Total synthesis of (+)-(2′S,3′R)-zoapatanol exploiting the B-alkyl Suzuki reaction and the nucleophilic potential of the sulfinyl group

Article abstract of DOI:10.1002/chem.201003666

A stereoselective synthesis of the diterpenoid oxepane (+)-zoapatanol is described. The key steps include a B-alkyl Suzuki cross-coupling reaction for the stereoselective synthesis of trisubstituted alkenes, creation of the two stereogenic centers on the oxepane ring by heterofunctionalization of an alkene through substrate control exploiting the nucleophilic potential of an intramolecular sulfinyl group, and transformation of a β-hydroxy sulfoxide into a terminal alkene. Copyright

Full text of DOI:10.1002/chem.201003666

FULL PAPER
DOI: 10.1002/chem.201003666
Total Synthesis of (+)-(2’S,3’R)-Zoapatanol Exploiting the B-Alkyl Suzuki
Reaction and the Nucleophilic Potential of the Sulfinyl Group
Sadagopan Raghavan* and Vaddela Sudheer Babu[a]
Abstract: A stereoselective synthesis of the diterpenoid oxepane (+)-zoapatanol is
described. The key steps include a B-alkyl Suzuki cross-coupling reaction for the
Keywords: asymmetric synthesis ·
stereoselective synthesis of trisubstituted alkenes, creation of the two stereogenic
cross-coupling · natural products ·
centers on the oxepane ring by heterofunctionalization of an alkene through sub-
oxepanes · total synthesis
strate control exploiting the nucleophilic potential of an intramolecular sulfinyl
group, and transformation of a b-hydroxy sulfoxide into a terminal alkene.
Introduction
Results and Discussion
Zoapatanol 1 is among the many diterpenoid oxepanes iso-
lated[1] from the leaves of the plant Montanoa tomentosa,
which Mexican women use to prepare “tea” to induce
menses and labor, and to terminate early pregnancy.[2] Inves-
We disclose herein a stereoselective total synthesis of (+)-1
taking advantage of the B-alkyl Suzuki cross-coupling reac-
tion for carbon–carbon bond formation and the nucleophilic
potential of a sulfinyl group for carbon–oxygen bond forma-
tion. Retrosynthetic analysis (Scheme 1) revealed that the
tigators have also suggested a potential use of zoapatanol
and its bicyclic analogues as anti-fertility agents.[3] Due to its
biological activity and novel structure, several groups have
disclosed total syntheses of racemic[4] and natural zoapata-
nol.[5] The issues to be addressed in an efficient synthesis of
zoapatanol include: 1) the stereocontrolled preparation of
the oxepane ring, 2) the geometrical isomerism of the allylic
system, and 3) the relative and absolute stereochemistry at
the two stereogenic centers in the ring.[6]
Scheme 1. Retrosynthetic disconnection of (+)-zoapatanol.
oxepane ring in 5 could be constructed by a Williamson-
type ether synthesis from 6, as demonstrated by Trost and
co-workers.[5a] Compound 6 was envisaged as being accessi-
ble by a B-alkyl Suzuki reaction of an organoborane derived
from terminal alkene 8 with the iodoalkene 7. The triol de-
rivative 8 was envisaged as being accessible from b-hydroxy
sulfoxide 9.
Our synthesis of (+)-zoapatanol started from 2-methyl-
pent-4-en-1-ol (10)[5c,7] (Scheme 2). Protection of the hy-
droxy group under classical conditions as its p-methoxyben-
zyl (PMB) ether 11 and hydroboration with 9-borabicyclo-
[a] Dr. S. Raghavan, V. Sudheer Babu
Organic Division I, Indian Institute of Chemical Technology
Hyderabad 500007 (India)
Fax : (+90)40-27160512
E-mail: sraghavan@iict.res.in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003666: Experimental proce-
dures for the preparation of 2-methylpent-4-enoic acid and the prepa-
ration of iodo alkene 7 from 1,4-butyne diol; copies of the spectra.
Chem. Eur. J. 2011, 17, 8487 – 8494
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8487

Si face of the alkene p-complexed to the bromonium ion,
followed by SN2 attack by water on the ensuing sulfoxonium
ion, thereby resulting in an inversion of the sulfoxide config-
uration. The stereochemistry at sulfur in compound 18 is
tentatively assigned as inverted, based on ample prece-
dent.[14] The transition state TS2 that would arise by nucleo-
philic attack of the sulfinyl group on the Re face of the
alkene, would be disfavored due to an unfavorable A1,3 in-
teraction between the OTBS and the alkene substituent and
syn-diaxial interactions of the p-Tol group with OTBS and
the alkene substituent. The structure of 18 was assigned by
1H NMR NOE studies on the benzylidene acetal 19, ob-
tained by deprotection of the TBS group followed by reac-
tion of the resulting diol with an excess of benzaldehyde di-
methyl acetal. The benzylidene proton showed NOEs with
the axial methyl and methine protons, as depicted in
Scheme 2. Furthermore, the 0.9 Hz coupling constant for
CHBr confirmed its equatorial placement.
Protection of the tertiary hydroxy group in 18 as an acetal
(ethoxyethyl ether, EE) to afford 20 gave an inseparable
mixture of diastereomers at the newly created stereocenter.
The 1,3-diol derivative 20 was transformed into a 1,2-diol
derivative 23 by treatment with TBAF in THF. It had been
our intention to deprotect the silyl group with TBAF, sub-
ject the ensuing bromohydrin to treatment under basic con-
ditions to secure an epoxide, and then perform reductive
elimination of the epoxy sulfoxide using Na/Hg to afford
1,2-diol derivative 8. However, under the basic conditions,
silyl deprotection is followed by epoxide formation and fur-
ther b-elimination in situ to give vinyl sulfoxide 23
(Scheme 3). Next, compound 23 was oxidized[16] to vinyl sul-
fone 24, which was subjected to reductive elimination with
Mg/Hg[17] to yield terminal alkene 8 (P=H). Acetylation of
the hydroxy group in 8 afforded 25, which was hydroborated
using 9-BBN dimer to yield organoborane 26. Organobor-
ane 26 was reacted with (Z)-iodoalkene 7[18] under the
Suzuki reaction conditions as employed earlier to yield the
trisubstituted alkene 27 with the requisite Z configuration.
Thus, two of the three key issues in the synthesis of zoapata-
nol had been addressed. The third, stereoselective construc-
tion of the oxepane ring, was also considered addressed
since we were to follow the precedent set by Trost and co-
workers.[5a] The cyclization precursor 28 was obtained by de-
protection of the TBS group in 27 using pyridinium p-tolue-
nesulfonate (PPTS) in methanol. Treatment of 28 with triflic
anhydride in the presence of 2,6-lutidine,[19] according to
Trostꢁs general method,[5a] selectively afforded the desired
product 29 in 68% yield.
Scheme 2. Stereoselective synthesis of bromohydrin 18. Reagents and
conditions: a) NaH, PMB-Br, THF, 92%; b) (i) 9-BBN dimer, THF;
(ii) 13, [Pd
d) DIBAL-H, THF, 81%; e) TBS-Cl, imidazole, CH2Cl2, 93%; f) NBS,
H2O, toluene 76%; g) (i) cat. CSA, MeOH, 77%; (ii) PhCH(OMe)2, cat.
CSA, CH2Cl2, 90%; h) ethyl vinyl ether, cat. CSA, CH2Cl2, 90%.
ACHTUNGTRENNUNG(PPh3)4], K3PO4, dioxane, 74%; c) 15, LDA, THF, 55%;
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG[3.3.1]nonane (9-BBN) dimer afforded the trialkylborane 12.
This was then subjected to a Suzuki cross-coupling[8] with
(Z)-vinyl triflate[9] 13 using Cossyꢁs method, with minor
modification to the structure of each component, in the
presence of [PdACHTUNGTRENNUNG(PPh3)4] and K3PO4 to give the a,b-unsatu-
rated ester 14 in 74% yield. The b-keto sulfoxide 16 was
then obtained[10] in 55% yield by addition of the lithio anion
of (R)-methyl p-tolyl sulfoxide[11] 15 to the unsaturated ester
14. Diastereoselective reduction[12] of 16 using diisobutylalu-
minum hydride (DIBAL-H) afforded anti-b-hydroxy-g,d-un-
saturated sulfoxide 9 (d.r.>95:5).[13] The unsaturated alcohol
was protected as a tert-butyldimethylsilyl ether under stan-
dard conditions to yield compound 17 (P=TBS), which was
suitably predisposed for vicinal heterofunctionalization[14] of
its trisubstituted double bond, taking advantage of the nu-
cleophilicity of the intramolecular sulfinyl group. Thus,
treatment of 17 with N-bromosuccinimide (NBS) in toluene
in the presence of water afforded the bromohydrin 18 as the
sole product in 76% yield. To rationalize the formation of
18, we propose the transition state TS1, resulting from nu-
cleophilic attack of the sulfinyl group in a 6-endo mode, as
would be expected based on Markovnikovꢁs rule,[15] on the
Having completed the synthesis of the oxepane core, the
side chain needed to be elaborated. To this end, the PMB
group in 29 was deprotected using 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ)[20] to give the primary alcohol 30.
Oxidation using 2,2,6,6-tetramethylpiperidine N-oxide
(TEMPO) in the presence of PhI
trile[21] yielded the acid 31 (Scheme 4). The acid was con-
verted into the Weinreb amide 32 (HN(OMe)Me·HCl, 1-
ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI),
ACHTUNGRTEN(NUNG OAc)2 in aqueous acetoni-
AHCTUNGTRENNUNG
8488
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8487 – 8494

Total Synthesis of (+)-(2’S,3’R)-Zoapatanol
FULL PAPER
include the stereo- and regioselective functionalization of a
trisubstituted alkene to synthesize a tertiary carbinol, and a
B-alkyl Suzuki coupling reaction to create trisubstituted al-
kenes stereoselectively. The methodology illustrates an at-
tractive alternative to preparing 1,2-diols, particularly from
trisubstituted alkenes. Another interesting feature of the
synthesis is the one-pot transformation of compound 20 to
23. The methodology may also be applied in the synthesis of
other oxepane diterpenoids and analogues of zoapatanol.
Experimental Section
2-Methylpent-4-en-1-ol (10): A solution of 2-methylpent-4-enoic acid
(5.3 g, 46.5 mmol) in THF (20 mL) was slowly added to a stirred suspen-
sion of LiAlH4 (1.8 g, 46.5 mmol) in anhydrous THF (100 mL). After
12 h at room temperature, the reaction mixture was cooled to 08C and
cautiously treated with water (1.8 mL), then with a 20% aqueous solu-
tion of NaOH (1.8 mL), and then with further water (5.5 mL). After stir-
ring for 1 h at room temperature, the resulting suspension was filtered
through Celite. The insoluble salts were washed with EtOAc and the fil-
trate was dried over Na2SO4. The organic layer was concentrated under
reduced pressure to afford the crude alcohol, which was purified by
column chromatography eluting with 12% EtOAc/hexane (v/v) to afford
the alcohol (4.2 g, 42.3 mmol) in 91% yield as a colorless liquid. Rf =0.3
(PE/EtOAc, 8.8:1.2); 1H NMR (200 MHz, CDCl3): d=5.90–5.63 (m,
1H), 5.11–4.89 (m, 2H), 3.58–3.25 (m, 2H), 2.28–2.00 (m, 2H), 1.78–1.56
(m, 1H), 0.90 ppm (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
136.8, 115.7, 67.2, 37.5, 35.3, 16.1 ppm; IR: n˜ =3352, 2956, 2908, 1612,
1512, 1093, 821 cmÀ1; ESI-MS: m/z: 123 [M+Na]+.
Scheme 3. Stereoselective synthesis of the oxepane core of (+)-zoapata-
nol. Reagents and conditions: a) TBAF, THF, 90%; b) mCPBA, CH2Cl2,
92%; c) Mg/Hg, MeOH, 76%; d) (i) 9-BBN dimer, THF; (ii) [PdACTHUNTRGNE(UNG PPh3)4],
K3PO4, dioxane, 72%; e) PPTS, MeOH, 86%; f) Tf2O, 2,6-lutidine,
CH2Cl2, 68%.
1-Methoxy-4-[(2-methylpent-4-enyloxy)methyl]benzene (11): n-Tetrabu-
tylammonium iodide (1.6 g, 10 mol%, 4.23 mmol) was added to a suspen-
sion of sodium hydride (1.7 g, 60% in Nujol, 50 mmol) in anhydrous
THF (80 mL) cooled to 08C, and then a solution of alcohol 10 (4.2 g,
42.3 mmol) in THF (40 mL) was added dropwise. The reaction mixture
was stirred at the same temperature for 30 min. Neat 4-methoxybenzyl
bromide (8.5 g, 42.3 mmol) was then added dropwise over a period of
10 min at 08C. The reaction mixture was stirred at RT for 4 h under an
atmosphere of nitrogen and then quenched with aqueous NH4Cl solution.
The layers were separated and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were washed successively
with water and brine, and then dried over Na2SO4. The organic layer was
concentrated under reduced pressure to afford the crude product, which
was purified by column chromatography eluting with 4% EtOAc/hexane
(v/v) to afford the ether 11 (8.56 g, 38.9 mmol) in 92% yield as a color-
less liquid. Rf =0.3 (PE/EtOAc, 9.5:0.5); 1H NMR (300 MHz, CDCl3):
d=7.19 (d, J=8.7 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 5.81–5.65 (m, 1H),
5.02–4.92 (m, 2H), 4.39 (s, 2H), 3.78 (s, 3H), 3.29–3.16 (m, 2H), 2.25–
2.12 (m, 1H), 1.95–1.73 (m, 2H), 0.90 ppm (d, J=6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=159.3, 137.1, 131.0, 129.1, 116.1, 113.9, 75.2, 72.8,
55.3, 38.1, 33.6, 17.0 ppm; IR: n˜ =2956, 2908, 1612, 1512, 1461, 1301,
1247, 1093, 1037, 821 cmÀ1; ESI-MS: m/z: 243 [M+Na]+; HRMS (ESI):
m/z: calcd for C14H20O2Na: 243.1370; found: 243.1360 [M+Na]+.
Scheme 4. Completion of the synthesis of (+)-zoapatanol. Reagents and
conditions: a) DDQ, CH2Cl2, H2O, 91%; b) TEMPO, PhI
ACHTUNGTRNEN(UNG OAc)2, CH3CN
(aq), 93%; c) HN(OMe)Me·HCl, EDCI, iPr2NEt, cat. DMAP, CH2Cl2,
ACHTUNGTRENNUNG
82%; d) prenyllithium, THF/Et2O (1:1), 72%.
iPr2NEt, 4-dimethylaminopyridine (DMAP)) in 82% yield.
Treatment[22] of 32 with prenyllithium[23] using Cossyꢁs meth-
od[5b,c] gave (+)-zoapatanol by concomitant deacetylation in
72% yield. The physical characteristics of the synthetic
sample were in excellent agreement with those reported in
the literature.[1,5a,c]
(Z)-Ethyl 8-(4-methoxybenzyloxy)-3,7-dimethyloct-2-enoate (14): A solu-
tion of 9-BBN dimer (2.5 mmol) in THF (5 mL) was added dropwise to a
solution of compound 11 (1.1 g, 5 mmol) in anhydrous THF (5 mL)
cooled to 08C. The solution was stirred at 08C until complete conversion
of the starting alkene (approximately 2 h, monitored by TLC). In another
round-bottomed flask, a suspension of K3PO4 (1.7 g, 7.5 mmol) and tri-
flate 13 (1.3 g, 5 mmol) in freshly distilled dioxane (15 mL) was degassed
for 30 min by bubbling nitrogen through it. The solution of the borane
and [PdACHTNUGTRNEUGN(PPh3)4] (0.14 g, 0.125 mmol) were then added to the triflate solu-
Conclusion
tion and the reaction mixture was heated for 8 h at 858C. After cooling
to room temperature, the unreacted borane was oxidized by the addition
of an aqueous solution of sodium acetate (1 mL, 3m) and hydrogen per-
oxide (30%, 1 mL). After stirring for 1 h at room temperature, the red
We have achieved an efficient stereoselective synthesis of
zoapatanol (2.8% overall yield in 20 steps). The key steps
Chem. Eur. J. 2011, 17, 8487 – 8494
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8489

S. Raghavan and V. Sudheer Babu
solution was diluted with diethyl ether and washed with saturated aque-
ous NH4Cl and brine. The combined organic extracts were dried over
Na2SO4. The organic layer was concentrated under reduced pressure to
afford the crude product, which was purified by column chromatography
eluting with 6% EtOAc/hexane (v/v) to afford the unsaturated ester 14
(1.23 g, 3.7 mmol) in 74% yield as a colorless liquid. Rf =0.3 (PE/EtOAc,
9:1); 1H NMR (300 MHz, CDCl3): d=7.19 (d, J=8.3 Hz, 2H), 6.81 (d,
J=8.3 Hz, 2H), 5.60 (s, 1H), 4.39 (s, 2H), 4.11 (q, J=7.5 Hz, 2H), 3.79
(s, 3H), 3.30–3.15 (m, 2H), 2.59 (t, J=7.5 Hz, 2H), 1.87 (d, J=1.5 Hz,
3H), 1.81–1.69 (m, 1H), 1.63–1.35 (m, 4H), 1.27 (t, J=7.5 Hz, 3H),
0.92 ppm (d, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=166.1,
160.1, 158.8, 130.7, 128.8, 115.9, 113.5, 75.3, 72.4, 59.1, 54.9, 33.5, 33.3,
33.1, 25.4, 24.9, 16.9, 14.1 ppm; IR: n˜ =2932, 2856, 1713, 1646, 1513, 1246,
1149, 1093, 757 cmÀ1; ESI-MS: m/z: 357 [M+Na]+; HRMS (ESI): m/z:
calcd for C20H30O4Na: 357.2044; found: 357.2041 [M+Na]+.
(d, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=158.7, 141.0, 139.8,
138.8, 130.4, 129.7, 128.8, 128.5, 124.8, 123.9, 123.6, 113.4, 75.14, 75.11,
72.3, 72.2, 63.7, 63.2, 62.9, 62.5, 54.9, 33.2, 32.9, 32.8, 32.7, 32.6, 25.0, 24.9,
24.5, 21.0, 16.8 ppm; IR: n˜ =3354, 2929, 2856, 1610, 1512, 1248, 1086,
810 cmÀ1; ESI-MS: m/z: 467 [M+Na]+; HRMS (ESI): m/z: calcd for
C26H36O4NaS: 467.2247; found: 467.2232 [M+Na]+. Note: The proton
count has been doubled since an equimolar epimeric mixture, differing at
the methyl-bearing stereogenic center, was obtained.
tert-ButylACTHUNRTGNEUNG[(2S,Z)-9-(4-methoxybenzyloxy)-4,8-dimethyl-1-(Rs)-(p-tolylsul-
finyl)non-3-en-2-yloxy]dimethylsilane (17): Imidazole (0.73 g, 10.7 mmol)
and tert-butyldimethylsilyl chloride (0.81 g, 5.3 mmol) were successively
added to a solution of allylic alcohol 9 (2.16 g, 4.86 mmol) in anhydrous
dichloromethane (20 mL) at ambient temperature. The reaction mixture
was stirred for 1 h, then diluted with dichloromethane, washed succes-
sively with water and brine, and dried over Na2SO4. The organic layer
was concentrated under reduced pressure to afford the diastereomeric
TBS ethers, differing at the methyl-bearing stereocenter, as a crude prod-
uct. A small sample of the diastereomers could be separated by column
chromatography eluting with 10% EtOAc/hexane (v/v). The bulk sample
(Z)-9-(4-Methoxybenzyloxy)-4,8-dimethyl-1-(Rs)-(p-tolylsulfinyl)non-3-
en-2-one (16): A solution of nBuLi (4.41 mL, 2.5m in hexanes, 11 mmol)
was added to a solution of diisopropylamine (1.62 mL, 11.5 mmol) in dry
THF (30 mL) at 08C. After 15 min, the resulting lithium diisopropyla-
mide solution was cooled to À408C, a solution of (R)-methyl p-tolylsulf-
oxide 15 (1.6 g, 10.5 mmol) in dry THF (12 mL) was added dropwise, and
the resulting mixture was stirred at the same temperature for 30 min. It
was then allowed to warm to 08C, whereupon a solution of the ester 14
(1.7 g, 5.25 mmol) in THF (6 mL) was added dropwise. The reaction mix-
ture was further stirred for 1 h at 08C. The reaction was then quenched
by the addition of saturated aqueous NH4Cl solution and then the solu-
tion was adjusted to pH 2 by the addition of 5% aqueous H2SO4. The
two layers were separated and the aqueous phase was extracted twice
with ethyl acetate. The combined organic layers were washed successively
with water and brine, and then dried over Na2SO4. The organic layer was
concentrated under reduced pressure to afford the crude product, which
was purified by column chromatography eluting with 30% EtOAc/
hexane (v/v) to afford the b-keto sulfoxide 16 (1.27 g, 2.9 mmol) in 55%
yield as a yellow gummy liquid. Rf =0.3 (PE/EtOAc, 3:2); [a]2D5 =+75
(c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.50 (d, J=8.3 Hz, 4H),
7.27 (d, J=8.3 Hz, 4H), 7.19 (d, J=8.3 Hz, 4H), 6.80 (d, J=8.3 Hz, 4H),
6.03 (s, 2H), 4.38 (s, 4H), 3.81 (d, J=12.8 Hz, 2H), 3.78 (s, 6H), 3.64 (d,
J=12.8 Hz, 2H), 3.30–3.11 (m, 4H), 2.48 (t, J=7.5 Hz, 4H), 2.41 (s, 6H),
1.87 (s, 6H), 1.81–1.54 (m, 2H), 1.53–1.07 (m, 8H), 0.90 ppm (d, J=
6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=189.7, 189.2, 163.6, 162.8,
158.4, 158.3, 141.2, 140.8, 139.5, 139.4, 130.2, 130.1, 129.4, 129.3, 128.5,
128.4, 123.6, 123.4, 122.7, 122.1, 113.1, 74.9, 74.7, 72.0, 69.3, 67.8, 66.2,
54.8, 54.5, 33.8, 33.1, 32.7, 32.6, 25.2, 24.9, 24.8, 24.3, 24.2, 20.8, 16.5 ppm;
IR: n˜ =2978, 2927, 2111, 1727, 1521, 1370, 1276, 1164, 1024 cmÀ1; ESI-
MS: m/z: 443 [M+H]+; HRMS (ESI): m/z: calcd for C26H35O4S:
443.2263; found: 443.2256 [M+Na]+. Note: The proton count has been
doubled since an equimolar epimeric mixture, differing at the methyl-
bearing stereogenic center, was obtained.
could only be isolated as
a mixture. The TBS ethers 17 (2.52 g,
4.51 mmol) were isolated in 93% combined yield as a colorless gummy
liquid. Diastereomer 1: Rf =0.3 (PE/EtOAc, 8.5:1.5); [a]2D5 =+68.4 (c=1,
CHCl3); 1H NMR (200 MHz, CDCl3): d=7.48 (d, J=8.3 Hz, 2H), 7.25
(d, J=8.3 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 5.09
(d, J=9.0 Hz, 1H), 4.97 (td, J=9.8, 3.0 Hz, 1H), 4.38 (s, 2H), 3.79 (s,
3H), 3.31–3.11 (m, 2H), 2.70 (dd, J=12.8, 9.8 Hz, 1H), 2.59 (dd, J=12.8,
3.0 Hz, 1H), 2.40 (s, 3H), 2.17–1.88 (m, 2H), 1.65 (s, 3H), 1.76–1.56 (m,
1H), 1.50–1.02 (m, 4H), 0.95 (s, 9H), 0.90 (d, J=6.8 Hz, 3H), 0.18 (s,
3H), 0.08 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=158.8, 141.8,
140.6, 137.4, 130.7, 129.7, 128.8, 126.7, 123.5, 113.5, 75.3, 72.4, 67.6, 63.8,
54.9, 33.5, 32.3, 25.7, 24.9, 22.8, 21.1, 18.0, 16.9, À4.3, À5.1 ppm; IR: n˜ =
2928, 2855, 1614, 1512, 1248, 1085, 771 cmÀ1; ESI-MS: m/z: 581 [M+Na]+
; HRMS (ESI): m/z: calcd for C32H50O4NaSiS: 581.3083; found: 581.3096
[M+Na]+. Diastereomer 2: Rf =0.3 (PE/EtOAc, 8:2); [a]2D5 =+80.4 (c=
1
1, CHCl3); H NMR (300 MHz, CDCl3): d=7.48 (d, J=8.3 Hz, 2H), 7.26
(d, J=8.3 Hz, 2H), 7.17 (d, J=8.3 Hz, 2H), 6.80 (d, J=8.3 Hz, 2H), 5.08
(d, J=8.3 Hz, 1H), 4.99–4.89 (m, 1H), 4.35 (s, 2H), 3.78 (s, 3H), 3.25–
3.09 (m, 2H), 2.71 (dd, J=12.1, 9.8 Hz, 1H), 2.60 (dd, J=12.1, 2.3 Hz,
1H), 2.40 (s, 3H), 1.98–1.83 (m, 2H), 1.66 (s, 3H), 1.50–0.99 (m, 5H),
0.94 (s, 9H), 0.88 (d, J=6.8 Hz, 3H), 0.18 (s, 3H), 0.08 ppm (s, 3H);
13C NMR (75 MHz, CDCl3): d=158.7, 141.5, 140.5, 137.1, 130.5, 129.5,
128.6, 125.7, 123.3, 113.3, 75.1, 72.2, 67.0, 63.9, 54.7, 33.0, 32.9, 25.5, 24.6,
24.5, 20.9, 16.8, À4.5, À5.3 ppm; IR: n˜ =2928, 2855, 1614, 1512, 1248,
1085, 771 cmÀ1
.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
3.75 mmol) followed by freshly recrystallized NBS (0.53 g, 3 mmol) were
added to a solution of the TBS ether 17 (2.5 mmol) in toluene (12.5 mL)
and the mixture was stirred at RT until TLC examination revealed com-
plete reaction (2 h). The reaction mixture was then diluted with diethyl
ether, washed successively with saturated aqueous NaHCO3 solution,
water, and brine, and dried over Na2SO4. The organic layer was concen-
trated under reduced pressure to afford the crude product, which was pu-
rified by column chromatography eluting with 15% EtOAc/hexane (v/v)
to afford the bromohydrin 18 as an equimolar mixture of diastereomers
differing at the methyl-bearing stereocenter (1.2 g, 1.9 mmol) in 76%
yield as a pale-yellow gummy liquid. A small portion of the diastereo-
meric mixture could be resolved and the pure diastereomers were indi-
ACHTUNGTRENNUNG(2S,Z)-9-(4-Methoxybenzyloxy)-4,8-dimethyl-1-(Rs)-(p-tolylsulfinyl)non-
3-en-2-ol (9): A solution of DIBAL-H (4.71 mL, 6.6 mmol, 1.4m in tolu-
ene) was added to a solution of 16 (2.6 g, 6 mmol) in anhydrous THF
(60 mL) cooled to À788C. After 1 h at À788C, the reaction was quenched
by the addition of methanol. The volatiles were evaporated under re-
duced pressure to afford the crude product. Water and EtOAc were
added at this stage, and the solution was adjusted to pH 2 by the addition
of 5% aqueous H2SO4. The aqueous phase was extracted with ethyl ace-
tate. The combined organic layers were washed successively with water
and brine, and dried over Na2SO4. The organic layer was concentrated
under reduced pressure to afford the crude product, which was purified
by column chromatography eluting with 35% EtOAc/hexane (v/v) to
afford the hydroxy sulfoxide 9 (2.16 g, 4.86 mmol) in 81% yield as a pale
yellow gummy liquid. Rf =0.3 (PE/EtOAc, 1:1); [a]2D5 =+45 (c=1,
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.50 (d, J=8.3 Hz, 2H), 7.46
(d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.19
(d, J=8.3 Hz, 2H), 7.16 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 4H),
5.20–5.06 (m, 2H), 4.88 (t, J=8.3 Hz, 2H), 4.38 (s, 2H), 4.35 (s, 2H), 3.78
(s, 6H), 3.25–3.12 (m, 4H), 3.06–2.79 (m, 2H), 2.68–2.50 (m, 2H), 2.42 (s,
3H), 2.41 (s, 3H), 2.22–2.06 (m, 4H), 2.00–1.82 (m, 2H), 1.73–1.59 (m,
2H), 1.46 (s, 6H), 1.41–1.01 (m, 8H), 0.89 (d, J=6.8 Hz, 3H), 0.86 ppm
vidually characterized. Diastereomer 1: Rf =0.3 (PE/EtOAc, 4:1); [a]D25
=
À42 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.50 (d, J=8.3 Hz,
2H), 7.34 (d, J=8.3 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz,
2H), 4.58–4.51 (m, 1H), 4.49 (d, J=3.0 Hz, 1H), 4.40 (s, 2H), 3.79 (s,
3H), 3.33–3.05 (m, 4H), 2.45 (s, 3H), 1.82–1.45 (m, 4H), 1.41 (s, 3H),
1.34–1.05 (m, 3H), 0.94 (d, J=6.8 Hz, 3H), 0.90 (s, 9H), 0.14 (s, 3H),
0.09 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=158.9, 141.8, 138.6,
130.8, 130.2, 129.1, 123.8, 113.7, 75.7, 75.5, 74.6, 72.6, 68.2, 63.5, 55.2, 34.0,
33.3, 25.7, 25.4, 21.4, 20.9, 17.9, 17.0, À3.4, À4.2 ppm; IR: n˜ =3447, 2930,
2856, 1637, 1512, 1463, 1366, 1248, 1089, 834, 776 cmÀ1; ESI-MS: m/z: 679
[M+Na]+; HRMS (ESI): m/z: calcd for C32H52O5SiSBr: 655.2468; found:
8490
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8487 – 8494

Total Synthesis of (+)-(2’S,3’R)-Zoapatanol
FULL PAPER
655.2464 [M+H]+. Diastereomer 2: Rf =0.2 (PE/EtOAc, 4:1); [a]2D5 =À38
(c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.49 (d, J=8.3 Hz, 2H),
7.32 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 6.82 (d, J=8.3 Hz, 2H),
4.56–4.49 (m, 2H), 4.41 (s, 2H), 3.79 (s, 3H), 3.68–3.54 (m, 1H), 3.33–
3.16 (m, 2H), 3.02–2.89 (m, 1H), 2.44 (s, 3H), 1.82–1.36 (m, 7H), 1.29 (s,
3H), 0.94 (s, 9H), 0.92 (d, J=6.8 Hz, 3H), 0.17 (s, 3H), 0.10 ppm (s,
3H); 13C NMR (75 MHz, CDCl3): d=158.9, 141.9, 139.9, 130.9, 130.2,
129.1, 124.0, 113.7, 75.6, 75.58, 74.5, 72.6, 66.5, 63.1, 55.2, 34.0, 33.3, 25.8,
24.7, 21.4, 20.5, 18.1, 17.1, À3.7, À4.3 ppm; IR: n˜ =3447, 2930, 2856, 1637,
ACHTUNGTRENNUNG
1512, 1463, 1366, 1248, 1089, 834, 776 cmÀ1
.
ACHTUNGTRENNUNG(4S,5S,6R)-5-Bromo-4-[5-(4-methoxybenzyloxy)-4-methylpentyl]-4-
methyl-2-phenyl-6-(Ss)-(p-tolylsulfinylmethyl)-1,3-dioxane (19): Camphor
sulfonic acid (CSA; 2 mg) was added to a solution of the bromohydrin 18
(25 mg, 0.035 mmol) in methanol cooled to 08C and the mixture was
stirred for 2 h, allowing the temperature to gradually rise to RT. A few
drops of triethylamine were added and the solvent was removed under
reduced pressure to afford the crude product, which was purified by
column chromatography eluting with 45% EtOAc/hexane (v/v) to afford
the pure bromodiol (15 mg, 0.027 mmol) in 77% yield as a pale yellow
liquid. Rf =0.3 (PE/EtOAc, 1:1); 1H NMR (300 MHz, CDCl3): d=7.52
(d, J=8.3 Hz, 4H), 7.32 (d, J=8.3 Hz, 4H), 7.19 (d, J=8.3 Hz, 4H), 6.81
(d, J=8.3 Hz, 4H), 4.57–4.48 (m, 2H), 4.38 (s, 4H), 4.20–4.12 (m, 2H),
3.78 (s, 6H), 3.27–3.18 (m, 4H), 3.14 (dd, J=13.6, 6.8 Hz, 2H), 2.93 (dd,
J=13.6, 5.3 Hz, 2H), 2.44 (s, 6H), 1.81–1.47 (m, 8H), 1.40 (s, 6H), 1.33–
1.06 (m, 6H), 0.91 ppm (d, J=6.8 Hz, 6H). Benzaldehyde dimethyl
acetal (12 mg, 0.08 mmol) followed by CSA (1 mg) were added to solu-
tion of the bromodiol (15 mg, 0.027 mmol) in dichloromethane (1 mL)
and the reaction mixture was stirred for 1 h at RT. A few drops of trie-
thylamine were then added and the solvent was removed under reduced
pressure to afford the crude product, which was purified by column chro-
matography eluting with 25% EtOAc/hexane (v/v) to afford the acetal
19 (14 mg, 0.024 mmol) in 90% yield as a colorless liquid. Rf =0.3 (PE/
EtOAc, 7.5:2.5); 1H NMR (300 MHz, CDCl3): d=7.41 (d, J=8.3 Hz,
4H), 7.23–7.06 (m, 18H), 6.74 (d, J=8.3 Hz, 4H), 5.56 (s, 2H), 4.61 (td,
J=6.0, 0.9 Hz, 2H), 4.32 (s, 4H), 3.98 (d, J=0.9 Hz, 2H), 3.72 (s, 6H),
3.21–3.10 (m, 6H), 3.04 (dd, J=13.8, 5.8 Hz, 2H), 2.30 (s, 6H), 1.85–1.60
(m, 4H), 1.55 (s, 6H), 1.47–1.01 (m, 10H), 0.86 ppm (d, J=6.6 Hz, 6H).
Note: The proton count has been doubled since an equimolar epimeric
mixture, differing at the methyl-bearing stereogenic center, was obtained.
AHCTUNGTERG(NNUN 3R,4S,E)-4-(1-Ethoxyethoxy)-9-(4-methoxybenzyloxy)-4,8-dimethyl-1-to-
sylnon-1-en-3-ol (24): m-Chloroperoxybenzoic acid (mCPBA; 295 mg,
1.72 mmol) was added to a solution of the allylic alcohol 23 (0.82 g,
1.56 mmol) in dichloromethane (5 mL) cooled to 08C and the mixture
was stirred at RT for 30 min. The reaction mixture was then diluted with
dichloromethane, washed successively with saturated aqueous NaHSO3,
saturated aqueous NaHCO3, water, and brine, and dried over Na2SO4.
The organic layer was concentrated under reduced pressure to afford the
crude product, which was purified by column chromatography eluting
with 20% EtOAc/hexane (v/v) to afford the sulfone 24 (0.79 g,
1.44 mmol) in 92% yield as a colorless gummy liquid. A small portion
could be separated into individual diastereomers (differing at the methyl-
bearing stereocenter) as epimeric ethyl vinyl ethers. Diastereomer 1: Rf =
0.3 (PE/EtOAc, 7:3); [a]D25 =+19 (c=1, CHCl3); 1H NMR (300 MHz,
CDCl3): d=7.73 (d, J=7.9 Hz, 2H), 7.66 (d, J=7.9 Hz, 2H), 7.27 (d, J=
7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 2H), 7.12 (d, J=8.1 Hz, 4H), 6.93–6.79
(m, 2H), 6.75 (d, J=8.1 Hz, 4H), 6.60–6.42 (m, 2H), 4.80–4.64 (m, 1H),
4.62–4.48 (m, 1H), 4.31 (s, 4H), 4.19–3.80 (m, 2H), 3.72 (s, 6H), 3.60–
3.20 (m, 4H), 3.19–2.95 (m, 4H), 2.40 (s, 3H), 2.34 (s, 3H), 1.76–1.52 (m,
4H), 1.47–0.90 (m, 28H), 0.89–0.72 ppm (m, 6H); 13C NMR (75 MHz,
CDCl3): d=158.9, 144.2, 143.8, 137.5, 131.5, 131.4, 129.7, 129.0, 127.5,
113.6, 94.6, 93.6, 81.1, 80.6, 76.0, 75.9, 75.6, 75.4, 72.5, 60.2, 57.9, 55.1,
36.8, 36.7, 33.9, 33.2, 33.0, 32.4, 22.1, 22.1, 21.5, 20.5, 20.4, 19.0, 17.0,
15.1 ppm; IR: n˜ =3480, 2928, 1609, 1512, 1310, 1248, 1143, 1087, 815,
547 cmÀ1; ESI-MS: m/z: 571 [M+Na]+; HRMS (ESI): m/z: calcd for
C30H44O7NaS: 571.2681; found: 571.2705 [M+Na]+. Note: The proton
count has been doubled since this compound was obtained as an epimeric
mixture of ethoxy acetals. Diastereomer 2: Rf =0.2 (PE/EtOAc, 7:3);
[a]2D5 =+23 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.74 (d, J=
8.1 Hz, 4H), 7.30 (d, J=8.1 Hz, 4H), 7.25 (d, J=8.5 Hz, 4H), 6.87 (d, J=
ACHTUNGTRENNUNG(5R,6S,7S)-6-Bromo-7-[5-(4-methoxybenzyloxy)-4-methylpentyl]-
2,2,3,3,7,9-hexamethyl-5-(Ss)-(p-tolylsulfinylmethyl)-4,8,10-trioxa-3-sila-
dodecane (20): Ethyl vinyl ether (0.55 mL, 5.7 mmol) followed by CSA
(22 mg, 0.09 mmol) were added to a solution of bromohydrin 18 (1.2 g,
1.9 mmol) in dichloromethane (9.5 mL) at 08C. The mixture was stirred
at the same temperature until TLC examination revealed completion of
the reaction (1 h). A few drops of triethylamine were then added and the
solvent was removed under reduced pressure. The bulk sample was used
directly for the next step. A small amount of the mixture was carefully
purified by column chromatography eluting with 15% EtOAc/hexane (v/
v) to afford a separable mixture of diastereomers (differing at the
methyl-bearing stereocenter), each of which was a mixture of acetals.
Diastereomer 1: 1H NMR (300 MHz, CDCl3): d=7.51 (d, J=8.3 Hz,
2H), 7.50 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz,
2H), 7.21 (d, J=8.3 Hz, 4H), 6.82 (d, J=8.3 Hz, 4H), 5.08–4.86 (m, 2H),
4.78–4.47 (m, 4H), 4.41 (s, 4H), 3.79 (s, 6H), 3.65–3.38 (m, 6H), 3.35–
3.14 (m, 6H), 2.43 (s, 6H), 1.87–1.65 (m, 4H), 1.63–1.04 (m, 28H), 1.01–
0.83 (m, 24H), 0.13 (s, 6H), 0.11 ppm (s, 6H); ESI-MS: m/z: 751
[M+Na]+. Note: The proton count has been doubled since this com-
pound was obtained as an epimeric mixture of ethoxy acetals. Diastereo-
mer 2: 1H NMR (300 MHz, CDCl3): d=7.52 (d, J=8.1 Hz, 2H), 7.50 (d,
J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 4H), 7.23 (d, J=8.1 Hz, 4H), 6.84 (d,
J=8.1 Hz, 4H), 4.99–4.86 (m, 2H), 4.70–4.49 (m, 4H), 4.41 (s, 4H), 3.79
(s, 6H), 3.66–3.39 (m, 6H), 3.34–3.13 (m, 6H), 2.43 (s, 6H), 1.92–1.67 (m,
4H), 1.66–1.50 (m, 4H), 1.52–1.04 (m, 24H), 0.95 (d, J=6.4 Hz, 6H),
0.93 (s, 18H), 0.09 (s, 6H), 0.07 ppm (s, 6H). Note: The proton count has
been doubled since this compound was obtained as an epimeric mixture
of ethoxy acetals.
Chem. Eur. J. 2011, 17, 8487 – 8494
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8491

S. Raghavan and V. Sudheer Babu
8.5 Hz, 4H), 6.74–6.63 (m, 4H), 4.81–4.68 (m, 2H), 4.42 (s, 4H), 4.23–
4.12 (m, 2H), 3.79 (s, 6H), 3.59–3.32 (m, 4H), 3.31–3.13 (m, 4H), 2.41 (s,
6H), 1.89–1.57 (m, 4H), 1.56–1.33 (m, 2H), 1.30–0.99 (m, 26H), 0.95–
0.85 ppm (m, 6H); 13C NMR (75 MHz, CDCl3): d=158.9, 144.2, 143.2,
143.1, 137.3, 131.8, 131.7, 131.4, 130.7, 129.8, 129.0, 127.6, 113.6, 94.5,
94.4, 82.0, 81.1, 75.7, 75.5, 75.4, 75.1, 72.6, 60.6, 59.5, 55.2, 34.7, 34.2, 34.0,
33.9, 33.3, 33.2, 21.5, 20.4, 20.2, 20.1, 20.0, 17.0, 16.9, 15.1, 15.0 ppm; IR:
n˜ =3480, 2928, 1609, 1512, 1310, 1248, 1143, 1087, 815, 547 cmÀ1. Note:
The proton count has been doubled since this compound was obtained as
an epimeric mixture of ethoxy acetals.
purified by column chromatography eluting with 5% EtOAc/hexane (v/
v) to afford the acetate 7 (1.8 g, 4.85 mmol) in 97% yield as a colorless
liquid. Rf =0.3 (PE/EtOAc, 9.7:0.3); 1H NMR (300 MHz, CDCl3): d=
6.21 (t, J=6.0 Hz, 1H), 4.66 (dt, J=6.0, 1.3 Hz, 2H), 4.24 (d, J=1.3 Hz,
2H), 2.08 (s, 3H), 0.93 (s, 9H), 0.10 ppm (s, 6H); 13C NMR (75 MHz,
CDCl3): d=170.6, 127.6, 109.8, 71.2, 67.8, 25.8, 20.8, À5.3 ppm; IR: n˜ =
2929, 2856, 1745, 1227, 1110, 840 cmÀ1; ESI-MS: m/z: 388 [M+NH4]+;
HRMS (ESI): m/z: calcd for C12H27NO3SiI: 388.0807; found: 388.0804
[M+NH4]+.
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
tion of 9-BBN dimer (134 mg, 0.55 mmol) in THF (2 mL) was added
dropwise to a solution of compound 25 (394 mg, 1 mmol) in anhydrous
THF (2 mL) cooled to 08C. The solution was stirred at 08C until com-
plete conversion of the starting alkene (approximately 3 h, monitored by
TLC). In another round-bottomed flask a suspension of K3PO4 (340 mg,
1.6 mmol) and iodide 7 (407 mg, 1.1 mmol) in freshly distilled dioxane
(4 mL) was degassed for 30 min by bubbling argon through it. The afore-
a
1.44 mmol) in MeOH (7 mL) at 08C. The reaction mixture was stirred
for 4 h, while gradually allowing it to warm to RT. The residue was fil-
tered off and washed with methanol. The combined filtrate and washings
were concentrated under reduced pressure to afford the crude product,
which was purified by column chromatography eluting with 15% EtOAc/
hexane (v/v) to afford the allylic alcohol 8 as an inseparable mixture of
diastereomers differing at the methyl-bearing stereocenter (0.43 g,
1.1 mmol) in 76% yield as a colorless liquid. Rf =0.3 (PE/EtOAc, 4:1);
[a]2D5 =+20 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.15 (d, J=
8.5 Hz, 4H), 6.87 (d, J=8.5 Hz, 4H), 5.94–5.72 (m, 2H), 5.39–5.13 (m,
4H), 4.88–4.74 (m, 2H), 4.42 (s, 4H), 4.02–3.82 (m, 2H), 3.80 (s, 6H),
3.58–3.40 (m, 4H), 3.32–3.13 (m, 4H), 1.82–1.65 (m, 4H), 1.49–1.02 (m,
28H), 0.96–0.82 ppm (m, 6H); 13C NMR (75 MHz, CDCl3): d=159.0,
136.6, 136.4, 130.8, 129.1, 117.2, 116.7, 113.7, 94.5, 94.2, 81.3, 80.7, 78.2,
77.9, 75.6, 75.5, 72.6, 60.4, 60.1, 59.7, 59.2, 55.2, 38.7, 38.6, 34.9, 34.8, 34.2,
34.1, 20.7, 20.6, 20.5, 20.3, 20.2, 19.5, 19.1, 17.1, 15.2 ppm; IR: n˜ =3450,
2923, 2852, 1610, 1513, 1461, 1249, 1092, 1035, 821 cmÀ1; ESI-MS: m/z:
417 [M+Na]+; HRMS (ESI): m/z: calcd for C23H38O5Na: 417.2614;
found: 417.2616 [M+Na]+. Note: The proton count has been doubled
since the reported data correspond to an equimolar epimeric mixture of
isomers differing at the methyl-bearing stereogenic center.
mentioned trialkylborane solution and [PdACHTNURTGNEUNG(PPh3)4] (58 mg, 0.05 mmol)
were then added to the iodide solution and the reaction mixture was
heated at 858C for 10 h. After cooling to room temperature, the unreact-
ed borane was oxidized by the addition of an aqueous solution of sodium
acetate (0.2 mL, 3m) and hydrogen peroxide (0.2 mL, 30%). After stir-
ring for 1 h at room temperature, the red solution was diluted with dieth-
yl ether. The organic layer was separated and washed with saturated
aqueous NH4Cl solution and brine. The combined organic phases were
dried over Na2SO4. The organic layer was concentrated under reduced
pressure to afford the crude product, which was purified by column chro-
matography eluting with 20% EtOAc/hexane (v/v) to afford the coupled
product 27 in 72% yield by concomitant deprotection of the ethyl vinyl
ether (437 mg, 0.72 mmol) as a colorless liquid. Rf =0.3 (PE/EtOAc, 3:1);
[a]2D5 =À22 (c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.23 (d, J=
8.5 Hz, 4H), 6.85 (d, J=8.5 Hz, 4H), 5.59 (t, J=7.2 Hz, 2H), 4.84–4.75
(m, 2H), 4.68–4.50 (m, 4H), 4.41 (s, 4H), 4.06 (s, 4H), 3.80 (s, 6H), 3.32–
3.15 (m, 4H), 2.11 (s, 6H), 2.10–2.05 (m, 4H), 2.04 (s, 6H), 1.82–1.55 (m,
8H), 1.53–1.20 (m, 10H), 1.12 (s, 6H), 0.95–0.85 (m, 24H), 0.06 ppm (s,
12H); 13C NMR (75 MHz, CDCl3): d=171.1, 169.8, 158.2, 144.1, 130.8,
129.1, 118.5, 113.7, 79.3, 79.2, 75.6, 75.5, 74.0, 72.6, 66.0, 60.5, 55.2, 38.0,
37.9, 34.2, 33.4, 28.6, 25.9, 25.0, 23.5, 23.4, 21.0, 20.5, 18.3, 17.1, 17.0,
ACHTUNGTRENNUNG(3R,4S)-4-(1-Ethoxyethoxy)-9-(4-methoxybenzyloxy)-4,8-dimethylnon-1-
en-3-yl acetate (25): Et3N (0.28 mL, 2.2 mmol) followed by acetic anhy-
dride (0.14 mL, 1.4 mmol) were added to a stirred solution of allylic alco-
hol 8 (0.43 g, 1.1 mmol) and DMAP (12 mg, 0.1 mmol) in anhydrous di-
chloromethane (8 mL). The reaction mixture was stirred for 1 h at RT
and then water was added. The clear layers were separated and the aque-
ous layer was extracted twice with dichloromethane. The combined or-
ganic layers were washed with water and brine, and dried over Na2SO4.
The organic layer was concentrated under reduced pressure to afford the
crude product, which was purified by column chromatography eluting
with 5% EtOAc/hexane (v/v) to afford the acetate 25 (0.46 g, 1.03 mmol)
in 94% yield as a colorless liquid. Rf =0.3 (PE/EtOAc, 9:1); [a]2D5 =+20
(c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.24 (d, J=8.1 Hz, 4H),
6.85 (d, J=8.1 Hz, 4H), 6.02–5.71 (m, 2H), 5.42–5.09 (m, 6H), 5.08–4.90
(m, 2H), 4.42 (s, 4H), 3.79 (s, 6H), 3.60–3.39 (m, 4H), 3.35–3.14 (m, 4H),
2.10 (s, 3H), 2.08 (s, 3H), 1. 90–1.66 (m, 4H), 1.56–1.01 (m, 28H),
0.91 ppm (d, J=6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=169.9,
158.9, 133.2, 132.8, 130.7, 128.9, 118.3, 117.9, 113.6, 93.9, 93.7, 80.9, 78.8,
78.7, 78.5, 78.4, 75.5, 72.5, 57.9, 57.8, 55.1, 37.6, 37.5, 36.4, 36.3, 34.1, 21.0,
20.9, 20.2, 19.9, 17.0, 15.2 ppm; IR: n˜ =2932, 2854, 1734, 1614, 1512, 1461,
1249, 1092, 1035, 821 cmÀ1; ESI-MS: m/z: 454 [M+NH4]+; HRMS (ESI):
m/z: calcd for C25H40O6N: 459.3175; found: 459.3168 [M+Na]+. Note:
The proton count has been doubled since the reported data correspond
to an equimolar epimeric mixture of isomers differing at the methyl-bear-
ing stereogenic center.
À5.4 ppm; IR: n˜ =3462, 2925, 2854, 1736, 1243, 1095, 1032, 838 cmÀ1
;
ESI-MS: m/z: 631 [M+Na]+; HRMS (ESI): m/z: calcd for C33H56O8NaSi:
631.3631; found: 631.3642 [M+Na]+. Note: The proton count has been
doubled since the reported data correspond to an equimolar epimeric
mixture of isomers differing at the methyl-bearing stereogenic center.
AHCTUNGTERG(NNUN 6R,7S,E)-7-Hydroxy-3-(hydroxymethyl)-12-(4-methoxybenzyloxy)-7,11-
dimethyldodec-2-ene-1,6-diyl diacetate (28): PPTS (18 mg, 0.072 mmol)
was added to a solution of 27 (437 mg, 0.72 mmol) in methanol and the
mixture was stirred at RT for 30 min. A few drops of triethylamine were
added and the solvent was removed under reduced pressure to afford the
crude product, which was purified by column chromatography eluting
with 40% EtOAc/hexane (v/v) to afford the diol 28 (305 mg, 0.62 mmol)
in 86% yield as a colorless liquid. Rf =0.3 (PE/EtOAc, 1:1); [a]2D5 =À18
(c=1, CHCl3); 1H NMR (300 MHz, CDCl3): d=7.24 (d, J=8.4 Hz, 4H),
6.86 (d, J=8.4 Hz, 4H), 5.61 (t, J=7.5 Hz, 2H), 4.81 (dd, J=9.8, 2.3 Hz,
2H), 4.69–4.51 (m, 4H), 4.41 (s, 4H), 4.06 (s, 4H), 3.80 (s, 6H), 3.32–3.16
(m, 4H), 2.27–2.08 (m, 4H), 2.11 (s, 6H), 2.04 (s, 6H), 1.86–1.55 (m, 8H),
1.52–1.29 (m, 10H), 1.12 (s, 6H), 0.90 ppm (d, J=6.0 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d=171.1, 170.9, 159.0, 144.2, 130.7, 129.1, 119.9, 113.7,
79.1, 79.0, 75.6, 75.5, 74.0, 72.6, 66.0, 60.4, 55.2, 38.2, 38.1, 34.2, 33.3, 33.2,
28.3, 25.1, 23.3, 23.2, 21.0, 20.9, 20.5, 20.4, 17.1, 17.0 ppm; IR: n˜ =3442,
2925, 2854, 1733, 1242, 1084, 1029 cmÀ1; ESI-MS: m/z: 515 [M+Na]+;
HRMS (ESI): m/z: calcd for C27H42O8Na: 515.2772; found: 515.2777
[M+Na]+. Note: The proton count has been doubled since the reported
data correspond to an equimolar epimeric mixture of isomers differing at
the methyl-bearing stereogenic center.
(Z)-4-(tert-Butyldimethylsilyloxy)-3-iodobut-2-enyl acetate (7): Et3N
(1.38 mL, 10 mmol) followed by acetic anhydride (0.56 mL, 5.5 mmol)
were added to a stirred solution of the iodo compound (1.6 g, 5 mmol)
and DMAP (61 mg, 0.5 mmol) in anhydrous dichloromethane (20 mL).
The reaction mixture was stirred for 1 h at RT and then water was added.
The clear layers were separated and the aqueous layer was extracted
twice with dichloromethane. The combined organic layers were washed
with water and brine, and dried over Na2SO4. The organic layer was con-
centrated under reduced pressure to afford the crude product, which was
(E)-2-{(6R,7S)-6-Acetoxy-7-[5-(4-methoxybenzyloxy)-4-methylpentyl]-7-
methyloxepan-3-ylidene}ethyl acetate (29): Triflic anhydride (0.13 mL,
0.74 mmol) was added to
a
solution of allylic alcohol 28 (305 mg,
8492
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 8487 – 8494

Total Synthesis of (+)-(2’S,3’R)-Zoapatanol
FULL PAPER
0.62 mmol) and 2,6-lutidine (0.14 mL, 1.24 mmol) in dichloromethane
(7 mL) at À788C. The reaction mixture was stirred at À788C for 6 h and
then slowly allowed to warm to À58C and stirred for a further 2 h. The
reaction was then quenched with pH 7 phosphate buffer (10 mL). The
mixture was extracted thrice with diethyl ether, and the combined ex-
tracts were washed with brine and dried over Na2SO4. The organic phase
was concentrated under reduced pressure to afford the crude product,
which was purified by column chromatography eluting with 20% EtOAc/
hexane (v/v) to afford the oxepane 29 (200 mg, 0.42 mmol) in 68% yield
as a colorless liquid. Rf =0.3 (PE/EtOAc, 3:1); [a]2D5 =À29 (c=1, CHCl3);
1H NMR (300 MHz, CDCl3): d=7.21 (d, J=8.4 Hz, 4H), 6.83 (d, J=
8.4 Hz, 4H), 5.38 (t, J=7.5 Hz, 2H), 4.75 (dd, J=9.1, 3.0 Hz, 2H), 4.65–
4.49 (m, 4H), 4.39 (s, 4H), 4.09 (s, 4H), 3.79 (s, 6H), 3.28–3.14 (m, 4H),
2.59–2.42 (m, 2H), 2.34–2.19 (m, 2H), 2.04 (s, 12H), 1.97–1.60 (m, 8H),
1.52–1.21 (m, 10H), 1.12 (s, 6H), 0.90 ppm (d, J=6.8 Hz, 6H); 13C NMR
(75 MHz, CDCl3): d=170.9, 170.1, 158.9, 145.0, 130.7, 129.0, 118.6, 113.6,
78.7, 77.9, 77.8, 75.5, 72.5, 68.6, 60.4, 55.1, 38.9, 34.0, 33.4, 33.3, 27.8, 23.8,
21.2, 20.9, 20.4, 20.3, 18.2, 18.1, 17.0 ppm; IR: n˜ =2928, 2855, 1733, 1249,
1086, 1045, 833 cmÀ1; ESI-MS: m/z: 499 [M+Na]+; HRMS (ESI): m/z:
calcd for C27H40O7Na: 499.2675; found: 515.2671 [M+Na]+. Note: The
proton count has been doubled since the reported data correspond to an
equimolar epimeric mixture of isomers differing at the methyl-bearing
stereogenic center.
droxylamine hydrochloride (25 mg, 0.26 mmol) and DMAP (5 mg,
0.035 mmol) were added to a solution of acid 31 (65 mg, 0.175 mmol) in
anhydrous CH2Cl2 (2 mL). After complete dissolution, the solution was
cooled to 08C and diisopropylethylamine (38 mL, 0.26 mmol) and EDCI
(50 mg, 0.26 mmol) were added. After stirring for 30 min at 08C and for
12 h at room temperature, the reaction mixture was washed with a satu-
rated aqueous solution of NaHCO3. The aqueous layer was extracted
with three portions of CH2Cl2 and the combined organic extracts were
washed with water, dried over Na2SO4, filtered, and concentrated under
reduced pressure to afford the crude product, which was purified by
column chromatography eluting with 30% EtOAc/hexane (v/v) to yield
the Weinreb amide 32 (58 mg, 0.14 mmol) in 82% yield as a colorless oil.
Rf =0.3 (PE/EtOAc, 3:2); [a]2D5 =+14 (c=1, CHCl3); 1H NMR
(300 MHz, CDCl3): d=5.37 (t, J=6.8 Hz, 2H), 4.79–4.68 (m, 2H), 4.66–
4.48 (m, 4H), 4.10 (dd, J=14.3, 7.5 Hz, 4H), 3.68 (s, 3H), 3.67 (s, 3H),
3.16 (s, 6H), 2.90–2.75 (m, 2H), 2.57–2.45 (m, 2H), 2.31–2.17 (m, 2H),
2.03 (s, 12H), 1.95–1.78 (m, 4H), 1.77–1.54 (m, 4H), 1.49–1.16 (m, 14H),
1.08 ppm (d, J=6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=177.7,
170.3, 169.6, 145.2, 118.7, 78.6, 77.7, 68.8, 68.7, 61.4, 60.3, 39.1, 35.3, 35.1,
34.3, 34.2, 32.4, 28.2, 24.0, 21.2, 21.1, 21.0, 20.9, 18.1, 17.8, 17.6 ppm; IR:
n˜ =2928, 2848, 1736, 1725, 1465, 1112, 1080, 740 cmÀ1; ESI-MS: m/z: 436
[M+Na]+; HRMS (ESI): m/z: calcd for C21H35O7NNa: 436.2432; found:
436.2438 [M+Na]+. Note: The proton count has been doubled since the
reported data correspond to an equimolar epimeric mixture of isomers
differing at the methyl-bearing stereogenic center.
(E)-2-[(6R,7S)-6-Acetoxy-7-(5-hydroxy-4-methylpentyl)-7-methyloxepan-
3-ylidene]ethyl acetate (30): DDQ (114 mg, 0.5 mmol) was added por-
tionwise over a period of 10 min to a solution of oxepane 29 (200 mg,
0.42 mmol) in a mixture of dichloromethane/water (19:1, 3 mL) cooled to
08C. The reaction mixture was stirred at the same temperature for
30 min and then diluted with further dichloromethane (10 mL). The pre-
cipitated solid was filtered off and the filtrate was washed successively
with saturated aqueous NaHCO3 solution, water, and brine, and dried
over Na2SO4. Evaporation of the solvent in vacuo afforded a crude prod-
uct, which was purified by column chromatography eluting with 30%
EtOAc/hexane (v/v) to yield the alcohol 30 (135 mg, 0.38 mmol) in 91%
9-[(2S,3R,E)-3-Hydroxy-6-(2-hydroxyethylidene)-2-methyloxepan-2-yl]-
2,6-dimethylnon-2-ene-5-one or (+)-(2’S,3’R)-zoapatanol (1): Lithium
(1.25 g) was added in small pieces to a solution of 3-methylbut-2-enyl
phenyl ether (1 g, 6.2 mmol) in dry diethyl ether/dry THF (5 mL of each)
under nitrogen, followed by three drops of methanol. At the first appear-
ance of a green coloration, the reaction mixture was cooled to 58C and
stirred for a further 2 h. The now orange solution was transferred to a
stirred solution of the Weinreb amide 32 (58 mg, 0.14 mmol) in dry dieth-
yl ether (4 mL) at À788C. The resulting mixture was stirred at the same
temperature for 30 min, and was then gradually allowed to warm to RT
over a period of 1 h. The reaction was then quenched by the slow addi-
tion of methanol (15 mL). Diethyl ether (40 mL) and water (40 mL) were
added, the phases were separated, and the aqueous phase was thrice ex-
tracted with diethyl ether. The combined extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated under reduced pres-
sure to afford the crude product, which was purified by column chroma-
tography eluting with 50% EtOAc/hexane (v/v) to afford zoapatanol 1
(33 mg, 0.1 mmol) in 72% yield as a colorless liquid. Rf =0.3 (PE/EtOAc,
2:3); [a]2D5 =+9.4 (c=1, CHCl3); (reported [a]2D0 =+12 (c=0.31,
CHCl3);[3] 1H NMR (400 MHz, CDCl3): d=5.45 (t, J=7.5 Hz, 2H), 5.28
(t, J=7.5 Hz, 2H), 4.17 (d, J=7.5 Hz, 4H), 4.13 (d, J=15.0 Hz, 2H), 4.08
(d, J=15.0 Hz, 2H), 3.54–3.48 (m, 2H), 3.12 (d, J=7.5 Hz, 4H), 2.57 (q,
J=7.5 Hz, 2H), 2.51–2.42 (m, 2H), 2.28–2.17 (m, 2H), 1.76 (s, 6H), 1.63
(s, 6H), 1.86–1.17 (m, 20H), 1.14 (s, 3H), 1.13 (s, 3H), 1.09 ppm (d, J=
7.5 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=213.3, 143.3, 135.5, 123.2,
115.9, 79.8, 76.4, 76.2, 69.2, 58.6, 45.8, 40.9, 40.8, 38.1, 38.0, 33.4, 31.6,
25.7, 23.4, 23.3, 21.0, 20.9, 18.4, 18.1, 16.6 ppm; IR: n˜ =3386, 2982, 1708,
1465, 1365, 1112, 1080, 740 cmÀ1; ESI-MS: m/z: 356 [M+NH4]+; HRMS
(ESI): m/z: calcd for C20H34O4Na: 361.2338; found: 361.2354 [M+Na]+.
Note: The proton count has been doubled since the reported data corre-
spond to an equimolar epimeric mixture of isomers differing at the
methyl-bearing stereogenic center.
yield as
a
viscous oil. Rf =0.3 (PE/EtOAc, 3:2); [a]2D5 =+12 (c=1,
CHCl3); 1H NMR (300 MHz, CDCl3): d=5.39 (t, J=6.8 Hz, 2H), 4.76
(dd, J=9.8, 3.0 Hz, 2H), 4.65–4.51 (m, 4H), 4.11 (s, 4H), 3.52–3.37 (m,
4H), 2.59–2.44 (m, 2H), 2.36–2.18 (m, 2H), 2.04 (s, 12H), 1.97–1.51 (m,
8H), 1.49–1.19 (m, 10H), 1.14 (s, 6H), 0.91 ppm (d, J=6.8 Hz, 6H);
13C NMR (75 MHz, CDCl3): d=171.0, 170.2, 145.0, 118.7, 78.8, 77.9, 68.7,
68.1, 60.5, 39.0, 35.6, 33.5, 27.9, 23.8, 21.2, 20.9, 20.3, 18.2, 18.1, 16.5 ppm;
IR: n˜ =3449, 2924, 2853, 1736, 1243, 1082, 1053, 773 cmÀ1; ESI-MS: m/z:
379 [M+Na]+; HRMS (ESI): m/z: calcd for C19H32O6Na: 379.2095;
found: 379.2096 [M+Na]+. Note: The proton count has been doubled
since the reported data correspond to an equimolar epimeric mixture of
isomers differing at the methyl-bearing stereogenic center.
5-[(2S,3R,E)-3-Acetoxy-6-(2-acetoxyethylidene)-2-methyloxepan-2-yl]-2-
methylpentanoic acid (31): TEMPO (12 mg, 0.076 mmol) followed by
PhIACHTUNGTRENNUNG(OAc)2 (245 mg, 0.76 mmol) were added to a solution of compound
30 (135 mg, 0.38 mmol) in CH3CN/H2O (1:1, 3.8 mL) at RT. The reaction
mixture was stirred at RT for 4 h. The solvent was then evaporated under
reduced pressure to afford the crude product, which was purified by
column chromatography eluting with 30% EtOAc/hexane (v/v) to yield
the acid 31 (130 mg, 0.35 mmol) in 93% yield as a colorless oil. Rf =0.3
(PE/EtOAc, 3:2); [a]D25 =+15 (c=1, CHCl3); 1H NMR (300 MHz,
CDCl3): d=5.39 (t, J=7.5 Hz, 2H), 4.75 (dd, J=9.8, 3.0 Hz, 2H), 4.65–
4.52 (m, 4H), 4.11 (s, 4H), 2.59–2.39 (m, 4H), 2.38–2.19 (m, 2H), 2.05 (s,
12H), 1.97–1.82 (m, 2H), 1.81–1.56 (m, 4H), 1.52–1.23 (m, 16H),
1.91 ppm (d, J=6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=182.2,
171.0, 170.3, 145.0, 118.7, 78.6, 77.9, 68.7, 60.5, 39.3, 39.1, 38.7, 38.6, 33.9,
33.8, 28.0, 23.9, 21.2, 20.9, 20.7, 20.6, 17.9, 17.8, 16.9, 16.8 ppm; IR: n˜ =
3442, 2926, 2855, 1740, 1736, 1243, 1058, 774 cmÀ1; ESI-MS: m/z: 393
[M+Na]+; HRMS (ESI): m/z: calcd for C19H31O7: 371.2066; found:
371.2069 [M+H]+. Note: The proton count has been doubled since the
reported data correspond to an equimolar epimeric mixture of isomers
differing at the methyl-bearing stereogenic center.
Acknowledgements
S.R. is thankful to Dr. J. M. Rao, Head, Org. Div. I, and Dr. J. S. Yadav,
Director, IICT, for continued support and encouragement. V.S.B. is
thankful to the CSIR, New Delhi, for a fellowship. Financial assistance
from the DST, New Delhi, is gratefully acknowledged. We thank Dr.
A. C. Kunwar for acquiring the NMR spectra and Dr. R. Srinivas for ac-
quiring the mass spectra.
(E)-2-((6R,7S)-6-Acetoxy-7-{5-[methoxy
ACHTUNGTRNE(NUNG methyl)amino]-4-methyl-5-oxo-
pentyl}-7-methyloxepan-3-ylidene)ethyl acetate (32): N,O-Dimethylhy-
Chem. Eur. J. 2011, 17, 8487 – 8494
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8493

S. Raghavan and V. Sudheer Babu
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[13] The Z configuration of allylic alcohol 9 was confirmed by 1H NMR
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[17] Attempted reductive elimination of the sulfone using Na/Hg afford-
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steps: i) selective monoprotection using TBS-Cl, NaH, THF; ii) hy-
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54.5% overall yield; see the Supporting Information.
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Received: December 20, 2010
Published online: June 10, 2011
8494
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 8487 – 8494