Tuning the reactivity of difluoromethyl sulfoximines from electrophilic to nucleophilic: Stereoselective nucleophilic difluoromethylation of aryl ketones

Article abstract of DOI:10.1021/ja308419a

A stereoselective synthesis of enantiomerically enriched difluoromethyl tertiary alcohols by tuning the reactivity of difluoromethyl sulfoximines from electrophilic to nucleophilic difluoromethylating agents is reported. The key feature of this chemistry is the diastereoselective addition of the difluoromethyl sulfoximine to the prochiral carbon of the ketone. The present method was used to prepare enantiomerically enriched difluoromethyl secondary alcohols and difluorinated analogues of the natural products gossonorol and boivinian B, demonstrating the potency of the method.

Full text of DOI:10.1021/ja308419a

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Communication
Tuning the Reactivity of Difluoromethyl Sulfoximines
from Electrophilic to Nucleophilic: Stereoselective
Nucleophilic Difluoromethylation of Aryl Ketones
Xiao Shen, Wei Zhang, Chuanfa Ni, Yucheng Gu, and Jinbo Hu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 28 Sep 2012
Downloaded from http://pubs.acs.org on October 1, 2012
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Page 1 of 5
Journal of the American Chemical Society
Tuning the Reactivity of Difluoromethyl Sulfoximines from
Electrophilic to Nucleophilic: Stereoselective Nucleophilic
Difluoromethylation of Aryl Ketones
1
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Xiao Shen,† Wei Zhang,† Chuanfa Ni,† Yucheng Gu,‡ and Jinbo Hu*,†
† Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Ling-Ling Road, Shanghai 200032, P. R. China
‡ Syngenta Jealott’s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom
Supporting Information Placeholder
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on the stereoselective nucleophilic difluoromethylation of
ketones to obtain optically pure difluoromethyl alcohols. In this
communication, we wish to disclose our recent success in
tackling this interesting synthetic problem via a chiral
α,α-difluoro carbanion strategy (see Scheme 1, eq 3).
ABSTRACT: A stereoselective synthesis of enantiomerically
enriched difluoromethyl tertiary alcohols by tuning the
reactivity of difluoromethyl sulfoximines from electrophilic to
nucleophilic difluoromethylating agents is reported. The key
feature of this chemistry is the diastereoselective addition of
difluoromethyl sulfoximine to the prochiral carbon center of
ketones. The present method has also been used to prepare
enantiomerically enriched difluoromethyl secondary alcohols as
well as two difluorinated analogues of natural products
(difluorinated gossonorol 7g and boivinian B 13), which
demonstrates the potency of the method.
Scheme 1. Electrophilic and Nucleophilic Difluoromethylation
Reactions with Different Sulfoximine Reagents
Our previous work (electrophilic difluoromethylation via :CF2)
O
OH
O
S
TsN
O
NTs
O
Ts
N
R
base
Ph
R
S
(1)
(2)
S
Ph
X
Ph
CF2
Ph
Ph
CF2H
(R = H, CH3)
F
F
3
Selective incorporation of fluorine atom(s) or fluoroalkyl
group(s) (such as CF3, CF2H, and CH2F) into an organic
molecule can often substantially change the latter’s biological
properties, thanks to the unique properties of fluorine.1 Many
studies have shown that fluorinated molecules offer improved
metabolic stability, increased binding affinity, and improved
membrane permeability and bioavailability.2,3 As a consequence,
organofluorine compounds have attracted much attention in the
life science-related fields. Among various fluoroalkyl groups,
the difluoromethyl (CF2H) group is of particular interest, as it is
known to be isosteric and isopolar to an OH or SH unit, and can
act as a hydrogen donor through hydrogen bonding.3 Therefore,
the difluoromethylated analogues of biologically active
compounds are strong candidates for pharmaceuticals. In some
cases, difluoromethylated compounds exhibit increased
bioactivity compared to their trifluoromethylated counterparts.4
Over the past decades, a variety of protocols have been devel-
oped for introducing the trifluoromethyl group.5 However, there
are few mild and efficient methods for difluoromethylations,
and stereoselective difluoromethylation methods of carbonyl
compounds are particularly sparse.6-9 In 2008, we reported the
enantioselective nucleophilic difluoromethylation of aromatic
aldehydes with PhSO2CF2SiMe3 and PhSO2CF2H reagents
catalyzed by chiral quaternary ammonium salts, with the
CF2H-substituted alcohol being obtained after removing the
PhSO2 group.7 Unfortunately, the enantioselectivity of the
reaction was low (466% ee).7 We also attempted the
diastereoselective nucleophilic difluoromethylation of carbonyl
compounds with PhSOCF2H, and found that the
diastereoselectivity was not high in these reactions either (1:1 to
1:2 dr).8 The synthesis of optically pure α-difluoromethylated
tertiary alcohols via a nucleophilic difluoromethylation strategy
is even more challenging.9 This is mainly attributed to the
instability of the difluoromethyl carbanion that is affected by
the ‘negative fluorine effect’ (NFE)10 and the challenges
associated with developing conditions for the selective addition
of the difluoromethyl carbanion to ketones (compared to
aldehydes), i.e. the lower reactivity of ketones and the smaller
steric differences between the two substituents on the prochiral
carbon. To the best of our knowledge, there has been no report
1
4
highly unstable
Nu
[:CF2]
Nu CF2H
Nu = C-, N-, S-nucleophiles
5
This work (nucleophilic difluoromethylation via chiral , -difluoro carbanion)
O
O
NTBS
O
NTBS
R2 OH
R1
CF2H
R1
R2
1)
base
S
S
(3)
Ph
CF2H
Ph
CF2
2) desulfoximination
2
6
7
more stable
Recently, we reported the first chiral α-fluoro
sulfoximine-mediated stereoselective fluoroalkylation reaction,
and a series of monofluorinated cyclopropanes were synthesized
in high yields and with excellent stereoselectivity using
(R)-PhSO(NTs)CH2F.11 In light of the ability of the PhSO(NTs)
group to give high levels of chiral induction, one may envision
that (R)-PhSO(NTs)CF2H [(R)-1] could be used to tackle the
challenge
of
synthesizing
enantiomerically
enriched
difluoromethyl alcohols. However, we found that the racemic
sulfoximine 1 was not a good nucleophilic difluoromethylating

agent (Scheme 1, eq 1), since its carbanion PhSO(NTs)CF2 (3)
is highly unstable and readily decomposes into difluorocarbene
(:CF2); and indeed, sulfoximine 1 can serve as an electrophilic
difluoromethylating agent via difluorocarbene intermediate
(Scheme 1, eq 2).12,13 Based on these results, we surmised that
in order to improve the stability of the carbanion, the structure
of sulfoximine 1 should be modified by changing the Ts group
(Ts = p-toluenesulfonyl) to a less electron-withdrawing
substituent to decrease the leaving ability (nucleofugality) of the
sulfonimidoyl group, and a more bulky group may also favor
chiral induction. In addition, the new substituent must be stable
enough under the basic conditions of the nucleophilic addition,
and must be easily removed after the addition reaction. With
these considerations in mind, we identified TBS
(tert-butyldimethylsilyl) as a good choice (see Scheme 1, eq 3).
(R)-N-tert-Butyldimethylsilyl-S-fluoromethyl-S-phenyl-sulfo
ximine (8) was readily prepared according to the literature
procedures.14 Introduction of a benzoyl group then gave
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Scheme 2. Preparation of (R)-N-tert-Butyldimethylsilyl-S-
Table 1. Survey of Reaction Conditionsa
Page 2 of 5
1
2
3
4
Difluoromethyl-S-Phenylsulfoximine 2
NH
O
Me
F
HO
Ph
O
NTBS
O
base
O
NTBS
S
O
O
S
O
NTBS
Ph
solvent,T, t
KHMDS
Ph
11a
Me
Ph
CF2H
S
O
F
12a
S
Ph
Ph
Ph
N
THF, 78 o
C
2
Ph
CH2F
F
entry
11a/2/base
base
solvent
T (oC)
t (h) yield (%)b drc
5
8
9
10 (95%)
6
7
8
9
O
NTBS
1) LiHMDS, NFSI, THF, 78 o
C
nBuLi
THF
THF
THF
THF
1.5/1.0/1.2
1.5/1.0/1.2
78
78
78
78
3
3
3
3
25
10
37
67
83/17
83/17
1
2
3
S
LiHMDS
2) NaOH (20% aq), rt
94%
Ph
CF2H
1.5/1.0/1.2 NaHMDS
87/13
90/10
2
4
5
1.5/1.0/1.2
1.5/1.0/1.2
KHMDS
KHMDS
THF/HMPA
(v/v=5/1)
10
11
12
13
14
15
16
17
18
19
20
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3
48
57/43
78
compound 10 in 95% yield. (R)-N-tert-Butyldimethylsilyl-S-dif-
luoromethyl-S-phenylsulfoximine (2) was obtained in 94% yield
by fluorination of 10 using N-fluorodibenzenesulfonimide
(NFSI) as the fluorinating agent, followed by removal of the
benzoyl group (Scheme 2). To our knowledge, compound 2 is
the first enantiopure difluoromethyl sulfoximine.
6
7
1.5/1.0/1.2
1.5/1.0/1.2
KHMDS
KHMDS
Et2O
3
3
54
57
84/16
83/17
78
78
PhCH3
8
9
1.5/1.0/1.2
1.5/1.0/1.2
1.5/1.0/1.5
KHMDS
KHMDS
KHMDS
CH2Cl2
THF
3
45
82
88
85/15
93/7
93/7
78
98
98
0.5
0.5
10
THF
11
12
13d
1.0/1.5/1.5
1.5/1.0/1.5
1.5/1.0/1.8
KHMDS
KHMDS
KHMDS
THF
THF
THF
98
98
98
0.5
0.5
0.5
98
97
93/7
93/7
With compound
2
in hand, we investigated the
diastereoselective synthesis of difluoromethyl tertiary alcohols
by using the chiral α,α-difluoro carbanion strategy.
Acetophenone (11a) was chosen as a model substrate on which
to test and then optimize the nucleophilic difluoromethylation
reaction; the results are summarized in Table 1. Typically, a
base was added to the mixture of 11a and 2, and the ratio of 11a,
2 and the base was 1.5/1.0/1.2. When n-BuLi was used as a base,
a yield of difluoromethylation products of only 25% was
observed via 19F NMR, and the diastereoselectivity was only
moderate (83/17 dr; Table 1, entry 1). The inefficiency of the
reaction was probably due to the competing reaction between
11a and nBuLi.15 When the base was changed to LiHMDS
(lithium hexamethyldisilazide), the yield decreased to 10%, and
the diastereoselectivity did not increase (Table 1, entry 2).
Encouragingly, both the yield and diastereoselectivity were
slightly improved (37% yield, 87/13 dr) when NaHMDS
(sodium hexamethyldisilazide) was employed as the base (Table
1, entry 3). Furthermore, KHMDS was found to be better still
for the model stereoselective difluoromethylation reaction (67%
yield, 90/10 dr; Table 1, entry 4). The screening of solvents
showed that THF was the best solvent (Table 1, entries 4-8). It
was found that hexamethylphosphoramide (HMPA) was fatal to
the reaction, with the yield and dr decreasing to 48% and 57/43,
respectively, when HMPA was used as a co-solvent (Table 1,
entry 5), indicating that alkali metal counterions are involved in
the transition state of the reaction. It is remarkable that, when
99 (88) 93/7
a Base was added slowly to the mixture of 11a (36 mg, 0.3 mmol) and 2 (61 mg, 0.2
mmol) in the solvent (2.5 mL) at the temperature shown, and stirred at the
temperature for indicated time. b,c The total yield of the both diastereoisomers and dr
were determined by 19F NMR. d The yield in the parentheses refers to the isolated
yield of the major diastereoisomer.
Scheme 3. Stereoselective Difluoromethylation of Ketones
and Aldehydesa
2 O
NH
R
HO
R1
O
NTBS
1) KHMDS, THF, 98 oC, 0.5 h
2) 12 M HCl, 98 oC ~ rt, 1 h
O
S
S
R1
R2
Ph
Ph
CF2H
F
F
12
11
2
NH
O
Me
HO
NH
O
Me
F
HO
S
X-Ray
Ph
S
Ph
F
F
F
F
12a
12b
95 (88)%b yield, 93/7 dr
91 (74)%c yield, 91/9 dr
NH
O
NH
O
NH
O
Me
Me
F
HO
Me
F
HO
HO
S
S
S
Ph
Ph
Ph
F
F
F
F
OMe
Cl
Br
12c
12d
12e
84 (70)%c yield, 90/10 dr
89 (68)%c yield, 90/10 dr
92 (80)%c yield, 95/5 dr
NH
O
Me
HO
NH
O
NH
O
HO
HO
S
Ph
S
S
Ph
F
F
Ph
F
F
F
12h
F
o
12f
12g
OMe
the reaction temperature was lowered to98 C, both the yield
92 (70)%c yield, 93/7 dr
92 (86)%b yield, 93/7 dr
77 (68)%b yield, 93/7 dr
and diastereoselectivity were substantially improved (82% yield,
93/7 dr; Table 1, entry 9). Further optimization of the reaction
conditions by changing the ratio of 11a, 2 and KHMDS to
1.5/1/1.8 gave an excellent yield (99%) and with 93/7 dr (Table
1, entry 13). It is noteworthy that N-methyl-, N-triisopropylsilyl-,
N-tris(trimethylsilyl)silyl-, N-benzoyl- and N-tosyl-substituted
difluoromethyl sulfoximines were found to be inferior to 2 for
the current stereoselective difluoromethylation reaction (for
details, see supporting information).
NH
O
NH
H
O
HO
NH
H
O
HO
Me
HO
S
S
S
Ph
Ph
Ph
F
F
F
F
F
F
O
MeO
Br
12i
88 (62)%c yield, 87/13 dr
12j
12k
90 (65)%b yield, 80/20 dr
91 (80)%b yield, 92/8 dr
a Typical procedure: under N2 atmosphere, KHMDS (1M/THF, 1.8 mL, 1.8 mmol) was added
slowly into the THF (5 mL) solution of 11a (180 mg, 1.5 mmol) and 2 (305 mg, 1 mmol) at 98
oC , and then stirred for 0.5 h, after which 12 M HCl (1 mL) was added, and the solution was
strirred for 1 h at room temperature; The isolated yield refers to the total yield of the two
diastereoisomers; the dr was determined by 19F NMR. b The yield in the parentheses refers to
c
Eventually, we chose the conditions shown under entry 13 in
Table 1 as standard conditions to examine the scope of the
reaction between ketones (or aldehydes) 11 and sulfoximine 2.
The results are summarized in Scheme 3. A variety of
structurally diverse aromatic ketones were successfully
difluoromethylated by 2. The products 12 were obtained in good
yields (7795%) and with good diastereoselectivity (87/1395/5 with 93/7 dr, respectively. In addition, difluoromethylation of a
dr). The reaction tolerates many substituents such as fluoro,
chloro, bromo and methoxy groups. 1-Phenylbutan-1-one and
the isolated yield of the major diastereoisomer by colum chromatography. The yield in the
parentheses refers to the isolated yield of the major diastereoisomer by recrystallization.
2-methyl-1-phenylpropan-1-one are also suitable substrates for
the difluoromethylation reaction, affording the corresponding
products 12g in 92% yield with 93/7 dr, and 12h in 77% yield
heteroaryl-substituted ketone was also successful, giving the
tertiary alcohol 12i in 88% yield with 87/13 dr. The reaction
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could also be applied to the synthesis of enantiomerically 7g and difluorinated boivinian B 13 (Scheme 5).20 Under the
enriched difluoromethyl secondary alcohols, and products 12j standard conditions, the reaction between sulfoximine 2 and
and 12k were obtained in 90% yield with 80/20 dr, and 91% ketone 11l proceeded smoothly, giving the product 12l in 95%
yield with 92/8 dr, respectively. The absolute configurations of yield and with 90/10 dr even on a 6 mmol scale, which indicates
12a and 12j were confirmed by X-ray crystal structure analysis, that the current method can be successfully scaled up. Under the
and the newly formed carbon stereocenters in 12a and 12j were Mg/MeOH conditions, 12l was converted to 7g in 75% yield
found to be in S-configuration.16 Those of the other products and with >98% ee. Upon treatment of 7g with 1.1 equivalents of
12b-i and 12k were assigned by analogy. It is interesting that an mCPBA in CH2Cl2 at room temperature for 18 h, compound 13
1
2
3
4
5
6
7
8
intermolecular (sp2)CH···FC interaction is observed in the
was obtained as a mixture of two diastereoisomers, both of
which possess high enantiomeric purity (99% ee), in 2/1 dr and
a combined yield of 70%.
X-ray crystal structure of 12a. The distance of the H···F
interaction is 2.46 Å, which is within the sum of the van der
Waals radii (ca. 2.55 Å; for details, see supporting information).
The stereocontrol mode of the present diastereoselective
difluoromethylation of ketones can be rationalized by
considering different boat- or chair-like cyclic six-membered
transition states such as A, B, and C (Figure 1). Due to the
flagpole interaction between Ar group and the oxygen atom of
sulfoximine,17 transition state B is disfavored. Furthermore, the
chair-like chelated transition state C, which leads to the
experimentally observed major diastereoisomer 12a, is
energetically less favorable because of the severe ArPh steric
hindrance (see Figure 1). Our proposed transition state A is
similar to that proposed by Pyne and co-workers regarding the
9
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12
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45
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47
48
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52
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60
Scheme 4. Synthesis of Chiral Difluoromethyl Alcohols via
Reductive Desulfoximination of 12a
2 O
NH
2 OH
R
HO
R1
R
Mg, NaOAc/HOAc/H2O
DMF, rt, 12 h
S
R1
CF2H
Ph
F
F
7
12
OH
Me
OH
OH
Me
Me
MeO
CF2H
CF2H
CF2H
F
7ab 77%
7b 68%
OH
7c 90%
reactions
of
lithiated
(S)-N-tert-
OH
butyl-diphenylsilyl-S-methyl-S-phenylsulfoximine
with
H
Me
OH
ketones.17 This chelated transition-state model is supported by
our experimental result that the use of the coordinating solvent
HMPA, which prevents the complexation of the sulfoximine
oxygen atom with the metal ion (i.e., K+), resulted in a
significantly decreased diastereoselectivity (Table 1, entry 5).
CF2H
CF2H
CF2H
O
Br
7d 83%
7e 84%
7fb 68%
a Typical procedure: Mg (180 mg, 7.5 mmol) was added into the solution of
12 (0.5 mmol) in NaOAc/AcOH/H2O (8 M of [ AcO ], 3.6 mL) and DMF (5 mL)
at room temperature in several portions and stirred overnight. b >99% ee.
Figure 1. Proposed Transition States for Diastereoselective
Difluoromethylation
Scheme 5. Synthesis of Difluorinated Analogs of Natural
Products 7g and 13
The products 12 could be readily converted to
enantiomerically enriched difluoromethyl alcohols 7 under the
reductive desulfoximination conditions using Mg/HOAc/
NaOAc.18 The results are summarized in Scheme 4. These
desulfoximination reactions proved to be efficient, and
difluoromethyl alcohols 7 were obtained in good yields. The
high optical purities of 7a and 7f (>99% ee) were determined by
chiral HPLC, which indicates that the above procedures are
reliable for the preparation of enantiomerically enriched
difluoromethyl alcohols. It is worthy to note that the alcohol 7f
has been described as a key intermediate in the synthesis of
1-((S)-3-(((S)-1-(4'-((S)-2,2-difluoro-1-hydroxyethyl)-[1,1'-biph
enyl]-4-yl)-2,2,2-trifluoroethyl)amino)-5-fluoro-5-methyl-2-oxo
hexyl)cyclopropanecarbonitrile, an orally bioavailable cathepsin
K inhibitor.19
In conclusion, an unprecedented and diastereoselective
nucleophilic difluoromethylation of aryl ketones has been
achieved by tuning the reactivity of difluoromethyl
sulfoximines
from
electrophilic
to
nucleophilic
Given the fact that the incorporation of fluorine into a
bioactive molecule can often impart highly interesting
biological properties, we decided to use the above
stereoselective difluoromethylation method to carry out the first
synthesis of two enantiomerically enriched difluorinated
analogues of natural products, namely difluorinated gossonorol
difluoromethylating agents. The nature of the N-substituent was
found to be crucial for the current reaction. The reaction was
shown to be general and a variety of structurally diverse ketones
were successfully difluoromethylated to give the corresponding
enantiomerically enriched difluoromethyl tertiary alcohols in
good yields and with good diastereoselectivity. The strategy
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Page 4 of 5
(6) For reviews, see: (a) Hu, J. J. Fluorine Chem. 2009, 130, 1130. (b)
was also amenable to the preparation of enantiomerically
enriched difluoromethyl secondary alcohols. The applications of
the reaction and its products illustrate the synthetic potential of
the new procedure. It should be pointed out that fluorinated
β-hydroxy sulfoximines 7 are promising candidates for chiral
ligands in many applications, in light of the known successful
applications of non-fluorinated β-hydroxy sulfoximines as
chiral ligands in organic synthesis.21 Further study in this
direction is currently under way in our laboratory.
Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465.
(7) Ni, C.; Wang, F.; Hu, J. Beilstein J. Org. Chem. 2008, 4, 21.
(8) Zhu, L.; Li, Y.; Ni, C.; Hu, J.; Beier, P.; Wang, Y.; Prakash, G. K.
S.; Olah, G. A. J. Fluorine Chem. 2007, 128, 1241.
1
2
3
4
5
6
7
8
(9)
There are a few reactions reported for the synthesis of
enantiomerically enriched difluoromethyl tertiary alcohols using
difluoromethyl ketones as substrates, but the substrate scopes were
not tested, probably due to the difficulty to obtain a variety of
difluoromethyl ketones. See: (a) Bandini, M.; Sinisi, R.;
Umani-Ronchi, A. Chem. Commun. 2008, 4360. (b) Nie, J.; Zhang,
G-W.; Wang, L.; Fu, A.; Zheng, Y. Ma, J-A. Chem. Commun.
2009, 2356.
9
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Supporting Information. Experimental procedures and
characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) For reviews, see: (a) Zhang, W.; Ni, C.; Hu, J. Top. Curr. Chem.
2012, 308, 25. (b) Ni, C.; Hu, J. Synlett, 2011, 770.
(11) Shen, X.; Zhang, W.; Zhang, L.; Luo, T.; Wan, X.; Gu, Y.; Hu, J.
Angew. Chem., Int. Ed. 2012, 51, 6966.
(12) (a) For the unsuccessful addition of 1 to benzaldehyde, see Zhang,
W. Ph.D. Dissertation, Shanghai Institute of Organic Chemistry
(China), 2010. (b) For the unsuccessful addition of 1 to
acetophenone, see supporting information. (c) Zhang, W.; Wang,
F.; Hu, J. Org. Lett. 2009, 11, 2109.
(13) Many fluorinated sulfoximines and fluorinated sulfoximiniun salts
have been reported as electrophilic fluoroalkylating agents. See: (a)
Mace, Y.; Magnier, E. Eur. J. Org. Chem. 2012, 2479. (b)
Nomura, Y.; Tokunaga, E.; Shibata, N. Angew. Chem., Int. Ed.
2011, 50, 1885. (c) Prakash, G. K. S.; Zhang, Z.; Wang, F.; Ni, C.;
Olah, G. A. J. Fluorine Chem. 2011, 132, 792. (d) Urban, C.;
Cadoret, F.; Blazejewski, J.-C.; Magnier, E. Eur. J. Org. Chem.
2011, 4862–4867. (e) Noritake, S.; Shibata, N.; Nakamura, S.;
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(14) Kahraman, M.; Sinishtaj, S.; Dolan, P. M.; Kensler, T. W.; Peleg,
S.; Saha, U.; Chuang, S. S.; Bernstein, G.; Korczak, B.; Posner, G.
H. J. Med. Chem. 2004, 47, 6854.
(15) For the effect of different bases on the nucleophilic
difluoromethylation with difluoromethyl phenyl sulfone, see: Liu,
J.; Hu, J. Chem. Eur. J. 2010, 16, 11443.
AUTHOR INFORMATION
Corresponding Author
jinbohu@sioc.ac.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Support of our work by the National Basic Research Program of
China (2012CB215500 and 2012CB821600), the National Natural
Science Foundation of China (20825209 and 20832008), the
Chinese Academy of Sciences, and the Syngenta PhD Studentship
(to X.S.) is gratefully acknowledged. We thank Dr. John Clough of
Syngenta at Jealott’s Hill International Research Centre for
proofreading of the manuscript.
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