Parallel synthesis of individual shikimic acid-like molecules using a mixture-operation strategy and ring-closing enyne metathesis

Article abstract of DOI:10.1016/j.tetlet.2007.03.118

Three new diastereomeric shikimic acid analogues (4-amino-3,5-dihydroxyl-cyclohex-1-en-carboxylic acids, 16) bearing a C-4 amino group were synthesized in parallel by a mixture-operation protocol. Ring-closing enyne metathesis (RCEYM) under ethylene atmos

Full text of DOI:10.1016/j.tetlet.2007.03.118

Tetrahedron Letters 48 (2007) 3511–3515
Parallel synthesis of individual shikimic acid-like molecules using
a mixture-operation strategy and ring-closing enyne metathesis
Fang Hu,a Yan-Hong Zhanga,b and Zhu-Jun Yaoa,*
aState Key Laboratory of Bioorganic and Natural Product Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
bDepartment of Analysis Chemistry, Hunan Traditional Chinese Medicine University, 113 Middle Shaoshan Road, Changsha,
Hunan 410007, China
Received 8 January 2007; revised 9 March 2007; accepted 22 March 2007
Available online 25 March 2007
Abstract—Three new diastereomeric shikimic acid analogues (4-amino-3,5-dihydroxyl-cyclohex-1-en-carboxylic acids, 16) bearing a
C-4 amino group were synthesized in parallel by a mixture-operation protocol. Ring-closing enyne metathesis (RCEYM) under eth-
ylene atmosphere was successfully employed to construct the desired carbocycles in high efficiency. The absolute configurations of
each final product were confirmed by the 1D and 2D NMR techniques.
Ó 2007 Elsevier Ltd. All rights reserved.
Olefin metathesis has attracted worldwide attention in
organic synthesis as a versatile carbon–carbon bond for-
mation method in recent years.1 Metal carbene complex-
catalyzed olefin metathesis has been known in polymer
chemistry for about 40 years.2 However, this reaction
became practically useful in organic synthesis only when
new catalysts were developed by Schrock and Grubbs
since early 1990s (Fig. 1). Based on the types of olefins
involved in the metathesis process, three categories that
can be identified are diene,1 enyne,3 and diyne metathe-
sis.4 A variety of synthetically useful transformations
have been developed on the basis of original olefin
metathesis concepts, including ring-opening metathesis
polymerization (ROMP), ring-closing metathesis
(RCM), acyclic diene metathesis polymerization (AD-
MET), ring-opening metathesis (ROM), and cross-
metathesis (CM or XMET). Among these, the RCEYM
reaction is a uniquely powerful and atom economical
method for the formation of dumbbell-shaped, multiply
fused,5 and bridged6 ring systems possessing a 1,3-diene
moiety via a tandem ring closure, if both the olefin and
acetylene functionalities are suitably positioned in the
linear substrates (Fig. 1). Herein, we report our recent
results on the synthesis of amino acid-derived linear
enyne precursors and subsequent generation of the
carbocycles by ring closing enyne metathesis in high
efficiency.7
The linear substrates bearing both olefin and acetylene
functionalities for RCEYM reaction were prepared at
first. Considering the stereochemical similarity to the
influenza drug, Tamiflu, a stereogenic amino group
was introduced into the substrates at C-4 position of
the carbocycle in order to explore the further applica-
tions of those formed carbocycles in the future. The syn-
thesis started from an optically active N-protected a-
amino aldehyde 5 (easily prepared from cheaper L-serine
(1)), which served as an equivalent of D-serinal (Scheme
1). After a simple two-step protection–deprotection
manipulation, L-serinol 2 was converted to alcohol 4.
Swern oxidation of alcohol 4 afforded the corresponding
aldehyde 5, which was immediately treated with vinyl-
magnesium bromide (1.5 equiv) in THF at ꢀ78 °C and
then to room temperature, giving a mixture of olefins
6a and 6b (ratio of 6a:6b = 1.28:1, 96% yield in two
steps). These two isomers could not be separated by
the silica gel column chromatography and their ratio
1
was determined by H NMR. Determination of stereo-
chemistry will be discussed in details together with three
final targets 16 at the last stage.
Keywords: Shikimic acid; Carbocycle; Ring-closing enyne metathesis;
Stereochemistry; Parallel synthesis.
To speed up the progress of parallel synthesis of sub-
strates with similar functionalities, a mixture-based
strategy was adopted in the following transformations
*
Corresponding author. Tel.: +86 21 54925133; fax: +86 21
64166128; e-mail: yaoz@mail.sioc.ac.cn
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.118

3512
F. Hu et al. / Tetrahedron Letters 48 (2007) 3511–3515
OH
PCy3
Ru
PCy3
Ru
N
Mes
N
Cl
Mes
OH
OH
OTBDPS
OTBDPS
Cl
Cl
H
Cl
Cl
H
Ph
O
O
Ph
Ph
O
O
OTBDPS
NHBoc
H
NBoc
NBoc
Ru
PCy3
PCy3
Cl
Ph
PCy3
a
b
6a
7a
8a
OH
Grubbs catalyst
Grubbs catalyst
2nd G. (B)
1st G. (A)
Grubbs, 1992
OTBDPS
NBoc
NBoc
NHBoc
6b
7b
8b
N
N
PCy3
Cl
Cl
Mes
Mes
Ru Cl
Ru
O
H
Cl
O
O
O
OH
O
OH
NBoc
9a
O
O
NBoc
NBoc
10aa
10ab
(not detected)
c
d
Hoveyda-Grubbs
Catalyst 1st G.
Hoveyda-Grubbs
Catalyst 2nd G.
O
NBoc
O
OH
O
OH
NBoc
10bb
n
n
tandem
RCEYM
9b
NBoc
10ba
or
n
m
m
m
m
n
n
n
tandem
RCEYM
O
OBz
OBz
O
OBz
NBoc
n
m
m
or
or
NBoc
11aa
11ab
(not detected)
e
n
tandem
RCEYM
m
n
m
m
O
O
OBz
NBoc
NBoc
11ba
Figure 1. Representative catalysts for the olefin metathesis, and several
11bb
typical ring systems formed by tandem RCEYMs.
Scheme 2. Reagents and conditions: (a) DMOP, PTSA (cat), DMF,
90 °C, 92%; (b) TBAF, THF, 70%; (c) (COCl)2, DMSO, CH2Cl2,
Et3N, ꢀ78 °C, 100%; (d) conditions shown in Table 1; (e) BzCl,
DMAP, Et3N.
(Scheme 2). Treatment of the mixture of 6a and 6b with
excess of 2,2-dimethoxypropane (DMOP) in DMF at
90 °C in the presence of catalytic amount of p-toluene-
sulfonic acid (PTSA) gave cyclic N,O-aminals 7 (92%).
Subsequent desilylation of 7 by tetrabutylammonium
fluoride (TBAF, 1.0 equiv) afforded alcohols 8. Swern
oxidation of alcohols 8 gave the corresponding alde-
hydes 9 (64% overall yield from alcohols 6) as a mixture
of two epimers, which was immediately treated with
propargyl bromide (3.0 equiv) and activated zinc dust
OH
OTBDPS
O
(S)
a
4 steps
O
O
HO
OH
NBoc
NBoc
NH2
L-serine, 1
OH OTBDPS
2
3
O
c
b
d
O
CO2Et
OTBDPS
NHBoc
4
NHBoc
AcHN
4
5
Tamiflu
NH2
OH
OH
HO
HO
CO2H
+
OTBDPS
NHBoc
6a
OTBDPS
NHBoc
6b
4
shikimic acid
OH
6a/6b = 1.28:1
Scheme 1. Reagents and conditions: (a) TBDPSCl, imidazole, CH2Cl2, rt, 99%; (b) BiBr3, acetonitrile, rt, 92%; (c) (COCl)2, DMSO, CH2Cl2, Et3N,
ꢀ78 °C; (d) vinylMgBr, THF, ꢀ78 °C to 0 °C, 96% for two steps.

F. Hu et al. / Tetrahedron Letters 48 (2007) 3511–3515
3513
(4.0 equiv) in DMF–ether (1:1) to give a mixture of dia-
stereomeric enynes 10 in 85% yield. Theoretically, all
four possible stereoisomers of 10 could be generated
by such a treatment. In deed, only three epimers
(10aa, 10ba, and 10bb) were obtained from the mixture
after careful isolation at this stage. The relative configu-
rations of 10aa, 10ba and 10bb were finally determined
after further transformations in parallel to the acids 16.
b
a
O
OH
O
OBoc
BocO
O
NBoc
NBoc
BocN
13aa
10aa
12aa
b
a
In order to make sure the crude products ratio (for more
sensitive HPLC measurements by a UV-detection
mode), a benzoic acid was then introduced to the crude
mixture alcohols 10 through a standard ester bond
formation reaction, giving a mixture of esters 11
(Scheme 2). The results are shown in Table 1. Obviously,
zinc-promoted propargylation of 9a gave 10aa (erythro)
as the only product. For 9b, both 10ba (erythro) and
10bb (threo) were generated in similar ratio
(11ba:11bb = 1.3:1 by HPLC). In order to obtain the
fourth isomer 10ab (threo), a number of propargylation
conditions were attempted, including Zn–C3H3Br in
DMF–ether, C3H3MgBr in THF and C3H3MgBr in
THF–HMPA (Table 1). To our disappointment, all
these efforts failed. Such results can be explained by
our previously proposed model8 that propargylation of
carbonyl compounds with propargyl bromide and zinc
dust favorably affords the erythro-diastereomer through
a Felkin–Ahn transition state, and the erythro/threo
selectivity is usually much higher if there is an oxygen-
ated five-membered ring flanking the aldehyde group
in the substrate. This means high steric congestion in
the transition state favors erythro selectivity in the prop-
argylation of aldehyde 9a. As mentioned above, none
10ab was detected though a variety of propargylation
conditions were examined, even by changing the elec-
tronic factors of the nucleophile (see the above text).
Obviously, steric factor of aldehyde 9a is a key determi-
nant in all examined propargylation reactions. There-
fore, we stopped further endeavor to acquire 10ab, and
continued exploring our mixture-operation protocol.
O
OH
O
OBoc
NBoc
NBoc
BocO
O
BocN
13ba
10ba
12ba
b
a
O
OH
BocO
O
OBoc
O
NBoc
BocN
13bb
NBoc
10bb
12bb
Scheme 3. Reagents and conditions: (a) Boc2O, DMAP, acetonitrile,
89% for 12aa, 83% for 12ba, and 85% for 12bb; (b) 5 mol % of 2nd G
catalyst (B in Fig. 1), CH2Cl2, ethylene atmosphere, rt, 91% for 13aa,
97% for 13ba, and 92% for 13bb.
the 1st generation Grubbs catalyst. After optimizations,
standard reaction conditions for enyne ring-closing
metathesis were fixed to use 5 mol % of catalyst B and
an initial 30–40 mM of substrate in CH2Cl2 under ethyl-
ene atmosphere (using an ethylene balloon). All three
linear substrates 12 were smoothly converted to the cor-
responding 1-vinylcyclohexenes 13 in excellent yields. In
a larger scale practice, it was found that these three car-
bocycles 13 were much easier to separate on the silica gel
column chromatography. Therefore, our mixture-opera-
tion was continued until the completion of enyne
metathesis.
As mentioned above, 1,3-dienes 13 are structurally very
close to the skeleton of shikimic acid. Therefore, they
could be the suitable precursors for the synthesis of shi-
kimic acid-like molecules. (ꢀ)-Shikimic acid is a natural
product with anti-thrombus and antitumor activities.
Also, it is the major industrial starting material for the
famous anti-influenza drug Tamiflu. Known as the shi-
kimate pathway, (ꢀ)-shikimic acid occupies an impor-
tant position in the biosynthesis pathway, along which
three aromatic amino acids (L-phenylalanine, L-tyrosine,
and L-tryptophan) are synthesized. More recently, shiki-
mic acid was also used as a combinational template to
synthesize natural product-like libraries with potential
With the above single epimers 10aa, 10ba, and 10bb in
hand, RCEYM reactions under ethylene atmosphere
were examined. Our practice found that existence of
the free hydroxyl group in substrates 10 affected the effi-
ciency of cyclization severely. Therefore, all three linear
enynes 10 were converted to the corresponding O-Boc
protected compounds 12 by treatment with Boc2O in
acetonitrile at room temperature in the presence of
catalytic amount of DMAP (Scheme 3). Further exami-
nation of the RCEYM reaction conditions under ethyl-
ene atmosphere showed that the 2nd generation Grubbs
catalyst was generally more efficient with comparison of
Table 1. Results of propargylation of 9 under various conditions
Entry
Conditionsa
Yielda
10aa:10bb:10bab
11aa:11bb:11bac (overall yield)
1
2
3
Zn, C3H3Br
C3H3MgBr
C3H3MgBr/HMPA
83%
62%
45%
3.5:1:1.7
1.6:1:1.9
3.3:1:1.8
4.9:1:1.3 (89%)
2:1:1.4 (91%)
7:1:1.7 (85%)
a For the propargylation step. All the reactions were performed in THF.
b Determined by 1HNMR after column chromatography isolation.
c Determined directly by HPLC.

3514
F. Hu et al. / Tetrahedron Letters 48 (2007) 3511–3515
uses in drug development.9 Today, shikimic acid receives
much more attention including the synthesis of diverse
analogues as a platform to find more selective and effec-
tive neuraminidase inhibitors. Using our synthesized six-
membered carbocycles 13 as precursors, three shikimic
acid analogues bearing a C-4 amino group (to replace
its original hydroxyl group) were successfully synthe-
sized. In parallel, regioselective oxidative cleavage of
of 16 are shown in Figure 2. Concomitantly, the abso-
lute configurations of precursors 10 and 6 are also
determined.
In conclusion, three new shikimic acid analogues 16
bearing an amino group at the C-4 position were synthe-
sized in parallel through multiple steps of mixture oper-
ations. Sequential vinylmagnesium bromide addition
and zinc-mediated propargylation of aldehydes, ring-
closing enyne metathesis and regioselective oxidation
of terminal olefin were successfuly performed in the syn-
10
the terminal olefins in 13 by OsO4–NaIO4 followed
t
by oxidation with NaClO2 in BuOH–water (4:1) gave
the corresponding acids 15. Global deprotection of
15aa/15ba/15bb was finally carried out in a dichloro-
methane solution containing 10% TFA, affording the
expected shikimic acid-like analogues 16aa/16ba/16bb
in quantitative yields,11 respectively (Scheme 4).
HO
O
H
H
O
1
3
HO
H2N
OH
OH
H
Absolute configurations of the three final acids 16ba,
16aa, and 16bb were determined by NMR experiments
(1H NMR, NOESY). Strong NOE between H-3, H-4,
and H-5 of 16ba was observed. Thus, H-3, H-4, and
H-5 of 16ba have cis–cis configuration. In 16aa, strong
NOE between H-4 and H-5 and comparatively weak
NOE between H-3 and H-4 was observed. Com-
bined with coupling constants showed by 1H NMR
(JH-3,H-4 = 9.9 Hz and JH-4,H-5 = 2.2 Hz), the relative
configurations were easily determined as trans for H-3
and H-4, and cis for H-4 and H-5. In 16bb, strong
NOE between H-3 and H-4 was observed, and no
NOE between H-4 and H-5 was found. Combined with
5
HO
OH
H
H
H
H
NOEs
NH2
(3R,
4R,
5R
)-16aa
HO
O
H
HO
3
O
1
H
H2N
OH
OH
H
5
HO
OH
H
H
NH2
NOEs
(
3
S,
4
R,
5
S
)-16ba
HO
O
H
HO
3
O
coupling constants (JH-3,H-4 = 4.5 Hz and JH-4,H-5
=
1
H
H2N
H
OH
H
10.8 Hz), the relative configurations were then deter-
mined as cis for H-3 and H-4, and trans for H-4 and
H-5. With all these information, re-analysis of the
NOESY and 1H NMR of epimers of 16 again confirmed
the above conclusion. The final absolute configurations
HO
S,
OH
5
NH2
H
OH
NOEs
H
(
4
R,
5
R
)-16bb
3
Figure 2. Illustration of NOESY result for final targets 16.
HO
O
O
HO
O
c
c
c
b
b
b
a
13aa
13ba
13bb
BocO
BocO
BocO
BocO
BocN
15aa
O
O
O
O
HO
OH
OH
OH
BocN
14aa
NH2
16aa
HO
O
O
HO
O
a
BocO
O
HO
BocN
14ba
BocN
NH2
16ba
15ba
HO
O
O
HO
O
a
BocO
BocN
15bb
O
HO
BocN
NH2
16bb
14bb
t
Scheme 4. Reagents and conditions: (a) OsO4, NaIO4, 2,6-lutidine, dioxane–water (3:1), 60%; (b) NaClO2, KH2PO4, 2-methyl-2-butene, BuOH–
water (4:1), 100%; (c) TFA, DCM, 100%.

F. Hu et al. / Tetrahedron Letters 48 (2007) 3511–3515
3515
4. (a) Furstner, A.; Seidel, G. Angew. Chem., Int. Ed. 1998,
¨
thesis. Commercially available L-serine was used as the
starting material to introduce the first essential stereo-
genic center economically. Our illustrated protocol using
a highly efficient RCEYM-based carbocycle-formation
combined with mixture operations provides a fast track
to those diverse molecules with similar structure to shi-
kimic acid and Tamiflu, which have potential applica-
tions in today’s new drug discovery including the
neuraminidase inhibitors.
37, 1734–1736; (b) Furstner, A.; Guth, O.; Rumbo, A.;
¨
Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108–11113.
5. (a) Fukumoto, H.; Esumi, T.; Ishihara, J.; Hatakeyama, S.
Tetrahedron Lett. 2003, 44, 8047–8049; (b) Honda, T.;
Namiki, H.; Kaneda, K.; Mzutani, H. Org. Lett. 2004, 6,
84–87; (c) Boyer, F. D.; Hanna, I.; Ricard, L. Org. Lett.
2004, 6, 1817–1820; (d) van Otterlo, W. A. L.; Ngidi, E.
L.; de Koning, C. B.; Fernandes, M. A. Tetrahedron Lett.
2004, 45, 659–662.
6. (a) Garcia-Fandino, R.; Codesido, E. M.; Sobarzo-
Sanchez, E.; Castedo, L.; Granja, J. R. Org. Lett. 2004,
6, 193–196; (b) Aggarwal, V. K.; Astle, C. J.; Rogers-
Evans, M. Org. Lett. 2004, 6, 1469–1471.
Acknowledgments
This work was financially supported by National Natu-
ral Science Foundation of China (20425205 and
20621062), and Shanghai Municipal Commission of Sci-
ence and Technology (04DZ14901 and 06QH14016).
7. (a) Cong, X.; Yao, Z.-J. J. Org. Chem. 2006, 71, 5365–
5368; (b) Cong, X.; Liao, Q.-J.; Yao, Z.-J. J. Org. Chem.
2004, 69, 5314–5321.
8. Wu, W.-L.; Yao, Z.-J.; Li, Y.-L.; Li, J.-C.; Xia, Y.; Wu,
Y.-L. J. Org. Chem. 1995, 60, 3257–3261.
9. Tan, D. S.; Foley, M. A.; Stockwell, B. R.; Shair, M. D.;
Schreiber, S. L. J. Am. Chem. Soc. 1999, 121, 9073–9087.
10. Yn, W. S.; Mei, Y.; Kang, Y.; Hua, Z. M.; Jin, Z. D. Org.
Lett. 2004, 6, 3217–3219.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.03.118.
25
11. Data for 16aa: ½aꢁD ꢀ4.9 (c 0.45, MeOH/H2O = 1:1); IR
1
(KBr): 3195, 1668, 1552, 1438, 1399, 1204, 1138 cmꢀ1; H
NMR (300 MHz, D2O): d 6.59 (s, 1H), 4.61–4.58 (m, 1H),
4.45 (m, 1H), 3.38 (dd, J = 9.1, 2.2 Hz, 1H), 2.73–2.72 (m,
1H), 2.59 (d, J = 19.2Hz, 1H) ppm;13C NMR (75 MHz,
D2O): d 171.4, 136.6, 134.1, 68.4, 67.9, 58.9, 35.3 ppm;
ESIMS (m/z, %): 174.1 (M+H+, 100%); HRMS (ESI)
Calcd for C7H12NO4 (M+H+): 174.0761. Found:
References and notes
1. Reviews on olefin metathesis, see: (a) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413–4450; (b) Furstner,
¨
23
174.0768. Data for 16ba: ½aꢁD 8.5 (c 0.18, MeOH/
A. Angew. Chem., Int. Ed. 2000, 39, 3013–3043; (c)
Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003,
42, 1900–1923; (d) Schrock, R. R.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2003, 42, 4592–4633; (e) Handbook of
Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim,
2003; Vol. 2.
H2O = 1:1). IR (KBr): 3379, 3181, 2891, 1544, 1401,
1
1368, 1347, 1326, 1309, 1078, 1060, 1037 cmꢀ1; H NMR
(300 MHz, D2O): d 6.44 (m, 1H), 4.49 (t, J = 4.5 Hz, 1H),
3.97 (ddd, J = 10.8, 9.3, 5.6 Hz, 1H), 3.25 (dd, J = 10.8,
4.2 Hz, 1H), 2.83 (dd, J = 17.4, 5.6 Hz, 1H), 2.21 (dd,
J = 17.4, 9.3 Hz, 1H) ppm;13C NMR (75 MHz, D2O): d
174.7, 136.8, 128.8, 64.0, 63.8, 55.5, 33.8 ppm; ESIMS
2. Ivin, K. J.; Mol, J. C. Olefin Metathesis and Metathesis
Polymerization; Academic Press: San Diego, 1997.
3. For reviews on enyne metathesis, see: (a) Mori, M. In
Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, 2003; Vol. 2, pp 176–204; (b) Giessert, A. J.;
Diver, S. T. Chem. Rev. 2004, 104, 1317–1382; For the first
example of enyne metathesis, see: (c) Katz, T. J.; Sivavec,
T. M. J. Am. Chem. Soc. 1985, 107, 737–738; For the first
enyne metathesis using Grubbs catalyst, see: (d) Kimo-
shita, A.; Mori, M. Synlett 1994, 1020–1022.
26
(m/z, %): 174.1 (M+H+, 100%). Data for 16bb: ½aꢁD 11.6
(c 0.10, MeOH/H2O = 1:1); IR (KBr): 3433, 3166, 1660,
1
1635, 1561, 1403, 1358, 1308, 1242, 1102, 1069 cmꢀ1; H
NMR (300 MHz, D2O): d 6.27 (s, 1H), 4.78 (s, 1H), 4.12–
4.07 (m, 1H), 3.43 (s, 1H), 2.53 (dd, J = 18.0, 10.5 Hz,
1H), 2.18 (dd, J = 18.0, 7.8 Hz, 1H) ppm; 13C NMR
(75 MHz, D2O): d 177.4, 137.2, 133.4, 67.8, 67.7, 56.2,
32.6 ppm; ESIMS (m/z, %): 174.2 (M+H+, 100%).