Exploring the reactivity of chiral glycidic amides for their applications in synthesis of bioactive compounds

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DOI: 10.1002/ejoc.201402221

Exploring the Reactivity of Chiral Glycidic Amides for Their Applications in

Synthesis of Bioactive Compounds

Francisco Sarabia,*^[a]Carlos Vivar-García,^[a]Cristina García-Ruiz,^[a]

Antonio Sánchez-Ruiz,^[a][‡]María Soledad Pino-González,^[a]Miguel García-Castro,^[a][‡‡]and

Samy Chammaa^[a][‡‡]

Dedicated to Professor Rosa María Claramunt on the occasion of her 65th birthday

Keywords: Synthetic methods / Nucleophilic substitution / Diastereoselectivity / Sulfonium salts / Glycidic amides

A new class of chiral sulfonium salts, derived from

L

- and

D

-

useful building blocks for the synthesis of different bioactive

products. Thus, the expedient synthesis of clavaminol H as

well as the synthesis of key precursors for other bioactive

compounds, for example, polyketide-derived natural prod-

ucts, have been achieved, demonstrating the synthetic effi-

ciency and utility of this chemistry.

methionine, has been designed and successfully employed

in our laboratories for the diastereoselective synthesis of

glycidic amides. The epoxy amides obtained were converted

cleanly into 1,2-difunctionalized products through oxirane

ring-opening reactions with different types of nucleophiles.

The resulting ring-opened products represent valuable and

trogen, sulfur and alkyl-type nucleophiles that could poten-

tially provide access to a wide array of 1,2-functionalized

systems through regio- and stereocontrolled ring-opening

Introduction

We recently described the design, synthesis and reactivity

of a new class of chiral sulfonium ylides derived from α-

amino acids, structurally characterized by the presence of a

bicyclic system.^[1,2]After an extensive study of these chiral

reagents, particularly those derived from l- and d-meth-

ionine, namely sulfonium salts 1 and 2, we demonstrated

their efficiency in the asymmetric synthesis of glycidic

amides 3 and 4, which were obtained in good-to-excellent

yields with exclusive trans selectivity and excellent dia-

stereoselectivity by using a broad range of aldehydes, in-

cluding aliphatic, aromatic, α,β-unsaturated and heterocy-

clic derivatives (Scheme 1).^[2]In continuation of these stud-

ies, the next step in this research was to explore the syn-

thetic possibilities that the resulting epoxy amides may pro-

vide in the field of asymmetric synthesis.^[3]To this end we

planned a study of the reactivity of these epoxy amides

towards nucleophilic reagents of various types, including ni-

[a] Department of Organic Chemistry, Faculty of Sciences,

University of Malaga,

Campus de Teatinos s/n, 29071 Málaga, Spain

E-mail: frsarabia@uma.es

http://webdeptos.uma.es/organica/

[‡] Current address: School of Chemistry, Manchester

Interdisciplinary Biocentre, University of Manchester,

Manchester, M1 7DN, UK

[‡‡] Current address: Max-Planck Institute fur Molekulare

Physiologie,

Otto-Hahn-Strasse 11, 44227 Dortmund, Germany

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201402221.

Scheme 1. Stereoselective synthesis of epoxy amides from a new

class of chiral sulfonium salts and their potential reactivity.

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reactions. The synthesis of 1,2-functionalized systems is of both the C-2 and C-3 ring-opened products. In particular,

great importance in organic synthesis, particularly in the we observed doublets in the range 3.61–4.83 ppm for all

field of natural products.^[4,5]For example, 1,2-amino these compounds, which did not allow an unambiguous as-

alcohols^[6]or polypropionate-derived chains^[7]represent signment of the regioisomer formed. However, the observa-

some of the many examples of 1,2-functionalized systems tion in the ¹³C NMR spectra of signals in the range 71.6–

that would be accessible by this methodology. In fact, we 75.9 ppm, assigned to C-3, is in accordance with the C-2

have already employed these chiral reagents in the asym- ring-opened products because the corresponding regioiso-

metric synthesis of bengamides and their analogues,^[8]glo- mers would show signals at around 85 ppm for C-2 due to

bomycin and related cyclodepsipeptides,^[9]and the natural the presence of a hydroxy group at this position. Further-

compounds sphingosine and sphinganine.^[2]In this article more, the reduction of the 2-azido-3-hydroxy derivative 23a,

we wish to report the utility of the epoxy amides prepared the structure of which was unambiguously assigned, as will

from this new class of sulfur ylides in the stereoselective be described later (see Scheme 3), furnished a product with

synthesis of 1,2-functionalized derivatives and their applica- identical physical and spectroscopic properties to that ob-

tion in the synthesis of some bioactive compounds of bio- tained for the ring-opening of epoxy amide 3a with ammo-

medical interest.

nia (compound 5), thus providing confirmation of the re-

gioselectivity of the reaction. On the other hand, the corre-

sponding syn ring-opened products were not detected,

which indicates that possible anchimeric assistance by the

methyl sulfide group during the oxirane ring-opening pro-

cess does not occur.

Results and Discussion

Ring-Opening Reactions with Nitrogen Nucleophiles and

their Synthetic Applications

For this initial study we selected simple epoxy amides,

prepared according to the methodology described in the

preceding article,^[2]as substrates. For the reactions with ni-

trogen nucleophiles, amines were tested and found to

smoothly open the oxirane ring of the epoxy amides in a

completely regioselective manner by heating at reflux in

methanol to give 2-amino-3-hydroxy amides.^[10]In general,

both primary and secondary amines, including ammonia

and aniline, were shown to be efficient nucleophiles, provid-

ing the corresponding ring-opened products 5–22 in yields

of 54–93% (Scheme 2 and Table 1). The complete regio-

and stereoselectivity displayed by these epoxy amides in

their reactions with amines and other nucleophiles, such as

carbon nucleophiles, have been theoretically rationalized^[11]

and extensively demonstrated by us in our previous contri-

butions in this field.^[3,12]Experimentally, NMR analysis of

the crude ring-opened products revealed complete regio-

Scheme 2. Reactions of epoxy amides with amines and azide. Rea-

gents and conditions: a) see Table 1 for conditions and yields; b) see

Table 2 for conditions and yields.

Another nitrogen nucleophile worthy of consideration is

selectivity in favour of the formation of the C-2 ring-opened the azide anion. In contrast to amines, with the azide as

products instead of the corresponding 3-amino-2-hydroxy nucleophile, we found remarkable differences depending on

regioisomers. Thus, for the aliphatic compounds 16–22, ob- the nature of the starting epoxy amide and the azide em-

1

servation of a H NMR signal as a doublet in the range ployed. For this study we started with the reactions of ep-

3.36–4.11 ppm and a downfield signal with different multi- oxy amides 3a and 3l with NaN₃in DMF at 70 °C or in

plicities are in accordance with oxirane ring-opened prod- MeOH at reflux, obtaining a 1:4 and 1:2 mixture of re-

ucts with an amino group installed at the 2-position. In gioisomers 23a/23b and 24a/24b in combined yields of 86

contrast, for the C-3 ring-opened products, we should ob- and 68%, respectively. The preference of the azide anion to

serve a downfield shift for the protons at the 2-position react at the 3-position in reactions with epoxy amides has

(4.39–4.50 ppm), which should be more deshielded by the already been reported by Sharpless and co-workers,^[13]

effect of the hydroxy group, and an upfield shift for the which was remarkably boosted by the use of Mg(N₃)₂,^[14]

protons at the 3-position (2.91–3.61 ppm). In addition, our and which we observed for 3a and 3l (see Table 2). Our

total syntheses of the natural products sphinganine and interest in the C-2 ring-opened products prompted us to

sphingosine from epoxy amides 3j and 3k^[2]via 2-amino-3- study this reaction in more detail by screening a variety

hydroxy amides 21 and 22 (entries 17 and 18, Table 1) un- of different reaction conditions, as summarized in Table 2.

ambiguously demonstrated the regioselectivity at C-2 of the Intriguingly, when acetic acid was used in stoichiometric

oxirane ring-opening reaction. Less clear was the establish- amounts in DMF, a significant reversal of regiochemistry

ment of the regioselectivity at the 2-position for the aro- in favour of the C-2 ring-opened product was observed,

matic compounds 5–15 because either proton at the 2- or particularly for aliphatic epoxy amide 3l, together with an

3-position could appear as a doublet in the same region for improvement in the combined yield compared with pre-

2

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Synthesis of Bioactive Compounds

Table 1. Reactions of epoxy amides 3 with amines.

Table 2. Reactions of epoxy amides 3 with azide.

Entry Epoxy amide (R)

X

Amino hydroxy

Epoxy amide

(R)

Reaction conditions^[a]

Azido alcohol (combined

yield [%]; C-2/C-3 ring-

opened products ratio)

amide^[a](Yield [%])

1

3a (R = C₆H₅)

NH₂

5 (69)

6 (72)

7 (75)

8 (93)

9 (54)

2

3a (R = C₆H₅)

NHMe

NHBn

NHAllyl

NHPh

NMe₂

NHMe

NH₂

NHMe

NH₂

3a (C₆H₅)

3l (CH₃)

A: MeOH, 70 °C

B: MeOH, MgSO₄, 70 °C 23a/23b (82; 0:100)

C: DMF, 70 °C

D: DMF, AcOH, 70 °C

A: MeOH, 70 °C

23a/23b (86; 1:4)

3

3a (R = C₆H₅)

4

3a (R = C₆H₅)

23a/23b (73; 1:4)

23a/23b (75; 1:2.5)

24a/24b (68; 1:2)

5

3a (R = C₆H₅)

6

3a (R = C₆H₅)

10 (68)

11 (71)

12 (65)

13 (83)

14 (74)

15 (74)

16 (62)

17 (73)

18 (84)

19 (73)

20 (65)

21 (72)

22 (75)

7

8

9

3b (R = 4-MeC₆H₄)

3c (R = 4-MeOC₆H₄)

3d [R = 3,4- (BnO)₂C₆H₃]

3e (R = 4-ClC₆H₄)

3f (R = CH₃CH₂)

3g [R = (CH₃)₂CH]

3h (R = Cy)

B: MeOH, MgSO₄, 70 °C 24a/24b (85; 1:4)

C: DMF, 70 °C

24a/24b (61; 1:2)

24a/24b (78; 3:1)

24a/24b (74; 2.6:1)

24a/24b (81; 3:1)

no reaction

D: DMF, AcOH, 70 °C

E: MeOH, NH₄Cl, 70 °C

F: DMF, TFA, 70 °C

FЈ: DMF, TFA, 25 °C

G: DMF, TfOH, 70 °C

10

11

12

13

14

15

16

17

18

24a/24b (73; 4:1)

NHMe

NH₂

H: DMF, Zn(OTf)₂, 70 °C 24a/24b (52; 1:2)

3m [CH₃(CH₂)₈] A: MeOH, 70 °C 25a/25b (72; 1.2:1)

B: MeOH, MgSO₄, 70 °C 25a/25b (86; 1:2.6)

3i (R = C₆H₅CH₂)

3j [R = CH₃(CH₂)₁₄]

3k [R = (E)-CH₃(CH₂)₁₂CH=CH] NH₂

C: DMF, 70 °C

D: DMF, AcOH, 70 °C

G: DMF, TfOH, 70 °C

25a/25b (56; 1:2)

25a/25b (75; 5:1)

25a/25b (92; 6:1)

26a/26b (85; 1.2:1)

26a/26b (94; 5:1)

27a/27b (76; 100:0)

[a] Reagents and conditions: 5.0 equiv. of amine or NH₃, MeOH,

reflux, 6–8 h.

3n [CH₃(CH₂)₉] A: MeOH, 70 °C

D: DMF, AcOH, 70 °C

3g [(CH₃)₂CH]

[a] All reactions were carried out by using 10.0 equiv. of NaN₃.

viously tested reaction conditions. A similar regioselectivity

was obtained when the reaction was performed in MeOH

in the presence of ammonium chloride and H₂O, although ucts. We have ascribed these results to the formation of hin-

a lower yield was obtained. In an attempt to improve the dered phosphazide or iminophosphorane intermediates

regioselectivity, other acids, such as TFA, TfOH and Lewis during the Staudinger reaction, which were unable to react

acids, were investigated. From these studies, TfOH (condi- with water and thus intramolecular attack of the hydroxy

tions G, Table 2) showed a slight increase of the C-2 ring- group on either the phosphazide or iminophosphorane in-

opened product compared with AcOH, with the other acids termediate was favoured, followed by an intramolecular

not proving beneficial. Although it is not clear what the Mitsunobu-type reaction of the resulting oxyphosphonium

role of the acid is in the regioselectivity of this reaction, we derivative to form the corresponding aziridines.^[16]To over-

surmised that the protonation of the relatively basic amide come this hurdle, we executed this reaction with Me₃P in

carbonyl group could activate the 2-position for nucleo- the presence of water to afford the corresponding amino

philic attack. Fortunately, for epoxy amides containing alcohols 5 and 17 from azido alcohols 23a and 27a with no

larger alkyl groups (epoxy amides 3m and 3n), the regiose- aziridines being detected (Scheme 3).

lectivity increased to 5:1 in favour of the C-2 ring-opened

On the other hand, when TMSN₃was used as the source

products (25a and 26a) under acidic conditions, reaching a of azide anion in the presence of a Lewis acid [Yb(OTf)₃,

ratio of 6:1 when TfOH was used in the reaction of 3m. Zn(OTf)₂or ZrCl₄],^[17]only aromatic epoxy amides reacted

More hindered epoxy amides, such as 3g, delivered the cor- to give the corresponding 3-azido-2-trimethylsilyloxy deriv-

responding 2-azido-3-hydroxy derivative 27a in a good yield atives 31–36. In these cases, the opposite regioselectivity ob-

(76%) with no detection of the 3-azido-2-hydroxy re- served with respect to the ring-opening reactions with

gioisomer 27b (Scheme 2 and Table 2).

amines is explained by the acidic conditions required for

Our interest in the azido ring-opened products lies in the the introduction of azide that leads to the activation of the

remarkable advantages that this functional group presents benzylic position, which is attacked by the azide nucleo-

compared with the corresponding amino ring-opened prod- phile. In contrast, aliphatic epoxy amides were unreactive

ucts, such as the ease of handling over their amino counter- towards TMSN₃, giving only the starting material. Even for

parts and, in addition, the possibility of being readily trans- the aromatic epoxy amides, we found a considerable differ-

formed into the corresponding aziridines, which are inter- ence in reactivity depending on the nature of the substituent

esting and useful building blocks.^[4]Thus, when azido present on the aromatic ring, with a p-methoxy substituent

alcohols 23a, 25a and 27a were treated with Ph₃P,^[15]azirid- being the most reactive and not requiring the presence of a

ines 28, 29 and 30 were efficiently obtained in yields of 62, Lewis acid to obtain the desired ring-opened product 31.

92 and 89%, respectively. Interestingly, when a mixture of Identical results were observed for the reactions of 3,4-di-

azido alcohols, such as 23a/23b, was used, only one azirid- O-benzyl and p-acetamide derivatives 3d and 3o, with the

ine (28) was obtained. In an attempt to obtain the corre- ring-opened products 32 and 33 being obtained in yields

sponding amino alcohols from the azido alcohols, these re- of 76 and 88%, respectively. For the unsubstituted phenyl

actions with Ph₃P were performed in the presence of water, derivative 3a, the p-methyl derivative 3b and the 2-naphthyl

however, the aziridines were again the only observed prod- derivative 3p, extended reaction times were required for

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Table 3. Reactions of aromatic and heterocyclic epoxy amides 3

with trimethylsilyl azide.

Scheme 3. Reactivity of azido alcohols: synthesis of aziridines and

amino alcohols. Reagents and conditions: a) 1.5 equiv. Ph₃P, THF,

25 °C, 6 h, 62% for 28, 92% for 29, 89% for 30; b) 1.5 equiv. Me₃P,

THF/H₂O, 25 °C, 6 h, 74% for 5, 86% for 17.

[a] Reagents and conditions: 2.5 equiv. TMSN₃, 0.2 equiv. Yb-

(OTf)₃, CH₂Cl₂, 25 °C, 6–8 h.

completion and the corresponding ring-opened products

34–36 were obtained in poor yields of 12, 15 and 23%,

Interestingly, during the optimization of this reaction, we

respectively. For other epoxy amides, such as the p-chloro found that, for example, for epoxy amides 3r and 3s, when

and p-nitro derivatives, ring-opened products were not de- these reactions were performed with Zn(OTf)₂as catalyst,

tected even after long reaction times. During the elabora- mixtures of diastereomeric C-3 ring-opened products 38/38Ј

tion of these reactions and subsequent purification and iso- and 39/39Ј were formed in an approximate ratio of 1:1

lation of the corresponding 3-azido ring-opened products, (Scheme 4). The epimerization at the 3-position could be

we observed in some cases the deprotection of the sensitive ascribed to the formation of the carbocation intermediate

trimethylsilyl group (products 33, 34 and 37; Table 3). The I, which can be stabilized by the electron-donating hetero-

extension of this reaction to heterocyclic epoxy amides was cyclic system through canonical form II, which can lead to

considered of interest because the corresponding ring- the loss of the C-3 stereochemical centre and subsequent

opened products frequently occur within the molecular epimerization at this position by nucleophilic attack by the

frameworks of many bioactive compounds. In addition, azide anion (Scheme 5, hypothesis I). However, the fact that

when we investigated the efficacy of this ring-opening reac- this isomerization was not observed when the reaction was

tion with heterocyclic epoxy amides, we came upon a carried out with Yb(OTf)₃led us to consider a more plaus-

number of interesting observations. Thus, when 3-furyl (3q), ible hypothesis. Thus, a second rationale to justify this

2-thienyl (3r) and 2-benzofuryl (3s) epoxy amides were sub- isomerization was based on the possible formation of a

mitted to the reaction with TMSN₃in the presence of cata- (TfO)ZnN₃or Zn(N₃)₂species^[18]that can coordinate to the

lytic Yb(OTf)₃, the C-3 ring-opened products 37, 38 and epoxy amide to form intermediate A and activate it for ring-

39 were cleanly formed. In contrast to electron-donating opening. From this intermediate A, two different pathways

heterocyclic systems, π-deficient heterocyclic systems con- are possible: an intramolecular attack of the azide anion on

taining epoxy amides (3t or 3u) were completely unreactive the epoxide at the 3-position with retention of the configu-

under these conditions. The use of other catalysts [Zn- ration (pathway a),^[19]which should deliver the products 38Ј

(OTf)₂, TiCl₄, BF₃], solvents (DMF, THF) or reaction tem- and 39Ј after silylation of intermediate B, or an intermo-

peratures (40, 70 °C) were similarly unsuccessful (Table 3).

lecular attack by the azide anion that would produce the

4

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Synthesis of Bioactive Compounds

expected anti products 38 and 39 via intermediate C (path-

way b). The observation of 1:1 mixtures of products 38/38Ј

or 39/39Ј should be the result of competition between the

two possible pathways. In the case of Yb(OTf)₃as catalyst,

it is likely that species of the type (TfO)₂YbN₃, (TfO)-

Yb(N₃)₂or Yb(N₃)₃are not formed^[20]due to the strong

acidic character of Yb³⁺in contrast to the soft anion azide.

Therefore, in this case, intramolecular attack does not occur

to produce exclusively the anti ring-opened product at the

3-position (Scheme 5).

Scheme 4. Reactions of heterocyclic epoxy amides with trimethyl-

silyl azide catalyzed by Zn(OTf)₂. Reagents and conditions:

a) 2.5 equiv. TMSN₃, 0.2 equiv. Zn(OTf)₂, 25 °C, 6 h, 73% for 38/

38Ј (1:1), 82% for 39/39Ј (1:1).

The synthetic value of the previously described amino

ring-opened products was demonstrated in our earlier stud-

ies through the efficient and expedient syntheses of sphin-

ganine (40) and sphingosine (41; see Scheme 6).^[2]In ad-

dition, many of the ring-opened products described above

are considered to be valuable building blocks for the synthe-

sis of other bioactive compounds. For example, amino hy-

droxy amide 19 represents the structural core of the potent

anti-HIV agent Aplaviroc^[21]and the thiophene derivative

38 represents the 3-amino-2-hydroxy system of the thio-

Scheme 5. Rationale of the epimerization of the reactions of hetero-

cyclic epoxy amides with trimethylsilyl azide catalyzed by Zn-

(OTf)₂.

phene analogue^[22]of the very well-known anti-HIV agent oxirane ring with the correct configuration. Thus, when

Nelfinavir.^[23]To prove the utility and generality of this decanal (44) was exposed to sulfonium salt 2 under basic

methodology in the synthesis of natural products, we ex- conditions, epoxy amide 4m was obtained in 82% yield as

tended our studies to other related sphingoid-type bases^[24]a single diastereoisomer. Following the synthetic scheme

such as clavaminol H (42) and the more structurally com- implemented for sphinganine and sphingosine, epoxy amide

plex and biologically relevant phytosphingosine (43).

4m was subjected to ammonia in methanol at reflux to pro-

Clavaminol H (42) belongs to the clavaminol family of vide 2-amino-3-hydroxy amide 45 in a good yield of 74%,

natural products, recently isolated from the Mediterranean which was treated with NH₃·BH₃/LDA to give the amino

ascidian Clavelina phlegraea.^[25]These natural products dis- diol 46, which corresponds to the deacetyl derivative of cla-

play cytotoxic activities against different cancer cell lines, vaminol H, in a reasonable yield of 61%. Finally, acetyl-

namely A549 (lung carcinoma), T47D (breast carcinoma) ation of 46 followed by selective ester cleavage furnished

and AGS (gastric carcinoma), by activation of apoptosis, clavaminol H (42) in almost quantitative yield, the physical

with clavaminol A being the most active member. Although and spectroscopic data of which are in complete agreement

clavaminol H is not as active as the other clavaminols, inter- with those reported for the natural product

estingly, deacetyl clavaminol H (46) retains significant ac- (Scheme 6).^[25–27]This synthesis represents the shortest

tivity against AGS carcinomas.^[25b]It is worth noting that route reported thus far for clavaminol H (eight steps), con-

the clavaminols possess the opposite configuration to that sidering the longest linear sequence includes the prepara-

of the well-known sphingolipids, which require the use of tion of the chiral sulfonium salt 2 from commercially avail-

the sulfonium salt 2 for the stereoselective synthesis of the able d-methionine, which was obtained in an overall yield

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of 25% and with the additional advantage of generating the merization side-reactions.^[39]Epoxy amide 50 was obtained

two required chiral centres in a single step compared with in 73% yield and with excellent stereoselectivity. With this

the synthesis reported previously in the literature^[26–28]in epoxy amide in hand, we proceeded with the ring-opening

which the two chiral centres were generated in different pro- reaction with ammonia following a similar strategy to that

cesses.

described above for sphingosine, sphingonine and clavami-

nol H. However, in contrast to the good results obtained

for the above cases and, in general, for the epoxy amides

described in Table 1, on this occasion the reaction was un-

successful with recovery of the starting material together

with the formation of degradation products with no detec-

tion of the desired amino derivative 51. In light of this dis-

couraging result, and with the experience gathered during

studies on the ring-opening reactions of this kind of epoxy

amides with sodium azide, we decided to attempt the instal-

lation of the amino group in the sterically hindered epoxy

Scheme 6. Synthesis of clavaminol H (42) and other sphingoid-type

bases from epoxy amides. Reagents and conditions: a) 1.0 equiv.

44, 1.0 equiv. 2, 1.0 equiv. 3.0 m aqueous NaOH solution, tBuOH,

25 °C, overnight, 82%; b) 5.0 equiv. 30% aqueous NH₃solution,

MeOH, 70 °C, 8 h, 74%; c) 7.0 equiv. LDA, 7.0 equiv. NH₃·BH₃,

THF, 0Ǟ25 °C, 0.5 h; then 1.0 equiv. 45, 25 °C, overnight, 61%;

d) 5.0 equiv. Ac₂O, pyr, 0 Ǟ25 °C, overnight; then 3.0 equiv.

NaOMe, MeOH 0 °C, 0.5 h, 98%. LDA = lithium diisoprop-

ylamide.

On the other hand, phytosphingosine (43)^[29]is a bio-

active metabolite extensively found in the membranes of

fungi, plants, bacteria and mammals, and is involved in the

cellular growth and heat stress response of yeast.^[30]In ad-

dition, phytosphingosine is the lipidic component of the

synthetic α-galactosyl ceramide KRN7000,^[31]an immuno-

stimulant of invariant natural killer cells with significant

biomedical implications.^[32]For all these reasons, phyto-

sphingosine represents a valuable synthetic target for or-

ganic chemists.^[33]The synthesis of this important natural

product commenced from epoxy amide 3v, prepared ac-

cording to our described asymmetric epoxidation method-

ology in a high yield of 89% from pentadecanal.^[2]The

Scheme 7. Synthesis of phytosphingosine (43) from epoxy amide

3v. Reagents and conditions: a) 3.0 equiv. LiEt₃BH, THF, 0 °C,

0.5 h, 89%; b) 1.2 equiv. TsCl, 1.5 equiv. Et₃N, 0.02 equiv. 4-

DMAP, CH₂Cl₂, 0 °C, 2 h; c) 4.0 equiv. KI, acetone/DMF (4:1),

reflux, 1.5 h; then 1.0 equiv. Ph₃P, 0.1 equiv. I₂, 0 °C, 1 h;

transformation of 3v into epoxy alcohol 47^[34]was followed d) 2.0 equiv. TBSCl, 2.5 equiv. imidazole, DMF, 25 °C, 6 h, 67%

by conversion to the olefin 48^[35]according to the method-

over three steps from 47; e) 1. 0.05 equiv. OsO₄, 2.0 equiv. NMO,

tBuOH/H₂O, 25 °C, 18–24 h, 89%; 2. 6.0 equiv. NaIO₄, MeOH/

ology developed by Ibuka and co-workers^[36]and not re-

H₂O (2:1), 0 °C, 2 h, quantitative; f) 1.2 equiv. 1, 1.2 equiv. 3.0 m

aqueous NaOH solution, CH₂Cl₂/H₂O (1:1), 25 °C, overnight,

quiring purification by chromatographic methods to give 48

in an overall yield of 67% from 47. Dihydroxylation of the

85%; g) 5.0 equiv. 30% aqueous NH₃solution, MeOH, 70 °C, 8 h,

decomposition; h) 10.0 equiv. NaN₃, 1.0 equiv. AcOH, DMF,

70 °C, 12 h, 92%; i) 7.0 equiv. LDA, 7.0 equiv. NH₃·BH₃, THF,

0Ǟ25 °C, 0.5 h; then 1.0 equiv. 52, 25 °C, overnight, degradation;

j) 10.0 equiv. LiAlH₄, THF, 65 °C, 8 h, 57%. 4-DMAP = 4-(di-

methylamino)pyridine, TBS = tert-butyldimethylsilyl, NMO = 4-

olefin^[37]and subsequent oxidative cleavage of the resulting

[38]

diol with NaIO₄

afforded the required aldehyde 49 in

89% yield. This aldehyde was then subjected to a second

sulfonium ylide reaction by treatment with 1 in the presence

of base using a two-phase protocol to avoid possible epi- methylmorpholine N-oxide.

6

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Synthesis of Bioactive Compounds

amide 50 by oxirane ring-opening with sodium azide, en- thiols made it necessary to employ epoxy alcohols (com-

visioning good regioselectivity at the 2-position, as was ob- pounds of the type 55) as starting materials for the instal-

tained previously. Thus, when 50 was exposed to an excess lation of sulfide moieties, as has already been carried out

of sodium azide in the presence of 1.0 equiv. of AcOH in by others to obtain products of the type 56, which have

DMF at 70 °C for 12 h, we obtained the 2-azido-3-hydroxy proven to be efficient chiral ligands for stereoselective reac-

amide derivative 52 in an excellent 92% yield and with com- tions mediated by palladium.^[43]

plete regioselectivity. Identical regioselectivity was found

when the reaction was carried out in DMF in the absence

of AcOH, albeit in a lower 75% yield and requiring a

longer reaction time (2–3 d) for completion. Having pre-

Ring-Opening Reactions with Me₂CuLi

pared the key product 52, we then attempted its direct re-

duction by reaction with H₃NBH₃in the presence of

LDA,^[40]as for compounds 21, 22 and 45. However, the

result was a complex mixture of degradation products, with

the desired amino diol 53 not being detected. Fortunately,

when 52 was reduced with an excess of LiAlH₄in THF at

65 °C,^[41]phytosphingosine 43 was obtained directly in a

reasonable yield of 57% as a result of the reduction of the

amide and azide functional groups and the cleavage of the

silyl ether of compound 53 (Scheme 7).

Carbon nucleophiles in the form of organocuprate rea-

gents were also considered to be of interest and synthetic

importance. In this case, treatment of aromatic or aliphatic

epoxy amides with the Gilman reagent^[44]smoothly pro-

vided the corresponding ring-opened products with com-

plete regioselectivity at the 2-position. It is important to

note this complete regioselectivity displayed by the epoxy

amides in their reactions with lithium dimethylcuprate,

which contrasts the mixed regioselectivity usually observed

in the reactions of simple epoxy alcohols.^[45]The crude ring-

opened products were transformed into the corresponding

silyl derivatives 57–66, which were purified and isolated in

good overall yields (52–94% yields; Table 4).

Ring-Opening Reactions with Thiols

With regard to sulfur-type nucleophiles such as thiols, we

found that they were less efficient, as expected.^[17]Thus, the

reaction proved to be feasible only for aromatic epoxy

amides in the presence of a Lewis acid.^[42]Furthermore,

only the p-methoxy derivative 3c displayed sufficient and

reproducible reactivity towards thiophenol to give the cor-

responding sulfide 54 in 77% yield following subsequent

acetal cleavage by using Yb(OTf)₃as catalyst in CH₂Cl₂at

0 °C (Scheme 8). For other aromatic epoxy amides (epoxy

amides 3a and 3b), a complex mixture of degradation prod-

ucts was obtained under the same conditions as used for

3c. The use of other Lewis acid catalysts [Zn(OTf)₂, ZrCl₄,

Sc(OTf)₃, TiCl₄, Ti(OiPr)₄, SnCl₄], various temperatures

(25, 40 °C, reflux) and solvents (THF, DMF, MeCN) were

fruitless in all cases, resulting in complex mixtures of degra-

dation products or recovery of the starting material. The

reduced efficiency displayed by these epoxy amides towards

Table 4. Reactions of epoxy amides 3 with Me₂CuLi.

Entry

Epoxy amide (R)

2-Methyl amide^[a](yield [%])

1

2

3

4

5

6

7

8

9

3a (R = C₆H₅)

3g [R = (CH₃)₂CH]

3h (R = Cy)

3i (R = C₆H₅CH₂)

3w [R = CH₃(CH₂)₃]

3x [R = CH₃(CH₂)₅]

3y [R = CH₃(CH₂)₇]

3z [R = CH₃(CH₂)₁₀]

3aЈ [R = CH₃(CH₂)₁₂]

3j [R = CH₃(CH₂)₁₄]

57 (69)

58 (72)

59 (75)

60 (58)

61 (54)

62 (78)

63 (94)

64 (72)

65 (52)

66 (56)

10

[a] Reagents and conditions: a) 2.5 equiv. Me₂CuLi, THF, 0 °C, 6–

8 h; b) 1.5 equiv. TBSOTf, 2.0 equiv. 2,6-lutidine, CH₂Cl₂, 0 °C,

0.5 h.

The excellent regioselectivity combined with the good

yields obtained in these ring-opening reactions of epoxy

amides with Me₂CuLi makes this methodology useful and

suitable for the synthesis of polypropionate-derived natural

products. In fact, we have successfully employed non-chiral

sulfonium salts in the synthesis of typical polypropionate

frameworks based on the asymmetric induction offered by

chiral aldehydes.^[46]In this case, however, the access to these

structural motifs was limited to the stereochemical induc-

Scheme 8. Reactions of epoxy amides with thiols. Reagents and

conditions: a) 2.5 equiv. PhSH, 0.3 equiv. Yb(OTf)₃, CH₂Cl₂, 0 °C,

2 d, 77% for 54; b) 3.0 equiv. Super-H, THF, 0 °C (see ref.^[2]); c) see

ref.^[43]

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F. Sarabia et al.

FULL PAPER

tion imposed by the starting aldehyde, the chirality of which products 70–72 in good overall yields (Scheme 9, part B).

usually favours the Felkin–Anh product. The use of the chi- All these compounds represent advanced and valuable syn-

ral sulfonium salts 1 and 2 should offer access to stereo- thetic intermediates for the synthesis of polyketide chains.

chemical diversity for the polyketide chains, although with For example, compound 71, which contains an anti,anti

the limitation of the relative trans stereochemistry of the stereo-triad, could be used for the synthesis of diverse natu-

generated epoxy amides. Having demonstrated the effi- ral compounds such as rifamycins, chaxamycins or salinis-

ciency and generality of these chiral sulfonium salts in reac- poramycin.^[49]On the other hand, compound 72 contains

tions with chiral α-methyl aldehydes, even for mismatched the main framework of diverse natural products such as in-

pairs (e.g., epoxy amide 73)^[2]in which the chirality of the victolide,^[50]the celebesides^[51]or the enantiomer of the anti-

starting aldehyde does not over-ride the asymmetric induc- biotic YM-47522.^[52]

tion biased by the sulfonium salt, the reaction with Me₂-

Thus, starting from compound 72, we decided to con-

CuLi would allow the preparation of typical dipropionate tinue the elongation of the polyketide chain to complete

stereo-triad units with relative syn,anti or anti,anti configu- the polypropionate system contained in celebeside A (73,

rations according to a matched or mismatched double Scheme 10) and therefore demonstrate the synthetic utility

asymmetric reaction, respectively (Scheme 9, part A). Par- of this chemistry in this class of natural products. In cele-

ticularly interesting are the anti,anti stereo-triads, a struc- besides we find a syn,anti,syn dipropionate-acetate stereo-

tural motif widely observed in many polyketide-type natural

products and the synthesis of which represents a challenge

by direct aldol or crotyl chemistry.^[47,48]Based on this, we

undertook the reaction of selected epoxy amides 67–69 with

Me₂CuLi to obtain, after protection of the resulting

alcohols as silyl ethers, the corresponding ring-opened

Scheme 10. Synthesis of the polyketide chain of celebeside A. Rea-

gents and conditions: a) 3.0 equiv. LDA, 3.0 equiv. NH₃·BH₃, THF,

0Ǟ25 °C, 0.5 h; then 1.0 equiv. 72, 25 °C, overnight, 88%;

b) 2.0 equiv. (COCl)₂, 4.0 equiv. DMSO, 6.0 equiv. Et₃N, CH₂Cl₂,

–78 °C, 0.5 h; c) 1.0 equiv. crude aldehyde 75, 1.0 equiv. 1,

1.0 equiv. 3.0 m aqueous NaOH solution, tBuOH, 25 °C, overnight,

42% over two steps from 74; d) 1.0 equiv. crude aldehyde 75,

4.0 equiv. 77, CH₂Cl₂, 25 °C, overnight, 68% over two steps from

74 (9:1 ratio for 78 and its β-epoxide); e) 3.0 equiv. Et₃BHLi, THF,

25 °C, 0.5 h, 91% from 76, 92% from 78; f) 2.2 equiv. Red-Al, THF,

25 °C, 18 h, 96%. Red-Al = sodium bis(2-methoxyethoxy)alumin-

ium hydride solution.

Scheme 9. Synthesis of advanced polyketide-type building blocks.

Reagents and conditions: a) see ref.^[2]; b) 5.0 equiv. Me₂CuLi, THF,

0 °C, 8 h; c) 1.5 equiv. TBSOTf, 2.0 equiv. 2,6-lutidine, CH₂Cl₂,

0 °C, 0.5 h, 73% for 71, 68% for 72 over two steps; d) 3.0 equiv.

TBSOTf, 4.0 equiv. 2,6-lutidine, CH₂Cl₂, 0 °C, 0.5 h, 67% for 70

over two steps.

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Synthesis of Bioactive Compounds

NMR) homogeneous materials unless otherwise stated. All solu-

tions used in work-up procedures were saturated unless otherwise

noted. All the reagents were purchased at the highest commercial

quality and used without further purification unless otherwise

stated. All reactions were monitored by TLC performed on

0.25 mm silica gel plates (60F-254) using UV light as visualizing

agent and 7% ethanolic phosphomolybdic acid or p-anisaldehyde

solution and heat as developing agents. Silica gel 60 (particle size

0.040–0.063 mm) was used for flash column chromatography. Pre-

parative TLC (PTLC) separations were carried out on 0.25, 0.50,

pentad unit, a polyketide fragment present in many other

natural products such as the aforementioned YM-47522,

the anti-fungal basiliskamide^[53]and the cyclodepsipeptide

lagunamide A.^[54]Thus, after the reduction of amide 72 by

the action of NH₃·BH₃/LDA, the resulting alcohol 74 was

subjected to a Swern oxidation^[55]to provide aldehyde 75,

which was directly treated with chiral sulfonium salt 1 un-

der basic conditions. The epoxy amide 76 was obtained in

an overall yield of 42% from 74, accompanied by the ex-

pected unsaturated epoxy amide isolated in 15% yield. The or 1 mm silica gel plates (60F-254). NMR spectra were recorded

with a 400 MHz instrument and calibrated by using the residual

undeuteriated solvent as internal reference. The following abbrevi-

ations were used to explain the multiplicities: s, singlet; d, doublet;

t, triplet; q, quartet; m, multiplet; band, several overlapping signals;

br., broad. Optical rotations were recorded with a polarimeter.

High-resolution mass spectra were recorded in an ESI-TOF mass

spectrometer in positive mode.

unsaturated epoxy amide, anticipated from previous stud-

ies,^[2]results from β-elimination due to the alkoxy group at

the β position of the starting aldehyde. In view of the re-

quired stereochemistry for the lipidic chain of celebeside A,

we performed this reaction with the known non-chiral

sulfur ylide 77,^[56]expecting efficient stereocontrol by the

starting chiral aldehyde 75 during the nucleophilic addition.

In fact, when this reaction was carried out, the result was

the formation of epoxy amide 78 as the major diastereo-

isomer together with its β-epoxide isomer in a ratio of 9:1

and in a combined yield of 68%. The reduction of epoxy

amide 76 or 78 provided epoxy alcohol 79 in yields of 91

and 92%, respectively. Finally, reduction of the epoxy

alcohol 79 with Red-Al^[57]afforded diol 80, which repre-

sents an advanced and complete polyketide fragment of

celebeside A (Scheme 10).

General Procedure for the Synthesis of 2-Amino-3-hydroxy Amides:

A solution of epoxy amide (1.0 equiv.) in methanol (0.1 m) was

treated with the corresponding amine (5.0 equiv.) and the reaction

mixture was heated at reflux for a period of 6–8 h. After this time,

the crude mixture was cooled to room temperature and concen-

trated under vacuum. Flash column chromatography (silica gel,

CH₂Cl₂Ǟ2–5% MeOH/CH₂Cl₂) afforded the corresponding

amino alcohol in a yields of 60–85%. In all cases, we started from

200 mg of epoxy amide.

Amino Alcohol 5: Yield 145 mg, 69%; colourless oil; R_f= 0.37

(silica gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +63.8 (c = 0.9, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 1.46 (s, 3 H), 1.44–1.47 (m, 1

H), 1.49 (s, 3 H), 1.67–1.76 (m, 1 H), 2.03 (s, 3 H), 2.26 (ddd, J =

13.1, 8.3, 7.4 Hz, 1 H), 2.36 (ddd, J = 13.1, 7.7, 5.3 Hz, 1 H), 2.64

(br. s, 3 H), 3.68 (d, J = 9.1 Hz, 1 H), 3.76 (ddd, J = 9.1, 4.8,

1.4 Hz, 1 H), 4.01 (ddd, J = 10.6, 4.7, 2.4 Hz, 1 H), 4.23 (br. s, 2

H), 7.23–7.33 (m, 5 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

16.0, 22.7, 26.2, 30.9, 33.7, 56.4, 59.1, 66.9, 73.5, 95.3, 127.5, 128.0,

128.6, 169.0 ppm. HRMS (ESI-TOF): calcd. for C₁₇H₂₆N₂O₃S [M

+ Na]⁺361.1562; found 361.1558.

Conclusions

We have demonstrated the versatility and utility of chiral

glycidic amides, efficiently prepared by a new asymmetric

epoxidation methodology, in the generation of a diverse ar-

ray of structural motifs by ring-opening with a variety of

nucleophiles. The oxirane ring-opening reactions proceeded

regio- and stereoselectively under very mild conditions and

generally in good yields, giving access to a broad range of

1,2-difunctionalized products that represent valuable build-

ing blocks for the asymmetric synthesis of compounds of

biological interest. To demonstrate the utility of this ap-

proach we have synthesized in a rapid and efficient manner

natural clavaminol H, phytosphingosine and several ad-

vanced intermediates useful for the synthesis of different

bioactive compounds, including advanced polyketide pre-

cursors such as the C5–C13 fragment of celebeside A.

Given the efficiency of this new methodology and the

utility of the synthesized epoxy amides, new synthetic appli-

cations are currently being investigated with particular em-

phasis on those directed towards the total synthesis of natu-

ral products of biological interest. The results will be de-

scribed in due course.

Amino Alcohol 6: Yield 157 mg, 72%; colourless oil; R_f= 0.42

(silica gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +83.1 (c = 1.8, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 0.98–1.01 (m, 1 H), 1.43 (s, 3

H), 1.48 (s, 3 H), 1.51–1.56 (m, 1 H), 1.98 (s, 3 H), 2.16–2.23 (m,

2 H), 2.26 (s, 3 H), 3.39 (br. s, 2 H), 3.62 (d, J = 9.1 Hz, 1 H), 3.67

(dd, J = 9.0, 4.6 Hz, 1 H), 3.88 (d, J = 4.9 Hz, 1 H), 3.92 (ddd, J

= 10.7, 4.0, 1.9 Hz, 1 H), 4.29 (d, J = 4.9 Hz, 1 H), 7.21–7.29 (m,

5 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.0, 22.7, 26.1, 30.8,

33.5, 33.7, 56.4, 66.8, 67.8, 72.0, 95.3, 128.1, 128.6, 137.8,

169.1 ppm. HRMS (ESI-TOF): calcd. for C₁₈H₂₈N₂O₃S [M +

Na]⁺375.1718; found 375.1719.

Amino Alcohol 7: Yield 199 mg, 75%; pale yellow oil; R_f= 0.56

(silica gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +45.4 (c = 1.1, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 0.94–1.00 (m, 1 H), 1.43 (s, 3

H), 1.44 (s, 3 H), 1.46–1.55 (m, 1 H), 1.96 (s, 3 H), 2.13–2.25 (m,

2 H), 3.52 (d, J = 13.1 Hz, 1 H), 3.63 (d, J = 9.1 Hz, 1 H), 3.73

(ddd, J = 9.1, 4.9, 1.1 Hz, 1 H), 3.81 (d, J = 13.1 Hz, 1 H), 3.93

(ddd, J = 10.7, 4.6, 2.3 Hz, 1 H), 4.05 (d, J = 5.0 Hz, 1 H), 4.32

(d, J = 5.0 Hz, 1 H), 7.17–7.24 (m, 5 H), 7.26–7.33 (m, 5 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 15.9, 22.6, 26.0, 30.7, 33.3, 50.3,

56.3, 64.9, 66.6, 71.6, 95.2, 127.3, 128.3, 128.4, 128.5, 128.7,

169.0 ppm. HRMS (ESI-TOF): calcd. for C₂₄H₃₂N₂O₃S [M +

Na]⁺451.2031; found 451.2029.

Experimental Section

General: All reactions were carried out under argon in dry, freshly

distilled solvents under anhydrous conditions unless otherwise

noted. THF was distilled from sodium/benzophenone, and di-

chloromethane (CH₂Cl₂) and benzene (PhH) from calcium hydride,

yields refer to chromatographically and spectroscopically (¹H

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Amino Alcohol 8: Yield 218 mg, 93%; colourless oil; R_f= 0.58

(silica gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +64.9 (c = 1.3, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 0.96–1.01 (m, 1 H), 1.43 (s, 6

H), 1.49–1.61 (m, 1 H), 1.98 (s, 3 H), 2.16–2.20 (m, 1 H), 2.23 (ddd,

J = 13.0, 7.8, 5.4 Hz, 1 H), 2.94 (dd, J = 14.0, 6.3 Hz, 1 H), 3.19

(dd, J = 14.0, 5.8 Hz, 1 H), 3.62 (d, J = 9.1 Hz, 1 H), 3.71 (ddd, J

= 9.1, 4.9, 1.3 Hz, 1 H), 3.92 (ddd, J = 10.7, 4.6, 2.0 Hz, 1 H), 3.97

(d, J = 5.2 Hz, 1 H), 4.26 (d, J = 5.2 Hz, 1 H), 5.01 (dd, J = 10.3,

Amino Alcohol 13: Yield 181 mg, 83%; colourless oil; R_f= 0.44

(silica gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +75.7 (c = 1.0, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 1.01–1.16 (m, 1 H), 1.43 (s, 3

H), 1.46 (s, 3 H), 1.52–1.59 (m, 1 H), 1.99 (s, 3 H), 2.15–2.23 (m,

2 H), 2.24 (s, 3 H), 3.25 (br. s, 1 H), 3.64 (d, J = 9.1 Hz, 1 H),

3.70–3.72 (m, 1 H), 3.74 (s, 3 H), 3.82 (d, J = 5.1 Hz, 1 H), 3.95

(ddd, J = 10.6, 4.6, 2.4 Hz, 1 H), 4.26 (d, J = 5.1 Hz, 1 H), 6.80

(d, J = 8.7 Hz, 2 H), 7.17 (d, J = 8.6 Hz, 2 H) ppm. ¹³C NMR

1.0 Hz, 1 H), 5.05 (dd, J = 17.3, 1.6 Hz, 1 H), 5.75–5.85 (m, 1 H), (100 MHz, CDCl₃): δ = 16.0, 22.7, 26.1, 30.8, 33.5, 33.6, 55.3, 56.5,

7.21–7.28 (m, 5 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.9, 66.8, 67.1, 72.0, 95.3, 114.0, 129.3, 159.4, 169.3 ppm. HRMS (ESI-

22.6, 26.0, 30.7, 33.3, 49.3, 56.3, 65.0, 66.6, 71.8, 95.1, 116.3, 125.7, TOF): calcd. for C₁₉H₃₀N₂O₄S [M + Na]⁺405.1824; found

128.1, 128.2, 128.5, 136.1, 169.1 ppm. HRMS (ESI-TOF): calcd.

405.1831.

for C₂₀H₃₀N₂O₃S [M + Na]⁺401.1875; found 401.1881.

Amino Alcohol 14: Yield 157 mg, 74%; colourless oil; R_f= 0.54

(silica gel, 1% MeOH/CH₂Cl₂). [α]²_D⁵= +10.5 (c = 0.4, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 1.05–1.15 (m, 1 H), 1.41 (s, 3

H), 1.54 (s, 3 H), 1.49–1.55 (m, 1 H), 1.94 (s, 3 H), 2.08–2.25 (m,

2 H), 2.20 (s, 3 H), 3.59 (d, J = 9.1 Hz, 1 H), 3.63–3.69 (m, 1 H),

3.93–3.98 (m, 1 H), 4.36 (br. s, 1 H), 5.09 (s, 4 H), 6.83–6.95 (m, 3

H), 7.20–7.31 (m, 5 H), 7.36–7.40 (m, 5 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 15.4, 29.5, 29.6, 30.1, 30.4, 30.5, 51.0, 55.1,

56.1, 64.7, 75.9, 95.2, 128.1, 113.7, 126.8, 127.6, 128.7, 129.1, 129.5,

130.3, 131.2, 131.7, 131.9, 134.3, 158.8, 172.9 ppm. HRMS (ESI-

TOF): calcd. for C₃₂H₄₀N₂O₅S [M + Na]⁺587.2556; found

587.2562.

Amino Alcohol 9: Yield 139 mg, 54%; yellow oil; R_f= 0.55 (silica

gel, 50% AcOEt/hexanes). [α]²_D⁵= +45.0 (c = 1.7, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = 0.56–0.71 (m, 1 H), 1.44 (s, 3 H),

1.43–1.49 (m, 1 H), 1.50 (s, 3 H), 1.99 (s, 3 H), 2.09–2.27 (m, 2 H),

3.67 (d, J = 9.1 Hz, 1 H), 3.81 (ddd, J = 9.1, 4.9, 1.4 Hz, 1 H), 3.95

(ddd, J = 10.7, 4.6, 2.3 Hz, 1 H), 4.44 (d, J = 4.3 Hz, 1 H), 4.83

(d, J = 4.3 Hz, 1 H), 6.64 (d, J = 7.3 Hz, 2 H), 7.03 (d, J = 7.2 Hz,

1 H), 7.05 (d, J = 7.2 Hz, 1 H), 7.18–7.26 (m, 5 H), 7.29–7.31 (m,

1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.1, 22.5, 25.9, 30.8,

32.9, 56.4, 61.7, 66.7, 71.2, 95.3, 127.6, 128.0, 128.7, 129.1,

169.2 ppm. HRMS (ESI-TOF): calcd. for C₂₃H₃₀N₂O₃S [M +

Na]⁺437.1875; found 437.1872.

Amino Alcohol 15: Yield 160 mg, 74%; colourless oil; R_f= 0.37

(silica gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +144.7 (c = 1.0, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 1.06–1.13 (m, 1 H), 1.42 (s, 3

H), 1.44 (s, 3 H), 1.57–1.65 (m, 1 H), 1.99 (s, 3 H), 2.21 (ddd, J =

13.0, 7.5, 5.7 Hz, 1 H), 2.22 (s, 3 H), 2.28 (ddd, J = 13.0, 7.8,

5.3 Hz, 1 H), 3.50 (br. s, 2 H), 3.66 (d, J = 9.1 Hz, 1 H), 3.73 (ddd,

J = 9.1, 4.8, 1.4 Hz, 1 H), 3.84 (d, J = 5.3 Hz, 1 H), 3.96 (ddd, J

= 10.6, 4.6, 2.4 Hz, 1 H), 4.25 (d, J = 5.3 Hz, 1 H), 7.19 (d, J =

8.7 Hz, 2 H), 7.26 (d, J = 8.5 Hz, 2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 16.0, 22.6, 26.1, 30.8, 33.7, 33.8, 56.4, 66.8, 67.2, 72.0,

95.3, 128.7, 129.6, 133.7, 136.5, 168.9 ppm. HRMS (ESI-TOF):

calcd. for C₁₈H₂₇ClN₂O₃S [M + Na]⁺409.1329; found 409.1333.

Amino Alcohol 10: Yield 154 mg, 68%; colourless oil; R_f= 0.57

(silica gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +53.9 (c = 1.4, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 1.10 (s, 3 H), 1.47 (s, 3 H), 1.79–

1.85 (m, 1 H), 1.89–1.97 (m, 1 H), 2.05 (s, 3 H), 2.23 (s, 6 H), 2.38

(dd, J = 7.9, 7.1 Hz, 2 H), 3.16 (ddd, J = 8.9, 4.7, 1.4 Hz, 1 H),

3.54 (d, J = 8.8 Hz, 1 H), 3.61 (d, J = 4.6 Hz, 1 H), 3.95 (ddd, J =

10.3, 4.5, 2.6 Hz, 1 H), 4.70 (d, J = 4.6 Hz, 1 H), 7.22–7.29 (m, 5

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.7, 22.6, 26.3, 31.1,

34.5, 43.6, 56.0, 66.8, 73.0, 73.3, 95.7, 127.9, 128.1, 129.4,

167.7 ppm. HRMS (ESI-TOF): calcd. for C₁₉H₃₀N₂O₃S [M +

Na]⁺389.1875; found 389.1876.

Amino Alcohol 16: Yield 138 mg, 62%; colourless oil; R_f= 0.35

(silica gel, 5% MeOH/CH₂Cl₂). [α]²_D⁵= –22.0 (c = 0.8, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = 0.96 (t, J = 7.0 Hz, 3 H), 1.30–1.38

(m, 1 H), 1.48 (s, 3 H), 1.49–1.54 (m, 1 H), 1.61 (s, 3 H), 1.75–1.82

(m, 1 H), 2.00–2.07 (m, 1 H), 2.08 (s, 3 H), 2.37 (s, 3 H), 2.40 (ddd,

J = 13.2, 9.1, 6.4 Hz, 1 H), 2.55 (ddd, J = 13.2, 6.8, 4.9 Hz, 1 H),

2.70 (br. s, 2 H), 3.36 (d, J = 5.2 Hz, 1 H), 3.57 (ddd, J = 9.1, 4.9,

3.0 Hz, 1 H), 3.81 (d, J = 9.1 Hz, 1 H), 3.89 (ddd, J = 9.1, 4.9,

1.5 Hz, 1 H), 4.08 (ddd, J = 10.7, 4.7, 2.7 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 10.4, 15.8, 22.6, 26.6, 30.9, 33.7, 34.6, 56.2,

65.6, 66.6, 73.0, 95.4, 169.4 ppm. HRMS (ESI-TOF): calcd. for

C₁₄H₂₈N₂O₃S [M + Na]⁺327.1718; found 327.1724.

Amino Alcohol 11: Yield 156 mg, 71%; colourless oil; R_f= 0.52

1

(silica gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +8.2 (c = 1.0, CH₂Cl₂). H

NMR (400 MHz, CDCl₃): δ = 1.03–1.17 (m, 1 H), 1.43 (s, 3 H),

1.46 (s, 3 H), 1.48–1.56 (m, 1 H), 1.97 (s, 3 H), 2.18–2.23 (m, 2 H),

2.27 (s, 3 H), 2.28 (s, 3 H), 3.63 (d, J = 9.1 Hz, 1 H), 3.70 (ddd, J

= 9.1, 4.8, 1.3 Hz, 1 H), 3.92 (d, J = 5.0 Hz, 1 H), 3.95 (ddd, J =

10.6, 4.6, 2.6 Hz, 1 H), 4.23 (br. s, 2 H), 4.33 (d, J = 5.0 Hz, 1 H),

7.08 (d, J = 8.7 Hz, 2 H), 7.15 (d, J = 8.5 Hz, 2 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 15.8, 21.0, 22.5, 26.0, 30.6, 33.3, 33.4, 56.4,

66.7, 67.4, 71.8, 95.2, 128.1, 129.3, 138.0, 169.0 ppm. HRMS (ESI-

TOF): calcd. for C₁₉H₃₀N₂O₃S [M + Na]⁺389.1875; found

389.1877.

Amino Alcohol 17: Yield 155 mg, 73%; colourless oil; R_f= 0.45

(silica gel, 1% MeOH/CH₂Cl₂). [α]²_D⁵= +27.5 (c = 1.0, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 0.95 (d, J = 6.8 Hz, 3 H), 1.00

(d, J = 6.8 Hz, 3 H), 1.54 (s, 3 H), 1.62 (s, 3 H), 1.86–1.94 (m, 1

H), 2.03–2.10 (m, 2 H), 2.12 (s, 3 H), 2.46 (ddd, J = 13.1, 7.8 Hz,

1 H), 2.56 (ddd, J = 13.2, 8.0, 5.2 Hz, 1 H), 2.79 (t, J = 6.3 Hz, 1

H), 2.88 (br. s, 3 H), 3.85 (d, J = 9.1 Hz, 1 H), 3.99 (dd, J = 9.1,

4.9 Hz, 1 H), 4.14 (d, J = 5.7 Hz, 1 H), 4.33 (ddd, J = 10.5, 4.7,

2.3 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.0, 18.5,

19.9, 22.5, 26.5, 29.7, 31.0, 34.4, 56.2, 60.5, 67.0, 69.9, 95.1,

169.4 ppm. HRMS (ESI-TOF): calcd. for C₁₄H₂₈N₂O₃S [M + H]⁺

305.1899; found 305.1887.

Amino Alcohol 12: Yield 136 mg, 65%; colourless oil; R_f= 0.35

(silica gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +54.0 (c = 0.8, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 1.35–1.45 (m, 1 H), 1.46 (s, 3

H), 1.51 (s, 3 H), 1.69–1.78 (m, 1 H), 2.03 (s, 3 H), 2.26 (ddd, J =

13.1, 7.8 Hz, 1 H), 2.36 (ddd, J = 13.1, 7.8, 5.3 Hz, 1 H), 2.60 (br.

s, 3 H), 3.69 (d, J = 9.1 Hz, 1 H), 3.74 (s, 3 H), 3.78 (ddd, J = 9.0,

4.8, 1.3 Hz, 1 H), 4.01 (ddd, J = 10.5, 4.6, 2.1 Hz, 1 H), 4.20 (br.

s, 2 H), 6.81 (d, J = 8.5 Hz, 2 H), 7.25 (d, J = 8.5 Hz, 2 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 16.0, 22.7, 26.2, 30.9, 33.7, 55.3,

56.4, 58.5, 66.9, 73.5, 95.3, 114.0, 128.6, 132.6, 159.3, 169.1 ppm.

HRMS (ESI-TOF): calcd. for C₁₈H₂₈N₂O₄S [M + Na]⁺391.1668;

found 391.1674.

Amino Alcohol 18: Yield 187 mg, 84%; white solid; m.p. 104–

106 °C; R_f= 0.33 (silica gel, EtOAc). [α]²_D⁵= +16.8 (c = 1.8,

10

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Synthesis of Bioactive Compounds

1

CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 0.90 (d, J = 6.8 Hz, 6

epoxy amide. To quantify the proportion of regioisomers, crude

H), 1.58 (s, 3 H), 1.60 (s, 3 H), 1.81–1.87 (m, 1 H), 1.88–1.92 (m, reaction mixtures were acetylated (Ac₂O, pyr) and the correspond-

1

1 H), 1.97–2.03 (m, 1 H), 2.07 (s, 3 H), 2.31 (s, 3 H), 2.33–2.43 (m, ing acetylated crude mixtures analysed by H NMR spectroscopy.

2 H), 2.54 (ddd, J = 13.2, 6.8, 5.1 Hz, 1 H), 3.28 (d, J = 7.4 Hz, 1

General Procedure A: A mixture of the epoxy amide (1.0 equiv.)

H), 3.40 (ddd, J = 7.4, 4.2 Hz, 1 H), 3.78 (d, J = 9.1 Hz, 1 H), 3.87

and NaN₃(10.0 equiv.) in methanol (0.1 m with respect to the ep-

(ddd, J = 9.1, 4.9, 1.5 Hz, 1 H); 4.15 (ddd, J = 10.9, 4.8, 2.6 Hz, 1

oxy amide) was heated at reflux for a period of 6–8 h. After this

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.0, 19.9, 22.4, 22.5,

time the crude mixture was cooled to room temperature, diluted

26.6, 30.2, 31.0, 33.5, 34.7, 56.1, 63.4, 66.5, 77.1, 95.3, 171.2 ppm.

with water and extracted with Et₂O three times. The resulting or-

HRMS (ESI-TOF): calcd. for C₁₅H₃₀N₂O₃S [M + Na]⁺341.1875;

ganic solution was washed with brine, dried (MgSO₄), filtered and

found 341.1877.

concentrated under reduced pressure. The crude product was puri-

Amino Alcohol 19: Yield 160 mg, 73%; yellow oil; R_f= 0.43 (silica

gel, 5% MeOH/CH₂Cl₂). [α]²_D⁵= +25.0 (c = 0.7, CH₂Cl₂). ¹H NMR

(400 MHz, CDCl₃): δ = 1.09–1.32 (m, 6 H), 1.56 (s, 3 H), 1.59–

1.64 (m, 3 H), 1.67 (s, 3 H), 1.75–1.87 (m, 2 H), 1.89–1.95 (m, 1

H), 2.07–2.11 (m, 1 H), 2.14 (s, 3 H), 2.39 (s, 3 H), 2.45 (ddd, J =

13.2, 6.8, 5.1 Hz, 1 H), 2.45 (ddd, J = 13.3, 9.2, 6.4 Hz, 1 H), 2.61

(ddd, J = 13.0, 6.8, 5.0 Hz, 1 H), 3.40 (d, J = 7.0 Hz, 1 H), 3.46

(dd, J = 7.0, 4.8 Hz, 1 H), 3.86 (d, J = 9.1 Hz, 1 H), 3.94 (ddd, J

= 9.1, 4.9, 1.2 Hz, 1 H); 4.19 (ddd, J = 10.8, 6.8, 3.3 Hz, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 16.0, 22.6, 26.1, 26.4, 26.5, 26.7,

30.6, 31.1, 33.8, 34.7, 40.5, 56.3, 63.0, 66.7, 77.2, 95.5, 171.4 ppm.

HRMS (ESI-TOF): calcd. for C₁₈H₃₄N₂O₃S [M + H]⁺359.2368;

found 359.2372.

fied by flash column chromatography (silica gel, 20% AcOEt in

hexanes) to afford the corresponding azido alcohol as a mixture of

regioisomers, the ratios of which are indicated below.

General Procedure B: Anhydrous MgSO₄(10.0 equiv.) was flame-

dried and, after cooling, MeOH and NaN₃(10.0 equiv.) were intro-

duced into the flask and sonicated for 10 min. Then a solution of

the epoxy amide (1.0 equiv.) in methanol (0.1 m) was added and the

mixture was heated at reflux for a period of 6–8 h. After this time

the crude mixture was cooled to room temperature and subjected

to work-up and purification as described for procedure A.

General Procedure C: As procedure A but in DMF (0.1 m).

General Procedure D: A mixture of the epoxy amide (1.0 equiv.),

AcOH (1.0 equiv.) and NaN₃(10.0 equiv.) in DMF (0.1 m) was

heated at 70 °C for a period of 6–8 h. After this time the crude

mixture was cooled to room temperature, diluted with Et₂O and

washed with a saturated aqueous solution of NaHCO₃. After sepa-

ration of the two phases, the aqueous layer was extracted with Et₂O

(twice), and the combined organic extracts were washed with brine,

dried (MgSO₄) and filtered. The resulting crude product was puri-

fied by flash column chromatography (silica gel, 20% AcOEt in

hexanes) to afford the corresponding azido alcohol as a mixture of

regioisomers, the ratios of which are indicated below.

Amino Alcohol 20: Yield 143 mg, 65%; yellow oil; R_f= 0.46 (silica

gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +47.1 (c = 0.9, CH₂Cl₂). ¹H NMR

(400 MHz, CDCl₃): δ = 1.49 (s, 3 H), 1.61 (s, 3 H), 1.67–1.73 (m,

1 H), 1.96–2.03 (m, 1 H), 2.05 (s, 3 H), 2.25–2.32 (m, 1 H), 2.39 (s,

3 H), 2.43 (ddd, J = 13.9, 7.6, 5.1 Hz, 1 H), 2.76 (dd, J = 14.0,

9.0 Hz, 1 H), 2.85 (br. s, 2 H), 2.95 (dd, J = 14.0, 3.7 Hz, 1 H),

3.36 (d, J = 6.3 Hz, 1 H), 3.75 (d, J = 9.1 Hz, 1 H), 3.84 (ddd, J =

9.1, 5.0, 1.3 Hz, 1 H), 3.86–3.93 (m, 2 H), 7.15–7.26 (m, 5 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 15.8, 22.5, 26.6, 30.7, 33.9, 34.6,

40.2, 56.1, 65.3, 66.6, 72.9, 95.4, 126.5, 128.4, 129.2, 137.9,

169.2 ppm. HRMS (ESI-TOF): calcd. for C₁₉H₃₀N₂O₃S [M +

Na]⁺389.1875; found 389.1868.

General Procedure E: NaN₃(10.0 equiv.), anhydrous NH₄Cl

(10.0 equiv.) and a few drops of water were added to a solution of

the epoxy amide (1.0 equiv.) in MeOH (0.1 m). Then the reaction

mixture was heated at reflux at 70 °C for a period of 6–8 h. After

this time the crude mixture was cooled to room temperature and

subjected to work-up and purification as described for pro-

cedure A.

Amino Alcohol 21: Yield 150 mg, 72%; yellow oil; R_f= 0.58 (silica

gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +34.5 (c = 0.5, CH₂Cl₂). ¹H NMR

(400 MHz, CDCl₃): δ = 0.87 (t, J = 6.7 Hz, 3 H), 1.24–1.29 (m, 26

H), 1.49–1.53 (m, 2 H), 1.55 (s, 3 H), 1.62 (s, 3 H), 1.83–1.90 (m,

1 H), 2.00–2.07 (m, 1 H), 2.13 (s, 3 H), 2.44–2.50 (m, 1 H), 2.56

(ddd, J = 13.1, 7.9, 5.2 Hz, 1 H), 3.13 (br. s, 4 H), 3.85 (d, J =

9.1 Hz, 1 H), 3.98 (ddd, J = 9.1, 4.9, 1.3 Hz, 1 H), 4.10 (d, J =

5.0 Hz, 1 H), 4.28 (ddd, J = 10.5, 4.8, 2.4 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 14.1, 15.9, 22.6, 22.7, 26.3, 26.5, 29.3, 29.5,

29.60, 29.65, 29.69, 30.9, 31.9, 32.2, 34.5, 54.9, 56.3, 67.1, 71.8,

95.4, 169.4 ppm. HRMS (ESI-TOF): calcd. for C₂₆H₅₂N₂O₃S [M

+ H]⁺473.3777; found 473.3778.

General Procedures F–H: The general procedures F–H were carried

out as procedure D but by using 1.0 equiv. of TFA, TfOH and

Zn(OTf)₂, respectively, instead of acetic acid.

Azido Hydroxy Amides 23a and 23b: Procedure A: starting from

epoxy amide 3a (25 mg, 0.078 mmol), 4.5 mg of 23a and 20.0 mg

of 23b were obtained (86% combined yield, 1:4 ratio of 23a/23b).

Procedure B: starting from epoxy amide 3a (25 mg, 0.078 mmol),

23.4 mg of 23b were obtained (82% yield, 0:100 ratio of 23a/23b).

Procedure C: starting from epoxy amide 3a (25 mg, 0.078 mmol),

4.2 mg of 23a and 16.6 mg of 23b were obtained (73% combined

yield, 1:4 ratio of 23a/23b). Procedure D: starting from epoxy

amide 3a (25 mg, 0.078 mmol), 5.9 mg of 23a and 15.5 mg of 23b

were obtained (75% combined yield, 1:2.5 ratio of 23a/23b).

Amino Alcohol 22: Yield 156 mg, 75%; yellow oil; R_f= 0.55 (silica

gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= +50.6 (c = 0.5, CH₂Cl₂). ¹H NMR

(400 MHz, CDCl₃): δ = 0.87 (t, J = 6.7 Hz, 3 H), 1.25–1.36 (m, 22

H), 1.55 (s, 3 H), 1.62 (s, 3 H), 1.84–1.89 (m, 1 H), 1.98–2.06 (m,

3 H), 2.11 (s, 3 H), 2.44 (dt, J = 13.2, 8.0 Hz, 1 H), 2.53 (ddd, J =

13.1, 7.9, 5.1 Hz, 1 H), 3.07 (br. s, 3 H), 3.63 (dd, J = 6.4 Hz, 1 H),

3.84 (d, J = 9.1 Hz, 1 H), 3.96 (ddd, J = 9.0, 4.8, 1.2 Hz, 1 H), 4.11

(d, J = 5.2 Hz, 1 H), 4.25 (ddd, J = 10.5, 4.8, 2.6 Hz, 1 H), 5.45

(dd, J = 15.3, 8.0 Hz, 1 H), 5.71 (dt, J = 15.3, 6.5 Hz, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 15.9, 22.6, 22.7, 26.5, 29.1,

29.2, 29.3, 29.5, 29.60, 29.65, 29.7, 30.9, 31.9, 32.4, 34.3, 56.4, 57.0,

67.0, 72.0, 95.3, 129.2, 134.9, 169.1 ppm. HRMS (ESI-TOF): calcd.

for C₂₆H₅₀N₂O₃S [M + H]⁺471.3620; found 471.3618.

23a: White solid; R_f= 0.43 (silica gel, 33% EtOAc/hexanes). [α]²_D⁵

1

= –68.3 (c = 0.3, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 1.36

(s, 3 H), 1.63 (s, 3 H), 1.66–1.74 (m, 1 H), 1.96 (ddt, J = 15.1, 10.4,

4.8 Hz, 1 H), 2.12 (s, 3 H), 2.29 (ddd, J = 13.8, 10.9, 4.5 Hz, 1 H),

2.56 (ddd, J = 13.8, 5.0 Hz, 1 H), 3.41 (ddd, J = 9.0, 5.0, 1.6 Hz,

1 H), 3.51 (ddd, J = 8.1, 5.1, 3.0 Hz, 1 H), 3.60 (d, J = 9.1 Hz, 1

H), 3.99 (d, J = 4.8 Hz, 1 H), 4.34 (d, J = 8.3 Hz, 1 H), 5.23 (dd, J

= 8.2, 4.8 Hz, 1 H), 7.31–7.43 (m, 5 H) ppm. ¹³C NMR (100 MHz,

Synthesis of Azido Hydroxy Amides 23–27: For the synthesis of the

azido hydroxy amides, we started with between 25–100 mg of the

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F. Sarabia et al.

CDCl₃): δ = 15.7, 22.3, 26.4, 30.9, 33.1, 56.4, 62.1, 66.7, 76.1, 95.8, 25a: Colourless oil; R_f= 0.37 (silica gel, 20% EtOAc/hexanes).

FULL PAPER

1

125.9, 128.4, 128.7, 140.1, 166.1 ppm. HRMS (ESI-TOF): calcd.

[α]²_D⁵= –40.4 (c = 2.5, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ =

0.88 (t, J = 7.0 Hz, 3 H), 1.27–1.39 (m, 14 H), 1.51–1.66 (m, 2 H),

1.57 (s, 3 H), 1.70 (s, 3 H), 1.84–1.91 (m, 1 H), 2.02–2.12 (m, 1 H),

2.14 (s, 3 H), 2.39 (ddd, J = 13.7, 10.3, 5.3 Hz, 1 H), 2.62 (ddd, J

= 13.6, 5.2 Hz, 1 H), 2.96 (d, J = 7.1 Hz, 1 H), 3.60 (d, J = 6.6 Hz,

1 H), 3.84 (d, J = 9.2 Hz, 1 H), 3.99 (ddd, J = 9.1, 5.1, 1.5 Hz, 1

H), 4.06 (dq, J = 7.3, 3.4 Hz, 1 H), 4.13 (ddd, J = 10.5, 4.9, 2.8 Hz,

1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 15.6, 22.6, 22.7,

25.3, 26.5, 29.3, 29.47, 29.51, 29.54, 30.9, 31.9, 33.1, 34.3, 56.7,

61.9, 66.9, 73.0, 95.8, 166.6 ppm. HRMS (ESI-TOF): calcd. for

C₂₀H₃₈N₄O₃S [M + H]⁺415.2743; found 415.2734.

for C₁₇H₂₄N₄O₃S [M + H]⁺365.1647; found 365.1656.

23b: White solid; R_f= 0.17 (silica gel, 33% EtOAc/hexanes). [α]²_D⁵

= +109.6 (c = 0.5, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.59

(s, 3 H), 1.61–1.63 (m, 1 H), 1.71 (s, 3 H), 2.13–2.16 (m, 1 H), 2.19

(s, 3 H), 2.45 (ddd, J = 13.3, 7.6, 6.4 Hz, 1 H), 2.61 (br. s, 1 H),

2.66 (ddd, J = 13.3, 5.6 Hz, 1 H), 3.87 (d, J = 9.1 Hz, 1 H), 3.96

(dd, J = 9.1, 4.5 Hz, 1 H), 4.18 (ddd, J = 8.6, 4.9 Hz, 1 H), 4.33

(dd, J = 9.1 Hz, 1 H), 4.89 (d, J = 9.0 Hz, 1 H), 7.39–7.43 (m, 5

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.2, 22.7, 26.3, 31.1,

34.0, 56.6, 67.0, 67.8, 72.9, 95.6, 128.3, 128.9, 129.0, 135.9,

168.3 ppm. HRMS (ESI-TOF): calcd. for C₁₇H₂₄N₄O₃S [M + H]⁺

365.1647; found 365.1641.

25b: Colourless oil; R_f= 0.24 (silica gel, 20% EtOAc/hexanes).

1

[α]²_D⁵= –4.5 (c = 0.4, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ =

0.88 (t, J = 6.6 Hz, 3 H), 1.22–1.38 (m, 14 H), 1.51–1.58 (m, 2 H),

1.58 (s, 3 H), 1.67 (s, 3 H), 1.83–1.92 (m, 1 H), 2.02–2.12 (m, 1 H),

2.14 (s, 3 H), 2.42 (ddd, J = 13.6, 9.4, 6.1 Hz, 1 H), 2.61 (dt, J =

13.3, 5.5 Hz, 1 H), 2.70–2.82 (br. s, 1 H), 3.62 (td, J = 9.3, 2.6 Hz,

1 H), 3.88 (d, J = 9.1 Hz, 1 H), 3.99 (dd, J = 8.9, 4.8 Hz, 1 H),

4.05 (dd, J = 10.8, 8.5 Hz, 1 H), 4.16–4.21 (m, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 14.1, 15.9, 22.6, 22.7, 25.8, 26.2, 29.3, 29.4,

29.5, 30.5, 31.0, 31.9, 33.5, 56.6, 58.1, 65.2, 67.0, 72.7, 95.6,

169.5 ppm. HRMS (ESI-TOF): calcd. for C₂₀H₃₈N₄O₃S [M + H]⁺

415.2743; found 415.2758.

Azido Hydroxy Amides 24a/24b: Procedure A: starting from epoxy

amide 3l (25 mg, 0.096 mmol), 19.7 mg of an inseparable mixture

of 24a/24b was obtained (68% combined yield, 1:2 ratio of 24a/

24b). Procedure B: starting from epoxy amide 3l (25 mg,

0.096 mmol), 24.7 mg of an inseparable mixture of 24a/24b was

obtained (85% combined yield, 1:4 ratio of 24a/24b). Procedure C:

starting from epoxy amide 3l (25 mg, 0.096 mmol), 17.8 mg of an

inseparable mixture of 24a/24b was obtained (61% combined yield,

1:2 ratio of 24a/24b). Procedure D: starting from epoxy amide 3l

(50 mg, 0.193 mmol), 45.5 mg of an inseparable mixture of 24a/24b

was obtained (78% combined yield, 3:1 ratio of 24a/24b). Pro-

cedure E: starting from epoxy amide 3l (25 mg, 0.096 mmol),

21.5 mg of an inseparable mixture of 24a/24b was obtained (74%

combined yield, 2.6:1 ratio of 24a/24b). Procedure F: starting from

epoxy amide 3l (25 mg, 0.096 mmol), 23.5 mg of an inseparable

mixture of 24a/24b was obtained (81% combined yield, 3:1 ratio

of 24a/24b). Procedure G: starting from epoxy amide 3l (25 mg,

Azido Hydroxy Amides 26a and 26b: Procedure A: Starting from

epoxy amide 3n (50 mg, 0.130 mmol), 26.0 mg of 26a and 21.4 mg

of 26b (85% combined yield, 1.2:1 ratio of 26a/26b). Procedure D:

starting from epoxy amide 3n (50 mg, 0.130 mmol), 43.8 mg of 26a

and 8.7 mg of 26b (94% combined yield, 5:1 ratio of 26a/26b).

26a: Colourless oil; R_f= 0.36 (silica gel, 20% EtOAc/hexanes).

[α]²_D⁵= –33.3 (c = 0.6, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ =

1

0.096 mmol), 21.2 mg of an inseparable mixture of 24a/24b was 0.88 (t, J = 7.0 Hz, 3 H), 1.25–1.40 (m, 16 H), 1.47–1.56 (m, 1 H),

obtained (73% combined yield, 4:1 ratio of 24a/24b). Procedure H:

starting from epoxy amide 3l (25 mg, 0.096 mmol), 15.1 mg of an

inseparable mixture of 24a/24b was obtained (52% combined yield,

1:2 ratio of 24a/24b).

1.56 (s, 3 H), 1.61–1.66 (m, 1 H), 1.70 (s, 3 H), 1.80–1.93 (m, 1 H),

2.02–2.11 (m, 1 H), 2.14 (s, 3 H), 2.39 (ddd, J = 13.6, 10.3, 5.2 Hz,

1 H), 2.62 (dt, J = 13.7, 5.3 Hz, 1 H), 2.94 (d, J = 7.3 Hz, 1 H),

3.60 (d, J = 6.5 Hz, 1 H), 3.85 (d, J = 9.2 Hz, 1 H), 3.98 (ddd, J =

9.1, 5.1, 1.6 Hz, 1 H), 4.06 (dq, J = 7.4, 3.5 Hz, 1 H), 4.14 (ddd, J

= 10.4, 4.9, 2.8 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

14.1, 15.6, 22.7, 25.3, 26.5, 29.3, 29.4, 29.51, 29.54, 30.9, 31.9, 33.1,

34.3, 56.7, 61.9, 66.9, 73.0, 95.8, 166.6 ppm. HRMS (ESI-TOF):

calcd. for C₂₁H₄₀N₄O₃S [M + H]⁺429.2899; found 429.2903.

Mixture of 24a and 24b (3:1): Colourless oil; R_f= 0.43 (silica gel,

1

50% EtOAc/hexanes). H NMR (400 MHz, CDCl₃, major isomer,

24a): δ = 1.35 (d, J = 6.4 Hz, 3 H), 1.56 (s, 3 H), 1.69 (s, 3 H),

1.82–1.90 (m, 1 H), 2.02–2.11 (m, 1 H), 2.13 (s, 3 H), 2.39 (ddd, J

= 13.6, 10.2, 5.4 Hz, 1 H), 2.61 (ddd, J = 13.6, 5.6 Hz, 1 H), 3.12

(br. s, 1 H), 3.56 (d, J = 6.8 Hz, 1 H), 3.84 (d, J = 9.2 Hz, 1 H),

3.98 (ddd, J = 9.2, 5.1, 1.6 Hz, 1 H), 4.13 (ddd, J = 10.4, 4.9,

2.8 Hz, 1 H), 4.23 (sext, J = 6.5 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃, major isomer, 24a): δ = 15.4, 15.9, 20.6, 22.7,

26.4, 30.9, 33.2, 56.7, 63.3, 66.9, 69.1, 95.8, 166.4 ppm. HRMS

(ESI-TOF): calcd. for C₁₂H₂₂N₄O₃S [M + H]⁺303.1491; found

303.1475.

26b: Colourless oil; R_f= 0.29 (silica gel, 20% EtOAc/hexanes).

1

[α]²_D⁵= +13.4 (c = 1.1, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ =

0.89 (t, J = 7.0 Hz, 3 H), 1.25–1.38 (m, 16 H), 1.48–1.56 (m, 1 H),

1.57 (s, 3 H), 1.58–1.64 (m, 1 H), 1.66 (s, 3 H), 1.86–1.92 (m, 1 H),

2.01–2.11 (m, 1 H), 2.13 (s, 3 H), 2.40 (ddd, J = 13.5, 9.5, 6.2 Hz,

1 H), 2.60 (ddd, J = 13.5, 6.2, 5.1 Hz, 1 H), 3.07 (d, J = 11.0 Hz,

1 H), 3.65 (dt, J = 9.0, 2.4 Hz, 1 H), 3.88 (d, J = 9.2 Hz, 1 H), 3.99

(ddd, J = 9.1, 4.8, 1.3 Hz, 1 H), 4.03 (dd, J = 11.0, 8.5 Hz, 1 H),

4.18 (ddd, J = 8.1, 4.9, 3.1 Hz, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 14.1, 15.9, 22.7, 22.8, 25.9, 26.2, 29.3, 29.4, 29.49,

29.50, 30.6, 30.9, 31.9, 33.5, 56.6, 65.2, 67.0, 72.7, 95.5, 169.4 ppm.

HRMS (ESI-TOF): calcd. for C₂₁H₄₀N₄O₃S [M + H]⁺429.2899;

found 429.2896.

Azido Hydroxy Amides 25a and 25b: Procedure A: starting from

epoxy amide 3m (25 mg, 0.067 mmol), 11.0 mg of 25a and 9.0 mg

of 25b were obtained (72% combined yield, 1.2:1 ratio of 25a/25b).

Procedure B: starting from epoxy amide 3m (25 mg, 0.067 mmol),

6.6 mg of 25a and 17.3 mg of 25b were obtained (86% combined

yield, 1:2.6 ratio of 25a/25b). Procedure C: starting from epoxy

amide 3m (25 mg, 0.067 mmol), 5.1 mg of 25a and 10.5 mg of 25b

were obtained (56% combined yield, 1:2 ratio of 25a/25b). Pro-

cedure D: starting from epoxy amide 3m (100 mg, 0.269 mmol),

70.2 mg of 25a and 13.3 mg of 25b were obtained (75% combined

yield, 5:1 ratio of 25a/25b). Procedure G: starting from epoxy

amide 3m (25 mg, 0.067 mmol), 21.8 mg of 25a and 3.8 mg of 25b

were obtained (92% combined yield, 6:1 ratio of 25a/25b).

2-Azido-3-hydroxy Amide 27a: Procedure D: starting from epoxy

amide 3g (100 mg, 0.348 mmol), 87.4 mg of 27a was obtained

(76%), 27b was not detected.

27a: Colourless oil; R_f= 0.40 (silica gel, 30% EtOAc/hexanes).

1

[α]²_D⁵= –69.3 (c = 2.7, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ =

0.93 (d, J = 7.0 Hz, 3 H), 0.96 (d, J = 6.9 Hz, 3 H), 1.49 (s, 3 H),

1.63 (s, 3 H), 1.79–1.91 (m, 2 H), 1.95–2.03 (m, 1 H), 2.07 (s, 3 H),

12

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Synthesis of Bioactive Compounds

2.32 (ddd, J = 13.5, 10.6, 4.8 Hz, 1 H), 2.56 (ddd, J = 13.4, 4.8 Hz,

15.7, 19.8, 19.9, 22.8, 26.4, 31.0, 33.1, 34.8, 45.6, 55.7, 66.9, 95.3,

1 H), 3.63 (d, J = 7.5 Hz, 1 H), 3.77 (d, J = 9.2 Hz, 1 H), 3.86 (dd, 167.0 ppm. HRMS (ESI-TOF): calcd. for C₁₄H₂₆N₂O₂S [M +

J = 7.5, 4.3 Hz, 1 H), 3.92 (ddd, J = 9.2, 5.2, 1.7 Hz, 1 H), 4.12

(ddd, J = 10.5, 4.9, 2.9 Hz, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 15.5, 15.9, 19.3, 19.4, 22.5, 26.4, 30.8, 32.9, 50.9, 56.4,

59.6, 66.7, 95.6, 166.8 ppm. HRMS (ESI-TOF): calcd. for

C₁₄H₂₆N₄O₃S [M + Na]⁺353.1623; found 353.1617.

Na]⁺309.1613; found 309.1617.

General Procedure for the Synthesis of 2-Amino-3-hydroxy Amides

5 and 17 from Azido Alcohols: H₂O (150 equiv.) followed by a solu-

tion of Me₃P in THF (1.5 equiv., 1.0 m in THF) were added to a

solution of the 2-azido-3-hydroxy amide (1.0 equiv.) in THF (0.1 m)

at room temperature. After 2 h, the reaction mixture was diluted

with water and Et₂O, the phases were separated and the aqueous

phase was extracted with Et₂O twice. The combined organic ex-

tracts were washed with brine, dried (MgSO₄), filtered and concen-

trated under reduced pressure. The crude product was purified by

flash column chromatography (silica gel, CH₂Cl₂Ǟ2–5% MeOH/

CH₂Cl₂) to afford the corresponding 2-amino 3-hydroxy amide.

Aziridine 28: A solution of azido alcohol 23a (20 mg, 0.05 mmol,

1.0 equiv.) in THF (2 mL) was treated with Ph₃P (22 mg,

0.08 mmol, 1.5 equiv.) at room temperature. After 6 h, the reaction

mixture was diluted with water and Et₂O, the phases were sepa-

rated and the aqueous phase was extracted with Et₂O twice. The

combined organic extracts were washed with brine, dried (MgSO₄),

filtered and concentrated under reduced pressure. The crude prod-

uct was purified by flash column chromatography (silica gel, 50%

EtOAc/hexanes) to afford aziridine 28 (10 mg, 62%) as a colourless

oil. R_f= 0.49 (silica gel, 50% AcOEt/hexanes). [α]²_D⁵= –57.0 (c =

0.5, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.50 (s, 3 H), 1.61

(s, 3 H), 1.88–1.93 (m, 1 H), 2.02 (s, 3 H), 2.03–2.10 (m, 1 H), 2.32

(ddd, J = 13.5, 9.6, 5.8 Hz, 1 H), 2.53 (ddd, J = 13.5, 6.1, 5.4 Hz,

1 H), 2.69 (br. s, 1 H), 3.08 (br. s, 1 H), 3.80 (d, J = 9.1 Hz, 1 H),

3.92 (ddd, J = 9.1, 4.9, 1.5 Hz, 1 H), 4.08 (ddd, J = 10.2, 4.8,

2.8 Hz, 1 H), 7.19–7.28 (m, 5 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 15.8, 22.9, 26.6, 30.9, 33.4, 39.89, 39.94, 55.9, 67.1,

95.5, 126.1, 127.6, 128.4, 138.4, 165.9 ppm. HRMS (ESI-TOF):

calcd. for C₁₇H₂₄N₂O₂S [M + Na]⁺343.1456; found 343.1463.

Amino Alcohol 5: Starting from 23a (65 mg), 45 mg of 5 (74%)

was obtained that displayed identical physical and spectroscopic

properties to amino alcohol 5 obtained from epoxy amide 3a.

Amino Alcohol 17: Starting from 27a (47 mg), 37 mg of 17 (86%)

was obtained that displayed identical physical and spectroscopic

properties to amino alcohol 17 obtained from epoxy amide 3g.

General Procedure for the Synthesis of 3-Azido-2-trimethylsilyloxy

Amides 31, 32, 35, 36, 38 and 39 and 3-Azido-2-hydroxy Amides

33, 34 and 37: Trimethylsilyl azide (2.5 equiv.) and solid Yb(OTf)₃

(0.2 equiv.) were added to a solution of the epoxy amide (1.0 equiv.)

in CH₂Cl₂(0.1 m) at 25 °C. After stirring at this temperature over-

night, the reaction mixture was diluted with Et₂O and the resulting

organic solution washed with a saturated aqueous solution of

NaHCO₃. After separation of the two phases, the aqueous layer

was extracted with Et₂O (twice) and the combined organic extracts

were washed with brine, dried (MgSO₄) and filtered. Concentration

under reduced pressure provided a crude product that was purified

by flash column chromatography (silica gel, 5% AcOEt in hexanes)

to afford the corresponding azido trimethylsilyloxy or azido-hy-

droxy amides. In all cases, we started from 100 mg of the epoxy

amide.

Aziridine 29: A solution of azido alcohol 25a (50 mg, 0.12 mmol,

1.0 equiv.) in THF (4 mL) was treated with Ph₃P (47 mg,

0.18 mmol, 1.5 equiv.) at room temperature. After 6 h, the reaction

mixture was diluted with water and Et₂O, the phases were sepa-

rated and the aqueous phase was extracted with Et₂O twice. The

combined organic extracts were washed with brine, dried (MgSO₄),

filtered and concentrated under reduced pressure. The crude prod-

uct was purified by flash column chromatography (silica gel, 50%

EtOAc/hexanes) to afford aziridine 29 (41 mg, 92%) as a colourless

oil. R_f= 0.45 (silica gel, 50% EtOAc/hexanes). [α]²_D⁵= –32.5 (c =

1.0, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.81 (t, J = 6.9 Hz,

3 H), 1.17–1.26 (m, 12 H), 1.37–1.42 (m, 4 H), 1.46 (s, 3 H), 1.57

(s, 3 H), 1.70–1.78 (m, 1 H), 1.84–1.93 (m, 1 H), 2.01–2.10 (m, 2

H), 2.05 (s, 3 H), 2.31 (d, J = 2.4 Hz, 1 H), 2.38 (ddd, J = 13.4,

10.1, 5.8 Hz, 1 H), 2.58 (ddd, J = 13.5, 6.0, 5.1 Hz, 1 H), 3.83 (d,

J = 9.4 Hz, 1 H), 3.94 (ddd, J = 9.2, 5.0, 1.6 Hz, 1 H), 4.13 (ddd,

J = 10.5, 4.7, 2.5 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 14.1, 15.9, 22.7, 23.0, 26.6, 27.3, 29.3, 29.4, 29.6, 31.1, 31.9, 32.8,

33.3, 35.9, 39.2, 55.9, 67.0, 95.4, 167.1 ppm. HRMS (ESI-TOF):

calcd. for C₂₀H₃₈N₂O₂S [M + H]⁺371.2732; found 371.2741.

3-Azido-2-trimethylsilyloxy Amide 31: Yield 111 mg, 85%; colour-

less oil; R_f= 0.56 (silica gel, 5% EtOAc/hexanes). [α]²_D⁵= –61.9 (c

= 1.6, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.18 (s, 9 H),

0.44–0.49 (m, 1 H), 1.29–1.37 (m, 1 H), 1.38 (s, 3 H), 1.44 (s, 3 H),

2.01 (s, 3 H), 2.10–2.19 (m, 2 H), 3.64 (d, J = 9.1 Hz, 1 H), 3.71

(s, 3 H), 3.73–3.75 (m, 1 H), 3.85 (ddd, J = 10.5, 4.5, 2.3 Hz, 1 H),

4.10 (d, J = 8.8 Hz, 1 H), 4.92 (d, J = 8.8 Hz, 1 H), 6.81 (d, J =

8.5 Hz, 2 H), 7.19 (d, J = 8.5 Hz, 2 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 0.3, 16.1, 22.4, 25.9, 31.0, 32.2, 55.2, 56.2, 66.2, 67.7,

76.7, 95.2, 114.2, 129.1, 159.6, 166.5 ppm. HRMS (ESI-TOF):

calcd. for C₂₁H₃₄N₄O₄SSi, [M + Na]⁺489.1968; found 489.1973.

Aziridine 30: A solution of azido alcohol 27a (30 mg, 0.09 mmol,

1.0 equiv.) in THF (2 mL) was treated with Ph₃P (35 mg,

0.14 mmol, 1.5 equiv.) at room temperature. After 6 h, the reaction

mixture was diluted with water and Et₂O, the phases were sepa-

rated and the aqueous phase was extracted with Et₂O twice. The

combined organic extracts were washed with brine, dried (MgSO₄),

filtered and concentrated under reduced pressure. The crude prod-

uct was purified by flash column chromatography (silica gel, 2%

MeOH/CH₂Cl₂) to afford aziridine 30 (23 mg, 89%) as a colourless

oil: R_f= 0.35 (silica gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= –59.8 (c =

1.2, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.93 (d, J = 6.6 Hz,

3 H), 0.97 (d, J = 6.8 Hz, 3 H), 1.31–1.38 (m, 1 H), 1.45 (s, 3 H),

1.56 (s, 3 H), 1.84–1.91 (m, 2 H), 2.05 (s, 3 H), 1.97–2.10 (m, 1 H),

2.34–2.43 (m, 2 H), 2.58 (ddd, J = 13.6, 5.3 Hz, 1 H), 3.83 (d, J =

3-Azido-2-trimethylsilyloxy Amide 32: Yield 92 mg, 76%; colourless

oil; R_f= 0.58 (silica gel, 5% EtOAc/hexanes). [α]²_D⁵= –85.5 (c =

0.5, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.18 (s, 9 H), 0.30–

0.40 (m, 1 H), 1.39 (s, 3 H), 1.48 (s, 3 H), 1.68–1.76 (m, 1 H), 1.97

(s, 3 H), 1.89–2.15 (m, 2 H), 3.63 (d, J = 9.1 Hz, 1 H), 3.73 (ddd,

J = 9.1, 4.5, 2.3 Hz, 1 H), 3.82–3.87 (m, 1 H), 4.10 (d, J = 8.8 Hz,

1 H), 4.90 (d, J = 8.8 Hz, 1 H), 5.03 (d, J = 11.8 Hz, 1 H), 5.05 (d,

J = 11.8 Hz, 1 H), 5.08 (s, 2 H), 7.20–7.40 (m, 13 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = –0.3, 15.4, 22.5, 25.9, 29.5, 30.1,

30.5, 51.0, 55.1, 56.1, 64.7, 72.9, 75.9, 95.2, 113.5, 126.9, 127.6,

128.7, 129.1, 129.5, 130.3, 131.2, 131.7, 134.3, 158.9, 172.9 ppm.

HRMS (ESI-TOF): calcd. for C₃₄H₄₄N₄O₅SSi [M + H]⁺649.2880;

found 649.2875.

9.1 Hz, 1 H), 3.94 (ddd, J = 9.1, 4.9, 1.5 Hz, 1 H), 4.13 (ddd, J = 3-Azido-2-hydroxy Amide 33: Yield 98.0 mg, 88%; white solid; m.p.

10.6, 4.8, 2.5 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 130–134 °C; R_f= 0.38 (silica gel, 5% MeOH/CH₂Cl₂). [α]²_D⁵= –49.9

Eur. J. Org. Chem. 0000, 0–0

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F. Sarabia et al.

(c = 1.4, CH₂Cl₂). ¹H NMR (400 MHz, [D₆]DMSO): δ = 0.89–0.96 2.38 (m, 1 H), 2.43 (ddd, J = 13.7, 9.9, 5.8 Hz, 1 H), 2.68 (dt, J =

FULL PAPER

(m, 1 H), 1.28 (s, 3 H), 1.38 (s, 3 H), 1.39–1.46 (m, 1 H), 2.00 (s, 6

H), 2.27–2.34 (m, 2 H), 3.76–3.80 (m, 2 H), 4.02 (br. d, J = 10.5 Hz,

1 H), 4.15 (dd, J = 8.9, 7.1 Hz, 1 H), 4.92 (d, J = 8.9 Hz, 1 H),

13.7, 5.1 Hz, 1 H), 3.88 (d, J = 9.0 Hz, 1 H), 3.93 (ddd, J = 9.0,

4.7, 1.4 Hz, 1 H), 4.12 (ddd, J = 10.5, 7.9, 4.6 Hz, 1 H), 4.14 (d, J

= 8.3 Hz, 1 H), 5.17 (d, J = 8.3 Hz, 1 H), 6.94 (dd, J = 5.0, 3.4 Hz,

6.37 (d, J = 7.2 Hz, 1 H), 7.18 (d, J = 8.6 Hz, 2 H), 7.50 (d, J = 1 H), 6.99–7.01 (m, 1 H), 7.22 (dd, J = 5.1, 1.3 Hz, 1 H) ppm. ¹³C

8.6 Hz, 2 H), 9.92 (br. s, 1 H) ppm. ¹³C NMR (100 MHz, [D₆]-

DMSO): δ = 15.5, 22.8, 24.5, 26.5, 30.1, 34.3, 56.1, 66.8, 67.2, 75.2,

94.3, 119.0, 128.6, 130.9, 139.6, 167.0, 168.8 ppm. HRMS (ESI-

NMR (100 MHz, CDCl₃): δ = –0.2, 16.1, 22.6, 26.8, 31.2, 33.2,

56.7, 66.4, 72.7, 75.4, 95.3, 124.5, 125.4, 126.2, 146.1, 168.4 ppm.

HRMS (ESI-TOF): calcd. for C₁₈H₃₀N₄O₃S₂Si [M + H]⁺443.1607;

found 443.1614.

TOF): calcd. for C₁₉H₂₇N₅O₄S [M

422.1857.

+

H]⁺422.1862; found

3-Azido-2-trimethylsilyloxy Amide 39: Yield 91 mg, 69%; colourless

oil; R_f= 0.45 (silica gel, 10% EtOAc/hexanes). [α]²_D⁵= +24.6 (c =

0.8, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.30 (s, 9 H), 0.96–

1.04 (m, 1 H), 1.47 (s, 3 H), 1.54 (s, 3 H), 2.10 (s, 3 H), 2.20–2.29

(m, 1 H), 2.48 (ddd, J = 14.0, 10.0, 5.0 Hz, 1 H), 2.73 (dt, J = 13.9,

4.9 Hz, 1 H), 3.75 (d, J = 9.2 Hz, 1 H), 3.86 (ddd, J = 9.2, 4.8,

1.8 Hz, 1 H), 4.08 (ddd, J = 11.0, 4.7, 2.4 Hz, 1 H), 4.58 (d, J =

8.8 Hz, 1 H), 5.18 (dd, J = 8.8, 0.5 Hz, 1 H), 6.73 (t, J = 0.8 Hz, 1

H), 7.23 (dd, J = 7.5, 1.3 Hz, 1 H), 7.26–7.30 (m, 1 H), 7.42 (dq,

J = 4.4, 0.9 Hz, 1 H), 7.52 (ddd, J = 7.5, 1.5, 0.5 Hz, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 0.5, 15.7, 22.7, 26.0, 30.9, 32.1,

56.3, 62.7, 66.2, 74.4, 95.4, 106.7, 111.2, 121.3, 123.3, 124.8, 127.7,

151.8, 155.1, 166.0 ppm. HRMS (ESI-TOF): calcd. for

C₂₂H₃₂N₄O₄SSi [M + H]⁺477.1992; found 477.1990.

3-Azido-2-hydroxy Amide 34: Yield 26 mg, 23%; white solid; R_f=

0.38 (silica gel, 5% EtOAc/hexanes). [α]²_D⁵= –20.5 (c = 0.9,

CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.65–0.72 (m, 1 H),

1.29–1.39 (m, 1 H), 1.44 (s, 3 H), 1.55 (s, 3 H), 2.18 (s, 3 H), 2.46

(ddd, J = 13.3, 8.2, 7.4 Hz, 1 H), 2.70 (dt, J = 13.3, 5.5 Hz, 1 H),

3.68 (d, J = 9.2 Hz, 1 H), 3.85–3.89 (m, 1 H), 4.03 (ddd, J = 10.6,

4.6, 3.4 Hz, 1 H), 4.33 (d, J = 8.1 Hz, 1 H), 5.24 (d, J = 7.8 Hz, 1

H), 7.48–7.54 (m, 3 H), 7.80–7.91 (m, 4 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 16.3, 25.9, 26.3, 31.2, 34.1, 56.6, 67.0, 68.0,

72.8, 95.7, 124.9, 126.5, 126.7, 127.8, 128.2, 128.9, 133.1, 133.2,

167.2 ppm. HRMS (ESI-TOF): calcd. for C₂₁H₂₆N₄O₃S [M + H]⁺

415.1804; found 415.1798.

3-Azido-2-trimethylsilyloxy Amide 35: Yield 16 mg, 12%; colourless

oil; R_f= 0.38 (silica gel, 5% EtOAc/hexanes). [α]²_D⁵= –7.8 (c = 0.7,

Synthesis of 3-Azido-2-trimethylsilyloxy Amides Catalysed by

Zn(OTf)₂: Trimethylsilyl azide (2.5 equiv.) and solid Zn(OTf)₂

(0.2 equiv.) were added to a solution of epoxy amide 3r or 3s

(1.0 equiv.) in CH₂Cl₂(0.1 m) at 25 °C. After stirring at this tem-

perature for 6 h, the reaction mixture was diluted with Et₂O and

the resulting organic solution washed with a saturated aqueous

solution of NaHCO₃. After separation of the two phases, the aque-

ous layer was extracted with Et₂O (twice) and the combined or-

ganic extracts were washed with brine, dried (MgSO₄) and filtered.

Concentration under reduced pressure provided the crude product,

which was purified by flash column chromatography (silica gel, 5%

AcOEt in hexanes) to afford the corresponding azido trimethyl-

silyloxy amide as an inseparable C-3 epimeric mixture in a ratio of

1:1. In these cases, we started from 50 mg of the epoxy amide.

1

CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 0.20 (s, 9 H), 1.53 (s,

3 H), 1.58–1.65 (m, 1 H), 1.68 (s, 3 H), 2.13–2.15 (m, 1 H), 2.17 (s,

3 H), 2.38 (ddd, J = 13.7, 9.3, 6.5 Hz, 1 H), 2.63–2.68 (m, 1 H),

3.83 (d, J = 9.0 Hz, 1 H), 3.87 (ddd, J = 9.0, 5.2, 1.0 Hz, 1 H), 4.07

(ddd, J = 9.0, 4.4 Hz, 1 H), 4.14 (d, J = 9.1 Hz, 1 H), 4.87 (d, J =

9.1 Hz, 1 H), 7.28–7.33 (m, 5 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = –0.3, 14.8, 26.9, 31.3, 34.2, 51.7, 65.4, 68.1, 76.3, 95.2,

126.8, 127.3, 128.2, 134.5, 167.4 ppm. HRMS (ESI-TOF): calcd.

for C₂₀H₃₂N₄O₃SSi [M + H]⁺437.2043; found 437.2056.

3-Azido-2-trimethylsilyloxy Amide 36: Yield 20 mg, 15%; colourless

oil; R_f= 0.52 (silica gel, 5% EtOAc/hexanes). [α]²_D⁵= –12.5 (c =

0.8, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.19 (s, 9 H), 0.79–

0.82 (m, 1 H), 1.22–1.30 (m, 1 H), 1.40 (s, 3 H), 1.45 (s, 3 H), 2.01

(s, 3 H), 2.05–2.15 (m, 1 H), 2.25 (s, 3 H), 2.60–2.65 (m, 1 H), 3.65

(d, J = 9.1 Hz, 1 H), 3.75 (ddd, J = 9.1, 4.8, 1.6 Hz, 1 H), 3.82–

3.87 (m, 1 H), 4.11 (d, J = 8.7 Hz, 1 H), 4.95 (d, J = 8.7 Hz, 1

H), 7.04 (d, J = 8.0 Hz, 2 H), 7.13–7.22 (m, 2 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = –0.3, 14.8, 22.3, 26.7, 34.2, 52.1, 65.9, 68.8,

76.4, 95.2, 126.8, 127.6, 128.0, 134.6, 167.5 ppm. HRMS (ESI-

TOF): calcd. for C₂₁H₃₄N₄O₃SSi [M + H]⁺451.2199; found

451.2203.

3-Azido-2-trimethylsilyloxy Amides 38/38Ј: The isomeric mixture

was separated by flash column chromatography (silica gel, 5%

EtOAc/hexanes) to obtain 23 mg of 38 together with 26 mg of 38Ј

(73% combined yield, 1:1 ratio).

38Ј: Pale-yellow oil; R_f= 0.41 (silica gel, 10% EtOAc/hexanes).

1

[α]²_D⁵= +12.6 (c = 0.3, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ =

0.26 (s, 9 H), 0.59–0.64 (m, 1 H), 1.24–1.33 (m, 1 H), 1.55 (s, 6 H),

2.09 (s, 3 H), 2.20–2.29 (m, 1 H), 2.34 (ddd, J = 13.2, 6.5, 4.8 Hz,

1 H), 3.77 (d, J = 9.0 Hz, 1 H), 3.85 (ddd, J = 9.1, 4.5, 1.4 Hz, 1

H), 3.96–4.01 (m, 1 H), 4.25 (d, J = 8.6 Hz, 1 H), 5.32 (d, J =

8.8 Hz, 1 H), 6.94 (dd, J = 5.0, 3.6 Hz, 1 H), 6.98–6.99 (m, 1 H),

6.94 (dd, J = 5.0, 1.3 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 0.1, 16.2, 22.6, 26.2, 31.1, 32.4, 56.4, 63.9, 66.3, 74.2, 95.6,

125.6, 125.8, 127.3, 140.3, 167.2 ppm. HRMS (ESI-TOF): calcd.

for C₁₈H₃₀N₄O₃S₂Si [M + H]⁺443.1607; found 443.1611.

3-Azido-2-hydroxy Amide 37: Yield 84 mg, 74%; colourless oil; R_f

= 0.32 (silica gel, 30% EtOAc/hexanes). [α]²_D⁵= –57.6 (c = 1.9,

CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 1.21–1.32 (m, 1 H),

1.57 (s, 3 H), 1.59 (s, 3 H), 1.79–1.91 (m, 1 H), 2.08 (s, 3 H), 2.33

(ddd, J = 13.3, 9.0, 6.7 Hz, 1 H), 2.46 (ddd, J = 12.3, 6.9, 5.1 Hz,

1 H), 3.24 (d, J = 8.2 Hz, 1 H), 3.81 (d, J = 9.1 Hz, 1 H), 3.94

(ddd, J = 8.9, 4.8, 1.3 Hz, 1 H), 4.13 (ddd, J = 6.8, 4.2, 1.8 Hz, 1

H), 4.25 (dd, J = 7.5 Hz, 1 H), 4.96 (d, J = 7.1 Hz, 1 H), 6.45 (s,

1 H), 7.42 (t, J = 1.4 Hz, 1 H), 7.50 (s, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 15.9, 22.6, 26.2, 30.9, 33.7, 56.2, 60.6, 66.9,

74.6, 95.6, 109.6, 120.6, 141.2, 143.6, 167.1 ppm. HRMS (ESI-

3-Azido-2-trimethylsilyloxy Amides 39/39Ј: The separation of the

isomers by flash column chromatography (silica gel, 5% EtOAc/

hexanes) was not possible in this case and 54 mg of a 1:1 isomeric

mixture of 39/39Ј (82% combined yield) was obtained.

TOF): calcd. for C₁₅H₂₂N₄O₄S [M

355.1435.

+

H]⁺355.1440; found

39Ј: NMR spectroscopic data for 39Ј obtained from the NMR

1

3-Azido-2-trimethylsilyloxy Amide 38: Yield 114 mg, 84%; pale-yel-

spectra of the mixture. H NMR (400 MHz, CDCl₃): δ = –0.07 (s,

low oil; R_f= 0.37 (silica gel, 10% EtOAc/hexanes). [α]²_D⁵= +44.0

9 H), 0.82–0.94 (m, 1 H), 1.24–1.30 (m, 1 H), 1.56 (s, 3 H), 1.61 (s,

1

(c = 0.5, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 0.03 (s, 9 H), 3 H), 2.13–2.20 (m, 1 H), 2.29–2.36 (m, 1 H), 2.32 (s, 3 H), 3.92

1.57 (s, 3 H), 1.70 (s, 3 H), 1.95–2.04 (m, 1 H), 2.24 (s, 3 H), 2.34–

14

(d, J = 9.0 Hz, 1 H), 3.97 (ddd, J = 9.1, 4.8, 1.6 Hz, 1 H), 4.29

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Synthesis of Bioactive Compounds

(ddd, J = 10.8, 4.5, 2.6 Hz, 1 H), 4.72 (d, J = 9.4 Hz, 1 H), 5.15

(d, J = 9.4 Hz, 1 H), 6.83 (d, J = 0.8 Hz, 1 H), 7.21 (dd, J = 6.2,

1.1 Hz, 1 H), 7.31 (ddd, J = 6.5, 2.4, 1.5 Hz, 1 H), 7.44 (dq, J =

concentrated under reduced pressure. The resulting crude product

was purified by flash column chromatography (silica gel,

CH₂Cl₂Ǟ10%

MeOH/CH₂Cl₂ǞCH₂Cl₂/MeOH/NH₄OH,

4.6, 0.6 Hz, 1 H), 7.59 (ddd, J = 7.6, 1.4, 0.6 Hz, 1 H) ppm. ¹³C 8:1:0.1) to obtain pure deacetyl clavaminol H (46; 72 mg, 61%) as

NMR (100 MHz, CDCl₃): δ = 0.1, 15.7, 22.6, 26.5, 31.1, 32.9, 56.5, a colourless oil. [α]²_D⁵= +6.3 (c = 0.1, MeOH) [ref.^[26]+6.6 (c = 0.6,

61.9, 66.5, 71.0, 95.6, 108.1, 111.1, 121.4, 123.1, 124.9, 127.6, 150.9,

154.6, 166.8 ppm.

MeOH)]. ¹H NMR (400 MHz, CD₃OD): δ = 0.89 (t, J = 6.9 Hz, 3

H), 1.24–1.40 (m, 13 H), 1.43–1.57 (m, 3 H), 3.20 (dd, J = 8.3,

4.0 Hz, 1 H), 3.70 (dd, J = 11.6, 8.5 Hz, 1 H), 3.78 (dd, J = 8.4,

4.4 Hz, 1 H), 3.83 (dd, J = 11.6, 4.0 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CD₃OD): δ = 14.4, 23.7, 27.0, 30.4, 30.5, 30.7, 33.0,

34.2, 58.5, 58.9, 70.3 ppm. HRMS (ESI-TOF): calcd. for

C₁₂H₂₇NO₂[M + H]⁺218.2120; found 218.2117.

Epoxy Amide 4m: A 3.0 m aqueous solution of NaOH (2.3 mL,

7.00 mmol, 1.0 equiv.) was added to a suspension of sulfonium salt

2 (2.20 g, 7.00 mmol, 1.0 equiv.) in tBuOH (20 mL) at room tem-

perature. After 30 min at this temperature, a solution of decanal

(44; 1.32 mL, 7.00 mmol, 1.0 equiv.) in tBuOH (5.0 mL) was added

and the resulting reaction mixture was stirred overnight. The crude

mixture was then diluted with Et₂O and the resulting organic solu-

tion washed with water. After separation of the two layers, the

aqueous phase was extracted with Et₂O (twice) and the combined

organic extracts were washed with brine, dried (MgSO₄) and fil-

tered. The resulting crude product was purified by flash column

chromatography (silica gel, 10% EtOAc/hexanes) to obtain pure

epoxy amide 4m (2.12 g, 82%) as a colourless oil. R_f= 0.32 (silica

gel, 20% EtOAc/hexanes). [α]²_D⁵= –29.5 (c = 0.8, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = 0.87 (t, J = 6.8 Hz, 3 H), 1.21–1.35

(m, 14 H), 1.42–1.49 (m, 2 H), 1.51 (s, 3 H), 1.63 (s, 3 H), 1.68–

1.91 (m, 2 H), 2.09 (s, 3 H), 2.45 (ddd, J = 13.0, 8.5, 7.1 Hz, 1 H),

2.58 (ddd, J = 13.0, 7.4, 5.3 Hz, 1 H), 3.15 (ddd, J = 6.4, 4.5,

2.0 Hz, 1 H), 3.32 (d, J = 2.0 Hz, 1 H), 3.86 (d, J = 9.2 Hz, 1 H),

3.98 (ddd, J = 9.1, 5.2, 1.5 Hz, 1 H), 4.27 (ddd, J = 10.5, 4.8,

3.3 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.1, 15.9,

22.6, 23.0, 25.9, 26.3, 29.30, 29.33, 29.46, 29.5, 29.6, 31.0, 31.5,

31.9, 34.6, 53.9, 55.7, 58.5, 66.9, 95.8, 164.3 ppm. HRMS (ESI-

TOF): calcd. for C₂₀H₃₇NO₃S [M + H]⁺372.2572; found 372.2565.

Clavaminol H (42): A solution of deacetyl clavaminol H (46; 52 mg,

0.24 mmol, 1.0 equiv.) in pyridine (3 mL) was treated with an excess

of Ac₂O (1.0 mL) at 0 °C. The resulting reaction mixture was

warmed up to room temperature and stirred overnight. After this

time the crude mixture was diluted with Et₂O and the resulting

organic solution sequentially washed with a 1.0 m aqueous solution

of HCl (twice), a saturated aqueous solution of NaHCO₃, water

and brine. The organic solution was then dried (MgSO₄), filtered

and concentrated under reduced pressure. The resulting crude

product was dissolved in MeOH (3 mL) and treated with a freshly

prepared 0.1 m solution of NaOMe in MeOH (1 mL). After stirring

for 30 min, the reaction mixture was diluted with EtOAc and

washed with a saturated aqueous solution of NH₄Cl. The organic

layer was separated and the aqueous phase was extracted with

EtOAc (twice). The combined organic solution was sequentially

washed with water and brine, dried (MgSO₄), filtered and concen-

trated under reduced pressure. The resulting crude product was

purified by flash column chromatography (silica gel,

CH₂Cl₂Ǟ10% MeOH/CH₂Cl₂) to obtain clavaminol H (42;

60 mg, 98%) as a white solid. R_f= 0.60 (silica gel, 5% MeOH/

CH₂Cl₂); m.p. 106–108 °C (ref.^[26]107–109 °C). [α]²_D⁵= +3.4 (c =

1.0, MeOH) [ref.^[26]+3.3 (c = 1.4, MeOH); ref.^[25b]+3.19 (c =

0.0013, MeOH)]. ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J =

6.9 Hz, 3 H), 1.21–1.42 (m, 13 H), 1.48–1.58 (m, 3 H), 2.03 (s, 3

H), 3.14 (br. s, 1 H), 3.26 (br. s, 1 H), 3.70–3.78 (m, 1 H), 3.74 (dd,

J = 11.3, 3.1 Hz, 1 H), 3.82 (dt, J = 11.2, 3.4 Hz, 1 H), 3.98 (ddd,

J = 11.4, 3.4 Hz, 1 H), 6.58 (d, J = 7.9 Hz, 1 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 14.1, 22.7, 23.4, 26.0, 29.3, 29.6, 31.9, 34.5,

53.9, 62.3, 74.1, 170.6 ppm. HRMS (ESI-TOF): calcd. for

C₁₄H₂₉NO₃[M + H]⁺260.2226; found 260.2245.

2-Amino-3-hydroxy Amide 45: Amino hydroxy amide 45 (275 mg,

74%) was obtained from epoxy amide 4m (355 mg, 0.96 mmol) by

treatment with a 30% aqueous solution of ammonia according to

the general procedure described above. Colourless oil; R_f= 0.47

(silica gel, 2% MeOH/CH₂Cl₂). [α]²_D⁵= –31.7 (c = 0.8, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 6.7 Hz, 3 H), 1.25–1.32

(m, 14 H), 1.52–1.66 (m, 2 H), 1.56 (s, 3 H), 1.68 (s, 3 H), 1.81–

1.92 (m, 1 H), 2.00–2.08 (m, 1 H), 2.11 (s, 3 H), 2.42–2.51 (m, 1

H), 2.58 (ddd, J = 13.3, 7.8, 5.1 Hz, 1 H), 3.09 (br. s, 4 H), 3.83

(d, J = 9.1 Hz, 1 H), 3.96 (ddd, J = 9.1, 5.0, 1.4 Hz, 1 H), 4.08 (d,

J = 4.9 Hz, 1 H), 4.19 (ddd, J = 10.5, 4.8, 2.7 Hz, 1 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 14.1, 15.9, 22.6, 22.7, 26.3, 26.5,

29.3, 29.5, 29.60, 29.65, 29.69, 30.7, 32.1, 32.8, 34.7, 55.1, 56.6,

67.5, 71.9, 95.5, 168.7 ppm. HRMS (ESI-TOF): calcd. for

C₂₀H₄₀N₂O₃S [M + H]⁺389.2838; found 389.2851.

Epoxy Alcohol 47:

A solution of epoxy amide 3v (1.75 g,

3.96 mmol, 1.0 equiv.) in THF (20 mL) was treated with lithium

triethylborohydride (Super-H; 11.88 mL, 1 m in THF, 11.88 mmol,

3.0 equiv.) at 0 °C. The reaction mixture was stirred at this tempera-

ture until the reaction was complete as judged by TLC (ca. 0.5 h).

The excess of Super-H was carefully quenched by the addition of

MeOH, and the resulting solution was diluted with Et₂O and

washed with a saturated aqueous solution of NH₄Cl. The organic

phase was separated, the aqueous layer was extracted with Et₂O

Deacetyl Clavaminol H (46): A freshly prepared solution of LDA

[diisopropylamine (0.56 mL, 3.78 mmol, 7.0 equiv.) was added to a

solution of nBuLi (1.6 m solution in hexanes, 2.36 mL, 3.78 mmol,

7.0 equiv.) in THF (10 mL) at 0 °C] was treated with the borane–

ammonia complex (120 mg, 3.78 mmol, 7.0 equiv.) at 0 °C. After (twice) and the combined organic extracts were washed with brine,

15 min at this temperature, the resulting suspension was stirred at

room temperature for an additional 30 min before cooling again

to 0 °C. Then a solution of 2-amino-3-hydroxy amide 45 (210 mg,

0.54 mmol, 1.0 equiv.) in THF (10 mL) was added. The reaction

mixture was warmed to room temperature and stirred overnight.

After this time, excess hydride was quenched by the careful addition

of MeOH at 0 °C and the crude mixture was diluted with EtOAc

and treated with a saturated aqueous solution of NH₄Cl. The or-

ganic layer was separated and the aqueous phase was extracted

with EtOAc (twice). The combined organic solution was sequen-

tially washed with water and brine, dried (MgSO₄), filtered and

dried (MgSO₄) and filtered. Concentration under reduced pressure

provided a crude product that was purified by flash column

chromatography (silica gel, 10% EtOAc/hexanes) to afford epoxy

alcohol 47 (953 mg, 89%) as a white solid, m.p. 75–77 °C; R_f=

0.44 (silica gel, 10% EtOAc/hexanes). [α]²_D⁵= +10.4 (c = 1.0,

1

CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 7.0 Hz, 3

H), 1.21–1.30 (m, 22 H), 1.39–1.47 (m, 1 H), 1.55–1.58 (m, 2 H),

1.60–1.65 (m, 1 H), 2.92 (dt, J = 4.7, 2.5 Hz, 1 H), 2.95 (dt, J =

5.6, 2.3 Hz, 1 H), 3.64 (ddd, J = 12.4, 7.3, 4.2 Hz, 1 H), 3.91 (ddd,

J = 12.5, 5.4, 2.6 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 14.1, 22.7, 25.9, 29.35, 29.40, 29.52, 29.54, 29.63, 29.64, 29.65,

Eur. J. Org. Chem. 0000, 0–0

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F. Sarabia et al.

FULL PAPER

29.67, 29.69, 31.6, 31.9, 55.9, 58.3, 61.7 ppm. HRMS (ESI-TOF):

calcd. for C₁₇H₃₄O₂[M + H]⁺271.2637; found 271.2648.

(250 mg, 0.67 mmol, 1.0 equiv.) in CH₂Cl₂(10 mL) were added to

a solution of sulfonium salt 1 (256 mg, 0.81 mmol, 1.2 equiv.) in

H₂O (10 mL). The reaction mixture was then vigorously stirred

overnight at 25 °C. After this time the two phases were separated

and the aqueous layer was extracted with CH₂Cl₂(twice). The com-

bined organic extracts were washed with brine, dried (MgSO₄), fil-

tered and concentrated under reduced pressure. Purification of the

resulting crude product by flash column chromatography (silica gel,

5% EtOAc/hexanes) afforded epoxy amide 50 (332 mg, 85%) as a

Olefin 48: A solution of epoxy alcohol 47 (416 mg, 1.54 mmol,

1.0 equiv.) in CH₂Cl₂(15 mL) was treated with NEt₃(0.32 mL,

2.31 mmol, 1.5 equiv.), 4-DMAP (3.8 mg, 0.031 mmol, 0.02 equiv.)

and p-toluenesulfonyl chloride (352 mg, 1.85 mmol, 1.2 equiv.) at

0 °C. After stirring for 2 h at this temperature, the reaction mixture

was diluted with Et₂O and washed with a saturated aqueous solu-

tion of NH₄Cl. The organic phase was separated, the aqueous layer

was extracted with Et₂O (twice) and the combined organic extracts

were washed with brine, dried (MgSO₄) and filtered. Concentration

under reduced pressure provided a crude tosylate that was used in

the next step without further purification. The crude tosylate (ca.

1.54 mmol) was dissolved in acetone (20 mL) and DMF (5.0 mL)

and treated with KI (1.0 g, 6.02 mmol, 4.0 equiv.). The reaction

mixture was then heated at reflux for 90 min. After this time the

reaction mixture was allowed to warm to room temperature and

then cooled to 0 °C and treated with Ph₃P (404 mg, 1.54 mmol,

1.0 equiv.) and I₂(39 mg, 0.154 mmol, 0.1 equiv.). After 1 h at 0 °C,

the crude mixture was diluted with Et₂O and washed with H₂O.

The organic phase was separated, the aqueous layer extracted with

Et₂O (twice) and the combined organic extracts were washed with

a saturated aqueous solution of Na₂S₂O₃and brine. After decan-

tation, the organic phase was dried (MgSO₄), filtered and concen-

trated under reduced pressure to obtain a crude product corre-

sponding to the allylic alcohol, which was used in the next step

without purification. A solution of the crude allylic alcohol (ca.

1.54 mmol) was dissolved in DMF (10 mL) and treated with tert-

butyldimethylsilyl chloride (464 mg, 3.08 mmol, 2.0 equiv.) and

imidazole (262 mg, 3.85 mmol, 2.5 equiv.) at 25 °C. After stirring

for 6 h, the reaction mixture was quenched by the addition of

MeOH (2.0 mL), diluted with Et₂O and washed with a saturated

aqueous solution of NH₄Cl. The organic phase was separated, the

aqueous layer was extracted with Et₂O (twice), and the combined

organic extracts were washed with brine, dried (MgSO₄) and fil-

tered. Concentration under reduced pressure provided a crude

product that was purified by flash column chromatography (silica

gel, 5% AcOEt/hexanes) to afford olefin 48 (380 mg, 67% over

three steps) as a colourless oil, the physical and spectroscopic data

of which are identical to those reported in the literature.^[35]

colourless oil. R_f= 0.45 (silica gel, 10% EtOAc/hexanes). [α]²_D⁵

=

+18.9 (c = 0.5, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.06 (s,

3 H), 0.08 (s, 3 H), 0.88 (t, J = 7.0 Hz, 3 H), 0.89 (s, 9 H), 1.21–

1.35 (m, 24 H), 1.54 (s, 3 H), 1.56–1.64 (m, 2 H), 1.66 (s, 3 H),

1.85–1.88 (m, 1 H), 2.02–2.10 (m, 1 H), 2.12 (s, 3 H), 2.45–2.60 (m,

2 H), 3.23 (dd, J = 1.9 Hz, 1 H), 3.57 (d, J = 1.9 Hz, 1 H), 3.92 (d,

J = 9.2 Hz, 1 H), 3.97 (ddd, J = 6.8, 4.9, 1.9 Hz, 1 H), 4.01 (ddd,

J = 9.1, 5.1, 1.4 Hz, 1 H), 4.25 (ddd, J = 10.3, 4.8, 3.0 Hz, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –4.9, –4.5, 14.1, 15.9,

18.3, 22.7, 23.0, 25.3, 25.77, 25.84, 25.88, 26.3, 29.4, 29.51, 29.58,

29.65, 29.67, 29.69, 30.8, 31.9, 34.7, 34.9, 49.5, 56.3, 60.8, 66.9,

68.5, 95.8, 164.4 ppm. HRMS (ESI-TOF): calcd. for

C₃₂H₆₃NO₄SSi [M + H]⁺586.4325; found 586.4338.

Azido Alcohol 52: NaN₃(163 mg, 2.50 mmol, 10.0 equiv.) and

AcOH (14.3 μL, 0.25 mmol, 1.0 equiv.) were added to a solution of

epoxy amide 50 (148 mg, 0.25 mmol, 1.0 equiv.) in DMF (5.0 mL).

The reaction mixture was then heated at 70 °C for 12 h. After this

time the crude mixture was cooled to room temperature, diluted

with Et₂O and washed with a saturated aqueous solution of

NaHCO₃. After separation of the two phases, the aqueous layer

was extracted with Et₂O (twice) and the combined organic extracts

were washed with brine, dried (MgSO₄) and filtered. The resulting

crude product was purified by flash column chromatography (silica

gel, 5% EtOAc/hexanes) to afford azido alcohol 52 (145 mg, 92%)

as a colourless oil. R_f= 0.32 (silica gel, 10% EtOAc/hexanes).

1

[α]²_D⁵= +7.5 (c = 0.3, CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ =

0.12 (s, 6 H), 0.88 (t, J = 7.0 Hz, 3 H), 0.90 (s, 9 H), 1.23–1.29 (m,

24 H), 1.58 (s, 3 H), 1.60–1.68 (m, 2 H), 1.70 (s, 3 H), 1.75–1.85

(m, 1 H), 2.00–2.09 (m, 1 H), 2.11 (s, 3 H), 2.39 (ddd, J = 13.7,

10.1, 4.9 Hz, 1 H), 2.60 (ddd, J = 13.7, 5.3 Hz, 1 H), 2.79 (d, J =

2.8 Hz, 1 H), 3.69 (d, J = 9.1 Hz, 1 H), 3.82 (d, J = 9.1 Hz, 1 H),

3.91–3.94 (m, 1 H), 3.97 (ddd, J = 9.0, 4.9, 1.3 Hz, 1 H), 4.08 (dt,

J = 9.0, 3.0 Hz, 1 H), 4.26 (ddd, J = 10.4, 4.4, 3.1 Hz, 1 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = –4.5, –4.4, 14.1, 15.8, 18.1, 22.6,

22.7, 25.7, 25.9, 26.7, 29.4, 29.59, 29.64, 29.65, 29.69, 29.9, 30.3,

31.0, 31.9, 33.3, 56.1, 58.8, 66.9, 72.9, 74.8, 95.8, 166.5 ppm.

HRMS (ESI-TOF): calcd. for C₃₂H₆₄N₄O₄SSi [M + H]⁺629.4496;

found 629.4476.

Aldehyde 49: OsO₄(2.5 wt.-% solution in tBuOH, 0.38 mL,

0.0375 mmol, 0.05 equiv.) was added to a stirred solution of N-

methylmorpholine N-oxide (176 mg, 1.50 mmol, 2.0 equiv.) and

olefin 48 (275 mg, 0.75 mmol, 1.0 equiv.) in THF (10 mL) at 25 °C.

When the reaction was complete (18–24 h), the crude mixture was

diluted with EtOAc and treated with a saturated aqueous solution

of Na₂SO₃. The organic phase was separated, the aqueous layer

was extracted with EtOAc (twice) and the combined organic ex-

tracts were washed with brine, dried (MgSO₄) and filtered. Concen-

tration under reduced pressure provided the crude diol, which was

purified by flash column chromatography (silica gel, 20% EtOAc/

hexanes) to afford pure diol (270 mg, 89%) as a colourless oil. Then

a solution of this diol (270 mg, 0.67 mmol, 1.0 equiv.) in MeOH/

H₂O (2:1; 9.0 mL) was treated with NaIO₄(860 mg, 4.02 mmol,

6.0 equiv.) at 0 °C. After stirring at this temperature for 2 h, the

reaction mixture was diluted with Et₂O and washed with H₂O and

brine. The ethereal layer was separated, dried (MgSO₄), filtered and

concentrated under reduced pressure to obtain pure aldehyde 49

(250 mg, quantitative) as a colourless oil that did not require fur-

ther purification.

Phytosphingosine (43): LiAlH₄(53 mg, 1.40 mmol, 10.0 equiv.) was

added to a solution of azido hydroxy amide 52 (90 mg, 0.14 mmol,

1.0 equiv.) in THF (15 mL) at 0 °C. The reaction mixture was

warmed to room temperature and then heated at 65 °C for 8 h.

After this time, the reaction mixture was cooled to 0 °C, diluted

with THF and carefully treated with a 5% aqueous solution of

NaOH. After the destruction of excess LiAlH₄, the crude mixture

was filtered through a pad of silica gel, which was washed with

MeOH. The organic solution was then concentrated under reduced

pressure and the resulting crude product was purified by flash col-

umn chromatography (silica gel, CH₂Cl₂Ǟ10% MeOH/

CH₂Cl₂ǞCH₂Cl₂/MeOH/NH₄OH, 18:6:1) to obtain a solid that

was dissolved in CHCl₃and filtered through a 0.45μ nylon filter.

The filtrate was then concentrated to obtain phytosphingosine (43;

25 mg, 57%) as a white solid. R_f= 0.52 (silica gel, CH₂Cl₂/MeOH/

NH₄OH, 18:6:1); m.p. 98–100 °C (ref.^[33c]99–101 °C). [α]²_D⁵= +8.2

Epoxy Amide 50: A 3.0 m aqueous solution of NaOH (0.27 mL,

0.81 mmol, 1.2 equiv.) followed by a solution of aldehyde 49

16

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Synthesis of Bioactive Compounds

(c = 0.2, C₅H₅N) [ref.^[33c]+8.0 (c = 0.8, C₅H₅N); ref.^[33d]+9.2 (c =

0.9, C₅H₅N)]. ¹H NMR (400 MHz, CD₃OD): δ = 0.92 (t, J =

7.1 Hz, 3 H), 1.29–1.39 (m, 24 H), 1.52–1.64 (m, 1 H), 1.71–1.82

0.62 (s, 9 H), 1.15 (d, J = 7.0 Hz, 3 H), 1.54 (s, 3 H), 1.61 (s, 3 H),

1.75–1.82 (m, 1 H), 2.03–2.12 (m, 1 H), 2.16 (s, 3 H), 2.42 (br. s, 1

H), 2.60 (br. s, 1 H), 3.21 (dq, J = 9.2, 7.2 Hz, 1 H), 3.82 (d, J =

(m, 1 H), 3.07 (ddd, J = 7.0, 5.2, 4.2 Hz, 1 H), 3.39 (dd, J = 8.0, 9.2 Hz, 1 H), 3.86 (ddd, J = 9.2, 4.5, 1.5 Hz, 1 H), 4.12 (ddd, J =

5.3 Hz, 1 H), 3.49–3.55 (m, 1 H), 3.61 (dd, J = 11.0, 7.0 Hz, 1 H), 11.0, 4.1, 2.5 Hz, 1 H), 4.32 (d, J = 9.2 Hz, 1 H), 7.25–7.13 (m, 5

3.81 (dd, J = 11.0, 4.1 Hz, 1 H) ppm. ¹³C NMR (100 MHz, H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –4.9, –4.6, 16.4, 18.0,

CD₃OD): δ = 14.5, 23.8, 26.7, 30.6, 30.78, 30.81, 31.1, 33.2, 34.8, 18.4, 22.7, 25.5, 26.4, 31.3, 34.2, 44.8, 56.3, 66.4, 76.3, 95.5, 126.5,

55.9, 64.2, 74.5, 76.6 ppm. HRMS (ESI-TOF): calcd. for

128.2, 128.6, 143.5, 168.7 ppm. HRMS (ESI-TOF): calcd. for

C₁₈H₃₉NO₃[M + H]⁺318.3008; found 318.3025.

C₂₄H₄₁NO₃SSi [M + Na]⁺474.2474; found 474.2469.

2-Methyl-3-tert-butyldimethylsilyloxy Amide 58: Yield 122 mg

(from 117 mg of 3g), 72% over two steps; colourless oil; R_f= 0.31

(silica gel, 10% EtOAc/hexanes). [α]²_D⁵= +11.6 (c = 2.3, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = –0.06 (s, 3 H), –0.02 (s, 3 H),

0.80 (s, 9 H), 0.84 (d, J = 7.0 Hz, 3 H), 0.90 (d, J = 7.0 Hz, 3 H),

0.98 (d, J = 6.8 Hz, 3 H), 1.49 (s, 3 H), 1.54 (s, 3 H), 1.71–1.76 (m,

1 H), 1.78 (dsept, J = 7.0, 1.5 Hz, 1 H), 1.94–2.02 (m, 1 H), 2.06

(s, 3 H), 2.36 (ddd, J = 13.0, 8.9, 6.9 Hz, 1 H), 2.52 (ddd, J = 13.0,

6.7, 5.8 Hz, 1 H), 2.67 (dq, J = 8.8, 6.9 Hz, 1 H), 3.74 (d, J =

9.1 Hz, 1 H), 3.79–3.83 (m, 2 H), 4.04 (ddd, J = 10.9, 4.5, 2.1 Hz,

1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –3.9, –3.7, 15.9, 16.1,

16.3, 18.2, 19.4, 24.2, 26.0, 26.3, 31.2, 31.3, 32.7, 44.1, 56.8, 66.6,

77.8, 94.8, 173.0 ppm. HRMS (ESI-TOF): calcd. for

C₂₁H₄₃NO₃SSi [M + Na]⁺440.2631; found 440.2635.

2-Hydroxy-3-phenylthio Amide 54: Thiophenol (78 μL, 0.73 mmol,

2.5 equiv.) and Yb(OTf)₃(54 mg, 0.09 mmol, 0.3 equiv.) were

added to a solution of epoxy amide 3c (102 mg, 0.29 mmol,

1.0 equiv.) in CH₂Cl₂(5 mL) at 0 °C. After stirring at this tempera-

ture for 2 d, the reaction mixture was diluted with Et₂O and the

resulting organic solution washed with a saturated aqueous solu-

tion of NaHCO₃. After separation of the two phases, the aqueous

layer was extracted with Et₂O (twice) and the combined organic

extracts were washed with brine, dried (MgSO₄) and filtered. Con-

centration under reduced pressure provided a crude product that

was purified by flash column chromatography (silica gel, 50%

EtOAc/hexanes) to afford sulfide 54 (94 mg, 77%) as a colourless

oil. R_f= 0.52 (silica gel, AcOEt). [α]²_D⁵= –118.0 (c = 1.0, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 1.67–1.73 (m, 2 H), 1.98 (s, 3

H), 2.42–2.48 (m, 1 H), 2.52–2.57 (m, 1 H), 3.33 (br. s, 1 H), 3.46

(dd, J = 11.5, 6.5 Hz, 1 H), 3.54 (dd, J = 11.5, 3.6 Hz, 1 H), 3.70

(s, 3 H), 3.92–3.95 (m, 1 H), 4.39 (d, J = 2.6 Hz, 1 H), 4.68 (d, J

= 2.6 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 2 H), 7.01 (d, J = 8.8 Hz, 1

H), 7.10–7.20 (m, 5 H), 7.34 (d, J = 8.5 Hz, 2 H) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 15.4, 29.6, 30.4, 51.0, 55.1, 56.2, 64.7, 75.9,

113.8, 126.9, 128.7, 129.4, 131.2, 131.5, 134.2, 158.9, 172.4 ppm.

HRMS (ESI-TOF): calcd. for C₂₁H₂₇NO₄S₂[M + Na]⁺444.1279;

found 444.1319.

2-Methyl-3-tert-butyldimethylsilyloxy Amide 59: Yield 227 mg

(from 217 mg of 3h), 75% over two steps; colourless oil; R_f= 0.37

(silica gel, 10% EtOAc/hexanes). [α]²_D⁵= +6.9 (c = 1.2, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = –0.08 (s, 3 H), –0.02 (s, 3 H),

0.79 (s, 9 H), 0.98 (d, J = 6.8 Hz, 3 H), 1.04–1.23 (m, 5 H), 1.38–

1.41 (m, 1 H), 1.48 (s, 3 H), 1.52 (s, 3 H), 1.55–1.73 (m, 6 H), 1.95–

2.02 (m, 1 H), 2.04 (s, 3 H), 2.33–2.42 (m, 1 H), 2.47–2.53 (m, 1

H), 2.69 (dq, J = 9.0, 6.9 Hz, 1 H), 3.73 (d, J = 9.0 Hz, 1 H), 3.74

(d, J = 9.0 Hz, 1 H), 3.79 (ddd, J = 9.0, 4.7, 1.2 Hz, 1 H), 4.01 (ddd,

J = 10.8, 4.5, 2.1 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= –3.82, –3.79, 15.8, 16.2, 18.2, 24.2, 26.1, 26.3, 26.7, 26.8, 26.9,

27.1, 29.7, 31.1, 32.7, 43.6, 56.8, 66.6, 77.8, 94.8, 173.1 ppm.

HRMS (ESI-TOF): calcd. for C₂₄H₄₇NO₃SSi [M + Na]⁺480.2944;

found 480.2956.

General Procedure for the Synthesis of 2-Methyl-3-tert-butyldi-

methylsilyloxy Amides 57–66: MeLi (1.6 m in Et₂O, 5.0 equiv.) was

added dropwise to a suspension of CuI (2.5 equiv.) in THF at 0 °C.

The resulting colourless solution of Me₂CuLi was added to a solu-

tion of the epoxy amide 3 (1.0 equiv.) in THF (0.1 m) at 0 °C. The

reaction mixture was stirred for 8 h at this temperature and

quenched by the careful addition of a saturated aqueous solution

of NH₄Cl, followed by dilution with Et₂O. After separation of the

two phases, the aqueous phase was extracted with Et₂O and the

combined organic layers were sequentially washed with a saturated

aqueous solution of NH₄Cl, water and brine. After treatment with

MgSO₄, the solvents were removed by reduced pressure to obtain

the crude 2-methyl 3-hydroxy amide, which was subjected to the

following step without purification. A solution of the hydroxy

amide (1.0 equiv.) in CH₂Cl₂(0.1 m) was treated with tert-butyldi-

methylsilyl trifluoromethanesulfonate (TBSOTf; 1.5 equiv.) at 0 °C

in the presence of 2,6-lutidine (2.0 equiv.). After 0.5 h at 0 °C, the

reaction mixture was quenched by the addition of MeOH followed

by the addition of a saturated aqueous solution of NH₄Cl and di-

lution with Et₂O. After separation of the two phases, the aqueous

phase was extracted with Et₂O (twice) and the combined organic

layers were washed with brine and dried with MgSO₄. After fil-

tration, the solvents were removed by reduced pressure to obtain

the crude product, which was purified by flash column chromatog-

raphy (silica gel, 10% EtOAc/hexanes) to afford the corresponding

silyl ether.

2-Methyl-3-tert-butyldimethylsilyloxy Amide 60: Yield 64.5 mg

(from 80 mg of 3i), 58% over two steps; yellow oil; R_f= 0.55 (silica

gel, 10% EtOAc/hexanes). [α]²_D⁵= +20.0 (c = 0.5, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = –0.08 (s, 3 H), –0.02 (s, 3 H), 0.85

(s, 9 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.51 (s, 3 H), 1.52 (s, 3 H), 1.55–

1.62 (m, 1 H), 1.77–1.87 (m, 1 H), 1.88 (br. s, 3 H), 1.98–2.05 (m,

1 H), 2.15–2.22 (m, 1 H), 2.46 (dq, J = 8.5, 6.8 Hz, 1 H), 2.70 (dd,

J = 14.8, 4.7 Hz, 1 H), 2.98 (dd, J = 14.8, 3.5 Hz, 1 H), 3.69 (d, J

= 9.0 Hz, 1 H), 3.69–3.72 (m, 1 H), 3.80 (ddd, J = 9.0, 4.8, 1.5 Hz,

1 H), 4.12 (ddd, J = 8.4, 4.5, 3.7 Hz, 1 H), 7.18–7.28 (m, 5 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = –5.0, –4.4, 14.4, 17.9, 23.7, 25.9,

26.3, 30.5, 39.3, 43.8, 56.9, 66.8, 74.3, 94.6, 126.1, 128.0, 130.0,

167.1 ppm. HRMS (ESI-TOF): calcd. for C₂₅H₄₃NO₃SSi [M +

Na]⁺488.2631; found 488.2628.

2-Methyl-3-tert-butyldimethylsilyloxy Amide 61: Yield 660 mg

(from 853 mg of 3w), 54% over two steps; colourless oil; R_f= 0.28

(silica gel, 10% EtOAc/hexanes). [α]²_D⁵= –0.9 (c = 0.9, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = –0.06 (s, 3 H), –0.02 (s, 3 H), 0.81

(s, 9 H), 0.85 (t, J = 7.0 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H), 1.15–

1.25 (m, 3 H), 1.41–1.49 (m, 3 H), 1.51 (s, 3 H), 1.52 (s, 3 H), 1.65–

1.72 (m, 1 H), 1.93–2.02 (m, 1 H), 2.06 (s, 3 H), 2.37 (ddd, J =

13.0, 8.9, 6.9 Hz, 1 H), 2.52 (ddd, J = 12.8, 7.0, 4.8 Hz, 1 H), 2.68

(dq, J = 8.8, 6.8 Hz, 1 H), 3.74 (d, J = 9.0 Hz, 1 H), 3.83 (ddd, J

= 9.0, 4.9, 1.6 Hz, 1 H), 3.93 (dt, J = 9.0, 3.4 Hz, 1 H), 4.09 (ddd,

J = 10.8, 4.7, 2.3 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

2-Methyl-3-tert-butyldimethylsilyloxy Amide 57: Yield 138 mg

(from 142 mg of 3a), 69% over two steps; colourless oil; R_f= 0.57

(silica gel, 10% EtOAc/hexanes). [α]²_D⁵= +12.5 (c = 3.0, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = –0.41 (s, 3 H), –0.19 (s, 3 H),

Eur. J. Org. Chem. 0000, 0–0

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F. Sarabia et al.

FULL PAPER

= –4.8, –4.1, 14.2, 14.9, 15.9, 17.9, 23.1, 23.7, 24.1, 25.9, 26.4, 31.1,

32.7, 33.2, 43.5, 56.5, 66.6, 73.8, 94.8, 172.8 ppm. HRMS (ESI-

TOF): calcd. for C₂₂H₄₅NO₃SSi [M + H]⁺432.2968; found

432.2975.

HRMS (ESI-TOF): calcd. for C₃₁H₆₃NO₃SSi [M + H]⁺558.4376;

found 558.4372.

2-Methyl-3-tert-butyldimethylsilyloxy Amide 66: Yield 162 mg

(from 225 mg of 3j), 56% over two steps; colourless oil; R_f= 0.60

(silica gel, 10% EtOAc/hexanes). [α]²_D⁵= –6.8 (c = 0.9, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = 0.00 (s, 3 H), 0.03 (s, 3 H), 0.85 (s,

9 H), 0.86 (t, J = 6.7 Hz, 3 H), 0.99 (d, J = 6.8 Hz, 3 H), 1.22–1.28

(m, 26 H), 1.51–1.54 (m, 2 H), 1.56 (s, 3 H), 1.58 (s, 3 H), 1.63–

1.82 (m, 1 H), 1.99–2.08 (m, 1 H), 2.12 (s, 3 H), 2.42 (ddd, J = 13.5,

8.9, 6.8 Hz, 1 H), 2.53–2.61 (m, 1 H), 2.74 (dq, J = 9.0, 6.8 Hz, 1

H), 3.79 (d, J = 9.0 Hz, 1 H), 3.88 (ddd, J = 9.0, 4.8, 1.5 Hz, 1 H),

3.99 (dt, J = 9.0, 3.2 Hz, 1 H), 4.15 (ddd, J = 10.7, 4.7, 2.1 Hz, 1

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –4.7, –4.1, 14.1, 14.9,

15.9, 17.9, 21.9, 22.7, 23.8, 25.9, 26.5, 29.3, 29.60, 29.65, 29.66,

29.68, 30.1, 31.2, 31.9, 33.1, 33.3, 43.6, 56.6, 66.6, 73.9, 94.8,

172.8 ppm. HRMS (ESI-TOF): calcd. for C₃₃H₆₇NO₃SSi [M +

H]⁺586.4689; found 586.4692.

2-Methyl-3-tert-butyldimethylsilyloxy Amide 62: Yield 3.70 g (from

3.40 g of 3x), 78% over two steps; colourless oil; R_f= 0.40 (silica

gel, 20% EtOAc/hexanes). [α]²_D⁵= –14.3 (c = 1.6, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = –0.05 (s, 3 H), –0.02 (s, 3 H), 0.80

(s, 3 H), 0.83 (t, J = 7.1 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H), 1.18–

1.23 (m, 12 H), 1.36–1.50 (m, 2 H), 1.51 (s, 3 H), 1.53 (s, 3 H),

1.62–1.72 (m, 1 H), 1.94–2.02 (m, 1 H), 2.07 (s, 3 H), 2.30–2.41 (m,

1 H), 2.48–2.57 (m, 1 H), 2.68 (dq, J = 13.7, 6.9 Hz, 1 H), 3.74 (d,

J = 9.1 Hz, 1 H), 3.84 (ddd, J = 9.0, 4.8, 1.5 Hz, 1 H), 3.94 (dt, J

= 9.0, 3.5 Hz, 1 H), 4.10 (ddd, J = 10.8, 4.8, 2.3 Hz, 1 H) ppm. ¹³

C

NMR (100 MHz, CDCl₃): δ = –4.9, –4.2, 13.9, 14.8, 17.8, 21.7,

22.5, 23.6, 25.8, 26.3, 29.6, 31.8, 32.9, 43.4, 56.4, 66.5, 73.7, 94.7,

172.6 ppm. HRMS (ESI-TOF): calcd. for C₂₄H₄₉NO₃SSi [M +

H]⁺460.3281; found 460.3308.

General Procedure for the Synthesis of 2-Methyl-3-tert-butyldi-

methylsilyloxy Amides 70–72: MeLi (1.6 m in Et₂O, 10.0 equiv.) was

added dropwise to a suspension of CuI (5.0 equiv.) in THF at 0 °C.

The resulting colourless solution of Me₂CuLi was added to a solu-

tion of epoxy amides 67–69 (1.0 equiv.) in THF (0.1 m) at 0 °C. The

reaction mixture was stirred for 8 h at this temperature and

quenched by the careful addition of a saturated aqueous solution

of NH₄Cl, followed by dilution with Et₂O. After separation of the

two phases, the aqueous phase was extracted with Et₂O and the

combined organic layers were sequentially washed with a saturated

aqueous solution of NH₄Cl, water and brine. After treatment with

MgSO₄, the solvents were removed under reduced pressure to ob-

tain crude 2-methyl 3-hydroxy amides, which were used in the fol-

lowing step without purification. A solution of the hydroxy amides

obtained from 68 and 69 (1.0 equiv.) in CH₂Cl₂(0.1 m) was treated

with tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf;

1.5 equiv.) at 0 °C in the presence of 2,6-lutidine (2.0 equiv.). After

0.5 h at 0 °C, the reaction mixture was quenched by the addition

of MeOH, followed by the addition of a saturated aqueous solution

of NH₄Cl and dilution with Et₂O. After separation of the two

phases, the aqueous phase was extracted with Et₂O (twice) and the

combined organic layers were washed with brine and dried with

MgSO₄. After filtration, the solvents were removed by reduced

pressure to obtain crude products, which were purified by flash

column chromatography (silica gel, 5 or 10% EtOAc/hexanes) to

afford the corresponding silyl ethers 71 and 72. For the synthesis

of 70, the silylation step was carried out with 3.0 equiv. of TBSOTf

and 4.0 equiv. of 2,6-lutidine to obtain bis-silyl ether 70 after purifi-

cation by flash column chromatography (silica gel, 5% EtOAc/hex-

anes).

2-Methyl-3-tert-butyldimethylsilyloxy Amide 63: Yield 450 mg

(from 351 mg of 3y), 94% over two steps; colourless oil; R_f= 0.28

(silica gel, 10% EtOAc/hexanes). [α]²_D⁵= –9.6 (c = 0.8, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = 0.04 (s, 3 H), 0.05 (s, 3 H), 0.86 (s,

9 H), 0.87 (t, J = 6.8 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.21–1.32

(m, 12 H), 1.42–1.53 (m, 2 H), 1.57 (s, 3 H), 1.58 (s, 3 H), 1.70–

1.78 (m, 1 H), 1.99–2.08 (m, 1 H), 2.12 (s, 3 H), 2.43 (ddd, J =

13.3, 9.0, 6.9 Hz, 1 H), 2.58 (ddd, J = 12.3, 6.8, 5.0 Hz, 1 H), 2.74

(dq, J = 8.9, 6.8 Hz, 1 H), 3.80 (d, J = 9.0 Hz, 1 H), 3.89 (ddd, J

= 9.0, 4.8, 1.3 Hz, 1 H), 3.99 (dt, J = 9.0, 3.3 Hz, 1 H), 4.16 (ddd,

J = 10.7, 4.6, 2.2 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= –4.7, –4.1, 14.1, 14.9, 15.9, 17.9, 21.9, 22.7, 23.8, 25.9, 26.5, 29.3,

29.7, 30.1, 31.2, 31.9, 33.1, 33.3, 43.6, 56.6, 66.7, 73.9, 94.8,

172.8 ppm. HRMS (ESI-TOF): calcd. for C₂₆H₅₃NO₃SSi [M +

H]⁺488.3594; found 488.3605.

2-Methyl-3-tert-butyldimethylsilyloxy Amide 64: Yield 822 mg

(from 860 mg of 3z), 72% over two steps; colourless oil; R_f= 0.32

(silica gel, 10% EtOAc/hexanes). [α]²_D⁵= –9.8 (c = 1.7, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = 0.01 (s, 3 H), 0.05 (s, 3 H), 0.87 (s,

9 H), 0.88 (t, J = 6.7 Hz, 3 H), 1.01 (d, J = 6.8 Hz, 3 H), 1.22–1.31

(m, 18 H), 1.48–1.55 (m, 2 H), 1.57 (s, 3 H), 1.59 (s, 3 H), 1.71–

1.78 (m, 1 H), 2.00–2.09 (m, 1 H), 2.13 (s, 3 H), 2.43 (ddd, J =

13.6, 9.0, 6.8 Hz, 1 H), 2.59 (ddd, J = 13.1, 7.1, 5.1 Hz, 1 H), 2.75

(dq, J = 9.1, 6.9 Hz, 1 H), 3.81 (d, J = 9.0 Hz, 1 H), 3.90 (ddd, J

= 9.0, 4.9, 1.7 Hz, 1 H), 4.00 (dt, J = 9.1, 3.5 Hz, 1 H), 4.16 (ddd,

J = 10.8, 4.7, 2.3 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= –4.7, –4.1, 14.1, 14.9, 15.9, 18.0, 21.9, 22.7, 23.8, 25.9, 26.5, 29.3,

29.62, 29.65, 29.67, 29.72, 30.1, 31.2, 31.9, 33.1, 33.3, 43.6, 56.6,

66.7, 73.9, 94.8, 172.8 ppm. HRMS (ESI-TOF): calcd. for

C₂₉H₅₉NO₃SSi [M + H]⁺530.4063; found 530.4065.

2-Methyl-3-tert-butyldimethylsilyloxy Amide 70: Yield 91.2 mg

(from 77.0 mg of 67), 67% over two steps; colourless oil; R_f= 0.65

(silica gel, 5% EtOAc/hexanes). [α]²_D⁵= –10.7 (c = 0.5, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = 0.00 (s, 3 H), 0.03 (s, 6 H), 0.04 (s,

3 H), 0.87 (s, 9 H), 0.90 (s, 9 H), 1.02 (d, J = 6.8 Hz, 3 H), 1.47–

2-Methyl-3-tert-butyldimethylsilyloxy Amide 65: Yield 426 mg

(from 628 mg of 3aЈ), 52% over two steps; colourless oil; R_f= 0.34

(silica gel, 10% EtOAc/hexanes). [α]²_D⁵= –8.0 (c = 0.9, CH₂Cl₂). ¹H

NMR (400 MHz, CDCl₃): δ = 0.01 (s, 3 H), 0.05 (s, 3 H), 0.86 (s, 1.52 (m, 4 H), 1.55 (s, 3 H), 1.57 (s, 3 H), 1.65–1.78 (m, 2 H), 1.99–

9 H), 0.88 (t, J = 6.7 Hz, 3 H), 1.01 (d, J = 6.8 Hz, 3 H), 1.24–1.28 2.11 (m, 2 H), 2.13 (s, 3 H), 2.43 (ddd, J = 13.6, 8.5, 7.1 Hz, 1 H),

(m, 22 H), 1.48–1.53 (m, 2 H), 1.58 (s, 3 H), 1.59 (s, 3 H), 1.68– 2.55 (ddd, J = 13.5, 8.1, 6.5 Hz, 1 H), 2.74 (dq, J = 8.7, 7.0 Hz, 1

1.79 (m, 1 H), 2.00–2.09 (m, 1 H), 2.13 (s, 3 H), 2.39–2.47 (m, 1 H), 3.61 (t, J = 7.2 Hz, 2 H), 3.82 (d, J = 9.1 Hz, 1 H), 3.90 (ddd,

H), 2.54–2.62 (m, 1 H), 2.75 (dq, J = 9.0, 6.8 Hz, 1 H), 3.81 (d, J J = 9.0, 4.7, 1.5 Hz, 1 H), 4.02 (dt, J = 9.0, 3.5 Hz, 1 H), 4.25 (ddd,

= 9.0 Hz, 1 H), 3.90 (ddd, J = 9.0, 4.9, 1.5 Hz, 1 H), 4.00 (dt, J =

J = 10.5, 4.8, 3.2 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

9.0, 3.4 Hz, 1 H), 4.16 (ddd, J = 10.7, 4.7, 2.3 Hz, 1 H) ppm. ¹³C = –4.8, –4.1, –3.8, 14.1, 15.1, 17.9, 18.1, 21.8, 25.7, 25.8, 25.9, 29.1,

NMR (100 MHz, CDCl₃): δ = –4.7, –4.1, 14.1, 14.9, 15.9, 18.0,

21.7, 22.7, 23.8, 25.9, 26.5, 29.4, 29.62, 29.65, 29.67, 29.69, 29.72,

30.1, 31.2, 31.9, 33.1, 33.3, 43.6, 56.6, 66.7, 73.9, 94.8, 172.8 ppm.

29.9, 31.5, 33.2, 33.3, 43.5, 56.8, 63.5, 67.1, 74.2, 94.9, 172.7 ppm.

HRMS (ESI-TOF): calcd. for C₂₈H₅₉NO₄SSi₂[M + H]⁺562.3782;

found 562.3772.

18

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Synthesis of Bioactive Compounds

2-Methyl-3-tert-butyldimethylsilyloxy Amide 71: Yield 245 mg

(from 270 mg of 68), 73% over two steps; colourless oil; R_f= 0.43

(silica gel, 10% EtOAc/hexanes). [α]²_D⁵= –7.4 (c = 0.5, CH₂Cl₂). ¹H

a solution of alcohol 74 (300 mg, 1.09 mmol, 1.0 equiv.) in CH₂Cl₂

(6 mL) was added at the same temperature. After stirring for

30 min at –78 °C, Et₃N (0.91 mL, 6.54 mmol, 6.0 equiv.) was added

NMR (400 MHz, CDCl₃): δ = –0.10 (s, 3 H), –0.06 (s, 3 H), 0.76 to the reaction mixture, which was allowed to warm to room tem-

(s, 9 H), 0.79 (d, J = 6.9 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H), 1.00 perature. Then the crude mixture was treated with a saturated aque-

(s, 9 H), 1.51 (s, 3 H), 1.53 (s, 3 H), 1.65–1.77 (m, 1 H), 1.79 (sept, ous solution of NH₄Cl and diluted with Et₂O. After separation of

J = 6.8 Hz, 1 H), 1.93–1.98 (m, 1 H), 2.02 (s, 3 H), 2.22–2.40 (m,

1 H), 2.45–2.63 (m, 1 H), 2.68 (dq, J = 9.0, 6.8 Hz, 1 H), 3.36 (dd,

J = 9.7, 7.4 Hz, 1 H), 3.54 (dd, J = 10.0, 7.5 Hz, 1 H), 3.72 (d, J

= 9.0 Hz, 1 H), 3.78 (d, J = 9.0, 4.6 Hz, 1 H), 3.97–4.00 (m, 1 H),

4.14 (d, J = 9.0 Hz, 1 H), 7.30–7.36 (m, 6 H), 7.58–7.61 (m, 4

H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –4.1, –4.0, 9.8, 16.1,

18.1, 19.1, 24.2, 25.2, 26.1, 26.2, 26.7, 26.8, 31.0, 32.6, 38.3, 44.1,

the two phases, the aqueous phase was extracted with Et₂O (twice)

and the combined organic layers were washed with brine and dried

with MgSO₄. After filtration, the solvents were removed by reduced

pressure to obtain the crude aldehyde 75, which was used in the

next step without further purification. Crude aldehyde 75 (100 mg,

0.36 mmol) was treated with sulfonium salt 1 (114 mg, 0.36 mmol,

1.0 equiv.) according to the procedure described above for the prep-

56.8, 66.5, 72.6, 94.8, 127.5, 127.7, 129.4, 133.7, 172.5 ppm. HRMS aration of epoxy amide 4m to obtain, after purification by flash

(ESI-TOF): calcd. for C₃₇H₆₁NO₄SSi₂[M + H]⁺672.3938; found column chromatography (silica gel, 20% EtOAc/hexanes), epoxy

672.3942.

amide 76 (73 mg, 42% over two steps from 74) as a colourless oil.

R_f= 0.42 (silica gel, 20% EtOAc/hexanes). [α]²_D⁵= +24.5 (c = 0.5,

2-Methyl-3-tert-butyldimethylsilyloxy Amide 72: Yield 140.5 mg

(from 145.0 mg of 69), 68% over two steps; colourless oil; R_f= 0.35

1

CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 0.07 (s, 3 H), 0.09 (s,

3 H), 0.88 (d, J = 7.0 Hz, 3 H), 0.89–0.92 (m, 12 H), 0.95 (d, J =

7.0 Hz, 3 H), 1.13–1.30 (m, 2 H), 1.33–1.42 (m, 2 H), 1.53 (s, 3 H),

1.63–1.69 (m, 1 H), 1.64 (s, 3 H), 1.80–1.89 (m, 2 H), 2.03–2.13 (m,

1 H), 2.12 (s, 3 H), 2.42–2.52 (m, 1 H), 2.56–2.63 (m, 1 H), 3.32

(dd, J = 5.3, 2.1 Hz, 1 H), 3.39 (d, J = 2.1 Hz, 1 H), 3.59 (dd, J =

5.7, 3.3 Hz, 1 H), 3.90 (dd, J = 9.2, 0.7 Hz, 1 H), 3.99 (dd, J = 9.2,

5.2, 1.5 Hz, 1 H), 4.29–4.33 (m, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = –4.3, 14.2, 15.4, 16.1, 17.6, 22.5, 24.9, 25.8, 26.2, 31.4,

34.7, 35.8, 37.6, 38.2, 53.9, 55.0, 59.8, 67.5, 82.2, 97.6, 168.8 ppm.

HRMS (FAB, NBA): calcd. for C₂₅H₄₉NO₄SSi [M + H]⁺488.3230;

found 488.3234.

(silica gel, 5% EtOAc/hexanes). [α]²_D⁵= +5.8 (c = 0.4, CH₂Cl₂). H

1

NMR (400 MHz, CDCl₃): δ = 0.01 (s, 3 H), 0.05 (s, 3 H), 0.85 (s,

9 H), 0.88–0.92 (m, 6 H), 1.08 (d, J = 6.8 Hz, 3 H), 1.16–1.31 (m,

2 H), 1.36–1.48 (m, 2 H), 1.57 (s, 3 H), 1.61 (s, 3 H), 1.62–1.68 (m,

1 H), 1.74–1.84 (m, 1 H), 1.99–2.06 (m, 1 H), 2.11 (s, 3 H), 2.45

(ddd, J = 13.7, 8.8, 7.5 Hz, 1 H), 2.58 (ddd, J = 13.6, 7.8, 6.5 Hz,

1 H), 2.78 (dq, J = 8.5, 7.0 Hz, 1 H), 3.81 (d, J = 9.1 Hz, 1 H),

3.88 (ddd, J = 9.0, 4.7, 1.5 Hz, 1 H), 3.94 (dd, J = 8.5, 3.1 Hz, 1

H), 4.12 (ddd, J = 8.7, 5.6, 3.5 Hz, 1 H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = –4.1, –4.0, 9.9, 15.1, 15.5, 15.9, 18.1, 22.8, 24.7, 25.6,

25.9, 26.1, 29.9, 31.2, 34.3, 56.8, 66.9, 74.1, 95.9, 172.5 ppm.

HRMS (ESI-TOF): calcd. for C₂₃H₄₇NO₃SSi [M + H]⁺446.3124; Epoxy Amide 78: Crude aldehyde 75 (105 mg, 0.39 mmol,

found 446.3118.

1.0 equiv.) was dissolved in CH₂Cl₂(5 mL), and N,N-dimethyl-2-

(dimethylsulfuranylidene)acetamide (77; 223 mg, 1.56 mmol,

4.0 equiv.) was added at room temperature. The reaction mixture

was stirred at room temperature until the reaction was complete as

judged by TLC (ca. 12 h). The solvents were removed by concentra-

tion under reduced pressure and the resulting crude product was

purified by flash column chromatography (silica gel, 50% AcOEt/

hexanes) to obtain epoxy amide 78 (95 mg, 68% over two steps

from 74) accompanied by its 2,3-diastereoisomer in a ratio of 9:1.

Alcohol 74: A freshly prepared solution of LDA [diisopropylamine

(1.24 mL, 8.34 mmol, 3.0 equiv.) was added to a solution of nBuLi

(1.6 m solution in hexanes, 5.21 mL, 8.34 mmol, 3.0 equiv.) in THF

(20 mL) at 0 °C] was treated with the borane–ammonia complex

(265 mg, 8.34 mmol, 3.0 equiv.) at 0 °C. After 15 min at this tem-

perature, the resulting suspension was stirred at room temperature

for an additional 30 min before cooling again to 0 °C. Then a solu-

tion of amide 72 (1.24 g, 2.78 mmol, 1.0 equiv.) in THF (15 mL)

was added. The reaction mixture was warmed to room temperature

and stirred overnight. After this time excess hydride was quenched

by the careful addition of MeOH at 0 °C and the crude mixture was

diluted with Et₂O and treated with a saturated aqueous solution of

NH₄Cl. The organic layer was separated and the aqueous phase

was extracted with Et₂O (twice). The combined organic solutions

were sequentially washed with water and brine, dried (MgSO₄), fil-

tered and concentrated under reduced pressure. The resulting crude

product was purified by flash column chromatography (silica gel,

5% EtOAc/hexanes) to obtain alcohol 74 (0.67 g, 88%) as a colour-

less oil. R_f= 0.35 (silica gel, 50% EtOAc/hexanes). [α]²_D⁵= –7.5 (c

= 0.6, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.09 (s, 3 H),

0.13 (s, 3 H), 0.90 (d, J = 6.7 Hz, 3 H), 0.92–0.94 (m, 12 H), 0.97

(d, J = 7.1 Hz, 3 H), 1.11–1.29 (m, 2 H), 1.35–1.49 (m, 2 H), 1.58–

1.69 (m, 1 H), 1.83–1.92 (m, 1 H), 2.27–2.40 (m, 1 H), 3.52 (dd, J

= 5.4, 4.0 Hz, 1 H), 3.60 (dd, J = 10.9, 6.0 Hz, 1 H), 3.65 (dd, J =

10.9, 4.4 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –4.1,

–4.0, 14.3, 15.2, 16.4, 20.8, 26.1, 35.3, 37.5, 38.1, 66.3, 81.2 ppm.

HRMS (FAB, NBA): calcd. for C₁₅H₃₄O₂Si [M + H]⁺275.2406;

found 275.2395.

1

78: Colourless oil; R_f= 0.38 (silica gel, 50% EtOAc/hexanes). H

NMR (400 MHz, CDCl₃): δ = –0.01 (s, 6 H), 0.90 (d, J = 6.7 Hz,

3 H), 0.80–0.86 (m, 12 H), 0.97 (d, J = 7.0 Hz, 3 H), 1.27–1.40 (m,

2 H), 1.51–1.65 (m, 2 H), 2.91 (s, 3 H), 3.10 (s, 3 H), 3.14 (dd, J =

6.8, 2.1 Hz, 1 H), 3.42 (d, J = 2.1 Hz, 1 H), 3.48 (dd, J = 5.0,

3.9 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = –4.1, 14.3,

14.6, 15.1, 18.3, 20.7, 26.0, 35.9, 37.6, 39.3, 53.5, 60.1, 78.4,

167.5 ppm. HRMS (FAB, NBA): calcd. for C₁₉H₃₉NO₃Si [M +

H]⁺358.2777; found 358.2785.

Epoxy Alcohol 79 from Epoxy Amide 76: A solution of epoxy amide

76 (72 mg, 0.148 mmol, 1.0 equiv.) in THF (5.0 mL) was treated

with lithium triethylborohydride (Super-H; 0.44 mL, 1 m in THF,

0.44 mmol, 3.0 equiv.) at 0 °C. The reaction mixture was stirred at

this temperature until the reaction was complete as judged by TLC

(ca. 0.5 h). The excess Super-H was carefully quenched by the ad-

dition of MeOH and the resulting solution was diluted with Et₂O

and washed with a saturated aqueous solution of NH₄Cl. The or-

ganic phase was separated, the aqueous layer was extracted with

Et₂O (twice) and the combined organic extracts were washed with

brine, dried (MgSO₄) and filtered. Concentration under reduced

pressure provided a crude product that was purified by flash col-

umn chromatography (silica gel, 20% EtOAc/hexanes) to afford ep-

Epoxy Amide 76: DMSO (0.31 mL, 4.38 mmol, 4.0 equiv.) was

added dropwise to

a solution of oxalyl chloride (0.28 mL,

2.19 mmol, 2.0 equiv.) in CH₂Cl₂(5 mL) at –78 °C. After 10 min, oxy alcohol 79 (43 mg, 91%) as a colourless oil. R_f= 0.45 (silica

Eur. J. Org. Chem. 0000, 0–0

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F. Sarabia et al.

FULL PAPER

gel, 20% EtOAc/hexanes). [α]²_D⁵= +9.5 (c = 0.5, CH₂Cl₂). ¹H NMR

(400 MHz, CDCl₃): δ = 0.06 (s, 3 H), 0.07 (s, 3 H), 0.87 (d, J =

6.9 Hz, 3 H), 0.82–0.95 (m, 15 H), 1.34–1.48 (m, 2 H), 1.57–1.64

(m, 2 H), 2.98–3.02 (m, 2 H), 3.52 (t, J = 4.2 Hz, 1 H), 3.58 (dd, J

= 12.6, 3.5 Hz, 1 H), 3.93 (dd, J = 12.6, 1.4 Hz, 1 H) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = –4.3, –4.2, 14.8, 15.1, 15.2, 18.1,

21.8, 26.9, 35.8, 38.2, 39.7, 58.4, 60.1, 62.4, 89.3 ppm. HRMS

(FAB, NBA): calcd. for C₁₇H₃₆O₃Si [M + H]⁺317.2512; found

317.2507.

A. Heras-López, M. S. Pino-González, J. Org. Chem. 1997, 62,

6056–6059; d) A. Heras-López, M. S. Pino-González, F. Sara-

bia-García, F. J. López-Herrera, J. Org. Chem. 1998, 63, 9630–

9634; e) F. Sarabia, L. Martín-Ortiz, F. J. López-Herrera, Org.

Lett. 2003, 5, 3927–3930; f) F. Sarabia, A. Sánchez-Ruiz, Tetra-

hedron Lett. 2005, 46, 1131–1135; g) F. Sarabia, A. Sánchez-

Ruiz, S. Chammaa, Bioorg. Med. Chem. 2005, 13, 1691–1705;

h) F. Sarabia, L. Martín-Ortiz, Tetrahedron 2005, 61, 11850–

11865; i) F. Sarabia, C. Vivar-García, C. García-Ruiz, L.

Martín-Ortiz, A. Romero-Carrasco, J. Org. Chem. 2012, 77,

1328–1339.

Epoxy Alcohol 79 from Epoxy Amide 78: Epoxy amide 78 (56 mg,

0.157 mmol) was treated with Super-H in THF according to the

same procedure described above. Purification by flash column

chromatography (silica gel, 20% EtOAc/hexanes) provided pure ep-

oxy alcohol 79 (46 mg, 92%), the physical and spectroscopic prop-

erties of which were identical to those obtained by using epoxy

amide 76.

[4]

[5]

A. K. Yudin (Ed.), Aziridines and Epoxides in Organic Synthe-

sis Wiley-VCH, Weinheim, Germany, 2006.

a) A. Gansäuer, C.-A. Fan, F. Keller, P. Karbaum, Chem. Eur.

J. 2007, 13, 8084–8090; b) C. Schneider, Synthesis 2006, 23,

3919–3944; c) M. Pineschi, Eur. J. Org. Chem. 2006, 4979–4988;

d) A. Riera, M. Moreno, Molecules 2010, 15, 1041–1073.

For reviews on 1,2-amino alcohols, see: a) S. C. Bergmeier, Tet-

rahedron 2000, 56, 2561–2576; b) F. Fache, E. Schulz, M. L.

Tommasino, M. Lemaire, Chem. Rev. 2000, 100, 2159–2231; c)

A. I. Meyers, J. Org. Chem. 2005, 70, 6137–6151; d) G.

Cardillo, C. Tomasini, Chem. Soc. Rev. 1996, 25, 117–128; e)

D. C. Cole, Tetrahedron 1994, 50, 9517–9582.

a) D. E. Ward, in: Modern Methods in Stereoselective Aldol Re-

actions (Ed.: R. Mahrwald), Wiley-VCH, Weinheim, Germany,

2013, p. 377–429; b) D. E. Ward, Chem. Commun. 2011, 47,

11375–11393; c) K. S. Yeung, I. Paterson, Chem. Rev. 2005,

105, 4237–4313.

a) F. Sarabia, F. Martín-Gálvez, S. Chammaa, L. Martín-Ortiz,

A. Sánchez-Ruiz, J. Org. Chem. 2010, 75, 5526–5532; b) F.

Martín-Gálvez, C. García-Ruiz, A. Sánchez-Ruiz, F. A. Valeri-

ote, F. Sarabia, ChemMedChem 2013, 8, 819–831; c) F. Sarabia,

F. Martín-Gálvez, C. García-Ruiz, A. Sánchez-Ruiz, C. Vivar-

García, J. Org. Chem. 2013, 78, 5239–5253.

[6]

Diol 80: Red-Al (0.08 mL, 3.2 m solution in toluene, 0.27 mmol,

2.2 equiv.) was added to a solution of epoxy alcohol 79 (39 mg,

0.123 mmol) in THF (2 mL) at 25 °C. After stirring for 18 h at this

temperature, AcOEt was added followed by a saturated aqueous

solution of Na⁺/K⁺tartrate. After separation of the two phases,

the aqueous layer was extracted with EtOAc (twice) and the or-

ganic extracts were washed with brine, dried (MgSO₄), filtered and

concentrated under reduced pressure. The crude product was puri-

fied by flash column chromatography (silica gel, 20% EtOAc/hex-

anes) to obtain diol 80 (37 mg, 96%) as a colourless oil. R_f= 0.38

(silica gel, 20% EtOAc/hexanes). [α]²_D⁵= +26.3 (c = 0.8, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 0.04 (s, 3 H), 0.06 (s, 3 H), 0.86

(d, J = 7.1 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.95 (s, 9 H), 1.15

(t, J = 6.4 Hz, 3 H), 1.21–1.40 (m, 2 H), 1.48–1.52 (m, 2 H), 1.58–

1.92 (m, 3 H), 3.57 (dd, J = 8.3, 3.7 Hz, 1 H), 3.85–3.96 (m, 2 H),

4.09 (dt, J = 10.9, 2.2 Hz, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = –4.3, –4.2, 13.3, 13.5, 14.8, 15.7, 16.1, 18.9, 21.7, 26.4, 35.4,

35.6, 36.8, 38.4, 39.0, 62.4, 72.1, 83.9 ppm. HRMS (FAB, NBA):

calcd. for C₁₇H₃₈O₃Si [M + H]⁺319.2668; found 319.2674.

[7]

[8]

[9]

F. Sarabia, S. Chammaa, C. García-Ruiz, J. Org. Chem. 2011,

76, 2132–2144.

[10]

For preliminary studies of reactions of glycidic amides with

amines, see: M. Valpuesta-Fernández, P. Durante-Lanes, F. J.

López-Herrera, Tetrahedron Lett. 1995, 36, 4681–4684.

a) J. Cardellach, J. Font, R. M. Ortuño, Tetrahedron Lett. 1985,

26, 2815–2816; b) C. Jaime, R. M. Ortuño, J. Font, J. Org.

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Supporting Information (see footnote on the first page of this arti-

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cle): H and ¹³C NMR spectra of all new compounds.

Acknowledgments

This work was financially supported by the Ministerio de Ciencia

e Innovación (MICINN) (ref. CTQ2010-16933) and Consejería de

Educación y Ciencia of Junta de Andalucía (FQM-03329). C. G.-

R. thanks the Ministerio de Educación y Ciencia for a predoctoral

fellowship. The authors thank Dr. J. I. Trujillo for assistance in the

preparation of this manuscript. The authors thank the Unidad de

Espectroscopía de Masas of the University of Granada and the

NMR facility of the University of Malaga for exact mass and

NMR spectroscopic assistance, respectively.

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Received: March 7, 2014

Published Online: ᭿

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F. Sarabia et al.

FULL PAPER

Chiral Glycidic Amides

F. Sarabia,* C. Vivar-García,

C. García-Ruiz, A. Sánchez-Ruiz,

M. Soledad Pino-González,

M. García-Castro,

S. Chammaa ................................... 1–22

The reactivity of chiral epoxy amides, ef-

ficiently prepared by a new asymmetric

epoxidation methodology, has been ex-

plored through their reactions with various

nucleophiles. The high regioselectivity and

complete stereoselectivity observed for

these ring-opening reactions were applied

to the synthesis of bioactive compounds.

Exploring the Reactivity of Chiral Glycidic

Amides for Their Applications in Synthesis

of Bioactive Compounds

Keywords: Synthetic methods / Nucleo-

philic substitution / Diastereoselectivity /

Sulfonium salts / Glycidic amides

22

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Eur. J. Org. Chem. 0000, 0–0

Article Doi

Exploring the reactivity of chiral glycidic amides for their applications in synthesis of bioactive compounds

DOI: 10.1002/ejoc.201402221

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201402221

Full text of DOI:10.1002/ejoc.201402221

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