Asymmetric total synthesis of 5′-epi-paecilomycin-F

Article abstract of DOI:10.1016/j.tetasy.2012.05.017

The asymmetric total synthesis of one of the stereoisomers of the naturally occurring 14-membered ring macrolide paecilomycin-F (5′-epi) has been reported in this article. The main highlight of the synthetic strategy involves the successful application of

Full text of DOI:10.1016/j.tetasy.2012.05.017

Tetrahedron: Asymmetry 23 (2012) 802–808
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric total synthesis of 50-epi-paecilomycin-F
⇑
Nandan Jana, Samik Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2012
Accepted 17 May 2012
The asymmetric total synthesis of one of the stereoisomers of the naturally occurring 14-membered ring
macrolide paecilomycin-F (50-epi) has been reported in this article. The main highlight of the synthetic
strategy involves the successful application of a ring closing metathesis (RCM) reaction at a late stage.
Asymmetric Keck allylation, Sharpless asymmetric dihydroxylation, and Mitsunobu esterification have
also been used successfully for the total synthesis of 50-epi-paecilomycin-F.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric dihydroxylation by AD-mix b which lead to 50-epi-pae-
cilomycin-F.
b-Resorcylic acid lactones (RALs) belong to a unique class of
fungal polyketide derived secondary metabolites, which are b-res-
orcylic acid derivatives containing a C11 side chain.1 In a majority
of cases, these RALs have a 14-membered ring lactone as one of the
core structural components. Their biological activity spans from
estrogenic, antifungal, cytotoxic, antimalarial properties and they
have also been shown to possess inhibitory effects against selective
enzymes, such as ATPases and kinases.2 Due to these important
biological properties, RALs have attracted a great deal of attention
from synthetic organic chemists. Recently six new b-RALs have
been isolated from a mycelial solid culture of Paecilomyces sp.
SC0924 (filamentous fungi found in South China Sea).3 These com-
pounds have been named as paecilomycins A–F 1–6, and their
structures have been elucidated by extensive NMR and X-ray
analyses. In addition to these six new RALs, five known RALs have
also been isolated from the same species; aigilomycin B 7, zeaenol
8, aigialomycin D 9, aigialomycin F 10, and aigialospirol (Fig. 1).
There are numerous reports on the total synthesis of RALs,4 but
to the best of our knowledge there is only one synthetic report
for the paecilomycins. Srihari et al.4e have reported the first total
synthesis of paecilomycin-E 5 by a chiral pool approach. The best
synthetic strategy reported for RALs involve a biomimetic synthe-
sis featuring a late stage aromatization of properly substituted tri-
keto esters as demonstrated by Barett et al. in their total synthe-
sis.4a,b We have recently accomplished the total synthesis of coch-
liomycin-A and zeaenol.5 Herein we report the asymmetric total
synthesis of 50-epi-paecilomycin-F 11. It should be noted that the
synthesis accomplished herein was not a target oriented synthesis,
rather it could be better described as a strategy oriented synthesis
as two hydroxyl stereocenters at C-50 and C-60 have been fixed by
2. Results and discussion
The retrosynthetic analysis of compound 11 is shown in
Scheme 1. We envisioned that the double bond between C-10 and
C-20 could be constructed from ester 12 by adopting an RCM reac-
tion. Ester 12 could be obtained from alcohol 13 and acid 14 with a
pendant vinyl group by a Mitsunobu esterification reaction. Tri-
substituted benzoic acid 14 with a pendant vinyl group was synthe-
sized from 3,5-dihydroxy benzoic acid in seven steps.5 The alcohol
fragment 13 was prepared from 1,5-pentanediol by applying a ster-
eoselective Keck allylation, Sharpless asymmetric dihydroxylation,
and ME-DKR reaction (metal–enzyme combined dynamic kinetic
resolution).
The synthesis of alcohol fragment 13 was initiated from 1,5-pen-
tanediol as a starting material. Monoprotection with PMB-Br (para-
methoxy benzyl bromide) afforded compound 15 in 82% yield.
Swernoxidation6 of compound 15 afforded aldehyde 16 in 90% yield.
The addition of a freshly generated solution of MeMgBr to aldehyde
16 yielded racemic secondary alcohol 17 in 85% yield. The DKR of the
secondary alcohol functionality in compound 17 was achieved by
coupling an enzyme-catalyzed transesterification reaction with a
metal-catalyzed (ruthenium based catalyst shown in Scheme 2)
racemization method as reported by Kim et al.7 Isopropenyl acetate
was used as the acyldonor in the DKR reaction. The DKR reactionwas
highly efficient for compound 17 since it yielded the corresponding
acetate 18 in 92% yield with excellent enantioselectivity (ee = 98%).8
The acetate functionality was removed by treatment with K2CO3 in
MeOH to yield enantiomerically pure (R)-17 in 94% yield. This type
of ME-DKR has already been successfully used9 for the synthesis of
valuable chiral intermediates. The free secondary hydroxy group
in compound 17 was protected as its TBDPS (tert-butyldiphenylsilyl)
ether by treatment with TBDPS-Cl and imidazole to produce
⇑
Corresponding author. Tel.: +91 3222 283328; fax: +91 3222 282252.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.05.017

N. Jana, S. Nanda / Tetrahedron: Asymmetry 23 (2012) 802–808
803
OH
O
OH
O
OH
O
O
OH
R2
O
O
O
MeO
MeO
OH
R1
R2
MeO
OH
OH
R1
OH
OH
O
HO
OH
OH
R1 = H, R2 = OH 3
R1 = OH, R2 = H
2
1
R1 = OH, R2 = H
4
R1 = H, R2 = OH 7
OH
O
O
OH
OH
O
O
O
O
OH
OH
OH
R2O
R1
MeO
OH
MeO
R1
R2
OH
OH
OH
10
OH
OH
R1 = H, R2 = OH
5
R1 = OH, R2 = Me
R
1 = OH, R2 = H 6
8
paecilomycin A-F 1-6
R1 = H, R2 = H 9
7
aigilomycin B
zeaenol 8
9
aigialomycin D
OH
O
aigialomycin F 10
1
9'
3
O
8'
1'
5'-epi-paecilomycin F 11
7'
MeO
OH
5
6'
5'
OH
2'
4'
3'
OH
Figure 1. Structures of the paecilomycins and other related RALs.
OH
O
OH
O
OH
O
1
9'
HO
3
O
O
OH
8'
1'
+
OP
7'
6'
MeO
OH
MeO
OH
MeO
5
5'
O
2'
14
4'
OH
O
3'
13
O
OH
O
5'-epi-paecilomycin F 11
12
P = MOM; methoxymethyl
P1 = TBDPS; tert-butyldiphenylsilyl
OH
P1O
HO
CO2H
HO
OH
OHC
O
1,5-pentanediol
3,5-dihydroxy-benzoicacid
O
Scheme 1. Retrosynthetic analysis of 50-epi-paecilomycin F.
compound 19 in 90% yield. Removal of the PMB group was achieved
with DDQ10 to afford compound 20 in 83% yield. The primary hydro-
xy group in compound 20 was transformed into its corresponding
aldehyde by another round of Swern oxidation to afford aldehyde
21 in 88% yield. The trans-selective HWE olefination of aldehyde
21 with triethyl phosphonoacetate yielded the E-ester 22 in 88%
yield (Z:E = 1:20). Dihydroxylation of ester 22 with AD mix-b11 pro-
duced the required diol 23 in 75% yield. Diol 23 was protected as its
acetonide by treatment with 2,2-DMP12 (2,2-dimethoxy propane) in
the presence of a catalytic amount of CSA (camphoresulfonic acid) to
afford 24 in 92% yield. Selective reduction of the ester functionality
in compound 24 with DIBAL-H afforded aldehyde 25 in 80% yield
(Scheme 2).
Aldehyde 25 was then subjected to a Keck asymmetric allyla-
tion13 reaction to produce allylic alcohol 26 in 78% yield with a
19:1 diastereomeric ratio. The protection of the free hydroxyl group
as its MOM (methoxy-methyl) ether14 was achieved by treating
compound 26 with DIPEA, MOM-Cl and a catalytic amount of TBAI
(tetra-n-butyl ammonium iodide, yield = 92%) to afford compound
27. Deprotection of the TBDPS group in compound 27 by TBAF15
afforded alcohol 13 in 86% yield. With the vinyl substituted benzoic
acid 14 and properly functionalized alcohol 13 in hand, the esteri-

804
N. Jana, S. Nanda / Tetrahedron: Asymmetry 23 (2012) 802–808
OH
a
b
c
OHC
HO
OH
HO
OPMB
OPMB
OPMB
15
16
17
OAc
OH
OTBDPS
f
e
d
OPMB
OPMB
OPMB
CO2Et
(R)-17
19
18
OTBDPS
OTBDPS
OTBDPS
i
g
h
CHO
OH
20
22
21
TBDPSO
OTBDPS
O
OTBDPS
OH
j
O
k
CO2Et
l
OHC
25
24
CO2Et
23
OH
O
O
Scheme 2. Reagents and conditions: (a) PMB-Br, NaH, TBAI (cat.), THF, rt, 2 h,(80%); (b) (COCl)2, DMSO, Et3N, ꢀ78 °C, 86%; (c) MeMgI, Et2O, ꢀ78 °C to rt, 2 h, 92%; (d) CAL-B,
isopropenyl acetate, chlorodicarbonyl(1-(isopropylamino)-2,3,4,5-tetraphenylcyclopentadienyl) ruthenium(II) [DKR catalyst], K2CO3, KOtBu, 92%; (e) K2CO3, MeOH, 94%; (f)
imidazole, TBDPS-Cl, DCM, rt, 95%; (g) DDQ, DCM/H2O (19:1), 86%; (h) (COCl)2, DMSO, Et3N, ꢀ78 °C, 84%; (i) triethylphosphano acetate, NaH, Et2O, ꢀ5 °C to rt, 96%; (j) AD-
mix-b, MeSO2NH2, tBuOH/H2O (1:1), 78%; (k) 2,2-dimethoxy propane, PTSA, DCM, rt, 80%; (l) DIBAL-H, DCM, ꢀ78 °C, 1 h, 70%.
fication reaction of the two fragments under Mitsunobu condi-
tions16 proceeded cleanly to generate ester 12 in 85% yield. In order
to complete the total synthesis, macrocyclization by RCM and
deprotection was required. Compound 12 with two terminal ole-
fins, upon treatment with Grubbs-II catalyst17 furnished macrolac-
tone 28 in 68% yield. Global deprotection of the MOM and acetonide
functionality was achieved by treating compound 28 with 2 M HCl
to afford 50-epi-paecilomycin-F in 88% yield (overall yield = 5.5%
from 1,5-pentanediol, Scheme 3).
hyde, an asymmetric dihydroxylation reaction by the Sharpless pro-
tocol and a late stage RCM reaction. Synthetic studies toward several
structurally related RALs (cochliomycin B and C, paecilomycin F) are
still under investigation.
4. Experimental
4.1. General
Unless stated otherwise, materials were obtained from com-
mercial suppliers and used without further purification. THF and
diethyl ether were distilled from sodium benzophenone ketyl.
Dichloromethane (DCM), dimethylformamide (DMF), and dimeth-
ylsulfoxide (DMSO) were distilled from calcium hydride. Diiso-
propylether (DIPE) was refluxed over P2O5 and distilled prior to
use. Vinyl acetate was freshly distilled prior to use. CAL-B (Candida
antartica lipase-B, Novozym-435, immobilized on acrylic resin)
3. Conclusion
In conclusion, we have synthesized a new RAL 50-epi-paecilomy-
cin-F starting from the commercially available, inexpensive starting
materials 3,5-dihydroxy benzoic acid and 1,5-pentanediol. The key
steps of our synthesis include a metal–enzyme combined DKR, an
effective Keck asymmetricallylation on an acetonide protected alde-
TBDPSO
TBDPSO
HO
TBDPSO
MOMO
c
a
b
OH
MOMO
OHC
O
O
O
O
O
O
O
O
27
25
26
13
OH
O
OH
O
OH
O
O
O
O
e
f
d
MeO
OR
MeO
OR
MeO
OH
O
O
OH
O
O
OH
R = MOM
R = MOM
28
5'-epi-peacilomycin F
12
Scheme 3. Reagent and conditions: (a) allyltributyltin, Ti(OPr)4, (S)-BINOL, toluene, ꢀ78 °C then ꢀ20 °C 72 h, 76%; (b) MOM-Cl, DIPEA, DCM, rt, overnight, 90%; (c) TBAF, THF,
rt, 4 h, 92%; (d) 14, DIAD, PPh3, toluene, 1.5 h, 85%; (e) Grubbbs II, DCM, 40 °C, 6 h, 72%; (f) 2 M HCl, THF, 20 h, 90%.

N. Jana, S. Nanda / Tetrahedron: Asymmetry 23 (2012) 802–808
805
were obtained from Sigma and used as obtained. Reactions were
monitored by thin-layer chromatography(TLC) carried out on
0.25 mm silica gel plates (Merck) with UV light, ethanolic anisalde-
hyde and phosphomolybdic acid/heat as developing agents. Silica
gel 100–200 mesh was used for column chromatography. Yields
refer to chromatographically and spectroscopically homogeneous
materials unless otherwise stated. NMR spectra were recorded on
Bruker 400 and 200 MHz spectrometers at 25 °C in CDCl3 using
TMS as the internal standard. Chemical shifts are shown in d. 13C
NMR spectra were recorded with a complete proton decoupling
environment. The chemical shift value is listed as dH and dC for
1H and 13C, respectively. Optical rotations were measured on a JAS-
CO P-1020 digital polarimeter. Chiral HPLC was performed using a
Chiral AS-H column (0.46 ꢁ 25 cm, Daicel industries) with a Shi-
madzu Prominence LC-20AT chromatograph coupled with a UV–
vis detector (254 nm). The eluting solvent used was different ratio
of hexane and 2-propanol. Mass spectral analysis was performed at
IICT, Hyderabad, India.
2,3,4,5-tetraphenylcyclopentadienyl) ruthenium(II) [DKR catalyst,
142 mg, 0.228 mmol] was added. The flask was successively
charged with alcohol 17 (1.36 g, 5.7 mmol) in 20 mL of dry toluene,
Na2CO3 (5.7 mmol), CAL-B (65 mg), and KOtBu (0.28 mmol) fol-
lowed by isopropenyl acetate (5 mmol). The reaction mixture
was stirred at room temperature under an argon atmosphere. After
6 h the reaction mixture was filtered off and the solution was evap-
orated to afford the crude acetate, which was subsequently puri-
fied by silica gel chromatography (7:1, hexane/EtOAc) to afford
the pure acetate 18 in 92% yield. dH (CDCl3, 200 MHz): 7.23 (d,
J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 4.95–4.79 (m, 1H), 4.41 (s,
2H), 3.78 (s, 3H), 3.42 (t, J = 6.4 Hz, 2H), 2.03 (s, 3H), 1.62–1.37
(m, 6H), 1.18 (d, J = 6.2 Hz, 3H). dC (CDCl3, 50 MHz): 170.7, 159.1,
130.7, 129.2 (CH), 113.7 (CH), 72.5 (CH2), 70.9 (CH), 69.8 (CH2),
55.2 (CH3), 35.7 (CH2), 29.6 (CH2), 22.1 (CH2), 21.3 (CH3), 19.9
(CH3). ½a 3D0
¼ ꢀ1:9 (c 2.0, MeOH). HRMS (ESI) for C16H24O4Na
ꢂ
[M+Na]+, calculated: 303.1572, found: 303.1579.
4.5. (R)-6-(4-Methoxybenzyloxy)hexan-2-ol 17
4.2. 5-(4-Methoxybenzyloxy)pentan-1-ol 15
The pure acetate 18 (3 g, 10.7 mmol) was taken in MeOH
(50 ml) followed by the addition of K2CO3 (1.48 g, 10.7 mol) and
the solution was stirred at room temperature for 2 h, after which
MeOH was evaporated and the residue was taken in DCM, and
washed successively with water and brine. The organic layer was
dried (MgSO4) and purified through silica gel chromatography
Pentane-1,5-diol (8 g, 77 mmol) was taken in 200 mL of dry
THF. NaH (60% dispersion in mineral oil, 3.11 g, 111 mmol) was
added portionwise at 0 °C. The reaction mixture was then stirred
at 0 °C for 1 h. Tetrabutylammonium iodide (TBAI, 5 mmol) was
then added to it followed by the addition of 4-methoxybenzylbro-
mide. The reaction mixture was stirred for a further 2 h at room
temperature. Water was then carefully added to the reaction mix-
ture to quench any excess NaH. The reaction mixture was extracted
with a large volume of EtOAc. The organic solution was washed
with water and brine. Evaporation and purification by means of sil-
ica gel chromatography (2.5:1, hexane/EtOAc) afforded the mono-
PMB protected alcohol 15 in 80% yield. dH (CDCl3, 200 MHz): 7.24
(d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 4.42 (s, 2H), 3.78 (s,
3H), 3.60–3.41 (m, 4H), 1.65–1.36 (m, 6H). dC (CDCl3, 50 MHz):
159.1, 130.6, 129.3 (CH), 113.8 (CH), 72.6 (CH2), 70.0 (CH2), 62.7
(CH2), 55.3 (CH3), 32.5 (CH2), 29.4 (CH2), 22.4 (CH2).
(5:1, hexane/EtOAc) to yield the (R)-alcohol 17. ½a D30
¼ þ7:6 (c
ꢂ
2.0, MeOH).
4.6. ((R)-6-(4-Methoxybenzyloxy)hexan-2-yloxy)(tert-butyl)
diphenylsilane 19
Compound 17 (5.5 g, 23.1 mmol) was taken in 100 mL of anhy-
drous DCM. Imidazole (3.13 g, 46.2 mmol) was then added to it at
room temperature. The reaction mixture was stirred for 15 min,
after which TBDPS-Cl (7.2 mL, 27.73 mmol) was added and the
reaction mixture was stirred overnight. After completion of the
reaction, water was added to the reaction mixture and the organic
layer was washed with excess water and brine. The organic layer
was dried (MgSO4) and evaporated to dryness to afford the crude
silylated compound 19, which was purified by silica gel chroma-
tography (15:1, hexane/EtOAc). dH (CDCl3, 200 MHz): 7.75–7.70
(m, 4H), 7.45–7.31 (m, 6H), 7.27 (d, J = 8.0 Hz, 2H), 6.89 (d,
J = 8.0 Hz, 2H), 4.44 (s, 2H), 3.91–3.85 (m, 1H), 3.88 (s, 3H), 3.41
(t, J = 6.4 Hz, 2H), 1.67–1.42 (m, 6H), 1.10 (12H). dC (CDCl3,
50 MHz): 159.1, 135.9, 135.0, 134.6, 133.8, 130.8, 129.5, 129.4,
129.3, 127.6, 127.5, 113.8, 72.6, 70.1, 69.6, 55.3, 39.3, 29.8, 27.1,
4.3. 6-(4-Methoxybenzyloxy)hexan-2-ol 17
Monoprotected alcohol 15 was oxidized under Swern oxidation
conditions in a dry, 250 ml, two-necked, round-bottomed flask
charged with an excess of Mg (1.2 g) and 100 ml of anhydrous
Et2O. To the stirred mixture was added dropwise a solution of
methyl iodide (6.25 g, 2.75 ml, 44 mmol) at such a rate to maintain
a gentle reflux. After the addition was complete, the mixture was
stirred for 30 min. To this a solution of crude aldehyde 16 (6.5 g,
29.2 mmol) in ether (30 ml) at ꢀ78 °C was added dropwise. The
resulting mixture was then stirred for 1 h at ꢀ78 °C, after which
it was allowed to warm to room temperature over 1 h. The reaction
mixture was quenched by adding cold saturated NH4Cl solution
and extracted with ethyl acetate. The organic phase was washed
with brine and dried over MgSO4. The crude reaction mixture
was filtered and concentrated under reduced pressure. Purification
by silica gel chromatography (5:1, hexane/EtOAc) afforded the
racemic alcohol 17 in 78% yield over two steps. dH (CDCl3,
200 MHz): 7.30 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 4.46 (s,
2H), 3.83 (s, 3H), 3.85–3.83 (m, 1H), 3.48 (t, J = 6.4 Hz, 2H), 1.69–
1.44 (m, 6H), 1.22 (d, J = 7.2 Hz, 3H). dC (CDCl3, 50 MHz): 159.1,
130.7, 129.3 (CH), 113.8 (CH), 72.5 (CH2), 69.9 (CH2), 67.9 (CH),
55.2 (CH3), 39.0 (CH2), 29.6 (CH2), 23.4 (CH3), 22.4 (CH2).
23.2, 21.9, 19.3. ½a D30
¼ þ8:4 (c 1.8, MeOH). HRMS (ESI) for
ꢂ
C
30H40O3NaSi [M+Na]+, calculated: 499.2644, found: 499.2649.
4.7. (R)-5-tert-Butyldiphenylsilyloxy-hexan-1-ol 20
Compound 19 (10.95 g, 23 mmol) was taken in 100 mL of DCM/
H2O (19:1). Next, DDQ (7.83 g, 34.5 mmol) was added to it in one
portion. The reaction mixture was stirred at room temperature
for 1 h. The reaction mixture was filtered off, and the filtrate was
washed with 5% NaHCO3 solution, water, and brine. The organic
layer was dried (MgSO4) and evaporated. Purification by silica gel
chromatography (3:1, hexane/EtOAc) afforded pure alcohol 20 in
86% yield. dH (CDCl3, 200 MHz): 7.74–7.69 (m, 4H), 7.44–7.34 (m,
6H), 3.92–3.83 (m, 1H), 3.55 (t, J = 6.4 Hz, 2H), 1.56–1.39 (m, 6H),
1.28–1.1 (12H). dC (CDCl3, 50 MHz): 135.9, 134.9, 134.6, 129.5,
129.4, 127.6, 127.5, 127.4, 69.5 (CH), 62.8 (CH2), 39.1 (CH2), 32.7
4.4. (R)-6-(4-Methoxybenzyloxy)hexan-2-yl acetate 18
(CH2), 27.1 (CH3), 23.2 (CH3), 21.4 (CH2), 19.3. ½a D30
¼ þ4:6 (c 1.3,
ꢂ
In a 100 mL round bottomed flask attached with a grease free
high vacuum stopcock, chlorodicarbonyl(1-(isopropylamino)-
MeOH). HRMS (ESI) for
379.2069, found: 379.2063.
C
22H32O2NaSi [M+Na]+, calculated:

806
N. Jana, S. Nanda / Tetrahedron: Asymmetry 23 (2012) 802–808
4.8. (R)-5-tert-Butyldiphenylsilanyloxy-hexanal 21
4.11. (4S,5R)-Ethyl-5-((R)-4-tert-butyldiphenylsilanyloxy-
pentyl)-2,2-dimethyl-1,3-dioxolane-4-carboxylate 24
Oxallyl chloride (2.6 mL, 29.6 mmol) was taken in anhydrous
DCM (100 mL). Then DMSO (4.2 mL, 59.1 mmol) was added to
the solution and kept at ꢀ78 °C. After 15 min, alcohol 20 (7 g,
19.7 mmol) was added to it, and the solution was stirred at the
To a stirred solution of diol 23 (4.3 g, 9.42 mmol) in DCM
(50 ml), 2,2-dimethoxypropane (1.96 g, 18.84 mmol) and 4-meth-
ylbenzenesulfonic acid (179 mg, 0.942 mmol) were added at room
temperature. After stirring for 1 h at rt, saturated NaHCO3 (aq.) was
added and the mixture was stirred for an additional 10 min. The
organic layer was separated and the aqueous layer was extracted
with DCM. The combined organic layers was dried over Na2SO4, fil-
tered and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (10:1, hexane/
EtOAc) to give acetonide protected ester 24 (95%) as a colorless li-
quid. dH (CDCl3, 400 MHz): 7.73–7.71 (m, 4H), 7.45–7.38 (m, 6H),
4.28–4.24 (m, 2H), 4.11–4.09 (m, 2H), 3.97–3.93 (m, 1H), 1.65–
1.52 (m, 6H), 1.5 (s, 6H), 1.32 (t, J = 7.2 Hz, 3H), 1.12 (12H). dC
(CDCl3, 100 MHz): 170.9, 135.9 (CH), 135.5 (CH), 134.7, 134.4,
129.5 (CH), 129.3 (CH), 127.5 (CH), 127.3 (CH), 110.6, 79.0 (CH),
78.8 (CH), 69.3 (CH), 61.2 (CH2), 39.2 (CH2), 33.4 (CH2), 27.1
(CH3), 26.5 (CH3), 25.6 (CH3), 23.1 (CH2), 21.2 (CH3), 19.2, 14.1
same temperature for
a further 45 min, after which Et3N
(16.6 mL, 118.2 mmol) was added slowly to the reaction mixture
at the same temperature. The reaction mixture was then allowed
to return to room temperature. Water was added to the solution,
and the mixture was extracted with DCM. The organic extract
was washed with water, NaHCO3 solution and brine. The organic
layer was dried (MgSO4) and evaporated. Purification by silica gel
chromatography yielded aldehyde 21 in 84% yield. dH (CDCl3,
200 MHz): 9.7 (t, J = 1.6 Hz, 1H), 7.74–7.69 (m, 4H), 7.47–7.36 (m,
6H), 3.97–3.68 (m, 1H), 2.47–2.23 (m, 2H), 1.69–1.55 (m, 4H),
1.13 (12H). dC (CDCl3, 50 MHz): 202.8 (CH), 136.0 (CH), 135.7
(CH), 134.8, 134.6, 129.7 (CH), 129.6 (CH), 127.7 (CH), 127.6 (CH),
69.2 (CH), 43.9 (CH2), 38.8 (CH2), 27.2 (CH3), 23.3 (CH3), 19.4,
17.9 (CH2). ½a 3D0
¼ þ8:2 (c 1.6, MeOH).
ꢂ
(CH3). ½a 3D0
¼ þ13:0 (c 1.7, MeOH). HRMS (ESI) for C29H42O5NaSi
ꢂ
4.9. (R,E)-Ethyl 7-tert-butyldiphenylsilanyloxy-oct-2-enoate 22
[M+Na]+, calculated: 521.2699, found: 521.2694.
To a stirred suspension of sodium hydride (796 mg, 19.9 mmol,
of a 60% dispersion in mineral oil) in freshly dried ether (60 ml) at
ꢀ5 °C was dropwise added diethylphosphono acetate (3.95 ml,
19.9 mmol). The yellowish suspension was then stirred for another
10 min until hydrogen evolution ceased. A solution of aldehyde 21
(6.7 g, 18.92 mmol) in 10 ml of freshly dried ether was dropwise
added to the Wadsworth–Horner–Emmons reagent, after which
the cooling bath was removed, and the mixture was stirred for
an additional 4 h. The non-volatile components of the reaction
mixture were then absorbed on silica by evaporation under re-
duced pressure and purified by column chromatography (15:1,
hexane/EtOAc) to give the target unsaturated ester 22 as a colorless
oil in 96% yield. dH (CDCl3, 200 MHz): 7.70–7.66 (m, 4H), 7.43–7.28
(m, 6H), 6.98–6.83 (m, 1H), 5.75 (d, J = 15.6 Hz, 1H), 4.18 (q,
J = 7.2 Hz, 2H), 3.89–3.81 (m, 1H), 2.1–2.06 (m, 2H), 1.48–1.44
(m, 4H), 1.29 (t, J = 7.2 Hz, 3H), 1.08 (12H). dC (CDCl3, 50 MHz):
166.9, 149.4 (CH), 136.1 (CH), 135.8 (CH), 135.0, 134.6, 129.7
(CH), 129.6 (CH), 127.7 (CH), 127.6 (CH), 121.5 (CH), 69.4 (CH),
60.3 (CH2), 39.0 (CH2), 32.3 (CH2), 27.2 (CH3), 23.8 (CH2), 23.4
4.12. (4S,5R)-5-((R)-4-tert-Butyldiphenylsilanyloxy-pentyl)-2,2-
dimethyl-1,3-dioxolane-4-carbaldehyde 25
To a solution of ester 24 (4.4 g, 8.83 mmol) in dry DCM (30 mL)
at ꢀ78 °C was added DIBAL-H (1 M solution in toluene, 9.7 mL,
9.7 mmol). After 1 h, the excess DIBAL-H was quenched with a sat-
urated solution of sodium potassium tartarate. The solid was fil-
tered off, and the filtrate was concentrated to give a residue,
which was purified by silica gel column chromatography (hex-
ane/EtOAc, 10:1) to give aldehyde 25 (70%) as a colorless oil. dH
(CDCl3, 400 MHz): 9.68 (d, J = 2.4 Hz, 1H), 7.69–7.67 (m, 4H),
7.44–7.35 (m, 6H), 3.99–3.94 (m, 1H), 3.88–3.84 (m, 2H), 1.64–
1.51 (m, 6H), 1.43 (s, 6H), 1.07 (12H). dC (CDCl3, 100 MHz): 200.9
(CH), 135.83 (CH), 135.81 (CH), 134.7, 134.4, 129.4 (CH), 129.3
(CH), 127.4 (CH), 127.3 (CH), 110.8, 84.6 (CH), 77.3 (CH), 69.2
(CH), 39.1 (CH2), 33.2 (CH2), 27.0 (CH3), 26.9 (CH3), 26.1 (CH3),
23.1 (CH3), 21.2 (CH2), 19.2. ½a D30
¼ þ5:2 (c 1.2, MeOH).
ꢂ
(CH3), 19.5, 14.5 (CH3). ½a D30
¼ þ11:5 (c 2.0, MeOH). HRMS (ESI)
ꢂ
4.13. (S)-1-((4R,5R)-5-((R)-4-tert-Butyldiphenylsilanyloxy-
pentyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-en-1-ol 26
for C26H36O3NaSi [M+Na]+, calculated: 447.2331, found: 447.2338.
A mixture of (S)-BINOL (114.4 mg, 0.398 mmol), 1 M Ti(OiPr)4 in
DCM (0.398 mL, 0.398 mmol), and oven-dried powdered 4 Å sieves
(800 mg) in DCM (8 mL) was heated at reflux for 1 h. The red-
brown mixture was cooled to room temperature and aldehyde 25
(1.79 g, 3.94 mmol) was added. After being stirred for 10 min, the
contents were cooled to ꢀ78 °C, and allyltri-n-butylstannane
(1.45 g, 4.38 mmol) was added. The reaction mixture was then stir-
red for 10 min and then placed in a ꢀ20 °C freezer for 72 h. Next,
saturated NaHCO3 (1 mL) was added, and the contents were stirred
for 1 h, then poured over Na2SO4 and filtered through a plug of Cel-
ite. The crude material was purified by flash chromatography, elut-
ing with hexane/EtOAc (15:1) to give (S)-allylic alcohol 26 (76%). dH
(CDCl3, 200 MHz): 7.63–7.59 (m, 4H), 7.37–7.28 (m, 6H), 5.88–5.68
(m, 1H), 5.14–5.02 (m, 2H), 3.97–3.77 (m, 4H), 2.30–2.18 (m, 2H),
1.68–1.5 (m, 6H), 1.44 (s, 6H), 1.01 (12H). dC (CDCl3, 50 MHz):
136.0 (CH), 135.9 (CH), 135.8 (CH), 134.7, 134.4, 129.5 (CH),
129.4 (CH), 127.5 (CH), 127.4 (CH), 118.6 (CH2), 108.4, 82.7 (CH),
78.1 (CH), 71.0 (CH), 69.5 (CH), 39.3 (CH2), 37.8 (CH2), 34.4 (CH2),
27.5 (CH3), 27.1 (CH3), 26.8 (CH3), 23.2 (CH3), 21.8 (CH2), 19.3.
4.10. (2S,3R,7R)-Ethyl 2,3-dihydroxy-7-tert-
butyldiphenylsilanyloxy-octanoate 23
To a vigorously stirring mixture of AD-mix-b (10 g) in tBuOH/
H2O (50 mL) at room temperature was added methanesulfonamide
(1.2 g, 12.7 mmol). Stirring was then continued for a further
15 min. after which olefinic ester 22 was added. After vigorous stir-
ring for 8–10 h, sodium sulfite (10 g) was added and stirring was
continued for a further 60 min. The mixture was then treated with
H2O (30 ml) and extracted with ethyl acetate, washed with 2 M
KOH, water, brine, dried over anhydrous MgSO4, and concentrated.
The residue was purified by silica gel column chromatography
(hexane/EtOAc, 1:3) to afford the dihydroxy compound 23 (78%).
dH (CDCl3, 400 MHz): 7.69–7.67 (m, 4H), 7.43–7.35 (m, 6H), 4.28
(q, J = 6.4 Hz, 2H), 3.99–3.80 (m, 3H), 1.53–1.34 (m, 6H), 1.3 (t,
J = 6.4 Hz, 3H), 1.08 (12H). dC (CDCl3, 100 MHz): 173.6, 135.8
(CH), 135.5 (CH), 134.8, 134.4, 129.5 (CH), 129.3 (CH), 127.5 (CH),
127.3 (CH), 72.9 (CH), 72.4 (CH), 69.3 (CH), 62.0 (CH2), 39.1 (CH2),
33.7 (CH2), 26.9 (CH3), 23.1 (CH3), 21.3 (CH2), 19.2, 14.1 (CH3).
½
a 3D0
ꢂ
¼ þ17:5 (c 1.8, MeOH). HRMS (ESI) for C30H44O4NaSi
½
a 3D0
ꢂ
¼ þ13:2 (c 1.6, MeOH). HRMS (ESI) for C26H38O5NaSi
[M+Na]+, calculated: 519.2907, found: 519.2912.
[M+Na]+, calculated: 481.2386, found: 481.2383.

N. Jana, S. Nanda / Tetrahedron: Asymmetry 23 (2012) 802–808
807
4.14. ((R)-5-((4R,5R)-5-((S)-1-(Methoxymethoxy)but-3-enyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)pentan-2-yloxy)(tert-butyl)
diphenylsilane 27
(CH), 76.8 (CH), 72.9 (CH), 56.0 (CH3), 55.6 (CH3), 36.0 (CH2), 35.8
(CH2), 34.4 (CH2), 27.5 (CH3), 27.2 (CH3), 22.3 (CH2), 20.2 (CH3).
½
a 3D0
ꢂ
¼ þ42:1 (c 0.5, MeOH). HRMS (ESI) for C26H38O8Na [M+Na]+,
calculated: 501.2464, found: 501.2458.
To a solution of allylic alcohol 26 (2.5 g, 5.04 mmol) in DCM
(30 mL) at 0 °C were added diisopropylethylamine (8.78 mL,
50.4 mmol) and chloromethylmethyl ether (1.95 mL, 25.2 mmol).
The reaction mixture was immediately allowed to warm to rt. After
10 h of stirring, saturated NaHCO3 (aq.) was added. The organic
layer was separated and the aqueous layer was extracted with
DCM. The combined organic layers was washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography to af-
ford compound 27 in 88% yield. dH (CDCl3, 400 MHz): 7.73–7.71
(m, 4H), 7.45–7.37 (m, 6H), 5.94–5.88 (m, 1H), 5.19–5.12 (m,
2H), 4.71 (s, 2H), 3.95–3.89 (m, 2H), 3.76–3.70 (m, 2H), 3.4 (s,
3H), 2.43–2.40 (m, 2H), 1.52–1.30 (m, 6H), 1.40 (s, 6H), 1.11
(12H). dC (CDCl3, 100 MHz): 136.1 (CH), 135.9 (CH), 134.9 (CH),
134.6, 134.5, 129.5 (CH), 129.4 (CH), 127.5 (CH), 127.4 (CH),
117.6 (CH2), 108.5, 96.2 (CH2), 81.6 (CH), 78.6 (CH), 77.3 (CH),
69.5 (CH), 55.8 (CH3), 39.4 (CH2), 35.7 (CH2), 34.5 (CH2), 27.5
(CH3), 27.2 (CH3), 27.1 (CH3), 23.1 (CH3), 21.7 (CH2), 19.3.
4.17. Compound 28
Ester 12 (90 mg, 0.188 mmol) was taken in anhydrous degassed
DCM (100 mL). Grubbs-second generation metathesis catalyst
(12 mg, 0.013 mmol, 7 mol %) was then added and the reaction
mixture was allowed to stir at 40 °C for 16 h. The solution was then
evaporated off and the contents of the flask were directly loaded on
a silica gel column. Purification by flash column chromatography
with hexane/EtOA (10:1) afforded RCM product 28 in 72% yield
as a white solid. dH (CDCl3, 400 MHz): 11.65 (s, 1H), 6.84 (d,
J = 15.2 Hz, 1H), 6.6 (d, J = 2.4 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H),
6.0–5.96 (m, 1H), 5.22–5.18 (m, 1H), 4.93–4.88 (m, 2H), 4.34–4.3
(m, 1H), 4.22–4.18 (m, 1H), 4.0–3.94 (m, 1H), 3.88 (s, 3H), 3.43
(s, 3H), 2.43–2.2 (m, 2H), 1.81–1.63 (m, 6H), 1.42 (9H). dC (CDCl3,
100 MHz): 170.5, 164.8, 163.8, 141.6, 133.0 (CH), 126.7 (CH),
108.3 (CH), 106.8, 100.1 (CH), 96.8 (CH2), 77.6 (CH), 74.5 (CH),
73.7 (CH), 72.8 (CH), 55.5 (CH3), 55.4 (CH2), 36.5 (CH2), 34.5
(CH2), 31.0 (CH2), 29.6, 27.0 (CH3), 26.7 (CH3), 22.4 (CH2), 17.8
½
a 3D0
ꢂ
¼ þ28:3 (c 0.8, MeOH). HRMS (ESI) for C32H48O5NaSi
[M+Na]+, calculated: 563.3169, found: 563.3162.
(CH3). ½a 3D0
¼ þ52:7 (c 0.7, MeOH). HRMS (ESI) for C25H36O7Na
ꢂ
[M+Na]+, calculated: 471.2359, found: 471.2351.
4.15. (R)-5-((4R,5R)-5-((S)-1-(Methoxymethoxy)but-3-enyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)pentan-2-ol 13
4.18. (E,7S,11R,12S,13S)-7,8,9,10,11,12,13,14-Octahydro-4,11,12,
13-tetrahydroxy-2-methoxy-7-methylbenzo[14]annulen-5(6H)-
one 11
Compound 27 (850 mg, 1.57 mmol) was taken in dry THF
(10 mL). Next, TBAF (1 M in THF, 3.14 mL, 2 equiv) was added,
and the reaction mixture was stirred for 24 h at room temperature.
After this time, the THF was evaporated, and water (5 mL) was
added to it. The reaction mixture was then extracted with EtOAc
(50 mL). The organic layer was washed with dilute NaHCO3 solu-
tion, and brine, dried over MgSO4, and purified by flash chromatog-
raphy with ethyl acetate/petroleum ether (1:3) to afford
compound 13 in 92% yield. dH (CDCl3, 400 MHz): 5.81–5.75 (m,
1H), 5.07–4.99 (m, 2H), 4.58 (s, 2H), 4.04–3.61 (m, 4H), 3.3 (s,
3H), 2.32–2.30 (m, 2H), 1.61–1.46 (m, 6H), 1.40 (s, 6H), 1.15 (d,
J = 6.8 Hz, 3H). dC (CDCl3, 100 MHz): 134.3 (CH), 117.5 (CH2),
108.5, 96.1 (CH2), 81.5 (CH), 78.5 (CH), 76.5 (CH), 67.7 (CH), 55.7
(CH3), 38.9 (CH2), 35.6 (CH2), 34.2 (CH2), 27.3 (CH3), 27.0 (CH3),
To a solution of compound 28 (50 mg, 0.11 mmol) in THF (5 mL)
was added HCl (2 N, 5 mL) and stirred for 20 h. The reaction was
quenched with saturated aqueous NaHCO3 solution and extracted
with EtOAc. The organic layers were combined, dried over anhy-
drous MgSO4, filtered, and concentrated under reduced vacuum.
The crude was purified by flash column chromatography with
ethyl acetate/petroleum ether (3:2) to yield epi-peacilomycin as a
white powder (36 mg, 90%). dH (CDCl3, 400 MHz): 11.02 (s, 1H),
6.71 (d, J = 15.6 Hz, 1H), 6.5 (s, 1H), 6.4 (s, 1H), 6.03–5.96 (m,
1H), 5.13 (br, 1H), 4.21–4.11 (m, 2H), 3.74 (s, 3H), 3.55–3.54 (m,
1H), 3.0 (br, 3H, –OH), 2.64–2.47 (m, 2H), 2.04–1.92 (m, 2H),
1.70–1.62 (m, 4H), 1.3 (d, J = 7.2 Hz, 3H). dC (CDCl3, 100 MHz):
170.2, 163.0, 161.2, 140.0, 128.3, 127.2, 108.0, 105.1, 99.6, 74.8
(CH), 73.7 (CH), 72.8 (CH), 68.2 (CH), 54.6 (CH3), 38.0 (CH2), 34.5
23.2 (CH3), 22.2 (CH2). ½a D30
¼ þ8:3 (c 0.8, MeOH). HRMS (ESI) for
ꢂ
C
16H30O5Na [M+Na]+, calculated: 325.1991, found: 325.1996.
(CH2), 33.7 (CH2), 31.0 (CH2), 17.2 (CH3). ½a D30
¼ þ30:7 (c 0.5,
ꢂ
4.16. (S)-5-((4R,5R)-5-((S)-1-(Methoxymethoxy)but-3-enyl)-2,2-
dimethyl-1,3-dioxolan-4-yl)pentan-2-yl 2-hydroxy-4-methoxy-
6-vinylbenzoate 12
MeOH). HRMS (ESI) for
387.1784, found: 387.1782.
C
20H28O6Na [M+Na]+, calculated:
Acknowledgements
Triphenylphosphine (135.3 mg, 0.516 mmol) and DIAD (102 lL,
Financial support from CSIR-India is gratefully acknowledged
(Grant: 02(0020)/11/EMR-II). We are also thankful to DST-India
(IRPHA) for an NMR instrument. One of the authors N.J. is thankful
to CSIR-India for providing a research fellowship.
0.516 mmol) were added sequentially to a stirred solution of acid
14 (50 mg, 0.258 mmol) and alcohol 13 (78 mg, 0.516 mmol) in
dry toluene (5 mL). After 1 h, EtOAc (10 mL) and H2O (5 mL) were
added. The layers were separated and the aqueous phase extracted
with EtOAc (2 ꢁ 10 mL). The combined organic portions were
washed with brine solution, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel col-
umn chromatography (1:20, hexane/EtOAc) to give ester 12 as a
colorless syrup (85%). dH (CDCl3, 400 MHz): 11.80 (s, 1H), 7.28
(dd, J = 17.2, 10.8 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 6.41 (d,
J = 2.4 Hz, 1H), 5.88–5.81 (m, 1H), 5.40 (d, J = 17.2 Hz, 1H), 5.42–
5.06 (m, 4H), 4.67 (dd, J = 11.6, 6.8 Hz, 2H), 3.93–3.92 (m, 1H),
3.82 (s, 3H), 3.73–3.66 (m, 2H), 3.34 (s, 3H), 2.37–2.35 (m, 2H),
1.79–1.5 (m, 6H), 1.35 (9H). dC (CDCl3, 100 MHz): 170.9, 165.1,
164.1, 143.9, 138.8 (CH), 134.4 (CH), 117.8 (CH2), 115.5 (CH2),
108.8, 108.5 (CH), 104.2, 100.3 (CH), 96.3 (CH2), 81.6 (CH), 78.6
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