Stereoselective allyl transfer to chiral α-methoxycarbaldehydes: A model study related to the C-9/C-15 fragment of geldanamycin

Article abstract of DOI:10.1016/j.bmc.2006.05.056

The enantiomerically pure α-methoxycarbaldehyde 3 was prepared from l-leucine in five steps and 31% overall yield. The aldehyde was subjected to a diastereoselective BF₃-mediated crotylation with silane 4 and to various reagent-controlled addit

Full text of DOI:10.1016/j.bmc.2006.05.056

Bioorganic & Medicinal Chemistry 14 (2006) 6223–6234
Stereoselective allyl transfer to chiral a-methoxycarbaldehydes:
A model study related to the C-9/C-15 fragment
of geldanamycin
Tony Horneff,a Eberhardt Herdtweck,b Soren Randollb,ꢀ and Thorsten Bacha,*
¨
aLehrstuhl fu¨r Organische Chemie I, Department of Chemistry, Technische Universita¨t Mu¨nchen,
Lichtenbergstr. 4, 85747 Garching, Germany
bLehrstuhl fu¨r Anorganische Chemie, Department of Chemistry, Technische Universita¨t Mu¨nchen,
Lichtenbergstr. 4, 85747 Garching, Germany
Received 6 February 2006; revised 22 March 2006; accepted 30 May 2006
Available online 21 June 2006
Abstract—The enantiomerically pure a-methoxycarbaldehyde 3 was prepared from L-leucine in five steps and 31% overall yield. The
aldehyde was subjected to a diastereoselective BF3-mediated crotylation with silane 4 and to various reagent-controlled addition
reactions. The configuration of aldol addition products 19 and 20 was proven by single crystal X-ray crystallography. Based on these
data spectral comparison allowed an unambiguous assignment of the desired anti,syn-crotylation product 2b and of the syn,syn-
crotylation product 2a. Unexpectedly, product 2a of the BF3-mediated crotylation is formally the product of chelation-control.
The anti,syn-crotylation product 2b, which is a model for the C-9/C-15 fragment of geldanamycin, was obtained by a reagent-con-
trolled crotylation with the chiral (Z)-crotylborane 23.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
and inhibits the ATPase activity which is essential for
the function of the enzyme.12 The Hsp90 chaperone
machinery in turn is a crucial enzyme apparatus re-
quired by many proteins overexpressed in cancer cells.13
The ansamycin1 antibiotic geldanamycin (1) was isolat-
ed as early as 19702 and its structure (Scheme 1) was elu-
cidated shortly thereafter.3 Although other ansamycin
antibiotics subsequently attracted synthetic attention
and total syntheses of macbecin I4 and herbimycin A5
were reported, geldanamycin was not a focus of synthet-
ic organic chemists until recently.6 The situation chan-
ged when the significant antitumour activity of
geldanamycin became public7 and it changed even more
so when its mode of action became increasingly appar-
ent.8 Without going into details9 it is now generally
accepted that at least part of the antitumour activity
of geldanamycin is attributed to its complexation to
the heat shock protein 90 (Hsp 90).10 It binds to the
N-terminal ATP/ADP-binding domain of Hsp 9011
So far, synthetic work on geldanamycin has resulted in
one total synthesis by Andrus and et al.14 Synthetic
modifications of natural geldanamycin have been
reported15 as have chimeric compounds16 combining
properties of both geldanamycin and other Hsp90 bind-
ing compounds. Synthetic approaches to geldanamycin
O
OH
15
MeO
15
9
O
N
OMe
2
H
O
MeO
9
OH
Keywords: Ansamycins; Allyl transfer; Felkin-Anh control; Chelation
control; Stereoselective synthesis.
O
CHO
OMe
MeO
+
TMS
*
Corresponding author. Tel.: +49 89 28913330; fax: +49 89
28913315; e-mail: thorsten.bach@ch.tum.de
Present address: Institut fur Anorganische und Analytische Chemie,
¨
O
NH2
3
4
1
ꢀ
Scheme 1. A possible access to a model (2) for the C-9/C-15 fragment
of geldanamycin (1) by allylsilane addition to the chiral aldehyde 3.
Technische Universita¨t Carolo-Wilhelmina, Hagenring 30, 38106
Braunschweig, Germany.
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.05.056

6224
T. Horneff et al. / Bioorg. Med. Chem. 14 (2006) 6223–6234
ed with sodium hydride and methyl iodide in DMF at
1. 4, BF3⋅OEt2
2. MeI, NaH
ambient temperature. The sequence esterification/meth-
ylation was higher yielding than the double methylation
of acid 9 with NaH/MeI (50% yield). Further conversion
to the desired aldehyde 3 was achieved by complete
reduction of ester 11 to alcohol 12 and subsequent
tetramethylpiperidine-N-oxyl(TEMPO)-catalyzed21 oxi-
dation. The enantiomeric purity of alcohol 12 was
determined by preparation of the corresponding a-meth-
oxy-a-trifluoromethylphenyl acetate (Mosher’s ester).
The diastereomerically pure product prepared from 12
and (S)-Mosher’s acid22 was compared with the dia-
stereomeric mixture prepared from 12 and racemic
Mosher’s acid. The crotylation reagent 4 was prepared
from (E)-crotyl chloride in two steps according to a
literature procedure.19
O
O
O
O
H
78%
MeO
MeO
O
O
O
OMe
d.r. = 81/10/9
5
6
OH
O
4, BF3⋅OEt2
O
O
N
N
74%
Boc
Boc
7
8
d.r. = 82/18
Scheme 2. Precedence for a Felkin-Anh type addition of (E)-crotylsi-
lane 4 to a-chiral aldehydes in the presence of BF3.
and syntheses of simplified geldanamycin analogues
have been published.17
The crotylation of aldehyde 3 was attempted under var-
ious conditions. Particular emphasis was given to non-
chelating Lewis acids as promoters in order to achieve
the desired Felkin-Anh-control. Indeed, BF3ÆOEt2
turned out to be an efficient catalyst and allowed for
the silane addition at ꢀ78 ꢁC (Scheme 4).
From an inspection of the Hsp90/geldanamycin com-
plex11a it is suggested that the stereogenic centres at
C-10 to C-12 and at C-14 play an important role in sta-
bilizing the C-shaped conformation of the bound mole-
cule. In a modular approach to geldanamycin analogues
it will consequently be important to successfully address
the question of how to stereoselectively construct this
part of the molecule. A possible access to the C-9/C-15
fragment of geldanamycin and more specifically to the
stereogenic centres at C-10 and C-11 is a substrate-
controlled Felkin-Anh type crotylation of an a-chiral
methoxycarbaldehyde with (E)-crotylsilane (4). Prece-
dence for diastereoeselective reactions of this type exists
(Scheme 2). Danishefsky et al.18 reported on the reaction
of aldehyde 5 with silane 4 in the presence of BF3ÆOEt2
and Taddei et al.19 observed a similar selectivity in the
addition to the chiral a-aminoaldehyde 7. In both cases
the Felkin-Anh products 6 and 8 predominated.
O
O
MeOH
TMSCl
NaH, MeI
(DMF)
OH
OMe
OH
OH
quant.
73%
9
10
O
LiAlH4
NaClO [TEMPO]
OH
(Et2O)
OMe
NaHCO3 (CH2Cl2)
3
OMe
OMe
97%
79%
11
12
Scheme 3. Preparation of aldehyde 3 from the L-leucine derived
enantiomerically pure a-hydroxycarboxylic acid 9.
Encouraged by this precedence we considered the c-
branched a-methoxycarbaldehyde 3 as a reasonable
model to mimic a more complex aldehyde related to gel-
danamycin (Scheme 1). We hoped for a selective addi-
tion of silane 4 to yield the anti,syn-diastereoisomer 2b
of alcohol 2. In this paper, we disclose the results of
our study. The preparation of aldehyde 3 and its croty-
lation are described. An unambiguous configuration
assignment required the synthesis of structurally charac-
terized 1,3-diols for comparison, the syntheses of which
are also presented. The unexpected result that the BF3-
promoted crotylation led to the syn,syn-alcohol 2a is dis-
cussed. Finally, it was shown that a reagent-controlled
crotylation of aldehyde 3 to 2b is feasible.
4, BF3⋅OEt2
(CH2Cl2)
NaH,BnBr
Bu4NI (DMF)
OH
*
3
*
d.r. = 90/10
60% (2 steps)
OMe
2a
O3, PPh3
(CH2Cl2/MeOH)
OBn
OBn
*
*
OMe
*
*
OMe
O
75%
13
14
OBn OH
H2 [Pd/C]
(EtOH)
NaBH4
(EtOH)
*
*
86%
68%
OMe
15
2. Synthesis of aldehyde 3 and crotylation
Ph
O
*
O
PhCHO, CH(OMe)3
TFA (CH2Cl2)
OH OH
The synthesis of aldehyde 3 commenced with the known
stereospecific hydroxy-de-amination of L-leucine con-
ducted with NaNO2 in 2 N H2SO4.20 Acid 9 furnished
methyl ester 10 upon activation with trimethylsilyl chlo-
ride (TMSCl) employing methanol as the solvent and
2,2-dimethoxypropane as additional dehydrating re-
agent (Scheme 3). The hydroxy ester 10 was O-methylat-
4
*
*
5
*
66%
OMe
OMe
16a
17a
Scheme 4. Allyltransfer to aldehyde 3 with (E)-crotylsilane 4 and
subsequent conversion of its product 2a to diol 16a and acetal 17a.

T. Horneff et al. / Bioorg. Med. Chem. 14 (2006) 6223–6234
6225
NaBH4
O
O
Overstoichiometric amounts of BF3ÆOEt2 (1.5 equiva-
O
OH
O
1. Bu2BOTf, i Pr2NEt
(aq.THF)
lents relative to 3) were employed to facilitate a smooth
conversion. 1H NMR analysis of the crude product mix-
ture revealed a diastereomeric ratio (d.r.) of 90/10 in fa-
vour of product 2a. The stereochemical result with two
equivalents BF3ÆOEt2 were similar (d.r. P90/10). One
equivalent of BF3ÆOEt2 delivered a mixture of three dia-
stereoisomers in a ratio of 2:1:1 with 2a being the pre-
dominant diastereoisomer. Due to its instability the
isolation and storage of major product 2a was difficult
and it was therefore converted into the benzyl ether
13. At the benzyl ether stage the separation of diastere-
oisomers was feasible and diastereomerically pure prod-
uct 13 was obtained in 60% from aldehyde 3 over two
steps.
2. 3 (CH2Cl2)
N
O
N
O
62%
63%
OMe
19
Bn
Bn
18
Ph
O
O
PhCHO, CH(OMe)3
TFA (CH2Cl2)
OH OH
4
5
66%
OMe
OMe
16b
17b
Scheme 5. Preparation of diol 16b and acetal 17b by auxiliary-
controlled Evans aldol addition to aldehyde
transformations.
3 and consecutive
In order to determine the relative configuration among
the newly formed stereogenic centres marked with an
compound 19 was established by single crystal X-ray
crystallography (Fig. 1). Suitable crystals were grown
by adding pentane to a saturated solution of 19 in
CH2Cl2. As soon as the solution became turbid it was
cooled to ꢀ5 ꢁC and allowed to stand at this tempera-
ture. The crystallographic result was in line with the
expectation for an auxiliary-controlled aldol addition
with N-propionyl-(S)-4-benzyl-2-oxazolidinone (18).24
Diol 16b, however, was not identical to diol 16a ob-
tained in the crotylation studies nor was the correspond-
ing 1,3-dioxane 17b identical with 17a.
asterisk ( ) benzyl ether 13 was converted to diol 16a
*
in three steps. Ozonolysis and reductive work-up yielded
aldehyde 14, which was further reduced to primary alco-
hol 15. Hydrogenolytic cleavage of the benzyl ether gave
the desired diol 16a. Acetal formation delivered 1,3-di-
oxane 17a which allowed for the assignment of the rela-
tive configuration at the stereogenic centres C-4 and C-5
3
in the dioxane ring. The coupling constant J between
H-4 and H-5 was determined as 2.3 Hz. Coupling con-
stants of H-5 to the protons at C-6 were equally small
(1.5 and 2.0 Hz) indicating that all hydrogen atoms are
in an anti- or synclinal conformation (eq/eq, eq/ax, or
ax/eq relative to each other). This observation leads to
the immediate conclusion that the phenyl group and
the substituent at C-4 are equatorially positioned and
the methyl group at C-5 axially. The simple diastereo-
selectivity of the crotylation step to product 2a had con-
sequently led to the expected syn-connectivity between
the methyl group and the hydroxy group.
1H NMR studies with dioxane 17b resulted in the cou-
pling constants (see chapter 2) typical for a syn-aldol
product, that is, the coupling constants for H-4 and
H-5 (3J = 2.3 Hz) as well as for H-5 and both protons
at C-6 (1.6 and 2.4 Hz) were small. Since the anti,syn-di-
ol 16b was not identical with 16a and since the relative
configuration of 16a is syn at the CHMe-CHOH part
(vide infra), diol 16a must have the syn,syn-configura-
tion resulting from a syn,syn-crotylation product 2a.
The configuration of the newly formed stereogenic cen-
tres relative to the stereogenic centre of the a-methoxy-
carbaldehyde (facial diastereoselectivity) had to be
proven by comparison with synthetic samples. Despite
the precedence for Felkin-Anh-control (Scheme 2) this
effort seemed appropriate because there was reasonable
doubt about the desired anti,syn-configuration of prod-
uct 2a. The doubt originated from the crotylation exper-
iments we conducted in the presence of chelating Lewis
acids, such as TiCl4. With TiCl4 as catalyst, two prod-
ucts were formed in equal quantities, one of which was
identical to compound 2a. It was difficult to understand
why TiCl4 should lead to the product resulting from
Felkin-Anh-control and it was equally difficult to
understand why BF3 would lead to the syn,syn
chelation-control product.
Additional proof for this assignment came from another
aldol addition we conducted with the propionate
equivalent 18 (Scheme 6). Under conditions earlier
described by Heathcock et al.25 using two equivalents
of Bu2BOTf a major addition product was isolated,
the configuration of which was also elucidated by single
crystal X-ray crystallography (Fig. 2). It turned out to
be the syn,syn-diastereoisomer 20. Reduction of product
20 gave diol 16a and further acetal formation yielded
17a.
By comparison of their analytical data, the identity of
compounds 16a and 17a obtained either from 20 or from
3. Aldol addition reactions to aldehyde 3
Diols 16 appeared to be easily accessible from the corre-
sponding aldol addition products by reduction. Using
the well-established Evans methodology,23 aldol addi-
tion product 19 was generated and subsequently reduced
to diol 16b (Scheme 5). The relative configuration of
Figure 1. Structure of compound 19 in the crystal.

6226
T. Horneff et al. / Bioorg. Med. Chem. 14 (2006) 6223–6234
TMS
1. Bu2BOTf (2eq.)
i Pr2NEt (CH2Cl2)
2. 3 (CH2Cl2)
O
NaBH4
OH
O
O
BF3⋅OEt2
(CH2Cl2)
OH
OH
(aq.THF)
N
O
+
18
60%
Ph
43%
OMe
20
OBn
OBn
OBn
d.r. = 35/65
Bn
21
22a
22b
O
O
PhCHO, CH(OMe)3
TFA (CH2Cl2)
OH OH
4
BF3
BF3
BF3
5
O
O
O
MeO
H
66%
OMe
OMe
BnO
MeO
16a
17a
H
H
H
H
H
Scheme 6. Preparation of syn,syn-diol 16a by aldol addition of a boron
enolate generated from N-propionyloxazolidinone 18 and 2 equiva-
lents Bu2BOTf.
A
B
C
Scheme 7. Allylation of aldehyde 21 and possible reactive conforma-
tions A–C for carbonyl addition to a-alkoxyaldehydes 21 and 3.
oxyaldehyde was involved as the electrophile but not
an a-methoxyaldehyde. An increase of formal chelation
product upon an increase in BF3ÆOEt2 concentration (3
equiv instead of 1.2. equiv) was observed in the addition
of allyltin compounds to cyclohexylidene glyceralde-
hyde.30 The BF3ÆOEt2-mediated crotylation of a chiral
a-benzyloxycarbaldehyde with crotylstannane resulted
in the preferred formation of the formal chelation versus
Felkin-Anh product (d.r. = 67/33).31
The fact that superstoichiometric amounts of BF3ÆOEt2
were required to achieve a high facial diastereoselectivity
in the crotylation of 3 (vide infra) indicates that more
than one molecule of BF3 is complexed to substrate 3.
From data of related methyl ethers the pKHB of the
methyl ether group in 3 is estimated at around 1.1, while
diethyl ether has a pKHB of 1.01 and benzyl ethers of
0.7.32 The pKHB of the carbonyl group in an aliphatic
aldehyde (acetaldehyde) was determined as 0.65.33 The
basicity of acetal groups ROCHR’OR (cf. substrate 5)
is lower (0.58 if statistically corrected for the presence
of two Lewis basic groups).32 Other studies support
the given order of Lewis basicity.34,35 Based on these
data it is assumed that BF3 complexation to aldehyde
3 occurs primarily at the methoxy group as depicted in
Figure 3. Reetz et al. have suggested that double Lewis
acid coordination of BF3 to 21 leads to a conformation
in which the carbonyl oxygen and the benzyloxy group
are antiperiplanar (Cornforth36 model).26b In our case,
we favour the notion that additional activation by a sec-
ond BF3 molecule leads to conformation C0 which in
turn accounts for the observed Si face attack. A Si face
view on the putative transition state TS-1 of the addition
of crotylsilane37 reveals that the incoming nucleophile
Figure 2. Structure of compound 20 in the crystal.
crotylation product 2a was unequivocally established.
The specific rotation of the compounds was identical
proving that all steps leading from acid 9 to product
17a had proceeded racemization-free.
It had to be concluded from these studies that the BF3-
promoted addition of crotylsilane 4 to aldehyde 3
(Scheme 4) proceeded to the formal product of a chela-
tion-controlled addition.
4. Discussion
Felkin-Anh-control has been observed in the BF3-pro-
moted addition of allyltrimethylsilane to aldehydes. A
typical substrate is the O-benzyl protected chiral alde-
hyde 21 (Scheme 7).26
The excess of product 22b has been interpreted by the
conformation A and a preferential Re face attack.27
A
BF3
BF3
H
similar conformation B for 3 is not in line with the result
we obtained. Rather it appears as if the iso-butyl group
resides in the position perpendicular to the carbonyl
group which is normally adopted by the best r*-accep-
tor (C).28 A conformation related to C has been suggest-
ed to account for a deviation from the Felkin-Anh
model in the BF3-mediated addition of a silyl enol ether
to an a-chiral aldehyde.29 In the latter case, an a-silyl-
O
CHO
O
O
H
F3B
F3B
O
O
F3B
H
H
SiMe3
3 ⋅ BF3
TS-1
C'
Figure 3. Model to explain the facial diastereoselectivity observed
upon allyltransfer to aldehyde 3.

T. Horneff et al. / Bioorg. Med. Chem. 14 (2006) 6223–6234
6227
Chemical shifts are reported relative to tetramethylsi-
lane as internal standard. Apparent multiplets which oc-
cur as a result of the accidental equality of coupling
constants of magnetically nonequivalent protons are
marked as virtual (virt.). The multiplicities of the 13C
NMR signals were determined by DEPT experiments.
IR: Perkin-Elmer 1600 FT-IR. MS: Finnigan MAT
8200 (EI). Elemental Analysis: Elementar Vario EL.
Flash chromatography was performed on silica gel 60
(Merck, 230–400 mesh) (ca. 50 g for 1 g of material to
be separated) with the indicated eluent. Common sol-
vents for chromatography [pentane (P), ethyl acetate
(EA), dichloromethane (CH2Cl2)] were distilled prior
to use.
see
scheme 4
OH
O
(PhMe)
B
16b
COOi Pr
3 +
23%
(5 steps)
O
OMe
2b
COOi Pr
23
Scheme 8. Reagent-controlled crotylation of aldehyde
syn,anti-product 2b and its conversion to diol 16b.
3
to the
can readily approach the doubly complexed aldehyde
without interfering with the methoxy group. It might
be this interaction which forces the methoxy group out
of its preferred position.38
The suggested transition state TS-1 accommodates the
simple diastereoselectivity of the C–C bond formation.
The Lewis-acid coordination to the methoxy group is
also in line with the outcome of the modified aldol reac-
tion depicted in Scheme 6 via an open transition state. Si
face attack at 3 and Re face attack at the chelated boron
enolate derived from 18 lead to the formation of the ob-
served major diastereoisomer 20. A related transition
state was put forward by Panek et al. to explain the
unexpectedly high diastereoselectivity observed in the
addition of a chiral silane to aldehyde 21.39
5.1.1. (S)-2-Hydroxy-4-methylpentanoic acid methyl ester
(10).
Trimethylsilylchloride
(190 lL,
163 mg,
1.50 mmol) was added to a solution of acid 920 (1.98 g,
15.0 mmol) in dimethoxypropane (24 mL) and MeOH
(6 mL). The mixture was stirred for 16 h at rt and the
solvent removed in vacuo. The residue was diluted with
Et2O (20 mL), washed with H2O (2· 20 mL) and brine
(20 mL), dried (Na2SO4), filtered and concentrated in
vacuo to give 10 as a colourless oil (2.19 g, 15.0 mmol,
20
D
100%) Rf = 0.49 (P/EA 8:2) [CAM]; ½aꢁ ꢀ14.5 (c 0.98,
Et2O); 1H NMR (360 MHz, CDCl3): d = 0.92 [d,
3
3J = 6.6 Hz, 3 H, CH(CH3)2], 0.94 [d, J = 6.6 Hz, 3 H,
CH(CH3)2], 1.53 [ddd, 1 H, 2J = 13.9 Hz,3J = 8.0 Hz,
Given the unexpected result of the crotylation studies
with 3 it appeared appropriate to test a well-established
reagent-controlled crotylation reaction for its suitability
in the reaction of a-methoxycarbaldehydes. The method
established by Roush et al.40 was chosen for this pur-
pose.41 It was shown by transformation to diol 16b that
reagent 23 indeed delivers the expected product 2b,
which contains the desired anti,syn-stereotriade of
geldanamycin.
3J = 6.2 Hz, CHHCH(CH3)2], 1.57 [ddd,
1
H,
3
2J = 13.9 Hz,3J = 7.9 Hz, J = 5.2 Hz, CHHCH(CH3)2],
3
1.67 [virt. septet, J ffi 6.9 Hz, 1 H, CH(CH3)2], 2.66 (s,
1 H, OH), 3.77 (s, 3 H, OCH3), 4.17–4.23 (m, 1 H,
CHOH); 13C NMR (90.6 MHz, CDCl3) d = 21.6 [q,
CH(CH3)2], 23.2 [q, CH(CH3)2], 24.4 [d, CH(CH3)2],
43.5 [t, CH2CH(CH3)2], 52.4 (q, CO2CH3), 69.1 (ꢀd1,
CHOH), 176.3 (s, COOCH3); IR (neat): m ¼ 3478 cm
(br, OH), 2959 (s, CH), 2871 (m, CH), 1740 (s, C@O),
1470 (m, CH2), 1439 (m), 1214 (s, COC), 1142 (s),
1089 (COC); MS (EI, 70 eV), m/z (%): 90 (26), 87 (43)
[C5H11O+], 69 (100), 59 (33) [C2H3O2+], 55 (11); elemen-
tal analysis calcd (%) for C7H14O3 (146.18): C, 57.51; H,
9.65. Found: C, 57.12; H, 9.80.
~
The reagent-controlled approach apparently offers a via-
ble solution for a diastereoselective anti,syn-crotylation
of aldehyde 3 (Scheme 8) and for an analogous anti,-
syn-aldol reaction (Scheme 5). Nonetheless, work in
our laboratory on selective substrate-controlled crotyla-
tion reactions of a-methoxycarbaldehydes continues and
will be reported in due course.
5.1.2. (S)-2-Methoxy-4-methylpentanoic acid methyl ester
(11). A solution of alcohol 10 (2.00 g, 13.6 mmol) in
DMF (5 mL) was slowly added at 0 ꢁC to a solution
of sodium hydride (60% in mineral oil; 1.09 g,
27.4 mmol) and methyl iodide (4.28 mL; 9.71 g,
68.4 mmol) in DMF (30 mL). The mixture was stirred
at rt for 5 h and then satd aq NH4Cl (20 mL) was added.
The mixture was diluted with H2O (350 mL) and
extracted with Et2O (3· 150 mL). The combined organic
layers were washed with brine (150 mL), dried (NaSO4),
filtered and concentrated in vacuo. The crude product
was purified by flash chromatography (P/EA 9/1) to give
11 as a colourless oil (1.59 g, 9.94 mmol, 73%). Rf = 0.34
5. Experimental section
5.1. General
All reactions involving water-sensitive chemicals were
carried out in flame-dried glassware with magnetic stir-
ring under argon. Tetrahydrofuran and diethyl ether
were distilled from sodium immediately prior to use.
Dichloromethane and diisopropylethylamine were dis-
tilled from calcium hydride. All other chemicals were
either commercially available or prepared according to
the cited references. TLC: Merck glass sheets (0.25 mm
silica gel 60, F254), eluent given in brackets. Detection
by UV or coloration with cerium ammonium molybdate
(CAM). Optical Rotation: Perkin-Elmer 241 MC.
20
1
(P/EA 9:1) [CAM]; ½aꢁ ꢀ45.1 (c 0.75, Et2O); H NMR
D
(360 MHz, CDCl3): d = 0.90 [d, 3J = 6.6 Hz, 3 H,
CH(CH3)2], 0.91 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 1.48
3
[ddd, 2J = 14.0 Hz,3J = 8.4 Hz, 3J = 4.5 Hz,
1
H,
CHHCH(CH3)2], 1.64 [ddd, 2J = 14.0 Hz,3J = 9.0 Hz,
3J = 5.4 Hz, 1 H, CHHCH(CH3)2], 1.67–1.84 [m, 1 H,
CH(CH3)2], 3.33 (s, 3 H, CHOCH3), 3.71 (s, 3 H,
1
NMR: Bruker AC-250, AV-360, AV-500. H and 13C
NMR spectra were recorded at ambient temperature.

6228
T. Horneff et al. / Bioorg. Med. Chem. 14 (2006) 6223–6234
COOCH3), 3.78 (dd, 3J = 9.0 Hz, 3J = 4.5 Hz, 1 H,
CHOCH3); 13C NMR (90.6 MHz, CDCl3) d = 21.7 [q,
CH(CH3)2], 22.9 [q, CH(CH3)2], 24.4 [d, CH(CH3)2],
41.7 [t, CH2CH(CH3)2], 51.7 (q, CO2CH3), 58.0 (q,
3J = 5.7 Hz, 1 H, CHHCH(CH3)2], 1.57–1.90 [m, 1 H,
CH(CH3)2], 3.40 (s,
3
H, OCH3), 3.60 (ddd,
3J = 8.8 Hz,3J = 4.8 Hz, 3J = 2.2 Hz, 1 H, CHOCH3),
3
9.64 (d, J = 2.2 Hz 1 H, CHO); 13C-NMR (90.6 MHz,
CHOCH3), 79.2 (d, CHOCH3), 173.6 (s, COOCH3);
ꢀ1
CDCl3) d = 21.9 [q, CH(CH3)2], 23.1 [q, CH(CH3)2],
24.2 [d, CH(CH3)2], 38.5 [t, CH2CH(CH3)2], 58.3 (q,
CHOCH3), 84.5 (dꢀ,1 CHOCH3), 204.0 (d, CHO); IR
~
IR (neat): m ¼ 2958 cm (s, CH), 2871 (m, CH), 2828
(m, CH), 1753 (s, C@O), 1468 (m, CH2), 1435 (m),
1270 (m), 1197 (s, COC), 1135 (s), 1113 (COC); MS
(EI, 70 eV), m/z (%): 101 (100) [C6H13O+], 69 (69), 59
(49) [C2H3O2+], 45 (40) [CHO2+]; elemental analysis
calcd (%) for C8H16O3 (160.21): C, 59.97; H, 10.07.
Found: C, 59.69; H, 10.02.
~
(neat): m ¼ 2958 cm (s, CH), 2872 (s, CH), 2826 (m,
CH), 1734 (s, C@O), 1468 (m, CH2), 1368 (m), 1100
(s, COC); MS (EI, 70 eV), m/z (%): 101 (91)
[C6H13O+], 71 (22), 69 (95), 59 (100) [C3H7O+], 55 (18)
[C4H7+].
5.1.3. (S)-2-Methoxy-4-methylpentan-1-ol (12). A solu-
tion of ester 11 (900 mg, 5.62 mmol) in Et2O (5 mL)
was slowly added at 0 ꢁC to a suspension of sodium hy-
dride (60% in mineral oil, 256 mg, 6.74 mmol) in Et2O
(20 mL). The mixture was stirred at rt for 3 h and then
H2O (20 mL) was added carefully. The organic layer
was separated, washed with satd aq NaHCO3 (2·
20 mL) and brine (20 mL), dried (NaSO4), filtered and
concentrated in vacuo to give 12 as a colourless oil
5.1.5. (3R,4S,5S)-5-Methoxy-3,7-dimethyl-oct-1-en-4-ol
(2a). A solution of aldehyde 3 (148 mg, 1.14 mmol) in
CH2Cl2 (3 mL) was added at ꢀ78 ꢁC to a solution of
BF3ÆEt2O (210 lL, 242 mg, 1.70 mmol) in CH2Cl2
(15 mL). After 20 min, the mixture was treated with
(E)-crotyltrimethylsilane19 (182 mg, 1.42 mmol) and
was stirred for 12 h at ꢀ78 ꢁC. H2O (20 mL) was added,
the layers separated and the aqueous layer extracted
with CH2Cl2 (2· 15 mL). The combined organic extracts
were combined, washed with satd aq NaHCO3 (25 mL)
and brine (25 mL), dried (NaSO4), filtered and concen-
trated to give the crude product (dr 9/1, determined by
1H NMR) as a yellow oil. The residue was purified by
flash chromatography for NMR analysis (P/Et2O 8/2)
to yield 2a as a colourless oil (35.4 mg, 190 lmol, 17%,
2 steps). Due to the instability of the compound, for pre-
parative purposes the crude product was directly used in
the next reaction leading to higher yields. Rf = 0.24 (P/
Et2O 8/2) [CAM]; 1H NMR (360 MHz, CDCl3):
d = 0.90 [d, 3J = 6.6 Hz, 3 H, CH(CH3)2], 0.94 [d,
(720 mg, 5.45 mmol, 97%). Rf = 0.27 (P/EA 9:1)
[CAM]; ½aꢁ
20
D
ꢀ7.9 (c = 1.0, Et2O); 1H NMR
(360 MHz, CDCl3): d = 0.88 [d, 3J = 6.6 Hz, 3 H,
CH(CH3)2], 0.89 [d, J = 6.6 Hz, 3 H, CH(CH3)2], 1.20
3
[ddd, 2J = 13.9 Hz, 3J = 7.2 Hz, 3J = 6.2 Hz,
1 H,
CHHCH(CH3)2], 1.45 [d virt. t, 2J = 13.9 Hz,
3J ffi 6.9 Hz, 1 H, CHHCH(CH3)2], 1.57–1.72 [m, 1 H,
CH(CH3)2], 2.41 (s, 1 H, OH), 3.29 (dd virt. t,
3
3
3J = 6.8 Hz, J = 3.3 Hz, J ffi 6.2 Hz, 1 H, CHOCH3),
3.37 (s,
3
H, OCH3), 3.42 (dd, 2J = 11.6 Hz,
3J = 6.0 Hz, 1 H, CHHOH), 3.65 (dd, 2J = 11.5 Hz,
3J = 3.3 Hz, 1 H, CHHOH); 13C NMR (90.6 MHz,
CDCl3) d = 22.8 [q, CH(CH3)2], 22.9 [q, CH(CH3)2],
24.7 [d, CH(CH3)2], 39.7 [t, CH2CH(CH3)2], 56.9 (q,
CHOCH3), 64.0 (t,ꢀ1CH2OH), 80.0 (d, CHOCH3); IR
3
3J = 6.6 Hz, 3 H, CH(CH3)2], 1.07 [d, J = 6.8 Hz, 3 H,
C(OH)CHCH3], 1.42 [virt. t, 3Jffi7.0 Hz,
1
1
H,
H,
CHHCH(CH3)2], 1.43 [virt. t, 3J ffi 6.6 Hz,
CHHCH(CH3)2], 1.67 [virt. septet, 3J ffi 6.7 Hz, 1 H,
3
CH(CH3)2], 2.09 (d, J = 7.6 Hz, 1 H, OH), 2.37 [virt.
~
(neat): m ¼ 3420 cm (br, OH), 2955 (s, CH), 2832 (s,
3
CH), 2870 (s, CH), 2826 (m, CH), 1467 (m, CH2),
1367 (m), 1100 (s, COC), 1053 (m); MS (EI, 70 eV), m/
z (%): 101 (100) [C6H13O+], 75 (22) [C3H7O2+], 69
(91), 59 (69) [C3H7O+], 45 (70) [C2H5O+], 43 (40); ele-
mental analysis calcd (%) for C7H16O2 (132.20): C,
63.60; H, 12.20. Found: C, 63.44; H, 12.33.
sex, J ffi 7.4 Hz, 1 H, C(OH)CHCH3], 3.18–3.24 (m, 1
3
H, CHOH), 3.30 (d virt. t, J = 3.1 Hz,3J ffi 6.6 Hz, 1
H, CHOCH3), 3.39 (s, 3 H, OCH3), 5.04 (ddd,
2J = 1.9 Hz, 3J = 10.3 Hz, 4J = 0.7 Hz, 1 H, CH@CHH),
2
3
4
5.07 (ddd, J = 1.9 Hz, J = 17.2 Hz, J = 1.0 Hz, 1 H,
CH@CHH), 5.73 (ddd, 3J = 17.2 Hz, 3J = 10.3 Hz,
3J = 8.2 Hz, 1 H, CH@CH2); 13C NMR (90.6 MHz,
CDCl3): d = 16.0 [q, C(OH)CHCH3], 22.8 [q,
CH(CH3)2], 23.1 [q, CH(CH3)2], 24.6 [d, CH(CH3)2],
39.8 [t, CH2CH(CH3)2], 41.7 [d, C(OH)CHCH3], 57.8
(q, OCH3), 76.2 (d, CHOH), 78.8 (d, CHOCH3), 114.9
5.1.4. (S)-2-Methoxy-4-methylpentanal (3). A solution of
TEMPO (1.77 mg, 11.0 lmol) and potassium bromide
(13.5 mg, 114 lmol) in 5% aq NaHCO3 (0.54 mL) and
CH2Cl2 (2.5 mL) was treated with alcohol 12 (150 mg,
1.14 mmol) in CH2Cl2 (5 mL) at 0 ꢁC. After addition
of 13% aq NaOCl (0.6 mL), the reaction mixture was
monitored by TLC and more aq NaOCl (0.3 mL) was
added (1 h). After complete conversion of the alcohol,
the layers were separated and the aqueous layer extract-
ed with CH2Cl2 (2· 3 mL). The combined organic layers
were washed with sat. aqueous NaHCO3 (2· 3 mL) and
brine (2· 3 mL), dried (Na2SO4), filtered and concen-
trated in vacuo to give 3 as a colourless oil (116 mg,
900 lmol, 79%). Rf = 0.89 (P/Et2O 4/6) [CAM]; 1H
NMR (360 MHz, CDCl3): d = 0.93 [d, 3J = 6.6 Hz, 3
(t, CH@CH2), 141.6 (d, CH@CH2); IR (neat):
ꢀ1
~
m ¼ 3458 cm (br, OH), 2958 (s, CH), 2933 (s, CH),
2870 (s, CH), 2825 (s, CH), 1640 (w, C@C), 1466 (m,
CH2), 1367 (m), 1102 (s, COC), 913 (m, C@C); MS
(EI, 70 eV), m/z (%): 131 (48) [C7H15O2+], 101 (83)
[C6H13O+], 81 (32), 74 (34), 69 (97), 59 (65) [C3H7O+],
55 (100); HRMS: m/z: calcd for C11H20O [M+ꢀH2O]:
168.1514; found: 168.1510.
5.1.6. 1-(((3R,4S,5S)-5-Methoxy-3,7-dimethyl-oct-1-on-
4-yloxy)-methyl)-benzene (13). Sodium hydride (60% in
mineral oil, 68.6 mg, 1.72 mmol), benzyl bromide
(328 lL, 469 mg, 2.74 mmol) and Bu4NI (5.07 mg,
13.7 lmol) were added at rt to the solution of the crude
3
H, CH(CH3)2], 0.94 [d, J = 6.7 Hz, 3 H, CH(CH3)2],
2
1.42 [ddd, J = 14.2 Hz, J = 8.3 Hz, J = 4.8 Hz 1 H,
3
3
2
3
CHHCH(CH3)2], 1.54 [ddd, J = 14.2 Hz, J = 8.8 Hz,

T. Horneff et al. / Bioorg. Med. Chem. 14 (2006) 6223–6234
6229
alcohol 2a in DMF (10 mL). After 1.5 h stirring at rt,
the suspension was treated with H2O (30 mL) and the
aqueous layer extracted with Et2O (3· 15 mL). The
combined organic layers were washed with H2O (2·
15 mL) and brine (2· 15 mL), dried (Na2SO4), filtered
and the solvent removed in vacuo. The crude product
was purified by flash chromatography (P/Et2O 97/3) to
[q, CH(CH3)2], 24.7 [d, CH(CH3)2], 38.9 [t,
CH2CH(CH3)], 46.8 [d, C(OBn)CHCH3], 57.8 (q,
OCH3), 73.1 (t, CH2Ph), 78.7 (d, CHOCH3), 80.4 (d,
CHOBn), 127.9 (d, CarH), 128.2 (d, CarH), 128.4 (d,
CarH), 137.ꢀ91 (s, Car), 202.4 (d, CHO); IR (neat):
~
m ¼ 2955 cm (s, CH), 2933 (s, CH), 2869 (s, CH),
2826 (m, CH), 1720 (s, C@O), 1454 (m, CH2), 1093 (s,
COC), 912 (m), 784 (s, CarH), 699 (m, CarH).
give 13 as a colourless oil (190 mg, 686 lmol, 60%, 2
20
D
steps). Rf = 0.20 (P/Et2O 97/3) [CAM]; ½aꢁ ꢀ43.3 (c
1
1.1, Et2O); H NMR (360 MHz, CDCl3): d = 0.91 [d,
5.1.8. (2R,3S,4S)-3-Benzyloxy-4-methoxy-2,6-dimethyl-
heptan-1-ol (15). Sodium borohydride (7.77 mg,
210 lmol) was added at rt to a solution of aldehyde 14
(52.0 mg, 187 lmol) in EtOH (5 mL). After stirring at
rt for 30 min, the reaction mixture was treated with
1 N HCl (5 mL) and the aqueous layer extracted with
Et2O (3· 10 mL). The combined organic layers were
washed with H2O (3· 10 mL) and brine (2· 10 mL),
dried (Na2SO4), filtered and the solvent removed in vac-
uo. The crude product was purified by flash chromatog-
raphy (P/Et2O 1/1) to give 15 as a colourless oil
(45.0 mg, 161 lmol, 86%). Rf = 0.21 (P/Et2O 1/1)
3J = 6.6 Hz, 3 H, CH(CH3)2], 0.92 [d, J = 6.6 Hz, 3 H,
CH(CH3)2], 1.09 [d, J = 6.9 Hz, 3 H, C(OBn)CHCH3],
3
3
2
3
3
1.34 [ddd, 1 H, J = 13.7 Hz, J = 8.2 Hz, J = 7.5 Hz,
CHHCH(CH3)2], 1.44 [ddd,
H, 2J = 13.7 Hz,
3J = 8.2 Hz, 3J = 5.7 Hz, CHHCH(CH3)2], 1.67–1.79
[m,
H, CH(CH3)2], 2.54 [dqddd, 3J = 7.3 Hz,
3J = 6.9 Hz, J = 6.4 Hz, J = 1.1 Hz, J = 0.9 Hz, 1 H,
1
1
3
4
4
3
3
C(OBn)CHCH3], 3.25 (dd, J = 6.4 Hz, J = 4.9 Hz, 1
3
3
H, CHOBn), 3.34 (d virt. t, J = 8.2 Hz, J ffi 4.8 Hz, 1
H, CHOCH3), 3.40 (s, 3 H, OCH3), 4.50–4.72 (m, 2
H, CH2Ph), 4.99 (ddd, 2J = 1.9 Hz, 3J = 10.3 Hz,
4J = 0.9 Hz, 1 H, CH=CHH), 5.06 (ddd, 2J = 1.9 Hz,
20
1
[CAM]; ½aꢁ ꢀ51.2 (c 2.0, Et2O), H NMR (360 MHz,
D
4
3
3J = 17.2 Hz, J = 1.1 Hz, 1 H, CH=CHH), 5.88 (ddd,
CDCl3): d = 0.92 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 0.93
[d, J = 6.9 Hz, 3 H, CH(CH3)2], 0.95 [d, J = 6.9 Hz, 3
3J = 17.2 Hz, 3J = 10.3 Hz, 3J = 7.3 Hz, 1 H, CH=CH2),
7.27–7.38 (m, 5 H, CHar); 13C NMR (90.6 MHz,
CDCl3): d = 15.5 [q, C(OH)CHCH3], 22.4 [q,
CH(CH3)2], 23.4 [q, CH(CH3)2], 24.6 [d, CH(CH3)2],
39.7 [t, CH2CH(CH3)], 40.2 [d, C(OBn)CHCH3], 58.6
(q, OCH3), 74.3 (t, CH2Ph), 80.4 (d, CHOCH3), 84.6
(d, CHOBn), 113.8 (t, CH@CH2), 127.4 (d, CarH),
127.8 (d, CarH), 128.4 (d, CarH), 139.ꢀ01 (s, Car), 142.1
3
3
H, C(OBn)CHCH3], 1.32–1.40 [m, H,
1
CHHCH(CH3)2], 1.42–1.51 [m, 1 H, CHHCH(CH3)2],
1.63–1.76 [m, 1 H, CH(CH3)2], 1.92–2.03 [m, 1 H,
C(OBn)CH(CH3)], 2.73 (s, 1 H, OH), 3.37–3.42 [m, 2
H, CH(OCH3)CH(OBn)], 3.44 (s, 3 H, OCH3), 3.49
(dd, 2J = 12.6 Hz, 3J = 8.2 Hz, 1 H, CHHOH), 3.59
(dd, 2J = 11.6 Hz, 3J = 4.2 Hz, CHHOH), 4.60–4.72
(m, 2 H, CH2Ph), 7.27–7.36 (m, 5 H, CHar); 13C NMR
(90.6 MHz, CDCl3): d = 12.8 [q, C(OBn)CHCH3], 22.2
[q, CH(CH3)2], 23.4 [q, CH(CH3)2], 24.7 [d, CH(CH3)2],
36.8 [d, C(OBn)CHCH3], 38.9 [t, CH2CH(CH3)], 58.4
(q, OCH3), 65.8 (t, CH2OH), 73.6 (t, CH2Ph), 80.2 (d,
CHOCH3), 81.8 (d, CHOBn), 127.6 (d, CarH), 128.0
~
(d, CH@CH2); IR (neat): m ¼ 2955 cm (s, CH), 2931
(s, CH), 2869 (s, CH), 1639 (w, C@C), 1465 (m, CH2),
1368 (m), 1093 (s, COC), 912 (m, C@C), 733 (m, CarH),
696 (s, CarH); MS (EI, 70 eV), m/z (%): 221 (17)
[C14H21O2+], 175 (6) [C12H15O+], 147 (8), 91 (100)
[C7H7+], 69 (25), 59 (13) [C3H7O+], 45 (14) [C2H5O+];
HRMS: m/z: calcd for C18H28O2: 267.2089; found:
267.2089.
(d, CarH), 128.3 (d, CarH), 138.5 (s, Car); IR (neat):
ꢀ1
~
m ¼ 2955 cm (s, CH), 2931 (s, CH), 2869 (s, CH),
1465 (m, CH2), 1368 (m), 1154 (m), 1104 (s, COC),
1028 (s), 734 (s, CarH), 698 (m, CarH); MS (EI, 70 eV),
m/z (%): 179 (13) [C11H15O2+], 101 (28) [C6H13O+], 91
(100) [C7H7+], 69 (30), 59 (15) [C3H7O+], 45 (17)
[C2H5O+]; HRMS: m/z: calcd for C17H28O3: 280.2039.
Found: 280.2037.
5.1.7. (2S,3S,4S)-3-Benzyloxy-4-methoxy-2,6-dimethylh-
eptanal (14). Olefin 13 (92.0 mg, 333 lmol) was dissolved
in CH2Cl2 (30 mL) and MeOH (8 mL). Ozone was bub-
bled through the solution at ꢀ78 ꢁC until the colourless
solution turned blue (2 min). After changing the atmo-
sphere to nitrogen (5 min), the mixture was treated with
triphenylphosphine (199 mg, 760 lmol), warmed to rt
(15 min) and stirred for 30 min. The solvent was re-
moved in vacuo and the crude product purified by flash
chromatography (P/Et2O 8/2) to give 14 as a colourless
oil (69.0 mg, 248 lmol, 75%). Rf = 0.21 (P/Et2O 8/2)
[CAM]; 1H NMR (360 MHz, CDCl3): d = 0.87 [d,
5.1.9. (2R,3S,4S)-4-Methoxy-2,6-dimethylheptan-1,3-diol
(16a). Method A (from 15). Palladium on carbon (10%,
10.6 mg, 9.99 lmol) was added to a solution of alcohol
15 (28.0 mg, 99.9 lmol) in EtOH (4 mL). This mixture
was vigorously stirred for 10 h under hydrogen atmo-
sphere (800–900 Torr) at rt. Evaporation of the solvent
in vacuo and flash chromatography (P/Et2O 1/9) of the
residue on silica gel afforded 16a as a colourless oil
(13.3 mg, 69.9 lmol, 70%). Method B (from 20): sodium
borohydride (127 mg, 3.36 mmol) was added at 0 ꢁC to a
solution of oxazolidinone 20 (110 mg, 303 mmol) in
THF/H2O (5/1, 5 mL). After stirring at rt for 10 h, the
reaction mixture was treated with 2 N HCl (4 mL) and
the aqueous layer extracted with Et2O (3· 5 mL). The
combined organic layers were washed with NaHCO3
(10 mL) and brine (10 mL), dried (Na2SO4), filtered
and the solvent removed in vacuo. The crude product
3
3J = 6.5 Hz, 3 H, CH(CH3)(CH3)], 0.88 [d, J = 6.5 Hz,
3 H, CH(CH3)(CH3)], 1.10 [d, 3J = 7.0 Hz, 3 H,
C(OBn)CHCH3], 1.40–1.46 [m, 2 H, CH2CH(CH3)2],
1.55 [m, 1 H, CH(CH3)2], 2.69 [qdd, 3J = 7.1 Hz,
3
3J = 5.5 Hz, J = 1.2 Hz, 1 H, C(OBn)CHCH3], 3.27 (s,
3
H,
OCH3),
3.29
(ddd,
3J = 7.1 Hz,
3J = 6.1 Hz,3J = 3.8 Hz, 1 H, CHOCH3), 3.71 (dd,
3J = 5.5 Hz, J = 3.7 Hz, 1 H, CHOBn), 4.57–4.71 (m,
3
2 H, CH2Ph), 7.27–7.38 (m, 5 H, CHar), 9.75 (d,
3J = 1.2 Hz, 1 H, CHO); 13C NMR (90.6 MHz, CDCl3):
d = 10.0 [q, C(OBn)CHCH3], 22.7 [q, CH(CH3)2], 22.9

6230
T. Horneff et al. / Bioorg. Med. Chem. 14 (2006) 6223–6234
was purified by flash chromatography (P/Et2O 1/9) to
give 16a as a colourless oil (42.0 mg, 221 lmol, 73%).
1.54–1.65 [m, 1 H, C(OR)CHCH3], 1.92 [dqqd,
3J = 10.1 Hz, J = 6.7 Hz, J = 6.7 Hz, J = 3.3 Hz, 1 H,
CH(CH3)2], 3.35 (ddd, 3J = 10.8 Hz, 3J = 8.6 Hz,
3J = 2.3 Hz, 1 H, CHOCH3), 3.54 (s, 3 H, OCH3), 3.85
(dd, 3J = 8.6 Hz, 3J = 2.3 Hz, 1 H, C(OCH3)CHOR),
3.85 [dd, 2J = 11.2 Hz, 3J = 1.5 Hz, 1 H, CHHOR], 4.08
(dd, 2J = 11.2 Hz, 3J = 2.0 Hz, 1 H, CHHOR), 5.55 (s, 1
H, CHCar), 7.29–7.40 (m, 5 H, CarH); 13C-NMR
(90.6 MHz, CDCl3): d = 11.2 [q, C(OR)CHCH3], 21.5
[q, CH(CH3)2], 24.0 [q, CH(CH3)2], 24.1 [d, CH(CH3)2],
30.2 [d, C(OR)CHCH3], 39.4 [t, CH2CH(CH3)2], 60.7
(q, OCH3), 73.7 (t, CH2OR), 79.5 (d, CHOCH3), 84.8
(d, C(CH3)COR), 101.5 (d, CHCar), 126.0 (d, CarH),
128.1 (d, CarH), 128.6 (d, CarH), 139.0 (s, Car); IR (neat):
3
3
3
20
Rf = 0.27 (P/Et2O 1/9) [CAM]; ½aꢁ ꢀ20.9 (c 1.0,
D
Et2O), 1H NMR (360 MHz, CDCl3): d = 0.93 [d,
3
3J = 6.8 Hz, 3 H, CH(CH3)2], 0.96 [d, J = 6.3 Hz, 3 H,
CH(CH3)2], 0.96 [d, J = 7.0 Hz, 3 H, C(OH)CHCH3],
3
2
1.31 [ddd, J = 14.4 Hz, J = 8.2 Hz, J = 4.9 Hz, 1 H,
3
3
2
3
CHHCH(CH3)2], 1.40 [ddd, J = 14.4 Hz, J = 7.0 Hz,
3J = 5.7 Hz, 1 H, CHHCH(CH3)2], 1.63–1.84 [m, 2 H,
C(OH)CHCH3, CH(CH3)2], 2.40 (br s, 2 H, OH), 3.26
(ddd, 3J = 7.1 Hz, 3J = 7.0 Hz, 3J = 4.9 Hz,
1
H,
CHOCH3), 3.45 (s, 3 H, OCH3), 3.65 [dd, J = 7.1 Hz,
3J = 2.7 Hz,
H, C(OCH3)CHOH], 3.65 (dd,
3
1
2J = 10.8 Hz, 3J = 6.1 Hz, 1 H, CHHOH), 3.72 (dd,
2J = 10.8 Hz, 3J = 4.3 Hz, 1 H, CHHOH); 13C NMR
(90.6 MHz, CDCl3): d = 10.3 [q, C(OH)CHCH3], 22.6
[q, CH(CH3)2], 23.5 [q, CH(CH3)2], 24.6 [d, CH(CH3)2],
36.7 [d, C(OH)CHCH3], 39.5 [t, CH2CH(CH3)], 57.6 (q,
OCH3), 67.2 (t, CH2OH), 75.4 (d, C(CH3)COH), 80.6
(d, CHOCH3); 1H NMR (360 MHz, C6D6): d = 0.85
m ¼ 2956 cmꢀ1 (s, CH), 1464 (m, CH2), 1378 (m), 1160 (s),
~
1112 (s, COC), 1056 (s), 1025 (s), 752 (m, C@C), 698 (s,
C@C); MS (EI, 70 eV), m/z (%): 278 (1) [M+], 177 (100),
107 (32), 101 (42), 79 (11), 59 (25), 40 (22); HRMS: m/z:
calcd for C17H26O3: 278.1882. Found: 278.1881.
[virt. t, 3J ffi 6.6 Hz,
6
H, CH(CH3)2], 0.96 [d,
5.1.11. (R)-4-Benzyl-3-((2R,3R,4S)-3-hydroxy-4-meth-
oxy-2,6-dimethylheptanoyl)-oxazolidin-2-one (19). Dibu-
tylboryl trifluoromethanesulfonate (1 M in CH2Cl2,
2.46 mL, 2.46 mmol) and diisopropylethylamine
(469 lL, 356 mg, 2.75 mmol) were added at 0 ꢁC to a
solution of oxazolidinone 1824b (536 mg, 2.30 mmol) in
CH2Cl2 (10 mL). After stirring for 45 min at 0 ꢁC, the
3J = 7.0 Hz,
2J = 14.3 Hz,
3
H, C(OH)CHCH3], 1.20 [ddd,
1
3J = 8.2 Hz,
3J = 4.7 Hz,
H,
2
3
CHHCH(CH3)2], 1.30 [ddd, J = 14.3 Hz, J = 7.3 Hz,
3J = 5.5 Hz, 1 H, CHHCH(CH3)2], 1.65–1.88 [m, 2 H,
C(OH)CHCH3, CH(CH3)2], 2.47 (br s, 1 H, OH), 2.78
(br s, 1 H, OH), 3.11 (s, 3 H, OCH3), 3.25 (ddd,
3
3
3J = 7.3 Hz, J = 7.1 Hz, J = 4.7 Hz, 1 H, CHOCH3),
3.59 [dd, 2J = 10.5 Hz, 3J = 4.7 Hz, 1 H, CHHOH],
3.62 (dd, 2J = 10.5 Hz, 3J = 4.3 Hz, 1 H, CHHOH),
3.65 (dd, 3J = 7.1 Hz, 3J = 3.6 Hz, 1 H, C(OCH3)-
CHOH), 13C NMR (90.6 MHz, C6D6): d = 10.6 [q,
C(OH)CHCH3], 22.6 [q, CH(CH3)2], 23.7 [q,
solution was treated with aldehyde
3
(359 mg,
2.76 mmol) at ꢀ78 ꢁC. The reaction mixture was stirred
for 1 h at ꢀ78 ꢁC and 1 h at ꢀ10 ꢁC, before a mixture of
MeOH (7.5 mL), pH 7, phosphate buffer (2.5 mL) and
30% H2O2/MeOH (1:2, 7.5 mL) was slowly added to
the solution (reaction temperature must be lower than
10 ꢁC). After stirring for 1 h at rt, the reaction mixture
was concentrated and the residue extracted with CH2Cl2
(3· 20 mL). The combined organic layers were washed
with brine (20 mL), dried (Na2SO4), filtered and the sol-
vent removed in vacuo. The crude product was purified
by flash chromatography (P/Et2O 1/1) and recrystallised
from P/CH2Cl2 to give 19 as colourless crystals (528 mg,
CH(CH3)2],
24.8
[d,
CH(CH3)2],
37.3
[d,
C(OH)CHCH3], 39.7 [t, CH2CH(CH3)], 57.5 (q,
OCH3), 66.9 (t, CH2OH), 74.9 (d, C(CH3)COH), 81.1
ꢀ1
~
(d, CHOCH3); IR (neat): m ¼ 3385 cm
(br, OH),
2956 (s, CH), 2931 (s, CH), 1466 (m, CH2), 1379 (m),
1096 (s, COC), 1041 (s); MS (EI, 70 eV), m/z (%): 131
(4) [C7H15O2+], 115 (4), 101 (100) [C6H13O+], 89 (10)
[C4H9O2+], 85 (6), 69 (85), 59 (46) [C3H7O+], 45 (50)
[C2H5O+], 43 (36) [C3H7+]; elemental analysis calcd
(%) for C10H22O3 (190.28): C, 63.12; H, 11.65. Found:
C, 63.42; H, 11.55.
1.45 mmol, 63%). Rf = 0.22 (P/Et2O 1/1) [CAM]; mp
20
D
85–86 ꢁC; ½aꢁ
ꢀ75.0 (c 1.0, Et2O); 1H NMR
(360 MHz, CDCl3): d = 0.90 [d, 3J = 6.6 Hz, 3 H,
CH(CH3)2], 0.93 [d, 3J = 6.6 Hz, 3 H, CH(CH3)2],
1.29 [ddd, 2J = 14.3 Hz,3J = 9.1 Hz,3J = 3.2 Hz,
1
H,
5.1.10. (2S,4S,5R)-4-((S)-1-Methoxy-3-methyl-butyl)-5-
methyl-2-phenyl-[1,3]dioxane (17a). Trifluoroacetic acid
(4.10 lL, 6.29 mg, 55.2 lmol) was added at rt to a solu-
tion of diol 16a (16.0 mg, 84.1 lmol), freshly distilled
benzaldehyde (12.0 lL, 12.5 mg, 118 lmol) and trim-
ethoxymethane (18.0 lL, 17.5 mg, 165 lmol) in CH2Cl2
(1 mL). After stirring at rt for 20 h, the reaction mixture
was treated with NaOMe (2 mg), diluted with Et2O
(2 mL) and filtered through a pad of Celiteꢂ. The solvent
was removed in vacuo and the crude product purified by
flash chromatography (P/Et2O 95/5) to give 17a as a col-
H, CHHCH(CH3)2], 1.36 (d, 3J = 6.8 Hz,
3
COCHCH3), 1.50 [ddd, 2J = 14.3 Hz, 3J = 8.8 Hz,
3J = 4.6 Hz,
1
H, CHHCH(CH3)2], 1.84 [dqqd,
3J = 9.0 Hz, 3J = 6.7 Hz,3J = 6.7 Hz, 3J = 4.4 Hz, 1 H,
2
CH(CH3)2], 2.65 (s, 1 H, OH), 2.79 (dd, J = 13.4 Hz,
3J = 9.5 Hz, 1 H, CHHPh), 3.22–3.27 (m, 2 H, CHHPh,
CHOCH3), 3.41 (s, 3 H, OCH3), 3.92–4.01 (m, 2 H,
CH(OH)CHCH3), 4.17–4.20 (m, 2 H, CH2OR), 4.69
(dddd,
3J = 9.5 Hz,
3J = 5.9 Hz,
3J = 4.6 Hz,
3J = 3.5 Hz, 1 H, CHNR2), 7.19–7.36 (m, 5 H, CHar);
13C NMR (90.6 MHz, CDCl3): d = 13.0 [q,
CH(CH3)COR], 22.1 [q, CH(CH3)2], 23.8 [q,
CH(CH3)2], 24.5 [d, CH(CH3)2], 37.8 (t, CH2Ph), 39.3
[d, CH(CH3)COR], 39.5 (t, CH2CHOMe), 55.1 (d,
CHNR2), 57.9 (q, OCH3), 66.1 (t, CH2OR), 72.7 (d,
CHOH), 80.0 (d, CHOMe), 127.4 (d, CarH), 129.0 (d,
CarH), 129.4 (d, CarH), 135.0 (s, Car), 152.7ꢀ(1s, COOR),
ourless oil (16.0 mg, 57.5 lmol, 68%). Rf = 0.27 (P/Et2O
20
9/1) [CAM]; ½aꢁ ꢀ48.4 (c = 0.72, Et2O); 1H NMR
D
(360 MHz, CDCl3): d = 0.96 [d, 3J = 6.7 Hz, 6 H,
CH(CH3)2], 1.11 [ddd, 2J = 13.9 Hz, 3J = 10.1 Hz,
3
3J = 2.3 Hz, 1 H, CHHCH(CH3)2], 1.18 [d, J = 6.4 Hz,
3
H, C(OR)CHCH3], 1.32 [ddd, 2J = 13.9 Hz,
3J = 10.8 Hz, 3J = 3.3 Hz,
1
H, CHHCH(CH3)2],
177.0 (s, CH2COR); IR (neat): m ¼ 3457 cm (br, OH),
~

T. Horneff et al. / Bioorg. Med. Chem. 14 (2006) 6223–6234
6231
2962 (m, CH), 2930 (m, CH), 1769 (s, COO), 1673 (s,
CON), 1380 (s), 1273 (m), 1106 (m), 970 (m), 765 (m,
C=C), 707 (m, C@C); MS (EI, 70 eV), m/z (%): 363 (1)
[M+], 331 (1) [M+ꢀOCH3], 306 (1) [M+ꢀC4H9], 262
(67), 233 (3) [C13H15NO3+], 178 (100), 149 (12), 117
(25), 101 (65), 69 (65), 45 (45); HRMS: m/z: calcd for
C20H29NO5: 263.2046. Found: 280.2048; elemental anal-
ysis calcd (%) for C20H29NO5 (363.44): C, 66.09; H,
8.04; N, 3.85. Found: C, 66.02; H, 8.13; N, 3.82.
[C6H13O+], 89 (9) [C4H9O2+], 85 (8), 69 (63), 59 (37)
[C3H7O+], 45 (40) [C2H5O+], 43 (27) [C3H7+]; elemental
analysis calcd (%) for C10H22O3 (190.28): C, 63.12; H,
11.65. Found: C, 62.91; H, 11.49.
5.1.13. (2R,4R,5S)-4-((S)-1-Methoxy-3-methyl-butyl)-5-
methyl-2-phenyl-[1,3]dioxane (17b). Trifluoroacetic acid
(7.36 lL, 11.3 mg, 99.1 lmol) was added at rt to a solu-
tion of diol 16b (29.0 mg, 152 lmol), freshly distilled
benzaldehyde (21.7 lL, 22.6 mg, 213 lmol) and trim-
ethoxymethane (31.4 lL, 32.4 mg, 305 lmol) in CH2Cl2
(1 mL). After stirring at rt for 20 h, the reaction mixture
was treated with NaOMe (3 mg), diluted with Et2O
(2 mL) and filtered through a pad of Celiteꢂ. The sol-
vent was removed in vacuo and the crude product was
purified by flash chromatography (P/Et2O 95/5) to give
17b as a colourless oil (28.0 mg, 100 lmol, 66%).
Rf = 0.27 (P/Et2O 9/1) [CAM]; 1H NMR (360 MHz,
5.1.12. (2S,3R,4S)-4-Methoxy-2,6-dimethylheptane-1,3-
diol (16b). Method A (from 19): sodium borohydride
(238 mg, 6.29 mmol) was added at 0 ꢁC to a solution of
oxazolidinone 19 (458 mg, 1.26 mmol) in THF/H2O (5/
1, 18 mL). After stirringat rt for 10 h, the reaction mixture
was treated with 2 N HCl (15 mL) and the aqueous layer
extracted with Et2O (3· 20 mL). The combined organic
layers were washed with satd aq NaHCO3 (20 mL) and
brine (20 mL), dried (Na2SO4), filtered and the solvent re-
moved in vacuo. The crude product was purified by flash
chromatography (P/Et2O 1/9) to give 16b as a colourless
oil (214 mg, 1.13 mmol, 89%). Method B (from 3): a solu-
tion of freshly prepared (S,S)-diisopropyl tartrate (Z)-
crotylboronate40 (115 mg, 385 lmol) in toluene (2 mL)
was treated with powdered molecular sieves (20 mg) and
then cooled to ꢀ78 ꢁC. A solution of freshly prepared
aldehyde 3 (40.0 mg, 307 lmol) in toluene (1 mL) was
then added over 15 min. The reaction mixture was stirred
over ꢀ78 ꢁC for 3 h and then treated with 2 N NaOH
(0.3 mL). The two-phase mixture was warmed to 0 ꢁC
and stirred for 20 min before being filtered through a
pad of Celiteꢂ. The aqueous layer was extracted with
Et2O (3· 3 mL), the combined organic phases dried
(Na2SO4), filtered and the solvent removed in vacuo to
yield compound 2b. Due to the instability of the com-
pound, the crude product was directly used in the next
reaction. Alcohol 2b was converted in four additional
steps into diol 16b (13.3 mg, 69.7 lmol, 23%). The proce-
dure was analogous to the conversion 2a ! 16a. The ana-
3
CDCl3): d = 0.95 [d, J = 6.6 Hz, 3 H, CH(CH3)2], 0.95
[d, J = 6.6 Hz, 3 H, CH(CH3)2], 1.24 [d, J = 6.8 Hz, 3
3
3
H, C(OR)CHCH3], 1.49 [ddd, 2J = 14.4 Hz, 3J =
6.9 Hz, J = 4.9 Hz, 1 H, CHHCH(CH3)2], 1.56 [ddd,
3
2J = 14.4 Hz, 3J = 8.2 Hz, 3J = 4.1 Hz, 1 H, CHH
CH(CH3)2], 1.91–1.96 [m,
2
H, C(OR)CHCH3,
CH(CH3)2], 3.38 (ddd, 3J = 8.5 Hz, 3J = 6.8 Hz,
3J = 4.1 Hz, 1 H, CHOCH3), 3.43 (s, 3 H, OCH3), 3.80
(dd, 3J = 8.5 Hz, 3J = 2.3 Hz, 1 H, C(OCH3)CHOR),
4.04 [dd, 2J = 11.2 Hz, 3J = 1.6 Hz, 1 H, CHHOR],
4.09 (dd, 2J = 11.2 Hz, 3J = 2.4 Hz, 1 H, CHHOR),
5.49 (s, 1 H, CHCar), 7.30–7.40 (m, 5 H, CarH); 13C
NMR (90.6 MHz, CDCl3): d = 11.9 [q, C(OR)CHCH3],
22.7 [q, CH(CH3)2], 23.9 [q, CH(CH3)2], 24.5 [d,
CH(CH3)2], 29.7 [d, C(OR)CHCH3], 40.2 [t,
CH2CH(CH3)2], 57.6 (q, OCH3), 74.2 (t, CH2OR),
78.0 (d, CHOCH3), 81.9 (d, C(CH3)COR), 101.7 (d,
CHCar), 126.0 (d, CarH), 128.1 (d, CarH), 128.6 (d,
CarH), 138.9 (s, Car).
5.1.14.
(R)-4-Benzyl-3-((2S,3S,4S)-3-hydroxy-4-meth-
lytic data of 16b so obtained were identical to the data of
oxy-2,6-dimethylheptanoyl)-oxazolidin-2-one (20). To a
solution of oxazolidinone 1824b (165 mg, 707 lmol) in
Et2O (2 mL) at 0 ꢁC was added dibutylboryl trifluorom-
ethanesulfonate (1 M in CH2Cl2, 1.41 mL, 1.41 mmol)
followed by diisopropylethylamine (138 lL, 105 mg,
2.75 mmol). The resultant yellow slurry was stirred for
30 min at 0 ꢁC and then cooled to ꢀ78 ꢁC. Over a
10 min period a solution of aldehyde 3 (115 mg,
883 lmol) was added at ꢀ78 ꢁC and the mixture was
stirred for 30 min. After addition of tartaric acid
(530 mg) at ꢀ78 ꢁC, the reaction mixture was warmed
to rt and the stirring was continued for 2 h. The suspen-
sion was diluted with water (5 mL) and Et2O (5 mL), the
layers separated and the aqueous layer was extracted
with Et2O (2· 10 mL). The combined organic layers
were washed with satd aq NaHCO3 (10 mL) and brine
(10 mL). The organic layer was cooled to 0 ꢁC to which
30% H2O2/MeOH (3:1, 2 mL) was added and stirred for
30 min at rt. After addition of H2O (5 mL) the layers
were separated and the aqueous layer extracted with
Et2O (2· 10 mL). The combined organic layers were
washed with NaHCO3 (30 mL) and brine (30 mL), dried
(Na2SO4), filtered and the solvent removed in vacuo.
The crude product was purified by flash chromatogra-
20
16b obtained from 19. Rf = 0.29 (P/Et2O 1/9) [CAM]; ½aꢁ
D
ꢀ8.3 (c 0.90, Et2O); 1H NMR (360 MHz, CDCl3):
d = 0.94 [d, 3J = 6.7 Hz, 3 H, CH(CH3)2], 0.95 [d,
3J = 6.7 Hz, 3 H, CH(CH3)2], 1.05 [d, J = 7.0 Hz, 3 H,
3
C(OH)CHCH3], 1.33 [ddd, 2J = 14.1 Hz, 3J = 8.7
Hz, 3J = 3.9 Hz, 1 H, CHHCH(CH3)2], 1.53 [ddd,
2J = 14.1 Hz, 3J = 8.8 Hz, 3J = 5.0 Hz, 1 H, CHH
CH(CH3)2], 1.78 [dqqd, 3J = 8.7 Hz, 3J = 6.7 Hz,
3J = 6.7 Hz, J = 5.0 Hz, 1 H, CH(CH3)2], 1.87 [qddd, 1
3
H, 3J = 7.0 Hz, 3J = 5.0 Hz, 3J = 4.8 Hz, 3J = 4.8 Hz,
C(OH)CHCH3], 2.49 (br s, 2 H, OH), 3.31 (ddd,
3J = 8.8 Hz, J = 4.9 Hz, J = 3.9 Hz, 1 H, CHOCH3),
3.45 (s, 3 H, OCH3), 3.62 [dd, 2J = 10.7 Hz, 3J = 5.0 Hz,
1 H, CHHOH], 3.65 (dd, 2J = 10.7 Hz, 3J = 4.8 Hz, 1 H,
CHHOH), 3.76 (dd, 3J = 4.9 Hz, 3J = 4.8 Hz, 1 H,
C(OCH3)CHOH); 13C NMR (90.6 MHz, CDCl3):
d = 11.6 [q, C(OH)CHCH3], 22.3 [q, CH(CH3)2], 23.7
[q, CH(CH3)2], 24.5 [d, CH(CH3)2], 36.2 [d,
C(OH)CHCH3], 39.1 [t, CH2CH(CH3)], 57.7 (q, OCH3),
66.8 (t, CH2OH), 73.9 (d, C(CꢀH1 3)COH), 80.8 (d,
3
3
~
CHOCH3); IR (neat): m ¼ 3404 cm (br, OH), 2955 (s,
CH), 1467 (m, CH2), 1384 (m), 1092 (s, COC), 1033 (s);
MS (EI, 70 eV), m/z (%): 131 (2) [C7H15O2+], 101 (100)

6232
T. Horneff et al. / Bioorg. Med. Chem. 14 (2006) 6223–6234
˚
phy (P/Et2O 1/1) and recrystallised from P/CH2Cl2 to
give 20 as colourless crystals (110 mg, 303 lmol, 43%).
b = 8.7691(1),
c = 13.4455(2) A,
b = 109.2870(5)ꢁ,
V = 1020.43(2) A , Z = 2, dcalc = 1.183 g cmꢀ3, F000
392, l = 0.084 mmꢀ1. Preliminary examination and data
collection was carried out on j-CCD device
3
˚
=
20
D
Rf = 0.28 (P/Et2O 1/1) [CAM]; mp 76–78 ꢁC; ½aꢁ
ꢀ23.7 (c 0.96, Et2O); 1H NMR (360 MHz, CDCl3):
a
3
d = 0.94 [virt. t, J ffi 6.6 Hz, 6 H, CH(CH3)2], 1.26 (d,
(NONIUS, MACH3) with an Oxford Cryosystems cool-
ing system at the window of a rotating anode (NONIUS
FR591) with graphite monochromated Mo-Ka radiation
3J = 6.8 Hz, 3 H, COCHCH3), 1.46–1.52 [m, 1 H,
CH2CH(CH3)2], 1.75 [virt. nonet, 3J ffi 6.7 Hz, 1 H,
2
CH(CH3)2], 2.52 (s, 1 H, OH), 2.74 (dd, J = 13.3 Hz,
˚
(k = 0.71073 A). Data collection were performed at 123
3J = 9.7 Hz, 1 H, CHHPh), 3.23 (ddd, 3J = 6.5 Hz,
3J = 6.5 Hz, 3J = 3.4 Hz, 1 H, CHOCH3), 3.31 (dd,
K within the H range of 2.35ꢁ < H < 25.31ꢁ. A total of
26,177 intensities were integrated. Raw data were cor-
rected for Lorentz, polarization, and, arising from the
scaling procedure, for latent decay and absorption ef-
fects. After merging (Rint = 0.040), 3716 [3559: Io > 2r(-
Io)] independent reflections remained and all were used
to refine 351 parameters. The structure was solved by
a combination of direct methods and difference-Fourier
syntheses. All non-hydrogen atoms were refined with
anisotropic displacement parameters. All hydrogen
atoms were found and refined with individual isotropic
displacement parameters. Full-matrix least-squares
3
2J = 13.3 Hz, J = 3.3 Hz, 2 H, CHHPh), 3.42 (s, 3 H,
OCH3), 3.87–4.05 (m, 2 H, CH(OH)CHCH3), 4.11–
4.26 (m, 2 H, CH2OR), 4.68–4.78 (m, 1 H, CHNR2),
7.21–7.37 (m, 5 H, CHar); 13C NMR (90.6 MHz,
CDCl3): d = 12.3 [q, CH(CH3)COR], 22.7 [q,
CH(CH3)2], 22.9 [q, CH(CH3)2], 24.5 [d, CH(CH3)2],
38.0 (t, CH2Ph), 38.4 (t, CH2CHOMe), 40.8 [d,
CH(CH3)COR], 55.1 (d, CHNR2), 57.8 (q, OCH3),
66.0 (t, CH2OR), 73.2 (d, CHOH), 80.3 (d, CHOMe),
127.3 (d, CarH), 128.9 (d, CarH), 129.4 (d, CarH),
135.2 (s, Car), 153.1 (s, COOR), 175.5 (s, CH2COR);
ꢀ1
refinements were carried out by minimizing
and converged with R1 = 0.0299
P
2
wðF 2o ꢀ F 2cÞ
~
IR (neat): m ¼ 3494 cm (br, OH), 2955 (s, CH), 1762
(s, COO), 1694 (s, CON), 1394 (s), 1219 (s), 1145 (m),
1092 (m), 969 (m), 766 (m, C@C), 699 (m, C@C); MS
(EI, 70 eV), m/z (%): 331 (1) [M+ꢀOCH3], 306 (1)
[M+ꢀC4H9], 262 (62), 233 (17) [C13H15NO3+], 178
(100), 142 (17), 117 (34), 101 (57), 91 (63) [C7H7+], 69
(55), 57 (80); elemental analysis calcd (%) for
C20H29NO5 (363.44): C, 66.09; H, 8.04; N, 3.85. Found:
C, 66.08; H, 8.13; N, 3.78.
[Io > 2r(Io)], wR2 = 0.0693 [all data], GOF = 1.082 and
shift/error <0.001. The final difference-Fourier map
shows no striking features (Demin/max = +0.13/
ꢀ3
ꢀ0.15 eA ).42
˚
Crystallographic data (excluding structure factors) for
the structures reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC-602502 (19)
and CCDC-602503 (20). Copies of the data can be ob-
tained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: (+44)1223-336-
033; e-mail: deposit@ccdc.cam.ac.uk).
Crystal structure analysis of compound 19: C20H29NO5,
Mr = 363.44, colourless fragment (0.32 · 0.34 · 0.51
mm3), orthorhombic, P212121 (No.: 19), a = 10.0837(1),
3
b = 10.1263(1), c = 19.5048(3) A, V = 1991.65(4) A ,
˚
˚
Z = 4, dcalc = 1.212 g cmꢀ3, F000 = 784, l = 0.086 mmꢀ1
.
Preliminary examination and data collection were car-
ried out on a j-CCD device (NONIUS, MACH3) with
an Oxford Cryosystems cooling system at the window
of a rotating anode (NONIUS FR591) with graphite
Acknowledgments
Support of our research by theDeutsche Forschungs-
gemeinschaft (DFG) and by the Fonds der Chemischen
Industrie is gratefully acknowledged. We thank Wac-
ker-Chemie (Munchen) for generous donations of
¨
chemicals.
˚
monochromated Mo-Ka radiation (k = 0.71073 A).
Data collection was performed at 173 K within the
H range of 2.27ꢁ < H < 25.33ꢁ. A total of 40,700 inten-
sities were integrated. Raw data were corrected for
Lorentz, polarization, and, arising from the scaling
procedure, for latent decay and absorption effects.
After merging (Rint = 0.045), 3608 [3357: Io > 2r(Io)]
independent reflections remained and all were used to
refine 243 parameters. The structure was solved by a
combination of direct methods and difference-Fourier
syntheses. All non-hydrogen atoms were refined
with an-isotropic displacement parameters. All
hydrogen atoms were placed in calculated positions
References and notes
1. (a) Prelog, V.; Oppolzer, W. Helv. Chim. Acta 1973, 56,
2279–2287; (b) Funayama, S.; Cordell, G. A. Stud. Nat.
Prod. Chem. 2000, 23, 51–106.
2. De Boer, C.; Meulman, P. A.; Wnuk, R. J.; Peterson, D.
H. J. Antibiot. 1970, 23, 442–447.
3. (a) Sasaki, K.; Rinehart, K. L., Jr.; Slomp, G.; Grostic, M.
F.; Olson, E. C. J. Am. Chem. Soc. 1970, 92, 7591–7593;
(b) Rinehart, K. L., Jr.; Shield, L. S. Fortschr. Chem. Org.
Naturst. 1976, 33, 231–307.
4. (a) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans.
1 1990, 47–65; (b) Evans, D. A.; Miller, S. J.; Ennis, M.
D. J. Org. Chem. 1993, 58, 471–485; (c) Panek, J. S.;
and refined using
a
riding model. Full-matrix
least-squares refinements were carried out by minimiz-
P
2
ing
[Io > 2r(Io)], wR2 = 0.0723 [all data], GOF = 1.086 and
shift/err <0.001. The final difference-Fourier map shows
wðF 2o ꢀ F 2cÞ and converged with R1 = 0.0335
no striking features (Demin/max = +0.11/ꢀ0.16 eAꢀ3).42
˚
´
Xu, F.; Rondon, A. C. J. Am. Chem. Soc. 1998, 120,
4113–4122.
Crystal structure analysis of compound 20: C20H29NO5,
Mr = 363.44,
colourless
fragment
(0.13 · 0.30 ·
5. (a) Nakata, M.; Osumi, T.; Ueno, A.; Kimura, T.;
Tamai, T.; Tatsuka, K. Bull. Chem. Soc. Jpn. 1992,
0.91 mm3), monoclinic, P21 (No. 4), a = 9.1693(1),

T. Horneff et al. / Bioorg. Med. Chem. 14 (2006) 6223–6234
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