The total synthesis of pamamycin-607. Part 2: Synthesis of the C6-C18 domain

Article abstract of DOI:10.1016/j.tet.2006.01.005

Synthesis of the C6-C18 domain of pamamycin-607 was achieved in ten steps and 7% overall yield from commercially available d-norvaline. The key asymmetric transformations included a Paterson anti aldol addition, an anti selective reduction of the resultan

Full text of DOI:10.1016/j.tet.2006.01.005

Tetrahedron 62 (2006) 2857–2867
The total synthesis of pamamycin-607. Part 2:
Synthesis of the C6–C18 domain
Benjamin H. Fraser,a Roger J. Mulderb and Patrick Perlmuttera,
*
aSchool of Chemistry, Monash University, PO Box 23, Victoria 3800, Australia
bCSIRO Molecular Science, Bag 10 Clayton South, Victoria 3169, Australia
Received 12 October 2005; revised 28 November 2005; accepted 5 January 2006
Available online 7 February 2006
Abstract—Synthesis of the C6–C18 domain of pamamycin-607 was achieved in ten steps and 7% overall yield from commercially available
D-norvaline. The key asymmetric transformations included a Paterson anti aldol addition, an anti selective reduction of the resultant
b-hydroxy ketone and a cis selective Bartlett type ring closure.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
structurally similar to the ionophore nonactin, pamamycin is
incapable of transporting cations from aqueous to organic
phases, but instead transports anions such as permanganate
(MnOK4 ) and dichromate (Cr2O27K) from aqueous (pHw5)
to organic phases.5–8 An interesting application of this was
Grafe’s demonstration of pamamycins capacity to transport
drug molecules through the membranes of pathogenic
bacteria.9 In addition to antibiotic activity, the pamamycins
also show autoregulatory activity by disrupting calcium ion
accumulation and affecting aerial mycelium growth in
S. alboniger.8
Pamamycin-607 1 (Scheme 1) is a member of a group of
homologous naturally-occurring macrodiolides first isolated
by Marumo from Streptomyces alboniger and Streptomyces
aurantiacus.1,2 Structurally, the interesting features include
a 16-member macrodiolide and three cis-2,5-disubstituted
tetrahydrofurans with adjacent methyl substituted stereo-
genic centres. Biologically, they show strong antibiotic
activity against Cochliobolus miyaneanus and Diaporthe
citri, but more importantly show potent activity against
multiple antibiotic resistant strains of Mycobacterium
tuberculosis.3 Interestingly, this activity is due to their
ability to inhibit adenine and uracil uptake.4 Although
The aforementioned biological properties and complex
stereochemistry make pamamycin-607 1 an interesting
NHCbz
OBn OH
13
6
O
18
15
O
6
NMe
2
H
H
O
O
H
H
O
18
C6–C18 domain 3
H
H
H
O
11'
H
1'
O
O
OH
8'
H
OMe
11'
pamamycin-607 1
H
O
1'
10'
O
C1'–C11' domain 2
Scheme 1. The C6–C18 (3) and C10–C110 2 domains of pamamycin-607 (1).
Keywords: Tetrahydrofuran; Cyclisation; anti Aldol; Pamamycin; Stereoselective.
*
Corresponding author. Tel.: C61 3 9905 4593; fax: C61 3 9905 4597; e-mail: patrick.perlmutter@sci.monash.edu.au
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.005

2858
B. H. Fraser et al. / Tetrahedron 62 (2006) 2857–2867
Previous work - established allylic oxygen control
OTBDPS
OTBDPS
OTBDPS
Electrophile (E)
+
OH
O
O
H
H
H
H
H
E
E
major
minor
This work - proposed allylic nitrogen control
NHCBz
13
NHCBz
NHCBz
Electrophile (E)
13
13
+
18
15
15
15
OH
O
O
H
E
H
H
H
H
E
major
minor
Scheme 2. Intramolecular electrophilic cyclisation of alkenes bearing a remote allylic heteroatom.
and challenging target for total synthesis, and indeed, so far
four groups have reported total syntheses.10–13 Towar0ds that
goal we previously reported a synthesis of the C1 –C110
2. Results and discussion
The synthesis began with the preparation of ring closure
precursors 12a and 12b and was achieved in seven steps
from commercially available D-norvaline 4 (Scheme 3).
Treatment of D-norvaline 4 with benzylchloroformate/NaH
gave CBz-D-norvaline 5b, whilst the Boc analogue 5a was
obtained from a commercial supplier. Subsequent DIBAL-
H reduction of the corresponding methyl esters 6a and 6b
gave aldehydes 7a and 7b from which Wittig chain
extension followed by DIBAL-H reduction afforded
alkenals 9a and 9b in good yield and high Z:E selectivity
(95:5, 96:4, respectively). Both aldehydes then underwent
highly diastereoselective anti aldol addition with the
(E)-enolate 10 of Paterson’s chiral ketone 10a16 to afford
diastereomerically pure aldols 11a and 11b after chroma-
tography. The stereochemical assignment of 11a and 11b
was consistent with literature precedent, and the J2,3
coupling constants of 7.0, 7.1 Hz, respectively, are within
the expected 7–9 Hz range for anti aldol adducts.17 A final
anti-selective reduction under Evans’ conditions gave ring
closure precursors 12a and 12b with excellent diastereo-
selectivity (both 12:1).18,19
domain 2.14 Herein, we report our synthesis of the C6–C18
domain 3 of pamamycin-607 1.
Unlike other approaches, in our planned route to pama-
mycin-607 1 the C15 allylic nitrogen was intended to be
present throughout the synthesis, obviating the need for
stereocontrolled introduction of nitrogen late in the
synthesis. We envisaged applying an intramolecular
electrophilic cyclisation reaction to form the key cis 2,5-
disubstituted tetrahydrofuran moiety 0in a similar manner
to that used to prepare the C10–C11 domain fragment 2
(Scheme 2).14 It was anticipated that the C15 allylic
nitrogen would influence the stereochemistry of the newly
formed C13 centre, consistent with our previous work on
related allylic oxygen systems.15
The diastereoselectivity of electrophilic cyclisations
of alkenes bearing a remote protected allylic amine
(Scheme 2) was not known at the beginning of this
investigation and some preliminary results of our studies
are included in this report.
Scheme 3. Synthesis of cyclisation precursors 12a and 12b. Reagents and conditions: (i) NaH, BnO2CCl, DMF, 3 h, 100%; (ii) CH2N2, Et2O, 0 8C, 1 h, 6a
100%, 6b 100%; (iii) DIBAL-H, toluene, K78 8C, 3 h; 7a 78%, 7b 97%; (iv) BrPh3P(CH2)3CO2Et, NaN(TMS)2, THF, 0 8C, 1 h; 8a 75%, 8b 78%; (v) DIBAL-
H, toluene, K78 8C, 3 h; 9a 85%, 9b 91%; (vi) 10, ether, K78 8C, 2 h, K20 8C, o/n; 11a 60%, 11b 85%; (vii) Me4NBH(OAc)3, 1:1 AcOH/MeCN, K20 8C,
4 h, 12a 68%, 12b 78%.

B. H. Fraser et al. / Tetrahedron 62 (2006) 2857–2867
2859
OBn OH
NHBoc
OBn OH
NHBoc
(i)
12a
+
3
3
O
O
H
H
H
H
HgCl
HgCl
13a
Scheme 4. Cyclisation of diol 12a. Reagents and conditions: (i) Hg(OAc)2, MeCN, 0 8C, 3 h; 92%.
13b
Investigation of electrophilic intramolecular cyclisations
began with Boc diol 12a (Scheme 4). Treatment with
Hg(OAc)2 at 0 8C in MeCN15 gave a 10:1 mixture of
trans-13a to cis-13b. Attempts to decrease or reverse this
selectivity by decreasing reaction temperature were
unsuccessful as reaction temperatures below 0 8C gave
slow and impractical reaction rates. The use of the
alternative electrophiles iodine and phenylselenium
bromide was also unsuccessful and resulted in a complex
mixture of inseparable products.
followed immediately by DIBAL reduction to give
aldehyde 17, which then underwent aldol addition to yield
adduct 18. A final anti-selective reduction afforded
precursor 19 in good yield (Scheme 6).
However, treatment of 19 with Hg(OAc)2 in acetonitrile at
0 8C, again favoured the undesired trans-tetrahydrofuran
20a over cis-20b, albeit with slightly improved (1:6)
diastereoselectivity.
As forming the desired cis stereochemistry was proving
difficult, we explored Bartlett’s method for cis selective
formation of 2,5-disubstituted tetrahydrofurans.21 A similar
approach was used by Kang, in their a total synthesis of
pamamycin-607, which involved an iodine promoted
cyclisation of a TES ether bearing a remote allylic oxygen
substituent.11 We first explored cyclisation of the TBS ether
23 derivative, which was easily prepared by treatment of
diol 12b with TBSOTf (Scheme 7).
In order to establish if the C3 alcohol was playing any
role in the observed trans selectivity, cyclisation of aldol
adduct 11a was carried out (Scheme 5). Treatment of 11a
with Hg(OAc)2 in acetonitrile gave a 9:1 mixture of trans
chloromercurial 14a to cis chloromercurial 14b.
A similar result was obtained with PhSeBr where trans-
tetrahydrofuran 15a was favoured (5:1) over cis-tetra-
hydrofuran 15b (Scheme 5). These results suggested that
the C3 hydroxy was not an important factor in the observed
trans selectivity.
Subsequent iodocyclization of 23 proceeded in favour of
trans-tetrahydrofuran 24. This result may be due to cleavage
of the TBS group being faster than the subsequent
cyclization reaction. In an effort to reverse this result, the
alternative electrophile Hg(O2CCF3)2 was utilized with
bis-TBS ether 23 in light of promising cis-selective
oxymercurations of bis-TBS ethers reported by Walkup
and co-workers.22 Subsequent cyclisation of bis-TBS 23
Our previous work had shown the diastereoselectivity
of this type of cyclisation was diminished for (E)-alkene
substrates.15 In an effort to reverse or suppress the
trans-selectivity, (E)-alkene cyclisation precursor 19 was
prepared by alkene isomerisation20 of (Z)-ester 8a. This was
OBn O
NHBoc
OBn O
NHBoc
(i) or (ii)
11a
+
O
O
H
H
H
H
E
E
14a E = HgCl
15a E = PhSe
14b = HgCl
15b = PhSe
Scheme 5. Cyclisation of aldol adduct 11a. Reagents and conditions: (i) Hg(OAc)2, MeCN, 0 8C, 2 h; 73%; (ii) PhSeBr, DCM, K78 8C, 2 h, 52%.
O
OBn O
OBn OH
(i–ii)
(iii)
(iv)
8a
H
OH
OH
BocHN
BocHN
BocHN
17 10:1 Z:E
18
19
OBn OH
NHBoc
OBn OH
NHBoc
19
+
O
O
H
H
H
H
HgCl
HgCl
20a
20b
Scheme 6. Synthesis and cyclisation of (E)-diol 19. Reagents and conditions: (i) Ph2S2, benzene, hy, 2 days, (7:1 E/Z); (ii) DIBAL-H, toluene, K78 8C, 3 h,
(10:1 E/Z); 51% over two steps; (iii) enolate 10, ether, K78 8C, 2 h, K20 8C, o/n, 50%; (iv) Me4NBH(OAc)3, 1:1 AcOH/MeCN, K20 8C, 4 h, 92%;
(v) Hg(OAc)2, MeCN, 0 8C, 5 h, 60%.

2860
B. H. Fraser et al. / Tetrahedron 62 (2006) 2857–2867
NHCBz
OBn OTBS
NHCBz
NHCBz
OBn OH
12b
(i)
(ii)
O
OTBS
H
H
I
23
24
NHCBz
OBn OH
OBn OH
23
(iii)
(iv)
O
O
H
H
H
H
HgCl
3
25
Scheme 7. Synthesis and cyclisation of ether 23. Reagents and conditions: (i) TBSOTf, 2,6-lutidine, THF, 0 8C, 4 h, 69%; (ii) I2, NaHCO3, MeCN, 0 8C, 3 h,
69%; (iii) Hg(O2CCF3)2, DCM, K78 8C, 6 h, NaCl (satd), 51%; (iv) Bu3SnH, AIBN, toluene, 60 8C, 3 h, 79%.
with Hg(O2CCF3)2 in MeCN afforded cis tetrahydrofuran
25 in a 4:1 diastereoselectivity and moderate 48% yield. The
cis-tetrahydrofuran stereochemistry was assigned by obser-
vation of an NOE between H2 and H5 of 25. Removal of the
chloromercurial group by treatment with tributylstannane
and AIBN afforded the C6–C18 domain 3 in overall 7%
yield from D-norvaline.
residual CHCl3 (7.26 ppm) signal as an internal reference.
Each resonance was reported according to the following
convention: chemical shift (d ppm) [multiplicity, coupling
constant(s) (Hz), number of hydrogens. Multiplicities are
designated as sZsinglet, dZdoublet, tZtriplet, qZquartet,
pZpentuplet and mZmultiplet. Carbon NMR (13C NMR)
were recorded at 75 MHz on a Varian Mercury spectrometer
or Bruker AM 300 spectrometer using deuterochloroform
(CDCl3) unless otherwise stated. The spectra were
referenced using the solvent carbon signal (CDCl3Z
77.16 ppm). 2D NMR techniques such as homonuclear
correlation spectroscopy (COSY), heteronuclear multiple
quantum coherence (HMQC), heteronuclear multiple bond
coherence (hmbc) and nuclear Overhauser effect spec-
troscopy (NOESY) were used to aid assignment of some
NMR spectra. Mass spectrometry (ESI) was performed on a
Micromass Platform QMS spectrometer. High-resolution
mass spectra (HRMS) were recorded on a Bruker BioApex
47e FTMS using NaI for accurate mass calibration. MC
refers to the molecular ion infrared spectra (IR) were
recorded on a Perkin Elmer 1600 Series Fourier Transform
spectrometer as neat solutions, chloroform (CHCl3)
solutions or as paraffin (Nujol) mulls of solids between
NaCl plates. Melting points were recorded on a Kofler hot
stage apparatus and are uncorrected.
3. Conclusions
The combination of a Paterson aldol addition and anti-
selective b-hydroxy ketone reduction has provided a very
efficient and highly diastereoselective means for installing
the four C7–C10 stereogenic centres of Pamamycin-607. A
Bartlett type ring closure, using a Hg(CO2CF3)2 electrophile
reversed what appeared a highly trans-selective ring closure
by providing a 4:1 cis selectivity. Further work is currently
underway on the C1–C6 domain in our laboratories to
complete our total synthesis of Pamamycin-607.
4. Experimental
4.1. General
Most chemicals were purchased from the Aldrich Chemical
Company (Sydney, Australia) and were used as supplied.
D-norvaline and Boc-D-norvaline were purchased from
Novabiochem. Drying agents and inorganic salts were
purchased from AJAX or BDH chemicals. Solvents were
purified as follows. Anhydrous diethyl ether was distilled
from sodium/benzophenone ketyl prior to use. Dichloro-
methane (DCM) was distilled from calcium hydride.
Hexanes were distilled prior to use and refer to the fraction
boiling between 40–60 8C. Silica gel used for chromato-
graphy was 40–63 mm (230–400 mesh) silica gel 60 (Merck
No. 9385). Analytical thin-layer chromatography (TLC)
was performed on Polygram Sil G/UV254 plastic sheets
coated with silica gel containing UV254 fluorescent indicator
and visualized under UV light and/or dipped in an
ammonium molybdate/cerium sulphate solution. Proton
NMR (1H NMR) spectra were recorded at 300 MHz on a
Varian Mercury spectrometer or Bruker AM 300 spec-
trometer and 400 MHz on a Bruker Avance DRX 400
spectrometer. Chemical shifts were recorded on the d scale
in parts per million (ppm). Unless otherwise stated, spectra
were measured in deuterochloroform (CDCl3) using the
4.1.1. (R)-2-Benzyloxycarbonylaminopentanoic acid
(5b). To a solution of D-norvaline (5 g, 42.5 mmol) in
THF (100 mL) at rt was added K2CO3 (29.4 g, 213 mmol)
and benzylchloroformate (14.5 g, 12.1 mL, 85 mmol). The
suspension was stirred o/n before being acidified to pH 1
with 2 M HCl. Ether (100 mL) was added and the organic
phase separated from the aqueous phase, and the aqueous
phase extracted with ether (3!20 mL). The combined
organic extracts were then washed (satd NaHCO3, brine),
dried (MgSO4) and the solvent removed under reduced
pressure to yield the title compound 5b as a colourless oil
(10.7 g, 100%). [a]D22 C19.5 (c 2.58, CHCl3) lit.23 (C14.1,
c 1, MeOH). 1H NMR (300 MHz, CDCl3) d 0.94 (3H, t, JZ
7.2 Hz, CH2CH3), 1.37–1.44 (2H, m, CH2), 1.65–1.85 (2H,
m, CH2), 4.41 (1H, m, CHN), 5.12 (2H, br s, CH2Ph), 5.36
(1H, d, JZ8.2 Hz, NH), 7.26–7.39 (5H, m, ArH).13C NMR
(75 MHz, CDCl3) d 13.7, 18.6, 34.5, 53.7, 67.3, 128.2,
128.3, 128.6, 136.2, 156.2, 177.5. IR (neat) ymax 3329, 3036,
2962, 2875, 1716 (broad), 1587, 1532, 1456, 1416, 1345,
1229, 1106, 1028, 910, 777, 735, 698 cmK1. MS m/z 274.1
(MCNaC). HRMS m/z calcd for C13H17NO4NaCZ
274.1055. Found m/z 274.1049. Anal. Calcd for

B. H. Fraser et al. / Tetrahedron 62 (2006) 2857–2867
2861
C13H17NO4: C, 62.1; H, 6.8; N, 5.6. Found: C, 62.2; H, 6.9;
N, 5.3.
d 0.94 (3H, t, JZ7.2 Hz, CH2CH3), 1.32–1.60 (2H, m,
CH2), 1.43 (9H, s, C(CH3)3), 1.76–1.90 (2H, m, CH2), 4.21
(1H, m, CHN), 5.06 (1H, br s, NH), 9.56 (1H, s, HC]O).
13C NMR (75 MHz, CDCl3) d 14.2, 18.9, 28.6, 31.6, 60.0,
80.2, 155.7, 200.1. IR (neat) ymax 3350, 2964, 2875, 2815,
1720, 1698, 1518, 1458, 1392, 1387, 1252, 1169, 1063,
1017, 876, 782, 740 cmK1. MS m/z 224.2 (MCNaC).
HRMS m/z calcd for C10H19NO3NaCZ224.1263. Found:
m/z 224.1253. Anal. Calcd for C10H19NO3: C, 59.7; H, 9.5;
N, 7.0%. Found: C, 59.8; H, 9.1; N, 7.2%.
4.1.2. Methyl (R)-2-tert-butoxycarbonylaminopentanoate
(6a). Diazomethane (generated from 5 g Diazaldw/satd
KOH) gas was passed through a solution of NBoc protected
norvaline (5 g, 21.6 mmol) in ether (50 mL) at 0 8C. The
solution immediately turned yellow and was allowed to stir
at 0 8C for 1 h. Nitrogen was passed continuously through
the solution until it became colourless, indicating dissipa-
tion of excess diazomethane. The ether was then removed
under reduced pressure to give the title compound 6a as a
colourless oil (5.32 g, 100%). [a]2D2 K2.7 (c 1.68, CHCl3).
1H NMR (300 MHz, CDCl3) d 0.90 (3H, t, JZ7.4 Hz,
CH2CH3), 1.26–1.38 (2H, m, CH2), 1.41 (9H, s, C(CH3)3),
1.46–1.80 (2H, m, CH2), 3.70 (3H, s, CH3 methyl ester),
4.26 (1H, m, CHN), 5.20 (1H, d, JZ7.8 Hz, NH). 13C NMR
(75 MHz, CDCl3) d 14.0, 19.0, 28.6, 35.2, 52.5, 53.5, 80.0,
155.5, 173.6. IR (neat) ymax 3364, 2962, 2876, 1715, 1505,
1455, 1391, 1366, 1304, 1163, 1105, 1055, 1014, 919, 871,
780, 760 cmK1. MS m/z 254.2 (MCNaC). HRMS m/z calcd
for C11H21NO4NaCZ254.1368. Found: 254.1374. Anal.
Calcd for C11H21NO4: C, 57.2; H, 9.2; N, 6.1. Found: C,
57.3; H, 9.4; N, 6.2.
4.1.5. (R)-2-Benzyloxycarbonylaminopentanal (7b). To a
solution of ester 6b (5.50 g, 19.7 mmol) in toluene (120 mL)
cooled to K78 8C was slowly added DIBAL-H (1 M in
toluene, 43.4 mL, 43.4 mmol). Care was taken to ensure
reaction temperature did not exceed K70 8C during
addition. The solution was stirred for 2 h at K78 8C and
was carefully quenched by addition of acetone (10 mL) and
satd NH4Cl (10 mL) whilst again being careful to maintain a
reaction temperature below K70 8C. The solution was then
warmed to rt, filtered, and the solvent removed under
reduced pressure. The resultant crude oil was purified by
flash chromatography (10% EtOAc/hexanes) yielding the
title compound 7b as a colourless oil (4.49 g, 97%). [a]D22
K40.7 (c 2.21, CHCl3). 1H NMR (300 MHz, CDCl3) d 0.94
(3H, t, JZ6.9 Hz, CH2CH3), 1.32–1.91 (4H, m, 2!C8H2),
4.28 (1H, apparent q, JZ7.2 Hz, CHN), 5.01 (2H, s,
CH2Ph), 5.50 (1H, d, JZ6.6 Hz, NH), 7.26–7.35 (5H, m,
ArH), 9.54 (1H, s, HC]O). 13C NMR (75 MHz, CDCl3) d
14.1, 18.8, 31.4, 60.4, 67.4, 128.3, 128.4, 128.7, 136.4,
156.3, 199.6. IR (neat) ymax 3332, 3066, 3033, 2961, 2934,
2874, 1712 (broad), 1521, 1456, 1405, 1381, 1339, 1256,
1179, 1065, 1028, 912, 843, 755, 698, 666 cmK1. MS m/z
257.9 (MCNaC). HRMS m/z calcd for C13H17NO3NaCZ
258.1106. Found: m/z 258.1112. Anal. Calcd for
C13H17NO3: C, 66.4; H, 7.3; N, 6.0%. Found: C, 66.3; H,
7.3; N, 6.1%.
4.1.3. Methyl (R)-2-benzyloxycarbonylaminopentanoate
(6b). Diazomethane (generated from 5 g Diazaldw/satd
KOH) gas was passed through a solution of NCBz protected
norvaline 5b (5 g, 18.9 mmol) in ether (50 mL) at 0 8C. The
solution immediately turned yellow and was allowed to stir
at 0 8C for 1 h. Nitrogen was then passed continuously
through the solution until it became colourless, indicating
dissipation of excess diazomethane. The ether was then
removed under reduced pressure giving pure methyl ester
6b as a colourless oil (5.28 g) in quantitative yield. [a]D22
K2.8 (c 2.75, CHCl3). 1H NMR (300 MHz, CDCl3) d
0.92 (3H, t, JZ7.3 Hz, CH2CH3), 1.31–1.41 (2H, m, CH2),
1.51–2.15 (2H, m, CH2), 3.63 (3H, s, OCH3), 4.37 (1H, m,
CHN), 5.11 (2H, s, CH2Bn CBz), 5.30 (1H, d, JZ7.2 Hz,
NH), 7.27–7.36 (5H, m, ArH). 13C NMR (75 MHz, CDCl3)
d 13.7, 18.6, 34.9, 52.3, 53.8, 67.1, 128.2, 128.6, 128.8,
136.4, 156.0, 173.2. IR (neat) ymax 3342, 3065, 3033, 2880,
2874, 1725, 1714, 1538, 1455, 1380, 1304, 1216, 1170,
1105, 1061, 1027, 911, 778, 740, 698 cmK1. MS m/z 288.1
(MCNaC). HRMS m/z calcd for C14H19NO4NaCZ
288.1212. Found: m/z 288.1216. Anal. Calcd for
C14H19NO4: C, 63.4; H, 7.2; N, 5.3. Found: C, 63.5; H,
7.2; N, 5.5.
4.1.6. Ethyl (4Z)-(6R)-6-tert-butoxycarbonylaminonon-
4-enoate (8a). To a stirred suspension of the triphenylpho-
sphonium salt of ethyl 4-bromobutyrate (23.9 g, 52.2 mmol)
in THF (150 mL) at 0 8C was added, dropwise, sodium
bistrimethylsilylamide (1 M in THF, 52.2 mL, 52.2 mmol).
Stirring continued at 0 8C for 1 h before aldehyde 7a
(3.00 g, 17.4 mmol) in THF (30 mL) was added dropwise
over 10 min. The solution was then stirred at 0 8C for a
further hour, after which time it was diluted with ether
(100 mL) and poured into satd NH4Cl (100 mL). The
organic phase was separated from the aqueous phase and
the aqueous phase extracted with ether (3!50 mL). The
combined organic extracts were washed (brine), dried
(MgSO4), filtered, and the solvent removed under reduced
pressure. The resulting crude yellow oil was subjected to
flash chromatography (20% EtOAc/hexanes) to yield the
title compound 8a as a colourless oil (3.91 g, 75%). [a]D22
K19.2 (c 1.34, CHCl3). 1H NMR (300 MHz, CDCl3) d 0.87
(3H, t, JZ6.9 Hz, CH2CH3), 1.21 (3H, t, JZ7.2 Hz,
CH2CH3 ethyl ester), 1.26–1.53 (4H, m, 2!CH2), 1.39
(9H, s, C(CH3)3), 2.28–2.46 (4H, m, 2!CH2), 4.06 (2H, q,
JZ7.2 Hz, CH2CH3 ethyl ester), 4.28 (1H, m, CHN), 4.45
(1H, br s, NH), 5.18 (1H, apparent t, JZ9.9 Hz, HC]C),
5.40 (m, 1H, C]CH). 13C NMR (75 MHz, CDCl3) d 14.3,
14.6, 19.3, 23.1, 23.5, 28.7, 34.5, 38.5, 60.6, 79.3, 129.8,
4.1.4. (R)-2-tert-Butoxycarbonylaminopentanal (7a). To
a solution of ester 6a (5.32 g, 18.9 mmol) in toluene
(150 mL) cooled to K78 8C was slowly added DIBAL-H
(1 M in toluene, 54 mL, 54 mmol). Care was taken to ensure
the reaction temperature did not exceed K70 8C during
addition. The solution stirred for 2 h at K78 8C and was
carefully quenched by addition of acetone (10 mL) and satd
NH4Cl (10 mL) whilst again being careful to maintain the
reaction temperature below K70 8C. The solution was then
warmed to rt, filtered, and the solvent removed under
reduced pressure. The resultant crude oil was purified by
flash chromatography (10% EtOAc/hexanes) yielding the
title compound 7a as a colourless oil (3.41 g, 78%). [a]D22
K56.9 (c 1.875, CHCl3). 1H NMR (300 MHz, CDCl3)

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B. H. Fraser et al. / Tetrahedron 62 (2006) 2857–2867
132.2, 155.2, 173.1. IR (neat) ymax 3376, 2977, 2933, 2874,
1733, 1714, 1514, 1456, 1391, 1367, 1300, 1246, 1174,
1114, 1078, 1050, 699, 868, 773, 741 cmK1. MS m/z 322.3
(MCNaC). HRMS m/z calcd for C16H29NO4NaCZ
322.1994. Found: m/z 322.1981. Anal. Calcd for
C16H29NO4: C, 64.2; H, 9.8; N, 4.7%. Found: C, 63.7; H,
9.7; N, 4.8%.
2873, 1721, 1694, 1515, 1456, 1392, 1366, 1331, 1246,
1172, 1112, 1080, 1053, 1006, 900, 869, 772 cmK1. MS m/z
278.2 (MCNaC). HRMS m/z calcd for C14H25NO3NaCZ
278.1732. Found: m/z 278.1738. Anal. Calcd for
C14H25NO3: C, 65.9; H, 9.9; N, 5.5%. Found: C, 66.2; H,
10.1; N, 5.5%.
4.1.9. (4Z)-(6R)-6-Benzyloxycarbonylaminonon-4-enal
(9b). DIBAL-H (1 M in toluene, 25 mL, 25 mmol) was
added slowly to a cooled solution of the ester 8b (3.80 g,
11.4 mmol) ensuring the reaction temperature did not
exceed K70 8C. The solution stirred for 2 h at K78 8C
and was then carefully quenched by addition of acetone
(5 mL) and satd NH4Cl (5 mL) whilst again being careful to
maintain a reaction temperature below K70 8C. The
solution was warmed to rt, which induced precipitation of
aluminium salts, was filtered and the solvent removed under
reduced pressure. The resultant crude oil, which was
subjected to flash chromatography (10% EtOAc/hexanes)
to yield the title compound 9b as a colourless oil (3.01 g,
4.1.7. Ethyl (4Z)-(6R)-6-benzyloxycarbonylaminonon-4-
enoate (8b). To a stirred suspension of the triphenylpho-
sphonium salt of ethyl 4-bromobutyrate (20.5 g, 44.7 mmol)
in THF (150 mL) at 0 8C was added, dropwise, sodium
bistrimethylsilylamide (1 M in THF, 44.7 mL, 44.7 mmol).
Stirring continued at 0 8C for 1 h and after which aldehyde
7b (3.50 g, 14.9 mmol) in THF (30 mL) was added
dropwise over 10 min. The solution was then stirred at
0 8C for another hour, after which time it was diluted with
ether (100 mL) and poured into satd NH4Cl (100 mL). The
organic phase was separated from the aqueous phase and the
aqueous phase extracted with ether (3!50 mL). The
combined organic extracts were washed (brine), dried
(MgSO4), filtered, and the solvent removed under reduced
pressure. The resulting crude yellow oil was subjected to
flash chromatography (20% EtOAc/hexanes) to yield the
title compound 8b as a colourless oil (3.80 g, 78%). [a]D22
K33.0 (c 1.55, CHCl3). 1H NMR (300 MHz, CDCl3) d 0.90
(3H, t, JZ7.1 Hz, CH2CH3), 1.24 (3H, t, JZ7.0 Hz,
CH2CH3 ethyl ester), 1.28–1.40 (2H, m, CH2), 1.46–1.58
(2H, m, CH2), 2.28–2.54 (4H, m, 2!CH2), 4.11 (2H, q, JZ
7.2 Hz, CH2CH3 ethyl ester), 4.39 (1H, m, CHN), 4.75 (1H,
br s, NH), 5.07 (2H, br s, CH2Ph), 5.21 (1H, m, HC]C),
5.47 (1H, m, C]CH), 7.26–7.39 (5H, m, ArH). 13C NMR
(75 MHz, CDCl3) d 14.3, 14.6, 19.3, 23.5, 34.5, 36.2, 48.7,
60.7, 66.8, 128.2, 128.4, 128.7, 130.2, 131.7, 136.7, 155.7,
173.1. IR (neat) ymax 3320, 2923, 2853, 1737, 1681, 1539,
1465, 1424, 1374, 1354, 1307, 1266, 1246, 1199, 1175.
1110, 1082, 1050, 1023, 1002, 723, 696 cmK1. MS m/z
356.3 (MCNaC). HRMS m/z calcd for C19H27NO4NaCZ
356.1838. Found: 356.1845. Anal. Calcd for C19H27NO4: C,
68.5; H, 8.2; N, 4.2%. Found: C, 68.8; H, 8.2; N, 4.1%.
1
91%). [a]2D2 K25.6 (c 2.0, CHCl3). H NMR (300 MHz,
CDCl3) d 0.87 (3H, t, JZ7.1 Hz, CH2CH3), 1.24–1.58 (4H,
m, 2!CH2), 2.32–2.60 (4H, m, 2!CH2), 4.38 (1H, m,
CHN), 4.65 (1H, m, NH), 5.06 (2H, br s, CH2Ph), 5.21 (1H,
apparent t, JZ9.9 Hz, HC]C), 5.41 (1H, m, C]CH). 13C
NMR (75 MHz, CDCl3) d 12.9, 18.0, 19.6, 36.9, 42.7, 47.4,
65.7, 127.2, 127.6, 127.9, 128.9, 130.9, 135.7, 154.7, 200.9.
IR (neat) ymax 3358, 1725, 1689 cmK1. MS m/z 312.2
(MCNaC). HRMS m/z calcd for C17H23NO3NaCZ
312.1276. Found: 312.1273. Anal. Calcd for C17H23NO3:
C, 70.6; H, 8.0; N, 4.8%. Found: C, 70.3; H, 8.2; N, 4.7%.
4.1.10. (4E)-(6R)-6-tert-Butoxycarbonylaminonon-4-enal
(17). To a solution of ester 8a (0.50 g, 1.67 mmol) in C6D6
was added Ph2S2 (72 mg, 0.33 mmol). The solution was
then irradiated with UV light for 3 days. Daily monitoring
of the reaction by 1H NMR revealed after 3 days the
isomerisation reaction had reached an equilibrium ratio of
7:1 E/Z alkenes. The solvent was then removed under
reduced pressure and the crude oil passed through a short
plug of silica gel (20% EtOAc/hexanes). The crude product
was immediately dissolved in toluene (50 mL) and cooled to
K78 8C. DIBAL (1 M in toluene, 2.5 mL, 2.5 mmol) was
slowly added ensuring the reaction temperature did not
exceed K70 8C. The solution stirred for 2 h at K78 8C and
was then carefully quenched by addition of acetone (2 mL)
and satd NH4Cl (2 mL) whilist again being careful to
maintain a reaction temperature below K70 8C. The
solution then warmed to rt, which induced precipitation of
aluminium salts, was then filtered and the solvent removed
under reduced pressure giving a crude oil, which was
subjected to flash chromatography (15% EtOAc/hexanes) to
yield the title compound 17 (10:1 E/Z) as a colourless oil
(217 mg, 51%). [a]D22 C6.3 (c 0.95, CHCl3). 1H NMR
(300 MHz, CDCl3) d 0.85 (3H, t, JZ7.2 Hz, CH2CH3),
1.17–1.42 (4H, m, 2!CH2), 1.38 (9H, s, C(CH3)3), 2.28
(2H, dtd, JZ6.4, 5.5, 1.1 Hz, CH2), 2.46 (2H, dt, JZ1.4,
5.5 Hz, CH2), 3.96 (1H, m, CHN), 4.42 (1H, m, NH), 5.32
(1H, ddt, JZ15.4, 6.2, 1.3 Hz, C]CH), 5.52 (1H, dtd, JZ
15.4, 6.3, 1.1 Hz, C]CH), 9.70 (1H, t, JZ1.6 Hz, HC]O).
13C NMR (75 MHz, CDCl3) d 13.8, 19.0, 24.9, 37.7, 28.4,
43.2, 52.1, 79.2, 128.4, 132.5, 155.4, 201.8. IR (neat) ymax
4.1.8. (4Z)-(6R)-6-tert-Butoxycarbonylaminonon-4-enal
(9a). DIBAL-H (1 M in toluene, 21 mL, 21 mmol) was
added slowly to a cooled solution of the ester 8a (2.50 g,
8.35 mmol) in toluene (100 mL) whilst ensuring the
reaction temperature did not exceed K70 8C. The solution
stirred for 2 h at K78 8C and was carefully quenched by
addition of acetone (10 mL) and satd NH4Cl (10 mL) whilst
again being careful to maintain a reaction temperature
below K70 8C. The solution then warmed to rt, which
induced precipitation of aluminium salts, was filtered and
the solvent removed under reduced pressure giving a crude
oil, which was subjected to flash chromatography (10%
EtOAc/hexanes) to yield the title compound 9a as a
colourless oil (1.81 g, 85%). [a]2D2 K16.2 (c 1.86, CHCl3).
1H NMR (300 MHz, CDCl3) d 0.80 (3H, t, JZ7.2 Hz,
CH2CH3), 1.20–1.45 (4H, m, 2!CH2), 1.34 (9H, s,
C(CH3)3), 2.25–2.48 (4H, m, 2!CH2), 4.23 (1H, m,
CHN), 4.48 (1H, d, JZ7.9 Hz, NH), 5.12 (1H, ddq, JZ
10.5, 7.9, 1.3 Hz, HC]C), 5.30 (1H, dt, JZ10.5, 6.8 Hz,
C]CH), 9.65 (1H, d, JZ1.4 Hz, HC]O). 13C NMR
(75 MHz, CDCl3) d 12.8, 17.9, 19.5, 27.3, 37.0, 42.6, 46.6,
80.6, 128.1, 131.3, 154.1, 200.8. IR (neat) ymax 3352, 2963,

B. H. Fraser et al. / Tetrahedron 62 (2006) 2857–2867
2863
3351, 2960, 2932, 2874, 2723, 1715, 1698, 1520, 1456,
1391, 1366, 1248, 1173, 1079, 1053, 1009, 971, 871,
778 cmK1. MS m/z 278.2 (MCNaC). HRMS m/z calcd for
C14H25NO3NaCZ278.1732. Found: m/z 278.1728. Anal.
Calcd for C14H25NO3: C, 65.9; H, 9.9; N, 5.5%. Found: C,
65.8; H, 10.0; N, 5.6%.
698 cmK1. MS m/z 518.3 (MCNaC). HRMS m/z calcd for
C30H41NO5NaCZ518.2882. Found: m/z 518.2885. Anal.
Calcd for C30H41NO5: C, 72.7; H, 8.3; N, 2.8%. Found: C,
72.5; H, 8.4; N, 3.0%.
4.1.13. tert-Butyl (1R,2Z,6R,7R,9R)-(10-benzyloxy-
6-hydroxy-7,9-dimethyl-8-oxo-1-propyl-dec-2-enyl)-
carbamate (11a). The general procedure of Paterson was
followed.16 To a stirred solution of dicyclohexylboronchlor-
ide (11.6 mL, 11.6 mmol, 1 M solution in hexanes) was
added ether (20 mL). The solution was cooled to 0 8C and
ketone 10a (1.49 g, 7.27 mmol) and Et3N (1.81 mL,
12.8 mmol) were added. The solution continued stirring
for 2 h at 0 8C and was then cooled to K78 8C (dry ice/
acetone bath) after which a solution of aldehyde 9a (2.32 g,
9.09 mmol) in ether (10 mL) was added dropwise. The
solution continued stirring at K78 8C for 4 h before being
transferred to a freezer (K20 8C) o/n. After removal from
the freezer, the solution was diluted with methanol (30 mL)
and pH 7 phosphate buffer (30 mL), and cooled to 0 8C.
Hydrogen peroxide (10 mL, 30% aqueous) was then added
dropwise and stirring continued for 3 h at rt. The solution
was then diluted with DCM (50 mL) and the aqueous and
organic phases separated. The aqueous phase was extracted
with DCM (3!30 mL) and the combined organic extracts
were washed (brine), dried (MgSO4) and the solvent
removed under reduced pressure to give a crude oil, which
after flash chromatography (20% EtOAc/hexanes) yielded
the title compound 11a as a colourless oil (2.01 g, 60%).
[a]2D2 K19.1 (c 2.65, CHCl3). 1H NMR (300 MHz, CDCl3) d
0.91 (3H, t, JZ7.1 Hz, CH2CH3), 1.04 (3H, d, JZ7.0 Hz,
CHCH3), 1.08 (3H, d, JZ7.1 Hz, CHCH3), 1.11–1.39 (2H,
m, CH2), 1.39 (9H, s, C(CH3)3), 1.68–1.79 (2H, m, CH2),
1.73–1.95 (2H, m, CH2), 2.10–2.23 (1H, m, one of CH2),
2.35–2.49 (1H, m, one of CH2), 2.75 (1H, dq, JZ7.0,
7.1 Hz, CHCH3), 3.06 (1H, ddq, JZ5.2, 8.9, 7.0 Hz,
CHCH3), 3.43 (1H, dd, JZ5.2, 8.9 Hz, one of CH2OBn),
3.62 (1H, m, CHOH), 3.67 (1H, dd, JZ8.9, 8.9 Hz, one of
CH2OBn), 3.72 (1H, m, OH), 4.33 (1H, m, CHN), 4.42 (1H,
m, NH), 4.44 (1H, d, JZ12.1 Hz, one of OCH2Ph), 4.50
(1H, d, JZ12.1 Hz, one of OCH2Ph), 5.16 (1H, ddt, JZ
10.6, 9.3, 1.3 Hz, HC]C), 5.47 (1H, dt, JZ10.6, 8.0 Hz,
C]CH), 7.25–7.37 (5H, m, ArH). 13C NMR (75 MHz,
CDCl3) d 12.3, 12.6, 12.9, 18.7, 27.5, 29.1, 34.9, 37.9, 39.1,
40.4, 52.8, 72.5, 74.1, 75.7, 79.6, 125.5, 126.7, 126.8, 127.4,
127.8, 136.9, 154.5, 216.3. IR (neat) ymax 3381, 2986, 2933,
2873, 1698, 1498, 1455, 1391, 1366, 1329, 1247, 1172,
1099, 1006, 755, 698, 666 cmK1. MS m/z 484.4 (MCNaC).
HRMS m/z calcd for C27H43NO5NaCZ484.3039. Found:
m/z 484.3031. Anal. Calcd for C27H43NO5: C, 70.3; H, 9.4;
N, 3.0%. Found: C, 70.6; H, 9.2; N, 3.1%.
4.1.11. (R)-1-Benzyloxy-2-methylpentan-3-one (10a). The
known three-step procedure of Paterson and co-workers was
followed and yielded the title compound 10a as a colourless
oil (8.78 g, 63% over three steps).24 [a]D22 K26.7 (c 8.0,
1
CHCl3) lit.24 (K25.8, c 8.2, CHCl3). H NMR (300 MHz,
CDCl3) d 1.06 (3H, t, JZ7.6 Hz, CH2CH3), 1.09 (3H, d, JZ
7.3 Hz, CHCH3), 2.52 (2H, q, JZ7.6 Hz, CH2CH3), 2.89 (1H,
dqd, JZ8.3, 7.3, 5.8 Hz, CHCH3), 3.43 (1H, dd, JZ9.4,
5.8 Hz, one of CH2OBn), 3.62 (1H, dd, JZ9.4, 8.3 Hz, one of
CH2OBn), 4.45 (1H, d, JZ12.8 Hz, OCH2Ph), 4.51 (1H, d,
JZ12.8 Hz, OCH2Ph). 13C NMR (75 MHz, CDCl3) d 7.6,
13.7, 35.6, 46.4, 72.5, 73.2, 127.8, 128.0, 128.8, 138.6, 214.1.
4.1.12. Benzyl (1R,2Z,6R,7R,9R)-10-benzyloxy-6-
hydroxy-7, 9-dimethyl-8-oxo-1-propyl-dec-2-enyl)-
carbamate (11b). The general anti aldol procedure of
Paterson was applied.16 To a stirred solution of
dicyclohexylboronchloride (11.1 mL, 11.1 mmol, 1 M
solution in hexanes) was added ether (20 mL). The solution
was cooled to 0 8C and ketone 10a (1.43 g, 6.93 mmol) and
Et3N (1.74 mL, 12.3 mmol) were added. The solution
continued stirring for 2 h at 0 8C and was then cooled to
K78 8C (dry ice/acetone bath). To this was added,
dropwise, a solution of aldehyde 9b (3.00 g, 10.4 mmol)
in ether (10 mL). The solution continued stirring at K78 8C
for 4 h before being transferred to a freezer (K20 8C) o/n.
After removal from the freezer, the solution was diluted
with methanol (30 mL) and pH 7 phosphate buffer (30 mL),
and cooled to 0 8C. Hydrogen peroxide (12.0 mL, 30%
aqueous) was then added dropwise and stirring continued
for 3 h at rt. The solution was then diluted with DCM
(50 mL) and the aqueous and organic phases separated. The
aqueous phase was extracted with DCM (3!30 mL) and the
combined organic extracts were washed (brine), dried
(MgSO4) and the solvent removed under reduced pressure
to give a crude oil, which after flash chromatography (25%
EtOAc/hexanes) yielded the title compound 11b as a
colourless oil (2.91 g, 85%). [a]2D2 K27.9 (c 2.11, CHCl3).
1H NMR (300 MHz, CDCl3) d 0.91 (3H, t, JZ7.1 Hz,
CH2CH3), 1.03 (3H, d, JZ7.0 Hz, CHCH3), 1.08 (3H, d,
JZ7.1 Hz, CHCH3), 1.20–1.41 (2H, m, CH2), 1.50–1.61
(2H, m, CH2), 1.69–1.93 (2H, m, CH2), 2.11–2.28 (2H, m,
CH2), 2.30–2.48 (1H, m, one of CH2), 2.73 (1H, apparent p,
JZ6.4 Hz, CHCH3), 3.08 (1H, m, CHCH3), 3.43 (1H, dd,
JZ5.0, 8.9 Hz, one of CH2OBn), 3.60 (1H, m, CHOH), 3.68
(1H, dd, JZ8.9, 8.7 Hz, one of CH2OBn), 3.72 (1H, br s,
OH), 4.41 (1H, m, CHN), 4.45 (1H, d, JZ12.0 Hz, one of
OCH2Ph), 4.50 (1H, d, JZ12.0 Hz, one of OCH2Ph), 4.69
(1H, br s, NH), 5.08 (2H, s, CBz OCH2Ph), 5.18 (1H, ddt,
JZ10.7, 7.9, 1.5 Hz, HC]C), 5.49 (dt, JZ10.7, 7.9 Hz,
1H, C]CH), 7.23–7.38 (m, 10H, ArH). 13C NMR
(75 MHz, CDCl3) d 13.3, 13.8, 14.0, 19.0, 24.2, 34.5,
35.6, 45.8, 48.5, 52.2, 66.7, 72.4, 73.1, 73.4, 127.7, 127.8,
128.2, 128.5, 128.6, 129.6, 130.7, 131.3, 158.1, 217.7. IR
(neat) ymax 3363, 3065, 3032, 2933, 2856, 1702, 1529, 1454,
1407, 1364, 1329, 1270, 1070, 1026, 970, 910, 844, 734,
4.1.14. tert-Butyl (1R,2E,6R,7R,9R)-(10-benzyloxy-
6-hydroxy-7,9-dimethyl-8-oxo-1-propyl-dec-2-enyl)-
carbamate (18). The general procedure of Paterson was
followed.16 To a stirred solution of dicyclohexylboronchlor-
ide (1.25 mL, 1.25 mmol, 1 M solution in hexanes) was
added ether (2 mL). The solution was cooled to 0 8C and
ketone 10a (161 mg, 0.78 mmol) and Et3N (195 ml,
1.38 mmol) were added. The solution continued stirring
for 2 h at 0 8C and was then cooled to K78 8C (dry ice/
acetone bath) after which a solution of aldehyde 17
(250 mg, 0.98 mmol) in ether (1 mL) was added dropwise.

2864
B. H. Fraser et al. / Tetrahedron 62 (2006) 2857–2867
The solution continued stirring at K78 8C for 4 h before
being transferred to a freezer (K20 8C) o/n. After removal
from the freezer, the solution was diluted with methanol
(3 mL) and pH 7 phosphate buffer (3 mL), and cooled to
0 8C. Hydrogen peroxide (1 mL, 30% aqueous) was then
added dropwise and stirring continued for 3 h at rt. The
solution was then diluted with DCM (5 mL) and the aqueous
and organic phases separated. The aqueous phase was
extracted with DCM (3!10 mL) and the combined organic
extracts were washed (brine), dried (MgSO4) and the
solvent removed under reduced pressure to give a crude
oil, which after flash chromatography (20% EtOAc/
hexanes) yielded the title compound 18 as a colourless
1710, 1506, 1455, 1333, 1270, 1074, 1028, 975, 909, 733,
698, 648 cmK1. MS m/z 520.4 (MCNaC). HRMS m/z calcd
for C30H43NO5NaCZ520.3039. Found: 520.3033. Anal.
Calcd for C30H43NO5: C, 72.4; H, 8.7; N, 2.8%. Found: C,
72.5; H, 9.0; N, 2.7%.
4.1.16. tert-Butyl (9S,8S,7R,6R,2E,1R)-(10-benzyloxy-
6,8-dihydroxy-7,9-dimethyl-1-propyl-dec-2-enyl)-carba-
mate (19). The general procedure of Evans was followed.18
To a solution of Me4NBH(OAc)3 (0.5 g, 1.9 mmol) in dry
1:1 acetonitrile/AcOH (3.6 mL) cooled to K15 8C was
added a solution of aldol adduct 18 (180 mg, 0.39 mmol) in
dry 1:1 acetonitrile/AcOH (3.6 mL). The solution was
stirred for 4 h at K15 8C before being quenched by sodium
potassium tartrate solution (0.5 M, 5 mL) and diluted with
DCM (5 mL). The aqueous phase was separated from the
organic phase and extracted with DCM (3!5 mL). The
combined organics were then washed (satd NaHCO3), dried
Mg(SO4) and the solvent removed under reduced pressure to
give a crude oil, which upon purification by flash
chromatography (40% EtOAc/hexanes) yielded the title
compound 19 as a colourless oil (166 mg, 92%). [a]2D1 C2.4
(c 1.66, CHCl3). 1H NMR (300 MHz, CDCl3) d 0.72 (3H, d,
JZ6.9 Hz, CHCH3), 0.88 (3H, t, JZ7.4 Hz, CH2CH3), 0.98
(3H, d, JZ7.0 Hz, CHCH3), 1.18–1.40 (4H, m, 2!CH2),
1.41 (9H, s, C(CH3)3), 1.53–1.78 (4H, m, 2!CH2), 1.89–
2.29 (2H, m, CH2), 3.40–3.72 (5H, m, 2!CHOH, CH2OBn
and OH), 3.86 (1H, d, JZ13.6 Hz, OH), 4.00 (1H, m, CHN),
4.37 (1H, br s, NH), 4.50 (2H, s, CH2Ph), 5.34 (1H, dd, JZ
15.2, 5.1 Hz, HC]C), 5.56 (1H, dt, JZ15.2, 6.5 Hz,
C]CH), 7.18–7.34 (5H, m, ArH). 13C NMR (75 MHz,
CDCl3) d 10.5, 13.3, 14.2, 19.1, 28.5, 29.4, 35.5, 35.9, 36.5,
37.9, 52.3, 72.3, 72.7, 75.6, 76.5, 77.7, 127.5, 127.6, 128.3,
130.8, 131.3, 137.7, 156.7. IR (neat) ymax 3450, 3349, 2931,
2873, 1694, 1504, 1455, 1392, 1366, 1333, 1248, 1172,
1098, 971, 870, 754, 698, 665 cmK1. MS m/z 486.4 (MC
NaC). HRMS m/z calcd for C27H45NO5NaC486.3195.
Found: 486.3194. Anal. Calcd for C27H45NO5: C, 69.9; H,
9.8; N, 3.0%. Found: C, 70.3; H, 10.0; N, 3.2%.
1
oil (180 mg, 50%). [a]2D1 C8.5 (c 1.76, CHCl3). H NMR
(300 MHz, CDCl3) d 0.89 (3H, t, JZ7.1 Hz, CH2CH3), 1.02
(3H, d, JZ7.0 Hz, CHCH3), 1.10 (3H, d, JZ7.1 Hz,
CHCH3), 1.18–1.38 (4H, m, 2!CH2), 1.43 (9H, s,
C(CH3)3), 1.48–1.64m (2H, m, CH2), 2.00–2.25 (2H, m,
CH2), 2.69 (1H, dq, JZ7.1, 7.1 Hz, CHCH3), 3.05 (1H, ddq,
JZ4.9, 8.9, 7.0 Hz, CHCH3), 3.40 (1H, dd, JZ4.9, 8.9 Hz,
one of CH2OBn), 3.68 (1H, dd, JZ8.9, 8.9 Hz, one of
CH2OBn), 3.68 (1H, br s, OH), 3.96 (1H, m, CHN), 4.40–
4.46 (1H, m, NH), 4.43 (1H, d, JZ12.0 Hz, CH2Ph), 4.48
(1H, d, JZ12.0 Hz, CH2Ph), 5.31 (1H, dd, JZ15.3, 6.4 Hz,
HC]C), 5.54 (1H, dt, JZ15.3, 6.7 Hz, C]CH), 7.20–7.36
(5H, m, ArH). 13C NMR (75 MHz, CDCl3) d 14.0, 14.1,
14.3, 19.4, 28.8, 29.0, 34.6, 38.2, 45.9, 52.4, 72.7, 73.2,
73.8, 79.5, 128.0, 128.1, 128.8, 130.7, 131.9, 137.2, 155.8,
218.2. IR (neat) ymax 3444, 2978, 2935, 2875, 1706, 1498,
1456, 1391, 1367, 1244, 1168, 1076 cmK1. MS m/z 484.3
(MCNaC). HRMS m/z calcd for C27H43NO5NaCZ
484.3039. Found: 484.3029. Anal. Calcd for C27H43NO5:
C, 70.3; H, 9.4; N, 3.0%. Found: C, 70.8; H, 9.3; N, 3.2%.
4.1.15. Benzyl (9S,8S,7R,6R,2Z,1R)-(10-benzyloxy-
6,8-dihydroxy-7,9-dimethyl-1-propyl-dec-2-enyl)-carba-
mate (12b). The general procedure of Evans was
followed.18 To a solution of Me4NBH(OAc)3 (12.6 g,
28.3 mmol) in dry 1:1 acetonitrile/AcOH (10 mL) cooled
to K15 8C was added a solution of aldol adduct 11b (2.80 g,
5.65 mmol) in dry 1:1 acetonitrile/AcOH (10 mL). The
solution was stirred for 4 h at K15 8C before being
quenched by sodium potassium tartrate solution (0.5 M,
40 mL) and diluted with DCM (20 mL). The aqueous phase
was separated from the organic phase and extracted with
DCM (3!10 mL). The combined organics were then
washed (satd NaHCO3), dried Mg(SO4) and the solvent
removed under reduced pressure to give a crude oil, which
upon purification by flash chromatography (40% EtOAc/
hexanes) yielded the title compound 12b as a colourless oil
(2.21 g, 78%). [a]D22 K59.9 (c 1.45, CHCl3). 1H NMR
(300 MHz, CDCl3) d 0.76 (3H, d, JZ7.0 Hz, CHCH3), 0.89
(3H, t, JZ7.5 Hz, CH2CH3), 0.99 (3H, d, JZ7.1 Hz,
CHCH3), 1.21–1.45 (4H, m, 2!CH2), 1.45–1.91 (4H, m,
CH2), 2.05–2.43 (2H, m, CH2), 3.49–3.65 (4H, m,
2!CHOH and CH2OBn), 3.85 (1H, d, JZ12.1 Hz, OH),
4.31–4.40 (1H, m, CHN), 4.45 (1H, m, OH), 4.52 (2H, br s,
CH2Ph), 4.75 (1H, br s, NH), 5.08 (2H, s, CH2Ph CBz), 5.19
(1H, dd, JZ9.3, 6.4 Hz, HC]C), 5.52 (1H, m, C]CH),
7.23–7.38 (m, 10H, ArH). 13C NMR (75 MHz, CDCl3) d
10.9, 14.3, 14.7, 19.8, 27.4, 36.8, 36.3, 36.5, 37.9, 46.4,
65.9, 70.2, 71.9, 76.5, 77.1, 128.4, 128.5, 128.8, 130.8,
131.3, 137.7, 156.7. IR (neat) ymax 3439, 2961, 2940, 2873,
4.1.17. tert-Butyl (9S,8S,7R,6R,2Z,1R)-(10-benzyloxy-
6,8-dihydroxy-7,9-dimethyl-1-propyl-dec-2-enyl)-carba-
mate (12a). The general procedure of Evans was followed.18
To a solution of Me4NBH(OAc)3 (1.34 g, 3.0 mmol) in dry
1:1 acetonitrile/AcOH (5 mL) cooled to K15 8C was added
a solution of aldol adduct 11a (0.5 g, 1.08 mmol) in dry 1:1
acetonitrile/AcOH (5 mL). The solution was stirred for 4 h
at K15 8C before being quenched by sodium potassium
tartrate solution (0.5 M, 10 mL) and diluted with DCM
(10 mL). The aqueous phase was separated from the organic
phase and extracted with DCM (3!5 mL). The combined
organics were then washed (satd NaHCO3), dried Mg(SO4)
and the solvent removed under reduced pressure to give a
crude oil, which upon purification by flash chromatography
(40% EtOAc/hexanes) yielded the title compound 12a as a
colourless oil (340 mg, 68%). [a]2D1 C1.3 (c 3.75, CHCl3).
1H NMR (300 MHz, CDCl3) d 0.83 (3H, d, JZ6.6 Hz,
CHCH3), 0.90 (3H, t, JZ7.3 Hz, CH2CH3), 0.96 (3H, d, JZ
6.9 Hz, CHCH3), 1.22–1.38 (4H, m, 2!CH2), 1.41 (9H, s,
C(CH3)3), 1.44–1.56 (4H, m, 2!CH2), 2.19–2.38 (1H, m,
one of CH2), 2.45–2.65 (1H, m, one of CH2), 3.43–3.61 (2H,
m, CHOH and one of CH2OBn), 3.61–3.73 (1H, m, one of
CH2OBn), 3.86 (1H, d, JZ9.6 Hz, OH), 4.14 (1H, s, OH),

B. H. Fraser et al. / Tetrahedron 62 (2006) 2857–2867
2865
4.35 (1H, m, CHN), 4.50 (1H, m, CHOH), 4.51 (1H, d, JZ
13.2 Hz, one of CH2Ph), 4.55 (1H, d, JZ13.2 Hz, one of
CH2Ph), 4.62 (1H, br s, NH), 5.16 (1H, apparent t, JZ
10.2 Hz, HC]C), 5.34 (1H, dt, JZ10.2 Hz, 4.5 Hz, C]CH),
7.22–7.39 (5H, m, ArH). 13C NMR (75 MHz, CDCl3) d 10.7,
13.8, 14.1, 19.1, 23.8, 28.6, 35.6, 36.7, 38.1, 38.9, 48.1, 73.1,
73.5, 74.3, 75.1, 80.0, 127.7, 127.8, 128.6, 130.9, 132.2,
138.7, 155.8. IR (neat) ymax 3430, 2962, 2932, 2873, 1688,
1520, 1455, 1366, 1247, 1170, 1086, 736, 697 cmK1. MS m/z
486.5 (MCNaC). HRMS m/z calcd for C27H45NO5NaCZ
486.3195. Found: 486.3187. Anal. Calcd for C27H45NO5: C,
69.9; H, 9.8; N, 3.0%. Found: C, 70.1; H, 9.7; N, 2.8%.
after purification flash chromatography (25% EtOAc/
hexanes) afforded the title compound 14a (110 mg, 73%)
as a semi-crystalline colourless oil. [a]2D1 C6.7 (c 3.02,
1
CHCl3). H NMR (300 MHz, CDCl3) d 0.90 (3H, t, JZ
7.2 Hz, CH2CH3), 0.97 (3H, d, JZ6.9 Hz, CHCH3), 1.09
(3H, d, JZ7.0 Hz, CHCH3), 1.21–61 (6H, m, 3!CH2),
2.01–2.21 (2H, m, CH2), 2.72–2.82 (1H, m, CHCH3), 2.96–
3.07 (2H, m, CHCH3 and CHHg), 3.47 (1H, dd, JZ5.5,
9.0 Hz, one of CH2OBn), 3.63 (1H, dd, JZ7.7, 9.0 Hz, one
of CH2OBn), 3.84–3.89 (1H, m, CHN), 4.10–4.21 (1H, m,
HCOC), 4.29–4.35 (1H, m, HCOC), 4.36 (1H, d, JZ
12.0 Hz, one of CH2Ph), 4.50 (1H, d, JZ12.0 Hz, one of
CH2Ph), 4.79 (1H, apparent d, JZ7.1 Hz, NH), 7.21–7.38
(m, 5H, ArH). 13C NMR (75 MHz, CDCl3) d 12.8, 13.6,
14.1, 19.9, 30.6, 35.4, 39.0, 47.1, 51.5, 54.1, 67.2, 72.7,
73.5, 79.0, 80.1, 81.0, 127.8, 127.9, 128.6, 138.4, 155.6,
215.1. IR (neat) ymax 3362, 2927, 1709, 1678, 1521, 1455,
1367, 1295, 1251, 1169, 1114, 1050, 994, 911, 730,
695 cmK1. MS m/z 720.2 (MCNaC). HRMS m/z calcd
for C27H42ClHgNO5NaCZ720.2355. Found: 720.2341.
Anal. Calcd for C27H42ClHgNO5: C, 46.6; H, 6.1; N,
2.0%. Found: C, 46.3; H, 6.3; N, 2.2%.
4.1.18. tert-Butyl (30S,20S,10S,500R,200R,1aR,1R)-((1-{[500-
(40-benzyloxy-20-hydroxy-10,30-dimethyl-butyl)-tetrahy-
dro-furan-200-yl]-chloromercurio-methyl}-butyl)-carba-
mate (13a). To a stirred solution of diol 12a (50 mg,
0.11 mmol) in acetonitrile (3 mL) at 5 8C was added
mercury (II) acetate (120 mg, 0.38 mmol). The hetereo-
geneous mixture was stirred for 5 h at 5 8C. Brine (3 mL)
was then added and stirring continued for another 1 h. The
organic and aqueous phases were then separated and
the aqueous phase extracted with DCM (3!2 mL). The
combined organic extracts were dried (MgSO4) and the
solvent removed under reduced pressure to give a 10:1
mixture of chloromercurials trans-13a and cis-13b, which
after purification by flash chromatography (25% EtOAc/
hexanes) afforded the title compound 13a (72 mg, 92%) as a
colourless oil. [a]2D1 C24.5 (c 1.6, CHCl3). 1H NMR
(300 MHz, CDCl3) d 0.81 (3H, d, JZ6.9 Hz, CHCH3), 0.83
(3H, d, JZ6.9 Hz, CHCH3), 0.89 (3H, t, JZ7.2 Hz,
CH2CH3), 1.22–1.71 (7H, m, 2!CH2, 2!CHCH3 and
one of CH2), 1.34 (9H, s, C(CH3)3), 1.88–2.17 (3H, m, three
of 2!CH2), 2.99 (1H, apparent t, JZ4.1 Hz, CHHg), 3.39
(1H, br s, OH), 3.53 (1H, d, JZ9.8 Hz, one of CH2OBn),
3.59 (1H, d, JZ9.8 Hz, one of CH2OBn), 3.75 (1H,
apparent dt, JZ2.3, 9.2 Hz, CHOH), 3.87 (1H, m, CHN),
4.05 (1H, m, HCOC), 4.25 (1H, dt, JZ4.1, 5.0 Hz, HCOC),
4.48 (1H, d, JZ11.8 Hz, one of CH2Ph), 4.55 (1H, d, JZ
11.8 Hz, one of CH2Ph), 4.89 (1H, d, JZ8.4 Hz, NH), 7.22–
7.34 (5H, m, ArH). 13C NMR (75 MHz, CDCl3) d 7.8, 12.6,
12.8, 18.7, 27.5, 29.6, 34.2, 34.9, 37.9, 39.1, 52.8, 66.1,
72.4, 74.1, 74.9, 77.0, 78.7, 79.5, 126.6, 126.7, 127.3, 136.9,
154.5. IR (neat) ymax 3440, 3011, 2967, 2932, 2872, 1698,
1501, 1455, 1392, 1367, 1247, 1216, 1167, 1076, 1028, 997,
758, 698, 667 cmK1. MS m/z 722.3 (MCNaC). HRMS m/z
calcd for C27H44ClHgNO5NaCZ722.2512. Found:
722.2500. Anal. Calcd for C27H44ClHgNO5: C, 46.4; H,
6.4, N, 2.0%. Found: C, 46.4; H, 6.5; N, 1.9%.
4.1.20. tert-Butyl (30R,10R,500R,200R,1aR,1R)-(1-{[500-(40-
benzyloxy-10,30-dimethyl-20-oxo-butyl)-tetrahydro-
furan-200-yl]-phenylselanyl-methyl}-butyl)-carbamate
(15a). To a stirred solution of PhSeBr (102 mg, 0.43 mmol)
in DCM (2 mL) at K78 8C was added a solution of ketone
11a (100 mg, 0.22 mmol) in DCM (2 mL). The homo-
geneous mixture stirred for 4 h at K78 8C before satd
NaHCO3 (4 mL) was added. The organic and aqueous
phases were then separated and the aqueous phase extracted
with DCM (3!3 mL). The combined organic extracts were
dried (MgSO4) and the solvent removed under reduced
pressure to give a 5:1 mixture of selenylphenyls trans-15a
and cis-15b, which after purification by flash chromatog-
raphy (20% EtOAc/hexanes) afforded pure 15a (70 mg,
52%) as pale yellow oil. [a]2D1 K23.8 (c 1.04, CHCl3). H
1
NMR (300 MHz, CDCl3) d 0.88 (3H, t, JZ7.3 Hz,
CH2CH3), 0.98 (3H, d, JZ6.0 Hz, CHCH3), 1.09 (3H, d,
JZ6.9 Hz, CHCH3), 1.21–1.65 (4H, m, 2!CH2), 2.00–
2.14 (4H, m, 2!CH2), 2.77–2.84 (1H, m, CHCH3), 3.01–
3.18 (1H, m, CHCH3), 3.50 (1H, dd, JZ5.7, 9.1 Hz), 3.52
(1H, m, CHSe), 3.64 (1H, dd, JZ7.4, 9.1 Hz, one of
CH2OBn), 3.87 (1H, m, CHN), 4.18 (1H, apparent dd, JZ
4.9, 9.4 Hz, HCOC), 4.22–4.29 (1H, m, HCOC), 4.46 (1H,
d, JZ12.0 Hz, one of CH2Ph), 4.51 (1H, d, JZ12.0 Hz, one
of CH2Ph), 5.00 (1H, d, JZ9.3 Hz, NH), 7.17–7.38 (8H, m,
ArH), 7.52–7.58 (2H, m, ArH). 13C NMR (75 MHz, CDCl3)
d 12.6, 12.9, 13.9, 19.5, 28.4, 30.8, 31.7, 34.6, 46.6, 51.6,
55.0, 59.3, 72.6, 73.2, 78.9, 79.6, 82.7, 126.9, 127.5, 127.7,
128.3, 129.0, 130.1, 133.6, 138.2, 156.1, 215.4. IR (neat)
ymax 3378, 2966, 2945, 1706, 1687, 1518, 1455, 1365, 1247,
1171, 1076, 1023, 738, 696 cmK1. MS. m/z 640.2 (MC
NaC). HRMS m/z calcd for C33H47NO5SeNaCZ640.2517.
Found: 640.2504. Anal. Calcd for C33H47NO5Se: C, 64.3;
H, 7.7, N, 2.3%. Found: C, 64.6; H, 7.8; N, 2.5%.
4.1.19. tert-Butyl (30R,20R,10R,500R,1aR,1R)-(1-{[500-
(40-benzyloxy-10,30-dimethyl-20-oxo-butyl)-tetrahydro-
furan-200-yl]-chloromercurio-methyl}-butyl)-carbamate
(14a). To a stirred solution of aldol adduct 11a (100 mg,
0.22 mmol) in acetonitrile (2 mL) at 5 8C was added
mercury (II) acetate (138 mg, 0.43 mmol). The hetereoge-
neous mixture was stirred for 2 h at 5 8C. Brine (3 mL) was
then added and stirring continued for another 1 h. The
organic and aqueous phases were then separated and the
aqueous phase extracted with DCM (3!2 mL). The
combined organic extracts were dried (MgSO4) and the
solvent removed under reduced pressure to give a 9:1
mixture of chloromercurials trans-14a and cis-14a, which
4.1.21. tert-Butyl (30S,20S,10S,500R,200R,1aS,1R)-(1-{[500-
(40-benzyloxy-20-hydroxy-10,30-dimethyl-butyl)-tetra-
hydro-furan-200-yl]-chloromercurio-methyl}-butyl)-
carbamate (20a). To a stirred solution of (E)-diol 19
(166 mg, 0.36 mmol) in acetonitrile (4 mL) at 0 8C was

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B. H. Fraser et al. / Tetrahedron 62 (2006) 2857–2867
added mercury (II) acetate (215 mg, 0.72 mmol). The
hetereogeneous mixture was stirred for 5 h at 5 8C before
warming to rt and stirring o/n. Brine (4 mL) was then added
and stirring continued for another 1 h. The organic and
aqueous phases were then separated and the aqueous phase
extracted with DCM (3!3 mL). The combined organic
extracts were dried (MgSO4) and the solvent removed under
reduced pressure to give a 4:1 mixture of chloromercurials
trans-20a and cis-20b, which after purification of the
mixutre by flash chromatography (25% EtOAc/hexanes)
gave pure 20a (150 mg, 60%) as a colourless oil. [a]D21
C15.1 (c 2.0, CHCl3). 1H NMR (300 MHz, CDCl3) d 0.79
(3H, d, JZ5.5 Hz, CHCH3), 0.81 (3H, d, JZ6.8 Hz,
CHCH3), 0.88 (3H, t, JZ7.3 Hz, CH2CH3), 1.11–1.65
(7H, m, 2!CH2, 2!CHCH3 and one of CH2), 1.85–1.98
(1H, m, one of CH2), 2.02–2.10 (1H, m, one of CH2), 2.15–
2.29 (1H, m, one of CH2), 2.85 (1H, apparent t, JZ4.5 Hz,
CHHg), 3.41 (1H, br s, OH), 3.53 (1H, d, JZ11.5 Hz, one of
CH2OBn), 3.72 (1H, dt, JZ11.5, 2.3 Hz, one of CH2OBn),
3.81–3.99 (1H, m, CHOH), 3.99–4.05 (1H, m, HCOC),
4.18–4.29 (1H, m, HCOC), 4.47 (1H, d, JZ11.9 Hz, one of
CH2Ph), 4.52 (1H, d, JZ11.9 Hz, one of CH2Ph), 4.80 (1H,
d, JZ8.2 Hz, NH), 7.21–7.33 (5H, m, ArH). 13C NMR
(75 MHz, CDCl3) d 7.8, 12.6, 12.9, 18.5, 27.6, 29.8, 34.6,
35.1, 37.7, 39.0, 51.9, 64.2, 72.4, 73.9, 74.7, 77.7, 80.8,
79.8, 126.6, 126.8, 127.4, 137.0, 154.4. IR (neat) ymax 3448,
3011, 2966, 2932, 2873, 1686, 1499, 1455, 1392, 1367,
1248, 1216, 1166, 1092, 1047, 1092, 1047, 951, 872, 759,
699, 668 cmK1. MS m/z 722.2 (MCNaC). HRMS m/z calcd
for C27H44ClHgNO5NaCZ722.2512. Found: 722.2508.
Anal. Calcd for C27H44ClHgNO5: C, 46.4; H, 6.4; N,
2.0%. Found: C, 46.3; H, 6.6; N, 2.1%.
1255, 1076, 1005, 835, 772, 734, 694 cmK1. MS m/z 748.5
(MCNaC). HRMS m/z calcd for C42H71NO5Si2NaCZ
748.4768. Found: 748.4765. Anal. Calcd for C42H71NO5Si2:
C, 69.5; H, 9.9; N, 1.9%. Found: C, 69.4; H, 10.0; N, 1.8%.
4.1.23. Benzyl (30S,20S,10S,500R,200R,1aR,1R)-(1-{[500-(40-
benzyloxy-20-hydroxy-10,30-dimethyl-butyl)-tetrahydro-
furan-200-yl]-iodo-methyl}-butyl)-carbamate (24). An
adaptation of the general iodocyclisation procedure of
Bartlett was followed.21 To a solution of TBS ether 23
(48 mg, 0.07 mmol) in acetonitrile (2 mL) at K10 8C was
added a solution of iodine (34 mg, 0.14 mmol) in
acetonitrile (2 mL). The solution was stirred for 1 h at
K10 8C before being quenched by pH 7 phosphate buffer
(5 mL) and satd sodium sulphite solution (2 mL). The
solution was then diluted with DCM (5 mL) and the organic
and aqueous phases separated. The aqueous phase was
extracted with DCM (3!3 mL) and the combined organic
extracts were washed (brine), dried (MgSO4) and the
solvent removed under reduced pressure to give a 5:1
crude mixture of cis/trans tetrahydrofurans, which after
purification by flash chromatography (25% EtOAc/hexanes)
yielded the title compound 24 (101 mg, 69%) as a colourless
oil. [a]2D2 K4.1 (c 0.6, CHCl3). 1H NMR (300 MHz, CDCl3)
d 0.84 (1H, d, JZ6.9 Hz, CHCH3), 0.85 (1H, d, JZ6.9 Hz,
CHCH3), 0.93 (3H, t, JZ7.3 Hz, CH2CH3), 1.30–1.55 (4H,
m, 2!CH2), 1.61–1.72 (2H, m, CH2), 1.78–2.18 (4H, m,
2!CHCH3 and CH2), 3.19 (1H, d, JZ3.0 Hz, OH), 3.51
(1H, d, JZ5.8 Hz, one of CH2OBn), 3.57–3.71 (1H, m, one
of CH2OBn), 3.57–3.61 (1H, m, CHN), 3.61–3.69 (1H, m,
HCOC), 3.72–3.78 (1H, dt, JZ9.2, 3.0 Hz, CHOH), 4.10–
4.17 (1H, m, HCOC), 4.39 (1H, apparent t, JZ3.5 Hz, CHI),
4.42 (1H, d, JZ11.8 Hz, one of CH2Ph), 4.48 (1H, d, JZ
11.8 Hz, one of CH2Ph), 5.10 (2H, s, CH2Ph CBz), 5.48
(1H, d, JZ9.0 Hz, NH), 7.24–7.36 (10H, m, ArH). 13C
NMR (75 MHz, CDCl3) d 9.1, 14.0, 14.1, 19.6, 30.6, 36.2,
36.6, 40.3, 48.6, 56.1, 66.8, 73.5, 75.4, 75.6, 78.5, 82.4,
127.7, 128.0, 128.1, 128.5, 128.6, 128.7, 136.3, 137.5,
155.8. IR (neat) ymax 3450, 3155, 2965, 1794, 1717, 1508,
1466, 1382, 1217, 1095, 912, 731, 651 cmK1. MS m/z 646.2
(MCNaC). HRMS m/z calcd for C30H42INO5NaCZ
646.2005. Found: 646.1990. Anal. Calcd for C30H42INO5:
C, 57.8; H, 6.8; N, 2.3%. Found: C, 57.5; H, 6.7; N, 2.1%.
4.1.22. Benzyl (9S,8R,7R,6R,2Z,1R) [10-benzyloxy-
6,8-bis-(tert-butyl-dimethyl-silanyloxy)-7,9-dimethyl-1-
propyl-dec-2-enyl]-carbamate (23). To a solution of diol
12b (100 mg, 0.20 mmol) in THF (3 mL) was added 2,6-
lutidine (155 ml, 1.34 mmol) and TBSOTf (230 ml,
1.0 mmol). The solution stirred for 4 h at rt before being
quenched by satd NH4Cl (5 mL). The solution was diluted
with DCM (5 mL) and the organic and aqueous phases
separated. The aqueous phase was extracted with DCM
(3!3 mL) and the combined organic extracts were washed
(brine), dried (MgSO4) and the solvent removed under
reduced pressure to give a crude oil, which after purification
by flash chromatography (25% EtOAc/hexanes) yielded the
title compound 23 (101 mg, 69%) as a colourless oil. [a]D22
4.1.24. Benzyl (30S,20S,10S,500R,200S,1aS,1R)-(1-{[500-(40-
benzyloxy-20-hydroxy-10,30-dimethyl-butyl)-tetrahydro-
furan-200-yl]-chloromercurio-methyl}-butyl)-carbamate
(25). An adaptation of the cyclisation procedure of Walkup
was used.22 To a solution of bis-TBS ether 23 (100 mg,
0.14 mmol) in acetonitrile (4 mL) at 0 8C was added
Hg(O2CCF3)2 (71 mg, 0.17 mmol). The solution was
warmed to rt and stirred for a further 2 h before being
quenched by addition of satd NH4Cl (4 mL) and brine
(4 mL). The solution was then stirred for another 1 h before
being diluted with DCM (4 mL) and the organic and
aqueous phases separated. The aqueous phase was extracted
with DCM (3!3 mL) and the combined organic extracts
were washed (brine), dried (MgSO4) and the solvent
removed under reduced pressure to give a 4:1 mixture of
cis/trans chloromercurials, which after purification by flash
chromatography (20% EtOAc/hexanes) yielded the title
compound 25 (52 mg, 51%) as a colourless oil. [a]2D1 C11.9
(c 2.3, CHCl3). 1H NMR (300 MHz, CDCl3) d 0.79 (3H, d,
1
K4.2 (c 1.7, CHCl3). H NMR (300 MHz, CDCl3) d 0.01
(12H, s, 2!Si(CH3)2), 0.85–0.90 (24H, m, 2!SiC(CH3)3,
CHCH3 and CH2CH3), 0.96 (3H, d, JZ6.9 Hz, CHCH3),
1.24–1.60 (6H, m, 3!CH2), 1.91–2.31 (3H, m, CH2 and
CHCH3), 3.25 (1H, dd, JZ8.1, 9.2 Hz, one of CH2OBn),
3.53 (1H, dd, JZ5.2, 9.2 Hz, CH2OBn), 3.59–3.65 (2H, m,
2!CHOTBS), 4.36 (1H, m, CHN), 4.44 (1H, d, JZ
12.0 Hz, CH2Ph), 4.49 (1H, d, JZ12.0 Hz, CH2Ph), 4.55
(1H, br s, NH), 5.05 (2H, br s, CH2Ph CBz), 5.15 (1H,
apparent dt, JZ10.7, 1.6 Hz, HC]C), 5.43 (1H, dt, JZ
10.7, 7.0 Hz, C]CH), 7.25–7.33 (10H, m, ArH). 13C NMR
(75 MHz, CDCl3) d K5.2, K5.2, K4.7, K4.6, 9.6, 12.9,
13.7, 17.1, 17.4, 24.9, 25.1, 31.2, 37.2, 38.5, 40.5, 47.7,
65.5, 71.6, 72.1, 73.1, 73.9, 126.4, 126.5, 126.6, 126.9,
127.3, 127.5, 129.3, 131.4, 135.7, 137.8, 156.1. IR (neat)
ymax 3334, 2956, 2930, 2857, 1712, 1498, 1463, 1361, 1339,

B. H. Fraser et al. / Tetrahedron 62 (2006) 2857–2867
2867
JZ6.9 Hz, CHCH3), 0.82 (3H, d, JZ6.9 Hz, CHCH3), 0.87
Supplementary data
(3H, t, JZ7.0 Hz, CH2CH3), 1.26–1.71 (6H, m, 3!CH2),
1.85–2.21 (4H, m, 2!CHCH3 and CH2), 2.81 (1H, dd, JZ
4.5, 6.1 Hz, CHHg), 3.53–3.57 (2H, m, one of CH2OBn and
OH), 3.68 (1H, m, one of CH2OBn), 3.79–3.86 (2H, m,
CHOH and HCOC), 3.92–4.01 (1H, m, CHN), 4.11–4.17
(1H, m, HCOC), 4.20 (1H, d, JZ11.7 Hz, CH2Ph), 4.52
(1H, d, JZ11.7 Hz, CH2Ph), 4.97 (1H, d, JZ9.6 Hz, NH),
7.22–7.32 (10H, m, ArH). 13C NMR (75 MHz, CDCl3) d
9.1, 13.5, 14.0, 19.2, 31.1, 31.7, 34.2, 36.1, 40.2, 41.5, 54.2,
67.5, 73.1, 77.1, 75.5, 78.6, 80.6, 81.3, 127.8, 127.8, 127.9,
127.9, 128.2, 128.3, 128.6, 128.7, 136.1, 137.2, 156.2. IR
(neat) ymax 3374, 2969, 2933, 1708, 1509, 1455, 1366, 1249,
1169, 1098, 912, 734, 698 cmK1. MS m/z 756.3 (MCNaC).
HRMS m/z calcd for C30H42ClHgNO5NaCZ756.2355.
Found: 756.2361. Anal. Calcd for C30H42ClHgNO5: C,
49.2; H, 5.8; N, 1.9%. Found: C, 49.1; H, 5.9; N, 2.0%.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2006.01.
005. NOESY spectra of 13a, 14a, 15a, 20a, 24 and 25 for
assignment of cis/trans tetrahydrofuran stereochemistry.
This information is available free of charge via the internet
at http://pubs.acs.org.
References and notes
1. Kondo, S.; Yasui, K.; Katayama, M.; Marumo, S.; Kondo, T.;
Hattari, H. Tetrahedron Lett. 1987, 28, 5861–5864.
2. McCann, P. A.; Pogell, B. M. J. Antibiot. 1979, 32, 673–678.
3. Pogell, B. M. Cell. Mol. Biol. 1998, 44, 461–463.
4. Natsume, M. Recent Res. Dev. Agric. Biol. Chem. 1999, 3,
11–55.
4.1.25. Benzyl (30S,20S,10S,500R,200S,1R)-{1-[500-(40-benzyl-
oxy-20-hydroxy-10,30-dimethyl-butyl)-tetrahydro-furan-
200-ylmethyl]-butyl}-carbamate (3). To a solution of
chloromercurial 25 (50 mg, 0.07 mmol) in toluene at rt
(2 mL) was added Bu3SnH (45 ml, 0.17 mmol) and AIBN
(7 mmol). Precipitation of metallic mercury occurred almost
immediately and stirring continued o/n after which CCl4
(2 mL) was added and stirring continued for a further 2 h.
The solution was then diluted with 25% DCM/hexanes
(10 mL) and washed with 5% KF solution (3!5 mL). The
organic phase was washed (brine), dried (MgSO4) and the
solvent removed under reduced pressure giving a crude grey
oil, which after purification by flash chromatography (20%
EtOAc/hexanes) yielded the title compound 3 as a colour-
less oil (27 mg, 79%). [a]2D1 K5.1 (c 1.12, CHCl3). 1H NMR
(300 MHz, CDCl3) d 0.84 (3H, d, JZ7.1 Hz, CHCH3), 0.88
(3H, d, JZ6.9 Hz, CHCH3), 0.96 (3H, t, JZ10.7 Hz,
CH2CH3), 1.21–1.64 (6H, m, 3!CH2), 1.88–2.21 (6H, m,
2!CH2 and 2!CHCH3), 3.40 (1H, br s, OH), 3.51 (1H, dd,
JZ6.6, 11.2 Hz, one of CH2OBn), 3.62 (1H, dd, JZ7.2,
11.2 Hz, one of CH2OBn), 3.78–3.85 (2H, m, CHOH and
HCOC), 3.89 (1H, m, CHN), 4.15 (1H, m, HCOC), 4.31
(1H, d, JZ10.8 Hz, CH2Ph), 4.58 (1H, d, JZ10.8 Hz,
CH2Ph), 4.78 (1H, d, JZ8.2 Hz, NH), 7.21–7.38 (10H, m,
ArH). 13C NMR (75 MHz, CDCl3) d 8.5, 12.3, 12.9, 18.4,
28.4, 30.7, 32.7, 36.4, 40.8, 49.2, 65.9, 72.8, 73.5, 75.6,
77.0, 78.3, 80.2, 80.7, 127.7, 127.8, 127.8, 127.9, 127.9,
128.1, 128.5, 128.9, 136.4, 136.8, 156.7. IR (neat) ymax
3482, 2946, 2917, 2853, 1460, 1348, 1245, 1235, 1145,
1095, 1045, 791, 773 cmK1. MS m/z 520.3 (MCNaC).
HRMS m/z calcd for C30H43NO5NaCZ520.3039. Found:
520.3046. Anal. Calcd for C30H43NO5: C, 72.4; H, 8.7; N,
2.8. Found: C, 72.7; H, 8.6; N, 2.8.
5. Kondo, S.; Yasui, K.; Natsume, M.; Katayama, M.; Marumo, S.
J. Antibiot. 1988, 41, 1196–1204.
6. Stengal, C.; Reinhardt, G.; Graefe, U. J. Basic Microbiol.
1992, 32, 339–345.
7. Walkup, R. D.; Kim, S. W. J. Org. Chem. 1994, 59,
3433–3441.
8. Chou, W.; Pogell, M. Biochem. Biophys. Res. Commun. 1981,
100, 344–358.
9. Grigoriev, P.; Berg, A.; Schlegel, R.; Graefe, U. Bioelectrochem.
Bioenerg. 1996, 39, 295–298.
10. Lee, E.; Jeong, E. J.; Kang, E. J.; Sung, L. T.; Hong, S. K.
J. Am. Chem. Soc. 2001, 123, 10131–10132.
11. Kang, S. K.; Jeong, J. W.; Hwang, Y. S.; Lee, S. B. Angew.
Chem., Int. Ed. 2002, 41, 1392–1395.
12. Germay, O.; Kumar, N.; Thomas, E. J. Tetrahedron Lett. 2001,
42, 4969–4974.
13. Wang, Y.; Bersmann, H.; Gruner, M.; Metz, P. Tetrahedron
Lett. 2001, 42, 7801–7804.
14. Mavropoulas, I.; Perlmutter, P. Tetrahedron Lett. 1996, 37,
3751–3754.
15. Bratt, K.; Garavelas, G.; Perlmutter, P.; Westman, G. J. Org.
Chem. 1996, 61, 2109–2117.
16. Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N.
J. Am. Chem. Soc. 2001, 123, 9535–9544.
17. Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.
1982, 13, 1–115.
18. Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27,
5939–5942.
19. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560–3578.
20. Lipshutz, B. H.; Barton, J. C. J. Am. Chem. Soc. 1992, 114,
1084–1086.
21. Bartlett, P. A.; Rychnovsky, S. D. J. Am. Chem. Soc. 1981,
103, 3963–3964.
22. Walkup, R. D.; Park, G. J. Am. Chem. Soc. 1990, 112,
1597–1603.
Acknowledgements
23. Morinere, J. L.; Danree, B.; Lemoine, J.; Guy, A. Synth.
Commun. 1988, 17, 1214–1215.
B.F. is grateful to the Australian government for an
Australian Postgraduate Research Award.
24. Paterson, I.; Norcross, R. D.; Ward, R. A.; Romea, P.;
Lister, M. A. J. Am. Chem. Soc. 1994, 116, 11287–11314.