Total synthesis of (-)-pateamine A, a novel immunosuppressive agent from Mycale sp

Article abstract of DOI:10.1139/v03-199

A convergent synthesis of the unique thiazole-containing polyene bis-lactone pateamine A (1) isolated from the marine sponge Mycale sp is described. The synthesis features the ubiquitous Stille sp²-sp ² coupling reaction to elaborate the E,Z-diene macrolide core 23 and the all-E polyenamine side chain in the natural product. It also highlights the scope for enantiopure sulfinimine intermediates in the synthesis of chiral β-amino ester moieties in complex structures.

Full text of DOI:10.1139/v03-199

353
Total synthesis of (–)-pateamine A, a novel
immunosuppressive agent from Mycale sp1
Gerald Pattenden, Douglas J. Critcher, and Modesto Remuiñán
Abstract: A convergent synthesis of the unique thiazole-containing polyene bis-lactone pateamine A (1) isolated from the
marine sponge Mycale sp is described. The synthesis features the ubiquitous Stille sp2–sp2 coupling reaction to elaborate
the E,Z-diene macrolide core 23 and the all-E polyenamine side chain in the natural product. It also highlights the scope
for enantiopure sulfinimine intermediates in the synthesis of chiral β-amino ester moieties in complex structures.
Key words: pateamine A, immunosuppressive agent from marine sponge Mycale sp, total synthesis, novel 19-membered
bis-lactone, thiazole metabolite, polyenamine, Stille reaction, sulfinimines, chiral β-amino esters.
Résumé : On décrit une synthèse convergente de la patéamine A (1), une bis-lactone polyénique unique contenant un
noyau thiazole isolée de l’éponge marine de l’espèce Mycale. La synthèse comprend une réaction omniprésente de cou-
plage sp2–sp2 de Stille pour élaborer le macrolide E,Z-diénique fondamental 23 et la chaîne latérale polyénamine com-
plètement E du produit naturel. Elle comporte aussi le moyen d’obtenir des intermédiaires sulfinimines énantiopurs
dans la synthèse des portions esters β-aminés chiraux des structures complexes.
Mots clés : patéamine A, agent immunosuppressant de l’éponge marine de l’espèce Mycale, synthèse totale, nouvelle
bis-lactone à 19 chaînons, métabolite thiazole, polyénamine, réaction de Stille, sulfinimines, esters β-aminés chiraux.
[Traduit par la Rédaction] Pattenden et al. 365
Introduction
pateamine, based on an intramolecuar sp2–sp2 Stille cou-
pling reaction (5, 6) to install the E,Z-1,3-diene unit as a key
stratagem (7). To develop this strategy to pateamine A itself,
we required a procedure for introducing the chiral β-amino
ester moiety into the macrolide core, and methodology to
elaborate the all-E-trienamine side chain in the natural prod-
uct. In this paper we describe solutions to these issues, which
have culminated in a new total synthesis of (–)- pateamine A
(8).
Pateamine A (1) is a novel thiazole-containing 19-
membered bis-lactone isolated by Munro and co-workers (1)
from the marine sponge Mycale sp located off the coast of
New Zealand. The natural product exhibits antifungal activ-
ity and also shows potent immunosuppresant properties with
low cytotoxicity.3 The bis-lactone core in pateamine accom-
modates an E,Z-1,3-diene unit together with a β-amino ester
residue, and is substituted by an unusual polyenamine side
chain. The absolute stereochemistry for pateamine A fol-
lowed from degradation studies, in concert with synthetic
work and NMR experiments (2). This stereochemical assign-
ment was corroborated by a total synthesis of (–)-pateamine
A presented by Romo et al. in 1998 (3). In an earlier publi-
cation from our laboratory (4) we layed the foundation for a
total synthesis of pateamine A by describing a synthesis of
the bis-lactone portion 2, corresponding to deammoniated
Synthetic strategy
Our overall synthetic strategy to pateamine A (1) was
based on utilization of the ubiquitous Stille sp2–sp2 coupling
reaction, firstly in an intramolecular manner to elaborate the
E,Z-diene macrolide core 5 from the vinyl stannane-vinyl io-
dide precursor 6, and secondly to produce the all-E polyene
side chain using an intermolecular reaction between the vi-
nyl iodide 4 and the dimethylaminostannane 3. In turn, we
planned to synthesize the stannane-iodide 6 from the 2,4-
disubstituted thiazolepropanal 7 using nucleophilic addition
of an appropriate carbanion to the corresponding chiral sulfi-
nimine, as a key step (Scheme 1).
Received 9 September 2003. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 20 February 2004.
This paper is dedicated to Professor E. Piers, who pioneered
the development and application of the intramolecular Stille
reaction in small ring synthesis, and made seminal
contributions in target natural product synthesis.
Synthesis of the thiazolepropanal 7
G. Pattenden,2 D.J. Critcher, and M. Remuiñán. School of
Chemistry, The University of Nottingham, Nottingham,
NG7 2RD, England.
The thiazolepropanal intermediate 7 was smoothly synthe-
sized starting from the chiral pool compounds dimethyl L-
malate 8 and S-methyl 3-hydroxy-2-methylpropionate 13a,
and utilizing a modified Hantzch reaction between the thio-
amide 12 and the α-bromoketone 15b as a key step. Thus,
starting with commercially available dimethyl L-malate, the
thioamide 12 was first elaborated in six straightforward steps
1This article is part of a Special Issue dedicated to Professor
Ed Piers.
2Corresponding author (e-mail: GP@Nottingham.ac.uk).
3G.T. Faircloth. PharmaMar Inc., M.A. Cambridge. Private
communication to Professor D. Romo and quoted in ref. 3.
Can. J. Chem. 82: 353–365 (2004)
doi: 10.1139/V03-199
© 2004 NRC Canada

354
Can. J. Chem. Vol. 82, 2004
Scheme 1. Retrosynthesis.
involving: (i) reduction using BH3SMe2–NaBH4 and protec-
tion of the resulting primary alcohol 9a as its TBDPS ether
9b; (ii) protection of the secondary alcohol group in 9b as
its PMB ether 10a followed by saponification of the result-
ing methyl ester to the corresponding carboxylic acid 10b;
and (iii) conversion of the acid 10b into the thioamide 12
via the amide 11. In a similar straightforward manner, com-
mercially available S-methyl 3-hydroxy-2-methylpropionate
13a was elaborated to the α-bromoketone 15b following:
(i) protection as the TBDMS ether 13b followed by conver-
sion into the Weinreb amide 14; and (ii) addition of methyl-
magnesium bromide to 14, and bromination of the resulting
methyl ketone 15a via its TMS enol ether using bromine at
–78 °C. A modified Hantzsch reaction (9) between 12 and
15b in the presence of 2,6-lutidine, followed by dehydration
of the thiazoline intermediate using TFAA, then gave the
2,4-disubstituted thiazole 16a in 64% overall yield. The thia-
zolepropanal intermediate 7 was then elaborated from the
TBDMS ether 16a in four straightforward steps using a one-
carbon homologation and proceding via the alcohol 16b, the
mesylate 16c and the nitrile 17 (Scheme 2).
Synthesis of the vinyl stannane – vinyl
iodide 22 and elaboration to the macrolide
23
Our next objective was to elaborate the substituted vinyl
iodide intermediate 22 from the thiazolepropanal 7, by addi-
tion of the enolate produced from the chiral acetate 19 to the
enantiopure sulfinimine 18 derived from 7 as a key and cru-
© 2004 NRC Canada

Pattenden et al.
355
Scheme 2. Reagents and conditions: (i) BH3·SMe2, NaBH4, THF, 92%; (ii) TBDPSCl, Et3N, DMAP, DCM, rt, 12 h, 93%;
(iii) PMBOC(=NH)CCl3, CSA, DCM, rt, 3 days, 76%; (iv) LiOH, H2O–THF, rt, 12 h, 90%; (v) ClCO2Et, Et3N, NH4OH, rt, 30 min,
93%; (vi) Lawesson’s reagent, THF, rt, 30 min, 99%; (vii) TBDMSCl, Et3N, DMAP, DCM, rt, 24 h, 95%; (viii) HNMeOMe·HCl,
AlMe3, DCM, ∆, 5 h, 61%; (ix) 1.5 equiv. MeMgBr, THF, 0 °C, 1 h, 94%; (x) LiHMDS, –78 °C, TMSCl, Br2, 86%; (xi) 2,6-lutidine,
DCM, rt, 12 h; (xii) (CF3CO)2O, Py, DCM, –30 °C, 30 min, 64% (two steps); (xiii) AcOH–THF–H2O, rt, 12 h, 92%; (xiv) MsCl,
Et3N, DCM, 0 °C, 1 h; (xv) NaCN, DMSO, 60 °C, 6 h, 77% (two steps); (xvi) DIBAL, toluene, 0 °C, 2 h, 85%.
cial step. Thus, following a procedure described by Davis et
al. (10), treatment of the thiazolepropanal 7 with (R)-p-
toluenesulfinamide in the presence of titanium(IV) ethoxide
at 50 °C first led to the chiral sulfinimine 18 in 64% yield.
Much to our pleasure deprotonation of the ester 19 derived
from the known corresponding chiral alcohol (11), using
LiHMDS at –78 °C, followed by addition of the sulfinimine
18 to the resulting enolate, gave the substituted β-amino es-
ter 20a in 63% yield and approximately 90% diastere-
selectivity. The ρ-toluenesulfinyl group in 20a was cleaved
by treatment with TFA–methanol to provide the (3R)-amine
20b whose configuration was established unambiguously us-
ing the NMR spectroscopic procedure reported by Riguera
and co-workers (12), in concert with comparison of data
with the corresponding (3S)-amine synthesized contempora-
neously. We commend highly this straightforward and re-
producible procedure for synthesizing reasonably complex
chiral β-amino esters via sulfinimines, such as 18. Hitherto,
we had examined the scope for adding chiral amine nucleo-
philes to Michael acceptors, similar to 2, and for chiral alco-
hol and azide precursors in preparing chiral β-amino ester
precursors similar to 20, but neither of these procedures
gave encouraging results (Scheme 3). In their total synthe-
sis of (–)-pateamine A, Romo et al. (3) used the ring open-
© 2004 NRC Canada

356
Can. J. Chem. Vol. 82, 2004
ing of a chiral β-lactam intermediate by an hydroxyl
nucleophile, as a stratagem to elaborate the β-amino
macrolide portion in the natural product.
perature for 3 days. The solvent was removed in vacuo, and
the residue was dissolved in a mixture of CH2Cl2 (100 mL)
and petroleum ether (bp 40–60 °C) (200 mL). The precipi-
tated solids were filtered off and the filtrate was then con-
centrated in vacuo. The residue was purified by flash
chromatography eluting with ethyl acetate:petroleum ether
(bp 40–60 °C, 1:9 → 1:7) to give the protected alcohol
(28.1 g, 76%) as a colourless oil. [α]2D4 –15.7 (c 1.35 in
CHCl3). IR νmax (cm–1, film): 2931, 1738, 1513, 1248, 1112,
703. 1H NMR (360 MHz, CDCl3) δ: 7.69–7.65 (4H, m,
ArH), 7.46–7.36 (6H, m, ArH), 7.19 (2H, d, J = 8.7,
MeOArH), 6.84 (2H, d, J = 8.7, MeOArH), 4.53 (1H, d, J =
11.1, CH2Ar), 4.47 (1 H, d, J = 11.1, CH2Ar), 4.04–4.00
(1H, m, CHOPMB), 3.80 (3H, s, OCH3), 3.74 (1H, dd, J 5.2
and 10.5, CH2OTPS), 3.67 (3H, s, OCH3), 3.63 (1H, dd, J =
5.7 and 10.5, CH2OTPS), 2.70 (1H, dd, J = 4.6 and 15.6,
CH2CO2Me), 2.57 (1H, dd, J = 8.3 and 15.6, CH2CO2Me),
1.06 (9H, s, ((CH3)3CSi). 13C NMR (90.6 MHz, CDCl3) δ:
171.8, 158.8, 135.2, 132.9, 132.8, 131.5, 130.2, 129.3,
129.0, 127.4, 113.4, 113.3, 75.9, 71.8, 64.8, 54.8, 51.2, 37.1,
26.4, 18.8. MS m/z (ES): 515.2203 (M + Na, C29H36O5SiNa
requires 515.2230).
With the chiral amine 20b in hand, we were now poised to
elaborate the key vinyl iodide – vinyl stannane intermediate
22 and study the critical intramolecular Stille reaction leading
to the macrolide core 23 in pateamine A. Thus, the amine 20b
was first protected as the corresponding trichloro-tert-
butoxycarbamate (TcBOC) 21a and the PMB ether group
was then cleaved leading to the secondary alcohol 21b.
Esterification of Z-3-tri-n-butylstannylpropenoic acid (13)
with the alcohol 21b, under Yamaguchi conditions (14), then
led to the Stille reaction precursor 22. Gratifyingly, when the
stannane–iodide 22 was treated under Farina’s conditions
(15) with Ph3As–Pd(O) dibenzylideneacetone in DMF at
55 °C for 1 h, it underwent smooth intramolecular sp2–sp2
coupling with complete preservation of the E- and Z-
stereochemistries of the reacting partners and produced the
Z,E-diene macrolide 23 in 65% yield (7, 16) (Scheme 4).
Introduction of the all-E-trienamine side
chain and completion of (–)-pateamine A
We examined a range of olefination and coupling methods
starting from the substituted bis-lactone 23 to install the all-
E trienamine side chain in pateamine A, and ultimately
elected to use a second (intermolecular) Stille reaction be-
tween the vinyl stannane 3 and the vinyl iododiene 26 de-
rived from 23 as the key step. Thus, deprotection of the silyl
ether group in 23, followed by oxidation of the resulting al-
cohol 24a, using a pyridine-buffered Dess–Martin perio-
dinane procedure first gave the aldehyde 24b. A Wittig
reaction between 24b and 2-(triphenylphosphoranylidene)
propionaldehyde next gave the homologated E-unsaturated
aldehyde 25, which was then converted into the vinyl iodide
26 using a Takai reaction (17). A Stille coupling reaction be-
tween the vinyl iododiene 26 and the dimethylamino-
substituted vinyl stannane 3, using Pd(CH3CN)2Cl2 in DMF
at room temperature (18) then led to TcBOC-protected pate-
amine A (27) in an unoptimized yield of 36%. Finally,
deprotection of 27 using a Cd–Pb couple in aq. NH4OAc
(19) gave (–)-pateamine A (1), which showed NMR spectro-
scopic and chiroptical data that were identical to those re-
ported for the natural product isolated from Mycale sp.
In conclusion, a convergent total synthesis of the novel
immunosuppressive agent, pateamine A, from the sponge
Mycale sp has been achieved. The synthesis is concise, and
features the Stille sp2–sp2 coupling reaction to elaborate key
stereodefined polyene units in this novel structure.
(S)-4-(tert-Butyldiphenylsilanyloxy)-3-(4-
methoxybenzyloxy)butyramide (11)
A solution of lithium hydroxide (1.5 mol L–1) in water
(113 mL) was added to a solution of the ester 10a (28 g,
56.9 mmol) in THF (250 mL) and MeOH (2 mL). The
biphasic mixture was stirred at room temperature for 48 h
and then acidified carefully with 2 N HCl (aq). The sepa-
rated aqueous layer was extracted with ethyl acetate (3 ×
200 mL) and the combined organic extracts were then dried
(MgSO4) and concentrated in vacuo. The residue was puri-
fied by flash chromatography, eluting with ethyl acetate:pe-
troleum ether (bp 40–60 °C, 1:1) to give the corresponding
carboxylic acid 10b (25 g, 90%) as a colourless oil. Ethyl
chloroformate (5.5 mL, 57.5 mmol) was added dropwise to a
solution of the carboxylic acid (25 g, 52.3 mmol) and trie-
thylamine (10.2 mL, 75.2 mmol) in THF (250 mL) at 0 °C.
The mixture was allowed to warm to room temperature and
stirred at this temperature for 30 min. Concentrated aqueous
ammonia (75 mL) was added rapidly at 0 °C and the mixture
was warmed to room temperature and then concentrated in
vacuo. 2 N HCl was added until the mixture was acidic, and
the aqueous layer was then extracted with ethyl acetate (3 ×
150 mL). The combined organic extracts were dried (MgSO4)
and evaporated to dryness in vacuo. The residue was purified
by flash chromatography, eluting with ethyl acetate:petro-
leum ether (bp 40–60 °C, 1:1 → 2:1) to give the amide
(23 g, 93%) as a colourless oil. [α]2D4 –16.8 (c 0.19 in
CHCl3). IR νmax (cm–1, film): 3346, 3193, 2930, 1681, 1513,
Experimental
1
1248, 1112, 703. H NMR (360 MHz, CDCl3) δ: 7.69–7.66
For general experimental details see ref. 20.
(4H, m, ArH), 7.47–7.36 (6H, m, ArH), 7.20 (2H, d, J = 8.7,
MeOArH), 6.85 (2H, d, J = 8.7, MeOArH), 6.07 (1H, br s,
NH), 5.26 (1H, br s, NH), 4.59 (1H, d, J = 11.0, CH2Ar),
4.44 (1H, d, J = 11.0, CH2Ar), 3.97–3.91 (1H, m,
CHOPMB), 3.81 (3H, s, CH3O), 3.76 (1H, dd, J = 5.1 and
10.7, CH2OTPS), 3.70 (1H, dd, J = 5.2 and 10.7,
CH2OTPS), 2.58 (1H, dd, J = 3.8 and 15.1, CH2CONH2),
2.47 (1H, dd, J = 8.1 and 15.6, CH2CONH2), 1.07 (9H, s,
(S)-4-(tert-Butyldiphenylsilanyloxy)-3-(4-
methoxybenzyloxy)butyric acid methyl ester (10a)
Camphorsulfonic acid (1.75 g, 7.5 mmol) was added in
one portion to a stirred solution of the alcohol 9b (21) (28 g,
75.26 mmol) and p-methoxybenzyltrichloroacetimidate (42.5 g,
150 mmol) in CH2Cl2 (250 mL) at 0 °C. The mixture was al-
lowed to warm to room temperature, and stirred at this tem-
13
((CH3)3CSi). C NMR (90.6 MHz, CDCl3) δ: 173.4, 159.2,
© 2004 NRC Canada

Pattenden et al.
357
Scheme 3. Reagents and conditions: (i) (R)-tolylsulfinamide, Ti(OEt)4, DCM, 50 °C, 4 h, 64%; (ii) LiHMDS, THF, –78 °C, 10 min,
63%; (iii) TFA, MeOH, rt, 4 h, 95%; (iv) TcBOCCl, Py, DCM, 0 °C, 2 h, 89%; (v) DDQ, DCM, H2O, rt, 2 h, 87%; (vi) (Z)-3-
tributylstannylpropenoic acid, 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, toluene, –30 °C, 1 h, 67%; (vii) Pd(dba)2, Ph3As, DMF,
55 °C, 1 h, 65%.
135.5, 133.1, 133.0, 131.6, 130.0, 129.7, 127.7, 127.6,
113.8, 76.6, 65.1, 55.2, 51.2, 38.7, 26.7, 19.1. MS m/z (ES):
500.2255 (M + Na, C28H35NO4SiNa requires 500.2233).
(4H, m, ArH), 7.55 (1H, br s, NH), 7.47–7.36 (6H, m, ArH),
7.19 (2H, d, J = 8.7, MeOArH), 6.85 (2H, d, J = 8.7,
MeOArH), 4.60 (1H, d, J = 10.9, CH2Ar), 4.42 (1H, d, J =
10.9, CH2Ar), 4.00–3.96 (1H, m, CHOPMB), 3.80 (3H, s,
CH3O), 3.75 (2H, d, J = 4.9, CH2OTPS), 3.06 (1H, dd, J =
3.3 and 14.7, CH2CSNH2), 2.96 (1H, dd, J = 8.1 and 14.7,
CH2CSNH2), 1.08 (9H, s, ((CH3)3CSi). 13C NMR
(90.6 MHz, CDCl3) δ: 207.5, 159.3, 135.5, 135.4, 133.0,
132.9, 129.8, 129.7, 129.5, 127.7, 127.6, 113.9, 78.8, 72.3,
64.8, 55.2, 47.4, 26.7, 19.1. MS m/z (ES): 494.2007 (M + H,
C28H36NO3SSi requires 494.2005).
(S)-4-(tert-Butyldiphenylsilanyloxy)-3-(4-
methoxybenzyloxy)thiobutyramide (12)
Lawesson’s reagent (8.12 g, 20.0 mmol) was added in one
portion to a stirred solution of the amide 11 (18.7 g,
39.4 mmol) in THF (250 mL) at room temperature and the
mixture was stirred at this temperature for 30 min and then
evaporated in vacuo. The residue was purified by flash chro-
matography, eluting with ethyl acetate:petroleum ether (bp
40–60 °C, 1:3 → 1:1) to give the thioamide (8.4 g, 99%) as a
yellow oil. [α]D25 –38.4 (c 0.50 in CHCl3). IR νmax (cm–1,
(S)-3-(tert-Butyldimethylsilanyloxy)-N-methoxy-2,N-
dimethylpropionamide (14)
1
film): 3308, 3187, 2930, 1613, 1249, 1112, 702. H NMR
A solution of trimethylaluminum (2.0 mol L–1) in toluene
(45 mL) was added dropwise over 45 min to a stirred solu-
(360 MHz, CDCl3) δ: 7.80 (1H, br s, NH), 7.70–7.66
© 2004 NRC Canada

358
Can. J. Chem. Vol. 82, 2004
Scheme 4. (i) TBAF, AcOH, THF, rt, 24 h, 78%; (ii) Dess–Martin, Py, DCM, 2 h, rt, 70%; (iii) 2-(triphenylphosphoralidene)propionaldehyde,
3 h, ∆, 73%; (iv) CrCl2, CHI3, THF, 1.5 h, rt, 68%; (v) Pd(CH3CN)2Cl2, DMF, rt, 6 h, 36%; (vi) 10% Cd/Pb, 1 mol L–1 NH4OAc, THF, rt,
5 h, 73%.
tion of N,O-dimethylhydroxylamine hydrochloride (8.8 g,
90.2 mmol) in CH2Cl2 (100 mL) at 0 °C. Once the gas evo-
lution had ceased, the mixture was allowed to warm to room
temperature and stirred at this temperature for 1 h. The solu-
tion was added dropwise via cannula to a stirred solution of
the ester 13b (10.44g, 45.1 mmol) in CH2Cl2 (30 mL) at
room temperature. The mixture was heated under reflux for
5 h and then stirred at room temperature for 12 h. The mix-
ture was poured cautiously into ice cold 2 N HCl, and the
separated aqueous layer was then extracted with CH2Cl2
(4 × 60 mL). The combined organic extracts were washed
with a saturated solution of NaHCO3 and then dried
(MgSO4). The solvent was removed at reduced pressure, and
the residue was purified by flash chromatography, eluting
with ethyl acetate:petroleum ether (bp 40–60 °C, 1:3 → 1:1)
to give the amide (7.1 g, 61%) as a colourless oil. [α]2D6 21.1
(c 0.38 in CHCl3). IR νmax (cm–1, film): 2930, 1667, 1103,
ether (15 mL) was added dropwise via syringe to a stirred
solution of the Weinreb amide 14 (6.8 g, 26.0 mmol) in di-
ethyl ether at 0 °C. The mixture was stirred at 0 °C for
30 min, and then allowed to warm to room temperature. An
ice cold saturated solution of NH4Cl was added and the sep-
arated aqueous layer was then extracted with diethyl ether
(3 × 50 mL). The combined organic extracts were washed
with a saturated solution of NaHCO3 and then dried
(MgSO4). The solvent was removed in vacuo and the crude
methyl ketone (5.56 g, 94%) was used directly in the next
step. [α]2D4 23.9 (c 0.20 in CHCl3). IR νmax (cm–1, film):
1
2930, 1717, 1092, 836. H NMR (360 MHz, CDCl3) δ: 3.73
(1H, dd, J = 7.2 and 9.8, CH2O), 3.65 (1H, dd, J = 5.5 and
9.5, CH2O), 2.77–2.71 (1H, m, CHCH3), 2.18 (3H, s,
CH3CO), 1.05 (3H, d, J = 6.9, CH3CH), 0.88 (9H, s,
((CH3)3CSi), 0.05 (3H, s, CH3Si), 0.04 (3H, s, CH3Si). 13C
NMR (90.6 MHz, CDCl3) δ: 211.5, 65.1, 48.9, 29.1, 25.4,
17.8, 12.5, –5.9.
1
837. H NMR (360 MHz, CDCl3) δ: 3.84 (1H, dd, J = 8.2
and 9.4), 3.72 (3H, br s, OCH3), 3.54 (1H, dd, J = 6.1 and
9.5), 3.20 (3H, br s, CH3), 3.22–3.16 (1H, m, CHCH3), 1.07
(3H, d, J = 6.9, CH3CH), 0.88 (9H, s, ((CH3)3CSi), 0.05
(3H, s, CH3Si), 0.04 (3H, s, CH3Si). 13C NMR (90.6 MHz,
CDCl3) δ: 176.1, 65.7, 65.1, 38.1, 29.7, 25.8, 18.2, 13.7, –5.45.
MS m/z (ES): 284.1609 (M + Na, C12H27NO3SiNa requires
284.1658).
(S)-1-Bromo-4-(tert-butyldimethylsilanyloxy)-3-
methylbutan-2-one (15b)
A solution of LiHMDS (1.0 mol L–1) in THF (23 mL) was
added dropwise over 30 min to a stirred solution of the
ketone 15a (4.7 g, 21.75 mmol) in THF (75 mL) at –78 °C
under an atmosphere of nitrogen. The mixture was stirred at
–78° for 1 h, then chlorotrimethylsilane (3.0 mL, 23.9 mmol)
was added, and the solution was allowed to warm to 0 °C
where it was stirred for 20 min. The solution was again
cooled to –78 °C, and bromine (1.12 mL, 20.5 mmol) was
(S)-4-(tert-Butyldimethylsilanyloxy)-3-methylbutan-2-one
(15a)
A solution of methylmagnesium bromide (3.0 mol L–1) in
© 2004 NRC Canada

Pattenden et al.
359
then injected rapidly. The orange solution was allowed to
warm to room temperature and then poured cautiously into a
mixture of a saturated solution of NH4Cl and a solution of
sodium thiosulfate. The mixture was shaken vigorously and
the separated aqueous layer was extracted with ethyl acetate
(3 × 30 mL). The combined organic extracts were dried
(MgSO4) and evaporated to dryness in vacuo. The residue
was purified by flash chromatography, eluting with ethyl ac-
etate:petroleum ether (bp 40–60 °C, 1:20 → 1:10) to give the
bromide (5.5 g, 86%) as a colourless oil. [α]2D7 99.9 (c 1.36
(R)-2-{2-[(S)-3-(tert-Butyldiphenylsilanyloxy)-2-(4-
methoxybenzyloxy)propyl]thiazol-4-yl}propan-1-ol (16b)
Acetic acid (120 mL) was added, in one portion to a
biphasic solution of the thiazole 16a (8 g, 10.6 mmol) in
THF:H2O (1:1, 120 mL), and the mixture was stirred at
room temperature for 14 h and then evaporated to dryness in
vacuo. The residue was dissolved in CH2Cl2 (200 mL), and
the solution was washed with a saturated solution of
NaHCO3, then dried (MgSO4) and evaporated in vacuo. The
residue was filtered through a short pad of silica gel eluting
with ethyl acetate:petroleum ether (bp 40–60 °C, 1:1) to give
the alcohol (6.1 g, 92%) as a colourless oil. [α]2D4 –18.5
(c 0.26 in CHCl3). IR νmax (cm–1, film): 3412, 2930, 1514,
1
in CHCl3). IR νmax (cm–1, film): 2930, 1718, 1095, 837. H
NMR (360 MHz, CDCl3) δ: 4.11 (1H, d, J = 13.2, CH2Br),
4.06 (1H, d, J = 13.2, CH2Br), 3.73–3.70 (2H, m, CH2O),
3.20–3.11 (1H, m, CHCH3), 1.11 (3H, d, J = 6.9, CH3CH),
0.91 (9H, s, ((CH3)3CSi), 0.08 (3H, s, CH3Si), 0.06 (3H, s,
CH3Si). 13C NMR(90.6 MHz, CDCl3) δ: 204.4, 66.0, 45.9,
35.7, 25.7, 18.0, 12.9, –5.7.
1
1112, 823, 702. H NMR (360 MHz, CDCl3) δ: 7.69–7.66
(4H, m, ArH), 7.46–7.35 (6H, m, ArH), 7.13 (2H, d, J = 8.8,
MeOArH), 6.84 (1H, s, ThzH), 6.81 (2H, d, J = 8.7,
MeOArH), 4.52 (1H, d, J = 11.1, CH2Ar), 4.39 (1H, d, J =
11.1, CH2Ar), 3.92–3.86 (1H, m, CHOPMB), 3.80–3.67
(4H, m, CH2OTPS and CH2OH), 3.79 (3H, s, CH3O), 3.36
(1H, dd, J = 4.1 and 15.0, CH2Thz), 3.20 (1H, dd, J = 8.2
and 15.0, CH2Thz), 3.13–3.08 (1H, m, CHThz), 1.30 (3H, d,
J = 7.0, CH3CH), 1.07 (9H, s, ((CH3)3CSi). 13C NMR
(90.6 MHz, CDCl3) δ: 167.6, 159.3, 159.1, 135.6, 135.5,
133.3, 133.2, 130.3, 129.7, 129.6, 127.7, 113.6, 112.5, 78.9,
72.0, 67.7, 65.1, 55.2, 37.7, 35.9, 26.8, 19.2, 16.1. MS m/z
4-[(R)-2-(tert-Butyldimethylsilanyloxy)-1-methylethyl]-2-
[(S)-3-(tert-butyldiphenylsilanyloxy)-2-(4-
methoxybenzyloxy)propyl]thiazole (16a)
A solution of the bromoketone 15b (7.73 g, 26.2 mmol) in
CH2Cl2 (60 mL) was added via cannula over 0.5 h to a
stirred solution of thioamide 12 (11.75 g, 23.8 mmol) and
2,6-lutidine (4.16 mL, 35.7 mmol) in CH2Cl2 (150 mL) at
0 °C. The mixture was stirred at room temperature for 14 h
and then the solvent was removed in vacuo. The residue was
purified by flash chromatography, eluting with ethyl ace-
tate:petroleum ether (bp 40–60 °C, 1:6 → 1:4) to give the
corresponding thiazoline (12.25 g, 73%) as a colourless oil,
which was used immediately in the next step.
(ES): 598.2403 (M
598.2423).
+ Na, C33H41NO4SSiNa requires
Methanesulfonic acid (R)-2-{2-[(S)-3-(tert-
butyldiphenylsilanyloxy)-2-(4-
methoxybenzyloxy)propyl]thiazol-4-yl}propyl ester (16c)
Methanesulfonyl chloride (0.98 mL, 12.7 mmol) was added
to a solution of the alcohol 16b (6.1 g, 10.6 mmol) and
triethylamine (2.1 mL, 4.52 mmol) in CH2Cl2 (80 mL) at
0 °C and the resulting mixture was then stirred at 0 °C for
1 h. The solution was washed successively with brine
(70 mL) and a saturated solution of NaHCO3 (70 mL), and
then evaporated to dryness in vacuo to leave the crude mesy-
late (96%), which was used directly in the next step. [α]D24
–20.6 (c 0.63 in CHCl3). IR νmax (cm–1, film): 2931, 1513,
Trifluoroacetic anhydride (7.43 mL, 52.6 mmol) was added
dropwise over 20 min to a stirred solution of the thiazoline
(9.3 g, 13.15 mmol) in CH2Cl2 (150 mL) at –30 °C. After
5 min, pyridine (7.43 mL, 52.7 mmol) was added and the
mixture was stirred at –30 °C for 20 min. The mixture was
quenched with brine (150 mL) and extracted with CH2Cl2
(2 × 150 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. The residue was puri-
fied by flash chromatography, eluting with ethyl acetate:pe-
troleum ether (bp 40–60 °C, 1:20 → 1:10) to give the
thiazole (7.9 g, 87%) as a colourless oil. [α]2D4 –28.2 (c 0.88
in CHCl3). IR νmax (cm–1, film): 2928, 1514, 1248, 1112,
1
1357, 823, 704. H NMR (360 MHz, CDCl3) δ: 7.72–7.69
(4H, m, ArH), 7.48–7.37 (6H, m, ArH), 7.16 (2H, d, J = 8.7,
MeOArH), 6.94 (1H, s, ThzH), 6.84 (2H, d, J = 8.7,
MeOArH), 4.56 (1H, d, J = 11.1, CH2Ar), 4.50 (1H, dd, J =
6.1 and 9.6, CH2OMs), 4.43 (1H, d, J = 11.1, CH2Ar), 4.36
(1H, dd, J = 6.6 and 9.6, CH2OMs), 3.95–3.90 (1H, m,
CHOPMB), 3.83–3.75 (2H, m, CH2OTPS), 3.81 (3H, s,
CH3O), 3.37 (1H, dd, J = 4.3 and 15.1, CH2Thz), 3.37–3.34
(1H, m, CHThz), 3.23 (1H, dd, J = 8.1 and 15.1, CH2Thz),
2.84 (3H, s, CH3SO2), 1.41 (3H, d, J = 7.0, CH3CH), 1.10
(9H, s, ((CH3)3CSi). 13C NMR (90.6 MHz, CDCl3) δ: 167.5,
159.0, 155.8, 135.5, 135.5, 133.2, 133.1, 130.2, 129.7,
129.2, 127.7, 114.1, 113.6, 78.8, 73.4, 71.9, 65.1, 55.2, 36.9,
35.9, 35.8, 26.7, 19.2, 16.4. MS m/z (ES): 654.2328 (M + H,
C34H44NO6S2Si requires 654.2379).
1
836, 702. H NMR (360 MHz, CDCl3) δ: 7.70–7.67 (4H, m,
ArH), 7.47–7.33 (6H, m, ArH), 7.16 (2H, d, J = 8.7,
MeOArH), 6.83 (1H, s, ThzH), 6.81 (2H, d, J = 8.6,
MeOArH), 4.54 (1H, d, J = 10.9, CH2Ar), 4.43 (1H, d, J =
11.0, CH2Ar), 3.95–3.88 (1H, m, CHOPMB), 3.87 (1H, dd,
J = 5.6 and 9.7, CH2OTPS), 3.80 (3H, s, CH3O), 3.79–3.76
(2H, m, CH2OTBS), 3.67 (1H, dd, J = 6.8 and 9.7,
CH2OTPS), 3.35 (1H, dd, J = 4.3 and 15.0, CH2Thz), 3.20
(1H, dd, J = 8.1 and 15.1, CH2Thz), 3.13–3.07 (1H, m,
CHThz), 1.31 (3H, d, J = 7.0, CH3CH), 1.07 (9H, s,
((CH3)3CSi), 0.86 (9H, s, ((CH3)3CSi), –0.02 (3H, s, CH3Si),
–0.03 (3H, s, CH3Si). 13C NMR (90.6 MHz, CDCl3) δ:
166.5(s), 159.1(s), 158.9(s), 135.7(d), 135.6(d), 133.4(s),
133.3(s), 130.6(s), 129.7(d), 129.4(d), 127.7(d), 127.6(d),
113.7(d), 112.9(d), 79.5(d), 72.1(t), 67.5(t), 65.4(t), 55.3(t),
39.1(d), 36.0(t), 26.9(q), 25.9(q), 19.3(s), 18.3(s), 16.6(q),
–5.3(q), –5.4(q). MS m/z (ES): 690.3519 (M + H,
C39H56NO4SSi2 requires 690.3486).
(S)-3-{2-[(S)-3-(tert-Butyldiphenylsilanyloxy)-2-(4-
methoxybenzyloxy)propyl]thiazol-4-yl}butyronitrile (17)
Sodium cyanide (4 g, 82.5 mmol) was added in one por-
tion to a stirred solution of the mesylate 16c (4.9 g,
7.5 mmol) in DMSO (40 mL) at room temperature, and the
© 2004 NRC Canada

360
Can. J. Chem. Vol. 82, 2004
mixture was then stirred at 60 °C for 5 h. The cooled mix-
ture was washed with water (75 mL) and the aqueous layer
was then extracted with ethyl acetate (5 × 50 mL). The com-
bined organic extracts were dried (MgSO4) and concentrated
in vacuo. The residue was purified by flash chromatography,
eluting with ethyl acetate:petroleum ether (bp 40–60 °C,
1:4 → 1:3) to give the nitrile (3.54 g, 80%) as a colourless
oil. [α]2D4 –32.1 (c 0.33 in CHCl3). IR νmax (cm–1, film):
2930, 1513, 1248, 703. 1H NMR (360 MHz, CDCl3) δ: 7.71–
7.68 (4H, m, ArH), 7.48–7.36 (6H, m, ArH), 7.15 (2H, d,
J = 8.7, MeOArH), 6.93 (1H, s, ThzH), 6.83 (2H, d, J = 8.7,
MeOArH), 4.56 (1H, d, J = 11.1, CH2Ar), 4.43 (1H, d, J =
11.1, CH2Ar), 3.95–3.89 (1H, m, CHOPMB), 3.82–3.74
(2H, m, CH2OTPS), 3.80 (3H, s, CH3O), 3.35 (1H, dd, J =
4.2 and 15.0, CH2Thz), 3.34–3.28 (1H, m, CHThz), 3.21
(1H, dd, J = 8.1 and 15.0, CH2Thz), 2.79 (1H, dd, J = 5.7
and 16.7, CH2CN), 2.64 (1H, dd, J = 7.5 and 16.7, CH2CN),
1.48 (3H, d, J = 7.0, CH3CH), 1.09 (9H, s, ((CH3)3CSi). 13C
NMR (90.6 MHz, CDCl3) δ: 167.9(s), 159.2(s), 157.2(s),
136.0(d), 135.7(d), 133.4(s), 133.3(s), 130.4(s), 129.8(d),
129.4(d), 127.8(d), 118.6(s), 113.7(d), 113.5(d), 78.9(d),
72.1(t), 65.3(t), 55.3(q), 36.0(t), 33.1(d), 27.0(q), 24.7(t),
19.3(s), 19.0(q). MS m/z (ES): 607.2463 (M + Na,
C34H40N2O3SSiNa requires 607.2427). Anal. calcd. for
C34H40N2O3SSi (%): C 69.8, H 6.9, N 4.8; found: C 70.15,
H 6.7, N 4.8.
The (R)-(–)-sulfinimine (18)
A solution of the aldehyde 7 (1.24 g, 2.11 mmol), (R)-(–)-
p-toluenesulfinamide (0.32 g, 2.4 mmol) (11) and titanium
ethoxide (2.21 mL, 10.5 mmol) in CH2Cl2 (30 mL) was
heated under reflux in a nitrogen atmosphere for 4 h. The
mixture was quenched at 0 °C by addition of H2O (15 mL)
and then stirred at 0 °C for 10 min. The white slurry was fil-
tered through Celite, and the filter cake was washed with
CH2Cl2 (2 × 30 mL). The aqueous layer was extracted with
CH2Cl2 (30 mL) and the combined organic extracts were
dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash chromatography on silica gel, which had
been treated previously with a few drops of Et3N, eluting
with ethyl acetate:petroleum ether (bp 40–60 °C, 1:4 → 1:2)
to give the sulfinimine (0.96 g, 64%) as a colourless oil. [α]D24
–99.9 (c 0.22 in CH2Cl21). IR νmax (cm–1, film): 2930, 1614,
1513, 1248, 1112, 703. H NMR(360 MHz, CDCl3) δ: 8.25
(1H, t, J = 5.0, CHN), 7.74–7.67 (4H, m, ArH), 7.54 (2H, d,
J = 8.2, SOArH), 7.47–7.36 (6H, m, ArH), 7.30 (2H, d, J =
8.3, SOArH), 7.18 (2H, d, J = 8.6, MeOArH), 6.84 (2H, d,
J = 8.6, MeOArH), 6.76 (1H, s, ThzH), 4.57 (1H, d, J =
11.1, CH2Ar), 4.45 (1H, d, J = 11.2, CH2Ar), 3.97–3.92
(1H, m, CHOPMB), 3.83–3.76 (2H, m, CH2OTPS), 3.79
(3H, s, CH3O), 3.39 (1H, sextet, J = 6.9, CHThz), 3.35 (1H,
dd, J = 4.3 and 15.0, CH2Thz), 3.22 (1H, dd, J = 8.0 and
15.0, CH2Thz), 2.98 (1H, ddd, J = 4.8, 6.4 and 15.3,
CH2C=N), 2.75 (1H, ddd, J = 5.3, 7.5, and 15.3, CH2C=N),
2.40 (3H, s, CH3Ar), 1.34 (3H, d, J = 6.9, CH3CH), 1.10
(9H, s, ((CH3)3CSi). 13C NMR(90.6 MHz, CDCl3) δ: 167.3,
165.9, 159.4, 159.0, 141.7, 141.6, 135.6, 135.5, 133.3,
133.2, 130.4, 129.7, 129.6, 129.3, 127.7, 124.5, 113.6,
112.2, 78.9, 72.0, 65.3, 55.2, 42.3, 35.9, 33.4, 26.8, 21.4,
(S)-3-{2-[(S)-3-(tert-Butyldiphenylsilanyloxy)-2-(4-
methoxybenzyloxy)propyl]thiazol-4-yl}butyraldehyde (7)
A solution of DIBAL-H (1.5 mol L–1) in toluene (2.5 mL)
was added dropwise over 20 min via syringe to a stirred so-
lution of the nitrile 17 (1.85 g, 3.16 mmol) in toluene
(16 mL) at –78 °C. The yellow solution was stirred at 0 °C
for 3 h and then quenched by adding a half-saturated solu-
tion of NaHSO4 (15 mL) dropwise. The biphasic mixture
was stirred at room temperature for 20 min and then ex-
tracted with ethyl acetate (3 × 25 mL). The combined or-
ganic extracts were dried (MgSO4) and concentrated in
vacuo. The residue was filtered through a plug of silica gel,
eluting with ethyl acetate:petroleum ether (bp 40–60 °C, 1:3)
to give the aldehyde (1.57 g, 85%) as a colourless oil. [α]D25
–14.9 (c 0.22 in CH2Cl2). IR νmax (cm–1, film): 2930, 1724,
20.0, 19.2. MS m/z (FAB): 725.2913 (M
C41H49N2O4S2Si requires 725.2903).
+
H,
Acetic acid (E)-(S)-4-iodo-1,3-dimethylbut-3-enyl ester (19)
A solution of trimethylaluminium (2.0 mol L–1) in toluene
(27 mL) was added dropwise over 30 min to a stirred solu-
tion of bis(cyclopentadienyl)zirconium dichloride (3.92 g,
13.4 mmol) in CH2Cl2 (50 mL) at room temperature and the
mixture was stirred for 15 min and then cooled to 0 °C. A
solution of (S)-(+)-pent-4-yn-2-ol (22) (1.5 g, 17.9 mmol) in
CH2Cl2 (5 mL) was added dropwise over 15 min and the re-
sulting solution was then stirred in the dark at room temper-
ature for 3 days. The solution was cooled to –40 °C and a
solution of iodine (5.0 g, 19.7 mmol) in THF (25 mL) was
then added dropwise via cannula over 20 min. The dark so-
lution was placed in an ice bath and a saturated solution of
NH4Cl (20 mL) was then added cautiously and the mixture
was stirred vigorously for 30 min. The precipitated solids
were filtrated off and the residue was washed with copious
amounts of CH2Cl2. The filtrate was washed with 2 N HCl
(50 mL) and then dried (MgSO4). The solvent was removed
at reduced pressure and the residue was purified by flash
chromatography, eluting with ethyl acetate:petroleum ether
(bp 40–60 °C, 1:1) to give the E-(S)-iodo-4-methylpent-4-
en-1-ol (11) (2.95 g, 73%) as a colourless oil. [α]2D4 24.1
(c 0.34 in CH2Cl2). IR νmax (cm–1, film): 3356, 2966, 1273,
1
1514, 1248, 1112, 823, 703. H NMR (360 MHz, CDCl3) δ:
9.76 (1H, t, J = 1.9, CHO), 7.70–7.68 (4H, m, ArH), 7.47–
7.35 (6H, m, ArH), 7.15 (2H, d, J = 8.7, MeOArH), 6.82
(2H, d, J = 8.6, MeOArH), 6.81 (1H, s, ThzH), 4.56 (1H, d,
J = 11.1, CH2Ar), 4.42 (1H, d, J = 11.2, CH2Ar), 3.96–3.90
(1H, m, CHOPMB), 3.81–3.75 (2H, m, CH2OTPS), 3.80
(3H, s, CH3O), 3.53 (1H, sextet, J = 6.9, CHThz), 3.34 (1H,
dd, J = 4.3 and 15.0, CH2Thz), 3.20 (1H, dd, J = 8.1 and
15.0, CH2Thz), 2.91 (1H, ddd, J = 1.9, 6.5 and 16.8,
CH2CHO), 2.62 (1H, ddd, J = 2.1, 7.4 and 16.8, CH2CHO),
1.37 (3H, d, J = 6.9, CH3CH), 1.09 (9H, s, ((CH3)3CSi). 13C
NMR (90.6 MHz, CDCl3) δ: 201.8(d), 167.3(s), 159.4(s),
159.0(s), 135.5(d), 135.5(d), 133.4(s), 133.2(s), 130.4(s),
129.6(d), 129.2(d), 127.6(d), 113.6(d), 112.2(d), 78.9(d), 71.9(t),
65.2(t), 55.2(q), 51.0(t), 35.9(t), 30.8(d), 26.8(q), 20.0(q),
19.2(s). MS m/z (ES): 588.2616 (M + H, C34H42NO4SSi re-
quires 588.2604). Anal. calcd. for C34H41NO4Ssi (%): C
69.5,H 7.0,N 2.4; found: C 69.3, H 6.9, N 2.4.
1
1118, 939. H NMR (360 MHz, CDCl3) δ: 6.02 (1H, c, J =
1.1, C=CH), 4.00–3.91 (1H, m, CH), 2.40–2.34 (2H, m,
© 2004 NRC Canada

Pattenden et al.
361
CH2), 1.88 (3H, d, J = 1.1, CH3C=C), 1.20 (3H, d, J = 6.4
CH3CH). 13C NMR (90.6 MHz, CDCl3) δ: 145.1, 62.3, 51.4,
49.3, 24.1, 23.0. Acetic anhydride (0.66 mL, 7.06 mmol)
was added to a solution of the alcohol (1.52 g, 6.7 mmol)
and triethylamine (1.03 mL, 7.4 mmol) in CH2Cl2 (30 mL)
at 0 °C. After 5 min, 4,4-dimethylaminopyridine (0.7 mmol)
was added in one portion and the mixture was stirred for 2 h
at room temperature. The solution was poured into a 1 N
HCl solution and extracted with CH2Cl2 (2 × 50 mL). The
combined organic extracts were washed with a saturated so-
lution of NaHCO3 (50 mL), dried (MgSO4) and concentrated
at reduced pressure to give the acetate (1.63 g, 91%) as a
yellow liquid. [α]2D4 –1.8 (c 0.34, CHCl3). IR νmax (cm–1,
77.6, 72.0, 68.5, 65.2, 55.2, 51.2, 45.7, 42.6, 41.4, 35.9,
32.8, 26.8, 24.0, 21.5, 21.3, 19.5, 19.1. MS m/z (FAB):
993.2885 (M + H, C49H62N2O6S2SiI requires 993.2863).
(3R,5S)-3-Amino-5-{2-[(S)-3-(tert-butyldiphenylsilanyloxy)-
2-(4-methoxybenzyloxy)propyl]thiazol-4-yl}hexanoic acid
(E)-(S)-4-iodo-1,3-dimethylbut-3-enyl ester (20b)
Trifluoroacetic acid (1.4 mL, 18.3 mmol) was added to a
solution of the sulfinamine 20a (0.91 g, 0.92 mmol) in dry
methanol (20 mL) al 0 °C and the mixture was stirred at
room temperature for 4 h and then concentrated at reduced
pressure below 35 °C. The residue was dissolved in CH2Cl2
(25 mL), and the solution was washed with a saturated solu-
tion of NaHCO3 (20 mL), and brine (20 mL), and then evap-
orated to dryness in vacuo. The residue was purified by flash
chromatography on silica gel, eluting with ethyl acetate:pe-
troleum ether (bp 40–60 °C, 1:3 → 1:0) to give the amine
(0.74 g, 95%) as a colourless oil. [α]2D4 –3.9 (c 0.31 in
CHCl3). IR νmax (cm–1, film): 3340, 2929, 1728, 1112, 702.
1H NMR (360 MHz, CDCl3) δ: 7.70–7.67 (4H, m, ArH),
7.45–7.34 (6H, m, ArH), 7.16 (2H, d, J = 8.7, MeOArH),
6.82 (2H, d, J = 8.7, MeOArH), 6.81 (1H, s, ThzH), 5.94
(1H, s, C=CH), 5.07–5.04 (1H, m, CHOCO), 4.54 (1H, d,
J = 11.0, CH2Ar), 4.42 (1H, d, J = 11.2, CH2Ar), 3.95–3.88
(1H, m, CHOPMB), 3.81–3.76 (2H, m, CH2OTPS), 3.80
(3H, s, CH3O), 3.36 (1H, dd, J = 4.2 and 15.1, CH2Thz),
3.21 (1H, dd, J = 8.2 and 15.0, CH2Thz), 3.17–3.11 (1H, m,
CH), 3.07–3.02 (1H, m, CH), 2.48–2.21 (4H, m, CH2CO2
and CH2C=C), 1.89–1.83 (1H, m, CH2CHN), 1.82 (3H, s,
CH3C=C), 1.64–1.56 (1H, m, CH2CHN), 1.31 (3H, d, J =
6.9, CH3CH), 1.18 (3H, d, J = 6.7, CH3CH), 1.08 (9H, s,
((CH3)3CSi). 13C NMR (90.6 MHz, CDCl3) δ: 171.7, 166.9,
160.6, 158.9, 143.9, 135.5, 135.5, 133.3, 133.2, 130.4,
129.6, 129.2, 127.9, 127.6, 117.8, 113.6, 111.9, 79.1, 77.7,
72.0, 68.1, 65.3, 55.2, 46.2, 45.7, 44.7, 42.9, 35.9, 33.0,
26.7, 25.0, 21.5, 19.8, 19.1. MS m/z (ES): 855.2663 (M + H,
C43H56N2O5SSiI requires 855.2724).
1
film): 2976, 1737, 1242. H NMR (360 MHz, CDCl3) δ:
6.01 (1H, s, C=CH), 5.06 (1H, sextet, J = 6.2, CH), 2.51
(1H, dd, J = 7.4 and 13.7, CH2), 2.32 (1H, dd, J = 5.6 and
13.7, CH2), 2.04 (3H, s, CH3CO), 1.87 (3H, s, CH3C=C),
1.21 (3H, d, J = 6.1, CH3CH). 13C NMR (90.6 MHz, CDCl3)
δ: 170.3, 143.9, 77.5, 68.1, 45.6, 24.0, 21.2, 19.6. MS m/z
(ES): 207.9751 (M – C2H4O2 requires 207.9749).
The sulfinamine 20a
A solution of LiHMDS (1.0 mol L–1) in THF (1.9 mL)
was added dropwise to a solution of the acetate 19 (0.51 g,
1.9 mmol) in dry THF (13 mL) at –78 °C under a nitrogen
atmosphere, and the yellow solution was stirred at –78 °C
for 50 min. A solution of the sulfinimine 18 (1.15 g,
1.58 mmol) in THF (13 mL) was added dropwise via can-
nula over 20 min at –78 °C, and the mixture was stirred at
–78 °C for 10 min and then quenched with a saturated solu-
tion of NH4Cl (20 mL). The mixture was allowed to warm to
room temperature and then diluted with ethyl acetate
(25 mL) and washed with water (30 mL). The separated
aqueous layer was extracted with ethyl acetate (2 × 30 mL)
and the combined organic extracts were dried (MgSO4) and
then evaporated to dryness in vacuo. The residue was puri-
fied by flash chromatography, eluting with ethyl acetate:pe-
troleum ether (bp 40–60 °C, 1:3 → 1:1) to give the
sulfinamine (0.98 g, 63%) as a pale yellow oil. [α]2D4 –17.3
(c 1.78 in CHCl3). IR νmax (cm–1, film): 2929, 1730, 1513,
1112, 702. 1H NMR (360 MHz, CDCl3) δ: 7.70–7.68
(4H, m, ArH), 7.62 (2H, d, J = 8.2, SOArH), 7.45–7.34
(6H, m, ArH), 7.29 (2H, d, J = 8.3, SOArH), 7.15 (2H, d,
J = 8.7, MeOArH), 6.94 (1H, s, ThzH), 6.82 (2H, d, J = 8.7,
MeOArH), 5.88 (1H, d, J = 1.0, C=CH), 5.06–5.03 (1H, m,
CHOCO), 4.79 (1H, d, J = 9.3, NH), 4.53 (1H, d, J = 11.0,
CH2Ar), 4.42 (1H, d, J = 11.2, CH2Ar), 3.97–3.91 (1H, m,
CHOPMB), 3.79–3.75 (2H, m, CH2OTPS), 3.78 (3H, s,
CH3O), 3.59–3.53 (1H, m, CHN), 3.35 (1H, dd, J = 4.3 and
15.2, CH2Thz), 3.31–3.26 (1H, m, CHThz), 3.21 (1H, dd,
J = 8.1 and 15.1, CH2Thz), 2.60 (1H, dd, J = 5.7 and 16.0,
CH2CO2), 2.53 (1H, dd, J = 5.0 and 16.0, CH2CO2), 2.45
(1H, dd, J 6.3 and 13.8, CH2C=C), 2.39 (3H, s, CH3Ar),
2.29 (1H, dd, J 5.6 and 13.2, CH2C=C), 2.01–1.93 (1H, m,
CH2CHN), 1.89–1.83 (1H, m, CH2CHN), 1.82 (3H, s,
CH3C=C), 1.33 (3H, d, J = 6.9, CH3CH), 1.18 (3H, d, J =
6.7, CH3CH), 1.08 (9H, s, ((CH3)3CSi). 13C NMR
(90.6 MHz, CDCl3) δ: 170.9, 167.2, 160.0, 159.0, 143.8,
142.6, 141.1, 135.6, 135.5, 133.3, 133.2, 130.4, 129.6,
129.4, 129.2, 127.9, 127.6, 125.9, 125.4, 113.6, 112.7, 79.1,
The amine was reacted with chiral α-methoxyphenylacetic
acid (MPA), and the NMR spectrum of the resulting MPA
amide, complexed with Ba(ClO4)2 was studied using the
procedure developed by Riguera and co-workers (12). A
similar NMR study was made with the enantiopure (3S)-
amine prepared from the ester 19 and the enantiomeric sulfi-
nimine corresponding to 18. Inspection and comparison of
relevant chemical shift data with the Ba(ClO4)2-complexed
MPA amides confirmed the 3R-amine configuration in 20b,
and hence in 20a.
(3R,5S)-5-{2-[(S)-3-(tert-Butyldiphenylsilanyloxy)-2-(4-
methoxybenzyloxy)propyl]thiazol-4-yl}-3-(2,2,2-trichloro-
1,1-dimethylethoxycarbonylamino)hexanoic acid (E)-(S)-
4-iodo-1,3-dimethylbut-3-enyl ester (21a)
A solution of the amine 20b (870 mg, 1 mmol) in CH2Cl2
(16 mL) was added dropwise over 30 min to a slurry of 1,1-
dimethyl-2,2,2-trichloroethyl chloroformate (1.22 g, 5.1 mmol)
in pyridine (12 mL) at 0 °C and the yellow suspension was
stirred at 0 °C for 1.5 h and then evaporated to dryness in
vacuo. The orange residue was purified by flash chromatog-
raphy on silica gel, eluting with ethyl acetate:petroleum
ether (bp 40–60 °C, 1:5 → 1:4) to give the TcBOC-protected
© 2004 NRC Canada

362
Can. J. Chem. Vol. 82, 2004
β-aminoester (950 mg, 89%) as a pale yellow oil. [α]2D4 –3.2
(c 0.31 in CHCl3). IR νmax (cm–1, film): 3418, 2930, 1731,
19.8, 19.2. MS m/z (ES): 937.1527 (M
C39H53N2O6SCl3SiI requires 937.1504).
+
H,
1
1513, 1112, 703. H NMR (360 MHz, CDCl3) δ: 7.71–7.69
(4H, m, ArH), 7.47–7.35 (6H, m, ArH), 7.18 (2H, d, J = 8.6,
MeOArH), 6.85 (1H, s, ThzH), 6.83 (2H, d, J = 8.7,
MeOArH), 6.01 (1H, br s, C=CH), 5.44 (1H, d, J = 9.0,
NH), 5.15–5.06 (1H, m, CHOCO), 4.57 (1H, d, J = 11.0,
CH2Ar), 4.44 (1H, d, J = 11.0, CH2Ar), 4.00–3.92 (1H, m,
CHOPMB), 3.90–3.85 (1H, m, CHN), 3.83–3.79 (2H, m,
CH2OTPS), 3.80 (3H, s, CH3O), 3.37 (1H, dd, J = 3.9 and
15.1, CH2Thz), 3.23 (1H, dd, J = 8.2 and 15.1, CH2Thz),
3.09–3.00 (1H, m, CHThz), 2.54–2.43 (3H, m, CH2CO2 and
CH2C=C), 2.33 (1H, dd, J = 5.2 and 13.9, CH2C=C), 2.00–
1.96 (1H, m, CH2CHN), 1.93 (3H, s, TcBOC), 1.92 (3H, s,
TcBOC), 1.88–1.79 (1H, m, CH2CHN), 1.86 (3H, s,
CH3C=C), 1.35 (3H, d, J = 6.9, CH3CH), 1.20 (3H, d, J =
6.3, CH3CH), 1.10 (9H, s, ((CH3)3CSi). 13C NMR (90.6 MHz,
CDCl3) δ: 170.4(s), 167.0(s), 159.6(s), 158.7(s), 153.9(s),
143.8(s), 135.3(d), 135.3(d), 133.0(s), 132.9(s), 130.2(s),
129.4(d), 129.0(d), 127.7(d), 127.4(d), 113.3(d), 112.5(d),
106.3(s), 88.1(s), 78.8(d), 77.7(s), 77.5(d), 71.8(t), 68.1(d),
65.1(t), 54.9(q), 46.0(q), 45.5(t), 40.2(t), 39.8(t), 35.7(t),
32.8(d), 26.5(q), 23.7(q), 21.7(q), 20.9(q), 18.9(s). MS m/z
(3R,5S)-5-{2-[(S)-3-(tert-Butyldiphenylsilanyloxy)-2-((Z)-3-
tributylstannanylacryloyloxy)propyl]thiazol-4-yl}-3-(2,2,2-
trichloro-1,1-dimethylethoxycarbonylamino)hexanoic acid
(E)-(S)-4-iodo-1,3-dimethylbut-3-enyl ester (22)
Lithium hydroxide monohydrate (65.0 mg, 1.55 mmol)
was added to a solution of (Z)-3-(tributylstannyl)propenoate
(0.5 g, 1.29 mmol) (13) in a mixture of THF:H2O (4:1) and
MeOH (1.5 mL) at room temperature. The mixture was
stirred at 60 °C for 48 h and then concentrated at reduced
pressure. The residue was acidified carefully with 1 mol L–1
HCl and the aqueous solution was then extracted with ethyl
acetate (3 × 15 mL). The combined organic extracts were
dried (MgSO4) and evaporated in vacuo to leave the Z-3-
1
tributylstannane propenoic acid as a colourless oil. H NMR
(360 MHz, CDCl3) δ: 7.40 (1H, d, J = 13.0, C=CH), 6.78
(1H, d, J = 13.0, C=CH), 1.52–1.46 (6H, m), 1.32–1.23
(6H, m), 1.00–0.96 (6H, m), 0.89 (9H, t, J = 7.3, CH3CH2).
13C NMR (90.6 MHz, CDCl3) δ: 171.5, 161.5, 134.1, 29.1,
27.2, 13.6, 11.0, which was used straightaway.
(ES): 855.2663 (M
855.2724).
+ H, C47H62N2Cl3O7SSiI requires
2,4,6-Trichlorobenzoyl chloride (0.24 mL, 1.57 mmol) was
added to a solution of the stannylpropenoic acid (570 mg,
1.57 mmol) and triethylamine in THF (6 mL) at room tem-
perature and the mixture was stirred at room temperature for
1 h. The volume of THF was reduced by evaporation in
vacuo and then replaced by toluene (3 mL). The solution
was cooled to –30 °C and then a solution of the alcohol 21b
(690 mg, 0.75 mmol) in toluene (4 mL) was added via can-
nula followed by DMAP (450 mg, 3.7 mmol). The mixture
was stirred at –30 °C for 40 min and then quenched with
1 N HCl (10 mL). The separated aqueous extract was ex-
tracted with ethyl acetate (3 × 15 mL), and the combined or-
ganic extracts were then dried (MgSO4) and evaporated to
dryness in vacuo. The residue was purified by flash chroma-
tography on silica gel, eluting with ethyl acetate:petroleum
ether (bp 40–60 °C, 1:12 → 1:8) to give the ester (640 mg,
67%) as a colourless oil. [α]2D4 1.21 (c 0.66 in CHCl3). IR
νmax (cm–1, film): 3426, 2955, 1714, 1199. 1H NMR
(360 MHz, CDCl3) δ: 7.68–7.65 (4H, m, ArH), 7.47–7.34
(6H, m, ArH), 7.25 (1H, d, J = 12.7, C=CH), 6.87 (1H, s,
ThzH), 6.78 (1H, d, J = 12.7, C=CH), 6.01 (1H, br s,
C=CH), 5.43 (1H, d, J = 9.2, NH), 5.44–5.39 (1H, m,
CHOCOC=C), 5.13–5.07 (1H, m, CHOCO), 3.90–3.83
(3H, m, CHNH and CH2OTPS), 3.55 (1H, dd, J = 5.2 and
15.2, CH2Thz), 3.43 (1H, dd, J = 7.6 and 15.1, CH2Thz),
3.08–3.02 (1H, m, CHThz), 2.54–2.48 (3H, m, CH2CO2 and
CH2C=C), 2.33 (1H, dd, J = 5.2 and 13.8, CH2C=C), 1.97–
1.92 (1H, m, CH2CHN), 1.92 (3H, s, TcBOC), 1.90 (3H, s,
TcBOC), 1.86–1.79 (1H, m, CH2CHN), 1.85 (3H, s,
CH3C=C), 1.54–1.48 (6H, m, Bu3Sn), 1.32–1.23 (9H, m,
CH3CH and Bu3Sn), 1.20 (3H, d, J = 6.3, CH3CH), 1.07
(9H, s, ((CH3)3CSi), 0.95–0.90 (6H, m, Bu3Sn), 0.89 (9H, t,
J = 7.3, Bu3Sn). 13C NMR (90.6 MHz, CDCl3) δ: 170.7,
166.8, 166.0, 159.9, 158.7, 153.3, 144.0, 135.5, 134.7,
133.1, 129.6, 127.8, 127.6, 113.1, 106.5, 87.8, 78.0, 73.1,
71.1, 68.4, 64.1, 46.2, 45.7, 40.4, 39.4, 34.2, 32.9, 29.1,
27.2, 26.7, 23.9, 21.6, 20.6, 19.7, 19.2, 13.7, 10.9.
(3R,5S)-5-{2-[(S)-3-(tert-Butyldiphenylsilanyloxy)-2-
hydroxypropyl]thiazol-4-yl}-3-(2,2,2-trichloro-1,1-
dimethylethoxycarbonylamino)hexanoic acid (E)-(S)-4-
iodo-1,3-dimethylbut-3-enyl ester (21b)
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (300 mg,
1.45 mmol) was added, in one portion, to a rapidly stirred
mixture of the p-methoxybenzylether 21a (900 mg,
0.85 mmol) in CH2Cl2 (30 mL) and H2O (1.2 mL) at room
temperature. The mixture was stirred at 0 °C for 1.5 h, then
at room temperature for 30 min, and quenched with satd. aq.
NaHCO3 (30 mL). The separated aqueous layer was ex-
tracted with CH2Cl2 (3 × 30 mL) and the combined organic
extracts were dried (MgSO4) and then evaporated to dryness
in vacuo. The residue was purified by flash chromatography
on silica gel, eluting with ethyl acetate:petroleum ether
(bp 40–60 °C, 1:4 → 1:3) to give the alcohol (690 mg, 87%)
as a colourless oil. [α]2D4 1.65 (c 0.24 in CHCl3). IR νmax
(cm–1, film): 3428, 2930, 1714, 1112, 756. 1H NMR
(360 MHz, CDCl3) δ: 7.69–7.66 (4H, m, ArH), 7.47–7.37
(6H, m, ArH), 6.85 (1H, s, ThzH), 6.01 (1H, br s, C=CH),
5.31 (1H, d, J = 9.2, NH), 5.12–5.06 (1H, m, CHOCO), 4.14
(1H, br s), 3.98 (1H, br s), 3.84–3.77 (1H, m, CHNH), 3.74
(1H, dd, J = 5.6 and 10.2, CH2OTPS), 3.65 (1H, dd, J = 5.9
and 10.1, CH2OTPS), 3.27 (1H, dd, J = 3.4 and 15.3,
CH2Thz), 3.12 (1H, dd, J = 8.2 and 15.4, CH2Thz), 3.06–
3.00 (1H, m, CHThz), 2.54–2.44 (3H, m, CH2CO2 and
CH2C=C), 2.33 (1H, dd, J = 5.1 and 13.7, CH2C=C), 1.93–
1.80 (2H, m, CH2CHN), 1.91 (3H, s, TcBOC), 1.90 (3H, s,
TcBOC), 1.85 (3H, s, CH3C=C), 1.31 (3H, d, J = 7.2,
CH3CH), 1.19 (3H, d, J = 6.3, CH3CH), 1.08 (9H, s,
((CH3)3CSi). 13C NMR (90.6 MHz, CDCl3) δ: 170.6, 167.6,
160.1, 153.3, 144.0, 135.5, 133.2, 132.9, 130.2, 129.7,
127.7, 112.4, 106.6, 87.8, 78.0, 77.7, 71.1, 68.5, 66.7, 46.1,
45.7, 40.7, 39.8, 39.5, 36.4, 32.9, 26.8, 23.9, 21.6, 20.5,
© 2004 NRC Canada

Pattenden et al.
363
(1H, dd, J = 11.0 and 13.3), 2.24 (1H, dd, J = 3.9 and 15.4),
2.16 (1H, d, J = 13.0), 2.10–2.03 (1H, m, CH2CHN), 1.99–
1.87 (1H, m, CH2CHN), 1.90 (6H, br s, TcBoc), 1.82 (3H, s,
CH3C=C), 1.24 (6H, d, J = 6.7, CH3CH). 13C NMR
(90.6 MHz, CDCl3) δ: 170.2, 165.7, 165.1, 161.1, 153.1,
146.4, 141.2, 124.0, 115.0, 112.6, 106.7, 87.8, 72.8, 67.6,
64.6, 47.9, 47.7, 40.7, 39.2, 34.8, 33.6, 29.0, 22.7, 21.7,
16.9. MS m/z (ES): 625.1292 (M + H, C26H36N2O7Cl3S re-
quires 625.1309).
[(6Z,8E)-(3S,11S,15R,17S)-3-(tert-
Butyldiphenylsilanyloxymethyl)-9,11,17-trimethyl-5,13-
dioxo-4,12-dioxa-20-thia-21-azabicyclo[16.2.1]henicosa-
1(21),6,8,18-tetraen-15-yl]carbamic acid 2,2,2-trichloro-
1,1-dimethylethyl ester (23)
A solution of the stannane-iodide 22 (641 mg, 0.5 mmol)
in degassed DMF (60 mL) was added to a solution of Pd(0)
bis-dibenzylidineacetone (46 mg, 0.05 mmol) and Ph3As
(107 mg, 0.35 mmol) in degassed DMF (60 mL), and the re-
sulting yellow mixture was stirred at 60 °C for 1 h under ar-
gon. The solvent was evaporated in vacuo and the residue
was purified by flash chromatography, eluting with ethyl ac-
etate:petroleum ether (bp 40–60 °C, 1:5 → 1:3) to give the
diene macrolide (278 mg, 65%) as a yellow oil. [α]2D4 –118.1
(c 0.17 in CHCl3). IR νmax (cm–1, film): 3416, 2945, 1721,
((6Z,8E)-(3S,11S,15R,17S)-3-Formyl-9,11,17-trimethyl-
5,13-dioxo-4,12-dioxa-20-thia-21-azabicyclo[16.2.1]
henicosa-1(21),6,8,18-tetraen-15-yl)carbamic acid 2,2,2-
trichloro-1,1-dimethylethyl ester (24b)
Dess–Martin periodinane (237 mg, 0.56 mmol) was added
in one portion to a mixture of the alcohol 24a (139 mg,
0.22 mmol) and pyridine (0.14 mL, 1.79 mmol) in CH2Cl2
(8 mL) at 0 °C. The white suspension was stirred at 0 °C for
30 min and then at room temperature for 3 h. The mixture
was poured into ethyl acetate (8 mL) and a saturated solu-
tion of NaHCO3 (8 mL), and the separated organic extract
was then washed with 1 mol L–1 Na2SO3. The combined
aqueous extracts were extracted with ethyl acetate (10 mL)
and the combined organic extracts were dried (MgSO4) and
concentrated at reduced pressure. The residue was purified
by flash chromatography, eluting with ethyl acetate:petro-
leum ether (bp 40–60 °C, 1:2 → 1:1) to give the aldehyde
(88 mg, 70%) as a colourless oil. [α]2D6 –178.4 (c 0.56 in
1
1163. H NMR (360 MHz, CDCl3) δ: 7.70–7.66 (4H, m,
ArH), 7.46–7.34 (6H, m, ArH), 7.07 (1H, d, J = 11.8,
C=CH), 6.80 (1H, t, J = 11.5, C=CH), 6.80 (1H, s, ThzH),
5.56 (1H, d, J = 11.3, C=CH), 5.54–5.51 (1H, m,
CHOCOC=C), 5.16–5.11 (1H, m, CHOCO), 4.84 (1H, d,
J = 7.3, NH), 3.86–3.77 (2H, m, CH2OTPS), 3.40–3.35
(1H, m, CHNH), 3.32 (1H, dd, J = 2.5 and 14.4, CH2Thz),
3.21 (1H, dd, J = 11.0 and 14.2, CH2Thz), 3.06–3.01
(1H, m, CHThz), 2.61 (1H, dd, J = 11.5 and 14.7), 2.39–
2.34 (2H, m), 2.18 (1H, d, J = 13.4), 2.13–2.06 (1H, m,
CH2CHN), 1.96–1.90 (1H, m, CH2CHN), 1.92 (6H, br s,
TcBoc), 1.84 (3H, s, CH3C=C), 1.25 (6H, d, J = 6.9,
CH3CH), 1.07 (9H, s, ((CH3)3CSi). 13C NMR (90.6 MHz,
CDCl3) δ: 170.1(s), 166.0(s), 165.3(s), 160.9(s), 153.1(s),
145.8(s), 135.5(d), 133.8(d), 133.0(s), 129.8(d), 128.1(d),
127.7(d), 124.0(d), 115.5(d), 112.3(d), 106.7(s), 87.7(s),
72.4(d), 67.5(d), 64.4(t), 47.9(d), 47.6(t), 40.7(t), 39.1(t),
36.4(t), 33.5(d), 29.0(s), 26.7(q), 22.8(q), 21.5(q), 20.9(q),
1
CHCl3). IR νmax (cm–1, film): 3431, 2947, 1714, 1163. H
NMR (360 MHz, CDCl3) δ: 9.70 (1H, s, CHO), 6.97 (1H, d,
J = 11.9, C=CH), 6.88 (1H, t, J = 11.8, C=CH), 6.84–6.73
(1H, m, CHCHO), 6.82 (1H, s, ThzH), 5.51 (1H, d, J = 11.0,
C=CHCO2), 5.13–5.08 (1H, m, CHOCO), 4.88 (1H, d, J =
5.8, NH), 3.65 (1H, dd, J = 2.8 and 15.2, CH2Thz), 3.49–
3.40 (1H, m, CHNH), 3.19 (1H, dd, J = 10.5 and 15.2,
CH2Thz), 3.05–2.99 (1H, m, CHThz), 2.56–2.49 (1H, m),
2.32–2.22 (2H, m), 2.18 (1H, d, J = 11.8), 1.98–1.73
(2H, m, CH2CHN), 1.89 (6H, br s, TcBoc), 1.84 (3H, s,
CH3C=C), 1.25 (6H, d, J = 6.9, CH3CH). 13C NMR
(90.6 MHz, CDCl3) δ: 198.0, 171.1, 164.8, 163.8, 161.4,
153.2, 147.1, 142.0, 124.0, 114.1, 112.9, 112.2, 106.6, 87.8,
75.8, 67.7, 47.6, 41.3, 39.3, 33.4, 33.0, 22.2, 21.6, 17.0. MS
m/z (ES): 623.1178 (M + H, C26H33N2O7Cl3S requires
623.1152).
19.2(s), 17.0(q). MS m/z (ES): 863.2452 (M
C42H54N2O7Cl3SSi requires 863.2487).
+ H,
((6Z,8E)-(3S,11S,15R,17S)-3-Hydroxymethyl-9,11,17-
trimethyl-5,13-dioxo-4,12-dioxa-20-thia-21-aza-
bicyclo[16.2.1]henicosa-1(21),6,8,18-tetraen-15-yl)carba-
mic acid 2,2,2-trichloro-1,1-dimethylethyl ester (24a)
A solution on TBAF (1 mol L–1) in THF (0.5 mL) was
added to a mixture of the macrolide silyl ether 23 (211 mg,
0.24 mmol) and acetic acid (70 µL, 1.2 mmol) in THF
(4.5 mL) at room temperature, and the mixture was stirred at
this temperature for 20 h. The mixture was poured into a sat-
urated solution of NaHCO3 (5 mL) and then extracted with
diethyl ether (3 × 10 mL). The combined organic extracts
were dried (MgSO4) and then evaporated to dryness in vacuo
to leave a residue which was purified by flash chromatogra-
phy, eluting with ethyl acetate:petroleum ether (bp 40–
60 °C, 1:2 → 3:2) to give the alcohol (117 mg, 78%) as a
colourless oil. [α]D24 –137.5 (c 2.42 in CHCl3). IR νmax (cm–1,
[(6Z,8E)-(3S,11S,15R,17S)-9,11,17-Trimethyl-3-((E)-2-
methyl-3-oxopropenyl)-5,13-dioxo-4,12-dioxa-20-thia-21-
azabicyclo[16.2.1]henicosa-1(21),6,8,18-tetraen-15-
yl]carbamic acid 2,2,2-trichloro-1,1-dimethylethyl ester
(25)
A solution of the aldehyde 24b (89 mg, 0.14mmol) and 2-
(triphenylphosphoranylidene)propionaldehyde
(46
mg,
1
film): 3431, 2947, 1714, 1163. H NMR (360 MHz, CDCl3)
0.14 mmol) in benzene (7 mL) was heated under reflux for
3 h under a nitrogen atmosphere. The mixture was cooled to
room temperature, quenched with water (7 mL), and then
extracted with diethyl ether (2 × 10 mL). The combined or-
ganic extracts were dried (MgSO4) and then evaporated to
dryness in vacuo. The residue was purified by flash chroma-
tography, eluting with ethyl acetate:petroleum ether (bp 40–
60 °C, 1:2 → 1:1) to give the unsaturated aldehyde (70 mg,
δ: 7.03 (1H, d, J = 11.9, C=CH), 6.83 (1H, t, J = 11.6,
C=CH), 6.79 (1H, s, ThzH), 5.54 (1H, d, J = 11.3, C=CH),
5.52–5.48 (1H, m, CHOCOC=C), 5.14–5.06 (1H, m,
CHOCO), 4.86 (1H, d, J = 6.9, NH), 3.85 (1H, dd, J = 4.0
and 11.9, CH2OH), 3.79 (1H, dd, J = 5.3 and 11.9, CH2OH),
3.43–3.33 (1H, m, CHNH), 3.30–3.20 (2H, m, CH2Thz),
3.03–2.98 (1H, m, CHThz), 2.55 (1H, app t, J = 14.0), 2.33
© 2004 NRC Canada

364
Can. J. Chem. Vol. 82, 2004
73%) as a colourless oil. [α]2D8 –171.8 (c 0.17 in CHCl3). IR
νmax (cm–1, film): 3460, 2957, 1729, 1157. 1H NMR
(360 MHz, CDCl3) δ: 9.48 (1H, s, CHO), 7.02 (1H, d, J =
11.9, C=CH), 6.83 (1H, s, ThzH), 6.81 (1H, t, J = 11.4,
C=CH), 6.46 (1H, dd, J = 1.35 and 8.1,HC=C-CHO), 6.31
(1H, app c, J 7.5, CH-C=C), 5.52 (1H, d, J = 11.3,
C=CHCO2), 5.15–5.07 (1H, m, CHOCO), 4.84 (1H, d, J =
5.3, NH), 3.44–3.35 (1H, m, CHNH), 3.28–3.24 (2H, m,
CH2Thz), 3.06–2.99 (1H, m, CHThz), 2.54 (1H, dd, J = 11.3
and 15.4), 2.38–2.24 (2H, m), 2.17 (1H, d, J = 13.1), 1.98–
1.75 (2H, m, CH2CHN), 1.95 (3H, s, CH3-C=C), 1.90
(6H, s, TcBOC), 1.83 (3H, s, CH3C=C), 1.25 (6H, d, J =
6.7, CH3CH). 13C NMR (90.6 MHz, CDCl3) δ: 194.4, 170.1,
164.4, 164.1, 161.2, 153.0, 147.6, 146.7, 141.5, 140.7,
123.8, 114.5, 113.0, 106.6, 87.8, 68.3, 67.5, 47.8, 47.7 40.8,
39.1, 37.5, 33.6, 22.6, 21.6, 21.0, 16.8, 9.9. MS m/z (ES):
663.1432 (M +H, C26H33N2O7Cl3S requires 623.1165).
due was poured into brine (25 mL) and the solution was then
extracted with diethyl ether (3 × 30 mL). The combined or-
ganic extracts were dried (MgSO4) and concentrated at re-
duced pressure. The residue was purified by flash
chromatography, eluting with petrol to give the correspond-
ing allylic bromide (1.1 g, 90%) as a pale yellow oil. A solu-
tion of dimethylamine (1 mol L–1) in THF) (10 mL) was
added to a stirred solution of the bromide in THF (5 mL) at
0 °C. The mixture was stirred at 0 °C for 2 h, then concen-
trated in vacuo and poured into a mixture of 1 N NaOH
(30 mL) and diethyl ether (40 mL). The separated organic
extract was dried (MgSO4) and evaporated to leave 3-
methyl-((E)-3-tributylstannanylbut-2-enyl)amine 3 (0.63 g,
1
63%) as a pale yellow oil. H NMR (360 MHz, CDCl3) δ:
5.63 (1H, t, J = 7.0, C=CH), 3.23 (2H, d, J 6.8, CH2N), 2.24
(6H, s, CH3N), 1.97 (3H, s, CH3-C=C), 1.52–1.46 (6H, m),
1.32–1.23 (6H, m), 1.00–0.96 (6H, m), 0.89 (9H, t, J = 7.3,
CH3CH2).
bis-Acetonitrile palladium dichloride (2 mg) was added to
a solution of the stannane 3 (28 mg, 0.0743 mmol) and the
vinyl iodide 26 (29 mg, 0.037 mmol) in degassed DMF
(1.5 mL), and the mixture was stirred at room temperature
for 6 h and then concentrated in vacuo. The residue was
purified by flash chromatography, eluting with ethyl
acetate:pentane (1:8 → 1:4) to acetone:pentane (1:4 → 1:1)
and triethylamine (1 drop per 10 mL) to give TcBOC
pateamine A (9 mg, 36%) as a pale yellow oil. [α]2D4 –235.03
[(6Z,8E)-(3S,11S,15R,17S)-3-((1E,3E)-4-Iodo-2-
methylbuta-1,3-dienyl)-9,11,17-trimethyl-5,13-dioxo-4,12-
dioxa-20-thia-21-azabicyclo[16.2.1]henicosa-1(21),6,8,18-
tetraen-15-yl]carbamic acid 2,2,2-trichloro-1,1-
dimethylethyl ester (26)
A solution of the unsaturated aldehyde 25 (70 mg,
0.1 mmol) and iodoform (250 mg, 0.63 mmol) in degassed
THF (4 mL) was added dropwise over 15 min to a slurry of
CrCl2 (305 mg, 2.5 mmol) in degassed THF (3 mL) at 0 °C
under an argon atmosphere. The mixture was stirred at room
temperature for 1.5 h, then quenched with water (8 mL), and
extracted with diethyl ether (2 × 10 mL). The combined or-
ganic extracts were dried (MgSO4) and concentrated at re-
duced pressure. The yellow residue was purified by flash
chromatography, eluting with ethyl acetate:petroleum ether
(bp 40–60 °C, 1:4 → 1:3) to give the vinyl iodide (57 mg,
68%) as a pale yellow oil. [α]2D5 –271.6 (c 0.54 in CHCl3).
1H NMR (360 MHz, CDCl3) δ: 7.07 (1H, d, J = 14.5,
C=CHI), 7.03 (1H, d, J = 13.0, C=CH), 6.81 (1H, s, ThzH),
6.78 (1H, t, J = 11.7,HC=C), 6.46 (1H, d, J = 14.7, HC=CI),
6.16 (1H, app c, J = 7.8, CH-C=C), 5.52 (1H, d, J = 9.2,
C=CH), 5.50 (1H, d, J = 11.5, C=CHCO2), 5.15–5.07
(1H, m, CHOCO), 4.84 (1H, br s, NH), 3.44–3.38 (1H, m,
CHNH), 3.23–3.17 (2H, m, CH2Thz), 3.05–3.00 (1H, m,
CHThz), 2.56 (1H, dd, J = 11.6 and 14.9), 2.34 (1H, dd, J =
11.2 and 13.3), 2.25 (1H, dd, J = 3.3 and 15.2), 2.16 (1H, d,
J = 12.8), 2.10–2.04 (1H, m), 1.92 (3H, s, CH3-C=C), 1.90
(7H, br s), 1.86 (3H, s, CH3C=C), 1.24 (3H, d, J = 6.5,
CH3CH), 1.23 (3H, d, J = 6.5, CH3CH). 13C NMR
(90.6 MHz, CDCl3) δ: 170.1, 165.0, 164.6, 161.0, 153.0,
148.4, 145.9, 140.7, 137.9, 129.6, 123.9, 115.2, 112.6,
106.6, 87.7, 77.7, 68.4, 67.8, 47.9, 47.7, 40.5, 39.1, 38.6,
33.6, 22.7, 21.6, 20.9, 16.7, 12.7. MS m/z (ES): 809.0441
(M +H, C26H33N2O7Cl3S requires 809.0458).
1
(c 0.1, CHCl3). H NMR (360 MHz, CDCl3) δ: 7.03 (1H, d,
J = 11.8, C=CH), 6.80 (1H, s, ThzH), 6.76 (1H, t,
J = 11.6,HC=C), 6.37 (1H, d, J = 15.9, HC=C), 6.23 (1H, d,
J = 15.9, HC=C), 6.27–6.17 (1H, m, CH-C=C), 5.65 (1H, t,
J = 6.8, C=CH), 5.56 (1H, d, J = 8.8, C=CH), 5.51 (1H, d,
J = 11.3, C=CHCO2), 5.16–5.08 (1H, m, CHOCO), 4.84
(1H, d, J = 7.2, NH), 3.45–3.38 (1H, m, CHNH), 3.21 (2H,
d, J 6.7, CH2N), 3.08–2.98 (1H, m, CHThz), 3.06 (2H, app
d, J = 7.0, CH2Thz), 2.58–2.53 (1H, m), 2.38–2.05 (4H, m),
2.25 (6H, s, CH3N), 1.97 (3H, s, CH3-C=C), 1.96–1.81
(1H, m), 1.91 (6H, br s, TcBOC), 1.81 (6H, bs, CH3C=C),
1.28–1.24 (6H, m, CH3CH). 13C NMR (125 MHz, CDCl3) δ:
170.1, 165.0, 164.6, 161.0, 153.0, 145.9, 140.6, 138.2,
136.5, 134.5, 130.7, 130.2, 128.6, 124.1, 115.7, 112.6,
106.7, 87.9, 69.2, 67.6, 56.9, 47.9, 47.8, 44.8, 40.5, 39.1,
39.1, 33.7, 23.0, 21.7, 21.0, 16.7, 13.4, 12.8. MS m/z (ES):
760.2601 (M + H, C26H33N2O7Cl3S requires 760.2534).
Pateamine A (1)
A 10% Cd/Pd (40 mg) couple was added to a solution of
the TcBOC pateamine 27 (8.5 mg, 0.011 mmol) in THF
(1 mL) and aq. NH4OAc (1 mol L–1) (1 mL) at room tem-
perature. The resulting slurry was stirred vigorously at room
temperature for 3 h, then additional Cd/Pd (30 mg) was
added and the mixture was stirred for a further 4 h. The mix-
ture was filtered through cotton wool and the residue was
washed with H2O and diethyl ether. The filtrate was ex-
tracted with diethyl ether (2 × 2 mL), and the combined ex-
tracts were dried (MgSO4) and then concentrated in vacuo.
The residue was purified by chromatography on a Varian
CBA cartridge eluting with 1% NH4OH in MeOH to give
pateamine A (4.5 mg, 73%) as an oil. [α]2D6 –302.8 (c 0.21 in
TcBOC pateamine A (27)
Carbon tetrabromide (1.83 g, 5.54 mmol) was added in
one portion to a solution of E-3-tributylstannanylbut-2-en-1-
ol (23) (1 g, 2.77 mmol), 2,6-lutidine (64 µL, 0.55 mmol),
and triphenylphosphine (1.45 g, 5.54 mmol) in acetonitrile
(15 mL), and the mixture was stirred at room temperature
for 1 h and then concentrated at reduced pressure. The resi-
1
MeOH). H NMR (360 MHz, CDCl3) δ: 7.00 (1H, d, J =
© 2004 NRC Canada

Pattenden et al.
365
reaction in target natural product synthesis from our laborato-
ries see: G. Pattenden and D.J. Sinclair. J. Organomet. Chem.
653, 261 (2002).
11.7, C=CH), 6.75 (1H, s, ThzH), 6.68 (1H, t, J = 11.5,
HC=C), 6.38 (1H, d, J = 15.9, HC=C), 6.30–6.22 (1H, m,
CH-C=C), 6.23 (1H, d, J = 15.8, HC=C), 5.65 (1H, t, J =
7.0, C=CH-CH2), 5.53 (1H, d, J = 8.8, C=CH), 5.41 (1H, d,
J = 11.4, C=CHCO2), 5.18–5.09 (1H, m, CHOCO), 3.25–
3.16 (2H, m), 3.14–3.05 (1H, m, CHThz), 3.10 (2H, d, J =
6.7), 2.55 (1H, app t, J = 10.6), 2.41 (1H, dd, J = 2.4 and
16.7), 2.36–2.26 (1H, m), 2.26 (6H, br s, CH3N), 2.20–1.91
(3H, m), 2.02 (3H, s, CH3-C=C), 1.84 (3H, s, CH3-C=C),
1.82 (3H, s, CH3-C=C), 1.80–1.65 (2H, br s), 1.39–1.26
(1H, m), 1.27 (3H, d, J = 7.8, CH3CH), 1.25 (3H, d, J = 6.7,
CH3CH). 13C NMR (125 MHz, CDCl3) δ: 172.3, 165.5,
164.5, 161.2, 145.5, 140.6, 138.1, 135.9, 134.0, 130.7,
130.5, 128.5, 123.8, 115.1, 112.4, 69.2, 67.2, 57.2, 48.2,
45.4, 45.1, 42.9, 39.1, 33.3, 22.8, 21.1, 16.8, 13.4, 12.7. MS
m/z (ES): 556.3246 (M + H, C26H33N2O7Cl3S requires
556.3209).
8. M.J. Remuiñán and G.Pattenden. Tetrahedron Lett. 41, 7367
(2000).
9. (a) M.W. Brendenkamp, C.W. Holzapfel, and W.J. van Zyl.
Synth. Commun. 22, 3029 (1992); (b) E. Anguilar and A.I.
Meyers. Tetrahedron Lett. 35, 2473 (1994).
10. (a) G.A. Davis, Y. Zhang, Y. Andemichael, T. Fang, D.A.
Fanelli, and H. Zhang. J. Org. Chem. 64, 1403 (1999); (b) For
a review of the chemistry of sulfinimines, see: F.A. Davis, P.
Zhou, and B.C. Chen. Chem. Soc. Rev. 27, 13 (1998).
11. C.L. Rand, D.E. Van Horn, M.W. Moore, and E. Negishi. J.
Org. Chem. 46, 4093 (1981); cf. ref. 2.
12. B. López, E. Quiñoá, and R. Riguera. J. Am. Chem. Soc. 121,
9724 (1999).
13. Ethyl Z-3-(tributylstannyl)propenoate was prepared from ethyl
propiolate, see: J.K. Stille and B.L. Broh. J. Am. Chem. Soc.
109, 813 (1987); saponification of the ethyl ester with lithium
hydroxide then gave Z-3-(tributylstannyl)propenoic acid.
14. J. Inanaga, K. Hirata, T. Katsuki, and M. Yamaguchi. Bull.
Chem. Soc. Jpn. 52, 1989. (1979).
Acknowledgements
We thank the (EPSRC) (Fellowship to DJC) and the (EU)
(Marie Curie Fellowship to MJR) for support of this re-
search. We also thank Pfizer Ltd. and Zeneca Strategic
Funding for financial support, and Dr. J.M. Clough (Zeneca
Agrochemicals) for his interest in this program.
15. V. Farina and B. Krishnan. J. Am. Chem. Soc. 113, 9585
(1991).
16. For a comparison of the Heck reaction with the Stille reaction
in elaborating the Z-2, E-4 – diene unit in the model com-
pound 2 see: C. Câline and G. Pattenden. Synlett, 1661 (2000).
17. K. Takai, K. Nitta, and K. Utimoto. J. Am. Chem. Soc. 108,
7408 (1986).
18. (a) D.E. Rudisill, L.A. Castonguay, and J.K. Stille. Tetrahe-
dron Lett. 29, 1509 (1988); (b) A.B. Smith, R.E. Maleczka,
J.L. Leazer, J.W. Leahy, J.A. McCauley, and S.M. Condon.
Tetrahedron Lett. 35, 4911 (1994).
19. Q. Dong, C.E. Anderon, and M.A. Ciufolini. Tetrahedron Lett.
36, 5681 (1995); this method was also used by Romo et al. in
their synthesis of pateamine.
20. S.K. Chattopadhyay, J. Kempson, A. McNeil, M. Reader, D.E.
Rippon, and D. Waite. J. Chem. Soc. Perkin Trans. 1, 2415
(2000).
21. S. Saito, T. Hasegawa, M. Inaba, R. Nishida, T. Fujii, S. Nomizu,
and T. Moriwake. Chem. Lett. 1389 (1984); G. Guanti, L. Banti,
and E. Narisano. Tetrahedron Lett. 40, 5509 (1989).
22. R. Jacobsen, R.J. Taylor, H.J. Williams, and L.R. Smith. J.
Org. Chem. 47, 3140 (1982).
23. J.-F. Betzer, F. Delalogue, B. Muller, A. Pancrazi, and J. Prunet.
J. Org. Chem. 62, 7768 (1997); H. Miyake and K. Yamamura.
Chem. Lett. 981 (1989).
References
1. P.T. Northcote, J.W. Blunt, and M.H.G. Munro. Tetrahedron
Lett. 32, 6411 (1991).
2. R.M. Rzasa, D. Romo, D.J. Stirling, J.W. Blunt, and M.H.G.
Munro. Tetrahedron Lett. 36, 5307 (1995).
3. D. Romo, R.M. Rzasa, H.A. Shea, K. Park, J.M. Langenhan, L.
Sun, A. Akhiezer, and J.O. Liu. J. Am. Chem. Soc. 120, 12 237
(1998).
4. J.D. Critcher and G. Pattenden. Tetrahedron Lett. 37, 9107
(1996).
5. E. Piers, R.W. Friesen, and B.A. Keay. J. Chem. Soc. Chem.
Commun. 809 (1985); E. Piers, R.W. Friensen, and B.A. Keay.
Tetrahedron, 47, 4555 (1991); E. Piers, R.W. Friesen, and S.J.
Rettig. Can. J. Chem. 70, 1385 (1992).
6. E. Piers and R.W. Friesen. J. Org. Chem. 51, 3405 (1986); E.
Piers and R.W. Friesen. Can. J. Chem. 70, 1204 (1992); E.
Piers and Y.-F. Lu. J. Org. Chem. 31, 926 (1988).
7. For a recent review of the Stille reaction see: M.A.J. Duncton
and G. Pattenden. J. Chem. Soc. Perkin Trans. 1, 1235 (1999);
For other illustrations of the scope for the intramolecular Stille
© 2004 NRC Canada