Enantioselective Preparation of (2R)- and (2S)-Azetidine-2-carboxylic Acids

Article abstract of DOI:10.1002/(SICI)1522-2675(19981007)81:10<1803::AID-HLCA1803>3.0.CO;2-4

The enantiomerically pure amino ketones 13 and 31 were prepared starting from the commercially available amino diol 9 and D-serine (21), respectively. Irradiation afforded highly functionalized azetidinols 15 and 33 in a fully stereoselective manner and i

Full text of DOI:10.1002/(SICI)1522-2675(19981007)81:10<1803::AID-HLCA1803>3.0.CO;2-4

Helvetica Chimica Acta ± Vol. 81 (1998)
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Enantioselective Preparation of (2R)- and (2S)-Azetidine-2-carboxylic Acids
by Pablo Wessig* and Jutta Schwarz
Institut für Chemie, Humboldt-Universität zu Berlin, Hessische Str. 1 ± 2, D-10115 Berlin
The enantiomerically pure amino ketones 13 and 31 were prepared starting from the commercially
available amino diol 9 and d-serine (21), respectively. Irradiation afforded highly functionalized azetidinols 15
and 33 in a fully stereoselective manner and in high yields, whereas N-phenacylglycine 5 gave only the secondary
products of a Norrish-Type-II cleavage. Compounds 15 and 33 were converted into (2R)- and (2S)-azetidine-2-
carboxylic acids 20 and 37, respectively, in several steps. The influence of H-bonds on efficiency, chemo-, and
stereoselectivity of the photochemical cyclization of 5, 13, and 31 was discussed. It was shown that
conformational analysis of corresponding triplet biradicals is often valuable in understanding the photo-
chemistry of amino ketones.
Introduction. ± The understanding of physiological effectivity of naturally occurring
peptides and the synthesis of new peptide drugs are central problems of current
chemistry. In this context, peptide conformation and the rules govering it are of crucial
importance. One of the most common synthetic concepts involves the incorporation of
unnatural amino acids into peptides in order to goal-directed change of peptide
conformation. This approach has proved to be very successful as shown by several
publications (e.g., [1][2]). Therefore, there is indeed a large demand for new, highly
stereoselective syntheses of unnatural amino acids.
Recently, we have published photochemical synthesis of highly functionalized
prolines following both the concepts of auxiliary control [3] and substrate control [4].
In the present paper, we report on two fully stereoselective synthetic routes leading to
both (2R)- and (2S)-azetidine-2-carboxylic acids from commercially available chirons.
The key step of our synthesis is a stereoselective photochemical ring closure of an
amino ketone. Some recent works about thermal synthesis of azetidine-2-carboxylic
acids confirm the great interest in this problem [5][6].
Results and Discussion. ± Retrosynthetic Approach. In continuation of our previous
work on stereoselective photocyclization of ketones, we were interested in a photo-
chemical synthesis of azetidine-2-carboxylic acids. Although several photocyclizations
of amino ketones giving azetidinols were published [7][8] nothing is known about an
appropriate synthesis of azetidine-2-carboxylic acids. This fact is surprising in view of
the cited successful azetidine ring-closure reactions. Below, we will discuss a probable
reason.
Firstly, we have defined protected azetidine-2-carboxylic acids 1 as target structure
of ring closure. Two routes of ring closure are possible: via Route A, the C(2) C(3)
bond of the azetidine ring is formed, whereas Route B leads to the formation of the
bond between C(3) and C(4) (Scheme 1). In analogy to our previous photochemical

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proline synthesis [3][4], it was very likely to build up the four-membered ring
according to Route A. This route involves an intramolecular photochemical alkylation
of a N-phenacylglycine 2.
Scheme 1. Retrosynthetic Approach of Azetidine-2-carboxylic Acids
Whereas the cyclization of the homologues N-(2-benzoylethyl)glycines was very
successful [3][4], we have found that methyl N-phenacyl-N-tosylglycinate 5 (cf.
Scheme 2) had a very low photoreactivity in aprotic solvents. Long irradiation times
afforded only polymeric decomposition products. As well-known, low decay quantum
yields of alkyl aryl ketones are due to predominant H back-transfer of the
corresponding hydroxy biradicals [9]. We wondered, of course, why 5 undergoes H
back-transfer exclusively in aprotic solvents. An answer could be obtained by looking at
the low energy conformer of the triplet biradicals shown in Fig. 1.
Fig. 1. Low-energy conformers of triplet biradicals BR-1 and BR-2
To simplify quantum-chemical calculations, we replaced the Ts groups by Ms
groups, respectively. BR-1 represents an analogue of triplet biradical formed upon
irradiation of 5, whereas BR-2 is derived by the homologue N-[2-(benzoyl)ethyl]gly-

Helvetica Chimica Acta ± Vol. 81 (1998)
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cine. The geometries shown in Fig. 1 were obtained by systematic conformational
analysis at semiempirical UHF/PM3 level. All H-atoms except those being transferred
upon irradiation (HX ) and those bonded on the glycine radical centres CG are omitted
in Fig. 1. It is seen that both BR-1 and BR-2 are stabilized by strong intramolecular H-
bonds. However, the effects of these H-bonds are not identical for BR-1 and BR-2 due
to the different distances between the radical centres. In BR-1, the distance between
the H-atom HX and the glycine radical centre CG is remarkably smaller than the
distance between the two radical centres CG and CH. On the other hand, the biradical
BR-2 is fixed in a conformation with nearly equal HX CG and CG CH distances.
Considering the longer range of a pZ orbital compared with an s orbital, it is
understandable that BR-1 should undergo H back-transfer exclusively, whereas BR-2
should preferentially undergo cyclization.
The H back-transfer can be suppressed by irradiation in protic solvents. Indeed, the
photoreactivity of 5 was highly increased in t-BuOH as solvent. Admittedly, the decay
of the reactant stops after some time, indicating that products were formed which also
absorb light at the irradiation wavelength. Upon chromatographic separation of the
reaction mixture, we have obtained acetophenone and methyl 4-oxo-4-phenyl-2-
(tosylamino)butanoate 8. Compound 8 was identified unambiguously by an indepen-
dent synthesis which we have described recently [4]. Formation of 8 can be explained
by an aldol-like reaction of the primary products of Norrish-Type-II cleavage. We
assume that enol 6 reacts with the highly reactive 2-(tosylimino)acetate 7 in the solvent
cage to yield 8. If either 6 or 7 escapes from the solvent cage or enol 6 is converted into
the much more stable ketone, 7 should undergo less selective decomposition and
acetophenone remains (Scheme 2). Enol 6 as primary product of Norrish-Type-II
cleavage was already described [10].
Scheme 2
Obviously, Norrish-Type-II cleavage of the biradical formed from 5 is the only
reaction taking place, if H back-transfer is suppressed. In our opinion, this is the main
reason why nothing was reported on the preparation of azetidine-2-carboxylic acids via
Route A.
Following Route B leads to b-keto ester 3 which should not be obtainable in
enantiomerically pure form due to rapid enolization. Therefore, we chose a lower
oxidation state in the form of 2-hydroxy-1-aminoethyl ketone 4. We will now describe
the syntheses of both (2R)- and (2S)-azetidine-2-carboxylic acids via 4 and its
enantiomer.

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(2R)-Azetidine-2-carboxylic Acids. Ketone 4 contains the framework of a
commercially available and cheap chiral synthon, the amino diol 9 (Scheme 3). To
prepare 4, the following synthetic steps must be followed: 1) N-methylation, 2) selective
protection of the primary OH group, and 3) oxidation of the secondary OH group.
Scheme 3
Thus, 9 was converted into 5-(formylamino)-1,3-dioxane 10a and then reduced with
LiAlH4, according to literature procedures, giving 10b [11]. After introduction of the (ben-
zyloxy)carbonyl group (Z) and opening of the ring, the diol 11 was obtained in good yields.
Selective protection of the primary OH group using (thexyl)(dimethyl)silyl chloride
(TDS-Cl; thexyl ˆ 1,1,2-trimethylpropyl) and subsequent oxidation with Dess-Martin
periodinane (DMP) affords ketone 13.

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Upon irradiation of 13 in CH2Cl2, the excited CˆO group abstracts a H-atom from
the N-Me group leading to the biradical 14 which undergoes cyclization to the
azetidinol 15 in excellent yield. Moreover, the ring closure occurs in a fully
diastereoselective manner giving a cis-product with respect to the OH and TDSOCH2
group. Another isomer could not be detected. Products of the Norrish-Type-II cleavage
were neither detectable. Below, we will discuss the reasons for this surprising selectivity.
The relative configuration of 15 was established by NOE experiments. To convert 15
into the target structure 1 we attempted to oxidize the primary OH group, after
deprotection. Unfortunately, treatment of the N-protected amino diol 16 with various
oxidation agents always provided several products. Obviously, oxidative ring cleavage
occurs due to the unprotected tertiary alcohol. To avoid this, the tertiary OH group was
methylated to 17, followed by desilylation yielding the 2-(hydroxymethyl)azetidine 18
in nearly quantitative yields. Several oxidation methods were tested to convert the
CH2OH group into a COOH group. The best yield (67%) for carboxylic acid 19 was
accomplished using Jones reagent (H2SO4/CrO3) which has been applied in a similar
system recently investigated by Hanessian et al. [5]. Our target compound, the N-
deprotected amino acid 20, was achieved by cleavage of the Z group upon catalytic
hydrogenation (Scheme 3).
(2S)-Azetidine-2-carboxylic Acids. Successful synthesis of (2R,3S)-3-methoxy-3-
phenylazetidine-2-carboxylic acid (20) encouraged us to develop a synthetic route to
the corresponding (2S)-derivative which is an analogue of the naturally occurring (2S)-
azetidinecarboxylic acid [12]. Unfortunately, the enantiomer of amino diol 9 is not
commercially available1). Therefore, we had to find another chiral synthon. The
unexpensive d-serine 21 contains a suitable pattern of substituents so that it was chosen
as the starting reactant.
Firstly, we protected all three functional groups with orthogonal protecting groups.
Thus, N,C-protected d-serine 22 was prepared according to a known procedure [14],
and finally the OH group was silylated with TDS-Cl leading to 23 (Scheme 4).
Attempts to introduce the N-Me group at the stage of 23 failed. The action of
strong bases upon 23, required for deprotonation of the N-atom, afforded only
decomposition products. Therefore, we prepared the N,O(3)-diprotected compound 26
in three steps. Reduction of 23 gave the optically active serinol 24 which was
subsequently oxidized to the aldehyde 25. Attempts to convert 23 into 25 directly using
DIBAH were unsuccessful. It should be noted that 24 retained its optical activity.
Indeed, this would be expected if 1,3 silyl migration takes place as described for other
monoprotected diols [15].
The addition of PhMgBr to the aldehyde 25 proceeds with high stereoselectivity
giving the threo-compound 26, with the same relative configuration as the products
derived from amino diol 9, unambiguously established upon comparison of the NMR
spectra and the optical rotations of 11 and 12 with the appropriate data of analogous
products prepared from 26 (vide infra).
To prepare the enantiomer of 11, the N-Me group must be introduced. Attempts
using 26 failed due to the unprotected secondary OH group. Protection with the
1
)
Amino diol 9 is a by-product of industrial synthesis of the antibiotic chloromycetine. The enantiomer of 9
is converted to a drug, whereas 9 remains [13].

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Scheme 4
TBDMS ((t-Bu)Me2Si) group afforded 27, which was N-methylated to give ent-11 in
good yields. Subsequent deprotection of both OH groups, followed by silylation of the
primary OH group, finally gave compound ent-12. The following steps to the (2S,3R)-3-
methoxy-3-phenylazetidine-2-carboxylic acid (ent-20) are analogous to those described
for the corresponding (2R)-enantiomer (Scheme 5).
Mechanism and Stereoselectivity. The cyclization of the chiral ketones 13 and ent-13
to the azetidinols 15 and ent-15, respectively, is remarkable in three different respects:
1) The cyclization yield is high (71% isolated product), and no products of Norrish-
Scheme 5

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Type-II cleavage could be isolated. 2) The diastereoselectivity of the cyclization is very
high (> 95%). 3) The quantum yield of decay of 13 and ent-13 amounts nearly unity
within experimental inaccuracies.
These results were surprising with respect to the otherwise well-known behavior of
alkyl aryl ketones. Normally, the irradiation of such ketones gives a considerable
amount of Norrish-Type-II cleavage products, and often the cleavage dominates the
cyclization [16]. On the other hand, it was observed that the introduction of a
heteroatom into the side chain of the ketone increases the cyclization yield [8][17].
This effect can be explained by the conjugation of a heteroatom lone pair with the
adjacent radical centre (see B in Fig. 2). The resulting conformation lacks an essential
prerequisite for a Norrish-Type-II cleavage, the overlap of both radical pz orbitals with
the hybrid orbitals of the cleaving bond (see A in Fig. 2).
Fig. 2. Stereoelectronic requirements of Norrish-Type-II cleavage (A) and circumstances in 1,4-biradicals
containing a heteroatom (B)
The very high quantum yield and diastereoselectivity have probably the same
origin. We assume a strong H-bonding in the triplet biradicals 14 and ent-14. This bond
holds the H-atom far away from the methylene-radical centre and thus prevents the
back-transfer of the H-atom which would lead to the starting molecule. It is generally
accepted that quantum yields of decay which are considerably smaller than unity result
from an efficient H back-transfer of the triplet biradical. Furthermore, it is known that
this process is prevented upon irradiation in highly polar solvents in which H-bonds of
the OH radical with the solvent are formed. To support this hypothesis, we performed a
conformational analysis of biradical 14 on a semiempirical level (UHF/PM3; for
simplification of calculations, Z and TDS groups were replaced by CHO and Me,
resp.). A low-energy conformer is reproduced in Fig. 3. One can see that the H-
bonding is also the reason for the observed high diastereoselectivity. Only the
diastereoisomer with cis-orientation of the OH and the TDSOCH2 group was obtained.
Conclusion. ± In this work, the synthesis of enantiomerically pure acetidine-2-
carboxylic acids 20 and ent-20 with (2R)- and (2S)-configuration, respectively, was
described. We pursued two aims in our project. On one hand, we presented a complex
synthetic route to highly functionalized molecules involving a photochemical key step.
On the other hand, interesting discoveries concerning the photochemical behavior of
alkyl aryl ketones were made. It was shown that H-bondings at the stage of triplet

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Fig. 3. Low-energy conformer of triplet biradicals, analogous to 14
biradicals have an important influence on success or failure of a planned photo-
cyclization. The results can be both drastically increasing (13 and ent-13) and
decreasing (2) quantum yields of decay. Furthermore, a very high diastereoselectivity
of ring closure can be the consequence as we have described previously [3][4][18][19].
Finally, it should be noted that a-substituted N-acyl-N-methylamino ketones seem to
be very suitable reactants for the synthesis of azetidines. Soon, we will report on further
application of the concept.
The financial support of the Deutsche Forschungsgemeinschaft (Bonn) is gratefully acknowledged.
Experimental Part
General. TLC: alumina sheets with silica gel 60 F254 (Merck), detection by UV light. Flash chromatography
(FC): silica gel, 40 ± 63 mm (Merck). M.p.: Boetius micro melting-point apparatus (Wagema), uncorrected.
Optical rotations: DIP 370 (Jasco); d 10 cm. UV: Uvikon 930 (Kontron). IR: Perkin-Elmer-881, solids as KBr
pastills, oils on NaCl crystals as film. NMR: Bruker DPX300 (1H: 300 MHz, 13C: 75.5 MHz), internal reference
Me4Si (ˆ 0 ppm). EI-MS: Hewlett-Packard 5995 A, 70 eVat 293 ± 593 K. Photochemistry: prep. irradiations with
a 150-W high-pressure Hg-arc lamp (Hanau), anal. irradiations with a 500-W high-pressure Hg-arc lamp
(OSRAM HBO-500), UV cuvet 1 Â 1 cm, and filter WG 295 (Schott).
Calculations. Semiempirical calculations were performed using the program MOPAC7 [20], the PM3
hamiltonian [21], and the spin-unrestricted Hartree-Fock method (UHF).
Methyl N-Phenacyl-N-tosylglycinate (5). Compound 5 was prepared in analogy to the procedure described
by Fuhrmann et al. [8] from methyl tosylglycinate and phenacyl bromide. Yield 65%. M.p. 93 ± 958. TLC (CH2Cl/
1
MeOH 100 :2): Rf 0.6. IR: 1752 (CO), 1705 (CO), 1345 (SO2, sym.), 1155 (SO2, asym.). H-NMR (CDCl3):
2.35 (s, 3 H); 3.56 (s, 3 H); 4.15 (s, 2 H); 4.91 (s, 2 H); 7.08 ± 7.85 (m, 9 H). 13C-NMR (CDCl3): 21.5 (Me); 48.0
(CH2); 52.1 (Me); 52.8 (CH2); 127.3, 127.9, 128.8, 129.5, 133.9, 134.6, 136.6, 143.6 (arom. C); 169.4 (CO); 193.4
‡
‡
‡
(CO). EI-MS: 302 (6, [M COOMe] ), 256 (56, [M PhCO] ), 228(11), 206(28), 155 (50, Ts ), 105 (50,
PhCO ), 91(100), 77(67).
‡
Methyl (RS)-4-Oxo-4-phenyl-2-(tosylamino)butanoate (8). Compound 5 (0.5 g, 1.4 mmol) was irradiated
in t-BuOH until the reactant had disappeared. After removal of the solvent in vacuo, the residue was purified by
FC (CH2Cl2/MeOH 100 :2): 0.1 g (20%) of 8. Colorless needles. TLC, IR, MS, and NMR data: identical to those
reported in [4].
(4S,5S)-5-[(Benzyloxycarbonyl)(methyl)amino]-2,2-dimethyl-4-phenyl-1,3-dioxan (10c). Compound 10b
(9.86 g, 44.62 mmol) was dissolved in 150 ml of CH2Cl2 and 5.4 ml (1.2 equiv.) of Et3N were added. After cooling
to 08, 7.9 ml of PhCH2OCOCl were added. After stirring at r.t. for 3 h, the mixture was washed successively with
50 ml of H2O, 50 ml of dil. HCl, and 2 Â 50 ml of H2O. Drying (MgSO4) and evaporation of the solvent in vacuo
led to 16.7 g (99%) of 10c. Pale-yellow oil. TLC (CH2Cl2/MeOH 100 : 1): Rf 0.4. IR: 2942, 1695 (CˆO), 1451,
1
1381, 1204, 1153, 698. H-NMR (CDCl3): 1.53 ± 1.67 (m, 6 H); 3.05; 3.17 (s, 3 H); 4.00 (dd, J ˆ 12.5, 1.5, 1 H);
4.29 ± 4.63 (m, 2 H); 4.86 (d, J ˆ 12.5, 1 H); 4.97 (d, J ˆ 12.5, 1 H); 5.14 ± 5.31 (m, 1 H); 7.06 ± 7.39 (m, 10 H).
13C-NMR (CDCl3): 19.0, 19.1 (Me); 29.2 (Me); 32.5; 33.1 (Me); 50.4; 50.7 (CH); 63.7; 64.0 (CH2); 66.7; 67.1
(CH2); 99.4 (Cq); 125.0, 125.4, 125.7, 127.0, 127.5, 128.0, 128.4, 128.6, 136.6, 137.5, 138.2, 138.4 (arom. C); 156.0,

Helvetica Chimica Acta ± Vol. 81 (1998)
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156.9 (CO). (Most of the signals appear twice due to hindered rotation around the N CO bond.) EI-MS:
‡
28(12), 43(16), 65(13), 91 (100, PhCH2 ), 100(24), 146(14), 191(8).
(1S,2S)-2-[(Benzyloxycarbonyl)(methyl)amino]-1-phenylpropane-1,3-diol (11). Compound 10c (23.73 g,
66.82 mmol) was dissolved in a soln. of I2 in MeOH (1 g/100 ml) and stirred at 408 for 2 h. The reaction course is
monitored by TLC (CH2Cl2/MeOH 100 :1). After complete disappearance of 10c, the soln. was evaporated in
vacuo and the residue redissolved in CH2Cl2 (100 ml). The soln. was washed with an aq. soln. of NaHCO3/
Na2S2O3 (25 g of Na2S2O3 in 100 ml of sat. NaHCO3 soln.), dried, and evaporated in vacuo: 16.62 g (79%) of 11.
White solid. M.p. 77 ± 798. TLC (CH2Cl2/MeOH 10 :1): Rf 0.4. [a]D ˆ ‡ 91.64 (c ˆ 1, CH2Cl2, 208). IR: 3423
1
(OH), 1669 (CˆO), 1333, 1160, 698. H-NMR (CD3OD): 2.97; 3.01 (s, 3 H); 3.41 ± 3.50 (m, 1 H); 3.60 ± 3.72
(m, 1 H); 4.25 ± 4.41 (m, 1 H); 4.72 ± 4.83 (m, 1 H); 5.08 (s, 2 H); 7.26 ± 7.37 (m, 10 H). 13C-NMR (CD3OD):
29.0 (br., Me); 60.4 (CH2); 65.4 (br., CH); 68.1; 68.2 (CH2); 73.2; 73.5 (CH); 127.7, 128.6, 128.8, 129.2, 129.4,
129.5, 138.1, 138.3, 143.8 (arom. C); 159.2, 159.3 (CO). (Some of the signals appear twice due to hindered
‡
‡
rotation around the N CO bond.) EI-MS: 42(15), 65(11), 74(41), 77 (20, Ph ), 79(18), 91 (100, PhCH2 ),
107(12).
(1S,2S)- and (1R,2R)-2-[(Benzyloxycarbonyl)(methyl)amino]-3-[(dimethyl)(1,1,2-trimethylpropyl)silyl-
oxy]-1-phenylpropan-1-ol (12 and ent-12, resp.). Compound 11 (ent-11) (2.29 g, 7.32 mmol), 0.98 g (2 equiv.
of imidazole), and 1.44 (1.1 equiv.) of (dimethyl)(1,1,2-trimethylpropyl)silyl chloride (TDSCl) were dissolved in
5 ml of DMF, and the mixture was stirred for 3 h. Crushed ice (50 g) was added and the product extracted with
4 Â 20 ml of Et2O. The org. phase was separated, dried, and evaporated in vacuo. Traces of DMF were removed
at < 1 torr. The product was purified by FC (CH2Cl2/MeOH 100 : 1): 3.24 g (97%) of 12 (ent-12). White solid.
M.p. 53 ± 568. TLC (CH2Cl2/MeOH 100 : 1): Rf 0.5. [a]D ˆ ‡ 48.50 (c ˆ 1, CH2Cl2, 208) (12), [a]D
ˆ
41.35 (c ˆ
1, CH2Cl2, 238) (ent-12). IR: 3406 (OH), 2958, 1700 (CˆO); 1494, 1452, 1343, 1251, 1109, 832. 1H-NMR
(CDCl3): 0.05 ± 0.12 (m, 6 H); 0.75 ± 0.90 (m, 12 H); 1.55 ± 1.65 (m, 1 H); 2.76 (s, 3 H); 3.55 ± 3.99 (m, 3 H);
4.90 ± 5.21 (m, 3 H); 7.21 ± 7.29 (m, 10 H). 13C-NMR (CDCl3): 3.7 (Me); 18.5 (Me); 20.3 (Me); 25.0 (Me);
25.7 (Cq); 30.9, 34.1 (CH); 61.3 (CH2); 67.2 (CH2); 73.3 (CH); 125.9, 126.5, 126.6, 126.7, 126.8, 127.1, 127.4,
127.8, 127.9, 136.6, 142.0 (arom. C); 157.9 (CO). (Some of the signals appear twice due to hindered rotation
‡
‡
around the N CO bond). EI-MS: 59(7), 73(11), 75(11), 77 (8, Ph ), 91 (100, PhCH2 ), 130(7).
(2S)- and (2R)-2-[(Benzyloxycarbonyl)(methyl)amino]-3-[(dimethyl)(1,1,2-trimethylpropyl)silyloxy]-1-
phenylpropan-1-on (13 and ent-13, resp.). Compound 12 (ent-12) (3.00 g, 6.56 mmol) was dissolved in 50 ml
of CH2Cl2, and 24.3 g (1 equiv.) of Dess-Martin periodinan [21] were added in portions. After stirring for 1 h, the
mixture was diluted with 50 ml of Et2O and washed with several portions of a soln. of NaHCO3/Na2S2O3 (25 g of
Na2S2O3 in 100 ml of sat. NaHCO3 soln.), until a clear org. phase was obtained. After drying and evaporation,
the residue was purified by FC (CH2Cl2): 1.75 g (60%) of 13 (ent-13). Stiffy oil. TLC (CH2Cl2): Rf 0.8. [a]D
ˆ
68.48 (c ˆ 1, CH2Cl2, 238) (13); [a]D ˆ ‡ 76.62 (c ˆ 1, CH2Cl2, 238) (ent-13). IR: 2958, 1704 ± 1689 (CˆO),
1449, 1397, 1116, 697. 1H-NMR (CDCl3): 0.03 ± 0.05 (m, 6 H); 0.71 ± 0.83 (m, 12 H); 1.45 ± 1.52 (m, 1 H); 2.77
(s, 3 H); 3.95 (d, J ˆ 6.8, 1 H); 4.95 ± 5.4 (m, 4 H); 7.17 ± 7.35 (m, 8 H); 7.73 (d, 1 H); 7.91 (d, 1 H). 13C-NMR
(CDCl3): 3.7 (Me); 18.4; 20.1 (Me); 25.0 (CH); 25.7 (Cq); 30.5; 31.0 (Me); 59.8 (CH2); 60.9; 61.4 (CH); 67.4,
67.7 (CH2); 127.4, 127.7, 127.9, 128.0, 128.2, 128.4, 128.6, 133.3, 135.7, 135.8, 136.6 (arom. CO); 155.8, 156.6,
198.1 (CO). (Some of the signals appear twice due to hindered rotation around the N CO bond.) EI-MS:
‡
‡
41(4), 43(7), 59(5), 65(5), 73(11), 77 (10, Ph ), 91 (100, PhCH2 ), 130(5).
(2R,3S)- and (2S,3R)-1-(Benzyloxycarbonyl)-2-[(dimethyl)(1,1,2-trimethylpropyl)silyloxymethyl]-3-phe-
nylazetidin-3-ol (15 and ent-15, resp.). Compound 13 (ent-13) (1.45 g, 3.19 mmol) was dissolved in 300 ml of
cyclohexane and irradiated for ca. 1 h, until the reactant is disappeared (TLC; CH2Cl2). The solvent was
evaporated and the product purified by FC (CH2Cl2/MeOH 100 :1): 1.16 g (80%) of 15 (ent-15). Pale-yellow oil.
TLC (CH2Cl2/MeOH 100 :1): Rf 0.7. [a]D ˆ ‡ 6.74 (c ˆ 1, CH2Cl2, 238) (15); [a]D
ˆ
5.46 (c ˆ 1, CH2Cl2, 238)
(ent-15). IR: 3456 (OH), 2958, 1709 (CˆO), 1451, 1418, 1354, 1253, 1113, 699. 1H-NMR (CDCl3): 0.14 ± 0.00
(m, 6 H); 0.66 ± 0.78 (m, 12 H); 1.47 ± 1.52 (m, 1 H); 3.87 ± 4.19 (m, 4 H); 4.90 ± 5.05 (m, 3 H); 7.12 ± 7.27
(m, 10 H). 13C-NMR (CDCl3): 3.8; 3.6 (Me); 18.5 (Me); 20.1 (Me); 25.0 (Cq); 25.7 (CH); 60.6 (CH2); 66.7
(CH2); 73.6 (CH); 124.2, 127.5, 127.9, 128.1, 128.3, 128.5, 137.2 (arom. C); 143.6 (CO). EI-MS: 55(16), 75(51),
‡
‡
77 (13, Ph ), 91 (100, PhCH2 ), 105(13), 117(7).
(2S,3S)-1-(Benzyloxycarbonyl)-2-(hydroxymethyl)-3-phenylazetidin-3-ol (16). Compound 15 (1.50 g,
3.30 mmol) was dissolved in 25 ml of MeCN and treated with 20 drops of aq. HF (40%). After stirring for
1 h at r.t., 0.5 g of NaHCO3 were added, filtered, and the solvent was evaporated in vacuo: 1.03 g (99%) of 16.
White solid. M.p. 72 ± 748. TLC (CH2Cl2/MeOH 10 :1): Rf 0.7. IR: 3420 (OH), 2855, 1697 (CˆO), 1432, 1189,
1080, 700. 1H-NMR (CDCl3): 3.88 (d, J ˆ 11.7, 1 H); 4.03 (m, 2 H); 4.24 (m,2 H); 4.99 (dd, 2 H); 7.12 ± 7.27
(m, 10 H). 13C-NMR (CDCl3): 60.6 (CH2); 64.9 (CH2); 67.0 (CH2); 73.5 (Cq); 73.7 (CH); 124.1, 124.4, 127.5,

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Helvetica Chimica Acta ± Vol. 81 (1998)
‡
127.7, 127.8, 128.1, 128.5, 136.1, 143.0 (arom. C); 156.4 (CO). EI-MS: 204 (4, [M PhCH2, H2O] ), 150(10),
‡
‡
‡
146(5), 132(6), 105 (26, PhCO ), 91 (100, PhCH2 ), 77 (15, Ph ).
(2R,3S)- and (2S,3R)-1-(Benzyloxycarbonyl)-2-[(dimethyl)(1,1,2-trimethylpropyl)silyloxymethyl]-3-me-
thoxy-3-phenylazetidin-3-ol (17 and ent-17, resp.) NaH (80%, 0.14 g, 1 equiv.) was suspended in 10 ml of DMF,
and a soln. of 2 g (4.40 mmol) of 15 (ent-15) in 2 ml of DMF was added at 308 during 30 min. The mixture was
stirred for 1 h, while the temp. was kept at 308. MeI (0.41 ml, 1.5 equiv.) was added, the mixture was heated up
to r.t. and stirred overnight. H2O (30 ml) was added and the product extracted with petroleum ether. The extract
was dried, evaporated in vacuo to give an oil (1.97 g, 96%), which was used without further purification. TLC
(CH2Cl2/MeOH 100 : 1): Rf 0.7. [a]D ˆ ‡ 21.04 (c ˆ 1, CH2Cl2, 208) (17); [a]D
ˆ
18.22 (c ˆ 1, CH2Cl2, 238)
1
(ent-17). IR: 2957, 1711 (CˆO), 1410, 1351, 1102, 1087. H-NMR (CDCl3): 0.03 ± 0.02 (m, 6 H); 0.75 ± 0.80
(m, 12 H); 1.49 ± 1.56 (m, 1 H); 2.89 (s, 3 H); 3.89 ± 4.31 (m, 5 H); 4.96 (dd, 2 H); 7.14 ± 7.25 (m, 10 H). 13C-
NMR (CDCl3): 3.6 (Me); 18.5 (Me); 20.26 (Me); 25.1 (Cq); 34.1 (CH); 51.8 (CH); 57.1 (CH2); 59.1 (CH2);
66.8 (CH2); 72.1 (CH); 78.2 (Cq); 124.2, 127.3, 127.5, 127.8, 128.0, 128.3, 128.4, 136.4, 139.9, 143.5 (arom. C);
‡
‡
156.9 (CO). EI-MS: 43(20), 59(8), 65(9), 73(10), 75(9), 77 (6, Ph ), 91 (100, PhCH2 ), 119(6), 133(10).
(2S,3S)- and (2R,3R)-1-(Benzyloxycarbonyl)-2-(hydroxymethyl)-3-methoxy-3-phenylazetidin-3-ol (18 and
ent-18). Compound 17 (ent-17) (1.97 g, 4.20 mmol) was dissolved in a mixture of 0.5 ml of aq. HF (40%) and
20 ml of MeCN and stirred for 30 min. Solid NaHCO3 (2 g) was added, filtered, and the filtrate was dried and
evaporated in vacuo: 1.37 g (99%) of 18 (ent-18); Colorless oil. TLC (CH2Cl2/MeOH 100 :2): Rf 0.4. [a]D
ˆ
‡ 55.2 (c ˆ 1, CH2Cl2, 218) (18); [a]D
ˆ
53.6 (c ˆ 1, CH2Cl2, 218) (ent-18). IR: 3447 ± 3423 (OH), 2946, 1705 ±
1688 (CˆO), 1448, 1424, 1353, 1110, 700. 1H-NMR (DMSO): 2.96 (s, 3 H); 3.80 ± 3.95 (m, 1 H); 4.00 ± 4.10
(m, 2 H); 4.27 ± 4.36 (m, 1 H); 4.66 (t, 1 H); 5.06 (s, 2 H); 7.33 ± 7.49 (m, 10 H). 13C-NMR (DMSO): 52.1
(Me); 57.2 (CH2); 58.8 (CH2); 66.8 (CH2); 73.2 (CH); 79.0 (Cq); 126.3, 127.9, 128.4, 128.6, 128.7, 128.8, 129.2,
‡
‡
129.3, 137.6, 140.7 (arom. C); 157.2 (CO). EI-MS: 43(12), 65(21), 77 (25, Ph ), 91 (100, PhCH2 ), 105(24),
133(49), 134(38).
(2R,3S)- and (2S,3R)-1-(Benzyloxycarbonyl)-3-methoxy-3-phenylazetidine-2-carboxylic Acid (19 and ent-
19, resp.). Compound 18 (ent-18) (1.40 g, 4.28 mmol) was dissolved in 14 ml of acetone. Then, 1.52 ml of Jones
reagent (2.6 mol/l, 1 equiv. [22]) were added slowly. After 30 min, the mixture was filtered over a plug of Celite
and evaporated in vacuo. The residue was treated with 10 ml of H2O and extracted with CH2Cl2. The org. phase
was evaporated again, and the residue was dissolved in sat. aq. NaHCO3 soln. The soln. was extracted with
3 Â 20 ml of Et2O, and the crude product was precipitated by addition of dil. HCl. Extraction with AcOEt,
drying, and evaporation of the solvent afforded 0.6 g of a stiffy resin which was used in the next step without
purification. TLC (AcOH/AcOEt/MeOH 0.5 : 50 : 2): Rf 0.7.
(2R,3S)- and (2S,3R)-3-Methoxy-3-phenylazetidine-2-carboxylic Acid (20 and ent-20, resp.). Compound 19
(ent-19) (0.60 g, 1.76 mmol) was dissolved in 20 ml of MeOH, and 0.5 g of Pd/C (10%) were added, followed by
addition of 0.37 ml (2.2 equiv.) of cyclohexa-1,4-diene. The mixture was refluxed for 30 min, cooled to r.t., and
filtered over a plug of Celite. The plug was washed with hot H2O, and the combined filtrates were evaporated in
vacuo. For purification, the crude amino acid was dissolved in 15 ml of 1m H3PO4, and the soln. was washed with
3 Â 10 ml of CH2Cl2. Then, the aq. soln. was applied to a column filled with 65 ml of cation exchanger Dowex
‡
50 WX8 (0.1 ± 0.2 mm, H form, capacity 110 mmol). The column was rinsed with 1 l of H2O, followed by 500 ml
of dil. aq. NH3. The NH3 soln. was evaporated in vacuo to give 0.26 g of white solid (29%, 2 steps). TLC
(EtOH/conc. NH3/H2O 20 : 5 : 2): Rf 0.8. [a]D
ˆ
80.88 (c ˆ 1, 10% HCl, 208) (20); [a]D ˆ ‡ 95.62 (c ˆ 1, 10%
HCl, 208) (ent-20). M.p. 190 ± 938. IR: 3435 ± 3415 (OH/NH), 3063, 1640 (CˆO), 1386, 1317. 1H-NMR (D2O):
2.89 (s, 3 H); 4.12 (d, J ˆ 11.3, 1 H); 4.51 (d, J ˆ 11.3, 1 H); 4.85 (s, 1 H); 7.38 ± 7.42 (m, 5 H). 13C-NMR (D2O):
51.2 (CH2); 51.7 (Me); 69.4 (CH); 81.2 (Cq); 127.1, 129.3, 129.7, 136.5 (arom. C); 169.5 (CO). EI-MS: 29(57),
‡
‡
43(37), 51(49), 77 (71, Ph ), 91 (51, PhCH2 ), 104(53), 133(100).
Methyl (R)-2-[(Benzyloxycarbonyl)amino]-3-[(dimethyl)(1,1,2-trimethylpropyl)silyl]propanoate (23).
Compound 22 (15.00 g, 59.25 mmol) was dissolved in 10 ml of DMF and treated with 7.26 g (1.8 equiv.) of
imidazole and 17.7 ml (1.1 equiv.) TDS-Cl. After stirring for 3 h, crushed ice was added to the mixture, and the
product was extracted with Et2O (4 Â 50 ml). The soln. was dried and the solvent evaporated in vacuo: 23 g
(99%) of 23. Colorless oil. TLC (CH2Cl2): Rf 0.6. [a]D
ˆ
18.56 (c ˆ 1, CH2Cl2, 208). IR: 2957, 1727 (CˆO),
1502; 1253, 1206, 106, 831. 1H-NMR (CDCl3): 0.04 ± 0.09 (m, 6 H); 0.77 ± 0.88 (m, 12 H); 1.52 (m, 1 H); 3.69
(s, 3 H); 3.75 ± 3.79 (m, 1 H); 3.96 ± 3.99 (m, 1 H); 4.34 ± 4.36 (m, 1 H); 5.08 (s, 2 H); 5.52 (d, NH); 7.21 ± 7.33
(m, 5 H). 13C-NMR (CDCl3): 3.8 (Me); 18.4 (Me); 20.3 (Me); 25.1 (Cq); 34.1 (CH); 52.3 (Me); 56.0 (CH);
63.5 (CH2); 66.9 (CH2); 125.9, 128.0, 128.1, 128.5, 136.3 (arom. C); 155.9 (CO); 170.9 (CO). EI-MS: 41(23),
‡
‡
‡
65(18), 77 (3, Ph ), 84(18), 91 (100, PhCH2 ), 135 (49, Z ), 165(67).

Helvetica Chimica Acta ± Vol. 81 (1998)
1813
(S)-2-[(Benzyloxycarbonyl)amino]-3-[(dimethyl)(1,1,2-trimethylpropyl)silyloxy]propan-1-ol (24). Com-
pound 23 (20.75 g, 52.37 mmol) was dissolved in 200 ml of dry MeOH, and 8 g (4 equiv.) of NaBH4 were added
portionwise with stirring. After the reactant was completely disappeared (TLC), 400 ml of H2O were added to
the mixture, and the product was extracted with Et2O (4 Â 50 ml). Drying and evaporation of the solvent:
17.94 g (93%) of 24. Colorless oil. TLC (CH2Cl2/MeOH 100 : 1): Rf 0.6. [a]D
ˆ
13.7 (c ˆ 1, CH2Cl2, 208). IR:
3441 ± 3386 (OH/NH), 2957, 2870, 1708, 1512, 1252, 1031, 831. 1H-NMR (CDCl3): 0.10 ± 0.05 (m, 6 H); 0.70 ±
0.83 (m, 12 H); 1.45 ± 1.60 (m, 1 H); 3.60 ± 3.80 (m, 5 H); 5.01 (s, 2 H); 5.29 (s, NH). 13C-NMR (CDCl3): 3.7
(Me); 18.4 (Me); 20.4 (Me); 25.1 (Cq); 34.1 (CH); 53.1 (CH); 63.5 (Ch2); 63.8 (CH2); 66.8 (CH2); 126.0, 126.8,
‡
128.1, 136.4 (arom. C); 156.4 (CO). EI-MS: 41(16), 75(19), 91 (100, PhCH2 ), 164(9).
(R)-2-[(Benzyloxycarbonyl)amino]-3-[(dimethyl)(1,1,2-trimethylpropyl)silyloxy]propanal (25). To a soln.
of 21.00 g (57.22 mmol) of 25 in 150 ml of dry CH2Cl2, 24.30 g (1 equiv.) Dess-Martin periodinan [23] were
added in portions. After stirring for 1 h, the mixture was diluted with 100 ml of Et2O and washed with several
portions of a soln. of NaHCO3/Na2S2O3 (25 g of Na2S2O3 in 100 ml of sat. NaHCO3 soln.), until a clear org. phase
was obtained. After drying and evaporation, the crude aldehyde 25 was used in the next step without further
purification. TLC (CH2Cl2/MeOH 100 :2): Rf 0.8. IR: 2958, 2968, 1722, 1506, 1253, 1111, 831. 1H-NMR (CDCl3):
0.01 ± 0.06 (m, 6 H); 0.81 ± 0.96 (m, 12 H); 1.51 ± 1.68 (m, 1 H); 3.88 ± 3.92 (m, 1 H); 4.20 ± 4.25 (m, 1 H);
4.33 ± 4.36 (m, 1 H); 5.17 (s, 2 H); 5.64 (d, NH); 7.34 ± 7.40 (m, 5 H); 9.68 (s, 1 H). 13C-NMR (CDCl3): 3.76
(Me); 0.30 (Me); 18.5 (Me); 20.4 (Me); 25.1 (Cq); 34.2 (CH); 61.1 (CH2); 61.9 (CH); 67.1 (CH2); 128.2, 128.3,
‡
‡
128.6, 136.2 (arom. C); 156.1 (CO); 198.7 (CO). EI-MS: 39(4), 41(5), 73(13), 77 (4, Ph ), 91 (100, PhCH2 ),
116(5).
(1R,2R)-2-[(Benzyloxycarbonyl)amino]-3-[(dimethyl)(1,1,2-trimethylpropyl)silyloxy]-1-phenylpropan-1-
ol (26). Crude aldehyde 25 (17.72 g, 48.55 mmol) was dissolved in 100 ml of dry THF and treated with 55 ml of
PhMgBr (1.1 equiv., 0.98m in Et2O) at 788. The mixture was stirred for 15 min at 788 and warmed up to r.t.
Stirring was continued for 5 h, and then 20 ml of sat. aq. NH4Cl soln. were added. The org. phase was separated
and the aq. soln. extracted with Et2O (3 Â 50 ml). The combined org. solns. were washed with brine, dried, and
evaporated in vacuo. The residue was purified by FC (CH2Cl2/MeOH 100 : 1): 9.52 g (44%) of 26. Colorless oil.
TLC (CH2Cl2/MeOH 100 : 1): Rf 0.6. [a]D
ˆ
35.25 (c ˆ 1, CH2Cl2, 208). IR: 3440 ± 3350 (OH/NH), 2957, 2868,
1705 (CˆO), 1252, 831. 1H-NMR (CDCl3): 0.02 ± 0.16 (m, 6 H); 0.83 ± 0.93 (m, 12 H); 1.51 ± 1.68 (m, 1 H);
3.58 ± 3.91 (m, 3 H); 5.05 (s, 2 H); 5.13 ± 5.16 (m, 1 H); 7.28 ± 7.39 (m, 5 H). 13C-NMR (CDCl3): 3.8 (Me);
18.4 (Me); 20.1 (Me); 25.1 (Cq); 34.1 (CH); 53.4 (CH); 56.9 (CH); 64.6 (CH2); 66.7 (CH2); 125.7, 125.9, 127.5,
127.6, 127.9, 128.0, 128.2, 128.3, 136.5, 141.0 (arom. C); 156.6 (CO). EI-MS: 41(5), 43(9), 73(14), 75(15), 77
‡
‡
(6, Ph ), 91 (100, PhCH2 ), 116(5).
(1R,2R)-2-[(Benzyloxycarbonyl)amino]-1-[(tert-butyl)(dimethyl)silyloxy]-3-[(dimethyl)(1,1,2-trimethyl-
propyl)silyloxy]-1-phenylpropan (27). Compound 26 (9.52 g, 21.49 mmol) was dissolved in 5 ml of DMF, and
treated with 2.65 g (1.8 equiv.) of imidazole and 3.67 g (1.1 equiv.) of TBDMS-Cl. The mixture was stirred
overnight at 408, crushed ice was added, and the product was extracted with Et2O (4 Â 50 ml). The org. phase
was dried with Na2SO4 and evaporated in vacuo: 10.86 g (98%) of 27. Pale-yellow oil. TLC (CH2Cl2): Rf 0.9.
[a]D
ˆ
17.16 (c ˆ 1, CH2Cl2, 258). IR: 2956, 2931, 1726 (CˆO), 1499, 1252, 1100, 837. 1H-NMR (CDCl3):
0.10 ± 0.20 (m, 12 H); 0.91 ± 1.12 (m, 21 H); 1.77 ± 1.81 (m, 1 H); 3.62 ± 3.71 (m, 1 H); 3.95 ± 4.02 (m, 1 H);
5.12 ± 5.31 (m, 4 H); 7.36 ± 7.51 (m, 10 H). 13C-NMR (CDCl3):
5.2 (Me);
4.6 (Me);
3.5 (Me); 18.1
(Me); 20.4 (Me); 25.0 (Cq); 25.1 (CH); 25.8 (Me); 34.2 (Me); 59.1 (CH); 61.5 (CH2); 66.5 (CH2); 71.9 (CH2);
126.2, 126.9, 127.3, 127.4, 127.8, 128.0, 128.1, 128.2, 128.4, 128.6, 142.3 (arom. C); 156.0 (CO). EI-MS: 43(13),
‡
72(39), 91 (100, PhCH2 ), 159(19), 221(21), 472(11).
(1R,2R)-2-[(Benzyloxycarbonyl)(methyl)amino]-1-[(tert-butyl)(dimethyl)silyloxy]-3-[(dimethyl)(1,1,2-
trimethylpropyl)silyloxy]-1-phenylpropane (28). Compound 27 (10.86 g, 19.49 mmol) was dissolved in 100 ml of
dry THF containing 9.7 ml (8 equiv.) of MeI. NaH (1.76 g, 3 equiv.) was added portionwise. The mixture was
stirred until the H2 evolution was completed. Then, same amounts of MeI and NaH were added. After stirring
overnight, the solvent was evaporated, the residue was triturated with H2O and extracted with Et2O (4 Â 50 ml).
After drying and evaporation in vacuo, the product was purified by FC (CH2Cl2): 8.75 g (79%) of 28. Pale-
yellow oil. TLC (CH2Cl2): Rf 0.7. [a]D
ˆ
20.36 (c ˆ 1, CH2Cl2, 238). IR: 2956, 1704 (CˆO), 1251, 1091, 836.
1H-NMR (CDCl3): 0.01 ± 0.03 (m, 12 H); 0.79 ± 0.85 (m, 21 H); 1.51 ± 1.62 (m, 1 H); 2.97 (s, 3 H); 3.61 ± 4.20
(m, 3 H); 4.72 ± 5.08 (m, 3 H); 7.19 ± 7.32 (m, 10 H). 13C-NMR (CDCl3): 5.4 (CH3); 4.7 (Me); 3.7 (Me);
17.9 (Me); 20.2 (Me); 25.0 (Cq); 25.7 (CH); 34.2 (Me); 60.7 (CH2); 66.9 (CH2); 73.2 (CH); 74.1 (CH); 126.5,
126.6, 126.9, 127.4, 127.5, 127.6, 127.8, 127.9, 128.0, 128.2, 128.3, 136.9 (arom. C); 156.5 (CO). EI-MS: 18(10),
‡
43(7), 57(5), 73(30), 91 (100, PhCH2 ), 130(7).
(1R,2R)-2-[(Benzyloxycarbonyl)(methyl)amino]-1-phenylpropane-1,3-diol (29). Compound 28 (5.78 g,
9.26 mmol) was dissolved in 50 ml of MeCN and treated with ca. 30 drops of HF (aq., 40%). After the reactant is

1814
Helvetica Chimica Acta ± Vol. 81 (1998)
disappeared (TLC), 5 g of solid NaHCO3 were added, filtered, and the dried soln. was evaporated in vacuo:
2.60 g (89%) of 29. White solid. M.p. 77 ± 798. TLC (CH2Cl2/MeOH 10 :): Rf 0.4. [a]D
ˆ
109.66 (c ˆ 1, CH2Cl2,
208). IR: 3423 (OH), 1669 (CˆO), 1333, 1160, 698. 1H-NMR (CD3OD): 2.97; 3.01 (s, 3 H); 3.41 ± 3.50
(m, 1 H); 3.60 ± 3.72 (m, 1 H); 4.25 ± 4.41 (m, 1 H); 4.72 ± 4.83 (m, 1 H); 5.08 (s, 2 H); 7.26 ± 7.37 (m, 10 H).
13C-NMR (CD3OD): 29.0 (br., Me); 60.4 (CH2); 65.4 (br., CH); 68.1, 68.2 (CH2); 73.2, 73.5 (CH); 127.7, 128.6,
128.8, 129.2, 129.4, 129.5, 138.1, 138.3, 143.8 (arom. C); 159.2, 159.3 (CO). (Some of the signals appear twice due
‡
to hindered rotation around the N CO bond.) EI-MS: 42(15), 65(11), 74(41), 77 (20, Ph ), 79(18), 91 (100,
‡
PhCH2 ), 107(12).
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Received April 14, 1998