Efficient diastereoselective synthesis of (2R,3R,4R)-2-amino-3-hydroxy-4,5- dimethylhexanoic acid, the lactone linkage unit of homophymine A

Article abstract of DOI:10.1248/cpb.c12-00944

For the total synthesis of novel cyclodepsipeptide homophymine A, (2R,3R,4R)-2-amino-3-hydroxy-4,5- dimethylhexanoic acid was successfully synthesized by Evans' asymmetric alkylation and the anti-selective asymmetric hydrogenation of a chiral α-amino-β-keto ester as the key steps.

Full text of DOI:10.1248/cpb.c12-00944

February 2013
Note
Chem. Pharm. Bull. 61(2) 245–250 (2013)
245
Efficient Diastereoselective Synthesis of (2R,3R,4R)-2-Amino-3-hydroxy-
4,5-dimethylhexanoic Acid, the Lactone Linkage Unit of Homophymine
A
Junpei Ohtaka, Akinari Hamajima, Tetsuhiro Nemoto, and Yasumasa Hamada*
Graduate School of Pharmaceutical Sciences, Chiba University; Inohana, Chuo-ku, Chiba 260–8675, Japan.
Received October 26, 2012; accepted November 14, 2012
For the total synthesis of novel cyclodepsipeptide homophymine A, (2R,3R,4R)-2-amino-3-hydroxy-4,5-
dimethylhexanoic acid was successfully synthesized by Evans’ asymmetric alkylation and the anti-selective
asymmetric hydrogenation of a chiral α-amino-β-keto ester as the key steps.
Key words homophymine A; β-hydroxy-α-amino acid; anti-selective asymmetric hydrogenation; Evans’
asymmetric alkylation
Homophymines (A–E and A1–E1), isolated from the New through the corresponding imidazolide of 4 (Table 1). The
Caledonian sponge Homophymia species, are a new family of reaction of methyl tert-butoxycarbonylaminomalonate half
novel dimethylglutamine-containing cyclodepsipeptides with ester (11)21) with the imidazolide failed to give α-tert-
interesting biological activities1–3) (Fig. 1). Homophymine butoxycarbonylamino-β-keto ester 10 (entry 1). To increase
A (1) is known to exhibit cytoprotective activity against the acylating ability, N,N-dimethylaminopyridine (DMAP) or
human immunodeficiency virus-1 (HIV-1) infection and 4-(1-pyrrolidinyl)pyridine (PPY) was added, but it proved to
moderate cytotoxicity. As part of the study on synthesiz- be ineffective (entries 2, 3, respectively). Therefore, we exam-
ing bioactive cyclodepsipeptides of marine origin,4–8) we ined the stepwise procedure using potassium methyl malonate
focused on homophymine A, which contains (2R,3R,4R,6R)- (12).22) Although the imidazolide with the magnesium methyl
3-hydroxy-2,4,6-trimethyloctanoic acid9) and novel amino acid malonate generated from the potassium salt 12, magnesium
residues: (2S,3S,4R)-3,4-dimethylglutamine,10,11) (2R,3R,4S)- chloride, and triethylamine in THF hardly reacted (entry 4),
4-amino-2,3-dihydroxy-1,7-heptandioic acid, and (2R,3R,4R)- an addition of 10mol% DMAP in the above reaction mixture
2-amino-3-hydroxy-4,5-dimethylhexanoic acid (2). In earlier dramatically improved the chemical yield to afford the corre-
studies, we demonstrated that the asymmetric hydrogenation sponding β-keto ester 9 in 95% yield (entry 5).
of α-amino-β-keto esters using chiral catalysts anti-selectively
The β-keto ester 9 was converted to the oxime 13 by reac-
proceeds to afford anti β-hydroxy-α-amino acids in a high tion with sodium nitrite in aqueous acetic acid, and the reduc-
diastereo- and enantioselective manner.12–20) Following is an tion of 13 with palladium on carbon and hydrogen afforded
example of an efficient diastereoselective hydrogenation of a the key intermediate 3 in two steps and in 80% yield (Chart
chiral substrate under the conditions of our developed anti- 3).
selective asymmetric hydrogenation, which provides an ef-
With the key intermediate, we examined the diastere-
ficient synthesis of (2R,3R,4R)-2-amino-3-hydroxy-4,5-dimeth- oselective hydrogenation of 3 under the conditions of our
ylhexanoic acid (AHDMHA, 2). Our synthesis is outlined by a developed anti-selective asymmetric hydrogenation, which
retrosynthetic analysis in Chart 1.
proceeds through dynamic kinetic resolution (DKR) (Table
Our synthesis commenced with the straightforward synthe- 2). Catalytic asymmetric hydrogenation through DKR is one
sis of (R)-2,3-dimethylbutanoic acid (4) (Chart 2). According of the most efficient methods for the preparation of opti-
to Evans’ procedure, the oxazolidinones (6a, 6b) were treated cally active compounds.23–26) The hydrogenation of 3 using
with n-butyl lithium at −78°C and the resulting lithium salts the 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP)-Ru
were acylated with isovaleryl chloride to give imides 7a and catalyst under the standard conditions produced, after N-
7b in 98% and 75% yield, respectively. The imides 7a and 7b tert-butoxycarbonyl protection, the desired anti β-hydroxy-
were treated with lithium diisopropylamide in tetrahydrofuran α-amino acid ester 15 with a 90:10 diastereoselectivity
(THF) at −78°C followed by methylation of the resulting eno-
lates with iodomethane to afford the methylated products 8a
and 8b in 80% and 45% yield, respectively. In this asymmet-
ric methylation, 7b was inferior to 7a in the diastereoselectiv-
ity. Although crude 8a was a 93:7 mixture of diastereomers,
the recrystallization of the crude material from n-hexane
provided pure 8a in diastereomeric purity and in 80% yield.
The cleavage of the chiral auxiliary was accomplished by the
treatment with alkaline hydrogen peroxide in aqueous THF.
In the next β-keto ester formation, it was found that the
acid chloride derived from 4 was volatile. To prevent the
loss of valuable 4, we first attempted the modified procedure
The authors declare no conflict of interest.
Fig. 1. Structure of Homophymine A (1)
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: hamada@p.chiba-u.ac.jp

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Vol. 61, No. 2
Chart 1. Retrosynthetic Analysis of (2R,3R,4R)-2-Amino-3-hydroxy-4,5-dimethylhexanoic Acid (2)
(2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid em-
ploying the diastereoselective hydrogenation of a chiral sub-
strate under the conditions of our developed anti-selective
asymmetric hydrogenation as a key step. This key step pro-
ceeds with reagent-control to afford the anti-hydroxyamino
acid in excellent diastereoselectivity and yield.
Experimental
Melting points were measured with a SIBATA NEL-270
melting point apparatus. Optical rotations were measured on
a JASCO DIP-14-polarimeter and JASCO P-1020 polarimeter
with a sodium lamp (589nm). Infrared spectra were recorded
on a JASCO FT/IR-230 fourier transform infrared spectro-
photometer. NMR spectra were recorded on JEOL JNM-GSX
400α (400MHz) and JNM ECP400 spectrometers (400MHz),
unless otherwise indicated. Chemical shifts are recorded in
parts per million (ppm) downfield from tetramethylsilane as
an internal standard. Mass spectra were obtained on a JEOL
Chart 2. Synthesis of (R)-2,3-Dimethylbutanoic Acid (4)
1
(judged by H-NMR analysis) in 70% conversion yield (entry HX-110A (LRFAB, LREI) spectrometer. HPLC analyses were
1). Because of the bulkiness of the substituent adjacent to carried out on a chiral column indicated in each experiment.
the carbonyl functionality, the reaction was incomplete even Column chromatography was performed with silica gel BW-
after 72h at 50°C. Although the recrystallization of the crude 820MH (Fuji Davison Co.). All reactions were carried out in
product furnished the diastereomerically pure 15 in 51% yield, oven-dried glassware with magnetic stirring unless otherwise
the chemical yield was unsatisfactory. However, using an noted.
increased amount of the catalyst provided a better diastereose-
(R)-4-Benzyl-3-(3-methylbutanoyl)oxazolidin-2-one (7a)
lectivity and improved the yield of pure 15 (entry 2). We also To a stirred solution of (R)-Evans oxazolidinone 6a (3.54g,
disclosed that Iridium-MeO-2,2′-dimethoxy-5,5′-bis(diphenyl- 20mmol) in THF (100mL) at −78°C was added a 1.6m solu-
phosphinio)biphenyl (BIPHEP) is an efficient catalyst for the tion of n-BuLi (in n-hexane, 13.1mL, 21mmol). After stirring
anti-selective asymmetric hydrogenation of alkyl substrate the reaction mixture for 30min, isovaleryl chloride (2.7mL,
with a bulky group at the 4 position.15–17) Therefore, we at- 22mmol) was added at −78°C and the reaction mixture was
tempted the hydrogenation of 3 using the Ir catalyst, but no stirred for 1h. The reaction mixture was quenched with a satd
reaction was observed. Nevertheless, it is noteworthy that, al- NH4Cl solution. (100mL) and separated. The aqueous layer
though the starting 3 is a mixture of diastereomers, the highly was extracted with EtOAc (200mL). The combined organic
stereoselective hydrogenation proceeds in a reagent-controlled layers were washed with a satd NaHCO3 solution (100mL),
manner to afford the anti product in a satisfactory yield and water (100mL), and brine (100mL), dried over Na2SO4, and
diastereoselectivity.
concentrated in vacuo to give a colorless residue. The crude
For the confirmation of stereochemistry, 15 was converted product was purified by silica gel column chromatography
to the acetonide 16 using 2,2-dimethoxypropane and boron (n-hexane–EtOAc=4:1) to give 7a (5.1g, 98%) as a colorless
trifluoride etherate (Chart 4). The acid hydrolysis of 16 in solid: [α]D20 −45.2 (c=0.76, CHCl3); mp 41–42°C; IR (neat)
1
refluxing 6m hydrochloric acid furnished (2R,3R,4R)-2-amino- ν 2958, 2926, 1780, 1698, 1389, 1306, 1210cm−1; H-NMR
3-hydroxy-4,5-dimethylhexanoic acid (2) in 94% yield. Its (400MHz, CDCl3) δ: 1.01 (3H, d, J=6.8Hz), 1.02 (3H, d,
NMR spectrum was identical with that of the natural 2 de- J=6.8Hz), 2.22 (1H, sept., J=6.8Hz), 2.75 (1H, m), 2.77 (1H,
rived from homophymine A.
dd, J=9.6, 6.8Hz), 2.89 (1H, dd, J=6.8, 16.0Hz), 3.31 (1H,
In addition, the anti-stereochemistry of 15 was unambigu- dd, J=3.2, 13.2Hz), 4.14–4.21 (2H, m), 4.65–4.71 (1H, m),
ously determined by the nuclear Overhauser effect (NOE) ex- 7.21–7.35 (5H, m); 13C-NMR (100MHz, CDCl3) δ: 23.4, 22.5,
periment of 16 and comparisons of their J-values with the 25.0, 37.9, 43.9, 55.1, 66.0, 127.3, 128.9, 129.4, 135.3, 153.4,
congener 18 derived from known (2R,3R)-3-hydroxyleucine 172.6; high resolution (HR)-MS (electrospray ionization-time-
(17) as shown in Fig. 2.
In conclusion, we succeeded in the first synthesis of Found 262.1440.
of-flight (ESI-TOF)) Calcd for C15H20NO3 [M+H]+ 262.1443,

February 2013
247
Table 1. Synthesis of β-Keto Esters
Entry
Malonate
Product
Additive
Yielda)
1
2
3
4
5
11
11
11
12
12
10
10
10
9
—
DMAP
PPY
—
DMAP
NR
NR
NR
∼10%
95%
9
a) Isolated yield. NR: no reaction.
Chart 3. Synthesis of α-Amino-β-keto Ester 3
Table 2. Asymmetric Hydrogenation of α-Amino-β-keto Ester 3 through Dynamic Kinetic Resolution
Entry
1
Conditions
Temp. and time
dra)
Yieldb) (in two steps)
51%c)
[RuCl2(C6H6)]2 (3mol%), (R)-BINAP
(6mol%), H2 (100atm), DCM (0.3m)
[RuCl2(C6H6)]2 (5mol%), (R)-BINAP
(10mol%), H2 (100 atm), DCM (0.3m)
[IrCl(cod)]2 (0.5mol%), (R)-MeO-BIPHEP
(1.3mol%), NaBARF (1mol%), AcONa
(1eq), H2 (4.5atm), AcOH (0.2m)
1
50°C, 72h
90:10
2
3
50°C, 72h
25°C, 96h
95:5
—
76%
NRd)
a) Diastereomeric ratio was determined by H-NMR analysis after Boc protection. b) Isolated yield of 15 after diastereomeric purification by recrystallization. c) The conver-
sion yield of the first step was 70% (judged by 1H-NMR analysis of the crude reaction mixture). d) No reaction.
(R)-4-Benzyl-3-((R)-2,3-dimethylbutanoyl)oxazolidin-2- water (100mL), and brine (100mL), dried over Na2SO4, and
one (8a) To a stirred solution of lithium diisopropylamide concentrated in vacuo to give the crude product in a 93:7
1
(LDA) (23.4mmol) in THF (100mL) at −78°C was added diastereoselectivity (judged by H-NMR spectrum). The crude
7a (5.1g, 19.5mmol). After stirring the mixture for 30min, product was purified by silica gel column chromatography
iodomethane (1.46mL, 23.4mmol) was added and the reac- (n-hexane–EtOAc=4:1) followed by recrystallization from n-
tion mixture was allowed to warm to 0°C and stirred at hexane to give diastereomerically pure 8a (4.65g, 80%) as col-
0°C for 3h. The reaction mixture was quenched with a satd orless needles: [α]D20 −86.4 (c=1.00, CHCl3); mp 52–53°C; IR
NH4Cl solution (100mL) and separated. The aqueous layer (neat) ν 2965, 2918, 1776, 1696, 1455, 1384, 1348, 1209cm−1;
was extracted with EtOAc (200mL). The combined organic 1H-NMR (400MHz, CDCl3) δ: 0.94 (3H, d, J=6.8Hz), 0.95
layers were washed with a satd NaHCO3 solution (100mL), (3H, d, J=6.8Hz), 1.17 (3H, d, J=6.8Hz), 1.99 (1H, octet, J=

248
Vol. 61, No. 2
Chart 4. Synthesis of (2R,3R,4R)-2-Amino-3-hydroxy-4,5-dimethylhex-
anoic Acid (2)
Fig. 2. NOE Experiment of 16
6.8Hz), 2.77 (1H, dd, J=9.6, 13.2Hz), 3.29 (1H, dd, J=3.2, (3H, d, J=6.8Hz), 1.05 (3H, d, J=6.8Hz), 1.98 (1H, octet, J=
13.2Hz), 3.60 (1H, quint., J=6.8Hz), 4.14–4.70 (2H, m), 4.67 6.8Hz), 2.44 (1H, quint., J=6.8Hz), 3.49 (2H, s), 3.74 (3H, s);
(1H, m), 7.21–7.35 (5H, m),; 13C-NMR (100MHz, CDCl3) δ: 13C-NMR (keto form, 100MHz, CDCl3) δ: 12.3, 18.5, 21.2,
13.8, 18.6, 21.2, 30.6, 37.9, 43.5, 55.5, 65.9, 127.3, 128.9, 129.4, 29.9, 48.1, 52.2, 53.0, 167.7, 206.5; HR-MS (ESI-TOF) Calcd
135.4, 153.1, 177.1; HR-MS (ESI-TOF) Calcd for C16H22NO3 for C9H16NaO3 [M+Na]+ 195.0997, Found 195.0994.
[M+H]+ 276.1600, Found 276.1588.
(R)-2-Hydroxyimino-4,5-dimethyl-3-oxo-hexanoic Acid
(R)-2,3-Dimethyl-butyric Acid (4) To a solution of 8a Methyl Ester (13) To a stirred solution of β-ketoester 9
(2.47g, 10.9mmol) in THF–H2O (1:1, 50mL) at 23°C was (270mg, 1.57mmol) in AcOH (4mL) at 0°C was added a
added LiOH H2O (684mg, 16.3mmol) followed by a 30% NaNO2 solution (325mg, 4.7mmol, in 4mL water). After
H2O2 solution (2.2mL, 20mmol). After stirring the mix- stirring the mixture at 23°C for 2h, the reaction mixture
ture at 23°C for 6h, the reaction mixture was acidified with was quenched with a satd NaHCO3 solution and extracted
a 1m KHSO4 solution (25mL) and extracted with EtOAc with EtOAc (100mL×2). The combined organic layers were
(150 m L×2). The combined organic layers were washed with washed with a satd NaHCO3 solution and brine, dried over
brine, dried over Na2SO4, and concentrated in vacuo to give Na2SO4, and concentrated in vacuo to give the crude product.
a colorless residue. The crude product was purified by silica The crude product was purified by silica gel column chroma-
gel column chromatography (n-hexane–EtOAc=4:1) to give tography (n-hexane–EtOAc=4:1) to give 13 (249mg, 80%)
4 (1.02g, 81%) as a colorless oil: [α]D20 −22.3 (c=0.74, CHCl3); as a colorless oil: [α]D20 −16.1 (c=3.85, CHCl3); IR (neat) ν
1
1H-NMR (400MHz, CDCl3) δ: 0.93 (3H, d, J=6.8Hz), 0.97 3342, 2963, 2875, 1731, 1677, 1435, 1292, 1212cm−1; H-NMR
(3H, d, J=6.8Hz), 1.13 (3H, d, J=6.8Hz), 1.95 (1H, octet, (400MHz, CDCl3) δ: 0.89 (3H, d, J=6.8Hz), 0.92 (3H, d,
J=6.8Hz), 2.27 (1H, quintet, J=6.8Hz); 13C-NMR (100MHz, J=6.8Hz), 1.07 (3H, d, J=6.8Hz), 2.02 (1H, octet, J=6.8Hz),
CDCl3) δ: 13.3, 18.9, 20.6, 30.7, 46.0, 182.9. The spectroscopic 3.21 (1H, quint., J=6.8Hz), 3.91 (3H, s), 9.13–9.32 (1H,
data for 4 were consistent with those of the literature.27)
brs); 13C-NMR (100MHz, CDCl3) δ: 12.8, 18.9, 21.2, 30.6,
(R)-4,5-Dimethyl-3-oxo-hexanoic Acid Methyl Ester (9) 46.8, 52.8, 150.6, 162.1, 200.0; HR-MS (ESI-TOF) Calcd for
To a stirred solution of carboxylic acid 4 (423mg, 3.64mmol) C9H15NNaO4 [M+Na]+ 224.0899, Found 224.0892.
in THF (50mL) was added carbonyldiimidazole (885mg,
5.46mmol) at 23°C. After stirring the mixture for 6h, the re- drochloride (3)
Methyl (4R)-2-Amino-4,5-dimethyl-3-oxohexanoate Hy-
suspension of oxime 13 (210mg,
A
action mixture was quenched with water (50mL) and extract- 1.04mmol), 2m HCl–MeOH (1.6mL, 3.2mmol), and 2.8
ed with EtOAc (50mL×2). The combined organic layers were wt% Pd–C (40mg, 0.01mmol) in MeOH (5mL) was stirred
washed with brine, dried over Na2SO4, and concentrated in under hydrogen atmosphere (1atm) at 23°C for 6h. The reac-
vacuo to give the crude imidazolide as a colorless oil. A sus- tion mixture was filtered through a celite pad and the filtrate
pension of potassium methyl malonate (1.1g, 7.0mmol), pow- was concentrated in vacuo to give 3 (232mg, quant. as a
dered MgCl2 (666mg, 7.0mmol), and Et3N (2mL, 14mmol) 1:1 mixture of diastereomers) as a colorless solid: [α]D20 17.1
in THF (35mL) was stirred at 23°C for 2h. The crude im- (c=1.20, MeOH); mp 123–125°C; IR (neat) ν 2962, 2875,
idazolide (499mg, 3.0mmol) and DMAP (37mg, 0.3mmol) 2624, 1752, 1726, 1585, 1508, 1439, 1369, 1277, 1139cm−1;
were added at 23°C and the reaction mixture was stirred for 1H-NMR (1:1 diastereomers, 400MHz, CDCl3) δ: 0.80 (3H,
48h. The reaction was quenched with a satd NH4Cl solution d, J=6.8Hz), 0.87 (3H, d, J=6.8Hz), 0.90 (3H, d, J=6.8Hz),
(25mL) and extracted with EtOAc (50mL×2). The combined 1.01 (6H, d, J=6.4Hz), 1.20 (3H, d, J=7.2Hz), 1.93–2.02 (1H,
organic layers were washed with a satd NaHCO3 solution and m), 2.15–2.23 (1H, m), 2.85–2.92 (1H, m), 2.98–3.05 (1H, m),
brine, dried over Na2SO4, and concentrated in vacuo to give 3.88 (3H, s), 3.91 (3H, s), 5.30 (1H, s), 5.38 (1H, s); 13C-NMR
the crude product. The crude product was purified by silica (1:1 diastereomers 100MHz, CDCl3) δ: 11.1, 14.4, 17.9, 18.9,
gel column chromatography (n-hexane–EtOAc=4:1) to give 21.1, 21.3, 29.3, 30.3, 49.5, 50.6, 54.1, 54.4, 61.2, 61.4, 163.3,
9 (583mg, 93% as a 78:22 mixture of keto and enol tauto- 163.5, 201.4; HR-MS (ESI-TOF) Calcd for C9H18NO3 [M+H]+
mers) as a colorless oil: [α]D20 −23.9 (c=0.8, CHCl3); IR (neat) 188.1287, Found 188.1315.
ν 2961, 2875, 2138, 1716, 1655, 1309, 1210cm−1; 1H-NMR
(keto form, 400MHz, CDCl3) δ: 0.87 (3H, d, J=6.8Hz), 0.94 anoate Hydrochloride (14) Ru-(R)-BINAP complex was
Methyl (2R,3R,4R)-2-Amino-3-hydroxy-4,5-dimethylhex-

February 2013
249
prepared from [RuCl2(C6H6)]2 (48mg, 0.096mmol) and (R)- 21.0, 21.1, 24.9, 25.8, 26.3, 27.3, 27.9, 28.0, 28.9, 29.0, 39.1,
BINAP (121mg, 0.195mmol) according to the literature proce- 39.3, 51.8, 51.9, 63.6, 63.8, 79.4, 79.6, 80.3, 80.7, 94.3, 95.1,
dure.28) The resulting red-brown catalyst was dried in vacuo at 151.9, 152.8, 171.3, 171.42; HR-MS (ESI-TOF) Calcd for
50°C for 2h. A degassed solution of α-amino-β-keto ester hy- C17H31NNaO5 [M+Na)]+ 352.2100, Found 352.2060.
drochloride 3 (449mg, 1.9mmol) in dichloromethane (DCM)
(2R,3R,4R)-2-Amino-3-hydroxy-4,5-dimethylhexanoic
(6mL) was added to the catalyst under an argon atmosphere. Acid (2) A solution of acetonide 16 (22mg, 0.067mmol) in
The reaction was carried out in a glassware placed in a stain- a 6m HCl solution (1mL) was heated to reflux for 12h. The
less autoclave apparatus. The mixture was hydrogenated at resulting solution was concentrated in vacuo to give crude
50°C under 100 atm of hydrogen for 72h. The solvent was amino acid. The residue was purified with Dowex 50W-X4
removed in vacuo to leave crude 14 and the residue was re- ion-exchange resin (H+ form) using a 2m pyridine solution
crystallized from DCM–EtOAc to give pure β-hydroxyamino as an eluent to give the desalted (2R,3R,4R)-hydroxyamino
acid 14 as colorless crystals (347mg, 81%, >99%dr): [α]D20 acid 2 (11mg, 94%) as a colorless powder: [α]D20 −22.9 (HCl
−14.4 (c=1.0, MeOH); mp 178–179°C; IR (neat): ν 3342, 2959, salt, c=0.55, MeOH); mp 195–197°C; IR (HCl salt, neat) ν
1
1747, 1508, 1234, 1033cm−1; H-NMR (400MHz, CD3OD) δ: 3411, 2962, 2875, 2632, 1752, 1726, 1594, 1508, 1439, 1369,
1
0.83 (3H, d, J=6.8Hz), 0.88 (3H, d, J=6.8Hz), 0.99 (3H, d, 1277, 1139cm−1; H-NMR (400MHz, CD3OD) δ: 0.80 (3H,
J=6.8Hz), 1.75–1.86 (1H, m), 2.16–2.28 (1H, m), 3.67–3.76 d, J=7.2Hz), 0.85 (3H, d, J=7.2Hz), 0.95 (3H, d, J=7.2Hz),
(1H, m), 3.88 (3H, s), 4.12–4.26 (1H, m); 13C-NMR (100MHz, 1.81–1.89 (1H, m), 2.19–2.26 (1H, m), 3.65 (1H, dd, J=2.4,
CDCl3) δ: 10.5, 15.7, 22.6, 28.1, 42.6, 54.3, 58.1, 75.3, 171.8; 10.4Hz), 3.72 (1H, dd, J=2.4Hz); 13C-NMR (100MHz,
HR-MS (ESI-TOF) Calcd for C9H20NO3 [M+H]+ 190.1443, CD3OD) δ: 9.5, 14.9, 21.4, 27.2, 41.2, 59.0, 74.0, 171.6; HR-MS
Found 190.1465. The diastereomeric ratio of crude 14 was de- (ESI-TOF) Calcd for C8H18NO3 [M+H]+ 176.1287, Found
1
1
termined by the analysis of its H-NMR spectrum to be 95:5. 176.1331. The NMR spectrum of natural AHDMHA: H-NMR
Methyl (2R,3R,4R)-2-(tert-Butoxycarbonylamino)-3-hy- (500MHz, CD3OD) δ: 0.80 (3H, d, J=7.0Hz), 0.85 (3H, d,
droxy-4,5-dimethylhexanoate (15) To a stirred solution of J=6.9Hz), 0.94 (3H, d, J=7.0Hz), 1.84 (1H, m), 2.22 (1H,
14 (300mg, 1.33mmol) in DCM (13mL) at 23°C was added m), 3.65 (1H, dd, J=2.6, 10.0Hz), 3.70 (1H, dd, J=2.6Hz);
DIEA (0.35mL, 2.0mmol) and Boc2O (440mg, 2.0mmol) 13C-NMR (125MHz, CD3OD) δ: 9.5, 14.9, 21.4, 27.2, 41.2,
and stirred for 12h. Then the mixture was quenched with a 59.0, 74.0, 171.5.
1m KHSO4 solution (20mL) and extracted by DCM (20mL).
The organic layer was washed with a satd NaHCO3 solu-
Acknowledgment This work was financially supported
tion (20mL) and brine (20mL), dried over Na2SO4, filtered, in part by a Grant-in-Aid for Scientific Research (B) from the
and concentrated in vacuo to give crude product. The crude Ministry of Education, Culture, Sports, Science and Technol-
product was purified by silica gel column chromatography (n- ogy of Japan.
hexane–EtOAc=4:1) to give 12 (361mg, 94%) as a colorless
solid: [α]D20 −14.5 (c=1.00, CHCl3); mp 70–71°C; IR (neat) ν
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3403, 2959, 1716, 1506, 1366, 1163cm−1; H-NMR (400MHz,
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CDCl3) δ: 0.77 (3H, d, J=6.8Hz), 0.80 (3H, d, J=6.8Hz), 0.92
(3H, d, J=6.8Hz), 1.45 (9H, s), 1.44–1.55 (1H, m), 2.11–2.23
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(4R,5R)-3-tert-Butyl-4-methyl-2,2-dimethyl-5-((R)-3-
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stirred solution of Boc-AHDMHA 15 (22mg, 0.076mmol) and
2,2-dimethoxypropane (47µL, 0.38mmol) in DCM (0.8mL) at
23°C was added BF3·OEt2 (0.5 µL, 0.0038mmol) and the reac-
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(5mL), dried over Na2SO4, and concentrated in vacuo to give
crude product. The crude product was purified by silica gel
column chromatography (n-hexane–EtOAc=4:1) to give 16
(18mg, 72%) as a colorless solid: [α]D20 −2.9 (c=0.37, CHCl3);
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