The first total synthesis of nhatrangin A

Article abstract of DOI:10.1039/c3ob40252e

The first total synthesis of nhatrangin A has been achieved. Pivotal bond forming events in the synthesis include Brown crotylboration, olefin cross-metathesis, Sharpless asymmetric dihydroxylation and Yamaguchi esterification. The Royal Society of Chemis

Full text of DOI:10.1039/c3ob40252e

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BiomolecularChemistry
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Volume 11 | Number 27 | 21 July 2013 | Pages 4421–4560
ISSN 1477-0520
PAPER
Ahmed Kamal and Saidi Reddy Vangala
The first total synthesis of nhatrangin A
1477-0520(2013)11:27;1-6

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The first total synthesis of nhatrangin A†
Cite this: Org. Biomol. Chem., 2013, 11, 4442
Ahmed Kamal* and Saidi Reddy Vangala
Received 4th February 2013,
Accepted 26th March 2013
The first total synthesis of nhatrangin A has been achieved. Pivotal bond forming events in the synthesis
include Brown crotylboration, olefin cross-metathesis, Sharpless asymmetric dihydroxylation and
Yamaguchi esterification.
DOI: 10.1039/c3ob40252e
www.rsc.org/obc
Introduction
Structurally infringing natural products, with a variety of bio-
logical activities, has been a useful starting point for drug dis-
covery over the years.1 Among the various sources of natural
products, marine cyanobacteria, especially Lyngbya majuscula,
have proven to be a versatile starting point from which a
number of secondary metabolites in excellent biological activi-
ties have been isolated.2 A series of toxins, viz., the aplysia-
toxins, isolated from L. majuscula, are especially noteworthy.
Many of the aplysiatoxins exhibit tumour-promoting activity
through the activation of protein kinase C and anti-prolifera-
tive activity against the alymphocytic urine leukaemia (P-388)
cell line.3,4 The two polyketide metabolites, nhatrangin A (1)
and nhatrangin B (Fig. 1), were isolated from a Vietnamese col-
lection of L. majuscula in 2009.5 The structures and relative
configuration of these two new compounds were elucidated by
extensive NMR spectroscopic techniques.
Fig. 1 Structures of nhatrangin A and nhatrangin B.
metathesis reaction between the alkenes 5 and 6, which can be
assembled from 3-hydroxybenzaldehyde 7 and methyl (S)-3-
hydroxy-2-methyl propionate 8, respectively. The acid inter-
mediate 4 could be constructed from propanediol 9.
As a part of our research program aimed at developing
stereoselective total syntheses of biologically active natural pro-
ducts6 for advanced biological screening, we undertook investi-
gations aimed at developing a concise and asymmetric total
synthesis of nhatrangin A (1). Herein, we report our successful
endeavor which culminated in the first total synthesis of
nhatrangin A (1). Pinane mediated crotylboration, Sharpless
asymmetric dihydroxylation (SAD) and lipase-mediated resolu-
tion were employed as key transformations to install the
various asymmetric centers that are present in 1.
The retrosynthetic analysis for nhatrangin A 1 is depicted in
Scheme 1. We envisioned constructing the target natural
product from compound 2, which in turn could be accessed
by a Yamaguchi esterification of fragments 3 and 4. The
β-hydroxy ester component 3 could be generated by a cross-
Results and discussion
Preparation of fragment 5
Our journey for the synthesis of nhatrangin A (1) began with
the preparation of 5 as depicted in Scheme 2. Commercially
available 3-hydroxybenzaldehyde (7) was treated with TBS-Cl in
the presence of imidazole to afford the TBS ether 10, followed
by the addition of vinyl Grignard reagent to furnish the
racemic allyl alcohol 11 in excellent yield. Lipase mediated
resolution7 of ( )-11 produced the desired (S)-enantiomer 12 in
98.2% ee (41% yield and the absolute configuration was deter-
mined by using the refined Mosher method) along with the
acetate of the (R)-enantiomer (12a, 53%, 91% ee). Methylation
of 12 using MeI and NaH furnished the methyl ether 5 in 85%
yield.
Preparation of fragment 3
Medicinal Chemistry and Pharmacology, CSIR-Indian Institute of Chemical
Technology, Hyderabad, 500007, India. E-mail: ahmedkamal@iict.res.in;
Fax: +91-40-27193189; Tel: +91-40-27193157
The other chiral alkene fragment 6 was prepared (Scheme 3)
from commercially available methyl (S)-3-hydroxyl-2-methyl-
propionate 8 (Roche ester). It was converted to the aldehyde 13
in three steps by following a known protocol8 to initiate the
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob40252e
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Scheme 1 Retrosynthetic approach for nhatrangin A (1).
Scheme 3 Preparation of fragment 3.
Scheme 2 Preparation of fragment 5.
preparation of fragment 3. Crotylboration with (+)-B-(Z)-crotyl
diisopinocampheylborane8 was carried out next to provide the
homoallylic alcohol 6 as a single diastereomer. The coupling
of two alkene fragments 5 and 6 was carried out by subjecting
them to cross-metathesis9 conditions using Grubbs 2nd gener-
ation catalyst afforded 15 in 94% yield. The product of the
metathesis 15 was hydrogenated with Pd–C/H2 to provide 16 in
92% yield. Double desilylation of the latter by treatment with
Scheme 4 Preparation of fragment 4.
Preparation of fragment 4
TBAF, selective sequential oxidations of the primary alcohol in After the preparation of 3, we focused our attention on the syn-
17 by TEMPO/BAIB10 and under Pinnick11 conditions and sub- thesis of the chiral carboxylic acid fragment 4 from commer-
sequent esterification with diazomethane generated the cially available 1,3-propanediol 9 as illustrated in Scheme 4.
β-hydroxy ester 18 in 72% yield over three steps. Treatment of α,β-Unsaturated ester 19 was synthesized from 9 as previously
18 with TBS-Cl in the presence of imidazole reintroduced the described (78% for 3 steps).12 19 then underwent Sharpless
silyl protecting group selectively onto the phenolic functional- asymmetric dihydroxylation12 (Admix-β) to afford the diol 20 in
ity and furnished the secondary alcohol 3.
89% yield and in 98% ee. It was protected as the acetonide by
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other isomers/congeners/analogues of this natural product.
Efforts in this direction are being pursued presently in our lab-
oratory and will be reported in due course.
Experimental section
General experimental
All 1H NMR and 13C NMR spectra were recorded in CDCl3
solvent on a Varian Bruker 300, a Varian Unity 400, and an
Innova 500 MHz spectrometer at ambient temperature, chemi-
cal shifts δ were given in ppm on a scale downfield from TMS,
and the coupling constants J are in Hz. The signal patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; m, multi-
plet; br, broad peak. FTIR spectra were recorded as neat.
Optical rotations were measured on a JASCO DIP-370 digital
polarimeter using a 2 mL cell with a 1 dm path length, and
the concentration c is given in g per 100 mL. Mass spectra
were obtained on a Finnegan Mat1020B, a micromass VG
70-70H or an Agilent Technologies LC/MSD treapSL spectro-
meter operating at 70 eV using the direct inlet system and
high-resolution mass spectra (HRMS) were recorded on a
QSTAR XL Hybrid MS/MS mass spectrometer. HPLC was
recorded on a SHIMADZU HPLC using Chiralcel OD-H,
n-hexane and isopropanol as eluents. All the reagents and sol-
vents were used without further purification unless specified
otherwise. Technical grade ethyl acetate and petroleum ether
used for column chromatography were distilled prior to use.
Tetrahydrofuran (THF) and diethyl ether, when used as a
solvent for reactions, were freshly distilled from sodium-benzo-
phenone ketyl. Column chromatography was carried out
using silica gel (60–120 mesh and 100–200 mesh) packed in
glass columns. All reactions were performed under a nitrogen
Scheme 5 Complete synthesis of nhatrangin A (1).
using 2,2-dimethoxypropane in the presence of a catalytic
amount of p-toluenesulphonic acid to give 21 in 92% yield.
A simple LiBH4 reduction furnished the primary alcohol 22 in
88% yield, which was then converted to the corresponding
tosylate 23 by using p-toluenesulphonyl chloride in the pres-
ence of triethyl amine in 90% yield. This was then treated with
LiAlH4 under reflux to obtain 24 in 73% yield. The oxidation of
the primary alcohol was carried out by using TEMPO13 com-
bined with BAIB in CH2Cl2–H2O (2/1) to afford the desired
carboxylic acid 4 in 79% yield (Scheme 5).
Completion of the synthesis of nhatrangin A
After synthesizing the fragments 3 and 4, assembly of these atmosphere and in flame-dried or oven-dried glassware with
two fragments was carried out by subjecting them to the magnetic stirring.
Yamaguchi esterification conditions,14 and the diester 2 was
Experimental procedures
produced in 84% yield. The methyl ester of nhatrangin A (14)
was obtained in 78% yield from 2 by treating it with PTSA in
methanol. Finally, methyl ester (14) was converted to nhatran-
gin A (1) by following a protocol developed by Nicolaou15 in
which the ester was exposed to Me3SnOH. Gratifyingly the
natural product nhatrangin A (1) was obtained after work-
up, albeit in 30% yield with [α]2D5 = +0.2 (c 0.05, MeOH).16
(1S)-1-(3-[1-(tert-Butyl)-1,1-dimethylsilyl]oxyphenyl)-2-propen-
1-ol (12). To a 250 mL Erlenmeyer flask were added HPLC
grade diisopropyl ether (100 mL), vinyl acetate (10 mL), lipase
Amino-I (5 g), and the appropriate alcohol 11 (5 g,
18.93 mmol). The Erlenmeyer flask was sealed using a rubber
stopper, and the reaction mixture was stirred in an orbital
shaker at 32 °C with 180 rpm. The reaction progress was moni-
tored by collecting samples and analyzing gas chromatography
with the chiral stationary phase. After 48 h the reaction was
complete, and the immobilized lipase was filtered off. The
filtrate was evaporated under reduced pressure. The residue
was purified by column chromatography (SiO2, 10% EtOAc
in hexane eluant), yielding the enantiomerically enriched
1
The H and 13C NMR spectra of the synthetic material were in
complete agreement with that reported for the natural
product.
Conclusion
In conclusion, the first total synthesis of nhatrangin A (1) has S-alcohol 12 (2.4 g, 45%, ee 98%) as a colorless oil; [α]D25
=
been achieved and thus the structure assigned to the natural +12.6 (c 0.3, CHCl3), 1H NMR (300 MHz, CDCl3): δ 0.19 (6H, s),
product has also been confirmed. The overall yield for the 0.98 (9H, s), 5.13 (1H, d, J = 5.86 Hz), 5.17 (1H, dd, J = 10.19,
14-step longest sequence, starting from methyl (2S)-3-hydroxy- 1.32 Hz), 5.32 (1H, dd, J = 16.99, 1.32 Hz), 6.01 (1H, m), 6.74
2-methylpropionate (Roche ester), is 5.8%. The convergent (1H, d, J = 8.12 Hz), 6.85 (1H, s), 6.92 (1H, d, J = 7.74 Hz), 7.19
approach employed herein is suitable for the synthesis of (1H, t, J = 7.93 Hz); 13C NMR (75 MHz, CDCl3): δ −4.4, 18.2,
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25.7, 75.1, 115.0, 117.9, 119.2, 119.3, 129.5, 140.2, 144.2, 155.8; completion of the reaction, the solution was filtered through a
IR (CHCl3, cm−1): νmax 3400, 2930, 1586, 1484, 1473, 1277, celite pad and the filtrate was concentrated under reduced
1259, 1003, 982, 840, 782 cm−1; MS (ESI): (M+ + Na) 287; pressure. The crude product was purified by column chromato-
HRMS (ESI): calcd for C15H24O2NaSi: 287.1457, found: graphy (SiO2, 5% EtOAc in hexane eluant) to give 16 (0.18 g,
1
287.1465.
92%) as a colorless liquid; [α]2D5 = −9.1 (c 0.5, CHCl3), H NMR
tert-Butyl 3-[(1S)-1-methoxy-2-propenyl]phenoxydimethylsi- (300 MHz, CDCl3): δ 0.12 (6H, s), 0.71 (3H, d, J = 6.79 Hz), 0.86
lane (5). To solution of the above alcohol 12 (2 g, (3H, d, J = 7.55 Hz), 0.97 (9H, s), 1.06 (9H, s), 1.21–1.94 (6H,
a
7.57 mmol) in THF (15 mL) was added NaH (181 mg, m), 3.18 (3H, s), 3.45 (1H, dd, J = 8.31, 2.33 Hz), 3.45–3.71 (2H,
7.57 mmol) at 0 °C and stirred for 10 min at the same tempera- m), 3.98 (1H, t, J = 7.36 Hz), 6.71–6.92 (3H, m), 7.21 (1H, m),
ture; to the reaction mixture was added MeI (1.2 g, 7.32–7.48 (6H, m), 7.61–7.73 (4H, m); 13C NMR (75 MHz,
7.69 mmol). After stirring for 3 h at the same temperature, the CDCl3): δ −4.4, 12.4, 13.3, 18.2, 19.1, 25.7, 26.8, 30.2, 35.3,
reaction mixture was quenched with a saturated solution of 36.3, 37.4, 56.6, 69.7, 78.6, 84.2, 118.3, 119.2, 119.8, 127.7,
aqueous NH4Cl. After removing THF under reduced pressure 129.2, 129.8, 132.8, 135.6, 144.3, 155.7; IR (CHCl3, cm−1): νmax
the reaction mixture was extracted with EtOAc, washed with 3491, 2961, 2930, 2851, 1483, 1427, 1275, 1096 cm−1; MS (ESI)
brine, dried (Na2SO4) and concentrated in vacuo. Purification m/z: (M+ + H) 635; HRMS (ESI): calcd for C38H59O4Si2:
by column chromatography (SiO2, 5 to 7% EtOAc in hexane 635.3867, found: 635.3880.
eluant) afforded 5 (1.77 g, 85%) as a pale yellow color oil; [α]D25
(2S,3R,4S,7S)-7-(3-Hydroxyphenyl)-7-methoxy-2,4-dimethyl-
= +8.5 (c 0.5, CHCl3), 1H NMR (300 MHz, CDCl3): δ 0.12 (6H, s), heptane-1,3-diol (17). A solution of 16 (0.5 g, 0.788 mmol) in
0.92 (9H, s), 3.24 (3H, s), 4.47 (1H, d, J = 6.86 Hz), 5.05–5.20 THF (10 mL) was cooled to 0 °C and TBAF (2.0 mL, 2.03 mmol,
(2H, m), 5.78–5.89 (1H, m), 6.67 (1H, d, J = 7.89 Hz), 6.74 (1H, 1.0 M solution in THF) was added dropwise. The resulting
s), 6.82 (1H, d, J = 6.86 Hz), 7.12 (1H, t, J = 7.89 Hz); 13C NMR brown solution was stirred at the same temperature for 2 h.
(75 MHz, CDCl3): δ −4.5, 18.1, 25.6, 56.3, 84.4, 116.1, 118.4, Then, a mixture of Et2O–H2O 1 : 1 (20 mL) was added. The
119.2, 119.8, 129.3, 138.6, 142.3, 155.7; IR (CHCl3, cm−1): νmax resulting layers were separated and washed with brine, dried
2952, 2930, 1601, 1483, 1443, 1276, 1154, 1095, 839, 781 cm−1
MS (ESI) m/z: (M+
Na) 301; HRMS (ESI): calcd for pressure. The residue was purified by column chromatography
C16H26O2NaSi: 301.1562, found: 301.1556. (SiO2, 25 to 30% EtOAc in hexane eluant) to obtain 203 mg
;
over Na2SO4 and the solvents were evaporated under reduced
+
(2S,3R,4S,5E,7S)-7-(3-[1-(tert-Butyl)-1,1-dimethylsilyl]oxyphenyl)- (81%) of triol 17 as a colorless gummy product; [α]2D5 = −14.8
1-(2,2-dimethyl-1,1-diphenylpropoxy)-7-methoxy-2,4-dimethyl- (c 0.2, CHCl3), 1H NMR (300 MHz, CDCl3): δ 0.73 (3H, d, J =
5-hepten-3-ol (15). To a stirred solution of olefin 6 (100 mg, 6.79 Hz), 0.82 (3H, d, J = 6.79 Hz), 1.25–1.91 (6H, m), 3.21 (3H,
0.261 mmol) and olefin 5 (376 mg, 1.31 mmol) in dry CH2Cl2 s), 3.42 (1H, dd, J = 9.06, 3.02 Hz), 3.61 (1H, dd, J = 10.57, 7.55
(5 mL) was added the second generation Grubbs catalyst (G-II) Hz), 3.69 (1H, dd, J = 1.57, 3.77 Hz), 4.04 (1H, t, J = 6.04 Hz),
(22 mg, 0.026 mmol). The solution was allowed to reflux under 6.74–6.79 (3H, m), 7.17 (1H, t, J = 7.55 Hz); 13C NMR (75 MHz,
nitrogen. After 24 hours, the solution was allowed to remain CDCl3): δ 12.3, 13.4, 29.7, 35.1, 35.5, 37.1, 56.6, 68.5, 79.6,
exposed to air at room temperature, and was subsequently con- 84.2, 113.3, 114.8, 118.6, 129.6, 143.6, 156.5; IR (CHCl3, cm−1):
centrated in vacuo, and purification by column chromato- νmax 3434, 2941, 1282, 1052, 669 cm−1; MS (ESI) m/z: (M+ + Na)
graphy (SiO2, 5 to 8% EtOAc in hexane eluant) afforded 15 305; HRMS (ESI): calcd for C16H26O4Na: 305.17233, found:
(150 mg, 94%) as a brown colored liquid; [α]2D7 = +16.5 (c 0.4, 305.17212.
CHCl3); 1H NMR (500 MHz, CDCl3): δ 0.12 (6H, s), 0.89 (3H, d,
(2R,3R,4S,7S)-Methyl 3-hydroxy-7-(3-hydroxyphenyl)-7-methoxy-
J = 6.79 Hz), 0.98 (9H, s), 1.06 (9H, s), 1.11 (3H, d, J = 7.55 Hz), 2,4-dimethylheptanoate (18). To a solution of compound 17
1.78 (1H, m), 2.35 (1H, m), 3.29 (3H, s), 3.41 (1H, q, J = 6.89, (0.25 g, 0.86 mmol) in dry CH2Cl2 (20 mL) were added TEMPO
3.81 Hz), 3.62 (1H, dd, J = 9.55, 5.81 Hz), 3.78 (1H, m), 4.52 (15 mg, 0.085 mmol) and BAIB (0.42 g, 1.33 mmol) at 0 °C and
(1H, d, J = 7.78 Hz), 5.51 (1H, dd, J = 15.55, 6.81 Hz), 5.73 (1H, it was stirred for 4 h at room temperature. CH2Cl2 was concen-
dd, J = 14.65, 7.78 Hz), 6.73 (1H, d, J = 7.78 Hz), 6.79 (1H, s), trated and directly transferred to a silica gel column and puri-
6.87 (1H, d, J = 7.78 Hz), 7.17 (1H, t, J = 7.78 Hz), 7.34–7.48 fied to obtain aldehyde, which was again dissolved in THF–
(6H, m), 7.65–7.69 (4H, m); 13C NMR (75 MHz, CDCl3): δ −4.5, H2O–tBuOH (6 mL/6 mL/1.2 mL) and to this solution were
14.2, 18.1, 19.1, 25.6, 26.7, 29.6, 36.8, 40.2, 56.1, 68.3, 79.2, added NaClO2 (0.175 g, 1.99 mmol) and NaH2PO4 (0.44 g,
84.0, 118.3, 119.1, 119.7, 127.7, 129.2, 129.7, 130.2, 132.7, 3.695 mmol) in 3 mL H2O at 0 °C and the reaction mixture was
135.6, 136.7, 143.1, 155.6; IR (CHCl3, cm−1): νmax 3352, 2987, stirred for 12 h at room temperature. THF was removed under
2950, 1682, 1474, 1457, 1203, 1182, 1132, 1035 cm−1; MS (ESI) reduced pressure and 25 mL 1 M HCl was added and then
m/z: (M+ + Na) 655; HRMS (ESI): m/z calcd for C38H56O4NaSi2: extracted with EtOAc. The organic layer was washed with brine,
655.3614, found: 655.3634.
dried over Na2SO4 and concentrated under reduced pressure to
(2S,3R,4S,7S)-7-(3-[1-(tert-Butyl)-1,1-dimethylsilyl]oxyphenyl)- obtain the residue, which was dissolved in 20 mL sat. NaHCO3
1-(2,2-dimethyl-1,1-diphenylpropoxy)-7-methoxy-2,4-dimethyl- and extracted with Et2O. The aqueous layer was acidified with
heptan-3-ol (16). To a solution of 15 (0.2 g, 0.316 mmol) in 10 mL 3 M HCl and then extracted with EtOAc. The organic
EtOAc (10 mL) was added 20 mg of 10% Pd/C and the mixture layer was washed with brine, dried over Na2SO4 and concen-
was stirred under a hydrogen atmosphere for 6 h. After the trated under reduced pressure to obtain carboxylic acid as a
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colourless liquid; without purification, this was taken up for 1H NMR (300 MHz, CDCl3): δ 1.05 (9H, s), 1.32 (3H, t, J = 6.79
the next step. Hz), 1.71–2.06 (2H, m), 3.01 (1H, d, J = 6.14 Hz), 3.31 (1H, d,
The intermediate acid was dissolved in dry ether and J = 6.74 Hz), 3.81–3.94 (2H, m), 4.05 (1H, dd, J = 6.79, 2.27 Hz),
treated with ethereal solution of diazomethane at 0 °C. After 4.29 (2H, q, J = 7.55, 6.79 Hz), 7.33–7.46 (6H, m), 7.66–7.69
stirring for 0.5 h, an aqueous NH4Cl solution was added and (4H, m); 13C NMR (100 MHz, CDCl3): δ 14.1, 18.9, 26.7, 35.3,
extracted with EtOAc. The combined organic layers, dried over 61.7, 62.1, 71.4, 73.5, 127.7, 129.7, 132.8, 133.1, 135.4, 173.2;
Na2SO4, filtered and concentrated in vacuo. The residue was IR (CHCl3, cm−1): νmax 3441, 2923, 2853, 1737, 1693, 1386,
purified by silica gel column chromatography (SiO2, 10 to 15% 1089, 1021, 703 cm−1; MS (ESI) m/z: (M+ + Na) 439; HRMS
EtOAc in hexane eluant) to obtain 18 (195 mg, 72%) as a color- (ESI): calcd for C23H32O5NaSi: 439.1916, found: 439.1921.
less oil; [α]2D5 = −28.2 (c 0.25, CHCl3), 1H NMR (300 MHz,
Ethyl (4S,5R)-5-(2-[1-(tert-butyl)-1,1-diphenylsilyl]oxyethyl)-
CDCl3): δ 0.84 (3H, d, J = 6.59 Hz), 1.09 (3H, d, J = 7.55 Hz), 2,2-dimethyl-1,3-dioxolane-4-carboxylate (21). To a solution of
1.35–1.45 (1H, m), 1.49–1.57 (1H, m), 1.61–1.69 (1H, m), the diol 20 (5 g, 12.01 mmol) in 20 mL of dry CH2Cl2 at 0 °C
1.77–1.85 (1H, m), 2.56–2.63 (2H, m), 3.21 (3H, s), 3.57 (1H, were added 2,2-dimethoxypropane (4.4 mL, 36.05 mmol) and
m), 3.68 (3H, s), 4.02 (1H, t, J = 6.59 Hz), 5.88 (1H, s) 6.74 (1H, TsOH (108 mg, 0.47 mmol) and the reaction mixture was
d, J = 7.69 Hz), 6.79 (1H, s), 6.81 (1H, d, J = 7.69 Hz) 7.18 (1H, stirred at ambient temperature for 3 h. The organic layer was
t, J = 7.69 Hz); 13C NMR (75 MHz, CDCl3): δ 12.6, 14.3, 29.8, evaporated under reduced pressure to afford the crude aceto-
34.8, 35.6, 43.1, 51.8, 56.6, 75.6, 84.1, 113.1, 114.6, 118.8, nide, which was purified by column chromatography (SiO2, 5
129.5, 143.8, 156.3, 177.2; IR (CHCl3, cm−1): νmax 3430, 2925, to 7% EtOAc in hexane eluant) to yield 21 (5.04 g, 92%) as a
1
1717, 1628, 1261, 1098, 791 cm−1; MS (ESI) m/z: (M+ + H) 311; colorless oil; [α]D25 = +12.8 (c 0.2, CHCl3), H NMR (300 MHz,
HRMS (ESI): calcd for C17H26O5Na: 333.16788, found: CDCl3): δ 1.05 (9H, s), 1.28 (3H, t, J = 7.17 Hz), 1.46 (6H, s),
333.16676.
1.82–2.14 (2H, m), 3.84 (2H, t, J = 6.42 Hz), 4.16–4.31 (3H, m),
(2R,3R,4S,7S)-Methyl 7-(3-(tert-butyldimethylsilyloxy)phenyl)- 4.35–4.43 (1H, m), 7.35–7.46 (6H, m), 7.66–7.69 (4H, m); 13C
3-hydroxy-7-methoxy-2,4-dimethylheptanoate (3). To a solu- NMR (100 MHz, CDCl3): δ 14.1, 19.2, 25.6, 26.7, 27.2, 36.3,
tion of the alcohol 18 (0.2 g, 0.645 mmol) in dry DCM (5 mL) 60.2, 61.2, 75.9, 78.9, 110.6, 127.5, 129.5, 133.6, 135.5, 170.6;
were added imidazole (0.08 g, 1.29 mmol) and TBDMSCl IR (CHCl3, cm−1): νmax 2932, 2858, 1756, 1598, 1367, 1177, 986,
(0.11 g, 0.71 mmol). The resulting mixture was stirred at room 740 cm−1; MS (ESI) m/z: (M+ + Na) 479; HRMS (ESI): calcd for
temperature for 4 h. Progress of the reaction was monitored by C26H36O5NaSi: 479.2229, found: 479.2241.
TLC and after completion of the reaction, it was poured into
[(4R,5R)-5-(2-[1-(tert-Butyl)-1,1-diphenylsilyl]oxyethyl)-2,2-
water (25 mL) and extracted with diethyl ether (3 × 30 mL). The dimethyl-1,3-dioxolan-4-yl]methanol (22). A solution of 21
combined ethereal layer was washed with brine (30 mL) and (5 g, 10.09 mmol), in Et2O (50 mL) and catalytic amount of
dried over anhydrous Na2SO4. The residue obtained after the water (1 mL), was treated with LiBH4 (0.48 g, 21.92 mmol) at
evaporation of the solvent was purified by column chromato- 0 °C. After stirring for 2 h at ambient temperature the reaction
graphy (SiO2, 7 to 10% EtOAc in hexane eluant) to afford 3 mixture was quenched with a saturated solution of aqueous
(0.24 g, 91%) as a colorless oil; [α]2D5 = −23.4 (c 0.25, CHCl3), 1H NH4Cl. After removing Et2O under reduced pressure the reac-
NMR (300 MHz, CDCl3): δ 0.19 (6H, s), 0.84 (3H, d, J = 6.79 tion mixture was extracted with EtOAc, washed with brine,
Hz), 0.98 (9H, s), 1.11 (3H, d, J = 7.55 Hz), 1.32–1.44 (1H, m), dried (Na2SO4) and concentrated in vacuo. Purification by
1.47–1.71 (2H, m), 1.73–1.86 (1H, m), 2.45 (1H, d, J = 6.78 Hz), column chromatography (SiO2, 10 to 12% EtOAc in hexane
2.61 (1H, m), 3.20 (3H, s), 3.56 (1H, m), 3.69 (3H, s), 4.01 (1H, eluant) afforded 22 (3.99 g, 88%) as a colorless oil; [α]D25
=
q, J = 6.04, 1.57 Hz), 6.74 (1H, d, J = 7.55 Hz), 6.77 (1H, s), 6.86 +13.4 (c 0.3, CHCl3), 1H NMR (500 MHz, CDCl3): δ 1.05 (9H, s),
(1H, d, J = 7.55 Hz), 7.19 (1H, t, J = 7.55 Hz); 13C NMR 1.36 (3H, s), 1.37 (3H, s), 1.79 (2H, m), 3.56 (1H, dd, J = 11.86,
(75 MHz, CDCl3): δ −4.4, 12.6, 14.4, 18.2, 25.6, 29.9, 34.9, 35.8, 2.96 Hz), 3.72–3.76 (2H, m), 3.79–3.82 (2H, m), 4.03 (1H, q, J =
42.9, 51.7, 56.5, 75.7, 83.9, 118.1, 119.2, 119.7, 129.2, 143.9, 7.94, 4.94 Hz), 7.33–7.41 (6H, m), 7.63–7.65 (4H, m); 13C NMR
155.7, 176.8; IR (CHCl3, cm−1): νmax 3432, 1726, 1638, 1281, (100 MHz, CDCl3): δ 19.3, 26.9, 27.1, 27.4, 35.9, 60.7, 61.8,
1124, 771 cm−1; MS (ESI) m/z: (M+ + Na) 447; HRMS (ESI): 74.1, 81.4, 108.5, 127.7, 129.7, 133.7, 135.6; IR (CHCl3, cm−1):
calcd for C23H40O5NaSi: 447.25416, found: 447.25435.
Ethyl (2S,3R)-5-[1-(tert-butyl)-1,1-diphenylsilyl]oxy-2,3-di- MS (ESI) m/z: (M+
νmax 3441, 2923, 2853, 1737, 1693, 1386, 1089, 1021, 703 cm−1
;
+
Na) 437; HRMS (ESI): calcd for
hydroxypentanoate (20). The solution of AD-mix-β (18.3 g) and C24H34O4NaSi: 437.2124, found: 437.2114.
CH3SO2NH2 (1.24 g, 13.08 mmol) in tBuOH–H2O 1 : 1 (200 mL)
[(4R,5R)-5-(2-[1-(tert-Butyl)-1,1-diphenylsilyl]oxyethyl)-2,2-
was stirred for 10 min at room temperature and then cooled to dimethyl-1,3-dioxolan-4-yl]methyl
4-methyl-1-benzenesulfo-
0 °C and alkene 19 (5 g, 13.08 mmol) was added and stirred at nate (23). To a stirred solution of compound 22 (3 g,
0 °C. After 24 h, the reaction mixture was quenched with 7.24 mmol) in dry CH2Cl2 (25 mL) was added TEA (23 mL,
sodium sulphite; it was diluted with EtOAc (20 mL), filtered 21.74 mmol) at room temperature and cooled to 0 °C; then
through celite and the filtrate was concentrated under reduced p-toluenesulfonyl chloride (1.52 g, 7.97 mmol) was added and
pressure to give a diol, which was purified by column chrom- the reaction mixture was stirred for 4 h at room temperature.
atography (SiO2, 20% EtOAc in hexane eluant) to give pure diol After the removal of the solvent under reduced pressure
20 (4.84 g, 89%) as a colorless oil; [α]2D5 = +4.8 (c 0.2, CHCl3), a residue was obtained, which was purified by column
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chromatography (SiO2, 4 to 6% EtOAc in hexane eluant) to (3 mL). The resulting solution was stirred for 10 h and to it
obtain the tosylate compound 23 (3.7 g, 90%) as a colorless oil; toluene (10 mL) and saturated aqueous NaHCO3 solution
1
[α]2D5 = +16.3 (c 0.3, CHCl3), H NMR (400 MHz, CDCl3): δ 1.03 (10 mL) were added. The layers were separated, and the
(9H, s), 1.29 (3H, s), 1.33 (3H, s), 1.69–1.87 (2H, m), 2.42 (3H, aqueous phase was extracted with toluene (3 × 5 mL). The com-
s), 3.74–3.80 (2H, m), 3.86–3.92 (1H, m), 4.02 (1H, dt, J = 7.36, bined organic phases were dried over Na2SO4, and the solvent
4.41 Hz), 4.12 (2H, m), 7.21 (2H, d, J = 8.09 Hz), 7.35–7.44 (6H, was removed under vacuum. The crude product was purified
m), 7.64–7.67 (4H, m), 7.78 (2H, d, J = 8.09 Hz); 13C NMR by flash column chromatography (SiO2, 8% EtOAc in hexane
(100 MHz, CDCl3): δ 19.1, 21.6, 26.6, 26.8, 27.2, 35.7, 60.3, eluant) to furnish diester 2 (58 mg, 84% yield) as a colorless
68.9, 74.6, 78.1, 109.3, 127.6, 127.9, 129.6, 129.8, 132.7, 133.5, liquid; [α]2D5 = −1.9 (c 0.45, CHCl3), 1H NMR (300 MHz, CDCl3):
135.5, 144.8; IR (CHCl3, cm−1): νmax cm−1; MS (ESI) m/z: δ 0.19 (6H, s), 0.88 (3H, d, J = 6.04 Hz), 0.98 (9H, s), 1.11 (3H,
(M+
591.2212, found: 591.2187.
+
Na) 591; HRMS (ESI): calcd for C31H40O6NaSiS: d, J = 6.79 Hz), 1.28 (3H, d, J = 6.04 Hz), 1.37 (3H, s), 1.41 (3H,
s) 1.35–1.45 (2H, m), 1.58–1.82 (3H, m), 2.41 (2H, m), 2.76 (1H,
2-[(4R,5R)-2,2,5-Trimethyl-1,3-dioxolan-4-yl]-1-ethanol (24). m), 3.18 (3H, s), 3.63 (3H, s), 3.74–3.81 (1H, m), 3.87–3.99 (2H,
To a stirred solution of tosylate 23 (5 g, 8.80 mmol) in THF m), 5.08 (1H, dd, J = 9.66, 3.77 Hz) 6.72 (1H, d, J = 7.55 Hz),
(50 mL) at 0 °C was added LiAlH4 (0.6 g, 17.60 mmol). The sus- 6.76 (1H, s), 6.86 (1H, d, J = 7.55 Hz), 7.18 (1H, t, J = 7.55 Hz);
pended mixture was stirred at reflux temperature for 12 h, 13C NMR (75 MHz, CDCl3): δ −4.4, 13.5, 13.7, 17.4, 18.2, 25.6,
cooled to 0 °C, diluted with 2 mL of THF, and then carefully 27.2, 27.3, 29.8, 33.8, 35.9, 37.8, 41.9, 51.7, 56.6, 76.8, 77.2,
treated successively with water and 10% aq. NaOH. The result- 78.3, 83.8, 108.3, 117.9, 119.2, 119.7, 129.3, 144.1, 155.7, 169.7,
ing mixture was stirred for 1 h and filtered through a celite 174.2; IR (CHCl3, cm−1): νmax 2965, 2938, 1743, 1702, 1266,
pad; the filtrate was dried with anhydrous Na2SO4 and concen- 755 cm−1; MS (ESI) m/z: (M+ + Na) 603; HRMS (ESI): calcd for
trated under reduced pressure. The crude residue was then C31H52O8NaSi: 603.33237, found: 603.33184.
purified by column chromatography (SiO2, 12 to 15% EtOAc in
hexane eluant) to obtain the alcohol 24 (1.02 g, 73%) as a col- 7-(3-hydroxyphenyl)-7-methoxy-2,4-dimethylheptanoate
(2R,3R,4S,7S)-Methyl 3-((3R,4R)-3,4-dihydroxy pentanoyloxy)-
(14).
orless oil; [α]2D5 = +14.8 (c 0.4, CHCl3), 1H NMR (300 MHz, To a stirred solution of diester 2 (50 mg, 0.344 mmol) in
CDCl3): δ 1.24 (3H, d, J = 6.04 Hz), 1.37 (3H, s), 1.38 (3H, s), MeOH (5 mL) was added PTSA. The resulting solution was
1.61–1.84 (2H, m), 3.57–3.66 (1H, td, J = 8.31, 3.02 Hz), stirred for 4 h. The organic layer was evaporated under
3.71–3.78 (3H, m); 13C NMR (75 MHz, CDCl3): δ 16.9, 27.1, reduced pressure to afford the crude product, which was puri-
27.2, 33.9, 60.6, 76.7, 81.3, 108.2; IR (CHCl3, cm−1): νmax 3444, fied by column chromatography (SiO2, 30% EtOAc in hexane
2983, 2360, 1635, 1372, 1220, 1090, 1002, 771 cm−1; MS (ESI) eluant) to yield 14 (29 mg, 78% yield) as a colourless gummy
m/z: (M+ + Na) 183; HRMS (ESI): calcd for C8H16O3Na: product; [α]D25 = −2.8 (c 0.25, CHCl3), 1H NMR (300 MHz,
183.0992, found: 183.0995.
CDCl3): δ 0.82 (3H, d, J = 6.79 Hz), 1.11 (3H, d, J = 6.79 Hz),
2-[(4R,5R)-2,2,5-Trimethyl-1,3-dioxolan-4-yl]acetic acid (4). 1.21 (3H, d, J = 6.79 Hz), 1.25–1.38 (2H, m), 1.61–1.88 (3H, m),
To a solution of the above alcohol 24 (1 g, 6.25 mmol) in 2.43 (2H, d, J = 6.04 Hz), 2.68–2.79 (1H, m), 3.18 (3H, s), 3.63
CH2Cl2–H2O (1 : 1) (10 mL) were added TEMPO (270 mg, (3H, s), 3.79 (1H, q, J = 6.79, 6.03 Hz), 4.01 (1H, t, J = 6.79 Hz),
1.57 mmol) and BAIB (6.03 g, 18.75 mmol). After stirring at 4.11 (1H, q, J = 6.79, 6.03 Hz), 5.15 (1H, dd, J = 9.06, 3.02 Hz),
0 °C for 3 h, the reaction mixture was diluted with CH2Cl2 and 6.72 (1H, d, J = 7.55 Hz), 6.76 (1H, s), 6.79 (1H, d, J = 7.55 Hz),
then washed with saturated aqueous Na2S2O3. The organic 7.18 (1H, t, J = 7.55 Hz); 13C NMR (75 MHz, CDCl3): δ 13.4,
layer was dried over Na2SO4, filtered, and the filtrate was con- 13.7, 18.9, 29.6, 33.8, 34.7, 37.8, 41.8, 52.1, 56.5, 69.8, 72.2,
centrated under reduced pressure to give the crude carboxylic 76.5, 83.8, 112.9, 115.2, 119.6, 129.5, 143.1, 156.4, 171.9, 174.9;
acid. The crude product was purified by filter chromatography IR (CHCl3, cm−1): νmax 3432, 2956, 2926, 1734, 1708, 1633,
(SiO2, 23 to 25% EtOAc in hexane eluant) to yield 4 (0.85 g, 1262, 1100, 791 cm−1; MS (ESI) m/z: (M+ + Na) 449; HRMS
1
79%) as a colorless gum; [α]2D5 = +4.8 (c 0.2, CHCl3), H NMR (ESI): calcd for C22H34O8Na: 449.21459, found: 449.21420.
(300 MHz, CDCl3): δ 1.29 (3H, d, J = 6.44 Hz), 1.38 (3H, s), 1.41
(2R,3R,4S,7S)-3-((3R,4R)-3,4-Dihydroxypentanoyloxy)-7-(3-
(3H, s), 2.48–2.68 (2H, m), 3.79 (1H, m), 3.91 (1H, q, J = 7.36, hydroxyphenyl)-7-methoxy-2,4-dimethylheptanoic acid (nhatrangin
4.44 Hz); 13C NMR (75 MHz, CDCl3): δ 17.2, 26.9, 27.2, 37.4, A (1)). To a solution of diester 5 (20 mg, 0.044 mmol) in anhy-
76.4, 78.0, 108.6, 173.3; IR (CHCl3, cm−1): νmax 3443, 2957, drous dichloroethane (2 mL) was added Me3SnOH (60 mg,
2932, 1786, 1639, 1242, 1174, 1056, 944 cm−1; MS (ESI) m/z: 0.464 mmol). The reaction mixture was stirred at 80 °C for
197 (M+ + Na); HRMS (ESI): m/z calcd for C8H14O4Na: 55 hours. The flask was then cooled to room temperature and
197.0942, found: 197.0952.
DCE was removed under reduced pressure and dissolved in
(2R,3R,4S,7S)-Methyl 7-(3-(tert-butyldimethylsilyloxy)phenyl)- 1 mL sat. NaHCO3 and extracted with Et2O. The aqueous layer
7-methoxy-2,4-dimethyl-3-(2-((4R,5R)-2,2,5-trimethyl-1,3-dioxolan- was acidified with 2 mL 3 M HCl and then extracted with
4-yl)acetoxy)heptanoate (2). To a stirred solution of acid 4 EtOAc. The organic layer was washed with brine, dried over
(54 mg, 0.22 mmol) in toluene (2 mL) were added triethyl- Na2SO4 and concentrated under reduced pressure to obtain
amine (0.06 mL, 0.43 mmol), 2,4,6-trichlorobenzoyl chloride the target molecule nhatrangin A 1 (5.6 mg, 30% yield and
(0.0 mL, 0.32 mmol), and DMAP (39.3 mg, 0.32 mmol). 55% starting material was recovered) as a brown colored oil;
Alcohol 3 (50 mg, 0.14 mmol) was then added in toluene [α]2D5 = +0.2 (c 0.05, MeOH), 1H NMR (500 MHz, DMSO-d6):
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δ 0.72 (3H, d, J = 6.8 Hz), 0.82 (3H, d, J = 7.4 Hz), 0.93 (3H, d,
J = 6.8 Hz), 1.23 (2H, m) 1.62 (2H, m), 1.67 (1H, m), 2.17 (1H,
dd, J = 15.4, 5.4 Hz), 2.25 (1H, d, J = 7.8 Hz), 2.36 (1H, dd, J =
15.4, 4.4 Hz), 3.08 (3H, s), 3.50 (1H, qd, J = 6.5, 6.03, 4.2 Hz),
3.74 (1H, m), 3.94 (1H, dd, J = 7.6, 4.4 Hz), 4.79 (1H, dd, J =
7.8, 4.4 Hz), 6.63 (1H, m), 6.65 (1H, m), 6.66 (1H, m), 7.11 (1H,
t, J = 7.55 Hz), 9.31 (1H, s); 13C NMR (125 MHz, DMSO-d6):
δ 13.9, 15.2, 18.0, 29.9, 33.3, 35.3, 38.3, 40.6, 55.9, 68.4, 70.9,
78.0, 83.2, 113.0, 114.2, 116.9, 129.1, 144.0, 157.4, 171.0, 176.5;
IR (CHCl3, cm−1): νmax 3473, 2956, 2928, 1726, 1623, 1465,
1275, 1096 cm−1; MS (ESI) m/z: (M − H)−: 411; HRMS (ESI):
calcd for C21H31O8: 411.20258, found: 411.20317.
7232; (f) A. Kamal, T. Krishnaji and G. B. R. Khanna, Tetra-
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16 Note: The optical rotations were measured at 0.05 c and
0.5 c. In the former, the rotation value obtained was +0.2
and in the latter the instrument showed an error message.
It seems that the solution of the brown colored compound
nhatrangin A (1) is not transparent enough at higher
concentration to make a measurement possible. The low
rotation value at 0.05 c may be due to the low magnitude of
the optical rotation of the natural product itself.
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