Hydroboration-azide alkylation as efficient tandem reactions for the synthesis of chiral non racemic substituted pyrrolidines

Article abstract of DOI:10.1016/S0022-328X(98)00665-2

The synthesis of chiral non racemic substituted pyrrolidines from homoallylic alcohols is presented. These precursors are readily converted via the azides to the corresponding pyrrolidines using hydroboration-cycloalkylation tandem reactions as key steps.

Full text of DOI:10.1016/S0022-328X(98)00665-2

Journal of Organometallic Chemistry 567 (1998) 31–37
Hydroboration–azide alkylation as efficient tandem reactions for the
synthesis of chiral non racemic substituted pyrrolidines
Anne Salmon, Bertrand Carboni *
Synthe`se et Electrosynthe`se Organiques, UMR 6510 Associe´e au CNRS, Uni6ersite´ de Rennes I, Campus de Beaulieu, 35042 Rennes Cedex, France
Received 8 October 1997; received in revised form 21 November 1997
Abstract
The synthesis of chiral non racemic substituted pyrrolidines from homoallylic alcohols is presented. These precursors are readily
converted via the azides to the corresponding pyrrolidines using hydroboration–cycloalkylation tandem reactions as key steps.
© 1998 Elsevier Science S.A. All rights reserved.
Keywords: Pyrrolidine; Azide; Organoborane; Tandem reactions; Non-racemic
1. Introduction
[6]. Another attractive route involves the application of
a hydroboration-azide alkylation sequence. Such an
approach can lead to several competitive reactions and
its success demands that the alkene hydroboration pre-
cedes the intramolecular reaction of the borane
(Scheme 2).
A very elegant preparation of a proline derivative
first exploited successfullly the stereoselective bromoac-
etate aldol reaction and the asymmetric induction in the
hydroboration step [7]. Another example using this
intramolecular cycloalkylation was more recently de-
scribed [8]. Previously, we examined the scope and
limitations of these tandem hydroboration-azide alkyla-
tion reactions [9,10]. We here report the synthesis of
chiral non-racemic 2-substituted and 2,3-disubstituted
pyrrolidines from the corresponding homoallylic alco-
hols (Scheme 3).
Pyrrolidines are an important class of five-membered
heterocycles with remarkable biological properties [1].
In addition to pharmaceutical applications, the pyrro-
lidine moiety has also seen wide use as a chiral auxiliary
for asymmetric synthesis [2]. Accordingly, development
of efficient general methods for the preparation of
chiral, non racemic pyrrolidines is of significant value
and an increasing number of papers and reports re-
cently appeared in the literature [3]. Besides these ele-
gant syntheses, we sought to develop an alternative
approach based on the intramolecular reaction of an
azide and an organoborane (Scheme 1) [4].
We showed that the treatment of ꢀ-azidobutyl-
boronates (R=OEt) with boron trichloride generated
the corresponding chloroboranes (R=Cl) which spon-
taneously cyclized to afford pyrrolidines [5]. A stereose-
lective synthesis of trans-cycloalkanopiperidines and
cycloalkanopyrrolidines have been achieved similarly
* Corresponding author. Tel.: +33 2 99286747; fax: +33 2 99
286955; e-mail: bertrand.carboni@univ-rennes1.fr
Scheme 1.
0022-328X/98/$19.00 © 1998 Elsevier Science S.A. All rights reserved.
PII S0022-328X(98)00665-2

32
A. Salmon, B. Carboni / Journal of Organometallic Chemistry 567 (1998) 31–37
Scheme 2.
2. Results and discussion
2.1. Synthesis of 2-substituted pyrrolidines
Scheme 3.
An attractive route to optically active homoallyl al-
cohols is presented by the addition of chirally modified
allylboranes to aldehydes [11]. We first selected B-al-
lyldiisopinocampheylborane [12] and octanal as exam-
possess a 92% enantiomeric purity by chiral HPLC
analysis of the N-benzoyl derivative (Scheme 6).
ples to prepare
a
non-racemic 2-alkylsubstituted
2.2. Synthesis of a 2,3-disubstituted pyrrolidine
pyrrolidine. The addition proceeded at −100°C to give
after oxidation (R)-1-heptylbut-3-en-1-ol 1 when start-
ing from a (+)-pinene derivative [13]. A 90% enan-
In addition, we were interested in developing a stereo-
controlled approach to 2,3-disubstituted pyrrolidines.
Allylboration of aldehydes with crotylboranes has been
extensively studied [11]. Recently H.C. Brown and
coworkers have prepared substituted allylboronates via
the one-carbon homologation of stereodefined alkenyl-
boronates using in situ generated bromomethyllithium
[23]. We used this efficient route to prepare homoallylic
alcohol 11 with high enantio- and diastereomeric excess
(Scheme 7).
1
tiomeric excess was determined by H-NMR analysis of
the corresponding Mosher ester derivative [14]. Treat-
ment of 1 with methanesulfonyl chloride in the presence
of DMAP, followed by nucleophilic substitution with
azide ion led to (S)-1-heptyl-1-azidobut-3-ene 2. Addi-
tion of thexylmonochloborane afforded the desired (S)-
2-heptylpyrrolidine 3 in a 64% yield and a 90% ee
determined by chiral HPLC (Scheme 4).
1
We then became interested in extending this prelimi-
nary result to the preparation of a 3-substituted 5-(2-
pyrrolidinyl)isoxazole which have been found to have
nanomolar affinities comparable to (S)-nicotine in a
preparation of a whole rat brain. For example, ABT
418, an analogue of (S)-nicotine in which the pyridine
ring is replaced by a 3-methyl-5-isoxazole moiety, has
been shown to possess intrinsic cognitive enhancing and
anxiolytic activities [15]. Our synthesis of 3-methyl-5-
(2(R)-pyrrolidinyl)isoxazole 4 began with the prepara-
tion of the aldehyde 5 from prop-2-yn-1-ol (Scheme 5).
Protection of the alcohol as its trimethylsilylether 6 [16]
was followed by the 1,3-dipolar cycloaddition of the
nitrile oxide generated in situ from nitroethane,
phenylisocyanate and triethylamine [17]. The resulting
isoxazole 7 was deprotected with citric acid in methanol
[18] and oxidized by pyridine-sulfur trioxide complex in
DMSO (Scheme 5) [19].
No syn isomer was detected by H and 13C-NMR
and the enantiomeric excess was determined by analysis
of the o-acetyllactic ester [20] on capillary gas chro-
matography. The alcohol so formed was converted to
the corresponding azide 13 via the mesylate 12 as
previously described in the synthesis of the (2S)-hep-
tylpyrrolidine. 13 readily cyclized to (2S,3S)-2-pentyl-3-
butylpyrrolidine 14 on treatment with diethylborane in
a 68% yield (Scheme 8).
(2S,3S)-2-Pentyl-3-butylpyrrolidine 14 was shown to
possess a 70% enantiomeric purity by capillary gas
chromatography of the o-acetyllactic ester. It is worthy
to note that pyrrolidines 3, 4 and 14 have been com-
pared with racemic samples which were prepared inde-
pendently according to the same sequences using
allyboronic esters derived from pinacol.
The formation of the pyrrolidine ring started from
enantioselective allylboration of
5 with B-allyldi-
isopinocampheylborane (92% ee determined by exami-
nation of the 1H-NMR spectrum of the
(S)-o-acetyllactic derivative) [20], followed by direct
conversion of the homoallylic alcohol 9 to the corres-
ponding azide 10 using diphenyl phosphorazidate to
minimize epimerization [21]. As in the synthesis of
(S)-2-heptylpyrrolidine, but with diethylborane instead
of thexylmonochloroborane [22], the hydroboration-cy-
cloalkylation sequence afforded a 69% yield 3-methyl-5-
(2(R)-pyrrolidinyl)isoxazole 4 which was shown to
Scheme 4.

A. Salmon, B. Carboni / Journal of Organometallic Chemistry 567 (1998) 31–37
33
Scheme 5.
In conclusion, we have developed an efficient prepa-
ration of enantiomerically enriched substituted pyrro-
lidines. This approach utilizes the hydroboration-azide
alkylation tandem reactions as key sequence and takes
advantage of the efficient stereocontrolled routes avail-
able to prepare the starting homoallylic alcohools. Ap-
plication of this method to the synthesis of other
natural and non-natural pyrrolidines is currently in
progress.
Scheme 7.
High resolution mass spectra were obtained on a
Varian MAT 311 (Centre Re´gional de Mesures
Physiques, Universite´ de Rennes I). Microanalysis were
performed at the Central Laboratory for Analysis,
CNRS, Lyon, France.
3. Experimental
Reactions involving boranes require an atmosphere
of dry nitrogen and were performed in flame-dried
glassware. Anhydrous CH2Cl2 was obtained by distilla-
tion over P2O5 and anhydrous THF over sodium ben-
zophenone. Melting points were measured on a Kofler
apparatus (uncorrected). NMR spectra were recorded
in CDCl3 solutions (except when another solvent is
3.1. Synthesis of (S)-2-heptylpyrrolidine 3
3.1.1. Allylboration of octanal
Anhydrous diethylether (60 ml) was added to 30
mmol of Ipc2BAll, [12] and the resulting solution was
cooled to −100°C. A solution of octanal (3.84 g, 30
mmol) in diethylether (30 ml), maintained at −78°C,
was slowly added along the side of the flask to the
solution of allylborane keeping the temperature at −
100°C. After 1 h at this temperature, methanol (5 ml)
was added to quench the reaction. The volatile compo-
nents were pumped off the reaction mixture and 12 ml
of a 3N NaOH, followed by 24 ml of 30% aqueous
H2O2, were added. The solution was heated for 3 h at
reflux. After cooling, the product was extracted into
diethylether (3×25 ml). The combined organic layers
1
precised) on a Bruker ARX 200 (200.131 MHz for H,
50.329 MHz for 13C-NMR) or a Bruker ACP 300
(300.13 MHz for 1H, 75.47 MHz for 13C-NMR). Chem-
ical shifts, l, are expressed in ppm downfield from
internal tetramethylsilane. Optical rotations were mea-
sured using a Perkin-Elmer 241 spectrophotometer.
Scheme 6.
Scheme 8.

34
A. Salmon, B. Carboni / Journal of Organometallic Chemistry 567 (1998) 31–37
were washed with water, dried over MgSO4 and the
solvent removed under reduced pressure. The crude
product was chromatographied on silica gel (heptane/
ethyl acetate: 8:2, Rf=0.15) to give 2.09 g of (R)-1-hep-
tylbut-3-en-1-ol 1. Yield 41%. B.p. (0.1 mm
Hg)=60–65°C. [h]D20= +6.25 (c=0.7, CHCl3) (lit.
[24] [h]2D0= +6.51°C (c=1.4, CHCl3). A 90% enan-
tiomeric purity was determined from the 1H-NMR
spectrum of the corresponding Mosher ester derivative
3.1.3. Hydroboration-cyclisation. Synthesis of
(S)-2-heptylpyrrolidine 3
To a stirred solution of 1.8 mmol of thexyl-
monochloroborane [25] in 5 ml of dichloromethane at
0°C, 351 mg (1.1 mmol) of (S)-1-heptyl-1-azidobut-3-
ene 2 was added dropwise. The mixture was allowed to
warm at r.t. and stirred overnight. After methanolysis
(0.5 ml), the reaction mixture was extracted with 1 N
aqueous HCl (6×10 ml). The acidic aqueous phases
were combined and most of water was removed using a
water aspirator. After adding diethylether (20 ml), the
residual material was made strongly alkaline by adding
solid sodium hydroxide. The organic phase was sepa-
rated and the aqueous layer extracted with diethylether
(2×20 ml). The combined organic phases were dried
over potassium carbonate and filtered. The pyrrolidine
was purified by bulb to bulb distillation to afford 122
mg (Yield=40%) of 3. B.p. (0.05 mm Hg)=50–55°C.
[a]D20= +20 (c=2, CHCl3). (lit [26]: [h]2D0= +14° (c=
1.1, CHCl3))1. H-NMR (CDCl3, 200 MHz) l: 0.88 (t,
J=6.4 Hz, CH3, 3H); 1.20–1.43 (m, 13H); 1.67–1.86
1
[14]. H-NMR (CDCl3, 300 MHz) l: 0.88 (t, J=6.7
Hz, CH3, 3H); 1.28–1.46 (m, CH2, 12H); 1.91 (s, OH,
1H); 2.09–2.34 (m, CH2
CHOH, 1H); 5.07–5.16 (m, CH2ꢀCH, 2H); 5.76–5.90
(m, CH2ꢀCH
, 1H). RMN 13C (CDCl3, 75 MHz) l: 14.1
6 CHꢀCH2, 2H); 3.60–3.68 (m,
6
(CH3); 22.7 (CH2); 25.7 (CH2); 29.3 (CH2); 29.7 (CH2);
31.9 (CH2); 36.8 (CH2); 41.9 (CH2); 70.7 (CHOH);
118.0 (C6 H2ꢀCH); 135.0 (CH2ꢀC6 H). HRMS m/z calc.
for C8H17O [M–C3H5· –N2]+: 129.1279; found:
129.1280.
3.1.2. Synthesis of (S)-1-heptyl-1-azidobut-3-ene 2
In a 50 ml round-bottom flask fitted with a magnetic
stirring bar and rubber septa, 20 ml of dichloro-
methane, 840 mg (4.94 mmol) of 1, 600 mg (5.93 mmol)
of triethylamine and 5 mg of DMAP are mixed. The
solution was cooled at 0°C and 590 mg (5.2 mmol) of
methanesulfonylchloride was added dropwise. After 5 h
at room temperature (r.t.), the solid was eliminated by
filtration and the filtrate was diluted with diethylether
(20 ml), washed with 0.1 N aqueous HCl (2×10 ml),
dried over MgSO4 and evaporated to give 1.03 g of the
mesylate as a a colorless oil. Yield=84%. 1H-NMR
(CDCl3, 300 MHz) l: 0.88 (t, J=6.7 Hz, CH3, 3H);
(m, 4H); 2.80–3.01 (m, CH6 2–NH–CH6
, 3H). 13C-NMR
(CDCl3, 50 MHz) l: 14.1 (CH3); 22.7 (CH2); 25.4
(CH2); 29.3 (CH2); 29.9 (CH2); 31.9 (CH2); 32.0 (CH2);
36.6 (CH2); 46.6 (CH2N); 59.4 (CHN).
3.1.4. Preparation of the N-benzoyl deri6ati6e of 3
A sample of 40 mg (0.24 mmol) of 3, 480 ml (0.48
mmol) of a 1 M aqueous NaOH, 34 mg (0.48 mmol) of
benzoyl chloride and 5 ml de CH2Cl2 were mixed and
stirred overnight at r.t. The organic phase was sepa-
rated and the aqueous layer was extracted with di-
ethylether (2×20 ml). The combined organic phases
were dried over anhydrous magnesium sulfate. Solvents
were evaporated and the residual material was analyzed
by HPLC using a Pirkle (S,S) WHELK-0 1 column (25
cm×4.6 mm i.d.). Eluent: hexane/isopropanol=9:1.
1.20-1.73 (m, CH2, 12H); 2.45–2.50 (m, CH2
6 CHꢀCH2,
2H); 3.00 (s, CH3SO3, 3H); 4,72 (quint, CHOMs, 1H);
6
5.13–5.19 (m, CH6 2ꢀCH, 2H); 5.73–5.87 (m, CH2ꢀCH6 ,
1H). 13C-NMR (CDCl3, 75 MHz) l: 14.1 (CH3); 22.6
(CH2); 25.0 (CH2); 29.1 (CH2); 29.3 (CH2); 31.6 (CH2);
34.2 (CH2); 38.7 (CH3SO3); 52.6 (CH2); 83.0 (C
6 HOMs);
3.2. Synthesis of
3-methyl-5-(2(R)-pyrrolidinyl)isoxazole
118.9 (CH2ꢀCH); 132.6 (CH2ꢀCH).
6
6
To a stirred solution of 1.02 g (4.11 mmol) of the
mesylate in 10 ml of DMSO, 401 mg (6.17 mmol) of
NaN3 was added. The reaction mixture was heated for
12 h at 60°C. The resulting slurry was partitioned
between diethylether (25 ml) and water (10 ml). The
organic phase was washed with brine (2×10 ml), dried
over MgSO4, evaporated and purified by Kugelrohr
distillation to afford 674 mg (Yield=84%) of 2. B.p.
3.2.1. Synthesis of 1-trimethylsilyloxy-prop-2-yne 6
To a mixture of 5.60 g (100 mmol) of propargyl
alcohol and 8.07 g (50 mmol) of hexamethyldilazane
543 mg (5 mmol) of trimethylsilyl chloride was added
and the solution was gradually heated to 50°C
overnight. The reaction mixture was cooled and dis-
tilled to afford 11.8 g (Yield=92%) of 6. B.p. (15 mm
Hg)=27°C. 1H-NMR(CDCl3, 300 MHz) l: 0.01(s,
Si(CH3)3, 9H); 2.24 (t, J=2.3 Hz, H–Cꢁ, 1H); 4.10 (d,
J=2.3 Hz, CH2–Cꢁ, 2H).
1
(0.1 mm Hg)=50–55°C. H-NMR (CDCl3, 300 MHz)
l: 0.88 (t, J=6.7 Hz, CH3, 3H); 1.18–1.56 (m, CH2,
12H); 2.27–2.32 (m, CH2
CHN3, 1H); 5.10–5.18 (m, CH2
(m, CH2ꢀCH
, 1H). RMN 13C (CDCl3, 75 MHz) l: 14.1
6
CHꢀCH2, 2H); 3.28–3.36 (m,
6
ꢀCH, 2H); 5.75–5.88
6
(CH3); 22.7 (CH2); 26.1 (CH2); 29.2 (CH2); 29.4 (CH2);
31.8 (CH2); 33.9 (CH2); 38.8 (CH2); 62.3 (CHN3); 118.0
3.2.2. Synthesis of
3-methyl-5-(trimethylsilyloxymethyl)isoxazole 7
To a solution of 6 g (46.8 mmol) of the trimethylsi-
lylether 6, 4.2 g (56.12 mmol) of nitroethane and 10.03
(C
6 H2ꢀCH); 134.1 (CH2ꢀC6 H). HRMS m/z calc. for
C8H16N [M–C3H5· –N2]+: 126.1283; found: 126.1284.

A. Salmon, B. Carboni / Journal of Organometallic Chemistry 567 (1998) 31–37
35
g (84.2 mmol) of phenylisocanate in 70 ml of anhydrous
toluene 0.1 ml of triethylamine was added dropwise.
After stirring at r.t. overnight, diphenylurea was sepa-
rated by filtration and the resulting solution concen-
trated. The residual material was purified by bulb to
bulb distillation to afford 5.26 g (Yield=65%) of 7. bp
(m, CH2ꢀCH
(CDCl3, 50 MHz) l: 11.3 (CH3); 40.2 (CH2); 66.1
(CHOH); 101.7 (CHꢀC); 119.0 (CH2ꢀCH); 132.8
6
, 1H); 6.05 (s, CHꢀC, 1H). 13C-NMR
6
6
(CH2ꢀC6 H); 159.7 (C); 174.0 (CꢀN). HRMS m/z calc.
for C5H6NO2 [M–C3H5·]+: 112.0398. Found 112.0399.
[a]2D0= −14 (c=1.02, MeOH). A 92% ee was deter-
1
1
0.01 mm Hg=35–40°C. H-NMR (CDCl3, 200 MHz)
mined by examination of the H-NMR spectrum of the
1
l: 0.17 (s, (CH3)3Si, 9H); 2.28 (s, CH3, 3H); 4.69 (s,
CH2, 2H); 6.04 (s, CHꢀC, 1H). 13C-NMR (CDCl3, 50
MHz) l: 0.6 (CH3Si); 12.5 (CH3); 57.7 (CH2); 103.6
(S)-o-acetyllactic derivative [20]. H-NMR (CDCl3, 200
MHz) l: 1.48 (1.50 minor diastereoisomer) (d, J=7.1
Hz, CH3
CH3–CH=N, 3H); 2.71–2.78 (m, CH2
2H); 5.02–5.21 (m, CHꢀCH2 and CHCO2, 3H); 5.61–
5.80 (m, CH –CH2,
6
–CH, 3H); 2.13 (s, CH3CO2, 3H); 2.29 (s,
(C6
HꢀC); 160.8 (C); 172.5 (CꢀN).
6
6
–CHꢀCH2,
6
3.2.3. Synthesis of 3-methyl-5-formylisoxazole 8
6 ꢀCH2, 1H); 5.92–6.00 (m, O–CH6
To a stirred solution of the ether 7 (7.47 g, 43.11
mmol) in 25 ml of methanol 83 mg (0.43 mmol) of citric
acid was added. The resultant mixture was kept at r.t.
for 4 h. The solution was concentrated and the residual
material was partitioned between diethylether and wa-
ter. The organic layer was washed with brine, dried
over MgSO4 and concentrated. The residue was purified
by bulb to bulb distillation to afford 2.8 g (Yield=
57%) of 8. bp 0.1 mm Hg=60–65°C. Lit [27]: M.p.=
1H); 6.06 (s, H4, 1H); 6.11 (minor diastereoisomer).
3.2.5. Synthesis of azide 10
To a solution of 100 mg (0.653 mmol) of the alcohol
5 and 216 mg (0.783 mmol) of (PhO)2PON3 in 5 ml of
dry toluene, 119 mg (0.783 mmol) of 1,8-diazabicy-
clo[5.4.0]undec-7-ene was added. The solution was
stirred at r.t. overnight, then heated at 60°C for 1 h.
After cooling, the reaction mixture was washed with
water (2×5 ml), 1 N aqueous HCl and dried over
MgSO4. The solvent was removed under reduced pres-
sure and the residue was purified by column chro-
matography on silica gel to afford 68 mg (Yield=58%)
1
47–48°C. H-NMR (CDCl3, 200 MHz) l: 2.27 (s, CH3,
3H); 3.0 (broad s, OH, 1H); 4.66 (s, CH2
(s, CHꢀC, 1H). 13C-NMR (CDCl3, 50 MHz) l: 11.3
(CH3); 55.9 (CH2); 102.6 (CHꢀC); 160.0 (Cꢀ); 171.7
(CꢀN).
6 OH, 2H); 6.08
6
1
of 10. Rf=0.2 (heptane/ethyl acetate=92:8). H-NMR
To a solution of 1.22 g of the alcohol 8 (10.8 mmol),
11.4 g (146 mmol) of dry DMSO and 5.45 g (54 mmol)
of dry triethylamine in dry dichloromethane (40 ml),
477 mg (30 mmol) of sulfur trioxide-pyridine complex
was added in small portions. After stirring for 1 h at
0°C, the resultant mixture was washed with 1 N
aqueous HCl (3×15 ml), dried over MgSO4 and con-
centrated. The product was used in the next step with-
(CDCl3, 200 MHz) l: 2.31 (s, CH3, 3H); 2.62 (m, CH2,
2H); 4.59 (t, J=7 Hz, CHN3, 1H); 5.14–5.26 (m,
CH2
CHꢀC, 1H). 13C-NMR (CDCl3, 50 MHz) l: 11.4
(CH3); 37.3 (CH2); 57.0 (CHN3); 102.9 (CHꢀC); 119.4
6 ꢀCH, 2H); 5.75–5.87 (m, CH2ꢀCH6 , 1H); 6.10 (s,
6
(C6 H2ꢀCH); 132.0 (CH2ꢀC6 H); 160.0 (C); 169.2 (CꢀN).
HRMS m/z calc. for C5H5NO4 [M–C3H5·]+: 137.0463.
Found 137.0464.
out
supplementary
purification.
m=1.02
g.
1
Yield=85%. H-NMR (CDCl3, 200 MHz) l: 2.42 (s,
CH3, 3H); 6.84 (s, CHꢀC, 1H); 9.96 (s, CHO, 1H).
3.2.6. Synthesis of
3-methyl-5-(2(R)-pyrrolidinyl)isoxazole 4
To a solution of diethylborane prepared from 54 mg
(0.549 mmol) of triethylborane and 25 vl (0.254 mmol)
of borane dimethylsulfide complex [22] in 5 ml of
diethylether, 68 mg (0.381 mmol) of azide 10 was added
dropwise at −15°C . The mixture was allowed to warm
at r.t., stirred overnight, methanolyzed (0.5 ml) and
extracted with 1 N aqueous HCl (6×10 ml). The acidic
aqueous phases were combined and most of water was
removed using a water aspirator. After adding di-
ethylether (20 ml), the residual material was made
strongly alkaline by adding solid sodium hydroxide.
The organic phase was separated and the aqueous layer
extracted with diethylether (2×20 ml). The combined
organic phase was dried over potassium carbonate and
filtered. The pyrrolidine was purified by bulb to bulb
distillation to afford 40 mg (Yield=69%) of 4. B.p.
(0.01 mm Hg)=65–70°C. 1H-NMR (CDCl3, 200
MHz) l: 1.76–1.86 (m, 3H); 2.07–2.24 (m, 2H); 2.19 (s,
3.2.4. Allylboration of the aldehyde 5
To a solution of 2.97 g (9.12 mmol) of Ipc2BAll [12]
in 18 ml of diethylether at −100°C, 1.01 g (9.12 mmol)
of 5 in 10 ml of diethylether maintained at −78°C was
added . The temperature was kept at −100°C for 1 h
and then was allowed to warm at r.t. and stirred
overnight. Methanol (5 ml) was added to quench the
reaction. The volatile components were pumped off
from the reaction mixture and the residual material was
partitioned between water and dichloromethane. The
organic layer was separated, dried over MgSO4 and
concentrated. The crude product was chromatogra-
phied on silica gel (heptane/ethyl acetate: 85:15, Rf=
0.1) to give 612 mg of 9. Yield=44%. 1H-NMR
(CDCl3, 300 MHz) l: 2.25 (s, CH3, 3H); 2.44–2.62 (m,
CH2, 2H); 3.88 (d, J=4.8 Hz, OH, 1H); 4.74–4.80 (m,
CH6 OH, 1H); 5.04–5.13 (m, CH6 2ꢀCH, 2H); 5.72–5.86

36
A. Salmon, B. Carboni / Journal of Organometallic Chemistry 567 (1998) 31–37
CH3, 3H); 2.92–3.06 (m, 2H); 4.23 (dd, J=5.4 and 7.4
Hz, 1H); 5.88 (s, CHꢀC, 1H). 13C-NMR (CDCl3, 50
MHz) l: 10.4 (CH3); 24.2 (CH2); 45.6 (CH2); 53.6
calc. for C13H24 [M–CH3SO3H]+ 180.1877. Tr.
180.1887.
To a stirred solution of 804 mg (3.09 mmol) of the
mesylate 12 in 10 ml of DMSO 301 mg (4.63 mmol) of
NaN3 was added. The reaction mixture was heated for
12 h at 60°C. The resulting slurry was partitioned
between diethylether (25 ml) and water (10 ml). The
organic phase was washed with brine (2×10 ml), dried
over MgSO4, evaporated and purified by column chro-
matography to afford 495 mg (Yield=72%) of 13.
Rf=0.7 (heptane). 1H-NMR (CDCl3, 300 MHz) l:
(CH); 61.4 (CH); 99.8 (C6 HꢀC); 158.6 (Cꢀ); 174.5
(CꢀN). HRMS calc. for C15H16O2N2 [M]+ 256.1211.
Found. 256.1203. [h]2D0= +11 (c=0.2, CHCl3). Lit
[[15]a]: [h]2D0= +11.6°C (c=1.0, MeOH). The ratio of
enantiomeric products (96:4) was determined by HPLC
of the N-benzoyl derivative (Pirkle column, (S,S)
WHELK-0 1 (25 cm×4.6 mm i.d.). Eluent: hexane/
isopropanol=85:15).
0.89 (t, CH3
6 CH2, 6H); 1.18–1.57 (m, CH2, 14H); 2.13
3.3. Synthesis of (2S)-pentyl-(3S)-butylpyrrolidine 14
(m, CH–CHꢀ, 1H); 3.09–3.22 (m, CHN3, 1H); 5.01–
5.13 (m, CH6 2ꢀCH, 2H); 5.47–5.65 (m, CH2ꢀCH6 , 1H).
3.3.1. Synthesis of (1R)-pentyl-(2S)-butylbut-3-en-1-ol
11
13C-NMR (CDCl3, 75 MHz) l: 14.0 (2CH3); 22.6
(CH2); 22.7 (CH2); 26.1 (CH2); 29.4 (CH2); 30.4 (CH2);
31.7 (2CH2); 48.9 (CH); 66.8 (CHN3); 117.1 (CH2ꢀCH);
138.9 (CH2ꢀCH). C13H25N3: Calc.: C 69.91; H 11.28; N
18.81. Found: C 70.0; H 11.2; N 19.1.
To a solution of 670 mg (6.69 mmol) of hexanal in 4
ml of dry THF, 6.69 mmol of the bis(2,4-dimethyl-3-
pentyl)-tartrate ester of hept-2-ene boronic acid was
added [23]. The reaction mixture was stirred overnight
at r.t. and partitioned between diethylether and water.
The solvent was removed under reduced pressure and
the residue was purified by column chromatography on
silica gel to afford 923 mg (Yield=70%) of 11. Rf=
3.4. Synthesis of (2S)-pentyl-(3S)-butylpyrrolidine 14
To a solution of diethylborane prepared from 126 mg
(1.29 mmol) of triethylborane and 60 vl (0.597 mmol)
of borane dimethylsulfide complex in 5 ml of di-
ethylether [22], 200 mg (0.895 mmol) of azide 13 was
added dropwise at −15°C. The mixture was allowed to
warm at r.t., stirred overnight and then extracted with
1 N aqueous HCl (6×10 ml). The acidic aqueous
phases were combined and most of water was removed
using a water aspirator. After adding diethylether (20
ml), the residual material was made strongly alkaline by
adding solid sodium hydroxide with stirring. The or-
ganic phase was separated and the aqueous layer ex-
tracted with diethylether (2×20 ml). The combined
organic phase was dried over potassium carbonate and
filtered. The pyrrolidine was purified by bulb to bulb
distillation to afford 120 mg (Yield=68%) of 14. B.p.
(0.01 mm Hg)=65–70°C. 1H-NMR (CDCl3, 200
1
0.06 (heptane/ethyl acetate=98:2). H-NMR (CDCl3,
200 MHz) l: 0.89 (t, CH3
and OH, 15H); 1.92–2.02 (m, CH, 1H); 3.41–3.48 (m,
CHOH); 5.03–5.20 (m, CH2ꢀCH, 2H); 5.55 (m,
CH2ꢀCH
, 1H). 13C-NMR (CDCl3, 50 MHz) l: 14.1 (2
6 CH2, 6H); 1.14–1.65 (m, CH2
6
6
CH3); 22.7 (CH2); 22.8 (CH2); 25.5 (CH2); 29.6 (CH2);
30.5 (CH2); 32.0 (CH2); 34.7 (CH2); 50.3 (CH); 73.7
(CHOH); 117.7 (C6 H2ꢀCH); 139.1 (CH2ꢀC6 H). HRMS
calc. for C7H14 98.1095. Found 98.1099. [h]2D0= +15
(c=1.15, CHCl3).
+
’
3.3.2. Synthesis of
(1R)-pentyl-(1R)-azido-(2S)-butylbut-3-ene 13
In a 50 ml round-bottom flask fitted with a magnetic
stirring bar and rubber septa, 20 ml of
dichloromethane, 700 mg (3.53 mmol) of 11, 428 mg
(4.24 mmol) of triethylamine and 5 mg of DMAP are
mixed. The solution was cooled at 0°C and 422 mg (3.7
mmol) of methanesulfonyl chloride was added drop-
wise. After 5 h at r.t., the solid was eliminated by
filtration and the filtrate was diluted with diethylether
(20 ml), washed with 0.1 N aqueous HCl (2×10 ml),
dried over MgSO4 and evaporated to give 901 mg of
MHz) 0.87 (t, CH6 3CH2, 6H); 1.06–1.55 (m, CH2, 12H);
1.77–2.01 (m, 2H); 2.19 (1H); 2.60–3.06 (m, 3H). 13C-
NMR (CDCl3, 50 MHz) l: 14.1 (CH3); 14.2 (CH3);
22.7 (CH2); 23.0 (CH2); 27.3 (CH2); 28.8 (CH2); 30.4
(CH2); 30.7 (CH2); 31.0 (CH2); 41.7 (CH); 44.7 (CH2N);
61.5 (CHN). C14H25N, C6H3N3O6 (picrate): Calc.: C
53.51; H 7.09; N 13.13. Tr: C 53.5; H 7.3; N 13.3. The
ratio of enantiomeric products (85:15) was determined
by capillary gas chromatography using a 30 m DB Wax
column and the (S)-o-acetyllactic ester [20].
1
the mesylate 12 as a a colorless oil. Yield=98%. H-
NMR (CDCl3, 300 MHz) l: 0.89 (t, CH6 3CH2, 6H);
1.20–1.69 (m, CH2, 14H); 2.30 (m, CH–CHꢀ, 1H); 3.00
(s, CH3S, 3H); 4.63–4.72 (m, CHOMs, 1H); 5.04–5.20
References
(m, CH6 2ꢀCH, 2H); 5.50–5.69 (m, CH2ꢀC6
H, 1H). 13C-
NMR (CDCl3, 75 MHz) l: 12.9 (CH3); 13.0 (CH3);
21.4 (CH2); 21.5 (CH2); 23.9 (CH2); 29.1 (CH2); 30.5
(CH2); 31.1 (CH2); 37.8 (CH3S); 46.5 (CH); 85.5
[1] (a) G. Massiot, C. Delaude in: A. Brossi (Ed.), The Alkaloids,
Academic Press, NY, 1986, p.27. (b) A. Numuta, T. Ibuka, in:
A. Brossi (Ed.), The Alkaloids, Academic Press, NY, 1987, p.31.
See also annual reviews in Natural Product Reports.
(CHOMs); 117.2 (C6 H2ꢀCH); 136.0 (CH2ꢀC6 H). HRMS

A. Salmon, B. Carboni / Journal of Organometallic Chemistry 567 (1998) 31–37
37
[2] (a) J.K. Whitesell, Chem. Rev. 89 (1989) 1581. (b) K. Tomioka,
Synthesis (1990) 541. (c) R. Noyori, M. Kitamura, Angew.
Chem. Int. Ed. Engl. 30 (1991) 49.
[8] P.P. Waid, G.A. Flynn, E.W. Huber, J.S. Sabol, Tetrahedron
Lett. 37 (1996) 4091.
[9] J.M. Jego, B. Carboni, M. Vaultier, Bull. Soc. Chim. Fr. 129
(1992) 554.
[3] For some leading references, see: (a) P.L. Keusenkothen, B.
Smith, J. Chem. Soc. Perkin. Trans. I. (1994) 2485. (b) H.
Takahata, H. Takehara, N. Okhubo, T. Momose, Tetrahedron:
Asymmetry, 1 (1990) 561. (c) S.G. Pyne, J. Safaei-G., F. Koller,
Tetrahedron Lett. 36 (1995) 2511. (d) L.M. Harwood, I.A.
Lilley, Tetrahedron: Asymmetry 6 (1995) 1557. (e) P. Allway, R.
Grigg, Tetrahedron Lett. 32 (1991) 5817. (f) S.E. Denmark, L.R.
Marcin, J. Org. Chem. 58 (1993) 3857. (g) Y. Takaoka, T.
Kajimoto, C.H. Wong, J. Org. Chem. 58 (1993) 4809. (h) J.
Mulzer, A. Meier, J. Buschmann, P. Luger, Synthesis (1996) 123.
(i) I. Robina, R.P. Gearing, J.G. Buchanan, R.H. Wightman, J.
Chem. Soc. Perkin. Trans. I. (1990) 2622. (j) B.J. Littler, T.
Gallagher, I.K. Boddy, P.D. Riordan, Synlett (1997) 22. (k) J.
Fitremann, A. Dure´ault, J.-C. Depezay, Tetrahedron Lett. 35
(1994) 1201. (l) S. Choi, I. Bruce, A.J. Fairbanks, G.W.J. Fleet,
A.H. Jones, R.J. Nash, L.E. Fellows, Tetrahedron Lett. 32
(1991) 5517. (m) B. Singaram, T. Nguyen, D. Sherman, D. Ball,
M. Solow, Tetrahedron: Asymmetry 4 (1993) 189. (n) T. Shono,
T. Fujita, Y. Matsumura, Chem. Lett. (1991) 81. (o) O. Provost,
J.P. Ce´le´rier, H. Petit, G. Lhommet, J. Org. Chem. 57 (1992)
2163. (p) A.I. Meyers, B. Santiago, Tetrahedron Lett. 36 (1995)
5877. (q) P. Beak, S.T. Kerrick, S. Wu, J. Chu, J. Am. Chem.
Soc. 116 (1994) 3231. (r) P. Beak, A. Basu, D.J. Gallagher, Y.
Sun Park, S. Thayumanavan, Acc. Chem. Res. 29 (1996) 552. (s)
C.A. Willoughby, S.L. Buchwald, J. Org. Chem. 58 (1993) 7627.
(t) S. Arseniyadis, P.Q. Huang, D. Piveteau, H.-P. Husson,
Tetrahedron 44 (1988) 2457. (u) A.I. Meyers, G.P. Brengel, J.
Chem. Soc.Chem. Commun. (1997) (v) M. Pichon, B. Figade`re,
Tetrahedron: Asymmetry 7 (1996) 927. (w) T. Harrison, Con-
temp. Org. Synth. 2 (1995) 259. (x) A.R. Pinder, Nat. Prod. Rep.
9 (1992) 17. (y) D.J. Robins, Nat. Prod. Rep. 7 (1990) 377. (z)
A.R. Pinder, Nat. Prod. Rep. 7 (1990) 447.
[10] B. Carboni, M. Vaultier, Bull. Soc. Chim. Fr. 131 (1995) 1003.
[11] (a) Y. Yamamoto, N. Asao, Chem. Rev. 93 (1993) 2207. (b)
W.R. Roush in: B.M. Trost, I. Fleming (Eds.), Comprehensive
Organic Synthesis, vol. 2, Pergamon Press, Oxford, 1991 p. 1.
[12] (a) H.C. Brown, P.K. Jadhav, K.S. Bhat, J. Am. Chem. Soc. 110
(1988) 1535. (b) P.K. Jadhav, K.S. Bhat, P.T. Perumal, H.C.
Brown, J. Org. Chem. 51 (1986) 432. (c) H.C. Brown, K.S. Bhat,
J. Am. Chem. Soc. 108 (1986) 5919.
[13] The low yield was the consequence of an unsatisfactory separa-
tion of isopinocampheol by chromatography on silica gel.
[14] J.A. Dale, D.L. Dull, H.S. Mosher, J. Org. Chem. 34 (1969)
1034.
[15] (a) D.S. Garvey, J.T. Wasicak, R.L. Eliott, et al., J. Med. Chem.
37 (1994) 4455. (b) R.L. Elliot, H. Kopecka, N.-H. Lin, Y. He,
D.S. Garvey, Synthesis (1995) 772. (c) N.H. Lin, Y. He, H.
Kopecka, Tetrahedron Lett. 36 (1995) 2563. (d) S.J. Witten-
berger, J. Org. Chem. 61 (1996) 356.
[16] C.C. Sweeley, R. Bentley, M. Makita, W.W. Wells, J. Am.
Chem. Soc. 85 (1963) 2497.
[17] T. Mukayama, T. Hoshino, J. Am. Chem. Soc. 82 (1960) 5339.
[18] G.L. Bundy, D.C. Peterson, Tetrahedron Lett. 1 (1978) 41.
[19] J.R. Luly, J.F. Dellaria, J.J. Plattner, J.L. Soderquist, N. Yi, J.
Org.Chem. 52 (1987) 1487.
[20] A. Mosandl, M. Gessner, C. Gu¨nther, W. Deger, G. Singer, J.
High Res. Chrom. Chrom. Comm. 10 (1987) 67.
[21] A.S. Thompson, G.R. Humphrey, A.M. De Marco, D.J.
Mathre, E.J.J. Grabowski, J. Org. Chem. 58 (1993) 5886.
[22] Diethylborane (F. Langer, A. Devasagayaraj, P.Y. Chavant, P.
Knochel, Synlett, (1994) 410) was chosen because its easy access
and its best chemioselectivity in the hydroboration step com-
pared with a halogenoborane as thexylchloroborane.
[23] H.C. Brown, A.S. Phadke, Synlett (1993) 927.
[24] A.L. Costa, M.G. Piazza, E. Tagliavini, C. Trombini, A. Umani-
Ronchi, J. Am. Chem. Soc. 115 (1993) 7001.
[4] The intermolecular reaction of organoboranes with azides was
pioneered by H.C. Brown et al. See: (a) A. Suzuki, S. Sono, M.
Itoh, H.C. Brown, M.M. Midland, J. Am. Chem. Soc. 93 (1971)
4329. (b) H.C. Brown, M.M. Midland, A.B. Levy, J. Am. Chem.
Soc. 94 (1972) 2114. (c) H.C. Brown, M.M. Midland, A.B. Levy,
J. Am. Chem. Soc. 95 (1973) 2394.
[25] A. Pelter, K. Smith, H.C. Brown, in: A.R. Katritzky, O. Meth-
Cohn, C.W. Rees (Eds.), Boranes Reagents, Academic Press,
New York, 1988, p. 432.
[5] J.M. Jego, B. Carboni, M. Vaultier, R. Carrie´, J. Chem. Soc.
Chem. Commun. (1989) 142.
[26] S. Arseniyadis, P.Q. Huang, H.P. Husson, Tetrahedron Lett. 29
(1988) 631.
[6] H.C. Brown, A.M. Salunkhe, Tetrahedron Lett. 34 (1993) 1265.
[7] D.A. Evans, A.E. Weber, J. Am. Chem. Soc. 109 (1987) 7151.
[27] D. Bell, E.A. Crowe, N.J. Dixon, G.R. Geen, I.S. Mann, M.R.
Shipton, Tetrahedron 50 (1994) 6643.
.
.