Tetrahydropyran synthesis by palladium(II)-catalysed hydroxycarbonylation of hexenols: Synthesis of (±)-diospongin A and (+)-civet cat compound

Article abstract of DOI:10.1016/j.tet.2011.04.045

A diastereoselective synthesis of 2,6-cis-tetrahydropyranyl acetic acids has been developed based on the palladium(II)-catalysed intramolecular hydroxycarbonylation of hexenols. This domino Pd-cyclisation/carbonylation/ hydroxylation of (2S)-hept-6-en-2-o

Full text of DOI:10.1016/j.tet.2011.04.045

Tetrahedron 67 (2011) 4980e4987
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Tetrahydropyran synthesis by palladium(II)-catalysed hydroxycarbonylation
of hexenols: synthesis of (ꢀ)-diospongin A and (þ)-civet cat compound
*
ꢀ
Ol’ga Karlubíkova, Matej Babjak, Tibor Gracza
ꢀ
Department of Organic Chemistry, Slovak University of Technology, Radlinskeho 9, SK-812 37 Bratislava, Slovakia
a r t i c l e i n f o
a b s t r a c t
Article history:
A diastereoselective synthesis of 2,6-cis-tetrahydropyranyl acetic acids has been developed based on the
palladium(II)-catalysed intramolecular hydroxycarbonylation of hexenols. This domino Pd-cyclisation/
carbonylation/hydroxylation of (2S)-hept-6-en-2-ol 15 and O-TBDPS protected 1-phenylhex-5-en-1,3-
diol 12, respectively, was used as a key step in the total syntheses of two natural products, civet cat (þ)-2-
[(2S,6S)-(6-methyltetrahydro-2H-pyran-2-yl)] acetic acid 1 and diospongin A 2. Moreover, an efficient
synthesis of 2 using a multi Pd-cyclisation/carbonylation/cross-coupling transformation has been
achieved.
Received 16 February 2011
Received in revised form 24 March 2011
Accepted 12 April 2011
Available online 20 April 2011
Keywords:
Palladium(II)-catalysis
Oxycarbonylation
Natural products
Civet cat compound
Diospongin
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
The synthesis and medicinal chemistry of substituted tetrahy-
dropyrans have attracted considerable attention due to the preva-
lence of the THP-ring backbone in natural products and biologically
active compounds.1 The cis-2,6-substituted tetrahydropyran ring
features in a large variety of biologically interesting natural prod-
ucts, such as (þ)-2-[(2S,6S)-(6-methyltetrahydro-2H-pyran-2-yl)]
acetic acid 1 and diospongin A 2 (Fig 1). The acetic acid derivative 1
was isolated by Maurer and co-workers from perianal glandular
pheromone secretion of the African civet cat (Vivierra civetta).2
Together with ambergris, castoreum and musk, it is one of the few
very expensive animal perfume materials.3 Diospongin A 2, along
with its 2-epimer diospongin B, have been found in rhizomes of
Dioscorea spongiosa.4 Both diastereomers have been showed to
exhibit an inhibitory activity against the bone resorption induced by
parathyroid hormone in a bone organ culture. Several synthetic-
strategies have already been employed for construction of 2,6-cis-
disubstituted THP-rings of diospongin A5 and the civet compound,6
including an intramolecular oxa-Michael addition,5c Prins reac-
Fig. 1. Structures of diospongin A and civet cat compound.
group7 and its application in natural product synthesis.8 In the
course of our long term program directed towards the exploitation
of Pd-catalysed oxidative carbonylation in domino reactions, we
have been interested in the transformation of homoallylic alcohols.
In this paper we report on the new intramolecular hydrox-
ycarbonylation of hex-5-enols and its application in the synthesis of
civet compound 1 and diospongin A 2.
tion,5d,e,6j
tandem
cross-metathesis/termal
SN20reaction,5h
2. Results and discussion
palladium-catalysed cyclisation of hept-2-ene-1,5,7-triols,5f and
Pd(II)-catalysed methoxycarbonylation.6a
The intramolecular Pd(II)-catalysed oxidative carbonylation is of
interest due to the facility of its incorporation into the multi-
transformation processes. Early examples of such domino reactions
include: Pd(II)-promoted cyclisationemethoxycarbonylation6a,9
and/or intramolecular alkoxylationelactonisation10 as described for
alkenols and 5-aminoalkenes providing heterocycles or fused
Recently we described the Pd(II)-catalysed oxycarbonylative
lactonisation of unsaturated polyols with an
a-allylic hydroxyl
* Corresponding author. Tel.: þ421 2 593 25 160; fax: þ421 2 529 68 560; e-mail
address: tibor.gracza@stuba.sk (T. Gracza).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.045

ꢀ
O. Karlubíkova et al. / Tetrahedron 67 (2011) 4980e4987
4981
bicyclic lactones. Intermediate acylpalladium complexes are trapped
bya second nucleophile, usually the solventor react intramolecularly
to give the product. Recently, oxidative formylation and ketonylation
of alkenyl amines and alkenyl alcohols were found,11 in which in-
termediate Pd-acyl species were transmetallated by a suitable or-
ganometallic reagent affording aldehydes or ketones (Scheme 1).
With this unexpected initial result, we decided to perform
screening of the substrate scope of the reaction and composition of
the catalytic mixture. Thus, we scrutinised the influence of the
nature of the O-protecting group, catalyst/re-oxidant and solvent
on the yield of 4 as well as the diastereoselectivity of hydroxy-
carbonylation. The results are summarised in Table 1.
In all successful cases (entries 1e4, 10), the predominant forma-
tion of 2,6-cis-THP-rings with high diastereoselectivity was ob-
served.12 All diastereomers of the unprotected 1-phenyl and
1-methyl diols 3, 5 were found to participate efficiently in this pro-
cess providing THP-ring containing acetic acids 4, 6 in good yields
(entries 1e4). The catalytic system based on PdCl2eCuCl2 in AcOH
worked well (entries 1e4, 10), while employment of Pd(OAc)2-BQ in
THF totally failed (entry 5). Interestingly, a solvent change from AcOH
to MeOH had an expressive effect on the course of the reaction. The
diols3aand9weretransformedtothelactones8and10, respectively,
instead to the expected sole tetrahydropyranyl methyl acetate6a,9 7
(entries 6e8). Moreover, using acetic acid as a solvent after pre-
liminarymigrationof thebenzylgroup, the3-O-benzylprotecteddiol
9 provided only the biscarbonylation product 11 (entry 9). Likewise,
the hexe-5-en-1,3-diols proved viable substrates for carbonylation,
leadingtolactones withincorporationof2 equivofcarbonmonoxide.
Scheme 1. Pd(II)-catalysed oxycarbonylations of unsaturated polyols.
As a part of our recent project dealing with the synthesis of
tetrahydropyran derivatives, we discovered the reaction of 1-phe-
nylhex-5-en-1,3-diol
3 with palladium(II) chloride (catalyst,
0.1 equiv), copper(II) chloride (oxidant, 3 equiv) and sodium ace-
tate (buffer, 3 equiv) in acetic acid under carbon monoxide at nor-
mal pressure and rt. This system, used in various Pd(II)-catalysed
reactions earlier,7,8,10 had been shown to be advantageous for car-
bonylative bicyclisation. Surprisingly, we obtained diastereomeric
2-tetrahydropyranyl acetic acids 4, products of hydroxy-
carbonylation (Scheme 2).
This constitutes a new mode of the carbonylation path of
a,g-diols
that has only been observed in the reaction of
a,b
-diols.7b The benzyl
protecting group having failed, O-silyl protection was tested. How-
ever, although the tert-butyldiphenylsilyl moiety was more stable for
deprotection, the yield of 13 dropped (entry 10).
As
a demonstration of the utility of the intramolecular
hydroxycarbonylation reaction for one-pot synthesis, we applied
the transformation to the synthesis of the civet cat compound 1.
The synthesis commenced with a regioselective ring-opening of the
Scheme 2. Pd(II)-catalysed hydroxycarbonylation of 1-phenylhex-5-en-1,3-diol.
Table 1
Pd(II)-catalysed oxycarbonylation of hex-5-enols
Entry
Substrate
Conditions
Product(s)
Yield % dr a
OH
O
OH
O
OH OH
PdCl2 (0.1 equiv), CuCl2 (3 equiv),
AcONa (3 equiv), AcOH, CO (balloon), rt, 22 h
O
1
63
53
>20:1
O
Ph
( )-4a
+
( )-4b
( )-3b (syn:anti, 1:1)
Ph
OH
Ph
OH
OH
OH
OH
OH OH
PdCl2 (0.1 equiv), CuCl2 (3 equiv),
AcONa (3 equiv), AcOH, CO (balloon), rt, 20 h
2
3
>20:1
>20:1
O
O
( )-6a
+
( )-6b
( )-5b (syn:anti, 1:1)
O
OH
O
OH
O
OH OH
O
PdCl2 (0.1 equiv), CuCl2 (3 equiv),
AcONa (3 equiv), AcOH, CO (balloon), rt, 12 h
( )-4a
88
65
Ph
Ph
OH
OH
( )-3a
OH
O
OH OH
O
PdCl2 (0.1 equiv), CuCl2 (3 equiv),
AcONa (3 equiv), AcOH, CO (balloon), rt, 12 h
4
>20:1
( )-4b
Ph
Ph
( )-3b
OH OH
Pd(OAc)2 (0.1 equiv), benzoquinone (2.5 equiv),
THF, CO (balloon), rt to rfx, 7 days
5
6
decomposition
d
d
Ph
( )-3a
OH
OH OH
O
O
PdCl2 (0.1 equiv), CuCl2 (3 equiv),
AcONa (3 equiv), MeOH, CO (balloon), rt, 72 h
O
26 32
>20:1 2:1
OH
O
Ph
( )-7
+
OMe
( )-8
( )-3a
Ph
O
OMe
(continued on next page)
Ph

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O. Karlubíkova et al. / Tetrahedron 67 (2011) 4980e4987
4982
Table 1 (continued )
Entry
Substrate
Conditions
Product(s)
Yield % dr a
O
OH OH
O
PdCl2 (0.1 equiv), CuCl2 (3 equiv),
OH
O
7
62
59
2:1
2:1
AcONa (3 equiv), MeOH, CO (balloon), 40 ꢂC, 10 h
OMe
OMe
OH
Ph
Ph
( )-8
( )-3a
Ph
Ph
Ph
O
OH OBn
O
PdCl2 (0.1 equiv), CuCl2 (3 equiv),
AcONa (3 equiv), MeOH, CO (balloon), rt, 3 days
OBn
OBn
O
8
9
( )-10
( )-9
O
OH OBn
O
PdCl2 (0.1 equiv), CuCl2 (3 equiv),
AcONa (3 equiv), AcOH, CO (balloon), rt, 3 days
O
73
40
>20:1
>20:1
Ph
Ph
( )-11
( )-9
OTBDPS
OH OTBDPS
PdCl2 (0.1 equiv), CuCl2 (3 equiv),
AcONa (3 equiv), AcOH, CO (balloon), rt, 12 h
10
O
( )-13
( )-12
Ph
O
OH
a
Dr of 2,6-cis to 2,6-trans-derivatives determined by 1H NMR analysis on crude reaction mixtures.
b Commercially available.
commercially available epoxide 14 to give (2S)-hept-6-en-2-ol 15,6g
with oxalyl chloride in toluene, followed by the Stille13 coupling
with Bu3PhSn in the presence of Pd(dba)2 (0.2 equiv) afforded 18 in
88% yield over two steps. Finally, deprotection of 18 using TBAF in
THF gave the target molecule 2 (83%).
In order to improve the efficiency of the diospongin synthesis, we
decided to explore the utility of the ketonylation methodology11 for
obtaining required tetrahydropyranylmethyl phenyl ketone. Both
partially protected and unprotected syn-diols 3a and 12, re-
spectively, were exposed to PdCl2(PhCN)2 (1.05 equiv) and Bu3PhSn
followed by Pd(II)-catalysed hydroxycarbonylation to produce tar-
25
get compound 1 in 70% overall yield (Scheme 3). Synthetic 1, [
a
a
]
]
D
31
25
þ21.9 (c 1.108, CHCl3), lit.,6g
[
a
]
D
þ20 (c 1.23, CHCl3), lit.,6h
[
D
þ26 (c 0.18, CHCl3), lit.,6k
[
a]
25 þ21 (c 0.3, CHCl3), showed physical
D
and spectroscopic data corresponding to the reported values.2,6
in
a
,
a
,
a
-trifluorotoluene under carbon monoxide at ꢁ10 ꢂC for 18 h
(Scheme 5). The domino reaction of 3a and 12 under Lambert’s re-
action conditions proceeded smoothly to provide the corresponding
2,6-cis-THP ketones 2 and 18 with excellent diastereoselectivity
(dr>20:1). In fact, utilisation of this process as a key step of the
synthesis rapidly enhanced the access to target molecule.
Scheme 3. Synthesis of the civet cat compound 1.
This new domino transformation was also applied to the syn-
thesis of dispongin A (Scheme 4). The key syn-diol 12 was obtained
from the known homoallylic alcohol 165c by a series of simple
protection and deprotection steps with high yields. The allylic al-
cohol function was first protected as a TBDPS ether followed by
selective cleavage of the TBDMS-protecting group with strong
acidic Dowex in methanol to afford 12 (76% over two steps).
Hydroxycarbonylation of partially protected diol 12 with carbon
monoxide in acetic acid using PdCl2 gave exclusively 2,6-cis-di-
astereomer 13 in moderate yield (entry 10, Table 1,). Next, the
carboxylic acid 13 was subjected to a two-step sequence in one-pot
to convert the carboxylic function to the ketone. Chlorination of 13
Scheme 5. Pd(II)-catalysed ketonylation of 1-phenylhex-5-en-1,3-diol.
3. Conclusions
In summary, we have explored the palladium(II)-catalysed
intramolecular hydroxycarbonylation of hexenols. The domino
Pd-cyclisation/carbonylation/hydroxylation
reaction provides
a new synthetic tool for the stereoselective synthesis of 2,6-cis-
tetrahydropyranyl acetic acids. The capability of such a domino
process has been demonstrated in the short and efficient syntheses
of two natural products, civet compound (þ)-2-[(2S,6S)-(6-meth-
yltetrahydro-2H-pyran-2-yl)] acetic acid 1 (two steps, 70% yield)
and diospongin A 2 (five steps, 22% from 16).
Next, Pd(II)-catalysed carbonylative ketonylation11 of hex-5-en-
1,3-diols has been explored and applied to a markedly shortened
and improved synthesis of diospongin A (56% br sm from 3a).
The method presents a practical entry to diverse THP-based
natural compounds and analogues. A special feature of these
methods is that no protection/deprotection of the hydroxyl groups
is necessary.
Scheme 4. Synthesis of diospongin A 2.

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O. Karlubíkova et al. / Tetrahedron 67 (2011) 4980e4987
4983
4. Experimental section
4.1. General methods
J3,4A¼J4A,5 7.1, J4A,4B 14.6 Hz, H-4A), 2.60 (m, 1H, H-4B), 2.89 (s, 3H,
SO2CH3), 4.74e4.84 (m, 2H, H-3, H-1), 5.11e5.20 (m, 2H, H-6),
5.70e5.87 (m, 1H, H-5), 7.20e7.38 (m, 5H, Ph); dC (75 MHz, CDCl3)
ꢁ5.1, ꢁ4.6 (all q, Si(CH3)2), 18.1 (s, C(CH3)3), 25.8 (q, C(CH3)3), 38.6
(q, SO2CH3), 38.9, 44.9 (all t, C-2, C-4), 71.6, 79.6 (all d, C-1, C-3),
119.1 (t, C-6), 126.1, 127.5, 128.3, 132.3 (all d, Ph, C-5), 143.8 (s, i-Ph).
HRMS (ESIþ) m/z found 402.2128 ([MþNH4]þ, C19H36NO4SSiþ re-
quires 402.2134).
Commercial reagents were used without further purification. All
solvents were distilled before use. Hexanes refer to the fraction
boiling at 60e65 ꢂC. Dowex 50 ionic resin was used in acidic Hþ
form. Flash column liquid chromatography (FLC) was performed on
silica gel Kieselgel 60 (40e63 mm, 230e400 mesh) using Buchi
SepacoreÒ preparative MPLC system and analytical thin-layer
chromatography (TLC) was performed on aluminium plates pre-
coated with either 0.2 mm (DC-Alufolien, Merck) or 0.25 mm sil-
ica gel 60 F254 (ALUGRAMÒ SIL G/UV254, MachereyeNagel). The
compounds were visualised by UV fluorescence and by dipping the
plates in an aqueous H2SO4 solution of cerium sulfate/ammonium
molybdate followed by charring with a heat-gun. Optical rotations
were measured with a JASCO P-2000 polarimeter and are given in
units of 10ꢁ1 deg cm2 gꢁ1. High resolution mass spectra (HRMS)
were recorded on a Q-Tof PremierTM mass spectrometer with
nanoACQUITY UPLCTM (Waters), and are accurate to ꢀ3 ppm. El-
emental analyses were run on FISONS EA1108 instrument. FTIR
spectra were obtained on a Nicolet 5700 spectrometer (Thermo
Electron) equipped with a Smart Orbit (diamond crystal ATR) ac-
cessory, using the reflectance technique (4000e400 cmꢁ1). 1H and
13C NMR spectra were recorded on either 300 (75) MHz Mercu-
ryPlus or 600 (150) MHz Unity Inova spectrometers from Varian.
4.3.2. Nucleophilic displacement of the mesyl group. A mixture of
Et3N (0.234 mL, 1.69 mmol) and benzoic acid (414 mg, 3.39 mmol)
were stirred in toluene (1 mL) at rt. After 30 min mesylate (217 mg,
0.564 mmol) was added and mixture was stirred at 80 ꢂC for 5 days.
After being cooled down to rt, the reaction mixture was diluted
with toluene (5 mL) and washed successively with aqueous HCl
solution (2 M, 2 mL), aqueous K2CO3 solution (10%, 3 mL) and brine
(10 mL). After the organic solution was dried over anhydrous
MgSO4, the solvent was removed by distillation in vacuo to give the
crude product, which was purified by flash chromatography to af-
ford corresponding benzoate (126 mg, 64%) as a colourless oil; Rf
0.9 (10% AcOEt/hexanes); nmax (ATR) 2953, 2928, 2856, 1716, 1693,
1643, 1451, 1269, 1096, 1068, 1026, 835, 776, 709, 700, 686 cmꢁ1
; dH
(300 MHz, CDCl3) ꢁ0.32, ꢁ0.08 (2ꢃ s, 6H, Si(CH3)2), 0.85 (s, 9H,
C(CH3)3), 1.97e2.03 (m, 2H, H-2), 2.45e2.53 (m, 2H, H-4), 4.77 (m,
1H, H-1), 5.02e5.10 (m, 2H, H-6), 5.31e5.41 (m, 1H, H-3), 5.73e5.89
(m,1H, H-5), 7.17e7.33 (m, 5H, Ph), 7.40e7.48 (m, 2H, Ph), 7.51e7.59
(m, 1H, Ph), 8.02e8.07 (m, 2H, Ph); dC (75 MHz, CDCl3) ꢁ5.3, ꢁ4.6
(all q, Si(CH3)2), 18.0 (s, C(CH3)3), 25.8 (q, C(CH3)3), 39.1, 45.2 (all t,
C-2, C-4), 71.5, 71.8 (all d, C-1, C-3), 118.0 (t, C-6), 125.8, 127.2, 128.2,
128.3, 129.4, 130.1, 132.7, 133.3 (all d, Ph, C-5), 130.8, 145.4 (all s, i-
Ph), 166.0 (s, CO). HRMS (ESIþ) m/z found 411.2387 ([MþH]þ,
C25H35O3Siþ requires 411.2355).
Chemical shifts (d) are quoted in parts per million and are refer-
enced to the tetramethylsilane (TMS) as internal standard.
4.2. ( )-(1S,3S)-1-Phenylhex-5-en-1,3-diol[( )-3a]
Dowex 50 (2 g) was added to a solution of TBDMS ether (ꢀ)-165c
(457 mg, 1.575 mmol) in ethanol (10 mL). The mixture was stirred
vigorously overnight; Dowex was then filtered off, washed with
EtOH and the washings concentrated. The crude product was pu-
rified by flash chromatography (50% AcOEt/hexanes) affording
unprotected diol (ꢀ)-3a as an off-white solid (280 mg, 93%); Rf 0.5
(50% AcOEt/hexanes); nmax (ATR) 3252, 2891, 1640, 1065, 1032,
4.3.3. (ꢀ)-(1S,3R)-1-Phenylhex-5-en-1,3-diol[(ꢀ)-3b]. To the solu-
tion of benzoate (60 mg, 0.146 mmol) in MeOH (5 mL) sodium
methoxide (24 mg, 0.44 mmol) was added. Mixture was stirred at rt
for 24 h, then 5 days at 40 ꢂC. After reaction was completed Dowex
50 (2 g) was added and mixture was stirred until complete con-
version (TLC control). When finished, reaction mixture was filtered
off, concentrated and the crude product purified by flash chroma-
tography to yield unprotected anti-diol 3b (19 mg, 68%) as a gel oil;
Rf 0.3 (40% AcOEt/hexanes); nmax (ATR) 3253, 3063, 2950, 2924,
1002, 916, 757, 702, 648, 588 cmꢁ1
; dH (300 MHz, CDCl3) 1.66e1.82
(m, 2H, H-2), 2.13e2.19 (m, 2H, H-4), 3.84e3.94 (m, 1H, H-3), 4.82
(dd, 1H, J1,2A 4.5, J1,2B 8.5 Hz, H-1), 4.99e5.03 (m, 1H, H-6A), 5.05 (m,
1H, H-6B), 5.64e5.79 (m, 1H, H-5), 7.15e7.30 (m, 5H, Ph); dC
(75 MHz, CDCl3) 42.4, 44.7 (all t, C-2, C-4), 71.5, 75.1 (all d, C-1, C-3),
118.3 (t, C-6), 125.6, 127.5, 128.4, (all d, Ph), 134.1 (d, C-5), 144.3þ(s, i-
Ph). HRMS (ESIþ) m/z found 215.1088 ([MþNa]þ, C12H16NaO2 re-
quires 215.1048).
1639, 1494, 1454, 1065, 1002, 909, 757, 702, 667, 605, 558 cmꢁ1
; dH
(300 MHz, CDCl3) 1.85e1.93 (m, 2H, H-2), 2.23e2.31 (m, 2H, H-4),
3.87e3.97 (m, 1H, H-3), 5.05 (dd, 1H, J1,2A 3.7, J1,2B 7.7 Hz, H-1),
5.08e5.16 (m, 2H, H-6), 5.70e5.85 (m, 1H, H-5), 7.22e7.38 (m, 5H,
Ph); dC (75 MHz, CDCl3) 41.9, 44.0 (all t, C-2, C-4), 68.0, 71.6 (all d, C-
1, C-3), 118.4 (t, C-6), 125.5, 125.7, 127.3, 128.4 (all d, Ph), 134.3 (d, C-
5), 144.4 (s, i-Ph). HRMS (ESIþ) m/z found 215.1094 ([MþNa]þ,
C12H16O2Naþ requires 215.1048).
4.3. Synthesis of ( )-(1S,3R)-1-phenylhex-5-en-1,3-diol
[( )-3b]
The title compound was obtained from 165c using Shi’s14 pro-
tocol for inversion of secondary alcohol in two steps.
4.4. Synthesis of ( )-(1S,3S)-3-Benzyloxy-1-phenylhex-5-en-1-
ol [( )-9]
4.3.1. Mesylation of (ꢀ)-16. To the solution of 16 (200 mg,
0.652 mmol) and pyridine (192
m
L, 2.39 mmol) in CH2Cl2 (6 mL)
The title compound was obtained in two steps, benzylation of
methanesulfonyl chloride (53
m
L, 0.685 mmol) was added dropwise
(ꢀ)-16 followed by removal of TBDMS-protecting group.
at 0 ꢂC. Reaction mixture was allowed to warm to rt and then
heated up to 40 ꢂC for 24 h. Mixture was concentrated, redissolved
in CH2Cl2 washed with water and with brine, dried over MgSO4 and
concentrated. After flash chromatography (5% EtOAc in hexanes)
the corresponding mesylate was obtained (217 mg, 86%) as
a slightly yellow oil; Rf 0.5 (10% AcOEt/hexanes); nmax (ATR) 2954,
2928, 2856, 1643, 1357, 1335, 1333, 1172, 1085, 902, 835, 776, 701,
4.4.1. Benzylation of (ꢀ)-16. A suspension of hexanes washed NaH
(60% in paraffin, 157 mg, 3.92 mmol, 1.2 equiv) in dry DMF (5 mL)
was cooled to ꢁ30 ꢂC and the solution of (ꢀ)-165c (1 g, 3.26 mmol)
in DMF (5 mL) was added dropwise over 10 min. The resulting
mixture was stirred for 15 min and benzyl bromide (470 mL,
3.92 mmol, 1.2 equiv) was added at once via syringe. The reaction
was left to stir at rt for 5 h, quenched with water (20 mL) and
extracted with ether (4ꢃ10 mL). Combined organic layers were
washed with water (2ꢃ10 mL) to remove DMF, dried over
526 cmꢁ1
;
dH (300 MHz, CDCl3) ꢁ0.19, 0.04 (2ꢃ s, 6H, Si(CH3)2),
0.88 (s, 9H, C(CH3)3), 2.01 (ddd, 1H, J2A,3¼J1,2A 6.2, J2A,2B 13.8 Hz, H-
2A), 2.23 (ddd, 1H, J2B,3¼J1,2B 6.4 J2A,2B 13.8 Hz, H-2B), 2.44 (ddd, 1H,

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O. Karlubíkova et al. / Tetrahedron 67 (2011) 4980e4987
4984
anhydrous MgSO4 and concentrated. The remainder was purified
by flash chromatography (silica gel, hexanes). Yield of benzyl-
protected diol was 1.2 g (93%), colourless oil; Rf 0.8, (10% EtOAc/
hexanes); nmax (ATR) 2936, 2860, 1639, 1453, 1087, 1061, 1020, 760,
4.6. ( )-(1S,3S)-3-(tert-Butydiphenylsilyloxy)-1-phenylhex-5-
en-1-ol [( )-12]
Dowex 50 (2 g) was added to a solution of silylated diol (ꢀ)-17
(824 mg, 1.512 mmol) in methanol (10 mL). After 10 h vigorous
stirring at rt the ionex was filtered off, washed with MeOH and
solution was concentrated. The crude product was purified by flash
chromatography (10% AcOEt/hexanes). The yield of (ꢀ)-17 as
a colourless oil: 510 mg (78%); Rf 0.5 (10% AcOEt/hexanes); nmax
(ATR) 3419, 2929, 2856, 1639, 1427, 1105, 1062, 1028, 998, 822, 738,
699 cmꢁ1
;
dH (300 MHz, CDCl3) 0.01, 0.03 (2ꢃ s, 6H, Si(CH3)2), 0.87
(s, 9H, C(CH3)3), 1.79 (ddd, 1H, J3,A 5.4, J4,5 6.7, JA,4 14.0 Hz, H-2A or
H-4A), 2.05 (ddd, 1H, J3,B 5.5, JB,5 8.2, JA,B 13.8 Hz, Hz, H-2B or H-4B),
2.08e2.18 (m, 1H, H-2A or H-4A) 2.22e2.34 (m, 1H, H-2B or H-4B),
3.82 (qd, 1H, J2B,3¼J3,4A¼J3,4B¼5.6, J2A,3 11.2 Hz, H-3), 4.21 (d, 1H, J
11.9 Hz, CH2Ph), 4.42 (d, 1H, J 11.7 Hz, CH2Ph), 4.44 (dd, 1H, J1,2A 2.8,
J1,2B 5.4 Hz, H-1), 4.93e5.04 (m, 2H, H-6), 5.71e5.87 (m, 1H, H-5)
7.22e7.40 (m, 10H, 2ꢃ Ph); dC (75 MHz, CDCl3) ꢁ4.5, ꢁ4.2 (all q,
Si(CH3)2), 18.1 (s, C(CH3)3), 25.0 (q, C(CH3)3), 41.4, 45.4 (all t, C-2, C-
4), 70.1 (t, CH2Ph), 69.0, 78.1 (all d, C-1, C-3), 116.8 (t, C-6), 126.9,
127.4, 127.6, 127.8, 128.3, 128.5 (all d, Ph), 135.2 (d, C-5), 138.5, 142.3
(all s, i-Ph). HRMS (ESIþ) m/z found 397.2590 ([MþH]þ, C25H37O2Siþ
requires 397.2563).
700, 611, 506 cmꢁ1
; dH (300 MHz, CDCl3) 1.09 (s, 9H, C(CH3)3),
1.85e1.93 (m, 2H, H-2), 2.08e2.22 (m, 2H, H-4), 4.00e4.11 (m, 1H,
H-3), 4.72e4.94 (m, 3H, H-1, H-6), 5.47e5.64 (m,1H, H-5) 7.22e7.35
(m, 5H, Ph), 7.35e7.50 (m, 6H, Ph), 7.70e7.80 (m, 4H, Ph); dC
(75 MHz, CDCl3) 19.3 (s, C(CH3)3), 27.0 (q, C(CH3)3), 41.8, 45.1 (all t,
C-2, C-4), 72.9, 73.1 (all d, C-1, C-3), 117.6 (t, C-6), 125.7, 127.3, 127.6,
127.7, 128.3, 129.7, 129.9, 133.9, 134.0, 135.9 (all d, Ph, C-5), 133.4,
134.8, 144.5 (all s, i-Ph). HRMS (ESIþ) m/z found 453.2271
([MþNa]þ, C28H34NaO2Siþ requires 453.2226).
4.4.2. (ꢀ)-(1S,3S)-3-Benzyloxy-1-phenylhex-5-en-1-ol [(ꢀ)-9]. For
removal of the TBDMS-group the benzylated diol (1.2 g, 3.03 mmol)
was dissolved in MeOH (20 mL), then Dowex 50 (4.5 g) was added
and the mixture was stirred vigorously at rt. After 12 h Dowex was
filtered off, washed with methanol and resulting solution was
concentrated. The crude product was purified by flash chroma-
tography (10% AcOEt/hexanes) to give (ꢀ)-9 as a colourless oil
(854 mg, 88%); Rf 0.3 (10% AcOEt/hexanes); nmax (ATR) 3445, 3063,
3029, 2912, 2865, 1640, 1494, 1454, 1086, 1063, 1025, 996, 759, 699,
4.7. (S)-Hept-6-ene-2-ol (15)
Following the procedure given by Ley and co-workers,6g a solu-
tion of (S)-propylene oxide (269 mg, 4.63 mmol) in dry THF (8 mL)
was cooled to ꢁ30 ꢂC and the catalytic amount of freshly prepared
Li2CuCl4 (0.463 mmol) in THF (5 mL) was added followed by
dropwise addition of the freshly prepared butenylmagnesium
bromide (6.945 mmol) in dry THF (15 mL). After 40 min the re-
action was quenched at ꢁ30 ꢂC by the addition of aqueous solution
of NH4Cl (6 mL). After warming up to rt the mixture was extracted
with Et2O (3ꢃ10 mL), combined organic layers were washed with
brine, dried over MgSO4 and concentrated. The crude product was
627, 568 cmꢁ1
; dH (300 MHz, CDCl3) 1.77 (ddd, 1H, J2A,3 2.0, J1,2A 3.8,
J2A,2B 14.6 Hz, H-2A), 1.97 (td, 1H, J2B,3¼J1,2B 9. 8, J2A,2B 14.6 Hz, H-
2B), 2.10e2.31 (m, 2H, H-4), 3.73 (s, 1H, OH), 3.87 (m, 1H, H-3), 4.25
(d, 1H, J 11.5 Hz, CH2Ph), 4.45 (d, 1H, J 11.5 Hz, CH2Ph), 4.60 (dd, 1H,
J1,2A 3.8, J1,2B 9.9 Hz, H-1), 5.01e5.10 (m, 2H, H-6), 5.72e5.88 (m, 1H,
H-5) 7.23e7.43 (m, 10H, 2ꢃ Ph); dC (75 MHz, CDCl3) 41.9, 44.5 (all t,
C-2, C-4), 70.5 (t, CH2Ph), 70.8, 82.1 (all d, C-1, C-3), 117.4 (t, C-6),
126.6, 127.8, 127.9, 128.0, 128.5, 128.6 (all d, Ph), 134.7 (d, C-5), 137.6,
141.4 (all s, i-Ph). HRMS (ESIþ) m/z found 305.1508 ([MþNa]þ,
C19H22NaO2þ requires 305.1517).
purified by distillation on Kugelrohr (20 mbar, 100 ꢂC). Product was
25
isolated as a colourless liquid in 88% yield (465 mg); [
a]
11.5
D
(c 1.43, CHCl3), lit.,6g
[a
]
31 þ6.5 (c 1.60, CHCl3). Spectral data were
D
in accordance with those previously reported.6g
4.8. General procedure for Pd(II)-catalysed hydroxycarbonyla
tion of hexenols
4.5. ( )-(1S,3S)-1-(tert-Butydimethylsilyloxy)-3-(tert-butydip
henylsilyloxy)-1-phenylhex-5-ene [( )-17]
A 25 mL flask equipped with side inlet with stopcock was
charged with AcONa (anhydrous, 3 equiv), CuCl2 (anhydrous,
3 equiv), and PdCl2 (0.1 equiv). The flask was evacuated; filled with
CO via balloon and solution of substrate (1.0 equiv) in glacial AcOH
(10e15 mL) was added. The mixture was vigorously stirred at rt
under CO atmosphere (balloon) until the colour of the mixture
changed from green to pale brown. The reaction mixturewas diluted
with EtOAc, filtered through a bed of Celite and concentrated. Crude
product was extracted between 1% water solution of NH3 and EtOAc.
Water layer was then acidified with aqueous HCl (5%) and released
free acid was extractedwith EtOAc(3ꢃ). Purificationbyflash column
chromatography on silica afforded the appropriate compound.
TBDPSCl (425 mL,1.63 mmol,1 equiv) was added dropwise to the
solution of (ꢀ)-16 (500 mg, 1.63 mmol) and imidazole (297 mg,
4.36 mmol, 2.7 equiv) in dry DMF (5 mL). The resulting mixture was
stirred for 6 h then water (10 mL) was added and the mixture
extracted with ether (4ꢃ10 mL). Combined organic layers were
washed with water (3ꢃ10 mL) to remove DMF, dried over anhy-
drous MgSO4 and concentrated. The product was purified by flash
chromatography (1% AcOEt/hexanes) and isolated as colourless oil
(862 mg, 97%); Rf 0.9 (10% AcOEt/hexanes); nmax (ATR) 2928, 2856,
1639, 1427, 1104, 1089, 1061, 835, 775, 699, 505 cmꢁ1
; dH (300 MHz,
CDCl3) ꢁ0.3, ꢁ0.1 (2ꢃ s, 6H, Si(CH3)2), 0.77, 1.07 (2ꢃ s, 18H, 2ꢃ
C(CH3)3), 1.78 (ddd, 1H, J1,2A 5.0, J2A,3 7.8, J2A,2B 13.8 Hz, H-2A), 1.97
(ddd, 1H, J2B,3 5.0, J1,2B 8.5, J2A,2B 13.7 Hz, H-2B), 2.19 (ddd, 1H, J3,4A
4.6, J4A,5 7.7, J4A,4B 14.0 Hz, H-4A), 2.34 (td, 1H, J3,4B¼J4B,5 6.0, J4A,4B
14.1 Hz, H-4B), 3.95 (qd, 1H, J2B,3¼J3,4A¼J3,4B 5.1, J2A,3 7.9 Hz, H-3),
4.68 (dd, 1H, J1,2A 4.9, J1,2B 8.5 Hz, H-1), 4.97 (br d, 1H, J5,6A 17.0 Hz,
H-6A), 5.00 (br d, 1H, J5,6B 10.0 Hz, H-6B), 5.79 (dddd, 1H, J4B,5 6.5,
J4A,5 7.7, J5,6B 10.3, J5,6A 16.8 Hz, H-5), 7.07e7.12 (m, 2H, Ph),
7.17e7.27 (m, 3H, Ph), 7.32e7.45 (m, 6H, Ph), 7.65e7.71 (m, 4H, Ph);
dC (75 MHz, CDCl3) ꢁ5.0, ꢁ4.5 (all q, Si(CH3)2), 18.0, 19.4 (all s, 2ꢃ
C(CH3)3), 25.8, 27.1 (all q, 2ꢃ C(CH3)3), 40.5, 46.9 (all t, C-2, C-4),
70.0, 72.4 (all d, C-1, C-3), 117.0 (t, C-6), 126.0, 126.9, 127.4, 127.5,
127.9, 129.4 (all d, Ph, C-5), 134.4, 134.5 (all s, i-Ph), 134.7, 135.9 (all
d, Ph, C-5), 145.3 (s, i-Ph). HRMS (ESIþ) m/z found 545.3322
([MþH]þ, C34H49O2Si2þ requires 545.3271).
4.8.1. (ꢀ)-(20R,40S,60S)-(40-Hydroxy-60-phenyltetrahydropyran-20-
yl)-acetic acid [(ꢀ)-4a]. Following the general procedure the mix-
ture of AcONa (384 mg, 4.68 mmol), CuCl2 (630 mg, 4.68 mmol),
PdCl2 (30 mg, 0.156 mmol) and syn-diol (ꢀ)-3a (300 mg,
1.56 mmol) in AcOH (15 mL) was stirred at rt for 12 h under CO
atmosphere. Workup in the described manner gave residue that
was purified by flash column chromatography (66% AcOEt/hex-
anes) to yield title compound (ꢀ)-4a (320 mg, 88%) as a viscous oil;
Rf 0.3 (50% AcOEt/hexanes); nmax (ATR) 3392, 3060, 3031, 2918,
1706, 1378, 1213, 1190, 1166, 1082, 1054, 979, 753, 697, 531 cmꢁ1
;
dH
0
0
0
0
0
0
(600 MHz, acetone-d6) 1.58 (dt, 1H, J3A ,4 5.0, J3A ,3B ¼J2 ,3A 13.5 Hz,
H-3A0), 1.65 (ddd, 1H, J4 5A 5.0, J5 A,6 11, J5A ,5B 13.5 Hz, H-5A0), 1.84
0
0
0
0
0
0
(br dd, 1H, J3B ,4 2.0, J3A ,3B 13.5 Hz, H-3B0), 1.92 (br dd, 1H, J4 5B 1.9,
0
0
0
0
0
0

ꢀ
O. Karlubíkova et al. / Tetrahedron 67 (2011) 4980e4987
4985
J5A ,5B 13.3 Hz, H-5B0), 2.47 (dd, 1H, J2A,2 5.0, J2A,2B 15.3 Hz, H-2A),
1065, 1026, 1012, 699, 541 cmꢁ1
; dH (300 MHz, CDCl3) 1.81 (ddd, 1H,
0
0
0
2.54 (dd, 1H, J2B,2 8.0, J2A,2B 15.3 Hz, H-2B), 4.28 (m, 1H, H-40), 4.47
J1A ,5 5.7, J1A ,2 7.5, J1A ,1B 13.6 Hz, H-1A00), 1.91 (ddd, 1H, J5 ,4A 4.4,
0
00
0
00 00
00
00
0
0
(m, 1H, H-20), 4.91 (br d, 1H, J5A ,6 11 Hz, H-60), 7.21 (t, 1H, J 7.3 Hz,
Ph), 7.29 (t, 2H, J 7.5 Hz, Ph), 7.34 (d, 2H, J 7.4 Hz, Ph); dC (150 MHz,
acetone-d6) 39.4 (t, C-30), 42.2 (t, C-50), 42.7 (t, C-2), 65.3 (d, C-20),
70.9 (d, C-40), 75.3 (d, C-60), 127.5, 128.6, 129.8 (all d, Ph), 144.3 (s, i-
Ph), 173.8 (s, C-1). HRMS m/z calcd for C13H17O4þ: 237.1127, found
237.1169 [MþH]þ.
J4A ,3 9.1, J4A ,4B 13.1 Hz, H-4A0), 2.10 (ddd, 1H, J5 4B 3.4, J4B ,3 9.6,
0
0
0
0
0
0
0
0
0
0
J4A ,4B 12.9 Hz, H-4B0), 2.28 (ddd, 1H, J1B ,2 6.8, J1B ,5 8.2, J1A ,1B
0
0
00 00
00
0
00
00
14.2 Hz, H-1B00), 2.48 (dd, 1H, Hz, J2A,3 8.5, J2A,2B 17.4 Hz, H-2A), 2.75
0
0
0
(dd, 1H, J2B,3 4.2, J2A,2B 17.4 Hz, H-2B), 2.92 (dddd, 1H, J2B,3 4.2,
J2A,3 ¼J4A ,3 ¼J4B ,3 9.3 Hz, H-30), 4.13 (d, 1H, J 12.9 Hz, CH2Ph),
0
0
0
0
0
4.28e4.38 (m, 2H, H-50, CH2Ph), 4.42 (t,1H, J1A ,2 ¼J1B ,2 ¼7.1 Hz, H-
200) 7.10e7.55 (m, 10H, Ph); dC (75 MHz, CDCl3) 32.6 (t, C-40), 34.5 (t,
C-2), 35.1 (d, C-30), 43.3 (t, C-100), 70.4 (t, CH2Ph), 75.7 (d, C-50), 77.8
(d, C-200), 127.0, 127.7, 127.8, 128.2, 128.4, 128.7 (all d, Ph), 137.9,
140.5 ( all s, i-Ph), 176.2, 177.8 (all s, 2ꢃ CO). HRMS m/z calcd for
C21H26NO5þ: 372.1811, found 372.1842 [MþNH4]þ.
00 00
00 00
4.8.2. (ꢀ)-(20R,40R,60S)-(40-Hydroxy-60-phenyltetrahydropyran-20-
yl)-acetic acid [(ꢀ)-4b]. According to general procedure: mixture of
anti-diol (ꢀ)-3b (100 mg, 0.52 mmol), AcONa (128 mg, 1.56 mmol),
CuCl2 (210 mg, 1.56 mmol), and PdCl2 (10 mg, 0.052 mmol) in AcOH
(5 mL); reaction at rt for 12 h; after flash column chromatography
(10% MeOH/CH2Cl2) a viscous oil was obtained. The yield of (ꢀ)-4b
(80 mg, 65%); Rf 0.7 (10% MeOH/CH2Cl2); nmax (ATR) 3350, 2921,
4.8.5. (ꢀ)-(20R,40S,60S)-(40-tert-Butyldiphenylsilyloxy-60-phenyl-
tetrahydropyran-20-yl)-acetic acid [(ꢀ)-13]. According to general
procedure: mixture of diol (ꢀ)-12 (223 mg, 0.52 mmol), AcONa
(128 mg, 1.56 mmol), CuCl2 (210 mg, 1.56 mmol) and PdCl2 (10 mg,
0.052 mmol) in AcOH (5 mL); reaction at rt for 12 h; after flash
column chromatography (10% AcOEt/hexanes) a viscous oil was
obtained. Yield of (ꢀ)-13 (101 mg, 40%); Rf 0.2 (10% AcOEt/hex-
anes); nmax (ATR) 3068, 2928, 2855, 1684, 1597, 1427, 1104, 1058,
1709, 1372, 1240, 1184, 1151, 1043, 989, 756, 698, 605 cmꢁ1
; dH
0
0
0
0
0
(300 MHz, CDCl3) 1.33 (t,1H, J3A ,3B ¼J2 ,3A 11.4 Hz, H-3A ),1.48 (t,1H,
J5A ,5B ¼J5A ,6 11.5 Hz, H-5A0), 2.05e2.23 (m, 2H, H-3B, H-5B), 2.55
0
0
0
0
0
0
(dd, 1H, J2A,2 5.7, J2A,2B 15.7 H-2A), 2.73 (dd, 1H, J2B,2 7.2, J2A,2B
15.8 Hz, H-2B), 3.88e4.03 (m, 2H, H-20, H-40), 4.39 (dd,1H, J5B ,6 , 1.9,
0
0
0
0
0
J5A ,6 11.5 Hz, H-6 ), 7.24e7.35 (m, 5H, Ph); dC (75 MHz, CDCl3) 40.1 (t,
C-30), 40.7 (t, C-50), 42.2 (t, C-2), 67.9, 72.1 (all d, C-20, C-40), 77.6 (d, C-
60),125.8,127.7,128.4 (all d, Ph),141.3 (s, i-Ph),175.5 (C-1). HRMS m/z
calcd for C13H20NO4þ: 254.1392, found 254.1422 [MþNH4]þ.
1026, 998, 741, 698, 505 cmꢁ1
;
dH (300 MHz,0 CDCl3) 1.13 (s, 9H,
0
0
0
0
0
0
C(CH3)3), 1.44 (t, 1H, J2 3A ¼J3A ,3B 12.5 Hz, H-3A ), 1.56 (dd, 1H, J5 A,6
10.7, J5A ,5B 13.5 Hz, H-5A0), 1.74 (br d, 1H, J3A ,3B 13.2 Hz, H-3B0),
0
0
0
0
1.84 (br d, 1H, J5A ,5B 13.5 Hz, H-5B0), 2.52 (dd, 1H, J2A,2 5.4, J2A,2B
0
0
0
4.8.3. (ꢀ)-(20R,40S,60S)-(40-Hydroxy-60-methyl-tetrahydropyran-20-
yl)-acetic acid [(ꢀ)-6a] and (ꢀ)-(20R,40R,60S)-(40-hydroxy-60-methyl-
tetrahydropyran-20-yl)-acetic acid [(ꢀ)-6b]. Following the general
procedure; the mixture of diasteromers (syn/anti 1:1) (ꢀ)-5
(200 mg, 1.536 mmol), PdCl2 (27 mg, 0.154 mmol), CuCl2 (619 mg,
4.609 mmol), AcONa (378 mg, 4.609 mmol) in AcOH (8 mL); re-
action at rt for 20 h; after flash chromatography (silica gel, elution
with 50% AcOEt/hexanes); fraction 2 (Rf 0.1) gave analytically pure 6
(140 mg, 53%, colourless oil). The product consisted of a 2:1 mixture
of 6a/6b as determined by 1H NMR; [Found: C, 55.24; H, 8.08.
C8H14O4 requires C, 55.16; H, 8.0]; nmax (ATR) 3402, 3090, 2972,
2936, 2642,1717,1419,1381,1242,1201,1174,1109,1078,1059,1006,
15.7 Hz, H-2A), 2.68 (dd, 1H, J2B,2 7.5, J2A,2B 15.7 Hz, H-2B), 4.29 (br
0
s, 1H, H-40), 4.62 (m, 1H, H-20), 5.1 (br d, 1H, J5A ,6 10.7 Hz, H-60),
7.20e7.72 (m,15H, 3ꢃ Ph); dC (75 MHz, CDCl3) 19.3 (s, C(CH3)3), 27.0
(q, C(CH3)3), 38.0 (t, C-30), 40.5 (t, C-50), 41.0 (t, C-2), 65.8 (d, C-40),
69.0 (d, C-20), 74.2 (d, C-60), 125.7, 127.3, 127.7, 128.3, 129.8, 135.7 (all
d, Ph), 133.7, 133.8, 142.3 (all s, i-Ph), 175.9 (s, C-1). HRMS m/z calcd
for C29H35O4Siþ: 475.2305, found 475.2344 [MþH]þ.
0
0
4.8.6. (þ)-2-[(2S,6S)-(6-Methyltetrahydro-2H-pyran-2-yl)]
acetic
acid (civet cat compound) (1). Following general procedure the
mixture of AcONa (321 mg, 3.91 mmol), CuCl2 (526 mg,
3.91 mmol), PdCl2 (23 mg, 0.13 mmol) and alcohol 15 (149 mg,
1.3 mmol) in AcOH (10 mL) was stirred at rt for 12 h under CO at-
mosphere. Workup in the usual manner gave residue that was
989 cmꢁ1
; dH (600 MHz, CDCl3) for 6a (major isomer): 1.19 (d, 3H,
0
0
0
0
0
0
0
J6 ,Me 6.2 Hz, Me), 1.47 (ddd, 1H, J3A ,4 2.9, J2 ,3A 11.5, J3A ,3B 14.2 Hz,
H-3A0), 1.52 (ddd, 1H, J4 ,5A 2.9, J5A ,6 11.5, J5A ,5B 14.2 Hz, H-5A0),
purified by flash column chromatography (50% AcOEt/hexanes) to
0
0
0
0
0
0
25
0
0
0
0
0
0
0
0
0
1.70 (dddd, 1H, J2 ,3B ¼J3B ,5B 2.1, J3B ,4 3.1, J3A ,3B 14.1 Hz, H-3B ), 1.75
yield title compound 1 (164 mg, 80%) as a yellow viscous oil; [
a
a
]
]
D
25
(dddd, 1H, J4 ,5B ¼J5B ,6 2.1, J4 ,5B 3.1, J5A ,5B 14.1 Hz, H-5B0), 2.47 (dd,
þ21.9 (c 1.108, CHCl3), lit.,6g
[
a
]
31 þ20 (c 1.23, CHCl3), lit.,6h
[
0
0
0
0
0
0
0
0
D
D
25
1H, J2A,2 5.4, J2A,2B 15.7 Hz, H-2A), 2.58 (dd, 1H, J2B,2 7.6, J2A,2B
þ26 (c 0.18, CHCl3), lit.,6k
[
a
]
þ21 (c 0.3, CHCl3); dH (300 MHz,
0
0
D
0
0
0
0
0
0
15.7 Hz, H-2B), 4.01 (ddq, 1H, J5B ,6 2.0, JMe,6 6.2, J5A ,6 11.6 Hz H-6 ),
CDCl3) 1.19 (d, 3H, J 6.2 Hz, CH3), 1.22e1.35 (m, 2H), 1.46e1.70 (m,
3H), 1.79e1.89 (m, 1H), 2.49 (ddd, 1H, J 1.0, J 5.1, J 15.7 Hz, H-2A),
2.58 (dd, 1H, J 7.6, J 15.7 Hz, H-2B), 3.51e3.58 (m, 1H), 3.73e3.83
(m, 1H). Physical and spectroscopic data were corresponding to the
reported values.2,6
4.25 (dddd, 1H, J2 ,3B 2.0, J2A,2 5.4, J2B,2 7.6, J2 ,3A 11.8 Hz, H-20), 4.27
0
0
0
0
0
(m, 1H, H-40); dH for 6b (minor isomer): 1.23 (d, 3H, J6 ,Me 6.2 Hz,
0
Me), 1.14e1.44 (m, 2H, H-3A0, H-5A0), 1.96 (dddd, 1H, J2 ,3B ¼J3B ,5B
0
0
0
0
2.0, J3B ,4 4.7, J3A ,3B 12.5 Hz, H-3B0), 2.03 (dddd, 1H, J3B ,5B ¼J5B ,6
0
0
0
0
0
0
0
0
2.0, J4 ,5B 4.7, J5A ,5B 12.5 Hz, H-5B0), 2.31 (dd, 1H, J2A,2 5.4, J2A,2B
0
0
0
0
0
0
15.7 Hz, H-2A), 2.65 (dd, 1H, J2B,2 7.6, J2A,2B 15.7 Hz, H-2B), 3.53
4.9. General procedure for Pd(II)-catalysed methoxycarbonyla
tion of hexenols
(ddq, 1H, J5B ,6 2.0, JMe,6 6.2, J5A ,6 11.0 Hz H-60), 3.78 (dddd, 1H,
0
0
0
0
0
J2 ,3B 2.0, J2A,2 5.4, J2B,2 7.6, J2 ,3A 11.4 Hz, H-20), 3.85 (dddd, 1H,
0
0
0
0
0
0
J3B ,4 ¼J4 ,5B 4.7, J3A ,4 ¼J4 ,5A 11.0 Hz, H-40); dC (150 MHz, CDCl3,
mixture of 6a/6b) 21.6, 21.7 (all q, Me), 37.7, 39.6, 40.4, 40.7, 40.8,
42.3 (all t, C-30, C-50, C-2), 64.3, 67.6, 68.2, 68.4, 71.7, 72.1 (all d, C-20,
C-40, C-60), 174.7, 174.9 (all s, C-1).
Using the Semmelhack protocol6a for methoxycarbonylation
a 25 mL flask with stopcock equipped side inlet was charged with
PdCl2 (10 mg, 0.052 mmol, 0.1 equiv), CuCl2 (210 mg, 1.56 mmol,
3 equiv) and AcONa (128 mg, 1.56 mmol, 3 equiv). Diol (ꢀ)-3a
(100 mg, 0.52 mmol) in MeOH (5 mL) was added and the flask was
purged with CO from a balloon. The mixture was vigorously stirred
under CO atmosphere overnight. Reaction mixture was diluted
with EtOAc, filtered through a bed of Celite and concentrated. The
residue was purified by chromatography (10% AcOEt/hexanes).
Fraction 1, THP-derivative (ꢀ)-7 (33 mg, 26%, a viscous oil); Rf 0.6
(10% AcOEt/hexanes). Fraction 2, a diastereomeric mixture of lac-
tones (ꢀ)-8 in the ratio 2:1 (46 mg, 32%) as a colourless oil; Rf 0.1
(10% AcOEt/hexanes).
0
0
0
0
0
0
0
0
4.8.4. [50-(200-Benzyloxy-200-phenylethyl)-20-oxo-tetrahydrofuran-30-
yl]-acetic acid [(ꢀ)-11]. The general procedure was followed: ben-
zylated diol (ꢀ)-9 (147 mg, 0.52 mmol), AcONa (128 mg,
1.56 mmol), CuCl2 (210 mg, 1.56 mmol), PdCl2 (10 mg, 0.052 mmol)
in AcOH (5 mL); reaction at rt for 3 days; after purification by flash
chromatography (30% AcOEt/hexanes) a single diastereomer (ꢀ)-11
was obtained (131 mg, 72%) as a viscous oil; Rf 0.2 (50% AcOEt/
hexanes); nmax (ATR) 3271, 2918, 2850, 1776, 1738, 1713, 1454, 1088,

ꢀ
O. Karlubíkova et al. / Tetrahedron 67 (2011) 4980e4987
4986
4.9.1. (ꢀ)-(20R,40S,60S)-Methyl (40-hydroxy-60-phenyltetrahydropyr-
an-20-yl)-acetate [(ꢀ)-7]. Data of (ꢀ)-7; nmax (ATR) 3435, 3030,
4.11. Diospongin A [( )-2]
2949, 2918, 1732, 1437, 1192, 1055, 754, 699, 532 cmꢁ1
;
dH
TBAFꢃ3H2O (65 mg, 0.206 mmol) was added to the solution
of (ꢀ)-18 (55 mg, 0.103 mmol) in THF (2 mL). The mixture was
stirred at 40 ꢂC for 5 days, then concentrated and after chro-
matography diospongin (ꢀ)-2 was isolated (25 mg, 83%); dH
(300 MHz, CDCl3) 1.56e1.75 (m, 2H), 1.89 (br d, 2H, J 13.7 Hz),
0
0
0
0
0
0
(600 MHz, CDCl3) 1.65 (dt, 1H, J3A ,4 2.5, J2 ,3A ¼J3A ,3B 12.8 Hz, H-
3A0), 1.65 (ddd, 1H, J4 ,5A 2.5, J5 A,6 11.7, J5A ,5B 14.0 Hz, H-5A0), 1.83
0
0
0
0
0
0
(br dd, 1H, J2 ,3B 2.0, J3A ,3B 13.8 Hz, H-3B0), 1.93 (br dd, 1H, J5B ,6
0
0
0
0
0
0
2.0, J5A ,5B 14.0 Hz, H-5B0), 2.48 (dd, 1H, J2A,2 6.1, J2A,2B 15.8 Hz, H-
0
0
0
0
0
0
2A), 2.67 (dd, 1H, J2B,2 7.1, J2A,2B 15.2 Hz, H-2B), 3.68 (s, 3H, Me),
3.00 (dd, 1H, J2A,2 6.9, J2A,2B 16.0 Hz, H-2A), 3.35 (dd, 1H, J2B,2
4.36 (br s, 1H, H-40), 4.45 (m, 1H, H-20), 4.91 (dd, 1H, J5B ,6 1.5, J5A 6
0 0
5.8, J2A,2B 16.0 Hz, H-2B), 4.28e4.33 (m, 1H), 4.52e4.63 (m, 1H),
4.86 (dd, 1H, J 1.9, 11.7 Hz), 7.12e7.96 (m, 10H, Ph). The 13C NMR
and IR spectral data were in good agreement with those
reported.4,5
0
0
11.7 Hz, H-60), 7.23e7.40 (m, 5H, Ph); dC (150 MHz, CDCl3) 37.9 (t,
C-30), 40.0 (t, C-50), 41.1 (t, C-2), 51.7 (q, Me), 64.6 (d, C-40), 68.8 (d,
C-20), 73.5 (d, C-60), 125.8, 127.3, 128.3 (all d, Ph), 142.6 (s, i-Ph),
171.6 (s, C-1). HRMS m/z calcd for C14H19O4þ: 251.1283, found
251.1307 [MþH]þ.
4.12. General procedure for Pd(II)-catalysed ketonylation of
hexenols
4.9.2. Methyl [50-(200-hydroxy-200-phenylethyl)-20-oxo-tetrahydrofu-
ran-30-yl]-acetate [(ꢀ)-8]. Data of (ꢀ)-8; nmax (ATR) 3435, 3030,
2952, 1763,1732, 1437, 1372, 1266, 1196, 1169, 1026, 993, 761, 702,
Following the procedure given by Lambert and co-workers,11
a round-bottom flask with a magnetic stir bar was charged with
PdCl2(PhCN)2 (1.05 equiv) and flame-dried, ground
560 cmꢁ1
; dH (300 MHz, CDCl3) 1.87e2.32 (m, 4H), 2.45e2.60 (m,
ꢁ
4
A
MS
1H), 2.62 (br s, 1H, OH), 2.73 (dd, 1H, J 4.2, J 17.0 Hz), 2.82e2.90
(m, 1H, minor) 2.97 (ddd, 1H, J 4.2, 9.2, 18.2 Hz, major), 3.61 (s,
3H, Me), 4.28 (ddd, 1H, J 5.2, 8.2, 10.4 Hz, H-50 minor), 4.36e4.46
(m, 1H, H-50 major), 4.75e4.86 (m, 1H, H-200), 7.16e7.36 (m, 5H,
Ph); dC (150 MHz, CDCl3) 32.9 (major), 34.0 (minor), 34.5 (major),
35.0 (all t, C-2, C-40 minor), 35.2 (major), 37.1 (all d, C-30 minor),
44.2 (t, C-100), 51.9 (minor), 52.0 (all q, Me major), 71.4, 76.3
(major), 76.7 (all d, C-200, C-50 minor), 125.9 (minor), 126.0 (ma-
jor), 127.9, 128.6 (all d, Ph), 143.2 (major), 143.3 (all s, i-Ph minor),
(238 mg). The flask was evacuated and backfilled with CO via bal-
loon (3ꢃ) and PhCF3 (4 mL) was added. The mixture was cooled to
ꢁ10 ꢂC in a salteice bath and stirred in the CO atmosphere (bal-
loon) for 30 min. A solution of a hexenol (1.0 equiv) in PhCF3 (2 mL)
was added. The mixture was stirred for 30 min tributylphenyl-
stanane was then added at ꢁ10 ꢂC and the mixture was stirred at
this temperature overnight, then filtered through a plug of Celite
and concentrated in vacuo. The product was purified by flash
chromatography (AcOEt/hexanes).
171.5 (major), 171.6 (minor), 177.3 (minor), 177.8 (all s, 2ꢃ CO,
þ
major). HRMS m/z calcd for C15H22NO5
296.1517 [MþNH4]þ.
: 296.1498, found
4.12.1. Compound [(ꢀ)-18]. Compound (ꢀ)-18 (74 mg, 39%, 52% br
sm) was obtained from (ꢀ)-12 (200 mg, 0.464 mmol) as a col-
ourless oil; Rf 0.7 (10% AcOEt/hexanes); nmax (ATR) 3062, 2918,
1720, 1688, 1595, 1449, 1283, 1197, 1058, 1000, 978, 749, 700, 689,
4.9.3. Methyl [50-(200-benzyloxy-200-phenylethyl)-20-oxo-tetrahydro-
furan-30-yl]-acetate [(ꢀ)-10]. According to general procedure:
mixture of diol (ꢀ)-9 (147 mg, 0.52 mmol), AcONa (128 mg,
1.56 mmol), CuCl2 (210 mg, 1.56 mmol) and PdCl2 (10 mg,
0.052 mmol) in MeOH (5 mL); reaction at rt for 3 days; after flash
column chromatography (10% AcOEt/hexanes) a viscous oil was
obtained. Yield of (ꢀ)-10 (112 mg, 59%); Rf 0.1 (10% AcOEt/hexanes);
nmax (ATR) 3030, 2951, 2866, 1768, 1735, 1454, 1436, 1257, 1198,
530 cmꢁ1 dH (300 MHz, CDCl3) 0.9e1.9 (m, 13H, C(CH3)3, H-30, H-
;
50), 3.00 (dd, 1H, J2A,2 6.6, J2A,2B 15.4 Hz, H-2A), 3.39 (dd, 1H, J2B,2
0
0
6.2, J2A,2B 15.4 Hz, H-2B), 4.29 (br s, 1H, H-40), 4.82 (dddd, 1H,
J2 ,3B 1.1, J2A,2 ¼J2B,2 6.4, J2 ,3A , 11.2 Hz, H-20), 5.08 (br d, 1H, J5A ,6
0
0
0
0
0
0
0
0
11.1 Hz, H-60), 7.25e7.60 (m, 14H, Ph) 7.65e7.74 (m, 4H, Ph),
7.97e8.02 (m, 2H, Ph); dC (75 MHz, CDCl3) 19.3 (s, C(CH3)3), 27.0
(q, C(CH3)3), 38.5, 40.7, 45.3 (all t, C-30, C-50, C-2), 66.1, 69.6, 73.9
(all d, C-40, C-20, C-60), 125.7, 127.1, 127.6, 128.2, 128.4, 128.5, 129.7,
132.9, 135.7, 135.8 (all d, Ph), 133.9, 134.1, 137.4, 142.9 (s, i-Ph),
198.3 (s, C-1). HRMS m/z calcd for C35H39O3Siþ: 535.2668, found
535.2677 [MþH]þ.
1168, 1090, 1067, 1012, 762, 738, 701 cmꢁ1
; dH (300 MHz, CDCl3,
mixture of diasteromers in ratio 2:1) 1.83e2.06 (m, 2H), 2.19 (ddd,
1H, J 3.5, 9.5, 13.1 Hz) 2.30e2.58 (m, 2H), 2.80 (dd, 1H, J 4.2, 17.2 Hz),
2.85e3.07 (m, 1H), 3.67 (s, 3H, Me), 4.18e4.26 (m, 2H, CH2Ph, H-3
minor), 4.36e4.46 (m, 2H, CH2Ph, H-3 major) 4.48e4.58 (m, 1H, H-
200), 7.22e7.44 (m, 10H, Ph); dC (150 MHz, CDCl3) 32.6 (major), 34.0
(minor), 34.5 (major), 34.8 (all t, C-2, C-40, minor), 35.2 (major), 37.3
(all d, C-30, minor), 43.2 (minor), 43.3 (all t, C-100, major), 51.8 (mi-
nor), 51.9 (q, Me major), 70.3 (t, CH2Ph), 75.4 (major), 75.9 (minor),
77.7 (minor), 77.8 (all d, C-50, C-200 major), 126.8 (minor),
126.9 (major), 127.6, 127.7, 128.0, 128.3, 128.6 (all d, Ph), 137.9, 140.5
4.12.2. Diospongin A [(ꢀ)-2]. Diospongin A (ꢀ)-2 was prepared
from (ꢀ)-3a (100 mg, 0.52 mmol) using PdCl2(PhCN)2 (200 mg,
ꢁ
0.52 mmol), tributylphenylstannane (187
m
L, 0.572), 4 A MS
(250 mg) in PhCF3 (5 mL). Purification by flash chromatography
(10% AcOEt/hexanes) gave the product (ꢀ)-2 (50 mg, 40%, 56% br
sm) as a colourless oil; Rf 0.1 (20% AcOEt/hexanes); dH (300 MHz,
CDCl3) 1.62e1.81 (m, 2H), 1.92 (br dd, 2H, J 1.8, 14.0 Hz), 3.09
(major), 140.6 (all s, i-Ph minor), 171.3 (major), 171.4 (minor), 177.2
þ
(minor), 177.7 (all s, 2ꢃ CO major). HRMS m/z calcd for C22H25O5
:
0
0
(dd, 1H, J2A,2 6.9, J2A,2B 16.1 Hz, H-2A), 3.43 (dd, 1H, J2B,2 5.8,
J2A,2B 16.1 Hz, H-2B), 4.35e4.40 (m, 1H), 4.62e4.72 (m, 1H), 4.95
(dd, 1H, J 1.8, 11.8 Hz), 7.20e8.03 (m, 10H, Ph). HRMS m/z calcd
for C19H21O3þ: 297.1491, found 297.1503 [MþH]þ. The 13C NMR
and IR spectral data were in good agreement with those
reported.4,5
369.1702, found 369.1699 [MþH]þ.
4.10. Ketone [( )-18] from acid ( )-13
To the solution of (ꢀ)-13 (100 mg, 0.211 mmol) in toluene (5 mL)
oxalyl chloride (362 mL, 4.22 mmol) was added dropwise and re-
action mixture was heated up and stirred at 80 ꢂC for 2 h. Mixture
was concentrated and crude chloride was dissolved in toluene
Acknowledgements
(5 mL) then Pd(dba)2 (24 mg, 0.042 mmol) and PhSnBu3 (87 mL,
0.254 mmol) were added and mixture was heated at 80 ꢂC over-
night. After removal of solvent a colourless oil of (ꢀ)-18 (100 mg,
88%) was obtained and without further purification used in the
next step.
This work was supported by Slovak Grant Agencies (VEGA,
Slovak Academy of Sciences and Ministry of Education, Bratislava,
projects No. 1/0115/10, No. 1/0236/09, and ASFEU, Bratislava, ITMS
project No. 26240120001, 26240120025).

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O. Karlubíkova et al. / Tetrahedron 67 (2011) 4980e4987
4987
€
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