Enantiodivergent formal total synthesis of aspercyclide C from l -(+)-tartaric acid

Article abstract of DOI:10.1055/s-0029-1218831

The enantiodivergent formal syntheses of both enantiomers of aspercyclide C is accomplished. Starting from l-(+)-tartaric acid, the key protected allylic alcohol, (3R,4R)-4-(methoxymethoxy)non-1-en-3-ol is prepared, and is then elaborated into both enantiomers of 3-[(4-methoxybenzyl)oxy]non-1-en-4-ol via Mitsunobu inversion. Esterification with a known biaryl acid, followed by ring-closing metathesis and deprotection completes the syntheses. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218831

PAPER
2521
Enantiodivergent Formal Total Synthesis of Aspercyclide C from
L-(+)-Tartaric Acid
F
ormal Total Synt
a
hesis of Asp
v
ercyclide
C
irayani R. Prasad,* Vasudeva Rao Gandi, John Eugene Nidhiry, Kavya S. Bhat
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Fax +91(80)23600529; E-mail: prasad@orgchem.iisc.ernet.in
Received 1 March 2010
of a suitably protected diene-ester 4. Preparation of the es-
ter 4 is anticipated by condensation between the biaryl
acid 5 and the homoallylic alcohol 6. Formation of 6
would be possible through Mitsunobu inversion of the C-
Abstract: The enantiodivergent formal syntheses of both enantio-
mers of aspercyclide C is accomplished. Starting from L-(+)-tartaric
acid, the key protected allylic alcohol, (3R,4R)-4-(methoxy-
methoxy)non-1-en-3-ol is prepared, and is then elaborated into both
enantiomers of 3-[(4-methoxybenzyl)oxy]non-1-en-4-ol via 4 hydroxy group in 7, which itself can be obtained from
Mitsunobu inversion. Esterification with a known biaryl acid, fol-
lowed by ring-closing metathesis and deprotection completes the
syntheses.
the allylic alcohol 8. By contrast, inversion of the allylic
hydroxy group (C-3) in 8 and further elaboration would
enable access to ent-6. The g-Hydroxy amide 9 derived
from the bis-Weinreb amide of L-(+)-tartaric acid 104 was
Key words: aspercyclide C, total synthesis, tartaric acid, Mitsunobu
inversion, ring-closing metathesis
identified as the appropriate starting material for the syn-
thesis of alcohol 8 (Scheme 1).
Aspercyclides A–C (Figure 1) are 11-membered biaryl
MeO
ether lactones which were isolated by Singh et al. via ex-
traction of the fermentation broth of Aspergillus sp.1 As-
O
percyclides are reported to be moderately active in IgE
receptor binding, which is key to the understanding of al-
OH
MeO
O
lergic disorders. The total syntheses of aspercyclides A–C
have been reported by Fürstner’s group,2a,b while a total
synthesis of aspercyclide A,2c and a formal total synthesis
of aspercyclide C2d have also recently been described. As
a part of our program on the synthesis of bioactive natural
products starting from chiral pool tartaric acid, we have
accomplished the synthesis a number of oxygenated natu-
ral products, including macrolactones.3 Herein, we dis-
close our efforts on the formal total syntheses of both
enantiomers of aspercyclide C starting from L-(+)-tartaric
acid.
O
OPMB
O
3
5
O
OPMB
4
HO
R = n-C5H11
R
6
ent-3
inversion
at C-4
inversion
at C-3
OPMB
OH
OPMB
HO
MOMO
HO
R
ent-6
R
8
OH
R
7
HO
R
OH
O
Me
N
O
O
Me
N
O
OH
O
O
OH
MeO
O
R
OMe
N
OMe
O
O
O
Me
O
O
O
9
10
R = CHO: aspercyclide A (1)
R = CH2OH: aspercyclide B (2)
aspercyclide C (3)
Scheme 1 Retrosynthesis of aspercyclide C (3) and its enantiomer
(ent-3)
Figure 1 Structures of aspercyclides A–C
The synthesis of aspercyclide C commenced with the con-
trolled addition of n-pentylmagnesium bromide to the bis-
Weinreb amide 105 to afford the mono keto amide 11
in 92% yield. Reduction of the keto group in 11 with
K-Selectride® furnished the corresponding alcohol 9 as a
single diastereomer in 87% yield,6 which was subsequent-
ly protected as the methoxymethyl ether 12 employing
standard conditions. Treatment of 12 with sodium borohy-
Our approach toward the synthesis of aspercyclide C is
depicted in Scheme 1. We envisaged formation of the key
double bond in aspercyclide C via ring-closing metathesis
SYNTHESIS 2010, No. 15, pp 2521–2526
x
x.
x
x
.
2
0
1
0
Advanced online publication: 18.06.2010
DOI: 10.1055/s-0029-1218831; Art ID: P03010SS
© Georg Thieme Verlag Stuttgart · New York

2522
K. R. Prasad et al.
PAPER
dride afforded the primary alcohol 13 in 98% yield which
was converted into the iodide 14 in 82% yield. Zinc-me-
diated Boord fragmentation7 of the iodide produced the
desired allylic alcohol 8 in an excellent 99% yield
(Scheme 2).
PPTS
t-BuOH
Δ, 2 h, 72%
MOMO
MOMO
R
NaH, PMBCl
R
DMF, 0 °C to r.t.
1 h, 85%
OH
OPMB
8
15
OH
OH
R
i) DIAD, Ph3P, PNBA, THF, r.t., 2 h
R
ii) K2CO3, MeOH, 0 °C to r.t.
0.5 h, 42% over two steps
O
O
Me
N
n-C5H11MgBr
K-Selectride
OPMB
7
OPMB
6
10
R
OMe
THF, –78 °C
1 h, 87%
THF, –15 °C, 1 h
92%
O
O
MOMO
R
MOMO
R
R = n-C5H11
11
i) DIAD, Ph3P, PNBA, toluene, r.t.
ii) K2CO3, MeOH, 0 °C to r.t.
0.5 h, 47% over two steps
OH
O
Me
N
MOMO
R
O
Me
OH
OH
MOMCl, i-Pr2NEt
16
N
8
CH2Cl2, r.t., 4 h
91%
R
OMe
OMe
O
O
O
O
12
OH
PPTS
t-BuOH
MOMO
R
9
NaH, PMBCl
R
DMF, 0 °C to r.t.
1 h, 83%
Δ, 2 h, 74%
MOMO
O
OPMB
ent-6
OPMB
Ph3P, I2, imidazole
NaBH4, MeOH
r.t., 3 h, 98%
17
OH
R
toluene, Δ, 1 h, 82%
Scheme 3 Enantiodivergent synthesis of both enantiomers of ho-
moallylic alcohol 6
O
13
MOMO
MOMO
O
Zn dust, EtOH
I
R
R
Δ, 1 h, 99%
OH
8
O
MeO
14
N
Cl
PMBO
HO
Et3N
I
Scheme 2 Synthesis of the key allylic alcohol 8 from bis-Weinreb
amide 10
Me
O
+
OH
O
toluene, Δ, 1 h
ii) NaH, 0 °C to r.t., 4 h
51%
R
6
62% for the enantiomer
Allylic alcohol 8 represented the point of divergence in
the synthesis of both enantiomers of homoallylic alcohol
6 (Scheme 3). Thus, protection of the hydroxy group in 8
as the p-methoxybenzyl ether (85% yield) followed by se-
lective deprotection of the methoxymethyl ether with py-
ridinium p-toluenesulfonate8 in refluxing tert-butanol
gave the alcohol 7 in 72% yield. Mitsunobu9 inversion of
the free alcohol in 7 afforded homoallylic alcohol 6 in
42% yield. For the synthesis of ent-6, inversion of 8 was
performed under Mitsunobu conditions leading to alkene
16 in 47% yield. Protection of the allylic alcohol group in
16 as the p-methoxybenzyl ether gave 17 (83% yield)
which underwent selective deprotection of the meth-
oxymethyl ether, as previously described, to afford ent-6
in 74% yield.
R = n-C5H11
5
MeO
Grubbs II
O
OPMB
toluene, Δ, 2 h
O
O
46%
74% for the enantiomer
R
4
MeO
O
AlCl3, EtSH, CH2Cl2
0.5 h, r.t., 51%
OPMB
O
O
R
Homoallylic alcohol 6 was next coupled with the known
biaryl acid 510 to produce the ester 4 in 51% yield follow-
ing the protocol described by Ramana et al.2d Ring-
closing metathesis of the ester using Grubbs’ second-gen-
eration catalyst produced the biaryl lactone 18 in 46%
yield. Deprotection of the p-methoxybenzyl ether in 18
with aluminum trichloride in the presence of ethanethiol
afforded lactone 19, the conversion of which into aspercy-
clide C (3) by deprotection of the aryl methyl ether was
described by Fürstner et al.2b Hence this synthetic se-
quence constitutes a formal synthesis of aspercyclide C
(Scheme 4). An analogous reaction sequence employing
ent-6 afforded the enantiomer of 19.
18
MeO
ref. 2a
O
3
OH
O
O
R
19
Scheme 4 Completion of the formal total synthesis of aspercyclide
C (3)
Synthesis 2010, No. 15, 2521–2526 © Thieme Stuttgart · New York

PAPER
Formal Total Synthesis of Aspercyclide C
2523
IR (neat): 3479, 2936, 2861, 1667, 1382, 728 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.77 (br s, 1 H), 4.37 (br s, 1 H),
In conclusion, we have accomplished the formal total syn-
theses of both enantiomers of the bioactive biaryl ether
lactone, aspercyclide C. Key features of the route include 3.74 (s, 3 H), 3.68–3.52 (m, 1 H), 3.22 (s, 3 H), 1.96 (d, J = 6.4 Hz,
1 H), 1.65–1.21 (m, 14 H), 0.87 (t, J = 6.8 Hz, 3 H).
the synthesis of both enantiomers of the chiral fragment 6
13C NMR (100 MHz, CDCl3): d = 170.5, 111.0, 80.9, 73.8, 70.3,
61.7, 34.6, 32.4, 31.7, 27.0, 26.1, 25.5, 22.6, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C14H27NO5Na: 312.1787;
found: 312.1777.
from a common precursor derived from L-(+)-tartaric
acid. Further examination of this approach for the synthe-
sis of other aspercyclide natural products and analogues is
underway.
(4R,5S)-N-Methoxy-5-[(1R)-1-(methoxymethoxy)hexyl]-N,2,2-
trimethyl-1,3-dioxolane-4-carboxamide (12)
Unless stated otherwise, all reagents were purchased from commer-
cial sources and were used without additional purification. All reac-
tions were performed under an inert atmosphere unless otherwise
stated. THF was freshly distilled from Na/benzophenone. Column
chromatography was performed on silica gel (Acme grade, 100–200
mesh). Petroleum ether (PE) refers to the fraction boiling in the 60–
80 °C range. TLC was accomplished using Merck 60F254 precoat-
ed silica gel plates which were made visual using either UV light,
an iodine chamber, or with phosphomolybdic acid spray. Melting
points were determined using a Büchi M 560 melting point appara-
tus and are uncorrected. Optical rotations were measured on a
JASCO DIP 370 digital polarimeter at 25 °C. IR spectra were ob-
To a soln of carboxamide 9 (1.20 g, 4 mmol) in anhyd CH2Cl2 (8
mL) were added DIPEA (2.2 mL, 12.4 mmol) and MOMCl (0.8
mL, 10.3 mmol) at 0 °C, and the resulting mixture stirred for 10 min
at 0 °C. The reaction mixture was warmed to r.t. and then stirred for
a further 4 h. After the reaction was complete (TLC), it was poured
into ice-cold H2O (15 mL) and extracted with Et2O (2 × 30 mL). The
combined ethereal extract was washed with brine (15 mL) and dried
over anhyd Na2SO4. Evaporation of the solvent followed by silica
gel column chromatography of the residue (PE–EtOAc, 7:3) yielded
compound 12 (1.24 g, 91%) as a colorless oil.
1
tained on a Perkin-Elmer spectrophotometer. H NMR and 13C
[a]D –4.3 (c 1.4, CHCl3).
IR (neat): 2987, 2836, 1673, 1462, 1214, 731 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.82–4.49 (m, 4 H), 3.76 (s, 3 H),
3.68 (dd, J = 11.7, 5.5 Hz, 1 H), 3.39 (s, 3 H), 3.23 (s, 3 H), 1.75–
1.22 (m, 14 H), 0.88 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.6, 111.1, 96.6, 79.6, 77.2,
73.2, 61.8, 55.9, 32.4, 31.9, 31.2, 27.0, 26.2, 25.3, 22.6, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C16H31NO6Na: 356.2049;
found: 356.2036.
NMR spectra were recorded on a Bruker spectrometer operating at
400 MHz and 100 MHz, respectively. HRMS spectra were obtained
on a Micromass Q-TOF apparatus.
(4R,5R)-5-Hexanoyl-N-methoxy-N,2,2-trimethyl-1,3-dioxolane-
4-carboxamide (11)
Bis-Weinreb amide 10 (1.60 g, 5.8 mmol) was dissolved in THF (20
mL) and cooled to –10 °C. A freshly prepared soln of n-pentylmag-
nesium bromide (24 mL, 0.5 M soln in THF, 12 mmol) was added
at such a rate that the internal temperature did not rise above –10 °C.
After the reaction was complete (TLC), it was quenched cautiously
by the addition of a sat. aq NH4Cl soln (15 mL), then poured into
H2O (15 mL) and extracted with EtOAc (2 × 35 mL). The combined
organic extract was washed with brine (20 mL) and dried over an-
hyd Na2SO4. Evaporation of the solvent followed by silica gel col-
umn chromatography of the residue (PE–EtOAc, 7:3) yielded 11
(1.53 g, 92%) as a colorless oil.
{(4S,5S)-5-[(1R)-1-(Methoxymethoxy)hexyl]-2,2-dimethyl-1,3-
dioxolan-4-yl}methanol (13)
To a round bottomed flask equipped with a CaCl2 guard tube was
added a soln of 12 (1.14 g, 3.34 mmol) in MeOH (15 mL). NaBH4
(0.76 g, 20 mmol) was added at 0 °C and the reaction mixture was
allowed to warm slowly to r.t. and then stirred for 3 h at this temper-
ature. Following completion (TLC), most of the MeOH was re-
moved under reduced pressure and H2O (20 mL) was added. The
mixture was extracted with EtOAc (2 × 30 mL) and the combined
organic layer washed with brine (15 mL) and dried over anhyd
Na2SO4. Evaporation of the solvent followed by silica gel column
chromatography of the residue (PE–EtOAc, 1:1) furnished primary
alcohol 13 (0.90 g, 98%) as a colorless oil.
[a]D +6.3 (c 2, CHCl3).
IR (neat): 2937, 2872, 1720, 1674, 1379, 1081, 862 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.04 (d, J = 4.9 Hz, 1 H), 4.82 (d,
J = 5.0 Hz, 1 H), 3.72 (s, 3 H), 3.24 (s, 3 H), 2.76–2.51 (m, 2 H),
1.75–1.55 (m, 2 H), 1.51 (s, 3 H), 1.44 (s, 3 H), 1.39–1.12 (m, 4 H),
0.90 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 208.4, 169.8, 112.7, 82.3, 73.9,
61.7, 39.3, 32.5, 31.3, 26.7, 26.2, 22.7, 22.4, 13.9.
HRMS (ESI): m/z [M + Na]+ calcd for C14H25NO5Na: 310.1630;
found: 310.1630.
[a]D +3.6 (c 1.4, CHCl3).
IR (neat): 3463, 2987, 2873, 1457, 1373, 854 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.74 (d, J = 6.8 Hz, 1 H), 4.67 (d,
J = 6.8 Hz, 1 H), 4.25–3.86 (m, 2 H), 3.84–3.51 (m, 3 H), 3.40 (s, 3
H), 2.40 (br s, 1 H), 1.90–1.21 (m, 14 H), 0.88 (t, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 108.8, 96.9, 78.9, 77.3, 77.2, 62.7,
56.0, 31.9, 30.7, 27.1, 27.0, 25.4, 22.6, 14.0.
(4R,5S)-5-[(1R)-1-Hydroxyhexyl]-N-methoxy-N,2,2-trimethyl-
1,3-dioxolane-4-carboxamide (9)
HRMS (ESI): m/z [M + Na]+ calcd for C14H28O5Na: 299.1834;
found: 299.1841.
To a soln of 11 (1.43 g, 5.0 mmol) in THF (15 mL) at –78 °C was
added K-Selectride® (7.5 mL, 1 M soln in THF, 7.5 mmol), drop-
wise, over a period of 10 min and the resulting mixture was stirred
for 1 h. After the reaction was complete (TLC), it was quenched
cautiously by the addition of H2O (10 mL) at –78 °C and then ex-
tracted with EtOAc (2 × 35 mL). The combined organic extract was
washed with brine (15 mL) and dried over anhyd Na2SO4. Evapora-
tion of the solvent followed by silica gel column chromatography of
the residue (PE–EtOAc, 1:1) yielded carboxamide 9 (1.25 g, 87%)
as a colorless oil.
(4R,5S)-4-(Iodomethyl)-5-[(1R)-1-(methoxymethoxy)hexyl]-
2,2-dimethyl-1,3-dioxolane (14)
To a soln of alcohol 13 (0.83 g, 3 mmol) in anhyd toluene (10 mL)
at r.t. were added Ph3P (2.33 g, 8.9 mmol), imidazole (0.61 g, 8.9
mmol) and I2 (1.51 g, 5.94 mmol) under an Ar atm. The reaction
mixture was heated at reflux temperature for 1 h. After the reaction
was complete (TLC), it was cooled to r.t., poured into H2O (10 mL)
and extracted with Et2O (2 × 30 mL). The combined ethereal layer
[a]D –4.6 (c 1.3, CHCl3).
Synthesis 2010, No. 15, 2521–2526 © Thieme Stuttgart · New York

2524
K. R. Prasad et al.
PAPER
was washed with brine (15 mL), sat. aq Na2S2O3 soln (10 mL) and
H2O (15 mL), and then dried over anhyd Na2SO4. Evaporation of
the solvent followed by silica gel column chromatography of the
residue (PE–Et2O, 95:5) yielded iodide 14 (1.05 g, 82%) as a color-
less oil.
HRMS (ESI): m/z [M + Na]+ calcd for C19H30O4Na: 345.2042;
found: 345.2034.
(3R,4R)-3-[(4-Methoxybenzyl)oxy]non-1-en-4-ol (7)
To a soln of alkene 15 (0.42 g, 1.3 mmol) in t-BuOH (5 mL) was
added PPTS (3.26 g, 13 mmol) and the reaction mixture was heated
at reflux temperature for 2 h. After the reaction was complete
(TLC), it was poured into ice-cold H2O (10 mL) and extracted with
Et2O (2 × 25 mL). The combined ethereal layer was washed with
brine (15 mL) and dried over anhyd Na2SO4. Evaporation of the sol-
vent followed by silica gel column chromatography of the residue
(PE–EtOAc, 9:1) afforded alcohol 7 (0.26 g, 72%) as a colorless oil.
[a]D –13.6 (c 1.1, CHCl3).
IR (neat): 2967, 2933, 1457, 1379, 1216, 889 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.73 (d, J = 6.8 Hz, 1 H), 4.68 (d,
J = 6.8 Hz, 1 H), 3.98–3.79 (m, 2 H), 3.70–3.63 (m, 1 H), 3.46–3.34
(m, 4 H), 3.32–3.21 (m, 1 H), 1.75–1.20 (m, 14 H), 0.90 (t, J = 6.9
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 109.3, 96.6, 82.2, 76.6, 75.7, 56.1,
[a]D –31.0 (c 1.0, CHCl3).
IR (neat): 3470, 2955, 2859, 1614, 1515, 1250 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.25 (d, J = 8.5 Hz, 2 H), 6.88 (d,
J = 8.5 Hz, 2 H), 5.73 (ddd, J = 17.7, 10.4, 7.9 Hz, 1 H), 5.37 (d,
J = 10.4 Hz, 1 H), 5.33 (d, J = 17.2 Hz, 1 H), 4.58 (d, J = 11.2 Hz,
1 H), 4.28 (d, J = 11.2 Hz, 1 H), 3.81 (s, 3 H), 3.63–3.47 (m, 2 H),
2.70 (br s, 1 H), 1.56–1.12 (m, 8 H), 0.88 (t, J = 6.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.2, 135.4, 130.1, 129.5, 120.0,
113.8, 84.2, 73.4, 70.0, 55.7, 55.2, 32.4, 31.9, 25.2, 22.6, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C17H26O3Na: 301.1780;
found: 301.1776.
31.9, 30.9, 27.5, 27.2, 25.4, 22.6, 14.0, 7.2.
HRMS (ESI): m/z [M + Na]+ calcd for C14H27IO4Na: 409.0852;
found: 409.0849.
(3R,4R)-4-(Methoxymethoxy)non-1-en-3-ol (8)
To a soln of the iodide 14 (1.00 g, 2.59 mmol) in absolute EtOH (12
mL) was added activated Zn dust (1.35 g, 20.72 mmol) at r.t., and
the reaction mixture was then heated at reflux temperature for 1 h.
After the reaction was complete (TLC), it was filtered through a
short pad of Celite and the residue was washed with Et2O (2 × 30
mL). Evaporation of the solvent followed by silica gel column chro-
matography of the crude (PE–EtOAc, 7:3) furnished alcohol 8 (0.51
g, 99%) as a colorless oil.
(3R,4S)-3-[(4-Methoxybenzyl)oxy]non-1-en-4-ol (6)
To a soln of alcohol 7 (0.24 g, 0.87 mmol) in anhyd THF (9 mL)
were added Ph3P (0.71 g, 2.61 mmol) and p-nitrobenzoic acid
(PNBA) (0.6 g, 2.61 mmol) under an N2 atm. The reaction mixture
was stirred for 10 min, cooled to 0 °C, and treated with DIAD (0.75
mL, 2.61 mmol) over a period of 3 min. The mixture was then
warmed to r.t. and stirred for 2 h. After the reaction was complete
(TLC), the volatiles were removed under reduced pressure and the
residue was purified by silica gel column chromatography (PE–
EtOAc, 95:5) to afford the p-nitrobenzoate ester of 6 which was
used as such in the next step. To a soln of the ester 6 in MeOH (5
mL) was added K2CO3 (0.23 g, 1.74 mmol) and the resulting mix-
ture was stirred for 0.5 h at 0 °C. After the reaction was complete
(TLC), the mixture was poured into H2O (5 mL) and extracted with
EtOAc (2 × 15 mL). The combined organic layer was washed with
brine (10 mL) and dried over anhyd Na2SO4. Evaporation of the sol-
vent followed by silica gel column chromatography of the residue
(PE–EtOAc, 7:3) afforded 6 (0.10 g, 42%) as a colorless oil.
[a]D –2.7 (c 1.5, CHCl3).
IR (neat): 3449, 3081, 2955, 1466, 1152, 920 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.87 (ddd, J = 16.9, 10.4, 6.2 Hz,
1 H), 5.36 (d, J = 17.2 Hz, 1 H), 5.22 (d, J = 10.4 Hz, 1 H), 4.74 (d,
J = 6.8 Hz, 1 H), 4.68 (d, J = 6.8 Hz, 1 H), 4.03 (t, J = 6.2 Hz, 1 H),
3.48–3.28 (m, 4 H), 3.14 (br s, 1 H), 1.62–1.23 (m, 8 H), 0.89 (t,
J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 137.5, 116.8, 97.3, 83.6, 74.7,
55.9, 31.9, 31.2, 24.9, 22.6, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C11H22O3Na: 225.1467;
found: 225.1474.
1-{[(3R,4R)-4-(Methoxymethoxy)non-1-en-3-yloxy]methyl}-4-
methoxybenzene (15)
To a cold (0 °C) soln of 8 (0.34 g, 1.69 mmol) in anhyd DMF (3 mL)
was added NaH (0.14 g of a 60% suspension in mineral oil, 3.38
mmol) portionwise under an N2 atm. After stirring for 15 min at 0
°C, PMBCl (0.50 mL, 3.38 mmol) was added dropwise at the same
temperature, and the mixture allowed to warm slowly to r.t. and then
stirred for 1 h. After the reaction was complete (TLC), it was
quenched cautiously with ice-cold H2O (10 mL) and extracted with
Et2O (2 × 20 mL). The combined ethereal layer was washed with
brine (15 mL) and dried over anhyd Na2SO4. Evaporation of the sol-
vent followed by careful silica gel column chromatography of the
residue (PE–EtOAc, 9:1) afforded 15 (0.45 g, 85%) as a colorless
oil.
[a]D –33.0 (c 1.0, CHCl3).
IR (neat): 3440, 2954, 2859, 1614, 1515, 1249 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.25 (d, J = 8.7 Hz, 2 H), 6.88 (d,
J = 8.6 Hz, 2 H), 5.84 (ddd, J = 18.1, 10.4, 7.9 Hz, 1 H), 5.39 (dd,
J = 10.5, 1.6 Hz, 1 H), 5.29 (dd, J = 17.4, 1.7 Hz, 1 H), 4.56 (d,
J = 11.4 Hz, 1 H), 4.31 (d, J = 11.4 Hz, 1 H), 3.81 (s, 3 H), 3.75–
3.64 (m, 2 H), 2.18 (br s, 1 H), 1.58–1.15 (m, 8 H), 0.88 (t, J = 6.8
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.2, 134.6, 130.3, 129.4, 120.0,
113.8, 83.2, 73.2, 69.9, 55.2, 32.1, 31.8, 25.5, 22.6, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C17H26O3Na: 301.1780;
found: 301.1776.
[a]D –7.9 (c 1.4, CHCl3).
IR (neat): 2953, 2930, 2860, 1613, 1514, 920 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.24 (d, J = 8.5 Hz, 2 H), 6.86 (d,
J = 8.6 Hz, 2 H), 5.84 (ddd, J = 17.6, 10.5, 7.6 Hz, 1 H), 5.42–5.21
(m, 2 H), 4.75 (d, J = 6.9 Hz, 1 H), 4.67 (d, J = 6.9 Hz, 1 H), 4.57
(d, J = 11.6 Hz, 1 H), 4.30 (d, J = 11.6 Hz, 1 H), 3.88–3.70 (m, 4 H),
3.55 (td, J = 7.7, 4.9 Hz, 1 H), 3.37 (s, 3 H), 1.74–1.15 (m, 8 H),
0.87 (t, J = 6.7 Hz, 3 H).
(3S,4R)-(4-Methoxymethoxy)non-1-en-3-ol (16)
To a soln of alcohol 8 (0.15 g, 0.75 mmol) in anhyd toluene (8 mL)
were added Ph3P (0.59 g, 2.3 mmol) and p-nitrobenzoic acid (0.38
g, 2.3 mmol) under an N2 atm. The reaction mixture was stirred for
10 min, cooled to 0 °C, and treated with DIAD (0.5 mL, 2.25 mmol)
in anhyd THF (1 mL) over a period of 3 min. The mixture was then
warmed to r.t. and stirred for 2 h. After the reaction was complete
(TLC), the volatiles were removed under reduced pressure and the
13C NMR (100 MHz, CDCl3): d = 159.0, 135.6, 130.5, 129.4, 118.5,
113.6, 96.9, 81.5, 79.8, 70.0, 55.7, 55.2, 31.9, 30.7, 25.1, 22.6, 14.0.
Synthesis 2010, No. 15, 2521–2526 © Thieme Stuttgart · New York

PAPER
Formal Total Synthesis of Aspercyclide C
2525
crude residue was purified by silica gel column chromatography
(PE–EtOAc, 95:5) to yield the corresponding p-nitrobenzoate ester.
To a soln of the ester in MeOH (3 mL) at 0 °C was added K2CO3
(0.23 g, 1.74 mmol) and the resulting mixture was stirred for 15 min
at 0 °C. After the reaction was complete (TLC), the mixture was
poured into H2O (3 mL) and extracted with EtOAc (2 × 10 mL). The
combined organic layer was washed with brine (5 mL) and dried
over anhyd Na2SO4. Evaporation of the solvent followed by silica
gel column chromatography of the residue (PE–EtOAc, 7:3) afford-
ed alcohol 16 (0.07 g, 47%) as a colorless oil.
J = 10.4 Hz, 1 H), 5.32 (d, J = 17.3 Hz, 1 H), 4.58 (d, J = 11.4 Hz,
1 H), 4.33 (d, J = 11.4 Hz, 1 H), 3.82 (s, 3 H), 3.72–3.64 (m, 2 H),
2.13 (br s, 1 H), 1.45–1.29 (m, 8 H), 0.89 (t, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.1, 134.5, 130.2, 129.3, 120.0,
113.7, 83.1, 73.1, 69.8, 55.2, 32.0, 31.8, 25.3, 22.5, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C17H26O3Na: 301.3814;
found: 301.1771.
(3R,4S)-{3-[(4-Methoxybenzyl)oxy]non-1-en-4-yl} 2-(2-Meth-
oxy-6-ethenylphenoxy)-6-methylbenzoate (4)
[a]D -27.0 (c 1.0, CHCl3).
IR (neat): 3444, 2955, 2874, 1464, 1037, 921 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.91 (ddd, J = 16.9, 10.5, 5.9 Hz,
1 H), 5.32 (d, J = 17.2 Hz, 1 H), 5.24 (d, J = 10.5 Hz, 1 H), 4.75 (d,
J = 6.9 Hz, 1 H), 4.66 (d, J = 6.9 Hz, 1 H), 4.07 (t, J = 6.0 Hz, 1 H),
3.62–3.55 (m, 1 H), 3.43 (s, 3 H), 3.39 (d, J = 7.9 Hz, 1 H), 1.58–
1.15 (m, 8 H), 0.89 (t, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 136.3, 116.5, 97.7, 84.8, 73.3,
55.9, 31.7, 31.1, 25.5, 22.5, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C11H22O3Na: 225.1467;
found: 225.1469.
To a soln of acid 510 (0.06 g, 0.22 mmol) in toluene (0.5 mL) was
added Et3N (0.1 mL, 0.66 mmol) and 1-methyl-2-chloropyridinium
iodide (0.06 g, 0.22 mmol) under an N2 atm. After stirring for 10
min, a soln of alcohol 6 (0.06 mg, 0.22 mmol) in toluene (0.5 mL)
was added and the resulting mixture heated at reflux temperature for
1 h. The mixture was cooled to 0 °C and NaH (0.02 g of a 60% sus-
pension in mineral oil, 0.22 mmol) was added and stirring continued
for 4 h at r.t. After the reaction was complete (TLC), it was
quenched cautiously with ice-cold H2O (2 mL) and extracted with
EtOAc (2 × 10 mL). The combined organic extract was washed with
brine (10 mL) and dried over anhyd Na2SO4. Evaporation of the sol-
vent followed by silica gel column chromatography of the residue
(PE–EtOAc, 95:5) afforded ester 4 (0.06 g, 51%) as a yellow liquid.
1-{[(3S,4R)-4-(Methoxymethoxy)non-1-en-3-yloxy]methyl}-4-
methoxybenzene (17)
[a]D –30.0 (c 1.0, CHCl3); (ent-4) [a]D +31.1 (c 1.1, CHCl3).
IR (neat): 2955, 1730, 1611, 1515, 1461, 1273 cm–1.
To a cold (0 °C) soln of alcohol 16 (0.06 g, 0.30 mmol) in anhyd
DMF (1 mL) was added NaH (0.03 g of a 60% suspension in min-
eral oil, 0.60 mmol), portionwise, under an N2 atm. After stirring for
15 min at 0 °C, PMBCl (0.10 mL, 0.60 mmol) was added dropwise
at the same temperature, the mixture allowed to warm slowly to r.t.,
and then stirred for 1 h. After the reaction was complete (TLC), it
was quenched cautiously with ice-cold H2O (5 mL) and extracted
with Et2O (2 × 10 mL). The combined ethereal layer was washed
with brine (5 mL) and dried over anhyd Na2SO4. Evaporation of the
solvent followed by silica gel column chromatography of the resi-
due (PE–EtOAc, 9:1) afforded 17 (0.10 g, 83%) as a colorless oil.
1H NMR (400 MHz, CDCl3): d = 7.22 (d, J = 8.5 Hz, 2 H), 7.21 (d,
J = 6.5 Hz, 1 H), 7.15 (t, J = 8.0 Hz, 1 H), 7.03 (t, J = 8.0 Hz, 1 H),
6.98–6.82 (m, 3 H), 6.81 (d, J = 8.5 Hz, 2 H), 6.23 (d, J = 8.3 Hz, 1
H), 5.89 (ddd, J = 17.5, 10.5, 7.5 Hz, 1 H), 5.74 (d, J = 17.7 Hz, 1
H), 5.36 (t, J = 4.4 Hz, 1 H), 5.34 (d, J = 10.4 Hz, 1 H), 5.30 (d,
J = 10.4 Hz, 1 H), 5.20 (d, J = 11.3 Hz, 1 H), 4.52 (d, J = 11.5 Hz,
1 H), 4.40 (d, J = 11.5 Hz, 1 H), 3.98 (dd, J = 7.3, 4.3 Hz, 1 H), 3.79
(s, 3 H), 3.68 (s, 3 H), 2.33 (s, 3 H), 1.74–1.10 (m, 8 H), 0.74 (t,
J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.7, 158.9, 155.3, 152.8, 140.3,
136.8, 135.1, 132.4, 130.6, 130.5, 129.7, 129.2, 125.6, 123.6, 123.1,
119.2, 117.7, 115.9, 113.5, 112.0, 110.5, 81.3, 76.1, 70.2, 56.0,
55.2, 31.7, 29.8, 29.7, 24.9, 22.4, 19.4, 13.9.
[a]D +55.7 (c 0.9, CHCl3).
IR (neat): 2953, 2873, 1614, 1515, 1249, 920 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.26 (d, J = 9.0 Hz, 2 H), 6.87 (d,
J = 8.5 Hz, 2 H), 5.85 (ddd, J = 17.7, 10.5, 7.8 Hz, 1 H), 5.35 (d,
J = 9.7 Hz, 1 H), 5.28 (d, J = 17.4 Hz, 1 H), 4.80 (d, J = 6.8 Hz, 1
H), 4.64 (d, J = 6.8 Hz, 1 H), 4.57 (d, J = 11.6 Hz, 1 H), 4.34 (d,
J = 11.6 Hz, 1 H), 3.82 (s, 3 H), 3.79 (dd, J = 7.8, 3.9 Hz, 1 H), 3.68
(dt, J = 7.6, 3.9 Hz, 1 H), 3.38 (s, 3 H), 1.58–1.15 (m, 8 H), 0.89 (t,
J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.0, 135.5, 130.6, 129.2, 119.0,
113.6, 96.4, 82.0, 79.2, 69.8, 55.7, 55.2, 31.8, 30.9, 25.2, 22.6, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C19H30O4Na: 345.2042;
found: 345.2071.
HRMS (ESI): m/z [M + Na]+ calcd for C34H40O6Na: 567.2723;
found: 567.2728.
4-Methoxybenzyl Protected Biaryl Lactone 18
In a two-neck 25 mL round bottom flask fitted with an addition flask
was placed a soln of diene 4 (0.05 g, 0.09 mmol) in anhyd toluene
(3 mL) under an N2 atm. The soln was heated to reflux temperature
followed by the slow addition of a soln of Grubbs’ second-genera-
tion catalyst (10 mol%) in anhyd toluene (3 mL) via the addition
flask. The mixture was stirred at reflux temperature for 2 h. After
the reaction was complete (TLC), the volatiles were evaporated un-
der reduced pressure and the residue was purified by silica gel col-
umn chromatography (PE–EtOAc, 95:5) to afford 18 (0.02 g, 46%)
as a brown sticky mass.
[a]D +78.0 (c 0.5, CHCl3) {Lit.2d [a]D +148.6 (c, 0.4, CHCl3)}; (ent-
18) [a]D –78.3 (c 0.5, CHCl3).
IR (CH2Cl2): 2956, 1739, 1612, 1586, 1461, 1251 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.24 (d, J = 10.1 Hz, 2 H), 7.15 (t,
J = 7.9 Hz, 1 H), 7.08 (t, J = 7.9 Hz, 1 H), 6.94 (d, J = 7.9 Hz, 1 H),
6.88 (d, J = 8.5 Hz, 2 H), 6.82 (dd, J = 11.5, 7.6 Hz, 1 H), 6.59 (d,
J = 8.4 Hz, 1 H), 6.29 (d, J = 16.0 Hz, 1 H), 5.98 (dd, J = 16.0, 9.7
Hz, 1 H), 5.36–5.24 (m, 1 H), 4.58 (d, J = 11.4 Hz, 1 H), 4.34 (d,
J = 11.4 Hz, 1 H), 3.91 (s, 3 H), 3.81 (s, 3 H), 3.75 (t, J = 9.5 Hz, 1
H), 2.34 (s, 3 H), 2.06–1.98 (m, 1 H), 1.54–1.12 (m, 8 H), 0.90 (t,
J = 7.2 Hz, 3 H).
(3S,4R)-3-[(4-Methoxybenzyl)oxy]non-1-en-4-ol (ent-6)
To a soln of alkene 17 (0.08 g, 0.25 mmol) in t-BuOH (2 mL) was
added PPTS (0.63 g, 2.5 mmol). The reaction mixture was heated at
reflux temperature for 2 h, and following completion (TLC), was
poured into ice-cold H2O (2 mL) and extracted with Et2O (2 × 5
mL). The combined ethereal layer was washed with brine (5 mL)
and dried over anhyd Na2SO4. Evaporation of the solvent followed
by silica gel column chromatography of the residue (PE–EtOAc,
9:1) afforded ent-6 (0.05 g, 74%) as a colorless oil.
[a]D +34.6 (c 2.4, CHCl3).
IR (neat): 3462, 2955, 2860, 1614, 1515, 821 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.26 (d, J = 8.7 Hz, 2 H), 6.90 (d,
J = 8.6 Hz, 2 H), 5.86 (ddd, J = 18.0, 10.4, 8.0 Hz, 1 H), 5.41 (d,
Synthesis 2010, No. 15, 2521–2526 © Thieme Stuttgart · New York

2526
K. R. Prasad et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 167.6, 159.2, 154.0, 153.8, 143.0,
136.8, 134.7, 133.7, 130.1, 129.7, 129.6, 129.4, 126.7, 125.4, 123.7,
121.6, 114.3, 113.8, 111.6, 82.9, 75.7, 70.5, 56.0, 55.3, 31.9, 31.7,
25.2, 22.5, 19.3, 14.0.
HRMS (ESI): m/z [M + Na]+ calcd for C32H36O6Na: 539.2410;
found: 539.2408.
(2) (a) Pospsil, J.; Müller, C.; Fürstner, A. Chem. Eur. J. 2009,
15, 5956. (b) Fürstner, A.; Müller, C. Chem. Commun. 2005,
5583. (c) Carr, J. L.; Offermann, D. A.; Holdom, M. D.;
Dusart, P.; White, A. J. P.; Beavil, A. J.; Leatherbarrow, R.
J.; Lindell, S. D.; Sutton, B. J.; Spivey, A. C. Chem.
Commun. 2010, 46, 1824. (d) Ramana, C. V.; Mondal, M.
A.; Puranik, V. G.; Gurjar, M. K. Tetrahedron Lett. 2007,
48, 7524.
(3) (a) Prasad, K. R.; Gandi, V. R. Synlett 2009, 2593.
(b) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73, 2.
(c) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73,
2916. (d) Prasad, K. R.; Swain, B. Tetrahedron: Asymmetry
2008, 19, 1134. (e) Prasad, K. R.; Gandi, V. Tetrahedron:
Asymmetry 2008, 19, 2616. (f) Prasad, K. R.;
Biaryl Lactone 19
To a soln of 18 (0.02 g, 0.03 mmol) in anhyd CH2Cl2 (0.5 mL) were
added ethanethiol (0.1 mL, 0.13 mmol) followed by anhyd AlCl3
(8 mg, 0.06 mmol) at r.t. under an N2 atm, and the resulting mixture
was stirred for 0.5 h. After the reaction was complete (TLC), it was
quenched with NaHCO3 (0.02 g) and then filtered through a Celite
pad and the residue rinsed with EtOAc. Evaporation of the solvent
followed by silica gel column chromatography of the residue (PE–
EtOAc, 7:3) afforded lactone 19 (0.01 g, 51%) as a colorless solid.
Mp 239–240 °C; [a]D +276.7 (c 0.6, CH2Cl2) {Lit.2d [a]D +330.5 (c
0.8, CH2Cl2)}; (ent-19) [a]D –277.3 (c 0.4, CH2Cl2).
IR (KBr): 3522, 2951, 1721, 1600, 1456, 1294 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.17–7.05 (m, 2 H), 6.94 (d,
J = 7.4 Hz, 1 H), 6.84 (d, J = 7.5 Hz, 1 H), 6.76 (d, J = 7.2 Hz, 1 H),
6.60 (d, J = 8.4 Hz, 1 H), 6.30 (d, J = 15.9 Hz, 1 H), 6.01 (dd,
J = 15.8, 9.5 Hz, 1 H), 5.23 (td, J = 9.6, 2.2 Hz, 1 H), 4.07 (t, J = 9.2
Hz, 1 H), 3.91 (s, 3 H), 2.36 (s, 3 H), 2.22–1.91 (m, 1 H), 1.85–1.11
(m, 8 H), 0.93 (t, J = 6.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 167.8, 154.0, 153.8, 143.0, 137.6,
134.7, 133.5, 129.7, 128.0, 126.6, 125.5, 123.8, 121.5, 114.4, 111.7,
56.0, 31.8, 31.6, 29.6, 25.3, 22.5, 19.3, 14.0.
Chandrakumar, A. J. Org. Chem. 2007, 72, 6312.
(g) Prasad, K. R.; Dhaware, M. Synthesis 2007, 3697.
(h) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2006, 71,
3643. (i) Prasad, K. R.; Anbarasan, P. Tetrahedron Lett.
2006, 47, 1433. (j) Prasad, K. R.; Anbarasan, P.
Tetrahedron: Asymmetry 2006, 17, 850. (k) Prasad, K. R.;
Anbarasan, P. Tetrahedron 2006, 62, 8303. (l) Prasad, K.
R.; Anbarasan, P. Synlett 2006, 2087.
(4) For an optimized synthesis of g-hydroxy amides from
tartaric acid amides, see: Prasad, K. R.; Chandrakumar, A.
Tetrahedron 2007, 63, 1798.
(5) (a) Nugiel, D. A.; Jakobs, K.; Worley, T.; Patel, M.;
Kaltenbach, R. F. III.; Meyer, D. T.; Jadhav, P. K.;
De Lucca, G. V.; Smyser, T. E.; Klabe, R. M.; Bacheler, L.
T.; Rayner, M. M.; Seitz, S. P. J. Med. Chem. 1996, 39,
2156. (b) McNulty, J.; Grunner, V.; Mao, J. Tetrahedron
Lett. 2001, 42, 5609.
HRMS (ESI): m/z [M + Na]+ calcd for C24H28O5Na: 419.1834;
found: 419.1809.
(6) Formation of the other diastereomer was not detected within
the limits of 1H NMR spectroscopy.
(7) (a) Swallen, L. C.; Boord, C. E. J. Am. Chem. Soc. 1930, 52,
651. For the application of this strategy in the synthesis of
allylic alcohols, see: (b) Schneider, C.; Kazmaier, U.
Synthesis 1998, 1314. (c) Rama Rao, A. V.; Reddy, E. R.;
Joshi, B. V.; Yadav, J. S. Tetrahedron Lett. 1987, 28, 6497.
(8) Ghosh, A. K.; Wang, Y.; Kim, J. T. J. Org. Chem. 2001, 66,
8973.
Acknowledgment
We thank DST, New Delhi for funding this project. K.R.P. is a
Swarnajayanthi fellow of the Department of Science and Technolo-
gy (DST). V.R.G. and J.E.N. thank CSIR for senior and junior re-
search fellowships, respectively.
(9) Mitsunobu, O. Synthesis 1981, 1.
(10) Biaryl acid 5 was prepared according to the method of
References
Ramana et al., see ref. 2d.
(1) Singh, S. B.; Jayasuriya, H.; Zink, D. L.; Polishook, J. D.;
Dombrowski, A. W.; Zweerink, H. Tetrahedron Lett. 2004,
45, 7605.
Synthesis 2010, No. 15, 2521–2526 © Thieme Stuttgart · New York