Preparation and reactions of enantiomerically pure α-functionalized grignard reagents

Article abstract of DOI:10.1021/ja4033956

A strategy for the generation of enantiomerically pure α- functionalized chiral Grignard reagents is presented. The approach involves the synthesis of α-alkoxy and α-amino sulfoxides in ≥99:1 dr and ≥99:1 er via asymmetric deprotonation (s-BuLi/chiral diamine) and trapping with Andersen's sulfinate (menthol derived). Subsequent sulfoxide → Mg exchange (room temperature, 1 min) and electrophilic trapping delivers a range of enantiomerically pure α-alkoxy and α-amino substituted products. Using this approach, either enantiomer of products can be accessed in 99:1 er from asymmetric deprotonation protocols without the use of (-)-sparteine as the chiral ligand. Two additional discoveries are noteworthy: (i) for the deprotonation and trapping with Andersen's sulfinate, there is a lack of stereospecificity at sulfur due to attack of a lithiated intermediate onto the α-alkoxy and α-amino sulfoxides as they form, and (ii) the α-alkoxy-substituted Grignard reagent is configurationally stable at room temperature for 30 min.

Full text of DOI:10.1021/ja4033956

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Article
Preparation and Reactions of Enantiomerically
Pure #-Functionalised Grignard Reagents
Peter J. Rayner, Peter O'Brien, and Richard A.J. Horan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja4033956 • Publication Date (Web): 06 May 2013
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Journal of the American Chemical Society
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Preparation and Reactions of Enantiomerically Pure α-
Functionalised Grignard Reagents
Peter J. Rayner,† Peter O’Brien*,† and Richard A. J. Horan‡
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†Department of Chemistry, University of York, Heslington, York YO10 5DD, U.K., ‡GlaxoSmithKline Research & Develꢀ
opment Ltd., Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
Supporting Information Placeholder
ABSTRACT: A strategy for the generation of enantiomerically pure αꢀfunctionalised chiral Grignard reagents is presented. The
approach involves the synthesis of αꢀalkoxyꢀ and αꢀamino sulfoxides in ≥99:1 dr and ≥99:1 er via asymmetric deprotonation (sꢀ
BuLi/chiral diamine) and trapping with Andersen’s sulfinate (mentholꢀderived). Subsequent sulfoxide → Mg exchange (room
temperature, 1 minute) and electrophilic trapping delivers a range of enantiomerically pure αꢀalkoxyꢀ and αꢀamino substituted
products. Using this approach, either enantiomer of products can be accessed in 99:1 er from asymmetric deprotonation protocols
without the use of (–)ꢀsparteine as the chiral ligand. Two additional discoveries are noteworthy: (i) for the deprotonation and trapꢀ
ping with Andersen’s sulfinate, there is a lack of stereospecificity at sulfur due to attack of a lithiated intermediate onto the αꢀ
alkoxyꢀ and αꢀamino sulfoxides as they form and (ii) the αꢀalkoxyꢀsubstituted Grignard reagent is configurationally stable at room
temperature for 30 minutes.
Introduction
ly, as well as delivering substituted products in ≥99:1 er, it
was anticipated that our methodology would not rely on (–
)ꢀsparteine for high enantioselectivity.
Asymmetric deprotonation α to oxygen1 or nitrogen2 in
carbamates 1 using a chiral base (e.g. sꢀBuLi/(–)ꢀsparteine)
is an established method for the generation of enantioenꢀ
riched αꢀfunctionalised organolithium reagents 2 (Scheme
1).3 Such methodology has been widelyꢀused in synthesis:
for example, Aggarwal et al. have developed molecular
assembly lines using Oꢀalkyl carbamates 4 and scientists at
Merck scaled up the asymmetric deprotonation of NꢀBoc
pyrrolidine to prepare ~0.7 kg of a glucokinase activator.5
However, two key limitations with this methodology reꢀ
main. First, enantiomer ratios (ers) of the products from
asymmetric deprotonations vary widely. This is especially
true for NꢀBoc heterocycles which typically range from
85:15ꢀ95:5 er. Indeed, the only examples which consistentꢀ
ly give 99:1 er are Hoppeꢀstyle deprotonations of Oꢀalkyl
carbamates using sꢀBuLi/(–)sparteine,3 and are thus limited
to one enantiomeric series. Second, over the last two years,
the commercial availability of (–)ꢀsparteine has been variaꢀ
ble. This is of much concern as (–)ꢀsparteine generally
gives the highest enantioselectivity over a wide range of
reaction types.
Scheme 1. Comparison of asymmetric deprotonation with
asymmetric deprotonation-chiral sulfinate trapping.
Er depends on substrate
and varies widely
(typically 85:15-95:5 er)
X
X
Chiral Base
Previous
work:
H
H
R
s
R
e.g. BuLi
H
Li
Availability of (–)-sparteine
is variable
(–)-sparteine
2
1
O
'
X =
= OCb or X = NRBoc
2
i
O
N Pr
X
s
X
X
1. BuLi
i
Tol
PrMgCl
THF, rt
chiral diamine
H
This
work:
R
S
H
R
R
H
MgCl
2. Andersen's
sulfinate
(S )-3
O
1
4
5
S
99:1 dr
99:1 er
99:1 er
Er does not depend on substrate:
99:1 er can be assured
O
S
p-Tol
O
Asymmetric deprotonation does
not require (–)-sparteine
i
Pr
(S )-3
S
A conceptually related approach to organolithiums 2 would
be to carry out Sn → Li exchange on enantiopure αꢀalkoxy
and αꢀaminoꢀstannanes. Such an approach was used by
Still in pioneering studies on the configurational stability of
αꢀalkoxy organolithiums7 and has been employed more
recently by Hammerschmidt8 and Aggarwal.9 However,
these methods do not represent a general route to organoꢀ
lithiums 2 of 99:1 er, especially for NꢀBoc heterocycles,
and it is necessary to carry out the Sn → Li exchange at low
temperaures (–78 °C) due to the configurational or chemiꢀ
cal instability of the organolithiums 2.10 In contrast, our
approach should deliver a wide range of αꢀfunctionalised
To address these two limitations, we set out to develop a
new approach in which the asymmetric deprotonation of
carbamates 1 using sꢀBuLi/chiral diamine (ideally not (–)ꢀ
sparteine) would be merged with electrophilic trapping usꢀ
ing Andersen’s chiral sulfinate (SS)ꢀ36 (Scheme 1). In this
way, we would improve on the moderate enantioselectivity
(85:15ꢀ95:5 er typically) engendered by the chiral base
through the generation of αꢀalkoxy and αꢀamino sulfoxides
4 in ≥99:1 dr and ≥99:1 er. Subsequent sulfoxide → Mg
exchange on αꢀfunctionalised sulfoxides 4 would then genꢀ
erate chiral αꢀfunctionalised Grignard reagents 5 (analoꢀ
gous to organolithiums 2) in ≥99:1 er (Scheme 1). Crucialꢀ
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Journal of the American Chemical Society
Page 2 of 8
Grignard reagents 5 in ≥99:1 er via the same general strateꢀ
gy. It was also envisioned that sulfoxide → Mg exchange
should be possible at temperatures above –78 °C as αꢀ
functionalised Grignard reagents have a higher degree of
configurational stability than their organolithium counterꢀ
parts.11 Whilst there are some related sulfoxide → Li exꢀ
changes12 (especially in the area of chiral ferrocene syntheꢀ
sis12a,12c), we know of only two specific cases where enantiꢀ
oenriched αꢀfunctionalised Grignards like 5 have been diꢀ
rectly prepared by sulfoxide → Mg exchange: αꢀaziridino
Grignards (Satoh13) and αꢀhaloꢀsubstituted Grignards
(Hoffmann14 and Blakemore15).16 In related work, Blakeꢀ
more has also reported a sulfoxide → Mg exchange route to
stereodefined αꢀmagnesiated S,Oꢀacetals17 and Bull has
recently described the synthesis and reactions of αꢀaziridino
Grignard reagents.18
er) and synꢀ6 (85:15 er) were isolated with only moderate
1
2
3
4
5
6
7
8
enantioselectivity indicating a lack of stereospecificity at
sulfur in the trapping with (SS)ꢀ3. Although there is some
limited precedent20 for this, no explanation has previously
been forwarded. Of note, there was no epimerisation of
Andersen’s sulfinate (SS)ꢀ3 during the reaction as the excess
(SS)ꢀ3 was recovered unchanged.
Scheme 2. Racemic deprotonation of O-alkyl carbamate 8
and trapping with Andersen’s sulfinate (SS)-3.
9
s
1. 1.2 eq. BuLi
1.2 eq. TMEDA
CbO
CbO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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52
53
54
55
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58
59
60
CbO
p-Tol
p-Tol
+
Ph
S
Ph
S
Ph
–78 °C, Et O
2
O
O
2. 2.0 eq.
8
anti-6
25%, 83:17 er
syn-6
O
S
21%, 85:15 er
i
p-Tol
O
Cb = C(O)N Pr
2
i
Pr
(S )-3
S
Our approach to enantiopure Grignard reagents 5 is summaꢀ
rised in Scheme 1: asymmetric deprotonation of carbamates
1 using sꢀBuLi/chiral diamine and trapping with Andersen’s
sulfinate (SS)ꢀ3 should generate αꢀalkoxy and αꢀamino sulꢀ
foxides 4 in ≥99:1 dr and ≥99:1 er. We anticipated needing
to carry out the lithiation reaction only once on each subꢀ
strate to generate 4. Subsequent sulfoxide → Mg exchange
on 4 would then deliver the Grignard reagents 5 on deꢀ
mand, potentially under mild conditions and in ≥99:1 er,
ready for electrophilic trapping to give a wide range of
products from just one asymmetric deprotonation reaction.
In this paper, we present the implementation of this strategy
with two examples: the preparation and reactions of enantiꢀ
omerically pure αꢀfunctionalised Grignard reagents derived
from sulfoxides antiꢀ6 and synꢀ7 (Figure 1), the synthesis of
which does not require (–)ꢀsparteine.
Our proposed mechanism to account for the lack of stereoꢀ
specificity in the trapping step is shown in Scheme 3.
Deprotonation of Oꢀalkyl carbamate
8
using sꢀ
BuLi/TMEDA will generate a 50:50 mixture of lithiated
carbamates (S)ꢀ9 and (R)ꢀ9. As an example, reaction of
organolithium (S)ꢀ9 with sulfinate (SS)ꢀ3 would give sulfoxꢀ
ide antiꢀ(S,SS)ꢀ6 and, as the amount of antiꢀ(S,SS)ꢀ6 inꢀ
creases, we suggest that competitive sulfoxide → Li exꢀ
change mediated by lithiated carbamate (S)ꢀ9 as shown in
Scheme 3 could occur to give diastereomeric sulfoxide synꢀ
(S,RS)ꢀ6. An analogous process (using (R)ꢀ9) would conꢀ
vert synꢀ(R,SS)ꢀ6 into antiꢀ(R,RS)ꢀ6 (Scheme 3). Such sulꢀ
foxide → Li exchange processes (attack of lithiated carbaꢀ
mates onto the sulfoxides) could account for the generation
of synꢀ(S,RS)ꢀ6 and antiꢀ(R,RS)ꢀ6, the enantiomers of the
expected major products antiꢀ(S,SS)ꢀ6 and synꢀ(R,SS)ꢀ6, and
would thus account for the lack of stereospecificity at sulfur
in the trapping with sulfinate (SS)ꢀ3.
Figure 1. α-Substituted sulfoxides anti-6 and syn-7.
CbO
p-Tol
p-Tol
S
N
Ph
S
Scheme 3. Proposed mechanism to account for lack of ste-
reospecificity in trapping with sulfinate (SS)-3.
Boc
O
O
syn-7
anti-6
CbO
CbO
CbO
p-Tol
p-Tol
+
+
+
(S)-9
(R)-9
Ph
Ph
S
Ph
Ph
S
Ph
Li
O
O
Results and Discussion
anti-6 (S,S )
(S)-9
syn-6 (S,R )
S
S
Preparation and Reactions of Enantiopure α-Alkoxy
Grignard Reagents
i
Cb = C(O)N Pr
2
CbO
CbO
CbO
p-Tol
p-Tol
The asymmetric deprotonation of Oꢀalkyl carbamates, first
reported by Hoppe in 1990,1 is now recognised as an imꢀ
portant synthetic method due primarily to Aggarwal’s reꢀ
cent extensive studies on boronate rearrangement methodꢀ
ology.4,9,19 As a result, we commenced our studies with Oꢀ
alkyl carbamates. Thus, racemic deprotonation of Oꢀalkyl
carbamate 8 using 1.2 eq. of sꢀBuLi/TMEDA in Et2O at –
78 °C and addition of 2.0 eq. of Andersen’s sulfinate (SS)ꢀ
36 to the solution of the organolithium reagent gave, after
warming to room temperature over 18 h, a separable mixꢀ
ture of sulfoxides antiꢀ6 (25%) and synꢀ6 (21%) (Scheme
2). The assignment of configuration in sulfoxides antiꢀ6
and synꢀ6 is presented later (vide infra). From this initial
experiment, we expected stereospecific substitution at sulꢀ
fur (with inversion of configuration6) to deliver the prodꢀ
ucts in high er. Disappointingly, sulfoxides antiꢀ6 (83:17
+
S
S
Ph
Li
O
O
syn-6 (R,S )
anti-6 (R,R )
(R)-9
S
S
To establish that the sulfoxide → Li exchange was occurꢀ
ring, a crossoverꢀtype experiment using two different Oꢀ
alkyl carbamates was devised. Thus, ethyl Oꢀalkyl carbaꢀ
mate 10 was deprotonated using 1.0 eq. of sꢀBuLi/TMEDA
in Et2O at –78 °C and then 1.0 eq. of sulfoxide antiꢀ6 (raꢀ
cemic) was added. After 1 h at –78 °C, the reaction was
quenched with MeOH. Purification by chromatography
gave a 96% yield (based on antiꢀ6) of a 13:12:70:5 mixture
of sulfoxides antiꢀ11, synꢀ11, antiꢀ6 and synꢀ6 (Scheme 4).
Crucially, the product mixture contained antiꢀ11 and synꢀ11
(separately synthesised and characterised, see Supporting
Information) indicating that the proposed sulfoxide → Li
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c
d
exchange was occurring, even at –78 °C. It is also notable
min. % Yield after chromatography. Er determined by
chiral stationary phase (CSP)ꢀHPLC.
1
2
3
4
5
6
7
8
that some synꢀ6 was also present. This suggests that lithiatꢀ
ed carbamates (S)ꢀ9 and (R)ꢀ9 are formed in the solution, as
necessitated by the sulfoxide → Li exchange.
Scheme 4. Crossover-type experiment to establish the via-
bility of the proposed sulfoxide → Li exchange process.
Next, we explored the use of chiral diamines with the intenꢀ
tion that high enantioselectivity in the asymmetric deprotoꢀ
nation could be coupled with ~90:10 stereospecificity at
sulfur in trapping with (SS)ꢀ3 to deliver the major diastereꢀ
omer in 99:1 er (together with reduced er of the minor diaꢀ
stereomeric sulfoxide). For comparison, the previously
reported enantioselectivity for the deprotonation (–78 °C,
Et2O) and trapping of Oꢀalkyl carbamate 8 are as follows:
(–)ꢀsparteine (99:1 er, Bu3SnCl);21 (+)ꢀsparteine surrogate
(94:6 er, Bu3SnCl)21 and diamine (R,R)ꢀ1222 (82:18 er,
CO2). To our delight, use of all three diamines gave the
major diastereomeric sulfoxide in 99:1 er (entries 4ꢀ7).
Sulfoxide antiꢀ6 (99:1 er) was isolated in 53ꢀ56% yield
using (–)ꢀsparteine or (R,R)ꢀ12 (entries 4/6) whereas synꢀ6
(99:1 er) with opposite configuration at the Oꢀalkyl carbaꢀ
mate stereogenic centre was accessible in 45ꢀ54% yield
using the (+)ꢀsparteine surrogate or (S,S)ꢀ12 (entries 5/7).
The known asymmetric induction with these diamines1,21,22
and the predominance for inversion of configuration at sulꢀ
fur in trapping with (SS)ꢀ36,20 allowed assignment of the
configurations in antiꢀ6 and synꢀ6. Given the recent variaꢀ
bility in the availability of (–)ꢀsparteine, it is significant and
synthetically useful that sulfoxides antiꢀ6 and synꢀ6 can be
accessed in 99:1 er using the commercially available diaꢀ
mines (R,R)ꢀ12 and (S,S)ꢀ12 (entries 6/7).
CbO
CbO
p-Tol
p-Tol
+
+
s
S
S
1. 1.0 eq. BuLi
CbO
1.0 eq. TMEDA
9
13
12
O
O
anti-11
syn-11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–78 °C, Et O
2
2. 1.0 eq.
CbO
CbO
CbO
10
p-Tol
p-Tol
p-Tol
Ph
S
O
i
+
Ph
S
Ph
S
anti-6
5
70
O
O
Cb = C(O)N Pr
anti-6
syn-6
2
With a mechanism for the lack of stereospecifity at sulfur
established, we then attempted to minimise the loss of er in
the trapping with Andersen’s sulfinate (SS)ꢀ3. The reaction
time was reduced from warming to room temperature over
18 h (conditions A) to 5 min at –78 °C (MeOH quench,
conditions B). We compared the reaction under normal
addition (addition of (SS)ꢀ3 to the lithiated carbamate) and
reverse addition (addition of lithiated carbamate to sulfinate
(SS)ꢀ3) which should mean that the organolithium reagent is
not present in excess. The results are summarised in Table
1. Use of both –78 °C for 5 min (conditions B) and reverse
addition of the lithiated carbamate to Andersen’s sulfinate
(SS)ꢀ3 led to increases in er of antiꢀ6 and synꢀ6 (87:13ꢀ91:9
er) (entries 2/3) compared to the original result (83:17ꢀ
85:15 er, entry 1, Scheme 2).
With antiꢀ6 and synꢀ6 of 99:1 er in hand, we then explored
the sulfoxide → Mg exchange and trapping. Optimisation
was carried out using racemic antiꢀ6 which was treated with
1.3ꢀ2.5 eq. of iꢀPrMgCl in THF at room temperature before
trapping with MeO2CCl. This gave ester 13 together with
the sulfoxide 14, the byꢀproduct of the sulfoxide exchange
process. In addition, some of Oꢀalkyl carbamate 8 and
starting material, antiꢀ6, were also isolated (Table 2).
Table 1. Synthesis of α-alkoxy sulfoxides anti-6 and syn-6.
s
CbO
CbO
1. BuLi, diamine
CbO
p-Tol
p-Tol
–78 °C, Et O
2
+
Ph
S
Ph
S
Ph
2. (S )-3, Normal or
Reverse addition
S
O
O
Table 2. Optimisation of sulfoxide → Mg exchange with
anti-6.
8
anti-6
syn-6
Conditions A or B
i
Cb = C(O)N Pr
2
Me
N
i
1. PrMgCl
THF, rt
CbO
CbO
t
H
N
Me
H
N
Bu
p-Tol
N
N
p-Tol
OMe
S
+
Ph
S
Ph
t
Bu
2. MeO CCl
2
N
O
O
14
O
H
Me
13
anti-6 (racemic)
(–)-sparteine
((–)-sp)
via:
Ph
CbO
(+)-sparteine surrogate
((+)-sp surr)
CbO
(R,R)-12
+
i
Cb = C(O)N Pr
2
MgCl
Ph
Entry Diaminea
Trapping
antiꢀ6
%,c erd
synꢀ6
%,c erd
15
8
conditionsb
Entry Eq. of
Time 13
14
8
anti-6
a
a
a
a
1
2
3
4
5
6
TMEDA
TMEDA
TMEDA
(–)ꢀsp
Normal, A
Normal, B
Reverse, B
Normal, A
25, 83:17 21, 85:15
23, 88:12 32, 91:9
25, 87:13 29, 90:10
iꢀPrMgCl min
%
%
%
14
6
%
1
2
3
4
5
1.3
1.3
1.5
1.5
2.5
5
1
5
1
1
48
65
42
67
75
81
73
82
84
84
4
8
0
0
0
53, 99:1
7, 87:13
56, 99:1
17, 95:5
0.2, nd
17
9
(+)ꢀsp surr Normal, A
45, 99:1
14, 93:7
54, 99:1
(R,R)ꢀ12
(S,S)ꢀ12
Reverse, B
Reverse, B
5
a % Yield after chromatography.
7
a
b
1.2 eq. sꢀBuLi/diamine, Et2O, –78 °C, 1 h. Normal =
Using 1.3 eq. of iꢀPrMgCl and trapping after 5 min gave a
moderate 48% yield of ester 13 even though the sulfoxide
→ Mg exchange must have been efficient, as shown by the
formation of sulfoxide 14 in 81% yield (entry 1). Better
addition of (SS)ꢀ3 to organolithium; Reverse = addition of
organolithium to (SS)ꢀ3; Trapping conditions A: –78 °C →
rt and then 18 h at rt; Trapping conditions B: –78 °C for 5
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2.5 eq.
CbO
CbO
results were obtained if the exchange time was reduced to
i
CbO
PrMgCl
RCHO
R
p-Tol
1
2
3
4
5
6
7
8
just 1 min: 65% yield of 13 (entry 2). To explain these
results, we suggest that the intermediate Grignard reagent
15 is chemically unstable either by deprotonation of sulfoxꢀ
ide 14 or via intramolecular nucleophilic attack onto the
C=O of the carbamate group, a known process for the orꢀ
ganolithium analogue at temperatures above –20 °C.4 Use
of 1.5 eq. or 2.5 eq. of iꢀPrMgCl and 1 min reaction times
ensured that no starting antiꢀ6 remained (entries 3ꢀ5). The
best results were obtained using 2.5 eq. of iꢀPrMgCl in
THF at room temperature for 1 min: after trapping, ester 13
was isolated in 75% yield (entry 5). This 75% yield of 13
is similar to the 84% yield of sulfoxide exchange byꢀ
product 14 indicating that any sideꢀreactions of Grignard
reagent 15 can be minimised with a 1 min reaction time.
Ph
Ph
S
Ph
MgCl
THF, rt
1 min
OH
O
99:1 er
i
anti-6
(S)-15
Cb = C(O)NPr
2
CbO
CbO
CbO
CbO
n
t
i
Bu
Ph
Pr
Bu
Ph
Ph
Ph
Ph
OH
OH
OH
OH
(R,S)-18, 99:1 er
71%, 90:10 dr
(R,S)-19, 99:1 er
78%, 70:30 dr
(R,S)-20, 99:1 er (R,S)-21, 99:1 er
70%, 99:1 dr
65%, 90:10 dr
t
i
n
BuCHO
PrCHO
BuCHO
PhCHO
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We also explored the use of sulfoxide antiꢀ6 (99:1 er) in
Aggarwalꢀstyle boronate rearrangement chemistry.4,9,19
Trapping Grignard reagent (S)ꢀ15 derived from antiꢀ6 with
iꢀBuBꢀpinacolate and subsequent oxidation (H2O2, NaOH)
gave alcohol (R)ꢀ22 in 68% yield but only 94:6 er (Scheme
7). Such a lack of stereospecificity in the rearrangement
with Mg is precedented15,19a and we turned to Li to solve
the problem. Thus, sulfoxide → Li exchange of sulfoxide
antiꢀ6 using nꢀBuLi (THF, –78 °C, 1 min) and reaction with
iꢀBuBꢀpinacolate (reflux, 16 h) followed by oxidation gave
alcohol (R)ꢀ22 in 72% yield and 99:1 er (Scheme 7).
Significantly, we then showed that the Grignard reagent (S)ꢀ
15 was configurationally stable at room temperature during
the sulfoxide → Mg exchange and trapping. Three examꢀ
ples are shown in Scheme 5. Sulfoxide antiꢀ6 of 99:1 er
was treated with iꢀPrMgCl in THF at room temperature for
1 min (to give Grignard reagent (S)ꢀ15) and then reacted
with MeO2CCl, CuBr•SMe2/allyl bromide or cyclohexaꢀ
none to give (R)ꢀ13 (of known configuration21d), (R)ꢀ16 and
(R)ꢀ17 respectively, each in 99:1 er. The enantiomers of the
products depicted in Scheme 5 are equally accessible startꢀ
ing from synꢀ6: for example, sulfoxide → Mg exchange on
synꢀ6 and trapping gave (S)ꢀ17 in 74% yield and 99:1 er.
Scheme 7. Use of sulfoxide anti-6 in boronate rearrange-
ment chemistry to give alcohol (R)-22 in 99:1 er.
i
i
1. BuB(pin)
2.5 eq. PrMgCl
THF, rt, 1 min
or
OH
CbO
reflux, 16 h
i
Pr
anti-6
n
Ph
Ph
M 2. H O , NaOH
2
2
2.5 eq. BuLi
99:1 er
rt, 2 h
THF, –78 °C, 1 min
M = MgCl
M = Li
(R)-22
Scheme 5. Synthesis of trapped products in 99:1 er via sul-
foxide → Mg exchange with anti-6.
Mg: 68%, 94:6 er
Li: 72%, 99:1 er
i
Cb = C(O)N Pr
2
2.5 eq.
PrMgCl
CbO
i
CbO
CbO
+
Finally, with simple access to Grignard reagent (S)ꢀ15 (of
99:1 er), we were in a position to investigate its configuraꢀ
tional stability over longer times than 1 min. With sulfoxꢀ
ide → Mg exchange reaction times of 15 and 30 min, trapꢀ
ping with cyclohexanone gave alcohol (R)ꢀ17 in 98:2 er
(34% and 24% yield respectively) (Scheme 8). The low
yields with extended sulfoxide → Mg exchange times are
due to the chemical instability of Grignard reagent (S)ꢀ15
(as discussed previously). From this marginal loss of er
(within the error limits of HPLC detection), we conclude
that αꢀfunctionalised Grignard reagent (S)ꢀ15 is configuraꢀ
tionally stable at room temperature for 30 min. This is a
significant observation in the context of configurational
stability of αꢀfunctionalised organometallic reagents.
E
p-Tol
Ph
S
Ph
MgCl
Ph
E
THF, rt
1 min
O
i
99:1 er
anti-6
(S)-15
Cb = C(O)N Pr
CbO
2
CbO
CbO
OMe
Ph
Ph
+
Ph
O
OH
(R)-17
(R)-13
(R)-16
70%, 99:1 er
73%, 99:1 er
= MeO CCl
71%, 99:1 er
= cyclohexanone
+
+
E
E
= CuBr•Me S
2
E
2
then allyl–Br
Reaction of the Grignard reagent (S)ꢀ15 derived from antiꢀ6
with aldehydes was also explored (Scheme 6). These reacꢀ
tions gave protected diols (R,S)ꢀ18ꢀ21 with antiꢀ
diastereoselectivity (70:30 to ≥99:1 dr, inseparable mixꢀ
tures) in 65ꢀ78% yields, each diastereomer being formed in
99:1 er. The relative configuration of (R,S)ꢀ21 was asꢀ
signed by conversion (using LiAlH4) into the known23 antiꢀ
diol with (R,S)ꢀ18ꢀ21 assigned by analogy. This methodolꢀ
ogy represents a new, connective strategy for the asymmetꢀ
ric synthesis of anti-1,2ꢀdiols24 which are typically syntheꢀ
sised in two steps (Wittig reaction and asymmetric dihyꢀ
droxylation).
Scheme 8. Investigation of the configurational stability of
α-functionalised Grignard reagent (S)-15.
2.5 eq.
PrMgCl
CbO
CbO
CbO
i
O
p-Tol
Ph
Ph
anti-6
S
Ph
MgCl
THF, rt
1-30 min
OH
O
(S)-15
(R)-17
99:1 er
Exchange time
1 min:
71%, 99:1 er
34%, 98:2 er
24%, 98:2 er
i
Cb = C(O)N Pr
2
15 min:
30 min:
Scheme 6. Synthesis of monoprotected diols in 99:1 er via
sulfoxide → Mg exchange with anti-6.
Preparation and Reactions Enantiopure of α-Amino
Grignard Reagents
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Journal of the American Chemical Society
Our attention then switched to NꢀBoc heterocycles. Unforꢀ As with the Oꢀalkyl carbamates, we explored shorter reacꢀ
1
tion times, reverse addition and chiral diamines in order to
prepare αꢀamino sulfoxide synꢀ7 in 99:1 er (Table 3). Usꢀ
ing TMEDA and reverse addition with a 5 min trapping
time at –78 °C, better results were obtained: sulfoxide synꢀ7
was formed in 39% yield and 89:11 er and sulfoxide antiꢀ7
was isolated in 44% yield and 88:12 er (entry 3). Before
investigating the chiral diamines in the synthesis of αꢀ
amino sulfoxides synꢀ7 and antiꢀ7, we explored their inherꢀ
ent enantioselectivity in the deprotonationꢀcyclisationꢀ
trapping of 4ꢀchloro NꢀBoc piperidine 25 (trapping with
PhNCO, see Supporting Information): (–)ꢀsparteine gave
56:44 er;26 (+)ꢀsparteine surrogate gave 54:46 er and diaꢀ
mine (S,S)ꢀ12 gave the highest enantioselectivity of 67:33
er. Not surprisingly, low enantioselectivity with (–)ꢀ
sparteine and the (+)ꢀsparteine surrogate led to moderate
yields and only slightly improved ers of the expected major
diastereomers synꢀ7 (27%, 96:4 er) and antiꢀ7 (27%, 93:7
er) respectively upon trapping with (SS)ꢀ3 (entries 4/5).
However, the combination of diamine (R,R)ꢀ12 and (SS)ꢀ3
was optimal and gave sulfoxide synꢀ7 in 53% yield and
99:1 er (entry 6). Notably, this synthesis of sulfoxide synꢀ7
in 99:1 er does not rely on the use of (–)ꢀsparteine. Finally,
starting from 25, use of diamine (S,S)ꢀ12 and trapping with
(SS)ꢀ3 gave sulfoxide antiꢀ7 in only 87:13 er (54% yield).
Unlike the Oꢀalkyl carbamates, it was not possible to access
both αꢀamino sulfoxides synꢀ7 and antiꢀ7 in 99:1 er. Preꢀ
sumably, the diamine plays a role in facilitating loss of er at
sulfur by sulfoxide → Li exchange, especially if the initial
enantioselectivity from the asymmetric deprotonation step
is moderate (67:33 er with diamine (R,R)ꢀ12 or (S,S)ꢀ12).
Nonetheless, (+)ꢀmenthol is commercially available and
thus would allow access to entꢀsynꢀ7 in 99:1 er via deproꢀ
tonation of 4ꢀchloro NꢀBoc piperidine 25 using diamine
(S,S)ꢀ12 and trapping with sulfinate (RS)ꢀ3.
tunately, attempts to prepare αꢀamino sulfoxides syn/antiꢀ
23 and syn/antiꢀ24 (Figure 2) by deprotonation (sꢀBuLi,
TMEDA, –78 °C) and sulfinate trapping of NꢀBoc pyrroliꢀ
dine and N-Boc piperidine respectively were unsuccessful.
Other routes to syn/antiꢀ23 and syn/antiꢀ24 (e.g. oxidation
of the sulfides) were explored with no success. We suspect
that αꢀamino sulfoxides syn/antiꢀ23 and syn/antiꢀ24 are
unstable due to αꢀelimination of the sulfoxide promoted by
the nitrogen lone pair. Our attention thus focused on αꢀ
amino sulfoxides syn/antiꢀ7 (derived from NꢀBoc chloropiꢀ
peridine 25 as reported by Beak,25 Figure 2) since αꢀ
elimination should be disfavoured by the [3.1.0] bicyclic
system. Furthermore, the highest enantioselectivity reportꢀ
ed for the sꢀBuLi/(–)ꢀsparteineꢀmediated desymmetrisation
of 4ꢀchloro and 4ꢀtosyl NꢀBoc piperidines was only 78:22
er.25b,25c Our sulfoxide methodology could thus provide a
significant improvement by generating products in 99:1 er.
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. α-Amino sulfoxides syn/anti-23, syn/anti-24 and
syn/anti-7.
Cl
H
S
H
S
p-Tol
p-Tol
p-Tol
N
S
N
N
N
Boc
Boc
Boc
O
O
O
Boc
25
syn/anti-7
syn/anti-23
syn/anti-24
To start with, racemic deprotonation of 4ꢀchloro NꢀBoc
piperidine 25 was carried out using 2.2 eq. of sꢀ
BuLi/TMEDA (Scheme 9). Mechanistically, the reaction
proceeds via cyclisation of αꢀlithiated piperidine 26 to cyꢀ
clopropane 27 which undergoes a second αꢀlithiation beꢀ
fore electrophilic trapping. In this case, addition of 2.2 eq.
of Andersen’s sulfinate (SS)ꢀ3 to the solution of the organoꢀ
lithium reagent gave, after warming to room temperature
over 18 h, sulfoxides synꢀ7 (38%, 58:42 er) and antiꢀ7
(45%, 70:30 er) (Scheme 9). Notably, αꢀamino sulfoxides
syn/antiꢀ7 were stable, isolable compounds unlike their
more simple pyrrolidine analogues syn/antiꢀ23. The lack of
stereospecificity at sulfur was more pronounced with αꢀ
amino sulfoxides synꢀ7 and antiꢀ7 compared to the correꢀ
sponding αꢀalkoxy carbmates antiꢀ6 and synꢀ6 (Scheme 2).
This probably reflects the fact that the lithated cyclopropyl
NꢀBoc pyrrolidine is the better leaving group in the sulfoxꢀ
ide → Li exchange process that results in the loss of er.
The configurational assignment of sulfoxides synꢀ7 and
antiꢀ7 is presented later (vide infra).
Table 3. Synthesis of α-amino sulfoxides syn-7 and anti-7.
Cl
s
1. BuLi, TMEDA
–78 °C, Et O
2
p-Tol
p-Tol
+
S
S
N
N
2. (S )-3, Normal or
Reverse addition
S
N
Boc
Boc
O
O
Boc
25
Conditions A or B
syn-7
anti-7
Me
t
N
H
N
Me
N
H
Bu
N
t
Bu
N
N
H
Me
(–)-sparteine
((–)-sp)
(+)-sparteine surrogate
((+)-sp surr)
(R,R)-12
Scheme 9. Racemic deprotonation of N-Boc chloropiperi-
dine 25 and trapping with Andersen’s sulfinate (SS)-3.
Entry Diaminea
Trapping
synꢀ7
antiꢀ7
%,c erd
conditionsb
%,c erd
Cl
s
1. 2.2 eq. BuLi
1
2
3
4
5
6
7
TMEDA
TMEDA
TMEDA
(–)ꢀsp
Normal, A
Normal, B
Reverse, B
Reverse, B
38, 58:42 45, 70:30
36, 80:20 47, 78:22
39, 89:11 44, 88:12
2.2 eq. TMEDA
p-Tol
p-Tol
+
S
S
N
N
–78 °C, Et O
2
N
Boc
Boc
O
O
2. 2.2 eq.
Boc
syn-7
38%, 58:42 er
anti-7
45%, 70:30 er
O
S
25
27, 96:4
26, 99:1
51, 99:1
24, 89:11
27, 93:7
p-Tol
O
(+)ꢀsp surr Reverse, B
i
via
Cl
Pr
(S )-3
S
N
(R,R)ꢀ12
(S,S)ꢀ12
Reverse, B
Reverse, B
25, 87:13
H
N
Li
Boc
26
27 Boc
12, 89:11 54, 87:13
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Journal of the American Chemical Society
Page 6 of 8
a
b
2.5 eq.
PrMgCl
2.2 eq. sꢀBuLi/diamine, Et2O, –78 °C, 1 h. Normal =
i
+
E
1
2
3
4
p-Tol
addition of (SS)ꢀ3 to organolithium; Reverse = addition of
organolithium to (SS)ꢀ3; Trapping conditions A: –78 °C →
rt and then 18 h at rt; Trapping conditions B: –78 °C for 5
min. % Yield after chromatography. Er determined by
chiral stationary phase (CSP)ꢀHPLC.
S
MgCl
E
N
N
N
THF, rt
1 min
Boc
Boc
Boc
O
syn-7
(R,R)-31
c
d
5
6
7
8
OMe
Ph
NHPh
N
N
N
N
The configuration of sulfoxide synꢀ7 was assigned based on
the known25c deprotonationꢀcyclisation of 4ꢀchloro NꢀBoc
piperidine 25 using sꢀBuLi/(–)ꢀsparteine, the known27
deprotonation of NꢀBoc piperidine using sꢀBuLi/(R,R)ꢀ12
and the conversion of synꢀ7 into known28 amino alcohol
cisꢀ30 (Scheme 10). Thus, the sulfoxide in synꢀ7 was reꢀ
duced to the sulfide 28 (using NaI and trifluoroacetic anꢀ
hdyride). Then, ligandꢀcontrolled diastereoselective lithiaꢀ
tion22 (sꢀBuLi/(+)ꢀsparteine surrogate), carbon dioxide
trapping and borane reduction gave alcohol cisꢀ29 as a sinꢀ
gle diastereomer. Use of sꢀBuLi/TMEDA gave cisꢀ29 in
only 68:32 dr. Finally, reductive cleavage of the sulfide
gave amino alcohol cisꢀ30. The relative and absolute conꢀ
figuration was established by comparison of spectroscopic
and optical rotation data with known cisꢀ30.28 The preparaꢀ
tion of cisꢀ30 also completes a formal synthesis of saxꢀ
agliptin, a drug for the treatment of type 2 diabetes.28,29
O
O
Boc
Boc
Boc
Boc
(S,R)-32
(S,R)-33
(R,R)-34
(S,R)-35
89%, 99:1 er
+
69%, 99:1 er
+
64%, 99:1 er
+
67%, 99:1 er
+
9
E
= MeO CCl
E
= CuBr•Me S
2
E
= CuBr•Me S
2
E = PhCNO
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
then allyl–Br
then allyl–Br
Finally, we also showed that αꢀfunctionalised Grignard
reagent (R,R)ꢀ31 derived from synꢀ7 could be coupled with
aryl bromides (via transmetallation to Zn and Pdꢀmediated
Negishi coupling18,24). In this way, arylated heterocycles
(S,R)ꢀ36ꢀ39 were generated in 99:1 er (Scheme 12). Thus,
a wide range of substituted NꢀBoc cyclopropyl pyrrolidines
are now accessible in 99:1 er via asymmetric deprotonation
using sꢀBuLi/diamine (R,R)ꢀ12, trapping with sulfinate (SS)ꢀ
3 and subsequent sulfoxide → Mg exchange and electroꢀ
philic trapping.
Scheme 10. Synthesis of known amino alcohol cis-30 from
sulfoxide syn-7 and formal synthesis of saxagliptin.
Scheme 12. Sulfoxide → Mg exchange and Negishi cou-
pling to give arylated products in 99:1 er from syn-7.
s
1. BuLi, (+)-sp surr
NaI, TFAA
acetone
–78 °C, Et O, 10 min
2
p-Tol
p-Tol
S
S
N
N
1. ZnCl
2.5 eq.
PrMgCl
2
2. CO
2
3. BH •Me S
–40 °C, 10 min
99%
i
Boc
Boc
2. 5 mol% Pd(OAc)
2
O
84%
p-Tol
3
2
S
MgCl
Ar
N
N
N
t
syn-7
28
THF, rt
1 min
6 mol% BuPHBF
4
Boc
Boc
Boc
O
Ar–Br, rt. 16 h
Raney Ni
p-Tol THF-EtOH
NC
syn-7
(R,R)-31
N
S
N
N
O
OMe
CO Me
2
rt, 5 h
73%
OH
OH
Boc
Boc
OH
NH
2
N
N
N
N
cis-29
cis-30
Saxagliptin
Boc
Boc
Boc
Boc
S
(S,R)-36
(S,R)-37
68%, 99:1 er
(S,R)-38
(S,R)-39
72%, 99:1 er
With ready access to αꢀamino sulfoxide synꢀ7 in 99:1 er,
sulfoxide → Mg exchange and subsequent trapping of αꢀ
functionalised Grignard reagent (R,R)ꢀ31 with electrophiles
was explored. The sulfoxide → Mg exchange on sulfoxide
synꢀ7 (99:1 er) worked well using 2.5 eq. of iꢀPrMgCl in
THF at room temperature for 1 min. Direct electrophilic
trapping delivered (S,R)ꢀ32ꢀ33, (R,R)ꢀ34 and (S,R)ꢀ35 in
99:1 er (64ꢀ89% yield) using MeO2CCl, allyl broꢀ
mide/CuBr•SMe2, benzyl bromide/CuBr•SMe2 and PhNCO
respectively (Scheme 11). In these cases, due to the bicyꢀ
clic system, configurational stability of the intermediate
Grignard reagent (R,R)ꢀ31 is assured.
68%, 99:1 er
74%, 99:1 er
Conclusion
In conclusion, we present a new strategy for the generation
of enantiopure αꢀfunctionalised chiral Grignard reagents
via asymmetric deprotonation, trapping with Andersen’s
sulfinate (SS)ꢀ3 and sulfoxide → Mg exchange. Using αꢀ
alkoxyꢀ and αꢀamino sulfoxides antiꢀ6 and synꢀ7 in ≥99:1
dr and ≥99:1 er, access to a range of enantiopure αꢀ
substituted products (via sulfoxide → Mg exchange at room
temperature for 1 min and trapping) is possible. Our methꢀ
odology does not rely on the use of (–)ꢀsparteine for the
asymmetric deprotonation step and delivers a wide range of
previously inaccessible αꢀsubstituted products in 99:1 er.
In the course of our studies, we have identified two imꢀ
portant aspects. First, in the deprotonation and trapping
with Andersen’s sulfinate (SS)ꢀ3, there is a lack of stereoꢀ
specificity at sulfur due to attack of a lithiated intermediate
onto the sulfur in the αꢀalkoxyꢀ and αꢀamino sulfoxides as
they form. Second, the αꢀalkoxyꢀsubstituted Grignard reaꢀ
gent (S)ꢀ15 is configurationally stable at room temperature
for 30 minutes. Finally, extension of this approach to acꢀ
Scheme 11. Synthesis of trapped products in 99:1 er via
sulfoxide → Mg exchange with syn-7.
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
16.
For an indirect sulfoxide → Mg exchange route which proꢀ
cess chiral αꢀfunctionalised Grignard reagents from a wide
range of asymmetric deprotonation reactions without the
need for (–)ꢀsparteine can be envisaged.
1
2
3
4
5
6
7
8
ceeds via cyclisation to generate an αꢀaminoꢀtetrahydroquinoline
Grignard reagent, see: (a) Satoh, T.; Ohbayashi, T.; Mitsunaga, S.
Tetrahedron Lett. 2007, 48, 7829. (b) Satoh, T.; Mitsunaga, S.;
Ohbayashi, T.; Sugiyama, S.; Saitou, T.; Tadokoro, M. Tetrahedron:
Asymmetry 2009, 20, 1697.
ASSOCIATED CONTENT
17.
Barsamiam, A. L.; Blakemore, P. R. Organometallics
Supporting Information. Full experimental procedures and specꢀ
troscopic data, copies of NMR spectra and CSPꢀHPLC data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
2012, 31, 19.
18.
Org. Chem. 2013, 78, 844.
19.
Hughes, M.; Boultwood, T.; Zeppetelli, G.; Bull, J. A. J.
(a) Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal,
9
V. K. Angew. Chem. Int. Ed. 2007, 46, 7491. (b) Stymiest, J. L.;
Bagutski, V.; French, R. M.; Aggarwal, V. K. Nature 2008, 456, 778.
AUTHOR INFORMATION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20.
(a) Rebière, F.; Riant, O.; Ricard, L.; Kagan, H. B. Angew.
Corresponding Author
* peter.obrien@york.ac.uk
Chem. Int. Ed. 1993, 32, 568. (b) Hua, D. H.; Lagneau, N. M.; Chen,
Y.; Robben, P. M.; Clapham, G.; Robinson, P. D. J. Org. Chem.
1996, 61, 4508. (c) El Ouazzani, H.; Khiar, N.; Fernández, I.; Alcuꢀ
dia, F. J. Org. Chem. 1997, 62, 287. (d) Riant, O.; Argouarch, G.;
Guillaneux, D.; Samuel, O.; Kagan, H. B. J. Org. Chem. 1998, 63,
3511.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by EPSRC and GlaxoSmithKline. We
are very grateful to Professor S. Hannessian for providing full
characterisation data for cisꢀ30.
21.
(a) O'Brien, P.; Dearden, M. J.; Firkin, C. R.; Hermet, J. P.
R. J. Am. Chem. Soc. 2002, 124, 11870. (b) O’Brien, P.; Wiberg, K.
B.; Bailey, W. F.; Hermet, J.ꢀP. R.; McGrath, M. J. J. Am. Chem. Soc.
2004, 126, 15480. (c) O'Brien, P. Chem. Comm. 2008, 655. (d) Carꢀ
bone, G.; O'Brien, P.; Hilmersson, G. J. Am. Chem. Soc. 2010, 132,
15445.
22.
1409.
23.
garwal, V. K. Org. Lett. 2009, 11, 165.
24.
C.; Marek, I.; Knochel, P. Synlett 1998, 1820. (b) Ma, L.; Zhao, D.;
Chen, L.; Wang, X.; Chen, Y.ꢀL.; Shen, J. Tetrahedron 2012, 68,
8704.
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