Lewis-acid catalyzed formation of dihydropyrans

Article abstract of DOI:10.1016/j.tet.2011.09.069

A methodology is described for the synthesis of 2,6-disubstituted dihydro[2H]pyrans through a Lewis-acid catalyzed 6-endo-trig cyclization of β-hydroxy-γ,δ-unsaturated alcohols. Employing alkyl-substituted allylic diols and catalytic amounts of a Lewis ac

Full text of DOI:10.1016/j.tet.2011.09.069

Tetrahedron 67 (2011) 9870e9884
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journal homepage: www.elsevier.com/locate/tet
Lewis-acid catalyzed formation of dihydropyrans
*
Stephen Hanessian , Thilo Focken, Rupal Oza
ꢀ
ꢀ
ꢀ
Department of Chemistry, Universite de Montreal, C. P. 6128, Succ. Centre-Ville, Montreal, P. Q., Canada H3C 3J7
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 August 2011
Received in revised form 14 September 2011
Accepted 15 September 2011
Available online 22 September 2011
A methodology is described for the synthesis of 2,6-disubstituted dihydro[2H]pyrans through a Lewis-
acid catalyzed 6-endo-trig cyclization of
b-hydroxy-g,d-unsaturated alcohols. Employing alkyl-
substituted allylic diols and catalytic amounts of a Lewis acid, such as BF3$OEt2, the corresponding syn-
pyrans are formed highly diastereoselectively and in good yields. The described process is simple to
execute, proceeds readily at ambient temperature, and is scalable.
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor Gilbert Stork whose
seminal contributions have inspired gener-
ations of synthetic chemists
Keywords:
Dihydropyran
Cyclization
Lewis-acid catalysis
Cycloetherification
Heterocyclization
1. Introduction
using a transition metal catalyzed methodology developed by
Uenishi and others (Scheme 1).16e19 Allylic diols undergo stereo-
Polysubstituted di- and tetrahydropyrans are ubiquitous struc-
tural elements in biologically important natural products.1 For ex-
ample, natural products incorporating dihydropyranyl moieties
include, among others, ambruticin S,2 jerangolid A,3 cacospongio-
nolide,4 4,5-deoxyneodolabelline,5 funiculosin,6 laulimalide,7 pen-
itrem D,8 scytophycin C,9 sorangicin A,10 swinholide A,11 and
wortmannilactone G12 (Fig. 1). Syn or anti disposition of sub-
stituents on the pyran ring affects the three dimensional shape of
the heterocyclic moiety and the biological activity of the molecule.
Although substantial efforts have been made to develop
methods for the construction of di- and tetrahydropyrans,13 the
stereocontrolled synthesis of these cyclic ethers and related het-
selective 6-exo- or 6-endo-trig cyclization upon treatment with
catalytic amounts of Pd(CH3CN)2Cl2 forming tetrahydro- or dihy-
dropyrans, respectively. Thus, reaction of
b-hydroxy-g,d-un-
saturated alcohols 2a,b affords either 2,6-syn- or 2,6-anti-3,6-
dihydro[2H]pyrans 1 via an overall syn-SN20 type process, with the
syn/anti selectivity being controlled by the relative configuration of
the diol. A majoradvantageof this methodology is the absence of any
by-products, as only water is eliminated during the cyclization.
In considering an approach to the trisubstituted dihydropyran
ring in ambruticin S2,14 and jerangold A,3,15 we attempted Uenishi’s
Pd-catalyzed cycloetherification protocol (Fig. 2). Our initial ex-
periments resulted in the formation of the desired products, albeit
as a mixture of diastereomers. However, a cationic Pd-catalyzed
cycloetherification led to the desired syn-isomer as the pre-
ponderant if not exclusive product. These results ultimately led to
the exploration of a novel Lewis-acid catalyzed 6-endo-trig cycli-
erocycles is still
a challenging and interesting task. 2,6-
Disubstituted dihydro[2H]pyrans are attractive targets, particu-
larly with regard to controlling the syn- and anti-disposition of the
substituents.
As part of a research program on antifungal polyketides, we de-
zation of b-hydroxy-g,d-unsaturated alcohols to give dihydro[2H]
pyrans. Herein, we report our initial results, the optimization
strategy, and substrate scope.
veloped a novel synthesis of ambruticin S14 and jerangolid A,15
which include the same dihydro[2H]pyran harboring
a tri-
substituted double bond (Figs. 1 and 2). Our synthetic plan toward
the construction of the dihydropyran ring was originally aimed at
2. Results
A series of E- and Z-
b-hydroxy-g,d-unsaturated alcohols was
* Corresponding author. E-mail address: stephen.hanessian@umontreal.ca
(S. Hanessian).
synthesized using three different synthetic approaches. The E-
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.069

S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
9871
HO
H
H
OH
MeO
HO
O
O
O
OH
HO
O
O
Jerangolid A
H
H
O
H
HO
O
Sorangicin A
OH
H
O
N
Me
O
Funiculosin
H
H
H
H
O
H
HO
H
O
H
HO
H
HO2C
OH
HO
H
O
O
OH
4,5-Deoxyneodolabelline
H
H
H
O
O
O
O
O
HO2C
H
O
H
O
O
OH
HO
Ambruticin S
Laulimalide
Cacospongionolide
OH
Fig. 1. Selected examples of dihydro[2H]pyran segment containing natural products.
Fig. 2. Retrosynthesis of ambruticin and jerangolid.
Scheme 1.
allylic diols were prepared either by route A or B as shown in
Schemes 2 and 3. Thus, route A involved opening of (R)-glycidol
benzyl ether (3) with dithiane 4a or 4b,20 respectively, followed by
unmasking of the enone system and stereoselective reduction.
Protection of the hydroxyl group in dithiane adducts 5a,b as TBS-
Scheme 3.
A
B
Scheme 2.

9872
S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
ethers proved to be necessary prior to unmasking the
a
,
b
-un-
While cyclization of compounds 9a and 9d proceeded as expected
under Uenishi’s conditions (Pd(CH3CN)2Cl2, THF) yielding the anti-
or syn-dihydropyran 14a selectively (Table 1, entries 1 and 2), we
were surprised to find that the introduction of a vinylic methyl
substituent was detrimental for selectivity. Thus, treatment of diols
9b and 9e with Pd(CH3CN)2Cl2 in THF, both led to a 1.4:1 syn/anti
mixture of dihydropyran 14b (Table 1, entries 3 and 4). The selec-
tivity could be improved to 6:1 favoring syn-14b by employing
chlorinated solvents such CH2Cl2 or CHCl3 (Table 1, entries 6 and 7).
The use of acetonitrile as solvent led to a 7:1 selectivity, albeit ac-
companied by a low yield of 14b (Table 1, entry 8).
saturated system. The dithiane moiety could then be removed by
treatment with benzeneseleninic anhydride21 giving the relatively
sensitive enones 6a and 6b in 85% and 73% yield, respectively
(Scheme 2A). In route B, dihydroxy ester 7,22 readily available from
D-malic acid, was used as the starting chiron (Scheme 2B). Con-
version of the primary hydroxyl group into a benzyl ether de-
rivative was achieved using Bu2SnO and benzyl bromide,
accompanied by concomitant transesterification. Protecting of the
secondary hydroxyl group as the TBS-ether gave 8, which was
treated with the Li anion of dimethyl methylphosphonate or diethyl
ethylphosphonate, respectively, to give the corresponding
phosphonates. These were subsequently converted into
b
a
-keto-
-un-
Table 1
,
b
Formation of dihydropyrans 14 from allylic 1,3-diols 9 with Pd(CH3CN)2Cl2
saturated ketones 6ceh using Paterson’s protocol for the
HornereWadswortheEmmons olefination.23
Reduction of enones 6aec with either (R)-Me-CBS or (S)-Me-
CBS followed by cleavage of the TBS-ether with TBAF furnished the
diastereomerically pure diols 9aef (63e95% yield, dr 94:6e99:1)
(Scheme 3). Alternatively, exposure of enones 6a,b and 6deh to
Luche reduction conditions followed by treatment with TBAF
yielded diols 9b,c and 9gek as mixtures of syn/anti diastereomers
favoring the syn-diol.
The Z-allylic diols 12a,b were synthesized through alkyne ad-
dition to aldehyde 10,24 the latter being prepared from DIBAL-H
reduction of benzyl ester 8 (61%, Scheme 4). Diastereomers 11a,b
thus obtained were separated and reduced under Lindlar condi-
tions to provide diols 12a,b in 19e25% yield (over 2 steps) as dia-
stereomerically pure materials (Scheme 4).
Entry
1
Diol
Solvent Product Yield (%) syn/antia
9a THF
9d THF
9b THF
14a
14a
14b
54
54
53
1:5
99:1
1.5:1
2
3
4
5
6
7
8
9e THF
14b
14b
53
53
56
57
21
1.4:1
3:1
9e C6H6
9e CH2Cl2 14b
6:1
9e CHCl3
14b
6:1
9e CH3CN 14b
9e Acetone 14b
7:1
Scheme 4.
The syn/anti-configuration of diols 9 and 12 was determined by
13C NMR analysis of the corresponding acetonides 13 prepared from
a few selected diols (Scheme 5).25
9
67
3:1
With a diverse set of allylic diols in hand, we were ready to study
the 6-endo-trig cyclization and the formation of dihydropyrans.
a
Determined by 1H NMR.
Other dichloro palladium(II) complexes, such as PdCl2 or
Pd(PPh3)2Cl2 failed to catalyze the conversion of diol 9e to dihy-
dropyran 14b (Table 2, entries 2 and 3). Inspired by Gouverneur’s
study on the formation of pyranones from enones,26 we also tested
the cationic complex Pd(CH3CN)4(BF4)2 as catalyst in the reaction.
Remarkably, syn-dihydropyran 14b was formed in excellent syn/anti
selectivity (>25:1) upon treatment of diol 9b with Pd(CH3CN)4(BF4)2
(Table 2, entry 4). We considered the possibility that the Lewis acidity
of thecationicPd complex might inducethecyclization, and therefore
tested the applicability of several other Lewis and Brønsted acids in
the reaction, including BF3$OEt2 and TfOH.27e29 Indeed, the desired
Scheme 5.

S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
9873
Table 2
>25:1 syn/anti selectivity and 81% yield, while the use of Fe(ClO4)2
gave slightly lower selectivity (Table 2, entries 5 and 6). Copper(II)
triflate provided 14b highly selectively, albeit only in moderate yield
(40%). We suspected that triflic acid generated from hydrolysis of
Cu(OTf)2 might be the active catalyst in this case, however, treatment
of diol 9b with TfOH gave 14b with a diastereomeric ratio of only 15:1
(Table 2, entry 8). Surprisingly, AuCl3 failed to catalyze the conversion
of diol 9b to 14b (Table 2, entry 10). The cyclization proceeded
smoothly on a multigram scale, using either Pd(CH3CN)4(BF4)2 or
BF3$OEt2 (Table 2, entries 4 and 5).
We next investigated the influence of the relative configuration
of the starting diol on the selectivity of the cycloetherification. The
diastereomeric diols 9a and 9d both yielded the same syn-dihy-
dropyran 14a in excellent diastereoselectivity (syn/anti >97:3)
upon treatment with BF3$OEt2 (Table 3, entries 1 and 2). The same
outcome was observed in the case of the methyl-substituted ana-
logues 9b and 9e. Using either BF3$OEt2 or Pd(CH3CN)4(BF4)2, the
syn-dihydropyran 14b was formed in excellent selectivity (syn/anti
>98:2) from both diols (Table 3, entries 7e10). Thus, the stereo-
chemistry of the allylic alcohol was of no importance in the cycli-
Optimization and catalyst screening
Entry
Diol
Catalyst (equiv)
Yield (%)
syn/antia
1
2
3
4
5
6
7
8
9
9e
9e
9e
9b
9b
9b
9b
9b
9b
9b
Pd(CH3CN)2Cl2 (1.0)
PdCl2 (1.0)
56
db
db
73
81
82
40
63
44
db
6:1
d
Pd(PPh3)2Cl2 (1.0)
Pd(CH3CN)4(BF4)2 (0.05)c,d
BF3$OEt2 (0.1)c,d
Fe(ClO4)2$xH2O (0.1)c
Cu(OTf)2 (0.1)c
d
25:1
25:1
18:1
25:1
15:1
7:1
d
TfOH (0.1)c
TsOH (0.1)c
10
AuCl3 (0.1)c
a
Determined by 1H NMR.
No conversion observed.
Using 9b obtained from Luche reduction of 6a, dr 4:1.
b
c
d
Multigram scale reaction.
zation reaction, strongly suggesting
a cationic mechanism.
Consequently, for preparative purposes, we later applied Luche
conditions (NaBH4 and CeCl3) for the reduction of enones 6
(Scheme 1 and 2) affording diastereomeric mixtures of diols 9.
syn-dihydropyran 14b was obtained in good to excellent selectivities,
and moderate to good yields upon treatment of 9b with Lewis acids.
Thus, exposure of diol 9b to BF3$OEt2 led to the formation of 14b in
Table 3
Formation of syn-dihydropyrans 14 from alkyl-substituted allylic 1,3-diols 9 and 12
Entry
Diol
Catalyst
BF3$OEt2
BF3$OEt2
Product
syn-14a
syn-14a
Yield (%)
75
syn/antib
97:3
1
2
9a
9d
72
98:2
3
BF3$OEt2
syn-14a
syn-14a
syn-14a
syn-14a
syn-14b
syn-14b
syn-14b
syn-14b
76
41
71
40
76
72
82
71
99:1
98:2
95:5
95:5
99:1
98:2
99:1
99:1
12a
12b
9b
4
Pd(CH3CN)4(BF4)2
BF3$OEt2
5
6
Pd(CH3CN)4(BF4)2
BF3$OEt2
7
8
Pd(CH3CN)4(BF4)2
BF3$OEt2
9
9e
10
Pd(CH3CN)4(BF4)2
11
9ba
Pd(CH3CN)4(BF4)2
syn-14b
73
98:2
a
Obtained from Luche reduction of 6a, dr 4:1.
Determined by HPLC.
b

9874
S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
Using a 4:1 mixture of diastereomers 9b and 9e, the same syn se-
lectivity was obtained in the cycloetherification (Table 3, entry 11).
Additional evidence for a cationic mechanism was obtained
from cyclization of diols 12a,b featuring a Z-double bond. Indeed,
subjecting the individual diastereomers of 12 to the conditions of
cycloetherification (BF3$OEt2 in CH2Cl2) afforded the same syn-
product 14a in excellent selectivity (syn/anti >95:5) and good
yields (Table 3, entries 3 and 5). Usage of the cationic palladium
complex Pd(CH3CN)4(BF4)2 resulted in the same selectivity, albeit
a lower yield of 14a (Table 3, entries 4 and 6).
The alkyl substituted dihydropyrans 14a,b are stable under the
reaction conditions and do not epimerize through a ring-opening/
ring-closing sequence when treated with BF3$OEt2. Thus, no
change in the syn/anti ratio was observed when diastereomerically
pure syn-14b or anti-14b were subjected to the reaction conditions
using BF3$OEt2 even after several days. However, aryl-substituted
dihydropyrans 14ceh readily epimerize under the reaction condi-
tions. For instance, treatment of diastereomerically pure para-
methoxyphenyl substituted dihydropyrans syn-14f or anti-14f with
BF3$OEt2 gave a 2:1 syn/anti ratio of the recovered pyrans after
<5 min of reaction time (Scheme 6).30
Further studies were conducted to test the effect of aryl sub-
stitution at the d-position of the diol scaffold on the selectivity.
Interestingly, when phenyl-substituted diol 9g (dr 2:1) was sub-
jected to the reaction conditions using BF3$OEt, dihydropyran 14c
was formed as a 3:1 mixture of diastereomers (Table 4, entry 1). A
similar outcome was observed with diastereomerically pure diols
9c and 9f. In both cases, a 2:1 mixture of 14d was obtained using
BF3$OEt as catalyst (Table 4, entries 3 and 5), favoring the syn-iso-
mer. Electron-donating as well as electron-withdrawing sub-
stituents on the aryl moiety seemed to have no effect in
combination with BF3$OEt2. Thus, reactions of diol 9h and diol 9j
provided the corresponding dihydropyrans in a 3:1 to 2:1 ratio of
diastereomers, respectively (Table 4, entries 4 and 6). Likewise,
diols 9i and 9k, bearing an additional methyl substituent on the
double bond, yielded the corresponding dihydropyrans 14f and
14h, respectively, in similar ratios (Table 4, entries 5 and 7).
Scheme 6.
Table 4
Formation of syn-dihydropyrans 14 from aryl-substituted allylic 1,3-diols 9
Entry
1
Diol
Product
R1
H
R2
H
Yield (%)
82
syn/antia
9g
9c
9f
9h
9i
14c
3:1
2
3
4
5
6
14d
14d
14e
14f
Me
Me
H
H
88
81
85
92
81
2:1
2:1
2:1
2:1
3:1
H
OMe
OMe
F
Me
H
9j
14g
7
9k
14h
Me
F
78
2:1
a
Determined by HPLC.

S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
9875
3. Discussion
The experimental data suggested that the stereochemistry of
the allylic alcohol was of no consequence in the cyclization re-
action. Therefore, the possibility of an ionic mechanism with for-
mation of an allyl cation followed by cyclization of the adjacent
hydroxyl group seemed likely.27,28 Additional support for this hy-
pothesis was provided by conversion of allylic diol 17 under stan-
dard cyclization conditions and comparison with diol 9g. As
expected, 17 and 9g afforded the same product 14c upon treatment
of with BF3$OEt2, presumably via the same cationic intermediate
(Scheme 7 and Table 4, entry 1).
Scheme 7.
Fig. 3. Postulated mechanism for Lewis-acid catalyzed cycloetherification.
On the basis of the experimental results we propose that after
coordination of the allylic hydroxyl group by the Lewis-acid and
subsequent partial or complete dissociation of the complexed
group, an allylic cation is formed. This cation then undergoes face-
selective attack by the adjacent hydroxyl group to yield dihy-
dropyrans 14 (Table 1). It should be noted that the formation of the
ethyl-substituted syn-dihydropyran 14b proceeds in excellent yield
and diastereoselectivity, even though the product is subject to A1,2
strain experienced by the juxtaposition of the vicinal methyl and
ethyl groups. The results can be rationalized considering a transi-
tion state model B leading to the preponderant formation of the
syn-isomer 14b via re-face attack of the hydroxyl group onto the
allylic system (Fig. 3, R¼Me).
and jerangolid A.3,15 The reaction proceeds through a Lewis-acid
catalyzed 6-endo-trig cyclization of -hydroxy- -unsaturated al-
cohols. In case of alkyl-substituted allylic diols, the corresponding
syn-dihydropyrans are formed in excellent diastereoselectivities.
The described process is simple to execute, proceeds readily at
ambient temperature, and is scalable. It is very attractive with re-
spect to atom-economy, as water is the only by-product formed.
b
g,d
4. Experimental section
4.1. General information
Although anti-dihydropyran 14b lacks A1,2 strain, its formation
would require the attacking hydroxyl group to approach the allylic
system from the si-face of the allylic cation adopting an energeti-
cally disfavored eclipsed conformation. In addition, the anti-dihy-
dropyran suffers from an energetic penalty associated with a 1,3-
diaxial interaction (Fig. 3, transition state model C).
All non-aqueous reactions were run in flame-dried glassware
under a positive pressure of argon with exclusion of moisture from
reagents and glassware using standard techniques for manipulating
air-sensitive compounds. Anhydrous solvents were obtained using
standard drying techniques. Unless stated otherwise, commercial
grade reagents were used without further purification. Reactions
were monitored by analytical thin-layer chromatography (TLC)
performed on pre-coated, glass-backed silica gel plates. Visualiza-
tion of the developed chromatogram was performed by UV absor-
bance, aqueous cerium ammonium molybdate, iodine, or aqueous
potassium permanganate. Flash chromatography was performed
on 230e400 mesh silica gel with the indicated solvent systems.
Yields refer to chromatographically and spectroscopically (1H and
13C NMR) homogeneous materials. Reversed-phase HPLC analyses
The diastereoselective formation of dihydropyran 14a from Z-al-
lylic alcohols 12a,b can be rationized in a similar fashion. The allylic
cation initially formed from 12a,b presumably undergoes isomeriza-
tion from an anti, anti-to a syn, anti-conformation in order to minimize
allylic strain. Re-face attack of the d-hydroxyl group then yields syn-
dihydropyran 14a (Fig. 3, transition state model A and B, R¼H).
The aryl-substituted pyrans 14ceh are most likely formed
through an analogous mechanism, however, they subsequently
isomerize under the reaction conditions to give a mixture of di-
astereomers. The diastereomeric ratios observed reflect the relative
thermodynamic stabilities of the aryl-substituted dihydropyrans,
with energetic penalties arising from A1,2 strain and 1,3-diaxial
repulsion in the syn- and anti-isomers, respectively.
were performed using a C18 column (250ꢀ4.6 mm, 5
mM) and
a 0.1% formic acid in water/acetonitrile gradient; UV detection at
254 nm. Melting points are uncorrected. Infrared spectra were
recorded on an FT-IR spectrometer and are reported in reciprocal
centimeters (cmꢁ1). Routine nuclear magnetic resonance spectra
were recorded either on AV-300, ARX-400, or AV-400 spectrome-
ter. Chemical shifts for 1H NMR spectra are recorded in parts per
million from tetramethylsilane with the solvent resonance as the
In summary, we developed a novel synthesis of enantiomerically
pure 2,6-disubstituted dihydropyrans, which are useful building
blocks to access biologically active targets, such as ambruticin S2,14

9876
S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
internal standard. Data are reported as follows: chemical shift,
multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet, qn¼quin-
tet, m¼multiplet, and br¼broad), coupling constant in hertz, and
integration. Chemical shifts for 13C NMR spectra are recorded in
parts per million from tetramethylsilane using the central peak of
the solvent resonance as the internal standard. All spectra were
obtained with complete proton decoupling. Optical rotations were
determined at 589 nm at ambient temperature. Data are reported
3.44 (dd, J¼9.6, 4.8 Hz, 1H), 3.39 (dd, J¼9.6, 6.3 Hz, 1H), 2.88e2.65
(m, 5H), 2.25e2.04 (m, 4H), 2.00e1.88 (m, 2H),1.77 (d, J¼0.6 Hz, 3H),
1.04 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 138.0,133.8,132.5,
128.3, 127.6, 127.6, 74.1, 73.2, 67.5, 58.3, 42.8, 27.3, 27.2, 25.0, 22.1,
14.0, 13.5; IR (film, NaCl) 2957, 2935, 2909, 2870, 1453, 1422, 1100,
1089, 736, 699 cmꢁ1; [
a
]
D ꢁ6.3 (c 1.58, CHCl3); HRMS (ESI) calcd for
C19H28NaO2S2 (MþNa)þ 375.1423, found 375.1434.
as follows: [
a
]D, concentration (c in g/100 mL), and solvent. High-
4.2.4. (R,E)-1-(Benzyloxy)-3-(2-(1-phenylprop-1-en-2-yl)-1,3-
dithian-2-yl)propan-2-ol (5b). The material was prepared from
dithiane 4b as a colorless oil as described for 5a in 86% yield: 1H
ꢀ
resolution mass spectra were performed by the Centre regional
ꢀ
ꢀ
de spectroscopie de masse de l’Universite de Montreal using fast
atom bombardment (FAB) or electrospray ionization (ESI) tech-
niques. Low-resolution mass spectra were obtained using electro-
spray ionization (ESI).
NMR (400 MHz, CDCl3) d 7.44e7.26 (m, 11H), 4.58 (s, 2H), 4.17 (br s,
1H), 3.50 (dd, J¼9.4, 3.9 Hz, 1H), 3.48e3.42 (m, 1H), 2.99e2.89 (m,
2H), 2.83e2.73 (m, 3H), 2.28 (dd, J¼15.2, 7.5 Hz, 1H), 2.14 (d,
J¼15.0 Hz, 1H), 2.04 (s, 3H), 2.02e1.93 (m, 2H); 13C NMR (100 MHz,
4.2. Experimental procedures
CDCl3) d 137.7,136.3,131.5,128.7,128.1,127.8,127.3,126.4, 73.9, 72.9,
67.1, 58.8, 43.1, 27.3, 27.1, 24.7, 15.3; IR (film, NaCl) 3461, 3027, 2910,
4.2.1. 2-((E)-Pent-2-en-2-yl)-1,3-dithiane (4a). A mixture of 1,3-
propanedithiol (7.50 mL, 75.0 mmol), boron trifluoride etherate
(9.5 mL, 75.0 mmol), and glacial acetic acid (18.0 mL, 0.32 mol) in
dichloromethane (125 mL) was cooled to ꢁ20 ꢂC. To the vigorously
stirred mixture was added slowly a solution of 2-methyl-2-
pentenal (8.55 mL, 75.0 mmol) in CH2Cl2 (50 mL) while maintain-
ing the temperature between ꢁ20 and ꢁ15 ꢂC. The reaction mix-
ture was stirred for 1 h at ꢁ20 ꢂC, and then siphoned into ice-cold
10% aqueous KOH solution. The temperature was maintained below
1599, 1494, 1453, 1378, 1277, 1097, 1028, 909, 870, 745, 699 cmꢁ1
;
[a
]
ꢁ21.7 (c 0.40, CHCl3); HRMS (ESI) calcd for C23H29O2S2
D
(MþH)þ: 401.1603, found 401.1600.
4.2.5. (R,E)-1-(Benzyloxy)-2-((tert-butyldimethylsilyl)oxy)-5-
methyloct-5-en-4-one (6a). A cold (0 ꢂC) solution of dithiane adduct
5a (10.4 g, 29.5 mmol) and 2,6-lutidine (8.6 mL, 74.1 mmol) in CH2Cl2
(380 mL) was treated with TBSOTf (13.6 mL, 59.2 mmol) for 1 h. The
reaction mixture was quenched with saturated NH4Cl solution, the
aqueous layer extracted with CH2Cl2, and the combined organic
phase dried (Na2SO4) and concentrated. The residue was purified by
flash chromatography (hexanes/EtOAc, 20:1 to 9:1) to yield 12.8 g
(93%) of the TBS-dithiane adduct as a colorless oil: 1H NMR
5
ꢂC during the quench. After dilution with diethyl ether, the or-
ganic phase was separated, washed with 10% KOH, water (3ꢀ),
brine, and dried (Na2SO4). Concentration in vacuo yielded 13.9 g
(99%) of the crude dithiane 4a as a 10:1 mixture of E/Z isomers. The
dithiane was used without further purification in the next step: 1H
(400 MHz, CDCl3) d 7.38e7.32 (m, 4H), 7.32e7.26 (m, 1H), 6.05e6.00
NMR (400 MHz, CDCl3, major isomer)
d
5.65e5.61 (m, 1H), 4.56 (s,
(m,1H), 4.53 (d, J¼12.2 Hz, 1H), 4.51 (d, J¼12.4 Hz,1H), 3.99e3.93 (m,
1H), 3.42 (dd, J¼9.9, 4.1 Hz, 1H), 3.36 (dd, J¼9.9, 5.6 Hz, 1H),
2.86e2.71 (m, 2H), 2.70e2.60 (m, 2H), 2.33 (dd, J¼14.9, 6.4 Hz, 1H),
2.18e2.09 (m, 2H), 2.06 (dd, J¼14.9, 3.9 Hz, 1H), 2.02e1.84 (m, 2H),
1.74 (s, 3H), 1.06 (t, J¼7.5 Hz, 3H), 0.89 (s, 9H), 0.10 (s, 3H), 0.05 (s,
1H), 2.98e2.90 (m, 3H), 2.87e2.81 (m, 2H), 2.08e2.01 (m, 2H),
1.82e1.76 (m, 4H), 0.97 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3,
major isomer) d 132.3, 131.6, 55.3, 31.6, 25.5, 21.3, 14.9, 13.7; IR (film,
NaCl) 2957, 2935, 2891, 1457, 1424, 1422, 1378, 1275, 1172, 745,
679 cmꢁ1; MS (ESI) calcd for C9H17S2 (MþH)þ 189.1, found 189.1.
3H); 13C NMR (100 MHz, CDCl3)
d 138.5, 134.1, 131.7, 128.2, 127.5,
127.3, 74.9, 73.1, 68.6, 58.6, 44.1, 27.5, 27.3, 26.0, 25.2, 22.2, 18.1, 14.2,
4.2.2. (E)-2-(1-Phenylprop-1-en-2-yl)-1,3-dithiane (4b). The mate-
rial was prepared from (E)-2-methyl-3-phenyl-2-propenal as a yel-
lowish oil as described for 4a (65% yield, 3:1 mixture of E/Z isomers):
13.7, ꢁ4.0, ꢁ4.5; IR (film, NaCl) 2957, 2928, 2855, 1478, 1456, 1454,
1251, 1097, 1004, 836, 776, 733, 697 cmꢁ1; [
a]D ꢁ6.4 (c 0.94, CHCl3);
MS (ESI) calcd for C25H43O2S2Si (MþH)þ 467.3, found 467.3.
1H NMR (400 MHz, CDCl3)
d
7.44e7.21 (m, 5H), 6.77 (br s, 1H, major
To a solution of the TBS-dithiane adduct (5.0 g, 10.7 mmol) in
CH2Cl2 (140 mL) was added benzeneseleninic acid anhydride (70%,
5.51 g,10.7 mmol) and propylene oxide (1 mL). The reaction mixture
was stirred for 16 h at room temperature, and solid NaHCO3 (5.0 g)
was added. The solvent was removed and the residue purified by
flash chromatography (hexanes/EtOAc,10:1 to 4:1) to give enone 6a
(3.20 g, 79%) as a light yellowish oil: 1H NMR (400 MHz, CDCl3)
isomer), 6.44e6.42 (m, 1H, minor isomer), 5.35 (br s, 1H, minor
isomer), 4.76 (br s, 1H, major isomer), 3.07e2.80 (m, 4H), 2.19e2.05
(m, 4H),1.97e1.84 (m, 1H); 13C NMR (100 MHz, CDCl3, major isomer)
d
137.0, 135.7, 129.1, 129.0, 128.1, 126.8, 55.8, 31.6, 25.4, 16.9; 13C NMR
(100 MHz, CDCl3, minor isomer) d 136.9(5), 134.8, 128.6, 128.4, 128.3,
126.9, 50.3, 30.7, 25.1, 20.7; IR (film, NaCl) 3054, 3023, 2897, 2827,
2339, 1953, 1897, 1645, 1598, 1575, 1493, 1422, 1379, 1274, 1248, 1171,
1111, 1075, 1020, 1003, 921, 866, 821, 741, 697, 678 cmꢁ1; MS (ESI)
calcd for C13H17S2 (MþH)þ: 237.1, found 237.2.
d
7.39e7.27 (m, 5H), 6.67 (dt, J¼7.0, 0.9 Hz, 1H), 4.56 (s, 2H), 4.43
(dddd, J¼7.4, 5.2, 5.2, 5.2 Hz, 1H), 3.49 (dd, J¼9.8, 5.1 Hz, 1H), 3.42
(dd, J¼9.7, 5.4 Hz, 1H), 2.95 (dd, J¼15.3, 7.4 Hz, 1H), 2.82 (dd, J¼15.3,
4.9 Hz, 1H), 2.27 (dq, J¼7.4, 7.4 Hz, 2H), 1.78 (s, 3H), 1.10 (t, J¼7.6 Hz,
3H), 0.86 (s, 9H), 0.07 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz, CDCl3)
4.2.3. (R,E)-1-(Benzyloxy)-3-(2-(pent-2-en-2-yl)-1,3-dithian-2-yl)
propan-2-ol (5a). To a ꢁ78 ꢂC solution of dithiane 4a (11.5 g,
61.0 mmol) in THF (60 mL) was added n-BuLi (33.3 mL of a 1.6 M
solution in hexanes, 53.3 mmol) dropwise. The reaction mixturewas
stirred for 5 min at that temperature, warmed to 0 ꢂC, and stirred for
30 min, before it was re-cooled to ꢁ78 ꢂC. A solution of (R)-benzyl
glycidol ether (3) (5.0 g, 30.5 mmol) in THF (40 mL) was then added
slowly. The reaction mixturewas stirred for 30 min and quenched by
addition of saturated NH4Cl solution. The aqueous layer was
extracted with EtOAc, the combined organic phase dried (Na2SO4),
and concentrated. The residue was purified by flash chromatogra-
phy (hexanes/EtOAc, 10:1 to 4:1) to give 10.5 g (97%) of dithiane
d
200.3, 145.0, 138.3, 137.4, 128.3, 127.5, 127.4(7), 74.4, 73.2, 69.0,
42.0, 25.8, 22.4,18.0,13.0,11.1, ꢁ4.6, ꢁ5.0; IR (film, NaCl) 2957, 2930,
2857, 1668, 1252, 1112, 836 cmꢁ1; [
a]
þ28.5 (c 2.0, CHCl3); HRMS
D
(ESI) calcd for C22H37O3Si (MþH)þ 377.2506, found 377.2526.
4.2.6. (R,E)-6-(Benzyloxy)-5-((tert-butyldimethylsilyl)oxy)-2-
methyl-1-phenylhex-1-en-3-one (6b). The material was prepared
from dithiane adduct 5b via the corresponding TBS-dithiane adduct
as a colorless oil as described for 6a (71% overall yield). TBS-
dithiane adduct: 1H NMR (400 MHz, CDCl3)
d 7.42e7.26 (m, 10H),
7.22 (br s, 1H), 4.52 (s, 2H), 4.14e4.08 (m, 1H), 3.46 (dd, J¼9.9,
4.3 Hz, 1H), 3.42 (dd, J¼9.9, 5.4 Hz, 1H), 2.97 (ddd, J¼14.4, 11.5,
3.1 Hz, 1H), 2.88 (ddd, J¼14.2, 11.3, 2.9 Hz, 1H), 2.74e2.66 (m, 2H),
adduct 5a as a colorless oil: 1H NMR (400 MHz, CDCl3)
(m, 5H), 6.05 (tq, J¼7.1, 1.2 Hz, 1H), 4.55 (s, 2H), 4.07e3.98 (m, 1H),
d 7.39e7.25

S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
9877
2.44 (dd, J¼14.9, 6.3 Hz, 1H), 2.16 (dd, J¼14.9, 4.1 Hz, 1H), 2.09e1.90
1336, 1283, 1255, 1203, 1182, 1157, 1106, 1044, 1025, 979, 911, 878,
(m, 5H), 0.91 (s, 9H), 0.14 (s, 3H), 0.09 (s, 3H); 13C NMR (100 MHz,
836, 811, 778, 743, 695 cmꢁ1; [
a]
þ35.2 (c 0.42, CHCl3); MS (ESI)
D
CDCl3)
d
138.5, 138.3, 136.2, 132.3, 129.1, 128.3, 128.2, 127.6, 127.4,
calcd for C25H35O3Si (MþH)þ: 411.2, found 411.3.
126.7, 75.0, 73.2, 68.6, 59.3, 44.6, 27.7, 27.6, 26.1, 25.2, 18.2, 15.8,
ꢁ3.8, ꢁ4.2; IR (film, NaCl) 3061, 3027, 2952, 2928, 2899, 2855, 1947,
1807, 1633, 1599, 1575, 1495, 1471, 1462, 1454, 1422, 1410, 1361,
1329, 1278, 1252, 1213, 1098, 1028, 1003, 939, 908, 868, 835, 811,
4.2.9. (R,E)-6-(Benzyloxy)-5-((tert-butyldimethylsilyl)oxy)-1-(4-
methoxyphenyl)hex-1-en-3-one (6e). The material was prepared
from benzyl ester 8 as a light yellow oil as described for 6c in 89%
777, 746, 698, 674 cmꢁ1; [
a]
D ꢁ23.0 (c 0.38, CHCl3); MS (ESI) calcd
yield: 1H NMR (400 MHz, CDCl3)
d 7.60e7.46 (m, 3H), 7.39e7.24 (m,
for C29H43O2S2Si (MþH)þ: 515.3, found 515.3. Enone 6b: 1H NMR
5H), 6.94 (d, J¼7.5 Hz, 2H), 6.66 (d, J¼15.5 Hz, 1H), 4.58 (s, 2H),
4.50e4.42 (m, 1H), 3.86 (s, 3H), 3.58e3.42 (m, 2H), 2.90 (d,
J¼5.8 Hz, 2H), 0.86 (s, 9H), 0.9 (s, 3H), 0.4 (s, 3H); 13C NMR
(400 MHz, CDCl3)
d 7.59 (s, 1H), 7.46e7.41 (m, 4H), 7.38e7.34 (m,
4H), 7.34e7.27 (m, 2H), 4.59 (s, 2H), 4.55e4.47 (m, 1H), 3.55 (dd,
J¼9.7, 5.0 Hz, 1H), 3.48 (dd, J¼9.7, 5.6 Hz, 1H), 3.12 (dd, J¼15.4,
7.4 Hz, 1H), 3.01 (dd, J¼15.4, 4.9 Hz, 1H), 2.08 (br s, 3H), 0.87 (s, 9H),
(100 MHz, CDCl3)
d 198.5, 161.2, 142.5, 137.9, 129.7, 127.9, 127.3,
127.2, 126.9, 124.8, 114.0, 74.0, 72.9, 68.5, 55.0, 45.2, 25.5, 17.7, ꢁ4.9,
ꢁ5.2; IR (film, NaCl) 3543, 3064, 3033, 3005, 2954, 2929, 2896,
2856, 2031, 1682, 1658, 1651, 1601, 1574, 1512, 1470, 1463, 1455,
1422, 1360, 1329, 1305, 1254, 1204, 1172, 1112, 1031, 1005, 981, 939,
0.11 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 200.5, 139.1,
137.9, 137.7, 135.7, 129.4, 128.1, 128.0, 127.9, 127.3, 127.2, 74.0, 72.9,
68.8, 42.2, 25.5, 17.7, 12.8, ꢁ4.9, ꢁ5.2; IR (film, NaCl) 3063, 3030,
2954, 2928, 2886, 2856, 1950, 1667, 1626, 1575, 1495, 1471, 1462,
1454,1388,1361, 1323, 1303, 1252, 1207,1091, 1048, 1029, 1005, 978,
906, 831, 778, 736, 698, 661 cmꢁ1; [
a]
D þ31.1 (c 0.29, CHCl3); HRMS
(ESI) calcd for C26H37O4Si (MþH)þ: 441.2456, found 441.2458.
939, 836, 811, 778, 736, 697 cmꢁ1; [
a
]
D
þ22.6 (c 0.42, CHCl3); MS
(ESI) calcd for C26H37O3Si (MþH)þ: 425.3, found 425.4.
4.2.10. (R,E)-6-(Benzyloxy)-5-((tert-butyldimethylsilyl)oxy)-1-(4-
methoxyphenyl)-2-methylhex-1-en-3-one (6f). The material was
prepared from benzyl ester 8 as a colorless oil as described for 6c in
4.2.7. (R,E)-1-(Benzyloxy)-2-((tert-butyldimethylsilyl)oxy)oct-5-en-
4-one (6c). To a ꢁ78 ꢂC solution of dimethyl methylphosphonate
(38.0 mL, 351 mmol) in THF (150 mL) was added n-BuLi (116 mL of
a 2.5 M solution in hexanes, 290 mmol). The reaction mixture was
stirred for 1 h at ꢁ78 ꢂC, after which a solution of benzyl ester 8
(24.0 g, 57.9 mmol) in THF (200 mL) was added to it. The reaction
mixture was allowed to slowly warm to room temperature and
stirred for 1 h. The mixture was quenched by addition of saturated
NH4Cl solution, concentrated in vacuo, and the remaining aqueous
phase extracted with EtOAc. The combined organic phase was
washed with brine, dried (Na2SO4), and concentrated. The crude
60% yield: 1H NMR (300 MHz, CDCl3)
d 7.53 (br s, 1H), 7.41 (d,
J¼8.8 Hz, 2H), 7.37e7.26 (m, 5H), 6.95 (d, J¼8.8 Hz, 2H), 4.57 (s, 2H),
4.53e4.43 (m, 1H), 3.86 (s, 3H), 3.52 (dd, J¼9.7, 5.0 Hz, 1H), 3.46 (dd,
J¼9.7, 5.5 Hz, 1H), 3.08 (dd, J¼15.3, 7.3 Hz, 1H), 2.97 (dd, J¼15.3,
5.0 Hz, 1H), 2.07 (d, J¼1.0 Hz, 3H), 0.85 (s, 9H), 0.08 (s, 3H), 0.03 (s,
3H); IR (film, NaCl) 3433, 2954, 2928, 2855, 1660, 1604, 1511, 1463,
1390, 1361, 1304, 1255, 1177, 1113, 1033, 833, 777, 735, 697 cmꢁ1
;
[a
]
þ22.1 (c 0.40, CHCl3); HRMS (ESI) calcd for C27H39O4Si
D
(MþH)þ: 455.2612, found 455.2603.
b
-ketophosphonate was used without further purification.
A solution of crude -ketophosphonate in THF (120 mL) was
4.2.11. (R,E)-6-(Benzyloxy)-5-((tert-butyldimethylsilyl)oxy)-1-(4-
fluorophenyl)hex-1-en-3-one (6g). The material was prepared from
benzyl ester 8 as a colorless oil as described for 6c in 85% yield: 1H
b
treated with freshly activated23 Ba(OH)2 (14.9 g, 87.0 mmol) for
30 min at 0 ꢂC, after which a solution of propionaldehyde (6.3 mL,
86.6 mmol) and water (6 mL) in THF (240 mL) was added to it. The
reaction mixture was allowed to warm to room temperature and
stirred for 2 h. Saturated NH4Cl solution was added, and the mix-
ture extracted with EtOAc. The combined organic phase was
washed with brine, dried (Na2SO4), and concentrated in vacuo. The
solvent was removed and the residue purified by flash chroma-
tography (hexanes/EtOAc, 20:1 to 10:1) to give enone 6c (13.27 g,
61% over 2 steps) as a light yellowish oil: 1H NMR (400 MHz, CDCl3)
NMR (400 MHz, CDCl3) d 7.56e7.50 (m, 3H), 7.38e7.27 (m, 5H), 7.10
(dd, J¼8.6, 8.6 Hz, 2H), 6.70 (d, J¼16.2 Hz, 1H), 4.57 (s, 2H),
4.49e4.42 (m, 1H), 3.53 (dd, J¼9.7, 5.0 Hz, 1H), 3.46 (dd, J¼9.7,
5.6 Hz,1H), 2.94e2.88 (m, 2H), 0.86 (s, 9H), 0.09 (s, 3H), 0.05 (s, 3H);
13C NMR (100 MHz, CDCl3)
d 198.8, 165.4, 162.9, 141.7, 138.4, 131.0,
130.9, 130.3, 130.2, 128.5, 127.8, 127.7, 127.1, 127.0, 116.1, 74.4, 73.5,
68.9, 45.9, 25.9, 18.2, -4.4, -4.7; IR (film, NaCl) 2954, 2927, 2855,
1687,1660, 1613,1599,1509,1462,1414, 1361, 1327, 1235, 1158, 1097,
981, 832, 778, 735, 697 cmꢁ1; [
a
]
D
þ31.3 (c 0.41, CHCl3); MS (ESI)
d
7.39e7.26 (m, 5H), 6.90 (dt, J¼15.9, 6.4 Hz, 1H), 6.13 (dt, J¼15.9,
calcd for C25H34FO3Si (MþH)þ: 429.2, found 429.3.
1.6 Hz, 1H), 4.56 (s, 2H), 4.41 (dddd, J¼6.8, 5.3, 5.3, 5.3 Hz, 1H), 3.42
(dd, J¼9.7, 5.5 Hz, 1H), 3.49 (dd, J¼9.7, 5.1 Hz, 1H), 2.81 (dd, J¼15.2,
7.0 Hz, 1H), 2.76 (dd, J¼15.2, 5.4 Hz, 1H), 2.26 (ddq, J¼7.5, 6.3, 1.6 Hz,
2H), 1.09 (t, J¼7.4 Hz, 3H), 0.87 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H); 13C
4.2.12. (R)-Benzyl
4-(benzyloxy)-3-((tert-butyldimethylsilyl)oxy)-
butanoate (8). A mixture of (R)-ethyl 3,4-dihydroxybutanoate22
(21.5 g, 145 mmol) and dibutyltin oxide (36.1 g, 145 mmol) in
benzene (200 mL) was heated under reflux for 18 h with azeotropic
removal of water using a DeaneStark trap. Benzyl bromide (43 mL,
362 mmol) and TBAI (2.5 g, 7.3 mmol) were then added and the
mixture heated under reflux for another 21 h. After evaporation of
all volatiles, the residue was purified by flash chromatography
(hexanes/EtOAc, 4:1 to 2:1) to give (R)-benzyl 4-(benzyloxy)-3-
hydroxybutanoate (28.47 g, 65%) as a yellowish oil.
NMR (100 MHz, CDCl3)
d 199.0, 149.2, 138.2, 130.4, 128.2, 127.5,
127.4(6), 74.3, 73.2, 68.5, 44.8, 25.8, 25.5, 18.0, 12.2, ꢁ4.6, ꢁ5.0; IR
(film, NaCl) 2956, 1669, 1627, 1462, 1361, 1252, 1112, 1005, 977, 836,
810, 778 cmꢁ1; [
a
]
þ31.4 (c 1.57, CHCl3); MS (ESI) calcd for
D
C21H35O3 (MþH)þ: 363.2, found 363.2.
4.2.8. (R,E)-6-(Benzyloxy)-5-((tert-butyldimethylsilyl)oxy)-1-
phenylhex-1-en-3-one (6d). The material was prepared from benzyl
ester 8 as a light yellow oil as described for 6c in 90% yield: 1H NMR
To a cold (0 ꢂC) solution of the hydroxyl benzyl ester (28.4 g,
94.6 mmol) in CH2Cl2 (140 mL) was added TBSCl (18.5 g,
122.7 mmol) and imidazole (9.7 g, 142.5 mmol). The reaction
mixture was allowed to warm to room temperature and stirred
overnight. After concentration in vacuo, the residue was purified by
flash chromatography (hexanes/EtOAc, 20:1 to 8:1) to give benzyl
ester 8 as a light yellow oil (28.3 g, 72%): 1H NMR (400 MHz, CDCl3)
(400 MHz, CDCl3) d 7.60e7.51 (m, 3H), 7.44e7.38 (m, 3H), 7.37e7.27
(m, 5H), 6.76 (d, J¼16.3 Hz, 1H), 4.56 (s, 2H), 4.50e4.41 (m, 1H), 3.52
(dd, J¼9.7, 5.0 Hz, 1H), 3.45 (dd, J¼9.7, 5.6 Hz, 1H), 2.93e2.89 (m,
2H), 0.85 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d 199.1, 143.1, 138.4, 134.7, 130.6, 129.1, 128.5, 128.4, 127.8,
127.7, 127.4, 74.4, 73.5, 68.9, 45.8, 26.0, 18.2, ꢁ4.4, ꢁ4.7; IR (film,
NaCl) 3419, 3086, 3063, 3030, 2953, 2927, 2856, 1954, 1881, 1810,
1682, 1660, 1652, 1634, 1621, 1607, 1576, 1495, 1471, 1452, 1361,
d
7.42e7.29 (m, 10H), 5.15 (d, J¼12.4 Hz, 1H), 5.10 (d, J¼12.4 Hz, 1H),
4.56 (d, J¼12.3 Hz, 1H), 4.53 (d, J¼12.6 Hz, 1H), 4.40e4.33 (m, 1H),
3.51 (dd, J¼9.6, 5.3 Hz, 1H), 3.41 (dd, J¼9.6, 6.2 Hz, 1H), 2.71 (dd,

9878
S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
J¼15.0, 4.7 Hz, 1H), 2.55 (dd, J¼15.0, 7.7 Hz, 1H), 0.88 (s, 9H), 0.08 (s,
3H), 0.07 (s, 3H); 13C NMR (100 MHz, CDCl3)
171.4, 138.1, 135.8,
128.5, 128.3, 128.2, 128.1, 127.6, 74.0, 73.3, 68.6, 66.2, 40.4, 25.7, 18.0,
128.4, 128.2, 127.8, 127.7, 77.5, 74.4, 73.3, 70.9, 37.9, 20.7, 14.0, 11.4;
d
IR (film, NaCl) 3391, 2960, 2930, 2917, 2871, 1454, 1364, 1306, 1091,
1074, 1028, 999, 860 cmꢁ1; [
a
]
D ꢁ11.0 (c 1.7, CHCl3); MS (ESI) calcd
ꢁ4.5, ꢁ5.1; IR (film, NaCl) 2954, 2929, 2886, 2856, 1738, 1455, 1253,
for C16H28NO3 (MþNH4)þ: 282.2, found 282.1.
Alternatively, diol 9b was obtained from Luche reduction of
enone 6a as a colorless oil as a mixture of diastereomers (dr 4:1 by
1H NMR).
1167, 1124, 1092, 1004, 836, 778, 736, 697 cmꢁ1; [
a
]
D þ19.4 (c 2.03,
CHCl3); MS (ESI) calcd for C24H35O4Si (MþH)þ: 415.2, found 415.2.
4.2.13. (2R,4S,E)-1-(Benzyloxy)oct-5-ene-2,4-diol (9a). A solution of
(R)-2-methyl-CBS-oxazaborolidine (0.60 mL of a 1 M solution in
toluene, 0.60 mmol) in THF (5 mL) was treated with BH3$DMS
(0.15 mL, 1.58 mmol) at 0 ꢂC for 15 min. A solution of enone 6c
(450 mg, 1.24 mmol) in THF (5 mL) was then added slowly at 0 ꢂC
and the reaction mixture stirred for 30 min at that temperature.
After addition of saturated NH4Cl solution, the aqueous layer was
extracted with EtOAc, the combined organic phase dried (Na2SO4),
and concentrated. Purification of the residue by flash chromatog-
raphy (hexanes/EtOAc, 8:1) yielded 285 mg (63%, dr 99:1) of the
4.2.15. Procedure for the Luche reduction of 6a and TBAF de-
protection. To a stirred solution of enone 6a (13.27 g, 35.2 mmol)
and cerium chloride heptahydrate (15.74 g, 42.2 mmol) in
300 mL of methanol was added sodium borohydride (1.6 g,
42.2 mmol) portionwise at 0 ꢂC. The reaction mixture was stirred
for 1 h at that temperature, after which acetone was added to
destroy residual sodium borohydride. All volatiles were evapo-
rated under reduced pressure and the residue was partitioned
between water and CH2Cl2. The aqueous phase was extracted
with CH2Cl2, the combined organic phase washed with brine,
dried (Na2SO4), and concentrated in vacuo to give the crude TBS-
diol (13.3 g) as an oil, which was used in the next step without
further purification.
To a solution of the crude TBS-diol (12.3 g, 32.5 mmol) in THF
(300 mL) was added TBAF (42.2 mL of a 1 M solution in THF,
42.2 mmol). The reaction mixture was stirred for 2 h, and sub-
sequently quenched by addition of saturated NH4Cl solution. After
evaporation of all volatiles and extraction of the remaining
aqueous layer with EtOAc, the combined organic phase was dried
(Na2SO4) and concentrated. Purification of the residue by flash
chromatography (hexanes/EtOAc, 4:1 to 1:1) gave 7.30 g (85% over
2 steps) of diastereomeric diols 9b and 9e as a colorless oil (9b:
9e¼4:1).
syn-TBS-diol as
a
colorless oil: 1H NMR (400 MHz, CDCl3)
d
7.41e7.27 (m, 5H), 5.80 (dddd, J¼15.4, 6.3, 6.3, 0.9 Hz, 1H), 5.49
(dddd, J¼15.4, 6.7, 1.5, 1.5 Hz, 1H), 4.56 (br s, 2H), 4.36e4.28 (m, 1H),
4.07 (dddd, J¼7.8, 5.0, 5.0, 5.0 Hz, 1H), 3.50 (dd, J¼9.6, 5.0 Hz, 1H),
3.43 (dd, J¼9.6, 5.7 Hz, 1H), 3.00 (br s, 1H), 2.13e2.03 (m, 2H), 1.84
(ddd, J¼14.2, 4.5, 4.5 Hz, 1H), 1.75 (ddd, J¼14.2, 8.0, 8.0 Hz, 1H), 1.03
(t, J¼7.5 Hz, 3H), 0.93 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d 137.9, 133.1, 131.4, 128.3, 127.6, 74.8, 73.3, 70.8,
70.7, 42.2, 25.8, 25.2, 18.0, 13.4, ꢁ4.2, ꢁ4.9; IR (film, NaCl) 3433,
2957, 2929, 2886, 2856, 1472, 1463, 1413, 1362, 1253, 1103, 1029,
1005, 969, 836, 810, 777, 735 cmꢁ1; [
a
]
D
þ14.3 (c 1.56, CHCl3); MS
(ESI) calcd for C21H40NO3Si (MþNH4)þ: 382.3, found 382.2.
To a solution of the syn-TBS-diol (265 mg, 0.73 mmol) in THF
(8 mL) was added TBAF (0.95 mL of a 1 M solution in THF). The
reaction mixture was stirred for 2 h, and subsequently quenched by
addition of saturated NH4Cl solution. After evaporation of all vol-
atiles and extraction of the remaining aqueous layer with EtOAc,
the combined organic phase was dried (Na2SO4) and concentrated.
Purification of the residue by flash chromatography (hexanes/
EtOAc, 2:1 to 1:1) gave 162 mg (89%, dr 99:1) of syn-diol 9a as
4.2.16. (2R,4S,E)-1-(Benzyloxy)-5-methyl-6-phenylhex-5-ene-2,4-
diol (9c). The material was prepared from enone 6b by CBS re-
duction via the corresponding syn-TBS-diol adduct as a colorless oil
as described for 9a (77% overall yield, dr 98:2). syn-TBS-diol: 1H
NMR (400 MHz, CDCl3) d 7.38e7.26 (m, 9H), 7.24e7.19 (m, 1H), 6.58
a colorless oil: 1H NMR (400 MHz, CDCl3)
d
7.42e7.27 (m, 5H), 5.73
(br s, 1H), 4.56 (s, 2H), 4.40e4.36 (m, 1H), 4.16e4.09 (m, 1H), 3.52
(dd, J¼9.6, 4.9 Hz, 1H), 3.45 (dd, J¼9.6, 5.9 Hz, 1H), 3.36 (d, J¼1.6 Hz,
1H), 1.98 (ddd, J¼14.4, 4.3, 3.1 Hz, 1H), 1.88 (d, J¼0.9 Hz, 3H), 1.81
(ddd, J¼14.5, 8.4, 8.4 Hz, 1H), 0.93 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H);
(dd, J¼14.8, 6.6 Hz, 1H), 5.47 (dd, J¼15.4, 6.8 Hz, 1H), 4.57 (br s, 2H),
4.41e4.29 (m, 1H), 4.11e4.01 (m, 1H), 3.51e3.38 (m, 2H), 3.30 (br s,
1H), 3.16 (br s, 1H), 2.12e2.01 (m, 2H), 1.74e1.60 (m, 2H), 1.01 (t,
J¼7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
137.8, 133.5, 131.2, 128.4,
13C NMR (100 MHz, CDCl3)
d 140.1, 138.0(3), 138.0, 129.1, 128.5,
127.7(4), 127.7, 74.3, 73.3, 72.7, 70.6, 39.8, 25.1, 13.3; IR (film, NaCl)
128.2, 127.9, 126.4, 125.2, 75.8, 74.8, 73.6, 71.6, 40.6, 26.0, 18.2, 14.1,
ꢁ4.0, ꢁ4.7; IR (film, NaCl) 3445, 3062, 3028, 2953, 2928, 2856,
1600, 1495, 1471, 1462, 1454, 1409, 1388, 1361, 1253, 1205, 1094,
3390, 2962, 2915, 2872, 1454, 1102, 969 cmꢁ1; [
a
]
D
ꢁ7.0 (c 1.65,
CHCl3); MS (ESI) calcd for C15H22NaO3 (MþNa)þ: 273.1, found 273.1.
1028, 1005, 960, 916, 835, 810, 777, 747, 697 cmꢁ1; [
a]
þ13.9 (c
D
4.2.14. (2R,4S,E)-1-(Benzyloxy)-5-methyloct-5-ene-2,4-diol
(9b). The material was prepared from enone 6a by CBS reduction
via the corresponding syn-TBS-diol as a colorless oil as described for
9a (84% overall yield, dr 94:6). syn-TBS-diol: 1H NMR (400 MHz,
0.48, CHCl3); MS (ESI) calcd for C26H38NaO3Si (MþNa)þ: 449.3,
found 449.2. Diol 9c: 1H NMR (400 MHz, CDCl3)
d 7.42e7.29 (m,
9H), 7.27e7.20 (m, 1H), 6.58 (br s, 1H), 4.60 (s, 2H), 4.50e4.44 (m,
1H), 4.18e4.11 (m, 1H), 3.55e3.50 (m, 1H), 3.49e3.43 (m, 1H), 3.24
(br s, 1H), 3.16 (br s, 1H), 1.92e1.87 (m, 3H), 1.83e1.76 (m, 2H); 13C
CDCl3) d 7.41e7.29 (m, 5H), 5.48e5.43 (m, 1H), 4.55 (s, 2H), 4.21 (dd,
J¼8.6, 3.3 Hz, 1H), 4.05 (dddd, J¼8.0, 5.4, 5.4, 4.7 Hz, 1H), 3.49 (dd,
J¼9.6, 5.0 Hz, 1H), 3.41 (dd, J¼9.6, 5.7 Hz, 1H), 3.00 (br s, 1H),
2.12e1.99 (m, 2H), 1.85 (ddd, J¼14.3, 4.4, 3.5 Hz, 1H), 1.73 (ddd,
J¼14.3, 8.3, 8.3 Hz, 1H), 1.63 (dd, J¼1.9, 0.9 Hz, 3H), 0.99 (t, J¼7.5 Hz,
3H), 0.92 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H); 13C NMR (100 MHz, CDCl3)
NMR (100 MHz, CDCl3) d 139.8, 137.9, 137.7, 129.1, 128.6, 128.2,
128.0, 127.9, 126.5, 125.6, 77.8, 74.4, 73.6, 71.1, 38.3, 13.8; IR (film,
NaCl) 3370, 3026, 2916, 2860, 1599, 1492, 1452, 1363, 1309, 1203,
1091,1027,1008, 918, 867, 748, 698 cmꢁ1; [
a
]
D þ15.3 (c 0.52, CHCl3);
HRMS (ESI) calcd for C20H24NaO3 (MþNa)þ: 335.1618, found
d
138.0, 136.1, 128.3, 127.8, 127.6, 75.5, 74.8, 73.3, 71.4, 40.3, 25.8,
335.1621.
20.8, 18.0, 14.0, 11.6, ꢁ4.2, ꢁ4.9; IR (film, NaCl) 3436, 2957, 2929,
Alternatively, diol 9c was obtained from Luche reduction of
enone 6b as a colorless oil as a mixture of diastereomers (dr 3:1 by
1H NMR).
2857, 1472, 1455, 1362, 1252, 1092, 1029, 1005, 835, 776, 734,
697 cmꢁ1; [
a
]
D þ3.8 (c 1.85, CHCl3); MS (ESI) calcd for C22H38NaO3Si
(MþNa)þ: 401.2, found 401.2. syn-Diol 9b: 1H NMR (400 MHz,
CDCl3)
d
7.38e7.27 (m, 5H), 5.42 (br t, J¼7.0 Hz, 1H), 4.55 (s, 2H),
4.2.17. (2R,4R,E)-1-(Benzyloxy)oct-5-ene-2,4-diol (9d). To a cold
4.25 (dd, J¼9.2, 3.6 Hz, 1H), 4.06e3.99 (m, 1H), 3.45 (dd, J¼9.5,
4.1 Hz, 1H), 3.40 (dd, J¼9.5, 6.9 Hz, 1H), 3.29 (br s, 1H), 2.99 (br s,
1H), 2.08e1.95 (m, 2H), 1.73e1.58 (m, 2H), 1.60 (dt, J¼1.4, 0.8 Hz,
(0 ꢂC) solution of (S)-2-methyl-CBS-oxazaborolidine (1.84 mL of
a 1 M solution in toluene, 1.84 mmol) in THF (10 mL) was added
BH3$DMS (0.17 mL, 1.83 mmol). The mixture was stirred for 15 min
at that temperature, after which a solution of enone 6c (607 mg,
3H), 0.95 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 137.8, 136.1,

S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
9879
1.67 mmol) in THF (10 mL) was added slowly. The reaction mixture
(400 MHz, CDCl3)
d
7.43e7.30 (m, 9H), 7.29e7.23 (m, 1H), 6.62 (br s,
was stirred for 30 min at 0 ꢂC. After addition of saturated NH4Cl
solution, the aqueous layer was extracted with EtOAc, the com-
bined organic phase dried (Na2SO4), and concentrated. Purification
of the residue by flash chromatography using a short plug of silica
gel (hexanes/EtOAc, 8:1) yielded 596 mg (98%, dr 99:1) of the anti-
1H), 4.63 (d, J¼12.1 Hz, 1H), 4.59 (d, J¼12.1 Hz, 1H), 4.49e4.43 (m,
1H), 4.29e4.22 (m,1H), 3.63e3.56 (m, 2H), 3.30 (br s,1H),1.95e1.87
(m, 5H), 0.98 (s, 9H), 0.19 (s, 3H), 0.16 (s, 3H); 13C NMR (100 MHz,
CDCl3)
d 140.6, 138.1, 138.0, 129.1, 128.5, 128.1, 127.8, 126.3, 124.6,
74.0, 73.7, 73.5, 70.1, 39.7, 26.0, 18.2, 14.2, ꢁ4.3, ꢁ4.9; IR (film, NaCl)
3436, 3063, 3028, 2954, 2929, 2886, 2857, 1948, 1653, 1600, 1495,
1471, 1463, 1454, 1409, 1361, 1324, 1253, 1205, 1091, 1028, 939, 917,
TBS-diol as a colorless oil: 1H NMR (400 MHz, CDCl3)
d 7.44e7.29 (m,
5H), 5.72 (dddd, J¼15.4, 6.2, 6.2, 0.9 Hz, 1H), 5.49 (dddd, J¼15.4, 6.5,
1.5, 1.5 Hz, 1H), 4.58 (d, J¼12.1 Hz, 1H), 4.54 (d, J¼12.1 Hz, 1H),
4.39e4.30 (m,1H), 4.19e4.13 (m,1H), 3.53 (dd, J¼9.5, 5.7 Hz,1H), 3.49
(dd, J¼9.5, 6.2 Hz, 1H), 3.07 (d, J¼1.7 Hz, 1H), 2.11e2.02 (m, 2H),
1.75e1.79 (m, 2H),1.02 (t, J¼7.5 Hz, 3H), 0.92 (s, 9H), 0.13 (s, 3H), 0.10
836, 810, 777, 748, 698 cmꢁ1; [
a
]
D
þ10.2 (c 0.51, CHCl3); MS (ESI)
calcd for C26H38NaO3Si (MþNa)þ: 449.3, found 449.2. anti-diol 9f:
1H NMR (400 MHz, CDCl3)
d 7.38e7.24 (m, 9H), 7.24e7.18 (m, 1H),
6.60 (br s, 1H), 4.58 (s, 2H), 4.50e4.43 (m, 1H), 4.19e4.11 (m, 1H),
3.55 (ddd, J¼9.3, 3.1, 3.1 Hz, 1H), 3.45 (ddd, J¼9.9, 7.6, 2.5 Hz, 1H),
2.71 (br s, 1H), 2.67 (br s, 1H), 1.85 (s, 3H), 1.83e1.76 (m, 2H); 13C
NMR (100 MHz, CDCl3) d 140.2,138.0,137.8,129.1,128.6,128.2,128.0,
127.9, 126.5, 125.1, 77.4, 74.5, 73.6, 68.2, 37.6, 14.4; IR (film, NaCl)
(s, 3H); 13C NMR (100 MHz, CDCl3)
d 138.0, 132.7, 131.7, 128.3, 127.6,
73.6, 73.3, 69.9, 69.4, 41.0, 25.8, 25.1, 18.0, 13.4, ꢁ4.5, ꢁ5.0; IR (film,
NaCl) 3426, 2978, 2929, 2878,1467,1457,1455,1424,1402,1361,1253,
1092,1054,1033,1011, 835, 777, 734 cmꢁ1; [
a]D þ24.1 (c 1.73, CHCl3);
MS (ESI) calcd for C21H40NO3Si (MþNH4)þ: 382.3, found 382.2.
To a solution of the anti-TBS-diol (800 mg, 2.20 mmol) in THF
(30 mL) was added TBAF (2.90 mL of a 1 M solution in THF,
2.90 mmol). The reaction mixture was stirred for 2 h, and sub-
sequently quenched by addition of saturated NH4Cl solution. After
evaporation of all volatiles and extraction of the remaining aqueous
layer with EtOAc, the combined organic phase was dried (Na2SO4)
and concentrated. Purification of the residue by flash chromatog-
raphy (hexanes/EtOAc, 2:1 to 1:1) gave 525 mg (95%) of anti-diol 9d
3400, 3026, 2916, 2860, 1599, 1493, 1452, 1364, 1205, 1074, 1028,
1009, 919, 868, 748, 698 cmꢁ1; [
a
]
þ14.6 (c 0.42, CHCl3); HRMS
D
(ESI) calcd for C20H24NaO3 (MþNa)þ: 335.1618, found 335.1612.
4.2.20. (2R,E)-1-(Benzyloxy)-6-phenylhex-5-ene-2,4-diol (9g). The
material was prepared from enone 6d as a colorless oil using the
Luche reduction procedure (68% overall yield, dr 2:1): 1H NMR
(300 MHz, CDCl3)
d
7.42e7.24 (m, 10H), 6.65 (dd, J¼15.8, 0.7 Hz, 1H,
minor isomer), 6.63 (d, J¼15.8 Hz, 1H, major isomer), 6.28 (dd,
J¼15.4, 6.2 Hz,1H, minor isomer), 6.23 (dd, J¼15.8, 6.4 Hz,1H, major
isomer), 4.67e4.54 (m, 3H), 4.25e4.09 (m, 1H), 3.57e3.39 (m, 2H),
3.20 (br s, 1H, major isomer), 3.00 (d, J¼1.68 Hz, 1H, minor isomer),
2.80e2.73 (m, 1H), 1.92e1.69 (m, 2H); 13C NMR (75 MHz, CDCl3,
as a light yellow oil: 1H NMR (400 MHz, CDCl3)
d 7.42e7.29 (m, 5H),
5.76 (ddt, J¼15.4, 6.3, 1.0 Hz, 1H), 5.54 (ddt, J¼15.4, 6.5, 1.5 Hz, 1H),
4.59 (s, 2H), 4.41 (ddd, J¼7.3, 7.3, 3.7 Hz, 1H), 4.16 (dddd, J¼8.7, 7.5,
3.6, 3.6 Hz, 1H), 3.53 (dd, J¼9.5, 3.7 Hz, 1H), 3.44 (dd, J¼9.4, 7.5 Hz,
1H), 2.75 (br s, 1H), 2.43 (br s, 1H), 2.12e2.03 (m, 2H), 1.76 (ddd,
J¼14.3, 8.7, 3.5 Hz, 1H), 1.65 (ddd, J¼14.4, 7.9, 3.4 Hz, 1H), 1.01 (t,
major isomer)
d 137.9, 136.8, 131.8, 130.2, 128.7, 128.6, 128.0, 127.9,
127.8, 126.6(2), 126.6, 74.4, 73.6, 72.7, 70.9, 40.0; IR (film, NaCl)
3381, 3060, 3028, 2916, 2859, 1952, 1810, 1654, 1599, 1578, 1541,
1495, 1453, 1417, 1364, 1310, 1260, 1205, 1094, 1072, 1028, 967, 912,
854, 747, 707 cmꢁ1; HRMS (ESI) calcd for C19H22NaO3 (MþNa)þ:
312.1461, found 321.1451.
J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 137.8, 133.0, 131.2, 128.4,
127.7, 127.6(8), 74.3, 73.2, 69.7, 67.7, 39.3, 25.1, 13.4; IR (film, NaCl)
3392, 2961, 2916, 1454, 1074, 968 cmꢁ1; [
a
]
þ3.5 (c 2.43, CHCl3);
D
MS (ESI) calcd for C15H22NaO3 (MþNa)þ: 273.1, found 273.1.
4.2.18. (2R,4R,E)-1-(Benzyloxy)-5-methyloct-5-ene-2,4-diol
(9e). The material was prepared from enone 6a by CBS reduction
via the corresponding anti-TBS-diol as a colorless oil as described
for 9d (92% overall yield, dr 99:1). anti-TBS-diol: 1H NMR (400 MHz,
4.2.21. (2R,E)-1-(Benzyloxy)-6-(4-methoxyphenyl)hex-5-ene-2,4-
diol (9h). The material was prepared from enone 6e as a colorless
oil using the Luche reduction procedure (71% overall yield, dr 2:1):
1H NMR (400 MHz, CDCl3)
d 7.42e7.30 (m, 7H), 6.90e6.85 (m, 2H),
CDCl3)
d
7.40e7.29 (m, 5H), 5.47e5.41 (m, 1H), 4.59 (d, J¼12.1 Hz,
6.59 (d, J¼15.9 Hz, 1H, minor isomer), 6.58 (d, J¼15.8 Hz, 1H, major
isomer), 6.15 (dd, J¼15.8, 6.1 Hz,1H, minor isomer), 6.10 (dd, J¼15.9,
6.6 Hz, 1H, major isomer), 4.63e4.54 (m, 3H), 4.26e4.18 (m, 1H,
minor isomer), 4.17e4.10 (m, 1H, major isomer), 3.83 (s, 3H),
3.57e3.42 (m, 2H), 3.13 (br s, 1H, major isomer), 3.06 (br s, 1H,
major isomer), 2.80 (br s, 1H, minor isomer), 2.73 (br s, 1H, minor
isomer), 1.91e1.69 (m, 2H); 13C NMR (100 MHz, CDCl3, major iso-
1H), 4.54 (d, J¼12.1 Hz, 1H), 4.25 (dd, J¼10.1, 1.9 Hz, 1H), 4.15 (dddd,
J¼5.8, 5.8, 5.8, 4.3 Hz, 1H), 3.53 (dd, J¼9.5, 5.7 Hz, 1H), 3.50 (dd,
J¼9.5, 6.1 Hz, 1H), 2.92 (br s, 1H), 2.10e2.00 (m, 2H), 1.81 (ddd,
J¼14.1, 9.8, 4.2 Hz, 1H), 1.73 (ddd, J¼14.3, 5.8, 2.9 Hz, 1H), 1.63 (s,
3H), 0.99 (t, J¼7.5 Hz, 3H), 0.92 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H); 13C
NMR (100 MHz, CDCl3)
d 138.1, 136.5, 128.3, 127.6, 127.5(9), 127.1,
73.7, 73.6(8), 73.3, 69.9, 39.4, 25.8, 20.8, 18.0, 14.0, 11.8, ꢁ4.5, ꢁ5.0;
mer) d 159.4, 137.9, 129.9, 129.6, 128.6, 128.0, 127.9, 127.8, 127.7(7),
IR (film, NaCl) 3426, 2978, 2929, 2878, 1467, 1457, 1455, 1424, 1402,
114.1, 74.5, 73.6, 72.9, 70.8, 55.4, 40.1; IR (film, NaCl) 3390, 3063,
3031, 3004, 2918, 2857, 2056, 1886, 1651, 1607, 1577, 1512, 1463,
1454, 1421, 1365, 1301, 1250, 1207, 1175, 1105, 1032, 969, 910, 842,
816, 738, 699 cmꢁ1; HRMS (ESI) calcd for C20H24NaO4 (MþNa)þ:
351.1567, found 351.1560.
1361, 1253, 1092, 1054, 1033, 1011, 835, 777, 734 cmꢁ1; [
a]
D þ16.2 (c
1.62, CHCl3). MS (ESI) calcd for C22H38NaO3Si (MþNa)þ: 401.2,
found 401.2. anti-diol 9e: 1H NMR (400 MHz, CDCl3)
d 7.38e7.27 (m,
5H), 5.44 (t, J¼7.1 Hz, 1H), 4.56 (s, 2H), 4.27 (dd, J¼7.1, 4.7 Hz, 1H),
4.10e4.03 (m, 1H), 3.51 (ddd, J¼9.5, 3.7, 0.9 Hz, 1H), 3.41 (dd, J¼9.3,
7.5 Hz, 1H), 2.86 (br s, 1H), 2.46 (br s, 1H), 2.07e1.98 (m, 2H),
1.70e1.64 (m, 2H), 1.59 (s, 3H), 0.96 (t, J¼7.5 Hz, 3H); 13C NMR
4.2.22. (2R,E)-1-(Benzyloxy)-6-(4-methoxyphenyl)-5-methylhex-5-
ene-2,4-diol (9i). The material was prepared from enone 6f as
a colorless oil using the Luche reduction procedure (70% overall
(100 MHz, CDCl3) d 137.9, 136.2, 128.4, 127.8, 127.7, 127.4, 74.3, 73.9,
73.3, 67.9, 37.5, 20.7, 14.0, 12.0; IR (film, NaCl) 3400, 2960, 2930,
yield, dr 3:1): 1H NMR (400 MHz, CDCl3)
d 7.41e7.30 (m, 5H),
2871, 1454, 1396, 1089, 1073, 1028, 998 cmꢁ1; [
a
]
þ7.7 (c 2.37,
7.25e7.22 (m, 2H), 6.92e6.87 (m, 2H), 6.54 (br s, 1H, minor isomer),
6.50 (br s, 1H, major isomer), 4.59 (s, 2H), 4.48e4.42 (m, 1H),
4.21e4.09 (m, 1H), 3.83 (s, 3H), 3.58e3.42 (m, 2H), 3.34 (br s, 1H),
2.96e2.83 (m, 1H), 1.90e1.88 (m, 3H, major isomer), 1.88e1.86 (m,
3H, minor isomer), 1.83e1.74 (m, 2H); 13C NMR (100 MHz, CDCl3,
D
CHCl3); HRMS (ESI) calcd for C16H24NaO3 (MþNa)þ: 287.1618, found
287.1611.
4.2.19. (2R,4R,E)-1-(Benzyloxy)-5-methyl-6-phenylhex-5-ene-2,4-
diol (9f). The material was prepared from enone 6b by CBS re-
duction via the corresponding anti-TBS-diol as a colorless oil as
described for 9d (71% overall yield, dr 98:2). anti-TBS-diol: 1H NMR
major isomer)
d 158.1, 138.1, 137.9, 130.2(4), 130.2, 128.6, 127.9,
127.8(9), 125.1, 113.6, 77.9, 74.5, 73.5, 71.0, 55.3, 38.2, 13.6; IR (film,
NaCl) 3391, 3063, 3031, 2915, 2860, 2058, 1607, 1574, 1520, 1463,

9880
S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
1454, 1417, 1365, 1298, 1250, 1178, 1109, 1034, 1007, 876, 830, 810,
738, 699 cmꢁ1; HRMS (ESI) calcd for C21H26NaO4 (MþNa)þ:
365.1723, found 365.1726.
Purification of the residue by flash chromatography (hexanes/
EtOAc, 8:1 to 4:1) yielded 142 mg (33%) of anti-propargylic alcohol
11b as a colorless oil as the first fraction and 165 mg (39%) of syn-
11a as a colorless oil as the second fraction. syn-11a: 1H NMR
4.2.23. (2R,E)-1-(Benzyloxy)-6-(4-fluorophenyl)hex-5-ene-2,4-diol
(9j). The material was prepared from enone 6g as a colorless oil
using the Luche reduction procedure (66% overall yield, dr 2:1): 1H
NMR (400 MHz, CDCl3) 7.42e7.30 (m, 7H), 7.02 (dd, J¼8.5, 8.5 Hz,
2H), 6.62 (d, J¼15.9 Hz, 1H, minor isomer), 6.60 (d, J¼15.9 Hz, 1H,
major isomer), 6.20 (dd, J¼15.9, 5.5 Hz, 1H, minor isomer), 6.15 (dd,
J¼15.8, 6.2 Hz, 1H, major isomer), 4.66e4.56 (m, 3H), 4.25e4.18 (m,
1H, minor isomer), 4.18e4.10 (m, 1H, major isomer), 3.57e3.40 (m,
2H), 3.30 (br s, 1H, major isomer), 3.01 (br s, 1H, major isomer), 2.86
(br s,1H, minor isomer), 2.78 (br s, 1H, minor isomer), 1.92e1.69 (m,
(400 MHz, CDCl3) d 7.39e7.27 (m, 5H), 4.63e4.56 (m, 1H), 4.56 (d,
J¼1.6 Hz, 2H), 4.18e4.12 (m, 1H), 3.51 (dd, J¼9.7, 5.2 Hz, 1H), 3.45
(dd, J¼9.7, 5.7 Hz, 1H), 3.01 (br s, 1H), 2.24 (dq, J¼7.5, 1.9 Hz, 2H),
1.98e1.94 (m, 2H), 1.16 (t, J¼7.5 Hz, 3H), 0.92 (s, 9H), 0.13 (s, 3H),
0.10 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 137.8, 128.2, 127.6, 127.5,
86.9, 80.2, 74.7, 73.3, 69.5, 60.3, 43.1, 25.7,17.9,13.7, 12.3, ꢁ4.5, ꢁ5.0;
IR (film, NaCl) 3410, 2954, 2928, 2884, 2856, 1471, 1462, 1454, 1361,
1252, 1127, 1088, 1029, 971, 836, 777, 698 cmꢁ1; [
a
]
D þ19.5 (c 1.29,
CHCl3); MS (ESI) calcd for C21H35O3Si (MþH)þ: 363.2, found 363.2.
anti-11b: 1H NMR (400 MHz, CDCl3)
d 7.40e7.27 (m, 5H), 4.63e4.57
2H); 13C NMR (100 MHz, CDCl3, major isomer)
d
164.1, 160.8, 137.9,
(m, 1H), 4.55 (s, 2H), 4.24 (dddd, J¼7.0, 5.6, 5.6, 4.3 Hz,1H), 3.50 (dd,
J¼9.6, 5.4 Hz, 1H), 3.45 (dd, J¼9.6, 5.9 Hz, 1H), 3.07 (d, J¼5.3 Hz, 1H),
2.24 (dq, J¼7.5, 2.0 Hz, 2H), 1.99 (ddd, J¼14.3, 8.2, 4.3 Hz, 1H), 1.93
(ddd, J¼14.3, 7.1, 3.9 Hz, 1H), 1.16 (t, J¼7.5 Hz, 3H), 0.92 (s, 9H), 0.15
133.0, 132.9, 131.5(3), 131.5, 129.0, 128.6, 128.2, 128.1, 127.9, 115.7,
115.4, 74.4, 73.6, 72.6, 70.9, 39.9. IR (film, NaCl) 3392, 2917, 1601,
1509, 1454, 1228, 1158, 1093, 968, 815, 737, 698 cmꢁ1; HRMS (ESI)
calcd for C19H21FNaO3 (MþNa)þ: 339.1367, found 339.1366.
(s, 3H), 0.11 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 138.0, 128.3, 127.6,
86.3, 80.5, 74.0, 73.3, 69.4, 59.7, 41.9, 25.8, 18.0, 13.8, 12.3, ꢁ4.5,
ꢁ5.0; IR (film, NaCl) 3425, 2956, 2928, 2891, 2856, 1471, 1462, 1454,
1388, 1361, 1319, 1253, 1205, 1120, 1090, 1005, 836, 811, 778, 736,
4.2.24. (2R,E)-1-(Benzyloxy)-6-(4-fluorophenyl)-5-methylhex-5-
ene-2,4-diol (9k). The material was prepared from benzyl ester 8
using the olefination procedure as described for 6c followed by
Luche reduction as described for 9b without purifying the enone
intermediate 6h (57% overall yield, dr 3:1): 1H NMR (400 MHz,
698 cmꢁ1; [
a]
D þ20.5 (c 1.03, CHCl3); MS (ESI) calcd for C21H35O3Si
(MþH)þ: 363.2, found 363.2.
CDCl3)
d
7.42e7.30 (m, 5H), 7.28e7.20 (m, 2H), 7.03 (dd, J¼8.7,
4.2.27. (2R,4S,Z)-1-(Benzyloxy)oct-5-ene-2,4-diol (12a). To a solu-
tion of alkyne 11a (165 mg, 0.46 mmol) in a mixture of EtOAc/1-
hexene/pyridine (1 mL, 8:1:1) was added Lindlar-catalyst (5% Pd/
CaCO3/Pb, 20 mg). The reaction mixture was stirred for 8 h under an
atmosphere of H2 and subsequently filtered (Celite). Evaporation of
all volatiles yielded the cis-alkene as a colorless oil, which was used
without further purification.
8.7 Hz, 2H), 6.57 (br s, 1H, minor isomer), 6.53 (br s, 1H, major
isomer), 4.59 (s, 2H), 4.49e4.41 (m, 1H), 4.21e4.09 (m, 1H),
3.59e3.41 (m, 2H), 3.23 (br s, 1H), 2.89 (br s, 1H), 1.89e1.74 (m, 5H);
13C NMR (75 MHz, CDCl3, major isomer)
d 162.7, 160.3, 139.8, 137.9,
133.7, 133.6(6), 130.7, 130.6, 128.6, 128.0, 127.9, 124.5, 115.2, 115.0,
77.7, 74.4, 73.6, 71.2, 38.3, 13.8; IR (film, NaCl) 3445, 3031, 2916,
2849, 1605, 1507, 1454, 1400, 1222, 1156, 1096, 1057, 1028 cmꢁ1; MS
(ESI) calcd for C20H23FNaO3 (MþNa)þ: 353.3, found 353.3.
To a solution of the crude reaction product in THF (4 mL) was
added TBAF (0.83 mL of a 1 M solution in THF, 0.83 mmol). The re-
action mixture was stirred for 1 h at room temperature, after which
saturated NH4Cl solution was added. After evaporation of all vola-
tiles in vacuo, the residue was extracted with CH2Cl2. The combined
organic phase was washed (brine), dried (Na2SO4), and concen-
trated. Purification of the residue by flash chromatography (hex-
anes/EtOAc, 2:1 to 1:1) yielded 66 mg (57%) of syn-cis-diol 12a as
4.2.25. (R)-4-(Benzyloxy)-3-((tert-butyldimethylsilyl)oxy)butanal
(10). To a cold (ꢁ78 ꢂC) solution of benzyl ester 8 (337 mg,
0.81 mmol) in CH2Cl2 (20 mL) was added dropwise DIBAL-H (0.81 mL
of a 1 M solution in CH2Cl2, 0.81 mmol). The reaction was stirred for
30 min at ꢁ78 ꢂC, and subsequently quenched by addition of satu-
rated NaK tartrate solution. The mixture was stirred at room tem-
perature until two clear phases were obtained. After phase
separation, the aqueous layer was extracted with CH2Cl2. The com-
bined organic phase was washed (brine), dried (Na2SO4), and con-
centrated invacuo. The residue was purified by flash chromatography
(hexanes/EtOAc, 8:1) to give 152 mg (61%) of aldehyde 10 as a color-
a colorless oil: 1H NMR (400 MHz, CDCl3)
d 7.41e7.27 (m, 5H), 5.48
(ddd, J¼10.8, 7.3, 7.3 Hz,1H), 5.41e5.34 (m,1H), 4.74 (ddd, J¼8.7, 8.7,
4.0 Hz, 1H), 4.57 (s, 2H), 4.09e4.01 (m, 1H), 3.47 (dd, J¼9.4, 3.9 Hz,
1H), 3.41 (dd, J¼9.4, 7.1 Hz, 1H), 3.28 (br s, 1H), 3.10 (br s, 1H),
2.22e2.02 (m, 2H), 1.73 (ddd, J¼14.2, 9.4, 9.4 Hz, 1H), 1.55 (ddd,
J¼14.3, 3.9, 2.9 Hz, 1H), 1.00 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz,
less oil: 1H NMR (400 MHz, CDCl3)
d
9.83 (dd, J¼2.6, 2.1 Hz, 1H),
CDCl3) d 14.3, 20.9, 39.8, 67.4, 70.4, 73.3, 74.4, 127.7, 127.75, 128.4,
7.42e7.26 (m, 5H), 4.56 (s, 2H), 4.39 (dddd, J¼6.3, 6.3, 5.2, 5.2 Hz,1H),
3.54 (dd, J¼9.5, 5.1 Hz, 1H), 3.43 (dd, J¼9.6, 6.2 Hz, 1H), 2.69 (ddd,
J¼15.9, 5.1, 2.0 Hz, 1H), 2.61 (ddd, J¼15.9, 6.6, 2.7 Hz, 1H), 0.89 (s, 9H),
131.3,133.6,137.8; IR (film, NaCl) 3369, 2963, 2933, 2872, 2913, 2872,
1455,1096,1005, 738, 698 cmꢁ1; [
a]
D þ47.9 (c 0.71, CHCl3); MS (ESI)
calcd for C15H26NO3 (MþNH4)þ: 268.2, found 268.1.
0.10 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 201.4, 137.9, 128.4, 127.7,
127.6, 74.0, 73.4, 67.3, 48.9, 25.7,18.0, ꢁ4.5, ꢁ5.0; IR (film, NaCl) 2954,
4.2.28. (2R,4R,Z)-1-(Benzyloxy)oct-5-ene-2,4-diol (12b). Following
the procedure for the preparation of 12a, anti-cis-diol 12b was
obtained as a colorless oil in 65% yield: 1H NMR (400 MHz, CDCl3)
2929, 2894, 2857,1728,1472,1463,1454,1362,1254,1103,1028,1005,
837, 811, 778, 736, 698 cmꢁ1; [
a
]D þ14.6 (c 1.81, CHCl3); MS (ESI) calcd
for C17H29O3Si (MþH)þ: 309.2, found 309.1.
d
7.41e7.29 (m, 5H), 5.48 (dd, J¼11.0, 2.3 Hz, 1H), 5.43 (dd, J¼10.9,
2.0 Hz, 1H), 4.80e4.73 (m, 1H), 4.58 (s, 2H), 4.19e4.12 (m, 1H), 3.52
(dd, J¼9.5, 3.7 Hz, 1H), 3.43 (dd, J¼9.4, 7.5 Hz, 1H), 3.09 (br s, 1H),
2.74 (br s, 1H), 2.18e2.02 (m, 2H), 1.68e1.63 (m, 2H), 0.99 (t,
4.2.26. (2R)-1-(Benzyloxy)-2-((tert-butyldimethylsilyl)oxy)oct-5-yn-
4-ol (11). To a ꢁ78 ꢂC solution of approximately 0.3 mL of 1-butyne
(3.76 mmol) in THF (5 mL) was added n-BuLi (1.48 mL of a 1.6 M
solution in hexanes, 2.37 mmol). The mixture was stirred for
30 min, and subsequently transferred to a ꢁ78 ꢂC solution of al-
dehyde 10 (364 mg, 1.18 mmol) in THF (5 mL). The reaction mixture
was allowed to slowly warm to room temperature, stirred for
30 min, and saturated NH4Cl solution was added. The mixture was
carefully extracted with CH2Cl2. The combined organic phase was
washed with brine, dried (Na2SO4), and concentrated in vacuo.
J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 137.8, 133.2, 131.5, 128.4,
127.74, 127.7, 74.4, 73.3, 67.7, 64.9, 39.7, 20.9, 14.3; IR (film, NaCl)
3391, 3008, 2963, 2934, 2873, 1455, 1366, 1306, 1073, 1029, 964,
737, 699 cmꢁ1; [
a]
þ25.0 (c 1.21, CHCl3); MS (ESI) calcd for
D
C15H26NO3 (MþNH4)þ: 268.2, found 268.1.
4.2.29. (4R,6S)-4-((Benzyloxy)methyl)-2,2-dimethyl-6-((E)-pent-2-
en-2-yl)-1,3-dioxane (13a). To
a solution of diol 9b (47 mg,

S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
9881
0.18 mmol) in a mixture of 2,2-dimethoxypropane (1 mL) and
CH2Cl2 (1 mL) was added p-toluenesulfonic acid monohydrate
(3 mg, 0.016 mmol). The reaction mixture was stirred for 1 h at
room temperature and subsequently quenched by addition of
solid NaHCO3. Filtration (Celite) and concentration gave 49 mg
(91%) of syn-acetonide 13a as a colorless oil: 1H NMR (400 MHz,
diastereomerically pure syn-pyran 14b was obtained as a color-
less oil.
4.2.34. (2R,6R)-2-(Benzyloxymethyl)-6-ethyl-3,6-dihydro-2H-pyran
(syn-14a). Using the general cyclization protocol, syn-14a was iso-
lated as a colorless oil: 1H NMR (400 MHz, CDCl3)
d 7.44e7.26 (m, 5H),
CDCl3)
d
7.42e7.29 (m, 5H), 5.49e5.44 (m, 1H), 4.64 (d,
5.84 (dddd, J¼10.0, 4.8, 1.2, 1.2 Hz, 1H), 5.68 (dddd, J¼10.2, 2.7, 1.3,
1.3 Hz,1H), 4.68 (d, J¼12.3Hz,1H), 4.61 (d, J¼12.3 Hz,1H), 4.17e4.10 (m,
1H), 3.90e3.83 (m, 1H), 3.60 (dd, J¼10.3, 6.5 Hz, 1H), 3.50 (dd, J¼10.3,
4.2 Hz,1H), 2.11e1.90 (m, 2H), 1.66e1.57 (m, 2H), 0.99 (t, J¼7.4 Hz, 3H);
J¼12.2 Hz, 1H), 4.58 (d, J¼12.2 Hz, 1H), 4.26 (dd, J¼11.4, 2.5 Hz,
1H), 4.20e4.12 (m, 1H), 3.55 (dd, J¼9.9, 5.8 Hz, 1H), 3.41 (dd,
J¼9.9, 4.9 Hz, 1H), 2.12e2.02 (m, 2H), 1.65 (dd, J¼2.0, 1.1 Hz, 3H),
1.57e1.51 (m, 4H), 1.48 (s, 3H), 1.50e1.39 (m, 1H), 0.99 (t,
13C NMR (100 MHz, CDCl3)
d 138.4,130.1,128.3,127.6,127.5,124.1, 75.7,
J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
138.2, 134.3, 128.6,
73.3, 73.2, 73.1, 28.3, 27.8, 9.3; IR (film, NaCl) 3030, 2963, 2921, 2857,
128.3, 127.7, 127.6, 98.7, 74.0, 73.6, 73.4, 68.5, 32.4, 30.1, 20.8,
19.8, 13.9, 12.0; MS (ESI) calcd for C19H32NO3 (MþNH4)þ: 322.2,
found 322.1.
1454, 1366, 1185, 1123, 1098, 1063, 1013 cmꢁ1; [
a]
D
þ29.6 (c 0.86,
CHCl3); MS (ESI) calcd for C15H21O2 (MþH)þ: 233.2, found 233.1.
4.2.35. (2R,6S)-2-(Benzyloxymethyl)-6-ethyl-3,6-dihydro-2H-pyran
4.2.30. (4R,6S)-4-((Benzyloxy)methyl)-2,2-dimethyl-6-((E)-pent-2-
en-2-yl)-1,3-dioxane (13b). Following the procedure for the prep-
aration of 13a, anti-acetonide 13b was obtained from 9e as a col-
(anti-14a). Using the general cyclization protocol, anti-14a was
isolated as a colorless oil: 1H NMR (400 MHz, CDCl3)
d 7.44e7.26 (m,
5H), 5.85e5.79 (m, 1H), 5.78e5.73 (m, 1H), 4.64 (d, J¼12.1 Hz, 1H),
4.60 (d, J¼12.1 Hz, 1H), 4.12e4.08 (m, 1H), 3.97e3.94 (m, 1H), 3.60
(dd, J¼10.1, 6.2 Hz, 1H), 3.52 (dd, J¼10.1, 4.5 Hz, 1H), 2.07e2.01 (m,
2H), 1.73e1.65 (m, 1H), 1.58e1.52 (m, 1H), 1.02 (t, J¼7.4 Hz, 3H); 13C
orless oil in 82% yield: 1H NMR (400 MHz, CDCl3)
d 7.41e7.29 (m,
5H), 5.46e5.41 (m, 1H), 4.66 (d, J¼12.2 Hz, 1H), 4.59 (d, J¼12.2 Hz,
1H), 4.23 (dd, J¼9.8, 6.0 Hz, 1H), 4.14e4.07 (m, 1H), 3.56 (dd,
J¼10.4, 6.4 Hz, 1H), 3.48 (dd, J¼10.4, 4.2 Hz, 1H), 2.11e2.02 (m,
2H), 1.88e1.80 (m, 1H), 1.71e1.63 (m, 4H), 1.44 (s, 6H), 0.99 (t,
NMR (100 MHz, CDCl3) d 138.4, 129.7, 128.3, 127.6, 127.5, 123.3, 74.0,
73.3, 72.8, 66.9, 29.7, 27.2, 10.4; IR (film, NaCl) 3032, 2961, 2919,
J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
138.2, 133.7, 128.3,
2851, 1454, 1105, 1058, 734, 697 cmꢁ1; [
a
]
D
þ46.6 (c 0.43, CHCl3);
128.2(5), 127.7, 127.5, 100.4, 73.3, 72.7, 71.4, 66.5, 32.6, 25.1, 24.9,
20.8, 13.9, 12.2; MS (ESI) calcd for C19H32NO3 (MþNH4)þ: 322.2,
found 322.1.
MS (ESI) calcd for C15H21O2 (MþH)þ: 233.2, found 233.1.
4.2.36. (2R,6R)-2-(Benzyloxymethyl)-6-ethyl-5-methyl-3,6-dihydro-
2H-pyran (syn-14b). Using the general cyclization protocol, syn-14b
4.2.31. (4R,6S)-4-((Benzyloxy)methyl)-6-((Z)-but-1-en-1-yl)-2,2-
dimethyl-1,3-dioxane (13c). Following the procedure for the prep-
aration of 13a, syn-acetonide 13c was obtained from 12a as a col-
was isolated as a colorless oil: 1H NMR (400 MHz, CDCl3)
d 7.42e7.34
(m, 4H), 7.34e7.27 (m, 1H), 5.60e5.56 (m, 1H), 4.68 (d, J¼12.3 Hz,
1H), 4.61 (d, J¼12.3 Hz, 1H), 4.12 (br s, 1H), 3.78 (dddd, J¼10.2, 6.4,
3.8, 3.8 Hz, 1H), 3.60 (dd, J¼10.3, 6.4 Hz, 1H), 3.50 (dd, J¼10.3, 4.2 Hz,
1H), 2.10e1.88 (m, 2H), 1.83 (ddq, J¼14.7, 7.4, 3.6 Hz, 1H), 1.63 (br s,
3H), 1.54 (ddq, J¼14.2, 7.2, 7.2 Hz, 1H), 0.95 (t, J¼7.3 Hz, 3H); 13C NMR
orless oil in 95% yield: 1H NMR (400 MHz, CDCl3)
d 7.42e7.27 (m,
5H), 5.53 (dt, J¼10.6, 7.2 Hz, 1H), 5.35 (dd, J¼10.1, 8.5 Hz, 1H),
4.77e4.70 (m, 1H), 4.21e4.12 (m, 1H), 4.63 (d, J¼12.2 Hz, 1H), 4.57
(d, J¼12.2 Hz, 1H), 3.54 (dd, J¼9.8, 5.8 Hz, 1H), 3.40 (dd, J¼9.8,
5.0 Hz, 1H), 2.21e2.01 (m, 2H), 1.54 (s, 3H), 1.52e1.24 (m, 2H), 1.46
(100 MHz, CDCl3)
d 138.5, 135.4, 128.3, 127.6, 127.4, 120.1, 77.9, 73.3,
73.2, 72.8, 28.1, 25.5, 19.0, 8.4; IR (film, NaCl) 2964, 2934, 2858, 1454,
(s, 3H), 1.01 (t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
138.6,
1368, 1118, 1062, 1028, 1005 cmꢁ1; [
a]
D þ74.7 (c 1.96, CHCl3); HRMS
134.5, 129.8, 128.4, 127.8, 127.6, 98.7, 73.6, 73.5, 68.2, 65.1, 33.9, 30.2,
21.2, 19.7, 14.3; MS (ESI) calcd for C18H30NO3 (MþNH4)þ: 308.2,
found 308.1.
(ESI) calcd for C16H22NaO2 (MþNa)þ: 269.1512, found 269.1514.
4.2.37. (2R,6S)-2-(Benzyloxymethyl)-6-ethyl-5-methyl-3,6-dihydro-
2H-pyran (anti-14b). Using the general cyclization protocol, anti-14b
4.2.32. General protocol for the cyclization of monoallylic diols 9 and
12. To a solution of diol 9 or 12 in the given solvent (0.04e0.08 M)
was added the catalyst (0.05e1.0 equiv) in one portion and the
reaction mixture was stirred at room temperature overnight. After
evaporation of all volatiles in vacuo, the residue was purified by
flash chromatography (hexanes/EtOAc, 20:1 to 10:1). Dihy-
dropyran syn-14 was obtained as the first fraction and dihy-
dropyran anti-14 as the second one. The syn/anti ratio was
determined by 1H NMR or HPLC analysis of the crude reaction
product after concentration in vacuo. The syn- and anti-assign-
ments of the pyran products are based on NMR experiments, in-
cluding 2D-NOESY.
was isolated as a colorless oil: 1H NMR (300 MHz, CDCl3)
d 7.44e7.28
(m, 5H), 5.51 (br s,1H), 4.68 (d, J¼12.1 Hz, 1H), 4.61 (d, J¼12.1 Hz, 1H),
3.99e3.87(m, 2H), 3.60 (dd, J¼10.1, 6.1 Hz,1H), 3.54 (dd, J¼10.1, 4.4 Hz,
1H), 2.13e1.90 (m, 2H), 1.74e1.58 (m, 5H), 1.09 (t, J¼7.4 Hz, 3H); 13C
NMR (75 MHz, CDCl3)d 138.4,136.1,128.2,127.5,127.4,118.3, 77.5, 73.3,
73.0, 66.1, 27.6, 24.5, 19.9,10.5; IR (film, NaCl) 2962, 2929, 2872, 1452,
1376, 1363, 1106, 1053, 1028, 994, 887, 735, 697 cmꢁ1; [
a]
D
þ52.1 (c
0.95, CHCl3); MS (ESI) calcd for C16H23O2 (MþH)þ: 247.2, found 247.1.
4.2.38. (2R,6S)-2-((Benzyloxy)methyl)-6-phenyl-3,6-dihydro-2H-py-
ran (syn-14c). Using the general cyclization protocol, syn-14c was
isolated as a colorless oil: 1H NMR (400 MHz, CDCl3)
d 7.43e7.29 (m,
10H), 5.99e5.91 (m, 1H), 5.78 (tdd, J¼10.2, 2.7, 1.4 Hz, 1H),
5.28e5.23 (m, 1H), 4.67 (d, J¼12.2 Hz, 1H), 4.59 (d, J¼12.2 Hz, 1H),
4.07 (tdd, J¼10.4, 6.1, 4.1 Hz, 1H), 3.69 (dd, J¼10.2, 6.2 Hz, 1H), 3.56
(dd, J¼10.2, 4.5 Hz, 1H), 2.29e2.16 (m, 1H), 2.15e2.03 (m, 1H); 13C
4.2.33. Lewis-acid catalyzed cyclization of diol 9b on a multigram
scale. Table 2, entry 4. Treatment of diol 9b (4.0 g, 15.1 mmol, dr
4:1) with Pd(MeCN)4(BF4)2 (340 mg, 0.76 mmol) in CH2Cl2
(100 mL) for 18 h at room temperature gave 2.71 g (73%) of
diastereomerically pure syn-pyran 14b as a colorless oil after
purification by flash chromatography (hexanes/EtOAc, 20:1 to
10:1). Table 2, entry 5. To a solution of diol 9b (4.53 g, 17.1 mmol,
dr 4:1) in CH2Cl2 (220 mL) was added BF3$OEt2 (0.22 mL,
1.7 mmol) in one portion. The reaction mixture was stirred for
18 h at room temperature. After purification by flash chroma-
NMR (100 MHz, CDCl3)
d 141.6, 138.5, 130.4, 128.6, 128.5, 127.9,
127.7, 127.3, 124.2, 77.6, 73.8, 73.6, 73.3, 27.8; IR (film, NaCl) 3032,
2858, 1651, 1604, 1495, 1454, 1364, 1272, 1203, 1181, 1095, 1028, 910,
874, 807, 739, 698 cmꢁ1; [
a
]
D ꢁ51.0 (c 0.38, CHCl3); MS (ESI) calcd
for C19H20NaO2 (MþNa)þ: 303.1, found 303.1.
4.2.39. (2R,6R)-2-((Benzyloxy)methyl)-6-phenyl-3,6-dihydro-2H-py-
tography (hexanes/EtOAc, 20:1 to 10:1), 3.40
g
(81%) of
ran (anti-14c). Using the general cyclization protocol, anti-14c was

9882
S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
isolated as a colorless oil: 1H NMR (400 MHz, CDCl3)
2H), 7.40e7.27 (m, 8H), 6.07e6.04 (m, 2H), 5.33 (br s, 1H), 4.54 (s,
2H), 3.90e3.81 (m,1H), 3.57 (dd, J¼10.3, 5.7 Hz,1H), 3.50 (dd, J¼10.3,
4.5 Hz, 1H), 2.30e2.18 (m, 1H), 2.09e1.99 (m, 1H); 13C NMR
d
7.47e7.43 (m,
protocol, syn-14f was isolated as a colorless oil: 1H NMR (400 MHz,
CDCl3) 7.39e7.23 (m, 7H), 6.92e6.86 (m, 2H), 5.72e5.66 (m, 1H),
d
5.00 (br s, 1H), 4.62 (d, J¼12.2 Hz, 1H), 4.54 (d, J¼12.2 Hz, 1H),
3.98e3.91 (m, 1H), 3.82 (s, 3H), 3.64 (dd, J¼10.1, 6.1 Hz, 1H), 3.50 (dd,
J¼10.1, 4.7 Hz, 1H), 2.27e2.16 (m, 1H), 2.12e2.02 (m, 1H), 1.39e1.36
(100 MHz, CDCl3)
d 141.1, 138.5, 128.4(3), 128.4, 128.0, 127.8, 127.7,
127.6(8), 127.6, 125.5, 74.1, 73.4, 72.8, 67.1, 27.5; IR (film, NaCl) 697,
(m, 3H); 13C NMR (100 MHz, CDCl3)
d 159.4, 138.5, 135.8, 133.2, 129.5,
734, 806, 868, 1028, 1069, 1196, 1260, 1362, 1452, 1494, 2922,
128.5, 127.9, 127.7, 120.0, 113.9, 81.2, 73.5, 73.4(5), 73.4, 55.4, 28.4,
19.7; IR (film, NaCl) 3583, 3031, 2915, 2854, 1611, 1587, 1513, 1454,
1376, 1333, 1302, 1271, 1240, 1205, 1172, 1098, 1055, 1035, 950, 862,
3031 cmꢁ1; [
a
]
þ48.7 (c 0.39, CHCl3); HRMS (ESI) calcd for
D
C19H20NaO2 (MþNa)þ: 303.1356, found 303.1355.
827, 735, 697 cmꢁ1; [
a]
D þ73.2 (c 0.45, CHCl3); HRMS (ESI) calcd for
4.2.40. (2R,6S)-2-((Benzyloxy)methyl)-5-methyl-6-phenyl-3,6-
dihydro-2H-pyran (syn-14d). Using the general cyclization pro-
tocol, syn-14d was isolated as a colorless oil: 1H NMR (400 MHz,
C21H24NaO3 (MþNa)þ: 347.1618, found 347.1617.
4.2.45. (2R,6R)-2-((Benzyloxy)methyl)-6-(4-methoxyphenyl)-5-
methyl-3,6-dihydro-2H-pyran (anti-14f). Using the general cycliza-
tion protocol, anti-14f was isolated as a colorless oil: 1H NMR
CDCl3) d 7.42e7.29 (m, 10H), 5.74e5.70 (m, 1H), 5.07 (br s, 1H), 4.66
(d, J¼12.2 Hz, 1H), 4.58 (d, J¼12.2 Hz, 1H), 4.03e3.95 (m, 1H), 3.68
(dd, J¼10.1, 6.1 Hz, 1H), 3.55 (dd, J¼10.1, 4.6 Hz, 1H), 2.33e2.22 (m,
1H), 2.15e2.06 (m, 1H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
(400 MHz, CDCl3)
d 7.36e7.22 (m, 7H), 6.93e6.87 (m, 2H),
5.81e5.76 (m, 1H), 5.02 (br s, 1H), 4.48 (d, J¼13.0 Hz, 1H), 4.44 (d,
J¼12.5 Hz, 1H), 3.83 (s, 3H), 3.82e3.72 (m, 1H), 3.47 (dd, J¼10.3,
5.3 Hz, 1H), 3.41 (dd, J¼10.3, 4.6 Hz, 1H), 2.29e2.15 (m, 1H),
2.10e1.99 (m, 1H), 1.63e1.56 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 159.5,138.5,133.5,131.6,130.7,128.4,127.8,127.6,121.2,113.7, 78.1,
73.2, 72.8, 65.6, 55.4, 27.9, 20.5; IR (film, NaCl) 3583, 2916, 2849,
d
140.9, 138.5, 135.5, 128.4, 128.3, 128.0, 127.8, 127.6, 120.0, 81.7,
73.5, 73.4, 73.3, 28.4, 19.6; IR (film, NaCl) 3418, 3063, 3031, 2918,
2852, 1751, 1694, 1682, 1598, 1495, 1452, 1373, 1315, 1273, 1206,
1176,1096,1028, 912, 737, 714, 700 cmꢁ1; [
a
]
D ꢁ15.8 (c 0.38, CHCl3);
HRMS (ESI) calcd for C20H23O2 (MþH)þ: 295.1693, found 295.1682.
2313, 1608, 1509, 1453, 1302, 1245, 1173, 1098, 1034, 868, 833,
4.2.41. (2R,6R)-2-((Benzyloxy)methyl)-5-methyl-6-phenyl-3,6-
dihydro-2H-pyran (anti-14d). Using the general cyclization protocol,
anti-14d was isolated as a white solid: mp 65e67 ꢂC; 1H NMR
696 cmꢁ1; [
a
]
D þ79.5 (c 0.31, CHCl3); HRMS (ESI) calcd for C21H25O3
(MþH)þ: 325.1798, found 325.1809.
(400 MHz, CDCl3)
d
7.44e7.23 (m, 10H), 5.83 (s, 1H), 5.08 (s, 1H), 4.49
4.2.46. (2R,6S)-2-((Benzyloxy)methyl)-6-(4-fluorophenyl)-3,6-
dihydro-2H-pyran (syn-14g). Using the general cyclization protocol,
syn-14g was isolated as a colorless oil: 1H NMR (400 MHz, CDCl3)
(d, J¼12.1 Hz, 1H), 4.46 (d, J¼12.1 Hz, 1H), 3.81 (dt, J¼9.5, 4.6 Hz, 1H),
3.50 (dd, J¼10.3, 5.5 Hz, 1H), 3.43 (dd, J¼10.3, 4.6 Hz, 1H), 2.30e2.19
(m, 1H), 2.13e2.04 (m, 1H), 1.66e1.61 (m, 3H); 13C NMR (100 MHz,
d
7.41e7.30 (m, 7H), 7.04 (dd, J¼8.4, 8.4 Hz, 2H), 5.99e5.91 (m, 1H),
CDCl3)
d
138.9,137.9,132.7,129.0,128.0,127.9,127.8,127.3,127.1,120.9,
5.73 (ddd, J¼10.3, 2.5, 1.3 Hz, 1H), 5.22 (br s, 1H), 4.65 (d, J¼12.2 Hz,
1H), 4.58 (d, J¼12.2 Hz, 1H), 4.05 (qd, J¼7.0, 3.8 Hz, 1H), 3.66 (dd,
J¼10.2, 6.3 Hz, 1H), 3.54 (dd, J¼10.2, 4.3 Hz, 1H), 2.26e2.15 (m, 1H),
78.1, 72.7, 72.3, 65.4, 27.3, 20.0; IR (film, NaCl) 3435, 3058, 3028, 2973,
2934, 2910, 2888, 2865, 2787,1964,1896,1825,1727,1604,1583,1490,
1470, 1453, 1437, 1407, 1377, 1362, 1354, 1339, 1308, 1256, 1191, 1170,
1158, 1138, 1102, 1086, 1066, 1026, 1001, 973, 950, 939, 924, 911, 883,
2.13e2.04 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 163.7, 161.3, 138.4,
137.4, 137.3(7), 130.1, 129.1, 129.0, 128.5, 127.9, 127.7, 124.5, 115.5,
115.3, 76.9, 73.9, 73.6, 73.3, 27.7; IR (film, NaCl) 3035, 2916, 2849,
1651, 1604, 1511, 1454, 1430, 1365, 1325, 1294, 1267, 1222, 1181, 1156,
860, 824, 796, 763, 742, 702 cmꢁ1; [
a]D þ94.7 (c 0.51, CHCl3); HRMS
(ESI) calcd for C20H22NaO2 (MþH)þ: 317.1512, found 317.1502.
1095, 1028, 1015, 911, 879, 832, 792, 736, 698, 658 cmꢁ1; [
a
]
D ꢁ58.3
4.2.42. (2R,6S)-2-((Benzyloxy)methyl)-6-(4-methoxyphenyl)-3,6-
dihydro-2H-pyran (syn-14e). Using the general cyclization protocol,
syn-14e was isolated as a colorless oil: 1H NMR (400 MHz, CDCl3)
(c 0.29, CHCl3); HRMS (ESI) calcd for C19H20FO2 (MþH)þ: 299.1442,
found 299.1435.
d
7.41e7.26 (m, 7H), 6.93e6.87 (m, 2H), 5.97e5.90 (m, 1H), 5.75 (d,
4.2.47. (2R,6R)-2-((Benzyloxy)methyl)-6-(4-fluorophenyl)-3,6-
dihydro-2H-pyran (anti-14g). Using the general cyclization pro-
tocol, anti-14g was isolated as a colorless oil: 1H NMR (400 MHz,
J¼10.2 Hz, 1H), 5.19 (br s, 1H), 4.65 (d, J¼12.1 Hz, 1H), 4.57 (d,
J¼12.2 Hz, 1H), 4.09e4.01 (m, 1H), 3.82 (s, 3H), 3.69e3.62 (m, 1H),
3.53 (dd, J¼10.3, 4.7 Hz, 1H), 2.25e2.14 (m, 1H), 2.12e2.02 (m, 1H);
IR (film, NaCl) 3437, 3010, 2918, 2851, 1723, 1613, 1586, 1514, 1463,
1455, 1365, 1303, 1247, 1216, 1174, 1092, 1036, 910, 877, 829, 755,
CDCl3)
d
7.44e7.40 (m, 2H), 7.38e7.29 (m, 5H), 7.05 (dd, J¼8.7,
8.7 Hz, 2H), 6.12e6.05 (m, 1H), 6.05e5.99 (m, 1H), 5.30 (br s, 1H),
4.55 (s, 2H), 3.84e3.78 (m, 1H), 3.57 (dd, J¼10.3, 5.8 Hz, 1H), 3.50
(dd, J¼10.3, 4.4 Hz, 1H), 2.24 (dddd, J¼17.3, 9.9, 4.8, 2.4 Hz, 1H), 2.05
698, 667 cmꢁ1; [
a
]
D
ꢁ18.1 (c 0.43, CHCl3); HRMS (ESI) calcd for
C20H23O3 (MþH)þ: 311.1642, found 311.1640.
(ddd, J¼17.6, 4.3, 4.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 163.7,
161.2, 138.4, 136.9, 136.9, 129.8, 129.7, 128.5, 127.7, 127.6, 127.5,
125.8, 115.3, 115.1, 73.4, 73.3, 72.7, 67.0, 27.4; IR (film, NaCl) 3035,
2916, 2849, 1602, 1506, 1454, 1362, 1264, 1223, 1157, 1075, 878, 838,
4.2.43. (2R,6R)-2-((Benzyloxy)methyl)-6-(4-methoxyphenyl)-3,6-
dihydro-2H-pyran (anti-14e). Using the general cyclization pro-
tocol, anti-14e was isolated as a colorless oil: 1H NMR (400 MHz,
793, 736, 698, 680 cmꢁ1; [
a]
þ86.2 (c 0.31, CHCl3); HRMS (ESI)
D
CDCl3)
d
7.40e7.26 (m, 7H), 6.93e6.88 (m, 2H), 6.10e6.04 (m, 1H),
calcd for C19H19FNaO2 (MþNa)þ: 321.1261, found 321.1258.
6.03e5.98 (m, 1H), 5.29 (br s, 1H), 4.55 (d, J¼12.9 Hz, 1H), 4.52 (d,
J¼12.5 Hz, 1H), 3.86e3.80 (m, 1H), 3.83 (s, 3H), 3.55 (dd, J¼10.3,
5.6 Hz, 1H), 3.51e3.47 (m, 1H), 2.30e2.19 (m, 1H), 2.09e2.00 (m,
4.2.48. (2R,6S)-2-((Benzyloxy)methyl)-6-(4-fluorophenyl)-5-methyl-
3,6-dihydro-2H-pyran (syn-14h). Using the general cyclization
protocol, syn-14h was isolated as a colorless oil: 1H NMR (400 MHz,
1H); 13C NMR (100 MHz, CDCl3)
d 159.2, 138.5, 133.2, 129.6, 128.4,
127.8, 127.8, 127.6, 125.4, 113.7, 73.8, 73.3, 72.8, 66.6, 55.4, 27.5; IR
CDCl3)
d
7.37e7.28 (m, 7H), 7.03 (dd, J¼8.6, 8.6 Hz, 2H), 5.69 (d,
(film, NaCl) 3033, 2917, 2850, 2246, 1610, 1583, 1510, 1454, 1362,
J¼5.8 Hz, 1H), 5.03 (br s, 1H), 4.62 (d, J¼12.2 Hz, 1H), 4.55 (d,
J¼12.3 Hz, 1H), 3.98e3.90 (m, 1H), 3.63 (dd, J¼10.1, 6.2 Hz, 1H),
3.54e3.49 (m, 1H), 2.29e2.16 (m, 1H), 2.11e2.02 (m, 1H), 1.38e1.33
1303, 1246, 1174,1070, 1036, 909, 876, 834, 782, 732, 697, 680 cmꢁ1
;
[
a]
þ45.9 (c 0.63, CHCl3); HRMS (ESI) calcd for C20H22NaO3
D
(MþNa)þ: 333.1461, found 333.1456.
(m, 3H); 13C NMR (100 MHz, CDCl3)
d 163.8, 161.4, 138.5, 136.8,
136.7(8), 135.4, 130.0, 129.9, 128.5, 127.9, 127.7, 120.3, 115.4, 115.2,
80.9, 73.5(4), 73.5, 73.3, 28.3, 19.6; IR (film, NaCl) 3445, 3031, 2916,
2849, 1728, 1605, 1509, 1454, 1366, 1294, 1266, 1222, 1156, 1096,
4.2.44. (2R,6S)-2-((Benzyloxy)methyl)-6-(4-methoxyphenyl)-5-
methyl-3,6-dihydro-2H-pyran (syn-14f). Using the general cyclization

S. Hanessian et al. / Tetrahedron 67 (2011) 9870e9884
9883
1057, 1028, 1015, 952, 900, 864, 831, 799, 751, 697, 666 cmꢁ1; [
a
]
127.9, 127.7(3), 127.7, 127.6, 127.5, 126.3, 126.2(7), 75.1, 75.0, 74.0,
73.9, 73.5, 70.0, 36.4, 36.3; IR (film, NaCl) 3390, 3031, 2917, 2247,
1603, 1494, 1454, 1093, 909, 731, 697 cmꢁ1; HRMS (ESI) calcd for
C19H22NaO3 (MþNa)þ: 321.1461, found 321.1464.
D
ꢁ37.6 (c 0.67, CHCl3); HRMS (ESI) calcd for C20H25FNO2 (MþNH4)þ:
330.1864, found 330.1877.
4.2.49. (2R,6R)-2-((Benzyloxy)methyl)-6-(4-fluorophenyl)-5-methyl-
3,6-dihydro-2H-pyran (anti-14h). Using the general cyclization
protocol, anti-14h was isolated as a colorless oil: 1H NMR (400 MHz,
Acknowledgements
CDCl3)
d
7.39e7.23 (m, 7H), 7.07 (dd, J¼8.7, 8.7 Hz, 2H), 5.83e5.79
We thank Syngenta (Basel, Switzerland) for generous financial
assistance. We also acknowledge funding from NSERC and FQRNT.
We are grateful to Stephane Dorich for help in the preparation of
this manuscript.
(m, 1H), 5.04 (br s, 1H), 4.50 (d, J¼12.8 Hz, 1H), 4.46 (d, J¼12.8 Hz,
1H), 3.75 (ddd, J¼9.7, 4.5, 4.5 Hz, 1H), 3.49 (dd, J¼10.3, 5.5 Hz, 1H),
3.42 (dd, J¼10.3, 4.5 Hz, 1H), 2.27e2.17 (m, 1H), 2.12e2.03 (m, 1H),
1.62e1.59 (m, 3H); IR (film, NaCl) 3584, 2917, 2850, 1603, 1506,
1454, 1223, 1157, 1096, 871, 841 cmꢁ1; [
a]
þ23.6 (c 0.47, CHCl3);
D
HRMS (ESI) calcd for C20H21FNaO2 (MþNa)þ: 335.1418, found
References and notes
335.1429.
1. For examples, see: (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1; (b) Norcross, R.
D.; Paterson, I. Chem. Rev. 1995ˇ , 95, 2041.
4.2.50. (R)-1-(Benzyloxy)pent-4-en-2-ol (15). To a ꢁ78 ꢂC solution
of (R)-benzyl glycidol ether (3) (1.0 g, 6.1 mmol) in THF (20 mL) was
added CuI (116 mg, 0.61 mmol) followed by vinyl magnesium
bromide (6.4 mL of a 1.0 M solution in THF, 6.4 mmol). The re-
action mixture was stirred for 2 h at ꢁ78 ꢂC, slowly warmed to
€
2. (a) Review: Michelet, V.; Genet, J.-P. Curr. Org. Chem. 2005, 9, 405; (b) Hofle, G.;
Steinmetz, H.; Gerth, K.; Reichenbach, H. Liebigs Ann. Chem. 1991, 941; (c)
Connor, D. T.; Greenough, R. C.; von Strandtmann, M. J. Org. Chem. 1977, 42,
3664; (d) Ringel, S. M.; Greenough, R. C.; Roemer, S.; Connor, D.; Gutt, A. L.;
Blair, B.; Kanter, G.; von Strandmann, M. J. Antibiot. 1977, 371.
€
3. (a) Reichenbach, H.; Hofle, G.; Gerth, K.; Washausen, P. PCT Int. Appl. WO97/
0
ꢂC, and stirred for one additional hour at that temperature. The
€
31912, 1997; (b) Gerth, K.; Washausen, P.; Hofle, G.; Irschik, H.; Reichenbach, H.
J. Antibiot. 1996, 49, 71.
mixture was quenched by addition of saturated NH4Cl solution and
concentrated under reduced pressure. The remaining aqueous
phase was extracted with Et2O, the combined organic phase dried
(MgSO4), and concentrated. The residue was purified by flash
chromatography (hexanes/EtOAc, 10:1 to 2:1) to give 0.9 g (77%) of
4. (a) De Rosa, S.; Carbonelli, S.; Iodice, C. Tetrahedron 2007, 63, 1959; (b) De Rosa,
S.; Crispino, A.; De Giulio, A.; Iodice, C.; Benrezzouk, R.; Terencio, M. C.; Fer-
randiz, M. L.; Alcaraz, M. J.; Paya, M. J. Nat. Prod. 1998, 61, 931.
5. Bowden, B. F.; Coll, J. C.; Gulbis, J. M.; Mackay, M. F.; Willis, R. H. Aust. J. Chem.
1986, 39, 803.
6. (a) Ando, K.; Matsuura, I.; Nawata, Y.; Endo, H.; Sasaki, H.; Okytomi, T.; Saehi, T.;
Tamura, G. J. Antibiot. 1978, 31, 533; (b) Ando, K.; Suzuki, S.; Saeki, T.; Tamura,
G.; Arima, K. J. Antibiot. 1969, 22, 189.
alcohol 15 as a colorless oil: 1H NMR (400 MHz, CDCl3)
d 7.42e7.30
(m, 5H), 5.85 (dddd, J¼17.2, 10.0, 7.1, 7.1 Hz, 1H), 5.18e5.10 (m, 2H),
4.59 (s, 2H), 3.95e3.88 (m, 1H), 3.55 (dd, J¼9.5, 3.4 Hz, 1H), 3.41
(dd, J¼9.4, 7.5 Hz, 1H), 2.35 (d, J¼3.3 Hz, 1H), 2.29 (dd, J¼6.6,
€
7. (a) For a review on laulimalide, see: Mulzer, J.; Ohler, E. Chem. Rev. 2003, 103,
3753; (b) Corley, D. G.; Herb, R.; Moore, R. E.; Scheuer, P. J.; Paul, V. J. J. Org.
ꢁ
Chem. 1988, 53, 3644; (c) Quinoa, E.; Kakou, Y.; Crews, P. J. Org. Chem. 1988, 53,
6.6 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 138.1, 134.3, 128.6, 127.9,
3642.
8. (a) De Jesus, A. E.; Steyn, P. S.; van Heerden, F. R.; Vleggaar, R.; Wessels, P. L.;
Hull, W. E. J. Chem. Soc., Perkin Trans. 1 1983, 1847; (b) De Jesus, A. E.; Steyn, P. S.;
van Heerden, F. R.; Vleggaar, R.; Wessels, P. L.; Hull, W. E. J. Chem. Soc., Chem.
Commun. 1981, 289.
127.8, 117.9, 74.0, 73.5, 69.9, 38.0; IR (film, NaCl) 3429, 3067, 3031,
2916, 2859, 1642, 1496, 1454, 1365, 1207, 1102, 997, 915, 737,
698 cmꢁ1; HRMS (ESI) calcd for C12H16NaO2 (MþNa)þ: 215.1043,
found 315.1036.
9. (a) Ishibashi, M.; Moore, R. E.; Patterson, G. M. L.; Xu, C.; Clardy, J. J. Org. Chem.
1986, 51, 5300; (b) Moore, R. E.; Patterson, G. M. L.; Mynderse, J. S.; Barchi, J., Jr.;
Norton, T. R.; Furusawa, E.; Furusawa, S. Pure Appl. Chem. 1986, 58, 263.
4.2.51. 1-Phenylprop-2-en-1-ol (16). To a 0 ꢂC solution of benzal-
dehyde (3.8 mL, 36.4 mmol) in THF (27 mL) was added vinyl
magnesium bromide (45 mL of a 1.0 M solution in THF, 45 mmol).
The reaction mixture was allowed to warm to room temperature
and stirred overnight. The mixture was quenched by addition of
saturated NH4Cl solution and concentrated under reduced pres-
sure. The remaining aqueous phase was extracted with EtOAc, the
combined organic phase dried (MgSO4), and concentrated to give
16 as a light yellow (3.9 g, 79%). The crude material was used
€
10. (a) Irschik, H.; Jansen, R.; Gerth, K.; Hofle, G.; Reichenbach, H. J. Antibiot. 1987,
€
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without further purification: 1H NMR (400 MHz, CDCl3)
d 7.42e7.39
(m, 4H), 7.38e7.31 (m, 1H), 6.08 (ddd, J¼17.0, 10.3, 6.0 Hz, 1H), 5.37
(ddd, J¼17.1, 1.4, 1.4 Hz, 1H), 5.23 (ddd, J¼10.3, 1.3, 1.3 Hz, 1H),
5.21e5.17 (m,1H), 2.75 (d, J¼3.7 Hz,1H); 13C NMR (100 MHz, CDCl3)
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d
142.6, 140.3, 128.5, 127.7, 126.4, 115.1, 75.2; IR (film, NaCl) 3363,
3064, 3030, 2982, 2872, 1643, 1602, 1494, 1454, 1417, 1280, 1195,
1116, 1074, 990, 928, 835, 762, 700 cmꢁ1; MS (ESI) calcd for C9H9
(MꢁOH)þ: 117.1, found 117.1.
4.2.52. (5R,Z)-6-(Benzyloxy)-1-phenylhex-2-ene-1,5-diol
(17). To
a solution of alcohols 15 (27 mg, 0.14 mmol) and 16 (150 mg,
1.12 mmol) was added Grubbs’ second generation catalyst (3.3 mg,
0.004 mmol) and the mixture was heated to reflux for 5 h. Con-
centration under reduced pressure followed by flash chromatog-
raphy of the residue (hexanes/EtOAc, 2:1 to 1:1) gave diol 17 as
a colorless oil as a mixture of diastereomers (30 mg, 72% yield, dr
1:1): 1H NMR (400 MHz, CDCl3)
d 7.41e7.29 (m, 10H), 5.82e5.76 (m,
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2H), 5.22e5.18 (m,1H), 4.57e4.54 (m, 2H), 3.90 (br s,1H), 3.54e3.47
(m, 1H), 3.41e3.34 (m, 1H), 2.63e2.15 (m, 4H); 13C NMR (100 MHz,
CDCl3)
d 143.1, 138.0(1), 138.0, 135.7, 135.6, 128.64, 128.6, 128.0,

9884
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a
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ꢀ
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bient temperature and monitored by 1H NMR.