Synthesis of Enantiopure 3-Hydroxypiperidines from Sulfinyl Dienyl Amines by Diastereoselective Intramolecular Cyclization and [2,3]-Sigmatropic Rearrangement

Article abstract of DOI:10.1021/acs.joc.5b01307

The highly diastereoselective base-promoted intramolecular cyclization of a variety of enantiopure sulfinyl dienyl amines provides novel sulfinyl tetrahydropyridines that are readily converted to 3-hydroxy tetrahydropyridines via sigmatropic rearrangement. The influence of N- and C- substituents on the process has been studied. Procedures to shorten the sequence such as the tandem cyclization followed by [2,3]-sigmatropic rearrangement, as well as cyclization of the free amine, under Boc- or ArSO- deprotection conditions have been examined. Good to excellent levels of selectivity are generally observed for the reported transformations (dr: 75/25 to >98/2). A novel protocol to access substituted amino dienyl sulfoxides is also reported.

Full text of DOI:10.1021/acs.joc.5b01307

Page 1 of 69
The Journal of Organic Chemistry
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Synthesis of Enantiopure 3ꢀHydroxypiperidines from
Sulfinyl Dienyl Amines by Diastereoselective
Intramolecular Cyclization and [2,3]ꢀSigmatropic
Rearrangement
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†
†
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†
Carmen Simal, Robert H. Bates, Mercedes Ureña, Irene Giménez, Christina Koutsou, Lourdes
‡
†
†
Infantes, Roberto Fernández de la Pradilla* and Alma Viso*
†
Instituto de Química Orgánica General, IQOGꢀCSIC, Juan de la Cierva 3, 28006 Madrid, Spain
Instituto de Química Física Rocasolano, IQFRꢀCSIC, Serrano 119, 28006 Madrid, Spain
‡
Fax: (+34) 915644853
Eꢀmail: iqofp19@iqog.csic.es (RFP); iqov379@iqog.csic.es (AV)
Table of Contents Graphic
R3
O
S
HO
pꢀTol
*
*
DBU-mediated
cyclization
H
[2,3]-sigmatropic
rearrangement
R2
N
R1
N
R3
PG
O
S
R3
2
0 examples
HO
49ꢀ88%
HO
*
pꢀTol
*
*
N
one-pot
cyclization/ [2,3]
R2
R1
nꢀPr
R2
NH
PG
R1
N
H—HCl
(+)ꢀpseudoconhydrine
hydrochloride
two new stereogenic
centers are created
PG
14 examples
42ꢀ80%
15 examples
5ꢀ83%
(
5-6 steps f rom menthyl sulfinate)
4
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Abstract: The highly diastereoselective baseꢀpromoted intramolecular cyclization of a variety of
enantiopure sulfinyl dienyl amines provides novel sulfinyl tetrahydropyridines that are readily converted
to 3ꢀhydroxy tetrahydropyridines via sigmatropic rearrangement. The influence of Nꢀ and Cꢀ substituents
on the process has been studied. Procedures to shorten the sequence such as the tandem cyclization
followed by [2,3]ꢀsigmatropic rearrangement, as well as cyclization of the free amine, under Bocꢀ or
ArSOꢀ deprotection conditions have been examined. Good to excellent levels of selectivity are generally
observed for the reported transformations (dr: 75/25 − >98/2). A novel protocol to access substituted
amino dienyl sulfoxides is also reported.
1
2
3
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9
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INTRODUCTION
The piperidine ring is one of the more frequently encountered substructure of biologically important
1
2
natural products. Their presence in conformationally restricted peptidomimetics, medicinally important
3
drugs, as well as in numerous compounds with significant pharmacological properties has attracted
4
considerable synthetic efforts to achieve the stereoselective or asymmetric synthesis of these targets.
The strategies used to access this privileged scaffold include the azaꢀDielsꢀAlder reaction using either
5
6
azaꢀdienes or azaꢀdienophiles, the additionꢀcyclization to imines, the ring expansion of furan
7
8
derivatives, the reduction of pyridine scaffolds, the ringꢀclosing metathesis of suitable nitrogenꢀ
9
containing dienes, and various approaches that rely on the nucleophilic attack of nitrogen onto different
1
0
acceptors.
Many of these protocols employ aminoacids or other chiral auxiliaries to obtain these products. The
11
sulfinyl group, broadly used in organic synthesis as stereodirecting functionality, has also been
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1
2
13
examined within this field by using sulfinimines, and alkenyl sulfoxides as substrates. Nonetheless,
the development of new synthetic approaches to access structurally diverse and enantiopure piperidine
derivatives through simple and general experimental protocols remains a challenge.
1
2
3
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5
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7
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9
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1
1
1
1
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RESULTS AND DISCUSSION
In the past years we have been engaged in the development of novel and efficient chirality transfer
1
4
methodologies based on the sulfinyl chiral auxiliary.
Within this context we envisioned two
complementary approaches to synthetically useful functionalized tetrahydropyridinꢀ3ꢀols, E, from amino
sulfinyl dienes C and H (Scheme 1). We considered that readily available aminoꢀ1ꢀsulfinyl diene
derivatives C, prepared in 1ꢀ3 steps from the condensation between a lithio sulfinyl diene derived from A
14d
and sulfinimine B, could undergo a baseꢀpromoted intramolecular cyclization to generate an allylic
sulfinyl intermediate D that would suffer a [2,3]ꢀsigmatropic rearrangement to the desired targets E.
Alternatively, the cyclization of isomeric amino 2ꢀsulfinyl dienes H, similarly to our findings for the
1
5
related hydroxy 2ꢀsulfinyl dienes, would produce ultimately the desired hydroxy piperidines E through
allylic sulfoxide intermediates D. Dienes H could be prepared by Stille coupling between iodo vinyl
1
6
sulfoxides G and amino stannanes F, in analogy with other sulfinyl dienes prepared in our group.
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Scheme 1. Proposed sulfinyl-mediated synthesis of functionalized tetrahydropyridines
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
4
5
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5
5
5
5
5
5
5
6
R3
O
S
R3
N
O
S
R3
O
S
H
base
base
pꢀTol
pꢀTol
pꢀTol
R2 HN
PG C
pꢀTol
R1
R2
R1
R2
NH R1
PG
PG
D
H
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
I
S
[2,3]
Stille
pꢀTol
S
LDA
N
O
R1
R3
B
R3
R1
G
R3
O
S
HO
R2
SnBu3
pꢀTol
N
R1
R2
NY
PG
R2
PG
A
E
F
Piperidinols from 1-sulfinyl dienes. To establish the viability of the process (C ꢀ E) we selected
14d
readily available dienyl sulfone (R)-1 and diastereomeric dienyl sulfoxides 2 and 3, and the results
17
obtained are shown in Scheme 2. Similarly to Back’s findings, the intramolecular cyclization of dienyl
sulfone (R)-1 took place in excellent yield (99%) to produce enantiopure piperidine (R)-4. In contrast,
the less electron withdrawing sulfoxide group (2, 3) required an excess of base and higher temperatures
(
50ꢀ70 ºC) to promote similar cyclizations. Diastereomer 2 was treated with K CO leading to a clean
2 3
crude reaction mixture that contained essentially ent-5a in moderate unoptimized yield. Unfortunately, 2
2
3
(1ꢀ(R), PG = Ts) derives from the minor diastereomeric product from the addition of lithiated A (R = R
1
14d
= H) to B (R = Ph) (C; dr: 13:87, PG = SOpꢀTol, Scheme 1) after a change of PG, which undermines
1
8
the efficiency of this route. In contrast, major diastereomer 3 (1ꢀ(S)) was particularly sluggish providing
mixtures of trans and cis tetrahydropyridinꢀ3ꢀols (5a/6a) in low yield or er (K CO ). Furthermore,
2
3
variable amounts of allylic sulfenates and vinyl sulfoxide intermediates were detected in the crude
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mixture. These results indicated that our preliminary hypothesis was correct (Scheme 1, C ꢀ E),
however, diastereomer 3 was not wellꢀbehaved and we tested a number of different reaction parameters
such as reaction time, solvents, bases and the nature of the group attached to nitrogen (PG = Ts, SOpTol,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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4
4
5
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5
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5
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5
5
5
5
6
1
Boc, H) with fruitless results. Introducing other substituents on C (R = iꢀPr) did not provide any
0
1
2
3
4
5
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7
8
9
0
1
2
3
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9
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0
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9
0
1
2
3
4
5
6
7
8
9
0
2
improvement and we did not envision any advantage for reactivity in attaching substituents, R , in these
1ꢀsulfinyl dienes.
The relative and absolute configuration of piperidinol ent-5a (from 2) was established by a detailed study
of their spectral features including NOE experiments and derivatization to the methoxyphenylacetate 7a.
Surprisingly, a similar study for transꢀpiperidinols from 3 revealed that the enantiomeric ratio was low or
completely opposite to our expectations providing ent-5a. This finding suggests that an alternative
reaction pathway entailing a loss of stereoselectivity (Cꢀ6S/C-6R) through a ringꢀcleavage/ringꢀclosure of
allylic sulfinyl anion (I) followed by sigmatropic rearrangement to transꢀpiperidinol (5a or ent-5a) is
operative in this case.
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Scheme 2. Base-promoted cyclization of amino 1-sulfonyl and 1-sulfinyl dienes
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
SO pꢀTol
SO pꢀTol
2
2
K CO rt
2
3,
HN
Ts
Ph
N
Ph
DMF:H O,10:1
2
Ts
(R)-4
99%
(
R)-1
Ph
O
O
S
MeO
S
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HO
O
pꢀTol
pꢀTol
K CO 60 ºC
2
3,
6S
HN
Ts
Ph
N
Ph
N
Ph
DMF:H O,10:1
2
Ts
7a
64%
Ts
trans-ent-5a
2
er>99:1
O
S
O
S
HO
HO
pꢀTol
+
HN
Ts
Ph
N
Ph
N
Ph
N
Ph
Ts
Ts
cis-6a
Ts
3
I
trans (5a / ent-5a)
K CO DMF:H O,10:1, 60 ºC, 43%
79 (er: 67/33)
95 (er: 0/100)
:
:
21
5
2
3,
2
Cs CO , DMF, 70 ºC, 38%
2
3
Piperidinols from 2-sulfinyl dienes.
Preparation of amino 2-sulfinyl dienes. The required iodo alkenyl sulfoxides 11 (Scheme 3) were
prepared from alkynyl sulfoxides 8 by our Pdꢀcatalyzed regioselective hydrostannylation, separation by
16
chromatography of major stannane 9 and tinꢀiodine exchange.
The synthesis of Nꢀprotected amino
19
vinyl stannanes 13 is outlined in Scheme 3. The known stannane with a free amino group 12, was
protected uneventfully with a variety of sulfonamides and Boc groups (PG) as representative examples of
amine protection, 13a-f. Alternatively, a Mitsunobu reaction with BocNHTs and hydroxy stannanes
15a
1
4a,b produced the substituted precursors 13g and 13h.
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Scheme 3. Synthesis of iodo alkenyl sulfoxides and amino vinyl stannanes
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
O
ꢀTol
p
O
S
O
S
S
Bu SnH
3
Bu Sn
3
Pd(Ph P)4
3
+
pꢀTol
pꢀTol
Toluene
R1
R1
Bu Sn
R1
a-g
3
_7
8 ºC to rt
3ꢀ92%
8
9a-g 98/2 ꢀ >90/10 10
5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
I , CH Cl
2
2
2
93ꢀ100%
1
) EtMgBr, Et O
2
_
2) ( )ꢀpꢀTolS(O)OMen
O
48ꢀ82%
H
I
S
pꢀTol
R1
R1
1
1a-g
1
R = nꢀBu, a; nꢀPr, b; tꢀBu, c; (CH ) Cl, d;
2 3
Ph, e; 4ꢀMeOꢀC H f; 4ꢀFꢀC H , g.
6
4,
6 4
Nꢀprotection
Et N, ArSO Cl
SnBu3
SnBu3
NHPG
3
2
NH2
or Boc O, CH Cl
2 2 2
0 ºC ꢀ rt, 16 h
3ꢀ86%
12
13a-f
6
PG = Ts, a; 4ꢀNO ꢀC H SO , b; 2ꢀNO ꢀC H SO , c;
2
6
4
2
2
6
4
2
2
,4,6ꢀtriꢀMeꢀC H SO , d; 2,4,6ꢀtriꢀiꢀPrꢀC H SO , e; Boc, f.
6
4
2
6
4
2
R3
Me
BocNHTs
SnBu3
OH
SnBu3
SnBu3
Ph P
or
3
R2
DIAD Me
NBocTs
NBocTs
13h 77%
2
3
13g 49%
1
4a, R = Me, R = H
2
3
1
4b, R = H, R = Me
At the early stage of the project we examined the synthesis of an unprotected amino dienyl sulfoxide by
Stille coupling between stannane 12 and iodide 11a. A variety of standard Stille conditions including
different solvents, temperatures and catalysts (Pd (dba) ·CHCl , Pd(PPh ) , Pd(CH CN) Cl ) were tested
2
3
3
3 4
3
2
2
with fruitless results. In all cases the majority of the iodide was recovered and the stannane was
consumed. It was decided then to address the coupling of iodides 11a-g with protected stannanes 13a-f to
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produce Z,Zꢀamino sulfinyl dienes 15a-m in fair unoptimized yields. Similarly, the coupling of isomeric
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
5a
iodide 11a’
with stannane 13a led to Z,Eꢀdiene 15n (Scheme 4). To access more substituted
1
5c
substrates, the coupling between iodide 11a and racemic stannane 13g led to a separable mixture of Nꢀ
Boc dienes that were transformed to the target Nꢀtosyl aminodienes 15o and 15p by removal of the Boc
group with TFA under standard conditions. The coupling between iodide 11a and stannane 13h did not
give rise to diene 15q. After considerable experimentation we could obtain the desired diene 15q by a
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5a
Mitsunobu reaction on the known hydroxy sulfinyl diene 16, and Boc deprotection. It should be
pointed out that the efficiency of the route was compromised by the unexpectedly low regioselectivity of
the Mitsunobu reaction since an equimolecular mixture of 17 and 15q’ was formed.
Scheme 4. Synthesis of protected amino 2-sulfinyl dienes
O
O
S
O
S
S
SnBu3
ꢀTol
p
I
pꢀTol
pꢀTol
NH
PG
3a-f
+
Me
NH nꢀBu
(
a)
O
S
R1
NH R1
PG
SnBu3
Ts
I
pꢀTol
15o
1
11a-g
(
a,b)
15a-m
Me
NTs
O
+
+
Boc
nꢀBu
11a
1
S
1
5a-f R = nꢀBu,
PG = Ts, a;
4ꢀNO ꢀC H SO , b;
1
15h R = tꢀBu, PG = Ts
pꢀTol
1
13g
15i,j
R = (CH ) Cl,
2
3
Me
NH nꢀBu
Ts
PG = Ts, i; Boc, j.
15k R = Ph, PG = Ts
5l R = 4ꢀMeOꢀC H , PG = Ts
2
6
4
2
1
2
ꢀNO ꢀC H SO , c;
2
6
4
2
1
2
,4,6ꢀtriꢀMeꢀC H SO , d;
1
1
6 4
15p
6
4
2
1
5m R = 4ꢀFꢀC H , PG = Ts
2
,4,6ꢀtriꢀiꢀPrꢀC H SO , e;
6 4
6
4
2
O
S
O
S
O
Me
Me
Boc, f.
S
1
1
5g R = nꢀPr, PG = Ts
Me
ꢀTol
pꢀTol
p
ꢀTol
p
(
c)
O
S
O
+
OH nꢀBu
NPG nꢀBu
BocN
nꢀBu
I
S
(
a)
pꢀTol
50:50
Ts
pꢀTol
Ts
1
3a +
16
15q' PG = Boc
17
TsHN
nꢀBu
n
ꢀ
Bu
(b)
1
1a'
15n
15q, PG = H
Reaction conditions: (a) Pd(CH CN) Cl , BHT, DMF, rt, 16 h, 45ꢀ83%; (b) i) TFA, CH Cl , ii) NaOH,
3
2
2
2
2
6
2ꢀ79%; (c) BocNHTs, Ph P, DEAD, Toluene, 0 ºC ꢀ rt, 38%.
3
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2
To develop a more general route to amino sulfinyl dienes substituted at Cꢀ1 (R ) we explored the addition
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
0
of ethynylmagnesium chloride to (S)ꢀpꢀtoluenesulfinimine 18a followed by treatment with LiHMDS
and Bu SnCl, to produce a 90/10 separable mixture of diastereomeric sulfinamides that provided a good
3
yield of sulfinamide (3S)ꢀ19a as major diastereomer. Purification on silica gel of (3S)ꢀ19a had to be
carried out rapidly to minimize destannylation. Similarly, from sulfinimine 18b, major stannane (3S)ꢀ19b
was obtained in 75% isolated yield. Subsequent Stille coupling of diastereomerically pure stannanes
(3S)ꢀ19a and (3S)ꢀ19b with vinyl iodide 11b gave rise to amino 1,3ꢀenynes 20a and 20b in fair isolated
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1a
yields.
Stereoselective hydrogenation of 20a,b with Wilkinson’s catalyst produced the desired Nꢀ
1
6,21b
sulfinyl amino dienes 15r and 15s as single diastereomers and in acceptable overall yields.
Scheme 5. Stereoselective synthesis of N-sulfinylamino 2-sulfinyl dienes
pꢀTol
pꢀTol
S
S
1)
HN
O
MgCl
N
O
2) Bu SnCl, LiHMDS
R2
3
R2
Toluene
SnBu3
2
1
8a,b
2
19a R = Ph, dr: 90/10, 86%
2
R = Ph, Et
19b R = Et, dr: 77/23, 75%
O
I
S
Ph As (0.2 equiv)
3
pꢀTol
10% Pd (dba) —CHCl
2
3
3
BHT, THF
nꢀPr
11b
pꢀTol
O
S
S
HN
R2
O
pꢀTol
H , Toluene
O
S
2
R2
NH nꢀPr
2
0% (Ph P) RhCl
3
3
pꢀTol
S
O
pꢀTol
nꢀPr
2
2
15r, R = Ph, 62%
20a, R = Ph, 48%
2
2
1
5s, R = Et, 70%
20b, R = Et, 62%
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Diastereoselective cyclization of amino dienyl sulfoxides. Initial studies probed the viability of this
baseꢀpromoted conjugate addition using sulfinyl diene 15a as a model substrate in the presence of strong
nonꢀnucleophilic bases such as LDA or NaH giving allylic sulfoxide 21a with good diastereoselectivity
but in low yields (27% and 19% respectively) along with uncharacterized byproducts. Further
optimization (Table 1, entries 1ꢀ3) led to the use of DBU in toluene for the synthesis of the desired Nꢀ
tosyl sulfinyl tetrahydropyridine 21a as a single isomer, in 78% isolated yield that could be stored for
months without noticeable loss of diastereomeric purity.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The influence of the Nꢀprotecting group on the process was next addressed by performing the reaction
with different sulfonamides 15b-e (Table 1, entries 4ꢀ7) that behaved largely as the simple Ts group both
in yields and stereoselectivities. In contrast, NꢀBoc dienyl sulfoxide 15f was unreactive to DBU and
required the use of NaH in THF to promote the cyclization (Table 1, entry 8) in good yield and
selectivity. It should be pointed out that the presence of rotamers in this case required additional
22
transformations to determine the diastereomeric ratio accurately. Therefore, to facilitate the analysis of
the data, the majority of the ensuing study was carried out on Nꢀtosyl amino dienyl sulfoxides.
1
Subsequent studies focusing on variation of substitution (R ) showed the generality of the DBUꢀpromoted
cyclization for Nꢀtosyl amino dienyl sulfoxides 15g,i and the use of NaH for NꢀBoc substrates, 15j. The
protocol readily accommodates alkyl substituents, except for the bulky tꢀBu group 15h (Table 1, entries
9
ꢀ12), as well as substituted aryl groups (Table 1, entries 13ꢀ15) with good yields and selectivities. The
influence of the geometry of the diene was then briefly examined, and the less reactive diene 15n required
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longer reaction times to give a moderate yield of cisꢀtetrahydropyridine 21n, along with a substantial
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
3
amount of the undesired cyclic vinyl sulfoxide, resulting from isomerization of the allylic double bond
in the final product (Table 1, entry 16).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The transformation is also compatible with the presence of an additional stereocenter in the dienamine
2
skeleton (R ). Thus, Cꢀ1 methyl substituted substrates 15o and 15p were converted into the expected
products 21o and 21p in good yield and selectivity although the cyclization of 15p required heating at 70
ºC. Moreover, the cyclization of Nꢀsulfinyl dienamine 15r, with a bulky Ph substituent took place
similarly. Further investigations demonstrated that the methodology can also tolerate an additional
3
substituent on the diene skeleton (R ), as shown by the transformation of 15q, with a Me group at Cꢀ3,
into sulfinyl piperidine 21q that underwent a slight epimerization at sulfur upon standing in solution
15,24
(Table 1, entries 17ꢀ20).
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TABLE 1. DBU-Promoted cyclization of Z,Z and E,Z amino dienyl sulfoxides
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R3
O
S
O
S
R3
O
S
H
H
DBU, Toluene
0 ºC to rt, 16 h
pꢀTol
pꢀTol
pꢀTol
3
2
R2
or
N
ꢀBu
NH
PG
R1
R2
R1
n
N
PG
PG
2
1a-r
21n
(Z,Z)-15a-q
E,Z)-15n
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
a
1
2
a
b
c
Entry
SM
15a
15a
15a
15b
15c
15d
15e
15f
PG
R
R
trans/cis
97/3
21 (yield %)
d
1
Ts
nꢀBu
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
21a (60)
e
2
3
4
5
6
7
8
9
Ts
nꢀBu
nꢀBu
nꢀBu
nꢀBu
nꢀBu
nꢀBu
nꢀBu
nꢀPr
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
90/10
>98/2
ꢀ
21a (69)
Ts
21a (78)
21b (64)
21c (62)
21d (62)
21e (76)
pNBS
oNBS
1
f
f
Ar SO
2
2
Ar SO
2
g
Boc
21f (81)
15g
15h
15i
Ts
Ts
21g (85)
ꢀ
1
0
1
2
tꢀBu
1
1
Ts
(CH
(CH
2
)
)
3
3
Cl
Cl
>98/2
80/20
>98/2
>98/2
97/3
21i (84)
g
15j
Boc
2
21j (63)
13
14
15k
15l
Ts
Ts
Ts
Ts
Ts
Ts
Ph
4ꢀMeOꢀC
4ꢀFꢀC
21k (71)
21l (68)
H
4
6
1
1
1
1
1
5
6
7
8
9
15m
15n
15o
15p
6
H
4
21m (70)
h
nꢀBu
nꢀBu
nꢀBu
nꢀPr
2/98
21n (51)
(S)ꢀMe
(R)ꢀMe
(R)ꢀPh
H
>98/2
>98/2
>98/2
96/4
21o (77)
i
21p (56)
15r S(O)pꢀTol
15q
Ts
21r (68)
j
20
nꢀBu
21q (64)
a
1
b
3
2,3ꢀtrans/cis ratio determined by H NMR analysis of crude reaction mixtures. R = H unless otherwise
c
d
e
f
1
2
stated. Yield of isolated major diastereoisomer of 21. In THF. In CH Cl . Ar = 2,4,6ꢀMe C H ; Ar
=
21q (R = Me). 3 h at 70 ºC.
2
2
3
6
4
g
h
2,4,6ꢀiꢀPr ꢀC H . NaH/THF; 21j was isolated along with a 20% of 2,3ꢀcisꢀ21j. 72 h at rt for 21n and
3 6 4
3
i
1
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Finally we pursued the direct cyclization of free amino functionalities that took place smoothly upon one
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
pot treatment of NꢀBoc (15f) or Nꢀsulfinyl dienyl sulfoxides (15r, 15s) with TFA followed by basification
2
5
with NaOH to produce 21s, 21t and 21u respectively (Table 2). In this manner, the cyclization of 15j,
1
with a functionalized side chain (R = (CH ) Cl), resulted in a concurrent second cyclization to afford
2
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
bicyclic allylic sulfoxide 21v with an indolizidine skeleton, identical to that obtained from NꢀBoc sulfinyl
piperidine 21j under similar conditions but in a shorter and more diastereoselective sequence (98/2 vs
80/20), (Table 2, entry 4 vs Table 1, entry 12).
TABLE 2. TFA/NaOH-Promoted cyclization of Z,Z-amino dienyl sulfoxides
O
S
O
S
O
S
H
H
1) TFA, CH Cl2
2
pꢀTol
pꢀTol
or
pꢀTol
H
2
) NaOH
R2
NH R1
PG
5f,j PG = Boc,
5r,s PG = ꢀS(O)ꢀpꢀTol
R1
R2
N
N
H
21s-u
2
1v
1
1
1
2
a,b
Entry
SM
15f
15r
15s
15j
R
R
21 (yield %)
21s (59)
21t (88)
1
2
3
4
nꢀBu
nꢀPr
H
(R)ꢀPh
(S)ꢀEt
H
nꢀPr
21u (60)
21v (49)
(CH ) Cl
2
3
a
1
b
2
,3ꢀtrans/cis ratio >98/2 determined by H NMR analysis of crude reaction mixtures. Yield of isolated
major diastereoisomer of 21.
The high stereoselectivity found for these cyclizations and the configurational stability at sulfur of the
resulting allylic sulfoxides are noteworthy. This process proceeds with complete stereoselectivity since
2
,3ꢀtrans (21a) or 2,3ꢀcis (21n) cyclic allylic sulfoxides were obtained from (Z,Z)ꢀ and (Z,E)ꢀdienes 15a
1
2
3
and 15n (R = nꢀBu, R = R = H), respectively (Table 1, entries 3 and 16). While these sulfinyl allylic
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tetrahydropyridines 21 were fully characterized by standard techniques, the 2,3ꢀtrans or 2,3ꢀcis
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
stereochemistry could not be firmly established therefore stereochemical assignments were secured by an
1
5c
Xꢀray crystal structure determination of 21o and subsequent comparison of the data.
In addition, the
results of the [2,3]ꢀsigmatropic rearrangements of these allylic sulfoxides to produce allylic alcohols (see
below) provided further evidence supporting these assignments. We rationalize the formation of 2,3ꢀ
trans or 2,3ꢀcis tetrahydropyridines 21, by assuming that (Z,Z) or (Z,E) dienes adopt an Sꢀcis eclipsed
conformation C=C/Sꢀ:, forcing the nucleophilic attack of nitrogen on the αꢀface of dienamines 15
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(Scheme 6). Subsequent protonation of the allylic sulfinyl anion on the same face would lead to 2,3ꢀ
trans-21 or 2,3-cis-21 cyclic products. It should be pointed out that this stereochemical outcome is
1
5
parallel to our findings on the cyclization of hydroxy dienyl sulfoxides, as well as other literature
2
6,13b
precedents.
Scheme 6. Stereochemical outcome of 2,3-trans 21
R3
R3
N
O
S
O
S
R3
H3
R2
H
pꢀTol
pꢀTol
1
H2
R1
R
N
H
S pꢀTol
GP
R2
N
R1
H
R2
O
PG
PG
trans
ꢀ21
(Z,Z)ꢀ15
J2ꢀ3 = <1ꢀ 2 Hz
Sigmatropic rearrangement of allylic sulfinyl tetrahydropyridines. The [2,3]ꢀsigmatropic
rearrangement of allylic sulfoxides leads reversibly to allylic sulfenates that, with an appropriate
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thiophile, produce allylic alcohols. However, the intrinsic configurational stability of the sulfur center in
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
7
2
1 suggests that the sigmatropic rearrangement might not be a favored pathway.
1
2
3
Substrate 21a (R = nꢀBu, R = R = H) was selected as a representative example to examine the
feasibility of the sigmatropic process. Treatment of 21a under standard conditions, P(OMe) in MeOH,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
gave a complex mixture of unidentified products. Performing the reaction in the presence of inorganic
bases such as K CO /DMFꢀH O or Cs CO /DMF required longer reaction times (48 h) and led to a
2
3
2
2
3
2
8
reduced selectivity (5b/6b, ca 70/30) that suggests a possible epimerization at C3 in 21a. Screening of a
range of thiophiles in toluene at 70 ºC, showed that DABCO, Et NH as well as phosphazene bases
2
(
BEMP) could trigger the sigmatropic rearrangement in 24 h. Finally, an excess of Et NH (10
2
equivalents) at higher temperature (90 ºC) proved optimal, in terms of reaction time (8 h), isolation and
yield (60%) with a reasonable high diastereomeric ratio (5b/6b, 88/12; Scheme 7).
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Scheme 7. Sigmatropic rearrangement of 2,3-trans and 2,3-cis 3-sulfinyl tetrahydropyridines 21
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R3
O
S
R3
R3
H
HO
HO
pꢀTol
Et NH
3
2
+
6
2
6
R1
R2
R1 R2
R1
R2
N
N
N
Toluene
0 ºC, 8 h
9
PG
PG
5, yield (%)
dr 5/6b
PG
6
a
21
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
H
S
HO
pꢀTol
+
ent-5b
N
nꢀBu
N
nꢀBu
Ts
21n
Ts
ent-6b
5
5
5
5
b, 60%, dr 88/12, PG = Ts
c, 56%, dr 88/12, PG = pꢀNbs
HO
HO
d, 50%, dr 75/25, PG = oꢀNbs
N
nꢀBu
1
c
e, 48%, dr 89/11, PG = Ar SO
2
,
2
c
PG
5f, 65% dr 79/21, PG = Ar SO
2
HO
HO
N
nꢀBu
N
nꢀPr
N
(CH ) Cl
2 3
Boc
Ts
Ts
5
g, 72%
5h, 62%
dr 89/11
5i, 69%
dr >98/2
dr 90/10
HO
HO
HO
N
N
N
Ts
Ts
Ts
OMe
HO
F
5
a, 76%
dr >98/2
5j, 80%
dr >98/2
Me
5k, 72%
dr >98/2
HO
Me
HO
nꢀBu
N
N
nꢀBu
N
nꢀBu
Ts
l, 56%e
dr >90/10
Ts
Ts
ent-6b, 49%c,d
5
5m, 65%d
dr 95/5
dr 97/3
a
b
1
Yield of isolated major diastereoisomer 3,6ꢀtrans 5. dr refers to 5/6 ratio determined by H NMR
c
1
2
analysis of crude reaction mixtures. Ar = 2,4,6ꢀMe C H ; Ar = 2,4,6ꢀiꢀPr ꢀC H ; variable small
3
6
4
3
6
4
d
e
amounts of regioisomeric 2ꢀalkylꢀ3ꢀhydroxyꢀtetrahydropyridines were also detected. 3 h, 70ꢀ90 ºC. 24
h, 110 ºC.
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Further studies probed the scope and generality of this transformation and the results are summarized in
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 7. Not too unexpectedly, small amounts of products arising from pyrolytic syn elimination of the
1
5
sulfinyl moiety or formal allylic hydroxyl isomerization were detected in some cases. Nevertheless,
under the optimized reaction conditions, this protocol accommodates a range of sulfinyl
tetrahydropyridines 21 with alkyl and aryl substituents at Cꢀ2, Cꢀ6 and even at Cꢀ4, giving the
corresponding 3ꢀhydroxy tetrahydropyridines 5a-m in moderate to good yields (up to 80%) and high
diastereoselectivity (up to >98/2 dr). Notable reactivity trends within these series indicate that C(2)ꢀaryl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
substituted (R = Ph, 4ꢀMeOꢀC H , 4ꢀFꢀC H ) gave higher product conversion and selectivity (5a, 5j and
4
6
4
6
1
5k, dr > 98/2), than their C(2)ꢀalkyl substituted counterparts (R = nꢀBu, nꢀPr, (CH ) Cl, 5b-i, dr: 75/25ꢀ
2
3
98/2); in particular, aryl units containing electron rich groups exhibit an increased reactivity relative to
those with electron deficient substituents (5j vs 5k). The process is compatible with different
sulfonamide groups (PG) but with decreased stereoselectivity for 5d, or with the production of
2
9
considerable amounts of regioisomeric 2ꢀalkylꢀ3ꢀhydroxyꢀtetrahydropyridines in the cases of 5e,f.
The rearrangement of allylic sulfoxide 21o, with S configuration at Cꢀ6, under the standardized reaction
conditions rendered a modest 46% conversion into product 5l; raising the temperature to 110 ºC led to an
increased 56% isolated yield. We observed an increased reactivity of the Cꢀ4 methyl substituted 21q and
2
9
2
,3ꢀcis diastereoisomer 21n that provided the related alcohols 5m (65%) and ent-6b (49%), in shorter
reaction times (3 h). In contrast, the (R)ꢀC6 stereoisomer 21p gave the (2R)ꢀmethyl substituted
dihydropyridine 22 as a major product (61% yield), arising from the pyrolytic synꢀelimination of the
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sulfoxide moiety, along with minor byꢀproducts in the crude mixture where the expected 3ꢀhydroxy
tetrahydropyridine was barely detected (Scheme 8).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 8. Pyrolytic syn-elimination of 21p
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
H
S
pꢀTol
Et NH
2
Me
N
nꢀBu
Me
N
nꢀBu
Toluene
Ts
22
Ts
90 ºC, 8 h
61%
2
1p
Interestingly, it was possible to perform the cyclization and [2,3]ꢀsigmatropic rearrangement in one step
DBU, then Et NH). Amino dienyl sulfoxide 15l was selected as representative example to give access to
(
2
tetrahydropyridinꢀ3ꢀol 5j in slightly lower unoptimized yield (48%) than the standard two step sequence
3
0
(54%) and without compromising the diastereocontrol of this transformation (Scheme 9).
Scheme 9. Tandem cyclization-sigmatropic rearrangement for 15l
O
HO
S
DBU (2 equiv)
Toluene, rt, 8 h
pꢀTol
N
NH
Ts
then
Ts
Et NH (10 equiv)
2
OMe
OMe
90 ºC, 16 h
48%
1
5l
5j
The results indicate that the nature of the protecting group on nitrogen influences the outcome of these
processes, either by conformational biases or by facilitating the ringꢀopening/ringꢀclosing pathway. To
test this hypothesis we examined the sigmatropic rearrangement on Nꢀunprotected substrates 21s and 21t
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that took place in increased yields and excellent selectivity (>98/2 dr) with regard to Nꢀprotected
substrates, to afford tetrahydropyridinꢀ3ꢀol 5n (72% yield) and of 5o (70% yield) (Scheme 10). It should
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
1
be mentioned that 5n was also prepared in good yields by deprotection of 5b with sodium naphthalenide
or of 5g with TFA. The rearrangement of bicyclic sulfoxide 21v led to unsaturated alcohol 5p in
moderate yield. Hydrogenation of 5p, under standard conditions, gave an excellent yield of indolizidine
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
alcohol 23, with identical spectral data to that reported in the literature. Notably the Nꢀunprotected
substrates provide a more efficient route to 2,3ꢀtetrahydropyridines 5n-p in terms of yields and
selectivities (6ꢀ7 linear steps from menthyl sulfinate).
Scheme 10. Sigmatropic rearrangement of sulfinyl piperidines with unprotected nitrogen
HO
NaꢀNaphth
_
THF, 78 ºC
O
2 h, 72%
N
nꢀBu
H
S
HO
pꢀTol Et NH (10 equiv)
Ts
5
b
2
N
nꢀBu
21s
Toluene, 90 ºC, 8 h
2%
N
H
5n
nꢀBu
H
7
HO
>98/2
TFA, CH Cl2
2
rt, 24 h, 61%
N
nꢀBu
O
S
H
Boc
5g
HO
pꢀTol
Et NH (10 equiv)
2
Ph
N
nꢀPr
Ph
N
H
nꢀPr
Toluene, 90 ºC, 8 h
70%
H
2
1t
5o
>
98/2
O
S
H
H
HO
HO
H (1 atm)
2
Et NH (10 equiv)
pꢀTol
2
H
H
N
N
Toluene, 90 ºC, 8 h
2%
10% Pd/C, MeOH
rt, 24 h, 99%
N
4
2
1v
5p
23
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Considering the [2,3]ꢀsigmatropic rearrangement of allylic sulfoxides as a concerted process where the
facial selectivity is determined by the configuration of the sulfurꢀbearing center, 3,6ꢀtrans and 3,6ꢀcis
alcohols (5, 6) would be obtained from 2,3ꢀtrans and 2,3ꢀcis tetrahydropyridines, respectively. The
relative configuration of these allylic alcohols 5 was assigned through NMR spectroscopic investigations
using a combination of NOE and coupling constant analysis measured between H ꢀH and H ꢀH ,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2eq
3
2ax
typically small (1ꢀ3.3 Hz) for transꢀisomers 5a-p and larger (6.4, 9.9 Hz) for cisꢀisomer ent-6b. In
3
3
addition 5b was transformed smoothly into 6b via the Mitsunobu protocol.
The absolute configuration of allylic alcohols transꢀ5b and cisꢀ6b was determined by the preparation of
34
the methoxyphenyl acetates 7 and careful comparison of the spectral data (Scheme 11). Derivatization
of 5b with (S)ꢀ(+)ꢀMPA (2ꢀmethoxyꢀ2ꢀphenylacetic acid) afforded 7b and 7c (98/2 dr) and with (R)ꢀ(–)ꢀ
MPA gave ent-7b and ent-7c (2/98 dr), indicating an excellent enantioselectivity in the sigmatropic
rearrangement (96% ee). Shielding effects observed on H and H of 7b (δH 5.91, δH 4.01 ppm) and
4
2eq
4
2eq
7
c (δH 5.61, δH 4.16 ppm) showed that the assignment for the alcohols was in agreement with the
4 2eq
results observed. The crude reaction mixture of 5b and 6b (88/12 dr), obtained from the cyclizationꢀ
rearrangement sequence of 21a was also functionalized with (+)ꢀMPA to afford an 88/12 mixture of trans
and cis diastereomers 7b and 7d (epimer of 7b at Cꢀ3, δH 5.30, δH 4.12 ppm). Comparison of the
4
2eq
spectral features of ester 7d thus obtained, with an identical sample derived by esterification with (+)ꢀ
MPA of pure 6b obtained by Mitsunobu inversion of 5b, indicated that the optical integrity of minor
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product 6b was not compromised under these conditions (DBU), in contrast to the findings with
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
28
Cs CO . All other tetrahydropyridinꢀ3ꢀols 5 were assigned by analogy.
2
3
Scheme 11. Derivatization of 5b and 6b with (S)- and (R)-MPA
Ph
Ph
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
S
O
O
MeO
MeO
δ = 5.91 ppm
δ = 5.61 ppm
(
S)ꢀ(+)ꢀMPA
O
O
EDC—HCl, DMAP
+
CH Cl , rt, 16 h
2
2
N
nꢀBu
N
nꢀBu
δ = 5.88 ppm
98%
HO
δ = 3.41 ppm
δ = 4.01 ppm
δ = 3.39 ppm
δ = 4.16 ppm
Ts
Ts
7
b (98)
7c (2)
N
nꢀBu
Ph
Ph
Ts
R
O
O
δ = 3.31 ppm
MeO
MeO
δ = 3.82 ppm
_
(
R)ꢀ( )ꢀMPA
O
O
5b
EDC—HCl, DMAP
+
nꢀBu
CH Cl , rt, 16 h
2
2
N
N
nꢀBu
82%
Ts
Ts
ent-7b (2)
ent-7c (98)
HO
Ph
O
Ph
O
S
MeO
MeO
N
nꢀBu
δ = 5.30 ppm
(S)ꢀ(+)ꢀMPA
O
O
Ts
δ = 5.88 ppm
EDC—HCl, DMAP
3
+
+
HO
CH Cl , rt, 16 h
2
2
N
nꢀBu
N
nꢀBu
δ = 2.94 ppm
δ = 4.12 ppm
Ts
Ts
N
nꢀBu
7b (88)
7d (12)
Ts
δ = 2.84 ppm
δ = 3.98 ppm
5b /6b 88/12 (from 21a)
A qualitative rationalization of these results considers the relative ease of attaining the reactive
conformations of 21 that place the sulfoxide in a pseudoaxial position with the oxygen oriented toward
the double bond, that maintain the bulky pꢀtolyl group pointing toward the tetrahydropyridine ring for this
2
7a
absolute configuration (Scheme 12, conformers I and II).
This unfavorable scenario could justify the
unusual stability of the starting allylic sulfoxides 21 that require high temperatures (90ꢀ110 ºC) to
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promote the rearrangement leading ultimately to allylic alcohols 5. In this rationale, we may assume that
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the reactive conformer would be more accessible for those substrates with increased size of the
1
substituent at Cꢀ2 (R ) that could force the adjacent sulfinyl moiety at Cꢀ3 to adopt a pseudoaxial position
1
to minimize 1,2ꢀstrain between the adjacent substituents (sulfoxide / R / PG). Then, conformations I and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
II would be in slow equilibrium for substrates with alkyl substituents at Cꢀ2, 21a-j, and that might
prompt, under reaction conditions, either a baseꢀmediated epimerization at the sulfur bearing center Cꢀ3
1
of 21, or a ringꢀopeningꢀclosing sequence with diminished selectivity of 5b-i (R = alkyl) in relation to
1
2
improved outcome for 5a,j,k (R = aryl). Likewise, the presence of an additional substituent (R = (R)ꢀ
Me) in 21p would disfavor conformer II due to 1,3ꢀdiaxial interactions Me/nꢀBu and that might explain
the decreased reactivity observed (Scheme 8). On the other hand, the rearrangement of Nꢀunprotected
substrates is more facile and displays a higher stereoselectivity (Scheme 10); this underlines the subtle
balance of stereodirecting effects that govern this process.
Scheme 12. Proposed reactive conformations for 21
PG
N
PG
N
pꢀTol
O
H2
S
H6
OH
H
R2
R1
S
H6
H
*
R2
H3
H2
R1
N
R2
H3
R1
PG
(2,3)-trans 21
(2,3)-trans 21
reactive conformer II
(3,6)ꢀtrans 5
conformer I
Synthesis of natural product (+)-pseudoconhydrine. Having demonstrated the suitability of this
methodology for the preparation of tetrahydropyridinꢀ3ꢀols 5 in good yields and selectivities, we further
applied this process to the synthesis of Hemlock alkaloid (+)ꢀpseudoconhydrine hydrochloride 25 to
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exemplify the synthetic utility of these synthetic strategies (Scheme 13). Hydrogenation of 5h, obtained
uneventfully on a 1 g scale, over Pd/C gave 24 in good yield. Subsequent removal of the Nꢀtosyl group
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
1
with sodium naphthalenide provided 25 as a single isomer with identical spectroscopic data to those in
3
5,1i
the literature.
Moreover, the synthesis of natural product 25 lent further support to the assignment of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the absolute configuration of our tetrahydropyridinꢀ3ꢀols 5.
Scheme 13. Synthesis of (+)-pseudoconhydrine hydrochloride 25
HO
HO
HO
H (1 atm)
NaꢀNaphthalene
2
Pd/C, MeOH
rt, 2 h, 66%
_
THF, 78 ºC, 2 h
94%
N
nꢀPr
N
nꢀPr
N
nꢀPr
H—HCl
Ts
Ts
5h
24
25
CONCLUSIONS
In summary, a general strategy to prepare stereodefined 4ꢀsulfinyl dienyl amine derivatives, with a broad
range of substituents, has been described. These substrates undergo a baseꢀpromoted intramolecular
cyclization to afford novel sulfinyl tetrahydropyridines, thus setting two new stereogenic centers in one
step with good yields and selectivities under mild reaction conditions. Subsequent [2,3]ꢀsigmatropic
rearrangement of these configurationally stable allylic sulfoxides yields a variety of tetrahydropyridinꢀ3ꢀ
ols with good to excellent levels of selectivity that were markedly dependent on the nature of the Nꢀ
protecting group. The application of this methodology to the synthesis of enantiopure Hemlock alkaloid
(+)ꢀpseudoconhydrine is also detailed herein.
EXPERIMENTAL SECTION
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Materials and methods
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Reactions involving moisture sensitive reagents were carried out under an argon atmosphere. Anhydrous
solvents were purified by filtration on a solvent purification system. Through this section, the volume of
solvents is reported in mL/mmol of starting material. All reactions were carried out under an argon
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
atmosphere. Diethylamine and DBU were purified by distillation from CaH . Alkynes were purified by
2
distillation under reduced pressure. Crude products were purified by chromatography on 230ꢀ400 mesh
silica gel. Analytical TLC was performed on silica gel plates with detection by ultraviolet light (254 nm),
followed by staining with iodine/silica and 10% phosphomolybdic acid solution in ethanol. Nuclear
1
magnetic resonance (NMR) spectra were acquired on 300, 400 or 500 MHz ( H) spectrometers at room
temperature. Chemical shifts are quoted in parts per million (ppm) and coupling constants, J, are quoted
in Hz. Infrared spectra (ν max) were recorded using either thin films on NaCl plates or KBr discs. High
resolution mass spectra (HRMS) were recorded using Accurate Mass QꢀTOF spectrometer. Optical
rotations were measured in CHCl3 unless other solvent is stated. Compounds 15a,g,k.l,n-q;
2
1a,f,g,k,lo,p,s; 5a,b,h,j,n; 24 and 25 were described in the Supporting Information of our preliminary
1
5c
communication.
Synthesis of piperidinols from 1-sulfinyl dienes.
General procedure for the synthesis of piperidinols and piperidines from 1-sulfinyl and sulfonyl
dienes.
1
4d
Method A: To a solution of sulfonamide 1-3 in DMF:H O 10:1 (10 mL/mmol) in a kimble vial, K CO
3
2
2
(1.0 equiv for 1, 4 equiv for 2 and 3) was added. Argon was bubbled through the mixture and it was
sealed. The reaction was stirred at rt for 1 and at 50ꢀ60 ºC for 2 and 3 (1 day), monitored by TLC. The
solvent was removed under reduced pressure and the crude mixture was purified by column
chromatography using the appropriate mixture of eluents.
Method B: To a solution of sulfonamide 3 in anhydrous DMF (10 mL/mmol) in a kimble vial, Cs CO
2
3
2
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(
2.0 equiv) was added. Argon was bubbled through the mixture and it was sealed. The reaction was
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
stirred at 60ꢀ70 ºC and monitored by TLC. The solvent was removed under reduced pressure and the
crude mixture was purified by column chromatography using the appropriate mixture of eluents.
Synthesis of (–)-(6R)-[1,5-Bis(p-tolylsulfonyl)-6-phenyl-1,2,3,6-tetrahydro]-pyridine, 4.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Method A: sulfonamide 1 (8 mg, 0.02 mmol) gave 4 (8 mg, 99%) as a colorless oil after purification by
2
0
chromatography (10ꢀ40% EtOAcꢀhexane). Data for 4: R 0.14 (30% EtOAcꢀhexane). [α]
–50.7 (c
D
f
1
0
.45, CHCl ). H NMR (300 MHz, CDCl ) δ 2.03ꢀ2.29 (m, 2 H), 2.33 (s, 3 H), 2.39 (s, 3 H), 2.99 (ddd, 1
3
3
H, J = 15.2, 11.2, 5.5 Hz), 3.70 (ddd, 1 H, J = 15.4, 6.7, 0.9 Hz), 5.93 (s, 1 H), 6.98ꢀ7.16 (m, 8 H), 7.19
13
(m, 2 H), 7.39 (dt, 2 H, J = 8.4, 1.8 Hz), 7.54 (dt, 2 H, J = 8.3, 1.8 Hz). C NMR (75 MHz, CDCl ) δ
3
21.5, 21.6, 24.1, 35.7, 55.1, 127.1 (2 C), 127.9, 128.2 (2 C), 128.3 (2 C), 128.7 (2 C), 129.4 (2 C), 129.7
(2 C), 136.2, 136.5, 137.3, 138.4, 139.9, 143.6, 144.3. IR (film): 3026, 2920, 1594, 1491, 1452, 1320,
−
1
+
+
1
302, 1161, 1147, 1082, 811, 755, 697, 676 cm . MS (ESI): 490 [M+Na] (100%), 468 [M+1] .
Synthesis of (–)-(3R,6S)-6-Phenyl-1-N-tosyl-1,2,3,6-tetrahydropyridin-3-ol, ent-5a.
Method A: sulfonamide 2 (36 mg, 0.08 mmol) after 4 days gave ent-5a (17 mg, 64%) as a colorless oil
after purification by chromatography (30ꢀ80% Et Oꢀhexane). Derivatization with (+)ꢀ(S)ꢀ2ꢀmethoxyꢀ2ꢀ
2
2
0
phenylacetic acid revealed essentially pure ent-5a. Data for ent-5a: R 0.30 (15% Et OꢀCH Cl ). [α]
f
2
2
2
D
1
–
1
4
227.4 (c 0.7, CHCl ). H NMR (300 MHz, CDCl ) δ 2.36 (s, 3 H), 2.40 (d, 1 H, J = 10.5 Hz), 3.21 (dd,
3
3
H, J = 15.0, 3.4 Hz), 3.67 (dd, 1 H, J = 15.0, 0.8 Hz), 3.99 (dt, 1 H, J = 10.5, 3.3 Hz), 5.65 (d, 1 H, J =
.0 Hz), 6.08 (ddd, 1 H, J = 10.4, 4.0, 0.5 Hz), 6.15 (ddt, 1 H, J = 10.2, 4.7, 1.2 Hz), 7.18 (dd, 2 H, J =
8.5, 0.6 Hz), 7.27 (m, 5 H), 7.59 (dd, 2 H, J = 8.2, 1.9 Hz). NOEꢀ1D between Hꢀ2ax/Ph (1.13%); Hꢀ
1
3
2
ax/Hꢀ3 (3.07%); Hꢀ3/(Hꢀ4+Hꢀ5) (1.06%); Hꢀ6/(Hꢀ4+Hꢀ5) (1.79%); Hꢀ3/Ph (0.15%). C NMR (75
MHz, CDCl ) δ 21.5, 46.2, 55.1, 62.0, 127.6 (2 C), 127.9, 128.2 (3 C), 128.5 (2 C), 129.5 (2 C), 130.1,
3
1
36.4, 137.2, 143.6. IR (film): 3496, 3061, 3032, 2920, 2867, 1597, 1491, 1454, 1333, 1158, 1067, 1005,
−
1
+
+
+
8
14, 700, 671 cm . MS (ESI): 681 [2M+Na] (100%), 352 [M+Na] , 330 [M+1] . HPLC: Daicel
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i
Chiralcel OD, 15% PrOHꢀhexane, 0.75 mL/min, t
= 16.7 min, tRmajor = 19.3 min, 95.2% ee.
Rminor
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Synthesis of (3S,6R)-6-Phenyl-1-N-tosyl-1,2,3,6-tetrahydropyridin-3-ol, 5a/ent-5a and 6a.
Method A: sulfonamide 3 (51 mg, 0.1 mmol) gave after 12 days a 79:21 mixture of 5a/ent-5a and 6a (16
mg, 43%) as colorless oil after purification by chromatography (20ꢀ80% Et Oꢀhexane). Derivatization of
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
a/ent-5a with (+)ꢀ(S)ꢀ2ꢀmethoxyꢀ2ꢀphenylacetic acid revealed a 67:33 mixture of 5a and ent-5a. Method
1
5c
B: sulfonamide 3 (44 mg) gave after 1 day a 95:5 mixture of 5a/ent-5a and 6a (12 mg, 38%).
Derivatization with (+)ꢀ(S)ꢀ2ꢀmethoxyꢀ2ꢀphenylacetic acid revealed a 0:100 mixture of 5a and ent-5a. A
1
2% of 6ꢀphenylpyridinꢀ3ꢀol was found in the crude mixture with identical data to that found in the
3
6
literature.
Preparation of starting materials.
15a
37
15a
15a
Alkynyl sulfoxides 8a,e; 8b,c; stannyl sulfoxides 9a,e; iodo vinyl sulfoxides 11a,e and 11’a were
1
9
prepared as described in the literature; amino vinyl stannane 12 has been reported.
Synthesis of alkynyl sulfoxides 8.
1
5a
Method C: A dry twoꢀnecked roundꢀbottomed flask fitted with reflux condenser, septum and magnetic
stirrer was charged with dry Mg turnings (1.6 equiv) under an argon atmosphere and anhydrous Et O was
2
added (0.1 mL/mmol Mg) and 5ꢀ10 drops of freshly distilled EtBr. The mixture was heated slowly until
the formation of the Grignard reagent was initiated. Then a solution of EtBr (1.7 equiv) in Et O (0.4
2
mL/mmol Mg) was added dropwise, maintaining a moderate reflux, and after the addition was complete,
the mixture was heated to reflux until complete disappearance of Mg was observed. To the solution of
EtMgBr at rt the alkyne (RꢀC≡CꢀH, 1.7 equiv) was added and the mixture was heated to reflux for 2 h.
The alkynyl Grignard was added (via syringe) to a cold solution (−20 ºC) of (−)ꢀmenthyl pꢀ
toluenesulfinate (1.0 equiv) in anhydrous toluene (5 mL/mmol sulfoxide) and the reaction was stirred at
the same temperature until disappearance of starting material was observed (TLC). The mixture was
quenched by addition of a saturated NH Cl solution (4 mL/mmol sulfoxide) and H O (4 mL/mmol
4
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2
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sulfoxide) and diluted with EtOAc. The layers were separated, the aqueous layer was extracted with
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
EtOAc and the combined organic layers were washed with brine, dried (Na SO ) and concentrated in
2
4
vacuo. The crude product was purified by column chromatography on silica gel with the appropriate
combination of solvents.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of (+)-(S)-5-Chloropentynyl p-tolyl sulfoxide, 8d.
Method C: 5ꢀchloropentyne (3.60 mL, 34.0 mmol) gave after chromatography (20ꢀ30% EtOAcꢀhexane)
2
0
8
d as a clear oil (2.80 g, 58%). Data for 8d: R 0.50 (30% EtOAcꢀhexane). [α] +60.3 (c 1.0, CHCl3).
f
D
1
H NMR (300 MHz, CDCl ) δ 1.96ꢀ2.05 (m, 2 H), 2.42 (s, 3 H), 2.62 (t, 2 H, J = 6.9 Hz), 3.59 (t, 2 H, J =
3
1
3
6
.2 Hz), 7.34 (d, 2 H, J = 8.1 Hz), 7.68 (d, 2 H, J = 8.1 Hz). C NMR (75 MHz, CDCl ) δ 16.9, 21.2,
3
30.0, 43.0, 79.2, 103.1, 124.8, 130.0, 140.8, 142.2. IR (film): 3052, 2960, 2923, 2183, 1595, 1492, 1441,
−1
+
1
087, 1056, 810 cm . HRMS (ESI) m/z Calcd for C H ClOS [M+H] 241.0448; Found 241.0441.
12 14
Synthesis of (+)-(S)-4-Methoxyphenyl-1-ethynyl p-tolyl sulfoxide, 8f.
Method C: 4ꢀmethoxyphenylacetylene (2.24 mL, 17.0 mmol) gave after chromatography (20ꢀ30%
EtOAcꢀhexane) 8f as a pale yellow solid (1.72 g, 64%). Data for 8f: R 0.45 (30% EtOAcꢀhexane). mp
f
2
0
1
9
8ꢀ100 ºC. [α] +49.5 (c 1.0, CHCl ). H NMR (300 MHz, CDCl ) δ 2.43 (s, 3 H), 3.82 (s, 3 H), 6.86
D
3
3
1
3
(d, 2 H, J = 8.9 Hz), 7.36 (d, 2 H, J = 8.1 Hz), 7.45 (d, 2 H, J = 8.9 Hz), 7.76 (d, 2 H, J = 8.1 Hz).
C
NMR (75 MHz, CDCl ) δ 21.5, 55.4, 85.3, 103.0, 111.6, 114.2 (2 C), 125.2 (2 C), 130.2 (2 C), 134.1 (2
3
C), 141.0, 142.3, 161.4. IR (KBr): 2965, 2874, 2181, 1493, 1462, 1087, 1058, 1015, 810, 622 cm−1.
+
HRMS (ESI) m/z Calcd for C H O S [M+H] 271.0787; Found 271.0789.
1
6
15
2
Synthesis of (+)-(S)-4-Fluorophenyl-1-ethynyl p-tolyl sulfoxide, 8g.
Method C: 4ꢀfluorophenylacetylene (1.40 mL, 12.2 mmol) gave after chromatography (15ꢀ20% EtOAcꢀ
hexane) 8g as a pale yellow solid (1.04 g, 56%). Data for 8g: R 0.30 (15% EtOAcꢀhexane). mp 58ꢀ60 ºC.
f
2
0
1
[
α] +19.8 (c 1.0, CHCl ). H NMR (300 MHz, CDCl ) δ 2.44 (s, 3 H), 7.05 (t, 2 H, J = 8.7 Hz), 7.37
D
3
3
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1
3
(
d, 2 H, J = 8.0 Hz,), 7.50 (dd, 2 H, J = 8.5, 6.0 Hz), 7.76 (d, 2 H, J = 8.5 Hz). C NMR (75 MHz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
CDCl ) δ 21.5, 86.2, 101.0, 116.1 (d, J = 22.4 Hz), 125.2, 130.1, 130.3, 134.5, 140.6, 142.5, 163.8. IR
3
CꢀF
−
1
(
film): 3061, 2923, 2164, 1599, 1505, 1451, 1235, 1087, 1059, 776 cm . HRMS (ESI) m/z Calcd for
+
C H FOS [M+H] 259.0587; Found 259.0582.
15
12
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of (E)-stannyl sulfoxides 9.
1
5a
Method D: To a solution of alkynyl sulfoxide 8 in anhydrous toluene (6.6 mL/mmol sulfoxide) at rt
under an argon atmosphere, Pd(Ph P) (0.02 equiv) was added. Argon was bubbled through the solution
3
4
for 10 min and the mixture was then cooled to −78 ºC. A solution of Bu SnH (1.1 equiv) in toluene (1.1
3
mL/mmol sulfoxide) was added and the reaction mixture was stirred and warmed up to rt until
disappearance of starting material (TLC). The solvent was removed in vacuo and the crude product was
purified by column chromatography on silica gel with the appropriate combination of solvents.
Synthesis of (–)-(S)-[(E)-1-(p-Tolylsulfinyl)pent-1-enyl]tributylstannane, 9b.
Method D: alkynyl sulfoxide 8b (4.04 g, 19.6 mmol) gave a 98:2 mixture of regioisomers 9b and 10b.
Chromatography (5ꢀ15% EtOAcꢀhexane) afforded 9b (5.75 g, 59%) as a yellow oil. Data for 9b: R 0.32
f
20
1
(
5% EtOAcꢀhexane). [α] –79.0 (c 1.0, CHCl ). H NMR (300 MHz, CDCl ) δ 0.77ꢀ0.97 (m, 15 H),
D
3
3
0
.95 (t, 3 H, J = 7.3 Hz), 1.14ꢀ1.53 (m, 14 H), 2.25ꢀ2.40 (m, 1 H), 2.33 (s, 3 H), 2.62ꢀ2.69 (m, 1 H), 6.14
13
(
dd, 1 H, J = 8.4, 5.7 Hz), 7.21 (d, 2 H, J = 8.3 Hz), 7.37 (d, 2 H, J = 8.3 Hz). C NMR (75 MHz,
CDCl ) δ 11.2, 13.5, 13.5, 21.2, 22.4, 27.1, 28.6, 34.7, 124.2 (2 C), 129.4 (2 C), 139.8, 142.4, 148.7,
3
56.3. IR (film): 2924, 2870, 1638, 1463, 1376, 1079, 1037, 803, 670, 534 cm−1.
1
Synthesis of (–)-(S)-[(E)-1-(p-Tolylsulfinyl)-3,3-dimethylbut-1-enyl]tributylstannane, 9c.
Method D: alkynyl sulfoxide 8c (220 mg, 1.00 mmol) gave a >90:10 mixture of regioisomers 9c and 10c.
Chromatography (20ꢀ30% EtOAcꢀhexane) afforded 9c as a yellow oil (270 mg, 53%). Data for 9c: Rf
2
0
1
0
.70 (20% EtOAcꢀhexane). [α] –42.7 (c 1.0, CHCl ). H NMR (300 MHz, CDCl ) δ 0.69ꢀ0.84 (m, 15
D
3
3
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H), 1.16ꢀ1.34 (m, 12 H), 1.26 (s, 9 H), 2.38 (s, 3 H), 6.23 (s, 1 H), 7.26 (d, 2 H, J = 8.1 Hz), 7.45 (d, 2 H,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
J = 8.1 Hz). C NMR (75 MHz, CDCl ) δ 11.7, 13.5, 21.0, 27.0, 28.6, 31.3, 31.3, 125.2, 129.3, 139.7,
3
−
1
1
42.1, 151.4, 158.0. IR (film): 3049, 2958, 2925, 2855, 1579, 1464, 1078, 1029, 807, 704 cm .
Synthesis of (–)-(S)-[(E)-5-Chloro-1-(p-tolylsulfinyl)pent-1-enyl]tributylstannane, 9d.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Method D: alkynyl sulfoxide 8d (534 mg, 2.22 mmol) gave a >90:10 mixture of regioisomers 9d and 10d.
Chromatography (20ꢀ30% EtOAcꢀhexane) afforded 9d as a yellow oil (737 mg, 62%). Data for 9d: Rf
2
0
1
0.65 (15% EtOAcꢀhexane). [α] –11.3 (c 1.0, CHCl ). H NMR (300 MHz, CDCl ) δ 0.75ꢀ0.93 (m, 15
D
3
3
H), 1.14ꢀ1.42 (m, 12 H), 1.87ꢀ2.02 (m, 2 H), 2.36 (s, 3 H), 2.48ꢀ2.60 (m, 1 H), 2.79ꢀ2.91 (m, 1 H), 3.49ꢀ
1
3
3
.63 (m, 2 H), 6.13 (dd, 1 H, J = 8.6, 5.7 Hz), 7.24 (d, 2 H, J = 8.2 Hz), 7.39 (d, 2 H, J = 8.2 Hz). C
NMR (75 MHz, CDCl ) δ 11.3, 13.5, 21.1, 27.1, 28.7, 30.0, 31.9, 43.9, 124.3 (2 C), 129.5 (2 C), 140.1,
3
−
1
1
42.2, 146.3, 158.2. IR (film): 2955, 2922, 1586, 1492, 1456, 1080, 1037, 1016, 805, 658 cm . HRMS
+
(
ESI) m/z Calcd for C H ClNaOSSn [M+Na] 555.1477; Found 555.1474.
2
4
41
Synthesis of (–)-(S)-[(E)-2-(4-Methoxyphenyl)-1-(p-tolylsulfinyl)vinyl]tributylstannane, 9f.
Method D: alkynyl sulfoxide 8f (1.30 g, 4.80 mmol) gave a 94:6 mixture of regioisomers 9f and 10f.
Chromatography (20ꢀ30% EtOAcꢀhexane) afforded 9f (2.49 g, 92%) as a yellow oil. Data for 9f: R 0.76
f
2
0
1
(
30% EtOAcꢀhexane). [α] –318.0 (c 1.0, CHCl ). H NMR (300 MHz, CDCl ) δ 0.82ꢀ1.00 (m, 15 H),
D
3
3
1
8
.18ꢀ1.50 (m, 12 H), 2.38 (s, 3 H), 3.83 (s, 3 H), 6.90 (d, 2 H, J = 8.8 Hz), 7.10 (s, 1 H), 7.25 (d, 2 H, J =
13
.4 Hz), 7.42ꢀ7.45 (m, 4 H). C NMR (75 MHz, CDCl ) δ 11.9, 13.6, 21.2, 27.3, 28.8, 55.3, 113.9 (2 C),
3
124.8 (2 C), 129.1, 129.6 (2 C), 131.4 (2 C), 140.0, 141.9, 144.3, 156.4, 159.9. IR (film): 2955, 2923,
−1
+
2
870, 1604, 1508, 1254, 1177, 1033, 807, 552 cm . HRMS (ESI) m/z Calcd for C H O SSn [M+H]
28 43 2
563.2006; Found 563.2027.
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Synthesis of (–)-(S)-[(E)-2-(4-Fluorophenyl)-1-(p-tolylsulfinyl)vinyl]tributylstannane, 9g.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Method D: alkynyl sulfoxide 8g (258 mg, 1.00 mmol) gave a >90:10 mixture of regioisomers 9g and 10g.
Chromatography (5ꢀ15% EtOAcꢀhexane) afforded 9g as a pale yellow oil (319 mg, 58%). Data for 9g: Rf
2
0
1
0.43 (5% EtOAcꢀhexane). [α] –206.6 (c 1.0, CHCl ). H NMR (300 MHz, CDCl ) δ 0.82ꢀ0.97 (m, 15
D
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
H), 1.00ꢀ1.49 (m, 12 H), 2.37 (s, 3 H), 7.06 (t, 2 H, J = 8.7 Hz), 7.11 (s, 1 H), 7.22 (d, 2 H, J = 8.2 Hz),
13
7.38 (d, 2 H, J = 8.2 Hz), 7.44 (dd, 2 H, J = 8.7, 5.3 Hz). C NMR (125 MHz, CDCl ) δ 11.9, 13.6, 21.2,
3
2
3
2
7.3, 28.8, 115.6 (d, J = 21.3 Hz, 2 C), 124.8 (2 C), 129.7 (2 C), 131.5 (d, J = 8.3 Hz, 2 C), 132.5
CꢀF CꢀF
4
1
(
d, J = 3.4 Hz), 140.3, 141.5, 143.5, 159.6, 162.6 (d, J = 250.0 Hz). IR (film): 2956, 2923, 2871,
CꢀF CꢀF
−
1
1
600, 1506, 1237, 1038, 807, 730, 550 cm .
Synthesis of iodo vinyl sulfoxides 11.
1
5a
Method E: To a solution of iodine (1.3 equiv) in CH Cl (6 mL/mmol sulfoxide) at rt under an argon
2
2
atmosphere was added a solution of stannyl sulfoxide (1.0 equiv) in CH Cl (5 mL/mmol sulfoxide). The
2
2
mixture was stirred at rt until disappearance of starting material (TLC), and then it was quenched with an
aqueous solution of Na S O (2 mL/mmol, 1 M). The layers were separated and the aqueous layer was
2
2
4
extracted with CH Cl . The combined organic layers were washed with brine, dried (Na SO ) and
2
2
2
4
concentrated in vacuo. The crude mixture was purified by column chromatography on silica gel with the
appropriate combination of solvents.
Synthesis of (–)-(S)-(E)-1-Iodo-1-(p-tolylsulfinyl)pentene, 11b.
Method E: stannyl sulfoxide 9b (4.58 g, 9.23 mmol) and I (3.05 g, 12.0 mmol) gave after
2
chromatography (5% EtOAcꢀCH Cl ) 11b as a white solid (3.08 g, 100%). Data for 11b: R 0.70 (5%
2
2
f
2
0
1
EtOAcꢀCH Cl ). mp 82ꢀ85 ºC. [α] –102.6 (c 1.0, CHCl ). H NMR (300 MHz, CDCl ) δ 1.01 (t, 3
2
2
D
3
3
H, J = 7.4 Hz), 1.51ꢀ1.63 (m, 2 H), 2.38 (s, 3 H), 2.49ꢀ2.61 (m, 1 H), 2.71ꢀ2.84 (m, 1 H), 6.85 (dd, 1 H, J
1
3
=
8.7, 7.1 Hz), 7.29 (d, 2 H, J = 8.2 Hz), 7.42 (d, 2 H, J = 8.2 Hz). C NMR (75 MHz, CDCl ) δ 13.6,
3
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