Practical asymmetric synthesis of both enantiomers of 6-(hydroxymethyl)piperidin-2-one

Article abstract of DOI:10.1055/s-1998-2123

A practical asymmetric synthesis of both enantiomers of 6 (hydroxymethyl)piperidin-2-one 1 is described. Asymmetric dihydroxylation (AD) of alkenyl ester 2 using the (DHQ)₂AQN ligand provides diol (5S)-3 in ≤95% ee after recrystallisation. This diol can subsequently be transformed into (6R)-1 using a five step reaction sequence. By employing (DHQD)₂AQN [1,4-bis(dihydroquininyl)anthraquinone] in the initial AD reaction, (6S)-1 can be prepared in an analogous fashion.

Full text of DOI:10.1055/s-1998-2123

SYNTHESIS
August 1998
1141
Practical Asymmetric Synthesis of Both Enantiomers of 6-(Hydroxymethyl)piperidin-
2-one
Timothy J. Hodgkinson, Michael Shipman*
Department of Chemistry, University of Exeter, Stocker Rd, Exeter, Devon, EX4 4QD, UK
Fax +44(1392)263434; E-mail: m.shipman@exeter.ac.uk
Received 26 January 1998
Abstract: A practical asymmetric synthesis of both enantiomers
of 6-(hydroxymethyl)piperidin-2-one 1 is described. Asymmetric
dihydroxylation (AD) of alkenyl ester 2 using the (DHQ)2AQN
mined by chiral HPLC (see Experimental). On the basis of
ligand provides diol (5S)-3 in ≥95% ee after recrystallisation. This
(DHQ)2AQN ligand under buffered dihydroxylation con-
ditions gives diol 3 in 81% yield and 86% ee as deter-
literature precedent, this diol was assigned the (5S)-con-
figuration, which was later confirmed by its conversion
into (6R)-1 (vide infra). Recrystallisation from diethyl
ether gives (5S)-3 in 56% yield from 2 in ≥95% ee
(Scheme). While attempts to recycle the chiral ligand by
extraction into aqueous acid as described by Sharpless led
to extensive decomposition of diol 3,7 the successful use
of low ligand loading (1 mol%) makes this reaction prac-
tical on a preparative (>80 mmol) scale.
diol can subsequently be transformed into (6R)-1 using a five step
reaction sequence. By employing (DHQD)2AQN [1,4-bis(di-
hydroquininyl)anthraquinone] in the initial AD reaction, (6S)-1
can be prepared in an analogous fashion.
Key words: 6-(hydroxymethyl)piperidin-2-one, asymmetric dihy-
droxylation, 1,4-bis(dihydroquininyl)anthraquinone, 4-methoxy-
phenylmethyl 5,6-dihydroxyhexanoate, 4-methoxyphenylmethyl
hex-5-enoate
As part of a programme directed towards the synthesis of
analogues of the azinomycins,1 an important class of anti-
tumour agents, we required access to both enantiomers of
6-(hydroxymethyl)piperidin-2-one (1). Lactam (6S)-1 has
previously been made from (S)-2-α-aminoadipic acid,2 or
alternatively from (S)-lysine.3, 4 The (S)-enantiomer of
this lactam has proven useful in the synthesis of confor-
mationally constrained pipecolic acid derivatives,5 and
some novel acyclic nucleic acid analogues.6 Furthermore,
Moloney et al. have demonstrated that this lactam can be
used to make a chiral bicyclic lactam template which can
be used to make other functionalised piperidines in a dia-
stereoselective fashion.3 Unfortunately, in order to access
the (R)-enantiomer of lactam 1 using the known prepara-
tive methods would necessitate the use of the unnatural
(R)-amino acids. The cost of such starting materials
makes these approaches impractical on a preparative
scale. In this paper, we disclose an alternative route to 6-
(hydroxymethyl)piperidin-2-one (1) which allows it to be
readily prepared in either enantiomerically enriched form.
Scheme
Selective protection of the primary hydroxyl group of diol
(5S)-3 as its tert-butyldiphenylsilyl ether furnished (5S)-4
in 91% yield. Conversion of the remaining secondary hy-
droxy group to the corresponding azide was accomplished
in two steps via mesylate 5 and involved stereochemical
Our approach to (6R)-6-(hydroxymethyl)piperidin-2-one inversion at C-5. Reduction of azide (5R)-6 by hydrogena-
does not rely on a starting material from the chiral pool but tion resulted in spontaneous lactamisation of the resultant
instead uses the excellent AD methodology developed by δ-amino ester yielding lactam (6R)-7. Final deprotection
Sharpless to introduce the stereochemistry at C-6.7, 8 Boger of the tert-butyldiphenylsilyl group using tetrabutylam-
et al. have recently described the asymmetric dihydroxy- monium fluoride gave lactam (6R)-1 in 29% overall yield
lation of alkenyl ester 2 with the commercially available from alkenyl ester 2. The optical rotation of this material,
(DHQD)2AQN in high yield and enantiomeric excess [α]D20 –28.1 (c = 1.1, CHCl3) [lit.2 [α]D22 +22.2 (c = 1.0,
(88–92% ee).9 The PMB (4-methoxyphenylmethyl) ester CHCl3) for (S)-enantiomer] confirmed that it possessed
was employed because it imparted crystallinity to the diol the (R)-configuration. The enantiomeric excess of our ma-
product enabling its optical purity to be further enriched by terial was determined to be ≥95% ee by conversion into
recrystallisation. We have established that asymmetric di- the corresponding MTPA ester and analysis by 1H NMR
hydroxylation of olefin 2 using the pseudo enantiomeric according to the method described by Weller et al.2

SYNTHESIS
Papers
1142
4-Methoxyphenylmethyl (5R)-5,6-Dihydroxyhexanoate [(5R)-3]:
Performing the asymmetric dihydroxylation of alkenyl es-
ter 2 with (DHQD)2AQN according to the method previ-
ously described by Boger gave diol (5R)-3 in 59% yield
and ≥95% ee after recrystallisation.7 Using the same se-
quence of reactions as outlined above, this diol was readi-
ly converted into lactam (6S)-1 [≥95% ee, [α]D20 +26.7
(c = 1.1, CHCl3)]. In summary, we have developed a prac-
tical route to both enantiomers of 6-(hydroxymethyl)pip-
eridin-2-one in excellent enantiomeric excess. We believe
that this strategy could be used to make other synthetically
useful functionalised δ-lactam derivatives.
A
stirred solution of 1,4-bis(dihydroquinidinyl)anthraquinone
(565 mg, 0.659 mmol), k3Fe(CN)6 (65.08 g, 0.198 mol), K2CO3
(27.30 g, 0.198 mol), NaHCO3 (16.62 g, 0.198 mol) and potassium os-
mate(VI) dihydrate (97.1 mg, 0.264 mmol) in t-BuOH (300 mL) and
water (300 mL) was prepared at r.t. The mixture was cooled to 0°C
whereupon some of the dissolved salts precipitated. 4-Methoxyphenyl-
methyl hex-5-enoate (2) (15.43 g, 65.9 mmol) was added in one portion
and the orange heterogeneous slurry was stirred at 0°C for 12 h. Work-
up and purification as described above gave (5R)-3 (14.67 g, 83%) as a
white solid (91% ee). Recrystallisation (Et2O) provided (5R)-3 (10.42
g, 59%) in ≥95% ee as white plates, mp 61–63°C (lit.9 mp 57–59°C);
[α]D20 +11.7 (c = 1.1, EtOH) [lit.9 [α]D22 +2.1 (c = 0.06, CHCl3)]. Spec-
troscopic data were identical with the corresponding (5S)-enantiomer
and those reported by Boger et al.9 4-Methoxybenzyl alcohol (1.21 g,
13%) was also isolated as a colourless liquid.
Reactions requiring anhydrous conditions were performed using
oven-dried glassware and conducted under a positive pressure of
N2. Light petroleum (40–60°C) and EtOAc were distilled from
CaCl2. CH2Cl2 was distilled from P2O5. Anhyd THF was prepared
by distillation from sodium-benzophenone ketyl under N2 immedi-
ately prior to use, or alternatively purchased from Aldrich in Sure/
Seal™ bottles. All other solvents and reagents were purified by
standard means. IR spectra were recorded in the range 4000–
600 cm–1 on a Nicolet Magna-550 FT-IR spectrometer with internal
calibration. Spectra were recorded as thin films or Nujol mulls.
NMR spectra were recorded on a Bruker DRX-400 spectrometer
with either TMS or residual protic solvent as internal reference. El-
emental analyses were carried out on a Perkin–Elmer 2400 CHN
elemental analyser. MS were recorded under EI or CI conditions on
a VG Analytical ZAB-E instrument, or under EI conditions on a
Kratos Profile HV-3 mass spectrometer.
4-Methoxyphenylmethyl (5S)-6-[(tert-Butyldiphenylsilyl)oxy]-5-
hydroxyhexanoate [(5S)-4]:
To a stirred solution of (5S)-3 (12.11 g, 45.2 mmol) and imidazole
(6.76 g, 99.4 mmol) in anhyd DMF (50 mL) at r.t. under N2 was added
TBDPSCl (13.64 g, 49.7 mmol) in DMF (50 mL). The mixture was
stirred for 12 h at r.t., quenched with water (100 mL) and extracted
with EtOAc (3 × 100 mL). The combined organic extracts were
washed with water (5 × 100 mL), dried (Na2SO4) and concentrated in
vacuo to give a pale yellow oil. Column chromatography (5 → 30%
EtOAc/light petroleum) gave (5S)-4 as a colourless oil (20.81 g,
91%); [α]D20 +1.19 (c = 2.2, CHCl3).
IR (thin film): νmax = 3505 (OH), 1734 (C=O), 1614, 1587, 1516 cm–1
(aromatic C=C).
1H NMR (400 MHz, CDCl3): δ = 7.66–7.64 (4H, m, ArH), 7.44–7.35
(6H, m, ArH), 7.26 (2H, d, J = 8.7 Hz, ArH), 6.86 (2H, d, J = 8.7 Hz,
ArH), 5.02 (2H, s, CO2CH2Ar), 3.77 (3H, s, OCH3), 3.69 (1H, m, H-
5), 3.63 (1H, dd, J = 10.1, 3.5 Hz, H-6), 3.48 (1H, dd, J = 10.1, 7.3
Hz, H-6), 2.50 (1H, br d, J = 3.4 Hz, OH), 2.32 (2H, t, J = 7.4 Hz, H-
2), 1.71 (2H, m), 1.41 (2H, m), 1.06 [9H, s, C(CH3)3].
4-Methoxyphenylmethyl (5S)-5,6-Dihydroxyhexanoate [(5S)-3]:
A stirred solution of 1,4-bis(dihydroquininyl)anthraquinone (700 mg,
0.817 mmol), K3Fe(CN)6 (80.61 g, 0.245 mol), K2CO3 (33.81 g,
0.245 mol), NaHCO3 (20.58 g, 0.245 mol) and potassium osmate(VI)
dihydrate (120 mg, 0.326 mmol) in t-BuOH (350 mL) and water (350
mL) was prepared at r.t. The mixture was cooled to 0°C whereupon
some of the dissolved salts precipitated. 4-Methoxyphenylmethyl
hex-5-enoate (2) (19.11 g, 81.7 mmol) was added in one portion and
the orange heterogeneous slurry was stirred at 0°C for 12 h. Anhyd
Na2SO3 (122.50 g, 0.972 mol) was added at 0°C and the mixture al-
lowed to warm to r.t. and stirred for 1 h. EtOAc (200 mL) was added
to the resulting green-brown mixture and, after separation of the lay-
ers, the aqueous phase was further extracted with EtOAc (3 ×
100 mL). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to give a yellow oil. Column chromatography
(30% EtOAc/light petroleum) provided 4-methoxybenzyl alcohol
(1.79 g, 16%) as a colourless liquid. Further elution (100% EtOAc)
gave (5S)-3 as a white solid (17.72 g, 81%) which was found to be
86% ee by HPLC analysis using a Chiralpak AD column (8% i-PrOH/
hexane; 0.7 mL min–1) [33.6 min (major); 36.1 min (minor)]. Recrys-
tallisation (Et2O) provided (5S)-3 (12.36 g, 56%) in ≥95% ee as white
plates, mp 61–63°C; [α]D20 –11.1 (c = 1.1, EtOH).
13C NMR (100.6 MHz, CDCl3): δ = 173.4 (s, C-1), 159.7 (s, ArC),
135.58 (d, ArCH), 135.56 (d, ArCH), 133.22 (s, ArC), 133.20 (s,
ArC), 130.1 (d, ArCH), 129.9 (d, ArCH), 128.3 (s, ArC), 127.8 (d,
ArCH), 114.0 (d, ArCH), 71.6 (d, C-5), 68.0 (t), 66.0 (t), 55.3 (q,
OCH3), 34.2 (t), 32.2 (t), 26.9 [q, C(CH3)3], 21.1 (t, C-3), 19.3 [s,
C(CH3)3].
MS (EI+): m/z (%) = 506 (M+, 0.1), 121 (100).
HRMS Observed (M+): 506.2500; C30H38O5Si requires 506.2489.
4-Methoxyphenylmethyl (5R)-6-[(tert-Butyldiphenylsilyl)oxy]-5-
hydroxyhexanoate [(5R)-4]:
To a stirred solution of (5R)-3 (10.20 g, 38.1 mmol) and imidazole
(5.69 g, 83.7 mmol) in anhyd DMF (40 mL) at r.t. under N2 was added
TBDPSCl (11.49 g, 41.9 mmol) in DMF (50 mL). The mixture was
stirred for 12 h at r.t. then quenched with water (100 mL). Workup
and purification as described above gave (5R)-4 (17.52 g, 91%) as a
colourless oil; [α]D20 –0.90 (c = 2.2, CHCl3) [lit.9 [α]D22 –0.92 (c = 2.1,
CHCl3)]. Spectroscopic data were identical with the (5S)-enantiomer
and those reported by Boger et al.9
IR (thin film): νmax = 3364 (OH), 1734 (C=O), 1614, 1587, 1518 cm–1
(aromatic C=C).
1H NMR (400 MHz, CDCl3): δ= 7.27 (2H, d, J = 8.8 Hz, ArH), 6.88
(2H, d, J = 8.8 Hz, ArH), 5.04 (2H, s, CO2CH2Ar), 3.79 (3H, s,
OCH3), 3.66 (1H, m, H-5), 3.59 (1H, m, H-6), 3.40 (1H, m, H-6), 3.18
(1H, br s, OH), 3.01 (1H, br s, OH), 2.36 (2H, t, J = 7.3 Hz, H-2), 1.74
(2H, m), 1.43 (2H, m).
4-Methoxyphenylmethyl (5S)-6-[(tert-Butyldiphenylsilyl)oxy]-5-
(methylsulfonyloxy)hexanoate [(5S)-5]:
To a stirred solution of (5S)-4 (20.64 g, 40.8 mmol) and Et3N
(8.51 mL, 61.2 mmol) in anhyd CH2Cl2 (100 mL) at 0°C under N2
was added MsCl (3.36 mL, 42.8 mmol) dropwise. The mixture was
stirred at 0°C for 1 hour and then sat. aq NaHCO3 (100 mL) was add-
ed. The organic layer was separated and the aqueous layer extracted
with CH2Cl2 (3 × 100 mL). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo to give a dark yellow oil. Col-
umn chromatography (100% CH2Cl2) provided (5S)-5 as a pale yel-
low oil (22.45 g, 94%); [α]D20 –6.38 (c = 1.0, EtOH).
13C NMR (100.6 MHz, CDCl3): δ = 173.8 (s, C-1), 159.7 (s, ArC),
130.1 (d, ArCH), 128.1 (s, ArC), 114.0 (d, ArCH), 71.8 (d, C-5), 66.6
(t), 66.1 (t), 55.3 (q, OCH3), 34.1 (t), 32.4 (t), 20.9 (t, C-3).
MS (EI+): m/z (%) = 268 (M+, 5), 121 (100).
Anal. Found: C: 62.96; H: 7.63; C14H20O5 requires C: 62.67; H: 7.51.
HRMS Observed (M+): 268.1310; C14H20O5 requires 268.1311.

SYNTHESIS
August 1998
1143
IR (thin film): νmax = 1734 (C=O), 1614, 1587, 1516 cm–1 (aromatic
C=C).
(6R)-6-[(tert-Butyldiphenylsilyl)oxymethyl]piperidin-2-one
[(6R)-7]:
1H NMR (400 MHz, CDCl3): δ= 7.67–7.62 (4H, m, ArH), 7.46–7.36
(6H, m, ArH), 7.26 (2H, d, J = 8.8 Hz, ArH), 6.86 (2H, d, J = 8.8 Hz,
ArH), 5.03 (2H, s, CO2CH2Ar), 4.72 (1H, m, H-5), 3.80 (1H, dd, J =
11.5, 6.1 Hz, H-6), 3.78 (3H, s, OCH3), 3.72 (1H, dd, J = 11.5, 3.9 Hz,
H-6), 2.95 (3H, s, OSO2CH3), 2.34 (2H, t, J = 6.9 Hz, H-2), 1.74–1.67
(4H, m, H-3, H-4), 1.06 [9H, s, C(CH3)3].
To a stirred solution of (5R)-6 (16.62 g, 31.3 mmol) in abs EtOH
(120 mL) was added 10% Pd/C (1.66 g, 10% w/w) and the suspension
stirred under H2 (1 atm) for 18 h at r.t. The black heterogeneous mix-
ture was filtered through a pad of Celite and the filtrate concentrated
in vacuo to give a pale yellow oil. Column chromatography (20%
EtOAc/light petroleum) provided a colourless liquid which was iden-
tified as 4-methoxybenzyl alcohol (3.81 g, 88%). Further elution
(50% EtOAc/light petroleum) gave (6R)-7 (9.62 g, 84%) as a white
crystalline solid, mp 91–93°C; [α]D20+6.74 (c = 1.1, CHCl3).
IR (Nujol): νmax = 3192 (NH), 1665 (C=O), 1587, 1506 cm–1 (aromat-
ic C=C).
13C NMR (100.6 MHz, CDCl3): δ = 172.9 (s, C-1), 159.7 (s, ArC),
135.6 (d, ArCH), 135.5 (d, ArCH), 132.9 (s, ArC), 132.7 (s, ArC),
130.11 (d, ArCH), 130.06 (d, ArCH), 130.0 (d, ArCH), 128.1 (s,
ArC), 127.9 (d, ArCH), 114.0 (d, ArCH), 83.1 (d, C-5), 66.1 (t), 65.3
(t), 55.3 (q, OCH3), 38.6 (q, OSO2CH3), 33.8 (t, C-2), 30.8 (t, C-4),
26.9 [q, C(CH3)3], 20.3 (t, C-3), 19.3 [s, C(CH3)3].
1H NMR (400 MHz, CDCl3): δ = 7.65–7.63 (4H, m, ArH), 7.44–7.37
(6H, m, ArH), 6.23 (1H, br s, NH), 3.61 (1H, dd, J = 9.3, 3.7 Hz, H-
7), 3.55 (1H, m, H-6), 3.47 (1H, dd, J = 9.3, 8.6 Hz, H-7), 2.40 (1H,
m, H-3), 2.26 (1H, m, H-3), 1.84 (1H, m), 1.76–1.62 (2H, m), 1.27
(1H, m), 1.06 [9H, s, C(CH3)3].
+
MS (CI): m/z (%) = 602 (MNH4 , 79), 121 (100).
+
HRMS Observed (MNH4 ): 602.2610; C31H44NO7SSi requires
602.2610.
13C NMR (100.6 MHz, CDCl3): δ = 171.9 (s, C-2), 135.5 (d, ArCH),
132.92 (s, ArC), 132.85 (s, ArC), 130.0 (d, ArCH), 127.9 (d, ArCH),
67.7 (t, C-7), 54.5 (d, C-6), 31.6 (t, C-3), 26.8 [q, C(CH3)3], 24.4 (t),
19.6 (t), 19.2 [s, C(CH3)3].
4-Methoxyphenylmethyl (5R)-6-[(tert-Butyldiphenylsilyl)oxy]-5-
(methylsulfonyloxy)hexanoate [(5R)-5]:
To a stirred solution of (5R)-4 (17.45 g, 34.5 mmol) and Et3N
(7.20 mL, 51.7 mmol) in anhyd CH2Cl2 (100 mL) at 0°C under N2
was added MsCl (2.80 mL, 36.2 mmol) dropwise. The mixture was
stirred at 0°C for 1 h and then sat. aq NaHCO3 (100 mL) was added.
Workup and purification as described above gave (5R)-5 (19.18 g,
95%) as a pale yellow oil; [α]D20 +7.77 (c = 1.0, EtOH). Spectroscopic
data were identical with the (5S)-enantiomer.
MS (CI): m/z (%) = 385 (MNH4 , 2), 368 (MH+, 100).
+
Anal. Found: C: 71.67; H: 7.96; N: 3.76; C22H29NO2Si requires C:
71.89; H: 7.95; N: 3.81.
(6S)-6-[(tert-Butyldiphenylsilyl)oxymethyl]piperidin-2-one [(6S)-
7]:
To a stirred solution of (5S)-6 (14.82 g, 27.9 mmol) in abs EtOH
(120 mL) was added 10% Pd/C (1.48 g, 10% w/w) and the suspension
stirred under H2 (1 atm) for 18 h at r.t. Workup and purification as
described above gave (6S)-7 (8.61 g, 84%) as a white crystalline solid,
mp 90–92°C; [α]D20 –6.41 (c = 1.1, EtOH). Spectroscopic data were
identical with the (6R)-enantiomer. 4-Methoxybenzyl alcohol (3.41 g,
89%) was also isolated as a colourless liquid.
4-Methoxyphenylmethyl (5R)-5-Azido-6-[(tert-butyldiphenyl-
silyl)oxy)]hexanoate [(5R)-6]:
A stirred solution of (5S)-5 (22.31 g, 38.2 mmol) and NaN3 (24.83 g,
0.382 mol) in anhyd DMF (150 mL) under N2 was heated at 80°C for
18 h. The resulting white heterogeneous mixture was quenched with
water (100 mL) and extracted with EtOAc (3 × 100 mL). The com-
bined organic extracts were washed with water (5 × 100 mL), dried
(Na2SO4) and concentrated in vacuo to give a yellow oil. Column
chromatography (10% EtOAc/light petroleum) provided (5R)-6 as a
colourless oil (16.72 g, 82%); [α]D20 +13.5 (c = 1.1, EtOH).
IR (thin film): νmax = 2106 (N3), 1734 (C=O), 1614, 1587, 1516 cm–1
(aromatic C=C).
(6R)-6-(Hydroxymethyl)piperidin-2-one [(6R)-1]:
To a stirred solution of (6R)-7 (500 mg, 1.36 mmol) in anhyd THF
(20 mL) at 0°C under N2 was added 1.0 M TBAF in THF (1.49 mL,
1.49 mmol), the mixture was allowed to warm to r.t. and stirred for 18
h. The resulting red-brown solution was quenched with glacial HOAc
(0.16 mL, 2.80 mmol) and concentrated in vacuo to give a brown
semi-solid. Column chromatography (100% EtOAc → 10% MeOH/
CH2Cl2) gave (6R)-1 (157 mg, 89%) as a white crystalline solid, mp
92–94°C; [α]D20 –28.1 (c = 1.1, CHCl3); preparation of the MTPA es-
ter according to the method of Weller et al.2 and subsequent 1H NMR
analysis of the crude product determined it to be ≥95% ee.
IR (Nujol): νmax = 3443 (OH), 3242 (NH), 1661 cm–1 (C=O).
1H NMR (400 MHz, CDCl3): δ = 7.33 (1H, br s, NH), 4.87 (1H, br s,
OH), 3.65–3.41 (3H, m, 1 × H-6, 2 × H-7), 2.30 (2H, m, H-3), 1.87
(2H, m), 1.71 (1H, m), 1.38 (1H, m).
1H NMR (400 MHz, CDCl3): δ= 7.68–7.66 (4H, m, ArH), 7.45–7.36
(6H, m, ArH), 7.27 (2H, d, J = 8.6 Hz, ArH), 6.86 (2H, d, J = 8.6 Hz,
ArH), 5.03 (2H, s, CO2CH2Ar), 3.78 (3H, s, OCH3), 3.70 (1H, dd, J
= 10.7, 3.9 Hz, H-6), 3.62 (1H, dd, J = 10.7, 6.9 Hz, H-6), 3.37 (1H,
m, H-5), 2.31 (2H, t, J = 7.4 Hz, H-2), 1.69 (2H, m), 1.42 (2H, m),
1.07 [9H, s, C(CH3)3].
13C NMR (100.6 MHz, CDCl3): δ = 173.0 (s, C-1), 159.7 (s, ArC),
135.67 (d, ArCH), 135.65 (d, ArCH), 133.12 (s, ArC), 133.06 (s,
ArC), 130.1 (d, ArCH), 129.9 (d, ArCH), 128.2 (s, ArC), 127.9 (d,
ArCH), 114.0 (d, ArCH), 67.0 (t), 66.1 (t), 63.6 (d, C-5), 55.3 (q,
OCH3), 34.0 (t), 29.8 (t), 26.8 [q, C(CH3)3], 21.6 (t, C-3), 19.2 [s,
C(CH3)3].
13C NMR (100.6 MHz, CDCl3): δ = 173.2 (s, C-2), 65.7 (t, C-7), 54.6
(d, C-6), 31.1 (t, C-3), 24.2 (t), 19.3 (t).
+
MS (CI): m/z (%) = 549 (MNH4 , 72), 504 (100).
+
HRMS Observed (MNH4 ): 549.2900; C30H41N4O4Si requires
MS (EI+): m/z (%) = 130 (MH+, 28), 129 (M+, 9), 55 (100).
Anal. Found: C: 55.67; H: 8.69; N: 10.63; C6H11NO2 requires C:
55.80; H: 8.58; N: 10.84.
549.2900.
HRMS Observed (M+): 129.0791; C6H11NO2 requires 129.0790.
4-Methoxyphenylmethyl (5S)-5-Azido-6-[(tert-butyldiphenyl-
silyl)oxy]hexanoate [(5S)-6]:
A stirred solution of (5R)-5 (19.68 g, 33.7 mmol) and NaN3 (21.90 g,
0.337 mol) in anhyd DMF (150 mL) under N2 was heated at 80°C for
18 h. The resulting white heterogeneous mixture was quenched with
water (100 mL). Workup and purification as described above gave
(5S)-6 (14.89 g, 83%) as a colourless oil; [α]D20 –13.8 (c = 1.1, EtOH).
Spectroscopic data were identical with the (5R)-enantiomer.
(6S)-6-(Hydroxymethyl)piperidin-2-one [(6S)-1]:
To a stirred solution of (6S)-7 (500 mg, 1.36 mmol) in anhyd THF
(20 mL) at 0°C under N2 was added 1.0 M TBAF in THF (1.49 mL,
1.49 mmol), the mixture was allowed to warm to r.t. and stirred for
18 h. Workup and purification as described above gave (6S)-1
(156 mg, 89%) as a white crystalline solid, mp 89.5–91.5°C (lit.2 mp

SYNTHESIS
Papers
1144
74°C); [α]D20 +26.7 (c = 1.1, CHCl3) (lit.2 [α]D22 +22.2 (c = 1.0,
CHCl3); preparation of the MTPA ester according to the method of
Weller et al.2 and subsequent 1H NMR analysis of the crude product
determined it to be ≥95% ee. Spectroscopic data were identical with
the (6R)-enantiomer and those reported by Weller.
(2) Huang, S.-B.; Nelson, J. S.; Weller, D. D. Synth. Commun. 1989,
19, 3485.
(3) Hermitage, S. A.; Moloney, M. G. Tetrahedron: Asymmetry,
1994, 5, 1463.
(4) Davies, C. E.; Heightman, T. D.; Hermitage, S. A.; Moloney, M.
G. Synth. Commun. 1996, 26, 687.
(5) Hanessian, S.; Reinhold, U.; Gentile, G. Angew. Chem., Int. Ed.
We gratefully acknowledge the financial support provided by the
Cancer Research Campaign and The Royal Society. We are indebted
to Dr J.A. Ballantine and his staff at the EPSRC national mass spec-
trometry service for performing some of the mass spectral measure-
ments.
Engl. 1997, 36, 1881.
(6) Huang, S.-B.; Nelson, J. S.; Weller, D. D. J. Org. Chem. 1991, 56,
6007.
(7) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483.
(8) Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
35, 448.
(1) Bryant, H. J.; Dardonville, C. Y.; Hodgkinson, T. J.; Shipman,
(9) Boger, D. L.; Hikota, M.; Lewis, B. M. J. Org. Chem. 1997, 62,
M.; Slawin, A. M. Z. Synlett 1996, 973.
1748.