A Doetz benzannulation route to the enantioselective synthesis of (-)- and (+)-juglomycin A

Article abstract of DOI:10.1016/j.tetasy.2011.07.018

Two synthetic routes based on a Doetz benzannulation toward the enantioselective synthesis of naphthoquinone antibiotics (-)- and (+)-juglomycin A are described. The stereoinducing step is based on asymmetric dihydroxylation. The syntheses are completed in seven to eight steps from Fischer carbene 12.

Full text of DOI:10.1016/j.tetasy.2011.07.018

Tetrahedron: Asymmetry 22 (2011) 1312–1319
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A Dötz benzannulation route to the enantioselective synthesis
of (ꢀ)- and (+)-juglomycin A
⇑
Rodney A. Fernandes , Vijay P. Chavan
Department of Chemistry, Indian Institute of Technology Bombay, Powai, 400 076 Mumbai, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Two synthetic routes based on a Dötz benzannulation toward the enantioselective synthesis of naphtho-
quinone antibiotics (ꢀ)- and (+)-juglomycin A are described. The stereoinducing step is based on asym-
metric dihydroxylation. The syntheses are completed in seven to eight steps from Fischer carbene 12.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 16 May 2011
Accepted 20 July 2011
Available online 16 August 2011
O
O
1. Introduction
O
O
O
O
O
O
Juglomycins A 1 and B 2 (Fig. 1) were isolated by Ono and
co-workers from Streptomyces sp. 190-2.1 The naphthoquinone
antibiotics have antitumor and antibacterial properties.1 Their
OH
OH
naphthoquinone-c-lactone motif is present in the higher related
OH
OH
molecules known as pyranonaphthoquinones, which include
(-)-juglomycin A 1
kalafungin 3,2 frenolicin B 4,3 nanaomycin D 5,4 arizonins,5 and di-
juglomycin B 2
meric molecules, such as crisamycin,6 -actinorhodin,7 etc. where
c
O
O
the free b-hydroxy group is involved in the pyran ring formation.
Juglomycin A 1 and B 2 were first synthesized in 1981 in their race-
mic forms by Giles et al.8a based on the alkylation of 3-bromojug-
lone with monomethyl glutarate, and the subsequent benzylic
O
O
O
O
O
O
bromination/elimination to afford a b,c-unsaturated ester, which
OH
R
O
OH
O
was then subjected to racemic dihydroxylation/lactonization. The
racemic synthesis reported by Kraus and Liu8b in 1996 was based
on the alkylation of a suitably substituted naphthol with the ethyl
ester of 3-formyl acrylic acid. Subsequent Michael addition and
R = Me (+)-kalafungin 3
R = n-Pr (+)-frenolicin B 4
(-)-nanaomycin D 5
Figure 1. Naphthoquinone-centered natural products.
quinone formation generated the
synthesis in 2004 was based on cyanohydrin formation,
ation with (E)-methyl 3-methoxyacrylate to generate a
ter. -Selectride reduction of the latter followed by cyclization
gave the
-lactone molecule ( )-1. Brimble and Ireland9 reported
c
-lactone structure. The Park8c
-alkyl-
-ketoes-
a
enantiomers of juglomycin A along with an alternative synthesis
of (ꢀ)-1 using a chiral alkyne.
c
L
c
the ( )-deoxyjuglomycin synthesis via the oxidative fragmentation
of furo[3,2-b]naphtha[2,1-d]furan using cerium ammonium ni-
trate. The first chiral synthesis of 1 was reported by Kraus and
Maeda10 in 1996. The diastereoselective arylation of the chiral
2. Results and discussion
The retrosynthetic analysis of (ꢀ)-1 and (+)-ent-1 is shown in
Scheme 1. Our earlier approach11 was a linear sequence based on
a Dötz benzannulation12 between Fischer carbene 12 and alkyne
11 to generate tetrasubstituted naphthalene 10. We then planned
aldehyde derived from
the b,
D-malic acid was the key step to obtain
c
-dihydroxy ester, which was subsequently lactonized. In a
preliminary communication,11 we described the second asymmet-
ric synthesis of both enantiomers of juglomycin A based on Dötz
benzannulation12 and asymmetric dihydroxylation.13 Herein we
report a detailed account on the asymmetric synthesis of both
to obtain the desired b,
tive Knoevenagel14 reaction of the aldehyde from
monomethyl malonate. Asymmetric dihydroxylation of 8 gave
the -lactone 7 or ent-7. Our new synthetic approach was to use
c-unsaturated ester 8 through deconjuga-
9
and
c
chiral alkyne 13 in Dötz benzannulation to give 6. Further steps
would involve primary hydroxyl desilylation, conversion to the
CO2H group, and lactonization to 7. Quinone formation and
⇑
Corresponding author. Fax: +91 22 25767152.
E-mail address: rfernand@chem.iitb.ac.in (R.A. Fernandes).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.018

R. A. Fernandes, V. P. Chavan / Tetrahedron: Asymmetry 22 (2011) 1312–1319
1313
O
O
O
O
O
O
O
O
OH
OH
OH
OH
ent-1
1
MeO
O
O
OMe
O
OMe
OMe
O
O
OH
OMe OMe
asymmetric
OR
OMe OMe
OMe OMe
dihydroxylation
O
8
6
O
7
O
or ent-7
EtO2C
O
Knoevenagel
reaction
OR
OR
14
Dötz benzannulation
13
OMe
OMe
asymmetric
OH
dihydroxylation
OR
Cr(CO)5
OR
OR
EtO2C
OMe OMe
OMe OMe
OMe OMe
R = TBDMS
15
11
12
10
9
Scheme 1. The retrosynthetic analysis of (ꢀ)-1 and (+)-ent-1.
demethylation of 7 would give juglomycin A 1. Similarly, ent-7
would give ent-1. The chiral alkyne 13 was designed to reduce
the number of steps after Dötz benzannulation from Fischer
dihydroxylation of 15 furnished diol 19 in good yield (94%) and
enantioselectivity (92% ee).15b Acetonide protection of diol 19 gave
14 (90%). The ester group reduction with DIBAL-H to the aldehyde
and alkyne formation using the Bestmann–Ohira reagent 2016 pro-
vided alkyne 13 in 76% yield over two steps.
carbene 12 to c-lactone 7. Asymmetric dihydroxylation of known
olefin ester 1515 and acetonide formation would give 14. Alkyne
13 would thus be obtained from the corresponding aldehyde of
14 through the use of the Bestmann–Ohira reagent.16
2.3. Synthesis of c-lactone 7 via Dötz benzannulation using
Fischer carbene 12 and alkyne 13
2.1. Synthesis of
c-lactone 7 and ent-7 through Dötz
benzannulation using Fischer carbene 12 and alkyne 11
An alternative synthesis of 7 via Dötz benzannulation using
Fischer carbene 12 and alkyne 13 is shown in Scheme 4. The
Dötz benannulation of 12 with alkyne 13 in toluene solvent at
45 °C afforded the trisubstituted naphthol 21 in 68% yield. The
methylation of the phenolic hydroxyl provided the trimethoxy-
naphthalene 6 (89%). Removal of the TBDMS ether in 6 quantita-
tively gave the primary alcohol 22. Subsequent PDC oxidation of
the primary hydroxyl functionality to the CO2H group (91%) and
Our first approach to the synthesis of c-lactone 7 using alkyne
11 and Fischer carbene 12 is shown in Scheme 2. Fischer carbene
complex 12 was prepared from 2-bromoanisole in 83% yield as re-
ported earlier.17 The Dötz benzannulation12 of 12 with alkyne 11 in
THF solvent at 45 °C afforded the trisubstituted naphthol 16 in 78%
yield. The methylation of the phenolic hydroxyl afforded trimeth-
oxynaphthalene 10 (81%). Removal of TBDMS ether in 10 quantita-
tively gave the primary alcohol 9. Subsequent Swern oxidation to
the aldehyde and decarboxylative deconjuagtive Knoevenagel14
condensation with monomethyl malonate provided the desired
lactonization afforded the b-hydroxy-c-lactone 7 in 87% yield. A
similar use of ent-13 [prepared using (DHQ)2-PHAL ligand in the
asymmetric dihydroxylation of 15] could be an alternative for
the synthesis of ent-7 following a similar sequence of reactions
as shown in Scheme 4.
b,
c-unsaturated ester 8 in good yield of 72% over two steps. Asym-
metric dihydroxylation13 of 8 using (DHQD)2-PHAL as the stereoin-
ducing ligand gave the b-hydroxy-
c
-lactone 7 in 84% yield with an
2.4. Synthesis of (ꢀ)- and (+)-juglomycin A from lactones 7 and
ent-7, respectively
excellent enantioselectivity of 99.5%ee.18 A similar dihydroxylation
of 8 using (DHQ)2-PHAL gave ent-7 in 83% yield and 98.5% ee.18
The completion of the synthesis of (ꢀ)- and (+)-juglomycin A
from lactones 7 and ent-7, respectively, is shown in Scheme 5. Oxi-
dation of 7 with cerium ammonium nitrate (CAN) afforded quinone
23 in excellent yield (94%). Demethylation of 23 with anhydrous
AlCl3 gave (ꢀ)-juglomycin A 1 in 92% yield as a yellow solid,
2.2. Synthesis of chiral alkyne 13
The synthesis of chiral alkyne 13 is shown in Scheme 3. Diol 19
was prepared following a similar literature procedure.15a The
mono-protection of 1,3-propane diol 17 as its TBDMS ether gave
18 in 90% yield. The PCC oxidation of 18 to the corresponding alde-
hyde and subsequent Horner–Wittig olefination19 provided the
½
a 2D5
ꢁ
¼ ꢀ51:6 (c 0.25, CHCl3), [lit.1 ꢀ51.9 (c 0.42, DMSO)], mp
171–173 °C (decomp. at 170 °C), [lit.10 175–177 °C (decomp.)].
Similarly, the oxidation of ent-7 to ent-23 and demethylation
a,b-unsaturated ester 15 in 82% yield over two steps. Asymmetric
provided (+)-juglomycin A ent-1, ½a D25
¼ þ49:2 (c 0.2, CHCl3), mp
ꢁ

1314
R. A. Fernandes, V. P. Chavan / Tetrahedron: Asymmetry 22 (2011) 1312–1319
OH
NaH, TBDMSCl, THF
oC to rt, 12 h, 90%
OH
17
OH
OH
18
OTBDMS
OTBDMS
11, THF, 45 °C
0
Cr(CO)5
OMe OMe
12
OTBDMS
12 h, 78%
OMe OMe
1) PCC, NaOAc, CH2Cl2
0 oC to rt, 4 h
O
O
16
OMe
EtO
EtO
2) (EtO)2POCH2COOEt, NaH
TBAF, THF
NaH, MeI, DMF
15
THF, 0 oC to rt, 12 h
82% over two steps
0 °C to rt, 3 h
81%
OTBDMS
rt, 2 h, quant.
OTBDMS
OH
K2OsO4·2H2O, (DHQD)2PHAL
K3[Fe(CN)6], K2CO3, NaHCO3
OMe OMe
10
OH
OMe
MeSO2NH2, t-BuOH:H2O (1:1)
0
1) (COCl)2, DMSO, -78 °C, 20 min, 9, 45 min
Et3N, -60 °C, 30 min, to rt, 1 h
oC, 24 h, 94%
19
OH
2) MeO2CCH2CO2H, Et3N, reflux, 12 h
72% (over two steps)
O
EtO
O
OMe OMe
2,2-DMP, p-TsOH, acetone
O
9
O
OTBDMS
rt, 12 h, 90%
OMe
O
14
MeO
O
OMe
(DHQD)2-PHAL
1) DIBAL-H, CH2Cl2, -78 oC, 2 h
OH
O
K3Fe(CN)6, K2CO3
NaHCO3, MeSO2NH2
O
2) 20, K2CO3, MeOH, rt, 16 h
76% over two steps
OMe OMe
OTBDMS
7
84%, 99.5% ee
K2OsO4.2H2O
t-BuOH/H2O (1:1)
0 °C, 24 h, rt, 12 h
OMe OMe
O
O
P
O
13
OEt
OEt
8
OMe
O
N2
20
(DHQ)2-PHAL
OH
Scheme 3. Synthesis of alkyne 13.
OMe OMe
ent-7
83%, 98.5% ee
OH
O
Scheme 2. Synthesis of c-lactone 7 and ent-7 using alkyne 11.
O
13, toluene
Cr(CO)5
OMe
45 oC, 24 h
68%
168–171 °C (decomp. at 168 °C). The spectroscopic and analytical
data of 1 were in full agreement with that reported.10 The spectro-
scopic and analytical data of ent-1 were similar to 1.
OMe
OMe OMe
OTBDMS
12
21
3. Conclusion
OMe
O
O
TBAF, THF
rt, 6 h, quant.
In conclusion, we have achieved a short enantioselective syn-
thesis of both (ꢀ)- and (+)-juglomycin A. The synthetic strategy
features an asymmetric dihydroxylation and condensation of an
achiral or chiral alkyne with Fischer carbene through Dötz benz-
annulation as the key steps. From Fischer carbene 12 the synthesis
of both antipodes of juglomycin A was completed in seven to eight
steps. The benzannulation strategy with a chiral alkyne can be
adopted toward the synthesis of other pyranonaphthoquinones
and unnatural analogs. Further work in this direction is currently
in progress in our laboratory.
MeI, NaH, DMF
oC to rt, 12 h
0
OMe OMe
OTBDMS
89%
6
O
OMe
O
OMe
O
1) PDC, DMF
rt, 24 h, 91%
O
OH
2) p-TsOH, MeOH
rt, 20 h, 87%
OMe OMe
OH
OMe OMe
22
4. Experimental
7
Scheme 4. Synthesis of
c
-lactone 7 using alkyne 13.
4.1. General information
Flasks were oven or flame dried and cooled in a desiccator. Dry
reactions were carried out under an atmosphere of Ar or N2. Sol-
vents and reagents were purified by standard methods. Thin-layer
chromatography was performed on EM 250 Kieselgel 60 F254 silica
gel plates. The spots were visualized by either staining with KMnO4
or under UV lamp. 1H NMR and 13C NMR were recorded on Varian
Mercury Plus, AS400 or Bruker, AVANCE III 400 spectrometer and
the chemical shifts are based on TMS peak at d = 0.00 ppm for 1H
NMR and CDCl3 peak at d = 77.00 ppm (t) in 13C NMR. IR spectra
were obtained on a Perkin Elmer FT-IR spectrometer. Optical
rotations were measured with a Jasco P-2000 digital polarimeter.
HRMS was recorded using a Micromass: Q-Tof micro (YA-105)
spectrometer.

R. A. Fernandes, V. P. Chavan / Tetrahedron: Asymmetry 22 (2011) 1312–1319
1315
4.1.3. tert-Butyldimethyl-[2-(10,40,50-trimethoxynaphthalen-20-
yl)-ethoxy]silane 10
O
O
OMe
O
O
O
O
(NH4)2Ce(NO3)6
MeCN/H2O (1:1)
To a solution of naphthol 16 (1.3 g, 3.58 mmol) in dry DMF
(15 mL) at 0 °C was added oil free NaH (0.26 g, 10.74 mmol, 3.0
equiv) in portions over 5 min. The reaction mixture was stirred
at room temperature for 20 min, then cooled to 0 °C and MeI
(0.70 mL, 11.2 mmol, 3.1 equiv) was added. The reaction mixture
was stirred at room temperature for 3 h. It was then quenched with
ice cold water (5 mL) and the solution extracted with EtOAc
(3 ꢂ 20 mL). The combined organic layers were washed with
water, brine, dried (Na2SO4), and concentrated. The residue was
purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 4:1) as eluent to give 10 (1.1 g, 81%) as a pale
OH
OH
rt, 15 min, 94%
OMe OMe
OMe
23
7
O
O
O
O
AlCl3, CH2Cl2
OH
0 °C, 10 min
rt, 45 min, 92%
(−)-juglomycin A 1
OH
yellow oil. IR (CHCl3)
m
= 3016, 2929, 2856, 1602, 1584, 1509, 1463,
1383, 1262, 1218, 1080, 1007, 929, 840, 770, 669 cmꢀ1
.
1H NMR
O
O
(400 MHz, CDCl3/TMS): d = 0.02 (s, 6H), 0.88 (s, 9H), 3.00 (t,
J = 7.0 Hz, 2H), 3.86 (s, 3H), 3.91 (t, J = 6.7 Hz, 2H), 3.93 (s, 3H),
3.97 (s, 3H), 6.73 (s, 1H), 6.84 (d, J = 7.6 Hz, 1H), 7.40 (t,
J = 7.9 Hz, 1H), 7.65 (dd, J = 8.2, 0.9 Hz, 1H). 13C NMR (100 MHz,
CDCl3): d = ꢀ5.4, 18.3, 25.9, 33.8, 56.4, 56.9, 61.8, 63.5, 106.0,
109.2, 114.7, 117.5, 126.4, 127.8, 131.3, 147.5, 153.0, 157.3. HRMS
(ESI-TOF): (m/z) calcd for [C21H32O4Si+H] 377.2148, found
377.2154.
OMe
O
O
O
O
(NH4)2Ce(NO3)6
MeCN/H2O (1:1)
OH
OH
rt, 15 min, 94%
OMe OMe
OMe
ent-23
ent-7
O
O
O
4.1.4. 2-(10,40,50-Trimethoxynaphthalen-20-yl)-ethanol 9
To a solution of compound 10 (0.40 g, 1.06 mmol) in dry THF
(20 mL) was added TBAF (1.27 mL, 1.27 mmol, 1 M solution in
THF, 1.2 equiv). The reaction mixture was stirred at room temper-
ature for 2 h. It was then quenched with water (10 mL) and stirred
for 10 min. Next, THF was removed under reduced pressure and
the solution was extracted with EtOAc (3 ꢂ 20 mL). The combined
organic layers were washed with water, brine, dried (Na2SO4), and
concentrated. The residue was purified by silica gel column chro-
matography using petroleum ether/EtOAc (9:1 to 3:2) as eluent
AlCl3, CH2Cl2
OH
0 °C, 10 min
rt, 45 min, 93%
(+)-juglomycin A ent -1
OH
O
Scheme 5. Synthesis of (ꢀ)-1 and (+)-ent-1.
4.1.1. Methoxy (o-methoxyphenyl)methylene pentacarbonyl
chromium 12
to give 9 (0.28 g, quant.) as a pale yellow oil. IR (CHCl3)
3019, 2936, 2842, 1602, 1584, 1509, 1464, 1383, 1263, 1217,
1126, 1073, 1043, 1006, 929, 853, 762, 669 cmꢀ1 1H NMR
m = 3460,
The carbene complex 12 was prepared as reported earlier17,20 as
brown-red oil which later solidified. Mp 70–71 °C, lit.20 71–74 °C.
.
IR (CHCl3)
1583, 1482, 1464, 1435, 1292, 1251, 1185, 1148, 1054, 1023,
925, 752, 668 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 3.82 (s,
m = 3008, 2952, 2062, 2017, 1929, 1848, 1730, 1599,
(400 MHz, CDCl3/TMS): d = 3.02 (t, J = 6.4 Hz, 2H), 3.84 (s, 3H),
3.91 (t, J = 6.7 Hz, 2H), 3.92 (s, 3H), 3.94 (s, 3H), 6.66 (s, 1H), 6.83
(d, J = 7.3 Hz, 1H), 7.39 (t, J = 8.2 Hz, 1H), 7.63 (dd, J = 8.6, 1.0 Hz,
1H). 13C NMR (100 MHz, CDCl3): d = 33.7, 56.3, 56.8, 61.6, 63.1,
106.2, 108.5, 114.6, 117.6, 126.7, 127.3, 131.3, 147.5, 153.5,
157.3. HRMS (ESI-TOF): (m/z) calcd for [C15H18O4+H] 263.1283,
found 263.1279.
.
3H), 4.15 (br s, 3H), 6.77 (dd, J = 7.5, 1.4 Hz, 1H), 6.92 (d,
J = 8.4 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.3 Hz, 1H). 13C
NMR (100 MHz, CDCl3): d = 55.6, 65.3, 110.9, 113.9, 120.6, 121.3,
129.4, 148.6, 159.5, 225.1, 216.0.
4.1.2. 2-[2-(tert-Butyldimethylsilyloxy)ethyl]-4,5-
dimethoxynaphthalen-1-ol 16
4.1.5. 4-(10,40,50-Trimethoxynaphthalene-20yl)methylbut-3-
enote 8
To a freshly prepared chromium carbene complex 12 (4.50 g,
13.15 mmol) in dry and degassed THF (7 mL) was added 1-(tert-
To a solution of DMSO (0.27 mL, 3.81 mmol, 2.0 equiv) in dry
CH2Cl2 (30 mL) at ꢀ78 °C was added oxalyl chloride (0.23 mL,
2.66 mmol, 1.4 equiv) dropwise and stirred for 20 min. Next, a
solution of alcohol 9 (0.5 g, 1.9 mmol) in CH2Cl2 (5 mL) was added.
The resulting reaction mixture was stirred for 45 min, warmed to
ꢀ60 °C and Et3N (1.06 mL, 7.6 mmol, 4.0 equiv) was added. The
mixture was then warmed to room temperature, stirred for 1 h
and then quenched with water (10 mL). The solution was extracted
with CH2Cl2 (3 ꢂ 20 mL). The combined organic layers were
washed with 1 M HCl (10 mL), sat. aq. NaHCO3 (10 mL), brine, dried
(Na2SO4), and concentrated. The crude aldehyde was used for the
next reaction without further purification. To the crude aldehyde
in Et3N (15 mL), the monomethyl ester of malonic acid (0.450 g,
3.81 mmol, 2.0 equiv) was added and the reaction mixture stirred
at 90 °C for 14 h. It was cooled and diluted with water (20 mL)
and EtOAc (10 mL). The organic layer was separated and the
aqueous layer extracted with EtOAc (3 ꢂ 30 mL). The combined or-
ganic extracts were washed with water, brine, dried (Na2SO4), and
concentrated. The residue was purified by silica gel column
butyldimethylsilyloxy)but-3-yne
11
(3.63 g,
19.72 mmol,
1.5 equiv). The reaction mixture was stirred at 45 °C for 12 h. It
was then cooled to room temperature, and exposed to air and stir-
red further for 30 min. The reaction mixture was concentrated and
the residue purified by silica gel column chromatography using
petroleum ether/EtOAc (9:1 to 4:1) as eluent to give 16 (3.72 g,
78%) as a yellow oil, which solidified upon cooling. Mp 80–82 °C.
IR (CHCl3)
1390, 1317, 1258, 1127, 1076, 1036, 925, 849, 837, 781, 754,
667 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 0.07 (s, 6H), 0.91
m = 3285, 2953, 2930, 2858, 1626, 1602, 1510, 1464,
.
(s, 9H), 2.99 (t, J = 5.2 Hz, 2H), 3.91 (s, 3H), 3.97 (s, 3H), 4.00 (t,
J = 5.2 Hz, 2H), 6.59 (s, 1H), 6.85 (d, J = 7.9 Hz, 1H), 7.36 (t,
J = 8.5 Hz, 1H), 7.92 (dd, J = 8.2, 0.9 Hz, 1H), 8.45 (s, 1H, OH). 13C
NMR (100 MHz, CDCl3): d = –5.7 (2C), 18.2, 25.8 (3C), 35.6, 56.4,
57.9, 65.9, 106.1, 111.3, 115.4, 117.8, 120.1, 125.4, 129.0, 145.4,
150.1, 156.5. HRMS (ESI-TOF): (m/z) calcd for [C20H30O4Si+H]
363.1992, found 363.1988.

1316
R. A. Fernandes, V. P. Chavan / Tetrahedron: Asymmetry 22 (2011) 1312–1319
chromatography using petroleum ether/EtOAc (9:1 to 4:1) as elu-
ent to give 8 (0.434 g, 72% over two steps) as a pale yellow oil. IR
1H), 3.73 (t, J = 5.5 Hz, 2H), 3.78 (t, J = 5.5 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d = –5.4 (2C), 18.1, 25.7 (3C), 34.1, 62.4, 62.8.
(CHCl3)
m
= 3004, 2954, 2912, 1732, 1597, 1461, 1440, 1382,
1350, 1203, 1165, 1124, 1006, 975, 913, 851 cmꢀ1
.
1H NMR
4.1.8. (E)-Ethyl 5-(tert-butyldimethylsilyloxy)pent-2-enoate 15
To a mixture of PCC (5.1 g, 23.64 mmol, 1.5 equiv) and NaOAc
(1.94 g, 23.64 mmol, 1.5 equiv) in dry CH2Cl2 (60 mL) was added
a solution of alcohol 18 (3.0 g, 15.76 mmol) in CH2Cl2 (15 mL) at
0 °C. The reaction mixture was stirred for 4 h at room temperature
and then diluted with petroleum ether/EtOAc (7:3, 80 mL). The
slurry was stirred and filtered through a pad of silica gel and Celite.
The residue was washed 3–4 times with petroleum ether/EtOAc
(7:3) and filtered. The filtrate was concentrated to give virtually
pure aldehyde (2.8 g), which was used directly in the next reaction.
(400 MHz, CDCl3/TMS): d = 3.35 (dd, J = 7.2, 1.5 Hz, 2H), 3.72 (s,
3H), 3.84 (s, 3H), 3.95 (s, 3H), 3.97 (s, 3H), 6.40 (dt, J = 16.1,
7.1 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.93 (s, 1H), 6.97 (dt, J = 16.1,
1.5 Hz, 1H), 7.39 (dd, J = 8.2, 8.1 Hz, 1H), 7.70 (dd, J = 8.4, 1.0 Hz,
1H). 13C NMR (100 MHz, CDCl3): d = 38.4, 51.7, 56.2, 56.7, 62.0,
103.1, 106.8, 114.8, 122.7, 126.7, 127.6, 118.0, 125.0, 131.5,
147.0, 153.4, 157.2, 171.8. HRMS (ESI-TOF): (m/z) calcd for
[C18H20O5+H] 317.1389, found 317.1381.
To
a stirred solution of triethyl phosphonoacetate (4.05 g,
4.1.6. (4R,5R)-4-Hydroxy-5-(10,40,50-trimethoxynaphth-20-yl)-
dihydrofuran-2(3H)-one 7 and ent-72e
18.07 mmol) in dry THF (60 mL) at 0 °C was added NaH (60% min-
eral oil suspension, 0.723 g, 18.07 mmol) in portions over 10 min.
The mixture was stirred at room temperature for 30 min, cooled
to 0 °C, and the above aldehyde (2.8 g, 15.08 mmol) in THF
(10 mL) was added. The reaction mixture was warmed to room
temperature, stirred for 12 h and then quenched with saturated
aq. NH4Cl solution (10 mL). The solution was extracted with EtOAc
(3 ꢂ 30 mL). The combined organic layers were washed with
water, brine, dried (Na2SO4), and concentrated. The residue was
purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1) as eluent to afford 15 (3.34 g, 82% overall) as a
colorless oil. IR (CHCl3)
1722, 1656, 1472, 1446, 1390, 1370, 1315, 1257, 1176, 1097,
1046, 980, 867, 837, 776, 668 cmꢀ1 1H NMR (400 MHz, CDCl3/
TMS): d = 0.04 (s, 6H), 0.88 (s, 9H), 1.27 (t, J = 7.0 Hz, 3H), 2.38–
2.43 (m, 2H), 3.71 (t, J = 6.4 Hz, 2H), 4.18 (q, J = 7.0 Hz, 2H), 5.85
(dt, J = 15.2, 1.5 Hz, 1H), 6.92 (dt, J = 15.8, 1.5 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d = –5.5, –5.4, 14.2, 18.3, 25.8 (3C), 35.7, 60.1,
61.5, 122.9, 145.8, 166.4.
To a mixture of K3Fe(CN)6 (4.22 g, 12.81 mmol, 3.0 equiv),
K2CO3 (1.77 g, 12.81 mmol, 3.0 equiv), MeSO2NH2 (406 mg,
4.27 mmol, 1.0 equiv), NaHCO3 (1.08 g, 12.81 mmol, 3.0 equiv),
(DHQD)2-PHAL (33.3 mg, 0.427 mmol, 1 mol %), K2OsO4ꢃ2H2O
(6.3 mg, 17.1 lmol, 0.4 mol %), t-BuOH (15 mL) and water
(25 mL) were added. The mixture was stirred for 5 min and cooled
to 0 °C in an ice bath. To the cooled mixture, a solution of b,
c
-
unsaturated ester 8 (1.35 g, 4.27 mmol) in t-BuOH (10 mL) was
added. The reaction mixture was stirred at 0 °C for 24 h and at
room temperature for 12 h. It was then quenched with solid
Na2SO3 (3.0 g) and stirred for 30 min. The solution was extracted
with EtOAc (3 ꢂ 50 mL). The combined organic layers were washed
with 1 M KOH (15 mL), water (50 mL), brine, dried (Na2SO4), and
concentrated. The residue was purified by silica gel column chro-
matography using petroleum ether/EtOAc (3:2 to 1:1) as eluent
m = 2955, 2930, 2858, 2886, 1722, 1656,
.
to afford
¼ ꢀ11:2 (c 0.6, CHCl3). IR (CHCl3)
2945, 2843, 1782, 1731, 1622, 1603, 1588, 1513, 1466, 1355,
1340, 1323, 1261, 1232, 1159, 1123, 1081, 1044, 984, 915 cmꢀ1
7
(1.14 g, 84%) as
a
white solid. Mp 134–136 °C.
½
a 2D5
ꢁ
m
= 3289, 3004, 2966,
.
4.1.9. (2S,3R)-Ethyl 5-(tert-butyldimethylsilyloxy)-2,3-
dihydroxypentanoate 1915
1H NMR (400 MHz, CDCl3/TMS): d = 2.05 (s, 1H, OH), AB signal
(dA = 2.73, dB = 2.91, JAB = 17.4 Hz, the A-part shows no additional
splitting by JA,4, in addition the B-part is split by JB,4 = 5.5 Hz, 2H),
3.86 (s, 3H), 3.95 (s, 3sH), 3.96 (s, 3H), 4.81–4.84 (m, 1H), 5.84
(d, J = 3.6 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.89 (s, 1H), 7.42 (dd,
J = 8.1, 8.1 Hz, 1H), 7.58 (dd, J = 8.4, 1.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d = 38.2, 56.5, 56.7, 61.9, 69.7, 81.8, 104.0,
107.2, 114.4, 117.1, 118.4, 122.3, 130.6, 145.9, 153.8, 157.5,
175.6. HRMS (ESI-TOF): (m/z) calcd for [C17H18O6+H] 319.1181,
found 319.1177. Similarly, the asymmetric dihydroxylation of
To a mixture of K3Fe(CN)6 (11.46 g, 34.82 mmol, 3.0 equiv),
K2CO3 (4.81 g, 34.82 mmol, 3.0 equiv), MeSO2NH2 (1.10 g,
11.60 mmol, 1.0 equiv), NaHCO3 (2.92 g, 34.82 mmol, 3.0 equiv),
(DHQD)2-PHAL (90.4 mg, 0.116 mmol, 1 mol %), K2OsO4ꢃ2H2O
(17.1 mg, 46.4 lmol, 0.4 mol %), t-BuOH (40 mL), and water
(60 mL) were added. The mixture was stirred for 5 min and cooled
to 0 °C in an ice bath. To the cooled mixture, a solution of the b,
c-
unsaturated ester 15 (3.0 g, 11.60 mmol) in t-BuOH (20 mL) was
added. The reaction mixture was stirred at 0 °C for 24 h. It was then
quenched with solid Na2SO3 (6 g) and stirred for 30 min. The solu-
tion was extracted with EtOAc (3 ꢂ 50 mL). The combined organic
layers were washed with brine, dried (Na2SO4), and concentrated.
The residue was purified by silica gel column chromatography
using petroleum ether/EtOAc (9:1 to 3:2) as eluent to afford 19
b,c-unsaturated ester 8 (1.0 g, 3.17 mmol) with (DHQ)2-PHAL li-
gand following the above procedure afforded ent-7 (0.835 g, 83%)
as a white solid. Mp 131–133 °C. ½a D25
¼ þ11:0 (c 0.4, CHCl3). Spec-
ꢁ
troscopic and analytical data same as 7. Enantiomeric excess (ee)
was determined by chiral HPLC as reported in the literature.2e
(3.2 g, 94%) as a colorless viscous oil. ½a D25
¼ ꢀ3:6 (c 0.9, CHCl3).
ꢁ
4.1.7. 3-(tert-Butyldimethylsilyloxy)propan-1-ol 1815a,21
IR (CHCl3)
m = 3472, 3020, 2957, 2931, 2859, 1737, 1472, 1388,
1258, 1217, 1129, 1097, 1026, 838, 759, 669 cmꢀ1 1H NMR
.
To a stirred solution of 1,3-propane diol 17 (3.0 g, 39.42 mmol)
in dry THF (40 mL) at 0 °C was added oil free NaH (0.95 g,
39.42 mmol, 1.0 equiv) in portions over 15 min. The reaction mix-
ture was stirred at room temperature for 30 min, then cooled to
0 °C after which TBDMSCl (5.94 g, 39.42 mmol, 1.0 equiv) was
added. The reaction mixture was stirred at room temperature for
12 h. It was then quenched with ice cold water (10 mL) and the
solution extracted with EtOAc (3 ꢂ 30 mL). The combined organic
layers were washed with water, brine, dried (Na2SO4), and concen-
trated. The residue was purified by silica gel column chromatogra-
phy using petroleum ether/EtOAc (9:1 to 4:1) as eluent to give 18
(400 MHz, CDCl3/TMS): d = 0.07 (s, 6H), 0.89 (s, 9H), 1.30 (t,
J = 7.1 Hz, 3H), 1.69–1.77 (m, 1H), 1.90–1.99 (m, 1H), 3.20 (d,
J = 7.1 Hz, 1H, OH), 3.25 (d, J = 4.9 Hz, 1H, OH), 3.80–3.93 (m, 2H),
4.06 (dd, J = 3.5, 1.9 Hz, 1H), 4.15–4.20 (m, 1H), 4.27 (q, J = 7.1 Hz,
2H). 13C NMR (100 MHz, CDCl3): d = –5.6 (2C), 14.1, 18.1, 25.8
(3C), 35.3, 61.6, 61.8, 72.1, 73.7, 173.2. HRMS (ESI-TOF): (m/z) calcd
for [C13H28O5Si+Na] 315.1598, found 315.1606. The ee was deter-
mined to be 92% by chiral HPLC of its dibenzoate.
4.1.10. (2S,3R)-Ethyl 2,3-isopropylidenedioxy-5-(tert-butyl-
dimethylsilyloxy)pentanoate 14
To a solution of diol 19 (3.0 g, 10.26 mmol) in dry acetone
(50 mL) was added 2,2-dimethoxy propane (3.78 mL, 30.77 mmol,
(6.75 g, 90%) as a colorless oil. IR (CHCl3)
1473, 1257, 1065, 985, 838, 774 cmꢀ1 1H NMR (400 MHz, CDCl3/
TMS): d = 0.033 (s, 6H), 0.86 (s, 9H), 1.71–1.74 (m, 2H), 2.93 (br s,
m = 3368, 2931, 2859,
.

R. A. Fernandes, V. P. Chavan / Tetrahedron: Asymmetry 22 (2011) 1312–1319
1317
3.0 equiv) followed by p-TsOH (5 mg). The reaction mixture was
stirred at room temperature for 12 h. Solid NaHCO3 (0.5 g) was then
added and stirred for 15 min. The solution was filtered through a
pad of silica gel and washed with EtOAc and concentrated. The res-
idue was purified by silica gel column chromatography using petro-
leum ether/EtOAc (9:1 to 4:1) as eluent to afford 14 (3.07 g, 90%) as
NMR (100 MHz, CDCl3): d = –5.4 (2C), 18.3, 25.9 (3C), 26.9, 27.1,
33.4, 56.4, 57.8, 59.4, 78.4, 82.2, 106.9, 107.0, 109.1, 112.9, 114.9,
118.2, 125.9, 128.6, 145.1, 150.0, 156.5. HRMS (ESI-TOF): (m/z)
calcd for [C25H38O6Si+H] 463.2516, found 463.2520.
4.1.13. (1R,2R)-tert-Butyldimethyl-[1-(10,40,50-trimethoxynaph-
thalen-20-yl)-1,2-isopropylidenedioxy-4-butoxy]-silane 6
a colorless oil. ½a D25
ꢁ
= +11.6 (c 1.16, CHCl3). IR (CHCl3) m = 2988, 2955,
2930, 2858, 1758, 1472, 1382, 1372, 1257, 1217, 1192, 1168, 1102,
To a solution of naphthol 21 (0.5 g, 1.08 mmol) in dry DMF
(10 mL) at 0 °C was added oil free NaH (78 mg, 3.24 mmol,
3.0 equiv) in portions over 5 min. The reaction mixture was stirred
at room temperature for 20 min, then cooled to 0 °C and MeI
(0.21 mL, 3.36 mmol, 3.1 equiv) was added. The reaction mixture
was warmed at room temperature and stirred for 12 h. It was then
quenched with ice cold water (5 mL) and the solution extracted
with EtOAc (3 ꢂ 20 mL). The combined organic layers were washed
with water, brine, dried (Na2SO4), and concentrated. The residue
was purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 4:1) as eluent to give 6 (0.459 g, 89%) as a pale
1036, 939, 837, 776, 759, 667 cmꢀ1 1H NMR (400 MHz, CDCl3/
.
TMS): d = 0.04 (s, 6H), 0.87 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H), 1.43 (s,
3H), 1.45 (s, 3H), 1.79–1.89 (m, 1H), 1.97–2.06 (m, 1H), 3.71–3.82
(m, 2H), 4.15–4.29 (m, 4H). 13C NMR (100 MHz, CDCl3): d = –5.5, –
5.4, 14.2, 18.2, 25.7, 25.8 (3C), 27.2, 36.5, 59.4, 61.3, 76.0, 78.1,
110.7, 170.7. HRMS (ESI-TOF): (m/z) calcd for [C16H32O5Si+H]
333.2097, found 333.2097.
4.1.11. (3R,4R)-3,4-Isopropylidenedioxy-6-(tert-butyldimethyl-
silyloxy)hex-1-yne 13
To a solution of 14 (1.5 g, 4.51 mmol) in dry CH2Cl2 (40 mL) at –
78 °C under an argon atmosphere was added DIBAL-H (5.0 mL,
5.0 mmol, 1 M in hexane, 1.1 equiv) dropwise over a period of
1 h. The reaction mixture was stirred at the same temperature
for 30 min. It was then quenched with a saturated aq. solution of
Rochelle’s salt (20 mL), warmed to room temperature and stirred
for 2 h. The solution was extracted with CH2Cl2 (3 ꢂ 40 mL) and
the combined organic layers were washed with water, brine, dried
(Na2SO4), and concentrated. The residue was purified by silica gel
column chromatography using petroleum ether/EtOAc (9:1) as elu-
ent to give the aldehyde (1.28 g). To the solution of the aldehyde
(1.28 g) in methanol (20 mL) was added freshly prepared Best-
mann–Ohira’s reagent 20 (1.17 g, 5.31 mmol, 1.2 equiv w.r.t alde-
hyde) followed by K2CO3 (1.53 g, 11.07 mmol, 2.5 equiv). The
resulting solution was stirred at room temperature for 16 h. It
was then quenched with water (10 mL) and methanol was re-
moved under reduced pressure. The solution was extracted with
EtOAc (3 ꢂ 20 mL) and the combined organic layers were washed
with water, brine, dried (Na2SO4), and concentrated. The residue
was purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 4:1) as eluent to afford alkyne 13 (0.98 g, 76%
yellow oil. ½a 2D5
ꢁ
¼ þ22:4 (c 0.86, CHCl3). IR (CHCl3)
m = 2952, 2895,
2856, 1601, 1586, 1492, 1464, 1437, 1380, 1305, 1286, 1255, 1166,
1129, 1086, 1051, 1025, 837, 757, 706, 661 cmꢀ1 1H NMR
.
(400 MHz, CDCl3/TMS): d = ꢀ0.08 (s, 3H), ꢀ0.03 (s, 3H), 0.79 (s,
9H), 1.56 (s, 3H), 1.61 (s, 3H), 1.79–1.91 (m, 2H), 3.69 (dd, J = 7.4,
5.7 Hz, 2H), 3.87 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 4.05 (dt, J =
8.5, 3.6 Hz, 1H), 5.14 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H),
6.91 (s, 1H), 7.41 (t, J = 8.3 Hz, 1H), 7.66 (dd, J = 8.4, 0.9 Hz, 1H).
13C NMR (100 MHz, CDCl3): d = 5.52, –5.5, 18.2, 25.8 (3C), 27.1,
27.5, 34.8, 56.5, 56.6, 59.8, 62.5, 77.2, 79.2, 104.0, 106.9, 108.7,
114.9, 118.4, 125.7, 126.8, 131.2, 148.1, 153.9, 157.4. HRMS
(ESI-TOF): (m/z) calcd for [C26H40O6Si+Na] 499.2492, found
499.2486.
4.1.14. (1R,2R)-1-(10,40,50-Trimethoxynaphthalen-20-yl)-1,2-
isopropylidenedioxybutan-4-ol 22
To a solution of compound 6 (0.11 g, 0.23 mmol) in dry THF
(10 mL) was added TBAF (0.3 mL, 0.3 mmol, 1 M in THF, 1.3 equiv).
The reaction mixture was stirred at room temperature for 6 h. It
was then quenched with water (5 mL) and stirred for 10 min. Next,
THF was removed under reduced pressure and the solution was ex-
tracted with EtOAc (3 ꢂ 20 mL). The combined organic layers were
washed with water, brine, dried (Na2SO4), and concentrated. The
residue was purified by silica gel column chromatography using
petroleum ether/EtOAc (9:1 to 7:3) as eluent to give 22 (83 mg,
overall) as a colorless oil. ½a D25
¼ þ7:7 (c 0.86, CHCl3). IR (CHCl3)
ꢁ
m
= 3309, 3019, 2953, 2990, 2931, 2858, 2990, 1472, 1383, 1259,
1218, 1093, 1052, 938, 838, 769, 669 cmꢀ1 1H NMR (400 MHz,
.
CDCl3/TMS): d = 0.05 (s, 3H), 0.06 (s, 3H), 0.89 (s, 9H), 1.40 (s,
3H), 1.45 (s, 3H), 1.74–1.97 (m, 2H), 2.49 (d, J = 2.1 Hz, 1H), 3.72–
3.81 (m, 2H), 4.16 (dt, J = 7.7, 4.6 Hz, 1H), 4.30 (dd, J = 7.8, 2.1 Hz,
1H). 13C NMR (100 MHz, CDCl3): d = –5.43, –5.4, 18.2, 25.9 (3C),
26.1, 27.1, 35.3, 59.4, 70.2, 74.5, 78.7, 80.7, 109.9. HRMS (ESI-
TOF): (m/z) calcd for [C15H28O3Si+H] 285.1886, found 285.1894.
quant.) as yellow solid. Mp 114–116 °C. ½a D25
¼ þ30:5 (c 0.24,
ꢁ
CHCl3). IR (CHCl3)
m = 3436, 3019, 2929, 2855, 1601, 1587, 1465,
1379, 1262, 1216, 1126, 1077, 762, 669 cmꢀ1 1H NMR (400 MHz,
.
CDCl3/TMS): d = 1.58 (s, 3H), 1.63 (s, 3H), 1.88–2.01 (m, 2H),
3.72–3.83 (m, 2H), 3.87 (s, 3H), 3.96 (s, 3H), 3.97 (s, 3H), 4.02 (dt,
J = 8.4, 3.7 Hz, 1H), 5.22 (d, J = 8.6 Hz, 1H), 6.89 (d, J = 7.1 Hz, 1H),
6.93 (s, 1H), 7.43 (t, J = 8.3 Hz, 1H), 7.64 (dd, J = 8.5, 1.0 Hz, 1H).
13C NMR (100 MHz, CDCl3): d = 27.1, 27.4, 33.6, 56.5, 56.7, 60.8.
62.3, 77.2, 82.0, 103.7, 106.8, 109.3, 114.8, 118.4, 125.5, 126.9,
131.2, 147.7, 154.1, 157.5. HRMS (ESI-TOF): (m/z) calcd for
[C20H26O6+Na] 385.1627, found 385.1624.
4.1.12. (10R,20R)-2-(10,20-Isopropylidenedioxy)-40-(tert-butyl-
dimethylsilyloxy)butyl-4,5-dimethoxynaphthalen-1-ol 21
To a freshly prepared chromium carbene complex 12 (0.9 g,
2.63 mmol) in dry and degassed toluene (6 mL) was added alkyne
13 (0.897 g, 3.15 mmol, 1.2 equiv). The reaction mixture was stir-
red at 45 °C for 24 h. It was then cooled to room temperature, ex-
posed to air and stirred for a further 30 min. The reaction mixture
was concentrated and the residue purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1 to 7:3) as elu-
4.1.15. (4R,5R)-4-Hydroxy-5-(10,40,50-trimethoxynaphth-20-
yl)dihydrofuran-2(3H)-one 7 from 22
To a solution of 22 (60 mg, 0.165 mmol) in DMF (3 mL) was
added PDC (0.218 g, 0.579 mmol, 3.5 equiv). The resulting reaction
mixture was stirred at room temperature for 24 h. It was then
quenched with water (10 mL) and the solution extracted with
EtOAc (3 ꢂ 20 mL). The combined organic layers were washed with
water, brine, dried (Na2SO4), and concentrated. The residue was
purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 3:2) as eluent to give the acid (57 mg, 91%)
ent to give 21 (0.827 g, 68%) as a pale yellow oil. ½a D25
¼ þ3:7 (c
ꢁ
0.48, CHCl3). IR (CHCl3)
m = 3368, 3017, 2956, 2931, 5858, 1658,
1601, 1464, 1382, 1308, 1257, 1217, 1089, 939, 838, 759,
669 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS): d = 0.04 (s, 3H), 0.06
.
(s, 3H), 0.87 (s, 9H), 1.55 (s, 3H), 1.65 (s, 3H), 1.84–1.98 (m, 2H),
3.70–3.76 (m, 2H), 3.89 (s, 3H), 3.97 (s, 3H), 4.09–4.14 (m, 1H),
4.99 (d, J = 8.9 Hz, 1H), 6.59 (s, 1H), 6.89 (d, J = 7.9 Hz, 1H), 7.38
(t, J = 8.1 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 8.45 (s, 1H, OH). 13C
as a white solid. Mp 128–130 °C. ½a D25
¼ þ19:4 (c 0.20, CHCl3). IR
ꢁ

1318
R. A. Fernandes, V. P. Chavan / Tetrahedron: Asymmetry 22 (2011) 1312–1319
(CHCl3)
m
= 3471, 2928, 2853, 1729, 1601, 1587, 1509, 1463, 1380,
1H
4.1.18. (20S,30S)-2-(30-Hydroxy-50-oxotetrahydrofuran-20-yl)-5-
methoxynaphthalene-1,4-dione ent-23
1264, 1221, 1127, 1079, 1004, 907, 850, 810, 758, 668 cmꢀ1
.
NMR (400 MHz, CDCl3/TMS): d = 1.58 (s, 3H), 1.63 (s, 3H), 2.69
(dd, J = 16.3, 8.7 Hz, 1H), 2.84 (dd, J = 16.3, 3.0 Hz, 1H), 3.86 (s,
3H), 3.97 (s, 6H), 4.19–4.26 (m, 1H), 5.21 (d, J = 8.6 Hz, 1H), 6.89
(d, J = 7.4 Hz, 1H), 6.96 (s, 1H), 7.42 (t, J = 8.2 Hz, 1H), 7.63 (d,
J = 7.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): d = 27.1, 27.2, 36.7,
56.5, 56.7, 62.2, 66.0, 78.7, 103.6, 107.1, 109.7, 114.8, 118.5,
125.3, 127.0, 131.1, 147.6, 154.1, 157.5, 174.3. HRMS (ESI-TOF):
(m/z) calcd for [C20H24O7+H] 377.1600, found 377.1589. To a solu-
tion of the acid (57 mg, 0.151 mmol) in MeOH (5 mL) was added p-
TsOH (4 mg). The resulting solution was stirred at room tempera-
ture for 20 h. It was then quenched with solid NaHCO3 (20 mg)
and concentrated. The residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1 to 3:2) as elu-
ent to give 7 (42 mg, 87%) as a white solid. Mp 132–134 °C.
The title compound was prepared from ent-7 (80 mg,
0.251 mmol) by a similar procedure as described for the conver-
sion of 7 to 23 with CAN to give ent-23 (68 mg, 94%) as a yellow
solid. Mp 171–173 °C (decomp. at 170 °C). ½a D25
ꢁ
= +55.9 (c 0.3,
CHCl3). The spectroscopic and analytical data were similar to 23.
4.1.19. (+)-Juglomycin A ent-1
The title compound was prepared from ent-23 (38 mg,
0.135 mmol) with AlCl3 by following a similar procedure as de-
scribed for the conversion of 23 to 1 to give ent-1 (34 mg, 93%)
as a yellow solid. Mp 168–171 °C (decomp. at 168 °C). ½a D25
ꢁ
=
+49.2 (c 0.2, CHCl3). The spectroscopic and analytical data were
similar to 1.
½
a 2D5
ꢁ
¼ ꢀ11:6 (c 0.46, CHCl3). The spectroscopic and analytical data
Acknowledgments
were the same as before.
The authors are indebted to the Board of Research in Nuclear
sciences (BRNS), Government of India (Grant No. 2009/37/25
BRNS) for financial support. V.P.C. thanks the Council of Scientific
and Industrial Research (CSIR), New Delhi for a Senior Research
Fellowship.
4.1.16. (20R,30R)-2-(30-Hydroxy-50-oxotetrahydrofuran-20-yl)-5-
methoxynaphthalene-1,4-dione 23
To the solution of compound 7 (0.1 g, 0.314 mmol) in CH3CN/
H2O (1:1, 10 mL) was added CAN (0.344 g, 0.628 mmol, 2.0 equiv).
The resulting solution was stirred at room temperature for 15 min.
Water (5 mL) was added and CH3CN removed under reduced pres-
sure. The solution was extracted with EtOAc (3 ꢂ 30 mL) and the
combined organic layers were washed with brine, dried (Na2SO4),
and concentrated. The residue was purified by silica gel column
chromatography using petroleum ether/EtOAc (9:1 to 4:1) as elu-
ent to afford 23 (85 mg, 94%) as a yellow solid. Mp 173–175 °C.
References
1. (a) Ushiyama, K.; Tanaka, N.; Ono, H.; Ogata, H. J. Antibiot. 1971, 24, 197; (b)
Tanaka, N.; Ogata, H.; Ushiyama, K.; Ono, H. J. Antibiot. 1971, 24, 222.
2. Isolation: (a) Bergy, M. E. J. Antibiot. 1968, 21, 454; Structure elucidation: (b)
Hoeksema, H.; Krueger, W. C. J. Antibiot. 1976, 29, 704; Syntheses: (c) Kraus, G.
A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.; Prugh, S. J. Org. Chem. 1983, 48,
3439; (d) Tatsuta, K.; Akimoto, K.; Annaka, M.; Ohno, Y.; Kinoshita, M. Bull.
Chem. Soc. Jpn. 1985, 58, 1699; (e) Fernandes, R. A.; Bruckner, A. Synlett 2005,
1281; (f) Donner, C. D. Tetrahedron Lett. 2007, 48, 8888.
3. Isolation: (a) Iwai, Y.; Kora, A.; Takahashi, Y.; Hayashi, T.; Awaya, J.; Masuma,
R.; Oiwa, R.; Omura, S. J. Antibiot. 1978, 31, 959; Syntheses: (b) Foland, L. D.;
Decker, O. H. W.; Moore, H. W. J. Am. Chem. Soc. 1989, 111, 989; (c) Ichihara, A.;
Ubukata, M.; Oikawa, H.; Murakawi, K.; Sakamura, S. Tetrahedron Lett. 1980, 21,
4469; (d) Kraus, G. A.; Li, J. J. Am. Chem. Soc. 1993, 115, 5859; (e) Contant, P.;
Haess, M.; Riegl, J.; Scalone, M.; Visnick, M. Synthesis 1999, 821; (f) Kraus, G. A.;
Li, J.; Gordon, M. S.; Jensen, J. H. J. Org. Chem. 1995, 60, 1154; (g) Masquelin, T.;
Hengartner, U.; Streith, J. Helv. Chim. Acta 1997, 80, 43.
½
a 2D5
ꢁ
¼ ꢀ57:8 (c 0.20, MeOH). IR (CHCl3)
2896, 1793, 1725, 1659, 1587, 1472, 1447, 1391, 1282, 1246,
1185, 1151, 1046, 877 cmꢀ1 1H NMR (400 MHz, CDCl3/TMS):
m = 3464, 3015, 2977,
.
d = 2.2 (br s, 1H, OH), AB signal (dA = 2.70, dB = 2.95, JAB = 17.8 Hz,
A-part shows no additional splitting by JA,4, in addition the B-part
is split by JB,4 = 5.9 Hz, 2H), 3.95 (s, 3H), 5.03 (d, J = 4.4 Hz, 1H),
5.54–5.56 (m, 1H), 7.01 (s, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.64–7.72
(m, 2H). 13C NMR (100 MHz, acetone-d6): d = 39.4, 56.7, 69.9,
81.0, 119.3, 119.6, 120.3, 135.1, 135.8, 137.1, 142.8, 160.6, 175.3,
183.6, 184.7. HRMS (ESI-TOF): (m/z) calcd for [C15H12O6+H]
289.0711, found 289.0709.
4. Isolation and structure elucidation: (a) Omura, S.; Tanaka, H.; Okada, Y.;
Marumo, H. J. Chem. Soc., Chem. Commun. 1976, 320; Syntheses: (b) Ref. 2c; (c)
Tatsuta, K.; Akimoto, K.; Annaka, M.; Ohno, Y.; Kinoshita, M. J. Antibiot. 1985,
38, 680; (d) see Ref.2d; (e) Winters, M. P.; Strandberg, M.; Moore, H. W. J. Org.
2e
Chem. 1994, 59, 7572; (f) see Ref.
5. Isolation and structure elucidation: (a) Hochlowski, J. E.; Brill, G. M.; Anders, W.
W.; Spanton, S. G.; McAlpine, J. B. J. Antibiot. 1987, 40, 401; Synthesis: (b)
Brimble, M. A.; Phythian, S. J.; Prabaharan, H. J. Chem. Soc., Perkin Trans. 1 1995,
2855.
6. Isolation: (a) Nelson, R. A.; Pope, J. A., Jr.; Luedemann, G. M.; McDaniel, L. E.;
Schaffner, C. P. J. Antibiot. 1986, 39, 335; Isolation and structure elucidation: (b)
Ling, D.; Shield, L. S.; Rinehart, K. L., Jr. J. Antibiot. 1986, 39, 345; Synthesis of a
racemic mixture with one diastereomer: (c) Li, Z.; Gao, Y.; Tang, Y.; Dai, M.;
Wang, G.; Wang, Z.; Yang, Z. Org. Lett. 2008, 10, 3017.
4.1.17. (ꢀ)-Juglomycin A 1
To a solution of 23 (45 mg, 0.156 mmol) in CH2Cl2 (10 mL) at
0 °C was added anhydrous AlCl3 (41.6 mg, 0.312 mmol, 2.0 equiv).
The reaction mixture was stirred for 10 min at 0 °C and then
warmed to room temperature and stirred for 45 min. It was then
quenched with ice cold water (5 mL) and the solution extracted
with CH2Cl2 (3 ꢂ 40 mL). The combined organic layers were
washed with brine, dried (Na2SO4), and concentrated. The residue
was purified by silica gel column chromatography using petroleum
ether/EtOAc (9:1 to 1:1) as eluent to afford 1 (39.4 mg, 92%) as a
7. (a) Brockmann, H.; Pini, H. Naturwissenschaften 1947, 34, 190; (b) Brockmann,
H.; Pini, H.; von Plotho, O. Chem. Ber. 1950, 83, 161.
8. (a) Giles, R. G. F.; Mitchell, P. R. K.; Roos, G. H. P.; Strümpfer, J. M. M. J. Chem.
Soc., Perkin Trans. 1 1981, 2091; (b) Kraus, G. A.; Liu, P. Synth. Commun. 1996, 26,
4501; (c) Min, J.-P.; Kim, J.-C.; Park, O.-S. Synth. Commun. 2004, 34, 383.
9. (a) Brimble, M. A.; Ireland, E. J. Chem. Soc., Perkin Trans. 1 1994, 1, 3109; (b)
Brimble, M. A.; Ireland, E.; Phythian, S. J. Tetrahedron Lett. 1991, 32, 6417.
10. Maeda, H.; Kraus, G. A. J. Org. Chem. 1996, 61, 2986.
yellow solid. Mp 171–173 °C (decomp. at 170 °C). ½a D25
¼ ꢀ51:6 (c
ꢁ
0.25, CHCl3). IR (CHCl3)
m = 3400, 3301, 3045, 3015, 1798, 1782,
11. Fernandes, R. A.; Chavan, V. P. Tetrahedron Lett. 2008, 49, 3899.
12. (a) Dötz, K. H. Angew. Chem. 1975, 87, 672. Angew. Chem., Int. Ed. Engl. 1975, 14,
644.; Reviews: (b) Dötz, K. H. Angew. Chem. 1984, 96, 573. Angew. Chem., Int. Ed.
Engl. 1984, 23, 587.; (c) Dötz, K. H.; Stendel, J., Jr. In Modern Arene Chemistry;
Astruc, D., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 250–296; (d) Ito, T.;
Minato, M. In Compounds of Groups 7–3, (Mn..., Cr..., V..., Ti..., Sc..., La..., Ac...)
Science of Synthesis: Houben-Weyl Methods of Molecular Transformations;
Imamoto, T., Ed.; Thieme: Stuttgart, Germany, 2002; pp 333–380. Vol. 2; (e)
Dötz, K. H.; Wenzel, B., Jr.; Jahr, H. C. Top. Curr. Chem. 2005, 248, 63; (f) Waters,
M. L.; Wulff, W. D. Org. React. 2008, 70, 121; (g) Couladouros, E. A.; Stromgilos,
A. T. In Quinones and Heteroatom Analogues Science of Synthesis Houben-Weyl
Methods of Molecular Transformations; Griesbeck, A. G., Ed.; Thieme: Stuttgart:
Germany, 2006; vol. 28, pp 217–322.
1667, 1647, 1619, 1578, 1458, 1366, 1342, 1312, 1252, 1197,
1150, 1074, 1055, 1021, 988, 895, 830, 805 cmꢀ1 1H NMR
.
(400 MHz, acetone-d6): d = 2.51 (d, J = 17.2 Hz, 1H), 3.15 (ddd,
J = 17.4, 5.3, 0.8 Hz, 1H), 4.74 (dd, J = 4.3, 0.9 Hz, 1H), 4.90–4.92
(m, 1H), 5.69 (dd, J = 3.7, 1.8 Hz, 1H), 6.94 (d, J = 1.8 Hz, 1H), 7.33
(dd, J = 8.5, 1.3 Hz, 1H), 7.61 (dd, J = 7.5, 1.3 Hz, 1H), 7.79 (dd,
J = 8.5, 7.5 Hz, 1H). 13C NMR (100 MHz, CDCl3): d = 39.4, 70.1,
81.3, 115.7, 119.6, 125.0, 133.1, 134.9, 137.6, 147.1, 162.0, 175.2,
183.8, 190.8. HRMS (ESI-TOF): (m/z) calcd for [C14H10O6+H]
275.0550, found 275.0551.

R. A. Fernandes, V. P. Chavan / Tetrahedron: Asymmetry 22 (2011) 1312–1319
1319
13. Recent reviews (a) Kolb, H. C.; Sharpless, K. B. In Transition Metals for Organic
Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
Vol. 2, pp 275–298; (b) Noe, M. C.; Letavic, M. A.; Snow, S. L.; McCombie, S. Org.
React. 2005, 66, 109; (c) Zaitsev, A. B.; Adolfsson, H. Synthesis 2006, 1725.
14. For modified Knoevenagel condensations see: (a) Ragoussis, N. Tetrahedron
Lett. 1987, 28, 93; (b) Yamanaka, H.; Yokoyama, M.; Sakamoto, T.; Shiraishi, T.;
Sagi, M.; Mizugaki, M. Heterocycles 1983, 20, 1541; (c) Ragoussis, N.; Ragoussis,
V. J. Chem. Soc., Perkin Trans. 1 1998, 3529; (d) Sampath Kumar, H. M.; Subba
Reddy, B. V.; Jagan Reddy, E.; Yadav, J. S. Tetrahedron Lett. 1999, 40, 2401; (e)
Corey, E. J. J. Am. Chem. Soc. 1952, 74, 5879.
16. (a) Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521; (b)
Dickson, H. D.; Smith, S. C.; Hinkle, K. W. Tetrahedron Lett. 2004, 45, 5597; (c)
Pietruszka, J.; Witt, A. Synthesis 2006, 4266.
17. Fernandes, R. A.; Chavan, V. P.; Mulay, S. V. Tetrahedron: Asymmetry 2011, 22,
487.
18. Enantiomeric excess (ee) was determined by chiral HPLC as reported in Ref. 2e
.
19. Wadsworth, W. S., Jr.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733.
20. Wulff, W. D.; Tang, P.-C.; Chan, K.-S.; McCallum, J. S.; Yang, D. D.; Gilberton, S.
R. Tetrahedron 1985, 45, 5813. Instead of methyl fluorosulfonate we used the
Meerwein salt Me3OBF4.
15. (a) Pilli, R. A.; Victor, M. M. Tetrahedron Lett. 1998, 39, 4421; (b) Enantiomeric
excess (ee) was determined by chiral HPLC of its dibenzoate derivative.
21. Yokoyama, H.; Hayashi, Y.; Nagasawa, Y.; Ejiri, H.; Miyazawa, M.; Hirai, Y.
Tetrahedron 2010, 66, 8458.