Stereoselective total synthesis of (-)-brevisamide

Article abstract of DOI:10.1016/j.tet.2013.07.072

The stereoselective total synthesis of (-)-brevisamide, a novel marine cyclic ether alkaloid isolated from dinoflagellate karenia brevis is described. The key steps involved in this synthesis are the Sharpless asymmetric epoxidation and regioselective rin

Full text of DOI:10.1016/j.tet.2013.07.072

Accepted Manuscript
Stereoselective total Synthesis of (-)-brevisamide
J.S. Yadav, N. Mallikarjuna Reddy, Md. Ataur Rahman, A.R. Prasad, B. V. Subba
Reddy
PII:
S0040-4020(13)01191-5
10.1016/j.tet.2013.07.072
TET 24654
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 April 2013
Revised Date: 13 July 2013
Accepted Date: 16 July 2013
Please cite this article as: Yadav JS, Reddy NM, Rahman MA, Prasad AR, Reddy BVS, Stereoselective
total Synthesis of (-)-brevisamide, Tetrahedron (2013), doi: 10.1016/j.tet.2013.07.072.
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Stereoselective total synthesis of (-)-
brevisamide
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J. S. Yadav,* N. Mallikarjuna Reddy, Md. Ataur Rahman , A. R. Prasad, B. V. Subba Reddy
OH
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Tetrahedron
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journal homepage: www.elsevier.com
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Stereoselective total Synthesis of (-)-brevisamide
J. S. Yadav,* N. Mallikarjuna Reddy, Md. Ataur Rahman, A. R. Prasad, B. V. Subba Reddy
Centre for Semiochemicals, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, Email: yadavpub@iict.res.in; Fax: 91-40-27160512
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ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The stereoselective total synthesis of (-)-brevisamide, a novel marine cyclic ether alkaloid
isolated from dinoflagellate karenia brevis is described. The key steps involved in this synthesis
are the Sharpless asymmetric epoxidation and regioselective ring opening of chiral epoxide by
Gilman’s reagent. The tetrahydropyran core has been constructed by an intramolecular SN2
cyclisation.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Sharpless asymmetric epoxidation,
Gilman’s reaction, SN2 cyclisation,
TEMPO-BIAB oxidation, Horner-Wadsworth-
Emmons reaction.
1. Introduction
Scheme 1 describes retrosynthetic analysis of (-)-brevisamide
(1) following convergent synthetic strategy. The
The dinoflagellate Karenia brevis produces polycyclic
ethers such as brevetoxins and brevenal.1-4 The brevetoxins
are found to exhibit potent neurotoxicity, which causes
massive killing of fish and marine animals such as dolphins
and manatees in the Florida coast. The brevenals display
antagonist activity against the brevetoxins.5 (-)-Brevisamide6
(1) is one of such brevenals which was isolated by Wright’s
group from dinoflagellate karenia brevis. Considering its
interesting biological activity, five research groups have
independently reported the total synthesis of brevisamide.7
a
functionalized tetrahydropyran ring moiety (3) could be
constructed from compound 4a via intramolecular SN2
cyclisation. The phosphonate ester 6 could be obtained from
acetoin. The target molecule might be achieved by the
coupling of compounds 3 and 6 using a Horner-Wadsworth-
Emmons reaction.
Our group recently published
a formal synthesis of
brevisamide.8 As part of our ongoing program towards the
total synthesis of biologically active complex natural
products,9 we herein, disclose a stereoselective total synthesis
of (-)-brevisamide.
Scheme 1. Retrosynthesis of brevisamide.
Figure 1. Structures of brevisamide (1) and brevenal (2).

2
Tetrahedron
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2. Results and discussion
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The synthesis of tetrahydropyran moiety 3 began with (R)-
2,3-O-isopropylidene glyceraldehyde 5. Treatment of the
aldehyde 5 with allyl bromide in the presence of zinc dust and
aqueous NH4Cl solution in THF at 0 oC afforded the
corresponding homoallyl alcohol 7 as a major diastereomer
favoring anti-isomer (anti/syn 96:4, from 1H NMR
spectrum).10 Protection of free hydroxyl group as its benzyl
ether using BnBr in the presence of NaH in THF gave the
compound 8 in 92% yield. Ozonolysis of the olefin 8 followed
12 with Gilman’s reagent i.e. lithium dimethylcuprate in ether
at -40 oC gave the 7:1 mixture of positional isomers 4a and 4b
respectively in 86% yield,11 which could be easily separated
by column chromatography (Scheme 2).
Mesylation of secondary hydroxyl group in 4a using MsCl,
TEA in CH2Cl2 followed by removal of acetonide using p-
TSA in MeOH gave the diol 14. An intramolecular SN2
cyclisation of compound 14 in the presence of NaH in THF
afforded a key intermediate, tetrahydropyran moiety 15 in
75% yield over three steps.12 Protection of the primary
hydroxyl group of compound 15 as its TBS ether using
TBSOTf and 2,6-lutidine in CH2Cl2 gave the compound 16 in
96% yield. Removal of both benzyl groups in compound 16
using Li/naphthalene in THF afforded the diol 17 in 93%
yield.13 Chemoselective oxidation of the primary alcohol from
diol 17 with TEMPO-BAIB in CH2Cl2 followed by Wittig
by Wittig olefination with
a
stable ylide i.e.
(ethoxycarbonylmethylene)triphenylphosphorane in CH2Cl2
gave the α,β-unsaturated ester 9 in 78% yield. Reduction of
the α,β-unsaturated ester 9 with DIBAL-H in CH2Cl2 afforded
the allylic alcohol 10 in 92% yield. The Sharpless asymmetric
epoxidation of allylic alcohol 10 using (-)-DIPT, Ti(OiPr)4 and
TBHP in CH2Cl2 furnished the epoxide 11 in 88% yield.
Protection of epoxy alcohol 11 as its benzyl ether with BnBr
in the presence of NaH in THF afforded the compound 12 in
94% yield. Regioselective ring opening of the chiral epoxide
olefination
with
a
stable
ylide,
i.e.
(ethoxycarbonylmethylene)triphenylphosphorane gave the α,
β-unsaturated ester 18 in 86% yield in a single step.14
Reduction of the double bond in ester 18 with PtO2 in

3
EtOAc followed by protection of secondary hydroxyl group
as TBS ether using TBSOTf and 2,6-lutidine in CH2Cl2
afforded the compound 20 in 96% yield over two steps.
Selective removal of the TBS group from compound 20 with
cat. CSA in CH2Cl2:MeOH (4:1) gave the primary alcohol 21
in 90% yield.15 Further treatment of compound 21 with TPP,
DPPA, and DIAD in THF under Mistunobu conditions gave
the azide 22 in 82% yield.16 Reduction of the azide in the
presence of Pd/C in MeOH/THF followed by acetylation of
the primary amine with Ac2O in the presence of NaHCO3
gave the acetyl amide 23 in 97% yield over two steps.
Reduction of the ester 23 with DIBAL-H in CH2Cl2 at -100 oC
afforded the aldehyde 3 in 80% yield (Scheme 3).
Wadsworth-Emmons reaction are employed as key steps in
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this synthesis. The present synthesis will provide access to a
variety of structural analogues for further studies.
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4. Experimental Section
All reactions were performed under inert atmosphere, if
argon mentioned. All glassware apparatus used for reactions
are perfectly oven/flame dried. Anhydrous solvents were
distilled prior to use: THF from Na and benzophenone;
CH2Cl2 from CaH2; MeOH from Mg cake. Commercial
reagents were used without purification. Column
chromatography was carried out by using silica gel (60–120
mesh) unless otherwise mentioned. Analytical thin layer
chromatography (TLC) was run on silica gel 60 F254 pre-
coated plates (250 μm thickness). Optical rotations [α]D were
measured on a polarimeter and given in 10-1 degcm2g−1.
Infrared spectra were recorded in CHCl3/KBr (as mentioned)
and reported in wave number (cm−1). Mass spectral data were
obtained using MS (EI) ESI, HRMS mass spectrometers.
High resolution mass spectra (HRMS) [ESI+] were obtained
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11 The phosphonate 6 was obtained from acetoin7d by using
simple chemical modifications. Wittig olefination followed by
bromination of action 24 produced bromoester 25. Reaction of
bromoester with triethyl phosphate afforded phosphonate
ester 6 in 95% yield. Finally, having the two fragments 3 and
6 in hand, we followed the Lindsley approach to achieve the
total synthesis of brevisamide7d (Scheme 4). The physical and
spectroscopic data of brevisamide were in good agreement
with the data reported to the natural brevisamide and
previously prepared synthetic brevisamide.
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1
using either a TOF or a double focusing spectrometer. H
NMR spectra were recorded at 300, 400, 500 MHz and 13C
NMR spectra 75 MHz in CDCl3, CD3OD solution, chemical
shifts are in ppm downfield from tetramethylsilane and
coupling constants (J) are reported in hertz (Hz). The
following abbreviations are used to designate signal
multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet, br = broad.
(R)-4-((S)-1-(Benzyloxy)but-3-en-1-yl)-2,2-dimethyl-1,3-
dioxolane (8):
To a stirred solution of aldehyde 5 (4.20 g, 32.27 mmol ) in
THF (50 mL) were added Zn (10.4 g, 161.23 mmol) dust and
allyl bromide (6.96 mL, 80.66 mmol) at 0 oC. To this mixture,
aqueous ammonium chloride (50 mL) was added drop wise at
the same temperature and the resulting mixture was allowed
to stir for 4 h. Up on completion, the reaction mixture was
filtered through celite pad and then extracted with EtOAc.
The combined organic fractions were collected and washed
with water (50 mL), brine solution (50 mL), dried over
Na2SO4 and concentrated under reduced pressure. The crude
product was purified by column chromatography (EtOAc-
hexane, 5:95) to afford the compound 7 as a major
1
diostereomer favoring anti-isomer (anti/syn 96:4, from the H
NMR spectrum) (5.21 g, 94%) as a colorless oil, which was
used as such for the next reaction.
To a stirred solution of alcohol 7 (3.60 g, 20.90 mmol) in
anhydrous THF (40 mL) was added NaH (60% suspension in
mineral oil; 1.25 g, 52.08 mmol). To this mixture, BnBr (2.97
mL, 25.02 mmol) was added at 0 oC under nitrogen
atmosphere. The resulting mixture was allowed to stir at room
temperature for 4h. Up on completion, the mixture was
quenched with saturated aqueous NH4Cl solution (30 mL) and
extracted with EtOAc (3x100 mL). The combined organic
fractions were collected and washed with water (50 mL),
brine (50 mL), dried over Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography (10% EtOAc/hexane) to afford the
compound 8 (4.55g, 92%) as a colourless oil. Rf=0.6 (10%
EtOAc/hexane); [α]D27: +31.3 (c 2.14, CHCl3); 1H NMR
(CDCl3, 300 MHz): δ 7.38-7.28 (m, 5H, ArH), 5.97-5.82 (m,
1H, olefinic), 5.19-5.04 (m, 2H, olefinic), 4.70-4.56 (m, 2H,
OCH2Ph), 4.14-4.00 (m, 2H, 2xOCH), 3.92-3.86 (m, 1H,
OCH), 3.60-3.53 (m, 1H, OCH), 2.48-2.20 (m, 2H, CHAHB),
1.41 (s, 3H, CCH3), 1.34 (s, 3H, CCH3); 13C NMR (CDCl3, 75
3. Conclusion
In summary, we have accomplished the total synthesis of
brevisamide from (R)-2,3-O-isopropylideneglyceraldehyde.
The Sharpless asymmetric epoxidation of allylic alcohol, the
regioselective ring opening of chiral epoxide with Gilman’s
reagent to introduce methyl group, the formation of
tetrahydropyran ring via SN2 cyclisation, one-pot
TEMPO_BIAB oxidation followed by Wittig olefination and
the stereoselective formation of E-olefin by Horner -

4
Tetrahedron
MHz): δ 138.2, 134.0, 128.2, 127.7, 127.5, 117.4, 108.9,
((2R,3R)-3-((S)-2-(Benzyloxy)-2-((R)-2,2-dimethyl-1,3-
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78.7, 77.0, 72.3, 66.3, 35.5, 26.5, 25.2; IR (neat): 2986,
2934, 2883, 1373, 1215, 1072, 772 cm-1; Mass (ESI-MS): m/z
285 (M+Na)+.
dioxolan-4-yl)ethyl)oxiran-2-yl)methanol (11):
To a solution of flame-dried 4 Ao molecular sieves (6 g) at -20
oC in CH2Cl2 (60 mL), Ti(OiPr)4 (0.757 mL, 2.66 mmol) and
(-)-DIPT (0.62 mL, 2.66 mmol) were added sequentially and
stirred for 20 min. To this mixture, a solution of allylic
alcohol 10 (5.20 g, 71.78 mmol) in CH2Cl2 (10 mL) was
added dropwise and the reaction was stirred for another 30
min. To this mixture, TBHP (3.3 M, 16.16 mL, 53.33 mmol)
was added dropwise and the stirring was continued at -20 C
for 10 h. A few drops of water was added to the above
mixture and then allowed it to stir for another 20 min. It was
warmed to 0 C and quenched with 1M NaOH (1 mL). It was
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(S,E)-Ethyl 5-(benzyloxy)-5-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)pent-2-enoate (9):
To a stirred solution of 8 (4.32 g, 16.46 mmol) in CH2Cl2 (50
mL) at –78 C, ozone was bubbled until no starting material
remains on TLC. The mixture was purged with N2 to remove
the excess ozone and cooled to 0 C and then Ph3P (8.62 g,
32.93 mmol) was added. The resulting mixture was allowed to
stir for 2 h. The solvent was removed and the residue was
diluted with hexane followed by filtered through celite pad
and then washed with hexane. The filtrate was dried over
Na2SO4 and concentrated under reduced pressure. The crude
aldehyde was subjected to the next reaction without further
purification.
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then allowed to stir at the same temperature for 30 min and
diluted with EtOAc (100 mL), washed with brine, dried over
Na2SO4 and concentrated in vacuo. Purification of the crude
by column chromatography (50% EtOAc/hexane) afforded
the compound 11 (4.82 g, 88 %) as a colourless oil. Rf=0.3
(50% EtOAc/hexane); [α]D27: +19.6 (c 0.51, CHCl3); 1H NMR
(CDCl3, 300 MHz): δ 7.39-7.29 (m, 5H, ArH), 4.67-4.56 (m,
2H, OCH2Ph), 4.18-4.05 (m, 2H, CH2OH), 3.92-3.86 (m, 2H,
2xOCH), 3.66-3.56 (m, 2H, 2xOCH), 3.15-3.08 (m, 1H,
OCH), 2.96-2.91 (m, 1H, OCH), 1.94-1.85 (m, 2H, CHAHB),
1.41 (s, 3H, CCH3), 1.36 (s, 3H, CCH3); 13C NMR (CDCl3, 75
MHz): δ 137.5, 128.4, 127.9, 127.7, 109.3, 78.8, 72.3, 66.7,
61.7, 62.8, 63.4, 33.5, 26.6, 25.2; IR (neat):  3414, 2925,
1454, 1375, 1259, 1213, 1068, 854, 743, 700 cm-1; ESI-
HRMS: m/z calcd. for C17H24O5Na [M+H]+ 331.15160, found:
331.15177.
To a solution of aldehyde in dry benzene (60 mL) was added
(carbethoxymethylene)triphenylphosphorane (11.46 g, 32.93
mmol) in one portion at room temperature. The resulting
mixture was stirred at the same temperature for 2h. The
solvent was removed under reduced pressure and the residue
was diluted with EtOAc (100 mL), washed with brine (2x50
mL), dried over Na2SO4 and concentrated in vacuo.
Purification
by
column
chromatography
(10%
EtOAc/Hexane) afforded the olefin 9 (4.11 g, 78%, 2 steps) as
a colourless oil. Rf=0.7 (10% EtOAc/Hexane); [α]D27: +3.5 (c
1
0.85, CHCl3); H NMR (CDCl3, 300 MHz): δ 7.36-7.28 (m,
5H, ArH), 7.07-6.97 (m, 1H, olefinic), 5.92 (d, J = 15.6 Hz,
1H, olefinic), 4.66-4.54 (m, 2H, OCH2Ph), 4.19 (q, J = 7.1
Hz, 2H, CO(CH2)CH3), 4.09-8-4.01 (m, 2H, 2xOCH), 3.91-
3.81 (m, 1H, OCH), 3.62-3.54 (m, 1H, OCH), 2.64-2.40 (m,
2H, CHAHB), 1.41 (s, 3H, CCH3), 1.34 (s, 3H, CCH3), 1.29 (t,
J = 7.1 Hz, 3H, OCH2(CH3)); 13C NMR (CDCl3, 75 MHz): δ
166.2, 144.5, 137.8, 131.2, 127.8, 123.9, 128.4, 109.3, 78.5,
76.8, 72.5, 66.6, 60.2, 33.8, 26.6, 25.2, 14.2; IR (neat): 
2986, 2936, 1719, 1262, 1212, 1175, 1073 cm-1; ESI-HRMS:
m/z calcd. for C19H26O5Na [M+Na]+ 357.16748, found:
357.16725.
(R)-4-((S)-1-(Benzyloxy)-2-((2R,3R)-3-
((benzyloxy)methyl)oxiran-2-yl)ethyl)-2,2-dimethyl-1,3-
dioxolane (12):
To a suspension of NaH (60%, 0.66 g, 27.72 mmol) in dry
THF (30 mL) was added a solution of alcohol 11 (3.42 g, 1.40
o
mmol) at 0 C. To this mixture, TBAI (0.05 g) and benzyl
bromide (1.60 mL, 13.3 mmol) were added subsequently and
the stirring was continued for 2h at the same temperature and
another 10 h at room temperature. The mixture was quenched
with crushed ice until a clear solution (biphasic) was formed.
The aqueous layer was extracted with ethyl acetate (2x30
mL). The combined organic extracts were washed with water
(20 mL), brine solution (20 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent followed by column
chromatography (10% EtOAc-hexane) gave the pure product
12 (4.14 g, 94% yield) as a colourless liquid. Rf=0.8 (10%
EtOAc-hexane); [α]D27: +11.7 (c 3.87, CHCl3); 1H NMR
(CDCl3, 300 MHz): δ 7.40-7.26 (m, 10H, 2xArH), 4.67-4.50
(m, 4H, 2xOCH2Ph), 4.18-4.02 (m, 2H, CH2OBn), 3.91-3.83
(m, 2H, 2xOCH), 3.74-3.58 (m, 1H, OCH), 3.49-3.41 (m, 1H,
OCH), 2.54-2.36 (m, 2H, 2xOCH), 1.94-1.80 (m, 2H,
CHAHB), 1.40 (s, 3H, CCH3), 1.34 (s, 3H, CCH3); 13C NMR
(CDCl3, 75 MHz): δ 137.9, 137.8, 128.3, 127.8, 127.6, 126.9,
126.8, 109.2, 77.5, 77.4, 73.2, 72.2, 70.1, 66.6, 56.9, 53.0,
33.6, 26.5, 25.1; IR (neat):  3347, 2933, 2878, 1453, 1373,
1211, 1071, 699 cm-1; ESI-HRMS: m/z calcd. for C24H30O5Na
[M+Na]+ 421.19855, found: 421.19833.
(S,E)-5-(Benzyloxy)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-
yl)pent-2-en-1-ol (10):
To a stirred solution of 9 (2.86 g, 8.92 mmol) in CH2Cl2 (30
o
mL) at 0 C, a solution of DIBAL-H in toluene (1.0 M, 17.81
mL, 17.81 mmol) was added dropwise. The mixture was
stirred for 1 h at the same temperature. The reaction was
quenched with MeOH (5 mL) followed by saturated aqueous
sodium potassium tartrate solution (15 mL). It was warmed to
0 oC and then stirred it for another 30 min. The aqueous layer
was extracted with EtOAc (3x50 mL) and washed with brine
(50 mL), dried over Na2SO4 and concentrated in vacuo.
Purification of the crude by column chromatography (30%
EtOAc/hexane) afforded the compound 10 (2.39 g, 92%) as a
51 colourless oil. Rf=0.35 (30% EtOAc/hexane) [α]D27: +14.8 (c
1
4.8, CHCl3); H NMR (CDCl3, 300 MHz): δ 7.37-7.29 (m,
5H, ArH), 5.78-5.66 (m, 2H, olefinic), 4.61 (d, J = 1.8 Hz,
2H, CH2OH), 4.12-4.04 (m, 4H, 4xOCH), 3.92-3.87 (m, 1H,
OCH), 3.59-3.51 (m, 1H, OCH), 2.48-2.26 (m, 2H, CHAHB),
1.42 (s, 3H,CCH3), 1.35 (s, 3H, CCH3); 13C NMR (CDCl3, 75
MHz): δ 138.1, 131.9, 128.3, 128.2, 127.8, 127.7, 127.6,
109.0, 78.7, 76.9, 72.3, 66.2, 63.3, 33.6, 26.5, 25.2; IR (neat):
 3398, 2930, 1718, 1273, 1069, 714 cm-1; Mass (ESI-MS):
m/z 291 (M-H)+.
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4.6. (2S,3S,5S)-1,5-Bis(benzyloxy)-5-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)-3-methylpentan-2-ol (4a):
To a cold suspension of copper(I) iodide (4.20 g, 22.12 mmol)
o
in dry ether (30 mL) at -23 C, a solution of MeLi (27 mL,
42.24 mmol, 1.6 M ) in ether was added dropwise until it
becomes clear solution. After 30 min, the solution was cooled
o
to -40 C , and then a solution of compound 12 (1.26 g, 3.16

5
o
mmol) in ether (20 mL) was added dropwise. After being
stirred for 3 h at -40 oC, the mixture was poured into saturated
aqueous NH4Cl (40 mL) and the aqueous layer was
thoroughly extracted with EtOAc (3x30 mL). The combined
organic layers were washed with brine (20 mL), dried over
anhydrous Na2SO4 and concentrated under reduced pressure.
The crude product was subjected to column chromatography
(20% EtOAc-Hexane) to afford the pure products 4a (0.98 g,
75.2% yield) and 4b (0.14 g, 10.7% yield) in 7:1 ratio as
colourless liquids. The data for the major isomer (4a):
Rf=0.32 (20% EtOAc/hexane); [α]D27: -2.6 (c 1.30, CHCl3);
1H NMR (CDCl3, 300 MHz): δ 7.40-7.28 (m, 10H, 2xArH),
4.79 (d, J = 11.3 Hz, 1H, OCHAHBPh), 4.58 (d, J = 12.0 Hz,
1H, OCHAHBPh), 4.54 (s, 2H, OCH2Ph), 4.16-4.08 (m, 1H,
OCH), 4.02 (t, J = 7.5 Hz, 1H, OCH), 3.93 (t, J = 7.5 Hz, 1H,
OCH), 3.76-3.66 (m, 1H, OCH), 3.64-3.47 (m, 2H, 2xOCH),
3.45-3.37 (m, 1H, OCH), 2.46 (brs, , 1H, OH), 1.93-1.79 (m,
1H, (CH)CH3), 1.63-1.54 (m, 2H, CHAHB), 1.43 (s, 3H,
CCH3), 1.36 (s, 3H, CCH3), 0.86 (d, J = 6.7 Hz, 3H,
CH(CH3)); 13C NMR (CDCl3, 75 MHz): δ 138.5, 138.0,
128.4, 128.3, 127.8, 127.7, 127.6, 127.5, 108.9, 78.9, 74.6,
72.5, 73.2, 65.6, 73.3, 34.4, 32.3, 25.2, 26.4, 15.8; IR (neat): 
3376, 2928, 2856, 1058, 837, 773 cm-1; ESI HRMS: m/z
calcd. for C25H34O5Na [M+Na]+ 437.22985, found:
437.22891.
at 0 C. The resulting mixture was stirred for 6 h at room
ACCEPTED MANUSCRIPT
temperature. Up on completion, the mixture was quenched by
crushed ice until a clear solution (biphasic) was formed. The
aqueous layer was extracted with ethyl acetate (2x20 mL).
The combined organic extracts were washed with water (10
mL), brine solution (10 mL) and dried over anhydrous
Na2SO4. Evaporation of the solvent followed by column
chromatography (30% EtOAc/hexane) afforded the pure
product 15 (1.82 g, 75% yield) as a colourless liquid. Rf=0.35
(30% EtOAc/hexane); [α]D27: +19.6 (c 3.95, CHCl3); 1H NMR
(CDCl3, 300 MHz): δ 7.33-7.21 (m, 10H, 2xArH), 4.49-
4.41(m, 4H, 2xOCH2Ph), 3.87-3.78 (m, 1H, OCH), 3.77-3.70
(m, 1H, OCH), 3.68-3.62 (m, 1H, OCH), 3.59-3.49 (m, 1H,
OCH), 3.48-3.41 (m, 1H, OCH), 3.35-3.24 (m, 2H, 2xOCH),
2.13-1.97 (m, 2H, CHaHe, (CH)CH3), 1.60 (dt, J = 4.5, 12.0,
16.6 Hz, 1H, CHaHe), 0.88 (d, J = 6.7 Hz, 3H, CH(CH3)); 13C
NMR (CDCl3, 75 MHz): δ 138.1, 137.8, 128.3, 127.7, 81.0,
78.1, 73.5, 70.9, 70.2, 36.3, 30.5, 12.6; IR (neat):  3412,
2924, 2861, 1454, 1094, 1072, 698 cm-1; ESI-HRMS: m/z
calcd. for C22H28O4Na [M+Na]+ 379.18798, found 379.18883.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
(((2R,3S,5S,6R)-3-(Benzyloxy)-6-((benzyloxy)methyl)-5-
methyltetrahydro-2H-pyran-2-yl)methoxy)(tert-
butyl)dimethylsilane (16):
To a solution of alcohol 15 (1.82 g, 5.11 mmol) in dry CH2Cl2
(5 mL) was added 2,6-lutidine (1.41 mL, 12.24 mmol) and
stirred for 10 min at room temperature. To this mixture,
TBSOTf (1.40 mL, 6.10 mmol) was added and then stirred it
for 1 h at room temperature. Up on completion, the mixture
was quenched with water and extracted with CH2Cl2, dried
over Na2SO4 and concentrated in vacuo. The crude mixture
(1S,3R,4S)-1,5-Bis(benzyloxy)-1-((R)-2,2-dimethyl-1,3-
dioxolan-4-yl)-4-methylpentan-3-ol (4b):
Rf=0.35 (20% EtOAc/hexane); [α]27: +4.54 (c 1.32, CHCl3);
1H NMR (CDCl3, 300 MHz): δ 7.36-7.27 (m, 10H, 2xArH),
4.76 (d, J = 11.4 Hz, 1H, OCHaCHbPh), 4.62 (d, J = 11.4 Hz,
1H, OCHACHBPh), 4.50 (s, 2H, OCH2Ph), 4.20 (q, J = 6.2,
was
purified
by
column
chromatography
(10%
29 10.3, Hz, 1H, OCH), 4.04 (t, J = 6.2 Hz, 1H, OCH), 3.91 (t, J
EtOAc/hexane) to afford the desired product 16 (2.30 g, 96%)
as a colourless oil. Rf=0.7 (10% EtOAc/hexane); [α]D27: +24.3
(c 0.80, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 7.35-7.27
(m, 10H, 2xArH), 4.62-4.45 (m, 4H, 2xOCH2Ph ), 3.98-3.82
(m, 2H, 2xOCH), 3.76-3.60 (m, 1H, OCH), 3.54-3.45 (m, 1H,
OCH), 3.41-3.33 (m, 1H, OCH), 3.27-3.18 (m, 1H, OCH),
2.03-1.93 (m, 2H, CHaHe, (CH)CH3), 1.66-1.54 (m, 1H,
CHaHe), 0.92 (s, 12H, SiC(CH3)3,CH(CH3)) 0.06 (s, 6H,
Si(CH3)2); 13C NMR (CDCl3, 75 MHz): δ 138.7, 138.3, 128.3,
128.2, 127.7, 127.6, 127.52, 127.50, 81.8, 78.1, 73.4, 71.3,
71.1, 69.3, 62.9, 36.8, 25.9, 25.6, 18.3, 12.5, -5.0, -5.2; Mass
(ESI-MS): m/z 475 (M+H)+. IR (neat):  2929, 2857, 1456,
1252, 1104, 835, 777, 736, 697 cm-1; ESI-HRMS: m/z calcd.
for C28H43O4Si [M+H]+ 471.29251, found: 471.29068.
=7.2 Hz, 1H, OCH), 3.87-3.82 (m, 1H, OCH), 3.80-3.74 (m,
1H, OCH), 3.50 (d, J = 6.2 Hz, 2H, 2xOCH), 1.90-1.83 (m,
30
31
1H, (CH)CH3), 1.77-1.72 (m, 1H, CHAHB), 1.70-1.62 (m, 1H,
CHAHB), 1.44 (s, 3H, CCH3), 1.36 (s, 3H, CCH3), 0.93 (d, J =
7.2 Hz, 3H, CH(CH3)). 13C NMR (CDCl3, 75 MHz): δ 138.1,
138.0, 128.4, 128.3, 127.9, 127.8, 127.6, 78.3, 78.0, 73.4,
73.2, 72.9, 65.9, 65.7, 38.9, 35.9, 26.4, 13.7; IR (Neat): 3489,
2982, 2933, 2878, 1454, 1373, 1211, 1070, 738, 698 cm-1;
ESI-HRMS: m/z calcd. for C25H34O5Na [M+Na]+ 437.22985,
found: 437.22891.
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
((2R,3S,5S,6R)-3-(benzyloxy)-6-((benzyloxy)methyl)-5-
methyltetrahydro-2H-pyran-2-yl)methanol (15):
To a mixture of alcohol 4a (2.12 g, 5.12 mmol) and
triethylamine (2.84 mL, 20.48 mmol) in CH2Cl2 (12 mL) at 0
oC was added methanesulfonyl chloride (0.783 mL, 10.24
mmol). After 1 h, the mixture was poured into ice-water (10
mL). The layers were separated and the organic phase was
washed with aqueous HCl (1M, 10 mL) followed by saturated
NaHCO3 solution (10 mL) and water (10 mL). The solvent
was removed and the crude mesylate 13 was used in the next
step without further purification.
(2R,3S,5S,6R)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-6-
(hydroxymethyl)-5-methyltetrahydro-2H-pyran-3-ol (17):
To a stirred solution of naphthalene (2.42 g, 5.14 mmol) in
THF (25 mL) at room temperature was added lithium metal
(180 mg, 25.71 mmol) and allowed the solution to stir at room
temperature for 3 h to generate Li-naphthalenide. To this dark
green color solution was added benzyl ether 16 (2.42 g, 5.14
o
mmol) at -23 C and allowed the mixture to stir at the same
temperature for 30 min. It was then quenched with aqueous
NH4Cl, extracted with EtOAc (3x30 mL), dried over Na2SO4,
concentrated in vacuo and purified by column
chromatography (50% EtOAc/hexanes) to give the diol 17
(1.38 g, 93 %). Rf=0.4 (50% EtOAc/hexanes); [α]D27: -11.7 (c
A solution of compound 13 in MeOH (15 mL) and a
catalytic amount of p-TSA (60 mg) was stirred for 3 h at room
temperature. Up on completion, the mixture was quenched
with a saturated aqueous NaHCO3 solution (5 mL) and
extracted with ethyl acetate (2 x 40 mL). The organic extracts
were washed with brine (20 mL) and dried over anhydrous
Na2SO4. Removal of the solvent gave the diol 14 which was
used in the next step without further purification.
1
0.81, CHCl3); H NMR (CDCl3, 300 MHz): δ 3.90-3.83 (m,
1H, OCH), 3.78-3.60 (m, 4H, 4xOCH), 3.55-3.46 (m, 1H,
OCH), 3.29-3.19 (m, 1H, OCH), 2.01-1.82 (m, 2H, CHaHe,
(CH)CH3), 1.72-1.61 (m, 1H, CHaHe), 0.93 (d, J = 7.5 Hz,
3H, CH(CH3)), 0.88 (s, 9H, SiC(CH3)3), 0.07 (s, 3H,
Si(CH3)2), 0.06 (s, 3H, Si(CH3)2); 13C NMR (CDCl3, 75
To a suspension of NaH (60%, 1.1 g, 12.80 mmol) in dry
THF (15 mL) was added a solution of diol 14 in THF (5 mL)

6
Tetrahedron
ACCEPTED MANUSCRIPT
MHz): δ 82.7, 80.5, 66.8, 66.2, 64.0, 39.0, 30.2, 25.7, 18.1,
mixture was purified by column chromatography (10%
13.0, -3.6; Mass (ESI-MS): m/z 313 (M+Na)+. IR (neat): 
3399, 2931, 2858, 2884, 1465, 1254, 1113, 1053, 836, 776
cm-1; ESI-HRMS: m/z calcd. for C14H31O4Si [M+H]+
291.19861. found: 291.19925.
EtOAc/hexane) to afford the compound 20 (1.53 g, 96 %) as a
colourless oil. Rf=0.7 (10% EtOAc/hexane); [α]D27: +13.0 (c
2.79, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 4.12 (q, J = 7.5,
14.3 Hz, 2H, O(CH2)CH3), 3.82-3.61 (m, 3H), 3.40-3.31 (m,
1H, OCH), 3.06-2.96 (m, 1H, OCH), 2.54-2.22 (m, 2H,
(CH2)CO), 1.88-1.50 (m, 5H, CH), 1.25 (t, J = 7.5 Hz, 3H,
OCH2(CH3)), 0.94 (d, J = 6.9 Hz, 3H, CH(CH3)), 0.89 (s, 9H,
SiC(CH3)3), 0.86 (s, 9H, , SiC(CH3)), 0.05 (s, 6H, Si(CH3)3),
0.04 (s, 6H, Si(CH3)3); 13C NMR (CDCl3, 75 MHz): δ 173.8,
83.5, 78.3, 62.8, 60.1, 41.0, 33.0, 31.1, 28.0, 25.7, 25.8, 18.3,
17.9, 14.2, 12.6, -4.3, -4.9, -5.0, -5.3; IR (neat):  2928, 2856,
1737, 1251, 1095, 835, 774 cm-1; ESI-HRMS: m/z calcd. for
C24H50O5NaSi2 [M+Na]+ 497.30890, found: 497.30955.
1
2
3
4
5
6
7
8
9
(E)-Ethyl 3-((2R,3S,5S,6R)-6-(((tert-
butyldimethylsilyl)oxy)methyl)-5-hydroxy-3-
methyltetrahydro-2H-pyran-2-yl)acrylate (18):
To a stirred solution of diol 17 (1.57 g, 5.41 mmol) in CH2Cl2
(15 mL) were added bis(acetoxy)iodobenzene (2.0 g, 6.21
mmol) and 2,2,6,6-tetramethylpiperidinyloxy (168 mg, 1.07
mmol). The resulting yellow solution was stirred for 2 h, and
then cooled it to 0 oC. To this mixture was added
(carbethoxymethylene)triphenyl phosphorane (2.45 g, 7.03
mmol). The resulting mixture was allowed to stir at room
temperature for 1 h. The solvent was removed in vacuo and
the residue was purified by column chromatography (30%
EtOAc/hexane) to afford the pure product 18 (1.67 g, 87%).
Rf=0.55 (30% EtOAc/hexane); [α]D27: +2.3 (c 1.2, CHCl3); 1H
NMR (CDCl3, 300 MHz): δ 6.80 (dd, J = 3.4, 15.6 Hz, 1H,
olefin), 6.00 (dd, J = 1.7, 15.8 Hz, 1H, olefinic), 4.19 (q, J =
6.9, 13.9 Hz, 2H, O(CH2)CH3), 3.97 ( dd, J = 4.5, 9.8 Hz, 1H,
OCH), 3.89-3.70 (m, 3H, 3xOCH), 3.33-3.23 (m, 1H, OCH),
2.11-1.99 (m, 2H, CHaHe, (CH)CH3), 1.76-1.64 (m, 1H,
CHaHe), 1.28 (t, J = 7.1 Hz, 3H, OCH2(CH3)), 0.91 (s, 12H,
SiC(CH3)3, CH(CH3)), 0.12 (s, 3H, Si(CH3)2), 0.11 (s, 3H,
Si(CH3)2); 13C NMR (CDCl3, 75 MHz): δ 166.4, 146.5, 120.6,
120.7, 81.8, 78.0, 79.5, 66.4, 63.4, 60.3, 38.4, 32.6, 29.7, 25.8,
18.5, 13.2, -5.6, -5.5; IR (neat):  3479, 2930, 2857, 1725,
1303, 1051, 837, 777 cm-1; ESI-HRMS: m/z calcd. for
C18H35O5Si [M+H]+ 359.22483, found: 359.22595.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
Ethyl 3-((2S,3S,5S,6R)-5-((tert-butyldimethylsilyl)oxy)-6-
(hydroxymethyl)-3-methyltetrahydro-2H-pyran-2-
l)propanoate (21):
The “bis-TBS” protected ester (0.92 g, 1.94 mmol) was
dissolved in a mixture of dry CH2Cl2 and MeOH (4:1, 15
mL). To this solution was added CSA (23 mg, 0.099 mmol)
and the resulting solution was stirred at room temperature for
2 h. The mixture was quenched with sodium bicarbonate (100
mg) solution and extracted with ethyl acetate (2x10 mL). The
combined organic layers were extracted with CH2Cl2, dried
over Na2SO4 and concentrated in vacuo. The resulting residue
was purified by silica gel column chromatography (20%
EtOAc/hexane) to afford the compound 21 (0.635 g, 91%) as
colourless oil. Rf=0.4 (20% EtOAc/hexane); [α]D27: +13.8 (c
1
0.72, CHCl3); H NMR (CDCl3, 300 MHz): δ 4.12 (q, J = 6.7
Hz, 2H, O(CH2)CH3), 3.84-3.74 (m, 1H, OCH), 3.69-3.51 (m,
2H, OCH), 3.48-3.42 (m, 1H, OCH), 3.18-3.11 (m, 1H,
OCH), 3.42-2.34 (m, 2H, OCH), 2.16 (brs, 1H, OH), 1.90-
1.77 (m, 2H, CH), 1.69-1.58 (m, 3H, CH), 1.25 (t, J = 6.7 Hz,
3H, OCH2(CH3)), 0.95 (d, J = 6.7 Hz, 3H, ), 0.86 (s, 9H), 0.05
(s, 6H); 13C NMR (CDCl3, 75 MHz): δ 173.9, 82.6, 78.9, 63.9,
63.1, 60.3, 40.8, 32.8, 31.6, 28.1, 25.6, 17.8, 14.1, 12.7, -4.2, -
4.9; IR (neat):  3507, 2931, 2888, 2858, 1735, 1254, 1097,
837 cm-1; ESI-HRMS: m/z calcd. for C18H36O5NaSi [M+Na]+
383.22348, found: 383.22168.
Ethyl 3-((2S,3S,5S,6R)-6-(((tert-
butyldimethylsilyl)oxy)methyl)-5-hydroxy-3-
methyltetrahydro-2H-pyran-2-yl)propanoate (19):
To a solution of 18 (1.42 g, 3.96 mmol) in EtOAc (30 mL)
was added PtO2 (45 mg, 0.19 mmol). After stirring the
mixture for 1 h under H2 atmosphere, the mixture was filtered
through Celite and concentrated in vacuo. The crude residue
was purified on silica gel column chromatography (30%
EtOAc/hexane) to afford the compound 19 (1.42 g,
quantitative) as colourless oil. Rf=0.55 (30% EtOAc/hexane);
Ethyl 3-((2S,3S,5S,6R)-6-(azidomethyl)-5-((tert-
butyldimethylsilyl)oxy)-3-methyltetrahydro-2H-pyran-2-
yl)propanoate (22):
[α]D27: +8.1 (c 1.66, CHCl3); H NMR (CDCl3, 300 MHz): δ
1
4.12 (q, J = 6.9, 14.1 Hz, 2H, O(CH2)CH3), 3.93-3.86 (m, 1H,
OCH), 3.84-3.72 (m, 1H, OCH), 3.54-3.37 (m, 2H, 2xOCH),
3.22-3.14 (m, 1H, OCH), 2.49-2.28 (m, 2H, (CH2)CO), 2.02-
1.93 (m, 1H, CH), 1.90-1.56 (m, 4H, CH), 1.25 (t, J = 6.9 Hz,
3H, OCH2(CH3)), 0.96 (d, J = 7.1 Hz, 3H, CH(CH3)), 0.90 (s,
9H, SiC(CH3)3), 0.10 (s, 6H, Si(CH3)2); 13C NMR (CDCl3, 75
MHz): δ 173.6, 79.6, 78.7, 67.2, 66.6, 60.2, 39.0, 32.2, 31.1,
27.9, 25.7, 14.2, 12.5, -5.6, -5.6; Mass (ESI-MS): m/z 383
(M+Na)+; IR (neat):  3478, 2931, 2858, 1736, 1254, 1106,
838, 778 cm-1; ESI-HRMS: m/z calcd. for C18H36O5NaSi
[M+Na]+ 383.22348, found: 383.22168.
A mixture of 21 (420 mg, 1.16 mmol) and triphenylphosphine
(611 mg, 2.33 mmol) in dichloromethane (5 mL) was chilled
to
0
oC.
To
this
solution
was
added
diisopropylazodicarboxylate (456 µL, 2.33 mmol), and then
diphenylphosphoryl azide (501 µL, 2.33 mmol). The resulting
solution was allowed to stir at room temperature for 4 h. The
solvent was removed in vacuum and the crude product was
purified by silica gel chromatography (10% EtOAc/hexane) to
afford the azide 22 as a colorless oil (368 mg, 82 %). Rf=0.65
1
(10% EtOAc/hexane); [α]D27: +1.6 (c 0.93, CHCl3); H NMR
(CDCl3, 300 MHz): δ 4.13 (q, J = 6.9 Hz, 2H, O(CH2)CH3),
3.71-3.63 (m, 1H, OCH), 3.49-3.36 (m, 2H, OCH), 3.36-3.22
(m, 2H, CH2N3), 2.55-2.32 (m, 2H, CH2CO), 1.93-1.73 (m,
3H, CH), 1.70-1.60 (m, 2H, CH), 1.26 (t, J = 7.1 Hz, 3H,
OCH2(CH3)), 0.99 (d, J = 6.9 Hz, 3H, CH(CH3)), 0.86 (s, 9H,
SiC(CH3)3), 0.06 (s, 3H, Si(CH3)2), 0.05 (s, 3H, Si(CH3)2); 13C
NMR (CDCl3, 75 MHz): δ 173.6, 82.4, 79.0, 64.3, 60.2, 51.8,
40.8, 32.9, 31.1, 27.9, 25.6, 17.8, 14.2, 12.7, -4.0, -4.8; IR
(neat): 3411, 2930, 2955, 2858, 2098, 1736, 1256, 1103,
862, 838, 777 cm-1; ESI-HRMS: m/z calcd. for
C18H35O4N3NaSi [M+Na]+ 408.22859, found: 408.22859.
Ethyl 3-((2S,3S,5S,6R)-5-((tert-butyldimethylsilyl)oxy)-6-
(((tert-butyldimethylsilyl)oxy)methyl)-3-methyltetrahydro-
2H-pyran-2-yl)propanoate (20):
To a solution of alcohol 19 (1.22 g, 3.38 mmol) in dry CH2Cl2
(15mL) was added 2,6-lutidine (940 mL, 4.06 mmol). The
mixture was stirred for 10 min at room temperature and then
TBSOTf (0.930 mL, 8.10 mmol) was added. The resulting
mixture was stirred for 1 h at room temperature and quenched
with water. The aqueous layer was extracted with CH2Cl2,
dried over Na2SO4 and concentrated in vacuo. The crude

7
aldehyde 3 (77 mg, 0.215 mmol) in THF (0.5 mL) was
ACCEPTED MANUSCRIPT
Ethyl 3-((2S,3S,5S,6R)-6-(acetamidomethyl)-5-((tert-
butyldimethylsilyl)oxy)-3-methyltetrahydro-2H-pyran-2-
yl)propanoate (23):
added dropwise. The resulting mixture was allowed to stir at
room temperature for overnight. The mixture was then
quenched with saturated NH4Cl and extracted with EtOAc.
The organic layer was washed with water, brine solution,
dried over Na2SO4, and concentrated in vacuo. Purification by
column chromatography (50% EtOAc/hexanes) gave the ester
27 (78.2 mg, 76%). Rf=0.45 (50% EtOAc/hexane); [α]D27: 1.8
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
A mixture of 22 (342 mg, 0.408 mmol) and Pd/C catalyst (10
wt %, 70 mg) in tetrahydrofuran and ethanol (3:1) was stirred
for 1 h under H2 atmosphere. The mixture was filtered to
remove the catalyst and then the filtrate was treated with
NaHCO3 (650 mg). To this mixture was added acetic
anhydride (838 µL, 8.88 mmol) and stirred for 20 min. The
solution was filtered and concentrated in vacuum. The crude
product was then passed through a short silica gel column
(30% EtOAc/hexane) to afford the compound 23 (345 mg) as
a viscous liquid. Rf=0.3 (30% EtOAc/hexane); [α]D27: +16.3
1
(c 1.10, CHCl3); H NMR (CDCl3, 300 MHz): δ 5.98 (brs,
1H, NH), 5.90 (t, J = 6.8 Hz , 1H, olefinic), 5.83 (s, 1H,
olefinic), 4.16 (q, J = 7.1, 14.3 Hz, 2H, O(CH2)CH3), 3.79-
3.69 (m, 1H, OCH), 3.62-3.47 (m, 1H, OCH), 3.43-3.32 (m,
1H, OCH), 3.22-3.06 (m, 2H, 2x OCH), 2.31 (s, 3H,
NHCO(CH3)), 2.27-2.20 (q, J = 7.1, 14.9 Hz, 1H), 2.01 (s,
3H, CCH3)), 1.91-1.83 (m, 2H, CH), 1.81 (s, 3H, CCH3),
1.68-1.56 (m, 3H, CH ), 1.46-1.36 (m, 2H, CH), 1.28 (t, J =
6.7 Hz, 3H, OCH2(CH3)), 0.95 (d, J = 6.9 Hz, 3H, CH(CH3)),
0.88 (s, 9H, SiC(CH3)3), 0.06 (s, 3H, Si(CH3)2), 0.05 (s, 3H,
Si(CH3)3); 13C NMR (CDCl3, 75 MHz): δ169.8, 167.4, 155.9,
136.6, 114.7, 81.2, 78.9, 65.7, 59.6, 41.5, 40.8, 32.7, 32.2,
25.7, 25.6, 23.8, 17.8, 15.4, 14.3, 14.0, 12.7, -4.1, -4.7; IR
(neat):  3360, 2929, 2857, 1714, 1651, 1549, 1452, 1375,
1256, 1175, 1104 cm-1; ESI-HRMS: m/z calcd. for
C26H48O5NSi [M+H]+ 482.32963, found: 482.32913.
1
(c 1.10, CHCl3); H NMR (CDCl3, 300 MHz): δ 6.16 (br, 1H,
NH), 4.13 (q, J = 7.5, 14.3 Hz, 2H, O(CH2)CH3), 3.85 (dddd,
J = 3.0, 6.7, 9.8, 16.6 Hz, 1H), 3.55-3.40 (m, 2H,), 3.43 (dt, J
= 3.7, 10.5, 12.8 Hz, 2H,), 3.08 (td, J = 9.0, 18.1 Hz, 1H,),
2.99-2.90 (m, 1H,), 2.48-2.27 (m, 2H, CH2CO), 2.02 (s, 3H,
NHCO(CH3)), 1.94-1.78 (m, 2H, CH), 1.68-1.56 (m, 1H,
CH), 1.26 (t, J = 7.5 Hz, 3H, OCH2(CH3)), 0.96 (d, J = 6.9
Hz, 3H, CH(CH3), 0.88 (s, 9H, SiC(CH3)3), 0.07 (s, 3H,
Si(CH3)2), 0.05 (s, 3H, Si(CH3)2),); 13C NMR (CDCl3, 75
MHz): δ 174.2, 170.2, 81.7, 79.4, 65.5, 60.3, 41.5, 40.9, 32.2,
28.3, 25.7, 23.0, 20.5, 17.9, 14.2, 12.8, -4.1, -4.7; IR (neat): 
3381, 2981,1732, 1658, 1255, 1102, 775 cm-1; ESI-HRMS:
m/z calcd. for C20H40O5NSi [M+H]+ 402.26703, found:
402.26639.
N-(((2R,3S,5S,6S)-3-Hydroxy-6-((3E,5E)-7-hydroxy-4,5-
dimethylhepta-3,5-dien-1-yl)-5-methyltetrahydro-2H-
pyran-2-yl)methyl)acetamide (28):
To a stirred solution of ester 27 (44 mg, 0.091 mmol) in
CH2Cl2 (2 mL) at -78 oC was added DIBAL-H (184 μL, 0.213
mmol, 1 M solution in toluene). After stirring for 15 min, the
reaction was quenched with MeOH and diluted with Et2O and
then filtered through a short silica gel column (Et2O and then
EtOAc). The filtrate was concentrated in vacuo to give the
crude allyl alcohol, which was used for the next reaction
directly. To a solution of the above allyl alcohol in THF at 0
oC was added TBAF (92 µL, 0.045 mmol, 1M solution in
THF). The mixture was stirred at room temperature for 2 h
and then quenched with NH4Cl, extracted with CHCl3, dried
over Na2SO4 and concentrated in vacuo. The crude product
was purified by column chromatography (5% MeOH/CHCl3)
to give the compound 28 (20.6 mg, 70% for 2 steps) as light
yellow oil. Rf=0.2 (5% MeOH/CHCl3); [α]D27: -22.6 (c 0.61,
(E)-ethyl 4-(diethoxyphosphoryl)-3-methylpent-2-
enoate(6):
o
Bromide (26) (597 mg, 2.71 mmol) was heated to 140 C in
triethylphosphite (0.4 mL, 2.45 mmol) overnight. The mixture
was cooled to room temperature and purified on silica gel
32 chromatography (60% EtOAc/hexane) to give phosphate (6)
(694 mg, 92%): colorless oil. Rf = 0.27 (60% EtOAc/Hexane);
1H NMR (CDCl3 300 MHz): δ 5.79 (d, J = 5.2 Hz, 1H, olefin),
4.17-4.02 (m, 6H, 3xO(CH2)CH3), 2.73 (q, J = 6.7, 14.3 Hz,
1H, (CH)PO), 2.26 (d, J = 3.0 Hz, 3H, CCH3), 1.40-1.22 (m,
12H). 13C NMR (CDCl3, 75 MHz): δ166.2, 155.4, 155.4,
118.7, 118.6, 62.3, 62,3, 62.2, 62.1, 59.6, 42.8, 41.8, 18.2,
16.3, 16.3, 14.2, 13.7, 13.6. IR (Neat): 2983, 1716, 1219,
1153, 1027, 960 cm-1; ESI-HRMS: m/z calcd. for
C12H23O5NaP [M+Na]+ 301.11753, found: 301.11728.
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
1
MeOH); H NMR (CD3OD, 300 MHz): δ 5.65 (t, J = 5.9 Hz,
1H, olefinic), 5.60 (t, J = 7.5 Hz, 1H, olefinic), 4.21 (d, J =
6.7 Hz, 1H, CH2OH), 3.58-3.52 (m, 1H, (CH)NHCO), 3.45-
3.36 (m, 3H, 2xOCH, 1x(CH)NHCO), 3.06 (ddd, J = 2.5, 7.5,
10.1 Hz, 1H, OCH), 2.34-2.15 (m, 2H, CH), 1.96 (s, 3H,
NHCO(CH3)), 1.94-1.87 (dm, 1H, CH), 1.80 (s, 3H, CCH3),
1.79 (s, 3H, CCH3), 1.69-1.54 (m, 2H, CH), 1.44-1.34 (m, 1H,
CH), 0.96 (d, J = 6.7 Hz, 3H, CH(CH3)); 13C NMR (CD3OD,
75 MHz): δ 173.8, 139.2, 137.4, 127.8, 125.6, 83.0, 80.3,
65.0, 60.0, 42.5, 40.8, 34.1, 26.1, 22.5, 14.2, 14.1, 13.0; IR
(neat):  3479, 2926, 1714, 1099, 1032 cm-1; ESI-HRMS: m/z
calcd. for C18H31O4NNa [M+Na]+ 348.21453, found:
348.21420.
(2E,4E)-Ethyl 7-((2S,3S,5S,6R)-6-(acetamidomethyl)-5-
((tert-butyldimethylsilyl)oxy)-3-methyltetrahydro-2H-
pyran-2-yl)-3,4-dimethylhepta-2,4-dienoate (27).
To a solution of 23 (110 mg, 0.274 mmol) in CH2Cl2 (2
o
mL) at –100 C was added a solution of DIBAL-H in toluene
(1.0 M, 548 µL, 0.548 mmol) dropwise and stirred for 1 h at
the same temperature. The mixture was quenched with MeOH
(0.5 mL) and saturated aqueous sodium potassium tartrate
o
solution (1 mL). It was then stirred at 0 C for 15 min. The
aqueous layer was extracted with EtOAc (3x5 mL) and
washed with brine (5 mL), dried over Na2SO4 and
concentrated in vacuo. Purification of the crude product by
flash column chromatography (50% EtOAc/hexane) afforded
the aldehyde 3 (77 mg, 80%) as a colourless oil.
N-(((2R,3S,5S,6S)-6-((3E,5E)-4,5-Dimethyl-7-oxohepta-
3,5-dien-1-yl)-3-hydroxy-5-methyltetrahydro-2H-pyran-2-
yl)methyl)acetamide (1):
To a solution of diol 25 (16 mg, 0.0492 mmol) in CH2Cl2 (2
mL) was added MnO2 (304 mg, 3.53 mmol) and stirred at
room temperature for 1.5 h. After stirring for 1 h, the mixture
was filtered through a short silica gel column (EtOAc), and
the filtrate was concentrated in vacuo. Purification by silica
gel chromatography (5% MeOH/CHCl3) gave the brevisamide
To a solution of phosphonate (6) (65 mg, 0.233 mmol) in
o
THF (2 mL) at -78 C was added n-BuLi (103 µL, 2.5M
solution in, hexane 0.233 mmol) dropwise. The mixture was
stirred at -78 oC for 10 min and then stirred at 0 oC for 50 min.
o
The mixture was re-cooled to -78 C and then a solution of

8
Tetrahedron
ACCEPTED MANUSCRIPT
11. (a) Johnson, M. R.; Kishi, Y. Tetrahedron Lett. 1979, 20
(1) (11.4 mg, 72%) as colourless oil. Rf=0.2 (5%
MeOH/CHCl3); [α]D27: -13.6 (c 0.56, MeOH); H NMR (CD-
3OD, 300 MHz): δ 10.11 (d, J = 7.7 Hz, 1H, CHO), 6.24 (t, J
= 7.5 Hz, 1H, olefinic), 6.05 (d, J = 7.9 Hz, 1H, olefinic),
3.55-3.51 (m, 1H, (CH)NHCO), 3.45-3.37 (m, 2H, 2xOCH),
3.35-3.33 (m, 1H, (CH)NHCO), 3.15 (ddd, J = 2.4, 6.7, 9.2
Hz, 1H, OCH), 2.39-2.36 (m, 2H, CH2), 2.34 (s, 3H,
NHCO(CH3)), 1.96 (s, 3H, CCH3), 1.93-1.91 (m, 1H, CH),
1.88 (s, 3H, CCH3), 1.87-1.82 (m, 1H, CH), 1.68-1.52 (m, 2H,
CH), 1.46-1.36 (m, 1H, CH), 0.97 (d, J = 6.9 Hz, 3H,
CH(CH3)); 13C NMR (CD3OD, 75 MHz): δ 194.7, 173.8,
158.6, 137.0, 135.9, 126.2, 83.1, 80.3, 64.9, 42.5, 40.8, 34.1,
33.6, 26.9, 22.4, 14.6, 14.1, 13.0; IR (neat): υ 3329, 2928,
2855, 1655, 1548, 1438, 1377, 1106, 1069, 755 cm-1; Mass
(ESI-MS): m/z 346 (M+Na)+. ESI-HRMS: m/z calcd. for
C18H30O4N [M+H]+ 324.21693, found: 324.21680.
1
4347. (b) Boeckman Jr, R. K.; Barta, T. E.; Nelson, S. G.
Tetrahedron Lett. 1991, 32, 4091.
12. Rychnovsky, D. S.; Griesgraber, G.; Schlegelt, R. J. Am.
Chem. Soc. 1995, 117, 197.
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2
3
4
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9
13. Liu, H. J.; Yip, J. Tetrahedron Lett. 1997, 38, 2253.
14. Vatele, M. J. Tetrahedron lett. 2006, 47, 715.
15. (a) Satoh, M.; Koshino, H.; Nakata, T. Org. Lett. 2008, 10,
1683. (b) Khalaf, J. K.; VanderVelde, D. G. Datta, A. J.
Org. Chem. 2008, 73, 5977.
16. Stork, G.; Niu, D.; Fujimoto, A; Koft, E. R.; Balkovec, J.
M.; Tata, J. R.; Dake, G. R. J. Am. Chem. Soc. 2001, 123,
3239.
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Acknowledgements
NMR thanks CSIR, New Delhi for the award of a fellowship.
References and Notes
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