A total synthesis of herboxidiene methyl ester

Article abstract of DOI:10.3987/COM-12-12597

The total synthesis of the methyl ester, 35, of herboxidiene (1, a.k.a. GEX1A and TAN-1609), a polyketide displaying both herbicidal and anti-tumor activity, is described. The convergent reaction sequence involves, in its closing stages, the union of the phosphine oxide 3 with the aldehyde 21 to deliver, via a Horner-Wittig reaction with accompanying epimerization at C12, compound 33 that after deprotection affords an alcohol, 34, capable of participating in a regioand diastereo-selective epoxidation reaction to give target 35. Phosphine oxide 3 was prepared via the intramolecular hetero-Michael addition of a secondary alcohol to a tethered and Z-configured acrylate while aldehyde 21 was generated, in the crucial step of the relevant reaction sequence, via an Ireland-Claisen rearrangement reaction.

Full text of DOI:10.3987/COM-12-12597

HETEROCYCLES, Vol. 85, No. 12, 2012
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HETEROCYCLES, Vol. 85, No. 12, 2012, pp. 2949 - 2976. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 4th October, 2012, Accepted, 18th October, 2012, Published online, 29th October, 2102
DOI: 10.3987/COM-12-12597
A TOTAL SYNTHESIS OF HERBOXIDIENE METHYL ESTER
Rajaratnam Premraj,1 Malcolm D. McLeod,1 Gregory W. Simpson,2 and
Martin G. Banwell1*
1 Research School of Chemistry, Institute of Advanced Studies, The Australian
2
National University, Canberra ACT 0200, Australia. CSIRO Materials Science
and Engineering, Clayton VIC 3169, Australia. E-mail: mgb@rsc.anu.edu.au
Abstract – The total synthesis of the methyl ester, 35, of herboxidiene (1, a.k.a.
GEX1A and TAN-1609), a polyketide displaying both herbicidal and anti-tumor
activity, is described. The convergent reaction sequence involves, in its closing
stages, the union of the phosphine oxide 3 with the aldehyde 21 to deliver, via a
Horner–Wittig reaction with accompanying epimerization at C12, compound 33
that after deprotection affords an alcohol, 34, capable of participating in a regio-
and diastereo-selective epoxidation reaction to give target 35. Phosphine oxide 3
was prepared via the intramolecular hetero-Michael addition of a secondary
alcohol to a tethered and Z-configured acrylate while aldehyde 21 was generated,
in the crucial step of the relevant reaction sequence, via an Ireland–Claisen
rearrangement reaction.
INTRODUCTION
In 1992 Issacs et al. reported1 the isolation of the polyketide herboxidiene (1) (a.k.a. GEX1A and TAN-
1609) from Streptomyces sp. A7847 and five years later Edmunds and co-workers detailed2 the
establishment of the absolute stereochemistry of the compound. Since this time five other structurally
related compounds (in the so-called GEX1 series) have been isolated by Yoshida et al.3 from the culture
broth of another Streptomyces sp. Herboxidiene was shown to exhibit selective phytotoxicity against a

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HETEROCYCLES, Vol. 85, No. 12, 2012
range of broadleaf annual weeds whilst being harmless to wheat.1,2 It also activates the LDL receptor,4
increases G1 and G2 cell phase populations5 and displays anti-tumor activity in various cell lines.3 Certain
aspects of the mechanism of action responsible for the latter effects appear to have been elucidated
recently by Mizukami et al.6 Specifically, this group has shown that herboxidiene targets the SAP155
protein, a subunit of SF3b responsible for pre-mRNA splicing and representing a novel target for anti-
tumor drugs.
The significant biological properties and intriguing structure of herboxidiene have prompted a number of
synthetic studies with the first total synthesis of the compound having been reported in 1999 by Kocienski
and co-workers.7 Groups lead by Panek,8 Forsyth,9 Ghosh10 and Urpi11 have each reported distinctive
syntheses in the interim, while Edmunds and his colleagues have described the preparation of a number of
aromatic hybrids.12 It is against this background that we now provide full details of a total synthesis of
herboxidiene methyl ester,13 the immediate precursor to compound 1 associated with Kocienski’s total
synthesis7 of the natural product. The retrosynthetic analysis of target 1 employed in the current study is
described in the following section.
OMe
H
11
O
H
18
16
12
19
10
O
OH
H
1
CO2H
1
Retrosynthetic Analysis
The key disconnection employed in the work described here was at C10/C11 and thus leading to side-
chain and pyran-core fragments 2 and 3, respectively, that would be joined in an Horner–Wittig reaction
to form the central diene unit of target 1 (Figure 1). Side-chain 2 was to be assembled via the Ireland–
Claisen rearrangement14 of the propionate ester 4 which would, in turn, be prepared from the vinyl ketone
5. On the other hand, and based on earlier model studies,15 the all-equatorially substituted pyran core 6
was to be assembled through an intramolecular hetero-Michael addition reaction involving the !-
hydroxylated and Z-configured ",#-unsaturated ester 7. Elaboration of compound 6 to the phosphine
oxide 3 would involve side-chain extension and Michaelis–Arbuzov16 reactions. The successful
implementation of the approach defined by this retrosynthetic analysis is presented in the following
sections.

HETEROCYCLES, Vol. 85, No. 12, 2012
2951
OMe
H
11
O
H
18
16
12
19
10
O
OH
H
CO2H
1
1
O
P
OMe
H
11
H
7
16
12
6
Ph
+
O
Ph 10
O
OH
H
2
CO Me
1
2
3
O
H
H
6
HO
OMe O
O
16
H
CO2Me
TBDMSO
4
6
O
OH
16
6
HO
OBn
CO2Me
5
7
Figure 1. Retrosynthetic analysis of herboxidiene (1) employed in the current study.
RESULTS AND DISCUSSION
(i) Assembly of the Side-chain 2
The synthesis of the vinyl ketone precursor 5 to the side-chain compound 2 is shown in Scheme 1. Thus,
the commercially available Roche ester 8 (>99% ee)17 was first converted into the corresponding and
previously reported O-benzyl ether 9 (97%) under conditions that avoid racemization.18 Treatment of the
latter compound with N,O-dimethylhydroxylamine hydrochloride in the presence of isopropylmagnesium
chloride then afforded the Weinreb amide 10 (95%) which upon reaction with vinylmagnesium bromide
gave the target ketone 5 in 92% yield.19 The spectral data derived from compound 5 were in full accord
with the assigned structure while the observation of a specific rotation {[!]D} of +13.5 indicated that, at
the very least, the material was enantiomerically enriched.

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HETEROCYCLES, Vol. 85, No. 12, 2012
i-PrMgCl
MeN(H)OMe•HCl
O
O
H2C=C(H)MgBr
16
16
MeO
16
MeO2C
OBn
OR
N
OBn
THF, –15 °C
0.5 h
THF, 0 °C
0.5 h
HN=C(CCl3)OBn
TfOH, C6H12
DCM, 0 °C, 16 h
10
5
8 R = H
9 R = Bn
Scheme 1. Synthesis of enone 5 from the Roche ester.
The route employed for the conversion of vinyl ketone 5 into the substrate (4) required for the proposed
Ireland–Claisen rearrangement is shown in Scheme 2. After considerable experimentation, it was
established that stereoselective reduction of ketone 5, so as to establish the required R-configuration at
C17 in target 1, was best effected using zinc borohydride20 in dichloromethane. Using this reagent a ca.
4:1 mixture of the alcohols 11 and C17-epi-11 was obtained (quantitative combined yield).
OR
(i) O3, CH2Cl2
–78 °C, 1 h
OMe
O
Zn(BH4)2, CH2Cl2
–78 to 0 °C, 4.5 h
O
OBn
OH
OBn
OBn
17
(ii) Me2S, CH2Cl2
–30 to 18 °C, 0.5 h
11 R = H
12 R = Me
5
MeI, KH, THF
0 to18 °C, 6 h
13
OMe
OMe
Me2Zn, TiCl4
THF, –78 °C, 0.5 h
H2, Pd(OH)2
THF, 18 °C, 1h
TBDMSCl
OR'
TBDMSO
RO
16
14 R = H, R' = Bn
15 R = TBDMS, R' = Bn
imidazole, DMF
60 °C, 3 h
(i) SO3•pyridine (ii) 16, Et3N
DMSO, CH2Cl2
0 to 18 °C, 4 h
CH2Cl2
0 °C, 1 h
O
OMe
OMe
H2C=C(Me)Br
t-BuLi, CuBr•Me2S
OH
OMe
(EtCO)2O
DMAP, pyridine
O
O
Et2O, –78 °C
3 h
18 °C
16 h
TBDMSO
TBDMSO
TBDMSO
18
4
17
Scheme 2. Synthesis of propionate ester 4 from enone 5.
Initially, the assignment of the illustrated stereochemistries to products 11 and C17-epi-11, which were
readily separated from one another using preparative HPLC, was based on the proposition that a
chelation-controlled reduction process21 is involved in the formation of the major product (Figure 2).

HETEROCYCLES, Vol. 85, No. 12, 2012
2953
H–
H
2+
Zn
O
Bn O
Me
Figure 2. Probable transition state associated with the zinc borohydride-mediated reduction of enone 5 to
allylic alcohol 11.
While the 1H and 13C NMR spectral data derived from alcohols 11 and C3-epi-11 matched those reported
by Burke et al. for their respective enantiomers,22 the S-configuration of the newly created stereocenter
within compound 11 was confirmed by converting it into its R- and S-Mosher esters and then undertaking
appropriate comparisons23 of the derived 300 MHz 1H NMR data (see Table 2, Experimental for details).
O-Methylation of alcohol 11 using methyl iodide in the presence of potassium hydride afforded the allylic
ether 12 (85%) that was then subjected to ozonolysis followed by reductive work-up with dimethylsulfide.
In this way the aldehyde 13 was obtained in 72% yield. Due to its rather unstable nature, compound 13
was immediately treated with dimethylzinc in the presence of titanium tetrachloride24 at !78 °C and so
generating, on an almost exclusive basis, the secondary alcohol 14 in 70% yield. The stereoselective
nature of the transformation 13 ! 14 presumably arises through the intermediacy of a chelate (Figure 3)
in which titanium is simultaneously co-ordinated to the aldehyde carbonyl and the !-related methoxy
group. Once again, the stereochemical outcome of this process was confirmed through a Mosher ester
analysis of the same type as used (vide supra) to establish the structure of precursor 11 (see Table 3,
Experimental for details).
Ti4+
O
MeO
H
3
BnO
H
Me–
H
Figure 3. Probable transition state associated with the TiCl4-mediated addition of dimethyl zinc to the
aldehyde 13 (and leading to alcohol 14).
Conversion of compound 14 into the corresponding tert-butyldimethylsilyl (TBDMS) ether 15 (80%) was
readily achieved under standard conditions and the latter compound was subjected to hydrogenolysis
using dihydrogen in the presence of Pearlman’s catalyst. In this manner the alcohol 16 was obtained in
97% yield. Oxidation of compound 16 using the Parikh–Doering reagent25 gave the corresponding but

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HETEROCYCLES, Vol. 85, No. 12, 2012
unstable aldehyde 17 (94%) which was immediately treated with the cuprate obtained by treating
2-bromopropene with tert-butyllithium then copper(I) bromide/dimethylsulfide.26 In this manner the
allylic alcohol 18 was produced in 70% yield and as essentially the exclusive product of reaction. The
stereoselective formation of compound 18 is, once again, attributed to the involvement of a chelation-
controlled process. The completion of the synthesis of the substrate for the proposed Ireland–Claisen
rearrangement involved acylation of alcohol 18 with propionic anhydride in the presence of 4-(N,N-
dimethylamino)pyridine (DMAP) and pyridine. By such means the target ester 4 was obtained in 90%
yield and the derived spectral data were in full accord with the assigned structure.
The pivotal Ireland–Claisen reaction14 was carried out under conditions defined by Smith et al.26 and
involved initial treatment of the ester 4 with LDA in HMPA/tetrahydrofuran (THF) at –78 °C and the
enolate so-formed was then intercepted with TBDMS-Cl and thereby generating the corresponding
O-silyl ketene acetal. Thermally-induced rearrangement of this last species was effected at 50 °C and
upon work-up the acid 19 incorporating the undesired configuration at C12 (herboxidiene numbering)
was obtained. This outcome is attributed to the selective formation of the Z-silyl ketene acetal which
engaged, via a chair-like transition state, in a [3,3]-sigmatropic rearrangement to give the observed
compound 19 that possesses the unwanted R-configuration at C-12 but the required E-geometry about the
"
14,15-double bond. Since the stereochemistry at C12 could be inverted in a subsequent step of the reaction
sequence (vide infra) compound 19 was carried through the synthetic sequence.27 Accordingly, acid 19
was subjected to lithium aluminium hydride-promoted reduction and thereby affording the corresponding
primary alcohol 20 which was obtained in 66% yield after chromatographic purification.28 Treatment of
the latter compound with the Dess–Martin periodinane (DMP)29 then afforded, in 62% yield, the
corresponding aldehyde 21, the C12-epimer of the desired side-chain aldehyde 2.
O
OMe
(i) LDA, HMPA/THF
–78 °C, 0.5 h
OMe
OMe
O
CO2H
(ii) TBDMSCl
50 °C, 6 h
TBDMSO
TBDMSO
TBDMSO
4
19
LiAlH4, THF, 0 to 18°C, 6 h
OMe
DMP, CH2Cl2
0 to 18 °C, 4 h
12
OH
O
TBDMSO
20
21
Scheme 3. Synthesis of aldehyde 21 from ester 4.

HETEROCYCLES, Vol. 85, No. 12, 2012
2955
(ii)
Assembly of Pyran-core 3
Our second-generation synthesis13d of the pyranyl-containing core of herboxidiene is shown in Scheme 4
and used the commercially available alcohol 22 as staring material. This was oxidized, under Swern-type
conditions, to the corresponding, previously reported30 and highly volatile aldehyde. The latter compound
was immediately subjected to an olefination reaction31 using the ylide derived from ethyl bromoacetate
and triphenylphosphine and thereby affording the E-configured !,"-unsaturated ester 23 in 98% yield
(from alcohol 22). Diisobutylalumium hydride (DIBAl-H)-mediated reduction of compound 23 afforded
the corresponding allylic alcohol 24 (85%) that was then subjected to Katsuki–Sharpless asymmetric
epoxidation (KSAE)32 using the usual combination of reagents including diethyl D-(–)-tartrate as the
chiral ligand. In this way the illustrated R,R-configured epoxy alcohol 25 was obtained in 70% yield and
>95% ee as determined by Mosher ester analysis.13d
Reaction of compound 25 with trimethylaluminium in dichloromethane at 0 to 18 °C lead, via a
chelation-controlled nucleophilic epoxide ring-opening reaction, to the methylated 1,2-diol 26 in 83%
yield.33 The readily derived diacetate 27 (96%) was then subjected to ozonolysis followed by reductive
work-up with triphenylphospine and so affording the aldehyde 28 in 79% yield. The spectral data derived
from this last compound were identical, in all respects, with those obtained on a sample generated by a
separate route.13c Subjection of compound 28 to the Still–Gennari modification34 of the Horner–
Wadsworth–Emmons reaction using the anion derived from the commercially available bis(2,2,2-
trifluoroethyl) (methoxycarbonylmethyl)phosphonate gave the !,"-unsaturated ester 29 in 80% yield. The
Z-configuration about the double bond within this product follows from the observation of a 11.5 Hz
coupling between the olefinic protons. In a pivotal conversion, diacetate 29 was subjected to reaction with
potassium carbonate in methanol and so resulting in the formation of the pyran 6 incorporating cis-related
and equatorial substituents at C3 and C7 (herboxidiene numbering). On the basis of our earlier studies of
related cyclization processes,15 we believe the conversion 29 ! 6 proceeds under kinetic control and that
the Z-configuration about the double-bond of the Michael acceptor ensures the observed stereochemical
outcome.
The elaboration of pyran 6 to the target building block 3 followed protocols related to those established
by Nicolaou and Ley during the course of their syntheses of indanomycin (X-14547A).35 Thus, oxidation
of the former compound with the Parikh–Doering reagent25 gave the corresponding aldehyde 30 in 60%
yield. This proved spectroscopically identical with the material we had obtained by our earlier route.13c In
light of its limited stability, compound 30 was immediately treated with methylmagnesium chloride. The
resulting diastereoisomeric mixture of secondary alcohols was oxidized to the methyl ketone 31, albeit in
just 17% yield, using DMP. Compound 31 corresponds to a degradation product derived from the
ozonolysis of herboxidiene and the spectral data, including specific rotation, derived from our sample

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HETEROCYCLES, Vol. 85, No. 12, 2012
matched those reported by Edmunds et al.2 Reaction of compound 31 with vinylmagnesium bromide and
treatment of the ensuing tertiary allylic alcohols (60%) with phosphorous tribromide then gave, in 93%
yield, the rearranged primary allylic bromide 32 incorporating the required E-configured double bond.
The latter compound was treated with diphenylethoxyphosphine and thus resulting in a Michaelis–
Arbuzov reaction leading to the targeted and crystalline phosphine oxide 3 that was obtained in 85% yield.
With the required side-chain and core compounds, 21 and 3 respectively, in hand the proposed (Figure 1)
coupling of these two building blocks using Horner–Wittig chemistry36 could be investigated. The
outcomes of relevant studies are presented in the following section.
DIBAl-H
hexane/CH2Cl2
(i) (COCl)2, DMSO, CH2Cl2
–78 °C, 0.25 h
HO
HO
EtO
(ii) 22, Et3N, CH2Cl2
–78 to 18 °C, 1 h
(iii) EtOCOCHPPh3, CH2Cl2
18 °C, 2 h
–78 to 18 °C, 2 h
O
22
23
24
D
-(–)-tartrate
OR
O
Me3Al, CH2Cl2
0 to 18 °C, 10 h
(i-PrO)4Ti, t-BuOOH
(R)
HO
RO
(R)
4 Å MS, CH2Cl2, i-Oct.
–40 to 18 °C, ca. 4 h
Ac2O
DMAP
18 °C, 3 h
26 R = H
27 R = Ac
25
(i) O3, CH2Cl2, –78 °C, 1 h
(ii) Ph3P, CH2Cl2, –30 to 18 °C, 0.5 h
H
H
(CF3CH2O)2P(O)CH2CO2Me
KN(SiMe3)2
6
HO
OAc
OAc
K2CO3, MeOH
O
6
AcO
AcO
O
H
18-C-6/MeCN complex
–78 °C, 1.5 h
18 °C, 24 h
CO2Me
CO2Me
28
29
6
H
H
H
H
(i) MeMgCl, THF
–78 to 0 °C, 1.5 h
SO3•pyridine
DMSO, Et3N, CH2Cl2
O
O
O
O
H
H
(ii) DMP, CH2Cl2
18 °C, 1 h
0 to 18 °C, 1.5 h
CO2Me
CO2Me
31
30
O
H
H
H
(i) H2C=CHMgBr
Br
H
P
Ph
Ph
EtOPPh2, THF
66 °C, 2 h
THF, –78 °C, 1.5 h
O
O
H
H
(ii) PBr3, Et2O
0 °C, 1 h
CO2Me
CO2Me
32
3
Scheme 4. Synthesis of the phosphine oxide 3.

HETEROCYCLES, Vol. 85, No. 12, 2012
2957
(iii) End-game – Union of Side-chain and Pyran-core
The foreshadowed linking of the herboxidiene subunits 3 and 21 involved treating the former compound
(Scheme 5) with sodium hydride so as to form the corresponding C10 anion (herboxidiene numbering)
and this was then reacted with the aldehyde 21 in THF at 55 °C. Cooling of the reaction mixture followed
by work-up revealed that while the desired coupling reaction had taken place an accompanying
saponification reaction had occurred and so giving, after acidic work-up, the C1 carboxylic acid rather
than the methyl ester of the required coupling product. Accordingly the crude reaction mixture was
treated with excess diazomethane. Analysis of the resulting esterified material revealed that it was
composed of a 3:2 mixture of the desired compound 33 (38%) and its C12-epimer (25%) reflecting the
stereochemistry of the starting aldehyde 21. The coupling products could be separated from one another
by preparative HPLC and the major one (33) was then treated with tetra-n-butylammonium fluoride
(TBAF) to give the alcohol 34 (68%) and thus setting up the possibility of a directed and
diastereofacially-selective epoxidation of the "14,15-double-bond within this compound. In the event, and
following a protocol established by Kocienski et al.7 during the closing stages of their synthesis of
herboxidiene, compound 34 was treated, at –8 °C, with tert-butylhydroperoxide in the presence of
VO(acac)237 and so providing herboxidiene methyl ester 35 (63%) together with very small amounts of
what is tentatively identified as the diastereoisomeric epoxide which could be separated from its major
co-product by semi-preparative HPLC.
O
P
OMe
H
H
Ph
+
O
Ph
10
O
(i) NaH, THF, 55 °C, 2 h
(ii) CH2N2, CH2Cl2
18 °C, 16 h
TBDMSO
H
CO2Me
21
3
OMe
OMe
TBAF, THF
0 to 18 °C, 6 h
H
H
H
H
12
O
O
10
HO
TBDMSO
H
H
CO2Me
CO2Me
34
33
t-BuOOH, VO(acac)2
CH2Cl2
OMe
H
O
H
–8 °C, 72 h
18
O
HO
H
CO2Me
35
Scheme 5. Completion of the synthesis of herboxidiene methyl ester (35).

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HETEROCYCLES, Vol. 85, No. 12, 2012
The spectral data derived from compound 35 were consistent with those recorded by Kocienski et al.7 for
13
the same compound. In particular, the chemical shifts observed in the C NMR spectra of the two
materials match particularly well (Table 1). In contrast, an analogous comparison of these data with those
reported by Panek for C-18-epi-35 reveals significant differences (see chemical shifts highlighted in bold)
and suggests this technique provides a sensitive tool for detecting variations in the configuration of
substituents along the herboxidiene framework. Since ester 35 has been hydrolyzed to the corresponding
free acid, viz. to herboxidiene,7 the present work constitutes a formal total synthesis of the natural product
itself.
Table 1. Comparison of the 13C NMR data (#) for herboxidiene methyl ester (35) and its C-18-epimer.
Compound 35a
Compound 35b
C-18 Epimer of Compound 35c
171.8 ("# –0.2)
139.2 ("# –0.2)
135.2 ("# –0.2)
128.1 ("# –0.2)
125.2 ("# –0.2)
90.6 ("# –0.2)
87.6 ("# –0.2)
73.8 ("# –0.2)
68.2 ("# –0.2)
66.0 ("# –0.2)
61.4 ("# –0.1)
61.3 ("# –0.2)
51.6 ("# –0.1)
46.9 ("# –0.2)
41.3 ("# –0.2)
35.3 ("# –0.2)
35.2 ("# –0.1)
32.2 ("# –0.2)
32.0 ("# –0.3)
31.6 ("# –0.2)
22.1 ("# –0.1)
19.0 ("# –0.2)
17.6 ("# –0.2)
16.5 ("# –0.2)
11.9 ("# –0.2)
11.9 ("# –0.1)
172.0
139.4
135.4
128.3
125.4
90.8
87.8
74.0
68.4
66.2
61.5
61.5
51.7
47.1
41.5
35.5
35.3
32.4
32.3
31.8
22.2
19.2
17.8
16.7
12.1
12.0
171.8
139.1
135.2
127.6
125.0
90.1
86.7
73.9
68.2
66.1
61.1
60.3
51.5
46.8
41.3
34.9
34.7
32.4
32.4
31.6
21.7
18.9
17.7
16.6
12.7
11.9
a Recorded in CDCl3 at 90 MHz (ex Kocienski).7 b Recorded in CDCl3 at 75.5 MHz (ex this work).
c Recorded in CDCl3 at 100 MHz (ex Panek).8

HETEROCYCLES, Vol. 85, No. 12, 2012
2959
CONCLUSION
The total synthesis of herboxidiene methyl ester (35) described herein exploits the Katsuki–Sharpless
asymmetric epoxidation reaction, a chiral pool starting material and substrate-directed transformations for
establishing the required stereochemistries associated with eight of the nine centers of chirality contained
in the target molecule. The combination of such techniques has resulted in a reasonably concise formal
total synthesis of herboxidiene and provides good prospects for acquiring useful quantities of this natural
product and a range of analogues that could be exploited in developing a detailed understanding of the
SAR associated with this class of compound.
EXPERIMENTAL
General Protocols
Proton (1H) and carbon (13C) NMR spectra were recorded on a Varian Gemini 300 spectrometer,
operating at 300 MHz for proton and 75.4 MHz for carbon. All such spectra were recorded in
deuterochloroform (CDCl3) solution at 22 °C. Chemical shifts are recorded as # values in parts per
1
million (ppm). For H NMR spectra recorded in deuterochloroform, the peak due to residual CHCl3 (#
7.26) was used as the internal reference. Data are recorded as follows: chemical shift (#), multiplicity (s :
singlet, d : doublet, t : triplet, q : quartet, p : pentet, m : multiplet, dd : doublet of doublets etc., br : broad),
coupling constant(s) (J Hz), relative integral (for proton spectra) and assignment (where possible). The
digital resolution within spectra varies slightly depending on the selection of spectral width and number
of data points allocated to the time domain. However, in all cases this is, at worst, of the order of 0.4
Hz/point for one dimensional spectra. The protonicities of the carbon atoms observed in 13C NMR spectra
were determined by attached proton test (apt) experiments, i.e. by the phase of the resonance relative to
the solvent signal, viz. C and CH2 were of the same phase as the CDCl3 “triplet”, whilst CH and CH3
resonances were of the opposite phase. The central peak (# 77.0) of the CDCl3 triplet was used as the
reference for {1H}13C NMR spectra. APT C NMR spectral data are recorded as follows: chemical shift
13
(#) and protonicity (C = quaternary, CH = methine, CH2 = methylene, CH3 = methyl, C/CH2 = quaternary
or methylene, CH/CH3 = methine or methyl). Infrared spectra were recorded with either a Perkin–Elmer
683G Infrared Spectrophotometer or a Perkin–Elmer 1800 Series Fourier Transform Infrared
Spectrophotometer. Samples were analyzed as thin liquid films on potassium bromide (KBr) plates. Low
and high resolution electron-impact mass spectra were recorded at 70 eV on a VG Fisons AUTOSPEC
three sector (E / B / E) double-focussing Mass Spectrometer, using positive-ion electron impact
techniques (unless otherwise specified). Chemical ionization (CI) mass spectra were recorded on the VG
Fisons AUTOSPEC spectrometer, with NH3 as the reactant gas. Mass spectral data are listed as mass-to-
charge ratio (m/z), assignment (where possible) and relative intensity (% of base peak). Optical rotations

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HETEROCYCLES, Vol. 85, No. 12, 2012
were measured using a Perkin–Elmer 241 Polarimeter at the sodium D line (589 nm) with spectroscopic
grade chloroform (CHCl3) as solvent (unless otherwise specified) at room temperature (ca. 22 °C) and
concentration (c) (g/100 mL) indicated in a cell with a path length (l) of 1 dm. Specific rotations {[!]DT}
were calculated using the equation: [!]DT = (100.!) / (l.c) and estimated to be within ± 0.05 $ 10–1 deg
cm2 g–1. Melting points were recorded with a Kofler hot stage apparatus and are uncorrected. Ozonolyses
were performed using a Wallace and Tiernan Ozonator with the oxygen flow rate and power adjusted to
approximately 25 L/h and 200 V, respectively. Analytical thin layer chromatography (TLC) was
conducted on aluminum-backed 0.2 mm thick silica gel 60 F254 plates (Merck) and the chromatograms
were visualized under a 254 nm UV lamp and/or by treatment with a reagent solution [either
anisaldehyde/sulfuric acid/ethanol (EtOH) (2:5:93), phosphomolybdic acid/EtOH (8 g:200 mL) or
phosphomolybdic acid/ceric (IV) sulfate/sulfuric acid/water (37.5 g:7.5 g:37.5 mL:720 mL)] followed by
heating with a hair dryer or on a hot plate. Flash chromatography was conducted according to the method
of Still and co-workers38 using 230–400 mesh silica and the analytical reagent (AR) grade solvents
indicated. High performance liquid chromatography (HPLC) was conducted on a Waters µ-PorasilTM
semi-preparative silica column (7.8 $ 300 nm) connected to an ISCO Model 2350 pump and eluting with
the indicated HPLC-grade solvents. The peaks were detected using a Waters Lambda-Max Model 481
UV Detector connected to a Spectra-Physics SP4270 Reporting Integrator. Many reagents were available
from the Aldrich Chemical Company and were used as supplied. Drying agents and other inorganic salts
were purchased from AJAX or BDH Chemicals. Reaction solvents and reagents were purified according
to established procedures.39 The concentrations of alkyl lithium solutions obtained from Aldrich were
determined by titration with sec-butanol (1.0 M solution in toluene) using 1,10-phenanthroline as
indicator.40 Tetrahydrofuran (THF) and diethyl ether (Et2O) were dried with sodium and then distilled
under nitrogen from sodium benzophenone ketyl. Benzene, toluene, dichloromethane (CH2Cl2), hexane
and N,N-dimethylformamide (DMF) were distilled from calcium hydride. Pyridine was distilled from and
stored over potassium hydroxide pellets. Diisopropylamine was refluxed over calcium hydride for 4 h
then distilled under vacuum and stored under nitrogen. Dimethyl sulfoxide (DMSO) was dried with 4 Å
molecular sieves, then distilled and stored over 4 Å molecular sieves. Triethylamine was refluxed over
calcium hydride for 2 h then distilled from calcium hydride and stored over potassium hydroxide pellets.
Reactions employing air- and/or moisture-sensitive reagents were carried out under an atmosphere of dry,
oxygen-free nitrogen in oven- or flame-dried apparatus. Organic solutions obtained from work-up and/or
extraction of reaction mixtures were dried with magnesium sulfate (MgSO4) unless otherwise specified.
Solutions were concentrated under reduced pressure on a rotary evaporator with the water bath
temperature generally not exceeding 30 °C. When reactions were conducted at, or below 0 °C, the
internal temperature was monitored using an alcohol thermometer.

HETEROCYCLES, Vol. 85, No. 12, 2012
2961
Specific Synthetic Conversions
Methyl (2S)-3-Benzyloxy-2-methylpropionate (9): Trifluoromethanesulfonic acid (3.40 mL, 38.1
mmol) was added, via syringe, to a magnetically stirred solution of methyl (2S)-3-hydroxy-2-
methylpropionate (8) (15.0 g, 127 mmol, ex SIGMA) and benzyl 2,2,2-trichloroacetimidate (28.3 mL,
152.4 mmol) in a mixture of cyclohexane (200 mL) and CH2Cl2 (100 mL) maintained under a nitrogen
atmosphere at 0 °C (ice bath). The reaction mixture was allowed to warm to room temperature, stirred for
16 h then filtered through a sintered glass funnel. The filtrate was washed with NaHCO3 (1 $ 200 mL of a
saturated aqueous solution) and water (1 $ 200 mL) then dried, filtered and concentrated under reduced
pressure. The oily residue thus obtained was subjected to flash chromatography (silica, 1:9 v/v ethyl
acetate (EtOAc)/hexane elution) and concentration of the appropriate fractions (Rf 0.25) afforded the title
1
compound 9 (25.6 g, 97%) as a clear, colorless oil, [!]D +12.5 (c 2.4); H NMR (300 MHz, CDCl3): #
7.30–7.38 (complex m, 5H), 4.52 (s, 2H), 3.70 (s, 3H), 3.68 (m, 1H), 3.50 (dd, J 9.1 and 5.9 Hz, 1H),
2.81–2.75 (complex m, 1H), 1.18 (d, J 7.1 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): # 175.6 (C), 138.4 (C),
128.6 (CH), 127.9 (CH), 127.8 (CH), 73.3 (CH2), 72.2 (CH2), 52.0 (CH3), 40.4 (CH), 14.2 (CH3); IR
(KBr): !max 2862, 1740, 1455, 1201, 1098, 738, 699 cm–1; MS (70 eV): m/z (%): 208 (9) [M]+•, 177 (4)
[M–CH3O•]+, 121 (16), 107 (53), 91 (100); HRMS (EI): m/z calcd for C12H16O3 [M]+•: 208.1099; found:
208.1096.
(2S)-3-Benzyloxy-N-methoxy-N-methyl-2-methylpropanamide (10): Isopropylmagnesium chloride
(155.8 mL of a 2.0 M solution in THF, 311.5 mmol, ex ALDRICH) was added, steadily and over 0.5 h, to
a magnetically stirred suspension of ester 9 (21.6 g, 103.8 mmol) and N,O-dimethylhydroxylamine
hydrochloride (15.7 g, 161.0 mmol) in THF (230 mL) maintained under a nitrogen atmosphere at –15 °C.
The resulting mixture was stirred for 0.5 h at –15 °C by which time TLC analysis revealed complete
consumption of the starting material. At this point the reaction mixture was quenched with NH4Cl (150
mL of a saturated aqueous solution), diluted with water (150 mL) and extracted with Et2O (3 $ 100 mL).
The combined organic extracts were washed with brine (1 $ 100 mL) then dried (MgSO4), filtered and
concentrated under reduced pressure. The oily residue thus obtained was subjected to flash
chromatography (silica, 3:7 v/v EtOAc/hexane elution) and concentration of the appropriate fractions (Rf
1
0.3) afforded the Weinreb amide 10 (23.4 g, 95%) as a clear, colorless oil, [!]D +4.62 (c 2.0); H NMR
(300 MHz, CDCl3): # 7.34–7.27 (complex m, 5H), 4.52 (ABq, J 12.1 Hz, 2H), 3.72 (app. t., J 8.6 Hz, 1H)
3.70 (s, 3H), 3.43 (dd, J 8.8 and 5.9 Hz, 1H), 3.25 (m, 1H), 3.22 (s, 3H), 1.12 (d, J 7.1 Hz, 3H); 13C NMR
(75.5 MHz, CDCl3): # 175.8 (C), 138.3 (C), 128.2 (CH), 127.5 (CH), 127.4 (CH), 73.1 (CH2), 72.5 (CH2),
61.5 (CH3), 35.8 (CH), 32.2 (CH3), 14.2 (CH3); IR (KBr): !max 2862, 1660, 1454, 1102, 994, 739, 699
cm!1; MS (70 eV): m/z (%): 238 (11) [M+H]+, 206 (11) [M–CH3O•]+, 177 (25), 131 (70), 91 (100), 77
(44), 65 (58); HRMS (EI): m/z calcd for C13H20NO3 [M+H]+: 238.1443; found: 238.1442.

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HETEROCYCLES, Vol. 85, No. 12, 2012
(2S)-1-Benzyloxy-2-methyl-4-penten-3-one (5): Vinylmagnesium bromide (126.4 mL of a 1.0 M
solution in THF, 126.4 mmol, ex ALDRICH) was added, dropwise, to a magnetically stirred solution of
Weinreb amide 10 (20.0 g, 84.3 mmol) in THF (833 mL) maintained under a nitrogen atmosphere at 0 °C
(ice bath). The reaction mixture was stirred for a further 0.5 h at this temperature then quenched with
NH4Cl (450 mL of a saturated aqueous solution). The aqueous layer was extracted with Et2O (3 $ 250
mL) and the combined organic extracts were washed with brine (1 $ 300 mL) then dried, filtered and
concentrated under reduced pressure. The oily residue thus obtained was subjected to flash
chromatography (silica, 1:4 v/v EtOAc/hexane elution) and concentration of the appropriate fractions (Rf
0.5) afforded the title ketone 5 (15.8 g, 92%) as a pale-yellow oil, [!]D +13.5 (c 2.8); 1H NMR (300 MHz,
CDCl3): # 7.35–7.25 (complex m, 5H), 6.45 (dd, J 17.5 and 10.4 Hz, 1H), 6.25 (dd, J 17.5 and 1.5 Hz,
1H), 5.79 (dd, J 10.4 and 1.5 Hz, 1H), 4.49 (ABq, J 12.1 Hz, 2H), 3.70 (dd, J 9.2 and 8.4 Hz, 1H), 3.47
13
(dd, J 9.2 and 5.9 Hz, 1H), 3.18 (m, 1H), 1.12 (d, J 7.0 Hz, 3H); C NMR (75.5 MHz, CDCl3): # 202.5
(C), 138.1 (CH2), 135.5 (CH), 128.4 (C), 128.3 (CH), 127.5 (CH), 73.2 (CH2), 72.0 (CH2), 43.6 (CH),
13.9 (CH3) (one signal obscured or overlapping); IR (KBr): !max 2859, 1697, 1678, 1454, 1198, 1101,
1028, 737, 698 cm–1; MS (70 eV): m/z (%): 205 (10) [M+H]+, 107 (35), 98 (75), 91 (100), 83 (48), 77 (25),
65 (35); HRMS (EI): m/z calcd for C13H17O3 [M+H]+: 205.1229; found: 205.1226.
(3S,4S)-4-Methyl-5-(phenylmethoxy)-1-penten-3-ol (11) and (3R,4S)-4-methyl-5-(phenylmethoxy)-1-
penten-3-ol (C17-epi-11): Zinc borohydride (318.1 mL of a 0.43 M solution in Et2O, 136.8 mmol, which
was prepared from zinc chloride and sodium borohydride20) was added, dropwise, to a magnetically
stirred solution of vinyl ketone 5 (18.6 g, 91.2 mmol) in CH2Cl2 (890 mL) maintained under a nitrogen
atmosphere at –78 °C. The resulting mixture was stirred for 2 h at –78 °C then warmed to 0 °C and stirred
at this temperature for a further 0.5 h. The reaction was then quenched by transferring the reaction
mixture, via cannula, to a rapidly stirred solution of HCl (600 mL of a 1 M aqueous solution) maintained
at 0 °C. The aqueous layer was extracted with CH2Cl2 (3 $ 250 mL) and the combined organic extracts
were washed successively with NaHCO3 (1 $ 250 mL of a saturated aqueous solution) and brine (1 $ 250
mL) then dried (MgSO4), filtered and concentrated under reduced pressure. The ensuing oily residue was
subjected to HPLC (µ-Porasil 40 $ 100 mm cartridge column, 1:9 v/v EtOAc/hexane elution, flow rate 30
mL/min) and two fractions, A and B, were obtained.
Concentration of fraction A (Rt 12 min) afforded compound 11 (15.4 g, 82%) as a clear, colorless oil, [!]D
–9.6 (c 2.8); 1H NMR (300 MHz, CDCl3): # 7.39–7.28 (complex m, 5H), 5.88 (ddd, J 17.2, 10.6 and 5.4
Hz, 1H), 5.33–5.16 (complex m, 2H), 4.51 (s, 2H), 4.28–4.25 (complex m, 1H), 3.56–3.49 (complex m,
2H), 3.0 (br s, 1H), 2.12–2.05 (complex m, 1H), 0.91 (d, J 7.0 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): #
138.5 (CH), 137.9 (CH2), 128.3 (CH), 127.6(1) (CH), 127.5(5) (CH), 115.0 (C), 75.0 (CH), 73.6 (CH2),
73.3 (CH2), 38.2 (CH), 11.5 (CH3); IR (KBr): !max 3440, 2966, 1454, 1097, 737, 698 cm–1; MS (70 eV):

HETEROCYCLES, Vol. 85, No. 12, 2012
2963
m/z (%): 206 (2) [M]+•, 188 (3), 144 (6), 108 (46), 91 (100); HRMS (EI): m/z calcd for C13H18O2 [M]+•:
206.1307; found: 206.1310.
Concentration of fraction B (Rt 16.5 min) afforded compound C3-epi-11 (3.40 g, 18%) as a clear,
colorless oil, [!]D +28.2 (c 2.5); 1H NMR (300 MHz, CDCl3): # 7.35–7.29 (complex m, 5H), 5.88 (ddd, J
17.2, 10.6 and 5.4 Hz, 1H), 5.29–5.13 (complex m, 2H), 4.52 (s, 2H), 4.03 (t, J 6.7 Hz, 1H), 3.62 (dd, J
9.3 and 4.3 Hz, 1H), 3.47 (dd, J 9.3 and 7.2 Hz, 1H), 3.37 (br s, 1H), 1.91 (m, 1H), 0.91 (d, J 7.1 Hz, 3H);
13C NMR (75.5 MHz, CDCl3): # 139.7 (CH), 138.1 (CH2), 128.7 (CH), 128.0 (CH), 127.9 (CH), 116.1
(C), 76.9 (CH), 74.8 (CH2), 73.7 (CH2), 38.8 (CH), 14.0 (CH3); IR (KBr): !max 3430, 2962, 2857, 1454,
1097, 737, 698 cm–1; MS (70 eV): m/z (%): 206 (4) [M]+•, 188 (5), 144 (8), 108 (50), 91 (100), 82 (55);
HRMS (EI): m/z calcd for C13H18O2 [M]+•: 206.1307; found: 206.1308.
(3R,4S)-4-Methyl-5-(phenylmethoxy)-1-penten-3-yl
(2R)-2-methoxy-2-phenyl-2-trifluoromethyl-
acetate [(R)-Mosher ester of compound 11]: Oxalyl chloride (12.5 µL, 0.14 mmol) then DMF (1 drop)
were added to a magnetically stirred solution of (R)-(+)-MTPA (74 mg, 0.32 mmol) in CH2Cl2 (2 mL)
maintained at 0 °C (ice bath) under a nitrogen atmosphere. The reaction mixture was allowed to warm to
room temperature, stirred for a further 0.75 h and then transferred, via cannula, to a chilled (0 °C) and
magnetically stirred solution of the alcohol 11 (24 mg, 0.12 mmol), triethylamine (34 µL, 0.24 mmol) and
DMAP (2 mg) in CH2Cl2 (3 mL). The cold bath was removed and the reaction mixture was stirred at
room temperature for 16 h. The solution was then partitioned between CH2Cl2 (10 mL) and NaHCO3 (10
mL of a saturated aqueous solution) and the phases separated. The aqueous layer was extracted with
CH2Cl2 (3 $ 10 mL) and the combined organic fractions were washed with brine (1 $ 10 mL) then dried,
filtered and concentrated under reduced pressure to give a pale-yellow oil. Subjection of the crude
material to flash chromatography (silica, 1:4 v/v EtOAc/hexane elution) provided, after concentration of
the appropriate fractions (Rf 0.4), the title ester (27 mg, 55%) as a clear, colorless oil. 1H NMR (300 MHz,
CDCl3): # 7.60–7.30 (complex m, 10H), 5.84 (ddd, J 17.2, 10.4 and 7.0 Hz, 1H), 5.67 (dd, J 7.1 and 4.4
Hz, 1H), 5.30 (m, 2H), 4.50–4.33 (m, 2H), 3.53 (s, 3H), 3.26 (dd, J 6.1 and 2.7 Hz, 2H), 2.10 (m, 1H),
0.90 (d, J 6.9 Hz, 3H).
(3R,4S)-4-Methyl-5-(phenylmethoxy)-1-penten-3-yl
(2S)-2-methoxy-2-phenyl-2-trifluoromethyl-
acetate [(S)-Mosher ester of compound 11]: Oxalyl chloride (25 µL, 0.29 mmol) then DMF (1 drop)
were added to a magnetically stirred solution of (S)-(–)-MTPA (120 mg, 0.51 mmol) in CH2Cl2 (2 mL)
maintained at 0 °C (ice bath) under a nitrogen atmosphere. The reaction mixture was allowed to warm to
room temperature, and stirred for a further 0.75 h and then transferred, via cannula, to a chilled (0 °C) and
magnetically stirred solution of the alcohol 11 (50 mg, 0.24 mmol), triethylamine (68 µL, 0.48 mmol) and
DMAP (2 mg) in CH2Cl2 (3 mL). The cold bath was removed and the reaction mixture was stirred at
room temperature for 16 h. The solution was then partitioned between CH2Cl2 (10 mL) and NaHCO3 (10

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HETEROCYCLES, Vol. 85, No. 12, 2012
mL of a saturated aqueous solution) and the phases separated. The aqueous layer was extracted with
CH2Cl2 (3 $ 10 mL) and the combined organic fractions were washed with brine (1 $ 10 mL) then dried,
filtered and concentrated under reduced pressure to give a pale-yellow oil. Subjection of the crude
material to flash chromatography (silica, 1:4 v/v EtOAc/hexane elution) provided, after concentration of
the appropriate fractions (Rf 0.4), the title compound (48 mg, 47%) as a clear, colorless oil. 1H NMR (300
MHz, CDCl3): # 7.52–7.30 (complex m, 10H), 5.76 (dd, J 10.6 and 4.0 Hz, 1H), 5.67 (complex m, 1H),
5.24 (d, J 16.5 Hz, 1H), 5.23 (s, 1H), 4.50 (ABq, J 14.3 Hz, 2H), 3.50 (s, 3H), 3.34 (d, J 6.6 Hz, 2H),
2.12–2.08 (complex m, 1H), 0.96 (d, J 7.0 Hz, 3H).
1
Table 2. Analysis of the differences in the H NMR chemical shifts for equivalent protons within the R-
and S-Mosher esters of compound 11.
Ph
O
Ph
O
6
6
5
5
Ph OMe
MeO Ph
O
O
R
CF3
S CF3
3
3
H
O
H
O
1
1
R-Ester of 11 [#]
S-Ester of 11 [#]
" [#(R) – #(S)]
Hydrogen
C1-trans H
C1-cis H
C2-H
5.3305
5.2825
5.8371
5.670
5.2415
5.232
5.750
5.664
2.111
3.342
4.466
0.961
+0.089
+0.050
+0.087
+0.006
–0.045
–0.082
–0.055
–0.061
C3-H
C4-H
2.066
C5-H
3.2596
4.411
C6-H
C4-Me
0.900
(3S,4S)-3-Methoxy-4-methyl-5-(phenylmethoxy)-1-pentene (12): A solution of alcohol 11 (4.50 g, 21.8
mmol) in THF (20 mL) was added, dropwise, to a magnetically stirred suspension of KH (6.3 g of 35%
(w/w) dispersion in mineral oil, 54.6 mmol) in THF (150 mL) maintained under a nitrogen atmosphere.
The resulting mixture was stirred at room temperature for 0.25 h then chilled (0 °C) and treated, via
syringe, with a solution of methyl iodide (3.4 mL, 54.6 mmol) in THF (25 mL). The reaction mixture was
then allowed to warm to room temperature and stirred for a further 0.25 h then cautiously poured onto ice
(50 g). The resulting mixture was extracted with Et2O (3 $ 200 mL) and the combined organic phases

HETEROCYCLES, Vol. 85, No. 12, 2012
2965
were dried, filtered and concentrated under reduced pressure. The ensuing oily residue was subjected to
flash chromatography (silica, 1:9 v/v EtOAc/hexane elution) and concentration of the appropriate
fractions (Rf 0.6) afforded the title bis-ether 12 (4.10 g, 85%) as a clear, colorless oil, [!]D +12.2 (c 1.3);
1H NMR (300 MHz, CDCl3): # 7.35–7.27 (complex m, 5H), 5.69 (ddd, J 16.5, 10.9 and 7.7 Hz, 1H),
5.24–5.17 (complex m, 2H), 4.50 (s, 2H), 3.62 (t, J 7.0 Hz, 1H), 3.51 (dd, J 8.1 and 4.5 Hz, 1H), 3.31 (dd,
13
J 9.0 and 6.4 Hz, 1H), 3.27 (s, 3H), 1.94–1.85 (complex m, 1H), 0.96 (d, J 7.1 Hz, 3H); C NMR (75.5
MHz, CDCl3): # 138.7 (C), 137.1 (CH), 128.3 (CH), 127.6 (CH), 127.5 (CH), 117.4 (CH2), 83.5 (CH),
73.1 (CH2), 72.4 (CH2), 56.8 (CH3), 38.5 (CH), 12.2 (CH3); IR (KBr): !max 2902, 2856, 1454, 1095, 925,
736, 698 cm–1; MS (70 eV): m/z (%): 220 (2) [M]+•, 205 (2), 188 (1), 129 (16), 112 (16), 91 (83), 82 (50),
71 (100), 67 (24); HRMS (EI): m/z calcd for C14H20O2 [M]+•: 220.1463; found: 220.1464.
(2R,3S)-2-Methoxy-3-methyl-4-(phenylmethoxy)butanal (13): A magnetically stirred solution of
alkene 12 (2.0 g, 9.1 mmol) in CH2Cl2 (200 mL) was cooled to %78 °C then treated with a stream of
ozone gas until a blue color persisted. The reaction mixture was then warmed to –30 °C and dimethyl
sulfide (DMSO) (1.3 mL, 18.2 mmol) added in small portions. The reaction mixture was allowed to warm
to room temperature and the solvent was removed under reduced pressure. The residue thus obtained was
subjected to flash chromatography (silica, 1:9 v/v EtOAc/hexane elution) and concentration of the
appropriate fractions (Rf 0.4) afforded the title aldehyde 13 (1.45 g, 72%) as a clear, colorless, but very
1
unstable oil, [!]D +22.5 (c 2.2); H NMR (300 MHz, CDCl3): # 9.68 (d, J 1.5 Hz, 1H), 7.35–7.29
(complex m, 5H), 4.50 (ABq, J 12.0 Hz, 2H), 3.72 (m, 1H), 3.45 (m, 2H), 3.43 (s, 3H), 2.31 (m, 1H),
0.91 (d, J 7.1 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): # 203.8 (CH), 138.1 (C), 128.4 (CH), 127.6 (CH),
86.5 (CH), 73.0 (CH2), 71.0 (CH2), 58.9 (CH3), 35.6 (CH), 11.5 (CH3) (one signal obscured or
overlapping); IR (KBr): !max 2934, 1732, 1454, 1204, 1091, 738, 699 cm–1; MS (70 eV): m/z (%): 193 (18)
[M–HCO•]+, 131 (18), 107 (40), 91 (100), 71 (24).
(2R,3R,4S)-3-Methoxy-4-methyl-5-(phenylmethoxy)pentan-2-ol (14): A magnetically stirred solution
of the aldehyde 13 (1.0 g, 4.5 mmol) in CH2Cl2 (45 mL) was cooled to –78 °C then treated with neat TiCl4
(0.5 mL, 4.5 mmol). After 0.08 h, (Me)2Zn (2.25 mL of 2.0 M solution in THF, 4.5 mmol) was added.
The resulting mixture was stirred at –78 °C for 0.25 h then water was cautiously added at !78 °C and the
reaction mixture allowed to warm to room temperature and extracted with CH2Cl2 (3 $ 100 mL). The
combined organic extracts were washed with brine (1 $ 25 mL) before being dried, filtered and then
concentrated under reduced pressure. The oily residue thus obtained was subjected to flash
chromatography (silica, 3:7 v/v EtOAc/hexane elution) and concentration of the appropriate fractions (Rf
1
0.25) afforded the title compound 14 (0.75 g, 70%) as a clear, colorless oil, [!]D +8.6 (c 2.8); H NMR
(300 MHz, CDCl3): # 7.35–7.31 (complex m, 5H), 4.51 (ABq, J 12.0 Hz, 2H), 3.80 (m, 1H), 3.48 (s, 3H),
3.44 (d, J 6.4 Hz, 2H), 3.07 (m, 1H), 2.60 (br s, 1H), 2.10–2.03 (complex m, 1H), 1.19 (d, J 6.4 Hz, 3H),

2966
HETEROCYCLES, Vol. 85, No. 12, 2012
0.92 (d, J 7.0 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): # 138.1 (C), 128.4 (CH), 127.7 (CH), 127.6 (CH),
86.4 (CH), 73.1 (CH2), 72.6 (CH2), 67.9 (CH), 61.0 (CH3), 35.2 (CH), 19.4 (CH3), 11.8 (CH3); IR (KBr):
!
max 3451, 2972, 1454, 1365, 1090, 737, 698 cm–1. MS (70 eV): m/z (%): 238 (1) [M]+•, 193 (21), 131 (20),
107 (13), 91 (100), 87 (40), 71 (24); HRMS (EI): m/z calcd for C14H22O3 [M]+•: 238.1569; found:
238.1560.
(2R,3R,4S)-3-Methoxy-4-methyl-5-(phenylmethoxy)pentan-2-yl
(2R)-2-methoxy-2-phenyl-2-tri-
fluoromethylacetate [(R)-Mosher ester of compound 14]: Oxalyl chloride (11.5 µL, 0.13 mmol) then
DMF (1 drop) were added to a magnetically stirred solution of (R)-(+)-MTPA (31 mg, 0.13 mmol) in
CH2Cl2 (0.5 mL) maintained at 0 °C (ice bath) under a nitrogen atmosphere. The reaction mixture was
allowed to warm to 18 °C, stirred for a further 0.75 h at this temperature then transferred, via cannula, to a
chilled (0 °C) and magnetically stirred solution of the alcohol 14 (15 mg, 63 µmol), triethylamine (18.4
µL, 0.13 mmol) and DMAP (2 mg) in CH2Cl2 (3 mL). The cold bath was removed, the reaction mixture
stirred at room temperature for 16 h then the solution partitioned between CH2Cl2 (10 mL) and NaHCO3
(10 mL of a saturated aqueous solution) and the phases separated. The aqueous layer was extracted with
CH2Cl2 (3 $ 10 mL) and the combined organic fractions were washed with brine (1 $ 10 mL) before
being dried, filtered and concentrated under reduced pressure to give a pale-yellow oil. Subjection of the
crude material to flash chromatography (silica, 1:4 v/v EtOAc/hexane elution) provided, after
concentration of the appropriate fractions (Rf 0.4), the title compound (19 mg, 65%) as a clear, colorless
oil. 1H NMR (300 MHz, CDCl3): # 7.55–7.28 (complex m, 10H), 5.17 (m, 1H), 4.49 (s, 2H), 3.54 (s, 3H),
3.47–3.41 (complex m, 2H), 3.33 (d, J 5.5 Hz, 1H), 3.31 (s, 3H), 2.05–1.90 (complex m, 1H), 1.23 (d, J
6.3 Hz, 3H), 0.87 (d, J 7.1 Hz, 3H).
(2R,3R,4S)-3-Methoxy-4-methyl-5-(phenylmethoxy)pentan-2-yl
(2S)-2-methoxy-2-phenyl-2-tri-
fluoromethylacetate [(S)-Mosher ester of compound 14]: Oxalyl chloride (11.5 µL, 0.13 mmol) then
DMF (1 drop) were added to a magnetically stirred solution of (S)-(–)-MTPA (31 mg, 0.13 mmol) in
CH2Cl2 (0.5 mL) maintained at 0 °C (ice bath) under a nitrogen atmosphere. The reaction mixture was
allowed to warm to room temperature, stirred for a further 0.75 h then transferred, via cannula, to a
chilled (0 °C) and magnetically stirred solution of the alcohol 14 (15 mg, 63 µmol), triethylamine (18.4
µL, 0.13 mmol) and DMAP (2 mg) in CH2Cl2 (3 mL). The cold bath was removed, the reaction mixture
stirred at room temperature for 16 h then partitioned between CH2Cl2 (10 mL) and NaHCO3 (10 mL of a
saturated aqueous solution) and the phases separated. The aqueous layer was extracted with CH2Cl2 (3 $
10 mL) and the combined organic fractions were washed with brine (1 $ 10 mL) before being dried,
filtered and concentrated under reduced pressure to give a pale-yellow oil. Subjection of the crude
material to flash chromatography (silica, 1:4 v/v EtOAc/hexane elution) provided, after concentration of
the appropriate fractions (Rf 0.4), the title compound (19 mg, 65%) as a clear, colorless oil. 1H NMR (300

HETEROCYCLES, Vol. 85, No. 12, 2012
2967
MHz, CDCl3): # 7.58–7.28 (complex m, 10H), 5.20 (m, 1H), 4.46 (s, 2H), 3.60 (s, 3H), 3.40–3.34
(complex m, 2H), 3.26 (dd, J 9.0 and 5.4 Hz, 1H), 3.05 (s, 3H), 1.94–1.90 (complex m, 1H), 1.29 (d, J 6.4
Hz, 3H), 0.84 (d, J 6.9 Hz, 3H).
1
Table 3. Analysis of the differences in the H NMR chemical shifts for equivalent protons within the R-
and S-Mosher esters of compound 14.
MeO
3
MeO
3
Ph OMe
MeO Ph
5
5
O
O
R
S
Ph
O
CF3
Ph
O
CF3
1
1
H
O
H
O
R-Ester of 14 [#]
S-Ester of 14 [#]
" [#(R) – #(S)]
Hydrogen
C1-Me
C1-H
1.232
5.169
3.307
3.323
0.871
1.990
3.438
4.491
1.293
5.198
3.050
3.256
0.841
1.929
3.367
4.456
–0.061
–0.029
+0.257
+0.067
+0.03
C2-OMe
C2-H
C3-Me
C3-H
+0.061
+0.071
+0.035
C4-H
C5-H
(2R,3R,4S)-2-(tert-Butyldimethylsiloxy)-3-methoxy-4-methyl-5-(phenylmethoxy)-pentane (15):
A
magnetically stirred solution of alcohol 14 (1.00 g, 4.2 mmol) and imidazole (0.43 g, 6.3 mmol) in DMF
(30 mL) maintained under nitrogen was treated with tert-butyldimethylsilyl chloride (TBDMSCl) (0.76 g,
5.04 mmol) and the resulting mixture was heated at 60 °C (oil bath) for 3 h. The reaction mixture was
then cooled, poured onto crushed ice (25 g) and extracted with Et2O (3 $ 40 mL). The combined organic
extracts were dried, filtered and then concentrated under reduced pressure. The oily residue thus obtained
was subjected to flash chromatography (silica, 1:4 v/v EtOAc/hexane elution) and concentration of the
appropriate fractions (Rf 0.7) then afforded the title compound 15 (1.20 g, 80%) as a clear, colorless oil,
[!]D +10.4 (c 1.5); 1H NMR (300 MHz, CDCl3): # 7.36–7.28 (complex m, 5H), 4.51 (s, 2H), 3.85 (m, 1H),
3.50 (m, 1H), 3.44 (s, 3H), 3.30 (dd, J 9.0 and 6.2 Hz, 1H) 3.10 (dd, J 7.1 and 3.4 Hz, 1H), 1.99 (m, 1H),
1.10 (d, J 6.4 Hz, 3H), 0.90 (s, 9H), 0.86 (d, J 7.0 Hz, 3H), 0.07 (s, 6H); 13C NMR (75.5 MHz, CDCl3): #
138.6 (C), 128.3 (CH), 127.7 (CH), 127.5 (CH), 85.5 (CH), 73.3 (CH2), 73.0 (CH2), 70.5 (CH), 61.0
(CH3), 35.0 (CH), 25.9 (CH3), 20.2 (CH3), 18.1 (C), 10.9 (CH3), –4.7 (CH3) (one signal obscured or
overlapping); IR (KBr): !max 2930, 1455, 1255, 1099, 834, 776 cm–1; MS (70 eV): m/z (%): 295 (6) [M–

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HETEROCYCLES, Vol. 85, No. 12, 2012
C4H9•]+, 203 (12), 187 (17), 173 (30), 159 (45), 91 (100), 73 (40); HRMS (EI): m/z calcd for C16H27O3Si
[M–C4H9•]+: 295.1730; found: 295.1730.
(2S,3R,4R)-4-(tert-Butyldimethylsiloxy)-3-methoxy-2-methylpentan-1-ol (16): A mixture of compound
15 (1.0 g, 2.84 mmol), palladium hydroxide on carbon (Pearlman’s catalyst) (0.15 g) and THF (50 mL)
was stirred vigorously under an atmosphere of hydrogen (760 mmHg) for 3 h. The reaction mixture was
then filtered through a 2 cm deep pad of TLC-grade silica and the filtrate concentrated under reduced
pressure. The ensuing oily residue was subjected to flash chromatography (silica, 3:7 v/v EtOAc/hexane
elution) and concentration of the appropriate fractions (Rf 0.5) then afforded the title alcohol 16 (0.7 g,
1
97%) as a clear, colorless oil, [!]D –3.6 (c 1.5); H NMR (300 MHz, CDCl3): # 4.04 (m, 1H), 3.60–3.45
(complex m, 2H), 3.43 (s, 3H), 2.90 (dd, J 7.2 and 4.9 Hz, 1H), 1.90–1.84 (complex m, 1H), 1.20 (d, J 6.3
Hz, 3H), 0.93 (d, J 6.8 Hz, 3H), 0.91 (s, 9H), 0.12 (s, 6H) (signal due to OH group proton not observed);
13C NMR (75.5 MHz, CDCl3): # 88.1 (CH), 69.2 (CH), 66.4 (CH2), 59.9 (CH3), 36.9 (CH), 25.8 (CH3),
18.4 (CH3), 18.0 (C), 13.2 (CH3), –4.8 (CH3), –4.9 (CH3); IR (KBr): !max 3444, 2961, 2888, 2861, 1463,
1256, 1094, 835, 809, 775, 734 cm–1; MS (70 eV): m/z (%): 263 (1) [M+H]+, 215 (7), 173 (67), 159 (84),
89 (55), 73 (100); HRMS (EI): m/z calcd for C13H31O3Si [M+H]+: 263.2043; found: 263.2047.
(2S,3R,4R)-4-(tert-Butyldimethylsiloxy)-3-methoxy-2-methylpentanal
(17):
A
solution
of
triethylamine (1.72 mL, 12.4 mmol) and alcohol 16 (0.5 g, 1.9 mmol) in CH2Cl2 (5 mL) was added,
dropwise, to a magnetically stirred solution of the sulfur trioxide/pyridine complex (1.2 g, 7.6 mmol) in
DMSO/CH2Cl2 (15.5 mL of a 3:2 v/v mixture) maintained at 0 °C (ice bath) under a nitrogen atmosphere.
The reaction mixture was allowed to warm to room temperature and stirred for a further hour before being
quenched with water (25 mL) and extracted with hexane (3 $ 25 mL). The combined organic extracts
were washed with brine (1 $ 15 mL), then dried, filtered and concentrated under reduced pressure. The
oily residue thus obtained was subjected to flash chromatography (silica, 1:9 v/v EtOAc/hexane elution)
and concentration of the appropriate fractions (Rf 0.4) afforded the title aldehyde 17 (0.5 g, 94%) as a
clear, colorless, but unstable oil. Since this aldehyde is highly prone to epimerization it was immediately
subjected to the next step of the reaction sequence.
(3R,4S,5R,6R)-6-(tert-Butyldimethylsiloxy)-2,4-dimethyl-5-methoxy-1-penten-3-ol
(18):
Neat
2-bromopropene (6.23 mL, 70.1 mmol) was added, dropwise, to a magnetically stirred solution of tert-
butyllithium (83.3 mL of a 1.7 M solution in pentane, 141.7 mmol, ex ALDRICH) in Et2O (180 mL)
maintained under a nitrogen atmosphere at –78 °C. The resulting mixture was stirred at this temperature
for 0.75 h and then treated with a solution of copper(I) bromide-dimethyl sulfide complex (7.3 g, 35.6
mmol) in DMSO (45 mL). The resulting mixture was stirred at –78 °C for a further 0.5 h and then treated
with a solution of aldehyde 17 (1.35 g, 5.18 mmol) in Et2O (20 mL). Stirring was continued at this
temperature for 0.5 h then the reaction mixture was quenched with NH4Cl (50 mL of a saturated aqueous

HETEROCYCLES, Vol. 85, No. 12, 2012
2969
solution). The slurry obtained in this manner was warmed to room temperature and extracted with Et2O (3
$ 50 mL). The combined organic extracts were then dried, filtered and concentrated under reduced
pressure. The ensuing residue was subjected to flash chromatography (silica, 1.5:8.5 v/v EtOAc/hexane
elution) and concentration of the appropriate fractions (Rf 0.4) afforded the title compound 18 (1.10 g,
70%) as a clear, colorless oil, [!]D +3.2 (c 1.2); 1H NMR (300 MHz, CDCl3): # 5.10 (s, 1H), 4.92 (s, 1H),
4.24 (s, 1H), 3.98 (m, 1H), 3.50 (s, 3H), 3.10 (dd, J 6.4 and 4.2 Hz, 1H), 1.84 (m, 1H), 1.68 (s, 3H), 1.14
(d, J 6.5 Hz, 3H), 0.90 (s, 9H), 0.84 (d, J 7.1 Hz, 3H), 0.10 (s, 6H) (signal due to OH group proton not
13
observed); C NMR (75.5 MHz, CDCl3): # 145.0 (C), 111.2 (CH2), 89.0 (CH), 77.2 (CH), 70.1 (CH),
60.3 (CH3), 36.1 (CH3), 25.9 (CH3), 19.5 (CH), 19.3 (CH3), 18.1 (C), 7.3 (CH3), –4.6 (CH3), –4.7 (CH3);
IR (KBr): !max 3447, 2931, 1462, 1256, 1093, 1068, 988, 900, 835, 776 cm–1; MS (70 eV): m/z (%): 245
(4) [M–C4H9•]+, 227 (4), 159 (100), 89 (49), 73 (100); HRMS (EI): m/z calcd for C12H25O3Si [M–C4H9•]+:
245.1573; found: 245.1570.
(2'R,3'S,4'S,5'R)-6'-(tert-Butyldimethylsiloxy)-2',4'-dimethyl-5'-methoxy-1'-penten-3'-yl propionate
(4): A magnetically stirred solution of allylic alcohol 18 (150 mg, 0.5 mmol) in pyridine (4 mL) was
treated with propionic anhydride (0.16 mL, 1.2 mmol) and a catalytic amount of DMAP (2 mg, 0.02
mmol). The resulting mixture was stirred at 18 °C for 16 h then poured onto crushed ice (ca. 10 g) and
extracted with Et2O (3 $ 25 mL). The combined organic extracts were then washed with HCl (1 $ 10 mL
of a 1 M aqueous solution) and brine (1 $ 10 mL) before being dried, filtered and concentrated under
reduced pressure. Subjection of this material to flash chromatography (silica, 1:4 v/v EtOAc/hexane
elution) gave, after concentration of the appropriate fractions (Rf 0.6), the title ester 4 (160 mg, 90%) as a
1
clear, colorless oil, [!]D –22 (c 1.6); H NMR (300 MHz, CDCl3): # 5.25 (d, J 8.0 Hz, 1H), 5.02–5.00
(complex m, 2H), 3.91 (m, 1H), 3.43 (s, 3H), 2.92 (dd, J 6.5 and 2.8 Hz, 1H), 2.34 (q, J 7.5 Hz, 2H),
2.06–1.99 (complex m, 1H), 1.70 (s, 3H), 1.14 (t, J 7.6 Hz, 3H), 1.10 (d, J 6.4 Hz, 3H), 0.90 (s, 9H), 0.89
13
(d, J 8.8 Hz, 3H), 0.08 (s, 6H); C NMR (75.5 MHz, CDCl3): # 173.5 (C), 142.0 (C), 115.5 (CH2), 85.0
(CH), 79.9 (CH), 70.2 (CH), 60.5 (CH3), 35.5 (CH3), 27.9 (CH2), 26.0 (CH3), 20.1 (CH), 18.1 (C), 18.0
(CH3), 9.6 (CH3), 9.2 (CH3), %4.6 (CH3) (two signals overlapping); IR (KBr): !max 2931, 1741, 1463, 1256,
1184, 1095, 1006, 903, 835, 776 cm–1; MS (70 eV): m/z (%): 301 (4) [M–C4H9•]+, 227 (18), 199 (37), 159
(100), 125 (75), 89 (60), 73 (92); HRMS (EI): m/z calcd for C15H29O4Si [M–C4H9•]+: 301.1835; found:
301.1839.
(2S,6S,7R,8R,4E)-8-(tert-Butyldimethylsiloxy)-7-methoxy-2,4,6-trimethyl-4-nonenoic acid (19): A
magnetically stirred solution of diisopropylamine (27 µL, 0.2 mmol) in THF (1.5 mL) was cooled to
!10 °C then treated with n-butyllithium (113 µL of a 1.6 M solution in hexane, 0.18 mmol, ex
ALDRICH). The resulting mixture was stirred at %10 °C for 0.25 h and then warmed to 18 °C and stirred
at this temperature for a further 0.25 h. After this time the reaction mixture was cooled to –40 °C and

2970
HETEROCYCLES, Vol. 85, No. 12, 2012
THF (0.3 mL) then dry HMPA (0.15 mL) were added. The reaction mixture was then cooled to !78 °C
and a solution of propionate ester 4 (50 mg, 0.14 mmol) was added dropwise over a period of 0.16 h.
After 0.25 h TBDMSCl (0.03 g, 0.19 mmol) in THF (0.1 mL) was added rapidly with vigorous stirring.
The resulting mixture was stirred at –78 °C for 0.25 h and then allowed to warm to 18 °C over a 0.75 h
period. After heating to 60 °C for 6 h, the reaction mixture was diluted with HCl (5 mL of a 1 M aqueous
solution) and extracted with Et2O (3 $ 10 mL). The combined organic phases were washed with brine (1
$ 10 mL) then dried, filtered and concentrated under reduced pressure. Subjection of this material to flash
chromatography (silica, 1.5:8.5 v/v EtOAc/hexane elution) gave, after concentration of the appropriate
1
fractions (Rf 0.2), the title acid 19 (38 mg, 75%) as a clear, colorless oil, [!]D +5.82 (c 2.15); H NMR
(300 MHz, CDCl3): # 5.20 (d, J 9.3 Hz, 1H), 3.83 (p, J 6.7 Hz, 1H), 3.43 (s, 3H), 2.80 (t, J 5.4 Hz, 1H),
2.65–2.53 (complex m, 2H), 2.38 (m, 1H), 2.05 (m, 1H), 1.61 (s, 3H), 1.13 (d, J 6.7 Hz, 3H), 1.11 (d, J
6.7 Hz, 3H), 1.00 (d, J 6.7 Hz, 3H), 0.90 (s, 9H), 0.06 (s, 6H) (signal due to CO2H group proton not
observed); 13C NMR (75.5 MHz, CDCl3): # 182.4 (C), 131.8 (CH), 130.1 (C), 89.7 (CH), 70.1 (CH), 60.8
(CH3), 43.7 (CH2), 37.9 (CH), 33.8 (CH), 25.9 (CH3), 20.1 (CH3), 18.1 (C), 16.4 (CH3), 15.8 (CH3), 15.4
(CH3), –4.5(6) (CH3), !4.6(2) (CH3); IR (KBr): !max 2958, 2931, 1709, 1254, 1093, 834, 776 cm–1; MS (70
eV): m/z (%): 358 (1) [M]+•, 301 (2) [M–C4H9•]+, 225 (8), 203 (90), 159 (57), 133 (59), 89 (69), 73 (100);
HRMS (EI): m/z calcd for C15H29O4Si [M–C4H9•]+: 301.1835; found: 301.1836.
(2S,6S,7R,8R,5E)-8-(tert-Butyldimethylsiloxy)-7-methoxy-2,4,6-trimethyl-4-nonen-1-ol (20): LiAlH4
(0.28 mL of a 1 M solution in THF, 0.28 mmol, ex ALDRICH) was added, dropwise, to a magnetically
stirred solution of the acid 19 (100 mg, 0.28 mmol) in Et2O (4 mL) maintained under a nitrogen
atmosphere at 0 °C. The resulting mixture was allowed to warm to room temperature and stirred for a
further 1 h then cooled and treated sequentially with water (2 mL), NaOH [2 mL of a 10% (w/v) aqueous
solution] and water (5 mL). The resulting precipitate was filtered off and the solids thus retained were
washed successively with Et2O (1 $ 50 mL) and hot CHCl3 (1 $ 25 mL). The combined filtrates were then
dried, filtered and concentrated under reduced pressure to give a light-yellow oil. Subjection of this
material to flash chromatography (silica, 1:4 v/v EtOAc/hexane elution) gave, after concentration of the
appropriate fractions (Rf 0.4), the title alcohol 20 (63 mg, 66%) as a clear, colorless oil, [!]D +6.4 (c 1.6);
1H NMR (300 MHz, CDCl3): # 5.20 (d, J 9.2 Hz, 1H), 3.83 (m, 1H), 3.53–3.47 (complex m, 2H), 3.44 (s,
3H), 2.80 (t, J 5.7 Hz, 1H), 2.58–2.55 (complex m, 1H), 2.10–2.03 (complex m, 1H), 1.87–1.80 (complex
m, 2H), 1.62 (s, 3H), 1.52 (br s, 1H), 1.12 (d, J 6.2 Hz, 3H), 0.92 (d, J 6.7 Hz, 3H), 0.87 (d, J 6.9 Hz, 3H),
0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (75.5 MHz, CDCl3): # 132.0 (C), 130.8 (CH), 89.7 (CH), 70.1 (CH),
68.6 (CH2), 60.9 (CH3), 44.4 (CH2), 33.7(2) (CH), 33.6(9) (CH), 26.0 (CH3), 20.1 (CH3), 18.1 (C), 16.9
(CH3), 16.1 (CH3), 15.4 (CH3), !4.5(6) (CH3), –4.6(0) (CH3); IR (KBr): !max 3337, 2957, 2930, 1461,
1384, 1255, 1093, 834, 775 cm!1; MS (70 eV): m/z (%): 344 (1) [M]+•, 312 (1), 287 (2) [M–C4H9•]+, 255

HETEROCYCLES, Vol. 85, No. 12, 2012
2971
(12), 203 (82), 159 (58), 133 (56), 89 (75), 73 (100); HRMS (EI): m/z calcd for C19H40O3Si [M]+•:
344.2747; found: 344.2750.
(2S,6S,7R,8R,5E)-8-(tert-Butyldimethylsiloxy)-7-methoxy-2,4,6-trimethyl-4-nonenal (21): The Dess–
Martin periodinane (90 mg, 0.22 mmol) was added to a magnetically stirred solution of alcohol 20 (51 mg,
0.15 mmol) in CH2Cl2 (1.5 mL) maintained at 18 °C under a nitrogen atmosphere. Stirring was continued
for 0.75 h then the reaction mixture was diluted with Et2O (2 mL), NaHCO3 (2 mL of a saturated aqueous
solution) and Na2S2O3 (2 mL of a 1 M aqueous solution) and stirring was continued until two clear layers
were observed. The separated aqueous layer was extracted with Et2O (2 $ 15 mL) and the combined
organic fractions were then dried, filtered and concentrated under reduced pressure to give a light-yellow
oil. Subjection of this material to flash chromatography (silica, 1:4 v/v EtOAc/hexane elution) gave, after
concentration of the appropriate fractions (Rf 0.7), the title compound 21 (31 mg, 62%) as a clear,
colorless oil. 1H NMR (300 MHz, CDCl3): # 9.61 (d, J 2.3 Hz, 1H), 5.22 (d, J 9.3 Hz, 1H), 3.83 (m, 1H),
3.43 (s, 3H), 2.80 (t, J 5.5 Hz, 1H), 2.59–2.38 (complex m, 3H), 2.04–1.94 (complex m, 1H), 1.61 (s, 3H),
1.11 (d, J 6.7 Hz, 3H), 1.04 (d, J 7.0 Hz, 3H), 0.91 (d, J 6.6 Hz, 3H), 0.90 (s, 9H), 0.06 (s, 6H).
This compound is unstable and was not, therefore, subjected to full characterization but, rather,
immediately subjected to the next step of the reaction sequence.
Methyl 2-{(2R,5S,6S)-6-[(E)-4-(diphenylphosphoryl)but-2-en-2-yl]-5-methyltetrahydro-2H-pyran-
2-yl}acetate (3): The title compound was prepared from 4-penten-1-ol (22, ex ALDRICH) using the
reaction sequence shown in Scheme 4 and according to a previously published procedure.13d The material
obtained by this means was identical, an all respects, with an authentic sample.
Methyl (2S,3S,6R)-{[1E,3E,7E,11R,10R,9R,5S]-11-tert-butyldimethylsiloxy-10-methoxy-1,5,7,9-
tetramethyldodeca-1,3,7-trienyl}-3-methyloxan-6-yl}ethanoate (33) and methyl (2S,3S,6R)-
{[1E,3E,7E,11R,10R,9R,5R]-11-tert-butyldimethylsiloxy-10-methoxy-1,5,7,9-tetramethyldodeca-1,3,7-
trienyl]-3-methyl-oxan-6-yl}ethanoate: A solution of phosphine oxide 3 (62 mg, 0.15 mmol) in THF (2
mL) was added, via syringe, to a magnetically stirred suspension of NaH (60 mg of a 35% w/w dispersion
in mineral oil, 1.5 mmol) in anhydrous THF (10 mL) maintained under a nitrogen atmosphere. The
resulting mixture was stirred at room temperature for 0.5 h and then treated with compound 21 (50 mg,
0.15 mmol). The reaction mixture was then heated to 55 °C and stirring was continued for 2 h. The cooled
reaction mixture was then poured onto crushed ice and the resulting melt was acidified with concentrated
HCl to pH~2–3. The mixture thus obtained was extracted with Et2O (3 $ 20 mL) and the combined
organic extracts were then dried, filtered and concentrated under reduced pressure to give a clear,
colorless oil. This material was treated with diazomethane (8 mL of a 0.35 M solution in Et2O, 2.8 mmol)
at 0 °C and the resulting mixture was allowed to warm to room temperature and left stirring for 0.5 h. The
light-yellow solution thus obtained was poured into water (10 mL) and extracted with Et2O (3 $ 10 mL).

2972
HETEROCYCLES, Vol. 85, No. 12, 2012
The combined organic extracts were then dried, filtered and concentrated under reduced pressure to give a
pale-yellow oil. This material was subjected to semi-preparative HPLC (2,3-propanediol column, 1:99 v/v
MTBE/hexane elution, flow rate 2 mL/min) and two fractions A and B were obtained.
Concentration of fraction A (Rt 30 min) afforded the title compound 33 (30 mg, 38%) as a clear, colorless
1
oil, [!]D +0.35 (c 2.3); H NMR (300 MHz, CDCl3): # 6.24–6.13 (complex m, 1H), 5.92–5.87 (complex
m, 1H), 5.55 (m, 1H), 5.13 (m, 1H), 3.86–3.72 (complex m, 2H), 3.66 (s, 3H), 3.44 (s, 3H), 3.32 (d, J 9.7
Hz, 1H), 2.80–2.75 (complex m, 1H), 2.65–2.48 (complex m, 2H), 2.38 (m, 2H), 2.07–1.95 (complex m,
1H), 1.93–1.76 (complex m, 2H), 1.70 (s, 3H), 1.58 (s, 3H), 1.55–1.20 (complex m, 4H), 1.12 (d, J 6.4
Hz, 3H), 0.95 (d, J 6.7 Hz, 3H), 0.93 (partially obscured m, 3H), 0.90 (s, 9H), 0.68 (d, J 6.5 Hz, 3H), 0.06
(s, 6H); 13C NMR (75.5 MHz, CDCl3): # 171.9 (C), 140.6 (CH), 134.1 (C), 131.5 (C), 130.8 (CH), 128.5
(CH), 123.8 (CH), 90.5 (CH), 89.8 (CH), 73.8 (CH), 70.1 (CH), 60.8 (CH3), 51.5 (CH3), 47.5 (CH2), 41.3
(CH2), 35.1 (CH), 33.7 (CH), 32.3 (CH2), 32.1 (CH), 31.6 (CH2), 26.0 (CH3), 20.2 (CH3), 20.1 (CH3), 18.1
(C), 17.7 (CH3), 16.2, (CH3), 15.5 (CH3), 12.0 (CH3), –4.6(0) (CH3) (one signal obscured or overlapping);
IR (KBr): !max 2954, 1743, 1455, 1254, 1197, 1067, 834, 775 cm!1; MS (70 eV): m/z (%): 550 (22) [M]+•,
493 (2), 449 (7), 347 (6), 265 (98), 203 (100), 159 (40), 133 (32), 95 (48), 73 (70); HRMS (EI): m/z calcd
for C32H58O5Si [M]+•: 550.4054; found: 550.4060.
Concentration of fraction B (Rt 26 min) afforded methyl (2S,3S,6R)-{[1E,3E,7E,11R,10R,9R,5R)-11-tert-
butyldimethylsiloxy-10-methoxy-1,5,7,9-tetramethyldodeca-1,3,7-trienyl]-3-methyloxan-6-yl}ethanoate
(20 mg, 25%) as a clear, colorless oil. 1H NMR (300 MHz, CDCl3): # 6.24–6.10 (complex m, 1H), 5.90 (d,
J 11.0 Hz, 1H), 5.60 (dd, J 15.1 and 7.3 Hz, 1H), 5.13 (d, J 9.5 Hz, 1H), 3.84–3.74 (complex m, 2H), 3.66
(s, 3H), 3.43 (s, 3H), 3.31 (d, J 9.8 Hz, 1H), 2.80–2.74 (complex m, 1H), 2.64–2.51 (complex m, 2H),
2.44–2.36 (complex m, 2H), 2.07–2.00 (complex m, 1H), 1.95–1.81 (complex m, 2H), 1.70 (s, 3H), 1.58
(br s, 3H), 1.57–1.20 (complex m, 4H), 1.12 (d, J 6.4 Hz, 3H), 0.93 (d, J 3.9 Hz, 3H), 0.91 (d, J 4.1 Hz,
3H), 0.90 (s, 9H), 0.69 (d, J 6.6 Hz, 3H), 0.06 (s, 6H); 13C NMR (75.5 MHz, CDCl3): # 171.9 (C), 140.7
(CH), 134.2 (C), 131.5 (C), 130.9 (CH), 128.4 (CH), 123.7 (CH), 90.8 (CH), 89.7 (CH), 73.8 (CH), 70.1
(CH), 60.9 (CH3), 51.5 (CH3), 47.5 (CH2), 41.3 (CH2), 34.8 (CH), 33.7 (CH), 32.3 (CH2), 32.2 (CH), 31.6
(CH2), 26.0 (CH3), 20.2 (CH3), 19.5 (CH3), 18.1 (C), 17.7 (CH3), 16.2, (CH3), 15.5 (CH3), 12.3 (CH3), –
4.60 (CH3) (two overlapping peaks); IR (KBr): !max 2954, 1743, 1455, 1254, 1197, 1067, 834, 775 cm!1;
UV (methanol): $max (%) 239 (21,080) nm; MS (70 eV): m/z (%): 550 (40) [M]+•, 493 (2), 449 (11), 347
(10), 265 (90), 203 (100), 159 (50), 133 (42), 95 (56), 73 (74), 59 (22); HRMS (EI): m/z calcd for
C32H58O5Si [M]+•: 550.4054; found: 550.4049.
Methyl (2S,3S,6R)-{[1E,3E,7E,11R,10R,9R,5S)-11-hydroxy-10-methoxy-1,5,7,9-tetramethyldodeca-
1,3,7-trienyl]-3-methyloxan-6-yl}ethanoate (34): Tetra-n-butylammonium fluoride (61 µL of a 1 M
solution in THF, 61 µmol) was added, dropwise, to a magnetically stirred solution of the compound 33

HETEROCYCLES, Vol. 85, No. 12, 2012
2973
(23 mg, 0.04 mmol) in THF (2 mL) maintained at 0 °C under a nitrogen atmosphere. The resulting
mixture was allowed to warm to room temperature and stirred for a further 6 h then water (5 mL) was
added and the phases separated. The aqueous layer was extracted with CH2Cl2 (3 $ 10 mL) and the
combined organic phases were washed with brine (1 $ 5 mL) then dried, filtered and concentrated under
reduced pressure to give a light-yellow oil. Subjection of this material to flash chromatography (silica, 3:7
v/v EtOAc/hexane elution) gave, after concentration of the appropriate fractions (Rf 0.4), the title
compound 34 (12 mg, 68%) as a clear, colorless oil. 1H NMR (300 MHz, CDCl3): # 6.23–6.13 (complex
m, 1H), 5.92–5.88 (complex m, 1H), 5.60–5.50 (complex m, 1H), 5.00–4.95 (complex m, 1H), 3.80–3.70
(complex m, 2H), 3.66 (s, 3H), 3.50 (s, 3H), 3.32 (d, J 9.7 Hz, 1H), 2.72–2.56 (complex m, 3H), 2.43–
2.36 (complex m, 2H), 2.10–1.80 (complex m, 3H), 1.70 (s, 3H), 1.61 (s, 3H), 1.57–1.23 (complex m,
4H), 1.19 (d, J 6.5 Hz, 3H), 0.95 (d, J 6.5 Hz, 3H), 0.69 (m, 6H) (signal due to OH group proton not
observed).
Methyl (2S,3S,6R)-{[1E,3E,11R,10R,9R,8R,7R,5S)-7,8-epoxy-11-hydroxy-10-methoxy-1,5,7,9-
tetramethyldodeca-1,3-dienyl]-3-methyloxan-6-yl}ethanoate
(35)
and
methyl
(2S,3S,6R)-
{[1E,3E,11R,10R,9R,8S,7S,5S)-7,8-epoxy-11-hydroxy-10-methoxy-1,5,7,9-tetramethyldodeca-1,3-
dienyl]-3-methyloxan-6-yl}ethanoate: A magnetically stirred solution of compound 34 (20 mg, 0.047
mmol) in anhydrous CH2Cl2 (0.4 mL) maintained at –8 °C (cryobath) under a nitrogen atmosphere was
treated with vanadyl bis(acetylacetonate) (0.12 mg, 0.5 µmol) then a solution of tert-butyl hydroperoxide
(TBHP) (28 µL of a 5.0 M solution in decane, 0.14 mmol) in anhydrous CH2Cl2 (0.4 mL) added via a
syringe pump over 48 h. After the complete addition of the stoichiometric oxidant the colorless solution
was allowed to stir for a further 24 h at –8 °C. After this time the reaction mixture was diluted with Et2O
(5 mL) and water (5 mL) and the layers shaken well and then separated. The aqueous phase was then
extracted with CH2Cl2 (3 $ 5 mL) and the combined organic extracts were washed with brine (1 $ 5 mL)
then dried before being filtered and concentrated under reduced pressure. The resulting yellow oil was
subjected to semi-preparative HPLC (2,3-propanediol column, 1.5:8.5 v/v MTBE/hexane elution, flow
rate 1 mL/min) and two fractions, A and B, were obtained.
Concentration of fraction A (Rt 35 min) afforded compound 35 (13 mg, 63%) as a clear, colorless oil,
[!]D +1.3 (c 0.2) {lit.7 [!]D +0.9 (c 0.7, CHCl3)}; 1H NMR (300 MHz, CDCl3): # 6.23 (dd, J 15.3 and 10.6
Hz, 1H), 5.90 (d, J 10.6 Hz, 1H), 5.43 (dd, J 15.3 and 8.8 Hz, 1H), 3.86–3.77 (complex m, 1H), 3.76–
3.75 (complex m, 1H), 3.66 (s, 3H), 3.54 (s, 3H), 3.32 (d, J 9.8 Hz, 1H), 2.97 (t, J 5.4 Hz, 1H), 2.63–2.54
(complex m, 2H), 2.43–2.36 (complex m, 2H), 1.92 (dd, J 13.7 and 4.7 Hz, 1H), 1.86–1.81 (complex m,
1H), 1.70 (s, 3H), 1.67–1.56 (complex m, 3H), 1.54–1.30 (complex m, 3H), 1.28 (s, 3H), 1.18 (d, J 6.4
Hz, 3H), 1.04 (d, J 6.7 Hz, 3H), 0.87 (d, J 6.7 Hz, 3H), 0.66 (d, J 6.6 Hz, 3H) (signal due to OH group
13
proton not observed); C NMR (75.5 MHz, CDCl3): # 171.8 (C), 139.2 (CH), 135.2 (C), 128.1 (CH),

2974
HETEROCYCLES, Vol. 85, No. 12, 2012
125.2 (CH), 90.6 (CH), 87.6 (CH), 73.8 (CH), 68.2 (CH), 66.0 (CH), 61.4 (CH3), 61.3 (C), 51.6 (CH3),
46.9 (CH2), 41.3 (CH2), 35.3 (CH), 35.2 (CH), 32.2 (CH2), 32.0 (CH), 31.6 (CH2), 22.1 (CH3), 19.0 (CH3),
17.6 (CH3), 16.5 (CH3), 11.9 (CH3), 11.9 (CH3); IR (KBr): !max 3454, 2917, 2849, 1738, 1455, 1068, 756
cm–1; UV (methanol): $max (%) 246 (21,000) nm; MS (70 eV): m/z (%): 452 (10) [M]+•, 434 (4), 351 (4),
305 (4), 278 (12), 265 (12), 237 (5), 197 (14), 169 (58), 157 (50), 129 (100), 95 (84), 69 (66); HRMS
(EI): m/z calcd for C26H44O6 [M]+•: 452.3138; found: 452.3137.
Concentration of fraction B (Rt 36 min) afforded trace amounts (<0.5 mg) of a light-yellow oil that is
tentatively identified as methyl (2S,3S,6R)-{[1E,3E,11R,10R,9R,8S,7S,5S)-7,8-epoxy-11-hydroxy-10-
methoxy-1,5,7,9-tetramethyldodeca-1,3-dienyl]-3-methyloxan-6-yl}ethanoate, the diastereoisomer of
herboxidiene methyl ester.
ACKNOWLEDGEMENTS
We thank the Institute of Advanced Studies (ANU) and Dunlena Pty Ltd for financial support. RP is the
grateful to the Australian Research Council for the provision of an APA(I) Scholarship.
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