Sulfinyl-Mediated Stereoselective Functionalization of Acyclic Conjugated Dienes

A Journal of

Accepted Article

Title: Sulfinyl-mediated stereoselective functionalization of acyclic

conjugated dienes.

Authors: Roberto Fernández de la Pradilla, Ignacio Colomer, Mercedes

Ureña, and Alma Viso

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To be cited as: Chem. Eur. J. 10.1002/chem.201905742

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Sulfinyl-mediated stereoselective functionalization of acyclic

conjugated dienes.

Ignacio Colomer, Mercedes Ureña, Alma Viso, and Roberto Fernández de la Pradilla*^[a]

Abstract: The chemo- and stereocontrolled functionalization of

conjugated sulfinyl dienes in a cascade process that involves a

conjugate addition, diastereoselective protonation and

a [2,3]-

sigmatropic rearrangement is reported. Enantioenriched 1,4-diol and

1,4-aminoalcohol derivatives are obtained in a very straightforward

manner. Further functionalization of these structures, including highly

stereoselective epoxidation, dihydroxylation and the stereodivergent

synthesis of several polyols in a controlled fashion is described.

Introduction

The chemo- and stereocontrolled functionalization of acyclic

molecules still remains a major challenge in synthetic organic

chemistry. Conjugated dienes have attracted the attention of

different groups and this has led to a variety of useful strategies

within this field.^[1]Readily available enantiopure sulfoxides are

also suitable precursors for acyclic stereocontrol,^[2]and the [2,3]-

sigmatropic rearrangement of allylic sulfoxides stands out as a

promising strategy to contribute in solving this problem.^[3]This

rearrangement, discovered independently by Mislow, Braverman

and Evans,^[4]allows for the transformation of allylic sulfoxides into

rearranged sulfenates that, in the presence of a thiophile, lead

irreversibly to allylic alcohols (Scheme 1a).

In connection with our interest in the development of

stereocontrolled methodologies using enantiopure sulfinyl

auxiliaries,^[5]and our interest in acyclic stereocontrol, we

considered that functionalized sulfinyl dienes A could undergo a

conjugate addition of an appropriate nucleophile,^[6]to generate

intermediate B (Scheme 1b). Subsequent protonation, either to

alkenyl sulfoxides B’ with ensuing isomerization, or to allylic

sulfoxides C, controlled by the preexisting contiguous chiral

center, would eventually trigger the highly selective [2,3]-

sigmatropic rearrangement to produce unsaturated 1,4-diol or

1,4-aminoalcohol derivatives D, after sulfenate cleavage by

excess nucleophile acting as thiophile.^[7]

Scheme 1. [2,3]-Sigmatropic rearrangement of allylic sulfoxides and proposed

cascade processes for the synthesis of 1,4-diol and 1,4-aminoalcohol

derivatives.

Existing approaches to prepare unsaturated 1,4-diols rely on

nucleophilic additions,^[9]reductions or metathesis,^[10]of

adequately

functionalized

precursors

and

suitable

transformations carried out on oxiranes,^[11]dienes and alkenes.^[12]

In contrast, the synthesis of the related 2-ene-1,4-aminoalcohol

derivatives is comparatively less well-developed involving Pd-

catalyzed allylic substitutions, alkylations of aminoaldehydes or

reductive cleavage of 1,2-oxazines obtained by [4+2]

cycloaddition.^[13]A recent report exemplifies the synthesis of

unsaturated 1,4-diols, 1,4-aminoalcohols and 1,4-diamines from

-thioaldehydes.^[14]

The 1,4-aminoalcohol and 1,4-diol are motifs found in a wide

range of natural and bioactive products, such as, halicholactone,

amphidinolide H and meglumine antimoniate, a treatment for

leishmaniasis (Figure 1).^[8]However, the development of new

methods to access these substructures has attracted much less

attention than the related 1,2-, 1,3-, or 1,5- compounds.

[a]

Dr. I. Colomer, Dr. M. Ureña, Dr. A. Viso, Prof. R. Fernández de la

Pradilla

Instituto de Química Orgánica General, CSIC. Juan de la Cierva 3,

28006 Madrid (Spain)

Figure 1. Natural and bioactive products containing the 1,4-diol substructure.

E-mail: rfpradilla@iqog.csic.es

Supporting information and the ORCID identification number(s) for

the author(s) of this article is available on the WWW under

We present herein a full account of the results of our study on the

stereoselective functionalization of acyclic sulfinyl 1,3-dienes to

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produce highly enantioenriched 1,4-diols and 1,4-aminoalcohols,

via [2,3]-sigmatropic rearrangement of an in-situ generated allylic

sulfoxide (Scheme 1).^[15]This transformation renders a net

chemo- and stereoselective 1,2-difunctionalization of the terminal

double bond in a sulfinyl 1,3-diene, along with removal of the

chiral auxiliary.

variety of dienyl sulfoxides 7a and 8a-f. On the other hand,

protection of diastereoisomeric alcohols 2 and 3 affords silyl

ethers 9 and 10, respectively, with very good yields, using the

appropriate silyl chloride or triflate and Et₃N.

Results and Discussion

Synthesis of starting materials: Enantiopure sulfinyl dienes 1a–

c were prepared as a mixture of Z/E isomers from the

corresponding menthyl sulfinate (Scheme 2).^[16]Lithiation of the

Z/E mixture of 1a–c at low-temperature took place with

concomitant isomerization to the E lithiated sulfinyl alkenes that

were trapped with the appropriate aldehydes to provide the

corresponding α-hydroxy sulfinyl dienes 2a–g and 3a–g in good

yields with low to moderate diastereoselectivity. A simple

chromatographic purification allowed for the separation of 2a–g

and 3a–g. Moreover, it is worth noting that the configuration of the

allylic center that supports the hydroxyl group has been

successfully inverted in many examples using Mitsunobu

conditions.^[17]

Scheme 3. Synthesis of α-amido and α-silyloxy dienyl sulfoxides.

Searching for optimal conditions: Our study started by

examining the reactivity of diastereomeric α-hydroxy dienes with

an aromatic allylic substituent, 2a (Table 1, entries 1-3) and 3a

(Table 1, entries 4-6), using different solvents (ethanol, toluene

and DMF). At this stage, we selected piperidine for its versatile

role as a good nucleophile to trigger the initial step, but also as an

excellent thiophile to promote sulfenate cleavage in the final stage.

In all cases we observed the expected 1,4-diol product in good to

excellent yields. Using the S isomer, 3a, an almost equimolecular

mixture of anti/syn 1,4-diols was obtained, regardless of the

solvent (Table 1, entries 4-6). In sharp contrast, the R isomer, 2a,

in toluene afforded a 90:10 ratio of diastereoisomers, with anti 11a

being the major one (Table 1, entry 2).

Scheme 2. Synthesis of α-hydroxy and α-sulfinamido dienyl sulfoxides.

Analogous α-amino sulfinyl dienes were prepared following a

similar strategy, in a process that involves lithiation of Z/E sulfinyl

diene 1a and trapping with the appropriate sulfinimine to obtain

sulfinamides 4a-c with high stereocontrol.^[18]Subsequent

deprotection (Scheme 3) affords amines 5a, 6a and 6b. Finally,

installing different protecting groups on nitrogen gives rise to a

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process in ethanol, leading to monoprotected anti 1,4-diol ent-13a

in 90:10 dr (Table 1, entry 10). Finally, to examine the influence

that the substitution on the sulfinyl group could have on the

stereoselection, 2-methoxynaphthylsulfinyl derivatives 2g and 3g

were prepared. Unfortunately, they did not improve the results

mentioned above (Table 1, entries 13-16).^[19]In summary, anti

1,4-diol 11 can be obtained in very high yield and stereoselectivity

from dienol 2 using toluene (Table 1, entry 2). Alternatively, the

monoprotected enantiomer ent-13 can be accessed by reacting

silyl ether 10 in ethanol (Table 1, entry 10).

Table 1. Screening of solvents and sulfinyl substitution.

It should be pointed out that, through these preliminary studies, at

short reaction times, small amounts of alkenyl sulfoxides of

general structure B’ (Scheme 1) were frequently isolated, leading

to 1,4-diol derivatives D under the reaction conditions.

Scope of the reaction: With these optimal conditions in hand, we

examined the scope of this new transformation. We first evaluated

the effect of substitution at the allylic carbon (R²) and at the

internal position of the diene (R¹) using the R isomer of -hydroxy

dienes 2 in toluene (Scheme 4). The transformation is compatible

with aromatic allylic substitution such as a phenyl ring for model

substrate (11a) and a 1-naphthyl moiety as well, although with

some loss of stereoselectivity (11b). Regarding aliphatic

substitution, both linear (11c, R²= Et) and branched aliphatic

chains (11d, R²= i-Pr) can be introduced with high yields and

moderate stereocontrol. Bulkier aliphatic substitution (11e, R²= t-

Bu) does not prevent the reaction but the stereoselectivity of the

process is severely reduced. Interestingly, diastereoisomeric

substrate 3e afforded the complementary anti 1,4-diol ent-11e

with remarkable selectivity.

Regarding internal substitution at the diene (R¹= Me), tertiary

alcohol 11f was obtained with excellent yield and stereoselectivity.

This result increases the utility of this method, considering the

challenging preparation of optically pure tertiary alcohols.

We then turned our attention to study the scope of the nucleophile

that triggers the cascade reaction by initial conjugate addition onto

the dienyl sulfoxide. Primary amines, such as benzylamine or

ethylamine, as well as functionalized secondary amines are well

tolerated, providing anti 1,4-diols 11g, 11h and 11i respectively in

very good yields with slightly diminished diastereoselectivity

(Scheme 4). The challenging use of p-toluenesulfonamide, with

reduced nucleophilicity, or aqueous ammonia allows to expand

the scope of the method, although the latter lacks the desired level

of stereoselectivity, probably due to the highly polar aqueous co-

solvent introduced (Scheme 4, 11j and 11k).

Major

Product

anti/syn dr^[a]

entry

SM (Ar, P)

Solvent

(yield %)^[b]

1

EtOH

toluene

DMF

11a

60:40 (89)

90:10 (97)

80:20 (72)

55:45 (90)

35:65 (78)

40:60 (90)

60:40 (88)

60:40 (93)

82:18 (91)

90:10 (92)^[c]

85:15 (92)

78:22 (92)

40:60 (89)

75:25 (90)

25:75 (95)

60:40 (92)

2

2a (p-Tol, H)

11a

3

11a

4

EtOH

toluene

DMF

ent-11a

ent-12a

13a

5

3a (p-Tol, H)

6

7

EtOH

toluene

DMF

8

9a (p-Tol, SiBu₃)

10a (p-Tol, SiBu₃)

13a

9

13a

10

11

12

13

14

15

16

EtOH

toluene

DMF

ent-13a

12a

EtOH

toluene

EtOH

toluene

2g (2-MeONaph, H)

3g (2-MeONaph, H)

11a

ent-12a

ent-11a

[a] Ratio determined by ¹H NMR analysis. [b] Combined yield. [c] Absolute

configuration at C-4 was determined by derivatization as (S)-MPA esters 15

and 16 (see Supporting Information for details).

To evaluate the effect that protecting the hydroxyl moiety could

have on the outcome of the reaction, silyl ethers 9a (Table 1,

entries 7-9) and 10a (Table 1, entries 10-12) were tested using

the same solvents. For the R isomer 9a, a low diastereoselectivity

(d.r. 60:40) was observed both in ethanol and toluene, while this

stereocontrol is increased up to 82:18 in DMF. Interestingly, the

S isomer, 10a, participated in a remarkably stereoselective

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Scheme 5. Scope for the synthesis of monoprotected anti 1,4-diols ent-13 from

silyloxy dienes 10. [a] Desilylation of ent-13a-c provides ent-11a-c in good

yields. [b] The absolute configuration was determined from the MPA esters 15

and 16. (see Supporting Information). [c] 3 equiv of DBU was added.

Scheme 4. Scope for the synthesis of anti 5-amino-1,4-diols 11 from dienols 2.

[a] THF was used as solvent. [b] DMF was used as solvent.

In an effort to extend this method to other nucleophiles, we

explored the use of alcohols as solvents and as the nucleophilic

initiators of the cascade process under basic conditions. The

treatment of diastereomers 2a and 3a in MeOH with the addition

of inorganic bases (K₂CO₃or Cs₂CO₃) produced the expected 1,4-

diols 11 and 12, however with no diastereocontrol (Scheme 6a).

Inspired by the results presented above, where silyloxy dienes 10

in EtOH gave the best results with amines (Scheme 5), we

examined the reaction of silyl ethers 9a and 10a under identical

conditions. Although the reactions worked nicely, unfortunately

we obtained, an equimolecular mixture of diastereoisomers of the

same 1,4-diols, presumably as a result of initial deprotection of

the silyl ether to generate alcohols 2a and 3a and subsequent

cascade reaction (Scheme 6b). Exploring different organic or

inorganic bases did not overcome this problem (Triton B, NaOMe,

DABCO, etc.). However, the use of a more robust protecting

group 9b (TIPS) avoids the undesired deprotection, and the

monoprotected anti 1,4-diol 13k is obtained in good yield with

improved stereocontrol (Scheme 6c).

Turning our attention to the S isomer of silyloxy dienes 10, and

carrying out the reaction in ethanol, both aromatic and aliphatic

groups at the allylic position are well tolerated (Scheme 5).

Besides the model substrate with a phenyl ring (Scheme 5, ent-

13a), the 1-naphthyl derivative shows an extremely high

stereocontrol (Scheme 5, ent-13b). Aliphatic substitution brings

about a significant erosion of the diastereomeric ratio (Scheme 5,

ent-13c). Nevertheless, this problem can be overcome by using

a

more hindered silyl-protecting group, increasing the

diastereoselectivity from 75:25 up to 90:10 ratio (Scheme 5, ent-

13c vs ent-13f and ent-13g). Similarly, the size of the silyloxy

group leads to higher diastereoselectivity (95:5) for aromatic

substituted substrates (Scheme 5, ent-13a vs ent-13e). As a

remarkable example, enantiopure tertiary alcohol ent-13d can be

obtained in good yield and selectivity.

Finally using benzylamine and p-toluenesulfonamide, either with

aromatic or aliphatic derivatives, smoothly led to the desired

silyloxy amino alcohols in high yield and stereoselectivity

(Scheme 5 ent-13h, ent-13i and ent-13j).

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Table 2. Screening of solvents and nucleophiles for the synthesis of 1,4-

aminoalcohols.

Major

Product

anti/syn dr

(yield %)^{[a], [b]}

entry

SM

NuH

Solvent

1

2

3

4

5

6

7a

8a

7a

8a

7a

8a

17a

83:17 (70) ^[c]

70:30 (79)

64:36 (85)

60:40 (88)

78:22 (73)

43:57 (94)

toluene

ent-17a

17a

Piperidine

EtOH

ent-17a

17b

BnNH₂

ent-18b

[a] Ratio determined by ¹H NMR analysis. [b] Combined yield. [c]

Absolute configuration at C-4 was determined by derivatization with (S)-

MPA to 15 and 16 (see Supporting Information).

Scheme 6. Scope for the synthesis of 5-methoxy 1,4-diols 11-14 from dienols

2-3 and silyloxy dienes 9-10.

Turning our attention to the use of methanol under basic

conditions, as a model of oxygen-based nucleophiles, and using

aminodiene 7a we observed an enriched mixture of the expected

anti 1,4-aminoalcohol 17c (Scheme 7a). However, when reacting

its diastereoisomer 8a, syn 1,4-aminoalcohol ent-18c was

unexpectedly obtained with a remarkably reinforcing effect

(judged by the high 13:87 dr vs. 65:35 for 17c). Having

established the viability of this new method to achieve the

synthesis of 1,4-aminoalcohols, we examined the effect that the

protecting group on nitrogen could have on the outcome of the

reaction (Scheme 7b). Modifying the N-Ts protecting group and

using other sulfonamides ent-18f-h, sulfinamide ent-18d,

carbamate ent-18i or the free amine ent-18e do not improve the

diastereoselectivity of the process. Finally keeping the N-Ts

protecting group we evaluated aliphatic substitution at the allylic

position with similar results to the aromatic one (Scheme 7b, ent-

18j).

While we have shown that it is possible to access a wide number

of 1,4-diols starting from readily available α-hydroxy sulfinyl

dienes, we thought that this method could be even more general

and powerful by installing different functional groups at the allylic

position. For example, from the related α-amino sulfinyl dienes we

could access the challenging and much less explored 1,4-

aminoalcohol motif. Thus, we performed a quick screening of

solvents and nucleophiles on both diastereoisomers of N-tosyl

aminodienes (7a and 8a). The reaction with piperidine as

nucleophile, for both isomers, led to the anti 1,4-aminoalcohols

(17 and ent-17 respectively) as the major products in high yields

with moderate to good diastereocontrol (Table 2, entries 1-4). The

reactions in toluene showed better selectivities than those in

ethanol (Table 2, entries 1-2 vs entries 3-4), with a clear

reinforcing effect for the R isomer, 7a, compared to the S isomer,

8a (Table 2, entry 1 vs 2). This effect becomes more pronounced

when using BnNH₂as nucleophile in EtOH (Table 2, entries 5-6).

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sulfoxide-sulfenate rearrangement to give anti ent-13 with high

diastereoselectivity (Scheme 9).

Scheme 8. Stereochemical outcome for the synthesis of 1,4-diols 11.

Scheme 7. Scope for the synthesis of 5-methoxy syn 1,4-aminoalcohols ent-18

from aminodienes 8. [a] The absolute configuration at C4 was determined by

derivatization with (S)- or (R)-MPA to afford 15 and 16. [b] Mono- and bis-

acetylation of ent-18c yielded 19 and 19’ used for structural elucidation (see

Supporting Information).

Stereochemical outcome: Our proposal to account for the

stereochemical outcome of the process for the synthesis of anti

1,4-diols 11 and anti 1,4-aminoalcohols 17 starting from (R)

dienes (2 or 7a respectively), is shown in Scheme 8. In toluene,

an intramolecular hydrogen bond between the sulfoxide and the

OH/NHTs group would determine the major chair-like six-

membered conformation for the allylic sulfoxides generated from

2/7, resulting in conformer (1R,2S)-I being more favored than

(1R,2R)-II. Subsequent sigmatropic rearrangement would lead

predominantly to anti 1,4-diols 11, or anti-1,4-aminoalcohol

17c.^[20]

Our rationalization for the results obtained from silyl ethers 10 is

shown in scheme 9. In ethanol, gauche interactions between the

groups on the C1-C2 bond would be responsible for the relative

stability of silylated allylic sulfoxides (1S,2R)-III vs. (1S,2S)-IV. In

addition, the strain is minimized in reactive conformer (1S,2R)-III,

by eclipsing H₃and H₁and the position of the sulfur p-tolyl group

leads to a more favored endo approach for the subsequent

Scheme 9. Stereochemical outcome for the synthesis of 1,4-silyloxyalcohols

ent-13.

Finally, the syn selective synthesis of 1,4-aminoalcohols ent-18

from (S) amino dienes 8 in MeOH with K₂CO₃could be

understood by considering the acidity of the sulfonamide proton,

and the ability to form a chelated transition state, involving the

sulfoxide, the nitrogen and the cation (K⁺). While amino diene 7a

would represent the non-reinforcing isomer, following the

outcome in Scheme 8, leading to anti 1,4-aminoalcohol 17c,

diastereomeric aminodiene 8 is the reinforcing isomer. The major

chair-like six-membered conformation for the allylic sulfoxides

generated from 8, results in conformer (1R,2S)-V to be more

favored than (1R,2R)-VI (Scheme 10). Subsequent sigmatropic

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rearrangement would lead predominantly to syn 1,4-aminoalcohol

ent-18.

Scheme 10. Stereochemical outcome for the synthesis of 1,4-aminoalcohols

ent-18.

Scheme 11. Protection of anti 1,4-diols ent-13 and highly stereoselective

epoxidation. Method A: Boc₂O, DIPEA, MeCN. Method B: Fmoc-Cl, Et₃N,

CH₂Cl₂. Method C: TsCl, Et₃N, THF. [a] Minor diastereoisomer 20’ was also

isolated. [b] To support structural elucidation, 20a was acetylated and

desilylated to render 23a and 24 (see Supporting Information). [c] ent-13j was

used as starting material.

Reactivity of 1,4-diols: To take advantage of these valuable

densely functionalized structures we decided to explore the

reactivity of the double bond in two fundamental processes in

organic chemistry such as epoxidation and dihydroxylation. We

selected monoprotected anti 1,4-diols ent-13h and ent-13i (with

aromatic and aliphatic allylic substitution, respectively) as

representative examples. We first explored the viability of

protecting the amine as carbamate (20a, 20b and 20d) or

sulfonamide (20c) under standard conditions (Scheme 11). The

epoxidation was examined next and the treatment of 20a, 20c and

20d (with aromatic allylic substitution) with m-CPBA afforded

epoxides 21a, 21c and 21d with high stereocontrol (dr 92:8) and

excellent yields (Scheme 11). Epoxidation of N-Boc carbamate

20b and N-Ts monoprotected 1,4-diol ent-13j under the same

conditions gave epoxides 21b and 21e in good yields, as single

detectable diastereoisomers.^[21]

Encouraged by the synthetic potential of these highly

functionalized epoxy diol derivatives 21, we examined further

stereoselective modifications at the epoxide and amino moieties.

Thus, treatment of 21a, 21b and desilylated 25 with TFA and then

with base provided 1,3-oxazin-2-ones 26a,b regio- and

stereoselectively, via a nucleophilic attack of the carbamate

oxygen onto the epoxide (Scheme 12).^[22]Acetylation of 26a

under standard conditions gave peracetylated compound 30 that

was useful to assign the relative stereochemistry. Alternative

treatment of 21c with Mg (powder) in MeOH resulted in silyl ether

deprotection followed by regio- and stereoselective epoxide

opening, presumably by Mg(OMe)₂formed in situ, via a chelated

intermediate, to afford monoprotected polyol 27 (Scheme 12).

Finally, deprotection of the Fmoc derivative 21d under standard

conditions with piperidine in THF gave amine 28 in good yields.

In sharp contrast, the use of piperidine in CH₂Cl₂, unexpectedly,

led to oxazolidine 29, in excellent yield with incorporation of the

methylene unit from the solvent under mild conditions.^[23]

Scheme 12. Reactivity of 2,3-epoxy 1,4-diol derivatives.

Alternatively, the dihydroxylation of 20a, for which

a

nonreinforcing array of allylic oxygenated stereocenters was

initially expected, under standard conditions, gave triol 31 with

excellent yield and very high diastereoselectivity (31:32, 94:6,

Scheme 13).^[24]This selectivity in the dihydroxylation of an acyclic

substrate is remarkable particularly compared with the analogous

dihydroxylation of 1,4-diol 20e (prepared by deprotection of 20a)

that affords 33 and 34 as a 50:50 mixture of diastereoisomers

(Scheme 13). A reasonable explanation for this result, based on

steric effects, could be found in a zig-zag arrangement of the

carbon chain, where the bulky silyl group would be in the same

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plane of the chain. In that scenario, OsO₄would approach from

the opposite face of the hydroxy group at C-4, in an anti fashion.

In order to confirm the configuration of the new stereocenters

cyclic 1,3-dioxolane 37 was synthesized and a detailed NMR

study was performed,^[25]in which the coupling constant (J_1,2= 8.9

Hz) revealed a trans configuration at C1-C2.^[26]It is important to

Experimental Section

General procedure for the synthesis of 5-amino-1,4-diols.

To a solution of 1.0 equiv of α-hydroxy sulfinyl diene in toluene, ethanol or

DMF, 5.0 equiv of amine (NuH) were added. The mixture was stirred at 70

ºC and monitored by TLC until completion. Then, the solvent was

evaporated under reduced pressure to give the corresponding alcohol that

was purified by chromatography on silica gel using the appropriate mixture

of eluents.

emphasize that 31 presents

a

complementary relative

stereochemistry to that of 27 (Scheme 12). This stereodivergency

is a noteworthy accomplishment of our methodology.

Synthesis of (–)-(1S,2E,4R)-1-Phenyl-5-(piperidin-1-yl)pent-2-ene-1,4-

diol, 11a, and (1S,2E,4S)-1-Phenyl-5-(piperidin-1-yl)pent-2-ene-1,4-

diol, 12a.

From α-hydroxy sulfinyl diene 2a (45 mg, 0.15 mmol, 1.0 equiv) and

piperidine (75 μL, 64 mg, 0.75 mmol, 5.0 equiv), in toluene, according to

the general procedure (2 d) and after chromatographic purification (CH₂Cl₂

 50% EtOH-CH₂Cl₂), a 90:10 mixture of alcohols 11a:12a was obtained

as a yellow oil (37 mg, 97%). Data for 11a (from the mixture): R_f0.20 (50%

EtOH-CH₂Cl₂). []²⁰_D–13.3 (c = 0.50). ¹H NMR (CDCl₃, 500 MHz)  1.38-

1.44 (m, 2 H, CH₂piperidine), 1.49-1.60 (m, 4 H, 2 x CH₂piperidine), 2.23-

2.32 (m, 3 H, H-5a + CH₂piperidine), 2.34 (dd, 1 H, J = 12.4, 3.7 Hz, H-

5b), 2.57 (br s, 2 H, CH₂piperidine), 4.15-4.18 (m, 1 H, H-4), 5.19 (d, 1 H,

J = 6.1 Hz, H-1), 5.70 (ddd, 1 H, J = 15.5, 6.0, 1.2 Hz, H-3), 5.95 (ddd, 1

H, J = 15.4, 6.1, 1.2 Hz, H-2), 7.23-7.26 (m, 1 H, Ph), 7.30-7.35 (m, 4 H,

Ph). ¹³C NMR (CDCl₃, 125 MHz)  24.2 (CH₂piperidine), 26.0 (2 x CH₂

piperidine), 54.4 (2 x CH₂piperidine), 64.3 (C-5), 66.6 (C-4), 74.3 (C-1),

126.30 (2 x Ph), 127.6 (Ph), 128.46 (2 x Ph), 131.3 (C-3), 133.7 (C-2),

142.7 (Ph). IR (film): 3391, 2938, 1639, 1562, 1493, 1452, 1413, 1267,

1034, 973, 758, 736, 701 cm^1. HRMS (ES) m/z calcd for C₁₆H₂₄NO₂

[M+H]⁺262.1807, found 262.1804. Partial data for 12a (from the mixture):

R_f0.20 (50% EtOH-CH₂Cl₂). The NMR signals overlapped with those of

11a, except for ¹H NMR (CDCl₃, 500 MHz)  5.67 (ddd, 1 H, J = 15.5, 6.0,

1.2 Hz, H-3), 5.94 (ddd, 1 H, J = 15.4, 6.1, 1.2 Hz, H-2). ¹³C NMR (CDCl₃,

125 MHz)  64.27 (C-5), 66.7 (C-4), 74.4 (C-1), 127.57 (Ph), 128.4 (2 x

Ph), 133.9 (C-2).

Scheme 13. Highly stereoselective dihydroxylation of 1,4-diol derivatives.

Finally, acetylation of triol 31 gave peracetylated compound 35

that, under acidic conditions seeking concurrent N-Boc cleavage

and silyl deprotection, interestingly, gave rise to mono

unprotected polyol 36, by selective silyl ether deprotection and an

unexpected complete acetyl migration from C3 to C1.

It is worth emphasizing the importance of these methodologies

that allow for the full functionalization of dienes 10 in a very short

and straightforward sequence (2-3 steps) and in a highly

stereoselective manner (4 new C-heteroatom bonds and 3

stereogenic centers).^[27]

General procedure for the synthesis of 5-amino-1-silyloxy-4-alcohols.

To a solution of 1.0 equiv of α-silyloxy sulfinyl diene in ethanol, toluene or

DMF, 5.0 equiv of amine (NuH) was added. The mixture was stirred at 70

ºC and monitored by TLC until completion. Then, the solvent was

evaporated under reduced pressure to give the corresponding alcohol, that

was purified by chromatography on silica gel using the appropriate mixture

of eluents.

Conclusions

In summary, a new general method for the synthesis of 1,4-diols

and 1,4-aminoalcohols from conjugated sulfinyl dienes has been

reported. This is the result of a cascade reaction encompassing a

conjugate addition followed by diastereoselective protonation to

an allylic sulfoxide and a [2,3]-sigmatropic rearrangement. The

process has been studied in depth and the advantages and

limitations for a numerous collection of compounds covering a

wide structural scope have been defined. This process is

compatible with both aliphatic and aromatic substitution in the

diene moiety, and both oxygen- and nitrogen-based nucleophiles

are competent initiators of the sequence. Furthermore, the

reactivity of the resulting unsaturated 1,4-diols towards

epoxidation and dihydroxylation has been explored with excellent

results.

Synthesis

of

(+)-(2S,3E,5R)-5-Phenyl-1-(piperidin-1-yl)-5-

(tributylsilyloxy)pent-3-en-2-ol, ent-13a, and (2R,3E,5R)-5-Phenyl-1-

(piperidin-1-yl)-5-(tributylsilyloxy)pent-3-en-2-ol, ent-14a.

From α-silyloxy sulfinyl diene 10a (40 mg, 0.09 mmol, 1.0 equiv) and

piperidine (45 μL, 38 mg, 0.45 mmol, 3.0 equiv), in ethanol, according to

the general procedure (5 d) and after chromatographic purification (CH₂Cl₂

 10% EtOH-CH₂Cl₂), a 90:10 mixture of alcohols ent-13a:ent-14a was

obtained as a colorless oil (29 mg, 92%). Data for ent-13a (from the

mixture): R_f0.29 (5% EtOH-CH₂Cl₂). []²⁰+22.6 (c = 0.27). ¹H NMR

D

(CDCl₃, 500 MHz)  0.51-0.58 (m, 6 H, 3 x CH₂n-Bu), 0.82 (t, 9 H, J = 6.8

Hz, 3 x CH₃n-Bu), 1.19-1.28 (m, 12 H, 6 x CH₂n-Bu), 1.39-1.45 (m, 2 H,

CH₂piperidine), 1.51-1.62 (m, 4 H, 2 x CH₂piperidine), 2.25-2.35 (m, 4 H,

CH₂piperidine + H-1), 2.59 (m, 2 H, CH₂piperidine), 4.15 (m, 1 H, H-2),

5.13 (d, 1 H, J = 6.1 Hz H-5), 5.61 (ddd, 1 H, J = 15.3, 6.1, 1.1 Hz, H-3),

5.81 (ddd, 1 H, J = 15.4, 6.1, 1.0 Hz, H-4), 7.18-7.21 (m, 1 H, Ph), 7.26-

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7.31 (m, 4 H, Ph). ¹³C NMR (CDCl₃, 125 MHz)  13.7 (3 x CH₂n-Bu), 13.8

(3 x CH₃n-Bu), 24.1 (CH₂piperidine), 25.4 (3 x CH₂n-Bu), 25.9 (2 x CH₂

piperidine), 26.6 (3 x CH₂n-Bu), 54.5 (2 x CH₂piperidine), 64.4 (C-1), 66.7

(C-2), 74.8 (C-5), 126.1 (2 x Ph), 127.0 (Ph), 128.1 (2 x Ph), 129.7 (C-3),

135.2 (C-4), 143.8 (Ph). IR (film): 3420, 2958, 2925, 2856, 2802, 1670,

1492, 1454, 1407, 1377, 1261, 1190, 1080, 1026, 963, 887, 797, 698

cm^1. MS (ES) m/z 460 [M+H]⁺(100%). Partial data for ent-14a (from the

mixture): R_f0.29 (5% EtOH-CH₂Cl₂). The NMR signals overlapped with

those of ent-13a, except for ¹H NMR (CDCl₃, 500 MHz)  5.59 (ddd, 1 H,

From sulfonamide 8a (40 mg, 0.09 mmol, 1.0 equiv) and Cs₂CO₃(87 mg,

0.27 mmol, 3.0 equiv), according to the general procedure (5 d) and after

chromatographic purification (30  80% EtOAc-CH₂Cl₂), a 22:78 mixture

of alcohols ent-17c:ent-18c was obtained as a colorless oil (28 mg, 88%).

Further crystallization (1:2 EtOAc-hexane) of the fraction yielded a

diastereomerically enriched mixture of alcohols (13:87). Data for ent-18c

(from the mixture): R_f0.17 (30% EtOAc-CH₂Cl₂). []²⁰_D+24.6 (c = 0.39).

¹H NMR (CDCl₃, 500 MHz)  1.62 (br s, 1 H, OH), 2.38 (s, 3 H, Me p-Tol),

3.09 (dd, 1 H, J = 9.5, 8.1 Hz, H-5a), 3.28 (dd, 1 H, J = 9.5, 3.3 Hz, H-5b),

3.34 (s, 3 H, OMe), 4.19-4.22 (m, 1 H, H-4), 4.81 (d, 1 H, J = 7.0 Hz, NH),

4.93 (ap t, 1 H, J = 6.5 Hz, H-1), 5.51 (ddd, 1 H, J = 15.4, 5.6, 1.5 Hz, H-

3), 5.81 (ddd, 1 H, J = 15.4, 6.1, 1.5 Hz, H-2), 7.03-7.10 (m, 2 H, Ar), 7.18-

7.22 (m, 5 H, Ar), 7.61 (dt, 2 H, J = 8.3, 1.7 Hz, Ar). ¹³C NMR (CDCl₃, 75

MHz)  21.5 (Me p-Tol), 58.9 (C-1), 59.0 (OMe), 70.2 (C-4), 76.1 (C-5),

127.0 (2 x Ar), 127.2 (2 x Ar), 127.8 (Ar), 128.7 (2 x Ar), 129.4 (2 x Ar),

130.9 (C-3), 131.2 (C-2), 137.7 (Ar), 139.4 (Ar), 143.2 (Ar). IR (film): 3272,

2925, 1598, 1453, 1326, 1158, 1092, 969, 814, 752 cm^1. MS (ES) m/z

384 [M+Na]⁺(100%). Partial data for ent-18c (from the mixture): R_f0.17

(30% EtOAc-CH₂Cl₂). The NMR signals overlapped with those of ent-17c,

except for ¹H NMR (CDCl₃, 500 MHz)  5.48 (ddd, 1 H, J = 15.4, 5.6, 1.5

Hz, H-3).

J = 15.3, 6.1, 1.1 Hz, H-3), 5.83 (ddd, 1 H, J = 15.4, 6.1, 1.0 Hz, H-4). ¹³

NMR (CDCl₃, 125 MHz)  126.2 (2 x Ph), 129.5 (C-3).

C

General procedure for the synthesis of 5-amino-1,4-aminoalcohols.

To a solution of 1.0 equiv of dienyl sulfonamide in toluene or ethanol, 5.0

equiv of amine (NuH) was added. The mixture was stirred at 70 ºC and

monitored by TLC until completion. Then, the solvent was evaporated

under reduced pressure to give the corresponding alcohol that was purified

by chromatography on silica gel using the appropriate mixture of eluents.

Synthesis of (–)-N-[(1S,2E,4R)-4-Hydroxy-1-phenyl-5-(piperidin-1-

yl)pent-2-en-1-yl]-p-tolylsulfonamide, 17a, and N-[(1S,2E,4S)-4-

Hydroxy-1-phenyl-5-(piperidin-1-yl)pent-2-en-1-yl]-p-

tolylsulfonamide, 18a.

General procedure for Boc protection of amines.

To a cold solution (0 ºC) of the starting material in CH₃CN (10 mL/mmol)

was added DIPEA (1.5 equiv) and Boc₂O (1.2 equiv). The mixture was

allowed to warm up to rt and monitored by TLC, until completion (1 h). The

crude was concentrated, and then was purified by column chromatography

on silica gel using a gradient of the appropriate solvents.

From sulfonamide 7a (34 mg, 0.075 mmol, 1.0 equiv) and piperidine (37

μL, 32 mg, 0.38 mmol, 5.0 equiv), in toluene, according to the general

procedure (2 d) and after chromatographic purification (CH₂Cl₂ 20%

EtOH-CH₂Cl₂), an 83:17 mixture of alcohols 17a:18a was obtained as a

yellow oil (22 mg, 70%). Data for 17a (from the mixture): R_f0.14 (20%

EtOH-CH₂Cl₂). []²⁰_D–16.2 (c = 1.79). ¹H NMR (CDCl₃, 500 MHz)  1.41

(m, 2 H, CH₂piperidine), 1.49-1.58 (m, 4 H, 2 x CH₂piperidine), 2.04 (ap

t, 1 H, J = 11.4 Hz, H-5a), 2.14 (dd, 1 H, J = 12.4, 3.7 Hz, H-5b), 2.26 (m,

2 H, CH₂piperidine), 2.37 (s, 3 H, CH₃p-Tol), 2.53 (m, 2 H, CH₂piperidine),

4.02 (m, 1 H, H-4), 4.91 (d, 1 H, J = 6.5 Hz, H-1), 5.38 (dd, 1 H, J = 15.4,

5.6 Hz, H-3), 5.76 (dd, 1 H, J = 15.4, 5.5 Hz, H-2), 7.08-7.11 (m, 2 H, Ph),

7.16-7.19 (m, 5 H, Ph + Ts), 7.60 (d, 2 H, J = 8.3 Hz, Ts). ¹³C NMR (CDCl₃,

125 MHz)  21.5 (CH₃p-Tol), 24.1 (CH₂piperidine), 26.0 (2 x CH₂

piperidine), 54.4 (2 x CH₂piperidine), 59.0 (C-1), 64.0 (C-5), 66.3 (C-4),

127.0 (2 x Ts), 127.17 (2 x Ts), 127.6 (Ph), 128.5 (2 x Ph), 129.4 (2 x Ph),

130.1 (C-2), 133.2 (C-3), 137.69 (Ar), 139.46 (Ar), 143.1 (Ar). IR (film):

3272, 3062, 2937, 2857, 1598, 1566, 1494, 1454, 1411, 1325, 1267, 1158,

1093, 1042, 969, 814, 736, 701, 666 cm^1. HRMS (ES) m/z calcd for

C₂₃H₃₁N₂O₃S[M+H]⁺415.2055, found 415.2062. Partial data for 18a (from

the mixture): R_f0.14 (20% EtOH-CH₂Cl₂). The NMR signals overlapped

with those of 17a, except for ¹H NMR (CDCl₃, 500 MHz)  2.15 (dd, 1 H, J

= 12.4, 3.7 Hz, H-5b), 4.93 (d, 1 H, J = 5.9 Hz, H-1), 5.41 (dd, 1 H, J = 15.4,

5.6 Hz, H-3), 5.77 (dd, 1 H, J = 15.4, 5.5 Hz, H-2). ¹³C NMR (CDCl₃, 125

MHz)  58.9 (C-1), 64.0 (C-5), 127.1 (Ts x 2), 127.16 (Ts x 2), 127.6 (Ph),

132.9 (C-3), 137.74 (Ar), 139.54 (Ar).

Synthesis of (+)-tert-Butyl benzyl [(2S,3E,5R)-2-hydroxy-5-phenyl-5-

(tributylsilyloxy)pent-3-en-1-yl]carbamate, 20a, and tert-Butyl benzyl

[(2R,3E,5R)-2-hydroxy-5-phenyl-5-(tributylsilyloxy)pent-3-en-1-

yl]carbamate, 20a’.

From a 90:10 mixture of amino alcohols ent-13h:ent-14h (172 mg, 0.36

mmol) in CH₃CN (3.6 mL), DIPEA (0.12 mL, 93 mg, 0.72 mmol, 2.0 equiv)

and Boc₂O (94.0 mg, 0.43 mmol, 1.2 equiv), following the general

procedure, and after chromatographic purification (10-60% EtOAc-

hexane) a pure fraction of 20a (181 mg, 88%) and a mixture of 20a:20a’

(10 mg, 4%) was obtained as orange oils. Data for 20a: R_f0.34 (20%

EtOAc-hexane). []²⁰_D+85.4 (c = 2.08). ¹H NMR (CDCl₃, 400 MHz, 50 ºC)

 0.49-0.53 (m, 6 H, 3 x CH₂n-Bu ), 0.79 (t, 9 H, J = 6.9 Hz, 3 x CH₃n-Bu),

1.17-1.24 (m, 12 H, 6 x CH₂n-Bu), 1.41 (s, 9 H, 3 x CH₃t-Bu), 3.20 (dd, 1

H, J = 14.1, 3.1 Hz, H-1a), 3.25-3.45 (m, 1 H, H-1b), 3.45 (br s, 1 H, OH),

4.28 (ddd, 1 H, J = 15.5, 10.2, 4.9 Hz, H-2), 4.34-4.48 (m, 2 H, CH₂benzyl),

5.11 (d, 1 H, J = 5.6 Hz, H-5), 5.60 (ddd, 1 H, J = 15.4, 5.7, 1.2 Hz, H-3),

5.80 (dd, 1 H, J = 15.3, 5.4 Hz, H-4), 7.13-7.16 (m, 2 H, Ar), 7.17-7.21 (m,

1 H, Ar), 7.22 (m, 1 H, Ar), 7.23-7.28 (m, 6 H, Ar). ¹³C NMR (CDCl₃, 100

MHz, 50 ºC)  13.7 (3 x CH₂n-Bu and 3 x CH₃n-Bu), 25.3 (3 x CH₂n-Bu),

26.6 (3 x CH₂n-Bu), 28.3 (3 x CH₃t-Bu), 52.5 (CH₂benzyl), 53.5 (C-1),

71.7 (C-2), 74.6 (C-5), 80.7 (C t-Bu), 126.1 (2 x Ar), 127.1 (4 x Ar), 127.2

(Ar), 128.1 (Ar), 128.5 (2 x Ar), 129.2 (C-3), 135.1 (C-4), 138.1 (Ar), 143.8

(Ar), 157.7 (C=O). IR (film): 3434, 3087, 3064, 3030, 2957, 2924, 2871,

1695, 1494, 1455, 1412, 1366, 1297, 1246, 1168, 1130, 1079, 1028, 967,

888, 758, 733, 699 cm^1. HRMS (ES) m/z calcd for C₃₅H₅₅NNaO₄Si

[M+Na]⁺604.3798, found 604.3816. Partial data for 20a’ (from the

mixture): R_f0.36 (20% EtOAc-hexane).

General procedure for the synthesis of 5-methoxy-1,4-aminoalcohols.

To a solution of 1.0 equiv of amide or amine 7/8 in methanol, 3.0 equiv of

Cs₂CO₃or K₂CO₃was added. The mixture was stirred at 50 ºC and

monitored by TLC until completion. Then, the solvent was evaporated

under reduced pressure to give the alcohol 17/18 that was purified by

chromatography on silica gel using the appropriate mixture of eluents.

General procedure for the epoxidation of alkenes.

Synthesis of (+)-N-[(1R,2E,4R)-4-Hydroxy-5-methoxy-1-phenylpent-2-

en-1-yl]-p-tolylsulfonamide, ent-17c, and N-[(1R,2E,4S)-4-Hydroxy-5-

methoxy-1-phenylpent-2-en-1-yl]-p-tolylsulfonamide, ent-18c.

To a solution of the alkene at 0 ºC in CH₂Cl₂(10 mL/mmol) m-CPBA (70%

purity) was added slowly, and the mixture was warmed up to rt. This

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mixture was stirred until disappearance (monitored by TLC) of the starting

material. The m-chlorobenzoic acid (white solid) generated in the reaction

was filtered. The resulting solution was treated with a saturated NaHCO₃

solution (5 mL/mmol) and H₂O (5 mL/mmol) and diluted with EtOAc (10

mL/mmol). The layers were separated and the aqueous layer was

extracted with EtOAc (3 × 5 mL/mmol), the combined organic extracts were

washed with a saturated NaHCO₃solution (5 mL/mmol), H₂O (5 mL/mmol)

and finally with a saturated NaCl solution. The mixture was dried over

Na₂SO₄and was concentrated under reduced pressure. The crude product

was purified by column chromatography on silica gel using a gradient of

the appropriate solvents.

500 MHz)  3.12 (ddd, 1 H, J = 12.4, 3.9, 1.5 Hz, H-4a), 3.58 (dd, 1 H, J =

12.3, 3.9 Hz, H-4b), 3.95 (t, 1 H, J = 5.8 Hz, H-1’), 4.16 (ddd, 1 H, J = 5.8,

3.7, 1.4 Hz, H-6), 4.28 (q, 1 H, J = 3.8 Hz, H-5), 4.42 (d, 1 H, J = 15.2 Hz,

Ha CH₂Bn), 4.66 (d, 1 H, J = 15.2 Hz, Hb CH₂Bn), 4.79 (d, 1 H, J = 5.7

Hz, H-2’), 7.24-7.27 (m, 2 H, Ar), 7.30-7.34 (m, 6 H, Ar), 7.43-7.45 (m, 2 H,

Ar). ¹³C NMR (CD₃OD, 125 MHz)  50.7 (C-4), 53.6 (CH₂benzyl), 62.0 (C-

5), 75.2 (C-2’), 75.7 (C-1’), 83.0 (C-6), 128.7 (4 x Ar), 128.9 (2 x Ar), 129.1

(2 x Ar), 129.7 (2 x Ar), 137.9 (Ar), 142.4 (Ar), 155.8 (C=O). NOESY 1D

(CD₃OD, 500 MHz): between H2’-H1’ 2.5%, between H2’-H5 1.6%,

between H2’-H6 0.8%, between H1’-H6 2.5%, between H1’-H5 0.7%,

between H1’-H4b 2.8%, between H5-H6 1.4%, between H5-H4a 1.7%,

between H5-H4b 4.2%, between H4a-H4b 22.0%, between H4a-HBna

1.3%, between H4b-HBnb 2.2%. IR (CH₂Cl₂): 3368, 2925, 1671, 1487,

1452, 1362, 1249, 1144, 1076, 1026, 864, 755, 700 cm^1. HRMS (ES):

calcd for C₁₉H₂₂NO₅[M+H]⁺344.1498, found 344.1493.

Synthesis of (+)-tert-Butyl benzyl[(2R,3S,4S,5S)-2-hydroxy-5-phenyl-

5-(tributylsilyloxy)-3,4-(oxiranyl)pentyl]carbamate, 21a, and tert-

Butyl benzyl[(2R,3R,4R,5S)-2-hydroxy-5-phenyl-5-(tributylsilyloxy)-

3,4-(oxiranyl)pentyl]carbamate, 22a.

Synthesis

of

(+)-N-Benzyl-N-(2R,3R,4S,5S)-2,4,5-trihydroxy-3-

methoxy-5-phenylpentyl)tosylsulfonamide, 27.

From carbamate 20a (46 mg, 0.079 mmol) and m-CPBA (21.0 mg, 0.09

mmol, 1.2 equiv) in CH₂Cl₂, according to the general procedure (4 h) and

after chromatographic purification (5-50% EtOAc-hexane) a pure fraction

of 21a (42 mg, 89%) and 22a (3 mg, 6%) was obtained as colorless oils.

To a cold solution of 1.0 equiv of epoxy sulfonamide 21c (8 mg, 0.012

mmol, 1.0 equiv) in MeOH, was added Mg powder (2 mg, 0.086 mmol, 7.0

equiv). The mixture was stirred from rt to 50 ºC and monitored by TLC until

completion (1 d). The solvent was evaporated and the crude was purified

by chromatography on silica gel (5-50% Et₂O-CH₂Cl₂) to obtain a pure

fraction of 27 as a colorless oil (5 mg, 85%). Data for 27: R_f0.20 (10%

Data for 21a: R_f0.30 (20% EtOAc-hexane). []²⁰+35.8 (c = 0.21). ¹H

D

NMR (CDCl₃, 400 MHz, 40 ºC)  0.48-0.53 (m, 6 H, 3 x CH₂n-Bu ), 0.81

(t, 9 H, J = 6.8 Hz, 3 x CH₃n-Bu), 1.15-1.28 (m, 12 H, 6 x CH₂n-Bu), 1.43

(s, 9 H, 3 x CH₃t-Bu), 3.02-3.05 (m, 2 H, H-3 and H-4), 3.23 (dd, 1 H, J =

14.3, 3.5 Hz, H-1a), 3.28-3.47 (br, 1 H, H-1b), 3.72-3.79 (m, 1 H, H-2), 4.34

(m, 2 H, CH₂benzyl), 4.69 (d, 1 H, J = 3.3 Hz, H-5), 7.12-7.19 (m, 2 H, Ar),

7.21-7.32 (m, 8 H, Ar). ¹³C NMR (CDCl₃, 100 MHz, 40 ºC)  13.7 (3 x CH₂

n-Bu and 3 x CH₃n-Bu), 25.3 (3 x CH₂n-Bu), 26.5 (3 x CH₂n-Bu), 28.4 (3

x CH₃t-Bu), 49.9 (C-1), 50.5 (CH₂benzyl), 56.8 and 56.9 (C-3 and C-4),

69.7 (C-2), 72.7 (C-5), 80.6 (C t-Bu), 126.4 (2 x Ar), 127.3 (4 x Ar), 127.8

(2 x Ar), 128.3 (Ar), 128.6 (Ar), 138.1 (Ar), 141.3 (Ar), 157.9 (C=O). IR

(film): 3364, 3065, 2957, 2924, 2872, 1674, 1575, 1488, 1454, 1367, 1251,

1142, 1076, 1028, 888, 753, 701 cm^1. HRMS (ES) m/z calcd for

C₃₅H₅₅NNaO₅Si [M+Na]⁺620.3747, found 620.3736. Partial data for 22a:

1

Et₂O-CH₂Cl₂). []²⁰_D+21.5 (c = 0.32). H NMR (CDCl₃, 500 MHz)  2.10

(d, 1 H, J = 6.4 Hz, OH), 2.43 (s, 3 H, CH₃Ts), 2.91 (d, 1 H, J = 5.3 Hz,

OH), 3.14 (s, 3 H, OMe), 3.15 (dd, 1 H, J = 13.2, 6.4 Hz, H-1a), 3.30 (dd,

1 H, J = 14.9, 8.2 Hz, H-1b), 3.36 (td, 1 H, J = 6.8, 1.5 Hz, H-3), 3.71-3.80

(m, 2 H, H-2 and H-4), 4.19 (d, 1 H, J = 6.6 Hz, H-5), 4.29 (d, 1 H, J = 14.6

Hz, Ha Bn), 4.35 (d, 1 H, J = 14.6 Hz, Hb Bn), 7.20-7.22 (m, 2 H, Ar), 7.28-

7.38 (m, 10 H, Ar), 7.70 (d, 2 H, J = 8.3 Hz, Ts). ¹³C NMR (CDCl₃, 125

MHz)  21.5 (CH₃Ts), 51.7 (C-1), 54.0 (CH₂Bn), 56.7 (OMe), 68.9 (C-2),

70.7 (C-3), 74.4 (C-4), 85.1 (C-5), 127.3 (2 x Ar), 127.9 (2 x Ar), 128.0 (Ar),

128.3 (Ar), 128.47 (2 x Ar), 128.53 (2 x Ar), 128.7 (2 x Ar), 129.9 (2 x Ar),

135.9 (Ar), 136.1 (Ar), 137.6 (Ar), 143.7 (Ar). IR (film): 3410, 3032, 2957,

2925, 2872, 2858, 1667, 1466, 1455, 1417, 1367, 1297, 1249, 1169, 1137,

1080, 964, 889, 700 cm^1. HRMS (ES) m/z calcd for C₂₆H₃₂NO₆S [M+H]⁺

486.1945, found 486.1950.

1

R_f0.35 (20% EtOAc-hexane). H NMR (CDCl₃, 400 MHz, 40 ºC)  0.49-

0.53 (m, 6 H, 3 x CH₂n-Bu ), 0.82 (t, 9 H, J = 6.8 Hz, 3 x CH₃n-Bu), 1.17-

1.27 (m, 12 H, 6 x CH₂n-Bu), 1.43 (s, 9 H, 3 x CH₃t-Bu), 3.02-3.05 (m, 2

H, H-3 and H-4), 3.23 (dd, 1 H, J = 14.5, 3.7 Hz, H-1a), 3.28-3.47 (br, 1 H,

H-1b), 3.72-3.79 (m, 1 H, H-2), 4.37-4.51 (m, 2 H, CH₂benzyl), 4.69 (d, 1

H, J = 3.2 Hz, H-5), 7.12-7.19 (m, 2 H, Ar), 7.21-7.32 (m, 8 H, Ar).

Synthesis of (+)-(2R,3S,4S,5S)-1-(Benzylamino)-3,4-(oxiranyl)-5-

phenyl-5-[(tributylsilyloxy]pentan-2-ol, 28.

General procedure for the synthesis of 1,3-oxazin-2-ones via epoxide

opening.

To a solution of 1.0 equiv of carbamate 21d (7.0 mg, 0.01 mmol) in THF

(0.1 mL) was added 5.0 equiv of piperidine (5 μL, 4 mg, 0.047 mmol). The

mixture was stirred at rt and monitored by TLC until completion (1 d). The

crude was concentrated and purified by chromatography on silica gel (20-

80% EtOAc-CH₂Cl₂) to obtain a pure fraction of 28 as a colorless oil (4 mg,

80%). Data for 28: R_f0.20 (80% EtOAc-CH₂Cl₂). []²⁰_D+69.5 (c = 1.15).

¹H NMR (CDCl₃, 500 MHz)  0.48-0.53 (m, 6 H, 3 x CH₂n-Bu), 0.80 (t, 9

H, J = 6.9 Hz, 3 x CH₃n-Bu), 1.17-1.25 (m, 12 H, 6 x CH₂n-Bu), 1.88 (br

s, 2 H, OH and NH), 2.72 (dd, 1 H, J = 12.1, 6.8 Hz, H-1a), 2.75 (dd, 1 H,

J = 12.2, 5.0 Hz, H-1b), 3.08 (dd, 1 H, J = 3.8, 2.2 Hz, H-4), 3.10 (dd, 1 H,

J = 3.9, 2.2 Hz, H-3), 3.63 (ddd, 1 H, J = 6.8, 4.9, 4.0 Hz, H-2), 3.74 (d, 1

H, J = 13.3 Hz, Ha Bn), 3.77 (d, 1 H, J = 13.3 Hz, Hb Bn), 4.66 (d, 1 H, J

= 3.8 Hz, H-5), 7.23-7.30 (m, 10 H, Ar). ¹³C NMR (CDCl₃, 125 MHz)  13.6

(3 x CH₂n-Bu), 13.7 (3 x CH₃n-Bu), 25.2 (3 x CH₂n-Bu), 26.5 (3 x CH₂n-

Bu), 52.0 (C-1), 53.6 (CH₂Bn), 57.4 (C-4), 58.9 (C-3), 68.3 (C-2), 72.7 (C-

5), 126.3 (2 x Ar), 127.1 (Ar), 127.8 (Ar), 128.1 (2 x Ar), 128.3 (2 x Ar),

128.5 (2 x Ar), 139.7 (Ar), 141.3 (Ar). NOESY 1D (CD₃OD, 500 MHz):

between H5-H4 4.0%, between H1-H3 2.0%, between H1-H2 4.0%. IR

(film): 2917, 2849, 1682, 1461, 1373, 1265, 1206, 1138, 1080, 742 cm^1.

HRMS (ES) m/z calcd for C₃₀H₄₈NO₃Si [M+H]⁺498.3398, found 498.3392.

To a solution of the epoxy carbamate at 0 ºC in CH₂Cl₂(10 mL/mmol) TFA

was added slowly. This mixture was stirred until disappearance (monitored

by TLC) of the starting material. The resulting solution was treated with a

solution of Na₂CO₃or NaOH (5 mL/mmol) until basic pH=11, and diluted

with CH₂Cl₂(10 mL/mmol). The layers were separated and the aqueous

layer was extracted with CH₂Cl₂(3 × 5 mL/mmol). The mixture was dried

over Na₂SO₄and was concentrated under reduced pressure. The crude

product was purified by column chromatography on silica gel using a

gradient of the appropriate solvents.

Synthesis

of

(+)-(5R,6R)-3-Benzyl-6-[(1S,2S)-1,2-dihydroxy-2-

phenylethyl]-5-hydroxy-1,3-oxazin-2-one, 26a.

From epoxy carbamate 21a (32 mg, 0.054 mmol) in CH₂Cl₂(0.6 mL) and

TFA (12 μL, 18 mg, 0.16 mmol, 3.0 equiv), according to the general

procedure and after chromatographic purification (5-50% Et₂O-CH₂Cl₂),

26a was obtained as a white solid (17 mg, 95%). Data for 26a: R_f0.20

(10% Et₂O-CH₂Cl₂). []²⁰_D+65.4 (c = 0.12). mp 145 ºC. ¹H NMR (CD₃OD,

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Synthesis of (+)-(5R)-3-Benzyl-5-[(1S,2S,3S)-1,2-epoxy-3-phenyl-3-

tributylsilyloxy]oxazolidine, 29.

3.82 (m, 1 H, H-2), 4.23-4.25 (m, 2 H, CH₂benzyl), 4.79 (d, 1 H, J = 5.9

Hz, H-5), 7.17-7.19 (m, 2 H, Ar), 7.26-7.32 (m, 8 H, Ar). HRMS (ES) m/z

calcd for C₃₅H₅₇NO₆Si [M+H]⁺616.4033, found 616.4028.

To a solution of 1.0 equiv of carbamate 21d (7.0 mg, 0.01 mmol) in CH₂Cl₂

(0.1 mL) was added 2.0 equiv of piperidine (2 μL, 2 mg, 0.02 mmol). The

mixture was stirred at rt and monitored by TLC until completion (1 day).

The crude was concentrated and purified by chromatography on silica gel

(20-80% EtOAc-CH₂Cl₂) to obtain a pure fraction of 29 as a colorless oil

(4.5 mg, 90%). Data for 29: R_f0.40 (80% EtOAc-CH₂Cl₂). []²⁰_D+50.3 (c

Synthesis

of

(+)-(2R,3R,4R,5S)-1-[Benzyl(tert-

butoxycarbonyl)amino]-3-hydroxy-1-phenylpentane-2,4,5-triyl

triacetate, 36.

To a cold solution (0 ºC) of 1.0 equiv of silyloxy triacetate 35 (32 mg, 0.054

mmol) in CH₂Cl₂(0.6 mL) was added TFA (12 μL, 18 mg, 0.16 mmol, 3.0

equiv). The mixture was stirred from 0 ºC to rt and monitored by TLC until

completion (1 d). The crude was treated with Na₂CO₃, extracted with

EtOAc, concentrated and purified by chromatography on silica gel (5-50%

Et₂O-CH₂Cl₂) to obtain a pure fraction of 36 as a colorless oil (17 mg, 95%).

Data for 36: R_f0.40 (40% EtOAc-hexane). []²⁰_D+51.4 (c = 0.86). ¹H NMR

(CDCl₃, 500 MHz)  1.25 (s, 9 H, 3 x CH₃t-Bu), 1.92 (s, 3 H, CH₃Ac), 1.97

(s, 3 H, CH₃Ac), 2.07 (s, 3 H, CH₃Ac), 3.11 (dd, 1 H, J = 15.9, 3.0 Hz, H-

1a), 3.30 (ddd, 1 H, J = 10.0, 4.7, 1.6 Hz, H-3), 3.91 (d, 1 H, J = 15.7 Hz,

H-1b), 4.00 (d, 1 H, J = 15.9 Hz, Ha Bn), 4.49 (d, 1 H, J = 15.9 Hz, Hb Bn),

4.74 (dt, 1 H, J = 9.9, 3.0 Hz, H-2), 5.11 (d, 1 H, J = 4.5 Hz, OH), 5.42 (d,

1 H, J = 9.1 Hz, H-4), 6.16 (d, 1 H, J = 9.7 Hz, H-5), 6.96 (d, 2 H, J = 7.7

Hz, Ar), 7.20-7.36 (m, 6 H, Ar), 7.51 (d, 2 H, J = 7.0 Hz, Ar). ¹³C NMR

(CDCl₃, 125 MHz)  20.8 (CH₃Ac), 20.9 (CH₃Ac), 21.0 (CH₃Ac), 28.2 (3

x CH₃t-Bu), 46.3 (C-1), 53.3 (CH₂Bn), 66.4 (C-3), 71.9 (C-2), 73.0 (C-4),

75.6 (C-5), 81.4 (C t-Bu), 126.9 (2 x Ar), 127.3 (Ar), 127.8 (2 x Ar), 128.5

(3 x Ar), 128.6 (2 x Ar), 136.8 (Ar), 137.4 (Ar), 157.8 (C=O Boc), 169.7

(C=O Ac), 170.0 (C=O Ac), 170.6 (C=O Ac). IR (film): 3357, 2926, 2855,

1739, 1668, 1456, 1438, 1373, 1239, 1179, 1120, 1084, 1029, 723, 697

cm^1. HRMS (ES) m/z calcd for C₂₉H₃₇NNaO₉[M+Na]⁺566.2361 found

566.2381.

1

= 0.85). H NMR (CDCl₃, 500 MHz)  0.49-0.53 (m, 6 H, 3 x CH₂n-Bu),

0.80 (t, 9 H, J = 6.9 Hz, 3 x CH₃n-Bu), 1.17-1.26 (m, 12 H, 6 x CH₂n-Bu),

2.78 (dd, 1 H, J = 11.4, 7.2 Hz, H-4a), 3.05 (dd, 1 H, J = 12.0, 7.2 Hz, H-

4b), 3.06 (dd, 1 H, J = 3.7, 2.2 Hz, H-2´), 3.15 (dd, 1 H, J = 4.6, 2.1 Hz, H-

1´), 3.66 (d, 1 H, J = 13.0 Hz, Ha Bn), 3.70 (d, 1 H, J = 13.0 Hz, Hb Bn),

3.92 (td, 1 H, J = 7.2, 4.6 Hz, H-5), 4.29 (d, 1 H, J = 5.4 Hz, H-2a), 4.32 (d,

1 H, J = 5.4 Hz, H-2b), 4.68 (d, 1 H, J = 3.6 Hz, H-3´), 7.28-7.31 (m, 10 H,

Ar). ¹³C NMR (CDCl₃, 125 MHz)  13.6 (3 x CH₂n-Bu), 13.7 (3 x CH₃n-

Bu), 25.2 (3 x CH₂n-Bu), 26.5 (3 x CH₂n-Bu), 54.5 (C-4), 56.3 (C-1´), 58.2

(CH₂Bn), 59.5 (C-2´), 72.6 (C-3´), 73.8 (C-5), 87.1 (C-2), 126.3 (2 x Ar),

127.3 (Ar), 127.8 (Ar), 128.3 (2 x Ar), 128.4 (2 x Ar), 128.8 (2 x Ar), 138.7

(Ar), 141.4 (Ar). IR (film): 3088, 3064, 3030, 2956, 2924, 2871, 1660, 1495,

1455, 1409, 1376, 1297, 1197, 1080, 1028, 998, 887, 746, 699 cm^1.

HRMS (ES) m/z calcd for C₃₁H₄₈NO₃Si [M+H]⁺510.3398, found 510.3422.

General procedure for the dihydroxylation of alkenes.

To a cold solution (0 ºC) of the carbamate in a 9:1 mixture of acetone-

water (10 mL/mmol) Me₃NO·2H₂O (4.0 equiv) and 5% mol of OsO₄(2.5%

wt in t-BuOH) was added slowly, and the mixture was warmed to rt until

disappearance of the starting material (monitored by TLC). The crude was

evaporated, dissolved in EtOAc and filtered through a pad of silica gel,

concentrated and purified by chromatography on silica gel using a gradient

of the appropriate solvents.

Synthesis of (+)-tert-Butyl benzyl{(2R,3R)-3-[(4R,5S)-2,2-dimethyl-5-

phenyl-1,3-dioxolan-4-yl]-2,3-dihydroxypropyl}carbamate, 37.

Synthesis of (+)-tert-Butyl benzyl [(2R,3R,4R,5S)-5-phenyl-5-

(tributylsilyloxy)-2,3,4-trihydroxypentyl]carbamate, 31, and tert-Butyl

To a cold solution (0 ºC) of 1.0 equiv of triol 31 (15 mg, 0.025 mmol) in

CH₂Cl₂(0.3 mL) was added 2.0 equiv of 2,2-dimethoxypropane (6 μL, 5.0

mg, 0.050 mmol) and 0.1 equiv of PPTS (1.0 mg, 0.003 mmol). The mixture

was stirred at rt and monitored by TLC until completion (1 day). The crude

was concentrated and purified by chromatography on silica gel (5-60%

Et₂O-hexane) to obtain a pure fraction of 37 as a colorless oil (8.0 mg,

70%). Data for 37: R_f0.38 (20% Et₂O-hexane). []²⁰_D+30.6 (c = 0.11). ¹H

NMR (CDCl₃, 500 MHz)  1.40 (s, 9 H, 3 x CH₃t-Bu), 1.50 (s, 3 H, CH₃),

1.53 (s, 3 H, CH₃), 2.88 (br d, 1 H, J = 9.1 Hz, OH-C3), 3.32 (td, 1 H, J =

9.0, 1.3 Hz, H-3), 3.40 (dd, 1 H, J = 14.7, 2.0 Hz, H-1a), 3.50-3.62 (m, 1 H,

H-1b), 3.67-3.72 (m, 1 H, H-2), 3.91 (br s, 1 H, OH-C2), 4.15 (br d, 1 H, J

= 8.3 Hz, H-4), 4.38 (d, 1 H, J = 15.7 Hz, Ha Bn), 4.51 (d, 1 H, J = 15.6 Hz,

Hb Bn), 5.02 (d, 1 H, J = 8.8 Hz, H-5), 7.17-7.19 (m, 2 H, Ar), 7.28-7.39

(m, 8 H, Ar). ¹³C NMR (CDCl₃, 125 MHz)  27.0 (CH₃), 27.3 (CH₃), 28.3 (3

x CH₃t-Bu), 50.7 (C-1), 52.6 (CH₂benzyl), 68.3 (C-3), 73.3 (C-2), 78.8 (C-

5), 81.0 (C t-Bu), 81.3 (C-4), 109.3 (C ketal), 126.8 (2 x Ar), 127.3 (2 x Ar),

127.4 (Ar), 127.7 (Ar), 128.3 (Ar), 128.5 (2 x Ar), 128.6 (2 x Ar), 137.9 (Ar),

158.4 (C=O). NOESY 1D (CDCl₃, 500 MHz): between H5-ArH 2.5%,

between H5-H4 0.2%, between H5-H3 1.3%, between H5-OH3 0.3%,

between CH₃-H5 0.75%. IR (film): 3410, 3088, 3065, 3032, 2957, 2925,

1667, 1606, 1587, 1496, 1466, 1455, 1417, 1367, 1297, 1249, 1169, 1137,

1080, 1028, 964, 889, 853, 828, 761, 732, 700 cm^1. HRMS (ES): calcd

for C₂₆H₃₆NO₆[M+H]⁺458.2543, found 458.2547.

benzyl

[(2R,3S,4S,5S)-5-phenyl-5-(tributylsilyloxy)-2,3,4-

trihydroxypentyl]carbamate, 32.

From carbamate 20a (120 mg, 0.206 mmol) in 2.1 mL of acetone-H₂O (9:1)

Me₃NO·2H₂O (92.0 mg, 0.824 mmol, 4.0 equiv) and OsO₄(130 μL, 3.0 mg,

0.010 mmol, 0.05 equiv), according to the general procedure (1 d) and

after chromatographic purification (20-80% Et₂O-hexane) a pure fraction

of 31 (102.0 mg, 80%) and 32 (6.5 mg, 5%) was obtained as colorless oils.

Data for 31: R_f0.42 (60% Et₂O-hexane). []²⁰_D+92.6 (c = 1.34). ¹H NMR

(CDCl₃, 400 MHz, 50 ºC)  0.44-0.51 (m, 6 H, 3 x CH₂n-Bu), 0.81 (t, 9 H,

J = 6.7 Hz, 3 x CH₃n-Bu), 1.14-1.28 (m, 12 H, 6 x CH₂n-Bu), 1.37 (s, 9 H,

3 x CH₃t-Bu), 2.99 (s, 1 H, OH), 3.05 (t, 1 H, J = 8.1 Hz, H-3), 3.31-3.51

(m, 2 H, H-1), 3.54-3.66 (m, 1 H, OH), 3.74-3.79 (m, 1 H, H-2), 3.85-3.89

(m, 1 H, H-4), 4.39 (d, 1 H, J = 15.8 Hz, Ha Bn), 4.48 (d, 1 H, J = 15.7 Hz,

Hb Bn), 4.79 (d, 1 H, J = 7.7 Hz, H-5), 7.15-7.17 (m, 2 H, Ar), 7.22-7.29

(m, 6 H, Ar), 7.33-7.35 (m, 2 H, Ar). ¹³C NMR (CDCl₃, 100 MHz, 50 ºC) 

13.6 (3 x CH₂n-Bu), 13.8 (3 x CH₃n-Bu), 25.3 (3 x CH₂n-Bu), 26.5 (3 x

CH₂n-Bu), 28.3 (3 x CH₃t-Bu), 50.56 (C-1), 50.6 (CH₂benzyl), 65.9 (C-3),

70.0 (C-2), 72.9 (C-4), 74.7 (C-5), 80.7 (C t-Bu), 127.2 (2 x Ar), 127.4 (4 x

Ar), 128.0 (2 x Ar), 128.3 (Ar), 128.5 (Ar), 138.3 (Ar), 141.0 (Ar), 158.4

(C=O). IR (film): 3410, 3088, 3065, 3032, 2957, 2925, 2872, 2858, 1667,

1606, 1587, 1496, 1466, 1455, 1417, 1367, 1297, 1249, 1169, 1137, 1080,

1028, 964, 889, 853, 828, 761, 732, 700 cm^1. HRMS (ES) m/z calcd for

C₃₅H₅₇NO₆Si [M+H]⁺616.4033, found 616.4033. Partial data for 32: R_f0.15

(60% Et₂O-hexane). ¹H NMR (CDCl₃, 400 MHz, 50 ºC)  0.48-0.54 (m, 6

H, 3 x CH₂n-Bu), 0.80 (t, 9 H, J = 6.8 Hz, 3 x CH₃n-Bu), 1.18-1.25 (m, 12

H, 6 x CH₂n-Bu), 1.42 (s, 9 H, 3 x CH₃t-Bu), 3.25 (dd, 1 H, J = 14.9, 4.4

Hz, H-1a), 3.34-3.49 (m, 1 H, H-1b), 3.65-3.70 (m, 2 H, H-3 and H-4), 3.78-

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Commun. 1981, 11, 697-708; f) E. Guittet, S. Julia, Synth. Commun.

1981, 11, 709-722. For some examples of remote nucleophilic

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Acknowledgements

This research was supported by CTQ2016-77555-C2-2-R and

MICINN (CTQ2009-07752). We also thank CM for additional

support to MU and MEC for a fellowship to I.C.

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Conflict of interest

The authors declare no conflict of interest.

Keywords: 1,4-aminoalcohols • 1,4-diols • [2,3]-sigmatropic

rearrangement • sulfenate • sulfoxide

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10.1002/chem.201905742

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Entry for the Table of Contents

FULL PAPER

Ignacio Colomer, Mercedes Ureña, Alma

Viso, and Roberto Fernández de la

Pradilla*

X = O, NH

OH

S*

stereoselective

cascade reaction

R

*

R

*

p-Tol

O

S

S* =

XP

Nu

XP

Page No. – Page No.

Sulfinyl-mediated stereoselective

functionalization of acyclic

conjugated dienes

A new methodology to prepare acyclic unsaturated 1,4-diol derivatives from

conjugated sulfinyl dienes has been developed. A cascade process that entails

nucleophilic addition to produce a functionalized allylic sulfoxide, followed by [2,3]-

sigmatropic rearrangement and sulfenate cleavage renders the target molecules

with high yields and selectivities.

Article Doi

Sulfinyl-Mediated Stereoselective Functionalization of Acyclic Conjugated Dienes

DOI: 10.1002/chem.201905742

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Authors:

Article abstract of DOI:10.1002/chem.201905742

Full text of DOI:10.1002/chem.201905742

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