A highly efficient enantioselective synthesis of 2-methyl chromans via four sequential palladium-catalyzed reactions

Article abstract of DOI:10.1016/j.tetlet.2004.12.043

An enantioselective synthesis of substituted 2-methyl chromans was accomplished in four steps using four sequential Pd-catalyzed reactions. A study of the key palladium-catalyzed regioselective aryl ether ring formation of two different substrates was also carried out to better understand the factors which affect the selectivity of the reaction.

Full text of DOI:10.1016/j.tetlet.2004.12.043

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 987–990
A highly efficient enantioselective synthesis of 2-methyl
chromans via four sequential palladium-catalyzed reactions
Michael Palucki* and Nobuyoshi Yasuda
Department of Process Research, Merck & Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 12 October 2004; revised 8 December 2004; accepted 8 December 2004
Available online 22 December 2004
Abstract—An enantioselective synthesis of substituted 2-methyl chromans was accomplished in four steps using four sequential Pd-
catalyzed reactions. A study of the key palladium-catalyzed regioselective aryl ether ring formation of two different substrates was
also carried out to better understand the factors which affect the selectivity of the reaction.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Chiral substituted 2-methyl chromans are found in
numerous pharmaceutically active compounds including
vitamin E (anti-oxidant),1 clusifoliol (anti-tumor),2 rho-
dodaurichromanic acid A (anti-HIV),3 siccanin (anti-
fungal),4 and troglitazone (diabetes).5 Consequently,
chiral 2-methyl chromans are considered high value tar-
gets in medicinal chemistry. Chiral 2-methyl chromans
have also been used as chiral dopants for nematic liquid
crystals.6 Hence, the development of an efficient and
reliable asymmetric synthesis of 2-methyl chromans
would find significant application.
around a target molecule which contains a readily reac-
tive functional group. This functional group could not
only be easily transformed to other functional groups
via traditional functional group manipulation, but could
also serve as a point of connection for incorporation
into the synthesis of biologically active molecules, thus
substantially increasing the usefulness of this methodol-
ogy. These traits along with our own drug development
needs resulted in the identification of chiral chroman 1
as our initial target.
Our retrosynthetic approach is shown in Scheme 1. We
envisioned that chiral chroman 1 can be made from its
acyclic diol 2 via Pd-catalyzed ring closing aryl ether for-
mation. Buchwald and co-workers recently described
three examples of a Pd-catalyzed cyclization of aryl
bromides containing a pendant diol.13 These substrates
contained a secondary alcohol that can cyclize to a
six-membered heterocycle and a primary alcohol that
can cyclize to a seven-membered heterocycle. In all three
cases, the six-membered heterocycle was formed exclu-
sively. In our case, however, the competition is between
a congested tertiary alcohol to forma six-membered het-
erocycle and a primary alcohol to from a seven-mem-
bered heterocycle.
Recently, Trost et al. have developed an elegant asym-
metric allylic alkylation (AAA) process for the prepara-
tion of chiral chromans.7 The methodology involves an
intramolecular Pd-catalyzed AAA reaction of a phenol
onto a pendant allyl carbonate to formthe chroman
ring. The methodology was applied to the total synthesis
of (+) clusifoliol, (À) siccanin, and the core of vitamin
E.8 Other recent methods for preparation of chiral chro-
mans include the use of resolved chroman carboxylic
acids,9 intermolecular Mitsunobu reactions between 2-
bromophenols and chiral halopropanols,10 enzymatic
desymmetrization of an achiral chroman derivative,11
and the stereoselective intramolecular 1,3-dipolar nit-
rone cycloaddition12 (Fig. 1).
While it is clear that formation of the six-membered
heterocycle should be more favorable relative to the
seven-membered heterocycle, it is unclear whether the
sterically congested tertiary alcohol would be more or
less reactive than the primary alcohol. The acyclic diol
2 can be prepared fromthe hydrogenated Heck product
of the Pd-catalyzed Heck reaction between 1-bromo-
chlorobenzene and the chiral allylic diol 5. The chiral
In our approach to developing an asymmetric synthesis
of 2-methyl chromans, we wanted to design the synthesis
Keywords: Palladium; Chroman; Asymmetric.
*
Corresponding author. Tel.: +1 732 594 8212; fax: +1 732 594
5170; e-mail: michael_palucki@merck.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.043

988
M. Palucki, N. Yasuda / Tetrahedron Letters 46(2005) 987–990
Me
HO
Me
Me
Me
Me
Me
O
Me
Vitamin E
Me
Me
OH
OH
O
Me
Me
Me
Me
Me
H
Me
O
Me
O
Me
Me
Siccanin
Clusifoliol
Me
Me
Me
Me
H
H
OH
HO
Me
HO2C
Me
H
H
O
O
N
S
O
O
Me
O
Me
Me
Troglitazone
Figure 1. Vitamin E, siccanin, clusifoliol, troglitazone, and rhododaurichromanic acid A.
Rhododaurichromanic acid A
allylic diol 5 can be obtained fromring opening of race-
mic methyl vinyl oxirane using TrostÕs Pd-catalyzed dy-
namic kinetic asymmetric transformation.14
Pd(OAc)2/P(o-tolyl)3 provided styrene derivative 3 in
84% isolated yield. Reduction of the double bond was
accomplished using catalytic 5% Pd/C under a H2 atmo-
sphere to give 2 in 83% isolated yield (Fig. 2).
The synthesis of cyclization substrate 2 starts with the
preparation of chiral butene diol 5 (Scheme 2). Follow-
ing the procedure of Trost et al., racemic methyl vinyl
oxirane was converted to 5 in 96% ee and in 60% iso-
lated yield. The palladium-catalyzed procedure was car-
ried out according to TrostÕs protocol without incident.
The palladium-catalyzed Heck reaction with 4 using
Me
OH
O
1
Figure 2. Chroman 1.
Br
Cl
Me
OH
Me
OH
OH
OH
4
Me
+
OH
O
Cl
Cl
Me
OH
OH
2
3
1
5
Scheme 1. Retrosynthesis of 1.
Br
Cl
Me
OH
OH
Me
Me
OH
OH
Pd2dba3, Trost Ligand
NaHCO3, H2O, CH2Cl2
60%
O
4
Pd(OAc)2, P-(O-tol)3
84%
5
racemic
Cl
90% ee
3
Pd/C
H2, EtOH
83%
(t-Bu)2P
Me
OH
OH
Me
+
Pd(OAc)2,
7
Me
OH
O
OH
Cs2CO3, Toluene
81%
O
6
Cl
2
1
94% ee
96% ee
Scheme 2. Asymmetric preparation of 1.

M. Palucki, N. Yasuda / Tetrahedron Letters 46(2005) 987–990
989
(t-Bu)2P
OH
OH
+
OH
OH
Pd(OAc)2,
7
O
Cl
O
12
Cs2CO3, Toluene
67%
13
Not detected
11
Scheme 3. Pd-catalyzed ring closing reaction of an analogous substrate.
Cyclization of 2 was carried out using the Buchwald
procedure employing Pd(OAc)2/ligand 7.15,16 Using
Cs2CO3 as base and toluene as solvent, an 81% isolated
yield of a 86:14 ratio of 1:6 was obtained at 90 ꢁC.17,18
Chiral HPLC analysis of the mixture showed 1 to be
96% ee and 6 to be 94% ee.19 The regioisomeric products
were not separable by silica gel chromatography, how-
ever, preparative HPLC separation gave a 64% overall
isolated yield of chroman 1 (>99% ee) fromsubstrate
2, and a 13% overall isolated yield of heterocycle 6
(>99% ee). Reducing the reaction temperature to 70 ꢁC
resulted in an 88:12 ratio of 1:6, whereas at 50 ꢁC,
<10% starting material conversion was observed.20
tion of 9 and 10 are irrelevant and that the activation en-
ergy to product will be the controlling factor in the
product distribution.
To further evaluate the factors that influence the selec-
tivity of this cyclization reaction, substrate 11 was pre-
pared and evaluated (Scheme 3). Substrate 11 was
prepared via Heck reaction of 2-bromochlorobenzene
with 3,4-butene diol, followed by hydrogenation. Using
the exact conditions used for the cyclization of 2, it was
found that substrate 11 cyclized to provide 12 as the sole
1
product. Secondary alcohol 13 was not detected by H
NMR or HPLCMS of the crude reaction mixture.24 Pri-
mary alcohol 12 was independently prepared fromchro-
man-2-carboxylic acid via formation of the ethyl ester
followed by DIBAL reduction.25
The observed 88:12 ratio of 1:6 can be rationalized in
two ways.21 First, formation of 1 over 6 is favored based
on the propensity for forming a seven-membered inter-
mediate palladacycle 9 versus an eight-membered palla-
dacycle 10 (Fig. 3). The larger ground state population
of 9 versus 10 results in formation of the six-membered
ring product versus the seven-membered ring product.
By contrast, one can also argue that the palladacycle
resulting fromcoordination of a tertiary alcohol would
reductively eliminate faster compared to a palladacycle
resulting fromcoordination of a primary alcohol in
order to minimize steric interactions in the coordination
sphere of palladium.22 It has been shown that increasing
the steric environment in the Pd-coordination sphere of
complexes of the type Pd(OR)(Ar)L facilitates reductive
elimination to form the aryl ether bond.23 Even though
palladacycle 9 may be lower in ground state energy than
10, if palladacycles 9 and 10 are in fast and reversible
equilibrium, Curtin–Hammett dictates that the popula-
The higher selectivity observed for the formation of the
six-membered heterocycle with substrate 11 compared
to substrate 2 suggest that steric factors influence prod-
uct distribution. Cyclization of a tertiary alcohol to
form a six-member ring is highly favored over cycliza-
tion of a primary alcohol to form a seven-member ring.
By comparison, cyclization of a secondary alcohol to
formsix-member rings is exclusively favored over cycli-
zation of a primary alcohol to form seven-member rings.
In summary, a novel, efficient, and highly selective meth-
od for the preparation of chiral 2-methyl chromans has
been developed. The method involves four sequential
palladium-catalyzed reactions. The palladium-catalyzed
aryl ether synthesis of an aryl chloride with a pendant
diol was carried out in good selectivity and yield. Inves-
tigation of a second substrate confirms that the steric
environment adjacent to the alcohol can influence the
selectivity in the ring closing reaction.
Me
OH
O
6
Acknowledgements
+
Pd(0)Ln
Dr. Pete Dormer is acknowledged for helpful NMR
assistance. Ms. Mirlinda Biba and Dr. Jennifer Albeneze-
Walker are acknowledged for helpful HPLC
assistance.
Me
OH
O
1
Me
OH
OH
Me
OH
References and notes
O
Pd
+
9
PdCl(L)n
1. (a) Burton, G. W.; Ingold, K. U. Ann. N.Y. Acad. Sci.
1989, 570, 7; (b) Vitamin E; Machlin, L. J., Ed.; Marcel
Dekker: New York, 1980.
2. (a) Seeram, N. P.; Jacobs, H.; McLean, S.; Reynolds, W.
F. Phytochemistry 1998, 49, 1389–1391; (b) Tanaka, T.;
Asai, F.; Iinuma, M. Phytochemistry 1998, 49, 229–
232.
Me
OH
8
Pd
O
Base
10
Figure 3. Catalytic cycle for the Pd-catalyzed aryl ether formation.

990
M. Palucki, N. Yasuda / Tetrahedron Letters 46(2005) 987–990
3. Kashiwada, Y.; Yamazaki, K.; Ikeshiro, Y.; Yamagishi,
m, 2H), 2.01–2.09 (m, 2H), 1.72–1.77 (m, 2H), 1.29 (s, 3H).
13C NMR 153.5, 129.5, 127.4, 121.1, 120.1, 117.2, 76.5,
69.2, 27.2, 21.7, 20.1. Anal. Calcd for C11H14O2: C, 74.13;
H, 7.92. Found: C, 74.14; H, 7.98.
T.; Fujioka, T.; Mihashi, K.; Mizuki, K.; Cosentino, L.
M.; Fowke, K.; Morris-Natschke, S. L.; Lee, K.-H.
Tetrahedron 2001, 57, 1559–1563.
4. Asabashi, K. J. Antibiot. Ser. A 1962, 15, 161–168.
5. Matsumoto, K.; Miyake, S.; Yano, M.; Ueki, Y.; Tom-
inaga, Y. Lancet 1997, 350, 1748–1749.
6. Shitara, H.; Aoki, Y.; Hirose, T.; Nohira, H. Bull. Chem.
Soc. Jpn. 2000, 73, 259–265.
19. SFC HPLC method: Chiralpak AD-H (250 · 4.6 mm), 4%
MeOH/CO2 for 4 min, ramp 2% per min to 40% MeOH/
CO2, hold 3 min, flow = 1.5 mL/min, 200 bar, 35 ꢁC,
25 min, 210 nm. 6, ret = 12.71 min; 6-ent, ret = 13.41 min;
1, ret = 14.07 min; 1-ent, ret = 14.75 min.
7. Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P. J. Am.
Chem. Soc. 2003, 125, 9276–9277.
20. Chroman 1 was independently prepared fromchroman-2-
carboxylic acid via esterification to the ethyl ester, a-
alkylation with methyl iodide, and reduction of the ethyl
ester to the corresponding alcohol using DIBAL.
8. Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P.;
Sylvain, C. J. Am. Chem. Soc. 2004, 126, 11966–11983.
9. See: Zhang, M.; Reeves, R.; Bi, C.; Dally, R.; Ladouceur,
G.; Bullock, W.; Chin, J. Tetrahedron Lett. 2004, 45,
5229–5231, and references sited therein.
10. Hodgetts, K. J. Tetrahedron Lett. 2000, 41, 8655–8659.
11. Chenevert, R.; Courchesne, G. Tetrahedron Lett. 2002, 43,
7971–7973.
12. Zhao, Q.; Han, F.; Romero, D. L. J. Org. Chem. 2002, 67,
3317–3322.
13. Kuwabe, S.-I.; Torraca, K. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 12202–12206.
14. Trost, B. M.; McEachern, E. J. J. Am. Chem. Soc. 1999,
121, 8649–8650.
15. (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 3395–3396; (b) Torraca, K. E.;
Kuwabe, S.-I.; Buchwald, S. L. J. Am. Chem. Soc. 2000,
122, 12907–12908.
16. Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.;
Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 4369–4378.
17. The 81% yield corresponds to the average of three runs.
18. Chroman 1: 1H NMR (CDCl3, 400 MHz) d 7.08–7.13 (m,
2H), 6.82–6.88 (m, 2H), 3.60–3.74 (m, 2H), 2.76–2.89 (br
21. One possible explanation for the observed selectivity is the
potential for palladacycle 10 to b-hydrogen eliminate to
provide an aldehyde product. NMR of the crude reaction
mixture showed no aldehydic resonances and in fact
showed clean reaction to the product heterocycles.
22. Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852–860.
23. (a) Widenhoefer, R. A.; Zhong, H. A.; Buchwald, S. L. J.
Am. Chem. Soc. 1997, 119, 6786–6795; (b) Mann, G.;
Incarbito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am.
Chem. Soc. 1999, 121, 3224–3225; (c) Aranyos, A.; Old, D.
W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 4369–4378.
24. Assuming 95% accuracy by 1H NMR, the selectivity of
this cyclization step is at least 95:5.
25. Chroman 12: 1H NMR (CDCl3, 400 MHz) d 7.06–7.13 (m,
2H), 6.842–6.89 (m, 2H), 4.12–4.16 (m, 1H), 3.86 (dd, 1H,
J = 11.7 and 3.4 Hz), 3.78 (dd, 1H, J = 11.7 and 6.3 Hz),
2.91 (dd, 1H, J = 16.4 and 6.3 Hz) 2.81 (dd, 1H, J = 16.4
and 2.8 Hz), 2.14 (br s, 1H), 1.95–2.012 (m, 1H), 1.82–1.93
(m, 1H). 13C NMR 154.5, 129.6, 127.3, 121.9, 120.4, 116.7,
76.4, 65.6, 24.5, 23.1. Anal. Calcd for C10H12O2: C, 73.15;
H, 7.37. Found: C, 73.23; H, 7.37.