Desymmetrization of hepta-1,6-dien-4-ol by prins reaction and subsequent cross-metathesis: Access to diospongine a homologues

Article abstract of DOI:10.1055/s-0031-1289588

A new tetrahydropyran scaffold has been efficiently prepared by Prins reaction between hepta-1,6-dien-4-ol and benzaldehyde. Subsequent functionalizations were further achieved by Mitsunobu reaction and/or by the way of cross-metathesis/Wacker oxidation s

Full text of DOI:10.1055/s-0031-1289588

PAPER
4037
Desymmetrization of Hepta-1,6-dien-4-ol by Prins Reaction and Subsequent
Cross-Metathesis: Access to Diospongine A Homologues
Synthesis of
D
io
u
spongine
A
d
H
omologue
s
ovic Raffier, Frédéric Izquierdo, Olivier Piva*
Université de Lyon - Université Lyon 1, Institut de Chimie et de Biochimie Moléculaire et Supramoléculaire (ICBMS), UMR 5246 CNRS,
Equipe SURCOOF, Bat Raulin-43, Bd du 11 novembre 1918, 69622 Villeurbanne cedex, France
Fax +33(4)72448136; E-mail: piva@univ-lyon1.fr
Received 28 September 2011; revised 10 October 2011
Kindly dedicated to Dr. Jacques Muzart
Diospongin A possesses important biological properties
Abstract: A new tetrahydropyran scaffold has been efficiently pre-
and could be a promising candidate to prevent osteoporo-
pared by Prins reaction between hepta-1,6-dien-4-ol and benzalde-
sis. Therefore, this compound has been the subject of
hyde. Subsequent functionalizations were further achieved by
great interest for synthetic chemists.8 While aza-
Mitsunobu reaction and/or by the way of cross-metathesis/Wacker
oxidation sequence to deliver diospongin A analogues.
analogues of 1a have been recently reported,9 we have
concentrated our own efforts to prepare new related
tetrahydropyran derivatives. We have considered the de-
sign of a common scaffold 4, which could be obtained by
desymmetrization of hepta-1,6-dien-4-ol 3 via a Prins re-
action promoted by a carboxylic acid like TFA.10–12 To
our knowledge, 3 has been implicated only once in a relat-
ed process during the synthesis of leucascandrolide A.13
Prins reaction between a secondary homoallylic alcohol
and an aldehyde is highly stereoselective leading mainly
to the stereomer possessing all substituents in equatorial
position. It was then anticipated that the resulting tetrahy-
dropyranyl alcohol could undergo an inversion of config-
uration on carbon atom 4. Obviously, Mitsunobu
conditions4,14 appears to be the solution of choice for this
purpose. By this way, 4¢ epimer of the aforementioned
structure could be easily obtained. Starting from these two
unsaturated tetrahydropyranols, it was envisioned that the
lateral double bond could be later modified by a subse-
quent CM reaction especially with different styrenes 5.
Varying the nature of the alkene, these common interme-
diates could lead to two libraries of new ‘octanoid’ struc-
tures. Since fluorinated compounds can significantly
modify the pharmacological properties in drug design,15
styryl derivatives 5 possessing a fluorine atom or a CF3
group on the phenyl ring have been more particularly con-
sidered. Finally, a Wacker-type oxidation8h,16 could deliv-
er the corresponding ketones leading to new homologues
7 and 7¢ of diospongin A (Scheme 1).
Key words: pyrans, Prins reaction, metathesis, Wacker oxidation,
natural product
Desymmetrization of bisfunctionnalized achiral com-
pounds is a very appealing and elegant approach for the
synthesis of complex structures and has found direct ap-
plications for the access to natural products.1,2 It usually
reduces the number of steps, avoiding, for example, trou-
blesome protection/deprotection sequences.3 In our con-
tinuous interest to synthesize natural products possessing
a tetrahydropyran (THP) subunit found in 1,7-diarylhep-
tanoids as diospongins 1a,b or more complex structures as
bistramide A 2 (Figure 1), we developed recently various
strategies including cyclizations of oxocarbenium ions4
and oxa-Michael reactions.5 Theses processes were di-
rectly combined with the functionalization of an already
present double bond by a cross-metathesis coupling
(CM).6,7
OH
OH
O
O
1
7
1
7
O
O
diospongine A (1a)
diospongine B (1b)
O
O
H
N
O
N
At first, hepta-1,6,dien-4-ol (3), which is commercialy
available or can be readily prepared by allyl Grignard ad-
dition on ethyl formate,17 was treated with one equivalent
of benzaldehyde in the presence of trifluoroacetic acid.
After methanolysis of the crude mixture, the expected
structure 4a was contaminated with bisallyl adduct 4b in
significant amounts (Scheme 2).
H
OH
O
O
O
OH
bistramide A (2)
Figure 1 Natural products possessing a THP subunit
Formation of this side product results from a well estab-
lished oxonia-Cope rearrangement,18 which could in situ
deliver but-3-enal 9. This carbonyl compound can then
compete with benzaldehyde to react with 3 present in the
medium (Scheme 3).
SYNTHESIS 2011, No. 24, pp 4037–4044
x
x.
x
x
.
2
0
1
1
Advanced online publication: 04.11.2011
DOI: 10.1055/s-0031-1289588; Art ID: T93211SS
© Georg Thieme Verlag Stuttgart · New York

4038
L. Raffier et al.
PAPER
OH
*
OH
*
longer observed. The resulting tetrahydropyran derivative
underwent methanolysis to furnish the single syn,syn-dia-
stereomer 4a in high yield. A Mitsunobu reaction allowed
the inversion of configuration on carbon 4 leading to key
synthetic diastereomer 4c in 88% yield (Scheme 4).
O
8
Ar
1
( )2
Ph
O
7
Ar
Ph
O
6
OH
*
OH
4
1) PhCHO (2 equiv)
TFA, CH2Cl2, 0 °C
HO
Ph
O
4
3
+
H
HO
Ph
Ph
O
2) K2CO3, MeOH
3
4a (67%)
Ar
OH
5
Ph
O
1) 4-O2NC6H4CO2H
DEAD, Ph3P, THF, r.t.
2) KOH
H2O, Δ
Scheme 1 Synthetic disconnection for the access new octanoid ho-
mologues 7 of diospongine A
4a
O
4c (88%)
O
Scheme 4 Access to tetrahydropyranols 4a and 4c
O
O
CF3
Cross-metathesis reactions of 4a were carried out with
commercially available styryl derivatives 5a–d in the
presence of Grubbs type II catalyst (5 mol%). In all cases,
the reaction proceeded efficiently with a high E-stereo-
control of the double bond on the lateral chain (Scheme 5,
Table 1). This attribution was easily made by measuring
the coupling constant between the two olefinic protons
(typically JH1-H2 = 15.0 Hz) for all compounds 6a–d. The
next crucial step consisted of the transformation of the
C=C double bond into a keto group under Wacker-type
oxidation. In order to minimize the number of steps,3 the
reaction was deliberately carried out on unprotected sub-
strates.
PhCHO (1 equiv)
TFA, CH2Cl2, 0 °C
HO
R
3
8a (R = Ph)
8b (R = allyl)
OH
O
OH
K2CO3
MeOH
+
Ph
O
58:42
4a
4b
Scheme 2 Prins reaction between alcohol 3 and benzaldehyde
OH
OH
Ar
Grubbs II (5 mol%)
TFA
H
Ar
Ar
8a
+
CH2Cl2, 40 °C, 8 h
HO
Ph
O+
Ph
O
Ph
O
Ph
Ph
O
4a
6a–d
–
CF3CO2
3
PdCl2
OH
OH
O2, CuCl
DMF–H2O
O
H
+
Ar
O+
Ph
O+
Ph
OH
55 °C, 72 h
Ph
O
Ph
O
O
+
O
7a–c
10a–c
9
Scheme 5 Access to homologues 7 and 10
OCOCF3
Table 1 Ketones 7 and 10 Prepared
HO
3
+
Yield (%)a
O
O
9
Ar
6/7/10
6
7
10
18
21
17
8b
Ph
a
b
c
68
53
48
58
24
26
16
14
Scheme 3 Oxonia-Cope rearrangement during the Prins cyclization
4-FC6H4
4-F3CC6H4
3-F3CC6H4
a Isolated yield.
In order to avoid the formation of trifluoroacetate 8b, the
reaction was conducted with an excess of benzaldehyde.
When performed with 2 equivalents, the reaction occurred
nicely and after cleavage of the ester group, 4a was isolat-
ed in a far better yield (67%) and the side product was no
b
d
–
b Degradation during flash-chromatographic purification.
Synthesis 2011, No. 24, 4037–4044 © Thieme Stuttgart · New York

PAPER
Synthesis of Diospongine A Homologues
4039
(2S*,4R*,6S*)-2-Allyl-6-phenyltetrahydro-2H-pyran-4-ol (4a)
To a solution of hepta-1,6-dien-4-ol (3; 5.27 g, 47.0 mmol) in anhyd
CH2Cl2 (150 mL) was added TFA (52 mL, 0.705 mmol) and benz-
aldehyde (9.6 mL, 94.0 mmol) at 0 °C. The mixture was stirred
from 0 °C to r.t. overnight. The reaction was carefully quenched by
adding sat. aq NaHCO3 (100 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 30 mL). The combined organic extracts were
washed with brine (30 mL), dried (MgSO4), filtered, and concen-
trated in vacuo. The resulting oil was taken up in MeOH (70 mL)
and K2CO3 (6.50 g, 47.0 mmol) was added. The reaction mixture
was stirred at r.t. for 1 h before quenching with sat. aq NH4Cl (20
mL). The mixture was extracted with CH2Cl2 (3 × 20 mL) and the
combined organic extracts were washed with brine (20 mL), dried
(MgSO4), filtered, and concentrated in vacuo. The resulting oil was
purified by silica gel flash chromatography (70:30 PE–EtOAc) to
afford 4a (6.87 g, 67%, 31.47 mmol) as a pale yellow oil.
According to similar reactions developed for previous
syntheses of diospongin 1a,b,8e–f,h these oxidations do not
significantly suffer from the presence of a free hydroxy
group. Under the conditions already published, the reac-
tion furnished with a low regioselectivity the correspond-
ing aryl ketones 7a–d and 10a–c. Nevertheless, the two
regioisomers were easily separated by flash chromatogra-
phy, whatever the nature of the aryl group. In this way,
two series of homologues were prepared. A similar set of
reactions was performed from unsaturated tetrahydropyr-
anol 4c with the same alkenes 5a–d. The cross metathesis
was achieved with the same high E-selectivity while the
Wacker oxidation delivered both homologues 12 and 13
(Scheme 6 and Table 2).
IR (neat): 3349 (br), 2939, 2919, 2846, 1640, 1495, 1451, 1367,
1322, 1144, 1064, 1028, 998, 984, 914, 757, 698 cm–1.
OH
OH
Ar
1H NMR (300 MHz, CDCl3): d = 7.39–7.25 (m, 5 H), 5.89 (dddd,
J = 17.1, 10.1, 7.2, 7.0 Hz, 1 H), 5.16–5.02 (m, 2 H), 4.38 (dd,
J = 11.4, 2.1 Hz, 1 H), 3.96 (tt, J = 11.4, 4.5 Hz, 1 H), 3.56 (dtd,
J = 11.4, 6.2, 2.1 Hz, 1 H), 2.52–2.41 (m, 1 H), 2.39–2.27 (m, 1 H),
2.21 (ddt, J = 12.4, 4.5, 2.1 Hz, 1 H), 2.06 (ddt, J = 12.4, 4.5, 2.1
Hz, 1 H), 1,55 (br s, 1 H), 1.47 (dt, J = 12.4, 11.4 Hz, 1 H), 1.29 (dt,
J = 12.4, 11.4 Hz, 1 H).
Grubbs II (7 mol%)
Ar
Ar
CH2Cl2, 40 °C, 8 h
Ph
O
Ph
O
4c
11a–d
PdCl2
OH
OH
O2, CuCl
DMF–H2O
O
+
13C NMR (75 MHz, CDCl3): d = 142.1, 134.5, 128.4, 127.5, 125.9,
117.2, 77.4, 75.5, 68.3, 42.8, 40.4, 40.2.
Ar
55 °C, 72 h
Ph
O
Ph
O
HRMS (ESI): m/z [M + Na+] calcd for C14H18O2 + Na: 241.1199;
found: 241.1197.
O
12a–d
13a–d
Scheme 6 Access to homologues 12 and 13
(2R*,4R*,6S*)-2,6-Diallyltetrahydro-2H-pyran-4-ol (4b)
Obtained as a by-product by using a similar protocol as above with
a 1:1 ratio of benzaldehyde and alcohol 3 (instead of 2:1 ratio); col-
orless oil.
Table 2 Ketones 12 and 13 Prepared
Yield (%)a
IR (neat): 3367, 3077, 2940, 2917, 2849, 1642, 1433, 1372, 1329,
1139, 1081, 1042, 997, 914 cm–1.
Ar
11/12/13
11
55
45
59
75
12
26
17
10
9
13
1H NMR (300 MHz, CDCl3): d = 5.83 (dddd, J = 17.0, 10.3, 7.5, 6.6
Hz, 2 H), 5.13–5.02 (m, 4 H), 3.78 (tt, J = 11.0, 4.7 Hz, 1 H), 3.34
(dtd, J = 11.2, 6.4, 1.7 Hz, 2 H), 2.37 (dtt, J = 14.1, 6.6, 1.3 Hz, 2
H), 2.20 (dddt, J = 14.1, 7.5, 6.3, 1.2 Hz, 1 H), 2.01–1.97 (m, 1 H),
1.96–1.93 (m, 1 H), 1.59 (br s, 1 H), 1.14 (ddd, J = 14.5, 11.2, 11.0
Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 134.7, 117.0, 75.2, 68.2, 40.7,
40.5.
HRMS (CI): m/z [M + H+] calcd for C11H18O2: 183.1380; found:
Ph
a
b
c
24
b
4-FC6H4
4-F3CC6H4
3-F3CC6H4
a Isolated yield.
–
18
22
d
b Degradation during flash-chromatographic purification.
183.1379.
In summary, the synthesis of four series of homologous
structures of diospongin, which present an additional
methylene group on the lateral chain has been achieved.
These compounds are currently under evaluation for bio-
logical properties and efforts are still in progress to im-
prove the regioselectivity and the overall yields of the
oxidation step.
(2S*,4R*,6S*)-2-Allyl-6-phenyltetrahydro-2H-pyran-4-ol (4c)
To a solution of 4a (1.50 g, 6.87 mmol) in toluene (40 mL) were
added successively 4-nitrobenzoic acid (1.38 g, 8.24 mmol), Ph3P
(2.16 g, 8.24 mmol), and diethyl azodicarboxylate (1.3 mL, 8.24
mmol) dropwise. The mixture was stirred at r.t. for 1 h. Silica gel
was added and the solvent was removed in vacuo. The resulting
powder was used for silica gel flash chromatography (90:10 PE–
EtOAc) to isolate the pure ester intermediate. The latter was taken
up in a mixture MeOH–THF–H2O (20:10:10 mL) and NaOH (300
mg, 7.56 mmol) was added. The reaction mixture was stirred over-
night and then partitioned between H2O (20 mL) and Et2O (50 mL).
The aqueous layer was extracted with Et2O (3 × 30 mL). The com-
bined organic extracts were washed with brine (20 mL), dried
(MgSO4), filtered, and concentrated in vacuo to give 4c (1.32 g,
88%, 6.05 mmol) as a pale yellow oil.
All commercially available compounds were used without further
purification. Solvents were dried according to standard procedures.
Petroleum ether (PE) refers to a hydrocarbon mixture with a boiling
range of 40–60 °C. Column chromatography was performed with
1
silica gel (0.040–0.063 mm, Macherey–Nagel). H NMR spectra
were recorded with a 300 and 500 MHz NMR spectrometer
(Bruker, AMX 300, DRX 500). Spectra were referenced to solvent
lines [CDCl3: d = 7.26 ppm (1H), 77.16 ppm (13C)].
IR (neat): 3414 (br), 3073, 3031, 2917, 2863, 1641, 1496, 1452,
1431, 1380, 1343, 1308, 1214, 1178, 1060, 997, 914, 753, 699 cm–1.
Synthesis 2011, No. 24, 4037–4044 © Thieme Stuttgart · New York

4040
L. Raffier et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 7.39–7.22 (m, 5 H), 5.91 (ddt,
J = 17.1, 10.1, 7.0 Hz, 1 H), 5.14–5.00 (m, 2 H), 4.87 (dd, J = 11.7,
2.4 Hz, 1 H), 4.35 (q, J = 3.0 Hz, 1 H), 4.04 (dtd, J = 11.7, 6.3, 2.4
Hz, 1 H), 2.47–2.34 (m, 1 H), 2.33–2.21 (m, 1 H), 1.92 (ddt,
J = 14.4, 3.0, 2.4 Hz, 1 H), 1.75 (ddd, J = 14.4, 11.7, 3.0 Hz, 1 H),
1.75 (ddt, J = 14.4, 3.0, 2.4 Hz, 1 H), 1.60 (ddd, J = 14.4, 11.7, 3.0,
1 H), 1.52 (br s, 1 H).
1H NMR (300 MHz, CDCl3): d = 7.56–7.52 (m, 2 H), 7.48–7.41 (m,
2 H), 7.40–7.26 (m, 5 H), 6.50 (d, J = 15.9 Hz, 1 H), 6.41 (dt,
J = 15.9, 6.3 Hz, 1 H), 4.41 (dd, J = 11.5, 2.1 Hz, 1 H), 4.06–3.96
(m, 1 H), 3.71–3.60 (m, 1 H), 2.69–2.46 (m, 2 H), 2.28–2.17 (m, 1
H), 2.14–2.05 (m, 1 H), 1.55 (br s, 1 H), 1.50 (q, J = 11.5 Hz, 1 H),
1.36 (q, J = 11.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 142.0, 141.0, 131.1, 129.3, 129.9
(q, J = 32.3 Hz), 128.5, 127.7, 126.3, 126.0, 125.5 (q, J = 3.7 Hz),
124.7 (q, J = 272.7 Hz), 77.6, 75.5, 68.4, 42.9, 40.5, 39.7.
13C NMR (75 MHz, CDCl3): d = 143.0, 134.8, 128.3, 127.2, 125.9,
116.8, 73.5, 71.6, 64.6, 40.6, 40.5, 37.7.
HRMS (ESI): m/z [M + Na+] calcd for C14H18O2 + Na: 241.1199;
found: 241.1199.
19F NMR (282 MHz, CDCl3): d = –62.87.
HRMS (ESI): m/z [M + Na+] calcd for C21H21F3O2 + Na: 385.1386;
found: 385.1373.
Olefin Cross-Metathesis; General Procedure
To a solution of tetrahydropyran 4a or 4c (300 mg, 1.37 mmol) in
anhyd CH2Cl2 (6 mL) was added the corresponding styrene deriva-
tive 5a–d (2.75 mmol) and 2nd generation Grubbs catalyst (58 mg,
69.0 mmol). The reaction mixture was stirred at reflux under a N2 at-
mosphere for 7 h. The solvent was removed in vacuo and the residue
was purified by silica gel flash chromatography (70:30 PE–EtOAc)
to afford 6a–d or 11a–d, respectively.
(2S*,4R*,6S*)-2-Phenyl-6-{(E)-3-[3-(trifluoromethyl)phe-
nyl]allyl}tetrahydro-2H-pyran-4-ol (6d)
Yield: 58%; pale brown oil.
IR (neat): 3305 (br), 3088, 3060, 3033, 2938, 2917, 2852, 1495,
1451, 1432, 1368, 1328, 1274, 1202, 1166, 1124, 1073, 1035, 965,
905, 897, 885, 872, 812, 790, 761, 698, 667, 587 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.61–7.28 (m, 9 H), 6.49 (d,
J = 15.9 Hz, 1 H), 6.37 (dt, J = 15.9, 6.9 Hz, 1 H), 4.41 (dd,
J = 11.4, 2.1 Hz, 1 H), 4.07–3.91 (m, 1 H), 3.65 (dtd, J = 11.4, 5.9,
2.1 Hz, 1 H), 2.68–2.57 (m, 1 H), 2.56–2.45 (m, 1 H), 2.22 (ddt,
J = 12.4, 4.6, 2.1 Hz, 1 H), 2.10 (ddt, J = 12.4, 4.6, 2.1 Hz, 1 H),
1.56 (br s, 1 H), 1.50 (dt, J = 12.4, 11.4 Hz, 1 H), 1.35 (dt, J = 12.4,
11.4 Hz, 1 H).
(2S*,4R*,6S*)-2-Cinnamyl-6-phenyltetrahydro-2H-pyran-4-ol
(6a)
Yield: 68%; pale brown oil.
IR (neat): 3369 (br), 3081, 3060, 3027, 2918, 2850, 1598, 1495,
1449, 1365, 1323, 1153, 1121, 1063, 1028, 966, 909, 880, 748, 696
cm–1.
13C NMR (75 MHz, CDCl3): d = 142.0, 138.3, 131.0, 130.9 (q,
J = 31.9 Hz), 129.3, 129.2, 129.0, 128.4, 127.6, 126.0, 124.3 (q,
J = 272.3 Hz), 123.7 (q, J = 3.9 Hz), 122.8 (q, J = 3.8 Hz), 77.6,
75.6, 68.3, 42.9, 40.4, 39.6.
19F NMR (282 MHz, CDCl3): d = –63.18.
HRMS (ESI): m/z [M + Na+] calcd for C21H21F3O2 + Na: 385.1386;
1H NMR (300 MHz, CDCl3): d = 7.44–7.18 (m, 10 H), 6.47 (d,
J = 15.9 Hz, 1 H), 6.29 (dt, J = 15.9, 7.5 Hz, 1 H), 4.40 (dd,
J = 11.4, 2.1 Hz, 1 H), 4.03–3.93 (m, 1 H), 3.69–3.58 (m, 1 H),
2.66–2.56 (m, 1 H), 2.54–2.43 (m, 1 H), 2.26–2.17 (m, 1 H), 2.14–
2.07 (m, 1 H), 1.58 (br s, 1 H), 1.49 (dt, J = 12.3, 11.4 Hz, 1 H), 1.35
(dt, J = 12.3, 11.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 141.8, 137.2, 132.0, 128.2, 128.1,
127.2, 126.8, 125.9, 125.8, 125.7, 76.5, 75.4, 67.8, 42.4, 39.9, 39.3.
found: 385.1392.
HRMS (ESI): m/z [M + Na+] calcd for C20H22O2 + Na: 317.1512;
found: 317.1514.
(2S*,4S*,6S*)-2-Cinnamyl-6-phenyltetrahydro-2H-pyran-4-ol
(11a)
Yield: 55%; pale brown oil.
(2S*,4R*,6S*)-2-[(E)-3-(4-Fluorophenyl)allyl]-6-phenyltet-
rahydro-2H-pyran-4-ol (6b)
Yield: 53%; pale brown oil.
IR (neat): 3400 (br), 3077, 3055, 3027, 2918, 2874, 1599, 1495,
1449, 1377, 1341, 1307, 1211, 1058, 966, 748, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.47–7.18 (m, 10 H), 6.46 (d,
J = 15.9 Hz, 1 H), 6.31 (dt, J = 15.9, 6.9 Hz, 1 H), 4.90 (dd,
J = 11.4, 2.4 Hz, 1 H), 4.40–4.32 (m, 1 H), 4.11 (dtd, J = 11.4, 6.0,
2.4 Hz, 1 H), 2.62–2.51 (m, 1 H), 2.48–2.38 (m, 1 H), 1.93 (dq,
J = 14.1, 2.4 Hz, 1 H), 1.80 (dq, J = 14.1, 2.4 Hz, 1 H), 1.77 (ddd,
J = 14.1, 11.4, 2.7 Hz, 1 H), 1.65 (ddd, J = 14.1, 11.4, 2.7 Hz, 1 H),
1.51 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 142.9, 137.6, 132.1, 128.5, 128.3,
127.2, 127.0, 126.5, 126.0, 125.9, 73.6, 71.8, 64.6, 40.4, 39.8, 37.7.
HRMS (ESI): m/z [M + Na+] calcd for C20H22O2 + Na: 317.1512;
found: 317.1498.
IR (neat): 3407 (br), 3060, 3027, 2942, 2917, 2850, 1651, 1602,
1508, 1452, 1366, 1322, 1307, 1226, 1157, 1064, 1029, 968, 853,
831, 757, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.45–7.25 (m, 7 H), 7.03–6.95 (m,
2 H), 6.43 (d, J = 15.8 Hz, 1 H), 6.21 (dt, J = 15.8, 7.2 Hz, 1 H), 4.37
(dd, J = 11.4, 1.8 Hz, 1 H), 3.92 (tt, J = 11.4, 4.5 Hz, 1 H), 3.59 (dtd,
J = 11.4, 5.9, 1.8 Hz, 1 H), 2.59 (m, 1 H), 2.46 (m, 1 H), 2.28 (br s,
1 H), 2.22–2.13 (m, 1 H), 2.10–2.00 (m, 1 H), 1.48 (q, J = 11.4 Hz,
1 H), 1.32 (q, J = 11.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 161.9 (d, J = 245.6 Hz), 142.0,
133.6 (d, J = 3.4 Hz), 130.9, 128.3, 127.4 (d, J = 7.8 Hz), 127.4,
126.0 (d, J = 2.2 Hz), 125.9, 115.3 (d, J = 21.6 Hz), 77.4, 75.6, 68.0,
42.7, 40.2, 39.4.
(2S*,4S*,6S*)-2-[(E)-3-(4-Fluorophenyl)allyl]-6-phenyltetrahy-
dro-2H-pyran-4-ol (11b)
Yield: 45%; pale brown oil.
19F NMR (282 MHz, CDCl3): d = –115.82.
HRMS (ESI): m/z [M + Na+] calcd for C20H21FO2: 335.1418; found:
335.1409.
IR (neat): 3406 (br), 3060, 3027, 2918, 1601, 1508, 1451, 1377,
1341, 1303, 1227, 1157, 1057, 969, 844, 754, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.49–7.23 (m, 7 H), 7.03–6.94 (m,
2 H), 6.41 (d, J = 15.9 Hz, 1 H), 6.22 (dt, J = 15.9, 6.9 Hz, 1 H), 4.89
(dd, J = 11.7, 2.4 Hz, 1 H), 4.41–4.33 (m, 1 H), 4.16–4.04 (m, 1 H),
2.60–2.48 (m, 1 H), 2.47–2.35 (m, 1 H), 1.93 (dq, J = 14.1, 2.4 Hz,
1 H), 1.79 (dq, J = 14.1, 2.4 Hz, 1 H), 1.77 (ddd, J = 14.1, 11.7, 2.7
Hz, 1 H), 1.64 (ddd, J = 14.1, 11.7, 2.7 Hz, 1 H), 1.50 (br s, 1 H).
(2S*,4R*,6S*)-2-Phenyl-6-{(E)-3-[4-(trifluoromethyl)phe-
nyl]allyl}tetrahydro-2H-pyran-4-ol (6c)
Yield: 48%; pale brown oil.
IR (neat): 3400 (br), 2944, 2912, 2851, 1615, 1326, 1163, 1121,
1067, 970, 755, 699 cm–1.
Synthesis 2011, No. 24, 4037–4044 © Thieme Stuttgart · New York

PAPER
Synthesis of Diospongine A Homologues
4041
13C NMR (75 MHz, CDCl3): d = 162.0 (d, J = 246.0 Hz), 143.0,
133.8 (d, J = 3.3 Hz), 130.9, 128.4, 127.6 (d, J = 7.8 Hz), 127.4,
126.3 (d, J = 2.2 Hz), 126.0, 115.4 (d, J = 21.5 Hz), 73.7, 71.9, 64.8,
40.5, 39.8, 37.8.
19F NMR (282 MHz, CDCl3): d = –115.96.
HRMS (ESI): m/z [M + Na+] calcd for C20H21FO2 + Na: 335.1418;
3-[(2S*,4R*,6S*)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-
yl]-1-phenylpropan-1-one (7a)
Yield: 24%; pale brown oil.
IR (neat): 3426 (br), 3062, 3031, 2921, 2852, 1683, 1598, 1580,
1495, 1449, 1365, 1316, 1271, 1212, 1180, 1156, 1119, 1066, 1028,
757, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.00–7.92 (m, 2 H), 7.57–7.51 (m,
1 H), 7.47–7.39 (m, 2 H), 7.35–7.25 (m, 5 H), 4.35 (dd, J = 11.4, 2.1
Hz, 1 H), 4.05–3.93 (m, 1 H), 3.64–3.53 (m, 1 H), 3.17 (t, J = 7.2
Hz, 2 H), 2.24–2.16 (m, 1 H), 2.13–1.94 (m, 4 H), 1.47 (dt, J = 12.3,
11.4 Hz, 1 H), 1.35 (dt, J = 12.3, 11.4 Hz, 1 H).
found: 335.1420.
(2S*,4S*,6S*)-2-Phenyl-6-{(E)-3-[4-(trifluoromethyl)phenyl]al-
lyl}tetrahydro-2H-pyran-4-ol (11c)
Yield: 59%; pale brown oil.
IR (neat): 3412 (br), 3064, 3032, 2920, 1652, 1614, 1495, 1453,
1414, 1379, 1326, 1212, 1164, 1119, 1067, 1016, 975, 952, 911,
860, 843, 755, 699 cm–1.
13C NMR (100 MHz, CDCl3): d = 200.5, 142.2, 137.0, 133.1, 128.6,
128.4, 128.2, 127.5, 125.9, 77.5, 75.0, 68.4, 43.0, 41.1, 34.6, 30.5.
HRMS (ESI): m/z [M + Na+] calcd for C20H22O3 + Na: 333.1461;
1H NMR (300 MHz, CDCl3): d = 7.59–7.51 (m, 2 H), 7.48–7.42 (m,
2 H), 7.60–7.24 (m, 5 H), 6.49 (d, J = 15.9 Hz, 1 H), 6.42 (dt,
J = 15.9, 6.1 Hz, 1 H), 4.90 (dd, J = 11.6, 2.1 Hz, 1 H), 4.42–4.35
(m, 1 H), 4.19–4.08 (m, 1 H), 2.63–2.52 (m, 1 H), 2.51–2.41 (m, 1
H), 1.98–1.97 (m, 1 H), 1.85–1.73 (m, 2 H), 1.71–1.60 (m, 1 H),
1.52 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 142.8, 141.0, 130.8, 129.5, 128.7
(q, J = 32.3 Hz), 128.4, 127.4, 126.2, 125.9, 125.4 (q, J = 3.8 Hz),
124.3 (q, J = 271.6 Hz), 73.7, 71.7, 64.6, 40.4, 39.8, 37.8.
found: 333.1457.
1-[(2R*,4R*,6S*)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-
yl]-3-phenylpropan-2-one (10a)
Yield: 18%; beige viscous liquid.
IR (neat): 3415 (br), 3060, 3030, 2939, 2920, 2852, 1714, 1496,
1454, 1367, 1329, 1218, 1157, 1064, 1028, 989, 754, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.37–7.23 (m, 8 H), 7.19–7.13 (m,
2 H), 4.38 (dd, J = 11.6, 2.1 Hz, 1 H), 4.06–3.93 (m, 2 H), 3.75 (d,
J = 15.4 Hz, 1 H), 3.72 (d, J = 15.4 Hz, 1 H), 2.89 (dd, J = 16.0, 7.2
Hz, 1 H), 2.57 (dd, J = 16.0, 5.2 Hz, 1 H), 2.24–2.16 (m, 2 H), 2.10–
2.02 (m, 1 H), 1.47 (q, J = 11.6 Hz, 1 H), 1.24 (q, J = 11.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 206.6, 141.7, 133.9, 129.6, 128.8,
128.4, 127.7, 127.1, 126.0, 77.6, 72.5, 68.1, 51.3, 48.0, 42.5, 40.6.
19F NMR (282 MHz, CDCl3): d = –62.87.
HRMS (ESI): m/z [M + Na+] calcd for C21H21F3O2 + Na: 385.1386;
found: 385.1382.
(2S*,4S*,6S*)-2-Phenyl-6-{(E)-3-[3-(trifluoromethyl)phenyl]al-
lyl}tetrahydro-2H-pyran-4-ol (11d)
Yield: 75%; pale brown oil.
HRMS (ESI): m/z [M + Na+] calcd for C20H22O3 + Na: 333.1461;
found: 333.1453.
IR (neat): 3401 (br), 3060, 3032, 2919, 2868, 1495, 1451, 1435,
1331, 1202, 1164, 1124, 1092, 1071, 965, 901, 804, 791, 753, 697
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.61–7.24 (m, 9 H), 6.48 (d,
J = 15.9 Hz, 1 H), 6.38 (dt, J = 15.9, 6.7 Hz, 1 H), 4.90 (dd,
J = 11.4, 2.4 Hz, 1 H), 4.40–4.34 (m, 1 H), 4.13 (dtd, 11.4, 5.9, 2.4
Hz, 1 H), 2.63–2.52 (m, 1 H), 2.51–2.40 (m, 1 H), 1.93 (dq,
J = 14.1, 2.4 Hz, 1 H), 1.80 (dq, J = 14.1, 2.4 Hz, 1 H), 1.78 (ddd,
J = 14.1, 11.4, 2.7 Hz, 1 H), 1.65 (ddd, J = 14.1, 11.4, 2.7 Hz, 1 H),
1.51 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 142.9, 138.4, 130.9 (q, J = 31.9
Hz), 130.8, 129.2, 129.0, 128.7, 128.4, 127.4, 126.0, 124.3 (q,
J = 272.2 Hz), 123.6 (q, J = 3.8 Hz), 122.8 (q, J = 3.8 Hz), 73.7,
71.7, 64.7, 40.5, 39.8, 37.8.
1-(4-Fluorophenyl)-3-[(2S*,4R*,6S*)-4-hydroxy-6-phenyltet-
rahydro-2H-pyran-2-yl]propan-1-one (7b)
Yield: 26%; pale brown oil.
IR (neat): 3411 (br), 3064, 3025, 2922, 2852, 1683, 1598, 1506,
1452, 1410, 1364, 1307, 1264, 1231, 1156, 1066, 838, 757, 690
cm–1.
1H NMR (300 MHz, CDCl3): d = 8.02–7.94 (m, 2 H), 7.39–7.24 (m,
5 H), 7.13–7.04 (m, 2 H), 4.33 (dd, J = 11.4, 1.8 Hz, 1 H), 4.06–3.91
(m, 1 H), 3.62–3.52 (m, 1 H), 3.18–3.09 (m, 2 H), 2.20 (dtd,
J = 12.4, 4.5, 1.8 Hz, 1 H), 2.13–1.92 (m, 3 H), 1.58 (br s, 1 H), 1.47
(dt, J = 12.4, 11.4 Hz, 1 H), 1.34 (dt, J = 12.4, 11.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 198.9, 166.0 (d, J = 253.0 Hz),
142.2, 133.5 (d, J = 3.1 Hz), 130.8 (d, J = 9.2 Hz), 128.4, 127.6,
125.9, 115.7 (d, J = 21.6 Hz), 77.5, 75.0, 68.4, 43.1, 41.1, 34.5,
30.6.
19F NMR (282 MHz, CDCl3): d = –63.20.
HRMS (ESI): m/z [M + Na+] calcd for C21H21F3O2 + Na: 385.1386;
found: 385.1377.
19F NMR (282 MHz, CDCl3): d = –105.97.
HRMS (ESI): m/z [M + Na+] calcd for C20H21FO3 + Na: 351.1367;
found: 351.1378.
Wacker Oxidation of Compounds 6a–d; General Procedure
O2 was bubbled through a 60% solution of PdCl2 (0.5 mmol, 0.5
equiv) and CuCl (1 mmol, 1 equiv) in a DMF–H2O (5:1 mL) mix-
ture for 30 min. Olefin 6 (1 mmol) was then added in a solution of
DMF (2 mL). The reaction mixture was allowed to stir at 55 °C for
72 h under an O2 atmosphere. The solids were removed on a short
pad of Celite and the filtrate was washed with H2O (10 mL). The re-
sulting aqueous layer was extracted with CH2Cl2 (3 × 15 mL) and
the combined organic extracts were washed with brine (15 mL),
dried (MgSO4), filtered, and concentrated in vacuo. Purification on
silica gel flash chromatography allowed the separation of the two
regioisomers 7 and 10.
1-(4-Fluorophenyl)-3-[(2R*,4R*,6S*)-4-hydroxy-6-phenyltet-
rahydro-2H-pyran-2-yl]propan-2-one (10b)
Yield: 21%; pale brown oil.
IR (neat): 3422 (br), 3060, 3035, 2921, 2851, 1716, 1602, 1509,
1452, 1367, 1330, 1222, 1158, 1063, 989, 829, 758, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.25 (m, 5 H), 7.11–7.06 (m,
2 H), 7.00–7.93 (m, 2 H), 4.37 (dd, J = 11.6, 2.0 Hz, 1 H), 4.00–3.89
(m, 2 H), 3.74 (d, J = 15.9 Hz, 1 H), 3.70 (d, J = 15.9 Hz, 1 H), 2.88
(dd, J = 15.7, 7.4 Hz, 1 H), 2.56 (dd, J = 15.7, 5.2 Hz, 1 H), 2.20 (br
s, 1 H), 2.15 (ddt, J = 12.4, 4.4, 2.0 Hz, 1 H), 2.01 (ddt, J = 12.4, 4.4,
2.0 Hz, 1 H), 1.45 (dt, J = 12.4, 11.6 Hz, 1 H), 1.25 (q, J = 12.4, 11.6
Hz, 1 H).
Synthesis 2011, No. 24, 4037–4044 © Thieme Stuttgart · New York

4042
L. Raffier et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 206.5, 162.0 (d, J = 245.1 Hz),
141.7, 131.2 (d, J = 8.1 Hz), 129.6 (d, J = 3.0), 128.43, 127.7,
126.0, 115.6 (d, J = 21.3 Hz), 77.6, 72.6, 68.0, 50.2, 48.0, 42.5,
40.6.
19F NMR (282 MHz, CDCl3): d = –63.21.
HRMS (ESI): m/z [M + Na+] calcd for C21H21F3O3 + Na: 401.1335;
found: 401.1322.
19F NMR (282 MHz, CDCl3): d = –116.23.
HRMS (ESI): m/z [M + Na+] calcd for C20H21FO3 + Na: 351.1367;
Wacker Oxidation of Compounds 11a–d; General Procedure
Same procedure as described above for substrates 6a–d and carried
out on 1 mmol scale led to 12a–d and 13a–d readily separated by
flash chromatography.
found: 351.1357.
3-[(2S*,4R*,6S*)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-
yl]-1-[4-(trifluoromethyl)phenyl] propan-1-one (7c)
Yield: 16%; pale yellow oil.
3-[(2S*,4S*,6S*)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-
yl)-1-phenylpropan-1-one (12a)
Yield: 26%; pale brown oil.
IR (neat): 3404 (br), 3060, 3027, 2924, 2853, 1689, 1451, 1410,
1367, 1326, 1168, 1129, 1066, 1015, 846, 834, 758, 699, 599 cm–1.
IR (neat): 3428 (br), 3060, 3027, 2920, 1682, 1597, 1580, 1449,
1211, 1091, 1056, 990, 753, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.02 (d, J = 8.2 Hz, 2 H), 7.66 (d,
J = 8.2 Hz, 2 H), 7.40–7.24 (m, 5 H), 4.31 (dd, J = 11.6, 2.0 Hz, 1
H), 3.98 (tt, J = 11.0, 4.7 Hz, 1 H), 3.60–3.54 (m, 1 H), 3.22–3.13
(m, 2 H), 2.39 (br s, 1 H), 2.18 (ddt, J = 12.5, 4.7, 2.0 Hz, 1 H),
2.14–1.96 (m, 3 H), 1.47 (ddd, J = 12.5, 11.6, 11.0 Hz, 1 H), 1.35
(ddd, J = 12.5, 11.6, 11.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 199.5, 142.1, 139.7, 134.3 (q,
J = 32.3 Hz), 128.6, 128.5, 127.6, 126.0, 125.7 (q, J = 3.8 Hz),
123.7 (q, J = 271.0 Hz), 77.7, 74.9, 68.5, 43.1, 41.2, 35.0, 30.5.
1H NMR (400 MHz, CDCl3): d = 8.02–7.98 (m, 2 H), 7.59–7.25 (m,
8 H), 4.88 (dd, J = 11.6, 2.0 Hz, 1 H), 4.40–4.33 (m, 1 H), 4.09–4.03
(m, 1 H), 3.25 (ddd, J = 17.2, 8.4, 6.0 Hz, 1 H), 3.14 (ddd, J = 17.2,
8.4, 6.8 Hz, 1 H), 2.27 (br s, 1 H), 2.07–2.91 (m, 3 H), 1.81 (dq,
J = 14.0, 2.0 Hz, 1 H), 1.76 (ddd, J = 14.0, 11.6, 2.8 Hz, 1 H), 1.67
(ddd, J = 14.0, 11.6, 2.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 200.8, 143.2, 137.1, 133.0, 128.6,
128.3, 128.2, 127.2, 125.9, 73.6, 71.3, 64.9, 40.7, 38.7, 34.8, 30.7.
HRMS (ESI): m/z [M + Na+] calcd for C20H22O3 + Na: 333.1461;
found: 333.1458.
19F NMR (282 MHz, CDCl3): d = –63.56.
HRMS (ESI): m/z [M + Na+] calcd for C21H21F3O3 + Na: 401.1335;
found: 401.1325.
1-[(2R*,4S*,6S*)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-
yl]-3-phenylpropan-2-one (13a)
Yield: 24%; pale brown viscous liquid.
1-[(2R*,4R*,6S*)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-
yl]-3-[4-(trifluoromethyl)phenyl]propan-2-one (10c)
Yield: 17%; pale brown viscous liquid.
IR (neat): 3422 (br), 3060, 3027, 2918, 1711, 1496, 1451, 1338,
1305, 1057, 979, 749, 699 cm–1.
IR (neat): 3418 (br), 3060, 3033, 2923, 2854, 1717, 1619, 1496,
1453, 1420, 1367, 1326, 1164, 1123, 1067, 1020, 820, 758, 700,
586 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.52 (d, J = 8.0 Hz, 2 H), 7.39–
7.27 (m, 5 H), 7.23 (d, J = 8.0 Hz, 2 H), 4.36 (dd, J = 11.5, 1.8 Hz,
1 H), 4.02–3.92 (m, 2 H), 3.84 (d, J = 16.0 Hz, 1 H), 3.79 (d,
J = 16.0 Hz, 1 H), 2.89 (dd, J = 15.5, 7.7 Hz, 1 H), 2.57 (dd,
J = 15.5, 4.8 Hz, 1 H), 2.22–2.13 (m, 1 H), 2.08–2.00 (m, 1 H), 2.06
(br s, 1 H), 1.48 (q, J = 11.5 Hz, 1 H), 1.29 (q, J = 11.5 Hz, 1 H).
1H NMR (400 MHz, CDCl3): d = 7.36–7.21 (m, 8 H), 7.18–7.13 (m,
2 H), 4.88 (dd, J = 11.6, 2.2 Hz, 1 H), 4.49–4.43 (m, 1 H), 4.31–4.26
(m, 1 H), 3.76 (d, J = 16.0 Hz, 1 H), 3.75 (d, J = 16.0 Hz, 1 H), 2.80
(dd, J = 15.6, 7.2 Hz, 1 H), 2.53 (dd, J = 15.6, 5.6 Hz, 1 H), 2.22 (br
s, 1 H), 1.53 (dq, J = 14.0, 2.2 Hz, 1 H), 1.75 (dq, J = 14.0, 2.2 Hz,
1 H), 1.70 (ddd, J = 14.0, 11.6, 2.8 Hz, 1 H), 1.53 (ddd, J = 14.0,
11.6, 2.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 207.1, 142.7, 134.1, 129.7, 128.7,
128.4, 127.4, 127.1, 125.9, 73.8, 69.1, 64.5, 51.1, 48.4, 40.1, 38.2.
HRMS (ESI): m/z [M + Na+] calcd for C20H22O3 + Na: 333.1461;
found: 333.1460.
13C NMR (100 MHz, CDCl3): d = 205.7, 141.6, 137.9, 130.1, 129.4
(q, J = 32.1 Hz), 128.5, 127.8, 126.0, 125.6 (q, J = 3.8 Hz), 124.2
(q, J = 270.5 Hz), 77.8, 72.7, 68.1, 50.7, 48.4, 42.5, 40.6.
19F NMR (282 MHz, CDCl3): d = –62.97.
HRMS (ESI): m/z [M + Na+] calcd for C21H21F3O3 + Na: 401.1335;
1-(4-Fluorophenyl)-3-[(2S*,4S*,6S*)-4-hydroxy-6-phenyltet-
rahydro-2H-pyran-2-yl]propan-1-one (12b)
Yield: 17%, pale yellow viscous liquid.
found: 401.1322.
IR (neat): 3446 (br), 3060, 3022, 2923, 2863, 1683, 1598, 1506,
1453, 1410, 1232, 1157, 1092, 1054, 987, 840, 754, 699 cm–1.
3-[(2S*,4R*,6S*)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-
yl]-1-[3-(trifluoromethyl)phenyl]propan-1-one (7d)
Yield: 14%; pale brown viscous liquid.
1H NMR (400 MHz, CDCl3): d = 8.00–7.95 (m, 2 H), 7.37–7.23 (m,
5 H), 7.07 (t, J = 8.7 Hz, 2 H), 4.82 (dd, J = 11.6, 2.2 Hz, 1 H), 4.38–
4.33 (m, 1 H), 4.05–3.98 (m, 1 H), 3.18 (ddd, J = 17.1, 8.4, 5.6 Hz,
1 H), 3.19 (br s, 1 H), 3.07 (ddd, J = 17.1, 8.4, 7.1 Hz, 1 H), 2.05–
1.86 (m, 3 H), 1.80–1.71 (m, 2 H), 1.66 (ddd, J = 14.0, 11.6, 2.7 Hz,
1 H).
13C NMR (100 MHz, CDCl3): d = 199.1, 165.7 (d, J = 254.0 Hz),
143.2, 133.6 (d, J = 3.1 Hz), 130.9 (d, J = 9.3 Hz), 128.4, 127.3,
125.9, 115.7 (d, J = 21.5 Hz), 73.7, 71.3, 65.0, 40.8, 38.7, 34.8,
30.8.
IR (neat): 3401 (br), 3066, 3027, 2924, 2852, 1691, 1610, 1451,
1366, 1330, 1259, 1168, 1127, 1072, 801, 757, 697 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.22–8.17 (m, 1 H), 8.14–8.10 (m,
1 H), 8.81–8.76 (m, 1 H), 8.58–8.51 (m, 1 H), 7.37–7.24 (m, 5 H),
4.34 (dd, J = 11.6, 2.0 Hz, 1 H), 3.99 (tt, J = 10.9, 4.8 Hz, 1 H),
3.64–3.55 (m, 1 H), 3.27–3.08 (m, 2 H), 2.20 (ddt, J = 12.2, 4.8, 2.0
Hz, 1 H), 2.14–1.95 (m, 3 H), 1.65 (br s, 1 H), 1.47 (ddd, J = 12.2,
11.6, 10.9 Hz, 1 H), 1.36 (ddd, J = 12.2, 11.6, 10.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 199.0, 142.1, 137.6, 131.4, 131.3
(q, J = 32.2 Hz), 129.5 (q, J = 3.5 Hz), 129.3, 128.5, 127.6, 125.9,
125.0 (q, J = 3.9 Hz), 123.7 (q, J = 270.9 Hz), 77.6, 74.9, 68.5, 43.2,
41.2, 34.8, 30.4.
19F NMR (282 MHz, CDCl3): d = –106.19.
HRMS (ESI): m/z [M + Na+] calcd for C20H21FO3 + Na: 351.1367;
found: 351.1361.
Synthesis 2011, No. 24, 4037–4044 © Thieme Stuttgart · New York

PAPER
Synthesis of Diospongine A Homologues
4043
3-[(2S*,4S*,6S*)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-
yl)-1-[4-(trifluoromethyl)phenyl]propan-1-one (12c)
Yield: 10%; pale brown viscous liquid.
1H NMR (400 MHz, CDCl3): d = 7.53–7.47 (m, 1 H), 7.44–7.24 (m,
8 H), 4.89 (dd, J = 11.8, 2.6 Hz, 1 H), 4.55–4.44 (m, 1 H), 4.32 (q,
J = 2.6 Hz, 1 H), 3.85 (d, J = 16.3 Hz, 1 H), 3.82 (d, J = 16.3 Hz, 1
H), 2.81 (dd, J = 15.2, 7.6 Hz, 1 H), 2.56 (dd, J = 15.2, 5.1 Hz, 1 H),
2.26 (br s, 1 H), 1.91 (dq, J = 14.1, 2.6 Hz, 1 H), 1.77 (dq, J = 13.9,
2.6 Hz, 1 H), 1.73 (ddd, J = 14.1, 11.8, 2.6 Hz, 1 H), 1.59 (ddd,
J = 13.9, 11.8, 2.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 206.3, 142.5, 135.0, 133.2, 130.9
(q, J = 32.2 Hz), 129.0, 128.4, 127.5, 126.5 (q, J = 3.8 Hz), 125.9,
124.1 (q, J = 272.5 Hz), 123.9 (q, J = 3.7 Hz), 73.9, 69.3, 64.6, 50.5,
48.7, 40.1, 38.2.
IR (neat): 3448 (br), 3060, 3033, 2925, 2863, 1686, 1509, 1495,
1325, 1168, 1130, 1066, 1051, 1016, 839, 754, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.03 (d, J = 8.1 Hz, 2 H), 7.65 (d,
J = 8.1 Hz, 2 H), 7.42–7.21 (m, 5 H), 4.80 (dd, J = 11.6, 2.1 Hz, 1
H), 4.39–4.32 (m, 1 H), 4.08–3.96 (m, 1 H), 3.33 (ddd, J = 17.2, 8.1,
5.9 Hz, 1 H), 3.11 (ddd, J = 17.2, 8.1, 6.9 Hz, 1 H), 2.03–1.87 (m, 3
H), 1.82–1.70 (m, 3 H), 1.65 (ddd, J = 14.0, 11.6, 2.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 199.7, 143.0, 139.8, 134.2 (q,
J = 32.7 Hz), 128.6, 128.4, 127.4, 125.9, 125.6 (q, J = 3.7 Hz),
123.8 (q, J = 271.0 Hz), 73.7, 71.2, 65.0, 40.8, 38.7, 35.2, 30.8.
19F NMR (282 MHz, CDCl3): d = –63.05.
HRMS (ESI): m/z [M + Na+] calcd for C21H21F3O3 + Na: 401.1335;
found: 401.1337.
19F NMR (282 MHz, CDCl3): d = –63.54.
HRMS (ESI): m/z [M + Na+] calcd for C21H21F3O3 + Na: 401.1335;
found: 401.1324.
Acknowledgment
L.R. thanks the ‘Ministère de l’Education Nationale, de la Re-
cherche et de la Technologie’ for a doctoral fellowship. Financial
support from Université de Lyon 1 and CNRS are gratefully
acknowledged.
1-[(2R*,4S*,6S*)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-
yl]-3-[3-(trifluoromethyl)phenyl] propan-2-one (13c)
Yield: 18%; pale brown oil.
IR (neat): 3448 (br), 3060, 3032, 2921, 1716, 1618, 1420, 1326,
1164, 1123, 1067, 1020, 981, 754, 699 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.53–7.51 (m, 2 H), 7.36–7.24 (m,
5 H), 7.24–7.22 (m, 2H ), 4.88 (dd, J = 11.8, 2.3 Hz, 1 H), 4.49
(dddd, J = 11.0, 7.8, 5.0, 2.8 Hz, 1 H), 4.33 (q, J = 2.8 Hz, 1 H), 3.86
(d, J = 16.1 Hz, 1 H), 3.83 (d, J = 16.1 Hz, 1 H), 2.81 (dd, J = 15.1,
7.8 Hz, 1 H), 2.55 (dd, J = 15.1, 5.0 Hz, 1 H), 2.18 (br s, 1 H), 1.92
(dq, J = 14.1, 2.8 Hz, 1 H), 1.82–1.70 (m, 2 H), 1.60 (ddd, J = 14.1,
11.8, 2.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 206.2, 142.5, 138.1, 130.1, 129.3
(q, J = 32.3 Hz), 128.4, 127.5, 125.9, 125.5 (q, J = 3.8 Hz), 124.3
(q, J = 270.3 Hz), 73.9, 69.3, 64.6, 50.5, 48.8, 40.1, 38.2.
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found: 401.1328.
3-[(2S*,4S*,6S*)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-
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IR (neat): 3439 (br), 3060, 3027, 2922, 1689, 1610, 1331, 1168,
1128, 1072, 752, 696 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.23–8.11 (m, 2 H), 7.81–7.75 (m,
1 H), 7.58–7.49 (m, 1 H), 7.38–7.20 (m, 5 H), 4.83 (dd, J = 11.7, 2.4
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2.11 (br s, 1 H), 2.04–1.86 (m, 3 H), 1.85–1.73 (m, 2 H), 1.66 (ddd,
J = 14.0, 11.7, 2.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 199.2, 143.1, 137.6, 131.5, 131.2
(q, J = 32.7 Hz), 129.4 (q, J = 3.6 Hz), 129.3, 128.4, 127.4, 125.9,
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found: 401.1351.
1-[(2R*,4S*,6S*)-4-Hydroxy-6-phenyltetrahydro-2H-pyran-2-
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Yield: 22%; pale brown viscous liquid.
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1124, 1075, 754, 700 cm–1.
Synthesis 2011, No. 24, 4037–4044 © Thieme Stuttgart · New York

4044
L. Raffier et al.
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