A further contribution to the study of sagittamide a: Synthesis of a pivotal intermediate belonging to a rare L-series

Article abstract of DOI:10.3390/molecules17077709

A key saggitamide intermediate corresponding to a rare sugar framework has been obtained. This approach should help to establish the overall configuration of more complex structures of the sagittamide family.

Full text of DOI:10.3390/molecules17077709

Molecules 2012, 17, 7709-7721; doi:10.3390/molecules17077709
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Further Contribution to the Study of Sagittamide A:
Synthesis of a Pivotal Intermediate Belonging to a Rare L-Series
Anne Humbert, Karen Plé, Dominique Harakat, Agathe Martinez and Arnaud Haudrechy *
Institut de Chimie Moléculaire de Reims, UMR CNRS 7312, Université de Reims, BP 1039,
F-51687 REIMS Cedex, France; E-Mails: anne.bak@hotmail.fr (A.H.); karen.ple@univ-reims.fr (K.P.);
dominique.harakat@univ-reims.fr (D.H.); agathe.martinez@univ-reims.fr (A.M.)
* Author to whom correspondence should be addressed; E-Mail: arnaud.haudrechy@univ-reims.fr;
Tel.: +33-2691-3236; Fax: +33-2691-3166.
Received: 3 May 2012; in revised form: 13 June 2012 / Accepted: 18 June 2012 /
Published: 25 June 2012
Abstract: A key saggitamide intermediate corresponding to a rare sugar framework has
been obtained. This approach should help to establish the overall configuration of more
complex structures of the sagittamide family.
Keywords: sagittamide; L-altrose; L-talose; epoxide opening; asymmetric dihydroxylation
1. Introduction
Sagittamides A–F (1–6, Figure 1) are unprecedented marine natural products isolated from an
unidentified tropical didemnid tunicate collected in Micronesia and described by Molinski [1,2]. These
compounds are characterized by an -dicarboxylic acid (C-26 or C-28) that is acylated at each
terminus by a different amino acid (L-ornithine or L-lysine and L-valine), and contain a stereocluster of
contiguous polyacetoxy 5,6,7,8,9,10-hexaols. After a first prediction of the stereochemistry of
Sagittamide A 1 using a detailed 1H-NMR analysis of the 3JH,H profiles [3], a second publication gave
another stereochemical attribution, discussing a similar approach but reaching different conclusions
(with 2D heteronuclear NMR experiments) [4], and finally a third publication extended the uncertainty,
describing three other structures (only 1a being compatible with Residual Dipolar Coupling Enhanced
NMR) [5].

Molecules 2012, 17
7710
Figure 1. Structures proposed for Sagittamides A–F 1–6.
HOOC
H2N
O AcO AcO AcO
H
N
3
iPr
Sagittamide A 1
Sagittamide B 2
Sagittamide C 3
N
H
3
15
O
COOH
OAc OAc OAc
HOOC
O AcO AcO AcO
H
N
3
H2N
iPr
N
H
3
15
OH OH OAc O
COOH
HOOC
O AcO AcO AcO
H
N
3
H2N
iPr
N
H
3
17
O
COOH
OAc OAc OAc
HOOC
O AcO AcO AcO
H
N
3
H2N
iPr
Sagittamide D 4
Sagittamide E 5
Sagittamide F 6
N
H
4
15
O
3
COOH
OAc OAc OAc
HOOC
O AcO AcO AcO
H
N
H2N
iPr
N
H
4
15
O
3
COOH
OAc OAc OAc
HOOC
O AcO AcO AcO
H
N
H2N
iPr
N
H
4
15
O
COOH
OAc OAc OAc
When regarding the exact configuration of Sagittamides A and B (1 and 2, Figure 1), two points
have been firmly established: (a) the configuration is S in positions 6 and 7; (b) There is a clear syn
relationship between positions 9 and 10 [5]. Thus, the five possible structures proposed for Sagittamide
A 1 are described in Figure 2.
Figure 2. Structures proposed for Sagittamide A 1.
AcO AcO AcO
HOOC
H2N
O
H
N
3
iPr
1a
1b
Proposed by Kishi and Griesinger
Proposed by Molinski
N
H
15 OAc OAc OAc O
COOH
3
AcO AcO AcO
HOOC
H2N
O
O
O
H
N
3
iPr
N
H
15 OAc OAc OAc O
COOH
3
AcO AcO AcO
HOOC
H2N
H
N
3
iPr
N
H
1c
1d
15 OAc OAc OAc O
COOH
3
AcO AcO AcO
HOOC
H2N
H
N
3
iPr
Alternative proposals compatible only
with available 3J data
N
H
15 OAc OAc OAc O
COOH
3
HOOC
O AcO AcO AcO
H
N
3
H2N
iPr
N
H
1e
3
15
OAc OAc OAc O
COOH

Molecules 2012, 17
7711
Using the Quiral program developed in our laboratory [6,7], which analyzes the 3D structure of a
target organic molecule to find which sugar(s) can be used as a starting material for its synthesis, a
careful study of the configurations for the central stereocluster of sagittamide A 1 (and related 2) was
performed. For each possible structure (compounds 1a–e, 3–6), three groups of six consecutive
carbons were analyzed, and their similarity to a known sugar identified in both directions (left to right
and right to left, see Figure 3). The large majority of the proposed structures involve L-sugars, as seen in
the summary table.
Figure 3. Use of the Quiral program for the study of carbohydrate backbones in the central
stereoclusters of Sagittamides A–F.
Of the nine possible carbohydrate structures shown in Scheme 3, the rare sugar couple L-altrose/
L-talose can be seen in seven cases (1a–c, 3–6). It thus appeared feasible to start from this backbone in
order to access the greatest number of structures, with any missing targets being obtained by a
Mitsunobu approach. Our research was focused on finding a controlled access to the diversely
protected structure 7 (Figure 4).

Molecules 2012, 17
7712
Figure 4. Targeted structure 7.
On the left-hand side of the target structure 7, the thiophenyl group is an aldehyde surrogate through
a Pummerer transformation, and on the right-hand side, the epoxide could be selectively opened by
diverse organometallic species.
2. Results and Discussion
The protected derivative 12 was easily obtained after several straightforward reactions of the known
D-ribose derivative 8 (Scheme 1) [8]. After a Wittig reaction on the lactol moiety in the presence of
DMSO, the previously described open carbohydrate 9 [9] was obtained in 81% yield. Noteworthy, the
use of potassium tert-butoxide in THF, as described in the literature [9], resulted in a substantial loss of
the TBDPS group. After several unsuccessful Mitsunobu attempts under various conditions (DEAD or
DIAD as activators, toluene or THF as a solvent, pNO2PhCOOH or ClCH2COOH as nucleophilic
moieties) [10–12], and inspired by some of our preliminary results [13–15], the necessary inversion of
configuration occurred very cleanly under mesylate activation, followed by an in situ formation of the
known epoxide 10 [16]. The direct opening of this epoxide with sodium phenylsulfide offered an
efficient access to the expected derivative 11 [17]. Finally, in order to install the left-hand side of our
target, the free hydroxy function was protected with a MPM group to form 12. This procedure was
clean and reproducible on a multigram scale.
Scheme 1. Synthesis of the alkene derivative 12.
Not surprisingly, the controlled oxidation of alkene 12 with one equivalent of MCPBA in CH2Cl2
very cleanly gave the corresponding sulfoxide in 84% yield. An obvious way to finalize the synthesis
involved the selective osmylation of the derivative 12. The use of osmium tetroxide (OsO4) seemed
unsuitable because of the concurrent reactivity of the sulfur. However, precedents in the literature were
found in which an AD-Mix type approach was effective for this transformation [18–22]. Thus, after a
first attempt in a tBuOH/water mixture at 0 °C that gave no reaction, the use of AD-Mix  in

Molecules 2012, 17
7713
acetone/water gave the S diastereoisomer as the major one, in 65% overall yield (d.r. = 80:20) with
11% of recovered starting material (Scheme 2). Interestingly, the use of AD-Mix  gave the same
major diastereoisomer, with a better diastereoselectivity (7.3:1), however in lower yield (54% overall
yield, with 20% of recovered starting material). This observation was quite surprising, even if a similar
case has previously been reported in the literature [23].
Scheme 2. Selective osmylation in the presence of a sulfur moiety and formation of MPA esters.
After protection of the primary hydroxyl group with a TBDMS ether, the secondary alcohol 14 was
esterified with (R) and (S)-MPA moieties, in order to prove the induced stereoselectivity (Figure 5) [24].
Figure 5. Comparison of selected 1H-NMR spectra of MPA ester derivatives of 14.
OCH3
OCH3
O
O
(R)
(S)
TBSO
O
Ph
TBSO
O
Ph
O
O
SPh
OMPM
SPh
(R) – (S) < 0
(R)
(R)
(S)
OMPM
O
O
(R) – (S) < 0
(R) – (S) > 0

Molecules 2012, 17
7714
With this method, comparison of the chemical shifts of the signals due to protons in L1 and L2 in
both the R and the S derivatives and calculation of the corresponding differences expressed as R/S,
helps to assign the S configuration (Scheme 3). Finally, the desired epoxide 7 was obtained after
selective intermediate tosylate activation, followed by a basic cyclization (Scheme 4). In our future
synthesis of sagittamide-type structures, this epoxide could be directly opened as in one of our
previously described transformations (10 to 11).
Scheme 3. General scheme for the assignment of R or S configuration.
Signals between 1.46 and 1.28
(Isopropylidene CH3)
PhS
OMPM
H
H
L1
> 0
MPAO
MPAO
H
O
O
L2
< 0
MPAO
TBSO
Values for R-S)
Signals between 0.87 and 0.77
(C(CH3)3)
Signals between 0.01 and -0.17
(SiCH3)
Scheme 4. Formation of target compound 7.
Ts-Imidazole
MPMO R1O
PhS
R1O
MPMO
PhS
NaH
THF
74%
OH
O
R2O
OH
R2O
R1-R2 = CMe2
7
13 R1-R2 = CMe2
3. Experimental
3.1. General
All reactions were performed under argon with magnetic stirring unless otherwise specified. Dry
solvents were used in all experiments. Thin layer chromatography was performed on E. Merck
pre-coated 60 F254 plates and compounds were observed by UV or by charring the plates with an acidic
anisaldehyde system. Flash chromatography was performed on an Armen SpotFlash with silica gel 60
(particle size 15–40 m). Optical rotations were measured on a Perkin-Elmer 341 polarimeter at 20 °C.
Electrospray ionization mass spectrometry experiments (MS and HRMS) were obtained on a hybrid
tandem quadrupole/time-of-flight (Q-TOF) instrument, equipped with a pneumatically assisted
electrospray (Z-spray) ion source (Micromass, Manchester, UK) operated in positive mode (EV = 30V,
80 °C, injection flow 5 L/min). NMR spectra were recorded on Bruker 600, 500 or 250 MHz
spectrometer. Chemical shifts were measured in (ppm) and coupling constants J in Hz (solvent peak
1
reference: = 7.27 for H, 77.0 for 13C). Multiplicities are indicated by s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet) or br (broad). Chemical shifts () reported are referred to internal
tetramethylsilane. FT-IR spectra were recorded on Nicolet Avatar 320 FT-IR as films. Elemental
analyses were performed with a Thermo Flash EA 1112 Series.

Molecules 2012, 17
7715
1,2-Dideoxy-6-O-(tert-butyldiphenylsilyloxy)-3,4-di-O-isopropylidene-D-ribo-hex-1-enitol (9)
A sodium hydride suspension in mineral oil (1.16 g, 28.9 mmol) was washed three times with
n-hexane and then suspended in DMSO (15.9 mL). After heating to 68 °C for 45 min, the grey-green
mixture was transferred via syringe to a suspension of methyltriphenylphosphonium bromide (10.33 g,
28.9 mmol, co-evaporated with toluene before use) in dry THF (110 mL). After stirring for 10 min, a
solution of lactol 8 (3 g, 7.23 mmol) in dry THF (50 mL) was transferred via a cannula. The yellow
mixture was stirred at room temperature for 16 h and then poured into ice water (200 mL). After
extraction with diethyl ether (3 × 500 mL), the combined organic phases were washed with a saturated
NaCl solution (50 mL). The organic phase was dried with MgSO4, and after filtration and evaporation
to dryness, the residue was purified by column chromatography to give 9 (2.17 g, 5.1 mmol, 81%) as a
1
slightly yellow oil. []20 = −0.4° (C = 1.04, CHCl3); H-NMR (CDCl3):  7.66–7.77 (m, 4 H, Ar),
D
7.34–7.51 (m, 6 H, Ar), 6.04 (ddd, 1 H, J2,1trans 17.1 Hz, J2,1cis 10.4 Hz, J2,3 6.7 Hz, H-2), 5.44 (d, 1 H,
J1trans,2 17.1 Hz, H-1trans), 5.30 (d, 1 H, J1cis,2 10.4 Hz, H-1cis), 4.73 (t, 1 H, J3,2 6.7 Hz, J3,4 6.7 Hz,
H-3), 4.17 (dt, 1 H, J4,5 13.7 Hz, J4,3 6.7 Hz, H-4), 3.87 (m, 2 H, H-6), 3.67-3.80 (m, 1 H, H-5), 2.65
(br s, 1 H, OH), 1.41 (s, 3 H, 1 CH3), 1.37 (s, 3 H, 1 CH3), 1.10 (s, 9 H, Si(CH3)3); 13C-NMR
(CDCl3):  136.1 (Cortho or Cmeta), 136.0 (Cortho or Cmeta), 134.5 (C-2), 133.5 (CqAr), 133.5 (CqAr), 130.3
(Cpara), 128.3 (CAr), 128.2 (CAr), 118.1 (C-1), 109.2 (Cq isopropylidene), 79.2 (C-3), 77.9 (C-4), 70.3
(C-5), 65.7 (C-6), 28.2 (CH3 isopropylidene), 27.3 (C(CH3)3), 25.9 (CH3 isopropylidene), 19.8
(C(CH3)3); IR (neat) max: 3564, 3481, 2934, 2859, 1429, 1218, 1114, 1059, 704 cm–1; HRMS (m/z,
ESI) calculated for C25H34O4NaSi: (M+Na) = 449.2124 (calculated), 449.2120 (found).
1,2-Dideoxy-3,4-di-O-isopropylidene-6-S-phenylthio-L-lyxo-hex-1-enitol (11)
Triethylamine (4.8 mL, 34.5 mmol) followed by methanesulfonyl chloride (1.16 mL, 15 mmol)
were added drop-wise to a solution of compound 9 (4.89 g, 11.5 mmol) in methylene chloride (70 mL)
at 0 °C. After stirring for 16 h at room temperature, the mixture was diluted with diethyl ether (300 mL),
washed with a saturated ammonium chloride solution (50 mL), and then with a saturated sodium
chloride solution (50 mL). The organic phase was dried with MgSO4, filtered and evaporated to
dryness. Dry THF (110 mL) was added and reaction mixture was cooled to 0 °C. A tetra-n-butyl
ammonium fluoride solution (1 M in THF; 23 mL) was added drop-wise, and the reaction mixture was
stirred at room temperature for 3 h. After addition of K2CO3 (2.8 g, 20 mmol) and stirring for 16 h, the
reaction mixture was diluted with water (25 mL) and extracted with diethyl ether (3 × 300 mL). The
combined organic phases were dried with MgSO4, filtered and evaporated to dryness. The crude

Molecules 2012, 17
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epoxide 10 was used in the next step without further purification. Dry THF (50 mL) was then
added and the reaction mixture was cooled to 0 °C, and a THF solution of sodium thiophenoxide was
added [prepared by addition of thiophenol (2.94 mL, 28.8 mmol) to a suspension of sodium (1.15 g,
28.8 mmol) in dry THF (50 mL)]. The reaction was stirred at room temperature for 16 h. The crude
mixture was then slowly quenched with methanol (5 mL), a half-saturated ammonium chloride
solution (30 mL) was added and the aqueous layer was extracted with diethyl ether (3 × 300 mL). The
combined organic phases were dried with MgSO4, filtered and evaporated, and the residue purified by
column chromatography to give 11 (2.56 g, 9.1 mmol, 80%) as a colorless oil. []20 = +27.3°
D
(C = 1.04, CHCl3); 1H-NMR (CDCl3):  7.13–7.43 (m, 5 H, HAr), 5.95 (ddd, 1 H, J2,1trans 17.4 Hz, J2,1cis
10.1 Hz, J2,3 8.1 Hz, H-2), 5.33 (d, 1 H, H-1trans), 5.24 (d, 1 H, H-1cis), 4.59 (t, 1 H, J3,4 7.5 Hz, H-3),
4.27 (dd, 1 H, J4,5 3.6 Hz, H-4), 3.68 (td, 1 H, J5,6 6.5 Hz, H-5), 3.05 (dd, 2 H, H-6), 2.44 (br s, 1 H,
OH), 1.52 (s, 3 H, 1 CH3), 1.38 (s, 3 H, 1 CH3); 13C-NMR (CDCl3): 135.9 (CqAr), 134.2 (C-2), 130.2
(Cortho or Cmeta), 129.4 (Cortho or Cmeta), 126.9 (Cpara), 120.3 (C-1), 109.3 (Cq isopropylidene), 79.5 (C-3 or
C-4), 78.9 (C-3 or C-4), 68.8 (C-5), 38.3 (C-6), 27.5 (CH3 isopropylidene), 25.3 (CH3 isopropylidene);
IR (neat) max: 3480, 2988, 2935, 1585, 1482, 1458, 1439, 1380, 1215, 1057, 741, 693 cm–1; HRMS
(m/z, ESI) calculated for C15H20O3NaS: (M+Na) = 303.1031 (calculated), 303.1038 (found).
1,2-Dideoxy-3,4-di-O-isopropylidene-5-O-(4-methoxybenzyl)-6-S-phenylthio-L-lyxo-hex-1-enitol (12)
HO
MPMO
PhS
NaH / MPMBr
PhS
O
O
TBAI / Imidazole
O
O
DMF
81%
11
12
A solution of 11 (2.38 g, 8.49 mmol) in a mixture of THF/DMF (18 mL/4.5 mL) was added
drop-wise to a stirring suspension of sodium hydride (560 mg, 17 mmol) in a mixture of THF/DMF
(18 mL/4.5 mL) at 0 °C. After addition of tetra-n-butylammonium iodide (314 mg, 0.85 mmol) and
imidazole (58 mg, 0.85 mmol), p-methoxybenzyl bromide (2.48 mL, 17 mmol) was added drop-wise
and the yellow suspension was stirred at room temperature for 16 h. The reaction was quenched by the
addition of methanol (5 mL) at 0 °C and after addition of water (30 mL), the reaction mixture was
extracted with diethyl ether (3 × 300 mL). The combined organic phases were dried with MgSO4,
filtered and evaporated, and the residue purified by column chromatography to give 12 (2.76 g,
6.89 mmol, 81%) as a colorless oil. []20D = −2.8° (C = 1.02, CH3OH); 1H-NMR (CDCl3):  7.11–7.50
(m, 7 H, HAr), 6.77–6.95 (m, 2 H, HAr), 5.84 (ddd, 1 H, J2,1trans 17.2 Hz, J2,1cis 10.2 Hz, J2,3 8.3 Hz,
H-2), 5.26 (d, 1 H, H-1trans), 5.16 (d, 1 H, H-1cis), 4.59 (s, 2 H, CH2Ph), 4.50 (dd, 1 H, J3,4 6.1 Hz,
H-3), 4.39 (t, 1 H, J4,5 6.1 Hz, H-4), 3.80 (s, 3 H, OMe), 3.55 (dd, 1 H, J5,6 11.7 Hz, H-5), 3.11 (dd, 2 H,
H-6), 1.52 (s, 3 H, 1 CH3), 1.37 (s, 3 H, 1 CH3); 13C-NMR (CDCl3): 159.5 (CqArOMe), 136.7
(CqArSPh), 134.8 (C-2), 130.9 (CqArCH2O), 130.3 (CAr), 129.8 (CAr), 129.3 (CAr), 126.7 (CAr/paraS), 119.6
(C-1), 114.1 (CAr/orthoOMe), 109.7 (Cq isopropylidene), 80.0 (C-4), 79.5 (C-3), 77.0 (C-5), 72.8
(CH2Ph), 55.7 (OMe), 35.5 (C-6), 28.0 (CH3 isopropylidene), 26.0 (CH3 isopropylidene); IR (neat)

max: 2986, 2935, 2837, 1613, 1614, 1248, 1038, 742, 693 cm–1; HRMS (m/z, ESI) calculated for
C23H28O4NaS: (M+Na) = 423.1606 (calculated), 423.1601 (found).

Molecules 2012, 17
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3,4-Di-O-isopropylidene-2-O-(4-methoxybenzyl)-1-S-phenylthio-L-altritol (13)
MPMO R1O
MPMO
AD-Mix 
PhS
PhS
OH
O
Acetone / H2O
0 °C
R2O
OH
O
65% (dr = 4 / 1)
13 R1-R2 = CMe2
12
A solution of 12 (654 mg, 1.63 mmol) in a mixture of acetone/water (4 mL 1:1) was added to
AD-Mix  (3 g) in a mixture of acetone/water (16 mL 1:1) at 0 °C. After stirring for 18 h, sodium
sulfite (3.34 g) was added. After dilution with water (2 mL), the reaction was extracted with methylene
chloride (3 × 100 mL). The combined organic phases were dried with MgSO4, filtered and evaporated,
and the residue purified by column chromatography to give 13 (368 mg, 52%) as the major
diastereoisomer, and 3,4-di-O-isopropylidene-2-O-(4-methoxybenzyl)-1-S-phenylthio-D-galactitol (92 mg,
13%) as the minor one, both as colorless oils (diastereoisomeric ratio 4/1), with 11% of recovered starting
material. The same reaction with AD-Mix  gave 13 (336 mg, 47.5%) as the major diastereoisomer,
and 3,4-di-O-isopropylidene-2-O-(4-methoxybenzyl)-1-S-phenylthio-D-galactitol (46 mg, 6.5%) as the
minor diastereoisomer, (diastereoisomeric ratio 7.3/1), with 20% of recovered starting material.
Major diol (13): []20D = −0.4° (C = 0.975, CH3OH); 1H-NMR (CDCl3):  7.10–7.46 (m, 7 H, HAr),
6.84 (d, 2 H, Jortho,meta/OMe 8.6 Hz, HAr), 4.70 (d, 1 H, JCHPh,CPh 10.9 Hz, CH2Ph), 4.52 (d, 1 H, CH2Ph),
4.41 (dd, 1 H, J3,4 6.1 Hz, J3,2 4.3 Hz, H-3), 4.09 (dd, 1 H, J4,5 9.3 Hz, H-4), 3.93–4.02 (m, 1 H, H-2),
3.84–3.93 (m, 1 H, H-5), 3.73–3.82 (m, 4 H, H-6a, OMe), 3.61 (dd, 1 H, J6b,6a 11.2 Hz, J6b,5 5.6 Hz,
H-6b), 3.42–3.56 (br s, 1 H, OH), 3.46 (dd, 1 H, J1a,2 5.0 Hz, J1a,1b 13.7 Hz, H-1a), 3.25 (dd, 1 H, J1b,2
13
7.2 Hz, H-1b), 2.22 (br s, 1 H, OH), 1.46 (s, 3 H, 1 CH3), 1.31 (s, 3 H, 1 CH3); C-NMR (CDCl3):
159.9 (CqArOMe), 136.7 (CqArSPh), 130.1 (CqArCH2O), 130.1 (CAr), 129.9 (CAr), 129.5 (CAr), 126.7
(CAr/paraS), 114.3 (CAr/orthoOMe), 109.2 (Cq isopropylidene), 78.0 (C-2), 77.8 (C-4), 77.6 (C-3), 73.3
(CH2Ph), 70.0 (C-5), 65.1 (C-6), 55.7 (OMe), 35.3 (C-1), 27.4 (CH3 isopropylidene), 25.5 (CH3
isopropylidene); IR (neat) max: 3422, 2987, 2933, 1612, 1514, 1249, 1070, 1035, 744 cm–1; HRMS
(m/z, ESI) calculated for C23H30O6NaS: (M+Na) = 457.1661 (calculated), 457.1649 (found).
Minor diol (3,4-di-O-isopropylidene-2-O-(4-methoxybenzyl)-1-S-phenylthio-D-galactitol): 1H-NMR
(CDCl3):  7.23-7.45 (m, 5 H, HAr), 7.19 (d, 2 H, Jortho,meta/OMe 8.6 Hz, H ortho,meta/OMe), 6.84 (m, 2 H, H
meta,ortho/OMe), 4.65 (d, 1 H, JCHPh,CPh 11.0 Hz, CH2Ph), 4.52 1 H, (dd, J3,4 6.6 Hz, J3,2 2.0 Hz, H-3), 4.40
(d, 1 H, CH2Ph), 4.02 (d, 1 H, H-4), 3,80 (s, 3 H, OMe), 3.68–3.76 (m, 1 H, H-2 or H-5), 3.61–3.68
(m, 1 H, H-2 or H-5), 3.56 (s, 1 H, OH), 3.50 (s, 2 H, H-6), 3.35 (dd, 1 H, J1a,2 4.1 Hz, J1a,1b 13.7 Hz,
H-1a), 3.22 (dd, 1 H, J1a,2 8.9 Hz, H-1b), 1.51 (s, 3 H, 1 CH3), 1.27 (s, 3 H, 1 CH3).
6-O-(tert-Butyldimethylsilyloxy)-3,4-di-O-isopropylidene-2-O-(4-methoxybenzyl)-1-S-phenylthio-L-
altritol (14)
MPMO R1O
PhS
MPMO R1O
PhS
TBDMSCl
OH
OTBDMS
Imidazole / DMAP
R2O
OH
R2O
OH
DMF
60%
13 R1-R2 = CMe2
14 R1-R2 = CMe2

Molecules 2012, 17
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Imidazole (28 mg, 0.4 mmol), TBDMSCl (67 mg, 0.44 mmol) and DMAP (10 mg, 80 mol) were
added to a solution of 13 (175 mg, 0.4 mmol) in dry DMF (4 mL) at 0 °C. After warming to room
temperature and stirring for 6 h, the reaction mixture was diluted with CH2Cl2 (50 mL), washed with
water (5 mL), and then with saturated NH4Cl (5 mL). The organic phase was dried with MgSO4,
filtered and evaporated, and the residue purified by column chromatography to give 14 (130 mg, 60%)
as a colorless oil. The crude alcohol 14 was used without any further purification.
6-O-(tert-Butyldimethylsilyloxy)-3,4-di-O-isopropylidene-2-O-(4-methoxybenzyl)-5-O-(R)-2-methoxy-
phenylacetyl-1-S-phenylthio-L-altritol (15) and 6-O-(tert-Butyldimethylsilyloxy)-3,4-di-O-isopropyl-
idene-2-O-(4-methoxybenzyl)-5-O-(S)-2-methoxyphenylacetyl-1-S-phenylthio-L-altritol (16)
MPMO R1O
PhS
OTBDMS
OMe
OMe
R2O
O
HO
Ph
(R)
Ph
(R)
O
MPMO R1O
PhS
O
15 R1-R2 = CMe2
DCC
DMAP
OTBDMS
R2O
OH
MPMO R1O
PhS
OTBDMS
OMe
OMe
Ph
14 R1-R2 = CMe2
HO
R2O
O
(S)
Ph
(S)
O
O
16 R1-R2 = CMe2
DMAP (3 mg, 20 mol), (−)-R-MPA (80 mg, 0.48 mmol) and DCC (99 mg, 0.48 mmol) were
added to a solution of 14 (65 mg, 120 mol) in dry CH2Cl2 (5 mL) at 0 °C. After stirring for 1 h, the
reaction mixture was diluted with CH2Cl2 (30 mL), washed with saturated NH4Cl (5 mL), and then
with brine (5 mL). The organic phase was dried with MgSO4, filtered and evaporated. The residue was
1
purified by column chromatography to give 15 as a colorless oil. H-NMR (CDCl3):  7.13–7.46 (m,
12 H, HAr), 6.85 (d, 2 H, Jortho,meta/OMe 8.6 Hz, HAr), 5.17 (m, 1 H, J5,4 8.0 Hz H-5), 4.63 (s, 3 H,
CHOMe), 4.58 (d, 1 H, JCHPh,CPh 11.1 Hz, CH2Ph), 4.50 (d, 1 H, CH2Ph), 4.47 (m, 2 H, H-3, H-4), 3.80
(s, 3 H, OMe), 3.73 (m, 2 H, 2 H-6), 3.44 (m, 1 H, H-2), 3.29 (m, 3 H, CHOMe), 3.23 (m, 2 H, 2 H-1),
1.46 (s, 3 H, 1 CH3), 1.34 (s, 3 H, 1 CH3), 0.77 (s, 9 H, 1 C(CH3)3), −0.11 (s, 3 H, SiCH3); −0.17 (2s,
2 × 3 H, 2 SiCH3). The same procedure with (+) S-MPA gave 16 as a colorless oil. 1H-NMR (CDCl3):
 7.11–7.47 (m, 12 H, HAr), 6.82 (d, 2 H, Jortho,meta/OMe 8.6 Hz, HAr), 5.20 (m, 1 H, J5,4 7.2 Hz H-5), 4.69
(s, 3 H, CHOMe), 4.52 (d, 1 H, JCHPh,CPh 11.0 Hz, CH2Ph), 4.37 (d, 1 H, CH2Ph), 4.34 (dd, 1 H, J4,3 6.2
Hz, H-4), 4.03 (dd, 1 H, J3,2 1.2 Hz, H-3), 3.91 (dd, 1 H, J6a,6b 11.5 Hz, J6a,5 1.5 Hz, H-6a), 3.78 (s, 3 H,
OMe), 3.76 (dd, 1 H, J6b,5 4.4 Hz, H-6b), 3.35 (m, 3 H, CHOMe), 3.12 (m, 1 H, H-2), 3.00 (dd, 1 H,
J
1a,2 4.5 Hz, J1a,1b 12.7 Hz, H-1a), 2.94 (dd, 1 H, H-1b), 1.41 (s, 3 H, 1 CH3), 1.28 (s, 3 H, 1 CH3), 0.87
(s, 9 H, 1 C(CH3)3), 0.01 (2s, 2 × 3 H, 2 SiCH3).
1,2-Anhydro-3,4-di-O-isopropylidene-2-O-(4-methoxybenzyl)-1-S-phenylthio-L-altritol (7)
Ts-Imidazole
MPMO R1O
PhS
MPMO R1O
PhS
NaH
THF
74%
OH
O
R2O
OH
R2O
13 R1-R2 = CMe2
7 R1-R2 = CMe2

Molecules 2012, 17
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Sodium hydride 60% suspension in mineral oil (56 mg, 1.7 mmol) was added to a solution of 13
(100 mg, 0.23 mmol) in dry THF (2.4 mL) at 0 °C After 15 min at 0 °C tosylimidazole (104 mg,
468 mol) was then added. The reaction mixture was stirred for 16 h. After addition of diethylether
(20 mL), washing with saturated sodium bicarbonate (5 mL), saturated ammonium chloride (5 mL)
and brine (5 mL), the combined organic phases were dried with MgSO4, filtered and evaporated, and
the residue purified by column chromatography to give 7 (71 mg, 74%) as a slightly yellow oil.
[]20D = −16.4° (C = 0.22, CHCl3); 1H-NMR (CDCl3): 7.43 (d, 2 H, Jmeta,ortho 7.7 Hz, HAr), 7. 3 (m, 4
H, HAr), 7.21 (m, 1 H, HAr), 6.87 (d, 2 H, Jortho 8.5 Hz, HAr), 4.67 (d, 1 H, Jgem 11.0 Hz, CH2Ph), 4.64
(d, 1 H, Jgem 11.0 Hz, CH2Ph), 4.52 (dd, 1 H, J3,4 5.7 Hz, J3,2 5.6 Hz, H-3), 3.96 (ddd, 1 H, J2,1 5.6 Hz,
H-2), 3.82 (s, 3 H, OMe), 3.59 (dd, 1 H, J4,5 8.1 Hz, H-4), 3.35 (dd, 1 H, Jgem 13.6 Hz, H-1a), 3.25 (dd,
1 H, H-1b), 3.12 (ddd, J5,6a 4.9 Hz, J5,6b 2.5 Hz, 1 H, H-5), 2.83 (dd, 1 H, H-6a), 2.62 (dd, 1 H, H-6b),
1.53 (s, 3 H, 1 CH3), 1.36 (s, 3 H, 1 CH3); 13C-NMR (CDCl3): 159.2 (CqArOMe), 136.3 (CqArSPh),
130.4 (CqArCH2O), 129.6 (2CAr), 128.9 (CAr), 126.2 (CAr/paraS), 113.7 (CAr/orthoOMe), 109.2 (Cq
isopropylidene), 78.8 (C-4), 78.7 (C-3), 76.3 (C-2), 72.3 (CH2Ph), s55.3 (OMe), 49.4 (C-5), 46.1
(C-6), 35.1 (C-1), 27.6 (CH3 isopropylidene), 25.3 (CH3 isopropylidene); IR (neat) max: 3057, 2989,
2933, 1653, 1615, 1559, 1540, 1515, 1248, 1086, 1038, 741 cm–1; HRMS (m/z, ESI) calculated for
C23H28O5NaS: (M+Na) = 439.1555 (calculated), 439.1557 (found).
4. Conclusions
We have developed a short and efficient procedure for the synthesis of a diversely protected rare
L-altritol derivative 7 (which could also be seen as a L-talitol derivative). This key compound offers
access to the central stereoclusters of the sagittamide backbones. Work is in progress to extend this
efficient pathway to making useful fragments in order to definitively establish the exact configurations
of these natural substances.
Acknowledgments
A. Humbert would especially like to thank the Ministry of Higher Education and Research (MESR)
for her PhD scholarship. Financial support from the CNRS, the Conseil Regional Champagne
Ardenne, the Conseil General de la Marne, and the EU-program FEDER for the PlAneT CPER project
is also gratefully acknowledged.
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