Sequential Baylis-Hillman/RCM protocol for the stereoselective synthesis of (+)-MK7607 and (+)-streptol

Article abstract of DOI:10.1016/j.tetlet.2010.02.080

Sequential Baylis-Hillman/ring-closing metathesis (RCM) approach toward the total synthesis of (+)-MK7607 and (+)-streptol starting from (R,R)-tartaric acid is reported.

Full text of DOI:10.1016/j.tetlet.2010.02.080

Tetrahedron Letters 51 (2010) 2586–2588
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Tetrahedron Letters
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Sequential Baylis–Hillman/RCM protocol for the stereoselective synthesis
of (+)-MK7607 and (+)-streptol
*
Palakodety Radha Krishna , Raghu Ram Kadiyala
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Sequential Baylis–Hillman/ring-closing metathesis (RCM) approach toward the total synthesis of
(+)-MK7607 and (+)-streptol starting from (R,R)-tartaric acid is reported.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 31 December 2009
Revised 11 February 2010
Accepted 15 February 2010
Available online 18 February 2010
Keywords:
Cyclitols
Diastereoselective Baylis–Hillman reaction
Ring-closing metathesis
Hoveyda–Grubbs catalyst
Sharpless asymmetric epoxidation
(R,R)-Tartaric acid
MK7607 (1), an unsaturated carbapyranose, commonly referred
to as cyclitol, was isolated from Curvularia eragrostidis D2452.1
Compound 1 is considered a natural mimic since it bears a close
envisaged for accessing cyclitols (+)-1 and (+)-2 from the Baylis–
Hillman adduct 3,8 identified as the common intermediate,
through an RCM reaction followed by the ester reduction and glo-
bal deprotection. Adduct 3 in turn could be obtained from allylic
alcohol 4 on oxidation followed by the Baylis–Hillman reaction
in the presence of ethyl acrylate. While allylic alcohol 4 could be
realized from its corresponding epoxide 5 (Scheme 2), conversion
to chloro epoxide, and metal-induced ring-opening reaction, the
epoxide 5 itself maybe readily obtained from the mono-protected
resemblance to
a-galactose that plays an important role in many
biological processes.2 Another structurally similar cyclitol deriva-
tive, a C4 epimer of 1 known as streptol (2), was isolated from
the culture filtrate of an unidentified Streptomyces sp. that inhib-
ited the germination of lettuce seedlings.3 The first total synthesis
of 1 was reported by Mehta et al.4a using a novel fragmentation
sequence of the norbornane system to provide a cyclohexenoid
building block that was extrapolated to the target compound.
Later, Kim and co-workers4b have relied on the stereospecific
PBr3-mediated allylic-transposed bromination followed by its
conversion to corresponding hydroxyl group. Additionally, some
synthetic analogs of 1 were also reported.4c–e However, to the best
of our knowledge, so far only one synthesis of 2 was reported.5 Our
recent work encompassing Baylis–Hillman reaction6 led to differ-
ent diastereomeric adducts which when involved in an RCM reac-
tion led to diverse scaffolds/building blocks.7 Herein, we report the
synthesis of two cyclitol derivatives 1 and 2 involving a Baylis–
Hillman/RCM as the key reaction to construct the diastereomeric
cyclohexenoids that were independently extrapolated to target
compounds.
(+)-2,3-O-isopropylidene-L-threitol that could eventually be made
from commercially available (R,R)-tartaric acid using the reported
procedure.9
Thus, the synthesis of these cyclitols (1 and 2) commenced
(Scheme 2) from the known9 epoxide 5 that was derived from
(R,R)-tartaric acid according to the reported procedure. Thus, the
epoxide 5 was transformed into allylic alcohol 6 through the
sodium-induced ring-opening reaction (Na/anhydrous Et2O/0 °C
to rt/12 h/85%) of the corresponding epoxy chloride obtained in
excellent yields under conventional methods (TPP/CCl4/cat.NaH-
CO3/reflux/3 h/93%). Hydroxy functionality in 6 was protected as
its MOM–ether (MOMCl/DIPEA/CH2Cl2/0 °C to rt) which on selec-
tive deprotection of benzyl group (DDQ/CH2Cl2:H2O, 19:1)/reflux/
3 h/75%) provided the primary alcohol 4. Swern oxidation of 4 fol-
lowed by the Baylis–Hillman reaction (ethyl acrylate/DABCO/DMF/
24 h/80%/30%de) furnished adduct 3 as an inseparable mixture.8
The diastereomeric ratio was evaluated based on the relative inte-
gration of the separable protons. For instance, 1H NMR of adduct 3
displayed one of the disubstituted olefinic protons at d 6.31 ppm as
The retrosynthetic analysis of (+)-1 and (+)-2 is shown in
Scheme 1. Accordingly,
a common synthetic strategy was
* Corresponding author. Tel.: +91 40 27160123; fax: +91 40 27160387.
E-mail address: prkgenius@iict.res.in (P.R. Krishna).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.080

P. R. Krishna, R. R. Kadiyala / Tetrahedron Letters 51 (2010) 2586–2588
2587
HO
HO
O
5
OH
MOMO
5
OH
OH
6
EtO
OH
OMOM
6
4
4
+
HO
1
3
1
3
HO
OH
HO
2
OH
2
O
O
O
O
OH
(+)-MK7607
1
(+)-streptol
2
4
3
(R,R)-Tartaric acid
Scheme 1. Retrosynthetic analysis.
O
BnO
OH
Ref. 9
a, b
(R,R)-Tartaric acid
O
O
5
O
MOMO
HO
EtO
OH
OMOM
HO
BnO
c, d
e, f
O
O
O
O
O
O
6
4
3
OEt
OH
O
OEt
OH
O
Mes
N
N
Mes
g
Cl
+
Ru
O
Cl
Me
MOMO
MOMO
O
O
O
Me
O
Hoveyda-Grubbs Catalyst
2
nd Generation
7
7a
( A)
OH
OH
i
h
1
7
MOMO
O
O
8
Scheme 2. Reagents and conditions: (a) Ph3P, CCl4, cat.NaHCO3, reflux, 3 h, 93%; (b) Na, anhydrous Et2O, 0 °C to rt, 12 h, 85%; (c) MOM–Cl, DIPEA, CH2Cl2, 12 h, 0 °C, 90%, (d)
DDQ, CH2Cl2/H2O (19:1), reflux, 3 h, 75%; (e) (COCl)2, DMSO, NEt3, CH2Cl2, 1.5 h, 87%; (f) DABCO, ethyl acrylate, DMF, 24 h, 80%, 30% de; (g) A (10 mol %), toluene, 24 h, reflux,
83%; (h) DIBAL-H, ꢀ10 °C, THF, 3 h, 99%; (i) DOWEX, MeOH, 70 °C, 2 h, 90%.
a singlet for the major isomer while the same proton resonated at d
6.20 ppm also as a singlet with the relative integration of 0.65:0.35.
The other olefinic proton resonated at d 5.93 ppm for the major
isomer while the same proton of the minor isomer showed at d
5.91 ppm. Likewise, the characteristic methine proton attached to
newly created chiral stereogenic center resonated at d 4.69 ppm
as a doublet (J = 6.7 Hz) for the minor isomer, while the same
proton resonated at d 4.66 ppm as a doublet (J = 6.7 Hz) with the
same integral ratio as mentioned above. Also, the MOM–CH3
protons resonated differently at d 3.35 ppm and at d 3.32 ppm as
singlets for the major and minor isomers, respectively. The
absolute stereochemistry of the major isomer was assigned as
‘S’ based on our earlier work.8 The bisolefin of adduct 3 on ring-
closing metathesis (RCM) employing Hoveyda–Grubbs second
generation catalyst10 {A (10 mol %)/toluene/110 °C/24 h/combined
yield 83%} afforded cyclic compounds 7 (65%) and 7a (35%) as
characterized by its spectral data. Thus, 1H NMR spectrum of
7 revealed the lone olefinic proton resonating at d 6.94 ppm as a
doublet (J = 6.0 Hz) and one of the two allylic protons appeared
at d 4.91 ppm as a doublet (J = 3.7 Hz), while the other one reso-
nated at d 4.54 ppm as a double doublet (J = 3.7, 5.6 Hz) with the
rest of the protons at their expected chemical shifts. Further, the
HRMS spectrum displayed the [M+Na]+ 325.1263, calculated
325.1267 for the molecular formula C14H22O7Na.
Initially, the major product 7 was taken up for the rest of the
synthetic sequence. Thus, ester group in the major product 7 was
reduced with DIBAL-H in THF to give the alcohol 8 in quantitative
yield. Since the final step of our synthetic endeavor comprises a
global deprotection of both acetal and MOM–ether, the same was
achieved with the acidic ion-exchange resin DOWEX4d (MeOH/
70 °C/2 h) to furnish the target
1 (90%). The physical and
spectroscopic data of synthetic 1 are consistent with the reported
chromatographically separable entities. Compound
7
was
values.4a,b,11 The HRMS spectrum displayed the [M+Na]+

2588
P. R. Krishna, R. R. Kadiyala / Tetrahedron Letters 51 (2010) 2586–2588
7. (a) Radha Krishna, P.; Narasingam, M. Tetrahedron Lett. 2004, 45, 4773–4775;
OH
(b) Radha Krishna, P.; Narasingam, M. J. Comb. Chem. 2007, 9, 62–69; (c) Radha
Krishna, P.; Reddy, P. S. J. Comb. Chem. 2008, 10, 426–435.
8. Radha Krishna, P.; Sachwani, R.; Kannan, V. Chem. Commun. 2004, 2580–2581.
9. Waanders, P. P.; Thijs, L.; Zwanenburg, B. Tetrahedron Lett. 1987, 28, 2409–
2412.
OH
O
a
b
7a
2
MOMO
10. (a) Garber, B. S.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 8168–8179; (b) Gessler, S.; Randi, S.; Blechert, S. Tetrahedron Lett.
2000, 41, 9973–9976; (c) Wang, H.; Matsuhashi, H.; Doan, D. B.; Goodmen, S.
N.; Ouyang, X.; Clark, W. M., Jr. Tetrahedron 2009, 65, 6291–6303.
O
9
Scheme 3. Reagents and conditions: (a) DIBAL-H, ꢀ10 °C, THF, 3 h, 98%; (b)
DOWEX, MeOH, 70 °C, 2 h, 90%.
11. Spectral data for selected compounds. Compound 4: Colorless syrup. ½a D25
ꢁ
+127.0
(c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3):
d 5.79–5.68 (m, 1H, olefinic),
5.36–5.31 (m, 2H, olefinic), 4.69 (d, 1H, J = 6.7 Hz, –OCH2), 4.52 (d, 1H,
J = 6.7 Hz, –OCH2), 4.10 (t, 1H, J = 6.6 Hz, allylic), 4.04–3.98 (m, 1H, methine),
3.85 (dd, 1H, J = 6.0, 7.9 Hz, methine), 3.75–3.64 (m, 2H, –OCH2), 3.36
(s, 3H, –OCH3), 1.40 (br s, 6H, 2 ꢂ CH3); 13C NMR (75 MHz, CDCl3): d 132.6,
118.1, 107.2, 94.4, 92.0, 75.2, 74.8, 61.2, 54.0, 25.4, 25.2; IR (neat): 3500,
199.0582, calculated 199.0590 for the molecular formula
C7H12O5Na.
1210 cmꢀ1 ESIMS: m/z 255 (M+Na)+, HRMS m/z: Calcd for C11H20O5Na:
Likewise, the minor isomer 7a (Scheme 3) when subjected to
same set of reactions as applied earlier afforded 9 (98%) which
was subsequently transformed into 2 (90%).5,11 In essence, both
the isomers obtained during the Baylis–Hillman reaction were
effectively converted into two target compounds through the
common synthetic methodology.
In summary, we achieved the synthesis of cyclitols, (+)-MK7607
(1), and its C4 epimer, (+)-streptol (2) by a hitherto less explored
sequential Baylis–Hillman/RCM reaction as the synthetic route to
build the cyclohexenoid derivatives that were independently
transformed into the target molecules. This report may renew
the interest in exploring Baylis–Hillman reaction-based strategies
for such natural product synthesis.
;
255.1210. Found; 255.1208. Compound 3: Colorless syrup. ½a D25
ꢁ
+52.0 (c 0.3,
CHCl3); 1H NMR (300 MHz, CDCl3): d 6.31 (s, 0.65H, olefinic), 6.20 (s, 0.35H,
olefinic), 5.93 (s, 0.65H, olefinic), 5.91 (s, 0.35H, olefinic), 5.84–5.17 (m, 1H,
olefinic), 5.39–5.20 (m, 2H, olefinic), 4.69 (d, 0.35H, J = 6.7 Hz, methine), 4.64
(d, 0.65H, J = 6.7 Hz, methine), 4.57–4.48 (m, 2H, –OCH2), 4.29–4.19 (m, 3H),
4.14–3.94 (m, 2H, –OCH2), 3.35 (s, 1.95H, –OCH3), 3.32 (s, 1.05H, –OCH3),
1.42–1.2 (m, 9H, 3 ꢂ CH3); IR (neat): 3400, 1735, 1610 cmꢀ1 ESIMS: m/z 353
;
(M+Na)+, HRMS m/z: Calcd for C16H26O7Na: 353.1563, Found: 353.1576.
Compound 7: Colorless syrup. ½a D25
ꢁ
+221.0 (c 0.37 CHCl3); 1H NMR (300 MHz,
CDCl3): d 6.94 (d, 1H, J = 6.0 Hz, olefinic), 4.91 (d, 1H, J = 3.7 Hz, allylic), 4.84 (d,
1H, J = 6.7 Hz, –OCH2), 4.62 (d, 1H, J = 6.7 Hz, –OCH2), 4.54 (dd, 1H, J = 3.7,
5.6 Hz, allylic), 4.30–4.21 (q, 2H, J = 7.1 Hz, –OCH2), 4.02 (dd, 1H, J = 3.7,
10.1 Hz, methine), 3.90 (dd, 1H, J = 3.7, 10.1 Hz, methine), 3.46 (s, 3H, –OCH3),
1.46 (br s, 6H, 2 ꢂ CH3), 1.34 (t, 3H, J = 6.7 Hz, CH3); 13C NMR (75 MHz,CDCl3): d
165.4, 135.2, 138, 110.9, 96.7, 96.1, 73.8, 72.8, 67.8, 63.8, 61.1, 55.4, 26.8, 26.7;
IR (neat): 3403, 1750, 1620 cmꢀ1; ESIMS: m/z 325 (M+Na)+, HRMS m/z: Calcd
for C14H22O7Na: 325.1267. Found: 325.1263. Compound 8: Colorless syrup.
½ ꢁ
a 2D5 +125.8 (c 0.5, CHCl3); 1H NMR (500 MHz, CDCl3): d 5.88 (d, 1H, J = 5.2 Hz,
Acknowledgments
olefinic), 4.84 (d, 1H, J = 6.4 Hz, –OCH2), 4.62 (d, 1H, J = 6.7 Hz, –OCH2), 4.40 (br
s, 1H, allylic), 4.43 (d, 2H, J = 5.2 Hz, allylic), 4.27–4.15 (m, 2H), 3.95
(s, 2H, –OCH2), 3.36 (s, 3H, –OCH3), 1.46 (br s, 6H, 2 ꢂ CH3); 13C NMR
(75 MHz, CDCl3): d 135.8, 124.8, 96.6, 73.8, 73.4, 70.3, 68.3, 65.7, 65.1, 55.5,
26.8, 26.7; ESIMS: m/z 283 (M+Na)+, HRMS m/z: Calcd for C12H20O6Na:
The authors are thankful to the DST, New Delhi for the financial
assistance of the Grants-in-Aid project under SERC with the grant
number SR/S1/OC-59/2006. One of the authors (R.R.K.) thanks CSIR,
New Delhi, for financial support in the form of a fellowship.
283.1149. Found: 283.1157. Compound 1: White solid: mp 157–159 °C. ½a D25
ꢁ
+201.3 (c 0.4, H2O); 1H NMR (500 MHz, D2O): d 5.71 (d, 1H, J = 4.6 Hz, olefinic),
4.18 (t, 1H, J = 3.8 Hz, allylic), 4.11 (d, 1H, J = 3.1 Hz, allylic), 4.00 (s, 2H, –OCH2),
3.74–3.69 (m, 2H); 13C NMR (75 MHz, D2O): d 141.2, 124.9, 69.5, 69.2, 67.6,
66.9, 62.9; IR (neat): 3372, 2955, 1634 cmꢀ1; ESIMS: m/z 199 (M+Na)+; HRMS
m/z: Calcd for C7H12O5Na: 199.0590. Found: 199.0582. Compound 7a: Colorless
References and notes
syrup. ½a 2D5
ꢁ
+178.9 (c 0.85, CHCl3); 1H NMR (300 MHz, CDCl3): d 6.88 (d, 1H,
1. Nobuji, Y.; Noriko, C.; Takashi, M.; Shigeru, U.; Kenzou, H.; Michiaki, I. Jpn.
Kokai Tokkyo Koho, JP, 06306000, 1994.
2. (a) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300–2324; (b) Arjona,
O.; Gómez, A. M.; López, J. C.; Plumet, J. Chem. Rev. 2007, 107, 1919–2036.
3. Isogai, A.; Sakuda, S.; Nakayama, J.; Watanabe, S.; Suzuki, A. Agric. Biol. Chem.
1987, 51, 2277–2279.
4. For earlier synthesis on (+)-MK7607, please see: (a) Mehta, G.; Lakshminath, S.
Tetrahedron Lett. 2000, 41, 3509–3512; (b) Lim, C.; Baek, D. J.; Kim, D.; Youn, S.
W.; Kim, S. Org. Lett. 2009, 11, 2583–2586; For the synthesis of (ꢀ)-MK7607,
see: (c) Song, C.; Jiang, S.; Singh, G. Synlett 2001, 1983–1985; Earlier synthesis
on 1-epi-(+)-MK7607, see: (d) Grondal, C.; Enders, D. Synlett 2006, 3507–3509;
5-Fluoro analog: (e) Sardinha, J.; Rauter, A. P.; Sollogoub, M. Tetrahedron Lett.
2008, 49, 5548–5550.
J = 5.2 Hz, olefinic), 4.84 (d, 1H, J = 6.7 Hz, –OCH2), 4.64 (d, 1H, J = 6.7 Hz,
–OCH2), 4.53 (d, 1H, J = 8.3 Hz, allylic), 4.48 (dd, 1H, J = 2.2, 3.7 Hz, allylic), 4.25
(q, 2H, J = 7.5 Hz, –OCH2), 4.06 (dd, 1H, J = 1.8, 6.3 Hz, methine), 3.71 (d, 1H,
J = 1.5 Hz, –OH), 3.43 (dd, 1H, J = 3.4, 6.7 Hz, methine), 3.39 (s, 3H, –OCH3), 1.50
(br s, 6H, 2 ꢂ CH3), 1.34 (t, 3H, J = 6.7 Hz, CH3); 13C NMR (75 MHz, CDCl3): d
166.0, 136.0, 135.0, 111.0, 96.7, 96.2, 76.0, 75.8, 70.8, 68.0, 61.4, 55.5, 27.2,
26.6; IR (neat): 3390, 1750, 1630 cmꢀ1; ESIMS: m/z 325 (M+Na)+, HRMS m/z:
Calcd for: C14H22O7Na: 325.1267. Found: 325.1263. Compound 2: ½a D25
ꢁ
+88.1 (c
0.3, H2O); 1H NMR (300 MHz, D2O): d 5.70 (d, 1H, J = 4.9 Hz, olefinic), 4.15 (dd,
1H, J = 4.3, 5.1 Hz, allylic), 4.10 (d, 1H, J = 15.4 Hz, –CH2), 4.00 (d, 1H,
J = 14.9 Hz, –CH2), 3.90 (dd, 1H, J = 7.6, 0.8 Hz, allylic), 3.61 (dd, 1H, J = 8.0,
11.0 Hz, methine), 3.47 (dd, 1H, J = 3.9, 11 Hz, methine); 13C NMR (75 MHz,
5. Mehta, G.; Pujar, S. R.; Ramesh, S. S.; Islam, K. Tetrahedron Lett. 2005, 46,
3373–3376.
6. Radha Krishna, P.; Rachna, S.; Reddy, P. S. Synlett 2008, 2897–2912.
D2O):
1634 cmꢀ1
199.0580. Found: 199.0570.
d
144.7, 124.9, 75.3, 75.0, 73.6, 68.6, 63.9; IR (neat): 3372, 2955,
;
ESIMS: m/z 199 (M+Na)+; HRMS m/z: Calcd for C7H12O5Na: