Organocatalytic enantioselective formal synthesis of HRV 3C-protease inhibitor (1R,3S)-thysanone

Article abstract of DOI:10.1016/j.tet.2008.12.060

A short and efficient organocatalytic enantioselective formal synthesis of HRV 3C-protease inhibitor (1R,3S)-thysanone is achieved in a nine-step with 98.7% enantiomeric excess, by employing l-proline-catalyzed asymmetric α-aminooxylation of aldehyde and

Full text of DOI:10.1016/j.tet.2008.12.060

Tetrahedron 65 (2009) 1599–1602
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Organocatalytic enantioselective formal synthesis of HRV 3C-protease inhibitor
(1R,3S)-thysanone
*
Rajiv T. Sawant, Suresh B. Waghmode
Department of Chemistry, University of Pune, Ganeshkhind, Pune 411 007, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 October 2008
Received in revised form 18 December 2008
Accepted 19 December 2008
Available online 25 December 2008
A short and efficient organocatalytic enantioselective formal synthesis of HRV 3C-protease inhibitor
(1R,3S)-thysanone is achieved in a nine-step with 98.7% enantiomeric excess, by employing
L-proline-
catalyzed asymmetric
steps.
a-aminooxylation of aldehyde and Oxa-Pictet–Spengler cyclization as the key
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric
Proline
a-aminooxylation
Pyranonaphthoquinones
Thysanone
Oxa-Pictet–Spengler cyclization
1. Introduction
thysanone using proline-catalyzed asymmetric
as the source of chirality.
a-aminooxylation
Pyran ring fused to a naphthoquinone nucleus is a ubiquitous
structural sub-unit present in a number of biologically active nat-
ural products (Fig. 1).1 Thysanone 1, eleutherin 2, ventiloquinone 3,
and nanomycin 4 are naturally occurring pyranonaphthoquinones,
which exhibits wide range of biological acivity.1c Thysanone 1,
possess C-1–C-3 trans stereochemistry on the pyran ring, which
shows promising antibiotic activity.1c It was isolated from the
fungus Thysanophora penicilloides by Singh and co-workers2 and is
one of the effective inhibitors of human rhinovirus 3C-protease and
therefore provides a lead compound for understanding the mech-
anism of 3C-protease inhibition. Due to significant biological ac-
tivity of 1, several approaches for the synthesis of 1 and its
analogues have been reported.3–9 Recently, Brimble and Sperry
reported stereospecific synthesis of (ꢀ)-1 using an o-toluate anion
Over past few years, the field of asymmetric organocatalysis is
an emerging area of research in organic synthesis to obtain chiral
compounds in high optical purity.10 Among the different organo-
catalysts; proline, a readily available (in both
D and L forms)
bi-functional amino acid, has been found to be an excellent orga-
nocatalyst.11 It has also been found to be an versatile organocatalyst
for the asymmetric
a
-hydroxylation of aldehydes and ketones.12
Herein we report for the first time a short and efficient organo-
catalytic enantioselective formal synthesis of (1R,3S)-thysanone 1
by using
L-proline-catalyzed asymmetric a-aminooxylation of
aldehyde12a and Oxa-Pictet–Spengler cyclization13 as the key steps
(Scheme 2).
OH
O
OH
OMe O
addition to chiral
a,b-unsaturated d
-lactone.9 The reported
O
O
methods (except Brimble and Sperry9) are either based on lengthy
chiral pool approach3 or enzymatic resolution4 while catalytic
asymmetric methods are rather rare.5
Due to their interesting structural features and the biological
significance of this class of compounds, we were encouraged to
design a short and effective route for the synthesis of (1R,3S)-
HO
O
O
Thysanone 1
Eleutherin 2
OH
O
OH
O
O
O
O
OH
MeO
O
O
Ventiloquinone L 3
Figure 1. Structure of some pyranonaphthoquinone antibiotics.
Nanomycin A 4
* Corresponding author. Tel.: þ91 20 25601397; fax: þ91 20 25691728.
E-mail address: suresh@chem.unipune.ernet.in (S.B. Waghmode).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.060

1600
R.T. Sawant, S.B. Waghmode / Tetrahedron 65 (2009) 1599–1602
2. Result and discussion
a
-aminooxylation12a in a two-step reaction sequence: (i) reaction
of 8 with nitrosobenzene as a source of oxygen in the presence of
Retrosynthetic strategy for the synthesis of (1R,3S)-thysanone is
L
-proline (25 mol %) in CH3CN at ꢀ20 ꢁC followed by treatment with
outlined in Scheme 1. Gill and Donner3 have reported 15-step
NaBH4 in MeOH gave the crude aminooxy alcohol and (ii) sub-
synthesis of (S)-bromopyranobenzoquinone 12 as
a
key in-
sequent reduction of the crude aminooxy alcohol with 30 mol %
25
termediate starting from ethyl (S)-lactate in 4.7% yield for the total
synthesis of (1R,3S)-thysanone 1. We envisaged a new and short
synthesis of important intermediate (þ)-12 from alcohol 10
through Oxa-Pictet–Spengler cyclization followed by oxidative
demethylation of pyran 11. Intermediate 10 can be prepared from
CuSO4$5H2O afforded chiral diol 9 [
a
]
þ20.7 (c 1, EtOH) in 73%
D
yield. Selective tosylation of primary hydroxyl functionality of diol 9
was carried out using catalytic amount of dibutyltin oxide (2 mol %)
and p-toluenesulfonyl chloride.15 The crude monotosylate was
reduced with LiAlH4 (4 equiv) in dry THF to afford the (þ)-alcohol
25
chiral diol 9, which in turn would be obtained by using
L
-proline-
10 [
a
]
D
þ21.0 (c 1, CHCl3) in 90% yield. The enantiomeric excess was
catalyzed asymmetric -aminooxylation of aldehyde 8. The aryl
a
98.7%, determined by HPLC equipped with chiral AD-H column.
Our next aim was to construct pyran ring of 11 through Oxa-
Pictet–Spengler reaction.13 We subjected alcohol 10 to the Oxa-
propanaldehyde 8 can be easily prepared from known aryl prop-
anoate 514 (Scheme 1).
Pictet–Spengler reaction with methoxymethyl chloride in presence
25
of ZnCl2 (30 mol %) in dry Et2O to afford pyran 11, mp 41–42 ꢁC [
a]
D
O
OH
O
OH
þ102.9 (c 1.1, CHCl3) in 80% yield. Although synthesis of racemic
pyran 11 is reported in the literature, its physical constant and
optical rotation are not known.3b The oxidative demethylation of 11
Br
Br
O
ref. 3
O
HO
with cerium(IV) ammonium nitrate (CAN) in aqueous CH3CN fur-
O
25
12
nished quinone 12, mp 101–104 ꢁC, [
a
]
þ192.4 (c 0.64, CHCl3)
O
1
D
{lit.3b mp 100–103 ꢁC [
a]
þ195 (c 0.64, CHCl3)} as a yellow, crys-
D
OMe
OMe
talline solid in 77% yield and >98.7% ee (Scheme 2). The physical
and spectroscopic data of the quinone 12 is in accordance with the
literature data.3b
Br
OH
H
We have executed a nine-step organocatalytic enantioselective
synthesis of (1R,3S)-thysanone intermediate (þ)-12 with an overall
yield of 27.3% and high optical purity (98.7% ee) from ester 5. Since,
the conversion of (þ)-12 to (1R,3S)-thysanone 1 through regiose-
lective Diels–Alder reaction and radical bromination followed by
hydroxylation has already been reported in the literature.3 Thus, an
organocatalytic formal enantioselective synthesis of 1 has been
accomplished. All compounds 5–12 have been fully characterized
by spectroscopic techniques.
OMe
10
OMe
8
O
Scheme 1. Retrosynthesis of (1R,3S)-thysanone.
The synthesis of (1R,3S)-thysanone intermediate 12 is depicted
in Scheme 2. Ethyl 3-(2,5-dimethoxyphenyl)propionate14 5 was
easily prepared from 2,5-dimethoxy benzaldehyde by Wittig olefi-
nation followed by hydrogenation. The regioselective aromatic
bromination of ester 5 using N-bromo succinimide (NBS) in CH3CN
at room temperature gave bromo compound 6 in 96% yield. Ester 6
was converted in to corresponding aldehyde 8 in high yield by
following two-step reaction sequences. Initially, bromo ester 6 was
reduced to alcohol 7 using LiAlH4 in dry THF in 81% yield, sub-
sequently, it was oxidized to corresponding aldehyde 8 with IBX
in DMSO at room temperature in 87% yield. Aldehyde 8 was con-
3. Conclusions
In summary, we have demonstrated a successful application of
L-proline-catalyzed asymmetric a-aminooxylation and Oxa-Pictet–
Spengler cyclization strategy to the asymmetric formal total syn-
verted in to diol 9 by using
L-proline-catalyzed asymmetric
thesis of HRV 3C-protease inhibitor (1R,3S)-thysanone in 27.3%
OMe
Br
OMe
OMe
Br
iii
vi
i
ii
OH
OEt
OEt
OMe
7
OMe
5
O
OMe
6
O
OMe
OMe
OMe
Br
Br
Br
Br
v
iv
OH
OH
OH
H
OMe
9
OMe
8
O
OMe
10
O
OMe
OH
O
OH
Br
vii
viii
O
O
O
HO
O
OMe
11
O
12
(1R,3S)-Thysanone 1
98.7% ee
Scheme 2. Reagents and conditions: (i) NBS, CH3CN, rt, 12 h, 96%; (ii) LiAlH4, THF, 0 ꢁC to rt, 8 h, 81%; (iii) IBX, DMSO, rt, 4 h, 87%; (iv) (a) PhNO, L-proline (25 mol %), CH3CN, ꢀ20 ꢁC,
24 h then MeOH, NaBH4, 30 min; (b) CuSO4$5H2O (30 mol %), 0 ꢁC MeOH, 12 h, 73% (two steps); (v) (a) Bu2SnO (2 mol %), p-TsCl (1.02 equiv), Et3N, CH2Cl2, 0 ꢁC to rt, 1 h; (b) LiAlH4
(4 equiv) THF, 0 ꢁC to rt, 5 h, 90% (two steps); (vi) MeOCH2Cl (20 equiv), ZnCl2 (30 mol %), Et2O, 0 ꢁC to rt, 6 h, 80%; (vii) CAN (3 equiv), CH3CN/H2O (4:1), 0 ꢁC to rt, 25 min, 77%; (viii)
See Ref. 3. (a) 1-Methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene, toluene, reflux, 3 h; (b) Br2 (1 equiv), CC14, hn, 0.5 h; then THF, H2O, rt, 1 h, 62% (two steps).

R.T. Sawant, S.B. Waghmode / Tetrahedron 65 (2009) 1599–1602
1601
yield with 98.7% ee. Good yield, environmentally friendly reaction
procedures and high enantioselectivity are some of the salient
features of our synthetic approach and represent a good alternative
to the known methods. We believe that the present synthetic
strategy would be potential route for the synthesis of related pyr-
anonaphthoquinones compounds such as eleutherin and nano-
mycin A. Efforts are in progress in this direction.
(6.4 g, 96%) as a pale yellow solid; mp 55–57 ꢁC. [Found C, 49.14; H,
5.46%. C13H17BrO4 requires C, 49.23; H, 5.40.] Rf (10% ethyl acetate/
hexane) 0.41; nmax (KBr) 1732, 1213, 1043, 964, 860, 786 cmꢀ1
; dH
(300 MHz, CDCl3) 1.25 (t, 3H, J¼7.2 Hz, CH3), 2.55 (t, 2H, J¼7.8 Hz,
CH2CO), 2.86 (t, 2H, J¼7.4 Hz, CH2Ar), 3.75 (s, 3H, OMe), 3.81 (s, 3H,
OMe), 4.09 (q, 2H, J¼7.2 Hz, OCH2), 6.74 (s, 1H, ArH), 6.98 (s, 1H,
ArH); dC (75 MHz, CDCl3) 14.2, 26.1, 34.0, 55.8, 56.8, 60.3, 108.8,
114.3, 115.4, 128.8, 149.5, 151.6, 172.7; MS: (m/z)¼318 (Mþ) 81Br, 316
(Mþ) 79Br.
4. Experimental section
4.1. General experimental details
4.4. 3-(4-Bromo 2,5-dimethoxyphenyl)propan-1-ol (7)
All solvents were purified and dried by standard procedures
prior to use. Melting points were recorded with Thomas Hoover
Capillary melting point apparatus and are uncorrected. Thin layer
chromatography was performed on Merck 60 F254 silica gel plates
and visualization was accomplished by irradiation with UV light
and/or by treatment with a solution of phosphomolybdic acid
(1.25 g) and Ce(SO4)2$H2O (0.5 g) solution in concd H2SO4/H2O
(3:47 mL) followed by heating. Crude products were purified by
column chromatography on silica gel of 100–200 mesh. IR spectra
were recorded on Shimadzu FTIR 8400 as a thin film or KBr pellets
and are expressed in cmꢀ1. Optical rotations were obtained on Jasco
P-1020 digital polarimeter. 1H and 13C NMR spectra were recorded
on Varian Mercury spectrometer on 300 and 75 MHz, respectively,
A solution of ester 6 (11.7 g, 37.0 mmol) in dry THF (25 mL) was
added dropwise to a cold (0 ꢁC) suspension of LiAlH4 (1.54 g,
40.7 mmol) in dry THF (90 mL). After stirring this suspension for 8 h
at room temperature, it was cooled to 0 ꢁC then quenched with wet
Na2SO4. The reaction mass was diluted with ethyl acetate (100 mL),
filtered through pad of Celite under vacuum and concentrated
under reduced pressure. The crude product was purified by silica
gel column chromatography using (18% ethyl acetate/hexane) to
give pure alcohol 7 (8.25 g, 81%) as a colorless oil. [Found C, 49.10;
H, 5.41%. C11H15BrO3 requires C, 48.02; H, 5.50%.] Rf (25% ethyl ac-
etate/hexane) 0.25; nmax (film) 3398, 2939, 1593, 1215, 1041, 910,
856, 856 cmꢀ1
;
dH (300 MHz, CDCl3) 1.81 (quin, 2H, J¼6.6 Hz,
CH2CH2Ar), 2.19 (br s, 1H, OH), 2.65 (t, 2H, J¼7.1 Hz, CH2Ar), 3.56–
3.60 (t, 2H, J¼6.3 Hz, CH2OH), 3.76 (s, 3H, OMe), 3.8 (s, 3H, OMe),
6.72 (s, 1H, ArH), 7.0 (s, 1H, ArH); dC (75 MHz, CDCl3) 26.1, 32.7, 56.1,
56.8, 61.6,108.3,114.2,115.6,130.1,149.7,151.5; MS: (m/z)¼276 (Mþ)
81Br, 274 (Mþ) 79Br.
using CDCl3 as a solvent. Chemical shifts were reported in
d units
(parts per million) with reference to TMS as an internal standard
and coupling constants (J) are given in hertz. GC mass spectra were
obtained on Shimadzu GCMS-QP5050A spectrometer. Elemental
analyses were carried out with Thermo-Electron Corporation CHNS
Analyzer, FLASH-EA 1112 at Shimadzu Analytical Centre, University
of Pune. Analytical HPLC was performed on chiral AD-H column
4.5. 3-(4-Bromo 2,5-dimehoxyphenyl)propanal (8)
(250 mmꢂ4.6 mmꢂ5
m
).
A mixture of alcohol 7 (3 g, 10.94 mmol) and IBX (3.98 g,
14.23 mmol) in DMSO (25 mL) was stirred for 4 h at room temper-
ature, then water was added to the reaction mixture and 2-iodo-
benzoic acid was filtered off. The filtrate was extracted with ether
(3ꢂ40 mL), combined organic layer washed with brine, dried over
Na2SO4, and concentrated under reduced pressure and the crude
product was purified by silica gel column chromatography (13%
ethyl acetate/hexane) to afford pure aldehyde 8 (2.59 g, 87%) as
a colorless oil. [Found C, 49.31; H, 5.92%. C11H13BrO3 requires C,
48.37; H, 5.80%.] Rf (30% ethyl acetate/hexane) 0.55; nmax (film) 1722,
4.2. Ethyl 3-(2,5-dimethoxyphenyl)propionate (5)14
A mixture of 2,5-dimethoxy benzaldehyde (7.0 g, 42.16 mmol)
and ethyl (triphenylphosphoranylidiene) acetate (17.6 g,
50.60 mmol) in toluene (120 mL) was stirred at 100 ꢁC. After 4 h,
reaction mixture was cooled to room temperature and solvent was
removed under reduced pressure and solid residue was purified
over silica gel column chromatography using ethyl acetate/hexane
(08:92) gave
a
,
b-unsaturated ester (9.9 g) as green oil. To a solution
1213, 1037, 910, 853, 736 cmꢀ1
; dH (300 MHz, CDCl3) 2.70 (t, 2H,
of unsaturated ester (9.9 g) in MeOH (60 mL) was added 10% Pd/C
(0.4 g). The reaction mixture was stirred for 12 h under hydrogen
(1 atm) and then catalyst was filtered off and filtrate concentrated
under reduced pressure. The crude product was purified over silica
gel column chromatography (5% ethyl acetate/hexane) to yield es-
ter 5 (9.8 g, 98% for two steps) as a colorless oil. [Found C, 65.62; H,
7.65%. C13H18O4 requires C, 65.53; H, 7.61%.] Rf (10% ethyl acetate/
J¼7.2 Hz, CH2CHO), 2.88 (t, 2H, J¼7.2 Hz, CH2Ar), 3.75 (s, 1H, OMe),
3.81 (s, 1H, OMe), 6.74 (s, 1H, ArH), 6.99 (s, 1H, ArH), 9.75 (s, 1H,
CHO); dC (75 MHz, CDCl3) 23.4, 43.5, 55.8, 56.7, 108.8, 114.3, 115.4,
128.6, 149.5, 151.4, 201.5; MS: m/z¼274 (Mþ) 81Br, 272 (Mþ) 79Br.
4.6. (R)-3-(4-Bromo 2,5-dimehoxyphenyl)1,2-propanediol (9)
hexane) 0.40; nmax (film) 1732, 1500, 1224, 1051, 864, 802 cmꢀ1
;
dH
To a stirred solution of aldehyde 8 (3.3 g, 12.14 mmol) and
(300 MHz, CDCl3) 1.23 (t, 3H, J¼7.2 Hz, CH3), 2.57 (t, 2H, J¼7.5 Hz,
CH2CO), 2.89 (t, 2H, J¼7.2 Hz, CH2Ar), 3.73 (s, 3H, OMe), 3.76 (s, 3H,
OMe), 4.11 (q, 2H, J¼7.2 Hz, OCH2CH3), 6.66–6.75 (m, 3H, ArH); dC
(75 MHz, CDCl3) 14.3, 26.3, 34.2, 55.6, 55.7, 60.2, 110.9, 111.3, 116.1,
129.9, 151.5, 153.1, 173.1; MS: (m/z)¼238 (Mþ).
nitrosobenzene (1.0 g, 9.34 mmol) in CH3CN (40 mL) was added
L
-proline (0.268 g, 2.33 mmol) at ꢀ20 ꢁC. The reaction was stirred at
the same temperature for 24 h and then diluted with MeOH
(15 mL) and to this solution NaBH4 (1.06 g, 28.03 mmol) was added.
After 25 min, the reaction mixture was quenched with saturated
aqueous NaHCO3, extracted with ethyl acetate (3ꢂ30 mL), dried
over Na2SO4, and concentrated under reduced pressure. The
CuSO4$5H2O (0.7 g, 2.8 mmol) was added at 0 ꢁC to the suspension
of crude product in MeOH (30 mL) and stirred for 10 h. The reaction
mixture was quenched with saturated aqueous NH4Cl solution
(30 mL) and extracted with ethyl acetate (3ꢂ40 mL), washed with
brine, dried over Na2SO4, and concentrated under reduced pres-
sure. The crude product was purified by silica gel column chro-
matography (40–50% ethyl acetate/hexane) to yield pure (þ)-diol 9
(1.97 g, 73%) as a white solid; mp 123–125 ꢁC. [Found C, 45.31; H,
4.3. Ethyl 3-(4-bromo 2,5-dimethoxyphenyl)propionate (6)
A
solution of ester 5 (5 g, 21.0 mmol) and NBS (3.74 g,
21.0 mmol) in CH3CN (35 mL) was stirred at room temperature for
12 h, then diluted with water (25 mL) and extracted with ethyl
acetate (3ꢂ25 mL). The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated under reduced pres-
sure. The crude product was purified by silica gel column chro-
matography (5% ethyl acetate/hexane) to give pure bromo ester 6

1602
R.T. Sawant, S.B. Waghmode / Tetrahedron 65 (2009) 1599–1602
5.26%. C11H15BrO4 requires C, 45.38; H, 5.19%.] Rf (50% ethyl acetate/
J¼15.6 Hz, ArCH2O), 4.96 (d, 1H, J¼15.7 Hz, ArCH2O), 6.85 (s, 1H,
ArH); dC (75 MHz, CDCl3) 21.6, 30.1, 55.6, 60.4, 64.6, 70.1,112.0,113.1,
123.2, 130.4, 146.2, 153.3; MS: (m/z)¼288 (Mþ) 81Br, 286 (Mþ) 79Br.
25
hexane) 0.12; [
a
]
þ20.7 (c 1, EtOH); nmax (KBr) 3319, 2847, 1577,
D
1496, 1388, 1211, 1080, 1032, 958, 852, 796 cmꢀ1
;
dH (300 MHz,
CDCl3) 2.17 (br s, 1H, OH), 2.35 (br s, 1H, OH), 2.71–2.86 (m, 2H,
CH2Ar), 3.49 (m, 1H, CH2OH), 3.61 (m, 1H, CH2OH), 3.79 (s, 3H,
OMe), 3.84 (s, 3H, OMe), 3.91 (m, 1H, CHOH), 6.75 (s, 1H, ArH), 7.04
(s, 1H, ArH); dC (75 MHz, CDCl3) 34.3, 56.1, 56.8, 65.8, 71.7, 109.1,
115.4, 115.6, 126.4, 149.7, 151.5; MS: (m/z)¼292 (Mþ) 81Br, 290 (Mþ)
79Br.
4.9. (S)-7-Bromo-3-methyl-3,4-dihydro-1H-2-benzopyran-
5,8-dione (12)3b
To a pre-cooled (0 ꢁC) solution of the (þ)-pyran 11 (0.11 g,
0.384 mmol) in CH3CN (8 mL) was added dropwise a solution of
CAN (0.632 g, 1.15 mmol) in water (2 mL). The mixture was stirred
for 25 min at room temperature, then diluted with water (10 mL),
extracted with ethyl acetate (3ꢂ10 mL). The combined layers were
dried over Na2SO4 and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography
(8% ethyl acetate/hexane) to afford (þ)-bromobenzoquinone 12
(0.076 g, 77%); as a yellow crystalline solid; mp 101–104 ꢁC; {lit.3b
mp 100–103 ꢁC}. [Found C, 46.64; H, 3.62%. C10H9BrO325requires C,
4.7. (S)-3-(4-Bromo 2,5-dimehoxyphenyl)-2-propanol (10)
To a stirred solution of (þ)-diol 9 (1.1 g, 3.79 mmol) in dry DCM
(15 mL), dibutyltin oxide (0.020 g, 0.079 mmol), triethylamine
(565 mL, 4.03 mmol), and p-toluenesulfonyl chloride (0.769 g,
4.03 mmol) was added at 0 ꢁC. The reaction mixture was stirred for
1 h at room temperature, diluted with water (20 mL), and the re-
action mixture was extracted with DCM (3ꢂ25 ml). The combined
organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure to afford crude mono-
tosylate. The crude monotosylate was used for next step without
any purification.
46.72; H, 3.53%.] Rf (20% ethyl acetate/hexane) 0.45; [
0.64, CHCl3); {lit.3b
þ195 (c 0.64, CHCl3)}; nmax (KBr) 2983,
2929, 2856, 1660, 1591, 1386, 1263, 1139 cmꢀ1
a
]
D
þ192.4 (c
[a]
D
;
dH (300 MHz, CDCl3)
1.35 (d, 3H, J¼6.0 Hz, CH3), 2.15–2.25 (m, 1H, CH2), 2.59 (d, 1H,
J¼19.2 Hz, CH2), 3.62–3.65 (m, 1H, CHOCH3), 4.41 (d, 1H, J¼18.7 Hz,
CH2O), 4.72 (d, 1H, J¼18.4 Hz, CH2O), 7.25 (s, 1H, CH); dC (75 MHz,
The solution of crude tosylate (1.68 g, 3.79 mmol) in dry THF
(15 mL) was added dropwise to the cooled (0 ꢁC) suspension of
LiAlH4 (0.576 g, 15.1 mmol) in dry THF (20 mL) and stirred for 5 h at
room temperature. The reaction mixture was quenched with wet
Na2SO4, diluted with ethyl acetate (40 mL), filtered through pad of
Celite under vacuum, and concentrated under reduced pressure.
The crude alcohol was purified by silica gel column chromatogra-
phy (20% ethyl acetate/hexane) to afford pure (þ)-alcohol 10
(0.92 g, 90%) as a white solid; mp 111–112 ꢁC. The enantiomeric
excess was found to be 98.7% (ee was determined by chiral HPLC
CDCl3)
d 21.1, 29.1, 63.2, 69.4, 136.8, 137.7, 140.1 (2C), 177.7, 183.2;
MS: (m/z)¼258 (Mþ) 81Br, 256 (Mþ) 79Br.
Acknowledgements
R.T.S. thanks CSIR, New Delhi, for senior research fellowship. We
are grateful to BCUD, University of Pune for financial support. Au-
thors are thankful to Prof. D.D. Dhavale, Mr. C.N. Potangale and
Shimadzu Analytical Centre for polarimeter facility, HPLC analysis
and spectral analysis, respectively.
equipped with chiral AD-H column (250 mmꢂ4.6 mmꢂ5
m) with
hexane/EtOH/TFA (90:9.9:0.1 v/v/v) as a eluent (flow rate 1.2 mL/
min)). The retention time for major and minor isomers was 7.3 and
References and notes
9.1 min, respectively. [Found C, 49.14; H, 5.42%. C11H15BrO3 requires
25
C, 48.02; H, 5.50%.] Rf (30% ethyl acetate/hexane) 0.30; [
a
]
D
þ21.0 (c
1. For a review on isolation, structure and synthesis of pyranonaphthoquinone
antibiotics, see: (a) Sperry, J.; Bachu, P.; Brimble, M. A. Nat. Prod. Rep. 2008, 25,
376; (b) Brimble, M. A.; Nairn, M. R.; Prabaharan, H. Tetrahedron 2000, 56, 1937;
(c) Brimble, M. A.; Nairn, M. R.; Duncalf, L. Nat. Prod. Rep. 1999, 16, 267.
2. Singh, S. B.; Cordingley, M. G.; Ball, R. G.; Smith, J. L.; Dombrowski, A. W.; Goetz,
M. A. Tetrahedron Lett. 1991, 32, 5279.
3. (a) Donner, C. D.; Gill, M. Tetrahedron Lett. 1999, 40, 3921; (b) Donner, C. D.; Gill,
M. J. Chem. Soc., Perkin Trans. 1 2002, 938.
4. Bachu, P.; Sperry, J.; Brimble, M. A. Tetrahedron 2008, 64, 4827.
5. (a) Brimble, M. A.; Houghton, S. I.; Woodgate, P. D. Tetrahedron 2007, 63, 880;
(b) Brimble, M. A.; Elliott, R. J. R. Tetrahedron 2002, 58, 183.
1, CHCl3); nmax (KBr) 3389, 2935, 2843, 1620, 1496, 1437, 1386, 1118,
1030, 943, 852 cmꢀ1
;
dH (300 MHz, CDCl3) 1.21 (d, 2H, J¼6.3 Hz,
CH3), 2.02 (br s, 1H, OH), 2.64 (dd, 1H, J¼13.4, 7.9 Hz, CH2Ar), 2.76–
2.82 (dd, 1H, J¼13.4, 4.4 Hz, CH2Ar), 3.76 (s, 3H, OMe), 3.83 (s, 3H,
OMe), 3.99–4.03 (m, 1H, CHOH), 6.73 (s, 1H, ArH), 7.02 (s, 1H, ArH);
dC (75 MHz, CDCl3) 23.0, 40.3, 56.0, 56.8, 67.6, 109.1, 115.4, 115.7,
127.1, 149.6, 151.7; MS: (m/z)¼276 (Mþ) 81Br, 274 (Mþ) 79Br.
6. Bulbule, V. J.; Koranne, P. S.; Deshpande, V. H.; Borate, H. B. Tetrahedron 2007,
63, 166.
7. Kraus, A. G.; Ogutu, H. Tetrahedron 2002, 58, 7391.
8. Singh, S. B.; Graham, P. L.; Reamer, R. A.; Cordingly, M. G. Bioorg. Med. Chem.
Lett. 2001, 11, 3143.
9. Sperry, J.; Brimble, M. A. Synlett 2008, 1910.
10. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726; (b) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138; (c) Houk, K. N.; List, B. Acc.
Chem. Res. 2004, 37, 487; (d) List, B.; Bolm, C. Adv. Synth. Catal. 2004, 346; (e)
List, B.; Seayad. J. Org. Biomol. Chem. 2005, 3, 719.
11. For a review of proline-catalyzed asymmetric reactions: (a) List, B. Synlett 2001,
1675; (b) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298, 1904; (c) List, B. Tet-
rahedron 2002, 58, 5573; (d) Dalko, P. I.; Moisan, L. Angew. Chem. 2001, 113, 3840;
Angew. Chem., Int. Ed. 2001, 40, 3726; (e) List, B. Acc. Chem. Res. 2004, 37, 548.
12. (a) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44,
8293; (b) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247; (c) Hayashi, Y.; Ya-
maguchi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2003, 43, 1112; (d)
Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003,
125, 10808; (e) Cordova, A.; Sunden, H.; Bogevig, A.; Johansson, M.; Himo, F.
Chem.dEur. J. 2004, 10, 3673; (f) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Hibino,
K.; Shoji, M. J. Org. Chem. 2004, 69, 5966; (g) Merino, P.; Tejero, T. Angew. Chem.
2004, 116, 3055; Angew. Chem., Int. Ed. 2004, 43, 2995.
13. (a) Larghi, E. L.; Kaufmann, T. S. Synthesis 2006, 187; (b) Wunsch, B.; Zoll, M.
Liebigs Ann. Chem. 1992, 39.
14. Srikrishna, A.; Satyanarayana, G.; Desai, U. V. Synth. Commun. 2007, 37, 965.
15. Martinelli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.;
Doecke, C. W.; Zollars, L. M. H.; Moher, E. D.; Khau, V. V.; Kosmrlj, B. J. Am. Chem.
Soc. 2002, 124, 3758.
4.8. (S)-7-Bromo-1-hydroxy-5,8-dimethoxy-3-methyl-3,4-
dihydro-1H-2-benzopyran (11)
To
a
pre-cooled (0 ꢁC) solution of (þ)-alcohol 10 (0.4 g,
1.45 mmol) and methoxymethyl chloride (2.21 mL, 29.1 mmol) in
dry diethyl ether (15 mL) was added anhydrous ZnCl2 (0.06 g,
0.43 mmol) under nitrogen and stirred at room temperature for 6 h.
To this reaction mixture water was added, stirred for 10 min and
extracted with diethyl ether (3ꢂ25 mL). The combined organic
layers were washed with aqueous solution of NaHCO3, water, brine,
dried over Na2SO4, and concentrated under reduced pressure. The
crude product was purified by silica gel column chromatography
(6% ethyl acetate/hexane) to give (þ)-pyran 1 (0.33 g, 80%) as col-
orless solid; mp 41–42 ꢁC. The spectroscopic data of (þ)-11 is in full
agreement with reported data of racemic pyran 11.3b [Found C,
50.11; H, 5.33%. C12H15BrO3 requires C, 50.19; H, 5.27%.] Rf (20% ethyl
25
acetate/hexane) 0.50; [
a
]
D
þ102.9 (c 1.1, CHCl3); nmax (KBr) 777,
952, 1130, 1180, 1230, 1471, 2893, 2933, 2962 cmꢀ1
; dH (300 MHz,
CDCl3) 1.37 (d, 3H, J¼6.0 Hz, CH3), 2.31 (dd, 1H, J¼16.5, 10.4 Hz,
CH2Ar), 2.70 (d, 1H, J¼17.1, 4.4 Hz, CH2Ar), 3.69–3.70 (m, 1H,
CHOCH3), 3.76 (s, 3H, OMe), 3.78 (s, 3H, OMe), 4.68 (d, 1H,