Stereoselective synthesis of (Z)-fluoroalkenes directed to peptide isosteres: Copper mediated reaction of trialkylaluminum with 4,4-difluoro-5-hydroxyallylic alcohol derivatives

Tetrahedron 61 (2005) 5741–5753

Stereoselective synthesis of (Z)-ﬂuoroalkenes directed to peptide

isosteres: copper mediated reaction of trialkylaluminum with

4,4-diﬂuoro-5-hydroxyallylic alcohol derivatives

Yuko Nakamura,^aMidori Okada,^aAzusa Sato,^aHiroaki Horikawa,^aMinoru Koura,^bAkio Saito^b

and Takeo Taguchi^b,

*

^aTokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan

^bTokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Received 26 March 2005; revised 16 April 2005; accepted 18 April 2005

Abstract—Copper mediated alkyl-transfer reaction of trialkylaluminum (R₃Al) with (E)-4,4-diﬂuoro-5-hydroxyallylic alcohol derivative

smoothly proceeded to give the corresponding 2-alkylated 4-ﬂuoro-5-hydroxyhomoallylic alcohol derivative with completely Z and 2,5-syn

selective manner. Regio- and stereoselective conversion of the C5-hydroxyl group of the ﬂuorooleﬁn thus obtained to amino group could be

achieved through one-pot mesylation and azidation reaction.

1. Introduction

Fluorooleﬁn (–CF]CH–) is considered to be an ideal

mimic for an amide bond (–CO–NH–) due to the close

similarities of the steric and electronic properties.¹Contrary

to these similarities, ﬂuorooleﬁn should be a non-hydrolyz-

able bond both chemically and enzymatically, and the lack

of rotational freedom of this bond is also a different property

from that of amide bond. On the basis of these unique

properties, utilization of (Z)-ﬂuoroalkene dipeptide or

depsipeptide isosteres as non-hydrolyzable and/or confor-

mationally restricted replacements for the parent amide

bonds has attracted much attention in the ﬁeld of medicinal

chemistry (Fig. 1).^2–6

Figure 1. Replacement of amide bond by Z-ﬂuorooleﬁn.

To develop synthetic methods for these ﬂuoroalkene

Each of such ﬂuoroalkene-modiﬁed dipeptide and depsi-

isosteres, stereochemical control of the oleﬁn-conﬁguration

(either Z or E) and the relative stereochemistry of the two

chiral carbon atoms (C2 and C5) and E/Z conﬁguration of

peptide isosteres has a set of eight stereoisomers due to two

chiral centers at C2 and C5 (either syn or anti) is a major

issue to be solved. Furthermore, the use of readily

oleﬁn part in the molecule. In Figure 1, a typical dipeptide

L-AA₁-L-AA₂consisting of two L-amino acids, a part of a

obtainable starting material is also important. So far,

depsipeptide ^D-OA₁-L-AA₂derived from D-oxy acid and

extensive efforts to develop highly stereoselective methods

L-amino acid, and the corresponding ﬂuoroalkene isosteres

for functionalized ﬂuorooleﬁnic compounds have been

are depicted.

reported.^7–15For example, directed to the preparation of

ﬂuoroalkene dipeptide isosteres, Fujii and Otaka et al.

recently demonstrated two types of deﬂuorinative reactions

Keywords: Fluoroalkene; Diﬂuoroallylic alcohol; Trialkylaluminum;

using g,g-diﬂuoro-a,b-enoate derivatives 1a as the starting

Cuprous iodide; Peptide isosteres.

material. That is, the diﬂuoro enoates 1a having amino

group at d-position could be converted to the dipeptide

*

Corresponding author. Tel./fax: C81 426 76 3257;

e-mail: taguchi@ps.toyaku.ac.jp

doi:10.1016/j.tet.2005.04.034

5742

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

realized. Further efforts were made to develop a highly

diastereoselective preparation of these compounds. We

found that Cu(I)-mediated alkyl-transfer reaction of tri-

alkylaluminum (R₃Al) with (E)-4,4-diﬂuoro-5-hydroxy-

allylic alcohol derivatives E-5 provided the corresponding

2-alkylated 4-ﬂuorohomoallylic alcohol derivatives 6 in

completely Z- and 2,5-syn-selective manner.¹⁹Furthermore,

regio- and stereoselective conversion of the secondary

chiral hydroxyl group in the diﬂuoroallylic alcohol 7 into

amino functionality could be achieved through one-pot

mesylation and azidation protocol (Scheme 3). In this paper,

we report these promising results directed to the stereo-

controlled preparation of (Z)-ﬂuoroalkene depsipeptide or

dipeptide isosteres in detail.

Scheme 1.

isostere form 2a by utilizing organocopper reagent under

reductive–oxidative alkylation conditions (Scheme 1, A).¹⁶

Furthermore, they also reported samarium diiodide (SmI₂)-

mediated reduction of 1a followed by the reaction with

carbonyl compounds to give a-substituted ﬂuoroalkenoates

3a (Scheme 1, B).¹⁷Although these reactions proceeded

with complete Z-selectivity, low diastereoselectivity

remained as a future subject to be solved.

2. Results and discussion

Independently, we have also reported that using the similar

diﬂuoro enoate derivatives 1b–d, a-alkylated (Z)-g-ﬂuoro-

b,g-enoate 2 can be synthesized upon treating with

trialkylaluminum (R₃Al) in the presence of Cu(I) or through

lithiocuprate (Me₂CuLi) mediated reductive deﬂuorination

followed by regioselective a-alkylation with alkyl halide

(Scheme 2, Eqs. 1 and 3).¹⁸In the lithiocuprate reaction,

reductive deﬂuorination product 4 was obtained by

quenching with H₂O instead of alkyl halide (Scheme 2,

Eq. 2).

2.1. Reaction with lithiocuprate

First, we examined the reactivity and stereoselectivity in the

reaction of (E)-4,4-diﬂuoro-5-hydroxyallylic alcohol

derivatives 5a, 5b with a copper reagent derived from

alkyllithium, typically such as Gilman reagent (Table 1).¹⁹

Contrary to the case of ester derivative 1b (YZOH) which

provided the reductive deﬂuorination product 4b rather than

expected 2-methylated product 2b (YZOH, R²ZMe) as

shown in Scheme 2, the reaction of these alcohol derivatives

5a, 5b with dialkylcopper lithium R₂CuLi proceeded in

SN2⁰manner giving rise to 2-alkylated homoallylic alcohol

Although these reactions proceeded in excellent Z-selectivity,

synthetically useful level of diastereo-control could not be

Scheme 2.

Scheme 3.

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

Table 1. Reaction of (E)-4,4-diﬂuoro-5-hydroxyallylic alcohol with R₂CuLi

5743

Entry

5

Reagent

Additive

R²

6

Yield (%)^a

Z/E^b

syn/anti^c

1

2

3

4

5a

Me₂CuLi

n-Bu₂CuLi

Me₂CuLi

—

Me

n-Bu

Me

6a-1

6a-3

6b-1

90

88

58

90

15

O95

13

2:1

95:1

Me₃Al

1.1:1^d

5b

11

^aIsolated yield.

1

^bDetermined by H NMR.

^cRatio for Z isomer.

^dRelative stereochemistry was not determined.

Scheme 4.

derivatives 6a, 6b.²⁰For example, by treating 5a with

Me₂CuLi (5 equiv) in THF at 0 8C for 2.5 h, 2-methylated

homoallylic alcohol 6a-1 was obtained in 90% yield with

relatively high Z selectivity (Z/EZ15), but with low

diastereoselectivity (syn/antiZ2 for Z isomer) (entry 1).

While limited to the case of phenyl derivative 5a and

Me₂CuLi, a remarkable improvement in diasterero-

selectivity was observed by the addition of Me₃Al

(entry 2). However, the additive effect of Me₃Al on the

stereoselectivity was not observed in the reaction of 5a with

n-Bu₂CuLi instead of Me₂CuLi or alkyl (b-phenylethyl)

derivative 5b with Me₂CuLi (entries 3 and 4).

Reactions of lithiocuprate with some structure modiﬁed

substrates were also examined. It was found that both allylic

alcohol structure and C5-hydroxyl group may be important

Table 2. Cu(I)-mediated reaction of (E)-4,4-diﬂuoro-5-hydroxyallylic alcohol with R₃Al

Entry

5

Reagent

R²

6

Yield (%)^a

Z/E^b

syn/anti^c

1

2

3

4

5

6

7

5a

Me₃Al

Me

i-Bu

Me

i-Bu

Me

i-Bu

—

0^d

77

68

65

66

98

78

—

Me₃Al, CuI$2LiCl

i-Bu₃Al, CuI$2LiCl

Me₃Al, CuI$2LiCl

i-Bu₃Al, CuI$2LiCl

Me₃Al, CuI$2LiCl

i-Bu₃Al, CuI$2LiCl

6a-1

6a-2

6b-1

6b-2

6c-1

6c-2

O95

O95:!1

5b

5c

^aIsolated yield.

1

^bDetermined by H NMR.

^cRatio for Z isomer.

^dWithout CuI$2LiCl, 5a was recovered in 90%.

5744

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

Table 3. Alkyl-transfer reaction of (Z)-4,4-diﬂuoro-5-hydroxyallylic alcohol

Entry

5

Reagent

Time (h)

R²

6

Yield (%)^a

syn/anti^b,c

5 (%)^b,d

1

2

3

4

5

5d

Me₃Al, CuI$2LiCl

i-Bu₃Al, CuI$2LiCl

Me₂CuLi

i-Bu₃Al, CuI$2LiCl

Me₂CuLi

22

4

22

4

Me

i-Bu

Me

i-Bu

Me

6a-1

6a-2

6a-1

6c-2

6c-1

52

23

76

32

89

1:10.5

1:5.8

1:4.7

1:2.9

1:2.0^e

41

60

—

32

—

5e

^aIsolated yield.

^bDetermined by ¹H and ¹⁹F NMR.

^cRatio for Z-isomer is shown.

^dRecovery of 5.

^eZ/E ratio of 6c-1 was 15:1.

for clean reaction, since the silylation of the primary

hydroxyl group (substrate 9a) or methylation of both

hydroxyl groups (substrate 9b) gave the 2-methylated

product 10 as a mixture of Z/E and syn/anti isomers along

with the formation of the diene compound 11. In the case of

9a, reductive deﬂuorination compound 12a was also

detected. With C5-amino substrate 13a, reaction proceeded

in completely non-diastereoselective manner to give the

2-methylated (Z)-ﬂuoroalkene compound 14a in 61% yield

(Scheme 4). From these results, a high level of stereocontrol

could not be achieved by lithiocuprate reactions.

conditions (Me₃Al, CuI$2LiCl, THF, 0 8C, 22 h) proceeded

more slowly than that of E-isomer 5a to give the

2-methylated 4-ﬂuorohomoallylic alcohol 6a-1 in moderate

yield (52%) along with the recovery of 5d (41%) (entry 1).

The stereochemistry of the product 6a-1 thus obtained

indicated that the reaction proceeded in highly Z-selective

manner (Z/EZO95) and in relatively highly anti-selective

manner (syn/antiZ1/10.5) opposite to that of E-isomer 5a.

Using i-Bu₃Al instead of Me₃Al under the similar

conditions, the reaction of 5d, 5e gave the desired products

6a-2, 6c-2 in low yields along with the recovery of 5d, 5e,

respectively (entries 2 and 4). In these cases complete

Z-selectivity and moderate 2,5-anti selectivity were also

observed. On the other hand, as shown in entries 3 and 5, the

reaction of Z-isomers 5d, 5e with lithiocuprate Me₂CuLi

proceeded smoothly to give 6a-1, 6c-1 in good yields (76

and 89%, respectively), but with lower diastereoselectivity

(syn/antiZ1/4.7 for 6a-1 and 1/2.0 for 6c-1). Although the

product yield should be improved in the case of Z-isomer of

diﬂuoroallylic alcohols 5d, 5e, the results mentioned above

indicated that both syn- and anti-isomer of 2-alkylated

(Z)-4-ﬂuoro-5-hydroxyhomoallylic alcohols 6 are stereo-

selectively constructed by the reaction with R₃Al and

CuI$2LiCl.

2.2. Reaction with trialkylaluminum in the presence of

CuI$2LiCl

Contrary to the low diastereoselectivity in the reaction with

lithiocuprate, when the reaction of (E)-diﬂuoroallylic

alcohols 5a–5c were conducted using a combination of

trialkylaluminum (R₃Al, 5–10 equiv) and CuI$2LiCl²¹

(2.5 equiv) in THF at 0 8C for 15–22 h, the desired

2-alkylated 4-ﬂuorohomoallylic alcohols 6a–6c were

obtained in good to excellent yields (62–98%) with

complete Z- and 2,5-syn selectivity (Table 2, entries 2–7).¹⁹

In the absence of CuI$2LiCl, no reaction occurred upon

treating 5a with Me₃Al to result in the recovery of 5a

(Table 2, entry 1). Thus, Cu(I) is a crucial additive for the

present alkyl-transfer reaction of trialkylaluminum to

proceed,^22,23possibly through the Al–Cu transmetalation

and activation of ﬂuorine atom as a leaving group by

aluminum–ﬂuorine interaction (see mechanistic dis-

cussion).^24,25As shown in Table 2, with either phenyl or

alkyl (phenethyl and benzyl) substituted derivatives, not

only methyl but also longer alkyl (iso-butyl) aluminum

reagent gave the satisfactory results. Thus, we could provide

a highly general and stereocontrolled method for 2-alkyl-

ated (Z)-2,5-syn-4-ﬂuoro-5-hydroxy-3-alkenols 6 from

E-isomer of diﬂuoroallylic alcohols 5.

Next, to see the substrate speciﬁcity of the present Cu(I)-

mediated alkyl-transfer reaction of trialkylaluminum with

Next, the reactivity of Z-isomer of diﬂuoroallylic alcohols

5d, 5e and their stereochemical outcome were compared

with those of E-isomers 5a, 5c. The results are shown in

Table 3. The reaction of Z-isomer 5d under the similar

Scheme 5.

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

5745

4,4-diﬂuoroallylic alcohol derivatives and for mechanistic

consideration about the excellent stereoselectivity observed

in the reaction with (E)-isomer of 5-hydroxyl derivatives 5

(see Table 2), we examined similar reactions using various

structure-modiﬁed substrates (Scheme 5).

involve Al–Cu transmetalation since without Cu(I) no

reaction occurred. Furthermore, on the basis of absolutely

essential functionality of the C5-hydroxyl group in the

substrate 5 as shown in Scheme 5 and relatively strong

ﬂuorine–aluminum coordination,^24,25it would be expected

that activation of ﬂuorine atom as a leaving group can be

gained by the formation of a ﬁve-membered complex A

easily formed when the substrate 5 is mixed with

trialkylaluminum. Due to the steric reason, the complex A

which is trans isomer with respect to the relative

stereochemistry between propenyl moiety and R substituent

may be more favorable as compared with complex B, the

corresponding cis isomer (Scheme 6, step 1).

First, the reaction of the substrate 9a prepared by silylation

of the primary hydroxyl group of 5a was examined to see

the effect of allylic alcohol structure on the reactivity. This

substrate 9a showed similar reactivity to that of non-

protected substrate 5a to give the 2-methylated product 10a

in 81% yield with an excellent Z-selectivity and high 2,5-syn

selectivity. On the other hand, etheriﬁcation of both

hydroxyl groups (substrate 9b) and removal of C5-hydroxyl

group (substrate 9c) resulted in complete recovery of these

substrates upon treating with Me₃Al and CuI$2LiCl in THF.

Moreover, replacement of C5-hydroxyl group by an amino

group such as 4-methoxyanilino derivative 13a also led to

the recovery of the starting material. From these results, it

was clearly demonstrated that the free hydroxyl group at

5-position should be essential for the Cu(I)-mediated alkyl-

transfer reaction of trialkylaluminum, while the allylic

alcohol structure is not always required.

Next, we analyzed alkyl-transfer process on the assumption

that in the complex form A the ﬂuorine atom coordinating to

aluminum acts as a leaving group²⁴and the reaction

proceeds via oxidative addition of aluminocuprate formed

by Al–Cu transmetalation.

From the accumulated data, the copper-mediated allylic

alkylation reactions proceed through either anti or syn to the

leaving group depending on the type of leaving group,

nature of organometallics used and sometimes on the

additive.^26–30In our reaction using E isomer of 4,4-

diﬂuoroallylic alcohol E-5, when the oxidative addition of

methylcopper occurs from anti to the leaving ﬂuorine atom

as shown in the model D^‡, the stereochemistry of the

product should be 3Z and 2,5-anti, although the observed

stereochemistry was 2,5-syn. Alternatively, if we consider

the syn-addition of copper to the leaving group through an

intramolecular process of the aluminocuprate as shown in

the model C^‡, the expected stereochemistry of the product is

essentially identical with the observed (3Z)-2,5-syn stereo-

chemistry (Scheme 6, step 2).

2.3. Mechanism

Although mechanistic detail is not clear at this moment, the

above mentioned alkyl-transfer reaction may involve Al–Cu

transmetalation and activation of ﬂuorine atom as a leaving

group through ﬂuorine–aluminum coordination.

As such examples of copper-mediated alkyl-transfer reac-

tions of alkylaluminum were reported conjugate addition

with a,b-enones²²and allylic substitution with allylic

phosphates and halides.²³Similar to these reactions, we

believe that the present deﬂuorinative allylic alkylation of

diﬂuoroallylic alcohol 5 with trialkylaluminum should

This intramolecular process may be similar to the syn allylic

Scheme 6. Mechanism for (3Z)-2,5-syn selectivity with E-5.

5746

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

substitution reaction with allylic NH-carbamate derivatives,

in which the carbamate anion acts as a ligand onto the

alkylcopper species to form the ate complex as shown in the

model E^‡, thereby the alkyl-transfer reaction occurs

intramolecularly in syn selective manner (Scheme 7).²⁸

Likewise, in the model C^‡, methyl group on the aluminum

coordinated by the ﬂuorine atom possibly acts as a ligand

onto methyl copper to form aluminocuprate ate complex

(Scheme 6).

mentioned ﬂuoroallylic alcohol derivative 6 prepared in

completely stereoselective manner (Table 2). In a literature,

although the substitution reaction of the primary hydroxyl

group of ﬂuoroallylic alcohols by the Mitsunobu reaction

(Ph₃P, DEAD, phthalimide) proceeded smoothly,^3,4those of

secondary allylic alcohols seem to be difﬁcult due to the low

reactivity.^1e,2a,16aSimilar tendency was also observed in our

case. That is, the Mitsunobu reactions of the pivaloyl ester

derivative 7b-1, 7c-1 were conducted, but these were not

fruitful to result in only recovery of the starting materials.

We also examined stepwise procedure involving sulfonyl-

ation of the hydroxyl group followed by the subsequent

substitution reaction with sodium azide or benzylamine

under various reaction conditions. Most of these experi-

ments resulted in a messy mixture due to the instability of

these allylic sulfonates. While such a problematic event in

allylic substitution reaction is quite common, there have

been some successful examples reported so far.^31,32For

example, by one-pot reaction of mesylation of hydroxyl

group in the presence of large excess amount of sodium

azide, a clean SN2 replacement of an optically pure benzylic

hydroxyl group (5,6,7,8-tetrahydroisoquinolinE-8-ol or

benzhydrol derivative) was reported.^33,34Similar one-pot

operation was found to work very nicely with our

ﬂuoroallylic alcohol derivatives 7b-1, 7c-1. Thus, after a

mixture of the alcohol 7b-1, dimethylaminopyridine

(DMAP, 3 equiv) and sodium azide (20 equiv) suspended

in CH₂Cl₂was treated with methanesulfonyl chloride

(3 equiv) for 30 min at room temperature, a clear solution

by the addition of DMSO was further stirred for 3 h at the

same temperature giving rise to the desired 5-azide

derivative 15b in high yield. Since the rearrangement of

the allylic azide forming 3-azide isomer seemed to easily

occur, conversion of the azide 15b to N-Boc-protected

amino derivative 8b was carried out immediately after

azidation reaction, while we obtained the desired 8b along

with the formation of rearranged isomer 17b as a by-

product. Thus, by treatment of crude 15b with LiAlH₄

followed by with di-t-butyl dicarbonate and triethylamine

we obtained 8b and 17b in 77% and 9% yield, respectively.

The 2,5-anti stereochemistry was unambiguously conﬁrmed

by X-ray analysis of 8b indicating that the present one-pot

azidation reaction proceeded in a complete inversion

Scheme 7. syn-Allylic substitution of NH-carbamate with alkylcuprate.

Contrary to the E isomer of the substrate E-5, in the case of

Z isomer Z-5, which showed lower reactivity and moderate

2,5-anti selectivity in the product (see Table 3), the ﬁve-

membered complex form F would be more unstable as

compared with the complex form A due to the unfavorable

steric interaction between C1 and C4 (fully substituted

carbon atom) in the complex F, thereby the reaction of Z-5

showed lower reactivity. Furthermore, as a possible

explanation for the moderate 2,5-anti selectivity, while the

intramolecular alkyl transfer through the model G^‡provides

the major 2,5-anti product, competitive intermolecular

oxidative anti-addition of methylcopper to the ﬂuorine

atom coordinating to aluminum as shown in the model H^‡

would be a reaction pathway for 2,5-syn product

(Scheme 8).

2.4. Conversion of chiral ﬂuoroallylic alcohol to N-Boc

amino derivative

As mentioned above, towards to the direct production of

peptide isostere the present Cu(I)-mediated alkyl-transfer

reaction could not be applicable to the substrate having

amino group at 5-position (see Scheme 5, 13a). Therefore,

we examined the regio- and stereoselective conversion of

C5-hydroxyl group to amino group using the above

Scheme 8. Mechanism for (3Z)-2,5-anti selectivity with Z-5.

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

5747

Scheme 9. Reagent and conditions: (1) DMAP (3 equiv), NaN₃(20 equiv), MsCl (3 equiv), CH₂Cl₂, rt, 30 min; (2) DMSO, rt, 3 h; (3) LiAlH₄, THF, 1.5 h; (4)

(Boc)₂O, Et₃N, CH₂Cl₂, rt, 30 min.

fashion. Similar stereoselective conversion from 7c-1 to 8c

was also achieved (Scheme 9). However, under the similar

reaction conditions the benzylic alcohol derivative 7a-1

(RZPh) gave a complex mixture, possibly due to the highly

labile nature of the corresponding mesylate.

benzotriﬂuoride (0 ppm) as an internal standard. Mass

spectra and HRMS were recorded by EI or ESI methods.

Column chromatography was performed on silica gel (70–

230 mesh). Medium-pressure liquid chromatography

(MPLC) was performed on a 30 cm!2.2 cm i.d. prepacked

column (silica gel, 50 mm) with a UV or RI detector.

It should be noted that ﬂuoroallylic azide 15b, 15c thus

obtained slowly isomerize to 3-azide derivatives.^32,35Thus,

when a solution of 5-azide 15b in CDCl₃was left at room

temperature for 3 days, 15b changed to a mixture of 15b and

the 3-azide isomer 16b in a ratio of 1.8:1 (Scheme 10).

4.2. Preparation of 5-substituted (E)-4,4-diﬂuoro-2-

pentene-1,5-diol (5)

A mixture of ethyl ester of 5-substituted (E)-4,4-diﬂuoro-5-

hydroxy-2-pentenoic acid¹⁷(5 mmol) and DIBAL (1 M

hexane solution, 15 mmol) in THF was stirred at K70 8C

for 30 min. The reaction mixture was quenched with 5%

HCl and extracted with AcOEt. The combined organic layer

was dried over anhydrous Na₂SO₄, and then concentrated in

vacuo. The residue was puriﬁed by silica gel column

chromatography to give E-5.

4.2.1. (E)-4,4-Diﬂuoro-5-phenyl-2-pentene-1,5-diol (5a).

Quant. Colorless oil. IR (CHCl₃) n cm^K1; 3622, 3150–3600,

2902, 1683. ¹H NMR (400 MHz, CDCl₃) d; 2.66 (1H, brs),

3.62 (1H, brs), 4.10 (2H, s), 4.84 (1H, t, JZ9.6 Hz), 5.73–

5.85 (1H, m), 6.07–6.17 (1H, m), 7.26–7.43 (5H, m). ¹³C

NMR (100.6 MHz, CDCl₃) d; 61.6, 75.8 (t, JZ30.5 Hz),

119.7 (t, JZ244.3 Hz), 121.5 (t, JZ25.4 Hz), 127.7, 128.2,

128.7, 136.2 (d, JZ2.7 Hz), 136.6 (t, JZ8.2 Hz). ¹⁹F NMR

(376.5 MHz, CDCl₃) d; K41.61 (1F, d, JZ247 Hz),

K45.09 (1F, dt, JZ247, 11 Hz). EI-MS m/z; 196 (M^CK

H₂O), 177, 107. HRMS; calcd for C₁₁H₁₀F₂O (M^CKH₂O):

196.0700. Found: 196.0712.

Scheme 10.

3. Conclusion

In conclusion, we have established a stereoselective

(completely Z and 2,5-syn selective) synthesis of

5-hydroxylated 2-alkyl-4-ﬂuoro-3-alkene-1-ol derivatives

through the deﬂuorinative allylic substitution reaction of

diﬂuoroallylic alcohol derivatives with trialkylaluminum

and Cu(I). Furthermore, a high yield and complete inversive

conversion of C5-hydroxyl group of these stereoselectively

synthesized ﬂuoroallylic alcohol derivatives to amino group

could be achieved through one-pot preparation of azide

compound. The present reaction should provide an efﬁcient

method for the preparation of functionalized Z-ﬂuorooleﬁns,

which, in particular, are applicable to the preparation of

depsipeptide isosteres and dipeptide isosteres.

4.2.2. (E)-4,4-Diﬂuoro-7-phenyl-2-heptene-1,5-diol (5b).

61% yield. Colorless oil. IR (CHCl₃) n cm^K1; 3622, 2932,

2866, 1683. ¹H NMR (400 MHz, CDCl₃) d; 1.70–1.84 (1H,

m), 1.90–2.04 (1H, m), 2.60–2.74 (1H, m), 2.84–2.96 (1H,

m), 3.45 (1H, s), 3.69 (1H, s), 3.74 (1H, m), 4.20 (2H, s),

5.80–5.96 (1H, m), 6.18–6.30 (1H, m), 7.21–7.32 (5H, m).

¹³C NMR (100.6 MHz, CDCl₃) d; 31.5, 61.5, 72.7 (t, JZ

30.2 Hz), 120.5 (t, JZ243.3 Hz), 121.6 (t, JZ25.6 Hz),

126.0, 128.4, 136.1 (t, JZ8.4 Hz), 141.1. ¹⁹F NMR

(376.5 MHz, CDCl₃) d; K42.42 (1F, d, JZ248 Hz),

K47.98 (1F, d, JZ248 Hz). EI-MS m/z; 242 (M^C), 224

(M^CKH₂O), 206, 117. HRMS; calcd for C₁₃H₁₆F₂O₂

(M^C): 242.1118. Found: 242.1104.

4. Experimental

4.1. General

Trimethylaluminum (1.0 M in hexane) and triisobutyl-

aluminum (1.0 M in hexane) are available commercially.

All reactions were conducted under an argon atmosphere.

¹H and ¹³C NMR spectra were measured at 400 and

100 MHz in CDCl₃, and the chemical shifts are given in

4.2.3. (E)-4,4-Diﬂuoro-6-phenyl-2-hexene-1,5-diol (5c).

97% yield. Colorless oil. IR (CHCl₃) n cm^K1; 3620, 3460,

2924, 1732, 1682. ¹H NMR (400 MHz, CDCl₃) d; 2.58 (1H,

brs), 2.69 (1H, dd, JZ14.2, 10.4 Hz), 2.90 (1H, d, JZ

8.0 Hz), 3.03 (1H, dd, JZ14.2, 2.4 Hz), 3.98 (1H, m),

4.23 (2H, s), 5.92–5.96 (1H, m), 6.29–6.34 (1H, m),

1

ppm using CHCl₃(7.26 ppm) in CDCl₃for H NMR and

CDCl₃(77.01 ppm) for ¹³C NMR as an internal standard,

respectively. ¹⁹F NMR spectra were measured at

376.5 MHz and the chemical shifts are given in ppm using

5748

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

7.24–7.36 (5H, m). ¹³C NMR (100.6 MHz, CDCl₃) d; 36.44,

61.65, 74.62 (t, JZ30.3 Hz), 120.18 (t, JZ243.5 Hz),

121.64 (t, JZ25.4 Hz), 126.69, 128.53, 129.35, 136.34

(t, JZ8.4 Hz), 137.31. ¹⁹F NMR (376.5 MHz, CDCl₃) d;

K42.38 (1F, d, JZ249 Hz), K48.46 (1F, dt, JZ249,

12 Hz). EI-MS m/z; 228 (M^C), 210 (M^CKH₂O), 190, 121.

HRMS; calcd for C₁₂H₁₄F₂O₂(M^C): 228.0962. Found:

228.0954.

residue was puriﬁed by silica gel column chromatography

[hexane/AcOEt (20:1)] to give a diastereomeric mixture of

ethyl (Z)-4,4-diﬂuoro-6-phenyl-5-(tetrahydro-2H-pyran-2-

yloxy)-2-hexenoate (1.25 g, 59% yield), which was separ-

ated by MPLC [hexane/AcOEt (5:1)] to give less polar

isomer and more polar isomer in the order of elution. Less

polar: colorless oil. IR (neat) n cm^K1; 1732. ¹H NMR

(400 MHz, CDCl₃) d; 1.29 (3H, t, JZ7.2 Hz), 1.21–1.33

(1H, m), 1.36–1.49 (1H, m), 1.56–1.73 (3H, m), 2.77–2.85

(1H, m), 2.86 (1H, dd, JZ14.2, 9.1 Hz), 2.98–3.05 (1H, m),

3.04 (1H, dd, JZ14.2, 4.2 Hz), 4.23 (2H, q, JZ7.2 Hz),

4.49–4.59 (1H, m), 4.95 (1H, t, JZ2.7 Hz), 5.97 (1H, dt,

JZ14.6, 12.7 Hz), 6.09 (1H, dt, JZ12.7, 1.6 Hz), 7.17–7.23

(1H, m), 7.25–7.32 (4H, m). ¹⁹F NMR (376.5 MHz, CDCl₃)

d; K38.7 (1F, ddd, JZ257, 13, 13 Hz), K40.9 (1F, ddd, JZ

257, 14, 8 Hz). EI-MS m/z; 355 (M^CCH), 252. Anal. Calcd

for C₁₉H₂₄F₂O₄: C, 64.39; H, 6.83. Found: C, 64.53; H,

4.2.4. (Z)-4,4-Diﬂuoro-5-phenyl-2-pentene-1,5-diol (5d).

To a suspension of 5% Pd–BaSO₄(183 mg, 0.54 mmol) in

MeOH (5 ml) was added dropwise quinoline (183 mg,

1.42 mmol) in MeOH (5 ml) at 0 8C and the mixture was

stirred at room temperature for 15 min. To this mixture was

added 5-{[tert-butyl(diphenyl)silyl]oxy}-2,2-diﬂuoro-1-

phenyl-3-pentyn-1-ol³⁶(1.971 g, 4.38 mmol) in DMF

(5 ml) at room temperature and then under a hydrogen

atmosphere the mixture was stirred at room temperature

for 4 h. The reaction mixture was ﬁltrated through celite

pad with the aid of AcOEt. The combined ﬁltrate was

diluted with water and extracted with AcOEt. The

combined organic layer was washed with brine, dried over

anhydrous Na₂SO₄, and evaporated in vacuo. The residue

was puriﬁed by silica gel column chromatography [hexane/

AcOEt (5:1)] to give TBDPS-5d (1.851 g, 93% yield).

After a mixture of TBDPS-5d (358 mg, 0.79 mmol) and

TBAF (1 M THF solution, 0.5 ml, 0.5 mmol) in THF (5 ml)

was stirred at room temperature for 3 h, the reaction

mixture was poured into water and extracted with AcOEt.

The organic layer was washed with brine, dried over

anhydrous Na₂SO₄, and evaporated in vacuo. The residue

was puriﬁed by silica gel column chromatography

[hexane/AcOEt (2:1)] to give 5d (97 mg, 57% yield) as

colorless oil. IR (neat) n cm^K1; 3608, 3448, 3048, 2896. ¹H

NMR (400 MHz, CDCl₃) d; 2.59 (1H, brs), 3.95–4.10 (2H,

br), 4.10–4.20 (1H, br), 4.85 (1H, t, JZ9.2 Hz), 5.36–5.49

(1H, m), 5.86–5.95 (1H, m), 7.33–7.40 (5H, m). ¹³C NMR

(100.6 MHz, CDCl₃) d; 58.6 (d, JZ3.2 Hz), 75.5 (t, JZ

30.3 Hz), 120.7 (t, JZ245.4 Hz), 122.0 (t, JZ26.5 Hz),

127.7, 128.1, 128.7, 136.0 (d, JZ3.6 Hz), 138.3 (t, JZ

5.1 Hz). ¹⁹F NMR (376.5 MHz, CDCl₃) d; K37.7 (1F,

ddd, JZ253, 12, 12 Hz), K38.9 (1F, ddd, JZ253, 12,

12 Hz). EI-MS m/z; 196 (M^CKH₂O), 107, 90, 77. HRMS;

calcd for C₁₁H₁₀F₂O (M^CKH₂O): 196.0700. Found:

196.0716.

1

6.83. more polar: colorless oil. IR (neat) n cm^K1; 1744. H

NMR (400 MHz, CDCl₃) d; 1.30 (3H, t, JZ7.2 Hz), 1.25–

1.47 (5H, m), 1.63–1.74 (1H, m), 2.83 (1H, dd, JZ14.0,

9.8 Hz), 3.11 (1H, dd, JZ14.0, 3.0 Hz), 3.32 (1H, dd, JZ

11.2, 4.9 Hz), 3.83 (1H, ddd, JZ11.5, 5.9, 5.9 Hz), 3.96

(1H, t, JZ3.5 Hz), 4.24 (2H, q, JZ7.2 Hz), 4.38–4.48 (1H,

m), 6.10–6.23 (2H, m), 7.20–7.31 (5H, m). ¹⁹F NMR

(376.5 MHz, CDCl₃) d; K37.2 (1F, ddd, JZ258, 9, 9 Hz),

K44.3 (1F, ddd, JZ258, 13, 13 Hz). EI-MS m/z; 355

(M^CCH), 271, 252. HRMS; calcd for C₁₉H₂₄F₂O₄Na

(M^CCNa): 377.1540. Found: 377.1555. To a solution of

the above obtained more polar isomer (1.25 g, 3.52 mmol)

in THF (20 ml) was added dropwise DIBAL (0.95 M

hexane solution, 15 ml, 14.0 mmol) at K78 8C, and then the

mixture was quenched with water after being stirred for

30 min. The organic layer was decanted and the residue was

washed with ether twice. The combined organic layer was

dried over anhydrous Na₂SO₄and concentrated in vacuo.

The residue was puriﬁed by silica gel column chromato-

graphy [hexane/AcOEt (3:1)] to give (Z)-4,4-diﬂuoro-6-

phenyl-5-(tetrahydro-2H-pyran-2-yloxy)-hexenol (THP-

5e). After a mixture of THP-5e and a catalytic amount of

p-toluenesulfonic acid in MeOH (10 ml) was stirred at room

temperature for 1 h, the reaction mixture was concentrated

in vacuo and the residue was puriﬁed by silica gel column

chromatography [hexane/AcOEt (2:1)] to give 5e (465 mg,

58% yield) as colorless oil. IR (CHCl₃) n cm^K1; 3608, 3440,

3024, 2932, 1954, 1660, 1602. ¹H NMR (400 MHz, CDCl₃)

d; 2.66 (1H, dd, JZ14.0, 10.6 Hz), 2.74 (1H, brs), 3.00 (1H,

dd, JZ14.0, 1.5 Hz), 3.16 (1H, d, JZ2.6 Hz), 3.87–4.00

(1H, m), 4.31 (2H, s), 5.58 (1H, dd, JZ15.6, 28.3 Hz), 5.95–

6.07 (1H, m), 7.22–7.33 (5H, m). ¹³C NMR (100.6 MHz,

CDCl₃) d; 36.4, 58.8, 74.5 (t, JZ30.2 Hz), 121.0 (t, JZ

244.6 Hz), 122.3 (t, JZ26.6 Hz), 126.8, 128.6, 129.3,

137.2, 138.5 (t, JZ5.2 Hz). ¹⁹F NMR (376.5 MHz,

CDCl₃) d; K37.7 (1F, dd, JZ256, 2 Hz), K43.0 (1F, dt,

JZ256, 14 Hz). EI-MS m/z; 229 (M^CCH), 210. HRMS;

calcd for C₁₂H₁₅F₂O₂(M^CCH): 229.1040. Found:

229.1070.

4.2.5. (Z)-4,4-Diﬂuoro-6-phenyl-2-hexene-1,5-diol (5e).

After a mixture of ethyl (Z)-2,2-diﬂuoro-4-phenyl-3-(tetra-

hydro-2H-pyran-2-yloxy)-butanoate (1.90 g, 5.98 mmol)

and Red-Ale (65% toluene solution, 4.3 ml, 7.18 mmol)

in THF (15 ml) was stirred at K78 8C for 30 min, the

reaction mixture was quenched with 5% HCl. Extractive

workup (AcOEt for extraction) followed by concentration

in vacuo left an oily aldehyde, which was used for the

next step without further puriﬁcation. Under an argon

atmosphere, to a mixture of NaH (60% in oil, 264 mg,

6.58 mmol) and triethyl phosphonoacetate (1.92 g,

5.98 mmol) in DMF (10 ml) at 0 8C was added the aldehyde

mentioned above in DMF (5 ml), and the mixture was

stirred for 20 min. The reaction mixture was quenched with

5% HCl, extracted with ether. The combined organic layer

was washed with NaHCO₃aq, brine and dried over

anhydrous Na₂SO₄and then evaporated in vacuo. The

4.3. Preparation of (E)-4,4-diﬂuoro-5-phenyl-2-pentenol

derivatives

4.3.1. 4,4-Diﬂuoro-5-phenyl-2-pentenol (9c). After a

mixture of ethyl 2,2-diﬂuoro-3-phenylpropionate³⁷(1.29 g,

7.6 mmol) in THF (10 ml) and DIBAL (11.4 ml, 1 M

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

5749

hexane solution, 11.4 mmol) was stirred at K78 8C for

30 min, the reaction mixture was quenched by water

followed by the similar extractive workup procedure used

for THP-5e gave an oily aldehyde, which was used for the

next step without further puriﬁcation. To a suspension of

NaH (60% oil, 334 mg, 8.36 mmol) in THF (10 ml) was

added triethyl phosphonoacetate (1.874 g, 8.36 mmol) in

THF (10 ml) at 0 8C, and after 10 min, to this mixture was

added the solution of previous aldehyde in THF (10 ml) at

0 8C. The mixture was stirred at 0 8C for 1 h and the reaction

mixture was quenched with 5% HCl, extracted with AcOEt.

The organic layer was washed with brine, dried over

anhydrous Na₂SO₄, and concentrated in vacuo. The residue

was puriﬁed by silica gel column chromatography [hexane/

AcOEt (20:1)] to give a crude mixture, which was further

separated by MPLC [hexane/AcOEt (30:1)] to give ethyl

(E)-4,4-diﬂuoro-5-phenylpent-2-enoate (310 mg, 17%

yield) and starting material (240 mg, 15% yield) in the

order of elution. Ethyl (E)-4,4-diﬂuoro-5-phenylpent-2-

enoate: colorless oil. IR (neat) n cm^K1; 3035, 2984, 2929,

1727. ¹H NMR (400 MHz, CDCl₃) d; 1.29 (3H, t, JZ

7.2 Hz), 3.25 (2H, t, JZ16.0 Hz), 4.21 (2H, q, JZ7.2 Hz),

6.18 (1H, dt, JZ15.6, 11.6 Hz), 6,76 (1H, dt, JZ15.6,

2.4 Hz), 7.22–7.38 (5H, m). ¹³C NMR (100.6 MHz, CDCl₃)

d;.13.79, 43.45 (t, JZ26.1 Hz), 60.79, 119.15 (t, JZ

241.4 Hz), 124.97 (t, JZ8.5 Hz), 127.34, 128.20, 130.17,

131.37, 138.60 (t, JZ27.3 Hz), 164.67. ¹⁹F NMR

(376.5 MHz, CDCl₃) d; K34.61 (2F, m). A mixture of the

above ester (51 mg, 0.21 mmol) in THF (5 ml) and DIBAL

(1 M hexane solution, 0.84 mmol) was stirred at K78 8C for

1 h. Usual extractive workup mentioned above and

puriﬁcation by silica gel column chromatography

[hexane/AcOEt (2:1)] gave 9c (42 mg, quantitative) as

colorless oil. IR (neat) n cm^K1; 3624, 3300–3600, 2932,

in THF (3 ml), was added at K30 8C the Gilman reagent

prepared from CuI (476 mg, 2.5 mmol) and MeLi (1.14 M

diethyl ether solution, 4.4 ml, 5 mmol) in THF (3 ml). After

being stirred at 0 8C for 1.5 h, the reaction mixture was

quenched with 5% HCl and ﬁltered through celite pad. The

ﬁltrate was extracted with AcOEt and washed with

NaHCO₃aq and brine. The organic layer was dried over

anhydrous Na₂SO₄, and then concentrated in vacuo. The

residue was puriﬁed by silica gel column chromatography

[hexane/AcOEt (1:1)] to give syn-6a-1 (92 mg, 88% yield)

as colorless crystals. Mp 102–104 8C. IR (CHCl₃) n cm^K1

;

1

3616, 3150–3555, 2968, 2878, 1707. H NMR (400 MHz,

CDCl₃) d; 1.01 (3H, d, JZ6.9 Hz), 1.68–1.90 (1H, brs),

2.79–2.90 (1H, m), 3.41 (1H, dd, JZ10.5, 7.8 Hz), 3.55

(1H, dd, JZ10.5, 5.6 Hz), 4.82 (1H, dd, JZ37.4, 9.6 Hz),

5.20 (1H, d, JZ10.7 Hz), 7.28–7.44 (5H, m). ¹³C NMR

(100.6 MHz, CDCl₃) d; 16.8, 32.0 (d, JZ2.6 Hz), 67.4, 72.5

(d, JZ33.1 Hz), 109.5 (d, JZ12.6 Hz), 126.7, 128.5 (d, JZ

22.5 Hz), 139.5, 158.6, 161.1. ¹⁹F NMR (376.5 MHz,

CDCl₃) d; K56.5 (1F, dd, JZ37.4, 10.5 Hz). EI-MS m/z;

190 (M^CKHF), 162, 147. Anal. Calcd for C₁₂H₁₅F₂O₂: C,

68.55; H, 7.19. Found: C, 68.51; H, 7.19.

4.4.2. (2R*,3Z,5R*)-4-Fluoro-2-methyl-6-phenyl-3-

hexene-1,5-diol (anti-6c-1) and (E)-4-ﬂuoro-2-methyl-6-

phenyl-3-hexene-1,5-diol (E-6c-1). Compound anti-6c-1

was prepared from 5e and Gilman reagent. Puriﬁcation by

silica gel column chromatography [hexane/AcOEt (1:1)]

gave a mixture of 6c-1 (100 mg, 89% yield, Z/EZ14:1, syn/

antiZ1:2 for Z-isomer), which was further puriﬁed by

MPLC [hexane/AcOEt (1:1)] to give E-6c-1, syn-6c-1, anti-

6c-1 in the order of elution. anti-6c-1: colorless oil. IR

(neat) n cm^K1; 3682, 3604, 3414, 3013, 2962, 2875, 2400,

1708. ¹H NMR (400 MHz, CDCl₃) d; 0.87 (3H, d, JZ

6.9 Hz), 2.30 (1H, brs), 2.71–2.84 (1H, m), 2.92 (1H, dd,

JZ13.6, 7.2 Hz), 3.00 (1H, dd, JZ13.6, 6.3 Hz), 3.15 (1H,

brs), 3.27 (1H, dd, JZ10.5, 8.2 Hz), 3.49 (1H, dd, JZ10.6,

5.2 Hz), 4.27 (1H, dt, JZ17.4, 6.7 Hz), 4.51 (1H, dd, JZ

37.5, 9.6 Hz), 7.20–7.32 (5H,m). ¹³C NMR (100.6 MHz,

CDCl₃) d; 16.6, 31.8 (d, JZ1.7 Hz), 40.1, 67.3, 71.8 (d, JZ

30.0 Hz), 110.1 (d, JZ12.9 Hz), 126.7, 128.4, 129.5, 137.1,

159.2 (d, JZ258.6 Hz). ¹⁹F NMR (376.5 MHz, CDCl₃) d;

K62.4 (1F, dd, JZ35, 18 Hz). EI-MS m/z: 224 (M^C), 207,

204. HRMS; calcd for C₁₃H₁₇FO₂(M^C); 224.1213. Found:

224.1208. E-6c-1: colorless oil. IR (neat) n cm^K1; 3687,

3599, 3424, 3028, 2965, 2930, 2875, 2401, 1697. ¹H NMR

(400 MHz, CDCl₃) d; 0.90 (3H, dd, JZ6.7, 0.6 Hz), 2.31–

2.48 (2H, m), 2.97 (1H, dd, JZ10.3, 8.6 Hz), 3.00 (1H, dd,

JZ13.3, 6.8 Hz), 3.04 (1H, dd, JZ13.3, 7.2 Hz), 3.23 (1H,

dd, JZ10.3, 4.8 Hz), 4.61 (1H, dt, JZ22.7, 7.0 Hz), 4.90

(1H, dd, JZ22.5, 10.7 Hz), 7.23–7.34 (5H, m). ¹⁹F NMR

(376.5 MHz, CDCl₃) d; K57.0 (1F, dd, JZ23, 23 Hz). EI-

MS m/z; 225 (M^CCH), 207 (M^CKOH), 187. HRMS; calcd

for C₁₃H₁₆FO (M^CKOH): 207.1185. Found: 207.1183.

1

1682, 1604. H NMR (400 MHz, CDCl₃) d;1.77–1.93 (1H,

brs), 3.20 (2H, t, JZ15.7 Hz), 4.08–4.16 (2H, brs), 5.71–

5.83 (1H, m), 6.05–6.14 (1H, m), 7.18–7.35 (5H, m). ¹³C

NMR (100.6 MHz, CDCl₃) d; 44.1 (t, JZ27.6 Hz),

61.6, 120.3 (t, JZ240.2 Hz), 124.4 (t, JZ26,6 Hz), 127.3,

128.3, 130.5, 132.8 (t, JZ4.2 Hz), 134.6 (t, JZ8.3 Hz). ¹⁹F

NMR (376.5 MHz, CDCl₃) d; K31.77 (2F, td, JZ22.5,

15 Hz).

4.3.2. 4,4-Diﬂuoro-5-(4-methoxyphenylamino)-5-phenyl-

2-penten-1-ol (13a). Compound 13a was prepared

from 3,3-diﬂuoro-1-(4-methoxyphenyl)-4-phenylazetidin-

2-one³⁸through the reduction by DIBAL followed

by Horner–Emmons reaction. Colorless oil. ¹H NMR

(300 MHz, CDCl₃) d; 1.40–1.65 (2H, br), 3.69 (3H, s),

4.17–4.27 (2H, m), 4.62 (1H, t, JZ11.0 Hz), 5.80–5.96

(1H, m), 6.16–6.20 (1H, m), 6.50–6.56 (2H, m), 6.64–

6.72 (2H, m), 7.24–7.45 (5H, m). ¹⁹F NMR

(376.5 MHz, CDCl₃) d; K40.4 (1F, d, JZ244 Hz), K42.0

(1F, dt, JZ244 Hz). EI-MS m/z; 319 (M^C), 212 (M^CK

Anis).

4.5. General procedure for the reaction of diﬂuoroallylic

alcohol derivatives 5 with trialkylaluminum in the

presence of CuI$2LiCl

4.4. General procedure for the reaction of diﬂuoroallylic

alcohol derivatives 5 with lithium dimethylcuprate in the

presence of Me₃Al

4.5.1. (2R*,3Z,5S*)-4-Fluoro-2-methyl-7-phenyl-3-hep-

tene-1,5-diol (syn-6b-1). To a solution of 5b (121 mg,

0.5 mmol) in THF (3 ml) was added Me₃Al (1 M hexane

solution, 2.5 ml, 2.5 mmol) at K30 8C, and then copper

4.4.1. (1R*,2Z,4S*)-2-Fluoro-4-methyl-1-phenyl-2-pen-

tene-1,5-diol (syn-6a-1). To a mixture of 5a (107 mg,

0.5 mmol) and Me₃Al (1 M hexane solution, 5 ml, 5 mmol)

5750

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

reagent prepared from CuI (468 mg, 2.5 mmol) and LiCl

(212 mg, 5 mmol) in THF (3 ml) was added at K30 8C.²¹

After being stirred at 0 8C for 20 h, the reaction mixture was

quenched with 5% HCl and ﬁltered through celite pad. The

ﬁltrate was extracted with AcOEt and washed with

NaHCO₃aq and brine. The organic layer was dried over

anhydrous Na₂SO₄, and then concentrated in vacuo.

Puriﬁcation by silica gel column chromatography [hexane/

AcOEt (1:1)] gave a mixture (115 mg) of syn-6b-1 (65%

yield) and 5b (31% recovery), which was further puriﬁed by

MPLC [hexane/AcOEt (1:1)] to give 5b and syn-6b-1 in the

125.9, 128.4, 128.5, 141.5, 161.9 (d, JZ257.2 Hz). ¹⁹F

NMR (376.5 MHz, CDCl₃) d; K56.8 (1F, dd, JZ38,

13 Hz). EI-MS m/z; 280 (M^C), 243, 232, 156, 91. HRMS;

calcd for C₁₇H₂₅FO₂(M^C): 280.1839. Found: 280.1821.

4.5.4. (2R*,3Z,5S*)-4-Fluoro-2-methyl-6-phenyl-3-hex-

ene-1,5-diol (syn-6c-1). Compound syn-6c-1 was prepared

from 5c and trimethylaluminum. Puriﬁcation by silica gel

column chromatography [hexane/AcOEt (1:1)] gave syn-6c-

1 (110 mg, 98% yield) as colorless oil. IR (CHCl₃) n cm^K1

;

3608, 3416, 3024, 2872, 1706. ¹H NMR (400 MHz, CDCl₃)

d; 0.93 (3H, d, JZ6.9 Hz), 2.70–2.83 (1H, m), 2.88 (1H, dd,

JZ13.6, 7.5 Hz), 2.99 (1H, dd, JZ13.6, 6.0 Hz), 3.24 (1H,

dd, JZ10.6, 7.8 Hz), 3.42 (1H, dd, JZ10.6, 5.4 Hz), 4.26

(1H, ddd, JZ13.6, 7.5, 6.0 Hz), 4.56 (1H, dd, JZ38.2,

9.6 Hz), 7.20–7.32 (5H, m). ¹³C NMR (100.6 MHz, CDCl₃)

d; 16.6, 31.7 (d, JZ2.7 Hz), 40.5, 67.1, 71.3 (d, JZ

31.9 Hz), 109.0 (d, JZ12.5 Hz), 126.6, 128.3, 129.4, 137.1,

159.7 (d, JZ257.9 Hz). ¹⁹F NMR (376.5 MHz, CDCl₃) d;

K61.0 (1F, dd, JZ38.2, 13.6 Hz). EI-MS m/z; 224 (M^C),

204, 187, 176, 91. HRMS; calcd for C₁₃H₁₇FO₂(M^C):

224.1213. Found: 224.1213.

order of elution. syn-6b-1: colorless oil. IR (CHCl₃) n cm^K1

;

1

3620, 3432, 3032, 2964, 2936, 2876, 1706, 1602. H NMR

(400 MHz, CDCl₃) d; 0.99 (3H, d, JZ6.8 Hz), 1.88–2.06 (2H,

m), 2.65–2.87 (3H, m), 3.37 (1H, dd, JZ10.5, 7.9 Hz), 3.55

(1H, dd, JZ10.5, 5.4 Hz), 4.09 (1H, ddd, JZ12.8, 7.6,

5.1 Hz), 4.72 (1H, dd, JZ38.3, 9.5 Hz), 7.16–7.34 (5H, m).

¹³C NMR (100.6 MHz, CDCl₃) d; 16.8, 31.5, 31.8 (d, JZ

2.7 Hz), 35.6, 67.4, 69.4 (d, JZ31.6 Hz), 108.4 (d, JZ

12.8 Hz), 125.9, 128.4, 128.4, 141.4, 160.9 (d, JZ257.8 Hz).

¹⁹F NMR (376.5 MHz, CDCl₃) d; K60.3 (1F, dd, JZ38,

15 Hz). EI-MS m/z; 238(M^C), 220(M^CKH₂O), 201, 190, 91.

HRMS; calcd for C₁₄H¹⁹FO₂(M^C): 238.1369. Found:

238.1370.

4.5.5. (2R*,3Z,5S*)-4-Fluoro-2-isobutyl-6-phenyl-3-hex-

ene-1,5-diol (syn-6c-2). Compound syn-6c-2 was prepared

from 5c and triisobutylaluminum. Puriﬁcation by silica gel

column chromatography [hexane/AcOEt (1:1)] gave a

mixture (125 mg) of syn-6c-2 (78% yield) and 5c (19%

recovery), which was further puriﬁed by MPLC [hexane/

AcOEt (1:1)] to give 5c and syn-6c-2 in the order of elution.

4.5.2. (1R*,2Z,4S*)-2-Fluoro-4-isobutyl-1-phenyl-2-pen-

tene-1,5-diol (syn-6a-2). Compound syn-6a-2 was prepared

from 5a and triisobutylaluminum. Puriﬁcation by silica gel

column chromatography [hexane/AcOEt (1:1)] afforded a

mixture (124 mg) of syn-6a-2 (68% yield) and 5a (30%

recovery), which was further puriﬁed by MPLC [hexane/

AcOEt (1:1)] to give 5a and syn-6a-2 in the order of elution.

syn-6a-2: colorless crystals. Mp 67–68 8C. IR (CHCl₃)

n cm^K1; 3616, 3150–3570, 2956, 1706, 1452. ¹H NMR

(400 MHz, CDCl₃) d; 0.85 (3H, d, JZ6.7 Hz), 0.88 (3H, d,

JZ6.7 Hz), 1.13 (2H, dd, JZ7.3 Hz), 1.54 (1H, qqt, JZ6.7,

6.7, 6.7 Hz), 2.77–2.89 (1H, m), 3.31 (1H, dd, JZ10.6,

8.5 Hz), 3.55 (1H, dd, JZ10.6, 4.7 Hz), 4.68 (1H, dd, JZ

37.4, 10.1 Hz), 5.17 (1H, d, JZ8.6 Hz), 7.28–7.44 (5H, m).

¹³C NMR (100.6 MHz, CDCl₃) d; 21.8, 23.4, 25.7, 35.4,

40.3, 66.4, 72.3 (d, JZ34.4 Hz), 108.4 (d, JZ12.4 Hz),

126.8, 128.2, 128.5, 139.7, 161.2 (d, JZ256.7 Hz). ¹⁹F

NMR (376.5 MHz, CDCl₃) d; K54.4 (1F, d, JZ37 Hz). EI-

MS m/z; 204 (M^CCHKH₂OKCH₂OH). HRMS; calcd for

C₁₄H₁₇F (M^CCHKH₂OKCH₂OH): 204.1314. Found:

204.1313.

syn-6c-2: colorless solid. Mp 70–72 8C. IR (CHCl₃) n cm^K1

;

3610, 3412, 2932, 2872, 1707. ¹H NMR (400 MHz, CDCl₃) d;

0.86 (3H, d, JZ6,4 Hz), 0.86 (3H, d, JZ6,7 Hz), 1,04–1.16

(2H, m), 1.39–1.54 (1H, m), 1.65 (1H, br), 2.59 (1H, br), 2.71–

2.83(1H, m), 2.92(1H, dd, JZ13.6, 7.1 Hz), 3.01(1H, dd, JZ

13.6, 6.2 Hz), 3.24 (1H, dd, JZ10.6, 8.0 Hz), 3.47 (1H, dd,

JZ10.6, 4.9 Hz), 4.26–4.37 (1H, m), 4.48 (1H, dd, JZ38.0,

10.1 Hz), 7.20–7.33 (5H, m). ¹³C NMR (100.6 MHz, CDCl₃)

d; 21.7, 23.5, 25.5, 35.5 (d, JZ1.5 Hz), 40.4, 40.6, 66.5,

71.5(d, JZ32.1 Hz), 108.2 (d, JZ12.5 Hz), 126.8, 128.5,

129.5, 137.0, 160.4 (d, JZ257.4 Hz). ¹⁹F NMR (376.5 MHz,

CDCl₃) d; K59.3 (1F, dd, JZ37.7, 10.5 Hz). EI-MS m/z; 267

(M^CCH), 246 (M^CKHF), 218, 91. HRMS; calcd for

C₁₆H₂₃FO₂(M^C): 266.1682. Found: 266.1692.

4.5.6. (1R*,2Z,4R*)-2-Fluoro-4-methyl-1-phenyl-2-pen-

tene-1,5-diol (anti-6a-1). Compound anti-6a-1 was pre-

pared from 5d and trimethylaluminum. Puriﬁcation by silica

gel column chromatography [hexane/AcOEt (1:1)] gave a

mixture (104 mg) of syn- and anti-6a-1 (52% yield, syn/

antiZ1:10.5) and 5d (41% recovery). This mixture was

puriﬁed by MPLC [hexane/AcOEt (2:3)] to give 5d, syn-6a-

1 and anti-6a-1 in the order of elution. anti-6a-1: colorless

crystals. Mp 56–58 8C. IR (CHCl₃) n cm^K1; 3608, 3396,

3040, 3016, 2968, 2872, 1700. ¹H NMR (400 MHz, CDCl₃)

d; 0.96 (3H, d, JZ6.8 Hz), 2.67–2.88 (1H, m), 3.34 (1H, dd,

JZ10.5, 8.2 Hz), 3.53 (1H, dd, JZ10.5, 5.3 Hz), 3.95 (1H,

brs), 4.80 (1H, dd, JZ36.7, 9.6 Hz), 5.17 (1H, d, JZ

16.7 Hz), 7.26–7.46 (5H, m). ¹³C NMR (100.6 MHz,

CDCl₃) d; 16.6, 31.9 (d, JZ2.2 Hz), 67.3, 72.8 (d, JZ

30.4 Hz), 110.5 (d, JZ12.9 Hz), 126.6, 128.1, 128.4, 139.3,

159.4 (d, JZ258.9 Hz). ¹⁹F NMR (376.5 MHz, CDCl₃) d;

K60.1 (1F, dd, JZ37, 17 Hz). EI-MS m/z; 190 (M^CKHF),

4.5.3. (2R*,3Z,5S*)-4-Fluoro-2-isobutyl-7-phenyl-3-hep-

tene-1,5-diol (syn-6b-2). Compound syn-6b-2 was prepared

from 5b and triisobutylaluminum. Puriﬁcation by silica gel

column chromatography [hexane/AcOEt (1:1)] gave a

mixture (127 mg) of syn-6b-2 (66% yield) and 5b (29%

recovery) which was further puriﬁed by MPLC [hexane/

AcOEt (1:1)] to give syn-6b-2 and 5b in the order of elution.

syn-6b-2: colorless oil. IR (CHCl₃) n cm^K1; 3616, 3416,

3020, 2960, 1706, 1602, 1452. ¹H NMR (400 MHz, CDCl₃)

d; 0.89 (3H, d, JZ6.2 Hz), 0.90 (3H, d, JZ6.3 Hz), 1.17

(2H, dd, JZ7.3, 7.3 Hz), 1.50–1.65 (1H, m), 1.87–2.05 (2H,

m), 2.71–2.83 (3H, m), 3.36 (1H, dd, JZ10.5, 8.2 Hz), 3.60

(1H, dd, JZ10.5, 4.9 Hz), 4.12–4.14 (1H, m), 4.66 (1H, dd,

JZ38.3, 10.1 Hz), 7.18–7.31 (5H, m). ¹³C NMR

(100.6 MHz, CDCl₃) d; 21.7, 23.5, 25.7, 31.5, 35.4, 35.9,

40.4, 66.6, 69.4 (d, JZ32.5 Hz), 107.2 (d, JZ12.9 Hz),

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

5751

162, 150, 147. HRMS; calcd for C₁₂H₁₄FO₂(M^CKHF):

190.0994. Found: 190.1008.

gel column chromatography [hexane/AcOEt (10:1)] gave 9a

(680 mg, quantitative) as colorless oil. IR (CHCl₃) n cm^K1

;

1

3680, 3616, 3028, 1602. H NMR (400 MHz, CDCl₃) d;

1.05 (9H, s), 2.53 (1H, d, JZ3.8 Hz), 4.24 (2H,m), 4.93

(1H, td, JZ9.4, 3.8 Hz), 5.90–6.03 (1H, m), 6.08–6.16 (1H,

m), 7.30–7.50 (11H, m), 7.59–7.68 (4H, m). ¹³C NMR

(100.6 MHz, CDCl₃) d; 19.2, 26.7, 62.6, 76.1 (t, JZ

30.0 Hz), 120.2 (t, JZ25.0 Hz), 120.2 (t, JZ244.1 Hz),

127.6, 127.8, 128.2, 128.6, 129.8, 133.1, 135.4, 136.2, 136.6

(t, JZ8.1 Hz). ¹⁹F NMR (376.5 MHz, CDCl₃) d; K43.3

(1F, d, JZ9.4 Hz), K43.5 (1F, d, JZ9.4 Hz). EI-MS m/z;

375 (M^CKPh), 305, 247. Anal. Calcd for C₂₇H₃₀F₂O₂Si: C,

71.65; H, 6.68. Found: C, 71.49; H, 6.70.

4.5.7. (1R*,2Z,4R*)-2-Fluoro-4-isobutyl-1-phenyl-2-pen-

tene-1,5-diol (anti-6a-2). Compound anti-6a-2 was pre-

pared from 5d and triisobutylaluminum. Puriﬁcation by

silica gel column chromatography [hexane/AcOEt (1:2)]

gave a mixture (94 mg) of syn- and anti-6a-2 (23% yield,

syn/antiZ1:5.8) and 5d (60% recovery), which was further

puriﬁed by MPLC [hexane/AcOEt (2:3)] to give 5d, syn-6a-

2 and anti-6a-2 in the order of elution. anti-6a-2: colorless

oil. IR (CHCl₃) n cm^K1; 3612, 3416, 3024, 2960, 2872,

1700, 1600, 1368. ¹H NMR (400 MHz, CDCl₃) d; 0.85 (3H,

d, JZ6,6 Hz), 0.89 (3H, d, JZ6,6 Hz), 1,13–1.21 (2H, m),

1.49–1.64 (1H, m), 1.85 (1H, brs), 2.76–2.88 (1H, m), 3.30

(1H, brs), 3.39 (1H, dd, JZ10.5, 8.1 Hz), 3.60 (1H, dd, JZ

10.5, 5.0 Hz), 4.76 (1H, dd, JZ36.7, 10.1 Hz), 5.22 (1H, d,

JZ15.5 Hz), 7.26–7.44 (5H, m).¹³C NMR (100.6 MHz,

CDCl₃) d; 21.8, 23.5, 25.7, 35.6, 40.4, 66.5, 72.8 (d, JZ

31.1 Hz), 109.5 (d, JZ12.9 Hz), 126.5, 128.2, 128.5, 139.4,

160.3 (d, JZ258.0 Hz). ¹⁹F NMR (376.5 MHz, CDCl₃) d;

K59.6 (1F, d, JZ35 Hz). EI-MS m/z; 232 (M^CKHF), 204,

150, 117, 91. HRMS; calcd for C₁₄H₁₇F (M^CKOHK

CH₂OH): 204.1314. Found: 204.1311.

4.6. Preparation of the pivalate

4.6.1. (2S*,3Z,5R*)-4-Fluoro-5-hydroxy-2-methyl-7-

phenyl-hept-3-enyl-2,2-dimethyl-propionate (7b-1).

After a mixture of syn-6b-1 (210 mg, 0.88 mmol), pivaloyl

chloride (121 mg, 1.0 mmol) and pyridine (0.20 ml) in

CH₂Cl₂(7 ml) was stirred at room temperature for 4.5 h,

usual extractive workup followed by the puriﬁcation by

silica gel column chromatography [hexane/AcOEt (5:1)]

gave 7b-1 (218 mg, 77% yield) as colorless oil. IR (neat)

n cm^K1; 3450, 2970, 1728, 1710. ¹H NMR (400 MHz,

CDCl₃) d; 1.05 (3H, t, JZ6.9 Hz), 1.20 (9H, s), 1.90–2.05

(2H, m), 2.12–2.28 (1H, brs), 2.66–2.81 (2H, m), 2.94–3.06

(1H, m), 3.92 (1H, dd, JZ10.7, 6.6 Hz), 3.96 (1H, dd, JZ

10.7, 6.1 Hz), 4.02–4.12 (1H, m), 4.71 (1H, dd, JZ37.3,

9.5 Hz), 7.17–7.22 (3H, m), 7.25–7.32 (2H, m). ¹³C NMR

(100.6 MHz, CDCl₃) d; 17.2, 27.1. 28.7 (d, JZ3.7 Hz),

31.4, 35.4, 38.8, 68.0, 69.7 (d, JZ30.3 Hz), 108.3 (d, JZ

13.2 Hz), 126.0, 128.4, 141.2, 159.9 (d, JZ259.1 Hz),

178.5. ¹⁹F NMR (376.5 MHz, CDCl₃) d; K60.7 (1F, dd, JZ

37.0, 2.0 Hz). EI-MS m/z; 304 (M^CKH₂O), 220. 202. Anal.

Calcd for C₁₉H₂₇FO₃: C, 70.78; H, 8.44. Found: C, 70.43;

H, 8.37.

4.5.8. (2R*,3Z,5R*)-4-Fluoro-2-isobutyl-6-phenyl-3-hex-

ene-1,5-diol (anti-6c-2). Compound anti-6c-2 was prepared

from 5e and triisobutylaluminum. Puriﬁcation by silica gel

column chromatography [hexane/AcOEt (1:1)] gave a

mixture (123 mg) of syn- and anti-6c-2 (32% yield, syn/

antiZ1:2.9) and 5e (32% recovery), which was further

puriﬁed by MPLC [hexane/AcOEt (1:1)] to give 5e, syn-6c-

2 and anti-6c-2 in the order of elution. anti-6c-2: colorless

solid. Mp 48–49 8C. IR (neat) n cm^K1; 3677, 3602, 3401,

2957, 2871, 1707. ¹H NMR (400 MHz, CDCl₃) d; 0.77 (3H,

d, JZ6.6 Hz), 0.79 (3H, d, JZ6.5 Hz), 0.90–1.06 (2H, m),

1.08–1.22 (1H, m), 2.40 (1H, br), 2.69–2.81 (1H, m), 2.97

(1H, dd, JZ13.8, 6.6 Hz), 3.00 (1H, dd, JZ13.8, 7.6 Hz),

3.24 (1H, dd, JZ10.5, 8.8 Hz), 3.44 (1H, br), 3.53 (1H, dd,

JZ10.5, 4.7 Hz), 4.31 (1H, dt, JZ19.8, 7.0 Hz), 4.38 (1H,

dd, JZ37.0, 10.2 Hz), 7.19–7.30 (5H, m). ¹³C NMR

(100.6 MHz, CDCl₃) d; 21.5, 23.6, 25.2, 35.6, 39.8, 40.1,

66.6, 72.3 (d, JZ29.5 Hz), 109.9 (d, JZ13.3 Hz), 126.6,

128.4, 129.4, 136.9, 159.9 (d, JZ258.8 Hz). ¹⁹F NMR

(376.5 MHz, CDCl₃) d; K64.2 (1F, dd, JZ37, 19 Hz). EI-

MS m/z; 289 (M^CCNa), 229. HRMS; calcd for

C₁₆H₂₃FO₂Na (M^CCNa); 289.1580. Found: 289.1575.

4.6.2. (2S*,3Z,5R*)-4-Fluoro-5-hydroxy-2-methyl-6-

phenyl-hex-3-enyl-2,2-dimethyl-propionate (7c-1). Com-

pound 7c-1 was prepared from syn-6c-1. Puriﬁcation by

silica gel column chromatography [hexane/AcOEt (5:1)]

afforded 7c-1 (80% yield) as colorless oil. IR (neat) n cm^K1

;

1

3456, 2972, 2929, 2876, 1730, 1712. H- NMR (400 MHz,

CDCl₃) d; 1.01 (3H, d, JZ6.9 Hz), 1.19 (9H, s), 2.02 (1H, d,

JZ4.9 Hz), 2.85–3.04 (3H, m), 3.82–3.91 (2H, m), 4.26–

4.32 (1H, m), 4.64 (1H, dd, JZ37.5, 9.5 Hz), 7.19–7.35

(5H, m). ¹³C NMR (100.6 MHz, CDCl₃) d; 17.1, 27.1, 28.7

(d, JZ3.8 Hz), 38.8, 40.7, 67.9, 71.2 (d, JZ31.4 Hz), 108.3

(d, JZ12.6 Hz), 126.8, 128.5, 129.5, 136.8, 159.2 (d, JZ

258.2 Hz), 178.4. ¹⁹F NMR (376.5 MHz, CDCl₃) d; K60.0

(1F, dd, JZ37, 13 Hz). EI-MS m/z; 331 (M^CCNa), 291,

189. HRMS; calcd for C₁₈H₂₅O₃FNa (M^CCNa): 331.1685.

Found: 331.1654. Anal. Calcd for C₁₈H₂₅FO₃: C, 70.10; H,

8.17. Found: C, 70.06; H, 8.14.

4.5.9. (Z)-5-[(tert-Butyldiphenylsilanyl)oxy]-2-ﬂuoro-4-

methyl-1-phenyl-2-penten-1-ol (10a). Compound 10a

was prepared from 9a and Me₃Al in the presence

CuI$2LiCl. Puriﬁcation by silica gel column chromato-

graphy [hexane/AcOEt (20:1)] afforded a mixture of syn-

10a (77% yield), anti-10a (4% yield) and 9a (4% recovery).

10a was desilylated with TBAF and the product was

identical with 6a-1.

4.7. Preparation of the N-Boc derivative 8 through one-

pot azidation reaction

4.5.10.

(E)-5-[(tert-Butyldiphenylsilanyl)oxy]-2,2-

diﬂuoro-1-phenyl-3-penten-1-ol (9a). A mixture of 5a

(321 mg, 1.5 mmol), imidazole (112 mg, 1.65 mmol) and

tert-butyldiphenylchlorosilane (454 mg, 1.65 mmol) in

DMF (6 ml) was stirred at room temperature for 3 h.

Extractive workup (AcOEt for extraction) followed by silica

4.7.1. (2S*,4Z,5S*)-5-[(tert-Butoxycarbonyl)amino]-4-

ﬂuoro-2-methyl-7-phenyl-hept-3-en-1-ol (8b) and

(2S*,3R*,4Z)-3-[(tert-butoxycarbonyl)amino]-4-ﬂuoro-

2-methyl-7-phenyl-hept-4-en-1-ol (17b). To a mixture of

5752

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

7b-1 (260 mg, 0.81 mmol), DMAP (367 mg, 3 mmol) and

NaN₃(1.63 g, 25.0 mmol) in CH₂Cl₂(10 ml) was added

methanesulfonyl chloride (229 mg, 2.0 mmol) at 0 8C. After

being stirred at room temperature for 30 min, to the reaction

mixture was added DMSO (5 ml), and then the whole was

stirred at room temperature for 3 h. The reaction mixture

was poured into water and extracted with a mixture of

AcOEt and hexane. The aqueous layer was re-extracted with

AcOEt, and the combined organic layer was washed with

brine, dried over anhydrous Na₂SO₄, and evaporated in

vacuo. The residue was puriﬁed by short silica gel column

chromatography [hexane/AcOEt (5:1)] to give crude 15b

(266 mg, 95% yield). To a suspension of LiAlH₄(76.0 mg,

2.0 mmol) in THF (3 ml) was added 15b (266 mg) in THF

(5 ml) at 0 8C, and then the whole was stirred at room

temperature for 90 min. To the reaction mixture was added

ice water dropwise at 0 8C and after being stirred for 10 min,

the mixture was extracted with AcOEt. The organic layer

was washed with brine, dried over anhydrous Na₂SO₄, and

evaporated in vacuo. The residue was dissolved in CH₂Cl₂

(2 ml) and to this solution were added Et₃N (0.28 ml,

0.28 mmol) and (Boc)₂O (218 mg, 1.0 mmol) in CH₂Cl₂

(2 ml). After being stirred at room temperature for 30 min,

the reaction mixture was poured into water and extracted

with AcOEt. The organic layer was washed with brine, dried

over anhydrous Na₂SO₄, and evaporated in vacuo. The

residue was puriﬁed by silica gel column chromatography

[hexane/AcOEt (4:1)] to give a mixture of 8b and 17b

(224 mg, 86% yield, 8b:17bZ8.4:1), which was further

separated by MPLC [hexane/AcOEt (3:1)]. 8b: colorless

solid. Mp 82–84 8C. IR (neat) n cm^K1; 3400, 3332, 2976,

2931, 1694. ¹H NMR (400 MHz, CDCl₃) d; 0.10 (3H, d, JZ

6.8 Hz), 1.44 (9H, s), 1.80–2.02 (2H, m), 2.18 (1H, brs),

2.66 (2H, t, JZ7.8 Hz), 2.76–2.89 (1H, m), 3.33–3.44 (1H,

m), 3.44–3.55 (1H, m), 4.00–4.18 (1H, m), 4.61 (1H, dd, JZ

37.5, 9.7 Hz), 4.71–4.82 (1H, brd), 7.15–7.22 (3H, m),

7.25–7.31 (2H, m). ¹³C NMR (100.6 MHz, CDCl₃) d; 16.7,

28.3, 32.1, 33.6, 52.2 (d, JZ30.2 Hz), 67.2, 80.0, 110.4 (d,

JZ12.0 Hz), 126.1, 128.3, 128.5, 140.9, 155.2, 155.7 (d,

JZ260.0 Hz). ¹⁹F NMR (376.5 MHz, CDCl₃) d; K62.8

(1F, dd, JZ37.0, 22.0 Hz). EI-MS m/z; 360(M^CCNa).

Anal. Calcd for C₁₉H₂₈FNO₃: C, 67.63; H, 8.36; N, 4.15.

Found: C, 67.66; H, 8.33; N, 4.13. 17b: colorless oil. IR

2872, 1697. ¹H NMR (400 MHz, CDCl₃, 50 8C) d; 0.92 (3H,

d, JZ6.9 Hz), 1.47 (9H, s), 1.67 (1H, brs), 2.77–2.83 (1H,

m), 2.95–3.15 (2H, m), 3.37 (1H, dd, JZ10.5, 7.3 Hz), 3.47

(1H, dd, JZ10.5, 5.8 Hz), 4.35–4.46 (1H, m), 4.44 (1H, dd,

JZ37.9, 9.5 Hz), 4.74 (1H, brs), 7.19–7.36 (5H, m). ¹³C

NMR (100.6 MHz, CDCl₃, 50 8C) d; 16.5, 28.3, 32.2 (d, JZ

2.5 Hz), 38.6, 53.7 (d, JZ29.2 Hz), 67.3, 80.0, 110.0 (d, JZ

12.9 Hz), 126.9, 128.4, 129.4, 136.8, 154.9, 157.4 (d, JZ

257.7 Hz). ¹⁹F NMR (376.5 MHz, CDCl₃) d; K61.0 (1F,

dd, JZ38.0, 20.0 Hz). ES-MS m/z; 346 (M^CCNa). HRMS

Calcd for C₁₈H₂₆FNO₃Na: 346.1795 (M^CCNa). Found:

346.1786.

References and notes

1. (a) Hann, M. M.; Sammes, P. G.; Kennewell, P. D.; Taylor,

J. B. J. Chem. Soc. Perkin Trans. 1 1982, 307–314. (b)

Abraham, R. J.; Ellison, S. L. R.; Schonholzer, P.; Thomas,

W. A. Tetrahedron 1986, 42, 2101–2110. (c) Cieplak, P.;

Kollman, P. A. J. Comput. Aided Mol. Des. 1993, 7, 291–304.

(d) Wipf, P.; Henninger, T. C.; Geib, S. J. J. Org. Chem. 1998,

63, 6088–6089 and references cited therein. (e) Welch, J. T. In

Biomedical frontiers of ﬂuorine chemistry; Ojima, I.,

McCarthy, J. R., Welch, J. T., Eds.; ACS Symposium Series

639; ACS: Washington, DC, 1996. (f) Howard, J. A. K.; Hoy,

V. J.; O’Hagan, D.; Smith, G. T. Tetrahedron 1996, 38,

12613–12622. (g) O’Hagan, D.; Rzepa, H. S. J. Chem. Soc.,

Chem. Commun. 1997, 645–652.

2. (a) Alemendinger, T.; Furet, P.; Hungerbuehler, E. Tetrahedron

Lett. 1990, 31, 7297–7300. (b) Alemendinger, T.; Felder, E.;

Hungerbuehler, E. Tetrahedron Lett. 1990, 31, 7301–7304.

3. Boros, L. G.; De Corte, B.; Gimi, R. H.; Welch, J. T.; Wu, Y.;

Handschumacher, R. E. Tetrahedron Lett. 1994, 35, 6033–6036.

4. (a) Welch, T.; Lin, J. Tetrahedron 1996, 52, 291–304. (b) Lin,

J.; Toscano, P. J.; Welch, J. T. Proc. Natl. Acad. Sci. U. S. A.

1998, 95, 14020–14024. (c) Zhao, K.; Lim, D. S.; Funaki, T.;

Welch, J. T. Bioorg. Med. Chem. 2003, 11, 207–215.

5. Bartlett, P. A.; Otake, A. J. Org. Chem. 1995, 60, 3107–3111.

6. Examples of triﬂuoromethyl substituted peptide mimetics,

[CH(CF₃)NH] as a replacement for [CONH] bond, see: (a)

Volonterio, A.; Bravo, P.; Zanda, M. Org. Lett. 2000, 2,

1827–1830. (b) Molteni, M.; Volonterio, A.; Zanda, M. Org.

Lett. 2003, 5, 3887–3890 and references cited therein.

7. Machleidt, H.; Wassendorf, R. Ann. 1964, 674, 1–10.

8. For a review of ﬂuoroalkene syntheses using phosphonium

ylides. Burton, D. J.; Yang, Z.-Y.; Qiu, W. Chem. Rev. 1996,

96, 1641–1715.

1

(neat) n cm^K1; 3393, 2976, 2933, 1693, 1499. H NMR

(400 MHz, CDCl₃) d; 0.94 (3H, d, JZ7.0 Hz), 1.45 (9H, s),

1.71 (1H, br), 2.32–2.50 (2H, m), 2.68 (2H, t, JZ7.6 Hz),

2.76 (1H, brs), 3.44 (1H, d, JZ11.0 Hz), 3.66 (1H, d, JZ

10.2 Hz), 4.02 (1H, dt, JZ24.3, 9.4 Hz), 4.81 (1H, dt, JZ

37.7, 7.5 Hz), 5.06 (1H, bd, d, JZ9.0 Hz), 7.11–7.19 (3H,

m), 7.19–7.29 (3H, m). ¹³C NMR (100.6 MHz, CDCl₃) d;

14.4, 25.1(d, JZ4.0 Hz), 28.3, 35.3, 37.4, 54.4 (d, JZ

27.4 Hz), 63.7, 80.3, 107.4 (d, JZ14.4 Hz), 126.0, 128.4 (d,

JZ9.1 Hz), 141.3, 156.3, 156.6 (d, JZ256.1 Hz). ¹⁹F NMR

(376.5 MHz, CDCl₃) d; K62.0 (1F, dd, JZ38, 24 Hz). EI-

MS m/z; 338 (M^CCH), 282, 264. HRMS; calcd for

C₁₉H₂₉FNO₃H (M^CCH); 338.2131. Found: 338.2130.

9. Kinetic separation of 1-bromo-1-ﬂuoroalkenes using palla-

dium chemistry, see: (a) Xu, J.; Burton, D. J. Org. Lett. 2002,

4, 831–833. (b) Xu, J.; Burton, D. J. Tetrahedron Lett. 2002,

43, 4565–4567. See also: (c) Gross, R. S.; Mehdi, S.;

McCarthy, J. R. Tetrahedron Lett. 1993, 34, 7197–7200.

10. Modiﬁcation of Horner–Emmons type ﬂuorooleﬁnation reac-

tions, see: (a) Sano, S.; Teranishi, R.; Nagao, Y. Tetrahedron

Lett. 2002, 43, 9183–9186. (b) Sano, S.; Yokoyama, K.;

Teranishi, R.; Shiro, M.; Nagao, Y. Tetrahedron Lett. 2002,

43, 281–284. (c) Sano, S.; Saito, K.; Nagao, Y. Tetrahedron

Lett. 2003, 44, 3987–3990.

4.7.2. tert-Butyl (1R*,2Z,4R*)-1-benzyl-2-ﬂuoro-5-

hydroxy-4-methyl-2-pentenyl carbamate (8c). Com-

pound 8c was prepared from 7c-1 (308 mg, 1.0 mmol).

Puriﬁcation by silica gel column chromatography [hexane/

AcOEt (5:1)] afforded 8c (235 mg) in 71% yield from 7c-1.

8c: colorless oil. IR (neat) n cm^K1; 3427, 3334, 2976, 2931,

11. Highly Z-selective ﬂuorooleﬁn synthesis via sulfoxide

elimination reaction, see: (a) Allemendinger, T. Tetrahedron

Y. Nakamura et al. / Tetrahedron 61 (2005) 5741–5753

5753

1991, 47, 4905–4914. (b) Nakazato, A.; Kumagai, T.; Sakagami,

K.; Yoshikawa, R.; Suzuki, Y.; Chaki, S.; Ito, H.; Taguchi, T.;

Nakanishi, S.; Okuyama, S. J. Med. Chem. 2000, 43, 4893–4909.

12. Hata, H.; Kobayashi, T.; Amii, H.; Uneyama, K.; Welch, J. T.

Tetrahedron Lett. 2002, 43, 6099–6102.

26. (a) Lipshuts, B. H.; Sengupta, S. Org. React. 1992, 41,

135–631. (b) Nakamura, E.; Mori, S. Angew. Chem., Int. Ed.

2000, 39, 3750–3771.

27. anti mode reaction with allylic esters, halides and phosphates:

(a) Goering, H. L.; Singleton, V. D. J. Am. Chem. Soc. 1976,

98, 7854–7855. (b) Goering, H. L.; Tseng, C. C. J. Org. Chem.

1983, 48, 3986–3990. (c) Goering, H. L.; Kantner, S. S. J. Org.

Chem. 1984, 49, 422–426. (d) Goering, H. L.; Kantner, S. S.;

Seitz, E. P. J. Org. Chem. 1985, 50, 5495–5499. (e) Goering,

H. L.; Kantner, S. S. J. Org. Chem. 1981, 46, 2144–2148. (f)

Tseng, C. C.; Paisley, S. D.; Goering, H. L. J. Org. Chem.

1986, 51, 2884–2891. (g) Tseng, C. C.; Yen, S.-J.; Goering,

H. L. J. Org. Chem. 1986, 51, 2892–2895. (h) Corey, E. J.;

Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063–3066. (i)

Nakamura, E.; Sekiya, K.; Arai, M.; Aoki, S. J. Am. Chem.

Soc. 1989, 111, 3091–3093. (j) Ibuka, T.; Nakao, T.; Nishii, S.;

Yamamoto, Y. J. Am. Chem. Soc. 1986, 108, 7420–7422.

28. syn mode reaction, in particular with allylic carbamate

derivatives, see: (a) Gallina, C.; Clattini, P. G. J. Am. Chem.

Soc. 1979, 101, 1035–1036. (b) Goering, H. L.; Kantner, S. S.;

Tseng, C. C. J. Org. Chem. 1983, 48, 715–721. (c) Goering,

H. L.; Tseng, C. C. J. Org. Chem. 1985, 50, 1597–1599. (d)

Ibuka, T.; Habashita, H.; Otaka, A.; Fujii, N. J. Org. Chem.

1991, 56, 4370–4382. (e) Smitrovich, J. H.; Woerpel, K. A.

J. Org. Chem. 2000, 65, 1601–1614.

13. 1-Arylsulfonyl-1-ﬂuoroalkenes as a building block, see: (a)

McCarthy, J. R.; Matthews, D. P.; Stemerick, D. M.; Huber,

E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.; Sunkara, P. S.

J. Am. Chem. Soc. 1991, 113, 7439–7440. (b) McCarthy, J. R.;

Huber, E. W.; Le, T.-B.; Mark Laskovics, F.; Mattews, D.

Tetrahedron 1996, 52, 45–58.

14. Ring-opening reaction of ﬂuorinated cyclopropane derivatives,

see: (a) Bessiere, Y.; Savary, D. N.-H.; Schlosser, M. Helv.

Chim. Acta 1977, 60, 1739–1746. (b) Bessiere, Y.; Bessard,

Y.; Kotani, T.; Schlosser, M. Tetrahedron 1991, 47,

4355–4360. (c) Taguchi, T.; Takigawa, T.; Tawara, Y.;

Morikawa, T.; Kobayashi, Y. Tetrahedron Lett. 1984, 25,

5689–5692.

15. Cr(II)-mediated reaction of dibromoﬂuoroacetate with alde-

hyde, see: Barma, D. K.; Kundu, A.; Zhang, H.; Mioskowski,

C.; Falk, J. R. J. Am Chem. Soc. 2003, 125, 3218–3219.

16. (a) Otaka, A.; Watanabe, H.; Mitsuyama, E.; Yukimasa, A.;

Tamamura, H.; Fujii, N. Tetrahedron Lett. 2001, 42, 285–287.

(b) Otaka, A.; Watanabe, H.; Yukimasa, A.; Oishi, S.;

Tamamura, H.; Fujii, N. Tetrahedron Lett. 2001, 42,

5443–5446. (c) Otaka, A.; Yukimasa, A.; Sasaki, Y.; Watanabe,

H.; Oishi, S.; Tamamura, H.; Fujii, N. Chem. Commun. 2003,

1834–1835. (d) Otaka, A.; Mitsuyama, E.; Watanabe, H.;

Tamamura, H.; Fujii, N. Chem. Commun. 2000, 1081–1082.

17. Otaka, A.; Watanabe, J.; Yukimasa, A.; Sasaki, Y.; Watanabe,

H.; Kinoshita, T.; Oishi, S.; Tamamura, H.; Fujii, N. J. Org.

Chem. 2004, 69, 1634–1645.

29. Effect of BF₃on the alkylation of allylic alcohol: Yamamoto,

Y.; Yamamoto, S.; Yatagai, H.; Maruyama, K. J. Am. Chem.

Soc. 1980, 102, 2318–2325.

30. SN2⁰addition to vinylic epoxide: (a) Marshall, J. A.; Andia,

V. H. J. Org. Chem. 1987, 52, 1106–1113. (b) Saddler, J. C.;

Fucks, P. L. J. Am. Chem. Soc. 1981, 103, 2112–2114.

31. Examples of allylic azide from allylic alcohol by the

Mitsunobu reaction, see: (a) Jarvest, R. L.; Berge, J. M.;

Brown, P.; Houge-Frydrych, C. S. V.; O’Hanlon, P. J.;

McNair, D. J.; Pope, A. J.; Rittenhouse, S. Bioorg. Med.

Chem. Lett. 2003, 13, 1265–1268. (b) Chandrasekhar, S.;

Raza, A.; Takhi, M. Tetrahedron: Asymmetry 2002, 13,

423–428. (c) Sen, S. E.; Roach, S. L. Synthesis 1995, 756–758.

32. SN2 and SN2⁰allylic azidation reaction of allylic mesylate or

bromide and rearrangement of allylic azide, see: (a) Hirasawa,

H.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2001, 42,

7587–7590. (b) Cardillo, G.; Fabbroni, S.; Gentilucci, L.;

Perciaccante, R.; Piccinelli, F.; Tolomelli, A. Org. Lett. 2005,

7, 533–536 and references cited therein.

18. Okada, M.; Nakamura, Y.; Sato, A.; Horikawa, H.; Saito, A.;

Taguchi, T. Chem. Lett. 2002, 28–29.

19. Okada, M.; Nakamura, Y.; Saito, A.; Sato, A.; Horikawa, H.;

Taguchi, T. Tetrahedron Lett. 2002, 43, 5845–5848.

20. Yamazaki, A.; Shinohara, N.; Kitazume, T.; Sato, S.

J. Fluorine Chem. 1997, 97, 91–96.

21. Lipshutz, B. H.; Segi, M. Tetrahedron 1995, 51, 4407–4420.

22. Copper-catalyzed conjugate additions of trialkylaluminium

with enones, see: (a) Kabbara, J.; Fleming, S.; Nickisch, K.;

Neh, H.; Westermann, J. Tetrahedron 1995, 51, 743–754. (b)

Takemoto, Y.; Kuraoka, S.; Hamaue, N.; Aoe, K.; Hiramatsu,

H.; Iwata, C. Tetrahedron 1996, 52, 14177–14188. (c) Benett,

S. M. W.; Brown, S. M.; Muxworthy, J. P.; Woodward, S.

Tetrahedron Lett. 1999, 40, 1767–1770. (d) Pamies, O.; Net,

G.; Ruiz, A.; Claver, C.; Woodward, S. Tetrahedron:

Asymmetry 2000, 11, 871–877. (e) Kraus, N.;

33. Uenishi, J.; Hamada, M. Synthesis 2002, 625–630.

34. Low temperature preparation of the mesylate of optically pure

benzhydrol followed by nucleophilic substitution, see:

Bolshan, Y.; Chen, C.-yi.; Chilenski, J. R.; Gosselin, F.;

Mathre, D. J.; O’Shea, P. D.; Roy, A.; Tillyer, R. D. Org. Lett.

2004, 6, 111–114.

¨

Hoffmann-Roder, A. Synthesis 2001, 171–196.

23. Copper-catalyzed SN2⁰substitution of allylic phosphates and

chlorides with trialkylaluminum, see: Fleming, S.; Kabbara, J.;

Nickish, K.; Westermann, J.; Mohr, J. Synlett 1995, 183–185.

24. Maruoka demonstrated several speciﬁc reactions of ﬂuorinated

molecules based on ﬂuorine–aluminum coordination. (a) Ooi,

T.; Uraguchi, D.; Kagoshima, N.; Maruoka, K. Tetrahedron

Lett. 1997, 38, 5679–5682. (b) Ooi, T.; Kagoshima, N.;

Uraguchi, D.; Maruoka, K. Tetrahedron Lett. 1998, 39,

7105–7108. (c) Ooi, T.; Kagoshima, N.; Maruoka, K. J. Am.

Chem. Soc. 1997, 119, 5754–5755. (d) Uraguchi, D.; Ooi, T.;

Maruoka, K. J. Synth. Org. Chem. Jpn. 2000, 58, 14–22. (e)

Plenio, H. Chem. Rev. 1997, 97, 3363–3384.

35. Kinetic of rearrangement of allylic azides, see: (a) Gragneux,

A.; Winstein, S.; Young, W. G. J. Am. Chem. Soc. 1960, 82,

5956–5957. (b) VanderWerf, C. A.; Heasley, V. L. J. Org.

Chem. 1966, 31, 3534–3539.

36. Kirihara, M.; Takuwa, T.; Takizawa, S.; Momose, T.; Nemoto,

H. Terahedron 2000, 56, 8275–8280.

37. Taguchi, T.; Kitagawa, O.; Morikawa, T.; Nishiwaki, T.;

Uehara, H.; Endo, H.; Kobayashi, Y. Tetrahedron Lett. 1986,

27, 6103–6106.

38. Taguchi, T.; Kitagawa, O.; Suda, Y.; Ohkawa, S.; Hashimoto,

A.; Iitaka, Y.; Kobayashi, Y. Tetrahedron Lett. 1988, 29,

5291–5294.

25. Ito, H.; Saito, A.; Taguchi, T. Tetrahedron: Asymmetry 1998,

9, 1989–1994.

Article Doi

Stereoselective synthesis of (Z)-fluoroalkenes directed to peptide isosteres: Copper mediated reaction of trialkylaluminum with 4,4-difluoro-5-hydroxyallylic alcohol derivatives

DOI: 10.1016/j.tet.2005.04.034

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2005.04.034

Full text of DOI:10.1016/j.tet.2005.04.034

Products guided by the article

R&D Labs maybe for 474974-07-7

Relevant to this article

Hot Product