Iterative iodocyclization: Total synthesis of polyrhacitide B

Article abstract of DOI:10.1055/s-0033-1341154

A highly stereoselective total synthesis of polyrhacitide B is reported. Key reactions are an iodocyclization protocol developed in our group, the Maruoka asymmetric allylation, the Bartlett-Smith iodocarbonate cyclization, and iodolactonization.

Full text of DOI:10.1055/s-0033-1341154

PAPER
▌1639
paper
Iterative Iodocyclization: Total Synthesis of Polyrhacitide B
Iterative Iodocyclization: Total Synthesis of Polyrhacitide B
Debendra K. Mohapatra,* P. Sivarama Krishnarao, Eswar Bhimireddy, Jhillu S. Yadav
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500 007, India
Fax +91(40)27160512; E-mail: mohapatra@iict.res.in
Received: 09.02.2014; Accepted after revision: 14.03.2014
ly stereoselective synthesis of trans-2,6-disubstituted
dihydropyran using molecular iodine as an inexpensive
and eco-friendly Lewis acid catalyst.10 As part of our on-
going research on iodocyclization reactions and their ap-
plications towards the assembly of complex natural
products, we have reported the highly stereoselective and
concise synthesis of polyrhacitides A and epi-cryptocary-
olone.11 Herein, we report the total synthesis of
polyrhacitide B by a successful implementation of a pre-
viously developed strategy in our laboratory for the syn-
thesis the trans-pyran ring. Other key steps include the
Bartlett–Smith iodocarbonate cyclization reaction to con-
struct the syn-1,3-polyol systems.
Abstract: A highly stereoselective total synthesis of polyrhacitide
B is reported. Key reactions are an iodocyclization protocol devel-
oped in our group, the Maruoka asymmetric allylation, the Bartlett–
Smith iodocarbonate cyclization, and iodolactonization.
Key words: natural products, total synthesis, iodine-catalyzed cy-
clization, asymmetric allylation, iodocarbonate cyclization, oxida-
tive cleavage
Two new aliphatic bicyclic polyketide lactones known as
polyrhacitide A (1) and polyrhacitide B (2) (Figure 1)
were isolated from the Chinese ant species Polyrhacis la-
mellidens by Jiang and Kouno in 2008.1 These ants are
widely distributed in mainland China and have been used
as an effective folk medicine to treat rheumatoid arthritis
and hepatitis.2 Polyrhacitides A (1) and B (2) have syn-
centered 1,3-polyhydroxy units with a bicyclic lactone
unit that is unusual in ants, although related compounds
occur in plants of various families.3 This unit was also
found to be present as a constituent in molecules obtained
from the tree extracts of Cryptocarya species.3c The struc-
tures of polyrhacitides A (1) and B (2) were determined by
exhaustive NMR investigations, whereas the absolute
configurations were ascertained by applying Rych-
novsky’s acetonide method4 and Mosher’s MTPA ester
method.5,6 Biological evaluation of extracts of P. lamelli-
dens demonstrated remarkable analgesic and anti-inflam-
matory activities, which supported the traditional use of
the medicinal ants in the treatment of various diseases as-
sociated with inflammation.7 The distinctive biological
activities, fascinating structural architecture, and scarce
availability of polyrhacitides have attracted our attention
to develop appropriate synthetic methods for these mole-
cules.
O
O
OH OH
H
O
polyrhacitide A (1)
O
O
OH OH
OH
H
O
polyrhacitide B (2)
Figure 1 Structures of polyrhacitides A and B
In our synthetic plan (Scheme 1), we envisaged that the
bicyclic lactone could be constructed from acid 3 via io-
dolactonization towards the end of the synthesis. Acid 3,
in turn, would arise from terminal epoxide 4, which could
be prepared from iodo derivative 5, which serves as an ad-
vanced intermediate for the synthesis of polyrhacitide B.
Iodocarbonate 5 could be obtained from the known inter-
mediate 6, which could be prepared from 7 by following
a recently reported protocol from our lab.10
Menz and Kirsch reported the first total synthesis of
polyrhacitides A and B by using the catalytic asymmetric
Overman esterification to install all the stereogenic cen-
ters.8 In all previously reported approaches to polyrhacit-
ides A and B, intramolecular Michael addition reaction
was the only route for the synthesis of the bicyclic lactone
core at the end, which restricts the generation of synthetic
analogues.9 Our efforts towards the total synthesis of
polyketide natural products have led to the development
of new strategies for these kinds of molecules by over-
coming this constraint. Recently, we have reported a high-
Accordingly, the synthesis began from known chiral ep-
oxide 7,12 which was converted into a trans-2,6-disubsti-
tuted dihydropyran ring system by following our recently
reported highly stereoselective iodine-catalyzed allylation
methodology (Scheme 2).10 Exposure of epoxide 7 to vi-
nylmagnesium bromide in the presence of a catalytic
amount of copper(I) iodide at −20 °C furnished homoallyl
alcohol 8 in 85% yield. Cross-metathesis (CM) between
homoallyl alcohol 8 and acrolein was carried out by using
the Hoveyda–Grubbs catalyst13 (10 mol%) in dichloro-
methane at room temperature for two hours, thus afford-
ing δ-hydroxy α,β-unsaturated aldehyde 9 in 86% yield.
Compound 9 was treated with molecular iodine (10
mol%) and allyltrimethylsilane in tetrahydrofuran at room
SYNTHESIS 2014, 46, 1639–1647
Advanced online publication: 11.04.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1341154; Art ID: SS-2014-T0095-OP
© Georg Thieme Verlag Stuttgart · New York

1640
D. K. Mohapatra et al.
PAPER
O
OR2 OR2 OR2
O
O
HO
OH OH
H
R1
O
OH
R1
O
3 R2 = TBS
2 R1 = C7H15; polyrhacitide B
O
OH
O
O
OPMB
O
I
O
OPMB
O
4
5
OPMB
O
OPMB
O
7
6
Scheme 1 Retrosynthetic analysis for polyrhacitide B
temperature, to give trans-2,6-disubstituted 3,6-dihydro- The conversion of intermediate 5 into fragment 17 by an
pyran 6 in 91% yield. By following Jin’s one-step dihy- iterative sequence is outlined in Scheme 3. Accordingly,
droxylation–oxidation protocol, the terminal olefin was iodocarbonate 5 was treated with potassium carbonate in
selectively oxidized to provide aldehyde 10 in 84% methanol; it rapidly underwent hydrolysis and epoxide
yield.14 The resulting aldehyde was subjected to asymmet- formation to provide syn-1,3-epoxy alcohol 4 in 95%
ric allylation under Maruoka conditions15 by using (R)- yield. The secondary alcohol was treated with tert-butyl-
(–)-1,1′-bi(2-naphthol) [(R)-BINOL] to afford homoallyl dimethylsilyl trifluoromethanesulfonate in the presence of
alcohol 11 as a single isomer. Compound 11 was treated 2,6-lutidine to form tert-butyldimethylsilyl (TBS) ether
with di-tert-butyl dicarbonate in the presence of 4-(N,N- 13 in 86% yield.18 Treatment of epoxide 13 with vinyl-
dimethylamino)pyridine to form homoallylic tert-butyl magnesium bromide in the presence of a catalytic amount
carbonate 12 in 88% yield.16 As per our retrosynthetic of copper(I) iodide19 at −20 °C afforded homoallyl alco-
strategy, the next stereogenic center of the polyol system hol 14 in 90% yield (Scheme 3).
with the desired stereochemistry was achieved through
Subsequently, we followed the same sequence of the
the Bartlett–Smith iodocarbonate cyclization reaction.17
Bartlett–Smith iodocarbonate cyclization reaction to ob-
Accordingly, exposure of compound 12 to N-iodosuccin-
tain epoxy alcohol 17 in 80% yield over two steps
imide in acetonitrile at −10 °C produced the desired iodo-
(Scheme 3).
carbonate derivative 5 in good yield as the only product
(Scheme 2).
CHO
MgBr
Hoveyda–Grubbs cat.
OPMB
OPMB
O
H
CH2Cl2
r.t., 2 h
86%
CuI, THF
–20 °C to r.t., 1 h
85%
OH
7
8
Z
OsO4, NaIO4
2,6-lutidine
TMS
OPMB
E
S
OPMB
S
R
O
dioxane–H2O
r.t., 4 h
I2, r.t., 45 min
91%
O
OH
6
9
84%
OH
OPMB
SnBu3
(Boc)2O, Et3N, DMAP
OHC
CH2Cl2, 0 °C to r.t.
O
O
OPMB
OPMB
(+)-BINOL, Ti(O-i-Pr)4
Ag2O, 0 °C, 24 h
81%
3 h
11
10
88%
O
NIS
OBoc
O
O
OPMB
I
MeCN, –10 °C, 1 h
89%
O
O
5
12
Scheme 2 Synthesis of key intermediate 5
Synthesis 2014, 46, 1639–1647
© Georg Thieme Verlag Stuttgart · New York

PAPER
Iterative Iodocyclization: Total Synthesis of Polyrhacitide B
1641
OH
OPMB
OH OTBS
TBSOTf
K2CO3
O
O
5
2,6-lutidine
CH2Cl2, r.t., 30 min
91%
MeOH, r.t., 1 h
95%
O
4
O
OPMB
H
H
17
OTBS
OPMB
MgBr
TBSOTf
2,6-lutidine
CH2Cl2, 0 °C, 30 min
86%
O
O
OR
OR
C6H13MgBr, CuI
OPMB
CuI, THF
–20 °C to r.t., 1 h
90%
O
13
–20 °C to r.t., 3 h
85%
O
H
H
18 R = TBS
(Boc)2O, Et3N, DMAP
OTBS
OH
CH2Cl2
0 °C to r.t., 5 h
88%
O
OPMB
TBSOTf
H
14
H
OH OR
OR
2,6-lutidine
CH2Cl2, r.t., 30 min
92%
O
OPMB
6
OBoc OTBS
OPMB
H
H
NIS
19 R = TBS
O
MeCN, –10 °C , 1 h
H
H
15
OR
OR
OR
DDQ
O
CH2Cl2/H2O
r.t., 3 h
O
OPMB
6
K2CO3
O
O
OTBS
OPMB
H
H
95%
20 R = TBS
I
MeOH, r.t., 1 h
80% over 2 steps
O
H
H
16
1. DMP, NaHCO3
0 °C to r.t., 2 h
OPMB
OH
OTBS
OR
OR
OR
OH
O
O
O
O
2. NaClO2, NaH2PO4
Me2C=CHMe, 3 h
85%
6
H
H
H
H
H
H
17
21 R = TBS
Scheme 3 Synthesis of epoxy alcohol 17
OR
OR
OR
O
The next task was to take forward epoxy alcohol 17 to ob-
tain polyrhacitide B. Epoxy alcohol 17 was protected as
its TBS ether 18 in 91% yield. Treatment of epoxide 18
with hexylmagnesium bromide in the presence of a cata-
lytic amount of copper(I) iodide20 at −20 °C afforded 19
in 85% yield. The resulting secondary hydroxyl group
was subsequently treated with tert-butyldimethylsilyl tri-
fluoromethanesulfonate and 2,6-lutidine to provide TBS
ether 20 in 92% yield. The p-methoxybenzyl group was
selectively cleaved by using 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) under standard reaction condi-
tions to afford primary alcohol 21 in 95% yield. Alcohol
21 was converted into acid 3 by a two-step oxidation se-
quence: first, the primary alcohol was converted into an
aldehyde by use of the Dess–Martin periodinane;21 then
Pinnick oxidation followed;22 this gave 3 in 85% yield
over the two steps (Scheme 4).
OH
6
3 R = TBS
Scheme 4 Synthesis of acid intermediate 3
OR
OR
OR
OR
OR
O
I2, KI, NaHCO3
H2O, r.t., 12 h 80%
O
OH
6
H
H
3 R = TBS
O
I
O
n-Bu3SnH, AIBN
OR
OR
toluene, reflux
30 min
O
6
H
H
O
93%
22 R = TBS
O
OR
OR
After preparation of the crucial acid fragment 3, the last
iodolactonization was carried out with molecular iodine in
the presence of potassium iodide in aqueous sodium bicar-
bonate solution23 to furnish the desired iodolactone 22 as
a single diastereomer in 80% yield (Scheme 5). The iodo
group was removed by following the Barton–McCombie
protocol24 by using tri-n-butyltin hydride in refluxing tol-
uene in the presence of catalytic 2,2′-azobis(isobutyroni-
trile); this gave 23 in 93% yield. Finally, deprotection of
the silyl groups by using hydrofluoric acid afforded
polyrhacitide B in 90% yield (Scheme 5).25 The structural
integrity of the synthetic polyrhacitide B was confirmed
aq HF (48%)
O
r.t., 5 h
90%
6
H
H
23 R = TBS
O
O
OH OH
OH
H
O
polyrhacitide B (2)
Scheme 5 Total synthesis of polyrhacitide B (2)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1639–1647

1642
D. K. Mohapatra et al.
PAPER
ESI-HRMS: m/z calcd for C12H16O3Na [M + Na]+: 231.0997; found:
231.1001.
by comparison of spectroscopic (1H and 13C NMR) and
25
15
analytical data {[α]D +7.1 (c 1.8, MeOH); Lit.1 [α]D
+7.2 (c 0.6, MeOH)}, which were in good agreement with
the reported values for the natural product.
(S)-6-(4-Methoxybenzyloxy)hex-1-en-4-ol (8)
To a solution of chiral epoxide 7 (13.0 g, 62.5 mmol) in anhydrous
THF (150 mL), CuI (1.18 g, 6.25 mmol) was added and the mixture
was stirred at 25 °C for 30 min. It was cooled to −20 °C and vinyl
magnesium bromide (1 M in THF, 125 mL, 125 mmol) was slowly
added at the same temperature. The reaction mixture was allowed to
stir for another 30 min at the same temperature. After completion of
the reaction (monitored by TLC), the reaction mixture was then
quenched with sat. aq NH4Cl (120 mL) and diluted with EtOAc
(200 mL). The two layers were separated and the aqueous layer was
extracted with EtOAc (2 × 100 mL). The combined organic layers
were washed with brine (2 × 100 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography (silica gel, hexane–
EtOAc, 5:1); this gave the desired product 8 (12.6 g, 85%).
In conclusion, we have achieved a highly stereoselective
total synthesis of polyrhacitide B in 21 steps, with 6.3%
overall yield starting from a known epoxide 7. The key re-
actions include iodocyclization developed in-house,
Maruoka asymmetric allylation, Bartlett–Smith iodocar-
bonate cyclization, and iodolactonization. Work in which
the same protocol is being followed to synthesize related
natural products is in progress and will be reported in due
course.
Air- and/or moisture-sensitive reactions were carried out in anhy-
drous solvents under an atmosphere of argon in oven- or flame-
dried glassware. All anhydrous solvents were distilled prior to use:
THF, toluene, and Et2O from Na and benzophenone; CH2Cl2,
DMSO, DMF, and hexane from CaH2; MeOH and EtOH from Mg
cake. Commercial reagents were used without purification. Experi-
ments which required an inert atmosphere were carried out under
anhydrous N2 in flame-dried glassware. Et2O and THF were freshly
distilled from sodium/benzophenone ketyl and transferred via sy-
ringe. Thin-layer chromatography was performed on pre-coated sil-
ica gel-60 F254 (0.5 mm) glass plates (Merck). Flash column
chromatography was carried out on 60–120 mesh or 100–200 mesh
silica gel (Merck). Optical rotations [α]D were obtained using a Per-
kin-Elmer model 343 apparatus and are given in 10–1 deg·cm2·g–1.
IR spectra were recorded using a Perkin-Elmer Infrared-683 spec-
[α]D25 −3.9 (c 1.8, CHCl3).
IR (neat): 3422, 2927, 2859, 1612, 1513, 1452, 1247, 1091, 1032
cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 8.4 Hz, 2 H), 6.87 (d,
J = 8.4 Hz, 2 H), 5.91–5.75 (m, 1 H), 5.15–5.06 (m, 2 H), 4.45 (s, 2
H), 3.85 (t, J = 6.0 Hz, 1 H), 3.80 (s, 3 H), 3.75–3.53 (m, 2 H), 2.24
(t, J = 6.7 Hz, 2 H), 1.81–1.70 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 159.2, 134.8, 129.9, 129.2, 117.4,
113.8, 72.9, 70.4, 68.6, 55.2, 41.8, 35.8.
ESI-MS: m/z = 259 [M + Na]+.
ESI-HRMS: m/z calcd for C14H20O3Na [M + Na]+: 259.1306; found:
259.1305.
trophotometer and are reported in wavenumbers (cm–1). 1H and 13
C
(S,E)-5-Hydroxy-7-(4-methoxybenzyloxy)hept-2-enal (9)
NMR spectra were recorded using Bruker Avance 300, Avance 500,
and Varian 400 spectrometers. Chemical shifts are reported in ppm
downfield from tetramethylsilane and coupling constants (J) are re-
ported in hertz (Hz). The following abbreviations are used to desig-
nate signal multiplicities: s = singlet, d = doublet, t = triplet, q =
quartet, quin = quintet, m = multiplet, br = broad. HRMS spectra
were obtained using a CEC-21-11013 double focusing mass spec-
trometer operating at 70 eV.
Homoallyl alcohol 8 (11.8 g, 50.0 mmol) and acrolein (5.06 mL, 75
mmol) were dissolved in CH2Cl2 (4.0 mL) and argon gas was
purged through the mixture for 10 min. The Grubbs 2nd generation
catalyst (1.56 g, 2.5 mmol) was added to the mixture at r.t. and it
was again degassed for 10 min. The reaction mixture was allowed
to stir for 2 h. After completion of the reaction (monitored by TLC),
the solvent was removed under reduced pressure and the mixture
was directly purified by column chromatography (silica gel, hex-
ane–EtOAc, 5:2); this afforded 9 (11.3 g, 86%) as a colorless liquid.
(R)-2-[2-(4-Methoxybenzyloxy)ethyl]oxirane (7)
[α]D25 −7.5 (c 1.5, CHCl3).
IR (neat): 3029, 2962, 2871, 1724, 1453, 1365, 1001 cm−1.
1H NMR (300 MHz, CDCl3): δ = 9.49 (d, J = 7.7 Hz, 1 H), 7.22 (d,
J = 8.7 Hz, 2 H), 6.90 (t, J = 7.2 Hz, 1 H), 6.85 (d, J = 7.7 Hz, 2 H),
6.12 (dd, J = 15.6, 7.7 Hz, 1 H), 4.44 (s, 2 H), 4.02–3.91 (m, 1 H),
3.80 (s, 3 H), 3.72–3.54 (m, 2 H), 2.46 (t, J = 6.0 Hz, 2 H), 1.85–
1.63 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 193.0, 159.5, 154.1, 134.8, 129.3,
114.0, 96.2, 73.2, 70.4, 68.6, 55.1, 40.5, 36.2.
ESI-MS: m/z = 287 [M + Na]+.
ESI-HRMS: m/z calcd for C15H20O4Na [M + Na]+: 287.1254; found:
(R,R)-Jacobsen’s catalyst (434 mg, 0.72 mmol, 0.005 equiv) was
added in toluene (10 mL) in a 100 mL flask equipped with a mag-
netic stir bar. It was subsequently treated with AcOH (2.8 mL, 7.2
mmol, 0.05 equiv). The solution was allowed to stir at r.t. in open
air for 30 min over which time the color changed from orange-red
to a dark brown. Toluene and AcOH were removed under reduced
pressure and the resulting brown catalyst residue was dissolved in
the racemic epoxide (30.0 g, 144.2 mmol) at r.t. The solution was
cooled to 0 °C and to it, H2O (1.42 mL, 79 mmol, 0.55 equiv) was
added dropwise over 10 min at the same temperature. The reaction
mixture was allowed to warm to r.t. and stirred for 24 h. The desired
chiral epoxide was separated by column chromatography (silica gel,
hexane–EtOAc, 9:1); this afforded 7 (13.5 g, 45%) as a colorless
liquid.
287.1250.
[α]D25 +12.0 (c 1.3, CHCl3).
IR (neat): 2928, 2857, 1611, 1586, 1512 cm−1.
(2S,6R)-6-Allyl-2-[2-(4-methoxybenzyloxy)ethyl]-3,6-dihydro-
2H-pyran (6)
To a stirred solution of aldehyde 9 (10.0 g, 35.7 mmol) in anhydrous
THF (100 mL) at 0 °C, allyltrimethysilane (8.12 mL, 53.5 mmol)
was added dropwise at r.t. The mixture was cooled to 0 °C and then
I2 (1.7 g, 7.14 mmol) was slowly added to it at the same tempera-
ture. The mixture was allowed to warm to r.t., stirred for a further 2
h and quenched with sat. aq Na2S2O3 (100 mL) to get a colorless
mixture. It was diluted with EtOAc (100 mL) and two layers were
separated. The aqueous layer was extracted with EtOAc (2 × 100
mL). The combined organic layers were washed with brine (2 × 100
1H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 8.3 Hz, 2 H), 6.82 (d,
J = 8.3 Hz, 2 H), 4.42 (s, 2 H), 3.78 (s, 3 H), 3.54 (dt, J = 5.2, 2.2
Hz, 2 H), 3.03–2.95 (m, 1 H), 2.71 (q, J = 5.2 Hz, 1 H), 2.45 (dd, J =
5.2, 3.8 Hz, 1 H), 1.92–1.80 (m, 1 H), 1.77–1.65 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 159.2, 130.3, 129.1, 113.7, 72.7,
66.6, 55.0, 49.8, 46.8, 33.0.
ESI-MS: m/z = 231 [M + Na]+.
Synthesis 2014, 46, 1639–1647
© Georg Thieme Verlag Stuttgart · New York

PAPER
Iterative Iodocyclization: Total Synthesis of Polyrhacitide B
1643
mL), dried over anhydrous Na2SO4, and concentrated under re-
duced pressure. The crude product was purified by flash column
chromatography (silica gel, hexane–EtOAc, 10:1); this gave the de-
sired cyclic product 6 (8.3 g, 91%) as a colorless liquid.
[α]D25 −6.0 (c 1.3, CHCl3).
IR (neat): 2927, 1738, 1502, 1511, 1464, 1247, 1036 cm−1.
crude product was purified by column chromatography (silica gel,
hexane–EtOAc, 5:1); this afforded the desired homoallyl alcohol 11
(4.6 g, 81%) as a colorless liquid.
[α]D25 −7.1 (c 1.7, CHCl3).
IR (neat): 3334, 2922, 2859, 1612, 1513, 1365, 1247, 1176, 1089
cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.22 (d, J = 8.4 Hz, 2 H), 6.84 (d,
J = 8.4 Hz, 2 H), 5.90–5.74 (m, 2 H), 5.68 (dd, J = 8.4, 2.7 Hz, 1 H),
5.13–4.99 (m, 2 H), 4.41 (s, 2 H), 4.20–4.11 (m, 1 H), 3.90–3.81 (m,
1 H), 3.79 (s, 3 H), 3.62–3.47 (m, 2 H), 2.44–2.32 (m, 1 H), 2.28–
2.15 (m, 1 H), 1.99–1.90 (m, 2 H), 1.80–1.71 (m, 2 H).
1H NMR (300 MHz, CDCl3): δ = 7.22 (d, J = 8.6 Hz, 2 H), 6.83 (d,
J = 8.6 Hz, 2 H), 5.90–5.75 (m, 2 H), 5.68 (dd, J = 10.4, 1.3 Hz, 1
H), 5.12–5.0 (m, 2 H), 4.41 (s, 2 H), 4.20–4.11 (m, 1 H), 3.90–3.82
(m, 1 H), 3.79 (s, 3 H), 3.65–3.47 (m, 3 H), 2.44–2.32 (m, 1 H),
2.27–2.15 (m, 1 H), 1.99–1.91 (m, 3 H), 1.81–1.69 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.2, 135.2, 130.7, 129.3, 129.2,
124.4, 116.7, 113.8, 72.7, 72.3, 66.6, 64.8, 55.2, 38.8, 35.6, 30.7.
ESI-MS: m/z = 289 [M + H]+, 311 [M + Na]+, 327 [M + K]+.
ESI-HRMS: m/z calcd for C18H24O3Na [M + Na]+: 311.1618; found:
13C NMR (75 MHz, CDCl3): δ = 159.2, 134.9, 130.9, 129.5, 129.2,
124.0, 117.7, 113.7, 72.7, 69.0, 67.6, 66.6, 65.2, 55.2, 42.1, 39.6,
34.9, 30.4.
ESI-MS: m/z = 355 [M + Na]+.
ESI-HRMS: m/z calcd for C20H28O4Na [M + Na]+: 355.1880; found:
311.1618.
355.1877.
2-{(2R,6S)-6-[2-(4-Methoxybenzyloxy)ethyl]-5,6-dihydro-2H-
pyran-2-yl}acetaldehyde (10)
tert-Butyl (R)-1-{(2R,6S)-6-[2-(4-Methoxybenzyloxy)ethyl]-5,6-
dihydro-2H-pyran-2-yl}pent-4-en-2-yl Carbonate (12)
2,6-Lutidine (12.1 mL, 104.1 mmol), OsO4 (130 mg, 0.51 mmol),
and NaIO4 (22.2 g, 104.1 mmol) were sequentially added to a solu-
tion of 6 (7.5 g, 26.04 mmol) in dioxane–H2O (3:1; 80 mL) at r.t.,
and the mixture was stirred for 4 h. After completion of the reaction
(monitored by TLC), the mixture was diluted with H2O (30 mL) and
the 1,4-dioxane was removed under reduced pressure. The residue
was extracted with CH2Cl2 (3 × 75 mL). The combined organic lay-
er was quickly washed with 1 M HCl (2 × 150 mL) to remove excess
2,6-lutidine, washed with brine (150 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure; this gave the
crude aldehyde, which was purified by short flash column chroma-
tography (silica gel, hexane–EtOAc, 5:2); this furnished 10 (6.8 g,
84%) as a colorless liquid.
To a solution of alcohol 11 (4.0 g, 12.0 mmol) in CH2Cl2 (40 mL),
(Boc)2O (5.4 mL, 24.1 mmol), followed by Et3N (3.38 mL, 24.1
mmol), and DMAP (74 mg, 0.6 mmol) were added at 0 °C and the
mixture was slowly warmed to r.t. After stirring overnight at r.t., the
mixture was quenched with 5% aq KHSO4 solution (30 mL). The
organic layer was separated and the aqueous layer was extracted
with CH2Cl2 (3 × 50 mL). The combined organic layer was washed
with brine (100 mL), dried over anhydrous Na2SO4, and concentrat-
ed under reduced pressure. The crude product was purified by col-
umn chromatography (silica gel, hexane–EtOAc, 19:1) to give the
Boc-protected compound 12 (4.5 g, 88%) as a colorless liquid.
[α]D25 +4.2 (c 1.4, CHCl3).
IR (neat): 2924, 2862, 1710, 1612, 1586, 1513, 1085 cm−1.
[α]D25 −13.6 (c 1.3, CHCl3).
IR (neat): 3434, 3029, 2962, 2871, 1724, 1453, 1365, 1001 cm−1.
1H NMR (300 MHz, CDCl3): δ = 9.71 (s, 1 H), 7.21 (d, J = 8.7 Hz,
2 H), 6.81 (d, J = 6.8 Hz, 2 H), 5.90–5.80 (m, 1 H), 5.66 (dd, J =
10.2, 1.7, Hz,1 H), 4.76–4.66 (m, 1 H), 4.38 (s, 2 H), 3.89–3.81 (m,
1 H), 3.79 (s, 3 H), 3.55–3.40 (m, 2 H), 2.68 (ddd, J = 16.0, 9.0, 3.0
Hz, 1 H), 2.42 (ddd, J = 16.0, 4.5, 1.7 Hz, 1 H), 2.03–1.92 (m, 2 H),
1.77–1.68 (m, 2 H).
1H NMR (300 MHz, CDCl3): δ = 7.22 (d, J = 8.4 Hz, 2 H), 6.81 (d,
J = 8.4 Hz, 2 H), 5.84–5.57 (m, 3 H), 5.11–4.96 (m, 2 H), 4.94–4.80
(m, 1 H), 4.33 (q, J = 10.3 Hz, 2 H), 4.23 (d, J = 9.1 Hz, 1 H), 3.87–
3.70 (m, 4 H), 3.71–3.58 (m, 1 H), 3.55–3.44 (m, 1 H), 2.31 (t, J =
6.7 Hz, 2 H), 2.01–1.89 (m, 2 H), 1.82–1.67 (m, 2 H), 1.52–1.34 (m,
11 H).
13C NMR (75 MHz, CDCl3): δ = 159.3, 153.0, 133.3, 130.6, 129.3,
129.1, 124.4, 118.0, 113.7, 81.7, 73.1, 72.6, 68.8, 66.4, 64.2, 55.2,
39.3, 37.2, 35.5, 30.8, 27.8.
13C NMR (75 MHz, CDCl3): δ = 201.0, 159.1, 130.4, 129.4, 127.7,
125.5, 113.7, 72.7, 67.9, 66.1, 64.9, 55.2, 47.7, 35.2, 30.3, 29.6.
ESI-MS: m/z = 291 [M + H]+.
ESI-MS: m/z = 455 [M + Na]+.
ESI-HRMS: m/z calcd for C17H22O4Na [M + Na]+: 313.1410; found:
ESI-HRMS: m/z calcd for C25H36O6Na [M + Na]+: 455.2404; found:
313.1417.
455.2417.
(R)-1-{(2R,6S)-6-[2-(4-Methoxybenzyloxy)ethyl]-5,6-dihydro-
2H-pyran-2-yl}pent-4-en-2-ol (11)
(4S,6S)-4-(Iodomethyl)-6-({(2R,6S)-6-[2-(4-methoxybenzyl-
oxy)ethyl]-5,6-dihydro-2H-pyran-2-yl}methyl)-1,3-dioxan-2-
one (5)
Ti(Oi-Pr)4 (0.7 mL, 2.45 mmol) was added to a solution of TiCl4
(0.5 mL, 0.25 mmol) in CH2Cl2 (15 mL) at 0 °C under an argon at-
mosphere. The solution was allowed to warm to r.t. After 1 h, Ag2O
(380 mg, 1.65 mmol) was added and the whole mixture was stirred
at r.t. for an additional 5 h under exclusion of direct light. The mix-
ture was diluted with CH2Cl2 (40 mL), and treated with (R)-binaph-
thol (940 mg, 3.3 mmol) at r.t. for 2 h to furnish chiral bis-(R)-
BINOLTi(IV) oxide. The in situ generated bis-(R)-BINOLTi(IV)
oxide in CH2Cl2 (55 mL) was cooled to −15 °C, and treated sequen-
tially with aldehyde 10 (5.0 g, 16.5 mmol) and allyltributyltin (10.3
mL, 24.5 mmol) at the same temperature. The whole mixture was
allowed to warm to 0 °C and stirred overnight. After completion of
the reaction (monitored by TLC), it was quenched with sat. aq
NaHCO3 (50 mL). The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3 × 70 mL). The combined organ-
ic layer was washed with brine (2 × 100 mL), dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
To a stirred solution of BOC-protected compound 12 (4.0 g, 9.2
mmol) in MeCN (60 mL), was added NIS (4.1 g, 18.5 mmol) at
−10 °C. The resulting mixture was stirred at −10 °C for 1 h. After
completion of the reaction (monitored by TLC), the mixture was
quenched with aq Na2S2O3 (30 mL), followed by aq NaHCO3 (30
mL). The MeCN was removed under reduced pressure and the
aqueous layer was extracted with CH2Cl2 (3 × 60 mL). The com-
bined organic layer was washed with brine (100 mL), dried over an-
hydrous Na2SO4, and concentrated under reduced pressure. The
crude product was quickly purified by flash column chromatogra-
phy (silica gel, hexane–EtOAc, 4:1); this furnished the desired io-
docarbonate derivative 5 (4.15 g, 89%) as a colorless liquid.
[α]D25 +7.9 (c 1.5, CHCl3).
IR (neat): 3466, 2923, 1705, 1612, 1513, 1248, 1182, 1098 cm−1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1639–1647

1644
D. K. Mohapatra et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 7.23 (d, J = 8.6 Hz, 2 H), 6.86 (d,
J = 8.6 Hz, 2 H), 5.89–5.80 (m, 1 H), 5.62 (dd, J = 10.0, 1.3 Hz, 1
H), 4.65–4.55 (m, 1 H), 4.49–4.34 (m, 3 H), 4.25–4.04 (m, 1 H),
3.90–3.76 (m, 4 H), 3.71–3.59 (m, 1 H), 3.55–3.46 (m, 1 H), 3.26
(dd, J = 10.7, 4.7 Hz, 1 H), 3.15 (dd, J = 6.7, 10.5 Hz, 1 H), 2.12 (dt,
J = 5.8, 2.8 Hz, 1 H), 2.05–1.95 (m, 2 H), 1.93–1.20 (m, 5 H).
13C NMR (75 MHz, CDCl3): δ = 159.1, 148.2, 130.5, 128.9, 128.5,
124.9, 113.7, 75.2, 73.3, 72.3, 67.4, 66.1, 64.4, 55.3, 38.9, 34.8,
33.6, 30.5, 5.5.
ESI-MS: m/z = 485 [M + Na]+.
ESI-HRMS: m/z calcd for C26H42O5SiNa [M + Na]+: 485.2693;
found: 485.2684.
(4R,6R)-6-(tert-Butyldimethylsiloxy)-7-{(2R,6S)-6-[2-(4-meth-
oxybenzyloxy)ethyl]-5,6-dihydro-2H-pyran-2-yl}hept-1-en-4-ol
(14)
To a solution of the terminal epoxide 13 (1.8 g, 3.86 mmol) in an-
hydrous THF (40 mL) under N2 atmosphere, CuI (74 mg, 0.386
mmol) was added and the resulting mixture was stirred at r.t. for 30
min. It was cooled to −20 °C and vinylMgBr (1.0 M in THF, 11.2
mL) was slowly added to it. The reaction mixture was stirred at the
same temperature for 30 min and slowly warmed to r.t. After com-
pletion of the reaction (monitored by TLC), the mixture was
quenched with sat. aq NH4Cl solution (30 mL) and diluted with
EtOAc (30 mL). The organic layer was separated and the aqueous
layer was extracted with EtOAc (3 × 40 mL). The combined organic
layers were washed with brine (50 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography (silica gel, hexane–
EtOAc, 5:1); this afforded the desired homoallyl alcohol 14 (1.71 g,
90%) as a colorless liquid.
ESI-MS: m/z = 503 [M + H]+.
ESI-HRMS: m/z calcd for C21H27IO6Na [M + Na]+: 525.0745;
found: 525.0777.
(S)-1-{(2R,6S)-6-[2-(4-Methoxybenzyloxy)ethyl]-5,6-dihydro-
2H-pyran-2-yl}-3-[(S)-oxiran-2-yl]propan-2-ol (4)
To a solution of iodocarbonate 5 (3.8 g, 7.56 mmol) in MeOH (60
mL), K2CO3 (3.1 g, 22.7 mmol) was added and the resulting mixture
was stirred at r.t. for 1 h. After completion of the reaction (moni-
tored by TLC), MeOH was evaporated under reduced pressure. The
residue was diluted with H2O (30 mL) and extracted with EtOAc (3
× 50 mL). The combined organic phase was washed with brine (75
mL), dried over anhydrous Na2SO4, and concentrated under re-
duced pressure; this gave the crude product, which on purification
by column chromatography (silica gel, hexane–EtOAc, 5:2) afford-
ed the desired epoxy alcohol 4 (2.49 g, 95%) as a colorless liquid.
[α]D25 −17.2 (c 1.3, CHCl3).
IR (neat): 3459, 2931, 2856, 1612, 1513, 1249, 1081 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 9.0 Hz, 2 H), 6.82 (d,
J = 9.0 Hz, 2 H), 5.81–5.56 (m, 3 H), 5.05–4.96 (m, 2 H), 4.42 (d,
J = 11.3 Hz, 1 H), 4.36 (d, J = 11.3 Hz, 1 H), 4.32–4.24 (m, 1 H),
4.14–4.02 (m, 1 H), 3.82–3.74 (m, 5 H), 3.53–3.42 (m, 2 H), 2.05 (t,
J = 6.7 Hz, 2 H), 198–1.88 (m, 2 H), 1.88–1.83 (m, 1 H), 1.62–1.48
(m, 2 H), 1.46–1.40 (m, 3 H), 0.89 (br s, 9 H), 0.10–0.09 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 159.3, 135.2, 130.4, 129.5, 129.2,
124.0, 117.2, 113.8, 71.9, 69.4, 68.2, 67.6, 65.8, 63.2, 55.3, 45.0,
42.6, 40.6, 34.9, 31.1, 25.9, 18.0, −4.2, −4.4.
[α]D25 −6.2 (c 1.7, CHCl3).
IR (neat): 3483, 3033, 2996, 1739, 1612, 1463, 1302 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 8.2 Hz, 2 H), 6.81 (d,
J = 8.2 Hz, 2 H), 5.86–5.72 (m, 1 H), 5.61 (d, J = 9.9 Hz, 1 H), 4.48–
4.36 (m, 3 H), 4.13–3.97 (m, 1 H), 3.96–3.83 (m, 1 H), 3.78 (s, 3 H),
3.64–3.41 (m, 2 H), 3.07–2.93 (m, 1 H), 2.80–2.65 (m, 2 H), 2.49–
2.39 (m, 1 H), 2.08–1.47 (m, 8 H).
13C NMR (75 MHz, CDCl3): δ = 159.1, 130.4, 129.2, 129.1, 124.1,
113.7, 72.6, 71.3, 68.7, 66.7, 66.5, 65.5, 55.2, 50.2, 46.6, 39.8, 34.6,
30.2.
ESI-MS: m/z = 513 [M + Na]+.
ESI-HRMS: m/z calcd for C28H46O5SiNa [M + Na]+: 513.3006;
found: 513.2999.
ESI-MS: m/z = 371 [M + Na]+.
ESI-HRMS: m/z calcd for C20H28O5Na [M + Na]+: 371.1828; found:
371.1828.
tert-Butyl (2R,4R)-2-(tert-Butyldimethylsilyloxy)-1-{(2R,6S)-6-
[2-(4-methoxybenzyloxy)ethyl]5,6-dihydro-2H-pyran-2-
yl}hept-6-en-4-yl Carbonate (15)
To a solution of alcohol 14 (1.6 g, 3.26 mmol) in CH2Cl2 (40 mL),
(Boc)2O (1.49 mL, 6.53 mmol), followed by Et3N (0.91 mL, 6.53
mmol) and DMAP (39 mg, 0.326 mmol) were added at r.t. After
stirring for 5 h, the mixture was quenched with 5% aq KHSO4 (25
mL). The organic layer was separated and the aqueous layer was ex-
tracted with CH2Cl2 (3 × 40 mL). The combined organic layer was
washed with brine (2 × 70 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure to give the crude product,
which on purification by column chromatography (silica gel,
hexane–EtOAc, 19:1) afforded the Boc-protected compound 15
(1.6 g, 88%) as a colorless liquid.
tert-Butyl((S)-1-{(2R,6S)-6-[2-(4-methoxybenzyloxy)ethyl]-5,6-
dihydro-2H-pyran-2-yl}-3-[(S)-oxiran-2-yl]propan-2-yloxy)di-
methylsilane (13)
To a stirred solution of alcohol 4 (2.1 g, 6.05 mmol) in CH2Cl2 (40
mL) at 0 °C was added 2,6-lutidine (1.05 mL, 9.05 mmol) and
TBSOTf (1.97 mL, 9.05 mmol). After 30 min, sat. aq NaHCO3 (40
mL) was added. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3 × 40 mL). The combined organ-
ic layer was dried over NaSO4 and concentrated under reduced
pressure. The crude product was purified by flash column chroma-
tography (silica gel, hexane–EtOAc, 10:1) to furnish TBS ether 13
(1.93 g, 86%) as a colorless liquid.
[α]D25 −11.3 (c 1.0, CHCl3).
[α]D25 −5.6 (c 2.1, CHCl3).
IR (neat): 3033, 2928, 2856, 1731, 1612, 1513, 1464, 1249, 1091
cm−1.
IR (neat): 3033, 2928, 2856, 1731, 1612, 1513, 1464, 1249, 1091
cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.19 (d, J = 8.4 Hz, 2 H), 6.81 (d,
J = 8.4 Hz, 2 H), 5.80–5.68 (m, 2 H), 5.60 (d, J = 10.4 Hz, 1 H),
5.12–5.02 (m, 2 H), 4.84–4.73 (m, 1 H), 4.42 (d, J = 11.5 Hz, 1 H),
4.36 (d, J = 11.5 Hz, 1 H), 4.29–4.20 (m, 1 H), 4.01–3.90 (m, 1 H),
3.78 (s, 3 H), 3.74–3.63 (m, 1 H), 3.53 (t, J = 6.7 Hz, 2 H), 2.35–
2.27 (m, 2 H), 1.98–1.90 (m, 2 H), 1.82–1.61 (m, 6 H), 1.45 (br s, 9
H), 0.89 (br s, 9 H), 0.06 (br s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 159.0, 153.0, 133.4, 130.2, 129.1,
123.7, 117.9, 113.7, 81.6, 73.2, 72.6, 68.9, 66.8, 65.8, 64.1, 55.2,
41.8, 40.2, 39.6, 35.7, 30.8, 27.7, 25.8, 18.0, −4.3, −4.7.
1H NMR (400 MHz, CDCl3): δ = 7.18 (d, J = 7.8 Hz, 2 H), 6.81 (d,
J = 7.8 Hz, 2 H), 5.79–5.72 (m, 1 H), 5.64 (d, J = 4.2 Hz, 1 H), 4.41
(d, J = 12.4 Hz, 1 H), 4.37 (d, J = 12.4 Hz, 1 H), 4.44–4.24 (m, 1 H),
4.11–4.02 (m, 1 H), 3.79 (s, 3 H), 3.77–3.69 (m, 1 H), 3.61–3.46 (m,
2 H), 2.96–2.89 (m, 1 H), 2.67–2.62 (m, 1 H), 2.36–2.30 (m, 1 H),
1.98–1.89 (m, 1 H), 1.82–1.70 (m, 3 H), 1.56–1.43 (m, 2 H), 1.42–
1.36 (m, 2 H), 0.89 (s, 9 H), 0.09 (s, 3 H), 0.06 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 159.1, 130.3, 129.1, 123.8, 113.7,
72.6, 69.1, 69.0, 66.6, 63.8, 55.2, 48.8, 46.6, 41.2, 40.9, 40.5, 35.7,
30.9, 29.6, 25.8, 17.9, −4.4, −4.7.
ESI-MS: m/z = 613 [M + Na]+.
Synthesis 2014, 46, 1639–1647
© Georg Thieme Verlag Stuttgart · New York

PAPER
Iterative Iodocyclization: Total Synthesis of Polyrhacitide B
1645
ESI-HRMS: m/z calcd for C33H54O7SiNa [M + Na]+: 613.3531;
found: 613.3515.
13C NMR (75 MHz, CDCl3): δ = 159.1, 130.1, 129.1, 123.8, 113.7,
72.6, 69.1, 68.1, 66.8, 66.7, 64.5, 55.2, 45.5, 42.0, 39.5, 35.6, 30.6,
29.7, 29.0, 25.9, 18.0, 18.0, −4.1, −4.3, −4.4, −4.4.
ESI-MS: m/z = 643 [M + Na]+;
ESI-HRMS: m/z calcd for C34H60O6Si2Na [M + Na]+: 643.3822;
(2R,4R)-4-(tert-Butyldimethylsiloxy)-5-{(2R,6S)-6-[2-(4-meth-
oxybenzyloxy)ethyl]-5,6-dihydro-2H-pyran-2-yl}-1-[(S)-oxi-
ran-2-yl]pentan-2-ol (17)
To a stirred solution of BOC-protected compound 15 (1.6 g, 2.71
mmol) in MeCN (30 mL) was added NIS (1.21 g, 5.42 mmol) at
−10 °C. The resulting mixture was warmed and stirred at 0 °C for 1
h. After completion of the reaction (monitored by TLC), the mixture
was quenched with sat. aq Na2S2O3 (25 mL) and sat. aq NaHCO3
(25 mL). MeCN was removed under reduced pressure and the aque-
ous layer was extracted with CH2Cl2 (3 × 50 mL). The organic layer
was washed with brine (100 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The crude product was
quickly purified through short plug of silica gel (hexane–EtOAc,
5:1); this afforded the iodocarbonate 16 as a colorless liquid which
was immediately used for the next reaction.
found: 643.3835.
(2S,4R,6R)-2,4-Bis(tert-butyldimethylsiloxy)-1-{(2R,6S)-6-[2-
(4-methoxybenzyloxy)ethyl]-5,6-dihydro-2H-pyran-2-yl}tri-
decan-6-ol (19)
CuI (28 mg, 0.144 mmol) was added to a solution of the terminal ep-
oxide 18 (900 mg, 1.44 mmol) in anhydrous THF (25 mL) under a
N2 atmosphere, and the resulting mixture was stirred at 25 °C for 30
min. It was cooled to −20 °C and to it C6H13MgBr (4.35 mL, 1.0 M)
was slowly added. The reaction mixture was stirred for 30 min at the
same temperature. It was slowly warmed to r.t. and stirred for an ad-
ditional 3 h. After completion of the reaction (monitored by TLC),
the mixture was quenched with sat. aq NH4Cl solution (25 mL) and
diluted with EtOAc (40 mL). The two layers were separated and the
aqueous layer was extracted with EtOAc (3 × 40 mL). The com-
bined organic layers were washed with brine (2 × 50 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure;
this gave the crude product, which on purification by column chro-
matography (silica gel, hexane–EtOAc, 10:1) furnished the desired
diol 19 (960 mg, 85%) as a colorless liquid.
To a solution of the iodocarbonate crude product 16 (1.8 g, 2.72
mmol) in MeOH (25 mL), K2CO3 (1.12 g, 8.18 mmol) was added
and the resulting mixture was stirred at 25 °C for 1 h. After comple-
tion of the reaction (monitored by TLC), excess MeOH was evapo-
rated under reduced pressure. The residue was diluted with H2O (40
mL) and extracted with EtOAc (3 × 60 mL). The combined organic
phase was washed with brine (2 × 70 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography (silica gel, hexane–
EtOAc, 5:2); this afforded the desired epoxy alcohol 17 (1.08 g,
80% over two steps) as colorless liquid.
[α]D25 −7.1 (c 1.9, CHCl3).
IR (neat): 3467, 3032, 2927, 2856, 1732, 1613, 1514, 1465, 1363,
1251, 1085, 1040 cm−1.
[α]D25 −8.2 (c 1.0, CHCl3).
IR (neat): 2922, 2852, 1219 cm−1.
1H NMR (500 MHz, CDCl3): δ = 7.20 (d, J = 8.3 Hz, 2 H), 6.81 (d,
J = 8.3 Hz, 2 H), 5.79–5.70 (m, 1 H), 5.61 (dd, J = 10.6, 3.0 Hz, 1
H), 4.42 (d, J = 11.4 Hz, 1 H), 4.37 (d, J = 11.5 Hz, 1 H), 4.24 (d,
J = 9.0 Hz, 1 H), 3.95–3.82 (m, 2 H), 3.78 (br s, 3 H), 3.72 (t, J =
6.0 Hz,1 H), 3.61–3.41 (m, 3 H), 1.97–1.87 (m, 2 H), 1.86–1.55 (m,
8 H), 1.41–1.24 (m, 12 H), 0.89 (br s, 21 H), 0.09–0.02 (m, 12 H).
13C NMR (75 MHz, CDCl3): δ = 159.1, 130.6, 130.3, 129.2, 123.6,
113.8, 72.6, 72.0, 69.4, 69.2, 66.7, 64.6, 55.2, 45.6, 42.2, 37.6, 37.5
35.6, 33.1, 32.9, 32.6, 32.5, 31.8, 30.6, 29.3, 25.9, 25.6, 22.6, 18.1,
18.0, 14.1, −4.1, −4.2, −4.3, −4.4.
1H NMR (300 MHz, CDCl3): δ = 7.20 (d, J = 8.6 Hz, 2 H), 6.82 (d,
J = 8.6 Hz, 2 H), 5.82–5.74 (m, 1 H), 5.64 (d, J = 10.0 Hz, 1 H), 4.43
(d, J = 11.3 Hz, 1 H), 4.35 (d, J = 11.5 Hz, 1 H), 4.33–4.25 (m, 2 H),
4.15–4.03 (m, 1 H), 3.89–3.83 (m, 1 H), 3.78 (s, 3 H), 3.71–3.59 (m,
1 H), 3.52–3.43 (m, 1 H), 3.40–3.32 (m, 1 H), 2.88–2.79 (m, 1 H),
2.63 (t, J = 4.9 Hz, 1 H), 2.37 (dd, J = 5.1, 2.6 Hz, 1 H), 1.96–1.77
(m, 2 H), 1.66–1.36 (m, 8 H), 0.89 (br s, 9 H), 0.09 (br s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 159.2, 130.3, 129.5, 124.0, 113.8,
71.8, 69.2, 67.4, 66.9, 65.8, 63.1, 55.2, 49.9, 46.7, 45.4, 40.5, 34.7,
31.0, 25.9, 18.0, −4.3, −4.5.
ESI-MS: m/z = 729 [M + Na]+.
ESI-HRMS: m/z calcd for C40H74O6Si2Na [M + Na]+: 729.4916;
ESI-MS: m/z = 529 [M + Na]+.
found: 729.4917.
ESI-HRMS: m/z calcd for C28H46O6SiNa [M + Na]+: 529.2956;
found: 529.2952.
(5R,7R,9S)-7-(tert-Butyldimethylsiloxy)-5-heptyl-9-({(2R,6S)-6-
[2-(4-Methoxybenzyloxy)ethyl]-5,6-dihydro-2H-pyran-2-
yl}methyl)-2,2,3,3,11,11,12,12-octamethyl-4,10-dioxa-3,11-disi-
latridecane (20)
(5S,7R)-5-({(2R,6S)-6-[2-(4-Methoxybenzyloxy)ethyl]-5,6-di-
hydro-2H-pyran-2-yl}methyl)-2,2,3,3,9,9,10,10-octamethyl-7-
[(S)-oxiran-2-ylmethyl]-4,8-dioxa-3,9-disilaundecane (18)
To a stirred solution of alcohol 17 (1.0 g, 1.97 mmol) in CH2Cl2 (25
mL) at 0 °C was added 2,6-lutidine (0.34 mL, 2.96 mmol) and
TBSOTf (0.68 mL, 2.96 mmol). After 30 min, sat. aq NaHCO3 (20
mL) was added. The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3 × 25 mL). The combined organ-
ic layer was dried over Na2SO4 and concentrated under reduced
pressure. The crude mass was purified by flash column chromatog-
raphy (silica gel, hexane–EtOAc, 10:1); this gave TBS ether 18
(1.12 g, 91%) as a colorless liquid.
2,6-Lutidine (0.14 mL, 1.272 mmol) and TBSOTf (0.29 mL, 1.272
mmol) were added to a stirred solution of alcohol 19 (600 mg, 0.848
mmol) in CH2Cl2 (30 mL) at 0 °C. After completion of the reaction
(monitored by TLC), the mixture was quenched with sat. aq
NaHCO3 (25 mL). The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (3 × 30 mL). The combined organ-
ic layer was dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column chro-
matography (silica gel, hexane–EtOAc, 9:1) to furnish TBS ether 20
(640 mg, 92%) as a colorless liquid.
[α]D25 −11.5 (c 1.1, CHCl3).
[α]D25 −19.8 (c 1.2, CHCl3);
IR (neat): 3032, 2931, 2857, 1740, 1613, 1513, 1465, 1364, 1251,
1082 cm−1.
IR (neat): 3033, 2928, 2856, 1731, 1612, 1513, 1464, 1249, 1091
cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.19 (d, J = 8.5 Hz, 2 H), 6.81 (d,
J = 8.5 Hz, 2 H), 5.74 (d, J = 9.5 Hz, 1 H), 5.61 (d, J = 10.5 Hz, 1
H), 4.41 (d, J = 11.3 Hz, 1 H), 4.35 (d, J = 11.3 Hz, 1 H), 4.29–4.19
(m, 1 H), 3.95–3.84 (m, 1 H), 3.79 (br s, 3 H), 3.76–3.66 (m, 2 H),
3.59 (d, J = 5.3 Hz, 1 H), 3.55–3.46 (m, 2 H), 1.98–1.91 (m, 2 H),
1.82–1.40 (m, 8 H), 1.32–1.22 (m, 12 H), 0.89 (br s, 30 H), 0.10–
0.01 (m, 18 H).
1H NMR (300 MHz, CDCl3): δ = 7.19 (d, J = 8.4 Hz, 2 H), 6.81 (d,
J = 8.4 Hz, 2 H), 5.80–5.70 (m, 1 H), 5.60 (d, J = 10.0 Hz, 1 H), 4.41
(d, J = 11.7 Hz, 1 H), 4.36 (d, J = 11.7 Hz, 1 H), 4.22 (d, J = 8.9 Hz,
1 H), 3.95–3.82 (m, 2 H), 3.78 (s, 3 H), 3.73 (t, d, J = 6.0 Hz, 1 H),
3.57–3.47 (m, 2 H), 2.43 (t, J = 7.5 Hz, 3 H), 1.98–1.82 (m, 2 H),
1.80–1.39 (m, 8 H), 092–0.82 (m, 18 H), 0.07 (S, 12 H).
© Georg Thieme Verlag Stuttgart · New York
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1646
D. K. Mohapatra et al.
PAPER
13C NMR (75 MHz, CDCl3): δ = 159.1, 130.6, 130.3, 129.2, 123.5,
113.7, 72.7, 72.5, 69.5, 69.4, 69.2, 66.8, 64.5, 55.2, 46.0, 42.3, 37.0,
35.5, 33.0, 32.8, 31.8, 30.6, 29.5, 25.9, 22.6, 18.1, 18.0, 18.0, 14.1,
−4.2, −4.4, −4.4.
ESI-MS: m/z = 843 [M + Na]+.
ESI-HRMS: m/z calcd for C46H88O6Si3Na [M + Na]+: 843.5780;
1H NMR (300 MHz, CDCl3): δ = 5.76 (d, J = 9.8 Hz, 1 H), 5.68 (d,
J = 9.8 Hz, 1 H), 4.35–4.27 (m, 1 H), 4.18–4.11 (m, 1 H), 3.97–3.76
(m, 2 H), 3.78–3.72 (m, 1 H), 2.48–2.40 (m, 2 H), 2.03–1.98 (m, 3
H), 1.79 (t, J = 10.7 Hz, 1 H), 1.60–1.49 (m, 4 H), 1.46–1.27 (m, 2
H), 1.31–1.24 (m, 10 H), 0.91 (br s, 30 H), 0.13–0.02 (m, 18 H).
13C NMR (75 MHz, CDCl3): δ = 172.5, 129.9, 122.7, 75.5, 70.1,
68.9, 66.1, 64.7, 42.6, 41.4, 40.6, 36.4, 31.8, 30.6, 30.1, 29.7, 29.2,
29.1, 26.1, 25.9, 22.6, 18.5, 18.0, 17.9, 14.0, −4.2, −4.4, −4.5, −4.6.
found: 843.5751.
ESI-MS: m/z = 737 [M + Na]+.
ESI-HRMS: m/z calcd for C38H78O6Si3Na [M + Na]+: 737.4998;
2-{(2S,6R)-6-[(2S,4R,6R)-2,4,6-Tris(tert-butyldimethylsil-
oxy)tridecyl]-3,6-dihydro-2H-pyran-2-yl}ethanol (21)
DDQ (198 mg, 0.732 mmol) was added in one portion to an ice-cold
mixture of PMB-protected compound 20 (400 mg, 0.487 mmol) in
CH2Cl2–H2O (5:1; 20 mL). The resulting mixture was stirred at r.t.
for 3 h. After completion of the reaction (monitored by TLC), the
mixture was quenched with sat. aq NaHCO3 solution (15 mL). The
two layers were separated and the aqueous layer was extracted with
CH2Cl2 (2 × 25 mL). The combined organic layer was washed with
brine (40 mL), dried over Na2SO4, and concentrated under reduced
pressure. The crude product was purified by column chromatogra-
phy (silica gel, hexane–EtOAc, 5:1) to furnish alcohol 21 (323 mg,
95%) as a colorless liquid.
found: 737.4987.
(1S,5S,7R,8S)-8-Iodo-7-[(2S,4R,6R)-2,4,6-tris(tert-butyldimeth-
ylsiloxy)tridecyl]-2,6-dioxabicyclo-[3.3.1]nonan-3-one (22)
A solution of I2 (105 mg, 0.419 mmol) and KI (115 mg, 0.695
mmol) in H2O (2 mL) was added over a period of 10 min to a stirred
solution of acid 3 (100 mg, 0.139 mmol) in sat. aq NaHCO3 solution
(8 mL) at r.t. in the dark. After stirring at the same temperature for
2 h, the reaction mixture was quenched with sat. aq Na2S2O3 (10
mL). The reaction mixture was extracted with EtOAc (3 × 25 mL).
The combined organic layer was washed with brine (2 × 40 mL),
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The crude residue was purified by column chromatogra-
phy (silica gel, hexane–EtOAc, 9:1); this gave iodolactone 22 (94
mg, 80%) as a light yellow liquid.
[α]D25 −4.8 (c 1.5, CHCl3).
IR (neat): 3465, 2953, 2930, 2857, 1732, 1465, 1254, 1071 cm−1.
1H NMR (300 MHz, CDCl3): δ = 5.82–5.74 (m, 1 H), 5.64 (d, J =
9.8 Hz, 1 H), 4.36 (d, J = 9.1 Hz, 1 H), 3.99–3.69 (m, 5 H), 3.61 (dd,
J = 9.8, 5.3 Hz, 1 H), 1.98–1.86 (m, 2 H), 1.80–1.37 (m, 8 H), 1.34–
1.20 (m, 12 H), 0.88 (s, 30 H), 0.09–0.02 (m, 18 H).
[α]D25 +4.8 (c 1.5, CHCl3).
IR (neat): 2953, 2929, 2856, 1747, 1465, 1253, 1070, 1048 cm−1.
13C NMR (75 MHz, CDCl3): δ = 129.5, 123.5, 72.8, 69.7, 69.4, 67.2,
67.1, 60.7, 44.6, 41.7, 37.5, 37.0, 32.7, 32.2, 31.9, 30.6, 29.7, 29.5,
25.9, 25.3, 22.6, 18.1, 18.0, 18.0, 14.0, −4.3, −4.4, −4.4.
ESI-MS: m/z = 723 [M + Na]+.
ESI-HRMS: m/z calcd for C38H80O5Si3Na [M + Na]+: 723.5204;
1H NMR (300 MHz, CDCl3): δ = 5.02–4.96 (m, 1 H), 4.31–4.26 (m,
2 H), 3.93–3.25 (m, 1 H), 3.80–3.65 (m, 1 H), 3.65–3.55 (m, 1 H),
3.33–3.25 (m, 1 H), 2.82–2.78 (d, J = 3.2 Hz, 2 H), 1.88–1.78 (m, 2
H), 1.66–1.58 (m, 4 H), 1.47–1.40 (m, 4 H), 1.32–1.25 (m, 11 H),
0.88 (br s, 30 H), 0.08–0.03 (m, 18 H).
13C NMR (75 MHz, CDCl3): δ = 168.2, 72.6, 69.5, 66.3, 65.8, 62.8,
46.0, 44.7, 37.2, 36.7, 35.9, 32.8, 32.2, 31.9, 29.6, 29.5, 25.9, 25.3,
22.6, 18.1, 18.0, 17.9, 14.1, −4.3, −4.4, −4.5.
found: 723.5216.
2-{(2S,6R)-6-[(2S,4R,6R)-2,4,6-Tris(tert-butyldimethylsil-
oxy)tridecyl]-3,6-dihydro-2H-pyran-2-yl}acetic Acid (3)
To a solution of alcohol 21 (250 mg, 0.356 mmol) in CH2Cl2 (10
mL), DMP (226 mg, 0.534 mmol) was added at 0 °C under a N2 at-
mosphere. Stirring was continued for 2 h at r.t. After complete con-
version of the starting material (monitored by TLC), the mixture
was quenched with sat. aq NaHCO3 solution (20 mL) and diluted
with CH2Cl2 (20 mL). The two layers were separated and the aque-
ous layer was extracted with CH2Cl2 (2 × 30 mL). The combined or-
ganic layer was washed with brine (40 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure; this gave a crude
product, which was quickly purified through a short plug of silica
gel (hexane–EtOAc = 5:1); this afforded the aldehyde (240 mg) as
a colorless liquid, which was immediately used for the next reac-
tion.
ESI-MS: m/z = 841 [M + H]+.
ESI-HRMS: m/z calcd for C38H78ISi3O6 [M + H]+: 841.4145; found:
841.4142.
(1R,5S,7S)-7-[(2S,4R,6R)-2,4,6-tris(tert-butyldimethylsil-
oxy)tridecyl]-2,6-dioxabicyclo[3.3.1]nonan-3-one (23)
AIBN (cat., 2 mg) followed by n-Bu3SnH (0.1 mL, 0.119 mmol)
were added to a solution of iodolactone 22 (50 mg, 0.059 mmol) in
toluene (2 mL), and the reaction mixture was stirred under reflux for
30 min. TLC monitoring showed complete disappearance of the
starting material. Toluene was removed under reduced pressure;
this afforded the crude product, which on purification by column
chromatography (silica gel, hexane–EtOAc, 9:1) furnished the de-
sired bicyclic lactone 23 (39 mg, 93%) as a colorless liquid.
To a stirred solution of the aldehyde (230 mg, 0.338 mmol) in t-
BuOH–H2O (4:1; 20 mL), 2-methylbut-2-ene (1 M in THF, 0.84
mL, 0.84 mmol) was added at r.t. NaClO2 (45 mg, 0.507 mmol) and
NaH2PO4 (158 mg, 1.04 mmol) were dissolved together in H2O (2
mL), and the resulting mixture was added portionwise to the above
solution of aldehyde at 0 °C. The reaction mixture was stirred for an
additional 3 h at r.t. After complete conversion of the starting mate-
rial (monitored by TLC), the mixture was diluted with H2O (20 mL)
and extracted with EtOAc (3 × 30 mL). The combined organic layer
was washed with brine (70 mL), dried over anhydrous Na2SO4, and
concentrated under reduced pressure; this gave crude acid, which on
purification by column chromatography (silica gel, hexane–EtOAc,
5:1) gave acid 3 (210 mg, 85% over two steps) as a colorless liquid.
[α]D25 +13.2 (c 1.5, CHCl3).
IR (neat): 3462, 2953, 2929, 2857, 1465, 1254, 1219, 1072 cm−1.
1H NMR (300 MHz, CDCl3): δ = 4.90–4.85 (m, 1 H), 4.34–4.29 (m,
1 H), 4.00–3.92 (m, 1 H), 3.87 (t, J = 6.0 Hz, 1 H), 3.79–3.72 (m, 1
H), 3.65–3.58 (m, 1 H), 2.84 (d, J = 18.9 Hz, 1 H), 2.76 (dd, J =
18.9, 4.9 Hz, 1 H), 2.05–1.97 (m, 2 H), 1.93–1.87 (m, 1 H), 1.67–
1.58 (m, 4 H), 1.46–1.34 (m, 5 H), 1.33–1.25 (m, 10 H), 0.89 (m, 30
H), 0.08–0.02 (m, 18 H).
13C NMR (75 MHz, CDCl3): δ = 169.4, 73.0, 72.4, 69.5, 66.1, 65.5,
62.5, 45.7, 44.5, 44.4, 37.7, 37.2, 37.0, 36.5, 32.1, 31.9, 29.9, 29.7,
29.5, 25.9, 22.6, 18.1, 17.9, 17.5, 14.1, −3.9, −4.2, −4.4, −4.5.
ESI-MS: m/z = 737 [M + Na]+.
ESI-HRMS: m/z calcd for C38H78O6Si3Na [M + Na]+: 737.4998;
[α]D25 −7.6 (c 1.2, CHCl3).
IR (neat): 2950, 2926, 2856, 1714, 1462, 1377, 1255, 1219, 1067
cm−1.
found: 737.4999.
Synthesis 2014, 46, 1639–1647
© Georg Thieme Verlag Stuttgart · New York

PAPER
Iterative Iodocyclization: Total Synthesis of Polyrhacitide B
1647
Polyrhacitide B (2)
41, 333. (e) Drewes, S. E.; Horn, M. M.; Mavi, S.
HF (48% aq solution, 0.4 mL) was added to a solution of 23 (35 mg,
0.05 mmol) in MeCN (3 mL) at r.t. in a Teflon vial, and the mixture
was stirred for 5 h. After completion of the reaction (monitored by
TLC), the mixture was quenched with sat. aq NaHCO3 (3 mL), di-
luted with H2O (5 mL), and extracted with EtOAc (4 × 15 mL). The
combined organic layer was washed with brine (2 × 25 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure;
this afforded the crude product, which on purification by column
chromatography (silica gel, CHCl3–MeOH, 98:2) afforded the final
product, polyrhacitide B (2) (16 mg, 90%) as a white amorphous
solid; mp 98–100 °C.
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IR (neat): 3400, 2926, 2856, 1725, 1337, 1219, 1076 cm−1.
1H NMR (500 MHz, CDCl3): δ = 4.88 (br s, 1 H), 4.40 (br s, 1 H),
4.13–4.01 (m, 3 H), 3.94–3.85 (m, 1 H), 2.90 (d, J = 18.7 Hz, 1 H),
2.81 (dd, J = 19.3, 5.2 Hz, 1 H), 2.70–1.91 (m, 3 H), 1.70–1.39 (m,
9 H), 1.34–1.23 (m, 12 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 169.2, 72.9, 72.5, 72.4, 72.4, 66.8,
66.0, 43.6, 43.4, 42.9, 37.7, 37.2, 36.4, 31.8, 29.7, 29.5, 29.3, 25.7,
22.6, 14.1.
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ESI-HRMS m/z calcd for C20H36O6Na [M + Na]+: 395.2404 found:
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395.2401.
Acknowledgment
The authors thank the Council of Scientific and Industrial Research
for a Research (CSIR), New Delhi, for financial support as part of
XII Five Year plan programme under the title ORIGIN (CSC-0108)
and CSIR Grant (P-81-113) (INSA Young Scientist Award
Scheme). P.S.K. and E.B.R. thank Council of Scientific and Indu-
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1639–1647