A novel DNA-catalyzed aldol reaction

Article abstract of DOI:10.1055/s-2008-1078058

A novel DNA-catalyzed aldol reaction in water has been developed. This approach will be helpful in learning the role of DNA as a catalyst in the early stage during the development of life on earth. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078058

LETTER
2491
A Novel DNA-Catalyzed Aldol Reaction
a
a
a
b
D
G
NA-Catalyzed
A
a
ldol Reactio
o
n
jun Sun, Jinmin Fan, Zhiyong Wang,* Yingfu Li*
a
Hefei National Laboratory for Physical Science at Microscale, Joint-Lab of Green Synthetic Chemistry and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui 230026, P. R. of China
Fax +86(551)3603185; E-mail: zwang3@ustc.edu.cn
Department of Biochemistry and Biomedical Science and Department of Chemistry, McMaster University, Hamilton, ON L8N3Z5,
Canada
b
Received 22 April 2008
was low, the result was very interesting that it intrigued us
to explore the reaction further.
Abstract: A novel DNA-catalyzed aldol reaction in water has been
developed. This approach will be helpful in learning the role of
DNA as a catalyst in the early stage during the development of life In order to promote the reaction, we investigated the ef-
on earth.
fects of reaction temperature, solvent, pH value, and DNA
Keywords: DNA, aldol reaction, catalyst, aqueous buffer
loading on the reaction (Table 1). When the reaction tem-
perature was raised from 16 °C to 40 °C, the yield was im-
proved from 9% to 25% (Table 1, entry 2). Then we
focused on the optimization of the amount of herring
sperm DNA. It was found that the yield could be im-
proved to 80% in the presence of 20 mg of herring sperm
DNA in 2.5 mL of reaction solution. Beyond 20 mg, the
increase of herring sperm DNA had little influence on the
yield of aldol product (Table 1, entry 7). Therefore 20 mg
of herring sperm DNA in 2.5 mL of reaction solution was
the best catalyst loading. In addition, in order to rule out
the possible influence from the impurities present in natu-
ral DNA, a small synthetic dsDNA [the self-complemen-
With its characteristic right-handed helix structure and
well-defined geometry, DNA has been employed in or-
ganic reactions by an ever-increasing number of chem-
1
ists. Recently, DNA-templated organic synthesis (DTS)
as a new concept was widely investigated. In these studies
two substrate molecules are linked to two separate and
complementary DNA strands, respectively, and are al-
2
lowed to undergo chemical transformations. With DTS,
the tested reaction could work smoothly without any other
catalyst or additive. Hence DTS is of great significance
for researchers to explore novel chemical transforma-
tary 16-mer (TCAG) (CTGA) ] was employed to catalyze
2
2
3
the aldol reaction of p-nitrobenzaldehyde with acetone. A
similar yield was obtained (Table 1, entry 16). Next, dif-
ferent solvents were employed in this reaction (Table 1,
entries 8–12). As shown in Table 1, when acetone was
employed as both the reaction substrate and the solvent,
the reaction gave the aldol product with the highest yield.
Besides acetone, the order of the performance of other sol-
vents on the reaction was presented as below: DMSO >
MeCN > DMF > THF > 1,4-dioxane. Therefore DMSO
was chosen as the reaction solvent when other aliphatic
ketones were employed as the reaction substrates. In order
to confirm the indispensably catalytic effect of DNA in
the aldol reaction, the reaction was also conducted in the
absence of DNA and, as expected, no desired products
were observed. In addition, the pH value of reaction mix-
ture was recorded. The pH value of the pure DNA solution
is 6.82. After the addition of the reactants, the reaction
mixture was 6.75 before the reaction. After the reaction of
this mixture, the pH value was unchanged and kept in
tions. In addition, because of the inherent chirality of
DNA, DNA-based asymmetric catalysis was also intro-
4
duced into organic reactions. Despite these reports, ex-
ploiting unmodified double-stranded DNA directly as a
catalyst for organic reactions has not been reported yet ex-
5
cept for a recent DNA-catalyzed Henry reaction.
Aldol reaction is an important carbon–carbon bond-for-
6
mation reaction widely used in organic synthesis. Usual-
ly, aldol reaction is performed under acidic or basic
environment and can be performed in organic solvents
7
and water. Recently, this reaction was found to be cata-
8
lyzed by small organic molecules. In particular, recent re-
ports demonstrated that proline-modified DNA could also
9
catalyze the aldol reaction, and a ribozyme-catalyzed al-
1
0
dol reaction was also reported. Herein we describe the
direct use of DNA as the catalyst to carry out aldol reac-
tion in the presence of water.
We initially tried the reaction of p-nitrobenzaldehyde and
acetone in the presence of herring sperm DNA at pH 6.50
in aqueous MOPS (3-(N-morpholino)propanesulfonic
acid) buffer at 16 °C. The reaction was monitored by TLC
and GC-MS. After 3.5 days, the aldol product was ob-
tained in 9% yield (Table 1, entry 1). Although the yield
6
.75. In terms of the experimental results above, the opti-
mal reaction conditions were established as follows: p-ni-
trobenzaldehyde (0.5 mmol), herring sperm DNA (20 mg)
in 1 mL of MOPS, at the temperature of 40 °C.
After optimization of reaction conditions, the scope of the
reaction substrates was explored. First, aromatic alde-
hydes with different substituents were tested in this aldol
reaction in the presence of herring sperm DNA at 40 °C.
The electronic effect of the substituents of aromatic alde-
SYNLETT 2008, No. 16, pp 2491–2494
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.09.2008
DOI: 10.1055/s-2008-1078058; Art ID: W06608ST
©
Georg Thieme Verlag Stuttgart · New York

2
492
G. Sun et al.
LETTER
Table 1 Aldol Reaction of p-Nitrobenzaldehyde with Acetone12 in
the Presence of Herring Sperm DNA
Table 2 Aldol Reaction of Different Electron-Poor Aromatic Alde-
a
hydes with Acetonea
OH
O
OH
O
O
O
DNA
H2O
DNA
H2O
O
O
+
R
+
R
O2N
O2N
1
2
1
2
pHb
Yield (%)c
Entry
R
Time (d)
Product
2a
Yield (%)b
Entry DNA
mg)
Co-solvent
Temp
(
(°C)
16
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
1
2
3
4
5
6
7
8
H
4
52
60
66
70
80
78
75
78
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
5
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
DMSO
6.50
6.50
6.50
6.50
6.50
6.50
6.50
6.50
6.50
6.50
6.50
6.50
5.50
7.50
8.40
6.50
9
4-F
4-Cl
4-Br
4
2b
5
25
30
44
60
80
82
65
41
54
25
38
70
33
18
82
3.5
3.5
3.5
3.5
3.5
8
2c
7.5
10
15
20
25
20
20
20
20
20
20
20
2d
4-NO2
2-NO2
4-CF3
2e
2f
2g
2h
N
O
DMF
a
The reactions were carried out at 40 °C with 1 (0.5 mmol), 1.5 mL
of 2, and 1 mL of aq MOPS buffer (c 30 mM).
1
1
1
1
1
1
MeCN
b
Isolated yield based on the amount of 1.
1,4-Dioxane
THF
ing products 2b,c and 2d were provided in good yields
(Table 2, entries 2–4). Benzaldehyde, which is neither an
electron-rich nor an electron-poor aromatic aldehyde, re-
acted with acetone smoothly to generate the desired prod-
uct 2a in a moderate yield (Table 2, entry 1).
Acetone
Acetone
Acetone
Acetone
20
–d
After examining the various aromatic aldehyde substrates,
we became interested in the scope of the aliphatic ketones
in this aldol reaction (Table 3). As shown in Table 3, var-
ious ketones were examined in this aldol reaction. Straight
chain ketones such as butan-2-one and 1-hydroxypropan-
2-one can react with 4-nitrobenzaldehyde to afford the
corresponding products in moderate yields and syn-dia-
stereoselectivity (Table 3, entries 1 and 2). It was noted
that hydroxyl group did not influence this reaction. When
the cyclic ketones were employed as the reaction sub-
strates, the reaction could be carried out smoothly to give
the the corresponding products. Compared to the aliphatic
ketones, cyclic ketones afforded products with lower
yields (Table 3, entries 3–5). The experimental results
showed that the increase in steric effect in the ketone sub-
strates had a negative influence on this aldol addition.
Therefore a higher reaction temperature was required for
this aldol addition reaction involving the ketones with
steric hindrance.
1
a
The reactions were carried out with 1 (0.5 mmol), 2 (1 mmol),
.5 mL of solvent, and 1 mL of aq buffer (c 30 mM).
Aqueous buffer: MOPS, pH = 6.50, 7.50; MES, pH = 5.50; Tris,
1
b
pH = 8.40.
c
Isolated yield based on the amount of 1.
d
DNA = synthetic duplex d(TCAG) (CTGA) (2.8 mM), p-nitrobenz-
aldehyde (23.2 mM), acetone (0.15 mL), NaCl (150 mM), MgCl (50
2
2
2
mM).
hydes has a great influence on this DNA-catalyzed Aldol
reaction. When electron-rich aromatic aldehydes such as
-methoxybenzaldehyde and 4-(dimethylamino)benzal-
dehyde were used as the reaction substrates, the aldol
products could not be obtained. On the other hand, elec-
tron-poor aromatic aldehydes favored the aldol reaction
and reacted smoothly with acetone. The reactions of p-ni-
trobenzaldehyde and o-nitrobenzaldehyde gave the aldol
products 2e and 2f, respectively, with the yields of 80%
4
and 78% (Table 2, entries 5 and 6). A strong electron- In summary, we have developed a novel DNA-catalyzed
withdrawing trifluoromethyl group on the aromatic ring aldol reaction under mild reaction conditions. The tested
also favored the aldol reaction, providing the correspond- double-stranded DNA was obtained from natural sources.
ing product with a good yield (Table 2, entry 7). Interest- As far as we know, this is the first report about using DNA
ingly, reaction of picolinaldehyde with acetone could also directly as an organic reaction catalyst, and we believe
give the corresponding product in 78% yield. As for aro- that this approach will be helpful in learning the role of
matic aldehydes bearing halogen groups, the correspond-
Synlett 2008, No. 16, 2491–2494 © Thieme Stuttgart · New York

LETTER
DNA-Catalyzed Aldol Reaction
2493
Table 3a Aldol Reaction of p-Nitrobenzaldehyde with Aliphatic
(2) (a) Kanan, M. W.; Rozenman, M. M.; Sakurai, K.; Snyder,
T. M.; Liu, D. R. Nature (London) 2004, 431, 545. (b) Li,
X. Y.; Liu, D. R. Angew. Chem. Int. Ed. 2004, 43, 4848; and
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G. F. Angew. Chem. Int. Ed. 2005, 44, 7580.
Ketones
OH
O
O
DNA
H2O
O +
O2N
O2N
1
2
Entry
2
Time (d) Product13
syn/antib
Yield
%)c
(
3) (a) Miller, S. J. Nat. Biotechnol. 2004, 22, 1378.
b) Rozenman, M. M.; Liu, D. R. ChemBioChem 2006, 7,
253. (c) Silverman, S. K. Org. Biomol. Chem. 2004, 2,
(
(
O
1
2
6
3a
3b
67:33
62:38
48
60
2701. (d) Gartner, Z. J.; Liu, D. R. J. Am. Chem. Soc. 2001,
123, 6961.
O
3.5
(
4) (a) Roelfes, G.; Feringa, B. L. Angew. Chem. Int. Ed. 2005,
44, 3230. (b) Coquire, D.; Feringa, B. L.; Roelfes, G.
Angew. Chem. Int. Ed. 2007, 46, 9308. (c) Roelfes, G.;
Boersma, A. J.; Feringa, B. L. Chem. Commun. 2006, 635.
HO
3
4
4
4
3c
60:40
50:50
51
36
O
(
2
d) Boersma, A. J.; Feringa, B. L.; Roelfes, G. Org. Lett.
007, 9, 3647. (e) Shibata, N.; Yasui, H.; Nakamura, S.;
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Chem. Commun. 2008, 3792.
6) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH:
Weinheim, 2004.
O
3d
(
(
5
O
O
4
3e
55:45
40
(7) (a) Zotova, N.; Franzke, A.; Armstrong, A.; Blackmond,
D. G. J. Am. Chem. Soc. 2007, 129, 15100. (b) Dipeptide-
catalyzed Aldol reactions can be carried out in water–
organic solvent mixtures; see: Dziedzic, P.; Zou, W.; Háfren,
J.; Córdova, A. Org. Biomol. Chem. 2006, 4, 38. (c) Font,
D.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2006, 8, 4653.
a
The reactions were carried out at 60 °C with 1 (0.5 mmol), 2 (1.0
mmol), 1.5 mL of DMSO, and 1 mL of aq MOPS buffer (c 30 mM).
(d) Fernandez-Lopez, R.; Kofoed, J.; Machuqueiro, M.;
b
c
1
Darbre, T. Eur. J. Org. Chem. 2005, 5268. (e) Chimni,
The ratio was determined by H NMR.
Isolated yield based on the amount of 1.
S. S.; Mahajan, D. Tetrahedron 2005, 61, 5019.
8) (a) List, B.; Lerner, R. A.; Barba, C. F. III J. Am. Chem. Soc.
(
2
000, 122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.;
DNA as a catalyst in an early stage during the develop-
ment of life on earth.
Barbas, C. F. III J. Am. Chem. Soc. 2001, 123, 5260.
1
1
(
(
c) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386.
d) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (e) Bui, T.;
Barbas, C. F. III Tetrahedron Lett. 2000, 41, 6951.
f) Còrdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.;
Barbas, C. F. III J. Am. Chem. Soc. 2002, 124, 1842.
g) Kumaragurubaran N., Juhl K., Zhuang W., Bøgevig A.,
Jørgensen K. A.; J. Am. Chem. Soc.; 2002, 124: 6254.
(
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(
(
(
h) List B.; J. Am. Chem. Soc.; 2002, 124: 5656.
i) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang,
Acknowledgment
The authors are grateful to National Natural Science Foundation of
China (20628202).
W.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2002, 41, 1790.
(j) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2
002, 124, 6798. (k) Còrdova, A.; Watanabe, S.; Tanaka, F.;
Notz, W.; Barbas, C. F. I. I. I. J. Am. Chem. Soc. 2002, 124,
866. (l) For reviews, see: Chen, J.-R.; Li, X.-Y.; Xing,
References and Notes
1
X.-N.; Xiao, W.-J. J. Org. Chem. 2006, 71, 8198. (m) List,
B. Tetrahedron 2002, 58, 5573. (n) List, B. Synlett 2001,
(
1) (a) Lu, Y.; Liu, J. W. Curr. Opin. Biotechnol. 2006, 17, 580.
b) Roelfes, G. Mol. BioSyst. 2007, 3, 126. (c) Scherer,
(
1
675.
9) (a) Tang, Z.; Marx, A. Angew. Chem. Int. Ed. 2007, 46,
297. (b) Tang, Z.; Goncalves, D. P. N.; Wieland, M.; Marx,
A.; Hartig, J. S. ChemBioChem 2008, 9, 1061.
L. J.; Rossi, J. J. Nat. Biotechnol. 2003, 21, 1457. (d) Liu,
J. W.; Lu, Y. J. Fluoresc. 2004, 14, 343. (e) Lu, Y.; Liu, J.
W. Acc. Chem. Res. 2007, 40, 315. (f) May, J. P.; Ting, R.;
Lermer, L.; Thomas, J. M.; Roupioz, Y.; Perrin, D. M. J. Am.
Chem. Soc. 2004, 126, 4145. (g) Isaka, Y. Curr. Opin. Mol.
Ther. 2007, 9, 132.
(
7
(
(
(
10) Fusz, S.; Eisenführ, A.; Srivatsan, S. G.; Heckel, A.;
Famulok, M. Chem. Biol. 2005, 12, 941.
11) (a) Gilbert, W. Nature (London) 1986, 319, 618. (b) Joyce,
G. F. Nature (London) 2002, 418, 214.
12) Typical Procedure for the Aldol Reaction of
p-Nitrobenzaldehyde with Acetone
To an aq MOPS buffer solution (30 mM, pH = 6.50) was
added DNA (herring sperm or salmon testes DNA 20 mg,
purchased from Sigma). After 10 min, p-nitrobenzaldehyde
(0.5 mmol) in acetone (1.5 mL) was added. After the mixture
Synlett 2008, No. 16, 2491–2494 © Thieme Stuttgart · New York

2
494
G. Sun et al.
LETTER
was heated at 40 °C for 3.5 d, the mixture was extracted three
7.48 (d, J = 7.8 Hz, 1 H), 5.22 (s, 1 H), 2.85 (d, J = 6.0 Hz,
times with CHCl . The combined organic extract was dried
2 H), 2.21 (s, 3 H).
3
with anhydrous Na SO and evaporated under reduced
pressure; the residue was then purified by column
4-Hydroxy-4-(pyridin-2-yl)butan-2-one (2h)
2
4
1
H NMR (300 MHz, CDCl ): d = 8.53 (d, J = 3.9 Hz, 1 H),
3
chromatography over SiO to afford the corresponding aldol
7.70 (t, J = 7.5 Hz, 1 H), 7.46 (d, J = 7.5 Hz, 1 H), 7.20 (t,
J = 5.1 Hz, 1 H), 5.20 (dd, J = 3.3 Hz, J = 8.1 Hz, 1 H),
2
product with high purity.
1
2
(
13) Spectroscopic Data for Products
All products are known compounds; see refs. 7d,e and 8a,l.
-Hydroxy-4-phenylbutan-2-one (2a)
4.25 (s, 1 H), 3.05 (dd, J = 3.3 Hz, J = 16.8 Hz, 1 H), 2.91
1 2
(dd, J = 8.4 Hz, J = 17.1 Hz, 1 H), 2.22 (s, 3 H).
1
2
4
2-[Hydroxy(4-nitrophenyl)methyl]cyclopentanone (3a)
1
1
H NMR (300 MHz, CDCl ): d = 7.36–7.27 (m, 4 H), 5.15
Mixture of syn- and anti-product: H NMR (400 MHz,
3
(
(
dd, J = 3.6 Hz, J = 8.7 Hz, 1 H), 2.88–2.83 (m, 3 H), 2.19
CDCl ): d = 8.23–8.19 (m, 4 H), 7.55–7.51 (m, 4 H), 5.42 (d,
1
2
3
s, 3 H).
J = 3.0 Hz, 1 H), 4.85 (d, J = 9.1 Hz, 1 H), 2.48–1.98 (m, 6
H), 1.75–1.55 (m, 2 H).
4
-(4-Fluorophenyl)-4-hydroxybutan-2-one (2b)
1
H NMR (300 MHz, CDCl ): d = 8.04 (d, J = 8.1 Hz, 2 H),
3,4-Dihydroxy-4-(4-nitrophenyl)butan-2-one (3b)
3
1
7.03 (t, J = 8.7 Hz, 2 H), 5.13 (t, J = 3.6 Hz, 1 H), 2.83 (d,
Mixture of syn- and anti-product: H NMR (300 MHz,
J = 7.5 Hz, 2 H), 2.20 (s, 3 H).
CDCl ): d = 8.25 (d, J = 8.4 Hz, 4 H), 7.61 (d, J = 8.4 Hz, 4
3
4
-(4-Chlorophenyl)-4-hydroxybutan-2-one (2c)
H NMR (300 MHz, CDCl ): d = 7.32 (t, J = 4.2 Hz, 2 H),
H), 5.22 (d, J = 1.3 Hz, 1 H), 5.09 (d, J = 4.5 Hz, 1 H), 4.47
(d, J = 4.5 Hz, 1 H), 4.41 (d, J = 2.1 Hz, 1 H), 3.72 (s, 2 H),
2.36 (s, 3 H), 2.03 (s, 3 H).
1
3
7.46 (d, J = 8.1 Hz, 2 H), 5.14 (t, J = 4.8 Hz, 1 H), 3.38 (d,
J = 1.5 Hz, 1 H), 2.85 - 2.81 (m, 2 H), 2.19 (s, 3 H).
4-Hydroxy-3-methyl-4-(4-nitrophenyl)butan-2-one (3c)
Mixture of syn- and anti-product: H NMR (300 MHz,
1
4
-(4-Bromophenyl)-4-hydroxybutan-2-one (2d)
1
H NMR (300 MHz, CDCl ): d = 7.47 (d, J = 8.4 Hz, 2 H),
CDCl ): d = 8.21 (d, J = 8.4 Hz, 4 H), 7.52 (d, J = 7.5 Hz, 4
3
3
7.23 (d, J = 8.1 Hz, 2 H), 5.10 (d, J = 3.6 Hz, 1 H), 3.41 (s,
H), 5.28 (s, 1 H), 4.86 (d, J = 1.4 Hz, 1 H), 3.42 (s, 1 H), 2.23
(d, J = 9 Hz, 3 H), 1.11 (s, 3 H), 1.06 (s, 3 H).
1
H), 2.83–2.75 (m, 2 H), 2.19 (s, 3 H).
4
-Hydroxy-4-(4-nitrophenyl)butan-2-one (2e)
2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (3d)
Mixture of syn- and anti-product: H NMR (300 MHz,
1
1
H NMR (300 MHz, CDCl ): d = 8.21 (d, J = 4.4 Hz, 2 H),
3
7.54 (d, J = 8.1 Hz, 2 H), 5.27 (dd, J = 4.8 Hz, J = 7.5 Hz,
CDCl ): d = 8.21 (d, J = 7.5 Hz, 4 H), 7.50 (dd, J = 6.0 Hz,
1
2
3
1
1
H), 3.57 (s, 1 H), 2.87–2.84 (m, 2 H), 2.23 (s, 3 H).
J2 = 8.1 Hz, 4 H), 5.49 (s, 1 H), 4.90 (d, J = 8.4 Hz, 1 H),
4.05 (s, 1 H), 3.15 (s, 1 H), 2.64–2.39 (m, 4 H), 2.36–2.09
(m, 2 H), 1.84–1.40 (m, 8 H).
4
-Hydroxy-4-(2-nitrophenyl)butan-2-one (2f)
1
H NMR (300 MHz, CDCl ): d = 7.96 (d, J = 8.1 Hz, 1 H),
3
7.90 (d, J = 7.8 Hz, 1 H), 7.67 (t, J = 7.5 Hz, 1 H), 7.44 (t,
Tetrahydro-3-[hydroxy(4-nitrophenyl)methyl]pyran-4-
one (3e)
J = 8.1 Hz, 1 H), 5.68 (d, J = 9.3 Hz, 1 H), 3.65 (s, 1 H), 3.14
1
(
dd, J = 1.5 Hz, J = 17.7 Hz,1 H), 2.72 (dd, J = 9.3 Hz,
Mixture of syn- and anti-product: H NMR (300 MHz,
1
2
1
J2 = 17.7 Hz, 1 H), 2.24 (s, 3 H).
-[4-(Trifluoromethyl)phenyl]-4-hydroxybutan-2-one
CDCl ): d = 8.22 (dd, J = 2.1 Hz, J = 8.7 Hz, 4 H), 7.52 (d,
3
1
2
4
J = 8.7 Hz, 4 H), 4.99 (d, J = 7.5 Hz, 1 H), 4.24–4.21 (m, 2
H), 3.87–3.73 (m, 8 H), 3.49–3.46 (m, 1 H), 2.97–2.91 (m, 3
H), 2.57–2.55 (m, 3 H), 2.51–2.45 (m, 3 H).
(
2g)
1
H NMR (300 MHz, CDCl ): d = 7.61 (d, J = 7.8 Hz, 2 H),
3
Synlett 2008, No. 16, 2491–2494 © Thieme Stuttgart · New York