related natural products myrtopsine (8t)3-5 and 7,8-dimethoxymyrtopsine (9t)6-7 with the
2,3-dihydro-3-hydroxy-2-(1-hydroxy-1-methylethyl)furans linearly fused to a 4-methoxyquinoline have
been reported (see Scheme 2). Myrtopsine was isolated from Myrtopsis sellingii3,4 and Halophyllum
foliosum,5 while 7,8-dimethoxymyrtopsine was isolated from Dutaillyea Bauduinii6 and Melicope
semecarpifolia7 and shown to have significant antiplatelet aggregation activity in vitro.7 We decided to
explore whether either of the above two routes could be used to prepare these natural products.
OMe
OH
OMe
N
OH
OH
OH
O
MeO
N
O
OMe
8t (myrtopsine)
9t (7,8-dimethoxymyrtopsine)
Scheme 2.

HETEROCYCLES, Vol. 70, 2006
281
RESULTS AND DISCUSSION
Reaction of 4-hydroxy-quinolin-2(1H)-one (10), 1.1 equiv of (±)-1,8 1.1 equiv of CaCl2 and 1-2 equiv of
KOH in MeOH for 3 d at 25 °C followed by flash chromatography on silica gel gave 6% of 11c and 17%
of 2:1 mixture of 11t and 12t (see Scheme 3). Reverse phase HPLC gave pure 11t and 12t. The
stereochemistry was assigned based on the 6.4 Hz vicinal coupling constant in cis isomer (11c) and 3.7
Hz and 3.1 Hz coupling constants in trans isomers (11t) and (12t), respectively.1 H5 in the linear isomer
(12t) absorbs at δ 8.24 while H5 in the angular isomers (11c) and (11t) absorb at δ 7.81 and 7.85
respectively, as observed in related systems.9 Treatment of 11c with 20:1 CH2Cl2/TFA for 40 min at
25 °C afforded furoquinoline (13) in 98% yield by an acid catalyzed fragmentation.1 The trans isomer
(11t) reacted about twice as fast to give 13 cleanly. The spectral data of 13 are identical to those
previously reported,10 and quite different from those of the linear analogue.11 This establishes that the
major products (11c) and (11t) are angularly fused and that only the minor product (12t) has the correct
linearly fused geometry needed for the preparation of myrtopsine. Reaction of 4-hydroxy-
quinolin-2(1H)-one (10), 1.1 equiv of (±)-1,8 1.1 equiv of Cs2CO3 in DMF for 3 d at 25 °C proceeded in
even poorer yield giving only 3% of 11c, 3% of a 2:1 mixture of 11t and 12t, and 8% of an
uncharacterized 2:1 adduct. The failure of this direct route to provide practical quantities of 12t led us to
explore the second route using 3-iodo-4-methoxy-quinolin-2(1H)-one (15). Introduction of the methyl
group before the coupling step will preclude the formation of the undesired angular products (11).
H5
O
OH
OH
OH
OH
H5
O
OH
CaCl2/KOH
MeOH, 3 d
O
+
O
O
+
N
H
N
H
O
N
O
(±)-1
H
12t, β-OH (3.7%)
11c, α-OH (6%)
11t, β-OH (10%)
10
20:1 CH2Cl2/TFA, 25 °C
20 min for 11t
O
40 min for 11c
N
H
O
13 (98%)
Scheme 3. Conversion of 1 and 10 to 11 and 12
This second approach provides a very direct route to myrtopsine. Iodination of 4-hydroxy-quinolin-
2(1H)-one (10) with iodine in aqueous dioxane by the literature procedure11 afforded 14 in 83% yield (see
Scheme 4). Reaction of 14 with excess diazomethane in EtOH for 3 h at 25 °C as previously
described13,14 provided the desired aryl iodide (15) in 52% yield. i-PrMgCl (3 equiv) was added to a

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HETEROCYCLES, Vol. 70, 2006
solution of 15 in THF at -30 °C and the solution was stirred for 10 min to effect halogen-metal exchange.2
Epoxy aldehyde (±)-(1) (3.1 equiv) was added and the solution was stirred for 30 min to give myrtopsine
(8t) in 35% yield, the cis isomer (8c) in 25% yield and byproduct (16)15 resulting from protonation of the
intermediate aryl Grignard reagent in 27% yield. The stereochemistry was assigned based on a vicinal
coupling constant of 1.8 Hz in 8t and 5.5 Hz in 8c as expected.1 At least two equivalents of Grignard
reagent are needed since reaction with the NH consumes one equivalent. We found that optimal results
were obtained using three equivalents of both i-PrMgCl and epoxy aldehyde. Comparable or worse
yields were obtained by using one equivalent of MeMgBr or PhMgCl to deprotonate 15, followed by one
equivalent of i-PrMgCl to effect halogen-metal exchange.2 Apparently, deprotonation of the NH with
i-PrMgCl is faster than halogen-metal exchange. Preparation of the Grignard reagent from 5 must be
carried out at -100 °C because it contains an aryl acetate.1 The Grignard reagent formed from 15 is more
stable and can be prepared at -30 °C. A similar reaction with (R)-116 gave (+)-myrtopsine (8t, [α]D
+10.4°) in 35% yield and 8c, ([α]D -100.4°) in 26% yield. Therefore natural myrtopsine ([α]D -5.0°)2 is
the enantiomer of 8t.
OMe
OH
OH
Na2CO3/H2O
I2/dioxane
reflux
CH2N2, EtOH
25 °C, 3 h
I
I
N
O
N
H
O
N
H
O
H
1) i-PrMgCl, THF
-30 °C, 10 min
O
14
10
(83%)
15
(52%)
(±)- or (R)-1
2)
O
-30 °C, 0.5 h
OH
OMe
OMe
N
OMe
OMe
MsCl, NEt3
CH2Cl2, 1 h
+
OH
+
OH
N
H
O
O
O
O
N
N
8t
)
(from
α
8c, -OH (25-26%)
8t, -OH (myrtopsine, 35%)
16
(27%)
18 (41%)
17
(dictamnine, 19%)
β
Scheme 4. Preparation of myrtopsine (8t)
We were quite surprised to find that 8t did not undergo acid catalyzed fragmentation to afford dictamnine
(17) as we had observed in the efficient conversion of 11 to 13 above. Fragmentation is initiated by
protonation of the secondary alcohol. The 4-methoxyquinoline moiety of 8 is much more basic than the
quinolin-2(1H)-one of 11.17 Apparently, protonation of 8 on the nitrogen prevents the fragmentation
because protonation of the secondary alcohol would form an unstable dication. Conversion of the
secondary alcohol of 8 to a good leaving group should permit this fragmentation to proceed under the
basic conditions that are standard for Grob fragmentations. Treatment of 8t with 2 equiv of Et3N and 1

HETEROCYCLES, Vol. 70, 2006
283
equiv of MsCl in CH2Cl2 for 1 h afforded dictamnine (17) in 19% yield and the elimination product (18)
in 41% yield. The spectral data for dictamnine did not correspond with those reported,18 but fit exactly
with those of a commercial sample.19 The spectral data of 18 fit well with the literature data except for
slight systematic differences due to sample referencing.14 Although the conversion of 8 to 17 and 18 is
not efficient, it serves to correlate these compounds confirming that they are all linearly fused.
Reaction of 2,3-dimethoxyaniline with malonic acid and POCl3 afforded 4-hydroxy-7,8-di-
methoxy-2-quinolone (19),20 which was treated with iodine in aqueous dioxane to give iodoquinolone
(20) in 66% yield (see Scheme 5). Reaction with diazomethane in ethanol gave 7,8-dimethoxy-
myrtopsine precursor (21) in 56% yield and the bis methylated product 3-iodo-2,4,7,8-
tetramethoxyquinoline in 14% yield.
OMe
OH
OH
Na2CO3/H2O
I2/dioxane
reflux
CH2N2, EtOH
25 °C, 40 min
I
I
MeO
N
H
O
MeO
N
H
O
MeO
N
H
O
OMe
OMe
OMe
19
21 (56%)
20 (66%)
Scheme 5. Preparation of 21
Reaction of 21 in THF at -30 °C with 3 equiv of i-PrMgCl for 20 min followed by the addition of 3 equiv
of epoxy aldehyde (1) afforded 7,8-dimethoymyrtopsine (9t)6,7 in 28% yield, the cis analogue (9c) in 10%
yield, and dihydropyran derivative (23c) in 10% yield (see Scheme 6). The stereochemistry was
OMe
OH
OMe OH
OH
1) i-PrMgCl, THF
O
OMe
O
-30 °C, 20 min
MeO
N
MeO
N
O
I
O
OMe
H
OMe
2)
22t
9t
(7,8-dimethoxymyrtopsine, 28%)
O
MeO
N
H
O
(±)- or (R)-1
OMe
OH
OMe
-30 °C, 0.5 h
OMe OH
21
OH
O
O
MeO
N
MeO
N
O
OMe
H
9c (10%)
OMe OH
OMe
22c
OH
MeO
N
O
OMe
23c
(10%)
Scheme 6. Preparation of 7,8-dimethoxymyrtopsine (9t)

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HETEROCYCLES, Vol. 70, 2006
assigned based on a vicinal coupling constant of 2.4 Hz in 9t and 6.1 Hz in 9c as expected.1 The
reported coupling constant for 7,8-dimethoxymyrtopsine is 3.0 Hz6 indicating that it is the trans isomer,
although it has been assigned as the cis isomer based on NOE studies.7 The cis stereochemistry of 23c
follows from the 4.3 Hz vicinal coupling constant.21 Halogen-metal exchange of 21 and addition to
epoxy aldehyde (1) gives a mixture of 22t, which cyclizes to give 9t, and 22c, which cyclizes to give a
mixture of 9c and 23c. In all the other cases we have examined, only the dihydrofurans are formed. It
is not clear why 22c gives both dihydrofuran (9c) and dihydropyran (23c). A similar reaction with
(R)-116 gave (+)-7,8-dimethoxymyrtopsine (9t, [α]D +17.0°) in 26% yield, 9c ([α]D -53.9°) in 9% yield,
and 23c ([α]D -4.6°) in 10% yield. Therefore natural 7,8-dimethoxymyrtopsine ([α]D +16.2°)7 is 9t.
Methyl 2,3-dihydro-3-hydroxy-2-(1-hydroxy-1-methylethyl)-benzofuran-5-carboxylate (28) was recently
isolated from Piper hispidum.22 We attempted unsuccessfully to prepare it from the reaction of
iodophenol (24) with i-PrMgCl and epoxy aldehyde (1). Knochel has recently shown that halogen-metal
exchange can be carried out on free iodophenols using 1 equiv of MeMgBr and 1 equiv of LiCl in THF
at -30 °C to generate the lithium phenoxide followed by treatment with 1 equiv of i-PrMgCl in THF
at -30 °C to generate the aryl Grignard reagent.23 Unfortunately, reaction of 24 with MeMgBr, LiCl and
then i-PrMgCl, followed by epoxy aldehyde (1) also failed to give 28 in acceptable yields. Since
Knochel had shown that the Grignard reagent prepared from 24 adds to benzaldehyde in 62% yield under
these conditions,23b we thought that epoxy aldehyde (1) might be incompatible with the LiCl or lithium
phenoxide. We therefore decided to use 3-methyl-2-butenal (25) instead of 1 and to epoxidize the allylic
alcohol after the coupling reaction.
Iodophenol (24) was treated with 1 equiv of MeMgBr and 1 equiv of LiCl in THF at -30 °C for 30 min.
1 equiv of i-PrMgCl was added and the solution was stirred for 30 min and treated with 1 equiv of 25 and
stirred for 1 h to give the unstable crude allylic alcohol (26) (see Scheme 7). Flash chromatography
gave a complex mixture including the 2,2-dimethyl-2H-chromene formed by dehydrative cyclization.24
Fortunately, treatment of crude 26 with 1 equiv of m-CPBA and 1.5 equiv of NaHCO3 in CH2Cl2 effected
oxidation to give 27 and cyclization to give 28 in 56% overall yield from 24. m-CPBA epoxidation of
1) MeMgBr, THF
-30 °C, 30 min
2) i-PrMgCl, 30 min
OH
OH
OH
OH
OH
m-CPBA/NaHCO3
CH2Cl2
MeO2C
I
MeO2C
MeO2C
O
OH
25
3)
27
24
O
26
-30 °C, 1 h
MeO2C
OH
O
28
(48-56%)
Scheme 7. Preparation of 28

HETEROCYCLES, Vol. 70, 2006
285
allylic alcohols with the substitution pattern of 26 is threo selective,25 so that epoxidation of 26 gives
mainly 27 which cyclizes with inversion to give the trans-dihydrobenzofuran (28). A similar sequence
omitting the LiCl in the formation of 26 gave 28 in 48% overall yield.
The one-step procedure using epoxy aldehyde (1) provides a diastereomeric mixture of alcohols such as
22c and 22t, which leads to mixtures of cis- and trans-dihydrofurans. However, this procedure can be
used to prepare optically pure products starting from optically pure epoxy aldehyde (1).1,16 The two-step
sequence starting with α,β-unsaturated aldehyde (25) to give an allylic alcohol such as 26, which
undergoes a threo-selective cyclization to give 27, gives only the trans-dihydrobenzofuran (28), but
cannot be used to make optically pure products because addition of the Grignard reagent to the aldehyde
gives a racemic mixture. We thought it would be useful to explore the scope of this reaction.
Reaction of 29 with 3 equiv of i-PrMgCl in THF at -30 °C for 30 min and addition of 3 equiv of 25 and
stirring for 1 h afforded allylic alcohol 30, which was treated with 4 equiv of NaHCO3 and 2.6 equiv of
m-CPBA in CH2Cl2 at -20 °C overnight to give vaginol (7t) in 53% overall yield (see Scheme 8). A
similar sequence converted 15 to myrtopsine (8t) in 55% overall yield, 21 to 7,8-dimethoxymyrtopsine
(9t) in 44% yield, and 2-iodophenol (31) to the parent dihydrobenzofuran (32) in 56% yield. These
results indicate that the two-step sequence provides a general route to racemic trans-2,3-dihydro-3-
hydroxy-2-(1-hydroxy-1-methylethyl)benzofurans in 44-56% overall yield.
1) i-PrMgCl, THF
m-CPBA/NaHCO3
-30 °C, 30 min
HO
O
O
O
O
O
HO
O
O
25
O
OH
CH2Cl2/H2O
OH
I
2)
29
HO
-30 °C, 1 h
30
7t (vaginol, 53%)
1) i-PrMgCl, THF
1) i-PrMgCl, THF
50 °C, 2 h
OMe
-30 °C, 30 min
OMe
N
OH
OH
I
I
25
25
OH
2)
OH
2)
O
OH
R
N
H
O
O
O
O
R
-30 °C, 1 h
R
31
-30 °C, 1 h
32 (56%)
R
3) m-CPBA/NaHCO3
3) m-CPBA/NaHCO3
15, R = H
21, R = OMe
CH2Cl2/H2O
CH2Cl2
8t, R = H (myrtopsine, 55%)
9t, R = OMe (7,8-dimethoxymyrtopsine, 44%)
Scheme 8.
In conclusion, we have completed the first syntheses of myrtopsine (8t) and 7,8-dimethoxymyrtopsine
(9t) by halogen-metal exchange of 3-iodo-4-methoxy-quinolin-2(1H)-ones (15) and (21) with i-PrMgCl
followed by addition of epoxy aldehyde (1). We have also developed a two-step sequence that leads
selectively to trans-dihydrobenzofurans (7t), (8t), (9t), (28), and (32) by addition of enal (25) to the

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HETEROCYCLES, Vol. 70, 2006
appropriate Grignard reagent followed by threo selective epoxidation of the resulting allylic alcohol and
cyclization with inversion.
EXPERIMENTAL
General Procedure. NMR spectra were recorded at 400 MHz with chemical shifts reported in δ and
coupling constants in Hz; IR spectra are reported in cm-1.
cis-3,5-Dihydro-3-hydroxy-2-(1-hydroxy-1-methylethyl)furo[3,2-c]quinolin-4(2H)-one (11c), trans-
3,5-Dihydro-3-hydroxy-2-(1-hydroxy-1-methylethyl)furo[3,2-c]quinolin-4(2H)-one (11t), and trans-
3,9-Dihydro-3-Hydroxy-2-(1-hydroxy-1-methylethyl)furo[2,3-b]quinolin-4(2H)-one (12t). A solution
of (±)-1 (220 mg, 2.2 mmol), 4-hydroxyquinolin-2(1H)-one (10, 322 mg, 2 mmol), CaCl2 (244 mg, 2.2
mmol), and KOH (123 mg, 2.2 mmol) in MeOH (40 mL) was stirred at 25 °C for 3 d. The reaction was
neutralized with 10% citric acid to pH 5-6 and extracted with EtOAc. The combined EtOAc extracts
were washed with water and brine, dried (MgSO4), and concentrated to yield 449.1 mg of crude product.
Flash chromatography on MeOH-deactivated silica gel (50:1 to 20:1 CH2Cl2/MeOH) yielded 30.3 mg
(6%) of pure 11c and 85.9 mg (17%) of a 2:1 mixture of 11t and 12t as determined by analysis of the 1H
NMR spectrum. Reverse phase preparative HPLC (Zorbex Eclipse XDB-C18 9.4 × 250 mm column,
3:1 H2O/MeOH, flow rate = 5 mL/min) of about 5.0 mg of this mixture gave 1.1 mg of 12t (tR = 13.1
min) and 2.9 mg of 11t (tR = 39.8 min).
A solution of (±)-1 (44 mg, 0.44 mmol), 4-hydroxyquinolin-2(1H)-one (10, 64.4 mg, 0.4 mmol), and
Cs2CO3 (142 mg, 0.44 mmol) in dry DMF (10 mL) was stirred under N2 at 25 °C for 3 d. The reaction
was neutralized with 10% citric acid to pH 5-6 and extracted with EtOAc. The combined EtOAc
extracts were washed with water and brine, dried (MgSO4), and concentrated to yield 98.6 mg of crude
product. Flash chromatography on MeOH-deactivated silica gel (50:1 to 20:1 CH2Cl2/MeOH) yielded
3.4 mg (3%) of pure 11c, 3.2 mg (3%) of a 2:1 mixture of 11t and 12t, and 15.0 mg (8%) of a two-to-one
adduct generated from two molecules of 4-hydroxyquinolin-2(1H)-one and one molecule of (±)-1.
Data for 11c: mp 169-170 °C; 1H NMR (CD3OD) 7.81 (dd, 1, J = 7.8, 1.2), 7.58 (ddd, 1, J = 7.8, 7.8, 1.2),
7.39 (d, 1, J = 7.8), 7.26 (dd, 1, J = 7.8, 7.8), 5.49 (d, 1, J = 6.4), 4.54 (d, 1, J = 6.4), 1.55 (s, 3), 1.52 (s,
13
3); C NMR (CD3OD) 167.7, 163.7, 141.6, 133.3, 124.2, 123.7, 117.2, 113.0, 112.9, 94.4, 73.3, 71.6,
27.3, 26.7; IR (KBr) 3274, 2977, 1658, 1623; HRMS (DEI) calcd for C14H16NO4 (MH+) 262.1079, found
262.1070.
Data for 11t: 1H NMR (CD3OD) 7.85 (dd, 1, J = 7.9, 1.2), 7.60 (ddd, 1, J = 7.9, 7.9, 1.2), 7.40 (d, 1, J =
13
7.9), 7.28 (dd, 1, J = 7.9, 7.9), 5.44 (d, 1, J = 3.7), 4.53 (d, 1, J = 3.7), 1.31 (s, 3), 1.30 (s, 3); C NMR
(CD3OD) 168.0, 164.3, 141.7, 133.2, 124.2, 123.7, 117.1, 113.0, 111.9, 101.3, 72.4, 72.0, 25.34, 25.32;
HRMS (DEI) calcd for C14H16NO4 (MH+) 262.1079, found 262.1069.

HETEROCYCLES, Vol. 70, 2006
287
1
Data for 12t: H NMR (CD3OD) 8.24 (d, 1, J = 7.9), 7.78-7.72 (m, 2), 7.46-7.42 (m, 1), 6.35 (d, 1, J =
3.1), 5.81 (s, 1, OH), 4.56 (d, 1, J = 3.1), 1.37 (s, 3), 1.33 (s, 3); 13C NMR (CD3OD) 133.6, 127.1, 125.3,
117.1, 96.1, 88.3, 83.2, 71.1, 25.6, 25.1 (four quaternary carbons were not observed); HRMS (DEI) calcd
for C14H16NO4 (MH+) 262.1079, found 262.1069.
Two-to-one adduct: 1H NMR (CD3OD) 7.99 (d, 1, J = 7.9), 7.87 (dd, 1, J = 7.9, 1.2), 7.54 (ddd, 1, J = 7.9,
7.9, 1.2), 7.49 (ddd, 1, J = 7.9, 7.9, 1.2), 7.36 (d, 1, J = 7.9), 7.28 (dd, 1, J = 7.9, 7.9), 7.27 (d, 1, J = 7.9),
7.22 (dd, 1, J = 7.9, 7.9), 5.19 (d, 1, J = 6.7), 5.07 (d, 1, J = 6.7), 1.37 (s, 3), 1.31 (s, 3).
Furo[3,2-c]quinolin-4(5H)-one (13). TFA (0.20 mL) was added to a suspension of 11c (38.6 mg, 0.15
mmol) in CH2Cl2 (4 mL) and the solution was stirred at 25 °C for 40 min. The solution was neutralized
with 30% NaOH saturated with NaCl and extracted with EtOAc (3 × 5 mL). The organic layer was
washed with water (2 × 2 mL), brine (2 × 2 mL), dried (MgSO4) and concentrated to yield 30.8 mg of
crude 13. Flash chromatography on silica gel (1:1 hexanes/EtOAc) gave 26.8 mg (98%) of pure 13: mp
1
245-247 °C (lit.10 mp 243-245 °C); H NMR (DMSO-d6) 8.08 (d, 1, J = 1.8), 7.91 (d, 1, J = 7.8), 7.51
13
(ddd, 1, J = 7.8, 7.8, 1.2), 7.45 (d, 1, J = 7.8), 7.28 (ddd, 1, J = 7.8, 7.8, 1.2), 7.07 (d, 1, J = 1.8); C
1
NMR (DMSO-d6) 158.9, 155.4, 145.5, 137.0, 129.5, 122.3, 120.2, 116.0, 115.5, 111.2, 107.7. The H
NMR and 13C NMR (DMSO-d6) spectral data match the literature data.10
4-Hydroxy-3-iodoquinolin-2(1H)-one (14) was prepared by the literature procedure.12 A solution of
iodine (1.75 g, 6.9 mmol) in warm dioxane (10 mL) was added in portions during 5 min to a refluxing
solution of 10 (1.0 g, 6.2 mmol) and Na2CO3 (1.25 g, 11.8 mmol) in water (25 mL). After refluxing for
22 h, the solution was cooled to 5 °C and acidified with AcOH. The precipitate was collected by
filtration and dried at 70 °C for 12 h to give pure 14 (1.49 g, 83%): 1H NMR (CD3OD) 8.01 (d, 1, J = 8.0),
7.58 (dd, 1, J = 8.0, 8.0), 7.34 (d, 1, J = 8.0), 7.26 (dd, 1, J = 8.0, 8.0).
3-Iodo-4-methoxyquinolin-2(1H)-one (15) was prepared by the literature procedure.13,14 A solution of
14 (1 g, 3.5 mmol) in EtOH (45 mL) was treated with a 4 molar excess of ethereal diazomethane and
stirred at 25 °C for 3 h. Excess CH2N2 was destroyed by the addition of glacial AcOH. Evaporation of
the solvent gave a gum which was dissolved in EtOAc (100 mL). The solution was washed with 1 M
NaOH (3 × 20 mL) and water (2 × 20 mL), dried (MgSO4), and concentrated to yield 1.09 g of crude 15.
Flash chromatography on silica gel (2:1 hexanes/EtOAc) yielded 0.55 g (52%) of 15: 1H NMR
(DMSO-d6) 7.76 (d, 1, J = 7.9), 7.59 (dd, 1, J = 8.5, 7.3), 7.37 (d, 1, J = 8.5), 7.24 (dd, 1, J = 7.9, 7.3),
13
3.94 (s, 3); C NMR (DMSO-d6) 166.8, 160.7, 138.8, 131.5, 122.7, 122.2, 115.59, 115.57, 88.8, 61.0.
The 1H NMR and 13C NMR (DMSO-d6) spectral data match the literature data.13
cis-2,3-Dihydro-3-hydroxy-4-methoxy-α,α-dimethylfuro[2,3-b]quinoline-2-methanol (8c), trans-2,3-
Dihydro-3-hydroxy-4-methoxy-α,α-dimethylfuro[2,3-b]quinoline-2-methanol (myrtopsine, 8t), and
4-Methoxyquinolin-2(1H)-one (16). A solution of 15 (240 mg, 0.8 mmol) in dry THF (20 mL) was

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HETEROCYCLES, Vol. 70, 2006
stirred under N2 at -30 °C for 5 min. i-PrMgCl (1.2 mL, 2 M in THF, 2.4 mmol, 3 equiv) was slowly
added and the solution was stirred for 10 min. Epoxide (±)-(1) (248 mg, 2.48 mmol, 3.1 equiv) was
added and the solution was stirred for 0.5 h. The reaction was then quenched with MeOH (1 mL) and
the resulting solution was poured into a mixture of saturated aqueous NH4Cl solution (2 mL) and water (2
mL). The mixture was extracted with CH2Cl2 and the organic layer was dried (MgSO4) and
concentrated to yield crude product. Flash chromatography on silica gel (50:1 to 20:1 CH2Cl2/MeOH)
yielded 71.7 mg of impure 8c, followed by 37.9 mg (27%) of 16, and 74.5 mg (35%) of 8t. Flash
chromatography of impure 8c on silica gel (3:2 hexanes/EtOAc) afforded 54.7 mg (25%) of 8c.
Data for 16: 1H NMR (DMSO-d6) 7.76 (d, 1, J = 7.9), 7.50 (dd, 1, J = 7.9, 7.9), 7.28 (d, 1, J = 7.9), 7.15
(dd, 1, J = 7.9, 7.9), 5.89 (s, 1), 3.92 (s, 3); 13C NMR (DMSO-d6) 163.3, 163.2, 138.6, 131.0, 122.2, 121.4,
1
13
115.2, 114.5, 96.7, 56.1. The H NMR and C NMR (DMSO-d6) spectral data match the literature
data.15
1
Data for 8c: mp 169-171 °C; H NMR (CD3OD) 8.12 (d, 1, J = 7.9), 7.63-7.62 (m, 2), 7.38-7.34 (m, 1),
13
5.81 (d, 1, J = 5.5), 4.64 (s, 1, OH), 4.45 (s, 3), 4.34 (d, 1, J = 5.5), 1.53 (s, 3), 1.51 (s, 3); C NMR
(CD3OD) 170.1, 162.4, 148.8, 132.0, 126.8, 124.8, 124.3, 121.2, 106.4, 89.7, 73.0, 71.6, 59.1, 27.4, 26.3;
IR (KBr) 3273, 2958, 1623, 1586; HRMS (DEI) calcd for C15H18NO4 (MH+) 276.1236, found 276.1240.
1
Data for 8t: mp 191-192 °C; H NMR (CD3OD) 8.13 (d, 1, J = 7.9), 7.62-7.60 (m, 2), 7.37-7.32 (m, 1),
13
5.72 (d, 1, J = 1.8), 4.52 (s, 3), 4.39 (d, 1, J = 1.8), 1.35 (s, 3), 1.27 (s, 3); C NMR (CD3OD) 170.6,
162.8, 148.9, 131.9, 126.7, 124.7, 124.2, 121.3, 105.8, 96.7, 72.1, 71.4, 59.2, 26.2, 25.2; IR (KBr) 3228,
1
2976, 1632, 1587; HRMS (DEI) calcd for C15H18NO4 (MH+) 276.1236, found 276.1241. The H NMR
spectral data correspond to the literature data.3
A similar sequence using 15 (192 mg, 0.64 mmol), i-PrMgCl (0.96 mL, 2 M in THF, 1.82 mmol, 3 equiv)
and (R)-1 (198.4 mg, 1.98 mmol, 3.1 equiv) gave 60.2 mg (35%) of (+)-8t and 46.3 mg (26%) of (-)-8c.
1
13
Data for (-)-8c: mp 158-159 °C; [α]21 -100.4° (c 0.5, CH3OH); the H NMR and C NMR spectral
D
data are identical to those of racemic 8c.
Data for (+)-8t: mp 199-200 °C (lit.,3 mp 208 °C, lit.,5 201-202 °C); [α]21 +10.4° (c 0.6, CH3OH)
D
{lit.,3,5 for enantiomer [α]20D -5.0° (c 1.0, CH3OH)}; the 1H NMR and 13C NMR spectral data are identical
to those of racemic 8t.
4-Methoxyfuro[2,3-b]quinoline (dictamnine, 17) and 4-Methoxy-α,α-dimethylfuro[2,3-b]quinoline-
2-methanol (18). A solution of 8t (27.8 mg, 0.1 mmol) in dry CH2Cl2 (40 mL) was treated with Et3N
(27.9 μL, 0.20 mmol) and MsCl (9.1 μL, 0.11 mmol) and then stirred at 25 °C under N2 for 1 h. The
organic solution was washed with water (2 × 10 mL), dried (MgSO4) and concentrated to yield 26.1 mg
of crude product. Flash chromatography on silica gel (4:1 to 2:1 hexanes/EtOAc) afforded 17 (3.8 mg,
19%) followed by 18 (10.7 mg, 41%).

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1
Data for dictamnine (17): mp 131-132 °C (lit.,14 mp 132-134 °C, lit.,4 mp 128-130 °C); H NMR
(CDCl3) 8.29 (d, 1, J = 7.8), 8.01 (d, 1, J = 7.8), 7.69 (dd, 1, J = 7.8, 7.8), 7.64 (d, 1, J = 2.8), 7.46 (dd, 1,
J = 7.8, 7.8), 7.10 (d, 1, J = 2.8), 4.47 (s, 3); 13C NMR (CDCl3) 163.8, 156.8, 145.6, 143.6, 129.6, 127.8,
123.7, 122.3, 118.7, 104.7, 103.4, 59.0. The 1H NMR and 13C NMR (CDCl3) spectral data match those
of a sample purchased from Apin Chemicals LTD.
1
Data for 18: H NMR (CDCl3) 8.26 (dd, 1, J = 7.9, 1.2), 7.98 (d, 1, J = 7.9), 7.67 (ddd, 1, J = 7.9, 7.9,
13
1.2), 7.44 (ddd, 1, J = 7.9, 7.9, 1.2), 6.90 (s, 1), 4.43 (s, 3), 1.72 (s, 6); C NMR (CDCl3) 163.7, 161.8,
156.3, 145.2, 129.4, 127.7, 123.7, 122.3, 118.9, 104.6, 97.9, 69.5, 59.0, 28.6 (2 C). These data
1
correspond to the literature data,14 except that our H NMR data are 0.1 to 0.15 ppm downfield and our
13C NMR data are all about 1.2 ppm downfield.
4-Hydroxy-3-iodo-7,8-dimethoxyquinolin-2(1H)-one (20). A solution of iodine (532 mg, 2.1 mmol)
in warm dioxane (3 mL) was added in portions during 5 min to a refluxing solution of
7,8-dimethoxy-4-hydroxyquinolin-2(1H)-one (19,20 416 mg, 1.9 mmol) and Na2CO3 (767 mg, 7.2 mmol)
in water (7.5 mL). After refluxing for 2 h, the solution was cooled to 5 °C and acidified with AcOH.
The precipitate was collected by filtration and dried at 70 °C for 12 h to give 438 mg (66%) of pure 20:
1
1
mp 183-184 °C; H NMR (CD3OD) 7.74 (d, 1, J = 9.2), 7.03 (d, 1, J = 9.2), 3.97 (s, 3), 3.92 (s, 3); H
NMR (DMSO-d6) 10.93 (br s, 1, NH), 7.70 (d, 1, J = 9.2), 7.00 (d, 1, J = 9.2), 3.83 (s, 3), 3.76 (s, 3); 13C
NMR (DMSO-d6) 162.9, 160.8, 153.5, 133.7, 132.8, 118.5, 109.3, 107.3, 74.6, 60.7, 56.2.
3-Iodo-4,7,8-trimethoxy-quinolin-2(1H)-one (21). A solution of 20 (420 mg, 1.21 mmol) in ethanol
(70 mL) was treated with a 4 molar excess of ethereal diazomethane and stirred at 25 °C for 40 min.
Excess CH2N2 was destroyed by the addition of glacial acetic acid. Evaporation of the solvent gave 458
mg of a gummy residue. Flash chromatography on silica gel (2:1 to 1:2 hexanes/EtOAc) yielded 64.4
mg (14%) of 3-iodo-2,4,7,8-tetramethoxyquinoline followed by 243 mg (56%) of 21.
Data for 3-iodo-2,4,7,8-tetramethoxyquinoline: 1H NMR (CDCl3) 7.69 (d, 1, J = 9.2), 7.14 (d, 1, J = 9.2),
4.15 (s, 3), 4.13 (s, 3), 4.02 (s, 3), 4.01 (s, 3); 13C NMR (CDCl3) 166.4, 160.4, 153.0, 142.2, 142.1, 117.6,
117.5, 112.0, 73.6, 6.1.8, 61.4, 56.8, 55.0.
1
Data for 21: mp 218-220 °C; H NMR (CD3OD) 7.60 (d, 1, J = 9.2), 7.09 (d, 1, J = 9.2), 4.02 (s, 3),
3.98 (s, 3), 3.92 (s, 3); 1H NMR (CDCl3) 9.49 (br, 1, NH), 7.51 (d, 1, J = 9.2), 6.87 (d, 1, J = 9.2), 4.02 (s,
3), 3.98 (s, 6); 13C NMR (CDCl3) 167.8, 161.3, 153.5, 133.9, 132.6, 118.7, 111.4, 107.9, 84.1, 61.3, 61.1,
56.2; HRMS (EI) calcd for C12H12NO4I (M+) 360.9811, found 360.9816.
cis-2,3-Dihydro-3-hydroxy-4,7,8-trimethoxy-α,α-dimethylfuro[2,3-b]quinoline-2-methanol (9c),
trans-2,3-Dihydro-3-hydroxy-4,7,8-trimethoxy-α,α-dimethylfuro[2,3-b]quinoline-2-methanol
(7,8-dimethoxymyrtopsine, 9t), and cis-3,4-Dihydro-5,8,9-trimethoxy-2,2-dimethyl-2H-pyrano-
[2,3-b]quinoline-3,4-diol (23c). A solution of 21 (72 mg, 0.2 mmol) in dry THF (5 mL) was stirred

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HETEROCYCLES, Vol. 70, 2006
under N2 at -30 °C for 5 min. i-PrMgCl (0.3 mL, 2 M in THF, 0.6 mmol, 3 equiv) was slowly added and
the solution was stirred for 20 min. Epoxide ((±)-1) (60 mg, 0.6 mmol, 3 equiv) was added and the
solution was stirred for 0.5 h. The reaction was then quenched with 1 mL of MeOH and the resulting
solution was poured into a mixture of saturated aqueous NH4Cl solution (2 mL) and water (2 mL). The
mixture was extracted with EtOAc and the organic layer was dried (MgSO4) and concentrated to yield
crude product. Flash chromatography on silica gel (50:1 to 20:1 CH2Cl2/MeOH) yielded 15.3 mg of a
1:1 mixture of 9c and 23c, followed by 19.0 mg (28%) of 9t. Preparative TLC (20:1 CH2Cl2/MeOH) of
the mixture afforded 6.8 mg (10%) of 9c and 6.8 mg (10%) of 23c.
Data for 9c: 1H NMR (CDCl3) 7.82 (d, 1, J = 9.2), 7.06 (d, 1, J = 9.2), 5.72-5.70 (dd, 1, J = 7.3, 6.1), 5.28
(d, 1, J = 7.3, OH), 4.40 (s, 3), 4.30 (d, 1, J = 6.1), 4.03 (s, 3), 3.99 (s, 3), 1.60 (s, 6); 13C NMR (CDCl3)
168.1, 160.9, 153.3, 143.5, 141.7, 118.7, 115.5, 110.3, 103.3, 86.2, 72.8, 71.0, 61.5, 58.3, 56.4, 28.9, 24.4.
Data for 9t: mp 194-196 °C; 1H NMR (CDCl3) 7.57 (d, 1, J = 9.2), 6.94 (d, 1, J = 9.2), 5.57 (br d, 1, J =
13
2.4), 4.49 (d, 1, J = 2.4), 4.41 (s, 3), 3.98 (s, 3), 3.97 (s, 3), 1.38 (s, 3), 1.33 (s, 3); C NMR (CDCl3)
168.4, 161.5, 153.3, 143.2, 141.6, 118.5, 115.3, 110.5, 101.7, 94.7, 71.3, 70.9, 61.4, 58.3, 56.6, 25.5,
24.7; IR (KBr) 3350, 2970, 1626, 1581, 1488, 1366, 1270; HRMS (EI) calcd for C17H21NO6 (M+)
335.1369, found 336.1371. The spectral data are identical to those reported for
7,8-dimethoxymyrtopsine.6,7
Data for 23c: 1H NMR (CDCl3) 7.64 (d, 1, J = 9.0), 7.14 (d, 1, J = 9.0), 5.21 (br, 1), 4.13 (s, 3), 4.04 (s, 3),
4.00 (s, 3), 3.90 (d, 1, J = 4.3), 1.60 (s, 3), 1.42 (s, 3); 1H NMR (CDCl3 + D2O) 5.21 (d, 1, J = 4.9), 3.89
(d, 1, J = 4.9); 13C NMR (CDCl3) 165.6, 159.2, 153.0, 143.5, 142.1, 117.5, 116.2, 112.1, 108.1, 79.0,
70.7, 63.6, 62.4, 61.6, 56.7, 24.6, 23.8.
A similar sequence using 21 (72 mg, 0.2 mmol), i-PrMgCl (0.3 mL, 2 M in THF, 0.6 mmol, 3 equiv) and
(R)-1 (60 mg, 0.6 mmol, 3 equiv) gave 17.6 mg (26%) of (+)-9t, and 6.2 mg (9%) of 9c and 6.5 mg (10%)
of 23c.
Data for (+)-9t: mp 166-168 °C; [α]21D +17.0° (c 0.165, CHCl3) {lit.,7 [α]23D +16.2° (c 0.165, CHCl3)};
the 1H NMR and 13C NMR spectral data are identical to those of racemic 9t.
Methyl trans-2,3-Dihydro-3-hydroxy-2-(1-hydroxy-1-methylethyl)benzofuran-5-carboxylate (26).
MeMgBr (1.36 mL, 1.1 M in THF, 1.5 mmol) was added dropwise to a solution of methyl
4-hydroxy-3-iodobenzoate (24, 420 mg, 1.5 mmol) and LiCl (63.6 mg, 1.5 mmol) in dry THF (5 mL)
under N2 at -30 °C and the solution was stirred for 30 min. Then, i-PrMgCl (0.75 mL, 2 M in THF, 1.5
mmol) was slowly added and the mixture was stirred for 30 min at -30 °C. 3-Methyl-2-butenal (25, 0.15
mL, 1.5 mmol) was added and the solution was stirred for 1 h. The solution was poured into a mixture
of saturated aqueous NH4Cl solution (2 mL) and water (2 mL). The phases were separated and the
aqueous phase was extracted with Et2O. The combined organic layers were dried (Na2SO4) and aqueous

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291
yield crude 26 that was used in the next step without purification.
A suspension of crude 26, NaHCO3 (189 mg, 2.2 mmol, 1.5 equiv), and m-CPBA (303 mg of 85% pure,
1.5 mmol, 1 equiv) in CH2Cl2 (15 mL) was stirred at 0 °C for 5 h. The reaction was quenched by adding
saturated Na2SO3 (5 mL). The phases were separated and the aqueous phase was extracted with Et2O (3
× 15 mL). The combined organic layers were washed with 1 M NaOH (3 × 10 mL) and brine, dried
(MgSO4) and concentrated to yield 452.5 mg of crude 28. Flash chromatography on silica gel (2:1
hexanes/EtOAc to 1:1 hexanes/EtOAc) yielded 211.5 mg (56%) of 28: 1H NMR (CD3OD) 8.03 (s, 1),
7.94 (d, 1, J = 8.2), 6.89 (d, 1, J = 8.2), 5.34 (d, 1, J = 4.3), 4.32 (d, 1, J = 4.3), 3.87 (s, 3), 1.27 (s, 6); 1H
NMR (acetone-d6) 8.01 (br s, 1), 7.91 (dd, 1, J = 8.5, 1.8), 6.85 (d, 1, J = 8.5), 5.45 (d, 1, J = 4.2), 4.36 (d,
13
1, J = 4.2), 3.83 (s, 3), 1.28 (s, 3), 1.27 (s, 3); C NMR (acetone-d6) 206.3, 167.0, 165.2, 132.9, 128.2,
123.5, 110.4, 99.1, 72.7, 71.1, 52.1, 25.9 (2 C); HRMS (DEI) calcd for C13H17O5 (MH+) 253.1076, found
253.1088. The 1H and 13C NMR (acetone-d6) spectral data match those of the authentic sample provided
by Prof. Jenett-Siems. The spectral data reported to be in CD3OD are actually in acetone-d6.22,26
Preparation of Vaginol (7t) from 25 and 29. i-PrMgCl (0.3 mL, 2 M in THF, 0.6 mmol, 3 equiv) was
added dropwise to a solution of 29 (58 mg, 0.2 mmol) in dry THF (3 mL) under N2 at -30 °C and the
solution was stirred for 30 min. Enal (25) (60 μL, 0.6 mmol, 3 equiv) was added and the solution was
stirred for 1 h. The solution was poured into a mixture of saturated aqueous NH4Cl solution (1 mL) and
water (1 mL). The phases were separated and the aqueous phase was extracted with Et2O. The
combined organic layers were dried (Na2SO4) and concentrated to yield crude 30 that was used in the next
step without purification.
To a suspension of crude 30 and NaHCO3 (69 mg, 0.8 mmol, 4 equiv) in H2O (1 mL) at -20 °C was added
under stirring a solution of m-CPBA (104 mg of 85% pure, 0.51 mmol, 2.6 equiv) in CH2Cl2 (4 mL).
The reaction was stirred overnight at -20 °C and quenched by adding saturated Na2SO3 (1 mL). The
phases were separated and the aqueous phase was extracted with Et2O. The combined organic layers were
washed with 1 M NaOH (3 × 2 mL) and brine, dried (MgSO4) and concentrated to yield crude product.
Flash chromatography on MeOH-deactivated silica gel (1:1 hexanes/EtOAc) yielded 27.8 mg (53%) of
vaginol (7t) identical to that obtained from 1.1
Preparation of Myrtopsine (8t) from 15 and 25. Reaction of 15 (60 mg, 0.2 mmol, 1 equiv),
i-PrMgCl (0.3 mL, 2 M in THF, 0.6 mmol, 3 equiv), and 3-methyl-2-butenal (25) (60 μL, 0.6 mmol, 3
equiv) was carried out using the procedure for preparation of 7t from 29. Epoxidation of the resulting
crude allylic alcohol with m-CPBA (104 mg of 85% pure, 0.51 mmol, 2.6 equiv) and NaHCO3 (69 mg,
0.8 mmol, 4 equiv) in CH2Cl2/H2O (4 mL/1 mL) at -20 °C gave 30.2 mg (55%) of myrtopsine (8t)
identical to that obtained from 15 and 1.
Preparation of 7,8-Dimethoxymyrtopsine (9t) from 21 and 25. Reaction of 21 (21.7 mg, 0.06 mmol),

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HETEROCYCLES, Vol. 70, 2006
i-PrMgCl (0.09 mL, 2 M in THF, 0.18 mmol, 3 equiv), and 3-methyl-2-butenal (18 μL, 0.18 mmol, 3
equiv) was carried out using the procedure for the preparation of 7t from 29. Epoxidation of the resulting
crude allylic alcohol with m-CPBA (37 mg of 85% pure, 0.18 mmol, 3 equiv) and NaHCO3 (20 mg, 0.24
mmol, 4 equiv) in CH2Cl2/H2O (2 mL/0.5 mL) at -20 °C gave 8.9 mg (44%) of 7,8-dimethoxymyrtosine
(9t) identical to that obtained from 21 and 1.
trans-2,3-Dihydro-3-hydroxy-α,α-dimethylbenzofuran-2-methanol (32). i-PrMgCl (1.0 mL, 2 M in
THF, 2 mmol, 2 equiv) was added dropwise to a solution of 2-iodophenol (31, 220 mg, 1 mmol) in dry
THF (2 mL) under N2 at 25 °C and the solution was stirred at 50 °C for 2 h. The exchange was
complete as indicated by TLC and the solution was cooled to -30 °C. Enal (25) (97 μL, 1 mmol) was
added and the solution was stirred for 1 h. The solution was poured into a mixture of saturated aqueous
NH4Cl solution (1 mL) and water (1 mL). The phases were separated and the aqueous phase was
extracted with Et2O. The combined organic layers were dried (Na2SO4) and concentrated to yield crude
product that was used in the next step without purification.
A suspension of the crude allylic alcohol, NaHCO3 (130 mg, 1.5 mmol, 1.5 equiv), and m-CPBA (202 mg
of 85% pure, 1 mmol) in CH2Cl2 (10 mL) was stirred at 0 °C for 5 h. The reaction was quenched by
adding saturated Na2SO3 (5 mL). The phases were separated and the aqueous phase was extracted with
diethyl ether (3 × 15 mL). The combined organic layers were washed with 1 M NaOH (3 × 10 mL) and
brine, dried (MgSO4) and concentrated to yield crude product. Flash chromatography on silica gel (2:1
hexanes/EtOAc) yielded 109.1 mg (56%) of 32: 1H NMR (CDCl3) 7.37 (d, 1, J = 7.9), 7.26 (dd, 1, J =
8.5, 7.3), 6.95 (dd, 1, J = 7.9, 7.3), 6.85 (d, 1, J = 8.5), 5.36 (d, 1, J = 4.5), 4.28 (d, 1, J = 4.5), 1.34 (s, 3),
13
1.27 (s, 3); C NMR (CDCl3) 159.7, 130.5, 128.5, 125.3, 121.2, 110.2, 96.7, 73.6, 71.3, 25.6, 24.4;
HRMS (DEI) calcd for C11H14O3Na (MNa+) 217.0841; found 217.0842.
ACKNOWLEDGEMENTS
We are grateful to the National Institutes of Health for financial support (GM-50151).
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