Traceless stereoinduction in the one-pot assembly of all three rings of hexahydrodibenzopyrans

Article abstract of DOI:10.1021/ja077579m

A one-pot method has been developed for the synthesis of all three rings of the hexahydrodibenzopyran ring system. This process involves a tandem sequence consisting of a benzannulation reaction of an alkenyl Fischer carbene complex and an alkyne followed by an elimination reaction that generates an o-quinone methide chromium tricarbonyl complex that is finally followed by an intramolecular heteroatom Diels-Alder cycloaddition. The stereoinduction for the overall process begins with the transfer of stereochemical information from the chiral center at the propargylic ether in the alkyne to the planar center of chirality in the in situ generated arene chromium tricarbonyl complexed intermediate and finally, after base-induced elimination to generate an o-quinone methide chromium tricarbonyl complexed intermediate, a transfer of chirality from the planar center of chirality in the o-quinone methide complex to the two new centers of chirality at positions 6a and 10a in the hexahydrodibenzopyran products upon intramolecular Diels-Alder reaction. The reactions of diastereomeric chiral propargyl ethers that contain an additional center of chirality can lead to high diastereoselectivity in the matched case and to low selectivity in the mismatched case. Copyright

Full text of DOI:10.1021/ja077579m

Published on Web 02/15/2008
Traceless Stereoinduction in the One-Pot Assembly of All Three Rings of
Hexahydrodibenzopyrans
Keith A. Korthals and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824-1322
Received October 2, 2007; E-mail: wulff@cem.msu.edu
Scheme 1
The chemistry associated with o-quinone methides is quite
extensive and includes a diverse array of cleverly designed tactics
for their generation, a host of elegant applications in the total
synthesis of natural products, their natural role as key intermediates
in biosynthetic pathways, and as reactive intermediates, the focal
point of a range of both natural and intelligently designed bio-
activity.1 The Diels-Alder reactions of o-quinone methides with
alkenes represents a well-established method for the synthesis of
chromanes.1 For o-quinone methides bearing a substituent on the
methide carbon (2, R1 * H), the stereochemistry at that carbon in
the precursor is lost and the cycloadduct is produced in racemic
form (eq 1). Asymmetric Diels-Alder reactions of o-quinone
methides that produce an asymmetric carbon at the benzylic position
are essentially nonexistent, which is undoubtedly a function of the
high reactivity of these fleeting intermediates. The one prominent
success was reported by Pettus and co-workers and involves an
auxiliary-mediated asymmetric cycloaddition of a chiral vinyl ether.2
The high diastereomeric excess that was observed was presumably
enabled by the low-temperature method for o-quinone methide
generation developed by the Pettus group.3
istry of 9 derives from the expectation that the cycloaddition should
occur anti to the metal.5
We report here that the reactions of chromium carbene complexes
of the type 11 with enynyl propargyl ethers 10 in the presence of
base will generate hexahydrodibenzopyrans after an oxidative
workup. The involvement of a [4 + 2] cycloaddition of a chromium
complexed o-quinone methide intermediate is inferred from the high
asymmetric induction observed. Since the origins of this stereoin-
duction cannot be discerned by examination of the product this is
termed a traceless stereoinduction.
We had previously found that the reactions of Fischer carbene
complexes with propargylic ethers in the presence of t-BuMe2SiCl
and a base provided good yields of TBS-protected phenol chromium
tricarbonyl complexes of the type 7 in which the chromium
tricarbonyl unit was installed with high diastereoselectivity relative
to the existing propargylic chiral center (Scheme 1).4 This reaction
presumably proceeded via the phenol complex 6, which was then
silylated to give the ultimate product 7. The question that arises is
if the reaction of complex 4 and propargyl ether 5 is performed in
the presence of base without a silylating agent, would elimination
occur to give the o-quinone methide complex 8, which is not known
but likely exists as an η6-complex?5b Metal complexes of o-quinone
methides are known for osmium (η2),6 tungsten (η2),7 rhodium, and
iridium (η4).8 Interestingly, the o-quinone methide in the Cp*Ir
complex has inverted reactivity and displays a nucleophilic methide
carbon although this would not be expected for the chromium
tricarbonyl complex 8. There is one example of the generation of
an o-quinone methide from the reaction of a chromium carbene
complex with a propargyl ether where a dimerization of the
o-quinone methide was observed.9 However, it was not established
whether the Diels-Alder reaction that led to the dimer involved
the cycloaddition of a chromium complexed or metal free o-quinone
methide. If in fact the chromium complex 8 would undergo a Diels-
Alder reaction before the chromium is lost then the product 9 should
contain the stereochemical information present in the propargyl ether
5 via a relay to the planar center of chirality present in the phenol
complex 6 and the o-quinone complex 8. The absolute stereochem-
The reaction of carbene complex 11a (R2 ) Me, R3 ) Ph) with
the 3S-enantiomer of the enyne 10a (R1 ) TIPS) was carried out
in toluene in the presence of 5 equiv of Hu¨nig’s base. A non-
oxidative workup gave inseparable mixtures with non-cyclized pro-
ducts but it was found that 12 could be isolated cleanly upon workup
with FeCl3‚DMF complex. Hexahydrodibenzopyran 12a was ob-
tained in 60% yield with 90% ee (Table 1, entry 2). The stereo-
chemistry of the ring junction was assigned as trans on the basis
of the 1H NMR spectrum (of the Cr(CO)3 complex, see Supporting
Information) and thus results from an exo transition state in the
intramolecular Diels-Alder reaction.10 The 3R,4R configuration is
assigned assuming that the propargyl ether delivers the Cr(CO)3
group to the lower face of the o-quinone methide 8 as indicated in
Scheme 1 and that the olefin participates in a Diels-Alder reaction
that involves approach anti to the chromium in the o-quinone meth-
ide complex 8.5,11 These assumptions are supported by the matched/
mismatched study discussed below. The asymmetric induction in
the formation 12a was determined by chiral HPLC after the methyl
ether was deprotected to give a phenol. The trityl protected enyne
9
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10.1021/ja077579m CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Sequential Benzannulation, o-quinone Methide
Formation, and IMDA Reactions of Carbene Complex 11 and
Enynyl Ether 10a
Scheme 2
R3
R2
R1
temp (
°
C)
time (h)
yield 12b
% ee 12c
C6H5
Me
TIPS
TIPS
TIPS
TBS
TBS
TBS
TBS
Trityl
TIPS
TIPS
90
100
110
90
100
100
110
100
100
100
24
48
24
24
24
48
24
48
48
48
42
60
48
39
39
51
58
45
48
40
94
90
92
94
94
92
88
86
93
91
C6H5
C8H5O
Bn
Bn
a All reaction were carried out at 0.03 M carbene complex in toluene
with 1.2 equiv of alkyne and 5 equiv of (i-Pr)2EtN under argon for the
indicated time and temperature followed by oxidative workup with
FeCl3‚DMF. b Isolated yield by chromatography on silica gel. c Determined
by HPLC after either demethylation or debenzylation to the free phenol.
trans-ring junction as indicated by 1H NMR analysis. The formation
of 16 is envisioned to occur via the Diels-Alder reaction indicated
by the conformation of the o-quinone methide intermediate 21
(Scheme 2). It is well-established that a methyl group at the C-9
position of the tether such as in 21 will enforce the formation of a
single diastereomer from the Diels-Alder reaction of a metal free
o-quinone methide and this occurs via a chair transition state for
an exo-cycloaddition in which the methyl group is in an equatorial
position.13 Such a chair transition state is possible in 21 with the
cycloaddition occurring anti to the chromium but not in diastere-
omer 22, where the chromium is on the opposite face of the
o-quinone methide and where the chair transition state for the exo-
cycloaddition anti to the metal has an axial methyl. The ((3S,5S)-
enyne 18 is the mismatched case and gives a mixture of diaster-
eomers, the two most predominate of which are formed via an exo-
cycloaddition with a chair transition state with an axial methyl (22)
and an endo-cycloaddition with a chair transition state with an
equatorial methyl (23).
Table 2. Matched and Mismatched Reactions with syn and anti
Alkynesa
Acknowledgment. This work was supported by a grant from
the NIH (GM 33589).
Supporting Information Available: Experimental procedures, and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) For an excellent review, see: Van De Water, R. W.; Pettus, T. R. R.
Tetrahedron 2002, 58, 5367-5405.
(2) Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2004, 69, 9196-9203.
(3) Van De Water, R. W.; Magdziak, D. J.; Chau, J. N.; Pettus, T. R. R. J.
Am. Chem. Soc. 2000, 122, 6502-6503.
(4) Hsung, R. P.; Wulff, W. D.; Rheingold, A. L. J. Am. Chem. Soc. 1994,
116, 6449; the dr decreased with electron poor ether groups.
(5) A Cr(CO)3 group has been used to control face selectivity in additions to
o-quinone dimethides: (a) Ku¨ndig, E. P.; Leresche, J.; Saudan, L.;
Bernardinelli, G. Tetrahedron 1996, 52, 7363-7378. (b) Ku¨ndig, E. P.;
Bernardinelli, G.; Leresche, J.; Romanens, P. Angew. Chem., Int. Ed. Engl.
1990, 29, 407 and references therein.
a Conditions given in Table 1; 80-90 °C, 24-30 h.
10c (R1 ) trityl) gave a slightly lower induction than either the
TBS or TIPS ethers, which was not expected on the basis of the
diastereoselectivities observed for the complexes 7.4 High asym-
metric inductions are also observed for the benzyl protected
complexes 11b (R2 ) Bn, R3 ) Ph) and 11c (R2 ) Bn, R3 )
C8H5O).
(6) (a) Kopach, M. E.; Harman, W. D. J. Am. Chem. Soc. 1994, 116, 6581-
6592. (b) Stokes, S. M., Jr.; Ding, F.; Smith, P. L.; Keane, J. M.; Kopach,
M. E.; Jervis, R.; Sabat, M.; Harman, W. D. Organometallics 2003, 22,
4170-4171.
(7) Todd, M. A.; Grachan, M. L.; Sabat, M.; Myers, W. H.; Harman, W. D.
Organometallics 2006, 25, 3948-3954.
(8) Lev, D. A.; Grotjahn, D. B.; Amouri, H. Organometallics 2005, 24, 4232-
4240 and references therein.
The reaction of the 1,7-enyne 13 with carbene complex 11b gave
the 6-6-5 tricyclic compound 14 in 94% ee as a single diaster-
eomer that was determined to have a trans ring fusion (eq 2). This
reaction is of interest since the generation of hexahydrocyclopenta-
benzopyrans via the intramolecular Diels-Alder reaction of an
o-quinone methide is limited to four reports, which describe either
the formation of the cis-adduct in low yields (12%),12a the formation
of cycloadducts with undetermined stereochemistry,12b or the
formation of mixtures of cis and trans isomers along with
eithercycloadducts with inverted regiochemistry12c or products
resulting from carbocation rearrangements.12d
(9) (a) Yamashita, A.; Scahill, T. A.; Chidester, C. G. Tetrahedron Lett. 1985,
26, 1159-1162. (b) Yamashita, A.; Timko, J. M.; Watt, W. Tetrahedron
Lett. 1988, 29, 2513-2516.
(10) The exo transition state is observed for the intramolecular Diels-Alder
reactions of metal-free o-quinone methides in the synthesis of hexahy-
drocannabinoids; see ref 1, pp 5369-5370.
(11) The reaction of 10b and 11a in the presence of TBSCl gives 7b (R4
)
Ph, R1 ) (CH2)4CHd(CH3)2 in 82% yield as one diastereomer (dr g 96:
4) (see Supporting Information). Thus the high selectivity for 12 is not
due to selective reactions of the diastereomers of 6.
(12) (a) Boeckelheide, V.; Mao, L. V. Proc. Natl. Acad. Sci. U.S.A. 1980, 77,
1732. (b) Gutsche, C. D.; Oude-Alink, B. A. M.; Chan, A. W. K. J. Org.
Chem. 1973, 38, 1993. (c) Hug, R.; Hansen, H. J.; Schmid, H. HelV. Chim.
Acta 1972, 55, 1675. (d) Shrestha, K. S.; Honda,K.; Asami, M.; Inoue, S.
Bull. Chem. Soc. Jpn. 1999, 72, 73.
The reaction was also investigated with enynes containing a
second chiral center in addition to the propargylic ether (Table 2).
The (3R,5S)-enyne 15 is the matched case and gives a 98:2 mixture
of diastereomers the major of which was assigned as 16 having a
(13) For examples, see ref 1 and (a) Chittiboyina, A. G.; Reddy, C. R.; Watkins,
E. B.; Avery, M. A. Tetrahedron Lett. 2004, 45, 1689. (b) Marino, J. P.;
Dax, S. L. J. Org. Chem. 1984, 49, 3672.
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