Synthesis of the alkaloid tyroscherin by an aldol/Curtius strategy

Article abstract of DOI:10.1016/j.tet.2010.02.034

The alkaloid tyroscherin (2), which contains a vicinal anti-amino alcohol subunit was prepared from 4-hydroxyphenylpropionic acid (5) and meso-diol 9. After desymmetrization of diol 9 and suitable protecting group manipulations, one terminus was extended via a Claisen rearrangement giving rise to enoate ent-15. The missing carbon on the other end could be incorporated using MeMgCl/CuBr·SMe₂ leading eventually to aldehyde ent-22. The acylated oxazolidinone 32 derived from acid 5 and aldehyde ent-22 were combined in an aldol reaction. A subsequent Curtius rearrangement on the carboxylic group furnished the amino function of tyroscherin (2). In a proof of concept study the same strategy was used to prepare tyroscherin analog 28.

Full text of DOI:10.1016/j.tet.2010.02.034

Tetrahedron 66 (2010) 2633–2641
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Synthesis of the alkaloid tyroscherin by an aldol/Curtius strategy
*
Markus Ugele, Martin E. Maier
Institut fu¨r Organische Chemie, Universita¨t Tu¨bingen, Auf der Morgenstelle 18, 72076 Tu¨bingen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The alkaloid tyroscherin (2), which contains a vicinal anti-amino alcohol subunit was prepared from
4-hydroxyphenylpropionic acid (5) and meso-diol 9. After desymmetrization of diol 9 and suitable
protecting group manipulations, one terminus was extended via a Claisen rearrangement giving rise to
enoate ent-15. The missing carbon on the other end could be incorporated using MeMgCl/CuBr$SMe2
leading eventually to aldehyde ent-22. The acylated oxazolidinone 32 derived from acid 5 and aldehyde
ent-22 were combined in an aldol reaction. A subsequent Curtius rearrangement on the carboxylic group
furnished the amino function of tyroscherin (2). In a proof of concept study the same strategy was used
to prepare tyroscherin analog 28.
Received 11 December 2009
Received in revised form 4 February 2010
Accepted 5 February 2010
Available online 10 February 2010
Keywords:
Alkaloid
Group selective reaction
Curtius
Ó 2010 Elsevier Ltd. All rights reserved.
Amine
Aldol reaction
1. Introduction
HO
HO
H
Me
N
6
12
3
The b-phenylethylamine substructure is present in a range of
2
8
10
1
natural and man-made molecules.1 An unique representative of
this class of compounds is tyroscherin,2 which is a hybrid between
tyrosine and a polyketide fragment. A possible biosynthetic pre-
cursor 3 is shown in Figure 1. In 2008, total synthesis studies led to
the conclusion that the original published stereostructure needed
revision.3,4,5 Thus, the syn-amino alcohol stereochemistry actually
has anti-configuration and the C8,C10-stereochemistry is opposite
to the originally proposed configurations. The molecule was
reported to inhibit the growth of cancer cells that depend on the
insulin-like growth factor (IGF). The IC50 value for MCF-7 human
breast cells containing IGF-1 (30 ng mLꢀ1) was 9.7 ng mLꢀ1. If the
growth-stimulating IGF-1 is replaced by fetal bovine serum, tyro-
scherin had essentially no activity on these cells. Thus, a concise
route to tyroscherin and possibly its stereoisomers seemed of in-
terest. In particular derivatives thereof might allow for identifica-
tion of the cellular target. The approach followed by Watanabe
et al.3,4 uses the Weinreb amide of N-Boc-N-methyl tyrosine for
chain extension. The section containing the two methyl groups was
later attached via a Julia olefination. We thought about forming the
C2–C3 bond via an asymmetric aldol reaction followed by Curtius
degradation of the carboxylic group.6 In the following we describe
the realization of this strategy.
HO
proposed structure of tyroscherin (1)
H
Me
N
HO
revised structure of tyroscherin (2)
polyketide part
HO
H
Me
COX
N
3
O
tyrosine
HO
Claisen condensation
Curtius
COX
1
aldol
HO
4
Figure 1. Structures of the proposed (1) and revised (2) tyroscherin together with the
biosynthesis precursor 3 and the retrosynthetic analysis.
2. Results and discussion
The synthesis of the carboxylic acid part for the aldol reaction
started with 4-hydroxyphenylpropionic acid (5) (Scheme 1). While
the corresponding 4-triisopropylsilyl and MOM ether and could
* Corresponding author. Tel.: þ49 7071 2975247; fax: þ49 7071 295137.
E-mail address: martin.e.maier@uni-tuebingen.de (M.E. Maier).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.034

2634
M. Ugele, M.E. Maier / Tetrahedron 66 (2010) 2633–2641
also be prepared, we faced severe problems in acylating the lithi-
ated Evans oxazolidinone 7 via the mixed anhydride.7 For some
reason the acylation with the acid8 6 containing a 4-methox-
yphenyl group worked nicely. The absolute configuration of the
chiral auxiliary was chosen in such a way that the 3-OH group
would have to be inverted at a later stage of the synthesis but the
carboxyl, respectively, amino group would be correct. Thus, in one
step a crucial carbon–carbon bond as well as two stereogenic
centers would be formed that would open the way to tyroscherin
and analogs. In addition, this strategy would allow for the prepa-
ration of oxazolidinone derivatives.9
unsaturated ester 15. Reduction of the ester 15 to alcohol 16,
protection as PMB ether 17, cleavage of the silyl ether of com-
pound 17 and tosylation of primary alcohol 18 provided tosylate
19. Substitution of the tosylate with MeMgCl in presence of
CuBr$SMe2 gave an excellent yield of the C3–C12 fragment 20.11,15
All these steps went with high chemical yields. In contrast,
cleavage of the PMB ether in alkene 20 turned out to be prob-
lematic and only proceeded with moderate efficiency. Finally,
oxidation of alcohol 21 furnished aldehyde 22, required for the
subsequent aldol reaction. An earlier introduction of the C12
methyl group was possible, but this aldehyde corresponding to 13
turned out to be rather volatile making its isolation and purifi-
cation difficult.
The propionic acid derivative 8 and aldehyde 22 were combined
via an Evans aldol reaction using Bu2BOTf and Et3N in CH2Cl2 at low
temperature (Scheme 3).16 The fact that we could only observe one
set of signals in the 13C NMR indicated the high diastereoselectivity
in the aldol reaction. MOM protection of the alcohol 23 followed by
saponification of the amide derivative led to acid 25. The Curtius
rearrangement was induced with diphenylphosphoryl azide17 in
presence of tert-butanol to provide BOC protected amine 26. This
was followed by N-methylation18 and cleavage of the MOM and
BOC protecting group under acidic conditions. The final cleavage of
the arylmethyl ether under various conditions (BBr3,19 9-I-BBN) did
give the desired product according to LC–MS. However, the product
was always contaminated with products resulting from addition of
HX (X¼Br, I) to the double bond. Therefore, another protecting
group was needed. Since at this time the correct structure also
became known,3,4 the synthesis was aimed at this diastereomer. In
fact, due to the C2–C3 anti-stereochemistry, the aldol/Curtius ap-
proach seemed even more suitable.
OMe
RO
1. PivCl, Et3N
THF
CO2H
O
2.
5 R = H
6 R = Me
O
O
Li
1. MeI, K2CO3
N
O
N
O
2. NaOH, MeOH
8
(92%)
Bn
(80%)
7
Bn
Scheme 1. Synthesis of propionyl oxazolidinone 8.
For the synthesis of the polyketide segment we started with
the known meso-diol 9 and relied on a desymmetrization via se-
lective enzyme-catalyzed monoacylation (Scheme 2).10,11 Simple
protecting group manipulations led via the tert-butyldiphenylsi-
lylether12 11 and 12 to aldehyde 13. Reaction of aldehyde 13 with
vinylmagnesium bromide furnished the vinylic alcohol 14 as
a diastereomeric mixture (2:1). This was subjected to a Johnson–
Claisen rearrangement13,14 leading in almost quantitative yield to
OMe
Amano AK
HO
OH
AcO
OR
10 R = H
Bn
vinyl acetate
nBu2BOTf, Et3N
CH2Cl2, –80 °C
9
TBDPSCl
8
Et3N, CH2Cl2
(98%)
O
N
add 22 (95%)
11 R = TBDPS
O
OR
O
23 R = H
K2CO3, MeOH
(98%)
PhI(OAc)2
TEMPO (88%)
MOMCl, Et3N
CH2Cl2 (95%)
H
24 R = MOM
O
TBDPSO
13
HO TBDPSO
MeO
12
LiOH, H2O2
CO2H
THF/H2O (87%)
CH2=CHMgBr
(EtO)3CCH3
OMOM
25
THF, –80 °C
(73%)
xylene, 140 °C
(96%)
HO TBDPSO
14
1. (PhO)2P(O)N3, Et3N
benzene
MeO
R
Boc
N
TBAF
DIBAL-H
CH2Cl2, –80 °C
(93%)
2. tBuOH, KOtBu
reflux (64%)
THF (95%)
TBDPSO
TBDPSO
15
OMOM
CO2Et
26 R = H
OR
NaH, MeI
DMF (85%)
PMBCl, NaH
TBAI, THF
(89%)
16 R = H
17 R = PMB
27 R = Me
MeO
Me
1
H
HCl, THF
N
6
3
55 °C (80%)
2
8
10
MeMgCl
CuBr·SMe2
28
OH
OR
THF (98%)
Scheme 3. Aldol reaction followed by Curtius-rearrangement leading to amino alcohol
26 and tyroscherin analog 28.
OPMB
TsCl, Et3N
CH2Cl2 (97%)
OR
18 R = H
20 R = PMB
21 R = H
DDQ
MeOH/CH2Cl2
(25%)
For the phenol protecting group we settled on an allyl ether. This
required a small detour since the acylation of the Evans oxazoli-
dinone only worked nicely with the methyl- or benzyl ether
(Scheme 4). Thus, after acylation of lithiated oxazolidinone 7 with
the mixed anhydride derived from propionic acid20 29, the benzyl
group was replaced with the allyl ether via hydrogenation and
Williamson etherification to yield amide derivative 32.
19 R = Ts
6
12
DMP, NaHCO3
CH2Cl2 (85%)
3
H
8
10
22
O
Scheme 2. Synthesis of alkenal 22, corresponding to the C3–C12 fragment of tyroscherin.

M. Ugele, M.E. Maier / Tetrahedron 66 (2010) 2633–2641
2635
combination of orthogonal protecting groups was chosen. Thus,
cleavage of the silyl ether yielding hydroxyester 36, and repro-
tection with the THP protecting group was followed by ester re-
duction and silylation. Now OH-11 (tyroscherin numbering) was set
free and alcohol 40 was converted via tosylate 41 to the alkenol ent-
21 and alkenal ent-22.
OBn
OBn
H2, Pd/C
1. PivCl, Et3N
O
2.
MeOH/EtOAc
(92%)
O
O
Li
CO2H
N
O
N
O
(82%)
Bn
30
29
The aldol reaction between acylated oxazolidinone derived
ent-7
Bn
from
L-phenylalanine in presence of TiCl4 and sparteine
OH
OAllyl
(2.5 equiv) gave a 70% yield of hydroxy acid derivative 43.22 With
the classical boron enolate (Bu2BOTf, Et3N, CH2Cl2) only a low
yield could be realized for this aldol reaction. The four-step se-
quence consisting of alcohol protection to MOM ether 44, re-
moval of the chiral auxiliary yielding acid 45, Curtius
rearrangement, and N-methylation of the carbamate 46 delivered
the tyroscherin precursor 47. The global deprotection required
O
O
O
N
O
K2CO3, AllylBr
DMF, r.t. (95%)
O
N
O
31
32
Bn
Bn
a Pd-catalyzed deallylation and acid hydrolysis of the BOC and
Scheme 4. Synthesis of aldol reagent 32 via the benzyl ether 30.
20
MOM groups. The optical rotation {[
a
]
ꢀ19.0 (c 0.35, MeOH)}
D
24
matched pretty well with the reported one2 {[
a
]
ꢀ21.0 (c 0.35,
D
MeOH)}. According to the 1H NMR the synthetic material corre-
sponds to the natural compound. However, we could not obtain
the sharp resolution as reported by Watanabe et al.3,4 The same
was the case for the trifluoroacetate salt. We made this salt be-
cause it has been reported that with an alkaloid this can lead to
better resolved spectra.23 The 13C NMR spectrum showed the
correct chemical shifts (Scheme 6).
In order to enter from monoacetate 10 into the enantiomeric
series of the aliphatic part some protecting group shuffling was
required (Scheme 5). Thus, at the stage of the bis-silyl ether 35 the
TBS ether could be cleaved by acid-induced transetherification in
MeOH.21 Oxidation of the derived ent-12 furnished aldehyde ent-
13. As before, the vinylation-Claisen sequence gave a high yield of
ester ent-15. To differentiate the two ends of the chain another
OAllyl
K2CO3, MeOH
Bn
TiCl4, sparteine
CH2Cl2, –80 °C
AcO
OR
10 R = H
(98%)
32
O
N
TBSCl
Et3N, CH2Cl2
RO
TBDPSCl
TBSO
add ent-22 (70%)
34 R = H
O
OR
O
33 R = TBS
(95%)
imidaz., CH2Cl2
(96%)
43 R = H
MOMCl, Et3N
CH2Cl2 (90%)
35 R = TBDPS
44 R = MOM
AllylO
CSA, MeOH
(91%)
PhI(OAc)2
H
TEMPO (90%)
LiOH, H2O2
CO2H
THF/H2O (85%)
O
TBDPSO
ent-13
TBDPSO
OH
ent-12
OMOM
45
1. (PhO)2P(O)N3, Et3N
benzene
AllylO
R
Boc
CH2=CHMgBr
(EtO)3CCH3
N
THF, –90 °C
(79%)
xylene, 140 °C
(97%)
HO TBDPSO
RO
2. tBuOH, KOtBu
reflux (63%)
CO2Et
ent-14
OMOM
ent-15 R = TBDPS
TBAF
THF (92%)
DHP
pTsOH (97%)
46 R = H
NaH, MeI
DMF (95%)
36 R = H
47 R = Me
37 R = THP
HO
Me
Boc
N
Pd(PPh3)4, THF
DIBAL-H
CH2Cl2, –40 °C
(94%)
pTsOH, EtOH
morpholine (79%)
THPO
65 °C (91%)
48
OMOM
HO
Me
H
OR
TBDPSCl
imidaz., CH2Cl2
(94%)
38 R = H
HCl, THF
N
39 R = TBDPS
55 °C (90%)
OH
tyroscherin (2)
MeMgCl
CuBr·SMe2
THF (96%)
11
8
OR
Scheme 6. Completion of the total synthesis of tyroscherin (2).
3
OTBDPS
OR
TBAF, THF
(91%)
42 R = TBDPS
ent-21 R = H
40 R = H
TsCl, Et3N
CH2Cl2 (96%)
3. Conclusion
41 R = Ts
In conclusion, we accomplished the synthesis of the alkaloid
tyroscherin and a diastereomer by a novel strategy. In the key step,
the C2–C3 bond was created by an aldol reaction. The carboxylic
function in the aldol product served as precursor for the 2-amino
group, obtained via Curtius degradation.
H
O
DMP, NaHCO3
CH2Cl2 (88%)
ent-22
Scheme 5. Synthesis of aldehyde ent-22 from monoacetate 10.

2636
M. Ugele, M.E. Maier / Tetrahedron 66 (2010) 2633–2641
4. Experimental section
aryl), 129.4 (CH aryl), 129.7 (CH aryl), 132.5 (C aryl), 135.2 (C aryl),
153.5 (C-2), 154.0 (CO aryl), 172.5 (C-10).
4.1. General
4.1.4. (4S)-3-{3-[4-(Allyloxy)phenyl]propanoyl}-4-benzyl-1,3-
oxazolidin-2-one (32). A mixture of phenol 31 (152 mg,
0.467 mmol), K2CO3 (162 mg, 1.168 mmol), and allyl bromide
4.1.1. 3-[4-(Benzyloxy)phenyl]propanoic acid (29). A mixture of
3-(40-hydroxyphenyl)propionic acid (4.99 g, 30 mmol), benzyl
chloride (13.9 mL, 120 mmol), KI (19.92 g, 120 mmol), and K2CO3
(16.59 g, 120 mmol) in acetone (70 mL) was refluxed for 36 h. After
cooling, water was added and the mixture extracted with CH2Cl2
(3ꢁ100 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The crude ester was taken up in
H2O/20% NaOH (100 mL,1:1) and the mixture refluxed for 2 h. After
cooling, CH2Cl2 (100 mL) was added, the layers were separated and
the CH2Cl2 layer washed with 5% NaOH (2ꢁ40 mL). The combined
water layers were acidified with concd HCl and extracted with
CH2Cl2 (3ꢁ80 mL). These combined CH2Cl2 layers were dried over
MgSO4, filtered, and concentrated in vacuo yielding acid 29 (6.30 g,
82%) as a colorless solid. Rf (petroleum ether/ethyl acetate, 1:1)
0.15; dH (400 MHz, CDCl3) 2.64 (t, J¼7.8 Hz, 2H, 2-H), 2.90 (t,
J¼7.8 Hz, 2H, 3-H), 5.03 (s, 2H, CH2 aryl), 6.50 (d, J¼8.7 Hz, 2H, aryl),
7.12 (d, J¼8.7 Hz, 2H, aryl), 7.29–7.33 (m, 1H, aryl), 7.35–7.43 (m, 4H,
aryl); dC (100 MHz, CDCl3) 29.8 (C-3), 35.7 (C-2), 70.1 (CH2 aryl),
114.9 (CH aryl), 127.5, 127.9, 128.6 (CH aryl), 129.3 (CH aryl), 132.5 (C
aryl), 137.1 (C aryl), 157.4 (CO aryl), 178.2 (C-1).
(82 mL, 0.934 mmol) in DMF (2 mL) was stirred for 10 h at room
temperature. Then water was added and the mixture extracted
with ethyl acetate (3ꢁ25 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. Purification
of the residue by flash chromatography (petroleum ether/ethyl
acetate, 1:1) provided allyl ether 32 (162 mg, 95%) as an amorphous
20
solid. Rf (petroleum ether/ethyl acetate, 2:1) 0.56; [
a]
þ44.3 (c 1.0,
D
CH2Cl2); dH (400 MHz, CDCl3) 2.74 (dd, J¼13.5, 9.7 Hz, 1H, PhCH2),
2.96 (ddd, J¼7.7, 2.8 Hz, 2H, 30-H), 3.16–3.32 (m, 3H, 20-H, PhCH2),
4.14–4.17 (m, 2H, 4-H), 4.50 (dt, J¼5.3, 1.4 Hz, 2H, OCH2CH]CH2),
4.65 (ddd, J¼13.0, 6.8, 3.6 Hz, 1H, 5-H), 5.26 (dd, J¼10.6, 1.4 Hz, 1H,
CH]CH2), 5.39 (dd, J¼17.2, 1.7 Hz, 1H, CH]CH2), 5.99–6.09 (m, 1H,
CH]CH2), 6.85 (d, J¼8.7 Hz, 2H, aryl), 7.15–7.18 (m, 4H, aryl), 7.25–
7.33 (m, 4H, aryl); dC (100 MHz, CDCl3) 29.4 (C-30), 37.3 (PhCH2),
37.8 (C-20), 55.1 (C-5), 66.1 (C-4), 68.8 (OCH2CH]CH2), 114.7 (CH
aryl), 117.5 (CH]CH2), 127.3 (CH aryl), 128.9 (CH aryl), 129.5 (CH
aryl), 132.7 (CH]CH2), 133.4 (C aryl), 135.2 (C aryl), 153.4 (C-2),
157.1 (CO aryl), 172.5 (C-10); HRMS (ESI): [MþNa]þ calcd for
C22H23NO4Na 388.15248, found 388.15256.
4.1.2. (4S)-4-Benzyl-3-{3-[4-(benzyloxy)phenyl]propanoyl}-1,3-
oxazolidin-2-one (30). To a solution of acid 29 (2.0 g, 7.80 mmol)
and Et3N (3.3 mL, 23.4 mmol) in THF (60 mL), was added pivaloyl
chloride (1.0 mL, 8.19 mmol) at ꢀ20 ꢂC followed by stirring of the
mixture at ꢀ20 ꢂC for 30 min and 30 min at room temperature. In
a separate flask the anion 7 of the oxazolidinone was prepared by
dropwise addition of nBuLi (3.28 mL, 8.19 mmol, 2.5 M in hexane)
to a solution of the auxiliary (1.38 g, 7.80 mmol) in THF (8 mL) at
ꢀ80 ꢂC followed by stirring for 15 min at this temperature. This
solution of anion 7 was added via cannula to the cooled (ꢀ80 ꢂC)
solution of the mixed anhydride. After complete addition, the
stirred mixture was allowed to reach room temperature. The
mixture was treated with satd NaHCO3 solution and extracted
with ethyl acetate (3ꢁ60 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. The crude
product was recrystallized from ethyl acetate to yield amide de-
4.1.5. (2S,4R)-5-{[tert-Butyl(dimethyl)silyl]oxy}-2,4-dimethylpentyl
acetate (33). To a solution of alcohol 10 (1.5 g, 8.6 mmol) and im-
idazole (940 mg, 13.8 mmol) in CH2Cl2 (20 mL) was added TBSCl
(1.56 g, 10.3 mmol) at 0 ꢂC. The cooling bath was removed and the
mixture stirred at room temperature for 30 min. The mixture was
treated with satd NH4Cl solution and extracted with CH2Cl2
(3ꢁ50 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was purified
by flash chromatography (petroleum ether/EtOAc, 25:1) to give silyl
ether 33 (2.36, 95%) as a colorless oil. Rf (petroleum ether/ethyl
20
acetate, 25:1) 0.45; [
a
]
D
þ23.0 (c 1.0, CHCl3); dH (400 MHz, CDCl3)
0.01 (s, 6H, (CH3)2Si), 0.87 (s, 9H, tBu), 0.88 (d, J¼6.6 Hz, 3H, 4-CH3),
0.90 (m, 1H, 3-H), 0.92 (d, J¼6.6 Hz, 3H, 2-CH3), 1.44 (m, 1H, 3-H),
1.67 (m, 4-H), 1.88 (m, 1H, 2-H), 2.02 (s, 3H, H3CCO2), 3.34 (dd,
J¼9.6, 6.3 Hz, 1H, 5-H), 3.41 (dd, J¼9.6, 5.6 Hz, 1H, 5-H), 3.80 (dd,
J¼10.9, 6.9 Hz, 1H, 1-H), 3.94 (dd, J¼10.9, 5.3 Hz, 1H, 1-H); dC
(100 MHz, CDCl3) ꢀ5.4 ((CH3)2Si), 17.4 (4-CH3), 17.8 (2-CH3), 18.2
(C(CH3)3), 20.9 (CH3CO2), 25.9 (C(CH3)3), 30.0 (C-2), 33.0 (C-4), 37.4
(C-3), 68.0 (C-5), 69.3 (C-1), 171.2 (CO).
rivative 30 (2.65 g, 82%) as colorless needles. Mp 106 ꢂC; Rf (pe-
20
troleum ether/ethyl acetate, 2:1) 0.23; [
a
]
þ48.0 (c 1.0, CHCl3);
D
dH (400 MHz, CDCl3) 2.74 (dd, J¼13.4, 9.5 Hz, 1H, PhCH2), 2.94–
2.98 (m, 2H, 30-H), 3.16–3.32 (m, 3H, 20-H, PhCH2), 4.14–4.16 (m,
2H, 4-H), 4.62–4.68 (m, 1H, 5-H), 5.04 (s, 2H, PhCH2O), 6.91 (d,
J¼8.7 Hz, 2H, aryl), 7.16–7.43 (m, 7H, aryl); dC (100 MHz, CDCl3)
29.4 (C-30), 37.3 (PhCH2), 37.8 (C-20), 55.1 (C-4), 66.2 (PhCH2O),
70.0 (C-5), 114.8 (CH aryl), 127.3 (CH aryl), 127.4 (CH aryl), 127.9
(CH aryl), 128.5 (CH aryl), 128.9 (CH aryl), 129.4 (CH aryl), 129.5
(CH aryl), 132.8 (C aryl), 135.2 (C aryl), 137.1 (C aryl), 153.4 (C-2),
157.4 (CO aryl), 172.5 (C-10).
4.1.6. (2S,4R)-5-{[tert-Butyl(dimethyl)silyl]oxy}-2,4-dimethylpentan-
1-ol (34). A mixture of acetate 33 (7.8 g, 27.09 mmol) and K2CO3
(4.88 g, 35.2 mmol) in MeOH (40 mL) was stirred for 2 h at room
temperature. The solids were filtered off and the filtrate concen-
trated in vacuo. The residue was taken up in CH2Cl2 (150 mL) and
extracted with water (3ꢁ80 mL). The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography (petroleum ether/EtOAc, 9:1) to
4.1.3. (4S)-4-Benzyl-3-[3-(4-hydroxyphenyl)propanoyl]-1,3-
oxazolidin-2-one (31). A solution of benzyl ether 30 (1.75 g,
4.21 mmol) in MeOH/ethyl acetate (80 mL, 1:1) containing Pd/C
(200 mg) was hydrogenated for 1.5 h at room temperature. The
catalyst was filtered off, and the filtrate was concentrated in vacuo.
The crude product was recrystallized from petroleum ether/ethyl
give alcohol 34 (6.61 g, 98%) as a colorless oil. Rf (petroleum ether/
20
ethyl acetate, 9:1) 0.3; [
a]
ꢀ2.0 (c 1.0, CHCl3); dH (400 MHz, CDCl3)
D
0.03 (s, 6H), 0.87–0.92 (m, 13H), 0.93 (d, J¼6.6 Hz, 3H), 1.43 (dt,
J¼13.6, 6.8 Hz, 1H), 1.61 (br s, 1H), 1.71 (m, 2H), 3.35–3.55 (m, 4H);
dC (100 MHz, CDCl3) ꢀ5.4 ((CH3)2SiC), 17.7 (4-CH3), 17.8 (2-CH3),
18.3 (C(CH3)3), 25.9 (C(CH3)3), 33.2 (C-2), 33.3 (C-4), 37.3 (C-3), 68.2
(C-1), 68.3 (C-5).
acetate, 1:8 to give phenol 31 (1.26 g, 92%) as a colorless solid. Rf
20
(petroleum ether/ethyl acetate, 2:1) 0.32; [
a]
ꢀ61.1 (c 1.0, CHCl3);
D
dH (400 MHz, CDCl3) 2.74 (dd, J¼13.4, 9.5 Hz, 1H, PhCH2), 2.92–2.97
(m, 2H, 30-H), 3.15–3.31 (m, 3H, 20-H, PhCH2), 4.14–4.17 (m, 2H, 4-
H), 4.62–4.68 (m, 1H, 5-H), 6.75 (d, J¼8.7 Hz, 2H, aryl), 7.11–7.33 (m,
7H, aryl); dC (100 MHz, CDCl3) 29.5 (C-30), 37.4 (PhCH2), 37.8 (C-20),
55.1 (C-4), 66.2 (C-5), 115.3 (CH aryl), 127.4 (CH aryl), 129.0 (CH
4.1.7. (2R,4S)-5-{[tert-Butyl(diphenyl)silyl]oxy}-2,4-dimethylpentan-
1-ol (ent-12). To a solution of alcohol 34 (5.28 g, 21.44 mmol),
imidazole (2.0 g, 30.0 mmol), and DMAP (187 mg, 1.53 mmol) in
CH2Cl2 (20 mL) was added TBDPSCl (6.76 g, 24.66 mmol) at 0 ꢂC.

M. Ugele, M.E. Maier / Tetrahedron 66 (2010) 2633–2641
2637
The cooling bath was removed and the mixture stirred at room
temperature for 45 min. The mixture was treated with satd NH4Cl
solution and extracted with CH2Cl2 (3ꢁ65 mL). The combined or-
ganic layers were dried over MgSO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromatography
(petroleum ether/EtOAc, 9:1) to give disilyl ether 35 (10.0 g, 96%) as
a slightly yellow oil.
129.5 (CH phenyl), 134.0 (C phenyl), 135.6 (CH phenyl), 139.9 (C-2);
HRMS (ESI): [MþNa]þ calcd for C25H36O2SiNa 419.23768, found
419.23763.
4.1.10. Ethyl (4E,6R,8S)-9-{[tert-butyl(diphenyl)silyl]oxy}-6,8-dime-
thylnon-4-enoate (ent-15). A mixture of allylalcohol ent-14 (6.10 g,
15.38 mmol), triethylorthoacetate (8.7 mL, 46.14 mmol), and pro-
A solution of disilyl ether 35 (10.0 g, 20.6 mmol) and CSA
(170 mg, 0.732 mmol) in MeOH (35 mL) was stirred for 2.5 h at
room temperature. Then Et3N (1 mL) was added, the solvent
evaporated in vacuo and the residue taken up in CH2Cl2 (90 mL).
The CH2Cl2 solution was washed with satd NH4Cl solution, dried
over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (petroleum ether/EtOAc, 5:1) to
give silyl ether ent-12 (6.94 g, 91%) as a colorless oil. Rf (petroleum
pionic acid (50 mL) in xylene (50 mL) was refluxed for 5 h. After
cooling the solvent was removed in vacuo and the residue purified
by flash chromatography (petroleum ether/EtOAc, 25:1) to give the
enoate ent-15 (6.96 g, 97%) as a colorless oil. Rf (petroleum ether/
20
ethyl acetate, 25:1) 0.22; [
a
]
ꢀ6.65 (c 2.0, CH2Cl2); dH (400 MHz,
D
CDCl3) 0.88 (d, J¼6.6 Hz, 3H, 8-CH3), 0.92 (d, J¼6.9 Hz, 3H, 6-CH3),
0.98–1.03 (m, 1H, 7-H), 1.05 (s, 9H, tBu), 1.24 (t, J¼7.1 Hz, 3H,
CH3CH2O), 1.32–1.39 (m, 1H, 7-H), 1.59–1.70 (m, 1H, 8-H), 2.09–2.19
(m, 1H, 6-H), 2.26–2.36 (m, 4H, 2-H, 3-H), 3.39–3.50 (m, 2H, 9-H),
4.12 (q, J¼7.1 Hz, 2H, CH3CH2O), 5.21–5.26 (m, 1H, 5-H), 5.32–5.39
(m, 1H, 4-H), 7.35–7.43 (m, 6H, phenyl), 7.66 (dd, J¼7.8, 1.7 Hz, 4H,
phenyl); dC (100 MHz, CDCl3) 14.2 (CH3CH2O), 16.7 (8-CH3), 19.3
(C(CH3)3), 21.8 (6-CH3), 26.9 (C(CH3)3), 27.9 (C-3), 33.4 (C-2), 34.2
(C-8), 34.5 (C-6), 40.7 (C-7), 60.2 (CH3CH2O), 69.3 (C-9), 126.4 (C-4),
127.5 (CH phenyl), 129.5 (CH phenyl), 134.1 (C phenyl), 135.6 (CH
phenyl), 137.5 (C-5), 173.2 (C-1); HRMS (ESI): [MþNa]þ calcd for
C29H42O3SiNa 489.28009, found 489.27981.
20
20
ether/ethyl acetate, 5:1) 0.43; [
a]
þ1.7 (c 0.2, CHCl3); Ref. 21
[a]
D
D
þ1.8 (c 0.23, CHCl3); dH (400 MHz, CDCl3) 0.88 (d, J¼6.6 Hz, 3H, 4-
CH3), 0.95 (d, J¼6.6 Hz, 3H, 2-CH3), 1.24–1.27 (m, 1H, 3-H), 1.42–1.48
(m, 1H, 3-H), 1.59–1.67 (m, 1H, 4-H), 1.69–1.77 (m, 1H, 2-H), 3.31–
3.37 (m, 1H, 1-H), 3.40–3.53 (m, 3H, 1-H, 5-H), 7.35–7.43 (m, 6H,
Phenyl), 7.65–7.67 (m, 4H, Phenyl); dC (100 MHz, CDCl3) 17.4 (4-
CH3), 17.9 (2-CH3), 19.3 (C(CH3)3), 26.9 (C(CH3)3), 33.1 (C-2), 33.2 (C-
4), 37.1 (C-3), 68.3 (C-1), 68.7 (C-5), 127.6 (CH aryl), 129.5 (CH aryl),
134.0 (C aryl), 135.6 (C aryl).
4.1.8. (2R,4S)-5-{[tert-Butyl(diphenyl)silyl]oxy}-2,4-dimethylpenta-
nal (ent-13). To a solution of alcohol ent-12 (8.31 g, 22.0 mmol) in
CH2Cl2 (90 mL) were added PhI(OAc)2 (10.6 g, 33.0 mmol) and
TEMPO (348 mg, 2.2 mmol) followed by stirring of the mixture for
2 h at room temperature. This was followed by the addition of 10%
aqueous Na2S2O3 solution (40 mL) and stirring for 15 min. The
mixture was extracted with CH2Cl2 (3ꢁ110 mL). The combined or-
ganic layers were washed with satd NaHCO3 solution, satd NaCl
solution, dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography (petroleum
4.1.11. Ethyl (4E,6R,8S)-9-hydroxy-6,8-dimethylnon-4-enoate (36). To
a solution of ester ent-15 (101 mg, 0.22 mmol) in THF (3 mL) was
added TBAF (102 mg, 0.33 mmol) and the mixture stirred for 3 h at
room temperature. Then satd NH4Cl solution was added and the
mixture extracted with Et2O (3ꢁ40 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography (petro-
leum ether/EtOAc, 3:1) to give hydroxyester 36 (45 mg, 92%) as
20
a colorless oil. Rf (petroleum ether/ethyl acetate, 2:1) 0.5; [a]
D
ꢀ23.8 (c 1.0, CH2Cl2); dH (400 MHz, CDCl3) 0.86 (d, J¼6.6 Hz, 3H, 8-
CH3), 0.94 (d, J¼6.9 Hz, 3H, 6-CH3), 0.98–1.04 (m, 1H, 7-H), 1.24 (t,
J¼7.1 Hz, 3H, CH3CH2O), 1.28–1.34 (m, 1H, 7-H), 1.55–1.63 (m, 1H,
8-H), 2.11–2.20 (m, 1H, 6-H), 2.26–2.36 (m, 4H, 2-H, 3-H), 3.36–
3.45 (m, 2H, 9-H), 4.10 (q, J¼7.1 Hz, 2H, CH3CH2O), 5.20–5.26 (m,
1H, 5-H), 5.33–5.40 (m, 1H, 4-H); dC (100 MHz, CDCl3) 14.2
(CH3CH2O), 16.3 (8-CH3), 21.9 (6-CH3), 27.9 (C-3), 33.5 (C-8), 34.4
(C-2), 34.5 (C-6), 40.7 (C-7), 60.3 (CH3CH2O), 68.7 (C-9), 126.7 (C-
4), 137.3 (C-5), 173.3 (C-1); HRMS (ESI): [MþNa]þ calcd for
C13H24O3Na 251.16231, found 251.16207.
ether/EtOAc, 60:1) to give aldehyde ent-13 (7.29 g, 90%) as a slightly
20
orange oil. Rf (petroleum ether/ethyl acetate, 60:1) 0.24; [
a
]
D
ꢀ6.6
20
(c 0.4, CHCl3); Ref. 21
[a
]
ꢀ6.3 (c 0.4, CHCl3); dH (400 MHz, CDCl3)
D
0.77 (d, J¼6.6 Hz, 3H, 4-CH3), 0.88 (d, J¼3.3 Hz, 3H, 2-CH3), 0.89 (s,
t
9H, Bu), 0.95 (dd, J¼19.9, 7.3 Hz, 1H, 5-H), 1.52–1.61 (m, 1H, 4-H),
1.68–1.76 (m, 1H, 5-H), 2.17–2.26 (m, 1H, 2-H), 3.31 (ddd, J¼12.0,
10.1, 5.9 Hz, 2H, 3-H), 7.18–7.24 (m, 6H, phenyl), 7.47–7.49 (m, 4H,
phenyl), 9.37 (d, J¼2.3 Hz, 1H, 1-H); dC (100 MHz, CDCl3) 14.1 (2-
CH3), 17.2 (4-CH3), 19.3 (C(CH3)3), 26.9 (C(CH3)3), 33.3 (C-3), 34.5 (C-
4), 44.0 (C-2), 68.4 (C-5),127.6 (CH phenyl),129.6 (CH phenyl),133.8
(C phenyl), 135.6 (CH phenyl), 205.3 (C-1).
4.1.12. Ethyl (4E,6R,8S)-6,8-dimethyl-9-(tetrahydro-2H-pyran-2-ylox-
y)non-4-enoate (37). A solution of hydroxyester 36 (1.65 g,
7.23 mmol), 3,4-dihydropyran (1.0 mL, 10.8 mmol), and pTsOH
(181 mg, 0.72 mmol) in CH2Cl2 (12 mL) was stirred for 3 h at room
temperature. Then satd NaHCO3 solution was added and the mixture
extracted with CH2Cl2 (3ꢁ60 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography (petroleum ether/
4.1.9. (4R,6S)-7-{[tert-Butyl(diphenyl)silyl]oxy}-4,6-dimethylhept-1-
en-3-ol (ent-14). To
a solution of aldehyde ent-13 (6.77 g,
18.4 mmol) in THF (90 mL) was added dropwise vinylmagnesium
bromide (27.6 mL, 1 M in THF) at ꢀ90 ꢂC. The stirred mixture was
allowed to warm to room temperature within 1 h. Then satd NH4Cl
solution was added and the mixture extracted with Et2O
(3ꢁ120 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. Purification of the residue by
flash chromatography (petroleum ether/ethyl acetate, 12:1) gave
vinyl alcohol ent-14 (5.76 g, 79%) as a colorless oil (roughly 2:1
mixture of C-3 diastereomers). Rf (petroleum ether/ethyl acetate,
12:1) 0.31; dH (400 MHz, CDCl3) 0.83 (d, J¼6.6 Hz, 3H, 6-CH3), 0.86–
0.93 (m,1H, 5-H), 0.96 (m, 3H, 4-CH3),1.05 (s, 9H, tBu),1.50–1.57 (m,
1H, 6-H), 1.58–1.66 (m, 1H, 5-H), 1.72–1.80 (m, 1H, 4-H), 3.40–3.55
(m, 2H, 7-H), 3.92–3.95 (m, 1H, 3-H), 5.11–5.15 (m, 1H, 1-H), 5.18–
5.23 (m, 1H, 1-H), 5.77–5.87 (m, 1H, 2-H), 7.35–7.44 (m, 6H, phenyl),
7.66 (dd, J¼7.8, 1.7 Hz, 4H, phenyl); dC (100 MHz, CDCl3) 14.6 (6-
CH3), 18.2 (4-CH3), 19.3 (C(CH3)3), 26.9 (C(CH3)3), 33.1 (C-9), 35.9 (C-
4), 36.7 (C-6), 68.4 (C-7), 76.3 (C-3), 115.0 (C-1), 127.6 (CH phenyl),
EtOAc, 12:1) to give THP ether 37 (2.19 g, 97%) as a colorless oil. Rf
20
(petroleum ether/ethyl acetate, 12:1) 0.4; [
a
]
ꢀ6.5 (c 1.0, CH2Cl2);
D
dH (400 MHz, CDCl3) 0.87 (dd, J¼8.5, 6.7 Hz, 3H, 8-CH3), 0.93 (d,
J¼6.6 Hz, 3H, 6-CH3), 0.97–1.04 (m, 1H, 7-H), 1.23 (t, J¼7.1 Hz, 3H,
CH3CH2O),1.28–1.37 (m,1H, 7-H),1.48–1.60 (m, 4H, 40-H, 50-H),1.65–
1.73 (m, 2H, 30-H), 1.78–1.85 (m, 1H, 8-H), 2.12–2.23 (m, 1H, 6-H),
2.25–2.35 (m, 4H, 2-H, 3-H), 3.07–3.20 (m, 1H, 9-H), 3.42–3.56 (m,
2H, 60-H), 3.80–3.86 (m, 1H, 9-H), 4.10 (q, J¼7.1 Hz, 2H, CH3CH2O),
4.51–4.55 (m, 1H, 20-H), 5.21–5.28 (m, 1H, 5-H), 5.32–5.39 (m, 1H, 4-
H); dC (100 MHz, CDCl3) 14.2 (CH3CH2O), 16.8, 16.9 (8-CH3), 19.5, 19.6
(C-40), 21.8 (6-CH3), 25.5 (C-50), 27.9 (C-3), 30.7 (C-30), 31.0, 31.1 (C-8),
34.2 (C-2), 34.5 (C-6), 41.0, 41.1 (C-7), 60.2 (CH3CH2O), 62.0, 62.2 (C-
60), 73.3, 73.5 (C-9), 98.7, 99.0 (C-20), 126.5 (C-4), 137.3 (C-5), 173.2 (C-

2638
M. Ugele, M.E. Maier / Tetrahedron 66 (2010) 2633–2641
1); HRMS (ESI): [MþNa]þ calcd for C18H32O4Na 335.21983, found
16.3 (2-CH3), 19.2 (C(CH3)3), 22.1 (4-CH3), 26.9 (C(CH3)3), 28.7 (C-8),
32.5 (C-7), 33.5 (C-2), 34.3 (C-4), 46.7 (C-3), 63.3 (C-9), 68.8 (C-1),
127.6 (CH aryl), 128.4 (C-6), 129.5 (CH aryl), 134.1 (C aryl), 135.5 (CH
aryl), 136.2 (C-5); HRMS (ESI): [MþNa]þ calcd for C27H40O2SiNa
447.26952, found 447.26935.
335.21933.
4.1.13. (4E,6R,8S)-6,8-Dimethyl-9-(tetrahydro-2H-pyran-2-ylox-
y)non-4-en-1-ol (38). To a solution of ester 37 (2.18 g, 7.0 mmol) in
abs Et2O (18 mL) was added DIBAL–H (21 mL, 1 M in hexane)
dropwise at ꢀ40 ꢂC. After complete addition, stirring was contin-
ued for 40 min at ꢀ40 ꢂC and 4 h at 0 ꢂC. The mixture was treated
with satd NaHCO3 solution and extracted with Et2O (3ꢁ50 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography (petroleum ether/EtOAc, 2:1) to give alcohol 38
4.1.16. (2S,4R,5E)-9-{[tert-Butyl(diphenyl)silyl]oxy}-2,4-dime-
thylnon-5-enyl 4-methylbenzenesulfonate (41). To a solution of al-
cohol 40 (2.28 g, 5.37 mmol) in CH2Cl2 (15 mL) were added Et3N
(1.74 mL, 12.35 mmol), DMAP (132 mg, 1.07 mmol), and tosyl
chloride (1.20 g, 6.15 mmol). The resulting mixture was stirred for
2 h at room temperature before it was treated with satd NH4Cl
solution and extracted with CH2Cl2 (3ꢁ50 mL). The combined or-
ganic layers were washed with satd NaCl solution, dried over
MgSO4, filtered, and concentrated in vacuo. Purification of the
residue by flash chromatography (petroleum ether/ethyl acetate,
(1.77 g, 94%) as a colorless oil. Rf (petroleum ether/ethyl acetate,
20
2:1) 0.4; [
a]
ꢀ8.3 (c 2.0, CH2Cl2); dH (400 MHz, CDCl3) 0.88 (t,
D
J¼6.7 Hz, 3H, 8-CH3), 0.94 (d, J¼6.6 Hz, 3H, 6-CH3), 0.98–1.05 (m,
1H, 7-H), 1.44–1.58 (m, 4H, 40-H, 50-H), 1.59–1.63 (m, 2H, 2-H), 1.65–
1.75 (m, 2H, 30-H), 1.77–1.84 (m, 1H, 8-H), 2.05 (q, J¼7.1 Hz, 2H, 3-
H), 2.13–2.23 (m, 1H, 6-H), 3.08–3.21 (m, 1H, 9-H), 3.43–3.58 (m,
2H, 60-H), 3.63 (q, J¼5.8, 2H, 1-H) 3.82–3.86 (m, 1H, 9-H), 4.52–4.55
(m, 1H, 20-H), 5.20–5.26 (m, 1H, 5-H), 5.33–5.40 (m, 1H, 4-H); dC
(100 MHz, CDCl3) 16.9 (8-CH3), 19.5, 19.6 (C-40), 21.9, 22.0 (6-CH3),
25.5 (C-50), 28.8 (C-3), 30.7 (C-30), 31.0, 31.1 (C-2), 32.4 (C-8), 34.3,
34.4 (C-6), 41.1 (C-7), 62.0 (C-1), 62.3, 62.4 (C-60), 73.3, 73.5 (C-9),
98.7, 99.1 (C-10), 127.9 (C-4), 136.8 (C-5); HRMS (ESI): [MþNa]þ
calcd for C16H30O3Na 293.205918, found 293.20575.
9:1) gave tosylate 41 (3.04 g, 96%) as a colorless oil. Rf (petroleum
20
ether/ethyl acetate, 9:1) 0.41; [
a]
ꢀ3.8 (c 1.0, CH2Cl2); dH
D
(400 MHz, CDCl3) 0.82 (d, J¼6.9 Hz, 3H, 2-CH3), 0.89 (d, J¼6.6 Hz,
t
3H, 4-CH3), 0.96–1.02 (m, 1H, 3-H), 1.04 (s, 9H, Bu), 1.16–1.23 (m,
1H, 3-H), 1.59 (ddd, J¼14.1, 6.9, 6.7 Hz, 2H, 8-H), 1.72–1.80 (m, 1H, 2-
H), 2.01–2.10 (m, 3H, 4-H, 7-H), 2.43 (s, 3H, aryl CH3), 3.64 (t,
J¼6.4 Hz, 2H, 9-H), 3.75 (dd, J¼9.4, 6.4 Hz, 1H, 1-H), 3.82–3.85 (m,
1H, 1-H), 5.08 (dd, J¼15.3, 8.4 Hz, 1H, 5-H), 5.26–5.33 (m, 1H, 6-H),
7.31–7.41 (m, 9H, aryl), 7.66 (dd, J¼7.6, 1.5 Hz, 4H, aryl), 7.77 (d,
J¼8.4 Hz, 2H, aryl); dC (100 MHz, CDCl3) 16.0 (2-CH3), 19.2
(C(CH3)3), 21.6 (4-CH3), 21.8 (CH3 aryl), 26.9 (C(CH3)3), 28.7 (C-7),
30.6 (C-2), 32.4 (C-8), 34.2 (C-4), 40.0 (C-3), 63.3 (C-9), 75.7 (C-1),
127.6 (CH aryl), 127.9 (CH aryl), 128.9 (C-6), 129.5 (CH aryl), 129.8
(CH aryl), 133.2 (C aryl), 134.0 (C aryl), 135.4 (C-5), 135.5 (CH aryl),
144.5 (CCH3 aryl); HRMS (ESI): [MþNa]þ calcd for C34H46O4SSiNa
601.27837, found 601.27831.
4.1.14. tert-Butyl{[(4E,6R,8S)-6,8-dimethyl-9-(tetrahydro-2H-pyran-
2-yloxy)non-4-enyl]oxy}diphenylsilane (39). To a solution of alcohol
38 (1.82 g, 6.73 mmol), imidazole (642 mg, 9.4 mmol), and DMAP
(83 mg, 0.67 mmol) in CH2Cl2 (12 mL) was added TBDPSCl (2.04 g,
7.40 mmol) at 0 ꢂC. The cooling bath was removed and the mixture
stirred at room temperature for 1 h. The mixture was treated with
satd NH4Cl solution and extracted with CH2Cl2 (3ꢁ50 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography (petroleum ether/EtOAc, 15:1) to give silyl ether
4.1.17. (4E,6R,8R)-1-{[tert-Butyl(diphenyl)silyl]oxy}-6,8-dimethyl-4-
decene (42). To a solution of tosylate 41 (2.95 g, 5.09 mmol) and
Cu(I)Br$SMe2 complex (1.26 g, 6.11 mmol) in THF (45 mL) was
added MeMgCl (18.7 mL, 56.1 mmol, 3 M in THF) ꢀ80 ꢂC in
a dropwise fashion. Stirring was continued for 1 h at ꢀ80 ꢂC and
36 h at 0 ꢂC. Then the mixture was treated with satd NH4Cl solution
and extracted with Et2O (3ꢁ70 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo. Puri-
fication of the residue by flash chromatography (petroleum ether/
39 (3.22 g, 94%) as a colorless oil. Rf (petroleum ether/ethyl acetate,
20
15:1) 0.43; [
a
]
ꢀ5.2 (c 1.0, CH2Cl2); dH (400 MHz, CDCl3) 0.88 (dd,
D
J¼9.7, 6.6 Hz, 3H, 8-CH3), 0.93 (d, J¼6.0 Hz, 3H, 6-CH3), 0.96–1.02
(m, 1H, 7-H), 1.04 (s, 9H, tBu), 1.25–1.37 (m, 1H, 7-H), 1.49–1.65 (m,
6H, 2-H, 40-H, 50-H), 1.66–1.85 (m, 3H, 8-H, 20-H) 2.06 (q, J¼7.0 Hz,
2H, 3-H), 2.13–2.20 (m, 1H, 6-H), 3.08–3.21 (m, 1H, 9-H), 3.45–3.50
(m, 2H, 60-H), 3.65 (t, J¼6.5 Hz, 2H, 1-H), 3.82–3.87 (m, 1H, 9-H),
4.52–4.56 (m, 1H, 10-H), 5.16–5.22 (m, 1H, 5-H), 5.30–5.37 (m, 1H, 4-
H), 7.35–7.43 (m, 6H, aryl), 7.63 (dd, J¼7.6, 1.5 Hz, 4H, aryl); dC
(100 MHz, CDCl3) 16.9, 17.0 (8-CH3), 19.2 (C(CH3)3), 19.5, 19.7 (C-40),
21.9, 22.0 (6-CH3), 25.5 (C-50), 26.9 (C(CH3)3), 28.8 (C-2), 30.7 (C-20),
31.7 (C-8), 32.6 (C-3), 34.2, 34.3 (C-6), 41.2 (C-7), 62.0, 62.2 (C-60),
62.3, 62,4 (C-1), 73.3, 73.5 (C-9), 98.7, 99.1 (C-10), 127.6 (CH aryl),
128.2 (CH aryl), 129.5 (CH aryl), 134.1 (C aryl), 135.6 (CH aryl), 136.3,
136.4 (C-5); HRMS (ESI): [MþNa]þ calcd for C32H48O3SiNa
531.32704, found 531.32689.
ethyl acetate, 9:1) gave alkene 42 (2.06 g, 96%) as a colorless oil. Rf
20
(petroleum ether/ethyl acetate, 9:1) 0.83; [
a]
ꢀ9.9 (c 1.0, CH2Cl2);
D
dH (400 MHz, CDCl3) 0.80 (d, J¼6.6 Hz, 3H, 8-CH3), 0.81–0.85 (m,
3H, 10-H), 0.91 (d, J¼6.6 Hz, 3H, 6-CH3), 0.94–1.01 (m, 1H, 7-H), 1.05
(s, 9H, tBu), 1.07–1.14 (m, 1H, 7-H), 1.17–1.36 (m, 3H, 8-H, 9-H), 1.58–
1.65 (m, 2H, 2-H), 2.07 (q, J¼6.9 Hz, 2H, 3-H), 2.11–2.17 (m, 1H, 6-H),
3.66 (t, J¼6.4 Hz, 2H, 1-H), 5.16–5.22 (m, 1H, 5-H), 5.28–5.35 (m, 1H,
6-H), 7.35–7.42 (m, 6H, aryl), 7.67 (dd, J¼7.8, 1.7 Hz, 4H, aryl); dC
(100 MHz, CDCl3) 11.3 (C-10), 19.0 (8-CH3), 19.2 (C(CH3)3), 21.8 (6-
CH3), 28.8 (C-2), 30.0 (C-9), 31.8 (C-3), 32.6 (C-8), 34.4 (C-6), 44.4
(C-7), 63.3 (C-1), 127.6 (CH aryl), 127.8 (C-4), 129.5 (CH aryl), 134.2
(C aryl), 135.6 (CH aryl), 136.8 (C-5); HRMS (ESI): [MþNa]þ calcd for
C28H42OSiNa 445.29026, found 445.29036.
4.1.15. (2S,4R,5E)-9-{[tert-Butyl(diphenyl)silyl]oxy}-2,4-dime-
thylnon-5-en-1-ol (40). A solution of THP ether 39 (3.11 g,
6.12 mmol) and PPTS (77 mg, 0.31 mmol) in EtOH (20 mL) was
stirred for 8 h at 55 ꢂC. Then the solvent was removed in vacuo and
the residue subjected to flash chromatography (petroleum ether/
4.1.18. (4E,6R,8R)-6,8-Dimethyldec-4-en-1-ol (ent-21). A solution of
silyl ether 42 (1.78 g, 4.21 mmol) and TBAF (1.86 g, 5.9 mmol) was
stirred for 4 h at room temperature. Then, satd NH4Cl solution was
added and the mixture extracted with Et2O (3ꢁ40 mL). The com-
bined organic layers were dried over MgSO4, filtered, and concen-
trated in vacuo. Purification of the residue by flash chromatography
(petroleum ether/ethyl acetate, 9:1) gave alkenol ent-21 (706 mg,
EtOAc, 9:1) to give alcohol 40 (2.36 g, 91%) as a colorless oil. Rf
20
(petroleum ether/ethyl acetate, 4:1) 0.47; [
a
]
ꢀ14.7 (c 1.0,
D
CH2Cl2); dH (400 MHz, CDCl3) 0.86 (d, J¼6.6 Hz, 3H, 2-CH3), 0.95 (d,
J¼6.6 Hz, 3H, 4-CH3), 0.97–1.03 (m, 1H, 3-H), 1.05 (s, 9H, tBu), 1.27–
1.33 (m, 1H, 3-H), 1.56–1.66 (m, 3H, 2-H, 2-H), 2.07 (q, J¼7.1 Hz, 2H,
7-H), 2.12–2.21 (m, 1H, 4-H), 3.34–3.47 (m, 2H, 1-H), 3.66 (t,
J¼6.4 Hz, 2H, 9-H), 5.15–5.21 (m, 1H, 5-H), 5.31–5.38 (m, 1H, 6-H),
7.35–7.44 (m, 6H, aryl), 7.66–7.68 (m, 4H, aryl); dC (100 MHz, CDCl3)
91%) as a colorless oil. Rf (petroleum ether/ethyl acetate, 4:1) 0.39;
20
[a
]
ꢀ33.4 (c 1.0, CH2Cl2); dH (400 MHz, CDCl3) 0.80 (d, J¼6.4 Hz,
D
3H, 8-CH3), 0.81–0.85 (m, 3H, 10-H), 0.92 (d, J¼6.6 Hz, 3H, 6-CH3),

M. Ugele, M.E. Maier / Tetrahedron 66 (2010) 2633–2641
2639
0.94–1.01 (m,1H, 7-H),1.05–1.14 (m,1H, 7-H),1.18–1.35 (m, 3H, 8-H,
9-H), 1.42 (br, 1H, OH), 1.58–1.65 (m, 2H, 2-H), 2.06 (q, J¼6.9 Hz, 2H,
3-H), 2.16 (ddd, J¼14.4, 7.0 Hz, 1H, 6-H), 3.63 (t, J¼6.6 Hz, 2H, 1-H),
5.20–5.26 (m, 1H, 5-H), 5.32–5.39 (m, 1H, 4-H); dC (100 MHz, CDCl3)
11.3 (C-10), 18.8 (8-CH3), 21.8 (6-CH3), 28.9 (C-3), 30.0 (C-9), 31.9 (C-
2), 32.5 (C-8), 34.4 (C-6), 44.4 (C-7), 62.6 (C-1), 127.5 (C-4), 137.2 (C-
5); HRMS (ESI): [MþNa]þ calcd for C12H24ONa 207.17248, found
207.17221.
one (44). To a solution of aldol adduct 43 (100 mg, 0.18 mmol) in
CH2Cl2 (4 mL) were added iPr2NEt (220
L, 1.28 mmol), and MOMCl
(160
L, 2.0 mmol) at 0 ꢂC. The mixture was stirred at room tem-
perature for 12 h. Then, satd NaHCO3 solution was added and the
mixture extracted with CH2Cl2 (3ꢁ40 mL). The combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the residue by flash chromatography (petroleum
m
m
ether/ethyl acetate, 3:1) gave MOM ether 44 (97 mg, 90%) as
20
a colorless oil. Rf (petroleum ether/ethyl acetate, 3:1) 0.49; [a]
D
4.1.19. (4E,6R,8R)-6,8-Dimethyldec-4-enal (ent-22). A mixture of
alcohol 21 (990 mg, 5.37 mmol), Dess–Martin periodinane (DMP,
3.99 g, 9.4 mmol), and NaHCO3 (2.1 g, 24.17 mmol) in CH2Cl2
(20 mL) was stirred for 2 h at room temperature. Then water
(30 mL) was added, and the mixture extracted with CH2Cl2
(3ꢁ70 mL). The combined organic layers were washed with a mix-
ture of satd NaHCO3/Na2S2O3 solutions (50 mL, 1:1), dried over
MgSO4, filtered, and concentrated in vacuo. Purification of the
residue by flash chromatography (petroleum ether/ethyl acetate,
þ59.1 (c 1.0, CH2Cl2); dH (400 MHz, CDCl3) 0.81 (d, J¼6.4 Hz, 3H,100-
CH3), 0.82–0.85 (m, 3H, 120-H), 0.93 (d, J¼6.6 Hz, 3H, 80-CH3), 0.96–
1.02 (m, 1H, 90-H), 1.06–1.14 (m, 1H, 90-H), 1.18–1.38 (m, 3H, 100-H,
110-H), 1.66–1.79 (m, 2H, 40-H), 1.98–2.08 (m, 1H, 50-H), 2.12–2.24
(m, 2H, 50-H, 80-H), 2.39 (dd, J¼13.5, 9.2 Hz, 1H, PhCH2), 2.86–2.93
(m, 2H, PhCH2, CH2 aryl), 3.04–3.10 (m, 1H, CH2 aryl), 3.37 (s, 3H,
OCH3), 3.81–3.85 (m, 1H, 30-H), 4.01 (dd, J¼9.2, 2.3 Hz, 1H, 5-H),
4.08 (t, J¼8.3 Hz, 1H, 20-H), 4.45–4.47 (m, 2H, CH2CH]CH2), 4.56 (d,
J¼7.4 Hz, 1H, OCH2OCH3), 4.55–4.61 (m, 2H, 4-H), 4.70 (d, J¼7.1 Hz,
1H, OCH2OCH3), 5.20–5.27 (m, 2H, 70-H, CH2CH]CH2), 5.32–5.37
(m, 2H, 60-H, CH2CH]CH2), 5.95–6.05 (m,1H, CH2CH]CH2) 6.82 (d,
J¼8.7 Hz, 2H, aryl), 6.94 (dd, J¼6.6, 2.5 Hz, 2H, aryl), 7.17–7.24 (m,
5H, aryl); dC (100 MHz, CDCl3) 11.3 (C-120), 19.0 (100-CH3), 21.8 (80-
CH3), 28.9 (C-50), 29.9 (C-110), 31.8 (C-100), 32.6 (C-40), 33.2 (CH2
aryl), 34.3 (CH2 aryl), 37.3 (C-80), 44.4 (C-50), 48.1 (C-20), 55.4
(OCH3), 56.2 (C-4), 65.6 (C-5), 68.8 (CH2CH]CH2), 78.4 (C-30), 96.4
(OCH2OCH3), 114.7 (CH aryl), 117.5 (CH2CH]CH2), 127.2 (CH aryl),
127.4 (C-60), 128.8 (CH aryl), 129.4 (CH aryl), 130.2 (CH aryl), 131.2 (C
aryl), 133.4 (CH2CH]CH2), 135.2 (C aryl), 137.2 (C-70), 153.0 (C-2),
157.2 (CO aryl), 173.5 (C-10); HRMS (ESI): [MþNa]þ calcd for
C36H49NO6H 592.36326, found 592.36352.
4:1) gave aldehyde ent-22 (860 mg, 88%) as a colorless oil. Rf (pe-
20
troleum ether/ethyl acetate, 4:1) 0.7; [
a]
ꢀ32.6 (c 1.0, CH2Cl2); dH
D
(400 MHz, CDCl3) 0.80 (d, J¼6.4 Hz, 3H, 8-CH3), 0.83 (t, J¼7.3 Hz,
3H, 10-H), 0.92 (d, J¼6.6 Hz, 3H, 6-CH3), 0.94–1.01 (m, 1H, 7-H),
1.05–1.14 (m, 1H, 7-H), 1.18–1.34 (m, 3H, 8-H, 9-H), 2.10–2.20 (m,
1H, 6-H), 2.32 (q, J¼7.2 Hz, 2H, 3-H), 2.45–2.49 (m, 2H, 2-H), 5.23–
5.28 (m, 1H, 5-H), 5.35 (dt, J¼15.3, 6.2 Hz, 1H, 4-H); dC (100 MHz,
CDCl3) 11.3 (C-10), 18.9 (8-CH3), 21.6 (6-CH3), 25.2 (C-3), 29.9 (C-9),
31.9 (C-8), 34.3 (C-6), 43.6 (C-2), 44.2 (C-7), 125.8 (C-4), 138.0 (C-4),
202.5 (C-1).
4.1.20. (4S)-3-{(2S,3R,6E,8R,10R)-2-[4-(Allyloxy)benzyl]-3-hydroxy-
8,10-dimethyldodec-6-enoyl}-4-benzyl-1,3-oxazolidin-2-one (43). To
a cooled solution of aldol reagent 32 (100 mg, 0.274 mmol) in
4.1.22. (2S,3R,6E,8R,10R)-2-[4-(Allyloxy)benzyl]-3-(methoxy-
methoxy)-8,10-dimethyldodec-6-enoic acid (45). To a solution of
amide derivative 44 (215 mg, 0.36 mmol) in THF/H2O (6 mL, 10:1)
CH2Cl2 (4.0 mL) was added slowly TiCl4 (32
m
L, 0.288 mmol) at 0 ꢂC
L,
followed by the immediate addition of (ꢀ)-spartein (160
m
0.684 mmol). The mixture was stirred for 1.5 h at 0 ꢂC. It was cooled
were added LiOH (61 mg, 1.45 mmol) and H2O2 (230 mL, 2.0 mmol,
to ꢀ80 ꢂC and then
a
solution of aldehyde ent-22 (54 mg,
30% in H2O) at 0 ꢂC followed by stirring of the mixture for 2 h at
room temperature. Thereafter, Na2S2O3 solution (10% in water) was
added, the mixture acidified with 1 N HCl and extracted with ethyl
acetate (3ꢁ30 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. Purification of the
residue by flash chromatography (petroleum ether/ethyl acetate,
0.301 mmol), dissolved in CH2Cl2 (1.0 mL) was added dropwise. The
mixture was allowed to warm to 0 ꢂC within 1 h. Now satd NH4Cl
solution (2 mL) was added and the mixture extracted with CH2Cl2
(3ꢁ30 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. Purification of the residue by
flash chromatography (petroleum ether/ethyl acetate, 2:1) gave
3:2) gave acid 45 (130 mg, 85%) as a colorless oil. Rf (petroleum
20
aldol product 43 (105 mg, 70%) as a slightly yellow oil. Rf (petro-
ether/ethyl acetate, 2:1) 0.46; [
a
]
ꢀ3.0 (c 1.0, CH2Cl2); dH
D
20
leum ether/ethyl acetate, 3:1) 0.23; [
a]
þ3.3 (c 0.25, CH2Cl2); dH
(400 MHz, CDCl3) 0.81 (d, J¼6.4 Hz, 3H, 10-CH3), 0.82–0.85 (m, 3H,
12-H), 0.91 (d, J¼6.6 Hz, 3H, 8-CH3), 0.94–1.01 (m, 1H, 9-H), 1.05–
1.14 (m, 1H, 9-H), 1.17–1.36 (m, 3H, 10-H, 11-H), 1.64–1.69 (m, 2H, 4-
H), 1.96–2.07 (m, 1H, 5-H), 2.10–2.20 (m, 2H, 5-H, 8-H), 2.71–2.77
(m, 1H, CH2 aryl), 2.93–3.00 (m, 2H, CH2 aryl, 2-H), 3.38 (s, 3H,
OCH2OCH3), 3.76–3.80 (m, 1H, 3-H), 4.48–4.50 (m, 2H,
CH2CH]CH2), 4.66 (dd, J¼18.6, 6.9 Hz, 2H, OCH2OCH3), 5.19–5.34
(m, 3H, 6-H, 7-H, CH2CH]CH2), 5.37–5.41 (m, 1H, CH2CH]CH2),
5.99–6.09 (m, 1H, CH2CH]CH2), 6.82 (d, J¼8.7 Hz, 2H, 30-H, 50-H),
7.09 (d, J¼8.7 Hz, 2H, 20-H, 60-H); dC (100 MHz, CDCl3) 11.3 (C-12),
19.0 (10-CH3), 21.7 (8-CH3), 28.5 (C-5), 29.9 (C-11), 31.6 (C-10), 31.8
(C-4), 32.6 (C-1), 34.3 (C-8), 44.3 (C-9), 51.3 (C-2), 56.0 (OCH3), 68.8
(CH2CH]CH2), 78.2 (C-3), 96.6 (OCH2OCH3), 114.8 (CH aryl), 117.6
(CH2CH]CH2), 127.1 (C-6), 129.7 (CH aryl), 131.3 (C aryl), 133.4
(CH2CH]CH2), 137.5 (C-7), 157.2 (CO aryl), 177.6 (CO2); HRMS (ESI):
[MþNa]þ calcd for C26H40O5Na 455.27680, found 455.27682.
D
(400 MHz, CDCl3) 0.81 (d, J¼6.4 Hz, 3H, 100-CH3), 0.81–0.85 (m, 3H,
120-H), 0.93 (d, J¼6.6 Hz, 3H, 80-CH3), 0.96–1.01 (m, 1H, 90-H), 1.07–
1.14 (m, 1H, 90-H), 1.18–1.35 (m, 3H, 100-H, 110-H), 1.50–1.66 (m, 2H,
40-H), 2.02–2.24 (m, 3H, 50-H, 80-H), 2.88 (dd, J¼13.5, 3.1 Hz,1H, CH2
aryl), 2.96 (dd, J¼13.6, 5.0 Hz, 1H, CH2 aryl), 3.04–3.10 (m, 1H, CH2
aryl), 3.92–4.00 (m, 2H, 30-H, 4-H), 4.08 (t, J¼8.4 Hz, 1H, 4-H), 4.45
(dd, J¼5.3, 4.1 Hz, 2H, CH2CH]CH2), 4.50–4.55 (m, 1H, 20-H), 4.59–
4.64 (m, 1H, 5-H), 5.21 (dd, J¼10.4, 1.3 Hz, 1H, 70-H), 5.25–5.29 (m,
1H, CH2CH]CH2), 5.32–5.37 (m, 2H, 60-H, CH2CH]CH2), 5.94–6.05
(m, 1H, CH2CH]CH2), 6.81 (d, J¼8.7 Hz, 2H, aryl), 6.94–6.96 (m, 2H,
aryl), 7.18 (d, J¼8.4 Hz, 2H, aryl), 7.23–7.25 (m, 3H, aryl); dC
(100 MHz, CDCl3) 11.3 (C-120), 19.0 (100-CH3), 21.8 (80-CH3), 29.1 (C-
50), 29.9 (C-110), 31.8 (C-100), 32.3 (C-40), 33.7 (CH2 aryl), 34.3 (CH2
aryl), 37.3 (C-80), 44.4 (C-90), 49.3 (C-20), 55.0 (C-5), 65.6 (C-4), 68.8
(CH2CH]CH2), 71.9 (C-30), 114.7 (CH aryl), 117.6 (CH2CH]CH2),
127.2 (CH aryl), 127.3 (C-60), 128.9 (CH aryl), 129.3 (CH aryl), 130.4
(CH aryl),130.8 (C aryl),133.3 (CH2CH]CH2),135.1 (C aryl),137.4 (C-
70), 153.3 (C-2), 157.3 (CO aryl), 175.2 (C-10); HRMS (ESI): [MþNa]þ
calcd for C34H45NO5Na 570.31899, found 570.31908.
4.1.23. tert-Butyl (1S,2R,5E,7R,9R)-1-[4-(allyloxy)benzyl]-2-(methoxy-
methoxy)-7,9-dimethylundec-5-enylcarbamate (46). A solution of
acid 45 (57 mg, 0.13 mmol), Et3N (56
nylphosphoryl azide (DPPA, 73 L, 0.26 mmol) in benzene (3 mL)
was refluxed for 2 h. After cooling to room temperature, BuOH
(100
L, 1.06 mmol) and KOtBu (120 mg, 1.06 mmol) were added
mL, 0.37 mmol), and diphe-
m
t
4.1.21. (4S)-3-[(2S,3R,6E,8R,10R)-2-[4-(Allyloxy)benzyl]-3-(methox-
ymethoxy)-8,10-dimethyldodec-6-enoyl]-4-benzyl-1,3-oxazolidin-2-
m

2640
M. Ugele, M.E. Maier / Tetrahedron 66 (2010) 2633–2641
followed by refluxing of the mixture for 1.5 h. The mixture was
treated with water and extracted with CH2Cl2 (3ꢁ20 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. Purification of the residue by flash chro-
matography (petroleum ether/ethyl acetate, 9:1) gave N-Boc-amine
12-H), 0.91 (d, J¼6.6 Hz, 3H, 8-CH3), 0.95–1.00 (m, 1H, 9-H), 1.04–1.28
(m, 4H, 9-H, 10-H, 11-H), 1.32 (s, 9H, tBu),1.44–1.55 (m,1H, 4-H),1.60–
1.72 (m, 1H, 4-H), 2.03–2.17 (m, 3H, 5-H, 8-H), 2.58 (s, 3H, NCH3), 2.74
(br, 2H, 1-H), 3.06 (dd, J¼13.7, 2.3 Hz, 3-H), 3.44 (s, 3H, OCH3), 3.61–
3.76 (m,1H, 2-H), 4.67 (d, J¼6.9 Hz,1H, OCH2OCH3), 4.75 (d, J¼6.9 Hz,
1H, OCH2OCH3), 5.18–5.23 (m, 1H, 7-H), 5.28–5.35 (m, 1H, 6-H), 6.73
(d, J¼8.4 Hz, 2H, 30-H, 50-H), 7.00 (d, J¼8.4 Hz, 2H, 20-H, 60-H); dC
(100 MHz, CDCl3) 11.3 (C-12), 18.9 (10-CH3), 21.8 (8-CH3), 27.5
(C(CH3)3), 28.1 (C-11), 28.3 (NCH3), 29.9 (C-5), 31.2 (C-10), 31.8 (C-4),
33.2 (C-1), 34.3 (C-8), 44.4 (C-9), 55.0 (OCH2OCH3), 55.1 (C-2), 79.1
(C(CH3)3), 80.0 (C-3), 96.5 (OCH2OCH3), 115.1, 115.2 (C-30, C-50), 127.7
(C-6), 127.9 (C-10), 129.8, 130.0 (C-20, C-60), 137.0 (C-7), 154.8 (CO2),
155.9 (C-40); HRMS (ESI): [MþNa]þ calcd for C28H47NO5Na
500.33464, found 500.33460.
46 (41 mg, 63%) as a colorless oil. Rf (petroleum ether/ethyl acetate,
20
4:1) 0.54; [
a
]
D
ꢀ36.5 (c 1.0, CH2Cl2); dH (400 MHz, CDCl3) 0.80 (d,
J¼6.4 Hz, 3H, 10-CH3), 0.81–0.85 (m, 3H, 12-H), 0.91 (d, J¼6.6 Hz,
3H, 8-CH3), 0.94–1.02 (m, 1H, 9-H), 1.05–1.13 (m, 1H, 9-H), 1.17–1.27
t
(m, 3H, 10-H, 11-H), 1.31 (s, 9H, Bu), 1.48–1.57 (m, 1H, 4-H), 1.60–
1.69 (m, 1H, 4-H), 1.97–2.09 (m, 1H, 5-H), 2.10–2.18 (m, 2H, 5-H, 8-
H), 2.56–2.62 (m, 1H, 1-H), 2.83 (dd, J¼14.2, 4.8 Hz, 1H, 1-H), 3.41 (s,
3H, OCH3), 3.59 (br, 1H, 3-H), 3.93 (d, J¼5.1 Hz, 1H, 2-H), 4.49 (d,
J¼5.3 Hz, 2H, CH2CH]CH2), 4.66 (dd, J¼24.2, 6.9 Hz, 2H,
OCH2OCH3), 4.97 (d, J¼8.7 Hz, 1H, NH), 5.18–5.34 (m, 3H, 6-H, 7-H,
CH2CH]CH2), 5.38 (dd, J¼17.3, 1.5 Hz, 1H, CH2CH]CH2), 5.98–6.00
(m, 1H, CH2CH]CH2), 6.82 (d, J¼8.7 Hz, 2H, 30-H, 50-H), 7.10 (d,
J¼8.7 Hz, 2H, 20-H, 60-H); dC (100 MHz, CDCl3) 11.3 (C-12), 18.9 (10-
CH3), 21.7 (8-CH3), 28.3 (C(CH3)3), 28.7 (C-11), 29.9 (C-5), 31.8 (C-
10), 31.9 (C-4), 34.3 (C-1), 34.9 (C-8), 44.4 (C-9), 54.0 (OCH3), 55.8
(C-7), 68.8 (C-70), 78.9 (C(CH3)3), 81.4 (C-3), 97.3 (OCH2OCH3), 114.6
(C-30, C-50), 117.5 (C-90), 127.2 (C-6), 129.6 (C-10), 130.1 (C-20, C-60),
133.5 (C-80), 137.4 (C-7), 155.4 (CO2), 157.1 (C-40); HRMS (ESI):
[MþH]þ calcd for C30H49NO5H 504.36835, found 504.36841.
4.1.26. 4-[(2S,3R,6E,8R,10R)-3-Hydroxy-8,10-dimethyl-2-(methyl-
amino)dodec-6-enyl]phenol (tyroscherin 2). To a solution of carba-
mate 48 (10 mg, 0.021 mmol) in MeOH (2 mL) was added concd HCl
(30 m
L) followed by stirring of the mixture for 1 h at 50 ꢂC. The
solvent was evaporated in vacuo and the residue purified by flash
chromatography (CHCl3/MeOH, 5:1) yielding tyroscherin (2)
(6.3 mg, 90%) as a slightly yellow oil.
Preparation of the TFA salt: A solution of tyroscherin amine
(6 mg, 0.02 mmol) in CH2Cl2 (5 mL) was treated with TFA (50 mL)
followed by stirring of the mixture for 1 h at room temperature. The
solvent was removed in vacuo and the residue further dried on an
4.1.24. tert-Butyl (1S,2R,5E,7R,9R)-1-[4-(allyloxy)benzyl]-2-(methoxy-
methoxy)-7,9-dimethylundec-5-enyl(methyl)carbamate (47). To
a solution of N-Boc-amine 46 (39 mg, 0.08 mmol) in DMF (2 mL)
was added NaH (4 mg, 0.16 mmol) at 0 ꢂC. After stirring for 20 min
oil pump. The salt was obtained in quantitative yield as a slightly
20
yellow oil. Rf (CHCl3/MeOH, 5:1) 0.31; [
a
]
ꢀ19.0 (c 0.35, MeOH);
D
dH (400 MHz, CDCl3) 0.82 (d, J¼6.1 Hz, 3H, 10-CH3), 0.83–0.86 (m,
3H, 12-H), 0.90 (d, J¼6.6 Hz, 3H, 8-CH3), 0.98 (ddd, J¼13.2, 8.4,
5.3 Hz, 1H, 9-H), 1.07–1.16 (m, 1H, 11-H), 1.19–1.23 (m, 1H, 9-H),
1.24–1.33 (m, 2H, 10-H, 11-H), 1.45–1.60 (m, 2H, 4-H), 1.99 (dd,
J¼14.2, 7.4 Hz, 1H, 5-H), 2.10–2.25 (m, 2H, 5-H, 8-H), 2.62 (s, 3H,
NCH3), 2.83–2.94 (m, 1H, 1-H), 3.31–3.38 (m, 1H, 2-H), 3.83 (d,
J¼8.1 Hz, 1H, 3-H), 5.18–5.24 (m, 1H, 7-H), 5.30–5.37 (m, 1H, 6-H),
6.77 (d, J¼7.9 Hz, 2H, 30-H, 50-H), 7.11 (d, J¼7.9 Hz, 2H, 20-H, 60-H); dC
(100 MHz, CDCl3) 11.7 (C-12), 19.3 (10-CH3), 22.3 (8-CH3), 29.9 (C-
5), 31.1 (C-11), 32.4 (NCH3, C-1), 33.0 (C-4), 33.1 (C-10), 35.7 (C-8),
45.5 (C-9), 66.8 (C-2), 68.7 (C-3),116.8 (C-30, C-50),127.6 (C-10),128.4
(C-6), 131.3 (C-20, C-60), 138.7 (C-7), 157.9 (C-40); HRMS (ESI):
[MþH]þ calcd for C21H36NO2H 334.27406, found 334.27418.
at this temperature, methyl iodide (12 mL, 0.19 mmol) was added
and the mixture allowed to reach room temperature. Stirring was
continued for 10 h before water was added and the mixture was
extracted with CH2Cl2 (3ꢁ20 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo. Puri-
fication of the residue by flash chromatography (petroleum ether/
ethyl acetate, 9:1) gave N-methylamine 47 (38 mg, 95%) as a color-
20
less oil. Rf (petroleum ether/ethyl acetate, 7:1) 0.21; [
a]
ꢀ40.0 (c
D
1.0, CH2Cl2); dH (400 MHz, CDCl3) 0.79 (d, J¼6.4 Hz, 3H, 10-CH3),
0.79–0.84 (m, 3H,12-H), 0.91 (d, J¼6.6 Hz, 3H, 8-CH3), 0.94–1.02 (m,
1H, 9-H), 1.05–1.12 (m, 1H, 9-H), 1.15–1.39 (m, 3H, 10-H, 11-H), 1.30
(s, 9H, tBu), 1.44–1.53 (m, 1H, 4-H), 1.60–1.70 (m, 1H, 4-H), 2.06–2.18
(m, 3H, 5-H, 8-H), 2.54 (s, 3H, NCH3), 2.68 (br, 2H, 1-H), 3.04–3.10
(m, 1H, 3-H), 3.42 (s, 3H, OCH2OCH3), 3.61–3.80 (m, 1H, 2-H), 4.48
(d, J¼5.3 Hz, 2H, CH2CH]CH2), 4.65–4.68 (m, 1H, OCH2OCH3),
4.71–4.75 (m, 1H, OCH2OCH3), 5.17–5.33 (m, 3H, 6-H, 7-H,
CH2CH]CH2), 5.37 (dd, J¼17.3, 1.5 Hz, 1H, CH2CH]CH2), 5.97–6.07
(m, 1H, CH2CH]CH2), 6.79–6.81 (m, 2H, 30-H, 50-H), 7.04 (d,
J¼8.7 Hz, 2H, 20-H, 60-H); dC (100 MHz, CDCl3) 11.3 (C-12), 18.9 (10-
CH3), 21.7 (8-CH3), 27.5 (C(CH3)3), 28.1 (C-11), 28.3 (NCH3), 29.9 (C-
5), 31.2 (C-10), 31.8 (C-4), 33.2 (C-1), 34.3 (C-8), 44.4 (C-9), 56.0
(C-2), 56.1 (OCH2OCH3), 68.9 (CH2CH]CH2), 79.1 (C(CH3)3), 79.5
(C-3), 96.5 (OCH2OCH3), 114.5, 114.6 (C-30, C-50), 117.5
(CH2CH]CH2), 127.7 (CH2CH]CH2), 127.9 (C-10), 129.8, 129.9 (C-20,
C-60), 133.4 (C-80), 136.9 (C-7), 155.6 (CO2), 157.1 (C-40); HRMS (ESI):
[MþNa]þ calcd for C31H51NO5Na 540.36594, found 540.36508.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article (remaining
procedures for Scheme 1–3, copies of NMR spectra) can be found in
the online version, at doi:10.1016/j.tet.2010.02.034.
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(petroleum ether/ethyl acetate, 3:1) 0.25; [
a
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D
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