Titanium(IV)-promoted regioselective nucleophilic ring-opening reaction of chiral epoxyallyl alcohols with acids as a tool for ready access to chiral 1,2,3-triol monoesters: Application to stereoselective total synthesis of macrolides

Article abstract of DOI:10.1021/jo202199g

Titanium(IV)-promoted regioselective ring-opening reaction of chiral epoxy-allyl alcohols (Sharpless conditions as the key strategic step) is developed as a tool for ready access to chiral 5,6-dihydroxyoct-7-en-4-yl alkoxylates. Later, the synthetic utility of products thereof was demonstrated through the RCM based stereoselective synthesis of various natural products.

Full text of DOI:10.1021/jo202199g

Note
pubs.acs.org/joc
Titanium(IV)-Promoted Regioselective Nucleophilic Ring-Opening
Reaction of Chiral Epoxyallyl Alcohols with Acids as a Tool for Ready
Access to Chiral 1,2,3-Triol Monoesters: Application to
Stereoselective Total Synthesis of Macrolides
Palakodety Radha Krishna* and D. Venkata Ramana
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology,
Hyderabad 500607, India
S
* Supporting Information
ABSTRACT: Titanium(IV)-promoted regioselective ring-
opening reaction of chiral epoxy−allyl alcohols (Sharpless
conditions as the key strategic step) is developed as a tool for
ready access to chiral 5,6-dihydroxyoct-7-en-4-yl alkoxylates.
Later, the synthetic utility of products thereof was demon-
strated through the RCM based stereoselective synthesis of
various natural products.
mediated regioselective ring-opening protocol is worth
mentioning.10
he ubiquitous presence of 1,2,3-triol segment in many
biologically active natural products has led to the
development of multiple synthetic strategies. As a consequence,
interest in the structure and biological feature of the polyol
containing macrolides1−6 as appealing synthetic targets
increased manifold (Figure 1).
T
Against this backdrop and mindful of the significance
attached to chiral 1,2,3-triol fragments, we devised a
Sharpless-based strategy of regioselective ring-opening reaction
of internal epoxy alcohols initially with benzoic acid and later
with unsaturated acid nucleophiles (Figure 2) as a new method
of accessing selectively derivatized polyol esters. Additionally, if
these esters (or their precursors) are endowed with
appropriately positioned (terminal) olefinic functional groups,
then they could undergo ring-closing metathesis (RCM) to
furnish a gamut of macrocyles that could be extrapolated to the
targets. Thus, the striking difference of the present disclosure is
the use of internal chiral epoxy allyl alcohol(s) and aliphatic
acid(s) as the nucleophile(s) to afford 1,2,3-triol monoester(s)
as valuable synthetic intermediates in a highly regioselective
manner (a C5-opening).
Accordingly, two enantiomeric epoxides (epoxy allyl alcohols
9 and ent-9, Scheme 1) selected for the study were accessed via
the Sharpless kinetic resolution of the corresponding racemic
divinyl methanol 811 that was in turn obtained from the
oxidation−vinylation reaction set of the commercially available
(E)-2-hexen-1-ol in good yields (for synthesis, see the
Supporting Information).
First, we validated the epoxide ring-opening reaction (9)
using benzoic acid as the nucleophile to afford the
corresponding 1,2,3-triol monoester derivative (in this case as
benzoate 10) as the sole product in good yield, favoring an
exclusive C5-attack (Scheme 1). To recount, the key
transformations are the titanium catalyzed C5-selective ring-
opening reaction of epoxy allyl alcohol 9 with benzoic acid,
Figure 1. Some representative examples of macrolides.
Conventionally 1,2,3-triol-containing molecules are accessed
from carbohydrates via their functional group manipulation,7
but ever since the discovery of Sharpless asymmetric
epoxidation in 1980,8 ring-opening reaction of enantiopure
2,3 epoxy alcohols with various nucleophiles emerged as an
alternate synthetic route to such systems. Interestingly, such a
ring-opening reaction has been extensively studied.9 Of the
many metal assisted intermolecular C3-selective substitution
reactions of 2,3-epoxy alcohols, Sharpless titanium(IV)-
Received: August 10, 2011
Published: December 12, 2011
© 2011 American Chemical Society
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Figure 2. Retrosynthesis of macrolides.
Scheme 1
acetonide furnished the derivatized bis-olefinic ester (15).
Similarly ring-opening reaction of epoxides 9 and ent-9 with
aliphatic olefinic acids 14 and ent-14 gave the respective bis-
olefinic esters 15a−c (see Scheme 3). These esters constitute
the late-stage intermediates in the synthesis of 10-membered
macrolides and some of them (15, 15a and 15b, Scheme 3) are
exemplified herein. Additionally, esters 15, 15a, and 15b were
independently synthesized by route B and their data correlated.
Though many syntheses were reported for the macrolides
listed in Figure 1, synthesis of select macrolides was undertaken
as “proof of concept” (Figure 2). For example, several reported
syntheses of herbarumin I (4), a biologically active natural
product, involved more than 10 steps,7a,12 but using these
sequential reactions 4 was obtained in 5 steps (vide infra,
Scheme 3). The use of the some of these esters as advanced
intermediates is showcased below.
Total synthesis of Herbarumin I and Formal Synthesis
of Stagonolide A. Herbarumin I 4, one of the bioactive
compounds of phytotoxin family was selected as the first target
molecule. Although many reported syntheses adopted chiron
approach, the one disclosed herein utilizes the present
methodology to result in stereoselective synthesis of 4 in five
steps (route A) and 7 steps (route B). Thus, the diene system
(15, Scheme 4) was prepared by two synthetic pathways (route
A, Scheme 3), one through the coupling of 9 with 5-hexenoic
acid in the presence of titanium(IV) complex, followed by
acetonide protection to afford the corresponding diene ester
15, another (route B, Scheme 3) by the conventional coupling
of alcohol (11) with 5-hexenoic acid to afford the same diene
ester 15 in equally good yields.
acetonide protection of the resultant (4R,5S,6S)-5,6-dihydrox-
yoct-7-en-4-yl benzoate (10) followed by its debenzoylation
reaction gave alcohol 11 (83% over two steps). Accordingly, the
synthesis of alcohol 11, identified as the crucial intermediate,
was accomplished by a three-step strategy. With this promising
result in hand the scope of this reaction is investigated.
Having realized that if RCM reaction could be used in
conjunction with this methodology an array of macrolides
could be synthesized in shorter sequence, next we turned our
attention to using aliphatic olefinic acids (hexenoic acid, 14 and
Scheme 2. Preparation of Acid Components
The crucial RCM of 15 using Grubbs-I catalyst furnished
macrolide 16 as an exclusive E-isomer in 76% yield. Macrolide
16 on TiCl4-mediated deprotection of the acetonide group
resulted in herbarumin I12 (4, 74%). Herbarumin I 4 itself
constitutes a late-stage intermediate in the synthesis of
stagonolide A 3. For instance, selective oxidation of allyl
alcohol 4 affords 3.13
Total Synthesis of Herbarumin II.14 The RCM of 15a
(Scheme 4) using Grubbs II catalyst gave macrolide 17 as the
Z-isomer in 88% yield. However, the corresponding major E-
isomer (16a) was obtained by Grubbs I catalyst albeit resulting
in a inseparable mixture of starting material 15a and macrolide
16a (80% combined yield). Hence, global deprotection of the
mixture with TiCl4 resulted in the isolation of herbarumin II14
(5, 56%) as a pure product.
Formal Synthesis of (+)-Lethaloxin. Similarly, RCM of
15b (Scheme 5) using Grubbs I catalyst afforded E-isomer 16b.
Later, debenzylation under DDQ reaction conditions resulted
in macrolide 18 (54%), which is a known intermediate in the
synthesis (+)-lethaloxin (7). Thus, synthesis of macrolide 18
constitutes the formal total synthesis of (+)-lethaloxin.15
ent-14, Scheme 2) as the nucleophiles in the ring-opening
reaction.
Accordingly, when epoxide 9 was treated with 5-hexenoic
acid under the standardized conditions (route A) gave the
corrresponding bis-olefinic ester, which on protection as
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a
Scheme 3. Preparation of Diene Esters under Different Routes
a
Reaction conditions: (route A) Ti(OiPr)4, CH2Cl2, corresponding acid, 0 °C to rt (Sharpless conditions); (route B) DCC, DMAP, CH2Cl2,
corresponding acid, 0 °C to rt.
Scheme 4. Synthesis of Macrolides
Scheme 5. Synthesis of (+) -Lethaloxin
cally the transformation described herein opens up new vistas
and shorter way of accessing building blocks that are commonly
encountered as part structures in many biologically active
natural products.
EXPERIMENTAL SECTION
■
CONCLUSION
■
General Experimental Procedures. All the reactions were
carried under nitrogen atmosphere (all except those involving water
in the reaction medium). The solvents used were purified by
distillation over the drying agents indicated and were transferred
under nitrogen atmosphere: CH2Cl2 (CaH2), Et3N (KOH), toluene
(Na), THF, and ether were dried by distillation from sodium using
sodium benzophenone ketyl as indicator. All organic extracts were
dried over anhydrous Na2SO4, All crude reaction products were
In summary, we have accomplished a titanium(IV) promoted
regioselective oxirane ring-opening reaction of chiral epoxy allyl
alcohols as a tool for the ready access to chiral 1,2,3-triol
monoesters. Further, the synthetic utility of such esters was
exemplified by the enantioselective total synthesis of bioactive
10-membered macrolides in shorter sequences. Thus, strategi-
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purified by column chromatography silica gel (60−120 mesh and
100−200 mesh) by using distilled ethyl acetate and petroleum ether.
1H NMR spectra were recorded at 300, 400, and 500 MHz (using
mixture was allowed to warm to room temperature and allowed to stir
for 2 h. The CH2Cl2 was evaporated under reduced pressure, the
mixture was diluted with diethyl ether (30 mL), and 3% H2SO4 (10
mL) was added, and the mixture was allowed to stir until two clear
layers were obtaine(1 h). The two layers were separated. The organic
layer was washed with a saturated aq solution of brine (20 mL) and
NaHCO3 (30 mL), dried (Na2SO4), and concentrated in vacuo. In
order to overcome the difficulty of separation of diol from the reaction
mixture and to check if the regioselective ring-opening of epoxy
alcohol favored the formation of 1,2-diols or 1,3-diols, the crude diol
was taken to the next step and protected as its acetonide derivative.
To a stirred solution of crude diol (3.9 g, 14.7 mmol) in CH2Cl2
(30 mL) at 0 °C was added PTSA (cat.) and the solution stirred for 20
min, and then 2,2-DMP (3.6 mL, 29.5 mmol) was added and the
solution stirred for ∼2 h. The reaction mixture was quenched with
Et3N (2.0 mL) and concentrated in vacuo. The crude residue was
purified by column chromatography (EtOAc/n-hexane 1:99) to obtain
the pure compound 10 (3.6 g, 83%) as a colorless liquid. [α]D25 = +20.6
(c 0.005, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.95 (d, 2H, J = 6.7
Hz), 7.52 (t, 1H, J = 7.5 Hz), 7.40 (t, 2H, J = 7.9 Hz), 5.78 (td, 1H, J =
7.1, 10.5, 17.3 Hz), 5.24 (d, 1H, J = 16.9 Hz), 5.13−5.05 (m, 2H), 4.62
(dd, 1H, J = 6.4, 13.5 Hz), 4.29 (dd, 1H, J = 6.4, 7.9 Hz), 1.85−1.67
(m, 2H), 1.45−1.34 (m, 2H), 0.93 (t, 3H, J = 7.1 Hz). 13C NMR (75
MHz, CDCl3): δ 175.8, 132.9, 132.8, 129.5, 128.3, 118.6, 108.8, 78.9,
78.4, 72.4, 33.5, 27.6, 25.2, 17.9, 14.0. IR (neat): 3448, 2962, 1720,
1069 cm−1. HRMS: m/z calcd for C18H24O4Na [M + Na]+ 327.1572,
found 327.1576.
(1R)-1-[(4R,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]butan-1-ol
(11). To a stirred solution of benzoate 10 (1.7 g, 5.5 mmol) in MeOH
was added K2CO3 (1.54 g, 11.5 mmol) and the solution stirred for 2 h.
Then MeOH was removed in vacuo, and the mixture was filtered
through Celite pad, washed with EtOAc (4 × 10 mL), concentrated in
vacuo, and then purified by column chromatography (EtOAc/n-
hexane 12:88) to obtain the pure compound 11 (1.0 g, 90%) as a
colorless liquid. [α]D25 = +9.0 (c 0.05, CHCl3). The spectral data was
matched with reported values.16
II). Synthesis of Acid Components. (i). (5R)-5-(Benzyloxy)-6-
[(4-methoxybenzyl)oxy]-1-hexene (12).17 A stirred suspension of Mg
(0.74 g, 30.8 mmol) in dry ether was treated with allyl chloride (1.67
mL, 20.5 mmol) at room temperature, the mixture was stirred for 30
min and allowed to cool to −20 °C, (2S)-2-[(benzyloxy)methyl]-
oxirane (2.0 g, 10.3 mmol) in ether (15 mL) was added dropwise at
−20 °C, the reaction mixture was allowed to stir for 30 min, and then
the reaction mixture was quenched with a saturated aq solution of
NH4Cl (10 mL) and extracted with diethyl ether (3 × 10 mL). The
combined organic layers were washed with brine (20 mL), dried
(Na2SO4), and concentrated in vacuo. Crude alcohol was directly used
for the next step.
TMS as a reference), and C13 were recorded at 75 and 100 MHz
(using the CDCl3 triplet centered at δ 77.0 Hz as reference) in CDCl3
as solvent at ambient temperature. Chemical shifts (δ) were recorded
in ppm, coupling constant J are in Hz, and signal patterns are indicated
as follows: s, singlet; d, doublet; dd, doublet of doublet; td, triplet of
doublet; t, triplet; m, multiplet; bs, broad singlet. FTIR spectra were
recorded as KBr thin films or neat. Optical rotations were measured at
25 °C. For low (MS) and high (HRMS) resolution, m/z ratios are
reported as values in atomic mass units.
I). Synthesis of Epoxyallyl Alcohol Components. (4E)-1,4-
Octadien-3-ol (8). DMSO (5.0 mL), in CH2Cl2 (60 mL) was added to
IBX (2.28 g, 8.1 mmol) at 0 °C followed by the addition of trans-2-
hexenol (5.0 g, 6.8 mmol) at 0 °C and allowed to stir for 1 h. The
crude reaction mixture was filtered through a Celite pad and washed
with CH2Cl2 (5 × 5.0 mL). The organic layer was washed with water
(2 × 10 mL) and brine (15 mL), dried (Na2SO4), and concentrated
under reduced pressure. The crude residue was directly used for the
next step. The crude aldehyde was taken in THF (100 mL), then
vinylmagnesium bromide (56 mL of 1 M solution) was added
dropwise at −20 °C, and the reaction mixture was allowed to stir for
15 min. The reaction mixture was quenched with a saturated aq
solution of NH4Cl (10 mL) and extracted with EtOAc (2 × 20 mL),
and the combined organic layers were washed with brine (50 mL),
dried (Na2SO4), and concentrated in vacuo. The crude residue was
purified by column chromatography (EtOAc/n-hexane 1:99) to afford
1
pure alcohol 8 (4.5 g, 71%) as a light yellow syrup. H NMR (400
MHz, CDCl3): δ 5.89−5.81 (m, 1H), 5.69−5.60 (m, 1H), 5.49−5.43
(dd, 1H, J = 6.5, 5.4 Hz), 5.2 (dd, 1H, J = 1.09, 17.2 Hz), 5.0 (d, 1H, J
= 10.2 Hz), 4.54−4.53 (br. s, 1H), 2.02 (q, 2H, J = 6.5 Hz), 1.40 (q,
2H, J = 7.3 Hz), 0.91 (t, 3H, J = 7.3 Hz). 13C NMR (100 MHz,
CDCl3): δ 139.8, 132.5, 131.0, 114.5, 73.7, 34.2, 22.1, 13.5. Anal. Calcd
for C8H14O (126.18) C, 76.14; H, 11.18. Found: C, 76.10; H, 11.12.
(1S)-1-[(2S,3S)-3-Propyloxiran-2-yl]-2-propen-1-ol (9). In a dried
two-necked round-bottom flask, 4 Å evacuated molecular sieves
powder (3.0 g) was taken, and then CH2Cl2 (100 mL) was added. The
solution was allowed to cool to −20 °C, and then Ti(OiPr)4 (11.33
mL, 39.6 mmol) and L-(+)-DIPT (11.15 g, 47.5 mmol) were added
sequentially, the mixture was allowed to stir for 10 min, and TBHP
(5.92 mL, 48.6 mmol, 3 M in CH2Cl2) was added dropwise for 15
min. After the mixture was stirred for 20 min at −20 °C, a solution of
allyl alcohol 8 (5.0 g, 39.68 mmol) in CH2Cl2 (15 mL) was added to
the reaction mixture and allowed it to stir for 18 h at the same
temperature (Sharpless kinetic resolution). Reaction mixture was
quenched by adding NaOH (2.5 g) in brine solution (25 mL) and
stirred at rt. The reaction mixture was filtered through Celite pad,
washed with EtOAc (4 × 15 mL), dried (Na2SO4), and concentrated
under reduced pressure. The residue was purified by column
chromatography (EtOAc/n-hexane 4:96) to obtain pure epoxy alcohol
9 (2.24 g, 40%) as a colorless liquid. [α]D25 = +17.0 (c 0.008, CHCl3).
1H NMR (400 MHz, CDCl3): δ 5.81 (sept, 1H, J = 5.8, 10.2 Hz), 5.33
(d, 1H, J = 17.5 Hz), 5.23 (d, 1H, J = 10.6 Hz), 4.26 (s, 1H), 2.94 (s,
1H), 2.77 (s, 1H), 1.59−1.42 (m, 4H), 0.97 (t, 3H, J = 6.9 Hz). 13C
NMR (75 MHz, CDCl3): δ 135.7, 117.2, 70.1, 60.0, 54.9, 33.4, 19.1,
13.0; IR (neat): 3427, 3084, 2962, 2872, 1382, 1079 cm−1. Anal. Calcd
for C8H14O2 (142.20): C, 67.57; H, 9.92. Found: C, 67.55; H, 9.89.
(1R)-1-[(2R,3R)-3-Propyloxiran-2-yl]-2-propen-1-ol (ent-9). Here-
in, the same procedure was adopted as described for compound 9.
Allyl alcohol 8 (1 g, 7.9 mmol), Ti(OiPr)4 (2.25 mL, 7.9 mmol), D-
(−)-DIPT (2.23 g, 9.5 mmol), TBHP (1.0 mL, 3.17 mmol, 3 M in
CH2Cl2). The residue was purified by column chromatography
(EtOAc/n-hexane 4:96) to obtain the pure epoxy alcohol ent-9
(0.42 g, 38%) as a colorless liquid. [α]D25 = −22.0 (c 0.007, CHCl3).
(1R)-1-[(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]butyl Ben-
zoate (10). To a stirred solution of epoxy allyl alcohol 9 (2.1 g, 14.7
mmol) in dry CH2Cl2 (30 mL) was added Ti(OiPr)4 (6.33 mL, 22.1
mmol) under argon (Sharpless conditions). The mixture was stirred
for 15 min, benzoic acid (2.7 g, 22.1 mmol) was added, and the
To a cooled (0 °C) suspension of NaH (0.81 g, 20.4 mmol, 60% w/
w dispersion in paraffin oil) in THF (15 mL) was added dropwise a
solution of alcohol (2.5 g, 10.3 mmol) in THF (10 mL). After 15 min,
benzyl bromide (1.63 mL, 13.3 mmol) was added dropwise at 0 °C
and the mixture allowed to stir for 6 h at room temperature. The
reaction mixture was quenched with a satd aq solution of NH4Cl (10
mL) and extracted with EtOAc (2 × 10 mL). The combined organic
layers were washed with water (100 mL) and brine (50 mL), dried
(Na2SO4), and concentrated in vacuo. The crude product was purified
by column chromatography (EtOAc/n-hexane 3:97) to afford
compound 12 (2.7 g, 80.3% in overall yield for two steps) as a light
1
yellow syrup. [α]D25 = +5.2 (c 0.15, CHCl3). H NMR (300 MHz,
CDCl3): δ 7.29−7.18 (m, 7H), 6.82 (d, 2H, J = 8.3 Hz), 5.81−5.67
(m, 1H), 4.97−4.89 (m, 2H), 4.67 (d, 1H, J = 11.7 Hz), 4.48 (d, 1H, J
= 11.8 Hz), 4.43 (s, 2H), 3.79 (s, 3H), 3.56−3.40 (m, 3H), 2.21−2.02
(m, 2H), 1.62 (q, 2H, J = 6.5 Hz). 13C NMR (75 MHz, CDCl3): δ
163.7, 143.4, 143.0, 135.0, 133.8, 132.8, 132.3, 132.0, 119.2, 118.3,
82.0, 81.6, 81.2, 59.8, 35.8, 34.2. HRMS: m/z calcd for C21H26O3Na
[M + Na]+ 349.1779, found 349.1774.
(ii). (2R)-2-(Benzyloxy)-5-hexen-1-ol (13). To a stirred solution of
compound 12 (2.60 g, 7.9 mmol) in CH2Cl2/H2O (19:1) (25 mL)
was added DDQ (2.17 g, 9.5 mmol) at 0 °C, and the reaction mixture
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was allowed to stir at room temperature for 1 h. Then satd aq
NaHCO3 (10 mL) was added and the mixture extracted with CH2Cl2
(2 × 20 mL). The combined organic layers were washed with water
(30 mL) and brine (20 mL), dried (Na2SO4), and concentrated in
vacuo, and the crude residue was purified by column chromatography
(EtOAc/n-hexane 10:90) to afford alcohol 13 (1.45 g, 88%) as a light
protection. The crude residue was purified by column chromatography
(EtOAc/:n-hexane 1.5:98.5) to obtain pure compound 15a (0.159 g,
54%) as a colorless liquid.
Route B. Alcohol 11 (0.05 g, 0.25 mmol), DCC (0.056 g, 0.27
mmol) and DMAP (0.033 g, 0.27 mmol), acid ent-14 (0.06 g, 0.27
mmol). The crude residue was purified by column chromatography
(EtOAc/n-hexane 1.5:98.5) to obtain pure compound 15a (0.086 g,
yellow syrup. [α]D25 = −16.2 (c 0.16, CHCl3). H NMR (500 MHz,
1
1
82%) as a colorless liquid. [α]D25 = +4.3 (c 0.03, CHCl3). H NMR
CDCl3): δ 7.33−7.25 (m, 5H), 5.82−5.70 (m, 1H), 4.96 (dd, 2H, J =
9.8, 18.2 Hz), 4.58 (d, 1H, J = 11.9 Hz), 4.54 (d, 1H, J = 11.9 Hz),
3.69−3.66 (m, 1H), 3.50−3.48 (m, 2H), 2.11 (dd, 2H, J = 6.7, 14.0
Hz), 1.76−1.69 (m, 2H), 1.62−1.55 (m, 1H). 13C NMR (75 MHz,
CDCl3): δ 138.3, 138.1, 128.4, 127.7, 114.9, 79.0, 71.5, 64.0, 30.0, 29.5.
HRMS: m/z calcd for C13H18O2Na [M + Na]+ 229.1204, found
229.1201.
(iii). (2R)-2-(Benzyloxy)-5-hexenoic Acid (14). DMSO (2.0 mL) in
EtOAc (20 mL) was added to IBX (2.28 g, 8.1 mmol) at 0 °C,
followed by the addition of alcohol 13 (1.4 g, 6.8 mmol) at 0 °C, and
allowed to reflux for 1 h.5 The crude reaction mixture was filtered and
washed with EtOAc (2 × 10 mL). The organic layer was washed with
water (2 × 10 mL) and brine (15 mL), dried (Na2SO4), and
concentrated under reduced pressure. The crude residue was purified
by column chromatography (EtOAc/n-hexane 18:82) to afford acid 15
(1.25 g, 83%) as a colorless liquid. [α]D25 = +23.3 (c 0.45, CHCl3). 1H
NMR (500 MHz, CDCl3): δ 7.32−7.26 (m, 5H), 5.80−5.68 (m, 1H),
4.97 (dd, 2H, J = 10.7, 17.0 Hz), 4.71 (d, 1H, J = 11.7 Hz), 4.41 (d,
1H, J = 11.7 Hz), 3.96 (dd, 1H, J = 6.3, 5.8 Hz), 2.27−2.14 (m, 2H),
1.90 (q, 2H, J = 7.3 Hz). 13C NMR (75 MHz, CDCl3): δ 177.8, 137.1,
130.0, 128.4, 128.1, 128.0, 115.6, 76.6, 72.5, 31.7, 29.1. IR (neat):
3071, 2925, 1109, 1024, 914 cm−1. HRMS: m/z calcd for C13H16O3Na
[M + Na]+ 243.0997, found 243.0992.
(500 MHz, CDCl3): δ 7.33−7.21 (m, 5H), 5.84−5.68 (m, 2H), 5.33
(d, 1H, J = 17.1 Hz), 5.21 (d, 1H, J = 10.3 Hz), 5.0−4.93 (m, 3H),
4.66 (d, 1H, J = 11.3 Hz), 4.53 (t, 1H, J = 6.7 Hz), 4.31 (d, 1H, J =
11.5 Hz), 4.15 (t, 1H, J = 6.9 Hz), 3.8 (dd, 1H, J = 5.1, 7.5 Hz), 2.25−
2.07 (m, 2H), 1.85−1.58 (m, 2H), 0.94 (t, 3H, J = 7.1 Hz). 13C NMR
(75 MHz, CDCl3): δ 169.5, 137.0, 132.6, 128.3, 128.2, 128, 127.9,
109.9, 78.6, 77.6, 74.5, 73.4, 71.4, 43.3, 35.7, 32.4, 28.0, 22.8, 18.0,
14.1. IR (neat): 3021, 2925, 1725 cm−1. HRMS: m/z calcd for
C24H34O5Na [M + Na]+ 425.2303, found 425.2301.
(1R)-1-[(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]butyl (2S)-
2-(Benzyloxy)-5-hexenoate (15b). Route A. The same procedure was
adopted as described for compound 10.
Epoxy allyl alcohol 9 (0.1 g, 0.70 mmol), Ti(OiPr)4 (0.3 mL, 1
mmol) acid ent-14 (0.185 g, 0.84 mmol), followed by acetonide
protection. The crude residue was purified by column chromatography
(EtOAc/n-hexane 1.5:98.5) to obtain pure compound 15b (0.144 g,
49%) as a colorless liquid.
Route B. Alcohol 11 (0.05 g, 0.25 mmol), DCC (0.056 g, 0.27
mmol) and DMAP (0.033 g, 0.27 mmol), acid ent-14 (0.06 g, 0.27
mmol). The crude residue was purified by column chromatography
(EtOAc:n-hexane 1.5:98.5) to obtain pure compound 15b (0.075 g,
72%) as a colorless liquid. [α]D25 = +65.4 (c 0.006, CHCl3). H NMR
1
(500 MHz, CDCl3): δ 7.37−7.17 (m, 5H), 5.83−5.67 (m, 2H), 5.32
(d, 1H, J = 16.7 Hz), 5.17 (d, 1H, J = 10.3 Hz), 5.0−4.94 (m, 3H),
4.66 (d, 1H, J = 11.5 Hz), 4.56 (t, 1H, J = 6.7 Hz), 4.29 (d, 1H, J =
11.5 Hz), 4.15 (t, 1H, J = 7.1 Hz), 3.82 (dd, 1H, J = 5.9, 6.3 Hz), 2.17
(q, 2H, J = 7.1 Hz), 1.80 (q, 2H, J = 7.1 Hz), 1.72−1.59 (m, 2H), 1.46
(br. s, 2H), 1.35 (br. s, 6H), 0.92 (t, 3H, J = 7.1 Hz). 13C NMR (75
MHz, CDCl3): δ 171.3, 137.3, 133.1, 128.4, 127.9, 118.6, 115.5, 108.8,
96.1, 78.7, 78.0, 77.1, 72.3, 33.3, 32.1, 29.5, 27.6, 25.3, 17.8, 14.1. IR
(neat): 3012, 2923, 1728, 1025 cm−1. HRMS: m/z calcd for
C24H34O5Na [M + Na]+ 425.2303, found 425.2295.
(iv). (5S)-5-(Benzyloxy)-6-[(4-methoxybenzyl)oxy]-1-hexene (ent-
12). NaH (0.56 g, 23.3 mmol, 60% w/w dispersion in paraffin oil) was
added to the alcohol (1.7 g, 7.2 mmol) followed by benzyl bromide
(1.14 mL, 9.3 mmol). After completion of the reaction, the crude
product was purified by column chromatography (EtOAc/n-hexane
3:97) to afford compound ent-12 (1.3 g, 82% overall yield for two
steps) as a light yellow syrup. [α]D25 = −2.9 (c 0.12, CHCl3).
(v). (2S)-2-(Benzyloxy)-5-hexen-1-ol (ent-13). To compound ent-
12 (1.3 g, 3.9 mmol), DDQ (1.08 g, 4.7 mmol) was added and the
crude product was purified by column chromatography (EtOAc:n-
hexane 10:90) to afford compound ent-13 (0.720 g, 87%) as a light
yellow syrup. [α]D25 = +25.4 (c 0.1, CHCl3).
(vi). (2S)-2-(Benzyloxy)-5-hexenoic Acid (ent-14). The same
procedure was adopted as described for compound 14. IBX (0.7 g,
3.39 mmol), alcohol ent-13 (1.14 g, 4.0 mmol). The crude product was
purified by column chromatography (EtOAc:n-hexane 15:85) to afford
compound ent-14 (0.55 g, 73%) as a light yellow syrup. [α]D25 = −22.2
(c 0.9, CHCl3).
(1S)-1-[(4R,5R)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]butyl (2R)-
2-(Benzyloxy)-5-hexenoate (15c). Route A. The same procedure was
adopted as described for compound 10.
Epoxy allyl alcohol 9 (0.100 g, 0.70 mmol), Ti(OiPr)4 (0.3 mL, 1
mmol) acid 14 (0.185 g, 0.84 mmol), followed by acetonide
protection. The crude residue was purified by column chromatography
(EtOAc/n-hexane 1.5:98.5) to obtain pure compound 15c (0.159 g,
1
54%) as a colorless liquid. [α]D25 = −83.3 (c 0.003, CHCl3). H NMR
(300 MHz, CDCl3): δ 7.35−7.22 (m, 5H), 5.86−5.66 (m, 2H), 5.32
(d, 1H, J = 17.3 Hz), 5.16 (d, 1H, J = 10.5 Hz), 4.99−4.93 (m, 3H),
4.68 (d, 1H, J = 11.3 Hz), 4.56 (t, 1H, J = 6.7 Hz), 4.28 (d, 1H, J =
11.3 Hz), 4.14 (dd, 1H, J = 6.4, 7.5 Hz), 3.82 (t, 1H, J = 6.4 Hz),
2.20−2.14 (m, 2H), 1.78 (q, 2H, J = 7.5 Hz), 1.71−1.58 (m, 2H), 1.46
(br. s, 2H), 1.35 (d, 6H, J = 7.1 Hz), 0.92 (t, 3H, J = 7.1 Hz). 13C
NMR (75 MHz, CDCl3): δ 171.7, 137.3, 137.2, 133.0, 128.3, 127.9,
127.8, 118.7, 115.4, 109.0, 78.7, 77.9, 77.1, 72.2, 72.2, 33.2, 32.1, 29.4,
27.5, 25.2, 17.8, 14.0. IR (neat): 3125, 2921, 1724, 1063 cm−1. HRMS:
m/z calcd for C24H34O5Na [M + Na]+ 425.2303, found 425.2299.
Synthesis of Herbarumin I. Macrolide (16). To a solution of
bis-olefin 15 (0.130 g, 0.43 mmol) in CH2Cl2 (120 mL) was added
Grubbs' first-generation catalyst (0.03 g, 10 mol %) and the mixture
allowed to stir at reflux for 18 h. The solvent was removed in vacuo,
and the crude residue was purified by column chromatography
(EtOAc/n-hexane 1:99) to afford macrolide 16 (0.090 g, 76%) as a
light yellow liquid. [α]D25 = +90.0 (c 0.05, CHCl3): The spectral data
was matched with reported values.18
III). Examples of Regioselective Ring-Opening Reaction of
Chiral Epoxyallyl Alcohols. (1R)-1-[(4S,5S)-2,2-Dimethyl-5-vinyl-
1,3-dioxolan-4-yl]butyl 5-Hexenoate (15). Route A. The same
procedure was adopted as described for compound 10.
Epoxy allyl alcohol 9 (0.100 g, 0.70 mmol), Ti(OiPr)4 (0.3 mL, 1
mmol), and commercially available 5-hexenoic acid (0.096 g, 0.84
mmol), followed by the acetonide protection. The crude residue was
purified by column chromatography (EtOAc/n-hexane 1:99) to obtain
pure compound 15 (0.135 g, 65%) as a colorless liquid.
Route B. To a stirred solution of alcohol 11 (0.05 g, 0.35 mmol) in
CH2Cl2 (2.0 mL) was added DCC (0.056 g, 0.27 mmol) and DMAP
(0.033 g, 0.27 mmol) at 0 °C, followed by 5-hexenoic acid (0.034 g,
0.29 mmol) was added at same temperature and allowed to stirr for 3
h, and the crude residue was purified by column chromatography
(EtOAc/n-hexane 1:99) to obtain pure compound 15 (0.058 g, 79%)
as a colorless liquid. [α]D25 = +18.9 (c 0.08, CHCl3). The spectral data
was matched with reported values.18
(1R)-1-[(4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl]butyl (2R)-
2-(Benzyloxy)-5-hexenoate (15a). Route A. The same procedure was
adopted as described for compound 10.
Herbarumin I (4). To a cooled solution of lactone 16 (0.070 g, 0.37
mmol) in CH2Cl2 was added TiCl4 (10 mol % in CH2Cl2), and
allowed to stir for 30 min. The reaction mixture was neutralized with a
saturated aq solution of NaHCO3 (3 mL) and extracted with EtOAc
Epoxy allyl alcohol 9 (0.100 g, 0.70 mmol), Ti(OiPr)4 (0.3 mL, 1
mmol) acid 14 (0.185 g, 0.84 mmol), followed by acetonide
678
dx.doi.org/10.1021/jo202199g | J. Org. Chem. 2012, 77, 674−679

The Journal of Organic Chemistry
Note
(4 × 5 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The residue was purified by column
chromatography (EtOAc/n-hexane 20:80) to afford the title
compound 4 (0.039 g, 74%) as a colorless syrup. [α]D25 = +33.0 (c
0.02, CHCl3). The spectral data was matched with reported values.18
Synthesis of Herbarumin II. Macrolide 16a. To a solution of
bis-olefin 15a (0.100 g, 0.37 mmol) in toluene (100 mL) was added
Grubbs’ first-generation catalyst (0.03 g, 10 mol %) and the mixture
allowed to stir for 36 h at reflux. The solvent was removed under
reduced pressure, and the crude residue was purified by column
chromatography (EtOAc/hexane 1:99) to afford macrolide 16a
(mixed with some unreacted starting material). We were not able to
isolate the pure trans-isomer due to little Rf difference between starting
material 15a (unreacted) and the product 16a. In order to overcome
this difficulty, we proceeded to the next step (global deprotection of
acetonide and benzyl ether groups) to afford the pure trans-isomer.
Macrolide (17). To a solution of bis-olefin 15a (0.100 g, 0.37
mmol) in dry toluene (100 mL) was added Grubbs' second-generation
catalyst (0.03 g, 10 mol %) and the mixture allowed to stir at reflux
temperature for 2 h. The solvent was removed under reduced pressure,
and the crude residue was purified by column chromatography
(EtOAc/n-hexane 2:98) to afford macrolide 17 (0.082 g, 88%) as a
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11.4 Hz), 4.13 (dd, 1H, J = 6.2, 9.8 Hz), 3.74 (q, 1H, J = 10.4 Hz),
2.21−2.14 (m, 2H), 1.85−1.74 (m, 2H), 1.65−1.58 (m, 1H), 1.45−
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Herbarumin II (5). To a cooled solution of macrolide 16a (0.080 g,
0.37 mmol) in CH2Cl2 was added TiCl4 (15 mol % in CH2Cl2) and
the mixture allowed to stir for 2 h. The reaction mixture was
neutralized with a saturated aq solution of NaHCO3 (10 mL) and
extracted with EtOAc (4 × 5 mL). The combined organic layers were
dried (Na2SO4) and evaporated, and the residue was purified by
column chromatography (EtOAc:n-hexane 35:65) to afford the title
compound 5 (0.028 g, 56%) as light yellow crystals. [α]D25 = +42.0 (c
0.06, CHCl3). The spectral data was matched with reported values.19
Formal Synthesis of (+)-Lethaloxin. Macrolide (18). To a
stirred solution of bis-olefin 15b (0.110 g, 0.37 mmol) in toluene (100
mL) was added Grubbs' first-generation catalyst (0.03 g, 10 mol %)
and the mixtrue allowed to stir at reflux temperature for 36 h, solvent
was removed under reduced pressure, and the crude residue was
purified by column chromatography (EtOAc/n-hexane 1:99) to afford
macrolide 16b (mixed with some unreacted starting material). The
same problem was encountered in the isolation of ring-closed product,
as observed in the case of herbarumin II. Since the scenario is similar
to the previous case, we proceeded to the next step, i.e., deprotection
of benzyl ether group under standard conditions, to afford the trans-
isomer 18 (0.042 g, 54%). [α]D25 = +72.8 (c 0.05, CHCl3). The spectral
data was matched with reported values.15
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ASSOCIATED CONTENT
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S
* Supporting Information
(16) Furstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.; Lehmann,
̈
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
C. W.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061−7069.
(17) Yadav, J. S.; Swamy, T.; Subba Reddy, B. V. Synlett 2008, 2773−
2776.
AUTHOR INFORMATION
Corresponding Author
*Fax: +914027160387. E-mail: prkgenius@iict.res.in.
(18) (a) Furstner, A.; Radkowski, K. Chem. Commun. 2001, 671−
̈
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672. (b) Sabino, A. A.; Pilli, R. Tetrahedron Lett. 2002, 43, 2819−2821.
(c) Kamal, A.; Venkat Reddy, P.; Prabhaker, S. Tetrahedron: Asymmetry
2009, 20, 1120−1124.
(19) Elena, D.; Dixon, D. J.; Ley, S. V.; Polara, A. Synlett 2003,
1186−1188.
ACKNOWLEDGMENTS
D.V.R. thanks the CSIR, New Delhi, for financial support in the
form of a fellowship.
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