Chiral base route to cyclic polyols: Asymmetric synthesis of aminodeoxyconduritols and conduritol F

Article abstract of DOI:10.1016/S0040-4039(01)01706-3

A chiral base route from a meso cyclohexene oxide to an allylic alcohol provides key intermediates for the synthesis of cyclic polyols. A Mitsunobu approach and an Overman rearrangement approach transform allylic alcohols into some aminodeoxyconduritols (95% ee). Elaboration of a chiral enone (89% ee) via (i) α-hydroxylation and (ii) stereoselective reduction completes a high yielding synthesis of the tetraacetate of conduritol F.

Full text of DOI:10.1016/S0040-4039(01)01706-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8081–8083
Chiral base route to cyclic polyols: asymmetric synthesis of
aminodeoxyconduritols and conduritol F
Simon E. de Sousa, Peter O’Brien* and Christopher D. Pilgram
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 9 August 2001; accepted 7 September 2001
Abstract—A chiral base route from a meso cyclohexene oxide to an allylic alcohol provides key intermediates for the synthesis of
cyclic polyols. A Mitsunobu approach and an Overman rearrangement approach transform allylic alcohols into some
aminodeoxyconduritols (95% ee). Elaboration of a chiral enone (89% ee) via (i) a-hydroxylation and (ii) stereoselective reduction
completes a high yielding synthesis of the tetraacetate of conduritol F. © 2001 Elsevier Science Ltd. All rights reserved.
The asymmetric synthesis of conduritols and related
cyclitols continues to attract considerable interest1–3 as
these compounds possess a range of useful biological
activity (e.g. insulin modulators and glycosidase
inhibitors).4 There has also been recent interest in the
preparation of amino conduritols.5 For the last few
years, we have been developing a concise, simple and
stereocontrolled entry into highly functionalised poly-
hydroxylated cyclohexenes.6–8 Our approach involves
epoxidation of cyclohexene 1 to give epoxide trans-2
followed by a chiral base-mediated desymmetrisation
reaction to generate allylic alcohol 4 in high enan-
tiomeric excess. We were particularly keen to extend
our methodology to the synthesis of some aminocondu-
ritol analogues and the tetraacetate of naturally occur-
ring (+)-conduritol F. These topics, together with some
new features of our route, are reported in this paper
(Scheme 1).
epoxide trans-2. Recently, we found that m-CPBA
epoxidation of 1 in cyclohexane proceeded with high
trans stereoselectivity (93:7 mixture of trans- and cis-
2)10 and this allowed us to isolate consistently high
yields of epoxide trans-2 (81%) on a multi-gram scale.
Enantioselective rearrangement of epoxide trans-2
using chiral base (1R,2S)-3, independently developed
by Ahlberg et al.11 and ourselves,6 gave reproducible
multi-gram quantities of allylic alcohol 4 in ]90% yield
and 88–95% ee. In order to achieve ]94% ee of allylic
alcohol 4 for larger scale reactions (10 mmol of trans-
2), it was important to add the epoxide slowly to the
chiral base solution and to keep the temperature
between 0 and −10°C during the addition. The diamine
corresponding to chiral base (1R,2S)-3 could easily be
recovered (]70%) by simple acid–base extraction.
Another limitation of our previously reported method-
ology was the inability to access epoxide cis-2 in a
stereoselective and high yielding fashion. To address
this, we decided to investigate an oxidation–reduction
sequence with allylic alcohol 4 as outlined below.
Although we have previously reported in detail the
stereoselective epoxidation of cyclohexenes like 1,9 we
had not described an efficient large scale synthesis of
Scheme 1.
Keywords: allylic alcohols; cyclitols; epoxides; rearrangement.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01706-3

8082
S. E. de Sousa et al. / Tetrahedron Letters 42 (2001) 8081–8083
Scheme 2.
Allylic alcohol 4 (95% ee) was oxidised using PCC to
give enone 5 in 90% yield. Subsequent reduction under
Luche conditions furnished a 90% yield of allylic alco-
hol 6 as a single diastereoisomer. As is shown in the
figure (R=H), the stereoselectivity is rationalised by
axial attack on a preferred conformation of enone 5.
Thus, using our new epoxidation conditions and this
redox sequence, we have developed efficient enantio-
and diastereocontrolled routes to allylic alcohols 4 and
6 (Scheme 2).
lation, the crude acetimidate was heated in xylene with
added potassium carbonate (Isobe’s modification14) to
give the rearranged allylic carbamate 10 in high yield.
In contrast, the rearrangement of allylic alcohol 6 was
less successful giving allylic carbamate 11 in only 35%
yield. The reduced yield can be ascribed to the steric
interactions encountered as the carbamate group rear-
ranges towards the bulky silyoxy group in producing 11
(Scheme 4).
Two different methods were explored for the conver-
sion of allylic alcohols 4 and 6 into amino conduritol
analogues. The first approach involved standard Mit-
sunobu substitution with an appropriate nitrogen-
derived nucleophile. A screen of the known12 reagents
indicated that the Fukuyama-like TsNHPMB 7 was the
reagent of choice. Under standard Mitsunobu condi-
tions using DIAD (optimised for each substrate), allylic
alcohols 4 and 6 gave allylic sulfonamides 8 (91% yield)
and 9 (60% yield), respectively. The absence of the
other diastereoisomer in each of these reactions indi-
cated the expected stereospecificity of the reactions
(Scheme 3).
Scheme 4.
As a final demonstration of the utility of the chiral base
chemistry in synthesis, we have completed a concise
total synthesis of the tetraacetate of conduritol F.1,2 In
order to synthesise the naturally occurring enantiomer,
enone ent-5 was required. Enone ent-5 (89% ee) was
prepared in high yield by rearrangement of epoxide
trans-4 with chiral base (1S,2R)-3 and subsequent PCC
oxidation. a-Hydroxylation of enone ent-5 was accom-
plished by deprotonation with sodium hexamethyldisil-
azide and enolate trapping with Davis’ oxaziridine.15
Interestingly, no b-elimination of the silyloxy group
was observed and a high yield of a single diastereoiso-
mer of hydroxy ketone 12 (91%) was obtained. The
relative stereochemistry was determined by X-ray analy-
sis of the acetate of 12 and presumably arises by enolate
attack trans to the bulky silyloxy groups, one of which
must occupy an axial position (Scheme 5).
Acetylation of hydroxy ketone 12 and then Luche
reduction afforded alcohol 13 as the only product in
quantitative yield. Axial attack of hydride on a pre-
ferred conformation of the enone (see figure, R=OAc)
accounts for the stereoselectivity in a similar fashion to
the reduction of enone 5 described previously. Finally,
TBAF deprotection and a final acetylation yielded con-
duritol F tetraacetate 14 (89% ee) in an overall 87%
yield over the last four steps of the synthesis. The
synthetic material exhibited [h]D +46.9 (c 1.0 in CHCl3)
Scheme 3.
The second approach utilised Overman rearrangement
reactions13 and enabled regioisomeric allylic carbamates
to be prepared. First of all, allylic alcohol 4 was con-
verted into the required acetimidate upon treatment
with trichloroacetonitrile and DBU. Then, without iso-

S. E. de Sousa et al. / Tetrahedron Letters 42 (2001) 8081–8083
8083
Scheme 5.
(lit.,16 [h]D +45.6 (c 1.1 in CHCl3)) and was identical
spectroscopically to the tetraacetate of the natural (+)-
conduritol F thus corroborating our assignment of
relative stereochemistry in 13 and 14.
Pollicino, S.; Ricci, A. Tetrahedron 2001, 57, 3439–3444;
(c) Desjardins, M.; Lallemand, M. C.; Freeman, S.;
Hudlicky, T.; Abboud, K. A. J. Chem. Soc., Perkin
Trans. 1 1999, 628; (d) Trost, B. M.; Chupak, L. S.;
Lu¨bbers, T. J. Am. Chem. Soc. 1998, 120, 1732–1740.
6. de Sousa, S. E.; O’Brien, P.; Stefens, H. C. Tetrahedron
Lett. 1999, 40, 8423–8425.
To summarise, crucial practical improvements to the
synthesis of allylic alcohol
4 (95% ee) and its
diastereoisomer 6 (95% ee) have been described. The
usefulness of these compounds for the preparation of
amino conduritol analogues and a high yielding synthe-
sis of (+)-conduritol F has also been demonstrated. Our
results suggest that enone 5 should now be regarded as
a useful chiral building block for synthesis.
7. Colman, B.; de Sousa, S. E.; O’Brien, P.; Towers, T. D.;
Watson, W. Tetrahedron: Asymmetry 1999, 10, 4175–
4182.
8. de Sousa, S. E.; O’Brien, P.; Poumellec, P. J. Chem. Soc.,
Perkin Trans. 1 1998, 1483–1492.
9. (a) de Sousa, S. E.; Kee, A.; O’Brien, P.; Watson, S. T.
Tetrahedron Lett. 1999, 40, 387–390; (b) de Sousa, S. E.;
O’Brien, P.; Pilgram, C. D.; Roder, D.; Towers, T. D.
Tetrahedron Lett. 1999, 40, 391–392.
Acknowledgements
10. For a related epoxidation in cyclohexane, see: Asami, M.
Bull. Chem. Soc. Jpn. 1990, 63, 1402–1408.
We thank the EPSRC for a grant (to S.E.dS.) and a
project studentship (to C.D.P.; reference GR/L 58439).
11. Petterson, D.; Amedjkouh, M.; Nilsson Lill, S. O.;
Dahle´n, K.; Ahlberg, P. J. Chem. Soc., Perkin Trans. 2
2001, 1654.
12. (a) Hughes, D. L. Org. React. 1992, 42, 335–656; (b) Bell,
K. E.; Knight, D. W.; Gravestock, M. B. Tetrahedron
Lett. 1995, 36, 8681–8684; (c) Decicco, C. P.; Grover, P.
Synlett 1997, 529–530; (d) Campbell, J. A.; Hart, D. J. J.
Org. Chem. 1993, 58, 2900–2903; (e) Berre´e, F.; Michelot,
G.; Le Corre, M. Tetrahedron Lett. 1998, 39, 8275–8276;
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