Highly diastereoselective aldol reactions with camphor-based acetate enolate equivalents

Article abstract of DOI:10.1021/jo990865z

New lithium enolates of α-hydroxy ketones, derived from camphor, are evaluated for asymmetric aldol reactions in the presence of lithium chloride. The diastereoselectivity of the reactions between the lithium enolate of 3 and a variety of achiral aldehydes is strongly influenced by the lithium chloride salt. In these instances, the achieved levels of asymmetric induction, typically 95:5 dr, are in the range of those attained in aldol reactions involving the lithium enolate of the methyl ketone 4, which is sterically more demanding. The resulting aldol adducts are easily transformed into β-hydroxy carboxylic acids, ketones, and aldehydes with concomitant recovery of the camphor, the chiral controller of the process, which can be reused.

Full text of DOI:10.1021/jo990865z

J . Org. Chem. 1999, 64, 8193-8200
8193
High ly Dia ster eoselective Ald ol Rea ction s w ith Ca m p h or -Ba sed
Aceta te En ola te Equ iva len ts
Claudio Palomo,*,† Mikel Oiarbide,† J esu´s M. Aizpurua,† Alberto Gonza´lez,‡ J esu´s M. Garc´ıa,‡
Cristina Landa,‡ Ibon Odriozola,† and Anthony Linden§
Departamento de Quı´mica Orga´nica, Facultad de Qu´ımica, Universidad del Paı´s Vasco, Apdo 1072,
20080 San Sebastia´n, Spain, Departamento de Qu´ımica Aplicada, Universidad Pu´blica de Navarra,
Campus de Arrosadı´a, E-31006 Pamplona, Spain, and Organisch-chemisches Institut der Universitat
Zu¨rich, Winterthurerstrasse 190, CH-8057, Zu¨rich, Switzerland
Received May 27, 1999
New lithium enolates of R-hydroxy ketones, derived from camphor, are evaluated for asymmetric
aldol reactions in the presence of lithium chloride. The diastereoselectivity of the reactions between
the lithium enolate of 3 and a variety of achiral aldehydes is strongly influenced by the lithium
chloride salt. In these instances, the achieved levels of asymmetric induction, typically 95:5 dr, are
in the range of those attained in aldol reactions involving the lithium enolate of the methyl ketone
4, which is sterically more demanding. The resulting aldol adducts are easily transformed into
â-hydroxy carboxylic acids, ketones, and aldehydes with concomitant recovery of the camphor, the
chiral controller of the process, which can be reused.
In tr od u ction
aldol reactions still continues to be a problem.9 Recent
research in this laboratory10 has led to the design of the
lithium enolate of the methyl ketone 4 (Scheme 1) that
helps to solve these limitations. The main distinguishing
features of our model are, firstly, the use of camphor and
acetylene, vide infra, as the inexpensive and readily
available starting materials for the preparation of the
methyl ketone reagent, secondly, the high diastereo-
selectivities attained in “acetate” aldol reactions and,
finally, an easy post-reaction/final recovery of the starting
The asymmetric aldol reaction has become a major tool
for the stereocontrolled construction of carbon-carbon
bonds.1 The significance of this reaction stems from the
fact that the aldol or derived 1,3-dioxygenated function-
ality is a key structural element of important classes of
natural products or their precursors, including mac-
rolides, ionophores, and â-lactam antibiotics.2 Among the
methodologies developed in the asymmetric aldol reac-
tion,1,3 the version that uses carboxylic acid derived chiral
enolates still continues to have extensive synthetic ap-
plications.4 Well-established examples of the latter are
the Evans R-amino acid derived N-acyloxazolidinones5
and the Oppolzer’s N-acylcamphorsultam derivatives.6
High diastereofacial selectivities have also been attained
in aldol reactions using chiral R-oxy and/or R-amino
ketone enolates.7 In these instances (Figure 1), however,
the access to the desired R-substituted â-hydroxy car-
boxylic acids involves the destruction of the source of
chiral information at a later stage.7,8 In addition, al-
though both the carboxylic acid derived enolate and the
R-oxy ketone enolate methodologies have proven to be
very effective for “propionate” aldol reactions, the insuf-
ficient stereoselectivity generally attained in “acetate”
(4) For detailed information on this topic, see: (a) Rahman, A.-ur.;
Shah, Z. Stereoselective Synthesis in Organic Chemistry; Springer-
Verlag: Berlin, 1993. (b) Seyden-Penne, J . Chiral Auxiliaries and
Ligands in Asymmetric Synthesis; J ohn Wiley: New York, 1995. (c)
Ager, D. J .; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96, 835. For
recent examples of chiral auxiliary methodology in aldol reactions,
see: From oxazinone-imide enolates. (d) Abbas, T. R. Cadogan, J . I.
G.; Doyle, A. A.; Gosney, I.; Hodgson, P. K. G.; Howells, G. E.; Hulme,
A. N.; Parsons, S.; Sadler, I. H. Tetrahedron Lett. 1997, 38, 4917. (e)
Banks, M. R.; Cadogan, J . I. G.; Gasney, I.; Gould, R. O.; Hodgson, P.
K. G.; McDougall, D. Tetrahedron 1998, 54, 9765. (f) Miyake, T.; Seki,
M.; Nakamura, Y.; Ohmizu, H. Tetrahedron. Lett. 1996, 37, 3129. From
oxazolidinone- and imidazolidinone-imide enolates (g) Sudo, A.; Saigo,
K. Tetrahedron: Asymmetry 1996, 7, 2939. (h) Ghosh, A. K.; Cho, H.;
Onishi, M. Tetrahedron: Asymmetry 1997, 8, 821. (i) Sibi, M. P.;
Deshapude, P. K.; J i, J . Tetrahedron Lett. 1995, 36, 8965. (j) Lu¨tzen,
A.; Ko¨ll, P. Tetrahedron: Asymmetry 1997, 8, 1193. (k) Ishizuka, T.;
Kunieda, T. J . Synth. Org. Chem. J pn. 1995, 53, 27. (l) Gabriel, T.;
Wessjohan, L. Tetrahedron Lett. 1997, 38, 4387. (m) Kagoshina, H.;
Hashimoto, Y.; Oguro, D.; Saigo, K. J . Org. Chem. 1998, 63, 691. (n)
Hintermann, T.; Seebach, D. Helv. Chim. Acta 1998, 81, 2093. From
amide-enolates (o) Ezquerra, J .; Rubio, A.; Martin, J .; Garc´ıa Nav´ıo,
J . L. Tetrahedron: Asymmetry 1997, 8, 669. (p) Boeckman, R. K.;
Connell, B. T. J . Am. Chem. Soc. 1995, 117, 12368. From ester enolates
(q) Ghosh, A. K.; Onishi, M. J . Am. Chem. Soc. 1996, 118, 2527. (r)
Abiko, A.; Liu, J i-F. J . Am. Chem. Soc. 1997, 119, 2586. (s) Ghosh, A.
K.; Fidanze, S.; Onishi, M.; Hussain, K. A. Tetrahedron Lett. 1997,
38, 7171.
(5) (a) Evans, D. A.; Nelson, J . V.; Taber, T. R. Top. Stereochem.
1982, 13, 1. (b) Evans, D. A. Aldrichimica Acta 1982, 15, 23. (c) Nerz-
Stormes, M.; Thornton, E. R. J . Org. Chem. 1991, 56, 2489. (d)
Crimmins, M. T.; King, B. W.; Tabet, E. A. J . Am. Chem. Soc. 1997,
119, 7883. (e) Ager, D. J .; Prakash, I.; Schaad, D. R. Aldrichim. Acta
1997, 30, 3.
(6) (a) Oppolzer, W.; Blagg, J .; Rodriguez, I.; Walther, E. J . Am.
Chem. Soc. 1990, 112, 2767. For reviews on camphor based chiral
auxiliaries, see: (b) Oppolzer, W. Tetrahedron 1987, 43, 1969. (c) Uang,
B.-J . In Modern Methodology in Organic Synthesis; Shono, T., Ed.;
VCH: Weinheim, 1992; p 373. (d) Uang, B.-J .; Po, S. Y.; Hung, S.-C.;
Liu, H.-H.; Hsu, C.-Y.; Lin, Y.-S.; Chang, J .-W. Pure Appl. Chem. 1997,
69, 615.
† Universidad del Pa´ıs Vasco.
‡ Universidad Pu´blica de Navarra.
§ Organisch-chemisches Institut der Universitat Zu¨rich.
(1) For recent reviews on asymmetric aldol reactions, see: (a)
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Heathcock,
C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2. (b) Heathcock, C. H. In
ref 1a, p 133. (c) Kim, M.; Williams, S. F.; Masamune, S. In ref 1a, p
239. (d) Paterson, I. In ref 1a, p 301. (e) Franklin, A. S.; Paterson, I.
Contemp. Org. Synth. 1994, 1, 317. (f) Braun, M.; Sacha, H. J . Prakt.
Chem. 1993, 335, 653. (g) Braun, M. In Stereoselective Synthesis
(Houben-Weyl); Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schau-
mann, E., Eds.; Thieme: Stuttgart, 1996; Vol. E21/3, p 1603. (h)
Cowden, C. J .; Paterson, I. Org. React. 1997, 51, 1.
(2) Hanessian, S. Total Synthesis of Natural Products: The Chiron
Approach; Pergamon: Oxford, 1983. (b) Nicolau, K. C.; Sorensen, E.
J . Classics in Total Synthesis; VCH: Weinheim, 1996.
(3) For recent reviews on catalytic enantioselective aldol additions,
see: (a) Mukaiyama, T. Aldrichim. Acta 1996, 29, 59. (b) Nelson, S.
G. Tetrahedron: Asymmetry 1998, 9, 357. (c) Gro¨ger, H.; Volg, E. M.;
Shibasaki, M. Chem. Eur. J . 1998, 4, 1137. (d) Mahrwald, R. Chem.
Rev. 1999, 99, 1095.
10.1021/jo990865z CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/06/1999

8194 J . Org. Chem., Vol. 64, No. 22, 1999
Palomo et al.
Sch em e 1
potential applicability for scaling-up and, formally, it
involves the conversion of acetylene11 into â-hydroxy
carboxylic acids, ketones, and aldehydes. Herein, we
present further evidence of the powerful ability of this
lithium enolate model to transfer chiral information in
those aldol reactions that inherently have particularly
poor diastereofacial selectivity.12
F igu r e 1. Array of chiral nonracemic R′-amino and R′-oxy
ketones developed for asymmetric aldol reactions. TBS: tert-
butyldimethylsilyl.
camphor that enables its reuse as the chiral controller
of the process. In this way the method appears to have
Resu lts a n d Discu ssion
(7) (a) Heathcock, C. H.; Pirrung, M. C.; Buse, C. T.; Hagen, J . P.;
Young, S. D.; Sohn, J . E. J . Am. Chem. Soc. 1979, 101, 7077. (b)
Heathcock, C. H.; Pirrung, M. C.; Lampe, J .; Buse, C. T.; Young, S. D.
J . Org. Chem. 1981, 46, 2290. (c) Van Draanen, N. A.; Arseniyadis, S.;
Crimmins, M. T.; Heathcock, C. H. Ibid. 1991, 56, 2499. (d) Heathcock,
C. H.; White, C. T.; Morrison, J . J .; Van Derveer, D. Ibid. 1981, 46,
1296. (e) Masamune, S.; Ali, S. K.; Snitman, D. L.; Garbey, D. S. Angew.
Chem. Int. Engl. 1980, 19, 557. (f) Masamune, S.; Choy, W.; Kerdesky,
F. A. L.; Imperiali, B. J . Am. Chem. Soc. 1981, 103, 1566. (g)
Masamune, S.; Kaiho, T.; Garvey, D. S. Ibid. 1982, 104, 5521. (h)
Masamune, S.; Lu, L. D. L.; J ackson, W. P.; Kaiho, T.; Toyoda, T. Ibid.
1982, 104, 5523. (i) Boschelli, D.; Ellingboe, J . W.; Masamune, S.
Tetrahedron Lett. 1984, 25, 3395. (j) Siegel, C.; Thornton, E. R. J . Am.
Chem. Soc. 1989, 111, 5722. (k) Panyachotipun, C.; Thornton, E. R.
Tetrahedron Lett. 1990, 31, 6001. (l) Choudhury, A.; Thornton, E. R.
Ibid. 1992, 48, 5701. (m) Choudhury, A.; Thornton, E. R. Ibid. 1993,
34, 2221. (n) Paterson, I.; Wallace, D. J .; Vela´zquez, S. M. Ibid. 1994,
35, 9083. (o) Figueras, S.; Martin, R.; Romea, P.; Urpi, F.; Vilarrasa,
J . Ibid. 1997, 38, 1637. (p) Evans, D. A.; Nelson, J . V.; Vogel, E.; Taber,
T. R. J . Am. Chem. Soc. 1981, 103, 3099. (q) Trost, B. M.; Urabe, H. J .
Org. Chem. 1990, 55, 3982. (r) Lagu, B. R.; Crane, H. M.; Liotta, D. C.
Ibid. 1993, 58, 4191. (s) Lagu, B. R.; Liotta, D. C. Ibid. 1994, 35, 4485.
(t) Goh, J . B.; Lagu, B. R.; Wurster, J .; Liotta, D. C. Ibid. 1994, 35,
6029. (u) Denmark, S. E.; Stavenger, R. A. J . Org. Chem. 1998, 63,
9524.
As we have previously reported,10 reactions between
the lithium enolate of 4 (Scheme 1) and some representa-
tive aldehydes yielded the corresponding aldol products
with remarkably high diastereoselectivity. The diaster-
eomeric ratio of the product was unchanged after desi-
lylation to afford the adducts 5/6, typically 95:5 (Table
1). In every case, the reactions were conducted at -78
°C by addition of a precooled (-78 °C) THF solution of
the respective aldehyde (2-3 equiv) to the previously
generated lithium enolate of 4. The latter was generated
at -78 °C in dry THF using lithium diisopropylamide
(LDA). We have now found that freshly generated LDA
is the most effective amide base compared with both
potassium bis(trimethylsilyl)amide (KHMDS) and so-
dium bis(trimethylsilyl)amide (NaHMDS). Thus, whilst
the treatment of benzaldehyde with the enolate gener-
ated from 4 and KHMDS afforded the corresponding
dehydrated enone, the same aldehyde upon treatment
with the enolate generated by using NaHMDS led to the
expected aldol adduct with a low 50% yield. At this point
it was our concern to investigate whether it is necessary
or not to have the trimethylsilyl group attached to the
R-hydroxy function in 4. If aldol reactions conducted with
the lithium enolate of 3 afforded similar results, it would
demonstrate the inherent ability of this particular model.
In this regard, prior studies have established that the
size of the R-OR group is one of the main stereochemical
control elements in lithium-mediated ketone aldol reac-
tions.7j-n,o It has also been found that aldol reactions
(8) (a) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M.
C.; Sohn, J . E. Lampe, J . J . Org. Chem. 1980, 45, 1066. (b) Heathcock,
C. H.; Young, S. D.; Hagen, J . P.; Pirrung, M. C.; White, C. T.; Van
Derveer, D. Ibid. 1980, 45, 3846. (c) Bal, B.; Buse, C. T.; Smith, K.;
Heathcock, C. H. Organic Syntheses; Wiley: New York, 1990; Collect.
Vol. 7, p 185.
(9) For detailed information on this topic, see: (a) ref 1f,g. (b) Braun,
M. Angew. Chem. Int. Engl. 1987, 26, 24. (c) Braun, M. In Advances
in Carbanion Chemistry; V. Snieckus, Ed.; J ai Press: London, 1992;
Vol. 1, p 177. For recent examples on acetate imide or thioimide
enolate, see: (d) Yan, T.-H.; Hung, A. W.; Lee, H.-C.; Chang, C.-S. J .
Org. Chem. 1994, 59, 8187. (e) Otsuka, K.; Ishizuka, T.; Kimura, K.;
Kunieda, T. Chem. Pharm. Bull. 1994, 42, 748. (f) Powers, T. S.; Shi,
Y.; Wilson, K. J .; Wolff, W. D. J . Org. Chem. 1994, 59, 6882. (g) Yan,
T. H.; Hung, A. W.; Lee, H.-C.; Chang, C. S.; Liu, W.-H. J . Org. Chem.
1995, 60, 3301. (h) Palomo, C.; Oiarbide, M.; Gonza´lez, A.; Garc´ıa, J .
M.; Berre´e, F.; Linden, A. Tetrahedron Lett. 1996, 37, 6931. (i) Bond,
S.; Perlmutter, P. J . Org. Chem. 1997, 62, 6397. For a recent example
on virtually complete asymmetric induction with a methyl ketone via
SAEP-hydrazone, see: (j) Enders, D.; Dyker, H.; Leusink, F. R. Chem.
Eur. J . 1998, 4, 311. For a recent ester acetate enolate, see: (k) Saito,
S.; Hatanaka, K.; Kano, T.; Yamamoto, H. Angew. Chem. Int. Ed. 1998,
37, 3378.
(11) For industrial applications of acetylene, see: Weissermel, K.;
Arpe, H.-J . In Industrial Organic Chemistry; VCH: Weinham, 1993;
p 89.
(12) For catalytic asymmetric aldol reactions solving this problem,
see: (a) Reference 36. (b) Groger, H.; Vogl, E. M.; Shibaski, M. Chem.
Eur. J . 1998, 4, 1137. (c) Yoshikawa, N.; Yamada, Y. M. A.; Das, J .;
Sasai, H.; Shibasaki, M. J . Am. Chem. Soc. 1999, 121, 4168.
(10) Palomo, C.; Gonza´lez, A.; Garc´ıa, J . M.; Landa, C.; Oiarbide,
M.; Rodr´ıguez, S.; Linden, A. Angew. Chem. Int. Ed. 1998, 37, 180.

Diastereoselective Aldol Reactions
J . Org. Chem., Vol. 64, No. 22, 1999 8195
Ta ble 1. Effect of th e Meta l Cou n ter ion u p on th e Dia ster eoselectivity of th e Ald ol Rea ction of th e En ola te of 3 a n d 4
w ith Rep r esen ta tive Ald eh yd esa
entry
aldehyde
C6H5CHO
lithium enolate of
additiveb (equiv)
selectivity ratio 5:6c
yield (%)d,e
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4
3
3
4
3
4
3
4
3
4
3
4
3
3
4
3
3
96:4
80 (100:0)
86 (100:0)
70 (85:15)
ND (80:20)
ND (40:60)
ND (50:50)
30 (100:0)
67 (85:15)
ND (85:15)
85 (100:0)
ND (100:0)
67 (100:0)
81 (100:0)
72 (85:15)
75 (95:5)
72:28
86:14
33:67
50:50
25:75
15:85
96:4
84:16
95:5
75:25
97:3
86:14
88:12
96:4
89:11
25:75
MgBr2 (2.2)
AlMe2Cl (1.2)
AlMe2Cl (2.4)
Ti(OiPr)3Cl (4.0)
Ti(OiPr)3Cl (4.0)
4-CH3C6H4CHO
PhCH2CH2CHO
i-C3H7CHO
ZnCl2 (2.2)
(CH3)2CHCH2CHO
ND (70:30)
71 (100:0)
Ti(OiPr)3Cl (4.0)
a
b
Reactions conducted at -78 °C on a 0.5 mmol scale by adding the aldehyde to the corresponding enolate in THF. Mg and Zn enolates
were prepared by transmetalation of the Li enolate with dry MgBr2 or ZnCl2, respectively, for 1 h at -78 °C; Ti and Al enolates were
prepared by transmetalation of the Li enolate with Ti(OiPr)3Cl or AlMe2Cl, respectively, for 1.5 h at -30 °C. c Ratios determined by 13C
NMR analysis of the reaction crudes. Values in parentheses represent the ratio product:starting ketone. e Combined yields of both
d
compounds 5 and 6 after purification of the crude product by column chromatography (eluant ethyl acetate:hexane); ND, not determined.
Ta ble 2. Ald ol Rea ction of th e Lith iu m En ola te of 3 w ith
involving the metal enolates of R-hydroxy ethyl ketones
provided substantially lower levels of diastereoselectivity
than those involving the respectively more sterically
demanding R-trimethylsilyloxy derivatives.8a On the basis
of these precedents, it was not a surprise to observe that
the lithium enolate of 3, generated at -78 °C with 2 equiv
of LDA in THF as solvent, reacted with benzaldehyde
and 4-methylbenzaldehyde to provide the corresponding
aldols with significantly lower selectivities compared with
those achieved with the lithium enolate of 4. For example,
as Table 1 shows, the diastereomeric ratio of aldols
dropped from 96:4 to 72:28 for the first case (Table 1,
entries 1 and 2) and from 96:4 to 84:16 for the latter
(Table 1, entries 8 and 9). The same trend was observed
in reactions of the lithium enolate 3 with aliphatic
aldehydes such as hydrocinnamaldehyde (Table 1, entries
10 and 11), isobutyraldehyde (Table 1, entries 12 and 13),
and isovaleraldehyde (Table 1, entries 15 and 16). At-
tempts to improve the results obtained with 3 through
transmetalation of its lithium enolate with MgBr2, AlMe2-
Cl, and ZnCl2 were unsuccessful. Of interest, however,
the transmetalation of the organolithium derived from
3, generated as above, with a 4-fold excess of Ti(OiPr)3Cl
according to Reetz and Peter13 and subsequent reaction
with benzaldehyde led to 5a /6a in a ratio of 15:85 (Table
1, entry 7). Under the same conditions, isovaleraldehyde
gave 5k /6k in a ratio of 25:75 (Table 1, entry 17). In both
cases, although the chemical yield and the attained
diastereoselectivity were low, a reversal in the ratio of
isomers was observed.
Rep r esen ta tive Ald eh yd es in th e P r esen ce of LiCla
entry
aldehyde
C6H5CHO
4-CH3C6H4CHO
C6H5-CHdCH-CHO
CH3CHO
selectivity ratiob 5:6 yield 5 (%)c
1
2
3
4
5
6
7
8
9
88:12
93:7
67
76
71
70d
65
61
60d
65
75
67
75
70
89:11
96:4
CH3CH2CHO
93:7
94:6
CH3(CH2)3CHO
CH3(CH2)4CHO
CH3(CH2)5CHO
C6H5CH2CH2CHO
i-C3H7CHO
94:6
91:9
88:12
95:5
10
11
12
(CH3)2CHCH2CHO
(CH3)3CCHO
93:7
>98:2
a
Reactions conducted at -78 °C on a 0.5 mmol scale by adding
a precooled (-78 °C) solution of the aldehyde in THF to the lithium
b
enolate of 3 and 6-fold excess of LiCl in the same solvent. Ratios
determined by both 13C NMR and HPLC analysis of the reaction
crudes. c Yields of pure compound 5 after purification of the crude
product by column chromatography and separation of diastereo-
mers by HPLC (Merck LiChrosorb Si 60 7 µm column, eluant ethyl
d
acetate:hexane). Yields of the mixture of both isomers 5 and 6
after purification of the crude product by column chromatography.
marizes the results achieved when the lithium enolate
of 3, generated as above but in the presence of a 6-fold
excess of LiCl, was treated with the respective precooled
aldehyde. As can be seen, the predicted enhancement of
the diastereoselectivity occurred in essentially all the
examples tested. When benzaldehyde was employed
(14) For some examples, see: (a) Yamamoto, Y.; Yamada, J . J . Chem.
Soc., Chem. Commun. 1988, 802. (b) Hall, P. L.; Gilchrist, J . H.;
Collum, D. B. J . Am. Chem. Soc. 1991, 113, 9571. (c) J uaristi, E.; Beck,
A. K.; Hansen, J .; Matt, T.; Mukhopadhyay, T.; Simson, M.; Seebach,
D. Synthesis 1993, 1271. For a recent study on structural consequences
of the addition of lithium halides in enolization and aldol reactions,
see: (d) Henderson, K. W.; Dorigo, A. E.; Liu, Q.-Y.; Williard, P. G.;
Schleyer, P. v. R.; Bernstein, P. R. J . Am. Chem. Soc. 1996, 118, 1339.
For a related work, see: (e) Abbotto, A.; Streitwieser, A.; Schleyer, P.
v. R. J . Am. Chem. Soc. 1997, 119, 11255.
(15) For more detailed information, see: Seebach, D. Angew. Chem.,
Int. Ed. Engl. 1988, 27, 1624. (b) Loupy, A.; Tchoubar, B. Salt Effects
in Organic and Organometallic Chemistry; VCH: Weinheim, 1992. (c)
Ru¨ck, K. Angew. Chem. Int. Engl. 1995, 34, 433. (d) Seebach, D.; Beck,
A. K.; Studer, A. In Modern Synthetic Methods; Ernst, B., Leumann,
C., Eds.; VCH: Weinheim, 1995; p 1. (e) Pauer, F.; Power, P. P. In
Lithium Chemistry-A Theoretical and Experimental Overview; Sapse,
A.-M., Schleyer, P. v. R., Eds.; Wiley: New York, 1995; p 295.
These discouraging results attained with the lithium
enolate of 3 could, however, be dramatically improved
by the presence of lithium chloride in the reaction.14 In
this regard, recent structural studies by Williard14d have
provided some key elements for the understanding of the
role that lithium halides play in the shape of the
aggregates formed in solution.15 From those studies, the
conclusion is that a greater degree of asymmetric induc-
tion can be predicted for the aldol reactions carried out
in the presence of a lithium halide salt. Table 2 sum-
(13) Reetz, M. T.; Peter, R. Tetrahedron Lett. 1981, 22, 4691. Also,
see: ref 7.

8196 J . Org. Chem., Vol. 64, No. 22, 1999
Palomo et al.
Sch em e 2
F igu r e 2. A simplified transition state that accounts for the
formation of the major aldol adduct 5.
Sch em e 3
a
b
Diastereomeric ratios from the enolate of 8. Diastereomeric
ratios from the lithium enolate of 9.
(entry 1 in Table 2), the stereoselectivity ratio 5a /6a was
slightly lower (88:12) compared to that attained with the
enolate of 4 (96:4, entry 1 in Table 1). However, nearly
the same stereoselectivity was observed when isobutyr-
aldehyde was used (entry 10 in Table 2, and entry 12 in
Table 1). Several other aldehydes were successfully
employed in the present asymmetric aldol reaction.16 In
all but three cases, the respective aldols 5/6 were
produced with almost the same level of diastereoselec-
tivity as that achieved from the lithium enolate of 4.
From the data in the Table 2, it is evident that the
reaction diastereoselectivity is independent of the nature
of the aldehyde. This shows generality for aromatic, R,â-
unsaturated and linear as well as branched chain ali-
phatic aldehydes. In every case, the diastereomeric ratios
were determined primarily by integration of the 13C NMR
signals corresponding to the newly generated carbinol
carbon, which are easily distinguishable for both diaster-
eomers in the 65-75 ppm region. To ensure the validity
of this measurement assay, each crude mixture was also
analyzed by HPLC, where the major isomer always shows
a longer retention time. In all cases, the diastereomeric
ratios measured by both techniques were essentially
equivalent. Next, we prepared the parent hydroxy and
silyloxy ketones 8 and 9 by following, from 7, the same
reaction sequence as that employed for the preparation
of 3 and 4 from camphor. Ketones 8 and 9 exhibit a
sterically more congested environment due to the pres-
ence of the ethyl group at the bridge instead of methyl.
However, as Scheme 2 illustrates, the aldol reaction of
the lithium enolate of either 8 or 9 with three represen-
tative aldehydes afforded adducts 10/11 with almost the
same level of diastereoselectivity as that attained in the
reaction of the lithium enolates of 3 and 4 with the same
aldehydes. Although we have not carried out any specific
investigation of the mechanism of this aldol reaction, the
Zimmerman-Traxler-type17,18 transition state depicted
in Figure 2 would nicely account for the observed ster-
eochemical course. In such a transition state, which for
simplification does not consider aggregation, the internal
chelation between lithium and both the enolate and the
silyloxy oxygens fixes the conformation of the enolate in
such a way that π-facial discrimination across the enolate
plane is very efficient. Thus, the aldehyde would prefer-
entially approach the enolate from its less-shielded rear
side with the R1 group in an equatorial-like arrangement.
Dou ble Asym m etr ic In d u ction . To provide further
insight into the ability of our model to transfer chiral
information in reactions of poor diastereofacial selectivity,
we next examined the concept of double asymmetric
induction19 (Scheme 3) in reactions of both the methyl
ketones 3 and 16, the latter prepared from (S)-camphor,
with either chiral (R)- or (S)-R-oxy and R-amino alde-
hydes. The reaction of the aldehyde (R)-12 with the
enolate of 13 is reported by Heathcock8b to afford a
mixture of aldols 14/15 in a ratio of 66:34, while the
enolate of 16 upon treatment with (R)-12 gave 17/18 in
a ratio of 98:2. Thus, in this case, where both reactants
are in a matched relationship, the preferred facial
selectivity of the enolate reinforces notably the preferred
selectivity of the aldehyde, which results in the almost
exclusive formation of 17. Likewise, when (S)-19 was
allowed to react with the lithium enolate of 3, where the
sense of asymmetric induction of both chiral reactants
was also matched, a mixture of diastereomeric aldols 20/
21 was obtained in a ratio of 97:3. The major isomer 20
was then separated by column chromatography as a
white solid in 75% yield and submitted to a single crystal
X-ray structure analysis to confirm the assigned config-
uration for the adduct. The same trend in stereoselec-
(16) For these reactions we have systematically employed a 6-fold
excess of LiCl. Nonetheless, we have found that as little as 3-fold excess
of LiCl, but not less, provides the same effect on diastereoselectivity.
(17) Zimmerman, H. E.; Traxler, M. D. J . Am. Chem. Soc. 1957,
79, 1920.
(18) For transition structures involved in aldol reactions of lithium
enolates, see: Li, Y.; Paddon-Row, M. N.; Houk, K. N. J . Org. Chem.
1990, 55, 481.
(19) For a review on double asymmetric induction, see: Masamune,
S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew. Chem., Int. Ed. Engl.
1985, 24, 1.

Diastereoselective Aldol Reactions
J . Org. Chem., Vol. 64, No. 22, 1999 8197
Sch em e 4
Sch em e 5
tivity was observed for the reactions between the lithium
enolate of 3 and the R-amino aldehydes (S)-22a and (S)-
22b to give the respective aldols 23a and 23b essentially
as single diastereomers. Unfortunately, the present
model provides unsatisfactory levels of diastereoselec-
tivity when both chiral reactants are mismatched. For
instance, the reaction of the lithium enolate of 3 with
(R)-25 (Scheme 4) exhibits opposing aldehyde and enolate
selectivities, leading to a mixture of 26/27 in a diaster-
eomeric ratio of 70:30. The major isomer 26 was isolated
in 40% yield by column chromatography and submitted
to a single crystal X-ray structure analysis to unequivo-
cally determine the sense of asymmetric induction for the
major isomer. The configurational assignment for the
the addition reaction of either Grignard or lithium
reagents to the carbonyl group of the corresponding aldol
products failed. Fortunately, by using organocerium
reagents,20 we found that we could prepare the carbinols
34, 35, and 36 in 85%, 90%, and 80%, yields, respectively.
Although these addition reactions proceeded with good
1
minor adduct 27 was done by comparison of its H NMR
1
spectrum with those corresponding to isomers 20 and 21,
which allowed the latter structures to be excluded. From
the assignments it is clear that the production of these
isomer distributions is due to the diastereoselectivity
inherent to those aldol reactions rather than to an
isomerization of the aldehydes under the reaction condi-
tions used. In a similar way, the aldehyde (R)-28, upon
treatment with the enolate 3, provided a mixture of 29/
30 in a ratio of 70:30. In this case, the configuration for
the major isomer was established by conversion of both
29 and 23a into the same compound 5c, which was
identical to that obtained by the aldol reaction using
cinnamaldehyde, vide supra.
diastereoselectivity, as judged by the H NMR spectra of
the resulting mixture of carbinols, they were neither
isolated nor characterized. Instead, each crude compound
was submitted to oxidative cleavage by treatment with
lead tetraacetate in benzene to give the â-hydroxy
ketones 37, 38, and 39, each in 80% yield. In a similar
way, the diborane reduction of the keto group in the TBS-
protected aldol 40, which was obtained by standard
silylation of 20, followed by oxidative work-up with lead
tetraacetate provided the R-unsubstituted â-silyloxy al-
dehyde 41 in 70% yield along with the recovery of the
starting camphor in 80% yield.21
P r ep a r a tion of â-Hyd r oxy Ca r bon yl Com p ou n d s.
As we had anticipated the oxidative cleavage of the
acyloin moiety in the aldol adducts provided the corre-
sponding â-hydroxy carboxylic acids along with the
starting camphor, which could be recovered and reem-
ployed. For example, as shown in Scheme 5, when 5a ,
5j, and 5l were submitted to treatment with sodium
periodate in methanol-water, compounds 31, 32, and 33
were isolated in yields of 70%, 80% and 75%, respectively.
Con clu sion s
The present study shows that the acetyl group attached
to the camphor moiety in the way delineated in Scheme
1 acts as a powerful “acetate” equivalent for aldol
reactions of inherently poor diastereofacial selectivity.
Particularly noteworthy are the results achieved with the
methyl ketone 3 in the presence of a 6-fold excess of LiCl,
which are almost the same as those attained with the
more sterically biased methyl ketone 4. This case repre-
sents the first example of highly diastereoselective aldol
reactions involving the lithium enolate of R-hydroxy
methyl ketones. Significantly, the procedure does not
destroy the auxiliary during work-up, and it can be
recovered. Therefore, the method is economically viable
for the preparation of R-unsubstituted â-hydroxy car-
In every case, the starting camphor (Aldrich, [R]D25
)
+42.2 (c ) 1, EtOH)) was easily recovered (recovered
material, [R]2D5 ) +41.5 (c ) 1, EtOH)) in yields of 85-
90% by simple aqueous work-up. Comparison of the
optical rotations of these â-hydroxy acids with those
previously described in the literature confirmed the
stereochemical assignments for the adducts. In addition,
a single crystal X-ray analysis of the starting aldol 5l
corroborated the assigned configuration for the adducts.
(20) Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.;
Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392.
(21) For a recent paper dealing with the one- or two-step synthesis
of ketones and aldehydes from N-acylbornane-10,2-sultam derivatives,
see: Oppolzer, W.; Darcel, C.; Rochet, P.; Rosset, S.; De Brabander, J .
Helv. Chim. Acta 1997, 80, 1319.
Problems arose, however, when we attempted the
preparation of â-hydroxy ketones through an organome-
tallic addition-diol cleavage sequence. In these instances,

8198 J . Org. Chem., Vol. 64, No. 22, 1999
Palomo et al.
pressure, and the solid crude product was purified by crystal-
boxylic acids, ketones, and aldehydes not only by using
the cheap (+)-(1R)-camphor but also the non-natural (-)-
(1S)-isomer. Further applications of this enolate model
will be reported in the near future.22
lization from hexane: yield 17.6 g, 90%, mp 90-95 °C; [R]D25
)
-65.6 (c )1.0, CH2Cl2); IR (KBr) υ 3421, 1690 cm-1; 1H NMR
(CDCl3, δ) 0.83 and 0.92 (s, 3H), 1.03-0.95 (m, 1H), 1.08 (s,
3H), 1.27-1.15 (m, 1H) 1.49-1.34 (m, 1H), 1.74-1.65 (m, 1H),
1.90-1.81 (m, 2H), 2.25 (s, 3H), 2.14-2.29 (m, 1H), 2.65 (s,
1H); 13C NMR (CDCl3, δ) 10.5, 20.3, 20.8, 26.4, 27.6, 30.1, 40.9,
Exp er im en ta l Section
45.0, 50.3, 52.1, 87.4, 211.8. Anal. Calcd for
C12H20O2
Gen er a l. Melting points were determined with capillary
apparatus and are uncorrected. Proton nuclear magnetic
resonance (200 MHz) spectra and 13C spectra (50 MHz) were
recorded at room temperature for CDCl3 solutions, unless
otherwise stated. All chemical shifts are reported as δ values
(ppm) relative to residual CDCl3 δH (7.26 ppm) and CDCl3 δC
(77.0 ppm) as internal standards, respectively. Optical rota-
tions were measured at 25 ( 0.2 °C. Enantiomeric excesses
were determined by comparison with racemic standards using
chiral HPLC (CHIRALPAK-AS 250 × 4.6 mm column; eluant
iPrOH/hexane 50:50; accuracy (0.1%) with flow rates of 0.5
mL/min and using a DAD (254 nm). Flash chromatography
was executed with Merck Kiesegel 60 (230-400 mesh) using
mixtures of EtOAc and hexane as eluants. THF was distilled
over sodium and benzophenone (indicator). X-ray structure
analyses of compounds 3, 5l, 20, and 26 were performed by
one of us (A.L.).23
(1R)-2-en do-Acetyl-1,7,7-tr im eth ylbicyclo[2.2.1]h epta n -
2-ol (en d o-2-a cetylisobor n eol) (3). An oven-dried, 1 L, three-
necked round-bottomed flask equipped with a thermometer
and a magnetic stirrer bar was flushed with nitrogen, charged
with THF (400 mL), and cooled to -78 °C. Butyllithium (2.5
M in hexane, 100 mL, 250 mmol) was added using a syringe,
and dry acetylene was blown over the yellow solution held
below -70 °C for 45 min.24 (R)-(+)-Camphor (15.23 g, 100
mmol) was then added over the clear solution of lithium
acetylide at the same temperature. After the addition, the cold
bath was removed and the mixture was stirred overnight at
room temperature. The flask was opened to the atmosphere,
and 1 M HCl (100 ml) was added slowly. The quenched
reaction was stirred for 1 h, and then the solvent was removed
at reduced pressure. CH2Cl2 (200 mL) was added, and the
mixture was transferred to a separatory funnel. The aqueous
layer was separated and the organic layer was washed with 1
M HCl. The combined aqueous layers were extracted with CH2-
(196.32): C, 73.41; H, 10.29. Found: C, 73.06; H, 10.32.
(1R)-2-en d o-Acetyl-1-eth yl-7,7-d im eth ylbicyclo[2.2.1]-
h ep ta n -2-ol (8). Exactly the same two-step procedure de-
scribed above was employed starting from ketone 725 (16.6 g,
100 mmol). The resulting crude product (endo:exo ratio 95:5)
was purified by column chromatography (eluant EtOAc/hexane
1:10) to afford 14.7g (70%) of the title compound: mp 45 °C;
[R]D25 ) -84.9 (c ) 1.0, CH2Cl2); IR (KBr) υ 3446, 1684 cm-1
;
1H NMR (CDCl3, δ) 0.73 (t, J ) 7.7 Hz, 3H), 0.86 and 1.09 (s,
3H), 1.20-1.91 (m, 9H), 2.31 (s, 3H), 3.62 (s, 3H); 13C NMR
(CDCl3, δ) 9.8, 18.5, 21.0, 21.1, 26.0, 26.6, 27.7, 43.0, 45.5, 51.0,
57.1, 87.5, 214.7. Anal. Calcd for C13H22O2 (210.31): C, 74.24;
H, 10.54. Found: C, 74.30; H, 9.83.
Gen er a l P r oced u r e for th e Silyla tion of 3 a n d 8.26 To
a mixture of the corresponding hydroxy ketone (10 mmol) and
3-trimethylsilyl-2-oxazolidinone TMSO (2.32 ml, 15 mmol)
under a nitrogen atmosphere was added one drop of trifluo-
romethanesulfonic acid. The reaction mixture was stirred at
room temperature for 1 h. CH2Cl2 (25 ml) was then added,
and the resulting solution was washed with a saturated
aqueous solution of NaHCO3. The organic layer was dried over
MgSO4 and filtered, and the solvent was removed under
reduced pressure. Hexane (15 mL) was added to the oily
residue, and the resulting white solid was filtered and washed
with additional hexane (15 mL). The solvent was evaporated,
and the crude product was purified by column chromatography
(eluant EtOAc/hexane 1:10).
(1R )-2-en d o-Ace t yl-2-exo-(t r im e t h ylsilyloxy)-1,7,7-
tr im eth ylbicyclo[2.2.1]h ep ta n e (4): yield 2.68 g, 100%, mp
38 °C; [R]2D5 ) -24.9 (c ) 1.0, CH2Cl2); IR (KBr) υ 1708 cm-1
;
1H NMR (CDCl3, δ) 0.06 (s, 9H), 0.76-0.08 (m, 1H), 0.80, 0.98
and 1.03 (s, 3H), 1.11-1.05 and 1.40-1.26 (m, 1H), 1.57 (s,
1H), 1.77-1.69 (m, 2H), 2.15 (s, 3H), 2.51-2.45 (m, 1H); 13C
NMR (CDCl3, δ) 1.7, 11.4, 20.3, 21.0, 25.8, 26.9, 30.1, 39.7,
Cl2, the combined organic extracts were washed with
a
45.3, 50.9, 51.6, 90.7, 209.3. Anal. Calcd for
C15H28O2Si
saturated solution of NaHCO3, dried over MgSO4, and filtered,
and the solvent was removed under reduced pressure to give
a mixture of ethynyl carbinols, endo:exo 97:3, as a dark oil.
This crude material was dissolved in acetone (1.3 L) and added
dropwise over a period of 1.5 hours to a warmed (60 °C)
mixture prepared previously as follows: In a three-necked
round-bottomed flask, equipped with a reflux condenser, a
magnetic stirrer bar and a dropping funnel, red mercuric oxide
(1.32 g) was dissolved in a solution of concentrated sulfuric
acid (2.1 mL), water (53 mL), and acetone (260 mL). The
resulting reaction mixture was stirred at 60 °C for an ad-
ditional 15 min and allowed to cool. A saturated aqueous
solution of NaHCO3 (250 mL) was added to the reaction
mixture, the solvent was removed under reduced pressure and
CH2Cl2 (250 mL) was added. The aqueous layer was separated,
and the organic layer was washed with saturated solution of
NaHCO3. The combined aqueous layers were extracted with
CH2Cl2, and the organic extracts were combined, dried over
MgSO4, and filtered. The solvent was removed under reduced
(268.52): C, 67.09; H, 10.53. Found: C, 66.75; H, 10.56.
(1R)-2-en d o-Acet yl-2-exo-(t r im et h ylsilyloxy)-1-et h yl-
7,7-d im eth ylbicyclo[2.2.1]h ep ta n e (9): yield 2.45 g, 98%,
colorless oil; [R]2D5 ) -41.2 (c ) 2.0, CH2Cl2); IR (KBr) υ 1705
1
cm-1; H NMR (CDCl3, δ) 0.06 (s, 9H), 0.87 (s, 3H), 0.90 (t, J
) 7.8 Hz, 3H), 1.08 (s, 3H), 1.77-1.52 (m, 7H), 2.16 (s, 3H),
2.44 (d, J ) 12.6 Hz, 1H); 13C NMR (CDCl3, δ) 1.5, 10.8, 18.7,
20.7, 22.1, 25.3, 26.0, 27.0, 40.5, 45.9, 51.5, 54.5, 91.8, 210.1.
Gen er a l P r oced u r e for Ald ol Rea ction s of 3 a n d 8 w ith
Ald eh yd es. A mixture of diisopropylamine (0.33 mL, 2.4
mmol) and anhydrous LiCl (0.25 g, 6 mmol) in dry THF (3
mL) was cooled to -78 °C under a nitrogen atmosphere and
n-butyllithium (1.6 M in hexane, 1.5 mL, 2.4 mmol) was added
dropwise. After 30 min of stirring at the same temperature, a
solution of 3 (0.20 g, 1 mmol) or 8 (0.21 g, 1 mmol) in THF (2
mL) was added dropwise. The resulting mixture was allowed
to stir for 1 or 2 h, respectively, at -78 °C, and then a precooled
(-78 °C) solution of the corresponding aldehyde (2.0 mmol) in
THF (10 ml) was added dropwise. The reaction was allowed
to stir from 1-7 h at -78 °C and then was quenched with 5
mL of saturated aqueous solution of NH4Cl. The resulting
mixture was allowed to warm to room temperature, after
which the layers were separated, and the aqueous layer was
extracted twice with CH2Cl2. The combined organics were dried
over MgSO4, and the solvent was removed under reduced
pressure to give the corresponding aldol product as a clear to
(22) Another paper will deal with the use of 4 for the asymmetric
Mannich-type reaction, see: Palomo, C.; Oiarbide, M.; Gonza´lez-Rego,
M. C.; Sharma, A. K.; Garc´ıa, J . M.; Gonza´lez, A.; Landa, C.; Linden,
A. Angew. Chem. Int. Ed., in press.
(23) Crystallographic data (excluding structure factors) for the
structure of 26 have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication no. CCDC-101850.
Copies of the data can be obtained free of charge on application to the
CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (fax (+44) 1223 336-
033; email deposit@ccdc.cam.ac.uk). For crystallographic data of the
structure 3, 5l, and 20, see ref 10.
(25) Fischer, N.; Opitz, G. Organic Syntheses: Wiley: New York,
1973; Collect. Vol. 5, p 877.
(24) Midland, M. M.; McLoughlin, J . I.; Werley, R. T., J r. Organic
Syntheses; Wiley: New York, 1993; Collect. Vol. 8, p 391.
(26) Aizpurua, J . M.; Palomo, C.; Palomo, A. L. Can. J . Chem. 1984,
62, 336.

Diastereoselective Aldol Reactions
J . Org. Chem., Vol. 64, No. 22, 1999 8199
light yellow oil. The diastereomeric ratio was determined in
each case by HPLC and 13C NMR analyses of the respective
crude product. Purification was effected by flash column
chromatography, using a 1:15 EtOAc-hexane mixture as the
eluant and then by preparative HPLC, except for the mixtures
5d /6d and 5g/6g.
128.6, 143.1, 216.4. Anal. Calcd for C20H28O3 (316.14): C, 75.90;
H, 8.92. Found: C, 75.90; H, 8.4.
Da ta for 20: yield 0.27 g, 70%, mp 89-91 °C; [R]2D5 ) +13.0
(c ) 1.02, CH2Cl2); IR (KBr) υ 3400, 1638 cm-1 1H NMR
;
(CDCl3, δ) 0.05 and 0.07 (s, 3H), 0.82 (s, 3H), 0.86 (s, 9H), 0.97
and 1.20 (s, 3H), 1.17 (d, J ) 6.0 Hz, 3H), 1.43-1.17, 1.67-
1.59 and 1.81-1.74 (m, 2H), 2.28 (m, 2H), 3.10 ( dd, J ) 8.0
Gen er a l P r oced u r e for Ald ol Rea ction s of 4 a n d 9 w ith
Ald eh yd es. A mixture of diisopropylamine (0.16 mL, 1.2
mmol) in THF (3 mL) was cooled to -78 °C, and n-butyllithium
(1.6 M in hexane, 0.75 ml, 1.2 mmol) was added dropwise. After
30 min of stirring, a solution of 4 (0.27 g, 1 mmol) or 9 (0.25
g, 1 mmol) in THF (2 mL) was added dropwise. The mixture
was allowed to stir for 1 or 2 h, respectively at -78 °C, and
then the precooled aldehyde (2.0 mmol) was added dropwise.
The reaction mixture was allowed to stir for 3-8 h at -78 °C,
and then the reaction was quenched with 5 mL of saturated
aqueous NH4Cl. The resulting mixture was allowed to warm
to room temperature, after which the layers were separated
and the aqueous layer was extracted twice with CH2Cl2. The
combined organic layers were dried over MgSO4, and the
solvent was removed under reduced pressure. The residue thus
obtained was desilylated by either one of the procedures that
follows with essentially same yield: (A) It was dissolved in
MeOH (4 mL) and after the addition of 1 N HCl (2 mL) the
mixture was stirred at room temperature for 3 h. CH2Cl2 (20
mL) was added, the organic layer was separated, washed with
a saturated aqueous solution of NaHCO3, dried over MgSO4,
and filtered, and the solvent was evaporated under reduced
pressure. Purification was effected by flash column chroma-
tography, using a 1:15 EtOAc-hexane mixture as the eluant
and then by preparative HPLC. (B) The residue was dissolved
in THF (3 mL), and after the addition of anhydrous 1 M TBAF
in THF (2 mL), the mixture was stirred at room temperature
for 5 min. Evaporation of solvent and purification by column
chromatography afforded the aldol products as clear to light
yellow oils. The diastereomeric ratio was determined in each
case by HPLC and 13C NMR analyses of the respective
unpurified product.
Hz, J ′ ) 14.0 Hz, 1H); 3.31 and 3.62 (s, 1H), 3.85 (m, 2H); 13
C
NMR (CDCl3, δ) -4.7, -4.5, 11.2, 18.1, 18.8, 20.5, 20.9, 25.8,
26.2, 30.3, 40.2, 41.2, 45.1, 50.9, 51.7, 71.6, 73.6, 87.8, 213.3.
Anal. Calcd for C21H40O4Si (384.70); C, 65.56; H, 10.50.
Found: C, 65.32; H, 10.45.
Gen er a l P r oced u r e for th e Oxid a tion of Ald ol P r od -
u cts. To a solution of the corresponding aldol 5 (1 mmol) in
methanol (6.6 mL) was added a solution of sodium periodate
(2.14 g, 10 mmol) in water (3.3 mL). The mixture was allowed
to stir at room temperature or at reflux until disappearance
of the starting material as monitored by TLC (EtOAc-hexane
1:3). The solvent was evaporated, the solid residue was
dissolved in a minimum amount of water, and the resulting
solution was extracted twice with Et2O. the combined ethereal
extracts were washed with 2 N NaOH, dried over MgSO4,
filtered, and the solvent was evaporated to afford the starting
(R)-(+)-camphor in 85-90% yield. The basic aqueous layer was
first acidified by adding concentrated HCl and then extracted
with Et2O. The combined extracts were dried over MgSO4 and
filtered, and the solvent was removed under reduced pressure
to afford the corresponding â-hydroxy acid in 70-80% yields.
Da ta for 31: yield 0.12 g, 70%; [R]2D5 ) +15.5 (c ) 0.9,
EtOH); (lit.27 [R]D25 ) +17.9 (c ) 2.3, EtOH 95%)); IR (KBr) υ
1
3510, 1711 cm-1; H NMR (CDCl3, δ) 2.77 (dd, J ) 3.9 Hz, J ′
) 16.8 Hz, 1H), 2.85 (dd, J ) 8.7 Hz, J ′ ) 16.5 Hz, 1H), 5.16
(dt, J ) 8.7, J ′ ) 3.9 Hz, 1H), 7.31-7.12 (m, 5H); 13C NMR
(CDCl3, δ) 42.7, 70.2, 125.7, 128.1, 128.7, 142.2, 177.2.
Da ta for 32: yield 0.10 g, 80%; [R]2D5 ) +41.7 (c ) 1.0,
CHCl3); (lit.27 [R]D25 ) +40.5 (c ) 0.6, CHCl3)); IR (KBr) υ
3448, 1712 cm-1; 1H NMR (CDCl3, δ) 0.93 and 0.95 (d, J ) 6.6
Hz, 3H), 1.79-1.66 (octet, J ) 6.6, 1H), 2.45 (dd, J ) 9.9 Hz,
J ′ ) 16.2 Hz, 1H), 2.55 (dd, J ) 3.3 Hz, J ′ ) 16.2 Hz, 1H),
3.83 (dt, J ) 12.3 Hz, J ′ ) 6.6 Hz, 1H); 13C NMR (CDCl3, δ)
17.6, 18.2, 33.1, 38.3, 68.7, 177.7.
Da ta for 5a : yield 0.20 g, 67%, colorless oil purified by
preparative HPLC; [R]D25 ) +35.3 (c ) 1.0, CH2Cl2); IR (film) υ
1
3427, 1702 cm-1; H NMR (CDCl3, δ) 0.82, 0.94 and 1.11 (s,
Da ta for 33: yield 0.11 g, 75%; [R]2D5 ) +53.0 (c ) 1.0,
CHCl3); (lit.28 [R]D25 ) +53.2 (c ) 1.0, CHCl3)); IR (KBr) υ
3H), 1.45-1.15, 1.75-1.62 and 1.83-1.77 (m, 2H), 2.30 (m,
1H), 2.55 (dd, J ) 2.2 Hz, J ′ ) 10.2 Hz, 1 H), 7.36-7.24 (m,
5H); 13C NMR (CDCl3, δ) 11.3, 20.6, 20.9, 26.3, 30.3, 41.4, 45.1,
48.2, 50.0, 51.8, 71.3, 87.8, 125.6, 128.3, 143.3, 212.2.
1
3458, 1730 cm-1; H NMR (CDCl3, δ) 0.93 (s, 9H), 2.41 (dd, J
) 10.3 Hz, J ′ ) 16.2 Hz, 1H), 2.60 (dd, J ) 2.4 Hz, J ′ ) 16.2
Hz, 1H), 3.74 (dd, J ) 2.4 Hz, J ′ ) 8.0 Hz, 1H); 13C NMR
(CDCl3, δ) 25.6, 34.5, 35.6, 75.6, 178.5.
Da ta for 5j: yield 0.18 g, 67%, mp 53-54 °C; [R]2D5 ) +19.6
(c ) 0.51, CH2Cl2); IR (KBr) υ 3382, 1692 cm-1 1H NMR
;
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
34-36. Imidazole (0.17 g, 2.5 mmol) and tert-butyldimethyl-
silyl chloride (0.23 g, 1.5 mmol) were successively added to a
solution of compound (5l) (0.28 g, 1 mmol) in dry DMF (1.5
mL), and the mixture was stirred overnight at room temper-
ature under a nitrogen atmosphere. Then additional imidazole
(0.17 g, 2.5 mmol) and tert-butyldimethylsilyl chloride (0.23
g, 1.5 mmol) were added, and the mixture was stirred for 72
h at room temperature. Finally the reaction mixture was
poured into water (10-15 mL) at 0 °C and was extracted twice
with Et2O. The combined organic layers were washed with
water and brine, dried over MgSO4, and filtered, and the
solvent was evaporated under reduced pressure to afford a
colorless oil. The resulting crude was purified by column
chromatography (eluant EtOAc-hexane 1:20) and used in next
reaction. Yield: 0.34 g, 86%.
(CDCl3, δ) 0.85 (s, 3H), 0.92 and 0.95 (d, J ) 3.2 Hz, 3H), 0.98
and 1.13 (s, 3H), 1.46-1.17 (m, 2H), 1.86-1.56 (m, 5H), 2.28
(m, 1H), 2.41 (dd, J ) 2.2 Hz, J ′ ) 15.4 Hz, 1H), 2.98 (dd, J )
10.4 Hz, J ′ ) 15.4 Hz, 1H), 3.33-3.32 (sb, 1H), 3.80 (ddd, J )
2.2 Hz, J ′ ) 10.4 Hz, J ′′ ) 5.5 Hz, 1H); 13C NMR (CDCl3, δ)
11.2, 17.8, 18.3, 20.6, 20.9, 26.2, 30.3, 33.6, 41.3, 42.7, 45.1,
50.9, 51.8, 73.8, 87.8, 213.8. Anal. Calcd for C16H28O3 (268.44);
C, 71.58; H, 10.53. Found: C, 71.20; H, 10.57.
Da ta for 5l: yield 0.20 g, 70%, mp 73-74 °C; [R]2D5 ) +21.7
(c ) 0.51, CH2Cl2); IR (KBr) υ 3404, 1690 cm-1 1H NMR
;
(CDCl3, δ) 0.83 (s, 3H), 0.90 (s, 9H), 0.96 and 0.11 (s, 3H), 1.45-
1.17, 1.70-1.61 and 1.84-1.73 (m, 2H), 2.25 (m, 1H), 2.38 (dd,
J ) 2.2 Hz, J ′ ) 14.8 Hz, 1H), 2.7 (sb, 1H), 2.96 (dd, J ) 10.6
Hz, J ′ ) 14.8 Hz, 1H); 3.4 (sb, 1H), 3.67 (dd, J ) 2.2 Hz, J ′ )
3.0 Hz, 1H); 13C NMR (CDCl3, δ) 11.2, 20.4, 20.7, 25.5, 25.6,
30.2, 34.5, 40.4, 41.2 44.9, 50.8, 51.5, 76.6, 87.7, 213.8. Anal.
Calcd for C17H30O3 (282.47); C, 72.28; H, 10.73. Found: C,
71.95; H, 10.77.
Cerium chloride heptahydrate (1.83 g, 5.0 mmol) was finely
powdered in a mortar and then placed into a 25-mL two-necked
flask. Most of the water of crystallization was removed in vacuo
by immersing the flask in an oil bath heated at 135-140 °C
for 2 h. A magnetic stir bar was then inserted, and the cerium
chloride was completely dried in vacuo with stirring at the
Da ta for 10a : yield 0.21 g, 66%, mp 103 °C; [R]2D5 ) +35.6
(c ) 0.51, CH2Cl2); IR (KBr) υ 3374, 1687 cm-1 1H NMR
;
(CDCl3, δ) 0.74 (t, J ) 7.6 Hz, 3H), 0.88 and 1.14 (s, 3H), 1.20-
1.90 (m, 9H), 2.02 (d, J ) 13 Hz, 1H), 2.65 (dd, J ) 2.8 Hz, J ′
) 14.9 Hz, 1H); 3.24-3,23 (m, 1H), 3.42 (dd, J ) 10.3 Hz, J ′
) 14.9 Hz, 1H); 3.69 (s, 1H) 5.09-5.03 (m, 1H), 7.39-7.25 (m,
5H); 13C NMR (CDCl3, δ) 10.3, 14.1, 18.4, 21.1, 21.5, 22.6, 25.8,
26.3, 31.6, 44.5, 45.7, 48.7, 51.8, 57.6, 72.4, 87.9, 125.6, 127.9,
(27) Helmchen, G.; Leikauf, U.; Tauferknopfel, I. Angew. Chem. Int.
Ed. Engl. 1985, 24, 874.
(28) Duthaler, R. O.; Herold, P.; Lottembach, W.; Oertle, K.;
Riediker, M. Angew. Chem. Int. Ed. Engl. 1989, 28, 495.

8200 J . Org. Chem., Vol. 64, No. 22, 1999
Palomo et al.
same temperature for 1 h. While the flask was still hot,
nitrogen gas was introduced and the flask was cooled in an
ice bath. Dry THF (8 mL) was then added with stirring, and
the resulting suspension was efficiently stirred for 2 h at room
temperature. The flask was again immersed in an ice bath,
and the Grignard reagent (1.67 ml, 5.0 mmol, 3 M in Et2O)
was added. After 1.5 h of stirring at 0 °C, a solution of the
corresponding â-tert-butyldimethylsilyloxy ketone (0.40 g, 1
mmol) in THF (3 ml), obtained as mentioned before, was
added, and the resulting mixture was stirred for 2 h at the
same temperature. The reaction mixture was treated with
water (5 mL) containing acetic acid (0.2 mL) and then
extracted with ether. The combined extracts were washed with
brine, aqueous NaHCO3 solution, and brine and then dried
over MgSO4, and the solvent was removed under reduced
pressure to afford compounds 34-36 as colorless oils in 80-
85% yield.
Da ta for 34: yield 0.35 g, 85%, colorless oil; 1H NMR (CDCl3,
δ) 0.11 and 0.13 (s, 3H), 0.80 (s, 3H), 0.86 (s, 9H), 0.89 (s, 9H),
0.94 and 1.08 (s, 3H), 1.30 (s, 3H), 2.04-1.12 (m, 9H), 2.05
and 2.87 (sb, 1H), 3.71-3.66 (dd, J ) 1.8 Hz, J ′ ) 7.2 Hz, 1H);
13C NMR (CDCl3 δ), -2.9, -2.7, 12.9, 19.0, 20.8, 21.9, 23.3,
26.6, 26.7, 29.3, 29.8, 36.4, 40.8, 44.6, 51.3, 53.1, 78.0, 78.5,
85.0.
Da ta for 35: yield 0.40 g, 85%, colorless oil; 1H NMR
(CDCl3, δ) -0.14 (s, 3H), 0.01 and 0.09 (s, 3H), 0.71 (s, 3H),
0.81 (s, 9H), 0.95 (s, 9H), 1.03 (s, 3H), 1.58-1.10 (m, 3H), 1.97-
1.72 (m, 4H), 2.23 (d, J ) 12.9 Hz, 1H), 2.49 (m, 1H), 2.86 (d,
J ) 15.3 Hz, 1H), 3.23 (d, J ) 8.8 Hz, 1H), 3.76 (s, 1H), 7.59-
7.20 (m, 3H), 7.95 (d, J ) 8.0 Hz, 2H); 13C NMR (CDCl3 δ),
-2.7, -1.5, 10.8, 19.1, 20.6, 21.9, 26.7, 26.9, 27.0, 28.4, 36.2,
39.6, 41.3, 44.8, 51.2, 53.7, 79.7, 81.1, 85.6, 127.0, 127.1, 128.6,
143.8.
Da ta for 36: yield 0.35 g, 80%, colorless oil; 1H NMR
(CDCl3, δ) 0.15 and 0.17 (s, 3H), 0.79 (s, 3H), 0.88 (s, 8H), 0.91
(s, 9H), 0.97 and 1.03 (s, 3H), 1.31-1.10 (m, 3H), 1.74-1.50
(m, 4H), 2.01 and 2.24 (m, 1H), 2.78-2.50 (m, 2H), 3.50 (s,
1H), 3.82 (d, J ) 8.0 Hz, 1H), 5.08 (m, 2H), 6.03 (m, 1H); 13C
NMR (CDCl3 δ), -2.6, -2.1, 13.2, 19.0, 20.6, 21.6, 26.1, 26.5,
26.8, 28.5, 36.4, 37.0, 41.4, 44.5, 51.2, 53.3, 78.9, 79.2, 86.4,
116.8, 135.7.
-3.9, 18.3, 26.1, 35.8, 42.8, 75.4, 128.1, 128.4, 132.9, 137.5,
199.1.
Da ta for 39: yield 0.23 g, 80%, bp 140 °C/0.4 Torr; [R]D25
)
+32.0 (c ) 1.06, CH2Cl2); IR (film) υ 1717 cm-1 1H NMR
;
(CDCl3, δ) -0.10 and 0.04 (s, 3H), 0.82 (s, 9H), 0.84 (s, 9H),
2.54 (dd, J ) 6.1 Hz, J ′ ) 17.4 Hz, 1H), 2.61 (dd, J ) 4.0 Hz,
J ′ ) 17.4 Hz, 1H), 3.10 (m, 2H), 3.96 (dd, J ) 4.0 Hz, J ′ ) 6.0
Hz, 1H); 5.11 and 5.17 (m, 1H), 5.91 (m, 1H); 13C NMR (CDCl3
δ), -4.8, -3.9, 18.3, 25.9, 26.1, 35.6, 46.8, 48.9, 74.7, 118.8,
130.3, 207.2.
P r ep a r a tion of Com p ou n d 40. Imidazole (0.17 g, 2.5
mmol) and tert-butyldimethylsilyl chloride (0.23 g, 1.5 mmol)
were successively added to a solution of compound 20 (0.38 g,
1 mmol) in dry DMF (1.5 mL), and the mixture was stirred
overnight at room temperature under a nitrogen atmosphere.
Additional imidazole (0.17 g, 2.5 mmol) and tert-butyldimeth-
ylsilyl chloride (0.23 g, 1.5 mmol) were then added and the
mixture was stirred for 5 h at room temperature. Finally, the
reaction mixture was poured into water (10-15 mL) at 0 °C
and was extracted twice with Et2O. The combined organic
layers were washed with water and brine, dried over MgSO4,
and filtered, and the solvent was evaporated under reduced
pressure to afford a colorless oil. The resulting crude was
purified by column chromatography (eluant AcOEt-hexane
1:20) and used in next reaction: yield 0.45 g, 90%, colorless
1
oil; H (CDCl3, δ) -0.02, 0.03, 0.05 and 0.07 (s, 3H), 0.81 (s,
3H), 0.83 (s, 9H) 0.87 (s, 9H), 0.93 (s, 3H), 1.06 (d, J ) 6.3 Hz,
3H), 1.10 (s, 3H), 1.41-1.15 and 1.84-1.54 (m, 3H), 2.20 (dd,
J ) 3.3 Hz, J ′ ) 14.9 Hz, 1H), 2.24 (m, 1H), 3.27 (dd, J ) 9.6
Hz, J ′ ) 14.9 Hz, 1H), 3.45 (s, 1H), 3.77 (dq, J ) 2.2 Hz, J ′ )
6.3 Hz, 1H), 4.06 (ddd, J ) 2.2 Hz, J ′ ) 1.1 Hz, J ′′ ) 9.0 Hz,
1H); 13C NMR (CDCl3, δ) -4.5, -4.2, -4.1, -2.8, 11.1, 18.2,
19.7, 20.5, 20.9, 25.8, 25.9, 26.1, 26.4, 30.2, 41.2, 41.8, 45.2,
50.8, 52.3, 72.3, 75.0, 87.6, 212.1.
P r ep a r a tion of Ald eh yd e 41. BH3‚THF complex (2 ml, 2
mmol, 1 M in THF) was added to a solution of compound 40
(0.50 g, 1 mmol) in dry THF (3 ml) at 0 °C. After 7 h of stirring
the reaction mixture at the same temperature, the mixture
was quenched with methanol (3 mL) and stirred for 30 min at
room temperature. Finally the solvent was removed under
reduced pressure to obtain a white solid. The solid residue thus
obtained was subjected to oxidation following the general
procedure for the oxidation of diol compounds indicated before
to obtain 41 in 70% yield (0.25 g): colorless oil; bp 150 °C/0.5
Gen er a l P r oced u r e for th e Oxid a tion of Diols 34-36.
A solution of the corresponding diol 34-36 (1 mmol) in benzene
(4 mL) was cooled to 5 °C and lead tetraacetate (0.87 g, 2
mmol) was added to the solution over a period of 5 min. After
the addition was complete, the mixture was stirred at the same
temperature for 2 h. Then, a saturated aqueous solution of
NaHCO3 (5 ml) was added, and the resulting mixture was
filtered through a pad of Celite and washed with CH2Cl2. The
organic solution was washed with water and dried over MgSO4,
and the solvent was removed under reduced pressure. The
crude product thus obtained was subjected to column chro-
matography (eluant EtOAc-hexane 1:50) to collect, as the first
compound, the corresponding ketone that was further purified
by distillation. In subsequent collected fractions the starting
(R)-(+)-camphor was recovered essentially pure in 80-90%
yield.
Torr; [R]2D5 ) +16.0 (c ) 5.0, CH2Cl2); IR (film) υ 1713 cm-1
;
1H NMR (CDCl3, δ) 0.04 (s, 9H), 0.05 (s, 3H), 0.85 (s, 18H),
1.1 (d, J ) 6.2 Hz, 1H), 2.46 (ddd, J ) 2.0 Hz, J ′ ) 5.3 Hz, J ′′
) 16.0 Hz, 1H), 2.58 (ddd, J ) 2.9 Hz, J ′ ) 5.1 Hz, J ′′ ) 16.0
Hz, 1H), 3.75 (dq, J ) 6.2 Hz, J ′ ) 4.5 Hz, 1H), 3.92 (d, J )
5.1 Hz, 1H), 9.81 (dd, J ) 2.1 Hz, J ′ ) 2.9 Hz, 1H); 13C NMR
(CDCl3, δ), -4.6, -4.5, -4.2, 18.1, 20.4, 25.9, 47.2, 72.3, 73.4,
202.0.
Ack n ow led gm en t. This work was financially sup-
ported by the Basque Government (Project EX-1998-
124), by the University of The Basque Country (UPV,
170.215-G47/98), and by the Government of Navarra
(Project O. F. 59/1996). Grants to C.L. from the Minis-
terio de Educacio´n y Cultura and to I.O. from UPV are
acknowledged.
Da ta for 37: yield 0.21 g, 80%, bp 70 °C/0.4 Torr; [R]D25
)
+30.4 (c ) 1.02, CH2Cl2); IR (film) υ 1723 cm-1 1H NMR
;
(CDCl3, δ) -0.06 and 0.06 (s, 3H), 0.84 (s, 9H), 0.86 (s, 9H),
2.15 (s, 3H), 2.48 (dd, J ) 6.0 Hz, J ′ ) 17.4 Hz, 1H), 2.62 (dd,
J ) 4.0 Hz, J ′ ) 17.2 Hz, 1H), 3.94 (dd, J ) 4.1 Hz, J ′ ) 6.0
Hz, 1H); 13C NMR (CDCl3 δ), -4.8, -4.0, 18.3, 25.9, 26.1, 31.3,
35.5, 48.1, 74.9, 207.5.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 5b-k , 10b,c, and 17, ORTEP diagrams
of 3, 5l, 20, and 26, including X-ray crystallographic data, and
copies of 1H and 13C NMR spectra of some representative
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Da ta for 38: yield 0.26 g, 80%, bp 135 °C/0.4 Torr; [R]D25
)
+37.9 (c ) 0.62, CH2Cl2); IR (film) υ 1690 cm-1 1H NMR
;
(CDCl3, δ) -0.20 and 0.07 (s, 3H), 0.82 (s, 9H), 0.90 (s, 9H),
3.08 (d, J ) 5.6 Hz, 2H), 4.20 (t, J ) 5.1 Hz, 1H), 7.61-7.33
(m, 3H), 7.95 (d, J ) 7.0 Hz, 2H); 13C NMR (CDCl3 δ), -4.7,
J O990865Z