total synthesis of these important targets, which we hoped
could be prepared efficiently from benzylidine-protected syn-
3,5-dihydroxy carboxylic esters 5 (Scheme 1).11 Accordingly,
Following our previously reported protocol the com-
mercially available ethyl sorbate15 4a was converted into the
protected diol 5a in four steps and a 35% overall yield
(Scheme 2).11 The Sharpless dihydroxylation of ethyl sorbate
4a gave diol 6 in a good yield (71%).16,17 Either enantiomer
of diol 6 can be obtained with enantiomeric excesses on the
order of 80% from the (DHQ)2PHAL ligand system and
>90% from the (DHQD)2PHAL ligand.
Scheme 1
Scheme 3
we have developed a concise and enantioselective four-step
protocol for the synthesis of protected 1,3-syn-diols such as
5 from achiral 1,3-dieneoates such as 4, where the asymmetry
was installed by the Sharpless asymmetric dihydroxylation
reaction.12 Thus, cryptocarya diacetate seemed an ideal target
to test the viability of this methodology for natural product
synthesis.
We envisioned that the C-5 through C-10 carbons of
cryptocarya diacetate could be derived from a commercially
available dienoate, ethyl sorbate. The C-7 and C-9 carbonol
stereocenters could be established by converting 4a to 5a
(Scheme 2). In addition, we planned for the introduction of
Scheme 2
To differentiate the diol functionality, 6 was converted into
a cyclic carbonate 7. The cyclic carbonate 7 was prepared
by treating a pyridine/CH2Cl2 solution of diol 6 with
triphosgene, providing 7 in an 87% yield. At this stage the
two hydroxyl groups were readily differentiated by taking
advantage of the fact that allylic carbonates are good leaving
groups for the formation of π-allyl palladium complexes.18
Treatment of 7 with a catalytic amount of palladium/
triphenylphosphine (2.5% Pd2(dba)3‚CHCl3/6.3% PPh3)19 and
a mild hydride source (Et3N/HCO2H) afforded an excellent
yield (89%) of the desired δ-hydroxy ester 8 with no loss
of enantiomeric excess.16 Exposing the δ-hydroxy enoate 8
to 3-4 equiv of benzaldehyde and a catalytic amount of
KOt-Bu led to a 64% yield of the benzylidene-protected 3,5-
dihydroxy carboxylic ester 5a.20 Thus, the ester 5a was
conveniently prepared as a single diastereomer (>95%) and
in 35% overall yield.
the C-5 stereocenter of cryptocarya diacetate by a dia-
stereoselective ketone reduction.13 Herein, we describe our
successful implementation of this strategy toward the syn-
thesis of the all-syn-1,3-triol-containing cryptocarya diacetate
1, the simplest member of this family of natural products
(Figure 1).14
(10) For some recent approaches to related 6-substituted 5,6-dihydro-
pyran-2-one containing natural products, see: (a) Gosh, A. K.; Bilcer, G.
Tetrahedron Lett. 2000, 41, 1003-1006. (b) Boger, D. L.; Ichikawa, D.;
Zhong, W. J. Am. Chem. Soc. 2001, 123, 4161. (c) Reddy, M. V. R.;
Rearick, J. P.; Hoch, N.; Ramachandran, P. V. Org. Lett. 2001, 3, 19-20.
(d) Smith, A. B.; Brandt, B. M. Org. Lett. 2001, 3, 1685-88. (e) Reddy,
M. V. R.; Yucel, A. J.; Ramachandran, P. V. J. Org. Chem. 2001, 66, 2512-
14.
(11) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 1049-1052.
(12) For other approaches to syn-3,5-dihydroxy carboxylic esters, see:
(a) Miyazawa, M.; Matsuoka, E.; Sasaki, S.; Oonuma, S.; Maruyam, K.
Miyashita, M. Chem. Lett. 1998, 109-110. (b) Evans, D. A.; Trotter, B.
W.; Coleman, P. J.; Cote, B.; Dias, L. C.; Rajpakse, H. A.; Tyler, A. N.
Tetrahedron 1999, 55, 8671-8726. (c) Solladie´, G.; Wilb, N.; Bauder, C.;
Bonini, C.; Viggiani, L.; Chiummiento, L. J. Org. Chem. 1999, 64, 5447-
52.
(14) The syn-1,3-diol structural unit is a common motif in many natural
products, with a wide range of biological activities. (a) Rychnovsky, S. D.;
Hoye, R. C. J. Am. Chem. Soc. 1994, 116, 1753-1765. (b) Rychnovsky,
S. D.; Khire, U. R.; Yang, G. J. Am. Chem. Soc. 1997, 119, 2058-2059.
(c) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021-40.
(15) The Aldrich Chemical Co. sells ethyl sorbate for $0.30/g.
(16) All levels of enantioinduction were determined by HPLC analysis
(8% IPA/hexane, Chiralcel OD) and/or Mosher ester analysis. (a) Sullivan,
G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143. (b)
Yamaguchi, S.; Yasuhara, F.; Kabuto, K. T. Tetrahedron 1976, 32, 1363.
(17) All new compounds were identified and characterized by 1H NMR,
13C NMR, FTIR, and HRMS.
(18) (a) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140. (b) Hughes,
G.; Lautens, M.; Wen, C. Org. Lett. 2000, 2, 107-110.
(19) This lower than normal (2:1 phosphine to palladium) ratio gave
higher yields and faster reaction times.
(20) Evans, D. A. Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446-
2453.
(13) Leighton has demonstrated that this can be accomplished by the
addition of allyl-(-)-diisopinocamphenylborane to similarly protected
aldehydes, but we hoped to find a less expensive alternative. Hornberger,
K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894.
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Org. Lett., Vol. 3, No. 17, 2001