Enantioselective pathway for the synthesis of laurenditerpenol

Article abstract of DOI:10.1021/ol1004802

Simple enantioselective routes to the two key intermediates shown above (at center) for the synthesis of laurenditerpenol have been developed using a Diels-Alder step and the same catalyst system for each.

Full text of DOI:10.1021/ol1004802

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1836-1838
Enantioselective Pathway for the
Synthesis of Laurenditerpenol
Santanu Mukherjee, Alex P. Scopton, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received February 25, 2010
ABSTRACT
Simple enantioselective routes to the two key intermediates shown above (at center) for the synthesis of laurenditerpenol have been developed
using a Diels-Alder step and the same catalyst system for each.
The diterpenoid laurenditerpenol (1, Scheme 1), isolated from
the marine alga Laurencia intricata, is of special interest
Scheme 1. (A) Intermediates for the Synthesis of Laurenditerpenol
because it inhibits hypoxia-inducible factor-1 (HIF-1), a
1 and (B) Chiral Oxazaborolidinium Triflimide 2
factor that promotes tumor growth.1 A synthesis of 1 and
diastereomers served to clarify the stereochemistry of this
quite active HIF-1 inhibitor (IC50 400 nM).2 A synthesis of
the racemate of 1 has also been recorded.3
We report herein a stereocontrolled pathway for the
enantioselective synthesis of 1. In this synthesis, both cyclic
subunits of 1 were constructed using the enantioselective
Diels-Alder reaction promoted by catalysis with a chiral
oxazaborolidinium cation (2).4 The subunits for the current
route to 1 were the enantiomerically pure forms of the same
two key intermediates, 3 and 4, that were employed in the
recent synthesis of (()-1 (Scheme 1).3
The route for the enantioselective synthesis of 3 (Scheme
2) started with the endo-adduct 5 (90% yield, 99% ee),
obtained via Diels-Alder reaction of acrylate ester and 1,3-
(1) Mohammed, K. A.; Hossain, C. F.; Zhang, L.; Bruick, R. K.; Zhou,
cyclohexadiene using the chiral oxazaborolidinium triflimide
(S)-2, as described previously.5 Nitrosobenzene-mediated
oxidative C-C bond cleavage6 of 5 afforded the bicyclic
ketone 6 (in 68% yield), which was easily transformed into
the hydroxy acid 8 following the sequence of Baeyer-
Y.-D.; Nagle, D. G. J. Nat. Prod. 2004, 67, 2002–2007.
(2) Chittiboyina, A. G.; Kumar, G. M.; Carvalho, P. B.; Liu, Y.; Zhou,
Y.-D.; Nagle, D. G.; Avery, M. A. J. Med. Chem. 2007, 50, 6299–6302.
(3) (a) Jung, M. E.; Im, G.-Y. J. Tetrahedron Lett. 2008, 49, 4962–
4964. (b) Jung, M. E.; Im, G.-Y. J. J. Org. Chem. 2009, 74, 8739–8753.
(4) For a recent review, see: Corey, E. J. Angew. Chem., Int. Ed. 2009,
48, 2100–2117.
10.1021/ol1004802  2010 American Chemical Society
Published on Web 03/25/2010

noate 10a in the presence of 10 mol % of the catalyst
(S)-2 (Scheme 3). The desired endo-product 11a was
Scheme 2. Enantioselective Synthesis of the Key Intermediate 3
Scheme 3. Asymmetric Diels-Alder Reaction of Allenic Ester
10a and Enantioselective Synthesis of Subunit 4
Villiger oxidation7 and alkaline hydrolysis of the lactone 7.
Dess-Martin periodinane (DMP) oxidation of the allylic
alcohol generated the enone 9, which without any purification
was treated with MeMgBr in THF at 0 °C. Simple aqueous
acid treatment of the resulting tertiary alcohol produced the
lactone 3 without any loss of enantiomeric purity.
obtained in 95% yield with 87:13 dr and 87% ee.
Reduction of the ester group followed by directed hydro-
genation10 using Wilkinson’s catalyst provided the desired
diastereomer 4 with good diastereoselectivity (dr 83:17)
without any optimization.
Although the subunit 4 could in principle be constructed
by an enantioselective Diels-Alder reaction of crotonalde-
hyde and 2,5-dimethylfuran followed by reduction of CHO
and CdC, in practice, this approach was not operable because
the required Diels-Alder step did not proceed, even at 0
°C. This failure is apparently due to strong steric repulsion
between the CH3 of crotonaldehyde and one of the CH3
groups of 2,5-dimethylfuran in the transition state. That
repulsion is especially consequential because the most
advanced bonding in the transition state involves C(ꢀ) of
the R,ꢀ-enal and C(R) of the furan component.8
The catalytic asymmetric Diels-Alder reaction exampli-
fied with allenic ester 10a in Scheme 3 has been found to
be quite general. Several other examples are summarized in
Table 1. The corresponding AlBr3-activated catalyst 13 (see
below) was found to be superior to catalyst 2 in most cases.
Diels-Alder adducts were obtained in high yields with
excellent levels of diastereoselectivity and enantioselectivity.
This difficulty in the synthesis of the subunit 4 was
overcome by use of an asymmetric Diels-Alder reaction
employing an allenic ester as the dienophile (Vide infra).
Allenic esters are a class of highly reactive dienophiles, and
the corresponding Diels-Alder adducts are of synthetic
value. Despite the existence of a number of reports9 on
substrate-controlled diastereoselectiVe Diels-Alder reactions
of allenic esters, a catalytic enantioselective version of this
reaction has remained elusive.
The usefulness of these Diels-Alder adducts is illustrated
in Scheme 4. Hydrogenation of cycloadduct 11b under
carefully controlled conditions leads to selective reduction
of the endocyclic double bond with concomitant migration
of the exocyclic double bond. The resulting R,ꢀ-unsaturated
ester 14 can be reduced further to produce the fully saturated
product 15 as a single diastereomer (Scheme 4, eq 1). In
contrast, the corresponding 2,5-dimethylfuran adduct 11a
undergoes hydrogenation without migration of the exocyclic
double bond (Scheme 4, eq 2), and further reduction produces
17 as a single diastereomer. The later result is noteworthy
since hydrogenation of the corresponding alcohol 12 occurs
at the opposite face of the exocyclic double bond, as shown
in Scheme 3.
With the goal of an efficient approach to 4, we studied
the reaction of 2,5-dimethylfuran and trifluoroethyl alle-
(5) (a) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc. 2003, 125, 6388–
6390. (b) Brown, M. K.; Corey, E. J. Org. Lett. 2010, 12, 172–175.
(6) (a) Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130,
12276–12278. (b) Li, P.; Payette, J. N.; Yamamoto, H. J. Am. Chem. Soc.
2007, 129, 9534–9535.
(7) The Baeyer-Villiger oxidation must be conducted at 0 °C. Even
though the reaction at rt was found to be complete within 45 min, a
substantial amount of epoxide formation from the starting ketone was
observed together with other byproducts (see the Supporting Informa-
tion).
(8) (a) Ryu, D. H.; Zhou, G.; Corey, E. J. Org. Lett. 2005, 7, 1633–
1636. (b) Mukherjee, S.; Corey, E. J. Org. Lett. 2010, 12, 1024–1027.
(9) (a) Oppolzer, W.; Chapuis, C. Tetrahedron Lett. 1983, 24, 4665–
4668. (b) Oppolzer, W.; Chapuis, C.; Dupuis, D.; Guo, M. HelV. Chim.
Acta 1985, 68, 2100–2114. (c) Henderson, J. R.; Chesterman, J. P.; Parvez,
M.; Keay, B. A. J. Org. Chem. 2010, 75, 988–991.
(10) (a) Thompson, H. W.; Mcpherson, E. J. Am. Chem. Soc. 1974, 96,
6232–6233. (b) Brown, J. M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190–
203. For a review on substrate-directable reactions, see: (c) Hoveyda, A. H.;
Fu, G. C.; Evans, D. A. Chem. ReV. 1993, 93, 1307–1370.
Org. Lett., Vol. 12, No. 8, 2010
1837

Table 1. Catalytic Enantioselective Diels-Alder Reactions of
Allenic Esters
Scheme 5. Alkylation of the Diels-Alder Adduct 11e
rapid cyclization to the tetracyclic compound 20. The
crystalline lactone 20 was subjected to X-ray crystallographic
analysis, which established the structure and absolute con-
figuration shown (Figure 1). This result supports the assig-
a The yields correspond to the amount of product obtained after column
chromatography. b Enantiomeric excess was determined by GC analysis
using a chiral column (see the Supporting Information). Diastereomeric ratios
1
were determined by H NMR analysis of the total product mixture.
The R-alkylation of the ꢀ,γ-unsaturated Diels-Alder
adduct 11e occurred exclusively from the exo-face9a as
demonstrated for methylation and allylation (Scheme 5). The
products were obtained in high yield and essentially as a
single diastereomer (dr > 98:2). Interestingly, treatment of
the allylated adduct 19 with formic acid at 95 °C causes
Figure 1. X-ray structure of the tetracyclic lactone 20.
ments of absolute configuration of the Diels-Alder adducts
shown in Table 1, which is as predicted by the previously
proposed stereochemical model.4
In summary, a simple and efficient synthetic approach to
the diterpenoid (-)-laurenditerpenol is reported using cata-
lytic asymmetric Diels-Alder reactions to generate both key
intermediates (3 and 4). The methodology used for generating
3 provides an interesting approach for the enantioselective
synthesis of other chiral bicyclic γ-lactones.
Scheme 4. Hydrogenation of the Allenic Ester Diels-Alder
Adducts
Acknowledgment. We thank Dr. Douglas Ho and Dr.
Shao-Liang Zheng of Harvard University for X-ray diffrac-
tion analysis. Dr. Nathan Wallock of Sigma Aldrich Co. is
gratefully acknowledged for a gift of the oxazaborolidine
precatalyst and triflimide.
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL1004802
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Org. Lett., Vol. 12, No. 8, 2010