Synthesis of bridged sugar amino acids: A new entry into conformationally locked δ- and ε-amino acids

Article abstract of DOI:10.1016/S0040-4020(03)00288-6

The synthesis of three methylene bridged sugar amino acids is described. Key transformations in the synthetic strategy are a CO-insertion on fully protected ribose, an aldol condensation with formaldehyde and an oxetane forming cyclisation step. A novel L

Full text of DOI:10.1016/S0040-4020(03)00288-6

Tetrahedron 59 (2003) 2423–2434
Synthesis of bridged sugar amino acids: a new entry into
conformationally locked d- and 1-amino acids
Renate M. van Well, Marlies E. A. Meijer, Herman S. Overkleeft, Jacques H. van Boom,
*
*
Gijsbert A. van der Marel and Mark Overhand
Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands
Received 7 November 2002; revised 18 February 2003; accepted 21 February 2003
Abstract—The synthesis of three methylene bridged sugar amino acids is described. Key transformations in the synthetic strategy are a
CO-insertion on fully protected ribose, an aldol condensation with formaldehyde and an oxetane forming cyclisation step. A novel Leu-
enkephalin analogue containing the d-SAA 1 was prepared using standard solution phase peptide chemistry. q 2003 Elsevier Science Ltd.
All rights reserved.
1. Introduction
Various laboratories, including our group, have used
furanoid sugar amino acids (SAAs) for the introduction of
conformational restriction in peptide-like oligomers.6
Although furanoid SAAs are capable of reducing the
conformational freedom in both linear and cyclic oligomers,
the furan ring often exists in an equilibrium of confor-
mations, rather than being frozen in one conformation.6c,e
For example, we recently demonstrated that the five-
membered ring in a cyclic furanoid SAA oligomer flips
between a north and a south conformation.6c It was
envisaged that the introduction of a bridging methylene
function over the five-membered ring of SAAs, in analogy
to the structure of 30 –40 LNA monomers, would stabilize a
south conformation of the furan ring. Consequently,
incorporation of such a bridged SAA (BSAA) into peptides
or SAA oligomers should result in more rigid three-
dimensional structures, which might have enhanced
recognition properties.
Some years ago, Wengel1a,b and Imanishi1c,d independently
introduced so-called locked nucleic acids (LNAs) as novel
nucleotides displaying interesting properties.1 For example,
20 –40 LNA monomers (Fig. 1) contain a methylene bridge
that connects the 20-oxygen of ribose with the 40-carbon,
which results in a locked C30-endo (north) conforma0tion for
the ribose ring.1c,2 On the other hand, 30 –4 LNA
monomers, containing a methylene bridge that connects
the 30-oxygen of ribose with the 40-carbon, adopt a C20-endo
(south) conformation.3 Incorporation of several 20 –40 LNA
monomers in a DNA strand increases the local organisation
of the phosphate backbone, and as a result improves the
affinity of the LNA/DNA chimera for complementary DNA
and RNA sequences.4 The incorporation of 30 –40 LNA
monomers results in a chimera with a preference for RNA
over DNA, due to destabilisation of the 30 –40 LNA/DNA
duplex.5
Here we present the synthesis of furanoid d- and 1-SAAs
(1–3) containing a furano-oxetane core as depicted in
Figure 2. In addition, the utility of the bridged SAAs in
standard peptide chemistry is demonstrated by incorporat-
ing 1 in Leu-enkephalin analogue 4, as a replacement for the
Gly-Gly dipeptide.6d,e,7
2. Results and discussion
Figure 1.
Retrosynthetic analysis revealed that the three BSAAs (1–
3) could be prepared starting from the commercially
available acetyl-2,3,5-tri-O-benzoyl-b-D-ribofuranoside (8
Scheme 1). Key steps in the synthesis are the formation of
the oxetane ring (i.e. 6!5), an aldol condensation with 7 for
Keywords: sugar amino acid; conformationally restricted; peptide isoster;
Leu-enkephaline.
*
Corresponding authors. Tel.: þ31-715274483; fax: þ31-715274307;
e-mail: overhand@chem.leidenuniv.nl, g.marel@chem.leidenuniv.nl.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00288-6

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R. M. van Well et al. / Tetrahedron 59 (2003) 2423–2434
Figure 2.
Scheme 1.
the introduction of the hydroxymethylene function, and a
CO-insertion in 8.
chloride in pyridine to give 19. Ensuing acetonide cleavage
under the agency of 4 M aq. HCl afforded diol 20 in good
yield. Ring closure of 20 under alkaline conditions afforded
exclusively the oxetane intermediate 21, which after
prolonged stirring at elevated temperature gave 22 in 81%
yield.12 The oxetane structure in 21 was confirmed by
acetylation of the remaining free hydroxyl, which resulted
in a strong downfield shift for H3.13 Furano-oxetane 22 was
converted into locked d-SAA 1 via the following two-step
sequence. First, the azide in 22 was transformed into the
Boc-protected amine 23 by a modified Staudinger reaction
using Me3P in the presence of 2-t-butoxycarbonyloxyimino-
2-phenylacetonitrile (Boc-ON).14 In the last step, TEMPO
oxidation of the primary alcohol in 23 in an aqueous
environment afforded 1 in 49% over the two steps.15
In Scheme 2 the synthesis of d-BSAA 1 as well as its
1-BSAA analogue 2 is depicted. As reported in the
literature,8 carbonyl insertion in 9 using Co2(CO)8 and
CO-gas in the presence of diethylmethylsilane (DEMS)
gave the silyl protected allitol derivative 10. Acidic removal
of the DEMS protective group (AcOH/H2O/THF, 3/1/6)
afforded 11 in 71% over the two steps. Reaction of 11 with
mesyl chloride in pyridine followed by treatment with
sodium azide gave azide 13 in 89%. Removal of the benzoyl
groups in 13 (KOtBu in MeOH) and subsequent protection
of the cis-diol in 14 by reaction with 2,2-dimethoxypropane
and pTsOH in acetone yielded 15 in 87% yield. The stage
was now set for the introduction of the hydroxymethylene
function via an aldol condensation. To this end the primary
alcohol in 15 was oxidised using the Dess–Martin reagent
to provide the required aldehyde 16.9 According to literature
precedent, treatment of the aldehyde with formaldehyde in
the presence of NaOH should, after an aldol condensation
directly followed by Cannizarro reduction, result in the
formation of 17.10 However, the latter reduction proved to
be very sluggish and low yielding when performed on
compound 16. After stirring for four days a yield of only
31% of 17 was obtained, together with a small amount of a
slightly lower running product, which turned out to be the
3,4-O-methylene analogue 18.11 Fortunately, by modifying
the reaction conditions, i.e. reduction of the initially formed
b-hydroxy aldehyde by addition of NaBH4 to the reaction
mixture after 1 h, the desired diol 17 was obtained in 52%
after a reaction time of 3 h, together with 13% of 18 and
10% of 15.10d Next, the primary alcohols were converted
into good leaving groups by reaction of 17 with mesyl
Having synthesised d-BSAA 1 it was envisaged that
intermediate 21 could also be converted into 2, the
1-BSAA congener of 1. To this end, the primary mesylate
in derivative 21 was transformed into the cyanide 24 with
sodium cyanide in DMF in a yield of 47%.16 Subsequent
reduction of the azide in 24 and protection of the resulting
amine in a one-pot procedure (vide supra), followed by
hydrolysis of the cyanide in 25 under basic conditions
furnished BSAA 2 in 66% over the two steps.
The synthesis of d-SAA 3 was initiated by silylation of the
primary alcohol in 11 using TBDPSCl in pyridine to afford
26 in 89% yield (Scheme 3). Subsequent debenzoylation
and introduction of the acetonide functionality gave 28 in
94% yield over the two steps. Introduction of the
hydroxymethylene group, followed by treatment of 29
with mesyl chloride in pyridine gave dimesylate 30 in 61%
yield. Removal of the isopropylidene protecting group in 30

R. M. van Well et al. / Tetrahedron 59 (2003) 2423–2434
2425
Scheme 2. Reagents and conditions: (i) Co2(CO)8, DEMS, CO-gas, DCM, 308C, 16 h; (ii) AcOH/H2O/THF (3/1/6, v/v/v), 08C, 2 h; (iii) MsCl, pyridine, 16 h;
(iv) NaN3, DMF, 758C, 2 h; (v) KOtBu, MeOH, 2 h; (vi) 2,2 dimethoxypropane, pTsOH, acetone, 3 h; (vii) Dess–Martin periodinane, DCM, 08C, 1 h;
(viii) CH2O, 2 M NaOH (aq.), dioxane, 08C, 1 h, then NaBH4, 2 h, 17: 52%, 18: 13%, 15: 10%; (ix) 4 M HCl (aq.), THF, 2 h; (x) 1 M NaOH (aq.), dioxane (xi)
Boc-ON, Me3P, THF, 5 h; (xii) TEMPO, KBr, NaOCl, aq. NaHCO3, aq. NaCl, H2O, 08C, 4 h; (xiii) NaCN, NaI, DMF, 708C, 1.5 h; (xiv) 4 M NaOH (aq.),
MeOH, 608C, 3 h.
under the influence of 4 M aq. HCl was accompanied by the
undesired cleavage of the TBDPS group. Fortunately,
reaction of 30 with FeCl3 in MeOH/DCM resulted in 53%
of the desired product 31, together with 17% of recovered
starting material 30.17,18 Treatment of 31 with NaOH in
dioxane exclusively led to the formation of the expected
fused furano-oxetane 32 (85% yield).19 Introduction of the
azide (32 to 33) and subsequent conversion of 33 into the
Boc-protected amine 34 as described above proceeded
efficiently. Finally, desilylation of 34 with TBAF and
TEMPO oxidation of the resulting primary hydroxyl in 35
provided the target BSAA 3 in 60% yield over the two steps.
pharmacophoric groups.20 The Gly-Gly dipeptide functions
as a spacer, and has been replaced by SAAs to influence the
spatial arrangement of the address and message compo-
nents.6d,e,7 The construction of Leu-enkephalin analogue 4
was performed as depicted in Scheme 4. The free
carboxylate in 1 was condensed with HCl·H-Phe-Leu-
OMe under the influence of N-(3-dimethylaminopropyl)-N0-
ethylcarbodiimide·hydrochloride (EDC·HCl), 1-hydroxy-
benzotriazole (HOBt) and N-methylmorpholine (NMM) to
give trimer 36 in 45%. Unmasking of the Boc-group in 36
(50% TFA/DCM), followed by condensation of the
resulting free amine with Boc-Tyr(tBu)-OH provided the
protected tetramer 37 in a yield of 70%. Removal of the Boc-
and tert-butyl protecting groups was accomplished by
treatment with a 90% TFA solution in H2O to give the
target compound 4 in quantitative yield. The structure of 4
was ascertained by NMR and MS. The large values found
for the J4,5 coupling constants of the BSAA residue in
Next, attention was focussed on the synthesis of Leu-
enkephalin analogue 4 containing the BSAA 1. The original
Leu-enkephalin peptide H-Tyr-Gly-Gly-Phe-Leu-OMe is a
selective d-opoid receptor ligand in which the N-terminal
Tyr residue and the C-terminal Phe-Leu dipeptide form the

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R. M. van Well et al. / Tetrahedron 59 (2003) 2423–2434
Scheme 3. Reagents and conditions: (i) TBDPSCl, pyridine, 16 h; (ii) KOtBu, MeOH, 2 h; (iii) 2,2-dimethoxypropane, pTsOH, acetone, 3 h; (iv) (a) Dess–
Martin periodinane, DCM, 08C, 30 min; (b) CH2O, 2 M NaOH, dioxane, 08C, 1 h, then NaBH4, 2 h; (v) MsCl, pyridine, 16 h; (vi) Fe3Cl, MeOH, DCM, 1 h;
(vii) 1 M NaOH, dioxane, rt, 1 h; (viii) NaN3, DMF, 758C, 1 h; (ix) Boc-ON, Me3P, THF, 5 h; (x) TBAF, THF, 1 h; (xi) TEMPO, KBr, NaOCl, aq. NaHCO3,
aq. NaCl, H2O, 08C, 4 h.
Scheme 4. Reagents and conditions: (i) HCl·H-Phe-Leu-OMe, EDC·HCl, HOBt, NMM, 16 h; (ii) (a) 50% TFA/DCM, 5 min; (b) Boc-Tyr(tBu)-OH, EDC·HCl,
HOBt, NMM, 16 h; (iii) 90% TFA/H2O, 1 h.
peptide 4 (8.8 Hz) as well as for the BSAA monomer 1
(8.3 Hz) are a strong indication that the furan ring in the
BSAA residue adopts a south conformation.21,22
spectra were recorded with PE/SCIEX API 165 with
electrospray interface. Infra-red spectra were recorded on
a FTIR-8300 (Shimadzu) spectrometer. Column chroma-
tography was performed on Fluka silica gel 60 (0.04–
0.063 mm). TLC analysis was conducted on DC plastik-
folien (Merck silica gel 60 F254) with detection by UV
absorption (254 nm) where applicable and by spraying with
20% H2SO4 in ethanol, a ninhydrin solution or ammonium
molybdate (25 g/L) and ceric ammonium sulfate (10 g/L),
followed by charring at ,1508C. Reactions were run at
ambient temperature, unless stated otherwise. Prior to
reactions that require anhydrous conditions, traces of
water were removed by coevaporation with toluene,
pyridine or DCE. Acetone (Acros, p.a.), DCE (Biosolve,
HPLC-grade), DMF (Baker, p.a.), toluene (Biosolve, p.a.),
1,4-dioxane (Baker, p.a.), pyridine (Baker, p.a.) and DCM
3. Conclusion
In summary, three novel bridged SAAs, i.e. the d-BSAAs 1
and 3, and the 1-BSAA 2, were successfully synthesised.
The key ring-closure of dimesylates 20 and 31 proceeded
regioselectively to exclusively afford the four-membered
ring. The d-BSAA 1 was employed for the construction of a
novel Leu-enkephalin analogue 4. Molecular modelling
studies of the BSAA monomers as well as the peptide 4 will
provide information whether the methylene bridge locks the
conformation of the furan ring in a specific south
conformation. The BSAAs will be used for the construction
of linear and cyclic homooligomers, and their ability to
adopt well-defined conformations will be evaluated.
˚
(Baker, p.a.) were stored over molecular sieves (4 A).
Acetonitrile (Biosolve, p.a.) and MeOH (Biosolve, p.a.)
˚
were stored over molecular sieves (3 A). THF (Merck) and
Et2O were boiled under reflux with LiAlH4 and distilled
immediately prior to use. Triethylamine (Acros) was boiled
under reflux for 3 h with CaH2, distilled and stored over
KOH. Diethylmethylsilane (DEMS, Acros), cobalt carbonyl
(Co2(CO)8, Fluka), 1-O-acetyl-2,3,5-tri-O-benzoyl-b-D-
ribose (Aldrich), trimethylphosphine (Acros), 2-(t-butoxy-
carbonyloxyimino)-2-phenylacetonitrile (Boc-ON, Janssen
chimica) were used as received.
4. Experimental
4.1. General experimental
1H and 13C NMR spectra were recorded with a Jeol JNM-
FX-200 (200/50.1 MHz), a Bruker WM-300 (300/
75.1 MHz), a Bruker AV-400 (400/100 MHz) or a Bruker
DMX-600 (600/150 MHz) spectrometer. Chemical shifts
are given in ppm (d) relative to tetramethylsilane as internal
standard. All given 13C spectra are proton decoupled. Mass
4.1.1. 2,5-Anhydro-3,4,6-tri-O-benzoyl-1-O-diethyl-
methylsilyl-D-allitol (10). After flushing a 100 mL flask
with CO-gas, Co2(CO)8 (0.341 g, 1 mmol) was added

R. M. van Well et al. / Tetrahedron 59 (2003) 2423–2434
2427
followed by diethylmethylsilane (9.11 mL, 62.5 mmol). To
this mixture, a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-
b-D-ribose (9, 12.6 g, 25 mmol) in DCM (30 mL) was
added slowly. The reaction mixture was stirred for 16 h
under an atmosphere of CO at 308C. The solution was
directly applied to a silica gel column, and elution with
EtOAc/light petroleum (0/1!3/7, v/v) gave 10 in 75%
(10.8 g) as a colourless oil. 1H NMR (CDCl3): d 7.98–7.80,
7.45–7.17 (2£m, 15H, Harom Bz), 5.57 (m, 2H, H3, H4),
4.60–4.27 (m, 4H, H2, H5, 2£H6), 3.77 (d, 2H, 2£H1,
J¼3.6 Hz), 1.61 (t, 6H, 2£CH3CSi, J¼7.3 Hz), 0.84 (q, 4H,
2£CH2Si, J¼8.0 Hz), 0.08 (s, 3H, CH3Si). 13C NMR
(CDCl3): d 165.7, 165.1, 164.9 (3£C(O) Bz), 132.9,
132.6, 129.3, 127.9 (CHarom Bz), 128.7 (Cq Bz), 83.0,
77.5, 72.8 (C2, C3, C4, C5), 64.4 (C6), 62.4 (C1), 6.14
(CH3CH2Si), 5.7 (CH2Si), 25.0 (CH3Si).
(MgSO4) of the combined organic phases and concentration
gave crude 13. After purification by column cromatography
(eluent: EtOAc/light petroleum, 1/9!4/6, v/v) the product
1
13 was obtained in 96% (5.24 g) as a colourless oil. H
NMR (CDCl3): d 8.11–7.92 (m, 6H, 6£Harom Bz), 7.52–
7.26 (m, 9H, 9£Harom Bz), 5.68 (q, 1H, H4, J¼5.8 Hz), 5.63
(q, 1H, H3, J¼5.8 Hz), 4.79–4.41 (m, 4H, H2, H5, 2£H6),
3.74 (dd, 1H, H1a, J1a,2¼2.9 Hz, J1a,1b¼13.2 Hz), 3.54 (dd,
1H, H1b, J1b,2¼4.4 Hz, J1a,1b¼13.5 Hz). 13C NMR
(CDCl3): d 165.6, 164.9, 164.8 (3£C(O) Bz), 132.9,
132.6, 129.2, 127.9 (CHarom Bz), 128.5 (Cq Bz), 80.4,
79.5, 72.3, 71.9 (C2, C3, C4, C5), 63.6 (C6), 51.2 (C1). ESI-
MS: m/z 524.5 [MþNa]þ, 1025.3 [2MþNa]þ.
4.1.5. 2,5-Anhydro-1-azido-1-deoxy-3,4-O-isopropyl-
idene-D-allitol (15). Compound 13 (5.24 g, 10.45 mmol)
was coevaporated with toluene (3£30 mL) and dissolved in
MeOH (50 mL). KOtBu (0.12 g, 1.05 mmol) was added and
the resulting mixture was stirred for 2 h. The solution was
neutralized with DOWEX-Hþ (50W£4), the ion exchange
resin was removed by filtration, and the filtrate concen-
trated. The crude product was dissolved in acetone (50 mL)
and 2,2-dimethoxypropane (1.94 mL, 15.7 mmol) and
pTsOH (cat) were added. After stirring the resulting mixture
for 3 h, the solution was neutralized with sat. aq. NaHCO3
and concentrated. The residue was taken up in EtOAc
(100 mL) and washed with H2O (1£50 mL), NaHCO3
(3£50 mL), brine (1£50 mL), dried (MgSO4) and concen-
trated. Purification by silica gel column chromatography
(eluent: EtOAc/light petroleum, 1/9!2/1, v/v) afforded 15
in 87% (2.08 g) as a colourless syrup. 1H NMR (CDCl3): d
4.70 (dd, 1H, H4, J4,5¼4.0 Hz, J3,4¼6.6 Hz), 4.57 (dd, 1H,
H3, J2,3¼4.8 Hz, J3,4¼6.6 Hz), 4.14–4.08 (m, 2H, H2, H5),
3.91–3.66 (m, 2H, 2£H6), 3.65 (dd, 1H, H1a, J1a,2¼3.3 Hz,
4.1.2. 2,5-Anhydro-3,4,6-tri-O-benzoyl-D-allitol (11).
Compound 10 (10.8 g, 18.8 mmol) was dissolved in a
mixture of AcOH/H2O/THF (100 mL, 3/1/6, v/v/v). After
stirring for 2 h, the solution was concentrated and the
resulting oil dissolved in EtOAc (100 mL), washed with
H2O (1£75 mL), sat. aq. NaHCO3 (2£75 mL), brine
(1£75 mL), dried (MgSO4) and concentrated. The crude
product was subjected to silica gel column chromatography
(EtOAc/light petroleum, 1/9!4/6, v/v) to give title
compound 11 in 95% (8.5 g) as a colourless syrup. 1H
NMR (CDCl3): d 8.11–7.93 (m, 6H, 6£Harom Bz), 7.58–
7.26 (m, 9H, 9£Harom Bz), 5.69 (m, 2H, H3, H4), 4.69–4.60
(m, 3H, H2, H5, H6a), 4.39 (m, 1H, H6b), 3.97 (dd, 1H,
H1a, J1a,2¼1.8 Hz, J1a,1b¼12.4 Hz), 3.82 (dd, 1H, H1b,
J1b,2¼2.6 Hz, J1a,1b¼12.4 Hz), 2.37 (bs, 1H, OH). 13C NMR
(CDCl3): d 165.9, 165.1, 164.9 (3£C(O) Bz), 132.9, 132.7,
129.2, 127.9 (CHarom Bz), 128.8, 128.7 (Cq Bz), 82.4, 79.2,
72.6, 71.9 (C2, C3, C4, C5), 64.0 (C6), 61.4 (C1).
J1a,1b¼12.8 Hz), 3.43 (dd, 1H, H1b, J1b,2¼4.4 Hz, J1a,1b
¼
13.2 Hz), 1.54, 1.35 (2£s, 6H, 2£CH3 isoprop). 13C NMR
(CDCl3): d 114.3 (Cq isoprop), 84.7, 82.9, 81.6, 81.3 (C2,
C3, C4, C5), 62.5 (C6), 52.1 (C1), 27.1, 25.1 (2£CH3
isoprop). ESI-MS: m/z 252.1 [MþNa]þ.
4.1.3. 2,5-Anhydro-3,4,6-tri-O-benzoyl-1-O-mesyl-D-alli-
tol (12). Compound 11 (5.6 g, 11.7 mmol) was dissolved in
pyridine (50 mL), methanesulfonyl chloride (1.09 mL,
14.0 mmol) was added and the reaction mixture was stirred
for 16 h. The solvent was removed under reduced pressure
and the residue was dissolved in EtOAc (100 mL). The
organic phase was washed with H2O (50 mL), sat. aq.
NaHCO3 (3£50 mL) and brine (50 mL), dried MgSO4 and
concentrated. The crude product was applied to a silica gel
column and eluted with EtOAc/light petroleum (1/9!4/6,
v/v) to afford compound 12 in 93% (6.04 g) as a colourless
4.1.6. 2,5-Anhydro-1-azido-1-deoxy-5-C-hydroxy-
methyl-3,4-O-isopropylidene-D-allitol (17). Compound
15 (0.79 g, 3.8 mmol) was dissolved in DCM (20 mL) and
the solution was cooled to 08C and Dess–Martin reagent
(1.93 g, 4.56 mmol) was added under an Ar atmosphere.
After stirring for 30 min the reaction mixture had turned
milky white and the reaction was finished. Sat. aq. Na2S2O3
(20 mL), sat. aq. NaHCO3 (20 mL) and EtOAc (40 mL)
were added and the reaction mixture was stirred vigorously
untill both phases were clear. The layers were seperated and
the organic phase was washed with H2O (3£30 mL) and
brine (30 mL), dried (MgSO4) and concentrated. The crude
aldehyde 16 together with CH2O (0.85 mL, 35% solution in
H2O) were dissolved in dioxane (10 mL). The resulting
mixture was cooled to 08C and NaOH aq. (3.8 mL, 2N in
H2O) was added. After 1 h, NaBH4 (0.73 g, 22.8 mmol) was
added and the reaction mixture was stirred for another 2 h.
The solution was neutralized with AcOH and concentrated,
the residue was dissolved in EtOAc and washed with H2O
(1£ mL), NaHCO3 (3£ mL), brine (1£ mL), dried (MgSO4)
and concentrated. Purification was accomplished by silica
gel column chormatography (eluent: EtOAc/light
petroleum, 1/9!1/1, v/v) to give pure title compound 17
1
oil. H NMR (CDCl3): d 8.11–7.92 (m, 6H, 6£Harom Bz),
7.59–7.32 (m, 9H, 9£Harom Bz), 5.63 (m, 2H, H3, H4),
4.78–4.13 (m, 6H, 2£H1, H2, H5, 2£H6), 2.99 (s, 3H, CH3
Ms). 13C NMR (CDCl3): d 165.5, 164.8, 164.7 (3£C(O)
Bz), 133.0, 132.7, 129.2, 127.9 (CHarom Bz), 128.5, 128.4,
121.1 (3£Cq Bz), 79.3, 79.1, 71.9, 71.2 (C2, C3, C4, C5),
67.9 (C1), 63.3 (C6), 36.6 (CH3 Ms). ESI-MS: m/z 577.4
[MþNa]þ, 1131.3 [2MþNa]þ.
4.1.4. 2,5-Anhydro-1-azido-3,4,6-tri-O-benzoyl-1-deoxy-
D-allitol (13). Compound 12 (6.04 g, 10.9 mmol) was
dissolved in DMF (50 mL), sodium azide (2.13 g,
32.7 mmol) was added and the resulting mixture was stirred
at 758C for 1.5 h. The reaction mixture was allowed to cool
to room temperature and subsequently diluted with H2O
(50 mL). Extraction with EtOAc (3£100 mL), drying

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R. M. van Well et al. / Tetrahedron 59 (2003) 2423–2434
in 52% (0.51 g) as a colourless oil together with 13% of a
slightly lower running fraction identified as the methylene
analog 18 and 10% of 15, both colourless oils. 17: 1H NMR
(CDCl3): d 4.82 (d, 1H, H4, J3,4¼6.6 Hz), 4.68 (dd, 1H, H3,
J2,3¼5.5 Hz, J3,4¼6.6 Hz), 4.18–4.07 (m, 1H, H2), 3.87–
4.1.9. 2,5-Anhydro-1-azido-1-deoxy-4-O,5-C-methylene-
D-allitol (22). Compound 20 (0.17 g, 0.46 mmol) was
dissolved in dioxane (4.6 mL) and NaOH (4.6 mL, 1 M in
H2O) was added. After stirring for 1 h, TLC analysis
showed complete conversion of the starting material in a
slightly lower running product. The reaction mixture was
heated to 858C and stirred for another 96 h, the solvent was
removed under reduced pressure and traces of H2O were
removed from the residue by coevaporation with toluene
(3£5 mL). Purification was accomplished by silica gel
column chromatography (eluent: EtOAc/light petroleum,
2/8!8/2, v/v) to furnish 22 in 81% (0.074 g) as a colourless
oil. 1H NMR (MeOD): d 4.94 (d, 1H, H4, J3,4¼4.8 Hz), 4.82
(d, 3H, 2£H6, H7, J7a,7b¼7.7 Hz), 4.46 (d, 1H, H7b,
3.66 (m, 4H, 2£H6, 2£H7), 3.65 (dd, 1H, H1a, J1a,2
¼
3.7 Hz, J1a,1b¼13.2 Hz), 3.47 (dd, 1H, H1b, J1b,2¼4.0 Hz,
J1a,1b¼12.8 Hz), 2.60 (bs, 2H, 2£OH), 1.56, 1.36 (2£s, 6H,
2£CH3 isoprop). 13C NMR (CDCl3): d 114.6 (Cq isoprop),
86.7 (C5), 83.3, 82.5, 82.0 (C2, C3, C4), 65.4, 62.8 (C6, C7),
52.4 (C1), 26.8, 24.9 (2£CH3 isoprop). ESI-MS: m/z 282.3
[MþNa]þ, 541.5 [2MþNa]þ. 18: 1H NMR (CDCl3): d 5.15
(d, 1H, CHa methylene, J¼21.2 Hz), 4.71 (m, 2H, H3, H4),
4.12 (m, 1H, H2), 3.73 (m, 6H, 2£H6, 2£H7, H1a, CHb
methylene), 3.53 (dd, 1H, H1b, J1b,2¼4.0 Hz, J1a,1b
¼
J7a,7b¼7.7 Hz), 2.30 (ddd, 1H, H2, J1a,2¼2.4 Hz, J1b,2¼
12.8 Hz), 2.39 (bs, 2H, 2£OH). 13C NMR (CDCl3): d 97.1
(CH2 methylene), 87.4 (C5), 83.3, 82.0, 80.5 (C2, C3, C4),
65.5, 62.8 (C6, C7), 52.5 (C1). ESI-MS: m/z 254.1
[MþNa]þ.
5.8 Hz, J2,3¼8.2 Hz), 3.79 (dd, 1H, H3, J2,3¼8.2 Hz,
J3,4¼4.8 Hz), 3.75 (dd, 1H, H1a, J¼2.4 Hz), 3.44 (dd, 1H,
H1b, J1b,2¼5.8 Hz, J1,1 ¼13.5 Hz). 13C NMR (MeOD): d
0
88.2, 81.8, 74.0 (C2, C3, C4), 87.1 (C5), 78.7 (C7), 62.6
(C6), 52.6 (C1). ESI-MS: m/z 224.0 [MþNa]þ.
4.1.7. 2,5-Anhydro-1-azido-1-deoxy-3,4-O-isopropyl-
idene-6-O-mesyl-5-C-mesyloxymethyl-D-allitol
(19).
4.1.10. 2,5-Anhydro-1-tert-butoxycarbonylamino-1-
deoxy-4-O,5-C-methylene-D-allitol (23). Compound 22
(0.074 g, 0.37 mmol) was dissolved in THF (2 mL), the
solution was placed under an argon atmosphere and Me3P
(0.45 mL, 1 M in toluene) was added. The reaction mixture
was stirred for 1 h and subsequently cooled to 2208C. A
solution of Boc-ON (0.11 g, 0.45 mmol) in toluene (0.5 mL)
was slowly added and the resulting mixture was stirred for
5 h. The solvent was removed in vacuo and the residue was
applied to a silica gel column, which was eluted with
EtOAc/light petroleum (8/2!1/0) followed by MeOH/
EtOAc (0/1!1/9, v/v) to give 23 in 70% (0.075 g) as a
colourless oil. 1H NMR (CDCl3): d 5.41 (bs, 1H, HN), 5.00
(d, 1H, H4, J3,4¼4.4 Hz), 4.73 (d, 1H, H7a, J7a,7b¼8.0 Hz),
4.49 (d, 1H, H7b, J7a,7b¼8.0 Hz), 4.18 (m, 1H, H2), 3.80–
3.72 (m, 3H, H3, 2£H6), 3.53–3.43 (m, 2H, 2£H1), 1.45 (s,
9H, tBu Boc). 13C NMR (CDCl3): d 156.5 (C(O) Boc), 86.9,
80.4, 72.9 (C2, C3, C4), 84.0 (C5), 79.2 (Cq Boc), 77.5 (C7),
61.8 (C6), 41.1 (C1), 28.0 (tBu Boc). ESI-MS: m/z 276.1
[MþH]þ, 298.2 [MþNa]þ, 573.5 [2MþNa]þ, 848.3
[3MþNa]þ.
Compound 17 (0.12 g, 0.46 mmol) was dissolved in
pyridine (4 mL), methanesulfonyl chloride (0.08 mL,
1.02 mmol) was added and the reaction mixture was stirred
for 16 h. The solvent was removed under reduced pressure
and the residue was dissolved in EtOAc (20 mL). The
organic phase was washed with H2O (10 mL), sat. aq.
NaHCO3 (3£10 mL) and brine (10 mL), dried (MgSO4) and
concentrated. The crude product was applied to a silica gel
column and eluted with EtOAc/light petroleum (1/9!1/1,
v/v) to afford compound 19 in 92% (0.18 g) as a colourless
oil. 1H NMR (CDCl3): d 4.79 (d, 1H, H4, J3,4¼6.6 Hz), 4.70
(dd, 1H, H3, J2,3¼4.4 Hz, J3,4¼6.7 Hz), 4.47–4.16 (m, 5H,
H2, 2£H6, 2£H7), 3.56 (dd, 1H, H1a, J1a,2¼3.7 Hz,
J1a,1b¼13.2 Hz), 3.42 (dd, 1H, H1b, J1b,2¼5.1 Hz, J1a,1b
¼
13.2 Hz), 3.10 (s, 6H, 2£CH3 Ms), 1.54, 1.34 (2£s, 6H,
2£CH3 isoprop). 13C NMR (CDCl3): d 115.2 (Cq isoprop),
82.9 (C5), 82.8, 81.9 (C2, C3, C4), 68.4 67.2 (C6, C7), 52.1
(C1), 37.6, 37.4 (2£CH3 Ms), 26.5, 24.8 (2£CH3 isoprop).
ESI-MS: m/z 438.1 [MþNa]þ, 853.4 [2MþNa]þ.
4.1.8. 2,5-Anhydro-1-azido-1-deoxy-6-O-mesyl-5-C-
mesyloxymethyl-D-allitol (20). Compound 19 (0.99 g,
2.38 mmol) was dissolved in a mixture of 4 M aq. HCl/THF
(20 mL, 1/1, v/v) and the resulting solution was stirred for
2 h. After neutralization with sat. aq. NaHCO3 the reaction
mixture was extracted with EtOAc (3£30 mL). The
combined organic layers were washed with sat. aq.
NaHCO3 (2£50 mL), brine (50 mL), dried (MgSO4) and
concentrated. The crude product was purified by silica gel
column chromatography (eluent: EtOAc/light petroleum,
2/8!8/2, v/v) to afford 20 in 89% (0.82 g) as a colourless
4.1.11. 2,5-Anhydro-6-tert-butoxycarbonylamino-6-
deoxy-2-C,3-O-methylene-L-allo-hexonic acid (1). Com-
pound 23 (0.29 g, 1.04 mmol), TEMPO (3 mg,
0.0016 mmol) and KBr (0.012 g, 0.11 mmol) were dis-
solved in H2O (5 mL) containing sat. aq. NaHCO3 (2.5 mL).
The reaction mixture was cooled to 08C, and a solution of
NaOCl (2 mL, 13% in H2O), sat. aq. NaHCO3 (1.25 mL)
and brine (2.5 mL) was added dropwise over a period of
15 min. Stirring was continued for another 4 h at 08C, then
the reaction mixture was neutralized with 4 M aq. HCl and
concentrated. The residue was dissolved in THF, mixed
with silica gel and evaporated to dryness uder reduced
pressure. The silica gel containing absorbed product was
applied to a silica gel column and purification using
EtOAc/MeOH/H2O/Et3N (50/45/5/3, v/v/v/v) afforded 1 in
70% (0.21 g) as a colourless syrup. nmax (neat): 3294.2,
1
oil. H NMR (CDCl3): d 4.47 (d, 2H, 2£H6, J¼1.7 Hz),
4.31 (d, 1H, H7a, J7a,7b¼10.4 Hz), 4.21 (d, 1H, H4,
J3,4¼5.4 Hz), 4.18 (d, 1H, H7b, J7a,7b¼10.4 Hz), 4.12 (m,
1H, H3), 4.03 (m, 1H, H2), 3.63 (dd, 1H, H1a, J1a,2¼2.0 Hz,
J1a,1b¼13.5 Hz), 3.35 (dd, 1H, H1b, J1b,2¼3.0 Hz,
J1a,1b¼13.5 Hz), 3.11 (s, 6H, 2£CH3 Ms), 2.88 (bs, 2H,
2£OH). 13C NMR (CDCl3): d 83.1 (C5), 81.1, 72.4,
71.2 (C2, C3, C4), 68.7, 68.1 (C6, C7), 51.5 (C1), 37.2
(2£CH3 Ms). ESI-MS: m/z 398.0 [MþNa]þ, 773.1
[2MþNa]þ.
1
1685.7, 1558.4, 1411.8, 1164.9 cm21. H NMR, COSY,
HMQC (MeOD): d 5.15 (d, 1H, H7a, J7a,7b¼7.3 Hz), 5.04
(d, 1H, H3, J3,4¼4.4 Hz), 4.49 (d, 1H, H7b, J7a,7b¼7.3 Hz),
4.18 (ddd, 1H, H5, J¼4.0 Hz, J¼4.4 Hz, J4,5¼8.8 Hz), 3.68

R. M. van Well et al. / Tetrahedron 59 (2003) 2423–2434
2429
(dd, 1H, H4, J4,5¼8.8 Hz, J3,4¼4.4), 3.48 (m, 1H,
H6a), 3.31 (m, 1H, H6b), 1.44 (s, 9H, tBu Boc). 13C
NMR (MeOD): d 174.9 (C1), 159.2 (C(O) Boc), 89.9
(C3), 86.1 (C2), 82.8 (C5), 80.9 (Cq Boc), 80.3 (C7), 72.7
(C4), 41.5 (C6), 28.7 (tBu Boc). ESI-MS: m/z 312.1
[MþNa]þ.
dryness uder reduced pressure. The silica gel containing
absorbed product was applied to a silica gel column and
purification (eluent: EtOAc/light petroleum, 9/1!1/0,
followed by MeOH/EtOAc, 0/1!1/20, v/v) afforded the
1
title compound 25 in 75% (0.040 g) as a colourless oil. H
NMR (CDCl3): d 5.04 (d, 1H, H4, J3,4¼4.8 Hz), 4.78 (d, 1H,
H7a, J7a,7b¼8.0 Hz), 4.60 (d, 1H, H7b, J7a,7b¼8.4 Hz), 4.22
(m, 1H, H2), 3.82 (dd, 1H, H3, J2,3¼8.4 Hz, J3,4¼4.8 Hz),
3.56 (m, 2H, 2£H1), 3.00 (s, 2H, 2£H6), 1.46 (s, 9H, tBu
Boc). 13C NMR (CDCl3): d 156.5 (C(O) Boc), 115.4 (CN),
87.9, 81.6, 72.9 (C2, C3, C4), 80.5 (C5), 79.9 (Cq Boc), 79.2
(C7), 41.0 (C1), 28.3 (tBu Boc), 23.4 (C6). ESI-MS: m/z
307.2 [MþNa]þ, 591.4 [2MþNa]þ.
4.1.12. 2,5-Anhydro-1-azido-1-deoxy-6-O-mesyl-4-O,5-
C-methylene-D-allitol (21). Compound 20 (0.12 g,
0.33 mmol) was dissolved in dioxane (3.3 mL) and 1 M
aq. NaOH (3.3 mL) was added. After stirring for 1 h, TLC
analysis showed complete conversion of the starting
material in a slightly lower running product. The reaction
mixture was neutralized with AcOH, concentrated and
traces of H2O were removed from the residue by
coevaporation with toluene (3£5 mL). Purification was
done by silica gel column chromatography (eluent: EtOAc/
light petroleum, 2/8!8/2, v/v) to furnish compound 21 in
89% (0.082 g) as a colourless oil. 1H NMR (CDCl3): d 5.06
(d, 1H, H4, J3,4¼4.8 Hz), 4.86 (d, 1H, H7a, J7a,7b¼8.3 Hz),
4.56 (d, 1H, H7b, J7a,7b¼8.3 Hz), 4.48 (d, 1H, H6a,
J6a,6b¼11.5 Hz), 4.40 (d, 1H, H6b, J6a,6b¼11.4 Hz), 4.25
(ddd, 1H, H2, J1a,2¼2.8 Hz, J1b,2¼5.2 Hz, J2,3¼8.0 Hz),
3.98 (dd, 1H, H3, J2,3¼8.0 Hz, J3,4¼4.8 Hz), 3.79 (dd, 1H,
H1a, J1a,2¼2.7 Hz, J1a,1b¼13.5 Hz), 3.48 (dd, 1H, H1b,
J1b,2¼5.2 Hz, J1a,1b¼13.5 Hz), 3.15 (bs, 1H, OH), 3.08 (s,
3H, CH3 Ms). 13C NMR (CDCl3): d 86.1, 81.6, 72.1 (C2,
C3, C4), 82.5 (C5), 77.3 (C7), 67.7 (C6), 50.8 (C1), 37.4
(CH3 Ms). ESI-MS: m/z 280.2 [MþH]þ, 302.0 [MþNa]þ,
581.2 [2MþNa]þ.
4.1.15. 3,6-Anhydro-7-tert-butoxycarbonylamino-2,7-
dideoxy-3-C,4-O-methylene-L-allo-heptonic acid (2).
Compound 25 (0.017 g, 0.06 mmol) was dissolved in a
mixture of dioxane/4 M aq. NaOH (2 mL, 1/1, v/v). The
reaction mixture was stirred at 608C for 4 h, after which
TLC analysis indicated the conversion of the starting
material into a lower running product. The solvent was
removed in vacuo and traces of H2O were removed from the
residue by coevaporation with toluene (3£2 mL). Purifi-
cation was accomplished by silica gel column chromato-
graphy (eluent: EtOAc/MeOH/H2O/Et3N, 50/45/5/3,
v/v/v/v) giving compound 2 as a colourless syrup in 88%
1
(0.016 g). H NMR, COSY, HMQC (400 MHz, CDCl3): d
4.92 (bs, 1H, HN), 4.61 (d, 1H, H8a, J8a,8b¼10.7 Hz), 4.31
(d, 1H, H8b, J8a,8b¼10.7 Hz), 4.14 (d, 1H, H4, J4,5¼4.9 Hz),
3.97 (m, 1H, H5), 3.93 (m, 1H, H6), 3.40 (ddd, 1H, H7a,
J¼3.8 Hz, J¼7.0 Hz, J7a,7b¼14.9 Hz), 3.33 (ddd, 1H, H7b,
J¼3.9 Hz, J¼5.6 Hz, J7a,7b¼14.9 Hz), 2.71 (d, 1H, H2a,
J2a,2b¼17.5 Hz), 2.55 (d, 1H, H2b, J2a,2b¼17.5 Hz), 1.44 (s,
9H, tBu Boc). 13C NMR (400 MHz, CDCl3): d 178.0 (C(O)
acid), 158.6 (C(O) Boc), 81.7 (C2), 74.6 (C4), 73.7 (C7),
72.2 (C3), 41.5 (C6), 39.7 (C1), 28.3 (tBu Boc). ESI-MS:
m/z 304.1 [MþH]þ, 326.0 [MþNa]þ, 342.1 [MþK]þ, 629.4
[2MþNa]þ.
4.1.13. 2,5-Anhydro-1-azido-6-C-cyano-1,6-dideoxy-4-
O,5-C-methylene-D-allitol (24). Compound 21 (0.13 g,
0.44 mmol) was dissolved in DMF (3 mL), NaCN (0.07 g,
1.32 mmol) was added and the resulting mixture was stirred
at 758C for 1.5 h. The reaction mixture was allowed to cool
to room temperature, and the solvent was removed in vacuo.
The crude product was purified by silica gel column
chromatography (eluent: EtOAc/light petroleum, 1/1!1/0,
v/v) to give compound 24 in 47% (0.043 g) as a colourless
oil. 1H NMR (CDCl3): d 5.05 (d, 1H, H4, J3,4¼4.8 Hz), 4.83
4.1.16. 2,5-Anhydro-3,4,6-tri-O-benzoyl-1-O-tert-butyl-
diphenylsilyl-D-allitol (26). Compound 11 (7.56 g,
16.1 mmol) was dissolved in pyridine (150 mL), TBDPSCl
(4.63 mL, 17.68 mmol) was added and the resulting mixture
stirred for 16 h. TLC analysis revealed complete conversion
of the starting material in a higher running product. MeOH
(1 mL) was added and the solvent was removed under
reduced pressure. The residue was taken up in EtOAc
(150 mL), washed with sat. aq. NaHCO3 (2£100 mL), brine
(100 mL), dried (MgSO4) and concentrated. Purification
was effected by silica gel column chromatography (eluent:
EtOAc/light petroleum, 0/1!3/7, v/v) to give 26 in 89%
(11.25 g) as a colourless oil. 1H NMR (CDCl3): d 8.11–7.92
(m, 6H, 6£Harom Bz), 7.81–7.66 (m, 4H, Harom TBDPS),
7.56–7.29 (m, 15H, 9£Harom Bz, 6£Harom TBDPS), 5.88
(dd, 1H, H3, J2,3¼4.4 Hz, J3,4¼5.5 Hz), 5.73 (t, 1H, H4,
J3,4¼J4,5¼5.5 Hz), 4.74–4.49 (m, 3H, H5, 2£H6), 4.41 (q,
1H, H2, J1a,2¼J1b,2¼J2,3¼3.7 Hz), 3.94 (d, 2H, 2£H1,
J¼3.3 Hz), 1.10 (s, 9H, tBu TBDPS). 13C NMR (CDCl3): d
165.8, 165.1, 164.9 (3£C(O) Bz), 135.4, 133.0, 132.7,
129.4, 128.0, 127.5 (CHarom Bz, TBDPS), 132.6, 129.1,
128.9 (Cq Bz, TBDPS), 82.8, 78.6, 72.7, 72.5 (C2, C3, C4,
C5), 64.5, 63.4 (C1, C6), 26.5 (tBu TBDPS), 18.9 (Cq tBu
TBDPS). ESI-MS: m/z 737.5 [MþNa]þ.
(d, 1H, H7a, J7a,7b¼8.4 Hz), 4.61 (d, 1H, H7b, J7a,7b
¼
8.4 Hz), 4.26 (ddd, 1H, H2, J1a,2¼2.9 Hz, J1b,2¼5.5 Hz,
J2,3¼8.4 Hz), 4.01 (dd, 1H, H3, J2,3¼8.4 Hz, J3,4¼4.8 Hz),
3.78 (dd, 1H, H1a, J1a,2¼2.9 Hz, J1a,1b¼13.5 Hz), 3.49
(dd, 1H, H1b, J1b,2¼5.5 Hz, J1a,1b¼13.5 Hz), 2.91 (s,
2H, 2£H6), 2.45 (bs, 1H, OH). 13C NMR (CDCl3): d
115.2 (CN), 87.4, 82.2, 72.4 (C2, C3, C4), 81.0 (C5),
79.2 (C7), 50.9 (C1), 23.4 (C6). ESI-MS: m/z 233.1
[MþNa]þ, 249.2 [MþK]þ, 443.3 [2MþNa]þ, 459.1
[2MþK]þ.
4.1.14. 2,5-Anhydro-1-tert-butoxycarbonylamino-6-C-
cyano-1,6-dideoxy-4-O,5-C-methylene-D-allitol
(25).
Compound 24 (0.040 g, 0.19 mmol) was dissolved in THF
(2 mL) and Me3P (0.21 mL of a 1 M solution in toluene)
was added. After 1 h, TLC analysis revealed that the starting
material was completely transformed into a lower running
product. The reaction mixture was cooled to 2208C and a
solution of Boc-ON (0.052 g, 0.21 mmol) in toluene
(0.5 mL) was added slowly. After stirring for 5 h, the
solvent was removed and the residue was redissolved in
THF (2 mL), mixed with silica gel and evaporated to

2430
R. M. van Well et al. / Tetrahedron 59 (2003) 2423–2434
4.1.17. 2,5-Anhydro-1-O-tert-butyldiphenylsilyl-3,4-O-
isopropylidene-D-allitol (28). Compound 26 (11.25 g,
15.75 mmol) was converted into compound 28 as described
for the azide analog 15. Purification of the crude product by
column chromatography (eluent: EtOAc/light petroleum
1/0!1/1, v/v) afforded 28 as a pale yellow oil in 94%
(1.47 g, 2.34 mmol) was dissolved in DCM (15 mL), FeCl3
(2.21 g, 8.19 mmol) and MeOH (0.19 mL, 4.68 mmol) were
added and the resulting mixture was stirred for 1.5 h. After
addition of sat. aq. NaHCO3 (10 mL), the solution was
extracted with EtOAc (3£20 mL). The combined organic
layers were washed with brine (50 mL), dried (MgSO4) and
concentrated. The crude product was purified by silica gel
column chromatography (eluent: EtOAc/light petroleum,
2/8!8/2, v/v) to afford 31 as a pale yellow oil in 53%
(0.73 g) together with 17% (0.25 g) of starting material. 1H
NMR (CDCl3): d 7.66 (m, 4H, Harom TBDPS), 7.40 (m,
Harom TBDPS), 4.51 (s, 2H, 2£H6), 4.32 (m, 2H, H2, H4),
4.15 (d, 1H, H7a, J7a,7b¼6.9 Hz), 4.08 (d, 1H, H7b,
J7a,7b¼7.0 Hz), 4.02 (m, 1H, H3), 3.85 (dd, 1H, H1a,
1
(6.58 g). H NMR (CDCl3): d 7.70–7.65 (m, 4H, Harom
TBDPS), 7.40 (m, 6H, Harom TBDPS), 4.80 (dd, 1H, H4,
J3,4¼6.2 Hz, J4,5¼4.4 Hz), 4.70 (dd, 1H, H3, J2,3¼3,3 Hz,
J3,4¼6.6 Hz), 4.17 (q, 1H, H2, J1a,2¼J1b,2¼J2,3¼3.3 Hz),
4.05 (dt, 1H, H5, J4,5¼4.4 Hz, J5,6a¼J5,6b¼2.9 Hz), 3.90
(dd, 1H, H1a, J1a,2¼2.9 Hz, J1a,1b¼11.3 Hz), 3.79 (dd, 1H,
H6a, J5,6a¼2.9 Hz, J6a,6b¼8.8 Hz), 3.69 (dd, 1H, H6b,
J5,6b¼2.9 Hz), 3.65 (dd, 1H, H1b, J1b,2¼3.3 Hz, J1a,1b
¼
12.1 Hz), 2.50 (bs, 1H, OH), 1.53, 1.36 (2£s, 6H, 2£CH3
isoprop), 1.08 (s, 9H, tBu TBDPS). 13C NMR (CDCl3): d
135.2, 135.1, 129.5, 127.4 (CHarom TBDPS), 132.5 (Cq
TBDPS), 113.1 (Cq isoprop), 84.6, 84.3, 81.7, 81.1 (C2, C3,
C4, C5), 63.9, 62.8 (C1, C6), 27.1, 25.1 (2£CH3 isoprop),
26.4 (tBu TBDPS), 18, 7 (Cq tBu TBDPS). ESI-MS: m/z
465.1 [MþNa]þ.
J1a2¼3.7 Hz, J1a,1b¼11.3 Hz), 3.76 (dd, 1H, H1b, J1b,2¼
3.7 Hz, J1a,1b¼11.3 Hz), 3.06, 2.95 (2£s, 6H, 2£CH3 Ms),
1.07 (s, 9H, tBu TBDPS). 13C NMR (CDCl3): d 135.3,
129.7, 127.6 (CHarom TBDPS), 132.8, 132.7 (2£Cq
TBDPS), 83.0, 73.2, 70.9 (C2, C3, C4), 82.5 (C5), 68.8,
68.3, 63.4 (C1, C6, C7), 37.1, 36.9 (2£CH3 Ms), 26.6 (tBu
TBDPS), 19.0 (Cq TBDPS). ESI-MS: m/z 611.3 [MþNa]þ.
4.1.18. 2,5-Anhydro-1-O-tert-butyldiphenylsilyl-3,4-O-
isopropylidene-5-C-hydroxy methyl-D-allitol (29). Com-
pound 28 (1.91 g, 4.33 mmol) was oxidized and treated with
CH2O, followed by NaBH4 as described for compound 17.
Purification of the crude mixture by column chromato-
graphy (eluent: EtOAc/light petroleum 1/0!1/1, v/v)
afforded the title compound 29 in 66% (1.14 g) as colourless
oil, together with 9% of starting material (0.16 g). 1H NMR
(CDCl3): d 7.69–7.64 (m, 4H, Harom TBDPS), 7.45–7.36
(m, 6H, Harom TBDPS), 4.94 (dd, 1H, H3, J2,3¼5.1 Hz,
J3,4¼6.6 Hz), 4.84 (d, 1H, H4, J3,4¼6.2 Hz), 4.08 (m, 1H,
H2), 3.90 (dd, 1H, H1a, J1a,2¼2.9 Hz, J1a,1b¼11.7 Hz),
3.81–3.67 (m, 5H, H1b, 2£H6, 2£H7), 2.84, 2.36 (2£bs,
2H, 2£OH), 1.54, 1.37 (2£s, 6H, 2£CH3 isoprop), 1.07 (s,
9H, tBu TBDPS). 13C NMR (CDCl3): d 135.4, 135.3, 129.7,
129.7, 127.6 (CHarom TBDPS), 132.5, 132.4 (2£Cq
TBDPS), 113.5 (Cq isoprop), 86.4 (C5), 84.3, 83.6, 81.3
(C2,C3, C4), 65.5, 63.9, 62.8(C1,C6,C7),26.6(tBuTBDPS),
18, 9 (Cq tBu TBDPS). ESI-MS: m/z 495.5 [MþNa]þ.
4.1.21. 2,5-Anhydro-1-O-tert-butyldiphenylsilyl-6-O-
mesyl-4-O,5-C-methylene-D-allitol (32). Compound 31
(2.06 g, 3.5 mmol) was converted into compound 32 as
previously described for the azide analogue 21. The crude
product was purified by column chromatography (eluent:
EtOAc/light petroleum, 1/9!6/4, v/v) to give 32 in 85%
(1.46 g) as a colourless syrup. 1H NMR (CDCl3): d 7.69 (m,
4H, Harom TBDPS), 7.39 (m, Harom TBDPS), 5.02 (d, 1H,
H4, J3,4¼4.7 Hz), 4.82 (d, 1H, H7a, J7a,7b¼8.2 Hz), 4.53 (d,
1H, H7b, J7a,7b¼8.2 Hz), 4.43 (d, 1H, H6a, J6a,6b¼11.3 Hz),
4.38 (d, 1H, H6b, J6a,6b¼11.3 Hz), 4.17 (ddd, 1H, H2,
J1a,2¼2.5 Hz, J1b,2¼4.0 Hz, J2,3¼8.0 Hz), 4.09 (m, 1H, H3),
4.06 (dd, 1H, H1a, J1a,2¼2.4 Hz, J1a,1b¼11.6 Hz), 3.95 (dd,
1H, H1b, J1b,2¼4.2 Hz, J1a,1b¼11.6 Hz), 2.93 (s, 3H, CH3
Ms), 1.07 (s, 9H, tBu TBDPS). 13C NMR (CDCl3): d 135.0,
129.3, 127.3 (CHarom TBDPS), 132.7, 132.6 (2£Cq
TBDPS), 86.0, 82.8, 70.8 (C2, C3, C4), 81.6 (C5), 77.0
(C7), 67.6, 62.2 (C1, C6), 36.9 (CH3 Ms), 26.3 (tBu
TBDPS), 18.8 (Cq TBDPS). ESI-MS: m/z 515.3 [MþNa]þ,
531.2 [MþK]þ.
4.1.19. 2,5-Anhydro-1-O-tert-butyldiphenylsilyl-3,4-O-
isopropylidene-5-C-mesyloxy methyl-6-O-mesyl-D-allitol
(30). Compound 29 (1.14 g, 2.51 mmol) was mesylated as
described for compound 19 and subsequent purification by
column chromatography (eluent: EtOAc/light petroleum
1/0!4/6, v/v) to give the title compound 30 in 93% (1.47 g)
as a colourless oil. 1H NMR (CDCl3): d 7.67–7.62 (m, 4H,
Harom TBDPS), 7.42 (m, 6H, Harom TBDPS), 4.82 (dd, 1H,
4.1.22. 2,5-Anhydro-6-azido-1-O-tert-butyldiphenylsilyl-
6-deoxy-4-O,5-C-methylene-D-allitol (33). Compound 32
(0.40 g, 0.81 mmol) was dissolved in DMF (3 mL), NaN3
(0.16 g, 2.43 mmol) was added and the reaction mixture was
stirred for 2 h. H2O (3 mL) was added, and the resulting
mixture was extracted with EtOAc (3£5 mL). The com-
bined organic layers were washed with brine (5 mL), dried
(MgSO4) and concentrated. The residue was purified by
column chromatography (eluent: EtOAc/light petroleum,
1/9!1/1, v/v) to give 33 in 95% (0.34 g) as a colourless
H3, J2,3¼3.7 Hz, J3,4¼6.2 Hz), 4.74 (d, 1H, H4, J3,4
¼
6.6 Hz), 4.41–4.07 (m, 3H, H2, 2£H6), 3.80 (dd, 1H, H1a,
J1a,2¼3.7 Hz, J1a,1b¼11.3 Hz), 3.72 (dd, 1H, H1b, J1b,2
¼
1
4.0 Hz, J1a,1b¼11.3 Hz), 3.06, 2.95 (2£s, 6H, 2£CH3 Ms),
1.53, 1.33 (2£s, 6H, 2£CH3 isoprop), 1.07 (s, 9H, tBu
TBDPS). 13C NMR (CDCl3): d 135.4, 129.8, 127.7 (CHarom
TBDPS), 132.6 (Cq TBDPS), 114.4 (Cq isoprop), 98.2 (C5),
84.4, 83.0, 81.7, (C2, C3, C4), 67.9, 64.0, 60.1 (C1, C6, C7),
37.4, 37.1(2£CH3 Ms), 26.9(tBuTBDPS), 26.7, 24.6(2£CH3
isoprop), 19.0 (Cq TBDPS). ESI-MS: m/z 651.3 [MþNa]þ.
syrup. H NMR (CDCl3): d 7.70 (m, 4H, Harom TBDPS),
7.39 (m, Harom TBDPS), 4.95 (d, 1H, H4, J3,4¼4.4 Hz), 4.76
(d, 1H, H7a, J7a,7b¼8.0 Hz), 4.55 (d, 1H, H7b,
J7a,7b¼8.0 Hz), 4.15 (m, 2H, H2, H3), 4.05 (dd, 1H, H1a,
J1a,2¼2.9 Hz, J1a,1b¼11.3 Hz), 3.95 (dd, 1H, H1b, J1b,2
¼
4.0 Hz, J1a,1b¼11.3 Hz), 3.60 (d, 1H, H6a, J6a,6b¼13.2 Hz),
3.51 (d, 1H, H6b, J6a,6b¼13.2 Hz), 1.07 (s, 9H, tBu
TBDPS). 13C NMR (CDCl3): d 135.4, 129.6, 127.5
(CHarom TBDPS), 133.0 (Cq TBDPS), 87.1, 83.2, 71.5
(C2, C3, C4), 83.5 (C5), 78.3 (C7), 62.7 (C1), 52.4 (C6),
4.1.20. 2,5-Anhydro-1-O-tert-butyldiphenylsilyl-5-C-
mesyloxymethyl-6-O-mesyl-D-allitol (31). Compound 30

R. M. van Well et al. / Tetrahedron 59 (2003) 2423–2434
2431
26.6 (tBu TBDPS), 19.1 (Cq TBDPS). ESI-MS: m/z 462.2
[MþNa]þ, 901.5 [2MþNa]þ.
(C6), 28.8 (tBu Boc). ESI-MS: m/z 304.1 [MþH]þ, 325.8
[MþNa]þ, 629.7 [2MþNa]þ.
4.1.23. 2,5-Anhydro-6-tert-butoxycarbonylamino-1-O-
tert-butyldiphenylsilyl-6-deoxy-4-O,5-C-methylene-D-
allitol (34). Compound 33 (0.34 g, 0.77 mmol) was
transformed into the Boc-protected analogue 34 as
described for compound 23. Purification of the crude
product was accomplished by column chromatography
(eluent: EtOAc/light petroleum, 1/9!1/1, v/v) to give 34
in 94% (0.36 g) as a colourless oil. 1H NMR (CDCl3): d 7.70
(m, 4H, Harom TBDPS), 7.40 (m, Harom TBDPS), 4.94 (d,
1H, H4, J3,4¼3.7 Hz), 4.73 (d, 1H, H7a, J7a,7b¼7.7 Hz),
4.64 (bs, 1H, HN), 4.48 (d, 1H, H7b, J7a,7b¼7.7 Hz), 4.07
(m, 3H, H2, H3, H1a), 3.92 (dd, 1H, H1b, J1b,2¼3.7 Hz,
J1a,1b¼11.7 Hz), 3.69 (dd, 1H, H6a, J6a,NH¼8.0 Hz,
J6a,6b¼14.0 Hz), 3.32 (dd, 1H, H6b, J6b,NH¼4.8 Hz,
J6a,6b¼13.9 Hz), 1.42 (s, 9H, tBu Boc), 1.07 (s, 9H, tBu
TBDPS). 13C NMR (CDCl3): d 155.9 (C(O) Boc), 135.4,
129.6, 127.5 (CHarom TBDPS), 133.0 (Cq TBDPS), 87.3,
82.6, 71.3 (C2, C3, C4), 83.5 (C5), 79.4 (Cq Boc), 78.6
(C7), 62.4 (C1), 42.6 (C6), 28.6 (tBu Boc), 26.7 (tBu
TBDPS), 19.1 (Cq TBDPS). ESI-MS: m/z 536.2 [MþNa]þ,
1049.6 [2MþNa]þ.
4.1.26. Boc-BSAA1-Phe-Leu-OMe (36). A solution of
Boc-Phe-Leu-OMe (0.055 g, 0.14 mmol) in DCM/TFA
(2 mL, 1/1, v/v) was stirred for 5 min. toluene was added
and the reaction mixture subsequently concentrated. Traces
of acid were removed from the residue by coevaporation
with toluene (3£2 mL) and the residue was dissolved in
DMF (1 mL). BSAA 1 (0.038 g, 0.13 mmol) was added and
the resulting mixture was cooled to 08C. HOBt (0.019 g,
0.14 mmol) and EDC·HCl (0.027 g, 0.14 mmol) were added
and the reaction mixture was neutralized with NMM. After
stirring for 16 h the reaction mixture was concentrated and
the residue redissolved in EtOAc (5 mL). The organic phase
was washed with H2O (3 mL), aq. NaHCO3 (2£3 mL), H2O
(3 mL), KHSO4 (2£3 mL) and brine (3 mL), dried (MgSO4)
and concentrated. Purification by silica gel column
chromatography (eluent: EtOAc/light petroleum, 1/1!1/0,
v/v) afforded 36 as an amorphous white solid in 45%
1
(0.033 g), mp 147–1498C. H NMR (CDCl3): d 7.30 (m,
6H, 5£Harom Phe, HN-Phe), 6.51 (d, 1H, HN-Leu,
J¼7.6 Hz), 5.20 (d, 1H, H7a, J7a,7b¼7.5 Hz), 5.15 (t, 1H,
HN-LSA1, J¼6.2 Hz), 4.80 (d, 1H, H4, J3,4¼4.6 Hz), 4.72
(m, 1H, Ha-Phe), 4.52 (m, 1H, Ha-Leu), 4.38 (d, 1H, H7b,
J7a,7b¼7.5 Hz), 4.21 (m, 1H, H2), 3.73 (s, 3H, OMe), 3.57
(dd, 1H, H3, J¼3.5 Hz, J¼5.9 Hz), 3.53 (m, 1H, H1a), 3.52
(m, 1H, H1b), 3.18 (dd, 1H, Hba-Phe, Ja,ba¼6.2 Hz,
Jba,bb¼14.0 Hz), 3.00 (dd, 1H, Hbb-Phe, Ja,bb¼8.4 Hz,
Jba,bb¼13.9 Hz), 1.62–1.46 (m, 3H, 2£Hb-Leu, Hg-Leu),
1.44 (s, 9H, tBu Boc), 0.89 (d, 3H, Hd-Leu, J¼3.5 Hz), 0.88
(d, 3H, Hd-Leu, J¼3.4 Hz). 13C NMR (CDCl3): d 172.8,
170.3, 167.0 (3£C(O), Leu, Phe, SAA-C1), 156.5 (C(O)
Boc), 136.4 (Cq Phe), 129.4, 128.5, 127.1 (CHarom Phe),
87.6 (C4), 83.8 (C5), 82.9 (C2), 80.0 (Cq Boc), 77.6 (C7),
72.8 (C3), 53.9 (Ca-Phe), 52.3 (OMe), 51.0 (Ca-Leu), 41.8
(C6), 41.3 (Cb-Leu), 37.8 (Cb-Phe), 28.4 (tBu Boc), 24.8
(Cg-Leu), 22.6, 21.9 (2£Cd-Leu). ESI-MS: m/z 564.4
[MþH]þ, 586.2 [MþNa]þ, 1149.6 [2MþNa]þ.
4.1.24. 2,5-Anhydro-6-tert-butoxycarbonylamino-6-
deoxy-4-O,5-C-methylene-D-allitol (35). Compound 34
(0.36 g, 0.68 mmol) and TBAF·3H2O (0.24 g, 0.76 mmol)
were dissolved in THF (2 mL). The reaction mixture was
stirred for 1 h, after which TLC analysis revealed complete
conversion of the starting material in a lower running
compound. The solvent was removed under reduced
pressure and the resulting crude oil was purified by silica
gel column chromatography (eluent: EtOAc/light
petroleum, 3/7!8/2, v/v) to yield 35 quantitatively
1
(0.20 g) as a colourless oil. H NMR (CDCl3): d 5.12 (bs,
1H, HN), 4.97 (d, 1H, H4, J3,4¼4.8 Hz), 4.76 (d, 1H, H7a,
J7a,7b¼7.7 Hz), 4.51 (d, 1H, H7b, J7a,7b¼8.0 Hz), 4.14 (ddd,
1H, H2, J1a,2¼2.6 Hz, J1b,2¼4.0 Hz, J2,3¼8.4 Hz), 4.03 (dd,
1H, H1a, J1,2¼2.7 Hz, J1a,1b¼12.4 Hz), 3.96 (m, 1H, H3),
3.81 (dd, 1H, H1b, J1b,2¼4.0 Hz, J1a,1b¼12.4 Hz), 3.63 (dd,
1H, H6a, J6a,NH¼7.3 Hz, J6a,6b¼14.6 Hz), 3.36 (dd, 1H,
H6b, J6b,NH¼5.1 Hz, J6a,6b¼14.6 Hz), 2.87 (bs, 1H, OH),
1.44 (s, 9H, tBu Boc). 13C NMR (CDCl3): d 156.5 (C(O)
Boc), 87.5, 81.8, 70.9 (C2, C3, C4), 83.9 (C5), 81.8 (Cq
Boc), 78.4 (C7), 60.4 (C1), 42.2 (C6), 27.9 (tBu Boc). ESI-
MS: m/z 276.1 [MþH]þ, 298.2 [MþNa]þ.
4.1.27. Boc-Tyr(tBu)-BSAA1-Phe-Leu-OMe (37). Com-
pound 36 (0.033 g, 0.06 mmol) was dissolved in TFA/DCM
(1 mL, 1/1, v/v) and the resulting mixture was stirred for
5 min, toluene was added and the reaction mixture
subsequently concentrated. Traces of acid were removed
from the residue by coevaporation with toluene (3£2 mL)
and the residue was dissolved in DMF (1 mL), Boc-Tyr-
(tBu)-OH (0.022 g, 0.065 mmol) was added and the reaction
mixture was cooled to 08C. HOBt (0,01 g, 0.065 mmol) and
EDC·HCl (0.012 g, 0.065 mmol) were added and the
reaction mixture was neutralized with NMM. After 16 h
the solvent was removed under reduced pressure and the
residue was taken up in EtOAc (5 mL) and washed with
H2O (3 mL), sat. aq. NaHCO3 (2£3 mL), H2O (3 mL), 1 M
aq. KHSO4 (2£3 mL) and brine (3 mL), the organic phase
was dried (MgSO4) and concentrated. The crude product
was applied to a silica gel column and eluted with
EtOAc/light petroleum (1/1!1/0, v/v) to give the title
compound 37 in 70% (0.033 g) as a white solid, mp 141–
4.1.25. 2,5-Anhydro-6-tert-butoxycarbonylamino-6-
deoxy-4-O,5-C-methylene-D-allo-hexonic acid (3). Oxi-
dation of compound 35 (0.20 g, 0.68 mmol) was performed
as described for compound 1 to afford 3 as a colourless oil in
60% (0.123 g) after purifucation by column chromato-
graphy (eluent: EtOAc/MeOH/H2O/Et3N, 50/45/5/3,
v/v/v/v). nmax (neat): 3256.5, 1697.7, 1577.7, 1421.7,
1165.7 cm21
.
1H NMR, COSY, HMQC (400 MHz,
MeOD): d 4.94 (d, 1H, H4, J3,4¼4.2 Hz), 4.74 (d, 1H,
H7a, J7a,7b¼7.9 Hz), 4.51 (d, 1H, H2, J2,3¼8.8 Hz), 4.49 (d,
1H, H7b, J7a,7b¼7.7 Hz), 3.86 (dd, 1H, H3, J2,3¼8.9 Hz,
J3,4¼4.2 Hz), 3.55 (d, 1H, H6a, J6a,6b¼15.0 Hz), 3.42 (d,
1H, H6b, J6a,6b¼15.0 Hz), 1.42 (s, 9H, tBu Boc). 13C NMR
(MeOD): d 177.8 (C1), 159.1 (C(O) Boc), 88.8 (C4), 86.2
(C5), 81.3 (C2), 80.6 (Cq Boc), 79.7 (C7), 75.6 (C3), 43.2
1
1438C. H NMR (CDCl3): d 7.29–7.19 (m, 7H, 5£Harom
Phe, HN-Phe, HN-SAA), 7.17 (d, 2H, 2£Harom Tyr,
J¼8.2 Hz), 6.88 (d, 3H, 2£Harom Tyr, HNLeu, J¼8.4 Hz),
5.30 (d, 1H, HN-Tyr, J¼7.2 Hz), 5.15 (m, 2H, Ha-Phe,

2432
R. M. van Well et al. / Tetrahedron 59 (2003) 2423–2434
1
H7a), 4.60 (m, 1H, Ha-Tyr), 4.46 (q, 1H, Ha Leu,
J¼6.8 Hz), 4.20 (m, 1H, H4), 4.00 (m, 1H, H7b), 3.67 (s,
3H, OMe), 3.60 (dd, 1H, H1a, J¼6.6 Hz, J¼12.6 Hz),
3.22–3.16 (m, 2H, H3, Hba-Phe), 3.05–2.88 (m, 4H,
2£Hb-Tyr, Hbb-Phe, H1b), 1.62–1.48 (m, 3H, 2£Hb-Leu,
Hg-Leu), 1.44, 1.31 (2£s, 18H, tert-Bu Boc, tert-Bu), 0.99
(d, 3H, Hd-Leu, Jg,d¼5.4 Hz), 0.94 (d, 3H, Hd-Leu,
Jg,d¼5.9 Hz). 13C NMR (CDCl3): d 173.0, 172.4, 171.5,
167.4 (4£C(O), Tyr, SAA, Phe, Leu), 156.0 (C(O) Boc),
154.3 (Cz-Tyr), 137.4, 131.6 (Cg-Tyr, Cg-Phe), 130.0,
124.1 (CHarom Tyr), 129.4, 128.3, 126.8 (CHarom Phe), 87.8
(C4), 83.6 (C5), 82.6 (C2), 80.12 (Cq Boc), 78.4 (C7), 73.0
(C3), 56.1 (Ca-Tyr), 54.4 (Ca-Phe), 52.1 (OMe), 51.5 (Ca-
Leu), 40.9 (C1, Cb-Leu), 38.6 (Cb-Phe), 38.2 (Cb-Tyr),
29.7 (Cq tert-Bu), 28.8, 28.4 (tert-Bu Boc, tert-Bu), 24.8
(Cg-Leu), 22.5, 22.2 (2£Cd-Leu). ESI-MS: m/z 783.5
[MþH]þ, 805.6 [MþNa]þ.
(0.029 g) as a colourless oil. H NMR, COSY (300 MHz,
CDCl3): d 5.31 (d, 1H, H4, J3,4¼4.4 Hz), 4.82 (d, 1H, H7a,
J7a,7b¼8.2 Hz), 4.80 (dd, 1H, H3, J2,3¼8.6 Hz, J3,4
¼
¼
4.4 Hz), 4.63 (m, 1H, H2), 4.58 (d, 1H, H7b, J7a,7b
8.2 Hz), 4.48 (d, 1H, H6a, J6a,6b¼11.4 Hz), 4.41 (d, 1H,
H6b, J6a,6b¼11.4 Hz), 3.77 (dd, 1H, H1a, J1a,2¼2.7 Hz,
J1a,1b¼13.6 Hz), 3.44 (dd, 1H, H1b, J1b,2¼4.8 Hz, J1a,1b
¼
13.6 Hz), 3.08 (s, 3H, Ms), 2.13 (s, 3H, CH3 Ac). ESI-MS:
m/z 322.1 [MþH]þ, 344.0 [MþNa]þ, 665.2 [2MþNa]þ.
4.1.30. 2,5-Anhydro-3-O-acetyl-1-O-tert-butyldiphenyl-
silyl-6-O-mesyl-4-O,5-C-methylene-D-allitol (39). Com-
pound 32 (0.059 g, 0.1 mmol) was dissolved in pyridine
(1 mL) and Ac2O (0.019 mL, 0.2 mmol) was added. The
reaction mixture was stirred for 3 h, and then concentrated
under reduced pressure. The residue was taken up in EtOAc
(5 mL), washed with sat. aq. NaHCO3 (2£3 mL), brine
(3 mL), dried (MgSO4) and concentrated. Purification was
affected by silica gel column chromatography (eluent:
EtOAc/light petroleum, 0/1!7/3, v/v) to give 39 in 88%
4.1.28. Tyr-BSAA1-Phe-Leu-OMe (4). Compound 37
(0.033 g, 0.042 mmol) was dissolved in a mixture of
TFA/H2O (1 mL, 9/1, v/v) and the reaction mixture was
stirred for 1 h and subsequently concentrated. Traces of
H2O and acid were removed from the residue by
coevaporation with toluene and the residue was applied to
a silica gel column. Elution with DCM!MeOH/DCM (1/9,
v/v) afforded compound 4 quantitatively (0.026 g) as a
colourless syrup. nmax (neat): 3394.4, 3274.9, 2958.6,
2920.0, 1735.8, 1662.5, 1515.9, 1442.7, 1207.4, 1137.9,
1029.9, 840.9, 821.6, 702.0 cm21. 1H NMR (CDCl3): d 7.31
(d, 2H, Hd-Phe, J¼7.3 Hz), 7.26 (t, 2H, H1-Phe, J¼7.4 Hz),
7.19 (t, 1H, Hz-Phe, J¼7.3 Hz), 7.09 (d, 2H, 2£Harom Tyr,
J¼8.4 Hz), 6.67 (d, 2H, 2£Harom Tyr, J¼8.5 Hz), 5.09 (d,
1H, H7a, J7a,7b¼7.2 Hz), 4.85 (dd, 1H, Ha-Phe, Ja,ba¼5.1
Hz, Ja,bb¼9.4 Hz), 4.62 (d, 1H, H4, J3,4¼4.5 Hz), 4.57 (t,
1H, Ha-Leu, Ja,b¼7.7 Hz), 4.25 (dt, 1H, H2, J¼2.7 Hz,
J¼8.3 Hz), 4.20 (d, 1H, H7b, J7a,7b¼7.2 Hz), 3.81 (dd, 1H,
H1a, J1a,2¼9.5 Hz, J1a,1b¼14.0 Hz), 3.76 (t, 1H, Ha-Tyr,
Ja,b¼5.4 Hz), 3.63 (s, 3H, OMe), 3.59 (dd, 1H, H3,
1
(0.053 g) as a colourless oil. H NMR, COSY (300 MHz,
CDCl3): d 7.66 (m, 4H, Harom TBDPS), 7.39 (m, 6H, Harom
TBDPS), 5.29 (d, 1H, H4, J3,4¼4.4 Hz), 4.92 (dd, 1H, H3,
J3,4¼4.4 Hz, J2,3¼8.4 Hz), 4.79 (d, 1H, H7a, J7a,7b
¼
8.1 Hz), 4.57 (d, 1H, H7b, J7a,7b¼8.2 Hz), 4.53 (m, 1H,
H2), 4.42 (2H, 2£H6), 4.03 (dd, 1H, H1a, J1a,2¼2.3 Hz,
J1a,1b¼11.8 Hz), 3.88 (dd, 1H, H1b, J1b,2¼3.7 Hz,
J1a,1b¼11.6 Hz), 2.96 (s, 3H, OMs), 2.07 (s, 3H, CH3 Ac),
1.06 (s, 9H, tert-Bu TBDPS). ESI-MS: m/z 557.2 [MþNa]þ,
1091.3 [2MþNa]þ.
4.1.31. Tricyclic compound (41). Compound 21 (0.50 g,
1.78 mmol) was dissolved in THF (10 mL), and Me3P
(2.14 mL of a 1 M solution in toluene) was added. After 1 h,
TLC analysis revealed that the starting material was
completely transformed into a lower running product. The
reaction mixture was cooled to 2208C and a solution of
Boc-ON (0.52 g, 2.14 mmol) in toluene (0.5 mL) was added
slowly. After stirring for 5 h, the solvent was removed and
the residue was redissolved in THF (10 mL), mixed with
silica gel and evaporated to dryness under reduced pressure.
The silica gel containing absorbed product was applied to a
silica gel column and purification (eluent: EtOAc/light
petroleum, 9/1!1/0, followed by MeOH/EtOAc,
0/1!1/20, v/v) afforded 11% of 40 (0.07 g) together with
60% of 41 (0.17 g), both colourless oils. 40: 13C NMR
(CDCl3): d 86.5, 81.2, 72.7 (C2, C3, C4), 82.1 (C5), 79.6
(Cq Boc), 77.1 (C7), 67.7 (C6), 40.9 (C1), 37.6 (CH3 Ms),
28.2 (tBu Boc). 41: 13C NMR (CDCl3): d 86.8, 81.7, 72.5
(C2, C3, C4), 85.3 (C5), 77.6 (C7), 62.4 (C6), 51.0 (C1).
J2,3¼8.0 Hz, J3,4¼4.5 Hz), 3.44 (dd, 1H, H1b, J1b,2
¼
2.6 Hz, J1a,1b¼14.5 Hz), 3.26 (dd, 1H, Hba-Phe, Ja,ba¼5.1
Hz, Jba,bb¼13.8 Hz), 3.07 (dd, 1H, Hbb-Phe, Ja,bb¼9.5 Hz,
Jba,bb¼13.7 Hz), 2.95 (d, 2H, 2£Hb-Tyr, Ja,b¼5.4 Hz),
1.59 (m, 1H, Hg-Leu), 1.55 (m, 2H, Hb-Leu), 0.81 (d, 3H,
Hd-Leu, Jg,d¼6.5 Hz), 0.80 (d, 3H, Hd-Leu, Jd,g¼6.5 Hz).
13C NMR (CDCl3): d 176.9, 173.3, 171.8, 167.6 (4£C(O),
Tyr, LSA1, Phe, Leu), 156.9 (Cz-Tyr), 138.5 (Cg-Phe),
131.7, 115.7 (CHarom Tyr), 130.5, 128.9, 127.3 (CHarom
Phe), 89.3 (C4), 84.9 (C5), 83.2 (C2), 77.5 (C7), 75.2 (C3),
60.1 (Ca-Tyr), 54.9 (Ca-Phe), 52.4 (OMe), 51.5 (Ca-Leu),
43.4 (C1), 41.4 (Cb-Leu), 38.8 (Cb-Phe), 36.9 (Cb-Tyr),
25.3 (Cg-Leu), 23.1, 21.9 (2£Cd-Leu). ESI-MS: m/z 627.5
[MþH]þ, 649.4 [MþNa]þ.
Acknowledgements
4.1.29. 2,5-Anhydro-3-O-acetyl-1-azido-1-deoxy-6-O-
mesyl-4-O,5-C-methylene-D-allitol (38). Compound 21
(0.028 g, 0.1 mmol) was dissolved in pyridine (1 mL) and
Ac2O (0.019 mL, 0.2 mmol) was added. The reaction
mixture was stirred for 3 h, and then concentrated under
reduced pressure. The residue was taken up in EtOAc
(5 mL), washed with sat. aq. NaHCO3 (2£3 mL), brine
(3 mL), dried (MgSO4) and concentrated. Purification was
effected by silica gel column chromatography (eluent:
EtOAc/light petroleum, 0/1!7/3, v/v) to give 38 in 90%
The authors would like to thank Hans van der Elst for
measuring Mass-spectra and Kees Erkelens for measuring
600 MHz NMR spectra.
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