First syntheses of lorneic acids A and B with potential PDE5 inhibition activity

Article abstract of DOI:10.1055/s-0031-1290352

Two natural products with potential PDE5 inhibition activity, lorneic acids A and B, have been synthesized for the first time in high yield using a chiral amide stereocontrolled addition of aryl lithium to aldehyde as the key step, and the configuration of the chiral benzylic alcohol in lorneic acid B was determined to be S. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290352

LETTER
607
First Syntheses of Lorneic Acids A and B with Potential PDE5
Inhibition Activity
F
irstSynthese
s
of
i
Lorneic
a
Acids Aa
n
nd
B
g Ma,a Yuting Song,a Hao Liu,a Ruijiao Chen,a Xiaochuan Chen*a,b
a
Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, P. R. of China
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(28)85413712; E-mail: chenxc@scu.edu.cn
Received 23 November 2011
mined. Compounds 1 and 2 showed significant selective
inhibition activity against phosphodiesterase (PDE), par-
ticularly PDE5. PDE5 inhibitors are of pharmacological
importance in treatment of some diseases such as erectile
dysfunctions and pulmonary hypertension.2 Structure of
lorneic acids is relatively rare, and among the known nat-
ural products only lorneamides A (3) and B (4)3 have the
common framework to 1 and 2. In addition, an evernino-
micin antibiotic from Micromonospora carbonaceae fer-
mentation, Sch 49088, contained a very similar trialkyl-
substituted aromatic acid subunit to lorneic acid B.4 Un-
usual structure, important bioactivity and natural scarcity
make lorneic acids a class of significant targets, yet the
synthesis of the compounds has not been reported up to
now. Herein we described the first synthesis of 1 and 2
from easily available 4-methylbenzoic acid (5).
Abstract: Two natural products with potential PDE5 inhibition ac-
tivity, lorneic acids A and B, have been synthesized for the first time
in high yield using a chiral amide stereocontrolled addition of aryl
lithium to aldehyde as the key step, and the configuration of the
chiral benzylic alcohol in lorneic acid B was determined to be S.
Key words: lorneic acid A/B, PDE5 inhibitor, asymmetric synthe-
sis, chiral auxiliary, ortho-lithiation
Lorneic acids A (1) and B (2) were found in 2009 from the
culture supernatant of an actinomyces strain (NPS554)
isolated from a marine sediment sample in Miyazaki Har-
bor, Japan.1 The two compounds possess same trialkyl-
substituted benzene skeleton just with different functional
group in the side chain (Figure 1). Instead of conjugated
double bond in 1, a chiral benzylic hydroxyl group exists
in (–)-2, which displays optical activity. However, the ab-
solute configuration of the chiral center is still not deter-
CHO OR
*
1 and 2
6
O
O
R2
HO
HO
R1
R3
R
R2
R1
R
R3
*
OH
*
*
O
N
COOH
N
O
OH
*
lorneic acid A (1)
8
5
lorneic acid B (2)
+
O
O
7
O
H2N
H2N
Scheme 1 Synthetic strategy of 1 and 2
OH
*
O
As shown in Scheme 1, aldehyde 6 which is derived from
7 by simple transformation is designed as the intermediate
for 1 and 2. The optically active benzyl alcohol 7 is ex-
pected to be formed via ortho-lithiation of chiral benz-
amide 8 followed by stereoselective addition to hexanal.
Chiral amide 8 could be obtained from some commercial
chiral amines. The secondary amide5 or tertiary amide6
functional groups on aryl ring have widely been reported
as efficient directors of ortho lithiation, and the resulting
aryl lithium could participate in diversified reactions.5–7
Nevertheless, in most cases achiral amides were em-
lorneamide A (3)
lorneamide B (4)
Figure 1
SYNLETT 2012, 23, 607–610
Advanced online publication: 13.02.2012
DOI: 10.1055/s-0031-1290352; Art ID: W70811ST
x
x
.
x
x
.
2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

608
X. Ma et al.
LETTER
ployed. Only very limited investigation on asymmetric in-
duction of chiral amides in the reactions of the aryl lithium
was carried out.8 We wish to expand this type of asymmet-
ric reactions and apply it to the synthesis of the natural
products with chiral benzyl alcohol such as 1 and 2.
O
MeO
Ph
O
O
*
HN
*
R
R
c
a
10
n-C5H11
15a (R = α-C5H11
)
Thus, 5 was converted into the corresponding acyl chlo-
ride with SOCl2 and coupled with L-phenylalaninol to
provide the desired peptide 9 in high yield (Scheme 2).
Peptide 9 was transformed to secondary amide 10 and ter-
tiary amide 11/12 by different modification. Their reac-
tions with hexanal were investigated after treatment of the
amides with alkyl lithium. Amides 10 and 11 could not be
lithiated by n-BuLi, whereas the amide bond of 12 was
cleaved to result in 1-para-tolylpentan-1-one under same
conditions. When the stronger base t-BuLi was employed,
the reactions of 11 or 12 were quite complex and no de-
sired product was detected. The lithiation of 10 with t-
BuLi did not work until the temperature was raised to 0 °C
from –78 °C. After optimization, treatment of 10 with t-
BuLi–TMEDA at 0 °C yielded the ortho-lithiated species
which attacked hexanal to provide the required adducts
13a and 13b as two diastereoisomers in 76% total yield
(91% based on conversion). Upon treatment of the mix-
ture with Boc2O the resulting O-Boc derivatives 14a and
14b,9 which are easier to isolate on column chromatogra-
phy, were obtained separately in a ratio of 4.6:1. In 1,4-di-
oxane containing HCl, pure 14a and 14b were converted
into enantiomeric lactones 15a and 15b, respectively by
removal of the O-Boc group and subsequent cyclization in
one pot, and the excised chiral auxiliary 16 could be recy-
cled to prepare 10 (Scheme 3).
15b (R = β-C5H11
)
13a (R = α-OH) + 13b (R = β-OH)
b
14a (R = α-OBoc) + 14b (R = β-OBoc)
+
MeO
Ph
d
NH2
16
Scheme 3 Synthesis of the lactone 15. Reagents and conditions: (a)
t-BuLi, TMEDA, THF, –78 °C, then warm to 0 °C , hexanal, 76%; (b)
Boc2O, DMAP, MeCN, r.t., 80% (14a) and 17% (14b); (c) HCl,
dioxane, 100 °C, 90% of 15a from 14a and 86% of 15b from 14b; (d)
5, SOCl2, Et3N, CH2Cl2, r.t., 93%.
OTBS
OTBS
O
H
O
H
MeO
H
MeO
Ph
O
O
Ph
H
shielded
(upfield)
shielded
(upfield)
18
17
Figure 2
at d = 2.08 ppm in 17 and upfield side-chain Me signal at
d = 0.86 ppm in 18)10 indicated S configuration of 15a and
hence that of the major isomer 13a according to Mosher
model extended by Trost (Figure 2).11
To determine the absolute configuration of the new ben-
zylic chiral center, major isomer 15a from 13a was con-
verted into both (S)- and (R)-O-methylmendelate
derivatives 17 and 18 in a three-step sequence. The proton
shift differences between 17 and 18 (upfield ArMe signal
(S)-Phthalide 15a was then employed to explore the sub-
sequent synthesis (Scheme 4). Phthalide 15a was reduced
with DIBAL to afford two inseparable hemiacetal diaste-
reoisomers (1:1), along with trace amount of aldehyde.
The olefination of the hemiacetal mixture with the Wittig
reagent derived from (2-carboxyethyl)triphenylphospho-
nium bromide (19)12 would give the target molecule 2 di-
rectly. However, no desired product 2 was detected under
the attempted conditions varying bases (NaH, BuLi, t-
BuOK), solvents (DMSO, THF and their mixture) and
feeding sequences. So we had to seek an alternative strat-
egy to accomplish the synthesis. Gratifyingly, the hemiac-
etal mixture was treated with another stabilized ylide 20,
methyl (triphenylphosphoranylidene)acetate,13 to provide
E-a,b-unsaturated ester 21 exclusively in 95% yield,
which was transformed to MOM ether 22. Reduction of
conjugated ester 22 with DIBAL gave the required alco-
hol 23. Iodination of allyl alcohol 23 with I2 and PPh3 af-
forded the crude iodide14 (without purification), which
was converted immediately into allylic cyanide 24 in 74%
yield in two steps.15 Allylic cyanide 24 also was obtained
by treatment of the corresponding methanesulfonate from
23 with lowly toxic CuCN16 with a slight drop in the over-
all yield (63%). In aqueous KOH solution nitrile 24 was
MeO
Ph
O
HO
Ph
O
HN
HN
b
a
5
10
9
d
c
Ph
MeO
Ph
O
N
O
MeN
O
12
11
Scheme 2 Preparation of the chiral amides 10–12 from 5. Reagents
and conditions: (a) SOCl2, Et3N, CH2Cl2, then L-phenylalaninol, r.t.,
92%; (b) NaH (1.5 equiv), MeI (1.5 equiv), THF, r.t., 80% (92% ba-
sed on conversion); (c) NaH (3.0 equiv), MeI (3.0 equiv), THF, r.t.,
73%; (d) 2,2-dimethoxypropane, toluene, reflux, 81%.
Synlett 2012, 23, 607–610
© Thieme Stuttgart · New York

LETTER
First Syntheses of Lorneic Acids A and B
609
HO
CO2Me
O
OH
O
O
OR
d
e,f
OMOM
b
a
n-C5H11
n-C5H11
15a
21 (R = H)
22 (R = MOM)
23
c
NC
HO2C
HO2C
g
OMOM
h
OMOM
OH
25
24
(–)-2
HO2C
NC
HO
CO2Me
g
e, f
d
i
21
26
28
27
1
Scheme 4 Synthesis of 1 and (–)-2 from 15. Reagents and conditions: (a) DIBAL, toluene, –78 °C, 98%; (b) 20, toluene, reflux, 95%; (c)
MOMCl, DIPEA, CH2Cl2, r.t., 95%; (d) DIBAL, toluene, –78 °C , 97% of 23 from 22, 96% of 27 from 26; (e) I2, Ph3P, CH2Cl2; (f) NaCN,
MeCN, 74% of 24 from 23 and 65% of 28 from 27 over two steps; (g) KOH, EtOH–H2O, reflux, 90% of 25 from 24 and 72% of 1 from 28; (h)
HCl, t-BuOH, 40 °C, 91%; (i) TsOH, toluene, reflux, 96%.
smoothly hydrolyzed to carboxylic acid 25, which upon
removal of MOM ether afforded the target acid 2.17,18 The
optical rotation value of the synthetic 2 consistent with
that of the reported 2 means that natural (–)-lorneic acid B
has S configuration.
Acknowledgment
We thank the Sichuan University Analytical and Testing Center for
NMR determination and Prof. Xiaoming Feng group for optical ro-
tation tests. This work was supported by grants from the National
Natural Science Foundation of China (No. 20802045 and
21172153), the National Basic Research Program of China (973
Program, No. 2012CB833200), and the Foundation of the Educati-
on Ministry of China for Returnees.
For the synthesis of 1, the mixture of 13a and 13b was di-
rectly cyclized to furnish the mixed enantiomers 15a and
15b in 98% yield, which was converted into 21 and its
enantiomer following the above way. Elimination of the
benzylic alcohol mixture under acidic conditions gave the
desired trans-olefin 26 as single isomer. Consistent with
the route to 2, 26 was reduced to furnish the alcohol 27,
which was transformed to nitrile 28 via the allylic iodide
intermediate in two steps. Finally, hydrolysis of nitrile 28
yielded the target carboxylic acid 1.19
References and Notes
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A.; Okita, T.; Kawahara, H. J. Nat. Prod. 2009, 72, 2046.
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T. M.; Puar, M. S.; Jenkins, J. K.; Maloney, D.; Cordero, M.;
Pramanik, B. N.; Bartner, P.; Das, P. R.; McPhail, A. T.;
Girijavallabhan, V. M.; Ganguly, A. K. Tetrahedron Lett.
1998, 39, 8441.
(5) (a) Puterbaugh, W. H.; Hauser, C. R. J. Org. Chem. 1964,
29, 853. (b) Baldwin, J. E.; Bair, K. W.; Vaulx, R. L.;
Puterbaugh, W. H.; Hauser, C. R. J. Org. Chem. 1964, 29,
3514. (c) Marxer, A.; Rodriguez, H. R. J. Org. Chem. 1975,
40, 1427.
In summary, we have reported the first synthesis of the
natural products 1 and (–)-2 with rare trialkyl-substituted
benzene structure. The key benzylic alcohol was efficient-
ly constructed via stereoselective addition of aryl lithium
to hexanal under induction of chiral amide. The facile ap-
proach should be amenable to the synthesis of both S- and
R-series lorneic acids and their analogues to further SAR
studies. We are further seeking the chiral amides with bet-
ter asymmetric induction by tuning their groups, and their
application in the synthesis of more related natural prod-
ucts.
(6) (a) Beak, P.; Brown, R. A. J. Org. Chem. 1977, 42, 1823.
(b) Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 34.
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102, 1457. (d) Beak, P.; Tse, A.; Hawkins, J.; Chen, C.-W.;
Mills, S. Tetrahedron 1983, 39, 1983.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
© Thieme Stuttgart · New York
Synlett 2012, 23, 607–610

610
X. Ma et al.
LETTER
(7) (a) Poolsak, S.; Nopporn, T.; Somsak, R. Synthesis 2005,
2934. (b) Anstiss, M.; Clayden, J.; Grube, A.; Youssef, L. H.
Synlett 2002, 290. (c) Gonnot, V.; Antheaume, C.; Nicolas,
M.; Mioskowski, C.; Baati, R. Eur. J. Org. Chem. 2009,
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3841. (e) Shankaran, K.; Snieckus, V. J. Org. Chem. 1984,
49, 5022.
0.05 (s, 3 H). Compound 18: 1H NMR (400 MHz, CDCl3):
d = 7.43–7.48 (m, 2 H), 7.30–7.38 (m, 3 H), 7.22 (d, J = 7.7
Hz, 1 H), 7.08 (s, 1 H), 7.03 (d, J = 7.8 Hz, 1 H), 5.92 (dd,
J = 4.2, 9.3 Hz, 1 H), 4.90 (d, J = 12.4 Hz, 1 H), 4.75 (s, 1
H), 4.67 (d, J = 12.4 Hz, 1 H), 3.37 (s, 3 H), 2.29 (s, 3 H),
1.61–1.77 (m, 2 H), 1.01–1.08 (m, 6 H), 0.91 (s, 9 H), 0.78
(t, J = 6.5, 13.4 Hz, 3 H), 0.10 (s, 3 H), 0.06 (s, 3 H).
(11) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M. J. Org. Chem. 1986, 51, 2370.
(8) Matsui, S.; Uejima, A.; Suzuki, Y.; Tanaka, K. J. Chem.
Soc., Perkin Trans. 1 1993, 701.
(9) A solution of 10 (0.13 g, 0.45 mmol) in THF (6 mL) was
added to a stirred mixture of t-BuLi (0.65 mL, 1.03 mmol)
and TMEDA (0.15 mL, 0.99 mmol) in THF (2 mL) at –78
°C. The mixture was warmed to 0 °C and stirred for 5 min,
then cooled to –78 °C again. To the mixture a solution of
hexanal (0.12 mL, 0.99 mmol) in THF (1 mL) was added and
stirred at –78 °C for 30 min. Then the mixture was warmed
to r.t. and stirred overnight, quenched with sat. NH4Cl and
extracted with EtOAc. The organic layer was washed with
brine, dried (Na2SO4) and concentrated. The residue was
purified by column chromatography to afford a mixture of
13a and 13b (0.13g, 76%). The mixture of 13a and 13b (0.13
g, 0.34 mmol) was dissolved in MeCN (9 mL), then DMAP
(12 mg, 0.10 mmol) and Boc2O (0.26 mL, 1.22 mmol) were
added, stirred overnight at r.t. After concentration the
residue was purified by column chromatography to afford
14a (0.13 g, 80%) and 14b (28 mg, 17%). Compound 14a:
[a]D25 –69 (c = 1.2, MeOH). IR (neat): 3326, 2929, 2859,
1739, 1655, 1529, 1370, 1280, 1163, 1089, 1026 cm–1. 1H
NMR (400 MHz, CDCl3): d = 7.20–7.28 (m, 8 H), 7.09 (d,
J = 7.9 Hz, 1 H), 5.88 (dd, J = 5.8, 8.0 Hz, 1 H), 4.49–4.53
(m, 1 H), 3.49 (dd, J = 4.0, 9.5 Hz, 1 H), 3.39 (dd, J = 4.8,
9.5 Hz, 1 H), 3.34 (s, 3 H), 2.97 (dd, J = 6.9, 13.6 Hz, 1 H),
2.93 (dd, J = 7.5, 13.3 Hz, 1 H), 2.35 (s, 3 H), 1.82–1.88 (m,
1 H), 1.68–1.74 (m, 1 H), 1.42 (s, 9 H), 1.23–1.25 (m, 6 H),
0.84 (t, J = 6.6, 13.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
d = 168.7, 153.6, 140.2, 138.7, 138.2, 133.2, 129.4, 128.6,
128.4, 127.6, 126.4, 126.3, 82.3, 76.4, 72.7, 58.8, 50.7, 37.6,
37.3, 31.5, 27.8, 25.3, 22.4, 21.4, 14.0. HRMS (ESI+):
m/z [M + Na]+ calcd for C29H41NO5Na: 506.2882; found:
506.2880. Compound 14b: [a]D25 –18 (c = 0.4, MeOH).
IR (neat): 3328, 2928, 2854, 1739, 1657, 1523, 1370, 1278,
1160, 1089, 1025 cm–1. 1H NMR (400 MHz, CDCl3): d =
7.20–7.33 (m, 8 H), 7.09 (d, J = 7.6 Hz, 1 H), 5.43 (t, J = 7.0,
14.0 Hz, 1 H), 4.53–4.59 (m, 1 H), 3.46 (dd, J = 4.0, 9.6 Hz,
1 H), 3.43 (dd, J = 5.9, 10.6 Hz, 1 H), 3.37 (s, 3 H), 3.05 (dd,
J = 6.9, 13.9 Hz, 1 H), 2.95 (dd, J = 8.1, 13.8 Hz, 1 H), 2.33
(s, 3 H), 1.55–1.72 (m, 2 H), 1.46 (s, 9 H), 1.10–1.26 (m, 6
H), 0.82 (t, J = 6.9, 14.2 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): d = 168.7, 153.5, 140.2, 138.4, 138.3, 133.2, 129.3,
128.6, 128.4, 127.9, 126.4, 126.1, 82.4, 76.4, 73.3, 59.0,
50.7, 37.3, 37.1, 31.6, 27.8, 24.8, 22.4, 21.4, 14.1. HRMS
(ESI+): m/z [M + Na]+ calcd for C29H41NO5Na: 506.2882;
found: 506.2877.
(12) (a) Narayanan, K. S.; Berlin, K. D. J. Org. Chem. 1980, 45,
2240. (b) Beugelmans, R.; Chastanet, J.; Ginsburg, H.;
Quintero-Cortes, L.; Roussi, G. J. Org. Chem. 1985, 50,
4933.
(13) (a) Nateuda, F.; Terashima, S. Tetrahedron 1988, 44, 4721.
(b) Kozikowski, A. P.; Lee, J. J. Org. Chem. 1990, 55, 863.
(14) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 4599.
(15) Fujioka, H.; Kitagawa, H.; Nagatomi, Y.; Kita, Y. J. Org.
Chem. 1996, 61, 7309.
(16) Sugai, T.; Katoh, O.; Ohta, H. Tetrahedron 1995, 51, 11987.
(17) Synthesis of (–)-2: A solution of 25 (35.3 mg, 0.11 mmol) in
t-BuOH (3 mL) containing concd HCl (0.3 mL) was stirred
at 40 °C for 6 h. After cooling, the mixture was extracted
with EtOAc. The extract was dried over Na2SO4 and
concentrated. The residue was purified by column chroma-
tography to afford (–)-2 as a colorless oil (27.7 mg, 91%);
[a]D21 –20 (c = 0.3, MeOH). IR (neat): 3405, 2928, 2861,
1710, 1613, 1458, 1398, 1206, 1061, 958 cm–1. 1H NMR
(400 MHz, CD3OD): d = 7.32 (d, J = 8.0 Hz, 1 H), 7.26 (s, 1
H), 7.01 (d, J = 7.7 Hz, 1 H), 6.81 (d, J = 15.6 Hz, 1 H), 6.12
(dt, J = 7.1, 15.6 Hz, 1 H), 4.94 (t, J = 6.5, 13.2 Hz, 1 H), 3.22
(d, J = 7.1 Hz, 2 H), 2.32 (s, 3 H), 1.64–1.67 (m, 2 H), 1.30–
1.42 (m, 6 H), 0.90 (t, J = 6.8, 11.4 Hz, 3 H). 13C NMR (100
MHz, CD3OD): d = 175.6, 143.4, 138.4, 133.5, 131.8, 128.8,
127.4, 127.3, 124.8, 71.3, 39.7, 39.2, 32.9, 26.7, 23.7, 21.4,
14.4. HRMS (ESI+): m/z [M + NH4]+ calcd for C17H28NO3:
294.2064; found: 294.2057.
(18) It is noteworthy that slight concentration-dependent changes
in the chemical shifts of the signals of the unsaturated
carboxyl acid chain were observed in NMR spectra of 2,
owing to variable aggregation extent via carboxyl group (see
Supporting Information).
(19) Synthesis of 1: A solution of 28 (91 mg, 0.38 mmol) and
KOH (0.31 g) in 30% EtOH–H2O (5 mL) was stirred for 8 h
at 100 °C. After cooling to r.t., the mixture was acidified
with 3 M HCl acid to pH 3, and was extracted with EtOAc.
The extract was washed with brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column
chromatography to afford 1 (70 mg, 72%) as a pale yellow
oil. IR (neat): 2958, 2928, 2855, 1709, 1605, 1460, 1222,
1163, 1094, 965 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.30
(d, J = 7.9 Hz, 1 H), 7.18 (s, 1 H), 6.98 (d, J = 8.4 Hz, 1 H),
6.74 (d, J = 15.7 Hz, 1 H), 6.59 (d, J = 15.6 Hz, 1 H), 6.09
(dt, J = 6.9, 15.6 Hz, 1 H), 6.04 (dt, J = 7.0, 15.6 Hz, 1 H),
3.28 (d, J = 6.9 Hz, 2 H) 2.31 (s, 3 H), 2.23 (q, J = 6.8 Hz, 2
(10) Compound 17: 1H NMR (400 MHz, CDCl3): d = 7.28–7.35
(m, 5 H), 7.13 (d, J = 7.7 Hz, 1 H), 6.94 (d, J = 7.5 Hz, 1 H),
6.62 (s, 1 H), 5.88 (dd, J = 4.2, 9.2 Hz, 1 H), 4.85 (d, J = 12.4
Hz, 1 H), 4.78 (s, 1 H), 4.63 (d, J = 12.4 Hz, 1 H), 3.39 (s, 3
H), 2.08 (s, 3 H), 1.66–1.85 (m, 2 H), 1.15–1.45 (m, 6 H),
0.90 (s, 9 H), 0.86 (t, J = 6.8, 13.4 Hz, 3 H), 0.09 (s, 3 H),
H), 1.33–1.48 (m, 4 H), 0.93 (t, J = 7.2, 14.2 Hz, 3 H). 13
C
NMR (100 MHz, CDCl3): d = 177.5, 137.2, 136.0, 133.6,
131.9, 131.5, 127.8, 127.5, 127.0, 126.4, 122.4, 38.8, 33.0,
31.6, 22.3, 21.2, 14.0. HRMS (ESI+): m/z [M + H]+ calcd for
C17H23O2: 259.1693; found: 259.1687.
Synlett 2012, 23, 607–610
© Thieme Stuttgart · New York

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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.