Stereoselective synthesis of the C13-32 spiroacetal fragment of spirangien A

Article abstract of DOI:10.1016/j.tet.2013.06.012

Stereoselective synthesis of an advanced intermediate towards the highly cytotoxic polyketide metabolite spirangien A was achieved. A key step in the synthesis was installation of the C23 stereocentre by a substrate controlled C22-23 aldol reaction. Compa

Full text of DOI:10.1016/j.tet.2013.06.012

Tetrahedron 69 (2013) 6845e6854
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of the C13e32 spiroacetal fragment
of spirangien A
*
Claire Gregg, Michael V. Perkins
School of Chemical and Physical Sciences, Flinders University, GPO Box 2100, Adelaide, South Australia 5001, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective synthesis of an advanced intermediate towards the highly cytotoxic polyketide metab-
olite spirangien A was achieved. A key step in the synthesis was installation of the C23 stereocentre by
a substrate controlled C22e23 aldol reaction. Comparison of this result with previous literature reports
suggests that the facial preference of the aldehyde controls the outcome of the C22e23 aldol coupling
and depends on the O27/25 protecting groups when reacting with complex ketones, which contain the
C17e15 stereochemistry.
Received 27 March 2013
Received in revised form 22 May 2013
Accepted 3 June 2013
Available online 11 June 2013
Keywords:
Polyketide
Spiroacetal
Aldol reaction
Cytotoxic
Ó 2013 Elsevier Ltd. All rights reserved.
Spirangien
1. Introduction
Spirangiens A (1) and B (2) (Scheme 1) are two structurally
related polyketide metabolites isolated from the epothilone-
producing myxobacterium Sorangium cellulosum, strain So
ce90.1,2 Spirangien A (1) exhibited potent antifungal activity and
was highly cytotoxic against the L929 mouse fibroblast cell line
(IC50 0.7 ng mLꢀ1).3 It was later found to be a potent inhibitor of
IL-8 expression (IC50 7.2ꢁ0.9 nM).4 Spirangiens A (1) and B (2)
differ in structure only by an additional methylene unit at C32 in
spirangien B and both compounds contain a complex pentaene
side-chain, a highly functionalised 6,6-spiroacetal core, 14 ster-
eocentres and a terminal carboxyl group. The absolute configura-
tion of the remote C3 stereocentre was determined by chemical
degradation of spirangien A and subsequent fragment analysis by
GC.3
Ethylene cross-metathesis of spirangien A (1) afforded a spi-
rangien diene analogue 3 (later named spirangien M522)4 (Scheme
1), which retained one tenth the cytotoxic activity of spirangien A
(IC50 7 ng mLꢀ1) and is also a potent inhibitor of IL-8 expression
Scheme 1. Spirangiens A (1) and B (2) and cross-metathesis to produce spirangien
M522 (3).
(IC50 90.7ꢁ19.8 nM).3 X-ray crystal structure analysis of spirangien
3
€
M522 by Hofle et al. allowed for the assignment of the relative
spirangien diene 3 and spirangien A (1) by Paterson et al.5e7
A
configuration of C14e28, while the absolute configuration of spi-
rangiens A and B was later determined by total synthesis of
number of other reports have emerged describing synthetic efforts
towards spirangien A, including our own studies on the stereo-
selectivity of the C22e23 aldol coupling for spirangiens A and B.5e14
Herein, we describe our synthesis of the C13e32 spiroacetal frag-
ment of spirangien A (1).
* Corresponding author. Tel.: þ61 8 8201 2496; fax: þ61 8 8201 2905; e-mail
address: mike.perkins@flinders.edu.au (M.V. Perkins).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.06.012

6846
C. Gregg, M.V. Perkins / Tetrahedron 69 (2013) 6845e6854
We envisaged a synthesis of spirangien A (1) via advanced in-
which was treated with 2,2-dimethoxypropane/PPTS and after
purification acetonide 13 was obtained as a single isomer (81%, two
steps). Finally, treatment with Hg(OAc)2/PPTS/pH 7 buffer in THF
brought about hydration of the terminal alkyne, giving ketone 7
(59%).
termediate 4 that could be used to furnish both spirangien M522
(3) and spirangien A (1). Spiroacetal 4 was anticipated to arise from
the spirocyclization of linear precursor 5, which in turn can be
prepared by the aldol union of aldehyde 6 and ketone 7 (Scheme 2).
Synthesis of aldehyde 6 was achieved via the sequence shown in
Scheme 4. Palladium-catalysed cross-coupling of zinc homoenolate
14 with (E)-2-bromo-2-butene, followed by DIBAL reduction at
ꢀ78 ꢂC gave ready access to chiral aldehyde 15.17 The highly dia-
stereoselective boron mediated aldol addition of Evans’ oxazolidi-
none auxiliary18e20 (R)-16 to chiral aldehyde 15 gave the antiesyn
aldol adduct 17 (>98% ds). TBS protection (TBSOTf/2,6-lutidine)21 of
the new hydroxyl was followed by reductive cleavage of the aux-
iliary (LiBH4/EtOH)22 and Swern15 oxidation to furnish aldehyde 18.
Aldol addition of the other enantiomer of Evans’ auxiliary18e20 (S)-
16 to aldehyde 18 gave the desired syneantiesyn configuration of
the C24e27 stereotetrad of aldol adduct 19 in high selectivity
(>98% ds) and afforded the opportunity for differential protection
of the anti-1,3-diol (O27/25 anti). To this end, protection of the C25
hydroxyl was achieved (2,6-lutidine/TESOTf), followed by reductive
cleavage of the auxiliary and Swern15 oxidation to give desired al-
dehyde 6 (11% yield, 10 steps).
Scheme 2. Retrosynthesis of spirangien A (1) via advanced intermediate 4.
2. Results and discussion
Synthesis of methyl ketone 7 began with preparation of
known13 alkyne 9 from commercially available (R)-Roche ester [(R)-
8] in 59% yield over nine steps (Scheme 3). Cleavage of the PMB
ether with DDQ and subsequent Swern15 oxidation furnished al-
dehyde 10 (96%, two steps) in preparation for aldol elaboration. The
Z-enolate of Roche ester derived chiral ketone (S)-11 was generated
using modified Ti aldol conditions (Ti(Oi-Pr)Cl3/i-Pr2NEt)16 and the
ensuing double stereodifferentiating aldol reaction with chiral al-
dehyde 10 proceeded in 87% ds and purification gave novel aldol
adduct 12 as a single isomer in 81% yield. The C14e17 stereotetrad
was completed by directed reduction using Me4NBH(OAc)3 to give
the anti-1,3-diol (O17/15 anti) as an 87:13 mixture of isomers,
Scheme 4. Synthesis of aldehyde 6.
The aldol coupling of ketone 7 with aldehyde 6 was achieved
using LiHMDS (2 equiv) at ꢀ78 ꢂC for 3 h to give adducts 5 and 20 in
a 2.5:1 ratio. Diastereomeric aldol adducts 5 and 20 were separable
by column chromatography and were treated independently for
stereochemical determination.
To elucidate the C23 stereochemistry, the C23 hydroxyl in minor
diastereomer 20 was methylated as per the natural product using
Meerwein’s salt.23, then subjected to buffered HFepyridine for 4 h
to cleave only the more labile TES protecting group. Cyclisation of
the newly liberated hydroxyl onto C21 ensued to afford hemiacetal
21 (Scheme 5).
Analysis of the diagnostic NOE interactions in hemiacetal 21 was
indicative of an (S)-configuration at C23, the unnatural isomer.
Major aldol diastereomer 5 was treated as per the minor isomer to
form hemiacetal 22 (Scheme 5). Analysis of the diagnostic NOE
correlations in hemiacetal 22 was complicated due to interfering
Scheme 3. Synthesis of ketone 7.

C. Gregg, M.V. Perkins / Tetrahedron 69 (2013) 6845e6854
6847
Scheme 5. Aldol coupling of aldehyde 6 and ketone 7.
NOESY signals for H23 and H25. However, there was a clear NOE
interaction between the methoxy protons and the C24 methyl
protons, which only occurs in the (23R) configuration. Notably,
there was also an absence of NOESY correlations between C24-Me
and H23. This was further evidence that the major aldol isomer 5
was the desired (23R) isomer.
In an attempt to complete the preparation of the desired spi-
roacetals the hemiacetals 21 and 22 were treated with CSA/
MeOH.5,12a However, when minor hemiacetal diastereomer 21 was
subjected to these conditions, elimination of MeOH across C22e23
was observed in the resulting spiroacetal 33, removing the crucial
C23 stereocentre. Fortunately, when major hemiacetal di-
astereomer 22 was treated under the same conditions, there was no
elimination of MeOH and spiroacetal 34 resulted (Scheme 5). Again
the diagnostic NOE interactions in spiroacetal 34 confirmed the (R)-
stereochemistry at C23, as evident from correlations between C23-
OMe and C24-Me, as well as correlations between C23-OMe and
both H22a and H22b. An NOE interaction between H23 and H25
was also observed, which is indicative of the (23R) isomer.
aldehyde 23c and ketone 26 (Table 1). Ketone 26 is analogous to our
ketone 7, while our aldehyde 6 has unconstrained silyl protecting
groups at O27/25 compared to Paterson’s cyclic acetonide, thus
implying that the aldehyde facial preference depends on the O27/
25 protecting groups and controls the outcome of the aldol
reaction.
This contrasts with the results for our model system13 (Table 1).
We now conclude that in this model Li aldol coupling (with both
O27/25 silyl and acetonide protected aldehydes, 30a and b), the 1,4-
anti preference10 of the simplified ketone 31 (lacking C17e15)
dominates, giving 3.5:1 and 3:1 dr in favour of the unwanted iso-
mers (23S)-32a and (23S)-32b, respectively. Thus the choice of O27/
25 protecting groups effects the facial preference of the aldehyde
and controls the outcome of the aldol reaction only when reacting
with the more complex ketones containing the C17e15 stereo-
centres, but not the simple ketone 31.
3. Conclusion
The selectivity observed (2.5:1) for the aldol coupling of O17/15
acetonide protected ketone 7 with O27/25 silyl protected aldehyde
6 is similar to the results of Kalesse and Lorenz9 and Cossy et al.12
who each obtained a 3:1 dr in favour of the desired isomers
(23R)-27 and (23R)-28, respectively, in the Li mediated aldol re-
action of an analogous aldehyde (O27/25 silyl) with an O17/15 silyl
protected ketone (Table 1). This suggests that the nature of the O17/
15 protecting groups on the ketone does not control the outcome of
the aldol reaction. On the other hand, Paterson et al.5 obtained the
opposite selectivity (3.5:1) in favour of the unnatural isomer (23S)-
29 in the Li aldol reaction between cyclic acetonide protected
In summary, a stereoselective synthesis of advanced C13e32
spiroacetal fragment 34 towards the synthesis of spirangien A (1)
and spirangien M522 (3) was achieved. A key step in the synthesis
was a substrate controlled C22e23 aldol reaction to install the C23
stereochemistry. Notably, protecting group manipulation of spi-
roacetal 34 would constitute a formal synthesis5,7 of spirangien A
(1) and work will continue to convert this compound to spirangien
A (1) and spirangien M522 (3). Comparison of the C22e23 aldol
coupling with previous literature reports5,9,12,13 suggests that the
facial preference of the aldehyde depends on the O27/25
protecting groups and controls the outcome of the C22e23 aldol

6848
C. Gregg, M.V. Perkins / Tetrahedron 69 (2013) 6845e6854
Table 1
Comparison of previous C22e23 aldol coupling results for spirangien A (1)
Authors
Aldehyde
Ketone
Conditions
Product
dr (R):(S)
This work
6: P1¼TBS, P2¼TES
7: P3¼TBS; P4¼P5¼C(CH3)2
24: P3¼P4¼P5¼TES
25: P3¼P4¼P5¼TBS
26: P3¼TES
LiHMDS
LiHMDS
LDA
LDA
(c-Hex)2BCl/Et3N
(ꢀ)-Ipc2BCl/Et3N
LiHMDS
5
2.5:1
3:1
3:1
1:3.5
1:5
2.5:1
1:3.5
1:3
Lorenz & Kalesse9
Cossy et al.12
Paterson et al.5
23a: P1¼P2¼TES
27
28
29
29
29
32a
32b
23b: P1¼P2¼TBS
23c: P1¼P2¼C(CH3)2
P4¼P5¼C(CH3)2
Gregg & Perkins13
30a: P1¼TBS; P2¼TES
30b: P1¼P2¼C(CH3)2
31: P3¼TBS
31: P3¼TBS
LiHMDS
coupling when reacting with ketones, which contain the C17e15
stereochemistry.
13C assignments were confirmed by conducting homonuclear
(1He1H) correlation spectroscopy (COSY), nuclear Overhauser ef-
fect (NOE) spectroscopy (NOESY) and heteronuclear (1He13C) cor-
relation spectroscopy (HMQC) experiments. Optical rotations were
recorded on a PolAAR 21 polarimeter, referenced to the sodium D
line (589 nm) at 20 ꢂC, using the spectroscopic grade solvent
specified (CHCl3 or CH2Cl2) and at the concentration (c, g/100 mL)
indicated. Measurements were carried out in a cell with a 1 dm
path length. Infrared (IR) spectra were recorded on either a Per-
kineElmer 1600 series FTIR, BIO-RAD FTS-40-A or Nicolet Avatar
370 DTGS Fourier Transform spectrophotometer, with the absorp-
tions recorded in wavenumbers (nmax/cmꢀ1). Liquid samples were
analysed as thin films on NaCl discs, with solids being dissolved in
CH2Cl2 or CHCl3 before being applied to the discs and the solvent
evaporated. High resolution mass spectra were recorded on either
a Bruker BioApex II 47e FTMS fitted with an Analytica ESI source (in
positive or negative ion mode) or an Agilent G1969A LC-TOF uti-
lising an Agilent 1100 Series LC.
4. Experimental
4.1. General
All reactions were carried out under an atmosphere of nitrogen
(N2) or argon (Ar) in oven-dried glassware. Most commercial
starting materials and reagents were used as supplied, or dried and
distilled using standard procedures.24 Tetrahydrofuran (THF) was
dried using sodium metal and then distilled, as required, from
sodium-benzophenone under N2. Dichloromethane (CH2Cl2) was
distilled from calcium hydride under N2 as required. Other solvents
used for reactions, extractions and purification were distilled prior
to use. Room temperature (rt) varied between 20 and 25 ꢂC. Ana-
lytical thin layer chromatography (TLC) was conducted on
aluminium-backed 0.2 mm thick silica gel 60 F254 plates (Merck)
and the plates were visualised under a 254 nm UV lamp and/or by
treatment with either anisaldehyde dip (p-anisaldehyde, 9.2 mL;
H2SO4, 12.5 mL; CH3CO2H, 3.75 mL; EtOH, 338 mL) or potassium
permanganate dip (KMnO4, 3 g; K2CO3, 20 g; 5% NaOH, 5 mL; H2O,
300 mL), followed by heating. Column chromatography was con-
ducted using silica gel 60 (mesh size 0.040e0.063 mm) as the
stationary phase and the analytical reagent (AR) solvents indicated.
When purifying compounds with acid sensitivity, column chro-
matography was performed on buffered silica as indicated. Buffered
silica was prepared by spinning 100 g of silica gel 60 (mesh size
0.040e0.063 mm) with 10 mL of pH 7 phosphate buffer on a rotary
evaporator overnight at atmospheric pressure.
4.2. Preparative procedures
4.2.1. (2S,4S)-4-(tert-Butyldimethylsilyloxy)-2-methyl-hex-5-ynyl-1-
ol (35). To a stirred solution of PMB ether 9 (481 mg; 1.33 mmol) in
CH2Cl2 (66 mL) at 0 ꢂC was added pH 7 phosphate buffer (13 mL),
followed by DDQ (452 mg; 1.99 mmol) and the resultant slurry was
stirred at 0 ꢂC for 3 h. The mixture was diluted with CH2Cl2 (75 mL)
and quenched with satd aq NaHCO3 (120 mL). The layers were
separated and the organic phase was washed with satd aq NaHCO3
(150 mL), H2O (150 mL) and brine (150 mL), then dried (Na2SO4)
and concentrated in vacuo. Purification by column chromatography
(buffered silica, 5% Et2O/CH2Cl2) gave alcohol 35 (313 mg; 97%) as
Proton (1H) and carbon (13C) NMR spectra were recorded on
a Bruker Avance II spectrometer at 400 or 600 MHz for proton and
100 or 151 MHz for carbon nuclei, respectively. Chemical shifts
a colourless oil. Rf¼0.31 (5% Et2O/CH2Cl2); ½a D20
ꢀ56.4 (c 1.46,
ꢃ
CHCl3); dH (400 MHz; CDCl3) 4.45 (1H, ddd, J¼8.3, 5.1, 2.1 Hz, H20),
3.46 (2H, d, J¼5.9 Hz, H17), 2.38 (1H, d, J¼2.1 Hz, H22), 2.28 (1H, br
s, OH), 1.88 (1H, m, H18), 1.82 (1H, ddd, J¼13.8, 8.3, 5.6 Hz, H19a),
1.49 (1H, ddd, J¼13.7, 7.6, 5.1 Hz, H19b), 0.93 (3H, d, J¼6.8 Hz,
C18eCH3), 0.88 (9H, s, SiC(CH3)3), ꢀ0.13 (3H, s, Si(CH3)CH3), ꢀ0.10
(3H, s, Si(CH3)CH3); dC (100 MHz; CDCl3) 85.9, 72.5, 68.1, 61.2, 42.5,
32.5, 25.8, 18.3, 16.9, ꢀ4.4, ꢀ5.0; IR (film, cmꢀ1) 3311, 2956, 2930,
were recorded as
acquired in deuterochloroform (CDCl3) at ambient temperature and
the peak due to residual CHCl3 7.26) was used as the internal
reference. For proton-decoupled 13C NMR spectra recorded in
CDCl3, the central peak ( 77.16) of the CDCl3 triplet was used as the
internal reference and all data are given as chemical shift (
). 1H and
d values in parts per million (ppm). Spectra were
(
d
d
d

C. Gregg, M.V. Perkins / Tetrahedron 69 (2013) 6845e6854
6849
2858, 2361, 2338; HRESIMS calculated for C21H36O3SiHþ: 243.1775;
found: 243.1783.
tetramethylammonium triacetoxyborohydride (467 mg; 2.20
mmol) and the resulting mixture was stirred at rt for 4 days. The
mixture was diluted with Et2O (10 mL) and quenched by careful
addition of satd aq NaHCO3 (15 mL). The layers were separated and
the aqueous phase was extracted with Et2O (4ꢄ15 mL), the com-
bined organic extracts were dried (Na2SO4) and concentrated in
vacuo. Purification by column chromatography (buffered silica, 10%
Et2O/CH2Cl2) to give 1,3-diol 36 (45.8 mg; 87%, as a 87:13 antiesyn
4.2.2. (2S,4S)-4-(tert-Butyldimethylsilyloxy)-2-methyl-hex-5-ynal
(10). To a stirred solution of DMSO (423 mL; 4.92 mmol) in CH2Cl2
(10 mL) at ꢀ78 ꢂC was added (COCl)2 (1.23 mL; 2 M in CH2Cl2;
2.46 mmol), dropwise and the resulting solution was stirred at
ꢀ78 ꢂC for 30 min. Alcohol 35 (399 mg; 1.64 mmol) was added
dropwise via cannula (CH2Cl2, 3 mL) and the mixture stirred at
ꢀ78 ꢂC for 45 min before Et3N (1.37 mL; 9.84 mmol) was added
dropwise. The mixture was stirred at ꢀ78 ꢂC for a further 30 min
before warming to 0 ꢂC for 30 min and the reaction was quenched by
addition of satd aq NH4Cl (25 mL). The product was extracted with
CH2Cl2 (3ꢄ20 mL), the combined organic extracts dried (Na2SO4)
and concentrated in vacuo. Purification by column chromatography
(buffered silica, 100% CH2Cl2) gave aldehyde 10 (395 mg; 99%) as
mix of isomers) as a yellow oil. Rf¼0.48 (10% Et2O/CH2Cl2); ½a D20
ꢃ
ꢀ23.0 (c 2.14, CHCl3); dH (400 MHz; CDCl3) 7.23 (2H, d, J¼8.4 Hz,
ArH), 6.87 (2H, d, J¼8.4 Hz, ArH), 4.56 (1H, ddd, J¼8.4, 5.2, 2.0 Hz,
H20), 4.45 (2H, ABq, J¼11.2 Hz, OCH2PMP), 3.80 (3H, s, OCH3), 3.61
(1H, dd, J¼4.0 Hz, H15), 3.60 (1H, dd, J¼8.6, 3.3 Hz, H13a), 3.54 (1H,
dd, J¼9.2, 2.8 Hz, H17), 3.47 (1H, dd, J¼8.6, 6.4 Hz, H13b), 2.38 (1H,
d, J¼2.0 Hz, H22), 2.21 (1H, ddd, J¼13.6, 8.8, 4.4 Hz, H19a),
2.16e2.10 (1H, m, H14), 1.86e1.78 (1H, m, H18), 1.82e1.78 (1H, m,
H16), 1.43 (1H, ddd, J¼13.6, 7.6, 5.2 Hz, H19b), 1.25 (1H, br s, OH),
1.03 (3H, d, J¼6.8 Hz, C14eCH3), 0.90 (9H, s, SiC(CH3)3), 0.84 (3H, d,
J¼6.8 Hz, C16eCH3), 0.80 (3H, d, J¼6.8 Hz, C18eCH3), 0.15 (3H, s,
Si(CH3)CH3), 0.12 (3H, s, Si(CH3)CH3); dC NMR (100 MHz; CDCl3)
159.5, 129.7, 129.5, 114.0, 86.3, 82.7, 76.1, 75.4, 73.3, 72.2, 61.8, 55.4,
42.9, 35.9, 34.8, 32.9, 25.9, 18.3, 16.6, 14.3, 10.7, ꢀ4.3, ꢀ4.9; IR (film,
cmꢀ1) 3423, 3309, 2958, 2931, 2856, 1613, 1513; HRESIMS calcu-
lated for C27H46O5SiNaþ: 501.3007; found: 501.3009.
a colourless oil. Rf¼0.56 (100% CH2Cl2); ½a D20
ꢀ40.5 (c 1.61, CHCl3); dH
ꢃ
(400 MHz; CDCl3) 9.63 (1H, d, J¼1.6 Hz, H17), 4.46 (1H, ddd, J¼7.6,
5.2, 2.0 Hz, H20), 2.62 (1H, m, C18), 2.41 (1H, d, J¼2.0 Hz, H22), 2.21
(1H, ddd, J¼14.4, 7.6, 6.4 Hz, H19a), 1.64 (1H, ddd, J¼13.6, 6.4, 5.2 Hz,
H19b), 1.13 (3H, d, J¼7.2 Hz, C18eCH3), 0.89 (9H, s, SiC(CH3)3), 0.14
(3H, s, Si(CH3)CH3), 0.11 (3H, s, Si(CH3)CH3); dC (100 MHz; CDCl3)
204.3, 85.0, 73.2, 60.8, 43.3, 39.4, 25.9, 18.3, 13.8, ꢀ4.4, ꢀ5.0; IR (film,
cmꢀ1) 3309, 2930, 2885, 2858, 2712, 1727.
4.2.3. (3S,5S,6S,7R,9S)-3-(tert-Butyldimethylsilyloxy)-6-hydroxy-10-
(4-methoxyphenyl)oxy-5,7,9-trimethyl-8-oxo-dec-1-yne
4.2.5. (3S,5S,6S,7R,8S,9S)-3-(tert-Butyldimethylsilyloxy)-10-(4-
methoxyphenyl)oxy-5,7,9-trimethyl-6,8-[(bis-dimethyl-methylene)
dioxy]-dec-1-yne (13). To a stirred solution of 1,3-diol 36 (24.3 mg;
(12). Titanium isopropoxide (135
mL; 456
mmol) was added drop-
wise to a solution of TiCl4 (1.37 mL; 914
mmol) in CH2Cl2 (3.3 mL) at
50.9 mmol) in CH2Cl2 (0.85 mL) was added 2,2-dimethoxypropane
0 ꢂC. The mixture was stirred for 10 min at 0 ꢂC and 10 min at rt and
diluted with CH2Cl2 (3.3 mL). The resulting colourless solution was
added via cannula to a solution of ketone (S)-11 (385 mg;
1.63 mmol) in CH2Cl2 (5 mL) at ꢀ78 ꢂC. The pale yellow solution was
(0.85 mL) and a few crystals of PPTS and the resulting solution was
stirred at rt for 3 h. The reaction mixture was diluted with CH2Cl2
(5 mL), washed with satd aq NaHCO3 (5 mL) and brine (5 mL), dried
(Na2SO4) and concentrated in vacuo. Purification by column chro-
matography (buffered silica, 100% CH2Cl2) gave acetonide 13 as
a single isomer (24.5 mg; 93%) as a clear, colourless oil. Rf¼0.55
stirred for 2 min and i-Pr2NEt (312
mL; 1.79 mmol) was added
dropwise. The resulting red-orange solution was stirred for 30 min
at ꢀ78 ꢂC before aldehyde 10 (392 mg; 1.63 mmol) was added via
cannula. After 3 h at ꢀ78 ꢂC the reaction was quenched by addition
of satd aq NH4Cl (30 mL) and vigorously stirred at rt. The mixture
was diluted with Et2O (40 mL) and washed with H2O (30 mL), satd
aq NaHCO3 (30 mL) and brine (30 mL). The aqueous layers were
extracted with Et2O (3ꢄ40 mL) and the combined organic extracts
were dried (Na2SO4) and concentrated in vacuo. Crude NMR
showed a 87:13 mixture of diastereomers, which were able to be
separated by column chromatography (buffered silica, 3% Et2O/
CH2Cl2) to give the single isomer, aldol adduct 12 (627 mg; 81%) as
(100% CH2Cl2); ½a D20
ꢀ7.3 (c 1.23, CHCl3); dH (400 MHz; CDCl3) 7.26
ꢃ
(2H, d, J¼8.8 Hz, ArH), 6.87 (2H, d, J¼8.4 Hz, ArH), 4.49 (1H, ddd,
J¼8.4, 6.0, 2.0 Hz, H20), 4.42 (2H, ABq, J¼7.2 Hz, OCH2PMP), 3.80 (3H,
s, OCH3), 3.55 (1H, dd, J¼9.2, 4.8 Hz, H13a), 3.32 (1H, dd, J¼8.8,
6.8 Hz, H13b), 3.29 (1H, dd, J¼10.8, 5.2 Hz, H15), 3.22 (1H, dd, J¼6.8,
5.6 Hz, H17), 2.37 (1H, d, J¼2.0 Hz, H22), 2.11 (1H, ddd, J¼13.2, 8.8,
4.4 Hz, H19a), 1.96e1.85 (1H, m, H14), 1.93e1.86 (1H, m, H16),
1.83e1.74 (1H, m, H18),1.27 (1H, m, H19b),1.27 (6H, s, C(CH3)2),1.00
(3H, d, J¼6.8 Hz, C14eCH3), 0.90 (9H, s, SiC(CH3)3), 0.84 (3H, d,
J¼6.8 Hz, C16eCH3), 0.83 (3H, d, J¼6.8 Hz, C18eCH3), 0.14 (3H, s,
Si(CH3)CH3), 0.11 (3H, s, Si(CH3)CH3); dC NMR (100 MHz; CDCl3)
159.2, 131.0, 129.3, 113.8, 100.4, 76.6, 74.0, 72.9, 72.2, 72.0, 61.6, 55.4,
42.8, 38.0, 35.3, 29.1, 25.9, 25.4, 23.7,18.3,15.8,14.4,12.5, ꢀ4.2, ꢀ4.9;
IR (film, cmꢀ1) 3309, 2959, 2932, 2856, 1613, 1586, 1513; HRESIMS
calculated for C30H50O5SiHþ: 519.3500; found: 519.3505.
a white amorphous solids. Rf¼0.28 (3% Et2O/CH2Cl2); ½a D20
ꢀ13.8 (c
ꢃ
1.38, CHCl3); dH (400 MHz; CDCl3) 7.18 (2H, d, J¼8.4 Hz, ArH), 6.86
(2H, d, J¼8.8 Hz, ArH), 4.55 (1H, ddd, J¼8.0, 5.6, 2.0 Hz, H20), 4.38
(2H, ABq, J¼11.6 Hz, OCH2PMP), 3.79 (3H, s, OCH3), 3.72 (1H, dd,
J¼9.6, 2.0 Hz, H17), 3.59 (1H, dd, J¼9.2, 7.9 Hz, H13a), 3.41 (1H, dd,
J¼8.8, 4.8 Hz, H13b), 3.17e3.10 (1H, ddq, J¼9.2, 6.8, 4.1 Hz, H14),
2.96 (1H, br s, OH), 2.82 (1H, dq, J¼7.2, 2.4 Hz, H16), 2.37 (2H, d,
J¼2.0 Hz, H22), 2.18 (1H, ddd, J¼13.2, 8.0, 4.0 Hz, H19a), 1.86e1.75
(1H, m, H18), 1.40 (1H, ddd, J¼13.6, 8.0, 5.6 Hz, H19b), 1.05 (3H, d,
J¼7.2 Hz, C14eCH3), 1.00 (3H, d, J¼6.8 Hz, C16eCH3), 0.89 (9H, s,
SiC(CH3)3) 0.84 (3H, d, J¼6.8 Hz, C18eCH3), 0.13 (3H, s, Si(CH3)CH3),
0.11 (3H, s, Si(CH3)CH3); dC NMR (100 MHz; CDCl3) 218.0, 159.5,
129.8, 129.4, 114.0, 86.3, 74.5, 73.3, 73.1, 72.1, 61.6, 55.3, 48.6, 44.4,
42.8, 31.9, 25.9, 18.3, 16.4, 13.9, 7.8, ꢀ4.3, ꢀ4.9; IR (film, cmꢀ1) 3505,
3307, 2933, 2857, 1711, 1613, 1586, 1513; HRESIMS calculated for
C27H44O5SiCle: 511.2652; found: 511.2655.
4.2.6. (3S,5S,6S,7R,8S,9S)-3-(tert-Butyldimethylsilyloxy)-10-(4-
methoxyphenyl)oxy-5,7,9-trimethyl-6,8-[(bis-dimethyl-methylene)
dioxy]-decan-2-one (7). To a stirred solution of alkyne 13 (21.5 mg;
41.4
62.2
12.4
m
m
m
mol) in THF (0.8 mL) was added sequentially PPTS (15.6 mg;
mol), pH 7 buffer (2 L; 111 mol) and Hg(OAc)2 (4.0 mg;
mol) and the resulting mixture was stirred at 45 ꢂC for 48 h.
m
m
The reaction was quenched by addition of satd aq NaHCO3 (2 mL)
and the mixture was extracted with Et2O (3ꢄ5 mL), the combined
organic extracts were dried (Na2SO4) and concentrated in vacuo.
Purification by column chromatography (buffered silica, 10% EtOAc/
hexanes) gave methyl ketone 7 (13.2 mg, 59%) as a colourless oil.
4.2.4. (3S,5S,6S,7R,8S,9S)-3-(tert-Butyldimethylsilyloxy)-6,8-
dihydroxy-10-(4-methoxyphenyl)oxy-5,7,9-trimethyl-dec-1-yne
Rf¼0.31 (10% EtOAc/hexanes);
½
a 2D0
ꢃ
ꢀ8.1 (c 1.24, CHCl3); dH
(400 MHz; CDCl3) 7.25 (2H, d, J¼8.8 Hz, ArH), 6.87 (2H, d, J¼8.8 Hz,
ArH), 4.41 (2H, ABq, J¼11.6 Hz, OCH2PMP), 4.07 (1H, dd, J¼9.6,
3.6 Hz, H20), 3.80 (3H, s, OCH3), 3.54 (1H, dd, J¼9.2, 4.8 Hz, H13a),
(36). To a stirred solution of
b-hydroxyketone 12 (52.5 mg;
110 mol) in a 1:1 mixture of AcOH/CH3CN (4.4 mL) was added
m

6850
C. Gregg, M.V. Perkins / Tetrahedron 69 (2013) 6845e6854
3.31 (1H, dd, J¼9.2, 7.2 Hz, H13b), 3.25 (1H, dd, J¼10.8, 4.0 Hz, H15),
3.22 (1H, dd, J¼6.8, 5.6 Hz, H17), 2.16 (3H, s, H22), 2.05 (1H, ddd,
J¼13.2, 9.6, 2.8 Hz, H19a), 1.94e1.85 (1H, m, H14), 1.89 (1H, ddd,
J¼13.6, 6.8, 3.6 Hz, H19b), 1.77e1.69 (2H, m, H16 and H18), 1.27 (3H,
s, C(CH3)CH3), 1.23 (3H, s, C(CH3)CH3), 0.99 (3H, d, J¼6.8 Hz,
C14eCH3), 0.92 (9H, s, SiC(CH3)3), 0.83 (3H, d, J¼6.8 Hz, C16eCH3),
0.80 (3H, d, J¼6.8 Hz, C18eCH3), 0.05 (3H, s, Si(CH3)CH3), 0.04 (3H,
s, Si(CH3)CH3); dC (100 MHz; CDCl3) 212.8, 159.2, 131.0, 129.3, 113.9,
100.5, 77.6, 76.7, 73.5, 72.9, 72.2, 55.4, 38.1, 38.0, 35.3, 28.7, 25.9,
25.3, 25.1, 23.6, 18.3,15.4,14.3,12.5, ꢀ4.6, ꢀ4.9; IR (film, cmꢀ1) 3411,
2957, 2932, 2857, 1715, 1612, 1586, 1513; HRESIMS calculated for
C30H52O6SiNaþ: 559.3425; found: 559.3427.
a white solid. Rf¼0.42 (5% Et2O/CH2Cl2); ½a D20
ꢀ45.9 (c 0.68, CHCl3);
ꢃ
dH (600 MHz; CDCl3) 7.35e7.32 (2H, m, ArH), 7.29e7.26 (1H, m, ArH),
7.22e7.20 (2H, m, ArH), 5.24 (1H, q, J¼6.6 Hz, H31), 4.69 (1H, m,
CHCH2Ph), 4.23 (1H, dd, J¼9.0, 7.2 Hz, CHCHAHBO), 4.19 (1H, dd,
J¼9.0, 2.4 Hz, CHCHAHBO), 3.97 (1H, dq, J¼6.6, 2.4 Hz, H26), 3.62 (1H,
ddd, J¼8.4, 2.4, 2.4 Hz, H27), 3.27 (1H, dd, J¼13.8, 3.6 Hz, CHAHBPh),
2.95(1H, d, J¼3.0Hz, OH), 2.79(1H, dd, J¼13.2, 9.6Hz, CHAHBPh), 2.52
(1H, d, J¼12.6 Hz, H29a),1.78e1.72 (1H, m, H28),1.70 (1h, dd, J¼13.2,
9.6 Hz, H29b), 1.60 (3H, s, C30eCH3), 1.58 (3H, d, J¼6.6 Hz, H32), 1.25
(3H, d, J¼7.2 Hz, C28eCH3), 0.80 (3H, d, J¼6.6 Hz, C26eCH3); dC
(151 MHz; CDCl3) 177.7, 153.1, 135.2, 135.0, 129.6, 129.1, 127.6, 120.7,
76.2, 66.3, 55.4, 44.2, 40.0, 37.9, 34.0, 15.7, 15.4, 13.5, 9.7; IR (film,
cmꢀ1) 3523, 2968, 2919, 1781, 1696; HRESIMS calculated for
C21H29NO4Hþ: 360.2169; found: 360.2170.
4.2.7. (2R,4E)-Methyl-2,4-dimethyl-hexanoate (37). To a stirred so-
lution of (E)-2-bromo-2-butene (500
mL; 4.93 mmol) in THF
(100 mL) at 0 ꢂC was added dropwise over 1 min a solution of (R)-3-
methoxy-2-methyl-3-oxopropylzinc bromide (14) (11.8 mL; 0.5 M in
4.2.10. [[3-(2R,3S,4S,6E)-4R]-3-(3-[tert-Butyldimethylsilyloxy]-2,4,6-
trimethyl-1-oxo-oct-6-enyl)-4-(phenylmethyl)]-2-oxazolidinone
(38). The procedure used for the preparation of TBS ether 9 was
THF; 5.90 mmol). Pd(PPh3)2Cl2 (97 mg; 246 mmol) was then added in
one portion and the mixture stirred at 0 ꢂC for 10 min, followed by rt
for 24 h. The reaction was quenched by addition of satd aq NH4Cl
(100 mL) and the product extracted with Et2O (3ꢄ100 mL). The
combined organic extracts were dried (Na2SO4) and concentrated in
vacuo. Purification by column chromatography (buffered silica, 50%
hexanes/CH2Cl2) gave methyl ester 37 (526 mg; 68%) as a colourless
followed with alcohol 17 (1.32 mg; 3.68 mmol), 2,6-lutidine (857 mL;
7.36 mmol), TBSOTf (1.27 mL; 5.52 mmol) and CH2Cl2 (37 mL). Pu-
rification by column chromatography (buffered silica, 50% hexanes/
CH2Cl2) gave TBS ether 38 (1.74 g; 99%) as white solid. Rf¼0.39 (50%
hexanes/CH2Cl2); ½a D20
þ20.7 (c 1.02, CHCl3); dH (400 MHz; CDCl3)
ꢃ
7.36e7.31 (2H, m, ArH), 7.30e7.25 (1H, m, ArH), 7.23e7.20 (2H, m,
ArH), 5.14 (1H, q, J¼6.0 Hz, H31), 4.63 (1H, m, CHCH2Ph), 4.19e4.13
(2H, m, CHCH2O), 3.97 (1H, dq, J¼6.4, 6.4 Hz, H26), 3.95 (1H, dd,
J¼6.4, 3.6 Hz, H27), 3.27 (1H, dd, J¼13.2, 3.2 Hz, CHAHBPh), 2.77 (1H,
dd, J¼13.6, 9.6 Hz, CHAHBPh), 2.19 (1H, d, J¼13.2 Hz, H29a),1.76e1.69
(1H, m, H28), 1.60 (1H, dd, J¼13.2, 10.8 Hz, H29b), 1.55 (3H, d,
J¼6.8 Hz, H32), 1.51 (3H, s, C30eCH3), 1.24 (3H, d, J¼6.8 Hz,
C26eCH3), 0.93 (9H, s, OSi(CH3)3), 0.85 (3H, d, J¼6.4 Hz, C28eCH3),
0.08 (3H, s, OSi(CH3)CH3), 0.05 (3H, s, OSi(CH3)CH3); dC (100 MHz;
CDCl3) 176.3, 153.0, 135.5, 134.3, 129.6, 129.1, 120.3, 76.9, 66.1, 55.8,
42.6, 41.3, 37.8, 36.8, 27.1, 26.3, 15.9, 15.5, 14.2, 14.1, 13.5, ꢀ3.6, ꢀ3.9;
IR (film, cmꢀ1) 3531, 3062, 3028, 2928, 2856, 1783, 1681; HRESIMS
calculated for C27H43O4NSiNaþ: 496.2854; found: 496.2880.
oil. Rf¼0.30 (50% hexanes/CH2Cl2); ½a D20
þ3.92 (c 1.02, CH2Cl2); dH
ꢃ
(600 MHz; CDCl3) 5.20 (1H, q, J¼6.6 Hz, H31), 3.62 (3H, s, OCH3), 2.59
(1H, ddq, J¼7.2, 7.2, 6.6 Hz, H28), 2.34 (1H, dd, J¼13.2, 7.2 Hz, H29a),
2.00 (1H, dd, J¼13.8, 7.8 Hz, H29b),1.55 (3H, s, C30eCH3),1.54 (3H, d,
J¼6.6 Hz, H32),1.06 (3H, d, J¼6.6 Hz, C28eCH3); dC (151 MHz; CDCl3)
177.2, 132.9, 121.1, 44.0, 38.0, 16.6, 15.4, 13.5 (two carbons).
4.2.8. (2R,4E)-2,4-Dimethyl-hexanal (15). To a stirred solution of
ester 37 (449 mg; 2.87 mmol) in CH2Cl2 (14 mL) at ꢀ78 ꢂC was
added dropwise a solution of DIBAL (3.01 mL; 1 M in hexanes;
3.01 mmol). The resulting solution was stirred at ꢀ78 ꢂC for 1 h,
quenched with satd aq NH4Cl (20 mL) and warmed to rt. A mixture
of satd aq potassium sodium tartrate (20 mL) and Et2O (20 mL) was
then added with vigorous stirring for 10 min. Layers were separated
and the aqueous layer extracted with Et2O (3ꢄ20 mL). The com-
bined organic extracts were washed with brine (20 mL), dried
(Na2SO4) and concentrated in vacuo. Purification by column chro-
matography (buffered silica, 100% CH2Cl2) gave aldehyde 15
4.2.11. (2S,3S,4S,6E)-3-(tert-Butyldimethylsilyloxy)-2,4,6-trimethyl-
octan-1-ol (39). To a stirred solution of oxazolidinone 38 (254 mg;
536
m
mol) in Et2O (5.4 mL) at ꢀ10 ꢂC was added EtOH (75
mL;
1.29 mmol) and LiBH4 (643 mL; 1 M in THF; 1.29 mmol) and the
resulting mixture was stirred at ꢀ10 ꢂC for 4 h. The reaction mix-
ture was warmed to 0 ꢂC and quenched by addition of 1 M NaOH
(10 mL). The mixture was poured into brine (10 mL) and extracted
with Et2O (4ꢄ15 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo. Purification by column chro-
matography (buffered silica, 50% CH2Cl2/hexanes) gave alcohol 39
(126 mg; 78%) as a colourless oil. Rf¼0.40 (50% CH2Cl2/hexanes);
(256 mg; 71%) as a colourless oil. Rf¼0.39 (100% CH2Cl2); ½a D20
þ6.79
ꢃ
(c 2.80, CH2Cl2); dH (400 MHz; CDCl3) 9.60 (1H, d, J¼2.0 Hz, H27),
5.25 (1H, m, H31), 2.49 (1H, dddq, J¼13.6, 8.0, 6.8, 2.0 Hz, H28), 2.40
(1H, m, H29a), 1.97 (1H, m, H29b), 1.59 (3H, m, C30eCH3), 1.57 (3H,
m, H32), 1.02 (3H, d, J¼7.2 Hz, C28eCH3); dC (100 MHz; CDCl3)
205.4, 132.3, 121.6, 44.6, 41.0, 15.7, 13.5, 13.3.
½
a 2D0
ꢃ
þ7.88 (c 1.02, CHCl3); dH (600 MHz; CDCl3) 5.20e5.16 (1H, m,
4.2.9. [[3-(2R,3S,4S,6E)-4R]-3-(3-Hydroxy-2,4,6-trimethyl-1-oxo-
oct-6-enyl)-4-(phenylmethyl)]-2-oxazolidinone (17). To a stirred so-
lution of oxazolidinone (S)-16 (1.57 g; 6.74 mmol) in CH2Cl2 (10 mL)
at 0 ꢂC was added Bu2BOTf (8.09 mL; 1 M in CH2Cl2; 8.09 mmol)
dropwise giving a red solution. After 30 min Et3N (1.22 mL;
8.76 mmol) was added and the resulting yellow solution was stirred
for a further 30 min before cooling to ꢀ78 ꢂC. Aldehyde 15 (850 mg;
6.74 mmol) in CH2Cl2 (4 mL) was added dropwise viacannula and the
reaction mixture stirred at ꢀ78 ꢂC for 30 min and then at 0 ꢂC for 4 h,
at which time the reaction was quenched by addition of pH 7 buffer
(10 mL) and MeOH (10 mL). A solution of 2:1 MeOH/H2O2 (20 mL)
was then added and the mixture stirred at rt for 1 h. The volatiles
were removed in vacuo and the resulting slurry was extracted with
CH2Cl2 (3ꢄ20 mL), the combined organic extracts washed with satd
aq NaHCO3 (20 mL) and brine (20 mL), dried (Na2SO4) and concen-
trated in vacuo. Purification by column chromatography (buffered
silica, 5% Et2O/CH2Cl2) gave aldol adduct 17 (1.32 g; 55%, >98% ds) as
H31), 3.58 (1H, dd, J¼5.4, 2.4 Hz, H27), 3.57 (1H, dd, J¼10.8, 7.8 Hz,
H25a), 2.46 (1H, dd, J¼10.8, 6.6 Hz, H25b), 2.44 (1H, dd, J¼13.2,
3.6 Hz, H29a), 1.93e1.87 (1H, m, H26), 1.85e1.77 (1H, m, H28), 1.73
(1H, br s, OH), 1.66 (1H, dd, J¼13.2, 10.2 Hz, H29b), 1.57 (3H, d,
J¼9.0 Hz, H32), 1.57 (3H, s, C30eCH3), 0.90 (9H, s, OSi(CH3)3) 0.88
(3H, d, J¼7.2 Hz, C26eCH3), 0.80 (3H, d, J¼6.6 Hz, C28eCH3), 0.06
(3H, s, OSi(CH3)CH3), 0.06 (3H, s, OSi(CH3)CH3); dC (151 MHz; CDCl3)
134.6, 120.4, 76.8, 66.8, 43.9, 38.7, 35.3, 26.2, 18.5, 16.2, 15.5, 13.3,
12.0, ꢀ3.8, ꢀ4.1; IR (film, cmꢀ1) 3332, 2957, 2929, 2857; HRESIMS
calculated for C17H36O2SiHþ: 301.2557; found: 301.2562.
4.2.12. (2R,3S,4S,6E)-3-(tert-Butyldimethylsilyloxy)-2,4,6-trimethyl-
octanal (18). The procedure used for the preparation of aldehyde 10
was followed with alcohol 39 (111 mg; 369
1.11 mmol), (COCl)2 (277 L; 2 M in CH2Cl2; 554
(309 L; 2.21 mmol) and CH2Cl2 (4 mL). Purification by column
chromatography (buffered silica, 100% CH2Cl2) gave aldehyde 18
mmol), DMSO (79
mL;
m
mmol), Et3N
m

C. Gregg, M.V. Perkins / Tetrahedron 69 (2013) 6845e6854
6851
(110 mg; 100%) as a colourless oil. Rf¼0.70 (100% CH2Cl2); ½a D20
ꢃ
(265
m
L; 2 M in THF; 531
m
mol) and Et2O (3 mL). Purification by col-
ꢀ24.5 (c 1.35, CHCl3); dH (400 MHz; CDCl3) 9.70 (1H, d, J¼1.2 Hz,
H25), 5.17e5.14 (1H, m, H31), 3.97 (1H, dd, J¼5.2, 3.2 Hz, H27), 2.49
(1H, ddq, J¼6.8, 3.6, 0.8 Hz, H26), 2.18e2.14 (1H, m, H29a),
1.88e1.76 (1H, m, H28), 1.67 (1H, dd, J¼13.2, 10.0 Hz, H29b), 1.56
(3H, m, H32), 1.54 (3H, s, C30eCH3), 1.10 (3H, d, J¼7.2 Hz, C26eCH3),
0.90 (9H, s, OSi(CH3)3) 0.81 (3H, d, J¼7.2 Hz, C28eCH3), 0.06 (3H, s,
OSi(CH3)CH3), ꢀ0.02 (3H, s, OSi(CH3)CH3); dC (100 MHz; CDCl3)
205.4, 134.0, 120.7, 75.0, 50.1, 43.3, 35.8, 26.0, 18.4, 15.7, 15.4, 13.5,
8.6, ꢀ4.0, ꢀ4.1; IR (film, cmꢀ1) 3435, 2929, 2857, 2708, 1727, 1691.
umn chromatography (buffered silica, 50% CH2Cl2/hexanes) gave al-
cohol 41 (76.9 mg; 74%) as a colourless oil. Rf¼0.40 (50% CH2Cl2/
hexanes); ½a 2D0
ꢀ7.44 (c 1.21, CHCl3); dH (600 MHz; CDCl3) 5.19 (1H, q,
ꢃ
J¼6.6 Hz, H31), 3.77 (1H, d, J¼7.2 Hz, H27), 3.57 (1H, dd, J¼3.0, 3.0 Hz,
H25), 3.52 (1H, dd, J¼10.0, 7.8 Hz, H23a), 3.46 (1H, dd, J¼10.0, 6.0 Hz,
H23b), 2.11 (1H, d, J¼10.0 Hz, H29a),1.84e1.81 (1H, m, H26),1.84e1.81
(1H, m, H24), 1.75 (1H, d, J¼10.0 Hz, H29b), 1.76e2.74 (1H, m, H28),
1.57 (3H, d, J¼6.6 Hz, H32), 1.57 (3H, s, C30eCH3), 1.53 (1H, br s, OH),
0.97 (9H, t, J¼7.8 Hz, OSi(CH2CH3)3), 0.92 (9H, s, OSi(CH3)3), 0.88 (3H,
d J¼6.6 Hz, C24eCH3) 0.87 (3H, d, J¼6.6 Hz, C26eCH3), 0.78 (3H, d,
J¼6.0 Hz, C28eCH3), 0.63 (6H, q, J¼7.8 Hz, OSi(CH2CH3)3), 0.07 (3H, s,
OSi(CH3)CH3), 0.06 (3H, s, OSi(CH3)CH3); dC (151 MHz; CDCl3) 134.5,
120.1, 77.0, 74.8, 67.2, 42.0, 41.3, 38.0, 37.1, 26.3, 18.7, 15.9, 15.7, 14.3,
13.5, 11.2, 7.2, 5.7, ꢀ3.4, ꢀ3.4; IR (film, cmꢀ1) 3355, 2957, 2878, 2858;
HRESIMS calculated for C26H56O3Si2Naþ: 495.3660; found: 495.3661.
4.2.13. [[3-(2S,3R,4S,5S,6S,8E)-4S]-3-(5-[tert-Butyldimethylsilyloxy]-
3-hydroxyl-2,4,6,8-tetramethyl-1-oxo-dec-8-enyl)-4-(phenyl-
methyl)]-2-oxazolidinone (19). The procedure used for the prepa-
ration of aldol adduct 17 was followed with oxazolidinone (S)-16
(112 mg; 481
(87 L; 625
m
mol), Bu2BOTf (577
m
L; 1 M in CH2Cl2; 577
mmol), Et3N
m
mmol), aldehyde 18 (144 mg; 481 m
mol) and CH2Cl2
(1 mL). Purification by column chromatography (buffered silica,
100% CH2Cl2) gave aldol adduct 19 (182 mg; 71%) as a white solid.
4.2.16. (2S,3R,4R,5S,6S,8E)-5-(tert-Butyldimethylsilyloxy)-3-
triethylsilyloxyl-2,4,6,8-tetramethyl-dec-8-en-1-al (6). The pro-
cedure used for the preparation of aldehyde 10 was followed with
Rf¼0.56 (100% CH2Cl2); ½a D20
þ20.7 (c 1.02, CHCl3); dH (600 MHz;
ꢃ
CDCl3) 7.34e7.31 (2H, m, ArH), 7.28e7.26 (1H, m, ArH), 7.22e7.20
(2H, m, ArH), 5.18 (1H, q, J¼6.6 Hz, H31), 4.71 (1H, m, CHCH2Ph), 4.21
(1H, dd, J¼8.4, 7.8 Hz, CHCHAHBO), 4.17 (1H, dd, J¼9.0, 3.0 Hz,
CHCHAHBO), 3.93 (1H, d, J¼10.2 Hz, H27), 3.87 (1H, dq, J¼6.6, 1.8 Hz,
H24), 3.80 (1H, dd, J¼6.0, 1.2 Hz, H25), 3.61 (1H, br s, OH), 3.10 (1H,
dd, J¼13.8, 3.6 Hz, CHAHBPh), 2.77 (1H, dd, J¼13.8, 9.6 Hz, CHAHBPh),
2.38 (1H, d, J¼13.2 Hz, H29a), 1.85e1.78 (2H, m, H26 and H28), 1.57
(1H, m, H29b),1.57 (3H, d, J¼6.6 Hz, H32),1.55 (3H, s, C30eCH3),1.21
(3H, d, J¼7.2 Hz, C24eCH3), 0.90 (9H, s, OSi(CH3)3), 0.87 (3H, d,
J¼7.2 Hz, C26eCH3), 0.79 (3H, d, J¼7.2 Hz, C28eCH3), 0.09 (3H, s,
OSi(CH3)CH3), 0.08 (3H, s, OSi(CH3)CH3); dC (151 MHz; CDCl3) 177.4,
153.1, 135.4, 134.7, 129.6, 129.1, 127.5, 120.3, 72.3, 66.3, 55.6, 44.2,
40.0, 39.0, 37.9, 34.8, 26.2, 26.0, 18.4, 16.4, 15.5, 13.5, 11.4, 8.7, ꢀ3.9,
ꢀ4.1; IR (film, cmꢀ1) 3531, 3062, 3028, 2928, 2856, 1783, 1681;
HRESIMS calculated for C30H49NO5Si: 532.3453; found: 532.3454.
the above alcohol 41 (23.2 mg; 49.1 mmol), DMSO (10
m
m
L;
L;
147
295
mmol), (COCl)2 (37 mL; 2 M in CH2Cl2; 73.7 mmol), Et3N (41
mmol) and CH2Cl2 (0.5 mL). Purification by column chroma-
tography (buffered silica, 50% hexanes/CH2Cl2) gave aldehyde 6
(23.1 mg; 100%) as a colourless oil. Rf¼0.66 (50% hexanes/CH2Cl2);
½
a 2D0
ꢃ
þ18.2 (c 1.16, CH2Cl2); dH (600 MHz; CDCl3) 9.69 (1H, s, H23),
5.19 (1H, q, J¼6.6 Hz, H31), 4.17 (1H, dd, J¼7.2,1.8 Hz, H27), 3.61 (1H,
dd, J¼3.6, 3.0 Hz, H25), 2.45 (1H, dq, J¼7.2, 1.8 Hz, H24), 2.10 (1H, d,
J¼10.8 Hz, H29a), 1.82 (1H, ddq, J¼7.2, 6.6, 2.4 Hz, H26), 1.78e1.72
(1H, m, H28), 1.71 (1H, d, J¼10.8 Hz, H29b), 1.58 (3H, d, J¼9.0 Hz,
H32), 1.57 (3H, s, C30eCH3), 1.12 (3H, d, J¼7.2 Hz, C24eCH3), 0.93
(9H, t, J¼7.8 Hz, OSi(CH2CH3)3), 0.90 (9H, s, OSi(CH3)3), 0.86 (3H, d,
J¼7.2 Hz, C26eCH3), 0.78 (3H, d, J¼6.0 Hz, C28eCH3), 0.57 (6H, q,
J¼7.8 Hz, OSi(CH2CH3)3), 0.07 (3H, s, OSi(CH3)CH3), 0.06 (3H, s,
OSi(CH3)CH3); dC (151 MHz; CDCl3) 205.5, 134.2, 120.2, 76.2, 73.2,
49.7, 42.6, 41.0, 37.6, 26.2, 18.6, 15.6, 15.5, 13.5, 11.9, 7.7, 7.1, 5.6, ꢀ3.4,
ꢀ3.6; IR (film, cmꢀ1) 2957, 2878, 2858, 2706, 1728.
4.2.14. [[3-(2S,3R,4R,5S,6S,8E)-4S]-3-(5-[tert-Butyldimethylsilyloxy]-
3-triethylsilyloxyl-2,4,6,8-tetramethyl-1-oxo-dec-8-enyl)-4-(phenyl-
methyl)]-2-oxazolidinone (40). The procedure used for the prepa-
ration of silyl ether 9 was followed with alcohol 19 (492 mg;
4.2.17. (2S,3S,4R,5S,6S,8S,11R,12R,13S,14R,15S,16S,18E)-1-(8,15-
Bis(tert-butyldimethylsilyloxy)-13-triethylsilyloxy-11-hydroxy-4-
methoxybenzyl)oxy-2,4,6,12,14,16,18-heptameth3-dimethyl-methy-
lene)dioxy]-icos-18-en-9-one (5) and (2S,3S,4R,5S,6S,8S,11S,12R,13S,
14R,15S,16S,18E)-1-(8,15-bis(tert-butyldimethylsilyloxy)-13-
triethylsilyloxy-11-hydroxy-4-methoxybenzyl)oxy-2,4,6,12,14,16,18-
heptamethyl-3,5-[(bis-dimethyl-methylene)dioxy]-icos-18-en-9-one
925
mmol), 2,6-lutidine (215 mL; 1.85 mmol), TESOTf (314 mL;
1.39 mmol) and CH2Cl2 (9 mL). Purification by column chromatog-
raphy (buffered silica, 50% CH2Cl2/hexanes) gave TES ether 40
(567 mg; 95%) as a clear, colourless liquid. Rf¼0.49 (50% CH2Cl2/
hexanes); ½a 2D0
þ20.0 (c 1.15, CHCl3); dH (600 MHz; CDCl3) 7.36e7.33
ꢃ
(2H, m, ArH), 7.30e7.26 (1H, m, ArH), 7.23e7.22 (2H, m, ArH), 5.18
(1H, m, H31), 4.60 (1H, m, CHCH2Ph), 4.18 (1H, dd, J¼9.6, 2.4 Hz,
CHCHAHBO), 4.13 (1H, dd, J¼9.0, 7.2 Hz, CHCHAHBO), 4.07 (1H, dd,
J¼6.6, 3.6 Hz, H27), 3.95 (1H, dq, J¼6.6, 4.2 Hz, H24), 3.57 (1H, dd,
J¼3.6, 3.0 Hz, H25), 3.27 (1H, dd, J¼13.8, 3.0 Hz, CHAHBPh), 2.78 (1H,
dd, J¼13.2, 9.6 Hz, CHAHBPh), 2.15 (1H, d, J¼10.2 Hz, H29a),1.86e1.80
(2H, m, H26 and H28),1.72 (1H, m, H29b),1.58 (3H, d, J¼6.0 Hz, H32),
1.58 (3H, s, C30eCH3), 1.21 (3H, d, J¼7.2 Hz, C24eCH3), 0.99 (9H, t,
J¼7.8 Hz, OSi(CH2CH3)3), 0.93 (3H, d, J¼7.2 Hz, C26eCH3), 0.91 (9H, s,
OSi(CH3)3), 0.77 (3H, d, J¼6.6 Hz, C28eCH3), 0.64 (6H, q, J¼7.8 Hz,
OSi(CH2CH3)3), 0.05 (3H, s, OSi(CH3)CH3), 0.05 (3H, s, OSi(CH3)CH3);
dC (151 MHz; CDCl3) 175.9, 152.9, 135.4, 134.5, 129.6, 129.1, 127.5,
120.0, 76.3, 74.8, 66.0, 55.9, 42.2, 41.8, 40.8, 37.7, 36.9, 34.8, 26.3,18.7,
16.3, 15.6, 13.5, 11.8, 7.3, 5.7, ꢀ3.2, ꢀ3.6; IR (film, cmꢀ1) 3027, 2956,
2878, 2857, 1784, 1701; HRESIMS calculated for C36H63NO5Si2Naþ:
668.4137; found: 668.4127.
(20). To a stirred solution of ketone 7 (79 mg; 147
m
mol) in THF
(0.4 mL) at ꢀ78 ꢂC was added LiHMDS (294
mL; 1 M in THF;
294
m
mol) dropwise and the mixture stirred at ꢀ78 ꢂC for 1 h. Al-
dehyde 6 (70 mg; 148 mmol) was added dropwise via cannula and
the reaction mixture was stirred at ꢀ78 ꢂC for 5 h. The reaction
mixture was diluted with Et2O (3 mL) and quenched with NaHCO3
(3 mL). The layers were separated and the aqueous layer extracted
with Et2O (3ꢄ5 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo. Purification by column chro-
matography (buffered silica, 100% CH2Cl2) gave aldol diastereomer
5 (51.2 mg; 35%) and aldol isomer 20 (21.8 mg, 15%) (NB on one
occasion when the reaction was performed on a larger scale
w130 mg ketone 7 the selectivity was observed to be reduced to
w1.5:1. This was apparently due to lack of temperature control in
this latter reaction). Compound 5: Rf¼0.57 (100% CH2Cl2); ½a D20
ꢃ
ꢀ2.20 (c 0.91, CHCl3); dH (600 MHz; CDCl3) 7.26 (2H, d, J¼9.0 Hz,
ArH), 6.87 (2H, d, J¼8.4 Hz, ArH), 5.20 (1H, q, J¼6.0 Hz, H31), 4.42
(2H, ABq, J¼11.4 Hz, OCH2PMP), 4.13 (1H, d, J¼7.2 Hz, H27), 4.11 (1H,
dd, J¼9.0, 3.6 Hz, H20), 3.80 (3H, s, OCH3), 3.77 (1H, m, H23), 3.61
(1H, dd, J¼3.0, 3.0 Hz, H25), 3.54 (1H, dd, J¼9.0, 4.8 Hz, H13a), 3.32
(1H, s, OH), 3.31 (1H, dd, J¼9.0, 7.2 Hz, H13b), 3.25 (1H, dd, J¼10.8,
4.2.15. (2R,3S,4R,5S,6S,8E)-5-(tert-Butyldimethylsilyloxy)-3-
triethylsilyloxyl-2,4,6,8-tetramethyl-dec-8-en-1-ol (41). The proce-
dure used for the preparation of alcohol 39 was followed with oxa-
zolidinone 40 (143 mg; 221 mmol), EtOH (31 mL; 531 mmol), LiBH4

6852
C. Gregg, M.V. Perkins / Tetrahedron 69 (2013) 6845e6854
4.2 Hz, H17), 3.22 (1H, dd, J¼7.2, 6.0 Hz, H15), 2.96 (1H, dd, J¼18.6,
1.8 Hz, H22a), 2.49 (1H, dd, J¼18.6, 9.0 Hz, H22b), 2.13 (1H, d,
J¼12.0 Hz, H29a), 2.08 (1H, ddd, J¼13.2, 9.6, 3.0 Hz, H19a),
1.93e1.88 (1H, m, H14), 1.91e1.86 (1H, m, H16), 1.81e1.76 (1H, m,
H28), 1.79e1.75 (1H, m, H26), 1.74e1.68 (1H, m, H18), 1.73 (1H, dd,
J¼12.6, 10.8, H29b), 1.63 (1H, dd, J¼9.0, 6.6 Hz, H24), 1.58 (3H, d,
J¼7.2 Hz, H32), 1.57 (3H, s, C30eCH3), 1.27 (3H, s, C(CH3)CH3), 1.23
(3H, s, C(CH3)CH3), 1.08 (1H, ddd, J¼13.2, 9.6, 4.2 Hz, H19b), 0.99
(3H, J¼6.6 Hz, C14eCH3), 0.97 (9H, t, J¼7.8 Hz, OSi(CH2CH3)3), 0.92
(9H, s, OSiC(CH3)3), 0.90 (9H, s, OSiC(CH3)3), 0.84 (3H, d, J¼7.2 Hz,
C28eCH3), 0.83 (3H, d, J¼6.6 Hz, C16eCH3), 0.81 (3H, d, J¼6.6 Hz,
C18eCH3), 0.78 (3H, d, J¼6.6 Hz, C26eCH3), 0.77 (3H, d, J¼6.6 Hz,
C24eCH3), 0.65 (3H, q, J¼7.8 Hz, OSi(CH2CH3)3), 0.64 (3H, q,
J¼7.8 Hz, OSi(CH2CH3)3), 0.08 (3H, s, OSi(CH3)CH3), 0.07 (3H, s,
OSi(CH3)CH3), 0.06 (3H, s, OSi(CH3)CH3), 0.04 (3H, s, OSi(CH3)CH3);
dC (151 MHz; CDCl3) 216.7, 159.2, 134.6, 130.9, 129.2, 119.9, 113.8,
100.5, 77.6, 76.7, 76.6, 73.4, 72.9, 72.1, 69.2, 55.38, 55.36, 42.0, 41.6,
41.3, 39.9, 38.07, 38.02, 37.4, 35.3, 28.8, 26.3, 25.9, 25.8, 25.4, 23.6,
18.7, 18.20, 18.17, 15.8, 15.6, 15.4, 13.5, 12.4, 12.41, 12.1, 10.6, 7.3, 5.8,
ꢀ3.4, ꢀ3.5, ꢀ4.6, ꢀ4.9; IR (film, cmꢀ1) 3527, 2957, 1706, 1613, 1586,
1513; HRESIMS calculated for C56H106O9Si3Naþ: 1029.7037; found:
(1H, dd, J¼10.2, 3.0 Hz, H20), 3.82 (1H, d, J¼5.4 Hz, H27), 3.80 (3H, s,
ArOCH3), 3.62 (1H, ddd, J¼7.8, 4.8, 3.0 Hz, H23), 3.54 (1H, dd, J¼9.6,
5.4 Hz, H13a), 3.47 (1H, d, J¼5.4 Hz, H25), 3.32 (1H, dd, J¼9.0,
6.6 Hz, H13b), 3.26 (1H, dd, J¼9.6, 3.6 Hz, H17), 3.25 (3H, s,
C23eOCH3), 3.23 (1H, dd, J¼6.6, 6.0 Hz, H15), 2.80 (2H, dd, J¼18.0,
8.4 Hz, H22a), 2.55 (1H, dd, J¼18.0, 3.0 Hz, H22b), 2.09 (1H, d,
J¼10.2 Hz, H29a), 2.04 (1H, ddd, J¼12.6, 9.6,1.8 Hz, H19a),1.94e1.88
(1H, m, H14), 1.91e1.85 (1H, m, H24), 1.90e1.84 (1H, m, H16),
1.85e1.80 (1H, m, H26), 1.85e1.80 (1H, m, H28), 1.83e1.78 (1H, m,
H29b), 1.77e1.72 (1H, m, H18), 1.58 (3H, d, J¼6.6 Hz, H32), 1.57 (3H,
s, C30CH3), 1.26 (3H, s, C(CH3)CH3), 1.22 (3H, s, C(CH3)CH3), 1.12 (1H,
ddd, J¼12.6, 10.2, 4.8 Hz, H19b), 1.00 (3H, d, J¼6.6 Hz, C14eCH3),
0.98 (9H, t, J¼7.8 Hz, OSi(CH2CH3)3), 0.91 (9H, s, OSiC(CH3)3), 0.91
(9H, s, OSiC(CH3)3), 0.89 (3H, d, J¼6.6 Hz, C26eCH3), 0.87 (3H, d,
J¼7.2 Hz, C24eCH3), 0.83 (3H, d, J¼6.6 Hz, C18eCH3), 0.81 (3H, d,
J¼6.6 Hz, C28eCH3), 0.79 (3H, d, J¼6.6 Hz, C16eCH3), 0.65 (6H, q,
J¼7.8 Hz, OSi(CH2CH3)3), 0.07 (3H, s, OSi(CH3)CH3), 0.06 (3H, s,
OSi(CH3)CH3), 0.05 (3H, s, OSi(CH3)CH3), 0.03 (3H, s, OSi(CH3)CH3);
dC (151 MHz; CDCl3) 212.5, 159.2, 134.4, 131.0, 129.3, 120.0, 113.8,
100.4, 80.0, 77.5, 77.2, 76.6, 73.4, 72.9, 72.5, 72.2, 58.0, 55.4, 42.9,
41.1, 39.5, 38.1, 37.4, 37.2, 35.8, 35.3, 28.9, 26.3, 25.9, 25.2, 23.5, 18.7,
18.4, 16.6, 15.6, 15.0, 14.3, 13.5, 12.5, 12.2, 11.3, 7.4, 5.9, ꢀ3.3, ꢀ4.4,
ꢀ4.96, ꢀ5.03; IR (film, cmꢀ1) 2957, 2857, 1716, 1700, 1615, 1514.
a 20
1029.7045. Compound 20: Rf¼0.40 (100% CH2Cl2); ½ ꢃD ꢀ16.0 (c
0.38, CHCl3); dH (600 MHz; CDCl3) 7.25 (2H, d, J¼8.4 Hz, ArH), 6.87
(2H, d, J¼9.0 Hz, ArH), 5.20 (1H, q, J¼6.6 Hz, H31), 4.41 (2H, ABq,
J¼11.4 Hz, OCH2PMP), 4.11 (1H, dd, J¼9.6, 3.6 Hz, H20), 4.06 (1H,
ddd, J¼8.4, 4.2, 4.2 Hz, H23), 3.84 (1H, dd, J¼5.4, 1.2 Hz, H27), 3.80
(3H, s, OCH3), 3.53 (1H, dd, J¼9.0, 4.8 Hz, H13a), 3.49 (1H, dd, J¼4.8,
1.2 Hz, H25), 3.31 (1H, dd, J¼9.0, 7.2 Hz, H13b), 3.24 (1H, dd, J¼10.2,
3.6 Hz, H17), 3.22 (1H, dd, J¼6.0, 5.4 Hz, H15), 3.02 (1H, s, OH), 2.73
(1H, dd, J¼18.0, 4.3 Hz, H22a), 2.66 (1H, dd, J¼18.0, 8.4 Hz, H22b),
2.09 (1H, d, J¼9.6 Hz, H29a), 2.06 (1H, ddd, J¼13.8, 7.8, 3.0 Hz,
H19a), 1.93e1.89 (1H, m, H14), 1.91e1.87 (1H, m, H16), 1.90e1.84
(1H, m, H28), 1.80e1.72 (1H, m, H26), 1.79e1.76 (1H, dd, J¼12.6,
10.8, H29b), 1.76e1.70 (1H, m, H18), 1.72e1.67 (1H, m, H24), 1.59
(3H, s, C30eCH3), 1.58 (3H, d, J¼7.2 Hz, H32), 1.26 (3H, s, C(CH3)
CH3), 1.22 (3H, s, C(CH3)CH3), 1.07 (1H, ddd, J¼13.2, 10.2, 3.6 Hz,
H19b), 0.99 (3H, J¼7.2 Hz, C14eCH3), 0.97 (9H, t, J¼7.8 Hz,
OSi(CH2CH3)3), 0.93 (3H, d, J¼6.6 Hz, C24eCH3), 0.91 (9H, s,
OSiC(CH3)3), 0.90 (9H, s, OSiC(CH3)3), 0.90 (3H, d, J¼7.2 Hz,
C28eCH3), 0.83 (3H, d, J¼6.6 Hz, C16eCH3), 0.82 (3H, d, J¼6.0 Hz,
C18eCH3), 0.78 (3H, d, J¼6.0 Hz, C26eCH3), 0.64 (6H, q, J¼7.8 Hz,
OSi(CH2CH3)3), 0.06 (6H, s, OSi(CH3)CH3), 0.05 (3H, s, OSi(CH3)CH3),
0.04 (3H, s, OSi(CH3)CH3); dC (151 MHz; CDCl3) 214.4, 159.2, 134.3,
130.9, 129.3, 120.2, 113.86, 100.4, 98.9, 77.3, 76.58, 76.55, 73.3, 72.9,
72.1, 71.4, 55.4, 42.01, 41.98, 41.7, 39.0, 38.0, 37.9, 36.2, 35.3, 33.1,
28.9, 26.3, 25.9, 25.4, 23.6, 18.7, 18.3, 16.1, 15.7, 15.3, 14.3, 13.5, 12.5,
4.2.19. (2S,3S,4R,5S,6S,8S,11S,12R,13S,14R,15S,16S,18E)-1-(8,15-
Bis(tert-butyldimethylsilyloxy)-13-triethylsilyloxy-11-methoxy-4-
methoxybenzyl)oxy-2,4,6,12,14,16,18-heptamethyl-3,5-[(bis-di-
methyl-methylene)dioxy]-icos-18-en-9-one (43). The procedure
used for the preparation of methyl ether 42 was followed with aldol
ꢀ
diastereomer 5 (68.4 mg; 67.9
proton sponge (87.3 mg; 407
m
m
mol) 4 A molecular sieves (130 mg),
mol), Me3OBF4 (60.2 mg; 407 mmol)
and CH2Cl2 (1.4 mL). Purification by column chromatography
(buffered silica, 100% CH2Cl2) gave methyl ether 43 (53.9 mg; 78%).
Rf¼0.43 (100% CH2Cl2); dH (600 MHz; CDCl3) 7.25 (2H, d, J¼8.4 Hz,
ArH), 6.87 (2H, d, J¼8.4 Hz, ArH), 5.20 (1H, q, J¼6.6 Hz, H31), 4.42
(2H, ABq, J¼11.4 Hz, OCH2PMP), 4.17 (1H, dd, J¼9.6, 3.0 Hz, H20),
3.83 (1H, d, J¼5.4 Hz, H27), 3.80 (3H, s, ArOCH3), 3.64 (1H, ddd,
J¼10.2, 7.8, 3.0 Hz, H23), 3.54 (1H, dd, J¼9.0, 4.8 Hz, H13a), 3.53 (1H,
m, H25), 3.31 (1H, dd, J¼9.0, 6.6 Hz, H13b), 3.25 (1H, dd, J¼9.0,
3.6 Hz, H17), 3.22 (3H, s, C23eOCH3), 3.22 (1H, m, H15), 2.80 (1H,
dd, J¼17.4, 8.4 Hz, H22a), 2.55 (1H, dd, J¼17.4, 3.0 Hz, H22b), 2.10
(1H, ddd, J¼13.2, 10.2, 2.4 Hz, H19a), 2.08 (1H, d, J¼8.4 Hz, H29a),
1.93e1.89 (1H, m, H14), 1.92e1.86 (1H, m, H24), 1.86e1.81 (3H, m,
H16), 1.84e1.79 (1H, m, H26), 1.82e1.77 (1H, m, H28), 1.79 (1H, d,
J¼7.8 Hz, H29b), 1.77e1.71 (1H, m, H18), 1.59 (3H, d, J¼5.4 Hz, H32),
1.58 (3H, s, C30eCH3), 1.26 (3H, s, C(CH3)CH3), 1.22 (3H, s, C(CH3)
CH3), 1.10 (1H, ddd, J¼13.8, 10.2, 3.6 Hz, H19b), 0.99 (3H, d, J¼6.6 Hz,
C14eCH3), 0.97 (9H, t, J¼7.8 Hz, OSi(CH2CH3)3), 0.92 (9H, s,
OSiC(CH3)3), 0.91 (9H, s, OSiC(CH3)3), 0.89 (3H, d, J¼7.2 Hz,
C26eCH3), 0.83 (3H, d, J¼6.6 Hz, C24eCH3), 0.83 (3H, d, J¼6.6 Hz,
C18eCH3), 0.80 (3H, d, J¼6.0 Hz, C28eCH3), 0.79 (3H, d, J¼7.2 Hz,
C16eCH3), 0.63 (6H, q, J¼7.8 Hz, OSi(CH2CH3)3), 0.07 (6H, s,
OSi(CH3)CH3), 0.06 (3H, s, OSi(CH3)CH3), 0.04 (3H, s, OSi(CH3)CH3);
dC (151 MHz; CDCl3) 212.4, 159.2, 134.4, 131.0, 129.3, 120.1, 113.8,
100.4, 79.8, 77.7, 76.6, 76.2. 73.7, 73.4, 72.9, 72.2, 57.2, 55.4, 42.5,
41.7, 40.2, 38.1, 37.7, 37.5, 36.8, 35.3, 28.9, 26.3, 26.0, 25.2, 23.6, 18.7,
18.3, 16.0, 15.7, 15.1, 14.3, 13.5, 12.5, 11.9, 10.3, 7.3, 5.8, ꢀ3.4, ꢀ3.6,
ꢀ4.4, ꢀ5.0; IR (film, cmꢀ1) 2925, 1717, 1613, 1586, 1513; HRESIMS
calculated for C57H108O9Si3Naþ: 1043.7193; found: 1043.7197.
12.3, 9.1, 7.2, 5.76, 5.74, ꢀ3.30, ꢀ3.35, ꢀ4.4, ꢀ4.9; IR (film, cmꢀ1
)
3504, 2951, 1712, 1613, 1586, 1513; HRESIMS calculated for
C56H106O9Si3Naþ: 1029.7037; found: 1029.7040.
4.2.18. (2S,3S,4R,5S,6S,8S,11S,12R,13S,14R,15S,16S,18E)-1-(8,15-
Bis(tert-butyldimethylsilyloxy)-13-triethylsilyloxy-11-methoxy-4-
methoxybenzyl)oxy-2,4,6,12,14,16,18-heptamethyl-3,5-[(bis-di-
methyl-methylene)dioxy]-icos-18-en-9-one (42). To a stirred solu-
tion of aldol diastereomer 20 (53.5 mg; 53.1
m
mol) in CH2Cl2
(1.1 mL) at 0 C was added sequentially 4 A molecular sieves
(100 mg), proton sponge (68.3 mg; 319 mol) and Me3OBF4
(47.2 mg; 319 mol). The reaction was warmed to rt for 1 h, before
ꢂ
ꢀ
m
m
quenching by addition of satd aq NaHCO3 (2 mL). The layers were
separated and the aqueous phase was extracted with CH2Cl2
(3ꢄ5 mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo. Purification by column chromatography
(buffered silica, 100% CH2Cl2) gave methyl ether 42 (41.4 mg; 76%).
4.2.20. (2R,4S,5R,6S)-2-[(1S,3S,4S,5R,6S,7S)-1-(tert-Butyldimethylsi-
lyloxy)-8-(4-methoxyphenyl)oxy-3,5,7-trimethyl-4,6-[(bis-dimethyl-
methylene)dioxy]-octanyl]-5-[(1S,2S,3S,5E)-2-(tert-butyldimethylsi-
lyloxy)-1,3,5-trimethyl-hept-5-enyl]-2-hydroxy-4-methoxyl-5-
methyl-tetrahydro-2H-pyran (21). To a Teflon cylinder containing
Rf¼0.52 (100% CH2Cl2); ½a D20
ꢀ11.0 (c 1.00, CHCl3); dH (600 MHz;
ꢃ
CDCl3) 7.25 (2H, d, J¼9.0 Hz, ArH), 6.87 (2H, d, J¼9.0 Hz, ArH), 5.20
(1H, q, J¼6.0 Hz, H31), 4.42 (2H, ABq, J¼11.4 Hz, OCH2PMP), 4.16
TES ether 42 (41.4 mg; 40.5 mmol) was added buffered pyridinium

C. Gregg, M.V. Perkins / Tetrahedron 69 (2013) 6845e6854
6853
hydrofluoride (1 mL) from a stock solution containing dry THF
(10 mL), pyridine (5 mL), pyridinium hydrofluoride (2.1 g) and H2O
(32 mL). The resulting solution was stirred at rt for 5 days, then
12.8, 10.7, 3.8, ꢀ3.68, ꢀ3.72, ꢀ3.9, ꢀ4.3; IR (film, cmꢀ1) 3377, 2930,
2857, 1717, 1613, 1513; HRESIMS calculated for C51H94O9Si2Naþ:
929.6329; found: 929.6323.
diluted with Et2O (15 mL), washed with satd aq CuSO4 (10 mL), satd
aq NaHCO3 (10 mL) and brine (10 mL), dried (Na2SO4) and con-
centrated in vacuo. Purification by column chromatography (buff-
ered silica, 15% EtOAc/hexanes) gave hemiacetal 21 (6.1 mg; 17%) as
a clear, colourless oil. The low yield of this reaction was in part
attributed to the limited solubility of the product in the extraction
4.2.22. (2S,3R,7R,9S,11S)-2-[(1S,2S,3S,5E)-2-(tert-Butyldimethylsily-
loxy)-1,3,5-trimethyl-hept-5-enyl]-8-[(1S,2S,3S)-4-(2-hydroxy-(4-
methoxyphenyl)oxy-1,3-dimethyl)-11-(tert-butyldimethylsilyloxy)-
3,9-dimethyl-1,7-dioxaspiro[6,6]undec-4-ene (33). To a stirred so-
lution of hemiacetal 21 (6.1 mg; 6.72 mmol) in MeOH (0.5 mL) was
solvent. Rf¼0.54 (100% CH2Cl2); ½a D20
ꢃ
þ6.57 (c 0.31, CHCl3); dH
added a few crystals of CSA and the resulting solution stirred at rt
for 16 h before quenching by addition of satd aq NaHCO3 (5 mL).
The mixture was extracted with CH2Cl2 (3ꢄ5 mL) and the combined
organic extracts were dried (Na2SO4) and concentrated in vacuo.
Purification by column chromatography (buffered silica, 100%
CH2Cl2) gave elimination product 33 (1.1 mg; 20%). Rf¼0.61 (100%
CH2Cl2); dH (600 MHz; CDCl3) 7.23 (2H, d, J¼8.4 Hz, ArH), 6.84 (2H,
d, J¼9.0 Hz, ArH), 5.96 (1H, dd, J¼10.2, 6.6 Hz, H23), 5.76 (1H, dd,
J¼10.2, 0.6 Hz, H22), 5.20 (1H, q, J¼6.6 Hz, H31), 3.84 (1H, dd,
J¼10.2, 1.2 Hz, H25), 3.79 (1H, dd, J¼6.6, 1.8 Hz, H17), 3.79 (3H, s,
OCH3), 3.56 (1H, dd, J¼8.4, 4.8 Hz, H13a), 3.56e3.53 (1H, m, H27),
3.54 (1H, dd, J¼9.0, 3.0 Hz, H15), 3.47 (1H, dd, J¼6.6, 6.0 Hz, H13b),
3.38 (1H, dd, J¼3.6, 1.8 Hz, H20), 3.29 (1H, br s, OH), 2.19 (1H, d,
J¼16.2 Hz, H29a), 2.17e2.10 (1H, m, H18), 2.06e2.00 (2H, m, H24
and H28), 1.90e1.86 (3H, m, H14, H16 and H26), 1.76 (1H, ddd,
J¼14.4, 13.2, 1.8 Hz, H19a), 1.71 (1H, dd, J¼13.2, 10.2 Hz, H29b), 1.58
(3H, s, H32),1.58 (3H, s, C30eCH3), 1.50 (1H, ddd, J¼13.2, 3.6, 3.0 Hz,
H19b), 1.25 (6H, s, OC(CH3)2), 1.05 (3H, d, J¼6.6 Hz, C14eCH3), 0.96
(3H, d, J¼7.2 Hz, C16eCH3), 0.90 (9H, s, OSiC(CH3)3), 0.89 (9H, s,
OSiC(CH3)3), 0.86 (3H, d, J¼7.2 Hz, C24eCH3), 0.84 (3H, d, J¼6.6 Hz,
C28eCH3), 0.78 (6H, d, J¼6.6 Hz, C18eCH3 and C26eCH3), 0.02 (3H,
s, OSi(CH3)CH3), 0.00 (3H, s, OSi(CH3)CH3), 0.00 (3H, s, OSi(CH3)
CH3), ꢀ0.01 (3H, s, OSi(CH3)CH3).
(600 MHz; CDCl3) 7.25 (2H, d, J¼9.0 Hz, ArH), 6.87 (2H, d, J¼9.0 Hz,
ArH), 5.17 (1H, q, J¼6.6 Hz, H31), 4.92 (1H, s, C21eOH), 4.42 (2H,
ABq, J¼11.4 Hz, OCH2PMP), 3.92 (1H, d, J¼5.4 Hz, H23), 3.90 (1H, d,
J¼9.0 Hz, H25), 3.80 (3H, s, ArOCH3), 3.54 (1H, dd, J¼9.0, 4.8 Hz,
H13a), 3.51 (1H, d, J¼3.0 Hz, H27), 3.47 (1H, d, J¼9.0 Hz, H20), 3.35
(3H, s, C23eOCH3), 3.32 (1H, dd, J¼9.0, 7.2 Hz, H13b), 3.22 (1H, dd,
J¼9.6, 3.0 Hz, H17), 3.21 (1H, dd, J¼6.6, 5.4 Hz, H15), 2.31 (1H, d,
J¼12.6 Hz, H29a), 1.95e1.90 (1H, m, H24), 1.94e1.89 (1H, m, H14),
1.93e1.87 (1H, m, H19a),1.89e1.85 (1H, m, H22a),1.88e1.84 (1H, m,
H16),1.71e1.66 (4H, m, H18, H22b, H26 and H28), 1.60e1.55 (1H, m,
H29b), 1.57 (3H, d, J¼7.2 Hz, H32), 1.55 (3H, s, C30eCH3), 1.27e1.23
(1H, m, H19b), 1.24 (3H, s, OC(CH3)CH3), 1.24 (3H, s, OC(CH3)CH3),
0.99 (3H, d, J¼6.6 Hz, C14eCH3), 0.90 (9H, s, OSiC(CH3)2), 0.89 (9H,
s, OSiC(CH3)2), 0.87 (3H, d, J¼7.2 Hz, C24eCH3), 0.84 (3H, d,
J¼6.6 Hz, C16eCH3), 0.79 (3H, d, J¼7.2 Hz, C28eCH3), 0.77 (3H, d,
J¼6.6 Hz, C18eCH3), 0.75 (3H, d, J¼6.6 Hz, C26eCH3), 0.12 (3H, s,
OSi(CH3)CH3), 0.08 (3H, s, OSi(CH3)CH3) 0.08 (6H, s OSi(CH3)CH3);
dC (151 MHz, CDCl3) 159.2, 134.9, 131.0, 129.3, 120.0, 113.8, 100.3,
98.7, 81.6, 77.6, 75.8, 72.9, 72.3, 61.8, 56.5, 55.4, 43.9, 38.2, 37.5, 36.9,
35.4, 29.9, 29.4, 26.5, 26.4, 25.8, 25.3, 23.6, 18.8, 18.6, 15.7, 15.5, 15.0,
14.3, 14.2, 13.5, 12.9, 10.1, 9.9, ꢀ3.0, ꢀ3.82, ꢀ3.88, ꢀ4.3; IR (film,
cmꢀ1) 3488, 2930, 2856, 1731, 1613, 1586, 1513.
4.2.21. (2R,4R,5R,6S)-2-[(1S,3S,4S,5R,6S,7S)-1-(tert-Butyldimethylsi-
lyloxy)-8-(4-methoxyphenyl)oxy-3,5,7-trimethyl-4,6-[(bis-dimethyl-
methylene)dioxy]-octanyl]-5-[(1S,2S,3S,5E)-2-(tert-butyldimethylsi-
lyloxy)-1,3,5-trimethyl-hept-5-enyl]-2-hydroxy-4-methoxyl-5-
methyl-tetrahydro-2H-pyran (22). The procedure used for the
preparation of minor hemiacetal 21 was followed with TES ether 43
4.2.23. (2S,3R,7R,9S,11S)-2-[(1S,2S,3S,5E)-2-(tert-Butyldimethylsily-
loxy)-1,3,5-trimethyl-hept-5-enyl]-8-[(1S,2S,3S)-2-hydroxy-4-(4-
methoxyphenyl)oxy-1,3-dimethyl]-11-(tert-butyldimethylsilyloxy)-4-
methoxy-3,9-dimethyl-1,7-dioxaspiro[6,6]undecane (34). The pro-
cedure used for the preparation of spiroacetal 23 was followed with
hemiacetal 22 (6.4 mg; 7.05 mmol), CSA (a few crystals) and MeOH
(53.9 mg; 52.8
m
mol), HF/pyr/pyr (1 mL) and H2O (40
m
L). Purifi-
(0.5 mL). Purification by column chromatography (buffered silica,
100% CH2Cl2) gave spiroacetal 34 (1.3 mg; 22%) as a clear, colourless
oil. Rf¼0.37 (100% CH2Cl2); dH (600 MHz; CDCl3) 7.23 (2H, d,
J¼9.0 Hz, ArH), 6.85 (2H, d, J¼8.4 Hz, ArH), 5.19 (1H, q, J¼6.6 Hz,
H31), 4.42 (2H, ABq, J¼11.4 Hz, OCH2PMP), 3.79 (3H, s, ArOCH3),
3.78 (2H, d, J¼7.8 Hz, H25), 3.73 (1H, dd, J¼10.8, 1.2 Hz, H17), 3.64
(1H, dd, J¼9.0, 4.8 Hz, H13a), 3.50 (1H, m, H23), 3.50 (1H, m, H27),
3.48 (1H, m, H13b), 3.45 (1H, m, H15), 3.37 (1H, br s, H20), 3.31 (3H,
s, C23eOCH3), 3.02 (1H, d, J¼7.8 Hz, OH), 2.15 (1H, d, J¼12.6 Hz,
H29a), 2.14e2.09 (1H, m, H26), 2.09e2.04 (1H, m, H18), 2.00 (1H,
dd, J¼13.2, 4.8 Hz, H22a), 1.95e1.90 (1H, m, H28), 1.93e1.88 (1H, m,
H14), 1.92e1.87 (1H, m, H24), 1.80 (1H, dq, J¼7.2, 6.6 Hz, H16), 1.74
(1H, dd, J¼12.6, 1.8 Hz, H19a), 1.71 (1H, dd, J¼13.2, 6.0 Hz, H29b),
1.57 (3H, d, J¼6.6 Hz, H32), 1.55 (3H, s, C30eCH3), 1.49 (1H, ddd,
J¼13.2, 3.6, 3.0 Hz, H19b), 1.17 (1H, dd, J¼12.6, 12.6 Hz, H22b), 1.09
(3H, d, J¼7.2 Hz, C14eCH3), 0.91 (3H, d, J¼6.6 Hz, C16eCH3), 0.89
(9H, s, OSiC(CH3)3), 0.89 (9H, s, OSiC(CH3)3), 0.84 (3H, d, J¼7.2 Hz,
C28eCH3), 0.77 (6H, d, J¼6.6 Hz, C18eCH3 and C24eCH3), 0.74 (3H,
d, J¼6.6 Hz, C26eCH3), 0.04 (3H, s, OSi(CH3)CH3), 0.04 (3H, s,
OSi(CH3)CH3), ꢀ0.01 (3H, s, OSi(CH3)CH3), ꢀ0.03 (3H, s, OSi(CH3)
CH3); dC (600 MHz; CDCl3) 130.7,129.3,119.5,113.8,112.8, 98.5, 76.8,
76.7, 73.3, 72.2, 70.8, 55.4, 55.2, 53.6, 40.2, 38.1, 37.9, 36.8, 36.0, 35.7,
33.3, 32.4, 29.9, 26.3, 25.9, 24.3, 18.7, 18.6, 18.1, 17.8, 16.2, 15.6, 13.6,
12.5, 11.0, 4.2, ꢀ3.2, ꢀ4.3, ꢀ4.2, ꢀ4.8; HRESIMS calculated for
C48H88O8Si2Naþ: 871.5910; found: 871.5910. dH (600 MHz, C6D6)
cation by column chromatography (buffered silica, 15% EtOAc/
hexanes) gave hemiacetal 21 (6.5 mg; 14%) as a clear, colourless oil.
The low yield of this reaction was in part attributed to the limited
solubility of the product in the extraction solvent. Rf¼0.43 (15%
EtOAc/hexanes); ½a D20
þ22.2 (c 0.36, CHCl3); dH (600 MHz; CDCl3)
ꢃ
7.25 (2H, d, J¼9.0 Hz, ArH), 6.87 (2H, d, J¼8.4 Hz, ArH), 5.14 (1H, q,
J¼6.6 Hz, H31), 4.41 (2H, ABq, J¼11.4 Hz, OCH2PMP), 3.82 (1H, d,
J¼5.4 Hz, H25), 3.80 (3H, s, ArOCH3), 3.69 (1H, ddd, J¼11.4, 4.8,
4.2 Hz, H23), 3.58 (1H, dd, J¼10.2, 1.2 Hz, H27), 3.53 (1H, dd, J¼9.0,
4.8 Hz, H13a), 3.51 (1H, dd, J¼9.0, 1.8 Hz, H20), 3.35 (3H, s,
C23eOCH3), 3.31 (1H, dd, J¼9.0, 6.6 Hz, H13b), 3.21 (1H, d,
J¼10.8 Hz, H17), 3.18 (1H, dd, J¼12.6, 1.8 Hz, H15), 2.18 (1H, d,
J¼13.2 Hz, H29a), 2.08 (1H, m, H22a), 2.03 (1H, ddd, J¼14.4, 9.0,
3.0 Hz, H19a), 1.94e1.88 (1H, m, H14), 1.89e1.84 (1H, m, H16),
1.73e1.68 (5H, m, H18, H22b, H24, H26 and H28), 1.55e1.50 (1H, m,
H29b), 1.55 (3H, d, J¼6.6 Hz, H32), 1.54 (3H, s, C30eCH3), 1.20 (3H, s,
OC(CH3)CH3), 1.18 (3H, s, OC(CH3)CH3), 1.09 (1H, ddd, J¼14.4, 10.2,
1.8 Hz, H19b), 0.99 (3H, d, J¼6.6 Hz, C14eCH3), 0.92 (9H, s,
OSiC(CH3)2), 0.90 (9H, s, OSiC(CH3)2), 0.83 (3H, d, J¼6.6 Hz,
C16eCH3), 0.79 (3H, d, J¼6.6 Hz, C24eCH3), 0.76 (3H, d, J¼7.2 Hz,
C28eCH3), 0.74 (6H, d, J¼6.6 Hz, C18eCH3), 0.74 (3H, d, J¼6.6 Hz,
C26eCH3), 0.09 (6H, s, OSi(CH3)CH3), 0.06 (3H, s, OSi(CH3)CH3) 0.02
(3H, s OSi(CH3)CH3); dC (151 MHz; CDCl3) 159.2, 134.7, 131.0, 129.3,
120.0, 113.8, 100.4, 97.8, 77.4, 76.6, 76.5, 75.1, 73.8, 73.1, 72.9, 72.2,
55.44, 55.41, 44.1, 38.2, 38.1, 36.6, 36.0, 35.3, 31.9, 31.5, 29.5, 26.23,
26.19, 25.9, 25.1, 23.6, 23.3, 18.5, 18.4, 15.7, 15.6, 15.5, 14.7, 14.3, 13.5,
d
7.16 (2H, d, J¼9.0 Hz, ArH), 6.81 (2H, d, J¼9.0 Hz, ArH), 5.44 (1H, q,
J¼6.6 Hz, H31), 4.27 (1H, d, J¼12.0 Hz, OCHAHBPMP), 4.26 (1H, s,

6854
C. Gregg, M.V. Perkins / Tetrahedron 69 (2013) 6845e6854
OH), 4.24 (1H, d, J¼5.4 Hz, H25), 4.17 (1H, dd, J¼10.8, 1.8 Hz, H17),
4.16 (1H, d, J¼11.4 Hz, OCHAHBPMP), 3.97 (1H, dd, J¼10.2, 1.8 Hz,
H27), 3.86 (1H, ddd, J¼11.4, 4.8, 4.2 Hz, H23), 3.77 (1H, ddd,¼9.0,
9.0, 3.6 Hz, H15), 3.66 (1H, dd, J¼3.0, 2.4 Hz, H20), 3.62 (1H, dd,
J¼9.0, 3.6 Hz, H13a), 3.32 (3H, s, ArOCH3), 3.27 (1H, dd, J¼9.0,
3.0 Hz, H13b), 3.12 (3H, s, C23eOCH3), 2.53 (1H, d, 13.8 Hz, H29a),
2.46 (1H, dd, J¼13.2, 4.2 Hz, H22a), 2.37e2.31 (1H, m, H28),
2.31e2.26 (1H, m, H18), 2.30e2.25 (1H, m, H26), 2.24e2.18 (1H, m,
H24), 2.11 (1H, dd, J¼13.8, 10.2 Hz, H29b), 2.08 (1H, ddd, J¼13.2,
13.2, 1.2 Hz, H19a), 1.89e1.86 (1H, m, H16), 1.86e1.83 (1H, m, H14),
1.70 (3H, s, C30eCH3), 1.66 (1H, ddd, J¼13.2, 3.6, 2.4 Hz, H19b),
1.59e1.55 (1H, m, H22b), 1.57 (3H, d, J¼6.6 Hz, H32), 1.30 (3H, d,
J¼7.2 Hz, C14eCH3), 1.26 (3H, d, J¼7.2 Hz, C28eCH3), 1.13 (9H, s,
OSiC(CH3)3), 1.04 (3H, d, J¼7.2 Hz, C24eCH3), 1.03 (3H, d, J¼7.2 Hz,
C18eCH3), 1.00 (9H, s, OSiC(CH3)3), 0.99 (3H, d, J¼7.2 Hz, C16eCH3),
0.89 (3H, d, J¼7.8 Hz, C26eCH3), 0.33 (3H, s, OSi(CH3)CH3), 0.21 (3H,
s, OSi(CH3)CH3), 0.01 (6H, s, OSi(CH3)CH3).
References and notes
€
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€
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€
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tone 25 with an alternative aldehyde, which terminates at C29 with a PMB
ether, resulting in the same (3:1) diastereoselectivity.
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The authors thank the Australian Research Council (Grant
DP0771098) and Flinders University for financial support. C.G. ac-
knowledges the receipt of an Australian Post Graduate Research
Award.
ꢁ
18. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 2127e2129.
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Supplementary data
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Copies of NMR spectra for all new compounds are available.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.06.012.