Enantiospecific synthesis of 3-aza-6,8-dioxa-bicyclo[3.2.1]octane carboxylic acids from erythrose

Article abstract of DOI:10.1016/S0040-4020(03)00773-7

New methodology for the synthesis of enantiopure 3-aza-6,8-dioxa-bicyclo[3.2.1]octane-carboxylic acids belonging to 7-endo-BTAa sub-class of γ/δ amino acids is described. The novelty is the use of 2,3-O-isopropylidene-erythrose instead of meso-tartaric ac

Full text of DOI:10.1016/S0040-4020(03)00773-7

Tetrahedron 59 (2003) 5251–5258
Enantiospecific synthesis of 3-aza-6,8-dioxa-bicyclo[3.2.1]octane
carboxylic acids from erythrose
Andrea Trabocchi, Gloria Menchi, Massimo Rolla, Fabrizio Machetti, Ilaria Bucelli and
*
Antonio Guarna
`
Dipartimento di Chimica Organica ‘Ugo Schiff’, Universita di Firenze, and Istituto di Chimica dei Composti Organometallici-C.N.R., Polo
Scientifico di Sesto Fiorentino, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Firenze, Italy
Received 31 January 2003; revised 22 April 2003; accepted 16 May 2003
Abstract—New methodology for the synthesis of enantiopure 3-aza-6,8-dioxa-bicyclo[3.2.1]octane-carboxylic acids belonging to 7-endo-
BTAa sub-class of g/d amino acids is described. The novelty is the use of 2,3-O-isopropylidene-erythrose instead of meso-tartaric acid
derivative, thus allowing us to perform an enantiospecific synthesis. Reductive amination of erythrolactol with aminoacetaldehyde
diethylacetal or benzylamine, and subsequent acid cyclisation gave directly the amino alcohol scaffold. Protection of nitrogen as urethane
and final alcohol oxidation afforded the Fmoc-, Boc-, and Cbz-amino acids. The new synthetic route was applied to multigram scale, thus
resulting in a marked improvement of the synthesis of enantiopure 7-endo-BTG and 7-endo-BTK amino acids. q 2003 Elsevier Science Ltd.
All rights reserved.
1. Introduction
purity and quantity, with a simpler and friendly synthetic
protocol. In this paper, we present a novel strategy to
prepare both enantiomers of 7-endo-BTG and 7-endo-BTK
scaffolds, which is based upon the use of an erythrose
derivative instead of a meso-tartaric acid one. 2,3-O-
Isopropilidene-erythrose 1 and 6 (Scheme 2) are known in
literature as valid building blocks, which find many
applications in reactions with organometallic reagents,6 in
Wittig olefinations,7 and in the synthesis of chiral
compounds such as pyrrolidines,8 nucleoside analogues,9
and nitrones.10 However, to our knowledge, no examples of
reductive amination of these compounds have been
reported. Many syntheses of compounds 1 and 6 starting
from carbohydrates have been described,11 and in particular
both protected erythrolactols are easily obtained in gram
quantities from cheap commercially available D- and L-
arabinose.8
During the last decade much interest has grown towards the
synthesis of new reverse turn inducers and the confor-
mational preferences imposed by turn-analogues when
inserted in protein secondary structure models.1 In the
course of development of a new class of 3-aza-6,8-dioxa-
bicyclo[3.2.1]octane g/d amino acids named BTAa and
BTK,2,3 7-endo-BTAa sub-family compounds proved to be
very interesting as dipeptide isostere reverse turn inducers
(Fig. 1).4,5
These amino acids are obtained from reduction of the
corresponding endocyclic amides 7-endo-BTAa(O), which
in turn derive from the combination of amino acids and
meso-tartaric acid derivatives. When aminoacetaldehyde
diethylacetal is used a racemic mixture of 7-endo-BTG(O)
and 7-endo-BtG(O) results (Scheme 1). Moreover, meso-
tartaric acid derivatives are prone to epimerization to the
more stable trans isomers, thus limiting their use as building
blocks in the synthesis of scaffolds.2
Starting from D-erythrolactol 1, it was possible to obtain the
scaffolds 7-endo-BTG 2 and 7-endo-BTK 3 belonging to the
‘T’ series,12 and from L-erythrolactol 6 the corresponding
Our need for multigram quantities of these scaffolds
carrying a 7-endo-carboxyl group as precursors for chemical
libraries, led us to develop an alternative synthetic method
in order to achieve enantiopure scaffolds with increased
Keywords: amino acids and derivatives; peptide mimetics; amination;
bicyclic heterocyclic compounds.
*
Corresponding author. Tel.: þ39-055-457-3481; fax: þ39-055-457-3569;
e-mail: antonio.guarna@unifi.it
Figure 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00773-7

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A. Trabocchi et al. / Tetrahedron 59 (2003) 5251–5258
reagent for the reductive amination process, which is known
to work in the presence of acid sensitive groups such as
acetals.14
Though in the work of Abdel-Magid et al.14 no examples of
reductive amination on lactols have been reported, the
reaction proved to be very efficient even in large scale,
giving the amino adduct (R,S)-12a, in 60% yield, and
10–15% of N-acetylated amine as by-product which were
easily separated by chromatography. The reaction was
monitored by TLC thus showing the presence of mainly
amine (R,S)-12a after 6 h at room temperature, though the
reaction times were prolonged overnight in order to achieve
completion. The reaction of 1 with amine 11b yielded 87%
of (R,S)-12b after stirring overnight. Benzylamine showed
similar reactivity with 1, as completion was achieved after
16 h reacting (41% yield, see Scheme 4). Cyclisation of
unprotected (R,S)-12a with TFA gave, after stirring for 2 h
at room temperature a mixture of desired 2a and partially
cyclised compound (R,S)-13a in about 1:1 ratio (Scheme 3),
as clearly shown by the presence of two acetal carbon
signals on 13C NMR spectrum. Attempts using forcing
reaction conditions by prolonging time and increased TFA
amounts failed. Compound (R,S)-12b also failed to cyclise,
giving only the monocyclic intermediate (R,S)-13b.
Attempts were made with TFA and prolonged reaction
times up to 24 h, or with H2SO4–SiO2 or PTSA as acid
catalysts, giving always incomplete conversions. The
presence of free amine in both cases suggested an
impediment towards double cyclisation. When compound
(R,S)-12a was protected at the amine function with Fmoc
group before acid cyclisation, giving (R,S)-12c, a marked
improvement was achieved. The cyclisation was initially
conducted in refluxing toluene with H2SO4–SiO2 as acid
catalyst in analogy with reported conditions,2 giving 2c with
34% yield after purification. The low yield was probably
due to partial degradation of intermediates in trans-
acetalisation process when carried out at high temperature.
An improvement was achieved by treating compound (R,S)-
12c with pure TFA at room temperature, which cyclised
Scheme 1.
enantiomer 7-endo-BtG 7 and 7-endo-BtK 8 of the ‘t’ series,
as shown in Scheme 2. Thus, either enantiomers 2 and 3, or
7 and 8 were synthesised by simply choosing the appropriate
sugar compound 1 or 6, obtaining 7-endo-BT(t)G scaffolds
by reaction with aminoacetaldehyde-diethylacetal, or 7-
endo-BT(t)K with the a-aminoketone derivative.
2. Results and discussion
2.1. Synthesis of 7-endo-BTG
The synthetic strategy consisted of a reductive amination
process of the erythrolactol 1 with aminoacetaldehyde
diethylacetal 11a followed by protection of the amine
function as urethane, and final acid cyclisation of resulting
(R,S)-12c with TFA to give 7-endo-BTG alcohol 2 (Scheme
3).13 In a first attempt the reductive amination was
conducted stepwise via imine preformation by reacting the
erythrolactol 1 with 11a in MeOH, but starting reagents
were obtained after 24 h, as shown by TLC. Direct use of
NaBH4 in the presence of 1 equiv. of acetic acid led to a
complex mixture. We next found NaBH(OAc)3 to be a valid
Scheme 2.

A. Trabocchi et al. / Tetrahedron 59 (2003) 5251–5258
5253
Scheme 3. (i) NaBH(OAc)3, THF, room temperature, overnight; (ii) Fmoc-O-Su, H2O–acetone, Na2CO3·H2O, 08C then room temperature, overnight; (iii)
Cbz-Cl, TEA, THF, 08C, 30 min, then room temperature, overnight; (iv) TFA, room temperature, overnight; (v) Jones reagent, room temperature, overnight;
(vi) piperidine, CH2Cl2, room temperature, 4 h, then Ambersep 900-OH, and elution with 0.5N HCl; (vii) piperidine, CH2Cl2, room temperature, 4 h, then
(Boc)2O, EtOH, 08C, then room temperature, overnight.
completely to give 2c in 78% yield after reacting overnight.
Cyclisation performed on (R,S)-12d, where the amine
function was protected with Cbz, led to partial deprotection
at the amine function, thus giving Cbz-scaffold 2d with
lower yield (16%) with respect to Fmoc analogue 2c
(Scheme 3); this was probably due to less tolerance of Cbz
group towards strongly acid conditions.15 The bicyclic
N-Fmoc-amino alcohol 2c was oxidized with Jones reagent
affording pure Fmoc-amino acid 4c in 75% yield
(Scheme 3).
piperidine (3 equiv.) in dichloromethane at room tempera-
ture, giving the corresponding deprotected amino acid 4a
(Scheme 3). Attempts to remove piperidine and other
organic by-products by conventional acid–base washings
resulted to be not very efficient in terms of purity of 4a; on
the contrary, a clean purification was obtained using
Ambersep basic ion-exchange resin. Compound 4a was
immobilized on the resin, and subsequent washings of all
non-acidic by-products and final elution with 0.5N HCl
afforded pure 4a as hydrochloride salt in 48% yield. The
hygroscopic compound 4a was then treated with (Boc)2O in
EtOH–CH2Cl2 to give pure 4e in poor yield. Consequently,
the conversion of Fmoc-7-endo-BTG-OH (4c) into the
corresponding Boc-amino acid 4e was performed in one pot,
by deprotection with piperidine and subsequent addition of
(Boc)2O without any purification of the intermediates,
giving pure 4e in 62% yield.
Boc-7-endo-BTG amino acid 4e was obtained from Fmoc-
amino acid 4c, because of incompatibility of Boc protecting
group with acid cyclisation. Thus, 4c was treated with
The synthetic protocol was also applied to the correspond-
ing enantiomeric 7-endo-BtG scaffold starting from L-
erythrose derivative 6, and the optical rotatory values of all
the intermediate compounds were in agreement with those
of compounds 2, 4 and (R,S)-12.
2.2. Synthesis of 7-endo-BTK
The same approach was also applied to the synthesis of 7-
endo-BTK scaffolds 3,5 and 8,10. In this case, a different
pathway was followed, in which the carbonyl and amine
functions were introduced separately (Scheme 4). Amine
moiety was introduced by reaction of 1 with benzylamine,
as above described, and the resulting compound (R,S)-14
was alkylated with phenacyl bromide in water-acetonitrile
using K2CO3 as base, thus giving (R,S)-15 in 55% yield. The
phenacyl moiety of (R,S)-15 cyclised with milder conditions
than corresponding acetaldehyde diethylacetal group of
(R,S)-12b, probably due to the stabilising effect of the
phenyl ring. Thus, cyclisation was performed with a 1:1
TFA–dichloromethane solution, giving 3b after 1 h with
excellent conversion.
Scheme 4. (i) NaBH(OAc)3, THF, room temperature, 16 h; (ii) PhCOCH2-
Br, K2CO3, H2O–CH3CN, room temperature, overnight; (iii) TFA-CH2Cl2
1:1, room temperature, 1 h; (iv) NH4CO2H, 10% Pd/C, reflux, 1 h; (v)
Fmoc-O-Su, H2O–acetone, Na2CO3, 08C, then room temperature, over-
night; (vi) (Boc)2O, DIPEA, CH2Cl2–EtOH 3:1, room temperature,
overnight; (vii) PDC, DMF, room temperature, 2 days.

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A. Trabocchi et al. / Tetrahedron 59 (2003) 5251–5258
Subsequent Pd-catalysed debenzylation of 3b afforded free
7-endo-BTK amino alcohol 3a, which was further protected
either as Boc and Fmoc derivatives 3e and 3c (Scheme 4).
Final oxidation of the N-protected amino alcohol to
corresponding amino acid with Jones reagent led to ring
opening, in agreement with previous considerations about
BTK lability in strongly acid conditions.3 Thus, the
oxidation was conducted with PDC in DMF.16
[1,3]dioxolan-4-yl}-methanol [(R,S)-12c]. To a solution of
(R,S)-12a (16.8 g, 60.6 mmol) in acetone (400 mL) was
added, at 08C and under a nitrogen atmosphere, Fmoc-O-Su
(20.6 g, 61.2 mmol) and a solution of Na2CO3·H2O (7.54 g,
60.6 mmol) in water (400 mL). The mixture was stirred
overnight at room temperature, then it was saturated with
NaCl, extracted with CH2Cl2 (3£400 mL), and dried over
anhydrous Na2SO4, to give, after solvent evaporation, a
crude oil that was purified by flash chromatography
(CH2Cl2–MeOH, 40:1, Rf 0.20), thus affording compound
(R,S)-12c as a pure yellow oil (21.80 g, 72%). [a]2D0¼234.2
3. Conclusion
1
(c 0.38, MeOH); H NMR d 7.73 (d, J¼7.3 Hz, 2H), 7.56
(m, 2H), 7.34 (m, 4H), 4.63 (m, 2H), 4.47–4.14 (m, 3H),
4.19 (t, J¼4.9 Hz, 1H), 3.74–3.02 (m, 10H), 1.42–1.04 (m,
12H); 13C NMR mixture of rotamers d 156.1 (s), 143.8 (d,
2C), 141.3 (d, 2C), 126.8 (d, 2C), 124.5 (d, 2C), 124.4 (d,
2C), 119.7 (d, 2C), 108.6 (s), 102.0 and 101.5 (d), 76.1 (d),
75.6 (d), 66.3 and 65.9 (t), 63.6 and 63.0 (t), 62.8 and 62.7
(t), 61.0 and 60.6 (t), 50.8 and 50.5 (t), 48.4 and 47.9 (t),
47.3 (d), 27.8 (q, 2C), 25.1 (q), 24.8 (q); MS m/z 483 (Mþ-
In conclusion, a new method for the enantiospecific
synthesis of formal glycine-derived 7-endo-BTAa and 7-
endo-BTK was developed starting from erythrose deriva-
tives, thus obtaining both enantiomers of N-protected amino
acids. It was possible to synthesise either 7-endo-BT(t)G or
7-endo-BT(t)K from D(L)-erythrolactol by choosing suit-
able aminocarbonyl derivatives. Moreover, the mild reac-
tion conditions and the cheap reagents used allowed us to
perform the synthesis of both enantiomers of 7-endo-BT(t)G
and 7-endo-BT(t)K amino acids on multigram scale.
17, 0.1), 179 (76); IR (CHCl3) 3454, 3011, 1710 cm21
.
Anal. calcd for C28H37NO7: C, 67.31; H, 7.46; N, 2.80.
Found: C, 67.39; H, 7.52; N, 2.71.
4.1.3. (1S,5S,7R)-3-(9-Fluorenylmethoxycarbonyl)-7-
endo-hydroxymethyl-6,8-dioxa-3-aza-bicyclo[3.2.1]oc-
tane (2c). Compound (R,S)-12c (19.3 g, 38.6 mmol) was
dissolved in trifluoroacetic acid (80 mL) and stirred over-
night at room temperature. After TFA evaporation, the
crude powder was dissolved in MeOH and filtered through
NaHCO3 and, after solvent evaporation, the product was
purified by flash chromatography (CH2Cl2–EtOAc, 2:1, Rf
0.26), thus affording pure 2c as a white powder (11.06 g,
78%). Mp 39–428C; [a]2D0¼232.2 (c 0.49, CHCl3); 1H
NMR d 7.77 (d, J¼7.0 Hz, 2H), 7.57 (d, J¼7.0 Hz, 2H),
7.38 (m, 4H), 5.51 (s, 1H), 4.92–2.95 (m, 12H); 13C NMR
mixture of rotamers d 155.8 (s), 143.7 (s, 2C), 141.2 (s, 2C),
127.6 (d, 2C), 127.0 (d, 2C), 124.7 (d, 2C), 119.9 (d, 2C),
98.6 and 98.1 (d), 77.8 and 77.6 (d), 72.3 and 71.7 (d), 67.5
(t), 66.9 and 66.3 (t), 48.2 (t), 47.9 (t), 47.1 (d); MS m/z 367
4. Experimental
4.1. General
Melting points are uncorrected. Chromatographic separ-
ations were performed on silica gel using flash-column
techniques; Rf values refer to TLC carried out on 25-mm
silica gel 60 F254 plates with the same eluent indicated for
1
column chromatography. H and 13C NMR spectra of all
compounds were recorded at 200 and 50.33 MHz, respect-
ively, using CDCl3 solutions, unless otherwise stated. EI
mass spectra were carried out at 70 eV ionizing voltage.
Acid silica gel (H2SO4–SiO2) was prepared as reported.17
4.1.1. (4R,5S)-(5-[(2,2-Diethoxy-ethylamino)methyl]-2,2-
dimethyl-[1,3]-dioxolan-4-yl(-methanol [(R,S)-12a]. To a
solution of 1 (18.3 g, 114 mmol) and 2,2-diethoxy-ethyl-
amine (11a) (16.6 mL, 114 mmol) in THF (600 mL) under a
nitrogen atmosphere and at 08C, NaBH(OAc)3 (31.4 g,
148.2 mmol) was added in portions, and the mixture was
stirred overnight at room temperature, then it was diluted
with saturated NaHCO3 solution (400 mL) and the organic
products were extracted with EtOAc (2 600 mL). The
organic phase was dried over anhydrous Na2SO4, filtered
and evaporated to give a crude oil that was purified by flash
chromatography (CH2Cl2–MeOH, 30:1, Rf 0.11), thus
obtaining (R,S)-12a as a pale yellow oil (19.0 g, 60%).
[a]2D0¼28.7 (c 0.54, CHCl3); 1H NMR d 4.83 (br, 2H), 4.59
(t, J¼5.5 Hz, 1H), 4.32 (m, 2H), 3.75–3.45 (m, 6H), 3.05–
2.83 (m, 2H), 2.79 (d, J¼5.5 Hz, 2H), 1.44 (s, 3H), 1.34 (s,
3H), 1.21 (t, J¼7.0 Hz, 6H); 13C NMR d 111.6 (s), 100.9
(d), 77.2 (d), 75.2 (d), 63.0 (t), 62.9 (t), 60.2 (t), 51.4 (t), 48.2
(t), 27.4 (q), 24.9 (q), 15.3 (q, 2C); MS m/z 278 (Mþþ1,
0.7), 103 (100); IR (CHCl3) 3450, 2987, 1670 cm21. Anal.
calcd for C13H27NO5: C, 56.30; H, 9.81; N, 5.05. Found: C,
56.41; H, 9.96; N, 5.01.
(Mþþ1, 0.03), 178 (100); IR (CHCl3) 3419, 1699 cm21
.
Anal. calcd for C21H21NO5: C, 68.65; H, 5.76; N, 3.81.
Found: C, 68.40; H, 5.61; N, 3.75.
4.1.4. (1S,5S,7S)-3-(9-Fluorenylmethoxycarbonyl)-6,8-
dioxa-3-aza-bicyclo[3.2.1]octane-7-endo-carboxylic acid
(4c). To a solution of 2c (8.55 g, 23.3 mmol) in acetone
(750 mL) was added Jones reagent at 08C, [prepared by slow
addition of H2SO4 (28.2 mL) to a solution of CrO3 (15.5 g,
155 mmol) in H2O (210 mL) at 08C], and the mixture was
stirred overnight at room temperature. Propan-2-ol was then
added until the color of the solution turned deep green/blue,
and the mixture was filtered through Celite and evaporated.
The crude product was dissolved in EtOAc (450 mL) and
washed with 10% aqueous NaHCO3 solution (2£400 mL).
The aqueous phase was then acidified to pH 1 with HCl and
extracted with EtOAc (3£400 mL). The organic phase was
dried over anhydrous Na2SO4, filtered and evaporated to
give a deep yellow crude oil that was purified by
chromatography (CH2Cl2–MeOH–TFA, 1000:30:1, Rf
0.53) affording pure 4c as a white powder (6.66 g, 75%).
1
Mp 79–828C; [a]2D3¼248.5 (c 0.80, CHCl3); H NMR d
4.1.2. (4R,5S)-{5-[N-(9-Fluorenylmethoxycarbonyl)-N-
(2,2-diethoxy-ethyl)-aminomethyl]-2,2-dimethyl-
7.75 (m, 2H), 7.53 (d, J¼7.0 Hz, 2H), 7.38 (m, 4H), 5.56 (s,

A. Trabocchi et al. / Tetrahedron 59 (2003) 5251–5258
5255
1H), 4.74 (m, 1H), 4.60 (m, 1H), 4.45 (m, 1H), 4.18 (m, 3H),
3.95 (d, J¼13.2 Hz, 1H), 3.25 (d, J¼14.0 Hz, 1H), 3.16
(m, 1H); 13C NMR d 170.3 (s), 155.8 (s), 141.1 (s, 2C),
141.0 (s, 2C), 127.6 (d, 2C), 127.0 (d, 2C), 125.1 (d), 124.8
(d), 119.8 (d, 2C), 99.2 (d), 75.9 (d), 73.2 (d), 68.2 (t), 48.0
(t), 46.9 (d), 44.1 (t); MS m/z 381 (Mþ, 0.2), 177 (100); IR
(CHCl3) 3445, 1701 cm21. Anal. calcd for C21H19NO6:
C, 66.13; H, 5.02; N, 3.67. Found: C, 66.21; H, 5.09; N,
3.59.
the residue dissolved in CHCl3. The solution was washed
with brine and the combined aqueous phases treated with
EtOAc. The combined organic phases were dried over
anhydrous Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by silica gel chromatog-
raphy (EtOAc–petroleum ether, 1:10, Rf 0.10, then EtOAc–
petroleum ether, 1:2, Rf 0.18) to give (R,S)-15 (36.3 g, 55%)
1
as a yellow oil. [a]D26¼þ19.4 (c 1.7, CHCl3); H NMR d
7.88–7.82 (m, 2H), 7.60–7.25 (m, 10H), 4.48–4.30 (m,
2H), 4.02 (part A of AB system, J¼12.8 Hz, 1H), 3.85 (part
B of AB system, J¼12.8 Hz, 1H) 3.80–3.60 (m, 2H) 3.20–
2.90 (m, 2H), 1.41 (s, 3H), 1.35 (s, 3H); 13C NMR d 197.1
(s), 136.6 (s), 135.6 (s), 133.5 (d), 129.7 (d, 2C), 128.6 (d,
2C), 128.5 (d, 2C), 127.8 (d), 127.7 (d, 2C), 108.2 (s), 77.5
(d), 75.9 (d), 60.4 (t), 59.5 (t), 58.7 (t), 54.1 (t), 27.8 (q), 25.1
(q); MS m/z 263 (51), 246 (41), 106 (39), 104 (58), 91 (100);
IR (CDCl3) 2988, 2934, 1694 cm21. Anal. calcd. for
C22H27NO4: C, 71.52; H, 7.37; N, 3.79. Found: C, 71.68;
H, 7.24; N, 3.80.
4.1.5. (1S,5S,7S)-3-tert-Butoxycarbonyl-6,8-dioxa-3-aza-
bicyclo[3.2.1]octane-7-endo-carboxylic acid (4e). To a
solution of 4c (3.6 g, 9.45 mmol) in CH2Cl2 (10 mL) was
added piperidine (2.81 mL, 28.35 mmol) and the mixture
was stirred at room temperature for 4 h. The solution was
then cooled to 08C, and a solution of (Boc)2O (11.3 g,
47.3 mmol) in ethanol (6 mL) was added, and the mixture
was stirred at room temperature overnight. The mixture was
then diluted with CH2Cl2 (70 mL) and the organic products
were extracted twice with 5% NaHCO3 (35 mL). The
aqueous phase was washed with CH2Cl2, then it was
acidified with 0.1 M HCl to pH¼5 and the organic product
was extracted with CH2Cl2. Solvent evaporation afforded
pure 4e (1.52 g, 62%) as a foamy hygroscopic powder.
[a]2D5¼262.4 (c 1.0, MeOH); 1H NMR d 7.63 (br, 1H), 5.56
(br, 1H), 4.71 (m, 1H), 4.57 (d, J¼5.6 Hz, 1H), 4.12–3.87
(m, 2H), 3.19 (d, J¼13.2 Hz, 1H), 3.05 (d, J¼13.2 Hz, 1H),
1.42 (s, 9H); 13C NMR d 170.6 (s), 155.0 (s), 99.4 (d), 81.3
(s), 75.9 (d), 73.7 (d), 48.2 (t), 43.4 (t), 28.2 (q, 3C); MS m/z
158 (Mþ2101, 46), 203 (73), 187 (10); IR (CHCl3) 3443,
1774, 1710 cm21. Anal. calcd for C11H17NO6: C, 50.96; H,
6.61; N, 5.40. Found: C, 50.90; H, 6.63; N, 5.35.
4.1.8. (1S,5S,7R)-3-Benzyl-5-phenyl-7-endo-hydroxy-
methyl-6,8-dioxa-3-aza-bicyclo[3.2.1]octane (3b). Ketone
(R,S)-15 (12.4 g, 34.7 mmol) was dissolved in a cooled 1:1
mixture of CH2Cl2–TFA (34 mL). The mixture was stirred
at room temperature for 1 h and then concentrated under
reduced pressure. The residue was dissolved in EtOAc
(240 mL) and washed with saturated NaHCO3. The
combined organic phases were dried over anhydrous
Na2SO4, filtered and concentrated under reduced pressure.
The alcohol 3b (9.4 g, 87%) was thereby obtained as a
viscous oil and resulted sufficiently pure to be used in the
next step without further purification. A sample for
elemental analysis was obtained by flash chromatography
on silica gel (EtOAc–petroleum ether, 1:2, Rf 0.20). White
4.1.6. (4R,5S)-[5-(Benzylamino-methyl)-2,2-dimethyl-
[1,3]dioxolan-4-yl]-methanol [(R,S)-14]. NaBH(OAc)3
(87 g, 410 mmol) was added portionwise to a cooled
(08C), stirred solution of lactol 1 (41.0 g, 256 mmol) and
benzylamine (42 mL, 384 mmol) in THF (1 L), and then the
reaction mixture was allowed to warm to room temperature.
After 16 h the mixture was concentrated under reduced
pressure to give an oil that was partitioned between EtOAc
and saturated NaHCO3. The aqueous layer was extracted
with EtOAc and the organic phase dried over Na2SO4,
filtered and the solvent evaporated under reduced pressure.
The residue was purified by chromatography on silica gel
(EtOAc–petroleum ether, 2:1, Rf 0.1; then EtOAc–
triethylamine, 100:1, Rf 0.36) to give (R,S)-14 (26.7 g,
41%) as a clear oil. [a]2D4¼29.1 (c 1.0, CHCl3); 1H NMR d
7.40–7.20 (m, 5H), 4.40–4.28 (m, 2H), 3.82 (s, 2H), 3.80–
3.60 (m, 2H), 3.15–2.80 (m, 2H), 1.45 (s, 3H), 1.36 (s, 3H);
13C NMR d 137.9 (s), 128.5 (d, 2C), 128.2 (d, 2C), 127.4
(d), 107.9 (s), 77.3 (d), 75.4 (d), 60.2 (t), 53.6 (t), 47.7 (t),
27.3 (q), 24.8 (q); MS m/z 221 (7), 105 (100), 99 (99); IR
(CDCl3) 2989, 2936, 1454, 1383 cm21. Anal. calcd. for
C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found: C, 66.88; H,
8.39; N, 5.53.
1
powder: mp 78–808C; [a]2D6¼214.1 (c 1.0, CHCl3); H
NMR d 7.60–7.50 (m, 2H), 7.41–7.20 (m, 8H), 4.58–4.56
(m, 1H), 4.34–4.32 (m, 1H), 4.26 (part A of AB system,
J¼12.1 Hz, 1H) 3.94 (part B of AB system, J¼12.1 Hz,
1H), 3.80 (part A of AB system, J¼12.5 Hz, 1H), 3.50 (part
B of AB system, J¼12.5 Hz, 1H), 3.18 (part A of AB
system, J¼11.5 Hz, 1H), 3.04 (part A of AB system,
J¼11.3 Hz, 1H), 2.82 (part B of AB system, J¼11.5 Hz,
1H), 2.49 (part B of AB system, J¼11.3 Hz, 1H); 13C NMR
d 138.2 (s), 135.0 (s), 129.4 (d, 2C), 128.8 (d), 128.6 (d, 2C),
128.1 (d, 2C), 127.8 (d), 125.2 (d, 2C), 105.2 (s), 79.2 (d),
75.9 (d), 61.7 (t), 60.0 (t), 59.2 (t), 52.5 (t); MS m/z 311
(Mþ, 6), 280 (2), 190 (100), 158 (48), 106 (33), 104 (61), 91
(100); IR (CDCl3) 3011, 2927, 2828, cm21. Anal. calcd. For
C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.21; H,
6.77; N, 4.59.
4.1.9. (1S,5S,7R)-5-Phenyl-7-endo-hydroxymethyl-6,8-
dioxa-3-aza-bicyclo[3.2.1]octane (3a). To a degassed
solution of benzyl amino alcohol 3b (9.4 g, 30.2 mmol) in
MeOH (300 mL) were added ammonium formate (8.8 g,
0.139 mmol), and 10% Pd/C (3.76 g). The resulting
suspension was heated to reflux under N2. After 1 h the
mixture was cooled, filtered through a short pad of Celite
and rinsed with MeOH. The filtrate was concentrated
obtaining 3a (6.56 g, 98%) as a white powder. Mp 125–
1278C; [a]2D4¼229.3 (c 1.0, CHCl3); 1H NMR d 7.65–7.58
(m, 2H), 7.50–7.35 (m, 3H), 4.60–4.50 (m, 1H), 4.42–4.22
(m, 2H), 4.04–3.96 (m, 1H), 3.40–3.16 (m, 4H); 13C NMR
4.1.7. (4R,5S)-[5-(N-Benzyl-N-phenacyl-aminomethyl)-
2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol
[(R,S)-15].
To a solution of alcohol (R,S)-14 (47.75 g, 190 mmol) in
CH3CN (1.2 L) and H2O (1.2 L) were added K2CO3 (39.4 g)
and 2-bromoacetophenone (37.8 g, 190 mmol) and then
stirred for 16 h. The reaction mixture was concentrated and

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A. Trabocchi et al. / Tetrahedron 59 (2003) 5251–5258
d 138.5 (s), 128.8 (d), 128.2 (d, 2C), 125.1 (d, 2C), 105.7 (s),
79.3 (d), 76.6 (d), 59.3 (t), 53.0 (t) 44.8 (t); MS m/z 120 (58),
4.1.13. (4S,5R)-{5-[N-(9-Fluorenylmethoxycarbonyl)-N-
(2,2-diethoxy-ethyl)-aminomethyl]-2,2-dimethyl-
[1,3]dioxolan-4-yl}-methanol [(S,R)-12c]. Compound
(S,R)-12a (26.8 g, 96.6 mmol) was treated as described for
the enantiomer, thus giving pure (S,R)-12c as an oil (33.3 g,
69%), with spectroscopic data as for the enantiomer.
[a]2D0¼þ35.1 (c 0.69, MeOH). Anal. calcd for
C28H37NO7: C, 67.31; H, 7.46; N, 2.80. Found: C, 67.11;
H, 7.38; N, 2.69.
91 (100); IR (CDCl3) 3064, 2892, 2849, 1602, 1451 cm21
.
Anal. calcd. for C12H15NO3: C, 65.14; H, 6.83; N, 6.33.
Found: C, 64.90; H, 6.95; N, 6.30.
4.1.10. (1S,5S,7R)-3-tert-Butoxycarbonyl-5-phenyl-7-
endo-hydroxymethyl-6,8-dioxa-3-aza-bicyclo[3.2.1]oc-
tane (3e). Boc2O (6.54 g, 29.6 mmol) was added portion-
wise to a solution of amine 3a (6.56 g, 29.6 mmol) and
DIPEA (6.1 mL, 29.6 mmol) in CH2Cl2–EtOH 3:1
(200 mL). The mixture was stirred at room temperature
for 16 h and then concentrated under reduced pressure. The
residue was partitioned between Et2O–CH2Cl2 2:1
(260 mL) and 10% NaHSO4 (160 mL). The aqueous layer
was treated with Et2O–CH2Cl2 2:1 (200 mL£3). The
solvent was evaporated to give 3e (6.95 g) as white powder
in 98% yield and sufficiently pure to be used directly in the
next step. A sample for elemental analysis was obtained by
flash chromatography on silica gel (EtOAc–petroleum
ether, 2:3, Rf 0.28). White powder. Mp 138–1418C;
4.1.14. (1R,5R,7S)-3-(9-Fluorenylmethoxycarbonyl)-7-
endo-hydroxymethyl-6,8-dioxa-3-aza-bicyclo[3.2.1]oc-
tane (7c). Compound (S,R)-12c (33.3 g, 66.6 mmol) was
treated as described for the enantiomer, thus giving pure 7c
as a white powder (18.3 g, 75%), with spectroscopic data as
for the enantiomer. Mp 39–428C; [a]2D0¼þ30.1 (c 1.62,
CHCl3). Anal. calcd for C21H21NO5: C, 68.65; H, 5.76; N,
3.81. Found: C, 68.48; H, 5.69; N, 3.75.
4.1.15. (1R,5R,7R)-3-(9-Fluorenylmethoxycarbonyl)-6,8-
dioxa-3-aza-bicyclo[3.2.1]octane-7-endo-carboxylic acid
(9c). Compound 7c (18.3 g, 49.8 mmol) was treated as
described for the enantiomer, thus giving pure 9c as a white
powder (13.9 g, 73%), with spectroscopic data as for the
enantiomer. Mp 71–818C; [a]2D0¼þ52.9 (c 0.50, CHCl3).
Anal. calcd for C21H19NO6: C, 66.13; H, 5.02; N, 3.67.
Found: C, 66.17; H, 5.01; N, 3.70.
1
[a]2D5¼24.6 (c 0.65, CHCl3); H NMR d 7.60–7.48 (m,
2H), 7.42–7.38 (m, 3H), 4.60–4.42 (m, 1H), 4.38–4.20 (m,
1H), 4.04–3.64 (m, 4H), 3.40–3.04 (m, 2H), 1.45 (s, 9H);
13C NMR d 155.1 (s), 137.8 (s), 129.0 (d), 128.3 (d, 2C),
125.3 (d, 2C), 105.0 (s), 80.6 (s), 78.8 (d), 74.1 (d), 61.2
(t),52.6 (t), 41.8 (t), 28.3 (q, 3C); MS m/z 265 (6), 240 (12),
105 (92), 57 (100); IR (CDCl3) 3011, 2981, 2920, 1688,
1416 cm21. Anal. calcd. for C17H23NO5: C, 63.54; H, 7.21;
N, 4.36. Found: C, 63.76; H, 7.27; N, 4.41.
4.1.16. (1R,5R,7R)-3-tert-Butoxycarbonyl-6,8-dioxa-3-
aza-bicyclo[3.2.1]octane-7-endo-carboxylic acid (9e).
Compound 9c (8.0 g, 20.98 mmol) was treated as described
for the enantiomer, thus giving pure 9e as a foamy
hygroscopic powder (3.21 g, 59%), with spectroscopic
data as for the enantiomer. [a]2D0¼þ52.9 (c 0.5, CHCl3).
Anal. calcd for C11H17NO6: C, 50.96; H, 6.61; N, 5.40.
Found: C, 50.81; H, 6.55; N, 5.36.
4.1.11. (1S,5S,7S)-3-tert-Butoxycarbonyl-5-phenyl-6,8-
dioxa-3-aza-bicyclo[3.2.1]octane-7-endo-carboxylic acid
(5e). PDC (43.6 g, 116.0 mmol) was added portionwise to a
solution of alcohol 3e (7.47 g, 23.2 mmol) in anhydrous
DMF (45 mL). The reaction mixture was stirred at room
temperature for 2 days and then diluted with H2O (125 mL)
and extracted with Et2O (6£125 mL). The organic phase
was dried over Na2SO4 and concentrated under reduced
pressure. The residue was taken with saturated NaHCO3,
washed with EtOAc (250 mL£4) and acidified with 20%
HCl until pH 5 and extracted with EtOAc (250 mL£5). The
combined organic phases were then dried over Na2SO4,
filtered and concentrated under reduced pressure to give
pure 5e as a white powder (19.4 g, 50%). Mp 142–1448C;
4.1.17. (4S,5R)-[5-(Benzylamino-methyl)-2,2-dimethyl-
[1,3]dioxolan-4-yl]-methanol [(S,R)-14]. Compound 6
(31 g, 194 mmol) was treated as described for the
enantiomer, thus giving (S,R)-14 (47 g) as a clear oil,
which was enough pure to be used in the next step, with
spectroscopic data as for the enantiomer. A sample for
elemental analysis was obtained by flash chromatography.
[a]2D6¼þ8.6 (c 1.04, CHCl3). Anal. calcd. for C14H21NO3:
C, 66.91; H, 8.42; N, 5.57. Found: C, 66.78; H, 8.37; N,
5.59.
[a]2D6¼239.1 (c 1.02, CHCl3); H NMR d 7.72–7.58 (m,
1
2H), 7.32–7.18 (m, 3H), 4.96 (br s, 1H), 4.80 (br s, 1H),
4.24–4.00 (m, 2H), 3.40–3.16 (m, 2H), 1.47 (s, 9H); 13C
NMR d 170.5 (s), 154.9 (s), 136.8 (s), 130.0 (d), 128.2 (d,
2C), 125.3 (d, 2C), 106.2 (s), 81.3 (s), 75.3 (d), 52.6 (t), 42.7
(t), 28.3 (q, 3C); MS m/z 279 (9), 106 (40), 104 (62), 55
4.1.18. (4S,5R)-[5-(N-Benzyl-N-phenacyl-aminomethyl)-
2,2-dimethyl-[1,3]dioxolan-4-yl]-methanol
[(S,R)-15].
Crude ((S,R)-14 (47 g) was treated as described for the
enantiomer, thus giving (S,R)-15 as a clear oil (36 g, 50%
from 6), with spectroscopic data as for the enantiomer.
[a]2D4¼220.2 (c 1.0, CHCl3). Anal. calcd. for C22H27NO4:
C, 71.52; H, 7.37; N, 3.79. Found: C, 71.59; H, 7.35; N, 3.68.
(100); IR (CDCl3) 2980, 2926, 2866, 1693, 1417 cm21
.
Anal. calcd. for C17H21NO6 (335.36): C, 60.89; H, 6.31; N,
4.18. Found: C, 60.68; H, 6.37; N, 4.42.
4.1.12. (4S,5R)-(5-[(2,2-Diethoxy-ethylamino)methyl]-
2,2-dimethyl-[1,3]-dioxolan-4-yl(-methanol [(S,R)-12a].
Compound 6 (25.8 g, 161 mmol) was treated as described
for the enantiomer, thus giving pure (S,R)-12a as an oil
(26.8 g, 60%), with spectroscopic data as for the enantio-
mer. [a]2D0¼þ9 (c 0.29, CHCl3). Anal. calcd for
C13H27NO5: C, 56.30; H, 9.81; N, 5.05. Found: C, 56.21;
H, 9.75; N, 4.98.
4.1.19. (1R,5R,7S)-3-Benzyl-5-phenyl-7-endo-hydroxy-
methyl-6,8-dioxa-3-aza-bicyclo[3.2.1]octane (8b). Com-
pound (S,R)-15 (36 g, 97.4 mmol) was treated as described
for the enantiomer, thus giving 8b as a white powder
(28.1 g, 93%), with spectroscopic data as for the enantio-
mer. A sample for elemental analysis was obtained by flash
chromatography. Mp 80–818C, [a]2D6¼þ14.9 (c 1.0,

A. Trabocchi et al. / Tetrahedron 59 (2003) 5251–5258
5257
CHCl3). Anal. calcd. for C19H21NO3: C, 73.29; H, 6.80; N,
4.50. Found: C, 73.21; H, 6.77; N, 4.48.
Anal. calcd for C21H33NO7: C, 61.30; H, 8.08; N, 3.40. Found:
C, 61.15; H, 7.91; N, 3.29.
4.1.20. (1R,5R,7S)-5-Phenyl-7-endo-hydroxymethyl-6,8-
dioxa-3-aza-bicyclo[3.2.1]octane (8a). Compound 8b
(28.1 g, 90.5 mmol) was treated as described for the
enantiomer, thus giving 8a as a yellow oil (20.0 g, 100%),
with spectroscopic data as for the enantiomer. [a]2D4¼þ26.6
(c 0.95, CHCl3). Anal. calcd. for C12H15NO3: C, 65.14; H,
6.83; N, 6.33. Found: C, 65.17; H, 6.79; N, 6.28.
4.1.25. (1S,5S,7R)-3-Benzyloxycarbonyl-7-endo-hydroxy-
methyl-6,8-dioxa-3-aza-bicyclo[3.2.1]octane (2d). Com-
pound (R,S)-12d (34 g, 83 mmol) was treated with TFA
(40 mL) as reported for (R,S)-12c, thus giving after flash
chromatography (EtOAc–CH2Cl2, 1:2) 2d (3.8 g, 16%) as an
oil. 1H NMR mixture of rotamers d 7.36(m, 5H), 5.56and 5.50
(s, 1H), 5.16 (s, 2H), 4.44–4.34 (m, 1H), 4.12 (m, 1H), 4.00–
3.63(m, 2H), 3.35(m, 1H), 3.13(m, 1H);13C NMR mixture of
rotamers d 155.5 (s), 136.1 (s), 128.4 (d, 2C), 128.0 (d, 2C),
127.6(d),98.5and98.0(d),77.6(d), 72.3and71.7(d),67.4(t),
60.7 (t), 48.2 (t), 43.4 and 43.0 (t); MS m/z 279 (Mþ, 0.1), 143
4.1.21. (1R,5R,7S)-3-tert-Butoxycarbonyl-5-phenyl-7-
endo-hydroxymethyl-6,8-dioxa-3-aza-bicyclo[3.2.1]oc-
tane (8e). Compound 8a (20.0 g, 90.4 mmol) was treated as
described for the enantiomer, thus giving 8e as a white
powder (21.3 g, 73%), with spectroscopic data as for the
enantiomer. A sample for elemental analysis was obtained
by flash chromatography (EtOAc–petroleum ether, 2:3, Rf
0.28). Mp 136–1378C. [a]2D6¼þ4.0 (c 0.98, CHCl3). Anal.
calcd. for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C,
63.61; H, 7.26; N, 4.41.
(2), 91 (70); IR (CDCl3) 2925, 1786, 1701 cm21
.
4.1.26. (1S,5S,7R) 3-(9-Fluorenylmethoxycarbonyl)-5-
phenyl-7-endo-hydroxymethyl-6,8-dioxa-3-aza-bicy-
clo[3.2.1]octane (3c). Compound 3c was obtained with the
same procedure reported for (R,S)-12c starting from 3a
(190 mg, 0.86 mmol), givingafter chromatography(CH2Cl2–
EtOAc, 2:1 Rf 0.3) pure 3c (42 mg, 11%) as a clear oil.
[a]2D4¼28.7 (c 1.05, CHCl3). 1H NMRd (mixtureofrotamers)
7.84–7.65 (m, 2H), 7.62–7.48 (m, 4H), 7.46–7.22 (m, 7H),
4.80–4.50 (m, 2H), 4.48–3.82 (m, 6H), 3.78–3.50 (m, 1H),
3.39–3.15(m, 2H);13C NMR d mixture of rotamers 155.5 and
155.4 (s), 143.8 (s, 2C), 141.3 (s, 2C), 137.5 (s), 129.1 (d),
128.3(d, 2C), 127.7(d, 2C), 127.1(d, 2C), 125.2(d, 2C), 124.8
(d, 2C), 120.0 (d, 2C), 105.0 and 104.9 (s), 78.9 and 78.3 (d),
74.2 and 73.6 (d), 67.5 and 66.7 (t), 61.2 and 61.0 (t), 52.2 and
51.8(t), 47.2(t), 42.3(d);MS m/z 443 (Mþ, ,1), 179 (80), 177
(100), 104 (60); IR (CDCl3) 3064, 2925, 1698 cm21. Anal.
calcd. for C27H25NO5: C, 73.12; H, 5.68; N, 3.16. Found: C,
73.24; H, 5.71; N, 3.22.
4.1.22. (1R,5R,7R)-3-tert-Butoxycarbonyl-5-phenyl-6,8-
dioxa-3-aza-bicyclo[3.2.1]octane-7-endo-carboxylic acid
(10e). Crude 8e (21.3 g, 66.3 mmol) was treated as
described for the enantiomer, thus giving pure 10e as a
white powder (9 g, 41%), with spectroscopic data as for the
enantiomer. Mp 141–1428C. [a]2D5¼þ38.0 (c 0.90, CHCl3).
Anal. calcd. for C17H21NO6: C, 60.89; H, 6.31; N, 4.18.
Found: C, 60.59; H, 6.61; N, 4.28.
4.1.23. (1S,5S,7S)-6,8-Dioxa-3-aza-bicyclo[3.2.1]octane-
7-endo-carboxylic acid hydrochloride (4a). To a solution
of 4c (5.2 g, 13.7 mmol) in CH2Cl2 (80 mL) was added
piperidine (4.1 mL, 41 mmol) and the mixture was stirred at
room temperature for 4 h. The solution was then diluted
with water and the aqueous phase was washed with EtOAc
and passed through a column of Ambersep 900-OH. After
resin washings with water and elution with 0.5 M HCl,
solvent evaporation afforded the corresponding free amino
4.1.27. (1S,5S,7S) 3-(9-Fluorenylmethoxycarbonyl)-5-
phenyl-6,8-dioxa-3-aza-bicyclo[3.2.1]octane-7-endo-car-
boxylic acid (5c). Compound 3c (15 mg, 0.034 mmol) was
treated as described for 5e, thus giving pure 5c (10 mg,
66%) as a white powder: mp 69–708C. [a]2D5¼236.7 (c 1.5,
1
1
acid 4a (1.29 g, 48%) as a very hygroscopic salt: H NMR
CHCl3); H NMR d 7.77–7.10 (m, 13H), 5.00–4.90 (m,
(D2O) d 5.88 (s, 1H), 4.97 (s, 1H), 4.65 (m, 1H), 3.58 (d,
J¼12.9 Hz, 2H), 3.39 (d, J¼15.4 Hz, 2H); MS m/z 158
(Mþ21, 7), 114 (13), 85 (69).
1H), 4.84–4.74 (m, 1H), 4.62–4.32 (m, 3H), 4.28–4.08 (m,
2H), 3.40–3.16 (m, 2H); 13C NMR d 170.6 (s), 155.7 (s),
141.3 (s, 2C), 141.2 (s, 2C), 136.5 (s), 129.5 (d, 2C), 128.4
(d, 2C), 127.7 (d, 2C), 127.1 (d, 2C), 125.3 (d, 2C), 124.9
(d), 119.9 (d, 2C), 106.4 (s), 76.8 (d), 75.7 (d), 68.2 (t), 52.3
(t), 47.0 (t), 43.5 (d); MS m/z 279 (1), 180 (100); IR (CDCl3)
1704 cm21. Anal. calcd. for C27H23NO6: C, 70.89; H, 5.07;
N, 3.06. Found: C, 70.69; H, 5.16; N, 3.24.
4.1.24. (4R,5S)-{5-[N-Benzyloxycarbonyl-N-(2,2-
diethoxy-ethyl)-aminomethyl]-2,2-dimethyl-[1,3]dioxo-
lan-4-yl}-methanol [(R,S)-12d]. To a solution of (R,S)-12a
(25.2 g, 91 mmol) and triethylamine (38 mL, 273 mmol) in
THF (400 mL) was dropwise added at 08C Cbz-Cl (28.3 mL,
200 mmol), and the mixture was stirred 30 min at 08C, and at
room temperature overnight. Then diethyl ether was added
and the organic phase was washed with water, giving 42 g of a
crude oil which was purified by flash chromatography
(CH2Cl2–MeOH, 20:1, Rf¼0.27), thus giving pure (R,S)-
Acknowledgements
`
The authors thank COFIN 2000–2002 and Universita degli
Studi di Firenze for financial support. M. R. thanks
`
CINMPIS-Universita di Bari for financial grant. Dr Elisa
Danieli is acknowledged for carrying out some experiments.
1
12d (35 g, 94%) as an oil. [a]2D4¼20.2 (c 1.5, CHCl3); H
NMR d 7.34 (m, 5H), 5.15 (s, 2H), 4.58–4.08 (m, 4H), 3.84–
3.29 (m, 10H), 1.39 (s, 3H), 1.24 (s, 3H), 1.09 (m, 6H); 13C
NMR mixture of rotamers d 155.5 (s), 135.8 (s), 127.7 (d, 4C),
127.3(d),107.8(s), 101.2and100.8(d), 76.6(d),75.3(d),66.6
(t),62.8(t),62.0(t), 60.1and59.6(t),50.0(t),47.8and47.3(t),
27.2 (q), 24.5 (q), 14.5 (q, 2C); MS m/z 276 (Mþ2Cbz-1, 1),
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