Synthesis of a C-9 to C-18 building block of the phenalamides

Article abstract of DOI:10.1055/s-2002-19806

In the context of a synthesis of phenalamide A2, the C-9 to C-18 building block 6 was synthesized. The stereogenic centers were generated by alkylation of an Evans oxazolidinone 12 and by a crotylboration reaction using the enantiomerically pure (E)-α-chlorocrotylboronate (4).

Full text of DOI:10.1055/s-2002-19806

PAPER
207
Synthesis of a C-9 to C-18 Building Block of the Phenalamides
Phenalamides,
(
C
e
-9 toC-18
i
Synth
n
esis hard W. Hoffmann,* Eckart Haeberlin, Thorsten Rohde
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany
Fax +49(6421)2828917; E-mail: rwho@chemie.uni-marburg.de
Received 29 August 2001; revised 22 October 2001
O
Abstract: In the context of a synthesis of phenalamide A2, the C-9
to C-18 building block 6 was synthesized. The stereogenic centers
Ph
were generated by alkylation of an Evans oxazolidinone 12 and by
OH
a crotylboration reaction using the enantiomerically pure (E)- -
chlorocrotylboronate (4).
3
4
Ph
+
Cl
Cl
O
Key words: allylboration reaction, diastereoselectivity, natural
products, stereoselective synthesis
O
5
B
O
tBuMe2SiO
The myxalamides (1) and the phenalamides (2) attracted
the attention of medicinal chemists because these com-
pounds are able to reverse the multidrug resistance of can-
cer cells (Scheme 1). It is their polyenic structure, which
poses a challenge to efficient synthesis.
Steps
Ph
6
Scheme 2
OH
7
Myxalamides
6
H3B•SMe2
R
Ph
Br
Ph
THF, 0 oC
R = Me, Et, iPr, sBu
+
MgCl
THF, 0 oC
96 %
7
1
OH
O
N
Swern-Ox.
NaOH
H2O2
H
Ph
OH
Ph
O
OH
O
7
Ph
75 %
rac-8
99 %
Li
rac-9
N
6
H
OH
6,7-Z: Phenalamide A1 , Stipiamide
6,7-E: Phenalamide A2
2a
2b
Ph
N
O
THF, -78 oC
71 %
Scheme 1
rac-3
Scheme 3
Pioneering studies in this area resulted in the total synthe-
sis of phenalamide A1 (stipiamide) and congeners by the
Andrus group,1–3 the synthesis of myxalamide A by
Heathcock,4 and our own synthesis of phenalamide A2.5
A common building block for the synthesis of the phe-
nalamides is the aldehyde 6.1,5,6 We describe here our
route to generate this aldehyde 6, using an allylation with
the chiral (E)- -chlorocrotylboronate (4) as key step to
create the stereogenic centers at C-12 and C-13 (phenala-
mide numbering) (Scheme 2).
The sequence started with the Grignard coupling of meth-
allylmagnesium chloride with benzyl bromide, which
gave the hydrocarbon 7 much more effectively (96%) than
the alternative coupling between benzylmagnesium chlor-
ide and methallyl bromide (44%). Hydroboration of 7
with borane dimethylsulfide gave the alcohol 87 in 75%
yield. Alcohol 8 was readily oxidized to the aldehyde 9
using the Swern protocol.8 The sequence was concluded
by a Wittig directed aldol condensation.9 This method is
more effective (71%) than the related Corey/Enders
(60%) approach.10 However, the aldehyde rac-3 obtained
was always contaminated with minor amounts of the start-
ing aldehyde 9. While this was not a problem for model
studies, it would be unacceptable for the synthesis of phe-
nalamide A2 itself.
For initial screening we needed a good supply of the alde-
hyde 3 in racemic form. This was secured by the follow-
ing reaction sequence (Scheme 3).
Synthesis 2002, No. 2, 01 02 2002. Article Identifier:
1437-210X,E;2002,0,02,0207,0212,ftx,en;T08601SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

208
R. W. Hoffmann et al.
PAPER
This endeavour required synthesis of the (S)-isomer of 9 rane,13 which proceeded with 7:1 diastereoselectivity. The
and its conversion to (S)-3. After our studies were com- minor diastereomer likely resulted from insufficient re-
pleted an elegant route to enantiomerically pure 9 was agent control of diastereoselectivity.13 We chose -chlo-
opened via an enantioselective cyclopropanation ro-(E)-crotylboronate (4)14 hoping for higher reagent
reaction11 to 10 followed by transformation to the alkene control of diastereoselectivity (Scheme 6).15 The reaction
11, a precursor for (S)-9 (Scheme 4).
with aldehyde 3 furnished the homoallylic alcohol 5
(53%). Traces of the other diastereomer 16 could easily be
separated owing to opposite configuration of the vinyl
chloride double bond.14
OH
OH
Ph
Ph
10
O
O
Ph
Ph
OH
Ph
Ph
Cl
91 % e.e.
9
11
3
4
Scheme 4
+
16
OH
Cl
Ph
O
In comparison, the route used by Andrus and similarly by
us is more conventional since it is based on the
alkylation12 of the Evans-enolate 12. This led to the -me-
thylated compound 13 in 77% yield (Scheme 5).
B
Cl
58 %
O
5
t
lutidine
BuMe2SiOTf,
CH2Cl2, 0 oC
tBuMe2SiO
Li
Ph
O
O
O
O
LDA, MeI
LiAlH4
NH3, -78 oC
Ph
THF, -78 oC
Ph
Ph
Cl
N
O
t
N
O
OSiMe2 Bu
82 %
17
Et2O, 0 oC
Ph
12
77 %
13
99 %
18
O
HO
Scheme 6
Swern-Oxid.
Ph3PCH(CH3)COOEt
C6H6 , 25 oC
Ph
CH2Cl2, -60 oC
Silyl-protection to give 17 was easily accomplished
(82%). In order to generate the next aldehyde 20 in the re-
action sequence, a selective cleavage of the terminal dou-
ble bond had to be realized. Ozonolytic cleavage of a
vinyl chloride is possible,16 but the reaction conditions are
too harsh to expect a differentiation between the two dou-
ble bonds. Therefore, a reductive dechlorination of 17 to
give 18 had to be performed. Fortunately, this step pro-
ceeded in essentially quantitative yield, a step which was
necessitated due to the use of the -chloro-(E)-crotyl-bor-
onate. In comparison to the study of Andrus (conversion
of 14 to 18 in four steps and 57% overall yield) we invest-
ed one additional step to reach a higher diastereoselectiv-
ity in the chain extension from 3 to 5, but had to accept a
lower overall yield of 44%.
91 %
8
99 %
9
OH
O
LiAlH4
Ph
Ph
OEt
Et2O, 0 oC
96 %
14
97 %
15
O
Swern-Oxid.
Ph
96 %
CH2Cl2, -60 oC
3
Scheme 5
Removal of the chiral auxiliary was effected using lithium
aluminium hydride to give the alcohol (S)-8 in 91% yield.
After oxidation to (S)-9 as before, we used a Wittig reac-
tion to generate ester 14. This seemingly simple transfor-
mation was quite difficult, giving a poor yield of 40%
when carried out in THF. Andrus6 used toluene at 90 °C
for the same transformation and obtained 55% of an 8:1
E:Z-mixture of 14. We found that the reaction carried out
in refluxing CH2Cl2 or in benzene at r.t. is higher yielding
(93% to 96%) and furnishes product 14 free of the corre-
sponding Z-isomer. Subsequent lithium aluminium hy-
dride reduction (97%) and Swern oxidation (96%)
routinely gave (S)-3.
Having secured compound 18, selective cleavage of the
terminal double bond was still a problem. Selectivity
could be attained by an OsO4 mediated dihydroxylation.
Thus, reaction of the alkene 18 with potassium osmate and
N-morpholine oxide followed by periodate cleavage gave
78% of the aldehyde 20 (Scheme 7).
We later turned to the AD-mix dihydroxylation of 18 re-
ported by Andrus,2 followed by cleavage of the diol 19
with lead tetraacetate to give aldehyde 20, which was im-
mediately converted to the , -unsaturated ester 21. Wit-
tig olefination of aldehyde 20 was again carried out in
benzene at r.t. to give only the (E)-product 21, whereas the
reaction conditions used by Andrus (90 °C, toluene) led to
For the chain extension of the aldehyde 3 to generate the
next two stereogenic centers, Andrus used Brown’s
crotylboration6 reaction with ( )-(ipc)2-(E)-crotylbo-
Synthesis 2002, No. 2, 207–212 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Phenalamides, (C-9 to C-18) Synthesis
2-Methyl-4-phenyl-1-butene (7)
To magnesium turnings (40.4 g, 1.66 mol) in anhyd THF (400 mL)
was added 2-methyl-2-propenyl chloride (10 mL) under a nitrogen
atmosphere. Further methallyl chloride (116 mL, 1.19 mol in total)
was added dropwise (the velocity of the reaction was controlled by
cooling the reaction with an ice-bath). After reaction completion,
the soln was transferred via canula to a storage vessel, titrated, and
was found to be 1.47 M.
209
tBuMe2SiO
tBuMe2SiO
OH
AD-mix
tBuOH, H2O
Ph
Ph
HO
18
19
99 %
tBuMe2SiO
O
Ph3PCH(CH3)COOEt
C6H6 , 25 oC
Pb(OAc)4
Ph
CH2Cl2, 0 oC
BnBr (78 g, 0.45 mol) was added at 0 °C over 5 h via a syringe
pump to a soln of the Grignard reagent (1.47 M, 350 mL, 0.5 mol).
After heating at reflux for 3 h, the mixture was cooled to 0 °C. Sat.
NH4Cl (200 mL) was added, the layers were separated and the aq
layer was extracted with Et2O (4 60 mL). The combined organic
layers were washed with brine (150 mL), dried (MgSO4), concen-
trated at 20 Torr, and fractionated to give compound 7 (63.0 g, 96%)
as a colourless liquid.
99 %
20
tBuMe2SiO
O
iBu2AlH
Ph
OEt
THF, -40 oC
Ph
t
OSiMe2 BuOH
95 %
21
Swern-Oxid.
CH2Cl2, -60 oC
Bp 74 76 °C, 12 Torr.
1H NMR (300 MHz, CDCl3): = 1.70 (s, 3 H), 2.22–2.28 (m, 2 H),
2.66–2.71 (m, 2 H), 4.66 (m, 2 H), 7.08–7.23 (m, 5 H).
97 %
22
tBuMe2SiO
Ph
O
13C NMR (75 MHz, CDCl3): = 22.6, 34.3, 39.6, 110.2, 125.8,
128.28, 128.31, 142.2, 145.4
92 %
6
Scheme 7
Anal. Calcd for C11H14 (146.2): C, 90.35; H, 9.65. Found: C, 90.22;
H, 9.76.
8:1 E:Z-mixture. In our hands, the conversion of 18 into
21 could thus be realized with 94% overall yield.
2-Methyl-4-phenyl-1-butanol (8)
BH3 SMe2 (10.0 M in DMS, 48.2 mL, 0.48 mol) was added drop-
wise at 0 °C to a soln of 7 (58.8 g, 0.40 mol) in THF (300 mL). The
mixture was stirred for 1 h at 0 °C and then at r.t. for 12 h. After
cooling to 0 °C aq NaOH (10%, 250 mL) and aq H2O2 (35%, 100
mL) were added dropwise resulting in the formation of a white pre-
cipitate. After stirring for 30 h at r.t., the mixture was transferred to
a separatory funnel. K2CO3 was added to saturation and the mixture
was extracted with tert-butylmethylether (4 100 mL). The com-
bined organic layers were washed with brine (50 mL), dried
(MgSO4), and concentrated. Distillation of the residue at 0.4 Torr
furnished alcohol 8 (49.5 g, 75%) as a colourless liquid.
The final steps to the target compound 6 were routine:
lithium aluminium hydride reduction (77%) followed by
Swern oxidation (92%). After the protocol of Andrus be-
came available, we likewise used DIBAL-H reduction
(97%) followed by Ley oxidation (80%) to obtain alde-
hyde 6 in high yield (Scheme 8).
At this point it should be mentioned that compound 6 was
t
OSiMe2 Bu
Bp: 100 105 °C at 0.4 Torr.
Ph
1H NMR (300 MHz, CDCl3): = 0.96 (d, J = 6.6 Hz, 3 H), 1.31–
1.40 (m, 1 H), 1.46 (broad s, 1 H, OH), 1.50–1.73 (m, 2 H), 2.59
(ddd, J = 13.7, 9.9, 6.4 Hz, 1 H), 2.71 (ddd, J = 13.7, 10.0, 5.5 Hz,
1 H), 3.35 (dd, J = 10.6, 6.3 Hz, 1 H), 3.43 (dd, J = 10.6, 5.8 Hz, 1
H), 7.06–7.22 (m, 5 H). Cf. the data in ref.7a
O
6
59 %
23
t
13C NMR (75 MHz, CDCl3): = 16.5, 33.3, 34.9, 35.3, 68.1, 125.7,
128.3, 142.6
OSiMe2 Bu
O
Ph
N
H
t
OSiMe2 Bu
2-Methyl-4-phenyl-butanal (9)
76 %
24
A soln of oxalyl chloride (21.8 g, 0. 17 mol) in CH2Cl2 (400 mL)
was cooled to –78 °C and a soln of DMSO (24.7 mL, 0.35 mol) in
CH2Cl2 (30 mL) was added dropwise to the oxalyl chloride. After
stirring for 10 min, the alcohol 8 (15.7 g, 0.10 mol) in CH2Cl2 (100
mL) was added dropwise. The mixture was stirred for further 20
min at –78 °C and Et3N (62.8 mL, 0.45 mol) was added dropwise
resulting in a thick suspension. The suspension was allowed to
reach r.t., H2O (300 mL) was added and the layers separated. The aq
layer was extracted with Et2O (3 175 mL). The combined organic
layers were washed with HCl (1%, 175 mL), sat. NaHCO3 (175
mL), brine (150 mL), dried (MgSO4) and concentrated. Distillation
of the residue furnished aldehyde 9 (13.9 g, 89%) as a clear liquid.
2b
Scheme 8
successfully converted5 to the alkapentaenal 23 using the
alkatrienal-homologation17 developed specifically for this
project. The aldehyde 23 was then transformed by Wittig
olefination to phenalamide A2.
The experimental details of the latter transformations have already
been published as supplementary material to ref.5 All temperatures
Bp: 54–57 °C/0.4 Torr.
quoted are uncorrected. H, 13C NMR were recorded on a Bruker
1H NMR (300 MHz, CDCl3): = 1.11 (d, J = 7.0 Hz, 3 H), 1.57–
1.69 (m, 1 H), 1.97–2.09 (m, 1 H), 2.33 (qddd, J = 7, 7, 7, 1.7 Hz,
1 H), 2.56–2.67 (m, 2 H), 7.15–7.33 (m, 5 H), 9.58 (d, J = 1.8 Hz,
1 H).
1
ARX-200, AC-300, AM-400, and AMX-500. Boiling range of pe-
troleum ether (PE) was 40 60 °C. Flash chromatography was pre-
formed with silica gel Si60, E. Merck KGaA, Darmstadt, 40–63 m.
Synthesis 2002, No. 2, 207–212 ISSN 0039-7881 © Thieme Stuttgart · New York

210
R. W. Hoffmann et al.
PAPER
13C NMR (75 MHz, CDCl3): = 13.2, 32.0, 32.9, 45.4, 125.6,
128.2, 128.3, 141.2, 204.4.
(2S)-2-Methyl-4-phenyl-butanal (9)
The alcohol (S)-8 (1.82 g, 11.1 mmol) was oxidized as described
above to furnish aldehyde 9 (1.78 g, 99%), which was pure accord-
ing to TLC and 1H NMR. For the spectroscopic data see above.
(4S)-3-(4’-Phenyl-butyryl)-4-isopropyl-oxazolidin-2-one (12)
BuLi in hexane (1.43 M, 99.4 mL, 142 mmol) was added dropwise
to a soln of (4S)-4-isopropyl-oxazolidin-2-one12 (17.34 g, 135
mmol) in THF (500 mL) at –78 °C. After stirring for 30 min, a soln
of 4-phenyl-butyryl chloride18 (27.19 g, 149 mmol) in THF (150
mL) was added dropwise. The mixture was stirred for 30 min at
–78 °C and allowed to reach r.t. over 8 h. Sat. NaHCO3 (1 L) was
added, the layers separated and the aq layer was extracted with tert-
butylmethylether (3 100 mL). The combined organic layers were
washed with sat. aq NaHCO3 (200 mL), brine (200 mL), dried
(MgSO4), and concentrated to give 12 (36.4 g, 98%) as a colourless
oil.
1H NMR (400 MHz, CDCl3): = 0.91 (d, J = 6.9 Hz, 3 H), 0.96 (d,
J = 7.0 Hz, 3 H), 2.05 (m, 2 H), 2.41 (sept. d, J = 7.0, 3.9 Hz, 1 H),
2.74 (t, J = 7.7 Hz, 2 H), 3.02 (m, 2 H), 4.23 (dd, J = 9.1, 3.2 Hz, 1
H), 4.28 (t, J = 8.6 Hz, 1 H), 4.46 (td, J = 7.6, 3.8 Hz, 1 H), 7.24 (m,
3 H), 7.33 (t, J = 7.4 Hz, 2 H).
(2E)-2,4-Dimethyl-6-phenyl-2-hexenal (3)
BuLi (1.51 M in hexane, 6.6 mL, 10.0 mmol) was added dropwise
to a soln of diisopropylamine (1.01 g, 10.0 mmol) in anhyd THF (10
mL) at –78 °C. After maintaining the mixture for 40 min at –65 °C,
a soln of N-cyclohexyl-N-propylidene-amine (1.39 g, 10.0 mmol) in
THF (10 mL) was added dropwise. After stirring for 35 min, the
mixture was cooled to –78 °C, a soln of aldehyde 9 (811 mg, 5.0
mmol) in THF (10mL) was added dropwise, and the mixture was al-
lowed to reach r.t. After stirring for 2 d, a soln of oxalic acid dihy-
drate (1.25 g) in MeOH (20 mL) was added and the soln was heated
to reflux for 2 h. H2O (1mL) was added and heating was continued
for 3 h. Sat. aq NH4Cl (50 mL) was added resulting in the formation
of a white precipitate. The mixture was extracted with tert-butyl-
methylether (3 50 mL). The combined organic layers were
washed with sat. aq NaHCO3 (40 mL), brine (40 mL), dried
(Na2SO4) and concentrated. Flash chromatography of the residue
with pentane Et2O (5:1) furnished a mixture (993 mg) of com-
pound 3 and residual 9 as a colourless liquid corresponding to 715
mg (71% yield) of 3.
13C NMR (75 MHz, CDCl3): = 14.8, 18.1, 26.2, 28.5, 35.1, 35.3,
58.5, 63.5, 126.1, 128.5, 128.6, 141.7, 173.1, 183.0.
HRMS: m/z calcd for C16H21NO3 (M+): 275.1521. Found: 275.1509.
Ethyl (2E,4S)-2,4-dimethyl-6-phenyl-2-hexenoate (14)
1-Ethoxycarbonylethylidene-triphenylphosphorane (12.0 g, 33
mmol) was added to a soln of (2S)-2-methyl-4-phenyl-butanal (9)
(1.78 g, 11.0 mmol) in benzene (100 mL). The mixture was stirred
until reaction completion (ca. 2 d). The soln was concentrated to ca.
50 mL and filtered over silica gel. The filtrate was concentrated and
the residue was added into vigorously stirred pentane (300 mL), re-
sulting in the slow precipitation of triphenylphosphine oxide and
excess ylide. The mixture was filtered and the filtrate was concen-
trated. Flash chromatography of the residue with pentane tert-
butylmethylether (4:1) furnished compound 14 (2.54 g, 96%) as a
colourless oil.
(2’S,4S)-3-[2’-Methyl-4’-phenyl-butyryl]-4-isopropyl-oxazol-
idin-2-one (13)
BuLi in hexane (1.43 M, 110 mL, 157 mmol) was added dropwise
at 0 °C to a soln of diisopropylamine (15.9 g, 157 mmol) in THF
(140 mL). The mixture was cooled to –78 °C and a soln of 12 (36.4
g, 132 mmol) in THF (100 mL) was added dropwise. After stirring
for 30 min at –78 °C methyl iodide (76.6 g, 540 mmol) was added
dropwise and after 6 h stirring at –78 °C, the mixture was allowed
to reach r.t. Sat. NH4Cl (130 mL) was added, the layers separated
and the aq layer was extracted with CH2Cl2 (3 200 mL). The com-
bined organic layers were washed with HCl (1 M, 200 mL), sat.
NaHCO3 (200 mL), brine (200 mL), dried (MgSO4), and concen-
trated. Flash chromatography of the residue with pentane tert-bu-
tylmethylether (1:1) furnished 13 (29.4 g, 77%) as a colourless
liquid.
1H NMR (500 MHz, CDCl3): = 0.86 (d, J = 6.9 Hz, 3 H), 0.90 (d,
J = 7.0 Hz, 3 H), 1.25 (d, J = 6.9 Hz, 3 H), 1.71 (m, 1 H), 2.12 (m,
1 H), 2.33 (sept,d, J = 7.0, 4.0 Hz, 1 H), 2.63 (m, 2 H), 3.81 (sext,
J = 6.9 Hz, 1 H), 4.16 (dd, J = 9.1, 3.2 Hz, 1 H), 4.20 (t, J = 8.0 Hz,
1 H), 4.35 (td, J = 7.6, 3.8 Hz, 1 H), 7.17 (m, 3 H), 7.27 (t, J = 7.4
Hz, 2 H).
[ ]20D +29.9 (c, 1.37, CHCl3).
1H NMR (300 MHz, CDCl3): = 1.04 (d, J = 6.7 Hz, 3 H), 1.31 (t,
J = 7.1 Hz, 3 H), 1.66 (m, 2 H), 1.81 (d, J = 1.4 Hz, 3 H), 2.57 (m,
3 H), 4.23 (q, J = 7.1 Hz, 2 H), 6.59 (dq, J = 10.1, 1.4 Hz, 1 H), 7.18
(m, 3 H), 7.26 (m, 2 H).
13C NMR (50 MHz, CDCl3): = 12.6, 14.3, 20.0, 32.8, 33.7, 38.5,
60.4, 125.8, 126.9, 128.3, 142.1, 147.4, 168.4, cf. the data reported
by Andrus6 (they give an additional methyl signal at 22.2 ppm,
which could arise from the Z-isomer).
13C NMR (50 MHz, CDCl3): = 14.9, 18.2, 18.5, 28.2, 34.1, 35.1,
37.8, 58.6, 63.4, 126.1, 128.6, 128.7, 142.0, 153.9, 177.0.
Anal. Calcd for C16H22O2 (246.3): C, 78.01; H, 9.00. Found: C,
77.90; H, 9.16.
Anal Calcd for C11H23NO3 (289.4): C, 70.56; H, 8.01; N, 4.84.
Found: C, 70.53; H, 8.03; N, 4 .89.
(2E,4S)-2,4-Dimethyl-6-phenyl-2-hexen-ol (15)
A soln of compound 14 (4.58 g, 18.6 mmol) in Et2O (20 mL) was
added dropwise at 0 °C into a suspension of LiAlH4 (1.42 g, 37.5
mmol) in Et2O (40 mL). After stirring for 15 min, TLC indicated the
complete consumption of the starting material. EtOAc (10 mL),
H2O (2.5 mL), aq NaOH (15%, 2.5 mL), and again H2O (7.5 mL)
were added sequentially. The resulting precipitate was filtered and
the filtrate was concentrated to give the alcohol 15 (3.69 g, 97%) as
(2S)-2-Methyl-4-phenyl-butanol (8)
A soln of 13 (12.0 g, 41.5 mmol) in Et2O (90 mL) was added drop-
wise at 0 °C to a soln of LiAlH4 (4.72 g, 124 mmol) in Et2O (200
mL). After stirring for 90 min at 0 °C, the mixture was allowed to
reach r.t. After reaction completion, the mixture was cooled to 0 °C
and EtOAc (20 mL) was added. Hydrolysis was affected by addition
of H2O (5 mL), aq NaOH (15%, 5 mL) and again H2O (15 mL). The
resulting precipitate was filtered and washed with tert-butylmethyl-
ether (50 mL). The filtrate was concentrated and the residue was
purified by flash chromatography with pentane tert-butylmethyl-
ether (1:1) to yield 8 (6.21 g, 91%) as a colourless liquid. For spec-
troscopic data see above.
1
a colourless oil. The material was pure according to TLC and H
NMR.
1H NMR (300 MHz, CDCl3): = 0.90 (d, J = 6.8 Hz, 3 H), 1.35
(broad s, 1 H), 1.53 (m, 1 H), 1.56 (d, J = 1.3 Hz, 3 H), 2.34 (m, 1
H), 2.50 (td, J = 8.0, 2.3 Hz, 2 H), 3.93 (s, 2 H), 5.14 (dq, J = 9.6,
1.3 Hz, 1 H), 7.09 (m, 3 H), 7.17 (m, 2 H); signal for OH is missing.
13C NMR (100 MHz, CDCl3): = 13.9, 21.0, 31.8, 34.8, 39.2, 69.0,
125.6, 128.2, 128.3, 132.3, 133.7, 142.8.
[ ]20
20.0 (c, 5.0, CHCl3).
D
Synthesis 2002, No. 2, 207–212 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Phenalamides, (C-9 to C-18) Synthesis
211
For analysis, a small sample was subjected to flash chromatography
with PE Et2O (4:1).
3 H), 1.61 (m, 2 H), 2.38 (m, 1 H), 2.52 (quint, d, J = 10.0, 6.4 Hz,
2 H), 2.92 (sext, d, J = 6.8, 2.4 Hz, 1 H), 3.75 (d, J = 6.5 Hz, 1 H),
5.10 (d, J = 9.5 Hz, 1 H), 5.64 (dd, J = 9.4, 7.1 Hz, 1 H), 5.95 (d,
J = 7.0 Hz, 1 H), 7.13 (m, 3 H), 7.22 (m, 2 H).
13C NMR (75 MHz, CDCl3): = –4.9, –4.3, 12.4, 17.1, 18.2, 21.1,
25.8, 31.7, 33.8, 36.9, 39.3, 81.2, 117.4, 125.5, 128.2, 128.3, 132.6,
134.7, 135.1, 143.0.
Anal. Calcd for C14H20O (204.3): C, 82.03; H, 9.98. Found: C,
82.03; H, 10.03.
(2E,4S)-2,4-Dimethyl-6-phenyl-2-hexenal (3)
A soln of DMSO(2.07 g, 26.5 mmol) in CH2Cl2 (10 mL) was added
dropwise at –60 °C into a soln of oxalyl chloride (1.70 g, 13.4
mmol) in CH2Cl2 (30 mL). After stirring for 2 min, a soln of 15
(2.45 g, 12.0 mmol) in CH2Cl2 (10 mL) was added. After stirring for
an additional 15 min at –60 °C, Et3N (6.07 g, 60 mmol) was added.
The mixture was stirred for 5 min at –60 °C and then allowed to
reach r.t. H2O (20 mL) was added, the layers separated and the aq
layer was extracted with CH2Cl2 (3 10 mL). The combined organ-
ic layers were washed with aq HCl (2 M, 20 mL), sat. aq NaHCO3
(20 mL), brine (20 mL), dried (MgSO4) and concentrated to furnish
aldehyde 3 (3.33 g, 96%) as a colourless liquid.
1H NMR (300 MHz, CDCl3): = 1.13 (d, J = 6.6 Hz, 3 H), 1.74 (d,
J = 1.1 Hz, 3 H), 1.83 (m, 2 H), 2.62 (td, J = 7.9, 2.1 Hz, 2 H), 2.75
(m, 1 H), 6.32 (dq, J = 9.9, 1.5 Hz, 1 H), 7.17 (d, J = 7.3 Hz, 2 H),
7.22 (d, J = 7.3 Hz, 1 H), 7.31 (t, J = 7.5 Hz, 2 H), 9.44 (s, 1 H).
13C NMR (100 MHz, CDCl3): = 9.3, 19.8, 33.0, 33.6, 38.2, 125.9,
128.2, 128.3, 138.3, 141.6, 159.8, 195.4.
Anal. Calcd for C24H39ClOSi (407.1): C, 70.81; H, 9.66. Found: C,
70.79; H, 9.60.
(3R,4R,5E,7S)-4-(tert-Butyldimethylsilyloxy)-3,5,7-trimethyl-9-
phenyl-1,5-nonadiene (18)
A soln of 17 (470 mg, 1.15 mmol) in THF (5 mL) was cooled to
–78 °C and gaseous NH3 was introduced until the volume of the liq-
uid increased by ca. 20 mL. Lithium-powder (ca. 100 mg) was add-
ed and the resulting blue soln was stirred for 3 h at –78 °C. Solid
NH4Cl was added in portions until the blue colour faded. The sol-
vents were allowed to evaporate overnight and the residue was par-
titioned between H2O (10 mL) and CH2Cl2 (10 mL). The layers
were separated and the aq layer was extracted with CH2Cl2 (3
5
mL). The combined organic layers were dried (MgSO4) and con-
centrated to furnish 18 (430 mg, 100%), which was pure according
to TLC and 1H NMR.
1H NMR (200 MHz, CDCl3): = –0.05 (s, 3 H), 0.00 (s, 3 H), 0.85
(s, 9 H), 0.90 (d, J = 7.0 Hz, 3 H), 0.93 (d, J = 6.5 Hz, 3 H), 1.48
(m, 2 H), 1.53 (s, 3 H), 2.38 (m, 1 H), 2.52 (quint. d, J = 10.0, 6.4
Hz, 2 H), 2.92 (sext.d, J = 6.8, 2.4 Hz, 1 H), 3.75 (d, J = 6.5 Hz, 1
H), 4.90–5.10 (m, 2 H), 5.12 (m, 1 H), 5.85 (m, 1 H), 7.13 (m, 3 H),
7.22 (m, 2 H).
13C NMR (50 MHz, CDCl3): = –4.9, –4.4, 11.4, 16.6, 18.3, 20.8,
25.9, 31.8, 34.1, 39.6, 42.0, 83.5, 113.6, 125.6, 128.2, 128.3, 133.7,
135.5, 142.3, 142.8.
Anal. Calcd for C14H18O (202.3): C, 83.12; H, 8.97. Found: C,
83.34; H, 9.10.
(1Z,2R,4R,5E,7S)-1-Chloro-3,5,7-trimethyl-9-phenyl-nona-1,5-
dien-4-ol (5)
A soln of 3 (728 mg, 3.6 mmol) in PE (6 mL) was added to a soln
of 2-([1’S,2’E]-1’-chloro-but-2’-enyl)-4,4,5,5-tetramethyl-[1,3,2]-
dioxaborolane (4) (1.125 g, 5.2 mmol) in PE (25 mL). After 4 d at
r.t., the mixture was poured into sat. NaHCO3 (10 mL). The layers
were separated and the aq layer was extracted with CH2Cl2 (3 10
mL). The combined organic layers were washed with brine (20
mL), dried (MgSO4), and concentrated. Flash chromatography of
the residue furnished 5 (555 mg, 53%) as a colourless oil.
For analysis, a small sample was subjected to flash chromatography
with PE.
Anal. Calcd for C24H40OSi (372.4): C, 77.35; H, 10.82. Found: C,
77.25; H, 10.85.
[ ]20D –16.5 (c, 1.20, CHCl3).
1H NMR (300 MHz, CDCl3): = 0.89 (d, J = 6.9 Hz, 3 H), 0.92 (d,
J = 6.7 Hz, 3 H), 1.47 (m, 2 H), 1.56 (d, J = 1.3 Hz, 3 H), 1.59 (m,
1 H), 2.41 (m, 1 H), 2.48 (m, 2 H), 2.93 (sext, d, J = 7.5, 1.2 Hz, 1
H), 3.71 (d, J = 8.1 Hz, 1 H), 5.14 (d, J = 9.7 Hz, 1 H), 5.65 (dd,
J = 9.4, 7.1 Hz, 1 H), 6.06 (dd, J = 7.1, 0.7 Hz, 1 H), 7.09 (m, 3 H),
7.21 (m, 2 H).
(2RS,3R,4R,5E,7S)-4-(tert-Butyldimethylsilyloxy)-1,2-di-
hydroxy-3,5,7-trimethyl-9-phenyl-5-nonene (19)
A soln of 18 (430 mg, 1.15 mmol) in t-BuOH (4 mL) was added to
a mixture of potassium osmate(VI)dihydrate (5 mg, 0.01 mmol),
hydroquinine-(1,4-phthalazine-diyl-diether ) (46 mg, 0.06 mmol),
potassium hexacyanoferrate (III) (1.16 g, 3.5 mmol), K2CO3 (534
mg, 3.86 mmol), H2O (11 mL), and t-BuOH (7 mL). After stirring
for 3.5 h, the reaction was terminated by addition of Na2SO3 (850
mg, 6.7 mmol). The layers were separated and the aq layer was ex-
tracted with CH2Cl2 (3 10 mL). The combined organic layers
were washed with brine (10 mL), dried (MgSO4), and concentrated
to give 19 (468 mg, 99%) as a mixture of diastereomers.
1H NMR (300 MHz, CDCl3): = –0.07 (s, 3 H), 0.00 (s, 3 H), 0.54
(d, J = 7.0 Hz, 3 H), 0.77 (s, 9 H), 0.81 (d, J = 6.9 Hz, 3 H), 1.39
(m, 1 H), 1.43 (d, J = 1.2 Hz, 3 H), 1.50 (m, 2 H), 1.71 (m, 1 H),
2.21–2.32 (m, 1 H), 2.45 (m, 2 H), 3.33–3.60 (m, 3 H), 3.75 (d,
J = 9.2 Hz, 1 H), 4.49 (s, 1 H), 5.04 (d, J = 9.1 Hz, 1 H), 7.02 (m, 3
H), 7.13 (m, 2 H).
13C NMR (75 MHz, CDCl3): = 11.5, 16.7, 20.9, 31.9, 34.0, 36.0,
39.3, 81.8, 119.1, 125.6, 128.26, 128.29, 134.2, 134.3, 134.8, 142.7.
Anal. Calcd for C18H25ClO (292.9): C, 73.83; H, 8.61. Found: C,
73.74; H, 8.71.
(1Z,3R,4R,5E,7S)-1-Chloro-4-(tert-butyldimethylsilyloxy)-
3,5,7-trimethyl-9-phenyl-1,5-nonadiene (17)
tert-Butyl-dimethylsilyl triflate (1.41 g, 5.33 mmol) was added
dropwise at r.t. to a soln of alcohol 5 (1.04 g, 3.55 mmol) and 2,5-
lutidine (0.76 g, 7.1 mmol) in CH2Cl2 (4 mL). Additional tert-butyl-
dimethyl-silyl triflate (0.5 mL) and 2,6-lutidine (0.5 mL) were add-
ed after 3 h at r.t. to bring the reaction to completion. After stirring
for 12 h, MeOH (15 mL) was added and stirring continued for a fur-
ther 20 min. the mixture was partitioned between tert-butylmethyl-
ether (20 mL) and sat. aq NH4Cl (20 mL). The layers were separated
and the aq layer was extracted with tert-butylmethylether (4 25
mL). The combined organic layers were washed with brine (20
mL), dried (MgSO4), and concentrated. Flash chromatography of
the residue with PE furnished 17 (1.18 g, 82%) as a colourless oil.
For analysis, a sample was purified by flash chromatography with
PE tert-butylmethylether (1:2).
Anal Calcd for C24H42O3Si (406.7.): C, 63.52; H, 11.33. Found: C,
63.30; H, 11.22
(2S,3R,4E,6S)-3-(tert-Butyldimethylsilyloxy)-2,4,6-trimethyl-8-
phenyl-4-octanal (20)
Na2CO3 (1.22 g, 11.5 mmol) and lead (IV)-acetate (510 mg, 1.15
mmol) were added sequentially into a soln of 19 (468 mg, 1.15
1H NMR (200 MHz, CDCl3): = –0.05 (s, 3 H), 0.00 (s, 3 H), 0.85
(s, 9 H), 0.90 (d, J = 7.0 Hz, 3 H), 0.93 (d, J = 6.5 Hz, 3 H), 1.53 (s,
Synthesis 2002, No. 2, 207–212 ISSN 0039-7881 © Thieme Stuttgart · New York

212
R. W. Hoffmann et al.
PAPER
(2E,4R,5R,6E,8S)-5-(tert-Butyldimethylsilyloxy)-10-phenyl-
mmol) in CH2Cl2 (50 mL) at 0 °C. The mixture was stirred for 2 h.
When reaction was complete (TLC), the mixture was filtered over
Kieselguhr and the filtrate was concentrated to give the crude alde-
hyde 20, which was used in the next step without purification.
13C NMR (75 MHz, CDCl3): = –5.2, –4.2, 11.1, 11.2, 18.1, 20.5,
25.7, 31.9, 33.9, 39.3, 50.0, 80.8, 125.7, 128.28, 128.31, 133.7,
135.4, 142.6, 205.2.
2,4,6,8-tetramethyl-2,6-decadienal (6)
The alcohol 22 (138 mg, 0.33 mmol) was oxidized as described
above for 3. Flash chromatography of the crude product with PE
tert-butylmethylether (20:1) furnished the aldehyde 6 (126 mg,
92%) as a colourless oil.
1H NMR (200 MHz, CDCl3): = –0.08 (s, 3 H), 0.04 (s, 3 H), 0.76
(s, 9 H), 0.92 (d, J = 6.5 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3 H), 1.44–
1.65 (m, 2 H), 1.50 (d, J = 1.3 Hz, 3 H), 1.69 (d, J = 1.3 Hz, 3 H),
2.42–2.50 (m, 3 H), 2.74–2.90 (m, 1 H), 3.76 (d, J = 7.6 Hz, 1 H),
5.10 (d, J = 9.5 Hz, 1 H), 6.29 (dd, J = 10.0, 1.3 Hz, 1 H), 7.13 (m,
5 H), 9.33 (s, 1 H).
A sample was purified by flash chromatography with PE ether
(30:1).
Anal Calcd. for C23H38O2Si (374.6): C, 73.74; H, 10.22. Found: C,
73.63; H, 10.18.
13C NMR (50 MHz, CDCl3): = –5.3, –4.7, 9.3, 11.2, 16.4, 17.8,
20.4, 25.4, 31.6, 33.8, 37.9, 39.1, 82.6, 125.4, 128.0, 134.3, 138.8,
142.3, 158.2, 195.1.
Ethyl (2E,4R,5R,6E,8S)-5-(tert-Butyldimethylsilyloxy)-2,4,6,8-
tetramethyl-10-phenyl-2,6-decadienoate (21)
Ethoxycarbonyl-ethylidene-triphenyl-phosphorane (1.15 g, 3.16
mmol) was added to a soln of 20 (395 mg, 1.05 mmol) in benzene
(20 mL). After stirring for 3 d at r.t., the soln was concentrated and
the residue was introduced into pentane (50 mL) under vigorous
stirring. This resulted in the precipitation of triphenylphosphine ox-
ide and residual ylide. The mixture was filtered and the filtrate was
concentrated. Flash chromatography of the residue with pentane
tert-butylmethylether (10:1) furnished 21 (458 mg, 95%) as a co-
lourless oil.
Anal. Calcd for C26H42O2Si (414.7): C, 75.30; H, 10.21. Found: C,
75.21; H, 10.14.
Acknowledgement
This study has been supported by the Deutsche Forschungsgemein-
schaft (SFB 260, Graduierten Kolleg „Metallorganische Chemie„)
and the Fonds der Chemischen Industrie.
1H NMR (500 MHz, CDCl3): = 0.01 (s, 3 H), 0.02 (s, 3 H), 0.86
(s, 9 H), 0.92 (s, 3 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.27 (t, J = 7.1 Hz,
3 H), 1.58 (s, 3 H), 1.62–1.69 (m, 2 H), 1.86 (s, 3 H), 2.43 (sept,
J = 6.2 Hz, 1 H), 2.50–2.56 (m, 1 H), 2.60–2.70 (m, 2 H), 3.78 (d,
J = 7.7 Hz, 1 H), 4.17 (m, 2 H), 5.17 (d, J = 9.6 Hz, 1 H), 6.66 (d,
J = 10.2 Hz, 1 H), 7.15–7.19 (m, 3 H), 7.26–7.29 (m, 2 H); signal
for OH is missing.
13C NMR (125 MHz, CDCl3): = –5.0, –4.5, 11.4, 12.6, 14.3, 16.6,
18.1, 21.1, 25.7, 31.8, 33.9, 38.1, 39.3, 60.2, 82.8, 125.6, 127.3,
128.2, 128.3, 134.0, 134.9, 142.8, 146.0, 168.3
References
(1) Andrus, M. B.; Lepore, S. D. J. Am. Chem. Soc. 1997, 119,
2327.
(2) Andrus, M. B.; Lepore, S. D.; Sclafani, J. A. Tetrahedron
Lett. 1997, 38, 4043.
(3) Andrus, M. B.; Turner, T. M.; Asgari, D.; Li, W. J. Org.
Chem. 1999, 64, 2978.
(4) Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64, 23.
(5) Hoffmann, R. W.; Rohde, T.; Haeberlin, E.; Schäfer, F. Org.
Lett. 1999, 1, 1713.
(6) Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am. Chem.
Soc. 1997, 119, 12159.
(7) (a) Namy, J.-L.; Boireau, G.; Abenhaim, D. Bull. Soc. Chim.
Fr. 1971, 3191. (b) Anastasis, P.; Freer, I.; Overton, K. H.;
Picken, D.; Rycroft, D. S.; Singh, S. B. J. Chem. Soc., Perkin
Trans. 1 1987, 2427.
Cf. the data reported by Andrus6 in which one methyl signal is miss-
ing, there is an additional signal at 38.6 ppm.
Anal Calcd. for C28H46O3Si (458.8): C, 73.31; H, 10.11. Found: C,
73.46; H, 10.22.
(2E,4R,5R,6E,8S)-5-(tert-Butyldimethylsilyloxy)-2,4,6,8-tetra-
methyl-10-phenyl-2,6-decadienol (22)
A soln of DIBAL-H (1.0 M, 0.52 mL) in PE was added at –40 °C
slowly into a soln of compound 21 (80 mg, 174 mol) in THF (2
mL). After stirring for 1 h at –40 °C MeOH (1 mL) was added and
the soln was allowed to reach r.t. Sat. aq potassium sodium tartrate
(2 mL) was added, the layers separated and the aq layer was extract-
ed with CH2Cl2 (3 5 mL). The combined organic layers were
washed with brine (10 mL) dried (MgSO4) and concentrated. Flash
chromatography of the residue with pentane tert-butylmethylether
(10:1) furnished 22 (70 mg, 97%) as a colourless oil.
(8) Manusco, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem.
1978, 43, 2480.
(9) Wittig, G.; Reiff, H. Angew. Chem. 1968, 80, 8; Angew.
Chem., Int. Ed. Engl. 1968, 7, 7.
(10) Corey, E. J.; Enders, D.; Bock, M. G. Tetrahedron Lett.
1976, 7.
(11) Charette, A. B.; Naud, J. Tetrahedron Lett. 1998, 39, 7259.
(12) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737.
1H NMR (200 MHz, CDCl3): = –0.12 (s, 3 H); 0.09 (s, 3 H), 0.75
(d, J = 5.8 Hz, 3 H), 0.77 (s, 9 H), 0.88 (d, J = 6.5 Hz, 3 H), 1.36–
1.54 (m, 2 H), 1.49 (d, J = 1.0 Hz, 3 H), 1.60 (d, J = 1.0 Hz, 3 H),
2.29–2.42 (m, 2 H), 2.42–2.59 (m, 2 H), 3.59 (d, J = 8.0 Hz, 1 H),
3.91 (s, 2 H), 5.01 (d, J = 9.8 Hz, 1 H), 5.16 (d, J = 9.8 Hz, 1 H),
7.05–7.10 (m, 3 H), 7.15–7.22 (m, 2 H).
(13) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem 1987,
52, 3701.
(14) Hoffmann, R. W.; Dresely, S.; Lanz, J. W. Chem. Ber. 1988,
121, 1501.
(15) Hoffmann, R. W.; Dresely, S.; Hildebrandt, B. Chem. Ber.
1988, 121, 2225.
(16) Hoffmann, R. W.; Dahmann, G.; Andersen, M. W. Synthesis
1994, 629.
(17) Hoffmann, R. W.; Schäfer, F.; Haeberlin, E.; Rohde, T.;
Körber, K. Synthesis 2000, 2060.
(18) Cromwell, N. H.; Creger, P. L.; Cook, K. E. J. Am. Chem.
Soc. 1956, 78, 4412.
13C NMR (50 MHz, CDCl3): = –5.0, –4.5, 11.3, 14.1, 17.6, 18.1,
20.7, 25.7, 31.8, 34.0, 36.5, 39.5, 69.2, 83.6, 125.6, 128.2, 128.3,
130.5, 133.7, 134.2, 135.4, 142.8.
Anal. Calcd for C26H44O2Si (416.3): C, 74.94; H, 10.64. Found: C,
74.80; H, 10.68.
Synthesis 2002, No. 2, 207–212 ISSN 0039-7881 © Thieme Stuttgart · New York