Stereoselectivity in (Z)-vinylmetal additions to the dictyostatin C1-C9 β-silyloxy aldehyde

Article abstract of DOI:10.1002/ejoc.201101201

(Z)-Vinyl iodides 6a-d were synthesized in high yield with good diastereo- and enantioselectivity using a Marshall-Tamaru, Pd-catalyzed allenylzinc reaction as the key step. The addition of 6a-d to the dictyostatin C1-C9 β-silyloxy aldehyde 5 was carried out through the vinyllithium and lithium vinylzincate routes. The lithium vinylzincate additions always proceeded in higher yields and gave fewer side products than the corresponding vinyllithium additions. The configuration of the newly created C9 stereocenter was assigned through Rychnovsky's acetonide ¹³C NMR method. The diastereoselectivity in this particular type of (Z)-vinylmetal addition reaction appears to be controlled by a subtle balance between the intrinsic stereochemical preference of the β-silyloxy aldehyde (1,3-anti-selective) and that of the chiral lithium (Z)-vinylzincates. The latter becomes more influential with increasing stereochemical complexity, that is, passing from a stereodyad (6a,6b) to a stereotriad (6c,6d).

Full text of DOI:10.1002/ejoc.201101201

FULL PAPER
DOI: 10.1002/ejoc.201101201
Stereoselectivity in (Z)-Vinylmetal Additions to the Dictyostatin C1–C9
β-Silyloxy Aldehyde
Andrea Ambrosi,[a] Luca Pignataro,[a] Chiara Zanato,[a] and Cesare Gennari*[a]
Keywords: Asymmetric synthesis / Diastereoselectivity / Lithiation / Total synthesis / Zinc
(Z)-Vinyl iodides 6a–d were synthesized in high yield with
good diastereo- and enantioselectivity using a Marshall–Ta- stereoselectivity in this particular type of (Z)-vinylmetal ad-
through Rychnovsky’s acetonide 13C NMR method. The dia-
maru, Pd-catalyzed allenylzinc reaction as the key step. The
addition of 6a–d to the dictyostatin C1–C9 β-silyloxy alde-
hyde 5 was carried out through the vinyllithium and lithium
vinylzincate routes. The lithium vinylzincate additions al-
ways proceeded in higher yields and gave fewer side prod-
ucts than the corresponding vinyllithium additions. The con-
figuration of the newly created C9 stereocenter was assigned
dition reaction appears to be controlled by a subtle balance
between the intrinsic stereochemical preference of the β-sil-
yloxy aldehyde (1,3-anti-selective) and that of the chiral lith-
ium (Z)-vinylzincates. The latter becomes more influential
with increasing stereochemical complexity, that is, passing
from a stereodyad (6a,6b) to a stereotriad (6c,6d).
uct (9R) when 3 was used.[8] This result disagrees with the
models mentioned above and dramatically contradicts a lit-
erature precedent where an almost identical reaction was
claimed to be 100% 1,3-anti-stereoselective.[9] On the other
hand, addition of 4 to 5 showed a distinct preference
(Ն95:5) for the 1,3-anti diastereomer (9S).
Curran and co-workers have reported that the addition
of several (Z)-vinyllithium compounds to similar aldehydes
gave 1,3-anti/1,3-syn ratios ranging from 67:33 to
34:66.[10–12] Based on these results (Table 1), we concluded
that the stereochemical course of this particular reaction is
mainly dependent on the induction of the chiral (Z)-vi-
nylmetal reagent rather than on the intrinsic preference of
the C1–C9 β-OTBS-substituted aldehyde. In addition to the
obvious relevance of the C12–C14 stereotriad (Table 1, En-
try 6 vs. 7), it is worth noting that the 1,3-stereoselectivity
was inverted as a result of remote, seemingly unimportant,
structural variations in the vinyl iodide portion (Table 1,
Entry 1 vs. 2 and Entry 3 vs. 4).
Introduction
1,3-Asymmetric induction in nucleophilic additions to β-
oxy-substituted aldehydes is an important tool in stereo-
selective synthesis and has been widely exploited. Models
for rationalizing the 1,3-stereoselectivity have been pro-
posed by Cram,[1] Reetz,[2] and Evans,[3,4] who invoked
steric hindrance, polar effects, and chelation as the ruling
factors. In the case of β-silyloxy aldehydes and when the
nucleophiles do not contain additional elements of stereo-
control (e.g. chiral auxiliaries, further stereocenters, etc.),
reactions generally show a moderate to high preference for
1,3-anti-stereoselectivity. Sterically encumbering silyl
groups usually favor a nonchelation pathway, which leads
to the preferential formation of 1,3-anti addition products
according to Evans’s polar model.[3] Exceptionally, the use
of aluminum Lewis acids provides chelation control by a
boat-like model, which reinforces the 1,3-anti stereochemi-
cal outcome.[4]
We have recently reported the total synthesis of 9-epi-
dictyostatin (1, Scheme 1) and 12,13-bis-epi-dictyostatin
(2).[5,6] The key step of the synthetic sequence involved the
addition of (Z)-vinyl iodides 3 and 4 to C1–C9 β-OTBS-
substituted aldehyde 5, which proceeded via the corre-
sponding lithium vinylzincates.[7] Surprisingly, we observed
a very high diastereoselectivity (Ն95:5) for the 1,3-syn prod-
Results and Discussion
Wishing to delve deeper into the matter, we decided to
investigate the addition of a set of model (Z)-vinyl iodides
(6a–d) to aldehyde 5 (Figure 1). Models 6a and 6b possess
a stereodyad that mimics the C10–C13 portion of vinyl io-
dides 3 and 4, respectively. Models 6c and 6d contain a
stereotriad that reproduces the C10–C14 portion of 3 and
4.
Models 6a and 6b were prepared starting from phenyl-
acetaldehyde (7, Scheme 2), which was subjected to a
Marshall–Tamaru, Pd-catalyzed allenylzinc addition[13,14]
with the enantiomeric mesylates of 3-butyn-2-ol. The (R)
[a] Università degli Studi di Milano,
Dipartimento di Chimica Organica e Industriale,
Centro Interdipartimentale C.I.S.I.,
Via G. Venezian 21, 20133 Milan, Italy
Fax: +39-02-50314072
E-mail: cesare.gennari@unimi.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101201.
144
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Stereoselectivity in (Z)-Vinylmetal Additions to C1–C9 β-Silyloxy Aldehyde
Table 1. Literature precedents.
Scheme 1. Vinylzincate addition step in the total synthesis of 1 and
2.
[a] Not reported.
enantiomer 8a led to a mixture of stereoisomers (68% yield)
with an 85:15 diastereomeric ratio (dr) in favor of the de-
sired anti adduct 9a (Ͼ96%ee by chiral HPLC), whereas
the (S) enantiomer 8b was used to access 9b in a similar
fashion.
In both cases, the minor syn isomer was completely re-
moved by flash chromatography during this and the follow-
ing two steps. TBS protection (TBSOTf, 2,6-lutidine) of
alcohols 9a and 9b afforded alkynes 10a and 10b (89–92%),
Figure 1. Model (Z)-vinyl iodides 6a–d (dictyostatin numbering).
which were lithiated (BuLi) and converted quantitatively not purified and directly subjected to Marshall–Tamaru,
into the corresponding alkynyl iodides 11a and 11b. Re- Pd-catalyzed allenylzinc addition.[13,14] Using the mesylate
duction of compounds 11 with diimide[15] provided 6a and of (R)-3-butyn-2-ol (8a), a mixture of stereoisomers was ac-
6b as single (Z)-diastereomers (91–94%).
cessed (85% yield), which contained 90% of the desired
The synthesis of 6c and 6d started from commercially anti,syn product 9c. The minor isomers (total 10%) were
available (S)-(–)-2-phenyl-1-propanol (12, Scheme 3). Dess– completely removed by chromatographic purification. The
Martin oxidation[16] afforded the corresponding aldehyde use of (S) mesylate 8b led to an inseparable mixture of iso-
13 with no racemization (99%ee by chiral GC), which was mers (87% yield), which contained 81% of the desired
Eur. J. Org. Chem. 2012, 144–153
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A. Ambrosi, L. Pignataro, C. Zanato, C. Gennari
FULL PAPER
Scheme 2. Synthetic route to 6a and 6b (dictyostatin numbering).
Scheme 4. Vinyllithium/lithium vinylzincate addition and acetonide
synthesis (dictyostatin numbering).
anti,anti adduct 9d. The synthetic sequence continued as
described above [TBS protection (100%), iodination (96%),
and diimide reduction (92–95%)] to give 6c and 6d. Re-
moval of minor isomers (total 19%) formed in the Mar-
shall–Tamaru step of the d series was possible only in the
last stage of the sequence.
The configuration of the newly created C9 stereocenter
was assigned by Rychnovsky’s acetonide 13C NMR
method.[18] For this purpose, both C9-epimers from each
model [7,9-anti (9S) and 7,9-syn (9R) 14a–d, eight products
in total] were isolated, fully deprotected (HF·Py), and con-
verted into the corresponding 7,9-anti (9S) and 7,9-syn (9R)
acetonides 15a–d (92–100%, two steps). Our experimental
results are in complete agreement with Rychnovsky’s
rule,[19] and the stereochemistry at C9 was unambiguously
assigned for all products (Table 2).
Table 2. Relevant 13C NMR resonances in 15a–d.
Compound
13C NMR chemical shifts [ppm]
Quaternary C
CH3
15a 7,9-anti (9S)
15a 7,9-syn (9R)
15b 7,9-anti (9S)
15b 7,9-syn (9R)
15c 7,9-anti (9S)
15c 7,9-syn (9R)
15d 7,9-anti (9S)
15d 7,9-syn (9R)
100.5
98.7
100.5
98.6
100.4
98.8
100.5
98.6
25.0, 24.4
30.0, 19.5
25.1, 24.4
30.2, 19.7
24.8, 24.4
30.1, 19.7
24.9, 24.3
30.1, 19.5
On the basis of the C9 configuration assignment for
15a–d, diastereomeric ratios of vinyllithium and lithium
vinylzincate additions were determined (Table 3).
Scheme 3. Synthetic route to 6c and 6d (dictyostatin numbering).
With 6a–d in hand, we examined their addition reactions
Lithium vinylzincate additions always proceeded in
to aldehyde 5.[5,6,17] As mentioned above, Curran reported higher yields and gave fewer side products than the corre-
moderate diastereoselectivities in similar reactions when the sponding vinyllithium additions. Although the vinyllithium
nucleophilic species was a vinyllithium (Table 1, Entries 1– vs. vinylzincate stereochemical trend is difficult to rational-
4). However, as conflictingly reported by Ramachandran ize, a relatively clear scenario emerges for the lithium vinyl-
(Table 1, Entry 5) and by us (Table 1, Entries 6 & 7), excep- zincate additions (Table 3). The addition of the enantio-
tional diastereoselectivities were observed when the nucleo- meric vinylzincates derived from 6a and 6b (simplified ver-
phile was a lithium vinylzincate. For this reason, each sions of 3 and 4, respectively) to 5 appears to be guided by
model 6a–d was added to 5 as both a vinyllithium and a the preference of the aldehyde for the 1,3-anti (9S) product
lithium vinylzincate, in order to assess the effect of the dif- stereochemistry (vide infra). In the case of 6b (Table 3, En-
ferent coupling conditions on the stereochemical outcome try 4) the two reactants are matched (1,3-anti/1,3-syn =
(Scheme 4).
86:14), whereas with 6a (Table 3, Entry 2) they are mis-
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Stereoselectivity in (Z)-Vinylmetal Additions to C1–C9 β-Silyloxy Aldehyde
Table 3. Stereochemical outcome and yield of vinyllithium and lith-
ium vinylzincate additions.
The preference of β-OTBS-substituted aldehydes for the
1,3-anti isomer is rationalized by the 1,3-asymmetric induc-
tion models that have been thoroughly investigated by Ev-
ans. Steric interactions in the aldehyde conformations are
minimized when the β-alkyl substituent (Rβ) is oriented
anti to the Cα-C=O bond as in the models A (Scheme 5).
β-OTBS-Substituted aldehydes preferentially afford the 1,3-
anti diastereomer according to the polar model A1, where
the dipoles are opposed.[3] Although a chelate organization
is unlikely for β-OTBS-substituted aldehydes in lithium-me-
diated additions,[20] the use of aluminum Lewis acids
(Me2AlCl or MeAlCl2) provides exceptional chelation con-
trol via a boat-like transition state, which reinforces the 1,3-
anti stereochemical outcome (model B, Re face attack).[4]
[a] Yields and diastereomeric ratios were determined from the
crude reaction mixtures by 1H NMR and/or 13C NMR spec-
troscopy. Reactions were repeated three times to obtain statistically
relevant ratios and yields.
matched (1,3-anti/1,3-syn = 68:32). These data suggest that
the vinylzincate derived from 6b must have a slight intrinsic
preference for the 1,3-anti (9S) diastereomer, whereas 6a
would preferentially form the 1,3-syn (9R) product if the
aldehyde control did not predominate. Passing from the
stereodyads to the stereotriads (6c and 6d), the preference
of the vinylzincate appears to exert a stronger influence on
the stereochemical outcome: the diastereoselectivity for the
1,3-anti (9S) product is enhanced in the matched case (1,3-
anti/1,3-syn = 88:12 with 6d, Table 3, Entry 8) and dimin-
ished in the mismatched case (1,3-anti/1,3-syn = 57:43 with
6c, Table 3, Entry 6). Thus, for the lithium vinylzincate ad-
ditions the following trend can be recognized: the influence
on the diastereoselectivity of the intrinsic preference of the
nucleophile increases with its stereochemical complexity.
The results we obtained in the reaction of the vinylzincates
derived from 3 and 4 with aldehyde 5 (Scheme 1, Table 1)
are in full agreement with this trend. Indeed, the reaction
of 4, the most complex member of the matched series (6b
Ǟ 6d Ǟ 4), is almost completely 1,3-anti (9S)-selective
(Table 1, Entry 7), whereas vinyl iodide 3, the extreme of
the mismatched series (6a Ǟ 6c Ǟ 3), completely over-
throws the preference of aldehyde 5, yielding the 1,3-syn
(9R) product as the major diastereomer (Table 1, Entry 6).
From these data we conclude that the diastereoselectivity in
this particular type of (Z)-vinylmetal addition reaction is
Scheme 5. 1,3-Asymmetric induction models.
The results obtained in this work (Table 3) and literature
precedents (Table 1)[6,10,11,21] suggest that models A2 and/
or B (Si face attack, half-chair-like transition state), which
lead to the 1,3-syn diastereomer, can make a substantial
impact in these addition reactions.
Conclusions
We have reported the addition of four (Z)-vinyl iodides
the result of a subtle balance between the intrinsic stereo- (6a–d) to the dictyostatin C1–C9 β-silyloxy aldehyde 5 as
chemical preferences of the nucleophile and the electro- both vinyllithium and lithium vinylzincate reagents. Lith-
phile: although the preference of the chiral β-silyloxy alde- ium vinylzincate additions always proceeded in higher
hyde for the 1,3-anti diastereomer prevails with relatively yields and gave fewer side products than the corresponding
simple chiral (Z)-vinylzincates, stereochemically more com- vinyllithium additions. Although the vinyllithium vs. vinyl-
plex lithium (Z)-vinylzincates are able to control the stereo- zincate stereochemical trend is difficult to rationalize, a rel-
chemical outcome, even overriding the aldehyde preference. atively clear scenario emerged for the lithium vinylzincate
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A. Ambrosi, L. Pignataro, C. Zanato, C. Gennari
FULL PAPER
for 30 min then warmed to room temperature over 30 min. After
quenching with saturated aqueous Na2S2O3 and brine, the mixture
was extracted into EtOAc and the combined organic layers were
washed with brine. The organic phase was dried and concentrated
under vacuum. The crude product was purified by flash chromatog-
raphy to give 11 as a colorless oil.
additions: the influence on the diastereoselectivity of the
intrinsic preference of the nucleophile increases with its
stereochemical complexity. It appears that, for the addition
of structurally complex chiral (Z)-vinylmetals, the 1,3-
asymmetric induction models have no predictive value as
the stereochemical outcome is mainly dependent on the in-
duction of the nucleophilic species rather than on the pref-
erence of the β-OTBS substituted aldehyde.
4. Diimide Reduction: A solution of 11 (1 equiv.) in 1:1 THF/iPrOH
(concentration of 11: 0.22 m) at room temperature was treated with
Et3N (1.3 equiv.) and 2-nitrobenzenesulfonylhydrazide[24] (NBSH,
1.1 equiv.). After 24 h, additional Et3N (0.6 equiv.) and NBSH
(0.5 equiv.) were added, and the mixture was stirred for a further
24 h. The reaction was quenched with water and the mixture was
extracted into EtOAc. The combined organic layers were washed
with brine, dried, and concentrated. The crude product was puri-
fied by flash chromatography to give 6 as a colorless oil.
Experimental Section
General: 1H (400.13 MHz) and 13C (100.58 MHz) NMR spectra
were recorded with a 400 MHz spectrometer. 1H NMR chemical
shifts are reported relative to TMS and the solvent resonance was
employed as the internal standard (CDCl3, δ = 7.26 ppm). 13C
NMR spectra were recorded with complete proton decoupling and
the chemical shifts are reported relative to TMS with the solvent
resonance as the internal standard (CDCl3, δ = 77.0 ppm). Optical
rotation values were measured with an automatic polarimeter with
a 1-dm cell at the sodium D line. HRMS were measured with a
Fourier Transform Ion Cyclotron Resonance (FT-ICR) Mass Spec-
trometer equipped with ESI source. All reactions were carried out
in oven- or flame-dried glassware under a nitrogen atmosphere un-
less stated otherwise. All commercially available reagents were used
as received. All solvents were dried by standard procedures before
use. Organic extracts were dried with anhydrous Na2SO4. Reactions
were magnetically stirred and monitored by TLC with silica gel (60
F254 pre-coated glass plates, 0.25 mm thickness). Visualization was
accomplished by irradiation with a UV lamp and/or staining with
a ceric ammonium molybdate or p-anisaldehyde solution. Flash
chromatography was performed with silica gel (60 Å, particle size
0.040–0.062 mm) according to the procedure of Still and cowork-
ers.[22] Yields refer to chromatographically and spectroscopically
pure compounds unless stated otherwise.
5a. Vinyllithium Addition: A solution of 6 (1 equiv.) in Et2O (con-
centration of 6: 0.095 m) was treated with tBuLi (1.6 m in pentane,
2.2 equiv.) at –78 °C under an argon atmosphere. After 30 min, a
solution of 5 (1 equiv.), which had been azeotropically dried with
toluene, in Et2O (concentration of 5: 0.20 m) was added dropwise
and the mixture was stirred for 1.5 h at –78 °C. The reaction was
quenched with saturated aqueous NH4Cl, warmed to room tem-
perature, and diluted with Et2O. The phases were separated, and
the aqueous layer was extracted into Et2O. The combined organic
extracts were washed with brine, dried, and concentrated under
vacuum. The crude mixture was analyzed by 1H and 13C NMR
spectroscopy to determine the dr, then purified by flash chromatog-
raphy to give 14 as a yellow oil.
5b. Lithium Vinylzincate Addition: To a solution of tBuLi (1.6 m in
pentane, 2.2 equiv.) in Et2O (concentration of tBuLi: 0.75 m) at
–78 °C under an argon atmosphere was added a solution of 6
(1 equiv.) in Et2O (concentration of 6: 0.30 m). After stirring for
30 min, dimethylzinc (2.0 m in toluene, 1.6 equiv.) was added drop-
wise, and the reaction mixture was stirred at –78 °C for a further
15 min. A solution of 5 (1 equiv.), which had been azeotropically
dried with toluene, in Et2O (concentration of 5: 0.35 m) was added
dropwise, and the mixture was stirred for 1.5 h at –78 °C. The reac-
tion was quenched with saturated aqueous NH4Cl solution,
warmed to room temperature, and diluted with Et2O. The phases
were separated, and the aqueous layer was extracted into Et2O.
The combined organic extracts were washed with brine, dried, and
concentrated under vacuum. The crude mixture was analyzed by
1H and 13C NMR spectroscopy to determine the dr, then purified
by flash chromatography to give 14 as a yellow oil.
General Procedures for the Synthesis of 9, 10, 11, 6, 14, and 15
1. Marshall–Tamaru Reaction: Triphenylphosphane (recrystallized
from ethanol prior to use, 0.05 equiv.), aldehyde 7 or 13[23]
(1 equiv.), and mesylbutynol 8[6] (1.5 equiv.) were sequentially
added to a cooled (–78 °C) solution of Pd(OAc)2 (0.05 equiv.) in
tetrahydrofuran (THF, aldehyde concentration: 0.10 m). Dieth-
ylzinc (1.0 m in hexane, 3 equiv.) was added over 15 min. After
10 min, the temperature was raised to –20 °C, and the reaction mix-
ture was stirred overnight. The mixture was quenched with satu-
rated aqueous NH4Cl solution and extracted into Et2O. The Et2O
layer was washed with brine, dried, and concentrated under vac-
uum. The residue was purified by flash column chromatography to
afford 9 as a yellow oil.
6. Deprotection and Synthesis of Acetonide: To a solution of 14
(1 equiv.) in THF (concentration of 14: 0.009 m) kept at 0 °C in a
plastic vial was added HF·Py (approximately 900 equiv.) dropwise
over 2 min, and the solution was allowed to slowly warm to room
temperature. The reaction was stirred for 24 h, cooled to 0 °C, di-
luted with EtOAc, and quenched with saturated aqueous NaHCO3
solution. The layers were separated, and the aqueous layer was ex-
tracted into EtOAc. The combined organic extracts were dried, and
the solvents were evaporated under vacuum. The crude mixture was
purified by flash chromatography (1:1 hexane/EtOAc) to give the
fully deprotected triol as a colorless oil, which was not charac-
terized and directly converted into the corresponding acetonide. A
small crystal of PPTS was added to a solution of the triol in 2,2-
dimethoxypropane/CH2Cl2, 8:2 (concentration of triol: 0.015 m).
The reaction mixture was stirred at room temperature for 1.5 h and
quenched with saturated aqueous NaHCO3 solution. The phases
were separated and the aqueous layer was extracted into CH2Cl2.
The combined organic extracts were dried and concentrated under
2. TBS Protection: Freshly distilled 2,6-lutidine (4 equiv.) and
TBSOTf (1.5 equiv.) were added to a stirred solution of 9 (1 equiv.)
in CH2Cl2 (concentration of 9: 0.04 m) at –20 °C (for 9a, 9b) or
room temperature (for 9c, 9d). On completion of the reaction (1–
2 h), the mixture was quenched with saturated aqueous NH4Cl
solution. The layers were separated, and the aqueous layer was ex-
tracted into CH2Cl2. The combined organic extracts were washed
with brine, dried, and concentrated. Purification of the crude prod-
uct by flash chromatography afforded 10 as a colorless oil.
3. Iodination: BuLi (1.6 m in hexane, 1.2 equiv.) was added dropwise
over 5 min to a solution of 10 (1 equiv.) in THF (concentration of
10: 2.0 m) at –50 °C. After 1 h, a solution of iodine (4.0 m,
1.7 equiv.) in THF was added. The mixture was stirred at –50 °C
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Stereoselectivity in (Z)-Vinylmetal Additions to C1–C9 β-Silyloxy Aldehyde
vacuum. The crude product was purified by flash chromatography
to give 15 as a colorless oil.
for the NMR characterization data. HRMS (ESI): calcd. for
C12H14ONa [M + Na]+ 197.09369; found 197.09391.
tert-Butyldimethyl[(2S,3R)-3-methyl-1-phenylpent-4-yn-2-yloxy]-
silane (10b): Prepared by following General Procedure 2. Flash
chromatography: 95:5 hexane/CH2Cl2. Yield: 386 mg (89%) of iso-
meric products, dr = 92:8 before chromatography, dr = 99:1 after
chromatography. [α]3D0 = +30.2 (c = 0.44 CHCl3); see 10a for the
(2R,3S)-3-Methyl-1-phenylpent-4-yn-2-ol (9a): Prepared by follow-
ing General Procedure 1 from 7 and 8a. Flash chromatography:
96:4 hexane/EtOAc. Yield: 510 mg (68%) of isomeric products, dr
= 85:15 before chromatography, dr = 91:9 after chromatography,
Ͼ96%ee by chiral HPLC. Rf = 0.52 (6:4 hexane/EtOAc). [α]2D9
=
–34.5 (c = 0.32 CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.33–
7.22 (m, 5 H), 3.70 (ddd, J = 7.6, 5.8, 3.8 Hz, 1 H), 2.94 (dd, J =
13.6, 5.8 Hz, 1 H, AB system), 2.87 (dd, J = 13.6, 7.6 Hz, 1 H, AB
system), 2.59 (m, 1 H), 2.21 (d, J = 2.4 Hz, 1 H), 1.60 (br. s, 1 H),
1.27 (d, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
138.1 (C0), 129.3 (CH), 128.5 (CH), 126.5 (CH), 84.8 (C0), 75.1
(CH), 71.3 (CH), 41.7 (CH2), 31.6 (CH), 17.4 (CH3) ppm. HRMS
NMR characterization data. HRMS (ESI): calcd. for C18H28
-
OSiNa [M + Na]+ 311.18016; found 311.18041.
tert-Butyl[(2S,3R)-5-iodo-3-methyl-1-phenylpent-4-yn-2-yloxy]di-
methylsilane (11b): Prepared by following General Procedure 3.
Flash chromatography: 95:5 hexane/CH2Cl2. Yield: 432 mg
(100%). [α]3D0 = +53.4 (c = 0.43 CHCl3); see 11a for the NMR
characterization data. HRMS (ESI): calcd. for C18H27OISiNa [M
+ Na]+ 437.07681; found 437.07730.
(ESI): calcd. for C12H14ONa [M
197.09400.
+
Na]+ 197.09369; found
tert-Butyl[(2S,3R,Z)-5-iodo-3-methyl-1-phenylpent-4-en-2-yloxy]-
dimethylsilane (6b): Prepared by following General Procedure 4.
Flash chromatography: 99:1 hexane/CH2Cl2. Yield: 382 mg (94%).
[α]3D0 = –63.5 (c = 0.53 CHCl3); see 6a for the NMR characteriza-
tion data. HRMS (ESI): calcd. for C18H29OISiNa [M + Na]+
439.09246; found 439.09311.
tert-Butyldimethyl[(2R,3S)-3-methyl-1-phenylpent-4-yn-2-yloxy]-
silane (10a): Prepared by following General Procedure 2. Flash
chromatography: 96:4 hexane/CH2Cl2. Yield: 564 mg (92%) of iso-
meric products, dr = 91:9 before chromatography, dr = 99:1 after
chromatography. Rf = 0.73 (8:2 hexane/EtOAc). [α]2D9 = –25.0 (c =
0.30 CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.33–7.21 (m, 5
H), 3.88 (ddd, J = 8.2, 4.9, 3.6 Hz, 1 H), 3.08 (dd, J = 13.2, 4.9 Hz,
1 H, AB system), 2.72 (dd, J = 13.2, 8.0 Hz, 1 H), 2.60 (m, 1 H),
2.19 (d, J = 2.5 Hz, 1 H), 1.24 (d, J = 7.1 Hz, 3 H), 0.88 (s, 9 H),
–0.03 (s, 3 H), –0.28 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 139.4 (C0), 129.8 (CH), 128.2 (CH), 126.1 (CH), 86.2 (C0), 76.1
(CH), 70.2 (CH), 40.0 (CH2), 31.7 (CH), 25.8 (CH3), 18.0 (C0),
15.3 (CH3), –4.9 (CH3), –5.1 (CH3) ppm. HRMS (ESI): calcd. for
C18H28OSiNa [M + Na]+ 311.18016; found 311.18037.
(2S,3S,4S)-4-Methyl-2-phenylhex-5-yn-3-ol (9c): Prepared by fol-
lowing General Procedure 1 from 13 and 8a. Flash chromatog-
raphy: 92:8 hexane/EtOAc. Yield: 276 mg (85%) of isomeric prod-
ucts, dr = 9:1 before chromatography, dr Ͼ 99:1 after chromatog-
raphy. Rf = 0.36 (7:3 hexane/EtOAc). [α]3D0 = –82.8 (c = 0.35
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.35–7.22 (m, 5 H), 3.43
(dd, J = 9.2, 2.7 Hz, 1 H), 2.97 (m, 1 H), 2.36 (m, 1 H), 2.20 (d, J
= 2.4 Hz, 1 H), 1.65 (br. s, 1 H), 1.42 (d, J = 7.0 Hz, 3 H), 1.21 (d,
J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.3
(C0), 128.6 (CH), 127.5 (CH), 126.6 (CH), 84.5 (C0), 79.2 (CH),
71.7 (CH), 45.0 (CH), 30.4 (CH), 18.4 (CH3), 18.1 (CH3) ppm.
HRMS (ESI): calcd. for C13H16ONa [M + Na]+ 211.10934; found
211.10958.
tert-Butyl[(2R,3S)-5-iodo-3-methyl-1-phenylpent-4-yn-2-yloxy]-
dimethylsilane (11a): Prepared by following General Procedure 3.
Flash chromatography: 95:5 hexane/CH2Cl2. Yield: 711 mg
(100%). Rf = 0.31 (9:1 hexane/CH2Cl2). [α]2D9 = –72.1 (c = 0.70
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.34–7.31 (m, 2 H),
7.26–7.22 (m, 3 H), 3.88 (m, 1 H), 3.04 (dd, J = 13.3, 4.8 Hz, 1 H,
AB system), 2.78 (m, 1 H), 2.72 (dd, J = 13.3, 7.9 Hz, 1 H, AB
system), 1.24 (d, J = 7.1 Hz, 3 H), 0.89 (s, 9 H), –0.02 (s, 3 H),
–0.27 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 139.2 (C0),
129.8 (CH), 128.2 (CH), 126.2 (CH), 96.5 (C0), 76.2 (CH), 40.2
(CH2), 34.2 (CH), 25.8 (CH3), 18.0 (C0), 15.2 (CH3), –4.9 (CH3),
–5.0 (C0), –5.1 (CH3) ppm. HRMS (ESI): calcd. for C18H27OISiNa
[M + Na]+ 437.07681; found 437.07803.
tert-Butyldimethyl[(2S,3S,4S)-4-methyl-2-phenylhex-5-yn-3-yloxy]-
silane (10c): Prepared by following General Procedure 2. Flash
chromatography: 95:5 hexane/EtOAc. Yield: 402 mg (100%). Rf =
0.79 (8:2 hexane/EtOAc). [α]3D0 = –24.8 (c = 0.60 CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.31–7.17 (m, 5 H), 3.65 (dd, J = 7.8,
2.9 Hz, 1 H), 3.14 (m, 1 H), 2.38 (m, 1 H), 2.04 (d, J = 2.5 Hz, 1
H), 1.30 (d, J = 7.1 Hz, 3 H), 1.15 (d, J = 7.2 Hz, 3 H), 0.95 (s, 9
H), 0.07 (s, 3 H), 0.00 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 145.4 (C0), 128.4 (CH), 127.8 (CH), 126.3 (CH), 85.9 (C0), 79.7
(CH), 70.2 (CH), 44.1 (CH), 31.4 (CH), 26.1 (CH3), 18.5 (C0), 18.4
(CH3), 18.2 (CH3), –3.7 (CH3) ppm. HRMS (ESI): calcd. for
C19H30OSiNa [M + Na]+ 325.19581; found 325.19624.
tert-Butyl[(2R,3S,Z)-5-iodo-3-methyl-1-phenylpent-4-en-2-yloxy]-
dimethylsilane (6a): Prepared by following General Procedure 4.
Flash chromatography: 99:1 hexane/CH2Cl2. Yield: 642 mg (91%).
Rf = 0.36 (9:1 hexane/CH2Cl2). [α]2D9 = +53.2 (c = 0.43 CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.29–7.26 (m, 2 H), 7.21–7.14 (m, 3
H), 6.37–6.28 (m, 2 H), 3.84 (td, J = 6.8, 2.6 Hz, 1 H), 2.71 (dd, J
= 13.3, 6.6 Hz, 1 H, AB system), 2.62 (dd, J = 13.3, 7.0 Hz, 1 H,
AB system), 2.55 (m, 1 H), 1.00 (d, J = 7.0 Hz, 3 H), 0.88 (s, 9 H),
0.05 (s, 3 H), 0.20 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 142.7 (CH), 138.8 (C0), 129.8 (CH), 128.3 (CH), 126.1 (CH), 82.5
(CH), 76.4 (CH), 43.7 (CH), 41.9 (CH2), 25.9 (CH3), 18.1 (C0),
15.8 (CH3), –4.5 (CH3), –4.8 (CH3) ppm. HRMS (ESI): calcd. for
C18H29OISiNa [M + Na]+ 439.09246; found 439.09305.
tert-Butyl[(2S,3R,4S)-6-iodo-4-methyl-2-phenylhex-5-yn-3-yloxy]-
dimethylsilane (11c): Prepared by following General Procedure 3.
Flash chromatography: 9:1 hexane/CH2Cl2. Yield: 536 mg (96%).
Rf = 0.25 (95:5 hexane/CH2Cl2). [α]3D0 = –62.5 (c = 0.61 CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.35–7.29 (m, 2 H), 7.26–7.21
(m, 3 H), 3.70 (dd, J = 7.5, 3.2 Hz, 1 H), 3.10 (m, 1 H), 2.62 (qd,
J = 7.1, 3.3 Hz, 1 H), 1.33 (d, J = 7.0 Hz, 3 H), 1.19 (d, J = 7.2 Hz,
3 H), 0.98 (s, 9 H), 0.10 (s, 3 H), 0.00 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 145.1 (C0), 128.4 (CH), 127.9 (CH), 126.4
(CH), 96.4 (C0), 79.9 (CH), 44.0 (CH), 33.8 (CH), 26.1 (CH), 18.4
(C0), 18.1 (CH3), 17.9 (CH3), –3.8 (CH3), –3.8 (CH3), –5.2 (C0)
ppm. HRMS (ESI): calcd. for C19H29OISiNa [M + Na]+
451.09246; found 451.09336.
(2S,3R)-3-Methyl-1-phenylpent-4-yn-2-ol (9b): Prepared by follow-
ing General Procedure 1 from 7 and 8b. Flash chromatography:
96:4 hexane/EtOAc. Yield: 324 mg (71%) of isomeric products, dr
= 85:15 before chromatography, dr = 92:8 after chromatography,
Ͼ96%ee by chiral HPLC. [α]3D0 = +38.2 (c = 0.31 CHCl3); see 9a
tert-Butyl[(2S,3S,4S,Z)-6-iodo-4-methyl-2-phenylhex-5-en-3-yl-
oxy]dimethylsilane (6c): Prepared by following General Pro-
Eur. J. Org. Chem. 2012, 144–153
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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149

A. Ambrosi, L. Pignataro, C. Zanato, C. Gennari
FULL PAPER
cedure 4. Flash chromatography: 100 % hexane. Yield: 482 mg
(92%). Rf = 0.49 (95:5 hexane/CH2Cl2). [α]3D0 = +103.6 (c = 0.79
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.30–7.26 (m, 2 H),
7.21–7.15 (m, 3 H), 6.18–6.14 (m, 1 H), 6.09 (d, J = 7.4 Hz, 1 H),
3.75 (dd, J = 8.3, 2.2 Hz, 1 H), 2.74 (m, 1 H), 2.42 (m, 1 H), 1.26
(d, J = 7.1 Hz, 3 H), 0.95 (s, 9 H), 0.94 (d, J = 7.8 Hz, 3 H), 0.11
(s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
144.7 (C0), 142.6 (CH), 128.4 (CH), 128.2 (CH), 126.2 (CH), 81.9
(CH), 80.1 (CH), 44.8 (CH), 44.3 (CH), 26.2 (CH3), 19.2 (CH3),
18.5 (C0), 17.1 (CH3), –3.4 (CH3), –3.6 (CH3) ppm. HRMS (ESI):
calcd. for C19H31OISiNa [M + Na]+ 453.10811; found 453.10849.
16.9 (CH3), –4.1 (CH3), –4.8 (CH3) ppm. HRMS (ESI): calcd. for
C19H31OISiNa [M + Na]+ 453.10811; found 453.10794.
(2Z,4E,6R,7S,9S,10Z,12S,13R)-Methyl-7,13-bis(tert-butyldimethyl-
silyloxy)-9-hydroxy-6,12-dimethyl-14-phenyltetradeca-2,4,10-tri-
enoate [14a, 7,9-anti (9S)] and (2Z,4E,6R,7S,9R,10Z,12S,13R)-
Methyl-7,13-bis(tert-butyldimethylsilyloxy)-9-hydroxy-6,12-di-
methyl-14-phenyltetradeca-2,4,10-trienoate [14a, 7,9-syn (9R)]: Pre-
pared by following General Procedure 5a. Flash chromatography:
96:4 hexane/EtOAc. Yield: 60 mg (56% yield by 1H NMR) of 9-
epimeric products, dr [7,9-anti (9S)/7,9-syn (9R)] = 49:51. Data for
14a 7,9-anti (9S): Rf = 0.17 (85:15 hexane/EtOAc). [α]3D0 = –1.5 (c
= 0.24 CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.40 (dd, J =
15.4, 11.3 Hz, 1 H), 7.28–7.12 (m, 5 H), 6.56 (t, J = 11.3 Hz, 1 H),
6.04 (dd, J = 15.4, 7.5 Hz, 1 H), 5.66–5.60 (m, 2 H), 5.49 (dd, J =
10.9, 8.8 Hz, 1 H), 4.54 (dd, J = 13.3, 8.1 Hz, 1 H), 3.95 (dd, J =
10.6, 5.2 Hz, 1 H), 3.77 (m, 1 H), 3.75 (s, 3 H), 2.69 (d, J = 6.5 Hz,
2 H), 2.61 (m, 2 H), 1.88 (br. s, 1 H), 1.58 (m, 2 H), 1.05 (d, J =
6.8 Hz, 6 H), 0.88 (s, 9 H), 0.87 (s, 9 H), 0.11 (s, 3 H), 0.09 (s, 3
H), 0.01 (s, 3 H), –0.31 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 166.9 (C0), 147.2 (CH), 145.4 (CH), 139.2 (C0), 133.0 (CH),
132.8 (CH), 129.6 (CH), 128.2 (CH), 126.8 (CH), 126.1 (CH), 115.7
(CH), 77.0 (CH), 72.9 (CH), 64.6 (CH), 51.1 (CH3), 42.7 (CH),
41.7 (CH2), 40.0 (CH2), 37.2 (CH), 25.9 (CH3), 25.9 (CH3), 18.3
(CH3), 18.0 (C0), 14.6 (CH3), –4.4 (CH3), –4.5 (CH3), –5.0 (CH3)
ppm. HRMS (ESI): calcd. for C35H60O5Si2Na [M + Na]+
639.38715; found 639.38838. Data for 14a 7,9-syn (9R): Rf = 0.37
(2S,3R,4R)-4-Methyl-2-phenylhex-5-yn-3-ol (9d): Prepared by fol-
lowing General Procedure 1 from 13 and 8b. Flash chromatog-
raphy: 97:3 hexane/EtOAc. Yield: 221 mg (87%) of inseparable iso-
meric products, dr = 81:19. Rf = 0.45 (7:3 hexane/EtOAc). [α]3D0
=
–29.6 (c = 0.29 CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.22–
7.34 (m, 5 H), 3.51 (dd, J = 8.0, 3.9 Hz, 1 H), 2.99 (m, 1 H), 2.74
(m, 1 H), 2.15 (d, J = 2.4 Hz, 1 H), 1.60 (br. s, 1 H), 1.31 (d, J =
7.0 Hz, 3 H), 1.31 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 143.4 (C0), 128.6 (CH), 128.2 (CH), 126.7 (CH), 84.7
(C0), 78.2 (CH), 70.8 (CH), 44.3 (CH), 29.9 (CH), 18.5 (CH3), 18.1
(CH3) ppm. HRMS (ESI): calcd. for C13H16ONa [M + Na]+
211.10934; found 211.10942.
tert-Butyldimethyl[(2S,3R,4R)-4-methyl-2-phenylhex-5-yn-3-yl-
oxy]silane (10d): Prepared by following General Procedure 2. Flash
chromatography: 95:5 hexane/EtOAc. Yield: 320 mg (100%) of in-
(85:15 hexane/EtOAc). [α]3D0 = +29.0 (c = 0.11 CHCl3). H NMR
1
separable isomeric products. Rf = 0.73 (8:2 hexane/EtOAc). [α]3D0
=
(400 MHz, CDCl3): δ = 7.36–7.19 (m, 6 H), 6.51 (t, J = 11.3 Hz, 1
H), 5.94 (dd, J = 15.4, 7.9 Hz, 1 H), 5.59 (d, J = 11.3 Hz, 1 H),
5.54–5.42 (m, 2 H), 4.23 (t, J = 7.2 Hz, 1 H), 3.87–3.78 (m, 2 H),
3.72 (s, 3 H), 2.72 (d, J = 6.6 Hz, 2 H), 2.49 (m, 2 H), 1.65 (m, 1
H), 1.33 (m, 1 H), 1.07 (d, J = 6.8 Hz, 3 H), 0.90 (m, 3 H), 0.90
(s, 9 H), 0.87 (s, 9 H), 0.09 (s, 3 H), 0.07 (s, 3 H), 0.01 (s, 3 H),
–0.21 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.8 (C0),
146.5 (CH), 145.3 (CH), 139.2 (C0), 133.1 (CH), 132.7 (CH), 129.7
(CH), 128.2 (CH), 127.1 (CH), 126.1 (CH), 115.7 (CH), 76.7 (CH),
74.6 (CH), 66.5 (CH), 51.0 (CH3), 42.3 (CH), 41.5 (CH2), 40.6
(CH2), 36.6 (CH), 25.9 (CH3), 25.8 (CH3), 18.1 (C0), 17.9 (CH3),
14.7 (CH3), –4.3 (CH3), –4.5 (CH3), –4.8 (CH3) ppm. HRMS (ESI):
calcd. for C35H60O5Si2Na [M + Na]+ 639.38715; found 639.38801.
–9.1 (c = 0.46 CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.27–7.17
(m, 5 H), 3.75 (dd, J = 6.6, 3.7 Hz, 1 H), 3.04 (m, 1 H), 2.66 (m,
1 H), 2.09 (d, J = 2.6 Hz, 1 H), 1.32 (d, J = 7.2 Hz, 3 H), 1.06 (d,
J = 7.2 Hz, 3 H), 0.84 (s, 9 H), –0.02 (s, 3 H), –0.40 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 144.9 (C0), 128.7 (CH), 128.1
(CH), 126.2 (CH), 86.6 (C0), 78.8 (CH), 70.2 (CH), 44.4 (CH), 30.9
(CH), 26.0 (CH3), 18.8 (CH3), 18.2 (C0), 16.8 (CH3), –4.4 (CH3),
–5.0 (CH3) ppm. HRMS (ESI): calcd. for C19H30OSiNa [M +
Na]+ 325.19581; found 325.19631.
tert-Butyl[(2S,3S,4R)-6-iodo-4-methyl-2-phenylhex-5-yn-3-yloxy]-
dimethylsilane (11d): Prepared by following General Procedure 3.
Flash chromatography: 9:1 hexane/CH2Cl2. Yield: 396 mg (96%)
of inseparable isomeric products. Rf = 0.31 (95:5 hexane/CH2Cl2).
(R,2Z,4E)-Methyl-6-[(4S,6S)-6-{(3S,4R,Z)-4-hydroxy-3-methyl-5-
phenylpent-1-enyl}-2,2-dimethyl-1,3-dioxan-4-yl]hepta-2,4-dienoate
[15a, 7,9-anti (9S)]: Prepared by following General Procedure 6.
Flash chromatography: 7:3 hexane/EtOAc. Yield: 14 mg (100%).
1
[α]3D0 = +3.6 (c = 0.80 CHCl3). H NMR (400 MHz, CDCl3): δ =
7.29–7.17 (m, 5 H), 3.75 (dd, J = 6.1, 4.2 Hz, 1 H), 3.00 (m, 1 H),
2.78 (qd, J = 7.1, 4.2 Hz, 1 H), 1.33 (d, J = 7.2 Hz, 3 H), 1.06 (d,
J = 7.1 Hz, 3 H), 0.87 (s, 9 H), 0.01 (s, 3 H), –0.31 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 144.5 (C0), 128.7 (CH), 128.1
(CH), 126.2 (CH), 97.0 (C0), 78.9 (CH), 44.2 (CH), 33.2 (CH), 26.0
(CH), 18.7 (CH3), 18.2 (C0), 16.8 (CH3), –4.4 (CH3), –4.8 (CH3),
–4.9 (C0 ) ppm. HRMS (ESI): calcd. for C1 9 H2 9 OISiNa
[M + Na]+ 451.09246; found 451.09312.
1
Rf = 0.46 (1:1 hexane/EtOAc). [α]2D5 = –9.0 (c = 0.62 CH2Cl2). H
NMR (400 MHz, CDCl3): δ = 7.43 (dd, J = 15.4, 11.3 Hz, 1 H),
7.36–7.24 (m, 5 H), 6.62 (t, J = 11.3 Hz, 1 H), 6.13 (dd, J = 15.5,
7.6 Hz, 1 H), 5.64 (d, J = 11.3 Hz, 1 H), 5.59–5.55 (m, 2 H), 4.56
(dd, J = 15.0, 6.3 Hz, 1 H), 3.80–3.77 (m, 1 H), 3.74 (s, 3 H), 3.68
(m, 1 H), 2.87 (dd, J = 13.7, 3.5 Hz, 1 H, AB system), 2.67–2.63
(m, 2 H), 2.45 (m, 1 H), 1.79–1.63 (m, 3 H), 1.38 (s, 3 H), 1.37 (s,
tert-Butyl[(2S,3R,4R,Z)-6-iodo-4-methyl-2-phenylhex-5-en-3-yloxy]-
dimethylsilane (6d): Prepared by following General Procedure 4.
Flash chromatography: 100% hexane. Yield: 359 mg (95%) of iso-
meric products, dr = 81:19 before chromatography, dr Ͼ 99:1 after
chromatography. Rf = 0.43 (95:5 hexane/CH2Cl2). [α]3D0 = –39.6 (c
3 H), 1.14 (d, J = 6.8 Hz, 3 H), 1.10 (d, J = 6.9 Hz, 3 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 169.1 (C0), 147.0 (CH), 145.5 (CH),
138.6 (C0), 134.2 (CH), 131.2 (CH), 129.4 (CH), 128.5 (CH), 126.9
(CH), 126.5 (CH), 115.6 (CH), 100.5 (C0), 75.7 (CH), 69.7 (CH),
63.4 (CH), 51.1 (CH3), 41.5 (CH), 41.1 (CH2), 38.1 (CH), 36.5
(CH2), 25.0 (CH3), 24.4 (CH3), 17.5 (CH3), 15.6 (CH3) ppm.
HRMS (ESI): calcd. for C26H36O5Na [M + Na]+ 451.24550; found
451.24566.
1
= 0.54 CHCl3). H NMR (400 MHz, CDCl3): δ = 7.32–7.20 (m, 5
H), 6.47 (dd, J = 8.6, 7.5 Hz, 1 H), 6.19 (d, J = 7.3 Hz, 1 H), 3.80
(dd, J = 6.6, 2.0 Hz, 1 H), 2.83 (m, 1 H), 2.70 (m, 1 H), 1.25 (d, J
= 7.2 Hz, 3 H), 0.93 (d, J = 7.1 Hz, 3 H), 0.90 (s, 9 H), 0.06 (s, 3
H), –0.34 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.7 (R,4E)-Methyl-6-[(4S,6R)-6-{(3S,4R,Z)-4-hydroxy-3-methyl-5-phen-
(C0), 143.3 (CH), 128.6 (CH), 128.2 (CH), 126.3 (CH), 81.2 (CH),
ylpent-1-enyl}-2,2-dimethyl-1,3-dioxan-4-yl]hepta-2,4-dienoate [15a,
80.1 (CH), 45.9 (CH), 42.1 (CH), 26.1 (CH3), 18.3 (C0), 17.9 (CH3), 7,9-syn (9R)]: Prepared by following General Procedure 6. Flash
150
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 144–153

Stereoselectivity in (Z)-Vinylmetal Additions to C1–C9 β-Silyloxy Aldehyde
chromatography: 8:2 hexane/EtOAc. Yield: 14 mg (92%). Rf = 0.51
(1:1 hexane/EtOAc). [α]2D5 = +33.0 (c = 0.57 CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 7.35 (dd, J = 15.4, 11.3 Hz, 1 H), 7.30–
7.18 (m, 5 H), 6.56 (t, J = 11.3 Hz, 1 H), 6.09 (dd, J = 15.5, 7.8 Hz,
1 H), 5.59 (d, J = 11.3 Hz, 1 H), 5.50–5.43 (m, 2 H), 4.50 (dd, J =
13.8, 5.5 Hz, 1 H), 3.75–3.73 (m, 1 H), 3.71 (s, 3 H), 3.59 (m, 1 H),
2.91 (dd, J = 13.9, 3.7 Hz, 1 H, AB system), 2.66 (dd, J = 13.9,
7.3 Hz, 1 H, AB system), 2.49 (m, 1 H), 2.38 (dd, J = 12.8, 6.7 Hz,
1 H), 2.32 (br. s, 1 H), 1.39–1.35 (m, 2 H), 1.34 (s, 3 H), 1.30 (s, 3
H), 1.05 (d, J = 6.8 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 167.0 (C0), 146.8 (CH), 145.5 (CH), 138.6 (C0), 135.6 (CH),
131.4 (CH), 129.8 (CH), 128.3 (CH), 126.9 (CH), 126.2 (CH), 115.5
(CH), 98.7 (C0), 75.0 (CH), 71.9 (CH), 65.2 (CH), 51.1 (CH3), 41.8
(CH), 40.5 (CH2), 37.8 (CH), 34.1 (CH2), 30.0 (CH3), 19.5 (CH3),
17.7 (CH3), 15.5 (CH3) ppm. HRMS (ESI): calcd. for C26H36O5Na
[M + Na]+ 451.24550; found 451.24564.
30.2 (CH3), 19.7 (CH3), 17.3 (CH3), 15.5 (CH3) ppm. HRMS (ESI):
calcd. for C26H36O5Na [M + Na]+ 451.24550; found 451.24586.
(2Z,4E,6R,7S,9S,10Z,12S,13S,14S)-Methyl-7,13-bis(tert-butyl-
dimethylsilyloxy)-9-hydroxy-6,12-dimethyl-14-phenylpentadeca-
2,4,10-trienoate [14c, 7,9-anti (9S)] and (2Z,4E,6R,7S,9R,
10Z,12S,13S,14S)-Methyl-7,13-bis(tert-butyldimethylsilyloxy)-9-hy-
droxy-6,12-dimethyl-14-phenylpentadeca-2,4,10-trienoate [14c, 7,9-
syn (9R)]: Prepared by following General Procedure 5b. Flash
chromatography: 96:4 hexane/EtOAc. Yield: 68 mg (69% yield by
1H NMR) of 9-epimeric products, dr [7,9-anti (9S)/7,9-syn (9R)] =
57:43. Data for 14c 7,9-anti (9S): Rf = 0.31 (85:15 hexane/EtOAc).
1
[α]3D0 = +1.4 (c = 0.18 CHCl3). H NMR (400 MHz, CDCl3): δ =
7.37 (dd, J = 15.3, 11.3 Hz, 1 H), 7.26–7.09 (m, 5 H), 6.56 (t, J =
11.3 Hz, 1 H), 6.02 (dd, J = 15.5, 7.5 Hz, 1 H), 5.59 (m, 2 H), 5.32
(m, 1 H), 4.35 (dd, J = 13.1, 8.3 Hz, 1 H), 3.89 (dd, J = 10.4,
5.1 Hz, 1 H), 3.73 (s, 3 H), 3.67 (dd, J = 7.1, 3.2 Hz, 1 H), 2.79
(m, 1 H), 2.54 (m, 2 H), 1.91 (br. s, 1 H), 1.45 (m, 2 H), 1.24 (d, J
= 7.1 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H), 1.01 (d, J = 7.0 Hz, 3
(2Z,4E,6R,7S,9S,10Z,12R,13S)-Methyl-7,13-bis(tert-butyldimethyl-
silyloxy)-9-hydroxy-6,12-dimethyl-14-phenyltetradeca-2,4,10-tri-
enoate [14b, 7,9-anti (9S)] and (2Z,4E,6R,7S,9R,10Z,12R,13S)- H), 0.92 (s, 9 H), 0.84 (s, 9 H), 0.05 (s, 6 H), 0.03 (s, 3 H), –0.14
Methyl-7,13-bis(tert-butyldimethylsilyloxy)-9-hydroxy-6,12-di-
methyl-14-phenyltetradeca-2,4,10-trienoate [14b, 7,9-syn (9R)]: Pre-
pared by following General Procedure 5b. Flash chromatography:
96:4 hexane/EtOAc. Yield: 132 mg (66% yield by 1H NMR) of a
mixture of inseparable 9-epimeric products and unreacted 5, dr
[7,9-anti (9S)/7,9-syn (9R)] = 86:14. Rf = 0.32 (85:15 hexane/
EtOAc). HRMS (ESI): calcd. for C35H60O5Si2Na [M + Na]+
639.38715; found 639.38812.
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.9 (C0), 147.4
(CH), 145.4 (CH), 145.3 (C0), 133.2 (CH), 132.2 (CH), 128.3 (CH),
127.8 (CH), 126.7 (CH), 126.2 (CH), 115.7 (CH), 80.7 (CH), 72.7
(CH), 64.5 (CH), 51.1 (CH3), 44.2 (CH), 42.7 (CH), 39.7 (CH2),
36.2 (CH), 26.3 (CH3), 25.9 (CH3), 20.1 (CH3), 18.5 (C0), 18.1
(CH3), 18.0 (C0), 14.6 (CH3), –3.2 (CH3), –4.0 (CH3), –4.5 (CH3),
–4.6 (CH3) ppm. HRMS (ESI): calcd. for C36H62O5Si2Na [M +
Na]+ 653.40280; found 653.40322. Data for 14c 7,9-syn (9R): Rf =
0.45 (85:15 hexane/EtOAc). [α]3D0 = +8.0 (c = 0.21 CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.34–7.20 (m, 6 H), 6.49 (t, J =
11.3 Hz, 1 H), 5.94 (dd, J = 15.5, 8.3 Hz, 1 H), 5.57 (d, J = 11.3 Hz,
1 H), 5.46 (t, J = 10.6 Hz, 1 H), 5.30 (dd, J = 11.1, 8.4 Hz, 1 H),
3.84 (t, J = 7.9 Hz, 1 H), 3.78–3.69 (m, 2 H), 3.73 (s, 3 H), 2.78
(m, 1 H), 2.37 (m, 2 H), 1.86 (br. s, 1 H), 1.56 (m, 1 H), 1.25 (d, J
= 7.0 Hz, 3 H), 1.24–1.21 (m, 1 H), 1.03 (d, J = 6.8 Hz, 3 H), 0.94
(s, 9 H), 0.89 (s, 9 H), 0.81 (d, J = 7.0 Hz, 3 H), 0.07 (s, 3 H), 0.06
(s, 3 H), 0.05 (s, 3 H), 0.00 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 166.6 (C0), 146.8 (CH), 145.7 (C0), 145.5 (CH), 132.8
(CH), 131.9 (CH), 128.4 (CH), 128.1 (CH), 127.0 (CH), 126.2
(CH), 115.4 (CH), 80.5 (CH), 73.9 (CH), 65.8 (CH), 51.0 (CH3),
45.0 (CH), 41.8 (CH), 41.3 (CH2), 35.9 (CH), 26.3 (CH3), 25.8
(CH3), 20.0 (CH3), 19.9 (CH3), 18.5 (C0), 18.0 (C0), 15.7 (CH3),
–3.2 (CH3), –3.6 (CH3), –4.4 (CH3), –4.4 (CH3) ppm. HRMS (ESI):
calcd. for C36H62O5Si2Na [M + Na]+ 653.40280; found 653.40313.
(R,2Z,4E)-Methyl-6-[(4S,6S)-6-{(3R,4S,Z)-4-hydroxy-3-methyl-
5-phenylpent-1-enyl}-2,2-dimethyl-1,3-dioxan-4-yl]hepta-2,4-di-
enoate [15b, 7,9-anti (9S)] and (R,4E)-Methyl-6-[(4S,6R)-6-
{(3R,4S,Z)-4-hydroxy-3-methyl-5-phenylpent-1-enyl}-2,2-dimethyl-
1,3-dioxan-4-yl]hepta-2,4-dienoate [15b, 7,9-syn (9R)]: Prepared by
following General Procedure 6. Flash chromatography: 95:5
CH2Cl2/EtOAc. Yield: 69 mg (95%) of 9-epimeric products. Data
for 15b 7,9-anti (9S): Rf = 0.18 (95:5 CH2Cl2/EtOAc). [α]2D6 = –112.7
1
(c = 1.02 CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.39 (dd, J
= 15.4, 11.3 Hz, 1 H), 7.32–7.20 (m, 5 H), 6.56 (t, J = 11.3 Hz, 1
H), 6.09 (dd, J = 15.5, 7.7 Hz, 1 H), 5.61 (d, J = 11.3 Hz, 1 H),
5.56–5.47 (m, 2 H), 4.51 (dd, J = 15.5, 6.5 Hz, 1 H), 3.76 (m, 1 H),
3.72 (s, 3 H), 3.62 (m, 1 H), 2.89 (dd, J = 13.8, 3.5 Hz, 1 H, AB
system), 2.65 (dd, J = 13.8, 8.3 Hz, 1 H, AB system), 2.55 (m, 1
H), 2.41 (m, 1 H), 2.12 (br. s, 1 H), 1.77–1.63 (m, 2 H), 1.33 (s, 3
H), 1.31 (s, 3 H), 1.08 (d, J = 5.8 Hz, 3 H), 1.06 (d, J = 6.2 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.9 (C0), 146.9 (CH), (R,2Z,4E)-Methyl-6-[(4S,6S)-6-{(3S,4S,5S,Z)-4-hydroxy-3-methyl-
145.5 (CH), 138.7 (C0), 134.7 (CH), 131.4 (CH), 129.5 (CH), 128.3 5-phenylhex-1-enyl}-2,2-dimethyl-1,3-dioxan-4-yl]hepta-2,4-dienoate
(CH), 126.9 (CH), 126.2 (CH), 115.6 (CH), 100.5 (C0), 75.3 (CH),
[15c, 7,9-anti (9S)]: Prepared by following General Procedure 6.
69.6 (CH), 63.2 (CH), 51.0 (CH3), 41.6 (CH), 40.9 (CH2), 37.9 Flash chromatography: 8:2 hexane/EtOAc. Yield: 16 mg (98%). Rf
(CH), 36.5 (CH2), 25.1 (CH3), 24.4 (CH3), 17.7 (CH3), 15.6 (CH3)
ppm. HRMS (ESI): calcd. for C26H36O5Na [M + Na]+ 451.24550;
found 451.24505. Data for 15b 7,9-syn (9R): Rf = 0.10 (95:5
CH2Cl2/EtOAc). [α]2D6 = –31.4 (c = 0.70 CH2Cl2). 1H NMR
= 0.48 (1:1 hexane/EtOAc). [α]2D6 = –45.1 (c = 0.71 CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 7.41 (dd, J = 15.5, 11.3 Hz, 1 H),
7.30–7.16 (m, 5 H), 6.60 (t, J = 11.4 Hz, 1 H), 6.08 (dd, J = 15.5,
7.7 Hz, 1 H), 5.63 (d, J = 11.3 Hz, 1 H), 5.60–5.44 (m, 2 H), 4.21
(400 MHz, CDCl3): δ = 7.40 (dd, J = 15.6, 11.4 Hz, 1 H), 7.35– (dd, J = 15.0, 8.5 Hz, 1 H), 3.73 (s, 3 H), 3.69 (m, 1 H), 3.52 (t, J
7.24 (m, 5 H), 6.61 (t, J = 11.3 Hz, 1 H), 6.14 (dd, J = 15.5, 7.7 Hz, = 5.9 Hz, 1 H), 2.80 (p, J = 6.9 Hz, 1 H), 2.50 (m, 1 H), 2.40 (m,
1 H), 5.63 (d, J = 11.3 Hz, 1 H), 5.55–5.48 (m, 2 H), 4.58 (m, 1 1 H), 1.68–1.54 (m, 3 H), 1.30 (d, J = 6.9 Hz, 3 H), 1.30 (s, 3 H),
H), 3.79 (m, 1 H), 3.74 (s, 3 H), 3.65 (m, 1 H), 2.90 (dd, J = 13.8,
1.23 (s, 3 H), 1.06 (d, J = 6.9 Hz, 3 H), 1.04 (d, J = 6.9 Hz, 3 H)
3.4 Hz, 1 H, AB system), 2.69–2.61 (m, 2 H), 2.42 (m, 1 H), 1.71 ppm. 13C NMR (100 MHz, CDCl3): δ = 166.9 (C0), 147.1 (CH),
(br. s, 1 H), 1.45 (s, 3 H), 1.41 (s, 3 H), 1.38–1.35 (m, 2 H), 1.13 145.5 (CH), 144.8 (C0), 134.5 (CH), 130.9 (CH), 128.4 (CH), 127.7
(d, J = 6.7 Hz, 3 H), 1.09 (t, J = 6.2 Hz, 3 H) ppm. 13C NMR
(CH), 126.9 (CH), 126.4 (CH), 115.6 (CH), 100.4 (C0), 79.1 (CH),
(100 MHz, CDCl3): δ = 166.9 (C0), 146.9 (CH), 145.6 (CH), 138.6 69.7 (CH), 63.2 (CH), 51.1 (CH3), 42.9 (CH), 41.4 (CH), 36.2
(C0), 134.4 (CH), 131.6 (CH), 129.4 (CH), 128.5 (CH), 126.8 (CH),
126.5 (CH), 115.5 (CH), 98.6 (C0), 75.6 (CH), 71.9 (CH), 65.6
(CH2), 35.7 (CH), 24.8 (CH3), 24.4 (CH3), 18.2 (CH3), 16.2 (CH3),
15.6 (CH3) ppm. HRMS (ESI): calcd. for C27H38O5Na [M + Na]+
(CH), 51.1 (CH3), 41.9 (CH), 40.7 (CH2), 38.2 (CH), 34.2 (CH2), 465.26115; found 465.26058.
Eur. J. Org. Chem. 2012, 144–153
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
151

A. Ambrosi, L. Pignataro, C. Zanato, C. Gennari
FULL PAPER
(R,4E)-Methyl-6-[(4S,6R)-6-{(3S,4S,5S,Z)-4-hydroxy-3-methyl-
5-phenylhex-1-enyl}-2,2-dimethyl-1,3-dioxan-4-yl]hepta-2,4-dienoate
[15c, 7,9-syn (9R)]: Prepared by following General Procedure 6.
Flash chromatography: 8:2 hexane/EtOAc. Yield: 19 mg (99%). Rf
= 0.53 (1:1 hexane/EtOAc). [α]2D6 = +49.7 (c = 0.60 CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 7.37 (dd, J = 15.5, 11.3 Hz, 1 H),
7.31–7.26 (m, 4 H), 7.21–7.17 (m, 1 H), 6.58 (t, J = 11.3 Hz, 1 H),
6.11 (dd, J = 15.5, 7.8 Hz, 1 H), 5.60 (d, J = 11.3 Hz, 1 H), 5.49–
5.42 (m, 2 H), 4.47 (m, 1 H), 3.76 (m, 1 H), 3.72 (s, 3 H), 3.42 (t,
J = 5.1 Hz, 1 H), 2.89 (m, 1 H), 2.52 (m, 1 H), 2.46 (br. s, 1 H),
2.39 (m, 1 H), 1.46 (s, 3 H), 1.41 (s, 3 H), 1.38–1.34 (m, 2 H), 1.28
(d, J = 7.0 Hz, 3 H), 1.07 (d, J = 6.9 Hz, 3 H), 1.01 (d, J = 6.7 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.0 (C0), 146.8
(CH), 145.6 (CH), 145.6 (C0), 135.4 (CH), 131.3 (CH), 128.2 (CH),
127.9 (CH), 126.8 (CH), 126.1 (CH), 115.5 (CH), 98.8 (C0), 78.2
(CH), 71.9 (CH), 65.2 (CH), 51.1 (CH3), 41.8 (CH), 36.4 (CH),
34.2 (CH2), 30.1 (CH3), 19.7 (CH3), 18.2 (CH3), 15.5 (CH3), 14.6
(CH3) ppm. HRMS (ESI): calcd. for C27H38O5Na [M + Na]+
465.26115; found 465.26127.
24.9 (CH3), 24.3 (CH3), 19.1 (CH3), 18.2 (CH3), 15.5 (CH3) ppm.
HRMS (ESI): calcd. for C27H38O5Na [M + Na]+ 465.26115; found
465.26067.
(R,4E)-Methyl-6-[(4S,6R)-6-{(3R,4R,5S,Z)-4-hydroxy-3-methyl-
5-phenylhex-1-enyl}-2,2-dimethyl-1,3-dioxan-4-yl]hepta-2,4-dienoate
[15d, 7,9-syn (9R)]: Prepared by following General Procedure 6.
Flash chromatography: 8:2 hexane/EtOAc. Yield: 3.0 mg (100%).
1
Rf = 0.56 (1:1 hexane/EtOAc). [α]2D7 = –7.6 (c = 0.21 CH2Cl2). H
NMR (400 MHz, CDCl3): δ = 7.37 (dd, J = 15.5, 11.3 Hz, 1 H),
7.31–7.21 (m, 5 H), 6.58 (t, J = 11.3 Hz, 1 H), 6.11 (dd, J = 15.5,
7.8 Hz, 1 H), 5.61 (d, J = 11.3 Hz, 1 H), 5.54–5.43 (m, 2 H), 4.35
(dd, J = 13.7, 7.6 Hz, 1 H), 3.72 (s, 3 H), 3.66 (dt, J = 8.0, 5.2 Hz,
1 H), 3.45 (t, J = 6.0 Hz, 1 H), 2.83 (m, 1 H), 2.53 (m, 1 H), 2.38
(m, 1 H), 1.40 (s, 3 H), 1.33 (d, J = 6.7 Hz, 3 H), 1.33–1.28 (m, 2
H), 1.30 (s, 3 H), 1.08 (d, J = 6.7 Hz, 3 H), 1.07 (d, J = 6.9 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 167.0 (C0), 146.9 (CH),
145.6 (CH), 143.1 (C0), 134.0 (CH), 131.9 (CH), 128.6 (CH), 128.3
(CH), 126.8 (CH), 126.6 (CH), 115.5 (CH), 98.6 (C0), 78.5 (CH),
71.9 (CH), 65.6 (CH), 51.1 (CH3), 42.7 (CH), 41.9 (CH), 36.0 (CH),
34.2 (CH2), 30.1 (CH3), 19.5 (CH3), 19.1 (CH3), 18.0 (CH3), 15.6
(CH3) ppm. HRMS (ESI): calcd. for C27H38O5Na [M + Na]+
465.26115; found 465.26066.
(2Z,4E,6R,7S,9S,10Z,12R,13R,14S)-Methyl-7,13-bis(tert-butyl-
dimethylsilyloxy)-9-hydroxy-6,12-dimethyl-14-phenylpentadeca-
2,4,10-trienoate [14d, 7,9-anti (9S)] and (2Z,4E,6R,7S,9R,10Z,
12R,13R,14S)-Methyl-7,13-bis(tert-butyldimethylsilyloxy)-9-
hydroxy-6,12-dimethyl-14-phenylpentadeca-2,4,10-trienoate [14d,
7,9-syn (9R)]: Prepared by following General Procedure 5b. Flash
chromatography: 96:4 hexane/EtOAc. Yield: 62 mg (75% yield by
1H NMR) of 9-epimeric products, dr [7,9-anti (9S)/7,9-syn (9R)] =
88:12. Data for 14d 7,9-anti (9S): Rf = 0.36 (85:15 hexane/EtOAc).
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of all new compounds; chiral HPLC
and GC chromatograms and conditions.
Acknowledgments
1
[α]3D0 = –20.5 (c = 0.40 CHCl3). H NMR (400 MHz, CDCl3): δ =
7.36 (dd, J = 15.3, 11.4 Hz, 1 H), 7.29–7.17 (m, 5 H), 6.54 (t, J =
11.3 Hz, 1 H), 6.01 (dd, J = 15.4, 7.6 Hz, 1 H), 5.68–5.58 (m, 2 H),
5.35 (m, 1 H), 4.48 (t, J = 8.2 Hz, 1 H), 3.89 (m, 1 H), 3.73 (s, 3
H), 3.71 (m, 1 H), 2.87 (m, 1 H), 2.64 (m, 1 H), 2.54 (dd, J = 12.3,
6.4 Hz, 1 H), 1.80 (br. s, 1 H), 1.58–1.40 (m, 2 H), 1.25 (d, J =
6.9 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.88 (s, 9 H), 0.87 (s, 9 H),
0.85 (d, J = 7.1 Hz, 3 H), 0.07 (s, 3 H), 0.06 (s, 3 H), 0.02 (s, 3 H),
–0.35 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.9 (C0),
147.2 (CH), 145.4 (CH), 144.9 (C0), 133.2 (CH), 131.6 (CH), 128.5
(CH), 128.2 (CH), 126.8 (CH), 126.3 (CH), 115.6 (CH), 80.5 (CH),
72.6 (CH), 64.3 (CH), 51.1 (CH3), 45.3 (CH), 42.9 (CH), 40.8
(CH2), 35.3 (CH), 26.2 (CH3), 25.8 (CH3), 20.3 (CH3), 18.4 (C0),
18.0 (C0), 17.2 (CH3), 14.6 (CH3), –3.9 (CH3), –4.4 (CH3), –4.5
(CH3), –4.8 (CH3) ppm. HRMS (ESI): calcd. for C36H62O5Si2Na
[M + Na]+ 653.40280; found 653.40352. Data for 14d 7,9-syn (9R):
the product could not be completely separated from unreacted 5.
Rf = 0.40 (85:15 hexane/EtOAc). HRMS (ESI): calcd. for C36H62O-
5Si2Na [M + Na]+ 653.40280; found 653.40437.
We thank the Ministero dell’Università e della Ricerca (MIUR)
for financial support (PRIN project 2008J4YNJY) and for a PhD
fellowship (Borsa di dottorato, Progetto giovani to C.Z.). L.P.
thanks Milan University for a postdoctoral fellowship (Assegno di
ricerca).
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(R,2Z,4E)-Methyl-6-[(4S,6S)-6-{(3R,4R,5S,Z)-4-hydroxy-3-methyl-
5-phenylhex-1-enyl}-2,2-dimethyl-1,3-dioxan-4-yl]hepta-2,4-dienoate
[15d, 7,9-anti (9S)]: Prepared by following General Procedure 6.
Flash chromatography: 8:2 hexane/EtOAc. Yield: 19 mg (100%).
Rf = 0.65 (1:1 hexane/EtOAc). [α]2D7 = –72.7 (c = 0.59 CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 7.34 (dd, J = 15.5, 11.3 Hz, 1 H),
7.27–7.17 (m, 5 H), 6.52 (t, J = 11.4 Hz, 1 H), 6.04 (dd, J = 15.5,
7.7 Hz, 1 H), 5.58–5.43 (m, 3 H), 4.38 (dd, J = 15.3, 7.8 Hz, 1 H),
3.71–3.65 (m, 1 H), 3.69 (s, 3 H), 3.41 (t, J = 6.1 Hz, 1 H), 2.80
(m, 1 H), 2.47 (m, 1 H), 2.36 (m, 1 H), 1.77 (br. s, 1 H), 1.62 (m,
2 H), 1.27 (d, J = 7.0 Hz, 3 H), 1.27 (s, 3 H), 1.17 (s, 3 H), 1.02 (d,
J = 6.8 Hz, 3 H), 1.00 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 166.9 (C0), 146.9 (CH), 145.5 (CH), 143.4
(C0), 134.5 (CH), 130.9 (CH), 128.6 (CH), 128.4 (CH), 126.8 (CH),
126.5 (CH), 115.5 (CH), 100.5 (C0), 78.6 (CH), 69.6 (CH), 63.0
(CH), 51.1 (CH3), 42.8 (CH), 41.5 (CH), 36.5 (CH2), 35.7 (CH),
[8] The lithium vinylzincate (derived from 3) coupling reaction to
5 was repeated five times: we could improve the yield (up to
40%), but did not observe any variation of the diastereomeric
ratio. The crude reaction mixtures were carefully analyzed for
the identification and isolation (flash chromatography) of the
1,3-syn and 1,3-anti diastereomers, see the experimental pro-
cedure reported in ref.[6] Although the assessment of yields and
diastereomeric ratios by weight determination of small samples
(5–50 mg) collected from flash chromatography fractions of
complex reaction mixtures is an inherently inaccurate pro-
cedure (see: M. Wernerova, T. Hudlicky, Synlett 2010, 2701–
2707), the experimental evidence gathered in our laboratory
(including the starting materials/reaction products mass bal-
ance) is sufficiently precise to prove that the 1,3-syn dia-
stereomer is selectively formed in this reaction.
[9] P. V. Ramachandran, A. Srivastava, D. Hazra, Org. Lett. 2007,
9, 157–160.
152
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 144–153

Stereoselectivity in (Z)-Vinylmetal Additions to C1–C9 β-Silyloxy Aldehyde
[10]
evant 13C NMR chemical shifts: in syn-1,3-diol acetonides,
CH3 signals should be observed at 30.0 and 19.6 ppm, and the
quaternary C signal at 98.5 ppm; in anti-1,3-diol acetonides,
CH3 signals occur at 24.6 ppm, and the quaternary C signal at
100.6 ppm.
W.-H. Jung, C. Harrison, Y. Shin, J.-H. Fournier, R. Balachan-
dran, B. S. Raccor, R. P. Sikorski, A. Vogt, D. P. Curran, B. W.
Day, J. Med. Chem. 2007, 50, 2951–2966.
W.-H. Jung, PhD Thesis, University of Pittsburgh, 2008, http://
etd.library.pitt.edu/ETD/available/etd-03252008–125826/.
W. Zhu, M. Jiménez, W.-H. Jung, D. P. Camarco, R. Balachan-
dran, A. Vogt, B. W. Day, D. P. Curran, J. Am. Chem. Soc.
2010, 132, 9175–9187.
Y. Tamaru, S. Goto, A. Tanaka, M. Shimizu, M. Kimura, An-
gew. Chem. 1996, 108, 962; Angew. Chem. Int. Ed. Engl. 1996,
35, 878–880.
[11]
[12]
[20] In the case of α-OTBS substituted aldehydes and ketones, the
addition of (Z)-disubstituted vinylzinc reagents has been shown
to proceed by a Cram-chelation mechanism in the presence of
added RZnX, see: G. R. Stanton, C. N. Johnson, P. J. Walsh,
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Received: August 15, 2011
Published Online: November 8, 2011
Eur. J. Org. Chem. 2012, 144–153
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