Practical enzymatic desymmetrization of 2-(ethoxycarbonyl)propane-1,3-diyl dihexanoate and model cyclization for the A-D ring system of lysergic acid

Article abstract of DOI:10.1002/hlca.200790144

Porcine pancreas lipase-catalyzed hydrolysis of symmetrical 2-(ethoxycarbonyl)propane-1,3-diyl dihexanoate, under the modified conditions of the Seebach protocol, afforded a desymmetrized monohexanoate in 40-51% yield with 91-94% ee, even in a gram-scale reaction. The absolute configuration of a half-hydrolyzed (-)-product was determined to be (R) by conversion to a known 2-methylpropane-1,3-diol derivative. Samarium iodide-induced radical cyclization of 2-oxo-3-phenylethylamine with a C₄ unit on the N-atom, derived from the racemic monohexanoate, afforded a 3-phenylpiperidine derivative as a model construction of the A-D ring system of lysergic acid.

Full text of DOI:10.1002/hlca.200790144

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Helvetica Chimica Acta – Vol. 90 (2007)
Practical Enzymatic Desymmetrization of 2-(Ethoxycarbonyl)propane-1,3-
diyl Dihexanoate and Model Cyclization for the A– D Ring System of Lysergic
Acid
by Sachiho Miyata, Takuya Kumamoto, and Tsutomu Ishikawa*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi, Inage, Chiba 263-8522, Japan
(phone: þ 81-43-290-2910; fax: þ 81-43-290-2910; e-mail: benti@p.chiba-u.ac.jp)
Porcine pancreas lipase-catalyzed hydrolysis of symmetrical 2-(ethoxycarbonyl)propane-1,3-diyl
dihexanoate, under the modified conditions of the Seebach protocol, afforded a desymmetrized
monohexanoate in 40 – 51% yield with 91 – 94% ee, even in a gram-scale reaction. The absolute
configuration of a half-hydrolyzed (À)-product was determined to be (R) by conversion to a known 2-
methylpropane-1,3-diol derivative. Samarium iodide-induced radical cyclization of 2-oxo-3-phenylethyl-
amine with a C4 unit on the N-atom, derived from the racemic monohexanoate, afforded a 3-
phenylpiperidine derivative as a model construction of the A – D ring system of lysergic acid.
1. Introduction. – Lysergic acid (1), a tetracyclic indole derivative with two
stereogenic centers, is the core unit of ergot alkaloids showing a wide spectrum of
biological activities [1] such as prolactin inhibition, anti-Parkinsonian effect, and
depression of hypertension. The total synthesis of racemic 1 has been reported by nine
research groups [2], and two groups have successfully achieved the asymmetric
synthesis [3]. We have explored a novel aziridination from guanidinium ylides and
aromatic (or unsaturated) aldehydes, applicable to asymmetric synthesis [4], and
designed the synthesis of bioactive N-containing compounds, including lysergic acid
(1), using the formed aziridine as a key synthetic intermediate. Our retrosynthetic
strategy of 1 is shown in Scheme 1, in which aziridine 3, derived from guanidinium ylide
4 and 4-formyl-1H-indole, is reacted with an isobutyl-like C4 unit 5 to build the D ring
after construction of the A – B – C tricyclic ring system 2. Recently, we reported the
cyclization from the 4-position of the 1H-indole skeleton to the 3-position by
application of the Vilsmeier – Haack reaction [5]. In this paper, we present the practical
preparation of an optically active C4 unit as the partial component of the D ring by
enzymatic desymmetrization of 2-(ethoxycarbonyl)propane-1,3-diyl dihexanoate and
the model cyclization for the A – D ring system of lysergic acid (1) by using the
corresponding racemic C4 unit.
2. Results and Discussion. – 2.1. Enzymatic Desymmetrization of 2-(Ethoxycarbo-
nyl)propane-1,3-diyl Dihexanoate (9). In 1990, Ehrler and Seebach reported the
enzymatic desymmetrization of 2-(ethoxycarbonyl)propane-1,3-diyl dihexanoate (9)
[6], in which a half-hydrolyzed (À)-monohexanoate (À)-10 was obtained in 48% yield
with 84% ee, when porcine pancreas lipase (PPL) was used as an enzyme in the
ꢀ 2007 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 90 (2007)
1421
Scheme 1. Retrosynthesis of Lysergic Acid (1) with Aziridine 3 as a Key Unit
presence of MeOH as co-solvent. Therefore, we decided to re-examine Seebachꢁs
protocol [6] using PPL and, thus, prepared the starting dihexanoate 9 and racemic
monohexanoate (Æ)-10, as an authentic half-hydrolyzed product, from diethyl
malonate according to the combination of reported procedures [6]1) as shown in
Scheme 2.
Scheme 2. Preparation of 2-(Ethoxycarbonyl)propane-1,3-diyl Dihexanoate (9) and the Racemic
Monohexanoate (Æ)-10
The results of the PPL-catalyzed desymmetrization are summarized in Table 1. At
first, reactions with a small scale (0.1 g) of the dihexanoate 9 were examined as
preliminary experiments (Entries 1 – 7). Application of the Seebachꢁs co-solvent system
[6] of MeOH (Entry 1) as well as the use of THF as co-solvent (Entry 7) satisfactorily
afforded an optically active half-hydrolyzed (À)-monohexanoate (À)-10, in spite of
1
)
For the conversion of diethyl malonate to 7, see [7a – d]. For the conversion of 7 to 8, see [7e]. For
the conversion of 8 to (Æ)-10, see [7f].

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Helvetica Chimica Acta – Vol. 90 (2007)
long reaction time in the latter case. Next, gram-scale reactions were carried out under
these two conditions. The product (À)-10 was obtained in increased chemical yield
without loss of enantioselectivity in the THF system (Entry 9), whereas lower
enantioselectivity was observed in the MeOH one (Entry 8). Unfortunately, trial of
further scale-up operation in the THF system resulted not only in longer reaction time,
but also in lower enantioselectivity. Thus, it was concluded that a few gram scale
operation in the THF system could be the best condition of this PPL-catalyzed
desymmetrization of 2-(ethoxycarbonyl)propane-1,3-diyl dihexanoate (9).
Table 1. PPL-Catalyzed Desymmetrization of 2-(Ethoxycarbonyl)propane-1,3-diyl Dihexanoate (9)
Entry
Scale [g]
Co-solventa)
Time [h]
(À)-10
Yield [%]b)
ee [%]
1
2
3
4
5
6
7
8
9
0.1
0.1
0.1
0.1
0.1
0.1
0.1
1
30% MeOH
None
1
4
2
2
1
1
20
1
7
168
25c)
12
1
11
12
90
–d)
–
–
–
10% tBuOH
10% DMSO
10% DMF
10% iPr2O
15% THF
30% MeOH
15% THF
15% THF
17
–
30c)
34c)
51c)
38c)
93
82
94
80
1
10
10
b
c
a) The percentage of co-solvent is a ratio to buffer solution. ) Estimated by 1H-NMR. ) Isolated yield.
d) Not measured.
Ehrler and Seebach had addressed the optical purity of the (À)-monohexanoate
(À)-10 by conversion to the corresponding Mosher ester [6]; however, we newly
applied chiral HPLC method after benzoylation, in which a CHIRALCEL OJ-H
column (hexane/iPrOH 100 :1) was used. The absolute configuration of the (À)-
monohexanoate (À)-10 has never been determined. Therefore, we determined it by
chemical correlation with the known (þ)-(R)-2-methyl-1,3-propanediol derivative (þ)-
(R)-16 [8] as shown in Scheme 3. The (À)-monohexanoate (À)-10 was reduced with
diisobutylaluminum hydride (DIBAH) after protection of the OH moiety with the (t-
Bu)Ph2Si (TBDPS) group (!(þ)-11). The obtained (þ)-alcohol (þ)-12 was subjected
to the successive treatments of protection with the (benzyloxy)methyl (BOM) group
(!(þ)-13), reduction with DIBAH (!(À)-14), introduction of a p-toluenesulfonyl
(Ts) group (!(À)-15), and reductive cleavage with sodium borohydride (NaBH4) in
DMSO to give (À)-2-methylpropanediol derivative (À)-16. Thus, the opposite sign of
optical rotation against the known (þ)-compound with (R)-configuration indicated

Helvetica Chimica Acta – Vol. 90 (2007)
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Scheme 3. Chemical Conversion of Enzymatically Hydrolyzed (À)-Monohexanoate (À)-10 to (À)-2-
Methylpropane-1,3-diol Derivative (À)-16
that the absolute configuration of (À)-monohexanoate (À)-10, obtained by PPL-
catalyzed desymmetrization of dihexanote 9, should be (R).
2.2. Model Construction of the A – D Ring System of Lysergic Acid (1). Next, we
planed to prepare 5-(ethoxycarbonyl)-1-methyl-3-phenylpiperidine core 21 by reaction
of the C4 unit 17, derivable from (Æ)-2-(ethoxycarbonyl)propane-1,3-diyl monohex-
anoate (Æ)-10, and N-methyl-2-oxo-2-phenylethylamine (18) for the model construc-
tion of 21, i.e., the A – D ring system of lysergic acid (1) as outlined in Scheme 4.
The starting amino ketone 18 was prepared as a trifluoroacetate salt from 2-
hydroxy-N-methyl-2-phenylethylamine (22) by Swern oxidation after protection of the
amino group with (tert-butoxy)carbonyl (Boc) group, followed by treatment with
trifluoroacetic acid (TFA). On the other hand, according to route A in Scheme 4,
conversion of the (Æ)-monohexanoate (Æ)-10 to phosphonium salt 27 through
bromination was attempted, but only elimination of the hexanoic acid moiety from
the bromo derivative 25 occurred to give an olefinic phosphonium salt 26.
Alternatively, introduction of a different leaving group to (Æ)-10 based on route B
was achieved by mesylation; however, trials for N-alkylation of the amino ketone 18 or
amino alcohol 22 using the mesylate 28 were failed; instead, mainly demesylation of 28
occurred (Scheme 5). These facts led us to alter the use of a C4 unit from the
monohexanoate 17 to the propane-1,3-diol derivative 31 lacking ester function
(Scheme 6).

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Helvetica Chimica Acta – Vol. 90 (2007)
Scheme 4. Synthetic Plan of 5-(Ethoxycarbonyl)-1-methyl-3-phenylpiperidine Core 21 for the Model
Construction of the A – D Ring System of Lysergic Acid (1)
Preparation of some propane-1,3-diol derivatives without an ester function is
depicted in Scheme 7. The key monosilyl derivative of 2-(ethoxycarbonyl)propane-1,3-
diol 33 was prepared from (Æ)-10 by silylation, followed by reductive hydrolysis. The
monosilyl derivative 33 was also prepared by silylation of ꢂ2-(ethoxycarbonyl)propane-
1,3-diolꢁ (¼ethyl 3-hydroxy-2-(hydroxymethyl)propanoate; 8) under controlled con-
ditions, in which the double-silylated product 34 was co-produced but could be re-used
through desilylation. After protection of the OH group in 33 with the BOM or
tetrahydropyranyl (THP) group, reduction with LiBH4 afforded the corresponding
diprotected 2-(hydroxymethyl)propane-1,3-diols 37 or 38. Chemical modifications of
them to bromides 39 and 40, or methanesulfonates 41 and 42, respectively, were
achieved by either displacement of the OH group with Br or by mesylation.
Trials for conversion of bromides 39 and 40 to the corresponding phosphonium salts
for Wittig reaction resulted in the recovery of the starting materials. On the other hand,
although trials for N-alkylation with methanesulfonates 41 or 42 by using the amino
ketone 18 as a nucleophile failed, desired alkylation products 43 or 44 were obtained as
an inseparable mixture of diastereoisomers in 61 and 73% yields, respectively, when
amino alcohol 22 was treated with Et3N and KI in DMF (Scheme 8). However, it was
found that oxidation products such as 45, produced by Swern oxidation, were quite
labile in pure forms. Survey of the literature indicated no reports on the oxidation of
amino alcohols like 43 or 44, whereas smooth conversion of a 1-alkyl- [9] or an N-acyl-
substituted amino alcohol, 46 and 48 [10], respectively, to the corresponding ketone
products 47 and 49, respectively, were observed. Therefore, the amines 43 or 44 for
oxidation were changed to the corresponding N-Boc-protected derivatives.
Oxidation of N-Boc-amino alcohol 51, derived from 2-hydroxy-2-phenylethylamine
(50), with pyridinium dichromate (PDC) in DMF, as expected, gave the ketone 52 in

Helvetica Chimica Acta – Vol. 90 (2007)
1425
Scheme 5. Preparation of N-Methyl-2-oxo-2-phenylethylamine (18), Manipulation of (Æ)-2-(Ethoxycar-
bonyl)propane-1,3-diyl Monohexanoate (Æ)-10, and Trials for N-Alkylation
Scheme 6. Alternation of a C4 Unit from the Monohexanoate 17 to Propane-1,3-diol Derivative 31 without
an Ester Function
94% yield (Scheme 9). However, treatment of these N-Boc-protected amines 51 or 52
with BOM-protected methanesulfonate 41 did not afford alkylation products 53 or 54.
Fortunately, it was found that the original amino alcohol 50 itself could serve as a

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Helvetica Chimica Acta – Vol. 90 (2007)
Scheme 7. Preparation of Differently Diprotected Propane-1,3-diol Derivatives 39 – 42
nucleophile to give the desired alkylation product 55 although in moderate yield. The
alcohol 55 was oxidized to N-Boc-amino ketone 54 by three kinds of methods with PDC
in DMF (67%), by Swern oxidation (71%), and with MnO2 in CH2Cl2 (83%), after
protection of the amino function with Boc group. 2-Oxo-2-phenylethylamines 57 or 58
carrying an isobutyl-like C4 unit as a precursor for the cyclization were prepared by
deprotection of the (t-Bu)Me2Si (TBS) group of 54, followed by displacement of the
OH group with a halogen atom (Scheme 9). The synthetic products 53 – 58 were formed
as an inseparable mixture of diastereoisomers.
For C – C bond-formation of the halides 57 or 58 under Wittig reaction conditions,
trials of conversion to the corresponding phosphonium salts were unsuccessful. Thus,
we turned our attention to radical cyclization. Although almost no reaction occurred in
the use of triethylborane-oxygen condition, application of samarium iodide (SmI2)-
induced cyclization to the iodide 58 in the presence of hexamethylphosphoric triamide
(HMPA) afforded the desired 3-phenylpiperidine 59 as a separable ca. 1:1 mixture of
diastereoisomers, albeit in 23% yield (see, Entry 1 in Table 2). Thus, we examined this
Barbier-type reaction under various conditions (Table 2), and slightly increased
formation of the cyclized product 59 (32%) was observed, when an excess of samarium
(Sm) [11] was used in the presence of HMPA under dilute concentration of the iodide
58 in THF (Entry 5). A cleaved product 60 was a major side-product in these reactions.

Helvetica Chimica Acta – Vol. 90 (2007)
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Scheme 8. Trials for Preparation of 2-Oxo-2-phenylethylamines with an Isobutyl-Like C4 Unit and
Reported Oxidations of 2-Hydroxy-2-phenylethylamine Derivatives 46 and 48
3. Conclusions. – In summary, we established the practical PPL-catalyzed
desymmetrization of 2-(ethoxycarbonyl)propane-1,3-diyl dihexanoate, in which the
best result in a few gram scale was obtained by the use of THF as co-solvent, and the
absolute configuration of the desymmetrized (À)-monohexanoate was determined to
be (R) by chemical conversion. Furthermore, SmI2-induced radical cyclization of 2-
oxo-3-phenylethylamine with an isobutyl-like C4 unit on the N-atom, derived from the
racemic monohexanoate, afforded 3-phenylpiperidine derivative as a model construc-
tion of A – D ring system of lysergic acid.
We thank Dr. Takeshi Sugai, Keio University, Japan, for his kind technical suggestion to enzymatic
hydrolysis.
Experimental Part
General. Anh. THF, CH2Cl2, and DMF, were purchased from Wako or Kanto Chemicals. PPL
Powder (Type II, Batch#114K0617) was purchased from Sigma. Et3N, MeCN, and MeOH were distilled

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Helvetica Chimica Acta – Vol. 90 (2007)
Scheme 9. Preparation of Precursors for Model Cyclization of the A – D Ring System of Lysergic Acid (1)
from KOH, CaH2, and Mg turnings, resp. Benzene and EtOH were stored with Na and mol. sieves (3 Š),
resp., after distillation. Org. solns. obtained in extractions were dried (MgSO4). For column
chromatography (CC), Kanto Chemicals, silica gel 60 (acidic) or silica gel 60N (neutral), and Fujisilicia,
Chromatorex NH-DM1020 (NH-type), and, for prep. TLC Merck, TLC plates silica gel 60 F254, were
used. M.p.: Yanaco MP-S3; uncorrected. [a]D Values: JASCO P-1020. IR Spectra: JASCO FT/IR-300E
spectrophotometer. 1H-NMR Spectra: in CDCl3 on a JEOL JNM ECP-400 (400 MHz) or ALPHA-500
(500 MHz) instruments, TMS as an internal standard, unless otherwise stated. 13C-NMR Spectra: JEOL
JNM ECP-400 (100 MHz) or ALPHA-500 (125 MHz), with the middle resonance of CDCl3 (77.0 ppm)
as an internal standard. LR- and HR-EI-MS: JEOL GC-mate with direct inlet. HR-FAB-MS: JEOL
JMS-HX 110A with 3-nitrobenzyl alcohol as a matrix.
Benzoylation of (Æ)-2-(Ethoxycarbonyl)-3-hydroxypropyl Hexanoate ((Æ)-10). To an ice-cooled
stirred soln. of (Æ)-10 (44 mg, 0.18 mmol) and pyridine (0.5 ml) was added a soln. of PhCOCl (BzCl) in
CH2Cl2 (0.1 ml), which was prepared from BzCl (0.22 ml, 1.9 mmol) in CH2Cl2 (0.8 ml), under Ar. After
stirring for 0.5 h under the same conditions, the mixture was diluted with Et2O (15 ml). The org. soln. was
washed with 2n aq. HCl (4 ml), sat. aq. NaHCO3 (4 ml), H2O (4 ml), and brine (4 ml), dried, and
evaporated. Purification of the residue by CC (acidic; hexane/AcOEt 20 :1) afforded the benzoate
(57 mg, 91%) as a colorless oil. Chiral HPLC (DAICEL CHIRALCEL OJ-H, 254 nm, 0.5 ml/min,

Helvetica Chimica Acta – Vol. 90 (2007)
Table 2. SmI2-Induced Cyclization of Iodide 58
1429
Entry
SmI2 [equiv.]
Conc. [mm]
Additive ([equiv.])
Yields [%]a)
59
58
60
1
2
3
4
5
6
7
8
3
5
3
3
4
4
3
3
30
30
30
30
5
5
5
5
HMPA (7)
None
23
–
–
20
32
–
18
3636
50
3
5
HMPA (7)/DMAE (3)
HMPA (17)/Sm (5)
HMPA (19)/Sm (6)
DMPU (18)/Sm (6)
Fe(acac)3 (cat)/Sm (5)
NiI2 (cat)/Sm (6)
–
–
–
18
38
25
4
45
24
22
–
–
a) Yield of isolated products.
hexane/iPrOH 100 :1): 31.7 and 33.5 min. IR (ATR): 1726(CO). 1H-NMR (400 MHz): 0.88 (t, J ¼ 6.8,
Me); 1.24 – 1.32 (m, CH2); 1.26( t, J ¼ 7.1, Me); 1.61 (quint., J ¼ 7.5, CH2); 2.31 (t, J ¼ 7.5, CH2); 3.17
(quint., J ¼ 6.0, CH); 4.21 (q, J ¼ 7.1, CH2); 4.41 (dd, J ¼ 11.0, 6.1, CH2); 4.46( dd, J ¼ 11.0, 6.1, CH2);
4.56( dd, J ¼ 11.0, 5.6, CH2); 4.62 (dd, J ¼ 11.0, 5.6, CH2); 7.44 (t, J ¼ 7.5, arom. H); 7.57 (t, J ¼ 7.5, arom.
H); 8.01 (d, J ¼ 7.5, arom. H). 13C-NMR (100 MHz): 13.8; 14.1; 22.2; 24.5; 31.1; 34.0; 44.2; 61.1; 61.2;
61.8; 128.4; 129.5; 133.1; 166.0; 170.3; 173.3. HR-EI-MS: 350.1702 (Mþ, C19H26O6þ ; calc. 350.1729).
Enzymatic Hydrolysis of 2-(Ethoxycarbonyl)propane-1,3-diyl Dihexanoate (9; Entry 9 in Table 1).
A mixture of 9 (1.04 g, 3.0 mmol) in 0.2 mol aq. KH2PO4 (28 ml), 0.2 mol aq. KOH (16ml), and anh.
THF (7.8 ml) was sonicated for 5 min, to which PPL powder (0.1 g) was added. The mixture was stirred at
308 (inner temp.) for 7 h and maintained at pH 6.9 – 7.1 by adding 1 mol aq. NaOH (total 3.3 ml,
3.3 mmol) during the stirring. After ice-cooling, cold acetone (350 ml), followed by Celite (ca. 0.5 g), was,
in one portion, added, and the whole mixture was stirred for 1.5 h under ice-cooling. The Celite-absorbing
PPL was removed by filtration and washed with a small amount of AcOEt. After evaporation of the
filtrate, brine (3 ml) was added to the residue, and the mixture was extracted with AcOEt (3 ꢀ 200 ml).
The org. soln. was dried and evaporated to give a pale yellow oil (quant.), purification of which by CC
(acidic, hexane/AcOEt 5 :1) afforded (À)-10 (0.380 g, 51%) and 8 (0.195 g, 44%).
(À)-2-(Ethoxycarbonyl)-3-hydroxypropyl Hexanoate ((À)-10): Colorless oil. Benzoate: Chiral
HPLC: 31.7 (97%) and 33.5 (3%) min (DAICEL CHIRALCEL OJ-H; 254 nm, 0.5 ml/min, hexane/
iPrOH 100 :1). [a]1D9 ¼ À10.2 (c ¼ 1.1, EtOH). IR (ATR): 3444 (OH), 1736(CO). 1H-NMR (400 MHz):
0.90 (t, J ¼ 7.0, Me); 1.27 – 1.35 (m, Me, 2 CH2); 1.58 – 1.65 (m, CH2); 2.31 (t, J ¼ 7.6, CH 2); 2.43 (t, J ¼
6.7, HO); 2.88 (quint., J ¼ 5.8, CH); 3.83 (dd, J ¼ 11.3, 6.3, 1 H, CH2); 3.89 (dd, J ¼ 11.3, 6.3, 1 H, CH2);
4.21 (q, J ¼ 3.6, CH2); 4.37 (dd, J ¼ 16.9, 5.8, 1 H, CH2); 4.41 (dd, J ¼ 16.9, 5.8, 1 H, CH2).
(þ)-(S)-3-[(tert-Butyl)diphenylsilyloxy]-2-(ethoxycarbonyl)propyl Hexanoate ((þ)-11). A soln. of
(À)-10 (173 mg, 0.70 mmol), 1H-imidazole (76mg, 1.12 mmol), and ( t-Bu)Ph2SiCl (TBDPSCl) (0.23 ml,
0.88 mmol) in DMF (0.95 ml) was stirred at r.t. for 1 h under Ar, the reaction was quenched with H2O
(10 ml), and the mixture was extracted with AcOEt (3 ꢀ 20 ml). The org. soln. was washed with H2O
(5 ꢀ 10 ml) and brine (10 ml), dried, and evaporated. Purification of the residue by CC (acidic, hexane/
AcOEt 50 :1) afforded (þ)-11 (315 mg, 93%). Colorless oil. [a]2D1 ¼ þ4.6( c ¼ 1.0, CHCl3). IR (ATR):

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Helvetica Chimica Acta – Vol. 90 (2007)
1738 (CO). 1H-NMR (400 MHz): 0.88 (t, J ¼ 7.0, Me); 1.03 (s, 3 Me); 1.25 – 1.29 (m, 2 CH2); 1.26( t, J ¼
7.1, Me); 1.57 (quint., J ¼ 7.5, CH2); 2.24 (t, J ¼ 7.5, CH2); 2.90 (quint., J ¼ 6.0, CH); 3.89 (dd, J ¼ 10.0,
5.4, 1 H, CH2); 3.93 (dd, J ¼ 10.0, 5.4, 1 H, CH2); 4.21 (q, J ¼ 7.1, CH2); 4.37 (dd, J ¼ 11.0, 6.5, 1 H, CH2);
4.43 (dd, J ¼ 11.0, 6.5, 1 H, CH2); 7.36– 7.45 ( m, arom. H); 7.64 (diffused t, J ¼ 6.4, arom. H). 13C-NMR
(100 MHz): 13.9; 14.2; 19.2; 22.3; 24.5; 26.7; 31.2; 34.1; 47.2; 60.7; 61.2; 61.3; 127.7; 129.7; 133.1; 135.5;
171.4; 173.4. HR-FAB-MS: 485.2706([ M þ H]þ, C28H41O5Siþ; calc. 485.2723).
Ethyl (þ)-(S)-3-[(tert-Butyl)diphenylsilyloxy]-2-hydroxymethylpropanoate ((þ)-12). A mixture of
(þ)-11 (349 mg, 0.72 mmol) in THF (5.6ml) and 1m soln. of DIBAH in toluene (1.4 ml, 1.4 mmol) was
stirred at À 788 for 2.5 h under Ar. After quenching with H2O (2 ml) at the same temp., H2O (8 ml),
Et2O (40 ml), and 1n aq. HCl (10 ml) were added, and the resulting mixture was extracted with Et2O
(2 ꢀ 30 ml). The org. soln. was washed with brine (10 ml), dried, and evaporated. Purification of the
residue by CC (acidic, hexane/AcOEt 20 :1) afforded (þ)-12 (175 mg, 63%) as a colorless oil together
with the starting (þ)-11 (84 mg, 24%). [a]1D9 ¼ þ5.6( c ¼ 1.1, CHCl3). IR (ATR): 3415 (OH), 1730 (CO).
1H-NMR (400 MHz): 1.04 (s, 3 Me); 1.26( t, J ¼ 7.1, Me); 2.36( t, J ¼ 6.4, HO); 2.79 (tt, J ¼ 6.5, 5.1, CH);
3.87 (ddd, J ¼ 11.3, 6.7, 4.9, 1 H, CH2); 3.91 (dd, J ¼ 10.0, 4.9, 1 H, CH2); 3.98 (dd, J ¼ 10.0, 6.2, 1 H,
CH2); 4.03 (ddd, J ¼ 11.3, 6.2, 6.2, 1 H, CH2); 4.16( dd, J ¼ 10.7, 7.1, 1 H, CH2); 4.18 (dd, J ¼ 10.7, 7.1, 1 H,
CH2); 7.37 – 7.46( m, arom. H); 7.64 – 7.67 (m, arom. H). 13C-NMR (100 MHz): 14.1; 19.2; 26.7; 49.7; 60.7;
61.2; 62.2; 127.70; 127.73; 129.8; 132.98; 133.0; 135.48; 135.51; 172.9. HR-FAB-MS: 387.1996 ([M þ H]þ,
C22H31O4Siþ; calc. 387.1992).
Ethyl (þ)-(S)-2-{[(Benzyloxy)methoxy]methyl}-3-[(tert-butyl)diphenylsilyloxy]propanoate ((þ)-
13). To a soln. of (þ)-12 (99 mg, 0.26mmol) and iPr2EtN (0.13 ml, 0.76mmol) in CH 2Cl2 (0.70 ml)
was added a soln. of (benzyloxy)methyl chloride (BOMCl) (0.05 ml, 0.36mmol) in CH 2Cl2 (0.30 ml)
under Ar. The mixture was stirred at 10 – 208 for 5.5 h, the reaction was quenched with aq. NH4Cl (5 ml),
and the mixture was extracted with AcOEt (3 ꢀ 15 ml). The org. soln. was washed with brine (10 ml),
dried, and evaporated. Purification of the residue by CC (acidic, hexane/Et2O 20 :1) afforded (þ)-13
(120 mg, 92%). Colorless oil. [a]1D8 ¼ þ1.6( c ¼ 1.0, CHCl3). IR (ATR): 1734 (CO). 1H-NMR (400 MHz):
1.03 (s, 3 Me); 1.26( t, J ¼ 7.2, Me); 2.89 (quint., J ¼ 6.0, CH); 3.82 (dd, J ¼ 9.8, 6.1, CH2); 3.89 – 3.96( m,
CH2); 4.17 (q, J ¼ 7.2, CH2); 4.53, 4.56( AB, J ¼ 12.2, CH2 (benzyl)); 4.71 (s, CH2; 7.31 – 7.42 (m, arom.
H); 7.64 – 7.66 (diffused d, J ¼ 7.8, arom. H). 13C-NMR (100 MHz): 14.2; 19.2; 26.7; 48.6; 60.6; 61.7; 65.4;
69.2; 94.7; 127.7; 127.9; 128.4; 129.7; 133.3; 135.5; 137.7; 172.3. HR-FAB-MS: 545.2078 ([M þ K]þ,
C30H38KO5Siþ; calc. 545.2126).
(À)-(S)-2-{[(Benzyloxy)methoxy]methyl}-3-[(tert-butyl)diphenylsilyloxy]propan-1-ol ((À)-14). A
soln. of (þ)-13 (42 mg, 0.08 mmol) and 1m soln. of DIBAH in toluene (0.42 ml, 0.42 mmol) in Et2O
(0.83 ml) was stirred at À 408 for 1 h under Ar. After quenching with H2O (1 ml) at the same temp.,
AcOEt (10 ml) and 1n aq. HCl (6ml) were added, and the resulting mixture was extracted with AcOEt
(2 ꢀ 10 ml). The org. soln. was washed with brine (6ml), dried, and evaporated. Purification of the
residue by CC (acidic, hexane/AcOEt 50 :1) afforded (À)-14 (24 mg, 61%). Colorless oil. [a]2D2 ¼ À2.4
(c ¼ 1.0, CHCl3). IR (ATR): 3448 (OH). 1H-NMR (400 MHz): 1.06( s, 3 Me); 2.08 (sept., J ¼ 5.9, CH);
2.43 (br. s, HO); 3.6 9 (dd, J ¼ 9.5, 6.3, 1 H, CH2); 3.70 (dd, J ¼ 9.5, 5.9, 1 H, CH2); 3.76( dd, J ¼ 10.2, 6.1,
1 H, CH2); 3.80 (dd, J ¼ 10.2, 5.4, 1 H, CH2); 3.81 (br. s, CH2); 4.55 (s, CH2); 4.71 (s, CH2); 7.27 – 7.45 (m,
arom. H); 7.65 – 7.68 (diffused d, J ¼ 8.0, arom. H). 13C-NMR (100 MHz): 19.2; 26.8; 43.2; 63.6; 67.3;
69.4; 94.8; 127.69; 127.72; 127.8; 128.4; 129.8; 133.14; 133.18; 135.53; 135.54; 137.7. HR-FAB-MS: 465.2422
([M þ H]þ, C28H37O4Siþ; calc. 465.2461).
(À)-(S)-2-{[(Benzyloxy)methoxy]methyl}-3-[(tert-butyl)diphenylsilyloxy]propan-1-yl p-Toluene-
sulfonate ((À)-15). A mixture of (À)-14 (148 mg, 0.32 mmol), TsCl (167 mg, 0.88 mmol), DMAP
(24 mg, 0.20 mmol), and Et3N (0.13 ml, 0.93 mmol) in CH2Cl2 (1.5 ml) was stirred at r.t. for 1.5 h under
Ar. After quenching with NH4Cl (71 mg, 1.33 mmol), followed by H2O (8 ml) under ice-cooling, the
resulting mixture was extracted with Et2O (3 ꢀ 25 ml). The org. soln. was washed with brine (12 ml),
dried, and evaporated. Purification of the residue by CC (acidic, hexane/AcOEt 15 :1) afforded (À)-15
1
(173 mg, 88%). Colorless oil. [a]2D2 ¼ À0.4 (c ¼ 1.1, CHCl3). H-NMR (400 MHz): 0.98 (s, 3 Me); 2.18
(quint., J ¼ 5.7, CH); 2.41 (s, Me); 3.54 (dd, J ¼ 9.4, 5.9, 1 H, CH2); 3.57 (dd, J ¼ 9.4, 5.3, 1 H, CH2); 3.61
(dd, J ¼ 10.1, 6.3, 1 H, CH2); 3.66 (dd, J ¼ 10.1, 5.4, 1 H, CH2); 4.16( dd, J ¼ 10.6, 5.6, 1 H, CH2); 4.20 (dd,
J ¼ 10.6, 5.6, 1 H, CH2); 4.48 (s, CH2); 4.61 (s, CH2); 7.26– 7.44 ( m, arom. H); 7.58 (d, J ¼ 7.1, arom. H);

Helvetica Chimica Acta – Vol. 90 (2007)
1431
7.76( d, J ¼ 7.9, arom. H). 13C-NMR (100 MHz): 19.2; 21.6; 26.7; 41.6; 61.0; 65.0; 68.2; 69.4; 94.7; 127.7;
127.85; 127.91; 128.4; 129.7; 129.8; 132.9; 133.1; 135.5; 137.7; 144.6. HR-FAB-MS: 657.2137 ([M þ K]þ,
C35H42KO6SSiþ; calc. 657.2108).
(À)-(S)-3-[(Benzyloxy)methoxy]-2-methylpropyl (tert-Butyl)diphenylsilyl Ether ((À)-16). A mix-
ture of (À)-15 (194 mg, 0.31 mmol) and NaBH4 (128 mg, 3.38 mmol) in DMSO (16ml) was stirred at 60 8
for 6.5 h under Ar. After quenching with H2O (6ml) and 5% aq. NH 4Cl (15 ml) under ice-cooling, the
resulting mixture was extracted with Et2O (3 ꢀ 40 ml). The org. soln. was washed with brine (10 ml),
dried, and evaporated. Purification of the residue by CC (acidic, hexane/AcOEt 30 :1) afforded (À)-16
1
(118 mg, 84%). Colorless oil. [a]1D8 ¼ À5.0 (c ¼ 1.0, CHCl3). H-NMR (400 MHz): 0.97 (d, J ¼ 7.0, Me);
1.05 (s, 3 Me); 1.99 (sext., J ¼ 6.3, CH); 3.51 (dd, J ¼ 9.4, 6.1, 1 H, CH2); 3.60 (dd, J ¼ 10.2, 5.6, 1 H,
CH2); 3.63 (dd, J ¼ 10.2, 5.6, 1 H, CH2); 3.64 (dd, J ¼ 9.4, 6.1, 1 H, CH2); 4.57 (s, CH2); 4.73 (s, CH2);
7.26– 7.42 ( m, arom. H); 7.66 (diffused d, J ¼ 5.7, arom. H). 13C-NMR (100 MHz): 14.1; 19.3; 26.9; 36.3;
65.8; 69.2; 70.2; 94.8; 127.6; 127.9; 128.4; 129.5; 133.9; 135.6; 138.0. FAB-MS: 487 ([M þ K]þ); 449 ([M þ
H]þ).
tert-Butyl N-(2-Hydroxy-2-phenylethyl)-N-methylcarbamate (23). A mixture of 22 (203 mg,
1.34 mmol), Et3N (0.21 ml, 1.51 mmol), and Boc2O (328 mg, 1.50 mmol) in CH2Cl2 (2 ml) was stirred
at r.t. for 1.5 h under Ar. After dilution with CH2Cl2 (10 ml), the mixture was washed with 10% aq. citric
acid (5 ml), sat. aq. NaHCO3 (5 ml), and brine (5 ml), and dried, and evaporated. Purification of the
residue by CC (neutral, CHCl3) afforded 23 (335 mg, 99%) as a colorless oil, which was solidified on
standing (m.p. 48.5 – 508). IR (ATR): 3413 (OH), 1664 (CO). 1H-NMR (400 MHz; 2 :1 mixture of
rotamers): 1.49 (s, 3 Me); 2.35 (s, 0.33 HO); 2.79 (br. s, 0.66 Me); 2.90 (br. s, 0.33 Me); 3.38 – 3.60 (m,
CH2); 4.21 (br. s, 0.66 HO); 4.95 (br. s, CH); 7.27 – 7.30 (m, arom. H); 7.34 – 7.38 (m, arom. H). FAB-MS:
503 ([2M þ H]þ), 274 ([M þ Na]þ), 252 ([M þ H]þ).
tert-Butyl N-Methyl-N-(2-oxo-2-phenylethyl)carbamate (24). To a soln. of oxalyl chloride (0.43 ml,
4.93 mmol) in CH2Cl2 (9 ml) was added a soln. of DMSO (0.55 ml, 7.75 mmol) in CH2Cl2 (4 ml), followed
by a soln. of 23 (879 mg, 3.5 mmol) in CH2Cl2 (4 ml) at À 788 under Ar, and then the mixture was stirred
at the same temp. for 1 h. After addition of Et3N (2.4 ml, 17.2 mmol) at the same temp., the mixture was
stirred for 3.5 h, and the reaction was quenched with H2O (5 ml). After further addition of H2O (5 ml) at
r.t., the mixture was extracted with CH2Cl2 (3 ꢀ 50 ml). The org. soln. was washed with H2O (5 ꢀ 15 ml)
and brine (15 ml), and dried and evaporated. Purification of the residue by CC (acidic, hexane/AcOEt
1
10 :1) afforded 24 (852 mg, 98%). Colorless oil. IR (ATR): 1687 (CO). H-NMR (400 MHz): 1.38 (s,
Me); 1.49 (s, Me); 2.94, 2.98 (2s, Me); 4.59 (s, CH2); 4.69 (s, CH2); 7.45 – 7.51 (m, arom. H); 7.56– 7.63 ( m,
arom. H); 7.94 (t, J ¼ 7.7, arom. H). EI-MS: 250 ([M þ H]þ), 249 (Mþ).
(Methyl)(2-oxo-2-phenylethyl)ammonium Trifluoroacetate (18). A soln. of 24 (150 mg, 0.6mmol)
and TFA (0.1 ml, 1.3 mmol) in CH2Cl2 (0.5 ml) was stirred at r.t. for 22 h under Ar. After evaporation of
the TFA and the solvent, trituration of the residue with hexane/Et2O 1:1, followed by recrystallization
from CH2Cl2, afforded 18 as TFA salt (154 mg, 97%). IR (ATR): 1739, 1682 (CO). 1H-NMR (400 MHz,
in CDCl3 þ CD3OD): 2.83 (s, Me); 3.76(br. s, NH2); 4.61 (s, CH2); 7.54 (t, J ¼ 7.8, 2 arom. H); 7.69 (tt, J ¼
7.4, 1.4, 1 arom. H); 7.97 (diffused dd, J ¼ 8.4, 1.3, 2 arom. H). 13C-NMR (100 MHz, in CDCl3 þ CD3OD):
32.4; 53.4; 116.3; 127.6; 128.6; 132.9; 134.5; 161.9; 190.8. HR-EI-MS: 149.0841 ([MÀTFA]þ, C9H11NOþ;
calc. 149.0811).
3-Bromo-2-(ethoxycarbonyl)propyl Hexanoate (25). A mixture of (Æ)-10 (166 mg, 0.67 mmol), CBr4
(346mg, 1.02 mmol), and PPh 3 (304 mg, 1.16mmol) in CH 2Cl2 (3 ml) was stirred for 2 h under ice-
cooling and Ar. After removal of precipitate by filtration, the filtrate was evaporated and purified by CC
(acidic, hexane/AcOEt 50 :1) to afford 25 (181 mg, 80%). Colorless oil. IR (ATR): 1738 (CO). 1H-NMR
(400 MHz): 0.90 (t, J ¼ 6.9, Me); 1.23 – 1.37 (m, 2 CH2); 1.29 (t, J ¼ 7.1, Me), 1.62 (quint., J ¼ 7.5, CH2);
2.31 (t, J ¼ 7.5, CH2); 3.11 (quint., J ¼ 5.9, CH); 3.61 (dd, J ¼ 10.4, 6.0, 1 H, CH2); 3.66 (dd, J ¼ 10.5, 5.9,
1 H, CH2); 4.22 (q, J ¼ 7.1, CH2); 4.37 (dd, J ¼ 11.2, 6.1, 1 H, CH2); 4.43 (dd, J ¼ 11.3, 5.6, 1 H, CH2).
13C-NMR (100 MHz): 13.9; 14.1; 22.3; 24.5; 29.0; 31.2; 34.0; 46.6; 61.4; 62.2; 170.0; 173.3. HR-EI-MS:
308.0622 ([M þ H]þ, C12H21BrOþ4 ; calc. 308.0623).
Trial for the Preparation of [2-(Ethoxycarbonyl)-3-hexanoyloxypropyl]triphenylphosphonium
Bromide (27): [2-(Ethoxycarbonyl)prop-2-enyl]triphenylphosphonium Bromide (26). A mixture of 25
(53 mg, 0.15 mmol) and PPh3 (38 mg, 0.15 mmol) in benzene (0.8 ml) was refluxed for 6h under Ar.

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Helvetica Chimica Acta – Vol. 90 (2007)
After removal of the solvent, the residue was purified by trituration with hexane/Et2O to afford 26
(59 mg, 90%). Colorless solid. IR (ATR): 1712 (CO). 1H-NMR (400 MHz): 1.06( t, J ¼ 7.1, Me); 3.81 (q,
J ¼ 7.1, CH2); 5.28 (d, J ¼ 15.0, CH2); 6.54 (d, J ¼ 5.7, CH2); 7.66 – 7.71 (m, arom. H); 7.79 (t, J ¼ 7.5, arom.
H); 7.90 (dd, J ¼ 12.7, 7.2, arom. H). FAB-MS: 376([ M þ H]þ); 375 (Mþ).
2-(Ethoxycarbonyl)-3-hexanoylpropyl Methanesulfonate (28).
A
soln. of (Æ)-10 (194 mg,
0.79 mmol), MsCl (0.12 ml, 1.6mmol), and pyridine (0.39 ml, 4.82 mmol) in CH 2Cl2 (2 ml) was stirred
at r.t. for 2.5 h under Ar. After dilution with CH2Cl2 (20 ml), the soln. was washed with sat. aq. CuSO4
(10 ml), sat. aq. NaHCO3 (10 ml), and brine (10 ml), and dried and evaporated. Purification of the
residue by CC (acidic, hexane/AcOEt 30 :1 then CHCl3/Et2O 10 :1) afforded 28 (248 mg, 97%).
Colorless oil. IR (ATR): 1734 (CO). 1H-NMR (400 MHz): 0.90 (t, J ¼ 6.9, Me); 1.27 – 1.32 (m, 2 CH2);
1.29 (t, J ¼ 7.1, Me), 1.61 (quint., J ¼ 7.5, CH2); 2.32 (t, J ¼ 7.5, CH2); 3.05 (s, Me); 3.11 (quint., J ¼ 6.0,
CH); 4.22 (q, J ¼ 7.1, CH2); 4.37 (dd, J ¼ 11.3, 6.0, 1 H, CH2); 4.40 (dd, J ¼ 11.3, 6.0, 1 H, CH2); 4.44 (dd,
J ¼ 10.2, 6.0, 1 H, CH2); 4.52 (dd, J ¼ 10.2, 6.0, 1 H, CH2). 13C-NMR (100 MHz): 13.7; 13.9; 22.1; 24.3;
31.1; 33.8; 37.1; 44.2; 60.3; 61.5; 66.0; 169.2; 173.1. HR-FAB-MS: 325.1304 ([M þ H]þ, C13H25O7Sþ; calc.
325.1321).
3-[(tert-Butyl)dimethylsilyloxy]-2-(ethoxycarbonyl)propyl Hexanoate (32). A soln. of ( Æ )-10
(240 mg, 0.98 mmol), 1H-imidazole (172 mg, 2.52 mmol), and TBSCl (228 mg, 1.48 mmol) in DMF
(1.8 ml) was stirred at r.t. for 1 h under Ar, the reaction was quenched with H2O (10 ml), and the mixture
was extracted with AcOEt (3 ꢀ 20 ml). The org. soln. was washed with H2O (3 ꢀ 10 ml) and brine
(10 ml), and dried and evaporated. Purification of the residue by CC (acidic, hexane/AcOEt 50 :1)
1
afforded 32 (285 mg, 81%). Colorless oil. IR (ATR): 1739 (CO). H-NMR (400 MHz): 0.04 (s, 2 Me);
0.87 (s, 3 Me); 0.89 (t, J ¼ 6.8, Me); 1.24 – 1.31 (m, CH2); 1.26( t, J ¼ 7.1, Me); 1.61 (quint., J ¼ 7.5, CH2);
2.29 (t, J ¼ 7.5, CH2); 2.85 (quint., J ¼ 6.0, CH); 3.86 (d, J ¼ 6.0, CH2); 4.16( q, J ¼ 7.1, CH2); 4.32 (dd,
J ¼ 10.9, 6.0, 1 H, CH2); 4.35 (dd, J ¼ 10.9, 6.0, 1 H, CH2). 13C-NMR (100 MHz): À 5.7; 13.8; 14.1; 18.1;
22.2; 24.6; 25.7; 31.2; 34.1; 47.4; 60.6; 61.3; 171.4; 173.4. HR-FAB-MS: 361.2386 ([M þ H]þ, C18H37O5Si;
calc. 361.2410).
Ethyl (Æ)-3-{[(tert-Butyl)dimethylsilyloxy]methyl}-2-hydroxypropanoate (33). To a soln. of 32
(75 mg, 0.21 mmol) in THF (1.4 ml) was added 1m soln. of DIBAH in toluene (0.7 ml, 0.7 mmol). The
mixture was stirred at À 788 for 3 h under Ar, and the reaction was quenched with H2O (3 ml) at the
same temp. After further addition of H2O (10 ml) at r.t., the mixture was extracted with AcOEt (30 ml).
The org. soln. was washed with 0.1% aq. HCl (5 ꢀ 10 ml), and the HCl washings were extracted with
AcOEt (2 ꢀ 30 ml). The org. solns. were combined and washed with brine (15 ml), and dried and
evaporated. Purification of the residue by CC (acidic, hexane/AcOEt 30 :1) afforded 33 (39 mg, 71%).
Colorless oil. IR (ATR): 3458 (OH), 1734 (CO). 1H-NMR (400 MHz): 0.06( s, 2 Me); 0.88 (s, 3 Me); 1.28
(t, J ¼ 7.1, Me); 2.68 (br. s, HO); 2.75 (quint., J ¼ 5.7, CH); 3.87 – 3.96( m, 2 CH2); 4.18 (q, J ¼ 7.1, CH2).
13C-NMR (100 MHz): À 5.8; À 5.7; 14.1; 18.0; 25.6; 49.7; 60.6; 61.1; 61.6; 172.8. HR-FAB-MS: 263.1665
([M þ H]þ, C12H27O4Siþ; calc. 263.1679).
Silylation of Ethyl 3-Hydroxy-2-(hydroxymethyl)propanoate (8). A soln. of 8 (962 mg, 6.49 mmol),
1H-imidazole (665 mg, 9.76 mmol), DMAP (237 mg, 1.94 mmol), and TBSCl (1.2 g, 7.81 mmol) in DMF
(6.7 ml) was kept at À 58 for 1.5 h under Ar, the reaction was quenched with H2O (10 ml), and the
mixture was extracted with AcOEt (3 ꢀ 20 ml). The org. soln. was washed with H2O (3 ꢀ 20 ml) and
brine (20 ml), and dried and evaporated. Purification of the residue by CC (acidic, hexane/AcOEt 20 :1)
afforded 33 (846mg, 50%) and 34 (576mg, 24%). Colorless oil.
Ethyl 3-[(tert-Butyl)dimethylsilyloxy]-2-{[(tert-butyl)dimethylsilyloxy]methyl}propanoate (34): IR
(ATR): 1738 (CO). 1H-NMR (400 MHz): 0.04 (s, 4 Me); 0.87 (s, 6Me); 1.26( t, J ¼ 7.1, Me); 2.69 (quint.,
J ¼ 6.0, CH); 3.83 (dd, J ¼ 9.9, 6.1, CH2); 3.86( dd, J ¼ 9.9, 5.9, CH2); 4.14 (q, J ¼ 7.1, CH2). 13C-NMR
(100 MHz): À 5.6; À 5.5; 14.2; 18.2; 25.8; 50.9; 60.2; 60.3; 172.6. HR-FAB-MS: 377.2537 ([M þ H]þ,
C18H41O4Siþ2 ; calc. 377.2543).
Desilylation of 34. To a soln. of 34 (3.5 g, 9.16mmol) in THF (8 ml) was added 1 mol soln. of TBAF
in THF (20 ml, 20 mmol). The mixture was stirred at r.t. for 1.5 h, quenched with sat. aq. NH4Cl (8 ml),
and extracted with AcOEt (3 ꢀ 70 ml). The org. soln. was washed with brine (30 ml), and dried (Na2SO4)
and evaporated. Purification of the residue by CC (acidic, hexane/AcOEt 1:1) afforded 8 (1.30 g, 96%).

Helvetica Chimica Acta – Vol. 90 (2007)
1433
Ethyl 2-{[(Benzyloxy)methoxy]methyl}-3-[(tert-butyl)dimethylsilyloxy]propanoate (35). To an ice-
i
cooled soln. of 33 (90 mg, 0.34 mmol) and Pr2EtN (0.17 ml, 1.0 mmol) in CH2Cl2 (0.7 ml) was added a
soln. of BOMCl (0.06ml, 0.41 mmol) in CH 2Cl2 (0.2 ml) under Ar. The mixture was stirred at r.t. for
2.5 h, the reaction was quenched with (2 ml), and the mixture was extracted with AcOEt (3 ꢀ 10 ml).
The org. soln. was washed with sat. aq. NaHCO3 (10 ml) and brine (10 ml), and dried and evaporated.
Purification of the residue by CC (neutral, hexane/Et2O 30 :1) afforded 35 (96mg, 73%). Labile colorless
oil. IR (ATR): 1736(CO). 1H-NMR (400 MHz): 0.04 (s, 2 Me); 0.87 (s, 3 Me); 1.26( t, J ¼ 7.1, Me); 2.84
(quint., J ¼ 6.0, CH); 3.81 (dd, J ¼ 9.8, 6.0, 1 H, CH2); 3.83 – 3.90 (m, 3 H, CH2); 4.16( q, J ¼ 7.1, CH2);
4.58 (s, CH2); 4.75 (s, CH2); 7.26– 7.35 ( m, arom. H). 13C-NMR (100 MHz): À 5.62; À 5.58; 14.2; 18.1;
25.7; 48.7; 60.5; 60.9; 65.3; 69.2; 94.7; 127.6; 127.9; 128.4; 137.7; 172.3. HR-FAB-MS: 383.2239 ([M þ H]þ,
C20H35O5Si; calc. 383.2254).
Ethyl 3-[(tert-Butyl)dimethylsilyloxy]-2-[(3,4,5,6-tetrahydropyran-2-yl)oxymethyl]propanoate (36).
A soln. of 33 (532 mg, 2.03 mmol), 3,4-dihydro-2H-pyran (0.28 ml, 3.1 mmol), and pyridinium p-
toluenesulfonate (53 mg, 0.21 mmol) in CH2Cl2 (5 ml) was stirred at r.t. for 2.5 h. After addition of
AcOEt (50 ml), the mixture was washed with sat. aq. NaHCO3 (5 ml), H2O (5 ml), and brine (5 ml), and
dried and evaporated. Purification of the residue by CC (neutral, benzene/Et2O 40 :1) afforded 36
(695 mg, 99%). Colorless oil. IR (ATR): 1736 (CO). 1H-NMR (400 MHz): 0.04 (s, 2 Me); 0.87 (s, 3 Me);
1.26( t, J ¼ 7.1, Me); 1.49 – 1.80 (m, CH2); 2.83 (dddd, J ¼ 12.0, 6.0, 6.0, 4.2, CH); 3.48 – 3.70 (m, CH2);
3.60 (dd, J ¼ 9.9, 6.6, 1 H, CH2); 3.66 (dd, J ¼ 9.7, 6.4, 1 H, CH2); 3.80 – 3.90 (m, CH2); 3.93 (dd, J ¼ 9.7,
6.0, 1 H, CH2); 3.98 (dd, J ¼ 9.9, 6.6, 1 H, CH2); 4.16( q, J ¼ 7.1, CH2); 4.62 (t, J ¼ 3.3, CH). 13C-NMR
(100 MHz): À 5.6; À 5.4; 14.2; 18.1; 19.1; 25.4; 25.7; 30.4; 48.6; 48.7; 60.3; 60.9; 61.7; 64.5; 64.7; 98.6; 98.7;
172.4. HR-FAB-MS: 347.2222 ([M þ H]þ, C17H35O5Siþ; calc. 347.2254).
2-{[(Benzyloxy)methoxy]methyl}-3-[(tert-butyl)dimethylsilyloxy]propan-1-ol (37). A soln. of 35
(35 mg, 0.09 mmol) and LiBH4 (8 mg, 0.36mmol) in THF (0.4 ml) and EtOH (0.1 ml) was stirred at r.t.
for 11 h and then at 408 for 8 h under Ar, the reaction was quenched with sat. aq. NH4Cl (1 ml), followed
by H2O (3 ml) under ice-cooling, and the mixture was extracted with AcOEt (3 ꢀ 8 ml). The org. soln.
was washed with brine (3 ml), and dried and evaporated. Purification of the residue by CC (acidic,
hexane/AcOEt 15 :1) afforded 37 (29 mg, 92%). Colorless oil. IR (ATR): 3415 (OH). 1H-NMR
(400 MHz): 0.07 (s, 2 Me); 0.89 (s, 3 Me); 2.01 (sept., J ¼ 5.7, CH); 2.76(br. s, HO); 3.65 (d, J ¼ 10.6, 1 H,
CH2); 3.69 (d, J ¼ 10.6, 1 H, CH2); 3.73 (dd, J ¼ 10.0, 6.0, 1 H, CH2); 3.77 (br. s, CH2); 3.79 (dd, J ¼ 10.0,
5.3, 1 H, CH2); 4.59 (s, CH2); 4.74 (s, CH2); 7.27 – 7.30 (m, arom. H); 7.35 (d-like, arom. H). 13C-NMR
(100 MHz): À 5.7; À 5.6; 18.1; 25.8; 42.9; 63.2; 63.7; 67.0; 69.4; 94.8; 127.7; 127.8; 128.4; 137.7. HR-FAB-
MS: 341.2120 ([M þ H]þ, C18H33O4Siþ; calc. 341.2148).
3-[(tert-Butyl)dimethylsilyloxy]-2-[(3,4,5,6-tetrahydropyran-2-yl)oxymethyl]propan-1-ol (38). A
soln. of 36 (153 mg, 0.44 mmol) and LiBH4 (45 mg, 1.84 mmol) in THF (14 ml), and EtOH (0.9 ml)
was stirred at r.t. for 17.5 h and then at 508 for 7.5 h under Ar, the reaction was quenched with sat. aq.
NH4Cl (2 ml), followed by H2O (4 ml) under ice-cooling, and the mixture was extracted with AcOEt
(3 ꢀ 15 ml). The org. soln. was washed with brine (5 ml), and dried and evaporated. Purification of the
residue by CC (neutral, hexane/AcOEt 50 :1) afforded 38 (131 mg, 97%). Colorless oil. IR (ATR): 3410
1
(OH). H-NMR (400 MHz): 0.07 (s, 2 Me); 0.90 (s, 3 Me); 1.49 – 1.62 (m, CH2); 1.69 – 1.83 (m, 2 CH2);
2.02 – 2.04 (m, CH); 2.85 (br. s, HO); 3.51 (dd, J ¼ 9.1, 6.0, 1 H, CH2); 3.53 (dd, J ¼ 9.8, 6.0, 1 H, CH2);
3.70 – 3.87 (m, CH2); 4.58 (diffused t, J ¼ 3.4, CH). 13C-NMR (100 MHz): À 5.7; 18.1; 19.5; 25.3; 25.7;
30.5; 43.0; 43.1; 62.2; 62.9; 63.5; 66.5; 99.0; 99.1. HR-FAB-MS: 305.2137 ([M þ H]þ, C15H32O4Siþ; calc.
305.2148).
3-[(Benzyloxy)methoxy]-2-(bromomethyl)propyl (tert-Butyl)dimethylsilyl Ether (39). A mixture of
37 (98 mg, 0.29 mmol), CBr4 (218 mg, 0.65 mmol), pyridine (0.09 ml, 1.11 mmol), and PPh3 (173 mg,
0.66 mmol) in CH2Cl2 (0.9 ml) was stirred at r.t. for 2.5 h under Ar and poured into AcOEt (20 ml). The
org. soln. was washed with 10% aq. CuSO4 (20 ml), sat. aq. NaHCO3 (20 ml), H2O (10 ml), and brine
(10 ml), and dried and evaporated. Purification of the residue by CC (acidic, hexane/AcOEt 50 :1)
afforded 39 (102 mg, 88%). Colorless oil. 1H-NMR (400 MHz): 0.06( s, 2 Me); 0.89 (s, 3 Me); 2.16( sept.,
J ¼ 5.8, CH); 3.56( d, J ¼ 5.5, CH2); 3.61 (dd, J ¼ 9.7, 6.5, 1 H, CH2); 3.64 (dd, J ¼ 9.9, 5.8, 1 H, CH2);
3.66 (dd, J ¼ 9.7, 5.8, 1 H, CH2); 3.71 (dd, J ¼ 9.9, 5.3, 1 H, CH2); 4.60 (s, CH2); 4.75 (s, CH2); 7.29 – 7.32
(m, arom. H); 7.34 – 7.36( m, arom. H); 7.36( d-like, arom. H). 13C-NMR (100 MHz): À 5.5; 18.2; 25.8;

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Helvetica Chimica Acta – Vol. 90 (2007)
32.8; 43.6; 61.6; 66.6; 69.4; 94.8; 127.7; 127.9; 128.4; 137.8. HR-FAB-MS: 403.1274 ([M þ H]þ,
C18H32BrO3Si; calc. 403.1304).
2-(Bromomethyl)-3-[2-(3,4,5,6-tetrahydropyran-2-yl)]propyl (tert-Butyl)dimethylsilyl Ether (40). A
mixture of 38 (51 mg, 0.17 mmol), CBr4 (116mg, 0.34 mmol), pyridine (0.05 ml, 0.62 mmol), and PPh
3
(90 mg, 0.34 mmol) in CH2Cl2 (0.6ml) was stirred at r.t. for 2.5 h under Ar and poured into AcOEt
(15 ml). The org. soln. was washed with 10% aq. CuSO4 (5 ml), sat. aq. NaHCO3 (5 ml), and brine
(5 ml), and dried and evaporated. Purification of the residue by CC (neutral, hexane/AcOEt 50 :1)
afforded 40 (58 mg, 95%). Colorless oil. 1H-NMR (400 MHz; mixture of diastereoisomers): 0.06( s,
2 Me); 0.89 (s, 3 Me); 1.48 – 1.63 (m, 2 CH2); 1.67 – 1.84 (m, CH2); 2.16( sept., J ¼ 5.9, CH); 3.39 (dd, J ¼
9.8, 6.6, 0.5 H, CH2); 3.44 (dd, J ¼ 9.8, 5.9, 0.5 H, CH2); 3.49 – 3.60 (m, 1 H, CH2); 3.56(diffused d, J ¼ 5.7,
CH2); 3.64 (dd, J ¼ 9.9, 6.2, 0.5 H, CH2); 3.66 (dd, J ¼ 9.8, 6.0, 0.5 H, CH2); 3.716( dd, J ¼ 9.9, 5.3, 0.5 H,
CH2); 3.719 (dd, J ¼ 10.1, 5.1, 0.5 H, CH2); 3.76( dd, J ¼ 9.8, 6.6, 0.5 H, CH2); 3.80 (dd, J ¼ 9.8, 5.6, 0.5 H,
CH2); 3.82 – 3.89 (m, 1 H, CH2); 4.59 (t, J ¼ 3.4, CH). 13C-NMR (100 MHz): À 5.5; 18.2; 19.3; 19.4; 25.4;
25.8; 30.5; 33.0; 33.1; 43.65; 43.69; 61.6; 61.7; 61.99; 62.3; 66.1; 66.2; 98.8; 99.0. HR-FAB-MS: 405.0858
([M þ K]þ, C15H31BrKO3Siþ; calc. 405. 0863).
2-{[(Benzyloxy)methoxy]methyl}-3-[(tert-butyl)dimethylsilyloxy]propyl Methanesulfonate (41). A
soln. of 37 (661 mg, 1.94 mmol), MsCl (0.23 ml, 2.97 mmol), and pyridine (0.60 ml, 7.42 mmol) in CH2Cl2
(1 ml) was stirred at r.t. for 6.5 h under Ar. After dilution with AcOEt (50 ml), the soln. was washed with
10% aq. CuSO4 (2 ꢀ 10 ml), sat. aq. NaHCO3 (2 ꢀ 10 ml), and brine (10 ml), and dried and evaporated.
Purification of the residue by CC (acidic, hexane ! hexane/CHCl3 1:1) afforded 41 (764 mg, 94%).
Colorless oil. 1H-NMR (400 MHz): 0.05 (s, 2 Me); 0.89 (s, 3 Me); 2.23 (sept., J ¼ 5.9, CH); 2.98 (s, Me);
3.60 (dd, J ¼ 10.0, 6.6, 1 H, CH2); 3.63 (dd, J ¼ 11.4, 5.9, 1 H, CH2); 3.68 (dd, J ¼ 11.4, 6.0, 1 H, CH2); 3.71
(dd, J ¼ 10.0, 5.3, 1 H, CH2); 4.32 (d, J ¼ 5.7, CH2); 4.60 (s, CH2); 4.75 (s, CH2); 7.28 – 7.40 (m, arom. H).
13C-NMR (100 MHz): À 5.5; 18.2; 25.8; 37.0; 41.7; 60.1; 65.1; 68.0; 69.5; 94.9; 127.75; 127.81; 128.4; 137.7.
HR-FAB-MS: 457.1480 ([M þ K]þ, C19H34KO6SSiþ; calc. 457.1482).
3-[(tert-Butyl)dimethylsilyloxy]-2-[(3,4,5,6-tetrahydropyran-2-yl)oxymethyl]propyl Methanesulfo-
nate (42). A soln. of 38 (457 mg, 1.50 mmol), MsCl (0.27 ml, 3.4 mmol), and pyridine (0.72 ml,
8.91 mmol) in CH2Cl2 (4 ml) was stirred at r.t. for 1 h and then at 408 for 1.5 h under Ar. After addition of
H2O (5 ml), the mixture was extracted with AcOEt (3 ꢀ 30 ml). The org. soln. was washed with 10% aq.
CuSO4 (10 ml), sat. aq. NaHCO3 (10 ml), and brine (10 ml), and dried and evaporated. Purification of
the residue by CC (neutral, hexane/CHCl3 1:1) afforded 42 (568 mg, 99%). Colorless oil. 1H-NMR
(400 MHz): 0.06( s, 2 Me); 0.89 (s, 3 Me); 1.48 – 1.62 (m, CH2); 1.68 – 1.83 (m, CH2); 2.24 (sept., J ¼ 6.0,
CH); 3.01 (s, Me); 3.41 (dd, J ¼ 9.8, 6.7, 1 H, CH2); 3.44 (dd, J ¼ 9.8, 6.0, 1 H, CH2); 3.48 – 3.54 (m, CH2);
3.63 – 3.85 (m, CH2); 4.33 – 4.36( m, CH2); 4.56( m, CH). 13C-NMR (100 MHz): complicated. HR-FAB-
MS: 383.1919 ([M þ H]þ, C16H35O6SSiþ; calc. 383.1924).
2-[(2-{[(Benzyloxy)methoxy]methyl}-3-[(tert-butyl)dimethylsilyloxy]propyl)(methyl)amino]-1-
phenylethanol (43). A soln. of 22 (79 mg, 0.52 mmol) in DMF (1 ml) was added to a mixture of 41
(169 mg, 0.40 mmol), KI (68 mg, 0.41 mmol), and Et3N (0.11 ml, 0.79 mmol) in DMF (0.8 ml), and the
resulting mixture was stirred at 658 for 17 h and then at 858 for 2.5 h. After addition of sat. aq. NaHCO3
(3 ml), followed by H2O (3 ml), the mixture was extracted with AcOEt (3 ꢀ 30 ml). The org. soln. was
washed with half-sat. brine (5 ꢀ 6ml) and brine (6ml), and dried (K 2CO3) and evaporated. Purification
of the residue by CC (acidic, hexane/AcOEt 20 :1) afforded 43 (116mg, 61%). Colorless oil. IR (ATR):
3427 (OH). 1H-NMR (400 MHz; mixture of diastereoisomers): 0.05 (s, 2 Me); 0.89 (s, 3 Me); 2.01 (sext.,
J ¼ 6.0, CH); 2.35 (s, Me); 2.33 – 2.37 (m, 0.5 H, CH2); 2.41 (dd, J ¼ 12.6, 6.7, 0.5 H, CH2); 2.45 – 2.50 (m,
CH2); 2.57 (dd, J ¼ 12.5, 7.7, 0.5 H, CH2); 2.63 (dd, J ¼ 12.5, 8.1, 0.5 H, CH2); 3.58 – 3.71 (m, 2 CH2); 4.61
(s, CH2); 4.69 (dd, J ¼ 9.4, 4.5, CH); 4.75 (d, J ¼ 7.7, 1 H, CH2); 4.77 (d, J ¼ 7.7, 1 H, CH2); 7.24 – 7.38 (m,
arom. H). 13C-NMR (100 MHz): À 5.5; 18.3; 25.9; 39.9; 42.4; 42.6; 56.7; 56.8; 61.6; 61.9; 66.8; 66.9; 67.2;
67.4; 69.35; 69.43; 95.0; 125.9; 127.4; 127.7; 127.8; 128.3; 128.4; 137.9; 142.1. HR-FAB-MS: 474.3054 ([M þ
H]þ, C27H44NO4Siþ; calc. 474.3040).
2-({3-[(tert-Butyl)dimethylsilyloxy]-2-[(3,4,5,6-tetrahydropyran-2-yl)oxymethyl]propyl}(methyl)-
amino)-1-phenylethanol (44). A soln. of 22 (1.14 g, 7.53 mmol) in DMF (18 ml) was added to a mixture of
42 (2.22 g, 5.79 mmol), KI (965 mg, 5.81 mmol), and Et3N (1.6ml, 11.5 mmol) in DMF (10 ml), and the
resulting mixture was stirred at 658 for 15.5 h and then at 858 for 2.5 h. After addition of sat. aq. NaHCO3

Helvetica Chimica Acta – Vol. 90 (2007)
1435
(10 ml), followed by H2O (10 ml), the mixture was extracted with AcOEt (3 ꢀ 150 ml). The org. soln.
was washed with half-sat. brine (5 ꢀ 30 ml) and brine (30 ml), and dried (K2CO3) and evaporated.
Purification of the residue by CC (neutral, hexane/AcOEt 10 :1) afforded 44 (1.86g, 73%). Colorless oil.
IR (ATR): 3460 (OH). 1H-NMR (400 MHz; mixture of diastereoisomers): 0.05, 0.06(2 s, 2 Me); 0.90 (s,
3 Me); 1.48 – 1.62 (m, 2 CH2); 1.68 – 1.74 (m, 1 H, CH2); 1.76– 1.85 ( m, 1 H, CH2); 2.01 (sept., J ¼ 6.0,
CH); 2.29 – 2.65 (m, 2 CH2); 2.35 (s, Me); 3.40 – 3.46( m, 1 H, CH2); 3.48 – 3.53 (m, 1 H, CH2); 3.62 – 3.75
(m, CH2); 3.78 (dd, J ¼ 9.5, 4.6, 0.5 H, CH2); 3.83 (dd, J ¼ 9.8, 5.8, 0.5 H, CH2); 3.84 – 3.90 (m, 1 H, CH2);
4.57 (dd, J ¼ 4.2, 2.7, CH); 4.66 – 4.72 (m, CH); 7.26 (tt, J ¼ 6.7, 1.6, arom. H); 7.33 (dd, J ¼ 7.7, 7.3, 2 arom.
H); 7.37 (diffused d, J ¼ 8.2, 2 arom. H). 13C-NMR (100 MHz): À 5.5; 18.3; 19.5; 19.6; 19.7; 25.4; 25.9;
30.6; 39.7; 39.9; 42.4; 42.5; 56.45; 56.49; 56.8; 56.9; 61.4; 61.7; 61.8; 61.9; 62.2; 62.3; 62.4; 66.1; 66.28; 66.34;
66.5; 66.8; 66.9; 66.97; 67.04; 69.4; 69.5; 69.6; 98.98; 99.03; 99.26; 99.32; 125.8; 127.3; 128.2; 142.18; 142.22;
142.24; 142.3. HR-FAB-MS: 438.3037 ([M þ H]þ, C24H44NO4Siþ; calc. 438.3040).
tert-Butyl N-(2-Hydroxy-2-phenylethyl)carbamate (51). A mixture of 50 (358 mg, 2.48 mmol), Et3N
(0.52 ml, 3.75 mmol), and Boc2O (647 mg, 2.97 mmol) in CH2Cl2 (4 ml) was stirred at r.t. for 1.3 h under
Ar. After addition of sat. aq. NH4Cl (10 ml), the mixture was extracted with CH2Cl2 (3 ꢀ 20 ml). The org.
soln. was washed with H2O (5 ml) and brine (10 ml), and dried (Na2SO4) and evaporated.
Recrystallization of the residue from benzene afforded 51 (537 mg, 91%). Colorless needles. M.p.
122 – 124.58. IR (ATR): 3363 (OH); 1674 (CO). 1H-NMR (400 MHz): 1.45 (s, 3 Me); 3.00 (s, HO); 3.27
(ddd, J ¼ 13.6, 8.0, 5.6, CH2); 3.47 – 3.52 (m, CH2); 4.84 (m, CH); 4.91 (br. s, HN); 7.28 – 7.31 (m, arom.
H); 7.34 – 7.37 (m, arom. H). EI-MS: 237 (Mþ).
tert-Butyl (2-Oxo-2-phenylethyl)carbamate (52). To a soln. of pyridinium dichromate (PDC; 268 mg,
0.70 mmol) in DMF (0.5 ml) was added an ice-cooled soln. of 51 (41 mg, 0.17 mmol) in DMF (0.5 ml)
under Ar, and then the mixture was stirred at r.t. for 21 h. After addition of brine (10 ml), followed by
H2O (5 ml), the mixture was extracted with Et2O (3 ꢀ 10 ml). The org. soln. was washed with brine
(10 ml), and dried and evaporated. Purification of the residue by CC (acidic, hexane/AcOEt 10 :1)
afforded 52 (38 mg, 94%). Colorless oil. IR (ATR): 3356(OH), 1714 (CO), 1685 (CO). 1H-NMR
(400 MHz): 1.48 (s, 3 Me); 4.67 (d, J ¼ 4.4, CH2); 5.56(br. s, HN); 7.49 (t, J ¼ 7.6, arom. H); 7.61 (diffused
t, J ¼ 6.0, arom. H); 7.96 (diffused d, J ¼ 8.3, arom. H). FAB-MS: 258 ([M þ Na]þ), 236([ M þ H]þ).
2-(2-{[(Benzyloxy)methoxy]methyl}-3-[(tert-butyl)dimethylsilyloxy]propylamino)-1-phenylethanol
(55). A soln. of 50 (225 mg, 1.56mmol) in DMF (3.5 ml) was added to a mixture of 41 (498 mg,
1.19 mmol), KI (195 mg, 1.18 mmol), and Et3N (0.36ml, 2.59 mmol) in DMF (2.5 ml), and the resulting
mixture was stirred at 658 for 18.5 h and then at 858 for 3 h. After addition of sat. aq. NaHCO3 (2 ml),
followed by H2O (5 ml), the mixture was extracted with AcOEt (3 ꢀ 30 ml). The org. soln. was washed
with brine (10 ml), dried (K2CO3), and evaporated. Purification of the residue by CC (NH-type, hexane/
1
benzene 5 :1) afforded 55 (275 mg, 50%). Colorless oil. IR (ATR): 3315 (OH). H-NMR (400 MHz):
0.04 (s, 2 Me); 0.88 (s, 3 Me); 1.96( sept., J ¼ 5.9, CH); 2.64 – 2.72 (m, CH2); 2.76( dd, J ¼ 6.0, 4.0, 1 H,
CH2); 2.79 (dd, J ¼ 6.4, 4.6, 1 H, CH2); 2.87 (dd, J ¼ 3.4, 1.7, 1 H, CH2); 2.90 (dd, J ¼ 3.4, 1.7, 1 H, CH2);
3.57 – 3.71 (m, CH2); 4.58 (s, CH2); 4.66 (dd, J ¼ 3.5, 2.0, 0.5 H, CH); 4.68 (dd, J ¼ 3.5, 2.0, 0.5 H, CH);
4.730 (s, 1 H, CH2); 4.734 (s, 1 H, CH2); 7.24 – 7.37 (m, arom. H). 13C-NMR (100 MHz): À 5.5; 18.2; 25.8;
41.5; 49.1; 57.4; 62.5; 62.6; 67.6; 67.7; 69.3; 71.39; 71.43; 94.8; 125.8; 127.4; 127.6; 127.8; 128.3; 128.4; 137.8;
142.6. HR-FAB-MS: 460.2871 ([M þ H]þ, C26H42NO4Siþ; calc. 460.2883).
tert-Butyl N-(2-Hydroxy-2-phenylethyl)-N-(2-{[(benzyloxy)methoxy]methyl}-3-[(tert-butyl)dimeth-
ylsilyloxy]propyl)carbamate (53). A mixture of 55 (124 mg, 0.19 mmol), Et3N (0.05 ml, 0.36mmol), and
Boc2O (62 mg, 0.29 mmol) in CH2Cl2 (1.5 ml) was stirred under ice-cooling for 1 h and then at r.t. for 1 h
under Ar. After addition of H2O (2 ml), followed by sat. aq. NaHCO3 (4 ml), the mixture was extracted
with AcOEt (3 ꢀ 20 ml). The org. soln. was washed with brine (10 ml), dried (K2CO3), and evaporated.
Purification of the residue by CC (acidic, hexane/AcOEt 10 :1) afforded 53 (100 mg, 97%). Colorless oil.
IR (ATR): 3425 (OH); 1693 (CO). 1H-NMR (400 MHz): 0.00 (s, Me); 0.02 (s, Me); 0.87, 0.88 (2s, 3 Me);
1.47 (s, 3 Me); 2.11 (br. s, CH); 3.14 (dd, J ¼ 14.2, 6.7, 1 H, CH2); 3.24 (br. s, 1 H, CH2); 3.38 – 3.60 (m,
CH2); 4.54 (s, 1 H, CH2); 4.56( s, 1 H, CH2); 4.696 (s, 1 H, CH2); 4.704 (s, 1 H, CH2); 4.93 – 4.95 (m, CH);
7.22 – 7.37 (m, arom. H). 13C-NMR (100 MHz): À 5.6; 18.2; 25.8; 28.4; 41.2; 41.3; 48.3; 56.9; 61.3; 61.4;
66.5; 66.7; 69.2; 74.1; 80.6; 94.8; 125.7; 125.8; 127.4; 127.6; 127.7; 128.3; 137.7; 142.4; 158.1. HR-FAB-MS:
582.3256([ M þ Na]þ, C31H49NNaO6Siþ; calc. 582.3227).

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Helvetica Chimica Acta – Vol. 90 (2007)
Oxidation of 53: tert-Butyl N-(2-{[(Benzyloxy)methoxy]methyl}-3-[(tert-butyl)dimethylsilyloxy]-
propyl)-N-(2-oxo-2-phenylethyl)carbamate (54). 1) With PDC. An ice-cooled soln. of 53 (40 mg,
0.07 mmol) in DMF (0.45 ml) was added to a soln. of PDC (60 mg, 0.94 mmol) in DMF (0.2 ml) under
Ar, and then the mixture was stirred at r.t. for 20 h. After addition of brine (3 ml), followed by H2O
(2 ml), the mixture was extracted with Et2O (3 ꢀ 10 ml). The org. soln. was washed with brine (10 ml),
dried, and evaporated. Purification of the residue by CC (acidic, hexane/AcOEt 20 :1) afforded 54
(27 mg, 67%). Colorless oil. IR (ATR): 1705 (CO). 1H-NMR (400 MHz): 0.03 (s, 2 Me); 0.85 (s, 3 Me);
1.34, 1.49 (2s, 3 Me); 2.09 (sept., J ¼ 6.2, CH); 3.27 (dd, J ¼ 14.7, 7.0, 1 H, CH2); 3.30 (dd, J ¼ 14.3, 7.1, 1 H,
CH2); 3.40 (dd, J ¼ 14.7, 7.0, 1 H, CH2); 3.47 (dd, J ¼ 14.3, 6.8, 1 H, CH2); 3.60 – 3.70 (m, CH2); 4.54 – 4.65
(m, 2 CH2); 4.70 – 4.77 (m, CH2); 7.29 – 7.34 (m, arom. H); 7.42 – 7.49 (m, arom. H); 7.54 – 7.61 (m, arom.
H); 7.91 (dd, J ¼ 9.0, 8.3, arom. H). 13C-NMR (100 MHz): À 5.51; À 5.49; 18.2; 25.8; 28.1; 28.4; 41.4; 41.6;
47.7; 54.3; 54.9; 61.4; 66.8; 66.9; 69.3; 79.9; 80.2; 94.95; 95.01; 127.6; 127.8; 128.4; 128.6; 128.7; 133.3; 135.4;
135.5; 137.8; 138.0; 155.7; 156.2; 194.9. HR-FAB-MS: 596.2763 ([M þ K]þ, C31H47KNO6Siþ; calc.
596.2810).
2) By Swern Oxidation. To a soln. of oxalyl chloride (0.01 ml, 0.12 mmol) in CH2Cl2 (0.1 ml) was
added a soln. of DMSO (0.01 ml, 0.17 mmol) in CH2Cl2 (0.1 ml), followed by a soln. of 53 (45 mg,
0.08 mmol) in CH2Cl2 (0.4 ml) at À 788 under Ar, and then the mixture was stirred at the same temp. for
1 h. After addition of a soln. of Et3N (0.06ml, 0.40 mmol) in CH 2Cl2 (0.1 ml) at the same temp., the
mixture was stirred for 1.5 h, the reaction was quenched with H2O (2 ml), and then the mixture was
extracted with CH2Cl2 (3 ꢀ 10 ml). The org. soln. was washed with brine (8 ml), dried, and evaporated.
Purification of the residue by CC (acidic, hexane/AcOEt 10 :1) afforded 54 (32 mg, 71%).
3) With MnO2. A mixture of 53 (503 mg, 0.90 mmol) and MnO2 (3.12 g) in CH2Cl2 (5 ml) was stirred
at r.t. for 2 d under Ar. After further addition of MnO2 (0.52 g), the resulting mixture was stirred under
the same conditions for 10 h. After removal of the MnO2 through Celiteꢃ pad, the filtrate was evaporated.
Purification of the residue by CC (acidic, hexane/AcOEt 15 :1) afforded 54 (417 mg, 83%).
tert-Butyl N-(3-{[(Benzyloxy)methoxy]methyl}-2-(hydroxymethyl)propyl)-N-(2-oxo-2-phenyl-
ethyl)carbamate (56). To a soln. of 54 (362 mg, 0.65 mmol) in THF (3.5 ml) was added 1 mol soln. of
TBAF in THF (0.78 ml, 0.78 mmol), and the mixture was stirred at r.t. for 4.5 h under Ar, and the
reaction was quenched with sat. aq. NH4Cl (2 ml), followed by H2O (15 ml), and the mixture was
extracted with AcOEt (3 ꢀ 20 ml). The org. soln. was washed with brine (20 ml), dried, and evaporated.
Purification of the residue by CC (acidic, hexane/AcOEt 2 :1) afforded 56 (266 mg, 93%). Colorless oil.
1
IR (ATR): 3427 (OH); 1699 (CO). H-NMR (400 MHz): 1.36, 1.44 (2s, 3 Me); 1.99 (br. s, CH); 3.22 –
3.32 (m, CH2); 3.46(br. s, HO); 3.55 – 3.67 (m, CH2); 3.75 (br. s, CH2); 4.51 – 4.66 (m, CH2); 4.56( s,
1 H, CH2); 4.60 (s, 1 H, CH2); 4.72 (s, 1 H, CH2); 4.74 (s, 1 H, CH2); 7.27 – 7.34 (m, 5 arom. H); 7.46( dd,
J ¼ 7.3, 6.8, 2 arom. H); 7.57 (t, J ¼ 6.8, arom. H); 7.89 (d, J ¼ 7.3, 2 arom. H). 13C-NMR (100 MHz): 28.1;
28.4; 40.8; 47.0; 47.5; 54.4; 55.1; 60.4; 62.4; 67.9; 68.5; 69.6; 69.7; 80.7; 80.9; 95.0; 127.7; 127.8; 127.9; 128.4;
128.7; 128.8; 133.6; 135.2; 137.7; 157.0; 194.5. HR-FAB-MS: 482.1920 ([ M þ K]þ, C25H33KNO6þ ; calc.
482.1945).
tert-Butyl N-(2-{[(Benzyloxy)methoxy]methyl}-3-bromopropyl)-N-(2-oxo-2-phenylethyl)carbamate
(57). A mixture of 56 (25 mg, 0.06mmol), CBr 4 (79 mg, 0.24 mmol), pyridine (0.03 ml, 0.32 mmol), and
PPh3 (67 mg, 0.25 mmol) in CH2Cl2 (0.25 ml) was stirred at r.t. for 2 h under Ar and poured into AcOEt
(20 ml). The org. soln. was washed with 10% aq. CuSO4 (4 ml), sat. aq. NaHCO3 (2 ml), H2O (2 ml), and
brine (2 ml), and dried and evaporated. Purification of the residue by CC (acidic, hexane/AcOEt 10 :1)
afforded 57 (23 mg, 80%). Colorless oil. IR (ATR): 1697 (CO). 1H-NMR (400 MHz): 1.34, 1.50 (2s,
3 Me); 2.31 (sept., J ¼ 6.0, 0.5 H, CH); 2.38 (sept., J ¼ 6.0, 0.5 H, CH); 3.32 – 3.52 (m, CH2); 3.56– 3.73 ( m,
CH2); 4.60 (s, CH2); 4.62 (s, CH2); 4.70 (s, CH2); 4.76( s, CH2); 7.29 – 7.36( m, arom. H); 7.44 – 7.51 (m,
arom. H); 7.56– 7.62 ( m, arom. H); 7.91 (t, J ¼ 8.5, arom. H). 13C-NMR (100 MHz): 28.1; 28.4; 33.9; 34.1;
40.6; 40.7; 49.1; 49.5; 54.7; 55.4; 67.1; 69.5; 69.6; 80.4; 80.7; 94.9; 127.7; 127.9; 128.39; 128.41; 128.7; 128.8;
133.5; 135.1; 137.6; 137.8; 155.7; 155.9; 194.7. HR-FAB-MS: 544.1083 ([M þ K]þ, C25H32BrKNO5þ ; calc.
544.1101).
tert-Butyl N-(2-{[(Benzyloxy)methoxy]methyl}-3-iodopropyl)-N-(2-oxo-2-phenylethyl)carbamate
(58). A mixture of 1H-imidazole (152 mg, 2.24 mmol) and PPh3 (294 mg, 1.12 mmol), and I2 (285 mg,
1.12 mmol) in CH2Cl2 (1 ml) was vigorously stirred at r.t. under Ar. To the resulting yellow suspension

Helvetica Chimica Acta – Vol. 90 (2007)
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was added a soln. of 56 (248 mg, 0.56mmol) in CH 2Cl2 (1.3 ml), and the mixture was stirred at r.t. for 4 h.
After removal of insoluble materials by filtration, the filtrate was evaporated. Purification of the residue
by CC (acidic, hexane/AcOEt 10 :1) afforded 58 (242 mg, 78%). Pale yellow oil. IR (ATR): 1701 (CO).
1H-NMR (400 MHz): 1.34, 1.50 (2s, 3 Me); 1.97 (sept., J ¼ 5.6, 0.5 H, CH); 2.06 (sept., J ¼ 5.6, 0.5 H, CH);
3.28 – 3.45 (m, CH2); 3.53 (dd, J ¼ 9.9, 6.6, 1 H, CH2); 3.57 (dd, J ¼ 9.8, 6.3, 1 H, CH2); 3.65 (dd, J ¼ 9.5,
4.4, 1 H, CH2); 3.69 (dd, J ¼ 9.9, 4.6, 1 H, CH2); 4.61 (s, CH2); 4.70 (d, J ¼ 7.1, CH2); 4.76( s, CH2); 7.22 –
7.30 (m, arom. H); 7.32 – 7.37 (m, arom. H); 7.44 – 7.52 (m, arom. H); 7.56– 7.62 ( m, arom. H); 7.92 (t, J ¼
8.3, arom. H). 13C-NMR (100 MHz): 8.5; 8.8; 28.1; 28.4; 40.2; 50.4; 50.7; 54.7; 55.4; 68.7; 69.6; 69.7; 80.4;
80.8; 94.9; 127.7; 127.9; 128.4; 128.7; 128.8; 133.5; 135.1; 135.2; 137.6; 137.8; 155.7; 155.9; 194.7. HR-FAB-
MS: 554.1415 ([M þ H]þ, C25H33INO5þ ; calc. 554.1404).
tert-Butyl (5-{[(Benzyloxy)methoxy]methyl}-3-hydroxy-3-phenylpiperidin-1-yl)carbamate (59; En-
try 5 in Table 2). A soln. of CH2I2 (0.03 ml, 0.31 mmol) in THF (0.1 ml) was added to a suspension of Sm
metal (128 mg, 0.85 mmol) in THF (2 ml) at r.t. under sonication in Ar atomsphere. After addition of
further THF (20 ml), the mixture was vigorously stirred for 1 h under sonication and for additional 0.5 h
without sonication, and cooled to 08. After addition of HMPA (0.28 ml, 1.61 mmol), the mixture was
stirred under the same conditions for 20 min, to which a soln. of 58 (48 mg, 0.09 mmol) in THF (1 ml) was
slowly added, and the mixture was stirred at 08 for 1 h. After quenching with sat. aq. Roschelle salt (6ml),
insoluble materials were filtered through Celiteꢃ pad, and the filtrate obtained was extracted with AcOEt
(3 ꢀ 10 ml). The org. soln. was washed with H2O (10 ꢀ 3 ml) and brine (10 ml), and dried and
evaporated. Purification of the residue by CC (acidic, hexane/AcOEt 8 :1), followed by prep. TLC
(hexane/acetone 5 :1, triple developments), afforded 59 as a mixture of the (3R*,5R*)- (5 mg, 13%; a
colorless oil) and the (3S*,5R*)-diastereoisomers (7 mg, 19%; a colorless oil).
Data of the (3R*,5R*)-Isomer: IR (ATR): 3442 (OH); 1685 (CO). 1H-NMR (400 MHz at 558; 1:1
mixture of rotamers): 1.48 (s, 3 Me); 1.70 (t, J ¼ 12.9, 1 H, CH2); 1.92, 1.95 (2quint., J ¼ 1.9, 1 H, CH2);
2.23 (br. s, HO); 2.31 – 2.41 (m, CH); 2.58 (t, J ¼ 12.5, 1 H, CH2); 3.02 (d, J ¼ 13.7, 1 H, CH2); 3.46( dd, J ¼
9.8, 6.2, 1 H, CH2); 3.53 (dd, J ¼ 9.8, 4.9, 1 H, CH2); 4.11 (d, J ¼ 13.7, 1 H, CH2); 4.32 (br. d, J ¼ 11.0, 1 H,
CH2); 4.59 (s, CH2); 4.72 (d, J ¼ 8.2, 1 H, CH2); 4.74 (d, J ¼ 8.2, 1 H, CH2); 7.26– 7.38 ( m, arom. H); 7.50
(diffused d, J ¼ 7.9, arom. H). 13C-NMR (100 MHz at 558): 28.5; 32.7; 40.5; 47.5; 54.9; 69.7; 70.5; 72.4;
80.2; 95.0; 124.8; 127.4; 127.8; 127.9; 128.45; 128.48; 138.0; 145.6; 156.2. HR-EI-MS: 427.2368 (Mþ,
C25H33NOþ5 ; calc. 427.2359).
Data of the (3S*,5R*)-Isomer: IR (ATR): 3406(OH); 1687 (CO). 1H-NMR (400 MHz at 558; 1:1
mixture of rotamers): 1.45 (s, 3 Me); 1.78 (dd, J ¼ 13.6, 7.9, 1 H, CH2); 1.90 (br. s, CH); 2.28 (br. s, HO);
2.29 (d, J ¼ 8.6, 1 H, CH2); 3.31 (br. s, 1 H, CH2); 3.44 (d, J ¼ 11.9, 1 H, CH2); 3.63 (d, J ¼ 6.2, 1 H, CH2);
3.68 (br. s, 1 H, CH2); 3.97 (d, J ¼ 13.5, 1 H, CH2); 4.58 (d, J ¼ 11.8, 1 H, CH2); 4.62 (d, J ¼ 11.8, 1 H,
CH2); 4.72 (d, J ¼ 10.3, 1 H, CH2); 4.76( d, J ¼ 10.3, 1 H, CH2); 7.26– 7.36( m, arom. H); 7.54 (diffused d,
J ¼ 7.9, arom. H). 13C-NMR (100 MHz at 558): 28.5; 34.1; 40.5; 46.0; 54.1; 69.6; 70.7; 72.0; 79.9; 95.1;
125.7; 127.6; 127.7; 127.9; 128.4; 138.0; 144.9; 155.0. HR-FAB-MS: 428.2436([ M þ H]þ, C25H34NO5; calc.
428.2437).
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Received May 9, 2007