Highly enantioselective Darzens reaction of a camphor-derived sulfonium amide to give glycidic amides and their applications in synthesis

Article abstract of DOI:10.1021/ja0272540

The reaction of an amide-stabilized sulfonium ylide bearing chiral groups on sulfur has been investigated. We have discovered that the camphor-derived amide-stabilized ylide reacts with aldehydes at -50 °C in ethanol to give glycidic amides in one step wi

Full text of DOI:10.1021/ja0272540

Published on Web 08/07/2002
Highly Enantioselective Darzens Reaction of a Camphor-Derived Sulfonium
Amide to Give Glycidic Amides and Their Applications in Synthesis
Varinder K. Aggarwal,* George Hynd, Willy Picoul, and Jean-Luc Vasse
School of Chemistry, Bristol UniVersity, Cantock’s Close, Bristol, BS8 1TS UK.
Received June 11, 2002
Table 1. Asymmetric Synthesis of (2R,3S)-2,3-Epoxyamides via
Camphor-Derived Sulfonium Salt 2
Glycidic esters and amides are very important synthetic inter-
mediates because of their rich and useful functionality. However,
few methods exist for their synthesis in a concise and highly
selective manner.1 The most direct method to date is an asymmetric
Darzens reaction2 and good ee’s have been achieved by employing
chiral auxiliaries3 or chiral reagents4 although in all of these
processes two separate steps are required: an aldol-type reaction
followed by ring closure.5 We now report the discovery that amide-
stabilized sulfur ylides6 bearing a readily available chiral camphor-
derived moiety react with aldehydes in the presence of base to give
glycidic amides directly with complete diastereocontrol and almost
complete control of enantioselectivity.7
c
entry
R
yield (%)
ee (%)
product, configuration
1
2
3
4
5
6
7
8
p-MeOC6H4
Ph
90
93
87
88
85
89
85
87
84
79
87
97
97
99
98
96
96
92
95
63
10
93
3a, (2R,3S)
3b, (2R,3S)
3c, (2R,3S)
3d, (2R,3S)
3e, (2R,3S)
3f, (2R,3S)
3g, (2R,3S)
3h, (2R,3S)
3i, (2R,3S)
3j,d
p-ClC6H4
p-MeC6H4
p-FC6H4
p-CF3C6H4
p-NO2C6H4
3-pyridyl
dodecyl
Sulfide 18 was synthesized in three steps from D-camphor and
subsequently alkylated with N,N-diethyl bromoacetamide to yield
the salt 2 as a 10:1 mixture of diastereoisomers. Recrystallization
from hexane/acetone gave diastereomerically pure 2. Brief opti-
mization of the reaction of the salt with benzaldehyde in the
presence of base revealed that very high enantioselectivity could
be achieved using KOH in ethanol at -50 °C. These conditions
were applied to a range of aldehydes and found to be general for
all aromatic and heteroaromatic aldehydes (Table 1, entries 1-8).
Aliphatic aldehydes behaved less predictably: tertiary and mono-
substituted aldehydes gave high enantioselectivities (entries 9, 11),
while secondary substituted aldehyde only gave low selectivity
(entry 10). In all cases complete diastereoselectivity in favor of
the trans isomer was observed. Furthermore, sulfide 1 could be
reisolated in essentially quantitative yield at the end of the reaction.
Efforts to understand the origin of the very high enantioselectivity
have only been partially successful. It had previously been reported
that the related sulfonium salt 4 reacted with aldehydes via transition
state A to give glycidic amides in low-to-moderate enantioselec-
tivity.9 It was proposed that hydrogen bonding controlled the
conformation of the ylide and that subsequent nonbonded inter-
actions in A were responsible for enantiocontrol (Scheme 1).
However, while it is known that amide-stabilized sulfonium
ylides react with aldehydes to give epoxides via betaine intermedi-
ates, we have discovered from simple crossover experiments that
betaine formation is reversible.10 Thus, enantiocontrol is achieved
not in the betaine-forming step (e.g., transition state A) but in one
of the subsequent steps converting the betaine into epoxide. From
ab initio calculations on related compounds,11 we found that the
slowest of these steps is the C-C bond rotation, which converts
the initially formed syn betaine adduct into the anti conformation.
It is highly likely that the same scenario applies to the current ylide
and thus conversion of 5A to 5B is the critical enantiodifferentiating
step. It is remarkable that such high enantioselectivity can be
achieved (up to 99% ee) through diastereomeric transition states
(5A/6A f 5B/6B) which have a high degree of conformational
9a
10b
11b
i-propyl
t-butyl
3k, (2R,3S)
a -30 °C. b -20 °C. c The absolute configuration of 3b and 3c have been
determined by comparison of HPLC elution orders and by comparison of
[R]D with the lit.,9 respectively. All others are given by analogy. d The
absolute configuration was not determined.
Scheme 1
Scheme 2
freedom through facile bond rotations around the C-S bonds
(Scheme 2).
Further studies revealed that both the temperature and diastereo-
meric purity of the salt influenced enantioselectivity (see Supporting
Information for full details). We studied the latter issue in further
detail, and from analysis of the stereochemical outcome of different
diastereomeric mixtures, we determined that the pure minor
diastereomer 2′ gave the same major enantiomer but with reduced
selectivity (54% ee) compared to the major diastereomer 2.12
* To whom correspondence should be addressed. E-mail: V.Aggarwal@
bristol.ac.uk.
9
9964
J. AM. CHEM. SOC. 2002, 124, 9964-9965
10.1021/ja0272540 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
In summary, we have described a completely diastereoselective,
highly enantioselective and practical synthesis of glycidic amides
and applied this new methodology to an asymmetric synthesis of
SK&F 104353. Although the origin of the enantioselectivity is not
completely understood, we have identified the enantiodifferentiating
step of the process. We are currently exploring the precise origin
of the enantiocontrol and new alternative methods for amide
hydrolysis to further expand the scope of this work.
Acknowledgment. We thank Bristol University and EPRSC for
financial support, and Paul Blackburn for preliminary experiments
and helpful discussions.
Scheme 4 a
Supporting Information Available: Full experimental details,
optimization results, and analytical data (including chiral HPLC data
of 3a-3k and 9) (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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Meth-Cohn, O.; Williams, D.; Chen, Y. Chem. Commun. 2000, 495. (d)
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a Conditions: a) see ref 16, 90%; b) 2, KOH, MeOH, -30 °C, 24 h,
77%; c) (i) PhLi, THF, -78 °C, 84%, (ii) mCPBA, CH2Cl2, ∆, 68%; d)
HS-(CH2)2-CO2Me, Yb(OTf)3, CH2Cl2, -78 °C to rt, 64%, e) NaOH,
MeOH, H2O, rt, 16 h, 81%.
Our new methodology allows access to a range of potential
building blocks through further selective transformations. The
epoxyamides can be converted directly into epoxyketones by
treatment with organolithium reagents with complete chemoselec-
tivity (Scheme 3).13 Epoxides can also be ring-opened by nucleo-
philes, and we had initially assumed that ring-opening would occur
regioselectively at the benzylic position. However, reaction of
thiophenol with 3b in different solvents with different bases
furnished a 1:1 mixture of regioisomers. Sharpless has described
the use of Ti(O-i-Pr)4 for C3 selective ring-opening of glycidic esters
and secondary amides,14 but this method also gave a 1:1 mixture
of regioisomers. Finally, we discovered that Yb(OTf)3 catalyzed
the ring-opening with complete regioselectivity for the C3 position
with both S and N nucleophiles (Scheme 3).
The usefulness of the new process is exemplified in a short
synthesis of SK&F 104353 14, a leukotriene D4 antagonist in the
potential treatment of bronchial asthma (Scheme 4).15 We were
delighted to find that ylide reaction with the sterically hindered
aldehyde 1016 furnished the glycidic amide 11 in 90% ee. Although
we were able to regioselectively open the epoxide with the required
thiol, we found it difficult to hydrolyze the amide in the presence
of the remaining functionality. However, we were able to convert
the epoxyamide into the corresponding epoxyester using a two-
step sequence involving addition of phenyllithium followed by
Baeyer-Villiger oxidation. Regioselective ring-opening of the
epoxyester with the required thiol and subsequent hydrolysis gave
the target molecule.
(6) (a) Ratts, K. W.; Yao, A. N. J. Org. Chem., 1966, 31, 1689. (b) M
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hedron 1990, 46, 7911.
(7) The sulfonium salt has recently been employed in asymmetric cyclopro-
panation with high enantioselectivity: Ye, S.; Huang, Z.-Z.; Xia, C.-A.;
Tang, Y.; Dai, L.-X. J. Am. Chem. Soc. 2002, 124, 2432.
(8) Li, A. H.; Dai, L. X.; Hou, X. L.; Huang, Y. Z.; Li, F. W. J. Org. Chem.
1996, 61, 489. Sulfide 1 was prepared according to the literature. However,
the precursor (1R, 3R)-3-(Methylthio)-1,7,7-trimethylbicyclo[2.2.1]-heptan-
2-one was prepared using DMPU (3 eq) instead of HMPA (3 eq), and
obtained as a colorless oil in 88% yield. [a]D +93.0° (c 2.0, acetone) [lit.,
[a]D +93.3° (c 2.0, acetone)].
(9) Zhou, Y. G.; Hou, X. L.; Dai, L. X.; Xia, L. J.; Tang, M. H. J. Chem.
Soc., Perkin Trans. 1 1999, 77.
(10) Aggarwal, V. K.; Blackburn, P.; Smith, C., unpublished results.
(11) The reaction of benzyl-stabilised ylide was studied: Aggarwal, V. K.;
Harvey, J. N.; Richardson, J. J. Am. Chem. Soc. 2002, 124, 5746.
(12) Although 2 and 2′ are crystalline, we have not been able to grow good
enough crystals yet to determine their relative stereochemistry. The
stereochemistry at S is tentatively assigned as (R) by analogy with the
salt described in ref 9.
(13) Meth-Cohn, O.; Chen, Y. Tetrahedron Lett. 1999, 40, 6069.
(14) Berhens, C. H.; Sharpless, K. B. J. Org. Chem. 1985, 50, 5696. Tertiary
amides were also tested but gave a mixture of regioisomers.
(15) Flisak, J. R.; Gombatz, K. J.; Holmes, M. M.; Jarmas, A. A.; Lantos, I.;
Mendelson, W. L.; Novack, V. J.; Remich, J. J.; Snyder, L. J. Org. Chem.
1993, 58, 6247.
(16) Forth, M. A.; Mitchell, M. B.; Smith, S. A. C. J. Org. Chem. 1994, 59,
2616.
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