Synthetic studies on the nhatrangins: Stereoselective access to an advanced aldehyde intermediate

Article abstract of DOI:10.1002/ejoc.201201338

Two different strategies have been considered to achieve the first total synthesis of nhatrangins A and B. The first approach based on a cross metathesis (CM) reaction was unsuccessful. The second, which combined a highly stereoselective alkylation, a diastereoselective aldolization, and finally an esterification, furnished an advanced aldehyde intermediate bearing the three contiguous stereogenic centres and the expected side-chain. Two strategies have been considered for the stereoselective synthesis of nhatrangins A and B. A sequence involving diastereoselective alkylation and aldolization employing ephedrine derivatives as chiral auxiliaries was the most efficient approach to deliver a key aldehyde framework. Copyright

Full text of DOI:10.1002/ejoc.201201338

Job/Unit: O21338
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Date: 16-01-13 11:51:46
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201201338
Synthetic Studies on the Nhatrangins: Stereoselective Access to an Advanced
Aldehyde Intermediate
Ludovic Raffier[a] and Olivier Piva*[a]
Keywords: Synthesis design / Natural products / Metathesis / Aldolization / Diastereoselectivity
Two different strategies have been considered to achieve the
first total synthesis of nhatrangins A and B. The first ap-
proach based on a cross metathesis (CM) reaction was unsuc-
cessful. The second, which combined a highly stereoselective
alkylation, a diastereoselective aldolization, and finally an
esterification, furnished an advanced aldehyde intermediate
bearing the three contiguous stereogenic centres and the ex-
pected side-chain.
These molecules possess a skeleton that is very similar to
the lateral chain of aplysiatoxins 2a,b,[6] oscillatoxins 3[6,7]
and manauealide 4,[8] macrocyclic compounds previously
isolated from other tropical marine algae (Figure 2).
Introduction
Marine cyanobacteria are the source of a large number
of secondary metabolites.[1] Of the known species, Lyngbia
majuscula has been extensively studied and revealed the
presence of natural products with a wide range of structural
diversity and biological activities.[2] Unfortunately, these
molecules are only isolated in amounts too small to permit
in-depth bioassays. Therefore the total synthesis of these
natural products seems to be the only reliable way to obtain
these molecules in reasonable quantities without destruc-
tion of the biotope. This strategy is also very appealing in
terms of access to their analogues for further pharmacolog-
ical studies. In this context, we have already described the
total syntheses of grenadamide[3] and hermitamides A and
B,[4] previously isolated from this genus. Recently, Orjala
and co-workers reported the isolation and structural deter-
mination of two new structures 1a,b, called nhatrangins A
and B, from Lyngbia sp. growing in the Nha Trang Bay in
Vietnam[5] (Figure 1).
Figure 2. Marine natural products similar to nhatrangins.
As a result of their noticeable cytotoxic activities, con-
siderable effort has been devoted to their access, culminat-
ing in the total synthesis of debromoaplysiatoxins and aply-
siatoxin by Kishi and co-workers in 1987.[9] Other groups,
including those of Ireland,[10] Nishiyama and Yama-
mura,[11] Toshima and Ichihara,[12] Walkup[13] and more re-
cently Urpi,[14] have reported the preparation of key frag-
ments. In parallel, Irie and co-workers have also described
the synthesis of an analogue of these compounds and dis-
covered a new synthetic drug that possesses a similar struc-
ture but with significant anti-proliferative activities.[15]
Although only very small amounts of pure compound 1a
were isolated from natural sources (Lyngbia sp.) (0.3 mg
from 2.5 g of extract), we have investigated its total synthe-
sis by using a strategy that could be applied to the synthesis
of structural analogues.
Figure 1. Structures of nhatrangins A and B.
[a] Université de Lyon 1, Institut de Chimie et Biochimie
Moléculaire et Supramoléculaire (ICBMS), UMR 5246 CNRS,
Bat. Raulin, 43, Bd. du 11 Novembre 1918, 69622 Villeurbanne
Cedex, France
E-mail: piva@univ-lyon1.fr
Homepage: http://surcoof.univ-lyon1.fr/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201338.
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FULL PAPER
alcohol 10, which was directly etherified with methyl iodide
under basic conditions to yield 7a. The key metathesis step
between the hindered β-aldol 6 and ether 7a was carried
out under a wide range of conditions in the presence of
Hoveyda–Grubbs (HG) catalyst (Scheme 3, Table 1). Un-
fortunately, in all cases, β-aldol 6 was recovered mostly un-
changed along with the homoallylic ether dimerization
product. An unsymmetrical bis-ether structure 7c resulting
from isomerization of the terminal double bond[22] followed
by subsequent CM was also detected. To favour the cross-
coupling reaction, homodimer 7b was selectively prepared
from 7a in the presence of Grubbs type I reagent. Per-
formed in the presence of the HG catalyst, the reaction be-
tween 6 and 7b furnished the expected cross-coupling prod-
uct 5 in a yield no better than 30%. Surprisingly, even with
7b as the coupling partner, the formation of 7c was still
observed, which demonstrates the low reactivity of 6 in the
metathesis processes.
Results and Discussion
Since the discovery of powerful catalysts that tolerate a
large number of functional groups, metathesis has become
a very efficient process for preparing highly substituted alk-
enes. In our first approach to 1a, we decided to take advan-
tage of a cross-metathesis reaction[16] between two readily
accessible subunits to construct the C1–C7 chain directly.
This strategy is depicted in Scheme 1. It was anticipated
that control of the configuration of the carbon atom bear-
ing the hydroxy group and the selective formation of the E
isomer of 5 could favour stereocontrol of the reductive step
and the creation of the third contiguous centre.[17]
Scheme 1. First synthetic approach to nhatrangin A.
First, γ,δ-unsaturated β-aldol 6 and homoallylic methyl
ether 7a were prepared according to well-established asym-
metric methods (Scheme 2).
Scheme 3. Cross-metathesis reactions between 6 and 7a or 7b.
Attempts to totally suppress this side-reaction by the ad-
dition of 2,6-DCBQ were unsuccessful.[23] To improve the
yield of 5, conditions recently advocated by Mauduit and
Grela and their co-workers were tested.[24,25] However, the
reaction performed in the presence of the catalyst M2 in a
perfluorinated solvent such as perfluorotoluene and under
microwave activation unfortunately led to a very low con-
version of 6, even after prolonged microwave irradiation.
The low reactivity of 6 in the metathesis reaction led us
to reconsider our initial strategy. We did not explore other
alternatives as processes involving a relay, which could be
Scheme 2. Synthesis of synthons 6 and 7a.
The aldolization reaction between the readily available more successful, but required major transformation of the
oxazolidinone 8 and methacrolein in the presence of magne- β-aldol starting material. Moreover, the use of a silyl tether
sium
chloride,
sodium
hexafluoroantimony,
and was also not considered; it was anticipated that the two sec-
TMSCl[18,19] furnished, after acid treatment, the desired ondary hydroxy groups implicated in such a linkage would
trans aldol product 9 in 73% yield. After removal of the be difficult to differentiate afterwards. We decided to con-
chiral auxiliary by smooth, epimerization-free methanolysis, centrate our efforts on the synthesis of aldehyde 11, a key
ester 6 was isolated in 81% yield.[20] Enantioselective allyl- structure that could give access to both 1a and 1b.
ation of m-anisaldehyde under the well-established condi-
The crucial control of the three contiguous stereogenic
tions of Brown[21] delivered the corresponding homoallylic centres was expected to be realized by a highly stereocon-
2
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Nhatrangins: Stereoselective Access to an Aldehyde Intermediate
Table 1. Results of the cross-metathesis reactions between 6 and 7a or 7b under various conditions.
Catalyst
Conditions
7a or 7b
5/6[a] (Yield [%])[b]
HG (5%)
DCM, reflux, 12 h
toluene, reflux, 5 h
toluene, reflux, 36 h
DCM, UV, 100 °C, 1 h 30 + 2 h
toluene, UV, 100 °C, 2 h
toluene, reflux, 6 h
7a (2 equiv.)
7a (1.5 equiv.)
7a (1.5 equiv.)
7a (1.5 equiv.)
7a (1.5 equiv.)
7b (1 equiv.)
7b (1 equiv.)
7b (1 equiv.)
7b (1 equiv.)
0:100
12:88
19:81
15:85
HG (20%)
HG (2ϫ5%)
HG (5 + 10%)
HG (5%)
HG (5%)
HG (2ϫ5%)
HG (5%)
10:90
24:76 (20%)
41:59 (30%)
5:95
toluene, reflux, 3 h
toluene, reflux, 4 h, 2,6-DCBQ (10%)[c]
CF3C6F5, UV, 120 °C, 2ϫ20 min
M2 (2ϫ2%)
17:83
[a] Ratio determined by NMR analysis of the crude mixture. [b] Yield of pure 5 isolated by flash chromatography. [c] Additive used to
prevent C=C bond isomerization.
trolled aldolization reaction (Scheme 4). Furthermore, the
introduction of the aryl moiety at a very late stage of the
synthesis has two advantages. First, the synthesis of both
nhatrangins A and B, which differ only in the presence of
one bromine atom, could be facilitated. Moreover, the in-
troduction of the presumably highly sensitive benzylic
methoxy group could be achieved in the very last sequence
before cleavage of the protecting groups used throughout
the synthesis.
Scheme 5. Synthesis of the lateral acid chain 17.
with Dess–Martin periodinane (DMP). The key aldol-
ization step was then conducted with a chiral propionate
derivative using Abiko’s conditions.[30] This process, known
to deliver mainly trans-β-aldol derivatives, was achieved in
a very high yield and significant diastereoselectivity (dr =
85:15).
Saponification of 25 afforded β-hydroxy acid 26 in 70%
Scheme 4. Second approach to nhatrangins A and B.
yield, which was then selectively protected as a methyl ester
First, the lateral acid chain was prepared from easily (27) by treatment with trimethylsilyldiazomethane in meth-
available alcohol 12. The sequence is summarized in anol.[31] At this stage, the minor diastereomer was discarded
Scheme 5. After protection as a TBDPS ether, the (E)-al- during the purification by flash chromatography. To avoid
kene was enantioselectively dihydroxylated[26] with AD-mix additional protection/deprotection steps, the free hydroxy
β with a selectivity of 27:1, as determined by HPLC. The group was esterified with the pentanoic acid side-chain 17.
resulting diol 14 was protected as a ketal. Orthogonal de- The conventional procedure performed with 1,3-dicyclo-
protection of the silyl ether was quantitatively achieved with hexylcarbodiimide (DCC) and 4-dimethylaminopyridine
TBAF. Primary alcohol 16 was first oxidized to the corre- (DMAP)[32] delivered ester 28 in 90% yield. Deprotection
sponding aldehyde, which was readily transformed into the of the silyl ether followed by oxidation of the primary
expected acid 17 by a Lindgren–Pinnick–Krause reac- alcohol furnished key aldehyde 11 in quantitative yield.
tion.[27]
To complete the synthesis, the regioselective 1,2-addition
The synthesis of key fragment 11 started from 1,3-prop- of aryl metal reagents was considered. With a preformed
anediol, which was monoprotected and then converted in aryllithium derivative, extensive degradation of the starting
a single step into the primary iodo derivative (Scheme 6). maand also the possible β-elimination of the lateral acid
This compound was then used in a highly diastereoselective chain could explain this result (Scheme 7). Consequently,
Myers-type alkylation.[28] As noted in the crude NMR spec- we next chose diarylzinc derivatives as less basic species,
trum, the selectivity was better than 95%. Removal of the which are usually more selective in 1,2-addition onto alde-
chiral auxiliary was easily achieved by reduction with the hydes.[33] In the case of success, this approach could be
borane·ammonia complex by an epimerization-free favourably extended to an enantioselective reaction by using
method.[29] The resulting alcohol 22 was efficiently oxidized β-amino alcohols as external chiral entities, the stereogenic
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centres present in nhatrangins A and B. Although our first
approach based on a cross-metathesis reaction failed, prob-
ably for steric reasons, the strategy involving diastereoselec-
tive alkylation and aldolization both induced by ephedrine
derivatives, was successful. Work is now underway to study
the selective addition of an aryl metal derivative onto the
aldehyde moiety with a view to then completing the total
synthesis of the two target molecules.
Experimental Section
General: 1H and 13C NMR spectra were recorded in CDCl3 as sol-
vent with Bruker ALS 300 MHz, 400 MHz and 500 MHz spec-
trometers at ambient temperature. The chemical shifts (δ) are given
in ppm, coupling constant (J)are in Hz. The chemical shifts are
reported in ppm upfield from TMS as internal standard and signal
patterns are indicated as follows: s, singlet; d, doublet; dd, doublet
of doublets; dt, doublet of triplets; t, triplet; m, multiplet, br. s,
broad singlet, sext.d sextuplet of doublets. HRMS analyses were
conducted with a Bruker MicroTOF-QII spectrometer. Optical ro-
tations were measured with a digital polarimeter using a 5 mL cell
with a 1 dm path length. IR spectra were measured with a Perkin–
Elmer Spectrum One FT-IR spectrometer. TLC analyses were per-
formed on precoated silica plates (layer thickness 0.25 mm) and
visualized by UV, phosphomolybdic acid or p-anisaldehyde solu-
tion. Column chromatography was performed on silica gel (40–
63 μm) using technical-grade ethyl acetate (EtOAc) and petroleum
ether (EP). When appropriate, solvents and reagents were dried by
distillation over an appropriate drying agent prior to use. Diethyl
ether and tetrahydrofuran (THF) were distilled from Na/benzo-
phenone and used fresh. Dichloromethane was distilled from
CaH2. All the reactions were performed under nitrogen in flame-
or oven-dried glassware with magnetic stirring. M2 catalyst was
purchased from Oméga Cat System.
β-Aldol 9: Triethylamine (4.47 mL, 32.18 mmol), methacrolein 90%
(1.78 mL, 21.45 mmol) and TMSCl (3.06 mL, 24.13 mmol) were
added to a solution of 8 (3.75 g, 16.09 mmol), magnesium chloride
(153 mg, 1.61 mmol) and NaSbF6 (1.25 g, 4.83 mmol) in EtOAc
(35 mL) under nitrogen. The reaction mixture was stirred at room
temp. for 45 h, but complete conversion was only observed after
adding more methacrolein (0.6 mL, 7.23 mmol) and TMSCl (1 mL,
7.89 mmol) and stirring for a further 24 h. The mixture was filtered
through a short pad of silica then washed with diethyl ether. The
filtrate was concentrated under vacuum and taken up in methanol
(70 mL). Three drops of TFA were added and the resulting reaction
mixture was stirred at room temp. Chromatography afforded com-
pound 8 (2.98 g, 9.18 mmol) as a colourless oil in 78% yield. 1H
NMR (300 MHz, CDCl3): δ = 7.76–7.63 (m, 4 H), 7.49–7.33 (m, 6
H), 5.53–5.37 (m, 2 H), 3.66 (t, J = 6.8 Hz, 2 H), 2.31–2.17 (m, 2
H), 1.63 (d, J = 4.7 Hz, 3 H), 1.04 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 135.7, 134.2, 129.6, 127.8, 127.7, 127.1, 64.2,
36.2, 27.0, 19.4, 18.2 ppm. The spectral data are in accordance with
the literature.[34]
Scheme 6. Synthesis of key aldehyde 11.
centres present in the substrates presumably being too far
from the prochiral centre to expect a significant induction.
Unfortunately, no conversion was noted, even after a long
reaction time.
Compound 6: A 5 °C precooled 0.5 m solution of MeONa in meth-
anol (1.8 mL, 0.90 mmol) was slowly added to a solution of 9
(261 mg, 0.86 mmol) in dry DCM (5 mL) at –25 °C under nitrogen.
The reaction mixture was stirred for 30 min at –25 °C and then
Amberlite IR-120 was added. The resulting mixture was stirred for
another 15 min and the resin was then removed by filtration. The
filtrate was concentrated under vacuum and the residue purified
Scheme 7. First attempts at the 1,2-addition of aryl metals to alde-
hyde 11.
Conclusions
We have achieved the stereoselective synthesis of a highly
functionalized fragment bearing the three contiguous by silica gel flash chromatography. Elution with PE/Et2O (50:50)
4
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Nhatrangins: Stereoselective Access to an Aldehyde Intermediate
afforded compound 6 (110 mg, 0.70 mmol) as a colourless oil in
81% yield. [α]D = +0.3 (c = 1.0, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 4.98 (dq, J = 1.6, 0.9 Hz, 1 H), 4.94 (qt, J = 1.6 Hz,
1 H), 4.15 (d, J = 8.2 Hz, 1 H), 3.72 (s, 3 H); 2.68 (dq, J = 8.2,
7.2 Hz, 1 H), 1.99 (br. s, 1 H), 1.73 (dd, J = 1.6, 0.9 Hz, 3 H), 1.11
(d, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 176.3,
144.4, 114.0, 78.0, 51.8, 43.1, 16.7, 14.3 ppm. HRMS (ESI): calcd.
for [M + Na]+ 181.0835; found 181.0839.
3.20–3.19 (m, 6 H), 2.52–2.41 (m, 2 H), 2.36–2.26 (m, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 159.7, 143.6, 143.5, 129.3, 129.2,
128.6, 127.3, 119.3, 119.2, 113.0, 112.9, 112.0, 111.9, 83.9, 83.6,
56.6, 55.2, 41.3, 36.0 ppm. HRMS (ESI): calcd. for [M + Na]+
379.1880; found 379.1880.
Compound 5: Grubbs–Hoveyda catalyst (7 mg, 11.0 μmol) was
added to a solution of 6 (35 mg, 0.22 mmol) and 7b (115 mg,
0.32 mmol) in toluene. The reaction mixture was heated at reflux
for 3 h. A second portion of the catalyst was added (7 mg,
11.0 μmol) and the mixture was heated for a further 3 h. A third
portion of catalyst was added (3.5 mg, 5.5 μmol) and again the mix-
ture was heated for a further 3 h. The solvent was then removed
under vacuum and the crude product was purified by silica gel flash
chromatography. Elution with PE/EtOAc (70:30) afforded com-
pound 5 (21 mg, 65.1 μmol) as a pale-brown oil in 30% yield. [α]D
= –8.8 (c = 0.2, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.24 (t,
J = 7.7 Hz, 1 H), 6.86–6.79 (m, 3 H), 5.41 (t, J = 6.9 Hz, 1 H),
4.11 (t, J = 6.9 Hz, 1 H), 4.05 (d, J = 9.3 Hz, 1 H), 3.80 (s, 3 H),
3.70 (s, 3 H), 3.21 (s, 3 H), 2.63–2.50 (m, 2 H), 2.43 (dt, J = 14.5,
6.9 Hz, 1 H), 2.34 (br. s, 1 H), 1.49 (d, J = 0.9 Hz, 3 H), 0.86 (d, J
= 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 176.6, 159.9,
143.4, 136.2, 129.5, 125.6, 119.3, 113.1, 112.3, 83.6, 80.1, 56.8, 55.3,
52.0, 43.2, 36.4, 14.3, 10.9 ppm. HRMS (ESI): calcd. for [M +
Na]+ 345.1672; found 345.1666.
Compound 7a: A 1 m solution of allylmagnesium bromide in diethyl
ether (22.03 mL, 22.03 mmol) was added to a solution of (–)-(Ipc)2-
BOMe (6.97 g, 22.03 mmol) in dry diethyl ether (25 mL) at 0 °C
under nitrogen. The reaction mixture was stirred for 1 h and the
solvent was then removed on a vacuum line. The resulting white
solid was washed with pentane (30 mL). A precipitate formed and
the supernatant was transferred through a cannula into another
flask under an inert atmosphere. This operation was repeated three
more times, each time with 15 mL of pentane. The solvent was then
removed on a vacuum line and the residue was solubilized in dry
diethyl ether (20 mL). The solution was cooled to –78 °C and then
transferred through a cannula into a solution of m-anisaldehyde
(2.00 g, 14.69 mmol) in dry diethyl ether (80 mL) at –78 °C under
nitrogen. The reaction mixture was stirred at –78 °C for 30 min and
at room temp. for 1 h. The temperature was lowered to –40 °C and
then methanol (2 mL) was added. The temperature was allowed to
rise to room temp. and was then treated with 1 n NaOH (20 mL)
and a 35% aqueous solution of H2O2 (40 mL). The reaction mix-
ture was stirred at room temp. overnight and the aqueous layer was
then extracted three times with diethyl ether. The combined organic
extracts were washed with brine, dried with MgSO4, filtered and
concentrated under vacuum. Elution with PE/EtOAc (80:20) on sil-
ica gel flash chromatography gave a mixture of the desired product
and a pinene derivative, which was used directly in the next step.
Compound 13: Imidazole (1.61 g, 23.68 mmol) and TBDPSCl (3.39,
13.03 mmol) were added to a solution of (E)-pent-3-en-1-ol (1.02 g,
11.84 mmol) in DMF (60 mL). The reaction mixture was stirred at
room temp. overnight. The reaction mixture was diluted with DCM
and the resulting mixture was extracted three times with 1 n HCl.
The organic layer was dried with MgSO4, filtered and concentrated
under vacuum. The crude product was purified by silica gel flash
chromatography. Elution with PE/EtOAc (90:10) afforded com-
1
pound 13 (2.98 g, 9.18 mmol) as a colourless oil in 78% yield. H
The above mixture was taken up in dry THF (60 mL) and the re-
sulting solution was treated with iodomethane (1.83 mL,
29.38 mmol) and 60% sodium hydride (1.17 g, 29.38 mmol). The
reaction mixture was stirred for 1 h before being quenched with
saturated aqueous NH4Cl. THF was removed under vacuum and
the aqueous layer was extracted three times with DCM. The com-
bined organic extracts were dried with MgSO4, filtered and concen-
trated under vacuum. The crude product was purified by silica gel
flash chromatography. Elution with PE/EtOAc (95:5) afforded
compound 7a (1.74 g, 9.11 mmol) as a colourless oil in 62% yield.
NMR (300 MHz, CDCl3): δ = 7.76–7.63 (m, 4 H), 7.49–7.33 (m, 6
H), 5.53–5.37 (m, 2 H), 3.66 (t, J = 6.8 Hz, 2 H), 2.31–2.17 (m, 2
H), 1.63 (d, J = 4.7 Hz, 3 H), 1.04 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 135.7, 134.2, 129.6, 127.8, 127.7, 127.1, 64.2,
36.2, 27.0, 19.4, 18.2 ppm. The spectral data are similar to those
reported in the literature.[34]
Compound 14: A suspension of AD-mix β (6.47 g) and methane-
sulfonamide (439 mg, 4.62 mmol) in tBuOH/H2O (1:1, 80 mL) was
stirred at room temp. until both phases cleared. The mixture was
cooled to 0 °C and compound 13 (1.5 g, 4.62 mmol) was then
added. The reaction mixture was stirred at 0 °C for 48 h. Sodium
sulfite (6.9 g) was added and the resulting mixture stirred for 1 h.
It was then extracted three times with EtOAc and the combined
organic layers were successively washed with 1 n NaOH and brine.
The organic layer was dried with MgSO4, filtered and concentrated
under vacuum. The crude product was purified by silica gel flash
chromatography. Elution with PE/EtOAc (50:50) afforded com-
pound 14 (1.43 g, 3.99 mmol) as a colourless oil in 86% yield. [α]D
1
[α]D = –47.1 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ =
7.26 (t, J = 8.1 Hz, 1 H), 6.89–6.80 (m, 3 H), 5.77 (ddt, J = 17.1,
10.2, 6.9 Hz, 1 H), 5.06 (ddt, J = 17.1, 2.1, 1.3 Hz, 1 H), 5.03 (ddt,
J = 10.2, 2.1, 1.3 Hz, 1 H), 4.14 (dd, J = 7.5, 5.7 Hz, 1 H), 3.82 (s,
3 H), 3.23 (s, 3 H), 2.55 (dddt, J = 14.2, 7.5, 6.9, 1.3 Hz, 1 H), 2.40
(dddt, J = 14.2, 6.9, 5.7, 1.3 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.8, 143.5, 134.8, 129.4, 119.2, 116.9, 113.1, 112.0,
83.6, 56.7, 55.1, 42.6 ppm. HRMS (ESI): calcd. for [M + Na]+
215.1043; found 215.1040.
1
= –3.3 (c = 1.0, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.71–
Compound 7b: Grubbs’ first-generation catalyst (77 mg, 93.6 μmol)
was added to a solution of 7a (180 mg; 0.94 mmol) in dry DCM
(5 mL). The reaction mixture was heated at reflux under nitrogen
for 6 h, but complete conversion was only observed after adding
more catalyst (38 mg; 47.0 μmol) and stirring for a further 12 h.
The mixture was concentrated under vacuum and the crude prod-
uct was purified by silica gel flash chromatography. Elution with
PE/EtOAc (90:10) afforded compound 7b (120 mg, 0.34 mmol) as
7.64 (m, 4 H), 7.49–7.37 (m, 6 H), 3.89 (dd, J = 6.0, 5.0 Hz, 2 H),
3.71–3.61 (m, 2 H), 2.20 (br. s, 2 H), 1.80–1.65 (m, 2 H), 1.18 (d,
J = 6.0 Hz, 3 H), 1.06 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 135.7, 135.6, 133.0, 132.9, 130.1, 130.0, 128.0, 75.7, 70.8, 62.9,
34.9, 26.9, 19.2, 19.1 ppm. HRMS (ESI): calcd. for [M + Na]+
381.1865; found 381.1860.
Compound 15: 2,2-Dimethoxypropane (0.21 mL, 1.67 mmol) and
PTSA·H2O (21 mg, 0.11 mmol) were added to a solution of 14
(444 mg, 1.23 mmol) in acetone (10 mL) and the reaction mixture
was stirred at room temp. overnight. After being quenched with
1
a pale-brown oil in 72% yield (an E/Z mixture was observed). H
NMR (300 MHz, CDCl3): δ = 7.27–7.21 (m, 2 H), 6.82–6.80 (m, 6
H), 5.44–5.36 (m, 2 H), 4.04 (t, J = 6.6 Hz, 2 H), 3.81 (s, 6 H),
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L. Raffier, O. Piva
1 n NaOH (10 mL), the mixture was extracted three times with aqueous NH4Cl and the aqueous layer was extracted three times
FULL PAPER
DCM. The combined organic extracts were washed with brine,
dried with MgSO4, filtered and concentrated under vacuum to af-
ford compound 15 (485 mg, 1.22 mmol) as a pale-yellow oil in 99%
yield without further purification. [α]D = +7.3 (c = 1.1, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 7.71–7.65 (m, 4 H), 7.44–7.34 (m, 6
H), 3.86–3.77 (m, 2 H), 3.77–3.69 (m, 2 H), 1.85–1.68 (m, 2 H),
1.39 (s, 3 H), 1.35 (s, 3 H), 1.25 (d, J = 5.7 Hz, 3 H), 1.05 (s, 9
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.7, 135.6, 134.0,
133.9, 129.8, 129.7, 127.8, 127.7, 107.8, 79.4, 76.9, 60.8, 35.3, 27.4,
27.3, 27.0, 19.3, 17.4 ppm. HRMS (ESI): calcd. for [M + Na]+
421.2169; found 421.2168.
with EtOAc. The combined organic extracts were dried with
MgSO4, filtered and concentrated under vacuum. The crude prod-
uct was purified by silica gel flash chromatography. Elution with
PE/EtOAc (70:30) afforded compound 21 (3.20 g, 6.19 mmol) as a
viscous colourless oil in 93% yield (a 6:1 mixture of rotamers was
observed). 1H NMR (300 MHz, CDCl3): δ = 7.70 7.61 (m, 4 H),
7.46–7.19 (m, 11 H), 4.60 (d, J = 7.6 Hz, 1 H), 4.37 (br. s, 1 H),
3.64–3.56 (m, 2 H), 2.79 (s, 3 H), 2.64–2.51 (m, 1 H), 1.71–1.59 (m,
1 H), 1.58–1.49 (m, 1 H), 1.49–1.39 (m, 2 H), 1.12 (d, J = 7.0 Hz,
3 H), 1.08 (d, J = 6.7 Hz, 3 H), 1.04 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 179.1, 142.7, 135.7, 135.6, 134.0, 129.7,
129.6, 128.4, 127.7, 127.6, 127.0, 126.3, 77.4, 76.6, 63.7, 36.4, 30.2,
30.1, 27.0, 19.3, 17.4, 14.6 ppm. HRMS (ESI): calcd. for [M +
Na]+ 518.3085; found 518.3088. The spectral data are in accord-
ance with the literature.[35]
Compound 16: A 1 m solution of TBAF in THF (5.98 mL,
5.98 mmol) was added to a solution of 15 (1.59 g, 3.99 mmol) in
dry THF (20 mL). The reaction mixture was stirred at room temp.
for 5 h and was then quenched with aqueous saturated NH4Cl.
The mixture was extracted three times with diethyl ether and the
combined organic layers were dried with MgSO4, filtered and con-
centrated under vacuum. The crude product was purified by silica
gel flash chromatography. Elution with PE/EtOAc (50:50) afforded
compound 16 (635 mg, 3.96 mmol) as a pale-yellow oil in 99%
Compound 22: A 2.4 m solution of nBuLi in hexane (2.06 mL,
4.95 mmol) was added to a solution of diisopropylamine (0.75 mL,
5.33 mmol) in dry THF (5 mL) at –78 °C under nitrogen. The reac-
tion mixture was stirred for 10 min at –78 °C and 10 min at 0 °C.
A 5.1 m solution of 90% BH3·NH3 in dry THF (1 mL, 5.10 mmol)
was then added. The resulting mixture was stirred for 15 min at
1
yield. H NMR (300 MHz, CDCl3): δ = 3.84–3.75 (m, 3 H), 3.68
(td, J = 8.5, 3.3 Hz, 1 H), 2.07 (br. s, 1 H), 1.89–1.79 (m, 1 H), 0 °C and 15 min at room temp. and then cooled back to 0 °C. A
1.77–1.67 (m, 1 H), 1.40 (s, 3 H), 1.39 (s, 3 H), 1.26 (d, J = 5.9 Hz, solution of 21 (660 mg, 1.27 mmol) in dry THF (3 mL) was added
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 108.2, 81.0, 76.8, 60.3,
34.2, 27.3, 27.1, 17.1 ppm. HRMS (ESI): calcd. for [M + Na]+
183.0992; found 183.0987.
and the mixture allowed to warm to room temp. over 4 h with
stirring and was then cooled back to 0 °C. After being quenched
with 1 n HCl, the aqueous layer was extracted three times with
diethyl ether. The combined organic extracts were successfully
washed with 1 n HCl, saturated aqueous NaHCO3 and brine. The
organic layer was dried with MgSO4, filtered and concentrated un-
der vacuum to afford compound 22 (453 mg, 1.27 mmol) in quanti-
tative yield as a colourless oil without further purification. 1H
NMR (300 MHz, CDCl3): δ = 7.69–7.64 (m, 4 H), 7.46–7.34 (m, 6
H), 3.65 (t, J = 6.4 Hz, 2 H), 3.48 (dd, J = 10.5, 5.8 Hz, 1 H), 3.40
(dd, J = 10.5, 6.4 Hz, 1 H), 1.70–1.38 (m, 6 H), 1.05 (s, 9 H), 0.90
(d, J = 6.7 Hz, 3 H) ppm. The spectral data are in accordance with
the literature.[36]
Compound 17: A 0.3 m solution of Dess–Martin periodinane
(10.9 mL, 3.26 mmol) was added to a solution of 16 (475 mg,
2.96 mmol) in dry DCM (10 mL). The reaction mixture was stirred
at room temp. for 1 h 30 min and the solvent was then evaporated
under vacuum. The residue was filtered through a pad of silica and
then washed with PE/EtOAc (50:50). The filtrate was concentrated
under vacuum and the crude product taken up in THF/H2O/
tBuOH (4:4:1 mL). NaH2PO4·H2O (3.27 g, 23.68 mmol), 2-meth-
ylbut-2-ene (3.13 mL, 29.60 mmol) and 80% sodium chlorite
(1.34 g, 11.84 mmol) were then added and the mixture was stirred
at room temp. overnight. THF was removed under vacuum and the
resulting solution was partitioned between DCM and water. The
aqueous layer was acidified with 1 n HCl until pH 3 and then ex-
tracted three times with DCM. The combined organic extracts were
dried with MgSO4, filtered and concentrated under vacuum to af-
ford compound 17 (380 mg, 2.18 mmol) as a pale-yellow oil in 74%
yield without further purification. [α]D = +10.2 (c = 0.5, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 6.0 (br. s, 1 H), 3.95 (ddd, J =
8.2, 6.4, 5.6 Hz, 1 H), 3.83 (dq, J = 8.2, 5.9 Hz, 1 H), 2.62–2.59
Aldehyde 23: 2-Iodoxybenzoic acid (IBX; 471 mg, 1.68 mmol) was
added to a solution of 22 (200 mg, 0.56 mmol) in EtOAc (6 mL).
The mixture was heated at reflux for 3 h. The solid was filtered off
and the filtrate concentrated under vacuum to afford compound 23
(196 mg, 0.55 mmol) in 99% yield as a pale-yellow oil without fur-
ther purification. [α]D = +11.1 (c = 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 9.60 (d, J = 1.9 Hz, 1 H), 7.69–7.62 (m, 4
H), 7.46–7.34 (m, 6 H), 3.70 (t, J = 6.1 Hz, 2 H), 2.33 (sext.d, J =
6.8, 1.9 Hz, 1 H), 1.86–1.73 (m, 1 H), 1.65–1.52 (m, 2 H), 1.52–
(m, 2 H), 1.43 (s, 3 H), 1.40 (s, 3 H), 1.30 (d, J = 5.9 Hz, 3 H) ppm. 1.39 (m, 1 H), 1.08 (d, J = 7.0 Hz, 3 H), 1.05 (s, 9 H) ppm. The
13C NMR (75 MHz, CDCl3): δ = 176.2, 108.8, 78.2, 76.5, 37.5, spectral data are in accordance with the literature.[35]
27.3, 27.0, 17.3 ppm. HRMS (ESI): calcd. for [M + Na]+ 197.0784;
Compound 25: A 1 m solution of (c-hex)2BOTf in hexane (2.49 mL,
2.49 mmol) was added dropwise to a solution of 24 (541 mg,
found 197.0782.
Compound 21: A 1.35 m solution of nBuLi in hexane (10.2 mL,
13.83 mmol) was slowly added to a suspension of LiCl (1.69 g,
1.13 mmol) and triethylamine (0.38 mL, 2.71 mmol) in dry DCM
(5 mL) at –78 °C under nitrogen. The reaction mixture was stirred
39.90 mmol) and diisopropylamine (2.1 mL, 14.96 mmol) in dry for 3 h at –78 °C and a solution of aldehyde 23 (400 mg,
THF (8 mL) under nitrogen at –78 °C. The reaction mixture was
stirred for 30 min at –78 °C and 10 min at 0 °C and was then cooled
1.13 mmol) in dry DCM (1 mL + 1 mL rinse) was added. The re-
sulting mixture was warmed to room temp. over 12 h with stirring.
The reaction was quenched with a pH 7 buffer solution and diluted
in methanol (20 mL). A 35% aqueous solution of H2O2 (5 mL) was
added and the resulting mixture was stirred overnight. The reaction
mixture was partitioned between DCM and water. The organic
layer was washed with water, dried with MgSO4, filtered and con-
centrated under vacuum. Mesitylene was added and the solvent
distilled off to remove residual cyclohexanol. The crude product
back to –78 °C.
A 0 °C precooled solution of 20 (1.47 g,
6.65 mmol) in dry THF (20 mL) was then added under nitrogen.
The mixture was stirred for 1 h at –78 °C, 30 min at 0 °C and
10 min at room temp., and was then cooled back to 0 °C. Com-
pound 19 (3.67 g, 8.65 mmol) was added and the resulting mixture
was allowed to warm to 0 °C to room temp. overnight with stirring.
The mixture was diluted with EtOAc, quenched with saturated
6
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Nhatrangins: Stereoselective Access to an Aldehyde Intermediate
was purified by silica gel flash chromatography. Elution with PE/
(td, J = 7.8, 4.9 Hz, 1 H), 3.76 (dq, J = 7.8, 6.0 Hz, 1 H), 3.66–
EtOAc (80:20) afforded compound 25 (914 mg, 1.10 mmol) as a 3.59 (m, 2 H), 3.64 (s, 3 H), 2.78 (dq, J = 8.5, 7.1 Hz, 1 H), 2.54
viscous yellow oil in 97% yield (diastereoisomer ratio dr = 6:1). (dd, J = 15.3, 7.8 Hz, 1 H), 2.46 (dd, J = 15.3, 4.9 Hz, 1 H), 1.80–
[α]D = +12.1 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3): δ = 1.70 (m, 1 H), 1.63–1.55 (m, 2 H), 1.44–1.37 (m, 1 H), 1.35 (s, 3
1
7.69–7.61 (m, 4 H), 7.44–7.33 (m, 6 H), 7.33–7.29 (m, 2 H), 7.25–
7.15 (m, 6 H), 6.88 (br. s, 2 H), 6.86–6.82 (m, 2 H), 5.82 (d, J =
4.1 Hz, 1 H), 4.79 (d, J = 16.5 Hz, 1 H), 4.56 (d, J = 16.5 Hz, 1
H), 4.09 (dq, J = 7.0, 4.1 Hz, 1 H), 3.64 (t, J = 6.5 Hz, 2 H), 3.61
(dd, J = 8.8, 2.9 Hz, 1 H), 2.57 (dq, J = 8.8, 7.1 Hz, 1 H), 2.50 (s,
H), 1.34 (s, 3 H), 1.28 (d, J = 6.0 Hz, 3 H), 1.25–1.18 (m, 1 H),
1.12 (d, J = 7.1 Hz, 3 H), 1.04 (m, 9 H), 0.87 (d, J = 6.8 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.4, 170.0, 135.7,
134.1, 129.7, 127.7, 108.4, 78.5, 77.5, 76.9, 64.0, 51.9, 42.1, 37.9,
33.8, 30.1, 29.8, 27.4, 27.3, 27.0, 19.3, 17.6, 14.0, 13.5 ppm. HRMS
6 H), 2.29 (d, J = 0.6 Hz, 3 H), 1.62–1.50 (m, 4 H), 1.47–1.39 (m, (ESI): calcd. for [M + Na]+ 621.3218; found 621.3194.
1 H), 1.39–1.30 (m, 1 H), 1.15 (d, J = 7.0 Hz, 3 H), 1.04 (s, 9 H),
Compound 29: A 1 m solution of TBAF (0.11 mL, 0.11 mmol) in
1.02 (d, J = 7.1 Hz, 3 H), 0.85 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR
THF was added to a solution of 28 (45 mg, 75.1 μmol) in dry THF
(100 MHz, CDCl3): δ = 175.2, 142.7, 140.4, 138.8, 138.4, 135.7,
(1 mL) and the mixture was stirred at room temp. for 1 h 30 min.
134.1, 133.6, 132.3, 129.7, 128.5, 128.4, 128.1, 127.8, 127.7, 127.3,
The reaction was then quenched with aqueous saturated NH4Cl,
126.0, 78.3, 75.4, 64.2, 56.9, 48.4, 43.6, 34.1, 30.3, 30.2, 27.0, 23.1,
the THF was removed under vacuum and the resulting solution
21.1, 19.4, 14.0, 13.6, 12.4 ppm. HRMS (ESI): calcd. for [M +
was diluted with diethyl ether. The aqueous layer was extracted
H]+ 834.4218; found 834.4208.
three times with diethyl ether and the combined organic extracts
Compound 26: LiOH·H2O (73 mg, 1.74 mmol) was added to a solu-
were washed with brine, dried with MgSO4, filtered and concen-
tion of 25 (290 mg, 0.35 mmol) in THF/MeOH/H2O (1:1:1 mL) trated under vacuum. The crude product was purified by silica gel
and the mixture was stirred at room temp. overnight. To reach com-
plete conversion, more LiOH·H2O (73 mg, 1.74 mmol) was added
and the reaction mixture stirred at room temp. overnight. The mix-
ture was then concentrated under vacuum and the resulting residue
purified by silica gel flash chromatography. Elution first with PE/
EtOAc (50:50) and then DCM/MeOH (90:10) afforded compound
flash chromatography. Elution with PE/EtOAc (50:50) afforded
compound 29 (23 mg, 63.8 μmol) as a yellow oil in 85% yield.
[α]D = +3.2 (c = 0.2, CHCl3). 1H NMR (500 MHz, CDCl3): δ =
5.15 (dd, J = 8.8, 3.6 Hz, 1 H), 3.93 (td, J = 8.0, 4.5 Hz, 1 H), 3.76
(dq, J = 8.0, 6.0 Hz, 1 H), 3.65 (s, 3 H), 3.60 (td, J = 6.4, 1.2 Hz,
2 H), 2.81 (dq, J = 8.8, 7.1 Hz, 1 H), 2.53 (dd, J = 15.3, 8.0 Hz, 1
H), 2.47 (dd, J = 15.3, 4.5 Hz, 1 H), 1.86 (br. s, 1 H), 1.83–1.74
(m, 1 H), 1.65–1.56 (m, 2 H), 1.43 (ddt, J = 13.4, 9.7, 6.6 Hz, 1 H),
1.38 (s, 3 H), 1.36 (s, 3 H), 1.28 (d, J = 6.0 Hz, 3 H), 1.26–1.18 (m,
1 H), 1.14 (d, J = 7.1 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H) ppm. 13C
26 (105 mg, 0.24 mmol) as a pale-yellow oil in 70% yield. [α]D
=
–1.8 (c = 0.7, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.68–7.64
(m, 4 H), 7.45–7.36 (m, 6 H), 4.98 (br. s, 1 H), 3.66 (td, J = 6.3,
0.8 Hz, 2 H), 3.62 (dd, J = 8.0, 3.6 Hz, 1 H), 2.65 (dq, J = 8.0,
7.2 Hz, 1 H), 1.66–1.49 (m, 4 H), 1.49–1.43 (m, 1 H), 1.38–1.30 (m, NMR (125 MHz, CDCl3): δ = 174.5, 170.2, 108.6, 78.6, 77.2, 76.9,
1 H), 1.18 (d, J = 7.2 Hz, 3 H), 1.05 (s, 9 H), 0.87 (d, J = 6.8 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 181.7, 135.7, 134.1,
129.7, 127.7, 75.9, 64.1, 43.3, 34.5, 30.2, 30.1, 27.0, 19.3, 14.3,
12.7 ppm. HRMS (ESI): calcd. for [M + Na]+ 451.2275; found
451.2265.
62.9, 52.0, 42.1, 37.9, 33.8, 30.3, 29.7, 27.4, 27.3, 17.5, 14.0,
13.6 ppm. HRMS (ESI): calcd. for [M + Na]+ 383.2040; found
383.2035.
Aldehyde 11: IBX (51 mg, 0.18 mmol) was added to a solution of
29 (22 mg, 61.0 μmol) in EtOAc (1 mL) and the mixture was heated
β-Hydroxy Methyl Ester 27: A 2 m solution of TMSCHN2 in di- at 50 °C for 6 h. The solid was then filtered through Celite and
ethyl ether (80 μL, 0.16 mmol) was added dropwise to a solution
of 26 (70 mg, 0.16 mmol) in methanol (1 mL). The reaction mixture
was stirred for 1 h 30 min, but complete conversion was only ob-
served after the addition of a further 2 equiv. of TMSCHN2
(0.16 mL, 0.32 mmol) and stirring for a further 10 min. The reac-
tion mixture was concentrated under vacuum and the crude prod-
uct was purified by silica gel flash chromatography. Elution with
PE/EtOAc (80:20) afforded compound 27 (63 mg, 0.14 mmol) as a
viscous pale-yellow oil in 87% yield. [α]D = –7.9 (c = 0.2, CHCl3).
washed with EtOAc. The filtrate was concentrated under vacuum
to afford compound 11 (21 mg, 61.0 μmol) as a pale-yellow oil in
quantitative yield without further purification. [α]D = +73.5 (c =
1.2, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 9.75 (t, J = 1.5 Hz,
1 H), 5.15 (dd, J = 9.0, 3.3 Hz, 1 H), 3.92 (td, J = 8.0, 4.7 Hz, 1
H), 3.76 (dq, J = 8.0, 6.0 Hz, 1 H), 3.65 (s, 3 H), 2.80 (dq, J = 9.0,
7.1 Hz, 1 H), 2.62–2.48 (m, 4 H), 1.80 (sext.d, J = 6.8, 3.3 Hz, 1
H), 1.70–1.61 (m, 1 H), 1.52 (dddd, J = 13.9, 8.8, 7.4, 6.8 Hz, 1
H), 1.38 (d, J = 0.4 Hz, 3 H), 1.36 (d, J = 0.4 Hz, 3 H), 1.28 (d, J
1H NMR (400 MHz, CDCl3): δ = 7.69–7.65 (m, 4 H), 7.45–7.36 = 6.0 Hz, 3 H), 1.14 (d, J = 7.1 Hz, 3 H), 0.91 (d, J = 6.8 Hz, 3
(m, 6 H), 3.70 (s, 3 H), 3.66 (t, J = 6.4 Hz, 2 H), 3.58 (dd, J = 7.7,
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 202.2, 174.4, 170.3,
3.7 Hz, 1 H), 2.64 (qt, J = 7.7 Hz, 1 H), 1.68–1.51 (m, 4 H), 1.50– 108.6, 78.6, 76.9, 76.5, 52.0, 42.2, 41.6, 37.9, 33.4, 27.4, 27.3, 25.7,
1.45 (m, 1 H), 1.37–1.28 (m, 1 H), 1.14 (d, J = 7.2 Hz, 3 H), 1.05 17.5, 14.0, 13.5 ppm. HRMS (ESI): calcd. for [M + Na]+ 381.1889;
(s, 9 H), 0.86 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 177.1, 135.7, 134.1, 129.7, 127.7, 76.0, 64.2, 51.9, 43.1,
34.9, 30.2, 30.1, 27.0, 19.3, 14.6, 12.9 ppm. HRMS (ESI): calcd. for
[M + Na]+ 465.2432; found 465.2415.
found 381.18998.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of all new compounds.
Diester 28: DCC (43 mg, 0.207 mmol) and DMAP (5 mg,
0.04 mmol) were added to a solution of 27 (61 mg, 0.138 mmol)
and 17 (36 mg, 0.207 mmol) in dry DCM and the mixture was
Acknowledgments
stirred at room temp. overnight. The solvent was removed under L. R. thanks the Ministère de l’Enseignement Supérieur et de la
vacuum and the crude product was purified by silica gel flash
chromatography. Elution with PE/EtOAc (85:15) afforded com-
Recherche for a Ph. D. grant. Support from the Centre National
de la Recherche Scientifique (CNRS) and the University Lyon 1
are acknowledged. The authors are indebted to Dr. M. Mauduit
pound 28 (74 mg, 0.124 mmol) as a yellow oil in 90% yield. [α]D
=
+2.5 (c = 0.5, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.67–7.64 (ENSC Rennes) for stimulating discussions. Prof. O. Baudoin
(m, 4 H), 7.44–7.35 (m, 6 H), 5.10 (dd, J = 8.5, 3.9 Hz, 1 H), 3.91
(UCBL) is warmly thanked for providing chiral HPLC facilities.
Eur. J. Org. Chem. 0000, 0–0
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L. Raffier, O. Piva
FULL PAPER
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Received: October 9, 2012
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21338
/KAP1
Date: 16-01-13 11:51:46
Pages: 9
Nhatrangins: Stereoselective Access to an Aldehyde Intermediate
Natural Product Synthesis
Two strategies have been considered for the
stereoselective synthesis of nhatrangins A
and B. A sequence involving diastereoselec-
tive alkylation and aldolization employing
ephedrine derivatives as chiral auxiliaries
was the most efficient approach to deliver
a key aldehyde framework.
L. Raffier, O. Piva* .......................... 1–9
Synthetic Studies on the Nhatrangins:
Stereoselective Access to an Advanced
Aldehyde Intermediate
Keywords: Synthesis design / Natural prod-
ucts / Metathesis / Aldolization / Diastereo-
selectivity
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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