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HETEROCYCLES, Vol. 87, No. 11, 2013, pp. 2267 - 2281. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 20th August, 2013, Accepted, 20th September, 2013, Published online, 3rd October, 2013
DOI: 10.3987/COM-13-12812

SYNTHESIS OF TETRASUBSTITUTED PYRROLIDINE DERIVATIVESEMPLOYING ! -LACTAM AS A CHIRAL BUILDING BLOCK
Genta Tadano,1 Koji Ishikura,1 and Keiji Tanino*2
1

Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1

Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.

2

Department ofChemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
E-mail: genta.tadano@shionogi.co.jp; ktanino@sci.hokudai.ac.jp
Abstract – A new method for constructing tetrasubstituted pyrrolidine derivatives
using the known !-lactam as a chiral building block was developed. After
construction of a carbapenem skeleton, the !-lactam moiety was cleaved to afford
a multi-substituted pyrrolidine. The present method was employed for thesynthesis of A-315675 analogs.

INTRODUCTION
Multi-substituted pyrrolidines are widely found as a substructure of natural and non-natural biologically
active compounds. For example, kainic acid is known as the potent glutamic acid receptor antagonist, andA-3156751 is a neuraminidase inhibitor developed by the Abott laboratories. The 3-hydroxypyrrolidine
derivatives such as detoxin A12 and lactacystin3 also have promising beneficial biological activities(Figure 1). Owing to this interest, we have been intrigued with the challenge of developing an efficientand stereocontrolled synthetic method for these types of pyrrolidines. We planned the synthesis of
A-315675 analogs 1 and 2 having a hydroxyl group at the C-3 position, because of our interest in theirpharmacological properties.

N
H

CO2H

kainic acid

OH OH

OAc

CO2H
AcHN

N
HH
OMe

A-315675

CO2H

H
N
NH2

O

OH

CO2H

O

detoxin A1

Figure 1. Structures of bioactive pyrrolidine derivatives

N
H

O
S

HO2C

NHAc

lactacystin

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HETEROCYCLES, Vol. 87, No. 11, 2013

RESULTS AND DISCUSSION
The strategy toward the stereoselective synthesis of 1 and 2 is shown in Scheme 1. We planned toconstruct the pyrrolidine ring through cyclization of optically active !-lactam 44 followed by ringcleavage of bicyclic compound 3. The Rh-catalyzed intramolecular N-H insertion reactions of diazo ketoester 4 have been commonly used for the synthesis of carbapenem antibiotics, and the rigid conformationof the bicyclic skeleton would be advantageous for controlling the stereochemistry of the highly
substituted pyrrolidine ring.
4

AcHN

5

1

OH

OTMS
H

OH

3

AcHN

N 2 CO2H
1'
HH
2'
OH

N
HH
OH

CO2H

OH

N

O

O

2

1

OH
NH O

O

OPMB

N2

OPMB

O

4

3

Scheme 1. Synthetic plan for 1 and 2
Carbapenem derivative 8 possessing the suitable protective groups was synthesized as shown in Scheme 2.
First, secondary alcohol 4 was treated with TMSCl and imidazole in THF-AcOEt to afford O-protecteddiazo compound 5 which was subjected to the intramolecular cyclization reaction catalyzed by Rh2(OAc)4.
Under the influence of N,N-diisopropylethylamine (DIPEA), ketone 6 underwent inversion of the C-4
methyl group located at the concave face, giving rise to the corresponding epimer 7. Reduction of ketone
7 with NaBH4 in THF-EtOH resulted in formation of alcohol 8 with high stereoselectivity. The
configuration of the hydroxyl group in 8 was established by NOESY experiments, showing that thehydride attack occurred from the convex face of bicyclic ketone 7.

OH

O

N2
NH O

OPMB

THF-AcOEt, 87%

O

O

OTMS

N2

NH O

4

OPMB

Rh2(OAc)4
CH2Cl2

O

5
OTMS

DIPEA
MeCN

TMSCl, imidazole

OTMS

O

O

N
O
7

NaBH4

OPMB

THF-EtOH
75% (3 steps)

O

N
6

OTMS

H

O

H
OH

N
O

OPMB

8

Scheme 2. Synthesis of carbapenem derivative 8

H

O

4

O
OPMB

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Protection of alcohol 8 by the reaction with TBSOTf and 2,6-lutidine in CH2Cl2 furnished 95 which was
further transformed into 2, the (1’S, 2’R)-diastereomer of 1 as shown in Scheme 3. Thus, carbapenem
derivative 9 was treated with TMSCl in allyl alcohol to afford allyl ester 10 through alcoholysis of the!-lactam moiety and removal of the TMS group. The Pd-catalyzed deallylation reaction of allyl ester 10
followed by protection of the secondary amine in the resulting carboxylic acid 11 with Boc2O afforded 12.
Introduction of an amino group on the side chain was accomplished by the Curtius rearrangement ofcarboxylic acid 12 employing diphenylphosphoryl azide (DPPA) to yield 2-oxazolidone derivative 13.
The conformationally fixed oxazolidone ring was useful for establishing the stereochemistry of the newly
formed C-N bond by the NOESY experiments. Cleavage of the oxazolidone ring was then achieved
through acetylation of 13 to afford imide 14 followed by treatment with Ba(OH)2, giving rise to a mixtureof 13 and alcohol 15. Finally, alcohol 15 was converted to 2 through removal of both the Boc and PMBgroups mediated by TFA and desilylation in aqueous TFA.

8

OTMS

TBSOTf2,6-lutidine
CH2Cl2, 53%

O

H
OTBS

N
O

OH

TMSCl
allyl alcohol

O

50%

OPMB

H

HN
O

OH
O

THF

H
OTBS

BocN
OH
O

OPMB

EtOH - H2O

HN
OH

O
O

tolueneHN
H BocN

OTBS

Ac2O
DMAP

O

O

HN
O

OTBS

BocN
O
15 (35%)

OPMB

TFA
70%

OTBS

BocN

OPMB

O
14

HO

H

OPMB

O

H
N

O

75%

OPMB

O

OTBS

11

13
HO

13 (49%)DPPA
TEA

52% (3 steps)

12

Ba(OH)2

THF

OPMB

O

O

H

10

9

Boc2O
TEA

OTBS

OH

Pd(PPh3)4morpholine

HN
O

H
OTBS

HN
O

OH

TFA
H2O
44%

16

OH
AcHN

N
HH
OH

CO2H

2

Scheme 3. Synthesis of 2, the (1’S, 2’R)-diastereomer of 1
Having established the method for conversion of the known compound 4 to tetrasubstituted pyrrolidine
derivative 2, the synthesis of its isomer 1 which possesses the stereochemistry similar to that of A-315675
was undertaken. Since it was necessary to invert the configurations at the C-1’ and C-2’ positions of 2,
the synthetic intermediate 10 was converted to ketone 18 through protection of the amino group and

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HETEROCYCLES, Vol. 87, No. 11, 2013oxidation with Dess-Martin periodinane6 (DMP) (Scheme 4). Treatment of the product with DIPEA gave
an inseparable mixture (1:1.2) of the C-1’ epimers 18a and 18b which was subjected to NaBH4 reductionin MeOH-DME. The resulting mixture involving the diastereomers of alcohol 17 was separated by silica
gel column chromatography, and alcohol 19, the configuration of which was not clear at this point, wasisolated in 29% yield. Though the other diastereomers were difficult to separate from each other, thesamples for NMR analysis were obtained in small amounts by HPLC. Figure 2 shows the partial 1H NMR
spectra of the alcohols; (A) alcohol 17, (B) the mixture of diastereomers obtained by NaBH4 reduction of

a 1:1.2 mixture of ketones 18a and 18b, (C) alcohol 19 after isolation from the mixture, (D) adiastereomer of 17 and 19, and (E) another diastereomer of 17 and 19. Alcohol 19 was then transformed
into 1 by a similar reaction sequence for the synthesis of 2. The Pd-catalyzed deallylation of 19 followedby the Curtius rearrangement of carboxylic acid 20 afforded oxazolidone 21, and the relative
stereochemistry at the C-1’ and C-2’ positions was determined by NOE experiments at this stage.
Acetylation of 21 using Ac2O and DMAP gave 22, and subsequent hydrolysis of oxazolidone with
Ba(OH)2 produced a separable mixture of alcohols 23 and 21. Finally, the desired compound 17 was

obtained from alcohol 23 through desilylation with TBAF and removal of the Boc and DMB group with
TFA.8
OH
10

Boc2O

O

THF, 97%

BocN
O
O

O

1) DMP, Py

H

CH2Cl2, 97%

OTBS2) DIPEA

OPMB

1'

O

MeCN, 97%

17
OH
O

H

BocN
O
O
19

OTBS
OPMB

O
Ac2O, DMAP
93%

O

OH

Pd(PPh3)4morpholine

O

THF, 91%

OTBS

BocN
OH

OPMB

HN
O

H
BocN
O
24

OH
OPMB

DPPA, TEA

Ba(OH)2OTBS
OPMB

EtOH - H2OOtoluene, 90%75%

21 (43%)

HN
O

H
BocN
O

OH
AcHN

N
HH
OH

OTBS
OPMB

21

23 (45%)TFA

HN
H BocNOHOO

MeOH-DME, 29%

OPMB

O

O
20

BocN

NaBH4

OTBS

H

22
HO

BocN
O
O

18
! : " = 1 : 1.2

H
N

O

H

CO2H

1

Scheme 4. Synthesis of A-315675 analog 1

OTBS
OPMB

TBAF
THF, 92%

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HO Hb
O

H

BocN
O
O

Ha
OTBS
OPMB

Figure 2. 1H NMR Spectra (400 MHz, partial) of (A) pure alcohol 17, (B) a mixture of diastereomers
obtained by NaBH4 reduction of ketones 18a and 18b, (C) pure alcohol 19, (D) a diastereomer of 17 and19 (containing a small amount of 19), and (E) another diastereomer of 17 and 19 (containing a small
amount of 17)
In summary, we have achieved the asymmetric synthesis of A-315675 analog 1 and its side chain
diastereomer 2, on the basis of the construction of a carbapenem skeleton and the ring opening reaction of
the !-lactam. This method shows promise for the stereocontrolled synthesis of various multi-substituted
pyrrolidine compounds. Synthetic application to new pyrrolidine derivatives is now under investigation.
EXPERIMENTAL
IR spectra were recorded on a JASCO FT/IR-4100 spectrophotometer using 5 mm NaCl or CaF2 plates.
Wavelength of maximum absorbance (V max) is quoted in cm-1. 1H-NMR spectra were recorded on a
Varian Unity INOVA 500 spectrometer (500 MHz) in CDCl3 ("H 7.26) with tetramethylsilane as aninternal standard. Chemical shifts are reported in part per million (ppm), and signal are expressed as
singlet (s), doublet (d), triplet (t), quartet (q), double doublet (dd), double triplet (dt), broad singlet (brs)and multiplet (m). 13C-NMR spectra were recorded on a Varian Unity INOVA 500 spectrometer (125MHz) in CDCl3 ("C 77.0) with tetramethylsilane as an internal standard. Chemical shifts are reported inpart per million (ppm). Electro splay ionization mass (ESI-MS) and high resolution mass (HR-MS)
spectra were recorded on a Thermo Scientific Exactive at the Instrumental Analysis Division, Equipment
Management Center Creative Research Institution, Hokkaido University. Reactions were monitored by

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LCMS (SHIMADZU LCMS-2010EV) or TLC with Merck Kieselgel 60 F254. The Silica gel used forcolumn chromatography was ISCO gold or Yamazen pre packed columns. All experiments were carriedout under positive pressure of dry nitrogen. All of the organic solvents used in this study were dried overappropriate drying agents.
O-Protected diazo compound (5). To a solution of 4 (10.0 g, 26.6 mmol) in THF (30 mL) and AcOEt(90 mL) was added imidazole (3.26 g, 48.0 mmol) and TMSCl (4.77 mL, 37.3 mmol) at room
temperature. After stirring for 1 h at the same temperature, the reaction mixture was treated with H2O andthe aqueous layer was extracted with AcOEt. The combined organic layer was washed with H2O andbrine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, the residue was purified byflash silica gel column chromatography (hexane-AcOEt = 1 : 1) to give 5 as a yellow oil (10.3 g, 23.1
mmol, 87%).
yellow oil. IR (neat) 3263, 2959, 2143, 1758, 1714, 1651, 1516, 1376, 1299, 1251, 991, 844 cm-1;
1

H-NMR (500 MHz, CDCl3) !: 0.10 (9H, s), 1.15 (3H, d, J = 6.8 Hz), 1.21 (3H, d, J = 6.1 Hz), 2.98-2.96(1H, m), 3.80 (1H, dd, J = 2.4, 4.9 Hz), 3.82 (3H, s), 3.95 (1H, ddd, J = 13.8, 6.8, 4.9 Hz), 5.20 (2H, dd, J= 18.4, 11.8 Hz), 5.95 (1H, s), 6.91 (2H, dt, J = 8.8, 2.2 Hz), 7.31 (2H, dt, J = 8.8, 2.2 Hz); 13C NMR (125MHz, CDCl3) !: 0.37, 22.64, 43.36, 52.65, 55.44, 61.33, 65.75, 67.21, 114.27, 127.11, 130.54, 160.16,
161.25, 168.21, 194.49; HRMS (ESI) Calcd for C21H29N3O6NaSi ([M+Na]+): 470.1718. Found 470.1715.
Ketone (6). To a solution of 5 (10.3 g, 23.1 mmol) in CH2Cl2 (40 mL) was added Rh2(OAc)4 (68.0 mg,
0.155 mmol) at room temperature. After stirring for 6 h at 43 °C, the reaction mixture was concentrated
under vacuum to give 6 that was used for the next step without purification.
purple oil. IR (neat) 3446, 2959, 1770, 1614, 1517, 1303, 1252, 1175, 1035, 845 cm-1; 1H-NMR (500
MHz, CDCl3) !: 0.13 (9H, s), 1.17 (3H, d, J = 7.8 Hz), 1.28 (3H, d, J = 6.1 Hz), 2.72-2.79 (1H, m), 3.19
(1H, dd, J = 6.1, 2.4 Hz), 3.80 (3H, s), 4.15 (1H, dd, J = 7.8, 2.4 Hz), 4.23-4.29 (1H, m), 4.64 (1H, s),5.13 (2H, s), 6.88 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.8 Hz); 13C NMR (125 MHz, CDCl3) !: 0.34,
12.53, 22.79, 41.76, 55.37, 55.71, 62.26, 62.58, 66.25, 67.88, 114.12, 127.05, 130.22, 159.96, 165.26,
172.82, 209.27
Ketone (7). To a solution of 6 (9.68 g, 23.1 mmol) in MeCN (40 mL) was added DIPEA (2.02 mL, 11.5mmol) at 0 °C. After stirring for 20 h at the same temperature, the reaction mixture was treated withaqueous citric acid and the aqueous layer was extracted with AcOEt. The combined organic layer waswashed with H2O and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum
to give 7 that was used for the next step without purification.
orange oil. IR (neat) 3447, 2961, 2839, 1767, 1517, 1251, 1175, 1035, 845 cm-1; 1H NMR (500 MHz,CDCl3) !: 0.13 (9H, s), 1.24 (3H, d, J = 7.1 Hz), 1.31 (3H, d, J = 6.1 Hz), 2.23-2.32 (1H, m), 3.13 (1H, d,

HETEROCYCLES, Vol. 87, No. 11, 2013

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J = 7.1 Hz), 3.60 (1H, d, J = 7.6 Hz), 3.81 (3H, s), 4.22-4.29 (1H, m), 4.72 (2H, s), 5.13 (3H, s), 6.89 (2H,d, J = 8.6 Hz), 7.29 (2H, d, J = 8.6 Hz); 13C NMR (125 MHz, CDCl3) !: 0.25, 11.84, 22.79, 47.54, 55.29,
59.02, 63.77, 66.30, 67.78, 68.54, 114.03, 126.98, 130.15, 159.87, 165.37, 171.97, 208.96
Alcohol (8). To a solution of 7 (9.68 g, 23.1 mmol) in THF (100 mL), EtOH (100 mL) was added NaBH4(436 mg, 11.5 mmol) at -78 °C After stirring for 1 h at the same temperature, to the mixture was added
AcOH (0.658 mL, 11.5 mmol) and stirred for 10 min at the room temperature. The reaction mixture wastreated with H2O and the aqueous layer was extracted with AcOEt. The combined organic layer waswashed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, the residue
was purified by flash silica gel column chromatography (hexane-AcOEt = 1 : 3) to give 8 as a yellow oil(7.30 g, 17.3 mmol, 75% for 3 steps).
yellow oil. IR (neat) 3460, 2959, 1746, 1614, 1516, 1251, 1174, 1111, 1034, 844 cm-1; 1H NMR (500
MHz, CDCl3) !: 0.11 (9H, s), 1.12 (3H, d, J = 6.6 Hz), 1.25 (3H, d, J = 6.4 Hz), 1.83-1.92 (1H, m), 2.92
(1H, br s), 3.00 (1H, d, J = 7.1 Hz), 3.29 (1H, d, J = 8.3 Hz), 3.80 (3H, s), 4.09-4.24 (3H, m), 5.13 (2H, s),
6.88 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz); 13C NMR (125 MHz, CDCl3) !:0.28, 13.65, 22.79,
46.20, 55.31, 60.27, 65.48, 65.80, 66.35, 67.13, 86.01, 114.05, 127.40, 130.20, 159.81, 170.56, 175.29;
HRMS (ESI) Calcd for C21H31NO6NaSi ([M+Na]+): 444.1813. Found 444.1805.
Silyl ether (9). To a solution of 8 (1.00 g, 2.37 mmol) in CH2Cl2 (10 mL) was added 2,6-lutidine (0.553
mL, 4.74 mmol) and TBSOTf (0.818 mL, 3.56 mmol) at 0 °C. After stirring for 30 min at the same
temperature, the reaction mixture was treated with aqueous citric acid and the aqueous layer was
extracted with AcOEt. The combined organic layer was washed with H2O and brine, dried over Na2SO4
and filtered. The filtrate was concentrated in vacuo, the residue was purified by flash silica gel column
chromatography (hexane-AcOEt = 5 : 1) to give 9 as a white solid (0.670 g, 1.25 mmol, 53%).
white solid. mp 71-73 °C; IR (neat) 2956, 2937, 2855, 1758, 1744, 1516, 1250, 1176, 837 cm-1; 1H NMR(500 MHz, CDCl3) !: 0.11 (6H, s), 0.83 (9H, s), 1.02 (3H, d, J = 7.1 Hz), 1.25 (3H, d, J = 6.1 Hz), 1.55
(9H, s), 1.87-1.94 (1H, m), 3.01 (1H, d, J = 7.1 Hz), 3.32 (1H, d, J = 6.8 Hz), 3.81 (3H, s), 4.09-4.16 (1H,m), 4.20 (1H, d, J = 5.4 Hz), 4.33 (1H, t, J = 5.4 Hz), 5.07-5.14 (2H, m), 6.87 (2H, d, J = 8.5 Hz), 7.30
(2H, d, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) !:-4.89, -4.82, 0.29, 14.60, 17.77, 22.81, 25.59, 47.11,
55.29, 61.02, 66.21, 66.63, 66.97, 67.02, 87.27, 113.93, 127.39, 130.32, 159.78, 170.30, 175.21; Calcd
for C27H45NO6NaSi2 ([M+Na]+): 558.2678. Found 558.2670.
Allyl ester (10). To a solution of 9 (510 mg, 0.952 mmol) in allyl alcohol (5.2 mL) was added TMSCl(1.22 mL, 9.52 mmol) at 0 °C. After stirring for 1.5 h at the same temperature, the reaction mixture wastreated with aqueous K2CO3 and the aqueous layer was extracted with AcOEt. The combined organic
layer was washed with H2O and brine, dried over Na2SO4 and filtered. The filtrate was concentrated invacuo, the residue was purified by flash silica gel column chromatography (hexane-AcOEt = 1 : 1) to give

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HETEROCYCLES, Vol. 87, No. 11, 201310 as a yellow oil (246 mg, 0.472 mmol, 50%).
yellow oil. IR (neat) 3345, 2956, 2931, 2857, 1733, 1517, 1251, 1173, 838 cm-1; 1H NMR (500 MHz,CDCl3) !: -0.01 (3H, s), 0.02 (3H, s), 0.86 (9H, s), 0.92 (3H, d, J = 6.4 Hz), 1.20 (3H, d, J = 6.4 Hz),2.05-2.12 (1H, m), 2.59-2.62 (1H, m), 3.30-3.34 (1H, m), 3.62 (1H, d, J = 4.2 Hz), 3.81 (3H, s), 3.94 (1H,t, J = 4.2 Hz), 4.24-4.31 (1H, m), 4.55-4.64 (2H, m), 5.06 (1H, d, J = 12.0 Hz), 5.14 (1H, d, J = 12.0 Hz),5.24 (1H, d, J = 10.3 Hz), 5.34 (1H, d, J = 17.1 Hz), 5.86-5.95 (1H, m), 6.88 (2H, d, J = 7.3 Hz), 7.29 (2H,d, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) !: -4.74, -4.71, 15.80, 17.90, 21.43, 25.70, 45.00, 53.30,
55.30, 62.68, 65.19, 66.55, 66.69, 66.82, 83.06, 113.95, 118.78, 127.49, 130.42, 131.86, 159.82, 172.40,
173.72; HRMS (ESI) Calcd for C27H44NO7Si ([M+H]+): 522.2882. Found 522.2872.
Amino acid (11). To a solution of 10 (340 mg, 0.652 mmol) in THF (4 mL) was added morpholine(0.114 mL, 1.30 mmol) and Pd(PPh3)4 (37.7 mg, 0.0330 mmol) at room temperature. After stirring for 30
min at the same temperature, to the mixture was further added morpholine (0.114 mL, 1.30 mmol) andPd(PPh3)4 (37.7 mg, 0.0330 mmol). After stirring for additional 30 min, the reaction mixture was treatedwith aqueous citric acid and the aqueous layer was extracted with AcOEt. The combined organic layer
was washed with H2O and brine, dried over Na2SO4 and filtered. The filtrate was concentrated undervacuum to give 11 that was used for the next step without purification.
colorless oil. IR (neat) 3250, 2927, 2856, 1741, 1614, 1558, 1515, 1397, 1248, 837 cm-1; 1H NMR (500
MHz, CDCl3) !: -0.11 (3H, s), -0.01 (3H, s), 0.79 (9H, s), 1.04 (3H, d, J = 6.1 Hz), 1.28 (3H, d, J = 6.4
Hz), 1.99-2.08 (1H, m), 2.40 (1H, d, J = 6.8 Hz), 3.68 (1H, d, J = 11.7 Hz), 3.78 (3H, s), 3.92 (1H, d, J =5.9 Hz), 4.01 (1H, t, J = 7.8 Hz), 4.06-4.13 (1H, m), 5.06 (1H, d, J = 11.7 Hz), 5.11 (1H, d, J = 11.7 Hz),6.82 (2H, d, J = 8.5 Hz), 7.24 (2H, d, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) !: -4.81, -4.47, 13.97,
17.82, 22.06, 25.63, 44.57, 53.34, 55.25, 59.92, 63.43, 66.15, 68.04, 80.54, 113.99, 126.53, 130.79,
160.01, 169.64, 177.11; HRMS (ESI) Calcd for C24H39NO7NaSi ([M+Na]+): 504.2388. Found 504.2384.
Boc carbamate (12). To a solution of 11 (314 mg, 0.652 mmol) in THF (3 mL) was added Boc2O (0.499
mL, 2.15 mmol) and Et3N (0.271 mL, 1.96 mmol) at room temperature. After stirring for 4 h at the same
temperature, the reaction mixture was treated with aqueous citric acid and the aqueous layer was
extracted with AcOEt. The combined organic layer was washed with H2O and brine, dried over Na2SO4
and filtered. The filtrate was concentrated under vacuum to give 12 that was used for the next step
without purification.
colorless oil. IR (neat) 3447, 2957, 2933, 2859, 1746, 1700, 1517, 1369, 1253, 1172, 838 cm-1; 1H NMR(500 MHz, CDCl3) !: 0.06 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.04 (3H, d, J = 7.3 Hz), 1.24 (3H, d, J =6.1 Hz), 1.34 (9H, s), 2.38-2.45 (1H, m), 3.09-3.12 (1H, m), 3.80 (3H, s), 3.91-3.97 (2H, m), 4.09-4.26(2H, m), 5.09 (1H, d, J = 11.7 Hz), 5.13 (1H, d, J = 11.7 Hz), 6.88 (2H, d, J = 8.3 Hz), 7.30 (2H, d, J =8.3 Hz); 13C NMR (125 MHz, CDCl3) !: -5.10, -4.96, 18.13, 19.11, 21.41, 25.71, 28.08, 45.02, 55.17,

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2275

55.31, 64.44, 65.85, 66.96, 70.21, 81.07, 82.39, 113.98, 127.31, 130.62, 154.32, 159.92, 170.87, 177.34;
HRMS (ESI) Calcd for C29H47NO9NaSi ([M+Na]+): 604.2912. Found 604.2907.
Carbamate (13). To a solution of 12 (379 mg, 0.652 mmol) in toluene (4 mL) was added Et3N (0.298
mL, 2.15 mmol) and DPPA (0.420 mL, 1.95 mmol) at room temperature. After stirring for 1 h at 80 °C,
the reaction mixture was treated with aqueous citric acid and the aqueous layer was extracted with AcOEt.
The combined organic layer was washed with H2O and brine, dried over Na2SO4 and filtered. The filtrate
was concentrated in vacuo, the residue was purified by flash silica gel column chromatography(hexane-AcOEt = 1 : 1) to give 13 as a white amorphous (197 mg, 0.340 mmol, 52% for 3 steps).
white amorphous. IR (neat) 3384, 2955, 2858, 1748, 1697, 1683, 1518, 1457, 1395, 1257, 1186, 839
cm-1; 1H NMR (500 MHz, CDCl3) !: 0.05 (3H, s), 0.09 (3H, s), 0.88 (9H, s), 1.01 (3H, d, J = 7.6 Hz),1.32 (3H, d, J = 6.4 Hz), 1.35 (9H, s), 1.79 (1H, q, J = 7.6 Hz), 3.81 (3H, s), 3.88 (1H, s), 3.95 (1H, d, J =9.5 Hz), 4.15 (1H, s), 4.29-4.33 (1H, m), 4.50-4.56 (1H, m), 5.05 (1H, d, J = 11.7 Hz), 5.17 (1H, d, J =11.7 Hz), 6.46 (1H, s), 6.88 (2H, d, J = 8.5 Hz), 7.29 (2H, d, J = 8.5 Hz); 13C NMR (125 MHz, CDCl3) !:-5.15, -4.90, 14.96, 17.12, 17.84, 25.67, 28.03, 45.48, 55.30, 60.82, 65.18, 67.00, 69.93, 75.40, 81.07,
81.78, 113.98, 127.27, 130.59, 155.49, 157.93, 159.98, 169.93; HRMS (ESI) Calcd for C29H46N2O8NaSi([M+Na]+): 601.2916. Found 601.2906.
Acetylated carbamate (14). To a solution of 13 (176 mg, 0.305 mmol) in Ac2O (4.32 mL, 45.7 mmol)
was added DMAP (37.2 mg, 0.305 mmol) at room temperature. After stirring for 5 h at 80 °C, thereaction mixture was treated with aqueous K2CO3 and the aqueous layer was extracted with AcOEt. The
combined organic layer was washed with H2O and brine, dried over Na2SO4 and filtered. The filtrate wasconcentrated in vacuo, the residue was purified by flash silica gel column chromatography(hexane-AcOEt = 1 : 1) to give 14 as a white amorphous (143 mg, 0.230 mmol, 75%).
white amorphous. IR (neat) 2955, 2933, 2857, 1792, 1748, 1715, 1517, 1374, 1252, 1204, 1173, 839
cm-1; 1H NMR (500 MHz, CDCl3) !: 0.00 (3H, s), 0.07 (3H, s), 0.87 (9H, s), 1.10 (3H, d, J = 7.3 Hz),1.33 (9H, s), 1.47 (3H, d, J = 6.6 Hz), 1.89-1.97 (1H, m), 2.44 (3H, s), 3.81 (3H, s), 3.87 (1H, s),
4.17-4.23 (2H, m), 4.60-4.69 (1H, m), 5.01-5.10 (1H, m), 5.04 (1H, d, J = 11.7 Hz), 5.14 (1H, d, J = 11.7
Hz), 6.87 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.8 Hz); 13C NMR (125 MHz, CDCl3) !: -5.36, -4.86,
14.10, 14.38, 17.76, 23.96, 25.63, 28.04, 55.27, 55.30, 61.71, 62.12, 66.67, 69.06, 74.30, 80.64, 82.66,
113.93, 127.43, 130.46, 153.26, 153.82, 159.84, 169.83, 170.85; HRMS (ESI) Calcd for C31H48N2O9NaSi([M+Na]+): 643.3021. Found 643.3012.
Alcohol (15). To a solution of 14 (142 mg, 0.229 mmol) in EtOH (1 mL) and H2O (0.5 mL) was added
Ba(OH)2 8H2O (216 mg, 0.686 mmol) at room temperature. After stirring for 1 h at the same temperature,
the reaction mixture was treated with aqueous citric acid and the aqueous layer was extracted with AcOEt.
The combined organic layer was washed with H2O and brine, dried over Na2SO4 and filtered. The filtrate

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was concentrated in vacuo, the residue was purified by flash silica gel column chromatography(hexane-AcOEt = 100 : 0 ~ 0: 100) to give 15 as a colorless oil (47.1 mg, 0.0790 mmol, 35%) and 13 as acolorless oil (65.3 mg, 0.113 mmol, 49%).
colorless oil. IR (neat) 3362, 2956, 2932, 2858, 1684, 1518, 1374, 1252, 1172, 839 cm-1; 1H NMR (500
MHz, CDCl3) !: 0.05 (3H, s), 0.06 (3H, s), 0.89 (9H, s), 1.00 (3H, d, J = 7.8 Hz), 1.11 (3H, d, J = 6.1 Hz),1.37 (9H, s), 2.17 (1H, q, J = 7.8 Hz), 3.81 (3H, s), 3.89 (2H, brs), 4.15 (1H, s), 4.41 (1H, d, J = 4.9 Hz),4.50-4.55 (1H, m), 5.05 (1H, d, J = 11.7 Hz), 5.17 (1H, d, J = 11.7 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.30 (2H,d, J = 8.8 Hz); 13C NMR (125 MHz, CDCl3) !: -5.09, -4.94, 17.23, 17.68, 17.88, 23.12, 25.66, 27.98,
45.37, 55.33, 61.24, 64.84, 66.93, 69.05, 69.97, 81.68, 81.95, 113.97, 127.35, 130.55, 156.90, 159.93,
170.29, 172.84; HRMS (ESI) Calcd for C30H50N2O8NaSi ([M+Na]+): 617.3229. Found 617.3218.
! -Siloxy amino acid (16). A mixture of 15 (37.5 mg, 0.0630 mmol) and TFA (0.704 mL, 9.14 mmol)
was stirred for 15 min at room temperature. The reaction mixture was treated with aqueous K2CO3 (pH =5) and the aqueous layer was extracted with AcOEt. The combined organic layer was dried over Na2SO4
and filtered. The filtrate was concentrated in vacuo, the residue was purified by flash silica gel column
chromatography (CHCl3 : MeOH : H2O = 32 : 9 : 1) to give 16 as a white amorphous (16.4 mg, 0.0440
mmol, 70%).
white amorphous. IR (neat) 3309, 2956, 2932, 2859, 1683, 1653, 1557, 1541, 1255, 1203, 1145, 839
cm-1; 1H NMR (500 MHz, CDCl3) !: 0.11 (3H, s), 0.12 (3H, s), 0.89 (9H, s), 1.12 (3H, d, J = 6.4 Hz),1.27 (3H, d, J = 5.9 Hz), 1.94-2.02 (1H, m), 2.06 (3H, s), 3.67 (1H, d, J = 11.5 Hz), 3.91-4.01 (2H, m),
4.05-4.19 (2H, m), 7.83 (1H, d, J = 9.0 Hz); 13C NMR (125 MHz, CDCl3) !: -4.72, -4.70, 13.84, 17.91,
20.77, 22.81, 25.67, 43.64, 52.03, 63.24, 65.10, 68.20, 79.74, 171.42, 172.15; HRMS (ESI) Calcd for
C17H35N2O5Si ([M+H]+): 375.2310. Found 375.2304.
! -Hydroxy amino acid (2). A mixture of 16 (10.0 mg, 0.0270 mmol), TFA (0.206 mL, 2.67 mmol), andH2O (0.0216 mL, 1.20 mmol) was stirred for 15 h at room temperature. The reaction mixture wasconcentrated in vacuo, the residue was washed with Et2O to give 2 as a white powder (4.40 mg, 0.0120
mmol, 44%).
white powder. [#]D27.4 +21.87 (c 0.49, MeOH). IR (neat) 3274, 2974, 2927, 1669, 1653, 1558, 1541, 1198,
1136 cm-1; 1H NMR (500 MHz, DMSO-d6) !: 1.00 (3H, d, J = 6.8 Hz), 1.13 (3H, d, J = 5.6 Hz),1.73-1.82 (1H, m), 1.91 (3H, s), 3.54 (1H, d, J = 11.0 Hz), 3.72-3.85 (4H, m), 7.66 (1H, d, J = 9.0 Hz);.
13

C NMR (125 MHz, DMSO-d6) !: 13.67, 20.88, 22.60, 42.05, 51.95, 61.95, 63.89, 66.22, 77.54, 169.72,

169.82; HRMS (ESI) Calcd for C11H21N2O5 ([M+H]+): 261.1445. Found 261.1444.
Boc carbamate (17). To a solution of 10 (1.83 g, 3.51 mmol) in THF (20 mL) was added Boc2O (2.69
mL, 11.6 mmol) at room temperature. After stirring for 13 h at 50 °C, the reaction mixture was

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concentrated in vacuo, the residue was purified by flash silica gel column chromatography(hexane-AcOEt = 2 : 1) to give 17 as a colorless oil (2.11 g, 3.39 mmol, 97%).
colorless oil. IR (neat) 3460, 2957, 2933, 2858, 1736, 1699, 1517, 1385, 1253, 1172, 839 cm-1; 1H NMR(500 MHz, CDCl3) !: 0.06 (3H, s), 0.07 (3H, s), 0.88 (9H, s), 1.03 (3H, d, J = 7.3 Hz), 1.18 (3H, d, J =6.1 Hz), 1.35 (9H, s), 2.42 (1H, d, J = 6.4 Hz), 3.12 (1H, d, J = 8.5 Hz), 3.80 (3H, s), 3.91 (1H, s),
4.08-4.26 (3H, m), 4.51-4.61 (2H, m), 5.10 (2H, s), 5.21 (1H, d, J = 10.0 Hz), 5.32 (1H, d, J = 17.1 Hz),5.85-5.94 (1H, m), 6.87 (2H, d, J = 7.3 Hz), 7.29 (2H, d, J = 7.3 Hz); 13C NMR (125 MHz, CDCl3) !:-4.90, -4.83, 18.29, 19.36, 21.62, 25.85, 28.23, 44.91, 55.46, 55.77, 64.74, 65.37, 65.96, 67.04, 70.45,
81.01, 82.54, 114.09, 118.61, 127.45, 130.75, 132.16, 154.37, 160.03, 171.12, 172.42; HRMS (ESI)
Calcd for C32H51NO9NaSi ([M+Na]+): 644.3225. Found 644.3213.
Ketone (18a). To a solution of 17 (1.53 g, 2.46 mmol) in CH2Cl2 (20 mL) was added pyridine (0.597 mL,
7.38 mmol) and DMP (2.09 g, 4.92 mmol) at room temperature. After stirring for 2 h at the same
temperature, the reaction mixture was treated with aqueous Na2S2O3 and the aqueous layer was extractedwith AcOEt. The combined organic layer was dried over Na2SO4 and filtered. The filtrate wasconcentrated in vacuo, the residue was purified by flash silica gel column chromatography(hexane-AcOEt = 2 : 1) to give 18a as a colorless oil (1.48 g, 2.39 mmol, 97%).
colorless oil. IR (neat) 2955, 2933, 2858, 1748, 1715, 1517, 1375, 1252, 1173, 839 cm-1; 1H NMR (500
MHz, CDCl3) !: 0.01 (3H, s), 0.04 (3H, s), 0.87 (9H, s), 1.06 (3H, d, J = 7.6 Hz), 1.33 (9H, s), 2.01-2.10(1H, m), 2.18 (3H, s), 3.81 (3H, s), 3.87 (1H, s), 4.19 (1H, s), 4.29-4.40 (2H, m), 4.52-4.62 (2H, m),
5.05-5.33 (4H, m), 5.85-5.98 (1H, m), 6.87 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.8 Hz); 13C NMR (125MHz, CDCl3) !: -5.12, -4.99, 17.81, 17.99, 25.73, 28.05, 30.67, 46.17, 55.31, 61.44, 64.17, 66.05, 66.79,
69.79, 80.64, 81.94, 113.94, 118.30, 127.43, 130.50, 131.92, 153.82, 159.86, 168.06, 170.61, 202.46;
HRMS (ESI) Calcd for C32H49NO9NaSi ([M+Na]+): 642.3069. Found 642.3062.
Ketone (18) (#:!=1:1.2). To a solution of 18a (1.48 g, 2.39 mmol) in MeCN (15 mL) was added DIPEA(0.417 mL, 2.39 mmol) at room temperature. After stirring for 1 h at 60 °C, the reaction mixture wastreated with H2O and the aqueous layer was extracted with AcOEt. The combined organic layer waswashed with H2O and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum
to give 18 as a colorless oil (1.44 g, 2.32 mmol, 97%) that was used for the next step without purification.
colorless oil. IR (neat) 2955, 2933, 2858, 1748, 1708, 1517, 1379, 1252, 1169, 839 cm-1; 1H NMR (500
MHz, CDCl3) !: 0.01 (3H, s), 0.04 (3H, s), 0.85 (9H, s), 1.07 (3H, d, J = 7.6 Hz), 1.31 (9H, s), 1.95-2.02(1H, m), 2.24 (3H, s), 3.81 (3H, s), 3.86 (1H, s), 4.14-4.44 (3H, m), 4.58-4.62 (2H, m), 5.03-5.34 (4H, m),
5.81-5.96 (1H, m), 6.87 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz); 13C NMR (125 MHz, CDCl3, major
peaks) !: -4.98, -4.93, 17.72, 17.82, 25.69, 28.00, 30.68, 47.01, 55.31, 63.87, 64.20, 65.77, 66.75, 69.59,
80.64, 82.13, 113.95, 119.04, 127.48, 130.51, 131.50, 153.71, 159.87, 168.95, 170.58, 201.46.

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Alcohol (19). To a solution of 18 (1.40 g, 2.26 mmol) in DME (14 mL), MeOH (14 mL) was added
NaBH4 (85.0 mg, 2.26 mmol) at -78 °C. After stirring for 1 h at 0 °C, to the mixture was further added
NaBH4 (85.0 mg, 2.26 mmol). After stirring for additional 15 min, the reaction mixture was added AcOH
(0.258 mL, 4.52 mmol) and stirred for 10 min at the room temperature .The reaction mixture was treatedwith H2O and the aqueous layer was extracted with AcOEt. The combined organic layer was washed withbrine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, the residue was purified byflash silica gel column chromatography (hexane-AcOEt = 100 : 0 ~ 50 : 50) to give 19 as a colorless oil(411 mg, 0.661 mmol, 29%).
colorless oil. IR (neat) 3446, 2956, 2932, 2858, 1733, 1698, 1684, 1518, 1395, 1253, 1173, 838 cm-1; 1H
NMR (500 MHz, CDCl3) !: -0.01 (3H, s), 0.01 (3H, s), 0.85 (9H, s), 1.07 (3H, d, J = 7.6 Hz), 1.25 (3H, d,
J = 7.1 Hz), 1.36 (9H, s), 2.00-2.06 (1H, m), 3.30 (1H, dd, J = 4.2, 9.0 Hz), 3.58 (1H, d, J = 9.0 Hz), 3.81
(3H, s), 3.83 (1H, s), 4.08 (1H, d, J = 1.2 Hz), 4.11-4.17 (1H, m), 4.29 (1H, dd, J = 1.2, 9.0 Hz), 4.56-4.60(1H, m), 5.07 (1H, d, J = 11.7 Hz), 5.15 (1H, d, J = 11.7 Hz), 5.22 (1H, dd, J = 1.2, 10.3 Hz), 5.32 (1H,
dd, J = 1.2, 17.1 Hz), 5.85-5.93 (1H, m), 6.88 (2H, d, J = 8.3 Hz), 7.29 (2H, d, J = 8.3 Hz); 13C NMR(125 MHz, CDCl3) !: -5.06, -4.96, 17.87, 17.95, 21.75, 25.70, 28.11, 46.97, 55.12, 55.30, 63.39, 65.19,
66.80, 67.53, 70.02, 81.18, 82.24, 113.95, 118.59, 127.41, 130.54, 132.00, 154.74, 159.88, 170.69,
172.93; HRMS (ESI) Calcd for C32H51NO9NaSi ([M+Na]+): 644.3225. Found 644.3219.
Carboxylic acid (20). To a solution of 19 (622 mg, 1.00 mmol) in THF (7 mL) was added morpholine(0.174 mL, 2.00 mmol) and Pd(PPh3)4 (57.8 mg, 0.0500 mmol) at room temperature. After stirring for 45
min at the same temperature, the reaction mixture was treated with aqueous citric acid and the aqueous
layer was extracted with AcOEt. The combined organic layer was washed with H2O and brine, dried over
Na2SO4 and filtered. The filtrate was concentrated in vacuo, the residue was purified by flash silica gelcolumn chromatography (hexane-AcOEt = 100 : 0 ~ 0 : 100) to give 20 as a white amorphous (529 mg,
0.909 mmol, 91%).
white amorphous. IR (neat) 3279, 2956, 2932, 2858, 1748, 1699, 1684, 1517, 1395, 1252, 1172, 839
cm-1; 1H NMR (500 MHz, CDCl3) !: 0.04 (6H, s), 0.87 (9H, s), 1.03 (3H, d, J = 7.6 Hz), 1.27 (3H, d, J =6.6 Hz), 1.37 (9H, s), 2.26-2.35 (1H, m), 3.16-3.22 (1H, m), 3.81 (3H, s), 3.89 (1H, s), 4.10-4.16 (3H, m),
5.07 (1H, d, J = 11.7 Hz), 5.17 (1H, d, J = 11.7 Hz), 6.88 (2H, d, J = 8.6 Hz), 7.29 (2H, d, J = 8.6 Hz);13

C NMR (125 MHz, CDCl3) !: -5.14, -5.03, 17.52, 17.86, 21.43, 25.65, 28.05, 47.84, 55.32, 55.99, 62.98,

66.91, 67.44, 70.09, 81.87, 82.07, 113.97, 127.32, 130.54, 155.42, 159.90, 170.32, 176.80; HRMS (ESI)
Calcd for C29H47NO9NaSi ([M+Na]+): 604.2912. Found 604.2907.
Carbamate (21). To a solution of 20 (529 mg, 0.909 mmol) in toluene (10 mL) was added Et3N (0.416
mL, 3.00 mmol) and DPPA (0.586 mL, 2.73 mmol) at room temperature. After stirring for 1 h at 80 °C,
the reaction mixture was treated with aqueous citric acid and the aqueous layer was extracted with AcOEt.

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The combined organic layer was washed with H2O and brine, dried over Na2SO4 and filtered. The filtrate
was concentrated in vacuo, the residue was purified by flash silica gel column chromatography(hexane-AcOEt = 100 : 0 ~ 50 : 50) to give 21 as a yellow amorphous (472 mg, 0.816 mmol, 90%).
yellow amorphous. IR (neat) 3383, 2956, 2933, 2858, 1771, 1749, 1698, 1517, 1374, 1254, 1174, 839
cm-1; 1H NMR (500 MHz, CDCl3) !: 0.15 (3H, s), 0.19 (3H, s), 0.93 (9H, s), 1.00 (3H, d, J = 7.6 Hz),1.34 (9H, s), 1.39 (3H, d, J = 6.6 Hz), 2.17 (1H, q, J = 7.6 Hz), 3.81 (3H, s), 3.96 (1H, s), 4.02 (1H, s),4.15 (1H, s), 4.39 (1H, d, J = 8.3 Hz), 4.80-4.87 (1H, m), 5.08 (1H, d, J = 11.7 Hz), 5.18 (1H, d, J = 11.7
Hz), 5.62 (1H, s), 6.88 (2H, d, J = 7.1 Hz), 7.30 (2H, d, J = 7.1 Hz); 13C NMR (125 MHz, CDCl3) !: -5.01,-4.85, 16.15, 17.87, 18.44, 26.11, 28.07, 41.86, 55.32, 57.13, 65.75, 67.11, 69.71, 75.01, 81.11, 82.31,
113.97, 127.24, 130.70, 154.41, 159.02, 159.98, 170.44; HRMS (ESI) Calcd for C29H46N2O8NaSi([M+Na]+): 601.2916. Found 601.2910.
Acetylated carbamate (22). To a solution of 21 (472 mg, 0.816 mmol) in Ac2O (4.63 mL, 48.9 mmol)
was added DMAP (100 mg, 0.816 mmol) at room temperature. After stirring for 1.5 h at 80 °C, thereaction mixture was treated with aqueous K2CO3 and the aqueous layer was extracted with AcOEt. The
combined organic layer was washed with H2O and brine, dried over Na2SO4 and filtered. The filtrate wasconcentrated in vacuo, the residue was purified by flash silica gel column chromatography(hexane-AcOEt = 100 : 0 ~ 50 : 50) to give 22 as a white amorphous (470 mg, 0.757 mmol, 93%).
white amorphous. IR (neat) 2974, 2931, 2360, 1715, 1698, 1684, 1558, 1541, 1519 cm-1; 1H NMR (500
MHz, CDCl3) !: 0.05 (3H, s), 0.05 (3H, s), 0.84 (9H, s), 1.18 (3H, d, J = 7.6 Hz), 1.39 (9H, s), 1.49 (3H,d, J = 6.8 Hz), 2.02-2.08 (1H, m), 2.47 (3H, s), 3.81 (3H, s), 3.88-3.91 (2H, m), 3.99-4.01 (1H, m),
4.66-4.75 (1H, m), 5.05 (1H, d, J = 11.7 Hz), 5.12 (1H, d, J = 11.7 Hz), 5.35 (1H, dd, J = 1.5, 7.6 Hz),6.87 (2H, d, J = 8.8 Hz), 7.29 (2H, d, J = 8.8 Hz); 13C NMR (125 MHz, CDCl3) !: -4.76, -4.37, 14.87,
18.67, 18.97, 23.84, 26.18, 28.14, 43.34, 55.31, 55.69, 65.85, 66.87, 69.67, 74.72, 80.81, 83.34, 113.94,
127.29, 130.75, 153.42, 154.06, 159.89, 170.16, 171.67; HRMS (ESI) Calcd for C31H48N2O9NaSi([M+Na]+): 643.3021. Found 643.3011.
Alcohol (23). To a solution of 22 (386 mg, 0.622 mmol) in EtOH (4 mL) and H2O (2 mL) was added
Ba(OH)2 8H2O (588 mg, 1.87 mmol) at room temperature. After stirring for 30 min at the same
temperature, the reaction mixture was treated with aqueous citric acid and the aqueous layer was
extracted with AcOEt. The combined organic layer was washed with H2O and brine, dried over Na2SO4
and filtered. The filtrate was concentrated in vacuo, the residue was purified by flash silica gel column
chromatography (hexane-AcOEt = 100 : 0 ~ 0: 100) to give 23 as a white amorphous (166 mg, 0.279
mmol, 45%) and 21 as a white amorphous (155 mg, 0.268 mmol, 43%).
white amorphous. IR (neat) 3355, 2933, 2859, 1698, 1684, 1557, 1541, 1520, 838 cm-1; 1H NMR (500
MHz, CDCl3) !: 0.09 (3H, s), 0.10 (3H, s), 0.90 (9H, s), 1.04 (3H, d, J = 7.6 Hz), 1.17 (3H, d, J = 6.4 Hz),

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HETEROCYCLES, Vol. 87, No. 11, 20131.33 (9H, s), 1.82 (1H, brs), 1.99 (3H, s), 2.35-2.41 (1H, m), 3.29 (1H, brs), 3.79-3.99 (7H, m), 4.14 (1H,s), 4.37-4.41 (1H, m), 5.09 (1H, d, J = 11.7 Hz), 5.13 (1H, d, J = 11.7 Hz), 6.88 (2H, d, J = 8.8 Hz), 7.30
(2H, d, J = 8.8 Hz); 13C NMR (125 MHz, CDCl3) !: -4.93, -4.80, 18.20, 18.82, 20.13, 23.49, 25.76, 28.06,
45.61, 55.33, 56.58, 67.03, 67.65, 68.45, 70.83, 81.23, 81.74, 113.98, 127.27, 130.67, 154.87, 159.96,
170.62, 170.82; HRMS (ESI) Calcd for C30H50N2O8NaSi ([M+Na]+): 617.3229. Found 617.3220.
Diol (24). To a solution of 23 (148 mg, 0.249 mmol) in THF (3 mL) was added 1.0M TBAF (0.498 mL,
0.498 mmol) at room temperature. After stirring for 30 min at the same temperature, the reaction mixture
was treated with brine and the aqueous layer was extracted with AcOEt. The combined organic layer waswashed with H2O and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo, theresidue was purified by flash silica gel column chromatography (CHCl3 : MeOH : H2O = 32 : 9 : 1) togive 24 as a white amorphous (110 mg, 0.229 mmol, 92%).
colorless oil. IR (neat) 3308, 2973, 2931, 1698, 1684, 1653, 1558, 1541, 1518, 1396, 1374, 1250, 1173
cm-1; 1H NMR (500 MHz, CDCl3) !: 0.99 (3H, d, J = 7.6 Hz), 1.21 (3H, d, J = 6.1 Hz), 1.32 (9H, s), 1.99
(3H, s), 2.41-2.49 (1H, m), 3.67 (1H, s), 3.80 (3H, s), 3.85-3.93 (2H, m), 4.22-4.28 (1H, m), 4.37 (1H, s),
5.08 (1H, d, J = 12.0 Hz), 5.14 (1H, d, J = 12.0 Hz), 6.87 (2H, d, J = 6.8 Hz), 7.30 (2H, d, J = 6.8 Hz);13

C NMR (125 MHz, CDCl3) !: 19.20, 20.62, 23.56, 28.00, 46.93, 55.32, 56.63, 67.00, 68.70, 69.22,

71.04, 79.96, 81.26, 113.97, 127.41, 130.62, 155.97, 159.89, 170.30, 171.07; HRMS (ESI) Calcd for
C24H36N2O8Na ([M+Na]+): 503.2364. Found 503.2360.
! -Hydroxy amino acid (1). A mixture of 24 (110 mg, 0.229 mmol) and TFA (1.06 mL, 13.7 mmol) was
stirred for 30 min at room temperature. The reaction mixture was concentrated in vacuo, the residue waswashed with Et2O to give 1 as a white powder (44.4 mg, 0.171 mmol, 75%).
white powder. [#]D28.6 -14.64 (c 0.54, MeOH). IR (neat) 3275, 2925, 1698, 1684, 1653, 1558, 1541, 1203,
1140 cm-1; 1H NMR (400 MHz, DMSO-d6) !: 1.03 (3H, d, J = 6.6 Hz), 1.10 (3H, d, J = 6.1 Hz), 1.89 (3H,s), 1.92-1.99 (1H, m), 3.55-3.67 (2H, m), 3.74 (1H, d, J = 5.6 Hz), 3.84 (1H, t, J = 6.1 Hz), 3.92-3.98 (1H,m), 8.03(1H, d, J = 8.6 Hz); 13C NMR (100 MHz, DMSO-d6) !: 16.06, 21.21, 22.39, 41.69, 55.23, 63.93,
64.14, 66.51, 78.41, 169.11, 171.30; HRMS (ESI) Calcd for C11H21N2O5 ([M+H]+): 261.1445. Found
261.1443.
ACKNOWLEDGEMENT
The authors are grateful to Mr. M. Ogawa and Dr. Y. Kashima for their helpful discussion and NMR
analysis.
REFERENCES (AND NOTES)
1.

(a) W. M. Kati, D. Montgomery, R. Carrick, L. Gubareva, C. Maring, K. McDaniel, K. Steffy, A.

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Molla, F. Hayden, D. Kempf, and W. Kohlbrenner, Antimicrob. Agents Chemother., 2002, 46, 1014;(b) M. G. Ison, V. P. Mishin, T. J. Braciale, F. G. Hayden, and L. V. Gubareva., J. Infect. Dis., 2006,
193, 765.
2.

W.-R. Li, S.-Y. Han, and M. M. Joullié, Heterocycles, 1993, 36, 359.

3.

T. Sunazuka, T. Nagamitsu, K. Matsuzaki, H. Tanaka, S. Omura, and A. B. Smith III, J. Am. Chem.
Soc., 1993, 115, 5302.

4.

(a) D. H. Shih, F. Baker, L. Cama, and B. G. Christensen, Heterocycles, 1984, 21, 29; (b) H. Onoe,
H. Ishitobi, and H. Ooka, JP06340618A.

5.

E. J. Corey, H. Cho, C. Rticker, and D. H. Hua, Tetrahedron. Lett., 1981, 22, 3455.

6.

D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.

7.

The following NOESY was observed.
NOESY
Me
HO
HN
O

H

H
OH

HN
Me
1

8.

Me

O

OH

In the synthesis of 2 (Scheme 3), purification of amino acid 16 was found to be difficult because of
its high polarity. The result led us to design a new sequence for the synthesis of 1 (Scheme 4),
employing ester 24 with a Boc-protected amino group as the precursor of the desired amino acid.