Stereoselective total synthesis of (+)-polyrhacitide A

Article abstract of DOI:10.1016/j.tetlet.2010.02.070

A facile stereoselective total synthesis of secondary metabolite (+)-polyrhacitide A is described. Stereoselective aldol reaction, Horner-Wardsworth-Emmons reaction, Evans acetal intramolecular oxa-Michael reaction and diastereoselective syn reduction reaction are the key steps involved in the target synthesis.

Full text of DOI:10.1016/j.tetlet.2010.02.070

Tetrahedron Letters 51 (2010) 2154–2156
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Stereoselective total synthesis of (+)-polyrhacitide A
*
J. S. Yadav , G. Rajendar, B. Ganganna, P. Srihari
Organic Division-I, 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:
A facile stereoselective total synthesis of secondary metabolite (+)-polyrhacitide A is described. Stereose-
lective aldol reaction, Horner–Wardsworth–Emmons reaction, Evans acetal intramolecular oxa-Michael
reaction and diastereoselective syn reduction reaction are the key steps involved in the target synthesis.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 January 2010
Revised 10 February 2010
Accepted 13 February 2010
Available online 18 February 2010
Secondary metabolites continue to address several problems to-
wards human health care despite the fact that they are not in-
volved in direct growth or reproduction of the producing
organism. The secondary metabolites comprising macrolide pep-
tides, alkaloids, terpenoids and polyketides obtained from several
sources have been found to display potent antibiotic, antifungal
and antiviral properties.1 Very recently, Jiang and Kouno have re-
ported the isolation of two unusual bicyclic lactone unit containing
compounds polyrhacitides A 1 and B 2 from the Chinese ant species
Polyrhacis lamellidens Smith.2 This unit was also found to be pres-
ent as a constituent in the molecules obtained from the tree ex-
tracts of Cryptocarya species 3–5 (Fig. 1).3 The ant P. lamellidens
has been used as a folk medicine in the treatment of rheumatoid
arthritis and hepatitis in China and the crude MeOH extract of this
ant was also found to display significant analgesic and anti-inflam-
matory effects.4 The structures of polyrhacitides A and B were
identified based on exhaustive NMR studies and the absolute con-
figuration was assigned based on acetonide and Mosher’s ester
method. As these natural products are available in very scarce
amounts, total synthesis becomes a viable approach for their avail-
ability towards exploring the biological properties. While there is
only one total synthesis for polyrhacitides A and B reported by
Menz and Kirsch5 involving an iterative approach, the strategy re-
quires lengthy steps and thus the new synthetic strategies are well
desired.
O
O
1
O
O
OH OH
OH OH OH
H
H
2
5
9
11
7
H
H
6
6
O
O
3
H
H
Polyrhacitide A 1
Polyrhacitide B 2
O
O
O
H
OR OR
H
O
H
O
O
H
H
H
R = H, Cryptocaryolone 3
Bicyclo compound 5
R = Ac, Cryptocaryolone diacetate 4
Figure 1.
sized from amide 8 following a seven-step sequence through an
intermediate 7 involving stereoselective reduction, Horner–Wads-
worth–Emmons–Wittig reaction and Evans acetal intramolecular
conjugate addition reaction as the key steps. The amide 8 in turn
can be obtained from 9 involving the auxillary cleavage, followed
by a Wittig reaction and subsequent Evans acetal intramolecular
Ph
Ph
O
O
O
O
In continuation of our long-term projects involving the total
synthesis of polyketides,6 we herein wish to report the stereoselec-
tive total synthesis of polyrhacitide A by successful implementa-
tion of the strategies developed towards the synthesis of the all
syn 1,3-polyol functionalities.
Retrosynthetically, it was envisaged that the target compound
could be obtained from the key precursor 6 which can undergo
acid-mediated one-pot dibenzylidene acetal deprotection, lacton-
ization and oxa-Michael reaction. The precursor 6 can be synthe-
1
COOMe
Ph
6
6
Ph
O
O
OH
O
O
O
O
N
6
6
7
8
OH
O
S
S
O
n-Octanal
+
N
N
6
S
S
9
Ph
Scheme 1. Retrosynthesis.
Ph
10
* Corresponding author. Tel.: +91 4027193030; fax: +91 4027160387.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.070

J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2154–2156
2155
O
S
OH
O
TiCl4, DIPEA,
dry DCM
S
1. DIBAL-H, THF
5 min, -78 ºC
N
N
1-Octanal
S
+
6
S
2. 11, DBU, LiCl,
-78 ºC, 45 min
52%
CH3CN:DCM (3:1)
Ph
O
10
Ph
rt, 18h, 67 % (overall)
9
Ph
Ph
OH
O
O
O
O
O
O
PhCHO, KOtBu,
DIBAL-H, THF
O
CHO
N
N
6
6
15 min, -78 ºC,
92 %
6
THF, 0 ºC,
4h, 90%
12
13
8
Ph
O
P
O
10, TiCl4, DIPEA
DCM
O
O
OH
O
S
EtO
EtO
OMe
N
N
S
0 ºC -rt, 1h
<20%
6
Me
14
11
Ph
Scheme 2.
Ph
Ph
Ph
LiI-LiAlH4 (1:1)
THF
O
O
O
OH
O
O
OH
O
O
AllylMgCl, THF
+
8
6
0 ºC, 30 min
82 %
6
6
-40 ºC to -100 ºC
30 min, 93 %
15
9 : 1
7
7a
(syn : anti)
Ph
Ph
Ph
O3, DCM, -78 ºC
5 min., then TPP
PhCHO, KOtBu
THF
O
O
O
OH
O
O
O
O
O
N
7
O
N
O
6
11, DBU, LiCl,
0 ºC, 4h, 86%
6
CH3CN:DCM (3:1)
16
(yield based on recovery
of starting material)
17
rt, 18h, 62 % for two steps
O
Ph
Ph
DIBAL-H, THF,
O
OH OH
30 min, -78 ºC, 83 %
O
O
O
O
80% AcOH
6
O
(CF3CH2O)2POCH2COOMe,
100 ºC, overnight
82%
COOMe
6
H
6
NaH, THF, -78 ºC,
Polyrhacitide A 1
45 min, 90%
Scheme 3.
oxa-Michael reaction. Compound 9 in turn is obtained from mod-
ified Evans aldol reaction of n-octanal and N-acetyl thiazolidinethi-
one 10 (Scheme 1).
7a in 9:1 ratio. Compound 7 was subjected to ozonolysis to get the
corresponding aldehyde and was immediately treated with 11 in
the presence of DBU and LiCl to get the
a,b-unsaturated amide
An important element to our synthetic strategy is the utility of
asymmetric aldol reaction to establish the initial asymmetry. Thus,
our synthesis commenced with an aldol reaction7 of (S)-1-(4-ben-
zyl-2-thioxothiazolidin-3-yl)ethanone and n-octanal in the pres-
ence of titanium(IV) chloride and diisopropylethylamine to
install the first stereogenic centre yielding 9 as the major diaste-
reomer (Scheme 2). The compound 9 was treated with DIBAL-H
and subjected to a Wittig–Horner reaction8 with N-methoxy N-
16. The compound 16 was again subjected to Evans acetal-forming
reaction to install the fourth stereocentre yielding the product 17.
With the installation of four stereocentres, the rest was to set a
stage for building up the six-membered lactone ring formation. To-
wards this, the compound 17 was treated with DIBAL-H to get the
corresponding aldehyde and then subjected to Horner–Wittig reac-
tion with bis(2,2,2-trifluoromethyl)(methoxy carbonylmeth-
yl)phosphonate12 to get the key precursor 6 with all syn bis
benzylidene-protected tetrol and an unsaturated ester. Exposure
of this key precursor 6 to 80% AcOH13 at 100 °C for 18 h yielded
the desired bicyclic product polyrhacitide A (Scheme 3). The ana-
lytical data14 were found to be identical and optical rotation was
comparable with the reported data of both the natural2 and syn-
thetic products.5
In conclusion, a concise total synthesis of polyrhacitide A has
been accomplished in 12 steps. Modified Evans aldol approach,
Evans acetal intramolecular oxa-Michael reaction and chelation-
controlled stereoselective keto reduction reactions are the key
steps involved in the target synthesis. This approach may find wide
utility in exploring the synthesis of other diastereomers for their
biological evaluation. The total synthesis of polyrhacitide B is being
currently investigated following the above-mentioned synthetic
strategy.
methyl diethylphosphonoacetamide 119 to obtain the
a,b-unsatu-
rated amide 12 exclusively as E-isomer. The compound 12 was
subjected to an Evans acetal intramolecular oxa-Michael reaction
with benzaldehyde and potassium tert-butoxide to yield the prod-
10
uct 8 in 90% yield installing the desired 2nd stereocentre.
The amide 8 was reduced with DIBAL-H to the corresponding
aldehyde 13. With the aldehyde in hand, we attempted similar
iterative steps to generate further two stereocentres. However, as
the aldol reaction was very sluggish and the yield was very low
(<20%) for the product 14, we had to alter our approach for install-
ing the third stereocentre with better yields.
Thus, the compound 8 was treated with allyl magnesium chlo-
ride to get ketone 15. The b-alkoxy ketone 15 was subjected to che-
lation-controlled syn reduction11 using LiAlH4 and LiI to get the
desired homoallyl alcohol 7 along with an easily separable isomer

2156
J. S. Yadav et al. / Tetrahedron Letters 51 (2010) 2154–2156
14. Spectral data for few selected compounds: (R)-1-((R)-4-benzyl-2-
Acknowledgement
thioxothiazolidin-3-yl)-3-hydroxydecan-1-one (9): Yellow oil, ½a D30
ꢁ169 (c
ꢀ
1.2 , CHCl3); IR (neat): 3155, 2925, 2854, 1695, 1603, 1490, 1262, 1162, 1039,
1007, 745, 700 cmꢁ1 1H NMR (300 MHz, CDCl3): d 0.88 (t, J = 6.9 Hz, 3H), 1.28
.
G.R. and B.G. thank CSIR, New Delhi for financial assistance.
References and notes
(br s, 9H), 1.40–1.61 (m, 3H), 2.68–2.82 (br s, 1H), 2.90 (d, J = 11.5 Hz, 1H), 3.0–
3.18 (m, 2H), 3.19–3.26 (dd, J = 3.9, 13.2 Hz, 1H); 3.40 (ddd, J = 0.7, 7.1, 11.5, Hz,
1H), 3.64 (dd, J = 2.4, 17.7 Hz, 1H), 4.10–4.19 (m, 1H), 5.36–5.44 (m, 1H), 7.24–
7.38 (m, 5H); 13C NMR (75 MHz, CDCl3): 14.0, 22.6, 25.5, 29.2, 29.4, 31.8, 32.0,
36.3, 36.8, 45.8, 67.8, 68.2, 127.2, 128.8, 129.3, 136.3, 173.2, 201.3. MS-ESIMS:
m/z 380 (M+H)+. HRMS calcd for C20H29NO2NaS2: 402.1537, found 402.1538.
2-((2R,4R,6R)-6-heptyl-2-phenyl-1,3-dioxan-4-yl)-N-methoxy-N-methylaceta-
1. For recent literature see: (a) Arif, T.; Bhosale, J. D.; Kumar, N.; Mandal, T. K.;
Bendre, R. S.; Lavekar, G. S.; Dabur, R. J. Asian Nat. Prod. Res. 2009, 11, 621–638;
(b) Piel, J. Nat. Prod. Rep. 2009, 26, 338–362; (c) Nicolaou, K. C.; Chen, J. S.;
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Itokawa, H.; Morris-Natschke, S. L.; Akiyama, T.; Lee, K.-H. J. Nat. Med. 2008, 62,
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3. (a) Drewes, S. E.; Sehlapelo, B. M.; Horn, M. M.; Scott-Shawt, R.; Sandor, P.
Phytochemistry 1995, 38, 1427–1430; (b) Drewes, S. E.; Horn, M. M.; Rameswar,
N. S.; Ferreira, D. Phytochemistry 1998, 49, 1683–1687.
mide (8): pale yellow oil: ½a D30
ꢀ
+22 (c 1.0, CHCl3), IR (neat): 2927, 2854, 2073,
1646, 1455, 1113, 1019, 771, 699 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 0.88 (t,
J = 6.7, Hz, 3H), 1.22–1.55 (m, 12H), 1.60–1.70 (m, 1H), 1.77 (dt, J = 2.0, 12.8 Hz,
1H), 2.48 (dd, J = 6.2, 15.6 Hz, 1H), 2.92 (dd, J = 6.7, 14.9 Hz, 1H), 3.16 (s, 3H),
3.65 (s, 3H), 3.77–3.87 (m, 1H), 4.27–4.38 (m, 1H), 5.51, (s, 1H), 4.25–7.34 (m,
3H), 7.41–7.47 (m, 2H); 13C NMR (75 MHz, CDCl3 + CCl4): 14.2, 22.7, 25.1, 29.3,
29.6, 31.9, 36.0, 37.0, 38.2, 61.2, 65.0, 73.4, 76.6, 100.6, 126.1, 127.9, 128.3,
138.8, 171.2; MS-ESIMS: m/z 364 (M+H)+, 386 (M+Na)+; HRMS calcd for
C21H33NO4Na: 386.2307, found 386.2324. (S)-1-((2R,4S,6R)-6-Heptyl-2-
phenyl-1,3-dioxan-4-yl)pent-4-en-2-ol (7): colourless liquid, ½a D30
ꢁ3.9 (c 1.1,
ꢀ
CHCl3); IR (neat): 3460, 2925, 1854, 2361, 1641, 1459, 1114, 1019, 768 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 0.88 (t, J = 6.9 Hz, 3H), 1.21–1.39 (br s, 9H), 1.41–
1.57 (m, 3H), 1.58–1.83 (m, 4H), 2.25 (t, J = 6.6 Hz, 2H), 3.18 (s, 1H), 3.77–3.87
(m, 1H), 3.92–4.01 (m, 1H), 4.0–4.15 (m, 1H), 5.08 (s, 1H), 5.13 (d, J = 7.1 Hz,
1H), 5.55 (s, 1H), 5.77–5.92 (m, 1H), 7.29–7.38 (m, 3H), 7.43–7.49 (m, 2H); 13C
NMR (75 MHz, CDCl3): 14.0, 22.6, 24.9, 29.1, 29.4, 31.7, 35.7, 37.0, 41.9, 41.9,
70.3, 76.9, 77.3, 100.5, 117.5, 125.9, 128.1, 128.6, 134.7, 138.3. MS-ESIMS: m/z
369 (M+Na)+; HRMS calcd for C22H34NaO3: 369.2303, found 369.2318.
(Z)-Methyl-4-((2S,4S,6S)-6-(((2R,4R,6R)-6-heptyl-2-phenyl-1,3-dioxan-4-yl)-
methyl)-2-phenyl-1,3-dioxan-4-yl)but-2-enoate (6): pale yellow viscous
4. Kou, J.; Ni, Y.; Li, N.; Wang, J.; Liu, L.; Jiang, Z.-H. Biol. Pharm. Bull. 2005, 28, 176–
180.
5. Menz, H.; Kirsch, S. F. Org. Lett. 2009, 11. 5634-563.
6. (a) Srihari, P.; Rajendar, G.; Rao, R. S.; Yadav, J. S. Tetrahedron Lett. 2008, 49,
5590–5592; (b) Sabitha, G.; Gopal, P.; Yadav, J. S. Helv. Chim. Acta 2008, 91,
2240–2246; (c) Sabitha, G.; Bhaskar, V.; Reddy, S. S.; Yadav, J. S. Tetrahedron
2008, 64, 10207–10213; (d) Yadav, J. S.; Rao, P. P.; Reddy, M. S.; Rao, N. V.;
Prasad, A. R. Tetrahedron Lett. 2007, 48, 1469–1471.
7. For the synthesis of N-acetylthiazolidinethione complex see: (a) Yadav, J. S.;
Naveen Kumar, V.; Srinivasa Rao, R.; Srihari, P. Synthesis 2008, 1938–1942; (b)
Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775–777; For the acetate syn
aldol approach see: (c) Hodge, M. B.; Olivo, H. F. Tetrahedron 2004, 60, 9397–
9403; (d) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894–902.
8. Etayo, P.; Badorrey, R.; Diaz-de-Villegas, M. D.; Galvez, J. A. J. Org. Chem. 2007,
72, 1005–1008.
9. Compound 11 was synthesized in three steps from bromoacetyl bromide
according to: Nuzillard, J.-M.; Boumendjel, A.; Massiot, G. Tetrahedron Lett.
1989, 29, 3779–3780.
10. Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446–2453. Yield has
been calculated based on recovery of the starting material..
11. (a) Mori, Y.; Kuhara, M.; Takeuchi, A.; Suzuki, M. Tetrahedron Lett. 1988, 29,
5419–5422; (b) Ghosh, A. K.; Lei, H. J. Org. Chem. 2002, 67, 8783–8788.
12. Ando, K. J. Org. Chem. 1997, 62, 1934–1939.
13. Similar procedure was adopted following: Hayakawa, H.; Miyashita, M.
Tetrahedron Lett. 2007, 47, 707–711. Longer reaction time was required to
get the desired bicyclic lactone exclusively.
liquid, ½a 3D0
ꢀ
ꢁ11 (c 1.4, CHCl3); IR (neat): 2923, 2854, 2362, 1723, 1647,
1458, 1179, 1018, 759, 696 cmꢁ1
.
1H NMR (300 MHz, CDCl3):
d
0.88 (t,
J = 7.1 Hz, 3H), 1.24–1.34 (m, 10H), 1.42–1.81(m, 7H), 2.09–2.22 (m, 1H), 2.86–
2.97 (m, 1H), 3.04–3.16 (m, 1H), 3.71 (s, 3H), 3.76–3.86 (m, 1H), 3.94–4.16 (m,
3H), 5.52 (s, 1H), 5.54 (s, 1H), 5.90 (d, J = 11.5 Hz, 1H), 6.42–6.53 (m, 1H), 7.31–
7.40 (m, 6H), 7.47–7.53 (m, 4H); 13C NMR (75 MHz, CDCl3): 14.0, 22.6, 25.0,
29.2, 29.5, 31.8, 35.1, 35.9, 36.3, 36.8, 41.7, 51.0, 73.0, 73.1, 75.9, 76.9, 100.5,
100.6, 120.8, 126.0, 126.0, 128.1, 128.1, 128.5, 128.6, 138.6, 138.9, 145.7, 166.7.
MS-ESIMS: m/z 537 (M+H)+, 559 (M+Na)+; HRMS calcd for C33H44O6Na:
559.3035, found 559.3063. Polyrhacitide-A 1: colourless solid, mp = 68–70 °C.
½
a 3D0
ꢀ
+7.8 (c 0.4, MeOH), IR (neat): 3459 (O–H), 2925, 2854, 1729 (C@O), 1384,
1220, 1076, 772, 677 cmꢁ1 1H NMR (300 MHz, CDCl3): d 0.88 (t, J = 6.7 Hz, 3H),
.
1.24–1.42 (m, 9H), 1.44–1.76 (m, 8H), 1.99–2.07 (m, 3H), 2.77 (dd, J = 5.1,
19.2 Hz, 1H), 2.88 (d, J = 19.2 Hz, 1H), 3.76–3.82 (m, 1H, H-11), 4.0–4.07 (m, 2H,
H-7, 9), 4.38 (br s, 1H, H-3), 4.83–4.86 (m, 1H, H-5). 13C NMR (75 MHz, CDCl3):
14.3, 22.8, 25.5, 29.4, 29.7, 29.7, 31.9, 36.5, 37.4, 37.9, 43.1, 43.5, 66.1 (C-3),
67.0 (C-7), 72.0 (C-11), 72.1 (C-9), 72.6 (C-5), 168.2 (C-1). MS-ESIMS: m/z 329
(M+H)+, 351(M+Na)+; HRMS calcd for C18H32O5Na: 351.2147, found 351.2160.