5
of (S)-CPT and a 6-step racemic synthesis. We had hoped
that our 6-step route could be modified to afford enantiopure
(S)-CPT; however, our efforts at preparing the key interme-
diate 4 in an asymmetric fashion were unsuccessful. To
accomplish our goal of a 6-step asymmetric synthesis of CPT,
we decided to explore the route depicted in Scheme 1.
To limit the total number of steps to six, the AB ring
precursor 6 had to be prepared from quinoline derivative 8
in a single step. The DE ring fragment 5 would have to be
made via intermediate 7 in only three steps from com-
mercially available material. We now report the successful
development of a 6-step CPT synthesis using this strategy.
To prepare the DE ring fragment 5 in three steps, a 2-step
synthesis of intermediate 7 was required. Commercially
available 2-methoxypyridine was lithiated at C-3 with
directly to 1,3-dioxane 7 on treatment with NaI/TMSCl/
paraformaldehyde in 87% yield. Conversion of 7 to CPT
intermediate 5 was carried out in a single step. Lithium-
halogen exchange was effected with n-BuLi followed by the
5b
addition of ketoester 11 to give alkoxide 12 in situ. Addition
of HCl/i-PrOH effected protonation, acetal hydrolysis, and
lactonization to afford the desired intermediate 5. The crude
material was extracted with hot hexanes to remove and
8
recover (94%) the chiral auxiliary, (-)-TCC. The remaining
6
mesityllithium and treated with N-formyl-N,N′,N′-trimeth-
solid residue was purified by chromatography and recrys-
ylethylenediamine to give an R-amino alkoxide in situ
tallization from methanol to afford a 60% yield of DE ring
(
Scheme 2). Addition of n-BuLi effected R-amino alkoxide
intermediate 5 as white crystals: mp 222-225 °C dec;
7
23
directed lithiation at C-4 to give the dianion 9. Addition of
iodine and workup with aqueous NaBH /CeCl provided a
6% yield of alcohol 10 via a one-pot process. After
considerable effort, it was found that 10 could be converted
[R]D +117.0 (c 0.3, MeOH) (93% ee).
4
3
With the desired DE ring synthesis in hand, we explored
a 1-step preparation of AB ring fragment 6 (Scheme 3). Initial
attempts to transform commercially available 2-chloro-3-
4
quinolinecarboxaldehyde (8) into iodide 6 using a literature
(
5) (a) Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc.
992, 114, 10971. (b) Comins, D. L.; Hong, H.; Jianhua, G. Tetrahedron
Lett. 1994, 35, 5331. (c) Comins, D. L.; Saha, J. K. Tetrahedron Lett. 1995,
6, 7995. (d) Comins, D. L.; Hong, H.; Saha, J. K.; Jianhua, G. J. Org.
Chem. 1994, 59, 5120.
9
2 2 3
procedure (NaI, TMSCl, (HMe Si) O, CH CN) for this type
1
of conversion were unsuccessful. Finally, it was found that
3
(
(
6) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1988, 29, 773.
7) (a) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1990, 55, 69. (b)
(8) TCC ) trans-2-(R-cumyl)cyclohexyl: (a) (+)- and (-)-TCC alcohols
are available from Aldrich Chemical Co. (b) Comins, D. L.; Salvador, J.
M. J. Org. Chem. 1993, 58, 4656 and references therein.
For a review of R-amino alkoxide directed lithiations, see: Comins, D. L.
Synlett 1992, 615.
(9) Aizpurua, J. M.; Palomo, C. Tetrahedron Lett. 1984, 25, 1103.
4256
Org. Lett., Vol. 3, No. 26, 2001