A flexible enantioselective total synthesis of diospongins A and B and their enantiomers using catalytic hetero-diels-alder/Rh-catalyzed 1,4-addition and asymmetric transfer hydrogenation reactions as key steps

Article abstract of DOI:10.1021/jo901739y

(Chemical Equation Presented) A unified enantioselective route to total synthesis of diospongins A and B and their enantiomers has been developed employing achiral starting materials. All three stereocenters were introduced by means of catalytic reactions

Full text of DOI:10.1021/jo901739y

pubs.acs.org/joc
show promising antiosteoporotic activity (45Ca release at
A Flexible Enantioselective Total Synthesis of
Diospongins A and B and Their Enantiomers Using
Catalytic Hetero-Diels-Alder/Rh-Catalyzed 1,4-
Addition and Asymmetric Transfer Hydrogenation
Reactions as Key Steps
200 μM (30.5%) and 20 μM (18.2%),3 hence, can be con-
sidered to be a lead for the discovery of potent and novel
antiosteoporotic agents (Figure 1)).
Gullapalli Kumaraswamy,*,† Gajula Ramakrishna,†
Police Naresh,‡ Bharatam Jagadeesh,‡ and
Balasubramanian Sridhar§
†Organic Division-III, Indian Institute of Chemical
Technology, Hyderabad, 500 007, India, ‡NMR Division,
Indian Institute of Chemical Technology, Hyderabad, 500 007,
§
India, and Laboratory of X-ray crystallography, Indian
Institute of Chemical Technology, Hyderabad, 500 007, India
gkswamy_iict@yahoo.co.in
Received August 12, 2009
FIGURE 1. Diospongins A and B and their enantiomers.
Diospongins A (2) and B (1) contain a six-membered cyclic
ether structural unit with 2-aryl and 6-phenacyl substitution.
Despite their structural similarity, they exhibit remarkable
differences in their biological profile. Diospongin B displays
potent inhibitory activity on bone resorption induced by
parathyroid hormone, which is comparable to that of elci-
tionin, a drug used clinically for osteoporosis while diospon-
gin A did not show any activity.
Initially, Jennings et al.4 not only achieved unambiguous
total syntheses of both (-)-diospongins A (2) and B (1) but
also validated the structures proposed by Kadota.3 Subse-
quently, a flurry of synthetic methods has appeared in the
literature for this class of compounds.4,5 Prevalent ap-
proaches used for the introduction of 2-aryl and 6-phenacyl
substitution of the diospongins are Keck allylation and
stereoselctive nucleophilic additions to the appropriate
oxocarbenium cations, respectively. With our continued
interest in developing catalytic routes to bioactive small
molecules,6 herein, we report a flexible route for the synthesis
of the diospongins based on three catalytic steps: (a) catalytic
asymmetric hetero-Diels-Alder reaction, (b) diastereoselec-
tive rhodium(I)-catalyzed 1,4-addition, and (c) catalytic
asymmetric transfer hydrogenation (CATHy) reaction
(Figure 1).
A unified enantioselective route to total synthesis of
diospongins A and B and their enantiomers has been
developed employing achiral starting materials. All three
stereocenters were introduced by means of catalytic reac-
tions.
Oxacycles possessing pharmacophoric active sites are
common structural motifs in several biologically active
natural products.1 In general, the aryl-substituted tetrahy-
dropyran core is prevalent in many of these biologically
significant small natural product molecules.2 Owing to their
privileged tetrahydropyran scaffold, these natural product
molecules exhibit potent inhibitory activity. Among them,
the intriguing C-aryl glycoside natural products diospongins
A (2) and B (1) which were isolated from the rhizomes of
Diocorea spongiosa through a bioassay-guided fractionation
The catalytic asymmetric hetero-Diels-Alder reaction
between Danishefsky’s diene 5 and furfuraldehyde 6 using
(4) Jennings, M. P.; Sawant, K. B. J. Org. Chem. 2006, 71, 7911.
(5) (a) Bressy, C.; Allais, F.; Cossy, J. Synlett 2006, 3455. (b) Bates, R. W.;
Song, P. Tetrahedron 2007, 63, 4497. (c) Hiebel, M.-A.; Pelotier, B.; Piva, O.
Tetrahedron 2007, 63, 7874. (d) Kawai, N.; Hande, S.-M.; Uenishi, J.
Tetrahedron. 2007, 63, 9049. (e) Yadav, J. S.; Padmavani, B.; Reddy, B. V.
S.; Venugopal, C.; Rao, A. B. Synlett 2007, 2045. (f) Sabitha, G.; Padmaja, P.
Helv. Chim. Acta 2008, 91, 2235. (g) Wang, H.; Shuhler, B. J.; Xian, M.
Synlett 2008, 2651. (h) Chandrasekhar, S.; Shyamsunder, T.; Jaya Prakash,
S.; Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett. 2006, 47, 47.
(6) (a) Kumaraswamy, G.; Sadaiah, K.; Ramakrishna, D. S.; Naresh, P.;
Sridhar, B.; Jagadeesh, B. Chem. Commun. 2008, 5324. (b) Kumaraswamy,
G.; Padmaja, M.; Markondaiah, B.; Jena, N.; Sridhar, B.; Udaya Kiran, M.
J. Org. Chem. 2006, 71, 337. (c) Kumaraswamy, G.; Padmaja, M. J. Org.
Chem. 2008, 73, 5198. (d) Kumaraswamy, G.; Markondaiah, B. Tetrahedron
Lett. 2007, 48, 1707. (e) Kumaraswamy, G.; Markondaiah, B. Tetrahedron
Lett. 2008, 49, 327.
*To whom correspondence should be addressed. Phone: þ 91-40-
27193154. Fax: þ 91-40-27193275.
(1) (a) Claeson. P.; Claeson. U. P.; Tuchinda. P.; Rentrakul. V. Studies in
Natural Product Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, The
Netherlands, 2002; Vol. 26, p 881. (b) Kadota, S.; Tezuka, Y.; Prasaim, J. K.; Ali,
M. S.; Banskota, A. H. Curr. Top. Med. Chem. 2003, 3, 203.
(2) (a) Tian, X.; Jaber, J. J.; Rychnovsky, S. D. J. Org. Chem. 2006, 71,
3176. (b) Ko, M. H.; Lee, D. G.; Kim, M. A.; Park, J. H.; Lee, M. S.; Lee, E.
Org. Lett. 2007, 9, 141. (c) Paterson, I.; Miller, N. A. Chem. Commun. 2008,
4708.
(3) Yin, J.; Kouda, K.; Tezuka, Y.; Le Tran, Q.; Miyahara, T.; Chen, Y.;
Kadota, S. Planta Med. 2004, 70, 54.
8468 J. Org. Chem. 2009, 74, 8468–8471
Published on Web 10/09/2009
DOI: 10.1021/jo901739y
r
2009 American Chemical Society

Kumaraswamy et al.
JOCNote
SCHEME 1. Synthesis of 8 and ent-8
TABLE 1. Reduction of Ketone 8 with Various Reducing Agents
SCHEME 2. Catalytic Asymmetric Transfer Hydrogenation
Reaction
10 mol % of the (S)-BINOL/Ti(OiPr)4 derived catalyst
generated dihydropyranone 7 with 96% enantiomeric ex-
cess.7 Further, single recrystallization of 7 from hexane:ether
(2:1) solvent mixture resulted in 99.9% enantiomeric excess
with 60% yield. With enantioenriched 7 in hand, we sought a
flexible and appropriate means for introducing a C-aryl
group into the pyranose ring. To this end, we have examined
the rhodium(I)-catalyzed stereoselective 1,4-addition of an
arylboronic acid to a cyclic enone, a protocol developed by
Miyaura,8a Hayashi,8b and Maddaford.9 Primarily, we have
explored Maddaford conditions. Accordingly, the reaction
of 7 with phenylboronic acid in the presence of 5 mol % of
Rh(cod)2BF4 in dioxane/water was heated to 100 °C for 2 h.
Surprisingly, after workup, only a trace amount of the
expected 1,4-addition product 8 was isolated. However, the
addition of 5 mol % of KOH to the reaction, under otherwise
identical conditions, furnished the product 8 in 70% yield. In
another set of reactions, when the molar ratio of the Rh
catalyst was reduced to 2.5 mol % and the KOH loading was
increased 2-fold (1:2 catalyst:KOH), the reaction proceeded
smoothly to yield the required product in 98%. The de was
determined to be >99.9% by chiral HPLC (ODH column,
2% isopropanol in hexane, flow rate 0.5 mL/min). As
proposed,9 the organometallic species ArRh(cod)2 addition
proceeded from the less hindered R-face of the enone
double bond and subsequent hydrolysis of Rh-O bond led
to high diastereoselectivity. The stereochemistry of 8
was assigned R configuration at the anomeric center based
on 1H NMR data reported in the literature.9 The 10 mol % of
(R)-BINOL/Ti(OiPr)4 derived catalyst generated ent-7.
Then, ent-7 was converted to ent-8 following the same
sequence of reagents (Scheme 1).
Next, we focused on the reduction of the keto group
of 8. An array of achiral and chiral reducing agents were
screened for this transformation and the results are shown in
Table 1. The experimental results reveal that the reduction
proceeded with Noyori’s catalyst, i.e., R,R-diamine-Ru cat-
alyst A (0.5 mol %) with the Et3N HCO2H azeotropic
3
mixture and heating at 50 °C for 3 h afforded the alcohol 9
in 96% isolated yield with >99.9% diastereoselectivity
(Chiral HPLC, ODH column, 10% isopropanol in hexane
at a flow rate of 0.5 mL/min) (Scheme 2). The absolute
configuration of the hydroxyl group was assigned as R based
on single X-ray crystallography of 9 (Figure 2). Our efforts to
synthesize the C4 epimer of 9, by using substrate 8 employing
S,S-diamine-Ru catalyst B (0.5 mol %), under otherwise
identical conditions resulted in a lower level of diastereos-
electivity (entry 5, Table 1). The R,R-diamine-Ru catalyst/
substrate 8 appears to be a matched combination, which has
overcome the inherent substrate bias, thus resulting in high
diastereoselectivity. On the other hand, S,S-diamine-Ru
catalyst/substrate 8 is a mismatched combination as evi-
denced by the modest level of diastereoselctivity.
(7) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem. 1995, 60,
5998.
(8) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T. J. Am. Chem. Soc. 1998,
120, 5579.
However, the reduction of the keto group of ent-8 with
R,R-diamine-Ru catalyst A (0.5 mol %), using a Et3N
3
HCO2H azeotropic mixture, smoothly furnished the alcohol
ent-9 in 98% yield. Further, the optical rotation of ent-9
was found to be approximately equal in magnitude to that
(9) Ramnauth, J.; Poulin, O.; Bratovanov, S. S.; Rakhit, S.; Maddaford,
S. P. Org. Lett. 2001, 3, 2571.
J. Org. Chem. Vol. 74, No. 21, 2009 8469

Kumaraswamy et al.
JOCNote
SCHEME 4. Synthesis of Diospongin B
FIGURE 2. ORTEP representation of 9 with 50% probability.
(CCDC reference no. 735811. The crystal obtained from 5% EtOAc
in hexane and crystal is weakly diffracting. For the crystal structure
of 7, please see the Supporting Information.)
of 9 but opposite in sign, indicating an enantiomeric relation-
ship. Consequently, the newly formed chirogenic center
absolute configuration was assigned as S (Scheme 3).
In principle, the ent-9 should be achieved by employing
the catalyst B. To our surprise, two enantiomeric ketones 8
and ent-8 are reduced with the same enantiomer of cata-
lyst A leading to a pair of enantiomers, i.e., 9 and ent-9.
These findings suggest that the enantiomeric Ru-template
SCHEME 5. Synthesis of ent-1
catalyst
A is efficiently differentiating diastereofaces
of pro chiral ketone 8 and ent-8. However, these findings
warrant a detailed investigation to establish the plausible
mechanism.
to rt, 6 h). Unexpectedly,11 deprotection of the TBDPS
group of compound 14 with excess TBAF12 in THF at
ambient temperature furnished product 2 in 86% yield.
Moreover, the optical data of 2 were in full agreement with
that of diospongin A reported in the literature4 ([R]23D -19.2
(c 1.2, CHCl3) {lit.4 [R]23D -19.6 (c 0.0084, CHCl3)}). Also
SCHEME 3. Catalytic Asymmetric Transfer Hydrogenation
Reaction
1
the H NMR and 13C NMR data were in full accord with
those reported for the natural product. Under identical
conditions ent-14 also resulted in ent-2. The structure of
1
ent-2 was confirmed by H and 13C NMR data.13 Further-
more, the optical rotation of ent-2 was found to be equal in
magnitude to 2, but opposite in sign, and hence was con-
sidered as enantiomer to 2 (Scheme 6).
The reaction could be rationalized on the basis of retro-
Michael opening of the pyran ring and the subsequent
intramolecular Michael reaction of the hydroxy nucleophile
to the enone leads to the thermodynamically more stable cis-
conformer (Scheme 7).
In conclusion, we have accomplished the total synthesis
of diospongins A (2) and B (1) and their enantiomers
employing achiral starting materials. To the best of our
knowledge, the syntheses of 2,6-trans isomer ent-1 and 2,6-
cis isomer ent-2 are described here for the first time. All three
Proceeding further, the hydroxy group 9 was converted to
a PMB ether 10 (NaH/PMBCl, THF, 0 °C to rt, 6 h) in 98%
yield. The furyl group of 10 was oxidatively cleaved to acid
(O3, 15 min, DCM/MeOH, [1:1]), and the resulting acid on
esterification with diazomethane (CH2N2, ether, 0 °C to rt)
gave methyl ester. Then, the methyl ester was subjected to
reduction (DIBAL-H, -78 °C) leading to 11 in 88% yield
(after 3 steps). The aldehyde 11 was then treated with the
anion derived from Horner-Emmons reagent 12 and sub-
sequent hydrolysis of intermediate enol ether resulted in 13
(75%).10
Finally, 13 was exposed to DDQ in DCM/H2O (9:1) for 1
h to furnish the target compound 1 in 92% isolated yield. The
chirooptical data of 1 were in full agreement with those
reported in the literature4 ([R]23D -22.5 (c 0.2, CHCl3) {lit.4
[R]23D -22.6 (c 0.0114, CHCl3)}) (Scheme 4).
(11) Initially, the hydroxyl group of 9 was protected with TBDPS and
carried out a complete sequence. To our surprise, the final product 1H NMR
and 13C data did not match to reported data of 1. Consequently, changing the
protecting group TBDPS to PMB followed by the same set of reactions
resulted in the expected product 1. The TBDPS protected 9 also exposed to
TBAF (10 equiv) but only deprotected 9 was recovered.
The 2,6-trans enantiomer ent-1 was synthesized in 67%
yield (over 6 steps) from ent-9 following the above-men-
tioned conditions (Scheme 5).
The C-5 hydroxyl group of diospongin B (1) was protected
as TBDPS ether to give 14 (tBu(Ph)2SiCl, Et3N, DCM, 0 °C
(12) Reaction did not proceed with less than 10 equiv of TBAF. Using
Aldrich supplied TBAF, reaction did not initiate whereas addition of 5 mol
equiv of H2O (based on TBAF mole equivalent) to the reaction under
otherwise identical conditions yielded the expected product 2. However,
TBAF supplied by Spectochem.Pvt.Ltd., India without addition of H2O
resulted in 2.
(10) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.; Ramtohul, Y. K.;
Tamber, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745.
(13) For complete details of 1H and 13C NMR data, please see the
Supporting Information.
8470 J. Org. Chem. Vol. 74, No. 21, 2009

Kumaraswamy et al.
JOCNote
SCHEME 6. Diospongin A and Enantiomer
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.9 Hz, 2H), 7.57
(t, J = 7.6 Hz, 1H), 7.47 (t, J = 8.2 Hz, 2H), 7.34 (m, 5H), 5.19 (t,
J = 4.4 Hz, 1H), 4.23 (m, 1H), 4.02 (m, 1H), 3.45 (dd, J = 7.0,
15.7 Hz, 1H), 3.17 (dd, J = 5.9, 15.7 Hz, 1H), 2.51 (ddd, J = 3.8,
5.1, 13.4 Hz, 1H), 2.05 (ddd, J = 4.4, 8.9, 14.6 Hz, 1H), 1.92
(ddd, J = 5.0, 9.7, 13.5 Hz, 1H), 1.50 (dt, J = 9.3, 12.3 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 198.3, 140.2, 137.2, 133.2, 128.6,
128.5, 128.3, 127.1, 126.3, 72.3, 66.9 64.2, 44.6, 40.1, 36.7; MS
(ES) m/z 319 (M þ Na)þ; HRMS (ESI) m/z 319.1301 (calcd for
C19H20O3Na 319.1310).
Diospongin A (2). To a stirred solution of 14 (0.853 g, 1.59
mmol) in THF (15 mL) was added TBAF (Specrochem Pvt.Ltd.,
India) (15.7 mL, 15.9 mmol, 1 M solution in THF) at 0 °C and
the reaction mixture was stirred at room temperature overnight.
The reaction mixture was quenched with H2O and extracted
with EtOAc (3 ꢀ 20 mL). The combined organic layers were
washed with brine solution and dried over anhydrous Na2SO4,
then concentrated under reduced pressure. The crude residue
was purified by column chromatography over silica gel (26%
EtOAc in hexane) to afford product 2 (0.238 g, 86%) as an
amorphous solid. [R]23D -19.2 (c 1.2, CHCl3); IR (KBr) 3624,
SCHEME 7
1
2925, 2857, 2312, 1740, 1682, 1515, 1452, 1174, 753 cm-1; H
NMR (400 MHz, CHCl3) δ 7.97 (d, J = 6.8 Hz, 2H), 7.53 (t, J =
6.8 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.22 (m, 2H), 4.90 (dd, J =
1.5, 11.3 Hz, 1H), 4.60 (m, 1H), 4.34 (t, J = 2.3 Hz, 1H), 3.39
(dd, J = 5.3, 15.9 Hz, 1H), 3.04 (dd, J = 7.5, 16.6 Hz, 1H), 1.95
(m, 2H), 1.67 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 198.3,
142.8, 137.5, 133.0, 128.5, 128.3, 128.2, 127.2, 125.8, 73.8, 69.1,
64.7, 45.2, 40.4, 38.8; MS (ESI) m/z 319 (M þ Na)þ HRMS
(ESI) m/z 319.1319 (calcd for C19H20O3Na 319.1310).
stereocenters are introduced by means of catalytic reactions
and this strategy in turn could be used to generate a library of
small molecules with varying substitutions in the aromatic
nucleus.
Acknowledgment. We are grateful to Dr. J. S. Yadav,
Director, IICT, for his constant encouragement. Financial
support was provided by the DST, New Delhi, India (Grant
No. SR/SI/OC-12/2007), and CSIR (New Delhi) is also
gratefully acknowledged for awarding a fellowship to
G.R.K. Thanks are also due to Dr. G. V. M. Sharma for
his support.
Experimental Section
Diospongin B (1). To a stirred solution of 13 (1.40 g,
3.37 mmol) in CH2Cl2:H2O (9:1) (70 mL) was added DDQ
(0.919 g, 4.05 mmol) at 0 °C and the reaction mixture was stirred
at room temperature for 1 h. The reaction mixture was quenched
with saturated NaHCO3 solution and extracted with EtOAc
(3 ꢀ 20 mL). The combined organic layers were washed with
H2O followed by brine solution and dried over anhydrous
Na2SO4, then concentrated under reduced pressure. The crude
residue was purified by flash column chromatography (30%
EtOAc in hexane) to afford the product 1 (0.91 g, 92%) as an
amorphous solid. [R]23D -22.5 (c 0.2, CHCl3); IR (KBr) 3624,
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds along
with copies of 1H, 13C NMR spectra, crystallographic data, and
NOE. This material is available free of charge via the Internet at
http://pubs.acs.org.
2925, 2857, 2312, 1740, 1682, 1515, 1452, 1174, 753 cm-1
;
J. Org. Chem. Vol. 74, No. 21, 2009 8471