Synthesis of 5-deazathiogirollines: Analogs of a natural antitumor agent

Article abstract of DOI:10.1016/S0040-4020(02)00383-6

2-Aminothiazole analogs of the natural antitumor agent, girolline, were prepared in natural stereochemistry series (threo) and in a non-natural series (erythro). The key-step involved a coupling reaction between 2,3-O-isopropylidene-D-glyceraldehyde and a properly protected 2-aminothiazole, via a dianion species. The biological activity of the prepared analogs was evaluated on human cancer cells to determine structure-activity relationship.

Full text of DOI:10.1016/S0040-4020(02)00383-6

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 4201±4215
Synthesis of 5-deazathiogirollines:
analogs of a natural antitumor agent
p
Bruno Schiavi, Alain Ahond, Ali Al-Mourabit, Christiane Poupat, Angele Chiaroni,
Christiane Gaspard and Pierre Potier
Á
Institut de Chimie des Substances Naturelles du Centre National dela Recherche Scienti®que, BP1, 91198 Gif-sur-Yvette cedex, France
Received 1 August 2001;revised 29 March 2002;accepted 2 April 2002
AbstractÐ2-Aminothiazole analogs of the natural antitumor agent, girolline, were prepared in natural stereochemistry series (threo) and in
a non-natural series (erythro). The key-step involved a coupling reaction between 2,3-O-isopropylidene-d-glyceraldehyde and a properly
protected 2-aminothiazole, via a dianion species. The biological activity of the prepared analogs was evaluated on human cancer cells to
determine structure±activity relationship. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
d-glyceraldehyde5 with the dianion of a protected 2-
aminothiazole.
Girolline 1 was extracted from a New Caledonian marine
Sponge,1 Cymbastela cantharella2 (previously Pseudaxinyssa
cantharella)3 which has shown in vitro cytotoxicity and in
vivo antitumor activity.4 Because the phase I clinical trials
with girolline have been discontinued due to undesired side-
effects, the synthesis of analogs might allow for improvement
of its biological pro®le.
After many trials, the acyl protecting group family proved to
be most suitable for this task. After optimization, the pival-
oyl protected 2-aminothiazole was prepared in 97% yield
from 4, in presence of triethylamine (TEA) and pivaloyl
chloride to yield compound 5. The triol 6 was prepared in
99% yield from 5 and 2,3-O-isopropylidene-d-glyceralde-
hyde, in the presence of an excess of lithium diisopropyl-
amide (LDA) in THF at 2788C. Two diastereoisomers were
formed (ratio 3:2) (Scheme 1).
Our goal is to synthesize some analogs in which the side-
chain of the natural product is preserved, while the 2-
aminoimidazole ring is replaced by a 2-aminothiazole
ring. This change results into two isomer analogs that
we have called: 5-deazathiogirolline 2 and 4-deazathio-
girolline 3. In this paper, we disclose the synthesis of
compound 2.
The two isomers 6A/6B proved to be very dif®cult to
separate by ¯ash chromatography. Eventually, a four-step
sequence was proposed to access stereochemically pure
alcohols 6A and 6B (Scheme 2).
2. Results and discussion
At ®rst, the mixture of alcohols 6A/6B was oxidized
into the single ketone 7 by treatment with manganese
dioxide in dioxane (82% yield). The ketone 7, whose
structure was secured by X-Ray analysis6 was then
converted into the single diastereoisomer 6A by use of
the l-Selectridew in THF at 2788C. Thus, by this route,
the pure compound 6A was easily prepared in two steps
(75% yield).
The key-step is the condensation of 2,3-O-isopropylidene-
Keywords: aminothiazole;antitumor compounds;marine metabolite;struc-
ture±activity.
Corresponding author. Tel.: 133-1-69-82-30-23;fax: 133-1-69-07-72-
47;e-mail: christiane.poupat@icsn.cnrs-gif.fr
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00383-6

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B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
Scheme 1. (a) PivCl, TEA, CH2Cl2, 97%;(b) 2,3- O-isopropyliden-d-glyceraldehyde, LDA, THF, 2788C, 99%.
Scheme 2. (a) MnO2, dioxane, rt,82%;(b) l-Selectridew,THF, rt, 91%;(c) PhCOOH, DEAD, PPh 3, THF, 2788C, 85%;(d) MeONa, THF, 100%.
Scheme 3.
Alcohol 6B was obtained by inverting the con®guration of
the free-alcohol 6A by a Dodge esteri®cation reaction.7 A
®rst attempt with the para-nitrobenzoic acid led to the
ester in quantitative yield but with partial epimerization at
C-10. This result was probably due to the strong electron-
withdrawing effect of the nitro group. The use of benzoic
acid provided 8 in 89% yield without any epimerization.
Methanolysis of ester 8 gave the diastereoisomer 6B in
100% yield. Thus, pure compound 6B could be easily
prepared in four steps (66% yield).
mixture of the expected diols but also a small amount of the
fully deprotected triols 10 and the unexpected methoxy 10-
substituted compound which was isolated as an unseparable
60/40 mixture of diastereoisomers 11. Use of the non-
nucleophilic solvent THF and a reduced amount of acid,
allowed elimination of these side-reactions (Scheme 3).
After several unsuccessful experiments to introduce an
amino group at position 30 followed by a chlorination at
position 20, the 20,30-bis-chlorination was preferred. It was
performed on 12A and 12B using 2.5 equiv. of triphenyl-
phosphine (PPh3) and N-chloro-succinimide (NCS)9 in 60
and 56% yield, respectively (Scheme 4);the concomitant
inversion of the con®guration at C-20 gave the absolute
con®guration observed in the natural girolline. Substitution
of the 30-chloro by an azide (NaN3, DMF)10 and catalytic
hydrogenation led to free amines 16A and 16B (Scheme 4).
At this point, it was expected that deprotection of both 10-
hydroxyl and 2-amino groups would provide the 5-
deazathiogirolline 2. Unfortunately, various attempts only
led to the degradation of the product, to unchanged starting
material or to the formation of the dehydration compound
17.
Functionalization of the side-chain could be easily effected
on each diastereoisomer. Firstly, the hydroxyl group in posi-
tion 10 was protected as thexyldimethylsilylether 9;this silyl
group is known to be 2±3 times more stable than t-butyldi-
methylsilyl (TBDMS).8 This protection was carried out in
100% yield on both 6A and 6B (Scheme 3).
The selective deprotection of the acetonide 9 was carried out
in THF in the presence of para-toluenesulfonic acid
(PTSA), at 48C for 6 days. The corresponding diols 12A
and 12B were isolated in 73 and 72% yield, respectively.
The use of more than 1.5 equiv. of PTSA in methanol gave a

B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
4203
Scheme 4. (a) PPh3 (2 equiv.), NCS (2 equiv.), THF, 608C;(b) PPh (2.5 equiv.), NCS (2.5 equiv.), THF, 608C;(c) NaN , DMF, 808C;(d) H , Pd 5%/C,
3
3
2
ethanol;(e) 6N HCl, T.608C.
Scheme 5. (a) Boc2O, TEA, DMAP, CH2Cl2, 89%;(b) 2,3- O-isopropyliden-d-glyceraldehyde, LDA, THF, 2788C, 93%;(c) MnO 2, dioxane, 85%;
(d) l-Selectridew, THF, 93%;(e) PhCOOH, DEAD, PPh 3, THF, 2788C, 90%;(f) MeONa, THF, 100%.
Scheme 6. (a) ThMe2SiCl, imidazole;(b) PTSA, THF, 4 8C, 6 days;(c) PPh 3, NCS;(d) NaN 3, DMF;(e) H 2, Pd 5%/C;(f) 6N HCl.
To overcome this dif®culty, another protective group was
chosen. 2-Aminothiazole 4 was protected as 2-N-tert-butoxy-
carbonylthiazole 18. The previously described sequences
were followed to yield diastereoisomers 19A and 19B in
65% (four steps) and 59% (six steps) yield, respectively
(Scheme 5).
all yield while the synthesis of its isomer 2A was completed
in 10 steps in 11.3% total yield.
The ®nal compounds as well as some intermediates were
tested on human cancerous cells. The in vitro cytotoxic
activities of the compounds were evaluated using KB
cells, derived from an epidermoid carcinoma in the mouth
of an adult Caucasian male in 1954.12 We originally
obtained this cell line from the American Type Culture
Collection. Results are summarized in Table 1.
The acetonides 19 were converted into 5-deazathiogirollines
2A and 2B in six steps (Scheme 6, Fig. 1).6,11
Thus, the total synthesis of 5-deazathiogirolline 2B could be
carried out from 2-aminothiazole 4 in 12 steps in 8.3% over-
Unfortunately, both compounds 2A and 2B were inactive;

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B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
Figure 1. X-Ray structure of 22B (the protective silyl group is only partially visible).
Scheme 7. (a) Bu4NF, AcOH, THF;(b) H 2, Pd 5%/C, ethanol.
Scheme 8. (a) CF3COOH, CH2Cl2;(b) H 2, Pd 5%/C, ethanol.
on the contrary, intermediates 15A, 16A and 26A (still
protected in positions 2 and 10) have shown an interesting
and unexpected in vitro activity: these three compounds
The silyl group was selectively removed by treatment of
azides 25 and 15 with tetrabutylammonium ¯uoride in the
presence of acetic acid, in order to prevent the degradation
of the starting material. Free hydroxyazides 27 and 29 were
isolated in good yield (87±96%) in both series (N-Piv and
N-Boc). The corresponding amines 28 and 30 were easily
prepared (one exception 28B) in 62±75% yields (Scheme 7).
have the opposite con®guration of the girolline;so, LD
50
is 3.4£1026 M for 16A while it is 2.8£1027 M for the girol-
line 1. Dilution experiments have shown that this activity
decreased promptly with the concentration.
To improve the knowledge of the structure±activity rela-
tionships, other analogs were prepared: we decided to selec-
tively deprotect each position of the bioactive molecules.
Selective deprotection of the 2-amino group of the azides 25
was effected by treatment with tri¯uoroacetic acid (TFA)
in CH2Cl2 (87±95%);catalytic hydrogenation provided
diamines 32 (67±69%) (Scheme 8).
Table 1. Activity of products tested on cancerous cells (KB): killed-cells %
at 5£1026 M concentration
Hydroxy-azides 34 were prepared from diols 12 by mono-
mesylation then displacement with azide (Scheme 9).
1
12A 12B 23A 23B 15A
100% 0% 17% 20% 33% 62%
14A 14B 25A 25B 16A
33% 29% 16% 18% 100% 0%
15B 25A 25B 2A
35% 9% 16% 0%
16B 26A 26B 2B
85% 42% 0%
In vitro cytotoxicity on KB cells was also evaluated for all
these analogs. None showed the activity of 16 and 26.

B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
4205
Scheme 9. (a) MsCl, pyridine;(b) NaN 3, DMF.
From these results, it can be concluded that chlorine and
nitrogen functional groups are necessary (amine better than
azide) for the activity. Also the 10-hydroxy group and 2-
aminogroup must be protected. The effect of the position
of the substituents and of the con®guration of the carbons of
the side-chain as well as the mechanism of cell toxicity are
under investigation.
monolayers with phosphate-buffered saline, lysis of the
cells with a 1% solution of sodium lauryl-dodecyl sulfate
and photometric quanti®cation of the extracted dye at
540 nm, using a ELX 800 microplate reader (BIO-TEK
Instruments, Inc.) as originally described by Borenfreund
and Puerner.13
3.2. Protection of the amino group of 2-aminothiazole
3. Experimental
3.2.1. By pivaloyl group: 2,2-dimethyl-N-thiazol-2-yl-
propionamide 5. 2-Aminothiazole 4 (100 g, 1 mol) was
dissolved in dichloromethane (800 mL) and treated at
258C (ice/salt) with triethylamine (280 mL, 2 equiv.) and
pivaloyl chloride (1.77 mL, 1.2 equiv.). The solution
was stirred at room temperature for 1 h. The mixture was
diluted with dichloromethane (400 mL) and washed with
0.1N HCl, brine and water. The organic layer was dried
over MgSO4, ®ltered and concentrated under reduced pres-
sure. Crystallization from heptane furnished compound 5
with 97% yield (179 g). C8H12N2OS. White crystals.
Mpˆ1418C (heptane). Rf: 0.8 (CH2Cl2/MeOH: 95/5). MS
3.1. General procedures
All reactions were carried out under an argon atmosphere,
using freshly distilled solvents under anhydrous conditions
unless otherwise stated. Methylene chloride was distilled
from calcium hydride, tetrahydrofuran (THF) was distilled
from sodium/benzophenone. Reaction temperatures were
measured externally. Analytical TLC, for monitoring
and measuring Rf values, was carried out on 0.25 mm
E.Merck precoated silicagel plates (60F254), using UV
light. Preparative ¯ash chromatography was performed
using silica Chromagel SDS 60 A(40±60 mm). H and 13C
CI (Tˆ1708C) m/z: 185 (M1H)1. IR (CHCl3, nmax
,
1
Ê
cm21): 3427 (NH), 2970±2870 (CH), 1680 (amide). UV
NMR spectra are recorded on a Bruker AC250, AM300
or AM400 spectrometer and calibrated by using TMS as
an internal reference. Chemical shifts (d) were measured
in parts per million, and coupling constants (J values) are
in Hertz (Hz). IR spectra were taken with a Perkin±
Elmer BX FT-IR spectrometer. [a]D were measured using
a Perkin±Elmer 241 MC polarimeter (589 nm, 208C).
Chemical ionization mass spectra were recorded on AEI
MS-9 spectrophotometer with isobutane as carrier, electron
impact spectra on AEI MS-50. UV spectra were taken with
a Varian Cary 100 spectrometer, using EtOH solution.
Melting points were determined using a BuÈchi BS540 and
are uncorrected.
1
(l, nm [e]): 266 (10500). H NMR (300 MHz) d (ppm):
9.65 (m, 1H, NH);7.49 (d, Jˆ5.5 Hz, 1H, H-4);7.00 (d,
Jˆ5.5 Hz, 1H, H-5);1.34 (s, 9H, (C H3)3C). 13C NMR
(75 MHz) d (ppm): 176.00 (CvO);158.45 (C-2);137.45
(C-4);113.85 (C-5);39.25 ( C(CH3)3);27.35 (C( CH3)3).
Calcd for C8H12N2OS: C, 52.15;H, 6.56;N, 15.20;found:
C, 52.21;H, 6.61;N, 15.36.
3.2.2. By tert-butoxycarbonyl group: 2-/tert-butoxy-
carbonylamino)-thiazole 18. 2-Aminothiazole (10 g,
0.1 mol) was dissolved in THF (50 mL);ditertbutyldicar-
bonate (24 g, 1.1 equiv.), triethylamine (17.8 mL, 1.2 equiv.)
and dimethylaminopyridine (DMAP, 10 mg) were added.
After stirring for 3 h at room temperature, the mixture
was diluted with dichloromethane (150 mL) and washed
with 0.1N HCl, brine then water and dried over MgSO4.
Solvent was removed under reduced pressure and the
residue was crystallized from heptane to yield 18
(17.7 g, 89%). C8H12N2O2S. White crystals. Mpˆ1838C
(heptane). Rf: 0.8 (CH2Cl2/MeOH: 95/5). MS CI (T ˆ
Biological procedure. The KB cells were serially cultured
in MEM (minimum essential medium, with Earle's salt
solution), purchased from Seromed, containing 10%
fetal calf serum, 2 mM/l-glutamine, 60 mg/mL penicillin
G and streptomycin sulfate and 40 mg/mL gentamycin.
For the tests, KB cells were grown as monolayers in 24-
well plastic plates (25000 cells seeded per well in 1 mL
medium). Serial dilutions of the stock solutions of the
compounds under test were made in the medium and
added to the cultures under a volume of 10 mL per well,
immediately after plating the cells. All cultures were
incubated at 378C in a 95% air-5% CO2 humidi®ed incu-
bator. After 3 days incubation, cell viability was deter-
mined by further 8±16 h incubation following addition
to each well of 100 mL of a 0.02% solution in medium
of the vital dye neutral red, followed by washing the cell
1708C), m/z: 201 (M1H)1;101 (Boc) 1. IR (KBr, nmax
,
cm21): 1722 (carbamate). UV (l, nm [e]): 257 (15400).
1H NMR (250 MHz) d (ppm): 11.82 (s large, 1H, NH);
7.38 (d, Jˆ3.7 Hz, 1H, H-5);6.88 (d, Jˆ3.7 Hz, 1H, H-4);
1.57 (s, 9H, (CH3)3C. 13C NMR (62.5 MHz) d (ppm):
162.05 (CvO);153.15 (C-2);136.95 (C-4);112.10 (C-5);
81.95 ((C(CH3)3);28.45 (C( CH3)3). Calcd for C8H12N2O2S:
C, 47.98;H, 6.04;N, 13.99;found: C, 47.81;H, 6.01;N,
13.87.

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B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
3.3. Condensation step of 2,3-O-isopropylidene-d-
glyceraldehyde via a dianion species. Compounds 6A,
6B, 19A, 19B
methanol: 99/1) of an aliquot, but most of the product was
isolated as a mixture of diastereoisomers.
3.3.2.
{5-[/2,2-Dimethyl-[1,3]dioxolan-4-yl)-hydroxy-
methyl]-thiazol-2-yl}-carbamic acid tert-butyl ester 19.
Compound 19A. C14H22N2O5S. White solid. Rf: 0.4
(CH2Cl2/MeOH: 95/5). MS CI (Tˆ1708C) m/z: 387
(M157)1, 331 (M1H)1, 313 (M1H±H2O)1. IR (CHCl3,
Diisopropylamine (2.2 equiv.) was dissolved in THF
(1.66 mL/mmol) and cooled to 2788C. The solution was
treated dropwise with 1.6 M n-butyllithium in hexane
(2.2 equiv.) and stirred for 30 min. The LDA solution was
then added by cannulation to a solution of compound 5
(1 equiv.) in anhydrous THF (3.6 mL/mmol) at 2788C
and stirred for 30 min. A solution of 2,3-O-isopropylidene-
d-glyceraldehyde (1.5 equiv.) in THF (0.3 mL/mmol) was
then added. The reaction was allowed to warm to room
temperature and stirred overnight. The reaction was
quenched by dropwise addition of water. The mixture was
diluted with dichloromethane (four volumes), washed with
water, dried over MgSO4, ®ltered and concentrated under
reduced pressure. The resulting solid was puri®ed by ¯ash
chromatography (dichloromethane/methanol: 99/1) to yield
a white solid of both diastereoisomers.
n
max, cm21): 1716 (carbamate). UV (l, nm [e]): 263
(11700). [a]Dˆ121 (cˆ0.19;ethanol). 1H NMR (250 MHz)
d (ppm): 12.08 (s large, 1H, NH);7.27 (s, 1H, H-4);4.76 (d,
Jˆ6.7 Hz, 1H, H-10);4.32 (m, 1H, H-2 ); 3.98 (dd, Jˆ6.6,
0
8.7 Hz, 1H, H-30);3.77 (dd, Jˆ5.7, 8.7 Hz, 1H, H-30);1.58
(s, 9H, (CH3)3C);1.49 (s, 3H, CC H3);1.39 (s, 3H, CC H3).
13C NMR (62.5 MHz) d (ppm): 162.70 (CvO);152.70 (C-
2);134.45 (C-4);129.80 (C-5);110.30 ( C(CH3)2);82.00
0
0
0
(C(CH3)3);79.25 (C-2 );69.45 (C-1 );66.00 (C-3 );28.15
(C(CH3)3);25.00±26.65 (C( CH3)2).
Compound 19B. C14H22N2O5S. White solid. Rf: 0.4
(CH2Cl2/MeOH: 95/5). MS CI (Tˆ1708C) m/z: 331
(M1H)1, 313 (M1H±H2O)1. IR (CHCl3, nmax, cm21):
1719 (carbamate). UV (l, nm [e]): 263 (11500). [a]D ˆ
223 (cˆ0.19;ethanol). 1H NMR (250 MHz) d (ppm):
11.85 (s large, 1H, NH);7.28 (s, 1H, H-4);4.97 (d,
The product 6 was isolated in 99% yield (3.35 g);both
diastereoisomers were characterized separately after column
chromatography on silica (dichloromethane/methanol: 99/1)
of an aliquot, but most of the product was isolated as a
mixture of diastereoisomers.
0
Jˆ5.2 Hz, 1H, H-10);4.29 (m, 1H, H-2 );4.04 (m, 2H, H-
30);1.57 (s, 9H, (C H3)3C);1.47 (s, 3H, CC H3);1.37 (s, 3H,
CCH3). 13C NMR (62.5 MHz) d (ppm): 162.00 (CvO);
152.90 (C-2);134.35 (C-4);130.40 (C-5);110.10
3.3.1. N-{5-[/2,2-Dimethyl-[1,3/S)]dioxolan-4-yl)-/S)-
hydroxy-methyl]-thiazol-2-yl}-2,2-dimethyl-propionamide
6. Compound 6A. C14H22N2O4S. White solid. Mpˆ1438C.
Rf: 0.4 (CH2Cl2/MeOH: 95/5). MS CI (Tˆ1708C), m/z: 315
(M1H)1;297 (M 1H±H2O)1. IR (CHCl3, nmax, cm21):
3424 (NH), 3400±3200 (alcohol), 1682 (amide). UV (l,
nm [e]): 271 (14600). [a]Dˆ17 (cˆ3.5;ethanol). 1H
NMR (250 MHz) d (ppm): 9.65 (s large, 1H, NH);7.36
(s, 1H, H-4);4.82 (d, Jˆ6.8 Hz, 1H, H-10);4.31 (m, 1H,
H-20);3.96 (dd, Jˆ6.6, 8.6 Hz, 1H, H-30);3.77 (dd, Jˆ5.5,
8.6 Hz, 1H, H-30);3.49 (s large, 1H, OH);1.49 (s, 3H,
CCH3);1.39 (s, 3H, CC H3);1.31 (s, 9H, (C H3)3). 13C
NMR (62.5 MHz) d (ppm): 176.45 (CvO);159.50 (C-2);
0
0
(C(CH3)2);82.25 ( C(CH3)3);79.10 (C-2 );68.65 (C-1 );
65.60 (C-30);28.45 (C( CH3)3);25.20±26.75 (C( CH3)2).
HRMS: m/z calcd for C14H23N2O5S: 331.1327;found:
331.1316.
3.4. Oxidation of the mixture of alcohols in position 10 to
the single ketone. Compounds 7, 20
The mixture of alcohols (1 equiv.) was dissolved in dioxane
(1.75 mL/mmol);the solution was then treated with man-
ganese dioxide (15 equiv.) and stirred overnight at room
temperature. The solution was treated with additional
manganese dioxide (15 equiv.) and stirred overnight. Filtra-
tion through a Celitew pad, concentration under reduced
pressure and ¯ash chromatography (dichloromethane/
methanol: 99/1) yielded the product as a white solid.
0
134.65 (C-4);131.40 (C-5);110.25 ( C(CH3)2);79.35 (C-2 );
0
69.50 (C-10);65.90 (C-3 );39.20 ( C(CH3)3);26.60 (C CH3);
26.25 (C(CH3)3);25.05 (C CH3). Calcd for C14H22N2O4S: C,
53.48;H, 7.05;N, 8.91;found: C, 53.33;H, 7.05;N, 8.74.
Compound 6B. C14H22N2O4S. White solid. Rf: 0.4 (CH2Cl2/
MeOH: 95/5). MS CI (Tˆ1708C) m/z: 315 (M1H)1, 297
(M1H±H2O)1. IR (CHCl3, nmax, cm21): 3425 (NH), 3400±
3200 (alcohol), 1682 (amide). UV (l, nm [e]): 271 (14200).
3.4.1. N-[5-/2,2-Dimethyl-[1,3/S)]dioxolane-4-carbonyl)-
thiazol-2-yl]-2,2-dimethyl-propionamide 7. Yield: 82%,
889 mg. C14H20N2O4S. White crystals. Mpˆ1258C (ethanol).
Rf: 0.8 (CH2Cl2/MeOH: 95/5). MS CI (Tˆ1708C) m/z: 313
(M1H)1. IR (CHCl3, nmax, cm21): 3420 (NH), 1690 (amide),
1654 (ketone). UV (l, nm [e]): 226 (10500), 308 (30600).
1
[a]Dˆ231 (cˆ2.0;ethanol). H NMR (400 MHz) d (ppm):
9.65 (s large, 1H, NH);7.32 (s, 1H, H-4);4.95 (d, Jˆ5.5 Hz,
0
1H, H-10);4.28 (m, 1H, H-2 );3.98 (ABX sys; Jˆ5.7,
1
8.6 Hz, 1H, H-30);3.97 (sys ABX; Jˆ6.6, 8.6 Hz, 1H, H-
30);1.46 (s, 3H, CC H3);1.35 (s, 3H, CC H3);1.30 (s, 9H,
(CH3)3C). 13C NMR (62.5 MHz) d (ppm): 176.75 (CvO);
159.50 (C-2);134.80 (C-4);132.45 (C-5);110.40
[a]Dˆ215 (cˆ2.30;ethanol). H NMR (250 MHz) d (ppm):
9.74 (s large, 1H, NH);8.42 (s, 1H, H-4);4.89 (t, Jˆ6.4 Hz,
1H, H-20);4.28 (d, Jˆ6.4 Hz, 2H, H-30);1.47 (s, 3H, CC H3);
1.46 (s, 3H, CCH3);1.34 (s, 9H, (C H3)3C). 13C NMR
(75 MHz) d (ppm): 191.75 (10-CvO);176.80 (C vO);
164.95 (C-2);146.45 (C-4);130.15 (C-5);111.50 ( C(CH3)2);
79.50 (C-20);66.80 (C-3 0);39.45 ( C(CH3)3);27.15
(C(CH3)3);25.40±26.05 (C( CH3)2). HRMS: m/z calcd for
C14H21N2O4S: 313.1221;found: 313.1221. Calcd for
C14H20N2O4S: C, 53.83;H, 6.45;N, 8.97;found: C, 53.49;
H, 6.39;N, 8.91.
0
0
0
(C(CH3)2));79.40 (C-2 );69.00 (C-1 );66.05 (C-3 );39.50
(C(CH3)3);27.00±27.55 (C( CH3)2);25.45 (C( CH3)3). HRMS:
m/z calcd for C14H23N2O4S: 315.1378;found: 315.1388.
The product 19 was isolated in 93% yield (15.3 g);both
diastereoisomers were characterized separately after
chromatography on a silica column (dichloromethane/

B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
4207
3.4.2. [5-/2,2-Dimethyl-[1,3]dioxolane-4-carbonyl)-thiazol-
2-yl]-carbamic acid tert-butyl ester 20. Yield 85%,
170 mg. C14H20N2O5S. White solid. Rf: 0.8 (CH2Cl2/
MeOH: 95/5). MS CI (Tˆ1708C) m/z: 329 (M1H)1, 272
(M1H257)1. IR (CHCl3, nmax, cm21): 1725 (carbamate),
1648 (ketone). UV (l, nm [e]): 218 (10600);308 (25900).
[a]Dˆ253 (cˆ1.4;chloroform). 1H NMR (400 MHz) d
(ppm): 8.36 (s, 1H, H-4);4.87 (dd, Jˆ5.7, 7.3 Hz, 1H, H-
20);4.32 (dd, Jˆ5.4, 8.6 Hz, 1H, H-30);4.25 (dd, Jˆ7.3,
8.6 Hz, 1H, H-30);1.57 (s, 9H, (C H3)3C);1.41 (s, 6H,
(CH2Cl2). MS CI (Tˆ1608C) m/z: 313 (M1H±PhCOOH).
IR (CHCl3, nmax, cm21): 1720. UV (l, nm [e]): 231
(11500);263 (11000). [ a]Dˆ114 (cˆ1.5;ethanol). 1H
NMR (250 MHz) d (ppm): 10.28 (s large, 1H, NH);8.04
(m, 2H, Ph);7.4 to 7.6 (m, 3H, Ph);7.27 (s, 1H, H-4);6.28
0
(d, Jˆ5.9 Hz, 1H, H-10);4.56 (m, 1H, H-2 );4.18 (dd,
Jˆ6.5, 8.6 Hz, 1H, H-30);4.03 (dd, Jˆ5.6, 8.6 Hz, 1H,
H-30);1.55 (s, 9H, (C H3)3C);1.43 (s, 3H, CC H3);1.37 (s,
3H, CCH3). 13C NMR (75 MHz) d (ppm): 165.30 (CvO);
152.80 (C-2);136.90 (C-4);133.40 (Ph);130.00 (C-5 or
Ph);129.60 (C-5 or Ph);128.60 (Ph);128.50 (Ph);110.60
13
(CH3)2C). C NMR (62.5 MHz) d (ppm): 191.20 (10-
0
0
CvO);177.65 (C vO);167.55 (C-2);146.40 (C-4);
129.60 (C-5);111.35 ( C(CH3)2);83.25 ( C(CH3)3);79.30
(C-20);66.50 (C-3 0);28.15 (C( CH3)3);25.35±25.95
(C(CH3)2).
(C(CH3)2);82.40 ( C(CH3)3);77.40 (C-2 );70.30 (C-1 );
66.45 (C-30);29.80 (C( CH3)3);25.25±26.70 (C( CH3)2).
3.7. Isolation of pure alcohol 6B or 19B by reduction of
the ketone, esteri®cation and methanolysis of ester
3.5. Isolation of pure alcohol 6A or 19A by reduction of
the ketone
The phenylester (8 or 21) was dissolved in THF (10 mmol/
mL) and treated at 08C with a 1N solution of NaOMe
(10 mmol/mL) and stirred at room temperature overnight.
The alcohol was extracted with dichloromethane. The
organic layer was dried over MgSO4, ®ltered, concentrated
under reduced pressure and puri®ed by ¯ash chromato-
graphy (dichloromethane/methanol: 99/1) to yield 6B and
19B.
The ketone (7 or 20) was dissolved in THF and treated at
2788C with 3 equiv. of l-Selectridew. After total disappear-
eance of the starting material, the reaction was quenched by
addition of methanol. The solution was then ®ltered through a
Celitew pad and the solvent removed under reduced pressure.
The residue was puri®ed by ¯ash chromatography (dichloro-
methane/methanol: 99/1) to yield alcohol 6A or 19A.
3.8. Protection of 10-hydroxyle by THDMS. Compounds
9A, 9B, 22A, 22B
3.6. Dodge reaction: inversion of stereochemistry of
alcohol in position 10. Compounds 8, 21
The alcohol (1 equiv.) was dissolved in DMF (0.29 mmol/mL);
imidazole (5 equiv.) anddimethylthexylsilyl chloride (2 equiv.)
were added. After stirring for 24 h at 408C the mixture was
diluted with dichloromethane (four volumes) and washed
with water. The organic layer was dried over MgSO4, ®ltered,
concentrated under reduced pressure and puri®ed by ¯ash
chromatography (dichloromethane/methanol: 99/1).
The alcohol (1 equiv.) was dissolved in THF (0.045 mmol/
mL) and treated with triphenylphosphine (4 equiv.) and
benzoic acid (4 equiv.). The mixture was cooled to 2788C
and treated with DEAD (4 equiv.). The mixture was allowed
to warm to room temperature and stirred for 3 h. The mix-
ture was then diluted with dichloromethane (four volumes),
washed with water (four volumes), dried over MgSO4,
®ltered and concentrated under reduced pressure. The
crude residue was puri®ed by ¯ash chromatography (hep-
tane/ethyl acetate: 7/3).
3.8.1. N-/5-{/2,2-Dimethyl-[1,3]dioxolan-4-yl)-[dimethyl-
/1,1,2-trimethyl-propyl)-silanyloxy]-methyl}-thiazol-2-
yl)-2,2-dimethyl-propionamide 9A. Quantitative yield,
7.9 g. C22H40N2O4SSi. Mpˆ1598C. Rf: 0.8 (CH2Cl2/
MeOH: 95/5). MS CI (Tˆ1808C) m/z: 457 (M1H)1. IR
(CHCl3, nmax, cm21): 3429 (NH), 1682 (amide), 1214 (Si±
O). UV (l, nm [e]): 271 (11900). [a]Dˆ238 (cˆ0.65;
3.6.1. Benzoic acid /2,2-dimethyl-[1,3]dioxolan-4-yl)-[2-
/2,2-dimethyl-propionylamino)-thiazol-5-yl]-methyl ester
8. Yield: 85%, 79 mg. C21H26N2O5S. White solid. Rf: 0.9
(CH2Cl2/MeOH: 95/5). MS CI (Tˆ1608C) m/z: 419
(M1H)1, 297 (M1H±PhCOOH)1. IR (CHCl3, nmax, cm21):
1722 (ester), 1682 (amide). UV (l, nm [e]): 271 (13700),
231 (15300). [a]Dˆ126 (cˆ2.41;ethanol). 1H NMR
(250 MHz) d (ppm): 9.54 (s large, 1H, NH);8.04 (m, 2H,
Ph);7.4 to 7.6 (m, 3H, Ph);7.44 (s, 1H, H-4);6.31 (d,
1
ethanol). H NMR (250 MHz) d (ppm): 9.80 (s large, 1H,
NH);7.31 (s, 1H, H-4);4.93 (d, Jˆ6 Hz, 1H, H-10);4.22 (m,
1H, H-20);3.84 (dd, Jˆ6, 8 Hz, 1H, H-30);3.69 (dd, Jˆ6,
8 Hz, 1H, H-30);1.62 (sept, Jˆ7 Hz, 1H, CH(CH3)2);1.35
(s, 3H, CCH3);1.33 (s, 3H, CC H3);1.29 (s, 9H, (C H3)3C);
0.87 (d, Jˆ7 Hz, 6H, CH(CH3)2);0.84 (s, 6H, C H3 thexyl);
0.13 (s, 3H, CH3±Si);0.02 (s, 3H, C H3±Si). 13C NMR
(75 MHz) d (ppm): 176.30 (CvO);159.40 (C-2);134.20
0
Jˆ5.8 Hz, 1H, H-10);4.56 (m, 1H, H-2 );4.18 (dd, Jˆ6.4,
8.4 Hz, 1H, H-30);4.00 (dd, Jˆ5.2, 8.4 Hz, 1H, H-30);1.44
(s, 3H, CCH3);1.37 (s, 3H, CC H3);1.30 (s, 9H, (C H3)3C).
13C NMR (75 MHz) d (ppm): 175.50 (CvO);159.20 (C-2);
137.40 (C-4);133.55 (Ph);129.95 (C-5);129.60 (Ph);
0
(C-4);132.50 (C-5);110.00 ( C(CH3)2));79.20 (C-2 );70.55
0
(C-10);65.55 (C-3 );39.15 ( C(CH3)3);34.15 ( CH(CH3)2);
27.30 (C(CH3)3);25.20±26.40 ( CH3 acetonide);25.10 (Si±
C(CH3)2(C3H7));18.60±18.70±20.20±20.31 (4 CH3 thexyl);
22.70 (Si±CH3); 22.90 (Si±CH3). Calcd for C22H40N2O4SSi:
57.89;H, 8.71;N, 5.83;found: C, 57.86;H, 8.83;N,
6.13%.
0
128.60 (Ph);127.85 (Ph);110.65 ( C(CH3)2);77.35 (C-2 );
70.25 (C-10);66.40 (C-3 0);39.20 ( C(CH3)3);27.30
(C(CH3)3);25.25±26.70 (C( CH3)2). HRMS: m/z calcd for
C21H27N2O5S: 419.1640;found: 419.1633.
3.6.2. Benzoic acid /2-tert-butoxycarbonylamino-thiazol-
5-yl)-/2,2-dimethyl-[1,3]dioxolan-4-yl)-methyl ester 21.
Yield 90%, 24 mg. C21H26N2O6S. White solid. Rf: 0.6
3.8.2. N-/5-{/2,2-Dimethyl-[1,3]dioxolan-4-yl)-[dimethyl-
/1,1,2-trimethyl-propyl)-silanyloxy]-methyl}-thiazol-2-yl)-
2,2-dimethyl-propionamide 9B. Quantitative yield, 73 mg.

4208
B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
C22H40N2O4SSi. White solid. Rf: 0.8 (CH2Cl2/MeOH: 95/5).
3.9. Selective deprotection of the 20,30-hydroxyles.
Compounds 10A, 10B, 11, 12A, 12B, 23A, 23B
MS CI (Tˆ1808C) m/z: 457 (M1H)1. IR (CHCl3, nmax
,
cm21): 3426 (NH), 1681 (amide), 1220 (Si±O). UV (l,
nm [e]): 273 (19900) [a]Dˆ138 (cˆ0.65;ethanol). 1H
NMR (300 MHz) d (ppm): 9.47 (s large, 1H, NH);7.29
(s, 1H, H-4);4.80 (d, Jˆ6.5 Hz, 1H, H-10);4.12 (m, 1H,
H-20);4.06 (dd, Jˆ5.8, 8.2 Hz, 1H, H-30);4.00 (dd, Jˆ5.8,
8.2 Hz, 1H, H-30);1.62 (sept, Jˆ6.9 Hz, 1H, CH(CH3)2);
1.44 (s, 3H, CCH3);1.31 (s, 12H, (C H3)3C1CCH3);0.88
(d, Jˆ6.9 Hz, 3H, CHCH3);0.87 (d, Jˆ6.9 Hz, 3H,
CHCH3);0.85 (s, 3H, C H3 thexyl);0.84 (s, 3H, C H3 thexyl);
0.16 (s, 3H, CH3±Si); 20.05 (s, 3H, CH3±Si). 13C NMR
(62.5 MHz) d (ppm): 176.30 (CvO);159.10 (C-2);134.40
The acetonide (1 equiv.) was dissolved in THF (0.25 mmol/
mL) and treated with PTSA (1.5 equiv.). After stirring for 6
days at 48C, the mixture was neutralized by addition of a
32% ammonia solution. After ®ltration, solvent was
removed under reduced pressure and the residue was puri-
®ed by ¯ash chromatography (dichloromethane/methanol:
99/1).
3.9.1. N-/5-{1-[Dimethyl-/1,1,2-trimethyl-propyl)-silanyl-
oxy]-2,3-dihydroxy-propyl}-thiazol-2-yl)-2,2-dimethyl-
propionamide 12A. Yield: 73%, 3.4 g. C19H36N2O4SSi.
White solid. Rf: 0.3 (CH2Cl2/MeOH: 95/5, revealed UV).
MS CI (Tˆ1808C) m/z: 473 (M157)1;417 (M 1H)1. IR
(CHCl3, nmax, cm21): 3426 (NH), 3400±3200 (alcohol),
1683 (amide). UV (l, nm [e]): 272 (14000). [a]Dˆ237
(cˆ1.62;ethanol). 1H NMR (250 MHz, CDCl311 drop
D2O) d (ppm): 7.30 (s, 1H, H-4);4.98 (d, Jˆ6.5 Hz, 1H,
H-10);3.75 (ddd, Jˆ3.6, 6.5, 11.6 Hz, 1H, H-20);3.67 (dd,
Jˆ3.6, 11.6 Hz, 1H, H-30);3.45 (dd, Jˆ5.1, 11.6 Hz, 1H, H-
30);1.63 (sept, Jˆ6.8 Hz, 1H, CH(CH3)2);1.32 (s, 9H,
(CH3)3C);0.89 (d, Jˆ6.8 Hz, 3H, CHCH3);0.88 (d,
Jˆ6.8 Hz, 3H, CHCH3);0.86 (s, 3H, C H3 thexyl);0.84 (s,
3H, CH3 thexyl);0.16 (s, 3H, C H3±Si); 20.05 (s, 3H, CH3±
Si). 13C NMR (62.5 MHz) d (ppm): 176.35 (CvO);159.40
(C-2);134.65 (C-4);132.75 (C-5).;76.25 (C-1 0);69.70 (C-
20);62.35 (C-3 0);39.15 ( C(CH3)3);34.10 ( CH(CH3)2);27.20
(C(CH3)3);25.05 (Si± C(CH3)2(C3H7));18.50±18.70±
20.10±20.40 (4CH3 thexyl); 22.40 (Si±CH3).; 23.20 (Si±
CH3). HRMS: m/z calcd for C19H37N2O4SSi: 417.2243;
found: 417.2224.
0
(C-4);134.35 (C-5);109.90 ( C(CH3)2);80.40 (C-2 );70.20
0
(C-10);66.75 (C-3 );39.20 ( C(CH3)3);34.20 ( CH(CH3)2);
27.30 (C(CH3)3);25.30±26.90 (C( CH3)2);25.10 (Si±
C(CH3)2(C3H7));18.75±20.30±20.35 (4 CH3 thexyl);9.90±
10.50 (Si±CH3). HRMS: m/z calcd for C22H41N2O4SSi:
457.2554;found: 457.2556.
3.8.3. /5-{/2,2-Dimethyl-[1,3]dioxolan-4-yl)-[dimethyl-
/1,1,2-trimethyl-propyl)-silanyloxy]-methyl}-thiazol-2-
yl)-carbamic acid tert-butyl ester 22A. Yield: 99%,
102 mg. C22H40N2O5SSi. White solid. Rf: 0.9 (CH2Cl2/
MeOH: 95/5). MS CI (Tˆ1708C) m/z: 473 (M1H)1. IR
(CHCl3, nmax, cm21): 1716 (carbamate). UV (l, nm [e]):
263 (13300). [a]Dˆ128 (cˆ1.6;ethanol).
1H NMR
(250 MHz, CD3OD/CDCl3: 9/1) d (ppm): 7.16 (s large,
1H, H-4);4.83 (d, Jˆ6.3 Hz, 1H, H-10);4.11 (m, 1H, H-
20);4.02 (dd, Jˆ6.1, 8.1 Hz, 1H, H-30);3.93 (dd, Jˆ6,
8.1 Hz, 1H, H-30);1.61 (sept, Jˆ6.9 Hz, 1H, CH(CH3)2);
1.51 (s, 9H, (CH3)3C);1.37 (s, 3H, CC H3);1.27 (s, 3H,
CCH3);0.87 (d, Jˆ6.9 Hz, 6H, CH(CH3)2);0.84 (s, 3H,
CH3 thexyl);0.83 (s, 3H, C H3 thexyl);0.14 (s, 3H, C H3±
Si); 20.06 (s, 3H, CH3±Si). 13C NMR (62.5 MHz, CD3OD/
CDCl3: 9/1) d (ppm): 162.30 (CvO);154.20 (C-2);135.80
(C-4);135.50 (C-5);110.80 ( C(CH3)2);82.90 ( C(CH3)3);
81.35 (C-20);71.15 (C-1 0);67.45 (C-3 0);35.30
(CH(CH3)2);28.50 (C( CH3)3);25.40 (C CH3);25.95 (Si±
3.9.2. N-/5-{1-[Dimethyl-/1,1,2-trimethyl-propyl)-silanyl-
oxy]-2,3-dihydroxy-propyl}-thiazol-2-yl)-2,2-dimethyl-
propionamide 12B. Yield: 72%, 2.3 g. C19H36N2O4SSi.
White solid. Mpˆ778C. Rf: 0.3 (CH2Cl2/MeOH: 95/5).
MS CI (Tˆ1808C) m/z: 473 (M157)1;417 (M 1H)1. IR
(CHCl3, nmax, cm21): 3426 (NH), 3400±3200 (alcohol),
1683 (amide). UV (l, nm [e]): 271 (14200). [a]Dˆ147
(cˆ1.6;ethanol). 1H NMR (400 MHz) d (ppm): 9.27 (s
large, 1H, NH);7.26 (s, 1H, H-4);4.93 (d, Jˆ5.6 Hz, 1H,
C(CH3)2(C3H7));27.05 (C CH3);19.10±20.80 (4
thexyl); 22.62 (CH3±Si); 22.06 (CH3±Si).
CH3
3.8.4. /5-{/2,2-Dimethyl-[1,3]dioxolan-4-yl)-[dimethyl-
/1,1,2-trimethyl-propyl)-silanyloxy]-methyl}-thiazol-2-
yl)-carbamic acid tert-butyl ester 22B. Yield: 99%,
124 mg. C22H40N2O5SSi. White solid. Rf: 0.9 (CH2Cl2/
MeOH: 95/5). MS CI (Tˆ1708C) m/z: 473 (M1H)1. IR
(CHCl3, nmax, cm21): 1716 (carbamate). UV (l, nm [e]):
0
0
H-10);3.80 (m, 1H, H-2 );3.69 (m, 2H, H-3 );1.63 (sept,
Jˆ6.8 Hz, 1H, CH(CH3)2);1.32 (s, 9H, (C H3)3C);0.88 (d,
Jˆ6.8 Hz, 3H, CHCH3);0.87 (d, Jˆ6.8 Hz, 3H, CHCH3);
0.85 (s, 3H, CH3 thexyl);0.84 (s, 3H, C H3 thexyl);0.16 (s,
3H, CH3±Si); 20.04 (s, 3H, CH3±Si). 13C NMR
(62.5 MHz) d (ppm): 176.15 (CvO);159.10 (C-2);0
134.90 (C-4);133.20 (C-5);75.80 (C-1 0);70.70 (C-2 );
63.05 (C-30);39.80 ( C(CH3)3);34.20 ( CH(CH3)2);27.30
(C(CH3)3);25.10 (Si± C(CH3)2(C3H7));18.70±18.80±
20.20±20.25 (4CH3 thexyl);10.00±10.70 (Si±( CH3)2).
Calcd for C19H36N2O4SSi: C, 54.77;H, 8.71;N, 6.72.
Found: C, 54.61;H, 8.52;N, 6.71%.
263 (12900). [a]Dˆ228 (cˆ2.8;ethanol).
1H NMR
(250 MHz) d (ppm): 7.20 (s large, 1H, H-4);5.30 (d,
0
Jˆ6.1 Hz, 1H, H-10);4.25 (m, 1H, H-2 );3.89 (dd, Jˆ6.7,
8.6 Hz, 1H, H-30);3.74 (dd, Jˆ6.4, 8.6 Hz, 1H, H-30);1.59
(sept, Jˆ6.9 Hz, 1H, CH(CH3)2);1.58 (s, 9H, (C H3)3C);
1.35 (s, 3H, CCH3);1.34 (s, 3H, CC H3);0.87 (d,
Jˆ6.9 Hz, 6H, CH(CH3)2);0.86 (s, 3H, C H3 thexyl);
0.84 (s, 3H, CH3 thexyl);0.15 (s, 3H, C H3±Si); 20.03
(s, 3H, CH3±Si). 13C NMR (62.5 MHz) d (ppm): 162.00
(CvO);152.95 (C-2);133.95 (C-4);131.00 (C-5);110.05
(C(CH3)2);81.90 ( C(CH3)3);79.40 (C-2 0);70.75 (C-
10);65.70 (C-3 0);34.20 ( CH(CH3)2);28.50 (C( CH3)3);
25.30±26.55 (C(CH3)2);25.13 (Si± C(CH3)2(C3H7));
18.60±18.65±20.25±20.35 (4CH3 thexyl);10.20±10.45
((CH3)2±Si).
The product 10A was isolated after chromatography with
dichloromethane/methanol: 95/5, as secondary product
from the formation of compound 12 when more than
1.5 equiv. of PTSA was used in methanol as solvent.
3.9.3. 2,2-Dimethyl-N-[5-/1,2,3-trihydroxy-propyl)-
thiazol-2-yl]-propionamide 10A. C11H18N2O4S. Rf: 0.1

B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
4209
0
(CH2Cl2/MeOH: 90/10). MS CI (Tˆ1908C) m/z: 275
(M1H)1. IR (KBr, nmax, cm21): 1654 (CvO). UV (l, nm
[e]): 270 (17700). [a]Dˆ277 [cˆ0.09;(NH 4)6Mo7O24.4H2O].
1H NMR (250 MHz, CD3OD) d (ppm): 7.30 (s, 1H, H-4);
Jˆ6.6 Hz, 1H, H-10);3.73 (m, 1H, H-2 );3.64 (dd, Jˆ3.3,
11.6 Hz, 1H, H-30);3.44 (dd, Jˆ5.1, 11.6 Hz, 1H, H-30);
1.57 (sept, Jˆ6.9 Hz, 1H, CH(CH3)2);1.55 (s, 9H,
(CH3)3C);0.87 (d, Jˆ6.9 Hz, 3H, CHCH3);0.86 (d,
Jˆ6.9 Hz, 3H, CHCH3);0.83 (s, 3H, C H3 thexyl);0.82 (s,
3H, CH3 thexyl);0.14 (s, 3H, C H3±Si); 20.06 (s, 3H, CH3±
Si). 13C NMR (75 MHz) d (ppm): 162.45 (CvO);152.05
(C-2);134.90 (C-4);131.40 (C-50);82.35 ( C(CH3)3);76.50
0
4.89 (d, Jˆ4.7 Hz, 1H, H-10);3.7 (m, 1H, H-2 );3.60 (dd,
Jˆ4.7, 11 Hz, 1H, H-30);3.45 (dd, Jˆ6.1, 11 Hz, 1H, H-30);
1.26 (s, 9H, (CH3)3C). 13C NMR (62.5 MHz, CD3OD) d
(ppm): 178.65 (CvO);160.50 (C-2);135.55 (C-4);
0
0
0
0
134.90 (C-5);76.60 (C-2 );69.30 (C-1 );64.00 (C-3 );
40.10 (C(CH3)3);27.30 (C( CH3)3). HRMS: m/z calcd for
C11H19N2O4S: 275.1065;found: 275.1091.
(C-20);69.90 (C-1 );62.60 (C-3 );34.35 ( CH(CH3)2);28.60
(C(CH3)3);25.30 (Si± C(CH3)2(C3H7));18.80±19.00±
20.35±20.70 (4CH3 thexyl); 22.05 (Si±CH3); 22.90 (Si±
CH3). HRMS: m/z calcd for C19H37N2O5SSi: 433.2192;
found: 433.2204.
The product 10B was isolated after chromatography with
dichloromethane/methanol: 95/5, as secondary product
from the formation of compound 12 when more than
1.5 equiv. of PTSA was used in methanol.
3.9.7. /5-{1-[Dimethyl-/1,1,2-trimethyl-propyl)-silanyl-
oxy]-2,3-dihydroxy-propyl}-thiazol-2-yl)-carbamic acid
tert-butyl ester 23B. Yield: 68%, 5.3 g. C19H36N2O5SSi.
White solid. Mpˆ788C. Rf: 0.3 (CH2Cl2/MeOH: 95/5).
MS ESI (methanol) m/z: 455 (M1Na)1;433 (M 1H)1. IR
(CHCl3, nmax, cm21): 1719 (carbamate). UV (l, nm [e]):
263 (10600). [a]Dˆ159 (cˆ0.94;ethanol). 1H NMR
(250 MHz) d (ppm): 11.90 (s large, 1H, NH);7.19 (0s, 1H,
H-4);4.88 (d, Jˆ5.5 Hz, 1H, H-10);3.81 (m, 1H, H-2 );3.68
(m, 2H, H-30);1.59 (sept, Jˆ6.9 Hz, 1H, CH(CH3)2);1.56
(s, 9H, (CH3)3C);0.88 (d, Jˆ6.9 Hz, 3H, CHCH3);0.87 (d,
Jˆ6.9 Hz, 3H, CHCH3);0.84 (s, 3H, C H3 thexyl);0.83 (s,
3H, CH3 thexyl);0.15 (s, 3H, C H3±Si); 20.34 (s, 3H, CH3±
Si). 13C NMR (75 MHz) d (ppm): 162.40 (CvO);152.80
(C-2);134.70 (C-4);131.40 (C-50);82.15 ( C(CH3)3);75.70
3.9.4. 2,2-Dimethyl-N-[5-/1,2,3-trihydroxy-propyl)-
thiazol-2-yl]-propionamide 10B. C11H18N2O4S. White
solid. Rf: 0.1 (CH2Cl2/MeOH: 90/10). MS CI (Tˆ2008C)
m/z: 275 (M1H)1, 257 (M2H2O)1. IR (KBr, nmax
,
cm21): 1654 (CvO). UV (l, nm [e]): 272 (19500).
[a]Dˆ165 [cˆ0.08;(NH 4)6Mo7O24.4H2O]. 1H NMR
(250 MHz, pyridine-D5) d (ppm): 8.00 (s, 01H, H-4);5.78
(d, Jˆ6.1 Hz, 1H, H-10);4.72 (m, 1H, H-2 );4.50 (m, 1H,
H-30);1.48 (s, 9H, (C H3)3C). 13C NMR (62.5 MHz, pyridine-
D5) d (ppm): 177.05 (CvO);159.90 (C-20);135.80 (C-4);
0
0
135.50 (C-5);76.80 (C-2 );70.60 (C-1 );64.90 (C-3 );
39.40 (C (CH3)3);27.30 (C( CH3)3).
(C-20);70.55 (C-1 );63.00 (C-3 );34.10 ( CH(CH3)2);28.40
0
The mixture of inseparable products 11 was isolated after
chromatography with dichloromethane/methanol: 98/2, as
secondary product from the formation of compound 12
when more than 1.5 equiv. of PTSA was used in methanol.
(C(CH3)3);25.05 (Si± C(CH3)2(C3H7));18.35±18.75±
20.20±20.35 (4CH3 thexyl); 22.35 (Si±CH3); 23.10 (Si±
CH3). Calcd for C19H36N2O5SSi: C, 52.75;H, 8.39;N, 6.47;
found: C, 52.61;H, 8.43;N, 6.16.
3.9.5. N-[5-/2,3-Dihydroxy-1-methoxy-propyl)-thiazol-2-
yl]-2,2-dimethyl-propionamide 11. C12H20N2O4S. White
solid. Rf: 0.4 (CH2Cl2/MeOH: 95/5). MS CI (Tˆ1708C)
3.10. Dichlorination of 20- and 30-hydroxyles.
Compounds 13A, 13B, 14A, 14B, 24A, 24B
m/z: 289 (M1H)1;270 (M 2H2O)1. IR (CHCl3, nmax
,
cm21): 3424 (NH), 3400±3200 (OH), 1682 (amide).
The diol (1 equiv.) was dissolved in THF (0.2 mmol/mL)
and treated with triphenylphosphine (2.5 equiv.) and N-
chlorosuccinimide (2.5 equiv.). Mixture was re¯uxed for
12 h. Solvent was removed under reduced pressure and
the residue puri®ed by ¯ash chromatography (dichloro-
methane/methanol: 98/2).
1
Major compound. H NMR (250 MHz) d (ppm): 9.57 (s
large, 1H, NH);7.31 (s, 1H, H-5);4.45 (d, Jˆ6 Hz, 1H,
0
0
H-10);3.93 (m, 1H, H-2 );3.71 (m, 1H, H-3 );3.25 (s,
3H, CH3O);1.31 (s, 9H, (C H3)3C). 13C NMR (75 MHz) d
(ppm): 176.90 (CvO);160.45 (C-2);137.15 (C-4);129.90
(C-5);79.14 (C-1 0);75.55 (C-2 0);63.70 (C-3 0);57.20 ( CH3±
O);39.60 ( C(CH3)3);27.55 (C( CH3)3). Minor compound. 1H
NMR (250 MHz) d (ppm): 9.57 (s large, 1H, NH);7.36 (s,
3.10.1. N-/5-{2,3-Dichloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-propyl}-thiazol-2-yl)-2,2-dimethyl-
propionamide 14A. Yield: 60%, 834 mg. C19H34Cl2N2O2SSi.
White solid. Rf: 0.7 (CH2Cl2/MeOH: 95/5). MS CI (Tˆ1708C)
m/z: 453/455/457 (M1H)1. IR (CHCl3, nmax, cm21): 3424
(NH), 2965±2870 (CH), 1683 (amide), 1407±1289 (C±Cl).
UV (l, nm [e]): 270 (10900). [a]Dˆ236 (cˆ1.09;ethanol).
1H NMR (200 MHz) d (ppm): 9.72 (s large, 1H, NH);7.37 (s,
1H, H-5);4.48 (d, Jˆ8 Hz, 1H, H-10);3.84 (m, 1H, H-2 );
0
3.67 (m, 1H, H-30);3.28 (s, 3H, C H3O);1.31 (s, 9H,
(CH3)3C). 13C NMR (75 MHz) d (ppm): 176.90 (CvO);
160.40 (C-2);137.20 (C-4);129.50 (C-5);78.50 (C-1
( CH3-O);39.60
0);
74.55 (C-20);63.00 (C-3 0);57.00
(C(CH3)3);27.55 (C( CH3)3).
1H, H-4);5.23 (d, Jˆ6.1 Hz, 1H, H-10);4.19 (m, 1H, H-2 );
0
3.9.6. /5-{1-[Dimethyl-/1,1,2-trimethyl-propyl)-silanyl-
oxy]-2,3-dihydroxy-propyl}-thiazol-2-yl)-carbamic acid
tert-butyl ester 23A. Yield: 68%, 6.8 g. C19H36N2O5SSi.
White solid. Rf: 0.3 (CH2Cl2/MeOH: 95/5). MS CI
(Tˆ1708C) m/z: 489 (M157)1;433 (M 1H)1. IR (CHCl3,
3.87 (dd, Jˆ5, 11.7 Hz, 1H, H-30);3.72 (dd, Jˆ5.3, 11.7 Hz,
1H, H-30);1.63 (sept, Jˆ6.9 Hz, 1H, CH(CH3)2);1.31 (s, 9H,
(CH3)3C);0.90 (d,
Jˆ6.9 Hz, 3H, CHCH3);0.89 (d,
Jˆ6.9 Hz, 3H, CHCH3);0.86 (s, 3H, C H3 thexyl);0.84 (s,
3H, CH3 thexyl);0.20 (s, 3H, C H3±Si); 20.05 (s, 3H, CH3±
Si). 13C NMR (75 MHz) d (ppm): 176.60 (CvO);159.55 (C-
n
max, cm21): 1719 (carbamate). UV (l, nm [e]): 263
(10400). [a]Dˆ248 (cˆ1.02;ethanol). 1H NMR (250 MHz)
2);135.95 (C-4);132.15 (C-5);70.00 (C-1 0);65.10 (C-2 );
0
d (ppm): 12.1 (s large, 1H, NH);7.22 (s, 1H, H-4);4.91 (d,
45.85 (C-30);39.50 ( C(CH3)3);34.10 ( CH(CH3)2);27.70

4210
B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
0
(C(CH3)3);25.15 (Si± C(CH3)2(C3H7));18.95±19.05±20.50±
20.70 (4CH3 thexyl); 22.10 (CH3±Si); 23.15 (CH3±Si).
H-10);3.96 (m, 1H, H-2 );3.70 (dd, Jˆ5.3, 11.2 Hz, 1H,
H-30);3.54 (dd, Jˆ4.8, 11.2 Hz, 1H, H-30);3.00 (s large,
1H, OH);1.62 (sept, Jˆ6.8 Hz, 1H, CH(CH3)2);1.30 (s, 9H,
(CH3)3C);0.88(d, Jˆ6.8 Hz, 3H, CHCH3);0.87(d, Jˆ6.8 Hz,
3H, CHCH3);0.84 (s, 3H, C H3 thexyl);0.83 (s, 3H, C H3
thexyl);0.17 (s, 3H, C H3±Si); 20.05 (s, 3H, CH3±Si). 13C
NMR (62.5 MHz) d (ppm): 176.30 (CvO);159.60 (C-2);
3.10.2. N-/5-{2,3-Dichloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-propyl}-thiazol-2-yl)-2,2-dimethyl-
propionamide 14B. Yield: 56%, 1.15 g. C19H34Cl2N2O2SSi.
Rf: 0.7 (CH2Cl2/MeOH: 95/5). MS CI (Tˆ1808C) m/z: 453/
455/457 (M1H)1, 383 (M22Cl)1, 369/371/373 (M2Piv)1.
IR (CHCl3, nmax, cm21): 3424 (NH), 2965±2870 (CH), 1683
(amide), 1407±1289 (C±Cl). UV (l, nm [e]): 272 (15000).
135.40 (C-4);132.20 (C-5);75.25 (C-2 0);70.05 (C-1 );
0
45.65 (C-30);39.20 ( C(CH3)3);34.15 ( CH(CH3)2);27.25
(C(CH3)3);25.10 (Si± C(CH3)2(C3H7));18.65±18.75±
20.20±20.40 (4CH3 thexyl);9.94±10.67 (Si±( CH3)2).
1
[a]Dˆ131 (cˆ1.02;ethanol). H NMR (250 MHz) d (ppm):
9.77 (s large, 1H, NH);7.39 (s, 1H, H-4);5.31 (d, Jˆ3.9 Hz,
0
1H, H-10);4.08 (m, 1H, H-2 );3.90 (dd, Jˆ6.2, 11.5 Hz, 1H,
3.10.5.
/5-{2,3-Dichloro-1-[dimethyl-/1,1,2-trimethyl-
H-30);3.53 (dd, Jˆ5.9, 11.5 Hz, 1H, H-30);1.64 (sept, Jˆ
6.8 Hz, 1H, CH(CH3)2);1.31 (s, 9H, (C H3)3C);0.90 (d, Jˆ
6.8 Hz, 3H, CHCH3);0.89(d, Jˆ6.8 Hz, 3H, CHCH3);0.88(s,
3H, CH3 thexyl);0.87 (s, 3H, C H3 thexyl);0.19 (s, 3H, C H3±
Si); 20.04 (s, 3H, CH3±Si). 13C NMR (62.5 MHz) d (ppm):
propyl)-silanyloxy]-propyl}-thiazol-2-yl)-carbamic acid
tert-butyl ester 24A. Yield: 59%, 1.99 g. C19H34Cl2N2O3SSi.
White solid. Rf: 0.6 (CH2Cl2/MeOH: 95/5). MS CI (Tˆ1808C)
m/z: 469/471/473 (M1H)1. IR (CHCl3, nmax, cm21): 1718.
1
UV (l, nm [e]): 263 (12400). [a]Dˆ230 (cˆ1.1;ethanol). H
0
NMR (250 MHz) d (ppm): 12.38 (s large, 1H, NH);7.28 (s,
159.50 (C-2);136.45 (C-4);132.00 (C-5);69.45 (C-1 );65.70
0
1H, H-4);5.19 (d, Jˆ6.1 Hz, 1H, H-10);4.19 (m, 1H, H-2 );
0
(C-20);46.80 (C-3 );40.90 ( C(CH3)3);34.25 ( CH(CH3)2);
3.95 (dd, Jˆ4.7, 11.7 Hz, 1H, H-30);3.72 (dd, Jˆ5.7, 11.7 Hz,
1H, H-30);1.60 (sept, Jˆ6.9 Hz, 1H, CH(CH3)2);1.59 (s, 9H,
(CH3)3C);0.88 (d, Jˆ6.9 Hz, 6H, CH(CH3)2);0.85 (s, 3H, C H3
thexyl);0.84 (s, 3H, C H3 thexyl);0.13 (s, 3H, C H3±Si); 20.37
(s, 3H, CH3±Si). 13C NMR (75 MHz) d (ppm): 162.60 (CvO);
153.00 (C-2);135.55 (C-4);130.40 (C-5);82.20 ( C(CH3)3);
27.45 (C(CH3)3);27.30 (Si± C(CH3)2(C3H7));18.70±18.80±
20.30±20.40 (4CH3 thexyl);10.10±10.70 (Si±( CH3)2).
The product 13A of monochlorination was isolated with
81% yield (88 mg) when only 2 equiv. of NCS and PPh3
were used.
70.00 (C-10);64.90 (C-2 );45.80 (C-3 );34.25 ( CH(CH3)2);
28.50 (CH(CH3)3);25.20 ( C(CH3)2 (C3H7));18.70±18.85±
20.45 (4 CH3 thexyl); 22.40 (CH3±Si); 23.10 (CH3±Si).
0
0
3.10.3. N-/5-{3-Chloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-2-hydroxy-propyl}-thiazol-2-yl)-2,2-
dimethyl-propionamide 13A. C19H35ClN2O3SSi. Rf: 0.4
(CH2Cl2/MeOH: 95/5). MS CI (Tˆ1808C) m/z: 435/437
(M1H)1. IR (CHCl3, nmax, cm21): 3425 (NH), 3400±
3200 (OH), 2965±2870 (CH3), 1682 (amide), 1467±1289
(C-Cl). UV (l, nm [e]): 271 (8700). [a]Dˆ229 (cˆ2.33;
3.10.6.
/5-{2,3-Dichloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-propyl}-thiazol-2-yl)-carbamic acid
tert-butyl ester 24B. Yield: 54%, 1.42 g. C19H34Cl2N2O3SSi.
White solid. Rf: 0.6 (CH2Cl2/MeOH: 95/5). MS CI (Tˆ1708C)
m/z: 469/471/473 (M1H)1, 369/371/373 (M1H-Boc)1. IR
(CHCl3, nmax, cm21): 1718 (carbamate). UV (l, nm [e]):
1
ethanol). H NMR (300 MHz) d (ppm): 9.92 (s large, 1H,
NH);7.35 (s, 1H, H-5);5.11 (d, Jˆ4.7 Hz, 1H, H-10);3.85
(m, 1H, H-20);3.61 (dd, Jˆ5.3, 11.3 Hz, 1H, H-30);3.40
(dd, Jˆ5.5, 11.3 Hz, 1H, H-30);3.08 (s large, 1H, OH);1.62
(sept, Jˆ6.8 Hz, 1H, CH(CH3)2);1.30 (s, 9H, (C H3)3C);
0.89 (d, Jˆ6.8 Hz, 3H, CHCH3);0.88 (d, Jˆ6.8 Hz, 3H,
CHCH3);0.86 (s, 3H, C H3 thexyl);0.85 (s, 3H, C H3 thexyl);
0.18 (s, 3H, CH3±Si); 20.03 (s, 3H, CH3±Si). 13C NMR
(75 MHz) d (ppm): 176.40 (CvO);159.70 (C-2);134.95
263 (7500). [a]Dˆ124 (cˆ1.2;ethanol).
1H NMR
(250 MHz) d (ppm): 9.86 (s large, 1H, NH);7.31 (s, 1H, H-
4);5.26 (d, Jˆ4.3 Hz, 1H, H-10);4.10 (m, 1H, H-2 0);3.89 (dd,
Jˆ6, 13.6 Hz, 1H, H-30);3.58 (dd, Jˆ5.7, 13.6 Hz, 1H, H-30);
1.62 (sept, Jˆ6.9 Hz, 1H, CH(CH3)2);1.58 (s, 9H, (C H3)3C);
0.90 (d, Jˆ6.9 Hz, 3H, CHCH3);0.89 (d, Jˆ6.9 Hz, 3H,
CHCH3);0.87 (s, 3H, C H3 thexyl);0.86 (s, 3H, C H3 thexyl);
0.19 (s, 3H, CH3±Si); 20.20 (s, 3H, CH3±Si). 13C NMR
(75 MHz) d (ppm): 162.30 (CvO);152.75 (C-2);134.90
0
(C-4);132.35 (C-5);75.70 (C-2 0);69.40 (C-1 );44.90 (C-
30);39.20 ( C(CH3)3);34.20 ( CH(CH3)2);27.25 (C( CH3)3);
25.15 (Si±C(CH3)2(C3H7));18.60±18.75±20.20±20.45
(4CH3 thexyl); 22.40 (CH3±Si); 23.10 (CH3±Si). HRMS:
m/z calcd for C19H36ClN2O3SSi: 435.1904 and 437.1874;
found: 435.1887 and 437.1852.
0
(C-4);130.10 (C-5);82.05 ( C(CH3)3);69.50 (C-1 );64.50
0
(C-20);45.20 (C-3 );34.10 ( CH(CH3)2);28.30 (( CH3)3C);
25.10 (C(CH3)2(C3H7));20.25 ( CH(CH3)2);18.55±18.60±
20.10 (4 CH3 thexyl); 22.60 (CH3±Si); 23.30 (CH3±Si).
The product 13B of monochlorination was isolated with
83% yield (59 mg) when only 2 equiv. of NCS and PPh3
were used.
3.11. Substitution of the terminal chlorine by an azido
group. Compounds 15A, 15B, 25A, 25B, 34A, 34B
The dichloro compound (1 equiv.) was dissolved in DMF
(0.2 mmol/mL) and treated with sodium azide (1.5 equiv.).
After heating at 808C for 12 h, solvent was removed under
reduced pressure and the residue was puri®ed by ¯ash
chromatography (dichloromethane/methanol: 99/1).
3.10.4. N-/5-{3-Chloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-2-hydroxy-propyl}-thiazol-2-yl)-2,2-
dimethyl-propionamide 13B. C19H35ClN2O3SSi. White
solid. Rf: 0.4 (CH2Cl2/MeOH: 95/5). MS CI (Tˆ1808C)
m/z: 435/437 (M1H)1. IR (CHCl3, nmax, cm21): 3425 (NH),
3400±3200 (OH), 2965±2870 (CH), 1682 (amide), 1467±
1289 (C±Cl). UV (l, nm [e]): 272 (7600). [a]Dˆ149
(cˆ3.04;ethanol). 1H NMR (250 MHz) d (ppm): 9.66 (s
large, 1H, NH);7.30 (s, 1H, H-5);4.99 (d, Jˆ5.8 Hz, 1H,
3.11.1.
N-/5-{3-Azido-2-chloro-1-[dimethyl-/1,1,2-tri-
methyl-propyl)-silanyloxy]-propyl}-thiazol-2-yl)-2,2-
dimethyl-propionamide 15A. Yield: 91%, 548 mg.
C19H34ClN5O2SSi. White solid. Rf: 0.4 (CH2Cl2/MeOH:

B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
4211
95/5). MS CI (Tˆ1808C) m/z: 460/462 (M1H)1. IR
(CHCl3, nmax, cm21): 2966±2870 (CH), 2107 (azide),
1682 (amide). UV (l, nm [e]): 270 (13400). [a]Dˆ245
(cˆ0.68;ethanol). 1H NMR (250 MHz) d (ppm): 9.91 (s
large,1H, NH);7.35 (s, 1H, H-5);5.08 (d, Jˆ6.7 Hz, 1H,
H-10);4.05 (ddd, Jˆ3.9, 5.3, 6.7 Hz, 1H, H-20);3.74 (dd,
Jˆ5.3, 13 Hz, 1H, H-30);3.68 (dd, Jˆ3.9, 13 Hz, 1H, H-30);
1.62 (sept, Jˆ6.8 Hz, 1H, CH(CH3)2);1.30 (s, 9H,
(CH3)3C);0.89 (d, Jˆ6.8 Hz, 3H, CHCH3);0.88 (d,
Jˆ6.8 Hz, 3H, CHCH3);0.85 (s, 3H, C H3 thexyl);0.84 (s,
3H, CH3 thexyl);0.19 (s, 3H, C H3±Si); 20.06 (s, 3H, CH3±
Si). 13C NMR (62.5 MHz) d (ppm): 176.55 (CvO);159.60
(C-2);135.75 (C-4);132.90 (C-5);70.60 (C-1 0);64.90 (C-
20);53.40 (C-3 0);39.25 ( C(CH3)3);34.10 ( CH(CH3)2);27.30
(C(CH3)3);25.15 (Si± C(CH3)2(C3H7));18.70±18.75±
20.20±20.40 (4 CH3 thexyl); 22.40 (CH3±Si); 23.15
(CH3±Si). HRMS: m/z calcd for C19H35ClN5O2SSi:
460.1969 and 462.1939;found: 460.1981 and 462.1965.
Rf: 0.4 (CH2Cl2/MeOH: 95/5). MS CI (Tˆ1808C) m/z: 476/
478 (M1H)1;399;376/378 (M 1H-Boc)1. IR (CHCl3, nmax
,
cm21): 2107 (azide), 1717 (CvO). UV (l, nm [e]): 263
(24300). [a]Dˆ113 (cˆ5.38, ethanol). 1H NMR (250 MHz)
d (ppm): 11.97 (s, 1H, NH);7.20 (s, 1H, H-4);5.00 (d,
Jˆ5.2 Hz, 1H, H-10);4.04 (ddd, Jˆ5.2, 3.9, 7.2 Hz, 1H, H-
20);3.97 (dd, Jˆ3.9, 13 Hz, 1H, H-30);3.62 (dd, Jˆ7.2,
13 Hz, 1H, H-30);1.52 (sept, Jˆ6.9 Hz, 1H, CH(CH3)2);
1.50 (s, 9H, (CH3)3C);0.88 (d, Jˆ6.9 Hz, 6H, CH(CH3)2);
0.85 (s, 3H, CH3 thexyl);0.84 (s, 3H, C H3 thexyl);0.09 (s,
3H, CH3±Si); 20.9 (s, 3H, CH3±Si). 13C NMR (75 MHz) d
(ppm): 162.35 (CvO);135.05 (C-4);129.90 (C-5);82.75
0
0
0
(C(CH3)3);70.75 (C-1 );64.60 (C-2 );53.65 (C-3 );34.20
(CH(CH3)2);28.40 (C( CH3)3);25.25 C(CH3)2(C3H7));
(
18.50±20.30±20.35 (4 CH3 thexyl); 22.50 (CH3±Si);
23.10 (CH3±Si).
3.12. Hydrogenation of the terminal azido group.
Compounds: 16A, 16B, 26A, 26B, 28A, 30A, 30B, 32A,
32B
3.11.2.
N-/5-{3-Azido-2-chloro-1-[dimethyl-/1,1,2-tri-
methyl-propyl)-silanyloxy]-propyl}-thiazol-2-yl)-2,2-
dimethyl-propionamide 15B. Yield: 70%, 345 mg.
C19H34ClN5O2SSi. White solid. Rf: 0.4 (CH2Cl2/MeOH:
95/5). MS CI (Tˆ1808C) m/z: 460/462 (M1H)1. IR
(CHCl3, nmax, cm21): 2966±2869 (CH), 2107 (azide), 1682
(amide). UV (l, nm [e]): 271 (20900). [a]Dˆ113 (cˆ2.41;
ethanol). 1H NMR (250 MHz) d (ppm): 10.00 (s large, 1H,
NH);7.37 (s, 1H, H-5);5.13 (d, Jˆ4.9 Hz, 1H, H-10);4.05
(ddd, Jˆ4, 4.9, 7.4 Hz, 1H, H-20);3.70 (dd, Jˆ4, 13 Hz, 1H,
H-30);3.33 (dd, Jˆ7.4, 13 Hz, 1H, H-30);1.63 (sept, Jˆ
6.8 Hz, 1H, CH(CH3)2);1.31 (s, 9H, (C H3)3C);0.89 (d,
Jˆ6.8 Hz, 6H, CH(CH3)2);0.86 (s, 3H, C H3 thexyl);0.85
(s, 3H, CH3 thexyl);0.18 (s, 3H, C H3±Si); 20.02 (s, 3H,
CH3±Si). 13C NMR (75 MHz) d (ppm): 176.65 (CvO);159.75
After bubbling a stream of argon through a solution of azide
(1 equiv.) in ethanol (0.7 mmol/mL), palladium on activated
carbon, 5% Pd (0.1 equiv.) was added and the mixture was
stirred under one atmosphere of H2 for 12 h. The solution
was then ®ltered through a Celitew pad to remove catalyst
and the solvent removed under reduced pressure. The resi-
due was puri®ed by ¯ash chromatography (dichloro-
methane/methanol: 98/2).
3.12.1.
N-/5-{3-Amino-2-chloro-1-[dimethyl-/1,1,2-
trimethyl-propyl)-silanyloxy]-propyl}-thiazol-2-yl)-2,2-
dimethyl-propionamide 16A. Yield: 61%, 19 mg.
C19H36ClN3O2SSi. White solid. Rf: 0.2 (CH2Cl2/MeOH:
95/5). MS CI (Tˆ1808C) m/z: 434/436 (M1H)1. IR
(CHCl3, nmax, cm21): 3425 (NH), 2964±2870 (CH), 1683
(amide), 1410±1256 (C±Cl). UV (l, nm [e]): 270 (16100).
[a]Dˆ232 (cˆ1.13;ethanol). 1H NMR (250 MHz) d
(ppm): 7.31 (s, 1H, H-4);5.05 (d, Jˆ6.5 Hz, 1H, H-10);
3.95 (m, 1H, H-20);3.20 (dd, Jˆ3.2, 13.9 Hz, 1H, H-30);
2.98 (dd, Jˆ7.6, 13.9 Hz, 1H, H-30);1.63 (sept, Jˆ6.8 Hz,
1H, CH(CH3)2);1.30 (s, 9H, (C H3)3C);0.89 (d, Jˆ6.8 Hz,
3H, CHCH3);0.88 (d, Jˆ6.8 Hz, 3H, CHCH3);0.85 (s, 3H,
CH3 thexyl);0.84 (s, 3H, C H3 thexyl);0.17 (s, 3H, C H3±Si);
20.06 (s, 3H, CH3±Si). 13C NMR (62.5 MHz) d (ppm):
0
(C-2);135.60 (C-4);131.55 (C-5);70.75 (C-1 0);64.60 (C-2 );
53.65 (C-30);39.40 ( C(CH3)3);34.30 ( CH(CH3)2);27.40
(C(CH3)3);25.30 (Si± C(CH3)2(C3H7));18.85±20.45 (4
CH3 thexyl); 22.45 (CH3±Si); 23.00 (CH3±Si).
3.11.3. /5-{3-Azido, 2-dichloro-1-[dimethyl-/1,1,2-tri-
methyl-propyl)-silanyloxy]-propyl}-thiazol-2-yl)-carbamic
acid tert-butyl ester 25A. Yield: 87%, 500 mg.
C19H34ClN5O3SSi. White solid. Rf: 0.4 (CH2Cl2/MeOH:
95/5). MS CI (Tˆ1808C) m/z: 476/478 (M1H)1, 376/378
(M1H-Boc)1. IR (CHCl3, nmax, cm21): 2107 (azide), 1717
(CvO). UV (l, nm [e]): 263 (12000). [a]Dˆ257 (cˆ5.38;
159.25 (C-2);134.95 (C-4);133.35 (C-5);71.00 (C-1
69.75 (C-20);44.35 (C-3 0);39.00 ( C(CH3)3);33.85
0);
1
ethanol). H NMR (300 MHz) d (ppm): 9.83 (s large, 1H,
NH);7.24 (s, 1H, H-4);5.02 (d, Jˆ6.8 Hz, 1H, H-10);4.04
(m, 1H, H-20);3.75 (sys ABX, Jˆ4.7, 13 Hz, 1H, H-30);
3.70 (sys ABX, Jˆ3.3, 13 Hz, 1H, H-30);1.61 (sept,
Jˆ6.8 Hz, 1H, CH(CH3)2);1.59 (s, 9H, (C H3)3C);0.89 (d,
Jˆ6.8 Hz, 3H, CHCH3);0.88 (d, Jˆ6.8 Hz, 3H, CHCH3);
0.85 (s, 3H, CH3 thexyl);0.84 (s, 3H, C H3 thexyl);0.19 (s,
3H, CH3±Si); 20.05 (s, 3H, CH3±Si). 13C NMR (75 MHz)
d (ppm): 162.10 (CvO);152.65 (C-2);135.05 (C-4);
(CH(CH3)2);27.00 (C( CH3)3);24.90 (Si± C(CH3)2(C3H7));
18.45±18.50±20.00±20.10 (4 CH3 thexyl); 22.60 (CH3±
Si); 23.30 (CH3±Si). HRMS (CI): C19H37ClN3O2SSi:
434.2063 and 436.2034;found: 434.2058 and 436.2044.
3.12.2.
N-/5-{3-Amino-2-chloro-1-[dimethyl-/1,1,2-
trimethyl-propyl)-silanyloxy]-propyl}-thiazol-2-yl)-2,2-
dimethyl-propionamide 16B. Yield: 72%, 47 mg.
C19H36ClN3O2SSi. White solid. Rf: 0.2 (CH2Cl2/MeOH:
95/5). MS CI (Tˆ1708C) m/z: 434/436 (M1H)1. IR
(CHCl3, nmax, cm21): 3425 (NH), 2964±2870 (CH), 1683
(amide), 1410±1256 (C-Cl). UV (l, nm [e]): 272 (17000).
[a]Dˆ230 (cˆ2.69;ethanol). 1H NMR (250 MHz) d
(ppm): 7.34 (s, 1H, H-4);5.11 (d, Jˆ5.3 Hz, 1H, H-10);
3.97 (ddd, Jˆ3.4, 5.3, 8.3 Hz, 1H, H-20);3.08 (dd, Jˆ3.4,
13.7 Hz, 1H, H-30);2.98 (dd, Jˆ8.3, 13.7 Hz, 1H, H-30);
0
0
130.95 (C-5);81.90 ( C(CH3)3);70.35 (C-1 );64.55 (C-2 );
53.25 (C-30);33.85 ( CH(CH3)2);28.20 (C( CH3)3);24.90
(C(CH3)2(C3H7));18.40±18.50±19.90±20.10 (4
thexyl); 22.65 (CH3±Si); 23.40 (CH3±Si).
CH3
3.11.4. 5-{3-Azido-2-dichloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-propyl}-thiazol-2-yl)-carbamic acid
tert-butyl ester 25B. Yield: 85%, 805 mg. C19H34ClN5O3SSi.

4212
B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
1.63 (sept, Jˆ6.9 Hz, 1H, CH(CH3)2);1.32 (s, 9H,
(CH3)3C);0.89 (d, Jˆ6.9 Hz, 6H, CH(CH3)2);0.86 (s,
3H, CH3 thexyl);0.85 (s, 3H, C H3 thexyl);0.17 (s, 3H,
CH3±Si); 20.02 (s, 3H, CH3±Si). 13C NMR (62.5 MHz)
d (ppm): 176.30 (CvO);159.15 (C-2);135.05 (C-4); 0
3.12.6.
N-[5-/3-Amino-2-chloro-1-hydroxy-propyl)-
thiazol-2-yl]-2,2-dimethyl-propionamide 30A. Yield: 64%,
23 mg. C11H18ClN3O3S. White solid. Rf: 0.1 (CH2Cl2/MeOH:
85/15). MS CI (Tˆ1708C) m/z: 292/294 (M1H)1. IR (CHCl3,
n
max, cm21): 1680 (amide). UV (l, nm [e]): 271 (11100).
0
0
132.40 (C-5);71.40 (C-1 );69.70 (C-2 );44.60 (C-3 );
39.25 (C(CH3)3);34.25 ( CH(CH3)2);27.30 (C( CH3)3);
25.15 (Si±C(CH3)2(C3H7));18.70±20.35 (4 CH3 thexyl);
22.50 (CH3±Si); 23.00 (CH3±Si).
[a]Dˆ112 (cˆ1.9;ethanol). 1H NMR (300 MHz, CD3OD)
d (ppm): 7.30 (s, 1H, H-4);4.97 (d, Jˆ6.5 Hz, 1H, H-10);4.06
(m, 1H, H-20);3.06 (dd, Jˆ3.8, 13.9 Hz, 1H, H-30);2.82 (dd,
Jˆ7.8, 13.9 Hz, 1H, H-30);1.21 (s, 9H, (C H3)3C). 13C NMR
(75 MHz, CD3OD) d (ppm): 178.80 (CvO);160.55 (C-2);
0
0
3.12.3. /5-{3-Amino-2-chloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-propyl}-thiazol-2-yl)-carbamic acid
tert-butyl ester 26A. Yield: 77%, 238 mg. C19H36ClN3O2SSi.
Rf: 0.2 (CH2Cl2/MeOH: 95/5). MS CI (Tˆ1708C) m/z: 506/
508 (M157)1;450/452 (M 1H)1. IR (CHCl3, nmax, cm21):
1717 (carbamate). UV (l, nm [e]): 263 (15300). [a]Dˆ239
136.55 (C-4);134.25 (C-5);71.30 (C-1 );68.85 (C-2 );45.80
(C-30);40.15 ( C(CH3)3);27.30 (C( CH3)3). HRMS: m/z calcd
for C11H18ClN3O2S: 292.0886 and 294.0856;found: 292.0881
and 294.0849.
3.12.7.
N-[5-/3-Amino-2-chloro-1-hydroxy-propyl)-
1
(cˆ1.56;ethanol). H NMR (200 MHz) d (ppm): 7.22 (s, 1H,
thiazol-2-yl]-2,2-dimethyl-propionamide 30B. Yield:
62%, 33 mg. C11H18ClN3O2S. White solid. Rf: 0.1
(CH2Cl2/MeOH: 85/15). MS CI (Tˆ1808C) m/z: 292/294
(M1H)1;256 (M 2Cl)1. IR (CHCl3, nmax, cm21): 1683
(amide). UV (l, nm [e]): 272 (12700). [a]Dˆ216
(cˆ1.3;ethanol). 1H NMR (300 MHz, CD3OD) d (ppm):
7.40 (d, Jˆ0.6 Hz, 1H, H-4);5.31 (dd, Jˆ0.6, 3.9 Hz, 1H,
0
H-4);4.99 (d, Jˆ6.6 Hz, 1H, H-10);3.95 (m, 1H, H-2 );3.22
(dd, Jˆ3.1, 13.9 Hz, 1H, H-30);2.99 (dd, Jˆ7.5, 13.9 Hz, 1H,
H-30);1.63 (sept, Jˆ7 Hz, 1H, CH(CH3)2);1.58 (s, 9H,
(CH3)3C);0.88 (d, Jˆ7 Hz, 3H, CHCH3);0.87 (d, Jˆ7 Hz,
3H, CHCH3);0.85 (s, 3H, C H3 thexyl);0.84 (s, 3H, C H3
thexyl);0.17 (s, 3H, C H3±Si); 20.05 (s, 3H, CH3±Si). 13C
NMR (75 MHz) d (ppm): 161.80 (CvO);152.80 (C-2);
H-10);4.16 (m, 1H, H-2 );3.32 (dd, Jˆ5.0, 13.5 Hz, 1H, H-
0
0
134.90 (C-4);132.15 (C-5);82.00 ( C(CH3)3);71.25 (C-1 );
30);3.18 (dd, Jˆ4.7, 13.5 Hz, 1H, H-30);1.32 (s, 9H,
(CH3)3C). 13C NMR (75 MHz, CD3OD) d (ppm): 178.75
(CvO);160.50 (C-2);135.95 (C-4);134.00 (C-5);70.55
70.00 (C-20);44.70 (C-3 0);34.00 ( CH(CH3)2);28.40
(C(CH3)3);25.10 (Si± C(CH3)2(C3H7));18.60±18.70±20.15±
20.30 (4 CH3 thexyl); 22.40 (Si±CH3); 23.10 (Si±CH3).
HRMS: m/z calcd for C19H37ClN3O2SSi: 452.1984 and
450.2013;found: 452.2006 and 450.2018.
(C-10);69.65 (C-2 );46.00 (C-3 );40.15 ( C(CH3)3);27.30
(C(CH3)3). HRMS (CI): calcd for C11H19ClN3O2S: 294.0857
and 293.0886;found: 294.0859 and 292.0893.
0
0
3.12.4. 5-{3-Amino-2-chloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-propyl}-thiazol-2-yl)-carbamic acid
tert-butyl ester 26B. Yield: 67%, 228 mg. C19H36ClN3O2SSi.
White solid. Rf: 0.2 (CH2Cl2/MeOH: 95/5). MS CI (Tˆ1708C)
m/z: 506/508 (M157)1;450/452 (M 1H)1. IR (CHCl3,
3.12.8. 5-{3-Amino-2-chloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-propyl}-thiazol-2-ylamine 32A. Yield
67%, 10 mg. C14H28ClN3OSSi. White solid. Rf: 0.1
(CH2Cl2/MeOH: 90/10). MS CI (Tˆ1808C) m/z: 350/352
(M1H)1. IR (CHCl3, nmax, cm21): 1602. UV (l, nm [e]):
n
max, cm21): 1717 (carbamate). UV (l, nm [e]): 263
264 (7600). [a]Dˆ248 (cˆ0.07;ethanol).
1H NMR
(14700). [a]Dˆ129 (cˆ1.17;ethanol).
1H NMR
(250 MHz, CD3OD) d (ppm): 6.80 (s, 1H, H-4);4.93 (d,
0
(200 MHz) d (ppm): 7.25 (s, 1H, H-4);5.05 (d,
Jˆ5.5 Hz, 1H, H-10);3.97 (m, 1H, H-2 0);3.08 (dd,
Jˆ3.3, 13.7 Hz, 1H, H-30);2.75 (dd, Jˆ8.4, 13.7 Hz,
1H, H-30);1.60 (sept, Jˆ7 Hz, 1H, CH(CH3)2);1.57 (s,
9H, (CH3)3C);0.88 (d, Jˆ7 Hz, 6H, CH(CH3)2);0.86 (s,
3H, CH3 thexyl);0.85 (s, 3H, C H3 thexyl);0.16 (s, 3H,
CH3±Si); 20.18 (s, 3H, CH3±Si). 13C NMR (75 MHz) d
(ppm): 162.00 (CvO);152.80 (C-2);134.50 (C-4);
Jˆ5.8 Hz, 1H, H-10);3.93 (m, 1H, H-2 );3.10 (dd, Jˆ3.4,
13.9 Hz, 1H, H-30);2.82 (dd, Jˆ8.6, 13.9 Hz, 1H, H-30);1.58
(sept, Jˆ6.9 Hz, 1H, CH(CH3)2);0.85 (d, Jˆ6.9 Hz, 3H,
CHCH3);0.84 (d, Jˆ6.9 Hz, 3H, CHCH3);0.80 (s, 3H, C H3
thexyl);0.79 (s, 3H, C H3 thexyl);0.18 (s, 3H, C H3±Si);0.00
(s, 3H, CH3±Si). 13C NMR (75 MHz, CD3OD) d (ppm):
172.20 (C-2);137.20 (C-4);128.10 (C-5);70.65 (C-1
0);
72.90 (C-20);45.65 (C-3 );35.50 ( CH(CH3)2);26.10 (Si±
C(CH3)2(C3H7));19.10±19.15±20.70±20.80 (4 CH3 thexyl);
22.45 (CH3±Si); 22.90 (CH3±Si). HRMS (CI):
C14H29ClN3OSSi: 350.1489 and 352.1459;found: 350.1470
and 352.1475.
0
0
130.60 (C-5);81.95 ( C(CH3)3);71.35 (C-1 );69.60 (C-
0
20);44.50 (C-3 );34.00 ( CH(CH3)2);28.30 (C( CH3)3);
25.05 (Si±C(CH3)2(C3H7));18.60±20.20 (4 CH3 thexyl);
22.70 (Si±CH3); 23.20 (Si±CH3).
3.12.5. [5-/3-Amino-2-chloro-1-hydroxy-propyl)-thiazol-
2-yl]-carbamic acid tert-butyl ester 28A. Yield: 75%,
20 mg. C11H18ClN3O3S. White solid. Rf: 0.3 (CH2Cl2/
MeOH: 95/5). MS ESI (methanol) m/z: 308/310 (M1H)1.
UV (l, nm [e]): 263 (8700). [a]Dˆ212 (cˆ1.3;ethanol).
1H NMR (250 MHz, CD3OD) d (ppm): 7.17 (d, Jˆ0.6 Hz,
1H, H-4);5.04 (dd, Jˆ0.6, 4.3 Hz, 1H, H-10);4.05 (m, 1H,
H-20);2.99 (dd, Jˆ4.3, 13.8 Hz, 1H, H-30);2.80 (dd, Jˆ8.3,
13.8 Hz, 1H, H-30);1.44 (s, 9H, (C H3)3C). 13C NMR
(62.5 MHz, CD3OD) d (ppm): 162.40 (CvO);136.10 (C-
3.12.9. 5-{3-Amino-2-chloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-propyl}-thiazol-2-ylamine 32B. Yield
69%, 18 mg. C14H28ClN3OSSi. White solid. Rf: 0.1
(CH2Cl2/MeOH: 90/10). MS CI (Tˆ1808C) m/z: 350/352
(M1H)1. IR (CHCl3, nmax, cm21): 1603. UV (l, nm [e]):
264 (11400). [a]Dˆ148 (cˆ0.09;ethanol).
1H NMR
(250 MHz, CD3OD) d (ppm): 6.85 (s, 1H, H-4);4.97 (d,
0
Jˆ5.6 Hz, 1H, H-10);3.93 (m, 1H, H-2 );2.93 (dd, Jˆ3.6,
13.7 Hz, 1H, H-30);2.71 (dd, Jˆ8.8, 13.7 Hz, 1H, H-30);1.63
(sept, Jˆ6.9 Hz, 1H, CH(CH3)2);0.87 (d, Jˆ6.9 Hz, 6H,
CH(CH3)2);0.83 (s, 3H, C H3 thexyl);0.81 (s, 3H, C H3
thexyl);0.14 (s, 3H, C H3±Si); 20.05 (s, 3H, CH3±Si). 13C
0
4);133.15 (C-5);82.95 ( C(CH3)3);70.55 (C-1 );69.05 (C-
0
20);45.90 (C-3 );28.45 (C( CH3)3).

B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
4213
NMR (62.5 MHz, CD3OD) d (ppm): 172.45 (C-2);136.95 (C-
3 h at room temperature, an additional equivalent of
Bu4NF was added. After 1 h at room temperature, the
solvent was removed under reduced pressure. The residue
was puri®ed by ¯ash chromatography (dichloromethane/
methanol: 99/1).
0
0
4);127.50 (C-5);72.60 (C-1 0);70.55 (C-2 );45.70 (C-3 );
35.50 (CH(CH3)2);26.10 (Si± C(CH3)2(C3H7));19.15±20.80
(4CH3 thexyl); 22.50 (CH3±Si); 22.90 (CH3±Si).
3.13. Deprotection of 2-aminothiazole and hydroxyle in
position 10. Compounds 17, 2A, 2B
3.14.1. [5-/3-Azido-2-chloro-1-hydroxy-propyl)-thiazol-
2-yl]-carbamic acid tert-butyl ester 27A. Yield 91%,
38 mg. C11H16ClN5O3S. White solid. Rf: 0.3 (CH2Cl2/
MeOH: 95/5). MS CI (Tˆ1708C) m/z: 334/336 (M1H)1.
IR (CHCl3, nmax, cm21): 2109 (azide);1718 (carbamate).
UV (l, nm [e]): 263 (15400). [a]Dˆ131 (cˆ1;ethanol).
1H NMR (250 MHz) d (ppm): 11.6 (s large, 1H, NH);7.32
(s, 1H, H-4);5.19 (d, Jˆ6.3 Hz, 1H, H-10);4.26 (m, 1H, H-
20);3.83 (dd, Jˆ6, 13.2 Hz, 1H, H-30);3.68 (dd, Jˆ4.4,
13.2 Hz, 1H, H-30);1.63 (s, 9H, (C H3)3C). 13C NMR
(62.5 MHz) d (ppm): 162.50 (CvO);152.90 (C-2);
135.30 (C-4);1029.90 (C-5);82.70 ( C(CH3)3);69.70 (C-
The amine 16A (1 equiv.) was dissolved in a 6N HCl solu-
tion (0.04 mmol/mL) and heated at 808C for 12 h. The
solvent was removed under reduced pressure and the residue
was puri®ed by ¯ash chromatography (ethyl acetate/
butanone/water/formic acid: 5/3/0.5/0.5ˆCTZZ), followed
by a ®ltration through a Sephadexw LH20 column, eluting
with methanol to yield a brown solid (86 mg, 60%).
3.13.1. 5-/3-Amino-2-chloro-propenyl)-thiazol-2-ylamine
17. C6H8ClN3S,2HCl. Light brown solid. Rf: 0.1 (CH2Cl2/
MeOH: 80/20). MS FAB: 190/192 (M1H)1. IR (KBr, nmax
,
0
10);63.65 (C-2 );53.60 (C-3 );28.40 (C( CH3)3).
cm21): 1635. UV (l, nm [e]): 307 (24200). 1H NMR
(300 MHz, CD3OD) d (ppm): 7.34 (s, 1H, H-4);7.00 (s,
1H, H-10);3.98 (s, 2H, H-3 0). 13C NMR (75 MHz,
3.14.2. [5-/3-Azido-2-chloro-1-hydroxy-propyl)-thiazol-
2-yl]-carbamic acid tert-butyl ester 27B. Yield 95%,
39 mg. C11H16ClN5O3S. White solid. Rf: 0.3 (CH2Cl2/
MeOH: 95/5). MS CI (Tˆ1708C) m/z: 334/336 (M1H)1.
IR (CHCl3, nmax, cm21): 2109 (azide);1718 (carbamate).
UV (l, nm [e]): 263 (8800). [a]Dˆ23 (cˆ1.25;ethanol).
1H NMR (250 MHz) d (ppm): 7.32 (s,01H, H-4);5.16 (d,
Jˆ5.2 Hz, 1H, H-10);4.19 (m, 1H, H-2 );3.73 (dd, Jˆ5.2,
13.1 Hz, 1H, H-30);3.55 (dd, Jˆ6, 13.1 Hz, 1H, H-30);1.59
(s, 9H, (CH3)3C). 13C NMR (62.5 MHz) d (ppm): 162.45
(CvO);152.85 (C-2);135.25 (C-4);129.25 (C-5);82.60
0
CD3OD) d (ppm): 130.70 (C-4);126.25 (C-2 or C-5);
0
0
122.85 (C-10);120.40 (C-2 or C-5);47.45 (C-3 ).
The amine 26A (1 equiv.) was dissolved in 6N HCl
(0.04 mmol/mL) and stirred at room temperature for 24 h.
The solvent was removed under reduced pressure and the
residue was ®ltered through a Sephadexw LH20 column,
eluting with methanol, to give 2A with 64% yield (70 mg).
0
0
0
3.13.2. 3-Amino-1-/2-amino-thiazol-5-yl)-2-chloro-propan-
1-ol 2A. C6H10ClN3OS, 2HCl. Brown solid. Rf: 0.3 (CTZZ).
MS FAB, m/z: 208/210 (M1H)1. IR (ethanol, nmax, cm21):
no characteristic wave (HATR). UV (l, nm [e]): 263
(7200). [a]Dˆ16 (cˆ0.10;ethanol). 1H NMR (250 MHz,
CD3OD) d (ppm): 7.22 (s, 1H, H-4);4.98 (d, Jˆ6.9 Hz, 1H,
H-10);4.30 (ddd, Jˆ3.5, 6.3, 9 Hz, 1H, H-20);3.51 (dd,
Jˆ3.5, 13.7 Hz, 1H, H-30);3.18 (dd, Jˆ9, 13.7 Hz, 1H,
H-30). 13C NMR (62.5 MHz, CD3OD) d (ppm): 177.90
(C-2);127.55 (C-5);125.05 (C-4);70.50 (C-1 0);61.60 (C-
(C(CH3)3);69.10 (C-1 );64.90 (C-2 );53.85 (C-3 );28.35
(C(CH3)3). HRMS: m/z calcd for C11H17ClN5O3S: 334.0740
and 336.0711;found: 334.0733 and 336.0751.
3.14.3. N-[5-/3-Azido-2-chloro-1-hydroxy-propyl)-thiazol-
2-yl]-2,2-dimethyl-propionamide 29A. Yield 96%, 38 mg.
C11H16ClN5O2S. White solid. Rf: 0.4 (CH2Cl2/MeOH: 95/5).
MS CI (Tˆ1708C) m/z: 318/320 (M1H)1. IR (CHCl3, nmax
,
cm21): 2109 (azide), 1683 (amide). UV (l, nm [e]): 272
(13800). [a]Dˆ127 (cˆ0.18;ethanol).
1H NMR
0
20);43.60 (C-3 ).
(250 MHz) d (ppm): 9.35 (s large, 1H, NH);7.39 (s, 1H,
H-4);5.19 (d, Jˆ6.2 Hz, 1H, H-10);4.23 (ddd, Jˆ6.2, 6.2,
4.5 Hz, 1H, H-20);3.77 (dd, Jˆ6.2, 13.2 Hz, 1H, H-30);3.63
(dd, Jˆ4.5, 13.2 Hz, 1H, H-30);1.33 (s, 9H, (C H3)3C). 13C
NMR (62.5 MHz) d (ppm): 176.40 (CvO);159.25 (C-2);
The same work-up as above afforded 2B (68%, 75 mg).
3.13.3. 3-Amino-1-/2-amino-thiazol-5-yl)-2-chloro-propan-
1-ol 2B. C6H10ClN3OS, 2HCl. Brown solid. Rf: 0.3 (CTZZ).
MS FAB, m/z: 208/210 (M1H)1. IR (CHCl3, nmax, cm21):
no characteristic wave (HATR method). UV (l, nm [e]):
136.00 (C-4);131.10 (C-5);69.85 (C-1 0);63.80 (C-2 );
0
53.55 (C-30);39.25 ( C(CH3)3);27.25 (C( CH3)3).
263 (10400). [a]Dˆ28 (cˆ0.16;ethanol).
1H NMR
3.14.4. N-[5-/3-Azido-2-chloro-1-hydroxy-propyl)-thiazol-
2-yl]-2,2-dimethyl-propionamide 29B. Yield 87%, 39 mg.
C11H16ClN5O2S. White solid. Rf: 0.4 (CH2Cl2/MeOH: 95/5).
(250 MHz, CD3OD) d (ppm): 7.05 (s, 1H, H-4);5.10 (d,
Jˆ3 Hz, 1H, H-10);4.33 (dt, Jˆ3, 9 Hz, 1H, H-20);3.40 (dd,
Jˆ3.5, 13.7 Hz, 1H, H-30);3.20 (dd, Jˆ9, 13.7 Hz, 1H, H-
30). 13C NMR (62.5 MHz, CD3OD) d (ppm): 172.05 (C-2);
MS CI (Tˆ1708C) m/z: 318/320 (M1H)1. IR (CHCl3, nmax
,
cm21): 2108 (azide), 1683 (amide). UV (l, nm [e]): 271
(11400). [a]Dˆ224 (cˆ0.21;ethanol).
1H NMR
(250 MHz) d (ppm): 9.22 (s large, 1H, NH);7.38 (s, 1H,
128.45 (C-5);127.30 (C-4);65.60 (C-1 0);63.10 (C-2 );
44.30 (C-30).
0
0
H-4);5.20 (d, Jˆ4.9 Hz, 1H, H-10);4.20 (m, 1H, H-2 );3.73
(dd, Jˆ5.4, 13 Hz, 1H, H-30);3.56 (dd, Jˆ6, 13 Hz, 1H, H-
30);1.33 (s, 9H, (C H3)3C). 13C NMR (62.5 MHz). d (ppm):
176.40 (CvO);159.10 (C-2);135.80 (C-4);131.00 (C-5);
3.14. Selective desilylation in position 10. Compounds:
27A, 27B, 29A, 29B
0
0
69.10 (C-10);65.00 (C-2 );53.40 (C-3 );39.30 ( C(CH3)3);
27.30 (C(CH3)3). HRMS: m/z calcd for C11H17ClN5O2S:
318.0791 and 320.0761;found: 318.0807 and 320.0778.
The azido compound (1 equiv.) was dissolved in anhydrous
THF (0.04 mmol/mL) and treated with acetic acid
(3 equiv.), then by Bu4NF (3 equiv.) slowly added. After

4214
B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
3.15. Selective elimination of the Boc group. Compounds
31A, 31B
(CHCl3, nmax, cm21): 1683 (amide), 1364±1176 (SO2). UV
1
(l, nm [e]): 271 (10000). [a]Dˆ218 (cˆ1.28;ethanol). H
NMR (300 MHz) d (ppm): 10.00 (s large, 1H, NH);7.32 (s,
1H, H-5);4.98 (d, Jˆ5 Hz, 1H, H-10);4.33 (dd, Jˆ3.7,
11 Hz, 1H, H-30);4.11 (dd, Jˆ6, 11 Hz, 1H, H-30);3.94
(m, 1H, H-20);3.15 (s large, 1H, OH);3.05 (s, 3H,
CH3SO2);1.60 (sept., Jˆ6.9 Hz, 1H, CH(CH3)2);1.29 (s,
9H, (CH3)3C);0.90 (d, Jˆ6.9 Hz, 3H, CHCH3);0.88 (d,
Jˆ6.9 Hz, 3H, CHCH3);0.86 (s, 3H, C H3 thexyl);0.85 (s,
3H, CH3 thexyl);0.13 (s, 3H, C H3±Si); 20,05 (s, 3H, CH3±
Si). 13C NMR (75 MHz) d (ppm): 176.55 (CvO);159.80
(C-2);135.00 (C-4);131.50 (C-5);73.70 (C-2 0);70.05 (C-
The N-protected compound 25 was dissolved in dichloro-
methane and treated with tri¯uoroacetic acid (one volume).
After 12 h at room temperature, the solvent was removed
under reduced pressure. Puri®cation of the crude medium
was made by preparative TLC. (dichloromethane/methanol:
99/1).
3.15.1. 5-{3-Azido-2-chloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-propyl}-thiazol-2-ylamine 31A. Yield
95%, 12.4 mg. C14H26ClN5OSSi. White solid. Rf: 0.2
(CH2Cl2/MeOH: 95/5). MS CI (Tˆ1808C) m/z: 432/434
(M157)1;376/378 (M 1H)1. IR (CHCl3, nmax, cm21):
2107 (azide). UV (l, nm [e]): 264 (7100). [a]Dˆ216
(cˆ1.24;ethanol). 1H NMR (250 MHz) d (ppm): 6.95 (s,
1H, H-4);5.04 (s large, 2H, NH 2);4.94 (d, Jˆ6.5 Hz, 1H, H-
0
30);69.35 (C-1 );39.10 ( C(CH3)3);37.60 (C H3SO2);34.05
(CH(CH3)2);27.10 (C( CH3)3);25.05 (Si± C(CH3)2(C3H7));
18.50±18.60±20.10±20.30 (4 CH3 thexyl); 22.65 (CH3±
Si); 23.45 (CH3±Si).
3.16.2. Methanesulfonic acid 3-[2-/2,2-dimethyl-pro-
pionylamino)-thiazol-5-yl-3-dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-2-hydroxy-propyl ester 33B. Yield
73%, 86 mg. C20H38N2O6SSi. White solid. Mpˆ698C. Rf:
0.5 (CH2Cl2/MeOH: 95/5). MS ESI (methanol), m/z: 533
(M1K)1;517 (M 1Na)1. IR (CHCl3, nmax, cm21): 1684
(amide), 1363±1175 (SO2). UV (l, nm [e]): 271 (11700).
[a]Dˆ148 (cˆ0.75;ethanol). 1H NMR (250 MHz) d
(ppm): 9.55 (s large, 1H, NH);7.28 (s, 1H, H-5);4.91 (d,
Jˆ5.9 Hz, 1H, H-10);4.31 (dd, Jˆ3.7, 10.8 Hz, 1H, H-30);
0
0
10);3.98 (m, 1H, H-2 );3.67 (m, 2H, H-3 );1.61 (sept,
Jˆ6.8 Hz, 1H, CH(CH3) 2);0.88 (d,
Jˆ6.8 Hz, 3H,
CHCH3);0.87 (d, Jˆ6.8 Hz, 3H, CHCH3);0.85 (s, 3H,
CH3 thexyl);0.84 (s, 3H, C H3 thexyl);0.16 (s, 3H, C H3±
Si); 20.35 (s, 3H, CH3±Si). 13C NMR (62.5 MHz) d (ppm):
168.25 (C-2);137.35 (C-4);128.65 (C-5);70.80 (C-1
0);
0
C(CH3)2 (C3H7));18.65±18.75±20.00±20.20 (4
64.90 (C-20);53.55 (C-3 );34.15 ( CH(CH3)2);25.20 (Si±
C H3
thexyl);10.15±10.75 (Si±(C H3)2). HRMS (CI):
C14H27ClN5OSSi: 376.1393 and 378.1364;found:
376.1377 and 378.1359.
0
4.24 (dd, Jˆ5.9, 10.8 Hz, 1H, H-30);4.02 (m, 1H, H-2 );
3.05 (s, 3H, CH3SO2);1.61 (sept.,
Jˆ6.9 Hz, 1H,
CH(CH3)2);1.32 (s, 9H, (C H3)3C);0.88 (d, Jˆ6.9 Hz, 3H,
CHCH3);0.87 (d, Jˆ6.9 Hz, 3H, CHCH3);0.85 (s, 3H, C H3
thexyl);0.83 (s, 3H, C H3 thexyl);0.16 (s, 3H, C H3±Si);
20.06 (s, 3H, CH3±Si). 13C NMR (62.5 MHz) d (ppm):
176.30 (CvO);159.50 (C-2);135.50 (C-4);132.05 (C-5);
3.15.2. 5-{3-Azido-2-chloro-1-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-propyl}-thiazol-2-ylamine 31B. Yield
87%, 35 mg. C14H26ClN5OSSi. White solid. Rf: 0.2
(CH2Cl2/MeOH: 95/5). MS CI (Tˆ1508C) m/z: 432/434
(M157)1;376/378 (M 1H)1. IR (CHCl3, nmax, cm21): 2107
(azide). UV (l, nm [e]): 266 (9400). [a]Dˆ124 (cˆ1.10;
0
0
73.85 (C-20);70.25 (C-3 );69.60 (C-1 );39.25 ( C(CH3)3);
37.55 (CH3SO2);34.20 ( CH(CH3)2);27.30 (C( CH3)3);25.10
(Si±C(CH3)2(C3H7));18.65±18.75±20.20±20.40 (4 CH3
thexyl); 22.40 (CH3±Si); 23.15 (CH3±Si). Calcd for
C20H38N2S2O6: C, 48.56;H, 7.77;N, 5.66;found: C,
48.26;H, 7.53;N, 5.46
1
ethanol). H NMR (250 MHz) d (ppm): 6.97 (s, 1H, H-4);
5.00 (s large, 2H, NH2);4.99 (d, Jˆ5.2 Hz, 1H, H-10);3.99
(m, 1H, H-20);3.65 (dd, Jˆ4.4, 13 Hz, 1H, H-30);3.41 (dd,
Jˆ7, 13 Hz, 1H, H-30);1.63 (sept, Jˆ6.8 Hz, 1H, CH(CH3)2);
0.89 (d, Jˆ6.8 Hz, 6H, CH(CH3)2);0.85 (s, 3H, C H3 thexyl);
0.84 (s, 3H, CH3 thexyl);0.18 (s, 3H, C H3±Si); 20.01 (s, 3H,
CH3±Si). 13C NMR (62.5 MHz) d (ppm): 168.65 (C-2);
3.17. Substitution of mesylate function by an azido
function. Compounds 34A, 34B
0
136.85 (C-4);127.30 (C-5);70.55 (C-1 0);64.85 (C-2 );
53.75 (C-30);34.25 ( CH(CH3)2);25.20 (Si± C(CH3)2(C3H7));
18.50±18.70±20.20±20.30 (4 CH3 thexyl); 22.65 (CH3±Si);
23.10 (CH3±Si).
The monomesylated compound 33 (1 equiv.) was dissolved
in DMF (0.026 mmol/mL) and treated with sodium azide
(1.6 equiv.) and heated at 808C overnight. The mixture was
diluted with dichloromethane, washed with water and dried
over MgSO4. After ®ltration, solvent was removed under
reduced pressure and the residue puri®ed by ¯ash chromato-
graphy (heptane/ethyl acetate: 6/4).
3.16. Monomesylation of the diol 22. Compounds 33A,
33B
The diol 22 (1 equiv.) was dissolved in freshly distilled
pyridine (0.05 mmol/mL). At 08C, the solution was treated
with mesyl chloride (1 equiv.) and stirred for 12 h at room
temperature. Then, the solvent was removed under reduced
pressure. The residue was puri®ed by ¯ash chromatography
(dichloromethane/methanol: 99/1).
3.17.1. N-/5-{3-Azido-1-[dimethyl-/1,1,2-trimethyl-propyl)-
silanyloxy]-2-hydroxy-propyl}-thiazol-2-yl)-2,2-dimethyl-
propionamide 34A. Yield 93%, 53 mg. C19H35N5O3SSi.
White solid. Rf: 0.5 (CH2Cl2/MeOH: 95/5). MS CI
(Tˆ1708C) m/z: 442 (M1H)1. IR (CHCl3, nmax, cm21):
2965, 2107 (azide), 1682 (amide). UV (l, nm [e]): 273
(18600). [a]Dˆ25 (cˆ3.6;ethanol). 1H NMR (300 MHz)
d (ppm): 9.64 (s large, 1H, NH);7.31 (s0, 1H, H-4);4.93 (d,
Jˆ6 Hz, 1H, H-10);3.82 (m, 1H, H-2 );3.38 (dd, Jˆ3.8,
12.7 Hz, 1H, H-30);3.14 (dd, Jˆ5.9, 12.7 Hz, 1H, H-30);
1.63 (sept, Jˆ6.8 Hz, 1H, CH(CH3)2);1.31 (s, 9H,
3.16.1. Methanesulfonic acid 3-[2-/2,2-dimethyl-propio-
nylamino)-thiazol-5-yl]-3-[dimethyl-/1,1,2-trimethyl-
propyl)-silanyloxy]-2-hydroxy-propyl ester 33A. Yield
79%, 93 mg. C20H38N2O6S2Si. Rf: 0.5 (CH2Cl2/MeOH: 95/
5). MS CI (Tˆ1808C) m/z: 495 (M1H)1;399 (M 2Ms)1. IR

B. Schiavi et al. / Tetrahedron 58 ,2002) 4201±4215
4215
2. Hooper, J. N. A.;Bergquist, P. R. Memoirs Queensland
Museum 1992, 32, 99±137.
(CH3)3C);0.90 (d, Jˆ6.8 Hz, 3H, CHCH3);0.88 (d,
Jˆ6.8 Hz, 3H, CHCH3);0.86 (s, 3H, C H3 thexyl);0.85 (s,
3H, CH3 thexyl);0.18 (s, 3H, C H3±Si); 20.05 (s, 3H, CH3±
Si). 13C NMR (75 MHz) d (ppm): 176.10 (CvO);159.10
(C-2);135.00 (C-4);132.20 (C-5);75.30 (C-2 0);69.90 (C-
10);52.20 (C-3 0);39.10 ( C(CH3)3);34.00 ( CH(CH3)2);27.10
(C(CH3)3);25.00 (Si± C(CH3)2(C3H7));18.40±18.65±
20.00±20.30 (4 CH3vthexyl); 22.50 (Si±(CH3)2). HRMS:
m/z calcd for C19H36N5O3SSi: 442.2308;found: 442.2288.
Â
3. Levi, C. Bull. Mus. natn. Hist. nat. Paris 1983; 4eme serie, 5,
Á
Â
section A 719±722.
4. Lavelle, F.;Fizames, C.;Ahond, A.;Poupat, C.;Curaudeau,
A. Symposium on New Drugs in Therapy, Amsterdam, March
1989.
5. (a) Schmidt, C. R.;Bryat, J. D. Org. Synth. 1995, 72, 6±13. (b)
Chittenden, G. J. F. Carbohydr. Res. 1980, 84, 350±352.
6. Crystallographic data (excluding structure factors) for the
compounds 7 and 22B have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 182695 (7) and 182696 (22B).
Copies of the data can be obtained free of charge, on applica-
tion to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
144-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
7. Dodge, J. A.;Nissen, J. S.;Presnell, M. Org. Synth. 1996, 73,
110±115.
3.17.2. N-/5-{3-Azido-1-[dimethyl-/1,1,2-trimethyl-propyl)-
silanyloxy]-2-hydroxy-propyl}-thiazol-2-yl)-2,2-dimethyl-
propionamide 34B. Yield 93%, 69 mg. C19H35N5O3SSi.
White solid. Rf: 0.5 (CH2Cl2/MeOH: 95/5). MS CI
(Tˆ1908C) m/z: 442 (M1H)1. IR (CHCl3, nmax, cm21):
2107 (azide), 1684 (amide). UV (l, nm [e]): 273 (9900).
[a]Dˆ123 (cˆ1.3;ethanol). 1H NMR (300 MHz) d
(ppm): 9.30 (s large, 1H, NH);7.28 (s, 1H, H-4);4.87 (d,
0
Jˆ5.8 Hz, 1H, H-10);3.89 (m, 1H, H-2 );3.37 (sys ABX
8. Wetter, H.;Oertle, K. Tetrahedron Lett. 1985, 26, 5515±5518.
9. (a) Bose, A. K.;Lal, B.;Hoffmman, III, W. A.;Manhas, M. S.
Tetrahedron Lett. 1973, 1619±1622. (b) Bose, A. K.;Lal, B.
Tetrahedron Lett. 1973, 3937±3940.
JAXˆ4.3 Hz; JBXˆ6.1 Hz; JABˆ12.6 Hz, 2H, H-30);1.61
(sept, Jˆ6.8 Hz, 1H, CH(CH3)2);1.32 (s, 9H, (C H3)3C);
0.88 (d, Jˆ6.8 Hz, 3H, CHCH3);0.87 (d, Jˆ6.8 Hz, 3H,
CHCH3);0.84 (s, 3H, C H3 thexyl);0.83 (s, 3H, C H3 thexyl);
0.16 (s, 3H, CH3±Si); 20.05 (s, 3H, CH3±Si). 13C NMR
(75 MHz d, (ppm): 176.15 (CvO);159.40 (C-2);135.40
10. Ahond, A.;Al-Mourabit, A.;Bedoya-Zurita, M.;Heng, R.;
Marques-Braga, R.;Poupat, C.;Potier, P. Tetrahedron 1992,
48, 4327±4346.
0
(C-4);132.35 (C-5);74.85 (C-2 0 0);70.35 (C-1 );52.70
11. The structures of 7 and 22B were secured by X-ray analysis
but the poor quality of the crystals of the ketone 7 and the large
disorder brought by the protective silyl group of the intermedi-
ate 22B have not allowed to obtain, in spite of several data
collections, a satisfying ®nal re®nement. The absolute con®g-
uration of 22B has been deduced from the differences between
(C-30);39.25
(
C(CH3)3);34.20 CH(CH3)2);27.30
(
(C(CH3)3);25.10 (Si± C(CH3)2(C3H7));18.65±18.75±
20.20±20.40 (4CH3 thexyl); 22.40 (CH3±Si); 23.15
(CH3±Si).
È
the Bijvoet pairs induced by the anomalous diffraction of the
sulphur atom and this study clearly established the stereo-
chemistry 10R, 20R.
References
12. Eagle, H. Proc. Soc. Exp. Biol. Med. 1995, 89, 362±364.
13. Borenfreund, E.;Puerner, J. A. Toxicol. Lett. 1985, 24, 119±
124.
1. Ahond, A.;Bedoya-Zurita, M.;Colin, M.;Fizames, C.;
Laboute, P.;Lavelle, F.;Laurent, D.;Poupat, C.;Pusset, J.;
Pusset, M.;Thoison, O.;Potier, P. C.R. Acad. Sci. Paris 1988,
307 (II), 145±148.