Synthesis and applications of (1R,5S,6S)-6-(2,2-dimethylpropanamido)spiro[4.4]nonan-1-ol as a chiral auxiliary in Diels-Alder reactions

Article abstract of DOI:10.1016/S0957-4166(00)00242-1

A short asymmetric synthesis of (1R,5S,6S)-6-(2,2-dimethylpropanamido)spiro[4.4]nonan-1-ol 7 is described along with its application as a chiral auxiliary in various Diels-Alder reactions. The enantioselectivity of the Diels-Alder adducts ranged from 86-98% ee. The Diels-Alder adducts were easily removed from the chiral auxiliary and the latter was recyclized. The absolute and relative stereochemistry of 7 was determined from an X-ray crystal structure of the p-bromobenzoate derivative of 7. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00242-1

Tetrahedron: Asymmetry 11 (2000) 2733±2739
Synthesis and applications of
(1R,5S,6S)-6-(2,2-dimethylpropanamido)spiro[4.4]nonan-1-ol
as a chiral auxiliary in Diels±Alder reactions
Michael J. Burke, Murray M. Allan, Masood Parvez1 and Brian A. Keay*
Department of Chemistry, University of Calgary, Calgary, Alberta T2N 1N4, Canada
Received 9 May 2000; accepted 13 June 2000
Abstract
A short asymmetric synthesis of (1R,5S,6S)-6-(2,2-dimethylpropanamido)spiro[4.4]nonan-1-ol 7 is
described along with its application as a chiral auxiliary in various Diels±Alder reactions. The enantio-
selectivity of the Diels±Alder adducts ranged from 86±98% ee. The Diels±Alder adducts were easily
removed from the chiral auxiliary and the latter was recyclized. The absolute and relative stereochemistry
of 7 was determined from an X-ray crystal structure of the p-bromobenzoate derivative of 7. # 2000
Elsevier Science Ltd. All rights reserved.
1. Introduction
In 1996 we reported2 that the mono-pivalate mono-acrylate diester of (+)-(1S,5S,6S)-spiro[4.4]-
nonane-1,6-diol 13 5 underwent a Diels±Alder reaction with cyclopentadiene to produce the
expected endo-bicyclo adduct 2 in >97% de (Scheme 1). Subsequent cleavage of the resulting
adduct by iodolactonization yielded iodolactone 3 in 70% yield with an ee of >97% and spiro-
alcohol 4 which could be reused. The major drawback of this procedure was that adduct 2 is a
diester and it was dicult to selectively hydrolyze the bicycloester in the presence of the pivalate.
Iodolactonization6 was the only method that allowed the selective removal of the bicyclo adduct
from the chiral auxiliary leaving the pivalate group intact (i.e. 4). We rationalized that if the
pivalate in 1 was changed to pivalamide 5, then the selective hydrolysis of the ester in adduct 6
would be straightforward. In addition, not many 1,3-aminoalcohols have been reported as chiral
auxiliaries.7 We herein report the asymmetric synthesis of (1R,5S,6S)-6-(2,2-dimethylpropan-
amido)spiro[4.4]nonane-1-ol 7 and its application as a chiral auxiliary in a variety of Diels±Alder
reactions.
* Corresponding author. E-mail: keay@ucalgary.ca
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00242-1

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M. J. Burke et al. / Tetrahedron: Asymmetry 11 (2000) 2733±2739
Scheme 1.
2. Results and discussion
Compound (+)-7 was prepared as shown in Scheme 2. The allylation of 2-ethoxycarbonyl-1-
cyclopentanone 8 has been reported using various bases and allyl bromide in moderate to high
yields.8 However, work on asymmetric allylations of b-ketoesters by Trost9 revealed that almost
Scheme 2.

M. J. Burke et al. / Tetrahedron: Asymmetry 11 (2000) 2733±2739
2735
quantitative yields can be obtained when palladium-catalyzed reaction conditions are used.
Although 9 was desired in enantiopure form, allylation of 9 via Trost's method gave poor ee's,10
so we decided to make 9 as a racemate. Ester 9 was formed in quantitative yield using Pd(PPh3)4
(0.4 mol%) and allyl acetate (1.2 equiv.). Baker's yeast reduction of (þ)-9 with CuO gave a
20
D
20
D
mixture of (^)-(2R)-10 (39%, ‰ꢀŠ ^37.8 (c 1.20, CHCl3)) and (+)-(1S,2S)-11 (40%, ‰ꢀŠ +27.9 (c
1.20, CHCl3)).11 Unfortunately, baker's yeast reduction of the ketone functionality in (þ)-10
provided the incorrect stereochemistry at the alcohol in (+)-11 for the synthesis of (+)-8.12
Therefore, the alcohol in (+)-11 was oxidized to ketone (+)-10 with Jones' reagent and sub-
sequently reduced with lithium t-butyldiisobutylaluminium hydride2 (1.1 equiv.) to provide
20
D
exclusively (+)-12 (‰ꢀŠ +19.1 (c 1.21, CHCl3)) in yields ranging from 72±94%. Conversion of the
alcohol in (+)-12 to the mesylate (2 equiv. MsCl and pyridine, 99%) followed by the treatment
24
D
with 4 equiv. sodium azide13 (DMSO) gave (+)-13 (62±76%, ‰ꢀŠ +43.2 (c 1.25, CHCl3)).
Treatment of (+)-13 according to the procedure reported by Thebtaranonth et al.14 with LDA (4
equiv., no TMEDA) at 0ꢀC provided a 72:18 mixture of 14:(+)-15. Stirring the mixture in ethanol
18
D
containing silica gel overnight a€orded only (+)-15 (‰ꢀŠ +47.8 (c 1.15, CHCl3)), which was
puri®ed on a silica gel column (76% yield). Catalytic hydrogenation of (+)-15 gave 16 in which
both the double bond and the azide were reduced. Ketone 16 was found to be unstable and was
treated immediately with pivalyl chloride (2 equiv.) in pyridine to a€ord pivalamide (^)-17 (68%,
20
D
two steps, ‰ꢀŠ ^73.2 (c 1.21, CHCl3)). We initially thought that the pivalamide would block the
top face of the ketone such that reduction would occur from behind ketone (^)-17 to a€ord the
cis,cis-relationship between the amide and the resulting alcohol. However, treatment of (^)-17
with a variety of reducing agents provided the cis,trans-isomer (+)-7 in 92% yield. The cis,trans-
relationship and the absolute stereochemistry of (+)-7 was proven by obtaining an X-ray crystal
structure on the p-bromobenzoate (^)-18 (Fig. 1).15 Finally, three Diels±Alder precursors (^)-19
(68±82% yield), (^)-20 (79% yield) and (^)-21 (69±78% yield after migration)16 were prepared by
treatment of (+)-7 with acryloyl chloride, methacryloyl chloride and trans-crotonyl chloride
respectively (Et3N, CH2Cl2).
Figure 1. ORTEP of p-bromobenzoate 18

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M. J. Burke et al. / Tetrahedron: Asymmetry 11 (2000) 2733±2739
The results from the Diels±Alder reactions of (^)-19, (^)-20 and (^)-21 with a variety of dienes
are summarized in Table 1. All reactions were performed using 2 equiv. of BCl3 at ^78ꢀC for 8 h
and gave adducts in yield ranging from 74±82%. Reaction of (^)-19 with cyclopentadiene and
1
cyclohexadiene a€orded only endo adducts and examination of the H NMR spectra indicated
that only one endo isomer was formed. Cleavage of the adduct from the auxiliary (NaOH,
MeOH, re¯ux 1 day) provided (+)-22 and (+)-23 with % ee's >98% (by optical rotation
measurements) along with alcohol (+)-7, which was easily separated (silica gel chromatography)
and recycled. The reaction of (^)-19 with furan gave a 2:1 ratio of endo:exo adducts (by 1H NMR
integration) having a % de of 79 and 78%, respectively (by 1H NMR integration). Unfortunately,
the adducts could not be separated either before or after cleavage from the chiral auxiliary
(NaOH, MeOH, re¯ux). The Diels±Alder reaction of (^)-7 with isoprene gave a mixture of dia-
stereomers that were hydrolyzed immediately in re¯uxing NaOH in MeOH to provide compound
(+)-25 with a 92% ee. When methacrylate (^)-20 was used as the dienophile component in the
Diels±Alder reaction with cyclopentadiene, only the endo isomer was formed but in a
disappointing 21% de and further experiments were not carried out on this system. Lower
Table 1
Diels±Alder results with (^)-19, (^)-20 and (^)-21a
diastereoselectivity was observed for precursor (^)-21 with cyclopentadiene; an 8:1 ratio of
1
endo:exo isomers was formed with 86 and 64% de's, respectively (by H NMR). Acid (+)-27 was
formed with an 86% ee after it was removed from the chiral auxiliary (NaOH, MeOH).
In summary, we have developed a short synthesis of spiroaminoalcohol (+)-7 and shown it to
be a useful chiral auxiliary for Diels±Alder reactions with a variety of dienophiles and dienes. The
presence of the pivalamide allows for the selective cleavage of the Diels±Alder adducts to provide
optically active acids and alcohol (+)-7, which can easily be separated and recycled. Further uses
of spiroaminoalcohol (+)-7 are currently underway including solid-phase applications.

M. J. Burke et al. / Tetrahedron: Asymmetry 11 (2000) 2733±2739
2737
3. General experimental procedures
3.1. General procedure for Diels±Alder reactions
The starting dienophile (^)-19, (^)-20, or (^)-21 (0.34 mmol) was placed in a dry 25 mL ¯ask
under N2 containing crushed and ¯ame dried 4 A molecular sieves (100 mg) in dry CH2Cl2 (7
mL). The mixture was cooled to ^78ꢀC and BCl3 (0.68 mmol of 1 M solution in CH2Cl2) was
added. The mixture was stirred at ^78ꢀC for 0.5 h at which point the dienophile (5 equiv. freshly
distilled or cracked and collected at ^78ꢀC) was added. The mixture was stirred at ^78ꢀC for 8 h
and then passed through a plug of silica gel packed in CH2Cl2. The silica gel was rinsed with Et2O
and the solvents combined and removed in vacuo. The residue was puri®ed by silica gel
chromatography (4:1 hexanes:EtOAc) to give the puri®ed product(s).
3.2. General procedure for the removal of the Diels±Alder adduct from the chiral auxiliary
The puri®ed Diels Alder adduct from the reaction of (^)-19 with cyclopentadiene (0.12 mmol)
was placed in a 25 mL round bottomed ¯ask containing a condenser. NaOH (10 mL of 5N) and
MeOH (2 mL) was added and the mixture re¯uxed at 110ꢀC for 1 day. The mixture was cooled to
rt and the MeOH removed in vacuo. H2SO4 (15%) was added at 0ꢀC until the pH of the solution
was 2±3. The mixture was extracted with EtOAc (3Â25 mL), dried (Na2SO4) and the solvent
removed to leave a mixture of the chiral auxiliary (+)-7 and adduct (+)-22. The mixture was
separated on a silica gel column (4:1 hexanes:EtOAc) to give 79% yield of (+)-22 (0.09 mmol) and
a 73% yield of recovered auxiliary (+)-7 (0.09 mmol).
Acknowledgements
We thank the Merck Frosst Center for Therapeutic Research and the Natural Sciences and
Engineering Research Council's (NSERC) IOR program for ®nancial support. In addition,
NSERC is thanked for an undergraduate scholarship (M.M.A.).

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M. J. Burke et al. / Tetrahedron: Asymmetry 11 (2000) 2733±2739
References
1. To whom correspondence regarding crystallographic data should be addressed.
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C.-P.; Jiang, Y.; Mi, A.; Yan, M.; Sun, J.; Lou, R.; Deng, J. J. Am. Chem. Soc. 1997, 119, 9570. (b) Hu, W.; Yan,
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1, 1795. (b) Sirbu, D.; Falck-Pedersen, M. L.; Rùmming, C.; Undheim, K. Tetrahedron 1999, 55, 6703. (c) Birman,
V. B.; Rheingold, A. L.; Lam, K.-C. Tetrahedron: Asymmetry 1999, 10, 125.
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A. R.; Ramos, M. C. K. V.; Aquino Neto, F. R. Chirality 1997, 9, 321.
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14. Prempree, P.; Siwapinyoyos, T.; Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron Lett. 1980, 21, 1169.
15. Compound (^)-18: monoclinic P21 (#4); a=8.979(2) A, b=10.228(4) A, c=10.910(3) A, ꢁ=93.02(2)o,
V=1000.6(5) A3; Z=2; R=0.044; Rw=0.091; Flack parameter=^0.01(2). Bijvoet analysis was performed. A
re®nement of the inverted structure was carried out which converged with R=0.069, Rw=0.157 and the Flack
parameter=1.01(2) and was therefore rejected as the absolute con®guration present in the crystal.
16. Interestingly, the initial product from the reaction of (+)-7 with trans-crotonyl chloride was ester 28 with a
unconjugated double bond. Treatment of ester 28 with cat. p-TsOH in THF at re¯ux for 24 h provided (^)-21 in
quantitative yield.
22
D
20
D
17. Compound (+)-22: ‰ꢀŠ +69.2 (c 0.48, CHCl3). Literature: ‰ꢀŠ ^68.7 (c 0.53, CHCl3): Oppolzer, W.; Wills, M.;
Kelly, M. J.; Signer, M.; Blagg, J. Tetrahedron Lett. 1990, 31, 5015.
18. Compound (+)-23: [ꢀ]2D1.6 +34.2 (c 0.581, EtOH). Literature: [ꢀ]D +34.8 (EtOH): Cervinko, O.; Kriz, O. Collect.
Czech. Chem. Commun. 1968, 33, 2342.

M. J. Burke et al. / Tetrahedron: Asymmetry 11 (2000) 2733±2739
2739
20
19. Compound (+)-25: [ꢀ]2D1.6 +98.4 (c 0.41, 95% EtOH). Literature: ‰ꢀŠ +107 (c 4.07, 95% EtOH): Argenti, L.;
D
Bellina, F.; Carpita, A.; Rossi, R. Synth. Commun. 1995, 25, 2909.
20. Compound (+)-27: [ꢀ]2D1.6 +115.9 (c 0.345, CHCl3). Literature: [ꢀ]D +134 (c 0.7, CHCl3): Kouklovsky, C.; Pouihes,
A.; Langlois, Y. J. Am. Chem. Soc. 1990, 112, 6672.